Apoptolidin A: Total synthesis and partially glycosylated analogues

Article abstract of DOI:10.1002/chem.200600462

The total synthesis of apoptolidin A is described employing an early glycosylation strategy. Strategic disconnections were chosen between C11-C12 (cross-coupling) and C19O-C1 (macrocyclization). The cis-selective glycosylation at C9-OH was achieved with the new SIBA protective group at O2/O3 of the L-glucose residue. Auxiliary substitutents at the 2-position of the 2-deoxy sugars were applied to form selectively the glycosidic linkages of the C27 disaccharide. The cross-coupling of the glycosylated northern half with the glycosylated southern half was achieved with Cu¹-thiophene carboxylate. The macrocyclization of a trihydroxy carboxylic acid produced the 20-membered macrolide selectively. H₂SiF₆ was suitable for the final deprotection of the silyl ethers and the conversion of the C21 methylketal into the hemiketal. The synthetic flexibility of the approach was proven by the synthesis of some glycovariants.

Full text of DOI:10.1002/chem.200600462

DOI: 10.1002/chem.200600462
Apoptolidin A: Total Synthesis and Partially Glycosylated Analogues
Hermut Wehlan,[a] Mario Dauber,[a] M. Teresa Mujica Fernaud,[a] Julia Schuppan,[a]
Sonja Keiper,[a] Rainer Mahrwald,[b] M.-Elisa Juarez Garcia,[a] and Ulrich Koert*[a]
Abstract: The total synthesis of apop-
tolidin A is described employing an
early glycosylation strategy. Strategic
disconnections were chosen between
C11–C12 (cross-coupling) and C19O–
C1 (macrocyclization). The cis-selective
glycosylation at C9-OH was achieved
with the new SIBA protective group at
O2/O3 of the l-glucose residue. Auxili-
ary substitutents at the 2-position of
the 2-deoxy sugars were applied to
form selectively the glycosidic linkages
of the C27 disaccharide. The cross-cou-
pling of the glycosylated northern half
with the glycosylated southern half was
achieved with CuI-thiophene carboxy-
late. The macrocyclization of a trihy-
droxy carboxylic acid produced the 20-
membered
macrolide
selectively.
H2SiF6 was suitable for the final depro-
tection of the silyl ethers and the con-
version of the C21 methylketal into the
hemiketal. The synthetic flexibility of
the approach was proven by the syn-
thesis of some glycovariants.
Keywords: apoptolidin
·
cross-
coupling · glycosylation · natural
products · total synthesis
Introduction
The glycosidic residues of natural product glycoconjugates
are usually essential for their biological function and phar-
maceutical application.[1] Representative examples for the
importance of the sugar moiety are the cardiac glycosides
(uptake,distribution and binding activity),macrolide antibio-
tics (ribosome binding) and the anthracyclines (DNA inter-
action).[2] The ability of apoptolidin A (1) to selectively
induce apoptosis (programmed cell death) in tumor cells
also depends on the presence of the glyco residues.[3] The
apoptolidins (A 1, B 2 and C 3) form a group of 20-mem-
bered ring macrocyclic natural products with 6-deoxy-4-O-
methyl-l-glucose (4) attached to O-9 and a disaccharide
consisting of l-olivomycose (5) and d-oleandrose (6) linked
to O-27 (Figure 1).[3] Apoptolidin A (1) was isolated by
Hayakawa et al. in 1997[4] and apoptolidines B (2) and C (3)
by Wender in 2005[5]—all three from the soil bacteria Nocar-
diopsis sp. The apoptotic activity of the apoptolidins was at-
tributed to the inhibition of mitochondrial F0-F1-ATPase.[6]
[a] Dr. H. Wehlan,M. Dauber,Dr. M. T. M. Fernaud,Dr. J. Schuppan,
Dr. S. Keiper,Dipl.-Chem. M.-E. J. Garcia,Prof. Dr. U. Koert
Fachbereich Chemie,Philipps-Universität Marburg
Hans-Meerwein-Strasse,35032 Marburg (Germany)
Fax : (+49)6421-282-5677
E-mail: koert@chemie.uni-marburg.de
[b] Priv.-Doz. Dr. R. Mahrwald
Figure 1. Structures of apoptolidin A,B,C ( 1, 2, 3),6-deoxy-4- O-methyl-
Institut für Chemie,Humboldt-Universität zu Berlin
Brook-Taylor-Strasse 2,12489 Berlin (Germany)
l-glucose (4), l-olivomycose (5), d-oleandrose (6) and apoptolidinone A
(7).
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FULL PAPER
In the course of studies on the chemistry and biology of
apoptolidin A (1) we had synthesized the aglycone apoptoli-
dinone A (7)[7] and noticed the lack of bioactivity due to the
absence of the sugar residues.[3] This observation drew our
attention to the introduction of the saccharide portions. The
preceding manuscript detailed our synthesis of the agly-
cone.[8] Reported herein are the details for the preparation
of the sugars,the glycosylation of the building blocks and
the completion of the total synthesis of apoptolidin A (1).[9]
The successful synthesis of apoptolidin A (1) has also been
achieved by Nicolaou.[10] Syntheses of apoptolidinone A (7)
were reported by Sulikowsky,[11] Crimmins[12] and by Nico-
laou.[10] In addition,several valuable studies on substructures
of the apoptolidins were published.[13]
ern half 10 (Scheme 1). A ring-size selective macrolactoniza-
tion without differentiation of the C16,C19 and C20 OH
groups followed by a global deprotection was planned for
the last stage of the synthesis.
Results and Discussion
As depicted in structure 8 (Figure 2) the apoptolidin glyco-
conjugation required the formation of an a glycoside at C1’
and C1’’ as well as a b glycoside at C1’’’. We intended to
Scheme 1. Retrosynthetic analysis of apoptolidin A (1).
The synthesis of the O27 disaccharide required the prepa-
ration of an l-olivomycose and a d-oleandrose building
block (Scheme 2). Starting from l-rhamnose (11) the 2,3-
benzylidine protected methyl acetal 12 was available.[14] The
latter could be converted with an excess of methyllithium
via a cyclohexenone intermediate to the glycal 13,which
was O3-TES-protected to the olivomycal building block
14.[15] Without protection of the 3-OH group the subsequent
Figure 2. Glycosylation strategy for apoptolidin A (1).
control the formation of the C1’ stereocenter via the direct-
ing anomeric effect and a passive protective group at C2’-
OH. Auxiliary groups at C2’’ and C2’’’ were envisaged for
the stereoselective formation of the glycosidic linkages at
the 2-deoxy sugars.
There are two strategies for the synthesis of glycoconju-
gates: The complete aglycone could be synthesized and then
loaded with the sugars. Alternatively,the saccharide por-
tions could be introduced at an earlier stage before the com-
plete assembly of the aglycon. Having already developed a
convergent strategy for apoptolidinone A (7),[7,8] we fav-
oured the second option in order to keep the advantages of
a convergent strategy. We also expected to avoid difficulties
with protective group differentiation,a major disadvantage
which would challenge us with the selective glycosylation of
apoptolidinone A (7). For these reasons our synthetic strat-
egy for apoptolidin A (1) was based on an early introduc-
tion of the sugar moieties and a late cross-coupling of a fully
glycosylated northern half 9 with a fully glycosylated south-
Scheme 2. a) i) MeOH,DOWEX 50WX-8-200; ii) PhCH
DMF; b) i) MeLi,THF,20 8C; ii) Ac2O,pyridine,DMAP,CH 2Cl2; c) i)
(OTf)2,26, -lu-
G
tidine,DMF/CH 2Cl2; ii) MeI,Ag 2O; e) i) TBAF,THF; ii) pTsCl,pyri-
dine,CH 2Cl2; iii) TBSOTf,lutidine,CH 2Cl2; f) i) PhSCl,CH 2Cl2; ii)
Ag2CO3,CH CN/H2O; iii) NaH,Cl CCN.
3
3
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U. Koert et al.
glycosylation with the oleandrose unit occurred not at the
desired O4 but at the undesired O3 position. The unprotect-
ed tertiary allylic alcohol (O3) proved to be more reactive
than the unprotected secondary alcohol (O4).
The synthesis of the oleandrose trichloroacetimidate 18
commenced with the 4,6-silyl protection of d-glucal (15) and
a subsequent O3 methyl ether formation to give 16. After
cleavage of the disilyl ether and a O6 tosylation followed by
a O4 TBS protection the glycal 17 was obtained. In prepara-
tion of a b-selective glycosylation an auxiliary SPh substitu-
ent was introduced at C2 of the d-oleandrose building
block.[16] Towards this end 17 was treated first with PhSCl,
then with Ag2CO3 in H2O/CH3CN and the resulting a-
anomeric hemiacetal was converted into the trichloroaceti-
midate 18.[17]
The synthesis of the l-olivomycose–oleandrose disacchar-
ide was addressed next (Scheme 3). Activation of the tri-
Scheme 4. a) MeI,KOH,DMF; b) pTsOH,MeOH; c) TBSCl,imidazole,
Scheme 3. a) TMSOTf,Et 2O, ꢀ60 ! ꢀ408C,1 h; b) i) NaI,DMF,90 8C;
ii) Bu3SnH,AIBN,toluene,100 8C.
DMAP; d) Dess–Martin periodinane,CH Cl2; e) NaBH4,MeOH,0 8C; f)
2
TBAF,THF; g) PhMgBr,Et 2O; h) 27,imidazole,DMF; i) MCPBA,
CH2Cl2, ꢀ78 ! ꢀ208C.
chloroacetimidate 18 with TMSOTf and treatment with the
alcohol 14 led to the disaccharide 19 in 87% yield with a
> 95:5 b-selectivity. The use of Et2O as the solvent was
better than CH2Cl2 which gave lower yields. The conversion
of the tosylate in 19 into an iodide and the subsequent com-
bined reductive removal of the iodo and the thio groups
completed the preparation of the protected 2-deoxy-disac-
charide building block 20. While the reduction of the iodide
occurred quite fast,the removal of the thioether required
the addition of AIBN at regular intervals.
l-Rhamnose was chosen as the starting material for the
synthesis of the O9 sugar residue (Scheme 4). The acetonide
protected l-rhamnose thioglycoside 21[18] was O-methylated
to obtain the O4 methyl ether 22.[19] C2 oxidation/reduction
inversion was intended next to convert the l-rhamnose de-
rivative into a 6-deoxy-l-glucose building block. After ace-
tonide cleavage,followed by O3 TBS protection ( 22 ! 23
! 24),the C2 hydroxy group was addressable for oxidation.
A Dess–Martin oxidation converted the alcohol 24 into the
ketone 25. A highly stereoselective reduction of 25 with
NaBH4 gave the corresponding alcohol,which was desilylat-
ed to the diol 27. The stereochemical assignment of 25 was
confirmed by X-ray structural analysis.[9]
lations the cis-selective counterparts pose a more significant
problem.[20] For our apoptolidin synthesis,the cis-selective
glycosylation demanded a passive O2 protecting group
which could be removed at the end without effecting the
highly unsaturated and acid sensitive target molecule. Silyl
ethers should be the best choice. After several unsuccessful
glycosylation attempts (trichloroacetimidate,glycosyl fluo-
ride,thioglycoside activation by PhSOTf) we focused on the
Kahne-glycosylation via sulfoxide activation.[21] Initially we
prepared and examined the bis
N
N
ed sulfoxides 32 and 33. However,these glycosyl donors
gave unsatisfying glycosylation results (see below) which
prompted us to develop a new protecting group. We rea-
soned that a covalent carbon bridge between the C2 and the
C3 silyloxy groups might lead to a passive blocking of the
C2 hydroxy function without to much steric shielding of the
anomeric center. The 1,1,4,4-tetraphenyl-1,4-disilabuta-1,4-
diyl substructure (SIBA) was devised as the protective
group of choice. The corresponding silylating reagent 1,4-di-
chloro-1,1,4,4-tetraphenyl-1,4-disilabutane (SIBACl2) 29
could be prepared from the hexachlorosilane 28 and phenyl
magnesium bromide. The disilylation of diol 27 with
SIBACl2 (29) provided the 2,3-diprotected l-glucose thioeth-
The attachment of the sugar unit 4 to O9 required a cis-
selective glycosylation. In contrast to trans-selective glycosy-
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Total Synthesis of Apoptolidin A
FULL PAPER
er 30. In preparation of the Kahne glycosylation, 30 was oxi-
dized with MCPBA to the sulfoxide 31.
The following efforts focused on the synthesis of the gly-
cosylated northern half 9 (Scheme 5). Because of the light
The alkenyl iodide 39 represents the complete northern
half of apoptolidin A (1) and was used successfully in cross-
coupling experiments with an alkenyl stannane of type 10.
The subsequent hydrolysis of the methyl ester of the cou-
pling product,a prerequisite for the macrolactonization,re-
quired harsh conditions (LiOH,THF/H O, > 608C,several
2
hours) which led to byproduct formation and yields lower
than 40%. This unacceptable low yield brought us to utilize
a cyanomethyl ester,which is more susceptible for nucleo-
philic attack than a methyl ester.[23] Guided by this idea,the
cyanomethyl ester 43 was synthesized (Scheme 6). First,the
Scheme 5. a) DIBAH,toluene, ꢀ788C; b) i) Ac2O,Et 3N,DMAP,CH 2Cl2;
ii) TBAF,THF; c) Tf 2O,26,- tert-butyl-4-methylpyridine, ꢀ808C,10 min;
addition of 31, ꢀ80 ! ꢀ358C, a/b 85:15; d) LiEt3BH,THF, ꢀ508C; e) i)
MnO2,CH Cl2; ii) Ph3P=C(CH3)CO2Me,toluene,90 8C.
A
2
Scheme 6. a) i) TBAF,THF; ii) TESCl,imidazole; b) i) LiOH,THF/
sensitivity of the conjugated triene (in compounds of type 9)
we decided to carry out the glycosylation at the diene stage.
The allylic alcohol 36 was chosen as the glycosyl acceptor.
The synthesis of 36 made use of the unsaturated ester 34[7,8]
from our aglycone synthesis. DIBAH reduction of 34 gave
the alcohol 35,which was acetylated and subsequently TBS
desilylated to deliver the desired glycosylation partner.
Various glycosylation conditions were evaluated for the
cis-selective attachment of the l-glucose sugar. Initial at-
MeOH/H2O 2:1:1; ii) MnO2,CH 2Cl2; c) i) (EtO)2P(O)CH(CH3)CO2H,
G
NaH,THF; ii) ClCH CN,Et N,MeCN,20 8C.
2
3
l-glucose SIBA protection was changed to a TES protection
in order to limit the number of different protective groups
used in the final global deprotection. This was best accom-
plished with the epimeric mixture of 37a/37b to give com-
pound 40. After cleavage of the acetate in 40 a subsequent
MnO2 oxidation of the resulting allylic alcohol gave the two
unsaturated aldehydes 41 and 42,which could be separated
by chromatography easily. The aldehyde 41 was converted
by a Horner–Emmons reaction into the corresponding unsa-
turated acid which was treated with ClCH2CN/Et3N to yield
the cyanomethyl ester 43. The epimeric aldehyde 42 was
transformed along the same route to the cyanomethyl ester
44.
Having the northern half in hand,the synthesis of the gly-
cosylated southern half was addressed next (Scheme 7).
Starting point was the (E)-alkene 45 from the aglycone syn-
thesis.[7,8] After TMS protection of the secondary alcohol
group in the THP ring the O19 and O20 hydroxy groups
were introduced simultaneously by a dihydroxylation using
[K2OsO2(OH)4] and NMO. The resulting diol was converted
into the diacetate 47. The diastereoselectivity of the sub-
tempts to use the bis(TES)-protected glycosyl sulfoxide 32
A
as glycosyl donor failed due to loss of the TES groups under
the Kahne conditions (Tf2O,DTBMP, ꢀ80 ! ꢀ358C).[21]
The more stable bis(TBS)-protected glycosylsulfoxide 33
A
gave the desired glycoside in 50% yield but with an unac-
ceptable low stereoselectivity (a/b 2:1). The reaction of the
SIBA-protected glycosylsulfoxide 31 with 36 under the
Kahne conditions gave the two epimeric products 37a and
37b in 65% yield with an acceptable stereoselectivity (a/b
85:15). Other glycosylation conditions were less satisfying
(NBS activation[22] of the thioether failed; trichloroacetimi-
date gave 60% yield, a/b 80:20). The two epimeric glycosy-
lation products 37a and 37b were separable by chromatog-
raphy and the desired epimer 37a was converted via the al-
lylic alcohol 38 and a subsequent MnO2 oxidation/Wittig re-
action sequence into the methyl ester 39.
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U. Koert et al.
could be oxidized to the aldehyde,which was transformed
into the complete southern half of apoptilidin A via a chela-
tion-controlled addition[25] of the Grignard reagent prepared
from 51[7,8] to produce the corresponding alcohol with a dia-
stereoselectivity of 96:4. Cleavage of the two acetates in the
Grignard product with KCN/MeOH led to the triol 52.
For the coupling of the northern half with the southern
half we relied on our good experiences with Liebeskindꢁs
CuI-thiophene carboxylate (CuTC) method[26] from the
apoptolidinone A work.[7,8] Much to our delight,coupling of
the alkenyl iodide 43 with the alkenyl stannane 52 proceed-
ed at 08C within 90 min to give the product 53 in 89% yield
(Scheme 8). Crucial for the success of the whole synthesis
was the following mild hydrolysis (LiOH,20 8C,3 h) of the
cyanomethyl ester to yield the trihydroxy carboxylic acid 54
in 88% yield. The initial attempts to hydrolyze the corre-
sponding methyl ester gave much lower yields. The macro-
cyclization of the trihydroxy carboxylic acid 54 under modi-
fied Yamaguchi conditions[27] produced the 20-membered
macrolide 55 as the only product. As in the case of the agly-
cone,[7,8] the ring-size selectivity of this reaction is remarka-
ble. In order to test the limitations of the ring-size selective
Scheme 7. a) TMS-imidazole,CH 2Cl2; b) i) [K2OsO2(OH)4],NMO,
tBuOH/H2O,0 8C; ii) Ac2O,DMAP,pyridine; c) TBAF,THF; d) i)
TESCl,imidazole,CH 2Cl2; ii) TBAF,THF,0 8C; e) i) 20,NIS,MS4Š,
CH2Cl2, 0 ! 208C; ii) Bu3SnH,AIBN,toluene,100
8C; iii) H2,Pd/C,
EtOH; f) i) Dess–Martin periodinane,pyridine,CH
2Cl2; ii) Mg,
BrCH2CH2Br, 51,Et 2O,20 8C,then ꢀ788C addition of aldehyde; 74%,
iii) KCN,MeOH,40 8C. NMO = N-methylmorpholine-N-oxide.
strate-controlled dihydroxylation was 87:13 and the unde-
sired minor isomer was separated by chromatography (best
at the diacetate stage). The next two steps served for the de-
protection of the C27 OH group and the installation of a
TES protective group at C22-OH (47 ! 48 ! 49). During
the course of the aglycone synthesis we had chosen a TBS
protective group for C23-OH and observed a long reaction
time necessary for the deprotection at this position. There-
fore,in the actual situation the more labile TES ether was
chosen. The alcohol 49 was allowed to react with the disac-
charide glycal 20 using Thiemꢁs NIS method[24] to deliver the
corresponding a glycoside with a high a-selectivity of
> 95:5. After reductive removal of the iodo group and a
fluoride treatment to remove the tin impurities of the previ-
ous step,a hydrogenolytic benzyl ether cleavage led to the
alcohol 50. Without the fluoride washing,the tin impurities
gave rise to numerous side products in the Pd-mediated hy-
drogenation of the benzyl ether. The primary alcohol 50
Scheme 8. a) CuI-thiophene carboxylate, N-methylpyrrolidinone,0 8C; b)
LiOH,THF/MeOH,20 8C; c) 2,4,6-trichlorobenzoyl chloride, Et3N,THF,
6 h; DMAP,toluene.
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Total Synthesis of Apoptolidin A
FULL PAPER
macrolactonization we examined the reaction of a substrate
like 54 with a fully deprotected l-glucose at C9,which gave
an unseparable mixture of numerous products.
The final part of the apoptolidin A synthesis consisted in
a careful examination of reagents and reaction conditions
for the global deprotection (Scheme 9). While the cleavage
dic linkage. Towards this goal,a southern building block
lacking the C27 disaccharide was prepared (Scheme 10).
The secondary alcohol in 49 was C27-OH TBS protected to
yield after benzyl ether cleavage the primary alcohol 58.
The latter was Dess–Martin oxidized to the corresponding
aldehyde. Addition of the Grignard reagent prepared from
51 to this aldehyde gave after cleavage of the acetates the
alkenyl stannane 59.
Scheme 10. a) i) TBSCl,imidazole,CH 2Cl2; ii) H2,Pd/C,EtOH; b) i)
Dess–Martin periodinane,pyridine,CH 2Cl2; ii) Mg,BrCH 2CH2Br, 51,
Et2O,20 8C,then ꢀ788C addition of aldehyde; 74%,iii) KCN,MeOH,
408C.
Cross-coupling of 59 with the a-glycosylated alkenyl
iodide 43 led to the product 60 (Scheme 11). After hydroly-
sis of the cyanomethyl ester the resulting trihydroxy carbox-
ylic acid could be cyclized to the 20-membered macrolide
Scheme 9. a) HF·pyridine,THF,20 8C,5 d; b)
CH3CN, ꢀ40 ! ꢀ208C,2 d, ꢀ108C,1 d.
H 2SiF6 25% in H2O,
of the numerous silyl ethers was more or less standard
chemistry,the conversion of the C21 methyl ketal into the
hemiketal in the presence of the acid labile 2-deoxy sugars
of the C27 disaccharide was very critical. First,all silyl
ethers were cleaved using HF·pyridine in THF/pyridine at
208C for 5 d to give synthetic 21-O-methyl apoptolidin A
(56) which proved to be identical with 56 derived from natu-
ral sources ([a]2D2 =ꢀ76 (c=0.55 in CHCl3),ref. [6e]: [ a]2D2 =
ꢀ67 (c=1.28 in CHCl3)). Now we turned our attention to a
complete deprotection in one step leading to apoptolidin A
[28]
(1). 25% aqueous H2SiF6
in CH3CN at ꢀ40 ! ꢀ108C
proved to be effective for cleavage of all silyl ethers and no-
tably the methyl ketal. Apoptolidin A (1) was isolated in
71% yield after chromatographic separation on desactivated
silica gel.[29] In addition,the cleavage of the O-27-disacchar-
ide was observed and 27-hydroxy apoptolidin A (57) was
isolated in 27% yield. With respect to physical and spectro-
scopical data,the synthetic apoptolidin A ( 1) was identical
with the natural one. (m.p. 129–1318C (MeOH),ref. [4]:
128–1308C; ([a]2D2 =ꢀ4.4 (c=0.70 in MeOH),ref. [4]: [ a]2D2 =
ꢀ5.2 (c=1.0 in MeOH).
With an efficient access to the natural product itself,the
way was paved for the synthesis of apoptolidin derivatives.
We intended to investigate the role of the sugar moieties
and focused on two points: the presence or absence of the
C27 disaccharide and the stereochemistry of the C9 glycosi-
Scheme 11. a) CuI-thiophene carboxylate, N-methylpyrrolidinone,0 8C;
b) i) LiOH,THF/MeOH,20 8C; ii) 2,4,6-trichlorobenzoyl chloride, Et3N,
THF,6 h; DMAP,toluene; c) H 2SiF6 25% in H2O,CH 3CN, ꢀ40 !
ꢀ108C.
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U. Koert et al.
61. The deprotection of all silyl ethers and conversion of the
C21 methyl ketal into the hemiketal yielded the 27-OH
apoptolidin A (57),a derivative of the natural product with
the disaccharide missing.
ed in an additional decrease of activity (64,IC
> 10 mm).
50
These data show the importance of the disaccharide portion
and the stereochemistry of the C9 glycosidic linkage for the
bioactivity of apoptolidine A (1).
The role of the stereochemistry at the C9 glycosidic link-
age was addressed by the synthesis of compound 64
(Scheme 12). The b-glycosylated alkenyl iodide 44 was
Conclusion
To summarize,a stereoselective total synthesis of apoptoli-
din A (1) has been achieved. The efficiency of our synthetic
strategy results from the high convergence. This conver-
gence was possible due to the early introduction of the
sugar residues using a new sugar protecting group (SIBA).
Key steps of the synthesis were a CuI-mediated cross-cou-
pling followed by a ring-size selective macrolactonization,
the mild hydrolysis of the cyanomethyl ester and the use of
H2SiF6 for the global deprotection. The variability of the ap-
proach was proven by the synthesis of some glycovariants of
apoptolidin. The synthetic products are of interest for fur-
ther apoptosis studies and have potential for antitumor ther-
apy.
Experimental Section
General methods: All reactions sensitive to air or moisture were con-
ducted in flame-dried glassware under an atmosphere of dry Argon. THF
and Et2O were distilled from sodium/benzophenone. CH2Cl2,toluene,
hexanes,pyridine,and Et 3N were distilled from CaH2. All starting mate-
rials and reagents were used as received unless noted otherwise. Thin
layer chromatography was performed on glass-supported Merck silica gel
60 F254 plates. Spots were visualized by UV light and by heat staining
with 2% molybdophosphoric acid in ethanol. Column chromatography
was performed on Merck silica gel 60 (63–200 mm). Melting points were
measured with a Büchi melting point apparatus and are not corrected. IR
Spectra were measured with a Bruker FT-IR spectrometer. 1H and
13C NMR spectra were recorded with Bruker spectrometers ARX-200,
AC-300,AV-300,AMX-400,DRX-400,DRX-500,DRX-600. CDCl
was
3
used as normal solvent. TMS was used as internal standard. Optical rota-
tions: Perkin-Elmer polarimeter 241,cuvette path length 10 cm; CHCl
3
Scheme 12. a) CuI-thiophene carboxylate, N-methylpyrrolidinone,0 8C;
b) i) LiOH,THF/MeOH,20 8C; ii) 2,4,6-trichlorobenzoyl chloride, Et3N,
THF,6 h; DMAP,toluene; c) H 2SiF6 25% in H2O,CH 3CN, ꢀ40 !
ꢀ108C.
for spectroscopy was filtered over basic aluminium oxide before use. Mi-
croanalysis: CHN rapid,Heraeus. HRMS: Finnigan LTQ FT (ESI).
MTBE=tert-butyl methyl ether; PE = petrol ether (b.p. range 60–608C.
3-O-Triethylsilyl-l-olivomycal (14): TES protection: Alcohol 13[14]
(960 mg,5.20 mmol) was dissolved in CH 2Cl2 (50 mL) and cooled to
ꢀ608C. Then 2,6-lutidine (2.8 mL, 24 mmol) and TESOTf (2.0 mL,
7.8 mmol) were added. After stirring for 30 min at ꢀ608C the reaction
was quenched by addition of NaHCO3 (50 mL). The aqueous layer was
extracted with CH2Cl2 (3”30 mL). The combined organic layers were
cross-coupled with the alkenyl stannane 59 to yield 62. The
ester hydrolysis followed by macrocyclization to 63 and a
final deprotection resulted in 64,a derivative of apoptoli-
dine A,which is epimeric at C1 ’ of the l-glucose and lacks
the disaccharide at the C27 position.
The antitumor activity of apoptolidin A (1) and its glyco-
variants was tested for MATU breast cancer cells.[3] The IC50
values for apoptolidin A (1, 1 nm) and 21-O-methyl apopto-
lidin (56, 2 nm) exhibit for both compounds a very strong ac-
tivity. The C21 methyl ketal has no pronounced effect. 27-
OH Apoptolidin A (57),the glycovariant with no disacchar-
ide at the C27 position showed a strong decrease in the cy-
totoxicity (IC50 =3 mm). Finally,the change of the a-glyco-
side to a b-glycosidic linkage to the C9 sugar residue result-
washed with brine (15 mL),dried with Na SO4 and concentrated.
2
Acetate deprotection: The crude TES ether was azeotroped with toluene
(3”10 mL),dissolved in CH 2Cl2 (50 mL),cooled to ꢀ788C,and DIBAH
(10 mL,1.0 m in PE,10 mmol) was added dropwise within 15 min. After
stirring for 45 min at ꢀ788C,the reaction was quenched by addition of
MeOH (1.6 mL). The reaction mixture was added to a solution of Ro-
chelles salt (100 mL,1.0 m). After 1 h stirring,the two layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3”40 mL). The
combined organic layers were washed with brine (80 mL),dried with
Na2SO4,concentrated and the residue was purified by flash chromatogra-
phy (100 g neutral silica gel,pentane/MTBE 8:1) to yield tertiary alcohol
14 (1.0 g,3.9 mmol,75% over 2 steps) as a colorless oil. Rf =0.39 (n-
hexane/MTBE 4:1); [a]2D0 =+13.1 (c=0.99,CHCl 3); 1H NMR (300 MHz,
C6D6): d=0.59 (q, J=7.9 Hz,6H,SiC H2CH3),0.98 (t, J=7.7 Hz,9H,
7384
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,7378 – 7397

Total Synthesis of Apoptolidin A
FULL PAPER
SiCH2CH3),1.30 (s,3H,3-CH 3),1.36 (d, J=6.1 Hz,3H,6-H 3),1.73 (d,
added to ice (100 g) and the aqueous layer was extracted with MTBE
(3”30 mL). The combined organic layers were washed with brine
(30 mL),dried with Na 2SO4 and concentrated. The residue was purified
by flash chromatography (100 g silica gel,pentane/MTBE 2:1) to give the
J=3.4 Hz,1H,OH),3.67 (dd,
J=10.0,3.4 Hz,1H,4-H),3.79 (dq,
J=
10.0,6.1 Hz,1H,5-H),4.63 (d,
J=6.1 Hz,1H,2-H),6.02 (d,
J=6.1 Hz,
1H,1-H); 13C NMR (75 MHz,C D6): d=6.9,7.3 (Si CH2CH3),18.1 (C-6),
6
25.7 (3-CH3),73.6 (C-3),74.0 (C-5),78.7 (C-4),108.4 (C-2),142.6 (C-1);
tosylate (3.70 g,11.8 mmol,94%) as a yellow oil.
Rf =0.45 (CHCl3/
MeOH 20:1); [a]2D2 =+5.7 (c=0.49,CHCl 3); 1H NMR (200 MHz,C 6D6):
d=1.77 (s,3H,Ph-CH 3),2.04 (d, J=3.5 Hz,1H,OH),3.00 (s,3H,
OCH3),3.46–3.55 (m,1H,3-H),3.61–3.74 (m,2H,4-H,5-H),4.21 (dd,
IR (film): n˜ =3500 (brs),3064 (m),2956 (s),2911 (s),2877 (s),1644 (s),
ꢀ1
1456 (s),1230 (s),1133 (s),1074 (s),863 (s),740 cm
(s); HR-MS (ESI):
m/z: calcd for C13H26O3SiNa: 281.1549; found 281.1538 [M+Na]+.
J=11.0,1.8 Hz,1H,6-H),4.33 (dd,
J=6.1,2.4 Hz,1H,2-H),5.95 (dd,
8.5 Hz,2H,arom.),7.72 (d,
C6D6): d=21.1 (Ph-CH3),55.8 (OCH ),67.2 (C-4),68.1 (C-6),76.1 (C-5),
J=10.9,4.6 Hz,1H,6-H),4.50 (dd,
J=6.1,1.4 Hz,1H,1-H),6.62 (d,
4,6-O-(Di-tert-butyl)-silyliden-3-O-methyl-d-glucal (16): Silyl ether for-
mation: d-Glucal (15) (5.00 g,34.2 mmol) was dissolved in DMF/CH 2Cl2
1:1 (170 mL) and cooled to ꢀ58C. 2,6-lutidine (12.0 mL, 103 mmol) and
tBu2SiOTf2 (13.7 mL,37.6 mmol) were added. The mixture was stirred
for 2 h at 208C. The reaction was quenched with NaHCO3 (300 mL). The
aqueous layer was extracted with CH2Cl2 (3”100 mL). The combined or-
ganic layers were dried with Na2SO4,concentrated and the residue was
purified by flash chromatography (200 g silica gel,pentane/MTBE 9:1) to
yield the 4,6-disilylated product (9.35 g, 32.6 mmol, 95%) as a white
solid. M.p. 798C (pentane); Rf =0.49 (n-hexane/MTBE 5:2); [a]2D2 =ꢀ16.3
(c=2.86,CHCl 3); 1H NMR (400 MHz,C 6D6): d=1.00,1.03 (2s,18H,
J=
J=8.3 Hz,2H,arom.); 13C NMR (50 MHz,
3
77.7 (C-3),100.1 (C-2),129.7 (CH,arom.),144.0 (C-1); IR (film):
n˜ =
3376 (brs),2935 (s),1648 (s),1364 (s),1176 (s),1094 (s),981 (s),954 (s),
ꢀ1
832 (s),672 cm
(s); elemental analysis calcd (%) for C14H18O6S
(314.35): C 53.49,H 5.77; found C 53.66,H 5.65.
TBS protection: The alcohol (1.80 g,5.74 mmol) was dissolved in CH 2Cl2
(50 mL) and cooled to ꢀ608C. 2,6-lutidine (2.0 mL, 17 mmol) and
TBSOTf (1.45 mL,6.30 mmol) were added. The reaction was stirred for
2 h at ꢀ608C and was then quenched with NaHCO3 (50 mL). The aque-
ous layer was extracted with CH2Cl2 (3”50 mL). The combined organic
layers were washed with brine (50 mL),dried with Na 2SO4,concentrated
and the residue was purified by flash chromatography (150 g silica gel,
pentane/MTBE 11:2) to yield silyl ether 17 (2.40 g,5.60 mmol,98%) as a
colorless oil. Rf =0.56 (n-hexane/MTBE 2:1); [a]2D2 =+19.6 (c=0.96,
CHCl3); 1H NMR (400 MHz,C 6D6): d=0.12,0.13 (2s,6H,SiCH 3),0.93
SiC
A
J=10.3,10.3,5.1 Hz,
1H,5-H),3.89 (t, J=10.4 Hz,1H,6-H a),3.94 (dd, J=10.2,7.3 Hz,1H,
4-H),4.10 (dd, J=10.3,5.1 Hz,1H,6-H b),4.18 (ddd, J=7.3,1.7,1.7 Hz,
1H,3-H),4.69 (dd, J=6.1,1.8 Hz,1H,2-H),6.02 (dd,
1H,1-H); 13C NMR (100.6 MHz,C 6D6): d=19.9,22.8 (Si C
27.6 (SiC(CH3)3),66.1 (C-6),70.2 (C-3),72.7 (C-5),77.9 (C-4),104.2 (C-
2),143.3 (C-1); IR (film): n˜ =3455 (brs),3084 (s),2935 (s),2895 (s),2860
J=6.1,1.8 Hz,
AHCTREUNG
ACHTREUNG
(s),1643 (s),1473 (s),1234 (s),1123 (s),1056 (s),827 (s),756 cm
emental analysis calcd (%) for C14H26O4Si (286.44): C 58.70,H 9.15;
found C 58.56,H 9.27.
ꢀ1 (s); el-
(s,9H,SiC (CH3)3),1.81 (s,3H,Ph-CH 3),2.93 (s,3H,OCH 3),3.50 (d, J=
E
6.2 Hz,1H,3-H),3.73–3.79 (m,1H,5-H),3.83 (dd,
H),4.30 (dd, J=10.8,5.5 Hz,1H,6-H),4.39 (dd,
H),4.52 (dd, J=6.1,2.1 Hz,1H,2-H),6.01 (d,
J=8.9,6.3 Hz,1H,4-
J=10.8,2.2 Hz,1H,6-
J=6.0 Hz,1H,1-H),6.68
J=8.2 Hz,2H,arom.);
13C NMR
Methylether formation: CaSO4 (16.2 g,119 mmol) and Ag 2O (17.3 g,
74.5 mmol) were added at 208C to a solution of the alcohol (8.53 g,
29.8 mmol) in MeI (40 mL). The mixture was stirred for 14 h at 208C.
Then Et2O (50 mL) was added,the suspension was filtered over a pad of
Celite and washed with Et2O (100 mL). The solvents were removed and
the residue was purified by flash chromatography (200 g silica gel,pen-
(d, J=8.4 Hz,2H,arom.),7.77 (d,
(100.6 MHz,C 6D6): d=ꢀ5.1, ꢀ4.1 (SiCH3),18.3 (Si C
(CH3)3),21.1 (Ph-
CH3),26.1 (SiC (CH3)3),54.9 (OCH 3),68.4 (C-4),68.5 (C-6),76.7 (C-5),
AHCTREUNG
78.4 (C-3),99.4 (C-2),129.7 (CH,arom.),134.2 (C q,arom.),144.1 (C-1),
144.2 (Cq,arom.); IR (film): n˜ =2954 (s),2930 (s),1495 (s),1363 (s),1177
(s),1097 (s),973 (s),872 (s),837 cm
for C20H32O6SSi (428.61): C 56.04,H 7.53; found C 56.35,H 7.27.
tane/MTBE 9:1,0.5% Et N) to yield methyl ether 16 (8.22 g,27.4 mmol,
3
ꢀ1
(s); elemental analysis calcd (%)
92%) as a white amorphous solid. M.p. 328C (pentane); Rf =0.49 (n-
hexane/MTBE 9:1); [a]2D1 =ꢀ13.2 (c=2.71,CHCl 3); 1H NMR (300 MHz,
O-(4-O-tert-Butyldimethylsilyl-2-deoxy-3-O-methyl-2-thiophenyl-6-O-
tosyl-a-d-glucopyranosyl)trichloroacetimidate (18): Thiophenoladdition:
PhSH (200 mL,1.95 mmol) was slowly added to a solution of NCS
(260 mg,1.95 mmol) in CH 2Cl2 (4 mL) and 4 Š MS (100 mg) at 208C.
The orange colored solution was stirred for 30 min and was then added
C6D6): d=1.02 (s,18H,SiC (CH3)3),3.41 (s,3H,OCH 3),3.73 (dt, J=
U
10.3,5.1 Hz,1H,5-H),3.86 (dt,
J=7.1,1.8 Hz,1H,3-H),3.92 (t,
J=
10.4 Hz,1H,6-H a),4.13 (dd, J=10.3,4.9 Hz,1H,6-H b),4.21 (dd, J=
10.3,7.1 Hz,1H,4-H),4.70 (dd, J=6.1,2.0 Hz,1H,2-H),6.05 (dd, J=
6.1,1.5 Hz,1H,1-H);
13C NMR (100.6 MHz,C 6D6): d=19.9,22.7 (Si C-
(CH3)3),27.2,27.5 (SiC (CH3)3),57.9 (OCH 3),66.2 (C-6),72.9 (C-5),77.0
(C-4),78.9 (C-3),102.7 (C-2),143.7 (C-1); IR (film): n˜ =3073 (s),2934
via dropping funnel to glycal 17 (750 mg,1.75 mmol) in CH Cl2 (6 mL) at
A
ACHTREUNG
2
208C. After 1 h stirring the solvent was removed in vacuo and the residue
was dried for 30 min in vacuo. The crude product was dissolved in
MeCN/H2O (25 mL,9:1). Ag 2CO3 (2.0 g,7.3 mmol) was added and mix-
ture was stirred for 14 h at 208C. THF (5 mL) was added,the suspension
was filtered over a pad of celite and washed with AcOEt (30 mL). The
solvents were removed and the residue was purified by flash chromatog-
raphy (100 g silica gel,pentane/MTBE 5:1) to yield the corresponding a-
glucopyranose (845 mg,1.52 mmol,87%) as a white solid. M.p. 125 8C
(pentane); Rf =0.36 (n-hexane/MTBE 2:1); [a]2D3 =+43.0 (c=1.63,
CHCl3); 1H NMR (400 MHz,C 6D6): d=0.11,0.13 (2s,6H,SiCH 3),0.90
(s),2890 (s),2860 (s),1650 (s),1473 (s),1235 (s),1159 (s),1081 (s),1058
ꢀ1
(s),869 (s),769 cm
(s); HR-MS (EI): m/z: calcd for C15H28O4Si:
300.1757; found 300.1758 [M]+.
4-O-tert-Butyldimethylsilyl-3-O-methyl-6-O-tosyl-d-glucal (17): Desilyla-
tion: TBAF (8.31 g,26.4 mmol) was added in portions at 0 8C to a solu-
tion of disilyl ether 16 (7.92 g,26.4 mmol) in THF (100 mL). After stir-
ring for 3 h at 08C,the yellow solution was added to brine (100 mL) and
ice (50 g). The aqueous layer was extracted with MTBE (3”50 mL). The
combined organic layers were dried with Na2SO4,concentrated and the
(s,9H,SiC
3.08 (dd, J=10.8,2.7 Hz,1H,2-H),3.45 (s,3H,OCH
8.9 Hz,1H,4-H),3.57 (dd, J=10.6,8.6 Hz,1H,3-H),4.01–4.08 (m,1H,
ACHTREUNG
residue was purified by flash chromatography (100 g silica gel,CHCl
MeOH 30:1) to yield the corresponding diol (3.11 g,19.4 mmol,74%) as
/
3
a white solid. M.p. 658C (CH2Cl2); Rf =0.53 (CHCl3/MeOH 11:2); [a]D20
=
ꢀ43.5 (c=0.77,CHCl 3); 1H NMR (400 MHz,C 6D6): d=2.49 (dd, J=7.3,
5-H),4.26 (dd, J=10.5,5.2 Hz,1H,6-H),4.37 (dd,
J=10.4,2.0 Hz,1H,
J=8.7 Hz,2H,arom.),
J=7.4,2H,Ph),7.45 (d, J=7.1 Hz,2H,
5.7 Hz,1H,6-OH),3.14 (s,3H,OCH
3),3.24 (d, J=4.4 Hz,1H,4-OH),
6-H),4.98 (dd, J=3.0,3.0 Hz,1H,1-H),6.74 (d,
6.89–6.97 (m,1H,Ph),7.00 (t,
Ph),7.83 (d, J=8.2 Hz,2H,arom.); 13C NMR (100.6 MHz,C 6D6): d=
3.65–3.97 (m,5H,6-H 2,3-H,4-H,5-H),4.61 (dd,
J=6.1,1.9 Hz,1H,2-
H),6.13 (d, J=6.1 Hz,1H,1-H); 13C NMR (100.6 MHz,C 6D6): d=55.9
(OCH3),62.0 (C-6),68.3,78.5,78.7 (C-4,C-5,C-3),100.1 (C-2),144.6 (C-
ꢀ4.7, ꢀ3.7 (SiCH3),18.1 (Si C
C
G
1); IR (film): n˜ =3384 (brs),2936 (s),1649 (m),1457 (m),1391 (m),1235
ꢀ1
(s),1190 (m),1085 (s),964 (m),748 cm
(m); elemental analysis calcd
(%) for C7H12O4 (160.17): C 52.49,H 7.55; found C 52.27,H 7.72.
144.3 (Cq,arom.); IR (film): n˜ =3525 (brs),2954 (s),2930 (s),1176 (s),
ꢀ1
1088 (s),1022 (s),986 (s),837 (s),815 (s),754 cm
(s); elemental analy-
Tosylation: The diol (2.00 g,12.5 mmol) was dissolved in CH Cl2 (70 mL)
2
sis calcd (%) for C26H38O7S2Si (554.79): C 56.29,H 6.90; found C 56.06,
H 7.00.
and cooled to 08C. Pyridine (1.2 mL,15 mmol) and TsCl (2.50 g,
13.1 mmol) were added. After stirring for 14 h at 208C the mixture was
Chem. Eur. J. 2006, 12,7378 – 7397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
7385

U. Koert et al.
Trichloroacetimidate formation: The a-glucopyranose (300 mg,541 mmol)
was dissolved in Cl3CCN (5.5 mL) and cooled to ꢀ408C. NaH (108 mg,
2.71 mmol,60% in mineral oil) was added in portions and the mixture
was allowed to warm to ꢀ58C within 2 h. The reaction was quenched by
careful addition of phosphate buffer (5 mL,1 m,pH 7) and MTBE
(10 mL). After separation of the two layers,the aqueous layer was ex-
tracted with MTBE (3”20 mL). The combined organic layers were
(s),1246 (s),1230 (s),1169 (s),1102 (s),1008 (s),874 (s),836 (s),
740 cmꢀ1 (s); HR-MS (ESI): m/z: calcd for C26H52O6Si2Na: 539.3200;
found 539.3184 [M+Na]+.
Phenyl
2,3-O-isopropyliden-4-O-methyl-1-thio-a-l-rhamnopyranoside
(22): Alcohol 21 (8.10 g,27.3 mmol) was dissolved in DMF (30 mL) at
08C and powdered KOH (4.60 g,82.0 mmol) was added. Then MeI
(5.4 mL,87 mmol) in DMF (15 mL) was added via cannula within 1 h.
The bay-colored suspension was stirred for 2 h at 08C. The mixture was
quenched with MeOH (30 mL). NH4Cl (40 mL) was added and the aque-
ous layer was extracted with AcOEt (3”40 mL). The combined organic
layers were washed subsequently with water (50 mL),brine (50 mL),
dried with Na2SO4,concentrated and the residue was purified by flash
chromatography (110 g silica gel,pentane/MTBE 10:1) to give methyl
ether 22 (8.41 g,27.1 mmol,99%) as a colorless oil. Rf =0.55 (n-hexane/
MTBE 9:1); [a]2D2 =ꢀ228.9 (c=5.16,CHCl 3); 1H NMR (300 MHz,
washed with brine (10 mL),dried with Na SO4,concentrated and the res-
2
idue was purified by flash chromatography (25 g silica gel,neutral,pen-
tane/MTBE 5:1) to yield amorphous trichloroacetimidate 18 (300 mg,
429 mmol,79%) as the pure a-anomer. Rf =0.36 (n-hexane/MTBE 2:1);
[a]2D3 =+43.0 (c=1.63,CHCl 3); 1H NMR (500 MHz,C 6D6): d=0.17,0.20
(2s,6H,SiCH 3),0.90 (s,9H,SiC
ACHTREUNG
J=10.5,3.4 Hz,1H,2-H),3.53 (s,3H,OCH
H),4.13–4.19 (m,1H,5-H),4.31 (dd,
J=10.8,2.1 Hz,1H,6-H),6.57 (d,
J=11.5,3.9 Hz,1H,6-H),4.43 (dd,
J=3.4 Hz,1H,1-H),6.68 (d,
J=
CDCl3): d=1.23 (d, J=6.1 Hz,3H,6-H 3),1.37,1.55 (2s,6H,CH
3),3.06
8.7 Hz,2H,arom.),6.91–7.01 (m,3H,Ph),7.39–7.42 (m,2H,Ph),7.77
(dd, J=9.8,7.1 Hz,1H,4-H),3.55 (s,3H,OCH
6.1 Hz,1H,5-H),4.19 (dd,
3),4.05 (dq, J=9.9,
J=5.6 Hz,
(d, J=8.3 Hz,2H,arom.),8.52 (s,1H,NH);
C6D6): d=ꢀ4.6, ꢀ3.6 (SiCH3),18.2 (Si C
13C NMR (125.8 MHz,
(CH3)3),21.1 (Ph-CH 3),26.2
(SiC(CH3)3),55.1 (C-2),61.7 (OCH 3),68.5 (C-6),71.7 (C-4),73.9 (C-5),
J=6.8,6.1 Hz,1H,3-H),4.33 (d,
AHCTREUNG
1H,2-H),5.72 (s,1H,1-H),7.25–7.35 (m,3H,Ph),7.43–7.51 (m,2H,
Ph); 13C NMR (75 MHz,CDCl 3): d=17.6 (C-6),26.4,28.0 (CH 3),59.5
A
83.7 (C-3),91.6 (-CCl 3),96.7 (C-1),127.3,128.3,129.3,129.7,131.7 (CH,
arom.),134.2,135.9,144.3 (C q,arom.),160.6 (C =NH); IR (film): n˜ =
(OCH3),66.3 (C-5),76.6 (C-2),78.1 (C-3),83.8 (C-4,C-1),109.4 (C
127.5,129.0,131.8 (CH,Ph),134.0 (C q,Ph); IR (film): n˜ =3059 (m),2986
(s),2896 (s),1480 (s),1381 (s),1220 (s),1111 (s),1071 (s),808 (s),
751 cmꢀ1 (s); elemental analysis calcd (%) for C16H22O4S (310.41): C
61.91,H 7.14; found C 61.87,H 7.23.
q),
3454 (brs),3062 (w),2957 (s),2926 (s),2898 (m),2853 (s),1674 (s),1468
ꢀ1
(m),1364 (s),1280 (m),1190 (s),1170 (s),986 (s),830 (m),796 cm
(m).
4-O-(4-O-tert-Butyldimethylsilyl-3-O-methyl-b-d-oleandropyranosyl)-3-
O-triethylsilyl-l-olivomycal (20): Glycosyl acceptor 14 (850 mg,
1.22 mmol) and glycosyl donor 18 (286 mg,1.11 mmol) were combined
and azeotroped with toluene (3”10 mL). After drying under high
vacuum for one hour,the mixture was dissolved in Et 2O (25 mL),MS
4 Š (1.25 g,powder) was added and the suspension was stirred for 1 h at
208C. The mixture was cooled to ꢀ608C and TMSOTf (6.5 mL,36 mmol)
was added via 10 mL glass syringe. The mixture was allowed to warm to
ꢀ408C within 1 h and was then quenched by addition of NEt3 (1 mL).
NaHCO3 (10 mL) was added and the molecular sieve was filtered over a
pad of Celite. The aqueous layer was extracted with MTBE (3”25 mL).
The combined organic layers were washed with brine (60 mL),dried with
Na2SO4, concentrated and filtered over 10 g silica gel (neutral) with pen-
tane/MTBE 15:1. The solvents were removed and crude disaccharide 19
obtained was used for the next step without further purification (n-
hexane/MTBE 4:1; Rf =0.47). The disaccharide was azeotroped with tol-
uene (3”5 mL),dried under high vacuum for 30 min and was dissolved
in DMF (10 mL). NaI (2.25 g,15.0 mmol) was added and mixture was
Phenyl 4-O-methyl-1-thio-a-l-rhamnopyranoside (23): Acetonide 22
(8.25 g,26.6 mmol) was dissolved in DMF (50 mL) and p-TsOH (200 mg,
1.05 mmol) was added at 208C. The solution was stirred for 6 h. NaHCO3
(20 mL) was added. The aqueous layer was extracted with AcOEt (3”
30 mL),the combined organic layers were washed with brine (30 mL),
dried with Na2SO4,and concentrated. The residue was recrystallized
from AcOEt to yield diol 23 (6.40 g,23.6 mmol,89%) as a colorless
solid. M.p. 908C (AcOEt); Rf =0.45 (CHCl3/MeOH 9:1); [a]2D1 =ꢀ252.6
(c=6.38,CHCl 3); 1H NMR (300 MHz,CDCl 3): d=1.32 (d, J=6.4 Hz,
3H,6-H 3),3.18 (t, J=9.3 Hz,1H,4-H),3.38 (brs,2H,OH),3.56 (s,3H,
OCH3),3.88 (dd, J=9.3,3.4 Hz,1H,3-H),4.12 (dq,
J=9.3,6.3 Hz,1H,
5-H),4.18–4.25 (m,1H,2-H),5.47 (s,1H,1-H),7.20–7.34 (m,3H,Ph),
7.40–7.49 (m,2H,Ph); 13C NMR (75 MHz,CDCl 3): d=17.8 (C-6),60.7
(OCH3),68.5 (C-5),71.6 (C-3),72.5 (C-2),83.3 (C-4),87.5 (C-1),127.3,
129.0,131.2 (CH,Ph),134.1 (C q,Ph); IR (film): n˜ =3281 (brs),2982 (m),
ꢀ1
2834 (m),1476 (m),1164 (m),1100 (s),1057 (s),840 (s),742 cm
(s);
HR-MS (EI): m/z: calcd for C13H18O4S: 270.0926; found 270.0936 [M]+.
stirred for 2 h at 908C. After cooling,NaHCO (10 mL) and aq Na2S2O3
3
Phenyl 3-O-tert-butyldimethylsilyl-4-O-methyl-1-thio-a-l-rhamnopyrano-
side (24): Diol 23 (300 mg,1.11 mmol) was dissolved in CH 2Cl2 (10 mL)
at 08C. Imidazole (420 mg,6.16 mmol),DMAP (38 mg,0.31 mmol)
TBSCl (1.86 g,6.16 mmol,50% in toluene) were added. After stirring at
208C for 16 h the reaction was quenched by addition of NH4Cl (20 mL).
The aqueous layer was extracted with MTBE (3”25 mL). The combined
organic layers were washed with brine (40 mL),dried with Na 2SO4,con-
centrated and the residue was purified by flash chromatography (10 g
silica gel,pentane/MTBE 10:1) to give monosilyl ether 24 (390 mg,
1.02 mmol,91%) as a colorless oil. Rf =0.21 (n-hexane/MTBE 9:1);
[a]2D2 =ꢀ183.9 (c=5.72,CHCl 3); 1H NMR (300 MHz,CDCl 3): d=0.16,
(20%; 3 mL) were added. The aqueous layer was extracted with MTBE
(3”30 mL). The combined organic layers were washed with brine
(30 mL),dried with Na 2SO4 and concentrated. The crude iodide was dis-
solved in toluene (10 mL) and Bu3SnH (2.7 mL,10 mmol) was added.
The mixture was degassed by FTP (freeze thaw process) and heated to
1008C. AIBN (0.82 g,5.0 mmol) was added in portions over 7 h and the
mixture was stirred over night at 1008C. After cooling the solvent was re-
moved in vacuo and the residue was purified by flash chromatography
(140 g silica gel,pentane/MTBE 100:1 ! 40:1) to yield disaccharide 20
(400 mg,774 mmol,70% over 3 steps) as colorless oil. Rf =0.43 (n-
1
hexane/MTBE 20:1); [a]2D0 =ꢀ19.0 (c=1.03,CHCl ); H NMR (300 MHz,
3
0.19 (2s,6H,SiCH 3),0.95 (s,9H,SiC
H3),2.64–2.92 (brs,1H,OH),3.10 (dd,
ACHTREUNG
C6D6): d=0.11,0.19 (2s,6H,SiCH 3),0.62 (q, J=8.1 Hz,6H,SiC H2CH3),
0.99 (s,9H,SiC (CH3)3),1.00 (t, J=7.7 Hz,9H,SiCH 2CH3),1.39 (d, J=
R
3H,OCH 3),3.88 (dd, J=8.8,3.4 Hz,1H,3-H),4.02 (dd,
5.7 Hz,3H,6-H olean.),1.44 (s,3H,3-CH
olivo.),1.52–1.66 (m,1H,2-
3
3
1H,2-H),4.00–4.15 (m,1H,5-H),5.52 (s,1H,1-H),7.20–7.25 (m,3H,
H olean.),1.60 (d, J=6.1 Hz,3H,6-H
1.8 Hz,1H,2-H olean.),3.03 (s,3H,OCH
olivo.),2.50 (ddd, J=12.3,4.9,
3),3.13 (ddd, J=11.5,8.2,
3
Ph),7.42–7.51 (m,2H,Ph);
(SiCH3),17.7 (C-6),17.9 (Si
13C NMR (75 MHz,CDCl 3): d=ꢀ4.9, ꢀ4.7
C
G
N
5.0 Hz,1H,3-H olean.),3.28 (t, J=8.5,1H,4-H olean.),3.39 (dq, J=8.8,
6.1 Hz,1H,5-H olean.),3.87 (dq, J=10.3,6.2 Hz,1H,5-H olivo.),4.14
(d, J=10.3 Hz,1H,4-H olivo.),4.63 (d, J=6.1 Hz,1H,2-H olivo.),5.15
68.8 (C-5),73.1 (C-3),73.3 (C-2),83.3 (C-4),86.7 (C-1),127.2,129.0,
131.3 (CH,Ph),134.2 (C q,Ph); IR (film): n˜ =3348 (brs),2931 (s),1441
ꢀ1
(s),1384 (s),1255 (s),1163 (s),1071 (s),840 (s),742 cm
(s); HR-MS
(dd, J=10.0,2.0 Hz,1H,1-H olean.),6.08 (d,
J=5.9 Hz,1H,1-H olivo.);
13C NMR (75.5 MHz,C D6): d=ꢀ4.6, ꢀ3.6 (SiCH3),7.1,7.3 (SiCH 2CH3),
(ESI): m/z: calcd for C19H32O4SiSNH4: 402.2134; found 402.2117
[M+NH4]+.
6
18.6 (SiC
A
(CH3)3),
Phenyl 3-O-tert-butyldimethylsilyl-4-O-methyl-2-oxo-1-thio-a-l-rhamno-
pyranoside (25): Alcohol 24 (1.73 g,4.50 mmol) was dissolved in CH 2Cl2
(60 mL) at 08C and Dess–Martin periodinane (3.8 g,9.0 mmol) was
added. The reaction mixture was stirred at 208C for 4 h. The reaction
26.8 (3-CH3 olivo.),36.3 (C-2 olean.),55.6 (OCH 3),73.0 (C-5 olean.),
74.0 (C-5 olivo.),74.9 (C-3 olivo.),77.4 (C-4 olean.),81.6 (C-3 olean.),
82.8 (C-4 olivo.),100.2 (C-1 olean.),108.5 (C-2 olivo.),143.1 (C-1 olivo.);
IR (film): n˜ =2957 (s),2934 (s),2879 (s),2858 (s),1646 (s),1462 (s),1388
7386
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,7378 – 7397

Total Synthesis of Apoptolidin A
FULL PAPER
was quenched with 50% satd aq NaHCO3 (100 mL) and Na2S2O3 (10 g).
The aqueous layer was extracted with MTBE (3”50 mL). The combined
organic layers were washed with brine (40 mL),dried with Na 2SO4,con-
centrated and the residue was purified by flash chromatography (150 g
silica gel,pentane/MTBE 20:1) to yield ketone 25 (1.38 g,3.61 mmol,
80%) as a colorless oil. Rf =0.68 (n-hexane/MTBE 9:1); [a]2D0 =ꢀ256.8
(c=8.15,CHCl 3); 1H NMR (300 MHz,CDCl 3): d=0.08,0.16 (2s,6H,
848C (pentane); 1H NMR (300 MHz,CDCl 3): d=1.45 (s,4H,SiCH 2),
7.32–7.51 (m,12H,Ph),7.55–7.69 (m,8H,Ph);
CDCl3): d=8.3 (SiCH2),128.2,130.6 (CH,Ph),132.9 (C
13C NMR (75 MHz,
q,Ph),134.4
(CH,Ph); IR (film): n˜ =3069 (m),3045 (m),3011 (m),1428 (m),1137
ꢀ1
(s),1116 (s),732 (s),716 (s),697 cm
(s); elemental analysis calcd (%)
for C26H24Cl2 Si2 (463.55): C 67.32,H 5.22; found C 67.59,H 5.35.
Phenyl 6-deoxy-4-O-methyl-2,3-O-(1,1,4,4-tetraphenyldisilabutandi-1,4-
yl)-1-thio-a-l-glucopyranoside (30): Diol 27 (500 mg,1.85 mmol) was dis-
solved in DMF (20 mL) and cooled to 08C. Imidazole (6.43 g,10.2 mmol)
and (ClSi(Ph)2CH2)2 29 (1.20 g,2.59 mmol) in DMF (7 mL) were added.
After stirring at 08C for 1 h the reaction was quenched by addition of
NH4Cl (35 mL) and MTBE (50 mL). The aqueous layer was extracted
with MTBE (3”30 mL). The combined organic layers were washed with
SiCH3),0.95 (s,9H,SiC
ACHTREUNG
J=9.4 Hz,1H,4-H),3.57 (s,3H,OCH
(d, J=9.3 Hz,1H,3-H),5.41 (s,1H,1-H),7.26–7.35 (m,3H,Ph),7.41–
7.52 (m,2H,Ph); 13C NMR (75 MHz,CDCl 3): d=ꢀ5.5, ꢀ4.8 (SiCH3),
17.4 (C-6),18.5 (Si C
N
N
79.3 (C-3),87.9 (C-4),90.1 (C-1),128.3,129.3,132.5 (CH,Ph),133.0 (C
,
q
Ph),198.5 (C-2); IR (film): n˜ =2934 (s),2857 (s),1690 (s),1383 (s),1254
brine (20 mL),dried with MgSO ,concentrated and the residue was puri-
4
ꢀ1
(m),1101 (s),877 (s),839 (s),743 cm
(s); HR-MS (ESI): m/z: calcd for
fied by flash chromatography (40 g silica gel,pentane/MTBE 20:1) to
yield bis(silyl ether) 30 (1.12 g,1.69 mmol,92%) as a colorless amor-
phous solid. M.p. 658C (pentane); Rf =0.33 (n-hexane/MTBE 10:1);
C19H30O4SSiNa: 405.1532; found 405.1533 [M+Na]+.
Phenyl 3-O-tert-butyldimethylsilyl-6-deoxy-4-O-methyl-1-thio-a-l-gluco-
pyranoside (26): A solution of ketone 25 (1.32 g,3.43 mmol) in MeOH
(50 mL) was treated with NaBH4 (0.16 g,4.1 mmol) at 0 8C. After 5 min
the reaction was quenched with NH4Cl (30 mL) at 08C. Then the cooling
bath was removed and stirring was allowed for 30 min at 208C. The aque-
ous layer was extracted with AcOEt (3”50 mL),the combined organic
layers were washed with brine (40 mL) and dried with Na2SO4. The sol-
vents were evaporated and alcohol 26 (1.28 g,3.33 mmol,97%) obtained
1
[a]2D4 =ꢀ6.6 (c=1.0,CHCl ); H NMR (500 MHz,CDCl ): d=0.98 (d, J=
3
3
6.2 Hz,3H,6-H 3),1.13–1.21 (m,2H,SiCH 2),1.34–1.46 (m,2H,SiCH 2),
2.71 (t, J=9.2 Hz,1H,4-H),3.28 (s,3H,OCH
1H,2-H),3.84 (t, J=8.9 Hz,1H,3-H),3.90 (dq,
3),3.76 (dd, J=9.2,5.5 Hz,
J=9.7,6.2 Hz,1H,5-
H),5.18 (d, J=5.5 Hz,1H,1-H),6.99–7.69 (m,25H,Ph);
(125 MHz,CDCl ): d=4.4,5.7 (SiCH ),17.6 (C-6),60.6 (OCH 3),67.4 (C-
13C NMR
3
2
5),74.0 (C-2),76.1 (C-3),86.0 (C-4),88.8 (C-1),126.9,127.78,127.84,
127.88,128.1,128.8,129.6,129.8,130.0,130.2,130.4,131.9 (CH,Ph),
134.1,134.2 (C q,Ph),134.4,134.5,134.7,134.87 (CH,Ph),134.91,135.0
was used for the next step without further purification. Rf =0.15 (n-
1
hexane/MTBE 9:1); [a]2D2 =ꢀ226.3 (c=3.47,CHCl ); H NMR (300 MHz,
3
CDCl3): d=0.12,0.13 (2s,6H,SiCH 3),0.94 (s,9H,SiC
J=6.4 Hz,3H,6-H 3),2.27–2.53 (brs,1H,OH),2.85 (t,
A
(Cq,Ph),135.3 (CH,Ph),136.3 (C q,Ph); IR (film): n˜ =3068 (m),2916 (s),
ꢀ1
1428 (m),1119 (s),1099 (s),874 (m),730 (s),701 cm
(s); HR-MS
H),3.60 (s,3H,OCH 3),3.77 (t, J=8.9 Hz,1H,3-H),3.85 (dd,
5.4 Hz,1H,2-H),4.07 (dq, J=9.6,6.2 Hz,1H,5-H),5.27 (d,
1H,1-H),7.19–7.34 (m,3H,Ph),7.40–7.49 (m,2H,Ph);
J=9.3,
J=5.1 Hz,
13C NMR
(ESI): m/z: calcd for C39H40O4SSi2K: 699.1823; found 699.1823 [M+K]+.
Phenyl 6-deoxy-4-O-methyl-2,3-O-(1,1,4,4-tetraphenyldisilabutandi-1,4-
yl)-1-sulfinyl-a-l-glucopyranoside (31): Thioglycoside 30 (950 mg,
1.44 mmol) was dissolved in CH2Cl2 (60 mL) at ꢀ788C and mCPBA
(390 mg,1.58 mmol,70%) was added in portions. The reaction mixture
was allowed to warm to ꢀ208C within 2 h. The clear solution was
(75 MHz,CDCl 3): d=ꢀ4.7, ꢀ4.5 (SiCH3),17.7 (C-6),18.1 (Si
C(CH3)3),
N
25.7 (SiC(CH3)3),60.5 (OCH ),67.4 (C-5),73.8 (C-2),75.0 (C-3),84.9 (C-
G
3
4),88.8 (C-1),127.0,128.8,131.8 (CH,Ph),134.8 (C
q,Ph); IR (film): n˜ =
3481 (brs),2930 (s),2896 (s),1254 (s),1134 (s),1083 (s),839 (s),
739 cmꢀ1 (s); elemental analysis calcd (%) for C19H32O4S (384.61): C
59.33,H 8.39; found C 59.21,H 8.58.
quenched with NaHCO3 (100 mL),water (20 mL) and Na S2O3 (5 g). The
2
cooling bath was removed and the mixture was stirred for 20 min at
208C. The aqueous layer was extracted with MTBE (3”40 mL). The
combined organic layers were washed with brine (30 mL),dried with
MgSO4,concentrated and the residue was purified by flash chromatogra-
phy (40 g silica gel,pentane/MTBE 3:1) to give sulfoxide 31 (896 mg,
Phenyl 6-deoxy-4-O-methyl-1-thio-a-l-glucopyranoside (27): TBS ether
26 (1.28 g,3.33 mmol) was dissolved in THF (60 mL) and cooled to 0 8C.
Then TBAF (1.1 g,4.1 mmol) was added in portions. After 10 min the
cooling bath was removed and the mixture was stirred for 3 h at 208C.
The reaction was quenched with phosphate buffer (1.0m,pH 7,50 mL)
and MTBE (50 mL). The aqueous layer was extracted with MTBE (3”
60 mL). The combined organic layers were washed with brine (60 mL),
dried with Na2SO4,concentrated and the residue was purified by flash
chromatography (150 g silica gel,CHCl 3/MeOH 20:1) to yield diol 27
(844 mg,3.12 mmol,94%) as a colorless solid. M.p. 90 8C (CH2Cl2); Rf =
0.44 (CHCl3/MeOH 10:1); [a]2D2 =ꢀ29.1 (c=0.18,CHCl 3); 1H NMR
(500 MHz,CDCl 3): d=1.32 (d, J=6.2 Hz,3H,6-H 3),2.39 (d, J=8.0 Hz,
1H,2-OH),2.73 (d, J=1.6 Hz,1H,3-OH),2.82 (t, J=9.2 Hz,1H,4-H),
1.32 mmol,92%) as
a
colorless amorphous solid. M.p.
> 808C
(decomp); Rf =0.19 (n-hexane/MTBE 2:1); [a]2D1 =+52.3 (c=1.10,
CHCl3); 1H NMR (500 MHz,CDCl 3): d=0.62 (d, J=6.2 Hz,3H,6-H 3),
1.31–1.45 (m,2H,SiCH 2),1.72–1.85 (m,2H,SiCH 2),2.48 (t, J=9.3 Hz,
1H,4-H),3.10 (dq, J=9.7,6.0 Hz,1H,5-H),3.23 (s,3H,OCH
(dd, J=9.1,5.8 Hz,1H,2-H),4.46 (t, J=9.1 Hz,1H,3-H),4.49 (d,
3),4.30
J=
6.0 Hz,1H,1-H),6.87–6.96 (m,3H,Ph),7.14–7.26 (m,7H,Ph),7.30–
7.39 (m,7H,Ph),7.81–7.86 (m,6H,Ph),8.31–8.35 (m,2H,Ph);
13C NMR (125 MHz,CDCl 3): d=4.0,5.8 (SiCH 2),17.2 (C-6),60.8
(OCH3),72.8 (C-5),75.3 (C-2),77.7 (C-3),85.0 (C-4),100.8 (C-1),126.6,
128.3,128.4,128.6,129.9,130.2,130.5,130.6,130.9 (CH,Ph),134.1,134.2
3.58–3.64 (m,4H,OCH 3,3-H),3.79–3.85 (m,1H,2-H),4.17 (dq,
J=9.6,
6.2 Hz,1H,5-H),5.49 (d,
J=5.3 Hz,1H,1-H),7.25–7.31 (m,3H,Ph),
(Cq,Ph),134.4,134.5,134.7,134.8 (CH,Ph),134.3,134.6,135.3 (C
134.9,135.4,135.7,136.0 (CH,Ph),137.2,143.3 (C q,Ph); IR (film): n˜ =
q,Ph),
7.45–7.49 (m,2H,Ph); 13C NMR (125 MHz,CDCl 3): d=17.8 (C-6),60.7
(OCH3),68.4 (C-5),72.4 (C-2),75.4 (C-3),85.1 (C-4),90.5 (C-1),127.6,
3070 (s),2976 (s),2934 (s),2881 (s),1428 (s),1175 (s),1120 (s),846 (s),
700 cmꢀ1 (s); HR-MS (ESI): m/z: calcd for C39H40O5SSi2H: 677.2213;
found 677.2224 [M+H]+.
129.1,131.8 (CH,Ph),134.3 (C q,Ph); IR (film): n˜ =3398 (brs),2915 (s),
ꢀ1
1126 (s),1106 (s),1080 (s),740 cm
(s); HR-MS (EI): m/z: calcd for
C13H18O4S: 270.0926; found 270.0916 [M]+.
(2E,4E,8E,6R,7S)-7-tert-Butylsilyloxy-1-hydroxy-9-iodo-2,4,6-trimethyl-
nona-2,4,8-triene (35): Ester 34 (571 mg,1.19 mmol) was dissolved in tol-
uene (17 mL) at ꢀ788C and DIBAH (2.6 mL,2.6 mmol,1.0 m in PE) was
added dropwise. After stirring for 30 min at ꢀ788C,the reaction was
quenched by addition via cannula to a cooled (08C) solution of Rochelles
salt (50 mL,1.0 m). After stirring for 1 h,the two layers were separated
and the aqueous layer was extracted with MTBE (3”40 mL). The com-
1,4-Dichloro-1,1,4,4-tetraphenyl-1,4-disilabutane (29): 1,2-Bis(trichlorosi-
lyl)ethane (28) (5.00 g,16.8 mmol) was dissolved in THF (85 mL) at 0 8C
and phenylmagnesium bromide (24 mL,3.0 m in Et2O,72 mmol) was
added via dropping funnel within 45 min. The mixture was stirred for
20 h at 208C. Subsequently THF was removed at 308C at reduced pres-
sure (0.1 mbar). The residue was taken up in pentane (100 mL,dest.
from CaH2) and the unsoluble magnesium salt was removed by filtration
under argon. The solvent was evaporated again (see below),pentane
(100 mL) was added and the salt was filtered again. Finally,pentane was
distilled,the residue was dried in high vacuum for 3 h to yield product 29
(4.96 g,10.7 mmol,64%) as a colorless,storeable (argon) solid. M.p.
bined organic layers were washed with brine (30 mL),dried with MgSO
,
4
concentrated and the residue was purified by flash chromatography (60 g
silica gel,pentane/MTBE 6:1 !4:1) to give alcohol 35 (510 mg,
1.17 mmol,98%) as a colorless oil. Rf =0.44 (CHCl3/MeOH 100:1);
[a]2D3 =ꢀ22.9 (c=0.19,CHCl 3); 1H NMR (200 MHz,CDCl 3): d=ꢀ0.01,
Chem. Eur. J. 2006, 12,7378 – 7397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
7387

U. Koert et al.
0.02 (2s,6H,SiCH 3),0.87 (s,9H,SiC
CH3),1.71 (d, J=1.0 Hz,3H,4-CH 3),1.77 (d, J=1.0 Hz,3H,2-CH 3),
2.41–2.61 (m,1H,6-H),3.84 (t, J=6.5 Hz,1H,7-H),4.03 (brs,2H,2-
H2),5.06 (d, J=9.8 Hz,1H,5-H),5.84 (s,1H,3-H),6.15 (dd,
1.0 Hz,1H,9-H),6.51 (dd, J=14.4,6.4 Hz,1H,8-H);
A
8.1 Hz,1H,8-H),7.16–7.33 (m,10H,Ph),7.39 (t,
7.69–7.73 (m,2H,Ph),7.79–7.86 (m,6H,Ph);
J=7.7 Hz,2H,Ph),
13C NMR (125 MHz,
C6D6): d=4.7,6.1 (SiCH 2),15.9 (2-CH 3),17.19,17.24 (6-CH 3,4-CH 3),
18.0 (C-6 gluco),20.5 (OAc),37.4 (C-6),60.7 (OCH 3),67.5 (C-5 gluco),
ACHTREUNG
70.3 (C-1),74.6 (C-2 gluco),75.9 (C-3 gluco),80.5 (C-9),82.4 (C-7),86.7
(C-4 gluco),95.8 (C-1 gluco),128.1,128.3,128.4,128.5,129.8,130.1,
130.3,130.63 (CH,Ph),130.58 (C-2 o. C-4),131.6 (C-5),132.4 (C-3),
133.5 (C-2 o. C-4),134.6 (C q,Ph),134.85,134.91 (CH,Ph),135.0 (C
(75 MHz,CDCl 3): d=ꢀ4.9, ꢀ4.4 (SiCH3),15.4 (2-CH 3),16.7 (4-CH 3),
17.3 (6-CH3),18.2 (Si C(CH3)3),25.8 (SiC (CH3)3),39.6 (C-6),69.3 (C-1),
A
ACHTREUNG
76.3 (C-7),79.2 (C-9),129.3 (C-3),131.7 (C-5),133.1 (C-2),134.7 (C-4),
,
q
148.0 (C-8); IR (film): n˜ =3332 (brs),2957 (s),2929 (s),2858 (s),1463
Ph),135.4,135.74 (CH,Ph),135.81,137.4 (C
q,Ph),144.6 (C-8),169.9
ꢀ1
(s),1361 (s),1257 (s),1165 (s),1068 (s),1006 cm
(s); HR-MS (ESI):
(OAc); IR (film): n˜ =3069 (s),3050 (s),2916 (s),2868 (s),1738 (s),1377
m/z: calcd for C18H33IO2SiNa: 459.1192; found 459.1198 [M+Na]+.
(s),1228 (s),1110 (s),1030 (s),700 cm
(s); HR-MS (ESI): m/z: calcd
ꢀ1
for C47H55IO7Si2NH4: 932.2875; found 932.2837 [M+NH4]+; b-anomer
37b: Rf =0.21 (cyclohexane/toluene/CH2Cl2/AcOEt 10:10:5:1); 1H NMR
(500 MHz,C 6H6): d=0.90 (d, J=6.8 Hz,3H,6-CH 3),1.13 (d, J=6.1 Hz,
(2E,4E,8E,6R,7S)-1-Acetoxy-7-hydroxy-9-iodo-2,4,6-trimethyl-2,4,8-nona-
triene (36): NEt3 (500 mL,4.10 mmol),Ac 2O (320 mL,3.51 mmol) and
DMAP (7 mg,6 mmol) were added to a solution of allylic alcohol 35
(510 mg,1.17 mmol) in CH 2Cl2 (13 mL) at 08C. After stirring for 1 h at
08C,the reaction was quenched by addition of NH 4Cl (3 mL) and H2O
(5 mL). The two layers were separated and the aqueous layer was ex-
tracted with MTBE (1”40 mL and 3”15 mL). The combined organic
layers were washed with brine (20 mL),dried with MgSO 4,concentrated
and the residue so obtained was used for the next step without purifica-
tion. The crude product from the acetate protection was dissolved in
THF (22 mL) and cooled to 08C. Then TBAF (1.11 g,3.51 mmol) was
added. After 10 min the cool bath was removed and the mixture was stir-
red for 2 h at 208C. The reaction was quenched with NH4Cl (10 mL) and
the aqueous layer was extracted with MTBE (3”30 mL). The combined
organic layers were washed with brine (20 mL),dried with MgSO 4,con-
centrated and the residue was purified by flash chromatography (40 g
silica gel,pentane/MTBE 3:1) to yield glycosyl acceptor 36 (393 mg,
1.08 mmol,92% for 2 steps) as a colorless oil. Rf =0.44 (CHCl3/MeOH
100:1); [a]2D0 =+41.7 (c=1.15,CHCl 3); 1H NMR (200 MHz,CDCl 3): d=
3H,6-H gluco),1.31–1.37 (m,2H,SiCH 2),1.46 (d, J=1.0 Hz,3H,4-
3
CH3),1.69 (2s,6H,OAc,2-CH
3),1.67–1.73 (m,2H,SiCH 2),2.47–2.55
(m,1H,6-H),2.56 (dd,
J=9.2,8.8 Hz,1H,4-H gluco),2.96 (dq,
J=9.5,
6.1 Hz,1H,5-H gluco),3.19 (s,3H,OCH
7-H),3.84 (dd, J=8.7,7.5 Hz,1H,2-H gluco),3.90 (dd,
1H,3-H gluco),4.11 (d, J=7.5 Hz,1H,1-H gluco),4.45 (s,2H, ,1-H
5.14 (d, J=9.6 Hz,1H,5-H),5.78 (s,1H,3-H),5.93 (dd,
3),3.59 (dd, J=6.8,6.3 Hz,1H,
J=8.3,8.3 Hz,
2),
J=14.3,1.0 Hz,
1H,9-H),6.56 (dd, J=14.3,6.7 Hz,1H,8-H),7.18–7.32 (m,12H,Ph),
7.76–7.88 (m,8H,Ph); 13C NMR (75.5 MHz,C 6D6): d=6.4,6.6 (SiCH 2),
15.8 (2-CH3),17.0,17.2 (6-CH 3,4-CH 3),17.9 (C-6 gluco),20.5 (OAc),
38.1 (C-6),60.8 (OCH 3),70.4 (C-1),71.2 (C-5 gluco),76.4 (C-2 gluco),
77.6 (C-9),79.2 (C-3 gluco),86.0 (C-7,C-4 gluco),102.6 (C-1 gluco),
128.1,128.2,129.9,130.0,130.45 (CH,Ph),130.48 (C-2 or C-4),130.52
(CH,Ph),132.0 (C-5),132.5 (C-3),132.8 (C-2 or C-4),134.3,134.5 (C
Ph),134.9,135.0,136.0,136.2,(CH,Ph),136.6,137.0 (C
8),169.9 (OAc).
,
q
q,Ph),146.5 (C-
0.86 (d, J=6.8 Hz,3H,6-CH 3),1.04–1.07 (brs,1H,OH),1.54 (d,
1.1 Hz,3H,4-CH 3),1.68 (2”s,6H,2-CH 3,OAc),2.26–2.38 (m,1H,6-
J=
(2E,4E,8E,6R,7S)-7-[6-Deoxy-4-O-methyl-2,3-O-(1,1,4,4-tetraphenyldisi-
labutan-1,4-diyl)-a-l-glucopyranosyl]-1-hydroxy-9-iodo-2,4,6-trimethyl-
H),3.41–3.46 (m,1H,7-H),4.46 (s,2H,1-H
5-H),5.82 (s,1H,3-H),5.99 (dd, J=14.4,1.1 Hz,1H,9-H),6.39 (dd,
14.4,5.9 Hz,1H,8-H);
13C NMR (75 MHz,CDCl 3): d=15.7 (2-CH3),
2),5.04 (d, J=10.0 Hz,1H,
2,4,8-nonatriene (38): Via KCN in MeOH: Acetate 37a (166 mg,
181 mmol) was dissolved in MeOH/CH2Cl2 (7:1,8 mL). KCN (5.5 mg,
84 mmol) was added and the mixture was heated to 408C for 3 h. After
cooling to 208C,phosphate buffer (10 mL,1.0 m,pH 7) was added and
the aqueous layer was extracted with MTBE (3”50 mL). The combined
organic layers were washed with brine (30 mL),dried with MgSO 4,con-
centrated and the residue was purified by flash chromatography (20 g
silica gel,pentane/MTBE 7:2) to give starting material 37a (63 mg,
69 mmol,38%) and alcohol 38 (84 mg,96 mmol,53%) as a colorless oil.
J=
16.3 (6-CH3),17.1 (4-CH ),20.4 (OAc),38.8 (C-6),70.3 (C-1),77.4 (C-9),
3
78.1 (C-7),130.6 (C-4),132.0 (C-5),132.3 (C-3),133.2 (C-2),147.7 (C-8),
170.0 (OAc); IR (film): n˜ =3448 (brs),2924 (s),2854 (s),1753 (s),1456
ꢀ1
(s),1377 (s),1233 (s),1167 (s),1022 cm
(s); HR-MS (ESI): m/z: calcd
for C14H21IO3K: 403.0173; found 403.0175 [M+K]+.
(2E,4E,8E,6R,7S)-1-Acetoxy-7-[6-deoxy-4-O-methyl-2,3-O-(1,1,4,4-tetra-
phenyldisilabutandi-1,4-yl)-a-l-glucopyranosyl]-9-iodo-2,4,6-trimethyl-
2,4,8-nonatriene (37): Glycosyldonor 31 (782 mg,1.16 mmol) and 26, - tert-
butyl-4-methyl pyridine (395 mg,1.92 mmol) were combined and azeo-
troped with toluene (3”10 mL). After drying under high vacuum for 1 h,
the mixture was dissolved in Et2O (30 mL),4 Š MS (powder; 1 g) was
added and the suspension was stirred for 1 h at 208C. The mixture was
cooled to ꢀ808C and Tf2O (0.19 mL,1.1 mmol) was added via glass sy-
ringe within 3 min. After 10 min stirring glycosyl acceptor 36 (275 mg,
Via LiEt3BH: Acetate 37a (63 mg,69 mmol) was dissolved in THF
(4 mL) and cooled to ꢀ788C. LiEt3BH (0.50 mL,1.0
m in THF,
0.50 mmol) was slowly added and the mixture was allowed to warm to
ꢀ508C within 1 h. The reaction was quenched by addition of phosphate
buffer (1m,pH 7,4 mL),the aqueous layer was extracted with MTBE
(3”10 mL) and dried with MgSO4. The solvents were removed and the
residue was purified by flash chromatography (7 g silica gel,pentane/
MTBE 4:1) to afford alcohol 38 (45 mg,52 mmol,75%). Rf =0.31 (tol-
uene/cyclohexane/CH2Cl2/AcOEt 10:5:5:1); [a]2D4 =+42.9 (c=0.70,
CHCl3); 1H NMR (400 MHz,C 6D6): d=0.90 (d, J=6.6 Hz,3H,6-CH 3),
755 mmol),dissolved in Et O (10 mL),was added dropwise within 10 min
2
at ꢀ808C. The mixture was allowed to warm to ꢀ358C within 2 h and
was then quenched with NEt3 (350 mL). The cooling bath was removed,
NaHCO3 was added and the aqueous layer was extracted with MTBE
(3”50 mL). The combined organic layers were washed with brine
1.20 (d, J=6.2 Hz,3H,6-H
J=1.1 Hz,3H,4-CH 3),1.66 (d, J=0.9 Hz,3H,2-CH 3),1.62–1.78 (m,2H,
SiCH2),2.48–2.59 (m,1H,6-H),2.70 (t, J=9.2 Hz,1H,4-H gluco),3.32
gluco),1.26–1.36 (m,2H,SiCH 2),1.54 (d,
3
(50 mL),dried with MgSO ,concentrated and the residue was purified by
(s,3H,OCH 3),3.73 (dd, J=7.6,6.7 Hz,1H,7-H),3.81–3.87 (m,2H,2-H,
5-H gluco),4.38 (dd, J=9.4,9.4 Hz,1H,3-H gluco),4.48 (s,2H, ,1-H
4.80 (d, J=3.9 Hz,1H,1-H gluco),4.99 (d, J=9.8 Hz,1H,5-H),5.82 (s,
4
flash chromatography (100 g silica gel,pentane/MTBE 10:1) to yield the
colorless,oily glycosylated products 37a/37b (452 mg,494 mmol,65%) as
an anomeric mixture (85:15, 1H NMR). The anomers could be separated
by repeated chromatography with neutral silica gel (toluene/cyclohexane/
CH2Cl2/AcOEt 40:40:20:1). a-anomer 37a: Rf =0.19 (cyclohexane/tol-
uene/CH2Cl2/AcOEt 10:10:5:1); [a]2D2 =+48.3 (c=0.85,MTBE);
1H NMR (500 MHz,C 6D6): d=0.84 (d, J=6.8 Hz,3H,6-CH 3),1.21 (d,
2),
1H,3-H),6.04 (dd, J=14.6,1.1 Hz,1H,9-H),6.50 (dd,
J=14.6,8.1 Hz,
1H,8-H),7.16–7.33 (m,10H,Ph),7.39 (t,
(m,2H,Ph),7.79–7.86 (m,6H,Ph);
J=7.7 Hz,2H,Ph),7.69–7.73
13C NMR (100.6 MHz,CDCl 3): d=
4.7,6.1 (SiCH 2),15.6 (2-CH 3),17.2,17.5 (4-CH 3,6-CH 3),18.0 (C-6
gluco),37.4 (C-6),60.7 (OCH 3),67.5,69.0 (C-1,C-5 gluco),74.6 (C-2
gluco),75.9 (C-3 gluco),80.4 (C-9),82.4 (C-7),86.7 (C-4 gluco),95.7 (C-1
gluco),128.1,128.4,128.5 (CH,Ph),128.8 (C-3),129.8,130.1,130.3,130.6
(CH,Ph),131.5 (C-5),133.4,134.6 (C-2 or C-4 or CH,Ph),134.86,
134.92,135.4 (CH,Ph),135.5 (C q,Ph),135.7 (CH,Ph),135.8,137.4 (C
J=6.2 Hz,3H,6-H gluco),1.25–1.36 (m,2H,SiCH 2),1.47 (d, J=0.9 Hz,
3
3H,4-CH ),1.67 (d, J=1.2 Hz,3H,2-CH 3),1.70 (s,3H,OAc),1.65–1.73
3
(m,2H,SiCH 2),2.48–2.59 (m,1H,6-H),2.70 (t,
gluco),3.32 (s,3H,OCH 3),3.73 (dd, J=7.6,6.7 Hz,1H,7-H),3.81–3.87
(m,2H,2-H,5-H gluco),4.38 (t, J=9.4 Hz,1H,3-H gluco),4.48 (s,2H, ,
1-H2),4.80 (d, J=3.9 Hz,1H,1-H gluco),4.99 (d,
J=9.2 Hz,1H,4-H
,
q
Ph),144.6 (C-8); IR (film): n˜ =3448 (brs),3068 (s),2973 (s),2928 (s),
ꢀ1
J=9.8 Hz,1H,5-H),
J=14.6,
2874 (s),1428 (s),1170 (s),1074 (s),861 (s),700 cm
(s); HR-MS (ESI):
5.82 (s,1H,3-H),6.04 (dd,
J=14.6,1.1 Hz,1H,9-H),6.50 (dd,
m/z: calcd for C45H53IO6Si2NH4: 890.2769; found 890.2755 [M+NH4]+.
7388
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,7378 – 7397

Total Synthesis of Apoptolidin A
FULL PAPER
(2E,4E,6E,10E,8R,9S)-Methyl 9-[6-deoxy-4-O-methyl-2,3-O-(1,1,4,4-tet-
raphenyldisilabutandi-1,4-yl)-a-l-glucopyranosyl]-11-iodo-2,4,6,8-tetra-
methylundecatetra-2,4,6,10-enoate (39): Allylic alcohol 38 (84 mg,
(SiCH2CH3),7.36,7.39 (SiCH 2CH3),15.9 (2-CH 3),17.1,17.2 (6-CH 3,4-
CH3),18.6 (C-6 gluco),20.4 (OAc),37.6 (C-6),61.0 (OCH
3),68.2 (C-5
gluco),70.3 (C-1),74.4,74.6 (C-2 gluco,C-3 gluco),81.0 (C-9),81.8 (C-
7),87.7 (C-4 gluco),96.3 (C-1 gluco),130.7,133.1 (C-2,C-4),131.7 (C-5),
132.3 (C-3),144.7 (C-8),169.8 (OAc); IR (film): n˜ =3020 (w),2958 (s),
96 mmol) was dissolved in CH2Cl2 (8 mL),MnO (590 mg,6.79 mmol)
2
was added and the mixture was stirred for 30 min at 208C. The mixture
was filtered over a pad of Celite and the residue was washed with
CH2Cl2 (100 mL). The solvent was removed and the aldehyde obtained
was used for the next step without purification. The crude aldehyde was
azeotroped with toluene (3”5 mL) and dissolved in toluene (5 mL).
2916 (s),2878 (s),1730 (s),1423 (s),1384 (s),1216 (s),1140 (s),1073 (s),
ꢀ1
1020 (s),982 (s),848 cm
(s); HR-MS (ESI): m/z: calcd for
C33H61IO7Si2NH4: 770.3344; found 770.3340 [M+NH4]+.
(2E,4E,8E,6R,7S)-7-[6-Deoxy-4-O-methyl-2,3-O-bis(triethylsilyl)-a-l-glu-
Ph3PC(CH3)CO2Me (0.20 g,0.58 mmol) was added and the mixture was
G
copyranosyl]-9-iodo-2,4,6-trimethylnona-2,4,8-trienal
(41)
and
heated to 908C and stirred for 44 h. After cooling to 208C the solvent
was removed,the residue was taken up in cyclohexane/CH 2Cl2 10:1
(1 mL) and purified by flash chromatography (10 g neutral silica gel,pen-
tane/MTBE 12:1) to yield methyl ester 39 (82 mg,87 mmol,91%,2 steps)
as a colorless oil. Rf =0.53 (n-hexane/MTBE 2:1); [a]2D9 =+95.1 (c=1.48,
CHCl3); 1H NMR (500 MHz,C 6D6): d=0.84 (d, J=6.7 Hz,3H,8-CH 3),
(2E,4E,8E,6R,7S)-7-[6-deoxy-4-O-methyl-2,3-O-bis(triethylsilyl)-b-l-glu-
copyranosyl]-9-iodo-2,4,6-trimethylnona-2,4,8-trienal (42): Acetate 40
(336 mg,446 mmol) was dissolved in THF/MeOH/H2O (12 mL,2:1:1) and
cooled to 08C. LiOH·H2O (56 mg,1.3 mmol) was added and the mixture
was stirred for 1 h at 08C. The reaction was quenched by addition of
NH4Cl (10 mL) and the aqueous layer was extracted with MTBE (3”
15 mL). The combined organic layers were washed with brine (30 mL),
dried with MgSO4 and concentrated to give the crude alcohol (263 mg,
370 mmol,83%) which was used without further purification for the next
reaction. The crude mixture of anomeric allylic alcohols (263 mg,
370 mmol) thus obtained was dissolved in CH2Cl2 (20 mL). MnO2 (1.3 g,
15.0 mmol) was added and the mixture was stirred at 208C. After 30 min
the mixture was filtered over a pad of celite and the residue was washed
with CH2Cl2 (60 mL). The solvent was removed and the residue was puri-
fied by flash chromatography (45 g silica gel,pentane/MTBE 15:1 !9:1)
to yield (34 mg,48 mmol,13%) b-anomer 42 and (203 mg,290 mmol,
78%) a-anomer 41 as colorless liquids. The aldehydes were used for the
next reaction within 24 h and they were stored in a cyclohexane matrix at
ꢀ288C. a-anomer 41: Rf =0.51 (n-hexane/MTBE 3:1); [a]2D1 =ꢀ55.5 (c=
0.85,CHCl 3); 1H NMR (400 MHz,C 6D6): d=0.70 (q, J=7.9 Hz,6H,
SiCH2CH3),0.84 (q, J=8.0 Hz,6H,SiC H2CH3),0.89 (d, J=6.8 Hz,3H,
6-CH3),1.07 (t, J=7.9 Hz,9H,SiCH 2CH3),1.13 (t, J=7.9 Hz,9H,
1.20 (d, J=6.2 Hz,3H,6-H
3H,6-CH 3),1.61–1.76 (m,2H,2-H SiCH 2),1.79 (s,3H,4-CH 3),2.10 (d,
J=0.7 Hz,3H,2-CH 3),2.49–2.59 (m,1H,8-H),2.69 (dd, J=9.1,9.1 Hz,
1H,4-H gluco),3.31 (s,3H,OCH 3),3.48 (s,3H,CO 2CH3),3.75 (dd, J=
gluco),1.25–1.38 (m,2H,SiCH 2),1.46 (s,
3
7.4,6.7 Hz,1H,9-H),3.79–3.87 (m,1H,5-H gluco),3.84 (dd,
J=9.3,
3.4 Hz,1H,2-H gluco),4.38 (t,
3.8 Hz,1H,1-H gluco),5.05 (d,
6.05 (d, J=14.5 Hz,1H,11-H),6.50 (dd,
7.17–7.34 (m,10H,Ph),7.38 (t,
J=9.0 Hz,1H,3-H gluco),4.80 (d, J=
J=9.8 Hz,1H,7-H),5.91 (s,1H,5-H),
J=14.6,8.0 Hz,1H,10-H),
J=7.3 Hz,2H,Ph.),7.44 (s,1H,3-H),
7.71 (d, J=6.7 Hz,2H,Ph),7.76–7.88 (m,2H,Ph);
13C NMR (125 MHz,
CDCl3): d=4.6,6.1 (SiCH ),14.5 (2-CH ),16.9,17.3 (6-CH 3,8-CH ),18.0
2
3
3
(C-6 gluco),18.6 (4-CH 3),37.5 (C-8),51.4 (CO 2CH3),60.8 (OCH 3),67.6
(C-5 gluco),74.6 (C-2 gluco),75.9 (C-3 gluco),80.6 (C-11),82.2 (C-9),
86.7 (C-4 gluco),95.8 (C-1 gluco),126.2 (C-2),128.1,128.2,128.4,128.5,
129.8,130.1,130.3,130.6 (CH,Ph),132.5 (C-4),132.9 (C-7),133.6 (C-6),
134.6 (Cq,Ph),134.8,134.89 (CH,Ph),134.93 (C
q,Ph),135.4,135.7 (CH,
Ph),137.4 (C q,Ph),139.1 (C-5),144.0 (C-3),144.4 (C-10),169.1 (C-1); IR
SiCH2CH3),1.29 (d, J=6.4 Hz,3H,6-H gluco),1.59 (d, J=1.2 Hz,3H,
3
(film): n˜ =3069 (s),2977 (s),2927 (s),2875 (s),1707 (s),1429 (s),1254
4-CH3),1.91 (d, J=0.9 Hz,3H,2-CH 3),2.50–2.60 (m,1H,6-H),2.62 (dd,
ꢀ1
(s),1118 (s),1028 (s),859 (s),700 cm
(s); HR-MS (ESI): m/z: calcd for
J=9.2,9.2 Hz,1H,4-H gluco),3.31 (s,3H,OCH
3.4 Hz,1H,2-H gluco),3.73–3.84 (m,2H,7-H,5-H gluco),4.07 (t,
9.0 Hz,1H,3-H gluco),4.78 (d, J=3.5 Hz,1H,1-H gluco),5.30 (d,
9.9 Hz,1H,5-H),6.11 (d, J=14.6 Hz,1H,9-H),6.23 (brs,1H,3-H),6.36
(dd, J=14.4,8.2 Hz,1H,8-H),9.30 (s,1H,1-H);
13C NMR (100.6 MHz,
3),3.62 (dd, J=9.3,
C49H57IO7Si2Na: 963.2585; found 963.2591 [M+Na]+.
J=
J=
(2E,4E,8E,6R,7S)-1-Acetoxy-7-[6-deoxy-4-O-methyl-2,3-O-di(triethylsil-
yl)-a,b-l-glucopyranosyl]-9-iodo-2,4,6-trimethylnona-2,4,8-triene
(40):
The a,b-mixture of SIBA-ethers 37a/37b (420 mg,460 mmol) was dis-
solved in THF (20 mL) and cooled to 08C. Then TBAF (305 mg,
966 mmol) was added. After 10 min the cooling bath was removed and
the mixture was stirred for 1 h at 208C. The reaction was quenched with
phosphate buffer (20 mL,1.0 m,pH 7) and the aqueous layer was extract-
ed with MTBE (3”15 mL). The combined organic layers were washed
with brine (20 mL),dried with MgSO 4,concentrated and the residue was
purified by flash chromatography (40 g silica gel,pentane/MTBE 1:3) to
yield the corresponding diol (240 mg,450 mmol,99%) as a colorless oil.
The diol (240 mg,450 mmol) was dissolved in CH2Cl2 (20 mL) and cooled
to 08C. Imidazole (312 mg,4.50 mmol) and TESCl (0.48 mL,2.7 mmol)
were added,the cooling bath was removed and the mixture was stirred
for 30 min at 208C. The reaction was quenched with phosphate buffer
solution (20 mL,1.0 m,pH 7) and the aqueous layer was extracted with
MTBE (3”20 mL). The combined organic layers were washed with brine
C6D6): d=5.6,5.8 (Si CH2CH3),7.3,7.4 (SiCH 2CH3),10.9 (2-CH 3),16.4
(2”C,6-CH ,4-CH ),18.5 (C-6 gluco),37.6 (C-6),61.1 (OCH 3),68.4 (C-
3
3
5 gluco),74.4,74.5 (C-2 gluco,C-3 gluco),81.4,81.5 (C-7,C-9),87.6 (C-4
gluco),96.3 (C-1 gluco),133.8,136.8 (C-2,C-4),139.5 (C-5),144.0 (C-8),
153.0 (C-3),194.7 (C-1); IR (film): n˜ =2957 (s),2913 (s),2875 (s),2831
ꢀ1
(s),1680 (s),1607 (s),1459 (s),1380 (s),1239 (s),1140 (s),1038 cm
(s).
b-anomer 42: Rf =0.58 (n-hexane/MTBE 3:1); [a]2D1 =+2.7 (c=1.00,
CHCl3); 1H NMR (400 MHz,C 6D6): d=0.79–0.94 (m,12H,SiC H2CH3),
0.91 (d, J=6.9 Hz,3H,6-CH 3),1.07–1.16 (m,18H,SiCH 2CH3),1.23 (d,
J=6.1 Hz,3H,6-H gluco),1.65 (d, J=1.3 Hz,3H,4-CH 3),1.88 (d, J=
3
1.1 Hz,3H,2-CH 3),2.58 (dd, J=8.7,8.7 Hz,1H,4-H gluco),2.72–2.83
(m,1H,6-H),3.10 (dq,
OCH3),3.53 (t, J=8.0 Hz,1H,2-H gluco),3.57 (t,
J=9.4,6.2 Hz,1H,5-H gluco),3.16 (s,3H,
J=8.3 Hz,1H,3-H
gluco),3.69 (t, J=7.0 Hz,1H,7-H),4.09 (d,
5.39 (d, J=9.8 Hz,1H,5-H),6.04 (dd,
J=7.2 Hz,1H,1-H gluco),
J=14.6,0.8 Hz,1H,9-H),6.23
(30 mL),dried with MgSO and the solvent was evaporated. The crude
4
product was purified by flash chromatography (40 g silica gel,pentane/
MTBE 5:2) to give bis(silyl ether) 40 (336 mg,446 mmol,99%) as a col-
orless oil. An analytical sample of anomeric mixture was separated by
chromatography (n-hexane/MTBE 4:1). Data of a-anomer: Rf =0.40 (n-
hexane/MTBE 4:1); [a]2D0 =ꢀ34.3 (c=0.89,CHCl 3); 1H NMR (500 MHz,
C6D6): d=0.72 (q, J=7.7 Hz,6H,SiC H2CH3),0.85 (q, J=7.5 Hz,6H,
SiCH2CH3),0.97 (d, J=6.9 Hz,3H,6-CH 3),1.09 (t, J=7.9 Hz,9H,
SiCH2CH3),1.14 (t, J=7.9 Hz,9H,SiCH 2CH3),1.31 (d, J=6.4 Hz,3H,
(brs,1H,3-H),6.70 (dd,
J=14.4,8.1 Hz,1H,8-H),9.30 (s,1H,1-H);
13C NMR (100.6 MHz,C 6D6): d=5.7,5.8 (Si CH2CH3),7.38,7.40
(SiCH2CH3),10.9 (2-CH 3),16.2 (4-CH 3),16.8 (6-CH 3),18.7 (C-6 gluco),
37.8 (C-6),60.4 (OCH ),71.5 (C-5 gluco),76.6 (C-2 gluco),78.5,78.6 (C-
3
9,C-3 gluco),86.2 (C-7),86.7 (C-4 gluco),102.4 (C-1 gluco),133.8,136.7
(C-2,C-4),139.2 (C-5),145.5 (C-8),153.0 (C-3),194.7 (C-1); IR (film):
n˜ =2954 (s),2909 (s),2872 (s),2830 (s),1675 (s),1607 (s),1462 (s),1414
(s),1379 (s),1281 (s),1154 (s),1116 (s),811 (s),747 cm
Cyanomethyl (2E,4E,6E,10E,8R,9S)-9-[6-deoxy-4-O-methyl-2,3-O-bis-
ꢀ1 (s).
6-H3 gluco),1.56 (s,3H,4-CH 3),1.70 (s,3H,OAc),1.74 (s,3H,2-CH
3),
2.55–2.63 (m,1H,6-H),2.64 (dd, J=9.1,9.1 Hz,1H,4-H gluco),3.33 (s,
(triethylsilyl)-a-l-glucopyranosyl]-11-iodo-2,4,6,8-tetramethylundecatetra-
2,4,6,10-enoate (43): Horner–Emmons olefination: (EtO)2P(O)CH-
3H,OCH 3),3.64 (dd, J=9.4,3.4 Hz,1H,2-H gluco),3.77 (t,
1H,7-H),3.81–3.91 (m,1H,5-H gluco),4.12 (t, J=9.1 Hz,1H,3-H
gluco),4.47 (s,2H, ,1-H 2),4.82 (d, J=3.2 Hz,1H,1-H gluco),5.06 (d, J=
9.6 Hz,1H,5-H),5.83 (s,1H,3-H),6.09 (d, J=14.4 Hz,1H,9-H),6.42
13C NMR (125 MHz,CDCl 3): d=5.6,5.8
J=7.9 Hz,
A
sion of NaH (88 mg,2.2 mmol,60% in mineral oil) in THF (8 mL) at
08C within 20 min. The reaction mixture was stirred for 20 min. Then al-
(dd, J=14.6,8.1 Hz,1H,8-H);
Chem. Eur. J. 2006, 12,7378 – 7397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
7389

U. Koert et al.
dehyde 41 (147 mg,207 mmol) in THF (5 mL) was added. The mixture
was stirred at 08C for 1 h and was then heated to 358C. The mixture
formed a gel after 20 min stirring at 358C. MTBE (10 mL) and NH4Cl
(10 mL) were added,the layers were separated and the aqueous layer
was extracted with MTBE (3”20 mL). The combined organic layers
were washed with brine (30 mL),dried with Na 2SO4 and the solvents
were evaporated. The crude product was purified by flash chromatogra-
phy (15 g silica gel,pentane/MTBE 6:2 ! 1:1) to give the corresponding
acid (137 mg,179 mmol,87%) as a colorless oil. Rf =0.20 (n-hexane/ace-
J=1.1 Hz,3H,4-CH 3),1.90 (d, J=1.1 Hz,3H,2-CH 3),2.58 (t, J=
8.9 Hz,1H,4-H gluco),2.76–2.87 (m,1H,8-H),3.11 (dq,
1H,5-H gluco),3.17 (s,3H,OCH 3),3.51–3.60 (m,2H,(2–3)-H gluco),
3.71 (t, J=7.2 Hz,1H,9-H),3.83 (s,2H,OCH 2CN),4.12 (d, J=7.0 Hz,
J=9.4,6.2 Hz,
1H,1-H gluco),5.21 (d, J=9.8 Hz,1H,7-H),5.89 (s,1H,5-H),6.05 (d,
J=14.4 Hz,1H,11-H),6.74 (dd, J=14.5,8.0 Hz,1H,10-H),7.23 (s,1H,
3-H); 13C NMR (100.6 MHz,CDCl 3): d=5.75,5.80 (2”Si CH2CH3),7.4
(2”SiCH2CH3),14.1 (2-CH 3),17.1,17.3 (8-CH 3,6-CH 3),18.2 (4-CH 3),
18.8 (C-6 gluco),38.0 (C-8),48.1 (O CH2CN),60.4 (OCH 3),71.5 (C-5
gluco),76.7 (C-2 gluco or C-3 gluco),78.4,78.5 (C-11,C-2 gluco or C-3
gluco),86.5 (C-9),86.7 (C-4 gluco),102.4 (C-1 gluco),115.0 (OCH 2CN),
124.1 (C-2),132.1,132.2 (C-4,C-6),133.6 (C-7),140.7 (C-5),146.0 (C-10),
146.3 (C-3),166.9 (C-1); IR (film): n˜ =2956 (w),2911 (s),2875 (s),1721
1
tone 3:1); [a]2D0 =+22.9 (c=1.20,CHCl ); H NMR (500 MHz,C D6): d=
3
6
0.72 (q, J=7.9 Hz,6H,SiC H2CH3),0.85 (q, J=7.9 Hz,6H,SiC H2CH3),
0.97 (d, J=6.9 Hz,3H,8-CH 3),1.09 (t, J=7.9 Hz,9H,SiCH 2CH3),1.14
(t, J=8.0 Hz,9H,SiCH 2CH3),1.31 (d, J=6.2 Hz,3H,6-H
(d, J=0.9 Hz,3H,6-CH 3),1.85 (d, J=1.0 Hz,3H,4-CH 3),2.06 (d, J=
1.2 Hz,3H,2-CH 3),2.56–2.65 (m,1H,8-H),2.64 (t, J=9.2 Hz,1H,4-H
gluco),3.32 (s,3H,OCH 3),3.65 (dd, J=9.3,3.3 Hz,1H,2-H gluco),3.80
gluco),1.56
3
(s),1607 (s),1461 (m),1417 (m),1301 (s),1239 (s),1168 (s),1107 (s),
ꢀ1
1085 (s),1007 cm
(s); HR-MS (ESI) m/z: calcd for C36H62INO7Si2Na:
826.3007; found 826.3001 [M+Na]+.
(dd, J=8.1,6.5 Hz,1H,9-H),3.86 (dq,
4.11 (t, J=9.1 Hz,1H,3-H gluco),4.83 (d,
5.13 (d, J=9.9 Hz,1H,7-H),5.91 (s,1H,5-H),6.11 (d,
11-H),6.42 (dd, J=14.6,8.4 Hz,1H,10-H),7.52 (s,1H,3-H);
J=9.6,6.2 Hz,1H,5-H gluco),
J=3.4 Hz,1H,1-H gluco),
(1’E,2R,3R,4S,5R,6R,4’S,2’’R)-2-[-5’-Benzyloxy-4’-methoxy-1’-pentenyl]-
6-[2’’-tert-butyldimethylsilyloxy-3’’-methoxypropyl]-4-hydroxy-2-me-
thoxy-3,5-dimethyl-4-trimethylsilyloxy-2,3,5,6-tetrahydro-4H-pyran (46):
Alcohol 45 (2.1 g,3.7 mmol) was dissolved in CH 2Cl2 (70 mL) and TMS-
imidazole (0.83 mL,5.6 mmol) was added at 0 8C. After stirring for 2.5 h
at 08C phosphate buffer (40 mL,1 m,pH 7) and MTBE (50 mL) were
added. The two layers were separated and the aqueous layer was extract-
ed with MTBE (3”40 mL). The combined organic layers were washed
with brine (80 mL),dried with MgSO 4,concentrated and the residue was
purified by flash chromatography (250 g silica gel,pentane/MTBE 5:1) to
yield silyl ether 46 (2.22 g,3.47 mmol,94%) as a colorless oil. Rf =0.29
(n-hexane/MTBE 4:1); [a]2D4 =+60.6 (c=1.21,CHCl 3); 1H NMR
J=14.4 Hz,1H,
13C NMR
(125 MHz,CDCl ): d=5.6,5.8 (2”Si CH2CH3),7.35,7.38 (2”SiCH 2CH3),
3
13.9 (2-CH3),16.9 (8-CH 3),17.2 (6-CH 3),18.4 (4-CH 3),18.6 (C-6 gluco),
37.7 (C-8),61.1 (OCH 3),68.3 (C-5 gluco),74.4,74.5 (C-2 gluco,C-3
gluco),81.1 (C-11),81.6 (C-9),87.7 (C-4 gluco),96.3 (C-1 gluco),125.5
(C-2),132.4,133.1 (C-4,C-6),133.5 (C-7),139.9 (C-5),144.5 (C-10),146.2
(C-3),174.7 (C-1); IR (film): n˜ =3460–3510 (brs),2957 (s),2875 (s),2851
(s),1683 (s),1463 (s),1415 (s),1379 (s),1278 (s),1239 (s),1173 (s),1112
ꢀ1
(s),749 cm (s); HR-MS (ESI): m/z: calcd for C34H61IO7Si2Na: 787.2898;
found 787.2861 [M+Na]+.
(300 MHz,CDCl ): d=0.05 (2s,6H,SiCH 3),0.09 (s,9H,Si
ACHTREUNG
3
Cyanomethylesterification: The acid (240 mg,450 mmol) was dissolved in
0.89 (m,15H,5-CH 3,3-CH 3,SiC
ACHTREUNG
MeCN (2 mL) and cooled to 08C. NEt3 (1.0 mL,72 mmol) and ClCH CN
1H,1 ’’-H),1.53 (dq, J=10.7,6.6 Hz,1H,3-H),1.60–1.71 (m,1H,5-H),
1.72 (ddd, J=14.3,8.2,4.6 Hz,1H,1 ’’-H),2.25–2.34 (m,2H,3 ’-H2),3.04
(s,3H,2-OCH 3),3.25 (dd, J=9.8,6.4 Hz,1H,3 ’’-H),3.30 (s,3H,OCH 3),
3.32–3.41 (m,2H,3 ’’-H,4 ’-H),3.39 (s,3H,OCH 3),3.41–3.48 (m,1H,5 ’-
2
(0.50 mL,7.9 mmol) were added. The cooling bath was removed and the
mixture was stirred for 14 h at 208C. The reaction was quenched with
MTBE (5 mL)/phosphate buffer (5 mL,1.0 m,pH 7),the layers were sep-
arated and the aqueous layer was extracted with MTBE (3”20 mL). The
combined organic layers were washed with brine (10 mL),dried with
MgSO4 and the solvent was evaporated. The crude product was purified
by flash chromatography (10 g silica gel,pentane/MTBE 8:1) to give cya-
nomethyl ester 43 (132 mg,164 mmol,92%) as a colorless oil. Rf =0.41
(n-hexane/MTBE 3:1); [a]2D0 =+17.9 (c=0.58,CHCl 3); 1H NMR
(500 MHz,C 6D6): d=0.72 (q, J=8.1 Hz,6H,SiC H2CH3),0.84 (q, J=
8.2 Hz,6H,SiC H2CH3),0.96 (d, J=6.6 Hz,3H,8-CH 3),1.09 (t, J=
8.0 Hz,9H,SiCH 2CH3),1.13 (t, J=8.0 Hz,9H,SiCH 2CH3),1.30 (d, J=
H2),3.76 (dd, J=10.6,4.8 Hz,1H,4-H),3.81–3.95 (m,2H,6-H,2
’’-H),
4.49 (d, J=12.2,1H,CHPh),4.54 (d, J=12.0,1H,CHPh),5.41 (brd, J=
15.6 Hz,1H,1 ’-H),5.74 (dt, J=15.6,7.3 Hz,1H,2
’-H),7.22–7.34 (m,
5H,Ph); 13C NMR (75.5 MHz,CDCl 3): d=ꢀ4.7, ꢀ3.8,0.3 (SiCH 3),5.1
(5-CH3),11.6 (3-CH 3),18.2 (Si C
A
N
38.7 (C-1’’),40.0 (C-5),40.6 (C-3),48.9 (2-OCH 3),57.5,58.8 (4 ’-OCH3,
3’’-OCH3),67.9 (C-6),70.2 (C-2 ’’),71.6 (C-5 ’),73.38 ( CH2Ph),73.42 (C-
4),77.8 (C-3 ’’),79.8 (C-4 ’),101.2 (C-2),127.59,127.63,128.4,138.2 (Ph),
128.8 (C-2’),131.9 (C-1 ’); IR (film): n˜ =2949 (s),2891 (s),2858 (s),1460
ꢀ1
6.4 Hz,3H,6-H
1.1 Hz,3H,4-CH 3),1.92 (d, J=1.4 Hz,3H,2-CH 3),2.55–2.64 (m,1H,8-
H),2.63 (t, J=9.2 Hz,1H,4-H gluco),3.32 (s,3H,OCH 3),3.64 (dd, J=
9.3,3.3 Hz,1H,2-H gluco),3.77–3.88 (m,2H,9-H,5-H gluco),3.81 (s,
gluco),1.57 (d, J=1.1 Hz,3H,6-CH 3),1.83 (d, J=
(m),1251 (s),1108 (s),1067 (s),838 cm
(s); HR-MS (EI): m/z: calcd
3
for C34H62O7Si2: 638.4034; found 638.4033 [M]+.
(2R,3R,4S,5R,6R,1’R,2’S,4’S,2’’R)-2-(1’,2’-Diacetoxy-5’-benzyloxy-4’-me-
thoxy-1’-pentyl)-6-(2’’-tert-butyldimethylsilyloxy-3’’-methoxypropyl)-2-
methoxy-3,5-dimethyl-4-trimethylsilyloxy-2,3,5,6-tetrahydro-4H-pyran
(47): Alkene 46 (2.18 g,3.41 mmol) was dissolved in tBuOH (30 mL) and
H2O (14 mL) and cooled to 08C. [K2OsO2(OH)4] (75 mg,0.20 mmol),
NMO (1.2 g,10 mmol) were added and the mixture was stirred for 7 d
between 0–88C (TLC control n-hexane/MTBE 1:1). The reaction was
quenched with Na2S2O3 (8 g) in H2O (50 mL) and MTBE (50 mL). The
yellow solution was stirred for 1 h meanwhile the color changed to black.
The aqueous layer was extracted with MTBE (3”40 mL). The combined
2H,OCH 2CN),4.10 (t, J=9.0 Hz,1H,3-H gluco),4.82 (d,
J=3.4 Hz,
1H,1-H gluco),5.15 (d, J=9.9 Hz,1H,7-H),5.88 (s,1H,5-H),6.12 (d,
J=14.4 Hz,1H,11-H),6.42 (dd, J=14.7,8.2 Hz,1H,10-H),7.23 (s,1H,
3-H); 13C NMR (125 MHz,CDCl 3): d=5.6,5.8 (2”Si CH2CH3),7.3,7.4
(2”SiCH2CH3),14.0 (2-CH 3),16.8 (8-CH 3),17.2 (6-CH 3),18.3 (4-CH 3),
18.6 (C-6 gluco),37.7 (C-8),48.1 (O CH2CN),61.1 (OCH 3),68.3 (C-5
gluco),74.4,74.5 (C-2 gluco,C-3 gluco),81.2 (C-11),81.6 (C-9),87.7 (C-4
gluco),96.3 (C-1 gluco),115.0 (OCH 2CN),124.2 (C-2),132.0,133.2 (C-4,
C-6),133.8 (C-7),140.3 (C-5),144.4 (C-10),146.2 (C-3),168.8 (C-1); IR
organic layers were washed with brine (80 mL),dried with MgSO and
4
(film): n˜ =2957 (s),2913 (s),2874 (s),2850 (s),2829 (s),1724 (s),1604
concentrated. The crude product was dissolved in pyridine (50 mL) at
cooled to 08C. Ac2O (17 mL,0.18 mmol) and DMAP (20 mg,0.16 mmol)
were added. The cooling bath was removed and the mixture was stirred
4 h at 408C. After cooling,phosphate buffer (50 mL,1 m,pH 7) and
MTBE (50 mL) were added. The two layers were separated and the
aqueous layer was extracted with MTBE (3”30 mL). The combined or-
ganic layers were washed with brine (50 mL),dried with MgSO 4,concen-
trated and the residue was azeotroped with toluene (3”20 mL). The
crude product was purified by flash chromatography (270 g silica gel,
ꢀ1
(s),1239 (s),1172 (s),1140 (s),1094 (s),748 cm
(s); HR-MS (ESI): m/
z: calcd for C36H62INO7Si2Na: 826.3007; found 826.3026 [M+Na]+.
Cyanomethyl (2E,4E,6E,10E,8R,9S)-9-[6-deoxy-4-O-methyl-2,3-O-bis-
(triethylsilyl)-b-l-glucopyranosyl]-11-iodo-2,4,6,8-tetramethylundecatetra-
2,4,6,10-enoate (44): According to the procedure for the conversion of
the a-anomer 41 into the a-anomeric cyanomethyl ester 43,the b-anome-
ric aldehyde 42 (34 mg,48 mmol) was transformed into the b-anomeric
cyanomethyl ester 44 (30 mg,37 mmol,78%). Rf =0.40 (n-hexane/MTBE
3:1); [a]2D0 =+57.9 (c=1.45,CHCl 3); 1H NMR (400 MHz,C 6D6): d=
0.77–0.92 (m,12H,2”SiC H2CH3),1.00 (d, J=6.8 Hz,3H,8-CH 3),1.11
(t, J=7.9 Hz,9H,SiCH 2CH3),1.12 (t, J=7.9 Hz,9H,SiCH 2CH3),1.23
pentane/MTBE 4:1) to yield bis(acetate) 47 (2.0 g,2.9 mmol,85%,two
E
steps) as a colorless oil. Furthermore,the minor diastereomer (315 mg,
416 mmol,12%) was obtained as a colorless oil. Rf =0.47 (n-hexane/
1
(d, J=6.4 Hz,3H,6-H
gluco),1.65 (d, J=0.9 Hz,3H,6-CH 3),1.82 (d,
MTBE 1:1); [a]2D6 =+38.7 (c=1.02,CHCl ); H NMR (300 MHz,CDCl ):
3
3
3
7390
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,7378 – 7397

Total Synthesis of Apoptolidin A
FULL PAPER
d=0.02,0.03 (2s,6H,SiCH 3),0.07 (s,9H,Si
G
MgSO4,concentrated and the residue was filtered over 10 g silica gel
(pentane/MTBE 2:1). The solvents were removed and the residue was
dissolved in THF (50 mL) and cooled to 08C. TBAF (530 mg,1.68 mmol)
in THF (5 mL) was added within 10 min. After stirring for 30 min at 08C
MTBE (70 mL) and phosphate buffer (50 mL,1 m,pH 7) were added.
The two layers were separated and the aqueous layer was extracted with
MTBE (3”50 mL). The combined organic layers were washed with brine
(50 mL),dried with MgSO 4,concentrated and the residue purified by
flash chromatography (40 g silica gel,pentane/MTBE 2:3) to yield mono-
silyl ether 49 (745 mg,1.09 mmol,77%,two steps) as a colorless oil. Rf =
0.34 (n-hexane/MTBE 1:2); [a]2D4 =+45.1 (c=0.85,CHCl 3); 1H NMR
(400 MHz,C 6D6): d=0.59 (q, J=8.1 Hz,6H,SiC H2CH3),0.99 (t, J=
7.9 Hz,9H,SiCH 2CH3),1.17 (d, J=6.9 Hz,3H,5-CH 3),1.25–1.34 (m,
SiC
7.8,3.4 Hz,1H,1 ’’-H),1.58–1.72 (m,3H,5-H,1 ’’-H,3 ’-H),1.83 (dq, J=
10.4,6.5 Hz,1H,3-H),1.94–2.03 (m,1H,3 ’-H),1.99,2.06 (2s,6H,OAc),
3.09 (s,3H,OCH 3),3.17–3.31 (m,3H,3 ’’-H2, 4’-H),3.27,3.35 (2s,6H,
OCH3),3.40–3.46 (m,2H,5-H 2),3.71 (dd, J=10.3,4.6 Hz,1H,4-H),
(CH3)3,5-CH 3),1.01 (d, J=6.6 Hz,3H,3-CH 3),1.44 (ddd, J=14.3,
3.79–3.93 (m,2H,2 ’’-H,6-H),4.51 (s,2H,CH
1H,1 ’-H),5.41 (ddd, J=9.5,6.2,3.2 Hz,1H,2
Ph); 13C NMR (75 MHz,CDCl 3): d=ꢀ5.0, ꢀ4.0,0.0 (SiCH 3),4.9 (5-
CH3),10.8 (3-CH 3),18.0 (Si C
A
35.5 (C-3’),36.1 (C-3),38.2 (C-1 ’’),39.4 (C-5),47.7 (2-OCH 3),57.9 (4 ’-
OCH3),58.5 (3 ’’-OCH3),68.7 (C-2 ’),68.9 (C-6),69.6 (C-2 ’’),72.0 (C-5 ’),
72.9 (C-4,C-1 ’),73.1 ( CH2Ph),76.3 (C-4 ’),77.3 (C-3 ’’),100.6 (C-2),
127.29,127.31,128.1,138.0 (Ph),169.6,169.8 (2”OAc); IR (film):
n˜ =
1H,1 ’’-H),1.52 (d, J=6.7 Hz,3H,3-CH 3),1.61–1.70 (m,1H,1
1.73–1.82 (m,1H,5-H),1.76,1.79 (2s,6H,OAc),1.89–1.98 (m,1H,3
’’-H),
’-
2953 (s),2932 (s),2893 (s),2858 (s),1748 (s),1463 (w),1248 (s),1102 (s),
ꢀ1
1072 (s),838 cm
(m); HR-MS (FAB): m/z: calcd for C38H68O11Si2Na:
H),2.11 (brs,1H,OH),2.20–2.33 (m,2H,3-H,3
8.5 Hz,1H,3 ’’-H),3.04–3.08 (m,1H,3 ’’-H),3.02,3.33,3.36 (3s,9H,
OCH3),3.34–3.47 (m,3H,5 ’-H2, 4’-H),3.99–4.07 (m,1H,2 ’’-H),4.08 (dd,
J=10.3,4.8 Hz,1H,4-H),4.27–4.36 (m,3H,6-H,CH 2Ph),5.49 (d, J=
5.0 Hz,1H,1 ’-H),5.90–5.97 (m,1H,2 ’-H),7.05–7.30 (m,5H,Ph);
’-H),2.92 (dd, J=8.3,
779.4198; found 779.4189 [M+Na]+; minor diastereomer: Rf =0.40 (n-
hexane/MTBE 1:1); [a]2D4 =+43.5 (c=1.00,CHCl 3); 1H NMR (300 MHz,
CDCl3): d=0.035,0.040,0.07 (3s,15H,Si-CH
5-CH3),0.86 (s,9H,Si-C (CH3)3),0.89 (d, J=6.8 Hz,3H,3-CH 3),1.44
(ddd, J=14.2,7.6,3.8 Hz,1H,1 ’’-H2),1.56–1.70 (m,2H,5-H,1 ’’-H2),
1.95–2.07 (m,3H,3-H,3 ’-H2),1.99,2.05 (2s,6H,OAc),3.21–3.37 (m,
3H,4 ’-H,3 ’’-H2),3.27,3.30,3.32 (3s,9H,2-OCH 3, 4’-OCH3, 3’’-OCH3),
3.40–3.47 (m,2H,5 ’-H2),3.64 (dd, J=10.3,4.8 Hz,1H,4-H),3.73–3.78
(m,1H,6-H),3.82–3.95 (m,1H,2 ’’-H),4.48–4.54 (m,2H,C H2Ph),5.19
3),0.81 (d, J=7.0 Hz,3H,
AHCTREUNG
13C NMR (100.6 MHz,C 6D6): d=5.4 (SiCH2CH3),5.8 (5-CH 3),7.2
(SiCH2CH3),11.8 (3-CH 3),20.55,20.60 (2”OAc),36.8,36.9 (C-1 ’’,C-3 ’),
37.6 (C-3),40.3 (C-5),48.1 (2-OCH 3),58.1,58.6 (2”OCH 3),66.7 (C-2 ’’),
68.1 (C-6),69.3 (C-2 ’),72.6 (C-5 ’),73.4 ( CH2Ph),73.6,73.7 (C-4,C-1 ’),
77.1 (C-4’),77.7 (C-3 ’’),101.4 (C-2),127.6,127.7,128.5 (Ph),139.1 (C
Ph),169.4,169.7 (OAc); IR (film): n˜ =3478 (brs),3064 (w),2950 (s),
-
q
(d, J=6.1 Hz,1H,1 ’-H),5.33–5.45 (m,1H,2 ’-H),7.22–7.36 (m,5H,Ph);
13C NMR (75 MHz,CDCl 3): d=ꢀ4.9, ꢀ4.0,0.0 (Si-CH 3),4.8 (5-CH 3),
2912 (s),2876 (s),1743 (s),1456 (s),1372 (s),1227 (s),1075 (s),850 (s),
743 cmꢀ1 (s); HR-MS (ESI): m/z: calcd for C35H60O11SiNa: 707.3803;
found 707.3777 [M+Na]+.
11.5 (3-CH3),18.0 (Si- C
A
(CH3)3),
33.6 (C-3’),37.3 (C-3),38.3 (C-1 ’’),39.2 (C-5),49.4 (2-OCH 3),56.8 (4 ’-
OCH3),58.5 (3 ’’-OCH3),69.0,69.1 (C-6,C-2 ’),69.8 (C-2 ’’),70.8 (C-5 ’),
73.0 (CH2Ph),73.7 (C-4),74.3 (C-1 ’),77.1 (C-4 ’),77.4 (C-3 ’’),101.0 (C-2),
(2R,3R,4S,5R,6R,1’R,2’S,4’S,2’’R)-2-(1’,2’-Diacetoxy-5’-hydroxy-4’-me-
thoxypentyl)-4-triethylsilyloxy-6-[2’’-{4-O-(4-O-tert-butyldimethylsilyl-3-
O-methyl-b-d-oleandropyranosyl)-3-O-triethylsilyl-l-olivomycopyrano-
syl}-3’’-methoxypropyl]-2-methoxy-3,5-dimethyl-2,3,5,6-tetrahydro-4H-
pyran (50): Glycosylation: Disaccharide glycosyldonor 20 (289 mg,
559 mmol) and glycosylacceptor 49 (322 mg,470 mmol) were combined
and azeotroped with toluene (3”5 mL). The mixture was dissolved in
CH2Cl2 (10 mL). MS 4 Š (1.4 g,powder) was added and the suspension
was stirred for 1 h at 208C. The mixture was cooled to 08C and NIS
(190 mg,844 mmol) was added in one portion. The mixture was allowed
to warm to 208C and was stirred for 72 h. The mixture was filtered over
pad of Celite and washed with MTBE (50 mL). NaHCO3 (15 mL) and
Na2S2O3 (3 g) were added and the mixture was stirred for 20 min. After
separation of the layers the aqueous layer was extracted with MTBE (3”
30 mL). The combined organic layers were washed with brine (50 mL),
dried with MgSO4,concentrated and filtered over 10 g silica gel with pen-
tane/MTBE 2:1. The solvents were removed and the crude glycoconju-
gate (329 mg,248 mmol,53%) so obtained was used for the next step
without further purification.
127.3,127.4,128.1,138.0 (Ph),169.7,169.8 (2 OAc); HR-MS (FAB):
m/z:
calcd for C38H68O11Si2Na: 779.4191; found 779.4189 [M+Na]+.
(2R,3R,4S,5R,6R,1’R,2’S,4’S,2’’R)-2-(1’,2’-Diacetoxy-5’-benzyloxy-4’-me-
thoxypentyl)-4-hydroxy-6-(2’’-hydroxy-3’’-methoxypropyl)-2-methoxy-3,5-
dimethyl-2,3,5,6-tetrahydro-4H-pyran (48): Disilyl ether 47 (2.0 g,
2.9 mmol) was dissolved in THF (30 mL) and cooled to 08C. TBAF
(2.75 g,8.7 mmol) was added and the cooling bath was removed. After
stirring for 16 h,phosphate buffer (30 mL,1 m,pH 7) was added and
aqueous layer was extracted with AcOEt (3”30 mL). The combined or-
ganic layers were washed with brine (50 mL),dried with MgSO 4,concen-
trated and the residue was purified by flash chromatography (40 g silica
gel,CHCl /MeOH 9:1) to yield diol 48 (1.61 g,2.82 mmol,97%) as a col-
3
orless oil. Rf =0.41 (CHCl3/MeOH 9:1); [a]2D1 =+37.4 (c=0.90,CHCl 3);
1H NMR (300 MHz,CDCl 3): d=0.77 (d, J=6.6 Hz,3H,5-CH 3),1.04 (d,
J=6.6 Hz,3H,3-CH 3),1.14–1.30 (m,1H,1 ’’-H),1.44–1.66 (m,1H,1 ’’-H,
3’-H),1.47 (d, J=5.5 Hz,1H,OH),1.67–1.82 (m,2H,3-H,5-H),1.85–
1.97 (m,1H,3 ’-H),1.94,2.01 (2s,6H,OAc),2.25 (d,
OH),3.05 (s,3H,OCH 3),3.06–3.21 (m,2H,4 ’-H,3 ’’-H),3.22–3.30 (m,
1H,3 ’’-H),3.27,3.29 (2s,6H,OCH 3),3.34 (dd, J=10.3,5.6 Hz,1H,5 ’-
H),3.40 (dd, J=10.3,4.3 Hz,1H,5 ’-H),3.71 (dt, J=10.4,5.1 Hz,1H,4-
J=3.3 Hz,1H,2 ’’-
Iodide reduction: The crude iodide was dissolved in toluene (10 mL) and
Bu3SnH (660 mL,2.50 mmol) was added. The mixture was degassed by
FTP (freeze/thaw process) and heated to 1008C. AIBN (41 mg,
0.25 mmol) was added in one portion and the mixture was stirred for
15 min. After cooling the solvent was removed in vacuo and the residue
was filtered over silica gel (10 g) with pentane/MTBE 50:1!3:1.
Fluoride washing: The solvents were removed and the residue was dis-
solved in Et2O (2.5 mL) and 1m KF (2.5 mL) was added. After 3 h the
mixture was filtered over pad of celite and washed with Et2O (15 mL).
The aqueous layer was extracted with MTBE (2”10 mL). The combined
H),3.83–3.98 (m,2H,2
’’-H,6-H),4.44 (s,2H,CH
2Ph),4.97 (d, J=
5.3 Hz,1H,1 ’-H),5.32–5.40 (m,1H,2
’-H),7.15–7.31 (m,5H,Ph);
13C NMR (75.5 MHz,CDCl 3): d=5.0 (5-CH3),10.7 (3-CH 3),20.89,20.92
(OAc),35.8 (C-3 ’),36.2 (C-1 ’’),36.5 (C-3),38.5 (C-5),47.8 (2-OCH 3),
58.1,58.9 (4 ’-OCH3, 3’’-OCH3),66.6 (C-2 ’’),67.8 (C-6),68.8 (C-2 ’),71.9
(C-5’),72.3 (C-4),72.9 (C-1 ’),73.3 ( CH2Ph),100.5 (C-2),127.49,127.54,
128.3,138.2 (Ph),169.8,170.1 (OAc); IR (film):
n˜ =3468 (brs),2926 (s),
ꢀ1
1744 (s),1459 (m),1229 (s),1099 (s),1048 (s),1026 (m),738 cm
(m);
organic layers were washed with brine (10 mL),dried with MgSO and
concentrated.
HR-MS (FAB): m/z: calcd for C29H46O11Na: 593.2938; found 593.2933
4
[M+Na]+.
Benzylether celavage: The crude product (288 mg,240 mmol,96%) was
dissolved in AcOEt/MeOH (14 mL,1:1). Ammonium formiate (66 mg,
1.0 mmol) and Pd(OH)2/C (250 mg,420 mmol) were added and the mix-
ture was stirred at 208C under a hydrogen atmosphere. The reaction was
followed by TLC (n-hexane/MTBE 1:2). After 1 h,125 mg of the catalyst
was added and the mixture was stirred for further 4 h. The mixture was
filtered over a pad of celite and the solvents were removed in vacuo. The
residue was purified by flash chromatography (25 g silica gel,pentane/
(2R,3R,4S,5R,6R,1’R,2’S,4’S,2’’R)-2-(1’,2’-Diacetoxy-5’-benzyloxy-4’-me-
thoxypentyl)-4-triethylsilyloxy-6-(2’’-hydroxy-3’’-methoxypropyl)-2-me-
thoxy-3,5-dimethyl-2,3,5,6-tetrahydro-4H-pyran (49): Diol 48 (813 mg,
1.42 mmol) was dissolved in CH2Cl2 (50 mL) and cooled to 08C. Imida-
zole (970 mg,14.2 mmol) and TESCl (1.2 mL,7.1 mmol) were added.
After 1 h stirring at 08C,MTBE (100 mL) and NaHCO (100 mL) were
3
added. The two layers were separated and the aqueous layer was extract-
ed with MTBE (3”80 mL). The combined organic layers were dried with
Chem. Eur. J. 2006, 12,7378 – 7397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
7391

U. Koert et al.
MTBE 2:3) to yield alcohol 50 (175 mg,157 mmol,76%) as a colorless
oil. Rf =0.42 (n-hexane/MTBE 1:4); [a]1D9 =ꢀ8.0 (c=1.13,CHCl 3);
1H NMR (500 MHz,C 6D6): d=0.12,0.20 (2s,6H,SiCH 3),0.53–0.63 (m,
heated to 408C and stirred for 16 h. After cooling MTBE (8 mL) was
added and the mixture was filtered over a pad of Celite. The solvents
were removed in vacuo and the residue was purified by flash chromatog-
raphy (12 g silica gel,neutral,pentane/MTBE 2:1) to yield triol
52
12H,2”SiC H2CH3),0.95–1.02 (m,27H,2”SiCH 2CH3,SiC (CH3)3),1.17
A
(84 mg,61 mmol,86%) as a colorless oil. Furthermore diacetate (10 mg,
7.0 mmol,10%) could be recovered. Rf =0.18 (n-hexane/MTBE 1:1);
[a]2D0 =ꢀ8.1 (c=0.80,CHCl 3); 1H NMR (500 MHz,C 6D6): d=0.12,0.21
(2s,6H,SiCH 3),0.55–0.64 (m,12H,SiC H2CH3),0.92–1.04 (m,42H,Sn-
(d, J=7.0 Hz,3H,5-CH 3),1.40 (d, J=6.0 Hz,3H,6-H olean.),1.50 (d,
J=6.6 Hz,3H,3-CH 3),1.60–1.67 (m,2H,5 ’-OH,2-H olean.),1.67–1.86
3
(m,3H,1 ’’-H,3 ’-H,5-H),1.69 (d, J=6.0 Hz,3H,6-H
olivo.),1.72 (s,
3
3H,3-CH olivo),1.74,1.78 (2s,6H,OAc),1.93 (dd,
J=12.7,4.1 Hz,
3
A
ACHTREUNG
1H,2-H olivo),2.01 (ddd, J=14.4,9.5,3.6 Hz,1H,1
13.0 Hz,1H,2-H olivo.),2.20–2.28 (m,1H,3-H),2.33 (ddd,
’’-H),2.07 (d, J=
J=14.5,9.1,
AHCTREUNG
AHCTREUNG
4.2 Hz,1H,3 ’-H),2.58 (ddd, J=12.3,4.7,1.4 Hz,1H,2-H olean.),3.11,
3.13 (2s,6H,2”OCH 3),3.15–3.24 (m,2H,4 ’-H,3-H-olean),3.19,3.28
(2s,6H,OCH 3),3.31 (dd, J=8.4,8.4 Hz,1H,4-H olean),3.33–3.43 (m,
2H,5 ’-H,5-H olean),3.45–3.51 (m,2H,3 ’’-H2),3.55–3.61 (m,1H,5 ’-H),
3
2.05–2.10 (m,1H,6-OH),2.12 (d,
J=12.6 Hz,1H,2-H olivo),2.37–2.46
(m,2H,4-H,3
’-H),2.48–2.57 (m,1H,4-H),2.60 (ddd, J=12.4,4.8,
3.73 (d, J=9.9 Hz,1H,4-H olivo.),3.87–3.93 (m,1H,2
’’-H),4.03–4.10
1.7 Hz,1H,2-H olean.),2.66 (d,
1H,9-OH),3.12,3.13 (2s,6H,OCH
1H,3-H olean),3.25,3.27 (2s,6H,OCH
olean),3.37–3.46 (m,3H,3 ’’-H,7-H,5-H olean),3.46 (dd, J=9.4,4.6 Hz,
1H,3 ’’-H),3.62 (dd, J=5.5,2.8 Hz,1H,10-H),3.60–3.66 (m,1H,6-H),
3.75 (d, J=9.9 Hz,1H,4-H olivo),3.89–3.95 (m,1H,2
J=5.5 Hz,1H,10-OH),3.08–3.14 (m,
3),3.19 (ddd, J=11.5,8.3,4.9 Hz,
(m,3H,6-H,4-H,5-H olivo),4.92 (d,
(dd, J=9.8,1.4 Hz,1H,1-H olean.),5.43 (d,
J=4.0 Hz,1H,1-H olivo.),5.12
J=5.8 Hz,1H,1 ’’-H),5.43
(d, J=5.0 Hz,1H,1 ’-H),5.77–5.83 (m,1H,2 ’-H); 13C NMR (125.8 MHz,
C6D6): d=ꢀ4.6, ꢀ3.6 (SiCH3),5.4 (Si CH2CH3),5.6 (5-CH 3),7.2,7.27,
3),3.31 (t, J=8.6 Hz,1H,4-H
7.34 (2”SiCH2CH3,Si CH2CH3),11.7 (3-CH 3),18.6 (Si C(CH3)3),18.9,
A
’’-H),4.01–4.10
J=
J=9.7,1.7 Hz,1H,1-H olean),5.74–
19.0 (C-6 olean,C-6 olivo),20.50,20.53 (2xOAc),24.0 (3-CH 3 olivo),26.3
(SiC(CH3)3),35.90,35.93 (C-1 ’’,C-3 ’),36.4 (C-2 olean),37.4 (C-3),40.3
(C-5),45.8 (C-2 olivo),48.1 (2-OCH 3),55.6,57.5,58.9 (3”OCH 3),63.6
(C-5’),66.9 (C-6),69.28,69.34 (C-2 ’,C-5 olivo.),73.1,73.2 (C-1 ’,C-5
(m,3H,6 ’-H,4 ’-H,5-H olivo),4.23–4.29 (m,1H,9-H),5.00 (d,
ACHTREUNG
4.1 Hz,1H,1-H olivo),5.12 (dd,
5.93 (m,1H,3-H); 13C NMR (125.8 MHz,C 6D6): d=ꢀ4.6, ꢀ3.6 (SiCH3),
5.5 (SiCH2CH3),5.8 5 ’-CH3),7.2,7.3,7.4 (2”SiCH 2CH3,Si CH2CH3),9.5
olean),73.6 (C-4),75.1 (C-2 ’’),75.5 (C-3 ’’),76.2 (C-3 olivo),77.5 (C-4
olean),78.4 (C-3 olean),81.8 (C-4 ’),85.5 (C-4 olivo),97.1 (C-1 olivo.),
101.1 (C-1 olean),101.5 (C-2),169.4,169.6 (2”OAc); IR (film): n˜ =3470
(brs),2984 (s),2959 (s),2876 (s),1751 (s),1737 (s),1468 (s),1373 (s),
1272 (s),1250 (s),1167 (s),1124 (s),875 (s),836 (s),759 cm
(SnCH2C3H7),12.4 (3 ’-CH3),13.9 (Sn
18.9 (C-6 olean,C-6 olivo.),19.4 (C-1),23.9 (3-CH
26.3 (SiC(CH3)3),27.8,29.7 (SnCH 2C2H4CH3),33.5 (C-5),36.1,36.4,
A
N
3
AHCTREUNG
ꢀ1
36.77,36.80 (C-8,C-3 ’,C-1 ’’,C-2 olean),40.3 (C-5 ’),45.8 (C-2 olivo),48.3
(2’-OCH3),55.7,58.8,59.0 (3”OCH 3),66.9 (C-5 olivo),67.9 (C-9),69.3
(C-6’),72.9 (C-6),73.1 (C-5 olean),73.8 (C-4 ’),75.0 (C-2 ’’),75.4 (C-10),
75.6 (C-3’’),76.1 (C-3 olivo),77.5 (C-4 olean),81.8 (C-3 olean),82.2 (C-
(s); HR-
MS (ESI): m/z: calcd for C54H106O17Si3Na: 1133.6636; found 1133.6650
[M+Na]+.
(2E,6S,7S,9S,10R,2’R,3’R,4’S,5’R,6’R,2’’R)-10-[6’-{2’’-(4-O-(4-O-tert-bu-
tyldimethylsilyl-3-O-methyl-b-d-oleandropyranosyl)-3-O-triethylsilyl-l-
olivomycopyranosyl)-3’’-methoxypropyl}-4’-triethylsilyloxy-2’-methoxy-
3’,5’-dimethyl-2’,3’,5’,6’-tetrahydro-4H-pyran-2’-yl]-6,9,10-trihydroxy-7-
methoxy-2-tri-n-butylstannyl-dec-2-ene (52): Dess–Martin oxidation:
Dess–Martin periodinane (430 mg,1.01 mmol) was dissolved in CH2Cl2
(4 mL) and pyridine (250 mL,3.07 mmol) was added at 20 8C. 1.4 mL of
this stock solution were added to alcohol 50 (128 mg,115 mmol) in
CH2Cl2 (2 mL) at 208C. After 1 h the mixture was quenched with
NaHCO3 (7 mL). Water (3 mL),Na 2S2O3 (1 g),MTBE (7 mL) were
added,the two layers were separated and the aqueous layer was extract-
ed with MTBE (3”10 mL). The combined organic layers were washed
with brine (10 mL),dried with MgSO 4,concentrated and the residue was
purified by flash chromatography (15 g silica gel,pentane/MTBE 3:1 !
1:1) to yield the corresponding aldehyde (107 mg,96 mmol,84%) as a
colorless oil.
7),85.4 (C-4 olivo),97.2 (C-1 olivo.),101.1 (C-1 olean),103.1 (C-2
138.4 (C-2),141.5 (C-3); IR (film): n˜ =3461 (brs),2980 (s),2957 (s),2873
(s),2848 (s),1461 (s),1378 (s),1244 (s),1193 (s),1119 (s),874 (s),
837 cmꢀ1 (s); HR-MS (ESI): m/z: calcd for C67H136O15Si3SnNa: 1407.8107;
found 1407.8069 [M+Na]+.
’),
(2E,4E,6E,10E,12E,8R,9R,16S,17S,19S,20R,2’R,3’R,4’S,5’R,6’R,2’’R)-20-
[6’-{2’’-(4-O-(4-O-tert-butyldimethylsilyl-3-O-methyl-b-d-oleandropyrano-
syl)-3-O-triethylsilyl-l-olivomycopyranosyl)-3’’-methoxypropyl}-4’-tri-
ethylsilyoxy-2’-methoxy-3’,5’-dimethyl-2’,3’,5’,6’-tetrahydro-4H-pyran-2’-
yl]-7-[6-deoxy-4-O-methyl-2,3-O-di(triethylsilyl)-a-l-glucopyranosyl]-
16,19,20-trihydroxy-17-methoxy-2,4,6,8,12-pentamethyl-2,4,6,10,12-eicosa-
pentaene acid (54): Cross-coupling: Alkenyl stannane 52 (95 mg,
69 mmol) and alkenyl iodide 43 (72 mg,89 mmol) were combined and
azeotroped with toluene (3”5 mL). After drying under high vacuum for
1 h,the mixture was dissolved in N-methylpyrrolidinone (1.5 mL) and
was degassed by FTP (freeze thaw process). The solution was cooled to
ꢀ58C,CuTC (40 mg,0.21 mmol) was added and the mixture was allowed
to warm to 08C within 90 min. MTBE (5 mL) was added,the mixture
was filtered over a pad of Celite and washed with MTBE (30 mL). The
solvents were removed in vacuo and the residue was azeotroped with tol-
uene (3”6 mL). The residue was dissolved in Et2O (2 mL) and 1m KF
(2 mL) was added. After 2.5 h the mixture was filtered over pad of celite
and washed with Et2O (40 mL). The organic layer was washed with brine
(10 mL),dried with Na 2SO4 and concentrated. The residue was purified
by flash chromatography (10 g silica gel,pentane/MTBE 1:1 !1:3!1:5)
to yield coupling product 53 (109 mg,61.5 mmol,89%) as a colorless
foam. The cyanomethyl ester was used directly for the following ester hy-
drolysis.
Grignard addition: Magnesium turnings (48 mg,2.0 mmol) were dried
under vacuum at 1008C with stirring. After cooling the flask was flushed
with argon and Et2O (1 mL,fresh distilled from K/Na) was added. Bro-
mide 51 (438 mg,1.00 mmol) was azeotroped with toluene (3”5 mL) and
dissolved in Et2O (1 mL). Dibromoethane (90 mL,1.0 mmol) was added
and the mixed bromides were slowly added to the magnesium turnings at
208C. After complete addition,the mixture was stirred for 1 h and the
volume was determined via syringe. Part of stock solution (1.3 mL,
0.68 mmol,7 equiv) was placed in 25 mL nitrogen flask. Et O (3 mL) was
2
added and the reaction was cooled to ꢀ788C. The aldehyde (107 mg,
96 mmol) was azeotroped with toluene (3”5 mL),dissolved in Et 2O
(1 mL) and slowly added to the Grignard solution. After 3 h stirring at
ꢀ788C the reaction was quenched with iPrOH (1 mL). The cooling bath
was removed,NH 4Cl (10 mL) was added and the aqueous layer was ex-
tracted with MTBE (3”15 mL). The combined organic layers were
Ester hydrolysis: To cyanomethyl ester 53 (100 mg,56.4 mmol) in THF
(3.9 mL) and water (1.3 mL) was added at 08C LiOH·H2O (7.0 mg,
0.17 mmol). After 3 h at 208C the reaction was quenched by addition of
phosphate buffer (5 mL,1 m,pH 7). The aqueous layer was extracted
with AcOEt (4”20 mL). The combined organic layers were washed with
brine (20 mL) and dried with Na2SO4. Chromatography (10 g silica gel,
pentane/MTBE 1:1 ! 1:7) gave trihydroxy acid 54 (85 mg,49 mmol,
88%) as a colorless oil. Rf =0.59 (CHCl3/MeOH 10:1); [a]2D0 =ꢀ5.4 (c=
0.70,CHCl 3); 1H NMR (500 MHz,C 6D6): d=0.13,0.22 (2s,6H,SiCH 3),
washed with brine (20 mL),dried with MgSO ,concentrated and the resi-
4
due was purified by flash chromatography (12 g silica gel,neutral,pen-
tane/MTBE 3:1
71 mmol,74%) as a colorless oil ( Rf =0.49,MTBE/ n-hexane 1:1).
!
1:1) to yield the bis(acetoxy) alcohol (104 mg,
A
Acetate cleavage: KCN (120 mg,1.8 mmol) at 20 8C was added to a solu-
tion of diacetate (104 mg,71 mmol) in MeOH (4 mL). The mixture was
7392
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,7378 – 7397

Total Synthesis of Apoptolidin A
FULL PAPER
0.56–0.65 (m,12H,SiC H2CH3),0.71 (q, J=8.0 Hz,6H,SiC H2CH3),0.89
4.8 Hz,1H,3 ’’’-H),3.26 (2s,6H,OCH 3),3.32 (t, J=8.6 Hz,1H,4 ’’’-H),
3.35 (s,3H,OCH 3),3.38–3.44 (m,1H,5 ’’’-H),3.45–3.55 (m,3H,16-H,
28-H2),3.73 (dd, J=9.3,3.5 Hz,1H,2 ’-H),3.76 (d, J=9.9 Hz,1H,4 ’’-H),
(q, J=8.2 Hz,6H,SiC
H2CH3),0.97–1.04 (m,27H,SiC
A
SiCH2CH3),1.08 (t, J=8.0 Hz,SiCH 2CH3),1.13 (d, J=6.8 Hz,3H,5 ’-
CH3),1.15–1.22 (m,12H,SiCH 2CH3,8-CH 3),1.38 (d, J=6.3 Hz,3H,6-
H3 gluco),1.40 (d, J=6.3 Hz,3H,3 ’-CH3),1.41 (d, J=5.8 Hz,3H,6-H
3.89 (t, J=4.7 Hz,1H,20-H),3.96 (dd,
J=9.1,9.8 Hz,1H,9-H),3.95–
’-H),4.08–4.15 (m,3H,23-H,25-
4.01 (m,1H,27-H),4.01–4.06 (m,1H,5
3
olean),1.49–1.58 (m,2H,15-H 2),1.62–1.75 (m,2H,1 ’’-H,2-H olean),
H,5 ’’-H),4.28 (t, J=9.1 Hz,1H,3 ’-H),5.02–5.06 (m,2H,7-H,1
’’-H),
1.64 (s,3H,6-CH 3),1.70 (d, J=6.1 Hz,3H,6-H
olivo),1.73 (s,3H,3-
5.08 (d, J=3.4 Hz,1H,1 ’-H),5.13 (dd, J=9.7,1.7 Hz,1H,1 ’’’-H),5.32
(dd, J=15.7,9.1 Hz,1H,10-H),5.53–5.59 (m,1H,13-H),5.89–5.95 (m,
1H,19-H),6.12 (d, J=15.6 Hz,1H,11-H),6.18 (s,1H,5-H),7.56 (s,1H,
3-H); 13C NMR (125.8 MHz,C 6D6): d=ꢀ4.6, ꢀ3.6 (SiCH3),5.4,5.6 (2”
SiCH2CH3),5.9 (2C,24-CH 3,Si CH2CH3),7.2,7.26,7.30,7.36,7.43 (4”
SiCH2CH3,Si CH2CH3),11.7,11.8 (12-CH 3,22-CH 3),14.2 (2-CH 3),16.0
3
CH3 olivo),1.76–1.90 (m,2H,18-H,5
3H,4-CH 3),1.92–2.02 (m,3H,18-H,1
’-H),1.86 (s,3H,12-CH 3),1.88 (s,
’’-H,2-H olivo),2.09 (s,3H,2-
CH3),2.13 (d, J=13.0 Hz,1H,2-H olivo),2.23–2.34 (m,1H,14-H),2.40–
2.51 (m,2H,14-H,3 ’-H),2.60 (ddd, J=12.2,4.6,1.1 Hz,1H,2-H olean),
2.70 (t, J=9.1 Hz,1H,4-H gluco),2.78–2.87 (m,1H,8-H),3.12,3.14 (2s,
6H,OCH 3),3.16–3.24 (m,1H,3-H olean),3.30 (2”s,6H,OCH
3),3.28–
(6-CH3),17.4 (4-CH ),18.4 (8-CH ),18.6 (Si C
ACHTREUNG
3
3
3.34 (m,1H,4-H olean.),3.36 (s,3H,OCH
3),3.38–3.44 (m,3H,17-H,
ACHTREUNG
3’’-H,5-H olean),3.48 (dd, J=9.4,4.4 Hz,1H,3 ’’-H),3.52–3.58 (m,1H,
16-H),3.66 (d, J=2.3 Hz,1H,20-H),3.70 (dd,
gluco),3.75 (d, J=9.8 Hz,1H,4-H olivo.),3.92–4.00 (m,2H,2
gluco),4.01–4.14 (m,4H,4 ’-H,6 ’-H,9-H,5-H olivo.),4.22 (t, J=9.0 Hz,
J=9.3,3.3 Hz,1H,2-H
24),45.8 (C-2 ’’),47.8 (21-OCH 3),55.6,58.8,60.3,61.0 (OCH
3),66.9 (C-
’’-H,5-H
5’’),67.9 (C-5 ’),69.4 (C-25),72.2 (C-19),73.1 (C-5 ’’’),73.3 (C-23),74.1
(C-16),74.75,74.82,74.91 (C-2 ’,C-3 ’,C-27),75.6 (C-28),75.9 (C-20),76.2
(C-3’’),77.5 (C-4 ’’’),81.8 (C-3 ’’’),82.3 (C-17),82.6 (C-9),85.5 (C-4 ’’),87.9
(C-4’),95.8 (C-1 ’),97.0 (C-1 ’’),101.1 (C-1 ’’’),102.2 (C-21),124.1 (C-2),
125.6 (C-10),132.1,132.4,133.5 (C-4,C-6,C-12),133.3 (C-13),140.5 (C-
1H,3-H gluco),4.26–4.32 (m,1H,19-H),5.03 (d,
gluco),5.06 (d, J=4.0 Hz,1H,1-H olivo.),5.13 (dd,
J=3.1 Hz,1H,1-H
J=9.8,1.1 Hz,1H,
1-H olean),5.32 (d, J=9.5 Hz,1H,7-H),5.50–5.58 (m,2H,10-H,13-H),
5.96 (s,1H,5-H),6.34 (d,
J=15.8 Hz,1H,11-H),7.50 (s,1H,3-H);
11),141.2 (C-7),144.9 (C-5),146.0 (C-3),169.8 (C-1); IR (film):
n˜ =3500
13C NMR (125.8 MHz,C 6D6): d=ꢀ4.6, ꢀ3.6 (SiCH3),5.5,5.6 (2”
SiCH2CH3),5.8 (5 ’-CH3),5.9 (Si CH2CH3),7.25 (2”SiCH 2CH3),7.3
(brm),2979 (s),2955 (s),2931 (s),2852 (s),1702 (s),1460 (s),1382 (s),
ꢀ1
1241 (s),1169 (s),1115 (s),1070 (s),841 (s),761 cm
(s); HR-MS (ESI):
(SiCH2CH3),7.36,7.44 (2”SiCH 2CH3),12.4 (12-CH ),12.5 (3 ’-CH3),14.1
m/z: calcd for C89H168O21Si5Na: 1736.0822; found 1736.0889 [M+Na]+.
3
(2-CH3),17.3,17.4 (8-CH 3,6-CH 3),18.4 (4-CH 3),18.6 (Si C
18.85,18.94 (C-6 gluco,C-6 olean.,C-6 olivo.),23.9 (3-CH
ACHTREUNG
21-O-Methylapoptolidin A (56): A HF·pyridine stock solution was pre-
pared by mixing at 08C HF·pyridine (0.8 mL,70% HF),THF (10 mL)
and pyridine (4 mL). To macrolactone 55 (24 mg,14 mmol) in THF
(4 mL) was added at 08C an aliquot of the HF·pyridine stock solution
(3 mL). After 24 h at 208C,the reaction mixture was cooled to 0 8C and
an aliquot of the HF·pyridine stock solution (0.5 mL) was added. This ad-
3
(C-14),26.3 (SiC
(C-3’),37.0 (C-1 ’’),38.8 (C-8),40.4 (C-5 ’),45.8 (C-2 olivo),48.5 (2 ’-
OCH3),55.7,58.9,59.2,61.0 (OCH 3),67.0 (C-5 olivo),67.8 (C-19),67.9
A
(C-5 gluco),69.3 (C-6 ’),72.9 (C-16),73.1 (C-5 olean),73.9 (C-4 ’),74.8
(2C,(C-2,C-3)-gluco),75.1 (C-2 ’’),75.4 (C-20),75.6 (C-3 ’’),76.1 (C-3
olivo),77.5 (C-4 olean),80.5 (C-9),81.8 (C-3 olean),82.3 (C-17),85.4 (C-
4 olivo),87.9 (C-4 gluco),95.2 (C-1 gluco),97.4 (C-1 olivo),101.1 (C-1
olean.),103.2 (C-2 ’),124.5 (C-10),125.4 (C-2),132.0,132.5,133.2 (C-4,
C-6,C-12),134.0 (C-13),135.0 (C-7),140.1 (C-5),140.6 (C-11),146.0 (C-
3),173.3 (C-1); IR (film): n˜ =3456 (brs),2981 (s),2958 (s),2875 (s),2853
(s),1680 (s),1462 (s),1380 (s),1241 (s),1067 (s),1003 (s),874 (s),
841 cmꢀ1 (s); HR-MS (ESI): m/z: calcd for C89H170O22Si5K: 1770.0667;
found 1770.0673 [M+K]+.
dition was repeated daily. After 6 d,NaHCO (10 mL) was added. The
3
aqueous layer was extracted with AcOEt (4”15 mL). The combined or-
ganic layers were washed subsequently with NaHSO4 (2”15 mL,0.5 m),
NaHCO3 (10 mL),and brine (20 mL) and dried with MgSO . Chromatog-
4
raphy (2 g silica gel,CH 2Cl2/MeOH 20:1,TLC control: MTBE/AcOEt/
CH2Cl2/MeOH 4:4:4:1) gave 21-O-methylapoptolidin (56) (6.0 mg,
5.2 mmol,38%).
Rf =0.15 (MTBE/AcOEt/CH2Cl2/MeOH 4:4:4:1);
HPLC: tR =13.6 min (Dynamax C18,A: H O,B: MeOH,70 !100% B in
2
25 min,0.7 mLmin ꢀ1,30 8C); [a]D20 =ꢀ76 (c=0.55,CHCl 3); 1H NMR
(500 MHz,CD 3OD): d=0.93 (d, J=7.1 Hz,3H,24-CH 3),1.11 (d, J=
6.6 Hz,3H,22-CH 3),1.14 (d, J=6.6 Hz,3H,8-CH 3),1.22 (d, J=6.4 Hz,
3H,6 ’’-H3),1.25 (d, J=6.2 Hz,3H,6 ’-H3),1.28 (d, J=6.2 Hz,3H,6 ’’’-
4’’’-O-tert-Butyldimethylsilyl-21-O-methyl-23O,2’O,3’O,3’’O-tetrakis(tri-
ethylsilyl)apoptolidin A (55): Et3N (2.29 mL, 2.1 mmol) and 2,4,6-tri-
chlorobenzoyl chloride (0.16 mL,1 mmol) were added subsequently at
08C to trihydroxycarboxylic acid 54 (85 mg,49 mmol) dissolved in THF
(6 mL). After 5 h at 208C,toluene (6 mL) was added. This solution was
added within 1 h to DMAP (508 mg,4.2 mmol) in toluene (150 mL). The
reaction mixture was stirred for 18 h at 208C. NH4Cl (60 mL) was added.
The aqueous layer was extracted with MTBE (3”50 mL). The combined
H3),1.24–1.37 (m,2H,15-H,2
’’’-H),1.35 (s,3H,3 ’’-CH3),1.40–1.47 (m,
1H,15-H),1.58 (ddd, J=14.7,7.3,3.2 Hz,1H,26-H),1.67 (s,3H,12-
CH3),1.73–1.86 (m,4H,22-H,24-H,26-H,2
’’-H),1.87–1.94 (m,3H,2 ’’-
H,18-H 2),1.90 (s,3H,6-CH 3),1.94–2.03 (m,1H,14-H),2.08 (s,3H,2-
CH3),2.14 (s,3H,4-CH 3),2.44 (ddd, J=12.2,5.0,1.9 Hz,1H,2
’’’-H),
organic layers were washed with NaHSO4 (50 mL; 1m),NaHCO
2.47–2.54 (m,1H,14-H),2.64–2.69 (m,1H,17-H),2.72 (t,
4’-H),2.68–2.79 (m,1H,8-H),2.97 (t, J=9.1 Hz,1H,4 ’’’-H),3.14–3.24
(m,2H,3 ’’’-H,5 ’’’-H),3.25 (s,3H,OCH 3),3.34 (d, J=9.6 Hz,1H,4 ’’-H),
3.34–3.37 (m,1H,16-H),3.39 (dd, J=9.7,3.8 Hz,1H,2 ’-H),3.43,3.44
(2s,6H,OCH 3),3.47 (dd, J=10.1,5.0 Hz,1H,28-H),3.53 (dd, J=10.1,
J=9.2 Hz,1H,
3
(50 mL),and brine (50 mL) and dried with MgSO 4. Chromatography
(10 g silica gel,cyclohexane/AcOEt 5:1 !2:1) gave macrolactone 55
(52 mg,30 mmol,62%) as a colorless oil. Further elution of the column
with CH2Cl2/MeOH 20:1 provided recovered starting material 54 (11 mg,
6.4 mmol,13%). Rf =0.44 (n-hexane/MTBE 1:1); [a]2D0 =ꢀ41.1 (c=0.85,
CHCl3); 1H NMR (500 MHz,C 6D6): d=0.12,0.21 (2s,6H,SiCH 3),0.55–
0.63 (m,12H,SiC H2CH3),0.71 (q, J=7.8 Hz,6H,SiC H2CH3),0.91 (q,
4.6 Hz,1H,28-H),3.58 (s,3H,OCH
3),3.68–3.77 (m,5H,20-H,23-H,3
’-
H,5 ’-H,5 ’’-H),3.78–3.88 (m,3H,9-H,25-H,27-H),4.81 (d,
J=3.9 Hz,
1H,1 ’-H),4.82–4.85 (1H,1 ’’’-H,covered by H 2O signal),4.95 (d, J=
4.1 Hz,1H,1 ’’-H),5.16 (d, J=10.5 Hz,1H,7-H),5.22 (dd, J=15.8,
9.2 Hz,1H,10-H),5.46–5.52 (m,1H,19-H),5.63 (dd, J=9.9,6.6 Hz,1H,
13-H),6.12 (s,1H,5-H),6.15 (d, J=15.8 Hz,1H,11-H),7.28 (s,1H,3-
J=7.8 Hz,6H,SiC
SiCH2CH3),1.06 (t,
H2CH3),0.95–1.03 (m,27H,SiC
J=7.8 Hz,SiCH 2CH3),1.18 (t,
ACHTREUNG
SiCH2CH3),1.22 (d, J=6.6 Hz,3H,8-CH 3),1.28 (d, J=6.9 Hz,3H,24-
CH3),1.41–1.51 (m,2H,15-H 2),1.41 (d, J=5.9 Hz,3H,6 ’’’-H3),1.42 (d,
J=6.0 Hz,3H,6 ’-CH3),1.53 (d, J=6.7 Hz,3H,22-H 3),1.58 (s,3H,6-
H); 13C NMR (125.8 MHz,CD 3OD): d=5.8 (24-CH3),11.5 (22-CH 3),
12.0 (12-CH3),14.3 (2-CH 3),16.7 (6-CH 3),18.0 (4-CH 3),18.25,18.32,
18.35 (8-CH3,C-6 ’,C-6 ’’’),18.9 (C-6 ’’),22.9 (3 ’’-CH3),25.2 (C-14),36.0,
36.1 (C-15,C-26),37.18,37.24 (C-22,C-2 ’’’),38.9 (C-8),39.5 (C-18),40.4
CH3),1.63–1.78 (m,2H,26-H,2
6.5 Hz,3H,6 ’’-H3),1.75 (s,3H,3 ’’-CH3),1.80 (s,3H,4-CH 3),1.84–1.91
(m,1H,24-H),1.98 (dd, J=12.7,4.8 Hz,1H,2 ’’-H),2.02–2.16 (m,3H,
14-H,26-H,2 ’’-H),2.11 (s,3H,2-CH 3),2.20–2.29 (m,2H,18-H,22-H),
2.34 (dd, J=14.3,8.5 Hz,1H,18-H),2.43 (d, J=4.3 Hz,1H,20-OH),
J=12.6,4.8,1.5 Hz,1H,2 ’’’-H),
J=9.0 Hz,1H,4 ’-H),3.04 (dd, J=8.4,
’’’-H),1.69 (s,3H,12-CH 3),1.71 (d, J=
(C-24),45.5 (C-2 ’’),48.1 (21-OCH 3),57.3,59.4,60.96,61.04 (4”OCH
3),
67.6 (C-5’’),68.2 (C-5 ’),70.2 (C-25),72.7 (C-19),73.1 (C-3 ’’),73.2 (2C,C-
23,C-5 ’’’),73.7 (C-2 ’),74.9 (C-3 ’),75.5,75.6 (C-16,C-20),75.9 (C-27),
76.6 (C-28),77.2 (C-4 ’’’),82.0 (C-3 ’’’),83.5 (C-17),84.5 (C-9),85.9 (C-4 ’’),
87.5 (C-4’),96.2 (C-1 ’),98.0 (C-1 ’’),101.9 (C-1 ’’’),102.9 (C-21),124.9 (C-
2),126.3 (C-10),133.0,132.3 (C-4,C-6),133.5 (C-13),134.5 (C-12),141.3
2.50–2.57 (m,1H,14-H),2.60 (ddd,
2.66–2.74 (m,1H,8-H),2.73 (t,
5.7 Hz,1H,17-H),3.12,3.13 (2”s,6H,OCH
3),3.20 (ddd, J=11.6,8.3,
Chem. Eur. J. 2006, 12,7378 – 7397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
7393

U. Koert et al.
(C-11),141.6 (C-7),145.0 (C-5),147.1 (C-3),170.7 (C-1); IR (film):
n˜ =
14.0 (2-CH3),16.5 (6-CH 3),17.8 (4-CH 3),18.2,18.3 (8-CH 3,C-6 ’),24.6
(C-14),36.4 (2C,C-15,C-22),38.4,38.5 (C-18,C-26),39.0 (C-8),40.8 (C-
24),59.4 (28-OCH 3),60.9 (4 ’-OCH3),61.3 (17-OCH 3),68.15,68.22 (C-27,
3445 (brs),2974 (s),2829 (s),1699 (s),1455 (s),1386 (s),1247 (s),1081
ꢀ1
(s),1014 (s),968 (s),846 (m),736 cm
(s); HR-MS (ESI): m/z: calcd for
C59H98O21Na: 1165.6498; found 1165.6470 [M+Na]+.
C-5’),69.2 (C-25),72.4 (C-19),73.7,73.8 (C-23,C-2
(C-3’),75.5 (C-20),78.7 (C-28),83.8 (C-17),84.3 (C-9),87.5 (C-4
’),74.6 (C-16),75.0
’),96.1
Apoptolin A (1) and 27-hydroxy apoptolidin A (57): H2SiF6 (3”100 mL,
aq 25–30%) was added at ꢀ408C to macrolactone 55 (41 mg,24 mmol) in
CH3CN (8 mL). After 2 d at ꢀ35 to ꢀ258C,further H 2SiF6 (150 mL,aq
25–30%) was added and the reaction mixture was stirred for 24 h at ꢀ25
to ꢀ158C. Then,the reaction mixture was stirred for 24 h at ꢀ15 to
ꢀ58C. Phosphate buffer (25 mL,pH 7,1 m) was added. The aqueous
layer was extracted with CHCl3/iPrOH (5”15 mL,5:1). The combined
org. layers were dried with Na2SO4. Chromatography (6 g neutral silica
gel,CH 2Cl2/MeOH 20:1!15:1!10:1) gave apoptolidin A (1) (19 mg,
17 mmol,71%) as a white solid. In addition,27-hydroxy apoptolidin A
(57) (5.5 mg,6.5 mmol,27%) was isolated. Apoptolidin A ( 1): M.p. 129–
(C-1’),101.3 (C-21),124.0 (C-2),126.4 (C-10),133.3 (C-13),132.2,133.4,
134.8 (C-4,C-6,C-12),141.2 (C-11),140.7 (C-7),147.0 (C-5),148.9 (C-3),
172.6 (C-1); IR (film): n˜ =3416 (brs),2978 (s),2935 (s),2842 (s),1666
(s),1598 (s),1455 (s),1389 (s),1258 (s),1084 (s),1029 (s),969 (s),
667 cmꢀ1 (s); HR-MS (ESI): m/z: calcd for C44H72O15Na: 863.4769; found
863.4769 [M+Na]+.
(2R,3R,4S,5R,6R,1’R,2’S,4’S,2’’R)-2-(1’,2’-Diacetoxy-5’-hydroxy-4’-me-
thoxypentyl)-6-(2’’-tert-butyldimethylsilyloxy-3’’-methoxypropyl)-4-tri-
ethylsilyloxy-2-methoxy-3,5-dimethyl-2,3,5,6-tetrahydro-4H-pyran
(58):
TBS protection: Imidazol (0.57 g,8.4 mmol),DMAP (51 mg,0.40 mmol)
and TBSCl (2.5 g,8.4 mmol,50% in toluene) were added subsequently
1318C (MeOH); Rf =0.12 (CHCl3/MeOH 8:1); HPLC: tR =14.3 min (Dy-
ꢀ1
namax C18,A: H 2O,B: MeOH,70 !100% B in 25 min,0.7 mLmin
,
at 08C to alcohol 49 (1.04 g,1.52 mmol) in CH Cl2 (25 mL). The reaction
2
308C); [a]2D1 =ꢀ4.4 (c=0.70,MeOH); 1H NMR (500 MHz,CD 3OD): d=
0.90 (d, J=6.7 Hz,3H,24-CH 3),1.04 (d, J=6.6 Hz,3H,22-CH 3),1.17 (d,
J=6.4 Hz,3H,8-CH 3),1.25 (d, J=6.1 Hz,3H,6 ’’-H3),1.29 (d, J=6.3 Hz,
3H,6 ’-H3),1.31 (d, J=6.1 Hz,3H,6 ’’’-H3),1.27–1.37 (m,1H,2 ’’’-H),1.35
(s,3H,3 ’’-CH3),1.40–1.57 (m,3H,15-H 2,26-H),1.58–1.65 (m,1H,26-
mixture was stirred for 14 h at 208C. The reaction was quenched by addi-
tion of MeOH (1 mL). NaHCO3 (15 mL) and MTBE (30 mL) were
added. The aqueous layer was extracted with MTBE (3”30 mL). The
combined organic layers were washed with brine (10 mL) and dried with
MgSO4. Chromatography (160 g silica gel,pentane/MTBE 3:2) gave the
corresponding TBS ether (724 mg,0.922 mmol,61%) and recovered
starting material (395 mg,0.577 mmol,38%).
H),1.71 (s,3H,12-CH 3),1.73–1.84 (m,2H,24-H,18-H),1.83 (dd,
13.5,4.2 Hz,1H,2 ’’-H),1.92–1.99 (m,1H,2 ’’-H),1.96 (s,3H,6-CH 3),
2.04–2.24 (m,3H,14-H,18-H,22-H),2.14 (s,3H,2-CH 3),2.21 (s,3H,4-
J=
Benzylether celavage: The benzylether (724 mg,922 mmol,96%) was dis-
solved in AcOEt/MeOH (5 mL,1:1). Ammonium formiate (30 mg,
1.0 mmol) and Pd(OH)2/C (150 mg,245 mmol) were added at 208C and
the mixture was stirred under a hydrogen atmosphere of 1 bar. After 5 h,
50 mg of the catalyst was added and the mixture was stirred for further
2 h. AcOEt (10 mL) was added and the mixture was filtered over a pad
of celite and the solvents were removed in vacuo. The residue was puri-
fied by chromatography (50 g silica gel,pentane/MTBE 1:1 ! 1:10) to
yield alcohol 58 (502 mg,708 mmol,77%) as a colorless oil. Rf =0.57
CH3),2.43–2.56 (m,2H,14-H,2 ’’’-H),2.72–2.84 (m,2H,17-H,8-H),2.75
(t, J=9.1 Hz,1H,4 ’-H),3.00 (t, J=8.9 Hz,1H,4 ’’’-H),3.14–3.27 (m,2H,
3’’’-H,5 ’’’-H),3.30 (s,3H,28-OCH 3),3.33–3.51 (m,5H,28-H 2, 4’’-H,16-
H,27-H),3.42 (dd, J=9.7,3.8 Hz,1H,2 ’-H),3.39 (s,3H,17-OCH 3),3.45
(s,3H,3 ’’’-OCH3),3.56 (d, J=0.9 Hz,1H,20-H),3.61 (s,3H,4
3.67–3.81 (m,4H,23-H,3 ’-H,5 ’-H,5 ’’-H),3.86 (t, J=9.2 Hz,1H,9-H),
3.96–4.02 (m,1H,25-H),4.83–4.89 (2H1, ’-H,1 ’’’-H,overlaid by H 2O
signal),4.97 (d, J=3.7 Hz,1H,1 ’’-H),5.26 (d, J=9.8 Hz,1H,7-H),5.26
(dd, J=15.8,9.2 Hz,1H,10-H),5.32 (d, J=11.3 Hz,1H,19-H),5.71 (t,
’-OCH3),
1
(CHCl3/MeOH 9:1); [a]1D9 =+47.9 (c=0.96,CHCl 3); H NMR (400 MHz,
J=7.2 Hz,1H,13-H),6.21 (d, J=16.0 Hz,1H,11-H),6.22 (s,1H,5-H),
C6D6): d=0.12,0.15 (2s,6H,SiCH 3),0.63 (q, J=7.9 Hz,6H,SiC H2CH3),
7.41 (s,1H,3-H); 13C NMR (125.8 MHz,CD OD): d=5.2 (24-CH3),12.0
3
1.00 (s,9H,SiC
7.0 Hz,3H,5-CH 3),1.51 (d, J=6.6 Hz,3H,3-CH 3),1.56–1.64 (m,1H,
1’’-H),1.65 (dd, J=6.9,5.8 Hz,1H,OH),1.72–1.82 (m,1H,3 ’-H),1.74,
1.79 (2s,6H,OAc),1.84–1.93 (m,2H,5-H,1 ’’-H),2.20–2.30 (m,1H,3-
(CH3)3),1.01 (t, J=7.9 Hz,9H,SiCH 2CH3),1.18 (d, J=
(12-CH3),12.2 (22-CH 3),14.2 (2-CH 3),16.5 (6-CH 3),17.9 (4-CH 3),18.2
(8-CH3),18.3 (2C,C-6 ’,C-6 ’’’),18.9 (C-6 ’’),22.8 (3 ’’-CH3),24.7 (C-14),
36.4,36.5 (C-15,C-22),37.2 (2C,C-26,C-2
’’’),38.4 (C-18),39.0 (C-8),
40.7 (C-24),45.5 (C-2 ’’),57.3 (3 ’’’-OCH3),59.5 (28-OCH 3),60.9 (4 ’-
H),2.28–2.37 (m,1H,3 ’-H),3.08 (s,3H,OCH 3),3.16–3.23 (m,3H,4 ’-H,
3’’-H2),3.19,3.32 (2s,6H,OCH 3),3.33–3.42 (m,1H,5 ’-H),3.55–3.62 (m,
1H,5 ’-H),4.07–4.14 (m,2H,2 ’’-H,4-H),4.16 (ddd, J=8.4,2.5,2.5 Hz,
1H,6-H),5.44 (d, J=5.1 Hz,1H,1 ’-H),5.80 (dt, J=8.6,4.5 Hz,1H,2 ’-
H); 13C NMR (100.6 MHz,C 6D6): d=ꢀ4.6, ꢀ3.4 (SiCH3),5.5
(SiCH2CH3),5.6 (5-CH 3),7.2 (SiCH 2CH3),11.7 (3-CH 3),18.5 (Si C-
OCH3),61.3 (17-OCH ),67.5 (C-5 ’’),68.2 (C-5 ’),69.4 (C-25),72.5 (C-19),
3
73.0 (C-3’’),73.2 (C-5 ’’’),73.7 (C-2 ’),73.9 (C-23),74.7 (C-16),75.0 (C-3 ’),
75.5 (C-20),76.8,76.9 (C-27,C-28),77.2 (C-4 ’’’),82.0 (C-3 ’’’),83.8 (C-17),
84.3 (C-9),85.9 (C-4 ’’),87.5 (C-4 ’),96.1 (C-1 ’),99.5 (C-1 ’’),101.3 (C-21),
101.9 (C-1’’’),123.9 (C-2),126.4 (C-10),133.1 (C-4),133.3 (C-13),133.5
(C-6),134.8 (C-12),141.2 (C-11),142.8 (C-7),146.9 (C-5),149.2 (C-3),
A
G
172.7 (C-1); IR (film): n˜ =3416 (brs),2976 (s),2934 (s),1666 (s),1599
ꢀ1
39.2 (C-1’’),40.6 (C-5),48.2 (2-OCH 3),57.5,58.5 (2”OCH 3),63.6 (C-5 ’),
69.3 (C-2’),69.6 (C-6),70.4 (C-4),73.2 (C-1 ’),73.8 (C-2 ’’),78.0,78.5 (C-
5’,C-3 ’’),101.5 (C-2),169.4,169.7 (OAc); IR (film): n˜ =3465 (brs),2988
(s),1454 (s),1387 (s),1256 (s),1080 (s),1027 (s),969 (s),667 cm
(s);
HR-MS (ESI): m/z: calcd for C58H96O21Na: 1151.6342; found 1151.6307
[M+Na]+.
(s),2957 (s),2878 (s),2855 (s),1754 (s),1469 (s),1416 (s),1365 (s),1256
27-Hydroxy apoptolidin A (57): Rf =0.27 (CHCl3/MeOH 8:1); HPLC:
ꢀ1
(s),1224 (s),830 cm
(s); HR-MS (ESI): m/z: calcd for C34H68O11Si2Na:
tR =8.2 min (Dynamax C18,A: H 2O,B: MeOH,70 !100% B in 25 min,
731.4205; found 731.4198 [M+Na]+.
1
0.7 mLminꢀ1,30 8C); [a]2D1 = +3.8 (c=1.05,CHCl ); H NMR (500 MHz,
3
(2E,6S,7S,9S,10R,2’R,3’R,4’S,5’R,6’R,2’’R)-10-[6’-(2’’-tert-Butyldimethylsi-
lyloxy-3’’-methoxypropyl)-4’-triethylsilyloxy-2’-methoxy-3’,5’-dimethyl-
2’,3’,5’,6’-tetrahydro-4H-pyran-2’-yl]-6,9,10-trihydroxy-7-methoxy-2-tri-n-
butyl stannyl-dec-2-ene (59): According to the procedure for the conver-
sion of alcohol 50 into alkenyl stannane 52 (Dess–Martin oxidation,
CD3OD): d=0.91 (d, J=6.9 Hz,3H,24-CH 3),1.06 (d, J=6.6 Hz,3H,22-
CH3),1.16 (d, J=6.6 Hz,3H,8-CH 3),1.29 (d, J=6.2 Hz,6 ’-H3),1.30–
1.36 (m,1H,26-H),1.40–1.49 (m,1H,15-H),1.50–1.59 (m,1H,15-H),
1.61 (ddd, J=14.1,8.8,2.6 Hz,1H,26-H),1.71 (s,3H,12-CH
(m,2H,18-H,24-H),1.96 (s,3H,6-CH 3),2.03–2.24 (m,3H,14-H,18-H,
22-H),2.14 (s,3H,2-CH 3),2.22 (s,3H,4-CH 3),2.45–2.54 (m,1H,14-H),
3),1.73–1.84
Grignard addition,acetate cleavage),alcohol
58 (482 mg,0.682 mmol)
was transformed into alkenyl stannane 59 (336 mg,0.342 mmol,48%).
2.72–2.83 (m,2H,8-H,17-H),2.75 (t,
9.5,6.3 Hz,1H,28-H),3.24 (dd,
J=9.3 Hz,1H,4 ’-H),3.20 (dd, J=
J=9.4,4.6 Hz,1H,28-H),3.33 (s,3H,
1
Rf =0.45 (MTBE/n-hexane 3:1); [a]19 =+32.4 (c=1.53,CHCl ); H NMR
3
D
(400 MHz,C 6D6): d=0.151,0.154 (2s,6H,SiCH
3),0.63 (q, J=7.9 Hz,
28-OCH3),3.39 (s,3H,17-OCH 3),3.43 (dd, J=9.7,3.8 Hz,1H,2 ’-H),
3.45–3.50 (m,1H. 16-H),3.55–3.63 (m,2H,20-H,27-H),3.61 (s,3H; 4 ’-
OCH3),3.75 (t, J=9.3 Hz,1H,3 ’-H),3.74–3.81 (m,2H,23-H,5 ’-H),3.86
(dd, J=9.3,9.3 Hz,1H,9-H),4.13 (ddd, J=8.8,3.0,2.2 Hz,1H,25-H),
4.84 (1H,1 ’-H,below H 2O-Signal),5.22–5.30 (m,2H,7-H,10-H),5.34
(d, J=11.2 Hz,1H,19-H),5.72 (dd, J=9.2,6.9 Hz,1H,13-H),6.21 (d,
J=15.6 Hz,1H,11-H),6.22 (s,1H,5-H),7.24 (s,1H,3-H);
13C NMR
(125.8 MHz,CD 3OD): d=5.3 (24-CH3),12.0 (12-CH 3),12.1 (22-CH 3),
6H,SiC H2CH3),0.95 (t, J=7.3 Hz,9H,Sn
A
24H,SiCH 2CH3,SiC (CH3)3,SnC H2C3H7),1.12 (d, J=6.9 Hz,3H,5 ’-
AHCTREUNG
CH3),1.35–1.44 (m,9H,3 ’-CH3,SnC 2H4CH2CH3),1.54–1.71 (m,9H,1 ’’-
H,5-H 2,SnCH 2CH2C2H5),1.76–1.91 (m,3H,1 ’’-H,5 ’-H,8-H),1.92–1.99
(m,1H,8-H),2.01 (t,
J(H,Sn)=23.8 Hz,3H,1-H 3),2.15 (d, J=5.5 Hz,
A
1H,6-OH),2.37–2.57 (m,4-H 2, 3’-H),2.65 (d, J=5.5 Hz,1H,10-OH),
3.05–3.10 (brs,1H,9-OH),3.08 (s,3H,OCH
3),3.14 (dd, J=9.4,4.6 Hz,
7394
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,7378 – 7397

Total Synthesis of Apoptolidin A
FULL PAPER
1H,3 ’’-H),3.18 (dd, J=9.4,6.2 Hz,1H,3
’’-H),3.28,3.29 (2s,6H,
12H,SiCH CH3,8-CH ),1.37 (d, J=6.1 Hz,3H,6-H gluco),1.41 (d, J=
2
3
3
OCH3),3.43 (ddd, J=8.5,4.5,4.0 Hz,1H,7-H),3.59–3.66 (m,2H,6-H,
10-H),4.04–4.11 (m,2H,2 ’’-H,4 ’-H),4.14–4.19 (m,1H,6 ’-H),4.24–4.31
6.5 Hz,3H,3 ’-CH3),1.50–1.62 (m,3H,15-H 2, 1’’-H),1.65 (s,3H,6-CH 3),
1.73–1.99 (m,4H,1 ’’-H,5 ’-H,18-H ),1.86 (s,3H,12-CH 3),1.89 (s,3H,4-
2
(m,1H,9-H),5.73–5.93 (m,1H,3-H);
ꢀ4.5, ꢀ3.6 (SiCH3),5.5 (Si CH2CH3),5.7 (5 ’-CH3),7.2 (SiCH 2CH3),9.5
(SnCH2C3H7),12.5 (3 ’-CH3),13.9 (Sn (CH2)3CH3),18.5 (Si C(CH3)3),19.4
(C-1),25.3 (C-4),26.2 (SiC (CH3)3),27.8,29.7 (SnCH 2C2H4CH3),33.4 (C-
13C NMR (100.6 MHz,C 6D6): d=
CH3),2.09 (s,3H,2-CH 3),2.25–2.35 (m,1H,14-H),2.40–2.53 (m,2H,
14-H,3 ’-H),2.69 (t, J=9.2 Hz,1H,4-H gluco),2.78–2.87 (m,1H,8-H),
3.09 (s,3H,OCH 3),3.13–3.24 (m,1H,3 ’’-H2),3.30,3.31,3.35 (3s,9H,
OCH3),3.37–3.43 (m,1H,17-H),3.50–3.57 (m,1H,16-H),3.65 (s,1H,
20-H),3.70 (dd, J=8.7,2.9 Hz,1H,2-H gluco),3.92–4.00 (m,1H,5-H
A
ACHTREUNG
AHCTREUNG
3’),36.6 (C-3 ’),37.8 (C-8),39.4 (C-1 ’’),40.7 (C-5 ’),48.5 (2 ’-OCH3),58.5,
59.1 (2”OCH3),67.8 (C-9),69.4 (C-6 ’),70.5 (C-4 ’),73.0 (C-6),74.0 (C-
2’’),75.3 (C-10),77.9 (C-3 ’’),82.1 (C-7),103.1 (C-2 ’),138.3 (C-2),141.5
gluco),4.06–4.14 (m,3H,2 ’’-H,4 ’-H,9-H),4.15.4.20 (m,1H,6
(t, J=9.1 Hz,1H,3-H gluco),4.29 (d, J=9.9 Hz,1H,19-H),5.03 (d, J=
2.9 Hz,1H,1-H gluco),5.35 (d, J=9.7 Hz,1H,7-H),5.49–5.59 (m,2H,
10-H,13-H),5.98 (s,1H,5-H),6.36 (d, J=16.1 Hz,1H,11-H),7.52 (s,
’-H),4.22
(C-3); IR (film): n˜ =3440 (brs),2959 (s),2929 (s),2876 (s),2853 (s),1465
ꢀ1
(s),1415 (s),1381 (s),1250 (s),1149 (s),1108 (s),1069 (s),1020 cm
HR-MS (ESI): m/z: calcd for C47H98O9Si2SnNa: 1005.5669; found
1005.5699 [M+Na]+.
(s);
1H,3-H); 13C NMR (125.8 MHz,C 6D6): d=ꢀ4.5, ꢀ3.6 (SiCH3),5.5,5.6
(2”SiCH2CH3),5.7 (5 ’-CH3),5.9 (Si CH2CH3),7.2,7.3 7.4 (SiCH 2CH3),
12.4,12.5 (12-CH 3, 3’-CH3),14.0 (2-CH 3),17.33,17.35 (8-CH 3,6-CH 3),
Cyanomethyl-(2E,4E,6E,10E,12E,8R,9R,16S,17S,19S,20R,2’R,3’R,4’S,5’R,
6’R,2’’R)-20-[6’-{2’’-tert-butyldimethylsilyloxy-3’’-methoxypropyl}-4’-tri-
ethylsilyloxy-2’-methoxy-3’,5’-dimethyl-2’,3’,5’,6’-tetrahydro-4H-pyran-2’-
yl]-9-[6-deoxy-4-O-methyl-2,3-O-bis(triethylsilyl)-a-l-glucopyranosyl]-
18.3 (4-CH3),18.5 (Si C
A
AHCTREUNG
(C-5’),48.6 (2 ’-OCH3),58.6,59.3,61.0 (3”OCH 3),67.7 (C-19),67.9 (C-5
gluco),69.4 (C-6 ’),70.4 (C-4 ’),73.0 (C-16),74.0 (C-2 ’’),74.8 (2C,(C-2,C-
3)-gluco),75.3 (C-20),77.9 (C-3 ’’),80.5 (C-9),82.3 (C-17),87.9 (C-4
gluco),95.2 (C-1 gluco),103.1 (C-2 ’),124.4 (2C,C-2,C-10),132.1,132.5,
133.2 (C-4,C-6,C-12),134.1 (C-13),135.1 (C-7),140.2 (C-5),140.6 (C-
11),146.1 (C-3),173.7 (C-1); IR (film): n˜ =3445 (brs),2985 (s),2958 (s),
16,19,20-trihydroxy-17-methoxy-2,4,6,8,12-pentamethyl
eicosapenta-
2,4,6,10,12-enoate (60): According to the cross-coupling procedure (43 +
52 ! 53),alkenyl stannane 59 (62 mg,60 mmol) and alkenyl iodide 43
(58 mg,72 mmol) were transformed with CuTC (36 mg,180 mmol) into cy-
anomethyl ester 60 (67 mg,49 mmol,82%). Rf =0.37 (n-hexane/MTBE
1:3); [a]1D9 =+27.8 (c=0.83,CHCl 3); 1H NMR (500 MHz,C 6D6): d=0.16
(s,6H,SiCH 3),0.64 (q, J=7.9 Hz,6H,SiC H2CH3),0.70 (q, J=7.9 Hz,
2876 (s),2854 (s),1708 (s),1466 (s),1415 (s),1382 (s),1242 (s),1141 (s),
ꢀ1
1111 (s),1069 (s),1005 (s),969 (s),845 (s),747 cm
(s); HR-MS (ESI):
m/z: calcd for C69H132O16Si4Na: 1351.8490; found 1351.8521 [M+Na]+.
6H,SiC H2CH3),0.84–0.91 (m,6H,SiC H2CH3),1.01 (s,9H,SiC
A
1.02 (t, J=7.9 Hz,9H,SiCH 2CH3),1.07 (t, J=7.9 Hz,9H,SiCH 2CH3),
1.13 (d, J=6.9 Hz,3H,5 ’-CH3),1.17 (t, J=7.9 Hz,9H,SiCH 2CH3),1.19
Macrolactonization: The trihydroxy acid (15 mg,11 mmol),Et 3N (65 mL,
0.47 mmol), 2,4,6-trichlorobenzoyl chloride (35 mL,0.23 mmol) in THF
(1.5 mL) was added to DMAP (119 mg,0.95 mmol) in toluene (35 mL)
as described for the macrolactonization (54 ! 55). After chromatogra-
phy (5 g silica gel,cyclohexane/AcOEt 8:1 ! 5:1) macrolactone 61
(10 mg,7.6 mmol,69%) was obtained as a colorless oil. Rf =0.51 (n-
hexane/MTBE 1:1); [a]1D9 =ꢀ19.1 (c=0.79,CHCl 3); 1H NMR (400 MHz,
C6D6): d=0.16,0.18 (2s,6H,SiCH 3),0.62 (q, J=8.0 Hz,6H,SiC H2CH3),
0.71 (q, J=8.1 Hz,6H,SiC H2CH3),0.91 (q, J=8.1 Hz,6H,SiC H2CH3),
(d, J=6.6 Hz,8-CH 3),1.37 (d, J=6.2 Hz,3H,6-H
gluco),1.40 (d, J=
3
6.6 Hz,3H,3 ’-CH3),1.49–1.62 (m,3H,15-H 2, 1’’-H),1.67 (s,3H,6-CH 3),
1.72–1.96 (m,4H,1 ’’-H,5 ’-H,18-H ),1.87 (brs,6H,12-CH 3,4-CH ),1.93
2
3
(d, J=1.1 Hz,3H,2-CH 3),2.07–2.17 (brs,1H,16-OH),2.26–2.35 (m,
1H,14-H),2.39–2.52 (m,2H,14-H,3 ’-H),2.64 (d, J=5.5 Hz,1H,20-
OH),2.69 (t, J=9.2 Hz,1H,4-H gluco),2.79–2.88 (m,1H,8-H),2.97–
3.10 (brs,1H,19-OH),3.08 (s,3H,OCH
3’’-H),3.19 (dd, J=9.4,6.2 Hz,1H,3
3),3.14 (dd, J=9.4,4.6 Hz,1H,
’’-H),3.285,3.293,3.35 (3s,9H,
0.97–1.09 (m,27H,SiC (CH3)3),2”SiCH 2CH3),1.18 (t, J=8.0 Hz,9H,
A
OCH3),3.34–3.39 (m,1H,17-H),3.49–3.54 (m,1H,16-H),3.61–3.64 (m,
1H,20-H),3.69 (dd, J=9.3,3.3 Hz,1H,2-H gluco),3.82 (s,2H,
OCH2CN),3.95 (dq, J=9.7,6.2 Hz,1H,5-H gluco),4.05–4.20 (m,4H,
2’’-H,4 ’-H,6 ’-H,9-H),4.21 (t, J=9.1 Hz,1H,3-H gluco),4.25–4.30 (m,
1H,19-H),5.02 (d, J=3.4 Hz,1H,1-H gluco),5.40 (d, J=9.9 Hz,1H,7-
SiCH2CH3),1.22 (d, J=6.9 Hz,3H,8-CH 3),1.29 (d, J=6.6 Hz,24-CH 3),
1.34–1.50 (m,2H,15-H 2),1.42 (d, J=6.3 Hz,3H,6 ’-H3),1.53 (d, J=
6.6 Hz,3H,22-CH 3),1.57 (s,3H,6-CH 3),1.61–1.98 (m,3H,26-H 2,24-
H),1.69 (s,3H,12-CH 3),1.80 (s,3H,4-CH 3),1.99–2.35 (m,5H,18-H
14-H,22-H,16-OH),2.11 (s,3H,2-CH 3),2.41 (brs,1H,20-OH),2.48–
,
2
H),5.51–5.60 (m,2H,10-H,13-H),5.95 (s,1H,5-H),6.38 (d,
1H,11-H),7.24 (s,1H,3-H);
J=15.6 Hz,
2.63 (m,1H,14-H),2.64–2.78 (m,1H,8-H),2.73 (dd,
4’-H),2.98–3.08 (m,1H,17-H),3.06 (s,3H,28-OCH
28-H2),3.29 (21-OCH 3),3.36 (17-OCH 3),3.38 (4 ’-OCH3),3.45–3.54 (m,
1H,16-H),3.73 (dd, J=9.3,3.4 Hz,1H,2 ’-H),3.90 (brd, J=5.3 Hz,1H,
J=9.1,9.1 Hz,1H,
3),3.15–3.23 (m,2H,
13C NMR (125.8 MHz,C 6D6): d=ꢀ4.5,
ꢀ3.6 (SiCH3),5.5,5.6 (2”Si CH2CH3),5.7 (5 ’-CH3),5.9 (Si CH2CH3),7.2,
7.3 7.4 (SiCH2CH3),12.4,12.5 (12-CH 3, 3’-CH3),14.1 (2-CH 3),17.2,17.3
(8-CH3,6-CH 3),18.3 (4-CH 3),18.5 (Si C
(CH3)3),18.7 (C-6 gluco),25.2
20-H),3.95 (t, J=9.1 Hz,1H,9-H),4.03 (dq,
4.10–4.18 (m,2H,23-H,27-H),4.18–4.23 (m,1H,25-H),4.28 (t,
9.0 Hz,1H,3 ’-H),5.01 (d, J=10.0 Hz,1H,7-H),5.07 (d, J=3.3 Hz,1H,
1’-H),5.32 (dd, J=15.7,9.2 Hz,1H,10-H),5.55 (dd, J=10.0,6.2 Hz,1H,
J=9.6,6.0 Hz,1H,5 ’-H),
(C-14),26.2 (SiC (CH3)3),33.4 (C-15),36.6 (C-3 ’),37.2 (C-18),38.8 (C-8),
ACHTREUNG
J=
39.4 (C-1’’),40.7 (C-5 ’),48.1 (O CH2CN),48.5 (2 ’-OCH3),58.5,59.3,61.0
(OCH3),67.6 (C-19),67.9 (C-5 gluco),69.4 (C-6 ’),70.4 (C-4 ’),73.0 (C-
16),73.9 (C-2 ’’),74.8 (2C,(C-2,C-3)-gluco),75.3 (C-20),77.9 (C-3
(C-9),82.2 (C-17),87.9 (C-4 gluco),95.1 (C-1 gluco),103.1 (C-2
’’),80.3
’),115.0
13-H),5.89–5.97 (m,1H,19-H),6.11 (d,
1H,5-H),7.53 (s,1H,3-H);
(SiCH3),5.5,5.6 (2”Si CH2CH3),5.8 (24-CH 3),5.9 (Si CH2CH3),7.2,7.3,
7.4 (3”SiCH2CH3),11.7,11.8 (12-CH 3,22-CH 3),14.2 (2-CH 3),16.1 (6-
CH3),17.4 (4-CH 3),18.4 (8-CH 3),18.6 (Si C
J=15.8 Hz,1H,11-H),6.15 (s,
13C NMR (125.8 MHz,C D6): d=ꢀ4.5, ꢀ3.5
6
(OCH2CN),124.0 (C-2),124.3 (C-10),131.7,132.4,133.2 (C-4,C-6,C-
12),134.2 (C-13),135.5 (C-7),140.6 (C-5),140.8 (C-11),146.5 (C-3),
166.9 (C-1); IR (film): n˜ =3490 (brs),2956 (s),2877 (s),1723 (s),1463
(s),1413 (s),1384 (s),1241 (s),1141 (s),1106 (s),1071 (s),1006 (s),
968 cmꢀ1 (s); HR-MS (ESI): m/z: calcd for C71H133NO16Si4Na: 1390.8599;
found 1390.8638 [M+Na]+.
(CH3)3),18.7 (C-6 ’),25.0 (C-
14),26.3 (SiC (CH3)3),34.8 (C-15),37.1 (C-22),38.2,38.3 (C-8,C-18),39.2
AHCTREUNG
(C-26),40.8 (C-24),47.9 (21-OCH 3),58.5 (17-OCH 3),60.3 (28-OCH 3),
61.0 (4’-OCH3),67.9 (C-5 ’),69.6 (C-25),70.6 (C-23),72.0 (C-19),73.5 (C-
27),74.2 (C-16),74.7,74.8 (C-2 ’,C-3 ’),75.9 (C-20),78.1 (C-28),82.3 (C-
17),82.6 (C-9),87.9 (C-4 ’),95.8 (C-1 ’),102.1 (C-21),124.2 (C-2),125.6
(C-10),132.1 (C-4),132.4 (C-6),133.2 (C-12),133.5 (C-13),140.5 (C-11),
27-O-tert-Butyldimethylsilyl-9-O-[6-deoxy-4-O-methyl-2,3-O-bis(triethyl-
silyl)-l-a-glucopyranosyl]-21-O-methyl-23-O-triethylsilyl-apoptolidinone
A (61): Ester hydrolysis: Cyanomethyl ester 60 (51 mg,49 mmol) dis-
solved in THF/H2O (4 mL,3:1) was hydrolyzed with LiOH monohydrate
(5.0 mg,0.11 mmol) according to the procedure ( 53 ! 54). The corre-
sponding trihydroxy acid (51 mg) was used without further purification
for the following macrolactonization step. Analytical data of the acid:
Rf =0.35 (CH2Cl2/MeOH 15:1); [a]1D9 =+25.3 (c=1.23,CHCl 3); 1H NMR
(500 MHz,C 6D6): d=0.16 (s,6H,SiCH 3),0.65 (q, J=8.0 Hz,6H,
SiCH2CH3),0.70 (q, J=7.9 Hz,6H,SiC H2CH3),0.89 (q, J=7.9 Hz,6H,
141.2 (C-7),144.8 (C-5),145.9 (C-3),169.7 (C-1); IR (film):
(brs),2955 (s),2877 (s),1699 (s),1602 (m),1463 (s),1415 (s),1386 (s),
n˜ =3507
ꢀ1
1246 (s),1106 (s),1017 (s),981 (s),838 (s),740 cm
(s); HR-MS (ESI):
m/z: calcd for C69H130O15Si4Na: 1333.8385; found 1333.8355 [M+Na]+.
27-Hydroxy apoptolidin A (57): H2SiF6 (4”100 mL,aq 25–30%) was
added at ꢀ408C to the protected macrolactone 61 (34 mg,26 mmol) in
CH3CN (8 mL). After 1 d at ꢀ40 to ꢀ308C,the reaction mixture was stir-
red for 20 h at ꢀ25 to ꢀ158C. Phosphate buffer (10 mL,pH 7,1 m) was
added. The aqueous layer was extracted with CHCl3/iPrOH (5”10 mL,
SiCH2CH3),0.99–1.05 (m,18H,SiC
A
8.0 Hz,9H,SiCH 2CH3),1.13 (d, J=6.8 Hz,3H,5 ’-CH3),1.15–1.21 (m,
Chem. Eur. J. 2006, 12,7378 – 7397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
7395

U. Koert et al.
5:1). The combined organic layers were dried with Na2SO4. Chromatog-
raphy (6 g neutral silica gel,CH 2Cl2/MeOH 25:1 ! 20:1) gave 27-hy-
droxy apoptolidin A (57) (17 mg,20 mmol,77%) as a white solid. The an-
alytical data were identical with the data obtained from the deprotection
starting with 55.
ꢀ4.5, ꢀ3.6 (SiCH3),5.5 (Si CH2CH3),5.7 (5 ’-CH3),5.78,5.83 (2”
SiCH2CH3),7.2,7.4,7.5 (SiCH 2CH3),12.5,12.6 (3 ’-CH3,12-CH ),14.1 (2-
3
CH3),17.3 (6-CH 3),17.8 (8-CH 3),18.3 (4-CH 3),18.5 (Si C
A
(C-6 gluco),25.2 (C-14),26.2 (SiC (CH3)3),33.4 (C-15),36.7,37.1 (C-3 ’,
AHCTREUNG
C-18),39.2,39.4 (C-8,C-1 ’’),40.7 (C-5 ’),48.5 (2 ’-OCH3),58.5,59.2,60.4
(3”OCH3),67.8 (C-19),69.4 (C-6 ’),70.4 (C-4 ’),71.2 (C-5 gluco),72.9 (C-
Cyanomethyl-(2E,4E,6E,10E,12E,8R,9R,16S,17S,19S,20R,2’R,3’R,4’S,5’R,
6’R,2’’R)-20-[6’-{2’’-tert-butyldimethylsiloxa-3’’-methoxypropyl}-4’-tri-
ethylsilyloxy-2’-methoxy-3’,5’-dimethyl-2’,3’,5’,6’-tetrahydro-4H-pyran-2’-
yl]-9-[6-deoxy-4-O-methyl-2,3-O-bis(triethylsilyl)-b-l-glucopyranosyl]-
16),74.0 (C-2 ’’),75.3 (C-20),77.1 (C-2 gluco),77.9 (C-3
’’),78.6 (C-3
gluco),82.2 (C-17),86.1 (C-9),87.0 (C-4 gluco),101.5 (C-1 gluco),103.1
(C-2’),125.3 (C-2),126.0 (C-10),132.2,132.5,133.2 (C-4,C-6,C-12),
133.7 (C-13),134.7 (C-7),138.5 (C-11),140.6 (C-5),146.2 (C-3),174.0 (C-
1); IR (film): n˜ =3447 (brs),2989 (s),2958 (s),1681 (s),1469 (s),1458
16,19,20-trihydroxy-17-methoxy-2,4,6,8,12-pentamethyl
eicosapenta-
2,4,6,10,12-enoate (62): According to the cross-coupling procedure (43 +
52 ! 53),alkenyl stannane 59 (30 mg,31 mmol) and alkenyl iodide 44
(30 mg,37 mmol) were transformed with CuTC (18 mg,93 mmol) into the
cyanomethyl ester 62 (33 mg,24 mmol,78%). Rf =0.34 (n-hexane/MTBE
1:3); [a]1D9 =+45.7 (c=1.25,CHCl 3); 1H NMR (500 MHz,C 6D6): d=
0.152,0.155 (2s,6H,SiCH 3),0.64 (q, J=7.9 Hz,6H,SiC H2CH3),0.80–
ꢀ1
(s),1415 (s),1360 (s),1278 (s),1238 (s),1060 (s),1006 (s),967 cm
(s);
HR-MS (ESI): m/z: calcd for C69H132O16Si4Na: 1351.8490; found
1351.8509 [M+Na]+.
Macrolactonization: Trihydroxy acid (31 mg,23 mmol),Et 3N (140 mL,
0.98 mmol), 2,4,6-trichlorobenzoyl chloride (75 mL,0.47 mmol) in THF
(3 mL) was added to DMAP (236 mg,1.94 mmol) in toluene (35 mL) as
described for the macrolactonization (54 ! 55). After chromatography
(5 g silica gel,cyclohexane/AcOEt 8:1 ! 5:1) macrolactone 63 (15 mg,
11 mmol,48%) was obtained as a colorless oil. Rf =0.31 (n-hexane/
MTBE 3:2); [a]1D9 =+16.0(c=0.55,CHCl 3); 1H NMR (500 MHz,C 6D6):
d=0.17,0.18 (2s,6H,SiCH 3),0.62 (q, J=8.0 Hz,6H,SiC H2CH3),0.83–
0.97 (m,12H,2”SiC H2CH3),1.01 (s,9H,SiC
A
9H,SiCH 2CH3),1.10–1.21 (m,24H,8-CH 3, 5’-CH3,2”SiCH 2CH3),1.24
(d, J=6.0 Hz,3H,6-H gluco),1.40 (d, J=6.6 Hz,3H,3 ’-CH3),1.50–1.61
3
(m,3H,15-H 2, 1’’-H),1.72–1.95 (m,4H,1 ’’-H,5 ’-H,18-H 2),1.76 (s,3H,
6-CH3),1.82 (s,3H,12-CH 3),1.88 (d, J=0.9 Hz,3H,4-CH 3),1.91 (d, J=
1.4 Hz,3H,2-CH 3),2.09–2.15 (brs,1H,16-OH),2.27–2.36 (m,1H,14-
H),2.40–2.51 (m,2H,14-H,3
’-H),2.69 (t, J=8,9 Hz, 1H, 4-H gluco),
1.04 (m,30H,2”SiC H2CH3,SiC (CH3)3,SiCH 2CH3),1.15 (t, J=8.0 Hz,
A
2.68 (d, J=5.5 Hz,1H,20-OH),3.03–3.10 (m,2H,8-H,19-OH),3.07 (s,
3H,OCH 3),3.13 (dd, J=9.4,4.6 Hz,1H,3 ’’-H),3.14–3.21 (m,2H,3 ’’-H,
9H,SiCH 2CH3),1.19 (t, J=7.8 Hz,9H,SiCH 2CH3),1.24 (d, J=6.1 Hz,
3H,6 ’-CH3),1.29 (d, J=7.0 Hz,24-CH 3),1.33 (d, J=6.7 Hz,3H,8-H 3),
5-H gluco),3.18,3.27,3.29 (3s,9H,OCH
3),3.34–3.39 (m,1H,17-H),
1.37–1.46 (m,1H,15-H),1.46–1.52 (m,1H,15-H),1.54 (d,
J=6.6 Hz,
3.50–3.56 (m,1H,16-H),3.58–3.68 (m,3H,20-H,(2,3)-H gluco),3.83 (s,
3H,22-CH 3),1.60 (s,3H,12-CH 3),1.66 (ddd, J=14.2,7.9,3.2 Hz,1H,
2H,OCH CN),4.04–4.11 (m,2H,2 ’’-H,4 ’-H),4.14–4.20 (m,2H,6 ’-H,9-
26-H),1.72 (s,3H,6-CH 3),1.83 (s,6H,4-CH 3),1.88–1.98 (m,2,24-H,26-
2
H),4.23–4.29 (m,1H,19-H),4.37 (d,
J=9.9 Hz,1H,7-H),5.57 (t, J=7.5 Hz,1H,13-H),5.90 (dd,
J=7.3 Hz,1H,1-H gluco),5.44 (d,
J=15.8,
J=15.6 Hz,1H,11-H),7.25
H),1.99–2.09 (m,1H,14-H),2.13 (s,3H,2-CH
3),2.18–2.33 (m,4H,18-
H2,22-H,16-OH),2.41 (brs,1H,20-OH),2.53–2.62 (m,1H,14-H),2.68
(t, J=9.0 Hz,1H,4 ’-H),2.85–2.94 (m,1H,8-H),3.01–3.08 (m,1H,17-
H),3.07 (s,3H,OCH 3),3.16–3.23 (m,3H,5 ’-H,28-H 2),3.19 (OCH 3),
8.5 Hz,1H,10-H),5.97 (s,1H,5-H),6.31 (d,
(s,1H,3-H); 13C NMR (125.8 MHz,C 6D6): d=ꢀ4.5, ꢀ3.6 (SiCH3),5.5
(SiCH2CH3),5.7 (5 ’-CH3),5.78,5.84 (2”Si
CH2CH3),7.2,7.4,7.5
3.29,3.38 (2”OCH ),3.47–3.54 (m,1H,16-H),3.65 (t,
J=8.5 Hz,1H,3 ’-
3
(SiCH2CH3),12.5 (3 ’-CH3),12.6 (12-CH 3),14.1 (2-CH 3),17.3 (6-CH 3),
17.8 (8-CH3),18.2 (4-CH 3),18.5 (Si C(CH3)3),19.0 (C-6 gluco),25.2 (C-
14),26.2 (SiC (CH3)3),33.4 (C-15),36.7 (C-3 ’),37.1 (C-18),39.1 (C-8),
H),3.71 (dd, J=8.2,7.7 Hz,1H,2 ’-H),3.90 (brd, J=4.9 Hz,1H,20-H),
A
3.95 (t, J=9.3 Hz,1H,9-H),4.11–4.18 (m,1H,27-H),4.16 (dd,
4.7 Hz,1H,23-H),4.21 (dt, J=8.1,2.7 Hz,1H,25-H),4.45 (d,
J=10.3,
J=7.4 Hz,
A
39.4 (C-1’’),40.7 (C-5 ’),48.1 (O CH2CN),48.5 (2 ’-OCH3),58.5,59.2,60.4
(OCH3),67.7 (C-19),69.4 (C-6 ’),70.4 (C-4 ’),71.2 (C-5 gluco),72.9 (C-
1H,1 ’-H),5.02 (d, J=10.1 Hz,1H,7-H),5.55–5.60 (m,2H,10-H,13-H),
5.95 (ddd, J=10.3,5.6,3.1 Hz,1H,19-H),6.02 (d, J=15.7 Hz,1H,11-
13C NMR (125.8 MHz,C 6D6):
CH2CH3),5.85 (24-CH ,
3
16),73.9 (C-2 ’’),75.3 (C-20),77.1 (C-2 gluco),77.9 (C-3
’’),78.6 (C-3
H),6.20 (s,1H,5-H),7.56 (s,1H,3-H);
d=ꢀ4.5, ꢀ3.5 (SiCH3),5.5,5.80 (2”Si
gluco),82.2 (C-17),86.1 (C-9),87.0 (C-4 gluco),101.5 (C-1 gluco),103.1
(C-2’),115.0 (OCH CN),123.9 (C-2),125.9 (C-10),131.8,132.4,133.7 (C-
SiCH2CH3),7.2,7.4 (2C) (3”SiCH 2CH3),11.7,11.9 (12-CH 3,22-CH 3),
2
4,C-6,C-12),133.4 (C-13),135.2 (C-7),138.6 (C-11),141.2 (C-5),146.5
(C-3),166.9 (C-1); IR (film): n˜ =3465 (brs),2987 (s),2958 (s),2876 (s),
14.2 (2-CH3),16.2 (6-CH 3),17.4 (4-CH 3),18.4 (8-CH 3),18.6 (Si C
19.0 (C-6’),25.1 (C-14),26.3 (SiC (CH3)3),34.8 (C-15),37.1 (C-22),38.3
(C-18),39.2 (C-26),39.6 (C-8),40.8 (C-24),47.9 (21-OCH 3),58.5,60.37,
60.41 (3”OCH3),69.6 (C-25),70.6 (C-5 ’),71.1 (C-23),72.0 (C-19),73.5
(C-27),74.3 (C-16),75.9 (C-20),77.2 (C-2 ’),78.1 (C-28),78.7 (C-3 ’),82.3
(C-17),87.0 (C-4 ’),87.8 (C-9),101.8 (C-1 ’),102.1 (C-21),124.2 (C-2),
126.7 (C-10),131.8,132.1 (C-4,C-6),132.7 (C-13),133.8 (C-12),138.4 (C-
G
ACHTREUNG
2854 (s),1721 (s),1469 (s),1458 (s),1385 (s),1360 (s),1239 (s),1108 (s),
ꢀ1
1063 (s),1006 (s),998 cm
(s); HR-MS (ESI): m/z: calcd for
C71H133O16Si4Na: 1390.8599; found 1390.8655 [M+Na]+.
27-O-tert-Butyldimethylsilyl-9-O-[6-deoxy-4-O-methyl-2,3-O-bis(triethyl-
silyl)-l-b-glucopyranosyl]-21-O-methyl-23-O-triethylsilyl-apoptolidinone
A (63): Ester hydrolysis: Cyanomethyl ester 62 (39 mg,29 mmol) dis-
solved in THF/H2O (4 mL,3:1) was hydrolyzed with LiOH monohydrate
(3.7 mg,87 mmol) according to the procedure (53 ! 54). The correspond-
ing trihydroxy acid (31 mg,24 mmol,83%) was used without further puri-
fication for the following macrolactonization step. Analytical data of the
acid: Rf =0.36 (CH2Cl2/MeOH 15:1); [a]1D9 =+43.2 (c=1.00,CHCl 3);
1H NMR (500 MHz,C 6D6): d=0.16 (s,6H,SiCH 3),0.64 (q, J=7.9 Hz,
11),141.4 (C-7),144.8 (C-5),145.8 (C-3),169.7 (C-1); IR (film):
n˜ =3501
(brs),2954 (s),2928 (s),2874 (s),2854 (s),1699 (s),1602 (s),1463 (s),
1418 (s),1386 (s),1247 (s),1087 (s),1017 (s),975 (s),937 (s),834 (s),
740 cmꢀ1 (s); HR-MS (ESI): m/z: calcd for C69H130O15Si4Na: 1333.8385;
found 1333.8326 [M+Na]+.
9-O-(6-Deoxy-4-O-methyl-l-b-glucopyranosyl)-apoptolidinone
A (64):
H2SiF6 (120 mL,aq 25–30%) was added at ꢀ408C to protected macrolac-
tone 63 (13 mg,10 mmol) in CH3CN (3 mL). After 1 d at ꢀ40 to ꢀ308C,
the reaction mixture was stirred for 20 h at ꢀ25 to ꢀ158C. Phosphate
buffer (10 mL,pH 7,1 m) was added. The aqueous layer was extracted
with CHCl3/iPrOH (5”10 mL,5:1). The combined org. layers were dried
with Na2SO4. Chromatography (6 g neutral silica gel,CH 2Cl2/MeOH
25:1!20:1) gave compound 64 (7.5 mg,8.9 mmol,89%) as an amorphous
solid. Rf =0.21 (CHCl3/MeOH 8:1); HPLC: tR =5.3 min (Dynamax C18,
6H,SiC H2CH3),0.79–0.98 (m,12H,2”SiC
(CH3)3),1.02 (t, J=7.9 Hz,9H,SiCH 2CH3),1.10–1.22 (m,24H,8-CH
5’-CH3,2”SiCH 2CH3),1.24 (d, J=6.1 Hz,3H,6-H gluco),1.41 (d, J=
H2CH3),1.01 (s,9H,SiC-
U
,
3
3
6.5 Hz,3H,3 ’-CH3),1.50–1.63 (m,3H,15-H 2, 1’’-H),1.72–1.99 (m,4H,
1’’-H,5 ’-H,18-H ),1.75 (s,3H,6-CH 3),1.82 (s,3H,12-CH 3),1.91 (s,3H,
2
4-CH3),2.07 (s,3H,2-CH 3),2.25–2.37 (m,1H,14-H),2.40–2.52 (m,2H,
14-H,3 ’-H),2.65 (t, J=89, Hz,1H,4-H gluco),3.01–3.12 (m,1H,8-H),
3.09 (s,3H,OCH 3),3.13–3.22 (m,3H,5-H gluco,3 ’’-H2),3.19,3.29,3.31
(3s,9H,OCH 3),3.35–3.43 (m,1H,17-H),3.52–3.58 (m,1H,16-H),3.58–
A: H2O,B: MeOH,70 !100% B in 25 min,0.7 mLmin ꢀ1,30 8C); [a]D21
+79 (c=0.60,CHCl 3); 1H NMR (500 MHz,CD 3OD): d=0.91 (d, J=
6.9 Hz,3H,24-CH 3),1.05 (d, J=6.6 Hz,3H,22-CH 3),1.21 (d, J=
6.46 Hz,3H,8-CH 3),1.24 (d, J=6.2 Hz,6 ’-H3),1.29–1.36 (m,1H,26-H),
3.70 (m,3H,20-H,(2,3)-H gluco),4.05–4.13 (m,2H,2
4.21 (m,2H,6 ’-H,9-H),4.25–4.32 (m,1H,19-H),4.39 (d,
’’-H,4 ’-H),4.13–
J=7.2 Hz,1H,
1-H gluco),5.40 (d, J=9.9 Hz,1H,7-H),5.57 (t,
5.90 (dd, J=15.7,8.5 Hz,1H,10-H),6.01 (s,1H,5-H),6.31 (d,
15.6 Hz,1H,11-H),7.54 (s,1H,3-H);
13C NMR (125.8 MHz,C 6D6): d=
J=7.3 Hz,1H,13-H),
1.40–1.48 (m,1H,15-H),1.51–1.60 (m,1H,15-H),1.61 (ddd,
9.1,2.5 Hz,1H,26-H),1.70 (s,3H,12-CH 3),1.72–1.83 (m,2H,18-H,24-
H),1.95 (s,3H,6-CH 3),2.03–2.24 (m,3H,14-H,18-H,22-H),2.14 (s,
J=14.1,
J=
7396
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,7378 – 7397

Total Synthesis of Apoptolidin A
FULL PAPER
3H,2-CH 3),2.21 (s,3H,4-CH 3),2.45–2.54 (m,1H,14-H),2.64–2.79 (m,
Chem. Int. Ed. 2001, 40,3849–3854; b) K. C. Nicolaou,Y. Li,K. C.
2H,8-H,17-H),2.74 (t,
2’-H,5 ’-H),3.32 (s,3H,28-OCH
(1H,3 ’-H,under 17-OCH 3),3.44–3.50 (m,1H,16-H),3.54–3.62 (m,2H,
20-H,27-H,under 4 ’-OCH3),3.58 (s,3H,4 ’-OCH3),3.78 (dd, J=11.1,
4.7 Hz,1H,23-H),3.86 (t, J=9.2 Hz,1H,9-H),4.12 (ddd, J=8.4,2.3,
2.1 Hz,1H,25-H),4.29 (d, J=8.0 Hz,1H,1 ’-H),5.23 (d, J=10.3 Hz,1H,
J=9.3 Hz,1H,4 ’-H),3.17–3.29 (m,4H,28-H
,
Fylaktakidou,H. J. Mitchell,K. Sugita,
Angew. Chem. 2001, 113,
2
3),3.39 (s,3H,17-OCH 3),3.38–3.43
3972–3976; Angew. Chem. Int. Ed. 2001, 40,3854–3857; c) K. C.
Nicolaou,K. C. Fylaktakidou,H. Monenschein,Y. Li,B. Weyer-
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7-H),5.33 (d, J=11.2 Hz,1H,19-H),5.40 (dd,
H),5.68 (dd, J=8.7,6.9 Hz,1H,13-H),6.11 (d,
6.21 (s,1H,5-H),7.39 (s,1H,3-H);
J=15.8,9.2 Hz,1H,10-
J=15.8 Hz,1H,11-H),
K. C. Fylaktakidou,D. Vourloumis,P. Giannakakou,A. OꢁBrate,
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6843; Angew. Chem. Int. Ed. 2004, 43,6673–6675.
J.
13C NMR (125.8 MHz,CD OD): d=
3
5.2 (24-CH3),12.1,12.2 (12-CH 3,22-CH 3),14.0 (2-CH 3),16.4 (6-CH 3),
17.8 (4-CH3),18.0 (8-CH 3),18.4 (C-6 ’),24.6 (C-14),36.4,36.5 (C-15,C-
[12] M. T. Crimmins,H. S. Christie,K. Chaudhary,A. Long,
J. Am.
22),38.4,38.5 (C-18,C-26),39.8 (C-8),40.8 (C-24),59.4 (28-OCH
3),60.9
Chem. Soc. 2005, 127,13810–13812.
(4’-OCH3),61.3 (17-OCH 3),68.1 (C-27),69.2 (C-25),72.2,72.3 (C-19,C-
5’),73.8 (C-23),74.6 (C-16),75.5 (C-20),75.9 (C-2 ’),78.1 (C-3 ’),78.6 (C-
28),83.8 (C-17),87.0 (C-4 ’),90.3 (C-9),101.3 (C-21),104.0 (C-1 ’),123.9
(C-2),128.8 (C-10),132.5 (C-13),132.1,133.2,134.9 (C-4,C-6,C-12),
137.9 (C-11),142.9 (C-7),147.1 (C-5),149.0 (C-3),172.6 (C-1); IR (film):
n˜ =3414 (brs),2977 (s),2931 (s),1666 (s),1597 (s),1455 (s),1388 (s),
1258 (s),1167 (s),1103 (s),1072 (s),1018 (s),967 (s),896 (s),667 cm
(s); HR-MS (ESI): m/z: calcd for C44H72O15Na: 863.4769; found 863.4743
[M+Na]+.
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Received: April 3,2006
Published online: July 25,2006
Chem. Eur. J. 2006, 12,7378 – 7397
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
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