A stereoselective total synthesis of 7,8-O-isopropylidene iriomoteolide-3a

Article abstract of DOI:10.1039/c0ob01253j

A stereoselective total synthesis of 7,8-O-isopropylidene iriomoteolide-3a has been achieved by using Yamaguchi esterification, Julia-Kocienski olefination, organocatalytic α-oxidation, and ring-closing metathesis reaction as key bond-forming steps.

Full text of DOI:10.1039/c0ob01253j

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PAPER
A stereoselective total synthesis of 7,8-O-isopropylidene iriomoteolide-3a†
Yao Zhang, Lisheng Deng and Gang Zhao*
Received 26th December 2010, Accepted 30th March 2011
DOI: 10.1039/c0ob01253j
A stereoselective total synthesis of 7,8-O-isopropylidene iriomoteolide-3a has been achieved by using
Yamaguchi esterification, Julia–Kocienski olefination, organocatalytic a-oxidation, and ring-closing
metathesis reaction as key bond-forming steps.
Table 1 Base and solvent effect on Julia–Kocienski olefinationa
A family of structurally diverse macrolides, iriomoteolides-1a–
c1 and iriomoteolide-3a2 were isolated from a marine benthic
Base
Solvent
Temp. (◦C)/t (h)
Yieldb
E/Zc
dinoflagellate Amphidinium sp. (strain HYA024). Iriomoteolide-
3a and its 7,8-O-isopropylidene derivative displayed a potent
KHMDS
KHMDS
KHMDS
LiHMDS
LiHMDS
DME
DME
DME/HMPA(9 : 1)
DMF/DMPU(1 : 3)
DMF/DMPU(1 : 3)
-78 ◦C/2 h–r.t.
-78 ◦C/6 h–r.t.
-78 ◦C/6 h–r.t.
-78 ◦C/2 h–r.t.
-78 ◦C/6 h–r.t.
38
40
42
58
68
5 : 1
5 : 1
5 : 1
10 : 1
10 : 1
cytotoxicity against human B lymphocyte DG-75 cells (IC50
=
0.08 and 0.02 mg mL-1, respectively) and Raji cells (IC50 = 0.05 and
0.02 mg mL-1, respectively). Iriomoteolide-3a is a 15-membered
macrolide bearing an allylic epoxide, three hydroxyl groups, and
four E-double bonds. The first total synthesis of iriomoteolide-3a
was accomplished by Nevado’s group recently.3 Considering better
bioactivity, we chose 7,8-O-isopropylidene iriomoteolide-3a as a
target molecule and described a full account of our efforts on total
synthesis of 7,8-O-isopropylidene iriomoteolide-3a as a part of our
ongoing studies directed toward the synthesis of amphidinolides.4
As shown in Scheme 1, Our retrosynthetic approach to 1
involved four major disconnections, which revealed key fragments
2–4. Fragment 4 was planned to construct C18–19 at the end
of our synthetic sequence by a Julia–Kocienski olefination. An
esterification and RCM reaction was envisioned to assemble
fragments 2 and 3. Fragment 2 was constructed by a Julia–
Kocienski olefination between 6 and 7. Fragment 3 was made
up by a lithium–iodine exchange of 9 and nucleophilic addition
to Weinreb amide 8. All the key fragments can be derived from
commercially available materials. Finally, we also tried to obtain
iriomoteolide-3a by deprotecting the 7,8-O-isopropylidene.
a Reaction conditions: 7 (1.0 equiv.), 6 (5.0 equiv.), base (1.5 equiv.).
b Yield of the isolated product after column chromatography of 18. c E/Z
Determined by isolate yield after column chromatography of 19.
Preparation of C1–C5 fragment 7
Fragment 7 (Scheme 3) was prepared by starting from com-
mercially available mono-ester 11 (ee > 90%). According to a
known procedure, we prepared 16 with mono-TBDPS protection.6
Substitution of the hydroxyl group of 16 with 1-phenyl-1H-
tetrazole-5-thiol via Mitsunobu reaction and H2O2 oxidation
catalyzed by ammonium molybdate in EtOH afforded the sulfone
7 in 59% overall yield.
The required building block 18 was prepared by Julia–Kocienski
olefination7 between aldehyde 6 and sulfone 7. Screening the bases
and solvents (Table 1), deprotonation of sulfone 19 by LiHMDS
in THF, then treatment by the aldehyde in DMF/DMPU (v/v =
1 : 3) gave a better yield and higher selectivity.
Removing the PMB group by DDQ afforded pure E-isomer of
alkene 19 (Scheme 4) which can be separated from the E/Z mixture
by flash column chromatography. Parikh–Doering oxidation of
19, followed by Wittig methylenation of the resulting aldehyde,
afforded the alkene 20. The conversion of alkene 20 to the desired
acid fragment 2 was successfully accomplished by the deprotection
of the TBDPS group of 20 with TBAF in THF, followed by Parikh–
Doering oxidation and NaClO2 oxidation, to carboxylic acid 2 in
83% overall yield for three steps.
Preparation of C6–C9 fragment 6
As outlined in Scheme 2, segment 6 was prepared via a sequence
of high-yielding steps. According to the known procedure, we
prepared methyl ester 13 from starting material L-tartaric acid.5
The reduction of 13 with LAH in THF provide diol 14. After
mono-protection by PMBCl, we provided the crude aldehyde 6
by Swern oxidation, which can be directly used in the next step
without purification.
Preparation of C10–C18 fragment 3
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai, 200032, P. R. China. E-mail: zhaog@mail.sioc.ac.cn
As shown in Scheme 5, the synthesis of the C10–15 fragment 8
was investigated using alcohol 12 as a starting material which can
be conveniently prepared via several steps from 1,4-butanediol
by a known procedure.8 A proline catalyzed a-oxyamination of
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of all new compounds, and chiral HPLC chromatograms for 2–8,
16–21 ( )-23, 26–35. See DOI: 10.1039/c0ob01253j
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Scheme 1 Retrosynthetic analysis.
Scheme 2 Synthesis of aldehyde 6.
Scheme 4 Synthesis of acid 2.
protection–deprotection sequence involving selective protection of
the primary hydroxyl group with TBSCl, secondary hydroxyl as
PMB ether under acid conditions, deprotection of primary TBS
ether with TBAF produced the alcohol 27 in 52% yield over three
steps. Alcohol 27 was oxidized by using Parikh–Doering oxidation
to the corresponding aldehyde, followed by using NaClO2 to
carboxylic acid, then treatment with CDI and Weinreb amide gave
the C10–15 fragment 8.
Scheme 3 Synthesis of sulfone 7.
The alkyl iodine 9 was prepared by the known method from
Roche Ester in multigram scale.10 Exchanging with t-BuLi in Et2O,
then treatment with Weinreb amide 8, provided C10–C18 ketone
27.
As shown in Scheme 6, the reduction of ketone 27 with L-
selectride, followed by protection of the secondary hydroxyl group
with TBSOTf provided 28 in a 90% yield (d.r. > 95 : 5). The THP
the aldehyde 22 can be accomplished with highly enantioselec-
tivity using nitrosobenzene as an electrophilic source of oxygen
(determined by chiral HPLC analysis).9 Water content played
a key role in this reaction: the yield raised notably with an
addition of 10% H2O (vDMSO/vH = 10 : 1) in the reaction system,
O
2
because of inhibition of self-aldol condensation of 22. A three-step
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Scheme 7 Synthesis of sulfone 4.
Completion of the total synthesis of 7,8-O-isopropylidene
iriomoteolide-3a
With the above three fragments 2, 3 and 4 in hand, our subsequent
designed strategy called for the assembly of the acid 2 and alcohol
3 first (Scheme 8). Thus, the esterification of carboxylic acid 2
with alcohol 3 was carried out under Yamaguchi conditions11
to produce compound 33 in a 90% yield. Reaction of 33 with
second-generation Grubbs’ catalyst in dichloromethane at room
temperature provided single E-isomers 34 in a 65% yield.12 We
removed the primary TBS group in the presence of secondary
OTBS groups in a mixed THF/H2O/HOAc solvent. The free
alcohol 35 was then oxidized by using Parikh–Doering oxidation
to give the corresponding aldehyde, following by addition to an
excess of sulfone 4 and KHMDS at -70 ◦C in DME solution,
to give crude product 36 with high E-selectivity, which need
not to be isolated. Finally, we afforded 7,8-O-isopropylidene
iriomoteolide-3a by removing the silyl groups with TBAF at room
temperature.
Scheme 5 Synthesis of fragment 8.
Scheme 6 Synthesis of fragment 3.
group was removed by MgBr2·Et2O to give allylic alcohol 29 in a
90% yield. The required chiral epoxide was introduced at this stage
via a Sharpless asymmetric epoxidation reaction, using (+)-diethyl
tartrate to yield epoxide 30 in 88% yield with good stereoselectivity
(d.r. > 95 : 5). The conversion of the epoxy alcohol 30 to allylic
epoxide 31 was accomplished by using Parikh–Doering oxidation
followed by one-carbon Wittig methylenation. We have chosen
DDQ at -15 ◦C to remove the PMB group of 31 to obtain
the free hydroxyl group of 3 for the esterification reaction with
fragment 2.
Preparation of C19–C23 fragment
Sulfone 4 was prepared from 10 in three steps (Scheme 7) by
Birch reduction, Mitsunobu displacement and oxidation by H2O2
catalyzed by ammonium molybdate in EtOH.
Scheme 8 Completion of the total synthesis of 7,8-O-isopropylidene
iriomoteolide-3a.
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2 h. The reaction mixture was diluted with EtOAc (100 mL),
after the EtOH was evaporated. The organic layer was washed
with brine and dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (25 : 1
PE/Et2O) on silica gel gave compound 7 (3.6 g, 6.6 mmol, 87%)
as a colorless oil: [a]2D0 -2.2 (c 1.00, CHCl3); IR (neat): 3070, 3050,
2930, 2931, 2858 1595, 1498, 1471, 1390, 1177, 824, 762, 708,
688 cm-1; 1H NMR (300 MHz, CDCl3) d 7.71–7.57(m,9H), 7.44–
7.35(m, 6H), 3.77–3.65(m, 4H), 1.97–1.77(m, 3H), 1.64–1.57(m,
1H), 1.44–1.38(m, 1H), 1.10(s, 9H), 0.94–0.92(d, J = 6.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 154.0, 136.1, 134.3, 133.6, 132.0,
130.2, 128.2, 125.6, 62.0, 54.5, 39.3, 29.3, 29.0, 27.4, 19.7; ESIMS
m/z 571.2 ([M + Na]+); HRESIMS Calcd for C29H36O3N4SSiNa:
([M + Na]+) 571.2159, found 571.2170.
Conclusion
In summary, we have achieved the total synthesis of 7,8-O-
isopropylidene iriomoteolide-3a via a concise, and convergent
strategy using readily available and inexpensive chiral building
blocks. Fragment 2 was synthesized in 9 steps and 40% overall
yield from the known compound 16; Fragment 3 was prepared in
16 steps and 11% overall yield from the known compound 12. We
completed the synthesis of 7,8-O-isopropylidene iriomoteolide-3a
in 21 steps for the longest linear sequence and 3.9% overall yield.
It is very disappointing that we failed to remove the 7,8-O-
isopropylidene even by trying a great many acidic systems because
the allylic epoxide is very unstable even in a weak acid.
Experimental
tert-Butyl(((S,E)-6-((4S,5S)-5-(((4-methoxybenzyl)oxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylhex-5-en-1-
yl)oxy)diphenylsilane (18)
General
1
The H NMR and 13C NMR spectra were recorded at ambient
temperature using a Varian Mercury 300 or a Bruker Avance
400 instrument. The FTIR spectra were scanned with a Nicolet
Avatar 360 FTIR. ESIMS and ESIHRMS were recorded with
a PE Mariner APITOF and an APEX III (7.0 Tesla) FTMS
mass spectrometer. Dry THF was distilled from Na under N2 and
dry DCM, DMSO, DMF, DMPU and DME was distilled from
CaH2 under N2 unless otherwise specified, all other solvents and
reagents were commercially available and used as received without
any further purification. PE (chromatography solvent) stands for
petroleum ether (60–90 ◦C).
LiHMDS (2.4 mL, 1.0 M in THF, 2.4 mmol), was added to a
solution of 7 (658 mg, 1.2 mmol) in 5.0 mL THF at -78 ◦C. Then
aldehyde 6 which was prepared via standard Swern oxidation in
DMF/THF solution (3 : 1, 20 mL) was added dropwise at this
temperature for 15 min. The reaction mixture was stirred for
another 6 h then was allowed to warm to room temperature
over night. Water was added to the mixture when TLC showed
completion of the reaction, then diluted with EtOAc (35 mL). The
organic layer was washed with water and brine then dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (40 : 1 PE/EtOAc) on silica gel gave
(R)-5-((5-((tert-Butyldiphenylsilyl)oxy)-3-methylpentyl)thio)-1-
phenyl-1H-tetrazole (17)
compound 18 (490 mg, 0.8 mmol, 63%) as a colorless oil: [a]D20
=
2.6 (c 1.00, CHCl3); IR (neat): 2955, 2930, 2858, 1605, 1513, 1248,
1095, 1089, 703, 613 cm-1; H NMR (400 MHz, CDCl3) d 7.75–
1
PTSH (3.56 g, 20 mmol) and PPh3 (5.24 g, 20 mmol) were added
◦
7.74(m, 4H), 7.50–7.44(m, 6H), 7.33(d, J = 7.6 Hz, 2H), 6.93(d,
J = 7.6 Hz, 3H), 5.78–5.72(m, 1H), 5.52–5.47(dd, J = 15.2, 7.2 Hz,
1H), 4.59(s, 2H), 4.24(t, J = 8.2 Hz, 1H), 3.93(br s, 1H), 3.87(s, 3H),
3.76(br s, 2H), 3.65–3.57(m, 2H), 2.17–2.10(m, 1H), 1.97–1.85(m,
1H), 1.78–1.62(m, 1H), 1.62–1.52(m,1H) 1.47(s, 6H), 1.40–1.30(m,
1H), 1.13(s, 9H), 0.90–0.88(d, J = 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) d 159.2, 135.6, 134.8, 134.0, 130.2, 129.6, 129.5,
128.4, 127.7, 113.8, 109.1, 80.3, 79.3, 73.2, 69.1, 62.1, 55.3, 39.7,
39.1, 29.5, 27.1, 27.0, 19.5, 19.3; ESIMS m/z 625.3 ([M + Na]+);
HRESIMS Calcd for C37H50O5SiNa: ([M + Na]+) 625.3329, found
625.3320.
to a solution of 16 (2.85 g, 8.0 mmol) in 100 mL THF at 0 C.
Then DIAD (3.94 mL, 30 mmol) was added dropwise at this
temperature. The reaction mixture was stirred for 1 h. Water
was added to the mixture when TLC showed completion of the
reaction, then diluted with EtOAc (100 mL). The organic layer was
washed with brine and dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromatography
(25 : 1 PE/EtOAc) on silica gel gave compound 17 (4.0 g, 7.6 mmol,
95%) as a colorless oil: [a]D20 -2.8 (c 1.00, CHCl3); IR (neat): 3070,
1
3050, 2930, 2857, 1597, 1110 1106, 760, 739, 704, 613 cm-1; H
NMR (300 MHz, CDCl3) d 7.66–7.34(m, 15H), 3.73–3.69(m, 2H),
3.43–3.37(m, 2H), 1.83–1.80(m, 2H), 1.65–1.60(m, 2H), 1.43(m,
1H), 1.03(s, 9H), 0.92–0.90(d, J = 6.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) d 154.6, 135.6, 133.9, 130.1, 129.8, 129.7, 127.7,
123.9, 123.7, 61.7, 39.1, 36.0, 31.3, 28.9, 26.9, 19.2; ESIMS m/z
539.2 ([M + Na]+); HRESIMS Calcd for C29H36ON4SSiNa: ([M +
Na]+) 539.2285, found 539.2271.
((4S,5S)-5-((S,E)-6-((tert-Butyldiphenylsilyl)oxy)-4-methylhex-1-
en-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (19)
DDQ (370 mg, 1.62 mmol) was added to a solution of 18 (490 mg,
0.81 mmol) in 10 mL DCM at room temperature. The reaction
mixture was stirred for 1 h. Water was added to the mixture when
TLC showed completion of the reaction, then diluted with EtOAc
(25 mL). The organic layer was washed with saturated Na2HCO3
solution and brine then dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromatography
(10 : 1 PE/EtOAc) on silica gel gave compound 19 (385 mg,
0.81 mmol, 100%) as a colorless oil: [a]2D0 = 4.0 (c 1.00, CHCl3);
IR (neat): 3473, 3071, 2956, 2858, 1472 1379, 1242, 1111, 737,
688 cm-1; 1H NMR (400 MHz, CDCl3) d 7.75–7.74(m, 4H),
(R)-5-((5-((tert-Butyldiphenylsilyl)oxy)-3-methylpentyl)sulfonyl)-
1-phenyl-1H-tetrazole (7)
Ammonium molybdate tetrahydrate (2.56 g, 1.5 mmol) was added
to a solution of 17 (4.0 g, 7.6 mmol) in 50 mL EtOH at 0 ◦C.
Then H2O2 (8.50 mL, 30%, 80 mmol) was added dropwise at this
temperature. The reaction mixture was stirred for 2.5 h. Saturated
Na2S2O3 solution was added to the mixture and stirred for another
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7.52–7.45(m, 6H), 5.84(m, 1H), 5.53–5.47(dd, J = 15.2, 7.2 Hz,
1H), 4.37(t, J = 8.0 Hz, 1H), 3.90–3.78(m, 4H), 3.70–3.60(m,
1H), 2.15–2.09(m, 2H), 2.04–1.96(m, 1H), 1.83–1.77(m, 1H), 1.71–
1.67(m, 1H) 1.52(s, 6H), 1.50–1.40(m, 1H), 1.13(s, 9H), 0.93(d,
J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 135.4, 133.9,
129.4, 127.9, 127.5, 108.8, 81.1, 78.1, 61.8, 60.7, 39.6, 38.9, 29.3,
27.0, 26.9, 26.8, 19.4, 19.1; ESIMS m/z 505.5 ([M + Na]+);
HRESIMS Calcd for C29H42O4SiNa: ([M + Na]+) 505.2745, found
505.2757.
NMR (100 MHz, CDCl3) d 134.5, 134.2, 127.3, 118.5, 108.8, 82.2,
82.1, 60.7, 39.6, 39.1, 29.4, 27.0, 26.9, 19.39; ESIMS m/z 263.2
([M + Na]+); HRESIMS Calcd for C14H24O3SiNa: ([M + Na]+)
263.1618, found 263.1622.
(S,E)-6-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-3-
methylhex-5-enoic acid (2)
DMSO (1.0 mL, 1.3 mmol) and DIPEA (0.75 mL, 2.0 mmol) were
added to a solution of 19 (150 mg, 0.63 mmol) in 6 mL DCM at
0
◦C. Then Py·SO3 complex (630 mg, 3.0 mmol) was added at
tert-Butyl(((S,E)-6-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-
this temperature. The reaction mixture was stirred for 1 h. Water
was added to the mixture when TLC showed completion of the
reaction, then diluted with Et2O (15 mL). The organic layer was
washed with brine and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation gave the aldehyde which was used
directly in the following step. NaH2PO4 (270 mg, 1.96 mmol) was
added to a solution of above aldehyde in 8 mL t-BuOH/H2O/2-
methyl-2-butene (V:V:V = 2 : 2 : 1) at 0 ◦C. Then NaClO2 (170 mg,
1.96 mmol) was added at this temperature The reaction mixture
was stirred for 30 min at 0 ◦C. Saturated Na2S2O3 solution was
added to the mixture and stirred for another 2 h when TLC showed
completion of the reaction, then diluted with EtOAc (20 mL). The
organic layer was washed with water and brine then dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (5 : 1 PE/EtOAc) on silica gel gave
yl)-3-methylhex-5-en-1-yl)oxy)diphenylsilane (20)
DMSO (1.1 mL, 1.5 mmol) and DIPEA (0.85 mL, 2.3 mmol)
were added to a solution of 19 (360 mg, 0.75 mmol) in 6 mL
DCM at 0 ◦C. Then Py·SO3 complex (750 mg, 3.75 mmol) was
added at this temperature. The reaction mixture was stirred for 1 h.
Water was added to the mixture when TLC showed completion of
the reaction, then diluted with Et2O (15 mL). The organic layer
was washed with brine and dried over anhydrous Na2SO4. The
solvent was removed by rotary evaporation and the residue was
used directly in the following step. NaHMDS (1.3 mL, 2.0 M
in THF 2.6 mmol) was added to a solution of PPh3P+CH3Br-
(950 mg, 2.63 mmol) in 10 mL THF at 0 ◦C The reaction mixture
was stirred for 30 min at 0 ◦C. Then a solution of above aldehyde in
3.0 mL THF was added to the mixture dropwise and stirred for 3 h.
Water was added to the mixture when TLC showed completion
of the reaction, then diluted with EtOAc (15 mL). The organic
layer was washed with water and brine then dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (100 : 1 PE/EtOAc) on silica gel gave compound
20 (320 mg, 0.67 mmol, 89%) as a colorless oil: [a]2D0 = 20.8
(c 1.00, CHCl3); IR (neat): 3120, 2985, 2931, 2859, 1473, 1428,
compound 2 (138 mg, 0.55 mmol, 82%) as a colorless oil: [a]D20
=
26.2 (c 1.00, CHCl3); IR (neat): 3100, 2987, 2932, 1703, 1380, 1239,
1055, 880, 813 cm-1; 1H NMR (400 MHz, CDCl3) d 5.82–5.68(m,
2H), 5.50–5.23(m, 3H), 4.07–4.03(m, 2H), 2.38(dd, J = 8.4, 2.0
Hz, 1H), 2.33–1.96(m, 4H), 1.44(s, 6H), 0.93(d, J = 6.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 179.4, 134.2, 133.6, 128.2, 118.8,
109.0, 82.4, 82.0, 40.6, 39.2, 29.9, 27.1, 27.0, 19.5; ESIMS m/z
277.2 ([M + Na]+); HRESIMS Calcd for C14H21O4: ([M - H]+)
253.1445, found 253.1454.
1
1370, 1239, 1111, 823, 688 cm-1; H NMR (400 MHz, CDCl3)
d 7.75–7.73(m, 4H), 7.52–7.44(m, 6H), 5.87–5.77(m, 2H), 5.60–
5.21(m, 1H), 4.13(d, J = 4.0 Hz, 2H), 3.74–3.71(m, 2H), 2.12–
1.85 (m, 2H), 1.80–1.70(m, 1H), 1.69–1.58(m, 1H) 1.52(s, 6H),
1.42–1.57(m, 1H), 1.13(s, 9H), 0.93(d, J = 6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 135.5, 134.8, 134.3, 134.0, 129.5, 127.5,
127.2, 118.3, 108.8, 82.2, 61.9, 39.7, 38.9, 29.4, 27.0, 26.9, 26.8,
19.5, 19.1; ESIMS m/z 501.3 ([M + Na]+); HRESIMS Calcd for
C30H42O3SiNa: ([M + Na]+) 501.2795, found 501.2810.
(2S,E)-6-((Tetrahydro-2H-pyran-2-yl)oxy)hex-4-ene-1,2-diol (24)
Water (0.3 mL) and D-proline (22 mg, 0.2 mmol) was added to
a solution of 22 (200, 1.0 mmol) in 3.0 mL DMSO at room
temperature. Then PhNO (80 mg, 0.5 mmol) was added in one
portion. The reaction mixture was stirred for 1 h. All the mixture
was allowed to transfer into another solution of NaBH4 (100 mg,
3 mmol) in EtOH (10.0 mL) and stirred for 30 min. Acetone
was added to the mixture when TLC showed completion of the
reaction, then diluted with EtOAc (25 mL). The organic layer
was washed with water and brine then dried over anhydrous
MgSO4. Removal of the solvent by rotary evaporation and column
chromatography (4 : 1 PE/EtOAc) on silica gel gave compound 23
as a dark brown oil. This compound was not very stable, so we
determined the ee value as quickly as possible and directly it used
in next step (for compound 23 see in the supporting information
95% e.e. (tR (major) = 38.26 min, tR (minor) = 27.73 min) as
determined by HPLC on a CHIRALPAK AS-H column (0.46
cm ¥ 25 cm) eluting with hexane/isopropanol = 9 : 1 at a flow rate
of 0.7 mL min-1 with the UV detector set to 254 nm.) Compound
23 was dissolved by a mixed solution of EtOH/HOAc = 3 : 1.
Zn powder (320 mg, 5 mmol) was added in one portion. Grey
solid was filtered when TLC showed completion of the reaction,
(S,E)-6-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-3-
methylhex-5-en-1-ol (21)
TBAF (1.0 mL, 1 M in THF, 1.0 mmol) was added to a solution
of 20 (320 mg, 0.67 mmol) in 10 mL THF at room temperature.
The reaction mixture was stirred for 2 h. Water was added to
the mixture when TLC showed completion of the reaction, then
diluted with EtOAc (30 mL). The organic layer was washed
with brine then dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (10 : 1
PE/EtOAc) on silica gel gave compound 21 (150 mg, 0.63 mmol,
95%) as a colorless oil: [a]2D0 = 36.0 (c 1.00, CHCl3); IR (neat):
3442, 2986, 2956, 2874, 1457, 1372, 1239, 1050, 878 cm-1; 1H NMR
(400 MHz, CDCl3) d 5.85–5.70(m, 2H), 5.64–5.22(m, 3H), 4.09–
4.03(br s, 2H), 3.71–3.65(m, 2H), 2.16–1.96(m, 2H), 1.71–1.56(m,
3H) 1.44(s, 6H), 1.42–1.30(m, 1H), 0.93(d, J = 6.0 Hz, 3H); 13C
4522 | Org. Biomol. Chem., 2011, 9, 4518–4526
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then diluted with EtOAc (30 mL), The organic layer was washed
with saturated Na2CO3 and brine then dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (1 : 1 PE/EtOAc) on silica gel gave compound 24
(70 mg, 0.32 mmol, 64%) as a colorless oil [a]2D0 = 2.69 (c 1.00,
CHCl3); IR (neat): 3406, 2940, 2870, 1441, 1117, 1010, 903, 813
completion of the reaction, then diluted with EtOAc (50 mL). The
organic layer was washed with water and brine then dried over
anhydrous MgSO4. Removal of the solvent by rotary evaporation
gave a residue which was directly used in the following step.
CDI (0.96 g, 6.0 mmol) was added to a solution of the above
◦
acid in 18 mL DCM at 0 C. Then HN(Me)(OMe)·HCl (0.73 g,
1
cm-1; H NMR (300 MHz, CDCl3) d 5.79–5.70(m, 2H), 4.64(t,
7.5 mmol) was added at this temperature. The reaction mixture
was stirred over night. Water was added to the mixture when
TLC showed completion of the reaction, then diluted with EtOAc
(30 mL). The organic layer was washed with brine then dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (4 : 1 PE/EtOAc) on silica gel gave
compound 8 (825 mg, 2.1 mmol, 69%) as a colorless oil: [a]D20
-33.0 (c 1.00, CHCl3); IR (neat): 2940, 2869, 1672, 1613, 1513,
1464, 1201, 1078, 817 cm-1; 1H NMR (300 MHz, CDCl3) d 7.26–
7.25(d, J = 8.4 Hz, 2H), 6.85–6.82(d, J = 8.4 Hz, 2H), 5.79–5.59(m,
2H), 4.58(d, J = 5.7 Hz, 1H), 4.31(d, J = 6.0 Hz, 1H), 4.16(dd,
J = 8.6, 2.0 Hz, 1H), 3.94–3.80(m, 2H), 3.77(s, 3H), 3.51(s, 3H),
3.46–3.41(m, 1H), 3.17(s, 3H), 2.58–2.38(m, 2H), 1.85–1.23(m,
6H); 13C NMR (100 MHz, CDCl3) d 172.6, 159.3, 129.8, 129.5,
129.4, 128.8, 113.7, 97.7, 74.8, 71.0, 67.3, 62.1, 61.2, 55.1, 35.2,
30.6, 25.4, 19.4; ESIMS m/z 416.3 ([M + Na]+); HRESIMS
Calcd for C21H31O6NNa: ([M + Na]+) 416.2051, found 416.
2044.
J = 3.9 Hz, 1H), 4.20(m, 1H), 4.05–3.83(m, 2H), 3.76(br s, 1H),
3.64(m, 1H), 3.58–3.42(m, 2H), 3.07(br s, 1H), 2.87(br s, 1H), 2.34–
2.17(m, 2H), 1.85–1.23(m, 6H); 13C NMR (100 MHz, CDCl3) d
129.8, 129.7, 129.4, 98.1, 98.0, 71.3, 67.8, 67.7, 66.1, 62.3, 36.3,
30.6, 25.3, 19.4; ESIMS m/z 239.1 ([M + Na]+); HRESIMS Calcd
for C11H20O4Na: ([M + Na]+) 239.1254, found 239.1257.
(2S,E)-2-((4-Methoxybenzyl)oxy)-6-((tetrahydro-2H-pyran-2-
yl)oxy)hex-4-en-1-ol (26)
Newly prepared PMB-trichloroacetonitrile complex (3.0 mmol),
CSA (10 mg, 5% mmol) was added to a solution of 25 (330 mg,
1.0 mmol) in 15 mL DCM at room temperature for 2 days. Water
was added to the mixture when TLC showed completion of the
reaction, then diluted with Et2O (30 mL). The organic layer was
washed with brine and dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation gave a residue which was
directly used in the following step. TBAF (2.0 mL, 1.0 M in THF,
2.0 mmol) was added to a solution of the above mixture in 10 mL
THF at room temperature. The reaction mixture was stirred for
2 h. Water was added to the mixture, then diluted with EtOAc
(30 mL). The organic layer was washed with brine then dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (5 : 1 PE/EtOAc) on silica gel gave
(2R,5S,E)-1-((tert-Butyldimethylsilyl)oxy)-5-((4-
methoxybenzyl)oxy)-2-methyl-9-((tetrahydro-2H-pyran-
2yl)oxy)non-7-en-4-one (27)
t-BuLi (2.5 mL, 1.6 M in pentane, 4.0 mmol) was added to a
◦
solution of 9 (630 mg, 2.0 mmol) in 6.0 mL Et2O at -78 C for
compound 26 (200 mg, 0.66 mmol, 60%) as a colorless oil: [a]D20
=
15 min. A solution of amide 8 (400 mg, 1.0 mmol) in 3.0 mL THF
was added to the mixture at the same temperature then stirred
for 1 h. Water was added when TLC showed completion of the
reaction, then diluted with EtOAc (30 mL). The organic layer was
washed with brine and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromatography
(20 : 1 PE/EtOAc) on silica gel gave compound 27 (400 mg,
0.76 mmol, 76%) as a colorless oil: [a]2D0 -15.1 (c 1.00, CHCl3);
IR (neat): 2952, 2857, 1715, 1613, 1514, 1250, 1092, 1026, 837,
777 cm-1; 1H NMR (400 MHz, CDCl3) d 7.29–7.27(d, J = 8.4 Hz,
2H), 6.91–6.89(d, J = 8.4 Hz, 2H), 5.71–5.69(m, 2H), 4.64(s, 1H),
4.48(AB q, J = 11.6 Hz, 2H), 4.20(dd, J = 8.0 Hz, 2.0 Hz, 1H),
3.97–3.83(m, 3H), 3.84(s, 3H), 3.54–3.49(m, 2H), 3.44–3.40(m,
1H), 2.73(dd, J = 8.0, 2.4 Hz, 1H), 2.46(t, J = 5.6 Hz, 2H), 2.42(dd,
J = 8.4, 4.0 Hz, 1H), 2.31–2.40(m, 1H), 1.89–1.50(m, 6H), 0.93–
0.88(m, 12H), 0.06(s, 6H); 13C NMR (100 MHz, CDCl3) d 212.4,
159.9, 130.2, 130.1, 128.8, 98.3, 84.6, 72.6, 67.9, 62.7, 55.8, 42.3,
35.8, 31.6, 31.1, 26.4, 26.0, 20.0, 18.8, 17.3, -4.9; ESIMS m/z
543.5 ([M + Na]+); HRESIMS Calcd for C29H48O6SiNa: ([M +
Na]+) 543.3112, found 543.3115.
13.8 (c 1.00, CHCl3); IR (neat): 3456,2939, 2869, 1612, 1513, 1248,
1076, 975, 818 cm-1; 1H NMR (300 MHz, CDCl3) d 7.27–7.24(d,
J = 8.4 Hz, 2H), 6.89–6.86(d, J = 8.4 Hz, 2H), 5.72–5.68(m, 2H),
4.64–4.48(m, 3H), 4.20(m, 1H), 3.97–3.82(m, 2H), 3.80(s, 3H),
3.65–3.43(m, 4H), 2.38–2.30(m, 2H), 2.01(br s, 1H), 1.85–1.23(m,
6H); 13C NMR (100 MHz, CDCl3) d 159.2, 130.3, 129.4, 129.1,
113.8, 97.8, 78.8, 71.2, 67.5, 64.0, 62.1, 55.2, 33.9, 30.6, 25.4, 19.4.;
ESIMS m/z 359.2 ([M + Na]+); HRESIMS Calcd for C19H28O5Na:
([M + Na]+) 359.1825, found 359.1829.
(2S,E)-N-Methoxy-2-((4-methoxybenzyl)oxy)-N-methyl-6-
((tetrahydro-2H-pyran-2-yl)oxy)hex-4-enamide (8)
DMSO (5.2 mL, 6.3 mmol), DIPEA (3.2 mL, 9.0 mmol) was
adde◦d to a solution of 26 (1.01 g, 3.0 mmol) in 30 mL DCM
at 0 C. Then Py·SO3 complex (3.0 g, 15.0 mmol) was added at
this temperature. The reaction mixture was stirred for 1 h. Water
was added to the mixture when TLC showed completion of the
reaction, then diluted with Et2O (15 mL). The organic layer was
washed with brine and dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation gave a residue which was
directly used in the following step. NaH2PO4 (1.5 g, 9.0 mmol) was
added to a solution of above aldehyde in 18 mL t-BuOH/H2O/2-
methyl-2-butene (V : V : V = 2 : 2 : 1) at 0 ◦C. Then NaClO2 (0.9 g,
9.0 mmol) was added at this temperature The reaction mixture
was stirred for 30 min at 0 ◦C. Saturated Na2S2O3 solution was
added to the mixture and stirred for another 2 h when TLC showed
(5S,7R)-5-((1S,E)-1-((4-Methoxybenzyl)oxy)-5-((tetrahydro-2H-
pyran-2-yl)oxy)pent-3-en-1-yl)-2,2,3,3,7,10,10,11,11-nonamethyl-
4,9-dioxa-3,10-disiladodecane (28)
L-selectride (1.6 mL, 1.0 M in THF, 1.6 mmol) was added to a
solution of 27 (415 mg, 2.0 mmol) in 6.0 mL THF at -78 ◦C
for 1 h. A solution of amide 8 (400 mg, 1.0 mmol) in 3.0 mL
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THF was added to the mixture at the same temperature then
stirred for 1 h. Acetone was added to the mixture when TLC
showed completion of the reaction, then diluted with EtOAc
(25 mL). The organic layer was washed with water and brine
then dried over anhydrous MgSO4. Removal of the solvent by
rotary evaporation gave a residue which was directly used in next
step. 2,6-Lutidine (0.35 mL, 2.0 mmol) was added to a solution
of above residue in DCM (5.0 mL) at 0 ◦C, TBSOTf (0.4 mL,
1.6 mmol) was added at this temperature. The reaction mixture
was stirred for 30 min at 0 ◦C Water was added to the mixture
when TLC showed completion of the reaction, then diluted with
EtOAc (15 mL). The organic layer was washed with brine then
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (50 : 1 PE/EtOAc) on
silica gel gave compound 28 (460 mg, 0.72 mmol, 90%) as a
colorless oil: [a]2D0 -19.7 (c 1.00, CHCl3); IR (neat): 2930, 2857,
1613, 1513, 1464, 1250, 1079, 1024, 836, 775 cm-1; 1H NMR (400
MHz, CDCl3) d 7.29–7.26(d, J = 8.4 Hz, 2H), 6.90–6.88(d, J =
8.4 Hz, 2H), 5.82–5.74(m, 1H), 5.70–5.62(m, 1H), 4.67(t, J =
3.6 Hz, 1H), 4.55–4.46(m, 2H), 4.21(m, 1H), 3.99–3.87(m, 3H),
3.83(s, 3H), 3.55–3.50(m, 2H), 3.43–3.45(m, 2H), 2.44–2.40(m,
1H), 2.24–2.08(m, 1H), 1.89–1.50(m, 6H), 1.23–1.17(m, 1H), 0.96–
0.88(m, 21H), 0.08–0.06(m, 12H); 13C NMR (100 MHz, CDCl3) d
159.2, 132.1, 131.0, 129.3, 128.0, 113.6, 97.6, 81.4, 71.8, 70.6, 67.9,
67.7, 62.2, 55.3, 35.1, 32.2, 32.0, 30.7, 26.0, 25.5, 19.5, 18.3, 18.0,
-4.2, -4.5, -5.3, -5.4; ESIMS m/z 659.6 ([M + Na]+); HRESIMS
Calcd for C35H64O6Si2Na: ([M + Na]+) 659.4134, found 659.
4137.
5.0 mL DCM and stirred for 30 min at -20 ◦C. t-BuOOH (0.24 mL,
5.5 M in toluene, 1.3 mmol) was added at this temperature and
stirred for another 40 min. Finally a solution of 29 (180 mg,
◦
0.32 mmol) was added and stirred at -20 C for 12 h. Saturated
Na2SO3 solution was added to the mixture and stirred for another
2 h when TLC showed completion of the reaction, then diluted
with EtOAc (15 mL). The organic layer was washed with water
and brine then dried over anhydrous MgSO4. Removal of the
solvent by rotary evaporation and column chromatography (10 : 1
PE/EtOAc) on silica gel gave compound 30 (170 mg, 0.31 mmol)
as a colorless oil: [a]2D0 -40.8 (c 1.00, CHCl3); IR (neat): 3449, 2954,
2857, 1612, 1514, 1471, 1251, 1087, 836, 775, 667 cm-1; 1H NMR
(400 MHz, CDCl3) d 7.26–7.23(d, J = 8.8 Hz, 2H), 6.89–6.86(d,
J = 8.4 Hz, 2H), 4..49(AB q, J = 11.2 Hz, 2H), 3.97–3.84(m, 2H),
3.80(s, 3H), 3.62–3.54(m, 2H), 3.50(dd, J = 7.2, 2.4 Hz, 1H), 3.41–
3.33(m, 1H), 3.06–3.02(m, 1H), 2.94(dd, J = 7.0, 2.0 Hz, 1H),
2.03(br s, 1H), 1.81–1.63(m, 4H), 1.20–1.12 (m, 1H), 0.96–0.88(m,
21H), 0.08–0.06(m, 12H); 13C NMR (100 MHz, CDCl3) d 159.3,
130.7, 129.3, 113.8, 79.1, 72.0, 69.8, 67.8, 61.7, 59.4, 55.3, 54.1,
34.8, 32.2, 31.3, 26.0, 18.5, 18.4, 18.0, -4.2, -4.5, -5.4; ESIMS
m/z 591.2 ([M + Na]+); HRESIMS Calcd for C30H56O6Si2Na:
([M + Na]+) 591.3508, found 591.3509.
(5S,7R)-5-((S)-1-((4-Methoxybenzyl)oxy)-2-((2R,3S)-3-
vinyloxiran-2-yl)ethyl)-2,2,3,3,7,10,10,11,11-nonamethyl-4,9-
dioxa-3,10-disiladodecane (31)
DMSO (0.5 mL, 0.67 mmol) and DIPEA (0.4 mL, 1.0 mmol) were
added to a solution of 30 (192 mg, 0.34 mmol) in 6 mL DCM at
0
(5S,6S,8R,E)-6,9-Bis((tert-butyldimethylsilyl)oxy)-5-((4-
methoxybenzyl)oxy)-8-methylnon-2-en-1-ol (29)
◦C. Then Py·SO3 complex (330 mg, 1.7 mmol) was added at
this temperature. The reaction mixture was stirred for 1 h. Water
was added to the mixture when TLC showed completion of the
reaction, then diluted with Et2O (15 mL). The organic layer was
washed with brine and dried over anhydrous Na2SO4. The solvent
was removed by rotary evaporation and the residue was directly
used in the following step. NaHMDS (0.85 mL, 2.0 M in THF
1.7 mmol) was added to a solution of PPh3P+CH3Br- (627 mg,
1.7 mmol) in 10 mL THF at 0 ◦C The reaction mixture was stirred
for 30 min at 0 ◦C. Then a solution of the above aldehyde in 3.0 mL
THF was added to the mixture dropwise and stirred at -40 ◦C for
3 h. Water was added to the mixture when TLC showed completion
of the reaction, then diluted with EtOAc (15 mL). The organic
layer was washed with water and brine, then dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (100 : 1 PE/EtOAc) on silica gel gave compound
31 (183 mg, 0.34 mmol, 98%) as a colorless oil: [a]2D0 -26.2 (c 1.00,
CHCl3); IR (neat): 2955, 2930, 2857, 1605, 1514, 1471, 1250, 1084,
837, 775 cm-1; 1H NMR (400 MHz, CDCl3) d 7.26–7.21(d, J = 8.8
Hz, 2H), 6.88–6.82(d, J = 8.4 Hz, 2H), 5.63–5.27(m, 3H), 4.50(AB
q, J = 11.2 Hz, 2H), 3.98–3.94(m, 1H), 3.80(s, 3H), 3.60–3.55(m,
1H), 3.43(dd, J = 7.2, 2.4 Hz, 1H), 3.36(dd, J = 7.8, 3.0 Hz, 1H),
3.15–3.12(dd, J = 7.0, 2.0 Hz, 1H), 2.94(t, J = 7.2 Hz, 1H), 1.86–
1.63(m, 4H), 1.18–1.06(m, 1H), 0.96–0.88(m, 21H), 0.08–0.06(m,
12H); 13C NMR (100 MHz, CDCl3) d 159.3, 136.0, 130.8, 129.4,
119.0, 113.8, 79.0, 72.0, 69.9, 67.8, 59.6, 58.6, 55.3, 34.8, 32.2,
31.7, 25.9, 18.5, 18.4. 18.0, -4.1, -4.6, -5.3; ESIMS m/z 587.2
([M + Na]+); HRESIMS Calcd for C31H56O5Si2Na: ([M + Na]+)
587.3559, found 587.3563.
MgBr2·Et2O (464 mg, 0.72 mmol) was added to a solution of
28 (460 mg, 072 mmol) in 10 mL Et2O at room temperature.
The reaction mixture was stirred for 2 h. Water was added to
the mixture when TLC showed no extra product appeared, then
diluted with EtOAc (10 mL). The organic layer was washed with
brine then dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (50 : 1 to 15 : 1
PE/EtOAc) on silica gel gave compound 28 (204 mg, 0.32 mmol)
and compound 29 (170 mg, 0.31 mmol) as a colorless oil: [a]D20
-29.8 (c 1.00, CHCl3); IR (neat): 3397, 2954, 2886, 2857, 1613,
1514, 1471, 1250, 1086, 836, 775 cm-1; 1H NMR (400 MHz,
CDCl3) d 7.34–7.30(d, J = 8.4 Hz, 2H), 6.95–6.93(d, J = 8.4 Hz,
2H), 5.77–5.74(m, 2H), 4.50(AB q, J = 11.6 Hz, 2H), 4.13(s, 2H),
3.98–3.96(m, 1H), 3.88(s, 3H), 3.57–3.40(m, 3H), 2.42–2.38(m,
1H), 2.29–2.21(m, 1H), 1.86–1.74(m, 2H), 1.34(br s, 1H), 1.28–
1.25(m, 1H), 0.96–0.88(m, 21H), 0.08–0.06(m, 12H); 13C NMR
(100 MHz, CDCl3) d 159.2, 130.9, 130.7, 129.4, 113.6, 81.5, 71.7,
70.5, 67.8, 63.8, 55.3, 35.1, 32.2, 31.8, 26.0, 25.9, 18.4, 18.1,
-4.2, -4.5, -5.4; ESIMS m/z 575.6 ([M + Na]+); HRESIMS
Calcd for C30H54O5Si2Na: ([M + Na]+) 575.3559, found 575.
3569
((2S,3R)-3-((2S,3S,5R)-3,6-Bis((tert-butyldimethylsilyl)oxy)-2-
((4-methoxybenzyl)oxy)-5-methylhexyl)oxiran-2-yl)methanol (30)
˚
Activated 4 A MS (100 mg) and D-(+)DET (90 mg, 0.32 mmol)
was added to a solution of Ti(i-PrO)4 (0.1 mL, 0.39 mmol) in
4524 | Org. Biomol. Chem., 2011, 9, 4518–4526
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(2S,3S,5R)-3,6-Bis((tert-butyldimethylsilyl)oxy)-5-methyl-1-
((2R,3S)-3-vinyloxiran-2-yl)hexan-2-ol (3)
rotary evaporation when TLC showed completion of the reaction
and column chromatography (30 : 1 PE/EtOAc) on silica gel gave
compound 34 (26 mg, 0.0377 mmol, 65%) as a colorless oil: [a]D20
=
DDQ (138 mg, 0.6 mmol) was added to a solution of 31 (180 mg,
0.34 mmol) in 10 mL DCM and pH = 7.0 buffer at -20 ◦C.
The reaction mixture was stirred for 1 h. Water was added to
the mixture when TLC showed completion of the reaction, then
diluted with EtOAc (25 mL). The organic layer was washed with
saturated Na2HCO3 solution and brine then dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (10 : 1 PE/EtOAc) on silica gel gave compound
19 (142 mg, 0.32 mmol, 96%) as a colorless oil: [a]2D0 -26.0 (c
1.00, CHCl3); IR (neat): 3489, 2955, 2929, 2887, 1472, 1256, 1080,
790, 776 cm-1; 1H NMR (400 MHz, CDCl3) d 5.63–5.30(m, 3H),
3.80–3.67(m, 2H), 3.50(dd, J = 7.0, 2.0 Hz, 1H), 3.40(dd, J = 7.8,
3.0 Hz, 1H), 3.17(dd, J = 7.0, 2.0 Hz, 1H), 3.10–3.06(m, 1H),
2.30(d, J = 8.0 Hz, 1H), 1.96–1.79(m, 2H), 1.76–1.65(m, 1H),
1.54–1.46(m, 1H), 1.25–1.16(m, 1H), 0.92–0.88(m, 21H), 0.08(s,
6H), 0.06(s, 6H); 13C NMR (100 MHz, CDCl3) d 135.7, 119.2,
73.2, 70.0, 68.5, 58.9, 58.3, 37.3, 32.2, 25.9, 18.3, 18.0, 17.2, -4.1,
-4.5, -5.4; ESIMS m/z 467.4 ([M + Na]+); HRESIMS Calcd for
C23H48O4Si2Na: ([M + Na]+) 467.2983, found 467.3003.
46.5 (c 1.00, CHCl3); IR (neat): 2955, 2930, 2857, 1738, 1471, 1370,
1
1255, 1056, 870, 776 cm-1; H NMR (400 MHz, CDCl3) d 5.92–
5.82(m, 2H), 5.50(dd, J = 12.0, 4.0 Hz, 1H), 5.36(dd, J = 12.4, 4.8
Hz, 1H), 5.20(dt, J = 10.0, 3.2 Hz, 1H), 4.04(t, J = 8.4 Hz, 2H),
3.94(t, J = 8.8 Hz, 2H), 3.82(q, J = 5.4 Hz, 2H), 3.45–3.36(m, 2H),
3.05(d, J = 9.6 Hz, 1H), 2.85(d, J = 10.0 Hz, 1H), 2.44(d, J = 14.8
Hz, 1H), 2.30–2.20(m, 2H), 1.95–1.85(m, 2H), 1.81–1.70(m, 2H),
1.65–1.56(m, 1H), 1.49–1.41(m, 6H), 1.23–1.17(m, 1H), 1.05(d,
J = 5.6 Hz, 3H), 0.98–0.90(m, 21H), 0.15(s, 3H), 0.09(s, 3H),
005(s, 6H); 13C NMR (100 MHz, CDCl3) d 172.6, 135.6, 135.0,
132.6, 127.5, 109.5, 83.0, 81.4, 72.5, 70.9, 67.9, 59.2, 58.2, 37.3,
36.5, 36.3, 33.3, 32.4, 31.7, 27.1, 26.0, 25.8, 21.1, 18.3, 18.0, 17.9,
-4.4, -5.4; ESIMS m/z 675.7 ([M + Na]+); HRESIMS Calcd for
C35H64O7Si2Na: ([M + Na]+) 675.4083, found 675.4104.
(3aS,4E,7S,11S,12aS,13aS,14E,15aS)-11-((1S,3R)-1-((tert-
Butyldimethylsilyl)oxy)-4-hydroxy-3-methylbutyl)-2,2,7-trimethyl-
6,7,8,11,12,12a,13a,15a-octahydro-[1,3]dioxolo[4,5-h]oxireno[2,3-
d][1]oxacyclopentadecin-9(3aH)-one (35)
(S,E)-(2S,3S,5R)-3,6-Bis((tert-butyldimethylsilyl)oxy)-5-methyl-
1-((2S,3S)-3-vinyloxiran-2-yl)hexan-2-yl-6-((4S,5S)-2,2-dimethyl-
5-vinyl-1,3-dioxolan-4-yl)-3-methylhex-5-enoate (33)
Compound 34 (40 mg, 0.061 mmol) was dissolved by a mixed
solution of THF/H2O/HOAc = 1 : 1 : 1, diluted with EtOAc
(30 mL), when TLC showed completion of the reaction The
organic layer was washed with saturated Na2CO3 and brine then
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (3 : 1 PE/EtOAc) on
silica gel gave compound 35 (28 mg, 0.051 mmol, 84%) as a white
solid. [a]2D0 = 56.4 (c 0.5, CHCl3); IR (neat): 3406, 2940, 2870, 1441,
Compound 2 (30 mg, 0.12 mmol), compound 3 (45 mg, 0.1 mmol)
and DMAP (65 mg, 0.5 mmol) were mixed together in 5 mL DCM
at 0 ◦C. Then 2,4,6-trichlorobenzoyl chloride (50 mg, 0.21 mmol)
was added. The reaction mixture was stirred for 24 h. Water
was added to the mixture when TLC showed completion of the
reaction, then diluted with Et2O (20 mL). The organic layer was
washed with brine and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromatography
(35 : 1 PE/EtOAc) on silica gel gave compound 33 (65 mg,
0.1 mmol, 97%) as a colorless oil: [a]2D0 -25.0 (c 1.00, CHCl3);
IR (neat): 2956, 2930, 2857, 1737, 1480, 1370, 1257, 1085, 1057,
837, 776 cm-1; 1H NMR (400 MHz, CDCl3) d 5.90–5.71(m, 2H),
5.60–5.44(m, 3H), 5.38–5.25(m, 3H), 5.04(dt, J = 10.0 Hz, 3.2 Hz,
1H), 4.11–4.07(m, 2H), 3.92–3.88(m, 1H), 3.42(dd, J = 7.2 Hz, 2.4
Hz, 1H), 3.37(dd, J = 7.8 Hz, 3.0 Hz, 1H), 3.10(dd, J = 7.0, 2.0
Hz, 1H), 2.87(dt, J = 5.6, 1.2 Hz, 1H), 2.40–2.30(m, 1H), 2.14–
2.00(m, 5H), 1.80–1.72(m, 2H), 1.64–1.56(m, 1H), 1.47(s, 6H),
1.24–1.16(m, 1H), 0.98–0.90(m, 24H), 0.15(s, 3H), 0.09(s, 3H),
0.05(s, 6H); 13C NMR (100 MHz, CDCl3) d 173.2, 135.6, 134.3,
133.5, 128.2, 119.3, 118.7, 109.0, 82.4, 82.1, 72.9, 70.2, 37.8, 59.0,
27.7, 41.1, 39.3, 35.7, 32.0, 31.6, 30.0, 27.1, 25.9, 19.5, 18.3, 18.0,
17.8, -4.3, -4.6, -5.4; ESIMS m/z 703.6 ([M + Na]+); HRESIMS
Calcd for C37H68O7Si2Na: ([M + Na]+) 70.3.4396, found 703.4396.
1
1117, 1010, 903, 813 cm-1; H NMR (400 MHz, CDCl3) d 5.93–
5.85(m, 2H), 5.50(dd, J = 12.0, 4.0 Hz, 1H), 5.40–5.25(m, 2H),
4.04(t, J = 8.4 Hz, 2H), 3.94(t, J = 8.8 Hz, 2H), 3.82(q, J = 5.4 Hz,
2H), 3.45–3.36(m, 2H), 3.05(d, J = 9.6 Hz, 1H), 2.85(d, J = 10.0
Hz, 1H), 2.44(d, J = 14.8 Hz, 1H), 2.30–2.20(m, 2H), 1.95–1.85(m,
2H), 1.71–1.70(m, 2H), 1.64–1.57(m, 1H), 1.49–1.41(m, 6H), 1.20–
1.12(m, 1H), 1.05(d, J = 5.6 Hz, 3H), 0.98–0.90(m, 12H), 0.13(s,
6H); 13C NMR (100 MHz, CDCl3) d 172.7, 135.6, 134.9, 132.8,
127.5, 109.6, 83.0, 81.4, 72.1, 71.5, 68.0, 59.3, 27.9, 37.5, 37.3, 36.5,
33.4, 33.1, 32.0, 27.1, 25.8, 21.2, 18.1, 18.0, -4.4, -4.5; ESIMS m/z
538.3 ([M + Na]+); HRESIMS Calcd for C29H50O7SiNa: ([M +
Na]+) 538.3026, found 538.3022.
7,8-O-Isopropylidene iriomoteolide-3a (1)
DMSO (0.06 mL, 0.1 mmol), DIPEA (0.05 mL, 0.1 mmol) was
added to a solution of 35 (25 mg, 0.046 mmol) in 4 mL DCM
at 0 ◦C. Then Py·SO3 complex (50 mg, 0.25 mmol) was added at
this temperature. The reaction mixture was stirred for 1 h. Water
was added to the mixture when TLC showed completion of the
reaction, then diluted with Et2O (15 mL). The organic layer was
washed with brine and dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation gave a residue which was
directly used in the following step. KHMDS (0.5 mL, 0.6 M in
toluene, 0.3 mmol), was added to a solution of 4 (56 mg, 0.2 mmol)
in 5.0 mL DME at -78 ◦C. Then the above aldehyde in DME
solution (2.0 mL) was added dropwise at this temperature for
15 min. The reaction mixture was stirred for another 3 h then
(3aS,4E,7S,11S,12aS,13aS,14E,15aS)-2,2,7-Trimethyl-11-
((5S,7R)-2,2,3,3,7,10,10,11,11-nonamethyl-4,9-dioxa-3,10-
disiladodecan-5-yl)-6,7,8,11,12,12a,13a,15a-octahydro-
[1,3]dioxolo[4,5-h]oxireno[2,3-d][1]oxacyclopentadecin-9(3aH)-
one (34)
Grubbs’ 2nd catalyst (9.6 mg, 0.012 mmol) was added to a solution
of 33 (40 mg, 0.058 mmol) in 50 mL DCM without oxygen. The
reaction mixture was stirred for 12 h. Removal of the solvent by
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was allowed to warm to room temperature for another 2 h. Water
was added to the mixture when TLC showed completion of the
reaction, then diluted with EtOAc (20 mL). The organic layer was
washed with water and brine then dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation gave a residue which
was directly used in the following step. TBAF (0.1 mL, 1 M
in THF, 0.1 mmol) was added to a solution of above mixture
in 3.0 mL THF at room temperature. The reaction mixture was
stirred for 2 h. Water was added to the mixture when TLC showed
completion of the reaction, then diluted with EtOAc (15 mL). The
organic layer was washed with brine then dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (8 : 1 PE/EtOAc) on silica gel gave compound 1
(13 mg, 0.027 mmol, 59%) as a white solid: [a]2D0 = 26.2 (c 0.5,
CHCl3); IR (neat): 3489, 2956, 2926, 2855, 1735, 1456, 1378,
Foundation of National Natural Science Foundation of China
(20525208) is gratefully acknowledged.
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1
1237, 1095, 970, 879 cm-1; H NMR (400 MHz, CDCl3) d 5.82–
5.74(m, 2H), 5.42–5.34(m, 2H), 5.32–5.20(m, 1H), 5.16–5.09(m,
2H), 3.95(t, J = 8.4 Hz, 2H), 3.85(t, J = 8.8 Hz, 2H), 3.52(br s,
1H), 2.99 (d, J = 9.2 Hz, 1H) 2.80(d, J = 9.6 Hz, 1H), 2.60(s, 2H),
2.41(d, J = 16.8 Hz, 1H), 2.30(br s, 1H), 2.20–2.10(m, 2H), 1.91–
1.75(m, 2H), 1.81–1.70(m, 2H), 1.64–1.55(m, 1H), 1.67–1.56(m,
4H), 1.37–1.35(m, 6H), 1.25–1.15(m, 2H), 0.98(d, J = 6.4 Hz, 3H),
0.94(d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 172.8,
135.6, 135.3, 134.9, 132.7, 129.5, 128.8, 127.6, 125.7, 109.6, 83.0,
81.4, 73.3, 70.9, 40.8, 37.2, 36.6, 35.5, 34.1, 33.5, 33.3, 29.7, 27.1,
21.7, 21.2, 17.9; ESIMS m/z 497.3 ([M + Na]+); HRESIMS Calcd
for C28H42O6Na: ([M + Na]+) 497.2884, found 497.2878.
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Research support from National Basic Research Program of
China (973 Program, 2010CB833200), the National Natural Sci-
ence Foundation of China (No.20172064, 203900502, 21032006),
Shanghai Natural Science Council, and Excellent Young Scholars
4526 | Org. Biomol. Chem., 2011, 9, 4518–4526
This journal is
The Royal Society of Chemistry 2011
©