Synthetic studies of nucleoside antibiotics: A formal synthesis of (+)-sinefungin

Article abstract of DOI:10.1039/a907228d

A formal synthesis of (+)-sinefungin 1 is described. The C-6′ and C-9′ stereogenic centers of sinefungin were constructed stereoselectively by efficient catalytic asymmetric syntheses. The key strategy for the construction of the C-6′ stereocenter involve

Full text of DOI:10.1039/a907228d

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Synthetic studies of nucleoside antibiotics: a formal synthesis
of (؉)-sinefungin
Arun K. Ghosh* and Yong Wang
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago,
Illinois 60607, USA
Received (in Cambridge, UK) 7th September 1999, Accepted 12th October 1999
A formal synthesis of (ϩ)-sinefungin 1 is described. The C-6Ј and C-9Ј stereogenic centers of sinefungin were
constructed stereoselectively by efficient catalytic asymmetric syntheses. The key strategy for the construction
of the C-6Ј stereocenter involves alkylation of a protected ribose-derived triflate with alkynyl-lithium, Sharpless
asymmetric epoxidation of the corresponding allylic alcohol followed by a regioselective epoxide-ring opening
with diisopropoxytitanium diazide. The C-9 amino acid stereochemistry was established by a rhodium chiral
bisphosphine-catalyzed asymmetric hydrogenation of an α-(acylamino)acrylate derivative. The resulting amino
acid derivative has been previously converted to (ϩ)-sinefungin 1.
Sinefungin 1, a novel nucleoside antibiotic isolated from
Streptomyces grisoleus,1 has shown many important biological
properties including antifungal, antitumor, antiparasitic and
antiviral activities.2 The biological properties of sinefungin
stem from inhibition of the S-adenoylmethionine (SAM)-
dependent methyl transferase enzymes.3 Clinical use of natural
sinefungin is restricted because of its severe in vivo toxicity.4
Thus, total synthesis, structural modifications and biology of
sinefungin derivatives have become the subject of much interest
over the years. A number of total syntheses of sinefungin have
been reported incorporating various strategies for stereocontrol
at the C-6Ј asymmetric center.5,6 The synthetic efforts towards
sinefungin subsequently led to the preparation of several
structural analogues of sinefungin.7 Recently, we have
described a stereoselective synthesis of sinefungin in which
both the C-6Ј and C-9Ј remote chiral centers were constructed
by asymmetric syntheses.8 As part of our continuing interest in
sinefungin chemistry, we have now devised a stereocontrolled
route to a sinefungin intermediate which has been previously
converted to sinefungin by us. The key steps involve an efficient
carbon–carbon bond formation between a protected ribose-
derived triflate and an alkynyl-lithium, Sharpless asymmetric
epoxidation of the corresponding allylic alcohol, followed by
a regio- and stereoselective epoxide-ring-opening reaction. The
C-9Ј amino acid stereochemistry was established by an asym-
metric hydrogenation of the corresponding α-(acylamino)-
acrylate derivative.
Scheme 1 Reagents, conditions (and yields): (a) Tf2O, 2,6-lutidine,
᎐
Ϫ78 to 23 ЊC, 1 h; (b) TBDMSOCH2C᎐CLi, THF, DMPU, Ϫ78 to
᎐
Ϫ20 ЊC, 2 h (86%); (c) n-Bu4NF, THF, 0 ЊC, 30 min; (d) LAH, THF,
t
50 ЊC, 2 h (77%); (e) BuOOH, Ti(OiPr)4, (ϩ)-DET, CH2Cl2, Ϫ23 ЊC,
24 h (88%); (f) Ti(N3)2(OiPr)2, PhH, 75 ЊC, 15 min (95%).
required carbon–carbon bond formation was accomplished by
the reaction of the 5Ј-O-triflate of the methyl glycoside 2 and
the prop-2-ynyloxysilane-derived alkynyl-lithium tBuMe2-
᎐
SiOCH C᎐CLi which proceeded smoothly in THF in the
᎐
2
presence of 1,3-dimethylpropyleneurea (DMPU) at Ϫ78 to
Ϫ20 ЊC and after 2 h provided the alkyne derivative 3 in
86% yield. The use of HMPA instead of DMPU resulted in
significantly lower yield (55%).10 The removal of the TBDMS
group by treatment with n-Bu4NF in THF at 0 ЊC, followed by
LAH reduction of the resulting alkyne in THF at 50 ЊC for
2 h, furnished exclusively the E-allylic alcohol 4 in 77%
yield. Sharpless asymmetric epoxidation of 4 with (ϩ)-diethyl
Results and discussion
As shown in Scheme 1, the known9 methyl glycoside 2 was
readily converted to prop-1-ynyl (propargyl) derivative 3. The
J. Chem. Soc., Perkin Trans. 1, 1999, 3597–3601
This journal is © The Royal Society of Chemistry 1999
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tion of the urethane NH is necessary for anomeric adenosyl-
ation.8 Thus, reaction of 9 with sodium hydride and benzyl
bromide in the presence of a catalytic amount of n-Bu4NI
furnished the N-benzylurethane 10 in 99% yield.
The olefin 10 was hydroborated with borane in THF to
furnish alcohol 11 after oxidative work-up with alkaline hydro-
gen peroxide. Swern oxidation of 11, followed by immediate
exposure of the resulting aldehyde to a Horner–Emmons olefin-
ation with the enolate derived from ethyl N-acetyl-α-(diethoxy-
phosphoryl)glycinate15 and potassium bis(trimethylsilyl)amide
in THF at Ϫ78 to 23 ЊC for 1 h, afforded a 1:5.4 mixture of E-
and Z-enamide 12 and 13 in 79% yield (from 11). This pro-
cedure is operationally simple and provided an improvement of
yield over the previous conditions.8 It has been previously dem-
onstrated that (cycloocta-1,5-diene)-[(R,R)-1,2-ethanediylbis-
[(O-methoxyphenyl)phenylphosphine]]rhodium tetrafluorobo-
rate [[Rh(COD)(R,R-DIPAMP)2]ϩBF4Ϫ] catalyst converts both
E- and Z-enamides to an (S)-α-amino acid enantioselectively.16
The E and Z isomers 12 and 13 were then exposed to asym-
metric hydrogenation in the presence of [Rh(COD)(R,R-
Ϫ
DIPAMP)2]ϩBF4 (10 mol%) catalyst17 in methanol under 50
psi hydrogen pressure at 23 ЊC for 12 h to establish the C-9Ј
stereocenter (9S-isomer) stereoselectively. The amino acid
derivative 14 {[α]D23 ϩ22.6,† (c 1.33, CHCl3)} was isolated in 94%
yield. The physical characteristics of the amino acid derivative
14 are identical with the sample made by us previously.8 The 1H
NMR spectrum of 14 revealed the presence of a 4:1 mixture
of rotational isomers; however, at coalescence temperature
(Tc ≈ 70 ЊC in DMSO-d6) the mixture of peaks merged into one
sharp spectrum. The methyl glycoside 14 has been previously
converted to (ϩ)-sinefungin by us.8 The sequence of reactions
involved the removal of isopropylidene protection and the
methyl acetal by treatment with aq. HCl in 1,4-dioxane, fol-
lowed by reaction of the triol with acetic anhydride in pyridine
to provide the triacetate (70%). Anomeric adenosylation with
bis-silyl-N-benzoyladenine and TMSOTf afforded the corre-
sponding β-nucleoside (93%). Finally, removal of various pro-
tecting groups by a one-pot, three-step procedure involving:
(1) reaction with K2CO3 in MeOH; (2) removal of methanol
and exposure to aq. hydrazine and, (3) catalytic hydrogenation
over Pearlman’s catalyst [20% Pd(OH)2 on carbon] provided
(ϩ)-sinefungin 1 after silica gel chromatography (72%).8
Thus a formal stereoselective synthesis of (ϩ)-sinefungin has
been accomplished. Our approach utilizes an efficient chain
elongation of a protected ribose derivative, Sharpless epoxid-
ation, regio- and stereoselective epoxide opening, and an
efficient catalytic hydrogenation. The synthesis is amenable to
the preparation of a variety of sinefungin analogues for further
biological studies.
Scheme 2 Reagents, conditions (and yields): (a) H2, 10% Pd–C,
MeOH, 6 h; (b) CbzCl, NaHCO3, 23 ЊC, 12 h (90%); (c) Ph2PC1, imid-
azole, I2, PhMe–MeCN (2:1), 90 ЊC, 4 h (69%); (d) NaH, PhCH2Br,
n-Bu4NI (cat.), THF, 23 ЊC, 12 h (99%); (e) BH3ؒTHF, THF, 23 ЊC,
1 h; then 30% H2O2, NaOH (57%); (f) DMSO, (COC1)2, CH2Cl2, Ϫ60
to Ϫ50 ЊC, 30 min; then Pr2NEt; (g) (TMS)2NK, THF, 18-crown-6,
(EtO)2P(O)CH(NHAc)CO2Et, Ϫ78 to 23 ЊC, 1 h (79%); (h) H2,
[Rh(COD)(R,R-DIPAMP)2]BF4, 50 psi, MeOH, 23 ЊC, 12 h (94%).
i
-tartrate [(ϩ)-DET] at Ϫ23 ЊC over 24 h provided the syn-
epoxide 5 stereoselectively (diastereomeric ratio 96:4 by 400
1
MHz H NMR) in 88% yield.11 Whereas the MCPBA epoxid-
Experimental
ation of a ribose-derived allylic alcohol bearing an allylic
asymmetric center can provide excellent stereocontrol, the
epoxidation of allylic alcohol 4 containing a more remote chiral
center resulted in a 2:1 mixture of diastereomers.12 To install
the C-6Ј amine functionality, epoxide 5 was exposed to a regio-
and stereoselective azide-induced opening reaction as described
by Sharpless and co-workers.13 Thus, treatment of epoxide 5
with diisopropoxytitanium() diazide in benzene at 75 ЊC
for 15 min afforded the azido diols 6 and 7 as an inseparable
mixture (19:1) in 95% combined yield. This mixture was
subjected to catalytic hydrogenation over 10% Pd–C and the
resulting amines were treated with benzyl chloroformate in
the presence of aq. NaHCO3 to afford the Cbz-derivative 8,
after silica gel chromatography (Scheme 2). The vicinal diol
functionality of 8 was transformed into the corresponding
olefin by reaction with chlorodiphenylphosphine, imidazole
and iodine in a mixture of toluene and acetonitrile (2:1) at
90 ЊC for 4 h.14 The olefin 9 was obtained in 69% yield after
silica gel chromatography. As described previously, the protec-
All mps were recorded on a Thomas-Hoover capillary melting
1
point apparatus and are uncorrected. H NMR and 13C NMR
spectra were recorded on Bruker AM-400, DPX-400, DRX-
500, and Varian VXR-300S spectrometers using tetramethyl-
silane as the internal standard. IR spectra were recorded on
a
Matteson Genesis FT-IR spectrometer. Mass spectra
were recorded on a Finnigan LCQ mass spectrometer. Optical
rotations were measured on a Perkin-Elmer 241 spectro-
polarimeter.† Anhydrous solvents were obtained as follows:
dichloromethane and benzene, distillation from CaH2; THF,
distillation from sodium and benzophenone. All other solvents
were HPLC grade. Column chromatography was performed
with Whatman 240–400 mesh silica gel under a low positive
pressure of 5–10 psi.‡ TLC was carried out with E. Merck silica
gel 60-F-254 plates.
† [α]D-Values are given in units of 10Ϫ1 deg cm2 gϪ1
‡ 1 psi = 6894.7 Pa.
.
3598
J. Chem. Soc., Perkin Trans. 1, 1999, 3597–3601

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Methyl 8-O-(tert-butyldimethylsilyl)-5,6,7-trideoxy-2,3-O-iso-
propylidene-ꢀ-D-ribo-oct-6-ynofuranoside 3
213 (Mϩ Ϫ OMe); HRMS (FAB) Calc. for C12H20O5: m/z
244.1311. Found: m/z 244.1319.
To a stirred solution of tert-butyldimethyl(prop-2-ynyloxy)-
silane (6.30 g, 36.9 mmol) in THF (20 mL) at Ϫ78 ЊC was added
n-BuLi (23 mL, 36.9 mmol; 1.6 M in hexane) dropwise under
nitrogen atmosphere. The resulting mixture was warmed to 0 ЊC
and stirred at this temperature for an additional 2 h before use
in the following alkylation step.
Methyl 6,7-anhydro-5-deoxy-2,3-O-isopropylidene-L-glycero-ꢀ-
D-allo-octofuranoside 5
To a suspension of powdered 4 Å molecular sieves (1.20 g) in
CH2Cl2 (25 mL) at Ϫ23 ЊC were sequentially added Ti(OiPr)4
(0.28 mL, 0.95 mmol) and (ϩ)-DET (0.2 mL, 1.2 mmol) under a
nitrogen atmosphere. The resulting mixture was stirred for 15
min at Ϫ23 ЊC and a solution of alcohol 4 (1.12 g, 4.57 mmol)
in CH2Cl2 (2 mL) was added dropwise. The mixture was stirred
for a further 15 min, and tert-butyl hydroperoxide (2.8 mL; 5 M
in n-decane) was added dropwise. The resulting mixture was
stirred at Ϫ23 ЊC for 30 min and then put into a freezer at
Ϫ23 ЊC for 24 h. After this period, aq. NaOH (4 M) buffered
with NaCl (5 mL) was added and the mixture was stirred at 0 ЊC
for 1 h. The mixture was filtered through a Celite pad, and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (3 × 15 mL). The organic layers were combined,
washed with brine, dried over anhydrous Na2SO4 and evapor-
ated. The resulting residue was chromatographed on silica gel
(50% EtOAc–hexanes) to furnish the epoxide 5 (Rf 0.20, 50%
EtOAc–hexanes) as a colorless oil (1.05 g, 88%); [α]D23 Ϫ56.6 (c
1.37, CHCl3); 1H NMR (400 MHz; CDCl3) δ 4.91 (s, 1 H), 4.57
(d, 1 H, J 5.9 Hz), 4.54 (d, 1 H, J 5.9 Hz), 4.25 (dd, 1 H, J 8.5,
6.0 Hz), 3.83 (dd, 1 H, J 12.6, 2.7 Hz), 3.58 (dd, 1 H, J 12.6, 4.5
Hz), 3.30 (s, 3 H), 3.04–3.00 (m, 1 H), 2.98–2.96 (m, 1 H), 2.59
(br s, 1 H), 1.99–1.91 (m, 1 H), 1.75–1.69 (m, 1 H), 1.42 (s, 3 H),
1.26 (s, 3 H); 13C NMR (100 MHz; CDCl3) δ 112.4, 109.5, 85.3,
84.2, 83.8, 61.5, 57.9, 54.8, 53.1, 36.5, 26.3, 24.8; MS (ESI) m/z
283 (Mϩ ϩ Na) (Calc. for C12H20O6: C, 55.33; H, 7.75%. Found:
C, 55.60; H, 7.67).
In a separate flask, a solution of 2,6-dimethylpyridine (2,6-
lutidine) (1.6 mL, 13.5 mmol) in CH2Cl2 (20 mL) was stirred at
Ϫ78 ЊC and Tf2O (2.2 mL, 12.9 mmol) was added dropwise over
a period of 5 min. The resulting green solution was stirred for
5 min and a solution of alcohol 2 (2.51 g, 12.3 mmol) in CH2Cl2
(4 mL) was added. The resulting mixture was stirred at Ϫ78 ЊC
for 1 h, the cooling bath was removed, and the mixture was
allowed to warm to 23 ЊC. The mixture was evaporated under
reduced pressure and the residue was dissolved in a mixture of
THF and DMPU (2:1; 15 mL). The resulting solution was
cooled to Ϫ78 ЊC. The above alkynyl-lithium solution was
taken up in a syringe and was added to the triflate solution
dropwise over a period of 5 min. Stirring was continued at
Ϫ78 ЊC for 1 h and the reaction mixture was warmed to Ϫ20 ЊC
and stirred at this temperature for an additional 1 h. The
reaction mixture was quenched with saturated aq. NH4Cl and
the solution was allowed to warm to 23 ЊC. The reaction
mixture was thoroughly extracted with EtOAc (3 × 50 mL) and
the combined organic extracts were dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The residue
was chromatographed on silica gel (10% EtOAc–hexanes) to
afford 3 (Rf 0.85, 25% EtOAc–hexanes) as a colorless oil (3.74 g,
1
86%); [α]D23 Ϫ46 (c 2.30, CHCl3); H NMR (200 MHz; CDCl3)
δ 4.92 (s, 1 H), 4.67 (d, 1 H, J 5.9 Hz), 4.57 (d, 1 H, J 5.9 Hz),
4.30–4.22 (m, 3 H), 3.30 (s, 3 H), 2.51–2.43 (m, 2 H), 1.44
(s, 3 H), 1.28 (s, 3 H), 0.88 (s, 9 H), 0.08 (s, 6 H); 13C NMR
(50 MHz; CDCl3) δ 112.1, 109.6, 85.1, 85.1, 83.2, 80.7, 80.5,
54.6, 51.7, 26.2, 25.7, 24.8, 24.8, 18.2, Ϫ5.3; MS (CI) m/z 355
(Mϩ Ϫ H), 325 (Mϩ Ϫ OMe) (Calc. for C18H32O5Si: C, 60.64;
H, 9.05%. Found: C, 60.56; H, 9.08).
Methyl 6-azido-5,6-dideoxy-2,3-O-isopropylidene-L-glycero-ꢁ-L-
talo-octofuranoside 6
To a stirred solution of Ti(OiPr)4 (1.55 mL, 5.22 mmol) in dry
benzene (30 mL) was added TMSN3 (1.39 mL, 10.44 mmol).
The resulting mixture was heated at 75 ЊC for 12 h. After this
period, a solution of epoxide 5 (905 mg, 3.48 mmol) in benzene
(3 mL) was added at 75 ЊC. The resulting mixture was stirred for
15 min, and the mixture was cooled to 23 ЊC. The reaction
mixture was then concentrated under reduced pressure and the
residue was diluted with THF (5 mL). Aq. potassium sodium
tartrate (20%; 5 mL) was added and the resulting mixture was
stirred vigorously at 23 ЊC for 2 h. After this period, the suspen-
sion was diluted with EtOAc (5 mL), filtered through Celite and
the layers were separated. The aqueous layer was extracted with
EtOAc (2 × 10 mL). The organic layers were combined, washed
with brine, dried over anhydrous Na2SO4, and evaporated to
give a residue, which was chromatographed over silica gel (50%
EtOAc–hexanes) to furnish an inseparable mixture of azido
diols 6 and 7 (Rf 0.64, EtOAc; isomer ratio 95:5 by 400 MHz
1H NMR) as a colorless oil (1.03 g, 95%); 1H NMR (400 MHz;
CDCl3) δ 4.93 (s, 1 H), 4.58 (d, 1 H, J 5.9 Hz), 4.54 (d, 1 H, J 5.9
Hz), 4.36 (dd, 1 H, J 11.5, 3.3 Hz), 3.59–3.72 (m, 4 H), 3.32 (s,
3 H), 1.84–1.77 (m, 1 H), 1.60–1.50 (m, 1 H), 1.45 (s, 3 H), 1.28
(s, 3 H); 13C NMR (50 MHz; CDCl3) δ 112.4, 110.0, 85.1, 84.2,
83.6, 73.9, 63.0, 61.3, 55.3, 35.4, 26.3, 24.8; MS (ESI) m/z 326
(Mϩ ϩ Na) (Calc. for C12H21N3O6: C, 47.52; H, 6.98%. Found:
C, 47.51; H, 7.02).
Methyl 5,6,7-trideoxy-2,3-O-isopropylidene-ꢀ-D-ribo-oct-6-eno-
furanoside 4
To a stirred solution of 3 (3.47 g, 9.73 mmol) in THF (20 mL) at
0 ЊC was added a solution of n-Bu4NF (12 mL, 12.0 mmol; 1 M
in THF). The resulting mixture was stirred at 0 ЊC for 30 min,
then the reaction mixture was quenched with saturated aq.
NH4Cl and the mixture was extracted with EtOAc (2 × 20 mL).
The combined organic layers were dried over anhydrous
Na2SO4 and evaporated to afford the crude alcohol which was
used directly in the following procedure without further
purification.
The above alcohol in THF (5 mL) was added dropwise over a
period of 5 min to a stirred suspension of LAH (1.90 g, 50.0
mmol) in THF (20 mL) at 0 ЊC. The resulting reaction mixture
was heated at 50 ЊC for 2 h. After this period, the reaction
mixture was cooled to 0 ЊC and excess of LAH was destroyed
by the dropwise addition of EtOAc. Saturated aq. NaHCO3
was then added dropwise. The resulting white suspension was
filtered through a pad of Celite and the latter was washed with
EtOAc. The filtrate was evaporated to give a residue, which was
chromatographed over silica gel (25% EtOAc–hexanes) to
afford the desired alcohol 4 (Rf 0.33, 50% EtOAc–hexanes) as a
colorless oil (1.82 g, 77%); [α]D23 Ϫ42 (c 2.30, CHCl3); 1H NMR
(400 MHz; CDCl3) δ 5.80 –5.64 (m, 2 H), 4.95 (s, 1 H), 4.61
(d, 1 H, J 5.9 Hz), 4.56 (d, 1 H, J 5.9 Hz), 4.21 (t, 1 H, J 7.8
Hz), 4.12 (d, 2 H, J 4.9 Hz), 3.34 (s, 3 H), 2.44–2.38 (m, 1 H),
2.32–2.24 (m, 1 H), 1.47 (s, 3 H), 1.31 (s, 3 H); 13C NMR
(50 MHz; CDCl3) δ 132.1, 128.0, 112.2, 109.4, 86.5, 85.4, 83.3,
63.4, 54.8, 37.8, 26.4, 24.9; MS (ESI) m/z 267 (Mϩ ϩ Na),
Methyl 6-(benzyloxycarbonylamino)-5,6-dideoxy-2,3-O-iso-
propylidene-L-glycero-ꢁ-L-talo-octofuranoside 8
To a stirred solution of azide 6 (567 mg, 1.87 mmol) in MeOH
(7 mL) was added 10% Pd/C (50 mg). The resulting suspension
was stirred under a hydrogen-filled balloon for 6 h. After this
period, the mixture was filtered through a Celite pad, and the
filter cake was washed thoroughly with EtOAc. Evaporation of
J. Chem. Soc., Perkin Trans. 1, 1999, 3597–3601
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the filtrate gave a residue, which was dissolved in THF (5 mL),
and CbzCl (0.32 mL, 2.25 mmol) followed by saturated aq.
NaHCO3 (1 mL) were added at 0 ЊC. The resulting mixture was
allowed to warm to 23 ЊC and stirred at that temperature for
12 h. The mixture was diluted with water and extracted with
EtOAc (3 × 10 mL). The organic layers were combined, then
dried over anhydrous Na2SO4 and evaporated. The residue was
purified by silica gel chromatography (75% EtOAc–hexanes) to
furnish 8 (Rf 0.43, EtOAc) as a white solid (694 mg, 90%), mp
NMR (100 MHz; DMSO-d6; 70 ЊC) δ 156.6, 139.7, 138.2, 137.7,
129.1, 129.0, 128.6, 128.4, 128.0, 127.7, 117.1, 112.5, 110.1,
85.8, 84.5, 84.2, 67.5, 58.2, 55.2, 50.1, 38.1, 27.3, 25.9; MS
(FAB) m/z 468 (Mϩ ϩ H), 436; HRMS (FAB) Calc. for
C27H34NO6: m/z, 468.2386. Found: m/z 468.2390.
Methyl 6-[benzyl(benzyloxycarbonyl)amino]-5,7-dideoxy-2,3-O-
isopropylidene-ꢁ-L-talo-octofuranoside 11
1
140–142 ЊC; [α]D23 ϩ0.4 (c 1.47, CHCl3); H NMR (400 MHz;
To a stirred solution of the urethane 10 (276 mg, 0.58 mmol) in
THF (1 mL) at 23 ЊC was added BH3 (1 M solution in THF;
0.87 mL, 0.87 mmol). The mixture was stirred at 23 ЊC for 1 h.
After this period, aqueous 4 M NaOH (0.3 mL) followed by
aq. 30% H2O2 (0.3 mL) were added. The mixture was stirred at
23 ЊC for 1 h. The mixture was extracted with ethyl acetate
(3 × 15 mL) and the combined organic layers were dried over
anhydrous Na2SO4 and evaporated. The residue was purified by
silica gel chromatography to furnish alcohol 11 (Rf 0.42, 50%
EtOAc–hexanes) as a colorless oil (159 mg, 57%), [α]D23 ϩ19.9
CDCl3) δ 7.36–7.31 (m, 5 H), 5.62 (d, 1 H, J 8.6 Hz), 5.10 (dd,
2 H, J 12.2, 8.0 Hz), 4.96 (s, 1 H), 4.61 (d, 1 H, J 5.9 Hz), 4.54
(d, 1 H, J 5.9 Hz), 4.41 (dd, 1 H, J 12.2, 2.5 Hz), 3.88–3.80 (m,
1 H), 3.68–3.62 (m, 2 H), 3.52 (d, 1 H, J 8.1 Hz), 3.34 (s, 3 H),
2.95 (br s, 1 H), 1.78–2.04 (m, 3 H), 1.46 (s, 3 H), 1.30 (s, 3 H);
13C NMR (100 MHz; CDCl3) δ 157.3, 136.1, 128.5, 128.2,
128.0, 112.4, 110.4, 85.1, 84.6, 83.7, 73.0, 67.1, 62.9, 55.6,
50.1, 34.9, 26.4, 24.8; MS (ESI) m/z 434 (Mϩ ϩ Na), 379
(Mϩ Ϫ OMe) (Calc. for C20H29NO8: C, 58.38; H, 7.10; N,
3.40%. Found: C, 58.13; H, 7.03; N, 3.39).
1
(c 1.58, CHCl3); H NMR (400 MHz; CDCl3) δ 7.38–7.25 (m,
10 H), 5.21 (s, 2 H), 4.95 (s, 2 H), 4.57 (d, 1 H, J 5.8 Hz), 4.44 (d,
1 H, J 5.8 Hz), 4.35–4.31 (m, 2 H), 4.13 (dd, 1 H, J 11.1, 3.8
Hz), 3.35 (s, 3 H), 3.40–3.27 (m, 2 H), 1.69–1.62 (m, 4 H), 1.45
(s, 3 H), 1.26 (s, 3 H); 13C NMR (100 MHz; CDCl3) δ 157.3,
138.4, 136.3, 128.5, 128.4, 128.0, 128.0, 127.8, 127.4, 112.1,
110.0, 85.4, 84.2, 83.7, 67.4, 58.9, 55.3, 51.6, 37.6, 35.9, 26.4,
24.8; MS (FAB) m/z 486 (Mϩ ϩ H), 454 (Mϩ Ϫ OMe); HRMS
(FAB) Calc. for C27H36NO7: m/z, 486.2492. Found: m/z,
486.2481.
Methyl 6-(benzyloxycarbonylamino)-5,6,7,8-tetradeoxy-2,3-O-
isopropylidene-ꢁ-L-talo-oct-7-enofuranoside 9
To a stirred suspension of 8 (694 mg, 1.69 mmol) in a mixture
(2:1) of toluene and acetonitrile (15 mL) at 23 ЊC were added
imidazole (460 mg, 6.76 mmol) and Ph2PCl (0.67 mL, 3.72
mmol). The resulting mixture was stirred for 5 min and a
solution of I2 (860 mg, 3.38 mmol) in toluene (4 mL) was added
dropwise. The resulting mixture was heated at 90 ЊC for 4 h.
After this period, the mixture was cooled to 23 ЊC, diluted with
EtOAc, and washed successively with 10% aq. Na2S2O3 and
brine. The mixture was extracted with EtOAc (3 × 15 mL) and
the combined organic extracts were dried over anhydrous
Na2SO4 and evaporated. The residue was purified by silica gel
chromatography (25% EtOAc–hexanes) to furnish 9 (Rf 0.29,
25% EtOAc–hexanes) as a white solid (442 mg, 69%), mp
Ethyl {methyl 9-acetamido-6-[benzyl(benzyloxycarbonyl)-
amino]-5,6,7,8,9-pentadeoxy-2,3-O-isopropylidene-ꢁ-L-talo-dec-
8-enofuranosid}uronate 12 and 13
To a stirred solution of DMSO (47 µL, 0.66 mmol) in CH2Cl2
(3 mL) at Ϫ60 ЊC was added oxalyl chloride (35 µL, 0.40
mmol) dropwise. After 2 min, alcohol 11 (121 mg, 0.25 mmol)
in CH2Cl2 (2 mL) was added dropwise. The resulting mixture
was stirred at Ϫ60 to Ϫ50 ЊC for 30 min and diisopropylethyl-
amine (0.24 mL, 1.33 mmol) was added dropwise. The resulting
mixture was stirred at Ϫ50 ЊC for an additional 2 min and then
allowed to warm to 23 ЊC. The reaction mixture was concen-
trated under reduced pressure, the residue was dissolved in
ethyl acetate, and the organic layer was washed successively
with cold aq. NaHSO4 (1 M) and brine, dried over anhydrous
Na2SO4, and evaporated to give the desired aldehyde. This was
used directly without further purification in the following
procedure.
1
107–108 ЊC; [α]D23 ϩ13 (c 0.48, CHCl3); H NMR (200 MHz;
CDCl3) δ 7.35–7.26 (m, 5 H), 5.88–5.72 (m, 1 H), 5.32 (d, 1 H,
J 8.1 Hz), 5.16 (d, 1 H, J 18.6 Hz), 5.11 (d, 1 H, J 10.5 Hz),
5.10 (s, 2 H), 4.95 (s, 1 H), 4.59 (d, 1 H, J 5.9 Hz), 4.52 (d, 1 H,
J 5.9 Hz), 4.43 (br s, 1 H), 4.32 (dd, 1 H, J 10.8, 4.1 Hz), 3.33 (s,
3 H), 1.97–1.82 (m, 1 H), 1.73–1.60 (m, 1 H), 1.45 (s, 3 H), 1.29
(s, 3 H); 13C NMR (50 MHz; CDCl3) δ 155.6, 137.8, 136.5,
128.4, 127.9, 115.0, 112.3, 110.0, 85.3, 84.4, 83.7, 66.6, 55.2,
50.8, 39.2, 26.4, 24.9; MS (ESI) m/z 400 (Mϩ ϩ Na); HRMS
(FAB) Calc. for C20H27NO6: m/z, 377.1838. Found: m/z,
377.1832.
To a stirred solution of N-acetyl-α-(diethoxyphosphoryl)-
glycine ethyl ester (112 mg, 0.4 mmol) and 18-crown-6 (105 mg,
0.4 mmol) in THF (3 mL) at Ϫ78 ЊC was added KN(TMS)2
(0.74 mL; 0.5 M solution in toluene). The mixture was stirred
for 15 min and then a solution of the above aldehyde in THF
(2 mL) was added dropwise. The resulting solution was stirred
at Ϫ78 ЊC for 30 min then allowed to warm to 23 ЊC and sub-
sequently quenched with saturated aq. NH4Cl. The reaction
mixture was diluted with EtOAc and water and the layers were
separated. The organic layer was washed with brine, dried over
anhydrous Na2SO4, and evaporated. The residue was purified
by silica gel chromatography (60% EtOAc–hexanes) to give a
mixture (1:5.4) of inseparable enamides 12 and 13 (Rf 0.15,
50% EtOAc–hexanes) as a pale yellow oil (121 mg, 79%); major
Methyl 6-[benzyl(benzyloxycarbonyl)amino]-5,6,7,8-tetradeoxy-
2,3-O-isopropylidene-ꢁ-L-talo-oct-7-enofuranoside 10
To a stirred suspension of NaH (60% oil dispersion; 281 mg,
7.03 mmol) and n-Bu4NI (10 mg) in THF (3 mL) at 23 ЊC was
added a solution of the urethane 9 (442 mg, 1.17 mmol) in THF
(2 mL). The mixture was stirred at 23 ЊC for 1 h and benzyl
bromide (0.84 mL, 7.03 mmol) was added. The resulting
reaction mixture was stirred at 23 ЊC for 12 h. The reaction
was quenched with saturated aq. NH4Cl and the mixture was
extracted with ethyl acetate. The combined extracts were
washed with brine and dried over anhydrous Na2SO4. Evap-
oration of the solvent followed by purification by silica gel
chromatography (15% EtOAc–hexanes) gave the N-benzyl
derivative 10 (Rf 0.53, 25% EtOAc–hexanes) as a colorless oil
(546 mg, 99%), [α]D23 Ϫ20.3 (c 2.90, CHCl3); 1H NMR (400 MHz;
DMSO-d6; 70 ЊC) δ 7.36–7.21 (m, 10 H), 5.93–5.85 (m, 1 H),
5.18 (s, 2 H), 5.04 (dd, 1 H, J 9.7, 1.0 Hz), 5.00 (dd, 1 H, J 17.4,
1.0 Hz), 4.84 (s, 1 H), 4.49 (d, 1 H, J 5.9 Hz), 4.46 (ABq, 2 H,
∆νAB 88.3 Hz, JAB 15.8 Hz), 4.43 (d, 1 H, J 5.9 Hz), 4.41–4.37
(m, 1 H), 3.94 (dd, 1 H, J 9.2, 5.7 Hz), 3.21 (s, 3 H), 2.02–1.95
(m, 1 H), 1.79–1.71 (m, 1 H), 1.36 (s, 3 H), 1.19 (s, 3 H); 13C
1
isomer: H NMR (400 MHz; DMSO-d6; 70 ЊC) δ 8.65 (s, 1H),
7.37–7.21 (m, 10 H), 6.21 (t, 1 H, J 7.1 Hz), 5.14 (s, 2 H), 4.82
(s, 1 H), 4.47 (d, 1 H, J 5.9 Hz), 4.44 (ABq, 2 H, ∆νAB 59.8 Hz,
JAB 15.7 Hz), 4.36 (d, 1 H, J 5.9 Hz), 4.10 (q, 2 H, J 7.0 Hz),
4.03–4.01 (m, 1 H), 3.94 (dd, 1 H, J 10.2, 4.8 Hz), 3.28 (s, 3H),
2.41 (t, 2 H, J 7.2 Hz), 1.98–1.88 (m, 1 H), 1.88 (s, 3 H), 1.64–
1.60 (m, 1 H), 1.35 (s, 3 H), 1.21 (s, 3 H), 1.17 (t, 3 H, J 7.0 Hz);
MS (CI) m/z 611 (Mϩ ϩ H).
3600
J. Chem. Soc., Perkin Trans. 1, 1999, 3597–3601

View Online
T. Martin and R. T. Borchardt, Carbohydr. Res., 1983, 113, 233;
Ethyl {methyl 9-acetamido-6-[benzyl(benzyloxycarbonyl)-
amino]-5,6,7,8,9-pentadeoxy-2,3-O-isopropylidene-D-glycero-ꢁ-
L-talo-decofuranosid}uronate 14
(c) J. W. Lyga and J. A. Secrist, III, J. Org. Chem., 1983, 48, 1982.
6 For total synthesis, see; (a) D. H. R. Barton, S. D. Gero, B. Quiclet-
Sire and M. Samadi, J. Chem. Soc., Perkin Trans. 1, 1991, 983; (b)
M. P. Maguire, P. L. Feldman and H. Rapoport, J. Org. Chem.,
1990, 55, 948; (c) J. G. Buchanan, A. Flinn, P. H. Mundill and R. H.
Wightman, Nucleosides, Nucleotides, 1986, 5, 313; (d) M. Geze,
P. Blanchard, J. L. Fourrey and M. Robert-Gero, J. Am. Chem. Soc.,
1983, 105, 7638; (e) G. A. Mock and J. G. Moffat, Nucleic Acids
Res., 1982, 10, 6223.
7 For synthesis of sinefungin analogues, see; (a) D. H. R. Barton,
S. D. Gero, F. Lawrence, M. Robert-Gero, B. Quiclet-Sire and
M. Samadi, J. Med. Chem., 1992, 35, 63; (b) D. H. R. Barton, S. D.
Gero, G. Negron, B. Quiclet-Sire, M. Samadi and C. Vincent,
Nucleosides, Nucleotides, 1995, 14, 1619; (c) P. Peterli-Roth, M. P.
Maguire, E. Leon and H. Rapoport, J. Org. Chem., 1994, 59, 4186.
8 A. K. Ghosh and W. Liu, J. Org. Chem., 1996, 61, 6175.
9 (a) A. K. Ghosh, S. P. McKee, W. M. Sanders, P. L. Darke, J. A.
Zugay, E. A. Emini, W. A. Schleif, J. C. Quintero, J. R. Huff and P. S.
Anderson, Drug Des. Discovery, 1993, 10, 77; (b) P. A. Levene and
E. T. Stiller, J. Biol. Chem., 1934, 104, 299.
10 H. Kotsuki, I. Kadota and M. Ochi, Tetrahedron Lett., 1990, 31,
4609.
11 (a) R. A. Johnson and K. B. Sharpless, in Catalytic Asymmetric
Synthesis, ed. I. Ojima, VCH Publishers, New York, 1993, pp. 103–
158; (b) Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko,
H. Masamune and K. B. Sharpless, J. Am. Chem. Soc., 1987, 109,
5765.
12 A. K. Ghosh and Y. Wang, J. Org. Chem., 1999, 64, 2789.
13 M. Caron, P. R. Carlier and K. B. Sharpless, J. Org. Chem., 1988, 53,
5185.
In a hydrogenation bottle, the mixture of enamides 12 and 13
(14 mg, 0.023 mmol) was dissolved in methanol (3 mL) and the
Ϫ
catalyst [Rh(COD)(R,R-DIPAMP)2]ϩBF4 (2 mg) was added.
The bottle was then charged with hydrogen to a pressure of 50
psi. The mixture was shaken on a Parr apparatus for 12 h under
50 psi at 23 ЊC. After this period, the reaction mixture was con-
centrated under reduced pressure and the residue was purified
by silica gel chromatography (50% EtOAc–hexanes) to give 14
(Rf 0.16, 50% EtOAc–hexanes) as a colorless oil (13.3 mg, 94%),
[α]D23 ϩ22.6 (c 1.33, CHCl3) {lit.8 [α]D23 ϩ24.3 (c 0.7, CHCl3)}; 1H
NMR (400 MHz; DMSO-d6; 70 ЊC) δ 7.85 (d, 1 H, J 7.3 Hz),
7.20–7.39 (m, 10 H), 5.13 (s, 2 H), 4.81 (s, 1 H), 4.45 (d, 1 H,
J 5.9 Hz), 4.41 (ABq, 2 H, ∆νAB 81 Hz, JAB 15.7 Hz), 4.35 (d, 1
H, J 5.9 Hz), 4.17–4.15 (m, 1 H), 4.03 (q, 2 H, J 7.1 Hz), 3.94–
3.91 (m, 2 H), 3.20 (s, 3 H), 1.82 (s, 3 H), 1.70–1.41 (m, 6 H),
1.33 (s, 3 H), 1.21 (s, 3 H), 1.15 (t, 3 H, J 7.0 Hz); MS (ESI) m/z
635 (Mϩ ϩ Na), 581 (Mϩ Ϫ OMe).
Acknowledgements
Financial support of our work by the National Institute of
Health (GM 55600) is gratefully acknowledged.
14 Z. Liu, B. Classon and B. Samuelsson, J. Org. Chem., 1990, 55,
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