Formation of tetrahydrofurans via a 5-endo-tet cyclization of aziridines-synthesis of (-)-pachastrissamine

Article abstract of DOI:10.1039/c3ob40797g

The formation of tetrahydrofurans from 2-hydroxyalkyl-oxirane or aziridine is reported. The 5-endo-tet cyclization/ring opening of aziridine proceeded smoothly to give tetrahydrofurans (THFs) under mild conditions. In contrast, the corresponding process of oxirane was unsuccessful and a sequence of S _N2 substitution/cyclization was required to form THFs. The application of the process to prepare ent-(-)-pachastrissamine is described.

Full text of DOI:10.1039/c3ob40797g

Organic &
Biomolecular Chemistry
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PAPER
Formation of tetrahydrofurans via a 5-endo-tet
cyclization of aziridines – synthesis of
(−)-pachastrissamine†
Cite this: Org. Biomol. Chem., 2013, 11,
5292
Chen-Wei Lin, Sin-Wei Liu and Duen-Ren Hou*
The formation of tetrahydrofurans from 2-hydroxyalkyl-oxirane or aziridine is reported. The 5-endo-tet
cyclization/ring opening of aziridine proceeded smoothly to give tetrahydrofurans (THFs) under mild
conditions. In contrast, the corresponding process of oxirane was unsuccessful and a sequence of
SN2 substitution/cyclization was required to form THFs. The application of the process to prepare
ent-(−)-pachastrissamine is described.
Received 20th April 2013,
Accepted 18th June 2013
DOI: 10.1039/c3ob40797g
www.rsc.org/obc
Introduction
Tetrahydrofurans (THFs) are often found in natural products
and bioactive compounds.1,2 Among the many synthetic
methods developed to prepare tetrahydrofurans, applying oxi-
ranes (epoxides) as the building blocks for THFs is a frequently
adopted approach.3 This approach is popular because many
optically active oxiranes are commercially available or efficien-
tly prepared by Sharpless asymmetric epoxidation (SAE),4 and
their transformations to other functionalities, including THFs,
have highly conserved regio- and stereochemistry. Most of the
reported cyclizations involving epoxides to THFs utilize the
kinetically favourable 5-exo-tet cyclization,3,5 and the corres-
ponding process for aziridine, the N-analogue of oxiranes, has
also been reported.6 On the other hand, applying the unfavour-
able 5-endo-tet cyclization to prepare heterocycles has been
less explored. Recently several groups reported that the intra-
molecular, 5-endo-tet cyclization of oxiranes can be syntheti-
cally useful, while the competing 5- or 6-exo-tet processes are
absent (Scheme 1).7 We noticed that the 5-endo-tet cyclization/
ring opening of the oxirane derived from the C2 symmetrical
(3R,4R)-1,5-hexadiene-3,4-diol (1)8 may be an attractive
approach to prepare the substituted THFs such as pachastriss-
Scheme 1 Intramolecular 5-exo- and 5-endo-tet cyclization and its application
to pachastrissamine.
of pachastrissamine has received substantial attention.11 Here,
we report our attempts to synthesize pachastrissamine, and we
find that the unusual intramolecular, 5-endo-tet cyclization/
ring opening of aziridines can be an efficient process by which
to generate THFs.
Results and discussion
Applying Sharpless asymmetric epoxidation to the allylic
alcohol 2, derived from mono-tert-butyldimethylsilyl (TBS)-
protected diene-diol 1, generated the oxirane 3 (Scheme 2).
The stereochemistry of 3 is consistent with a previous report12
and the general reaction model for SAE.13 The remaining
hydroxyl group was further protected by a methoxymethyl
(MOM) group. After the removal of the TBS protective group
with fluoride, cross metathesis (CM) was performed to
elongate the carbon skeleton and generate 5. Hydrogenation
with Pd/C provided the saturated compound 6, which allowed
us to study the formation of THF by 5-endo-tet cyclization.
However, we were unable to produce any product with the THF
moiety, such as compound 7, under various reaction con-
ditions, including those previously reported.7,14 The successful
formation of THF from 4-chloroalcohols recently reported
by Britton’s group inspired us to adopt a similar strategy
amine ( jaspine B),
a phytosphingosine derived, natural
marine product with anti-cancer activity.9 Recent studies
showed that its cytotoxicity to melanoma cells is due to the
inhibition of sphingosine and related protein kinases.10 The
high levels of biological activity and relatively simple structure
Department of Chemistry, National Central University, 300 Jhong-Da Road, Jhong-Li,
Taoyuan, Taiwan. E-mail: drhou@ncu.edu.tw; Fax: +886-3-4227664;
Tel: +886-3-4227151, ext. 65981
†Electronic supplementary information (ESI) available: Copies of the 1H NMR
and 13C NMR spectra for the new compounds. See DOI: 10.1039/c3ob40797g
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Scheme 2 Initial attempt to form THF.
Scheme 4 Synthesis of ent-(−)-pachastrissamine.
sequence of iodination (13) and Staudinger type reaction.20 We
noticed that the aziridine moiety could not be generated when
the diol 11 was protected as an acetonide. The amino group of
14 was further masked with a benzyloxycarbonyl (Cbz) group
to give the carbamate 15. To our delight, the cyclization of 15
occurred simultaneously during the HF-promoted deprotec-
tion of the TBS groups and provided the desired THF 17 at
room temperature. The total synthesis of ent-(−)-pachastriss-
amine (18) was achieved after the sequence of cross metathesis
with 1-tetradecene, subsequent hydrogenation of the resulting
alkene and hydrogenolysis of the Cbz protecting group. The
natural (+)-pachastrissamine could be prepared by the same
approach using the known (3S,4S)-1,5-hexadiene-3,4-diol21 and
(+)-DIPT.
Further studies on the cyclization process found that an
acidic condition is required. When the aziridine 15 was treated
with the basic tetrabutylammonium fluoride (TBAF), the ring-
opening product 19, derived from the addition of methanol,
was obtained (eqn (1)). To our knowledge, only two reports
have described the intramolecular 5-endo-tet cyclization of
aziridines.22 In both cases, the reaction sites for the nucleo-
philic attack of the hydroxyls are tertiary carbons under Lewis-
acid catalyzed conditions. Here, we provide an example that
the ring opening occurred at the less substituted carbon.
Scheme 3 Synthesis of (2R,3R,4S)-isomer of pachastrissamine (10).
(Scheme 3).15 Thus, epoxide 6 was converted to the iodide 8,
and the formation of THF 9 was achieved under microwave
irradiated thermal conditions (in methanol, 40 minutes at
120 °C). Later, the addition of propylene oxide removed the
byproduct, hydrogen iodide, and provided the product 7,
whose MOM group remained intact.16,17 The sequence of
tosylation, nucleophilic substitution with sodium azide,
deprotection, and reduction provided the (2R,3R,4S)-isomer of
pachastrissamine.11l
Although the ring opening of epoxide by LiI and the sub-
sequent intramolecular SN2 reaction yielded the THF moiety,15
we still looked for substrates suitable for 5-endo-tet cyclization
to allow direct preparation of THF. Since one of the C–N bonds
is replaced with the thermodynamically more stable C–O bond
during the ring opening of aziridine to THF (Scheme 1),18 we
suspected that the corresponding ring opening of aziridine
should be more feasible than that of oxirane.
Thus, the stereochemically inverted (2S)-oxirane 11 was
prepared from the diene-diol 1 according to the report by
Takano’s group (Scheme 4).19 Both hydroxyl groups were then
protected with the tert-butyldimethylsilyl (TBS) group to give
12, and the oxirane was converted to aziridine 14 after the
ð1Þ
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CHCl3); H NMR (CDCl3, 300 MHz) δ 0.06 (s, 3H), 0.09 (s, 3H),
0.90 (s, 9H), 2.35 (br, 1H), 2.72–2.80 (m, 2H), 2.98–3.02
Conclusions
In conclusion, applying the 5-endo-tet cyclization of oxiranes (m, 1H), 3.30–3.33 (m, 1H), 4.27–4.30 (m, 1H), 5.18–5.21 (d,
and aziridines to prepare natural products with a tetrahydro- 1H, J = 10.5 Hz), 5.26–5.32 (d, 1H, J = 17.1 Hz), 5.83–5.94 (m,
furan moiety, such as pachastrissamine, is reported. Although 1H); 13C NMR (CDCl3, 75 MHz) δ −5.1, −4.3, 18.1, 25.8, 45.5,
this approach was unsuccessful for the oxirane 6, the alterna- 51.9, 74.1, 74.7, 116.6, 137.4; HRMS (ESI) calcd for [M + Na]+
tive sequence of iodination and intramolecular SN2 reaction at (C12H24O3SiNa) 267.1392, found 267.1397.
elevated temperature generated THF 7, leading to the synthesis
(5R,6R)-8,8,9,9-Tetramethyl-5-((R)-oxiran-2-yl)-6-vinyl-2,4,7-
of (2R,3R,4S)-isomer of pachastrissamine. The 5-endo-tet cycli-
trioxa-8-siladecane (4)
zation of aziridine 15, on the other hand, went smoothly
in HF/acetonitrile at room temperature, and the synthesis of Chloromethyl methyl ether (617 mg, 7.66 mmol) was added to
ent-(−)-pachastrissamine was achieved in eight steps. These the solution of epoxide 3 (936 mg, 3.83 mmol), N,N-diisopropyl-
results suggest that the 5-endo-tet cyclization/ring opening of ethylamine (1.50 g, 11.5 mmol) and dichloromethane (9 mL)
aziridines may be a synthetically useful process.
at 0 °C. The reaction mixture was heated to reflux for 16 h,
cooled to rt, NaHCO3(aq.) (3 wt%, 20 mL) was added, and
extracted with dichloromethane (10 mL × 3). The combined
organic layers were dried with Na2SO4(s), filtered and concen-
trated. The crude product was further purified by column
chromatography (SiO2, EtOAc–hexanes, 1 : 9; Rf 0.56) to give 4
(1.01 g, 3.51 mmol, 92%) as a light yellow oil. [α]2D0 +51.9
Experimental section
(3R,4R)-4-(tert-Butyldimethylsilyloxy)hexa-1,5-dien-3-ol (2)
tert-Butyldimethylsilyl chloride (TBSCl, 1.58 g, 10.5 mmol) was
added to the solution of diene-diol 1 (1 g, 8.76 mmol), imida-
zole (895 mg, 13.1 mmol) and dichloromethane (50 mL) at
0 °C. The reaction mixture was heated to reflux for 16 h,
quenched with water (30 mL) and extracted with diethyl ether
(40 mL × 3). The combined organic layers were washed with
1
(c 1.23, CHCl3); H NMR (CDCl3, 300 MHz) δ 0.04 (s, 3H), 0.07
(s, 3H), 0.88 (s, 9H), 2.67–2.74 (m, 2H), 3.07–3.10 (m, 1H), 3.31
(s, 3H), 3.48–3.51 (m, 1H), 4.28–4.32 (m, 1H), 4.56–4.58 (d, J =
6.6 Hz, 1H), 4.62–4.64 (d, J = 6.6 Hz , 1H), 5.12–5.15 (d, 1H, J =
10.5 Hz), 5.24–5.30 (d, 1H, J = 17.1 Hz), 5.85–5.96 (m, 1H);
13C NMR (CDCl3, 75 MHz) δ −5.1, −4.7, 18.2, 25.8, 44.9,
50.6, 55.4, 74.4, 78.2, 96.8, 115.8, 137.2; HRMS (ESI) calcd for
[M + Na]+ (C14H28O4SiNa) 311.1655, found 311.1656.
HCl(aq.) (0.1 N, 50 mL) and sat. NaCl(aq.), dried with Na2SO4(s)
,
filtered and concentrated. The crude product was further puri-
fied by column chromatography (SiO2, EtOAc–hexanes, 1 : 9;
Rf 0.6) to give 2 (1.20 g, 5.25 mmol, 60%) as a colorless oil.
[α]2D0 +8.94 (c 2.05, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 0.03 (s,
3H), 0.05 (s, 3H), 0.88 (s, 9H), 2.53 (s, 1H, J = 4.5 Hz), 3.91–3.97
(m, 2H), 5.14–5.32 (m, 4H), 5.73–5.86 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 18.1, 25.8, 75.6, 77.4, 116.4, 117.0, 136.9,
137.7; IR (neat): 3465 (br), 3080 (w), 2930 (m), 2857 (m),
1245 (m), 836 (m), 777 (m) cm−1; HRMS (ESI) calcd for
[M + Na]+ (C12H24NaO2Si) 251.1443, found 251.1440.
(E,1S,2R)-1-(Methoxymethoxy)-1-((R)-oxiran-2-yl)hexadec-3-en-
2-ol (5)
Tetrabutylammonium fluoride (TBAF, 1 Min THF, 5 mL,
5 mmol) was added to the solution of 4 (962 mg, 3.33 mmol)
and THF (30 mL). The reaction mixture was stirred at rt for
4 h, diluted with water (20 mL) and extracted with diethyl
ether (20 mL × 3). The combined organic layers were dried
with Na2SO4(s), filtered and concentrated. The residue was
purified by column chromatography (SiO2, EtOAc–hexanes,
1 : 1; Rf 0.40) to give (1S,2R)-1-(methoxymethoxy)-1-((R)-oxiran-
(1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-((R)-oxiran-2-yl)but-3-
en-1-ol (3)
Compound 2 (1.0 g, 4.38 mmol) in dichloromethane (3 mL) 2-yl)but-3-en-2-ol (515 mg, 2.96 mmol, 89%) as a light
was added to the suspension of (+)-diisopropyl L-tartrate yellow oil. [α]2D0 +9.08 (c 1.04, CHCl3); 1H NMR (CDCl3,
(1.30 mL, 6.14 mmol), titanium tetraisopropoxide (1.49 g, 300 MHz) δ 2.45 (br, 1H), 2.75–2.82 (m, 2H), 3.06–3.10 (m, 1H),
5.26 mmol), molecular sieves (3 Å, 1.33 g) and dichloro- 3.35 (s, 3H), 3.33–3.37 (m, 1H), 4.22–4.26 (m, 1H), 4.60–4.62
methane (25 mL) at −30 °C. After stirring for 1 h, tert-butyl (d, J = 6.6 Hz, 1H), 4.69–4.71 (d, J = 6.6 Hz , 1H), 5.22–5.26
hydroperoxide (3 M in toluene, 2.60 mL, 7.89 mmol) was (d, 1H, J = 10.5 Hz), 5.36–5.42 (d, 1H, J = 17.1 Hz), 5.88–5.99
added to the above solution at −30 °C. The reaction mixture (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 45.4, 50.6, 55.7, 73.4,
was stirred at −20 °C for another 72 h, quenched with a solu- 79.2, 96.6, 116.6, 136.8; HRMS (ESI) calcd for [M + Na]+
tion of ferrous sulfate heptahydrate (1.46 g, 5.26 mmol), citric (C8H14O4Na) 197.0790, found 197.0793.
acid (505 mg, 2.63 mmol) and water (15 mL). The mixture was
A solution of the above alcohol (382 mg, 2.19 mmol), 1-tetra-
stirred at −20 °C for another 1 h, warmed to rt, filtered, and decene (1.73 g, 8.77 mmol), Grubbs catalyst, 2nd generation
the filtrate was extracted with dichloromethane (20 mL × 3). (56 mg, 3 mol%) and dichloromethane (33 mL) was heated to
The combined organic layers were washed with sat. NaCl(aq.) reflux for 2 h under an atmosphere of nitrogen. The reaction
(20 mL), dried with Na2SO4(s), filtered and concentrated. The mixture was concentrated, and the residue was purified by
crude product was further purified by column chromatography column chromatography (SiO2, EtOAc–hexanes, 1 : 5; Rf 0.23)
(SiO2, EtOAc–hexanes, 1 : 5; Rf 0.31) to give 3 (816 mg, to give 5 (514 mg, 1.50 mmol, 69%) as a light brown oil. [α]D20
1
3.34 mmol, 76%) as a light yellow oil. [α]2D0 +12.8 (c 1.00, −3.62 (c 0.65, CHCl3); H NMR (CDCl3, 300 MHz) δ 0.83–0.88
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(t, J = 6.6 Hz, 3H), 1.23 (br, 20H), 2.01–2.08 (m, 2H), 2.47–2.49 δ 0.83–0.87 (t, J = 6.9 Hz, 3H), 1.23 (br, 24H), 1.59–1.66 (m,
(d, J = 5.1 Hz, 1H), 2.73–2.79 (m, 2H), 3.04–3.07 (m, 1H), 2H), 2.46 (br, 1H), 2.66 (br, 1H), 3.63–3.72 (m, 2H), 3.81–3.86
3.34–3.38 (m, 4H), 4.13–4.17 (m, 1H), 4.61–4.63 (d, J = 6.6 Hz, (dd, J = 6.6 Hz, 9.6 Hz, 1H), 4.04 (br, 1H), 4.36–4.38 (m, 1H);
1H), 4.70–4.72 (d, J = 6.6 Hz, 1H), 5.49–5.57 (dd, J = 6.8 Hz, 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.7, 26.1, 29.0, 29.3, 29.6,
15.5 Hz, 1H), 5.74–5.84 (m, 1H); 13C NMR (CDCl3, 75 MHz) 29.7, 31.9, 72.0, 72.2, 72.4, 81.9.
δ
14.1, 22.7, 29.0, 29.2, 29.3, 29.5, 29.6, 31.9, 32.3,
(3R,4R,5R)-4-(Methoxymethoxy)-5-tetradecyltetrahydrofuran-
3-ol (7)
45.1, 50.8, 55.8, 73.5, 79.6, 96.8, 128.2, 134.4; HRMS
(ESI) calcd for [M + Na]+ (C20H38O4Na) 365.2668, found
365.2674.
The solution of 8 (36.0 mg, 0.076 mmol), propylene oxide
(18 µL, 0.26 mmol) and methanol (0.8 mL) in a sealed tube
was heated to 120 °C in a microwave oven (CEM Discover,
(1S,2R)-1-(Methoxymethoxy)-1-(oxiran-2-yl)hexadecan-2-ol (6)
A suspension of 5 (514 mg, 1.50 mmol), palladium on carbon 50 W) for 40 min. After cooling to rt, the reaction mixture
(10 wt%, 80 mg) and methanol (10 mL) was stirred for 40 min was diluted with ethyl acetate (10 mL) and washed with sat.
at rt under hydrogen (1 atm). The suspension was filtered NaCl(aq.) (5 mL). The organic layer was separated, dried with
and concentrated. The crude product was further purified by Na2SO4(s), filtered and concentrated. The crude product was
column chromatography (SiO2, EtOAc–hexanes, 1 : 5; Rf 0.23) further purified by column chromatography (SiO2, EtOAc–
to give 6 (381.0 mg, 0.75 mmol, 74%) as a colorless solid. hexanes, 1 : 3; Rf 0.58) to give 7 (25 mg, 0.073 mmol, 96%) as a
M.p. 38.0–40.0 °C; [α]2D0 −4.91 (c 1.04, CHCl3); 1H NMR colorless solid. M.p. 73.0–75.0 °C; [α]D20 −3.70 (c 0.99, CHCl3);
(CDCl3, 300 MHz) δ 0.83–0.88 (t, J = 6.6 Hz, 3H), 1.23 (br, 1H NMR (CDCl3, 300 MHz) δ 0.83–0.86 (t, J = 6.9 Hz, 3H), 1.22
24H), 1.51–1.56 (m, 2H), 2.72–2.74 (dd, J = 2.7 Hz, 5.1 Hz, (br, 24H), 1.58–1.65 (m, 2H), 2.91–2.93 (d, J = 7.2 Hz, 1H),
1H), 2.80–2.83 (dd, J = 2.7 Hz, 5.1 Hz, 1H), 3.02–3.06 (m, 3.42 (s, 3H), 3.67–3.83 (m, 3H), 4.01–4.04 (m, 1H), 4.29–4.32
1H), 3.20–3.23 (dd, J = 4.5 Hz, 6.0 Hz, 1H), 3.37 (s, 3H), (m, 1H), 4.66–4.68 (d, J = 6.6 Hz, 1H), 4.75–4.77 (d, J =
3.67–3.73 (m, 1H), 4.60–4.62 (d, J = 6.6 Hz, 1H), 4.73–4.75 (d, 6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.7, 26.3,
J = 6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.7, 25.6, 29.3, 29.7, 31.9, 56.2, 71.8, 72.2, 79.4, 80.6, 97.7; HRMS
29.3, 29.6, 31.9, 33.3, 45.8, 50.8, 55.8, 72.4, 79.6, 96.6; HRMS (ESI) calcd for [M + Na]+ (C20H40O4Na) 367.2824, found
(ESI) calcd for [M + Na]+ (C20H40O4Na) 367.2824, found 367.2834.
367.2819.
(2R,3R,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol (10)
(2S,3S,4R)-1-Iodo-3-(methoxymethoxy)octadecane-2,4-diol (8)
p-Toluenesulfonyl chloride (238 mg, 1.25 mmol) was added to
The solution of 6 (150 mg, 0.44 mmol), lithium iodide the solution of 7 (43 mg, 0.13 mmol) and pyridine (1 mL) at
(117.0 mg, 0.87 mmol), acetic acid (56 μL, 1.31 mmol) and 0 °C. The reaction mixture was stirred in a 50 °C oil bath for
THF (2.6 mL) was stirred at rt for 16 h. Sat. NaCl(aq.) (5 mL) 16 h, sat. NaHCO3(aq.) (2 mL) was added and extracted with
was added to the reaction mixture and extracted with ethyl dichloromethane (5 mL × 3). The combined organic layers
acetate (10 mL × 3). The combined organic layers were dried were dried with Na2SO4(s), filtered and concentrated. The
with Na2SO4(s), filtered and concentrated. The crude product crude product was further purified by column chromatography
was further purified by column chromatography (SiO2, EtOAc– (SiO2, EtOAc–hexanes, 1 : 5; Rf 0.58) to give the tosylate (60 mg,
hexanes, 1 : 3; Rf 0.77) to give 8 (194 mg, 0.41 mmol, 94%) as a 0.12 mmol, 96%) as a light yellow oil. [α]2D0 −31.8 (c 0.80,
1
colorless solid. M.p. 43.0–45.0 °C; [α]2D0 +13.9 (c 0.81, CHCl3); CHCl3); H NMR (CDCl3, 300 MHz) δ 0.82–0.87 (t, J = 6.9 Hz,
1H NMR (CDCl3, 300 MHz) δ 0.82–0.87 (t, J = 6.9 Hz, 3H), 1.22 3H), 1.22 (br, 24H), 1.57–1.60 (m, 2H), 2.42 (s, 3H), 3.34 (s,
(br, 24H), 1.50 (br, 2H), 2.63 (br, 1H), 3.28–3.34 (m, 1H), 3H), 3.75–3.81 (m, 3H), 4.11–4.14 (t, J = 4.5 Hz, 1H), 4.58–4.60
3.40–3.46 (m, 4H), 3.50–3.53 (m, 2H), 3.78 (br, 2H), 4.66–4.68 (d, J = 6.9 Hz, 1H), 4.66–4.68 (d, J = 6.9 Hz, 1H), 4.89–4.95 (m,
(d, J = 6.6 Hz, 1H), 4.76–4.78 (d, J = 6.6 Hz, 1H); 13C NMR 1H), 7.31–7.33 (d, J = 8.1 Hz, 2H), 7.75–7.78 (d, J = 8.1 Hz, 2H);
(CDCl3, 75 MHz) δ 11.1, 14.1, 22.6, 25.8, 29.3, 29.5, 29.6, 31.9, 13C NMR (CDCl3, 75 MHz) δ 14.1, 21.6, 22.7, 25.9, 29.2, 29.3,
33.3, 56.2, 71.5, 71.7, 82.4, 97.8.
29.5, 29.6, 31.9, 56.1, 68.1, 75.7, 78.4, 80.0, 96.7, 127.8, 129.9,
133.3, 145.1; HRMS (ESI) calcd for [M + Na]+ (C27H46O6SNa)
521.2913, found 521.2921.
(2R,3R,4R)-2-Tetradecyltetrahydrofuran-3,4-diol (9)
The solution of 8 (36.0 mg, 0.076 mmol) and methanol
A solution of the above tosylate (29 mg, 0.058 mmol),
(0.8 mL) in a sealed tube was heated to 120 °C in a microwave sodium azide (38 mg, 0.58 mmol) and DMF (1 mL) was stirred
oven (CEM Discover, 50 W) for 40 min. After cooling to rt, the in a 100 °C oil bath for 16 h. After cooling to rt, the reaction
reaction mixture was diluted with ethyl acetate (10 mL) and mixture was diluted with ethyl acetate (5 mL) and washed with
washed with sat. NaCl(aq.) (5 mL). The organic layer was sepa- sat. NaCl(aq.) (2 mL). The organic layer was separated, concen-
rated, dried with Na2SO4(s), filtered and concentrated. The trated, and methanol (4.3 mL) and HCl(aq.) (3 M, 1.3 mL) were
crude product was further purified by column chromatography added to the residue. The solution was stirred at 55 °C for 5 h
(SiO2, EtOAc–hexanes, 1 : 3; Rf 0.32) to give 9 (13.2 mg, and concentrated. The crude product was further purified
0.044 mmol, 58%) as a colourless solid. M.p. 97.0–99.0 °C; by column chromatography (SiO2, EtOAc–hexanes, 1 : 5; Rf 0.31)
[α]2D0 −13.1 (c 0.63, CHCl3); 1H NMR (CDCl3, 300 MHz) to give (2R,3R,4S)-4-azido-2-tetradecyltetrahydrofuran-3-ol
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(14 mg, 0.043 mmol, 74%) as a colourless solid. M.p. quenched with water (30 mL) and extracted with diethyl ether
54.0–56.0 °C; [α]D20 +6.30 (c 0.68, CHCl3); 1H NMR (CDCl3, (20 mL × 3). The combined organic layers were dried with
300 MHz) δ 0.83–0.88 (t, J = 6.9 Hz, 3H), 1.23 (br, 24H), Na2SO4(s)
, filtered and concentrated. The crude product
1.51–1.66 (m, 2H), 1.74 (br, 1H), 3.62–3.67 (dd, J = 2.7 Hz, was further purified by column chromatography (SiO2, EtOAc–
9.9 Hz, 1H), 3.76–3.82 (m, 1H), 3.99–4.05 (m, 2H), 4.16–4.21 hexanes, 1 : 15; Rf 0.78) to give 12 (752 mg, 2.10 mmol, 91%) as
(dd, J = 5.7 Hz, 9.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, a colourless oil. [α]2D0 +36.2 (c 1.12, CHCl3); 1H NMR (CDCl3,
22.7, 26.2, 28.2, 29.4, 29.5, 29.7, 31.9, 67.6, 70.0, 76.4, 81.1; 300 MHz) δ 0.039 (q, 12H), 0.89 (d, J = 3.6 Hz, 18H), 2.63 (t, J =
HRMS (FAB) calcd for [M + H]+ (C18H36N3O2) 326.2808, found 3.8 Hz, 1H), 2.74 (t, J = 3.7 Hz, 1H), 2.91 (d, J = 2.7 Hz, 1H),
326.2808.
3.20 (t, J = 5.6 Hz, 1H), 4.13 (s, 1H), 5.15 (d, J = 10.5 Hz, 1H),
A suspension of the azido-alcohol (12 mg, 0.037 mmol), 5.28 (d, J = 17.1, 1H), 5.99–6.10 (m, 1H); 13C NMR (CDCl3,
palladium on carbon (10 wt%, 4 mg) and TFA–methanol 75 MHz) δ −2.95, 18.1, 25.7, 25.8, 44.9, 53.1, 75.3, 77.7, 115.2,
(1% v/v, 4 mL) was stirred for 5 h at rt under hydrogen (1 atm). 136.8; HRMS (ESI) calcd for [M + Na]+ (C18H38O3Si2Na)
The suspension was filtered, neutralized with NaHCO3(s) 381.2257; found 381.2253.
and concentrated. The crude product was further purified by
(2R,3R,4R)-3,4-Bis((tert-butyldimethylsilyl)oxy)-1-iodohex-5-en-
column chromatography (SiO2, methanol–dichloromethane–
2-ol (13)
ammonium hydroxide, 10 : 90 : 1; Rf 0.37) to give 10 (8.0 mg,
0.027 mmol, 72%) as a colorless solid.11l M.p. 86.0–88.0 °C; The solution of 12 (700 mg, 1.95 mmol), lithium iodide
[α]2D0 −5.1 (c 0.15, CHCl3); 1H NMR (CDCl3, 500 MHz) (522.47 mg, 3.91 mmol), acetic acid (335 μL, 5.86 mmol) and
δ 0.84–0.87 (t, J = 6.9 Hz, 3H), 1.23 (br, 24H), 1.55–1.67 (m, THF (15 mL) was stirred at rt for 6 h. Sat. NaCl(aq.) (20 mL) was
5H), 3.37–3.39 (dd, J = 2.5 Hz, 9.0 Hz, 1H), 3.47 (br, 1H), 3.80 added to the reaction mixture and extracted with ethyl acetate
(br, 1H), 3.86–3.89 (m, 1H), 4.18–4.21 (dd, J = 6.0 Hz, 9.0 Hz, (20 mL × 3). The combined organic layers were dried with
1H); 13C NMR (CDCl3, 125 MHz) δ 14.1, 22.7, 26.4, 28.5, 29.4, Na2SO4(s), filtered and concentrated. The crude product was
29.5, 29.6, 29.7, 29.7, 29.8, 31.9, 59.9, 73.7, 79.8, 80.7; HRMS further purified by column chromatography (SiO2, EtOAc–
(FAB) calcd for [M
300.2664.
+
H]+ (C18H38NO2) 300.2897, found hexanes, 1 : 15; Rf 0.62) to give 13 (788 mg, 1.62 mmol, 83%) as
1
a light yellow oil. [α]D20 +16.6 (c 0.605, CHCl3); H NMR (CDCl3,
300 MHz) δ 0.059 (q, 12H), 0.87 (d, J = 18.3 Hz, 18H), 2.76 (d,
J = 6.3 Hz, 1H), 3.18 (q, 2H), 3.84 (t, J = 3 Hz, 2H), 4.13–4.16
(1S,2R)-1-((S)-Oxiran-2-yl)but-3-ene-1,2-diol (11)
Diene-diol 1 (1.0 g, 8.76 mmol) in dichloromethane (6 mL) (m, 1H), 5.15 (d, J = 10.5 Hz, 1 Hz), 5.23 (d, J = 17.1 Hz, 1H),
was added to the solution of (−)-diisopropyl D-tartrate 5.92–6.01 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ −2.95, 9.7,
(1.80 mL, 8.76 mmol), titanium tetraisopropoxide (2.6 mL, 18.0, 18.2, 25.8, 25.9, 69.6, 74.6, 115.6, 136.5; HRMS (ESI)
8.76 mmol) and dichloromethane (50 mL) at −30 °C. After stir- calcd for [M
ring for 1 h, tert-butyl hydroperoxide (3 M in toluene, 4.38 mL, 509.1374.
13.14 mmol) was added to the above solution at −30 °C. The
+
Na]+ (C18H39IO3Si2Na) 509.1380, found
(R)-2-((5R,6R)-2,2,3,3,8,8,9,9-Octamethyl-6-vinyl-4,7-dioxa-3,8-
reaction mixture was stirred at −20 °C for another 10 h, and
disiladecan-5-yl)aziridine (14)
quenched with a solution of ferrous sulfate heptahydrate
(1.46 g, 5.26 mmol), citric acid (505 mg, 2.63 mmol) and water A solution of 13 (500 mg, 1.03 mmol), sodium azide (334 mg,
(15 mL). The mixture was stirred at −20 °C for another 1 h, 5.15 mmol) and DMF (30 mL) was stirred in a 40 °C oil bath
warmed to rt, filtered, and the filtrate was extracted with for 16 h. The reaction mixture was diluted with ethyl acetate
dichloromethane (25 mL × 3). The combined organic layers (30 mL) and washed with sat. NaCl(aq.) (20 mL). The organic
were washed with sat. NaCl(aq.) (20 mL), dried with Na2SO4(s)
,
layer was separated, dried with Na2SO4(s), filtered and concen-
filtered and concentrated. The crude product was further trated. The crude product was further purified by column
purified by column chromatography (SiO2, EtOAc–hexanes, chromatography (SiO2, EtOAc–hexanes, 1 : 15; Rf 0.62) to give
1 : 1; Rf 0.16) to give 11 (376 mg, 2.89 mmol, 33%) as a the azide (409 mg, 1.02 mmol, 99%) as a colorless oil. [α]2D0 +29
1
light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 2.72–2.79 (m, (c 0.5, CHCl3); H NMR (CDCl3, 300 MHz) δ 0.04 (q, 12H), 0.89
2H), 2.86 (br, 1H), 2.90 (br, 1H), 3.08–3.12 (m, 1H), 3.43 (s, (t, J = 9.5 Hz, 18H), 2.53 (d, J = 5.7 Hz, 1H), 3.25 (q, 2H), 3.62 (t,
1H), 4.17 (t, J = 6.5 Hz, 1H), 5.23–5.42 (m, 2H), 5.82–5.93 (m, J = 4.4 Hz, 1H), 3.86–3.93 (m, 1H), 4.16–4.19 (m, 1H), 5.14–5.29
1H); 13C NMR (CDCl3, 75 MHz) δ 44.6, 52.4, 73.2, 74.6, 118.2, (m, 2H), 5.94–6.05 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ −2.95,
136.3; HRMS (EI+) calcd for [M + H]+ (C6H11O3) 131.0708, 18.0, 18.1, 25.8, 25.9, 53.9, 69.3, 74.0, 74.5, 115.6, 136.4; HRMS
found 131.0708.
(ESI) calcd for [M + H]+ (C18H40N3O3Si2) 402.2608, found
402.2611.
A solution of the above azide (300 mg, 0.75 mmol), triphe-
nylphosphine (294 mg, 1.12 mmol) and toluene (35 mL) was
(5R,6R)-2,2,3,3,8,8,9,9-Octamethyl-5-((S)-oxiran-2-yl)-6-vinyl-
4,7-dioxa-3,8-disiladecane (12)
tert-Butyldimethylsilyl chloride (TBSCl, 0.87 g, 5.76 mmol) was heated to reflux for 6 h. Diethyl ether (20 mL), was added to
added into the solution of 11 (0.30 g, 2.30 mmol), imidazole the reaction mixture filtered and concentrated. The crude
(471 mg, 6.92 mmol) and dichloromethane (50 mL) at 0 °C. product was further purified by column chromatography (SiO2,
The reaction mixture was heated to reflux for 16 h, EtOAc–hexanes, 1 : 5; Rf 0.61) to give 14 (188 mg, 0.53 mmol,
5296 | Org. Biomol. Chem., 2013, 11, 5292–5299
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70%) as a colorless oil. [α]2D0 +16.9 (c 0.1, CHCl3); 1H NMR and washed with dichloromethane (2 mL × 3). The aqueous
(CDCl3, 300 MHz) δ 0.05 (d, J = 3.9 Hz, 12H), 0.87 (d, J = layer was basified with NaOH(aq.) (5 N), and extracted with
10.5 Hz, 18H), 1.45 (t, J = 5.5 Hz, 1H), 1.58 (d, J = 3 Hz, 1H), dichloromethane (2 mL × 3). The combined organic layers
2.13 (s, 1H), 3.62 (s, 1H), 4.19 (t, J = 4.7 Hz, 1H), 5.09–5.27 (m, were dried with Na2SO4(s), filtered and concentrated. The
2H), 5.88–5.99 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ −2.95, crude product was further purified by column chromatography
18.0, 18.1, 22.0, 25.7, 25.8, 30.4, 75.9, 115.4, 137.1; HRMS (ESI) (SiO2, methanol–dichloromethane–ammonium hydroxide,
calcd for [M + H]+ (C18H40NO2Si2) 358.2598, found 358.2591.
10 : 90 : 1; Rf 0.37) to give ent-(−)-pachastrissamine (4.5 mg,
0.015 mmol, 40%) as a colorless solid.11f M.p. 89.0–91.0 °C;
(R)-Benzyl 2-((5R,6R)-2,2,3,3,8,8,9,9-octamethyl-6-vinyl-4,7-
dioxa-3,8-disiladecan-5-yl)aziridine-1-carboxylate (15)
1
[α]2D0 −7.0 (c 0.1, CHCl3); H NMR (CDCl3, 500 MHz) δ 3.51 (q,
1H), 3.62 (q, 1H), 3.72 (q, 1H), 3.82 (q, 2H); 13C NMR (CDCl3,
Benzyl chloroformate (77.94 μL, 0.55 mmol) was added to the 125 MHz) δ 14.1, 21.7, 22.0, 22.7, 28.5, 29.1, 29.7, 30.0, 31.4,
solution of 14 (130 mg, 0.36 mmol), triethylamine (101.47 μL, 31.9, 52.7, 69.8, 70.7, 81.1.
0.73 mmol) and dichloromethane (5 mL) at 0 °C. The reaction
Benzyl ((2R,3R,4R)-3,4-dihydroxy-1-methoxyhex-5-en-2-yl)-
mixture was stirred at rt for 16 h, quenched with sat. NaHCO3
carbamate (19)
(2 mL), extracted with dichloromethane (10 mL × 3). The
(aq.)
combined organic layers were dried with Na2SO4(s), filtered
and concentrated. The crude product was further purified by
column chromatography (SiO2, EtOAc–hexanes, 1 : 9; Rf 0.60)
to give 15 (168 mg, 0.34 mmol, 95%) as a light yellow oil. [α]D20
+43.2 (c 0.65, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 0.08 (q,
12H), 0.91 (d, J = 11.1 Hz, 18H), 1.62 (s, 1H), 2.17 (d, J = 6.3 Hz,
1H), 2.24 (d, J = 3.9 Hz, 1H), 2.77–2.81 (m, 1H), 3.99 (q, J =
1.5 Hz, 1H), 5.09–5.19 (m, 3H), 5.26–5.33 (m, 1H), 5.90–6.00
(m, 1H), 7.34–7.41 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ −2.9,
18.0, 25.7, 27.6, 37.7, 67.6, 71.5, 74.8, 115.1, 127.7, 128.0,
128.4, 136.1, 136.4, 163.7; HRMS (FAB) calcd for [M + H]+
(C26H46O4NSi2) 492.2965, found 492.2974.
Tetrabutylammonium fluoride trihydrate (79 mg, 0.25 mmol)
was added to the solution of 15 (15 mg, 0.03 mmol) and
methanol (0.75 mL). The reaction mixture was stirred at rt for
16 h, quenched with sat. NaHCO3(aq.) (1 mL), and extracted
with ethyl acetate (2 mL × 3). The combined organic layers
were washed with sat. NaCl(aq.) (1 mL), dried with Na2SO4(s), fil-
tered and concentrated. The crude product was further puri-
fied by column chromatography (SiO2, ethyl acetate–hexanes,
1 : 1; Rf 0.64) to give 19 (7.2 mg, 0.24 mmol, 81%) as a light
1
yellow oil. H NMR (CDCl3, 300 MHz) δ 3.33 (s, 3H), 3.34–3.51
(m, 2H), 3.64–3.69 (t, J = 7.9 Hz, 1H), 3.78–3.82 (q, 1H),
4.18–4.19 (d, J = 3 Hz, 1H), 5.10 (s, 2H), 5.23–5.26 (d, J = 9 Hz,
1H), 5.43–5.51 (t, J = 12.5 Hz, 1H), 5.82–5.93 (m, 1H), 7.34 (s,
5H); 13C NMR (CDCl3, 75 MHz) δ 52.4, 59.2, 70.7, 71.0, 72.8,
116.7, 128.2, 128.4, 128.6, 136.7, 157.4; HRMS (ESI) calcd for
[M + H]+ (C14H16NO4) 262.1498, found 296.1505.
Benzyl ((3R,4R,5R)-4-hydroxy-5-vinyltetrahydrofuran-3-yl)-
carbamate (17)
Hydrofluoric acid (48 wt% in H2O, 163 μL, 4.50 mmol) was
added to the solution of 15 (30 mg, 0.06 mmol) and aceto-
nitrile (1.5 mL). The reaction mixture was stirred at rt for 16 h,
quenched with sat. NaHCO3(aq.) (2 mL), and extracted with
ethyl acetate (3 mL × 3). The combined organic layers were
washed with sat. NaCl(aq.) (2 mL), dried with Na2SO4(s), filtered
and concentrated. The crude product was further purified by
column chromatography (SiO2, methanol–dichloromethane,
1 : 9; Rf 0.76) to give 17 (10.3 mg, 0.04 mmol, 65%) as a light
yellow oil. [α]D20 −9.7 (c 0.35, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 3.45–3.63 (m, 1H), 3.75–3.79 (m, 1H), 3.91–3.98
(m, 1H), 4.02–4.15 (m, 1H), 2.24 (s, 1H), 5.10 (d, J = 9 Hz, 2H),
5.25–5.45 (m, 3H), 5.78–5.93 (m, 1H), 7.34–7.35 (br, 5H); 13C
NMR (CDCl3, 75 MHz) δ 70.1, 72.4, 74.3, 82.4, 94.9, 118.9,
128.2, 128.3, 128.5, 134.1, 136.5, 171.2; HRMS (ESI) calcd for
[M − H]− (C14H16NO4) 262.1079, found 262.1079.
Acknowledgements
This research was supported by the National Science Council
(NSC; 98-2119-M-008-001-MY3), Taiwan. We are grateful to
Ms. Ping-Yu Lin at the Institute of Chemistry, Academia
Sinica, and Valuable Instrument Center in National Central
University for obtaining mass analysis.
Notes and references
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