New approaches towards the synthesis of the side-chain of mycolactones A and B

Article abstract of DOI:10.1039/b505980a

New approaches towards the synthesis of the C1′-C16′ side-chain of mycolactones A and B from Mycobacterium ulcerans are reported. Chiral building block 4 (Fig. 2) with the correct stereochemistry was obtained starting from naturally occurring monosacchari

Full text of DOI:10.1039/b505980a

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
New approaches towards the synthesis of the side-chain of
mycolactones A and B
Ruben P. van Summeren, Ben L. Feringa* and Adriaan J. Minnaard*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
E-mail: B.L.Feringa@rug.nl, A.J.Minnaard@rug.nl; Fax: +31-503634296
Received 28th April 2005, Accepted 20th May 2005
First published as an Advance Article on the web 15th June 2005
New approaches towards the synthesis of the C1ꢀ–C16ꢀ side-chain of mycolactones A and B from Mycobacterium
ulcerans are reported. Chiral building block 4 (Fig. 2) with the correct stereochemistry was obtained starting from
naturally occurring monosaccharides, i.e. D-glucose or L-rhamnose. The polyunsaturated moiety 3 was synthesized in
only 3 steps from 2,4-dimethylfuran. The building blocks were connected through a Sonogashira coupling resulting
in the fast and convergent assembly of an 8,9-dehydro analogue 2 of the side-chain of mycolactones A and B. The
synthesis of 1 is at this stage hampered by the lack of a selective partial hydrogenation protocol for alkynes embedded
in a conjugated system. Alternative strategies involving palladium catalyzed sp2–sp2 coupling between C7ꢀ and C8ꢀ or
C9ꢀ and C10ꢀ (Fig. 1) were also explored.
a Sharpless asymmetric dihydroxylation reaction to introduce
Introduction
the stereogenic centers on C12ꢀ and C13ꢀ (a : b ratio of 3.8 : 1),
Buruli Ulcer is a severe skin disease, caused by Mycobacterium
ulcerans, occurring primarily in tropical countries. Infection by
M. ulcerans results in the formation of large, painless necrotic
while Gurjar and Cherian started from D-glucose. At first glance,
the choice to use a chiral catalyst instead of a compound from
the natural pool can be appreciated, as the naturally occurring
ulcers in the absence of an acute inflammatory response.1,2 Small
sugars with the correct stereochemistry are rare and expensive L-
and co-workers showed that the bacterium uses a heterogeneous
sugars (D-sugars result in C15ꢀ-epimers). Nonetheless, we believe
mixture of polyketide toxins known as mycolactones A, B, C
that using monosaccharides is preferable, because it provides
and D for tissue destruction and immune suppression.3,4,5,6 In
absolute stereocontrol and the correct stereochemistry can be
2002, Kishi and co-workers reported the first total synthesis
installed in a straightforward manner by epimerization of a sin-
of mycolactones A and B (Fig. 1), confirming the relative and
gle stereocenter. Moreover, sugars offer an easy method to make
absolute stereochemistry.7,8 Further research into the (biologi-
analogues due to the wide variety of monosaccharides available.
cal) properties of mycolactones A and B and analogues thereof
As outlined in the retrosynthetic analysis (Fig. 2), we planned
has been impeded by the difficulty of obtaining the compounds
to synthesize the C1ꢀ–C16ꢀ side-chain of mycolactone A and B
in sufficient quantities. A general and efficient synthetic route
which would allow easy access to the target compound as well as
analogues is therefore highly desirable. In our efforts to achieve
(1) by partial hydrogenation of an 8,9-dehydro analogue 2. The
assembly of 2 was envisioned by connection of conjugated unit
3 (C1ꢀ–C9ꢀ) to chiral moiety 4 (C10ꢀ–C16ꢀ) via Sonogashira
this goal, we initially restricted our target to the unsaturated
coupling. For the synthesis of fragment 3 a new strategy was
side-chain 1 (C1ꢀ–C16ꢀ; Fig. 1) of the molecule.
Fig. 1 Mycolactones A and B are related to each other through
cis–trans isomerisation at the C4ꢀ–C5ꢀ double bond.
Retrosynthesis
Until today, the synthesis of the C1ꢀ–C16ꢀ fragment of myco-
lactones A and B has only been reported by Kishi et al. in
2002.7 Prior to that, when the stereochemistry was still unknown,
the synthesis of a C15ꢀ-epimer was published by Gurjar and
Cherian.9 Both syntheses are based on the coupling of a chiral
moiety to a conjugated chain, which is assembled by a series
of Horner–Wadsworth–Emmons chain-elongation reactions.
Kishi’s approach towards the chiral part (C8ꢀ–C16ꢀ) relied on
Fig. 2 Retrosynthetic analysis.
2 5 2 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

View Article Online
chosen, which significantly reduces the number of steps in the
preparation of the conjugated system as compared to previous
routes.7,9 For the assembly of 4, two routes starting from different
monosaccharides were explored.
A building block with the correct stereochemistry (13) was
synthesized in only six steps from D-glucose according to the
procedure of Redlich et al. (Scheme 2).14 First, the reduction
of the 4- and 6-hydroxyl moieties was realized in two steps
without protecting the 2- and 3-hydroxyl functions; methyl a-D-
glucopyranoside (8) was reacted with sulfuryl chloride resulting
in dichloro compound 9 (56%) with exclusively the galacto-
configuration as described by Jones et al.15 Subsequent radical
reduction with tributyltin hydride and a catalytic amount of
AIBN gave the reduced product 10 in 89% isolated yield. Ring-
opening and protection of the aldehyde were achieved in one
pot by stirring in 37% HCl in the presence of 1,3-propanedithiol
leadingtodithioacetal 11 (87%). The 2- and 3-hydroxyl functions
were regioselectively protected as their acetonide by reaction
with acetone under acidic conditions (12; 95%), after which the
5-hydroxyl group was epimerized in a Mitsunobu reaction with
benzoic acid resulting in 13 (82%) and a dehydrated side product
(16%).14 Comparison of the 13C-NMR spectra of 13 with its
epimer obtained from the reaction of 12 with benzoyl chloride
showed that there was only one diastereoisomer present.
Results and discussion
Synthesis of the conjugated building block (3)
2,4-Dimethylfuran was synthesized according to the procedure
of Morel and Verkade in two steps starting from mesityl
oxide.10 It was subsequently submitted to a rhodium-catalyzed
reaction with ethyl diazoacetate to give a mixture of 5a
(18% isolated yield) and the desired 5b (47% isolated yield),
which were separated by column chromatography (Scheme 1).11
Horner–Wadsworth–Emmons reaction of 5b with diethyl (3-
trimethylsilyl-2-propynyl) phosphonate (6),12 gave 7 in 61% yield
as a mixture of cis–trans-isomers which could not be separated
at this stage.13 The preparation of the conjugated building
block was concluded by cleavage of the TMS-group with TBAF
resulting in the unstable terminal alkyne 3a (80%).
Scheme 1 Synthesis of conjugated system 3a; (a) 0.4 mol% Rh2(OAc)4,
CH2Cl2, EDAa, 15 h; (b) I2, CH2Cl2, 12 h (5a 18%, 5b 47%);
(c) NaHMDS, HPO(OEt)2, THF, −10 ◦C, 1 h (78%); (d) n-BuLi, THF,
0 ◦C to rt, 3.5 h (61%); (e) TBAF, THF, EtOAc, 0 ◦C, 45 min (80%). a
EDA = ethyl diazoacetate.
Synthesis of the chiral building block (4)
In order to obtain chiral building block 4 with the required
stereochemistry, two routes were explored starting from either
cheap and readily available methyl a-D-glucopyranoside or
methyl a-L-rhamnopyranoside. In the case of D-glucose, the
hydroxyl moieties at the 4- and 6-positions need to be reduced
and the stereocenter at the 5-position needs to be epimerized. L-
rhamnose requires reduction at the 4-position and epimerization
at the 3-position (see Fig. 3).
Scheme
2
Synthesis of 4a from methyl a-D-glucopyranoside;
(a) SO2Cl2, pyridine, CHCl3, −78 to 50 ◦C, 7 h (56%); (b) Bu3SnH,
AIBNa, toluene, reflux, 12 h (89%); (c) 1,3-propanedithiol, 37% HCl,
12 h (87%); (d) acetone, CuSO4, H2SO4, 12 h (95%); (e) PPh3, BzOH,
DEADb, THF, 1.5 h (82%); (f) MeI, acetone, H2O, 2,4,6-collidine, reflux,
12 h;◦(g) PPh3, CBr4, CH2Cl2, 0 ◦C to rt, 1.5 h (72%); (h) LDAc, THF,
−78 C, 2 h (88%); (i) LDAc, HMPAd, MeI, THF, −78 to −10 ◦C,
2 h (88%); (j) PdCl2(PPh3)2, Bu3SnH, pentane (63%); (k) CH2Cl2, I2,
−78 ◦C to rt, 20 min (99%). a AIBN = 2,2ꢀ-azobis(2-methylpropionitrile),
b DEAD = diethyl azodicarboxylate, c LDA = lithium diisopropylamide,
dHMPA = hexamethylphosphoramide.
With the stereochemistry in place, the next objective was to
elongate the chain of 13 in order to make it suitable for coupling.
Deprotection of the aldehyde proved not to be straightforward as
the dithioacetal was resistant to mercury salts16 and low yields
were obtained with NBS17 in acetone and water. Eventually,
treatment with MeI and 2,4,6-collidine in a refluxing mixture of
acetone and water gave the aldehyde (14; no epimerization at
C2 observed), which was used without further purification.18
Reaction of 14 with CBr4 and PPh3 under Corey–Fuchs
Fig. 3 Target chiral building block from D-glucopyranoside and
L-rhamnopyranoside; in the case of glucose, C4–OH and C6–OH have
to be reduced and C5–OH epimerized. In the case of rhamnose, C4–OH
has to be reduced and C3–OH epimerized.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3
2 5 2 5

View Article Online
conditions gave dibromo-olefin 15 in 72% yield over 2 steps.19,20
Elimination of HBr by treatment with LDA followed by a protic
work-up resulted in the terminal alkyne 16 (88%),21 which was
converted into the methylated alkyne 17 (88%) by reaction with
LDA and MeI in the presence of HMPA.22 The direct synthesis
of 17 from 15 by treatment with MeI and n-BuLi or t-BuLi
was unsuccessful, due to the intolerance of the benzoyl-group to
these conditions.
Palladium-catalyzed hydrostannation of the internal alkyne
was troublesome, due to palladium-black formation.23 Increas-
ing the catalyst-loading resulted in additional side-product
formation. Fortunately, changing the solvent from THF to
pentane prevented Pd-black formation improving the yield of
18 from 45% to 63%.24 Moreover, the regioselectivity of the
reaction was superior in pentane enhancing the ratio of terminal
to internal hydrostannation product from 2.6 : 1 in THF to 6.3 :
1 in pentane (2D-1H-NMR). The synthesis of the chiral moiety
was completed by exchange of the tributyltin moiety with iodine
to give 4a (99%).23
An alternative synthesis from methyl a-L-rhamnopyranoside
(19; Scheme 3) started with regioselective protection of the
C2- and C3-hydroxyl moieties as their acetonide by reaction
with acetone under acidic conditions leading to 20 (90%).25
The remaining free C4–OH was then reacted with 1,1ꢀ-
thiocarbonyldiimidazole to give the activated precursor 21 for
a Barton–McCombie reduction in quantitative yield.26 Radical
reduction of 21 gave the deoxygenated product 22.21,27 Cleavage
of the acetonide was first attempted with trifluoroacetic acid
(55% over 2 steps), but the results with the milder amberlite
H+-resin proved to be superior giving the diol 23 in 71%
over 2 steps.28 Selective protection of the C2–OH was then
achieved by reaction of 23 with trimethyl orthoacetate followed
by partial hydrolysis of the resulting orthoester 24 leading to the
formation of monoacetate 25 (80%).26 It should be noted that
the regioselectivity in the hydrolysis step strongly depended on
the choice of solvent. In acetonitrile a 3 : 1 mixture of C2 : C3 O-
acetylated regioisomers was obtained, while in dichloromethane
only the desired C2 O-acetylated product was observed.
Subsequent epimerization of the C3-center proved not to
be straightforward. Mitsunobu conditions gave only very low
conversions (<10%) and the alternative procedure comprising
formation of trifluoromethylsulfonate 26 followed by an SN2
substitution with tetraethylammonium acetate gave no conver-
sion at all. However, changing to tetrabutylammonium acetate
showed a remarkable improvement leading to the formation
1
of 27 in 71% yield.29,30 Comparison of the H- and 13C-NMR
spectra of 27 with the acetylated product of 23 proved that
epimerization had indeed taken place. An attempt was made to
deprotect the hydroxyl moieties and to form the dithioacetal
in one pot by stirring 27 in HCl (37% aq.) in the presence
of 1,3-propanedithiol, but only 21% of 29 was isolated. The
acetyl-groups were therefore first removed under mildly basic
conditions (pH 9) giving 28, after which ring opening proceeded
very well providing 29 in 89% yield over two steps. Acetonide-
protection of two hydroxyl moieties by an acid catalysed
reaction with acetone gave the two regioisomers 30 (8%) and
the desired 31 (78%), which could be separated by column
chromatography.14 After protection of the remaining C5–OH of
31 with TBDMSCl (84%, 32),31 the dithioacetal was deprotected
as before to give aldehyde 33 in 89% yield. Unfortunately, the
TBDMS–ether was not stable under Corey–Fuchs conditions
giving a complex mixture of products. Obviously, the target
molecule 4a can be synthesized from 31 as described above for
D-glucose when a benzoyl ester is chosen as a protecting group.
Overall, the route from D-glucose was preferred as it is more
cost-effective and concise; less steps are required and the overall
yield is higher.
Coupling of the building blocks and partial hydrogenation
Sonogashira coupling of terminal alkyne 3a to vinyl iodine 4a
proceeded quantitatively resulting in the isolation of 2a in an
excellent 94% yield (Scheme 4). We anticipated that partial cis-
hydrogenation of the internal alkyne of 8,9-dehydro analogue 2a
would lead to 1 after deprotection and isomerization to its all
trans configuration.13,32
Scheme 4 Coupling of the building blocks and subsequent partial
hydrogenation; (a) Pd(PPh3)4, CuI, iPr–NH2, 2 h (94%); (b) H2, Lindlar
catalyst, hexanes, EtOAc, quinoline, 12 h; (c) Zn, Cu(OAc)2·H2O,
AgNO3, H2O, MeOH, 12 h; (d) H2, THF, Elsevier catalyst, 3 h;
(e) Ni(OAc)2·4H2O, EtOH, hydrazine, NaBH4, H2; see text for details.
Scheme 3 Synthesis of 33 from methyl a-L-rhamnopyranoside; (19 →
20) acetone, CuSO4, H2SO4, 12 h (90%); (20 → 21) 1,2-dichloroethane,
1,1ꢀ-thiocarbonyldiimidazole, reflux, 2 h (quant.); (21 → 22) toluene,
AIBNb, tris(trimethylsilyl)silane, reflux, 30 min; (22 → 23) water,
1,4-dioxane, amberlite(120)H+, 12 h (71% from 21); (23 → 25)
(i) p-toluenesulfonic acid·H2O, acetonitrile, trimethyl orthoacetate,
10 min, (ii) CH2Cl2, 90% CF3COOH, 5 min (80%); (25 → 26) CH2Cl2,
pyridine, Tf2O, −10 ◦C to rt, 1.5 h; (26 → 27) toluene, Bu4NOAc, 12 h
(71% from 25); (27 → 28) THF, MeOH, NaOMe (pH 9) 2 h; (28 → 29)
1,3-propanedithiol, 37% aq. HCl, 0 ◦C, 2 h (89% from 27); (29 → 30 +
31) acetone, CuSO4, H2SO4, 12 h (30 in 8% and 31 in 78%); (31 → 32)
DMF, TBDMSCl, imidazole, 70 ◦C, 12 h (84%); (32 → 33) MeI, acetone,
H2O, 2,4,6-collidine, reflux, 12 h (89%). a Itc = imidazolylthiocarbonyl,
Disappointingly, to date, partial hydrogenation of the internal
alkyne to the alkene has not shown sufficient selectivity to be
useful on a preparative scale. Lindlar catalyst was typically un-
reactive regardless of the solvent, temperature, catalyst loading,
and/or hydrogen pressure. Only at 65 bar of hydrogen some
conversion was observed, but with a lack of selectivity leading
to overreduction. The Zn(Cu/Ag)-reduction method in aqueous
MeOH as developed by Boland et al., is known to selectively
hydrogenate triple bonds which are embedded in a conjugated
system and has been successfully used on systems similar to
2a.33,34 However, Zn(Cu/Ag)-reduction resulted in a mixture of
b
AIBN = 2,2ꢀ-azobis(2-methylpropionitrile).
2 5 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3

View Article Online
(over)reduced products containing only traces of a compound
with the correct mass (as observed with GC-MS). Even though
the desired product was likely to be in the mixture, this could
not be confirmed by isolation and full characterization. In any
case, the lack of selectivity in the partial reduction of the alkyne
precludes this strategy as a viable synthetic pathway at this stage.
To the best of our knowledge, the partial reduction of alkynes
in conjugation with an ester using Zn(Cu/Ag) is not known
in literature.35 Moreover, free hydroxyl moieties are known to
occasionally aid the selectivity of Zn(Cu/Ag)-reductions. We
therefore decided to attempt the partial reduction of the internal
alkyne on the analogue of 2a having a terminal alcohol instead
of an ethyl ester. This approach did not lead to a significant
improvement of selectivity. Removal of the isopropylidene-
moiety of 2a was not beneficial either. An effort was made
with a homogeneous palladium catalyst developed by Elsevier
for selective alkyne hydrogenation, but no conversion was
seen in this case.36 Ni-catalysed reduction with NaBH4 on the
other hand proved to be too active and gave only overreduced
product.37
after deprotection with TBAF. Compound 36 was then used in a
Negishi coupling to 35 resulting in the isolation of the terminal
alkene 37 and the starting material 35 suggesting that at least
the initial hydrozirconation was successful.43 Hydrostannation
of 36 using a stannylcuprate gave 38 in low yield (16%),38a but
Stille coupling to 34 was unsuccessful once again.44
Conclusions
From the above results it is concluded that the application of
monosaccharides is a viable alternative to asymmetric catal-
ysis for the synthesis of the chiral part of the side-chain of
mycolactones A and B and analogues thereof. Furthermore,
it has been demonstrated that an efficient route is available
to rapidly assemble a conjugated building block 3a from 2,4-
dimethylfuran. The Pd-catalyzed coupling of the conjugated
3a and the chiral building block 4a constitutes a concise
and efficient synthesis of an 8,9-dehydro analogue 2a of the
side-chain of mycolactones A and B. Although Zn(Cu/Ag)-
reduction of 2a seems to give small quantities of the desired
product, the lack of selectivity in this reaction still obstructs the
synthesis of 1 on a synthetically useful scale at this stage.
Alternative strategies
As an alternative approach, we tried to functionalize ter-
minal alkyne 3a to obtain an olefin suitable for palladium
catalyzed sp2–sp2 coupling. In our hands, however, compound
3a was unreactive towards stannylcupration (Bu3SnH, CuCN,
n-BuLi),38 and hydrozirconation (Schwartz reagent),39 while
palladium catalyzed hydrostannation resulted exclusively in the
undesired internal regioisomer.40 Even though it is known that
palladium catalyzed hydrostannation on terminal alkynes in
direct conjugation with an ester predominately gives the a-
addition product,23,41 we were surprised to find that this also
holds true when the ester and terminal alkyne are separated by
three double bonds.
In a final attempt, the point of connection of the building
blocks was changed from C9ꢀ–C10ꢀ to C7ꢀ–C8ꢀ (see Fig. 2). This
new strategy implied that the conjugated building block needed
to be one double bond shorter (i.e. 34 and 35), while the chiral
building block required elongation by two carbon atoms (i.e.
36).
Experimental
General experimental remarks: reagents were purchased from
Aldrich, Acros Chimica, Merck or Fluka and were used as
received unless otherwise stated. All solvents were reagent grade
and were dried and distilled before use according to standard
procedures. Chromatography: silica gel, Merck type 9385 230–
400 mesh, TLC: silica gel 60, Merck, 0.25 mm. Components
were visualized by staining with (a) KMnO4 or (b) a mixture
of phosphomolybdic acid (25 g), cerium(IV) sulfate (7.5 g),
H2O (500 mL) and H2SO4 (25 mL). Optical rotations were
measured on a Perkin-Elmer 241 or 241 MC polarimeter.
1
Mass spectra (HRMS) were recorded on an AEI MS-902. H
and 13C NMR spectra were recorded on a Varian Gemini-
200 (50.32 MHz), a Varian VXR300 (75.48 MHz) or a Varian
AMX400 (100.59 MHz) spectrometer in CDCl3. Chemical shift
values are denoted in d values (ppm) relative to residual solvent
1
peaks (CHCl3, H d = 7.26, 13C d = 76.9). Carbon types were
determined from APT 13C experiments.
The first objective was met by reacting 5b in a Wittig
reaction with BrCH2PPh3Br (34, 40% isolated yield) or its
iodine analogue (35, 13% isolated yield; Scheme 5).42 The
second goal was realized by Sonogashira coupling of 4a with
trimethylsilylacetylene (97%),32 giving the free alkyne 36 (86%)
4-Methyl-6-oxo-hepta-2,4-dienoic acid ethyl ester (5a and 5b)
Rh2(OAc)4 (10 mg, 23 lmol) and 2,4-dimethylfuran (1.0 g,
10.4 mmol, 2.0 eq) were dissolved in dichloromethane (14.3 mL)
under argon and a solution of ethyl diazoacetate (0.55 mL,
5.2 mmol) in dichloromethane (3.6 mL) was slowly added over
10 h employing a syringe pump. The resulting solution was
stirred for another 5 h at which point the catalyst was removed
by filtration over a Florisil column. The green solution was then
concentrated and the residue was taken up in dichloromethane
(14.3 mL) and stirred overnight under argon in the presence
of a catalytic amount of I2. The resulting black solution was
washed with Na2S2O3 (10% aq.) and brine, dried (Na2SO4) and
concentrated. The product was purified by column chromatog-
raphy (hexane–EtOAc 9 : 1) to give 5a (0.17 g, 0.93 mmol, 18%)
and the all-trans-isomer 5b (0.44 g, 2.4 mmol, 47%). The latter
was a yellow liquid which became crystalline upon standing at
4 ◦C. When 5a was treated with I2 in dichloromethane, a mixture
of 5a and 5b in the same ratio as before was formed. 1H-NMR
5a (CDCl3, 300 MHz) d = 1.30 (t, 3H, CH3CH2O, J = 7.2 Hz),
2.01 (s, 3H, CH3), 2.25 (s, 3H, C7-H), 4.23 (q, 2H, CH3CH2O,
J = 7.2 Hz), 6.17 (d, 1H, C2-H, J = 15.9 Hz), 6.27 (s, 1H, C5-H),
8.39 (d, 1H, C3-H, J = 16.2 Hz) ppm.
Scheme 5 Alternative coupling strategies; (a) n-BuLi, piperidine,
XCH2PPh3X, THF, 8 h (40% for 34 and 13% for 35); (b) Pd(PPh3)4,
CuI, i-PrNH2, TMS–acetylene 1 h (97%); (c) TBAF, THF, 0 ◦C, 1 h
(86%); (d) (i) 36, THF, ZrHClCp2, 5 h; (ii) PdCl2(PPh3)2, DIBAL-H,
35, 15 min; (iii) solution of 35 added to solution of 36, ZnCl2, 12 h;
(e) CuCN, n-BuLi, Bu3SnH, THF, −30 ◦C (16%); (f) Pd(PhCN)2Cl2,
DMF, THF, (i-Pr)2NEt.
1H-NMR 5b (CDCl3, 300 MHz) d = 1.30 (t, 3H, CH3CH2O,
J = 7.2 Hz), 2.22 (s, 3H, CH3), 2.26 (s, 3H, C7-H), 4.23 (q, 2H,
CH3CH2O, J = 7.2 Hz), 6.24 (d, 1H, C2-H, J = 15.6 Hz), 6.36
(s, 1H, C5-H), 7.24 (d, 1H, C3-H, J = 15.6 Hz) ppm. 13C-NMR
5b (CDCl3, 50.3 MHz) d = 13.6 (q), 14.1 (q), 32.0 (q), 60.7 (t),
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3
2 5 2 7

View Article Online
124.2 (d), 131.8 (d), 146.7 (s), 147.3 (d), 166.2 (s), 198.9 (s)
ppm. MS(EI) for C10H14O3: m/z = 182 [M+], HRMS calcd for
C10H14O3: 182.094, found: 182.095.
2.04 (s, 3H, C4-CH3), 3.22 (d, 1H, C9-H, J = 2.4 Hz), 4.21 (q,
2H, CH3CH2O), 5.49 (s, 1H, C7-H), 5.94 (d, 1H, C2-H, J =
15.6 Hz), 6.71 (s, 1H, C5-H), 7.39 (d, 1H, C3-H, J = 16.0 Hz)
ppm. MS(EI) for C13H16O2: m/z = 204 [M+], HRMS calcd for
C13H16O2: 204.115, found: 204.116.
(3-Trimethylsilanyl-prop-2-ynyl)-phosphonic acid diethyl ester
(6)
Methyl 4,6-dideoxy-4,6-dichloro-a-D-galactopyranoside (9)
To a solution of NaHMDS (1.0 M in THF, 26 mL, 26 mmol) at
◦
−10 C was added diethyl phosphonate (3.4 mL, 26 mmol) in
Methyl a-D-glucopyranoside (8) (42.5 g, 218 mmol) was dis-
solved in pyridine–chloroform (430 mL, 1 : 1 v/v) and sulfuryl
chloride (142 mL, 236 g, 1.75 mol, 8 eq.) was added dropwise at
−78 ◦C under argon. The resulting yellow solution was stirred
for 2 h while slowly warming to rt. Subsequently, the solution
was heated to 50 ◦C and stirred for another 5 h. After cooling to
rt, the solution was diluted with MeOH and water, neutralized
with Na2CO3·10H2O and quenched with a NaI-solution (16 g
in 40 mL water–MeOH, 1 : 1 v/v). The resulting solution
was concentrated in vacuo by co-evaporation with toluene and
purified by continuous liquid–liquid extraction from water with
chloroform. Concentration in vacuo gave a brown–red solid
which was further purified by crystallization from chloroform to
give white crystals (28.1 g, 122 mmol, 55.8%). 1H-NMR (CDCl3,
300 MHz) d = 2.20 (br s, 2H, C2-OH, C3-OH), 3.48 (s, 3H, C1-
OCH3), 3.68 (d, 2H, C6-H, J = 6.6 Hz), 3.85 (dd, 1H, C2-H,
J = 3.6, 9.6 Hz), 3.99 (dd, 1H, C3-H, J = 3.6, 9.6 Hz), 4.14 (t,
1H, C5-H, J = 6.6 Hz), 4.53 (d, 1H, C4-H, J = 3.3 Hz), 4.86
(d, 1H, C1-H, J = 3.6 Hz) ppm. 13C-NMR (DMSO, 50.3 MHz)
d = 44.4 (t), 54.7 (q), 64.9 (d), 67.6 (d), 67.7 (d), 69.3 (d), 99.9
(d) ppm.
THF (8.0 mL) under argon. This solution was stirred for 15 min
and then treated with (3-bromo-prop-1-ynyl)-trimethylsilane
(3.7 mL, 26 mmol) in THF (8.0 mL) maintaining the temperature
at −10 ◦C. After stirring for 1 h, the reaction was quenched with
water and the aqueous layer was extracted with EtOAc (× 2). The
combined organic layers were washed with HCl (2 M) and water,
dried (Na2SO4) and concentrated. The product was purified by
column chromatography (pentane–EtOAc 4 : 1 to 1 : 1) giving 6
1
(5.1 g, 20 mmol, 78%) as a colorless liquid. H-NMR (CDCl3,
300 MHz) d = 0.14 (s, 9H, TMS), 1.34 (t, 6H, CH3CH2O, J =
7.2 Hz), 2.80 (d, 2H, CH2, J = 22.2 Hz), 4.18 (q, 4H, CH3CH2O)
ppm. 13C-NMR (CDCl3, 50.3 MHz) d = −0.3 (q), 16.2 (q), 16.3
(q), 17.8 (t), 20.6 (t), 62.9 (t), 63.0 (t) ppm.
4,6-Dimethyl-9-trimethylsilanyl-nona-2,4,6-trien-8-ynoic acid
ethyl ester (7)
6 (1.0 g, 4.0 mmol, 2.0 eq) was dissolved in THF (20 mL) and
n-BuLi (1.6 M in hexane, 2.5 mL, 4.0 mmol) was added at 0 ◦C
under argon. After stirring for 30 min of which the last 10 were
at rt, the solution had turned dark red. At this point, a solution
of 5b (367 mg, 2.01 mmol) in THF (8.0 mL) was added upon
which the color slowly changed to brown. The reaction mixture
was stirred for 3 h and then quenched with NH4Cl (sat). The
aqueous layer was extracted with Et2O (× 3) and the combined
organic layers were washed with brine (sat.), dried (Na2SO4) and
concentrated. 7 (336 mg, 1.22 mmol, 61%, mixture of 2 cis–trans
isomers with a ratio of approximately 4 : 1) was isolated as a
yellow solid after column chromatography (hexane–EtOAc 98 :
2 to 95 : 5 to 4 : 1). 1H-NMR major isomer (CDCl3, 500 MHz)
d = 0.22 (s, 9H, TMS), 1.30 (t, 3H, CH3CH2O, J = 7.0 Hz), 2.00
(s, 3H, C6-CH3), 2.14 (s, 3H, C4-CH3), 4.21 (q, 2H, CH3CH2O),
5.59 (s, 1H, C7-H), 5.91 (d, 1H, C2-H, J = 15.5 Hz), 6.28 (s, 1H,
C5-H), 7.32 (d, 1H, C3-H, J = 15.5 Hz) ppm. 13C-NMR (CDCl3,
50.3 MHz) d = −0.1 (q), 13.9 (q), 14.2 (q), 19.7 (q), 60.2 (t), 103.0
(s), 103.5 (s), 113.2 (d), 117.8 (d), 134.5 (s), 140.3 (d), 147.3
Methyl 4,6-dideoxy-a-D-xylo-hexopyranoside (10)
Bu3SnH (30 mL, 32 g, 0.11 mol) was added dropwise to a
solution of 9 (5.3 g, 23 mmol) in refluxing dry toluene (180 mL)
under argon and AIBN (catalytic) was added. The resulting
solution was refluxed overnight and then cooled to rt and
concentrated in vacuo. The obtained oil was diluted with CH3CN
and washed with hexanes (× 2). Concentration gave a solid
which was dissolved in water and washed with Et2O (× 3).
Concentration of the aqueous layer gave a white solid which was
further purified by column chromatography (dichloromethane–
MeOH 19 : 1 to 9 : 1) to give pure 10 (3.3 g, 20 mmol, 89%).
When the reaction was performed on larger scale, purification
1
was done by crystallization from chloroform and pentane. H-
NMR (CDCl3, 300 MHz) d = 1.21 (d, 3H, C6-H, J = 6.3 Hz),
1.36 (q, 1H, C4-H), 1.98 (ddd, 1H, C4-Hꢀ, J = 2.4, 5.1, 12.9 Hz),
2.05 (d, 1H, OH, J = 10.2 Hz), 2.46 (d, 1H, OH, J = 2.1), 3.33–
3.44 (m, 1H, C2-H), 3.41 (s, 3H, C1-OCH3), 3.77–3.95 (m, 2H,
C3-H, C5-H), 4.75 (d, 1H, C1-H, J = 3.6 Hz) ppm. 13C-NMR
(CDCl3, 50.3 MHz) d = 20.7 (q), 39.6 (t), 55.1 (q), 64.0 (d), 68.9
(d), 74.3 (d), 99.7 (d) ppm.
1
(s), 149.7 (d), 167.1 (s) ppm. H-NMR minor isomer (CDCl3,
500 MHz) d = 0.18 (s, 9H, TMS), 1.31 (t, 3H, CH3CH2O), 1.95
(s, 3H, C6-CH3), 2.04 (s, 3H, C4-CH3), 4.21 (q, 2H, CH3CH2O),
5.53 (s, 1H, C7-H), 5.94 (d, 1H, C2-H, J = 14.5 Hz), 6.68 (s,
1H, C5-H), 7.39 (d, 1H, C3-H, J = 15.5 Hz) ppm. MS(EI)
for C16H24O2Si: m/z = 276 [M+], HRMS calcd for C16H24O2Si:
276.155, found: 276.155.
4,6-Dideoxy-D-xylo-hexose-trimethylen-dithioacetal (11)
4,6-Dimethyl-nona-2,4,6-trien-8-ynoic acid ethyl ester (3a)
1,3-Propanedithiol (6.8 mL, 7.1 g, 65 mmol) was added to a
solution of 10 (6.0 g, 37 mmol) in 37% HCl (68 mL) and
stirred overnight. The solution was then neutralized with 25%
ammonia and concentrated in vacuo. The resulting white solid
was stirred in acetone for 1 h after which the suspension was
filtered and the filtrate concentrated. Purification by column
chromatography (dichloromethane–MeOH 9 : 1) gave 11 (7.7 g,
32 mmol, 87%) as a white solid. Alternatively, 11 could be
purified by crystallization from dichloromethane–MeOH. [a]D
TBAF (1.0 M in THF, 1.45 mL, 1.45 mmol, 4.0 eq) was stirred for
30 min under argon in the presence of EtOAc (47 ll, 0.48 mmol).
The solution was cooled to 0 ◦C and 7 (100 mg, 0.36 mmol) in
dry THF (1.8 mL) was added. The mixture was stirred for 45 min
◦
at 0 C and then quenched with NH4Cl (sat.), dried (Na2SO4)
and concentrated. 3a (59 mg, 0.29 mmol, 80%) was isolated
after column chromatography (pentane–EtOAc 95 : 5) as a
colorless oil, which turned brown within 15 min. The product
was therefore immediately used in the next step. 1H-NMR major
isomer (CDCl3, 200 MHz) d = 1.29 (t, 3H, CH3CH2O, J =
7.0 Hz), 1.99 (d, 3H, C6-CH3, J = 0.8 Hz), 2.13 (s, 3H, C4-
CH3), 3.38 (d, 1H, C9-H, J = 2.4 Hz), 4.21 (q, 2H, CH3CH2O),
5.54 (s, 1H, C7-H), 5.91 (d, 1H, C2-H, J = 15.6 Hz), 6.28 (s, 1H,
C5-H), 7.31 (d, 1H, C3-H, J = 15.6 Hz) ppm.
20
−30.3 (c 1.09 in MeOH), (lit.,9 [a]D −29.5 (c 1.00 in MeOH)).
1H-NMR (CDCl3, 300 MHz) d = 1.27 (d, 3H, C6-H, J = 6.3 Hz),
1.60 (ddd, 1H, C4-H), 1.89 (ddd, 1H, C4-Hꢀ), 2.03 (m, 2H,
dithian-H), 2.70 (m, 2H, dithian-H), 2.92 (m, 2H, dithian-H),
3.74 (d, 1H, C2-H, J = 8.1 Hz), 4.03 (d, 1H, C3-H, J = 8.1 Hz),
4.17 (m, 1H, C5-H), 4.31 (d, 1H, C1-H, J = 9.6) ppm. 13C-
NMR (CDCl3, 50.3 MHz) d = 23.6 (q), 25.3 (t), 26.8 (t), 27.4
(t), 42.3 (t), 47.6 (d), 65.3 (d), 67.7 (d), 73.3 (d) ppm. MS(EI)
1H-NMR minor isomer (CDCl3, 200 MHz) d = 1.30 (t, 3H,
CH3CH2O, J = 7.0 Hz), 1.95 (d, 3H, C6-CH3, J = 1.0 Hz),
2 5 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3

View Article Online
for C9H18O3S2: m/z = 238 [M+], HRMS calcd for C9H18O3S2:
acetone was removed in vacuo. The remaining solution was
diluted with dichloromethane, washed with 2 M HCl (× 3),
NaHCO3 (sat.) and brine, dried over MgSO4 and concentrated.
The crude 14 was used without purification in the next step
after overnight drying in vacuo over P2O5. Triphenylphosphine
(18.6 g, 71.1 mmol, 4eq) was dissolved in freshly distilled dry
dichloromethane (47 mL) and CBr4 (sublimed prior to use,
11.8 g, 35.6 mmol, 2 eq) in dichloromethane (47 mL) was
238.070, found: 238.069.
4,6-Dideoxy-2,3-O-isopropyliden-D-xylo-hexose-trimethylen-
dithioacetal (12)
11 (2.2 g, 9.2 mmol) was dissolved in dry acetone and CuSO4
(2.9 g, 18.5 mmol, 2 eq) and a drop of H2SO4 were added. The re-
sulting green suspension was stirred overnight and then filtered.
The filtrate was neutralized with 25% ammonia and the resulting
blue suspension was filtered again. The filtrate was concentrated,
suspended in brine and extracted with dichloromethane (× 3).
The combined organic layers were dried (Na2SO4), filtered and
concentrated. Purification by column chromatography (hexane–
EtOAc 4 : 1) gave 12 (2.4 g, 8.7 mmol, 95%) as a colorless oil. [a]D
◦
added at 0 C under argon. The resulting yellow–red solution
was stirred for 10 min after which the crude aldehyde in
dichloromethane (42 mL) was added dropwise. The solution
was then allowed to reach rt and was stirred until TLC showed
the reaction to be complete (approximately 1 h, hexane–EtOAc
4 : 1 to see the product and dichloromethane–MeOH 98 : 2 to see
the aldehyde). The reaction was quenched with sat. NaHCO3,
the aqueous layer was extracted with dichloromethane (× 2),
the combined organic layers were washed with water and brine,
dried (MgSO4) and concentrated. The resulting brown solid was
first filtered over silica (CHCl3) and then further purified by
column chromatography (hexane–EtOAc 9 : 1) to give 15 (5.7 g,
13 mmol, 72%) as a colorless oil. 1H-NMR (CDCl3, 200 MHz)
d = 1.36 (m, 6H, CMe2), 1.42 (d, 3H, C7-H, J = 6.3 Hz), 1.94
(ddd, 1H, C5-H, J = 4.2, 6.2, 14.2 Hz), 2.14 (ddd, 1H, C5-Hꢀ,
J = 14.2 Hz), 3.92 (ddd, 1H, C4-H, J = 4.2, 8.0, 8.0 Hz), 4.34
(dd, 1H, C3-H, J = 8.0, 8.0 Hz), 5.34 (m, 1H, C6-H), 6.42 (d,
1H, C2-H, J = 8.6 Hz), 7.39–7.60 (m, 3H, Bz-H), 8.02–8.07 (m,
2H, Bz-H) ppm. 13C-NMR (CDCl3, 50.3 MHz) d = 20.0 (q), 26.5
(q), 27.0 (q) 38.0 (t), 68.9 (d), 76.8 (d), 80.7 (d), 94.5 (s), 109.6
(s), 128.1 (d), 129.4 (d), 130.6 (s), 132.7 (d), 135.0 (d), 165.8 (s)
ppm. MS(CI) for C17H20O4Br2: m/z = 466 (M + NH4)+.
−55.0 (c 1.04 in MeOH), (lit.,9 [a]D −64.8 (c 1.17 in MeOH)).
20
1H-NMR (CDCl3, 300 MHz) d = 1.24 (d, 3H, C6-H, J = 6 Hz),
1.44 (m, 6H, CMe2), 1.71–2.17 (m, 4H, C4-H, Hꢀ, dithian-H),
2.31 (br s, 1H, OH), 2.77–2.96 (m, 4H, dithian-H), 3.95 (dd, 1H,
C2-H, J = 5.7, 7.8 Hz), 4.08 (m, 1H, C5-H), 4.13 (d, 1H, C1-H,
J = 5.4 Hz), 4.34 (ddd, 1H, C3-H, J = 3.3, 7.8, 7.8 Hz) ppm.
13C-NMR (CDCl3, 50.3 MHz) d = 23.5 (q), 25.6 (t), 26.7 (q),
27.3 (q), 29.2 (t), 29.5 (t), 41.3 (t), 48.0 (d), 65.1 (d), 76.1 (d),
82.2 (d), 109.5 (s) ppm. MS(EI) for C12H22O3S2: m/z = 278 [M+],
HRMS calcd for C12H22O3S2: 278.101, found: 278.101.
5-O-benzoyl-4,6-dideoxy-2,3-O-isopropyliden-L-arabino-hexose-
trimethylen-dithioacetal (13)
Triphenylphosphine (13 g, 50 mmol) and benzoic acid (5.8 g,
48 mmol) were added to a solution of 12 (6.2 g, 22 mmol)
in dry THF (115 mL) at rt. Subsequently, a solution of
diethylazodicarboxylate (DEAD, 8.4 g, 48 mmol) in dry THF
(30 mL) was added over 20 min. The resulting mixture was
stirred for 1 h and then quenched with MeOH and concentrated
in vacuo. Water was added to the resulting oil and the product
was extracted with Et2O (× 3). The combined organic layers were
dried (MgSO4), filtered and concentrated. 13 (7.0 g, 18 mmol,
82%) was obtained as a yellow oil after purification by column
chromatography (hexane–EtOAc 9 : 1 to 4 : 1). The remaining
Benzoic acid 2-(2,2-dimethyl-5-prop-1-ynyl-[1,3]dioxolan-4-yl)-
1-methyl-ethyl ester (17)
To a solution of 15 (3.0 g, 6.7 mmol) in dry THF (77 mL), was
added LDA (0.43 M in THF–hexane, 34 mL, 14.6 mmol, 2.2 eq)
at −78 ◦C under argon. The resulting solution was stirred for 2 h,
after which TLC showed complete conversion. The reaction was
quenched with water, extracted with Et2O (× 2), dried (MgSO4),
filtered and concentrated. The product was purified by column
chromatography (hexane–EtOAc 9 : 1) to give the free alkyne
(16, 1.7 g, 5.9 mmol, 88%) as a colorless oil. 1H-NMR (CDCl3,
200 MHz) d = 1.38–1.45 (m, 9H, C7-H, CMe2, J = 6.2 Hz), 1.97
(ddd, 1H, C5-H), 2.16 (ddd, 1H, C5-Hꢀ), 2.48 (d, 1H, C1-H, J =
1.8 Hz), 4.22 (m, 2H, C3-H, C4-H), 5.36 (m, 1H, C6-H), 7.39–
7.60 (m, 3H, Bz-H), 8.02–8.08 (m, 2H, Bz-H) ppm. 13C-NMR
(CDCl3, 50.3 MHz) d = 20.0 (q), 26.0 (q), 26.9 (q), 38.0 (t), 68.7
(d), 70.1 (d), 74.9 (s), 78.4 (d), 110.1 (s), 128.2 (d), 129.4 (d), 130.5
(s), 132.7 (d), 165.8 (s) ppm. MS(CI) for C17H20O4: m/z = 306
(M + NH4)+, HRMS calcd for C17H20O4–CH3: 273.113, found:
273.114.
16 (425 mg, 1.47 mmol) was dissolved in dry THF (3.7 mL)
and added to a solution of LDA (0.43 M in THF–hexane,
10.2 mL, 4.4 mmol, 3.0 eq) at −78 ◦C under argon. After 3 min,
HMPA (1.28 mL, 1.32 g, 7.37 mmol, 5.0 eq) was added and
after 5 more min, MeI (0.28 mL, 0.63 g, 4.4 mmol, 3.0 eq) was
added. The resulting solution was warmed to −10 ◦C over 2 h,
after which GC-MS showed the reaction to be complete. The
reaction was quenched with 1 M HCl, extracted with Et2O (× 2),
dried (MgSO4), filtered and concentrated. Purification by
column chromatography (pentane–EtOAc 95 : 5 to 9 : 1) gave 17
(392 mg, 1.30 mmol, 88%) as a colorless oil. 1H-NMR (CDCl3,
300 MHz) d = 1.36–1.44 (m, 9H, C8-H, CMe2), 1.75 (s, 3H,
C1-H), 1.93 (ddd, 1H, C6-H), 2.16 (ddd, 1H, C6-Hꢀ), 4.11 (ddd,
1H, C5-H), 4.24 (d, 1H, C4-H, J = 8.1 Hz), 5.35 (m, 1H, C7-
H), 7.41–7.57 (m, 3H, Bz-H), 8.04–8.06 (d, 2H, Bz-H) ppm.
13C-NMR (CDCl3, 50.3 MHz) d = 3.5 (q), 20.1 (q), 26.3 (q),
27.0 (q), 38.0 (t), 68.9 (d), 70.7 (d), 74.7 (s), 78.3 (d), 83.5 (s),
109.3 (s), 128.2 (d), 129.4 (d), 130.6 (s), 132.7 (d), 165.8 (s) ppm.
1
18% was isolated as the dehydrated side product. H-NMR 13
(CDCl3, 200 MHz) d = 1.39–1.44 (m, 9H, C6-H, CMe2), 1.82–
2.20 (m, 4H, C4-H, Hꢀ, dithian-H), 2.67–2.97 (m, 4H, dithian-
H), 3.96 (dd, 1H, C2-H, J = 5.2, 7.6), 4.12 (d, 1H, C1-H, J =
5.2 Hz), 4.26 (ddd, 1H, C3-H, J = 4.4, 7.6, 7.6 Hz), 5.38 (m,
1H, C5-H), 7.38–7.60 (m, 3H, Bz-H), 8.03–8.09 (m, 2H, Bz-H)
ppm. 13C-NMR (CDCl3, 50.3 MHz) d = 19.8 (q), 25.6 (t), 26.7
(q), 27.3 (q), 29.1 (t), 29.5 (t), 39.5 (t), 48.2 (d), 69.0 (d), 75.5 (d),
82.6 (d), 109.6 (s), 128.1 (d), 129.5 (d), 130.6 (s), 132.6 (d), 165.9
(s) ppm. MS(EI) for C19H26O4S2: m/z = 282 [M+], HRMS calcd
for C19H26O4S2: 282.127, found: 282.126.
The C5-epimer of 13 was synthesized by reaction of 12 with
benzoyl chloride in pyridine. 1H-NMR C5-epimer of 13 (CDCl3,
300 MHz) d = 1.39–1.43 (m, 9H, C6-H, CMe2), 1.82–2.25 (m,
4H, C4-H, Hꢀ, dithian-H), 2.74–2.98 (m, 4H, dithian-H), 3.93
(dd, 1H, C2-H, J = 5.7, 7.5), 4.11 (d, 1H, C1-H, J = 5.4 Hz),
4.24 (ddd, 1H, C3-H, J = 2.1, 8.3, 8.3 Hz), 5.32 (m, 1H, C5-H),
7.41–7.71 (m, 3H, Bz-H), 8.06–8.18 (m, 2H, Bz-H) ppm. 13C-
NMR (CDCl3, 50.3 MHz) d = 20.6 (q), 25.6 (t), 26.8 (q), 27.3
(q), 29.1 (t), 29.4 (t), 40.5 (t), 48.05 (d), 69.4 (d), 75.6 (d), 82.6
(d), 109.7 (s), 128.2 (d), 129.5 (d), 130.5 (s), 132.7 (d) ppm.
6-O-benzoyl-1,1-dibromo-5,7-dideoxy-3,4-O-isopropyliden-L-
arabino-hept-1-ene (15)
13 (6.8 g, 18 mmol) was dissolved in acetone (140 mL) and water
(35 mL) and 2,4,6-collidine (23.4 mL, 21.5 g, 178 mmol) and
MeI (11.1 mL, 25.2 g, 178 mmol) were added. The resulting
solution was refluxed under argon for 3.5 h at which point
another portion of MeI (11.1 mL) was added. After refluxing
for another 4.5 h, the mixture was cooled to rt and the
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3
2 5 2 9

View Article Online
MS(CI) for C18H22O4: m/z = 320 (M + NH4)+, HRMS calcd for
cooling to rt, the solvent was removed and the product was
purified by crystallization from ether–hexane and/or by column
chromatography (hexane–EtOAc 4 : 1 to 1 : 1) giving a white
solid (19.0 g, 54.8 mmol, 99.7%). 1H-NMR (CDCl3, 300 MHz)
d = 1.28 (d, 3H, C6-H, J = 6.3 Hz), 1.36, 1.61 (2s, 6H, CMe2),
3.43 (s, 3H, OMe), 3.95 (dq, 1H, C5-H, J5,6 = 6.3 Hz), 4.22 (d,
1H, C2-H, J = 5.4 Hz), 4.37 (dd, 1H, C3-H), 4.95 (s, 1H, C1-H),
5.74 (dd, 1H, C4-H, J = 7.8, 9.9 Hz), 7.07, 7.65, 8.40 (3s, 3H,
imidazole) ppm. 13C-NMR (CDCl3, 50.3 MHz) d = 17.0 (q),
26.1 (q), 27.4 (q), 55.1 (q), 63.6 (d), 75.1 (d), 75.8 (d), 83.0 (d),
97.8 (d), 110.2 (s), 118.0 (d), 130.8 (d), 136.7 (d), 183.8 (s) ppm.
MS(CI) for C14H20N2O5S: m/z = 329 (M + H)+.
C18H22O4–CH3: 287.128, found: 287.129.
Benzoic acid 2-(2,2-dimethyl-5-(2-tributylstannanyl-propenyl)-
[1,3]dioxolan-4-yl)-1-methyl-ethyl ester (18)
17 (230 mg, 761 lmol) was added to a suspension of
PdCl2(PPh3)2 (27 mg, 38 lmol, 5 mol%) in pentane (6.9 mL)
under argon and after stirring for 10 min, Bu3SnH (0.83 mL,
3.1 mmol, 4 eq) was added over 2 min. After 45 min, TLC
showed complete conversion and the mixture was concentrated.
The product was purified by column chromatography (benzene–
cyclohexane 9 : 1) giving 18 (282 mg, 475 lmol, 63%) and the
internal hydrostannylation side product (45 mg, 76 lmol, 10%)
both as colorless liquids. 1H-NMR (CDCl3, 500 MHz) d = 0.70–
1.03 (m, 15H, Bu-Sn), 1.19–1.60 (m, 21H, C8-H, CMe2, Bu-Sn),
1.77 (ddd, 1H, C6-H), 1.96 (d, 3H, C1-H, J = 1.6 Hz), 2.06 (ddd,
1H, C6-Hꢀ), 3.75 (ddd, 1H, C5-H), 4.54 (m, 1H, C4-H), 5.31 (m,
1H, C7-H), 5.47 (dd, 1H, C3-H, J = 1.9, 8.6 Hz), 7.41–7.56 (m,
3H, Bz-H), 8.02–8.06 (m, 2H, Bz-H) ppm. 13C-NMR (CDCl3,
50.3 MHz) d = 9.0 (t), 13.6 (q), 19.9 (q), 27.0 (q), 27.2 (q), 27.2
(t), 29.0 (t), 37.8 (t), 69.2 (d), 76.0 (d), 77.7 (d), 108.5 (s), 128.1
(d), 129.4 (d), 130.7 (s), 132.6 (d), 135.6 (d), 147.5 (s), 165.8 (s)
ppm. MS(EI) for C30H50O4Sn: m/z = 593 [M+].
Methyl-4,6-dideoxy-2,3-O-isopropylidene-a-L-lyxo-
hexapyranoside (22)
21 (2.0 g, 6.1 mmol) was dissolved in toluene (27 mL) and AIBN
(0.3 g, 1.8 mmol, 30 mol%) and tris(trimethylsilyl)silane (2.3 mL,
7.5 mmol, 1.2 eq) were added. The resulting solution was slowly
heated to 110 ◦C and then refluxed for 30 min under argon,
after which TLC showed complete conversion. After cooling
to rt, NaHCO3 (20% aq. solution) was added and the product
was extracted with EtOAc (× 3). The combined organic layers
were dried (MgSO4) and concentrated below 30 ◦C using MeOH
to remove the toluene. 22 was isolated as a yellow oil after
column chromatography (hexane–EtOAc 98 : 2 to 95 : 5). Due
to volatility of the product, the yield was determined in the next
step. 1H-NMR (CDCl3, 300 MHz) d = 1.22 (d, 3H, C6-H, J =
6.3 Hz), 1.34, 1.52 (2s, 6H, CMe2), 1.47 (m, 1H, C4-H), 1.86
(m, 1H, C4-Hꢀ), 3.38 (s, 3H, OMe), 3.77 (m, 1H, C5-H), 3.92 (d,
1H, C2-H, J = 5.4 Hz), 4.30 (m, 1H, C3-H), 4.91 (s, 1H, C1-H)
ppm. 13C-NMR (CDCl3, 50.3 MHz) d = 21.1 (q), 26.2 (q), 28.1
(q), 36.0 (t), 54.7 (q), 61.9 (d), 70.9 (d), 72.6 (d), 98.7 (d), 108.6
(s) ppm. MS(CI) for C10H18O4: m/z = 220 (M + NH4)+.
Benzoic acid 2-[5-(2-iodo-propenyl)-2,2-dimethyl-[1,3]dioxolan-
4-yl]-1-methyl-ethyl ester (4a)
18 (200 mg, 0.34 mmol) was dissolved in dichloromethane
(2.7 mL) and I2 (114 mg, 0.45 mmol, 1.3 eq) in dichloromethane
(0.7 mL) was added at −78 ◦C under argon. The resulting
solution was stirred for 10 min at −78 ◦C and then warmed to
rt. The solution was concentrated and 4a (144 mg, 0.33 mmol,
99%) was isolated as a yellow oil after column chromatography
(hexane–EtOAc 39 : 1; 2.5 volume-% Et3N was used during the
1
preparation of the column). H-NMR (CDCl3, 300 MHz) d =
Methyl-4,6-dideoxy-a-L-lyxo-hexapyranoside (23)
1.35–1.42 (m, 9H, C8-H, CMe2), 1.84 (ddd, 1H, C6-H), 2.06
(ddd, 1H, C6-Hꢀ), 2.49 (s, 3H, C1-H), 3.84 (ddd, 1H, C5-H),
4.29 (m, 1H, C4-H), 5.31 (m, 1H, C7-H), 6.14 (d, 1H, C3-H,
J = 8.7 Hz), 7.41–7.58 (m, 3H, Bz-H), 8.04 (m, 2H, Bz-H) ppm.
13C-NMR (CDCl3, 50.3 MHz) d = 19.9 (q), 26.7 (q), 27.1 (q),
28.4 (q), 37.5 (t), 68.9 (d), 76.9 (d), 77.7 (d), 101.5 (s), 109.0 (s),
128.1 (d), 129.4 (d), 130.5 (s), 132.6 (d), 137.0 (d), 165.7 (s) ppm.
MS(CI) for C18H23IO4: m/z = 448 (M + NH4)+, HRMS calcd
for C20H23IO4: 430.064, found: 430.066.
Amberlite-120-(Na+)-resin was stirred in 2 M HCl-solution for
1.5 h and then filtered off and flushed with 2 M HCl-solution
twice. 4.0 g of the thus obtained resin was added to a solution of
22 (1.23 g, 6.10 mmol) in water (37 mL) and 1,4-dioxane (37 mL).
After stirring for 12 h, the resin was filtered off and the solution
was neutralized with 1 M NaOH (aq) and then concentrated.
After column chromatography (CHCl3–EtOH 9 : 1), 23 (703 mg,
4.33 mmol, 71% from 21) was isolated as a white foam. 1H-NMR
(CDCl3, 300 MHz) d = 1.23 (d, 3H, C6-H, J = 6.0 Hz), 1.47 (m,
1H, C4-H), 1.74–1.87 (m, 3H, C4-Hꢀ, 2-OH), 3.37 (s, 3H, OMe),
3.72 (s, 1H, C2-H), 3.84 (m, 1H, C3-H), 3.96 (m, 1H, C5-H),
4.73 (s, 1H, C1-H) ppm. 13C-NMR (CDCl3, 50.3 MHz) d = 21.0
(q), 36.3 (t), 54.8 (q), 63.7 (d), 65.6 (d), 68.6 (d), 101.2 (d) ppm.
MS(CI) for C7H14O4: m/z = 180 (M + NH4)+.
Methyl-(2,3-O-isopropylidene-a-L-rhamnopyranoside) (20)
19 (21.5 g, 110 mmol) was dissolved in dry acetone and CuSO4
(34 g, 220 mmol, 2 eq) and H2SO4 (1.7 mL) were added. The
resulting green suspension was stirred overnight under argon
and then filtered. The filtrate was made basic (pH 9) with 25%
ammonia and the resulting blue suspension was filtered again.
The filtrate was concentrated, suspended in brine and extracted
with dichloromethane (× 3). The combined organic layers
were dried (Na2SO4), filtered and concentrated. Purification by
column chromatography (hexane–EtOAc 9 : 1 to 4 : 1) gave 20
as an oil (23.3 g, 98.6 mmol, 90%). 1H-NMR (CDCl3, 300 MHz)
d = 1.31 (d, 3H, C6-H, J = 6.3 Hz), 1.35, 1.53 (2s, 6H, CMe2),
2.16 (d, 1H, OH), 3.39 (s, 3H, OMe), 3.39 (m, 1H, C4-H), 3.65
(m, 1H, C5-H), 4.07 (t, 1H, C3-H, J = 6.6 Hz), 4.13 (d, 1H,
C2-H, J = 6.0 Hz), 4.85 (s, 1H, C1-H) ppm. 13C-NMR (CDCl3,
50.3 MHz) d = 17.3 (q), 26.0 (q), 27.8 (q), 54.8 (q), 65.6 (d),
74.3 (d), 75.6 (d), 78.3 (d), 98.0 (d), 109.3 (s) ppm. MS(CI) for
C10H18O5: m/z = 236 (M + NH4)+.
Methyl-2-O-acetyl-4,6-dideoxy-a-L-lyxo-hexapyranoside (25)
23 (670 mg, 4.13 mmol) was dissolved in acetonitrile (13 mL),
and p-toluenesulfonic acid monohydrate (41 mg) and trimethyl
orthoacetate (0.95 mL, 7.43 mmol, 1.8 eq) were added. The
resulting solution was stirred for 10 min and then concentrated.
The residue was dissolved in dichloromethane (13 mL) and 90%
aqueous trifluoroacetic acid (4.06 mL) was added. The thus
obtained mixture was stirred for 5 min after which TLC (hexane–
EtOAc 4 : 1) showed complete conversion. After concentration,
the residue was taken up in dichloromethane, washed with
NaHCO3 (5% aq.) and water, dried (Na2SO4) and concentrated
to give 25 (675 mg, 3.30 mmol, 80%) as an oil, which was used in
the next step without further purification. 1H-NMR of the crude
product showed only 1 regioisomer present: (CDCl3, 300 MHz)
d = 1.24 (d, 3H, C6-H, J = 6.3 Hz), 1.56 (m, 1H, C4-H), 1.77
(m, 2H, C4-Hꢀ, OH), 2.14 (s, 1H, OAc), 3.35 (s, 3H, OMe), 3.87
(m, 1H, C5-H), 4.12 (m, 1H, C3-H), 4.71 (s, 1H, C1-H), 4.92
(br s, 1H, C2-H) ppm.
Methyl-4-O-(imidazol-1-ylthiocarbonyl)-2,3-O-isopropylidene-
a-L-rhamnopyranoside (21)
A solution of 20 (13.5 g, 57.1 mmol) and 1,1ꢀ-thiocarbonyldi-
imidazole (12.8 g, 71.5 mmol, 1.3 eq) in anhydrous 1,2-
dichloroethane (200 mL) was refluxed for 2 h under argon. After
2 5 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3

View Article Online
Methyl-2,3-di-O-acetlyl-4,6-dideoxy-a-L-arabino-
hexopyranoside (27)
were dried (Na2SO4) and concentrated. Purification by column
chromatography (hexane–EtOAc 95 : 5 to 4 : 1) gave 31 (549 mg,
1.97 mmol, 78%) and 30 (55 mg, 0.20 mmol, 8%) as colorless
Trifluoromethanesulfonic anhydride (7.45 mL, 44.1 mmol, 3.0
eq) was slowly added to a solution of 25 (3.0 g, 14.7 mmol) and
pyridine (7.2 mL, 88.2 mmol, 6.0 eq) in dichloromethane (70 mL)
1
oils. H-NMR 31 (CDCl3, 200 MHz) d = 1.21 (d, 3H, C6-H,
J = 6 Hz), 1.43, 1.45 (2s, 6H, CMe2), 1.67 (m, 1H, C4-H), 1.86–
2.17 (m, 3H, C4-Hꢀ, dithian-H), 2.74–3.01 (m, 4H, dithian-H),
3.09 (br s, 1H, OH), 3.93 (dd, 1H, C2-H, J = 5.8, 8.0 Hz), 4.05
(m, 1H, C5-H), 4.11 (d, 1H, C1-H, J = 5.2 Hz), 4.21 (ddd, 1H,
C3-H, J = 2.6, 7.6, Hz) ppm. 13C-NMR (CDCl3, 50.3 MHz)
d = 23.2 (q), 25.6 (t), 26.8 (q), 27.2 (q), 29.2 (t), 29.4 (t), 42.3
(t), 47.9 (d), 67.2 (d), 78.8 (d), 82.9 (d), 110.0 (s) ppm. MS(EI)
for C12H22O3S2: m/z = 278 [M+], HRMS calcd for C12H22O3S2:
278.101, found: 278.101.
◦
at −10 C under argon. The mixture was slowly warmed to rt
and after stirring for an additional 1.5 h, the solution was diluted
with dichloromethane and poured into ice-cold NaHCO3 (20%
aq.). The organic layer was washed with 1 M HCl, water and
NaHCO3 (sat.), dried (Na2SO4) and concentrated to give 26. 1H-
NMR (CDCl3, 300 MHz) d = 1.28 (d, 3H, C6-H, J = 6.3 Hz),
1.98–2.13 (m, 5H, C4-H, Hꢀ, OAc), 3.35 (s, 3H, OMe), 3.93 (m,
1H, C5-H), 4.72 (s, 1H, C1-H), 5.14 (s, 1H, C2-H), 5.29 (m, 1H,
C3-H) ppm. 13C-NMR (CDCl3, 50.3 MHz) d = 20.6 (2q), 34.5
(t), 55.0 (q), 63.7 (d), 67.5 (d), 81.6 (d), 98.8 (d), 121.4 (s), 169.6
(s) ppm. 19F-NMR (CDCl3) d = 1.81 ppm.
1H-NMR 30 (CDCl3, 300 MHz) d = 1.20 (d, 3H, C6-H, J =
6.3 Hz), 1.40, 1.46 (2s, 6H, CMe2), 1.50 (m, 1H, C4-H), 1.92–
2.14 (m, 3H, C4-Hꢀ, dithian-H), 2.74–2.96 (m, 5H, dithian-H,
OH), 3.64 (m, 1H, C-H), 4.03 (m, 1H, C-H), 4.14 (d, 1H, C1-H,
J = 7.0 Hz), 4.25 (m, 1H, C-H) ppm.
A solution of the crude triflate 26 and tetrabutylammonium
acetate (48.7 g, 162 mmol, 11.0 eq) in dry toluene (40 mL) was
stirred overnight under argon. The mixture was concentrated
and purified by column chromatography (hexane–EtOAc 4 : 1)
to give 27 (2.6 g, 10.4 mmol, 71% from 25) as an oil and a
side product resulting from dehydration (0.2 g, 1.2 mmol, 8%).
1H-NMR 27 (CDCl3, 500 MHz) d = 1.22 (d, 3H, C6-H, J =
6.5 Hz), 1.70 (m, 1H, C4-Heq, J4eq,4ax = 14.5, J4eq,5 = 2.5 Hz),
1.81 (ddd, 1H, C4-ax, J3,4ax = 3.5, J4ax,5 = 11.0 Hz), 2.08, 2.09 (2s,
6H, 2OAc), 3.38 (s, 3H, OMe), 4.14 (m, 1H, C5-H), 4.60 (s, 1H,
C1-H), 4.74 (m, 1H, C2-H), 4.91 (m, 1H, C3-H) ppm. 13C-NMR
(CDCl3, 50.3 MHz) d = 20.7 (q), 20.8 (q), 21.0 (q), 32.6 (t), 55.1
(q), 59.7 (d), 66.5 (d), 67,2 (d), 98.7 (d), 169.3 (s), 170.0 (s) ppm.
MS(EI) for C11H18O6: m/z = 215 (M + H–MeOH)+, MS(CI) =
264 (M + NH4)+.
5-O-tert-butyl-dimethyl-silyl-4,6-dideoxy-2,3-O-isopropyliden-
L-arabino-hexose-trimethylen-dithioacetal (32)
31 (500 mg, 1.80 mmol) was dissolved in DMF and TBDMSCl
(541 mg, 3.59 mmol, 2.0 eq) and imidazole (245 mg, 3.59 mmol,
2.0 eq) were added. The resulting solution was stirred for 12 h at
70 ◦C under argon. After cooling to rt, the reaction mixture was
diluted with water, extracted with Et2O (× 2), dried (Na2SO4)
and concentrated. Purification by column chromatography
(hexane–EtOAc 95 : 5 to 9 : 1) gave 32 (593 mg, 1.51 mmol,
1
84%) as an oil. H-NMR (CDCl3, 300 MHz) d = 0.06 (s, 6H,
2 MeSi), 0.88 (s, 9H, tBuSi), 1.20 (d, 3H, C6-H, J = 6.3 Hz),
1.40, 1.42 (2s, 6H, CMe2), 1.72–2.14 (m, 4H, C4-H, Hꢀ, dithian-
H), 2.74–2.97 (m, 4H, dithian-H), 3.90 (dd, 1H, C2-H, J = 5.1,
7.5 Hz), 4.01–4.15 (m, 3H, C1-H, C3-H, C5-H) ppm. 13C-NMR
(CDCl3, 50.3 MHz) d = −4.9 (q), −4.7 (q), 18.0 (s), 22.8 (q),
25.7 (t), 25.8 (q), 26.8 (q), 27.3 (q), 29.1 (t), 29.5 (t), 43.6 (t),
47.9 (d), 66.1 (d), 75.9 (d), 83.2 (d), 109.3 (s) ppm. MS(EI) for
C18H36O3S2Si: m/z = 392 [M+], MS(CI) for C18H36O3S2Si: m/z =
393 (M + H)+, 410 (M + NH4)+, HRMS calcd for C18H36O3SiS2:
392.188, found: 392.188.
1H-NMR of the C3-epimer of 27 obtained from acetylation
of 23: (CDCl3, 300 MHz) d = 1.24 (d, 3H, C6-H, J = 6.3 Hz),
1.74 (m, 2H, 2C4-H), 1.99 (s, 3H, OAc), 2.12 (s, 3H, OAc), 3.35
(s, 3H, OMe), 3.94 (m, 1H, C5-H), 4.65 (s, 1H, C1-H), 5.05 (s,
1H, C2-H), 5.21 (m, 1H, C3-H) ppm.
4,6-Dideoxy-L-arabino-hexose-trimethylen-dithioacetal (29)
27 (100 mg, 0.41 mmol) was dissolved in MeOH–THF (2.0 mL,
1 : 1 v/v) and NaOMe was added until pH 9 was reached. The
thus obtained reaction mixture was stirred for 2 h and then
concentrated. The residue was dissolved in 37% HCl (1.0 mL),
after which 1,3-propanedithiol (85 lL, 0.82 mmol, 2.0 eq) was
added dropwise. The resulting solution was stirred for 24 h and
then neutralized with 25% ammonia. Subsequently the aqueous
layer was washed with petroleum–ether (40–60; × 5) and
concentrated to give a white solid which was suspended in
acetone and stirred for 5 min. The solid was filtered off and
the filtrate concentrated affording 29 (87 mg, 0.36 mmol, 87%)
as a white solid. 1H-NMR (CDCl3, 300 MHz) d = 1.24 (d, 3H,
C6-H, J = 6.3 Hz), 1.64 (m, 1H, C4-H), 1.81 (m, 1H, C4-Hꢀ),
2.05 (m, 2H, dithian-H), 2.67–2.97 (m, 4H, dithian-H), 3.70 (d,
1H, C2-H, J = 8.1 Hz), 4.05 (d, 1H, C3-H, J = 8.4 Hz), 4.15 (m,
1H, C5-H), 4.31 (d, 1H, C1-H, J = 9.6) ppm. 13C-NMR (CDCl3,
50.3 MHz) d = 23.9 (q), 25.3 (t), 27.0 (t), 27.6 (t), 42.2 (t), 47.7
(d), 67.9 (d), 70.9 (d), 73.5 (d) ppm. MS(EI) for C9H18O3S2:
m/z = 238 [M+], HRMS calcd for C9H18O3S2: 238.070, found:
238.071.
5-O-tert-butyl-dimethyl-silyl-4,6-dideoxy-2,3-O-isopropyliden-
L-arabino-hexanal (33)
32 (137 mg, 0.35mmol) was convertedinto 33 (94mg, 0.31 mmol,
1
89%) using a procedure analogous to the synthesis of 14. H-
NMR (CDCl3, 200 MHz) d = 0.06 (s, 6H, 2 MeSi), 0.87 (s,
9H, tBuSi), 1.19 (d, 3H, C6-H, J = 6.0 Hz), 1.42, 1.47 (2s, 6H,
CMe2), 1.70–1.97 (m, 2H, C4-H, Hꢀ), 3.97–4.06 (m, 2H, C2-H,
C5-H), 4.18 (ddd, 1H, C3-H, J = 5.0, 7.6, 7.6 Hz), 9.72 (d, 1H,
O CH, J = 2.4 Hz) ppm. 13C-NMR (CDCl3, 50.3 MHz) d =
=
−5.0 (q), −4.5 (q), 17.9 (s), 23.2 (q), 25.7 (q), 26.1 (q), 27.0 (q),
42.8 (t), 65.6 (d), 73.9 (d), 85.0 (d), 110.8 (s), 200.6 (d) ppm.
Benzoic acid-2-[5-(10-ethoxycarbonyl-2,6,8-trimethyl-deca-
1,5,7,9-tetren-3-ynyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-1-
methyl-ethyl ester (2a)
4a (122 mg, 0.28 mmol, 1.2 eq) was dissolved in iPrNH2 (1.0 mL)
and Pd(PPh3)4 (5.3 mg, 4.6 lmol, 2 mol%) was added. The
solution was stirred under argon at ambient temperature for
5 min, after which CuI (0.9 mg, 4.6 lmol, 2 mol%) was added.
After 5 min, 3a (47 mg, 0.23 mmol) in iPrNH2 (0.85 mL) was
added and the mixture was stirred for 2 h and then concentrated.
The residue was dissolved in Et2O, washed with NH4Cl (sat.) and
brine, dried (Na2SO4) and concentrated. 2a (109 mg, 0.22 mmol,
94%) was isolated as a yellow oil after purification by column
chromatography (hexane–EtOAc 19 : 1 to 9 : 1) and what was left
of 4a (20 mg, 0.05 mmol, 20%) was recovered. 1H-NMR major
isomer (CDCl3, 200 MHz) d = 1.30 (t, 3H, CH3CH2O, J =
7.0 Hz), 1.34–1.42 (m, 9H, C16-H, CMe2), 1.76–2.20 (m, 11H,
4,6-Dideoxy-2,3-O-isopropyliden-L-arabino-hexose-trimethylen-
dithioacetal (31)
29 (600 mg, 2.52 mmol) was dissolved in dry acetone and
CuSO4 (778 mg, 3.06 mmol, 1.2 eq) and a drop of H2SO4 were
added. The resulting green suspension was stirred overnight
and then filtered. The filtrate was neutralized with 25% NH3
and the resulting blue suspension was filtered again. The
filtrate was concentrated, suspended in brine and extracted
with dichloromethane (× 3). The combined organic layers
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3
2 5 3 1

View Article Online
C4-, C6-, C10-CH3, C14-H2), 3.85 (ddd, 1H, C13-H), 4.22 (q,
2H, CH3CH2O), 4.39 (m, 1H, C12-H), 5.31 (m, 1H, C15-H),
5.67 (s, 1H, C7-H), 5.74 (dd, 1H, C11-H, J = 1.6, 9.0 Hz), 5.91
(d, 1H, C2-H, J = 15.6 Hz), 6.31 (s, 1H, C5-H), 7.30–7.59 (m,
5H, Bz-H, C2-H), 8.03 (m, 2H, Bz-H) ppm. 13C-NMR (CDCl3,
50.3 MHz) d = 13.9 (q), 14.2 (q), 17.9 (q), 19.5 (q), 19.9 (q), 26.7
(q), 27.1 (q), 37.6 (t), 60.1 (t), 69.0 (d), 71.1 (d), 77.6 (d), 87.0 (s),
99.9 (s), 108.9 (s), 113.4 (d), 117.6 (d), 124.4 (s), 128.1 (d), 129.4
(d), 130.6 (s), 132.2 (d), 132.6 (d), 134.2 (s), 140.5 (d), 146.1 (s),
149.7 (d), 165.7 (s), 167.0 (s) ppm. MS(EI) for C31H38O6: m/z =
506 [M+], HRMS calcd for C31H38O6: 506.267, found: 506.268.
a colorless oil after purification by column chromatography
(pentane–EtOAc 97 : 3 to 95 : 5). 1H-NMR (CDCl3, 300 MHz)
d = 1.39 (m, 9H, C9-H, CMe2), 1.78–1.89 (m, 4H, C7-H, C3-
CH3), 2.05 (ddd, 1H, C7-Hꢀ), 2.86 (s, 1H, C1-H), 3.84 (ddd, 1H,
C6-H), 4.36 (t, 1H, C5-H, J = 8.7 Hz), 5.32 (m, 1H, C8-H), 5.82
(d, 1H, C4-H, J = 9.0 Hz), 7.40–7.57 (m, 3H, Bz-H), 8.03 (d, 2H,
Bz-H, J = 7.2 Hz) ppm. 13C-NMR (CDCl3, 50.3 MHz) d = 17.8
(q), 19.9 (q), 26.7 (q), 27.1 (q), 37.6 (t), 69.0 (d), 77.0 (d), 77.6
(d), 85.2 (s), 109.1 (s), 123.2 (s), 128.1 (d), 129.4 (d), 130.7 (s),
132.6 (d), 134.0 (d), 165.8 (s) ppm. MS(EI) for C20H24O4: m/z =
328 [M+], HRMS calcd for C20H24O4: 328.167, found: 328.167.
7-Bromo-4,6-dimethyl-hepta-2,4,6-trienoic acid ethyl ester (34)
Benzoic acid 2-[2,2-dimethyl-5-(2-methyl-buta-1,3-dienyl)-
[1,3]dioxolan-4-yl]-1-methyl-ethyl ester (37)
BrCH2PPh3Br (479 mg, 1.10 mmol, 2.0 eq) was suspended in dry
THF (2.7 mL) under argon and piperidine (108 ll, 1.10 mmol,
2.0 eq) and n-BuLi (1.6 M in hexane, 0.69 mL, 1.10 mmol, 2.0 eq)
were added upon which the solution turned brown–red. After
stirring for 15 min, 5b (100 mg, 0.55 mmol) in THF (2.2 mL)
was added and the reaction was stirred for 6 h. The reaction was
quenched with NH4Cl (sat.), the aqueous layer was extracted
with Et2O (× 3) and the combined organic layers were washed
with brine, dried (Na2SO4) and concentrated. Purification by
column chromatography (pentane–EtOAc 95 : 5) gave 34 (57 mg,
1H-NMR (CDCl3, 400 MHz) d = 1.39 (m, 9H, C9-H, CMe2),
1.78–1.89 (m, 4H, C7-H, C3-CH3), 2.08 (ddd, 1H, C7-Hꢀ), 3.83
(ddd, 1H, C6-H), 4.47 (t, 1H, C5-H, J = 8.8 Hz), 5.08 (d, 1H,
C1-H, J = 10.4 Hz), 5.23 (d, 1H, C1-Hꢀ, J = 17.6 Hz), 5.30 (m,
1H, C8-H), 5.38 (d, 1H, C4-H, J = 8.8 Hz), 6.32 (dd, 1H, C2-H,
J = 10.8, 17.2 Hz), 7.43 (t, 2H, Bz-H, J = 7.6 Hz), 7.55 (t, 1H,
Bz-H, J = 7.6 Hz), 8.03 (d, 2H, Bz-H, J = 7.6 Hz) ppm.
Benzoic acid 2-[2,2-dimethyl-5-(2-methyl-4-tributylstannanyl-
buta-1,3-dienyl)-[1,3]dioxolan-4-yl]-1-methyl-ethyl ester (38)
1
0.22 mmol, 40%) as a mixture of isomers. H-NMR (CDCl3,
300 MHz) major isomer d = 1.30 (t, 3H, CH3CH2O, J =
7.0 Hz), 1.91 (s, 3H, C6-CH3), 1.94 (s, 3H, C4-CH3), 4.21 (q,
2H, CH3CH2O), 5.92 (d, 1H, C2-H, J = 15.6 Hz), 6.17 (s, 1H,
C5-H), 6.24 (s, 1H, C7-H), 7.31 (d, 1H, C3-H, J = 15.3 Hz) ppm.
Minor isomer d = 1.31 (t, 3H, CH3CH2O, J = 7.0 Hz), 1.88 (s,
3H, C6-CH3), 1.96 (s, 3H, C4-CH3), 4.21 (q, 2H, CH3CH2O),
5.95 (d, 1H, C2-H, J = 15.6 Hz), 6.14 (s, 1H, C5-H), 6.35 (s, 1H,
C7-H), 7.39 (d, 1H, C3-H, J = 15.9 Hz) ppm.
CuCN (5.1 mg, 57 lmol, 1.1 eq) was suspended in dry THF
(0.27 mL) under argon and n-BuLi (1.6 M in hexane, 71 ll, 114
◦
lmol, 2.2 eq) was added at −40 C giving a colorless solution
after 20 min. The solution was then warmed to −30 ◦C and
Bu3SnH (31 ll, 114 lmol, 2.2 eq) was added resulting in a yellow
solution. 36 (17 mg, 52 lmol) in THF (0.11 mL) was added to
the cuprate and the mixture was stirred for 75 min. Even though
TLC showed that conversion was not complete, the reaction
was quenched with firstly MeOH and then NH4Cl (sat.)–NH3
(12.5%) 4 : 1 (v/v). The aqueous layer was extracted with Et2O
(× 3) and the combined organic layers were dried (Na2SO4) and
concentrated. Even though GC-MS showed only 1 product apart
from starting material, 38 (5 mg, 8.1 lmol, 16%) was isolated in
low yield after performing column chromatography twice (AlOx
basic, pentane–EtOAc 39 : 1). 1H-NMR (CDCl3, 300 MHz) d =
0.89 (m, 15H, Bu-Sn), 1.19–1.54 (m, 21H, Bu-Sn, C9-H, CMe2),
1.83 (m, 4H, C7-H, C3-CH3), 2.05 (m, 1H, C7-Hꢀ), 3.84 (m,
1H, C6-H), 4.48 (m, 1H, C5-H), 5.32 (m, 3H, C1-H, C4-H, C8-
7-Iodo-4,6-dimethyl-hepta-2,4,6-trienoic acid ethyl ester (35)
Preparation as described for 34. 35 (70 mg, 0.23 mmol, 13%) was
isolated as a single isomer from 5b (321 mg, 1.76 mmol) using
1
1.91 g of ICH2PPh3I (3.53 mmol, 2.0 eq). H-NMR (CDCl3,
400 MHz) d = 1.30 (t, 3H, CH3CH2O, J = 7.2 Hz), 1.89 (s, 3H,
C6-CH3), 1.99 (s, 3H, C4-CH3), 4.21 (q, 2H, CH3CH2O), 5.93
(d, 1H, C2-H, J = 16.0 Hz), 6.21 (s, 1H, C5-H), 6.31 (s, 1H,
C7-H), 7.30 (d, 1H, C3-H, J = 16.0 Hz) ppm.
1
H), 6.39 (dd, 1H, C2-H, J = 19.2, J H–117Sn = J1H–119Sn =
Benzoic acid 2-[2,2-dimethyl-5-(2-methyl-but-1-en-3-ynyl)-
[1,3]dioxolan-4-yl]-1-methyl-ethyl ester (36)
72.3 Hz), 7.43 (m, 2H, Bz-H), 7.55 (m, 1H, Bz-H), 8.03 (d, 2H,
Bz-H, J = 8.1 Hz) ppm.
Ethynyl-trimethylsilane (99 ll, 0.70 mmol, 1.5 eq) was dissolved
in iPrNH2 (1.7 mL) and Pd(PPh3)4 (10.7 mg, 9.3 lmol, 2 mol%)
was added. The solution was stirred under argon at ambient
temperature for 5 min, after which CuI (1.8 mg, 9.3 lmol,
2 mol%) was added. After 5 min, 4a (200 mg, 0.46 mmol) in
iPrNH2 (1.4 mL) was added and the mixture was stirred for 1 h
and then concentrated. The residue was dissolved in Et2O and
washed with NH4Cl (sat.). The aqueous layer was extracted with
Et2O (× 3) and the combined organic layers were washed with
brine, dried (Na2SO4) and concentrated. The product (180 mg,
0.45 mmol, 97%) was isolated as a colorless oil after purification
by column chromatography (pentane–EtOAc 19 : 1). 1H-NMR
(CDCl3, 200 MHz) d = 0.16 (s, 9H, TMS), 1.38 (m, 9H, C9-H,
CMe2), 1.74–1.87 (m, 4H, C7-H, C3-CH3), 2.03 (ddd, 1H, C7-
Hꢀ), 3.82 (ddd, 1H, C6-H), 4.34 (t, 1H, C5-H, J = 8.6 Hz), 5.32
(m, 1H, C8-H), 5.78 (dd, 1H, C4-H, J = 1.6, 9.0 Hz), 7.41–7.58
(m, 3H, Bz-H), 8.04 (m, 2H, Bz-H) ppm.
The TMS–alkyne (180 mg, 0.45 mmol) was dissolved in dry
THF (2.2 mL) and TBAF (1.0 M in THF, 0.90 mL, 0.90 mmol,
2.0 eq) was added at 0 ◦C. The resulting solution was stirred
under argon for 1 h and then quenched with NH4Cl (sat.). The
aqueous layer was extracted with Et2O (× 3) and the combined
organic layers were washed with brine, dried (Na2SO4) and
concentrated. 36 (127 mg, 0.39 mmol, 86%) was isolated as
Acknowledgements
Financial support from the Dutch Organization for Scientific
Research (NWO) is gratefully acknowledged. The authors wish
to thank A. Kiewiet (MS) for technical support. Prof. Dr
C. J. Elsevier is kindly acknowledged for providing us with a
sample of his homogeneous Pd(0)-catalyst.36
References
1 K. M. George, D. Chatterjee, G. Gunawardana, D. Welty, J. Hayman,
R. Lee and P. L. C. Small, Science, 1999, 283, 854.
2 T. S. van der Werf, W. T. A. van der Graaf, J. W. Tappero and K.
Asiedu, Lancet, 1999, 354, 1013.
3 G. Gunawardana, D. Chatterjee, K. M. George, P. Brennan, D.
Whittern and P. L. C. Small, J. Am. Chem. Soc., 1999, 121, 6092.
4 A. B. Benowitz, S. Fidanze, P. L. C. Small and Y. Kishi, J. Am. Chem.
Soc., 2001, 123, 5128.
5 S. Fidanze, F. Song, M. Szlosek-Pinaud, P. L. C. Small and Y. Kishi,
J. Am. Chem. Soc., 2001, 123, 10117.
6 A. Mve-Obiang, R. E. Lee, F. Portaels and P. L. C. Small, Infect.
Immun., 2003, 71, 774.
7 F. Song, S. Fidanze, A. B. Benowitz and Y. Kishi, Org. Lett., 2002,
4, 647.
2 5 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3

View Article Online
8 During the course of our research, it was brought to our attention
by Prof. Dr J. Lugtenburg, that 1,3-steric interactions between the
methyl substituents on C4ꢀ and C6ꢀ of the side-chain of mycolactones
A and B will force the side-chain into the 5ꢀ-s-cis conformation
rather than the 5ꢀ-s-trans conformation which is depicted in Figs. 1
and 2 and Scheme 4. However, for ease of presentation and to
avoid unnecessary confusion, we have chosen to follow the literature
precedents.
29 A minor amount (8%) of side product resulting from dehydration of
the C3–C4 bond was found.
30 P. Ferna´ndez, J. Jime´nez-Barbero, M. Mart´ın-Lomas, D. Sol´ıs and T.
D´ıaz-Maurin˜o, Carbohydr. Res., 1994, 256, 223.
31 Y. Arroyo-Go´mez, J. A. Lo´pez-Sastre, J. F. Rodr´ıguez-Amo, M.
Santos-Garc´ıa and M. A. Sanz-Tejedor, Tetrahedron: Asymmetry,
1999, 10, 973.
32 K. Sonogashira, T. Yatake, Y. Tohda, S. Takahashi and N. Hagihara,
J. Chem. Soc., Chem. Commun., 1977, 9, 291.
33 W. Boland, N. Schroer, C. Sieler and M. Feigel, Helv. Chim. Acta,
1987, 70, 1025.
34 (a) Y. Fujimoto, J. Ishihara, S. Maki, N. Fujioka, T. Wang, T. Furuta,
N. Fishkin, B. Borhan, N. Berova and K. Nakanishi, Chem.–Eur. J.,
2001, 7, 4198; (b) E. Quesada, A. U. Acun˜a and F. Amat-Guerri,
Eur. J. Org. Chem., 2003, 1308; (c) A. R. Rodr´ıguez and B. W. Spur,
Tetrahedron Lett., 2001, 42, 6057.
9 M. K. Gurjar and J. Cherian, Heterocycles, 2001, 55, 1095.
10 (a) Th. Morel and P. E. Verkade, Recl. Trav. Chim. Pays-Bas, 1949,
68, 619; (b) Th. Morel and P. E. Verkade, Recl. Trav. Chim. Pays-Bas,
1951, 70, 35.
11 E. Wenkert, H. Khatuya and P. S. Klein, Tetrahedron Lett., 1999, 40,
5171.
12 A. W. Gibson, G. R. Humphrey, D. J. Kennedy and S. H. B. Wright,
Synthesis, 1991, 414.
13 B. Borhan, M. L. Souto, J. M. Um, B. Zhou and K. Nakanishi,
Chem.–Eur. J., 1999, 5, 1172.
14 H. Redlich, B. Schneider, R. W. Hoffmann and K.-J. Geueke, Liebigs
Ann. Chem., 1983, 393.
15 H. J. Jennings and J. K. N. Jones, Can. J. Chem., 1963, 41, 1151.
16 C. Vogel, C. Bergemann, A. J. Ott, T. K. Lindhorst, J. Thiem, W. V.
Dahlhoff, C. Hallgren, M. M. Palcic and O. Hindsgaul, Liebigs
Ann./Recl., 1997, 601.
17 M. Miljkovic, D. Dropkin, P. Hagel and M. Habash-Marino,
Carbohydr. Res., 1984, 128, 11.
35 In light of the difficulties we have encountered in the partial
hydrogenation of 2a, we believe that the selective partial reduction of
alkynes embedded in an alkene-system and in conjugation with an
electron withdrawing moiety constitutes a general problem in organic
synthesis. In this respect, it should be noted that also in the elegant
total synthesis of 6,7-dehydrostipiamide as described by Negishi and
co-workers, the final reduction to stipiamide itself is not reported. X.
Zeng, F. Zeng and E. I. Negishi, Org. Lett., 2004, 6, 3245.
36 M. W. van Laren and C. J. Elsevier, Angew. Chem., Int. Ed., 1999, 38,
3715.
18 H. Redlich, W. Sudau, A. K. Szardenings and R. Vollerthun,
Carbohydr. Res., 1992, 226, 57.
19 E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 13, 3769.
20 H. Yamada, S. Aoyagi and C. Kibayashi, J. Am. Chem. Soc., 1996,
118, 1054.
21 J. M. Aurrecoechea, B. Lo´pez and M. Arrate, J. Org. Chem., 2000,
65, 6493.
22 (a) J. A. Marshall and M. M. Yanik, J. Org. Chem., 1999, 64, 3798;
(b) S. Paik, S. Carmeli, J. Cullingham, R. E. Moore, G. M. L.
Patterson and M. A. Tius, J.Am. Chem. Soc., 1994, 116, 8116.
23 H. X. Zhang, F. Guibe´ and G. Balavoine, J. Org. Chem., 1990, 55,
1857.
37 (a) Y.-G. Suh, K.-H. Min, Y.-S. Lee, S.-Y. Seo, S.-H. Kim and H.-J.
Park, Tetrahedron Lett., 2002, 43, 3825; (b) C. A. Brown and V. K.
Ahuja, J. Org. Chem., 1973, 38, 2226.
38 (a) B. H. Lipshutz, E. L. Ellsworth, S. H. Dimock and D. C. Reuter,
Tetrahedron Lett., 1989, 30, 2065; (b) P. Le Me´nez, V. Fargeas, I.
Berque, J. Poisson, J. Ardisson, J.-Y. Lallemand and A. Pancrazi,
J. Org. Chem., 1995, 60, 3592; (c) A. Wada, K. Fukunaga and M.
Ito, Synlett, 2001, 800.
39 D. W. Hart, T. F. Blackburn and J. Schwartz, J. Am. Chem. Soc.,
1975, 97, 679.
40 For a review on metal-catalyzed hydrostannations: N. D. Smith, J.
Mancuso and M. Lautens, Chem. Rev., 2000, 100, 3257.
41 (a) J. C. Cochran, B. S. Bronk, K. M. Terrence and H. K. Phillips,
Tetrahedron Lett., 1990, 31, 6621; (b) R. Rossi, A. Carpita and P.
Cossi, Tetrahedron Lett., 1992, 33, 4495.
42 D. Seyferth, J. K. Heeren, G. Singh, S. O. Grim and W. B. Hughes,
J. Organomet. Chem., 1966, 5, 267.
43 J.-C. Shi, X. Zeng and E.-i. Negishi, Org. Lett., 2003, 5, 1825.
44 For a review on the use of Stille-type couplings in conjugated systems
see: B. Dom´ınguez, B. Iglesias and A. R. de Lera, Tetrahedron, 1999,
55, 15071.
24 M. F. Semmelhack and R. J. Hooley, Tetrahedron Lett., 2003, 44,
5737.
25 E. E. Percival and E. G. V. Percival, J. Chem. Soc., 1950, 690.
26 L. A. Mulard and C. P. J. Claudemans, Carbohydr. Res., 1995, 274,
209.
27 C. Mathe´, J.-L. Imbach and G. Gosselin, Carbohydr. Res., 2000, 323,
226.
28 P. R. Ashton, C. L. Brown, S. Menzer, S. A. Nepogodiev, J. F. Stoddart
and D. J. Williams, Chem.–Eur. J., 1996, 2, 580.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 2 4 – 2 5 3 3
2 5 3 3