Synthesis of (R)-(+)-tanikolide through stereospecific C-H insertion reaction of dichlorocarbene with optically active secondary alcohol derivatives

Article abstract of DOI:10.1248/cpb.52.848

Stereospecific α C-H insertion reaction of protected chiral 1,2-glycols, (S)-1,2-isopropylidenedioxytridecane (3) and ethyl (S)-4,5-isopropylidenedioxy-pentanoate (4), prepared from (R)-glyceraldehyde acetonide (2), with dichlorocarbene generated from CHC

Full text of DOI:10.1248/cpb.52.848

848
Chem. Pharm. Bull. 52(7) 848—852 (2004)
Vol. 52, No. 7
Synthesis of (R)-(ꢀ)-Tanikolide through Stereospecific C–H Insertion
Reaction of Dichlorocarbene with Optically Active Secondary Alcohol
Derivatives
Hideki ARASAKI, Masashi IWATA, Miyuki MAKIDA, and Yukio MASAKI*
Gifu Pharmaceutical University; 5–6–1 Mitahora-Higashi, Gifu 502–8585, Japan.
Received April 12, 2004; accepted May 6, 2004
Stereospecific a C–H insertion reaction of protected chiral 1,2-glycols, (S)-1,2-isopropylidenedioxytridecane
(3) and ethyl (S)-4,5-isopropylidenedioxy-pentanoate (4), prepared from (R)-glyceraldehyde acetonide (2), with
dichlorocarbene generated from CHCl3/50% NaOH/cetyltrimethylammonium chloride (as ptc.) took place with
complete retention of configuration to provide (S)-4-dichloromethyl-2,2-dimethyl-4-undecyl-1,3-dioxolane (5) and
ethyl (S)-3-(4-dichloromethyl-2,2-dimethyl-1,3-dioxolan-4-yl)-propanoate (8), respectively. The ester (8) was
transformed to 5 by elongation of the side chain. The glycol derivative (5) was converted into O-TBDPS-pro-
tected (S)-2-hydroxymethyl-2-undecyloxirane (16). Reaction of 16 with a cuprate reagent containing homoallylic
carbon chain followed by oxidative manipulation of the terminal olefin afforded (R)-(ꢀ)-tanikolide (1).
Key words tanikolide; chiral synthesis; C–H insertion; dichlorocarbene; dichloromethylcarbinol; tertiary alcohol
Optically active tertiary alcohols and the related com- presence of phase transfer catalyst (ptc.) to provide chiral ter-
pounds are widely distributed in biologically active com- tiary alcohol building blocks with complete retention of con-
pounds including medicine.1) Chiral tertiary alcohol deriva- figuration of the stereogenic center in the starting alcohols
tives as building blocks for the synthesis of such bioactive (Chart 1).38)
compounds have generally been prepared synthetically by bi-
(ꢁ)-Tanikolide (1) is a d-lactone metabolite of marine
ological and chemical methods including kinetic resolution cyanobacterium Lyngbya majuscul collected at Tanikeli Is-
of racemates,2—4) enantioselective oxygenation of 1,1-disub- land, Madagascal39) and exhibits toxic and antifungal activi-
stituted olefins or substituted aromatics,5—12) desymmetriza- ties. The absolute structure of 1 containing an asymmetric
tion of prochiral tertiary alcohols,13—15) enantioselective carbon of (R) configuration has been determined syntheti-
alkylation of ketones,16—23) and asymmetric alkylation of chi- cally by Ogasawara and coworkers.40) Several Chemists have
ral secondary carbinol carbon with memory of chirality.24—27) achieved syntheses of optically active 1 so far.41—44) This
High levels of chiral induction (ꢀ95% ee), however, have paper reports on a demonstration of the utilities of
been hardly attained by these methods. On the other hand, dichloromethylcarbinol derivatives, prepared by dichlorocar-
several excellent practical methods have been developed to bene C–H insertion reaction of protected chiral secondary al-
obtain optically active secondary alcohols in nearly perfect cohols, for synthesis of an optically active tertiary alcohol
enantioselectivity.28—37) Devices for introduction of carbon natural product (R)-(ꢁ)-tanikolide (1) as shown in Chart 2:
substituents into the a-methine C–H bond of such optically Application of the method to chiral glycol acetonides (A)
active secondary alcohols with complete stereospecificity in prepared from D-mannitol via glyceraldehyde acetonide (2)
the sense of retention or inversion of configuration would and utilization of the chiral tertiary alcohol building blocks
offer facile methods for production of optically active tertiary (B) obtained to the synthesis of 1.
alcohol derivatives.
We have recently found a C–H insertion reaction of chiral Results and Discussion
protected alcohol derivatives with dichlorocarbene generated
The synthesis has been started with glycol derivatives
from chloroform and 50% NaOH aqueous solution in the (3)45) and (4)46) prepared from (R)-glyceraldehyde acetonide
(2) (Chart 3). Treatment of (S)-tridecane-1,2-diol acetonide
(3) with chloroform and 50% aqueous NaOH in the presence
of cetyltrimethylammonium chloride as a phase transfer cata-
lyst (ptc.)47) at 80 °C for 12 h afforded the corresponding
dichloromethylated compound (5) in 58% yield with 24% re-
1
covery of starting material (3). H-NMR and MS data of 5
supported the structure of 5, and enantiomeric purity of 5
Chart 1. Dichlorocarbene C–H Insertion Reaction of Secondary Alcohol
Derivatives
Chart 2. Synthesis of (R)-(ꢁ)-Tanikolide from D-Mannitol
* To whom correspondence should be addressed. e-mail: masaki@gifu-pu.ac.jp
© 2004 Pharmaceutical Society of Japan

July 2004
849
Chart 3. Synthesis of Tertiary Dichloromethylcarbinol Derivative (5)
Chart 4. Synthesis of Epoxy-Alcohol Derivative (16), Key Intermediate for 1
including reduction with n-Bu3SnH,49) we found LiAlH4 as a
useful reagent for the transformation. Thus, treatment of 5
with 2 eq of LiAlH4 in THF for 14 h at room temperature
gave a 60% yield of the desired chloromethylcarbinol deriva-
tive (12) with a small amount of a methyl carbinol (13) (8%).
The epoxide (16), a key intermediate for tanikolide (1) was
obtained from 12 through a three step sequence of reactions
in a high overall yield (85%): acidic deacetonidation provid-
ing a diol (14), OH-protection of 14 to give a mono-TBDPS
ether (15), and treatment of 15 with K2CO3. The epoxide
(16) was provided from 5 through another route by way of
the glycol (6). Acidic treatment of (5) followed by stirring of
the intermediate glycol (6) with K2CO3 in MeOH for 20 min
at room temperature afforded successfully an epoxy-aldehyde
(17) in 71% yield. Reduction of the epoxy-aldehyde (17)
with NaBH4 furnished in a high yield an epoxy-alcohol (18),
which was led to the corresponding TBDPS-ether (16)
(Chart 4).
The procedure for the three step conversion from (5) to
(18) mentioned above, could be carried out in successive
one-pot treatment in MeOH. Homogeneity concerning the
stereochemistry and structure of the epoxide (16) prepared
via the epoxyaldehyde (17) were determined by chiral HPLC
analysis and identification with the compound (16) which
was obtained from the chloromethylcarbinol (12). The trans-
formation of the glycol (6) to the epoxy-aldehyde (17) is in-
terpreted to proceed with tandem epoxide migration closely
related to the Payne rearrangement50—52) illustrated in Chart
5.
was determined to be over 98% ee by chiral HPLC analysis
of the glycol mono-t-butyldiphenylsilyl (TBDPS) ether (7),
which was derived from 5 through acidic hydrolysis provid-
ing a glycol (6), followed by TBDPS-protection of the pri-
mary hydroxyl group as shown in Chart 3. The absolute con-
figuration (S) of the quaternary carbon was assigned on the
bases of the previous results38) and verified finally by deriva-
tion of (R)-(ꢁ)-tanikolide (1) from 5. On the other hand, the
carbene reaction of a glycol-ester derivative (4) under the
same reaction conditions gave a low yield (21%) of the de-
sired compound (8) with a large amount of recovery of the
starting material (4) after esterification by treatment of the
crude product mixture containing carboxylic acids with 2,2-
diethoxypropane in the presence of catalytic p-TsOH at
80 °C for 12 h. The yield of 8 was improved upto 34% by ad-
dition of dichloroethane as a cosolvent, although a large
amount (53%) of the starting material (4) was recovered after
the same treatment of the crude product.48) The stereochemi-
cal purity of the compound (8) was demonstrated by conver-
sion of 8 through acidic treatment affording g-hydroxy-
methyl-g-lactone (9) followed by etherification of the alcohol
with t-butyldiphenylsilyl chloride (TBDPS-Cl) into the
TBDPS-derivative (10), which showed purity over 98% ee on
the chiral HPLC. The ester (8) was converted into the com-
pound (5) with a long carbon chain by three step sequence of
reactions in 44% overall yield through reduction with di-
isobytylaluminum hydride (DIBAH) giving aldehyde (11),
Wittig reaction using n-octylidenephosphorane, and hydro-
genation of the produced olefin (Chart 3).
In extensive trials for reductive mono-dechlorination of 5
Having the key intermediate (16) for the synthesis of (R)-

850
Vol. 52, No. 7
tures.45,46)
(S)-4-Dichloromethyl-2,2-dimethyl-4-undecyl-1,3-dioxolane (5) To
aq. 50% NaOH (50 g) was added a solution of an acetonide 3 (1.90 g, 7.4
mmol) and cetyltrimethylammouium chloride (CTAC) (5 mg) in CHCl3 (20
ml), and the mixture was warmed at 80 °C for 12 h under vigorous stirring.
After neutralization by addition of dil. H2SO4, the product was extracted
with ether. The organic layer was washed with brine, dried over Na2SO4, and
evaporated to give a crude mass, which was chromatographed on silica gel
(hexane : EtOAcꢄ50 : 1) to give a dichloromethylcarbinol 5 (1.46 g, 58%)
and the starting acetonide 3 (456 mg, 24%). 5: Colorless oil. [a]D21 ꢂ11.3°
(cꢄ0.9, CHCl3). 1H-NMR d: 0.88 (3H, t, Jꢄ6.6), 1.27—1.51 (18H, m), 1.41
(3H, s), 1.48 (3H, s), 177—1.88 (1H, m), 1.95—2.02 (1H, m), 3.90 (1H, d,
Jꢄ9.8), 4.19 (1H, d, Jꢄ9.3), 5.78 (1H, s). IR (neat) cmꢂ1: 2989, 2926, 2855,
1466, 1382, 1372, 1253, 1214, 1065, 777. FAB-MS m/z: 339 (MꢁH)ꢁ; HR-
FAB-MS m/z: Calcd for C17H33O2Cl2 (MꢁH)ꢁ: 339.1857, Found: 339.1866.
Chart 5. Tandem Epoxide Migration
(S)-2-Dichloromethyltridecane-1,2-diol (6) To
a solution of 4-
dichloromethyl-1,3-dioxolane 5 (100 mg, 0.3 mmol) in MeOH (2 ml) was
added c. HCl (0.2 ml) and the mixture was stirred for 7 h at room tempera-
ture. The whole was concentrated and chromatographed on silica gel
(hexane : EtOAcꢄ7 : 1) to give a 1,2-diol 6 (78 mg, 89%) as an oil. [a]D20
ꢁ2.1° (cꢄ0.46, CHCl3). 1H-NMR d: 0.86 (3H, t, Jꢄ6.6), 1.18—1.26 (18H,
m), 1.65—1.79 (2H, m), 3.71 (1H, d, Jꢄ11.7), 3.88 (1H, d, Jꢄ11.7), 5.96
(1H, s). IR (neat) cmꢂ1: 3418, 2918, 2849, 1473, 1463. EI-MS m/z: 297
(MꢂH)ꢁ, 269, 267, 215.
(S)-2-t-Butyldiphenylsilyloxymethyl-1,1-dichlorotridecane-2-ol (7) To
a solution of the glycol 6 (20 mg, 0.07 mmol) and imidazole (10.0 mg, 0.15
mmol) in THF (1.0 ml) was added t-butyldiphenylsilyl chloride (TBDPS-Cl)
(39 ml, 0.15 mmol) at 0 °C, and the whole was stirred for 12 h at room tem-
perature. The mixture was concentrated and chromatographed on silica gel
(hexane : EtOAcꢄ20 : 1) to give a TBDPS-ether 7 (26 mg, 72%) as an oil.
Chiral HPLC of 7 was performed on CHIRALCEL OD-H using a mixed
solvent system of hexane–2-PrOH (500 : 1), and a peak was observed at the
retention time (RT) of 11.17 min, indicating the enantio-excess (ee) to be
over 98% by comparison with the racemic one (RT: 8.92, 11.17 min). 1H-
NMR d: 0.90 (3H, t, Jꢄ6.6), 1.11 (9H, s), 1.17—1.50 (18H, br), 1.55—1.88
(2H, m), 2.60 (1H, s), 3.70 (1H, d, Jꢄ9.0), 3.84 (1H, d, Jꢄ9.0), 6.01 (1H, s),
7.35—7.52 (6H, m), 7.64—7.73 (4H, m).
Chart 6. Synthesis of (R)-(ꢁ)-Tanikolide (1)
(ꢁ)-tanikolide (1) in hand, construction of the d-lactone
skeleton was performed according to Chart 6. Homoallyla-
tion using a 5 eq of a cuprate reagent prepared from 3-
butenyl Grignard reagent and CuI in THF at ꢂ30 °C for 0.5 h
gave a tertiary alcohol derivative (19) in 59% yield. The ter-
minal olefin was designed as the latent carboxyl group. Thus,
Lemiux oxidation of (19) with catalytic OsO4 and an 10 eq of
NaIO4 in aqueous dioxane at room temperature for 1 h pro-
vided a crude hemiacetal, which was successfully oxidized
with Jones reagent to an optically pure d-lactone derivative
(20) in 64% overall yield. The final deprotection of TBDPS-
group with tetrabutylammonium fluoride (TBAF) proceeded
smoothly to give the target molecule, (R)-(ꢁ)-tanikolide (1),
which was identified with the natural one39,40) in spectro-
scopic comparisons including specific optical rotation.
In conclusion, optically active natural (R)-(ꢁ)-tanikolide
(1) was synthesized stereospecifically from (R)-glyceralde-
hyde acetonide (2) easily prepared from D-mannitol as a chi-
ral source via stereospecific insertion reaction of chiral sec-
ondary alcohol derivatives with dichlorocarbene. Reduction
of dichloromethyl group (5) with LiAlH4 providing chloro-
methyl group (12) and basic treatment of dichloromethylated
glycol system (6) leading to epoxy-aldehyde (17) function-
ality with complete inversion of configuration of the starting
alcohol offer novel methods for transformations of the di-
chloromethyl carbinol group to synthetically versatile func-
tionalities.53,54)
Ethyl (S)-3-(4-Dichloromethyl-2,2-dimethyl-1,3-dioxolan-4-yl)-propa-
noate (8) To 50% aq. NaOH (10 g) was added a solution of an acetonide 4
(100 mg, mmol) and cetyltrimethylammonium chloride (0.2 mg) in CHCl3
(1.0 ml) and 1,2-dichloethane (0.5 ml) and the mixtute was vigorously stirred
at 80 °C for 5 h, while 6 portions of CHCl3 (0.5 ml) were added in every
40 min interval. After neutralization of the mixture by addition of 2%
H2SO4, the whole was extracted with ethyl acetate. The organic layer was
washed with brine, dried over Na2SO4, and concentrated to give a crude
product, which was heated in 2,2-diethoxypropane (2.0 ml) with p-TsOH (5
mg) for 12 h at 80 °C. The whole was concentrated in vacuo, and chro-
matographed on silica gel (hexane : EtOAcꢄ7 : 1) to give a dichloromethyl
derivative 8 (48 mg, 34%) and the starting material 4 (53 mg, 53%). 8: Col-
orless oil. [a]D23 ꢂ11.3° (cꢄ0.9, CHCl3). H-NMR d: 1.27 (3H, d, Jꢄ7.1),
1
1.41 (3H, s), 1.47 (3H, s), 2.15—2.29 (1H, m), 2.36—2.56 (3H, m), 3.89
(1H, d, Jꢄ9.8), 4.16 (2H, q, Jꢄ7.2), 4.20 (1H, d, Jꢄ9.8), 5.77 (1H, s). IR
(neat) cmꢂ1: 2988, 2940, 1736, 1448, 1383, 1374, 1306, 1255, 1215, 1186,
1160, 1082, 1064, 875, 773. FAB-MS m/z: 285 (MꢁH)ꢁ; HR-FAB-MS m/z
Calcd for C11H19O4Cl2 (MꢁH)ꢁ: 285.0660, Found: 285.0650.
Experimental
(S)-5-Dichloromethyl-5-hydroxymethyl-2,3,4,5-tetrahydrofuran-2-one
(9) A a solution of the acetonide (8) (187 mg, 0.68 mmol) in MeOH (5.0
ml) was added c. HCl (0.2 ml), and the mixture was stirred at room tempera-
ture for 2 h. The whole was concentrated and the residue was chro-
matographed on silica gel (hexane : EtOAcꢄ3 : 1ÆEtOAc) to give a crys-
talline lactone 9 (131 mg, 97%). Colorless needle. mp. 75.0—76.0 °C
(ether–hexane). [a]D21 ꢁ61.3° (cꢄ1.1, CHCl3). 1H-NMR d: 2.11—2.86 (4H,
Melting points (mp) were measured with a Yanagimoto micromelting
point apparatus and are uncorrected. IR spectra were recorded on a Perkin-
Elmer Spectrum One FT-IR spectrometer. 1H-NMR spectra was recorded on
a JEOL JNM-GX-270 (270 MHz) spectrometer in CDCl3 with SiMe4 as an
internal standard; J values are given in hertz (Hz). Mass spectra (MS) and
high-resolution mass spectra (HR-MS) were recorded on a JEOL JMS-D300
or a JEOL JMS-SX102A spectrometer. High performance liquid chromatog-
raphy (HPLC) was carried out on Shimadzu LC-6A using solvents and
columns (25 cmꢃ4.6 mmf) indicated in the text with a flow rate of 1.0
ml/min, and peaks were observed using an UV detector (254 nm). Specific
optical rotation [a]D was measured by JASCO DIP-360 digital polarimeter
using a cell (50 mmꢃ3 mmf). Products were purified by silica gel chro-
matography or preparative TLC. Tetrahydrofuran (THF) and diethyl ether
(ether) were freshly distilled from sodium benzophenone ketyl prior to use.
Dichloromethane and 1,2-dichloroethane were distilled from CaH2 and
stored over molecular sieves. The starting materials, (S)-1,2-isopropylidene-
dioxytridecane (3) and ethyl (S)-4,5-isopropylidenedioxypentanoate (4) were
prepared from (R)-glyceraldehyde acetonide (2) according to the litera-
m), 3.86 (1H, d, Jꢄ12.7) 3.99 (1H, d, Jꢄ12.2), 6.05 (1H, s). IR (KBr) cmꢂ1
:
3235, 1780, 1220, 1184, 1127, 1065, 941, 785. Anal. Calcd for C6H8Cl2O3:
C, 36.21; H, 4.05. Found: C, 36.39; H, 4.18.
(S)-5-Dichloromethyl-5-t-butyldiphenylsilyloxymethyl-2,3,4,5-tetrahy-
drofuran-2-one (10) To a solution of the hydroxylactone 9 (20 mg, 0.1
mmol) and imidazole (13.6 mg, 0.2 mmol) in THF (1.0 ml) was added t-
butyldiphenylsilyl chloride (TBDPS-Cl) (52 ml, 0.2 mmol) at 0 °C, and the
whole was stirred for 12 h at room temperature. The mixture was concen-
trated and chromatographed on silica gel (hexane : EtOAcꢄ30 : 1) to give a
TBDPS-ether 10 (31 mg, 72%) as an oil. Chiral HPLC of 10 was performed
on CHIRALCEL OD-H using a mixed solvent system of hexane–2-PrOH
(500 : 1), and a peak was observed at RT of 38.61 min to be over 98% ee by

July 2004
851
comparison with the racemic one (RT: 29.81, 38.61). 1H-NMR d: 1.05 (9H,
s), 1.94—2.05 (1H, m), 2.44—2.79 (3H, m), 3.82 (1H, d, Jꢄ9.0), 3.90 (1H,
d, JJꢄ9.0), 6.10 (1H, s), 7.32—7.50 (6H, m), 7.62—7.80 (4H, m).
2.67 (1H, d, Jꢄ4.9), 3.69 (2H, s) 7.35—7.46 (6H, m), 7.66—7.69 (4H, m).
IR (neat) cmꢂ1: 3071, 3050, 2928, 2856, 1465, 1427, 1113, 824, 740, 702.
FAB-MS m/z: 467 (MꢁH)ꢁ; HR-FAB-MS m/z Calcd for C30H47O2Si
(MꢁH)ꢁ: 467.3345, Found: 467.3356.
(R)-2-Undecyloxirane-2-carboxyaldehyde (17) A mixture of the 1,2-
diol 6 (470 mg, 1.6 mmol) and K2CO3 (1.10 g, 8 mmol) in MeOH (10 ml)
was stirred for 20 min at room temperature. After neutralization of the mix-
ture with 2% HCl, the whole was concentrated to give a crude product which
was purified by chromatography on silica gel to afford an aldehyde 17
(270 mg, 77%). [a]D20 ꢁ36.1° (cꢄ0.96, CHCl3). 1H-NMR d: 0.88 (3H, t, Jꢄ
6.6), 1.20—1.45 (18H, m), 1.66—1.73 (1H, m), 1.89—1.94 (1H, m), 3.03
(2H, s), 8.88 (1H, s). IR (neat) cmꢂ1: 2925, 2854, 1735, 1466, 1378. EI-MS
m/z: 226 (M)ꢁ, 208, 197, 179.
(S)-3-(4-Dichloromethyl-2,2-dimethyl-1,3-dioxolane-4-yl)propanal
(11) To a cold solution (ꢂ78 °C) of the ester 8 (271 mg, 0.95 mmol) in
CH2Cl2 (10 ml) was added a solution of diisobutylaluminum hydride
(DAIBH) (0.95 M/hexane, 1.2 ml, 1.14 mmol), and the mixture was stirred
for 20 min at the temperature. After quenching the reaction by addition of
MeOH, the whole was extracted with ether. The organic layer was washed
with brine, dried over Na2SO4, and concentrated to give a crude aldehyde 11
(188 mg, 86%). 1H-NMR d: 1.33 (3H, s), 1.40 (3H, s), 2.08—2.19 (1H, m),
2.32—2.43 (1H, m), 2.54—2.62 (2H, m, 2H), 3.80 (1H, d, Jꢄ9.8), 4.14 (1H,
d), 5.70 (1H, s), 9.75 (1H, s).
Side Chain Elongation of 11 Providing 5 To a cold solution (0 °C) of
n-octyltriphenylphosphonium bromide (0.2 g/ml ether solution, 4.6 ml, 2.0
mmol) in ether (20 ml) was added n-BuLi (1.2 m1, 1.50 mol/l in hexane, 1.8
mmol) under nitrogen atmosphere. After stirring the mixture for 5 min, a so-
lution of an aldehyde 11 (188 mg, 0.78 mmol) in ether (20 ml) was added.
The mixture was stirred for 10 min at 0 °C. The mixture was filtered, and the
filtrate was concentrated and chromatographed on silica gel (hexane :
CHCl3ꢄ20 : 1) to give an olefin, (S)-4-dichloromethyl-2,2-dimethyl-4-(3-un-
decen-1-yl)-1,3-dioxolane (185 mg, 62%) as an oil. A mixture of the olefin
(185 mg) in ethanol (2 ml) and 5% Pd/C (10 mg) was vigorously stirred
under atmosphere of H2 for 2.5 h, and the whole was filtered through celite,
concentrated, and chromatographed on silica gel to give 5 (155 mg, 83%
(44% overall yield from 8)).
(S)-2-Hydroxymethyl-2-undecyloxirane (18) To a solution of the alde-
hyde 17 (250 mg, 1.1 mmol) in MeOH (10 ml) was added NaBH4 (300 mg,
8 mmol), and the whole was stirred for 30 min at the temperature. The reac-
tion was quenched by addition of acetone (2.0 ml), and the whole was di-
luted with ether and passed through a silica gel column and concentrated to
leave a crude oil, which was purified by silica gel chromatography
(hexane : EtOAcꢄ7 : 1) to give an epoxyalcohol 18 (212 mg, 84%) as an oil.
[a]D22 ꢂ13.8° (cꢄ0.46, CHCl3). 1H-NMR d: 0.88 (3H, t, Jꢄ6.5), 1.18—1.39
(18H, m), 1.45—1.80 (2H, m), 2.66 (1H, d, Jꢄ4.6), 2.88 (1H, d, Jꢄ4.6),
3.60—3.68 (1H, dd, Jꢄ12.2, 8.39), 3.75—3.81 (1H, dd, Jꢄ12.2, 3.9). IR
(neat) cmꢂ1: 3460, 2918, 2849, 1472, 1462. EI-MS m/z: 229 (MꢁH)ꢁ, 228
(M)ꢁ, 197.
One-Pot Transformation of the Dichloromethyl-acetonide (5) to
Epoxy-alcohol (18) A solution of the dichloromethyl-acetonide 5 (50 mg,
0.15 mmol) in MeOH (1 ml) was stirred with a HCl/MeOH solution (0.2 ml,
3.3 M/HCl in MeOH) for 15 h at room temperature. To the mixture was
added K2CO3 (200 mg, 1.50 mmol) and the whole was stirred for 0.5 h.
Then, NaBH4 (28 mg, 0.75 mmol) was added and the whole was sirred for
additional 20 min. The reaction was quenched by acetone, and the whole
was diluted with ether and passed through a silica gel column. The filtrate
was concentrated and chromatographed on silica gel (hexane : EtOAcꢄ7 : 1)
to give the epoxy-alcohol 18 (18 mg, 53%).
Silylation of 18 Providing 16 A mixture of the epoxyalcohol 18 (100
mg, 0.4 mmol), imidazole (90 mg, 1.3 mmol), and t-butyldiphenylsilyl chlo-
ride (TBDPS-Cl) (340 ml, 1.3 mmol) in THF (5.0 ml) was stirred for 12 h at
room temperature. After concentration, the whole was chromatographed on
silica gel (hexane : EtOAcꢄ30 : 1) to give a TBDPS-ether 16 (180 mg, 88%)
as an oil. This compound was identical with that obtained from 12 via 15 by
spectral comparisons and chiral HPLC, which showed a single peak at the
RT of 6.8 min using CHIRALCEL OD-H (hexane : 2-PrOHꢄ500 : 1) indi-
cating over 98% ee by comparison with the racemic one (TR: 5.6, 6.8 min).
(R)-6-(t-Butyldiphenylsiloxymethyl)heptadec-1-en-6-ol (19) Under ni-
(S)-4-Chloromethyl-2,2-dimethyl-4-undecyl-1,3-dioxolane (12) Under
nitrogen atmosphere, a solution of a dichloromethyl-acetonide 5 (1.0 g,
2.95 mmol) in THF (3 ml) was added dropwise into a suspension of LiAlH4
(140 mg, 3.69 mmol) in THF (8 ml) at 0 °C over 10 min. The mixture was
stirred for 5 h at room temperature, and then another portion of LiAlH4
(70 mg, 1.85 mmol) in THF (3 ml) was added and the stirring was continued
for 9 h. After careful addition of water to quench the reaction, the whole was
filtered through celite. The filtrate was concentrated and chromatographed
on silica gel (hexane : EtOAcꢄ50 : 1) to give a chloromethyl-acetonide 12
(540 mg, 60%) and 2,2,4-trimethyl-4-undecyl-1,3-dioxolane (13) (64 mg,
8%). 12: Colorless oil. [a]D19 ꢂ9.5° (cꢄ1, CHCl3). H-NMR d: 0.88 (3H, t,
1
Jꢄ6.8), 1.26—1.31 (18H, m), 1.38 (3H, s), 1.43 (3H, s), 1.60—1.79 (2H, m)
, 3.49 (2H, s), 3.75 (1H, d, Jꢄ9.3), 4.03 (1H, d, Jꢄ8.8). IR (neat) cmꢂ1
:
2988, 2926, 2855, 1467, 1458, 1381, 1371, 1254, 1210, 1062, 874, 820, 739.
FAB-MS m/z: 305 (MꢁH)ꢁ; HR-FAB-MS m/z Calcd for C17H34O2Cl
(MꢁH)ꢁ: 305.2248, Found: 305.2253. 13: Colorless oil. 1H-NMR d: 0.88
(3H, t, Jꢄ6.8), 1.25—1.65 (20H, m), 1.60 (3H, s), 1.38 (3H, s), 1.40 (3H, s),
3.69 (1H, d), 3.78 (1H, d, Jꢄ8.3). EI-MS m/z: 270 (M)ꢁ, 269, 255.
(S)-2-Chloromethyltridecane-1,2-diol (14) A solution of the acetonide
12 (230 mg, 0.75 mmol) in MeOH (3 ml) was stirred with c. HCl (0.1 ml) at
room temperature for 5 h. The mixture was concentrated and chro-
matographed on silica gel (hexane : EtOAcꢄ1 : 1) to give a diol (14) (184
mg, 92%). Colorless oil. [a]D20 ꢁ2.3° (c 0.9, CHCl3). 1H-NMR d: 0.88 (3H,
t, Jꢄ6.6), 1.26—1.30 (18H, m), 1.51—1.59 (2H, m) , 1.91 (1H, br s) , 2.35
(1H, br s), 3.54 (1H, d, Jꢄ4.9) , 3.59 (1H, d, Jꢄ4.9), 3.62 (1H, d, Jꢄ6.8),
3.66 (1H, d, Jꢄ6.8). IR (neat) cmꢂ1: 3391, 2925, 2854, 1466, 1060, 799,
740, 722. EI-MS m/z: 233 (MꢂCH2OH)ꢁ; HR-EI-MS Calcd for C16H30OCl
(MꢂCH2OH)ꢁ: 233.1672, Found: 233.1678.
trogen atmosphere, to
a cold suspension (ꢂ30 °C) of CuI (92 mg,
0.48 mmol) in THF (1.0 ml) was added dropwise a solution of 3-butenyl-
magnesium bromide (0.30 mol/THF, 3.2 ml, 0.96 mmol) over 5 min, and the
mixture was stirred for an additional 5 min at ꢂ30 °C. To the mixture was
added a solution of the epoxide 16 (50 mg, 0.11 mmol) in THF (2.0 ml) at
the temperature, and the whole was stirred for 30 min. After quenching the
reaction by addition of sat. aq. NH4Cl, the whole was extracted with ether.
The organic layer was washed successively with sat. NH4Cl and brine, dried
over Na2SO4, and evaporated to give a crude oil, which was purified by chro-
matography on silica gel (hexane : EtOAcꢄ50 : 1) to give an alcohol 19 (33
mg, 59%). Colorless oil. [a]D23 ꢂ0.7° (cꢄ0.8, CHCl3). 1H-NMR d: 0.88 (3H,
t, Jꢄ6.6), 1.07 (9H, s), 1.25—1.38 (20H, br s), 1.44—1.46 (4H, m), 2.02
(2H, q, Jꢄ6.8), 3.47 (2H, s) , 4.94 (1H, d, Jꢄ8.8), 4.99 (1H, d, Jꢄ15.6),
5.73—5.83 (1H, m), 7.35—7.47 (6H, m), 7.64—7.67 (4H, m). IR (neat)
cmꢂ1: 3576, 3469, 3072, 3051, 2928, 2856, 1641, 1428, 1113, 910, 823,
740, 702. EI-MS m/z: 465(Mꢂt-Bu)ꢁ; HR-EI-MS m/z Calcd for C30H45O2Si
(Mꢂt-Bu)ꢁ: 465.3189, Found: 465.3183.
(R)-6-(t-Butyldiphenylsiloxymethyl)-6-undecyltetrahydropyran-2-one
(20) To an aqueous solution of OsO4 (1.6 mg, 0.006 mmol) and NaIO4
(135 mg, 0.63 mmol) in water (0.3 ml) was added a solution of the olefin 19
(33 mg, 0.063 mmol) in dioxane (1.0 ml), and the mixture was stirred for 1 h
at room temperature. The whole was extracted with ether and the organic
layer was washed with brine, dried over Na2SO4, and concentrated. The
residue was dissolved in acetone (1.0 ml) and cooled to 0 °C. To the mixture
was added Jones reagent (0.5 ml) and the whole was stirred for 30 min at
0 °C. The whole was extracted with ether, washed with brine, dried over
Na2SO4, and concentrated to give a crude product, which was chro-
matographed on silicagel (hexane : EtOAcꢄ7 : 1) to give a lactone 20 (21
mg, 64%) as a colorless oil. Chiral HPLC of 20 was performed on CHIRAL-
(S)-1-(t-Butyldiphenylsilyloxy)-2-chloromethyl-2-tridecanol (15) To a
solution of the diol (14) (202 mg, 0.76 mmol) and imidazole (104 mg,
1.5 mmol) in THF (3 ml) was added t-butyldiphenylsilyl chloride (TBDPS-
Cl) (400 ml, 1.53 mmol) at 0 °C, and the whole was stirred for 12 h at room
temperature. The mixture was concentrated and chromatographed on silica
gel (hexane : EtOAcꢄ50 : 1) to give a mono-TBDPS ether (15) (363 mg,
95%). Colorless oil. [a]D20 ꢁ1.7° (cꢄ1.1, CHCl3); H-NMR d: 0.88 (3H, t,
1
Jꢄ6.6), 1.07 (9H, s), 1.25 (18H, m), 1.51—1.54 (2H, m), 3.49 (1H, d,
Jꢄ9.8) , 3.62 (2H, s), 3.68 (1H, d, Jꢄ9.8), 7.37—7.48 (6H, m), 7.64—7.68
(4H, m). IR (neat) cmꢂ1: 3557, 3072, 3050, 2927, 2856, 1465, 1428, 1114,
824, 740, 701; EI-MS m/z: 445 (Mꢂt-Bu)ꢁ ; HR-EI-MS m/z Calcd for
C26H38O2ClSi (Mꢂt-Bu)ꢁ: 455.2330, Found: 455.2336.
(R)-2-t-Butyldiphenylsilyloxymethyl-2-undecyloxirane (16) To a solu-
tion of the chloromethylcarbinol 15 (364 mg, 0.72 mmol) in MeOH (5 ml)
was added K2CO3 (0.50 g, 3.60 mmol) at room temperature and the mixture
was stirred for 1 h. After dilution with ether (50 ml), the whole was filtered
and concentrated. The residue was chromatographed on silica gel (hexane :
EtOAcꢄ7 : 1) to give an epoxide 16 (326 mg, 97%). Colorless oil. [a]D26
1
ꢁ0.9° (cꢄ0.9, CHCl3). H-NMR d: 0.88 (3H, t, Jꢄ6.3), 1.06 (9H, s), 1.25
(18H, m), 1.52—1.60 (1H, m), 1.73—1.81 (1H, m), 2.59 (1H, d, Jꢄ4.9),

852
Vol. 52, No. 7
CEL OD-H using a mixed solvent system of hexane/2–PrOH (100 : 1), and a
peak was observed at the RT of 9.2 min, indicating over 98% ee by compari-
21) Ramon D. J., Yus M., Tetrahedron Lett., 39, 1239—1242 (1998).
22) Cunningham A., Woodward S., Synthesis, 2002, 43—44 (2002).
son with the racemic one (RT: 7.8, 9.2 min). [a]D18 ꢂ8.7° (cꢄ0.2, CHCl3). 23) Evans D. A., Tregay S. W., Burgey C. S., Paras N. A., Vojkovsky T., J.
1H-NMR d: 0.88 (3H, t, Jꢄ7.1), 1.06 (9H, s), 1.25 (18H, br s), 1.59—1.70,
1.74—1.83, 1.99—2.04 (6H, m), 2.43 (2H, t, Jꢄ6.6), 3.58 (2H, dd, Jꢄ14.7, 24) Capriati V., Florio S., Luisi R., Salomone A., Org. Lett., 4, 2445—
10.3), 7.36—7.47 (6H, m), 7.63—7.66 (4H, m). IR (neat) cmꢂ1: 3072, 3050,
2448 (2002).
Am. Chem. Soc., 122, 7936—7943 (2000).
2928, 2856, 1738, 1464, 1428, 1248, 1114, 824, 741, 702. FAB-MS m/z: 25) Yamauchi Y., Katagiri T., Uneyama K., Org. Lett., 4, 173—176
523 (MꢁH)ꢁ; HR-FAB-MS m/z Calcd for C33H51O3Si (MꢁH)ꢁ: 523.3607,
(2002).
Found: 523.3600.
26) Paulsen H., Graeve C., Hoppe D., Synthesis, 1996, 141—144 (1996).
27) Derwing C., Hoppe D., Synthesis, 1996, 149—154 (1996).
28) Besse P., Veschambre H., Tetrahedron, 50, 8885—8927 (1994).
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3826 (1996).
(R)-6-Hydroxymethyl-6-undecyltetrahydropyran-2-one (1: Tanikolide
)
To a solution of the silyl ether 20 (40 mg, 0.08 mmol) in THF (2.0 ml) was
added an aq. solution of n-Bu4NF-3H2O (120 mg, 0.4 mmol) and the mixture
was stirred for 1.5 h at room temperature. The whole was concentrated and
the residue was chromatographed on silica gel (hexane : EtOAcꢄ1 : 1) to 30) Theil F., Chem. Rev., 95, 2203—2227 (1995).
give tanikolide 1 (17 mg, 78%). Colorless crystal. mp. 39—41 °C. [a]D20 31) Stecher H., Faber K., Synthesis, 1997, 1—16 (1997).
1
ꢁ2.5° (cꢄ0.44, CHCl3). H-NMR d: 0.88 (3H, t, Jꢄ6.6), 1.26 (18H, br s), 32) Hudlicky T., Gonzalez D., Gibson D. T., Aldrichimica Acta, 32, 35—
1.57—1.91 (6H, m), 2.46—2.52 (2H, m), 3.55 (1H, dd, Jꢄ11.7, 4.6), 3.66
62 (1999).
(1H, dd, Jꢄ11.7, 4.6); IR (KBr) cmꢂ1: 3393, 2923, 2852, 1705. EI-MS m/z: 33) Jacobsen E. N., “Catalytic Asymmetric Synthesis,” Chapter 4.2, ed. by
253 (MꢂCH2OH)ꢁ; HR-EI-MS m/z Calcd for C16H29O2 (MꢂCH2OH)ꢁ:
Ojima I., VCH, New York, 1993.
253.2168, Found: 253.2162.
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2483—2547 (1994).
Acknowledgements This work was partially supported by Grant-in-Aid
for Scientific research (No. 14657566) from the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan.
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