β-alkoxycarbonyl enol triflates as precursors of stereopure 3-ene-1,5- diyne building blocks for the chromophores of neocarzinostatin, C-1027, kedarcidin, maduropeptin, and N1999A2

Article abstract of DOI:10.1055/s-2000-6366

A 5-step synthesis of α-alkoxymethyl-, α-siloxymethyl-and α- (carbamoyloxy)methyl-substituted enediynes 7 from type 23 β-oxo esters was developed following the strategy of Scheme 2. Specifically, the β-oxo esters 33, 36 and 38 (prepared as shown in Scheme 4) and NaH (or t-BuLi) gave Z- enolates in THF and E-enolates in DMF which were scavenged as enol triflates Z-27a-c and E-27a-c, respectively, upon treatment with triflimides 40 or 41 (Scheme 5). The Z-configurated enol triflates underwent Cacchi couplings with (trimethylsilyl)acetylene to give the pent-2-en-4-yne-1-carboxylates E-42a-c (Scheme 5). These were reduced to the corresponding aldehydes E-44a-c (Scheme 6) which were homologated with lithio(trimethylsilyl)diazomethane to furnish the desired enediynes 45a-c as pure E-isomers.

Full text of DOI:10.1055/s-2000-6366

588
FEATURE ARTICLE
b-Alkoxycarbonyl Enol Triflates as Precursors of Stereopure 3-Ene-1,5-diyne
Building Blocks for the Chromophores of Neocarzinostatin, C-1027,
Kedarcidin, Maduropeptin, and N1999A2
Olaf Gebauer,a Reinhard Brücknerb‡*
aGeschäftsbereich Pflanzenschutz, BAYER-AG, PF-F-S1 Fungizide, Alfred-Nobel-Str. 50, 40789 Monheim, Germany
Fax +49(2173)383926; E-mail: olaf.gebauer.og@bayer-ag.de
bInstitut für Organische Chemie der Georg-August-Universität, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(761)2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
Received 13 December 1999
O
Abstract: A 5-step synthesis of a-alkoxymethyl-, a-siloxymethyl-
sugar-O
and a-(carbamoyloxy)methyl-substituted enediynes 7 from type 23
O-sugar
b-oxo esters was developed following the strategy of Scheme 2.
Specifically, the b-oxo esters 33, 36 and 38 (prepared as shown in
O
O
O
Scheme 4) and NaH (or t-BuLi) gave Z-enolates in THF and E-enol-
ates in DMF which were scavenged as enol triflates Z-27a-c and E-
27a-c, respectively, upon treatment with triflimides 40 or 41
(Scheme 5). The Z-configurated enol triflates underwent Cacchi
couplings with (trimethylsilyl)acetylene to give the pent-2-en-4-
yne-1-carboxylates E-42a-c (Scheme 5). These were reduced to the
corresponding aldehydes E-44a-c (Scheme 6) which were homolo-
gated with lithio(trimethylsilyl)diazomethane to furnish the desired
enediynes 45a-c as pure E-isomers.
1
Cl
N
NH-C(=O)Ar
sugar-O
HO
O
O2CAr
Cl
2
O
O
Key words: C-C couplings, enediynes, enynes, b-oxo esters,
stereoselective enolate formation
H2N
The enediyne antiobiotics are highly cytotoxic natural
products.1 One of their important common structural fea-
tures is either a cis-configured hex-3-ene-1,5-diyne sub-
unit or the corresponding epoxide. According to the
substitution pattern of this hex-3-ene-1,5-diyne or its ep-
oxide, the enediyne antibiotics can be subdivided into two
groups. In the first group there is no substituent at C-3 of
the substructure in question - i. e., the hexenediyne is of
type 6 and the epoxide is derived from 6 - while in the
second group there is such a 3-substituent - which means
that the hexenediyne looks like compound 7 (FG is for
functional group) and the epoxide is derived therefrom
(Figure). The first group of enediyne antibiotics consists
of esperamycin,2 calicheamicin3 and dynemicin.4 The sec-
ond group comprises the kedarcidin chromophore (1),5 the
C-1027 chromophore (2),6 the maduropeptine chro-
mophore (3),7 the neocarzinostatin chromophore (4)8 and
a compound named N1999A2 (5);9 of the latter com-
pounds, 1-3 are 3-substituted hexenediynes while 4 and 5
are 3-substituted 3,4-epoxyhexenediynes.
sugar-O
HO
O
3
N
O
MeO
Cl
OH
sugar-O
O
O
O
O
4
5
O
Ar-CO2
OH
OH
Ar-CO2
R2
R2
6
6
Syntheses of natural products 1-5 or derivatives thereof
may entail or do entail the use of end-group-differentiated
enediynes of the already mentioned structure 7 as key in-
termediates. Accordingly, routes to such hexenediynes
were developed by several groups (Scheme 1).
5
2
5
4
3
4
H
H
H
6
7
FG
*
3
2
R1
R3
R1
1
1
Figure
The first approaches depicted stem from Myers´ laborato-
ry. One is based on a double Sonogashira-Tohda-Hagi-
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chromophores of Neocarzinostatin, C-1027, Kedarcidin, Maduropeptin, and N1999A2
589
hara coupling of the stereoselectively accessible 22 were functionalized in such a way that they themselves
dibromoacrylate 8 providing the ester 10.10 This can be re- or derivatives thereof would be suitable for synthesizing
duced to the underlying alcohol in which a regioselective the (epoxy)enediyne portions of the enediyne antibiotics
desilylation of that Me3Si group is possible which is clos- 1-5.
er to the OH group. Myers´ other approach to a cis-hex-3-
ene-1,5-diyne of type 7 was the Wittig reaction between
The strategy of Scheme 2 suggested the feasability of ste-
reocontrol because of the following literature observa-
tions: Weiler et al. had shown a while ago that the
ylide 11 and ketone 12; however, compound 13 was pro-
duced with a cis,trans selectivity no greater than 3:1.11
deprotonation of b-oxo esters with NaH in THF (or, as one
Another synthesis of such enediynes was realized by Dai
now knows, in diethyl ether17) gives a single sodium en-
and Meyer.12 Starting from aldehyde 14, they prepared al-
olate which is scavenged by diethyl chlorophosphate to
give an enol phosphate with >99% Z configuration; con-
lyl alcohol 15, which underwent an acid-catalyzed nucleo-
philic substitution with close-to-perfect SN1´ vs SN1
versely, the same b-oxo esters and the same phosphorylat-
regioselectivity and perfect stereocontrol at the crucial
ing agent furnish enol phosphates with 98% E-
C=C bond. Recently, Trost et al. developed an elegant ap-
configuration in the presence of triethylamine and
proach to type-7 enediynes through the Pd-catalyzed ste-
HMPA.18,19 Similarly, N-phenyltriflimide20 reacts in THF
reo- and chemoselective addition of electron-rich alkynes
with the Z-configured potassium enolates 25 of b-oxo es-
ters 24 to give Z-enol triflates Z-27, while triflic anhydride
reacts in CH2Cl2 with the E-configured ethyldiisopropyl-
like compound 18 to acceptor-substituted alkynes such as
compound 17.13 The initial C=C bond configuration (in
addition product 19) was subsequently inverted to a con-
(column2)ammonium enolates 26 of the same b-oxo esters
siderable extent by a light-induced radical chain isomer-
24 to give the isomeric E-triflates E-27 (Scheme 3).21 Al-
ization.14 Thus the isomer 21 was obtained, which was
so, N-phenyltriflimide20 transforms the Z-configured sodi-
converted via the corresponding aldehyde and the Corey-
um enolates 28 obtained from b-oxo esters 24 and NaH in
THF into enol triflates Z-27 and the E-configured sodium
Fuchs sequence to the desired hexenediyne 20.
Scheme 2 outlines the strategy which we pursued in the enolates 29 obtained from b-oxo esters 24 and NaH in
quest of stereopure enediynes with the substitution pattern DMF into the isomeric enol triflates E-27.22
7: we desired to elaborate them from stereodefined enol
The b-oxo ester substrates of the present study, namely
triflates15 of structure Z-22. The R1-C∫C moiety of our
compounds 33, 36 and 38 (Scheme 4), differ from all pre-
targets was intended to be introduced via the Cacchi
viously used b-oxo ester precursors 24 of stereopure enol
coupling16 with a suitable terminal alkyne R1-C∫C-H
triflates by the presence of at least one heteroatom in the
while the R2-C∫C moiety would result from the kind of
C1 elongation used by Trost et al. for the conversion
21Æ20. The substituents CHR3(FG) of the key triflates Z-
substituent R3. The presence of these heteroatoms makes
the target enediynes Z-44a-c (Scheme 6) into building
Biographical Sketches
Reinhard Brückner (born Reinhard W. Hoffmann at was a visiting professor at
in 1955) prepared his doc- the Philipps-Universität the Universities of Wiscon-
toral thesis at the Ludwig- Marburg he became an asso- sin / Madison and Santiago
Maximilians-Universität ciate professor at the Julius- de Compostela / Spain. His
München under the supervi- Maximilians-Universität research interests include
sion of Professor Rolf Huis- Würzburg (1990). He was a rearrangements of organo-
gen (1984) and was full professor at the Georg- lithium compounds and the
a
postdoctoral fellow with August-Universität Göttin- synthetic chemistry of di-
Professor Paul A. Wender at gen (1992) and moved to enediynes, polyols, butyro-
Stanford University. After Freiburg six years later. Be- lactones and butenolides.
habilitating with Professor ing a dedicated teacher, he
Olaf Gebauer was born in he joined the BAYER com-
Kiel in 1967. He studied pany´s crop-protection re-
chemistry at the universities search center in Monheim.
of Kiel, Braunschweig and There he is currently synthe-
Göttingen and received his sizing and developing fun-
Dr. rer. nat. in 1999 (Prof. gicides.
R. Brückner) synthesizing
models of the dienediyne
antibiotic neocarzinostatin
chromophore. In July 1999,
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

590
O. Gebauer, R. Brückner
FEATURE ARTICLE
Br
,
R2
Me3Si
2) 2
1) Br2; 89%
RO2C
TfO
RO2C
(ref.10
)
PdCl2(PPh3)2, CuI;
88%
CO2Et
Br
CO2Et
FG
FG
FG
O
8
R1
R3
R3
Z-23
R3
Me3Si
Me3Si
7
24
3) DIBAL; 82%
4) NaBH(OMe)3; 60%
TfO = F3C-SO2-O
CO2Et
OH
Me3Si
Scheme 2
9
10
tBuSiMe2
Scheme 4 shows how the properly functionalized b-oxo
esters 33, 36 and 38 were prepared. The aldehyde precur-
sor 31 of b-oxo esters 33 was obtained in 78% overall
yield through the tert-butyldiphenylsilylation of allyl al-
cohol and the ozonolysis of the resulting silyl ether 30.23
An aldol addition of the lithium enolate of ethyl acetate
transformed this aldehyde into the b-hydroxy ester 32
which was carried on to the b-oxo ester 33 by a Swern ox-
idation.24 This 2-step sequence totalled 53% yield. Hence,
tBuSiMe2
PPh3
+
11
>79%
(ref.11
O
O
)
Me3Si
O
O
O
Me3Si
13 (E:Z = 3:1)
12
PhS
OH
O
1) PhS
R1O2C
O
R2
R3
Li
ref.21: KHMDS,
THF;
ibid.: iPr2NEt,
71% (ref.12
)
CH2Cl2,
Alk
Ph
Alk
Ph
14
15
24
2) CSA, MeOH;
73%
PhS
δ
R1O
O
R2
R2
OR1
δ
O
OMe
iPr2NEtH
δ
K
δ
O
R3
Alk
Ph
O
R3
16
25 (Z)
26 (E)
CO2Me
CO2Me
1) Pd(OAc)2, P[2,6-C6H3(OMe)2]3,
PhNTf2
Tf2O
OSiMe2tBu
OSiMe2tBu
R1O2C
TfO
R2
R3
R2
CO2R1
R3
17
18
19
88% (cf. ref.13
)
TfO
E-27
PhNTf2
2) Ph2Se2, hν (ref.14 );
95%
Z-27
PhNTf2
MeO2C
δ
3 steps
74%
R1O
Me2N
NMe2
O
OSiMe2tBu
OSiMe2tBu
R2
R3
O
R2
O
OR1
δ
O
Na
O
20
21 (E:Z = 89:11)
O
δ
Na
δ
Me2N
O
O
R3
NMe2
Scheme 1
28 (Z)
29 (E)
R1O2C
R2
R3
ref.22: NaH,
THF;
ibid.: NaH,
blocks for the synthesis of enediynes like compounds 1-
5. Hence, it remained to be seen how these heteroatoms
affect the delicate bias between Z- and E-selective ester
enolate formation.
DMF;
O
24
Scheme 3
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chromophores of Neocarzinostatin, C-1027, Kedarcidin, Maduropeptin, and N1999A2
591
Last, but not least, a Claisen condensation of the lithium
enolate derived from tert-butyl acetate with Garner´s ester
3729 furnished 90% of b-oxo ester 38. As expected, the 1H
NMR spectra of the oxo esters 33, 36 and 38 of Scheme 4
displayed the (O=)CCH2C(=O) protons as a singlet at
d = 3.63 (33) or as AB spectra dA = 3.60 / dB = 3.66 (36,
38). In addition, there were the less intense singlets of the
C=C-H (d ª 5.0-5.5 ppm) and C=C-OH substructures (d
ª 12.0-12.3 ppm) of the tautomeric enols iso-33, iso-36
and iso-38 as which 13-17% of the material was present.
OLi
O3, CH2Cl2,
EtO2C
HO
-78°C; Me2S,
EtO
Ra
O
(1.1 equiv.),
THF, -78°C,
3 h; 75%
Ra
OSiPh2tBu
r.t.
78% (ref.23
)
30
31
32
Ra
Swern oxidation; 71%
EtO2C
O
EtO2C-CH=N=N,
The stereoselective conversion of the b-oxo esters 33, 36
and 38 into ester-containing Z-configured enol triflates re-
quired generating the respective b-oxo ester enolates Z-se-
lectively. According to Scheme 3, this is tantamount to
generating cation-bridged b-oxo ester enolates. For pre-
liminary tests we deprotonated the b-oxo ester 33 (Table
1). Using KHMDS in dry-ice cooled THF for that pur-
pose, i. e. the Z-favoring conditions of reference 21, and
sulfonylating with McMurry´s phenyl triflimide 39,20 we
isolated just 27% of the desired triflate 27a (entry 1). It
was the pure Z-isomer as was the crude product according
Ra
BF3•Et2O
CH2Cl2; <15%
33
δ = 5.54
85
EtO2C
H
:
δ = 12.20
Ra
15
HO
iso-33
O
O
Rb
1
to the H NMR spectrum. Deprotonating the b-oxo ester
O
33 with NaH 22,30 in THF and now at 0 °C Æ room tem-
perature increased the yield of Z-27a to 43% (entry 2). Re-
placing the phenyl triflimide 3920 by Comins´ pyridyl
triflimide 4031 under the otherwise unchanged deprotona-
tion conditions, the desired enol triflate Z-27a became
available in 53% yield (entry 3). Finally, by heating the
last-mentiond sulfonylating mixture at 55 °C for extended
times - 6 h in the case of entry 4 of Table 1 - the yield of
Z-27a rose to 83% (taking 21% of recovered b-oxo ester
33 into account). That this temperature turned out to be so
beneficial is remarkable because there are ester-contain-
ing enol triflates which undergo a b-elimination of triflic
acid under much milder conditions - i. e., in the presence
of triethylamine within 3 h at room temperature32 - and
34
OLi
(1.1 equiv.), THF, -78°C, 3 h; 73%
EtO2C
δ = 5.38
EtO
Rb
EtO2C
H
EtO2C
HO
Dess-Martin
Rb
HO
Rb
oxidation; 67%
O
35
36
83 : 17
iso-36
δ = 12.00
δ = 5.03
OLi
OMe
tBuO2C
H
tBuO2C
Boc
N
tBuO
O
Table 1
Rc
(2.2 equiv.),
THF, -78°C,
12 h; 90%
HO
Rc
O
O
Cl
37
38
87 : 13
iso-38
Rc
Triflate donors:
NTf2
N
NTf2
N
NTf2
δ = 12.28
3920
4030
4130
Scheme 4
EtO2C
EtO2C
"conditions"
conditions
Ra
=
OSiPh2tBu
Ra
TfO
Ra
it was superior to a 1-step conversion of aldehyde 31 into
b-oxo ester 33 which we attempted following a general
procedure from Roskamp´s group, i. e., by treating alde-
hyde 31 with ethyl diazoacetate and BF3-diethyl ether
complex:25 On a reasonably large scale we could not ad-
vance to reproducible yields >15%. D-Glyceraldehyde ac-
etonide (34) was prepared by the usual sodium periodate
cleavage26 of D-mannitol bisacetonide.27 Adding ethyl
lithioacetate to this aldehyde led to the b-hydroxy ester 35
as a 89:11 mixture of unassigned diastereomers (73%
yield). Oxidation with the Dess-Martin periodinane28 de-
livered 67% of the acetonide-containing b-oxo ester 36.
O
33
Z-27a
base triflate
donor
yielda
entry
1
2
3
4
KHMDS 39 -78°C
room temp.; overnight
room temp.; overnight
27%
43%
53%
NaH
NaH
NaH
39
40
40
0°C
0°C, 20 min; room temp., 6 h
0°C, 20 min; room temp., 30 min; 55°C, 6 h 83%b
a Small amounts of E-27 were separated by flash chromatography.
b Taking into account that 21% of the starting material were recovered; isolated yield:
65%.
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

592
O. Gebauer, R. Brückner
FEATURE ARTICLE
give an allenic ester thereby. The 1H NMR spectra of the ters. The triflation of the acetonide-containing b-oxo ester
crude enol triflate revealed that even when the sulfonylat- 36 worked best with NaH and the chlorinated pyridyl tri-
ing agent was triflimide 40 there was at most 1% of E-27a flimide 41. The Boc-containing b-oxo ester 38 was best
formed. In contrast to that, Gibbs et al. had found in a re- deprotonated with t-BuLi.
lated sulfonylation that the use of 40 vs. 39 tends to in-
In order to assess the stereoselectivity of the trifluo-
crease the proportion of the E-product to >5%.33 It should
romethanesulfonylations of Table 1 and Scheme 5 (upper
be noted that we could not use Comins´ pyridyl triflimide
left), we needed to know, besides the 1H NMR shifts of the
4131 for preparing the enol triflate Z-27a since both com-
1
desired Z-isomers, the H NMR shifts of the E-isomers.
pounds co-chromatographed.
Therefore, we were pleased to find that we could - as did
Keenan et al.22 - prepare the E-triflates E-27a-c from the
b-oxo esters 33, 36 and 38, NaH and a suitable triflimide
(vide infra) in DMF (Scheme 5, upper right). These com-
pounds were isolated as a 95:5 mixture in the case of Z-
and E-27a or isomerically pure - after the initially ob-
tained 99:1 E:Z mixtures had been chromatographed - in
the case of Z-27b and c.
R1O2C
O
R2
i)
ii)
33, 36, 38
R1O2C
TfO
CO2R1
R2
The alkenic nuclei 2-H and C-2 of the ester-containing
enol triflates Z- and E-27a-c reveal configuration-depen-
dent d-values: (1) In triflates Z-27a and Z-27b, d2-H
= 6.23 ppm (2 ¥) is at lower field than in the isomeric tri-
flates E-27a (5.89 ppm) and E-27b (6.04 ppm). In con-
trast, there is a high-field shift of 2-H in triflate Z-27c
(d2-H = 5.84) compared with the isomeric triflate E-27c
(d2-H = 5.98). Yet, the configurational assignment of com-
pound Z-27c is safe since it is based on the occurrence of
a cross-peak between the alkenic and the allylic proton in
the NOESY spectrum. (2) The alkenic dC-2 value in tri-
flates Z-27a and Z-27b is highfield with respect to dC-2
in the respective E isomer, while it appears at lower field
in triflate Z-27c compared with E-27c. Thus, the configu-
rational assignment of ester-substituted enol triflates of
type 7 cannot be based on the sign of Dd2-H or DdC-2 val-
ues.
R2
TfO
Z-27a-c
E-27a-c
iii)
iv)
R1O2C
CO2R1
R2
E-42a-ca)
R2
Me3Si
Me3Si
Z-42a-cb)
a) This is not a Z-isomer because of the hetero-substituent at C-α of R2.
b) This is not an E-isomer because of the hetero-substituent at C-α of R2.
a (and 33)
b (and 36)
c (and 38)
tBu
Next, enol triflates 27a-c and (trimethylsilyl)acetylene as
a particularly reactive and synthetically widely manipula-
ble acetylene were subjected to the Cacchi couplings16
shown in Scheme 5.33b Using 5 mol-% of PdCl2(PPh3)2 as
a catalyst, 15 mol-% CuI as a co-catalyst and 3:1 THF/
iPr2NH as the solvent, i. e., the conditions from reference
19, these couplings occurred at room temperature within
2 h and in yields of 67-88%. They proceeded with com-
plete retention of the double bond configuration, no mat-
ter whether we started from the Z-configured enol triflates
- as our synthetic objective demands - or from the E-con-
figured enol triflates - in order to acquire NMR reference
data for analyzing the isomer composition of the coupling
products. Accordingly, the Cacchi couplings of the 100%
stereopure enol triflates Z-27a-c, E-27b and E-27c fur-
nished the coupling products E-42a-c, Z-42b and Z-42c,
respectively, 100% stereopure (note that in these reactions
the conversion of Z- into E-isomers and vice versa corre-
sponds to the retention of configuration). Similarly, the
95:5 mixture of enol triflates E- and Z-27a reacted with
(trimethylsilyl)acetylene to provide the crude coupling
R1
R2
Et
Et
= Ra
=
= Rb
=
= Rc
=
Boc
N
O
OSiPh2tBu
O
O
i) For a: 33, NaH, THF, r.t., 20 min; 40 (1.2 equiv.), 30 min; 55 °C, 6
h; 83% based on recovered starting material (65% isolated).-For b:
36, NaH, THF, r.t., 20 min; 41 (1.2 equiv.), 30 min, 70 °C, 3.5 h;
62%.- For c: 38, t-BuLi (1.0 equiv.), THF, -78 °C, 30 min; 40 (1.2
equiv.), r.t., 30 min; 55 °C, 14 h; 71%. ii) NaH, DMF, r.t., 20 min; 40
(1.2 equiv.), 4 h; a: 52%; b: 67%; c: 72%. iii) Me3Si-C∫C-H (1.2
equiv.), PdCl2(PPh3)2 (5 mol-%), CuI (15 mol-%), 3:1 i-Pr2NH/THF,
r.t.; a (16 h): 72%; b (2 h): 82%; c (2 h): 85%. iv) Same as (iii), 2 h;
a: 67%; b: 82%; c: 88%.
Scheme 5
The ester-containing enol triflates Z-27b and c were sim-
ilarly prepared (Scheme 5) as enol triflate Z-27a (Table 1)
and were likewise isolated as pure Z-isomers, now, how-
ever, after flash chromatographic separation from 96:4
Z:E mixures initially obtained. Yield optimization re-
quired considerable fine-tuning of the reaction parame-
1
product 42a as a 95:5 Z:E mixture as evidenced by H
NMR analysis. Since the minor isomer could be separated
by flash chromatography, the major coupling product Z-
42a was isolable 100% stereopure, too. In pairs of isomer-
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chromophores of Neocarzinostatin, C-1027, Kedarcidin, Maduropeptin, and N1999A2
593
ic coupling products 42 the 1H and 13C NMR shifts of the The final goal was to transform the CO2R1 groups of the
alkenic CH group are ordered as in the corresponding iso- coupling products E-42 into the C∫C-H groups of the tar-
mer pairs of their respective enol triflate precursor 27: The get enediynes E-45. To this end, the esters E-42 were first
alkenic dC-1H values in E-42a and E-42b - but not in E- converted into the corresponding aldehydes E-44
42c - are lowfield compared with the respective Z-isomer (Scheme 6). In the case of the esters E-42a and b this was
while the alkenic d13C-H values in E-42a and E-42b - but done in two steps. We reduced them with 2.7 equiv. of
not in E-42c - are highfield compared with the respective DIBAL to give the allyl alcohols E-43a and b and oxi-
Z-isomer. Thus, there is again no 1:1 correspondence be- dized those with the Dess-Martin reagent28 to provide the
tween the configuration of these compounds and the rela- aldehydes E-44a and b in 66% and 71% yields, respec-
tive magnitude of the Csp2-H shifts.
tively. The Boc-containing ester E-42c could be reduced
one-step to the aldehyde E-44c at -78 °C by treatment
with 1.1 equiv. of DIBAH in toluene (81% yield).
R1O2C
For the remaining conversion of the aldehydes 44 into the
enediynes 45 we envisioned the Corey-Fuchs sequence.34
Accordingly, we dibromomethylenated aldehyde E-44a
with CBr4 (2.0 equiv.), PPh3 (4.0 equiv.) and Et3N (1.0
equiv.) and obtained the dibromodienyne E-46a in 72%
yield. However, treatment of this compound with MeLi or
BuLi led to a rapid decomposition and not to the desired
enediyne E-45a. In principle, a one-step alternative for
alkyne formation from the aldehydes 44 could have been
their Horner-Wadsworth-Emmons reaction with a depro-
tonated dimethyl diazomethanephosphonate35 but the eas-
ier-to-perform Ohira modification of this reaction36 was
not applicable: Instead of the desired transformation -
C=C-CH=O Æ -C=C-C∫C-H it is reported to effect -
C=C-CH=O Æ -C(OMe)C-CH-C∫C-H.37 Thus, we
took recourse to the method of Shioiri et al. from which it
was known that it does effect the particular conversion -
C=C-CH=O Æ -C=C-C∫C-H.38 Accordingly, we treat-
ed the aldehydes E-44a-c with lithio(trimethylsilyl)di-
azomethane - prepared at -78 °C from freshly prepared
LDA and the commercially available solution of (trimeth-
ylsilyl)diazomethane in THF - as described, i. e., for 1 h
at -78 °C and for 3 h at reflux temperature. What oc-
curred was nothing but decomposition. However, when
we warmed the reaction mixtures from -78 °C slowly to
no more than room temperature, the desired alkynes E-
45a-c formed. The feasability of synthesizing functional-
ized 3-substituted cis-configured hex-3-ene-1,5-diynes
from b-oxo esters - in a total of 4-5 steps - has hereby
been demonstrated. The modest yields of the last step -
49%, 39% and 41%, respectively - seems to reflect the in-
herent instability of the enediynes and not so much a
weakness of their formation reactions since the latter were
spot-to-spot conversions as judged by TLC.
R2
Me3Si
E-42a-ca)
i)
ii)
HO
R2
Me3Si
E-43a,ba)
iii)
O
R2
Me3Si
E-44a-ca)
iv)
Br
Br
R2
R2
E-46aa)
Me3Si
Me3Si
E-45a-ca)
a) This is not a Z-isomer because of the hetero-substituent at C-α of R2.
R1 and R2 as in Scheme 5
i) For a: DIBAL (2.7 equiv.), CH2Cl2, -78 °C Æ r.t., 3 h; 81%. For b:
DIBAL (2.7 equiv.), EtO2/toluene, -78 °C, 3 h; r.t., 30 min; 88%. ii)
For c: DIBAL (1.3 equiv., toluene, -78 °C, 30 min; MeOH; 81%. iii)
Dess-Martin periodinane (1.2 equiv.), CH2Cl2, r.t., 1 h (a) or 20 min
(b); for a: 81%; for b: 82%. iv) LDA (1.2 equiv.), Me3Si-CH=N=N,
THF, -78 °C, 30 min; addition of respective aldehyde 44; 1.5 h (a, b)
or 3 h (c); r.t., 4 h (a) or 20 min (b, c); for a: 49%; for b: 39%; for c:
41%.
All reactions were performed in oven-dried (100 °C) glassware un-
der anhyd N2. THF, Et2O and toluene were freshly distilled from K
before use, CH2Cl2, DMSO, DMF and amines from CaH2; MeOH
was dried with Mg. Titration of RLi according to Suffert.39 Products
purified by flash chromatography40 on Macherey&Nagel silica gel
60 (particle size 0.040-0.063 mm, 230-240 mesh ASTM; column
diameter, eluents and product-containing fractions given in brack-
ets; fraction volumes chosen as a function of the diameter of the
used column: 1.0 cm fi 5 mL, 1.5 cm fi 10 mL, 2.0 cm fi 15 mL,
2.5 cm fi 20 mL, 4.0 cm fi 50 mL, 6.0 cm fi 100 mL). Yields refer
to analytically pure samples. Optical rotations: Perkin-Elmer pola-
rimeter 241 MC, Na lamp, 589 nm. 1H NMR spectra (unless speci-
Scheme 6
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

594
O. Gebauer, R. Brückner
FEATURE ARTICLE
fied differently: TMS or CHCl3 as internal standard working in
CDCl3; occasionally: MeOH as internal standard working in
CD3OD): VXL-200 (Varian), AMX300 (Bruker) and VXR-500S
(Varian). Integrals in accord with assignments; coupling constants
in Hz; AB spectra: HA refers to high- and HB to low-field resonance;
all signals except AB signals evaluated by first-order splitting. APT
13C NMR spectra: same instruments, "+" for CH or CH3, "-" for CH2
or Cquaternary. IR spectra (film or solution in CDCl3; selected bands
only are listed in the following): Perkin Elmer FT-IR 1600. MS and
HRMS were registered by Dr. G. Remberg, Institut für Organische
Chemie der Universität Göttingen, on a Finnigan MAT 95 spec-
trometer. Combustion analyses: M. Beller and F. Hambloch, Institut
für Organische Chemie der Universität Göttingen.
E-27a
1H NMR (300 MHz): d = 1.08 (s, t-Bu), 1.17 (t, J2"’,1’" = 7.2, 2'"-H3),
4.06 (q, J1’",2’" = 7.2, 1"'-H2), 4.81 (s, 1"-H2), 5.89 (s, 2'-H), 7.36-
7.47 (m, 6 meta- and para-HAr), 7.69 (dd, Jmeta = 7.7, Jortho = 1.7, 4
ortho-HAr).
13C NMR (APT spectrum at 50 MHz, contains unidentified peak at
"+" 135.54): d = "+" 13.90 (C-2'"), "-" 19.15 [C(CH3)3], "+" 26.52
[C(CH3)3], "-" 59.87 and "-" 61.34 (C-1", C-1"'), "+" 113.16 (C-2'),
"-" 118.49 (three lines of q, JC,F = 320.5, CF3), "+" 127.79 (4 meta-
C), "+" 129.95 (2 para-C, because the intensity of this resonance is
only half that of the 4 meta- and the 4 ortho-C’s), "-" 132.30 (2 ipso-
C), "+" 135.60 (4 ortho-C), "-" 161.55 and "-" 163.17 (C-1', C=O).
Z-27a
Ethyl (Z)-4-[tert-Butyl(diphenyl)siloxy]-3-{[(trifluoromethyl)-
sulfonyl]oxy}but-2-enoate (Z-27a)
1H NMR (300 MHz): d = 1.34 (t, J2"’,1’" = 7.2, 2'"-H3), 4.23 (d,
J1",2’= 1.5, 1"-H2), 4.28 (q, J1’",2"’= 7.2, 1'"-H2), 6.23 (t, J2’,1" = 1.7, 2'-
H), 7.64 (dd, Jmeta = 7.7, Jortho = 1.7, 4 ortho-HAr); the residual reso-
nances are superimposed by those of E-27a.
13C NMR (APT spectrum at 50 MHz, contains unidentified peak at
"+" 135.54): d = "+" 15.18 (C-2'"), "+" 26.61 [C(CH3)3], "-" 60.76
and "-" 61.95 (C-1", C-1"'), "+" 111.05 (C-2'), "+" 128.05 (4 meta-
C), "+" 130.30 (2 para-C, because the intensity of this resonance is
only half that of the 4 meta- and the 4 ortho-C’s ist), "+" 135.31 (4
ortho-C); the residual resonances are superimposed by those of E-
27a.
At 0 °C a solution of b-oxo ester 33 (0.970 g, 2.52 mmol) in THF (4
mL) was added carefully to a suspension of NaH (0.079 g, 3.3
mmol, 1.3 equiv.) in THF (4 mL). Stirring was continued at r. t. for
20 min whereupon triflimide 40 was added (1.08 g, 3.02 mmol, 1.2
equiv.). After stirring for 30 min at r. t. and for 6 h at 55 °C the heat-
ing bath was removed and Et2O (20 mL) added. Successive extrac-
tions with H2O (3 ¥ 5 mL), sat. NH4Cl (5 mL), sat. NaHCO3 (5
mL) and finally brine (5 mL) ensued. After drying (Na2SO4) the sol-
vent was removed in vacuo. Purification by flash chromatography
gave the title compound >99% isomer-free from E-27a [1.5 cm, pe-
troleum ether/t-BuOMe 20:1, F7-12, 0.849 g, 65%]. Some of the
starting oxo ester 33 was re-isolated (F15-22; 0.206 g, 21%) so that
the yield of Z-27a based on recovered starting material measures
83%.
IR (CDCl3): n = 1725 and 1665 (C=O and C=C st), 1380 and 1225
cm-1 (S=O st).
No satisfactory combustion analysis could be obtained.
1H NMR (300 MHz): d = 1.09 (s, t-Bu), 1.34 (t, J2"’,1"’= 7.2, 2'"-H3),
4.23 (d, J1",2’= 1.5, 1"-H2), in touch with 4.28 (q, J1"’,2"’= 7.1, 1"'-
H2), 6.23 (t, J2’,1" = 1.7, 2'-H), 7.38-7.48 (m, 6 meta- and para-HAr),
7.63 (dd, Jortho = 7.9, Jmeta = 1.5, 4 ortho-HAr).
13C NMR (APT spectrum at 50 MHz, contains unidentified peak at
d = "+" 127.98): d = "+" 14.06 (C-2'"), "-" 19.16 [C(CH3)3], "+"
26.62 [C(CH3)3], "-" 61.40 and "-" 61.81 (C-1", C-1"'), "+" 111.03
(C-2'), "-" 118.19 (only the innermost lines of q, JC,F = 319.6, CF3),
"+" 128.03 (4 meta-C), "+" 130.27 (2 para-C, because the intensity
of this resonance is only half that of the 4 meta- and the 4 ortho-
C’s), "-" 131.72 (2 ipso-C), "+" 135.29 (4 ortho-C), "-" 156.37 (C-
1'), "-" 162.55 (C=O).
Ethyl (Z)-3-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-{[(trifluo-
romethyl)sulfonyl]oxy}prop-2-enoate (Z-27b)
Prepared as described for Z-27a from the b-oxo ester 36 (7.39 g,
34.2 mmol) in THF (74 mL), a suspension of NaH (0.813 g, 33.9
mmol, 1.0 equiv.) in THF (74 mL) and the triflimide 41 (16.1 g,
41.1 mmol, 1.2 equiv.) except that the latter was allowed to react 30
min at r. t. and 3.5 h at 70 °C. Extractive workup and flash chroma-
tography (6 cm, petroleum ether/t-BuOMe 12:1, F23-38) provided
the title compound (7.32 g, 62%). According to the extremely weak
2'-H 1NMR signal it was >99% isomer-free from E-27b.
[a]D26 = -41.1 (c = 1.82 in CHCl3).
1H NMR (300 MHz): d = 1.32 (t, J2’,1’= 7.2, 2'-H3), 1.41 and 1.51 [2
s, 2"-(CH3)2], AB signal (dA = 4.02, dB = 4.31, JAB = 9.0, in addition
split by JA,4" = 5.3, JB,4" = 7.0, 5"-H2), 4.20 (mc, 1'"-H2), 4.63 (poorly
resolved ddd, J4",5"-H(B) = 6.8, J4",5"-H(A) = 5.3, 4J4",2’= 1.1, 4"-H), 6.23
(d, 4J2’,4" = 1.5, 2'-H).
MS (EI/70 eV): m/z = 559 (22%), 516 (2%, M+), 501 (8%, M+ -
Me), 471 (9%, M+ -EtOH), 459 (100%, M+ -tert-butyl), 431 (7%),
357 (7%), 309 (8%), 271 (90%), 238 (32%), 199 (70%), 127 (12%),
+
105 (40%), 91 (12%).- MS (DCI/pos., NH4 ): m/z = 534 (100%,
+
M+ +NH4 ), 475 (10%), 402 (18%), 384 (38%), 356 (10%).
NOESY spectrum for configurational assignment: The resonances
at d = 4.63 (4"-H) and 6.23 (2'-H) exhibit a cross-peak, which
proves the cis-configuration of the C=C bond.
IR (CDCl3): n = 1725 and 1690 (C=O and C=C st), 1385 and 1185
cm-1 (S=O st).
Anal. Calcd for C23H27O6F3SSi (516.6): C 53.48; H 5.28. Found C
54.48; H 5.24; a better combustion analysis could not be obtained.
13C NMR (APT spectrum at 50 MHz): d = "+" 13.97 (C-2'"), "+"
25.01 and "+" 26.11 [2"-(CH3)2], "-" 61.48 (C-1"'), "-" 67.62 (C-5"),
"+" 73.48 (C-4"), "+" 111.60 (C-2" and C-2'), "-" 118.30 (q,
JC,F = 320, CF3), "-" 155.94 (C-1'), "-" 162.29 (C=O).
Ethyl (E)-4-[tert-Butyl(diphenyl)siloxy]-3-{[(trifluoromethyl)-
sulfonyl]oxy}but-2-enoate (E-27a) in a 94:6 Mixture with Z-27a
At 0 °C a solution of the b-oxo ester 33 (0.174 g, 0.450 mmol) in
DMF (1 mL) was added carefully to a suspension of NaH (0.014 g,
0.590 mmol, 1.3 equiv.) in DMF (1 mL). After stirring at r. t. for 20
min, the triflimide 40 (0.194 g, 0.540 mmol, 1.2 equiv.) was added
and stirring continued for 4 h. Diluting with Et2O (20 mL), washing
successively with H2O (3 ¥ 5 mL), sat. NH4Cl (5 mL), sat. NaHCO3
(5 mL) and brine (5 mL), drying (Na2SO4), removing the solvent in
vacuo and purifying by flash chromatography (1.5 cm, petroleum
ether/t-BuOMe 30:1, F8-12) gave the title compound (0.122 g,
52%); it was a 94:6 E:Z mixture according to the 1H NMR integral
ratio over the 2´-H resonances.
IR (CDCl3): n = 1725 and 1685 (C=O and C=C st), 1380 and 1300
cm-1 (S=O st).
Anal. Calcd for C11H15O7F3S (348.3): C 37.93; H 4.35. Found C
38.03; H 4.38.
Ethyl (E)-3-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-{[(trifluo-
romethyl)sulfonyl]oxy}prop-2-enoate (E-27b)
Prepared as described for E-27a from the b-oxo ester 36 (0.100 g,
0.460 mmol) in DMF (1 mL), NaH (0.011 g, 0.46 mmol, 1.0 equiv.)
in DMF (1 mL) and triflimide 40 (0.197 g, 0.550 mmol, 1.2 equiv.).
Flash chromatography (1.5 cm, petroleum ether/t-BuOMe 10:1, F4-
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chromophores of Neocarzinostatin, C-1027, Kedarcidin, Maduropeptin, and N1999A2
595
6) provided the title compound (0.108 g, 67%); the E:Z ratio was
>99:1 according to the integrals of the 2'-H´s.
[a]D25 = +40.4 (c = 1.55 in CHCl3).
1H NMR (300 MHz): d = 1.32 (t, J2’",1’" = 7.2, 2"'-H3), 1.42 and 1.52
[2 s, 2"-(CH3)2], AB signal (dA = 3.90, dB = 4.37, JAB = 8.6, in addi-
tion split by JA,4" = 6.4, JB,4" = 7.3, 5"-H2), 4.23 (q, J1"’,2’" = 7.2, 1"'-
H2), 5.69 (incompletely resolved ddd, J4",5"-H(A) ª J4",5"-H(B) ª 7.7,
4J4",2’= 0.8, 4"-H), 6.04 (d, 4J2’,4" = 0.8, 2'-H).
mmol, 1.2 equiv.). Flash chromatography (1.5 cm, petroleum ether/
t-BuOMe 10:1, F16-22) gave the title compound (0.236 g, 72%).
According to the 1H NMR integrals over the 4´´-H signals it consti-
tutes a 65:35 mixture of rotamers E-27c and iso-E-27c; the integrals
over the 2'-H resonances prove that it was >99% isomer-free from
Z-27c.
[a]D26 = +12.6 (c = 1.30 in CHCl3).
E-27c
NOESY spectrum for configurational assignment: The absence of a
cross-peak between the resonances at d = 5.69 (4"-H) and 6.04 (2'-
H) proves the trans configuration of the C=C bond.
1H NMR (300 MHz): d = 1.49 (s, 2 ¥ t-Bu), 1.53 and 1.65 [2"-
(CH3)2], AB signal (dA = 3.97, dB = 4.30, JAB = 9.4, in addition split
by
JA,4" = 2.9, JB,4" = 7.7, 5"-H2), 5.72 (dd, J4",5"-H(B) = 7.4,
13C NMR (APT spectrum at 50 MHz): d = "+" 14.01 (C-2"'), "+"
25.19 and "+" 25.40 [2"-(CH3)2], "-" 61.69 (C-1"'), "-" 68.01 (C-5"),
"+" 76.36 (C-4"), "-" 111.83 (C-2"), "+" 114.43 (C-2'), "-" 118.34
(q, JC,F = 319.4, CF3), "-" 161.10 (C-1'*), "-" 163.49 (C=O*); *as-
signments interchangeable.
J
4",5"-H(A) = 2.9, 4"-H), 5.98 (s, 2'-H).
NOESY spectrum for configurational assignment: The absence of a
cross-peak between the resonances at d = 5.72 (4"-H) and 5.98 (2'-
H) is in accord with the trans configuration of the C=C bond.
13C NMR (APT spectrum at 50 MHz): d = "+" 23.41 and "+" 24.78
[2"-(CH3)2], "+" 28.00 [2 ¥ C(CH3)3], "+" 55.15 (C-4"), "-" 67.07
(C-5"), "-" 80.88 and "-" 82.49 [2 ¥ C(CH3)3], "-" 95.48 (C-2"), "+"
112.45 (C-2'), "-" 118.16 (q, JC,F = 320.1, CF3), "-" 151.21 (carba-
mate C=O), "-" 161.65 and "-" 163.07 (C-1', C-3').
IR (CDCl3): n = 1720 and 1655 (C=O and C=C st), 1380 and 1215
cm-1 (S=O st).
Anal. Calcd for C11H15O7F3S (348.3): C 37.93; H 4.34. Found C
37.81; H 4.40.
1
iso-E-27c: H NMR (300 MHz): d = 1.41 (s, 2 ¥ t-Bu), 1.60 and
tert-Butyl (4S)-4-((Z)-3-Butoxy-3-oxo-1-{[(trifluoromethyl)sulf-
onyl]oxy}prop-1-enyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxy-
late (Z-27c)
1.61 [2"-(CH3)2], 5.65 (poorly resolved dd, J4",5"-H(B) = 6.4,
J4",5"-H(A) = 3.6, 4"-H); the other resonances are superimposed by
those of E-27c.- 13C NMR (APT spectrum at 50 MHz): d = "+"
24.68 and "+" 25.56 [2"-(CH3)2], "+" 28.00 (which superimposes -
as can be inferred from its greater intensity in comparison to the
peak at d = 28.33 - an analogous resonance of E-27c) and "+" 28.23
[2 ¥ C(CH3)3], "+" 56.24 (C-4"), "-" 67.39 (C-5"), "-" 80.19
[C(CH3)3], "-" 94.78 (C-2"), "+" 112.81 (C-2'), "-" 152.00 (carbam-
ate C=O); the residual resonances are superimposed by those of E-
27c.
At -78 °C t-BuLi (1.18 M; 375 ml, 0.443 mmol, 1.0 equiv.) was
added within 40 min dropwise and under continued stirring to a so-
lution of the b-oxo ester 38 (0.152 g, 0.443 mmol) in THF (2.0 mL).
After 30 min, triflimide 40 (0.192 g, 0.535 mmol, 1.2 equiv.) was
added, and the mixture was allowed to warm to r. t. within 30 min.
Thereafter, it was heated at 55 °C for 14 h. Workup through diluting
with t-BuOMe (30 mL), washing with H2O (4 ¥ 6 mL), sat. NH4Cl
(6 mL), sat. NaHCO3 (6 mL) and finally brine (6 mL), drying
(Na2SO4), removing the solvent in vacuo and flash chromatography
(1.5 cm, petroleum ether/t-BuOMe 10:1, F12-21) gave the title
compound (0.150 g, 71%). The Z:E ratio was >99:1 according to the
4"-H 1H NMR signals.
IR (CDCl3): n = 1710 and 1655 (C=O and C=C st), 1370 and 1215
cm-1 (S=O st).
Anal. Calcd for C18H28NO8F3S (475.5): C 45.47; H 5.94. Found C
45.87; H 5.94.
[a]D26 = -4.67 (c = 1.30 in CHCl3).
2-(tert-Butyldiphenylsiloxy)acetaldehyde (31)
1H NMR (300 MHz; contains an extra peak at d = 4.57 which is sup-
posed to stem from a rotamer): d = 1.45 and 1.53 [2 s, 2"-(CH3)2],
1.51 (s, 2 ¥ t-Bu), AB signal (dA = 4.07, dB = 4.13, JAB = 9.4, in ad-
dition split by JA,4" = 1.9, JB,4" = 6.4, 5"-H2), 4.42 (br d, J4",5"-
H(B) = 5.7, 4"-H), 5.84 (s, 2'-H).
16.6 g, 78%; Prepared by the ozonolysis of allyl ether 30 (21.1 g,
71.3 mmol) in CH2Cl2 (250 mL) followed by reductive workup with
Me2S (16.0 mL, 225 mmol, 3 equiv.) and flash chromatography [6
cm, petroleum ether/t-BuOMe 5:1, F12-24].23
NOESY spectrum for configurational assignment: The resonances
at d = 4.42 (4"-H) and 5.84 (2'-H) exhibit a cross-peak which proves
the cis-configuration of the C=C bond.
13C NMR [APT spectrum at 50 MHz; contains unidentified peak at
d = "+" 28.13 which might be due to 2 ¥ C(CH3)3 of a rotamer]:
d = "+" 22.74 and "+" 26.48 [2"-(CH3)2], "+" 27.92 [2 ¥ C(CH3)3],
"+" 58.69 (C-4"), "-" 65.79 (C-5"), "-" 81.62 and "-" 82.85 [2 ¥
C(CH3)3], "-" 95.24 (C-2"), "+" 113.18 (C-2'), "-" 118.33 (q,
Ethyl 4-(tert-Butyldiphenylsiloxy)-3-hydroxybutanoate (32)
At -20 °C BuLi (2.18 M in hexane; 7.00 mL, 15.3 mmol, 1.05
equiv. with respect to 31) was added dropwise to a solution of i-
Pr2NH (2.11 mL, 1.52 g, 16.1 mmol, 1.10 equiv. with respect to 31)
in THF (14 mL). Stirring at that temperature was continued for 40
min. At -78 °C a solution of EtOAc (1.45 mL, 14.6 mmol, 1.0
equiv. with respect to 31) in THF (7.8 mL) was added whereupon
stirring was continued for 1 h. Aldehyde 31 (4.35 g, 14.6 mmol) in
THF (10 mL) was added and stirring at -78 °C continued for anoth-
er 3 h. The reaction was quenched by adding sat. NH4Cl (11 mL).
Extraction with Et2O (3 ¥ 100 mL), washing the combined extracts
with brine (10 mL), drying over Na2SO4, removing the solvent in
vacuo and flash chromatography (4 cm, petroleum ether/t-BuOMe
5:1, F7-15) led to the title compound (4.24 g, 75%).
JC,F = 320.7, CF3), "-" 151.11 and "-" 155.14 (C-1', C-1"'), "-"
161.55 (CCO2t-Bu).
IR (CDCl3): n = 1710 (C=O st), 1370 and 1215 cm-1 (S=O st).
Anal. Calcd for C18H28NO8F3S (475.5): C 45.47; H 5.94. Found C
45.70; H 5.86.
1H NMR (300 MHz): d = 1.06 (s, t-Bu), 1.24 (t, J2’,1’ = 7.2, 2’-H3),
extreme AB signal (dA = 2.51, dB = 2.57, JAB = 15.8, in addition split
by JA,3 = 7.4, JB,3 = 5.1, 2-H2), 2.94 (br d, JOH,3 = 4.6, exchangeable
with D2O, OH), extreme AB signal (dA = 3.63, dB = 3.67, JAB = 10.2,
in addition split by JA,3 = 6.0, JB,3 = 5.1, 4-H2), 4.14 (q, J1’,2’ = 7.1,
1’-H2), superimposed by ca. 4.15 (mc, 3-H), 7.35-7.45 (m, 6 meta-
and para-HAr), 7.63-7.67 (m, 4 ortho-HAr).
tert-Butyl (4S)-4-((E)-3-Butoxy-3-oxo-1-{[(trifluoromethyl)sulf-
onyl]oxy}prop-1-enyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxy-
late (E-27c) in a 65:35 Mixture with a Rotamer (iso-E-27c)
Prepared as described for E-27a from the b-oxo ester 38 (0.237 g,
0.690 mmol) in DMF (1.5 mL), NaH (0.016 g, 0.69 mmol, 1.0
equiv.) in DMF (1.5 mL) and the triflimide 40 (0.294 g, 0.820
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

596
O. Gebauer, R. Brückner
FEATURE ARTICLE
13C NMR (APT spectrum at 50 MHz): d = "+" 14.15 (C-2’), "-"
19.22 [C(CH3)3], "+" 26.80 [C(CH3)3], "-" 38.05 (C-2), "-" 60.64 (C-
1’), "-" 66.85 (C-4), "+" 68.60 (C-3), "+" 127.73 (4 meta-C), "+"
129.79 (2 para-C because this resonance is half as intense as for
ortho- and meta-C), "-" 132.95 and "-" 132.98 (2 ¥ 1 ipso-C), "+"
135.48 (4 ortho-C), "-" 172.02 (C-1).
MS (EI/70 eV): m/z = 341 (24%, M+ -EtOH), 329 (21%, M+ -t-bu-
tyl), 283 (12%, 341 -t-butyl-H), 251 (100%, 329 -PhH), 241 (60%,
329 -EtOAc), 223 (48%), 199 (88%, 241 -C2H2O), 181 (50%), 163
(29%).
Anal. Calcd for C22H28O4Si (384.6): C 68.70; H 7.34. Found C
68.74; H 7.30.
(4R)-2,2-Dimethyl-1,3-dioxolane-4-carbaldehyde (34)
Compound 34 was obtained by known protocols26 from D-
diisopropylidenemannitol27 (39.3 g, 150 mmol) and NaIO4 (48.0 g,
215 mmol, 1.5 equiv.) as a colorless liquid (25.9 g, 67%; lit. 67%)
after distillation (bp. 47 °C20 mbar; lit. 72-74 °C30 Torr).
Ethyl (3R*,4"R)-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-hydroxy-
propionate (35) in a 83:17 Mixture with the Diastereomer Ethyl
(3S*,4"R)-(2,2-Dimethyl-1,3-dioxolan-4-yl]-3-hydroxypro-
pionate (epi-35)
+
MS (DCI/pos., NH3): m/z = 404 (100%, M+ +NH4 ), 358 (12%, 404
-EtOH), 326 (44%, 358 -MeOH), 309 (10%), 291 (5%), 274
(28%), 231 (8%).
*configurational assignments interchangeable
IR (CDCl3): n = 3575 (O-H st), 1725 (C=O st) cm-1.
At -20 °C BuLi (2.18 M in hexane; 55.0 mL, 120 mmol, 1.05
equiv.) was added dropwise to a solution of i-Pr2NH (17.0 mL, 12.3
g, 121 mmol, 1.10 equiv.) in THF (112 mL). After stirring for 40
min the temperature was lowered to -78 °C. EtOAc (12.0 mL, 123
mmol, 1.1 equiv.), dissolved in THF (55 mL), was added and 1 h lat-
er aldehyde 34 (15.1 g, 116 mmol), equally dissolved in THF (88
mL). After stirring for another 3 h at -78 °C the reaction was
quenched by the addition of sat. NH4Cl (100 mL). Extractive work-
up as described for 32 and flash chromatography (6 cm, petroleum
ether/t-BuOMe 1.5:1, F13-36) rendered the title compound (18.5 g,
73%). As determined by the 1H NMR integrals over the 2"-methyl
groups, it was a 83:17 mixture of unassigned diastereomers.
Anal. Calcd for C22H30O4Si (386.6): C 68.34; H 7.82. Found C
68.30; H 7.72.
Ethyl [4-(tert-Butyldiphenylsiloxy)-3-oxobutanoate] (33) in a
85:15 Mixture with the Tautomeric Enol Ethyl (Z)-[4-(tert-Bu-
tyldiphenylsiloxy)-3-hydroxybut-2-enoate] (iso-33)
At -65 °C a solution of trifluoroacetic anhydride (7.90 mL, 11.7 g,
54.3 mmol, 1.5 equiv. with respect to 32) in CH2Cl2 (19 mL) was
added within 10 min to a solution of DMSO (5.25 mL, 72.4 mmol,
2.0 equiv. with respect to 32) in the same solvent (37 mL). After an-
other 10 min a solution of the b-hydroxy ester 32 (14.0 g, 36.2
mmol) in CH2Cl2 (26 mL) was added. 10 min later the cooling bath
was removed so that the mixture warmed to r. t. over 40 min. Et3N
(8.40 mL, 106 mmol, 2.9 equiv. with respect to 32) was added and
another 10 min later H2O (158 mL). The aqueous phase was extract-
ed with CH2Cl2 (2 ¥ 300 mL). The combined extracts were washed
with HCl (1%, 175 mL), sat. NaHCO3 (175 mL) and brine (175
mL). After drying (Na2SO4) the solvent was removed in vacuo.
Flash chromatography (6 cm, petroleum ether/t-BuOMe 8:1, F7-15)
furnished the title compound (9.87 g, 71%).
[a]D26 = -8.53 (c = 1.50 in CHCl3).
35
1H NMR (300 MHz): d = 1.28 (t, J2’,1’= 7.2, 2'-H3), 1.35 and 1.41 [2
s, 2"-(CH3)2], AB signal (dA = 2.47, dB = 2.70, JAB = 16.4, in addi-
tion split by JA,3 = 8.1, JB,3 = 2.4, 2-H2), 3.32 (br d, JOH,3 = 3.0, ex-
changeable with D2O, OH), 3.85-4.13 (m, 3-H, 4"-H and 5"-H2), in
touch with 4.18 (q, J1’,2’= 7.2, 1'-H2).
13C NMR (APT spectrum at 50 MHz): d = "+" 14.11 (C-2'), "+"
25.10 and "+" 26.60 [2"-(CH3)2], "-" 37.65 (C-2), "-" 60.80 (C-1'),
"-" 66.59 (C-5"), "+" 69.14 (C-3), "+" 77.51 (C-4"), "-" 109.44 (C-
2"), "-" 172.65 (C-1).-epi-351H NMR (300 MHz): d = 1.37 and
1.45 [2 s, 2"-(CH3)], AB signal (evaluable speculatively in the fol-
lowing way: dA = 2.47, dB = 2.55, JAB = 16.6, in addition split by
33
1H NMR (300 MHz, CDCl3): d = 1.09 (s, t-Bu), 1.26 (t, J2’,1’ = 7.2,
2’-H3), 3.63 (s, 2-H2), 4.18 (q, J1’,2’ = 7.2, 1’-H2), in touch with 4.23
(s, 4-H2), 7.37-7.45 (m, 6 meta- and para-HAr), 7.63 (dd,
Jortho = 7.9, Jmeta = 1.5, 4 ortho-HAr).
JB,3 = 7.9, 2-H2), 2.99 (br d, JOH,3 = 5.6, exchangeable with D2O,
13C NMR (APT spectrum at 50 MHz; contained unidentified peaks
at d = "-" 77.82 and "+" 130.23): d = "+" 14.06 (C-2’), "-" 19.16
[C(CH3)3], "+" 26.68 [C(CH3)3], "-" 45.83 (C-2), "-" 61.37 (C-1’), "-"
69.43 (C-4), "+" 127.91 (4 meta-C), "+" 130.08 (2 para-C), "-"
132.13 (2 ipso-C), "+" 135.44 (4 ortho-C), "-" 167.14 (C-1),"-"
203.41 (C-3).
OH); the residual resonances are superimposed by those of 35.
13C NMR (APT spectrum at 50 MHz): d = "+" 26.32 (2"-CH3), "-"
38.17 (C-2), "-" 65.54 (C-5"), "+" 68.25 (C-3), "-" 103.71 (C-2"),
"-" 171.76 (C-1); the residual resonances are superimposed by those
of 35.
IR (CDCl3): n = 3575 (O-H st), 1720 cm-1 (C=O st).
iso-33
No satisfactory combustion analysis could be obtained.
1H NMR (300 MHz, CDCl3): d = 1.33 (t, J2’,1’ = 7.2, 2’-H3), 4.20 (d,
4J4,2 = 1.1, 4-H2), superimposed by 4.21 (q, J2’,1’ = 7.9, 1’-H2), 5.54
(t, J2,4 = 1.1, 2-H); the residual resonances are superimposed by
those of 33.- 13C NMR (APT spectrum at 50 MHz): d = "-" 60.16
(C-1’), "-" 62.73 (C-4), "+" 87.50 (C-2), "+" 127.83 (4 meta-C), "+"
129.93 (2 para-C); the residual resonances are superimposed by
those of 33.
MS (EI/70 eV): m/z = 384 (1%, M+), 353 (4%), 339 (6%), 327
(100%, M+ - tert-butyl), 281 (22%, 327 -EtOH), 253 (72%, 281 -
CO), 221 (14%), 199 (86%), 181 (12%), 177 (12%), 135 (10%), 115
(8%).
Ethyl (4"R)-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-oxopropionate
(36) in a 83:17 Mixture with the Tautomeric Enol Ethyl (4"R)-
(Z)-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-hydroxyprop-2-enoate
(iso-36)
At 0 °C Dess-Martin reagent28 (19.2 g, 45.4 mmol, 1.1 equiv.) was
added to a solution of b-hydroxy ester 35 (9.00 g, 41.2 mmol) in
CH2Cl2 (380 mL). After stirring for 1.5 h at r. t. the reaction was
quenched by the addition of sat. NaHCO3 (250 mL) and sat.
Na2S2O3 (10%, 250 mL). After 10 min, the resulting mixture was
extacted with CH2Cl2 (2 ¥ 200 mL). Washing with (55 mL), drying
(Na2SO4), evaporating the solvent in vacuo and purifying by flash
chromatography (6 cm, petroleum ether/t-BuOMe 7:1, F9-24) led to
the title compound (5.94 g, 67%); as determined by the 1H NMR in-
tegrals over the 2"-methyl resonances, it was a 83:17 mixture of ke-
tone 36 and enol iso-36. [a]D26 = +73.7 (c = 1.50 in CHCl3).
HRMS (EI/70 eV): m/z = 384.1756 (M+) confirms the molecular
formula C22H28O4Si with a precision of 2 mDa.
+
+
MS (DCI/pos., NH4 ): m/z = 402 (100%, M+ +NH4 ).
IR (CDCl3): n = 1740 and 1720 cm-1 (C=O st).
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chromophores of Neocarzinostatin, C-1027, Kedarcidin, Maduropeptin, and N1999A2
597
36
95.19 (C-2"), "-" 151.18 (N-CO2t-Bu), "-" 166.10 (C-1), "-" 201.76
1H NMR (300 MHz): d = 1.28 (t, J2’,1’= 7.1, 2’-H3), 1.38 and 1.49 [2
s, 2"-(CH3)2], AB signal (dA = 3.60, dB = 3.66, JAB = 16.2, 2-H2),
4.10 (dd, Jgem = 9.0, J5"-H(1), 4" = 5.2, 5"-H1), 4.17 - ca. 4.25 (m, 5"-H2,
1’-H2), 4.53 (dd, J4",5"-H(2) = 7.8, J4",5"-H(1) = 5.5, 4"-H). 13C NMR
(APT spectrum at 50 MHz): d = "+" 14.02 (C-2’), "+" 24.71 and "+"
25.88 [2"-(CH3)2], "-" 45.66 (C-2), "-" 61.36 (C-1’), "-" 66.44 (C-
5"), "+" 79.85 (C-4"), "-" 111.14 (C-2"), "-" 166.90 (C-1), "-"
203.85 (C-3).
(C-3).
38b
1H NMR (300 MHz): d = 1.43 (s, t-Bu), 1.63 (s, 2"-CH3), AB signal
(dA = 3.47, dB = 3.58, JAB = 15.9, 2-H2), AB signal (dA = 4.06,
dB = 4.13, JAB = 8.3, in addition split by JA,4" = 2.2, JB,4" = 5.6, 5"-
H2), 4.55 (dd, J4”,5”-H(B) = 6.4, J4”,5”-H(A) = 3.4, 4"-H); the residual res-
onances are superimposed by those of 38a.
13C NMR (APT spectrum at 50 MHz): d = "+" 24.84 "+" 25.90 [2"-
(CH3)2], "+" 28.09 and "+" 28.17 [2 ¥ C(CH3)3], "-" 47.71 (C-2), "+"
64.74 (C-4"), "-" 65.23 (C-5"), "-" 94.49 (C-2"), "-" 152.41 (N-
CO2t-Bu), "-" 166.41 (C-1), "-" 201.47 (C-3); the residual resonanc-
es are superimposed by those of 38a.
iso-36
1H NMR (300 MHz): d = 1.31 (t of which only the low-field peak is
not superimposed, J2’,1’= 6.9, 2’-H3), 1.41 (s, 2"-CH3), 3.99 (dd,
J
gem = 8.9, in addition split by J5"-H(1),4" = 9.0, 5"-H111111111 1), ca.
4.17 - 4.30 (m, 5"-H2, 1’-H2), 5.38 (s, 4"-H), 12.00 (s, OH); the re-
sidual resonances are superimposed by those of 36.
iso-38a and iso-38b:
13C NMR (APT spectrum at 50 MHz): d = "+" 14.17 (C-2’), "+"
25.29 and "+" 25.99 [2"-CH3)2], "-" 60.28 (C-1’), "-" 68.03 (C-5"),
"+" 74.39 (C-4"), "+" 88.23 (C-2), "-" 110.59 (C-2"), "-" 175.20 (C-
1); the residual resonances are superimposed by those of 36.
1H NMR (300 MHz): d = 5.03 (s, 2-H), 12.28 and 12.33 (2 br s,
OH*); the residual resonances are superimposed by those of 38a
and 38b.
IR (CDCl3): n = 1795 and 1700 cm-1 (C=O st).
IR (CDCl3): n = 1740 and 1720 cm-1 (C=O st).
Anal. Calcd for C17H29NO6 (343.4): C 59.46; H 8.51. Found C
59.30; H 8.37.
Anal. Calcd for C10H16O5 (216.2): C 55.55; H 7.47. Found C 55.44;
H 7.61.
Ethyl (E)-(3-tert-Butyldiphenylsiloxymethyl)-5-(trimethylsi-
lyl)pent-2-en-4-ynoate (E-42a)
3-(tert-Butyl) 4-Methyl (4S)-2,2-Dimethyl-1,3-oxazolidine-3,4-
dicarboxylate (iso-37)
Prepared as described for E-42c from PdCl2(PPh3)2 (0.122 g, 0.170
mmol, 0.06 equiv.) and CuI (0.102 g, 0.540 mmol, 0.16 equiv.) in
degassed THF (46 mL), triflate Z-27a (1.59 g, 3.08 mmol), (tri-
methylsilyl)acetylene (601 mL, 0.418 g, 4.24 mmol, 1.4 equiv.) and
degassed i-Pr2NH (15.3 mL, 11.1 g, 110 mmol, 36 equiv. with re-
spect to Z-27a) except that the reaction lasted 16 h. Purification by
flash chromatography (2.5 cm, petroleum ether/t-BuOMe 20:1, F8-
13) gave the title compound (1.03 g, 72%) which - according to the
1H NMR integrals over the 2-H resonances - was >99% isomer-free
from Z-42a.
Prepared by a published procedure29 from the methyl ester of N-
Boc-L-serine29 (52.6 g, 240 mmol) and 2,2-dimethoxypropane (60.1
mL, 493 mmol, 2.0 equiv.) and purified by distillation (bp. 83-
85 °C0.40 mbar; lit. 102 °C2 Torr) to give the title compound (51.2 g,
83%; lit. 70-89%) which solidified in the refrigerator.
tert-Butyl (4S)-4-[3-(tert-Butoxy)-3-oxopropanoyl]-2,2-dimeth-
yl-1,3-oxazolidine-3-carboxylate (38; 63:37 Mixture* of Rotam-
ers 38a and 38b) in a 87:13 Mixture** with the Tautomeric Enol
tert-Butyl (4S)-4-[(Z)-3-(tert-Butoxy)-1-hydroxy-3-oxoprop-1-
enyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate [iso-38; Un-
specified Mixture of Rotamers iso-38a and iso-38b]
1H NMR (300 MHz): d = 0.19 [s, Si(CH3)3], 1.09 (s, t-Bu), 1.34 (t,
J
2',1' = 7.2, 2’-H3), 4.26 (q, J1',2' = 7.1, 1’-H2), low-field part superim-
posed by 4.27 (d, 4J1",2 = 2.2, 1"-H2), 6.54 (t, 4J2,1" = 2.1, 2-H), 7.37-
7.48 (m, 6 meta- and para-HAr), 7.65-7.69 (m,. 4 ortho-HAr).
1
*determined H NMR spectroscopically by the integral ratio over
the 4´´-H resonances
13C NMR (APT spectrum at 75 MHz): d = "+" -0.43 [Si(CH3)3],
"+" 14.24 (C-2’), "-" 19.19 [C(CH3)3], "+" 26.68 [C(CH3)3], "-"
60.34 (C-1’), "-" 65.99 (C-1"), "-" 99.52 and "-" 107.34 (C-4, C-5),
"+" 122.81 (C-2), "+" 127.91 (4 meta-C), "+" 129.96 (2 para-C), "-"
132.76 (2 ipso-C), "+" 135.47 (4 ortho-C), "-" 137.21 (C-3), "-"
165.41 (C-1).
**determined 1H NMR spectroscopically by the integral ratio over
the 2-H resonances
At -20 °C BuLi (2.35 M in hexane; 51.7 mL, 121 mmol, 2.10
equiv.) was added dropwise to a solution of i-Pr2NH (16.1 mL, 11.6
g, 121 mmol, 2.10 equiv.) in THF (100 mL). After stirring for 40
min the temperature was decreased to -78 °C. tert-BuOAc (16.4
mL, 121 mmol, 2.10 equiv.), dissolved in THF (50 mL), was added,
stirring at -78 °C continued for 1 h, and ester 37 (15.0 g, 57.9
mmol), also dissolved in THF (51 mL) was added. After stirring for
another 12 h at -78 °C, the reaction was quenched by the addition
of sat. NH4Cl (300 mL). Extractive workup with t-BuOMe (3 ¥ 500
mL), washing with brine (200 mL) and flash chromatography (6
cm, petroleum ether/t-BuOMe 6:1, F12-32) gave the title compound
(17.9 g, 90%) as a colorless solid (mp. 78 °C).
IR (CDCl3): n = 2255 (C∫C st), 1705 and 1620 cm-1 (C=O and C=C
st).
Anal. Calcd for C27H36O3Si2 (464.7): C 69.78; H 7.81. Found C
69.77; H 7.94.
Ethyl (Z)-(3-tert-Butyldiphenylsiloxymethyl)-5-(trimethylsilyl)-
pent-2-en-4-ynoate (Z-42a)
Prepared as described for E-42c from PdCl2(PPh3)2 (0.012 g, 0.017
mmol, 0.05 equiv.) and CuI (0.010 g, 0.051 mmol, 0.16 equiv.) in
degassed THF (4.5 mL), triflate E-27a (0.159 g, 0.308 mmol), (tri-
methylsilyl)acetylene (52 ml, 0.036 g, 0.370 mmol, 1.2 equiv.) and
degassed i-Pr2NH (1.5 mL, 1.1 g, 11 mmol, 36 equiv.). Purification
by flash chromatography (1.5 cm, petroleum ether/t-BuOMe 40:1,
F8-16) gave the title compound (0.096 g, 67%) which was - ac-
[a]D26 = -61.7 (c = 1.30 in CHCl3)
38a
1H NMR (300 MHz): d = 1.47 and 1.48 (2 s, 2 ¥ t-Bu), 1.51 and 1.69
[2 s, 2"-(CH3)2], 3.45 (br s, 2-H2), AB signal (dA = 4.01, dB = 4.18,
JAB = 9.0, in addition split by JA,4" = 3.0, JB,4" = 8.5, 5"-H2), 4.40 (dd,
1
J4",5"-H(B) = 7.6, J4",5"-H(A) = 3.0, 4"-H).
cording to the H NMR integrals over the 2-H´s - >99% isomer-
13C NMR (APT spectrum at 50 MHz): d = "+" 23.54 and "+" 25.22
[2"-(CH3)2], "+" 27.84 [2 ¥ C(CH3)3], "-" 46.76 (C-2), "+" 65.16 (C-
4"), "-" 65.42 (C-5"), "+" 81.03 and "+" 82.01 [2 ¥ C(CH3)3], "-"
free from E-42a.
1H NMR (300 MHz): d = 0.22 [s, Si(CH3)3], 1.09 (s, t-Bu), 1.17 (t,
J
2’,1’= 7.0, 2'-H3), 4.04 (q, J1’,2’= 7.2, 1'-H2), 4.78 (d, 4J1",2 = 2.3, 1"-
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

598
O. Gebauer, R. Brückner
FEATURE ARTICLE
H2), 6.09 (t, 4J2,1" = 2.1, 2-H), 7.34-7.44 (m, 4 meta- HAr and 2 para-
HAr), 7.70-7.74 (m, 4 ortho-HAr).
4, C-5), "-" 110.42 (C-2"), "+" 126.43 (C-2), "-" 141.41 (C-3), "-"
165.00 (C-1).
IR (CDCl3): n = 2255 and 2150 (C∫C st), 1705 and 1610 cm-1 (C=O
and C=C st).
13C NMR (APT spectrum at 50 MHz): d = "+" - 0.43 [Si(CH3)3], "+"
14.24 (C-2’), "-" 19.19 [C(CH3)3], "+" 26.68 [C(CH3)3], "-" 60.34
(C-1’*), "-" 65.99 (C-1"*), "-" 99.52 and "-" 107.34 (C-4, C-5), "+"
122.81 (C-2), "+" 127.91 (4 meta-C), "+" 129.96 (2 para-C), "-"
132.76 (2 ipso-C), "+" 135.47 (4 ortho-C), "-" 137.21 (C-3), "-"
165.41 (C-1); *so assigned because of the similar chemical environ-
ment of C-1’here and C-1’in compound 33 and because of the sim-
ilar chemical environment of C-1" here and C-4 in compound 33.
Anal. Calcd for C15H24O4Si (296.4): C 60.78; H 8.16. Found C
60.95; H 8.01.
tert-Butyl E-(4"R)-[3-N-(tert-Butoxycarbonyl)-2,2-dimethylox-
azolidin-4-yl]-5-(trimethylsilyl)pent-2-en-4-ynoate (E-42c) in a
68:32 Mixture* with a Rotamer (iso-E-42c)
IR (CDCl3): n = 2250 and 2150 (C∫C st), 1705 and 1605 cm-1 (C=O
and C=C st).
*determined 1H NMR spectroscopically by the integral ratios over
the 4”-H´s
Anal. Calcd for C27H36O3Si2 (464.7): C 69.78; H 7.81. Found C
69.58; H 7.90.
At r.t. triflate Z-27c (0.300 g, 0.631 mmol), (trimethylsilyl)acety-
lene (106 ml, 0.074 g, 0.757 mmol, 1.2 equiv.) and degassed
i-Pr2NH (2.93 mL, 2.12 g, 21.1 mmol, 33 equiv.) were added in this
order to a stirred suspension of PdCl2(PPh3)2 (0.023 g, 0.032 mmol,
0.05 equiv.) and CuI (0.020 g, 0.095 mmol, 0.15 equiv.) in degassed
THF (8.8 mL). After 2 h t-BuOMe (4 mL) was added. Washings
with sat. NH4Cl (3 ¥ 3 mL) and brine (3 mL), drying (Na2SO4),
evaporation of the solvent in vacuo and flash chromatography (1.5
cm, petroleum ether/t-BuOMe 10:1, F9-22) gave the title compound
(0.227 g, 85%) which - according to the 1H NMR integrals over the
2-H´s - was >99% isomer-free from Z-42c.
Ethyl (4"R)-(E)-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(trimethyl-
silyl)pent-2-en-4-ynoate (E-42b)
Prepared as described for E-42c from PdCl2(PPh3)2 (0.024 g, 0.033
mmol, 0.05 equiv.) and CuI (0.021 g, 0.099 mmol, 0.15 equiv.) in
degassed THF (9 mL), triflate Z-27b (0.226 g, 0.649 mmol), (tri-
methylsilyl)acetylene (109 ml, 0.076 g, 0.779 mmol, 1.2 equiv.) and
degassed i-Pr2NH (3.00 mL, 2.17 g, 21.6 mmol, 33 equiv.). Purifi-
cation by flash chromatography (1.5 cm, petroleum ether/t-BuOMe
20:1, F22-35) gave the title compound (0.158 g, 82%) which was -
according to the 1H NMR integrals over the 2-H´s - >99% isomer-
free from Z-42b.
[a]D24 = -68.7 (c = 2.53 in CHCl3).
E-42c
[a]D25 = +32.8 (c = 1.83 in CHCl3).
1H NMR (300 MHz): d = 0.20 [s, Si(CH3)3], 1.49 (2 ¥ t-Bu), 1.54
and 1.64 [2 s, 2"-(CH3)2], AB signal (dA = 3.97, dB = 4.09, JAB = 8.8,
in addition split by JA,4" = 5.3, JB,4" = 6.8, 5"-H2), 4.54 (dd,
1H NMR (300 MHz): d = 0.17 [s, Si(CH3)3], 1.24 (t, J2’,1’= 7.2, 2'-
H3), 1.34 and 1.39 [2 s, 2"-(CH3)2], AB signal (dA = 3.87, dB = 4.20,
JAB = 8.3, in addition split by JA,4" ª JB,4" ª 6.8, 5"-H2), high-field
portion of B-part superimposed by 4.13 (q, J1’,2’= 7.1, 1'-H2), 4.54
(dd, J4",5"-H(A) ª J4",5"-H(B) ª 6.8, 4"-H), 6.29 (hardly resolved d,
4J2,4" = 1.1, 2-H).
13C NMR (APT spectrum at 50 MHz): d = "+" -0.40 [Si(CH3)3],
"+" 14.22 (C-2'), "+" 25.76 and "+" 26.17 [2"-(CH3)2], "-" 60.44 (C-
1'), "-" 69.00 (C-5"), "+" 77.67 (C-4"), "-" 99.41 and "-" 108.74 (C-
4, C-5), "-" 110.77 (C-2"), "+" 123.96 (C-2), "-" 136.34 (C-3), "-"
164.72 (C-1).
J4",5"-H(A) = J4",5"-H(B) = 5.7, 4"-H), 5.95 (s, 2-H).
13C NMR (APT spectrum at 50 MHz): d = "+" -0.32 [Si(CH3)3],
"+" 24.31 and "+" 25.44 [2"-(CH3)2], "+" 28.14 [2 ¥ C(CH3)3], "+"
62.61 (C-4"), "-" 67.51 (C-5"), "-" 80.38 and "-" 80.97 [2 ¥
C(CH3)3], "-" 94.90 (C-2"), "-" 99.41 and "-" 108.74 (C-4, C-5), "+"
127.19 (C-2), "-" 135.14 (C-3), "-" 152.21 (N-CO2t-Bu), "-" 163.96
(C-1).- iso-E-42c: 1H NMR (300 MHz): d = 1.41 (2 ¥ t-Bu), 4.49
(mc, 4"-H); the residual signals are superimposed by those of E-42c.
13C NMR (APT spectrum at 50 MHz): d = "+" 24.85 and "+" 25.88
[2"-(CH3)2], "+" 28.19 [2 ¥ C(CH3)3], "-" 67.31 (C-5"), "-" 80.44
and "-" 80.91 [2 ¥ C(CH3)3], "-" 99.76 (C-2"),"+" 127.26 (C-2); the
residual signals are superimposed by those of E-42c.
IR (CDCl3): n = 2250 and 2145 (C∫C st), 1710 and 1625 cm-1 (C=O
and C=C st).
Anal. Calcd for C15H24O4Si (296.4): C 60.78; H 8.16. Found C
61.05; H 8.09.
IR (CDCl3): n = 2255 and 2145 (C∫C st), 1695 (C=C st) cm-1.
Anal. Calcd for C22H37NO5Si (423.6): C 62.38; H 8.82. Found C
62.28; H 8.67.
Ethyl (4"R)-(Z)-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(trimethyl-
silyl)pent-2-en-4-ynoate (Z-42b)
Prepared as described for E-42c from PdCl2(PPh3)2 (0.030 g, 0.042
mmol, 0.05 equiv.) and CuI (0.026 g, 0.13 mmol, 0.15 equiv.) in de-
gassed THF (11 mL), triflate E-27b (0.288 g, 0.827 mmol), (tri-
methylsilyl)acetylene (139 ml, 0.097 g, 0.992 mmol, 1.2 equiv.) and
degassed i-Pr2NH (3.80 mL, 2.74 g, 27.4 mmol, 33 equiv.). Purifi-
cation by flash chromatography (1.5 cm, petroleum ether/t-BuOMe
20:1, F12-20) gave the title compound (0.202 g, 82%) which was -
according to the 1H NMR integrals over the 2-H´s - >99% isomer-
free from E-42b.
[a]D25 = +59.9 (c = 1.55 in CHCl3).
1H NMR (300 MHz): d = 0.19 [s, Si(CH3)3], 1.25 (t, J2’,1’= 7.2, 2'-
H3), 1.39 and 1.49 [2 s, 2"-(CH3)2], AB signal (dA = 3.78, dB = 4.32,
JAB = 8.5, in addition split by JA,4" = 7.0, JB,4" = 6.8, 5"-H2), 4.13 (q,
tert-Butyl (Z)-(4"R)-[3-N-(tert-Butoxycarbonyl)-2,2-dimethyl-
oxazolidin-4-yl]-5-(trimethylsilyl)pent-2-en-4-ynoate (Z-42c) in
a 68:32 Mixture* with a Rotamer (iso-Z-42c )
*determined 1H NMR spectroscopically by the integral ratios over
the 2-H´s.
Prepared as described for E-42c from PdCl2(PPh3)2 (0.011 g, 0.015
mmol, 0.05 equiv.) and CuI (0.010 g, 0.047 mmol, 0.15 equiv.) in
degassed THF (4.3 mL), triflate E-27c (0.146 g, 0.307 mmol), (tri-
methylsilyl)acetylene (51 ml, 0.035 g, 0.37 mmol, 1.2 equiv.) and
degassed i-Pr2NH (1.43 mL, 1.03 g, 10.3 mmol, 33 equiv.). Flash
chromatography (1.5 cm, petroleum ether/t-BuOMe 12:1, F10-21)
afforded the title compound (0.114 g, 88%) which was - according
to the 1H NMR integrals over the 2-H´s - >99% isomer-free from
E-42c).
J
1’,2’= 7.1, 1'-H2), 5.60 (ddd, J4",5"-H(A) = 7.0, J4",5"-H(B) = 6.8,
4J4",2 = 1.2, 4"-H), 6.18 (d, 4J2,4" = 1.5, 2-H).
[a]D25 = -64.5 (c = 1.82 in CHCl3).
13C NMR (APT spectrum at 50 MHz): d = "+" -0.44 [Si(CH3)3],
"+" 14.09 (C-2'), "+" 25.74 and "+" 26.13 [2"-(CH3)2], "-" 60.55 (C-
1'), "-" 69.15 (C-5"), "+" 72.81 (C-4"), "-" 101.59 and "-" 103.40 (C-
Z-42c 1H NMR (300 MHz): d = 0.15 [s, Si(CH3)3], 1.40 and 1.45 [2
s, 2"-(CH3)2], 1.67 (2 x t-Bu), AB signal (dA = 3.79, dB = 4.26,
JAB = 9.2, in addition split by JA,4" = 4.7, JB,4" = 7.3, 5"-H2), 5.40
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chromophores of Neocarzinostatin, C-1027, Kedarcidin, Maduropeptin, and N1999A2
599
4
(ddd, J4",5"-H(B) = 7.3, J4",5"-H(A) = 5.2, J4",2 = 1.2, 4"-H), 6.11 (d,
4J2,4" = 1.2, 2-H).
J
B,4’= 6.4, 5'-H2), 4.38 (mc, 1-H2), 4.47 (dd, J4’,5’-H(A) = J4’,5’-H(B) = 6.8,
4'-H), 6.22 (t, J2,1 = 6.4, 2-H).
13C NMR (APT spectrum at 75 MHz): d = "+" -0.49 [Si(CH3)3],
"+" 24.35 and "+" 25.03 [2"-(CH3)2], "+" 28.08 and "+" 28.17 [2 ¥
C(CH3)3], "+" 56.93 (C-4"), "-" 68.78 (C-5"), "-" 79.76 and "-"
80.91 [2 ¥ C(CH3)3], "-" 94.73 (C-2"), "-" 102.21 and "-" 102.57 (C-
4, C-5), "+" 127.04 (C-2), "-" 142.96 (C-3), "-" 151.40 (N-CO2t-
Bu), "-" 164.79 (C-1).
13C NMR (APT spectrum at 50 MHz): d = "+" -0.21 [Si(CH3)3],
"+" 26.00 and "+" 26.27 [2'-(CH3)2], "-" 61.00 (C-1), "-" 68.57 (C-
5'*), "+" 77.81 (C-4'), "-" 98.97 and "-" 102.63 (C-4, C-5), "-"
109.98 (C-2'), "-" 123.10 (C-3), "+" 138.85 (C-2); *assignment
based on the similarity of the chemical environment here with that
in compound E-42b.
iso-Z-42c 1H NMR (300 MHz): d = 1.42 and 1.48 [2 s, 2"-(CH3)2],
1.65 (2 ¥ t-Bu), AB signal (A part superimposed, dB = 4.32,
IR (CDCl3): n = 3610 (O-H st), 2250 and 2145 cm-1 (C∫C st).
AB = 9.4, in addition split by JB,4" = 7.1, 5"-H2), 6.15 (d, 4J2,4" = 1.5,
Anal. Calcd for C13H22O3Si (254.4): C 61.37; H 8.73. Found C
61.35; H 8.82.
J
2-H); the other resonances are superimposed by those of Z-42c.
13C NMR (APT spectrum at 75 MHz): d = "+" -0.37 [Si(CH3)3],
"+" 25.14 and "+" 25.83 [2"-(CH3)2], "+" 28.49 [C(CH3)3], "+"
57.76 (C-4"), "-" 69.34 (C-5"), "-" 80.17 and "-" 80.73 [2 ¥
C(CH3)3], "-" 94.19 (C-2"), "-" 101.80 and "-" 102.73 (C-4, C-5),
"+" 127.65 (C-2), "-" 143.06 (C-3), "-" 152.08 (N-CO2t-Bu), "-"
164.69 (C-1); the other resonances are superimposed by those of Z-
42c.
(E)-3-[(tert-Butyldiphenylsiloxy)methyl]-5-(trimethylsilyl)pent-
2-en-4-ynal (E-44a)
Dess-Martin reagent28 (2.35 g, 5.32 mmol, 1.2 equiv.) was added
to a solution of alcohol E-43a (2.02 g, 4.43 mmol) in CH2Cl2 (36
mL) at r.t. After stirring for 1 h the mixture was poured into sat.
NaHCO3 (42 mL) and sat. Na2S2O3 (10%, 42 mL) and stirring con-
tinued for 10 min. Extractive workup with CH2Cl2 (2 ¥ 40 mL) and
brine (10 mL), drying (Na2SO4) evaporation of the solvent in vacuo
and flash chromatography (4 cm, petroleum ether/t-BuOMe 30:1,
F6-13) gave the title compound (1.80 g, 81%).
IR (CDCl3): n = 2255 and 2145 (C∫C st), 1695 cm-1 (C=O st).
Anal. Calcd for C22H37NO5Si (423.6): C 62.38; H 8.82. Found C
62.41; H 8.71.
1H NMR [300 MHz; contained aliphatic contaminant(s)]: d = 0.19
4
(E)-3-[(tert-Butyldiphenylsiloxy)methyl]-5-(trimethylsilyl)pent-
2-en-4-yn-1-ol (E-43a)
[s, Si(CH3)3], 1.08 (s, t-Bu), 4.33 (d, J1’,2 = 1.9, 1'-H2), 6.72 (dt,
J
2,1 = 8.4, 4J2,1’= 2.1, 2-H), 7.38-7.49 (m, 4 meta- and 2 para-HAr),
At -78 °C DIBAL (1.0 M in CH2Cl2, 12.0 mL, 12.0 mmol, 2.7
equiv.) was added to a solution of ester E-42a (2.06 g, 4.43 mmol)
in CH2Cl2 (12 mL). Within 3 h the temperature was gradually raised
to 0 °C. The reaction was quenched by the addition of sat. K,Na tar-
trate (42 mL). After stirring for 40 min, the phases were separated
and the organic phase was extracted with CH2Cl2 (3 ¥ 100 mL).
Washing with brine (10 mL), drying (Na2SO4) removal of the sol-
vent in vacuo and flash chromatography (4 cm, petroleum ether/t-
BuOMe 30:1, F6-13) furnished the title compound (1.80 g, 81%).
7.66 (mc, 4 ortho-HAr), 10.17 (d, J1,2 = 8.7, 1-H).
13C NMR (APT spectrum at 50 MHz): d = "+" -0.45 [Si(CH3)3], "-"
19.26 [C(CH3)3], "+" 26.71 [C(CH3)3], "-" 65.43 (C-1'), "-" 99.52
(C-4), "-" 107.34 (C-5), "+" 127.88 (4 meta-C), "+" 129.99 (2 para-
C), "+" 132.34 (C-2), "-" 132.47 (2 ipso-C), "+" 135.40 (4 ortho-C),
"-" 145.64 (C-3), "+" 192.68 (C-1).
IR (CDCl3): n = 2860 (carbonyl-H st), 2255 (C∫C st), 1670 cm-1
(C=O st).
1H NMR (300 MHz): d = 0.19 [s, Si(CH3)3], 1.09 (s, t-Bu), 1.68 (br
Anal. Calcd for C25H32O2Si2 (420.7): C 71.37; H 7.67. Found C
71.07; H 7.69.
4
s, OH), 4.20 (br d, J1’,2 = 1.5, 1'-H2), 4.43 (br d, J1,2 = 6.8, 1-H2),
4
6.23 (tt, J2,1 = 6.6, J2,1’= 1.8, 2-H), 7.37-7.48 (m, 4 meta- and 2
(4’S)-(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(trimethylsilyl)-
pent-2-en-4-ynal (E-44b)
para-HAr), 7.71 (mc, 4 ortho-HAr).
13C NMR (APT spectrum at 50 MHz): d = "+" -0.15 [Si(CH3)3], "-"
19.27 [C(CH3)3], "+" 26.76 [C(CH3)3], "-" 61.15 (C-1*), "-" 65.34
(C-1'*), "-" 100.20 and "-" 101.28 (C-4, C-5), "-" 124.47 (C-3), "+"
127.70 (4 meta-C), "+" 129.73 (2 para-C), "-" 133.20 (2 ipso-C),
"+" 135.09 (C-2), "+" 135.51 (4 ortho-C); *so assigned because of
the similar chemical environment of C-1' here and C-1' in com-
pound E-44a.
Prepared as described for E-44a from Dess-Martin reagent28 (0.519
g, 1.18 mmol, 1.1 equiv.) and alcohol E-43b (0.272 g, 1.07 mmol)
in CH2Cl2 (7 mL) except that the reaction was allowed to proceed
for 20 min. Purification by flash chromatography (1.5 cm, petro-
leum ether/t-BuOMe 10:1, F15-25) furnished the title compound
(0.220 g, 82%).
[a]D23 = +24.6 (c = 1.99 in CHCl3).
IR (CDCl3): n = 3610 (O-H st), 2255 and 2145 cm-1 (C∫C st).
1H NMR (300 MHz): d = 0.21 [s, Si(CH3)3], 1.39 and 1.43 [2 s, 2'-
(CH3)2], AB signal (dA = 3.93, dB = 4.27, JAB = 8.5, in addition split
by JA,4’= 6.4, JB,4’= 7.0, 5'-H2), 4.65 (ddd, J4’,5’-H(A) = J4’,5’-H(B) = 6.7,
Anal. Calcd for C25H34O2Si2 (422.7): C 71.03; H 8.11. Found C
70.80; H 8.39.
4
4J4’,2 = 1.2, 4'-H), 6.48 (dd, J2,1 = 8.3, J2,4’= 1.5, 2-H), 10.08 (d,
(4’S)-(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(trimethylsilyl)-
pent-2-en-4-yn-1-ol (E-43b)
J1,2 = 8.3, 1-H).
13C NMR (APT spectrum at 50 MHz): d = "+" -0.59 [Si(CH3)3],
"+" 25.56 and "+" 26.06 [2'-(CH3)2], "-" 68.72 (C-5'), "+" 77.00 (C-
4'), "-" 97.32 and "-" 109.29 (C-4*, C-5*), "-" 111.02 (C-2'*), "+"
133.30 (C-2), "-" 144.17 (C-3), "+" 192.19 (C-1); *distinguishable
because of the lower intensity of quaternary acetylenic 13C nuclei.
At -78 °C DIBAL (1.05 M in toluene, 46.2 mL, 48.5 mmol, 2.5
equiv.) was added to a solution of ester E-42b (5.85 g, 19.7 mmol)
in Et2O (57 mL). Stirring was continued for 3 h at -78 °C. Then,
within 30 min, the temperature was gradually raised to r. t., then the
mixture was poured into sat. K,Na tartrate (150 mL). After 20 min
a similar workup followed as described for E-43a, which was tem-
inated by a flash chromatography (4 cm, petroleum ether/t-BuOMe
2:1, F13-25) providing the title compound (4.43 g, 88%).
IR (CDCl3): n = 2845 (carbonyl-H st), 2255 and 2145 (C∫C st),
1680 cm-1 (C=O st).
Anal. Calcd for C13H20O3Si (252.3): C 61.88; H 8.01. Found C
61.61; H 7.74.
[a]D25 = +36.7 (c = 2.07 in CHCl3).
1H NMR (300 MHz): d = 0.18 [s, Si(CH3)3], 1.39 and 1.44 [2 s, 2'-
(CH3)2], 2.06 (br s, exchangeable with D2O, OH), AB signal
(dA = 3.88, dB = 4.13, JAB = 8.2, in addition split by JA,4’= 7.9,
(4’R)-(Z)-3-[N-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidin-4-
yl]-5-(trimethylsilyl)pent-2-en-4-ynal (E-44c) in a 68:32 Mix-
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

600
O. Gebauer, R. Brückner
FEATURE ARTICLE
ture* with a Rotamer (iso-E-44c)
26.74 [C(CH3)3], "-" 64.99 (C-1'), "-" 81.12 (C-5), "+" 83.84 (C-6),
"-" 100.43 and "-" 103.57 (C-1, C-2), "+" 112.71 (C-4), "+" 127.80
(4 meta-C), "+" 129.84 (2 para-C), "-" 132.82 (2 ipso-C), "+"
135.41 (4 ortho-C), "-" 135.99 (C-3).
IR (CDCl3): n = 3305 (∫C-H st), 2255 and 2145 cm-1 (C∫C st).
HRMS (EI/70 eV): m/z = 401.1756 (M+ -Me): confirms the frag-
*determined 1H NMR spectroscopically by the integral ratio over
the 4´-H´s
At -78 °C DIBAL (1.05 M in toluene, 1.14 mL, 1.20 mmol, 1.3
equiv.) was added to a solution of ester E-42c (0.390 g, 0.921 mmol)
in toluene (2.7 mL) within 10 min. Stirring at -78 °C was continued
for 30 min. MeOH (300 ml), cooled to -78 °C, was added. The re-
sulting mixture was poured into sat. K,Na tartrate (6 mL). After 20
min, a similar workup followed as described for E-43a which was
terminated by a flash chromatography (1.5 cm, petroleum ether/t-
BuOMe 7:1, F18-28) leading to the title compound (0.261 g, 81%).
ment
formula C25H29OSi2 with a precision of
2 mDa;
m/z = 359.1287 (M+ -t-Bu): confirms the fragment formula
C22H23OSi2 with a precision of 2 mDa; the mole peak was not in-
tense enough for HRMS.
MS (DCI/pos., NH4 ): m/z = 434 (100%, M+ +NH4 ), 391 (8%), 363
(3%), 346 (5%), 302 (10%), 291 (12%), 274 (93%), 254 (5%), 216
(4%), 196 (12%). Because of its lability no correct combustion anal-
ysis could be obtained of compound E-45a.
+
+
[a]D23 = -76.8 (c = 2.85 in CHCl3).
E-44c
1H NMR (300 MHz; slightly contaminated in the aliphatic region):
d = 0.21 [s, Si(CH3)3], 1.37 (s, t-Bu), 1.54 and 1.64 [2 s, 2'-(CH3)2],
AB signal (dA = 3.97, dB = 4.09, JAB = 8.8, in addition split by
(E)-(4S)-2,2-Dimethyl-4-{1-[2-(trimethylsilyl)ethynyl]but-1-en-
3-ynyl}-1,3-dioxolane (E-45b)
JA,4’= 5.3, JB,4’= 6.8, 5'-H2), 4.43 (br dd, J4’,5’-H(B) = 6.4, J4’,5’-
Prepared as described for E-45a from BuLi (1.49 M in hexane; 255
ml, 0.380 mmol, 1.2 equiv.), i-Pr2NH (50.0 ml, 0.035 g, 0.380 mmol,
1.2 equiv.) in THF (2.5 mL), (trimethylsilyl)diazomethane (2.0 M
in hexane; 190 ml, 0.380 mmol, 1.2 equiv.) and aldehyde E-44b
(0.080 g, 0.317 mmol) in THF (650 ml) except that the latter reacted
at -78 °C for 1.5 h, during warming to r.t. for 1 h and at r.t. for an-
other 20 min. Flash chromatography (0.8 cm, petroleum ether/t-
BuOMe 30:1, F4-8) provided the title compound (0.031 g, 39%).
H(A) = 4.2, 4'-H), 6.22 (d, J2,1 = 8.2, 2-H), 10.09 (d, J1,2 = 7.9, 1-H).
13C NMR (APT spectrum at 75 MHz; contained unidentified peaks
at d = "-" 26.84 and d = "+" 26.91): d = "+" -0.58 [Si(CH3)3], "+"
23.92 and "+" 25.40 [2'-(CH3)2], "+" 28.21 [C(CH3)3], "+" 61.90 (C-
4'), "-" 67.53 (C-5'), "-" 80.61 [C(CH3)3], "-" 94.63 (C-2'), "-" 98.03
and "-" 109.51 (C-4, C-5), "+" 134.15 (C-2), "-" 145.88 (C-3), "-"
151.26 (N-CO2t-Bu), "-" 192.35 (C-1).
[a]D22 = +43.5 (c = 1.32 in CHCl3).
iso-E-44c
1H NMR (300 MHz; slightly contaminated in the aliphatic region):
d = 1.47 (s, t-Bu), 1.51 and 1.60 [2 s, 2'-(CH3)2], 4.57 (br dd, J4’,5’-
H(B) = 6.0, J4’,5’-H(A) = 2.3, 4'-H), ca. 10.07 (br d, J1,2 ª 8 Hz, 1-H); the
other resonances are superimposed by those of E-44c.
1H NMR (300 MHz; slightly contaminated in the alkyl region):
d = 0.22 [s, Si(CH3)3], 1.40 and 1.45 [2 s, 2-(CH3)2], 3.32 (d,
4J4’,2’= 2.3, 4'-H), AB signal (dA = 3.89, dB = 4.19, JAB = 8.3, in ad-
dition split by JA,4’= 6.8, JB,4’= 6.4, 5-H2), 4.56 (ddd, J4,5-H(A) = J4,5-
H(B) = 6.8, 4J4,2’= 1.1, 4-H), 6.04 (dd, 4J2’,4’= 2.5, 4J2’,4 = 1.4, 2'-H).
13C NMR (APT spectrum at 75 MHz): d = "+" -0.22 [Si(CH3)3],
"+" 25.88 and "+" 26.24 [2-(CH3)2], "-" 68.98 (C-5), "+" 77.09 (C-
4), "-" 80.54 (C-3'), "+" 84.62 (C-4'), "-" 99.98 and "-" 104.88 (C-
1", C-2"), "-" 110.46 (C-2), "+" 114.95 (C-2'), "-" 135.12 (C-1').
13C NMR (APT spectrum at 75 MHz; contained unidentified peaks
at d = "-" 26.84 and d = "+" 26.91): d = "+" 24.69 and "+" 26.39 [2'-
(CH3)2], "+" 28.29 [C(CH3)3], "-" 67.16 (C-5'), "-" 81.08 [C(CH3)3],
"-" 95.14 (C-2'), "-" 97.68 and "-" 109.03 (C-4, C-5), "+" 133.74 (C-
2), "-" 144.99 (C-3), "-" 151.99 (N-CO2t-Bu), "+" 192.49 (C-1); the
other resonances are superimposed by those of E-44c.
IR (CDCl3): n = 3305 (∫C-H st), 2255 and 2145 cm-1 (C∫C st).
IR (CDCl3): n = 2850 (carbonyl-H st), 2255 and 2145 (C∫C st),
HRMS (EI/70 eV): m/z = 248.1232 (M+); confirms the molecular
formula C14H20O2Si with a precision of 2 mDa. Because of its la-
bility no correct combustion analysis could be obtained of com-
pound E-45b.
1700 and 1680 cm-1 (C=O st).
Anal. Calcd for C18H29NO4Si (351.5): C 61.50; H 8.33. Found C
61.70; H 8.57.
(E)-3-[(tert-Butyldiphenylsiloxy)methyl]-1-(trimethylsilyl)hex-
3-ene-1,5-diyne (E-45a)
tert-Butyl 2,2-Dimethyl-4-{(E)-1-[2-(trimethylsilyl)ethynyl]but-
1-en-3-ynyl}-1,3-oxazolidine-3-carboxylate (E-45c) in a 62:38
Mixture* with a Rotamer (iso-E-45c)
At -78 °C BuLi (1.49 M in hexane; 154 ml, 0.230 mmol, 1.2 equiv.)
was added dropwise to a solution of i-Pr2NH (30.0 ml, 0.021 g, 0.230
mmol, 1.2 equiv.) in THF (1.5 mL). After stirring for 10 min (tri-
methylsilyl)diazomethane (2.0 M in hexane; 115 ml, 0.230 mmol,
1.2 equiv.) was added dropwise, too. After stirring for another 30
min a pre-cooled (-78 °C) solution of aldehyde E-44a (0.080 g,
0.190 mmol) in THF (420 ml) was added, again dropwise. After stir-
ring at -78 °C for another 1.5 h, the cooling bath was removed so
that r.t. was attained within 4 h. After stirring for another 20 min the
reaction was quenched by adding H2O (2 mL) and t-BuOMe (12
mL). Extraction with t-BuOMe (3 ¥ 12 mL), washing with brine (5
mL) and drying (Na2SO4) led to the title compound (0.039 g, 49%)
after flash chromatography (0.8 cm, petroleum ether/t-BuOMe
50:1, F7-9).
*determined 1H NMR spectroscopically by the integral ratios over
the 4-H´s
Prepared as described for E-45a from BuLi (2.35 M in hexane; 146
ml, 0.342 mmol, 1.2 equiv.), i-Pr2NH (45.0 mL, 0.031 g, 0.342
mmol, 1.2 equiv.) in THF (2.2 mL), (trimethylsilyl)diazomethane
(2.0 M in hexane; 171 mL, 0.342 mmol, 1.2 equiv.) and aldehyde E-
44c (0.101 g, 0.285 mmol) in THF (600 mL) except that the latter re-
acted at -78 °C for 3 h, during warming to r.t. for 30 min and at
r.t. for another 20 min. Flash chromatography (1.5 cm, petroleum
ether/t-BuOMe 20:1, F28-38) gave the title compound (0.041 g,
41%).
[a]D25 = -116 (c = 1.70 in CHCl3).
1H NMR (300 MHz): d = 0.19 [s, Si(CH3)3], 1.08 (s, t-Bu), 3.33 (d,
E-45c
4
4J6,4 = 2.2, 6-H), 4.25 (incompletely resolved dd, J1’,4 = 1.9,
1H NMR (300 MHz; contaminated in the alkyl region): d = 0.20 [s,
Si(CH3)3], 1.42 (t-Bu), 1.48 oder 1.54 and 1.64 [2 s, 2-(CH3)2], 3.30
(br d, 4J4’,2’= 1.9, 4'-H), AB signal (dA = 3.93, dB = 4.07, JAB = 9.0, in
6J1’,6 = 0.8, 1’-H2), 6.24 (dt, 4J4,1’ = 4J4,6 = 2.3, 4-H), 7.37-7.45 (m, 4
meta- and 2 para-HAr), 7.66 (mc, 4 ortho-HAr).
13C NMR (APT spectrum at 50 MHz, contains unidentified peak at
addition split by JA,4 = 5.1, JB,4 = 6.8, 5-H2), 4.31 (br dd, J4,5-H(A)
J4,5-H(B) ª 5.7, 4-H), 5.76 (br s, 2'-H).
ª
d = "-" 135.53): d = „+“ -0.16 [Si(CH3)3], "-" 19.29 [C(CH3)3], "+"
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Chromophores of Neocarzinostatin, C-1027, Kedarcidin, Maduropeptin, and N1999A2
601
13C NMR (APT spectrum at 75 MHz; contaminated in the alkyl re-
gion): d = "+" -0.27 [Si(CH3)3], "+" 24.27 and "+" 25.37 [2-
(CH3)2], "+" 28.27 [C(CH3)3], "+" 61.45 (C-4), "-" 67.67 (C-5), "-"
80.27 and "-" 80.59 [C-3’, C(CH3)3], "+" 84.17 (C-4’), "-" 94.81 (C-
2), "-" 100.35 and "-" 104.85 (C-1", C-2"), "+" 115.04 (C-2’), "-"
136.69 (C-1’), "-" 151.58 (N-CO2t-Bu).
Revised structure: Kawata, S.; Ashizawa, S.; Hirama, M. J.
Am. Chem. Soc. 1997, 119, 12012.
(6) Yoshida, K.-i.; Minami, Y.; Azuma, R.; Saeki, M.; Otani, T.
Tetrahedron Lett. 1993, 34, 2637.
(7) Schroeder, D. R.; Colson, K. L.; Klohr, S. E.; Zein, N.;
Langley, D. R.; Lee, M. S.; Matson, J. A.; Doyle, T. W. J. Am.
Chem. Soc. 1994, 116, 9351.
(8) Koide, Y.; Ishi, F.; Hasuda, K.; Koyama, Y.; Edo, K.;
Katamine, S.; Kitame, F.; Ishida, N. J. Antibiot. 1980, 33, 342
Edo, K.; Katamine, S.; Kitame, F.; Ishida, N.; Koide, Y.;
Kusano, G.; Nozoe, S. J. Antibiot. 1980, 33, 347 (partially
revised in Shibuya, M.; Toyooka, K.; Kubota, S. Tetrahedron
Lett. 1984, 25, 1171).
iso-E-45c
1H NMR (300 MHz; contaminated in the alkyl region): d = 4.46 (br
s, 4-H), 5.81 (br s, 2’-H); the other resonances are superimposed by
those of E-45c.
13C NMR (APT spectrum at 75 MHz; contaminated in the alkyl re-
gion): d = "+" 24.94 and "+" 26.49 [2-(CH3)2], "+" 28.29 [C(CH3)3],
"+" 61.29 (C-4), "-" 67.37 (C-5), "-" 80.76 and "-" 80.78 [C-3’,
C(CH3)3], "-" 94.33 (C-2), "+" 135.91 (C-1’), "-" 151.94 (N-CO2t-
Bu); the other resonances are superimposed by those of E-45c IR
(CDCl3): n = 3305 (∫C-H st), 2255 and 2145 (C∫C st), 1695 cm-1
(C=O st).
HRMS (EI/70 eV): m/z = 347.1916 (M+); confirms the molecular
formula C19H29NO4Si with a precision of 2 mDa. Because of its
lability no correct combustion analysis could be obtained of com-
pound E-45c.
Edo, K.; Akiyama, Y.; Saito, K.; Mizugaki, M.; Koide, Y.;
Ishida, N. J. Antibiot. 1986, 39, 1615.
Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc.
1988, 110, 7212.
(9) Ando, T.; Ishii, M.; Kajiura, T.; Kameyama, T.; Miwa, K.;
Suguira, Y. Tetrahedron Lett. 1998, 39, 6495.
(10) Myers, A. G.; Alauddin, M. M.; Fuhry, M. M.; Dragovich, P.
S.; Finney, N. S.; Harrington, P. M. Tetrahedron Lett. 1989,
30, 6997.
(11) Myers, A. G.; Hammond, M.; Wu, Y.; Xiang, J. N.;
Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1996, 118,
10006-
Myers, A. G.; Liang, J.; Hammond, M.; Harrington, P. M.;
Wu, Y.; Kuo, E. Y. J. Am. Chem. Soc. 1998, 120, 5319.
(12) Dai, W.-M.; Fong, K. C. Tetrahedron Lett. 1996, 37, 8413.
(13) Method: Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.;
Rüther, G. J. Am. Chem. Soc. 1997, 119, 698.
Trost, B. M.; McIntosh, M. C. Tetrahedron Lett. 1997, 38,
3207.
Acknowledgement
We are indebted to Brigitte Worbs for skilled technical support and
grateful to Schering AG (Berlin) and Metallgesellschaft GmbH
(Langelsheim) for supporting the present study with chemicals and
appreciate the advice on C1 elongations -CH=O Æ -C∫C-H with
lithiated (trimethylsilyl)diazomethane by Prof. Shioiri (Nagoya
City University, Japan).
(14) Trost, B. M.; Hachiya, I.; McIntosh, M. C. Tetrahedron Lett.
1998, 39, 6445.
(15) Synthesis applications of enol triflates were reviewed by
Ritter, K. Synthesis 1993, 735.
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Article Identifier:
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1437-210X,E;2000,0,04,0588,0602,ftx,en;H09999SS.pdf
Synthesis 2000, No. 4, 588–602 ISSN 0039-7881 © Thieme Stuttgart · New York