Synthesis of a novel taxa-oxa-sugar hybrid core structure by tandem cross-enyne metathesis/IMDA

Article abstract of DOI:10.1002/ejoc.201000001

This paper describes our design and efforts in synthesizing new scaffolds with taxol-eleutherobin hybrid core structures and a taxol-sugar hybrid. The synthesis of taxol-eleutherobin hybrids involved the synthesis of the A-ring fragment from carvone and t

Full text of DOI:10.1002/ejoc.201000001

FULL PAPER
DOI: 10.1002/ejoc.201000001
Synthesis of a Novel Taxa-Oxa-Sugar Hybrid Core Structure by Tandem
Cross-Enyne Metathesis/IMDA
Rahul S. Nandurdikar,[a] Ayyagari V. Subrahmanyam,[a] and Krishna P. Kaliappan*[a]
Keywords: Antitumor agents / Taxol / Eleutherobin / Hybrid structure / Metathesis / Cycloaddition
This paper describes our design and efforts in synthesizing
new scaffolds with taxol-eleutherobin hybrid core structures
and a taxol-sugar hybrid. The synthesis of taxol-eleutherobin
hybrids involved the synthesis of the A-ring fragment from
to couple the A- and C-ring fragments of these hybrid struc-
tures. Unfortunately, another key reaction (RCM) failed to
form the B-ring and essentially the core unit. However, a tan-
dem enyne cross-metathesis/intramolecular Diels–Alder
strategy was utilized for the synthesis of a taxa-oxa-sugar
hybrid.
carvone and the C-ring fragment from either
D-mannose or
D-glucose. The Shapiro reaction was used as the key reaction
molecular design, and a diverse array of these has been re-
ferred to in the literature as “hybrid molecules” or new
types of molecules. During the past two decades the design
of such entities has been receiving increasing attention and
these “conjugates” or “chimeras” or even “mermaids” and
a large number of molecular hybrids have been designed
and synthesized.[3] Our laboratory is involved in the synthe-
sis of biologically active natural products and their hybrid
systems.[4] This line of interest motivated us to design and
to synthesize new types of hybrid structures that might have
potential anti-cancer activities. This paper details our de-
sign and efforts in synthesizing new taxa-sugar, taxa-oxa-
sugar, and taxol-eleutherobin hybrid structures.
Introduction
Nature has been and still continues to be the prime
source of most pharmaceutical leads in the form of biolo-
gically active natural products. It is also the main inspira-
tional leader for an organic chemist synthetically to mimic
such natural products with their varied complex molecular
architectures and also to access new chemical entities such
as natural product analogues for understanding key bio-
logical events. Moreover, as the number of drug-resistant
diseases continues to increase, it becomes necessary to use
combinations of two or more drugs to cure particular dis-
eases. Medicinal chemists are therefore on constant look-
out for new drugs that could be used individually to cure
various diseases.
Although there may be several ways to make new mole-
cules, one interesting way would be to couple the active
components of two or more natural products by making
hybrid structures.[1,2] By definition, hybrid systems are con-
structs formed from different molecular entities, natural or
unnatural, to generate functional molecules in which the
characteristics of various components are modulated. From
a synthetic point of view, based on this hybrid concept and
also mimicking nature, one can design and synthesize new
types of molecules possessing the structural features of two
(or more) different classes of known natural/unnatural
products with interesting biological activities. The idea of
generating novel molecular entities by combination of two
or more different classes of compounds is appealing be-
cause this approach may provide numerous possibilities for
Background and Significance
Taxol® (paclitaxel, 1, Figure 1) was isolated in 1967 from
the bark of Taxus brevifolia by Wall and Wani.[5a] Hor-
witz[5b] reported a completely new mechanism of action for
taxol. According to this new mechanism, it promotes the
assembly of the proteins α- and β-tubulin into microtubules,
which in vitro disturbs the polymerization/depolymerization
dynamics of microtubules by binding with the microtubules,
making them extremely stable. This inhibits their cell divi-
sion, resulting in cell death.[5b] The outstanding biological
profile of 1 attracted many synthetic groups, but only six
were able to complete its total synthesis.[5c] The mid- to late
1990s witnessed the discoveries of four natural products –
epothilones A and B (2),[6] eleutherobin[7] (3, Figure 1) and
discodermoldide[8] – that showed anti-cancer activities com-
parable to those of 1. Although structurally dissimilar from
1, these compounds each displayed a paclitaxel-like mecha-
nism of action. Eleutherobin (3) was isolated by Fenical and
co-workers from a marine soft coral found in the Indian
Ocean.[9] It is a member of the eunicellanes, a class of ma-
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Mumbai 400 076, India
Fax: +91-22-25723480
E-mail: kpk@chem.iitb.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000001.
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Synthesis of a Novel Taxa-Oxa-Sugar Hybrid Core Structure
rine diterpenes, and is closely related to sarcodictyins[10] and structures exhibit significant biological activities and vari-
valdivones.[11] Two groups succeeded in the total synthesis ous concepts for utilization of multiple anti-tumor activity
of eleutherobin,[12] whereas several groups pursued strate- mechanisms have been proposed. Most of these hybrids,
gies for the core structure and its formal synthesis.[13]
however, show diminished cytotoxic activities in relation to
their parent structures, probably due to decreased affinities
of targets resulting from their increased steric bulks. More-
over, many of these reported taxol hybrids involve the con-
struction of a complex skeleton as in taxol.
Design of the Hybrid Systems
Prior to attempts to design taxol-eleutherobin hybrids,
the available structure/activity relationship (SAR) studies of
these two natural products were considered in depth. SAR
studies of eleutherobin and sarcodictyins by Nicolaou’s
group had found[27] that the side chain is crucial for bio-
logical activity (Figure 2). Both nitrogen atoms in the side
chain are essential for the activity, but substitutions on the
dihydrofuran ring are tolerated well. Esters are preferred
over alcohols and amides and even other substitutions are
Figure 1. Structures of taxol, eleutherobin, and epothiolones.
In view of the biological significance of taxol and eleu- also tolerated. Another report[28] also suggests that a double
therobin, we developed an interest in their syntheses[14,15] bond in the side chain is vital for tubulin binding in the
and furthermore became engrossed in designing a new class eleuthesides.
of hybrid molecules of these two natural products. To the
On taxol, SAR studies[5c] have been carried out fairly
best of our knowledge there is so far no report of any taxol- thoroughly. It is generally believed that the A-ring side
eleutherobin hybrid structure, though there are other re- chain in taxol at C-13 is essential for its biological activity.
ports in which new hybrid molecules of taxol and other It is also reported, however, that substituents on the C-2
natural products have been synthesized and studied. Dani- benzoyloxy group have significant effects on the biological
shefsky and co-workers were probably the first to report a activity of taxol. Taxol analogues possessing bulky substitu-
cholesterol-baccatin hybrid,[16] primarily synthesized to ents at the para position, for example, are inactive,[29]
check the feasibility of the key “Heck reaction” in the total whereas those with the same substituents at the meta posi-
synthesis of taxol. Ojima’s[17] and Kingston’s[18] groups have tion are more active.[30] Kingston and Horwitz disclosed the
synthesized and evaluated taxol-epothilone hybrids, which surprising observation that 2-m-azidobaccatin III, a taxol
provided evidence in support of a common pharmacophore analogue lacking the C-13 side chain but with the m-azido
for these two drugs, which share the same tubulin-binding group at the C-2 position, possesses all of the biological
mechanism of action. Hybrid structures of taxol with por- activities of taxol.[31] At the same time, however, the p-azido
phyrins,[19] calicheamicin,[20] steroids,[21] daunorubicin,[22] substitution product did not show any biological activity.
epipodophyllotoxin,[23] thiocolchicine,[24] chloroambucil,[25] This highlights the significance of the m-azidobenzoyl side
camptothecin,[26] etc. have also been reported in the litera- chain for the new hybrid structures. A common pharmaco-
ture. The syntheses of these hybrid structures involved ele- phore that unites taxol, epothilones, eleutherobin, and dis-
gant synthetic strategies, including modern metathesis ap- codermolide has also been proposed.[32] However, our cur-
proaches. The non-taxane components in these hybrid rent strategies relating to tubulin-binding hybrid agents re-
Figure 2. Representation of SAR studies for eleutherobin and taxol.
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FULL PAPER
Scheme 1. Designed taxa-sugar and taxol-eleutherobin hybrid structures.
volve around epothilones and taxol. In view of the above be derivable from dihydrocarvone to constitute the A-ring
requirement, we decided that hybrid systems of taxol and system whereas the C-ring aldehyde 14 should be accessible
eleutherobin might provide more information relating to from diacetone -glucose. The synthesis of other hybrid
the mechanism of binding of taxol-eleutherobin to tubulin. structures should be achievable by changing the electro-
We thus set out to design, to synthesize, and to evaluate philes in the Shapiro reaction. The epoxide 15, derived from
new, simple hybrid structures of taxol and eleutherobin (4 -glucose, should be utilizable to synthesize the hybrid sys-
to 11, Scheme 1). These molecules were designed for the tems 5 and 9. The epoxide 15 and the -mannose-derived
following reasons. Like eleutherobin, the proposed hybrid aldehyde 16 should be exploitable in the Shapiro reaction
structures each have a rigid A-ring with a cis-AB and cis- to form the AC-ring adducts of the hybrid structures 6/10,
BC fused skeleton. Although there is no double bond pres- and 7/11, respectively.
ent in the C-ring, it is substituted with an additional ring.
The compounds each have a common 1,5-disubstituted cy-
clohexene A-ring with a gem-dimethyl group, as is typical
of a taxol A-ring. Compounds 4 to 7 also each have an
additional isopropyl group reminiscent of eleutherobin.
Each possesses a 13- to 15-membered fused ring system so
that it can retain either the taxol or the eleutherobin back-
bone. The complex C- and D-ring system of taxol has been
replaced by a simple tetrahydrofuran ring so that it can have
the effect of eleutherobin as well as epothilones. The size of
the B-ring varies from eight to nine members, it having been
kept in mind that taxol has an eight-membered B-ring and
eleutherobin has a nine-membered B-ring. The side chain
would be either m-azidobenzoyl or methyl uraconic acid,
as required for taxol and eleutherobin, respectively. All the
molecules are designed to represent simple hybrid structures
of taxol and eleutherobin with all the special features and
active sites of both taxol and eleutherobin.
Retrosynthetic Analysis
An illustrative retrosynthetic analysis of the hybrid struc-
Scheme 2. An illustrative retrosynthesis for the hybrid structure 4
ture 4 is shown in Scheme 2. The strategy involves the con-
and structures of all electrophiles required for the Shapiro reaction.
struction of the B-ring of the hybrid system through
a
ruthenium-carbene-catalyzed ring-closing metathesis
(RCM)[33] reaction and the attachment of different side
chains. The RCM precursor 12 should be obtainable
through a Shapiro reaction between the vinyllithium species
13 and the aldehyde 14, followed by subsequent protection
Results and Discussion
Synthesis of the A-Ring Fragment
Initially, our focus was to synthesize the hybrids 8–11,
of the hydroxy group. The vinyllithium species 13 should starting from (S)-carvone. Our synthesis, as outlined in
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Synthesis of a Novel Taxa-Oxa-Sugar Hybrid Core Structure
Scheme 3, commenced with the 1,4 addition of a vinylcop-
per reagent to (S)-carvone (18), followed by quenching of
the enolate with iodomethane in the presence of N,NЈ-di-
methylpropyleneurea (DMPU) to afford the ketones 19 and
20 in a combined yield of 92%. GC analysis of the crude
product showed that 19 and 20 were present in a ratio of
ca. 6:1. It had previously been reported[34] that the addition
of a nucleophile to (S)-carvone occurs preferentially from
the pseudoaxial position, thus leading to a trans 1,3-disub-
stituted ketone. The ketone 19, obtained as the major prod-
uct, was further converted into its tosylhydrazone derivative
21 in good yield.[35] The ketone 19 was also treated with
trisyl hydrazide (TrisNHNH2) in THF in the presence of
catalytic amounts of p-toluenesulfonic acid (pTsA) to pro-
vide the trisylhydrazone 22 in 62% yield.[36]
Scheme 4. Reagents and conditions: a) vinylmagnesium bromide,
THF, 0 °C, 42 h; b) NaH, THF, 0 °C, MeI, 60% (two steps); c) aq.
AcOH (60%), 24 h, room temp., 68%; d) silica-supported NaIO4,
CH2Cl2, 1.5 h, room temp.; e) TPP, DIAD, molecular sieves (4 Å),
toluene, 80 °C, 76 %.
The synthesis of the C-ring fragments for the hybrids 10
and 11 started from mannose diacetonide (27, Scheme 5).
The diol 28 was synthesized by the protocol developed in
our laboratory[42] and was then easily converted into the
aldehyde 16 by the protocol used for compound 14. Like
the aldehyde 14, the aldehyde 16 was freshly prepared and
used immediately for the Shapiro reaction.
Scheme 3. Reagents and conditions: a) vinylmagnesium bromide,
CuI, THF, –78 °C, DMPU, MeI, 92%; b) pTsNHNH2, absolute
EtOH, concd. HCl (cat.), 6 h, room temp., 80%; c) TrisNHNH2,
THF, pTsA (cat.), 24 h, room temp., 62%.
Synthesis of the C-Ring Fragments
The synthesis of the C-rings in hybrids 5, 6, 9, and 10
started from the -glucose-derived ketone 23 (Scheme 4).[37]
Stereoselective addition[37,38] of vinylmagnesium bromide to
a THF solution of ketone 23 afforded the tertiary alcohol
24. The crude alcohol 24 was then transformed into its
methyl ether 25 in 60% yield over two steps.[39] The more
labile acetonide protection in the methyl ether 25 was re-
moved with aqueous acetic acid (60%). The resulting diol
26 was oxidatively cleaved with silica-supported sodium
periodate[40] in dry CH2Cl2 to afford the aldehyde 14. Be-
cause the aldehyde 14 was unstable, it was freshly prepared
and used immediately, without purification, for the Shapiro
reaction.
The synthesis of hybrid 9 would require the epoxide 15
(Scheme 4) as an electrophile for the Shapiro reaction, so
the required epoxide 15 was synthesized by treatment of the
diol 26 with triphenylphosphane (TPP), diisopropyl azo-
dicarboxylate (DIAD), and molecular sieves (4 Å) in tolu-
ene at 80 °C.[41]
Scheme 5. Reagents and conditions: a) silica-supported NaIO4,
CH2Cl2, 1 h, room temp.; b) pTsCl, py., 0 °C to RT, 12 h, 88%;
c) NaOMe, 0 °C to RT, 2 h, 75%.
Finally, the epoxide 17 (Scheme 5) was synthesized from
the diol 28 in a couple of steps. The primary hydroxy group
of the diol 28 was selectively tosylated (pTsCl in pyridine)
to afford 29 (88%), and this was subsequently transformed
into the epoxide 17 on treatment with sodium ethoxide.
Coupling of A- and C-Rings by Shapiro Reaction
After the successful syntheses of the key intermediates
for the Shapiro reactions, the next key task was to couple
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the A- and C-ring fragments of the hybrids. To start with,
we first attempted a Shapiro reaction between the tosyl-
hydrazone 21 and the aldehyde 14 (Scheme 6). The tosyl-
hydrazone 21 was treated with nBuLi (3.3 equiv.) in THF
to generate the vinyllithium species,[35] which was quenched
with the aldehyde 14 to give a mixture of the separable epi-
meric alcohols 30 and 31 in almost 1:1 ratio (32% com-
bined yield). The yield of the Shapiro reaction was im-
proved substantially (60%) by using the trisylhydrazone 22
instead of 21 (Scheme 6).
Scheme 7. Reagents and conditions: a) nBuLi (2.2 equiv.), THF,
–78 °C, 30 min, then 0 °C 5 min, 16 added at –78 °C, 46 %;
b) nBuLi (3.3 equiv.), THF, –78 °C, 30 min, then room temp.
15 min, BF3·OEt2 and 17 added at –78 °C; c) nBuLi (2.2 equiv.),
THF, –78 °C, 30 min, then 0 °C, 5 min, CuBr·SMe2 in THF and 18
added at –78 °C.
the Shapiro reaction, and use of catalytic and equimolar
amounts of BF3·OEt2 also did not afford the desired prod-
uct 35.
Attempted RCM to Make the B-Ring
The next important phase in the synthesis of hybrid mo-
lecules involved the key RCM of the available Shapiro reac-
tion products. If successful, RCM would provide the B-
rings of the hybrids and attachment of the side chains at C-
2 would furnish the desired hybrid systems.
For the synthesis of hybrid molecules of type 8, the po-
lar –OH functional group in one of the Shapiro reaction
products was protected as its acetate 39 (Scheme 8), in or-
der to avoid any undesired interference in the RCM reac-
tion. Attempted RCM in the presence of the first-genera-
tion Grubbs catalyst 36 (10 mol-%) at high dilution
Scheme 6. Reagents and conditions: a) nBuLi (3.3 equiv.), THF,
–78 °C, 30 min, then room temp. 12 min, 14 added at –78 °C, 32 %;
b) nBuLi (2.2 equiv.), THF, –78 °C, 30 min, then 0 °C 5 min, 14
added at –78 °C, 60%; c) nBuLi (3.3 equiv.), THF, –78 °C, 30 min,
then room temp. 15 min, BF3·OEt2 and 15 added at –78 °C:
d) nBuLi (3.3 equiv.), THF, –78 °C, 30 min, then room temp.
15 min, CuBr·SMe2 in THF and 15 added at –78 °C.
The synthesis of a hybrid of type 10 required the cou- (0.003 ) in CH2Cl2 at reflux, as well as under a variety of
pling of hydrazone 21 and epoxide 15 (Scheme 6). Unfortu- other conditions, often led to the recovery of the starting
nately, quenching of the vinyllithium species generated in material. Because the substrate contains many oxygen func-
the Shapiro reaction with the epoxide 15 in the presence of tionalities it was presumed that the active ruthenium car-
a Lewis acid such as BF3·OEt2 failed to produce the re- bene complex might be becoming chelated at these oxygen
quired product 32. However, on transmetallation with the centers, making it unavailable for the reaction. Ti(OiPr)4 is
CuBr·SMe2 complex it was possible to open the epoxide known to prevent such chelation of the active ruthenium
ring of 15 to give the alcohol 32 in 30% yield.
carbene with oxygen functionalities, thus making it avail-
The trisylhydrazone 22 was treated with nBuLi able for RCM (Scheme 8),[43] so Ti(OiPr)4 (10 mol-%) was
(2.2 equiv.) in THF at low temperature and the aldehyde 16 added prior to the catalyst 37 either in CH2Cl2 or in tolu-
in THF was added to this reaction mixture to afford the ene, both at reflux, and yet the results remain the same.
alcohols 33 and 34 in 46% yield, but these were found to Even the use of three equivalents of Ti(OiPr)4 with respect
be inseparable by column chromatography (Scheme 7).
to the substrate did not change the course of the reac-
For the synthesis of the hybrid structure of type 7, the tion.[44] Attempts to carry out RCM in the presence either
vinylcopper species generated by treatment of the tosyl- of the second-generation Grubbs catalyst 37 or of the phos-
hydrazone 21 with nBuLi and transmetallation with the phane-free and more functional-group-tolerant Hoveyda–
CuBr·SMe2 complex could not open the epoxide 17 to form Grubbs catalyst 38 also did not succeed in furnishing the
the product 35 (Scheme 7). The use of trisylhydrazone 22 in product 40.
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Synthesis of a Novel Taxa-Oxa-Sugar Hybrid Core Structure
tion of enone 43 in the presence either of the second-gener-
ation Grubbs catalyst 37 (5 mol-%) or of the Hoveyda–
Grubbs catalyst 38 (1 mol-%) failed to produce the required
cyclized products. Similar failures were experienced for the
mixture of alcohols 33 and 34 under various conditions.
Scheme 9. Reagents and conditions: a) DMP, CH2Cl2, room temp.,
8 h, 67%; b) 36 (10 mol-%), Ti(OiPr)4 (10 mol-%), CH2Cl2, reflux,
12 h; c) 37 (5 mol-%), CH2Cl2, reflux, 24 h; d) 38 (1 mol-%),
CH2Cl2, reflux, 24 h.
The attempts to construct eight- and nine-membered
rings in the hybrid systems by means of the key RCM reac-
tion were thus unsuccessful. Construction of medium-sized
rings by RCM is a difficult task, but there are reports of
syntheses of seven- to nine-membered rings by RCM, in-
cluding a few from our laboratory.[15] Probably the high
steric congestion in the RCM precursors is presenting ad-
ditional complication for the construction of these medium-
sized rings. So far our attempts have revolved around the
use of RCM precursors with different functional groups at
the junctions of their A- and C-rings. It is evident from
these failures that new structural changes to minimize the
steric congestion in the RCM precursors are essential. Ef-
forts in this direction are underway.
Scheme 8. Reagents and conditions: a) Ac2O, Py, DMAP (cat.),
90%; b) 36 (10 mol-%), CH2Cl2, reflux, 12 h; c) 36 (10 mol-%),
Ti(OiPr)4 (10 mol-%) CH2Cl2, reflux, 12 h; d) 36 (10 mol-%),
Ti(OiPr)4 (10 mol-%), toluene, 80 °C, 12 h; e) 37 (5 mol-%),
CH2Cl2, reflux, 24 h; f) 37 (5 mol-%), CH2Cl2, reflux, 24 h; g) 38
(3 mol-%), CH2Cl2, reflux, 24 h; h) oxalyl chloride, DMSO,
CH2Cl2, –78 °C, TEA, 75%.
However, we have also been engaged in exploring an al-
ternative strategy to synthesize some new taxol hybrids.
From our previous experience in enyne metathesis[4] and the
Diels–Alder reaction,[14] a domino enyne metathesis/intra-
molecular Diels–Alder (IMDA) reaction[47–49] has been
considered as a plausible strategy to synthesize interesting
hybrid molecules of this type. We designed a few hybrid
molecules such as the taxa-oxa-sugar 45, the taxa-sugar hy-
brids 46, and the taxa-eleutherobin hybrid 47 (Scheme 10)
After the failure of attempted RCM with the acetate 39,
we switched over to the allylic alcohols 30 and 31
(Scheme 8), transforming them into the enone 41 under
Swern conditions[45] and studying their reactivity towards
RCM. Attempted RCM of the enone 41 in the presence of
the Grubbs catalyst 37 (10 mol-%) and Ti(OiPr)4 (10 mol-
%) in CH2Cl2 at reflux or in toluene at 80 °C failed to give
the product 42. Independent attempts to perform RCM in
the presence variously of catalyst 36 (10 mol-%) with
[Ti(OiPr)4] (3 equiv.) as an additive, of the Grubbs catalyst
37 (5 mol-%), and of the Hoveyda–Grubbs catalyst 38
(1 mol-%) in CH2Cl2 at reflux also failed.
Attempted RCM of the allylic alcohols 30 and 31 under
conditions similar to those used with the acetate 39 and the
enone 41 also did not succeed.
In parallel, for the other set of hybrid structures, the mix-
ture of allylic alcohols 33 and 34 (Scheme 9) was oxidized
to the corresponding ketone 43 with Dess–Martin
periodinane[46] (DMP) in CH2Cl2 in 67% yield. Unfortu-
Scheme 10. Designed taxa-oxa-sugar, taxa-sugar, and taxaol-eleu-
nately though, attempts to perform the key metathesis reac- therobin hybrid structures.
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and set out to construct their A-rings by domino enyne me- the high steric congestion in the RCM precursors, which
tathesis. would be disadvantageous to the formation of the thermo-
This new synthetic route began with alkylation of diace- dynamically less favored eight- and nine-membered rings.
tone--glucose (48) with propargyl bromide to furnish the However, we have successfully synthesized the core struc-
propargyl ether 50 in good yield (Scheme 11). The alkyne ture of a taxa-oxa-sugar hybrid by utilizing tandem enyne
49 was subsequently methylated by treatment with nBuLi cross-metathesis/IMDA as a key step. Efforts in elaborating
and iodomethane to afford the required product 50. The this successful domino approach for the synthesis of various
more labile acetonide in 50 was selectively removed under taxa-sugar hybrids and in evaluating their biological activi-
mild acidic conditions to give the diol 51, which was further ties are underway.
oxidatively cleaved with silica-gel-supported NaIO4 to af-
ford an aldehyde. This was then treated with vinylmagne-
sium bromide, leading to a mixture of allyl alcohols 52 in
1:2 ratio, and these were further oxidized to 53 with DMP.
Experimental Section
General: Unless otherwise noted, all starting materials and reagents
were obtained from commercial suppliers and were used without
further purification. Tetrahydrofuran was distilled from sodium
benzophenone ketyl. Dichloromethane and hexanes were freshly
distilled from calcium hydride. DMF was distilled from calcium
hydride and stored over molecular sieves (4 Å). Solvents for routine
isolation of products and chromatography were reagent grade and
glass-distilled. Reaction flasks were dried in an oven at 100 °C for
12 h before use. Air- and moisture-sensitive reactions were per-
formed under argon/UHP nitrogen. Column chromatography was
performed with silica gel (100–200 mesh, Acme) and indicated sol-
vents. All reactions were monitored by thin-layer chromatography
carried out on E. Merck silica plates (0.25 mm, 60F-254) with UV
light as visualizing agent and ethanolic phosphomolybdic acid
(7%) and heat as developing agents. Optical rotations were re-
corded with a Jasco DIP-370 digital polarimeter. IR spectra were
recorded with a Thermo Nicolet Avatar 320 FT-IR and a Nicolete
Impact 400 machine. Mass spectra were obtained with a Waters
Micromass-Q-Tof microTM (YA105) spectrometer. Elemental
analysis was recorded with a Thermo Finnigan Flash EA 1112 in-
strument. 1H and 13C NMR spectra were recorded with Varian
AS 400, Varian AS 500, or Varian ASM 300 instruments in CDCl3
solutions. 1H NMR spectroscopic data are reported in the order of
chemical shift (δ in ppm), multiplicity (s, singlet; d, doublet; t, trip-
let; q, quartet; m, multiplet), number of protons, and coupling con-
stant (J) in Hertz [Hz].
Scheme 11. Reagents and conditions: a) NaH, DMF, propargyl bro-
mide, 0 °C to room temp., 12 h, 95%; b) nBuLi, MeI, THF, HMPA,
–78 °C to room temp., 3 h, 80%; c) aq. AcOH (60%), room temp.,
12 h, 91%. d) i) silica-supp. NaIO4, CH2Cl2, room temp., 2 h, ii) vi-
nylmagnesium bromide, THF, 0 °C to room temp., 12 h, 54% (for
2 steps); e) DMP, CH2Cl2, room temp., 12 h, 77%; f) 37 (10 mol-
%), toluene, 80 °C, 12 h, 57%.
The tandem enyne/cross-metathesis/IMDA reaction of
compound 53 under ethylene (1 atm) in the presence of the
second-generation Grubbs catalyst 37 in toluene at 80 °C
gave the core structure of the taxa-oxa-sugar hybrid 54 in
57% yield. The alternative strategy has thus been success-
fully used to synthesize the core structure 54 and currently
our laboratory is engaged in attaching the side chain and
extending the protocol to synthesize other hybrid struc-
tures.
(3S,5S)-5-Isopropenyl-2,2-dimethyl-3-vinylcyclohexanone (19 and
20): Vinylmagnesium bromide solution (67.2 mL, 67.2 mmol) was
added under argon at –50 °C to a suspension of CuI (2.56 g,
13.44 mmol) in THF (45 mL) and the mixture was stirred for
30 min. A solution of (S)-carvone (18, 5.23 mL, 33.6 mmol) in
THF (20 mL) was added dropwise at –78 °C. After 1 h the reaction
mixture was allowed to warm to room temp. and stirred for 2 h. It
was then cooled to –78 °C and DMPU (16.25 mL, 134.4 mmol)
was added, followed by methyl iodide (20.91 mL, 336 mmol). The
flask was then allowed to warm to room temp., and the mixture
was stirred for 2 h. The reaction mixture was quenched with satu-
rated ammonium chloride solution and extracted with ethyl acetate
(4ϫ50 mL). The combined organic layer was washed with satu-
rated sodium thiosulfate solution, water, and brine, and dried with
anhydrous sodium sulfate. Solvent was evaporated at low pressure.
The crude product was subjected to column purification by eluting
with hexanes to afford the isomeric ketones 19 and 20 along with
some mixture of the two with a global yield of 92% as colorless
oils.
Conclusions
In conclusion, we have designed a new class of taxa-oxa-
sugar, taxa-sugar, and taxol-eleutherobin hybrid systems
that might be synthesizable from various sugars. The C-ring
fragments were successfully synthesized from -glucose and
-mannose. The A- and C-ring fragments of the hybrid sys-
tems were coupled through Shapiro reactions. Unfortu-
nately, however, all attempts to carry out the key RCM re-
actions with the Shapiro reaction products and their deriva-
GC analysis: Rt for 19 = 1.145 min Rt for 20 = 0.975 min (in 10%
carbowax column, oven temp. 150 °C, injection port temp. 200 °C,
tives failed. The failure of the RCM could be attributed to detector temp. 200 °C, flow rate 30 mLmin–1).
2794
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2788–2799

Synthesis of a Novel Taxa-Oxa-Sugar Hybrid Core Structure
Data for 19: Rf = 0.71 (hexanes/ethyl acetate 9.5:0.5). [α]2D5 = –15.19
(c = 1.58, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.00 (s, 3 H),
brine solution and dried with anhydrous sodium sulfate. The or-
ganic extract was concentrated by evaporation of solvent at reduced
1.18 (s, 3 H), 1.73 (s, 3 H), 1.80–1.87 (m, 1 H), 2.00–2.07 (m, 1 H), pressure to obtain crude 24 used for the following step.
2.36–2.41 (m, 2 H), 2.46–2.51 (m, 2 H), 4.72 (d, J = 0.6 Hz, 1 H),
Sodium hydride (2.9 g, 72.64 mmol) was washed with dry hexanes
4.82 (d, J = 0.6 Hz, 1 H), 5.02–5.06 (m, 2 H), 5.72–5.78 (m, 1
(3ϫ10 mL) and suspended in dry THF (20 mL) under argon at
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 21.2, 21.8, 24.9, 31.6,
0 °C. A solution of the crude alcohol 24 (5.2 g, 18.16 mmol) in
40.8, 42.0, 47.4, 49.8, 110.9, 116.4, 138.2, 147.1, 215.6 ppm. IR
THF (80 mL) was added dropwise and the reaction mixture was
(film): ν = 3091, 2973, 2940, 2888, 1716, 1644, 1137 cm–1. HRMS
˜
left to stir at room temp. for 1 h. Methyl iodide (5.65 mL,
(ESI): calcd. for C13H21O [M + H]+ 193.1592; found 193.1598.
90.8 mmol) was added dropwise. TBAI (a catalytic amount) was
Data for 20: Rf = 0.74 (9.5:0.5 hexanes/ethyl acetate). [α]2D5 = –11.38
added and the reaction mixture was stirred for 12 h at room temp.
Methanol (6 mL) was slowly added, followed by addition of water
(c = 2.46, CHCl3). 1H NMR (CDCl3, 200 MHz): δ = 0.97 (s, 3 H),
1.30 (s, 3 H), 1.73 (s, 3 H), 2.17 (m, 3 H), 2.42–2.49 (m, 2 H), 2.70–
2.76 (m, 1 H), 4.75 (s, 1 H), 4.78 (s, 1 H), 4.99–5.07 (m, 2 H), 5.58–
5.71 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 21.4, 22.0,
25.1, 31.7, 41.0, 42.1, 47.5, 49.9, 110.8, 116.3, 138.1, 147.0,
(10 mL). The aqueous layer was extracted with ethyl acetate
(4ϫ50 mL). The combined extracts were washed with brine, dried
with anhydrous sodium sulfate, and filtered. Concentration of the
filtrate followed by column chromatography (hexanes/ethyl acetate
9:1) afforded the methyl ether 25 (3.98 g, 60% for two steps). Rf =
0.39 (hexanes/ethyl acetate 4:1). [α]2D5 = +54.17 (c = 2.40, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.34 (s, 3 H), 1.37 (s, 3 H), 1.43
(s, 3 H), 1.61 (s, 3 H), 3.39 (s, 3 H), 3.87–3.99 (m, 2 H), 4.06–4.17
(m, 2 H), 4.56 (d, J = 3.7 Hz, 1 H), 5.26 (d, J = 17.9 Hz, 1 H), 5.49
(d, J = 11.4 Hz, 1 H), 5.75 (d, J = 3.7 Hz, 1 H), 5.78 (dd, J = 17.9,
11.4 Hz, 1 H) ppm. 13C NMR (75 MHz): δ = 25.4, 26.6, 27.1, 53.2,
66.8, 73.8, 81.3, 82.3, 85.3, 104.1, 109.2, 112.9, 118.9, 135.1 ppm.
215.3 ppm. IR (film): ν = 3072, 2986, 2933, 2888, 1716, 1637, 1466,
˜
1394 cm–1. HRMS (ESI): calcd. for C13H21O [M + H]+ 193.1592;
found 193.1587.
Synthesis of the Tosylhydrazone 21: p-Tolylsulfonyl hydrazide
(0.59 g, 3.172 mmol) and a drop of concd. HCl were added to a
solution of the ketone 19 (0.47 g, 2.44 mmol) in absolute ethanol
(3 mL), and the mixture was stirred at 40 °C for 20 min. This solu-
tion was then allowed to warm to room temp. and stirred for 6 h.
The solvent was evaporated and the crude mass was recrystallized
from hexanes to afford white crystals of 20 (0.706 g, 80%). Rf =
0.42 (hexanes/ethyl acetate 4:1); m.p. 84–86 °C. [α]2D5 = +50.39 (c =
1.27, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.95 (s, 3 H), 1.10
(s, 3 H), 1.57–1.65 (m, 2 H), 1.68 (s, 3 H), 1.8–1.95 (m, 2 H), 2.01–
2.38 (m, 2 H), 2.43 (s, 3 H), 4.60 (s, 1 H), 4.72 (s, 1 H), 4.88–5.07
(m, 2 H), 5.42–5.54 (m, 1 H), 7.31 (d, J = 8.1 Hz, 2 H), 7.85 (d, J
= 8.1 Hz, 2 H) ppm. 13C NMR (75 MHz): δ = 21.1, 21.7, 24.3,
26.8, 27.1, 32.6, 39.5, 41.4, 50.3, 110.2, 115.8, 128.3, 129.3, 135.2,
IR (film): ν = 2987, 2939, 2834, 1635, 1457, 1377, 1218, 1164, 1077,
˜
1030 cm–1. HRMS (ESI): calcd. for C15H24NaO6 [M + Na]+
323.1471; found 323.1481. C15H24O6: calcd. C 59.98, H 8.05; found
C 60.46, H 8.04.
3-O-Methyl-1,2-O-isopropylidene-3-C-vinyl-α-D-allofuranose (26):
The methyl ether 25 (3.45 g, 11.48 mmol) was dissolved in aqueous
acetic acid (60%, 40 mL) and the solution was stirred at room
temp. for 24 h. The acetic acid and water were removed by repeated
co-evaporation in vacuo with toluene. The yellow syrup was puri-
fied by column chromatography (hexanes/ethyl acetate 3:2) to give
the diol 26 (2 g, 68%). Rf = 0.16 (hexanes/ethyl acetate 2:1). [α]2D5
= +56.76 (c = 1.11, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.38
(s, 3 H), 1.62 (s, 3 H), 2.57 (br. s, 2 H), 3.44 (s, 3 H), 3.62–3.77 (m,
3 H), 4.06 (d, J = 7.3 Hz, 1 H), 4.57 (d, J = 3.7 Hz, 1 H), 5.33 (d,
J = 18.3 Hz, 1 H), 5.55 (d, J = 11 Hz, 1 H), 5.78 (d, J = 3.7 Hz, 1
H), 5.83 (dd, J = 18.3, 11 Hz, 1 H) ppm. 13C NMR (100 MHz): δ
= 26.5, 26.8, 53.5, 64.2, 70.2, 79.4, 80.6, 86.1, 104.2, 113.2, 119.0,
138.9, 143.9, 147.5, 165.2 ppm. IR (in CH Cl ): ν = 3218, 3072,
˜
2
2
1699, 1644, 1598, 1167 cm–1. HRMS (ESI): calcd. for
C20H29N2O2S [M + H]+ 361.1950; found 361.1965.
Synthesis of the Trisylhydrazone (22): A catalytic amount of p-tolu-
enesulfonic acid was added to the mixture of ketone 19 (0.5 g,
2.6 mmol) and 2,4,6-triisopropylbenzenesulfonyl hydrazide (1.0 g,
3.38 mmol) in dry THF at room temp. After 24 h, the solvent was
evaporated under reduced pressure and the white solid product 22
(0.76 g, 62%) was obtained after column chromatographic purifica-
tion on basic alumina with hexanes/ethyl acetate (8:2) as eluent. Rf
133.8 ppm. IR (film): ν = 3464, 3090, 2988, 2939, 1640, 1457, 1425,
˜
1378, 1219, 1096, 1025 cm–1. HRMS (ESI): calcd. for C12H20NaO6
[M + Na]+ 283.1158; found 283.1169. C12H20O6 (260.29): calcd. C
55.37, H 7.74; found C 55.84, H 7.91.
= 0.32 (hexanes/ethyl acetate 9.5:0.5); m.p. 108–110 °C. [α]2D5
=
1
+40.39 (c = 1.20, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.82
(s, 3 H), 1.05 (s, 3 H), 1.23–1.27 (m, 18 H), 1.67 (s, 3 H), 2.08–2.19
(m, 2 H), 2.28–2.44 (m, 3 H), 2.84–2.93 (m, 1 H), 4.10–4.18 (m, 3
H), 4.67 (s, 1 H), 4.76 (s, 1 H), 4.90 (dd, J = 17.2, 10.0 Hz, 2 H),
5.46–5.55 (m, 1 H), 7.16 (s, 2 H) ppm. 13C NMR (75 MHz): δ =
20.9, 23.6, 24.4, 24.9, 25.0, 26.9, 30.0, 32.6, 34.3, 39.5, 41.2, 50.2,
110.4, 115.8, 123.5, 131.4, 139.0, 147.4, 151.2, 153.2, 162.6 ppm.
Epoxide 15: DIAD (0.28 mL, 1.44 mmol) was slowly added at room
temp. to a mixture of the diol 26 (0.34 g, 1.31 mmol), tri-
phenylphosphane (0.376 g, 1.44 mmol), and molecular sieves (4 Å)
in toluene (15 mL), and the mixture was then heated to 80 °C for
8 h. It was then allowed to cool to room temp., quenched with
water (10 mL), extracted with ethyl acetate (3ϫ15 mL), washed
with brine, dried with anhydrous sodium sulfate, and concentrated.
Column chromatographic purification (hexanes/ethyl acetate
9.2:0.8) gave the epoxide 15 (0.24 g, 76%). Rf = 0.48 (hexanes/ethyl
acetate 2:1). [α]2D5 = +35.45 (c = 1.10, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.37 (s, 3 H), 1.59 (s, 3 H), 2.74–2.80 (m, 2 H), 3.01–
3.04 (m, 1 H), 3.42 (s, 3 H), 3.94 (d, J = 6.0 Hz, 1 H), 4.55 (d, J =
3.6 Hz, 1 H), 5.38 (d, J = 18.0 Hz, 1 H), 5.54 (d, J = 11.2 Hz, 1
H), 5.78 (d, J = 3.6 Hz, 1 H), 5.83 (dd, J = 18.0, 11.2 Hz, 1 H) ppm.
13C NMR (100 MHz): δ = 26.5, 27.0, 45.3, 49.4, 53.4, 81.0, 81.5,
IR (KBr): ν = 3224, 2962, 2929, 2872, 1639, 1458, 1380 cm–1.
˜
HRMS (ESI): calcd. for C28H45N2O2S [M + H]+ 473.3202; found
473.3208.
3-O-Methyl-1,2:5,6-di-O-isopropylidene-3-C-vinyl-α-D-allofuranose
(25): The ketone 23[37] (6.5 g, 25.19 mmol) was dehydrated by azeo-
tropic distillation with dry toluene. Dry THF (80 mL) was added
to this ketone and the mixture was cooled to 0 °C. A solution of
vinylmagnesium bromide (1 , 37.8 mL, 37.8 mmol) was added
dropwise and the mixture was stirred at room temp. for 42 h. The
reaction mixture was cooled to 0 °C and quenched with saturated
ammonium chloride and the residue was extracted with ethyl acet-
ate (3 ϫ40 mL). The combined organic extracts were washed with
85.8, 104.4, 113.2, 119.3, 134.2 ppm. IR (film): ν = 1648, 1463,
˜
1259, 1213, 1113, 1034 cm–1. HRMS (ESI): calcd. for C12H18NaO5
[M + Na]+ 265.1052; found 265.1044.
Eur. J. Org. Chem. 2010, 2788–2799
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2795

R. S. Nandurdikar, A. V. Subrahmanyam, K. P. Kaliappan
FULL PAPER
Tosylate 29: pTsCl (0.33 g, 1.75 mmol) was added portionwise to a
solution of the diol 28[42] (0.38 g, 1.46 mmol) in dry pyridine
(3 mL), and the mixture was stirred for 2 h at 0 °C and then for
12 h at room temperature. The reaction mixture was quenched with
saturated NaHCO3 (20 mL) and extracted with ethyl acetate
(3ϫ20 mL). The combined organic extracts were dried with anhy-
drous sodium sulfate and evaporated under reduced pressure to
give a residue that was purified by silica gel chromatography (hex-
anes/ethyl acetate 4:1) to afford 29 (0.54 g, 88%) as a colorless oil.
Rf = 0.6 (hexanes/ethyl acetate 3:2). [α]2D5 = +60.4 (c = 0.48, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.29 (s, 3 H), 1.40 (s, 3 H), 2.45
(s, 3 H), 3.09 (s, 3 H), 3.81 (dd, J = 8.4, 3.9 Hz, 1 H), 4.23–4.11
(m, 3 H), 4.35 (dd, J = 10.5, 2.7 Hz, 1 H), 4.45 (d, J = 6.0 Hz, 1
H), 4.85 (dd, J = 5.7, 3.9 Hz, 1 H), 5.42–5.41 (m, 2 H), 5.66 (dd,
J = 7.8, 6.3 Hz, 1 H), 7.35 (dd, J = 8.4, 1.5 Hz, 2 H), 7.83 (dd, J
= 6.6, 1.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.7,
24.7, 25.9, 49.0, 68.1, 71.8, 76.6, 86.3, 108.0, 113.0, 119.9, 128.1,
–78 °C to a solution of the trisylhydrazone 22 (0.8 g, 1.69 mmol)
in THF (0.6 mL). After stirring for 30 min at –78 °C, the reaction
mixture was stirred at 0 °C for 5 min and cooled to –78 °C, the
aldehyde 14 or 16 was added slowly, and the mixture was stirred
for 1 h. The reaction mixture was allowed to stir at room temp.
for 2 h and then quenched with saturated ammonium chloride and
extracted with ethyl acetate (3ϫ20 mL), washed with brine, dried
with anhydrous sodium sulfate, and concentrated. Column chroma-
tographic purification gave the epimeric alcohols 30 (0.16 g) and
31 (0.17 g) in a combined yield of 60% or the epimeric mixture of
alcohols 43 and 34 (0.25 g, 46%).
Data for Alcohol 30: Rf = 0.59 (hexanes/ethyl acetate 2:1). [α]2D5
=
1
+11.36 (c = 0.44, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.85
(s, 3 H), 1.11 (s, 3 H), 1.37 (s, 3 H), 1.61 (s, 3 H), 1.63–1.73 (m, 2
H),1.74 (s, 3 H), 2.06–2.11 (m, 1 H), 2.36 (d, J = 2.8 Hz, 1 H), 2.80
(dd, J = 10.0, 5.0 Hz, 1 H), 3.44 (s, 3 H), 4.15–4.16 (m, 2 H), 4.56
(d, J = 3.6 Hz, 1 H), 4.69 (s, 1 H), 4.79 (s, 1 H), 4.97–5.02 (m, 2
H), 5.33 (d, J = 18.0 Hz, 1 H), 5.58 (d, J = 11.2 Hz, 1 H), 5.72 (d,
J = 3.6 Hz, 1 H), 5.77 (d, J = 4.4 Hz, 1 H), 5.81–5.91 (m, 2 H,
2ϫCH=) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.8, 22.8, 26.7,
27.1, 27.4, 29.2, 36.6, 40.8, 47.5, 53.6, 68.5, 80.9, 81.5, 86.7, 103.9,
111.5, 112.9, 115.0, 118.9, 126.9, 134.2, 141.0, 145.7, 148.1 ppm.
129.9, 131.9, 132.9, 145.0 ppm. IR (film): ν = 3486, 3104, 2940,
˜
1657 cm–1. HRMS (ESI): calcd. for C19H26NaO8S [M + Na]+
437.1246; found 437.1231.
Epoxide 17: A solution of NaOMe (0.13 g, 2.41 mmol) in methanol
(2 mL) was added at 0 °C to a stirred solution of 29 (0.5 g,
1.2 mmol) in dry methanol (20 mL), and the mixture was stirred
for 1 h at 0 °C and then for 2 h at room temp. The reaction mixture
was quenched with water (25 mL) and extracted with ethyl acetate
(3ϫ20 mL). The combined organic layers were washed with brine,
dried with anhydrous sodium sulfate, concentrated in vacuo, and
purified by silica gel chromatography (hexanes/ethyl acetate 9:1) to
afford the epoxide 17 (0.22 g, 75%) as a colorless oil. Rf = 0.8
(hexanes/ethyl acetate 3:2). [α]2D5 = +64.4 (c = 1.64, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.33 (s, 3 H), 1.46 (s, 3 H), 2.81 (dd,
J = 5.2, 2.9 Hz, 1 H), 2.95–2.92 (m, 1 H), 3.13 (s, 3 H), 3.35–3.32
(m, 1 H), 3.57 (dd, J = 6.0, 4.0 Hz, 1 H), 4.49 (d, J = 5.6 Hz, 1 H),
4.89 (dd, J = 6.0, 3.6 Hz, 1 H), 5.49 (m, 2 H), 5.73 (dd, J = 17.6,
10.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.8, 26.1,
46.2, 48.9, 79.3, 80.7, 86.5, 108.1, 113.0, 119.9, 132.2 ppm. IR
IR (film): ν = 3522, 3075, 1640, 1376, 1219, 1112 cm–1. HRMS
˜
(ESI): calcd. for C24H36NaO5 [M + Na]+ 427.2460; found 427.2454.
Data for Alcohol 31: Rf = 0.46 (hexanes/ethyl acetate 2:1). [α]2D5
=
+16.99 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.01
(s, 3 H), 1.06 (s, 3 H), 1.39 (s, 3 H), 1.50 (s, 3 H), 1.60–1.72 (m, 2
H), 1.73 (s, 3 H), 2.05–2.11 (m, 1 H), 2.27 (d, J = 7.6 Hz, 1 H),
3.35 (s, 3 H), 4.21 (d, J = 0.8 Hz, 1 H), 4.33 (d, J = 7.6 Hz, 1 H),
4.60 (d, J = 3.2 Hz, 1 H), 4.70 (s, 1 H), 4.79 (s, 1 H), 4.97–5.02 (m,
2 H), 5.28 (d, J = 12.0 Hz, 1 H), 5.48 (d, J = 11.2 Hz, 1 H), 5.81–
5.98 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.7, 23.0,
26.8, 27.1, 27.3, 29.1, 36.6, 40.8, 47.3, 53.0, 65.5, 80.1, 84.0, 84.8,
104.0, 111.6, 113.0, 115.2, 117.7, 126.7, 135.6, 140.6, 147.0,
148.2 ppm. IR (film): ν = 3499, 3084, 1640, 1379, 1219, 1112 cm–1.
˜
HRMS (ESI): calcd. for C24H36NaO5 [M + Na]+ 427.2460; found
427.2474.
(film): ν = 3065, 2923, 1663, 1104 cm–1. LRMS (ESI): m/z =
˜
265.0534 [M + Na]+. HRMS (ESI): calcd. for C12H18NaO5 [M +
Na]+ 265.1062; found 265.1052.
Compound 32: nBuLi in hexane (1.6 , 2.06 mL, 3.3 mmol) was
added dropwise to a solution of the tosylhydrazone 21 (0.36 g,
1 mmol) in THF (3 mL). The deep red solution was stirred at
–78 °C for 30 min and was then allowed to warm slowly to room
temp. After 12 min of stirring at room temp., the reaction mixture
was cooled to –78 °C and CuBr·SMe2 in THF (3 mL) was added.
After 15 min the epoxide 15 (0.17 g, 0.7 mmol) was added and the
mixture was allowed to warm to room temp, stirred at room temp.
for 8 h, quenched with saturated ammonium chloride solution, ex-
tracted with ethyl acetate, and dried with sodium sulfate. The crude
product obtained after concentration was purified by column
chromatography (hexanes/ethyl acetate 9:1) to afford the alcohol
General Procedures for the Shapiro Reactions: Silica-supported
[40]
NaIO4 was added portionwise to a stirred solution of diol 26 or
28[42] (0.42 g, 1.61 mmol) in CH2Cl2 (20 mL). The reaction mixture
was stirred vigorously for 1–1.5 h and filtered, and the residue was
washed with CH2Cl2 (2ϫ20 mL). The combined CH2Cl2 extracts
were concentrated and the resultant pale yellow syrup (0.41 g) was
used immediately for the next step.
Method with the Tosylhydrazone as Starting Material: nBuLi in hex-
ane (1.6  solution, 3.5 mL, 5.58 mmol) was slowly added at –78 °C
to a solution of the tosylhydrazone 21 (0.667 g, 1.69 mmol) in THF
(0.6 mL). The deep red solution was stirred at –78 °C for 30 min
and then allowed to warm to room temp. After 12 min of stirring at
room temp (until all the nitrogen bubbling had ceased), the reaction
mixture was cooled to –78 °C and a solution of aldehyde 14 (pre-
viously dried by azeotropic distillation with toluene) in THF
(1 mL) was added dropwise. The reaction mixture was allowed to
stir at room temperature for 2 h and was then quenched with satu-
rated ammonium chloride solution at 0 °C, extracted with ethyl
acetate (3ϫ20 mL), and dried with anhydrous sodium sulfate. The
crude product was purified by column chromatography (hexanes/
ethyl acetate 9.5:0.5) to afford the epimeric alcohols 30 (0.08 g) and
31 (0.09 g) as colorless oils in 32% combined yield.
32 (0.088 g, 30%). Rf = 0.31 (hexanes/ethyl acetate 4:1). [α]2D5
=
+19.99 (c = 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.89
(s, 3 H), 1.00 (s, 3 H), 1.38 (s, 3 H), 1.63 (s, 3 H), 1.65–1.73 (m, 2
H), 1.73 (s, 3 H), 2.01–2.11 (m, 2 H), 2.32 (s, 1 H), 2.55 (dd, J =
15.2, 1.2 Hz, 1 H), 2.77–2.79 (m, 1 H), 3.42 (s, 3 H), 3.79–3.90 (m,
2 H), 4.59 (d, J = 3.2 Hz, 1 H), 4.68 (d, J = 0.8 Hz, 1 H), 4.78 (d,
J = 0.8 Hz, 1 H), 5.00–5.01 (m, 2 H), 5.30 (d, J = 18 Hz, 1 H),
5.43 (d, J = 4 Hz, 1 H), 5.52 (d, J = 11.2 Hz, 1 H), 5.75–5.94 (m,
3 H) ppm. IR (film): ν = 3431, 3286, 1657, 1462, 1379, 1106 cm–1.
˜
LRMS (ESI): m/z = 441.2486 [M + Na]+. HRMS (ESI): calcd. for
C25H38NaO5 [M + Na]+ 441.2617; found 441.2613.
Method with the Trisylhydrazone as Starting Material: nBuLi (1.6 
solution in hexane, 2.3 mL, 3.72 mmol) was added dropwise at
Synthesis of the Acetate 39: Acetic anhydride (0.5 mL) and a cata-
lytic amount of DMAP were added to the alcohol 30 (0.07 g,
2796
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2788–2799

Synthesis of a Novel Taxa-Oxa-Sugar Hybrid Core Structure
0.17 mmol) in pyridine (0.75 mL) at room temp. After the system (100 MHz, CDCl3): δ = 22.1, 22.6, 25.0, 25.2, 26.0, 27.7, 29.8, 36.8,
had been kept for 8 h at room temp., toluene (10 mLϫ3) was re-
peatedly added and then removed under reduced pressure. The
crude residue was chromatographically purified with hexanes/ethyl
acetate 95:5 as eluent. The acetate 39 was obtained (0.07 g, 90%)
41.6, 46.0, 49.4, 81.7, 82.0, 86.2, 107.8, 113.1, 113.4, 116.0, 120.6,
132.0, 139.5, 146.6, 147.1, 193.7 ppm. IR (film): ν = 3075, 1678,
˜
1641, 1377, 1219, 1113, 1032 cm–1. HRMS (ESI): calcd. for
C24H34NaO5 [M + Na]+ 425.2304; found 425.2321.
as a colorless oil. Rf = 0.53 (hexanes/ethyl acetate 4:1). [α]2D5
=
6-(But-2-ynyloxy)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-
tetrahydrofuro[3,2-d][1,3]dioxole (50): A solution of the alcohol 48
(6.5 g, 25 mmol) in DMF (20 mL) was added dropwise at 0 °C to
a suspension of sodium hybrid (3.6 g, 75 mmol, 60% dispersion in
mineral oil) in dry DMF (20 mL) and the mixture was stirred for
30 min. Propargyl bromide (5.2 mL, 62.5 mmol) was added to this
mixture, which was stirred at 0 °C for 1 h and then at room tem-
perature for 12 h. It was then quenched with saturated ammonium
chloride solution (30 mL). The mixture was extracted with ethyl
acetate (3ϫ50 mL), and the organic layer was dried with anhy-
drous sodium sulfate, filtered, concentrated in vacuo, and purified
by silica gel column chromatography (hexanes/ethyl acetate 4:1) to
give 49 (7.12 g, 95%) as a colorless oil.
+32.49 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.79
(s, 3 H), 1.00 (s, 3 H), 1.29 (s, 3 H), 1.54 (s, 3 H), 1.56–1.63 (m, 2
H), 1.64 (s, 3 H), 1.94 (s, 3 H), 1.96–2.01 (m, 1 H), 2.76 (dd, J =
10.0, 6.8 Hz, 1 H), 3.27 (s, 3 H), 4.19 (d, J = 9.6 Hz, 1 H), 4.50 (d,
J = 3.2 Hz, 1 H), 4.59 (s, 1 H), 4.68 (s, 1 H), 4.88–4.94 (m, 2 H),
5.06 (d, J = 18 Hz, 1 H), 5.42 (d, J = 9.2 Hz, 1 H), 5.45 (d, J =
11.6 Hz, 1 H), 5.61 (d, J = 3.6 Hz, 1 H), 5.71 (d, J = 4.0 Hz, 1 H),
5.77 (ddd, J = 19.6, 10.0, 9.2 Hz, 1 H); 5.90 (dd, J = 18.4, 11.6 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 21.8, 22.5, 26.8,
27.1, 27.4, 28.6, 36.7, 41.0, 47.2, 53.2, 67.1, 81.0, 82.9, 85.1, 103.8,
112.2, 112.8, 115.6, 116.6, 128.9, 134.4, 140.3, 142.4, 147.7,
169.6 ppm. IR (film): ν = 2962, 2931, 1740, 1657, 1374, 1240,
˜
1097 cm–1. HRMS (ESI): calcd. for C26H38NaO6 [M + Na]+
469.2566; found 469.2556.
nBuLi (1.6  solution in hexane, 19.3 mL, 31 mmol) was added at
–78 °C over a period of 10 min to a solution of the alkyne 49
(7.12 g, 23.8 mmol) in THF (100 mL). The reaction mixture was
stirred at –78 °C for 45 min, followed by addition of HMPA
(4.2 mL, 24.5 mmol) and methyl iodide (2.9 mL, 47.7 mmol). After
the mixture had been stirred for 1 h at –78 °C and for 2 h at room
temp., saturated ammonium chloride solution (30 mL) was added
and the mixture was extracted with ethyl acetate (3ϫ50 mL). The
combined organic phase was concentrated in vacuo and the residue
was purified by flash column chromatography with hexanes/ethyl
acetate 4:1 to afford 50 (6 g, 80%) as a pale yellow syrup. Rf = 0.53
(hexanes/ethyl acetate 2:1) [α]2D5 = –42.57 (c = 0.14, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.35 (s, 3 H), 1.43 (s,
3 H), 1.50 (s, 3 H), 1.86 (t, J = 2.4 Hz, 3 H), 4.01–3.98 (m, 1 H),
4.11–4.07 (m, 2 H), 4.16–4.13 (m, 1 H), 4.26 –4.22 (m, 2 H), 4.31–
4.28 (m, 1 H), 4.61 (d, J = 3.6 Hz, 1 H), 5.87 (d, J = 3.6 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 111.7, 108.8, 105.1,
82.8, 82.7, 81.0, 80.9, 74.5, 72.5, 67.0, 58.5, 26.7, 26.7, 26.1, 25.3,
Compound 41: DMSO (0.025 mL, 0.47 mmol) in CH2Cl2 (0.1 mL)
was added at –78 °C to a solution of oxalyl chloride (0.019 mL,
0.218 mmol) in dry CH2Cl2 (0.5 mL), and the mixture was stirred
for 15 min. The solution of the mixture of alcohols 30 and 31
(0.08 g, 0.19 mmol) in CH2Cl2 (0.4 mL) was added dropwise, the
mixture was stirred for 35 min, and then triethylamine (0.14 mL,
0.98 mmol) was added. After 30 min of stirring the reaction mix-
ture was allowed to attain room temp. and further stirred for 2 h.
The reaction mixture was quenched with water (1 mL) and ex-
tracted with CH2Cl2 (4ϫ10 mL). The combined organic layers
were washed with brine and dried with sodium sulfate and concen-
trated. Column chromatographic purification (9.5:0.5) gave the en-
one 41 (0.06 g, 75%). Rf = 0.59 (hexanes/ethyl acetate 2:1). [α]2D5
=
+14.99 (c = 2.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.11
(s, 3 H), 1.14 (s, 3 H), 1.39 (s, 3 H), 1.62 (s, 3 H), 1.70–1.78 (m, 2
H), 1.81 (s, 3 H), 2.05–2.10 (m, 1 H), 2.95–2.99 (m, 1 H), 3.35 (s,
3 H), 4.58 (d, J = 3.7 Hz, 1 H), 4.86 (s, 1 H), 4.91 (s, 1 H), 4.99–
5.05 (m, 2 H), 5.20 (d, J = 17.1 Hz, 1 H), 5.34 (s, 1 H), 5.40 (d, J
= 11 Hz, 1 H), 5.57 (d, J = 17.1, 11 Hz, 1 H), 5.76–5.85 (m, 1 H),
5.95 (d, J = 3.7 Hz, 1 H), 6.93 (d, J = 3.7 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.1, 22.5, 26.5, 26.7, 27.2, 28.2, 36.5, 42.1,
47.6, 53.0, 81.4, 82.3, 86.4, 104.0, 113.0, 113.1, 115.9, 118.9, 133.3,
3.5 ppm. IR (film): ν = 2986, 2937, 2227, 1644, 1455, 1374, 1255,
˜
1164, 1075, 850 cm–1. HRMS (ESI): calcd. for C16H24NaO6 [M +
Na]+ 335.1471; found 335.1462.
1-[6-(But-2-ynyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-
yl]ethane-1,2-diol (51): AcOH in water (60%, 90 mL) was added to
the alkyne 50 (6 g, 19.2 mmol) and the mixture was stirred for 12 h
at room temp. Toluene (3ϫ20 mL) was then repeatedly added and
the solvents were evaporated in vacuo to remove traces of water
and acetic acid. The crude diol was purified by flash column
chromatography with hexanes/ethyl acetate 1:4 to afford the diol
51 (4.8 g, 91%) as a pale yellow syrup. Rf = 0.18 (hexanes/ethyl
acetate 1:4). [α]2D5 = –48.57 (c = 0.28, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.32 (s, 3 H), 1.50 (s, 3 H), 1.86 (t, J = 2.8 Hz, 3 H),
3.75–3.71 (m, 1 H), 3.87–3.84 (m, 1 H), 4.11 (br. s, 1 H), 4.19–4.16
(m, 2 H), 4.24 (d, J = 3.6 Hz, 1 H), 4.29 (t, J = 2.4 Hz, 1 H), 4.56
(d, J = 4.0 Hz, 1 H), 5.92 (d, J = 3.6 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 111.7, 105.2, 83.7, 82.0, 80.9, 79.7, 74.4,
139.7, 144.7, 146.2, 146.6, 194.7 ppm. IR (film): ν = 3076, 1681,
˜
1641, 1456, 1378, 1113, 1044 cm–1. HRMS (ESI): calcd. for
C24H34NaO5 [M + Na]+ 425.2304; found 425.2293.
Synthesis of the Enone 43: A solution of a mixture of allylic
alcohols 33 and 34 (0.06 g, 0.15 mmol) in CH2Cl2 (3 mL) was
added at room temp. to a suspension of DMP (0.251 g, 0.60 mmol)
in CH2Cl2 (10 mL), the mixture was stirred for 8 h at room temp.,
and then a solution of sodium thiosulfate and sodium hydrogen
carbonate (5 mL) was added. After the solution had become clear,
it was extracted with CH2Cl2 (3ϫ10 mL). The combined organic
layers were washed with brine, dried with anhydrous sodium sul-
fate, and concentrated in vacuo. The crude product was purified by
column chromatography (hexanes/ethyl acetate 9.4:0.6) to afford
the enone 43 (0.04 g, 67%) as a colorless oil. Rf = 0.59 (hexanes/
ethyl acetate 4:1). [α]2D5 = –30.49 (c = 2.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.16 (s, 3 H), 1.19 (s, 3 H), 1.23 (s, 3 H),
69.1, 64.1, 57.9, 26.6, 26.1, 3.4 ppm. IR (film): ν = 3436, 2985,
˜
2937, 2241, 1645, 1455, 1376, 1256, 1164, 1076, 887 cm–1. HRMS
(ESI): calcd. for C13H20NaO6 [M + Na]+ 295.1158; found 295.1148.
1-[6-(But-2-ynyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-
[40]
1.35 (s, 3 H), 1.61–1.81 (m, 2 H), 1.83 (s, 3 H), 2.10–2.18 (m, 1 H), yl]prop-2-en-1-ol (52): Silica-supported NaIO4 (96 g) was added
2.91–2.95 (m, 1 H), 3.17 (s, 3 H), 4.45 (d, J = 5.7 Hz, 1 H), 4.76 portionwise to the diol 51 (4.8 g, 16.76 mmol) in CH2Cl2 (500 mL)
(s, 1 H), 4.93 (s, 1 H), 4.99 (d, J = 4.5 Hz, 1 H), 5.05–5.12 (m, 3
H), 5.51 (dd, J = 10.8, 2.1 Hz, 1 H), 5.66 (dd, J = 17.7, 2.1 Hz, 1
H), 5.77–5.87 (m, 2 H), 6.59 (d, J = 3.9 Hz, 1 H) ppm. 13C NMR
at room temp. After 1 h, the reaction mixture was filtered and the
residue was washed with CH2Cl2 (2ϫ25 mL). The filtrate was con-
centrated in vacuo. The crude aldehyde was used in the next step
Eur. J. Org. Chem. 2010, 2788–2799
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2797

R. S. Nandurdikar, A. V. Subrahmanyam, K. P. Kaliappan
FULL PAPER
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without further purification. Vinylmagnesium bromide (13.73 mL,
13.73 mmol) was added dropwise to a stirred solution of the alde-
hyde (1.65 g, 6.86 mmol) in dry THF (40 mL), which was stirred
for 1 h at 0 °C under argon, and then for 12 h at room temperature.
The reaction mixture was quenched with saturated ammonium
chloride solution (30 mL), extracted with ethyl acetate (3ϫ50 mL),
washed with brine, and dried with anhydrous sodium sulfate. The
resulting mixture was concentrated in vacuo and purified by silica
gel column chromatography (hexanes/ethyl acetate 2:1) to afford
the two diastereomeric alcohols 52 in 1:1 ratio as a colorless oil in
54% yield. Rf = 0.46, 0.4 (hexanes/ethyl acetate 1:2). [α]2D5 = –50.21
(c = 0.47, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.32 (s, 3 H),
1.49 (s, 3 H), 1.86 (t, J = 2.8 Hz, 3 H), 2.62 (br. s, 1 H), 4.35–4.03
(m, 3 H), 4.51–4.47 (m, 1 H), 4.62 (d, J = 4.8 Hz, 1 H), 5.25 (dt, J
= 2.0, 4.0 Hz, 1 H), 5.48 (dt, J = 2.0, 4.0 Hz, 1 H), 6.00–5.88 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.5, 117.0, 111.9,
105.0, 83.6, 83.2, 82.2, 81.2, 74.1, 70.9, 57.7, 26.8, 26.3, 3.5 ppm.
[4]
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[9]
IR (film): ν = 3500, 2987, 2933, 2224, 1645, 1454, 1375, 1259, 1217,
˜
1165, 1139, 1076, 1025, 853 cm–1. HRMS (ESI): calcd. for
C14H20NaO5 [M + Na]+ 291.1208; found 291.1200.
Compound 54: DMP (5.62 g, 13.27 mmol) was added at 0 °C in one
portion to a solution of 52 (1.45 g, 6.03 mmol) in CH2Cl2 (60 mL).
The reaction mixture was stirred for 2 h at room temp. It was then
quenched with saturated aqueous NaHCO3 (4 mL, containing 0.5 g
of Na2S2O3), and the crude enone was isolated by extraction with
CH2Cl2 (2ϫ20 mL). The organic extracts were washed with brine,
dried (Na2SO4), and concentrated. The residue was purified on sil-
ica gel with hexanes/ethyl acetate (4:1) to yield 53 (1.1 g, 77%) as
a colorless oil. A solution of 53 (0.5 g, 1.87 mmol) in toluene
(50 mL) was purged with ethylene for 20 min, a solution of the
Grubbs catalyst 37 (0.159 g, 0.187 mmol) in toluene (2 mL) was
added, and the mixture was then heated at 80 °C for 24 h. DMSO
(0.1 mL) was then added to the reaction mixture, which was stirred
for 12 h at room temp. The solvent was evaporated and the crude
product was purified by column chromatography (hexanes/ethyl
acetate 6:1) to afford 54 (0.32 g, 57%) as a white solid. Rf = 0.78
(hexanes/ethyl acetate 1:1). [α]2D5 = –45.71 (c = 0.28, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.33 (s, 3 H), 1.48 (s, 3 H), 1.63 (s,
3 H), 1.79–1.70 (m, 2 H), 2.17–2.02 (m, 3 H), 3.01–2.93 (m, 2 H),
3.86 (dd, J = 2.4, 1.2 Hz, 1 H), 4.11 (s, 2 H), 4.45 (d, J = 2.8 Hz,
1 H), 4.56 (dd, J = 3.6, 1.2 Hz, 1 H), 6.06 (d, J = 4.0 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 208.2, 136.8, 128.3, 112.5, 104.6,
84.6, 84.5, 83.4, 68.3, 45.3, 28.4, 26.9, 26.5, 24.4, 22.5, 18.3 ppm.
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[13]
IR (film): ν = 2985, 2934, 1701, 1455, 1383, 1375, 1259, 1216, 1163,
˜
1100, 1020, 869 cm–1.HRMS (ESI): calcd. for C16H22NaO5 [M +
Na]+ 317.1365; found 317.1364.
[14]
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We gratefully acknowledge the financial support received from the
Department of Science and Technology, New Delhi. One of us
(A. V. S.) thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a fellowship. We are also grateful for the
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2798
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2788–2799

Synthesis of a Novel Taxa-Oxa-Sugar Hybrid Core Structure
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Received: January 1, 2010
Published Online: March 31, 2010
Eur. J. Org. Chem. 2010, 2788–2799
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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