Total synthesis and NMR investigations of cylindramide

Article abstract of DOI:10.1002/chem.200501274

Cylindramide (1) was built up from three components: a hydroxyornithine derivative 7, a tetrazolylsulfone 8, and a substituted pentalene subunit 9. Derivative 7 was prepared in a six-step reaction sequence involving the Wittig reaction and a Sharpless asy

Full text of DOI:10.1002/chem.200501274

DOI: 10.1002/chem.200501274
Total Synthesis and NMR Investigations of Cylindramide
Nicolai Cramer,[a] Maria Buchweitz,[a] Sabine Laschat,*[a] Wolfgang Frey,[a]
Angelika Baro,[a] Daniel Mathieu,[b] Christian Richter,[b] and Harald Schwalbe[b]
Dedicated to Professor Gerhard Erker on the occasion of his 60th birthday
Abstract: Cylindramide (1) was built
up from three components: a hydroxy-
ornithine derivative 7, a tetrazolylsul-
fone 8, and a substituted pentalene
subunit 9. Derivative 7 was prepared in
a six-step reaction sequence involving
the Wittig reaction and a Sharpless
asymmetric dihydroxylation starting
from N-Boc-3-aminopropanal (12). Tet-
razolylsulfone 8 was accessible in four
steps from dioxinone 22. The synthesis
of the pentalene fragment 9 started
from cycloocta-1,5-diene 26, that was
converted into enantiopure bicyclo-
[3.3.0]octanedione 29. The latter was
functionalized to give derivative 9. The
total synthesis was accomplished by in-
tions, macrocyclization, and subsequent
Lacey–Dieckmann condensation to
form the tetramic acid unit. As indicat-
1
ed by extensive H and 13C NMR spec-
ꢀ
ducing C C bond formation by Sono-
troscopic investigations (DQF-COSY,
ROESY spectra), the stereochemistry
of synthetic cylindramide (1) corre-
sponds with that of the naturally occur-
ring product. ROE data were used for
molecular modeling of the lowest-
energy structures for cylindramide.
gashira coupling of derivatives 9 and 7
followed by olefination with tetrazolyl-
sulfone 8 under Julia–Kocienski condi-
Keywords: lactams · macrocycles ·
NMR spectroscopy · tetramic acid ·
total synthesis
Introduction
duced by a Streptomyces species of a japanese marine mol-
lusc,[5,6] maltophilin (5) from Stenotrophomonas maltophil-
ia,[7,8] and geodin A magnesium salt (2) that was recently
isolated from the southern australian marine sponge Geodia
(Scheme 1).[9]
Characteristic structural features of these compounds are
the substituted bicyclo[3.3.0]octane unit and the tetramic
acid moiety. Despite the cytotoxic, antibiotic, and fungicidal
activities of compounds 1–6,[2–9] the chemistry remains unex-
plored, and only a model study[10] as well as two total syn-
theses of the structurally related ikarugamycin[11,12] have
been published so far. This prompted us to investigate the
tetramic acid lactams in more detail. Our efforts recently re-
sulted in the enantioselective total synthesis of cylindramide
1 (Scheme 2).[13]
Marine organisms have been found to be a rich source of
many natural products with pharmacological relevance.[1]
During such bioprospecting cylindramide (1) was isolated in
1993 by Fusetani and co-workers from the Okinawan
sponge Halichondria cylindrata.[2]
Cylindramide belongs to the class of complex tetramic
acid lactams and displays prominent cytotoxicity against
human B16 melanoma cells.[2] Other members of this class
are discodermide (6) from the Caribbean marine sponge
Discodermia dissoluta,[3] alteramide A (3) from the bacteri-
um Alteromonas sp., an endosymbiotic species of the
sponge Halichondria okadai,[4] aburatubolactam A (4) pro-
The key steps are a Sonogashira coupling of the hydroxy-
ornithine moiety 7, a Julia–Kocienski olefination of the N-
phenyl-tetrazolylsulfone 8, and a Lacey–Dieckmann cycliza-
tion. The highly functionalized pentalene system 9 was ob-
tained from pentalenone 10 through a tandem Michael-addi-
tion/electrophilic-trapping reaction. At the start of our ex-
periments the stereoselective formation of the bicyclo-
[3.3.0]octane unit and the macrolactamization were consid-
ered as the most critical steps, and thus, several strategies
were evaluated. The results of these studies and the total
[a] Dr. N. Cramer, Dipl.-Chem. M. Buchweitz, Prof. Dr. S. Laschat,
Dr. W. Frey, Dr. A. Baro
Institut für Organische Chemie der Universität Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax: (+49)711-685-4285
E-mail: sabine.laschat@oc.uni-stuttgart.de
[b] D. Mathieu, Dr. C. Richter, Prof. Dr. H. Schwalbe
Institut für Organische Chemie und Chemische Biologie
Zentrum für Biomolekulare Magnetische Resonanz
Johann Wolfgang Goethe-Universität Frankfurt
Marie-Curie-Strasse 11, 60439 Frankfurt/Main (Germany)
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FULL PAPER
Scheme 3. Preparation of the hydroxyornithine subunit 7. a) AD-mix-a,
tBuOH, H2O, MeSO2NH2, 08C, 18 h; b) SOCl2, pyridine, CH2Cl2, 08C,
30 min; c) NaN3, DMF, 508C, 16 h; d) NsCl, NEt3, CH2Cl2, 48C, 12 h;
Scheme 1. Cylindramide (1) and related structures of compounds 2–6
from the class of tetramic acid lactams.
e) 1. TBSCl, DMAP, DMF, RT, 24 h; 2. TFA, CHCl2, 08C, 2 h.
2
was further subjected to Sharpless asymmetric dihydroxyla-
tion[14] giving diol 15 in 95% yield and 96% ee. Conversion
to the a-azido ester 16 was achieved through formation of
the cyclic sulfite intermediate 14 and treatment with NaN3
in DMF[15] in 38% yield over two steps.
The deactivation of the b-hydroxy group in diol 15 by an
intramolecular hydrogen bond[16] leading to regioselective
nosylation of the a-hydroxy function was more effective.
Subsequent treatment of nosylate 17 with NaN3 in DMF
yielded a-azido ester 16 in 98% with a diastereomeric ratio
96:4. After silylation of the remaining hydroxy group with
tert-butyldimethylsilylchloride (TBSCl), the diastereomers
could be separated by chromatography. Final deprotection
of the amino group with trifluoroacetic acid in dichlorome-
thane gave derivative 18 quantitatively after removal of all
volatile materials by azeotropic distillation with benzene.
However, considerable experimentation was required to
couple derivative 18 with 3-iodoacrylic acid 19[17] (Table 1).
Under classical coupling conditions with 1-[3-(dimethyl-
amino) propyl]-3-ethylcarbodiimide hydrochloride (EDC)
and 1-hydroxybenzotriazole (HOBt)[18] or with mesitylsulfo-
chloride as the coupling agent only lactam 20[19] could be
Scheme 2. Retrosynthetic pathway of cylindramide 1.
synthesis are reported below. During our initial investiga-
tions the NMR spectra of the target compound 1 turned out
to be surprisingly complex.[13] In order to understand the ob-
served phenomena in more detail, the behavior of com-
pound 1 was thoroughly investigated by NMR spectroscopy
and the results are also discussed.
Table 1. Coupling of hydroxyornithine derivative 18 to fragment 7.
Conditions
20 Yield
7 Yield
(%)
(%)
19 EDC, HOBt, THF, RT, 3 h
19 NEt3, mesitylsulfochloride, CH2Cl2, RT, 5 h
3-iodoacrylic acid chloride, DMAP, pyridine,
CH2Cl2, RT, 3 h
CH2Cl2, NEt3, RT, 10 min
19 DEPC, DMF, NEt3, 08C, 18 h
19 FDPP, DMF, iPr2NEt, RT, 3 h
75
>70
>70
–
–
5
Results and Discussion
Formation of the hydroxyornithine subunit 7: The synthesis
strategy for compound 7 is outlined in Scheme 3. N-Boc-3-
aminopropanal (12) was converted to the a,b-unsaturated
ester 13 in 87% yield by using a Wittig reaction. Ester 13
99
–
–
–
83
81
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S. Laschat et al.
isolated (Table 1). When 3-iodoacrylic acid chloride was em-
ployed, lactam 20 was obtained as the major product
(>70%) together with 5% of the desired acyclic target
compound 7. Neutralization of derivative 18 with NEt3 in di-
chloromethane caused complete aminolysis to lactam 20
within 10 min. By using diethyl cyanophosphonate (DEPC)
and pentafluorophenyl diphenylphosphinate (FDPP)[20,21] we
were finally able to overcome this problem. Both reagents
completely suppressed the lactam formation and the amide
7 could be isolated in 83 and 81% yield, respectively.
Formation of the bicyclo[3.3.0]octane precursor 11: The syn-
thesis approach to pentalene derivative 11 starting from
commercially available cycloocta-1,5-diene (26) analogous
to a literature procedure is depicted in Scheme 5. Diene 26
Formation of the tetrazolylsulfone 8: As shown in Scheme 4,
deprotonation of dioxinone 22 with lithium diisopropyl-
amide (LDA) followed by allylation and ozonolysis in
Scheme 5. Preparation of enantiomerically pure dienedione (3aR,6aR)-
11.
Scheme 4. Preparation of subunit 8. a) 1. LDA, DMPU, THF, 22, 08C,
1 h, 23, ꢀ408C!RT, 16 h, 50 %; 2. O3, MeOH/CH2Cl2/pyridine 4:4:1,
ꢀ788C, NaBH4, 64%; b) PPh3, DEAD, THF, 08C, 1 h; c) (NH4)6Mo7O24,
H2O2, EtOH, 08C!RT, 3 h.
undergoes a transannular Pd-catalyzed ring-closure with
Pb(OAc)4 in HOAc.[25] Removal of the acetyl groups[26] and
subsequent enzymatic resolution with lipase Amano PS and
vinyl acetate in methyl tert-butyl ether[26,27] gave the diol
(1S,3aR,4S,6aR)-28 in 44% yield and both the correspond-
ing monoacetate (8% yield) and the (1R,3aS,4R,6aS)-config-
ured diacetate (38%), that could be separated by chroma-
tography. Diol (1S,3aR,4S,6aR)-28 was converted into enan-
tiopure bicyclo[3.3.0]octanedione (3aR,6aR)-29[28] by Swern
oxidation[29] with DMSO, (COCl)2. This route allowed the
preparation of dione 29 on a 50 g-scale that was purified by
distillation.
Next, we attempted to convert diketone 29 directly into
the dienedione 11.[30] For example, treatment of 29 with po-
tassium hexamethyldisilazane (KHMDS) and phenylselenyl-
bromide followed by H2O2 oxidation[31] gave 30% of an in-
separable 1:1:1 mixture of starting material 29, dienedione
11, and the corresponding bicyclo[3.3.0]oct-3-ene-2,6-dione.
Enol ether formation with trimethylsilyl triflate (TMSOTf),
NEt3,[32] and Saegusa oxidation with Pd(OAc)2/benzoqui-
none[33] resulted in a complex mixture containing 41% of
derivative 11, whereas a modified procedure[34] gave no
trace of the target compound 11. Direct oxidation with
HIO3 in DMSO[35] or 2-iodoxybenzoic acid (IBX) in
DMSO[35] gave 35–40% of a mixture of enedione and diene-
dione 11. Further procedures[36,37] again gave only mixtures
of starting material 29, enedione, and dienedione 11, or
poor yields.
MeOH/CH2Cl2/pyridine with reductive workup yielded alco-
hol 24 in 32% total yield over two steps. Treatment of alco-
hol 24 with phenyltetrazolylsulfide under Mitsunobu condi-
tions[22] gave derivative 25 in 72% yield. The latter was oxi-
dized in the presence of catalytic amounts of ammonium
[23]
molybdate and aqueous H2O2
to afford the desired N-
phenyltetrazolylsulfone 8 in 93% yield. Recrystallization of
8 from MeOH gave single crystals suitable for X-ray crystal-
lographic analysis (Figure 1).[24]
Figure 1. ORTEP view of N-phenyltetrazolylsulfone 8.
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Cylindramide Total Synthesis
FULL PAPER
Due to the failure of the direct oxidation, an alternative
approach to obtain enantiomerically pure diketone
(3aR,6aR)-11 was carried out by using the modified Farnum
route (Scheme 5).[30] Bromoacetalization[38] of (3aR,6aR)-29
to dibromo derivative 30 (84% yield) was achieved with
Functionalization of the bicyclo[3.3.0]octane moiety: De-
spite the apparently straightforward manipulation, diene-
dione (3aR,6aR)-11 did not provide a suitable synthesis
route (Scheme 6). Neither direct 1,4-addition of cuprates to
give b-methylketone 32 nor the tandem Michael-addition/
electrophilic-trapping reaction to afford derivative 33 were
successful. Only polymerization of derivative (3aR,6aR)-
11[39] or quantitative recovery of the starting material was
observed. In an effort to avoid these problems, dienedione
11 was converted to the tartrate-derived monoacetal 34 in
only 30% yield along with 66% of recovered starting mate-
rial 11. Any attempt to improve the conversion of the start-
ing material failed. Monoacetal 34 underwent the Lewis
acid catalyzed tandem Michael-addition/electrophilic-trap-
ping reaction to result in the functionalized ketone 35a
(X = O). Sc(OTf)3 effectively catalyzed the Michael reac-
tion of the silyl ketene acetal and monoacetal 34. The inter-
mediate silyl enol ether was treated with formaldehyde di-
benzylacetal (BnO)2CH2 in the presence of triflate TMSOTf
and 2,6-di-tert-butylpyridine to give the ketone 35a building
block.[40] Unfortunately, removal of the ketone group by
Mozingo desulfurization[41] and by reduction of the tosylhy-
drazone,[42] respectively, failed. Under the conditions of thio-
acetalization only decomposition was observed, whereas
ketone 35a did not react to produce the tosylhydrazone
even at higher temperature. Also reduction and subsequent
Barton–McCombie deoxygenation[43] did not give the de-
sired product 35b (X = H2).
ꢀ
PhN+Me3Br3 instead of pyridinium tribromide and ethyl-
ene glycol. Base-induced elimination of the bromo-substitu-
ents occurred to give dienediacetal 31 in 99% yield, and
subsequent cleavage of the acetal groups with pyridinium p-
toluenesulfate (PPTS) resulted in enantiopure dienedione
(3aR,6aR)-11 (83% yield over two steps). Recrystallization
of both enantiopure dibromide 30 and dienedione 11 gave
single crystals which were suitable for X-ray crystal-struc-
ture analysis, confirming the absolute configuration of deriv-
ative (3aR,6aR)-11 (Figures 2 and 3).[24]
Figure 2. ORTEP view of dibromo acetal 30 derived from enantiopure
(3aR,6aR)-29.
Scheme 6. Attempted functionalization of dienedione (+)-11. a) (R,R)-di-
methyl tartrate, BF3·OEt2, CH2Cl2, 08C!RT, 2 d; b) Sc(OTf)3, CH2Cl2,
ꢀ788C, then (BnO)2CH2, TMSOTf, 2,6-di-tert-butylpyridine, CH2Cl2,
ꢀ788C!RT.
The sluggish reactivity of compound 11 towards acetal for-
mation might be due to orbital repulsion in the preceding
tetrahedral intermediate A between the p-orbitals of the
convex pentalene system and the lone pairs of the OBF3
group (Scheme 7). A possible reason for the failure of the
Barton–McCombie deoxygenation might be the intermedi-
ate carbon radical B. Instead of hydrogen abstraction it
might undergo a 3-exo-trig cyclization to the cyclopropyl-
methyl radical C. According to the Baldwin rules[44] this cyc-
Figure 3. ORTEP view of enantiomerically pure dienedione (3aR,6aR)-
11.
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S. Laschat et al.
ketone 37 in 85% yield by reaction with aqueous HCl in
THF. Ketone 37 was oxidized to the corresponding enone
38 according to Nicolaouꢁs procedure[36] by using IBX for
the oxidation of the intermediate silyl enol ether generated
from ketone 37 with LDA and trimethylsilyl chloride
(TMSCl). The 1,4-addition of Me2CuLi followed by trapping
of the intermediate lithium enolate with Cominsꢁ reagent[45]
yielded 47% of the desired triflate 40 together with 39% of
ketone 41. The latter was converted to 40 (72% yield) by re-
peated deprotonation and quenching with Cominsꢁ reagent.
Due to the butterfly-shaped pentalene the attack from the
convex side is favored, resulting exclusively in diastereomer
40. Pd-catalyzed reduction of the triflate moiety with
Et3SiH[46] afforded pentalene 42 in 90% yield. Removal of
the acetal group[47] and subsequent Nicolaou oxidation gave
enone 10 in 87% yield.
Product 10 was treated with TMS-protected propynyl cup-
rate followed by orthoformate in the presence of BF3·OEt2
to give ketone 43 in 63% yield. The carbonyl group in
ketone 43 was removed following the Barton–McCombie[43]
procedure. After reduction with NaBH4, the alcohol 44 was
isolated as a 1:1 mixture of diastereoisomers, that was sub-
jected to Barton deoxygenation using a five-fold excess of
thiocarbonyldiimidazole at 808C to afford the pentalene de-
rivative 45 in 57% yield over both steps. Desilylation of de-
rivative 45 with K2CO3 in MeOH finally gave the desired
fragment 9 in 99% yield.
Scheme 7. Hypothesis for the low reactivity of compound 11 towards
acetal formation and for the failure of Barton–McCombie deoxygena-
tion.
lization is allowed and the butterfly-shape of the pentalene
system provides some steric preorganization.
Owing to these difficulties we had to change our synthesis
strategy as outlined in Scheme 8. Diketone (3aR,6aR)-29
was treated with ethylene glycol (1.2 equiv) in the presence
of toluenesulfonic acid to give a mixture of mono- (37)
(80%) and diacetal 36 (13%), that could be converted into
Elaboration of the couplingand macrocyclization condi-
tions: Next, we followed our synthesis route to prepare the
macrocycle in order to complete the synthesis of cylindra-
mide 1 (Scheme 9). The reaction sequence started with a So-
nogashira coupling[48] of the pentalene fragment 9 with the
freshly prepared hydroxyornithine unit 7 to give the corre-
sponding enyne 46 in 91% yield. After hydrolysis of the di-
methyl acetal group with PPTS[47] and subsequent Julia–Ko-
cienski olefination[49] of intermediate aldehyde 47 with tetra-
zolylsulfone 8 (3 equiv) in the presence of NaHMDS, the E-
configured product 48 was isolated exclusively in 53% yield
over both steps. Further isomers such as the corresponding
cis-olefin or products epimerized in the a-position could not
be detected. Staudinger reduction of the azide group with
[50]
PPh3 led to the free amine intermediate, which cyclized to
lactam 49 in 82% yield over two steps under dilution (2.5”
10ꢀ4 m) and heating the dilute solution at reflux. Under
these conditions the trimethyldioxinone function underwent
a retro Diels–Alder reaction to form an acylketene, that was
trapped by the free amino group under cyclization. The Lin-
dlar reduction[51] of the enyne 49 giving the corresponding
Z,E-diene 51, after deprotection of the TBS ether 50, turned
out to be difficult. The amount of catalyst and the reaction
times had to be carefully monitored, and incomplete conver-
sion was essential, otherwise considerable overreduction was
observed. Overreduction could be suppressed by using the
smallest amount possible of the catalyst Pd/BaSO4 that must
be activated by hydrogen saturation prior to addition of sub-
strate, and the Z,E-diene 50 was isolated in 80% yield at
Scheme 8. Synthesis of the functionalized pentalene fragment 9. a) 1n
HCl, THF, RT, 30 min, 85% (37); b) LDA, THF, TMSCl, ꢀ78!ꢀ208C,
4-methoxypyridin-N-oxide (MPO), IBX, DMSO, CH2Cl2, RT, 45 min;
c) Me2CuLi, THF, then 39, ꢀ78!08C; d) 1. PPTS, acetone, H2O, reflux,
3 h, quant, 2. LDA, THF, TMSCl, ꢀ788C!ꢀ208C, then MPO, IBX,
ꢁ
DMSO, CH2Cl2, RT, 30 min; e) TMS-C CCH3, tBuLi, TMEDA, THF,
ꢀ788C, 1 h, CuI, THF, ꢀ78!08C; 10, TMSCl, ꢀ40!ꢀ158C, 2 h, then
BF3·OEt2, HC(OMe)3, CH2Cl2, ꢀ208C, 1 h; f) NaBH4, MeOH, 08C;
g) 1. (Im)2CS (5 equiv), DMAP (5 equiv), DCE, 808C, 18 h; 2. Bu3SnH,
AIBN, toluene, 1108C, 45 min; h) K2CO3, MeOH, RT, 20 h.
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Cylindramide Total Synthesis
FULL PAPER
The proposed stereochemis-
try is supported by the semi-
quantitative analysis of cross-
peak intensities in the ROESY
and COSY experiments. Fig-
ure 4e and f show selected re-
gions in the {1H}1H ROESY
spectrum. The indicated peaks
are in agreement with the rela-
tive stereochemistry of the ring
atoms C13, C14, C18, and C20.
3
The J(H,H) coupling constants
of protons H8–H11, H21, and
H22
extracted
from
IP-
COSY[53] data support the de-
picted stereochemistry of the
double bonds (3J(H8,H9)=
16.8 Hz,
10.5 Hz,
7.8 Hz,
E;
E;
Z;
3J(H9,H10)=
3J(H10,H11)=
3J(H21,H22)=
15 Hz). A qualitative analysis
of the cross-peak intensity due
to scalar couplings in the
{1H}1H COSY allowed a predic-
tion of the relative configura-
tion of the stereochemistry of
Scheme 9. Coupling of the fragments 9, 7, and 8, and final macrocyclization. a) 7, [Pd(PPh3)4], CuI, NEt3, THF,
RT, 1 h; b) 1. PPTS, acetone, H2O, reflux, 3 h, 2. NaHMDS, DME, ꢀ558C, 1 h, then 8 (3 equiv), ꢀ558C!RT,
18 h; c) 1. PPh3, THF, H2O, RT, 24 h, 2. toluene, 2.5”10ꢀ4 m, reflux, 7 h; d) H2, Pd/BaSO4, quinoline, MeOH,
51% conversion (based on recovered starting material); e) HF/MeCN, RT, 2 h.
51% conversion (based on recovered 49). Subsequent desi-
lylation with HFgave macrolactam 51 in 96% yield. Thus,
the overall yield starting from enyne 48 was 63%. Lacey–
Dieckmann cyclization[52] of macrolactam 51 finally gave cy-
lindramide 1 in 79% yield as an epimeric mixture 1/2-epi-1
53%:26%, that could be separated by reversed-phase chro-
matography on an RP18 phase. This isomeric ratio was ob-
served independently of reaction time, amount of NaOMe,
and conversion, thus reflecting the thermodynamic equilibri-
um in favor of the natural isomer 1.
the bicyclo[3.3.0]octane unit. In addition, we can differenti-
ate between the diastereotopic protons at the C19 center.
Proton H18 shows a stronger cross-peak signal to the trans
H19b than to the cis H19a proton, and H19b gives a more
intense cross-peak signal to proton H20. The cross-peak sig-
nals H20/H13 and H13/H14 also strongly support a trans
configuration between protons H20 and H13. Table 2 sum-
marizes all NMR data extracted from the recorded spectra.
The expected configuration derived from the analysis of
the COSY spectra is in good agreement with the intensities
in the {1H}1H ROESY spectrum (Figures 4e and f). Only
proton H19b in a trans configuration to proton H18 shows
ROE peaks to the protons H13, H21, and H22. A strong
ROE peak is also observed for H14 to the protons H12a,
H12b, and H11. The relative configuration around the ste-
reogenic centers C2 and C3 cannot be determined from the
NMR data because of the overlap of H3 and H2 protons
and a missing correlation from proton H2 in the NOESY
and HMBC spectra.
NMR studies of cylindramide: The current analysis was per-
formed in MeOD and builds on a previous NMR investiga-
tion of cylindramide in MeOD/CDCl3 1:1 by Kanazawa and
co-workers.[2] For the chemical shift assignment, the protons
from the high-field-shifted methyl group H17Me (d=
0.96 ppm, referenced relative to MeOH) could be easily
identified by peak integration of the proton one-dimensional
spectrum. The spin system could be identified by continuous
correlation peaks from protons H7–H24 as shown in the
{1H}1H DQF-COSY spectrum in Figure 4c and d. The
second spin system, from protons H2–H5, is also visible in
the DQF-COSY spectrum.
The proton chemical shifts of H2 and H3 are not resolved
even at 900 MHz, but can be separated in the heteronuclear
correlation experiment ({1H}13C HSQC, Figure 4b). The
chemical shift assignment for most of the carbon resonances
could be achieved in a straightforward manner since most of
proton chemical shifts are resolved. The quaternary carbons
C1, C7, C25, C26, and C27 could be assigned by long-range
correlation in the {1H}13C HMBC experiments.
To further support the stereospecific assignment of the
stereogenic centers, long-range C–H coupling constants
were also interpreted. Long-range J(C,H) coupling constants
were obtained from quantitative analysis of the cross-peak
signals in the {1H}13C HMBC spectra compared with the
1J(C,H) coupling constants determined in coupled {1H}13C
HSQC experiments[54] (2J(C1,H2)=4.0; 3J(C27,H2)=2.4;
3J(C4,H2)=3.1;
2J(C8,H9)=8.9;
3J(C5,H3)=3.3;
2J(C10,H9)=8.9;
3J(C7,H9)=9.5;
2J(C15,H14)=8.3;
3J(C16,H14)=8.3 Hz).
Distances derived from ROE data were used as experi-
mental restraints for an initial structure calculation (given in
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S. Laschat et al.
Figure 4. a) Constitution and configuration of cylindramide. b) Aliphatic region of the {1H}13C HSQC spectrum obtained at 600 MHz. The signals from
cylindramide are assigned and the signals due to impurities are indicated with a star. c) and d) show two regions in the {1H}1H DQF-COSY spectrum.
The connectivity walk is indicated by lines. e) and f) show selected regions in the {1H}1H ROESY spectrum recorded at 600 MHz from cylindramide by
using a mixing time of 400 ms.
Table 2). Figure 5 shows two lowest-energy structures from
two different structure calculations of cylindramide.[55] Both
structures differ mainly in the orientation of the amide
bond. The amide proton could not be observed due to fast
exchange with the solvent. In addition, the five-membered
lactam ring has a slightly different orientation in the struc-
tures. The proton-rich region around the bicyclo-
[3.3.0]octane unit occurs in both structures in good agree-
ment. While a structure refinement will be performed in the
future using residual dipolar couplings, we can at this point
2494
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem.Eur.J. 2006, 12, 2488 – 2503

Cylindramide Total Synthesis
FULL PAPER
Table 2. NMR data of cylindramide (1) in MeOD (previous investigations by Fusetani and co-workers[2] used
MeOD/CDCl3 1:1 as solvent).
acid moiety. Further investiga-
tions as to how the conforma-
tion might effect biological
properties are currently being
performed.
Group
d
13C [ppm] d 1H [ppm] COSY correlations HMBC correlations
ROESY correlations
1
2
3
4a
4b
5a
5b
6
194.1
69.3
69.9
31.0
–
–
–
–
–
–
3.96
3.97
1.51
1.36
3.48
2.89
–
1, 4, 27
5
5
–
4a, 4b
4a, 5b
3, 4b, 5a
4a, 5a, 5b
4b, 5b, 8
3, 4a, 4b
–
3, 4b, 5a, 5b
3, 4a, 5a, 5b
4a, 4b, 5b
4a, 4b, 5a
–
36.8
3
Experimental Section
3, 4, 7
–
–
7
8
9
168.5
123.8
136.7
128.7
136.4
28.2
–
–
9
–
–
General methods: Column chromatog-
raphy was carried out on silica gel 60
(grain size 0.04–0.063 mm, Fluka) with
hexanes (PE, b.p. 40–608C) and ethyl
acetate (EtOAc) as eluents. HPLC
was performed by using a Nucleosil C-
18 AB column (250”21 mm, grain size
7 mm) (Macherey–Nagel); MPLC was
performed on Nucleosil 1525 CN
(grain size 10–15 mm) (Macherey–
Nagel). 1H and 13C NMR spectra were
5.88
7.41
6.20
5.93
2.63
2.24
1.32
3.03
5.64
5.46
2.37
0.96
2.09
1.97
1.05
2.01
5.21
5.24
2.20
2.05
3.05
2.18
–
7, 10
7, 8, 10
8, 9, 12
9, 12, 13
10, 11, 13, 14
9, 10, 13, 20
–
5b, 9, 10
8, 10, 12a
9, 11
8, 10, 12a, 12b, 14, 10, 20
9, 11, 12b, 13, 14
11, 12a, 13, 14, 15
12a, 12b, 15, 19b
11, 12a, 15, 16, 18
8, 10
9, 11
10
11
12a
12b
13
14
15
16
17
17Me
18
19a
19b
20
21
22
23a
23b
24a
24b
25
26
27
10, 12a, 12b
11, 13, 12b
11, 13, 12a
12a, 12b, 14, 20
13, 15, 17, 18
14, 16, 17
15, 17
52.6
54.3
132.9
135.2
48.0
21.8
50.1
40.9
12, 13, 15, 16, 18, 19
14, 15, 16, 17, 17Me, 18 12b, 13, 14, 16, 17
14, 15, 17, 17Me, 18
15, 16, 17Me, 19
16, 17, 18
12, 15, 16, 17Me
13, 14, 20
17, 18, 20
13, 14, 21
13, 19, 20, 23
20, 23
14, 15, 17, 17Me
15, 16, 17Me, 18, 19a, 19b
16, 17
14, 17
17, 19b
13, 17, 19a, 20, 21, 22
11, 19b, 21, 22
19b, 20, 22
19b, 20, 21, 23a, 23b
22, 23b, 24a, 24b
22, 23a, 24a, 24b
23a, 23b, 24b
23a, 23b, 24a
–
14, 16, 17Me, 18
17
14, 17, 19a, 19b
17, 18, 19b, 20
17, 18, 19a, 20
13, 19a, 19b, 21
20, 22
21, 23a, 23b
22, 23b, 24b
22, 23a, 24a
23b
recorded on
a
Bruker AC250
(250 MHz and 62.5 MHz, respective-
ly), a Bruker ARX300 (300 MHz and
75 MHz, respectively),
a
Bruker
ARX500 (500 MHz and 125 MHz, re-
spectively), and a Bruker Avance900
(900 MHz and 225 MHz, respectively)
spectrometer. 13C NMR multiplicities
were determined with DEPT experi-
ments. FTIR spectra were recorded on
49.5
133.8
131.6
31.1
25, 22
25, 22
21, 23, 26
25, 26
–
34.9
a
Bruker Vektor22 spectrometer.
24a
–
–
–
Mass spectra were measured on a Fin-
nigan MAT95 (CH4, chemical ioniza-
190.0
101.0
177.0
–
–
–
–
–
–
tion) and
a Varian MAT711 (EI,
70 eV). Optical rotations were mea-
sured on a Perkin–Elmer Polarimeter
241.
Compounds 12,[59] 19,[17] (S,S)-28,[25–27]
[(1-ethoxyvinyl)oxy]trimethylsilane,[60]
conclude that the stereochemistry also fulfils all the experi-
mental restraints.
IBX,[61] and MPO = 4-methoxypyridin-N-oxide[62] were prepared accord-
ing to literature procedures.
Methyl (2E)-5-[(tert-butoxycarbonyl)amino]pent-2-enoate (13): Methyl
triphenylphosphoranylacetate (25.0 g, 74.0 mmol) was added to a solution
of freshly prepared compound 12 (12.3 g, 71.2 mmol) in CH2Cl2 (230 mL)
at 08C and the reaction mixture was stirred for 4 h at 08C, and for a fur-
ther 16 h at RT. The solvent was removed under vacuum, the residue
taken up in cold Et2O, and crystalline triphenylphosphine oxide was sepa-
rated. The residue was purified by chromatography (Rf =0.38, PE/EtOAc
4:1) to give compound 13 (14.17 g, 87%, 98% GC purity) as a viscous
colorless oil. The spectroscopic data corresponded with those in the liter-
ature.[59]
Conclusion
A highly convergent approach to the cytotoxic tetramic acid
lactam cylindramide (1) has been developed and the overall
yield from our previous total synthesis could be improved
from 1.0 to 2.1% (starting from ketone 37). In addition, the
C2-symmetric bicyclo[3.3.0]octa-3,7-diene-2,6-dione 11 was
prepared on a gram-quantity scale in an enantiomerically
pure form. Although compound 11 seemed to be an attrac-
tive building block for further functionalization towards cy-
lindramide and related natural products, the high tendency
to undergo polymerization and sluggish reactivity with cup-
rates or other nucleophiles prevented its further use in syn-
thesis.
Detailed NMR investigations proved the structural identi-
ty of the synthesized compound 1 to be comparable to that
of the natural product isolated by Fusetani. ROESY data
were consistent with two lowest-energy conformations that
differ in the orientations of the amide bond and the tetramic
Methyl (2R,3S)-5-[(tert-butoxycarbonyl)amino]-2,3-dihydroxypentanoate
(15): Compound 13 (3.20 g, 14.0 mmol) was added to an ice-cold solution
of AD-mix-a (19.8 g) and methanesulfonamide (1.4 g, 14 mmol) in
tBuOH/H2O 1:1 (140 mL) and the biphasic mixture was stirred for 24 h.
Then Na2SO3 (21 g, 170 mmol) was added and, after stirring for 30 min,
the organic layer was separated. The aqueous layer was extracted with
EtOAc (4”70 mL). The combined organic layers were washed with
brine, dried (MgSO4), and concentrated. The residue was taken up in
some cold Et2O and solid methanesulfonamide was separated to give
compound 15 (3.58 g, 96% ee, 95%, 94% purity as indicated by NMR
spectroscopy) as a colorless resin that was used without further purifica-
tion. Rf =0.20 (PE/EtOAc 1:1); [a]2D0 =ꢀ15.8 (c=1.00 in CHCl3);
1H NMR (500 MHz, CDCl3): d=1.41 (s, 9H; (CH3)3C), 1.63–1.73 (m,
1H; H4), 1.77–1.87 (m, 1H; H4), 3.16–3.25 (m, 1H; H5), 3.30–3.45 (m,
1H; H5), 3.62 (br, 1H; NH), 3.79 (s, 3H; CO2Me), 3.95 (d, J=9.7 Hz,
Chem.Eur.J. 2006, 12, 2488 – 2503
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2495

S. Laschat et al.
analysis calcd (%) for C17H24N2O10S: C 45.53, H 5.39, N 6.25, S 7.15;
found: C 45.60, H 5.42, N 6.22, S 7.19.
Methyl (2S,3S)-5-ammonium-2-azido-3-(tert-butyldimethylsilyloxy)penta-
noate trifluoroacetate (18): a) Powdered sodium azide (16.3 g, 251 mmol)
was added to a solution of compound 17 (16.7 g, 37.2 mmol) in DMF
(420 mL) and the suspension stirred for 16 h at 508C. The solvent was re-
moved under high vacuum and the residue taken up in H2O (150 mL)
and EtOAc (400 mL). The organic layer was dried (MgSO4) and concen-
trated. The pale-yellow resinous methyl (2S,3S)-2-azido-5-[(tert-butoxy-
carbonyl)amino]-3-hydroxypentanoate (16) (95% NMR purity) was used
without further purification. [a]2D0 =ꢀ26.7 (c=1.00 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.42 (s, 9H; (CH3)3C), 1.62–1.72 (m, 2H; H4),
3.10–3.20 (m, 1H; H5), 3.39–3.55 (m, 1H; H5), 3.80 (s, 3H; CO2Me),
3.95–4.01 (m, 2H; H2, H3), 4.11 (br, 1H; OH), 4.90 ppm (br, 1H; NH);
13C NMR (125 MHz, CDCl3): d=28.2 ((CH3)3C), 33.5 (C4), 36.7 (C5),
52.6 (CO2Me), 66.1 (C2), 69.1 (C3), 79.9 ((CH3)3C), 157.2 (NCO2),
169.2 ppm (CO2Me); FTIR (ATR): n˜ =3388 (s), 2978 (m), 2110 (vs), 1744
(s), 1685 (vs), 1518 (s), 1367 (s), 1438 (m), 1364 cmꢀ1 (s); MS (DCI,
NH3): m/z (%): 594 (25) [2M+NH4]+, 577 (30) [2M+H]+, 306 (85)
[M+NH4]+, 289 (100) [M+H]+, 250 (75), 233 (25), 189 (15), 135 (15);
HRMS (DCI): calcd for C11H21N4O5: 289.1506; found: 289.1499 [M+H]+.
b) A solution of compound 16 (see above), TBSCl (9.00 g, 58.6 mmol),
imidazole (8.20 g, 120 mmol), and DMAP (300 mg, 2.40 mmol) in dry
DMF(24 mL) was stirred for 1 d at RT. After addition of H 2O (50 mL)
and EtOAc (100 mL), the layers were separated and the organic layer
was washed with brine, dried by using MgSO4, and concentrated. The res-
idue was purified by chromatography (PE/EtOAc 3:1) to give methyl
(2S,3S)-2-azido-5-[(tert-butoxycarbonyl)amino]-3-(tert-butyldimethylsiloxy)-
pentanoate (14.85 g, 99% over two steps, >95% NMR purity) as a pale
yellow oil. Rf =0.33 (PE/Et2O 6:1); [a]2D0 =+2.3 (c=1.00 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.11 (s, 3H; Me2Si), 0.12 (s, 3H; Me2Si),
0.90 (s, 9H; (CH3)3CSi), 1.44 (s, 9H; (CH3)3C), 1.62–1.76 (m, 1H; H4),
1.87 (ddt, J=13.6, 7.7, 7.6 Hz, 1H; H4), 3.21 (dd, J=12.6, 6.4 Hz, 2H;
H5), 3.79 (s, 3H; CO2Me), 4.09 (d, J=4.8 Hz, 1H; H2), 4.18 (dt, J=6.9,
4.4 Hz, 1H; H3), 4.69 ppm (br, 1H; NH); 13C NMR (125 MHz, CDCl3):
d=ꢀ4.7 (Me2Si), ꢀ4.6 (Me2Si), 17.8 (Me3CSi), 25.6 (Me3CSi), 28.3
((CH3)3C), 32.8 (C4), 36.9 (C5), 52.6 (CO2Me), 66.5 (C2), 71.5 (C3), 79.1
((CH3)3C), 155.7 (NCO2), 168.5 ppm (C1); FTIR (ATR): n˜ =3368 (m),
2955 (m), 2931 (m), 2888 (m), 2858 (m), 2108 (vs), 1744 (s), 1702 (vs),
1473 (s), 1463 (m), 1437 (m), 1391 (m), 1365 cmꢀ1 (s); MS (CI, NH3): m/z
(%): 420 (6) [M+NH4]+, 403 (28) [M+H]+, 347 (16), 303 (24), 289 (100)
[M+HꢀTBS]+, 232 (30), 200 (28), 171 (30), 73 (25), 57 (23); HRMS
(DCI): calcd for C17H35N4O5Si: 403.2371; found: 403.2370 [M+H]+.
Figure 5. Lowest-energy structures for two different structure calculations
of cylindramide (1). The rmsd (root-mean-square deviation) value of
each run was 0.2 Š.
1H; H3), 4.08 (d, J=1.9 Hz, 1H; H2), 4.95 (br, 1H; OH), 5.24 ppm (br,
1H; OH); 13C NMR (125 MHz, CDCl3): d=28.3 ((CH3)3C), 33.9 (C4),
37.1 (C5), 52.6 (CO2Me), 69.8 (C3), 73.7 (C3), 79.6 ((CH3)3C), 156.9
(NCO2), 173.5 ppm (C1); FTIR (ATR): n˜ =3343 (s), 3224 (m), 2948 (m),
1747 (vs), 1679 (vs), 1518 (vs), 1454 (s), 1439 (s), 1384 (m), 1364 cmꢀ1 (s);
MS (EI): m/z (%): 263 (0.5) [M]+, 128 (30), 118 (69), 90 (14), 74 (20), 57
(100); elemental analysis calcd (%) for C11H21NO6: C 50.18, H 8.04, N
5.32; found: C 50.22, H 8.01, N 5.15; GC: Astec GTA (30 m”0.25 mm),
H2 (flow 6 mLminꢀ1), 1 min at 608C, then 108Cminꢀ1 gradient,
tR(2R,3S)-15: 15.11 min, 96% ee, tR(2S,3R)-15: 15.43 min.
c) TFA (24 mL) was added dropwise over 15 min to an ice-cold solution
of methyl (2S,3S)-2-azido-5-[(tert-butoxycarbonyl)amino]-3-(tert-butyldi-
methylsiloxy)pentanoate (1.60 g, 4.00 mmol) in dry CH2Cl2 (24 mL).
After stirring for 2 h at 08C, the solvent was removed under vacuum at
08C. The residue was treated with dry benzene (2”15 mL), concentrated
under vacuum at 08C, and dried for 3 h under high vacuum to give com-
pound 18 (99%, >95% NMR purity) as a colorless, highly hygroscopic
solid. 1H NMR (500 MHz, CD2Cl2): d=0.14 (s, 3H; Me2Si), 0.16 (s, 3H;
Me2Si), 0.90 (s, 9H; Me3CSi), 1.92–1.98 (m, 2H; H4), 3.21–3.35 (m, 2H;
H5), 3.79 (s, 3H; CO2Me), 4.31 (d, J=4.1 Hz, 1H; H2), 4.36 (td, J=4.7,
4.1 Hz, 1H; H3), 7.58 ppm (br, 3H; NH3); 13C NMR (125 MHz, CD2Cl2):
d=ꢀ5.4 (Me2Si), ꢀ5.2 (Me2Si), 17.6 (Me3CSi), 25.2 (Me3CSi), 29.8 (C4),
36.8 (C5), 52.9 (CO2Me), 67.1 (C2), 70.1 (C3), 115.3 (q, J=288 Hz;
CF3CO2ꢀ), 160.6 (q, J=40 Hz; CF3CO2ꢀ), 168.4 ppm (C1).
Methyl (2R,3S)-5-[(tert-butoxycarbonyl)amino]-3-hydroxy-2-O-[(4-nitro-
phenyl)sulfonyl]pentanoate (17): NEt3 (10 mL, 72.0 mmol) and 4-nitro-
benzenesulfonyl chloride (7.98 g, 36.0 mmol) were added to a solution of
compound 15 (9.50 g, 36.0 mmol) in dry CH2Cl2 (325 mL) at 48C and the
reaction mixture was stirred for 16 h at 48C. The solvent was removed
under vacuum, the residue was dissolved in EtOAc (450 mL) and was
successively washed with 0.5m HCl, satd NaHCO3 solution, and brine
(72 mL each). The organic layer was dried (MgSO4), concentrated, and
the residue washed with some cold Et2O to give compound 17 (10.5 g,
65%, 95% NMR purity) as a white solid. M.p. 1408C; [a]2D0 =ꢀ14.2 (c=
1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d=1.43 (s, 9H; (CH3)3C),
1.55–1.65 (m, 1H; H4), 1.77 (ddt, J=14.2, 10.5, 4.2 Hz, 1H; H4), 3.10–
3.20 (m, 1H; H5), 3.42–3.54 (m, 1H; H5), 3.70 (s, 3H; CO2Me), 3.95 (d,
J=4.6 Hz, 1H; H3), 4.12–4.20 (m, 1H; OH), 4.77 (br, 1H; NH), 5.04 (d,
J=3.3 Hz, 1H; H2), 8.18 (d, J=8.7 Hz, 2H; Ar), 8.38 ppm (d, J=8.7 Hz,
2H; Ar); 13C NMR (125 MHz, CDCl3): d=28.2 ((CH3)3C), 33.9 (C4),
36.4 (C5), 52.8 (CO2Me), 68.2 (C3), 80.3 ((CH3)3C), 81.1 (C2), 124.1 (Ar),
129.5 (Ar), 142.0 (Ar), 150.8 (Ar), 157.5 (NCO2), 167.0 ppm (C1); FTIR
(ATR): n˜ =3342 (m), 3296 (w), 3109 (w), 2975 (w), 1756 (s), 1608 (w),
1531 (s), 1447 (m), 1405 (w), 1370 (s), 1350 (s), 1279 (s), 1243 (m), 1188
(vs), 994 (s), 850 (s), 738 (s), 618 cmꢀ1 (s); MS (FAB, NBA): m/z (%):
471 (10) [M+Na]+, 449 (55) [M+H]+, 393 (100), 349 (85); elemental
Methyl (2S,3S)-2-azido-3-(tert-butyldimethylsilyloxy)-5-[(E-3-iodoprop-2-
enoyl]amino)pentanoate (7): DEPC (200 mL, 1.20 mmol) was added to
an ice-cold solution of compounds 18 (416 mg, 1.00 mmol) and 19
(198 mg, 1.00 mmol) in dry DMF(5 mL) followed by addition of NEt
3
(320 mL, 2.28 mmol) after 15 min. After stirring for 16 h at 08C, EtOAc
(25 mL) was added and the reaction mixture was washed successively
with a cold solution of KHSO4 (1m), satd NaHCO3, and brine (15 mL
each). The organic layer was dried (MgSO4) and concentrated. The resi-
due was subjected to chromatography (Rf =0.37, PE/EtOAc 3:1) to give
compound 7 (364 mg, 83%, >95% NMR purity) as a viscous colorless
oil. [a]2D0 =+10.8 (c=1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
2496
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem.Eur.J. 2006, 12, 2488 – 2503

Cylindramide Total Synthesis
FULL PAPER
0.12 (s, 6H; Me2Si), 0.90 (s, 9H; Me3CSi), 1.71–1.81 (m, 1H; H4), 1.85–
1.93 (m, 1H; H4), 3.30–3.39 (m, 1H; H5), 3.41–3.49 (m, 1H; H5), 3.79 (s,
3H; CO2Me), 4.10 (d, J=4.9 Hz, 1H; H2), 4.18–4.23 (m, 1H; H3), 5.83
(br, 1H; NH), 6.78 (d, J=14.5 Hz, 1H; H8), 7.67 ppm (d, J=14.5 Hz,
1H; H8); 13C NMR (125 MHz, CDCl3): d=ꢀ4.7 (Me2Si), ꢀ4.6 (Me2Si),
17.9 (Me3CSi), 25.6 (Me3CSi), 32.2 (C4), 35.8 (C5), 52.7 (CO2Me), 66.4
(C2), 71.5 (C3), 94.5 (C8), 138.5 (C7), 163.7 (C6), 168.5 ppm (C1); FTIR
(ATR): n˜ =3287 (m), 2952 (s), 2929 (s), 2885 (m), 2856 (m), 2107 (vs),
1740 (vs), 1641 (vs), 1588 (s), 1546 (vs), 1252 (vs), 1110 (vs), 941 (s), 835
(vs), 776 cmꢀ1 (vs); MS (DCI, NH3): m/z (%): 500 (20) [M+NH4]+, 483
(100) [M+H]+, 425 (20), 368 (15), 200 (15); HRMS (DCI): calcd for
C15H28IN4O4Si: 483.0919; found: 483.0931 [M+H]+.
H6), 5.27 (s, 1H; H2), 7.53–7.59 ppm (m, 5H; Ar); 13C NMR (125 MHz,
CDCl3): d=25.0 (C8), 25.5 (C5), 32.2 (C6), 32.3 (C4), 93.9 (C2), 106.6
(C7), 123.7 (Ar), 129.8 (Ar), 130.2 (Ar), 133.5 (Ar), 153.7 (Ar), 160.8
(C3), 169.8 ppm (C1); FTIR (ATR): n˜ =1713 (vs), 1638 (vs), 1596 (m),
1498 (s), 1373 (vs), 1275 (vs), 1236 (vs), 1200 (vs), 1011 (vs), 760 (vs),
688 cmꢀ1 (vs); MS (DCI, NH3): m/z (%): 364 (30) [M+NH4]+, 347 (5)
[M+H]+, 289 (100) [M+Hꢀacetone]+; elemental analysis calcd (%) for
C16H18N4O5S: C 55.48, H 5.24, N 16.17; found: C 55.42, H 5.25, N 16.37.
2,2-Dimethyl-6-{3-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl]propyl}-4H-1,3-
dioxin-4-one (8): A solution of compound 25 (1.56 g, 4.50 mmol) in
EtOH (50 mL) was added to an ice-cold solution of ammonium heptamo-
lybdate (12.2 g, 0.98 mmol) and 30% H2O2 (40.5 mL). After stirring for
1 h at 08C, the mixture was warmed to RT within 3 h and the suspension
was filtered through Celite. A satd solution of NH4Cl (100 mL) was
added to the filtrate that was then extracted with CH2Cl2 (2”150 mL).
The combined organic layers were washed with brine, dried (MgSO4),
and concentrated. The residue was purified by chromatography (Rf =0.5,
PE/EtOAc 1:1) to give compound 8 (1.585 g, 93%, >95% NMR purity)
as a colorless solid. M.p. 79–818C; 1H NMR (300 MHz, CDCl3): d=1.70
(s, 6H; H8), 2.24–2.32 (m, 2H; H5), 2.48 (t, J=7.4 Hz, 2H; H4), 3.77–
3.82 (m, 2H; H6), 5.30 (s, 1H; H2), 7.59–7.71 ppm (m, 5H; Ar);
13C NMR (125 MHz, CDCl3): d=18.8 (C5), 25.0 (C8), 31.7 (C4), 54.8
(C6), 94.4 (C2), 106.8 (C7), 124.9 (Ar), 129.7 (Ar), 131.5 (Ar), 132.8
(Ar), 153.2 (Ar), 160.5 (C3), 168.4 ppm (C1); FTIR (ATR): n˜ =1718 (vs),
1632 (vs), 1497 (s), 1390 (s), 1376 (s), 1338 (vs), 1201 (vs), 1152 (vs),
1010 cmꢀ1 (vs); MS (DCI, NH3): m/z (%): 396 (100) [M+NH4]+, 379 (5)
[M+H]+, 338 (30), 321 (20), 295 (10), 218 (10), 210 (10), 76 (18); elemen-
tal analysis calcd (%) for C16H18N4O5S: C 50.78, H 4.79, N 14.81; found:
C 50.56, H 4.80, N 14.69.
6-(3-Hydroxypropyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (24): a) 1,3-Di-
methyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU) (7 mL) was
added to a freshly prepared solution of LDA (45.0 mmol, prepared from
dry diisopropylamine (7.30 mL) and BuLi (28.3 mL, 1.6m in hexane),
15 min at 08C) in dry THF(30 mL). After 15 min, compound 22 (7.10 g,
46.0 mmol) was slowly added and the reaction cooled from 0 to ꢀ408C
after 20 min. Then compound 23 (5.50 mL, 60.0 mmol) was added drop-
wise and the mixture was allowed to warm to RT (16 h). The reaction
was quenched with cold HCl (75 mL, 1n), Et2O (150 mL) was added,
and the layers were separated. The organic layer was washed with brine,
dried by using MgSO4, and concentrated. The residue was purified by
chromatography (PE/EtOAc 2:1; Rf =0.20, PE/Et2O 3:1) to separate non-
polar
byproducts.
6-(But-3-enyl)-2,2-dimethyl-4H-1,3-dioxin-4-one
(6.00 g, approximately 50%, about 70% NMR purity) was obtained as a
pale-yellow oil that was used directly without further purification.
1H NMR (500 MHz, CDCl3): d=1.68 (s, 6H; H9), 2.29–2.33 (m, 4H; H4,
H5), 5.04 (dd, J=10.8, 0.9 Hz, 1H; H7), 5.07 (d, J=15.5 Hz, 1H; H7),
5.24 (s, 1H; H2), 5.73–5.83 ppm (m, 1H; H6); 13C NMR (125 MHz,
CDCl3): d=24.9 (C9), 29.5 (C5), 32.7 (C4), 93.3 (C2), 106.2 (C8), 116.0
(C7), 135.8 (C6), 161.0 (C3), 170.8 ppm (C1); FTIR (ATR): n˜ =1722 (vs),
1632 (vs), 1373 (vs), 1269 (vs), 1250 (s), 1200 (vs), 1104 (m), 1011 (vs),
899 (s), 803 cmꢀ1 (s); MS (CI): m/z (%): 365 (90) [2M+H]+, 183 (100)
[M+H]+, 125 (50), 124 (30), 96 (15), 87 (20); HRMS (CI): calcd for
C10H15O3: 183.1016; found: 183.1021 [M+H]+.
(3aR,6aR)-Hexahydropentalene-1,4-dione (29):
A solution of DMSO
(123 mL, 1.74 mol) in CH2Cl2 (40 mL) was slowly added to a solution of
oxalyl chloride (73.4 mL, 778 mmol) in CH2Cl2 (750 mL) at ꢀ608C fol-
lowed by addition of a solution of (S,S)-28 (51.5 g, 362 mmol) in dry
CH2Cl2 (160 mL). The temperature was not allowed to exceed ꢀ608C.
After stirring for 20 min, NEt3 (515 mL, 4.25 mol) was added dropwise
over 35 min, the mixture was stirred for a further 10 min and was then al-
lowed to warm to RT. The reaction was quenched with H2O (400 mL)
and the layers were separated. The organic layer was washed with brine,
dried (MgSO4), and concentrated. The residue was distilled under
vacuum to give compound 29 (44.9 g, 90%, 97% GC purity) as a pale-
yellow oil. B.p. 62–648C (0.07 Torr); [a]2D0 =ꢀ412 (c=1.00 in CHCl3);
ref. [28c]: ꢀ457 (c=1 in CH2Cl2); GC: GTA (20 m”0.25 mm), carrier gas
H2 (flow: 5 mLminꢀ1), 808C, then 58Cminꢀ1 gradient, tR1 =17.13 min,
b) A slow stream of O3 was passed through a solution of 6-(but-3-enyl)-
2,2-dimethyl-4H-1,3-dioxin-4-one (182 mg, 1.00 mmol) in MeOH/CH2Cl2/
pyridine 4:4:1 (9 mL) at ꢀ788C until a light-blue color was visible. Then
N2 gas was passed through for 1 min, NaBH4 (109 mg, 2.80 mmol) was
added, and the reaction mixture was allowed to warm to 108C. After
quenching with a satd solution of NH4Cl (15 mL), the reaction mixture
was extracted with EtOAc (3”25 mL). The combined organic layers
were washed with brine, dried (MgSO4), and concentrated. The residue
was purified by chromatography (Rf =0.4, PE/EtOAc 1:2) to give com-
t
R2 =18.68 min, 98% ee. The spectroscopic data agreed with those in the
literature.[28]
1
(2’R,3a’R,5’R,6a’R)-2,5-Dibromohexahydrodispiro[1,3-dioxolane-2,1’-
pentalene-4’,2’’-[1,3]dioxolane] (30): A solution of compound 29 (3.45 g,
25 mmol) and PhNMe3Br3 (24.3 g, 65 mmol) in THF/ethylene glycol 1:1
(120 mL) was stirred for 2 d at 308C. The reaction was quenched with a
bisulfite and a satd NaHCO3 solution and extracted with Et2O (2”
250 mL). The organic layer was washed with H2O and brine, dried
(MgSO4), and concentrated. The crude product was recrystallized from
boiling MeOH to give compound 30 (8.04 g, 84%, >95% NMR purity)
as colorless crystals. M.p. 118–1208C; [a]2D0 =ꢀ106.3 (c=1.00 in CHCl3).
The spectroscopic data agreed with those in the literature.[30]
pound 24 (119 mg, 64%, >95% NMR purity) as a colorless oil. H NMR
(500 MHz, CDCl3): d=1.60 (br, 1H; OH), 1.69 (s, 6H; H8), 1.76–1.84
(m, 2H; H5), 2.32–2.37 (m, 2H; H4), 3.69 (t, J=6.0 Hz, 2H; H6),
5.26 ppm (s, 1H; H2); 13C NMR (125 MHz, CDCl3): d=25.0 (C8), 28.6
(C5), 30.0 (C4), 61.4 (C6), 93.3 (C2), 106.3 (C8), 161.2 (C3), 171.4 ppm
(C1); FTIR (ATR): n˜ =3426 (s), 2998 (m), 2942 (m), 2877 (m), 1705 (vs),
1628 (vs), 1389 (vs), 1374 (vs), 1271 (vs), 1253 (s), 1200 (vs), 1055 (vs),
1010 (vs), 902 (s), 805 cmꢀ1 (s); MS (CI, CH4): m/z (%): 187 (60)
[M+H]+, 129 (100), 128 (40), 111 (20), 87 (30); HRMS (CI): calcd for
C9H15O4: 187.0965; found: 187.0966 [M+H]+.
(3a’R,6a’R)-Dihydrodispiro[1,3-dioxolane-2,1’-pentalene-4’,2’’-[1,3]dioxo-
lane] (31): Compound 30 (5.73 g, 14.92 mmol) was added to a solution of
NaOMe (4.82 g, 89.2 mmol) in DMSO (27 mL), whereby the temperature
did not exceed 608C, and the mixture was heated for 2 h at 708C. Then
H2O (200 mL) was added and the mixture extracted with Et2O (3”
150 mL). The combined organic layers were washed with brine, dried
(MgSO4), and concentrated to give compound 31 (3.29 g, 99%, >95%
NMR purity) as colorless crystals. M.p. 100–1028C; [a]2D0 =ꢀ217 (c=1.00
in CHCl3). The spectroscopic data agreed with those in the literature.[30]
2,2-Dimethyl-6-{3-[(1-phenyl-1H-tetrazol-5-yl)thio]propyl}-4H-1,3-dioxin-
4-one (25): A solution of compound 24 (1.86 g, 10.0 mmol) in dry THF
(5 mL) was added to a solution of 1-phenyl-1H-tetrazole-5-thiol (2.67 g,
15.0 mmol), diethyl azodicarboxylate (DEAD) (40% in toluene, 4.12 mL,
15 mmol), and triphenylphosphine (3.92 g, 15.0 mmol) in dry THF
(60 mL) at 08C, and the mixture was stirred for 1 h. Then a satd solution
of NaHCO3 (100 mL) was added and the mixture extracted with CH2Cl2
(2”150 mL). The combined organic layers were washed with brine, dried
(MgSO4), and concentrated. The residue was purified by chromatography
(Rf =0.5, PE/EtOAc 1:1) and was recrystallized from CH2Cl2/diisopropyl
ether to give compound 25 (2.49 g, 72%, >95% NMR purity) as color-
less crystals. M.p. 73–758C; 1H NMR (500 MHz, CDCl3): d=1.69 (s, 6H;
H8), 2.11–2.18 (m, 2H; H5), 2.39–2.43 (m, 2H; H4), 3.40–3.44 (m, 2H;
(3aR,6aR)-Dihydropentalene-1,4-dione (11): A solution of compound 31
(3.29 g, 14.8 mmol) and PPTS (2.22 g, 8.80 mmol) in acetone/3% H2O
(300 mL) was heated for 3 h at reflux. The solvent was removed under
vacuum, the residue was taken up in Et2O (200 mL), and was washed
Chem.Eur.J. 2006, 12, 2488 – 2503
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2497

S. Laschat et al.
with brine. The organic layer was dried (MgSO4) and concentrated to
ing compound 37 (Rf =0.25, 27.66 g, 80%, 95% GC purity) and com-
pound 29 (1.27 g, 5%) as pale-yellow oils.
give compound 11 (1.68 g, 84%, 99% GC purity) as a colorless solid.
M.p. 72–748C; [a]2D0 =ꢀ1493 (c=1.00 in CHCl3); GC: Bondex un
a
b) HCl (25 mL, 1n) was added to a solution of compound 36 (9.26 g,
41.0 mmol) in THF/MeOH/acetone 6:1:1 (250 mL) and the reaction mix-
(20 m”0.25 mm), carrier gas: H2 (0.4 bar), 3 min at 408C, then
2.58Cminꢀ1 gradient, tR1 =35.43 min, tR2 =37.29 min, 99.4% ee. The spec-
troscopic data agreed with those in the literature.[30]
ture was stirred for 1 h. After quenching with
a satd solution of
NaHCO3, the mixture was extracted with EtOAc (300 mL). The organic
layer was dried (MgSO4) and concentrated. The residue was purified by
chromatography (PE/EtOAc 2:1) to give compound 37 (6.34 g, 85%,
97% GC purity) and compound 36 (0.62 g, 11%). The spectroscopic data
of compound 37 agreed with those in the literature.[27]
Bisacetal 36: [a]2D0 =ꢀ60.3 (c=1.00 in CHCl3); 1H NMR (250 MHz,
CDCl3): d=1.62–1.83 (m, 8H; H2, H3), 2.43–2.53 (m, 2H; H4), 3.89–
3.92 ppm (m, 8H; OCH2CH2O); 13C NMR (62.5 MHz, CDCl3): d=23.7
(C3), 34.5 (C2), 47.7 (C4), 63.9 (OCH2CH2O), 64.9 (OCH2CH2O),
118.9 ppm (C1).
Dimethyl (3a’R,4R,5R,6a’R)-4’-oxo-4’,6a’-dihydro-3a’H-spiro[1,3-dioxo-
lane-2,1’-pentalene]-4,5-dicarboxylate (34): BF3·OEt2 (180 mL, 4.80 mmol)
was added to a solution of compound 11 (264 mg, 2.00 mmol) and (R,R)-
dimethyl tartrate (1.07 g, 6.00 mmol) in dry CH2Cl2 (4 mL) at 08C, and
the mixture was stirred for 20 h at RT. After quenching with a solution of
satd NaHCO3, the reaction mixture was extracted with CH2Cl2 (2”
40 mL). The combined organic layers were washed with brine, dried
(MgSO4), and concentrated. The residue was purified by chromatography
(PE/EtOAc 1:1; Rf =0.23, PE/EtOAc 2:1) to give compound 34 (176 mg,
30%, >95% NMR purity) as a colorless resin together with compound
11 (174 mg, 66%). [a]2D0 =ꢀ327 (c=1.00 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=3.43–3.46 (m, 1H; H4), 3.77 (s, 3H; CO2Me), 3.83 (s, 3H;
CO2Me), 3.87–3.90 (m, 1H; H8), 4.89 (d, J=3.3 Hz; H2’), 4.90 (d, J=
3.3 Hz; H3’), 5.68 (dd, J=5.6, 2.3 Hz, 1H; H7), 5.95 (dd, J=5.7, 2.0 Hz,
1H; H2), 6.14 (dd, J=5.6, 2.7 Hz, 1H; H6), 7.53 ppm (dd, J=5.7, 3.0 Hz,
1H; H3); 13C NMR (125 MHz, CDCl3): d=52.7 (CO2Me), 53.1 (C4), 55.2
(C8), 77.3, 77.7 (C2’, C3’), 121.9 (C5), 131.3 (C2), 131.5 (C7), 135.5 (C6),
161.3 (C3), 169.3, 169.7 (C1’, C4’), 207.0 ppm (C1); FTIR (ATR): n˜ =
2956 (m), 1756 (vs), 1707 (vs), 1437 (s), 1343 (s), 1228 (vs), 1177 (s), 1151
(vs), 1097 (vs), 1004 (s), 968 (s), 887 (m), 827 (m), 762 (m), 676 cmꢀ1 (m);
MS (EI): m/z (%): 294 (100) [M]+, 266 (10), 235 (20), 175 (15), 106 (20),
84 (35), 78 (35); HRMS (EI): calcd for C14H14O7: 294.0740; found:
294.0738 [M]+.
Monoacetal 37: [a]2D0 =ꢀ175 (c=1.00 in CHCl3); ref. [27]: ꢀ160 (c=1.35
in CHCl3).
(3a’R,6a’R)-2’,3’,3a’,6a’-Tetrahydro-4’H-spiro[1,3-dioxolane-2,1’-penta-
len]-4’-one (38): A solution of compound 37 (1.12 g, 6.16 mmol) in THF
(10 mL) was added to a freshly prepared solution of LDA (7.40 mmol) in
dry THF(15 mL) at ꢀ788C followed by addition of TMSCl (1.17 mL,
12.7 mmol) after 30 min. The mixture was allowed to warm to 108C
within 3 h and then ice-cold pentane (100 mL) was added. The mixture
was washed successively with a satd solution of NH4Cl, H2O, and brine
(30 mL each). The organic layer was dried (MgSO4) and concentrated.
The obtained intermediate was dissolved in CH2Cl2 (5 mL) and added in
the absence of light to a solution of IBX (2.58 g, 9.24 mmol) and 4-me-
thoxypyridin-N-oxide monohydrate (1.32 g, 9.24 mmol) in DMSO
(24 mL). After stirring for 30 min, the mixture was poured into a mixture
of ice-cold satd NaHCO3 solution and Et2O (150 mL), and was then fil-
tered through Celite. The filtrate was extracted with Et2O (3”70 mL)
and the combined organic layers were washed with brine (70 mL), dried
(MgSO4), and concentrated. The residue was purified by chromatography
(Rf =0.35, PE/EtOAc 2:1) to give compound 38 (700 mg, 63%, 95%
Dimethyl (3a’R,4R,5R,5’R,6R,6a’R)-5’-[(benzyloxy)methyl]-6’-(2-ethoxy-
2-oxoethyl)-4’-oxo-4’,5’,6’,6a’-tetrahydro-3a’H-spiro[1,3-dioxolane-2,1’-
pentalene]-4,5-dicarboxylate (35a): [(1-Ethoxyvinyl)oxy]trimethylsilane
(75 mg, 467 mmol) was added to a solution of compound 34 (55 mg,
187 mmol) and scandium triflate (15 mg, 30.5 mmol) in dry CH2Cl2
(1.5 mL) at ꢀ708C. After stirring for 30 min, the mixture was added
through a cannula to a stirred mixture of 2,6-di-tert-butylpyridine (45 mL,
200 mmol), TMSOTf (36 mL, 200 mmol), and formaldehyde dibenzylacetal
(200 mg, 1.00 mmol) in CH2Cl2 (2 mL) at 08C, and the reaction mixture
stirred for 1 h at 08C, and for a further 3 h at RT. After quenching with a
satd solution of NaHCO3, the mixture was extracted with CH2Cl2 (3”
25 mL). The combined organic layers were dried (MgSO4) and concen-
trated. The residue was purified by chromatography (Rf =0.22, PE/
EtOAc 2:1) to give compound 35a (79 mg, 84%, >95% NMR purity) as
1
NMR purity) as a colorless oil. [a]2D0 =ꢀ290 (c=1.00 in CHCl3); H NMR
(500 MHz, CDCl3): d=1.56 (ddd, J=13.1, 13.0, 7.7 Hz, 1H; H6), 1.62
(dd, J=13.0, 7.0 Hz, 1H; H6), 1.84 (ddt, J=13.1, 7.7, 1.2 Hz, 1H; H7),
1.92–2.01 (m, 1H; H7), 2.76 (dd, J=9.4, 5.6 Hz, 1H; H8), 3.17–3.22 (m,
1H; H4), 3.86–4.06 (m, 4H; OCH2CH2O), 6.24 (dd, J=5.6, 1.9 Hz, 1H;
H2), 7.62 ppm (dd, J=5.6, 2.9 Hz, 1H; H3); 13C NMR (125 MHz,
CDCl3): d=24.5 (C7), 31.8 (C6), 47.0 (C4), 53.5 (C8), 63.9 (OCH2), 65.2
(OCH2), 116.1 (C5), 135.6 (C2), 163.8 (C3), 212.3 ppm (C1); FTIR
(ATR): n˜ =2951 (s), 2881 (s), 1701 (vs), 1585 (m), 1456 (m), 1439 (m),
1323 (s), 1270 (s), 1232 (s), 1172 (vs), 1102 (vs), 1015 (vs), 998 (vs), 923
(s), 873 (s), 840 (vs), 768 (s), 643 cmꢀ1 (s); MS (EI): m/z (%): 180 (15)
[M]+, 99 (100), 94 (12), 86 (22), 79 (10), 66 (20); HRMS (EI): calcd for
C10H12O3: 180.0786; found: 180.0783 [M]+.
a
viscous colorless oil. [a]2D0 =ꢀ209 (c=1.00 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=1.23 (t, J=7.2 Hz, 3H; CH3CH2O), 2.59–2.69 (m,
3H; H3, H9), 2.73–2.79 (m, 1H; H2), 3.18 (t, J=8.5 Hz, 1H; H4), 3.59–
3.60 (m, 3H; H8, H10), 3.83 (s, 3H; CO2Me), 3.85 (s, 3H; CO2Me), 4.04–
4.16 (m, 2H; CH3CH2O), 4.43 (d, J=12.2 Hz, 1H; PhCH2), 4.46 (d, J=
12.2 Hz, 1H; PhCH2), 4.89 (d, J=2.9 Hz, 1H; H2’), 4.99 (d, J=2.9 Hz,
1H; H3’), 5.83 (dd, J=5.5, 3.0 Hz, 1H; H7), 6.04 (dd, J=5.5, 2.4 Hz, 1H;
H6), 7.23–7.35 ppm (m, 5H; Ar); 13C NMR (125 MHz, CDCl3): d=14.1
(CH3CH2O), 35.7 (C3), 36.5 (C9), 48.9 (C4), 52.7 (CO2Me), 55.2 (C2),
58.2 (C8), 60.1 (CH3CH2O), 67.4 (C10), 73.0 (PhCH2), 77.1, 77.6 (C2’,
C3’), 125.0 (C5), 127.3 (Ar), 127.3 (Ar), 128.1 (Ar), 132.2 (C6), 134.2
(C7), 138.2 (Ar), 169.5, 169.8, 172.0 (CO2Me, C1’, C2’), 212.5 ppm (C1);
FTIR (ATR): n˜ =2955 (m), 1759 (vs), 1737 (vs), 1437 (m), 1354 (m), 1221
(s), 1148 (vs), 1095 (vs), 1020 (s), 984 (s), 741 (m), 700 cmꢀ1 (m); MS
(DCI, NH3): m/z (%): 502 (2) [M]+, 457 (2), 394 (30), 349 (10), 307 (5),
(3a’R,6’S,6a’R)-6’-Methyl-3’,3a’,6’,6a’-tetrahydro-2’H-spiro[1,3-dioxolane-
2,1’-pentalen]-4’-yltrifluoromethanesulfonate (40): Methyllithium (68 mL,
1.6m in Et2O) was added dropwise to a suspension of copper iodide
(10.5 g, 55.0 mmol) in dry THF(150 mL) at 0 8C. After formation of a
clear solution, the mixture was cooled to ꢀ788C and a solution of com-
pound 38 (5.76 g, 32.0 mmol) in THF(20 mL) was added followed by a
solution of compound 39 (21.8 g, 56.0 mmol) in THF(100 mL) after
30 min. The mixture was allowed to warm to 08C within 5 h. After
quenching with a solution of satd NH4Cl (100 mL), Et2O (250 mL) and a
satd solution of EDTA (150 mL) were added, the layers were separated
and the aqueous layer was extracted with Et2O (250 mL). The combined
organic layers were washed with brine (200 mL), dried (MgSO4), and
concentrated. The residue was purified by chromatography (PE/EtOAc
2:1) to give a first fraction containing compound 41 (Rf =0.55, 2.47 g,
39%, 95% GC purity) and a second fraction containing compound 40
(Rf =0.47, 4.99 g, 47%, 95% NMR purity) as colorless oils. Compound
233 (10), 108 (100), 91 (50), 79 (75); HRMS (EI): calcd for C26H30O10
:
502.1839; found: 502.1840 [M]+.
(3aR,6aR)-Hexahydro-4’H-spiro[1,3-dioxolane-2,1’-pentalen]-4’-one (37):
a) A solution of compound 29 (25.6 g, 190 mmol), toluenesulfonic acid
monohydrate (2.50 g, 13.0 mmol), and ethylene glycol (12.7 mL,
228 mmol) in dry toluene (1 L) was heated for 8 h at reflux (water trap).
Then the mixture was washed with a satd solution of NaHCO3 and brine
(250 mL each), dried (MgSO4), and concentrated. The residue was puri-
fied by chromatography (PE/EtOAc 3:1) to give a first fraction contain-
ing compound 36 (Rf =0.40, 5.58 g, 13%) and a second fraction contain-
1
40: [a]2D0 =+41 (c=1.00 in CHCl3); H NMR (500 MHz, CDCl3): d=1.11
(d, J=7.1 Hz, 3H; 3-Me), 1.69–1.87 (m, 4H; H6, H7), 2.17 (ddd, J=8.5,
3.2, 1.0 Hz, 1H; H4), 2.88 (qq, J=7.1, 2.9 Hz, 1H; H8), 3.38 (tdt, J=8.5,
3.4, 1.6 Hz, 1H; H3), 3.84–3.97 (m, 4H; OCH2CH2O), 5.53 ppm (t, J=
1.9 Hz, 1H; H2); 13C NMR (125 MHz, CDCl3): d=22.1 (Me-C3), 25.4
2498
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem.Eur.J. 2006, 12, 2488 – 2503

Cylindramide Total Synthesis
FULL PAPER
(C7), 32.5 (C6), 37.4 (C3), 45.8 (C8), 54.2 (C4), 63.8 (OCH2), 65.2
(OCH2), 117.7 (C5), 118.6 (q, J=320 Hz; CF3), 121.6 (C2), 148.3 ppm
(C1); FTIR (ATR): n˜ =2960 (m), 2879 (m), 1660 (m), 1419 (vs), 1342
(m), 1300 (w), 1248 (s), 1203 (vs), 1138 (vs), 1108 (vs), 1040 (s), 1017
(vs), 942 (vs), 840 (vs), 749 (m), 609 (vs), 579 cmꢀ1 (vs); MS (CI): m/z
(%): 329 (100) [M+H]+, 284 (20), 195 (8), 179 (11), 99 (5); HRMS (CI):
calcd for C12H16F3O5S: 329.0665; found: 329.0672 [M+H]+.
slow addition of TMSCl (2.55 mL, 20.0 mmol) after 45 min. The mixture
was allowed to warm to ꢀ208C within 2 h. Then ice-cold pentane
(250 mL) was added and the mixture washed successively with a satd so-
lution of NH4Cl, H2O, and brine (100 mL each). The organic layer was
dried (MgSO4) and carefully concentrated under vacuum (maximum
100 mbar, 408C bath temperature). The resultant silyl enol ether was dis-
solved in CH2Cl2 (10 mL) and added in the absence of light to a solution
of IBX (5.23 g, 18.7 mmol) and MPO (2.67 g, 18.7 mmol) in DMSO
(47 mL). After stirring for 35 min, the mixture was poured into a solution
of ice-cold satd NaHCO3 and Et2O (300 mL) and filtered through Celite.
The filtrate was extracted with Et2O (3”100 mL). The combined organic
layers were washed with brine (150 mL), dried (MgSO4), and concentrat-
ed under 800 mbar pressure. After chromatography (pentane/Et2O 3:1;
Rf =0.23, PE/Et2O 4:1), the filtrate was concentrated to an approximately
30% solution in Et2O due to the volatility of compound 10 (87% by
NMR integration). Compound 10 can be stored for the short-term at
ꢀ288C. 1H NMR (500 MHz, CDCl3): d=1.21 (d, J=7.0 Hz, 3H; 3-Me),
2.57 (dd, J=5.7, 3.2 Hz, 1H; H2), 2.85–2.93 (m, 1H; H3), 4.00–4.04 (m,
1H; H6), 5.57 (dt, J=5.6, 2.1 Hz, 1H; H4), 5.69 (dt, J=5.6, 2.1 Hz, 1H;
H5), 6.02 (dd, J=5.6, 1.6 Hz, 1H; H8), 7.72 ppm (dd, J=5.6, 2.8 Hz, 1H;
H7); MS (EI): m/z (%): 134 (100) [M]+, 119 (60), 105 (25), 91 (75), 79
(20), 78 (16), 77 (20); HRMS (EI): calcd for C9H10O: 134.0732; found:
134.0723 [M]+.
(3a’R,6’S,6a’R)-6’-Methylhexahydro-4’H-spiro[1,3-dioxolane-2,1’-penta-
len]-4’-one (41): [a]2D0 =ꢀ79.5 (c=1.00 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.16 (d, J=6.8 Hz, 3H; Me), 1.68–1.73 (m, 2H; H3, H6),
1.79–1.86 (m, 1H; H7), 1.91–2.06 (m, 2H; H2), 2.15–2.24 (m, 1H; H8),
2.28 (dd, J=9.6, 6.1 Hz, 1H; H3), 2.45 (dd, J=17.5, 7.7 Hz, 1H; H6),
2.79 (t, J=10.2 Hz, 1H; H4), 3.87–4.02 ppm (m, 4H; OCH2CH2O);
13C NMR (125 MHz, CDCl3): d=21.8 (Me), 24.5 (C3), 30.8 (C7), 34.2
(C2), 47.1 (C6), 49.6 (C4), 54.5 (C8), 64.2 (OCH2CH2O), 65.1
(OCH2CH2O), 118.7 (C1), 211.8 ppm (C5); FTIR (ATR): n˜ =2957 (s),
2879 (s), 1735 (vs), 1459 (m), 1332 (m), 1199 (s), 1119 (s), 1017 (m), 946
(m), 845 cmꢀ1 (m); MS (EI): m/z (%): 196 (10) [M]+, 126 (8), 125 (10),
123 (6), 113 (5), 100 (60), 99 (100), 86 (40); HRMS (EI): calcd for
C11H16O3: 196.1099; found: 196.1087 [M]+.
(3a’S,6’S,6a’R)-6’-Methyl-3’,3a’,6’,6a’-tetrahydro-2’H-spiro[1,3-dioxolane-
2,1’-pentalene] (42): Triethylsilane (0.40 mL, 2.50 mmol) was added to a
solution of compound 40 (285 mg, 0.87 mmol) and [PdCl2(dppf)] (16 mg,
0.02 mmol) in DMF(5 mL) at 60 8C, and the mixture was heated at 608C
for 1 h. Then Et2O (25 mL) and H2O (15 mL) were added, the layers
were separated, and the aqueous layer was extracted with Et2O (25 mL).
(2R,3R,3aR,6S,6aR)-2-(Dimethoxymethyl)-6-methyl-3-[3-(trimethylsilyl)-
prop-2-ynyl]-3,3a,6,6a-tetrahydropentalen-1(2H)-one (43): tert-Butyllithi-
um (34.8 mL, 1.6m in pentane) was added to a solution of N,N,N’,N’-tet-
ramethylethylenediamine (TMEDA) (8.6 mL, 57 mmol) and 1-trimethyl-
silylpropyne (8.2 mL, 55 mmol) in dry THF(90 mL) at ꢀ788C. After stir-
ring for 1 h, this solution was added through a cannula to a suspension of
copper iodide (5.29 g, 27.8 mmol) in THF(30 mL) at ꢀ408C. The mix-
ture was warmed to 08C and, after clearing, immediately cooled to
ꢀ788C. A solution of compound 10 (around 18.6 mmol) in THF(10 mL)
was slowly added dropwise followed by addition of TMSCl (5.4 mL,
42.0 mmol) and the reaction mixture was warmed to ꢀ408C within 2 h.
After quenching with a solution of satd NH4Cl/EDTA (200 mL), the mix-
ture was extracted with pentane (2”250 mL). The combined organic
layers were dried (MgSO4) and concentrated. The residue was taken up
in dry CH2Cl2 (50 mL), cooled to ꢀ208C, and trimethyl formate
(13.1 mL, 120.0 mmol) and BF3·OEt2 (12.0 mL, 94.6 mmol) were succes-
sively added slowly. After 1 h, the reaction was quenched with a satd so-
lution of NaHCO3 (100 mL). The mixture was extracted with CH2Cl2 (2”
150 mL), the combined organic layers were washed with brine (50 mL),
dried (MgSO4), and concentrated. The residue was purified by chroma-
tography (PE/Et2O 5:1; Rf =0.39, PE/Et2O 4:1) to give compound 43
(3.73 g, 63%, >95% NMR purity) as a colorless oil. [a]2D0 =+43 (c=1.00
in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.12 (s, 9H; Si(CH3)3), 1.12
(d, J=7.0 Hz, 3H; 3-Me), 2.33–2.44 (m, 1H; H7), 2.46 (dd, J=16.5,
6.4 Hz, 1H; H9), 2.57 (dd, J=16.5, 4.5 Hz, 1H; H9), 2.58 (ddd, J=8.9,
3.7, 1.2 Hz, 1H; H2), 2.68 (ddd, J=7.5, 4.0, 1.6 Hz, 1H; H8), 2.90–2.97
(m, 1H; H3), 3.27–3.31 (m, 1H; H6), 3.34 (s, 3H; OMe), 3.36 (s, 3H;
OMe), 4.55 (d, J=4.0 Hz, 1H; CH(OMe)2), 5.56 (dt, J=5.6, 1.9 Hz, 1H;
H4), 5.72 ppm (dt, J=5.6, 1.9 Hz, 1H; H5); 13C NMR (125 MHz, CDCl3):
d=0.0 (SiMe3), 21.2 (Me-C3), 26.0 (C9), 39.9 (C7), 43.5 (C3), 50.9 (C6),
55.1 (OMe), 56.2 (OMe), 57.2 (C8), 59.3 (C2), 86.5 (C11), 104.6 (C-
(OMe)2), 105.0 (C10), 132.5 (C5), 135.6 (C4), 218.4 ppm (C1); FTIR
(ATR): n˜ =3046 (m), 2956 (s), 2927 (s), 2900 (s), 2870 (m), 2832 (m),
2172 (m), 1966 (w), 1732 (vs), 1453 (m), 1350 (m), 1308 (w), 1249 (s),
1218 (m), 1190 (m), 1132 (m), 1095 (s), 1069 (vs), 1036 (m), 1005 (m),
942 (m), 838 (vs), 758 (vs), 743 (vs), 697 cmꢀ1 (s); MS (DCI, CH4): m/z
(%): 319 (3) [MꢀH]+, 305 (10), 289 (25), 288 (20), 273 (16), 245 (4), 217
(5), 209 (10), 207 (15), 199 (8), 184 (18), 181 (15), 177 (10), 169 (5), 156
(10), 149 (4), 89 (10), 75 (100); HRMS (EI): calcd for C18H27O3Si:
319.1729; found: 319.1748 [M+H]+.
The combined organic layers were washed with
a satd solution of
NaHCO3 and brine (25 mL), dried (MgSO4), and concentrated. The resi-
due was purified by chromatography (PE/Et2O 5:1; Rf =0.74, PE/Et2O
3:1) to give compound 42 (141 mg, 90%, >95% NMR purity) as a color-
1
less liquid. [a]2D0 =+133 (c=1.00 in CHCl3); H NMR (500 MHz, CDCl3):
d=1.04 (d, J=7.1 Hz, 3H; 3-Me), 1.41–1.46 (m, 1H; H7), 1.59–1.69 (m,
2H; H6), 1.79–1.86 (m, 1H; H7), 2.06 (ddd, J=8.3, 3.7, 0.6 Hz, 1H; H4),
2.80–2.87 (m, 1H; H3), 3.27–3.29 (m, 1H; H8), 3.87–3.97 (m, 4H;
OCH2CH2O), 5.46 (dt, J=5.5, 2.2 Hz, 1H; H1), 5.53 ppm (dt, J=5.5,
2.1 Hz, 1H; H2); 13C NMR (125 MHz, CDCl3): d=22.4 (Me-C3), 28.0
(C7), 32.7 (C6), 42.9 (C3), 48.0 (C8), 55.7 (C4), 63.6 (OCH2), 65.0
(OCH2), 118.7 (C5), 132.2 (C1), 135.7 ppm (C2); FTIR (ATR): n˜ =3042
(m), 2952 (s), 2868 (s), 1454 (m), 1436 (m), 1371 (m), 1339 (m), 1318 (m),
1261 (m), 1195 (s), 1151 (s), 1109 (vs), 1100 (vs), 1037 (vs), 1013 (vs), 943
(vs), 853 (s), 739 cmꢀ1 (s); MS (CI): m/z (%): 181 (100) [M+H]+, 179
(30), 165 (20), 137 (55), 119 (20), 99 (40), 83 (30); HRMS (EI): calcd for
C11H16O2: 180.1150; found: 180.1143 [M]+.
(3aR,6S,6aR)-6-Methyl-6,6a-dihydropentalen-1(3aH)-one (10): a) A solu-
tion of compound 42 (1.99 g, 11.0 mmol) and pyridinium tosylate
(753 mg, 3.00 mmol) in acetone/H2O 95:5 (150 mL) was heated at reflux
for 4 h. After removal of the solvent under reduced pressure (400 mbar,
408C bath temperature), the residue was taken up in Et2O (150 mL),
washed with H2O and brine (75 mL each), and dried (MgSO4). The sol-
vent was removed under reduced pressure (800 mbar) and the residue
was filtered through a short pad of silica gel (pentane/Et2O 4:1). The fil-
trate was concentrated to 3–4 mL at 800 mbar pressure to give
(3aS,6S,6aR)-6-methyl-3,3a,6,6a-tetrahydropentalen-1(2H)-one (quanti-
fied by NMR integration). The volatile product can be stored at ꢀ288C.
1H NMR (500 MHz, CDCl3): d=1.08 (d, J=7.0 Hz, 3H; 3-Me), 1.93–2.26
(m, 4H; H7, H8), 2.29 (d, J=7.3 Hz, 1H; H2), 2.86–2.92 (m, 1H; H3),
3.57 (tt, J=7.5, 2.2 Hz, 1H; H6), 5.55 (dt, J=5.6, 1.6 Hz, 1H; H4),
5.69 ppm (dt, J=5.6, 2.4 Hz, 1H; H5); 13C NMR (125 MHz, CDCl3): d=
21.2 (Me-C3), 25.2 (C7), 36.3 (C8), 45.5 (C6), 46.4 (C3), 57.5 (C2), 132.2
(C5), 137.2 (C4), 211.8 ppm (C1); FTIR (ATR): n˜ =3045 (m), 2955 (m),
2900 (m), 2868 (m), 1732 (vs), 1454 (m), 1406 (m), 1372 (m), 1350 (m),
1307 (m), 1255 (m), 1226 (m), 1195 (m), 1151 (s), 1110 (m), 1093 (s), 943
(m), 918 (m), 877 (s), 807 (m), 738 (vs), 722 cmꢀ1 (vs); MS (EI): m/z (%):
136 (70) [M]+, 121 (25), 108 (50), 94 (20), 93 (20), 92 (20), 91 (20), 80
(90), 79 (100).
(2S,3R,3aR,6S,6aR)-2-(Dimethoxymethyl)-6-methyl-3-[3-(trimethylsilyl)-
prop-2-ynyl]-1,2,3,3a,6,6a-hexahydropentalen-1-ol (44):
A solution of
compound 43 (965 mg, 3.01 mmol) in dry MeOH (5 mL) was added to a
solution of NaBH4 (171 mg, 4.50 mmol) in dry MeOH (15 mL) at 08C.
After stirring for 30 min at 08C, the reaction was quenched by careful ad-
dition of a satd solution of NH4Cl (25 mL). The mixture was extracted
b) A solution of 6-methyl-3,3a,6,6a-tetrahydropentalen-1(2H)-one (ap-
proximately 11.0 mmol) in THF(10 mL) was added to a freshly prepared
solution of LDA (15.0 mmol) in dry THF(40 mL) at ꢀ788C followed by
Chem.Eur.J. 2006, 12, 2488 – 2503
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2499

S. Laschat et al.
with EtOAc (3”50 mL) and the combined organic layers were washed
with brine (25 mL), dried (MgSO4), and concentrated. The residue was
filtered through silica gel (PE/EtOAc 2:1; Rf =0.24, PE/Et2O 3:1) to give
compound 44 (967 mg, 99%, >95% NMR purity) as a colorless oil in a
J=8.6, 6.3, 2.4 Hz, 1H; H6), 3.30 (s, 3H; OMe), 3.33 (s, 3H; OMe), 4.15
(d, J=7.0 Hz, 1H; CH(OMe)2), 5.49 (dt, J=5.5, 2.3 Hz, 1H; H4),
5.65 ppm (dt, J=5.5, 1.9 Hz, 1H; H5); 13C NMR (125 MHz, CDCl3): d=
21.4 (Me-C3), 23.3 (C9), 35.6 (C1), 45.9 (C7), 46.7 (C3), 47.0 (C8), 48.6
(C2), 52.7 (OMe), 54.0 (OMe), 56.1 (C6), 68.7 (C11), 83.8 (C10), 108.1
(C(OMe)2), 133.2 (C5), 134.4 ppm (C4); FTIR (ATR): n˜ =3305 (s), 3040
(m), 2952 (vs), 2921 (vs), 2867 (s), 2830 (s), 2115 (m), 1451 (m), 1372
(m), 1248 (m), 1188 (s), 1138 (vs), 1116 (vs), 1053 (vs), 957 (vs), 908 (m),
770 (m), 735 (m), 628 cmꢀ1 (s); MS (CI, NH3): m/z (%): 234 (4) [M]+,
220 (10), 204 (15), 203 (100), 202 (60), 195 (20), 188 (12), 171 (40), 163
(40), 155 (5), 131 (15), 75 (75); HRMS (EI): calcd for C15H22O2:
234.1620; found: 234.1620 [M]+.
1
diastereomeric ratio 1:1. H NMR (300 MHz, CDCl3): d=0.15 (s, 9H; Si-
(CH3)3), 0.16 (s, 9H; Si(CH3)3*), 1.04 (d, J=7.0 Hz, 3H; 3-Me*), 1.05 (d,
J=7.0 Hz, 3H; 3-Me), 1.50–1.70 (m, 2H; OH, OH*), 1.93–2.12 (m, 5H),
2.17–2.37 (m, 3H), 2.52–2.76 (m, 3H), 2.85–2.93 (m, 1H), 3.03–3.20 (m,
2H), 3.33 (s, 3H; OMe*), 3.36 (s, 3H; OMe*), 3.39 (s, 3H; OMe), 3.41
(s, 3H; OMe), 3.63 (t, J=9.0 Hz, 1H; H1*), 4.22–4.27 (m, 1H; H1), 4.34
(d, J=7.2 Hz, 1H; CH(OMe)2*), 4.53 (d, J=6.4 Hz, 1H; CH(OMe)2),
5.54 (dt, J=5.5, 2.2 Hz, 1H; H4*), 5.63 (dt, J=5.5, 1.8 Hz, 1H; H5*),
5.67 (dt, J=5.5, 2.2 Hz, 1H; H4), 5.77 ppm (dt, J=5.5, 1.8 Hz, 1H; H5);
13C NMR (125 MHz, CDCl3): d=0.0 (SiMe3*), 0.1 (SiMe3), 21.3 (Me-
C3*), 21.4 (Me-C3), 24.2 (C9*), 24.4 (C9), 38.7 (C7*), 42.7 (C7), 43.8
(C3*), 44.9 (C3), 51.7 (OMe*), 51.9 (C2*), 52.4 (OMe*), 52.5 (C2), 53.6
(OMe), 53.8 (C6*), 54.0 (C6), 54.9 (C8*), 55.5 (OMe), 55.6 (C8), 75.1
(C1*), 79.8 (C1), 85.4 (C11*), 85.6 (C11), 105.8 (C*(OMe)2), 105.9
(C10*), 106.3 (C10), 108.1 (C(OMe)2), 133.2 (C5*), 133.7 (C5), 134.9
(C4*), 136.5 ppm (C4) (* signals of the second diastereomer); FTIR
(ATR): n˜ =3501 (m), 3041 (m), 2954 (s), 2922 (s), 2832 (m), 2172 (m),
1454 (m), 1371 (m), 1249 (s), 1189 (m), 1142 (m), 1124 (s), 1094 (s), 1052
(vs), 959 (m), 895 (m), 842 (vs), 792 (m), 759 cmꢀ1 (s); MS (DCI, CH4):
m/z (%): 323 (2) [M+H]+, 322 (2) [M]+, 321 (4) [MꢀH]+, 307 (5), 305
(5), 291 (35), 290 (20), 275 (40), 273 (20), 243 (20), 219 (10), 204 (25), 186
(20), 169 (35), 89 (20), 87 (20), 75 (100), 73 (40); HRMS (EI): calcd for
C18H30O3Si: 322.1964; found: 322.1958 [M]+.
Methyl
(2S,3S)-2-azido-3-O-[tert-butyl(dimethyl)silyl]-5-(2E)-6-
[(1R,2R,3aR,4S,6aS)-(dimethoxymethyl)-4-methyl-1,2,3,3a,4,6a-hexahy-
dropentalen-1-yl]hex-2-en-4-ynylamidopentanoate (46): Under Ar gas a
solution of compound 7 (630 mg, 1.30 mmol) and compound 9 (276 mg,
1.18 mmol) in dry THF(1.6 mL) was added to a stirred suspension of
[Pd(PPh3)4] (19 mg, 16.0 mmol) and copper iodide (9 mg, 47.0 mmol) in
NEt3 (2.8 mL). After 1 h, the solvent was removed under vacuum and
the residue was purified by chromatography (Rf =0.32, PE/EtOAc 3:1) to
give compound 46 (630 mg, 91%, >95% NMR purity) as a yellow resin.
[a]2D0 =ꢀ41 (c=1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.13 (s,
6H; (CH3)2SitBu), 0.90 (s, 9H; (Me2SiC(CH3)3), 0.99 (d, J=7.0 Hz, 3H;
3-Me), 1.15 (t, J=11.0 Hz, 1H; H1), 1.63–1.70 (m, 1H; H7), 1.71–1.79
(m, 1H; H16), 1.85–1.94 (m, 1H; H16), 1.95–2.07 (m, 2H; H8, H1), 2.11–
2.18 (m, 1H; H2), 2.37–2.45 (m, 2H; H9), 2.73 (ddd, J=17.0, 4.0, 2.2 Hz,
1H; H3), 3.02 (ddq, J=8.6, 6.2, 2.3 Hz, 1H; H6), 3.30 (s, 3H; OMe), 3.32
(s, 3H; OMe), 3.31–3.41 (m, 1H; H15), 3.41–3.51 (m, 1H; H15), 3.78 (s,
3H; CO2CH3), 4.09 (d, J=4.8 Hz, 1H; H18), 4.15 (d, J=7.0 Hz, 1H; CH-
(OMe)2), 4.17–4.27 (m, 1H; H17), 5.49 (dt, J=5.1, 2.3 Hz, 1H; H4), 5.61
(dt, J=5.1, 1.9 Hz, 1H; H5), 5.78 (br, 1H; NH), 6.09 (d, J=15.3 Hz, 1H;
H13), 6.71 ppm (dt, J=15.3, 1.8 Hz, 1H; H12); 13C NMR (125 MHz,
CDCl3): d=ꢀ4.7, ꢀ4.5 (2”Me2SitBu), 17.9 (SiC(CH3)3), 21.4 (Me-C3),
24.7 (C9), 25.6 (SiC(CH3)3), 32.4 (C16), 35.6 (C1), 35.9 (C15), 46.1 (C7),
46.8 (C3), 47.3 (C8), 48.6 (C2), 52.6 (CO2Me), 52.8 (OMe), 54.1 (OMe),
56.4 (C6), 66.5 (C18), 71.5 (C17), 78.7 (C11), 98.1 (C10), 108.1 (C-
(OMe)2), 122.5 (C12), 131.3 (C13), 133.0 (C5), 134.6 (C4), 164.8 (C14),
168.5 ppm (C19); FTIR (ATR): n˜ =3286 (m), 3042 (m), 2953 (s), 2928
(s), 2899 (m), 2859 (m), 2831 (m), 2214 (m), 2109 (vs), 1750 (vs), 1646
(vs), 1614 (vs), 1548 (vs), 1471 (s), 1462 (s), 1450 (s), 1437 (s), 1360 (m),
1329 (m), 1257 (s), 1205 (s), 1115 (s), 1053 (s), 1005 (m), 958 (m), 839 (s),
779 cmꢀ1 (s); MS (FAB): m/z (%): 611 (4) [M+Na]+, 587 (4) [MꢀH]+,
557 (100), 531 (30), 474 (4), 394 (3), 303 (3), 255 (20), 216 (10), 171 (30),
163 (20), 131 (20), 74 (80), 73 (95), 71 (20); HRMS (FAB): calcd for
C30H48N4NaO6Si: 611.3235; found: 611.3226 [M+Na]+.
{3-[(1R,2R,3aR,4S,6aS)-2-(Dimethoxymethyl)-4-methyl-1,2,3,3a,4,6a-hex-
ahydropentalen-1-yl]prop-1-ynyl}trimethylsilane (45): A solution of com-
pound 44 (65 mg, 0.20 mmol), thiocarbonyldiimidazole (178 mg,
1.00 mmol), and DMAP (122 mg, 1.00 mmol) in CH2Cl2 (4 mL) was
heated at reflux for 16 h. The mixture was then filtered through silica gel
with Et2O to give a yellow oil (79 mg, 91%), that was dissolved in dry
toluene (8 mL). After addition of Bu3SnH (250 mL, 0.93 mmol) and
AIBN (5 mg, 30.5 mmol), a slow stream of dry Ar gas was passed through
for 10 min and the mixture was heated at 1108C for 30 min. The solvent
was removed under vacuum and the residue purified by chromatography
with PE followed by PE/Et2O 9:1 (Rf =0.50) to give compound 45
(35 mg, 57%, 94% NMR purity) as a colorless oil. [a]2D0 =+89.5 (c=1.00
in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.15 (s, 9H; Si(CH3)3), 0.99
(d, J=7.0 Hz, 3H; 3-Me), 1.44–1.56 (m, 1H; H1), 1.04–1.26 (m, 1H; H1),
1.79–2.04 (m, 3H; H2, H7, H8), 2.09 (dd, J=16.9, 8.2 Hz, 1H; H9), 2.20–
2.31 (m, 1H; H6), 2.45 (dd, J=16.9, 4.4 Hz, 1H; H9), 2.85–2.93 (m, 1H;
H3), 3.15 (s, 3H; OMe), 3.17 (s, 3H; OMe), 4.16 (d, J=6.9 Hz, 1H; CH-
(OMe)2), 5.47 (dt, J=5.5, 2.2 Hz, 1H; H4), 5.65 ppm (dt, J=5.5, 1.8 Hz,
1H; H5); 13C NMR (75 MHz, CDCl3): d=0.1 (SiMe3), 21.4 (Me-C3), 24.9
(C9), 35.5 (C1), 46.1 (C7), 46.7 (C3), 47.2 (C8), 48.6 (C2), 52.8 (OMe),
53.7 (OMe), 56.4 (C6), 84.9 (C11), 106.9 (C10), 108.0 (C(OMe)2), 133.5
(C5), 134.2 ppm (C4); FTIR (ATR): n˜ =3041 (m), 2954 (s), 2921 (s), 2868
(m), 2829 (m), 2173 (s), 1493 (m), 1452 (m), 1373 (w), 1305 (w), 1248 (s),
1184 (s), 1138 (s), 1116 (s), 1054 (s), 957 (s), 841 (vs), 759 (s), 642 cmꢀ1
(m); MS (DCI, CH4): m/z (%): 307 (2) [M+H]+, 306 (4) [M]+, 305 (4)
[MꢀH]+, 291 (18), 275 (90), 274 (60), 259 (20), 244 (20), 243 (35), 242
(25), 229 (10), 203 (20), 195 (25), 171 (15), 163 (35), 162 (20), 161 (25),
155 (10), 131 (15), 89 (10), 75 (100), 73 (20); HRMS (EI): calcd for
C18H30O2Si: 306.2015; found: 306.2007 [M]+.
Methyl
(2S,3S)-2-azido-3-O-[tert-butyl(dimethyl)silyl]-5-(2E)-6-
{(1S,2S,3aR,4S,6aS)-2-[(1E)-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-
yl)but-1-enyl]-4-methyl-1,2,3,3a,4,6a-hexahydropentalen-1-yl}hex-2-en-4-
ynylamidopentanoate (48): a) A solution of compound 46 (1.06 g,
1.80 mmol) and PPTS (150 mg, 0.60 mmol) in acetone/5% H2O (30 mL)
was heated at reflux for 3 h. The solvent was removed under vacuum, the
residue was taken up in EtOAc and washed with a satd solution of
NaHCO3 and brine. The organic layer was dried (MgSO4) and concen-
trated to give compound 47 as a colorless oil that was reacted without
further purification. 1H NMR (500 MHz, CDCl3): d=0.12 (s, 6H; Me2Si),
0.89 (s, 9H; Me3CSi), 1.02 (d, J=7.0 Hz, 3H; 3-Me), 1.56–1.62 (m, 1H;
H1), 1.71–1.79 (m, 1H; H16) 1.85–1.93 (m, 1H; H16), 2.16–2.22 (m, 2H;
H2, H7), 2.29–2.35 (m, 1H; H1), 2.46–2.56 (m, 4H; H3, H8, H9), 3.02–
3.07 (m, 1H; H6), 3.35–3.42 (m, 1H; H15), 3.43–3.49 (m, 1H; H15), 3.79
(s, 3H; CO2Me), 4.10 (d, J=4.7 Hz, 1H; H18), 4.21 (dt, J=6.5, 4.7 Hz,
1H; H17), 5.56 (dt, J=5.5, 2.3 Hz, 1H; H5), 5.61 (dt, J=5.5, 1.9 Hz, 1H;
H4), 5.71 (br, 1H; NH), 6.11 (d, J=15.4 Hz, 1H; H13), 6.69 (dt, J=15.4,
2.3 Hz, 1H; H12), 9.57 ppm (d, J=3.0 Hz, 1H; H20).
(1R,2R,3aR,4S,6aS)-2-(Dimethoxymethyl)-4-methyl-1-prop-2-ynyl-
1,2,3,3a,4,6a-hexahydropentalene (9): Finely powdered potassium carbon-
ate (420 mg, 3.04 mmol) was added to
a solution of compound 45
(830 mg, 2.71 mmol) in MeOH (14 mL) and the suspension was stirred
for 20 h at RT. After addition of H2O (10 mL), the reaction mixture was
extracted with EtOAc (2”50 mL). The combined organic layers were
washed with brine, dried (MgSO4), and concentrated to give compound 9
(630 mg, 99%, >95% NMR purity) as a colorless oil. [a]2D0 =+149 (c=
1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.99 (d, J=7.0 Hz, 3H;
3-Me), 1.11–1.22 (m, 1H; H1), 1.64 (tdd, J=8.4, 6.2, 4.1 Hz, 1H; H7),
1.95 (t, J=2.6 Hz, 1H; H11), 1.98–2.07 (m, 2H; H1, H8), 2.16 (qt, J=8.2,
1.8 Hz, 1H; H2), 2.27 (ddd, J=16.7, 8.0, 2.6 Hz, 1H; H9), 2.41 (qq, J=
7.0, 2.2 Hz, 1H; H3), 2.56 (ddd, J=16.7, 4.2, 2.6 Hz, 1H; H9), 3.06 (ddq,
b) A solution of NaHMDS in dimethoxyethane (DME) (6 mL, 1.0m) was
slowly added to a solution of compound 8 (2.27 g, 6.00 mmol) in dry
DME (20 mL) at ꢀ558C, and the mixture was stirred for 1 h. Then a so-
lution of the intermediate 47 in dry DME (5 mL) was slowly added and
after stirring for 1 h at ꢀ558C, the mixture was allowed to warm to RT
2500
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem.Eur.J. 2006, 12, 2488 – 2503

Cylindramide Total Synthesis
FULL PAPER
(16 h). After quenching with a satd solution of NH4Cl, the mixture was
extracted with EtOAc (2”250 mL). The combined organic layers were
washed with brine, dried (MgSO4), and concentrated. The residue was fil-
tered through a short pad of SiO2 with EtOAc, and the crude product
was purified by MPLC on a CN phase (PE/EtOAc 3:1) to give compound
Methyl
(10S,11S,19aS,20aR,21S,23aS,23bS)-10-hydroxy-21-methyl-
6,13,15-trioxo-6,7,8,9,10,11,12,13,14,15,16,17,19a,20,20a,21,23a,23b-octade-
cahydro-1H-pentaleno[1,2-m,1,6]diazacyclohenicosine-11-carboxylate
(51): a) Pd/BaSO4 (35 mg, 5% Pd) was briefly heated, dry MeOH (3 mL)
was added, and the mixture ultrasonificated. Synthetic quinoline (6 mL,
50.6 mmol) was added followed by a solution of compound 49 (328 mg,
537 mmol) in dry MeOH (5 mL) and the mixture was vigorously stirred
under H2 atmosphere (1 atm) for 25 min. Then Celite was added and the
mixture filtered through Celite. The filtrate was concentrated under
vacuum and the residue purified by MPLC on a CN phase (PE/EtOAc
3:1) to give a first fraction containing compound 49 (160 mg, 49%), a
second fraction (Rf =0.40, PE/EtOAc 3:1) containing compound 50
(135 mg, 80% based on conversion, >95% NMR purity), and a third
fraction (Rf =0.27, PE/EtOAc 3:1) containing the overreduced compound
(11% based on conversion) as colorless viscous resins.
Compound 50: [a]2D0 =+68 (c=1.00 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.01 (s, 3H; Me2Si), 0.04 (s, 3H; Me2Si), 0.84 (s, 9H; Me3CSi),
0.99 (d, J=7.0 Hz, 3H; 3-Me), 1.03–1.12 (m, 1H; H1), 1.19–1.28 (m, 1H;
H8), 1.82–1.92 (m, 2H; H16), 1.94–2.10 (m, 3H; H1, H2, H23), 2.11–2.17
(m, 1H; H7), 2.17–2.25 (m, 1H; H9), 2.29–2.37 (m, 1H; H9), 2.37–2.42
(m, 1H; H3), 2.62–2.69 (m, 1H; H23), 2.73 (td, J=7.1, 3.2 Hz, 2H; H22),
2.87–2.92 (m, 1H; H6), 3.29–3.80 (m, 1H; H15), 3.45 (d, J=15.3 Hz, 1H;
H25), 3.53 (d, J=15.3 Hz, 1H; H25), 3.57–3.66 (m, 1H; H15), 3.74 (s,
3H; CO2Me), 4.10 (dt, J=7.3, 4.4 Hz, 1H; H17), 4.68 (dd, J=7.4, 4.8 Hz,
1H; H18), 5.25 (dd, J=15.1, 8.0 Hz, 1H; H20), 5.38 (ddd, J=15.1, 8.0,
5.1 Hz, 1H; H21), 5.49 (dt, J=5.6, 1.8 Hz, 1H; H4), 5.59 (dt, J=5.6,
1.5 Hz, 1H; H5), 5.84 (d, J=15.1 Hz, 1H; H14), 5.90 (ddd, J=11.5, 10.5,
6.7 Hz, 1H; H10), 6.08 (t, J=11.5 Hz, 1H; H11), 6.43 (t, J=6.2 Hz, 1H;
NH), 7.42 (dd, J=15.1, 11.5 Hz, 1H; H12), 7.99 ppm (d, J=7.5 Hz, 1H;
NH); 13C NMR (125 MHz, CDCl3): d=ꢀ5.1 (Me2Si), ꢀ4.6 (Me2Si), 17.8
(Me3CSi), 21.7 (Me-C3), 25.5 (Me3CSi), 26.1 (C9), 31.8 (C23), 34.0 (C16),
35.6 (C15), 40.7 (C1), 43.1 (C22), 46.6 (C3), 49.3 (C7), 50.2 (C8), 50.8
(C2), 51.8 (C25), 52.2 (CO2Me), 56.0 (C6), 56.9 (C18), 71.4 (C17), 124.2
(C12), 127.1 (C21), 128.5 (C11), 132.7 (C5), 134.2 (C20), 134.6 (C4),
135.4 (C13), 138.1 (C10), 166.0 (C14), 166.9 (C26), 170.4 (C19),
204.3 ppm (C24); FTIR (ATR): n˜ =3298 (s), 3039 (s), 2951 (vs), 2927
(vs), 2857 (vs), 1742 (vs), 1721 (vs), 1651 (vs), 1617 (vs), 1543 (vs), 1436
(s), 1409 (m), 1361 (s), 1335 (s), 1256 (vs), 1201 (s), 1179 (m), 1118 (vs),
1034 (m), 1004 (m), 967 (m), 910 (m), 837 (vs), 732 cmꢀ1 (vs); MS (FAB):
m/z (%): 613 (40) [M+H]+, 555 (10), 436 (8), 419 (100), 391 (5), 310 (5),
394 (20), 279 (20), 161 (5); HRMS (FAB): calcd for C34H53N2O6Si:
613.3667; found: 613.3669 [M+H]+.
48 (660 mg, 53%, >95% NMR purity) as a viscous colorless oil. [a]D20
=
+39.5 (c=1.00 in CHCl3); Rf =0.22 (PE/EtOAc 2:1); 1H NMR
(500 MHz, CDCl3): d=0.12 (s, 6H; Me2Si), 0.91 (s, 9H; Me3CSi), 1.01 (d,
J=7.0 Hz, 3H; 3-Me), 1.12 (q, J=11.7 Hz, 1H; H1), 1.36 (dtd, J=11.4,
7.7, 3.9 Hz, 1H; H8), 1.67 (s, 6H; H28), 1.73–1.81 (m, 1H; H23), 1.87–
1.94 (m, 1H; H23), 2.04–2.09 (m, 1H; H1), 2.10–2.20 (m, 1H; H7), 2.21–
2.31 (m, 5H; H9, H16, H22), 2.38–2.45 (m, 1H; H3), 2.55 (ddd, J=16.4,
3.8, 2.2 Hz, 1H; H9), 2.95–3.01 (m, 1H; H6), 3.35–3.43 (m, 1H; H15),
3.43–3.50 (m, 1H; H15), 3.78 (s, 3H; CO2Me), 4.10 (d, J=6.7 Hz, 1H;
H18), 4.21 (dt, J=6.7, 4.5 Hz, 1H; H17), 5.23 (s, 1H; H25), 5.29 (dd, J=
15.0, 8.1 Hz, 1H; H20), 5.40 (dt, J=15.0, 6.0 Hz, 1H; H21), 5.51 (dt, J=
5.5, 2.0 Hz, 1H; H5), 5.66 (dt, J=5.5, 1.7 Hz, 1H; H4), 5.85 (t, J=5.4 Hz,
1H; NH), 6.11 (d, J=15.4 Hz, 1H; H13), 6.71 ppm (dt, J=15.4, 2.2 Hz,
1H; H12); 13C NMR (125 MHz, CDCl3): d=ꢀ4.7, ꢀ4.5 (2”Me2Si), 17.9
(Me3CSi), 21.7 (C3-Me), 22.7 (C9), 25.0 (C27A), 25.1 (C27B), 25.6
(Me3CSi), 28.5 (C22), 32.5 (C23), 33.6 (C16), 35.9 (C15), 40.4 (C1), 46.8
(C3), 49.1 (C7), 49.4 (C8), 50.2 (C2), 52.6 (CO2Me), 55.7 (C6), 66.5
(C18), 71.5 (C17), 79.0 (C11), 93.5 (C25), 97.1 (C10), 106.3 (C27), 122.3
(C13), 128.0 (C20), 131.5 (C4), 132.5 (C5), 134.3 (C12), 134.8 (C21),
161.2 (C24), 164.8 (C14), 168.5 (C19), 171.2 ppm (C26); FTIR (ATR):
n˜ =3303 (s), 3041 (w), 2951 (s), 2927 (s), 2896 (s), 2857 (s), 2211 (m),
2108 (vs), 1731 (vs), 1647 (vs), 1633 (vs), 1614 (vs), 1543 (s), 1461 (m),
1436 (s), 1389 (s), 1375 (s), 1327 (s), 1271 (vs), 1253 (vs), 1202 (vs), 1114
(s), 1012 (vs), 837 (vs), 777 (vs), 736 cmꢀ1 (s); MS (FAB): m/z (%): 717
(10) [M+Na]+, 695 (100) [M+H]+, 637 (60), 580 (10), 171 (20), 73 (65);
HRMS (FAB): calcd for C37H55N4O7Si: 695.3835; found: 695.3832
[M+H]+.
Methyl
(10S,11S,19aS,20aR,21S,23aS,23bS)-10-{[tert-butyl-
(dimethyl)silyl]oxy}-21-methyl-6,13,15-trioxo-2,3-didehydro-
6,7,8,9,10,11,12,13,14,15,16,17,19a,20,20a,21,23a,23b-octadecahydro-1H-
pentaleno[1,2-m,1,6]diazacyclohenicosine-11-carboxylate (49): A solution
of triphenylphosphine (140 mg, 0.53 mmol) and compound 48 (320 mg,
0.46 mmol) in THF(3 mL) was stirred for 3 h at RT. After addition of
H2O (100 mL), the mixture was stirred for a further 18 h. The solvent was
removed under vacuum, the residue was dried azeotropically with tolu-
ene and then heated at reflux for 7 h in dry toluene (1.9 L) under N2 gas.
The solvent was removed under vacuum and the residue purified by
MPLC (Rf =0.75, PE/EtOAc 1:1) to give compound 49 (231 mg, 82%,
>95% NMR purity) as a viscous colorless resin. [a]2D0 =+139 (c=1.00 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=ꢀ0.02 (s, 3H; Me2Si), ꢀ0.01 (s,
3H; Me2Si), 0.82 (s, 9H; Me3CSi), 1.00 (d, J=7.0 Hz, 3H; Me-C3), 1.19
(td, J=12.1, 9.8 Hz, 1H; H1), 1.42–1.49 (m, 1H; H8), 1.83–1.90 (m, 1H;
H16), 1.95–2.02 (m, 1H; H16), 2.02–2.10 (m, 1H; H1), 2.10–2.17 (m, 1H;
H7), 2.21–2.35 (m, 4H; H2, H9, H23), 2.39–2.40 (m, 1H; H3), 2.62–2.81
(m, 4H; H6, H22, H23), 3.16 (ddt, J=14.9, 10.8, 4.1 Hz, 1H; H15), 3.32
(d, J=13.3 Hz, 1H; H25), 3.52 (d, J=13.3 Hz, 1H; H25), 3.79 (s, 3H;
CO2Me), 3.90 (ddd, J=10.3, 4.5, 1.2 Hz, 1H; H17), 3.92–3.97 (m, 1H;
H15), 4.60 (dd, J=6.5, 1.2 Hz, 1H; H18), 5.47–5.50 (m, 2H; H21, H22),
5.52 (dt, J=5.4, 2.0 Hz, 1H; H4), 5.62 (dd, J=5.4, 1.9 Hz, 1H; H5), 6.23
(d, J=15.6 Hz, 1H; H13), 6.59 (dt, J=15.6, 2.2 Hz, 1H; H12), 6.97 (d,
J=6.4 Hz, 1H; NH), 7.54 ppm (dd, J=8.3, 4.3 Hz, 1H; NH); 13C NMR
(125 MHz, CDCl3): d=ꢀ5.1, ꢀ4.6 (2”Me2Si), 17.7 (Me3CSi), 21.7 (Me-
C3), 23.7 (C23), 25.5 (Me3CSi), 26.3 (C9), 33.5 (C16), 35.5 (C15), 40.9
(C1), 43.5 (C22), 47.2 (C3), 48.6 (C7), 50.3 (C8), 50.7 (C2), 50.7 (C25),
52.5 (CO2Me), 56.1 (C18), 56.9 (C6), 73.4 (C17), 79.4 (C11), 96.7 (C10),
121.0 (C12), 127.8 (C21), 131.5 (C4), 133.1 (C20), 133.6 (C13), 135.3
(C5), 165.0 (C14), 166.4 (C26), 169.0 (C19), 203.0 ppm (C24); FTIR
(ATR): n˜ =3289 (s), 3038 (m), 2952 (s), 2928 (s), 2898 (s), 2858 (s), 2213
(w), 1747 (vs), 1720 (vs), 1646 (vs), 1616 (vs), 1541 (vs), 1437 (s), 1361
(s), 1328 (s), 1253 (s), 1205 (s), 1112 (vs), 960 (vs), 910 (s), 837 (vs),
778 cmꢀ1 (vs); MS (FAB): m/z (%): 633 (30) [M+Na]+, 611 (45) [M+H]+,
595 (5), 553 (20), 479 (20), 171 (35), 128 (35), 73 (100); HRMS (FAB):
calcd for C34H51N2O6Si: 611.3511; found: 611.3502 [M+H]+.
b) A solution of compound 50 (120 mg, 197 mmol) in MeCN (2 mL) was
added to a solution of MeCN (6 mL) and HF/H2O (48%, 1.3 mL) in a
Teflon vessel. After stirring for 2 h at RT, brine (15 mL) was added and
the mixture extracted with chloroform (2”35 mL). The combined organic
layers were dried (MgSO4) and concentrated. The residue was purified
by MPLC on a CN phase (CHCl3/MeOH 99:1; Rf =0.4, PE/EtOAc/
CH2Cl2 2:2:1) to give compound 51 (98 mg, 96%, >95% NMR purity)
as a colorless amorphous solid. M.p. 1848C (decomp); [a]2D0 =+107 (c=
1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.99 (d, J=7.0 Hz, 3H;
3-Me), 1.01–1.10 (m, 1H; H1), 1.13–1.20 (m, 1H; H8), 1.22 (br, 1H;
OH), 1.64–1.72 (m, 1H; H16), 1.83 (ddt, J=14.3, 9.9, 4.1 Hz, 1H; H16),
1.95 (ddd, J=14.8, 9.5, 6.5 Hz, 1H; H23), 1.97–2.07 (m, 2H; H1, H2),
2.16 (qq, J=9.2, 1.9 Hz, 1H; H7), 2.20–2.28 (m, 1H; H9), 2.28–2.34 (m,
1H; H9), 2.37–2.43 (m, 1H; H3), 2.52–2.68 (m, 2H; H22), 2.73 (ddd, J=
14.5, 10.8, 4.1 Hz, 1H; H23), 2.91 (qq, J=9.6, 2.2 Hz, 1H; H6), 3.15 (dq,
J=14.2, 4.8 Hz, 1H; H15), 3.38 (d, J=14.8 Hz, 1H; H25), 3.45 (d, J=
14.8 Hz, 1H; H25), 3.75–3.82 (m, 1H; H15), 3.77 (s, 3H; CO2Me), 3.84
(dt, J=10.3, 3.6 Hz, 1H; H17), 4.59 (dd, J=8.3, 3.9 Hz, 1H; H18), 5.26
(dd, J=15.4, 7.5 Hz, 1H; H20), 5.42 (dt, J=15.4, 6.1 Hz, 1H; H21), 5.49
(dt, J=5.5, 2.1 Hz, 1H; H4), 5.59 (dt, J=5.5, 1.8 Hz, 1H; H5), 5.82 (d,
J=14.9 Hz, 1H; H13), 5.90–5.95 (m, 1H; H10), 5.97 (dd, J=10.5, 5.6 Hz,
1H; NH), 6.08 (dd, J=11.5, 10.5 Hz, 1H; H11), 7.29 (d, J=8.3 Hz, 1H;
NH), 7.49 ppm (dd, J=14.9, 11.5 Hz, 1H; H12); 13C NMR (125 MHz,
CDCl3): d=21.6 (Me-C3), 25.9 (C9), 32.3 (C23), 34.2 (C16), 36.0 (C15),
40.5 (C1), 42.5 (C22), 46.5 (C3), 49.3 (C7), 50.6 (C8), 50.8 (C2), 51.5
(C25), 52.5 (CO2Me), 56.5 (C6), 56.5 (C18), 69.4 (C17), 122.8 (C12),
126.3 (C21), 128.1 (C11), 132.8 (C5), 133.4 (C20), 134.7 (C4), 136.8
Chem.Eur.J. 2006, 12, 2488 – 2503
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2501

S. Laschat et al.
(C13), 139.4 (C10), 165.3 (C14), 168.2 (C26), 169.9 (C19), 204.1 ppm
(C24); FTIR (ATR): n˜ =3282 (s), 3038 (m), 2950 (s), 2925 (s), 2889 (s),
2863 (s), 1744 (vs), 1716 (vs), 1646 (vs), 1619 (vs), 1537 (vs), 1436 (s),
1331 (s), 1256 (s), 1204 (s), 1130 (m), 1098 (s), 1019 (m), 958 (vs), 870 (s),
731 cmꢀ1 (vs); MS (FAB, NBA): m/z (%): 521 (40) [M+Na]+, 499 (100)
[M+H]+, 481 (20) [MꢀH2O+H]+, 419 (10); HRMS (FAB): calcd for
C28H39N2O6: 499.2803; found: 499.2797 [M+H]+.
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254.
Cylindramide (1) and 2-epi-cylindramide (2-epi-1): A freshly prepared
1.45m solution of NaOMe (275 mL, 0.40 mmol) was added to a briefly ul-
trasonificated suspension of compound 51 (46 mg, 92.3 mmol) in freshly
distilled dry MeOH (5 mL) and the mixture was heated at 558C for 1.5 h.
H2O (20 mL) was added, the mixture was adjusted to pH 2.0 with 1n
HCl and extracted with n-butanol (2”25 mL). The combined organic
layers were washed with H2O (10 mL) and the solvent removed. The resi-
due was dissolved in MeOH (4.5 mL) and purified (aliquots of 600 mL
each) by preparative HPLC on Nucleosil C-18 AB (250”21 mm) with
CH3CN/H2O 55:45, 0.05% TFA, 6 mg Titriplex II per 2.5 L eluent (flow
50 mLminꢀ1) to give a first fraction containing epi-1 (11.3 mg, 26%, 97%
HPLC purity) and a second fraction containing 1 (23.0 mg, 53%, 96%
HPLC purity) as amorphous beige solids.
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Berg, H. Bahl, J.Antibiot. 1996, 49, 1101–1104.
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Cylindramide (1): HPLC: 17.33 min (CH3CN/H2O 50:50, 0.05% TFA;
1.0 mLminꢀ1, 263 nm); [a]2D0 =+171 (c=0.32 in MeOH); FTIR (ATR):
n˜ =3318 (s), 2951 (m), 2923 (m), 2864 (m), 1714 (m), 1654 (vs), 1604 (vs),
1536 (m), 1479 (m), 1329 (m), 1281 (m), 1208 (m), 1122 (m), 1088 (m),
1014 (m), 993 (m), 964 (m), 867 cmꢀ1 (m); ref. [2]: (KBr): n˜ =3330, 2940,
1660, 1610, 1520, 1440, 1330, 1280, 1210, 960, 860 cmꢀ1; UV (MeOH):
lmax (e)=264 nm (19800 molꢀ1 dm3 cmꢀ1). MS (FAB): m/z (%): 529 (63)
[M+Cu]+, 511 (12) [MꢀH+2Na]+, 505 (15) [M+K]+, 489 (50) [M+Na]+,
467 (100) [M+H]+, 449 (20) [MꢀH2O]+; HRMS (FAB): calcd for
C27H35N2O5: 467.2540; found: 467.2565 [M+H]+.
2005, 44, 820–
1991, 56, 2869–
epi-Cylindramide (2-epi-1): HPLC: 16.01 min (CH3CN/H2O 50:50,
0.05% TFA; 1.0 mLminꢀ1, 263 nm); [a]2D0 =+21 (c=0.50 in MeOH);
1H NMR (500 MHz, MeOD/CDCl3 1:1): d=0.97 (d, J=6.9 Hz, 3H; 17-
Me), 1.09 (q, J=13.1 Hz, 1H; H19), 1.20–1.32 (m, 2H; H4, H13), 1.63–
1.74 (m, 1H; H4), 1.92–2.04 (m, 2H; H19, H20), 2.07–2.20 (m, 3H; H12,
H18, H23), 2.29–2.36 (m, 2H; H23, H24), 2.36–2.44 (m, 1H; H17), 2.47–
2.58 (m, 1H; H12), 2.87–2.96 (m, 1H; H14), 3.04–3.13 (m, 1H; H5),
3.33–3.40 (m, 1H; H24), 3.40–3.49 (m, 1H; H3), 3.60–3.67 (m, 1H; H5),
3.68–3.74 (m, 1H; H2), 5.15–5.37 (m, 2H; H21, H22), 5.47 (d, J=5.1 Hz,
1H; H15), 5.57 (d, J=5.1 Hz, 1H; H16), 5.82–5.92 (m, 1H; H11), 5.86
(d, J=15.2 Hz, 1H; H8), 6.10 (t, J=11.0 Hz, 1H; H10), 7.23 ppm (dd,
J=15.2, 11.0 Hz, 1H; H9); 13C NMR (125 MHz, MeOD/CDCl3 1:1): d=
21.9 (C17-Me), 29.4 (C12), 31.6 (C4), 32.7 (C23), 34.9 (C24), 36.3 (C5),
40.9 (C19), 47.3 (C17), 50.0 (C20), 50.2 (C18), 52.0 (C13), 56.0 (C14),
66.5 (C2), 70.6 (C3), 102.1 (C26), 125.2 (C8), 127.9 (C22), 128.2 (C10),
133.4 (C15), 135.2 (C21), 135.3 (C16), 135.3 (C9), 138.1 (C11), 169.3
(C7), 175.9 (C27), 190.7 (C25), 195.1 ppm (C1); FTIR (ATR): n˜ =3311
(s), 3043 (m), 2951 (s), 2918 (s), 2861 (s), 1716 (s), 1658 (vs), 1603 (vs),
1545 (vs), 1439 (vs), 1348 (s), 1262 (s), 1225 (s), 1192 (s), 1112 (m), 1009
(s), 975 (s), 963 (s), 910 (m), 831 (m), 763 (s), 733 (s), 647 cmꢀ1 (s); MS
(FAB): m/z (%): 589 (8) [M+Na]+, 467 (100) [M+H]+, 449 (8)
[MꢀH2O]+, 299 (10), 247 (14), 155 (50); HRMS (FAB): calcd for
C27H35N2O5: 467.2540; found: 467.2544 [M+H]+.
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Received: October 13, 2005
Published online: January 3, 2006
Chem.Eur.J. 2006, 12, 2488 – 2503
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2503