Synthesis of furanomycin derivatives by gold-catalyzed cycloisomerization of α-hydroxyallenes

Article abstract of DOI:10.1055/s-2007-990860

The novel furanomycin analogues 8 and 17 were synthesized as mixture of two diastereomers using the gold-catalyzed cycloisomerization of α-hydroxyallenes as the key step. Compared to the traditional use of stoichiometric amounts of silver salts, gold catalysis is much more efficient for the cyclization of highly functionalized substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990860

FEATURE ARTICLE
3741
Synthesis of Furanomycin Derivatives by Gold-Catalyzed Cycloisomerization
of a-Hydroxyallenes
G
J
old-Cata
ö
lyzedSynthe
r
sis of Fu
g
ranomycinDeriva
E
tives rdsack, Norbert Krause*
Organic Chemistry II, University of Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany
Fax +49(231)7553884; E-mail: norbert.krause@uni-dortmund.de
Received 17 September 2007
3d
Van Brunt and Standaert have reported an enantioselec-
tive synthesis of (+)-furanomycin (1) from Garner’s alde-
hyde (R)-2, using the silver-mediated cyclization of a
Abstract: The novel furanomycin analogues 8 and 17 were synthe-
sized as mixture of two diastereomers using the gold-catalyzed cy-
cloisomerization of a-hydroxyallenes as the key step. Compared to
the traditional use of stoichiometric amounts of silver salts, gold ca- chiral a-hydroxyallene, which was prepared by S 2¢-re-
N
talysis is much more efficient for the cyclization of highly function- duction of propargyl silyl ether with lithium aluminum
alized substrates.
hydride. Our approach, on the other hand, takes advantage
Key words: allenes, amino acids, cycloisomerization, furanomy- of the copper-mediated S 2¢-substitution of propargylox-
N
cin, gold catalysis
iranes, which provides a versatile and reliable access to a-
hydroxyallenes.6 Thus, Garner’s aldehyde (S)-2 was
subjected to Wittig alkenation with the propargylphos-
phonium salts 3a,b to give the conjugated enynes 4a,b in
–11 12
The nonproteinogenic a-amino acid (+)-furanomycin (1,
Figure 1) is one of very few natural products containing a
6
2% and 68% yield, respectively and with good trans se-
lectivity (Scheme 1). The use of the corresponding prop-
argylphosphonates was less effective in terms of both
yield and selectivity. Smooth desilylation of 4b was
2
,5-dihydrofuran ring. It was first isolated in 1967 by Kat-
1
agiri et al. from Streptomyces threomyceticus and it is
one of the smallest antibiotic natural products, inhibiting
bacterial protein synthesis by mimicking isoleucine. Due achieved with cesium fluoride in acetonitrile–water13 to
2
to its activity and moderate chemical complexity, several give 4c in 83% yield, whereas other fluoride sources (n-
3
4
syntheses of furanomycin and derivatives thereof have Bu NF·3 H O, THF or KF·2 H O, DMF) or strongly basic
4 2 2
1
4
been disclosed, often using sugars as the starting material. conditions (KOH, MeOH, reflux) were less effective.
Unfortunately, the enynes 4 were very unreactive towards
common double bond oxidizing agents (MCPBA; OsO4,
CO2H
NMO; RuCl , NaIO ); the only exception is the reaction
3 4
O
15
H
of 4a with an excess of dimethyldioxirane (DMDO) for
six days, which afforded the labile propargyloxirane 5 as
a 2:1 mixture of diastereomers. The next step, the copper-
NH2
+)-furanomycin (1)
(
Figure 1
mediated S 2¢ substitution of 5 with three equivalents of a
N
magnesium cyanocuprate, provided the desired a-hy-
droxyallenes 6a,b in 40% and 33% yield, respectively,
over two steps. The excess of cuprate is necessary due to
deactivation by coordination of the reagent to the hetero-
atoms of the substrate.
By taking advantage of the high reactivity and axial
chirality of allenes, we have recently established an effi-
cient and stereoselective synthesis of 2,5-dihydrofurans
5
by gold-catalyzed cycloisomerization of a-hydroxyal-
6
lenes. This reaction takes place with axis-to-center For the formation of the 2,5-dihydrofuran by cycloisomer-
chirality transfer and was subsequently expanded to the ization of the a-hydroxyallene 6a, gold(III) chloride in
6
d
corresponding gold-catalyzed cyclization of b-hydroxyal- tetrahydrofuran was identified as the best precatalyst, af-
7
7,8
9
lenes, a-/b-aminoallenes, and a-sulfanylallenes to af- fording the dihydrofuran 7a in 86% yield. Just 1 mol% of
ford five- or six-membered heterocycles. The utility of the the gold catalyst was sufficient for complete conversion of
method was also demonstrated by the first total synthesis 6a; in contrast to this, the silver-mediated hydroxyallene
of the b-carboline alkaloids (–)-isocyclocapitelline and cyclization used in the synthesis of (+)-furanomycin re-
1
0
3d
(
–)-isochrysotricine. Even though furanomycin shows a quired stoichiometric amounts of silver nitrate. Low
2
rather narrow structure–activity relationship, we became temperature (0 °C) is necessary to avoid acetal cleavage
interested in the synthesis of unusual amino acids of this by the gold salt, which was also observed with prolonged
type, which may find use in artificial peptides; this would reaction times and less coordinating solvents like dichlo-
further broaden the scope of the gold-catalyzed cycliza- romethane. Not surprisingly, the sterically demanding
tion of functionalized allenes.
tert-butyl-substituted allene 6b reacted more sluggishly
and gave the dihydrofuran 7b in only 34% yield, accom-
panied by several side products. The final steps to the ami-
no acid were carried for 7a and followed well-established
procedures:3 N,O-acetal cleavage with 4-toluenesulfonic
SYNTHESIS 2007, No. 23, pp 3741–3750
x
x.
x
x
.
2
0
0
7
Advanced online publication: 29.10.2007
DOI: 10.1055/s-2007-990860; Art ID: Z22407SS
,4
©
Georg Thieme Verlag Stuttgart · New York

3
742
J. Erdsack, N. Krause
FEATURE ARTICLE
PPh3Br
a: R1 = n-Bu
R1
O
O
3
NBoc
NBoc
1
NBoc
CHO
3b: R = SiMe3
O
O
O
KHMDS
THF, –78 °C
H
0 °C to r.t., 6 d
R1 = n-Bu
H
O
H
R1
2
n-Bu
a: R1 = n-Bu (62%, E/Z = 89:11)
b: R = SiMe3 (68%, E/Z = 91:9)
5 (dr = 2:1)
4
4
1
2
CsF
R MgCl (6 equiv)
c: R1 = H (83%)
CuCN (3 equiv)
THF
4
NH2
AuCl3
(1 mol%)
1
2
. PTSA (83%)
. Dess–Martin periodinane
NBoc
NBoc
O
HO2C
O
H
H
•
n-Bu
O
3. NaClO2, NaH2PO4,
-methylbut-2-ene (53%)
4. TFA (58%)
THF, 0 °C
n-Bu
O
H
2
n-Bu
OH
R2
Me
R2
8
6a: R2 = Me (40%)
6b: R2 = t-Bu (33%)
7
7
a: R2 = Me (86%)
b: R = t-Bu (34%)
R2 = Me
2
Scheme 1 Synthesis of the furanomycin derivative 8 by gold-catalyzed cycloisomerization of a-hydroxyallene 6a
1
6
acid, two-step oxidation using Dess–Martin periodinane
ple bond instead of the double bond. Again starting from
1
7
and sodium chlorite in buffered solution, and finally Garner’s aldehyde 2, we employed the well-known Co-
18
cleavage of the Boc group with trifluoroacetic acid. Puri- rey–Fuchs homologation to obtain the dibromoalkene 9
fication of the crude product by ion exchange chromatog- in good yield (80%, Scheme 2). Here, the use of 4 equiv-
raphy gave the new furanomycin derivative 8 as a 2:1 alents of triphenylphosphine (instead of 2 equiv as de-
1
9
mixture of diastereomers (accompanied by small amounts scribed by Reginato et al. ) gave reproducible results.
20
of a third isomer).
The Stille coupling of 9 with tributylvinyltin according
to a procedure described by Shen and Wang21 furnished
the desired enyne 10 in 49% yield. The presence of copper
iodide as a co-catalyst is essential, otherwise complete de-
Due to the lack of reactivity of the enynes 4, we did not
pursue a diastereoselective synthesis of the propargylox-
irane 5 or related allene precursors. Rather, we turned our
attention to enynes bearing the oxazolidine ring at the tri-
2
2
composition takes place. However, the allene synthesis
Biographical Sketches
Jörg Erdsack was born in Friedrich-Schiller-Univer-
search focuses on the appli-
Halle an der Saale in 1977. sität Jena in 2005. Since cation of homogeneous gold
He studied chemistry in 2005, he has been a Ph.D. catalysis for the synthesis of
Magdeburg and Jena and student in Prof. Krause’s biologically active target
obtained his Diploma from group in Dortmund. His re- molecules.
Norbert Krause obtained 1993, he became Associate ‘Japan Society for the Pro-
his Ph.D. in 1986 at the Professor at Bonn Universi- motion of Science (JSPS)
Technical University of ty in 1994, and later Full Fellowship’ (2003). He is
Braunschweig and was a Professor at Dortmund Uni- member of the Editorial
Postdoctoral Fellow at the versity in 1998. His research Board of the European Jour-
ETH Zürich (Switzerland) in organometallic and allene nal of Organic Chemistry
and Yale University (New chemistry has been recog- (since 2006) and was Guest
Haven, USA). He obtained nized through the award of Professor at the Université
his Habilitation for Organic the Heinz-Maier-Leibnitz- Catholique de Louvain
Chemistry at the Technical Preis (1991), a Heisenberg (Louvain-la-Neuve, Belgium)
University of Darmstadt in scholarship (1994), and a in 2007.
Synthesis 2007, No. 23, 3741–3750 © Thieme Stuttgart · New York

FEATURE ARTICLE
Gold-Catalyzed Synthesis of Furanomycin Derivatives
3743
by epoxidation of 10 with dimethyldioxirane and treat- the substrate 14. Finally, stereoselective allene formation
ment of the crude propargyloxirane with tert-butylcyano- was achieved by using equimolar amounts of butylmagne-
cuprate was rather unrewarding, affording the desired a- sium chloride, copper bromide–dimethyl sulfide complex,
28
hydroxyallene 11 in only 29% yield over two steps. Ex- and lithium bromide. This afforded the desired allene 15
tensive variation of the copper reagent and the reaction as a 1:1 mixture of two diastereomers. Again, an excess of
conditions did not improve this result.
the cuprate is necessary to ensure complete conversion of
the substrate.
In order to render the enyne more electron rich and thus
more susceptible to epoxidation, we next prepared the al- The cycloisomerization of 15 in the presence of 1 mol%
lene precursor 13 bearing an endocyclic double bond. The of gold(III) chloride in tetrahydrofuran proceeded
required alkyne 12 was obtained in 88% yield by treating smoothly and in high yield (89%) on a 20-mg scale to af-
dibromoalkene 9 with a slight excess of propylmagnesium ford the bicyclic dihydrofuran 16 with concomitant acetal
2
3
chloride, a procedure that avoids ring degradation, cleavage. On a larger scale (150 mg of 15), however, the
which is observed when butyllithium is used as the base.19 yield dropped to 48%. The following oxidation of the pri-
With this protocol in hand, the synthesis of 12 starting mary alcohol to the carboxylic acid was difficult. Treat-
from 2 was achieved in high yield on a multigram scale, ment of the crude aldehyde (obtained by oxidation of 16
16
which, in our hands, is more convenient than the one-step with Dess–Martin periodinane ) with sodium chlorite in
2
4
17
homologation with the Bestmann–Ohira reagent. The the presence of 2-methylbut-2-ene similar to the se-
1
4,25
Sonogashira coupling
of 12 with 1-bromocyclooctene quence shown in Scheme 1 gave the Boc-protected amino
in tetrahydrofuran as solvent proceeded smoothly to af- acid in low yield (<20%) and with unsatisfactory purity.
2
6
ford the enyne 13 in 79% yield. As expected, epoxidation Problems with the oxidation step in the synthesis of unsat-
2
3b,29
of 13 is very facile, taking place even upon exposure to urated amino acids are not uncommon.
Other oxida-
air; accordingly, the reaction of 13 with 3-chloroperben- tion methods3 did not solve the problem; for example,
zoic acid is fast (complete conversion after 3 h at 0 °C) the reaction of 16 with pyridinium dichromate in N,N-
and furnished oxirane 14 (1:1 mixture of diastereomers) in dimethylformamide4b,31 stopped at the aldehyde stage.
0,31
7
9% yield.
Further experiments with sodium chlorite as the oxidizing
agent revealed that a somewhat higher yield of the carbox-
ylic acid (35% over 2 steps) can be achieved by using
resorcinol32 instead of 2-methylbut-2-ene as a scavenger
for electrophilic chlorine. Gratifyingly, the final cleavage
of the Boc group with trifluoroacetic acid took place with-
out problem to afford the bicyclic furanomycin derivative
The conversion of propargyloxirane 14 into a-hydroxyal-
lene 15 was first carried out as in Scheme 1 using a mag-
nesium cyanocuprate, but this afforded a mixture of four
diastereomers, indicating epimerization of the allene by
1
1
the copper reagent. The use of phosphines or phosphites
as an additive prevented the epimerization,11 but separa-
1
7 as a 1:1 mixture of diastereomers. We are now investi-
gating the diastereoselective epoxidation of enyne 13 in
tion of the product from the additive was difficult. Appli-
cation of iron catalysis as described by Fürstner and
Mendez also failed because of insufficient reactivity of
2
7
PPh3 (4 equiv)
NBoc
NBoc
NBoc
CBr4 (2 equiv)
Et3N (1 equiv)
n-Bu SnCH=CH2
1. DMDO
NBoc
CHO
3
O
O
O
•
O
Pd dba ⋅CHCl (2.5 mol%)
2
3
3
2. t-BuMgCl (6 equiv)
CuCN (3 equiv)
H
H
H
OH
(
4-MeOC6H4)3P (15 mol%)
H
t-Bu
1 (29%)
Br
Br
O
CuI (10 mol%)
2
1
9
(80%)
10 (49%)
n-PrMgCl
2.1 equiv)
(
NBoc
NBoc
NBoc
1-bromocyclooctene
MCPBA
Na2HPO4
O
O
PdCl2(PPh)3 (2 mol%)
CuBr⋅SMe2 (4 mol%)
i-Pr2NH, THF
H
H
H
n-BuMgCl (4 equiv)
CuBr⋅SMe2 (4 equiv)
LiBr (4 equiv)
O
1
2 (88%)
13 (79%)
14 (79%, dr = 1:1)
AuCl3
(1 mol%)
NH2
NHBoc
HO
1. Dess–Martin periodinane
NBoc
HO2C
O
•
2
. NaClO2, NaH2PO4,
resorcinol (35%)
. TFA (quant.)
THF, r.t.
H
n-Bu
H
n-Bu
O
O
H
HO
n-Bu
3
17
16 (48–89%)
1
5 (81%)
Scheme 2 Synthesis of the bicyclic furanomycin derivative 17 by gold-catalyzed cycloisomerization of a-hydroxyallene 15
Synthesis 2007, No. 23, 3741–3750 © Thieme Stuttgart · New York

3
744
J. Erdsack, N. Krause
FEATURE ARTICLE
order to obtain the amino acid 17 in diastereo- and enan- °C under argon. With stirring, 0.5 M KHMDS in toluene (2.27 mL,
1
.13 mmol, 1.3 equiv) was added dropwise to give an orange-red
tiomerically pure form.
1
2b
soln. After 5 min the mixture was cooled to –78 °C and a soln of 2
In summary, we have developed new pathways towards
(
200 mg, 0.87 mmol, 1.0 equiv) in anhyd THF (2 mL) was added
unconventional furanomycin derivatives based on the slowly by syringe on the inner surface of the flask. The mixture was
gold-catalyzed cycloisomerization of a-hydroxyallenes allowed to warm to r.t. overnight (~12 h). It was diluted with Et
O
2
and sat. aq NH Cl (10 mL) was added dropwise. The organic phase
derived from conjugated enynes. Compared to the tradi-
tional use of stoichiometric amounts of silver salts, gold
catalysis is much more efficient even for the highly func-
tionalized substrates examined here. The low reactivity of
the enynes 4 and 10 towards double bond oxidizing agents
4
was separated, the residue was diluted with H O and extracted with
2
Et O (3 × 10 mL). The combined organic layers were washed with
2
brine, dried (MgSO ), and filtered and the solvent was evaporated.
4
The residue was purified by column chromatography (silica gel,
isohexane–EtOAc, 93:7) to give enyne 4a (166 mg, 62%) as a mix-
prevented a stereoselective synthesis of the corresponding ture of isomers (E/Z 89:11, GC). For analytical purposes, small
furanomycin derivatives; in contrast to this, the facile ep- samples of the pure isomers were obtained by repeated column
chromatography.
oxidation of enyne 13 suggests that a completely stereose-
lective synthesis of furanomycin analogues of the type 17
(
E)-4a
should be possible. These results demonstrate that homo-
geneous gold catalysis is a highly useful tool for the prep-
aration of complex target products, and we are currently
pursuing further applications of this method.
Colorless oil; R = 0.45 (isohexane–EtOAc, 9:1).
f
2
0
[
a]D +190.4 (c 0.99, CHCl3).
IR (film): 2978, 2934, 2872, 2210 (C≡C), 1700, 1478, 1456, 1383,
1
–
1
313, 1254, 1176, 1096, 1056, 853, 770 cm .
1
H NMR (400 MHz, DMSO-d ): d = 5.91 (dd, J = 7.3 Hz, 15.7 Hz,
H), 5.57 (d, J = 15.7 Hz, 1 H), 4.30 (br d, 1 H), 4.00 (dd, J = 6.2,
.0 Hz, 1 H), 3.70 (dd, J = 2.2, 9.0 Hz, 1 H), 2.31 (t, J = 6.0 Hz, 2
6
Melting points were determined with a Reichert thermovar melting
point apparatus and are uncorrected. IR spectra were obtained with
a Nicolet Avatar 320 FT-IR spectrophotometer either as KBr pellets
or as a liquid film between NaCl plates. H and C NMR spectra
were recorded with a Bruker DRX 400 or a Bruker DRX 500 spec-
trometer using the signals of the undeuterated solvent as the stan-
dard. Chemical shifts were determined relative to the residual
1
9
H), 1.49–1.37 (m, 19 H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, DMSO-d
): d = 151.0 [NCO
111.1, 110.8 [3 HC=CH], 93.0, 92.9 [2 C(CH ], 79.3 [C(CH
91.2, 78.8, 78.3 [3 C≡C], 67.2, 67.0 [2 OCH ], 58.3, 58.1 [2 CHN],
30.2 [CH ], 27.9 [C(CH ], 27.1, 26.1, 24.3, 23.3 [4 C(CH ],
21.3, 18.2 [2 CH ], 13.4 [CH ].
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 308.2226;
1
13
C(CH )
2 3 3
], 140.5,
],
6
)
)
3 3
3
2
2
solvent peaks (CHCl : d = 7.26 for protons, d = 77.0 for carbon at-
2
3
)
3
)
3 2
3
oms; C D : d = 7.27 for protons, d = 128.0 for carbon atoms;
2
3
6
6
DMSO-d : d = 2.50 for protons, d = 39.7 for carbon atoms;
6
1
8
30
3
CD OD: d = 3.31 for OH-proton, d = 49.05 for carbon atoms; D O:
3
2
found: 308.2198.
d = 4.81 for protons). Carbon atoms were assigned with APT exper-
iments. The products bearing a Boc group often show broadened
and/or duplicated peaks in NMR spectra due to slow conformational
inversion. In diastereomeric mixtures, the peaks of the main isomer
were assigned with an asterisk (*) if possible. FAB MS spectra were
measured with a JEOL JMS-SX102A mass spectrometer, ESI spec-
tra with a LTQ ORBITRAP equipped with a Hypersil gold column
(
Z)-4a
Colorless oil; R = 0.54 (isohexane–EtOAc, 9:1).
f
2
0
[
a]D +174.3 (c 0.79, CHCl3).
IR (film): 2978, 2934, 2872, 2210 (C≡C), 1701, 1456, 1382, 1366,
1253, 1176, 1096, 1056, 852, 769 cm .
–
1
(
diameter 50 × 1 mm, particle size 1.9 mm). Optical rotations were
1
H NMR (400 MHz, C D ): d = 5.81 (t, J = 9.2 Hz, 1 H), 5.55 (d,
6
6
determined with a Perkin-Elmer 341 polarimeter. Diastereomeric
ratios were determined on an AS800 (CE Instruments) gas chro-
matograph equipped with a CP-SIL-5CB column (low bleed 30 m,
J = 10.0 Hz, 1 H), 5.06 (br s, 1 H), 3.99 (t, 1 H), 3.67 (br d, J = 7.2
Hz, 1 H), 2.25 (t, J = 5.9 Hz, 2 H), 1.84–1.36 (m, 19 H), 0.88 (t,
J = 7.1 Hz, 3 H).
0
.32 mm ID, DF 0.25 mm) with helium as carrier gas if not other-
1
3
C NMR (100 MHz, C D ): d = 152.0 [NCO C(CH ) ], 142.3,
wise noted. All reactions were carried out under an argon atmo-
sphere in oven-dried glassware. THF was distilled from Na/
benzophenone, CH Cl and DMF were distilled from CaH prior to
use. TLC plates were visualized by immersion in a soln of alkaline
permanganate [KMnO (2 g), Na CO (10 g), H O (200 mL)], fol-
lowed by heating. Silica gel (particle size 0.035–0.070 mm) and
Florisil (60–100 mesh) were purchased from ACROS. Grignard re-
agents were titrated with salicylaldehyde phenylhydrazone accord-
ing to the procedure of Love and Jones. Tris(4-methoxy-
phenyl)phosphine was purchased from Aldrich and was recrystal-
lized from acetone–MeOH (1:1) prior to use. CBr was recrystal-
lized from anhyd EtOH prior to use. The AuCl stock soln were
prepared by dissolving the gold salt in the appropriated volume of
anhyd MeCN in a dry Schlenk tube under argon and cooling with
ice. DOWEX 50W-X8 cation exchange resin was purchased from
Fluka.
6
6
2
3 3
1
7
2
10.3 [2 HC=CH], 96.0 [C(CH ) ], 94.4 [C≡C], 79.4 [C(CH ) ],
3 2
3 3
7.3 [C≡C], 68.6 [OCH ], 57.2 [CHN], 31.1 [CH ], 28.6 [C(CH ) ],
2
2
3 3
2
2
2
6.8, 24.2 [2 C(CH ) ], 22.2, 19.5 [2 CH ], 13.7 [CH ].
3
2
2
3
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 308.2226;
found: 308.2201.
4
2
3
2
18 30 3
tert-Butyl (R)-2,2-Dimethyl-4-(4-trimethylsilylbut-1-en-3-
ynyl)oxazolidine-3-carboxylate (4b)
In a 50-mL Schlenk tube equipped with a magnetic stirrer bar, a sus-
pension of (trimethylsilylpropargyl)triphenylphosphonium bro-
mide (3b) (1.19 g, 2.62 mmol, 1.5 equiv) in anhyd THF (15 mL)
was cooled to 0 °C under argon. With stirring, 0.5 M KHMDS in
toluene (5.24 mL, 2.62 mmol, 1.5 equiv) was added dropwise to
give a reddish-brown soln. After 5 min the mixture was cooled to
–
3
3
4
35
3
12b
78 °C and a soln of 2 (400 mg, 1.74 mmol, 1.0 equiv) in anhyd
THF (5 mL), was added slowly by syringe on the inner surface of
the flask. The mixture was kept at –78 °C for 30 min and then grad-
ually warmed with careful TLC monitoring to avoid partial de-
silylation due to the strong basic conditions. After complete
consumption of the starting material at –40 °C and 2 h, the mixture
tert-Butyl (R)-2,2-Dimethyl-4-(oct-1-en-3-ynyl)oxazolidine-3-
carboxylate (4a)
In a 50-mL Schlenk tube equipped with a magnetic stirrer bar, a sus-
3
4
pension of (hept-3-ynyl)triphenylphosphonium bromide (3a, 496
mg, 1.13 mmol, 1.3 equiv) in anhyd THF (10 mL) was cooled to 0
Synthesis 2007, No. 23, 3741–3750 © Thieme Stuttgart · New York

FEATURE ARTICLE
Gold-Catalyzed Synthesis of Furanomycin Derivatives
3745
was poured quickly into stirred aq phosphate buffer (pH 7, 40 mL).
Workup was carried out as for 4a, and purification by column chro-
matography (silica gel, isohexane–EtOAc, 93:7) gave of (E)-4b
Epoxidation of Enynes followed by Copper-Mediated S 2¢ Sub-
N
stitution; General Procedure
In a flask equipped with a magnetic stirrer bar, a soln of the enyne
(1.0 mmol, 1.0 equiv) in anhyd CH Cl (1 mL) was cooled to 0 °C
(347 mg, 62%) and (Z)-4b (35 mg, 6%).
2
2
under argon. With stirring, an excess of a freshly prepared soln of
1
5
(
E)-4b
DMDO in acetone (0.1 mol/L) was added quickly by syringe. The
temperature was kept between 0 °C and r.t. After complete con-
sumption of the starting material (TLC monitoring), the solvent was
removed in vacuo. The crude epoxide was used in the next step
without delay.
Colorless solid; mp 48–49 °C; R = 0.27 (isohexane–EtOAc, 93:7).
f
20
[
a]D –121.0 (c 0.62, CHCl3).
IR (KBr): 2975, 2936, 2149 (C≡C), 1697, 1385, 1365, 1253, 1176,
1
–
1
147, 1116, 1086, 1055, 1023, 988, 850, 781, 766 cm .
In a Schlenk tube equipped with a magnetic stirrer bar, CuCN (3.0
mmol, 3.0 equiv) was suspended in anhyd THF (15 mL) under ar-
gon. After cooling to –30 °C, a soln of the Grignard reagent (3.0
mmol, 3.0 equiv) was added dropwise by syringe and stirring was
continued for 30 min. A soln of the propargyloxirane (1.0 mmol, 1.0
equiv) in anhyd THF (5 mL) was added slowly by syringe on the in-
ner surface of the flask; the reaction was monitored by TLC. After
0 min stirring at –30 °C, the soln was allowed to warm up slowly
to 0 °C. After complete conversion of the starting material, sat. aq
NH Cl (3 mL) was added dropwise, the cooling bath was removed,
and the mixture was stirred at r.t. for 30 min. The suspension was
1
H NMR (400 MHz, CDCl ): d = 6.11 (m, 1 H), 5.65 (dd, J = 15.7
3
Hz, 1 H), 4.35 (2 br s, 1 H), 4.03 (m, J = 6.6, 8.5 Hz, 1 H), 3.74 (dd,
J = 8.9 Hz, 1 H), 1.60–1.44 (m, 15 H), 0.18 (s, 9 H).
1
3
C NMR (100 MHz, CDCl ): d = 151.8, 151.6 [2 NCO C(CH ) ],
3
2
3 3
1
9
42.5, 142.2, 111.5, 111.3 [4 HC=CH], 102.9, 102.5 [2 C≡C], 95.2,
4.0 [2 C(CH ) ], 93.6 [C≡C], 80.4, 79.9 [2 C(CH ) ], 67.6, 67.5 [2
3
2
3 3
6
OCH ], 58.8, 58.7 [2 CHN], 28.3 [C(CH ) ], 27.2, 26.4, 24.5, 23.5
2
3 3
[
4 C(CH ) ], –0.2 [Si(CH ) ].
3
2
3 3
+
4
HRMS (FAB): m/z [M – H] calcd for C H NO Si: 322.1838;
found: 322.1814.
1
7
28
3
diluted with Et O and filtered through a small pad of silica gel. The
2
filtrate was washed with H O, the aqueous phase was washed with
2
(
Z)-4b
Et O (2 ×), and the combined organic extracts were washed with
2
Colorless solid; mp 48–50 °C; R = 0.40 (isohexane–EtOAc, 93:7).
f
brine and dried (MgSO ). Filtration and evaporation of the solvent
4
20
[
a]D +142.2 (c 0.40, CHCl3).
gave a crude product that was purified by column chromatography
(
silica gel).
IR (KBr): 2975, 2936, 2149 (C≡C), 1697, 1385, 1365, 1253, 1176,
–
1
1
147, 1116, 1086, 1055, 1023, 988, 850, 781, 765 cm .
tert-Butyl (4S)-4-(1-Hydroxy-4-methylocta-2,3-dienyl)-2,2-di-
methyloxazolidine-3-carboxylate (6a)
1
H NMR (400 MHz, CDCl ): d = 5.95 (m, 1 H), 5.55 (d, J = 10.8
3
Hz, 1 H), 4.84 (br m, 1 H), 4.14 (m, 1 H), 3.78 (br m, 1 H), 1.60–
1
According to the general procedure, enyne 4a (3.3 g, 10.2 mmol)
was epoxidized with DMDO (190 mL, ca. 19 mmol) for 6 d; during
this time, the mixture was concentrated twice carefully at r.t. and
was treated with freshly prepared DMDO (200 mL, ca. 20 mmol)
again. Reaction of the crude oxirane (3.3 g) with MeMgCl (21.5
mL, 61.2 mmol, 22 wt% in THF) and CuCN (2.74 g, 30.6 mmol) af-
forded a-hydroxyallene 6a (1.37 g, 40%) as a yellow oil; mixture of
diastereomers (dr = 2:1) together with a small amount of a third di-
.44 (m, 15 H), 0.18 (s, 9 H).
1
3
C NMR (100 MHz, CDCl ): d = 151.9 [NCO C(CH ) ], 144.0,
3
2
3 3
1
[
09.8 [2 HC=CH], 100.8, 100.3 [2 C≡C], 94.1 [C(CH ) ], 79.9
C(CH ) ], 68.3 [OCH ], 56.8 [CHN], 28.5 [C(CH ) ], 26.5, 23.9 [2
3
2
3 3 2 3 3
C(CH ) ], –0.1 [Si(CH ) ].
3
2
3 3
+
HRMS (FAB): m/z [M – H] calcd for C H NO Si: 322.1838;
found: 322.1814.
1
7
28
3
astereomer (5–10%, by NMR analysis); R = 0.36 (isohexane–
f
EtOAc, 85:15).
tert-Butyl (R,E)-4-(But-1-en-3-ynyl)-2,2-dimethyloxazolidine-3-
carboxylate (4c)
In a 20-mL round-bottom flask equipped with a magnetic stirrer bar,
IR (film): 3467 (br, OH), 2977, 2960, 2933, 2874, 1967 (C=C=C),
1698, 1386, 1366, 1257, 1174, 1097, 849, 808, 767 cm .
–
1
enyne (E)-4b (115 mg, 0.36 mmol) was dissolved in MeCN (3 mL)
1
H NMR (400 MHz, C D ): d = 5.39 (br d, 1 H), 4.52 (br m, 1 H),
6
6
and H O (0.1 mL). CsF (162 mg, 1.07 mmol) was added in one por-
2
4.22 (br m, 1 H), 3.95 (br d, 1 H), 3.82 (dd, J = 6.5, 8.7 Hz, 1 H),
1.98–1.46 (m, 24 H), 0.99 (t, J = 7.1 Hz, 3 H).
13C
tion and the mixture was stirred at r.t. for 2.5 h. H O (10 mL) was
2
added and the mixture was extracted with Et O (3 × 15 mL). The
2
NMR (100 MHz, C D ): d = 201.1 [C=C=C], 152.1
6 6
combined organic layers were dried (MgSO ) and concentrated un-
4
[
NCO C(CH ) ], 101.9, 101.5 [2 HC=C=C ], 94.5 [C(CH ) ], 93.1,
2 3 3 q 3 2
der reduced pressure. The crude product was purified by column
chromatography (silica gel, isohexane–EtOAc, 9:1) to give enyne
9
6
2
1
2.1 [2 HC=C=C ], 80.4, 79.5 [2 C(CH ) ], 72.5, 72.2 [2 CHOH],
q 3 3
5.2 [OCH ], 63.1, 61.8 [2 CHN], 34.0, 33.9, 30.0, 29.9 [4 CH ],
2
2
4
c (74 mg, 83%) as a colorless oil that darkened upon storage;
8.3 [C(CH ) ], 26.8, 25.1 [2 C(CH ) ], 22.7 [CH ], 19.0 [CH ],
3
3
3 2
2
3
Rf = 0.77 (isohexane–EtOAc, 4:1).
4.2 [CH3].
20
[
a]D –66.3 (c 1.35, CHCl3).
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 340.2488;
found: 340.2478.
1
9
34
4
IR (film): 3293 (C≡CH), 2980, 2936, 2876, 2104 (C≡C), 1697,
1
7
1
478, 1457, 1385, 1367, 1255, 1207, 1173, 1098, 1059, 953, 852,
70 cm .
–1
tert-Butyl (4S)-4-(4-tert-Butyl-1-hydroxyocta-2,3-dienyl)-2,2-
dimethyloxazolidine-3-carboxylate (6b)
H NMR (400 MHz, CDCl ): d = 6.14 (dd, J = 7.7, 14.6 Hz, 1 H),
3
5
.61 (dd, J = 15.4 Hz, 1 H), 4.35 (2 br s, 1 H), 4.04 (m, 1 H), 3.75
The crude propargylic oxirane 5 (222 mg, prepared as in the synthe-
sis of 6a) was treated with t-BuMgCl (2.7 mL, 4.3 mmol, 20 wt% in
THF) and CuCN (194 mg, 2.16 mmol) to give a-hydroxyallene 6b
(
dd, J = 1.9, 9.0 Hz, 1 H), 2.89 (s, 1 H), 1.60–1.43 (m, 15 H).
1
3
C NMR (100 MHz, CDCl ): d = 151.6 [NCO C(CH ) ], 143.5,
3
2
3 3
(
91 mg, 33%) as a yellow oil; mixture of diastereomers (dr = 2:1;
1
43.2, 110.5, 110.3 [4 HC=CH], 94.2, 93.7 [2 C(CH ) ], 80.5
3 2
NMR analysis); R = 0.56 (isohexane–EtOAc, 4:1).
f
[
5
C≡C], 80.0 [C(CH ) ], 78.1 [C≡CH], 67.6, 67.5 [2 OCH ], 58.8,
3
3
2
8.7 [2 CHN], 28.3 [C(CH ) ], 27.4, 26.5, 24.6, 23.6 [4 C(CH ) ].
IR (film): 3470 (br, OH), 2963, 2933, 2873, 1954 (C=C=C), 1700,
1
8
3
3
3 2
477, 1459, 1390, 1377, 1366, 1255, 1206, 1174, 1103, 1088, 1067,
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 252.1600;
1
4
22
3
–1
49 cm .
found: 252.1577.
Synthesis 2007, No. 23, 3741–3750 © Thieme Stuttgart · New York

3
746
J. Erdsack, N. Krause
FEATURE ARTICLE
1
H NMR (400 MHz, C D ): d = 5.51 (br d, 1 H), 4.63 (br d, 1 H),
under reduced pressure and partitioned between H O (20 mL) and
EtOAc (50 mL). The organic phase was separated and the aqueous
6
6
2
4
1
.25 (br s, 1 H), 4.09 (br m, 1 H), 3.83 (br m, 1 H), 1.99 (br m, 2 H),
.74–1.46 (m, 19 H), 1.17 (d, 9 H), 1.04 (dt, J = 7.2 Hz, 3 H).
layer was washed with EtOAc (2 × 25 mL). The combined organic
1
3
layers were dried (MgSO ) and filtered and the solvent was evapo-
4
C NMR (100 MHz, C D ): d = 200.0 [C=C=C], 153.9, 151.9 [2
6
6
rated to give the crude hydroxycarbamate (540 mg, 83%, 2:1 mix-
ture of diastereomers together with a small amount of a third
isomer), which was used directly in the next step. For analytical pur-
poses, a small amount was purified by column chromatography (sil-
NCO C(CH ) ], 116.4 [HC=C=C ], 96.0, 95.2 [2 HC=C=C ], 94.4
2
3
3
q
q
[
[
[
[
C(CH ) ], 80.2, 79.7 [2 C(CH ) ], 72.2, 71.3 [2 CHOH], 64.9, 64.4
3 2 3 3
2 OCH ], 62.9, 62.0 [2 CHN], 33.8, 31.0, 29.6 [3 CH ], 28.3
2
2
C(CH ) ], 27.2, 26.9, 26.9, 26.8, 24.9, 24.9 [6 CH /CH ], 23.0
3
3
2
3
ica gel, isohexane–EtOAc, 3:2); colorless oil; R = 0.48 (isohexane–
f
C(CH ) ], 14.3 [CH ].
3
3
3
EtOAc, 3:2).
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 382.2957;
found: 382.2942.
2
2
40
4
IR (film): 3444, 2964, 2933, 2873, 1701, 1502, 1457, 1391, 1366,
–
1
1
247, 1172, 1048, 856, 827, 779, 731 cm .
1
tert-Butyl (4S)-4-(5-Butyl-5-methyl-2,5-dihydrofuran-2-yl)-2,2-
dimethyloxazolidine-3-carboxylate (7a); Typical Procedure
A soln of a-hydroxyallene 6a (74 mg, 0.23 mmol) in THF (4 mL)
H NMR (400 MHz, CDCl ): d = 5.85–5.71 (m, 2 H), 5.15–4.87 (m,
3
2 H), 3.89–3.63 (m, 3 H), 2.99 (br s, 1 H), 1.57 (m, 2 H), 1.43*/1.40
(2 s, 9 H), 1.30–1.22 (m, 7 H), 0.88 (m, 3 H).
was cooled to 0 °C and treated with 0.165 M AuCl in MeCN (14
13
3
C NMR (100 MHz, C D ): d = 156.1 [NCO C(CH ) ], 136.0,
6
6
2
3 3
mL, 1 mol%). The mixture was stirred at 0 °C for 2 h, diluted with
EtOAc, and filtered through a short plug of Celite. The filtrate was
concentrated and the residue was purified by column chromatogra-
phy (silica gel, isohexane–EtOAc, 9:1) to give dihydrofuran 7a (64
mg, 86%) as a pale yellow oil; mixture of diastereomers (dr = 2:1;
1
7
4
2
35.5, 127.1, 126.7 [4 C=C], 90.6, 90.6 [2 C ], 86.8, 85.6 [2 CH],
q
9.0, 78.8 [2 C(CH ) ], 64.7, 62.8 [2 OCH ], 55.9, 54.1 [2 CHN],
3
3
2
1.2, 41.2 [2 CH ], 28.4 [C(CH ) ], 27.2, 27.1, 25.7, 25.5 [4 CH ],
2
3 3
2
3.5, 23.5 [2 CH ], 14.3, 14.3 [2 CH ].
3
3
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 300.2175;
NMR analysis); R = 0.40, 0.43 (PE–EtOAc, 9:1).
16 30
4
f
found: 300.2204.
In a Schlenk tube equipped with a magnetic stirrer bar, a soln of the
hydroxycarbamate (300 mg, 1.0 mmol) in anhyd CH Cl (8 mL)
was cooled to 0 °C. With vigorous stirring, Dess–Martin
periodinane (555 mg, 1.3 mmol) was added in one portion. After
IR (film): 2974, 2934, 2873, 1700, 1479, 1456, 1385, 1365, 1257,
–
1
1
176, 1083, 1052, 850, 770, 732 cm .
1
2
2
H NMR (400 MHz, C D ): d = 6.07–5.88 (m, 1 H), 5.70–5.53 (m,
6
6
1
1
H), 5.39–5.05 (m, 1 H), 4.50–3.94 (m, 2 H), 3.79 (m, 1 H), 1.90–
.74 (m, 24 H), 0.89 (m, 3 H).
16
1
h, TLC monitoring indicated complete consumption of the start-
1
3
C NMR (125 MHz, C D ): d = 152.7, 152.2 [2 NCO C(CH ) ],
ing material. The mixture was diluted with Et O (10 mL) and treated
with sat. aq NaHCO (5 mL), sat. aq Na S O (5 mL), and Et O (10
6
6
2
3 3
2
1
34.5, 134.3, 134.2 [3 HC=CH], 94.4, 93.8 [2 C(CH ) ], 90.5, 90.2
3
2
3
2
2
3
2
[
[
2 C ], 86.6, 85.6 [2 CH], 79.5 [C(CH ) ], 66.0, 65.1 [2 OCH ], 62.0
mL). After a few min with stirring at r.t., the biphasic mixture be-
came clear. The organic phase was separated and the aqueous layer
q
3 3
2
CHN], 41.5, 41.4, 41.4 [3 CH ], 28.5, 28.4 [2 C(CH ) ], 28.0, 27.5,
2 3 3
2
7.4, 27.3, 27.2, 26.8, 26.8, 26.6, 26.6, 25.4, 24.8, 23.5, 23.1[13
was washed with Et O (3 × 15 mL). The combined organic layers
2
CH /CH ], 14.3 [CH ].
were washed with sat. aq NaHCO and brine and dried (MgSO ).
2
3
3
3
4
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 340.2488;
found: 340.2482.
Filtration and evaporation of the solvent gave the crude aldehyde,
which was used in the next step without delay.
1
9
34
4
In a round-bottom flask equipped with a magnetic stirrer bar, the
crude aldehyde was dissolved in a mixture of t-BuOH (6 mL) and
2-methylbut-2-ene (15 mL) and was cooled to 0 °C. With vigorous
tert-Butyl (4S)-4-(5-Butyl-5-tert-butyl-2,5-dihydrofuran-2-yl)-
,2-dimethyloxazolidine-3-carboxylate (7b)
According to the synthesis of 7a, reaction of a-hydroxyallene 6b
2
stirring, a soln of NaClO (339 mg, 3.0 mmol, 80%, technical grade)
2
(
300 mg, 0.79 mmol) with 0.165 M AuCl in MeCN (48 mL, 1
and NaH PO ·H O (414 mg, 3.0 mmol) in H O (2.5 mL) was slowly
3
2
4
2
2
mol%) gave dihydrofuran 7b (102 mg, 34%) as a colorless solid;
added dropwise by syringe over 30 min. The mixture became yel-
low and was allowed to stir at r.t. overnight. The reaction was
mixture of diastereomers (dr = 2:1; NMR analysis); R = 0.86 (iso-
f
hexane–EtOAc, 9:1).
quenched with sat. aq NaHCO and was extracted with hexanes
3
(
2 × 25 mL). The aqueous layer was mixed with Et O and cooled to
2
IR (KBr): 2974, 2934, 2873, 1691, 1478, 1387, 1254, 1176, 1121,
–
1
0 °C. With stirring, 1 M HCl was added dropwise to adjust the pH
to 2–3. The organic phase was separated and the residue was
washed with Et O (3 × 50 mL). The combined organic layers were
dried (MgSO ) and filtered and the solvent was evaporated to give
the Boc-protected amino acid (165 mg, 53%) as a colorless oil;
Rf = 0.43 (isohexane–EtOAc–AcOH, 8:2:1).
1
083, 1049, 850 cm .
1
H NMR (400 MHz, C D ): d = 6.32–5.99 (m, 1 H), 5.56–5.41 (m,
6
6
2
1
H), 4.93 (m, 1 H), 4.50–4.01 (m, 2 H), 3.81 (m, 1 H), 1.87–1.43
4
(
m, 21 H), 1.06 (m, 12 H).
1
3
C NMR (125 MHz, C D ): d = 152.7, 152.2 [2 NCO C(CH ) ],
6
6
2
3 3
1
8
30.4, 129.7 [2 HC=CH], 98.5, 98.2 [2 C ], 94.4, 93.8 [2 C(CH ) ],
8.1, 87.6 [2 CH], 79.5 [C(CH ) ], 66.3, 65.5 [2 OCH ], 61.5
q
3
2
IR (film): 3446 (br), 2972, 2873, 1715, 1505, 1456, 1368, 1245,
1167, 1102, 1058, 1024, 907, 748 cm .
–1
3
3
2
[
CHN], 39.6 [C(CH ) ], 33.0 [CH ], 28.6 [C(CH ) ], 28.3, 27.8 [2
3 3 2 3 3
1
H NMR (400 MHz, CDCl ): d = 8.23 (br s, 1 H), 5.91 (dd, J = 2.0,
3
C(CH ) ], 28.1 [CH ], 26.7, 26.0 [2 C(CH ) ], 25.8 [C(CH ) ], 23.7
3
3
2
3 3
3 3
6
5
.0 Hz, 1 H), 5.71 (d, J = 6.0 Hz, 1 H), 5.19 (d, J = 8.2 Hz, 1 H),
.07 (d, J = 4.8 Hz, 1 H), 4.46 (m, 1 H), 1.58 (m, 2 H), 1.48–1.41
[
CH ], 23.0 [C(CH ) ], 14.6, 14.5 [2 CH ].
2 3 3 3
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 382.2957;
2
2
40
4
(m, 10 H), 1.29–1.24 (m, 6 H), 0.88 (m, 3 H).
13C
[
[
found: 382.2961.
NMR (100 MHz, CDCl ): d = 173.7 [COOH], 155.2
3
NCO C(CH ) ], 137.2, 137.0, 125.2, 124.3 [4 HC=CH], 91.8, 91.4
2 3 3
(
2R)-2-Amino-2-(5-butyl-5-methyl-2,5-dihydrofuran-2-yl)ace-
2 C ], 85.2, 84.4 [2 CH], 80.4, 79.9 [2 C(CH ) ], 56.9 [CHN], 41.0,
q 3 3
tic Acid (8)
4
0.8 [2 CH ], 28.3 [C(CH ) ], 26.9, 26.7 [2 CH ], 25.5, 25.4 [2
2 3 3 2
In a round-bottom flask equipped with a magnetic stirrer bar, a soln
CH ], 23.1, 23.1 [2 CH ], 14.0 [CH ].
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 314.1967;
3
2
3
of 7a (738 mg, 2.17 mmol) and p-TsOH·H O (41 mg, 0.22 mmol,
2
0
.1 equiv) in MeOH (20 mL) was stirred at r.t. overnight. Sat. aq
16 28 5
NaHCO (5 mL) was then added and the mixture was concentrated
found: 314.1947.
3
Synthesis 2007, No. 23, 3741–3750 © Thieme Stuttgart · New York

FEATURE ARTICLE
Gold-Catalyzed Synthesis of Furanomycin Derivatives
3747
2
0
In a round-bottom flask equipped with a magnetic stirrer bar, a soln
of the Boc-protected amino acid (56 mg, 0.18 mmol) in CH Cl (2
mL) was cooled to 0 °C. TFA (1 mL) was added, and the soln was
stirred at r.t. for 2 h. Evaporation of the solvent under reduced pres-
sure gave the crude amino acid, which was purified by passing
[a]D –123.1 (c 2.69, CHCl3).
2
2
IR (film): 2980, 2936, 2874, 2220 (C≡C), 1704, 1478, 1456, 1382,
264, 1246, 1174, 1132, 1092, 1056, 864, 846, 770, 723, 672 cm .
–1
1
1
H NMR (400 MHz, CDCl ): d = 5.78 (dd, J = 11.1, 17.5 Hz, 1 H),
.60 (d, J = 17.3 Hz, 1 H), 5.45 (d, J = 10.9 Hz, 1 H), 4.67 (br d, 1
H), 4.02 (m, 2 H), 1.61 (s, 3 H), 1.48 (br s, 12 H).
3
5
through a column of Dowex 50W-X8. Elution with 10% aq NH OH
4
gave 8 (22 mg, 58%) as a colorless oil that became a solid upon stor-
age; mixture of diastereomers (dr = 2:1) together with small amount
of a third isomer (NMR analysis).
13
C NMR (100 MHz, CDCl ): d = 151.5 [NCO C(CH ) ], 127.1
3
2
3 3
[
HC=CH ], 116.8 [HC=CH ], 94.3, 93.9 [2 C(CH ) ], 88.7 [C≡C],
2
2
3 2
8
0.8 [C≡C], 80.2 [C(CH ) ], 68.7 [OCH ], 49.0 [CHN], 28.4
IR (film): 3438 (br), 3075 (br), 2960, 2933, 2872, 1631, 1502, 1468,
3 3
2
–
1
[C(CH ) ], 27.0, 25.8, 25.2, 24.4 [4 C(CH ) ].
1
384, 1203, 1181, 1137, 1048, 831, 722 cm .
3
3
3
2
+
1
HRMS (FAB): m/z [M – H] calcd for C H NO : 251.1443; found:
14 20 3
50.1484.
H NMR (400 MHz, D O): d = 6.20* (dd, J = 2.1, 6.1 Hz)/6.16 (dd,
2
2
J = 2.1, 6.2 Hz, 1 H), 5.80 (d, J = 6.0 Hz)/5.63* (d, J = 6.1 Hz, 1 H),
5
.34*/5.27 (2 br s, 1 H), 3.98* (d, J = 4.1 Hz)/3.83 (d, J = 4.0 Hz, 1
tert-Butyl (4R)-4-(1-tert-Butyl-4-hydroxybuta-1,2-dienyl)-2,2-
dimethyloxazolidine-3-carboxylate (11)
According to the general procedure, treatment of enyne 10 (50 mg,
H), 1.64 (m, 2 H), 1.35–1.28 (m, 9 H), 0.87 (t, J = 6.9 Hz, 3 H).
1
3
C NMR (100 MHz, D O): d = 170.9 [COOH], 139.7*, 138.7,
2
1
5
2
21.4*, 123.5 [4 HC=CH], 92.8*, 92.9 [2 C ], 82.2*, 82.8 [2 CH],
q
0
.20 mmol) with DMDO (4 mL, ca. 0.4 mmol) at 0 °C for 16 h fol-
6.7*, 57.3 [2 CHN], 40.2*, 40.1 [2 CH ], 26.3*, 26.4 [2 CH ],
2
2
lowed by reaction of the crude propargyloxirane with 1.7 M t-
BuMgCl in THF (0.7 mL, 1.2 mmol) and CuCN (50 mg, 0.56
mmol) gave a-hydroxyallene 11 (18 mg, 29%) as a pale yellow oil;
3.6*, 24.2 [2 CH ], 22.6*, 22.6 [2 CH ], 13.3 [CH ].
3
2
3
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 214.1443;
found: 214.1424.
1
1
20
3
R = 0.43 (isohexane–EtOAc, 4:1).
f
IR (film): 3455, 2971, 2870, 1960 (C=C=C), 1697, 1478, 1391,
tert-Butyl (R)-4-(2,2-Dibromovinyl)-2,2-dimethyloxazolidine-3-
carboxylate (9)
–1
1
250, 1207, 1173, 1094, 1067, 938, 853, 807, 770, 555, 517 cm .
1
H NMR (400 MHz, C D ): d = 5.37 (br d, 1 H), 4.31 (br s, 1 H),
In a 3-necked 500-mL flask equipped with a magnetic stirrer bar
and N inlet, a soln of Ph P (32.0 g, 122 mmol, 4.0 equiv) in anhyd
6
6
4
.20–4.11 (m, 2 H), 3.88–3.82 (m, 2 H), 3.22 (br s, 1 H), 1.73 (s, 3
2
3
H), 1.56 (s, 3 H), 1.49 (s, 9 H), 1.22 (s, 9 H).
CH Cl (200 mL) was cooled to 0 °C under argon. With stirring,
2
2
CBr (20.5 g, 61.8 mmol, 2.0 equiv) was added slowly in small por-
13C NMR (100 MHz, C D ): d = 196.8 [C=C=C], 152.5
4
6
6
tions to give an orange-red soln. After 15 min, the mixture was
[
[
NCO C(CH ) ], 119.8 [HC=C=C ], 98.8 [HC=C=C ], 93.5
2 3 3 q q
1
2b
cooled to –78 °C and a soln of 2 (7.0 g, 30.5 mmol, 1.0 equiv) and
Et N (3.1 g, 30.6 mmol, 1.0 equiv) in anhyd CH Cl (20 mL) was
C(CH ) ], 80.2 [C(CH ) ], 69.3 [OCH ], 59.0 [CH ], 57.3 [CHN],
3
2
3 3
2
2
3
2
2
33.6 [C(CH ) ], 30.0, 28.3 [C(CH ) ], 26.4, 25.0 [2 C(CH ) ].
3 3 3 3 3 2
added slowly by syringe. The mixture was allowed to warm to r.t.
overnight, poured into pentane (500 mL), and the resulting suspen-
sion was stirred for 30 min. The precipitate was filtered off and the
solvent was evaporated. The residue was treated with isohexane
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 326.2331;
found: 326.2304.
1
8
32
4
tert-Butyl (R)-4-Ethynyl-2,2-dimethyloxazolidine-3-carboxy-
late (12)
In a 3-necked 500-mL flask equipped with a magnetic stirrer bar
(200 mL), the suspension was stirred vigorously for 20 min and fil-
tered again. The collected residue was dissolved in a small amount
of CH Cl and an excess of pentane was added. After filtration, this
2
2
and an N inlet, a soln of dibromide 9 (15.8 g, 41.0 mmol) in anhyd
2
process was repeated once more. The combined filtrates were con-
centrated under reduced pressure and the residue was purified by
column chromatography (silica gel, isohexane–EtOAc, 93:7) to
give dibromide 9 (9.4 g, 80%) as a colorless solid (mp 55 °C), which
should be stored under argon to avoid decomposition. The spectro-
scopic data were in full agreement with those reported in the litera-
THF (80 mL) was cooled to 0 °C under argon. With stirring, 1.7 M
n-PrMgBr in THF (51 mL, 86.7 mmol, 2.1 equiv) was added slowly
by cannula. The mixture was stirred for 30 min at 0 °C and
quenched by dropwise addition of sat. aq NH Cl (100 mL). After di-
4
lution with Et O (50 mL) and H O, the organic phase was separated
2
2
ture.1
9b
and the aqueous layer was washed with Et O (2 × 50 mL). The com-
2
bined organic layers were washed with brine, dried (MgSO ), and
4
filtered and the solvent was evaporated. The residue was purified by
column chromatography (silica gel, isohexane–EtOAc, 93:7) to
give alkyne 12 (8.1 g, 88%). The spectroscopic data were in full
tert-Butyl (R)-4-(But-3-en-1-ynyl)-2,2-dimethyloxazolidine-3-
carboxylate (10)
In a Schlenk tube equipped with a Star Head magnetic stirrer bar,
dibromide 9 (50.0 mg, 0.130 mmol), tris(4-methoxyphenyl)phos-
phine (4.6 mg, 0.013 mmol), and tributyl(vinyl)tin (43.0 mg, 40 mL,
1
9c
agreement with those reported in literature.
tert-Butyl (R)-4-[(Cyclooct-1-enyl)ethynyl]-2,2-dimethyloxazo-
lidine-3-carboxylate (13)
In a 50-mL Schlenk tube equipped with a magnetic stirrer bar,
0
.137 mmol) were dissolved in anhyd DMF (1.3 mL) under argon,
and the soln was degassed with 3 freeze-pump–thaw cycles. Freshly
distilled i-Pr NEt (25.2 mg, 34 mL, 0.195 mmol) was added, fol-
2
PdCl (PPh ) (0.174 g, 0.25 mmol) and CuBr·SMe (0.102 g, 0.50
2
3 2
2
lowed by Pd dba ·CHCl (3.0 mg, 0.003 mmol) and CuI (2.5 mg,
2
3
3
mmol) were suspended in anhyd THF (50 mL) under argon. Freshly
0
8
.013 mmol). The tube was sealed with a stopper and was stirred at
0 °C in a preheated oil bath. After 12 h the mixture was cooled to
3
6
distilled 1-bromocyclooctene (2.34 g, 12.4 mmol) and freshly dis-
tilled i-Pr NH (3.96 g, 39.1 mmol) were added, and the tube was
2
r.t., diluted with Et O (10 mL), and filtered through a short plug of
2
sealed with a rubber septum. With stirring, a soln of alkyne 12 (2.94
g, 13.1 mmol) in anhyd THF (15 mL) was added slowly over 30
min. The deep green suspension became yellow and was stirred at
r.t. for 16 h, after which TLC monitoring indicated complete con-
sumption of the starting material. The solvent was evaporated, the
residue was taken up in isohexane–EtOAc (1:1) and filtered through
a thin pad of silica gel. The filtrate was concentrated and the residue
was purified by column chromatography (silica gel, isohexane–
Celite [rinsing with Et O (10 mL)]. The filtrate was stirred for 5 h
2
with an aq alkaline KF soln [sat. aq KF (20 mL) + concd NH OH (2
4
mL)]. The organic phase was separated and the aqueous layer was
washed with Et O (2 × 10 mL). The combined organic layers were
2
dried (MgSO ) and filtered and the solvent was evaporated. The res-
4
idue was purified by column chromatography (silica gel, isohex-
ane–EtOAc, 93:7) to give enyne 10 (16.0 mg, 49%) as a pale yellow
oil; R = 0.58 (isohexane–EtOAc, 9:1).
f
Synthesis 2007, No. 23, 3741–3750 © Thieme Stuttgart · New York

3
748
J. Erdsack, N. Krause
FEATURE ARTICLE
EtOAc, 93:7) to give enyne 13 (3.27 g, 79%) as a pale yellow oil
that should be stored under argon at –20 °C to avoid air epoxidation;
Rf = 0.25 (isohexane–EtOAc, 93:7).
Et O (2 ×), and the combined organic extracts were washed with
2
brine, dried (MgSO ), and filtered and the solvent was evaporated.
4
The residue was purified by column chromatography (silica gel,
isohexane–EtOAc, 85:15) to give a-hydroxyallene 15 (0.91 g, 81%)
as a colorless oil; mixture of diastereomers (dr = 1:1) together with
20
[
a]D –110.0 (c 1.02, CHCl3).
IR (film): 2979, 2929, 2853, 1704, 1451, 1384, 1263, 1245, 1174,
a small amount of a third isomer; R = 0.47, 0.51 (isohexane–
f
–
1
1
144, 1097, 1084, 1059, 841 cm .
EtOAc, 85:15).
1
H NMR (400 MHz, CDCl ): d = 6.03 (t, J = 8.3 Hz, 1 H), 4.61 (br
3
IR (film): 3467, 2929, 2871, 1961 (C=C=C), 1699, 1678, 1478,
s, 1 H), 4.00 (m, 2 H), 2.26 (t, 2 H), 2.14 (br m, 2 H), 1.62–1.48 (m,
1
7
457, 1385, 1366, 1249, 1206, 1173, 1106, 1059, 865, 847, 808,
68 cm .
2
3 H).
–1
1
3
C NMR (100 MHz, CDCl ): d = 151.6 [NCO C(CH ) ], 137.5,
1
3
2
3 3
H NMR (400 MHz, CDCl ): d = 4.29 (t, J = 5.9 Hz, 1 H), 4.05 (m,
3
1
6
2
23.2 [2 C=C], 94.2 [C(CH ) ], 84.9, 84.5 [2 C≡C], 80.0 [C(CH ) ],
9.0 [OCH ], 49.1 [CHN], 29.9, 29.7 [2 CH ], 28.4 [C(CH ) ], 28.3,
6.9, 26.3 [3 CH ], 25.8 [C(CH ) ], 25.7 [CH ], 24.6 [C(CH ) ].
3
2
3 3
1 H), 3.99 (dd, 1 H), 3.88 (dd, 1 H), 2.29 (m, 1 H), 1.97 (m, 4 H),
2
2
3 3
1.67–1.42 (m, 29 H), 0.87 (t, J = 6.3 Hz, 3 H).
2
3 2
2
3 2
13
C NMR (100 MHz, CDCl ): d = 197.5, 195.1 [2 C=C=C], 152.9,
3
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 334.2382;
2
0
32
3
152.2 [2 NCO C(CH ) ], 114.0, 112.6 [2 C=C=C], 108.8, 108.3 [2
2
3 3
found: 334.2356.
C=C=C], 93.7, 93.6 [2 C(CH ) ], 80.6, 80.5 [2 C(CH ) ], 71.1, 70.4
3
2
3 3
[
2 CHOH], 67.5, 66.6 [2 OCH ], 61.3, 59.3 [2 CHN], 33.7, 32.2,
0.5, 30.1, 29.9, 29.6 [6 CH ], 28.4, 28.3 [2 C(CH ) ], 28.0, 28.2,
2 3 3
2
tert-Butyl (4R)-2,2-Dimethyl-4-[(9-oxabicyclo[6.1.0]nonan-1-
yl)ethynyl]oxazolidine-3-carboxylate (14)
In a 250-mL round-bottom flask equipped with a magnetic stirrer
3
2
1
7.4, 26.7, 25.2, 25.1, 22.5, 22.5, 22.0, 21.9 [10 CH /CH ], 13.9,
2
3
3.9 [2 CH3].
bar, enyne 13 (1.83 g, 5.49 mmol) was dissolved in CH Cl (75 mL)
2
2
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 408.3114;
found: 408.3026.
2
4
42
4
and Na HPO ·2 H O (1.96 g, 11.0 mmol) was added in one portion.
2
4
2
The stirred mixture was cooled to 0 °C, MCPBA (2.37 g, 11.0
mmol, ca. 70%) was added in one portion and the mixture was
stirred at 0 °C for 3 h. The reaction was quenched by addition of sat.
aq Na SO (100 mL) and the biphasic mixture was stirred at r.t. for
tert-Butyl (1S)-1-(2-Butyl-2,4,5,6,7,8,9,9a-octahydrocyclo-
octa[b]furan-2-yl)-2-hydroxyethylcarbamate (16)
In a Schlenk tube with a magnetic stirrer bar, a-hydroxyallene 15
(
argon. 0.165 M AuCl in MeCN (3.0 mL) was added by syringe and
the yellow mixture was stirred at r.t. for 3 d. The mixture was dilut-
ed with Et O (2 mL) and quenched with sat. aq NaHCO (2 mL).
The organic phase was separated and the residue was washed with
Et O (3 × 2 mL). The combined organic layers were washed with
brine, dried (MgSO ), and filtered and the solvent was evaporated.
The residue was purified by column chromatography (silica gel,
isohexane–EtOAc, 7:3) to give hydroxycarbamate 16 (16 mg, 89%)
as a colorless oil; mixture of diastereomers (dr = 1:1; NMR analy-
2
3
3
0 min. The organic phase was separated and the aqueous layer was
20 mg, 0.05 mmol) was dissolved in anhyd THF (0.35 mL) under
washed with CH Cl (2 × 50 mL). The combined organic layers
2
2
3
were washed with sat. aq NaHCO (50 mL), H O (50 mL), and brine
3
2
(
50 mL), dried (MgSO ), and filtered and the solvent was evaporat-
4
2
3
ed. The residue was purified by column chromatography (silica gel,
isohexane–EtOAc, 85:15) to give oxirane 14 (1.51 g, 79%) as a pale
2
yellow oil; mixture of diastereomers, 1:1; R = 0.51 (isohexane–
f
4
EtOAc, 85:15).
IR (film): 2977, 2931, 2863, 1704, 1458, 1379, 1263, 1174, 1086,
–
1
1
059, 928, 843, 770 cm .
1
sis); R = 0.32, 0.36 (isohexane–EtOAc, 7:3).
H NMR (400 MHz, CDCl ): d = 4.56 (m, 1 H), 3.98 (m, 2 H), 3.03
f
3
(
dd, J = 10.3, 4.1 Hz, 1 H), 2.15 (m, 2 H), 1.74–1.31 (m, 25 H).
IR (film): 3452 (br), 2930, 2860, 1699, 1501, 1456, 1390, 1366,
1249, 1173, 1058, 1054, 1030, 756 cm .
–
1
1
3
C NMR (100 MHz, CDCl ): d = 151.3 [NCO C(CH ) ], 94.3
3
2
3 3
[
C(CH ) ], 81.6, 81.4 [2 C≡C], 80.2 [C(CH ) ], 68.7, 68.5 [2
1
3
2
3
3
H NMR (400 MHz, CDCl ): d = 5.42/5.36 (2 s, 1 H), 5.18 (d, J =
3
OCH ], 63.5, 63.4 [2 CH], 53.6 [C ], 48.5 [CHN], 30.5, 30.4 [2
2
q
8.9 Hz)/5.06 (d, J = 9.1 Hz, 1 H), 4.77/4.67 (2 br s, 1 H), 4.05–3.34
CH ], 28.4 [C(CH ) ], 27.0, 26.3, 26.0 [3 CH ], 25.9 [C(CH ) ],
2
3 3
2
3 2
(m, 3 H), 2.46 (m, 1 H), 2.07–1.28 (m, 26 H), 0.88 (m, 3 H).
13
2
5.7, 25.1 [2 CH ], 24.3 [C(CH ) ].
2 3 2
C NMR (100 MHz, CDCl ): d = 156.8, 156.1 [2 NCO C(CH ) ],
3
2
3 3
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 350.2331;
2
0
32
4
145.0, 143.9 [2 HC=C ], 126.0, 125.3 [2 HC=C ], 95.1, 92.5 [2 C ],
q
q
q
found: 350.2369.
8
5
2
8.0, 87.6 [2 CH], 79.4, 79.0 [2 C(CH ) ], 63.4, 62.6 [2 OCH ],
3 3 2
7.5, 55.3 [2 CHN], 37.3, 32.0 [2 CH ], 28.3 [C(CH ) ], 28.1, 27.0,
2
3 3
tert-Butyl (4R)-4-{1-[(2-Hydroxycyclooctylidene)methyl-
ene]pentyl}-2,2-dimethyloxazolidine-3-carboxylate (15)
Anhyd LiBr (0.96 g, 11.0 mmol, 4.0 equiv) was transferred into a
Schlenk tube equipped with a magnetic stirrer bar. The tube was
evacuated and heated with a heat gun. After cooling, the tube was
6.8, 26.6, 26.4, 26.2, 26.2, 25.0, 24.9, 23.2, 23.1, 22.3, 22.1 [13
CH ], 14.0 [CH ].
HRMS (FAB): m/z [M + H]+ calcd for C H NO : 368.2801;
found: 368.2792.
2
3
2
1
38
4
flushed with argon and CuBr·SMe (2.26 g, 11.0 mmol, 4.0 equiv)
and anhyd THF (40 mL) were added. The suspension was cooled to
2
(
2R)-2-Amino-(2-butyl-2,4,5,6,7,8,9,9a-octahydrocyclo-
octa[b]furan-2-yl)acetic acid (17)
The oxidation of 16 (115 mg, 0.31 mmol) in anhyd CH Cl (3 mL)
with Dess–Martin periodinane (226 mg, 0.53 mmol) was carried
out as in the synthesis of 8; the crude aldehyde was used in the next
step without delay.
–
15 °C, n-BuMgCl (6.4 mL, 11.0 mmol, 20 wt% in THF–toluene)
2
2
was added dropwise by syringe and stirring was continued for 30
min. The mixture was cooled to –60 °C and a soln of oxirane 14
1
6
(0.96 g, 2.75 mmol, 1.0 equiv) in anhyd THF (10 mL) was slowly
added by syringe on the inner surface of the flask. After 15 min, the
soln was allowed to warm to 0 °C over 3 h and stirring was contin-
ued for 1 h, after which TLC monitoring indicated complete conver-
sion of the starting material. The reaction was quenched by
A soln of the crude aldehyde and resorcinol (45 mg, 0.41 mmol) in
dioxane (30 mL) was cooled to 12 °C. With vigorous stirring, a soln
of NaClO2 (138 mg, 1.22 mmol, 80%, technical grade) and
NaH PO ·H O (168 mg, 1.22 mmol) in H O (4 mL) was added
dropwise addition of sat. aq NH Cl (8 mL), the cooling bath was re-
4
2
4
2
2
moved, and the mixture was stirred for 30 min. The suspension was
dropwise by syringe over 30 min. After 15 min with stirring at 12
diluted with Et O, filtered through a thin pad of silica gel, and the
°C, the slightly yellow mixture was poured into sat. aq NaHCO (15
2
3
filtrate was washed with H O. The aqueous layer was washed with
mL). The biphasic mixture was concentrated to its half volume un-
2
Synthesis 2007, No. 23, 3741–3750 © Thieme Stuttgart · New York

FEATURE ARTICLE
Gold-Catalyzed Synthesis of Furanomycin Derivatives
3749
der reduced pressure. The residue was diluted with H O until the
(3) (a) Semple, J. E.; Wang, P. C.; Lysenko, Z.; Joullié, M. M.
J. Am. Chem. Soc. 1980, 102, 7505. (b) Kang, S. H.; Lee, S.
B. Chem. Commun. 1998, 761. (c) Zhang, J. H.; Clive, D. L.
J. J. Org. Chem. 1999, 64, 1754. (d) VanBrunt, M. P.;
Standaert, R. F. Org. Lett. 2000, 2, 705. (e) Zimmermann,
P. J.; Blanarikova, J.; Jäger, V. Angew. Chem. Int. Ed. 2000,
39, 910; Angew. Chem. 2000, 112, 936.
2
precipitate was dissolved. CHCl (40 mL) was added and after cool-
3
ing to 0 °C, 1 M HCl was added dropwise with stirring to adjust the
pH to 2–3. The organic phase was separated, and the aqueous layer
was washed with CHCl (2 ×). The combined organic layers were
3
dried (MgSO ) and filtered and the solvent was evaporated to give
4
the crude Boc-protected amino acid, which was dissolved up in
CHCl and put on a column (silica gel). Elution with isohexane–
(4) (a) Kazmaier, U.; Pähler, S.; Endermann, R.; Häbich, D.;
Kroll, H.-P.; Riedl, B. Bioorg. Med. Chem. 2002, 10, 3905.
(b) Jirgenson, A.; Marinozzi, M.; Pellicciari, R. Tetrahedron
2005, 61, 373. (c) Lee, J. Y.; Schiffer, G.; Jäger, V. Org.
Lett. 2005, 7, 2317. (d) Chattopadhyay, S. K.; Sarkar, K.;
Karmakar, S. Synlett 2005, 2083.
(5) Modern Allene Chemistry; Krause, N.; Hashmi, A. S. K.,
Eds.; Wiley-VCH: Weinheim, 2004.
(6) (a) Hoffmann-Röder, A.; Krause, N. Org. Lett. 2001, 3,
3
EtOAc (1:1) removed resorcinol and chlorinated byproducts. Fur-
ther elution with isohexane–EtOAc–AcOH (8:2:1) gave the prod-
uct, which was coevaporated with toluene (3 × 2 mL) to remove
AcOH to give the Boc-protected amino acid (42 mg, 35%) as a col-
orless oil; mixture of diastereomers (dr = 1:1; NMR analysis);
Rf = 0.60, 0.68 (isohexane–EtOAc–AcOH, 8:2:1).
IR (film): 3342 (br), 3059, 2933, 2872, 1713, 1509, 1457, 1393,
–
1
1
368, 1251, 1163, 1055, 854, 738, 7037 cm .
2537. (b) Krause, N.; Hoffmann-Röder, A.; Canisius, J.
1
H NMR (500 MHz, CDCl ): d = 5.42 (br s, 1 H), 5.36 (d, J = 8.6
3
Synthesis 2002, 1759. (c) Hoffmann-Röder, A.; Krause, N.
Org. Biomol. Chem. 2005, 3, 387. (d) Deutsch, C.; Gockel,
B.; Hoffmann-Röder, A.; Krause, N. Synlett 2007, 1790.
7) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
Hz)/5.21 (br s, 1 H), 4.83 (br s, 1 H), 4.42 (d, J = 8.1 Hz)/4.34 (d, J
=
8.6 Hz, 1 H), 2.50 (m, 1 H), 2.07 (m, 1 H), 1.94 (m, 1 H), 1.81–
1
.25 (m, 24 H), 0.89 (t, J = 6.9 Hz, 3 H).
(
1
3
(8) (a) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.
b) Morita, N.; Krause, N. Eur. J. Org. Chem. 2006, 4634.
9) Morita, N.; Krause, N. Angew. Chem. Int. Ed. 2006, 45,
897; Angew. Chem. 2006, 118, 1930.
C NMR (100 MHz, CDCl ): d = 174.7 [COOH], 155.8, 155.4 [2
3
(
NCO C(CH ) ], 145.6 [HC=C ], 125.0, 124.8 [2 HC=C ], 92.7,
2
3
3
q
q
(
9
3
2
2.6 [2 C ], 88.2, 87.5 [2 CH], 79.8 [C(CH ) ], 59.5 [CHN], 36.6,
q
3
3
1
1.7, 31.4 [3 CH ], 28.3 [C(CH ) ], 28.1, 28.0, 26.7, 26.7, 26.5,
2
3 3
(
(
10) Volz, F.; Krause, N. Org. Biomol. Chem. 2007, 5, 1519.
11) Krause, N.; Hoffmann-Röder, A. Tetrahedron 2004, 60,
6.2, 26.2, 25.0, 23.0, 22.9, 22.2 [11 CH ], 14.0 [CH ].
2
3
+
HRMS (ESI): m/z [M + H] calcd for C H NO : 382.2588; found:
2
1
36
5
11671.
3
82.2588.
(
12) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
(b) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N.
Synthesis 1994, 31.
Analogous to the synthesis of 8, treatment of the Boc-protected ami-
no acid (15.7 mg, 0.04 mmol) in CH Cl (1 mL) with TFA (0.25
2
2
mL) at 0 °C gave amino acid 17 (12.3 mg, quantitative yield); mix-
ture of diastereomers (dr = 1:1; NMR analysis). This was purified
by filtration through a small column (Florisil, MeOH) to give a yel-
low oil, which became a solid upon storage.
(13) Pitsch, W.; Russel, A.; Zabel, M.; König, B. Tetrahedron
2001, 57, 2345.
(14) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627.
(
15) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991,
124, 2377.
IR (film): 3383 (br), 2930, 2860, 1720, 1614, 1385, 1210, 1161,
–1
1
047, 757 cm .
(
16) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Boeckmann, R. K. Jr.; Shao, P.; Mullins, J. J. Org. Synth.
Coll. Vol. X; John Wiley & Sons: London, 2004, 696.
17) Bal, B. S.; Childers, W. E. Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091.
1
H NMR (400 MHz, CD OD): d = 5.48 (br s, 1 H), 4.78/4.72 (2 br
3
s, 1 H), 4.52/4.40 (2 s, 1 H), 3.82/3.74 (2 s, 1 H), 2.53 (m, 1 H),
2
.11–1.34 (m, 18 H), 0.91 (t, J = 6.1 Hz, 3 H).
(
1
3
C NMR (125 MHz, CD OD): d = 175.4, 174.9 [2 COOH], 147.0,
3
1
8
2
46.3 [2 HC=C ], 127.6, 126.2 [2 HC=C ], 93.9, 93.7 [2 C ], 89.2,
8.5 [2 CH], 63.0, 62.6 [2 CHN], 38.6, 36.5, 32.9, 32.5, 29.4, 29.3,
8.3, 27.9, 27.8, 27.6, 27.1, 27.0, 26.1, 24.3, 24.3, 23.6, 23.5 [17
(18) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(19) (a) Reginato, G.; Mordini, A.; Degl’Innocenti, A.;
Caracciolo, M. Tetrahedron Lett. 1995, 36, 8275.
q
q
q
CH ], 14.5, 14.5 [2 CH ].
(b) Reginato, G.; Mordini, A.; Caracciolo, M. J. Org. Chem.
2
3
1
997, 62, 6187. (c) Crisp, G. T.; Jiang, Y.-L.; Pullman, P. J.;
+
HRMS (ESI): m/z [M + H] calcd for C H NO : 282.2069; found:
1
6
28
3
De Savi, C. Tetrahedron 1997, 53, 17489.
2
82.2065.
(
20) (a) Stille, J. K. Angew. Chem. Int. Ed. 1986, 25, 508; Angew.
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Acknowledgment
Continuous support of our work by the Deutsche Forschungsge-
meinschaft, the Fonds der Chemischen Industrie, and the European
Community is gratefully acknowledged.
2
005, 981.
(
(
21) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873.
22) The ‘copper effect’ in Stille cross-coupling reactions is well
documented: Wang, Y.; Burton, D. J. Org. Lett. 2006, 8,
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