Enantioselective total synthesis of vicenistatin, a novel 20-membered macrocyclic lactam antitumor antibiotic

Article abstract of DOI:10.1039/b111146a

Enantioselective total synthesis of an antitumor antibiotic, vicenistatin, featuring a 20-membered macrocyclic lactam glycoside with the amino sugar vicenisamine, has been achieved. Key reactions in the synthesis of macrolactam aglycone involved Suzuki cross-coupling and Evans asymmetric aldol reaction. Penultimate glycosidation of the O-TMS-aglycone with appropriately protected 1-O-acetyl amino sugar and final deprotection allowed accomplishment of the total synthesis.

Full text of DOI:10.1039/b111146a

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Enantioselective total synthesis of vicenistatin, a novel
20-membered macrocyclic lactam antitumor antibiotic
Yoshitaka Matsushima,a Hiroaki Itoh,a Takuya Nakayama,a Sayo Horiuchi,a Tadashi Eguchib
and Katsumi Kakinuma*a
1
a Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku,
Tokyo 152-8551, Japan
b Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-okayama,
Meguro-ku, Tokyo 152-8551, Japan
Received (in Cambridge, UK) 6th December 2001, Accepted 12th February 2002
First published as an Advance Article on the web 4th March 2002
Enantioselective total synthesis of an antitumor antibiotic, vicenistatin, featuring a 20-membered macrocyclic
lactam glycoside with the amino sugar vicenisamine, has been achieved. Key reactions in the synthesis of
macrolactam aglycone involved Suzuki cross-coupling and Evans asymmetric aldol reaction. Penultimate
glycosidation of the O-TMS-aglycone with appropriately protected 1-O-acetyl amino sugar and final
deprotection allowed accomplishment of the total synthesis.
Vicenistatin (1), an antitumor antibiotic isolated from Strepto-
myces sp. HC-34, is interesting because of its novel structural
features, including a 20-membered macrocyclic lactam aglycone
and a new amino sugar (vicenisamine) as shown in Fig. 1.1
showed no cytotoxicity, which strongly suggested that the vice-
nisamine amino sugar plays an important role in exerting the
antitumor activity of vicenistatin.
To explore the chemical features essential to its biological
activities, we have been engaged in synthetic studies of viceni-
statin. Previously, we reported the synthesis of the aglycone
part.8 Furthermore, we have developed a new synthetic stra-
tegy for 2,6-dideoxyamino sugars, by which the synthesis of
-vicenisamine and -kedarosamine was furnished.9 Along
these lines, we report herein the enantioselective total synthesis
of vicenistatin.
Our convergent synthetic plan, which should be flexible in
view of possible future structure modifications, is shown in
Scheme 1. The final stage of the synthesis was to be glycos-
idation, however, a difficulty had already been found in that the
free aglycone was extremely insoluble in most solvents.7 There-
fore, the aglycone part had to be prepared in a suitably pro-
tected form for glycosidation. Consequently, O-TMS (trimeth-
ylsilyl) protected aglycone 2 was envisaged as a glycosyl
acceptor, and N,O-protected 1-O-acetyl sugar 3 was chosen as a
glycosyl donor, because of the ease of preparation of the free 1-
O-acetyl sugar and its usefulness in glycosidation with O-TMS-
alcohol.7,10 Accordingly, our previous synthetic strategy through
the N-PMB (p-methoxybenzyl)-protected aglycone8 was modi-
fied for the synthesis of O-TMS-aglycone 2, especially about
the time point of introduction of the nitrogen functional group.
We further envisaged that lactam formation should be as the
final macrocyclization for the aglycone. The crucial precursor A
was expected to be synthesized from the triene-alcohol B by
Evans asymmetric aldol reaction11 and subsequent Wittig–
Horner chain elongation, and the intermediate B seemed to be
stereoselectively constructable by Suzuki cross-coupling12 of C
and D. The vinyl iodide C should be derived from cyclopropyl
methyl ketone 4, and the vinylboronate counterpart D could be
derived from (S)-citronellol 5 via a corresponding acetylene DЈ.
Fig. 1 Structures of vicenistatin and BE-14106 (GT-32A).
A major biological characteristic is its significant inhibitory
activity, especially against HL-60 (human leukaemia) and
COLO205 (human colon carcinoma) in vitro and Co-3 (human
colon carcinoma) in vivo.1 The structure shown was determined
mainly by extensive NMR spectral analysis1 and the absolute
stereochemistry of the aglycone part was determined by the
synthetic approach.2 So far, several kinds of macrocyclic lactam
antibiotics have been reported including ansamycin antibiotics,
hitachimycin3 (stubomycin4) and BE-141065 (GT32-A6). In
particular, BE-14106 should be noted here because of its 20-
membered macrocyclic lactam structure. However, vicenistatin
is distinct from those antibiotics by containing an amino sugar
and by exhibiting intriguing antitumor activities. Recently,
we have reported vicenistatin M, a neutral congener having
-mycarose instead of vicenisamine, and have determined its
absolute structure by synthesis from synthetic -mycarose and
the naturally derived aglycone.7 Interestingly, vicenistatin M
Results and discussion
According to the above-mentioned strategy, our work started
from the preparation of two components, C (≡ 11) and DЈ
(= 14), which is depicted in Scheme 2. The homopropargyl
alcohol 6, which was obtained from cyclopropyl methyl ketone
DOI: 10.1039/b111146a
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This journal is © The Royal Society of Chemistry 2002
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Scheme 1 Retrosynthetic analysis for vicenistatin.
4 by Grignard reaction, was stereoselectively converted to (E)-
homoallylic bromide 7 (E : Z ≈ 14 : 1) with hydrobromic acid;
the classical Julia method.13 The bromide 7 was displaced with
caesium acetate to introduce an oxygen functionality as acetate
8.14 After deprotection of the acetyl group of 8 under neutral
conditions,15 the hydroxy group of the resulting alcohol 9
was reprotected to give tert-butyldiphenylsilyl (TBDPS) ether
10. Subsequently, the terminal acetylene 10 was converted to
(E)-2-methylalk-1-enyl iodide 11 by Negishi’s method.16
A vinylboronate counterpart D was synthesized from the
corresponding acetylene. The starting (S)-citronellol TBS
ether 12 was subjected to ozonolysis in MeOH to give aldehyde
13, which was then transformed into the acetylenic compound
14 by the Corey–Fuchs method (82%, 2 steps).17 The Ohira–
Bestmann one-pot procedure18 was also applicable to the
aldehyde 13. Thus, treatment of 13 in MeOH with dimethyl
(1-diazo-2-oxopropyl)phosphonate 15 in the presence of potas-
sium carbonate furnished the acetylene 14 in 80% yield.
The crucial Suzuki coupling12 of these two components 11
and 14 and subsequent transformations were carried out as
follows (Scheme 3). The vinylboronate D, prepared in situ
by hydroboration of 14 with catecholborane, was treated with
the vinyl iodide 11 in the presence of tetrakis(triphenyl-
phosphine)palladium catalyst and NaOH as a base to give a
coupling product 16 in moderate yield. The TBS protecting
group of the resulting diene 16 was then selectively removed
with aqueous acetic acid in THF to give alcohol 17. This was
then oxidized to aldehyde 18 by Swern oxidation19 and the
aldehyde 18 was further oxidized by sodium chlorite in a mix-
ture of tert-butyl alcohol and phosphate buffer in the presence
of 2-methylbut-2-ene as a scavenger20 to afford carboxylic acid
19 in good yield. For the introduction of a nitrogen functional
group, Curtius rearrangement21 was carried out in refluxing
benzene with diphenylphosphoryl azide and triethylamine in
the presence of allyl alcohol to afford allyloxycarbonyl (Alloc)-
protected amine 20 in 68% yield. Then, the remaining silyl
protecting group of compound 20 was cleaved with hydrogen
fluoride–pyridine22 in THF to give alcohol 21.
Scheme 2 Synthesis of coupling precursors (11 and 14). Reagents,
conditions and yields: (a) propargyl bromide, Mg, cat. HgCl2, Et2O
(87%); (b) 47% HBr; (c) CsOAc, DMF (79%, 2 steps); (d) KCN, EtOH
(99%); (e) TBDPSCl, Imid., DMF (99%); (f ) AlMe3, cat. ZrCl2; I2,
CH2Cl2 (88%); (g) TBSCl, Imid., DMF (quant.); (h) O3, CH2Cl2,
MeOH, Py.; Me2S (94%); (i) Method A: (1) CBr4, PPh3, Py., CH2Cl2
(93%); (2) BunLi, THF (88%); Method B: 15, K2CO3, MeOH (80%).
Subsequent key manipulations included construction of two
contiguous chiral centers (C-6, -7) (Scheme 3), chain elongation
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Scheme 4 Synthesis of O-TMS-aglycone (2)-2. Reagents, conditions
and yields: (a) Dess–Martin periodinane, CH2Cl2; (b) 26, LiN(TMS)2,
THF (58%, 2 steps); (c) Pd(PPh3)4, dimethylbarbituric acid, THF
(65%); (d) TBAF, THF; (e) (EtO)2P(O)CN, Et3N, DMF (28%, 2 steps);
(f ) PPTS, MeOH; TMSCl, Et3N, DMAP, CH2Cl2 (92%).
Scheme 3 Synthesis of O-TMS-aglycone (2)-1. Reagents, conditions
and yields: (a) catecholborane, THF: 11, cat. Pd(PPh3)4, 2 M NaOH,
benzene (72% from 11); (b) AcOH, H2O, THF (60%); (c) (COCl)2,
DMSO; Et3N, CH2Cl2 (82%); (d) NaClO2, 2-methylbut-2-ene,
NaH2PO4, ButOH, H2O (99%); (e) (PhO)2P(O)N3, Et3N; allyl alcohol,
benzene (68%); (f ) HFؒPy, THF (89%); (g) Dess–Martin periodinane,
ω-amino carboxylic acid, the precursor for the macrolactam-
ization. Subsequently, the final cyclization was successfully per-
formed under high dilution (0.002 M) in DMF with diethyl
cyanophosphonate and triethylamine at 0 ЊC (Shioiri’s con-
ditions for peptide synthesis27) to construct the macrolactam
ring 28 (28%, 2 steps). The EE protecting group of 28 was
finally removed by acid-catalyzed methanolysis and the result-
ing 7-hydroxy group was immediately reprotected to give the
desired O-TMS-aglycone 2. Its spectroscopic properties were
identical with those of an authentic specimen, which was
obtained from natural vicenistatin (1) in two steps, i.e. acidic
solvolysis and O-TMS protection.7 At this stage, we were
successful in synthesizing the 20-membered macrocyclic lactam,
O-TMS-aglycone (2) as the glycosyl acceptor.
CH2Cl2; (h) 22, Bun BOTf, Et3N, CH2Cl2 (62%, 2 steps); (i) EVE, PPTS,
2
CH2Cl2 (86%); (j) LiBH4, MeOH, THF (74%).
(C-1–C-5) and the final macrolactamization (Scheme 4). Dess–
Martin oxidation23 of the alcohol 21 gave the corresponding
aldehyde, but considerable decompostion was observed during
the work-up and purification. Therefore, the highly unstable
aldehyde had to be immediately subjected to Evans aldol reac-
tion.11 Thus, a reaction mixture of the oxidation was directly
injected into a boron enolate solution, which previously had
been prepared from chiral oxazolidinone 22, to give an aldol
product 23 in moderate yield. After protection of the resulting
7-hydroxy group as its 1-ethoxyethyl (EE) ether, compound 24
was reduced with lithium borohydride to give primary alcohol
25. The alcohol 25 was then oxidized by Dess–Martin pro-
cedure to give the corresponding aldehyde, which in turn was
subjected to Wittig–Horner chain elongation with phosphonate
26 to give (E,E)-diene ester 27.
The glycosyl donor was then prepared from N-Fmoc
(fluoren-9-ylmethoxycarbonyl)-protectedmethylα-vicenisamin-
ide 29, the synthesis of which was recently reported.9 Thus, the
C-3 hydroxy group of 29 was first protected as an acetate 30
(Scheme 5). After hydrolysis of 30 in aqueous acetic acid, the
Removal of amino- and carboxy-protecting groups and sub-
sequent macrolactamization were performed as follows. Initial
palladium-catalyzed deprotection of the Alloc group of 27 was
somewhat troublesome, i.e. the deprotected free amine hap-
pened to react with dimedone, which was the generally used
allyl-transfer reagent, to form an enamine (m/z 669 [M Ϫ H]Ϫ)
as a by-product shown in Scheme 4.24 Fortunately, this side
reaction could be avoided by using 2-ethylhexanoic acid25 or,
more favorably, 1,3-dimethylbarbituric acid26 as allyl-transfer
reagent in the presence of tetrakis(triphenylphosphine)pal-
ladium to yield an intermediary seco-ester. The remaining
TMS-ethyl protecting group of the seco-ester was immediately
cleaved by tetra-n-butylammonium fluoride (TBAF) to give an
Scheme 5 Synthesis of glycosyl donor. Reagents, conditions and yield:
(a) Ac2O, DMAP, Py. (89%); (b) AcOH, H2O; (c) Ac2O, DMAP, Py.
(97%, 2 steps).
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resulting free sugar was further acetylated to give the desired
glycosyl donor 1,3-di-O-acetyl-N-Fmoc-vicenisamine 31. It
turned out that these N-Fmoc-protected compounds bore a
slight disadvantage in that slow rotation around the urethane
C–N bond resulted in complicated NMR spectra due to the
presence of rotational isomers. However, the Fmoc protecting
group was chosen because of its ease of removal in the final
stage of the synthesis (See Scheme 6).
mol%) in dry Et2O (80 cm3) was added dropwise propargyl
bromide (6.92 cm3, 91.9 mmol) at a rate to maintain gentle
reflux under Ar. To an ice-cooled solution of the resulting
Grignard reagent was added dropwise a solution of cyclopropyl
methyl ketone 4 (5.00 g, 59.4 mmol) in dry Et2O (15 cm3) and
the reaction mixture was stirred at rt for 2 h. The reaction was
quenched by addition of saturated aq. NH4Cl at 0 ЊC, and the
resulting mixture was extracted four times with Et2O. The
combined extract was washed with brine, dried (MgSO4)
and concentrated in vacuo. The residue was vacuum-distilled at
80.5–81.0 ЊC (32 mmHg) to give compound 6 as a colorless oil
(6.42 g, 87%) {HREIMS m/z 124.0842 [(M)ϩ; Calc. for C8H12O:
m/z, 124.0888]}; νmax (neat)/cmϪ1 3423 (br), 3303, 3086, 2117,
1375 and 636; δH (300 MHz; CDCl3) 0.33–0.48 (m, 4H), 0.99–
1.09 (m, 1H), 1.24 (s, 3H), 2.09 (t, J = 2.2 Hz, 1H) and 2.38–2.51
(m, 2H); δC (75 MHz; CDCl3) 0.03, 0.23, 19.9, 25.0, 32.7, 69.5,
70.5 and 80.4.
(E )-7-Acetoxy-4-methylhept-4-en-1-yne 8
To a solution of 47% aq. HBr (15 cm3) was added dropwise the
alcohol 6 (6.40 g, 51.5 mmol) at Ϫ24 ЊC. After the reaction
mixture had been stirred for 3 hr at 0 ЊC, it was extracted four
times with pentane. The combined extract was washed suc-
cessively with saturated aq. NaHCO3 and brine, dried (MgSO4)
and concentrated in vacuo. The residual crude bromide 7
(9.26 g, 96%) was immediately used for the next step without
further purification.
To a solution of bromide 7 (9.26 g, ≈ 49.5 mmol) in dry DMF
(20 cm3) was added caesium acetate (15.0 g, 78.1 mmol) and the
reaction mixture was stirred for 19 h at rt. The mixture was
poured into water and extracted four times with Et2O. The
combined extract was washed successively with water, saturated
aq. NaHCO3 and brine, dried (MgSO4) and concentrated in
vacuo. The residue was purified by column chromatography
(hexane–EtOAc, 50 : 1 to 20 : 1) to give acetate 8 as a colorless
oil (6.77 g, 79% in 2 steps) {HREIMS m/z 166.0966 [(M)ϩ; Calc.
for C10H14O2: m/z, 166.0994]}; νmax (neat)/cmϪ1 3284, 2117,
1739, 1245 and 1036; δH (300 MHz; CDCl3) 1.72 (s, 3H), 2.05 (s,
3H), 2.09 (t, J = 2.2 Hz, 1H), 2.38 (q, J = 6.6 Hz, 2H), 2.91 (s,
2H), 4.07 (dt, J = 7.1, 2.5 Hz, 2H) and 5.43 (dt, J = 7.1, 1.2 Hz,
1H); δC (75 MHz; CDCl3) 16.0, 20.9, 27.5, 28.5, 63.7, 70.4, 81.6,
120.9, 132.6 and 171.1.
Scheme 6 Synthesis of vicenistatin (1). Reagents, conditions and yields:
(a) SnCl4, AgClO4, 31 CH2Cl2, 0 ЊC (59% from 2); (b) DBU, EtOAc:
PLC separation (32: 46%; α-isomer: 46%); (c) conc KOH aq., MeOH, rt
(83%).
Glycosidation of the O-TMS-aglycone 2 with 31 was
achieved using Mukaiyama’s protocol.10 In the event, treatment
of an ice-cooled solution of 2 and 31 in dry CH2Cl2 in the
presence of SnCl4–AgClO4, followed by warming of the hetero-
geneous mixture, provided a inseparable anomeric mixture in
59% yield as shown in Scheme 6. The Fmoc proctective group
of the mixture was subsequently cleaved with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU)28 to afford the desired β-glycoside
32 (1Ј-H: dd, J = 1.8, 9.8 Hz) and an α-anomer (1Ј-H: d, J =
4.2 Hz), which were separated by preparative thin-layer chrom-
atography (PLC) (α : β ≈ 1 : 1). The 3Ј-O-acetyl group of the
thus obtained β-glycoside 32 was deprotected by alkaline
hydrolysis to afford vicenistatin (1). All the spectral data of the
synthetic 1 were identical in every aspect to those of natural
vicenistatin.
(E )-4-Methylhept-3-en-6-yn-1-ol 9
A solution of acetate 8 (4.14 g, 24.5 mmol) and potassium cyan-
ide (1.36 g, 20.0 mmol) in ethanol (83 cm3) was stirred for 5 days
at rt. The reaction was quenched by addition of water (30 cm3),
and the solvent was removed in vacuo. The residue was dis-
solved in water and extracted three times with Et2O. The
combined extract was washed with brine, dried (MgSO4) and
concentrated in vacuo. The residue was purified by column
chromatography (hexane–EtOAc, 10 : 1 to 5 : 1) to give alcohol
9 as a colorless oil (3.07 g, 99%) {HREIMS m/z 124.0930 [(M)ϩ;
Calc. for C8H12O: m/z, 124.0888]}; νmax (neat)/cmϪ1 3373 (br),
3298, 2117, 1421 and 1047; δH (300 MHz; CDCl3) 1.73 (s, 3H),
2.13 (t, J = 2.4 Hz, 1H), 2.38 (q, J = 6.4 Hz, 2H), 2.92 (s, 2H),
3.65 (dt, J = 7.1, 2.5 Hz, 2H) and 5.46 (dt, J = 7.1, 1.2 Hz, 1H);
δC (75 MHz; CDCl3) 16.2, 28.5, 31.5, 62.2, 70.5, 81.7, 121.8 and
132.7.
In conclusion, we were successful in enantioselectively syn-
thesizing vicenistatin. The convergent synthetic strategy
described above appears to be applicable to the synthesis of
various vicenistatin derivatives.
Experimental
All mps are uncorrected. NMR spectra were recorded on a
1
JEOL LA-300, or a Bruker DRX-500 spectrometer. H-NMR
and 13C-NMR chemical shifts were reported in δ-values based
on internal tetramethylsilane (δH = 0), or solvent signal (CDCl3
δC = 77.0; pyridine-d5 δH = 7.20, δC = 135.5) as reference. IR
spectra were recorded on a Horiba FT-710 Fourier-transform
infrared spectrometer. Optical rotations were measured on a
JASCO DIP-360 polarimeter, and [α]D-values are given in
units of 10Ϫ1 deg cm2 gϪ1. Mass spectra were measured on a
JEOL AX-505HA mass spectrometer. Silica gel column chrom-
atography was carried out with Merck Kieselgel 60, Art. Nr.
7734, and flash column chromatography was carried out with
Merck Kieselgel 60, Art. Nr. 9385.
(E )-7-(tert-Butyldiphenylsilyloxy)-4-methylhept-4-en-1-yne 10
To an ice-cooled solution of alcohol 9 (523.3 mg, 4.21 mmol)
and imidazole (456 mg, 6.70 mmol) in DMF (5 cm3) was added
dropwise tert-butyldiphenylsilyl chloride (1.26 cm3, 4.85 mmol)
and the mixture was stirred for 0.5 h at 0 ЊC. The reaction
mixture was poured into cold water and the mixture was
extracted twice with pentane. The combined extract was
washed successively with saturated aq. NaHCO3 and brine,
dried (MgSO4) and concentrated in vacuo. The residue was
2-Cyclopropylpent-4-yn-2-ol 6
To a suspension of magnesium turnings (2.66 g, 110 mmol)
and mercury(II) chloride (24.2 mg, 8.91 × 10Ϫ2 mmol, 0.15
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purified by column chromatography (hexane–Et2O, 50 : 1) to
give silyl ether 10 as a colorless oil (1.51 g, 99%) (Found: C,
79.37; H, 8.42. Calc. for C24H30OSi: C, 79.50; H, 8.34%); νmax
(neat)/cmϪ1 3309, 2119, 1427, 1113, 823 and 702; δH (300 MHz;
CDCl3) 1.05 (s, 9H), 1.63 (s, 3H), 2.07 (t, J = 2.7 Hz, 1H), 2.30
(q, J = 6.8 Hz, 2H), 2.86 (s, 2H), 3.66 (t, J = 6.8 Hz, 2H), 5.46 (tt,
J = 1.4, 7.3 Hz, 1H), 7.28–7.43 (m, 6H) and 7.66–7.69 (m, 4H);
δC (75 MHz; CDCl3) 16.0, 19.1, 26.8, 28.5, 31.5, 63.4, 70.3, 81.9,
122.4, 127.6, 129.5, 131.3, 134.0 and 135.6.
CHCl3); νmax (neat)/cmϪ1 2713, 1728, 1471, 1463, 1255 and
1095; δH (300 MHz; CDCl3) 0.05 (s, 6H), 0.89 (d, J = 10 Hz,
3H), 0.84 (s, 9H), 1.34–1.74 (m, 5H), 2.40–2.47 (m, 2H), 3.58–
3.70 (m, 2H) and 9.78 (t, J = 1.7 Hz, 1H); δC (75 MHz; CDCl3)
Ϫ5.3, 17.5, 18.3, 19.6, 25.5, 25.7, 26.0, 29.1, 37.3, 40.0, 61.3,
125.0 and 130.7.
(S)-7-tert-Butyldimethylsilyloxy-5-methylhept-1-yne 14
Method A. To an ice-cooled solution of triphenylphosphine
(86.1 g, 328 mmol) in CH2Cl2 (600 cm3) and pyridine (16 cm3)
was added portionwise carbon tetrabromide (52.6 g, 159
mmol). After the mixture had been stirred for 10 min, a sol-
ution of aldehyde 13 (20.0 g, 81.8 mmol) in CH2Cl2 (20 cm3)
was added over a period of 10 min. The mixture was stirred for
2 h at 0 ЊC, and was then poured into a stirred mixture of
hexane and saturated aq. NaHCO3. The whole was extracted
three times with hexane. The combined extract was washed
twice with brine, dried (MgSO4) and concentrated in vacuo.
Insoluble material was filtered off when generated during the
concentration. The residue was purified by column chrom-
atography (hexane–EtOAc, 30 : 1) to give an intermediary
dibromo olefin as a colorless oil (30.6 g, 93%) (Found: C, 42.24;
H, 7.22. Calc. for C14H28Br2OSi: C, 42.01; H, 7.05%); [α]2D5
Ϫ1.51 (c 1.27, CHCl3); νmax (neat)/cmϪ1 2954, 2856, 1625, 1471,
1461, 1255 and 1095; δH (300 MHz; CDCl3) 0.05 (s, 6H), 0.89
(s, 9H), 0.90 (d, J = 6.1 Hz, 3H), 1.20–1.65 (m, 5H), 2.02–2.18
(m, 2H), 3.60–3.69 (m, 2H) and 6.37 (t, J = 7.3 Hz, 1H);
δC (75 MHz; CDCl3) Ϫ5.3, 18.3, 19.4, 26.0, 29.0, 30.6, 34.9,
40.0, 61.1, 88.5 and 138.8.
To a solution of the dibromo olefin (21.47 g, 53.7 mmol) in
THF (250 cm3) was added dropwise n-butyllithium (87.5 cm3;
1.53 M solution in hexane, 134 mmol) at Ϫ78 ЊC. The solution
was then stirred for 1 h at Ϫ78 ЊC, and for 3.5 h at rt. Saturated
aq. NH4Cl (30 cm3) was added slowly to the mixture. The sol-
vent was removed in vacuo. The residue was diluted with Et2O
(40 cm3) and water (50 cm3). The aqueous layer was extracted
three times with Et2O. The combined extract was washed with
brine, dried (MgSO4) and concentrated in vacuo. The residue
was purified by column chromatography (hexane–EtOAc,
50 : 1) to give alkyne 14 as a colorless oil (11.34 g, 88%) (Found:
C, 69.67; H, 11.52. Calc. for C14H28OSi: C, 69.93; H, 11.74%);
[α]2D6 Ϫ0.07 (c 1.19, CHCl3); νmax (neat)/cmϪ1 3315, 2119, 1255
and 1093; δH (300 MHz; CDCl3) 0.01 (s, 6H), 0.84 (s, 9H), 0.85
(d, J = 4.4 Hz, 3H), 1.22–1.39 (m, 2H), 1.47–1.58 (m, 2H), 1.60–
1.73 (m, 1H), 1.88 (t, J = 2.5 Hz, 1H), 2.12–2.21 (m, 2H) and
3.55–3.67 (m, 2H); δC (75 MHz; CDCl3) Ϫ5.3, 16.1, 18.3, 19.1,
25.9, 28.8, 35.7, 39.5, 61.2, 68.0 and 84.7.
(1E,4E )-7-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-i1-odo-
hepta-1,4-diene 11
To an ice-cooled suspension of dichlorobis(η5-pentadienyl)-
zirconium (156 mg, 5.34 × 10Ϫ1 mmol) in dry CH2Cl2 (2.5 cm3)
were added dropwise a solution of alkyne 10 (865 mg, 2.39
mmol) in dry CH2Cl2 (3.0 cm3) and trimethylaluminium (2.50
cm3, 2.0 M solution in toluene, 5.0 mmol) in that order under
Ar. The resulting mixture was warmed to rt and stirred for an
additional 5.5 h. To the mixture was added dropwise a solution
of iodine (940 mg, 3.70 mmol) in THF (3 cm3) at 0 ЊC and the
mixture was stirred at the same temperature for 1 h. The reac-
tion was carefully quenched by addition of cold water and the
mixture was extracted twice with pentane. The combined
extract was washed successively with 0.5 M HCl, saturated aq.
NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo.
The residue was purified by column chromatography (hexane–
EtOAc, 100 : 1) to give iodide 11 as a colorless oil (1.06 g, 88%)
{HREIMS m/z 505.1389 [(M)ϩ; Calc. for C25H34IOSi: m/z,
505.1424]}; νmax (neat)/cmϪ1 3070, 1589, 1471, 1427, 1110 and
701; δH (300 MHz; CDCl3) 1.04 (s, 9H), 1.47 (s, 3H), 1.73 (s,
3H), 2.28 (q, J = 7.3 Hz, 2H), 2.82 (s, 2H), 3.65 (t, J = 6.8 Hz,
2H), 5.21 (t, J = 7.3 Hz, 1H), 5.90 (s, 1H), 7.24–7.45 (m, 6H)
and 7.65–7.69 (m, 4H); δC (75 MHz; CDCl3) 15.5, 19.2, 23.3,
26.8, 31.6, 49.8, 63.5, 75.8, 123.8, 127.6, 129.5, 133.5, 134.0,
135.6 and 146.2.
(S)-8-tert-Butyldimethylsilyloxy-2,6-dimethyloct-2-ene [(S)-
citronellol tert-butyldimethylsilyl ether] 12
To an ice-cooled solution of (S)-citronellol 5 (147.0 g, 941
mmol) and imidazole (96.1 g, 1.41 mol) in dry DMF (750 cm3)
was added portionwise tert-butyldimethylsilyl chloride (165.7 g,
1.10 mol). The mixture was stirred for 3 h at 0 ЊC. The reaction
mixture was poured into water and the mixture was extracted
three times with Et2O. The combined extract was washed with
brine, dried over (MgSO4) and concentrated in vacuo. The resi-
due was purified by column chromatography (hexane–EtOAc,
50 : 1) to give silyl ether 12 as a colorless oil (266.9 g, quant.)
(Found: C, 71.21; H, 12.72; Calc. for C16H34OSi: C, 71.04; H,
12.67%); [α]2D4 Ϫ1.42 (c 1.01, CHCl3); νmax (neat)/cmϪ1 2956,
2857, 1471, 1255 and 1097; δH (300 MHz; CDCl3) 0.05 (s, 6H),
0.89 (d, J = 10 Hz, 3H), 0.90 (s, 9H), 1.08–1.20 (m, 1H),
1.29–1.39 (m, 2H), 1.50–1.56 (m, 2H), 1.58 (s, 3H), 1.68 (s, 3H),
1.90–2.05 (m, 2H), 3.57–3.70 (m, 2H) and 5.10 (t, J = 7.3 Hz,
1H); δC (75 MHz; CDCl3) Ϫ5.3, 17.5, 18.3, 19.6, 25.5, 25.7,
26.0, 29.1, 37.3, 40.0, 61.3, 125.0 and 130.7.
Method B. To a solution of aldehyde 13 (1.59 g, 6.50 mmol)
and potassium carbonate (1.81 g, 13.1 mmol) in MeOH (98
cm3) was added dimethyl (1-diazo-2-oxopropyl)phosphonate
1518 (1.52 g, 7.91 mmol). The reaction mixture was stirred for
5 h at rt. After the solvent had been removed in vacuo, the
residue was suspended in water and extracted twice with Et2O.
The combined extract was washed successively with saturated
aq. NaHCO3 and brine, dried (MgSO4) and concentrated
in vacuo. The residue was purified by flash column chrom-
atography (hexane) to afford alkyne 14 (1.26 g, 80%).
(S)-6-tert-Butyldimethylsilyloxy-4-methylhexanal 13
To a mixture of alkene 12 (35.2 g, 129 mmol), MeOH (120 cm3),
CH2Cl2 (120 cm3), and pyridine (2 cm3) was introduced ozone at
Ϫ78 ЊC until the color of the resulting solution became pale
blue. Excess ozone was purged with a stream of argon, and
dimethyl sulfide (11.0 cm3, 150 mmol) was added dropwise
to the mixture at Ϫ78 ЊC. The solution was allowed to warm
gradually to rt with stirring for 18 h. The mixture was con-
centrated in vacuo and the residue was purified by column
chromatography (hexane–EtOAc, 20 : 1) to give aldehyde 13 as
a colorless oil (29.9 g, 94%) (Found: C, 63.66; H, 11.64. Calc.
for C13H28O2Si: C, 63.88; H, 11.54%); [α]2D9 ϩ5.38 (c 1.86,
(3E,6E,8E,12S)-14-tert-Butyldimethylsilyloxy-1-tert-butyl-
diphenylsilyloxy-4,6,12-trimethyltetradeca-3,6,8-triene 16
To a solution of alkyne 14 (10.52 g, 43.78 mmol) in THF
(120 cm3) was added catecholborane (52.2 cm3; 1.0 M solution
in THF, 52 mmol) and the mixture was refluxed for 3 h. After
the solvent had been removed in vacuo, the residue was dis-
solved in benzene (100 cm3). To the solution were added the
vinyl iodide 11 (20.08 g, 39.80 mmol), tetrakis(triphenyl-
phosphine)palladium (1.45 g, 1.25 mmol, 3 mol%), and 2 M
NaOH (43 cm3) and the resulting mixture was refluxed for 10 h.
J. Chem. Soc., Perkin Trans. 1, 2002, 949–958
953

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After the solution had been cooled to 0 ЊC, a mixture of 35%
H2O2 (15 cm3) and 2 M NaOH (22 cm3) was added slowly. The
solvent was then removed in vacuo and the residue was
extracted three times with Et2O. The combined extract was
washed with brine, dried (MgSO4) and concentrated in vacuo.
The residue was purified by flash column chromatography
(hexane–EtOAc, 100 : 1) to give triene 16 as a colorless oil
(17.86 g, 72% from 11), which was used for the next reaction
without further purification; νmax (neat)/cmϪ1 1471, 1255, 1110
and 701; δH (300 MHz; CDCl3) 0.06 (s, 6H), 0.87–0.90 (m,
12H), 1.02 (s, 9H), 1.21–1.76 (m, 11H), 2.05–2.15 (m, 2H),
2.25–2.32 (m, 2H), 2.66 (s, 2H), 3.60–3.71 (m, 4H), 5.18 (dt,
J = 7.1, 1.2 Hz, 1H), 5.57 (dt, J = 7.1, 15.1 Hz, 1H), 5.79 (d, J =
10.7 Hz, 1H), 6.23 (dd, J = 10.7, 15.1 Hz, 1H), 7.34–7.45 (m,
6H, aromatic) and 7.66–7.70 (m, 4H, aromatic); δC (75 MHz;
CDCl3) Ϫ5.2, 15.6, 15.9, 19.2, 19.6, 26.0, 26.8, 29.1, 30.4, 31.7,
36.9, 39.8, 50.4, 61.4, 63.7, 122.5, 126.2, 126.5, 127.6, 129.5,
132.8, 134.0, 134.4, 134.9 and 135.6.
(3S,6E,8E,11E )-14-tert-Butyldiphenylsilyloxy-3,9,11-
trimethyltetradeca-6,8,11-trienoic acid 19
To an ice-cooled solution of 18 (3.63 g, 7.22 mmol) in 2-
methylbut-2-ene (40.0 cm3, 376 mmol) and tert-butyl alcohol
(55 cm3) was added dropwise a solution of sodium chlorite
(6.01 g, 665 mmol) and sodium dihydrogen phosphate dihydrate
(7.83 g, 50.2 mmol) in water (65 cm3). The mixture was stirred
for 30 min and extracted three times with Et2O. The combined
extract was washed with brine, dried (MgSO4) and concentrated
in vacuo. The residue was purified by column chromatography
(hexane–EtOAc, 2 : 1 to 1 : 1) to give acid 19 (3.74 g, 99%) as a
colorless oil (Found: C, 76.15; H, 9.05. Calc. for C33H46O3Si: C,
76.40; H, 8.94%); [α]2D5 Ϫ5.23 (c 1.03, CHCl3); νmax (neat)/cmϪ1
3089, 2857, 1709, 1427, 1110 and 823; δH (300 MHz; CDCl3)
0.98 (d, J = 6.4 Hz, 3H), 1.05 (s, 9H), 1.26–1.34 (m, 1H), 1.47
(s, 3H), 1.62 (s, 3H), 1.96–2.40 (m, 8H), 2.65 (s, 2H), 3.65 (t, J =
6.9 Hz, 2H), 5.18 (t, J = 6.8 Hz, 1H), 5.55 (dt, J = 15.1, 6.9 Hz,
1H), 5.79 (d, J = 10.7 Hz, 1H), 6.24 (dd, J = 10.1, 15.1 Hz, 1H),
7.23–7.39 (m, 6H) and 7.66–7.69 (m, 4H); δC (75 MHz; CDCl3)
15.7, 16.0, 19.2, 19.5, 26.8, 29.7, 30.3, 31.7, 36.4, 41.5, 50.4,
63.7, 122.6, 126.1, 127.0, 127.6, 129.5, 131.9, 134.0, 134.8,
135.0, 135.6 and 179.6.
(3S,6E,8E,11E )-14-tert-Butyldiphenylsilyloxy-3,9,11-trimethyl-
tetradeca-6,8,11-trien-1-ol 17
A mixture of bis-silyl ether 16 (1.48 g, 2.38 mmol) in THF
(9 cm3), acetic acid (20 cm3) and water (4 cm3) was stirred for
40 h at rt. To the solution was added dropwise conc. aq. NaOH
(13.9 g in 40 cm3 of water) at 0 ЊC. The whole mixture was
extracted four times with Et2O. The combined extract was
washed successively with saturated aq. NaHCO3 and brine,
dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane–EtOAc,
20 : 1 to 5 : 1) to give alcohol 17 as a colorless oil (722 mg, 60%)
(Found: C, 78.31; H, 9.88. Calc. for C33H48O2Si: C, 78.51; H,
9.58%); [α]2D6 Ϫ1.18 (c 1.50, CHCl3); νmax (neat)/cmϪ1 1471, 1255,
1110 and 701; δH (300 MHz; CDCl3) 0.87 (d, J = 6.8 Hz, 3H),
1.04 (s, 9H), 1.17–1.66 (m, 11H), 2.05–2.15 (m, 2H), 2.29 (q, J =
7.1 Hz, 2H), 2.65 (s, 2H), 3.65 (t ϩ overlapping signals, J = 7.0
Hz, 4H), 5.18 (dt, J = 7.3, 1.1 Hz, 1H), 5.55 (dt, J = 15.1, 7.3 Hz,
1H), 5.79 (d, J = 10.7 Hz, 1H), 6.23 (ddt, J = 10.7, 15.1, 1.5 Hz,
1H), 7.34–7.44 (m, 6H, aromatic) and 7.66–7.70 (m, 4H,
aromatic); δC (75 MHz; CDCl3) 15.6, 15.9, 19.1, 19.4, 26.8, 29.0,
30.3, 31.6, 36.8, 39.8, 50.3, 61.0, 63.7, 122.5, 126.2, 126.6, 127.5,
129.5, 132.6, 134.0, 134.5, 135.0 and 135.5.
(3E,6E,8E,12S)-13-Allyloxycarbonylamino-1-tert-butyl-
diphenylsilyloxy-4,6,12-trimethyltrideca-3,6,8-triene 20
A solution of acid 19 (3.73 g, 7.20 mmol), diphenylphosphoryl
azide (1.87 cm3, 10.1 mmol), and triethylamine (1.20 cm3, 9.36
mmol) in benzene (60 cm3) was refluxed for 3 h. After addition
of allyl alcohol (2.55 cm3, 39.6 mmol), the reaction mixture was
refluxed again for another 24 h. The reaction was quenched by
addition of water and the resulting mixture was extracted three
times with Et2O. The combined extract was washed with brine,
dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane–EtOAc,
30 : 1) to give carbamate 20 (2.81 g, 68%) as a colorless oil
(Found: C, 75.20; H, 8.99; N, 2.53. Calc. for C36H51NO3:
C, 75.34; H, 8.96; N, 2.44%); [α]2D8 Ϫ1.63 (c 0.877, CHCl3);
νmax (neat)/cmϪ1 3070, 2856, 1703, 1427, 1113 and 739; δH (75
MHz; CDCl3) 0.90 (d, J = 6.4 Hz, 3H), 1.05 (s, 9H), 1.26–1.34
(m, 2H), 1.47 (s, 3H), 1.62 (s, 3H), 1.96–2.40 (m, 8H), 3.65
(t, J = 6.9 Hz, 2H), 4.55 (d, J = 5.6 Hz, 2H), 4.73 (br s, 1H), 5.18
(d, J = 6.8 Hz, 1H), 5.21 (dq, J = 10.4, 1.4 Hz, 1H), 5.30 (dq,
J = 17.3, 1.4 Hz, 1H), 5.55 (dt, J = 15.1, 6.9 Hz, 1H), 5.79 (d,
J = 10.1 Hz, 1H), 5.92 (ddt, J = 10.4, 17.3, 5.6 Hz, 1H), 6.23 (dd,
J = 10.1, 15.1 Hz, 1H), 7.35–7.42 (m, 6H, aromatic) and 7.66–
7.69 (m, 4H, aromatic); δC (75 MHz; CDCl3) 15.6, 15.9, 17.3,
19.1, 26.8, 30.2, 31.6, 33.0, 33.9, 46.8, 50.3, 63.7, 65.4, 117.6,
122.5, 126.1, 126.9, 127.5, 129.5, 132.0, 133.0, 134.0, 134.8,
134.9, 135.5 and 156.4.
(3S,6E,8E,11E )-14-tert-Butyldiphenylsilyloxy-3,9,11-trimethyl-
tetradeca-6,8,11-trien-al 18
A solution of Swern reagent was prepared by dropwise addition
of DMSO (2.00 cm3, 28.2 mmol) to a stirred solution of oxalyl
dichloride (7.34 cm3; 2.0 M solution in CH2Cl2, 14.7 mmol) in
CH2Cl2 (60 cm3) at Ϫ78 ЊC under Ar and stirring was continued
for 30 min. To the solution was added dropwise a solution of
alcohol 17 (4.95 g, 9.78 mmol) in CH2Cl2 (20 cm3) at Ϫ78 ЊC,
and the mixture was stirred for 30 min. Triethylamine (5.40 cm3,
38.7 mmol) was added to the mixture at Ϫ78 ЊC, and the
temperature was allowed to rise gradually to rt over 2 h. The
mixture was poured into water and extracted three times with
Et2O. The combined extract was washed with brine, dried
(MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography (hexane–EtOAc, 10 : 1) to give
aldehyde 18 as a colorless oil (3.63 g, 82%) (Found: C, 78.71;
H, 9.40. Calc. for C33H46O2Si: C, 78.83; H, 9.22%); [α]2D5 Ϫ11.5
(c 1.60, CHCl3); νmax (neat)/cmϪ1 2713, 1726, 1427 and 1110;
δH (300 MHz; CDCl3) 0.97 (d, J = 6.6 Hz, 3H), 1.04 (s, 9H),
1.27–1.69 (m, 9H), 2.11 (q, J = 6.8 Hz, 2H), 2.20–2.32 (m, 2H),
2.41 (ddd, J = 2.0, 3.8, 11.9 Hz, 2H), 2.66 (s, 2H), 3.65 (t, J =
6.9 Hz, 2H), 5.18 (d, J = 6.7 Hz, 1H), 5.54 (dt, J = 15.0, 6.8 Hz,
1H), 5.79 (d, J = 10.5 Hz, 1H), 6.24 (dd, J = 10.5, 15.0 Hz, 1H),
7.34–7.44 (m, 6H, aromatic), 7.66–7.70 (m, 4H, aromatic) and
9.75 (t, J = 2.3 Hz, 1H); δC (75 MHz; CDCl3) 15.7, 16.0, 19.2,
26.8, 27.7, 30.3, 31.7, 36.6, 50.4, 51.0, 63.7, 122.6, 126.0, 127.1,
127.6, 129.5, 131.7, 134.0, 134.9, 135.6 and 202.9.
(3E,6E,8E,12S)-13-Allyloxycarbonylamino-4,6,12-trimethyl-
trideca-3,6,8-trien-1-ol 21
To a solution of silyl ether 20 (808 mg, 1.41 mol) in THF
(15 cm3) was added dropwise HF–pyridine (1.5 cm3; ≈ 70% HF,
58 mmol) and the mixture was stirred for 6 h at rt before being
carefully poured into saturated aq. NaHCO3 and extracted
twice with Et2O. The combined extract was washed with brine,
dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography (hexane–EtOAc, 5 : 1 to
2 : 1) to give alcohol 21 as a colorless oil (422 mg, 89%) (Found:
C, 71.35; H, 10.08; N, 3.93. Calc. for C20H33NO3: C, 71.60;
H, 9.91; N, 4.18%); [α]2D9 Ϫ2.19 (c 0.42, CHCl3); νmax (neat)/cmϪ1
3344 (br), 3018, 2875, 1701, 1537, 1250 and 1047; δH (300 MHz;
CDCl3) 0.91 (d, J = 6.6 Hz, 3H), 1.15–1.51 (m, 3H), 1.57–1.68
(m, 9H), 2.02–2.19 (m, 2H), 2.32 (q, J = 6.8, 2H), 2.45 (s, 2H),
3.01 (quintet, J = 7.1 Hz, 1H), 3.63 (t, J = 6.3 Hz, 2H), 5.19
(d, J = 6.8 Hz, 1H), 5.21 (dq, J = 10.4, 1.4 Hz, 1H), 5.30 (dq,
J = 17.3, 1.4 Hz, 1H), 5.57 (dt, J = 15.1, 6.9 Hz, 1H), 5.81 (d, J =
954
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10.7 Hz, 1H), 5.93 (ddt, J = 10.4, 17.3, 5.6 Hz, 1H) and 6.24 (dd,
J = 10.7, 15.1 Hz, 1H); δC (75 MHz; CDCl3) 15.7, 15.9, 17.3,
30.1, 31.6, 33.0, 33.8, 46.8, 50.3, 62.3, 65.4, 117.5, 121.9, 126.2,
126.8, 132.2, 132.9, 134.3, 136.5 and 156.4.
1.4 Hz, 1H), 5.56 (dt, J = 15.1, 6.8 Hz, 1H), 5.80 (d, J = 10.7 Hz,
1H), 5.92 (ddt, J = 10.7, 17.3, 5.6 Hz, 1H), 6.23 (dd, J = 10.7,
15.1 Hz, 1H) and 7.20–7.34 (m, 5H, aromatic); δC (75 MHz;
CDCl3) 12.5, 12.7, 14.2, 15.2, 15.3, 15.4, 15.7, 17.3, 20.0, 20.5,
30.2, 31.3, 32.1, 33.1, 33.9, 37.8, 41.2, 46.9, 50.5, 55.7, 59.6,
60.4, 60.7, 65.4, 65.8, 66.0, 75.3, 98.6, 100.0, 117.6, 121.8, 122.2,
126.2, 126.3, 126.9, 127.3, 128.9, 129.4, 132.1, 133.0, 134.6,
134.7, 135.1, 135.3, 135.4, 152.7, 156.4, 175.1 and 175.4.
(4R)-3-[(2R,3S,5E,8E,10E,14S)-15-Allyloxycarbonylamino-
3-hydroxy-1,2,6,8,14-tetramethylpentadeca-5,8,10-trienoyl]-
4-benzyloxazolidin-2-one 23
To a solution of alcohol 21 (1.58 g, 4.71 mmol) in CH2Cl2
(42 cm3) was added Dess–Martin periodinane (2.82 g, 6.65
mmol). The mixture was stirred for 45 min at rt. The resulting
aldehyde solution was kept at 0 ЊC until it was used for the next
step.
(2S,3S,5E,8E,10E,14S)-15-Allyloxycarbonylamino-3-(1-eth-
oxyethoxy)-2,6,8,14-tetramethylpentadeca-5,8,10-trien-1-ol 25
To an ice-cooled solution of amide 24 (335 mg, 5.24 × 10Ϫ1
mmol) in MeOH (0.46 cm3) and THF (5.5 cm3) was added
dropwise a solution of lithium borohydride (2.80 cm3; 2.0 M
solution in THF, 5.6 mmol). After being stirred for 1 h, the
reaction mixture was quenched by addtion of water. The
solvent was removed in vacuo, and the resulting slurry was
extracted three times with Et2O. The combined extract was
washed with brine, dried (MgSO4) and concentrated in vacuo,
and the residue was purified by flash chromatography (hexane–
EtOAc, 3 : 1) to give alcohol 25 (90.8 mg, 37%) (Rf 0.34
[hexane–EtOAc 2 : 1]) and its diastereomer (90.3 mg, 37%) (Rf
0.23 [hexane–EtOAc 2 : 1]) as a colorless oil (Found: C, 69.43;
H, 10.29; N, 3.22. Calc. for C27H47NO5: C, 69.64; H, 10.17; N,
3.01%); [α]2D9 Ϫ2.2 (c 0.875, CHCl3); δH (300 MHz; CDCl3) (Rf
0.34) 0.82 (d, J = 7.1 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 1.23 (t,
J = 7.1 Hz, 3H), 1.27 (d, J = 5.1 Hz, 3H), 1.31–1.66 (m, 8H),
1.83 (br s, 1H), 2.04–2.43 (m, 4H), 2.68 (m, 2H), 2.99–3.16 (m,
2H), 3.41–3.59 (m, 5H), 3.83 (dt, J = 6.9, 2.7 Hz, 1H), 4.56
(d, J = 5.6 Hz, 2H), 4.68 (q, J = 5.1 Hz, 1H), 4.76 (br s, 1H), 5.18
(d, J = 6.8 Hz, 1H), 5.20 (dq, J = 10.4, 1.4 Hz, 1H), 5.29 (dq,
J = 17.3, 1.4 Hz, 1H), 5.56 (dt, J = 15.1, 6.8 Hz, 1H), 5.80 (d,
J = 10.7 Hz, 1H), 5.93 (ddt, J = 10.7, 17.3, 5.6 Hz, 1H) and 6.24
(dd, J = 10.7, 15.1 Hz, 1H) and (Rf 0.23) 0.89 (d, J = 7.3 Hz,
3H), 0.91 (d, J = 7.3 Hz, 3H), 1.19 (t, J = 7.3 Hz, 3H), 1.32 (d,
J = 5.4 Hz, 3H), 1.40–1.68 (m, 8H), 1.86–2.38 (m, 4H), 2.68 (s,
2H), 2.99–3.13 (m, 2H), 3.48–3.73 (m, 6H), 4.56 (d, J = 5.6 Hz,
2H), 4.72–4.81 (m, 2H), 5.19–5.33 (m, 3H), 5.56 (dt, J = 15.1,
6.8 Hz, 1H), 5.79 (d, J = 10.7 Hz, 1H), 5.93 (ddt, J = 10.7, 17.3,
5.6 Hz, 1H) and 6.24 (dd, J = 10.7, 15.1 Hz, 1H); δC (75 MHz;
CDCl3) (Rf 0.34) 9.9, 15.1, 15.8, 16.1, 17.3, 20.2, 30.1, 30.8,
33.1, 33.9, 46.8, 50.4, 61.5, 65.1, 65.4, 76.3, 100.1, 117.5, 122.3,
126.3, 126.8, 133.0, 134.4, 134.8 and 156.4; (Rf 0.23) 11.2, 15.2,
15.8, 16.0, 17.3, 20.3, 30.1, 30.2, 33.0, 33.9, 37.5, 46.8, 50.4,
60.4, 65.4, 65.6, 78.2, 99.5, 117.5, 122.6, 126.2, 126.9, 132.2,
133.0, 134.5, 134.8 and 156.4.
To a solution of chiral oxazolidinone 2211 (1.57 g, 6.73
mmol) in CH2Cl2 (28 cm3) were successively added dropwise
di(n-butyl)boryl trifluoromethanesulfonate (7.65 cm3; 1.0 M
solution in CH2Cl2, 7.7 mmol) and triethylamine (1.19 cm3,
8.54 mmol) at below Ϫ8 ЊC. To the resulting solution was added
dropwise the above aldehyde solution at below Ϫ70 ЊC. The
mixture was stirred for 50 min at Ϫ78 ЊC and then for 2 h at
0 ЊC. The reaction was quenched by addition of phosphate buf-
fer (pH 7.4; 18.4 cm3) and methanol (6.1 cm3). To the mixture
was added a 2 : 1 mixture of methanol–35% H2O2 (18.2 cm3) at
such a rate as to keep the internal temperature below 8 ЊC. After
stirring for an additional 1 h, the mixture was evaporated in
vacuo. The resulting slurry was extracted three times with Et2O.
The combined extract was washed successively with saturated
aq. NaHCO3 and brine, dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash chromatography
(hexane–EtOAc, 2 : 1) to give alcohol 23 as a colorless oil
(1.65 g, 62% from 21) (Found: C, 69.64; H, 8.31; N, 4.97. Calc.
for C33H46N2O6: C, 69.94; H, 8.18; N, 4.94%); [α]2D9 Ϫ42.7 (c
0.375, CHCl3); νmax (neat)/cmϪ1 3388 (br), 1782, 1722, 1242 and
704; δH (300 MHz; CDCl3) 0.91 (d, J = 6.5 Hz, 3H), 1.28 (d, J =
6.8 Hz, 3H), 1.42–1.64 (m, 6H), 2.05–2.40 (m, 7H), 2.70 (s, 2H),
2.79 (dd, J = 9.5, 13.2 Hz, 1H), 2.97–3.15 (m, 2H), 3.25 (dd, J =
3.2, 13.2 Hz, 1H), 3.89 (dt, J = 3.2, 6.9 Hz, 1H), 4.00 (br s, 1H),
4.18–4.23 (m, 2H), 4.56 (br d, J = 5.6 Hz, 2H), 4.64–4.71 (m,
1H), 4.85 (br s, 1H), 5.18 (d, J = 6.8 Hz, 1H), 5.20 (dq, J = 10.4,
1.4 Hz, 1H), 5.29 (dq, J = 17.3, 1.4 Hz, 1H), 5.56 (dt, J = 15.1,
6.8 Hz, 1H), 5.80 (d, J = 10.7 Hz, 1H), 5.92 (ddt, J = 10.7, 17.3,
5.6 Hz, 1H), 6.23 (dd, J = 10.7, 15.1 Hz, 1H) and 7.20–7.34 (m,
5H, aromatic); δC (75 MHz; CDCl3) 10.6, 15.8, 16.0, 17.3, 30.1,
32.6, 33.0, 33.9, 37.7, 41.5, 46.9, 50.4, 55.1, 65.4, 66.1, 71.5,
117.6, 121.6, 126.3, 126.9, 127.4, 129.0, 129.4, 132.2, 133.0,
134.5, 135.0, 136.5, 152.9, 156.4 and 177.3.
(4R)-3-[(2R,3S,5E,8E,10E,14S)-15-Allyloxycarbonylamino-
3-(1-ethoxyethoxy)-2,6,8,14-tetramethylpentadeca-5,8,10-
trienoyl]-4-benzyloxazolidin-2-one 24
(2R,3S,5E,8E,10E,14S)-15-Allyloxycarbonylamino-3-(1-ethoxy-
ethoxy)-2,6,8,14-tetramethylpentadeca-5,8,10-trienal
A solution of alcohol 25 (103 mg, 2.21 × 10Ϫ1 mmol) in CH2Cl2
(2.5 cm3) was cooled to 0 ЊC and Dess–Martin periodinane
(154 mg, 3.63 × 10Ϫ1 mmol) was added. The reaction mixture
was stirred for 30 min at rt. The reaction was quenched by
addition of 10% aq. Na2S2O3. The mixture was then extracted
twice with Et2O. The combined extract was washed successively
with saturated aq. NaHCO3 and brine, dried (MgSO4) and con-
centrated in vacuo. The residue was purified by column chrom-
atography (hexane–EtOAc, 3 : 1) to give title aldehyde as a
colorless oil (61.7 mg, 60%); νmax (neat)/cmϪ1 3348 (br), 2721,
1728, 1703, 1533 and 1246; δH (300 MHz; CDCl3) 0.91 (d, J =
6.8 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H),
1.27 (d, J = 5.4 Hz, 3H), 1.40–1.67 (m, 8H), 2.04–2.51 (m, 4H),
2.74 (s, 2H), 2.97–3.17 (m, 2H), 3.36–3.65 (m, 3H), 4.08–4.13
(m, 1H), 4.55 (br d, J = 5.4 Hz, 2H), 4.75 (dq, J = 18.2, 5.4 Hz,
1H), 4.88 (br s, 1H), 5.15 (t, J = 6.8 Hz, 1H), 5.20 (dq, J = 10.4,
1.4 Hz, 1H), 5.30 (dq, J = 17.3, 1.4 Hz, 1H), 5.56 (dt, J = 15.1,
6.8 Hz, 1H), 5.79 (d, J = 10.7 Hz, 1H), 5.92 (ddt, J = 10.7, 17.3,
5.6 Hz, 1H), 6.23 (dd, J = 10.7, 15.1 Hz, 1H) and 9.75 (s, 1H);
δC (75 MHz; CDCl3) 7.7, 15.1, 15.2, 15.8, 16.0, 17.2, 20.1, 20.2,
To a solution of alcohol 23 (1.65 g, 2.91 mmol) in ethyl vinyl
ether (EVE) (45 cm3) and CH2Cl2 (25 cm3) was added pyridin-
ium toluene-p-sulfonate (PPTS, 160 mg, 6.37 × 10Ϫ1 mmol)
at 0 ЊC. After being warmed to rt, the solution was stirred for
1.5 h. The reaction was quenched by addition of saturated
aq. NaHCO3 and the aqueous layer was extracted twice with
Et2O. The combined extract was washed with brine, dried
(MgSO4) and concentrated in vacuo. The reaction mixture was
purified by flash chromatography (hexane–EtOAc, 10 : 1) to
give the ether 24 as a colorless oil (1.77 g, 86%) (Found: C,
69.51; H, 8.70; N, 4.17. Calc. for C37H54N2O7: C, 69.56; H, 8.52;
N, 4.39%); [α]2D9 Ϫ42.7 (c 0.375, CHCl3); νmax (neat)/cmϪ1 3388
(br), 1782, 1722, 1242 and 704; δH (300 MHz; CDCl3) 0.91 (d,
J = 6.8 Hz, 3H), 1.15–1.30 (m, 12H), 1.63 (s, 3H), 1.67 (s, 2H),
2.05–2.25 (m, 2H), 2.30–2.37 (m, 2H), 2.68 (s, 2H), 2.76 (ddd,
J = 2.2, 9.9, 13.0 Hz, 1H), 2.90 (m, 2H), 3.29 (dq, J = 13.0, 3.6
Hz, 1H), 3.27–3.61 (m, 3H), 3.88–4.16 (m, 4H), 4.56 (br d, J =
5.6 Hz, 2H), 4.61 (br s, 1H), 4.73–4.77 (m, 1H), 5.18 (d, J =
6.8 Hz, 1H), 5.20 (dq, J = 10.4, 1.4 Hz, 1H), 5.29 (dq, J = 17.3,
J. Chem. Soc., Perkin Trans. 1, 2002, 949–958
955

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30.1, 30.6, 31.5, 33.0, 33.8, 46.8, 49.5, 49.7, 59.7, 60.1, 65.3,
75.0, 75.5, 98.8, 99.7, 117.4, 121.2, 121.4, 126.3, 126.7, 132.3,
133.0, 134.1, 136.3, 156.3, 204.4 and 204.6.
The residue was dissolved in dry DMF (80 cm3) and cooled in
an ice–water-bath. To the ice-cooled solution were added drop-
wise diethyl cyanophosphonate (140 mm3; 93% purity 8.59 ×
10Ϫ1 mmol) and triethylamine (150 mm3, 1.08 mmol). The reac-
tion mixture was stirred for an additional 3 h at 0 ЊC. The
mixture was then poured into water and extracted three times
with Et2O. The combined extract was washed successively with
water, saturated aq. NaHCO3 and brine, dried (MgSO4) and
concentrated in vacuo. The residue was purified by PLC
(hexane–EtOAc, 2 : 1) to give lactam 28 as a colorless solid
(17.6 mg, 28%) {HRFABMS (NBA matrix) m/z 430.3366
[(M ϩ H)ϩ; Calc. for C27H44NO3: m/z, 430.3321]}; [α]2D6 ϩ 65 (c
0.563, CHCl3); νmax (CHCl3)/cmϪ1 2978, 2929, 1658, 1631, 1604,
1379, 1120, 1095, 1030 and 997; δH (300 MHz; CDCl3) 0.95 (d,
J = 7.1 Hz, 3H), 1.07–1.14 (m, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.33
(d, J = 5.1 Hz, 3H), 1.50 (s, 3H), 1.71 (s, 3H), 2.07–2.42 (m, 6H),
2.71–2.92 (m, 2H), 3.14–3.32 (m, 2H), 3.40–3.72 (m, 4H), 4.72
(q, J = 5.4 Hz, 1H), 4.83 (q, J = 5.4 Hz, 1H), 5.14 (dt, J = 8.6,
17.3 Hz, 1H), 5.53–5.84 (m, 5H), 6.34 (dd, J = 10.7, 15.1 Hz,
1H) and 6.91 (dd, J = 11.2, 14.9 Hz, 1H).
2-Trimethylsilylethyl (2E,4E,6S,7S,9E,12E,14E,18S)-19-allyl-
oxycarbonylamino-7-(1-ethoxyethoxy)-6,10,12,18-tetramethyl-
nonadeca-2,4,9,12,14-pentaenoate 27
To a solution of Wittig–Horner reagent 26 (107 mg, 3.32 × 10Ϫ1
mmol) in THF (1.5 cm3) was added dropwise lithium hexa-
methyldisilazide (0.31 cm3; 1.0 M in THF, 3.1 × 10Ϫ1 mmol) at
Ϫ78 ЊC. After stirring of this mixture for 10 min, a solution of
the aldehyde (61 mg, 1.3 × 10Ϫ1 mmol) in THF (2 cm3) was
slowly added. The resulting mixture was warmed to Ϫ25 ЊC,
and was stirred for an additional 40 min. Water (2 cm3) was
added to the reaction mixture to quench the reaction. The sol-
vent was then removed in vacuo, and the aqueous layer was
extracted three times with Et2O. The combined extract was
washed with brine, dried (MgSO4) and concentrated in vacuo.
The residue was purified by flash chromatography (hexane–
EtOAc, 2 : 1) to give ester 27 (80 mg, 96%) as a colorless oil
(Found: C, 68.30; H, 9.94; N, 2.12. Calc. for C36H61NO6Si: C,
68.42; H, 9.73; N, 2.22%); [α]2D8 Ϫ24.1 (c 0.87, CHCl3);
νmax (neat)/cmϪ1 3354 (br), 1730, 1712, 1250, 860 and 837; δH
(300 MHz; CDCl3) 0.05 (s, 9 H), 0.91 (d, J = 6.8 Hz, 3H), 1.02
(t, J = 8.6 Hz, 2H), 1.09 (d, J = 6.8 Hz, 3H), 1.15–1.26 (m, 8H),
1.28 (d, J = 5.1 Hz, 3H), 1.50 (s, 3H), 1.64 (s, 3H), 2.09–2.23 (m,
2H), 2.68 (s, 2H), 2.97–3.18 (m, 2H), 3.43–3.65 (q and m, J =
7.1 Hz, 4H), 4.24 (t, J = 8.6 Hz, 2H), 4.56 (d, J = 5.6 Hz, 2H),
4.75 (q, J = 5.1 Hz, 2H), 5.19 (d, J = 6.8 Hz, 1H), 5.21 (dq, J =
10.4, 1.4 Hz, 1H), 5.30 (dq, J = 17.3, 1.4 Hz, 1H), 5.56 (dt, J =
15.1, 6.8 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 5.78 (d, J = 14.7 Hz,
1H), 5.92 (ddt, J = 10.7, 17.3, 5.6 Hz, 1H), 6.15–6.18 (m, 2H),
6.24 (dd, J = 10.7, 15.1 Hz, 1H) and 7.24 (ddt, J = 7.8, 14.7, 2.0
Hz, 1H); δC (75 MHz; CDCl3) Ϫ1.5, 14.1, 14.4, 15.0, 15.3, 15.8,
16.0, 17.3, 20.2, 20.4, 30.1, 30.3, 31.0, 33.1, 33.4, 40.1, 40.8,
46.8, 50.4, 59.7, 59.8, 60.3, 62.3, 65.3, 79.1, 80.1, 98.8, 99.8,
119.8, 119.9, 121.9, 122.3, 126.2, 126.3, 126.8, 127.9, 128.0,
132.2, 133.0, 134.4, 134.5, 134.9, 135.1, 144.7, 144.8, 146.3,
146.6, 156.3 and 167.3.
(6S,7S,18S)-20-Aza-6,10,12,18-tetramethyl-7-(trimethylsilyl-
oxy)cycloicosa-2,4,9,12,14-pentaenone (O-TMS-aglycone) 2
To a solution of compound 28 (21.1 mg, 4.91 × 10Ϫ2 mmol) in
MeOH (10 cm3) was added PPTS (8.0 mg, 3.2 × 10Ϫ2 mmol) at
rt. The reaction mixture was stirred for 5 h. The mixture
was treated with Et3N (0.30 cm3, 2.15 mmol) and concentrated
in vacuo. To an ice-cooled mixture of the residue in CH2Cl2
(7 cm3) containing DMAP (7.5 mg, 3.0 × 10Ϫ2 mmol) and Et3N
(1.00 cm3, 7.17 mmol) was added dropwise TMSCl (0.30 cm3,
2.36 mmol), and the reaction mixture was stirred for 45 min.
The reaction was quenched by addition of ice–water and the
resulting mixture was extracted twice with Et2O. The combined
extract was washed successively with saturated aq. NaHCO3
and brine, dried (MgSO4) and concentrated in vacuo. The resi-
due was purified by flash column chromatography (hexane–
EtOAc, 7 : 1 to 4 : 1) to afford title compound 2 (19.5 mg, 92%);
Methyl 3-O-acetyl-2,4,6-trideoxy-4-[fluoren-9-ylmethoxy-
carbonyl(methyl)amino]-ꢀ-D-ribo-hexopyranoside 30
(6S,7S,18S)-20-Aza-6,10,12,18-tetramethyl-7-(1-ethoxy-
ethoxy)cycloicosa-2,4,9,12,14-pentaenone (O-EE-aglycone) 28
To an ice-cooled solution of compound 299 (128.5 mg, 3.23 ×
10Ϫ1 mmol) and DMAP (65 mg, 5.3 × 10Ϫ1 mmol) in pyridine
(4.0 cm3) was added Ac2O (0.50 cm3, 5.30 mmol) and the mix-
ture was stirred at rt for 1 h. The reaction was quenched by
addition of ice–water at 0 ЊC and the resulting mixture was
stirred for several minutes at rt, and extracted twice with Et2O.
The combined extract was washed successively with water,
saturated aq. NaHCO3 and brine, dried (MgSO4) and con-
centrated in vacuo. The residue was purified by flash column
chromatography (hexane–EtOAc, 5 : 1 to 2 : 1) to afford acetate
To a solution of ester 27 (140.7 mg, 2.23 × 10Ϫ1 mmol) and
1,3-dimethylbarbituric acid (228 mg, 1.46 mmol) in THF
(15 cm3) was added tetrakis(triphenylphosphine)palladium
(43.9 mg, 3.79 × 10Ϫ2 mmol, 17 mol%), and the resulting
mixture was stirred at rt for 27 h. The mixture was then poured
into saturated aq. NaHCO3 and extracted four times with Et2O.
The combined extract was dried (MgSO4) and concentrated
in vacuo. The residue was purified by chromatography (CHCl3–
MeOH, 20 : 1 to 2 : 1) to give the corresponding free amino
ester as a colorless oil (79.5 mg, 65%) {LRFABMS (NBA
matrix) m/z, 548.3 [(M ϩ H)ϩ; Calc. for C32H58NO4Si: m/z
548.1]}; νmax (neat)/cmϪ1 2958, 1701, 1215 and 758; δH (300
MHz; CDCl3) 0.05 (s, 9 H), 0.92 (d, J = 6.3 Hz, 3H), 0.99–1.10
(m, 8H), 1.18 (t, J = 7.1 Hz, 3H), 1.28 (d, J = 5.1 Hz, 3H), 1.50
(s, 3H), 1.64 (s, 3H), 1.90 (br s, 2H), 2.10–2.25 (m, 3H), 2.48–
2.74 (m, 4H), 3.46–3.64 (m, 3H), 4.23 (t, J = 8.5 Hz, 2H), 4.73
(dq, J = 5.3, 15.1 Hz, 1H), 5.58 (dt, J = 6.8, 15.1 Hz, 1H), 5.78
(d, J = 10.7 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 5.79 (d, J =
14.7 Hz, 1H), 6.12–6.18 (m, 2H), 6.25 (dd, J = 10.7, 15.1 Hz,
1H) and 7.24 (ddt, J = 14.7, 7.8, 2.0 Hz, 1H).
30 as
a colorless, amorphous solid (126.3 mg, 89%)
{HRFABMS (NBA matrix) m/z 440.2112 [(M ϩ H)ϩ; Calc. for
C25H30NO6: m/z, 440.2073]}; mp 95.5–98.0 ЊC; [α]2D6 ϩ 162 (c
0.585, CHCl3); νmax (CHCl3)/cmϪ1 1736, 1693, 1321, 1252, 1128
and 1066; δH (500 MHz; CDCl3) 1.02 (d, J = 6.2 Hz, 3H, H-6),
1.17 (d, J = 6.3 Hz, 3H, H-6), 1.57 (ddd, J = 3.9, 3.9, 15.2 Hz,
1H, H-2ax), 1.96 (ddd, J = 4.1, 4.1, 15.3 Hz, 1H, H-2ax), 2.00 (s,
3H, Ac), 2.06 (s, 3H, Ac), 2.07 (dd, J = 2.2, 15.2 Hz, 1H, H-2eq),
2.19 (dd, J = 2.3, 15.3 Hz, 1H, H-2eq), 2.78 (s, 3H, NMe), 2.80 (s,
3H, NMe), 3.30 (s, 3H, OMe), 3.34 (s, 3H, OMe), 3.39 (dd, J =
2.7, 10.1 Hz, 1H, H-4), 4.03 (br s, 1H, H-4), 4.17–4.24 (m, 1H,
H-5), 4.21–4.27 (m, 2H, Fmoc CH2), 4.33 (br s, 1H, H-5), 4.47
(d, J = 6.7 Hz, 2H, Fmoc CH2), 4.48–4.53 (m, 1H, Fmoc CH ),
4.59 (d, J = 4.2 Hz, 1H, H-1), 4.61–4.67 (m, 2H, H-3 and Fmoc
CH ), 4.67 (d, J = 4.2 Hz, 1H, H-1), 5.08 (ddd, J = 2.2, 2.3, 4.1
Hz, 1H, H-3), 7.28–7.35, (m, 4H, Fmoc Ar), 7.36–7.42 (m, 4H,
Fmoc Ar), 7.51–7.60 (m, 4H, Fmoc Ar) and 7.73–7.77 (m, 4H,
Fmoc Ar); δC (126 MHz; CDCl3) 18.2, 18.3, 21.4, 21.5, 31.1,
33.3, 33.5, 47.26, 47.32, 55.2, 57.7, 60.4, 60.6, 66.9, 67.3, 70.3,
To an ice-cooled solution of the amino ester (79.5 mg, 1.45 ×
10Ϫ1 mmol) in THF (10 cm3) was added TBAF (0.40 cm3 of
1.0 M THF solution, 4.0 × 10Ϫ1 mmol). After being stirred at rt
for 24 h, the mixture was poured into water and extracted six
times with CHCl3. The combined extract was dried (MgSO4)
and concentrated in vacuo. The residue was used for the next
step without further purification.
956
J. Chem. Soc., Perkin Trans. 1, 2002, 949–958

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97.1, 97.3, 119.8, 119.9, 124.5, 124.6, 124.8, 124.9, 126.96,
126.98, 127.0, 127.1, 127.6, 141.25, 141.27, 141.3, 143.8, 143.9,
156.1, 156.6, 170.16 and 170.25.
To a solution of 3Ј-O-acetyl-4Ј-N-Fmoc-vicenistatin (12.3
mg, 1.60 × 10Ϫ2 mmol) in EtOAc (5 cm3) was added DBU
(20 mm3, 1.3 × 10Ϫ1 mmol), and the mixture was stirred for
0.5 h at rt. The mixture was diluted with EtOAc and washed
with saturated aq. NaHCO3. The aqueous washings were
extracted twice with EtOAc. The combined extract was dried
(MgSO4) and concentrated in vacuo. The residue was purified
by PLC (benzene–acetone, 25 : 4) to afford 3Ј-O-acetyl-
vicenistatin 32 (4.0 mg, 46%) and its α-anomer (4.0 mg, 46%);
δH (500 MHz; CDCl3) 0.95 (d, J = 6.9 Hz, 3H, H-23), 1.05 (d,
J = 6.6 Hz, 3H, H-20), 1.32 (d, J = 6.2 Hz, 3H, H-6Ј), 1.41–1.47
(m, 2H, H-17), 1.54 (s, 3H, H-21), 1.65–1.75 (m, 1H, H-18),
1.74 (ddd, J = 2.9, 9.9, 14.2 Hz, 1H, H-2Ј), 1.77 (s, 3H, H-22),
2.01–2.10 (m, 1H, H-16), 2.12 (s, 3H, Ac), 2.14 (ddd, J = 2.1,
3.3, 14.2 Hz, 1H, H-2Ј), 2.21–2.28 (m, 2H, H-8 and H-16), 2.28
(dd, J = 3.0, 9.7 Hz, 1H, H-4Ј), 2.32–2.38 (m, 1H, H-6), 2.39 (s,
3H, NMe), 2.58 (d, J = 14.7 Hz, 1H, H-11), 2.66 (d, J = 14.7 Hz,
1H, H-11), 2.60–2.70 (m, 1H, H-8), 3.10 (ddd, J = 4.2, 8.3, 13.6
Hz, 1H, H-19), 3.26 (ddd, J = 1.6, 7.8, 9.3 Hz, 1H, H-7), 3.39
(ddd, J = 7.6, 9.8, 13.6 Hz, 1H, H-19), 3.65 (dq, J = 6.2, 9.7 Hz,
1H, H-5Ј), 4.74 (dd, J = 1.8, 9.8 Hz, 1H, H-1Ј), 5.09 (dd, J = 7.1,
7.1 Hz, 1H, H-9), 5.42 (ddd, J = 3.0, 3.0, 3.0 Hz, 1H, H-3Ј), 5.56
(ddd, J = 7.3, 7.3, 14.7 Hz, 1H, H-15), 5.62 (dd, J = 4.3, 7.1 Hz,
1H, NH-19), 5.69 (d, J = 15.2 Hz, 1H, H-2), 5.74 (d, J =
11.0 Hz, 1H, H-13), 5.75 (dd, J = 9.5, 15.2 Hz, 1H, H-5), 6.05
(dd, J = 10.9, 15.2 Hz, 1H, H-4), 6.33 (dd, J = 11.0, 15.1 Hz, 1H,
H-14) and 6.95 (dd, J = 10.9, 15.1 Hz, 1H, H-3); δC (126 MHz;
CDCl3) 17.16, 17.19, 18.4, 18.7, 19.1, 21.1, 28.5, 33.3, 33.6,
34.0, 35.2, 36.2, 43.7, 45.0, 49.3, 62.8, 67.5, 70.9, 85.4, 99.7,
121.9, 123.8, 126.2, 128.0, 128.3, 132.5, 134.3, 134.7, 139.4,
142.5, 166.0 and 170.3.
1,3-Di-O-acetyl-2,4,6-trideoxy-4-[fluoren-9-ylmethoxycarbonyl-
(methyl)amino]-ꢀ-D-ribo-hexopyranose 31
A solution of glycoside 30 (122.5 mg, 2.79 × 10Ϫ1 mmol) in
AcOH (8.2 cm3) and water (1.7 cm3) was heated at around 95 ЊC
for 2.5 h. The reaction mixture was evaporated in vacuo with
an aid of azeotropic distillation with toluene. To a solution of
the obtained crude hemiacetal and DMAP (3.2 mg, 2.6 ×
10Ϫ2 mmol) in pyridine (2.0 cm3) was added Ac2O (0.25 mm3,
2.65 mmol) and the mixture was stirred at rt for 1 h. The reac-
tion was quenched by addition of ice–water at 0 ЊC and the
resulting mixture was stirred for several minutes at rt, and
extracted twice with Et2O. The combined extract was washed
successively with water, saturated aq. NaHCO3 and brine,
dried (MgSO4) and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (hexane–EtOAc, 5 : 1 to
2 : 1) to afford diacetate 31 as a colorless powder (125.9 mg,
97%) {HRFABMS (NBA matrix) m/z 468.2026 [(M ϩ H)ϩ;
Calc. for C26H30NO7: m/z, 468.2022]}; mp 50.0–55.0 ЊC;
[α]2D6 ϩ79 (c 0.530, CHCl3); νmax (CHCl3)/cmϪ1 1743, 1697, 1317,
1240 and 1066; δH (500 MHz; CDCl3) 0.96 (d, J = 6.2 Hz, 3H,
H-6), 1.06 (br d, J = 5.2 Hz, 3H, H-6), 1.16 (d, J = 6.2 Hz, 3H,
H-6), 1.20 (d, J = 6.1 Hz, 3H, H-6), 1.55 (ddd, J = 3.0, 10.6,
13.8 Hz, 1H, H-2ax), 1.55–1.61 (m, 1H, H-2), 1.91–1.98 (m, 1H,
H-2), 1.93–1.98 (m, 1H, H-2), 2.01 (s, 3H, Ac), 2.04 (s, 6H, Ac),
2.076 (s, 3H, Ac), 2.078 (s, 3H, Ac), 2.09 (s, 3H, Ac), 2.10 (s, 3H,
Ac), 2.11 (s, 3H, Ac), 2.03–2.12 (m, 2H, H-2 × 2), 2.07–2.13 (m,
1H, H-2), 2.22–2.27 (m, 1H, H-2), 2.73 (s, 3H, NMe × 2), 2.76
(s, 3H, NMe), 2.78 (s, 3H, NMe), 3.28 (dd, J = 2.5, 10.3 Hz, 1H,
H-4), 3.35 (br d, J = 8.8 Hz, 1H, H-4), 4.01 (br s, 1H, H-4), 4.12
(br s, 2H, H-4 and H-5), 4.21–4.28 (m, 3H, Fmoc CH × 2 and
H-5), 4.21–4.30 (m, 3H, Fmoc CHH × 2 and H-5), 4.40–4.47
(m, 1H, H-5), 4.46–4.52 (m, 4H, Fmoc CH × 2 and Fmoc
CHH × 2), 4.52–4.59 (m, 1H, Fmoc CHH), 4.54–4.60 (m, 1H,
Fmoc CHH), 4.55–4.60 (m, 1H, H-3), 4.65 (dd, J = 5.1, 10.7 Hz,
1H, Fmoc CHH), 4.70 (dd, J = 4.7, 10.7 Hz, 1H, Fmoc CHH),
4.82 (br s, 1H, H-3), 5.14 (br q, J = 2.2 Hz, 1H, H-3), 5.34 (br q,
J = 2.8 Hz, 1H, H-3), 5.82 (br d, J = 10.0 Hz, 1H, H-1), 5.94 (dd,
J = 2.1, 10.2 Hz, 1H, H-1), 6.00 (d, J = 4.0 Hz, 1H, H-1), 6.10 (d,
J = 4.0 Hz, 1H, H-1), 7.29–7.36 (m, 8H, Fmoc Ar), 7.37–7.43
(m, 8H, Fmoc Ar), 7.51–7.59 (m, 8H, Fmoc Ar) and 7.74–7.79
(m, 8H, Fmoc Ar); δC (126 MHz; CDCl3) 18.2, 18.4, 18.5, 21.02,
21.03, 21.06, 21.1, 21.2, 21.3, 30.8, 30.9, 32.4, 32.7, 34.9, 35.1,
47.26, 47.33, 47.4, 57.3, 57.7, 63.1, 63.3, 66.8, 67.1, 67.4, 68.6,
68.7, 69.8, 70.9, 71.1, 90.0, 90.2, 90.3, 90.4, 119.88, 119.90,
119.93, 119.95, 120.0, 124.36, 124.42, 124.45, 124.52, 124.81,
124.83, 127.00, 127.02, 127.08, 127.10, 127.2, 127.5, 127.65, 127.67,
127.73, 141.3, 141.4, 143.78, 143.81, 143.88, 143.90, 155.9, 156.0,
156.6, 169.17, 169.19, 169.3, 169.4, 169.56, 169.61 and 169.7.
To a solution of acetate 32 (4.3 mg, 7.9 × 10Ϫ3 mmol) in
MeOH (5 cm3) was added 5.0 M KOH (3.0 cm3, 15 mmol)
and the mixture was stirred at rt for 3 days. The reaction
mixture was evaporated, and the residue was dissolved in a
minimum amount of water and extracted three times with
EtOAc. The combined extract was dried (MgSO4) and con-
centrated in vacuo. The residue was purified by PLC (CHCl3–
MeOH, 3 : 1) to afford vicenistatin 1 (3.3 mg, 83%);
{HRFABMS (NBA matrix) m/z 501.3698 [(M ϩ H)ϩ; Calc.
for C30H49N2O4: m/z, 501.3692]}; δH (500 MHz; pyridine-d5)
0.84 (d, J = 6.9 Hz, 3H, H-23), 1.08 (d, J = 6.6 Hz, 3H, H-20),
1.42–1.50 (m, 1H, H-17), 1.51–1.63 (m, 1H, H-17), 1.52 (d, J
= 6.2 Hz, 3H, H-6Ј), 1.70 (s, 3H, H-21), 1.80–1.88 (m, 1H, H-
18), 1.91 (ddd, J = 3.0, 10.1, 13.1 Hz, 1H, H-2Јax), 1.95 (s, 3H,
H-22), 2.02–2.10 (m, 1H, H-16), 2.24 (dd, J = 2.9, 9.6 Hz, 1H,
H-4Ј), 2.27 (ddd, J = 8.4, 8.4, 13.9 Hz, 1H, H-8), 2.33–2.43
(m, 1H, H-16), 2.37–2.45 (m, 1H, H-6), 2.41 (s, 3H, NMe),
2.38–2.48 (m, 1H, H-2Јeq), 2.62 (d, J = 15.1 Hz, 1H, H-11),
2.74 (d, J = 15.1 Hz, 1H, H-11), 3.03 (ddd, J = 2.8, 4.7, 13.4
Hz, 1H, H-19), 3.09 (dd, J = 8.3, 13.8 Hz, 1H, H-8), 3.37 (dd,
J = 8.8, 8.8 Hz, 1H, H-7), 4.01 (dq, J 6.2, 9.7 Hz, 1H, H-5Ј),
3.98–4.07 (m, 1H, H-19), 4.39 (ddd, J = 2.9, 2.9, 2.9 Hz, 1H,
H-3Ј), 5.20 (dd, J = 7.5, 7.5 Hz, 1H, H-9), 5.30 (dd, J = 1.7,
9.6 Hz, 1H, H-1Ј), 5.69 (ddd, J = 5.2, 9.3, 14.7 Hz, 1H, H-15),
5.86 (dd, J = 9.6, 15.1 Hz, 1H, H-5), 5.96 (d, J = 11.0 Hz, 1H,
H-13), 6.21 (dd, J = 11.3, 15.2 Hz, 1H, H-4), 6.26 (d, J = 15.0
Hz, 1H, H-2), 6.80 (dd, J = 11.1, 14.9 Hz, 1H, H-14), 7.60
(dd, J = 11.2, 15.0 Hz, 1H, H-3), 8.49 (dd, J = 2.1, 9.2 Hz,
1H, NH); δC (126 MHz; pyridine-d5) 17.3, 17.7, 17.9, 18.7,
19.5, 27.7, 32.7, 33.5, 34.0, 36.6, 39.4, 43.1, 46.3, 49.3, 63.2,
65.2, 70.5, 86.0, 100.8, 122.0, 124.6, 128.0, 128.4, 128.4, 132.6,
134.0, 135.1, 140.3, 143.3 and 166.3.
Vicenistatin [(6S,7S,18S)-20-aza-6,10,12,18-tetramethyl-7-O-
(2Ј,4Ј,6Ј-trideoxy-4Ј-methylamino-ꢁ-D-ribo-hexopyranosylcyclo-
icosa-2,4,9,12,14-pentaenone] 1
To a suspension of AgClO4 (7.0 mg, 3.4 × 10Ϫ2 mmol) in dry
CH2Cl2 (5 cm3) was added dropwise SnCl4 (35 mm3; 1 M in
CH2Cl2, 3.5 × 10Ϫ2 mmol) at rt. The mixture was shielded from
light and stirred for 1 h. To the ice-cooled mixture was added
dropwise a solution of 31 (46.4 mg, 9.92 × 10Ϫ2 mmol) and 2
(19.5 mg, 4.53 × 10Ϫ2 mmol) in dry CH2Cl2 (2.4 cm3), and the
whole was stirred for 1 h. The mixture was treated with satur-
ated aq. NaHCO3 and extracted twice with Et2O. The combined
extract was dried (MgSO4) and concentrated in vacuo. The
residue was purified by PLC (hexane–EtOAc, 1 : 1) to afford
3Ј-O-acetyl-4Ј-N-Fmoc-vicenistatin (20.6 mg, 59%; mixture of
α- and β-anomer), which was used for the next step without
further purification.
Acknowledgements
We thank Dr K. Shindo of Kirin Brewery Co. Ltd. for kindly
supplying natural vicenistatin. (S)-Citronellal was kindly pro-
vided by Takasago International Co. Ltd. This work was sup-
ported partly by the ‘Research for the Future’ Programme of
J. Chem. Soc., Perkin Trans. 1, 2002, 949–958
957

View Article Online
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