A new synthetic approach toward (+)-ambruticin analogs: Preparation of a C10-C11 cis-isomer fragment

Article abstract of DOI:10.1002/(SICI)1099-0690(199911)1999:11<2885::AID-EJOC2885>3.0.CO;2-J

A new methodology has been applied to synthesize an isomer of the west part of (+)-ambruticin based on an efficient asymmetric de novo access to the A unit and sequential stereospecific reactions catalyzed by Pd₀ for the construction of the B unit.

Full text of DOI:10.1002/(SICI)1099-0690(199911)1999:11<2885::AID-EJOC2885>3.0.CO;2-J

FULL PAPER
A New Synthetic Approach Toward (؉)-Ambruticin Analogs: Preparation of a
C10–C11 cis-Isomer Fragment
[a]
[a]
[a]
[a]
´
ˆ
Veronique Michelet, Kouacou Adiey, Bruno Bulic, Jean-Pierre Genet,*
[b]
[b]
[b]
[c]
¨
Gilles Dujardin, Sandrine Rossignol, Eric Brown, and Loıc Toupet
Keywords: Ambruticin / Asymmetric synthesis / Pyranose / Carbohydrates / C-Glycosylation / Alkylations / Palladium
A new methodology has been applied to synthesize an
isomer of the west part of (+)-ambruticin based on an
efficient asymmetric de novo access to the A unit and
sequential stereospecific reactions catalyzed by Pd0 for the
construction of the B unit.
volves C7ϪC8 and C13ϪC14 disconnections. As part of
our ongoing program on the synthesis of optically active
vinylcyclopropanes,[8] we have long been interested in the
synthesis of (ϩ)-ambruticin (1). We wish to report herein
our recent results concerning a new strategy for the prep-
aration of an isomeric fragment of 1. We envisaged the
C13ϪC14 disconnection leading to the west part 2 (Scheme
1). The west part 2, previously reported as a derivative of
enantiomerically pure A and B units, was seen as an entire
building block resulting from the cyclopropanation of 3, as
catalyzed by Pd0 complexes. Disconnection of 3 leads to
two fragments, the β-C-glycosyl aldehyde 4[9] and the pro-
pargylic alcohol 5.[10] We have already validated the meth-
odology on the basis of a regio-, stereo- and enantiospecific
alkylation and cyclopropanation starting from benzal-
dehyde as a simple model of 4, and proved that (R)-but-1-
yn-3-ol was the appropriate enantiomer for the B unit.[8]
Introduction
Ambruticin (1), an antifungal antibiotic discovered[1] in
the late 1970s, has been isolated from fermentation extracts
of the Myxobacteria species Polyangium cellulosum var. ful-
vum. Its complete structure was determined through elegant
spectroscopic analyses,[2] degradative studies and chemical
transformation, and by single-crystal X-ray analysis of a
derivative.[3] Interest in the synthesis of this compound
stems not only from its particular structure, but is also due
to its unique oral in vivo activity against histoplasmosis and
coccidiomycosis.[4] More recently,[5] HöfleЈs group has iso-
lated analogs of (ϩ)-ambruticin bearing an amino group at
the C5 position from the Myxobacteria Sorangium cellulo-
sum So ce10. The mode of action of (ϩ)-ambruticin is still
unknown, which makes the synthesis of analogs for further
study and modification of its biological activity even more
important.
Despite widespread interest among chemists, only one to-
tal synthesis of ambruticin has been published to date, that
by KendeЈs group.[6] Several fragments[7] of the molecule
have, however, been described in the literature. A common
strategy for the construction of the whole framework in-
Scheme 1. Retrosynthesis
[a]
`
´
Laboratoire de Synthese Selective Organique et Produits Natu-
rels, UMR 7573 CNRS, E.N.S.C.P.,
11, rue P. et M. Curie, F-75231 Paris Cedex 05, France
E-mail: genet@ext.jussieu.fr
Laboratoire de Synthese Organique, UPRES-A 6011 CNRS,
Results and Discussion
[b]
[c]
`
´
´
Universite du Mans, Faculte des Sciences,
B. P. 535, avenue Olivier Messiaen, F-72017 Le Mans Cedex,
France
We have shown that β-C-glycosyl aldehydes of type 4 can
be synthesized starting from the corresponding gluconolac-
tone.[9] As the lactone precursor of the A unit required a
long synthetic scheme,[7c] a more straightforward access to
E-mail: dujardin@univ-lemans.fr
`
´
´
Groupe Matiere Condensee et Materiaux, UMR 6626 CNRS,
´
Universite de Rennes I,
Bat. 11-A, Campus de Beaulieu, F-35042 Rennes Cedex, France 4 was needed.
Eur. J. Org. Chem. 1999, 2885Ϫ2892
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1111Ϫ2885 $ 17.50ϩ.50/0
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J.-P. Genet et al.
FULL PAPER
Scheme 2. a) 2.5% Eu(fod)3, petroleum ether/toluene, ∆T; b) LiAlH4; c) BH3·Me2S, THF; d) NaOH, H2O2; e) TrCl, Pyr; f) BnBr, NaH,
DMF; g) 6  HCl, THF
Synthesis of the A Unit of (؉)-Ambruticin
stereomeric purification step, which was efficiently carried
out at the stage of the triol 10 on a ten-gram scale.
For this purpose, we anticipated that the -2-deoxy sugar
13,[11] de novo synthesized from the key heteroadduct 8
(Scheme 2), would serve as an efficient precursor of 4. Thus,
the seven-step synthesis of 13 was successfully scaled up
with some improvements relating to the required dia-
The absolute configurations at the four stereogenic cen-
ters created have previously been assigned following a
three-step conversion of 10 into -3,4,6-tribenzyl-2-deoxy-
gluconolactone.[11a,12] The relationship between the in-
ducing and induced stereogenic centers was definitively es-
tablished by X-ray structure analysis of the crystalline diol
9 (Figure 1). Moreover, the permanent (R) character of
the inducing center was evidenced by the specific rotation
of the phenylethanediol[13] obtained together with lactol
13. Both these factors were fully supportive of the struc-
tural assignments.
In 1996, Liu and Donaldson[7e] described an access to
the hydroxy ester 14-β involving a five-step procedure. At
the same time, we investigated a more straightforward
route to the ester 14-β from the lactol 13 by direct intro-
duction of the methoxycarbonylmethyl moiety (Scheme 3).
To the best of our knowledge, such stereocontrolled C-
glycosylations on a substrate bearing a free hydroxy group
at C-6 had not previously been reported.[14] As mentioned
previously in the case of fully protected glucose,[15] Hor-
nerЈs reagent was found to give the best results, leading in
this case to the expected hydroxy ester 14 in 72% yield. In
accordance with the findings of Monti et al.,[15] the use of
THF as solvent ensured completion of the presumed se-
cond step, i.e. Michael cyclization of the transient methyl
octenoate, but led to a moderate β selectivity (β:α ϭ
70:30). Base-catalyzed epimerization (conditions: NaOMe/
NaOH/60°C) of the mixture of C-deoxyglycosides 14 was
found to proceed smoothly (β:α ϭ 95:5)[16] and subsequent
refluxing in an excess of anhydrous methanolic HCl re-
sulted in efficient in situ reesterification (80% overall yield
from the 70:30 mixture of 14). The aldehyde 4 was finally
Figure 1. ORTEP drawing of the crystal structure of the allylic
diol 9 · H2O
2886
Eur. J. Org. Chem. 1999, 2885Ϫ2892

A New Synthetic Approach Toward (ϩ)-Ambruticin Analogs
FULL PAPER
Scheme 3. a) NaH, THF, (MeO)2POCH2CO2Me; b) MeONa, MeOH, ∆T; c) MeOH, HCl, ∆T; d) DMSO, (COCl)2, NEt3, CH2Cl2
obtained in 74% yield by employing Swern conditions at allyloxycarbonyl group then gave the propargylic alcohol
low temperature.
19. Partial hydrogenation was achieved in the presence of
Pd/C, poisoned[18] with pyridine, leading to 20 (Scheme 4).
The allylic alcohol 20 was then subjected to pal-
ladium(0)-catalyzed alkylation, which was readily carried
out at room temperature in THF using in situ preformed
Pd(dppe)2 with subsequent addition of sodium dimethyl
Synthesis of a C10 Isomer of the West Part of
(؉)-Ambruticin
With fragment A in hand, and anticipating that we malonate. We were delighted to find that the alkylation oc-
needed the (R,R) configuration for the alkenyl side chain of curred exclusively on the carbon atom bearing the carbon-
the required intermediate, we chose to condense the alde- ate group to give a single isomer 21 with purely (E) stereo-
hyde 4 with a protected derivative 5 of (R)-but-1-yn-3-ol chemistry at the double bond. Compound 21 was then con-
under chelating Grignard conditions.[17] After numerous verted into the corresponding benzoate 22 using 2,4-di-
unsuccessful attempts using (R)-O-ethyloxycarbonylbut-1- chlorobenzoyl chloride. The final cyclopropanation step
yn-3-ol, we were pleased to find that (R)-O-tert-butyldi- was carried out in THF at room temperature using in situ
methylsilylbut-1-yn-3-ol reacted with the aldehyde 4 to give preformed Pd(dppe)2 as catalyst and DBU as base. The re-
the alcohols 15 in 49% yield and with a diastereoselectivity action was very clean and led exclusively to the cis-disubsti-
of 85:15 (29% of aldehyde 4 was recovered). Protection of tuted cyclopropane 23, which was accompanied only by a
the free OH group of the major epimer 15 using allyl small amount of starting material. The cis relationship of
chloroformate led to 16 in quantitative yield. Selective re- the methyl group and the vinylic chain, the β configuration
moval of the trialkylsilyl group from 16 using nBu4NF gave at the anomeric center (J ϭ 9 Hz), the (E) stereochemistry
the alcohol 17 (93% yield), which upon treatment with ethyl of the double bond (J ϭ 15.5 Hz), and the cis stereochem-
chloroformate afforded 18 (94% yield). Selective removal of istry of the cyclopropane ring (J ϭ 9.6 Hz) were confirmed
Scheme 4. a) (R)-BrMgCϵCϪCH(Me)(OTBDMS), MgBr2, Et2O, Ϫ60°C to room temp., 49%; b) ClCO2CHϭCH2, pyridine, CH2Cl2,
0°C to room temp., 99%; c) Bu4NF, THF, 0°C to room temp., 93%; ClCO2Et, pyridine, CH2Cl2, 0°C to room temp., 94%; e) Pd(OAc)2/
TPPTS, CH3CN/H2O 6:1, Et2NH, room temp., 91%; f) Pd/C, pyridine, MeOH, H2, room temp., 56%; g) 10% Pd(OAc)2/dppe, then
NaCH(CO2Me)2, THF, room temp., 60%; h) 2,4-Cl2-C6H3ϪCOCl, pyridine, CH2Cl2, 0°C to room temp., 89%; i) 10% Pd(OAc)2/dppe,
then DBU, THF, room temp., 60%
Eur. J. Org. Chem. 1999, 2885Ϫ2892
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J.-P. Genet et al.
FULL PAPER
22.521(2) A, V ϭ 1971.3(5) AϪ3, Z ϭ 4, Dx ϭ 1.262 Mg.mϪ3, λ
˚
1
at this stage by H- and 13C-NMR spectroscopy and by
(Mo-Kα) ϭ 0.71073 A, µ ϭ 0.90 cmϪ1, F(000) ϭ 800, T ϭ 253 K.
˚
NOE experiments. We have previously shown that the con-
figuration of the cyclopropane[8] is dictated by the absolute
configuration at the carbon atom bearing the free OH
group in 15. Thus, the configuration of the major alcohol
15 is (S), which does not conform to CramЈs chelating rule
for the addition of a Grignard to a C-glycosyl aldehyde.[17]
This unprecedented diastereoselectivity is currently under
investigation in our laboratory and will be applied to the
Crystal dimensions: 0.35 ϫ 0.24 ϫ 0.12 mm. The intensity data
were collected with a Nonius CAD-4 automatic diffractometer
using graphite-monochromated Mo-Kα radiation.[19] The cell par-
ameters were obtained by fitting a set of 25 high-θ reflections. The
data collection [2θmax ϭ 54°, scan ω/2θ ϭ 1, tmax ϭ 60 s, hkl ranges:
h ϭ 0.11, k ϭ 0.12, l ϭ 0.28, intensity controls without appreciable
decay (0.25%)] gave 2454 reflections, of which 1641 were indepen-
dent with I > 2 σ(I). After Lorentz and polarization corrections,[20]
total synthesis of (ϩ)-ambruticin and analogs. Further re- the structure was solved with SIR-97,[21] which revealed the nonhy-
drogen atoms of the structure and the water molecule. After aniso-
tropic refinement, all the hydrogen atoms of the structure were lo-
cated on a Fourier difference map. The whole structure was refined
with SHELXL-97[22] using full-matrix least-squares techniques
{use of F2 magnitude: x, y, z, βij for C and O atoms, x, y, z for H
atoms; 323 variables and 2454 observations [1641 with I > 2 σ(I)];
calcd. w ϭ 1/[σ2(Fo2) ϩ (0.0528 P)2 ϩ 0.0755 P], where P ϭ (Fo2 ϭ
sults will be reported in due course.
Conclusion
We have described a new synthetic approach to the (ϩ)-
ambruticin skeleton. A new method for preparing the A
ring has been described and has proved to be highly ef-
ficient. Our methodology has led to the synthesis of an ep-
imer of the west part of (ϩ)-ambruticin, which broadens
the access to analogs.
2
2 Fc )/3 with the resulting R ϭ 0.042 and SW ϭ 1.001 (residual
∆ρ ϭ 0.166eAϪ3)}. Atomic scattering factors were taken from the
˚
International Tables for X-ray Crystallography (1992). The ORTEP
view was created with the program PLATON-98.[23] All calcu-
lations were performed with a Silicon Graphics Indy computer.
Crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDC-112890. Copies of the data can be obtained free of charge
on application to the CCDC, 12 Union Road, Cambridge CB2
1EZ, U.K. [Fax: (internat.) ϩ 44-1223/336-033; E-mail: deposit@-
ccdc.cam.ac.uk].
Experimental Section
General: 1H-NMR spectra: Bruker AC 200, AM 250 or AC 400
spectrometers; 200, 250 or 400 MHz, respectively; chemical shifts
(δ) are reported in ppm units by reference to Me4Si; coupling con-
stants (J) are reported in Hertz and refer to apparent peak multi-
plicities. Ϫ 13C-NMR spectra: Bruker AC 200, AM 250 or AC 400;
50, 63 or 100 MHz, respectively. Ϫ High-resolution mass spectra:
Varian MAT311 at the C.R.M.P.O. (Rennes). Low-resolution mass
measurements: Fisons Hewlett Packard 5989 instrument. Ϫ Optical
rotations: PerkinϪElmer 241 polarimeter at 589 nm. Ϫ IR spectra:
Bruker FT-IR 45 or Mattson Genesis spectrophotometer. Ϫ El-
emental analyses were performed at the “Service Regional de Mic-
(R)-2-Hydroxy-1-phenylethyl-3-O-Benzyl-2-deoxy-L-glucoside (10,
Large-Scale Procedure): A mixture of adducts 8 and 8Ј [48 mmol,
21.9 g, diastereomeric ratio 8 (2S,4S,1ЈR)/8Ј (2R,4R,1ЈR) ϭ 90:10]
was dissolved in anhydrous Et2O (100 mL) under argon and treated
at 0°C with lithium aluminum hydride (3.6 g, 96 mmol) in anhy-
drous Et2O (400 mL). After 15 h at 20°C, satd. aqueous Na2SO4
(16 mL) was added at 0°C. After 1 h, AcOEt (100 mL) was added
and the organic layer was filtered, dried with MgSO4, and filtered
once more. Removal of the solvent left a colorless oil, which was
used for the next step without further purification. The minor dia-
stereomer (2R,4R,1ЈR) of 9 was detected in the 1H-NMR spectrum
of the crude product (400 MHz, CDCl3) by the signals at δ ϭ 5.20
(d, 1 H, 5-H) and 5.13 (t, 1 H, 2-H). Ϫ To a solution of the afore-
mentioned crude allylic diol 9 (16 g) in anhydrous THF (400 mL),
BH3 · Me2S (2.25 equiv., 49 mL of a 2  solution in THF) was
added dropwise at 0°C. After stirring for 1 h at 0°C and for 40 h at
room temp., the reaction mixture was treated with 25% aq. sodium
hydroxide (20 mL), followed by 30% aqueous H2O2 (20 mL) and
then refluxed for 2 h. After cooling, satd. aqueous NaCl (240 mL)
was added and the THF was removed in vacuo. The remaining
aqueous phase was extracted with Et2O (3 ϫ 60 mL) and EtOAc
(3 ϫ 60 mL), the combined organic layers were dried with MgSO4,
and the solvents were evaporated. Flash chromatography of the
crude product (eluent: cyclohexane/EtOAc, 1:1 to 3:7) afforded first
the diastereomerically pure triol 10 (11.2Ϫ11.8 g, 62Ϫ66% over the
two steps) as a colorless oil, Rf ϭ 0.23 (cyclohexane/EtOAc, 3:7),
´
roanalyse” (Universite Pierre et Marie Curie) and at CNRS-ICSN
(Gif-sur-Yvette). Ϫ Thin-layer chromatography: Silica-gel plates
(Merck F254); spots were detected by exposure to UV and/or vanil-
lin. Ϫ Anhydrous THF and diethyl ether were distilled from so-
dium/benzophenone; CH2Cl2 was distilled from calcium hydride.
(1ЈR,4S,6S)-4-Benzyloxy-2,3-dihydro-2-hydroxymethyl-6-(2-hy-
droxy-1-phenylethoxy)-4H-pyran (9): Diastereomerically pure ad-
duct 8[11] (4.8 mmol, 2.2 g) was dissolved in anhydrous Et2O
(10 mL) under argon and treated at 0°C with lithium aluminum
hydride (0.36 g, 9.6 mmol) in anhydrous Et2O (40 mL). After 15 h
at 20°C, satd. aqueous Na2SO4 (16 mL) was added at 0°C, and,
after 1 h at 20°C, the organic layer was filtered and concentrated
under reduced pressure. The diol 9 crystallized from the cold Et2O
solution in the form of white needles (1.45 g, 85%), m.p. 60°C,
[α]D20 ϭ Ϫ 0.8 (c ϭ 1, CH2Cl2). Ϫ Rf ϭ 0.44 (cyclohexane/EtOAc,
1
3:7). Ϫ H NMR (400 MHz, CDCl3): δ ϭ 1.98 (ddd, J ϭ 2.8, 5.9,
14.5 Hz, 1 H, 5-Hax), 2.38 (dt, 1 H, 5-Heq), 3.28 (m, OH),
3.52Ϫ3.70 (m, 4 H, 2 CH2OH), 4.06 (m, 1 H, 4-H), 4.54 (d, J ϭ
12.0 Hz, 1 H, CH2Ph), 4.62 (dd, J ϭ 3.6, 8.7 Hz, 1 H, CHPh), 4.64
(d, J ϭ 12.0 Hz, 1 H, CH2Ph), 5.11 (d, J ϭ 4.3 Hz, 1 H, 2-H), 5.28
(t, J ϭ 3.1 Hz, 1 H, 5-H), 7.15Ϫ7.40 (m, 10 H, Harom). Ϫ 13C NMR
(100 MHz, CDCl3): δ ϭ 32.1 (C-4), 62.3, 65.7, 67.2, 70.5 (CH2Ph),
82.5 (CHPh), 97.2, 97.3, 126.0Ϫ129.0, 138.3, 139.3, 152.2 (C-2). Ϫ
IR (neat): ν˜ ϭ 3380 cmϪ1 (OH), 1685 (CϭC).
26
1
[α]D ϭ ϩ1.2 (c ϭ 1.7, CH2Cl2). Ϫ H NMR (400 MHz, CDCl3):
δ ϭ 1.50 (m, OH), 1.65 (q, J ϭ 11.4 Hz, 1 H, 2-Hax), 1.80 (m, OH),
2.42 (ddd, J ϭ 1.9, 4.5, 12.3 Hz, 1 H, 2-Heq), 3.18 (m, 1 H, 5-H),
3.35Ϫ3.50 (m, 3 H, 3,4,6-H), 3.68 (m, 2 H, 2Ј,6-H), 3.80 (m, 1 H,
2Ј-H), 4.49 (d, J ϭ 11.6 Hz, 1 H, Hbenz), 4.67 (dd, J ϭ 3.7, 8.5 Hz,
1 H, 1Ј-H), 4.70 (d, J ϭ 11.6 Hz, 1 H, Hbenz), 4.73 (dd, J ϭ 1.9,
X-ray Crystal Structure Determination of 9: C21H24O5·H2O; Mr ϭ 9.8 Hz, 1 H, 1-H), 7.30Ϫ7.40 (m, 10 H). Ϫ 13C NMR (100 MHz,
374.42, orthorhombic, P212121, a ϭ 8.883(1), b ϭ 9.854(2), c ϭ
CDCl3): δ ϭ 35.8, 62.6, 65.8, 70.9, 70.9, 75.5, 78.8, 82.9, 100.3,
Eur. J. Org. Chem. 1999, 2885Ϫ2892
2888

A New Synthetic Approach Toward (ϩ)-Ambruticin Analogs
125.3Ϫ129.0, 137.9, 139.4. Ϫ IR (neat): ν˜ ϭ 3400 cmϪ1 (OH), 3031,
FULL PAPER
26
(α.β ϭ 2:1), [α]D ϭ Ϫ18.6 (c ϭ 1.29, EtOH), which slowly crys-
1
2929, 2873 cmϪ1. Ϫ C21H26O6 (374.42): calcd. C 67.36, H 7.00; tallized; m.p. 92Ϫ95°C. Ϫ IR (neat): ν˜ ϭ 3400 cmϪ1 (OH). Ϫ H
found. C 67.03, H 7.31. Ϫ The minor isomer 10Ј (1.2 g, 7%) was NMR (400 MHz, CDCl3): δ ϭ 1.51 (ddd, 11 Hz < J < 12.2 Hz, 1
next eluted and isolated, Rf ϭ 0.16 (cyclohexane/EtOAc, 3:7) as a
β-H, 2-Hax), 1.58 (ddd, J ϭ 3.3, 11.5, 12.5 Hz, 1 Hα, 2-Hax), 2.23
(dd, J ϭ 4.9, 12.5 Hz, 1 Hα, 2-Heq), 2.32 (ddd, J ϭ 1.7, 4.9, 12.5 Hz,
1 Hβ, 2-Heq), 3.32Ϫ3.55 (m, 2 Hβ and 1 Hα), 3.58 (m, 2 Hβ and 1
26
colorless oil, [α]D ϭ Ϫ75.5 (c ϭ 0.95, CH2Cl2). Ϫ 1H NMR
(400 MHz, CDCl3): δ ϭ 1.71 (q, J ϭ 12 Hz, 1 H, 2-Hax), 2.00 (m,
OH), 2.32 (m, 1 H, 2-Heq), 3.1Ϫ3.9 (m, 7 H), 4.46 (d, J ϭ 12 Hz, Hα), 3.75 (dd, J ϭ 11.6 Hz, 1 Hα,β, 6-H), 3.94 (m, 1 Hα, 5-H), 4.05
1 H, Hbenz), 4.48 (m, 1 H, 1Ј-H), 4.67 (d, J ϭ 12 Hz, 1 H, Hbenz), (m, 1 Hα, 3-H), 4.59Ϫ4.70 (m, 3 Hαβ, Hbenz), 4.78 (m, 1 Hβ, 1-H),
4.88 (dd, 1 H, 1-H), 7.30Ϫ7.40 (m, 10 H).
4.87 (d, J ϭ 11.0 Hz, 1 Hβ, Hbenz), 4.88 (d, J ϭ 10.8 Hz, 1 Hα,
Hbenz), 5.34 (s, 1 Hα, 1-H), 7.20Ϫ7.40 (m, 10 H, Harom). Ϫ 13C
NMR (100 MHz, CDCl3): δ ϭ 35.5, 37.9, 62.1, 62.4, 71.5, 71.7,
71.7, 74.9, 75.5, 77.0, 78.4, 78.9, 92.0, 94.1, 127.6Ϫ128.4,
138.1Ϫ138.5. Ϫ HR MS (LSI): calcd. for [M Ϫ Hϩ] 343.1545
(C20H23O5); found 343.1563.
(R)-1-Phenyl-2-(␣,␣-diphenylbenzyloxy)ethyl-3-O-Benzyl-2-deoxy-
6-O-(␣,␣-diphenylbenzyl)-L-glucoside (11): To a solution of triol 10
(27 mmol, 10.1 g) in freshly distilled pyridine (50 mL) was added
trityl chloride (18.8 g, 2.5 equiv.). After stirring for 4 d at room
temp. under argon, the solvent was evaporated in vacuo and the
residue was taken up in AcOEt (50 mL). The resulting solution was
washed with satd. aqueous NaCl (3 ϫ 50 mL), dried with MgSO4,
and concentrated to dryness. The crude product was purified by
column chromatography (cyclohexane/EtOAc, 95:5) furnishing 9
[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-gluco-β-C-
pyranosyl]methanol (14): To a suspension of NaH (previously rinsed
with hexane to remove mineral oil, 0.99 g, 41.25 mmol, 2.5 equiv.)
in dry THF (130 mL) at 0°C, a solution of trimethyl phos-
phonoacetate (6.00 g, 33 mmol, 2 equiv.) in dry THF (10 mL) was
added dropwise. After stirring for 3 h at 0Ϫ20°C and for 5 h at
room temp., a solution of the lactol -13 (5.68 g, 16.5 mmol) in dry
THF (100 mL) was slowly added to the white suspension. After
stirring for 40 h at room temp., the yellow mixture was refluxed for
6 h. The cooled reaction mixture was then treated with 0.01  aq.
HCl (to pH ϭ 2) and extracted with EtOAc (3 ϫ 60 mL). The com-
bined extracts were washed with aqueous NaCl (10 mL), dried with
MgSO4, and the solvent was evaporated. Flash chromatography of
the crude product (cyclohexane/EtOAc, 5:1 to 3:7) afforded
hydroxy ester 14 (4.76 g, 72%), Rf ϭ 0.60 (cyclohexane/EtOAc, 3:7)
as a clear oily mixture of isomers (β.α ϭ 70:30). This product was
then added to a methanolic solution of sodium methoxide obtained
from sodium (0.51 g) and dry methanol (250 mL). After refluxing
for 40 h, the cooled mixture was treated with excess dry HCl in
methanol and was then refluxed for a further 1 h. After cooling
once more, dry NaHCO3 was added until neutrality was reached
and the solvent was removed. The crude residue was chromato-
graphed (cyclohexane/EtOAc, 7:3), giving the hydroxy ester 14[7e]
(3.81 g, 80%, 58% overall yield based on 13), Rf ϭ 0.60 (cyclohex-
ane/EtOAc, 3:7), contaminated with 5% of the α isomer. Ϫ IR
(neat): ν˜ ϭ 3490 cmϪ1 (OH), 1739 (CϭO) cmϪ1. Ϫ 1H NMR
(400 MHz, CDCl3): δ ϭ 1.41 (q, J ϭ 11.3 Hz, 1 H, 2-Hax), 2.00
(m, 1 H, OH), 2.22 (ddd, J ϭ 2.0, 4.9, 12.8 Hz, 1 H, 2-Heq), 2.45
(dd, J ϭ 5.7, 15.4 Hz, 1 H, 1Ј-H), 2.62 (dd, J ϭ 7.4, 15.4 Hz, 1 H,
1Ј-H), 3.29Ϫ3.37 (m, 1 H), 3.43 (t, J ϭ 9.8 Hz, 1 H), 3.62Ϫ3.74
(m, 2 H), 3.68 (s, 3 H), 3.80Ϫ3.90 (m, 2 H), 4.63 (d, J ϭ 11.3 Hz,
1 H), 4.70 (d, J ϭ 10.7 Hz, 1 H), 4.78 (d, J ϭ 11.3 Hz, 1 H), 4.94
(d, J ϭ 10.7 Hz, 1 H), 7.30Ϫ7.40 (m, 10 H, Harom). The α isomer
was detected by the following proton signals:[7e] δ ϭ 1.76 (ddd, 1
H), 1.95 (ddd, 1 H), 2.43 (dd, 1 H), 2.68 (dd, 1 H), 4.55 (ABq, 1
H). Ϫ 13C NMR (100 MHz, CDCl3): β isomer: δ ϭ 36.6, 40.4,
51.8, 62.4, 71.5, 71.9, 75.1, 78.1, 79.0, 80.5, 127.6Ϫ128.4, 138.3,
138.4, 171.2; α isomer: δ ϭ 32.2, 38.2, 51.9, 60.6, 64.9, 71.4, 73.2,
74.8, 75.0, 77.3, 127.6Ϫ128.4, 138.0, 138.1, 171.8.
20
(19.8 g, 85%) as a powder, m.p. 82°C, [α]D ϭ ϩ31.8 (c ϭ 0.67,
CH2Cl2). Ϫ Rf ϭ 0.10 (cyclohexane/EtOAc, 9:1). Ϫ IR (neat): ν˜ ϭ
3455 cmϪ1 (OH). Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ 1.67 (q, J ϭ
11.5 Hz, 1 H, 2-Hax), 2.45 (dd, J ϭ 4.2, 11.6 Hz, 1 H, 2-Heq),
3.25Ϫ3.40 (m, 4 H), 3.50 (m, 3 H), 4.55 (d, J ϭ 11.7 Hz, 1 H,
Hbenz), 4.68 (d, J ϭ 11.7 Hz, 1 H, Hbenz), 4.82 (dd, J ϭ 3.6, 7.8 Hz,
1 H, 2Ј-H), 4.94 (dd, J ϭ 8.2 Hz, 1 H, 1-H), 7.10Ϫ7.50 (m, 40 H,
Harom). Ϫ C59H54O6 (859.022): calcd. C 82.49, H 6.34; found C
82.46, H 6.51.
(R)-1-Phenyl-2-(␣,␣-diphenylbenzyloxy)ethyl-3,4-Di-O-benzyl-2-de-
oxy-6-O-(α,α-diphenylbenzyl)-L-glucoside (12): To a suspension of
NaH (previously rinsed with hexane to remove mineral oil, 0.82 g,
34 mmol) in DMF (30 mL) at 0°C were successively added drop-
wise a solution of tris(ether) 11 (19.5 g, 22.7 mmol ) in DMF
(50 mL) and benzyl bromide (4.1 mL, 34 mmol). After stirring for
24Ϫ48 h at room temp. (during which gas evolution ceased and
an almost clear yellow solution was obtained), the reaction was
quenched with H2O (50 mL) at 0°C. The resulting mixture was
extracted with Et2O (4 ϫ 100 mL), the combined extracts were
dried (MgSO4), and the solvent was evaporated. Chromatography
(cyclohexane/EtOAc, 95:5) of the residue gave benzyl ether 12
26
(20.7 g, 96%) as a powder, m.p. 76°C, [α]D ϭ ϩ4.1 (c ϭ 0.61,
CH2Cl2). Ϫ Rf ϭ 0.25 (cyclohexane/EtOAc, 9:1). Ϫ 1H NMR
(400 MHz, CDCl3): δ ϭ 1.83 (q, J ϭ 11 Hz, 1 H, 2-Hax), 2.53 (m,
1 H, 2-Heq), 3.32 (dd, J ϭ 10.4, 3.6 Hz, 1 H, 6-H), 3.35 (m, 2 H,
2Ј,5-H), 3.50 (m, 2 H, 2Ј,6-H), 3.64 (m, 2 H, 3,4-H), 4.32 (d, J ϭ
10.3 Hz, 1 H, Hbenz), 4.62 (d, J ϭ 11.7 Hz, 1 H, Hbenz), 4.69 (d,
J ϭ 11.7 Hz, 1 H, Hbenz), 4.73 (d, J ϭ 10.3 Hz, 1 H, Hbenz), 4.90
(m, 2 H, 1,1Ј-H), 6.90 (m, 2 H, Harom), 7.10Ϫ7.40 (m, 43 H, Harom).
Ϫ C66H60O6 (949.19): calcd. C 83.52, H 6.37; found C 83.33, H
6.71.
3,4-Di-O-benzyl-2-deoxy-L-glucopyranose (13): To a solution of
tetrakis(ether) 12 (20.2 g, 21.5 mmol) in THF (300 mL) at room
temperature was added 3  aqueous HCl (200 mL). After stirring
for 48Ϫ96 h (during which a clear solution was maintained by di-
lution with THF as necessary), the mixture was poured into satd.
aqueous NaHCO3 (400 mL) and exhaustively extracted with hot
EtOAc (10 ϫ 100 mL). The combined organic layers were washed
[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-gluco-β-C-
pyranosyl]aldehyde (4): To a solution of DMSO (2.88 mL, 4 equiv.)
in anhydrous CH2Cl2 (12 mL) at Ϫ75°C, a solution of oxalyl chlo-
ride (1.68 mL, 2.2 equiv.) in CH2Cl2 (12 mL) was added dropwise,
with satd. aqueous NaCl (20 mL), dried (MgSO4), and concen- followed, after 15 min, by a solution of hydroxy ester 14 (3.6 g,
trated. The residue was chromatographed (cyclohexane/EtOAc, 9:1 9 mmol) in CH2Cl2 (70 mL). After stirring for 1 h at Ϫ75°C, the
to 3:7), giving first (Ϫ)-1-phenyl-1,2-ethanediol (2.37 g), Rf ϭ 0.36 reaction mixture was allowed to warm slowly and at Ϫ45°C NEt3
20
(cyclohexane/EtOAc, 3:7), [α]D ϭ Ϫ68 (c ϭ 1, CHCl3), and then
lactol -13 (5.78 g, 78%, 90Ϫ95% based on 12 consumed), Rf ϭ
0.30 (cyclohexane/EtOAc, 3:7), as a clear oily mixture of anomers
(6 mL, 5 equiv.) was slowly added. After stirring at Ϫ45°C for 8 h,
the reaction was quenched with H2O at Ϫ25°C and the resulting
mixture was extracted with CH2Cl2 (4 ϫ 100 mL). The combined
Eur. J. Org. Chem. 1999, 2885Ϫ2892
2889

ˆ
J.-P. Genet et al.
FULL PAPER
extracts were dried (MgSO4), the solvent was evaporated, and the
(1S,4R)-1-O-Allyloxycarbonyl-4-O-tert-butyldimethylsilyl-1-[2,3-
residue was purified by chromatography (Et2O/petroleum ether,
di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-gluco-β-C-
26
1:1) to give the β-aldehyde 4 (2.7 g, 74%) as an oil; [α]D ϭ Ϫ8.5 pyranosyl]pent-2-yne-1,4-diol (16): To a solution of alcohol 15a
(c ϭ 1, CHCl3). Ϫ Rf ϭ 0.6 (cyclohexane/EtOAc, 3:7). Ϫ 1H NMR
(400 MHz, CDCl3): δ ϭ 1.43 (ddd, 11 Hz < J < 12.2 Hz, 1 H, 2-
(218 mg, 1 equiv.) and pyridine (48 µL, 2 equiv.) in anhydrous
CH2Cl2 (2 mL), allyloxycarbonyl chloride (60 µL, 1.2 equiv.) was
Hax), 2.22 (ddd, J ϭ 2.0, 4.4, 14 Hz, 1 H, 2-Heq), 2.49 (dd, J ϭ 6.0, slowly added at 0°C. The resulting mixture was stirred for 1 h at
15.9 Hz, 1 H, 1Ј-H), 2.72 (dd, J ϭ 7.0, 15.9 Hz, 1 H, 1Ј-H), 3.53 0°C and then for 1 h at room temp. After completion of the reac-
(dd, J ϭ 8.7, 9.9 Hz, 1 H, 4-H), 3.70 (s, 3 H), 3.77 (m, 1 H, 1-H tion, the mixture was washed with 5% aqueous HCl and brine to
or 3-H), 3.82 (dd, J ϭ 0.9, 9.9 Hz, 1 H, 5-H), 3.90 (m, 1 H, 3-H pH ϭ 7. The organic phase was dried with MgSO4, filtered, and
or 1-H), 4.64 (d, J ϭ 11.4 Hz, 1 H, Hbenz), 4.66 (d, J ϭ 10.8 Hz, 1 concentrated under reduced pressure. Column chromatography
H, Hbenz), 4.71 (d, J ϭ 11.4 Hz, 1 H, Hbenz), 4.90 (d, J ϭ 10.8 Hz,
(SiO2, cyclohexane/EtOAc, 9:1) of the residue afforded the dipro-
1 H, Hbenz), 7.30Ϫ7.40 (m, 10 H, Harom), 9.63 (d, J ϭ 0.9 Hz, 1 H, tected derivative 16 as a colorless oil (256 mg, 99%), Rf ϭ 0.5
20
6-H). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 36.0, 36.3, 51.9, 71.6, (cyclohexane/EtOAc, 8:2), [α]D ϭ 15 (c ϭ 1.1, CHCl3). Ϫ 1H
72.1, 75.0, 77.6, 80.3, 81.8, 127.5Ϫ128.5, 137.6, 138.0, 170.9, 197.5.
NMR (200 MHz, CDCl3): δ ϭ 0.12, 0.13 (2 s, 6 H, SiMe2), 0.89
Ϫ HR MS (LSI): calcd. for [M ϩ Hϩ] 399.1808 (C23H27O6); (s, 9 H, tBu), 1.39 (d, J ϭ 6.5 Hz, 3 H, CHMe), 1.38 (m, 1 H, 4Ј-
found. 399.1807.
Hax), 2.3 (m, 1 H, 4Ј-Heq), 2.45, 2.79 (2 dd, J ϭ 15.8, 7.6, 5.6 Hz,
2 H, 6Ј-H), 3.69 (s, 3 H, CO2Me), 3.43Ϫ3.90 (m, 4 H, 1Ј,2Ј,3Ј,5Ј-
H), 4.51 (qd, J ϭ 6.5, 1.4 Hz, 1 H, 4-H), 4.65 (m, 2 H, CH2CHϭ
CH2), 4.60, 4.65/4.71, 4.96 (2 AB system, J ϭ 10.8, 11.5 Hz, 4 H,
CH2Ph), 5.27 (dq, J ϭ 10.4, 1.4 Hz, 1 H, CHϭCH2), 5.36 (dq, J ϭ
16.1, 1.4 Hz, 1 H, CHϭCH2), 5.69 (pseudo t, J ϭ 1.7 Hz, 1 H, 1-
H), 5.92 (ddt, J ϭ 16.1, 10.4, 5.7 Hz, 1 H, CHϭCH2), 7.28Ϫ7.37
(m, 10 H, Harom). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ Ϫ4.9, Ϫ4.5
(SiMe2), 18.1 [C(Me)3], 25.0 (CHMe), 25.7 (CMe3), 36.1, 40.0 (C-
4Ј,6Ј), 51.6 (OMe), 58.8 (C-4), 67.9 (C-1), 68.6 (OCH2CHϭCH2),
71.3 (CH2Ph), 71.7 (CHpyran), 75.1 (CH2Ph), 78.5 (CHpyran), 79.1
(CHpyran), 80.3 (CHpyran), 90.5 (CϵC), 118.8 (CHϭCH2), 127.5,
127.9, 128.3 (Carom), 131.3 (CHϭCH2), 138.0, 138.2 (Carom), 153.9
(OCO2), 171.0 (CO2Me). Ϫ MS (CI, NH3): m/z ϭ 684 [M ϩ 18].
(4R)-4-(O-tert-Butyldimethylsilyl)-1-[2,3-di-O-benzyl-4,6-dide-
oxy-6-(methoxycarbonyl)-D-gluco-β-C-pyranosyl]pent-2-yne-1,4-diol
(15): Two solutions of MgBr2 in diethyl ether (5 mL) were prepared
by adding 1,2-dibromoethane (0.59 mL, 8 equiv.) to magnesium
(166 mg, 8 equiv.). To a solution of methyllithium (2.2 mL, 4 equiv.)
in diethyl ether (3.3 mL) at Ϫ5°C was added (R)-3-(tert-butyldi-
methylsilyloxy)but-1-yne (703 mg, 4.4 equiv.). After 30 min, the
first MgBr2 solution (8 equiv.) was added. The resulting mixture
was cooled to Ϫ60°C, whereupon a precipitate appeared. The se-
cond MgBr2 solution was added to a solution of the aldehyde 4
(345 mg, 1 equiv.) in diethyl ether (3.5 mL) and then this mixture
was added to the acetylenic Grignard reagent. The resulting mix-
ture was stirred at Ϫ60°C for 1 h, allowed to warm to room tem-
perature, and then slowly quenched with cold aqueous NH4Cl. The
aqueous phase was extracted with diethyl ether. The combined or-
ganic extracts were washed with water, dried with Na2SO4, filtered,
and concentrated under reduced pressure. Column chromatography
(SiO2, cyclohexane/EtOAc, 8:2 then 7:3) of the residue afforded two
diastereomers 15 (37 mg, 108 mg, diastereomer ratio: 15:85, 49%),
(1S,4R)-1-O-Allyloxycarbonyl-1-[2,3-di-O-benzyl-4,6-dideoxy-6-
(methoxycarbonyl)-D-gluco-β-C-pyranosyl]pent-2-yne-1,4-diol (17):
To a solution of the O-silyl compound 16 (246 mg, 1 equiv.) in
anhydrous THF (4 mL) at 0°C was slowly added tetrabutylam-
monium fluoride (440 µL, 1  in THF, 1.2 equiv.). The resulting
mixture was stirred for 1 h at 0°C and then for 1 h at room temp.
After completion of the reaction, water was added and the aqueous
phase was extracted with diethyl ether. The organic phase was
washed with aqueous NaCl, dried with Na2SO4, filtered, and con-
centrated under reduced pressure. Column chromatography (SiO2,
cyclohexane/EtOAc, 7:3) of the residue afforded the alcohol 17 as
a colorless oil (189 mg, 93%), Rf ϭ 0.17 (cyclohexane/EtOAc, 7:3),
Rf ϭ 0.73, 0.61 (cyclohexane/EtOAc, 6:4), along with 101 mg of
recovered starting material 4. Ϫ Major Diastereomer 15a: [α]D
20
ϭ
Ϫ20 (c ϭ 1, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 0.12,
0.13 (2 s, 6 H, SiMe2), 0.89 (s, 9 H, tBu), 1.41 (d, J ϭ 6.5 Hz, 3 H,
CHMe), 1.42 (m, 1 H, 4Ј-Hax), 2.24 (m, 1 H, 4Ј-Heq), 2.45, 2.67 (2
dd, J ϭ 15.8, 5.8, 7.2 Hz, 2 H, 6Ј-H), 2.5 (br. s, 1 H, OH), 3.44
(dd, J ϭ 9.4, 3 Hz, 1 H, 1Ј-H), 3.54 (pseudo t, J ϭ 9.4 Hz, 1 H,
2Ј-H), 3.68 (s, 3 H, CO2Me), 3.70Ϫ3.90 (m, 2 H, 3Ј,5Ј-H), 4.53 (qd,
J ϭ 6.5, 1.3 Hz, 1 H, 4-H), 4.58Ϫ4.96 (m, 5 H, CH2Ph), 7.25Ϫ7.36
(m, 10 H, Harom). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ Ϫ4.9, Ϫ4.5
(SiMe2), 18.1 [C(Me)3], 25.3 (CHMe), 25.7 (CMe3), 36.3, 40.0 (C-
4Ј,6Ј), 51.7 (OMe), 58.9, 62.6 (C-1,4), 71.4 (CH2Ph), 72.0 (CHpyran),
75.1 (CH2Ph), 79.6 (CHpyran), 80.4 (C-1Ј), 88.8 (CϵC), 127.5,
127.9, 128.3, 138.1, 138.2 (Carom), 170.9 (CO). Ϫ MS (CI, NH3):
20
1
[α]D ϭ 1 (c ϭ 1.2, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ
1.39 (d, J ϭ 6.6 Hz, 3 H, CHMe), 1.45 (m, 1 H, 4Ј-Hax), 1.94 (br.
s, 1 H, OH), 2.29 (m, 1 H, 4Ј-Heq), 2.49, 2.75 (2 dd, J ϭ 15.8, 7.1,
5.8 Hz, 2 H, 6Ј-H), 3.69 (s, 3 H, CO2Me), 3.89Ϫ3.47 (m, 4 H,
1Ј,2Ј,3Ј,5Ј-H), 4.45 (qd, J ϭ 6.6, 1.5 Hz, 1 H, CHOH), 4.65 (dt,
J ϭ 5.7, 1.4 Hz, 2 H, CH2CHϭCH2), 4.61, 4.74/4.71, 4.98 (2 AB
system, J ϭ 11.0, 11.4 Hz, 4 H, CH2Ph), 5.28 (dq, J ϭ 10.4, 1.4 Hz,
1 H, CHϭCH2), 5.37 (dq, J ϭ 16.1, 1.4 Hz, 1 H, CHϭCH2), 5.66
(pseudo t, J ϭ 1.8 Hz, 1 H, 1-H), 5.94 (ddt, J ϭ 16.1, 10.4, 5.7 Hz,
1 H, CHϭCH2), 7.27Ϫ7.38 (m, 10 H, Harom). Ϫ 13C NMR
(50 MHz, CDCl3): δ ϭ 25.8 (CHMe), 35.9, 39.9 (C-4Ј,6Ј), 51.7
(OMe), 58.0 (C-4), 67.9 (C-1), 68.7 (OCH2CHϭCH2), 71.4
(CH2Ph), 71.7 (CHpyran), 74.8 (CH2Ph), 78.1, 79.0, 80.4 (CHpyran),
89.9 (CϵC), 118.9 (CHϭCH2), 127.5, 127.6, 128.0, 128.4 (Carom),
131.2 (CHϭCH2), 138.1 (Carom), 153.9 (OCO2), 171.0 (CO2Me). Ϫ
MS (CI, NH3): m/z ϭ 570 [M ϩ 18].
1
m/z ϭ 583 [M ϩ 1], 600 [M ϩ 18]. Ϫ Minor Diastereomer 15b: H
NMR (200 MHz, CDCl3): δ ϭ 0.14, 0.15 (2 s, 6 H, SiMe2), 0.92
(s, 9 H, tBu), 1.43 (d, J ϭ 6.5 Hz, 3 H, CHMe), 1.45 (m, 1 H, 4Ј-
Hax), 2.31 (m, 1 H, 4Ј-Heq), 2.48, 2.71 (2 dd, J ϭ 15.7, 6.5, 6.7 Hz,
2 H, 6Ј-H), 2.6 (br. s, 1 H, OH), 3.36 (dd, J ϭ 9.1, 1.5 Hz, 1 H, 1Ј-
H), 3.72 (s, 3 H, CO2Me), 3.64Ϫ3.90 (m, 3 H, 2Ј,3Ј,5Ј-H),
4.56Ϫ5.06 (m, 6 H, CH2Ph, H1,4), 7.29Ϫ7.36 (m, 10 H, Harom). Ϫ
13C NMR (50 MHz, CDCl3): δ ϭ Ϫ5.0, Ϫ4.6 (SiMe2), 18.1 (1S,4R)-1-O-Allyloxycarbonyl-1-[2,3-di-O-benzyl-4,6-dideoxy-6-
[C(Me)3], 25.3 (CHMe), 25.7 (CMe3), 36.3, 40.2 (C-4Ј,6Ј), 51.7 (methoxycarbonyl)- -gluco-β-C-pyranosyl]-4-O-ethoxycarbonylpent-
D
(OMe), 58.9, 61.8 (C-1,4), 71.3 (CH2Ph), 72.1 (CHpyran), 75.2 2-yne-1,4-diol (18): To a solution of alcohol 17 (189 mg, 1 equiv.)
(CH2Ph), 78.4 (CHpyran), 80.0 (CHpyran), 80.4 (C-1Ј), 82.0, 88.8 and pyridine (55 µL, 2 equiv.) in anhydrous CH2Cl2 (3 mL) at 0°C
(CϵC), 127.5, 127.8, 128.0, 128.3, 138.1, 138.2 (Carom), 170.9 (CO).
Ϫ MS (CI, NH3): m/z ϭ 583 [M ϩ 1], 600 [M ϩ 18].
was slowly added ethyl chloroformate (39 µL, 1.2 equiv.). The re-
sulting mixture was stirred for 1 h at 0°C and then for 1 h at room
2890
Eur. J. Org. Chem. 1999, 2885Ϫ2892

A New Synthetic Approach Toward (ϩ)-Ambruticin Analogs
FULL PAPER
temp. After completion of the reaction, the mixture was washed
with 5% aqueous HCl and brine to pH ϭ 7. The organic phase
was dried with MgSO4, filtered, and concentrated under reduced
pressure. Column chromatography (SiO2, cyclohexane/EtOAc, 8:2)
5Ј-H), 4.08 (q, J ϭ 7.1 Hz, 2 H, OCH2Me), 4.55Ϫ4.95 (m, 5 H,
CH2Ph, CHOH), 5.67 (m, 3 H, CHϭCH, CHMe), 7.32Ϫ7.26 (m,
10 H, Harom). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 14.3 (OCH2Me),
21.1 (CHMe), 36.5, 40.4 (C-4Ј,6Ј), 51.8 (OMe), 63.8 (OCH2Me),
68.2 (C-1), 71.5 (CH2Ph), 71.6 (C-4), 74.7 (CH2Ph), 71.9, 79.2, 80.6
(CHpyran), 81.0 (C-1Ј), 127.7, 128.0, 128.4, 128.5 (Carom), 129.2,
133.9 (CHϭCH), 138.3 (Carom), 154.5 (OCO2), 171.1 (CO2Me). Ϫ
MS (CI, NH3): m/z ϭ 560 [M ϩ 18].
of the residue afforded the diprotected derivative 18 as a colorless
20
oil (202 mg, 94%), Rf ϭ 0.31 (cyclohexane/EtOAc, 8:2), [α]D
ϭ
1
30 (c ϭ 1, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.30 (t,
J ϭ 7.1 Hz, 3 H, OCH2Me), 1.50 (d, J ϭ 6.6 Hz, 3 H, CHMe),
1.43 (m, 1 H, 4Ј-Hax), 2.31 (m, 1 H, 4Ј-Heq), 2.49, 2.79 (2 dd, J ϭ
15.8, 7.3, 5.8 Hz, 2 H, 6Ј-H), 3.71 (s, 3 H, CO2Me), 3.49Ϫ3.85 (m,
4 H, 1Ј,2Ј,3Ј,5Ј-H), 4.20 (q, J ϭ 7.1 Hz, 2 H, OCH2Me), 4.59Ϫ5.02
(m, 6 H, CH2CHϭCH2, CH2Ph), 5.33 (m, 3 H, 4-H, CHϭCH2),
5.69 (m, 1 H, 1-H), 5.96 (ddt, J ϭ 16.1, 10.4, 5.7 Hz, 1 H, CHϭ
CH2), 7.38Ϫ7.28 (m, 10 H, Harom). Ϫ 13C NMR (50 MHz, CDCl3):
δ ϭ 14.2 (OCH2Me), 21.0 (CHMe), 36.0, 40.0 (C-4Ј,6Ј), 51.7
(OMe), 63.8 (OCH2Me), 64.2 (C-4), 67.7 (C-1), 68.8 (OCH2CHϭ
CH2), 71.4 (CH2Ph), 71.7 (CHpyran), 75.1 (CH2Ph), 78.4 (CHpyran),
78.8 (CϵC), 78.9, 80.3 (CHpyran), 85.7 (CϵC), 119.0 (CHϭCH2),
127.6, 128.0, 128.4 (Carom), 131.3 (CHϭCH2), 138.0, 138.2 (Carom),
153.9 (OCO2), 171.0 (CO2Me). Ϫ MS (CI, NH3): m/z ϭ 642 [M
ϩ 18].
Methyl
carbonyl)-
(3S,4E,6S)-6-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxy-
D-gluco-β-C-pyranosyl]-6-hydroxy-2-methoxycarb-
onyl-3-methylhex-4-enoate (21): Pd(OAc)2 (3.7 mg, 10 mol-%) and
bis(diphenylphosphanyl)ethane (9.9 mg, 1.5 equiv./Pd) were stirred
in anhydrous THF (0.8 mL) at 30°C under argon for 30 min. To
this orange mixture, a solution of 20 (90 mg, 1 equiv.) in THF
(0.4 mL) was added at room temp. Dimethyl malonate (27 µL, 1.4
equiv.) was added to a suspension of NaH (9 mg, 1.4 equiv., 60%
in oil) in THF (1.6 mL). After 15 min at room temp., the catalyst
mixture was added to the anion of the dimethyl malonate. After 1
h, the mixture was treated with aqueous NH4Cl and the aqueous
phase was extracted with diethyl ether. The combined organic ex-
tracts were dried with Na2SO4, filtered, and concentrated under
reduced pressure. Column chromatography (SiO2, cyclohexane/
(1S,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
gluco-β-C-pyranosyl]-4-O-ethoxycarbonylpent-2-yne-1,4-diol (19): EtOAc, 7:3) afforded 21 as a colorless oil (58 mg, 60%), Rf ϭ 0.15
To a solution of the allyloxycarbonyl compound 18 (202 mg, 1
equiv.) and diethylamine (73 µL, 2.2 equiv.) in acetonitrile (4.3 mL)
(cyclohexane/EtOAc, 7:3). 29 mg (32%) of starting material 20 was
20
recovered. Ϫ [α]D ϭ Ϫ11 (c ϭ 0.8, CHCl3). Ϫ 1H NMR
was added a mixture of Pd(OAc)2 (7 mg, 10 mol.%) and TPPTS (250 MHz, CDCl3): δ ϭ 1.05 (d, J ϭ 6.8 Hz, 3 H, CHMe), 1.36
(110 mg, 20 mol.%) in water (0.7 mL). The resulting mixture was
vigorously stirred at room temperature until completion of the re-
action and then concentrated under reduced pressure. The resulting
aqueous phase was extracted with ethyl acetate, and the combined
extracts were dried with Na2SO4, filtered, and concentrated under
reduced pressure. Column chromatography (SiO2, cyclohexane/
(m, 1 H, 4Ј-Hax), 2.23 (m, 1 H, 4Ј-Heq), 2.45, 2.64 (2 dd, J ϭ 15.7,
7.2, 5.7 Hz, 2 H, 6Ј-H), 2.96 (m, 1 H, 3-H), 3.23 (t, J ϭ 9.7 Hz, 1
H, 2Ј-H), 3.29 (d, J ϭ 8.6 Hz, 1 H, 2-H), 3.43 (dd, J ϭ 9.7, 3 Hz,
1 H, 1Ј-H), 3.66 (s, 3 H, CO2Me), 3.70 [s, 6 H, CH(CO2Me)2],
3.71Ϫ3.84 (m, 2 H, 3Ј,5Ј-H), 4.30 (dd, J ϭ 7.1, 3.0 Hz, 1 H, 6-H),
4.54Ϫ4.98 (m, 4 H, CH2Ph), 5.55 (dd, J ϭ 15.5, 7.1 Hz, 1 H, 5-
EtOAc, 7:3) of the residue afforded 19 as a colorless oil (160 mg, H), 5.67 (dd, J ϭ 15.5, 7.5 Hz, 1 H, 4-H), 7.26Ϫ7.31 (m, 10 H,
20
91%), Rf ϭ 0.28 (cyclohexane/EtOAc, 7:3), [α]D ϭ 5 (c ϭ 0.8,
Harom). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 18.1 (CHMe), 37.0
(C-3), 36.4, 40.4 (C-4Ј,6Ј), 51.9 (CO2Me), 52.5 [CH(CO2Me)2], 57.6
1
CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.29 (t, J ϭ 7.1 Hz,
3 H, OCH2Me), 1.40 (m, 1 H, 4Ј-Hax), 1.54 (d, J ϭ 6.7 Hz, 3 H, (C-2), 71.2 (C-6), 71.3 (CH2Ph), 72.6 (CHpyran), 74.6 (CH2Ph),
CHMe), 1.71 (br. s, 1 H, OH), 2.24 (m, 1 H, 4Ј-Heq), 2.48, 2.69 (2 79.1, 81.0 (CHpyran), 81.1 (C-1Ј), 127.7, 127.8, 128.5 (Carom), 129.5,
dd, J ϭ 15.8, 7.2, 5.7 Hz, 2 H, 6Ј-H), 3.71 (s, 3 H, CO2Me),
3.42Ϫ3.91 (m, 4 H, 1Ј,2Ј,3Ј,5Ј-H), 4.19 (q, J ϭ 7.1 Hz, 2 H,
OCH2Me), 4.72 (m, 1 H, 1-H), 4.62, 4.71/4.67, 4.97 (2 AB system,
J ϭ 10.8, 11.5 Hz, 4 H, CH2Ph), 5.34 (qd, J ϭ 6.7, 1.6 Hz, 1 H, 4-
H), 7.37Ϫ7.27 (m, 10 H, Harom). Ϫ 13C NMR (50 MHz, CDCl3):
δ ϭ 14.2 (OCH2Me), 21.3 (CHMe), 36.4, 40.1 (C-4Ј,6Ј), 51.9
(OMe), 62.7 (C-1), 64.0 (C-4), 64.4 (OCH2Me), 71.6 (CH2Ph), 72.2
(CHpyran), 76.4 (CH2Ph), 79.7, 80.1 (CHpyran), 80.5 (C-1Ј), 83.1,
84.1 (CϵC), 127.7, 128.0, 128.5, 138.0 (Carom), 154.1 (OCO2), 171.0
(CO2Me). Ϫ MS (CI, NH3): m/z ϭ 541 [M ϩ 1], 558 [M ϩ 18].
135.3 (C-4,5), 138.4, 138.6 (Carom), 168.5, 168.7 [CH(CO2Me)2],
171.1 (CO2Me). Ϫ MS (CI, NH3): m/z ϭ 602 [M ϩ 18].
Methyl
carbonyl)-
(3S,4E,6S)-6-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxy-
D-gluco-β-C-pyranosyl]-6-(2,4-dichlorobenzoyloxy)-
2-methoxycarbonyl-3-methylhex-4-enoate (22): To a solution of al-
cohol 21 (57 mg, 1 equiv.) and pyridine (16 µL, 2 equiv.) in anhy-
drous CH2Cl2 (1 mL) at 0°C was slowly added 2,4-dichlorobenzoyl
chloride (22 µL, 1.2 equiv.). The resulting mixture was stirred for
1 h at 0°C and then for 1 h at room temp. After completion of the
reaction, the mixture was washed with 5% aqueous HCl and brine
to pH ϭ 7. The organic phase was dried with MgSO4, filtered,
(1S,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
gluco-β-C-pyranosyl]-4-O-ethoxycarbonylpent-2-ene-1,4-diol (20): and concentrated under reduced pressure. Column chromatography
To a solution of 19 (160 mg, 1 equiv.), containing suspended Pd/C
(16 mg, 10% w/w) in methanol (1.5 mL), was added pyridine (15
µL, 5% w/w) and the reaction mixture was stirred under hydrogen
at room temp. for 1 h. After filtering through a short plug of silica
gel using diethyl ether as eluent, the solvent was evaporated under
reduced pressure. Column chromatography (SiO2, cyclohexane/
(SiO2, cyclohexane/EtOAc, 8:2) of the residue afforded the benzoyl
derivative 22 as a colorless oil (66 mg, 89%), Rf ϭ 0.45 (cyclohex-
20
ane/EtOAc, 7:3), [α]D ϭ Ϫ10 (c ϭ 0.9, CHCl3). Ϫ 1H NMR
(250 MHz, CDCl3): δ ϭ 1.05 (d, J ϭ 6.8 Hz, 3 H, CHMe), 1.38
(m, 1 H, 4Ј-Hax), 2.23 (m, 1 H, 4Ј-Heq), 2.45, 2.65 (2 dd, J ϭ 15.5,
7.3, 5.6 Hz, 2 H, 6Ј-H), 2.97 (m, 1 H, 3-H), 3.23 (dd, J ϭ 9.8,
EtOAc, 8:2 then 7:3) afforded 20 as a colorless oil (90 mg, 56%), 8.6 Hz, 1 H, 2Ј-H), 3.29 (d, J ϭ 8.6 Hz, 1 H, 2-H), 3.60 (dd, J ϭ
Rf ϭ 0.28 (cyclohexane/EtOAc, 7:3), [α]20 ϭ Ϫ21 (c ϭ 0.7,
CHCl3). Ϫ H NMR (250 MHz, CDCl3): δ ϭ 1.23 (t, J ϭ 7.1 Hz,
9.8, 1.4 Hz, 1 H, 1Ј-H), 3.66 (s, 3 H, CO2Me), 3.67, 3.70 [2 s, 6 H,
CH(CO2Me)2], 3.71Ϫ3.87 (m, 2 H, 3Ј,5Ј-H), 4.55Ϫ4.99 (m, 4 H,
D
1
3 H, OCH2Me), 1.38 (d, J ϭ 5.8 Hz, 3 H, CHMe), 1.39 (m, 1 H, CH2Ph), 5.74 (m, 3 H, 4,5,6-H), 7.26Ϫ7.37 (m, 11 H, Harom), 7.44
4Ј-Hax), 2.25 (ddd, J ϭ 12.7, 4.9, 1.6 Hz, 1 H, 4Ј-Heq), 2.44, 2.62
(2 dd, J ϭ 15.6, 7.1, 5.9 Hz, 2 H, 6Ј-H), 2.85 (d, J ϭ 6.7 Hz, 1 H,
(d, J ϭ 1.9 Hz, 1 H, CHbenzoyl), 7.78 (d, J ϭ 8.4 Hz, 1 H, CHbenzoyl).
Ϫ
13C NMR (63 MHz, CDCl3): δ ϭ 18.0 (CHMe), 36.3 (CH2pyran),
OH), 3.78 (t, J ϭ 9.7 Hz, 1 H, 2Ј-H), 3.44 (dd, J ϭ 9.7, 3.3 Hz, 1 37.1 (C-3), 40.5 (CH2pyran), 51.8 (CO2Me), 52.5, 52.6
H, 1Ј-H), 3.68 (s, 3 H, CO2Me), 3.74 (m, 1 H, 3Ј-H), 3.84 (m, 1 H, [CH(CO2Me)2], 57.4 (C-2), 71.3 (CH2Ph), 71.8 (CHpyran), 74.6
Eur. J. Org. Chem. 1999, 2885Ϫ2892
2891

ˆ
J.-P. Genet et al.
FULL PAPER
[5]
[6]
G. Höfle, H. Steinmetz, K. Gerth, H. Reichenbach, Liebigs
Ann. Chem. 1991, 941Ϫ945.
(CH2Ph), 75.6, 78.0 (CHpyran), 79.9 (C-6), 80.9 (C-1Ј), 124.5 (CHϭ
CH), 125.1, 127.0, 127.7, 127.8, 127.9, 128.5, 130.9, 132.8, 138.2,
138.4, 138.5 (Carom), 139.6 (CHϭCH), 163.6 (COAr), 168.3, 168.6
[CH(CO2Me)2], 171.2 (CO2Me). Ϫ MS (CI, NH3): m/z ϭ 774 [M
ϩ 18].
A. S. Kende, Y. Fujii, J. S. Mendoza, J. Am. Chem. Soc. 1990,
112, 9645Ϫ9646. A. S. Kende, J. S. Mendoza, Y. Fujii, Tetra-
hedron 1993, 49, 8015Ϫ8038. J. S. Mendoza, A. S. Kende, Re-
cent Prog. Chem. Synth. Antibiot. Relat. Microb. Prod. 1994,
405.
[7]
[7a]
[7b]
Synthesis of the A unit:
Ref.[3b]
Ϫ
N. J. Barnes, A. H.
Methyl (2S,3R)-3-[(E)-2-(2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxy-
ycarbonyl)-D-gluco-β-C-pyranosyl)ethenyl]-2-methylcyclopro-
Davidson, L. R. Hughes, G. Procter, J. Chem. Soc., Chem. Com-
[7c]
mun. 1985, 1292. Ϫ
P. Sinay¨, J.-M. Beau, J.-M. Lancelin,
pane-1,1-dicarboxylate (23): Pd(OAc)2 (1.9 mg, 10 mol-%) and
bis(diphenylphosphanyl)ethane (5.1 mg, 1.5 equiv./Pd) were stirred
in anhydrous THF (0.4 mL) at 30°C for 30 min under argon. To
this orange mixture containing the catalyst, a solution of the ben-
zoyl compound 22 (65 mg, 1 equiv.) in THF (0.2 mL) was added
at room temp., followed by DBU (18 µL, 1.4 equiv.). After 1 h at
room temp., the reaction mixture was treated with aqueous NH4Cl
and the aqueous phase was extracted with diethyl ether. The com-
bined organic extracts were washed with brine, dried with Na2SO4,
and concentrated under reduced pressure. Column chromatography
(SiO2, cyclohexane/EtOAc, 8:2) of the residue afforded 23 as a col-
In Organic Synthesis: An Interdisciplinary Challenge, Blackwell
Scientific Publications, London, 1985, p. 307. P. Sinay¨, in Bioor-
ganic Heterocycles 1986: Synthesis, Mechanism and Bioactivity,
[7d]
Elsevier, Amsterdam, 1986, p. 59Ϫ70. Ϫ
I. E. Marko, D. J.
[7e]
Bayston, Tetrahedron Lett. 1993, 34, 6595Ϫ6597. Ϫ
L. Liu,
W. A. Donaldson, Synlett 1996, 103Ϫ104. Ϫ Synthesis of the
[7f]
[7g]
B unit:
Ref.[3b]
Ϫ
N. J. Barnes, A. H. Davidson, L. R.
Hughes, G. Procter, V. Rajcoomar, Tetrahedron Lett. 1981, 22,
1751Ϫ1754. Ϫ [7h] Ref.[7c]
Ϫ
[7i] T. Nagasawa, Y. Handa, Y. Ono-
[7j]
guchi, S. Ohba, K. Suzuki, Synlett 1995, 739Ϫ744. Ϫ
H.
Wakamatsu, N. Isono, M. Mori, J. Org. Chem. 1997, 62,
[7k]
[7l]
8917Ϫ8927. Synthesis of the C unit:
Ref.[3b]
Ϫ
S. D.
Burke, D. M. Armistead, F. J. Schoenen, J. M. Fevig, Tetra-
[7m]
1
hedron 1986, 2787. Ϫ
A. H. Davidson, N. Eggleton, I. H.
orless oil (28 mg, 60%), Rf ϭ 0.4 (cyclohexane/EtOAc, 7:3). Ϫ H
[7n]
Wallace, J. Chem. Soc., Chem. Commun. 1991, 378. Ϫ
I. E.
NMR (250 MHz, CDCl3): δ ϭ 1.19 (d, J ϭ 6.7 Hz, 3 H, CHMe),
1.43 (q, J ϭ 11.5 Hz, 1 H, 4Ј-Hax), 1.95 (m, 1 H, 2-H), 2.23 (ddd,
J ϭ 12.6, 4.9, 1.7 Hz, 1 H, 4Ј-Heq), 2.37 (t, J ϭ 9.6 Hz, 1 H, 3-H),
2.44, 2.65 (2 dd, J ϭ 15.4, 6.9, 6.2 Hz, 2 H, 6Ј-H), 3.18 (t, J ϭ 9 Hz,
1 H, 2Ј-H), 3.69 (s, 3 H, CO2Me), 3.72, 3.75 [2 s, 6 H, C(CO2Me)2],
3.62Ϫ3.78 (m, 2 H, 1Ј,3Ј-H), 3.85 (m, 1 H, 5Ј-H), 4.63, 4.70/4.70,
4.85 (2 AB system, J ϭ 11.0, 11.6 Hz, 4 H, CH2Ph), 5.59 (dd, J ϭ
15.5, 9.6 Hz, 1 H, CHϭCH), 5.79 (dd, J ϭ 15.5, 6 Hz, 1 H, CHϭ
CH), 7.29Ϫ7.37 (m, 20 H, Harom). Ϫ 13C NMR (63 MHz, CDCl3):
δ ϭ 10.0 (CHMe), 26.9 (C-2), 34.5 (C-3), 36.8 (CH2pyran), 38.8 (C-
1), 40.6 (CH2pyran), 51.8 (CO2Me), 52.3, 52.8 [C(CO2Me)2], 71.7
(CHpyran), 71.8, 75.1 (CH2Ph), 79.2, 80.3 (CHpyran), 82.3 (C-1Ј),
127.6, 127.7, 128.3, 128.4, 128.5 (Carom), 126.5, 132.2 (CHϭCH),
138.5, 138.6 (Carom), 167.0, 170.9 [C(CO2Me)2], 171.3 (CO2Me). Ϫ
MS (CI, NH3): m/z ϭ 584 [M ϩ 18].
Marko, D. J. Bayston, Tetrahedron 1994, 50, 7141. I. E. Marko,
D. J. Bayston, Synthesis 1996, 297Ϫ304.
[8]
[9]
ˆ
V. Michelet, I. Besnier, J.-P. Genet, Synlett 1996, 215Ϫ217; V.
ˆ
Michelet, J.-P. Genet, Bull. Soc. Chim. Fr. 1996, 133, 881Ϫ889
and references cited therein.
The synthesis of an analog of 4 has been described: M. E. Las-
terra Sanchez, V. Michelet, I. Besnier, J.-P. Genet, Synlett
ˆ
1994, 705Ϫ708.
[10]
ˆ
V. Michelet, I. Besnier, S. Tanier, A. M. Touzin, J.-P. Genet, J.-
P. Demoute, Synthesis 1995, 165Ϫ167.
[11] [11a]
G. Dujardin, S. Rossignol, E. Brown, Tetrahedron Lett.
[11b]
1996, 37, 4007Ϫ4010. Ϫ
G. Dujardin, S. Rossignol, E.
Brown, Synthesis 1998, 763Ϫ770.
[12]
The specific optical rotations reported for hemisynthetic -
20
3,4,6-tribenzyl-2-deoxygluconolactone are: [α]D ϭ ϩ48 (c ϭ
´
1, EtOH): C. Bernasconi, G. Cottier, G. Descotes, G. Remy,
Bull. Soc. Chim. Fr. 1979, 5Ϫ6, II-332Ϫ336; [α]D20 ϭ ϩ44 (c ϭ
1, EtOH): P. A. M. Van der Klein, A. E. J. De Nooy, G. A. Van
der Marel, J. H. Van Boom, Synthesis 1991, 347Ϫ349; [α]D20 ϭ
ϩ37 (c ϭ 0.6, CHCl3): F. Y. Dupradeau, S. Hakomori, T.
Toyokuni, J. Chem. Soc., Chem. Commun. 1995, 221.
[13]
20
Acknowledgments
The specific rotation, [α]D ϭ Ϫ68 (c ϭ 1, CHCl3), of the 1-
phenyl-1,2-ethanediol so obtained was identical to that of the
pure (R) enantiomer of commercial origin (Acros).
M. H. D. Postema, Tetrahedron 1992, 48, 8545Ϫ8600.
D. Monti, P. Gramatica, G. Speranza, P. Manitto, Tetrahedron
Lett. 1987, 28, 5047Ϫ5048.
`
V. Michelet is grateful to the Ministere de lЈEducation Nationale,
de la Recherche et de la Technologie for a grant (1993Ϫ1996). K.
Adiey is grateful to the Ministere de lЈEducation Nationale et de
[14]
[15]
`
´
ˆ
[16]
lЈEnseignement Superieur et Technologique de Cote dЈIvoire for a
grant (1997Ϫ2000). We are also thankful to Marie-Noelle Rager
for performing the NOE experiments.
Various other basic conditions, including those used by Liu and
Donaldson[7e] (MeONa, MeOH, toluene, 60°C), failed in our
hands to ensure β-epimerization of 15-α to less than a 5:95 ra-
tio.
S. Czernecki, J.-M. Valery, J. Carbohydr. Chem. 1988, 7,
151Ϫ156. S. Czernecki, S. Horns, J.-M. Valery, J. Org. Chem.
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D. T. Connor, R. C. Greenough, M. von Strandtmann, J.
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Received February 12, 1999
[O99094]
2892
Eur. J. Org. Chem. 1999, 2885Ϫ2892