Synthesis of cystothiazole E and formal syntheses of cystothiazoles A and C by Pd0-catalyzed cross-coupling reactions

Article abstract of DOI:10.1002/1521-3765(20021216)8:24<5585::AID-CHEM5585>3.0.CO;2-1

The synthesis of the naturally occurring bithiazole (+)-cystothiazole E (1e) is described starting from oxazolidinone 2. It proceeded in 10 steps and an overall yield of 37%. The key reaction of the sequence was a Suzuki cross-coupling between bromobithia

Full text of DOI:10.1002/1521-3765(20021216)8:24<5585::AID-CHEM5585>3.0.CO;2-1

FULL PAPER
Synthesis of Cystothiazole E and Formal Syntheses of Cystothiazoles A and C
by Pd0-Catalyzed Cross-Coupling Reactions
[a]
Thorsten Bach*and Stefan Heuser
Abstract: The synthesis of the naturally
occurring bithiazole (‡)-cystothiazole E
(1e) is described starting from oxazol-
idinone 2. It proceeded in 10 steps and
an overall yield of 37%. The key reac-
tion of the sequence was a Suzuki cross-
coupling between bromobithiazole 4
and the (E)-alkenylboronic acid derived
from alkyne 18 (94% yield). Prior to the
synthesis, more general investigations
related to the cross-coupling of bromo-
bithiazole 4 were undertaken. Whereas
Heck reactions failed Suzuki and Stille
cross-coupling reactions were success-
fully conducted. By this means, the
alkenylboronic acid derived from alkyne
11 and stannane 12 could be trans-
formed into the corresponding alkenyl-
bithiazoles 13 (92%) and 14 (52%). The
Stille cross-coupling of compound 4 and
stannane 5 allowed access to aldehyde
21 (97% yield) and paved the way for an
alternative route to (‡)-cystothiazole E
(1e). In addition, aldehyde 21 was trans-
formed into aldol product 22 (72%)
which has been used in previous syn-
theses of cystothiazole A (1a) and C
(1c). In this respect, the preparation of
compound 21 represents a formal total
synthesis of these cystothiazoles.
Keywords:
aldol reaction
¥
asymmetric synthesis ¥ cross-coupling
¥ heterocycles ¥ total synthesis
OR1
Introduction
R
Cystothiazoles (1)
N
N
R2
In 1998 Sakagami et al. reported on the isolation and structure
elucidation of a series of structurally related bithiazoles from
the myxobacterium Cystobacter fuscus.[1] The compounds
were named cystothiazoles (1) and differ from each other in
the substitution at three positions around a central skeleton
(Figure 1). All cystothiazoles except cystothiazole E (1e)
contain at one terminus (R in Figure 1) a b-methoxyacrylate
moiety which is a frequently encountered motif in natural
products isolated from myxobacteria.[2] The constitution and
configuration of these cystothiazoles (1a d, f) was deduced
from spectroscopic analyses and comparison with known data.
As no comparable spectral data were available for the ketone
cystothiazole 1e its configuration remained unclear and only
its constitution had been established so far. All cystothiazoles
display antifungal activity and inhibit the growth of a
phytopathogenic fungus, Phytophthora capsici. The activity
decreases in the order 1a > 1 f > 1b > 1e  1c  1d with
compound 1a being 100 times more potent in the chosen assay
than the least active compound 1d.[1a]
S
S
A (1a)
B (1b)
C (1c)
D (1d)
E (1e)
F (1f)
R
OMe
OMe
OMe
OMe
OMe
O
CO2Me
Me
CO2Me
Me
CO2Me
H
CO2Me
H
CO2Me
Me
R1
R2
Me
OH
OH
Figure 1. The structure of naturally occurring cystothiazoles (1) found in
the myxobacterium Cystobacter fuscus.[1]
ourselves.[6] In a preliminary communication we reported on
the first synthesis of a cystothiazole, cystothiazole E (1e).[6]
We were able to elucidate its relative and absolute config-
uration based on NMR data and on the optical rotation. The
syntheses of cystothiazoles A and C were reported shortly
thereafter.[3, 4] Strategically, our retrosynthetic considerations
were based on a disconnection directly at the 4-position of a
2'-alkyl-4-bromo-2,4'-bithiazole which was in turn obtained
from 2,4-dibromothiazole by regioselective cross-coupling
reactions. Contrary to that, the other reported syntheses[3, 4]
employed the Hantzsch reaction for the bithiazole formation
and established the crucial connection of the bithiazole by
Synthetic efforts towards cystothiazoles have been reported
by the groups of Williams,[3] Akita,[4] Panek,[5] and by
[a] Prof. Dr. T. Bach, Dipl.-Chem. S. Heuser
Lehrstuhl f¸r Organische Chemie I
Technische Universit‰t M¸nchen, Lichtenbergstrasse 4
85747 Garching (Germany)
Fax : (‡49)8928913315
E-mail: thorsten.bach@ch.tum.de
Chem. Eur. J. 2002, 8, No. 24
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5585

T. Bach and S. Heuser
FULL PAPER
carbonyl olefination at the a-carbon atom of a preformed
4-substituted bithiazole.
bond formation. In route I which has already been published
in preliminary form[6] we followed a convergent approach and
tried to establish bond b as late as possible in the synthesis. As
it turned out, the aldol reaction of the N-propionyl oxazoli-
dinone 2 and aldehyde 3 proceeded readily (bond c) but it was
not sensible from a practical point of view to establish bond d
prior to the cross-coupling (see below). Route II has been
developed more recently which aimed at a bond construction
in the order a-b-c-d. Although more linear than route I it was
appealing to us because it allowed for a formal access to other
cystothiazoles such as cystothiazoles A (1a) and C (1c).
Stannane 5[8] proved to be the key building block in this
strategy.
In this paper we provide a full account on our endeavour
directed towards the synthesis of cystothiazoles. Two path-
ways have been explored which differ in the order of events
and which are depicted for cystothiazole E as possible target
in Scheme 1. Both routes rely on the readily available 2'-
isopropyl-4-bromo-2,4'-bithiazole (4). Its synthesis has been
O
O
Br
O
N
N
O
N
MeMgCl
H
S
TBDMS
S
Ph
2
3
4
route I
Results and Discussion
O
OMe
b
c
d
4 N
S
a
Attempted cross-coupling reactions with substrate 4: Previous
work in our group had revealed that a Pd-catalyzed cross-
coupling with a 2-arylsubstituted 4-bromothiazole is not easy
to achieve.[9, 10] Suzuki reactions with arylboronic acids,
however, have been shown to work quite well.[11] In addition,
there was literature precedence for successful Stille and
Sonogashira cross-coupling reactions[12] conducted with 4-bro-
mothiazoles[13, 14] and with the activated 4,4'-dibromo-2,2'-
bithiazole.[15] Stannylations at 4-bromothiazoles with hexa-
methylditin had also been reported.[16] We were most in-
trigued by the fact that Heck reactions had been carried out
with 4-bromothiazole although the reported yields were low
(5 19%).[14a] In fact, a Heck reaction would have allowed for
a connection between a complete aldol fragment and
bithiazole 4. Preliminary experiments were conducted with
alkenes 6, 7, and 8 (Figure 2) but there was no indication for a
successful coupling to bithiazole 4. Conditions [Pd(OAc)2,
P(o-Tol)3, K2CO3 in N,N-dimethylacetamide (DMA)], which
in our hands facilitated a rapid and smooth Heck reaction of
acrylate 8 with bromobenzene, failed completely for the
4-bromobithiazole 4.
Cystothiazole E (1e)
N
5
2'
S
5'
route II
O
N
O
Br
O
N
N
O
MeMgCl
H
SnBu3
S
S
Ph
2
4
5
Scheme 1. Retrosynthetic strategy for the preparation of cystothiazole E
(1e) from precursors 2 5.
optimized[7] and it is available from 2,4-dibromothiazole in
70% overall yield. Crucial to the success of all pathways is the
cross-coupling at the 4-position of this substrate. The reac-
tivity at this position is low and careful experimentation was
À
necessary to find suitable conditions which allowed for a C C-
Abstract in German: Die Synthese des nat¸rlich vorkommen-
den Bithiazols (‡)-Cystothiazol E (1e) wird ausgehend von
Oxazolidinon 2 beschrieben. Sie verl‰uft in 10 Stufen und einer
Gesamtausbeute von 37%. Schl¸sselschritt der Sequenz ist eine
Suzuki-Kreuzkupplung zwischen Brombithiazol 4 und der
von Alkin 18 abgeleiteten (E)-Alkenylborons‰ure (94% Aus-
beute). Im Vorfeld der Synthese wurden Untersuchungen zur
Kreuzkupplung von Brombithiazol 4 durchgef¸hrt. W‰hrend
Heck-Reaktionen scheiterten, waren Suzuki- und Stille-Kreuz-
kupplungen erfolgreich. Auf diese Weise konnten die von
Alkin 11 abgeleitete Alkenylborons‰ure und das Stannan 12 in
die entsprechenden Alkenylbithiazole 13 (92%) und 14 (52%)
umgewandelt werden. Die Stille-Kreuzkupplung zwischen
Verbindung 4 und Stannan 5 erlaubte einen Zugang zu
Aldehyd 21 (97% Ausbeute) und erˆffnete damit einen
alternativen Syntheseweg zu (‡)-Cystothiazol E (1e). Aldehyd
21 wurde ¸berdies in das Aldolprodukt 22 umgewandelt
(72%), das in bekannten Synthesen der Cystothiazole A (1a)
und C (1c) als Intermediat verwendet worden war. Folglich
repr‰sentiert die Herstellung von 21 eine formale Totalsynthese
dieser Cystothiazole.
OEt
6
O
O
OMe
H
EtO
7
8
9
O
OMe
OTBDMS
OH
O
N
SnBu3
10
11
12
Figure 2. Potential reaction partners 6 12 for a Heck reaction or a cross-
coupling reaction with bithiazole 4.
We next tried to employ the Suzuki cross-coupling as an
alternative C C-bond forming reaction. Hydroboration of an
À
alkyne with catecholborane and subsequent hydrolysis[17] was
expected to deliver an E-alkenyl boronic acid which could be
attached to the bithiazole fragment by Pd0 catalysis. As the
hydroborating reagent also reduces carbonyl groups the
strategy required appropriate protection of ketones and
aldehydes. Initial attempts with propargyl methyl ether (9)
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Chem. Eur. J. 2002, 8, No. 24

Cystothiazoles
5585 5592
were hampered by its volatility. Cross-coupling products were
not observed and there were indications that the hydro-
boration reaction itself had not properly worked. This
suspicion was confirmed when we used the more sophisticated
alkyne 10 which was available from the corresponding aldol
product (see below). Under a wide variety of conditions a
hydroboration of this substrate with catecholborane could not
be achieved. In all instances unreacted starting material was
recovered almost completely. NMR spectra of crude product
gave no indication for a hydroboration. Luckily, we had also
employed the tert-butyldimethylsilyl (TBDMS) ether 11[18] in
parallel experiments. Its hydroboration proceeded smoothly.
The success of the hydroboration was proven by cross-
coupling of the corresponding alkenyl boronic acid to
bromobenzene. The reaction proceeded nicely following a
standard protocol[19] {[Pd(PPh3)4], K2CO3, PhH/H2O/EtOH
5:1:1, 908C} in 71% yield. 4-Bromobithiazole (4), however,
remained inert towards a cross-coupling with the same alkenyl
boronic acid under identical conditions. Since the counterion
of the hydroxide base used in Suzuki cross-coupling reactions
has been shown to strongly affect the velocity of the
reaction[20] we varied the base. Indeed, this variation led to a
reliable and high-yielding protocol for the Suzuki cross-
coupling of 4-bromobithiazoles which was also employed in
the synthesis of cystothiazole E. The key to the success was
the use of CsOH as the base. The reaction of compounds 11
and 4 to product 13 is depicted in Scheme 2.
bithiazole 4 we executed the synthesis of cystothiazole E as
outlined in Scheme 1 (route I). Since we had determined the
absolute configuration of the target in our preliminary work[6]
we chose the oxazolidinone 2[22] which is derived from (R)-
phenylalanine to finally obtain the naturally occurring (‡)-
cystothiazole E. The sequence of steps is depicted in
Scheme 3. Within usual limits the yields we achieved were
identical to the yields previously reported for the synthesis of
(À)-cystothiazole E (ent-1e). The previously reported syn-
thesis commenced with oxazolidinone ent-2 derived from (S)-
phenylalanine.
O
O
OR
R = H 15
R = Me 16
b)
a)
2
O
N
TBDMS
Ph
OH OMe
TBDMSO
OMe
c)
d), e)
TBDMS
OMe
17
18
TBDMSO
f)
g)
N
N
S
S
19
OH OMe
h), i), j)
1.
O
O
N
1e
N
S
BH, 70 °C; H2O
OTBDMS
S
4
2. 4, CsOH, [Pd(PPh3)4], 95 °C
N
N
4'
20
(PhH/H2O/EtOH 5/1/1)
2
2'
S
11
S
Scheme 3. Individual steps and yields in the synthesis of (‡)-cystothiazo-
le E (1e) according to route I: a) i) Bu2BOTf (1.1 equiv), EtNiPr2
(1.2 equiv) in CH2Cl2, 08C, 45 min; ii) aldehyde 3 (1.35 equiv) in CH2Cl2,
À78 ! À108C, 1 h, 86%; b) Me3O BF4 (2.1 equiv), 1,8-bis(N,N-dime-
thylamino)naphthalene (1.4 equiv) in CH2Cl2, RT, 2 d, 61%; c) LiAlH4
(1.1 equiv) in THF, 08C, 2 h, quant.; d) TBAF (1.2 equiv) on silica in THF,
RT, 1 h; e) TDBDMSCl (1.2 equiv), imidazole (2.5 equiv) in DMF/CH2Cl2,
RT, 1 d, quant. (two steps); f) i) catecholborane (1.5 equiv), neat, RT !
958C, 3h; ii) 4 (0.3equiv), [Pd(PPh 3)4] (0.015 equiv), CsOH (1.2 equiv) in
92%
13
‡
À
OH
4
4, [Pd(PPh3)2Cl2], 100 °C
N
N
4'
(dioxane)
2
S
2'
12
S
52%
14
H2O/EtOH/PhH, RT
!
958C, 16 h, 94% (relative to 4); g) PPTS
Scheme 2. The two most relevant cross-coupling reactions conducted in
model studies with bithiazole 4.
(0.5 equiv) in EtOH, 558C, 24 h, 82%; h) Dess Martin periodinane
(1.2 equiv) in CH2Cl2, RT, 2 h, quant.; i) MeMgCl (4 equiv) in THF, RT,
1 h, 91%; j) Dess Martin periodinane (1.3equiv) in CH 2Cl2, RT, 3 h,
quant.
A final set of experiments was directed towards a Stille
cross-coupling of bithiazole 4 with appropriate stannanes. Test
reactions conducted with alkenylstannane 12[21] and
[Pd(PPh3)4] in N,N-dimethyl acetamide (DMA) did not yield
the desired product. Modifications of the reaction conditions
were also successful in this instance and the clean formation of
alcohol 14 was observed with [PdCl2(PPh3)2] in dioxane at
1008C (Scheme 2, 52% yield). Even more remarkably, the
same conditions were applicable to the cross-coupling of
stannane 5. The implementation of the latter reaction step in
route II to cystothiazoles will be discussed in one of the
following sections.
Aldol reaction[23] of oxazolidinone 2 with aldehyde 3
provided access to the diastereomerically pure aldol product
15 (syn/anti >98:2; >95% de).[24] Methylation with the
Meerwein salt trimethyloxonium tetrafluoroborate in the
presence of the proton sponge 1,8-bis(N,N-dimethylamino)-
naphthalene[25] converted the secondary alcohol into its
methyl ether 16. Attempts to employ other methylating
agents (methyl iodide, dimethyl sulfate, methyl triflate) for
this conversion were unsuccessful. Methylation was achieved
with MeI and K2CO3 in refluxing acetone but partial
epimerization occurred. Reduction of the N-acyloxazolidi-
none with lithium aluminium hydride yielded the primary
alcohol 17 and the recoverable auxiliary. Subsequent protec-
Synthesis of (‡)-cystothiazole E according to route I: Based
on the cross-coupling of an alkenyl boronic acid with
Chem. Eur. J. 2002, 8, No. 24
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T. Bach and S. Heuser
FULL PAPER
tive group manipulations included the cleavage of the
TBDMS group from intermediate 16 (tetrabutylammonium
fluoride, TBAF) to liberate the free alkyne and the installa-
tion of a protective group at the hydroxy group. For the latter
purpose the TBDMS group was selected. Alkyne 18 under-
went a smooth hydroboration with catecholborane. After
hydrolysis the intermediate alkenyl boronic acid was not
isolated but directly subjected to the Suzuki cross-coupling
reaction with bithiazole 4. The reaction which was conducted
in full analogy to the transformation 11 ! 13 produced the
desired cystothiazole precursor 19 in excellent yield (94%).
As the fluoride promoted deprotection of the silyl ether in
compound 19 failed (e.g. TBAF in THF at RT, TBAF on silica
gel in THF at RT, or TBAF/HOAc in THF at RT) we
employed acidic conditions (pyridinium p-toluenesulfonate,
PPTS) to generate the primary alcohol 20. Oxidation under
Dess Martin conditions[26] yielded the corresponding alde-
hyde to which methyl magnesium chloride was added. The
resulting secondary alcohol was obtained as a mixture of
diastereoisomers (d.r. 3:1) which were not separated but
oxidized directly to the desired product, (‡)-cystothiazole E
(1e). Its identity with the natural product was proven by
comparison with reported NMR data. The optical rotation
O
a)
b)
N
4 + 5
N
S
S
21
O
O
OH
c), d)
O
N
N
N
S
Ph
S
22
O
OMe
O
e)
N
N
1e
N
S
S
23
Scheme 4. Individual steps and yields in the synthesis of (‡)-cystothiazo-
le E (1e) acording to route II: a) 4 (1 equiv), 5 (3equiv), NEt 3 (2 equiv),
[PdCl2(PPh3)2] (0.05 equiv) in dioxane, 1008C, 16 h, 97%; b) i) Bu2BOTf
(1.2 equiv), EtNiPr2 (1.5 equiv) in CH2Cl2, 08C, 45 min; ii) aldehyde 21
(0.75 equiv) in CH2Cl2, À788C ! À108C, 1 h, 86% (relative to 21);
c) i) AlMe3 (9 equiv), HNMe(OMe) ¥ HCl (9 equiv) in THF, 08C, 30 min;
ii) 22 (1 equiv) in THF, À158C ! RT, 1 h; d) Me3O BF4À (6.4 equiv), 1,8-
‡
bis(N,N-dimethylamino)naphthalene (6.4 equiv) in CH2Cl2, RT, 2 d, 17%.
(two steps); e) MeMgCl (6.5 equiv) in Et2O/THF, RT, 1 h, 95%.
was positive as expected for the (3R,4S)-stereoisomer {[a]D20
ˆ
‡17.6 (c ˆ 0.12, CHCl3)} and compared well with the optical
rotation determined for the natural product {[a]2D0 ˆ ‡17.8
(c ˆ 0.2, CHCl3)}.[1a] Overall, the synthesis of cystothiazole E
along route I proceeded in 10 steps and 37% yield starting
from the oxazolidinone 2.
converted into the desired product by nucleophilic attack with
magnesium methyl chloride.[28] Despite its linearity, route II
requires less steps than route I as it completely lacks any
protective group manipulations. In this respect, it is straight-
forward and includes only seven synthetic transformations
starting from the readily available 2,4-dibromothiazole. It is,
however, hampered by the low yields achieved in the
methylation step (30 35%).
Intermediate 22 has been elegantly converted to cysto-
thiazoles A and C in recent syntheses by Williams et al.
(Scheme 5).[3, 29] Cystothiazole A (1a) was obtained in 41%
yield and cystothiazole C (1c) in 29% yield starting from
aldol product 22.
Synthesis of cystothiazole E and formal syntheses of cysto-
thiazoles A and C according to route II: Whereas the order of
bond connection in route I was–according to Scheme 1–
(c/a)/b/d we considered in a second route the linear bond
connection in the order a/b/c/d which would enable facile
access to other cystothiazoles. Key intermediate was aldehyde
21 (Scheme 4) which can be directly employed for an aldol
reaction with chiral enolate equivalents and which has been
previously synthesized.[3] The synthesis of this aldehyde based
on cross-coupling methodology was possible from the corre-
sponding alcohol 14 by Swern oxidation (89% yield). Alcohol
14 was available either directly from bithiazole 4 by Stille
cross-coupling (Scheme 2) or from silyl ether 13 by depro-
tection (TBAF in THF, RT; 78% yield). In attempts to find a
shorter route to aldehyde 21 we discovered that the Stille
cross-coupling reaction of b-stannyl acrolein 5 and bithiazole
4 was a facile reaction which proceeded in 97% yield. By this
means, key intermediate 21 was accessible in three consec-
utive cross-coupling steps from 2,4-dibromothiazole in a total
yield of 68%.
8 steps[3]
7 steps[3]
1a
22
1c
41%
29%
Scheme 5. Syntheses of cystothiazole A (1a) and cystothiazole C (1c)
from intermediate 22 according to Williams et al.[3]
In view of these results, our synthesis of intermediate 22
represents a formal access to these cystothiazoles. The
calculated overall yield for cystothiazole A is 20% in eleven
steps and 14% for cystothiazole C in twelve steps starting
from 2,4-dibromothiazole.
The aldol reaction of aldehyde 21 with the O-(Z)-boron
enolate derived from N-propionyloxazolidinone (2) proceed-
ed smoothly and yielded the known syn-aldol product 22 (syn/
anti >98:2; >95% de).[3] Its conversion to cystothiazole E
was achieved in three steps which were not further optimized.
Following the standard protocol[27] the oxazolidinone was
substituted by N-methoxy-N-methylamine in the presence of
trimethylaluminium. After O-methylation of the secondary
alcohol the intermediate Weinreb amide 23 could be directly
Conclusion
In summary, the 4-bromobithiazole (4) was shown to be a
versatile building block for the syntheses of cystothiazoles A,
C, and E. The starting material is available from 2,4-
dibromothiazole in two consecutive cross-coupling reactions
(70% yield). The pivotal cross-coupling at the 4-position of
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Cystothiazoles
5585 5592
ˆ
(PhCH2CH), 63.7 (OCH2CHN), 66.2 (CHOH), 88.8 (C CSi), 104.4
4-bromobithiazole (4) was closely studied. The Suzuki cross-
coupling with alkenyl boronic acids and the Stille cross-
coupling with alkenyl stannanes proceeded well under
optimized conditions. Suzuki cross-coupling of bithiazole 4
with the boronic acid derived from aldol fragment 18 (94%
yield) allowed for a convergent synthesis of cystothiazole E
(route I). A linear but equally efficient pathway to the same
target was paved by the Stille cross-coupling of bithiazole 4
and alkenyl stannane 5 (97% yield). The aldehyde 21 thus
obtained is a versatile intermediate for the synthesis of
cystothiazoles. Based on the presented cross-coupling meth-
odology other biologically active bithiazoles should be equally
well accessible. Studies along these lines are currently under-
way in our laboratory.
ˆ
(C CSi), 127.4 (CHar), 128.9 (CHar), 129.4 (CHar), 134.9 (Car), 152.9
(OCONCO), 175.2 (OCONCO); IR (KBr): nÄ ˆ 3494 (brs; OH), 2931 (m;
CHal), 2860 (m; CHal), 1801 (s), 1670 (s; C O), 1385 (s), 1210 cmÀ1 (s); MS
ˆ
‡
(CI, isobutane): m/z (%): 401 (4) [M ]; elemental analysis calcd (%) for
C22H31NO4Si (401.58): C 65.80, H 7.78; found: C 65.85, H 7.69.
(3S)-Methoxy-(2S)-methylpentyncarboxylic acid-N-methoxy-N-methyl-
amide (10): A 2m solution of trimethylaluminium in hexane (2.25 mL,
4.50 mmol) was added at 08C to a slurry of N,O-dimethylhydroxylamine
hydrochloride (439 mg, 4.50 mmol) in THF (12 mL). After 30 min the
resulting solution was cooled to À158C and a solution of oxazolidinone ent-
15 (200 mg, 500 mmol) in THF (10 mL) was added. The temperature was
kept at À158C for 1 h and at 08C for 1 h. After additional stirring at room
temperature for 3h the reaction was quenched by the careful addition of
dichloromethane (19 mL) and a 0.5m aqueous HCl solution (12.5 mL). The
aqueous layer was extracted with dichloromethane (3 Â 30 mL). The
combined organic layers were washed with brine (20 mL), dried over
Na2SO4 and filtered. After removal of the solvent the crude residue was
purified by flash chromatography (P/EtOAc 70:30) to afford the Weinreb
amide (100 mg, 70%) as a white solid. Rf ˆ 0.34 (P/EtOAc 70:30); 1H NMR
(250 MHz): d ˆ 0.11 [s, 6H; Si(CH3)2], 0.94 [s, 9H; SiC(CH3)3], 1.36 (d, 3J ˆ
7.0 Hz, 3H; NCOCHCH3), 3.20 (s, 3H; NCH3), 3.74 (s, 3H; OCH3), 4.08
4.16 (m, 1H; NCOCHCH3), 4.72 (virt. t, 3J 3.1 Hz, 1H; CHOH); MS (EI,
Experimental Section
General: All reactions involving water-sensitive chemicals were carried out
in flame-dried glassware with magnetic stirring under Ar. Tetrahydrofuran
(THF) and diethyl ether (Et2O) were distilled from potassium immediately
prior to use. N,N-Diisopropylethylamine was distilled from calcium
hydride. [Pd(PPh3)4],[30] [PdCl2(PPh3)2],[31] and [Pd2(dba)3],[32] and dppf[33]
were prepared according to literature procedures. All other chemicals were
either commercially available or prepared according to the cited refer-
ences. TLC: Merck glass sheets (0.25 mm silica gel 60, F254), eluent given in
brackets. Detection by UV or coloration with ceric ammonium molybdate
(CAM). Optical rotation: Perkin Elmer 241 MC. Melting points (un-
corrected): Reichert hot bench. NMR: Bruker spectrometers ARX-200,
‡
‡
70 eV): m/z (%): 270 (3) [M À Me], 228 (100) [M À tBu].
A solution of the obtained Weinreb amide (100 mg, 350 mmol) in dichloro-
methane (3mL) was submitted to methylation by addition of proton
sponge (375 mg, 1.75 mmol) and trimethyloxonium tetrafluoroborate
(259 mg, 1.75 mmol). After stirring at room temperature for 2d the
resulting slurry was filtered and the solvent was removed in vacuo. The
residue was purified by flash chromatography (P/EtOAc 80:20) and the
desired methyl ether (51.8 mg, 51%) was obtained as a colorless oil. Rf ˆ
0.18 (P/EtOAc 80:20); [a]2D0 ˆ À78.6 (c ˆ 0.79 in CH2Cl2); 1H NMR
(250 MHz): d ˆ 0.06 [s, 6H; Si(CH3)2], 0.90 [s, 9H; SiC(CH3)3], 1.20 (d,
3J ˆ 6.7 Hz, 3H; NCOCHCH3), 3.16 (s, 3H; NCH3), 3.11 3.26 (m, 1H;
NCOCHCH3), 3.41 (s, 3H; CHOCH3), 3.70 (s, 3H; NOCH3), 4.08 (d, 3J ˆ
9.2 Hz, 1H; CHOCH3); 13C NMR (62.9 MHz): d ˆ -4.7 [Si(CH3)2], 14.1
(NCOCHCH3), 16.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 32.1 (NCH3), 41.4
(NCOCHCH3), 56.6 (CHOCH3), 61.5 (NOCH3), 72.9 (CHOCH3), 89.4
1
AC-250, AC-300 and AX-500. H and 13C NMR spectra were recorded in
CDCl3 at ambient temperature unless stated otherwise. Chemical shifts are
reported relative to tetramethylsilane as internal standard or distinguished
solvent signals. Apparent multiplets which occur as a result of the
accidental equality of coupling constants of magnetically nonequivalent
protons are marked as virtual (virt.). IR: Bruker IFS 200 or Perkin Elmer
1600 FT-IR. MS: Varian CH7 (EI) or Finnigan MAT 8200 (EI, CI). HRMS:
Finnigan MAT 8200 (EI). GC-MS: Agilent 6890 (GC system), Agilent 5973
(Mass selective detector, EI), Column: HP 5MS (30 m). Elemental
analysis: Microanalytical laboratory Beller (Gˆttingen). Flash chromatog-
raphy:[34] Merck silica gel 60 (230 400 mesh, ca. 50 g for 1 g of material to
be separated), eluent given in brackets. Eluents [Et2O, ethyl acetate
(EtOAc) and pentane (P)] were distilled prior to use.
(CCSi), 104.0 (CCSi), 174.3(N COCHCH3); IR (neat): nÄ ˆ 2933 (m; CHal),
À1
ˆ
ˆ
2171 (w; C C), 1666 (s; C O), 1463(m), 1102 cm (m); MS (EI, 70 eV):
‡
‡
‡
m/z (%): 284 (6) [M À Me], 268 (4) [M À OMe], 242 (100) [M À tBu];
elemental analysis calcd (%) for C15H29NO3Si (299.48): C 60.16, H 9.76;
found: C 60.30, H 9.89.
To cleave off the TBDMS group a solution of the obtained methyl ether
(24.0 mg, 80.1 mmol) in THF (2 mL) was treated with tetrabutylammonium
fluoride (TBAF) on silica (100 mg, ꢀ100 mmol). The slurry was stirred for
2 h at room temperature. After the solvent had been removed in vacuo, the
residue was purified by flash chromatography (P/EtOAc 70:30) and the
desired terminal alkyne 10 (14.8 mg) was obtained as a colorless oil. Rf ˆ
0.48 (P/EtOAc 80:20); [a]2D0 ˆ 46.3( c ˆ 0.52 in CH2Cl2); 1H NMR
(360 MHz): d ˆ 1.19 (d, 3J ˆ 7.1 Hz, 3H; NCOCHCH3), 2.42 (d, 4J ˆ
(4S)-Benzyl-3-[5-(tert-butyldimethylsilyl)-(3S)-hydroxy-(2S)-methyl-4-
pentynyl]-oxazolidin-2-one (ent-15):[24] A 1m solution of di-n-butylboron-
triflate in dichloromethane (14.0 mL, 14.0 mmol) and N,N-diisopropyl-
ethylamine (2.00 g, 15.5 mmol) were carefully added to a solution of the
oxazolidinone ent-2 (3.00 g, 12.9 mmol)[22] in dichloromethane (30 mL) so
that the temperature remained between 0 and 58C. After 45 min the
reaction mixture was cooled to À788C and a solution of aldehyde 3 (2.90 g.
17.5 mmol) in dichloromethane (10 mL) was added over a period of 1 h
through a syringe pump. After 1 h at À788C the mixture was stirred for one
additional hour at À108C before it was quenched by successive addition of
pH 7 phosphate buffer (15 mL), methanol (42 mL) and a 1:2 mixture of
ˆ
2.0 Hz, 1H; C CH), 3.16 (s, 3H; NCH3), 3.16 3.22 (m, 1H; NCOCHCH3),
3.39 (s, 3H; CHOCH3), 3.69 (s, 3H; NOCH3), 4.05 (dd, 3J ˆ 9.0 Hz, 4J ˆ
2.0 Hz, 1H; CHOCH3); 13C NMR (90 MHz): d ˆ 14.1 (NCOCHCH3), 31.9
(NCH3), 41.3(NCO CHCH3), 56.8 (CHOCH3), 61.5 (NOCH3), 72.5
ˆ
ˆ
(CHOCH3), 74.4 (C CH), 81.5 (C CH), 174.1 (NCOCH); IR (neat): nÄ ˆ
ˆ
ˆ
ˆ
3242 (s, C CH), 2939 (s, CHal), 2111 (w, C C), 1651 (s, C O), 1462 (m),
‡
1100 (m), 997 cmÀ1 (m); MS (EI, 70 eV): m/z (%): 170 (8) [M À Me], 125
30% H O2/MeOH (45 mL) keeping the temperature between 0 and 108C.
2
‡
‡
(46) [M À N(CH3)OCH3], 69 (100) [CH(OCH3)CCH ]; HRMS: m/z
After 1 h the mixture was concentrated in vacuo and the resultant slurry
was extracted with dichloromethane (3 Â 100 mL). The combined organic
layers were washed with brine (50 mL), dried over Na2SO4 and filtered.
After removal of the solvent the crude residue was purified by flash
chromatography (P/EtOAc 80:20) to afford ent-15 (4.42 g, 86%) as a white
solid. Rf ˆ 0.27 (P/EtOAc 80:20); m.p. 858C; [a]2D0 ˆ 65.8 (c ˆ 0.40 in
CH2Cl2); 1H NMR (250 MHz): d ˆ 0.11 [s, 6H; Si(CH3)2], 0.93[s, 9H;
‡
calcd for C8H12NO3 [M À Me]: 170.0817, found: 170.0818.
4-[3-(tert-Butyldimethylsiloxy)-propenyl]-2'-isopropyl-2,4'-bithiazole (13):
Catecholborane (989 mg, 8.25 mmol) was slowly added to 3-(tert-butyldi-
methylsiloxy)-1-propyne (11)[18] (935 mg, 5.50 mmol) and after 5 min the
temperature was raised to 708C for 1 h and then to 958C for additional 2 h.
After cooling to room temperature, water (8.25 mL) was added rapidly and
the resulting slurry was stirred for 1 h. Ethanol (12 mL) was added to dilute
the white precipitate. The obtained solution of the boronic acid was
2
3
SiC(CH3)3], 1.43(d, 3J ˆ 7.1 Hz, 3H ; CH CH3), 2.81 (dd, J ˆ 13.3 Hz, J ˆ
9.3Hz, 1H; PhCH H), 3.24 (dd, 2J ˆ 13.3 Hz, 3J ˆ 3.3 Hz, 1H; PhCHH),
3.96 (dq, 3J ˆ 7.1 Hz, 3J ˆ 4.4 Hz, 1H; CHCH3), 4.19 4.23(m, 2H;
NCHCH2O), 4.68 4.73(m, 2H; NC HCH2O, CHOH), 7.19 7.36 (m, 5H;
CHar); 13C NMR (62.9 MHz): d ˆ À4.8 [Si(CH3)2], 12.3(NCOCH CH3),
16.4 [SiC(CH3)3], 26.0 [SiC(CH3)3], 37.7 (PhCH2), 44.0 (NCOCH), 55.1
quantitatively given to
a mixture of bromobithiazole 4 (612 mg,
2.12 mmol), [Pd(PPh3)4] (120 mg, 106 mmol) and a 50% (w/w) aqueous
CsOH solution (953mg, 6.36 mmol) in benzene (60 mL). The blue solution
was heated to 958C for 16 h. After cooling to room temperature, water
Chem. Eur. J. 2002, 8, No. 24
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0824-5589 $ 20.00+.50/0
5589

T. Bach and S. Heuser
FULL PAPER
(20 mL) was added and the aqueous layer was extracted with pentane (2 Â
50 mL) and dichloromethane (2 Â 50 mL). The combined organic layers
were washed with brine (50 mL), dried over Na2SO4 and filtered. After
removal of the solvent the crude residue was purified by flash chromatog-
raphy (P/EtOAc 98:2) to afford 13 (742 g, 92%) as a yellow oil. Rf ˆ 0.18
(P/EtOAc 97:3); 1H NMR (360 MHz): d ˆ 0.11 [s, 6H; Si(CH3)2], 0.94 [s,
9H; SiC(CH3)3], 1.43[d, 3J ˆ 6.9 Hz, 6H; CH(CH3)2], 3.36 [sept, 3J ˆ
6.9 Hz, 1H; CH(CH3)2], 4.38 (d, 3J ˆ 3.9 Hz, 2H; OCH2), 6.60 6.75 (m,
2H; OCH2CHCH), 7.04 (s, 1H; CHar), 7.86 (s, 1H; CH'ar); 13C NMR
(90 MHz): d ˆ À5.2 [Si(CH3)2], 18.5 [SiC(CH3)3], 23.1 [CH(CH3)2], 26.0
[SiC(CH3)3], 33.3 [CH(CH3)2], 63.3 (OCH2CHCH), 114.8 (CHar), 114.9
(CHar), 122.0 (OCH2CHCH), 132.4 (OCH2CHCH), 148.7 (4'-Car), 154.7
(4-Car), 162.7 (NCS-thiazole), 178.6 (NCS-iPr); IR (neat): nÄ ˆ 3102
(w; CHar), 2953(m; CH al), 1497 (m), 1255 (m), 1111 cmÀ1 (m); MS
5-(tert-Butyldimethylsilyl)-(3R)-methoxy-(2S)-methyl-4-pentyn-1-ol (17):
A solution of oxazolidinone 16 (2.67 g, 6.43mmol) in THF (40 mL) was
added at 08C to a slurry of lithium aluminium hydride (268 mg, 7.10 mmol)
in THF (100 mL) over a period of 1 h through syringe pump. After stirring
for 1 h at 08C, water (267 mL), 15% aqueous NaOH (800 mL), water
(800 mL) and some Na2SO4 were successively added. The mixture was
filtered, the solvent was removed in vacuo and the resulting residue was
purified by flash chromatography (P/EtOAc 70:30). 17 (1.56 g, quant.) was
obtained as a light red oil. Rf ˆ 0.33 (P/EtOAc 85:15); [a]2D0 ˆ À71.2 (c ˆ
1.10 in CH2Cl2); 1H NMR (360 MHz): d ˆ 0.11 [s, 6H; Si(CH3)2], 0.93[s,
9H; SiC(CH3)3], 0.95 (d, 3J ˆ 7.5 Hz, 3H; CHCH3), 2.06 2.14 (m, 1H;
CHCH3), 3.40 (s, 3H; CHOCH3), 3.55 (dd, 2J ˆ 10.9 Hz, 3J ˆ 3.8 Hz, 1H;
HOCHH), 3.80 (dd, 2J ˆ 10.9 Hz, 3J ˆ 7.5 Hz; HOCHH), 4.07 (d, 3J ˆ
4.0 Hz, 1H; CHOCH3); 13C NMR (90 MHz): d ˆ À4.6 [Si(CH3)2], 12.7
[CH(CH3)], 16.5 [SiC(CH3)3], 26.1 [SiC(CH3)3], 39.7 [CH(CH3)], 56.9
(CHOCH3), 65.6 (HOCH2), 76.1 (CHOCH3), 91.1 (CCSi), 102.8 (CCSi); IR
‡
‡
(EI, 70 eV): m/z (%): 380 (42) [M ], 323 (100) [M À tBu], 249 (63)
‡
[M À OTBDMS]; elemental analysis calcd (%) for C18H28N2OS2Si
ˆ
(380.65): C 56.80, H 7.41; found: C 56.72, H 7.36.
(neat): nÄ ˆ 3373 (b; OH), 2929 (s; CHal), 2857 (s; CHal), 2169 (m; C C),
1471 (s), 1250 (s), 1096 cmÀ1 (s); MS (CI, isobutane): m/z (%): 243(6)
4-(3-Hydroxypropenyl)-2'-isopropyl-2,4'-bithiazole (14) from silyl ether 13:
A 1m solution of tetrabutylammonium fluoride (TBAF) in THF (0.60 mL,
0.60 mmol) was added to a solution of silyl ether 13 (150 mg, 394 mmol) in
THF (5 mL) and the mixture was stirred for 3h at ambient temperature.
After the solvent had been removed in vacuo, the residue was purified by
flash chromatography (P/Et2O 30:70). The known compound 14[3] (82.0 mg,
78%) was obtained as a white solid. Rf ˆ 0.23(P/Et 2O 30:70); 1H NMR
‡
[M ‡H].
1-tert-Butyldimethylsiloxy-(3R)-methoxy-(2R)-methyl-4-pentyne (18): To
cleave off the TBDMS group a solution of alcohol 17 (1.00 g, 4.13mmol) in
THF (40 mL) was treated with tetrabutylammonium fluoride (TBAF) on
silica (5.00 g, ꢀ5.00 mmol). The slurry was stirred for 1 h at room
temperature. After the solvent had been removed in vacuo, the residue
was purified by flash chromatography (P/Et2O 50:50) and the desired
terminal alkyne (529 mg, quant.) was obtained as a colourless oil. Rf ˆ 0.52
(P/EtOAc 50:50). The resulting alcohol was diluted in DMF (35 mL).
Dichloromethane (15 mL), imidazole (703mg, 10.3mmol) and a 2.9 m
solution of tert-butyldimethylsilylchloride in toluene (1.71 mL, 4.96 mmol)
were added. After stirring for 1 d at room temperature, water (100 mL) was
added and the aqueous layer was extracted with dichloromethane (2 Â
150 mL) and pentane (2 Â 150 mL). The combined organic layers were
washed with brine (100 mL), dried over Na2SO4 and filtered. After removal
of the solvent the crude residue was purified by flash chromatography (P/
Et2O 98:2) to afford 18 (1.00 g, quant.) as a colorless oil. Rf ˆ 0.67 (P/Et2O
95:5); [a]2D0 ˆ 53.9 (c ˆ 0.54 in pentane); 1H NMR (250 MHz): d ˆ 0.02 [s,
3
(250 MHz): d ˆ 1.41 [d, J ˆ 6.9 Hz, 6H; CH(CH3)2], 2.08 (brs, 1H; OH),
3.34 [sept, 3J ˆ 6.9 Hz, 1H; CH(CH3)2], 4.33 (d, 3J ˆ 4.8 Hz, 2H; OCH2),
6.62 (d, 3J ˆ 15.6 Hz, 1H; OCH2CHCH), 6.75 (dt, 3J ˆ 4.8 Hz, 3J ˆ 15.6 Hz,
1H; OCH2CHCH), 7.05 (s, 1H; CHar), 7.85 (s, 1H; CH'ar); 13C NMR
(62.9 MHz): d ˆ 23.1 [CH(CH3)2], 33.3 [CH(CH3)2], 63.1 (OCH2CHCH),
115.0 (CHar), 115.4 (CHar), 123.4 (OCH2CHCH), 131.8 (OCH2CHCH),
148.5 (4'-Car), 154.2 (4-Car), 162.9 (NCS-thiazole), 178.7 (NCS-iPr); MS (EI,
‡
70 eV): m/z (%): 266 (15) [M ], 237 (100).
4-(3-Hydroxypropenyl)-2'-isopropyl-2,4'-bithiazole (14) by Stille coupling
between bithiazole 4 and stannane 12: Bromobithiazole (4; 42.1 mg,
145 mmol), tributylstannyl-2-propen-1-ol (12)[21] (157 mg, 453 mmol) and
[PdCl2(PPh3)2] (5.1 mg, 7.3 mmol) in dioxane (8 mL) were heated to 1008C
for 16 h. After the solvent had been removed in vacuo, the residue was
purified by flash chromatography (P/Et2O 30:70). 14 (20.0 mg, 52%) was
obtained as a white solid. The spectroscopical data were identical to those
obtained for the deprotection product of 13.
6H; Si(CH3)2], 0.87 [s, 9H; SiC(CH3)3], 0.97 (d, 3J ˆ 7.0 Hz, 3H; CHCH3),
4
ˆ
1.84 1.97 (m, 1H; CHCH3), 2.40 (d, J ˆ 2.1 Hz, 1H; C CH), 3.38 (s, 3H;
CHOCH3), 3.52 (dd, 2J ˆ 9.8 Hz, 1H; SiOCHH), 3.61 (dd, 2J ˆ 9.8 Hz, 3J ˆ
3
4
5.8 Hz, 1H; SiOCHH), 4.04 (dd, J ˆ 4.6 Hz, J ˆ 2.1 Hz, 1H; CHOCH3);
13C NMR (62.9 MHz): d ˆ À5.5 [Si(CH3)2], 11.6 [CH(CH3], 18.3
[SiC(CH3)3], 25.9 [SiC(CH3)3], 41.0 [CH(CH3], 57.0 (CHOCH3), 65.2
(4R)-Benzyl-3-[5-(tert-butyldimethylsilyl)-(3R)-hydroxy-(2R)-methyl-4-
pentynyl]-oxazolidin-2-one (15): Aldol product 15 was prepared as
described for its enantiomer starting from 2 (1.00 g, 4.30 mmol), di-n-
butylborontriflate (1m in CH2Cl2, 4.67 mL, 4.67 mmol), N,N-diisopropyl-
ethylamine (667 mg, 5.17 mmol) and aldehyde 3 (967 mg, 5.83mmol).
After purification by flash chromatography (P/EtOAc 80:20) product 15
(1.47 g, 86%) could be obtained as a white solid. Rf ˆ 0.27 (P/EtOAc
80:20); m.p. 858C; [a]2D0 ˆ À66.1 (c ˆ 0.53in CH 2Cl2). The spectroscopic
data were identical to those of ent-15.
ˆ
ˆ
(SiOCH2), 71.6 (C CH), 74.1 (CHOCH3), 82.2 (C CH); IR (neat): nÄ ˆ
2929 (m; CHal), 2858 (m; CHal), 1472 (m), 1258 cmÀ1 (s); MS (CI,
‡
isobutane): m/z (%): 243(100) [ M ‡H].
4-[5-(tert-Butyldimethylsiloxy)-(3S)-methoxy-(4R)-methylpent-1-enyl]-2'-
isopropyl-2,4'-bithiazole (19): Catecholborane (673mg, 5.60 mmol) was
slowly added to alkyne 18 (905 mg, 3.74 mmol) and after 5 min the
temperature was raised to 708C for 1 h and then to 958C for further 2 h.
After cooling to room temperature, water (7.5 mL) was added rapidly and
the resulting slurry was stirred for 1 h. Ethanol (12 mL) was added to dilute
the white precipitate. The obtained solution of the boronic acid was
(4R)-Benzyl-3-[5-(tert-butyldimethylsilyl)-(3R)-methoxy-(2R)-methyl-4-
pentynyl]-oxazolidin-2-on (16): Proton sponge (3.34 g, 15.6 mmol) and
trimethyloxonium tetrafluoroborate (3.50 g, 23.4 mmol) were added to a
solution of the alcohol 15 (4.50 g, 11.1 mmol) in dichloromethane (80 mL).
After stirring at room temperature for 2 d the resultant slurry was filtered
and the solvent was removed in vacuo. The residue was purified by flash
chromatography (P/EtOAc 90:10) and the desired methyl ether 16 (2.79 g,
61%) was obtained as a white solid. Rf ˆ 0.57 (P/EtOAc 80:20); m.p.
1358C; [a]2D0 ˆ À34.2 (c ˆ 0.61 in CH2Cl2); 1H NMR (250 MHz): d ˆ 0.10 [s,
6H; Si(CH3)2], 0.92 [s, 9H; SiC(CH3)3], 1.35 (d, 3J ˆ 6.4 Hz, 3H;
quantitatively given to
a mixture of bromobithiazole 4 (314 mg,
1.10 mmol), [Pd(PPh3)4] (87.0 mg, 55.0 mmol) and a 10% (w/w) aqueous
CsOH solution (7.50 mL, 4.50 mmol) in benzene (70 mL). This blue
solution was heated to 958C for 16 h. After cooling to room temperature,
water (40 mL) was added and the aqueous layer was extracted with pentane
(2 Â 100 mL) and dichloromethane (2 Â 100 mL). The combined organic
layers were washed with brine (100 mL), dried over Na2SO4 and filtered.
After removal of the solvent the crude residue was purified by flash
chromatography (P/Et2O 95:5) to afford 19 (448 g, 94%) as a yellow oil.
Rf ˆ 0.35 (P/EtOAc 90:10); [a]2D0 ˆ 8.9 (c ˆ 0.40 in pentane); 1H NMR
(250 MHz): d ˆ 0.02 [s, 6H; Si(CH3)2], 0.88 [s, 9H; SiC(CH3)3], 0.92 (d, 3J ˆ
6.2 Hz, 3H; SiOCH2CHCH3), 1.41 [d, 3J ˆ 6.9 Hz, 6H; CH(CH3)2], 1.77
1.87 (m, 1H; SiOCH2CHCH3), 3.31 (s, 3H; CHOCH3), 3.33 [sept, 3J ˆ
2
3
NCOCHCH3), 2.79 (dd, J ˆ 16.0 Hz, J ˆ 9.6 Hz, 1H; PhCHH), 3.28 (dd,
2J ˆ 16.0 Hz, 3J ˆ 3.1 Hz, 1H; PhCHH), 3.42 (s, 3H; CHOCH3), 4.14 4.25
(m, 4H; CH3CHCHOCH3, NCHCH2O), 4.64 4.69 (m, 1H; NCHCH2O),
7.19 7.29 (m, 5H; CHar); 13C NMR (62.9 MHz): d ˆ -4.3[Si(CH 3)2], 13.9
(NCOCHCH3), 16.9 [SiC(CH3)3], 26.4 [SiC(CH3)3], 38.2 (PhCH2), 43.3
(NCOCH), 55.8 (OCH2CHN), 56.8 (CHOCH3), 66.5 (OCH2CHN), 72.7
2
3
ˆ
ˆ
(CHOCH3), 87.5 (C CSi), 90.6 (C CSi), 127.7 (CHar), 129.3(CH ar), 129.8
6.9 Hz, 1H; CH(CH3)2], 3.48 (dd, J ˆ 9.7 Hz, J ˆ 5.7 Hz, 1H; SiOCHH),
2
3
3
(CHar), 135.6 (Car), 153.4 (OCONCO), 173.9 (OCONCO); IR (KBr): nÄ ˆ
3.60 (dd, J ˆ 9.7 Hz, J ˆ 6.7 Hz, 1H; SiOCHH), 3.85 (virt. t, J 5.0 Hz,
1H; CHOCH3), 6.45 6.61 (m, 2H; CH3OCHCHCH), 7.05 (s, 1H; CHar),
7.84 (s, 1H; CH'ar); 13C NMR (62.9 MHz): d ˆ À5.5 [Si(CH3)2], 11.6
(SiOCH2CHCH3), 18.2 [SiC(CH3)3], 23.1 [CH(CH3)2], 25.9 [SiC(CH3)3],
33.3 [CH(CH3)2], 41.0 (SiOCH2CH), 57.1 (CHOCH3), 64.8 (SiOCH2), 82.1
À1
ˆ
ˆ
2934 (m; CHal), 1769 (s; C O), 1684 (s; C O), 1384 (m), 1208 cm (m);
‡
‡
MS (EI, 70 eV): m/z (%): 415 (2) [M ], 400 (5) [M À Me], 358 (100)
‡
[M À tBu]; elemental analysis calcd (%) for C23H33NO4Si (415.60): C
66.47, H 8.00; found: C 66.41, H 7.95.
5590
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0824-5590 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 24

Cystothiazoles
5585 5592
‡
(CHOCH3), 114.9 (CH'ar), 115.0 (CHar), 124.8 (CH3OCHCHCH), 132.2
(CH3OCHCHCH), 148.7 (4'-Car), 154.4 (4-Car), 162.7 (NCS-thiazole), 178.6
(NCS-iPr); IR (neat): nÄ ˆ 3110 (w; CHar), 2928 (m; CHal), 2856 (m; CHal),
279 (84) [M À MeCH(OH)CH(Me)], 261 (100); HRMS: m/z calcd for
C17H24N2O2S2: 352.1279, found: 352.1282.
The mixture of alcohols (48.0 mg, 137 mmol) was dissolved in dichloro-
methane (5 mL) and the Dess Martin periodinane (76.3mg, 180 mmol)
was added. After being stirred at ambient temperature for 3h, the reaction
was quenched by the addition of diethyl ether (20 mL) and a saturated
aqueous solution of NaHCO3 containing 5% Na2S2O3 (6 mL). After further
15 min the aqueous phase was extracted with diethyl ether (2 Â 20 mL).
The combined organic phases were washed with brine (20 mL), dried over
Na2SO4 and filtered. After removal of the solvent the crude residue was
purified by flash chromatography (P/Et2O 70:30) to afford (‡)-cystothia-
zole E (1e) (48.0 mg, quant.) as a yellow oil. Rf ˆ 0.65 (P/Et2O 50:50);
[a]2D0 ˆ 17.6 (c ˆ 0.12 in CHCl3); 1H NMR (360 MHz): d ˆ 1.19 (d, 3J ˆ
À1
‡
1463(s), 1255 cm (s); MS (EI, 70 eV): m/z (%): 452 (12) [M ], 437 (8)
‡
‡
‡
[M À Me], 395 (50) [M À tBu], 305 (41), 289 (27), 279 (100) [M
À
TBDMSOCH2CH(Me)]; HRMS: m/z calcd for C22H36N2O2S2Si:
452.1988, found: 452.1982.
5-(2'-Isopropyl-2,4'-bithiazolyl-4-yl)-(3S)-methoxy-(2S)-methyl-4-penten-
1-ol (20): Silyl ether 19 (410 mg, 905 mmol) and pyridinium para-toluene-
sulfonate (PPTS) (116 mg, 450 mmol) in ethanol (20 mL) were heated to
558C for 24 h. After removal of the solvent the residue was purified by flash
chromatography (P/Et2O 50:50). 20 (250 mg, 82%) was obtained as a
colourless oil. Rf ˆ 0.28 (P/Et2O 30:70); [a]2D0 ˆ 41.9 (c ˆ 0.83in diethyl
ether); 1H NMR (250 MHz): d ˆ 0.93(d, 3J ˆ 7.0 Hz, 3H; HOCH2CHCH3),
3
7.0 Hz, 3H; CH3COCHCH3), 1.44 [d, J ˆ 7.0 Hz, 6H; CH(CH3)2], 2.20 (s,
3
3H; CH3CO), 2.79 (virt. quin, 3J 6.5 Hz, 1H; CH3COCH), 3.34 (s, 3H;
CHOCH3), 3.37 [sept, 3J ˆ 7.0 Hz, 1H; CH(CH3)2], 4.02 (virt. t, 3J 6.6 Hz,
1.42 [d, J ˆ 7.0 Hz, 6H; CH(CH3)2], 2.05 2.11 (m, 1H; HOCH2CHCH3),
3.33 (s, 3H; CHOCH3), 3.34 [sept, 3J ˆ 7.0 Hz, 1H; CH(CH3)2], 3.58 (dd,
2J ˆ 10.8 Hz, 3J ˆ 4.3Hz, 1H; HOCH H), 3.73 (dd, 2J ˆ 10.8 Hz, 3J ˆ 7.5 Hz,
1H; HOCHH), 3.90 (virt. t, 3J 4.9 Hz, 1H; CHOCH3), 6.50 6.65 (m, 2H;
CH3OCHCHCH), 7.10 (s, 1H; CHar), 7.89 (s, 1H; CH'ar); 13C NMR
(62.9 MHz): d ˆ 12.2 (HOCH2CHCH3), 23.1 [CH(CH3)2], 33.3
[CH(CH3)2], 39.8 (HOCH2CH), 57.0 (CHOCH3), 66.0 (HOCH2), 85.6
(CHOCH3), 115.3(CH 'ar), 115.7 (CHar), 126.1 (CH3OCHCHCH), 130.0
(CH3OCHCHCH), 148.4 (4'-Car), 153.8 (4-Car), 163.0 (NCS-thiazole), 178.7
(NCS-iPr); IR (neat): nÄ ˆ 3420 (brs; OH), 3122 (w; CHar), 2971 (s; CHal),
3
3
1H; CHOCH3), 6.46 (dd, J ˆ 7.2 Hz, J ˆ 15.8 Hz, 1H; CH3OCHCHCH),
3
6.61 (d, J ˆ 15.8 Hz, 1H; CH3OCHCHCH), 7.11 (s, 1H; Har), 7.87 (s, 1H;
H'ar); 13C NMR (90 MHz): d ˆ 11.8 (CH3COCHCH3), 23.0 [CH(CH3)2],
29.8 (CH3COCHCH3), 33.3 [CH(CH3)2], 51.9 (CH3COCHCH3), 56.9
(CHOCH3), 82.6 (CHOCH3), 115.0 (5'-CHar), 115.7 (5-CHar), 126.1
(CH3OCHCHCH), 130.1 (CH3OCHCHCH), 148.5 (4'-Car), 153.8 (4-Car),
162.8 (NCS-thiazole), 178.5 (NCS-iPr), 210.3(CH 3CO); IR (neat): nÄ ˆ 3103
(m; CHar), 2970 (s; CHal), 2932 (s; CHal), 1712 cmÀ1 (s; C O); MS (EI,
ˆ
‡
‡
‡
‡
70 eV): m/z (%): 350 (2) [M ], 335 (12) [M À Me], 279 (89) [M À Me-
COCHMe], 275 (100); elemental analysis calcd (%) for C17H23N2O2S2
(350.50): C 58.25, H 6.33; found: C 58.06, H 6.13.
1498 (m), 1081 cmÀ1 (s); MS (EI, 70 eV): m/z (%): 338 (10) [M ], 323 (13)
‡
‡
[M À Me], 279 (100) [M À HOCH2CHMe]; elemental analysis calcd (%)
for C16H22N2O2S2 (338.49): C 56.77, H 6.55; found: C 57.01, H 6.66.
3-(2'-Isopropyl-2,4'-bithiazolyl-4-yl)-propenal (21): Bromobithiazole
4
(‡)-Cystothiazole E (1e): Dess Martin periodinane[26] (93.1 mg,
220 mmol) was added to a solution of alcohol 20 (62.0 mg, 183 mmol) in
dichloromethane (2 mL). After being stirred at ambient temperature for
2 h, the reaction was quenched by the addition of diethyl ether (12 mL) and
a saturated aqueous solution of NaHCO3 containing 5% Na2S2O3 (4 mL).
After additional 15 min the aqueous phase was extracted with diethyl ether
(2 Â 20 mL). The combined organic phases were washed with brine
(10 mL), dried over Na2SO4 and filtered. After removal of the solvent
the crude residue was purified by flash chromatography (P/Et2O 60:40) to
afford the desired aldehyde (61.0 mg, quant.) as a yellow oil. Rf ˆ 0.39
(P/Et2O 50:50); 1H NMR (250 MHz): d ˆ 1.18 (d, 3J ˆ 7.0 Hz, 3H;
OHCCHCH3), 1.44 [d, 3J ˆ 6.9 Hz, 6H; CH(CH3)2], 2.62 2.67 (m, 1H;
OHCCHCH3), 3.35 [sept, 3J ˆ 6.9 Hz, 1H; CH(CH3)2], 3.36 (s, 3H;
CHOCH3), 4.19 (dd, 3J ˆ 4.3Hz, 3J ˆ 7.0 Hz, 1H; CHOCH3), 6.53(dd,
(217 mg, 751 mmol), tributylstannyl-2-propen-1-al (5)[8] (777 mg,
2.25 mmol) triethylamine (152 mg, 1.50 mmol) and [PdCl2(PPh3)2]
(26.4 mg, 37.6 mmol) in dioxane (40 mL) were heated at 1008C for 16 h.
After the solvent had been removed in vacuo, the residue was purified by
flash chromatography (P/Et2O 70:30). The known aldehyde 21[3] (192 mg,
97%) was obtained as a yellow solid. Rf ˆ 0.48 (P/EtOAc 75:25); 1H NMR
(250 MHz): d ˆ 1.42 [d, 3J ˆ 7.0 Hz, 6H; CH(CH3)2], 3.34 [sept, 3J ˆ 7.0 Hz,
1H; CH(CH3)2], 7.05 (dd, 3J ˆ 7.9 Hz, 3J ˆ 15.6 Hz, 1H; OHCCHCH), 7.42
3
(d, J ˆ 15.6 Hz, 1H; OHCCHCH), 7.55 (s, 1H; CHar), 7.88 (s, 1H; CH'ar),
9.71 (d, 3J ˆ 7.9 Hz, 1H; OHCCHCH); 13C NMR (62.9 MHz): d ˆ 23.1
[CH(CH3)2], 33.3 [CH(CH3)2], 116.0 (CH'ar), 123.4 (CHar), 130.5
(OHCCHCH), 143.6 (OHCCHCH), 147.9 (4'-Car), 152.2 (4-Car), 163.9
(NCS-thiazole), 178.9 (NCS-iPr), 193.6 (OHCCHCH); MS (EI, 70 eV): m/z
‡
‡
‡
(%): 264 (64) [M ], 236 (100) [M À CO], 221 (95) [M À iPr].
3
3
3J ˆ 7.0 Hz, J ˆ 15.6 Hz, 1H; CH3OCHCHCH), 6.67 (d, J ˆ 15.6 Hz, 1H;
CH3OCHCHCH), 7.14 (s, 1H; CHar), 7.88 (s, 1H; CH'ar), 9.82 (d, 3J ˆ
1.2 Hz, 1H; OHCCHCH3); 13C NMR (62.9 MHz): d ˆ 8.7 (OHCCHCH3),
23.1 [CH(CH3)2], 33.3 [CH(CH3)2], 51.1 (OHCCHCH3), 57.0 (CHOCH3),
81.5 (CHOCH3), 115.1 (CH'ar), 116.2 (CHar), 126.4 (CH3OCHCHCH),
129.4 (CH3OCHCHCH), 148.5 (4'-Car), 153.6 (4-Car), 163.0 (NCS-thiazole),
178.7 (NCS-iPr), 203.8 (OHCCHCH3); IR (neat): nÄ ˆ 3215 (m; CHar), 2969
(4R)-Benzyl-3-[(3S)-hydroxy-5-(2'-isopropyl-2,4'-bithiazolyl-4-yl)-(2R)-
methyl-4-pentenoyl]-oxazolidin-2-one (22): A 1m solution of di-n-butyl-
borontriflate in dichloromethane (370 mL, 370 mmol) and N,N-diisopropyl-
ethylamine (61.5 mg, 476 mmol) were carefully added to a solution of the
oxazolidinone 2 (74.0 mg, 318 mmol) in dichloromethane (4 mL) so that the
temperature was between 0 and 58C. After 45 min the reaction mixture was
cooled to À788C and a solution of aldehyde 21 (64.0 mg, 242 mmol) in
dichloromethane (2 mL) was added over a period of 1 h through syringe
pump. After 1 h the mixture was stirred for 2 h at 08C before it was
quenched by successive addition of pH 7 phosphate buffer (1 mL),
methanol (2 mL) and a 1:2 mixture of 30% H2O2/MeOH (2 mL) keeping
(m; CHal), 1727 (s; C O), 1617 (s), 1079 cmÀ1 (s); MS (EI, 70 eV): m/z (%):
336 (4) [M ], 321 (4) [M À Me], 279 (100) [M À OHCCHMe].
ˆ
‡
‡
‡
To a solution of the aldehyde (61.0 mg, 182 mmol) in THF (5 mL) a 3m
solution of methyl magnesium chloride in THF (242 mL, 726 mmol) was
added at room temperature. After stirring for 1 h, a saturated aqueous
solution of NH4Cl (5 mL) was added. The aqueous phase was extracted
with diethyl ether (3 Â 20 mL). The combined organic phases were washed
with brine (15 mL), dried over Na2SO4 and filtered. After removal of the
solvent the crude residue was purified by flash chromatography (P/Et2O
60:40) to afford the desired secondary alcohol (58.2 mg, 91%) as a yellow
oil. It was obtained as a 3:1 mixture of diastereoisomers. Rf ˆ 0.15 and 0.18
(P/Et2O 50:50); 13C NMR (62.9 MHz): major diastereoisomer: d ˆ 12.8
the temperature between
0 and 108C. After 1 h the mixture was
concentrated in vacuo and the resulting slurry was extracted with EtOAc
(3 Â 50 mL). The combined organic phases were washed with brine
(30 mL), dried over Na2SO4 and filtered. After removal of the solvent
the crude residue was purified by flash chromatography (P/EtOAc 60:40)
to afford the known aldol product 22[3] (87.0 mg, 72%) as a white foam.
Rf ˆ 0.33 (P/EtOAc 50:50); 13C NMR (90 MHz): d ˆ 11.2 (NCOCHCH3),
23.1 [CH(CH3)2], 33.2 [CH(CH3)2], 37.6 (PhCH2), 42.6 (NCOCHCH3), 55.1
(PhCH2CH), 66.1 (PhCH2CHCH2), 71.9 (CHOH), 115.2 (CHar), 115.9
(CHar), 123.9 (HOCHCHCH), 127.3(CH Ph), 128.9 (CHPh), 129.4 (CHPh),
131.7 (HOCHCHCH), 134.9 (CPh), 148.3(4 '-Car), 153.0 (OCONCO), 153.9
(4-Car), 162.8 (NCS-thiazole), 176.6 (OCONCO), 178.7 (NCS-iPr).
(HOCHCHCH3),
20.9
(CH3CHOH),
23.1
[CH(CH3)2],
43.7
(HOCHCHCH3), 56.8 (OCH3), 70.8 (HOCH), 86.9 (CHOCH3), 115.0
(CH'ar), 115.7 (CH'ar), 125.2 (CH3OCHCHCH), 131.1 (CH3OCHCHCH),
148.4 (4'-Car), 153.9 (4-Car), 162.9 (NCS-thiazole), 178.6 (NCS-iPr); minor
diastereoisomer: d ˆ 15.2 (HOCHCHCH3), 21.5 (CH3CHOH), 23.1
[CH(CH3)2], 44.1 (HOCHCHCH3), 56.9 (OCH3), 69.8 (HOCH), 85.5
(CHOCH3), 115.0 (CH'ar), 115.6 (CH'ar), 126.3(CH 3OCHCHCH), 129.4
(CH3OCHCHCH), 148.4 (4'-Car), 153.8 (4-Car), 162.8 (NCS-thiazole), 178.6
(NCS-iPr); IR (KBr): nÄ ˆ 3440 (brs; OH), 3124 (m; CHar), 2970 (s; CHal),
5-(2'-Isopropyl-2,4'-bithiazolyl-4-yl)-(3S)-methoxy-(2R)-methylpent-4-en-
carboxylic acid-N-methoxy-N-methylamide (23): A 2m solution of trime-
thylaluminium in hexane (0.79 mL, 1.58 mmol) was added at 08C to a slurry
of N,O-dimethylhydroxylamine hydrochloride (154 mg, 1.58 mmol) in THF
(5 mL). After 30 min the resulting solution was cooled to À158C and a
solution of aldol product 22 (87.0 mg, 175 mmol) in THF (5 mL) was added.
‡
‡
1498 cmÀ1 (s); MS (EI, 70 eV): m/z (%): 352 (8) [M ], 337 (6) [M À Me],
Chem. Eur. J. 2002, 8, No. 24
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0824-5591 $ 20.00+.50/0
5591

T. Bach and S. Heuser
FULL PAPER
The temperature was kept at À158C, 08C and ambient temperature for 1 h.
The reaction was stopped by the careful addition of a 0.5m aqueous HCl
solution (4 mL) at 08C. The aqueous phase was extracted with dichloro-
methane (2 Â 15 mL). The combined organic phases were washed with
brine (10 mL), dried over Na2SO4 and filtered. After removal of the solvent
the crude residue was purified by flash chromatography (P/EtOAc 40:60)
to afford a mixture (85.0 mg) of the Weinreb amide and the Evans auxiliary
as a yellow oil which still contained some EtOAc. Rf ˆ 0.18 (P/EtOAc
50:50); 1H NMR (360 MHz): d ˆ 1.22 (d, 3J ˆ 7.3Hz, 3H; NCOCHC H3),
1.44 [d, 3J ˆ 6.9 Hz, 6H; CH(CH3)2], 2.87 (m, 1H; NCOCHCH3), 3.22 (s,
Antibiot. 1979, 32, 1112 1117; c) W. Trowitzsch-Kienast, V. Wray, K.
Gerth, H. Reichenbach, G. Hˆfle, Liebigs Ann. Chem. 1986, 93 98;
d) H. Sauter, T. Anke, W. Steglich, Angew. Chem. 1999, 111, 1416
1438; Angew. Chem. Int. Ed. 1999, 38, 1328 1349.
[3] D. R. Williams, S. Patnaik, M. P. Clark, J. Org. Chem. 2001, 66, 8463
8469.
[4] K. Kato, A. Nishimura, Y. Yamamoto, H. Akita, Tetrahedron Lett.
2002, 43, 643 645.
[5] M. Sui, J. S. Panek, Org. Lett. 2001, 3, 2439 2442.
[6] T. Bach, S. Heuser, Angew. Chem. 2001, 113, 3283 3284; Angew.
Chem. Int. Ed. 2001, 40, 3184 3185.
[7] T. Bach, S. Heuser, J. Org. Chem. 2002, 67, 5789 5795.
[8] H. Oda, T. Kobayashi, M. Kosugi, T. Migita, Tetrahedron 1995, 51,
695 702.
3
3H; NCH3), 3.38 [sept, J ˆ 6.9 Hz, 1H; CH(CH3)2], 3.73 (s, 3H; OCH3),
4.12 (m, 1H; CHOH), 6.62 (dd, 3J ˆ 4.6 Hz, 3J ˆ 15.4 Hz, 1H;
HOCHCHCH), 6.76 (d, 3J ˆ 15.4 Hz, 1H; HOCHCHCH), 7.09 (s, 1H;
CHar), 7.87 (s, 1H; CH'ar); 13C NMR (90 MHz): d ˆ 10.4 (NCOCHCH3),
23.0 [CH(CH3)2], 31.7 (CH3NCO), 33.2 [CH(CH3)2], 38.9 (NCOCHCH3),
61.6 (H3CONCH3), 71.3(CHOH), 114.9 (CH ar), 115.6 (CHar), 123.3
(HOCHCHCH), 131.9 (HOCHCHCH), 148.4 (4'-Car), 154.1 (4-Car), 162.6
(NCS-thiazole), 177.6 (H3CNCO), 178.6 (NCS-iPr).
[9] S. Heuser, Diplomarbeit, Universit‰t Marburg (Germany), 1999.
[10] For a successful Negishi cross-coupling, see: S.-T. Huang, D. M.
Gordon, Tetrahedron Lett. 1998, 39, 9335 9338.
[11] T. Bach, S. Heuser, Tetrahedron Lett. 2000, 41, 1707 1710.
[12] For references on cross-coupling reactions of heterocycles, see: a) J. J.
Li, G. Gribble, Palladium in Heterocyclic Chemistry, Pergamon Press,
Oxford, 2000; b) L. Brandsma, S. F. Vasilevsky, H. D. Verkruijsse,
Application of Transition Metal Catalysts in Organic Synthesis,
Springer, Berlin, 1999; c) F. Diederich, P. J. Stang, Metal-Catalyzed
Cross-coupling Reactions, Wiley-VCH, Weinheim, 1998.
[13] A. Dondoni, M. Foganolo, A. Medici, E. Negrini, Synthesis 1987, 185
186.
[14] a) T. Sakamoto, H. Nagata, Y. Kondo, M. Shiraiwa, H. Yamanaka,
Chem. Pharm. Bull. 1987, 35, 823 828; b) T. X. Neenan, G. M.
Whitesides, J. Org. Chem. 1988, 53, 2489 2496; c) A. Arcadi, O. A.
Attanasi, B. Guidi, E. Rossi, S. Santeusanio, Chem. Lett. 1999, 59 60.
[15] T. Nussbaumer, R. Neidlein, Heterocycles 2000, 52, 349 364.
[16] a) T. R. Kelly, C. T. Jagoe, Z. Gu, Tetrahedron Lett. 1991, 32, 4263
4266; b) K. C. Nicolaou, Y. He, F. Roschangar, N. P. King, D.
Vourloumis, T. Li, Angew. Chem. 1998, 110, 89 92; Angew. Chem.
Int. Ed. 1998, 37, 84 87; c) K. C. Nicolaou, N. P. King, R. V. Finlay, Y.
He, F. Roschangar, D. Vourloumis, H. Vahlberg, F. Sarabia, S.
Ninkovic, D. Hepworth, Bioorg. Med. Chem. 1999, 7, 665 697.
[17] H. C. Brown, S. K. Gupta, J. Am. Chem. Soc. 1975, 97, 5249 5255.
[18] B. C. Bishop, I. F. Cottrell, D. Hands, Synthesis 1997, 1315 1320.
[19] a) A. Suzuki, J. Organomet. Chem. 1999, 576, 147 168; b) N. Miyaura,
A. Suzuki, Chem. Rev. 1995, 95, 2457 2483.
Proton sponge (240 mg, 1.12 mmol) and trimethyloxonium tetrafluorobo-
rate (166 mg, 1.12 mmol) were added to a solution of the above mixture
(85 mg) in dichloromethane (5 mL). After stirring at room temperature for
2 d the resulting slurry was filtered and the solvent was removed in vacuo.
The residue was purified by flash chromatography (P/EtOAc 50:50) and
the desired methyl ether 23 (12.0 mg, 17%) was obtained as a yellow oil.
Rf ˆ 0.37 (P/EtOAc 50:50); [a]D20 ˆ 20.0 (c ˆ 0.13in diethyl ether); 1H NMR
(250 MHz): d ˆ 1.23(d, 3J ˆ 7.3Hz, 3H; NCOCHC H3), 1.42 [d, 3J ˆ 6.9 Hz,
6H; CH(CH3)2], 3.11 (s, 3H; NCH3), 3.16 (m, 1H; NCOCHCH3), 3.31 (s,
3H; CHOCH3), 3.34 [sept, 3J ˆ 6.9 Hz, 1H; CH(CH3)2], 3.64 (s, 3H;
3
3
CH3NOCH3), 3.86 (m, 1H; CHOCH3), 6.48 (dd, J ˆ 4.6 Hz, J ˆ 15.4 Hz,
1H; CH3OCHCHCH), 6.72 (d, 3J ˆ 15.4 Hz, 1H; CH3OCHCHCH), 7.09 (s,
1H; CHar), 7.84 (s, 1H; CH'ar); 13C NMR (62.9 MHz): d ˆ 14.2
(NCOCHCH3), 23.1 [CH(CH3)2], 32.3 (H3CONCH3), 33.3 [CH(CH3)2],
41.1 (NCOCHCH3), 57.1 (CHOCH3), 61.5 (H3CONCH3), 83.7 (CHOCH3),
115.0 (CHar), 115.6 (CHar), 126.0 (CH3OCHCHCH), 131.2
(CH3OCHCHCH), 148.6 (4'-Car), 154.1 (4-Car), 162.6 (NCS-thiazole),
177.6 (H3CNCO), 178.6 (NCS-iPr); IR (neat): nÄ ˆ 3102 (m; CHar), 2969 (m;
À1
ˆ
CHal), 1654 (s; C O), 1458 (m), 1181 (m), 1094 cm (s); MS (EI, 70 eV):
‡
‡
‡
m/z (%): 395 (24) [M ], 380 (16) [M À Me], 279 (100) [M À MeON-
(Me)COCHMe); HRMS: m/z calcd for C18H25N3O3S2: 395.1337, found:
395.1339.
Cystothiazole E (1e): A 3m solution of methyl magnesium chloride in THF
(50.0 mL, 150 mmol) was added to a solution of the Weinreb amide 23
(9.0 mg, 23.0 mmol) in diethyl ether (2 mL) at 08C. After stirring at 08C for
1 h, a saturated aqueous solution of NH4Cl (2 mL) was added and the
aqueous layer was extracted with diethyl ether (3 Â 20 mL). The combined
organic layers were washed with brine (10 mL), dried over Na2SO4 and
filtered. The solvent was removed in vacuo to yield pure (‡)-cystothiazo-
le E (1e) (8.0 mg, 95%) as a yellow oil. The spectroscopical data were
identical with those determined for the product obtained according to
route I and with those reported for the natural product.
[20] a) J. I. Uenishi, J. M. Bean, R. W. Armstrong, Y. Kishi, J. Am. Chem.
Soc. 1987, 109, 4756 4758; b) T. Watanabe, N. Miyaura, A. Suzuki,
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[21] M. Lai, D. Li, E. Oh, H. Liu, J. Am. Chem. Soc. 1993, 115, 1619 1628.
[22] J. R. Gage, D. A. Evans, Org. Synth. 1990, 68, 77 91.
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51, 1 200.
[24] K. E. Drouet, E. A. Theodorakis, J. Am. Chem. Soc. 1999, 121, 456
457.
[25] a) H. Meerwein, F. Werner, H. Schˆn, G. Stopp, Liebigs Ann. 1961,
641, 1 23; b) D. A. Evans, A. M. Ratz, B. E. Huff, G. S. Sheppard, J.
Am. Chem. Soc. 1995, 117, 3448 3467.
[26] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4156 4158.
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[28] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815 3818.
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Martin, J. M. Claugh, G. Pattenden, I. R. Waldron, Tetrahedron Lett.
1993, 34, 5151 5154; b) D. Backhaus, Tetrahedron Lett. 2000, 41,
2087 2090.
Acknowledgements
This project was supported by the Deutsche Forschungsgemeinschaft
(Ba 1372/5-2) and by the Fonds der Chemischen Industrie. We would like to
thank Sven Schrˆter and Andreas Suppan (undergraduate research
participants) for skillful technical assistance. The donation of chemicals
by OMG AG (Hanau-Wolfgang) and by Wacker-Chemie (M¸nchen) is
gratefully acknowledged.
[30] D. R. Coulson, Inorg. Synth. 1972, 13, 121 124.
[31] F. R. Hartley, Organomet. Chem. Rev. Sect. A 1970, 6, 119 137.
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266.
[33] M. Piber, Diplomarbeit, Universit‰t Marburg, (Germany), 1999.
[34] W. C. Still, M. Kahn, A. J. Mitra, J. Org. Chem. 1978, 43, 2923 2925.
[1] a) Y. Suzuki, M. Ojika, Y. Sakagami, R. Fudou, S. Yamanaka,
Tetrahedron 1998, 54, 11399 11404; b) Y. Suzuki, M. Ojika, Y.
Sakagami, R. Fudou, S. Yamanaka, A. Tsukamoto, T. Yoshimura, J.
Antibiot. 1998, 51, 275 281.
[2] a) T. Anke, F. Oberwinkler, W. Steglich, G. Schramm, J. Antibiot. 1977,
30, 806 810; b) T. Anke, H. J. Hecht, G. Schramm, W. Steglich, J.
Received: June 12, 2002 [F4174]
5592
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0824-5592 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 24