Synthesis of chiral epoxyalkynes

Article abstract of DOI:10.1016/S0957-4166(98)00221-3

The synthesis of novel chiral propargylic epoxides ((R)-1-t- butyldimethylsilyl-3,4-epoxy-1-butyne, (3S,4S)-3,4-epoxy-1-octyne, (3R,4S)- 1-t-butyldimethylsilyl-3,4-epoxy-1-pentyne) has been developed starting from the readily available tartaric acid deriv

Full text of DOI:10.1016/S0957-4166(98)00221-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2499–2508
Synthesis of chiral epoxyalkynes
Tõnis Kanger,a,∗ Piret Niidas,a Aleksander-Mati Müürisepp,a Tõnis Pehk b and
Margus Lopp a,∗
aInstitute of Chemistry at Tallinn Technical University, Akadeemia tee 15, EE0026 Tallinn, Estonia
bInstitute of Chemical Physics and Biophysics, Akadeemia tee 23, EE0026 Tallinn, Estonia
Received 22 May 1998; accepted 28 May 1998
Abstract
The synthesis of novel chiral propargylic epoxides ((R)-1-t-butyldimethylsilyl-3,4-epoxy-1-butyne, (3S,4S)-3,4-
epoxy-1-octyne, (3R,4S)-1-t-butyldimethylsilyl-3,4-epoxy-1-pentyne)has been developed starting from the readily
available tartaric acid derivative, (S,S)-(+)-2,3-O-isopropylidene-L-threitol.© 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Chiral α-functionalised alkyne units are often essential fragments of naturally occurring molecules that
show interesting and important biological (e.g. cytotoxic and antifungal)1,2 activity. For the preparation
of such compounds and many other complex chiral structures, enantiomerically pure α-epoxyalkynes
may serve as versatile building blocks. However, the synthesis of enantiomerically pure epoxyalkynes
has received surprisingly little attention, if compared to the variety of methods for the synthesis of
enantiomerically pure α-epoxyalkenes and epoxyalkanes (Sharpless epoxidation,3 direct asymmetric
epoxidation with salen complexes,4,5 hydrolytic kinetic resolution6). To date Grandjean7–9 has described
the only method for the asymmetric synthesis of these compounds. For this reason, the search for methods
of the synthesis of acetylenic epoxides from readily available natural compounds is still of interest.
We have developed a general route for the synthesis of propargylic epoxides (terminal epoxides,
disubstituted cis-epoxides and trans-epoxides)10,11 starting from a readily available tartaric acid deriva-
tive — (S,S)-(+)-2,3-O-isopropylidene-L-threitol 1 (Scheme 1). The key reaction of the route is the
stereospecific base-induced double elimination of the appropriately substituted and protected chloride 2
with LiNH2 in liquid ammonia.12 The obtained monoprotected propargylic diol 3 is converted selectively
into one of the possible different halohydrins or monotosylates 3a, 3b, 3c or 3d, which have a strictly
∗
Corresponding authors. E-mail: kanger@boc.ic.ee and lopp@argus.chemnet.ee
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00221-3

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defined configuration of the substituents (Scheme 2). The absolute configuration at the propargylic centre
may remain the same as in the starting monoprotected diol 3 in the case of 3a and 3d, (double SN2
reaction). An inversion of the configuration at C-3 takes place with compounds 3b and 3c. The geometry
of the epoxide (cis or trans) is determined by the configuration of the alkyl substituent, and also by the
choice of the OH group for the nucleophilic ring formation reaction (the α-OH or the β-OH-group).
Scheme 1.
Scheme 2.
The main possibilities to obtain cis- and trans-epoxides of different configuration are presented in
Scheme 2. The route is completely stereoconvergent, which means that epoxides with different absolute
configuration and geometry may be obtained from one stereoisomeric propargylic diol.
The basic problems arising from the current route are: (a) the synthesis of the appropriately protected
and substituted triol chlorides 2 with a strictly determined configuration of the alkyl group (syn or anti
to the OH group(s)); (b) the appropriate manipulation of the OH groups in diol 3 before epoxidation (the
selection of groups, one of which will act as a nucleophile and the other as a leaving group; inversion or
retention of the configuration at the chiral centre with the leaving group before epoxidation).
The possibilities of the route are presented below.
2. Results and discussion
2.1. Terminal propargylic epoxide
This is the least complicated case. The absolute configuration of the final epoxide is determined by
the selection of a nucleophile and leaving group. The following is an example of how bromohydrin 8

T. Kanger et al. / Tetrahedron: Asymmetry 9 (1998) 2499–2508
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is made by means of the stereoselective conversion of the secondary OH-group into a bromide group
(inversion of configuration). The primary OH-group acts in this case as a nucleophile in the oxirane
formation reaction (case 3d on Scheme 2, R2=H). The synthesis starts from selective monobenzylation
of tartaric acid derivative 1 followed by chlorination under non-acidic conditions13 (Scheme 3). The
obtained chloroacetal 5 is a key synthon for base-induced eliminations12 with LiNH2 in liquid ammonia
affording propargylic alcohol 6 in 70% yield. Although it has been stated that no epimerization takes
place under these conditions,14 we checked the enantiomeric excess of intermediate 6 prior to subsequent
conversions. The corresponding ester from (R)-α-methoxy-α-trifluoro-methylphenylacetic acid did not
reveal any traces of the other diastereomer by means of HPLC and NMR analyses. Also, in order to
verify the absolute configuration, compound 6 was hydrogenated (H2/Pd on C) to give (R)-1,2-butanediol
([α]D20=+14.8, lit15 [α]D20=+12.6).
Scheme 3. Reagents and conditions: (a) NaH, BnCl, THF, 0°C, 1 h r.t., 86%; (b) Ph3P, CCl4, 70°C, 2 h, 95%; (c) LiNH2, liq.
NH3, −33°C, 0.5 h, 70%; (d) BuLi, THF, −78°C followed by t-BuMe2SiCl, −20°C to r.t., 6 h, 59%; (e) BBr3, CH2Cl2, −70°C,
15 min, 85%; (f) K2CO3, acetone/H2O, 30 min, r.t., 70%
The terminal triple bond and the OH group in compound 6 were silylated with TBDMSCl, affording
propargylic alcohol 7. The debenzylation reaction of 7 with BBr3 occurred simultaneously with a highly
stereoselective propargylic bromination (substitution of TBDMSO group) affording bromohydrin 8. A
similar conversion of alkyl, benzyl and adamantyl alcohols to the corresponding bromides with BBr3 is
known from the literature.16,17 However, our example is the first application of this reaction to propargylic
silyl ethers. The bromination reaction is stereoselective (as can be seen from the enantiomeric excess
of the target compound) and chemoselective (only the propargylic silyl ether is replaced by bromide,
the primary OH function remains unchanged),† resulting in a high yield (85%) of bromohydrin 8. The
final step of the route is the conversion of bromohydrin 8 under the basic conditions into the target
epoxide 9 (intramolecular SN2 reaction). The stereoconvergent synthesis that allows the synthesis of the
other enantiomeric epoxide (where the propargylic OH-group is converted to a tosylate with retention of
configuration) is demonstrated on the example of the substituted trans-epoxides.
2.2. Synthesis of substituted propargylic epoxides
2.2.1. trans-Epoxides
In the synthesis of disubstituted epoxides, the key intermediate is the protected triol chloride 2. The
configuration of the stereogenic centre on the alkyl chain determines the configuration of the β-carbon
†
Debenzylation of unprotected alcohol 6 afforded but-3-yn-1,2-diol, no bromination was detected.

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T. Kanger et al. / Tetrahedron: Asymmetry 9 (1998) 2499–2508
atom of the α-epoxyalkyne. The geometry of the epoxide is determined by the relative configuration of
the leaving group/nucleophilic group (see Scheme 2). Although the synthetic route is stereoconvergent as
well as convergent in respect of the geometry of the epoxide function, the selectivity of the alkylation is
of great importance for achieving the strictly defined stereochemistry of intermediate 3. For that reason
we tried to control (and direct) the selectivity of alkylation.
The alkyl chain is introduced via nucleophilic addition to aldehyde 10 (Scheme 4). The alkylation with
different organometallic nucleophiles afforded a mixture of diastereomeric alcohols 11a and 11b, which
are easily separable by column chromatography. The ratio of diastereomers was determined by HPLC
and the results are presented in Table 1. The ratio of derived alcohols 11a(S):11b(R) is dependent on the
alkylation reagent. The highest excess of desired isomer 11a was obtained with BuLi (entry 1). Various
Lewis acid additives (ZnCl2, Ti(i-PrO)3Cl, BF3·Et2O, entries 2–4) increased the amount of the undesired
isomer 11b. Alkylation with BuMgBr and Bu2CuLi reagents gave an even lower ratio of isomers. Lewis
acid additives did not change the ratio considerably (entries 5–11). It was assumed that four heteroatoms
in the molecule of aldehyde 10 might form several chelates (the five-, six- or seven-membered ring,
Scheme 5). These possible chelates may exist simultaneously in the reaction medium and direct the attack
of the nucleophile in the opposite direction, which results in poor diastereoselection. Despite the fact that
the ratio of diastereomeric alcohols was the highest in the case of BuLi, the reaction with BuMgBr
gave a better isolated yield of product 11a (40% after chromatographic purification) and, therefore, the
preparative synthesis was carried out using the Grignard reagent.
Scheme 4. Reagents and conditions: (a) lit.10,11; (b) BuMgBr, Et2O, r.t., 12 h; 61%; (c) separation of isomers on silica gel; (d)
TBDMSCl, imidazole, DMF, 40°C, 38 h, 90%; (e) Na, liq. NH3, −33°C, 4 h, 80%; (f) PPh3, CCl4, 3 h, 78%; (g) LDA, THF,
−78°C to r.t., 3 h, 72%; (h) TsCl, Py, CH2Cl2, r.t., 24 h, 84%; (i) Bu4NF, THF, −78°C to 0°C, 2 h, 55%
The choice of benzyl as a protecting group for the primary alcohol group in compounds 10–12 enables
its selective removal in compound 12 in the presence of acid sensitive silyl and acetal groups, affording
intermediate 13. This compound was chlorinated with PPh3/CCl4 and transformed to propargylic alcohol
15 (3 equiv. of LDA in THF at −78°C) in good yield (72%).‡ HPLC, 1H and 13C NMR analyses did not
reveal any trace of the diastereomeric alcohol. Alcohol 15 was converted into tosylate 16 with tosyl
chloride in 84% yield. This intermediate corresponds to compound 3b in Scheme 2. The following
‡
The same results were obtained when running the reaction in liq. NH3 with NaNH2.

T. Kanger et al. / Tetrahedron: Asymmetry 9 (1998) 2499–2508
2503
Table 1
Alkylation of aldehyde 10 with organometallic reagents
Scheme 5.
desilylation with Bu4NF led to the desired propargylic epoxide 17 in one step.18 The trans-configuration
at the oxirane ring was confirmed by the 2.0 Hz vicinal coupling constant.11
2.2.2. cis-Epoxides
The synthetic route to cis-epoxide 22 generally follows the same scheme. A cis-configuration of the
target compound was achieved via syn-configuration in intermediate 21 (Scheme 6). Since the selection
of the leaving group and the nucleophile is the same as in the case of terminal epoxide, the obtained
target compound has the same absolute configuration at C-3. This process has been described in detail in
our recent work11 and now only the principles are presented.
Chloroacetal 18 (derived from diol 1) was converted into monoprotected propargylic diol 19 in
good yield (82%). Its disilylation followed by bromination results in bromohydrin 21 with an inverted

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T. Kanger et al. / Tetrahedron: Asymmetry 9 (1998) 2499–2508
Scheme 6. Reagents and conditions: (a) lit.11; (b) LDA, THF, −78°C to r.t., 1 h, 82%; (c) BuLi, THF, −78°C followed by
t-BuMe2SiCl, −20°C to r.t., 4 h, 60%; (d) BBr3, CH2Cl2, −70°C, 2 h, 91%; (f) K2CO3, acetone/H2O, 30 min, r.t., 92%
configuration at the propargylic carbon atom (it corresponds to the intermediate 3d on Scheme 2). The
synthesis was completed with a nucleophilic attack of the β-OH group affording cis-epoxide 22.
2.3. Determination of the absolute configuration of α-epoxyalkynes
The absolute configuration of the target compounds was determined via products obtained by the
epoxide opening reaction. Epoxide 9 was converted to oct-1-yn-3-ol with dibutylcuprate. The specific
rotation ([α]D20=−21, lit.14 [α]D20=−23) corresponds to oct-1-yn-3-ol having an S-configuration. In
1
1
addition, NMR analysis was performed with the use of 2D H–1H and H–13C COSY correlation
diagrams from the esters made from the alcohol and (R)-(−)-α-methoxyphenylacetic acid and α-
methoxy-α-trifluoromethylphenylacetic acid, as described earlier.19 This method enables us to assign 1H
chemical shifts from the overlapping parts of the NMR spectra and in this way can be obtained a whole
set of chemical shifts for the determination of the absolute configuration on the basis of ring current
effects from the aromatic nucleus of chiral acid. The spectra of these esters confirm the S-configuration
of oct-1-yn-3-ol, which, in turn, corresponds to the R-configuration of epoxide 9. trans-Epoxide 17 was
1
regioselectively reduced with LiAlH4 to the homopropargylic alcohol.§ The H and 13C NMR spectra
of the O-methyl mandelic acid ester of the derived octynol¶ showed a high enantiomeric purity of the
compound (ee 98%) and 4S configuration at the stereogenic centre. This conclusion is drawn from the
high field shifts of alkyl protons from H-6, H-7 and H-8 in the (R)-(−)-α-methoxyphenylacetic acid
ester of 4-hydroxy-1-octyne, because in the 4S-enantiomer the phenyl ring is orientated towards the
saturated side chain of this homopropargylic alcohol. The absolute configuration of cis-epoxide 22 was
determined by its regioselective reduction to homopropargylic alcohol with LiAlH4. Its specific rotation
([α]D20=−19.8) confirms the 4S configuration in 22 ([α]D20=−20.0 for (S)-4-pentyn-2-ol20 ).
3. Conclusions
The proposed approach provides a simple route to the synthesis of various useful propargylic epoxides.
As different protective groups and syn- or anti-substituted intermediates can be used, the method becomes
enantioconvergent and stereoconvergent with respect to double bond geometry. Since the starting diol
§
4(S)-Hydroxy-1-octyne: 13C NMR, CDCl3: 70.72 (C-1), 80.91 (C-2), 27.76 (C-3), 69.86 (C-4), 35.91 (C-5), 27.33 (C-6),
22.58 (C-7), 13.98 (C-8).
¶
(R)-(−)-α-Methoxyphenylacetic acid ester of 4(S)-hydroxy-1-octyne: 1H NMR, CDCl3, chemical shifts, assigned by 2D
1H–1H and H–13C COSY correlation diagrams: 1.97 (H-1), 2.48 (H-3), 4.97 (H-4), 1.56 (H-5), 0.94 (H-6), 1.11 (H-7), 0.72
(H-8). 13C NMR; CDCl3: 70.45 (C-1), 79.52 (C-2), 24.05 (C-3), 72.50 (C-4), 32.57 (C-5), 26.76 (C-6), 22.16 (C-7), 13.76
(C-8).
1

T. Kanger et al. / Tetrahedron: Asymmetry 9 (1998) 2499–2508
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1 is available in both enantiomeric forms, all stereoisomers of a certain propargylic epoxide could be
synthesised.
4. Experimental
4.1. General data
13C NMR spectra were obtained on a Bruker AMX-500 spectrometer in CDCl3 solution. The chem-
ical shifts are reported relative to the TMS signal. Mass spectra were recorded on a Hitachi M80B
spectrometer at an ionizing potential of 70 eV. Optical rotations were obtained using a Polamat A
polarimeter. HPLC analyses were performed using a LKB liquid chromatograph equipped with a UV
spectrophotometric detector (206 nm, 254 nm, 278 nm, column Zorbax Sil 4.6×250 mm). Epoxide 22
was synthesised according to the literature procedure.11
4.2. (2R,3S)-4-Benzyloxy-1-chloro-2,3-isopropylidenedioxybutane 5
Diol 1 was converted into compound 5 via known methods. Selective monobenzylation was carried
out according to the literature21 followed by nonacidic chlorination13 affording chloro acetal 5 in 81%
yield.
4.3. (R)-1-Benzyloxy-but-3-yne-2-ol 6
A solution of chloride 5 (2.06 g, 7.62 mmol) in THF (10 ml) was added to freshly prepared LiNH2
(1.05 g, 45.7 mmol) in liquid ammonia (300 ml). After 30 minutes, solid NH4Cl (802 mg, 15 mmol)
was added and ammonia was allowed to evaporate. Water was added to the residue and it was extracted
with Et2O (3×50 ml). The extracts were dried over MgSO4, solvent was evaporated and the product was
purified by flash chromatography on silica gel affording butynediol 6 (939 mg, yield 70%). 13C NMR:
δC=73.67 (C-1), 81.67 (C-2), 61.49 (C-3), 73.47 (C-4), 73.37 (CH2), 137.48 (s), 127.78 (o), 128.47 (m),
127.91 (p). [α]D20=−8.5 (c 2.68, CHCl3).
4.4. (R)-1-Benzyloxy-4-tert-butyldimethylsilyl-2-tert-butyldimethylsilyloxy-3-butyne 7
A solution of BuLi in hexanes (1.6 M, 1.86 ml, 3.0 mmol) was added to a solution of butynediol 6 (250
mg, 1.4 mmol) in THF (4 ml) at −78°C under an Ar atmosphere. The mixture was allowed to warm to
−20°C and tert-butyldimethylsilyl chloride (440 mg, 2.94 mmol) was added. The reaction mixture was
stirred at room temperature overnight, and then quenched with saturated solution of NH4Cl and extracted
with Et2O (3×20 ml). Extracts were dried over MgSO4, solvent was evaporated and the product was
purified by flash chromatography on silica gel affording disilylated compound 7 (385 mg, yield 68%).
MS: m/z=347 (M+−t-Bu), 283, 241, 117, 91. [α]D20=−28.8 (c 5.63, CHCl3).
4.5. (S)-2-Bromo-4-tert-butyldimethylsilyl-but-3-yne-1-ol 8
Boron tribromide (0.91 ml, 9.85 mmol) was added dropwise to a solution of compound 7 (3.98 g, 9.85
mmol) in methylene chloride (20 ml) at −70°C under an Ar atmosphere. The mixture was stirred at this
temperature for 15 minutes and water (10 ml) was added. The mixture was allowed to warm up to room

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T. Kanger et al. / Tetrahedron: Asymmetry 9 (1998) 2499–2508
temperature, layers were separated, the organic fraction was dried over MgSO4, solvent was evaporated
and product was purified by flash chromatography on silica gel affording bromohydrin 8 (2.20 g, 85%).
13C NMR: δC=100.87 (C-1), 92.87 (C-2), 39.53 (C-3), 67.00 (C-4), −4.90 (Me2Si), 16.56, 25.89 (t-Bu).
[α]D20=−2.66 (c 4.66, CHCl3).
4.6. (R)-1-tert-Butyldimethylsilyl-3,4-epoxy-but-1-yne 9
A solution of bromohydrin 8 (2.29 g, 8.7 mmol) and K2CO3 (1.80 g, 13.1 mmol) in acetone:water (2:1,
15 ml) was stirred at room temperature for 30 minutes. Acetone was evaporated, the residue was extracted
with with Et2O (3×30 ml). Extracts were dried over MgSO4, solvent was evaporated and the product
was purified by flash chromatography on silica gel (eluent: pentane/methylene chloride) affording target
epoxide 9 (1.11 g, yield 70%). 13C NMR: δC=102.53 (C-1), 87.55 (C-2), 39.89 (C-3), 48.95 (C-4), −4.82
(Me2Si), 16.43, 25.98 (t-Bu). MS: m/z=182 (M+), 166, 125. [α]D20=−72.3 (c 5.63, CH2Cl2).
4.7. (2S,3S)-1-Benzyloxy-2,3-isopropylidenedioxy-4-octanol (mixture of 4S and 4R isomers) 11a and
11b
To stirred solution of BuMgBr (20 mmol) in Et2O (40 ml) at −60°C was added dropwise a solution of
aldehyde 1011 (1.02 g, 4.1 mmol) in Et2O (10 ml). The mixture was allowed to warm to 0°C and stirred
for 3 hours, the temperature increased to room temperature and the mixture was stirred for a further 12
hours. After addition of a saturated solution of NH4Cl, the layers were separated and the aqueous layer
was extracted with EtOAc (3×30 ml). The combined extracts were dried (MgSO4) and the solvent was
evaporated. Isomers were separated by column chromatography on silica gel to give 544 mg of epimer
11a and 227 mg of epimer 11b. The total yield of isomers was 61%. MS: m/z=293 (M+−15), 250,
221, 129, 91. 11a: [α]D20=−4.4 (c 4.1, CHCl3). IR (film) ν=3360, 2980, 1550, 1490, 1380, 1260, 1220,
1090 cm−1 .13C NMR: δC=13.98 (C-1), 22.64 (C-2), 27.62 (C-3), 32.89 (C-4), 71.66 (C-5), 81.73 (C-6),
77.32 (C-7), 70.85 (C-8), 73.62 (CH2Ph), 137.43 (s), 127.81 (o), 128.42 (m), 127.83 (p), 26.83 and 26.94
(Me2), 108.85 (C–Me2).
4.8. (2S,3S,4S)-1-Benzyloxy-4-tert-butyldimethylsiloxy-2,3-isopropylidenedioxyoctane 12
To a solution of compound 11a (392 mg, 1.27 mmol) in DMF (8 ml) tert-butyldimethylsilyl chloride
(220 mg, 1.47 mmol) and imidazole (122 mg, 1.8 mmol) were added at room temperature. The mixture
was stirred at 40°C for 38 hours, cooled to room temperature, poured into water and extracted with
EtOAc. The extracts were washed with brine, dried (MgSO4) and evaporated. The residue was purified
by flash chromatography on silica gel affording (90%) 12 in 90% yield (482 mg). MS: m/z=407 (M+−15),
307, 221, 91. [α]D20=−5.36 (c 1.3, CHCl3). IR (film) ν=3030, 2870, 1550, 1490, 1260, 1090, 840 cm−1
4.9. (2S,3S,4S)-4-tert-Butyldimethylsiloxy-2,3-isopropylidenedioxy-1-octanol 13
.
To a solution of compound 12 (1.30 g, 2.44 mmol) in liquid ammonia (30 ml), sodium (224 mg, 9.76
mmol) was added in pieces. The dispersion was stirred for 4 hours, solid NH4Cl was added and NH3
was evaporated in the flow of Ar. The residue was dissolved in water and extracted with EtOAc. The
organic layers were washed with water, dried (MgSO4) and evaporated. The residue was purified by flash
chromatography on silica gel affording alcohol 13 (684 mg, yield 80%). MS: m/z=317 (M+−15), 275,
201, 131, 75. [α]D20=−1.92 (c 3.1, CHCl3).

T. Kanger et al. / Tetrahedron: Asymmetry 9 (1998) 2499–2508
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4.10. (2R,3S,4S)-4-tert-Butyldimethylsiloxy-1-chloro-2,3-isopropylidenedioxyoctane 14
A solution of alcohol 13 (427 mg, 1.29 mmol) and Ph3P (673 mg, 2.5 mmol) in anhydrous CCl4 (5
ml) was stirred at 80°C for 3 h. The mixture was allowed to cool to room temperature and the insoluble
material was filtered off. The solvent was evaporated, the residue triturated with hexane (5×4 ml). The
insoluble residue was filtered, the crude product concentrated and passed through a short column of silica
gel affording chloride 14 (353 mg, yield 78%). MS: m/z=335 (M+−15), 293, 149. [α]D20=−3.19 (c 2.16,
CHCl3). IR (film) ν=3030, 2980, 1490, 1380, 1260, 1090, 840 cm−1
4.11. (3R,4S)-4-tert-Butyldimethylsiloxy-1-octyn-3-ol 15
.
A solution of BuLi in hexanes (1.6 M, 2.94 ml) was added dropwise to a stirred solution of
diisopropylamine (0.66 ml, 4.7 mmol) in THF (10 ml) at −40°C under an Ar atmosphere and the mixture
was stirred for 30 min. The solution was cooled to −78°C, chloride 14 (326 mg, 0.93 mmol) was added
in THF (2 ml) and the mixture was stirred at this temperature for 30 minutes. The mixture was warmed to
0°C over 3 hours and quenched with a saturated solution of NH4Cl. The solution was extracted with Et2O,
dried (MgSO4) and the solvent was evaporated. Flash chromatography on silica gel afforded propargylic
alcohol 15 (171 mg, yield 72%). [α]D20=−9.56 (c 10.1, CHCl3). IR (film) ν=3360, 2890, 2240, 1490,
1380, 1260, 1090, 840 cm−1 13C NMR: δC=74.21 (C-1), 81.65 (C-2), 65.84 (C-3), 74.69 (C-4), 31.97
.
(C-5), 27.52 (C-6), 22.73 (C-7), 13.96 (C-8), 25.76 and 18.06 (t-Bu), −4.40 and −4.50 (Me2Si).
4.12. (3R,4S)-4-tert-Butyldimethylsiloxy-3-tosyloxy-1-octyne 16
A solution of tosyl chloride (200 mg, 1.05 mmol) in CH2Cl2 (2 ml) was added slowly to a solution
of propargylic alcohol 15 (230 mg, 0.90 mmol) in CH2Cl2 (3 ml) and pyridine (3 ml) at 0°C. The
mixture was stirred at room temperature for 24 hours, poured into ice–water and extracted with EtOAc.
The extract was washed with 0.1 M HCl, water, saturated solution of NaHCO3, dried (MgSO4) and
evaporated. The residue was passed through a short column of silica gel to give 310 mg (84%) of tosylate
16. MS: m/z=319 (M+−91), 255, 171, 155. [α]D20=−49.8 (c 9.3, CHCl3). IR (film) ν=3030, 2890,
2240, 1640, 1490, 1390, 1260, 1180, 970, 840 cm−1 13C NMR: δC=77.13 (C-1), 76.81 (C-2), 74.05
.
(C-3), 73.72 (C-4), 32,76 (C-5), 27.14 (C-6), 22.52 (C-7), 13.90 (C-8), 25.77 and 18.11 (t-Bu), −4.50
and −4.65 (Me2Si), 144.75, 129.25, 128.07, 133.90, 21.62 (Tos).
4.13. (3S,4S)-Epoxy-1-octyne 17
To a tosylate 16 (280 mg, 0.68 mmol) in THF (14 ml) at −78°C under an Ar atmosphere was slowly
added 1 M solution of Bu4NF in THF (0.78 ml, 0.78 mmol). The mixture was allowed to warm to 0°C
and stirred for 2 hours at this temperature. The reaction mixture was quenched with brine (10 ml) and
extracted with Et2O. The extracts were washed with water, dried (MgSO4) and evaporated. The crude
product was passed through a short column of silica gel eluting with pentane:Et2O (100:2.5) to afford 46
mg (55%) of epoxide 17. The yield of the target compound is relatively low because of its high volatility.
MS: (CI) m/z=125 (M+−1), 107, 95, 55. 1H NMR: δH=0.889 (t, J=7.1 Hz, H-8), 1.386 (m, H-7), 1.446
(m, H-6), 1.564 (m, H-5), 2.143 (d, J=1.7 Hz, H-1), 3.10 (m, H-3), 3.11 (m, H-4); the first order spectrum
from oxirane ring protons was obtained by adding C6D6: 2.975 (t, J=2×2.0 Hz, H-3), 3.020 (d, J=2.0 Hz,
H-2 to H-3 and J=2×5.5 Hz, H-2 to H-4), a 2.0 Hz vicinal coupling constant of oxirane protons points
to trans-substitution, in the cis-isomer it should be about 4 Hz.7 13C NMR: δC=71.64 (d, J=253 Hz; d,

2508
T. Kanger et al. / Tetrahedron: Asymmetry 9 (1998) 2499–2508
J=4.2 Hz; C-1), 80.59 (d, J=49.6 Hz; d, J=4.8 Hz; d, J=2.5 Hz; C-2), 44.84 (d, J=185 Hz, C-3), 60.37 (d,
J=174 Hz, C-4), 31.33 (t, C-5), 27.66 (t, C-6), 22.38 (t, C-7), 13.89 (q, C-8). [α]D20=−9.8 (c 3.0, Et2O).
IR (film) ν=2980, 2890, 2240, 1000, 850 cm−1
.
Acknowledgements
We thank the Estonian Science Foundation for support (Grant Nos. 2076 and 2293).
References
1. Bohlmann, F.; Burkhardt, T.; Zdero, C. Naturally Occurring Acetylenes; Academic Press, New York, 1973.
2. Takahashi, A. B.; Endo, T.; Nozoe, S. Chem. Pharm. Bull., 1992, 40, 3181–3184.
3. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc., 1987, 109,
5765–5780.
4. Chang, S.; Galvin, J. M.; Jacobsen, E. N. J. Am. Chem. Soc., 1994, 116, 6937–6938.
5. Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem., 1993, 58, 6939–6941.
6. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. Science, 1997, 277, 936–938.
7. Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett., 1992, 33, 5355–5358.
8. Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron, 1993, 49, 5225–5236.
9. Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron: Asymmetry, 1993, 4, 1991–1994.
10. Lopp, M.; Kanger, T.; Müraus, A.; Pehk, T.; Lille, Ü. Tetrahedron: Asymmetry, 1991, 2, 943–944.
11. Kanger, T.; Liiv, M.; Pehk, T.; Lopp, M. Synthesis, 1993, 91–93.
12. Yadav, J. S.; Chander, M. C.; Joshi, B. V. Tetrahedron Lett., 1988, 29, 2737–2740.
13. Gruber, L.; Tömösközi, I.; Radics, L. Synthesis, 1975, 708.
14. Kang, S. K.; Lee, D. H.; Lee, J. M. Synlett, 1990, 591–593.
15. Chenault, H. K.; Kim, M. J.; Akiyama, A.; Miyazawa, T.; Simon, E. S.; Whitesides, G. M. J. Org. Chem., 1987, 52,
2608–2611.
16. Amrollah-Madjdabadi, A.; Pham, T. N.; Ashby, E. C. Synthesis, 1989, 614–616.
17. Hudson, H. R.; Kinghorn, R. R. F.; Murphy, W. S. J. Chem. Soc. C, 1971, 3593–3596.
18. Battistini, C.; Giordani, A.; Ermoli, A.; Franceshi, G. Synthesis, 1990, 900–905.
19. Pehk, T.; Lippmaa, E.; Lopp, M.; Paju, A.; Borer, C. B.; Taylor, R. J. K. Tetrahedron: Asymmetry, 1993, 4, 1527–1532.
20. Jacobson, R.; Taylor, R. J.; Williams, H. J.; Smith, L. R. J. Org. Chem., 1982, 47, 3140–3142.
21. McDougal, G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org. Chem., 1986, 51, 3388–3390.