Asymmetric total synthesis of (-)-callystatin A and (-)-20-epi-callystatin A employing chemical and biological methods

Article abstract of DOI:10.1002/1521-3765(20020916)8:18<4272::AID-CHEM4272>3.0.CO;2-K

An efficient asymmetric total synthesis of the potent cytotoxic marine natural product (-)-callystatin A and its 20-epi analogue has been achieved. The synthetic pathway involved the preparation of three fragments to be coupled with each other at the end of the route. The first fragment 3 was obtained using a biocatalytic enantioselective reduction of a 3,5-dioxocarboxylate as the key step. For the second intermediate 4 the asymmetric α-alkylation of an O-protected derivative of 4-hydroxybutanal was performed exploiting the SAMP/ RAMP hydrazone alkylation methodology, and followed by a highly Z-selective Homer-Wadsworth-Emmons reaction under modified conditions. For the synthesis of the polypropionate fragment 5 a diastereoselective syn-aldol reaction was employed between a chiral ethyl ketone and an α-substituted chiral aldehyde, both prepared in enantiopure form again by means of the asymmetric alkylation of their corresponding RAMP hydrazones. Finally, these three building blocks were coupled using highly E-selective Wittig reactions via allyltributylphosphonium ylides to afford the target compounds after a final oxidation/deprotection sequence.

Full text of DOI:10.1002/1521-3765(20020916)8:18<4272::AID-CHEM4272>3.0.CO;2-K

FULL PAPER
Asymmetric Total Synthesis of (À)-Callystatin A and (À)-20-epi-Callystatin A
Employing Chemical and Biological Methods
Dieter Enders,*[a] Jose L. Vicario,[a] Andreas Job,[a] Michael Wolberg,[b] and
Michael M¸ller[b]
Dedicated to Professor Hans Paulsen on the occasion of his 80th birthday
Abstract: An efficient asymmetric total
synthesis of the potent cytotoxic marine
natural product (À)-callystatin A and its
20-epi analogue has been achieved. The
synthetic pathway involved the prepara-
tion of three fragments to be coupled
with each other at the end of the route.
The first fragment 3 was obtained using
a biocatalytic enantioselective reduction
of a 3,5-dioxocarboxylate as the key
step. For the second intermediate 4 the
asymmetric a-alkylation of an O-pro-
tected derivative of 4-hydroxybutanal
was performed exploiting the SAMP/
RAMP hydrazone alkylation method-
ology,and followed by a highly Z-
tween a chiral ethyl ketone and an a-
substituted chiral aldehyde,both pre-
pared in enantiopure form again by
means of the asymmetric alkylation of
their corresponding RAMP hydrazones.
Finally,these three building blocks were
coupled using highly E-selective Wittig
reactions via allyltributylphosphonium
ylides to afford the target compounds
after a final oxidation/deprotection se-
quence.
selective
Horner Wadsworth Em-
mons reaction under modified condi-
tions. For the synthesis of the polypro-
pionate fragment 5 a diastereoselective
syn-aldol reaction was employed be-
Keywords: asymmetric synthesis
enzymes hydrazones natural
products ¥ total synthesis
¥
¥
¥
Introduction
(À)-Callystatin A is a potent cytotoxic polyketide isolated
from the marine sponge Callyspongia truncata by Kobayashi
et al. in 1997.[1] Its structure was elucidated by physicochem-
ical methods[2] and shortly afterwards its absolute configu-
ration was confirmed by the same authors through total
synthesis.[3] Some structural analogues were also synthesised
to establish some structure activity relationships.[4] The
structure of (À)-callystatin A shows a polypropionate chain
and a lactone ring connected to each other by two diene
systems separated by two sp3-hybridised carbon atoms (Fig-
ure 1). This arrangement is structurally related to several
antitumour antibiotics such as anguinomycin,[5] (À)-leptomy-
cin B,[6] (À)-kazusamycin,[7] (‡)-fostriecin,[8] (‡)-leptofura-
nin[9] or (‡)-ratjadone,[10] (À)-pironetin A,[11] (‡)-discoder-
[a] Prof. Dr. D. Enders,Dr. J. L. Vicario,Dr. A. Job
Institut f¸r Organische Chemie
Rheinisch-Westf‰lische Technische Hochschule
Professor Pirlet-Strasse 1,52074 Aachen (Germany)
Fax : (‡49)241-8092-127
E-mail: enders@rwth-aachen.de
[b] Dr. M. Wolberg,Dr. M. M¸ller
Institut f¸r Biotechnologie 2
Forschungszentrum J¸lich GmbH,52425 J¸lich (Germany)
Figure 1. (À)-Callystatin A and other structurally related natural products.
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4272 4284
molide[12] as well as (À)-ebelactone A[13] (enzyme inhibitor).
These compounds have been the focus of much attention from
organic chemists in recent years,not only because of the
promising biological activities shown,but also for the elegant
total syntheses in which several research groups have been
involved.
The fact that only very small amounts of this compound can
be obtained from natural sources (1.0 mg of the natural
product was isolated from 10 kg of sponge) makes (À)-
callystatin A a very attractive target for total synthesis. In fact,
some reports have very recently appeared covering the
preparation of this polyketide. Shortly after the isolation
and first total synthesis by Kobayashi et al. in 1998,[3] a total
synthesis was published by Crimmins et al.,[14] in which a
chiral auxiliary aldol methodology was employed to build up
the polypropionate chain which was coupled with the other
subunits by means of allylic Wittig reactions. In 2001 Smith
et al.[15] reported the total synthesis of (À)-callystatin A using
a combination of the Evans aldol methodology with two Julia
olefination reactions. Kalesse et al.[16] accomplished a total
synthesis employing Heck and Wittig reactions to construct
centres.[19] In addition,a flexible and convergent synthetic
route should be of great interest in the sense that structural
analogues with potentially improved biological activity could
be readily accessible.
Our retrosynthetic approach (Scheme 1) is based on
À
À
disconnections of the C6 C7 and C12 C13 double bonds,which
can be built up by means of highly E-selective Wittig
olefinations between allyltributylphosphorous ylides derived
from the corresponding allylic bromides 2 and 4.[20] Aldehyde
3 is accessible from keto ester 6,which can be prepared in an
almost enantiopure form by biocatalytic enantioselective
reduction of a 6-chloro-3,5-dioxohexanoate under conditions
recently published by us.[21] Bromide 4 can be obtained by
selective olefination of functionalised aldehyde 7,which is a
suitable compound to be prepared by asymmetric a-alkyla-
tion of the corresponding (S)-1-amino-2-methoxymethylpyr-
rolidine (SAMP) hydrazone. Finally,bromide 2 can be
synthesised from triol 5,which should be obtained by means
of a syn-selective aldol reaction between the enolate derived
from 8 and chiral aldehyde 9. The latter compounds can also
be provided as virtually single enantiomers by standard
SAMP/RAMP hydrazone alkylation procedures.
À
the C1 C20 chain and performed a final diastereoselective
aldol reaction in order to complete the synthesis. Most
recently Marshall et al.[17] have reported a total synthesis of
this polyketide in which the key attribute implicated the
formation of the polypropionate chain by stereoselective
addition of chiral allenylmetals to aldehydes. One common
feature in all reported syntheses so far is that at least one of
the stereogenic centres present in the skeleton of the natural
product was introduced from a chiral-pool building block.
In this context,and in view of the challenging structure of
(À)-callystatin A,in 1998 we determined to engage in its total
synthesis[18] as a unique opportunity to expand the scope of
our SAMP/RAMP asymmetric hydrazone alkylation method-
ology for the introduction of several of the stereogenic
Abstract in German: Durch eine effiziente asymmetrische
Totalsynthese wurde der stark cytotoxische marine Naturstoff
(À)-Callystatin A und dessen 20-epi Analogon erhalten. Die
Syntheseroute basiert auf der Darstellung von drei Fragmen-
ten, die gegen Ende der Synthese miteinander gekuppelt
werden. Das erste Fragment 3 wurde mittels einer biokatalyti-
schen, enantioselektiven Reduktion eines 3,5-Dioxocarboxylats
als Schl¸sselschritt erhalten. Zur Darstellung des zweiten
Intermediats 4 wurde eine asymmetrische a-Alkylierung eines
O-gesch¸tzten 4-Hydroxybutanals unter Anwendung der
SAMP/RAMP-Hydrazon-Methode durchgef¸hrt, gefolgt von
einer hoch Z-selektiven modifizierten Horner Wadsworth
Emmons-Reaktion. F¸r die Synthese des Polypropionatfrag-
ments 5 wurde eine diastereoselektive syn-Aldol-Reaktion
zwischen einem chiralen Ethylketon und einem a-substituier-
ten chiralen Aldehyd, beide in enantiomerenreiner Form ¸ber
asymmetrische Alkylierung der entsprechenden RAMP-Hy-
drazone hergestellt, verwendet. Schlie˚lich wurden die drei
Bausteine unter Verwendung von hoch E-selektiven Wittig-
Reaktionen via Allyltributylphosphonium Ylide miteinander
gekuppelt, um nach Oxidation und Entfernung der Schutz-
gruppe die Zielmolek¸le zu erhalten.
Scheme 1. Retrosynthetic analysis for (À)-callystatin A.
Results and Discussion
Synthesis of the aldehyde 3: For the generation of the
stereogenic centre in the key intermediate 3 (Scheme 2),we
exploited the already mentioned enantioselective biocatalytic
reduction of 3,5-dioxocarboxylates developed recently.[21a,b]
Treatment of tert-butyl 6-chloro-3,5-dioxohexanoate with
dried baker×s yeast in a biphasic system (water/XAD-7
adsorber resin) furnished the regio- and enantioselective
reduced hydroxy keto ester 6 in 94% enantiomeric excess. The
Chem. Eur. J. 2002, 8,No. 18
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FULL PAPER
Table 1. Alkylation of hydrazones 13 and 15a b. All reactions were
carried out by deprotonation of the hydrazone with LDA in THFat 08C for
5 h followed by addition of the electrophile at À1008C.
Substrate Electrophile
Product
R
Yield [%] de [%][a]
1
2
3
4
5
13
13
13
15a
15b
BrCH2CH2OTBS 14a
BrCH2CH2OIPS 14b
ICH2CH2OPMB 14c
TBS
IPS
PMB
TBS
14
34
79
85
87
84
72[b]
> 95
> 95
MeI
MeI
16a
16b
TBDPS 80
[a] Determined by 13C NMR of the crude reaction mixture. [b] Determined
by 13C NMR on product 25 (OPMB instead of OTBDPS) obtained
afterwards during the synthesis. TBS ˆ tert-butyldimethylsilyl,IPS ˆ iso-
propyldimethylsilyl,PMB ˆ para-methoxybenzyl,TBDPS ˆ tert-butyldi-
phenylsilyl.
Scheme 2. Synthesis of the aldehyde 3. a) dried baker×s yeast,XAD-7/
H2O,RT,50%. b) 1) NaBH 4,EtOH,0 8C; 2) pTsOH (cat),toluene,120 8C,
78%. c) 1) DIBAL-H,CH 2Cl2, À788C; 2) iPrOH,PPTS,benzene,80 8C,
79%. d) TBAA,NMP,85 8C,89%. e) K 2CO3,MeOH,97%. f) (COCl)
,
2
DMSO,EtN( iPr)2,CH 2Cl2, À788C,95%. TBAA ˆ tetrabutylammonium
acetate,NMP ˆ N-methyl-2-pyrrolidinone.
remaining keto group in this compound was then reduced
with sodium borohydride and upon treatment with a catalytic
amount of pTsOH in refluxing toluene underwent lactonisa-
tion together with elimination to provide the a,b-unsaturated
d-lactone 10 in good yield. The enantiomeric excess of 10 was
determined by means of HPLC analysis on a chiral stationary
phase.[22]
Scheme 3. Synthesis of the a-alkylated hydrazones 14a c and 16a b.
a) see Table 1.
Our first attempts towards the exchange of the chlorine
atom into the desired hydroxy functionality by applying
tetrabutylammonium acetate (TBAA) in the presence of N-
methylpyrrolidinone (NMP)[23] to lactone 10 led to decom-
position of the starting material. Similar observations were
made by Lichtenthaler and co-workers during the reaction of
the iodosubstituted lactone with triphenylphosphine.[24]
As a consequence we protected the lactone moiety as an
acetal by DIBAL-H reduction followed by an acid-catalysed
acetalisation with isopropanol in refluxing benzene. The
reaction was highly diastereoselective,providing the thermo-
dynamically preferred a-anomer 11[25] together with 5 8% of
the other epimer. Because this acetal would be reoxidised in
the final step of the synthesis it could be used as a mixture of
diastereoisomers,even though the separation of both was
possible using column chromatography. The conversion of the
chlorine atom into a hydroxy group was achieved by a chloro-
acetoxy substitution reaction of the protected intermediate 11
with TBAA in NMP,followed by saponification of the newly
generated ester functionality with potassium carbonate in
MeOH.[23] Finally,treatment of 12 under standard Swern
oxidation conditions furnished the aldehyde 3.
a-alkylated products by this procedure suffered from lack of
selectivity or low yields (see Table 1).
Therefore,we inverted the order of assembly of the
reagents in the construction of the stereogenic centre and
proceeded with the alkylation of the SAMP hydrazones of
O-protected 4-hydroxybutanal 15a b with iodomethane. In
this case the reactions occurred with good yields and very high
diastereoselectivities,affording the a-alkylated products with
the required (R) configuration at the newly created stereo-
genic centre (Scheme 3,Table 1).
The virtually enantiopure aldehydes 7a b were obtained
after clean removal of the auxiliary by ozonolysis (Scheme 4).
In this reaction,( S)-2-(methoxymethyl)-1-nitrosopyrrolidine,
produced together with the aldehyde 7a b,can be separated
from the latter by column chromatography and recycled to
SAMP by LiAlH4 reduction.[26] For the Z-selective installation
of the double bond in the a,b-unsaturated esters 18a b we
Synthesis of allylic bromide 4: To obtain the required chiral a-
substituted aldehyde 7,our first approach was to alkylate the
SAMP hydrazone of propanal (13) with several O-protected
2-iodo- or 2-bromoethanol derivatives (Scheme 3,Table 1).
The selection of the protecting groups was made according to
their ability to be removed under non-reductive conditions in
À
the presence of C C double bond moieties,as it is required in
our case. Although the configuration of the newly created
stereogenic centre is the opposite to the desired one,the
reaction should give us information about the viability of
this approach. Unfortunately,all attempts to obtain the
Scheme 4. Synthesis of the allylic bromides 4a b. a) O3,CH 2Cl2, À788C,
86% (7a),77% ( 7b). b) 17b,NaH,THF,0 8C,85 % ( 18a),91% ( 18b).
c) DIBAL-H,CH 2Cl2, À788C,95% ( 19a),96% ( 19b). d) CBr4,PPh
,
3
CH3CN,RT,5% ( 4a, R ˆ TBS),95% ( 4b, R ˆ TBDPS).
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(À)-Callystatin A
4272 4284
investigated modified Horner Wadsworth Emmons condi-
tions. In this context,the use of the reagent 17a introduced by
Still and Gennari[27] gave the olefination product with a
a similar approach,we prepared ( S)- and (R)-2-methylbutanal
9 and ent-9 by a-alkylation of butanal-RAMP or butanal-
SAMP hydrazones 20 or ent-20 with iodomethane,respec-
tively. Again it should be pointed out that the chiral auxiliaries
SAMP or RAMP could be recycled by LiAlH4 reduction of
the nitrosamine isolated after the ozonolysis step.[26]
moderate degree of diastereoselection (Z/E ratio of 8:1),as
17]
known from the literature.[2,14
Further investigations re-
vealed a much higher Z-selectivity employing the aryl
substituted phosphonate 17b,obtained according to a proto-
col developed by Ando.[28] This protocol uses simpler reaction
conditions (e.g. no crown ether is needed),and the esters
18a b were obtained in good yields and with excellent
diastereoselectivities (Z/E ratio of 34:1).
The next task was to install two new stereogenic centres
through a syn-selective aldol reaction between 8 and 9.
IV
(Scheme 5).[32] In a first attempt,the Ti
enolate of 8 was
reacted with aldehyde 9 and,although the aldol adduct was
obtained in good yields and excellent 4,5-syn selectivity,the
facial diastereoselectivity was not good enough and aldol
adduct 22a was obtained together with the corresponding 2,4-
anti-4,5-syn diastereomer (62:38 ratio). When the same
reaction conditions were employed on the enantiomeric
aldehyde ent-9,the matched aldol product 22b was obtained
in good yield and 94% ds. On the other hand,when we tried
the SnII mediated mismatched aldol reaction between ketone
8 and aldehyde 9,[33] aldol 22a was obtained in excellent yield
and 97% ds. It should be noted that the use of commercially
available Sn(OTf)2 for this reaction led to 0% yield,[34] only
after washing the purchased material several times with dry
diethyl ether did the reaction proceed with the given results.
In any case both aldol products 22a and 22b were obtained as
single diastereomers after column chromatography. This
matched/mismatched behaviour of the substrates in the aldol
reaction enabled us to access the natural product employing
the adduct 22a and its C-20-epimer using 22b,which
constitutes also the correct configuration of the ebelactone A
side chain.
DIBAL-H reduction of the a,b-unsaturated esters 18a
b
afforded cleanly the corresponding allylic alcohols 19a b. At
this point the enantiomeric excess could be accurately
determined by GC analysis to be >98% for each compound.
Finally,the bromination of 19a b employing CBr4/PPh3 in
acetonitrile led to the allylic bromides 4a b. In the case of 4a,
only a small amount of material (5%) together with a
complex mixture of by-products could be isolated after the
reaction. We thought that cleavage of the TBS group under
the reaction conditions could occur due to the formation of
HBr as by-product.[29] Although the yields were increased
when the reaction was repeated in the presence of a base such
as triethylamine (14%),pyridine (19%) or 26,-lutidine
(21%),they did not reach the level required for preparative
purposes. Nevertheless,the bromination reaction of the
O-TBDPS protected allylic alcohol 19b afforded the desired
bromide 4b with excellent yield and without the presence of a
base.
Synthesis of the polypropionate fragment 2:[30] For the
synthesis of the allylic bromide 2 we first had to provide the
chiral building blocks 8 and 9. Asymmetric alkylation of
3-pentanone via its (R)-1-amino-2-methoxymethylpyrrolidine
(RAMP) hydrazone derivative 21 with benzyloxymethyl
chloride (BOMCl) and subsequent cleavage of the auxiliary
afforded ketone 8 in 96% ee and good yield (Scheme 5).[31] In
Continuing with the synthesis,aldols 22a b were protected
as the corresponding TBS ethers and subsequent debenzyla-
tion with hydrogen over Pd/C afforded b-hydroxy ketones
23a b (Scheme 6). The enantiomeric excess of these com-
Scheme 6. Synthesis of allylic bromides 2a b. a) TBSOTf,26,-lutidine,
CH2Cl2,RT,98 % ( 22a),99% ( 22b). b) H2,Pd/C,EtOH,RT,95% ( 23a),
98% (23b). c) DIBAL-H,CH 2Cl2, À788C,87%
( 5a),86% ( 5b).
ˆ
d) 1) (COCl)2,DMSO,EtN( iPr)2,CH 2Cl2, À788C; 2) Ph3P C(CH3)CO2Et,
CH2Cl2,reflux,79% ( 24a),52% ( 24b). e) DIBAL-H,CH 2Cl2, À788C.
f) CBr4,PPh 3,26,-lutidine,CH 3CN,RT,76% ( 2a),81% ( 2b) over two
steps.
Scheme 5. Diastereoselective aldol coupling between 8 and 9. a) 1) LDA,
THF,0 8C; 2) MeI, À1008C. b) O3,CH 2Cl2, À788C,72% ( 9),67% ( ent-9)
over two steps. c) 1) LDA,Et 2O,0 8C; 2) BOMCl, À1008C. d) O3,CH 2Cl2,
À788C,79% over two steps. e) 1) Sn(OTf) 2,Et 3N,CH 2Cl2, À788C; 2) 9,
À788C,87% (97% ds). f) 1) TiCl4,EtN( iPr)2,CH 2Cl2, À788C; 2) ent-9,
À788C,96% (94% ds).
pounds was determined to be >96% by the NMR analysis of
the corresponding Mosher esters. Reduction with DIBAL-H
in CH2Cl2 at low temperature yielded stereopentads 5a
b
with excellent diastereoselectivities (de 91% and 86% for 5a
[35]
and 5b,respectively).
Subsequent Swern oxidation of the
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D. Enders et al.
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primary hydroxy group followed by a Wittig reaction with
base at lower temperature (À788C) instead enable the
coupling of both phosphonium salts derived from 2a and 2b
with aldehyde 1. The pentaenes 26a b were obtained in good
yield and again as single E-isomers concerning the newly
generated double bond. Treatment of these pentaenes with
PCC led to oxidation of the lactol moiety and the unprotected
hydroxy group in C1 and C17 position,respectively. Finally the
TBS ether was deprotected with HF/pyridine complex in THF
to obtain the natural (À)-callystatin A and its 20-epi analogue.
The spectroscopic data observed for our synthetic (À)-
callystatin A were identical in all respects with those reported
for the natural material (1H and 13C NMR,HRMS,[ a]D20 and
ˆ
Ph3P C(CH3)CO2Et afforded the E isomers of a,b-unsatu-
rated esters 24a b as the only detectable products. No
oxidation of the secondary alcohol functionality could be
observed even though an excess of oxidative reagent was
applied. Because ester 24a is a known compound we could
confirm the proposed absolute configuration of this building
block by comparison with the data reported in the literatur-
e.[30a] Finally,DIBAL-H reduction of the ester moiety and
selective bromination[36] of the primary alcohol with CBr4/
PPh3 furnished the desired polypropionate fragment 2a b.
Notably,in this case,the bromination reaction had to be
carried out in the presence of one equivalent of a base such as
2,6-lutidine to prevent the generation of a significant amount
of the corresponding TBS-deprotected analogue.
3]
IR).[1
Conclusion
Assembling of the synthetic intermediates and synthesis of
(À)-callystatin A and (À)-20-epi-callystatin A: In order to
build up the skeleton of the target compounds,allylic bromide
4b was converted into the corresponding tributylphosphoni-
um salt by treatment with PBu3 in acetonitrile. The Wittig
reaction of the salt with aldehyde 3 in the presence of KOtBu
afforded the Western part 25 of the target molecules in good
yield and as a single E isomer concerning the newly formed
double bond (Scheme 7). Deprotection of the TBDPS ether
A concise and flexible asymmetric total synthesis of the
cytotoxic polyketide (À)-callystatin A has been achieved. The
key steps of this synthesis rely on the creation of all
stereogenic centres in the first stages by using the SAMP/
RAMP hydrazone alkylation protocol together with an
enantioselective biocatalytic reduction and a syn-selective
aldol protocol. We therefore achieved the first asymmetric
and non ex-chiral pool synthesis of this natural product. As
another interesting feature of this synthesis the two diene
systems have been built up using highly diastereoselective
Wittig and Horner Wadsworth Emmons reactions. While
optimising the reaction conditions for the diastereoselective
aldol reaction that was intended for the preparation of the
polypropionate chain of the target compound,efficient
conditions for the synthesis of an epimeric intermediate were
found. This intermediate was also employed in the reaction
sequence providing the previously unknown 20-epi analogue
of (À)-callystatin A. The overall yield of both the natural
product (18%) and its C-20 epimer (17%,13 steps for the
longest linear reaction sequence) is comparable or better as in
17]
the previous reported syntheses.[3,14
Experimental Section
General methods: Solvents were purified and dried prior to use.
Tetrahydrofuran (THF),diethyl ether,benzene and toluene were freshly
distilled from sodium/benzophenone under argon. Dichloromethane,
acetonitrile,dimethylsulfoxide (DMSO),diisopropylamine,triethylamine,
diisopropylethylamine (DIPEA) and N-methyl-2-pyrrolidinone (NMP)
were distilled from CaH2 and stored under argon. Methanol was distilled
from magnesium methoxide. Diethyl ether and pentane for column
chromatography were distilled prior to use. Analytical glass-backed TLC
plates (silica gel 60 F254) and silica gel (400 630 mesh) were purchased
from Merck. nBuLi was used as 1.5 1.4m solution in hexane (Merck) and
titrated regularly with diphenylacetic acid before use. (S)- and (R)-1-
Amino-2-methoxymethylpyrrolidine,[37] hydrazones 13,[38] 20a b,[38] and
21,[39] benzyloxymethyl chloride (BOMCl)[40] and lactone 10[21b] were
prepared according to literature procedures. Reagents of commercial
quality were used from freshly opened containers unless otherwise stated.
Ozone was generated with Fischer Ozon apparatus M502,the flow of
oxygen is given in the reaction procedures. Melting points were measured
Scheme 7. Synthesis of (À)-callystatin A and its C-20-epimer. a) PBu3,
CH3CN, RT. b) 3,KO tBu,toluene,0 8C,86% over two steps. c) TBAF,
THF,RT. d) (COCl) 2,DMSO,EtN( iPr)2,CH Cl2, À788C,91% over two
2
steps. e) 1,LiCH 2S(O)CH3,toluene, À788C,76% ( 26a),73% ( 26b).
f) PCC,AcOH,4 ä MS,C
6H6,RT. g) HF ¥ pyridine,THF,RT,72%
(callystatin A),69% (20- epi-callystatin A). TBAF ˆ tetrabutylammonium
fluoride,PCC ˆ pyridinium chlorochromate.
took place smoothly employing TBAF in THF and Swern
oxidation yielded aldehyde 1 ready for the next Wittig
coupling reaction with the polypropionate fragments 2a b.
During the final assembly step the allyltributylphosphoni-
um salt derived from allylic bromide 2a failed to react with
aldehyde 1 under the conditions previously employed (KOtBu
in toluene at 08C). Nevertheless,the use of LiCH 2S(O)CH3 as
on
a B¸chi apparatus and are uncorrected. Optical rotations were
measured using a Perkin-Elmer P241 polarimeter and solvents of Merck
UVASOL quality. Microanalyses were obtained with a CHN-O-RAPID
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(À)-Callystatin A
4272 4284
elemental analyser. 1H and 13C NMR spectra were recorded on a Varian
Unity 500 (500 and 125 MHz,respectively),Varian Inova 400 (400 and
100 MHz,respectively) or Varian Gemini 300 (300 and 75 MHz,respec-
tively) in CDCl3 using tetramethylsilane as internal standard unless
otherwise noted. IR spectra were measured on Perkin-Elmer FT/IR 1750
and 1720X spectrophotometers as films or in CHCl3 solutions. Mass spectra
were obtained on a Varian MAT 212 or a Finigan MAT SSQ 7000,EI 70 eV
or CI 100 eV (relative intensities in parentheses). High resolution mass
spectra were measured on a Finigan MAT 95.
1402,1382,1318,1242,1138,1126,1104,1039,1017,976,954,931,906,846,
825,794,719,633,508 cm À1; MS (CI,100 eV,isobutane): m/z (%): 173 (42)
‡
[M ‡H],114 (7),113 (100); elemental analysis calcd (%) for C 9H16O3: C
62.77,H 9.36; found: C 62.63,H 9.08.
(2R,6R)-6-Isopropoxy-3,6-dihydro-2H-pyran-2-carbaldehyde (3): Oxalyl
chloride (0.57 mL,6.52 mmol) was added at À788C to a solution of
DMSO (0.92 mL,13.04 mmol) in dry CH 2Cl2 (20 mL). After stirring for
10 min,a solution of the alcohol 12 (1.02 g,5.93 mmol) in CH 2Cl2 (15 mL)
was carefully added and the mixture was stirred for an additional 15 min.
DIPEA (5.16 mL,29.65 mmol) was added at once and,after 10 min,it was
allowed to reach RT and quenched with water (30 mL). The organic layer
was separated and the aqueous phase was extracted with Et2O (3 Â 25 mL).
The combined organic fractions were dried over Na2SO4,filtered and the
solvent was removed under reduced pressure. The obtained oil was
dissolved in Et2O and filtered through a short path of silica gel,eluting with
Et2O/pentane 1:1,and afforded crude aldehyde 3 as a yellowish oil,which
was used directly in the next step without further purification (0.96 g,
95%). 1H NMR (400 MHz): d ˆ 1.20 (d, J ˆ 6.2 Hz,3H),1.25 (d, J ˆ 6.2 Hz,
(2R,6R)-(‡)-2-Chloromethyl-6-isopropoxy-3,6-dihydro-2H-2-pyran (11):
A 1m solution of DIBAL-H in CH2Cl2 (7.48 mL,7.48 mmol) was slowly
added to a cold (À788C) solution of chlorolactone 10 (1.00 g,6.80 mmol) in
CH2Cl2 (30 mL). After stirring for 30 min,the reaction was quenched with
1m HCl solution (20 mL) and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (3 Â 15 mL) and the combined organic fractions
were dried over Na2SO4,filtered and the solvent was removed under
reduced pressure. The resulting oil was taken up in benzene (30 mL) and
isopropanol (1.56 mL,20.41 mmol) and PPTS (25 mg) was added. The
mixture was heated under reflux for 3 h and quenched with water. The
mixture was extracted with CH2Cl2 (3 Â 20 mL) and the combined organic
fractions were dried over Na2SO4,filtered and the solvent was removed
under reduced pressure,affording lactol 11 after flash column chromatog-
raphy (Et2O/pentane 1:9) as a colourless oil (1.03 g,79%). [ a]2D0 ˆ ‡19.1
(c ˆ 1.4,CHCl 3); 1H NMR (400 MHz): d ˆ 1.18 (d, J ˆ 6.0 Hz,3H),1.25 (d,
3H),2.11 2.27 (m,2H),4.06 (sept,
4.7 Hz,1H),5.21 (m,1H),5.75 (dtd,
J ˆ 6.2 Hz,1H),4.41 (dd, J ˆ 11.3,
J ˆ 10.2,2.9,1.7 Hz,1H),6.02 (m,
1H),9.73 (s,1H); 13C NMR (100 MHz): d ˆ 21.94,23.73,24.88,70.06,70.95,
92.92,126.32,126.64,200.78.
4-(tert-Butyldimethylsilyloxy)butanal: 1,4-Butanediol (720 mg, 8.09 mmol)
was slowly added to a suspension of NaH (194 mg,8.09 mmol) in dry THF
(50 mL) at 08C. After stirring for 1 h at this temperature and for 2 h at RT,
the mixture was cooled down to 08C and TBSCl (1.17 g,8.09 mmol) was
added at once. The mixture was stirred at RT for 2 h and quenched with
water (20 mL). The obtained oil was dissolved in dry CH2Cl2 (10 mL) and
added to a cold (À788C) solution of Swern reagent (prepared by addition
of oxalyl chloride (0.78 mL,8.90 mmol) to a solution of DMSO (1.26 mL,
17.79 mmol) in dry CH2Cl2 (50 mL) at À788C followed by 30 min stirring at
this temperature). The mixture was stirred for 1 h and Et3N (6.23 mL,
44.48 mmol) was added at once. After stirring for 30 min at À788C the
mixture was allowed to reach to RT,stirred for further 30 min and
quenched with water (20 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 Â 25 mL). The combined
organic fractions were dried over Na2SO4,filtered and the solvent was
removed under reduced pressure,affording the pure aldehyde after flash
column chromatography (Et2O/pentane 1:3) as a colourless oil (1.45 g,89%
J ˆ 6.0 Hz,3H),2.04 (dddd, J ˆ 17.5,5.4,3.9,1.5 Hz,1H),2.13 (ddtd,
17.5,10.7,2.5,1.5 Hz,1H),3.59 (d,
J ˆ 5.5 Hz,2H),4.07 (sept, J ˆ 6.2 Hz,
1H),4.18 (dtd, J ˆ 10.7,5.3,3.9 Hz,1H),5.13 (dd, J ˆ 1.5,1.3 Hz,1H),5.74
J ˆ
(dtd, J ˆ 10.0,2.9,1.5 Hz,1H),5.98 (dddd,
J ˆ 10.0,5.6,2.3,1.3 Hz,1H);
13C NMR (100 MHz): d ˆ 21.80,23.76,27.97,46.98,66.17,69.35,92.91,
126.12,127.58; IR (film): nÄ ˆ 2971,2928,2901,1660,1466,1428,1402,1382,
1318,1260,1230,1183,1141,1126,1101,1066,1035,1017,977,956,931,897,
874,856,841,815,797,742,717,686,636,578,506,492 cm
À1; MS (CI,100 eV,
‡
isobutane): m/z (%): 193 (15),191 (47) [ M ‡H],133 (34),131 (100);
elemental analysis calcd (%) for C9H15ClO2: C 56.69,H 7.93; found: C
56.55; H 7.85.
(2R,6R)-(‡)-(6-Isopropoxy-3,6-dihydro-2H-6-pyran-2-yl)methanol (12):
Tetrabutylammonium acetate (2.28 g,17.15 mmol) was placed in a flask
under argon and a solution of the chlorolactol 11 (1.31 g,6.86 mmol) in
NMP (10 mL) was added. The mixture was heated to 858C for 3 h,cooled
to RT and water (30 mL) was added. The mixture was extracted with Et2O
(3 Â 25 mL) and the combined organic fractions were dried over Na2SO4,
filtered and the solvent was removed under reduced pressure,affording the
desired acetoxylactol after flash column chromatography purification
(Et2O/pentane 1:2) as a colourless oil (1.31 g,89%). [ a]2D0 ˆ ‡31.7 (c ˆ
1.4,CHCl 3); 1H NMR (300 MHz): d ˆ 1.18 (d, J ˆ 6.3 Hz,3H),1.25 (d, J ˆ
1
yield over two steps). H NMR (400 MHz): d ˆ 0.04 (s,6H),0.89 (s,9H),
1.87 (m,2H),2.51 (dt, J ˆ 7.2,1.6 Hz,2H),3.66 (t, J ˆ 6.0 Hz,2H),9.79 (t,
J ˆ 1.9 Hz,1H); 13C NMR (100 MHz): d ˆ À5.41,18.25,25.47,25.85,40.72,
61.98,202.26; IR (film): nÄ ˆ 2930,2887,2857,2716,1727,1472,1440,1410,
1389,1361,1255,1099,1017,980,939,836,810,777,663 cm
À1; MS (EI,
‡
70 eV): m/z (%): 145 (75) [M À C4H9],127 (11),115 (12),89 (6),75 (100),
59 (9),45 (5).
6.3 Hz,3H),1.94 (m,1H),2.06 (m,1H),2.09 (s,3H),4.02 (sept,
J ˆ 6.3 Hz,
1H),4.16 (m,2H),4.20 (m,1H),5.11 (dd,
J ˆ 1.5,1.1 Hz,1H),5.75 (dtd,
4-(tert-Butyldiphenylsilyloxy)butanal: The same procedure as described
for the previous aldehyde using 1,4-butanediol (3.50 g, 38.83 mmol), NaH
(0.93g,38.83 mmol) TBDPSCl (10.67 g,38.83 mmol),oxalyl chloride
J ˆ 10.2,2.7,1.5 Hz,1H),5.99 (dddd,
J ˆ 10.2,5.8,1.9,1.1 Hz,1H);
13C NMR (75 MHz): d ˆ 20.83,22.11,23.68,26.47,64.42,66.27,69.83,93.14,
126.15,127.76,170.88; IR (film): nÄ ˆ 3046,2971,2930,2899,1743,1659,
1455,1429,1407,1369,1318,1285,1238,1184,1127,1096,1042,1032,978,
(3.74 mL,42.72 mmol),DMSO (6.06 mL,85.44 mmol) and Et
3N
(27.1 mL,194.15 mmol) afforded the aldehyde as a colourless oil (12.10 g,
95%). 1H NMR (400 MHz): d ˆ 1.05 (s,9H),1.89 (m,2H),2.54 (dt, J ˆ 7.1,
1.5 Hz,2H),3.69 (t, J ˆ 7.1 Hz,2H),7.35 7.45 (m,6H),7.63 7.68 (m,4H),
9.78 (t, J ˆ 1.5 Hz,1H); 13C NMR (100 MHz): d ˆ 19.14,25.19,26.77,40.67,
961,933,915,862,845,826,802,719,646,607,513,472 cm
À1; MS (EI,
‡
70 eV): m/z (%): 213 (0.6) [M À H],155 (86),141 (21),112 (19),95 (100),
81 (9),70 (23),67 (20); elemental analysis calcd (%) for C 11H18O4: C 61.66,
H 8.47; found: C 61.53,H 8.31.
62.81,127.49,129.47,133.36,135.15,202.13; IR (film):
nÄ ˆ 3070,3049,2955,
2931,2890,2858,2720,1726,1471,1428,1390,1110,1012,823,739,704,613,
The acetoxylactol (1.30 g,6.07 mmol) was dissolved in dry methanol
(15 mL) and K2CO3 (420 mg,3.04 mmol) was added in one portion. After
stirring for 30 min at RT the solvent was removed under reduced pressure
and the residue was taken up in water (10 mL) and CH2Cl2 (10 mL). The
506 cmÀ1; MS (EI,70 eV): m/z (%): 269 (100) [M À C4H9],227 (6),199
‡
(72),191 (20),181 (15),161 (11),139 (34),131 (19),129 (12),105 (19).
(S)-(À)-1'-(4-tert-Butyldimethylsilyloxy-1-butylidenamino)-2'-(methoxy-
methyl)pyrrolidine (15a): SAMP (0.65 g,4.95 mmol) was added to 4- tert-
butyldimethylsilyloxybutanal (1.00 g,4.95 mmol) at 0 8C and the mixture
was stirred for 3 h at RT. Et2O (10 mL) and Na2SO4 were added and the
mixture was stirred for a further 30 min. After filtration and removal of the
solvent under reduced pressure,pure hydrazone 15a was obtained after
flash column chromatography (Et2O/pentane 1:1‡3% Et3N) as a colour-
less oil. (1.34 g,86%). [ a]D20 ˆ À34.9 (c ˆ 0.9,CHCl 3); 1H NMR (400 MHz):
d ˆ 0.05 (s,6H),0.89 (s,9H),1.21 (t, J ˆ 7.1 Hz,2H),1.70 (m,2H),1.92 (m,
2H),2.27 (m,2H),2.74 (q, J ˆ 8.5 Hz,1H),3.27 (m,1H),3.37 (s,3H),3.43
layers were separated,the aqueous phase was extracted with CH Cl2 (3 Â
2
25 mL) and the combined organic fractions were dried over Na2SO4,
filtered and the solvent was removed under reduced pressure,affording the
hydroxylactol 12 after flash column chromatography (Et2O/pentane 1:1) as
a white solid (1.01 g,97%). M.p. 39 42 8C; [a]2D0 ˆ ‡36.5 (c ˆ 0.3,CHCl 3);
1H NMR (400 MHz): d ˆ 1.18 (d, J ˆ 6.0 Hz,3H),1.25 (d, J ˆ 6.3 Hz,3H),
1.89 (dddd, J ˆ 17.6,5.8,3.3,1.4 Hz,1H),2.15 (dddt,
1.9 Hz,1H),2.21 (brs,1H),3.60 (dd,
11.5,3.2 Hz,1H),4.00 (sept, J ˆ 6.2 Hz,1H),4.07 (m,1H),5.11 (m,1H),
J ˆ 17.6,11.3,2.5,
J ˆ 11.5,6.0 Hz,1H),3.72 (dd, J ˆ
5.73 (dtd, J ˆ 10.0,3.0,1.5 Hz,1H),5.99 (dddd,
J ˆ 10.0,5.6,1.4,1.4 Hz,
(m,1H),3.49 (q, J ˆ 7.1,1H),3.56 (dd, J ˆ 8.8,3.6 Hz,1H),3.65 (t,
J ˆ
1H); 13C NMR (100 MHz): d ˆ 21.91,23.78,25.98,65.17,66.61,69.41,92.66,
125.75,127.99; IR (film): nÄ ˆ 3447,3044,2971,2927,2889,1658,1466,1425,
6.3 Hz,2H),6.65 (t, J ˆ 5.5 Hz,1H); 13C NMR (100 MHz): d ˆ À5.26,
18.34,22.13,25.95,26.56,29.56,30.84,50.33,59.10,62.58,63.41,74.74,
Chem. Eur. J. 2002, 8,No. 18
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
0947-6539/02/0818-4277 $ 20.00+.50/0
4277

D. Enders et al.
FULL PAPER
138.40; IR (film): nÄ ˆ 2953,2928,2886,2856,1471,1462,1387,1361,1255,
(15),129 (39),89 (17),75 (94),73 (17),59 (11); elemental analysis calcd (%)
for C11H24O2Si: C 61.05,H 11.18; found: C 60.98,H 11.17.
1196,1099,1006,972,836,813,776 cm À1; MS (EI,70 eV): m/z (%): 314 (11)
‡
[M ],269 (100),106 (6),101 (5),89 (6),73 (28),70 (10),59 (10); 45 (9);
(R)-(À)-4-tert-Butyldiphenylsilyloxy-1-methylbutanal (7b): The same pro-
cedure as described for the previous ozonolysis using hydrazone 16b
(2.16 g,4.78 mmol) afforded 7b as a colourless oil (1.15 g,77%). [ a]D20
À29.5 (c ˆ 0.3,CHCl 3); 1H NMR (400 MHz): d ˆ 1.04 (s,9H),1.08 (d, J ˆ
6.8 Hz,3H),1.63 (m,1H),1.98 (m,1H),2.53 (m,1H),3.71 (m,2H),7.36
(m,6H),7.62 (m,4H),9.67 (d, J ˆ 1.7 Hz,1H); 13C NMR (100 MHz): d ˆ
13.12,19.21,26.77,33.44,43.44,61.02,127.56,129.46,133.36,135.39,204.54;
elemental analysis calcd (%) for C16H34N2O2Si: C 61.10,H 10.90,N 8.91;
found: C 61.01,H 11.11,N 9.16.
ˆ
(S)-(À)-1'-(4-tert-Butyldiphenylsilyloxy-1-butylidenamino)-2'-(methoxy-
methyl)pyrrolidine (15b): The same procedure as described for the
previous hydrazone using SAMP (2.22 g,17.07 mmol),and 4- tert-butyldi-
phenylsilyloxybutanal (5.60 g,17.07 mmol) afforded 15b as a colourless oil
(7.13 g,95%). [ a]2D0 ˆ À69.4 (c ˆ 0.8,CHCl 3); 1H NMR (400 MHz): d ˆ 1.06
(s,9H),1.72 1.96 (m,6H),2.33 (q, J ˆ 7.1 Hz,2H),2.54 (dq, J ˆ 7.1,2.5 Hz,
1H),2.68 (q, J ˆ 8.2 Hz,1H),3.21 (m,1H),3.36 (s,3H),3.41 (m,1H),3.55
(dd, J ˆ 8.2,3.0 Hz,1H),3.71 (t, J ˆ 6.3,1H),6.61 (t, J ˆ 5.5 Hz,1H),7.34
IR (film): nÄ ˆ 2959,2931,2858,1728,1708,1472,1462,1428,1112,1006,998,
‡
823,738,703,688,614,505 cm
À1; MS (EI,70 eV): m/z (%): 325 (3) [M
À
CH3],294 (11),283 (100),253 (15),227 (11),205 (51),199 (93),183 (19),181
(20),175 (43),139 (25),135 (11),105 (12); elemental analysis calcd (%) for
C21H28O2Si: C 74.07,H 8.29; found: C 73.94,H 8.23.
7.43 (m,6H),7.63 7.70 (m,4H);
26.54,26.82,29.55,30.66,50.26,59.09,63.30,63.35,74.73,127.39,129.31,
13C NMR (100 MHz): d ˆ 19.18,22.11,
Ethyl di-(2-methoxyphenyl)phosphonobutyrate (17b): Phosphorus penta-
chloride (50.4 g,240 mmol) was added in portions to triethyl 2-phospho-
nobutyrate (24.1 g,95 mmol) at RT. After stirring for 15 min at this
temperature the mixture was heated to 758C in a distillation apparatus for
8 h. After cooling to RT the flask with the crude product was connected
with a receiver flask which was cooled with liquid nitrogen and POCl3 was
vacuum transferred at RT. After 30 min maintaining this temperature the
flask was heated to 1008C and surplus PCl5 was vacuum transferred to the
receiver flask. After 1 h the receiver flask was disconnected and the
yellowish oil (21.7 g) was used in the next steps without further purification.
1H NMR (300 MHz): d ˆ 1.11 (td, J ˆ 7.4,1.4 Hz,3H),1.33 (t, J ˆ 7.1 Hz,
133.76,135.33,138.29; IR (film): nÄ ˆ 3070,2930,2891,2858,1472,1462,
1428,1196,1111,823,740,703,688,614,506 cm
À1; MS (EI,70 eV): m/z (%):
‡
438 (8) [M ],393 (100),197 (7),168 (16),135 (17),70 (6),45 (5); elemental
analysis calcd (%) for C26H38N2O2Si: C 71.19,H 8.73,N 6.39; found: C
71.08,H 8.70,N 6.27.
(2'S,2R)-(À)-1'-(4-tert-Butyldimethylsilyloxy-2-methyl-1-butylidenami-
no)-2'-(methoxymethyl)pyrrolidine (16a): A solution of the hydrazone 15a
(0.90 g,3.19 mmol) in dry THF (15 mL) was added to a cooled (0 8C)
solution of LDA (0.38 g,3.51 mmol) in THF (20mL). After stirring for 5 h,
the mixture was cooled down to À1058C and a solution of MeI (0.22 mL,
3.51 mmol) in THF (10 mL) was slowly added. The mixture was stirred at
this temperature for 3 h,allowed to warm to RT and quenched with water
(20 mL). The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 Â 15 mL). The combined organic fractions were
dried over Na2SO4,filtered and the solvent removed under reduced
pressure to afford the a-alkylated hydrazone 16a after flash column
chromatography (Et2O/pentane 1:5‡3% Et3N) as a colourless oil (0.81 g,
85%). [a]2D0 ˆ À79.7 (c ˆ 0.8,CHCl 3); 1H NMR (400 MHz): d ˆ 0.04 (s,
3H),2.18 (m,2H),3.50 (ddd,
J ˆ 17.6,9.4,5.3 Hz,1H),4.31 (m,2H);
13C NMR (75 MHz): d ˆ 12.56 (d, J ˆ 6.9 Hz),14.02,21.38 (d, J ˆ 5.1 Hz),
60.19 (d, J ˆ 90.5 Hz),62.64,165.79 (d, J ˆ 3.5 Hz).
Triethylamine (30 mL) were added at 08C to a solution of the crude
dichloride (19.2 g) and guajacol (27.9 g,225 mmol) in benzene (120 mL).
After stirring for 1.5 h at this temperature and an additional 1.5 h at RT the
solution was filtered,diluted with diethyl ether (80 mL) and washed with
1m NaOH solution (3 Â 15 mL). After washing with pH 7 buffer (1 Â
15 mL) and brine (1 Â 15 mL) the organic phase was dried over Na2SO4.
After filtration and evaporation of the solvent under reduced pressure the
pure phosphonate (15.5 g,45%) was obtained after flash chromatography
(Et2O/petroleum ether 1:2). 1H NMR (300 MHz): d ˆ 1.09 (td, J ˆ 7.3,
1.1 Hz,3H),1.25 (t, J ˆ 7.0 Hz,3H),2.26 (m,2H),3.34 (ddd, J ˆ 23.4,9.3,
3H),0.05 (s,3H),0.90 (s,9H),1.06 (d,
J ˆ 6.9 Hz,3H),1.55 (m,1H),1.70
(m,1H),1.75 1.98 (m,4H),2.45 (m,1H),2.70 (m,1H),3.31 (m,2H),3.37
(s,3H),3.42 (m,1H),3.57 (dd, J ˆ 9.1,3.6 Hz,1H),3.66 (t, J ˆ 6.6 Hz,2H),
6.50 (d, J ˆ 6.0 Hz,1H); 13C NMR (100 MHz): d ˆ À5.25, À5.23,18.31,
19.15,22.01,25.95,26.52,33.74,38.31,50.16,59.08,61.18,63.35,74.62,
143.20; IR (film): nÄ ˆ 2955,2929,2859,1463,1386,1254,1197,1101,1005,
987,898,837,810,776,898,837,810,776 cm
À1; MS (EI,70 eV): m/z (%): 328
5.2 Hz,1H),3.77 (s,3H),3.79 (s,3H),4.23 (q,
J ˆ 7.0 Hz,2H),6.81 7.25
‡
(18) [M ],283 (100),214 (6),170 (5),113 (7),89 (16),73 (25),70 (14),59
(5),45 (5); elemental analysis calcd (%) for C 17H36N2O2Si: C 62.14,H 11.04,
N 8.53; found: C 62.03,H 10.92,N 8.58.
(m,8H); 13C NMR (75 MHz): d ˆ 13.09 (d, J ˆ 17.2 Hz),14.09,20.86 (d, J ˆ
5.7 Hz),48.18 (d, J ˆ 135.1 Hz),55.88,55.90,61.48,112.76,120.69,125.81,
122.07 (d, J ˆ 5.7 Hz),122.18 (d, J ˆ 5.7 Hz),139.60 (d, J ˆ 9.1 Hz),139.72
(d, J ˆ 9.1 Hz),150.83 (d, J ˆ 4.6 Hz),150.86 (d, J ˆ 4.6 Hz),168.49 (d, J ˆ
4.6 Hz); IR (film): nÄ ˆ 2976,2939,2879,1735,1604,1589,1504,1458,1263,
(2'S,2R)-(À)-1'-(4-tert-Butyldiphenylsilyloxy-2-methyl-1-butylidenami-
no)-2'-(methoxymethyl)pyrrolidine (16b): The same procedure as descri-
bed for the previous alkylation using hydrazone 15b (3.0 g,6.85 mmol),
LDA (0.81 g,7.53 mmol) and MeI (0.45 mL,7.53 mmol) afforded 16b as a
colourless oil (2.47 g,80%). [ a]2D0 ˆ À105.7 (c ˆ 0.7,CHCl 3); 1H NMR
(400 MHz): d ˆ 1.03 (d, J ˆ 6.9 Hz,3H),1.05 (s,9H),1.61 (m,2H),1.68
1.94 (m,4H),2.54 (m,2H),2.68 (m,1H),3.21 (m,1H),3.33 (s,3H),3.64
1210,1197,1170,1112,1043,1026,946,800,754 cm
À1; MS (EI,70 eV): m/z
‡
‡
(%): 409 (12) [M ‡H],408 (61) [ M ],363 (20),293 (9),286 (14),285 (100)
‡
[M À C7H7O2],257 (29),239 (24),215 (35),211 (10),187 (95),172 (26),138
‡
(13),124 (23),123 (9),109 (13),77 (13); HRMS: calcd for [C 20H25PO7] :
408.1338; found: 408.1337.
(m,1H),3.55 (dd, J ˆ 8.8,3.3 Hz,1H),3.75 (m,2H),6.48 (d,
J ˆ 8.2 Hz,
(3Z,5R)-(‡)-7-tert-Butyldimethylsilyloxy-3-ethoxycarbonyl-5-methyl-
hept-3-ene (18a): A solution of the phosphonate 17b (319 mg,0.78 mmol)
in dry THF (5 mL) was added over a cooled (08C) suspension of NaH
(32 mg,0.78 mmol) in THF (5 mL). After stirring for 3 h at this temper-
ature,a solution of the aldehyde 7a (130 mg,0.60 mmol) in THF (5 mL)
was added at once and the reaction was stirred for 1 h at 08C,allowed to
warm to RT and quenched with water (15 mL) when TLC analysis of
aliquots indicated full conversion (typically 4 5 h). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (3 Â 10 mL).
The combined organic fractions were dried over Na2SO4,filtered and the
solvent removed under reduced pressure to afford the a,b-unsaturated
ester after flash column chromatography (Et2O/pentane 1:2) as a colourless
oil (160 mg,85%). [ a]2D0 ˆ ‡21.4 (c ˆ 0.3,CHCl 3); 1H NMR (400 MHz):
1H),7.34 (m,6H),7.68 (m,4H);
13C NMR (100 MHz): d ˆ 19.02,19.21,
22.07,26.65,28.85,33.77,38.13,50.15,59.12,62.01,63.31,74.60,127.57,
129.33,133.93,135.45,143.00; IR (film): nÄ ˆ 2957,2929,2857,1472,1461,
1428,1389,1195,1111,998,899,823,739,703,688,614,506 cm
À1; MS (EI,
‡
70eV): m/z (%): 452 (19) [M ],407 (100),197 (6),183 (6),175 (10),135
(15),70 (7); elemental analysis calcd (%) for C 27H40N2O2Si: C 71.63,H 8.91,
N 6.19; found: C 71.73,H 8.82,N 6.23.
(R)-(À)-4-tert-Butyldimethylsilyloxy-1-methylbutanal (7a): Hydrazone
16a (3.17 g,10.71 mmol) was dissolved in CH 2Cl2 and the solution was
cooled to À788C. Ozone (60 LhÀ1) was bubbled through the solution until
persistent blue colour was observed and then argon was bubbled until the
blue colour disappeared. The solution was allowed to warm to RT and the
solvent was removed under reduced pressure. Pure aldehyde 7a (1.99 g,
86%) was obtained after flash column chromatography (Et2O/pentane
1:2). [a]2D0 ˆ À17.6 (c ˆ 0.5,CHCl 3); 1H NMR (400 MHz): d ˆ 0.04 (s,6H),
0.89 (s,9H),1.12 (d, J ˆ 7.1 Hz,3H),1.54 (m,1H),1.96 (m,1H),2.52 (m,
d ˆ 0.03 (s,6H),0.89 (s,9H),1.00 (d,
J ˆ 6.4 Hz,3H),1.03 (t, J ˆ 7.4 Hz,
J ˆ 1.1,7.4 Hz,
3H),1.24 (t, J ˆ 7.1 Hz,3H),1.45 1.63 (m,2H),2.25 (dq,
2H),3.06 (m,1H),3.58 (t, J ˆ 6.9 Hz,2H),4.19 (q, J ˆ 7.1 Hz,2H),5.58 (dt,
J ˆ 10.2,1.4 Hz,1H); 13C NMR (100 MHz): d ˆ À5.33, À5.31,13.66,14.25,
18.29,20.78,25.91,27.58,30.35,40.34,59.91,61.52,132.52,144.78,168.09; IR
(film): nÄ ˆ 2957,2929,2898,2857,1717,1471,1463,1380,1254,1237,1203,
1H),3.64 3.78 (m,2H),9.65 (d,
J ˆ 1.9 Hz,1H); 13C NMR (100 MHz):
d ˆ À5.45,13.07,18.24,25.84,33.66,43.48,60.15,204.59; IR (film):
nÄ ˆ
2955,2931,2885,2858,1728,1709,1471,1388,1256,1103,836,811,777,
1161,1138,1098,1028,1006,902,837,811,776 cm
(%): 299 (3) [M À CH3],269 (10),257 (100),211 (12),133 (9),109 (28),103
À1; MS (EI,70 eV): m/z
734 cmÀ1; MS (EI,70 eV): m/z (%): 201 (1) [M À CH3],159 (100),141
‡
‡
4278
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
0947-6539/02/0818-4278 $ 20.00+.50/0
Chem. Eur. J. 2002, 8,No. 18

(À)-Callystatin A
4272 4284
(15),95 (13),75 (27),73 (18),59 (15),57 (14),55 (13); elemental analysis
calcd (%) for C17H34O3Si: C 64.92,H 10.90; found: C 64.84,H 11.17.
129.36,140.82; IR (film): nÄ ˆ 2958,2930,2857,1462,1255,1068,839,
775 cmÀ1; MS (EI,70 eV): m/z (%): 307 (1),279 (10),277 (10),123 (100),95
(11),81 (43),75 (32),73 (22),69 (29),59 (18),55 (14),45 (13); elemental
analysis calcd (%) for C15H31BrOSi: C 53.72,H 9.32; found: C 53.78,H 9.28.
(3Z,5R)-(‡)-7-tert-Butyldiphenylsilyloxy-3-ethoxycarbonyl-5-methylhept-
3-ene (18b): The same procedure as described previously using aldehyde
7b (300 mg,0.96 mmol),phosphonate 17b (471 mg,1.15 mmol) and NaH
(3Z,5R)-(‡)-3-Bromomethyl-7-tert-butyldiphenylsilyloxy-5-methylhept-3-
ene (4b): The same procedure as previously described using a,b-
(28 mg,1.15 mmol) afforded 18b as a colourless oil (418 mg,91%). [ a]D20
ˆ
‡23.6 (c ˆ 0.4,CHCl ); 1H NMR (400 MHz): d ˆ 0.95 (d, J ˆ 5.8 Hz,3H),
unsaturated ester 19b (37 mg,0.093 mmol),PPh (61 mg,0.21 mmol) and
3
3
0.99 (t, J ˆ 6.2 Hz,3H),1.03 (s,9H),1.23 (t, J ˆ 7.1 Hz,3H),1.51 1.73 (m,
CBr4 (77 mg,0.21 mmol) afforded 4b as a colourless oil (41 mg,95%).
[a]2D0 ˆ ‡51.6 (c ˆ 0.7,CHCl 3); 1H NMR (400 MHz): d ˆ 0.96 (d, J ˆ 6.6 Hz,
3H),1.01 (t, J ˆ 7.4 Hz,3H),1.06 (s,9H),1.44 (m,1H),1.60 (m,1H),2.15
(dq, J ˆ 7.1,1.1 Hz,2H),2.71 (m,1H),3.62 (dt, J ˆ 5.8,1.4 Hz,2H),3.88 (d,
J ˆ 9.9 Hz,1H),4.12 (d, J ˆ 9.6 Hz,1H),5.08 (dt, J ˆ 9.9,0.6 Hz,1H),
2H),2.24 (m,2H),3.15 (m,1H),3.62 (m,2H),4.15 (q,
J ˆ 7.1 Hz,2H),5.52
(dt, J ˆ 9.9,1.4 Hz,1H),7.48 (m,6H),7.65 (m,4H);
13C NMR (100 MHz):
d ˆ 13.65,14.42,19.18,20.76,26.87,27.61,30.34,40.10,59.97,62.20,127.49,
129.37,132.59,133.88,135.38,144.80,168.06; IR (film): nÄ ˆ 3071,2961,2931,
2897,2858,1715,1472,1462,1428,1388,1237,1203,1161,1137,1110,1028,
7.34 7.44 (m,6H),7.66 (m,4H);
13C NMR (100 MHz): d ˆ 12.55,19.14,
‡
823,793,739,704,614,506 cm
C2H5O],381 (100),231 (5),227 (13),199 (15),183 (13),135 (5),109 (4);
À1; MS (EI,70 eV): m/z (%): 393 (5) [M
À
20.66,26.84,27.94,28.88,31.08,39.83,61.79,127.39,129.34,133.74,135.33,
135.71,135.92; IR (film): nÄ ˆ 2960,2930,2858,1471,1460,1428,1205,1110,
823,737,703 cm À1; MS (EI,70 eV): m/z (%): 403 (10),401 (10),263 (26),
261 (25),199 (12),197 (11),183 (10),181 (9),135 (11),123 (100),97 (10),95
(11),81 (36),67 (10); elemental analysis calcd (%) for C 25H35BrOSi: C
65.34,H 7.68; found: C 65.43,H 7.71.
elemental analysis calcd (%) for C27H38O3Si: C 73.92,H 8.73; found: C
74.11,H 8.66.
(3Z,5R)-(À)-7-tert-Butyldimethylsilyloxy-3-hydroxymethyl-5-methylhept-
3-ene (19a): A 1m solution of DIBAL-H in CH2Cl2 (0.86 mL,0.86 mmol)
was slowly added to a cold (À788C) solution of the a,b-unsaturated ester
18a (110 mg,0.35 mmol) in CH 2Cl2 (10 mL). After stirring for 30 min,the
reaction was quenched with 1m HCl solution (20 mL) and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 Â 5 mL) and
the combined organic fractions were dried over Na2SO4,filtered and the
solvent was removed under reduced pressure,affording allylic alcohol 19a
after flash column chromatography (Et2O/pentane 1:2) as a colourless oil
(83 mg,95%). GC analysis on chiral stationary phase (chirasil-dex 25 m),
showed an ee of >98% for 19a (tR ˆ 36.75 and 37.12 min for the R and S
(R)-(À)-1-Benzyloxy-2-methylpentan-3-one (8): A solution of the hydra-
zone 21 (397 mg,2.00 mmol) in dry Et 2O (5 mL) was added to a cooled
(08C) solution of LDA (235 mg,2.20 mmol) in Et 2O (7 mL). After stirring
for 5 h,the mixture was cooled down to À1058C and a solution of BOMCl
(375 mg,2.40 mmol) in Et O (10 mL) was slowly added. The mixture was
2
stirred at this temperature for 3 h,allowed to warm to RT and quenched
with water (20 mL). The organic layer was separated and the aqueous layer
was extracted with Et2O (3 Â 15mL). The combined organic fractions were
dried over Na2SO4,filtered and the solvent removed under reduced
pressure,to afford the a-alkylated hydrazone after flash column chroma-
tography (Et2O/pentane 1:2‡3% Et3N) as a colourless oil (522 mg,82%).
[a]2D0 ˆ À114.6 (c ˆ 1.0,CHCl 3); 1H NMR (500 MHz,C 6D6): d ˆ 0.88 (d,
J ˆ 7.1 Hz,3H),1.23 (t, J ˆ 7.3 Hz,3H),1.58 1.79 (m,3H),2.02 (m,1H),
2.13 (dq, J ˆ 13.5,7.3 Hz,2H),2.53 (m,1H),2.94 (m,1H),3.13 (s,3H),
enantiomers,respectively).
[
a]2D0 ˆ À51.8 (c ˆ 0.6,CHCl 3); 1H NMR
(400 MHz): d ˆ 0.07 (s,3H),0.09 (s,3H),0.90 (s,9H),0.97 (d,
J ˆ 6.6 Hz,
3H),1.04 (t, J ˆ 7.4 Hz,3H),1.24 (m,1H),1.65 (m,1H),2.11 2.25 (m,
2H),2.73 2.85 (m,1H),3.56 3.67 (m,2H),3.72 3.82 (m,2H),4.29 (d,
J ˆ 11.8 Hz,1H),4.94 (dd, J ˆ 10.4,0.6 Hz,1H); 13C NMR (100 MHz): d ˆ
À5.31, À5.01,12.97,18.29,21.91,25.86,27.97,28.82,40.19,60.35,61.02,
131.82,140.72; IR (film): nÄ ˆ 3406,2957,2858,1472,1463,1389,1362,1256,
3.18 3.57 (m,5H),3.98 (m,1H),4.27 (d,
12.1 Hz,1H),7.05 7.33 (m,5H);
14.60,22.35,24.53,27.59,34.96,55.90,58.81,66.76,72.70,72.79,76.26,
126.82,127.62,128.52,139.20,173.08; IR (film): nÄ ˆ 2970,2932,2873,2732,
2066,1950,1872,1808,1716,1631,1587,1496,1455,1375,1361,1280,1252,
J ˆ 12.1 Hz,1H),4.37 (d, J ˆ
13C NMR (125 MHz,C 6D6): d ˆ 11.35,
1095,1018,986,955,899,873,836,810,776,662 cm
À1; MS (EI,70 eV): m/z
‡
(%): 272 (1) [M ],215 (5),197 (5),145 (16),123 (95),105 (74),97 (15),95
(18),81 (91),75 (100),73 (24),67 (20),57 (26),55 (23); elemental analysis
calcd (%) for C15H32O2Si: C 66.11,H 11.84; found: C 65.94,H 11.89.
1201,1184,1100,1049,1028,995,970,914,737,698,608,533,463 cm
À1; MS
‡
(EI,70 eV): m/z (%): 318 (7) [M ],273 (96),227 (8),98 (9),91 (100),70
(3Z,5R)-(À)-7-tert-Butyldiphenylsilyloxy-3-hydroxymethyl-5-methylhept-
3-ene (19b): The same procedure as described previously using a,b-
unsaturated ester 18b (444 mg,1.08 mmol) and 1 m DIBAL-H solution
(2.71 mL,2.71 mmol) afforded 19b as a colourless oil (412 mg,96%). GC
analysis on chiral stationary phase (chirasil-dex 25 m) showed an ee of
>98% for 19e (tR ˆ 36.53 and 36.91 min for the R and S enantiomers,
respectively). [a]2D0 ˆ À12.9 (c ˆ 0.5,CHCl 3); 1H NMR (400 MHz): d ˆ 0.92
(d, J ˆ 6.6 Hz,3H),1.02 (t, J ˆ 7.4 Hz,3H),1.07 (s,9H),1.22 (m,1H),1.53
(11),56 (9); elemental analysis calcd (%) for C 19H30N2O2: C 71.66,H 9.50,
N 8.80; found: C 71.89,H 9.40,N 8.34.
The above a-alkylated hydrazone (485 mg,1.52 mmol) was dissolved in
CH2Cl2 and the solution was cooled to À788C. Ozone (60 LhÀ1) was
bubbled through the solution until persistent blue colour was observed and
then argon was bubbled until the blue colour disappeared. The solution was
allowed to warm to RT and the solvent was removed under reduced
pressure. Pure ketone 8 (302 mg,96%) was obtained after flash column
chromatography (Et2O/pentane 1:2). GC analysis on chiral stationary
phase (chirasil-dex 25 m) showed an ee of 96% for ketone 8 (tR ˆ 31.74 and
32.07 min for the R and S enantiomers,respectively). [ a]2D0 ˆ À25.3 (c ˆ 1.0,
CHCl3); lit.[33b] [a]D20 ˆ ‡25.8 (c ˆ 8.2,CHCl 3) for the opposite enantiomer;
1H NMR (400 MHz,C 6D6): d ˆ 0.87 (d, J ˆ 7.1 Hz,3H),0.97 (t, J ˆ 7.3 Hz,
(m,1H),2.01 (brs,1H),2.14 (qt
3.70 (m,2H),3.97 (d, J ˆ 11.8 Hz,1H),4.24 (d, J ˆ 12.4 Hz,1H),4.95 (d,
13C NMR
J ˆ 7.4,1.6 Hz,2H),2.81 (m,1H),3.58
J ˆ 10.2 Hz,1H),7.35 7.45 (m,6H),7.63 7.69 (m,4H);
(100 MHz): d ˆ 12.96,19.11,21.82,26.85,28.10,28.31,39.93,60.53,61.99,
127.45,127.46,129.44,129.50,132.41,133.39,133.58,135.33,135.43,139.96;
IR (film): nÄ ˆ 3405,3070,2959,2930,2859,1471,1428,1111,1011,823,738,
‡
703,614,506 cm À1; MS (EI,70 eV): m/z (%): 397 (1) [M ],339 (7),269 (8),
3H),2.10 (dq, J ˆ 18.1,7.3 Hz,1H),2.20 (dq, J ˆ 18.1,7.3 Hz,1H),2.56
(qdd, J ˆ 7.1,7.7,5.4 Hz,1H),3.21 (dd, J ˆ 8.8,5.4 Hz,1H),3.46 (dd, J ˆ 8.8,
7.7 Hz,1H),4.24 (m,2H),7.06 7.23 (m,5H);
13C NMR (100 MHz,C 6D6):
229 (13),211 (5),199 (100),181 (7),139 (7),137 (6),123 (74),81 (28),67 (6),
57 (8),55 (7); elemental analysis calcd (%) for C 25H36O2Si: C 75.70,H 9.15;
found: C 75.67,H 9.08.
d ˆ 7.75,13.57,35.23,46.15,72.62,73.11,127.50,127.52,128.36,138.67,
211.19. All analytical data match with those given in the literature.[33b]
(3Z,5R)-(‡)-3-Bromomethyl-7-tert-butyldimethylsilyloxy-5-methylhept-
3-ene (4a): PPh3 (287 mg,1.09 mmol) and CBr 4 (363 mg,1.09 mmol) were
sequentially added to a solution of allylic alcohol 19a (118 mg,0.47 mmol)
in CH3CN (10 mL) at RT. After stirring for 30 min the mixture was
quenched with water (10 mL) and extracted with pentane (5 Â 10 mL). The
combined organic fractions were dried over Na2SO4,filtered and the
solvent was removed under reduced pressure,affording allylic bromide 4a
after flash column chromatography (pentane) as a colourless oil (7.4 mg,
5%). [a]2D0 ˆ ‡23.1 (c ˆ 0.1,CHCl 3); 1H NMR (400 MHz): d ˆ 0.07 (s,3H),
0.09 (s,3H),0.90 (s,9H),0.98 (d, J ˆ 6.6 Hz,3H),1.01 (t, J ˆ 7.4 Hz,3H),
1.73 (m,1H),1.86 (m,1H),2.11 (dq, J ˆ 7.1,1.1 Hz,2H),2.67 (m,1H),3.28
(S)-(‡)-2-Methylbutanal (9): A solution of the hydrazone 20 (1.00 g,
5.43 mmol) in dry THF (7 mL) was added to a cooled (08C) solution of
LDA (640 mg,5.98 mmol) in THF (10 mL). After stirring for 5 h,the
mixture was cooled to À1058C and a solution of MeI (0.37 mL,5.98 mmol)
in THF (10 mL) was added slowly. The mixture was stirred at this
temperature for 3 h,allowed to warm to RT and quenched with water
(20 mL). The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 Â 15mL). The combined organic fractions were
dried over Na2SO4,filtered and the solvent removed under reduced
pressure,to afford the a-alkylated hydrazone after flash column chroma-
tography (Et2O/pentane 1:2‡3% Et3N) as a colourless oil (978 mg,91%).
The a-alkylated hydrazone thus obtained was dissolved in CH2Cl2 and the
solution was cooled to À788C. Ozone (60 LhÀ1) was bubbled through the
(m,1H),3.39 (m,1H),4.15 (dd,
J ˆ 11.5,0.6 Hz,1H),4.22 (dd, J ˆ 11.8,
0.8 Hz,1H),4.87 (dt, J ˆ 10.1,0.5 Hz,1H); 13C NMR (100 MHz): d ˆ
À5.33, À5.28,12.88,18.30,21.22,25.91,27.31,30.55,32.24,40.45,60.65,
Chem. Eur. J. 2002, 8,No. 18
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
0947-6539/02/0818-4279 $ 20.00+.50/0
4279

D. Enders et al.
FULL PAPER
solution until persistent blue colour was observed and then argon was
bubbled until the blue colour disappeared. The solution was allowed to
warm to RTand water (15 mL) was added. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (3 Â 15 mL). The
combined organic fractions were washed with 4m HCl (2 Â 20 mL) and
water (2 Â 20 mL),dried over Na 2SO4 and filtered. CH2Cl2 was removed by
distillation and the pure aldehyde 9 (336 mg,79%) was obtained after
distillation of the residue through a short vigreux column. [a]2D0 ˆ ‡33.1
were dried over Na2SO4,filtered and the solvent removed under reduced
pressure to afford the desired O-protected product after flash column
chromatography (Et2O/pentane 1:9) as a colourless oil (429 mg,98%).
[a]2D0 ˆ À18.5 (c ˆ 0.4,CHCl 3); 1H NMR (500 MHz): d ˆ 0.04 (s,3H),0.06
(s,3H),0.79 (d, J ˆ 6.7 Hz,3H),0.82 (t, J ˆ 7.3 Hz,3H),0.90 (s,9H),1.07
(d, J ˆ 6.1 Hz,3H),1.11 (d, J ˆ 6.1 Hz,3H),1.30 (m,2H),1.41 (m,1H),
2.89 (m,1H),3.02 (m,1H),3.40 (dd, J ˆ 9.1,5.8 Hz,1H),3.65 (dd, J ˆ 9.1,
7.6 Hz,1H),3.90 (dd, J ˆ 7.3,2.4 Hz,1H),4.44 (d, J ˆ 11.9 Hz,1H),4.49 (d,
(c ˆ 1.3,CHCl 3); lit.[41] [a]2D0 ˆ ‡32.6 (c ˆ 2.7,acetone);
1H NMR
J ˆ 11.9 Hz,1H),7.24 7.34 (m,5H);
13C NMR (125 MHz): d ˆ À3.99,
(500 MHz): d ˆ 0.95 (t, J ˆ 7.6 Hz,3H),1.09 (d, J ˆ 7.0 Hz,3H),1.45 (m,
À3.69,12.20,13.59,14.09,14.49,18.48,26.09,26.99,40.19,46.17,49.78,
1H),1.74 (m,1H),2.23 (m,1H),9.62 (d,
J ˆ 1.8 Hz,1H); 13C NMR
72.26,73.26,75.33,127.53,127.58,128.28,138.13,215.90; IR (film):
nÄ ˆ 3031,
(125 MHz): d ˆ 11.41,12.96,23.60,47.88,205.34. All analytical data match
with those given in the literature.[41] We proceeded analogously for the
synthesis of (R)-2-methylbutanal (ent-9) starting from hydrazone ent-20
(67%).
2960,2932,2857,1712,1460,1362,1254,1108,1059,1004,836,798,775,736,
‡
698,673 cm À1; MS (EI,70 eV): m/z (%): 349 (9) [M À C4H9],263 (36),201
(9),171 (16),145 (9),91 (100),75 (16),73 (15); elemental analysis calcd (%)
for C24H42O3Si: C 70.88,H 10.41; found: C 70.73,H 10.24.
The obtained O-protected aldol (418 mg,1.08 mmol) was dissolved in
EtOH and Pd/C was added. The mixture was stirred under H2 atmosphere
(balloon) for 6 h after which it was filtered and the solvent was removed
under reduced pressure,affording ketone 23a after flash column chroma-
tography (Et2O/pentane 1:2) as a colourless oil (323 mg,95%). [ a]2D0 ˆ À3.6
(c ˆ 0.2,CHCl 3); 1H NMR (500 MHz): d ˆ 0.07 (s,6H),0.85 (d, J ˆ 7.0 Hz,
3H),0.87 (t, J ˆ 7.3 Hz,3H),0.91 (s,9H),1.09 (d, J ˆ 7.0 Hz,3H),1.15 (d,
J ˆ 7.6 Hz,3H),1.19 (m,1H),1.31 (m,1H),1.43 (m,1H),2.40 (brs,1H),
(2R,4S,5R,6S)-(À)-1-Benzyloxy-5-hydroxy-2,4,6-trimethyloctan-3-one
(22a): Commercially available Sn(OTf)2 was washed several times with dry
Et2O under argon. After drying under high vacuum for 12 h the acid free
Sn(OTf)2 (728 mg,1.74 mmol) was suspended in dry CH Cl2 (10 mL) and
2
Et3N (0.28 mL,2.04 mmol) was added at once. The mixture was then
cooled to À788C and a solution of ketone 8 (300 mg,1.46 mmol) in CH 2Cl2
(7 mL) was added slowly. After 2 h a solution of the aldehyde 9 (138 mg,
1.60 mmol) in CH2Cl2 (10 mL) was slowly added and the mixture was
stirred for an additional 4 h before it was quenched with a 4m HCl solution
(10 mL). The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 Â 15 mL). The combined organic fractions were
dried over Na2SO4,filtered and the solvent removed under reduced
pressure to afford the desired aldol product 22a after flash column
chromatography (Et2O/pentane 1:2) as a colourless oil (370 mg,87%).
[a]2D0 ˆ À39.7 (c ˆ 0.3,CHCl 3); 1H NMR (500 MHz): d ˆ 0.86 (t, J ˆ 7.3 Hz,
3H),0.95 (d, J ˆ 6.4 Hz,3H),1.03 (d, J ˆ 6.7 Hz,3H),1.08 (d, J ˆ 7.0 Hz,
2.87 (m,1H),2.95 (m,1H),3.65 (dd,
J ˆ 11.3,4.3 Hz,1H),3.73 (dd, J ˆ
11.3,7.0 Hz,1H),3.82 (dd, J ˆ 7.6,2.4 Hz,1H); 13C NMR (125 MHz): d ˆ
À3.98, À3.72,12.26,13.43,13.84,14.68,18.45,26.12,27.02,40.00,48.39,
48.89,64.22,76.47,218.32; IR (film): nÄ ˆ 3502,2965,2934,2875,1706,1496,
1455,1376,1147,1099,1028,987,737,698 cm
À1; MS (EI,70 eV): m/z (%):
‡
259 (6) [M À C4H9],201 (10),173 (100),155 (11),115 (5),87 (5),81 (5),75
(26),73 (11),59 (10); elemental analysis calcd (%) for C 17H36O3Si: C 64.50,
H 11.46; found: C 64.49,H 11.36.
3H),1.37 (m,1H),1.46 (m,1H),2.6 2.8 (m,2H),2.88 (dq,
J ˆ 7.0,3.0 Hz,
(2R,4S,5R,6R)-(‡)-5-tert-Butyldimethylsilyloxy-1-hydroxy-2,4,6-trimethyl-
octan-3-one (23b): The same procedure as previously described using aldol
22b (555 mg,1.90 mmol),26, -lutidine (0.66 mL,5.70 mmol) and TBSOTf
(653 mg,2.47 mmol) afforded the corresponding O-protected derivative as
a colourless oil (761 mg,99%). [ a]2D0 ˆ ‡4.6 (c ˆ 1.3,CHCl 3); 1H NMR
1H),3.14 (m,1H),3.45 (dd, J ˆ 8.8,4.9 Hz,1H),3.63 (t, J ˆ 8.8 Hz,1H),
3.73 (dd, J ˆ 7.9,3.0 Hz,1H),4.43 (d, J ˆ 12.2 Hz,1H),4.47 (d, J ˆ 12.2 Hz,
1H),7.24 7.35 (m,5H); 13C NMR (125 MHz): d ˆ 8.92,10.97,13.70,14.95,
25.42,36.53,44.64,48.58,73.24,73.50,73.85,127.76,127.86,128.44,137.63,
218.01; IR (CHCl3): nÄ ˆ 3494,2959,2927,2856,1707,1456,1216,759,
(300 MHz): d ˆ 0.02 (s,3H),0.06 (s,3H),0.82 (t,
J ˆ 6.7 Hz,3H),0.89 (s,9H),1.00 (m,1H),1.07 (d,
J ˆ 7.2 Hz,3H),0.87 (d,
J ˆ 7.1 Hz,3H),1.10 (d,
‡
669 cmÀ1; MS (EI,70 eV): m/z (%): 274 (1) [M À H2O],235 (5),186 (4),
172 (7),107 (11),100 (25),91 (100),87 (8),85 (7),57 (13); elemental
analysis calcd (%) for C18H28O3: C 73.93,H 9.65; found: C 73.88,H 9.56.
J ˆ 7.1 Hz,3H),1.40 (m,2H),2.86 (m,1H),3.03 (m,1H),3.38 (dd,
J ˆ 9.1,
6.0 Hz,1H),3.64 (dd, J ˆ 9.1,7.7 Hz,1H),3.94 (dd, J ˆ 5.4,3.4 Hz,1H),
4.43 (d, J ˆ 12.1 Hz,1H),4.48 (d, J ˆ 12.1 Hz,1H),7.22 7.35 (m,5H);
13C NMR (75 MHz): d ˆ À4.25, À3.98,12.13,13.68,14.21,15.83,18.38,
24.56,26.10,40.85,45.73,48.73,72.28,73.26,75.27,127.55,127.59,128.30,
138.19,215.43; IR (film): nÄ ˆ 2958,2931,2879,2857,1713,1496,1471,1462,
(2R,4S,5R,6R)-(À)-1-Benzyloxy-5-hydroxy-2,4,6-trimethyloctan-3-one
(22b): A 1m solution of TiCl4 in CH2Cl2 (1.53 mL,1.53 mmol) was added to
a cold (À788C) solution of ketone 8 (287 mg,1.39 mmol) in dry CH 2Cl2
(10 mL). After stirring for 5 min,DIPEA (0.29 mL,1.67 mmol) was added
and the mixture was stirred for 2 h at this temperature. A solution of
aldehyde ent-9 (144 mg,1.69 mmol) in CH 2Cl2 (10 mL) was slowly added
and the mixture was allowed to stir for additional 2 h before it was
quenched with water (20 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 Â 15 mL). The combined
organic fractions were dried over Na2SO4,filtered and the solvent removed
under reduced pressure to afford the desired aldol product 22b after flash
column chromatography (Et2O/pentane 1:2) as a colourless oil (391 mg,
96%). [a]2D0 ˆ À15.4 (c ˆ 0.9,CHCl 3); 1H NMR (400 MHz,C 6D6): d ˆ 0.68
(d, J ˆ 6.9 Hz,3H),0.80 (d, J ˆ 6.9 Hz,3H),0.91 (t, J ˆ 7.6 Hz,3H),1.08 (d,
1407,1382,1361,1254,1103,1057,1028,1004,837,776,735,698 cm
À1; MS
‡
(EI,70 eV): m/z (%): 349 (11) [M À C4H9],263 (49),241 (94),201 (26),171
(28),155 (87),145 (11),91 (100),75 (64),73 (34),69 (35); elemental analysis
calcd (%) for C24H42O3Si: C 70.88,H 10.41; found: C 70.53,H 10.25.
Hydrogenolysis of the obtained O-protected aldol (600 mg,1.55 mmol)
under the conditions previously described yielded hydroxyketone 23b as a
colourless oil (479 mg,98%). [ a]2D0 ˆ ‡9.7 (c ˆ 0.1,CHCl 3); 1H NMR
(400 MHz): d ˆ 0.09 (s,6H),0.83 (t, J ˆ 7.3 Hz,3H),0.88 (d, J ˆ 6.4 Hz,
3H),0.91 (s,9H),1.11 (d, J ˆ 6.3 Hz,3H),1.15 (d, J ˆ 7.6 Hz,3H),1.21 (m,
1H),1.44 (m,2H),2.25 (brs,1H),2.86 (m,1H),2.94 (m,1H),3.66 (dd,
J ˆ
J ˆ 7.1 Hz,3H),1.26 (m,1H),1.52 (m,1H),1.96 (m,1H),2.69 (dq,
J ˆ 7.1,
11.0,4.1 Hz,1H),3.73 (dd, J ˆ 11.3,6.9 Hz,1H),3.82 (dd, J ˆ 7.1,2.5 Hz,
1H); 13C NMR (100 MHz): d ˆ À3.97, À3.72,12.19,13.41,13.82,14.66,
2.4 Hz,1H),2.84 (m,1H),3.10 (dd,
J ˆ 8.5,4.7 Hz,1H),3.12 (brs,1H),
3.48 (dd, J ˆ 9.3,8.5 Hz,1H),3.79 (m,1H),4.10 (d,
J ˆ 11.8 Hz,1H),4.14
18.41,26.00,26.08,40.64,47.95,48.83,64.19,76.48,218.05; IR (film):
nÄ ˆ
(d, J ˆ 11.8 Hz,1H),7.06 7.20 (m,5H); 13C NMR (100 MHz,C D6): d ˆ
3502,2963,2928,2875,1704,1495,1147,1111,1028,988,737,698 cm
À1; MS
6
‡
8.16,11.11,13.69,14.99,25.62,36.85,44.30,48.73,73.33,73.46,73.62,127.59,
(EI,70 eV): m/z (%): 259 (12) [M À C4H9],201 (9),173 (100),155 (35),115
(28),87 (10),81 (15),75 (33),73 (9),59 (7); elemental analysis calcd (%) for
C17H36O3Si: C 64.50,H 11.46; found: C 64.59,H 11.56.
127.72,128.39,137.96,216.87; IR (film):
nÄ ˆ 3501,3088,3064,2966,2934,
2876,1706,1496,1455,1377,1329,1308,1243,1206,1147,1098,1029,987,
738,699,609,519,456 cm À1; MS (CI,100 eV,isobutane): m/z (%): 293 (67)
(2R,3S,4R,5R,6S)-(À)-5-tert-Butyldimethylsilyloxy-2,4,6-trimethyloctan-
1,3-diol (5a): DIBAL-H (0.38 mL,0.38 mmol) was slowly added to a cooled
(À788C) solution of hydroxyketone 23a (60 mg,0.19 mmol) in dry CH 2Cl2
(15 mL). After stirring for 1 h at this temperature the mixture was
quenched with 4m HCl (10 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 Â 15 mL). The combined
organic fractions were dried over Na2SO4,filtered and the solvent removed
under reduced pressure to afford the diol 5a after flash column
chromatography (Et2O/pentane 1:1) as a colourless oil (53 mg,87%).
[a]2D0 ˆ À9.3 (c ˆ 0.3,CHCl 3); 1H NMR (500 MHz): d ˆ 0.10 (s,3H),0.14 (s,
‡
[M ‡H],275 (12),207 (100); elemental analysis calcd (%) for C 18H28O3: C
73.93,H 9.65; found: C 73.85,H 9.74.
(2R,4S,5R,6S)-(À)-5-tert-Butyldimethylsilyloxy-1-hydroxy-2,4,6-trimethyl-
octan-3-one (23a): 2,6-Lutidine (0.39 mL, 3.39 mmol) was added to a
solution of 22a (330 mg,1.13 mmol) in CH 2Cl2 (15 mL) at 08C. After
stirring for 1 h at this temperature TBSOTf (0.4 mL,1.47 mmol) was added
at once. Then,the mixture was stirred for 18 h at RT and it was quenched
with water (10 mL). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3 Â 15 mL). The combined organic fractions
4280
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
0947-6539/02/0818-4280 $ 20.00+.50/0
Chem. Eur. J. 2002, 8,No. 18

(À)-Callystatin A
4272 4284
‡
3H),0.83 (d, J ˆ 7.0 Hz,3H),0.89 (t, J ˆ 7.3 Hz,3H),0.92 (s,9H),0.97 (d,
J ˆ 6.7 Hz,3H),1.14 (d, J ˆ 7.0 Hz,3H),1.21 (m,1H),1.42 (m,1H),1.59
(18),57 (8); HRMS: calcd for [C 22H44O4Si À C4H9] : 343.2305; found
343.2304.
(m,1H),1.72 (m,1H),2.06 (m,1H),3.57 (dd,
J ˆ 11.0,4.3 Hz,1H),3.71
(2E,4R,5S,6R,7R,8S)-(À)-1-Bromo-7-tert-butyldimethylsilyloxy-5-hy-
droxy-2,4,6,8-tetramethyldec-2-ene (2a): A 1m solution of DIBAL-H in
CH2Cl2 (2.34 mL,2.34 mmol) was slowly added to a cold ( À788C) solution
(dd, J ˆ 9.1,3.0 Hz,1H),3.83 (t, J ˆ 2.7 Hz,1H),3.93 (dd, J ˆ 11.0,3.0 Hz,
1H),OH×s could not be detected; 13C NMR (125 MHz): d ˆ À4.56, À4.22,
12.26,13.86,15.28,15.58,18.09,25.89,28.46,35.76,36.60,40.23,64.62,79.68,
of the a,b-unsaturated ester 24a (312 mg,0.78 mmol) in CH Cl2 (10 mL).
2
80.22; IR (film): nÄ ˆ 3365,2958,1464,1385,1362,1338,1254,1216,1079,
After stirring for 30 min,the reaction was quenched with 1 m HCl solution
(20 mL) and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (3 Â 5 mL) and the combined organic fractions were dried
over Na2SO4,filtered and the solvent was removed under reduced pressure,
affording the corresponding allylic alcohol after flash column chromatog-
raphy (Et2O/pentane 1:1) as a colourless oil (238 mg,85%). The obtained
alcohol (57 mg,0.16 mmol) was dissolved in dry acetonitrile (5 mL) and
‡
1026,972,940,836,775,669 cm À1; MS (EI,70 eV): m/z (%): 261 (5) [M
C4H9],259 (9),201 (100),173 (32),161 (91),145 (11),129 (40),115 (18),105
(11),83 (15),75 (54),73 (42),59 (12),57 (16); elemental analysis calcd (%)
for C17H38O3Si: C 64.09,H 12.02; found: C 64.13,H 12.01.
À
(2R,3S,4R,5R,6R)-(À)-5-tert-Butyldimethylsilyloxy-2,4,6-trimethyloctan-
1,3-diol (5b): The same procedure as previously described using hydrox-
yketone 23b (456 mg,1.44 mmol) and 1 m solution of DIBAL-H in CH2Cl2
(2.88 mL,2.88 mmol) afforded diol 5b as a colourless oil (395 mg,86%).
[a]2D0 ˆ À7.5 (c ˆ 0.8,CHCl 3); 1H NMR (400 MHz): d ˆ 0.06 (s,3H),0.07 (s,
PPh3 (96 mg,0.37 mmol),26,-lutidine (18 mg,0.16 mmol) and CBr
4
(121 mg,0.37 mmol) were sequentially added at RT. After stirring for
30 min the mixture was quenched with water (10 mL) and extracted with
pentane (5 Â 10 mL). The combined organic fractions were dried over
Na2SO4,filtered and the solvent was removed under reduced pressure,
affording allylic bromide 2a after flash column chromatography (Et2O/
pentane 1:9) as a colourless oil (60 mg,89%). [ a]2D0 ˆ À49.5 (c ˆ 0.2,
3H),0.88 0.92 (m,6H),0.91 (s,9H),0.97 (d,
J ˆ 6.9 Hz,3H),0.99 (d, J ˆ
6.9 Hz,3H),1.07 (m,1H),1.47 (m,1H),1.54 (m,1H),1.81 (m,1H),1.86
(m,1H),2.30 (brs,2H),3.56 (dd, J ˆ 5.5,1.9 Hz,1H),3.66 3.72 (m,3H);
13C NMR (100 MHz): d ˆ À4.07, À3.60,9.60,10.53,12.16,15.26,18.39,
26.04,26.88,36.98,37.52,40.69,67.43,77.32,77.42; IR (film):
nÄ ˆ 3387,2958,
CHCl3); 1H NMR (400 MHz): d ˆ 0.09 (s,3H),0.11 (s,3H),0.72 (d,
J ˆ
1463,1385,1361,1077,1025,1005,974,939,836,773,674 cm
À1; MS (CI,
6.8 Hz,3H),0.83 (t, J ˆ 7.2 Hz,3H),0.91 (d, J ˆ 6.8 Hz,3H),0.94 (s,9H),
1.03 (d, J ˆ 6.6 Hz,3H),1.10 (m,1H),1.35 (m,1H),1.58 (m,1H),1.75 (m,
1H),1.78 (d, J ˆ 1.6 Hz,3H),2.12 2.25 (brs,1H),2.47 (m,1H),3.34 (dd,
J ˆ 9.3,1.9 Hz,1H),3.72 (dd, J ˆ 4.7,2.7 Hz,1H),3.92 (d, J ˆ 9.6 Hz,1H),
3.96 (d, J ˆ 9.6 Hz,1H),5.33 (d, J ˆ 10.2 Hz,1H); 13C NMR (100 MHz):
d ˆ À4.54, À3.39,11.13,12.43,15.05,15.03,16.87,18.24,26.01,26.11,36.33,
‡
100 eV,isobutane): m/z (%): 319 (100) [M ‡H],261 (8),187 (30),169 (17);
elemental analysis calcd (%) for C17H38O3Si: C 64.09,H 12.02; found: C
63.83,H 12.27.
(2E,4R,5S,6R,7R,8S)-(‡)-Ethyl 7-tert-butyldimethylsilyloxy-5-hydroxy-
2,4,6,8-tetramethyldec-2-enoate (24a): Oxalyl chloride (150 mg,
1.18 mmol) was added to a cooled (À788C) solution of DMSO (184 mg,
2.35 mmol) in dry CH2Cl2 (15 mL). After stirring for 10 min at this
36.71,40.84,41.36,80.39,131.69,133.90; IR (film):
nÄ ˆ 3350,2965,2920,
2870,1460,1355,1214,1190,1162,1095,1073,955,840,610,524 cm
À1; MS
‡
(EI,70 eV): m/z (%): 365 (7) [M À C4H9],363 (8),259 (15),201 (100),173
(38),161 (58),145 (8),119 (12),115 (15),83 (9),75 (36),73 (32),57 (8);
elemental analysis calcd (%) for C20H41BrO2Si: C 56.99,H 9.80; found: C
56.90,H 9.95.
temperature,a solution of diol 5a (340 mg,1.07 mmol) in CH Cl2 (5 mL)
2
was added and the mixture was stirred for further 10 min before DIPEA
(0.93 mL,5.35 mmol) was added at once. After stirring for 10 min at
À788C the mixture was allowed to warm to RT and filtered through a pad
of silica gel (5 cm),eluting with Et O/pentane 1:1. The obtained yellowish
(2E,4R,5S,6R,7R,8R)-(À)-1-Bromo-7-tert-butyldimethylsilyloxy-5-hy-
droxy-2,4,6,8-tetramethyldec-2-ene (2b): The same procedure as previous-
ly described using a,b-unsaturated ester 24b (262 mg,0.65 mmol) and 1 m
DIBAL-H (1.96 mL,1.96 mmol) solution,yielded the corresponding allylic
alcohol (231 mg,99%). Bromination of this alcohol (200 mg,0.56 mmol)
2
ˆ
oil was dissolved in dry CH2Cl2 (10 mL) and Ph3P C(CH3)CO2Et (543 mg,
1.50 mmol) was added. The mixture was refluxed for 4 h after which it was
quenched with water (15 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 Â 15 mL). The combined
organic fractions were dried over Na2SO4,filtered and the solvent removed
under reduced pressure to afford a,b-unsaturated ester 24a after flash
column chromatography (Et2O/pentane 1:2) as a colourless oil (337 mg,
79%). [a]2D0 ˆ ‡21.8 (c ˆ 1.1,CHCl 3); lit.[30a] [a]D20 ˆ ‡22.2 (c ˆ 1.2 CHCl3);
1H NMR (400 MHz): d ˆ 0.07 (s,3H),0.12 (s,3H),0.75 (d, J ˆ 6.6 Hz,3H),
with PPh3 (335 mg,1.28 mmol),26, -lutidine (60 mg,0.56 mmol) and CBr
4
(425 mg,1.28 mmol) afforded allylic bromide 2b as a colourless oil (194 mg,
82%). [a]2D0 ˆ À30.2 (c ˆ 0.6,CHCl 3); 1H NMR (300 MHz): d ˆ 0.09 (s,
3H),0.11 (s,3H),0.86 0.94 (m,9H),0.92 (s,9H),1.03 (d,
1.11 (m,1H),1.26 1.76 (m,3H),1.78 (d,
J ˆ 6.6 Hz,3H),
J ˆ 1.4 Hz,3H),2.38 (brs,1H),
0.89 (t, J ˆ 7.3 Hz,3H),0.93 (s,9H),1.02 (d,
J ˆ 6.6 Hz,3H),1.12 (d, J ˆ
J ˆ 7.1 Hz,1H),
2.48 (m,1H),3.33 (dd, J ˆ 8.9,1.5 Hz,1H),3.72 (dd, J ˆ 4.9,3.0 Hz,1H),
3.94 (m,2H),5.30 (dd, J ˆ 10.0,1.4 Hz,1H); 13C NMR (75 MHz): d ˆ
À4.57, À3.38,7.86,12.45,15.07,15.09,16.90,18.25,26.04,26.14,36.35,36.74,
6.8 Hz,3H),1.25 (t, J ˆ 6.9 Hz,3H),1.13 1.39 (m,2H),1.61 (m,1H),1.77
(m,1H),1.86 (d, J ˆ 1.7 Hz,3H),2.60 (m,1H),3.44 (d,
3.51 (t, J ˆ 3.5 Hz,1H),4.11 4.22 (m,2H),4.2 4.35 (brs,1H),6.98 (dq,
J ˆ 10.5,1.2 Hz,1H); 13C NMR (100 MHz): d ˆ À4.82, À4.12,12.13,12.52,
14.01,14.31,15.36,16.80,18.09,25.89,29.20,35.50,36.40,41.71,60.35,71.83,
40.88,41.42,80.53,131.89,134.10; IR (film):
nÄ ˆ 3529,2958,2930,2876,
2857,1462,1387,1255,1094,1051,1005,986,836,774 cm
À1; MS (EI,70 eV):
‡
m/z (%): 365 (4) [M À C4H9],363 (7),259 (12),201 (100),173 (38),161
(59),145 (9),131 (7),119 (14),115 (15),109 (10),83 (11),75 (28),73 (23),69
(8); elemental analysis calcd (%) for C20H41BrO2Si: C 56.99,H 9.80; found:
C 57.01,H 9.93.
80.86,127.55,142.56,168.24; IR (film):
nÄ ˆ 3500,2957,2933,2871,1685,
1464,1374,1302,1247,1146,1099,1060,1004,857,837,776,755 cm
À1; MS
‡
(EI,70 eV): m/z (%): 343 (27) [M À C4H9],259 (14),257 (12),201 (100),
173 (21),161 (27),142 (17),127 (11),115 (13),113 (14),109 (16),105 (6),75
(29),73 (31),69 (13),57 (11); elemental analysis calcd (%) for C 22H44O4Si:
C 66.95,H 11.07; found: C 66.11,H 11.11.
(2'R,6'R,1E,3Z,5R)-(‡)-7-tert-Butyldiphenylsilyloxy-1-(5',6'-dihydro-2'H-
2'-isopropoxypyran-6'-yl)-3-ethyl-5-methylhepta-1,3-diene (25): Allylic
bromide 4b (84 mg,0.18 mmol) was dissolved in dry acetonitrile (5 mL)
and tributylphosphine (52 mg,0.26 mmol) was added at once. After stirring
for 30 min at RT the solvent was evaporated under reduced pressure and
the resulting viscous oil was dried under high vacuum. The residue was
dissolved in dry toluene,a solution of the aldehyde 3 (33 mg,0.19 mmol) in
toluene (5 mL) was added and the mixture was cooled to 08C,at which
temperature a solution of KOtBu (31 mg,0.26 mmol) in THF (1 mL) was
added slowly. After stirring for 1 h at this temperature,the reaction was
quenched with water (5 mL),the organic layer was separated and the
aqueous layer was extracted with Et2O (3 Â 15 mL). The combined organic
fractions were dried over Na2SO4,filtered and the solvent removed under
reduced pressure to afford triene 25 after flash column chromatography
(Et2O/pentane 1:9) as a colourless oil (82 mg,86%). [ a]2D0 ˆ ‡53.6 (c ˆ 0.4,
CHCl3); 1H NMR (400 MHz): d ˆ 0.94 (d, J ˆ 6.8 Hz,3H),1.01 (t, J ˆ
7.4 Hz,3H),1.03 (s,9H),1.16 (d, J ˆ 6.0 Hz,3H),1.20 (d, J ˆ 6.9 Hz,3H),
1.48 (m,1H),1.61 (m,1H),2.03 2.11 (m,2H),2.12 2.22 (m,2H),2.84 (m,
1H),3.61 (t, J ˆ 6.6 Hz,2H),3.98 (sept, J ˆ 6.0 Hz,1H),4.46 (m,1H),5.09
(2E,4R,5S,6R,7R,8R)-(‡)-Ethyl 7-tert-butyldimethylsilyloxy-5-hydroxy-
2,4,6,8-tetramethyldec-2-enoate (24b): The same procedure as previously
described using diol 5b (138 mg,0.43 mmol),oxalyl chloride (75 mg,
0.59 mmol),DMSO (93 mg,1.20 mmol),DIPEA (0.43 mL,2.50 mmol) and
ˆ
Ph3P C(CH3)CO2Et (272 mg,0.75 mmol) afforded ester 24b as a colour-
less oil (60 mg,67% conversion,52%). [ a]2D0 ˆ ‡5.9 (c ˆ 0.3,CHCl 3);
1H NMR (300 MHz): d ˆ 0.09 (s,3H),0.11 (s,3H),0.84 0.92 (m,9H),0.92
(s,9H),1.09 (d, J ˆ 6.6 Hz,3H),1.29 (t, J ˆ 7.1 Hz,3H),1.34 (m,1H),
1.55 1.74 (m,3H),1.87 (d, J ˆ 1.4 Hz,3H),2.48 (brs,1H),2.63 (m,1H),
3.46 (m,1H),3.74 (dd, J ˆ 4.1,3.6 Hz,1H),4.19 (m,2H),6.50 (dq, J ˆ 10.4,
1.4 Hz,1H); 13C NMR (75 MHz): d ˆ À4.49, À3.42,8.02,12.39,12.60,
14.27,15.34,16.51,18.29,25.89,26.07,37.15,37.41,40.72,60.49,79.74,80.12,
127.33,143.85,168.13; IR (film): nÄ ˆ 3525,2959,2858,1713,1463,1387,
1369,1256,1139,1096,1052,1004,836,774,753 cm
À1; MS (EI,70 eV): m/z
‡
(%): 343 (33) [M À C4H9],259 (8),257 (21),201 (100),173 (60),161 (39),
142 (30),127 (8),115 (28),113 (24),109 (18),105 (11),75 (69),73 (59),69
Chem. Eur. J. 2002, 8,No. 18
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
0947-6539/02/0818-4281 $ 20.00+.50/0
4281

D. Enders et al.
FULL PAPER
(m,2H),5.72 (m,2H),5.95 (m,1H),6.59 (d,
J ˆ 15.9 Hz,1H),7.32 7.44
21.04,22.48,24.27,25.97,26.30,26.92,31.44,32.57,37.31,37.60,41.08,41.43,
67.39,69.76,79.85,80.25,93.83,126.28,126.69,127.21,127.57,129.76,133.15,
(m,6H),7.61 7.69 (m,4H); 13C NMR (100 MHz): d ˆ 13.44,19.24,21.38,
22.06,23.87,26.30,26.83,28.05,30.71,40.37,61.90,65.85,69.46,93.18,
125.99,127.40,127.75,128.13,128.47,129.33,133.80,134.80,135.44,136.07;
IR (CHCl3): nÄ ˆ 3070,3046,2964,2930,2894,1469,1428,1381,1316,1182,
133.62,135.05,136.45; IR (CHCl 3): nÄ ˆ 3396,2929,2874,2858,1463,1381,
1254,1121,1049,1027,1005,979,868,836,774 cm
À1; MS (EI,70 eV): m/z
‡
(%): 556 (1) [M À C3H9O],499 (3),298 (15),257 (39),229 (8),207 (12),
201 (100),190 (41),173 (23),161 (23),145 (11),141 (26),127 (9),109 (40),
99 (15),93 (14),75 (21),73 (30),57 (8); elemental analysis calcd (%) for
C38H68O4Si: C 73.97,H 11.11; found: C 74.06,H 11.07.
1108,1029,1001,965,947,823,800,757,704,614,506 cm
À1; MS (EI,70 eV):
‡
m/z (%): 532 (1) [M ],475 (27),417 (11),415 (16),363 (53),285 (16),253
(10),225 (17),217 (12),199 (100),183 (33),173 (11),147 (25),135 (34),121
(21),109 (17),105 (16),91 (14),70 (34),55 (10); elemental analysis calcd
(%) for C34H48O3Si: C 76.64,H 9.08; found: C 76.56,H 9.10.
(2'R,6'R,8E,10E,14Z,16E,3R,4R,5R,6S,7R,13R)-(‡)-4-tert-Butyldime-
thylsilyloxy-17-(5',6'-dihydro-2'H-2'-isopropoxypyran-6'-yl)-15-ethyl-6-hy-
droxy-3,5,7,9,13-pentamethylheptadeca-8,10,14,16-tetraene (26b): The
same procedure as previously described using allylic bromide 2b (12 mg,
(2'R,6'R,4Z,6E,3R)-7-(5',6'-Dihydro-2'H-2'-isopropoxypyran-6'-yl)-5-eth-
yl-3-methylhepta-4,6-dien-1-al (1): Triene 25 (197 mg,0.37 mmol) was
dissolved in THF (5 mL) and TBAF (1m solution in THF,0.74 mL,
0.74 mmol) was added at once. After stirring for 3 h at RT,the mixture was
quenched with water (5 mL) and extracted with CH2Cl2 (3 Â 10 mL). The
combined organic fractions were dried over Na2SO4,filtered and the
solvent removed under reduced pressure to afford the corresponding
alcohol after flash column chromatography (Et2O/pentane 1:9) as a
colourless oil (106 mg,95%). [ a]2D0 ˆ ‡4.7 (c ˆ 0.6,CHCl 3); 1H NMR
(400 MHz): d ˆ 1.00 (d, J ˆ 6.7 Hz,3H),1.06 (t, J ˆ 7.4 Hz,3H),1.17 (d, J ˆ
6.0 Hz,3H),1.25 (d, J ˆ 6.3 Hz,3H),1.31 (m,1H),1.48 1.55 (m,1H),
0.028 mmol),aldehyde
1 (8.2 mg,0.028 mmol), nBuLi (0.031 mmol),
DMSO (2.7 mg,0.034 mmol) and tributylphosphine (8 mg,0.040 mmol)
afforded pentaene 26b as a colourless oil (12 mg,73%). [ a]2D0 ˆ ‡64.7 (c ˆ
0.1,CHCl 3); 1H NMR (400 MHz): d ˆ 0.07 (s,3H),0.10 (s,3H),0.81 0.90
(m,9H),0.94 (s,9H),0.99 (d, J ˆ 6.6 Hz,3H),1.02 1.11 (m,6H),1.18 (t,
J ˆ 7.2 Hz,3H),1.25 (d, J ˆ 6.6 Hz,3H),1.30 (m,1H),1.45 (m,1H),1.58
(m,1H),1.70 (d, J ˆ 1.2 Hz,3H),1.73 (m,1H),2.03 2.11 (m,4H),2.21
2.35 (m,2H),2.65 (m,1H),2.74 (m,1H),3.36 (d,
1H),4.03 (sept, J ˆ 6.0 Hz,1H),4.64 (m,1H),5.06 (d,
J ˆ 9.0 Hz,1H),3.70 (m,
J ˆ 10.1 Hz,1H),
1.60 1.71 (m,1H),2.00 2.14 (m,2H),2.19 (q,
J ˆ 7.4 Hz,2H),2.86 (m,
5.11 5.20 (m,2H),5.48 (m,1H),5.73 (m,2H),5.98 6.09 (m,2H),6.59 (d,
J ˆ 15.8 Hz,1H),OH could not be detected; 13C NMR (100 MHz): d ˆ
À4.48, À3.41,7.98,12.38,12.82,13.49,15.27,17.57,18.27,20.56,22.14,23.85,
25.88,26.03,26.32,30.84,31.97,36.50,36.59,40.71,40.88,67.06,69.57,80.26,
80.50,93.19,125.64,125.97,127.19,128.31,129.81,132.09,133.28,135.31,
135.98; IR (CHCl3): nÄ ˆ 3510,2961,2929,1720,1689,1462,1381,1254,1216,
1H),3.58 3.63 (m,2H),4.07 (sept, J ˆ 6.0 Hz,1H),4.52 (m,1H),5.09 (d,
J ˆ 1.2 Hz,1H),5.15 (d, J ˆ 8.5 Hz,1H),5.70 5.81 (m,1H),5.88 (dd, J ˆ
15.9,6.0 Hz,1H),5.98 6.09 (m,1H),6.62 (d,
J ˆ 15.9 Hz,1H); 13C NMR
(100 MHz): d ˆ 13.40,21.55,22.14,23.82,26.32,28.40,30.80,40.37,61.14,
66.93,69.66,93.19,126.98,127.15,128.31,128.75,134.87,136.41; IR
(CHCl3): nÄ ˆ 3420,2966,2927,1459,1400,1378,1316,1181,1127,1100,
1106,1004,976,939,877,836,757,668 cm
À1; MS (EI,70 eV): m/z (%): 543
1052,1030,1000,964,870,718 cm À1; MS (EI,70 eV): m/z (%): 294 (3) [M ],
234 (18),205 (19),179 (11),161 (12),139 (11),121 (11),112 (34),109 (24),
105 (11),97 (13),93 (15),91 (17),81 (17),70 (100),55 (24),45 (31);
elemental analysis calcd (%) for C18H30O3: C 73.43,H 10.27; found: C
73.52,H 10.40.
(1) [M À C4H10O],299 (15),257 (21),229 (33),201 (100),190 (15),173
(61),161 (22),145 (10),115 (20),109 (18),75 (58),73 (42),57 (61);
elemental analysis calcd (%) for C38H68O4Si: C 73.97,H 11.11; found: C
74.08,H 11.19.
‡
‡
(À)-Callystatin A: A solution of the pentaene 26a (8.0 mg,0.013 mmol) in
benzene (1 mL) was treated with PCC (14 mg,0.065 mmol),4 ä molecular
sieves (3 g,3 beads,crushed) and AcOH (7.8 mg,0.13 mmol). After stirring
at RT for 2.5 h,water (2 mL) was added and the reaction mixture was
extracted with Et2O (3 Â 5 mL). The combined organic fractions were dried
over Na2SO4,filtered and the solvent removed under reduced pressure to
afford the corresponding O-TBS protected derivative of callystatin A
(6.0 mg,81%) after flash column chromatography (Et 2O/pentane 1:1).
Afterwards,this derivative (3.7 mg,0.0065 mmol) was placed in a plastic
vial,dissolved in THF (0.2 mL) and HF ¥ pyridine (0.2 mL) was added at
once. After stirring for 72 h the reaction was quenched with 1m Na2CO3
(3 mL) and extracted with Et2O (5 Â 5 mL). The combined organic
fractions were dried over Na2SO4,filtered and the solvent removed under
reduced pressure to afford synthetic (À)-callystatin A (2.6 mg,89%) after
The obtained alcohol (31 mg,0.11 mmol) was dissolved in dry CH 2Cl2
(5 mL) and added to a cooled (À788C) solution of Swern reagent
(prepared from oxalyl chloride (15 mg,0.12 mmol) and DMSO (19 mg,
0.24 mmol) in CH2Cl2). After stirring for 10 min at this temperature,
DIPEA (72 mg,0.55 mmol) was added at once and the mixture was stirred
for further 15 min at À788C. The reaction was allowed to warm to RT and
filtered through a pad of silica gel (5 cm),eluting with Et 2O/pentane 1:1,to
yield crude aldehyde 1 which was used in the following step without further
purification 31 mg,96%).
(2'R,6'R,8E,10E,14Z,16E,3S,4R,5R,6S,7R,13R)-(‡)-4-tert-Butyldimethyl-
silyloxy-17-(5',6'-dihydro-2'H-2'-isopropoxypyran-6'-yl)-15-ethyl-6-hy-
droxy-3,5,7,9,13-pentamethylheptadeca-8,10,14,16-tetraene (26a): nBuLi
(0.047 mmol) was added to a cold (À788C) solution of DMSO (4.0 mg,
0.051 mmol) in dry toluene (5 mL). The mixture was stirred for 5 min at this
temperature and for 15 min at RT,after which it was cooled again to
À788C. In a separate flask,allylic bromide 2a (18 mg,0.043 mmol) was
dissolved in dry acetonitrile (5 mL) and tributylphosphine (12 mg,
0.060 mmol) was added at once. After stirring for 30 min at RT the solvent
was evaporated under reduced pressure and the resulting viscous oil was
dried under high vacuum. The obtained residue was dissolved in dry
toluene and added to the LiCH2S(O)CH3 solution at À788C. A solution of
the aldehyde 1 (13 mg,0.045 mmol) in toluene (5 mL) was also added and,
after stirring for 2 h at À788C,the reaction was quenched with water
(5 mL). The organic layer was separated and the aqueous layer was
extracted with Et2O (3 Â 5 mL). The combined organic fractions were dried
over Na2SO4,filtered and the solvent removed under reduced pressure to
afford pentaene 26a after flash column chromatography (Et2O/pentane
1:5) as a colourless oil (20 mg,76%). [ a]2D0 ˆ ‡64.7 (c ˆ 0.1,CHCl 3);
1H NMR (400 MHz): d ˆ 0.10 (s,3H),0.16 (s,3H),0.71 (d, J ˆ 7.1 Hz,3H),
0.89 (d, J ˆ 7.4 Hz,3H),0.94 (d, J ˆ 6.9 Hz,3H),0.98 (t, J ˆ 7.5 Hz,3H),
1.02 (s,9H),1.07 (d, J ˆ 6.1 Hz,3H),1.11 (t, J ˆ 7.2 Hz,3H),1.18 (d, J ˆ
6.6 Hz,3H),1.28 (d, J ˆ 6.3 Hz,3H),1.32 (m,1H),1.42 (m,1H),1.60 (m,
1H),1.75 (d, J ˆ 1.1 Hz,3H),1.79 (m,1H),1.91 (m,1H),2.08 (m,3H),2.19
column chromatography (Et2O/pentane 1:1). [a]2D0 ˆ À102.6 (c ˆ 0.02,
[14]
MeOH); lit[1] [a]D20 ˆ À107 (c ˆ 0.1,MeOH); lit
[a]2D0 ˆ À105 (c ˆ 0.1,
MeOH); 1H NMR (500 MHz): d ˆ 0.87 (t, J ˆ 7.5 Hz,3H),0.91 (d, J ˆ
6.9 Hz,3H),0.98 (d, J ˆ 6.5 Hz,3H),1.05 (t, J ˆ 7.5 Hz,3H),1.09 (d, J ˆ
7.1 Hz,3H),1.15 (d, J ˆ 7.0 Hz,3H),1.28 1.46 (m,4H),1.82 (d, J ˆ 1.2 Hz,
3H),2.12 (m,2H),2.18 (m,2H),2.48 (m,2H),2.68 (m,1H),2.84 (m,1H),
3.51 (dd, J ˆ 7.0,4.4 Hz,1H),3.68 (m,1H),5.00 (m,1H),5.15 (d,
J ˆ
9.6 Hz,1H),5.25 (d, J ˆ 9.6 Hz,1H),5.59 (m,1H),5.74 (dd,
J ˆ 15.9,
7.1 Hz,1H),6.01 (d, J ˆ 15.5 Hz,1H),6.07 (dq, J ˆ 9.8,1.8 Hz,1H),6.65 (d,
J ˆ 16.1 Hz,1H),6.90 (m,1H);
13C NMR (125 MHz): d ˆ 10.92,11.23,
13.02,13.33,14.28,16.01,20.74,25.76,26.23,30.15,32.11,36.65,40.78,45.61,
45.50,74.43,78.90,121.66,124.53,127.58,128.30,129.91,135.22,135.40,
136.27,137.04,144.75,164.15,216.33; IR (CHCl
3): nÄ ˆ 3516,3407,2965,
2930,1715,1459,1381,1250,1112,970,818,756,667 cm
À1; MS (EI,70 eV):
‡
m/z (%): 456 (0.7) [M ],206 (100),159 (10),121 (24),108 (31),97 (33),93
‡
(28),86 (12),69 (13),57 (39); HRMS: calcd for [C 29H44O4] : 456.3239;
found: 456.3238.
(À)-20-epi-Callystatin A: The same procedure as previously described
using pentaene 26b (10 mg,0.016 mmol),PCC (17 mg,0.081 mmol),4 ä
molecular sieves (3 g,3 beads,crushed),AcOH (9.6 mg,0.16 mmol) and
HF ¥ pyridine (0.2 mL) afforded 20-epi-callystatin A (1.9 mg,69% yield
(m,2H),2.67 (m,1H),2.78 (m,1H),3.43 (d,
J ˆ 9.1 Hz,1H),3.75 (t, J ˆ
4.1 Hz,1H),3.98 (sept, J ˆ 6.0 Hz,1H),4.69 (m,1H),5.19 (m,3H),5.57
(m,1H),5.75 (m,2H),5.87 (dd, J ˆ 15.9,5.8 Hz,1H),6.15 (d, J ˆ 15.7 Hz,
over two steps) after column chromatography (Et2O/pentane 1:1). [a]D20
ˆ
À97.4 (c ˆ 0.01,MeOH); 1H NMR (400 MHz): d ˆ 0.87 (t, J ˆ 7.4 Hz,3H),
0.93 (d, J ˆ 6.6 Hz,3H),0.98 (t, J ˆ 7.5 Hz,3H),1.03 (d, J ˆ 6.5 Hz,3H),
1.10 (d, J ˆ 6.4 Hz,3H),1.12 (d, J ˆ 7.1 Hz,3H),1.21 1.43 (m,4H),1.79 (d,
1H),6.81 (d, J ˆ 15.9 Hz,1H),OH could not be detected;
13C NMR
(100 MHz): d ˆ À4.21, À3.42,8.87,12.64,13.11,13.90,15.87,17.82,18.06,
4282
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
0947-6539/02/0818-4282 $ 20.00+.50/0
Chem. Eur. J. 2002, 8,No. 18

(À)-Callystatin A
4272 4284
J ˆ 1.4 Hz,3H),2.09 (m,2H),2.15 (m,2H),2.43 (m,2H),2.61 (m,1H),
Ogawa, Chem. Commun. 1997,1043 1044; g) G. E. Keck,C. E.
Knutson,S. A. Wiles, Org. Lett. 2001, 3,707 710.
2.80 (m,1H),3.63 (m,1H),3.91 (m,1H),5.00 (m,1H),5.12 (d,
J ˆ 9.4 Hz,
1H),5.22 (d, J ˆ 9.7 Hz,1H),5.53 (m,1H),5.79 (dd, J ˆ 15.7,7.2 Hz,1H),
6.01 (d, J ˆ 15.7 Hz,1H),6.06 (dq, J ˆ 9.7,1.8 Hz,1H),6.61 (d, J ˆ 16.3 Hz,
1H),6.87 (m,1H); 13C NMR (100 MHz): d ˆ 11.04,12.24,12.97,13.41,
14.85,16.04,20.64,23.99,26.34,30.04,32.06,36.65,40.78,45.31,47.98,75.83,
78.68,121.51,124.44,126.92,128.44,129.56,135.53,135.91,136.88,137.43,
144.40,164.23,216.10; IR (CHCl 3): nÄ ˆ 3356,2964,2929,2877,1716,1460,
[12] a) S. P. Gunasekera,M. Gunasekera,R. E. Longley,G. K. Schulte, J.
Org. Chem. 1990, 55,4912 4915; b) J. B. Nerenberg,D. T. Hung,P. K.
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1495 1499; c) I. Paterson,A. N. Hulme, J. Org. Chem. 1995, 60,
3288 3300.
1381,1256,1118,817,757,619 cm À1; MS (EI,70 eV): m/z (%): 456 (1) [M ],
‡
206 (100),188 (12),159 (20),121 (22),108 (30),97 (39),93 (25),86 (15),69
‡
(16),57 (38); HRMS: calcd for [C 29H44O4] : 456.3239; found: 456.3236.
[14] M. T. Crimmins,B. W. King, J. Am. Chem. Soc. 1998, 120,9084 9085.
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Acknowledgements
[17] J. A. Marshall,M. P. Bourbeau, J. Org. Chem. 2002, 67,2751 2754.
[18] a) Part of this work has been published in a preliminary form: J. L.
Vicario,A. Job,M. Wolberg,M. M¸ller,D. Enders, Org. Lett. 2002, 4,
1023 1026; b) A. Job,Dissertation,RWTH Aachen (Germany),
2001.
[19] a) D. Enders,in Asymmetric Synthesis, Vol. 3 (Ed.: J. D. Morrison),
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2253 2329.
This work has been generously supported by the Deutsche Forschungsge-
meinschaft (Sonderforschunsgbereich 380 and Graduiertenkolleg 440) and
the Fonds der Chemischen Industrie. J.L.V. thanks the Basque Government
(programas de perfeccionamiento y movilidad de personal investigador de
la UPV/EHU) for financial support. A.J. gratefully acknowledge the
contributions of Mareile Haas,Christian Steffens,Jochen E˚er and Jˆrg
Gries during their advanced chemistry courses. We thank Degussa AG,
BASF AG,Bayer AG and Aventis AG for the donation of chemicals.
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