Ring-closing metathesis protocol for a diastereocontrolled synthesis of (-)-shikimic acid

Article abstract of DOI:10.1055/s-2000-7100

A new entry to (-)-shikimic acid, the key intermediate in the shikimate pathway in plants and microorganisms, has been devised by employing a ring-closing metathesis reaction as the key step starting with a 6,8-dioxabicyclo[3.2.1]octenone chiral building block.

Full text of DOI:10.1055/s-2000-7100

PAPER
1375
Ring-Closing Metathesis Protocol for a Diastereocontrolled Synthesis of
(-)-Shikimic Acid
Miwako Takeuchi, Takahiko Taniguchi, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)2176845; E-mail: konol@mail.cc.tohoku.ac.jp
Received 14 April 2000; revised 20 May 2000
Dedicated to Professor Richard Neidlein on the occasion of his 70th birthday.
all yield after removal of the exo-isomer (14%) by silica
gel column chromatography. The stereochemistry of 5
was confirmed by NOE experiments, which indicated
the exo-configuration of the vinyl functionality and the
endo-configuration of the MOM-oxy functionality. On
desilylation, 5 gave the primary alcohol 6, which was
transformed into the iodide 7 by treating with iodine and
triphenylphosphine in the presence of imidazole.11 Treat-
ment of 7 with zinc in methanolic acetic acid1,3,4 induced
reductive cleavage to yield the hemiacetal mixture 8,
which was immediately reduced with lithium aluminum
hydride to give the divinyl diol 9. The overall yield of 9
from 1 was 48% in 6 steps. The key ring-closing
metathesis was carried out at this stage by refluxing 9
with Grubbs’ catalyst12 (10 mol%) in dichloromethane
(0.02 M) for 12 h to give the desired cyclohexenol 10
accompanied with a minor amount of inseparable coloring
material derived from the catalyst. Without further purifi-
cation, its primary hydroxy functionality was chemoselec-
tively protected to give the pure tert-butyldimethylsilyl
(TBS) ether 11 in 77% yield from 9 with removal of the
impurities (Scheme 2).
Abstract: A new entry to (-)-shikimic acid, the key intermediate in
the shikimate pathway in plants and microorganisms, has been de-
vised by employing a ring-closing metathesis reaction as the key
step starting with a 6,8-dioxabicyclo[3.2.1]octenone chiral building
block.
Key words: shikimic acid, chiral building block, enantiocontrolled
synthesis, diastereocontrolled synthesis, ring-closing metathesis
Quite recently, we prepared a chiral building block having
a 6,8-dioxabicyclo[3.2.1]octane framework 1 for sugar
synthesis from furfural by employing either a catalytic1 or
an enzymatic2 procedure. As expected, it allowed diaste-
reocontrolled preparation of all of the eight possible
diastereomers1,3 of aldohexoses as well as a rare sugar
(+)-noviose4 on the basis of its high functionality confined
in a biased framework. We wish to report here an addi-
tional utilization of the building block 1 for a diastereo-
controlled synthesis of (-)-shikimic acid 2 by employing
a ring-closing metathesis5 as the key step (Scheme 1).
To install the requisite functionality for the target mole-
cule, the allyl alcohol 11 was first treated with m-chloro-
perbenzoic acid13 in dichloromethane to carry out epoxi-
dation diastereoselectively from the same face to the
allylic hydroxy functionality. However, the oxidation pro-
ceeded with considerable decomposition under these con-
ditions to give a complex mixture, presumably owing to
liberating m-chlorobenzoic acid. The reaction was then
carried out in the presence of powdered disodium hydro-
Scheme 1
(-)-Shikimic acid 2 was first isolated in 18856 and is one gen phosphate,14 in order to neutralize the liberating acid,
of the most often synthesized natural products owing to its to furnish the desired syn-epoxide 12 in 60% yield without
biogenetic importance in the shikimate pathway7 in plants decomposition after separation of the undesired anti-ep-
and microorganisms as well as its appropriate structure for oxide (13%) by silica gel column chromatography. On se-
testing new synthetic methodology.8,9 In order to display quential MOM protection followed by desilylation, 12
a new example in the showcase of shikimic acid synthesis afforded the primary alcohol 14, via 13, which was trans-
and to demonstrate a new utility of the building block 1, formed into the methyl ester 15 by sequential Jones oxida-
we treated first the enantiopure enone (+)-1 with vinyl- tion and methylation. It was noteworthy that the epoxy
magnesium bromide in the presence of copper(I) bromide functionality was found to be intact under these acidic ox-
to give the 1,4-adduct 3, diastereoselectively, by convex- idation conditions. Upon stirring with 1,8-diazabicyc-
face selective reaction. Although the reduction10 of the ke- lo[5.4.0]undec-7-ene (DBU) in benzene at room
tone functionality of 3 did not take place in complete di- temperature, 15 allowed facile b-elimination to give rise
astereoselection from the convex-face, the desired to 4,5-di-O-MOM-protected methyl shikimate 16, which
diastereomer 4 having the endo-hydroxy functionality afforded methyl shikimate 17 on treatment with methan-
was generated as the major product. It was isolated in pure olic hydrogen chloride.15 Transformation of 17 into
form as the methoxymethyl (MOM) ether 5 in 75% over- (-)-shikimic acid 2 was thus established as we have
Synthesis 2000, No. 10, 1375–1379 ISSN 0039-7881 © Thieme Stuttgart · New York

1376
M. Takeuchi et al.
PAPER
Scheme 2
already done in the previous synthesis.9e,15 Overall yield
of methyl shikimate 17 from the key intermediate 11 was
22% in 7 steps (Scheme 3).
graphed (SiO2, 10 g, EtOAc/hexane, 1:30) to give the vinyl ketone
3 (269 mg, 77%) as a pale yellow oil.
[a]D25 +13.5 (c 1.06, CHCl3).
IR (film): n = 1737 cm-1.
1H NMR (300 MHz, CDCl3): d = 5.83 (ddd, 1H, J = 17.0, 10.4, 8.0
Hz), 5.46 (s, 1H), 5.18 (dt, 1H, J = 10.4, 1.1 Hz), 5.16 (dt, 1H,
J = 17.0, 1.1 Hz), 4.38 (s, 1H), 4.09 (dd, 1H, J = 8.2, 5.5 Hz), 3.63
(dd, 1H, J = 10.2, 5.5 Hz), 3.46 (dd, 1H, J = 10.2, 8.2 Hz), 2.84 (td,
1H, J = 8.0, 3.4 Hz), 2.68 (dd, 1H, J = 17.0, 3.4 Hz), 2.36 (dd, 1H,
J = 17.0, 3.4 Hz), 0.89 (s, 9H), 0.06 (s, 6H).
In conclusion, an alternative route to (-)-shikimic acid 2
has been established by employing a ring-closing met-
athesis reaction on the basis of the stereochemical and
chemical functionalities of the chiral building block 1
having a biased 6,8-dioxabicyclo[3.2.1]octenone frame-
work.
13C NMR (75 MHz, CDCl3): d = 204.8, 136.9, 117.5, 104.4, 80.8,
78.2, 62.8, 46.3, 38.1, 25.8, 18.2, -5.4, -5.5.
HRMS: m/z calcd for C15H26O4Si (M+): 298.1600. Found:
Mps are uncorrected. IR spectra were recorded on a Jasco-IR-700
1
spectrometer. H NMR spectra were recorded on a Gemini 2000
(300 MHz for 1H and 75 MHz for 13C). Mass spectra were recorded
on a JMS-DX300 instrument. Optical rotations were measured with
a Jasco-DIP-370 digital polarimeter.
298.1605.
(1S,2R,4S,5R,7S)-7-tert-Butyldimethylsiloxymethyl-2-methoxy-
methoxy-4-vinyl-6,8-dioxabicyclo[3.2.1]octane (5)
(1R,4S,5R,7S)-7-tert-Butyldimethylsiloxymethyl-4-vinyl-6,8-di-
oxabicyclo[3.2.1]oct-2-one (3)
To a stirred solution of the ketone 3 (751 mg, 2.52 mmol) and
CeCl3·7H2O (2.82 g, 7.56 mmol) in MeOH (15 mL) was added
NaBH4 (286 mg, 7.56 mmol) at -30 °C, and stirring was continued
for 24 h at the same temperature. After removal of the solvent under
reduced pressure, the residue was diluted with H2O (5 mL) and ex-
tracted with EtOAc (2 ¥ 20 mL). The extract was washed with brine
(10 mL), dried (MgSO4), evaporated under reduced pressure, and
chromatographed (SiO2, 15 g, EtOAc/hexane, 1:2) to give the endo-
alcohol 4 containing an inseparable exo-isomer.
To a stirred solution of Me2S·CuBr (49 mg, 1.18 mmol) in THF
(4 mL) containing hexamethylphosphoramide (HMPA) (616 mL,
3.54 mmol) was added vinylmagnesium bromide (1 M in THF,
3.42 mL, 3.42 mmol) at -20 °C and, after 30 min, the mixture was
cooled to -78 °C. After 30 min, to this stirred solution was added
the enone (+)-1 (318 mg, 1.18 mmol) in THF (2 mL) at the same
temperature. After 30 min at the same temperature, the reaction was
quenched by addition of sat. NH4Cl (1 mL) and extracted with Et2O
(2 ¥ 10 mL). The extract was washed with brine (5 mL), dried
(MgSO4), evaporated under reduced pressure, and chromato-
The mixture was dissolved in CH2Cl2 (15 mL) and treated with
methoxymethyl chloride (287 mL, 3.78 mmol) and ethyldiisopropy-
lamine (878 mL, 5.04 mmol) at 0 °C, and then refluxed for 3 h. After
Scheme 3
Synthesis 2000, No. 10, 1375–1379 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Ring-closing Metathesis Protocol for a Diastereocontrolled Synthesis
1377
cooling, the mixture, diluted with EtOAc (40 mL), was washed with
brine (10 mL), dried (MgSO4), evaporated under reduced pressure,
and chromatographed (SiO2, 15 g, EtOAc/hexane, 1:30) to give the
MOM ether 5 (649 mg, 75% from 3) and the exo-isomer (118 mg,
14% from 3) as colorless oils.
13C NMR (75 MHz, CDCl3): d = 136.8, 116.9, 104.7, 95.5, 78.4,
75.2, 68.8, 55.7, 44.8, 28.5, 7.3.
HRMS: m/z calcd for C11H17IO4 (M+): 340.0172. Found: 340.0191.
(3R,4R,6S)-3-Hydroxy-6-hydroxymethyl-4-methoxymethoxy-
1,7-octadiene (9)
Compound 5
To a stirred solution of the iodide 7 (763 mg, 2.24 mmol) in MeOH
(15 mL) and HOAc (1.5 mL), activated zinc powder (2.93 g,
44.8 mmol) was added at r.t., and the stirring was continued for 1 h
at the same temperature. The mixture was diluted with EtOAc (50
mL) and filtered through a Celite pad. The filtrate was washed suc-
cessively with brine (10 mL) and 5% NaHCO3, dried (MgSO4),
evaporated under reduced pressure, and chromatographed (SiO2, 15
g, EtOAc/hexane, 1:2) to give the hemiacetal 8 as an epimeric mix-
ture which was used immediately.
[a]D24 +18.0 (c 1.04, CHCl3).
1H NMR (300 MHz, CDCl3): d = 5.86 (ddd, 1H, J = 17.0, 10.7, 8.0
Hz), 5.25 (s, 1H), 5.13 (d, 1H, J = 17.0 Hz), 5.11 (d, 1H, J = 10.7
Hz), 4.65 (s, 2H), 4.33 (d, 1H, J = 3.8 Hz), 4.28 (dd, 1H, J = 8.0,
5.5 Hz), 3.95 (ddd, 1H, J = 10.6, 6.6, 3.8 Hz), 3.62 (dd, 1H,
J = 10.2, 5.5 Hz), 3.46 (dd, 1H, J = 10.2, 8.0 Hz), 3.36 (s, 3H), 2.51
(br t, 1H, J = 6.0 Hz), 1.97-1.84 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
13C NMR (75 MHz, CDCl3): d = 137.4, 116.6, 103.8, 95.5, 76.3,
75.0, 69.2, 63.9, 55.5, 45.3, 28.7, 25.8, 18.3, -5.4, -5.5.
HRMS: m/z calcd for C17H32O5Si (M+): 344.2019. Found:
344.2046.
The mixture was dissolved in THF (15 mL) and to this solution was
added LiAlH4 (170 mg, 4.48 mmol) in portions at 0 °C with stirring.
After stirring for 1.5 h at the same temperature, the reaction was
quenched by addition of H2O (1 mL) and the mixture was diluted
with Et2O (50 mL) and dried (MgSO4). After evaporation of the sol-
vent, the residue was chromatographed (SiO2, 15 g, EtOAc/hexane;
1:1) to give the diol 9 (307 mg, 94% from 7) as a colorless oil.
Anal. Calcd for C17H32O5Si: C, 59.27; H, 9.36. Found: C, 59.36; H,
9.40.
(1S,2R,4S,5R,7S)-7-Hydroxymethyl-2-methoxymethoxy-4-vi-
nyl-6,8-dioxabicyclo[3.2.1]octane (6)
[a]D25 -13.5 (c 1.03, CHCl3).
IR (film): n = 3408 cm-1.
1H NMR (300 MHz, CDCl3): d = 5.82 (ddd, 1H, J = 17.0, 10.4, 6.6
Hz), 5.58 (ddd, 1H, J = 17.0, 10.2, 9.1 Hz), 5.36 (dt, 1H, J = 17.0,
1.4 Hz), 5.25-5.14 (m, 3H), 4.75 (d, 1H, J = 6.7 Hz), 4.67 (d, 1H,
J = 6.7 Hz), 4.04-3.98 (m, 1H), 3.56 (ddd, 1H, J = 10.4, 7.7, 5.5
Hz), 3.50-3.41 (m, 6H), 2.51-2.44 (m, 1H), 1.62-1.43 (m, 3H).
13C NMR (75 MHz, CDCl3): d = 139.4, 137.1, 118.1, 117.2, 98.0,
82.5, 75.3, 66.0, 55.9, 43.2, 32.6.
HRMS: m/z calcd for C11H21O4 (M++H): 217.1440. Found:
To a stirred solution of 5 (130 mg, 0.38 mmol) in THF (3 mL) was
added tetrabutylammonium fluoride (TBAF) (1.0 M in THF, 567
mL, 0.57 mmol) at 0 °C, and the mixture was stirred at r.t. for 2 h.
The mixture was diluted with EtOAc (20 mL), washed with brine
(5 mL), dried (MgSO4), evaporated under reduced pressure, and
chromatographed (SiO2, 2 g, EtOAc/hexane, 1:2) to give the alco-
hol 6 (84 mg, 97%) as a colorless oil.
[a]D27 -25.2 (c 1.07, CHCl3).
IR (film): n = 3466 cm-1.
1H NMR (300 MHz, CDCl3): d = 5.86 (ddd, 1H, J = 17.0, 10.7, 8.0
Hz), 5.33 (d, 1H, J = 1.6 Hz), 5.14 (d, 1H, J = 17.0 Hz), 5.13 (d,
1H, J = 10.7 Hz), 4.71 (d, 1H, J = 7.1 Hz), 4.64 (d, 1H, J = 7.1 Hz),
4.39 (t, 1H, J = 5.5 Hz), 4.32 (d, 1H, J = 1 Hz), 3.93 (ddd, 1H,
J = 9.3, 7.6, 3.8 Hz), 3.68-3.55 (m, 2H), 3.36 (s, 3H), 2.54 (br s,
1H), 1.94-1.79 (m, 3H).
13C NMR (75 MHz, CDCl3): d = 137.1, 116.7, 104.0, 96.0, 76.5,
75.1, 70.1, 64.4, 55.5, 45.1, 2.6.
HRMS: m/z calcd for C11H18O5 (M+): 230.1154. Found: 230.1176.
217.1426.
(1R,4S,6R)-4-tert-Butyldimethylsiloxymethyl-6-methoxy-meth-
oxy-cyclohex-2-en-1-ol (11)
A freeze-degassed solution of the diene 9 (444 mg, 2.06 mmol) in
CH2Cl2 (103 mL) was refluxed with Grubbs’ catalyst10 [bis(tricy-
clohexylphosphine)benzylideneruthenium(IV)dichloride] (169 mg,
0.21 mmol) for 12 h under Ar. After cooling, the solvent was evap-
orated under reduced pressure and the residue was chromato-
graphed (SiO2, 10 g, EtOAc/hexane, 2:1) to give the cyclohexene
10, which was immediately used for the next reaction.
Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.41; H,
7.86.
Thus, 10 was treated with tert-butyldimethylsilyl chloride (372 mg,
2.46 mmol), Et3N (430 mL, 3.08 mmol) and 4-N,N-dimethylami-
nopyridine (13 mg, 0.10 mmol) in CH2Cl2 (9 mL) for 16 h at r.t. The
mixture, after dilution with EtOAc (30 mL), was washed with brine
(2 ¥ 10 mL), dried (MgSO4), evaporated under reduced pressure,
and chromatographed (SiO2, 10 g, EtOAc/hexane, 1:6) to give the
silyl ether 11 (480 mg, 77% from 9) as a colorless oil.
[a]D28 -126.0 (c 1.05, CHCl3).
IR (film): n = 3445 cm-1.
1H NMR (300 MHz, CDCl3): d = 5.64 (s, 2H), 4.81 (d, 1H, J = 7.1
Hz), 4.77 (d, 1H, J = 7.1 Hz), 4.15-4.11 (m, 1H), 3.88 (d, 1H,
J = 2.5 Hz), 3.54-3.22 (m, 3H), 3.46 (s, 3H), 2.54-2.64 (m, 1H),
2.07 (dt, 1H, J = 12.6, 4.4 Hz), 1.35 (q, 1H, J = 12.6 Hz), 0.89 (s,
9H), 0.04 (s, 6H).
13C NMR (75 MHz, CDCl3): d = 129.8, 129.1, 97.0, 83.2, 72.2,
66.9, 55.5, 39.5, 31.1, 25.8, 18.2, -5.5.
(1S,2R,4S,5R,7S)-7-Iodomethyl-2-methoxymethoxy-4-vinyl-
6,8-dioxabicyclo[3.2.1]octane (7)
To a stirred solution of 6 (410 mg, 1.78 mmol) in toluene (15 mL)
was added imidazole (303 mg, 4.45 mmol), iodine (542 mg,
2.14 mmol) and triphenylphosphine (1.40 g, 5.34 mmol) and stir-
ring was continued for 2 h at 80 °C. After cooling, the mixture was
diluted with EtOAc (20 mL), washed with brine (10 mL), dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed (SiO2, 8 g, EtOAc/hexane, 1:20) to give the iodide 7
(524 mg, 86%) as a colorless oil.
[a]D28 +43.0 (c 1.06, CHCl3).
1H NMR (300 MHz, CDCl3): d = 5.84 (ddd, 1H, J = 17.6, 10.2, 7.8
Hz), 5.37 (d, 1H, J = 1.9 Hz), 5.14 (dt, 1H, J = 17.6, 1.4 Hz), 5.13
(dt, 1H, J = 10.2, 1.4 Hz), 4.68 (s, 2H), 4.52 (dd, 1H, J = 8.0, 6.0
Hz), 4.38 (d, 1H, J = 3.8 Hz), 3.94 (ddd, 1H, J = 10.7, 7.4, 3.8 Hz),
3.39 (s, 3H), 3.21 (dd, 1H, J = 9.9, 6.0 Hz), 3.13 (dd, 1H, J = 9.9,
8.0 Hz), 2.51 (br t, 1H, J = 5.8 Hz), 1.92-1.82 (m, 2H).
HRMS: m/z calcd for C13H25O2Si (M+-C2H5O2): 241.1624. Found:
241.1637.
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1378
M. Takeuchi et al.
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(1R,2S,3R,4R,5R)-5-tert-Butyldimethylsiloxymethyl-1,2-di-
methoxymethoxy-3,4-epoxycyclohexane (13)
chromatographed (SiO2, 1 g, EtOAc/hexane, 1:10) to give the me-
thyl ester 15, which was immediately used for the next reaction.
To a stirred solution of the allyl alcohol 11 (230 mg, 0.76 mmol) in
CH2Cl2 (5 mL) was added Na2HPO4 (216 mg, 1.52 mmol), followed
by m-chloroperbenzoic acid (70% 282 mg, 1.14 mmol) at r.t., and
the stirring was continued for 21 h at the same temperature. The
mixture was diluted with EtOAc (20 mL) and washed successively
with 5% NaHCO3 (2 ¥ 5 mL) and brine (5 mL), dried (MgSO4),
evaporated under reduced pressure, and chromatographed (SiO2,
5 g, EtOAc/hexane, 1:5) to give the epoxy-alcohol 12, which was
immediately used for next reaction.
Thus, 15 was stirred with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) (15 mL, 0.10 mmol) in benzene (1 mL) at r.t. for 30 min. The
mixture, diluted with EtOAc (20 mL), was washed with brine (2 ¥
5 mL), dried (MgSO4), evaporated under reduced pressure, and
chromatographed (SiO2, 5 g, EtOAc/hexane, 1:2) to give the shiki-
mate 16 (12 mg, 51% from 14) as a colorless oil.
[a]D29 -55.1 (c 0.57, CHCl3).
IR (film): n = 3460 cm-1.
1H NMR (300 MHz, CDCl3): d = 6.84 (d, 1H, J = 1.4 Hz), 4.78 (d,
1H, J = 6.7 Hz), 4.75 (d, 1H, J = 6.7 Hz), 4.71 (d, 1H, J = 6.9 Hz),
4.68 (d, 1H, J = 6.9 Hz), 4.54-4.47 (m, 1H), 4.18-4.13 (m, 1H),
3.88 (d, 1H, J = 5.5, 4.4 Hz), 3.76 (s, 3H), 3.41 (s, 3H), 3.37 (s, 3H),
3.05 (d, 1H, J = 9.1 Hz), 2.71-2.62 (m, 1H), 2.47-2.40 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 167.01, 138.31, 128.79, 97.54,
95.90, 72.23, 65.69, 55.90, 55.56, 51.80, 27.83.
Thus, 12 was refluxed with methoxymethyl chloride (87 mL,
1.14 mmol) and ethyldiisopropylamine (265 mL, 1.52 mmol) in
CH2Cl2 (5 mL) for 9 h. The mixture, after cooling, was diluted with
EtOAc (20 mL) and washed with brine (2 ¥ 5 mL), dried (MgSO4),
evaporated under reduced pressure, and chromatographed (SiO2, 5
g, EtOAc/hexane, 1:10) to give the epoxy-ether 13 (165 mg, 60%
from 11) as a colorless oil.
[a]D27 -11.0 (c 0.83, CHCl3).
HRMS: m/z calcd for C12H20O7 (M+): 276.1209. Found: 276.1224.
1H NMR (300 MHz, CDCl3): d = 4.89 (d, 1H, J = 6.9 Hz), 4.82 (d,
1H, J = 6.9 Hz), 4.73 (d, 1H, J = 6.7 Hz), 4.67 (d, 1H, J = 6.7 Hz),
3.80 (dd, 1H, J = 8.2, 1.6 Hz), 3.77-3.67 (m, 2H), 3.56 (dd, 1H,
J = 9.9, 6.3 Hz), 3.46 (s, 3H), 3.39 (dd, 1H, J = 3.8, 1.6 Hz), 3.36
(s, 3H), 3.21 (d, 1H, J = 3.0 Hz), 2.25-2.15 (m, 1H), 1.84-1.77 (m,
1H), 1.27 (q, 1H, J = 12.1 Hz), 0.89 (s, 9H), 0.06 (s, 6H).
13C NMR (75 MHz, CDCl3): d = 97.04, 96.46, 78.99, 74.57, 64.55,
56.96, 56.38, 55.37, 55.24, 36.97, 30.95, 25.70, 18.08, -5.65.
HRMS: m/z calcd for C15H29O4Si (M+-C2H5O2): 301.1836. Found:
301.1830.
Methyl Shikimate (17)
To a stirred solution of 16 (39.4 mg, 0.14 mmol) in MeOH (1 mL)
was added acetyl chloride (1 mL, 14 mmol) at 0 °C and the stirring
was continued for 16 h at r.t. To this mixture was added NaHCO3
(124 mg, 1 mmol) and, after 10 min, the solvent was evaporated un-
der reduced pressure. The residue was chromatographed (SiO2, 1 g,
EtOAc/MeOH, 95:5) to give the methyl shikimate 17 (22.4 mg,
83%) as colorless crystals.
30
Mp: 112-113 °C, [a]D -130 (c 0.45, EtOH) [Lit.15 mp: 116.5-
117.5 °C, [a]D29 -130 (c 0.91, EtOH)].
IR (Nujol): n = 3305, 1715 cm-1.
(1R,2S,3R,4R,5R)-3,4-Epoxy-5-hydroxymethyl-1,2-dimethoxy-
methoxycyclohexane (14)
1H NMR (300 MHz, CDCl3): d = 6.71-6.69 (m, 1H), 4.29 (br s,
1H), 3.94-3.88 (m, 1H), 3.66 (s, 3H), 3.60 (dd, 1H, J = 7.3, 4.3
Hz), 3.24-3.21 (m, 1H), 2.61 (ddt, 1H, J = 18.3, 4.8, 2.2 Hz), 2.12
(ddt, 1H, J = 18.3, 5.4, 1.6 Hz).
13C NMR (75 MHz, CDCl3): d = 168.89, 139.27, 130.32, 72.59,
68.42, 67.28, 52.37, 31.43.
To a stirred solution of the silyl ether 13 (145 mg, 0.40 mmol) in
THF (3 mL) was added tetrabutylammonium fluoride (1.0 M in
THF, 601 mL, 0.60 mmol) at 0 °C and the mixture was stirred at r.t.
for 1 h. After dilution with EtOAc (20 mL), the mixture was washed
with brine (2 ¥ 5 mL), dried (MgSO4), evaporated under reduced
pressure, and chromatographed (SiO2, 2 g, EtOAc/hexane, 2:1) to
give the primary alcohol 14 (95 mg, 96%) as a colorless oil.
[a]D27 -3.1 (c 1.00, CHCl3).
IR (film): n = 3460 cm-1.
HRMS: m/z calcd for C8H12O5(M+): 188.0685. Found: 188.0665.
These spectral data were identical with those of an authentic mate-
rial.9c,15
1H NMR (300 MHz, CDCl3): d = 4.88 (d, 1H, J = 6.7 Hz), 4.82 (d,
1H, J = 6.7 Hz), 4.73 (d, 1H, J = 6.9 Hz), 4.68 (d, 1H, J = 6.9 Hz),
3.85 (dd, 1H, J = 8.0, 1.9 Hz), 3.80-3.60 (m, 3H), 3.46 (s, 3H),
3.43-3.41 (m, 1H), 3.37 (s, 3H), 3.26 (d, 1H, J = 3.8 Hz), 2.30-
2.20 (m, 1H), 1.93-1.85 (m, 1H), 1.72 (br s, 1H), 1.27 (q, 1H,
J = 12.0 Hz).
13C NMR (75 MHz, CDCl3): d = 96.87, 96.27, 78.37, 74.31, 64.20,
56.20, 56.14, 55.34, 55.24, 36.78, 30.68.
HRMS: m/z calcd for C10H17O5 (M+-CH3O): 217.1076. Found:
217.1088.
References
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(5) Pertinent reviews, see: Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413.
(3R,4S,5R)-1-Carbomethoxy-4,5-dimethoxymethoxycyclohex-
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To a stirred solution of the primary alcohol 14 (21 mg, 85 mmol) in
acetone (1 mL) was added Jones’ reagent (3.3 M, 130 mL, 425
mmol) at 0 °C and the stirring was continued for 10 min at the same
temperature. The mixture was diluted with EtOAc (20 mL) and the
solution was washed with brine (2 ¥ 5 mL), dried (MgSO4), and
evaporated under reduced pressure to leave a residue containing the
carboxylic acid. The residue, dissolved in CH2Cl2 (1 mL), was treat-
ed with diazomethane-Et2O solution at 0 °C. The solvent was evap-
orated under reduced pressure to leave the crude ester 15, which was
Synthesis 2000, No. 10, 1375–1379 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Ring-closing Metathesis Protocol for a Diastereocontrolled Synthesis
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Article Identifier:
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Synthesis 2000, No. 10, 1375–1379 ISSN 0039-7881 © Thieme Stuttgart · New York