Synthesis and conformational analysis of geodiamolide analogues

Article abstract of DOI:10.1002/ejoc.200700024

Starting with the ω-hydroxy and ω-amino acid derivatives 13 and 21, the two closely related geodiamolide analogs 32 and 35, respectively, were prepared. Compared to the natural cyclodepsipeptide geodiamolide (1), the macrocycles 32 and 35 have a smaller r

Full text of DOI:10.1002/ejoc.200700024

FULL PAPER
DOI: 10.1002/ejoc.200700024
Synthesis and Conformational Analysis of Geodiamolide Analogues
Srinivasa Marimganti,[a] Ralph Wieneke,[b] Armin Geyer,[b] and Martin E. Maier*[a]
Keywords: Depsipeptides / Peptidomimetics / Amino acids / Hydroxy acids / Conformation
Starting with the ω-hydroxy and ω-amino acid derivatives 13
and 21, the two closely related geodiamolide analogs 32 and
35, respectively, were prepared. Compared to the natural
cyclodepsipeptide geodiamolide (1), the macrocycles 32 and
35 have a smaller ring size (17- vs. 18-membered). Confor-
mational analysis by ROESY spectroscopy and molecular dy-
namics simulation revealed that the reduced ring size causes
the polypropionate sector to flip with regard to the geo-
diamolide conformation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
the marine sponge Geodia sp. shows activity against
fungi.[12–14] The tripeptide fragment and the polypropionate
form an 18-membered ring. The natural product jasplakin-
olide[15] (2), which is produced by the marine sponge Jaspis
sp., contains the same ω-hydroxy acid. With one β-amino
acid instead of an α-amino acid, jasplakinolide features a
19-membered ring. In the depsipeptide doliculide (3), iso-
lated from the sea hare Dolabella auricularea,[16] the poly-
propionate is longer at the expense of an amino acid, re-
sulting in a 16-membered macrocycle. Regarding the bio-
logical activity, jasplakinolide and doliculide are rather sim-
ilar in that they arrest cells at the G2/M phase of the cell
cycle.[17] Both compounds enhance the assembly of actin
into F-actin.
While hard conformational constraints such as rings may
enhance the enthalpy of binding to a receptor, this may be
offset by unfavorable binding entropies.[18] In contrast, soft
constraints should allow for a smooth and movable fit be-
tween ligand and receptor. As indicated in Figure 2, the hy-
droxy acid of jasplakinolide and geodiamolide features two
syn-pentane and one 1,3-allylic interaction.[19] With acid 4
and related hydroxy acids as lead structures we set out to
design simpler or truncated versions giving novel ω-hydroxy
or ω-amino acids.
These analogues might then be bridged with peptide
fragments to give macrocycles.[20] By comparing related
compounds it might then be possible to delineate the effect
of these modifications on the conformation and the overall
flexibility of the respective macrocycles. For example, we
found that jasplakinolide analogs based on ω-amino acid 5
have a conformation comparable to jasplakinolide, but the
macrocycles seem to be more rigid than the natural prod-
uct.[21] In this paper we describe the synthesis of 7-hydroxy
and 7-amino acids of type 6, truncated versions of hydroxy
acid 4, and the synthesis of geodiamolide analogs 32 and
35.
Introduction
In general, peptide modifications are performed with the
aim of finding more selective ligands to increase bioavail-
ability and stability or to mimic certain folds.[1] Typical
modifications are the replacement of peptide bonds with
isosteric functional groups or the replacement of amino ac-
ids with side-chain-modified or other amino acid ana-
logs.[2,3] For example, pseudopeptides in which cyclopro-
pane rings rigidify the Cα, Cβ, and the NH group of an
amino acid have been prepared. Also, pseudopeptides with
trisubstituted (E)-alkene dipeptide isosteres were recently
described.[4] Frequently, such modifications are incorpo-
rated into macrocyclic core structures.[5–8] Alternatively,
small rings can be fused to the macrocycle,[9] or regions
with small rings may be part of the macrocycle.[10,11] In na-
ture, related strategies that influence the conformation of a
macrocyclic ligand can be identified in cyclodepsipeptides.
In these natural products, -configured amino acids, β-
amino acids, or N-methylated amino acids can be found
that, in part, determine the conformation of the macrocycle.
In addition, polypropionate-derived ω-hydroxy acids are
typical fragments of cyclodepsipeptides. With several
methyl groups in a 1,3-configuration, the polypropionate
part can impose soft conformational constraints on the
macrocycle conformation. Figure 1 depicts three represen-
tative cyclodepsipeptides. Geodiamolide (1), isolated from
[a] Universität Tübingen, Institut für Organische Chemie,
Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax: +49-7071-295137
E-mail: martin.e.maier@uni-tuebingen.de
[b] Philipps-Universität Marburg, Fachbereich Chemie,
Hans Meerwein Strasse, 35032 Marburg, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Figure 2. Design of conformationally constrained ω-amino and ω-
hydroxy acids based on hydroxy acid 4.
polar additives, which promote the desired equilibration.
Adding ester 10 to an LDA solution in THF/HMPA (7:3)
followed by trapping of the enolate after 10 min with tert-
butyldimethylsilyl chloride and heating of the mixture
brought about the desired Claisen rearrangement. However,
the 1,4-unsaturated acid 11 was obtained as a 3:1 dia-
stereomeric mixture at C-2. It was surmised that after
10 min, the enolate equilibrium was not yet reached. In fact,
when the enolate solution was allowed to stir for 40 min
prior to the addition of the silyl chloride, the subsequent
Claisen rearrangement produced the desired acid 11 essen-
tially as a single diastereomer (see transition state model
A).
With a view to prepare a geodiamolide analog from hy-
droxy acid 11, the carboxylic acid was converted into the
corresponding tert-butyl ester 12 under Yamaguchi condi-
tions.[25] Cleavage of the silyl ether then led to hydroxy ester
13. The idea was to engage this hydroxy group with an N-
protected amino acid. The resulting fragment could then
Figure 1. Structures of three representative cyclodepsipeptides.
Results and Discussion
The silyl-protected hydroxy acid 11 was prepared from be transformed by two amide-bond-forming reactions into
the known aldol adduct 7 (Scheme 1).[22] Reductive removal geodiamolide analogs. In the event, N,N-dicyclohexylcar-
of the chiral auxiliary gave diol 8. Selective protection of bodiimide (DCC) mediated esterification of Fmoc--valine
the primary alcohol afforded silyl ether 9. Subsequent acyl- with hydroxy ester 13 furnished the diester 14 in 88% yield.
ation of the secondary alcohol with propionyl chloride in Finally, removal of the Fmoc protecting group with dieth-
the presence of pyridine gave ester 10 in good yield. As ylamine in THF led to amine 15.
described by Heathcock et al.,[23] related esters can be re-
The synthesis of the corresponding amino acid 21 started
arranged to the 2,6-anti products by the application of the with the syn-aldol product 7 as well. Silylation of the sec-
Ireland–Claisen rearrangement.[24] In order to reach the de- ondary alcohol led to compound 16 (Scheme 2). Hydrolysis
sired configuration at C-2, the corresponding (Z)-enolate of of the acylated oxazolidinone gave carboxylic acid 17. This
ester 10 was needed. The thermodynamically more stable acid could be smoothly converted to amide 18 with 2-
(Z)-ester enolates can be generated in the presence of di- ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
(EEDQ)
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Synthesis and Conformational Analysis of Geodiamolide Analogues
FULL PAPER
Scheme 2. Synthesis of the ω-amino acid derivative 21 by an aldol/
Claisen strategy.
examination of the NMR spectra of 25, it turned out that
racemization had occurred during the N-methylation step
(Scheme 3).
Scheme 1. Synthesis of ω-silyloxy acid 11 and its conversion to
fragment 15.
and ammonium hydrogen carbonate. Reduction of amide
18 with LiAlH4 produced the corresponding amino alcohol,
which was N-protected to give 19 with BOC anhydride in
the presence of triethylamine. Acylation of alcohol 19 with
propionyl chloride provided ester 20, the required substrate
for the Ireland–Claisen rearrangement. After some trials it
was found that the use of NaN(SiMe3)2 (6 equiv.) in THF/
HMPA (7:3) was suitable for enolate formation. Trapping
of the enolate with Me3SiCl, followed by heating of the in-
termediate ketene acetal delivered the desired amino acid
21 in 64% yield with excellent diastereoselectivity.
As a key building block in the assembly of the tripeptide
sector of the geodiamolide analogs, we envisioned the N-
protected dipeptide acid 30. As described in the literature,
Scheme 3. Initial attempt at synthesizing the dipeptide fragment 25.
Therefore, methylation was performed on the free acid
-tyrosine benzyl ester 22 was converted into the Boc-pro- 28, which can be obtained from Boc-protected tyrosine
tected derivative, which was then silylated on the phenolic (Scheme 4). Treatment of acid 28 with t-BuLi (2.5 equiv.) at
OH group. Subsequent N-methylation of 23 with a 60% –78 °C followed by the addition of MeI (4 equiv.) to the
dispersion of NaH in mineral oil as the base together with dianion provided the N-Boc-N-methyl tyrosine derivative
MeI provided the N-methyl--tyrosine derivative 24.[13b] Af- 29.[13a] After conversion of acid 29 to benzyl ester 30 and
ter cleavage of the N-Boc protecting group with TFA, the cleavage of the N-Boc protecting group, the resulting N-
crude amine was coupled with N-Boc--alanine in the pres- methylamine was condensed with N-Boc--alanine, leading
ence of PyBroP. However, the desired dipeptide 25 was ob- to dipeptide 25. The same sequence was performed with the
tained as a diastereomeric mixture (ratio 3:2). Since rota- -tyrosine derivative, which proved that the earlier racemi-
mers around the N-Boc group could be ruled out, we sus- zation had occurred during the N-methylation of ester 23.
pected that this problem might have occurred either in the Continuing with the synthesis, the benzyl ester of 25 was
N-methylation step or the peptide coupling. After careful cleaved by hydrogenolysis, giving the pure acid 30.
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S. Marimganti, R. Wieneke, A. Geyer, M. E. Maier
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salt was carried out in DMF under high-dilution conditions
(0.001 ) in the presence of TBTU/HOBt. In this way, the
TBS-protected cyclic depsipeptide could be secured. A final
deprotection step with TBAF furnished the desired cyclode-
psipeptide 32.
In order to reach the amide analog (35) of cyclodepsipep-
tide 32, we decided to assemble a tripeptide fragment and
combine it with amino acid 30. This strategy was attractive
since ω-amino acid 21 was obtained in its N-Boc-protected
form. The synthesis of geodiamolide analogue 35 started
with dipeptide acid 30, which was coupled with -valine
methyl ester to give tripeptide 33 (Scheme 6). At this point,
the Boc protecting group at the N-terminus was removed
with TFA. The resulting amine salt was condensed with
amino acid 21 under the action of TBTU, leading to linear
tetrapeptide 34. The hydrolysis of 34 with LiOH in aqueous
THF not only cleaved the ester group but the phenolic silyl
ether as well. The deprotection of the Boc group produced
the seco acid, which on macrolactamization with TBTU/
HOBt, furnished the desired macrolactam 35.
Scheme 4. Racemization-free synthesis of dipeptide fragment 30.
To fashion a cyclodepsipeptide, featuring a tripeptide
subunit and the hydroxy acid 11, we planned to attach
amine 15 to an N-protected dipeptide acid like the -Tyr-
-Val derivative 30. Accordingly, the coupling of acid 30
with amine 15 mediated by TBTU provided the linear de-
psipeptide 31 in 51% yield (Scheme 5). The two tert-butyl-
based protecting groups could now be removed in one step
with TFA. After concentration of the reaction mixture,
macrolactam formation on the corresponding ammonium
Scheme 6. Synthesis of cyclopeptide 35.
Conformational Analysis
1
Both macrocyclic rings 32 and 35 exhibit single H- and
13C-NMR signal sets in [D6]DMSO. Homo- and heteronuc-
lear signal assignments were based on DQF-COSY, HSQC,
and HMBC spectra. Rotating-frame NOESY (ROESY)
and NOESY spectra corroborate these signal assignments.
All amide bonds in 32 and 35 assume the trans configura-
tion as indicated by the absence of NOE contacts expected
Scheme 5. Synthesis of the cyclodepsipeptide 32.
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Synthesis and Conformational Analysis of Geodiamolide Analogues
FULL PAPER
3
2
for cis-amide bonds. Coupling constants JHH and JHH analogs investigated here and the parent macrolide geodia-
were taken directly from the well-resolved 1H NMR spectra molide[12] is an approximately 180° rotation of the propi-
after Lorentz–Gauss transformation. The temperature de- onate relative to the tripeptide unit. As a consequence, the
pendence of the NH chemical shifts yields information 6-Me group is oriented to the opposite side of the macro-
about the solvent accessibility of the amide protons.[26] Val- cyclic rings, which is documented by the intense transannu-
ues between –5.8 and –7.6 ppbK–1 exclude relevant intra- lar 13-NMe–6-Me NOE. The distance between these two
molecular hydrogen bonding for both molecules.
groups is 7.7 Å in geodiamolide where they are positioned
The NMR measurements yielded 57 ROEs for lactone on opposite ring sides (Figure 3). Such a strong effect of a
32 and 45 ROEs for lactam 35. The volume integrals were ring contraction from an 18-membered ring in geodiamol-
translated into average proton-proton distances according ide to a 17-membered ring in 32 and 35 is completely unex-
to published methods.[27] The common Val--Tyr-Ala motif pected but well documented by the solution-phase NMR
adopts a mainly extended conformation with interresidue spectroscopic data analyzed here.
CαHi–NHi+1 average distances between 2.2 Å and 2.4 Å
and intraresidue CαHi–NHi distances approaching 3 Å.
The 1,3-allylic strain in the polypropionate moiety is docu-
mented by the strong 4H–6H3 ROE contact in both mole-
3
cules. JHH values and ROEs allowed the prochiral assign-
ment of the pro-R and pro-S protons of the C-3 and C-7
methylene groups, which form the flexible joints between
both termini of the polypropionate unit and the tripeptide
3
unit. In both molecules, one of the JH3,H4 and one of the
3JH7,H8 values is small (Table 1), as expected if a single con-
formation around the C-2–C-4 and C-7–C-8 bonds pre-
dominates. Differences between 32 and 35 are detected only
for the C-3 protons, which neighbors the lactone (32) or the
amide (35) groups, respectively. The gauche-anti orientation
dominates in lactam 35, as does the gauche-gauche orienta-
tion in lactone 32. The C-18 protons are well resolved in
the case of the lactone but form a higher-order spin system
in the case of the lactam. Chemical-shift differences be-
tween compounds 32 and 35 are restricted to the Northern
half of the macrocyclic rings in the region of the Val residue.
Figure 3. Energy-minimized structures for geodiamolide, lactam
35, and lactone 32.
3
Table 1. 2J and J values (given in Hz) for lactone 32 and lactam
35.
Entry
Coupling
32 (ester)
35 (amide)
1
2
3
4
5
6
2JH3h,H3t
3JH3h,H4
3JH3t,H4
2JH7h,H7t
3JH7h,H8
3JH7t,H8
10.9
2.5
5.4
15.1
Ͻ2
11.1
12.9
9.1
2.6
16.0
Conclusions
Two ring-contracted geodiamolide analogs, the cyclo-
depsipeptide 32 and the cyclopeptide 35, were prepared,
and their solution conformations were studied by NMR
spectroscopy. In contrast to the geodiamolides, the ana-
logues contain simplified ω-hydroxy and ω-amino acids,
Ͻ2
≈10 (COSY)
Molecular dynamics simulations were carried out with respectively. Both of these building blocks could be easily
the MM+ force field, as implemented in HyperChem. synthesized from the aldol product 7. After suitable func-
3
NOEs and J values were incorporated as additional dis- tionalizations, an Ireland–Claisen rearrangement led to the
tance or torsional restraints, respectively, in the empirical polypropionate fragments 11 and 21, respectively. With a
force field. Backbone NOEs are in agreement with one syn-pentane and a 1,3-allylic interaction, these acids feature
main conformation for each macrocycle. Fast conforma- two non-bonded interactions that impose soft conforma-
tional averaging is only of relevance for the amino acid side tional constraints. Classical peptide chemistry was then
chains. The average structures represent minima on the po- used to fashion the analogs 32 and 35. Conformational
tential energy surface, and the energy-minimized structures analysis by NMR spectroscopy and molecular dynamics
are shown in Figure 3. Structural differences are confined simulation revealed that the reduced ring size causes the
to the amino acid Val. The more folded structure of the polypropionate sector to flip with regard to the geodiamol-
lactone brings the 13-NMe and 6-Me groups into closer ide conformation. A comparison between the ester and
contact, which is documented by a particularly short NOE amide analogs shows that in lactone 32 the valine part is
of 3.1 Å. The main difference between the ring-constrained folded towards the macrocyclic ring. This study further
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S. Marimganti, R. Wieneke, A. Geyer, M. E. Maier
5:95). [α]2D0 = –6.5 (c = 1.0, CH Cl ). IR (film): ν = 3370, 2965,
FULL PAPER
˜
underscores the fact that small structural changes can have
a profound effect on the conformation of a macrocyclic
compound.
2
2
2931, 1446, 1095 cm–1. H NMR (400 MHz, CDCl3): δ = 0.87 (d,
J = 6.8 Hz, 3 H, CH3CH), 1.06 (s, 9 H, tBu), 1.66 (s, 3 H,
CH3C=CH), 1.83–1.90 (m, 1 H, CHCH2O), 3.68 (dd, J = 10.1,
5.6 Hz, 1 H, CH2O), 3.71–3.75 (m, 1 H, CH2O), 4.33 (br. s, 1 H,
CHO), 4.90 (s, 1 H, alkene H), 5.03 (s, 1 H, alkene H), 7.37–7.43
(m, 6 H, aromatic H), 7.66–7.72 (m, 4 H, aromatic H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 9.7 (CH3CH), 19.2 [(CH3)3CSi], 19.4
(CH3C=C), 26.5, 26.9 (3 C, tBu), 37.3 (CHCH3), 68.0 (CH2OH),
76.3 (CHOH), 110.5 (alkene CH2), 127.7, 129.7, 134.8, 135.6, 135.7
(aromatic), 145.7 (alkene) ppm. HRMS (ESI): calcd. for
C23H22O2Si [M + Na]+ 391.20638; found 391.20627 (∆m =
0.28 ppm).
1
Experimental Section
General: 1H and 13C NMR: Bruker Avance 400 spectrometer; spec-
tra were recorded at 295 K in CDCl3; chemical shifts are calibrated
to the residual proton and carbon resonance of the solvent: CDCl3
(δH = 7.25 ppm, δC = 77.0 ppm), C6D6 (δH = 7.16 ppm, δC
=
128.0 ppm), and [D6]DMSO (δH = 2.49 ppm, δC = 39.5 ppm). Melt-
ing points: Büchi Melting Point B-540 apparatus, uncorrected. IR:
Jasco FT/IR-430 apparatus [cm–1]. MS: Finnigan Triple-Stage-
Quadrupole TSQ-70 spectrometer (ionizing voltage of 70 eV).
HRMS (FT-ICR): Bruker Daltonic APEX 2 spectrometer with
electron spray ionization (ESI). The minimal resolution of this ma-
chine is 1 ppm (∆m/mϫ106). Flash chromatography: J. T. Baker
silica gel, 43–60 µm. Thin-layer chromatography: Macherey–Nagel
Polygram Sil G/UV254 plates. All solvents used in the reactions
were distilled before use. Dry diethyl ether, tetrahydrofuran, and
toluene were distilled from sodium and benzophenone, whereas dry
CH2Cl2, dimethylformamide, pyridine, and triethylamine were dis-
tilled from CaH2. Petroleum ether with a boiling range of 40–60 °C
was used. Reactions were generally performed under an argon at-
mosphere. All commercially available compounds were used as re-
ceived, unless stated otherwise.
(1S)-1-[(1R)-2-{[tert-Butyl(diphenyl)silyl]oxy}-1-methylethyl]-2-
methylprop-2-enyl Propionate (10): To a solution of alcohol 9
(500 mg, 1.36 mmol) in dry CH2Cl2 (5 mL) were added pyridine
(0.22 mL, 2.68 mmol) and n-propionyl chloride (0.18 mL,
2.00 mmol) at 0 °C. The reaction mixture was warmed to room
temperature and stirred for 12 h. It was then diluted with CH2Cl2
(4 mL), washed with saturated aqueous NaCl, dried (Na2SO4), fil-
tered, and concentrated in vacuo to give the crude ester, which was
purified by flash chromatography (ethyl acetate/petroleum ether,
5:95), providing the propionate 10 (500 mg, 87% yield) as a gel. Rf
= 0.55 (ethyl acetate/petroleum ether, 5:95). [α]2D0 = –11.0 (c = 1.02,
CH Cl ). IR (film): ν = 3066, 2938, 2865, 1739, 1519, 1461, 1095
˜
2
2
1
cm–1. H NMR (400 MHz, CDCl3): δ = 0.87 (d, J = 6.8 Hz, 3 H,
CH3CH), 1.05 (s, 9 H, tBu), 1.12 (t, J = 7.6 Hz, 3 H, CH2CH3),
1.67 (s, 3 H, CH3C=CH), 1.96–2.02 (m, 1 H, CHCH2O), 2.31 (q,
J = 7.6 Hz, 3 H, CH2CH3), 3.48–3.51 (m, 2 H, CH2O), 4.84 (s, 1
H, alkene H), 4.87 (s, 1 H, alkene H), 5.34 (d, J = 5.1 Hz, 1 H,
CHO), 7.35–7.42 (m, 6 H, aromatic H), 7.64 (t, J = 5.1 Hz, 4 H,
aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ = 9.2
(CH2CH3), 11.2 (CH3CH), 19.0 (CH3C=C), 19.2 [(CH3)3CSi], 26.8
(3 C, tBu), 27.7 (CH2CH3), 37.3 (CHCH3), 65.4 (CH2OH), 76.5
(CHOH), 112.0 (alkene CH2), 127.6, 129.6, 133.6, 133.7, 135.6,
135.6 (aromatic), 142.3 (alkene), 173.4 (CO) ppm. HRMS (ESI):
calcd. for C26H36O3Si [M + Na]+ 447.23259; found 447.23264.
(2R,3S)-2,4-Dimethylpent-4-ene-1,3-diol (8): To a solution of aldol
product[22] 7 (1.0 g, 3.30 mmol) in THF (90 mL) was added NaBH4
in H2O (20 mL) at 0 °C. After complete addition, the mixture was
warmed to room temperature and stirred for 7 h. The mixture was
treated with saturated aqueous NH4Cl (20 mL) and stirred for 1 h
at room temperature. After separation of the layers, the aqueous
layer was extracted with ethyl acetate (3ϫ50 mL). The combined
organic layers were washed with saturated aqueous NaHCO3
(50 mL) and saturated aqueous NaCl (50 mL), dried (Na2SO4), fil-
tered, and concentrated in vacuo to give the crude diol, which was
purified by flash chromatography (ethyl acetate/CH2Cl2, 5:95), re-
sulting in pure diol 8 as a colorless oil (365 mg, 85% yield). Rf =
0.23 (ethyl acetate/CH2Cl2, 5:95). [α]2D0 = –14.2 (c = 1.02, CH2Cl2).
(2S,4E,6S)-7-{[tert-Butyl(diphenyl)silyl]oxy}-2,4,6-trimethylhept-4-
enoic Acid (11): A solution of diisopropylamine (0.20 mL,
1.40 mmol) in dry THF (2 mL) was treated with nBuLi (2.5  solu-
tion in hexane, 0.56 mL, 1.40 mmol) at 0 °C. Stirring was continued
for 30 min at 0 °C before HMPA (0.5 mL) was added, and the mix-
ture was cooled to –78 °C. Propionate 10 (500 mg, 1.17 mmol) in
dry THF (0.3 mL) was added dropwise to the above solution. After
stirring for 1 h at –78 °C, TBDMS-Cl (265 mg, 1.76 mmol) in THF
(0.6 mL) was added dropwise. Stirring was continued for 30 min at
–78 °C before the cooling bath was removed, and the reaction mix-
ture was brought to room temperature. The mixture of the ketene
acetal was stirred for 10 h at 60 °C. After cooling to room tempera-
ture, the mixture was treated with saturated aqueous NH4Cl
(5 mL), diluted with 1 N HCl (5 mL), and stirred for 5 min. The
mixture was extracted with ethyl acetate (3ϫ10 mL). The com-
bined ethyl acetate layers were washed with saturated aqueous
NaCl, dried (Na2SO4), filtered, and concentrated in vacuo to give
the crude acid, which was purified by flash chromatography (ethyl
acetate/petroleum ether, 1:3), furnishing pure hydroxy acid 11
IR (film): ν = 3370, 2965, 2931, 1446, 1095 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 0.86 (d, J = 6.8 Hz, 3 H, CH3CH), 1.69 (s,
3 H, CH3C=C), 1.84–1.89 (m, 1 H, CHCH2O), 2.51 (br. s, 1 H,
OH), 2.60 (br. s, 1 H, OH), 3.63–3.71 (m, 2 H, CH2O), 4.22 (br. s,
1 H, CHO), 4.91 (s, 1 H, alkene H), 4.93 (s, 1 H, alkene H) ppm.
13C NMR (100 MHz, CDCl3): δ = 9.7 (CH3CH), 19.3 (CH3C=C),
37.1 (CHCH3), 66.8 (CH2OH), 76.9 (CHOH), 110.6 (alkene CH2),
146.3 (alkene C) ppm.
(3S,4R)-5-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dimethylpent-1-en-3-ol
(9): To a stirred solution of diol 8 (300 mg, 2.30 mmol) in dry DMF
(10 mL) were added imidazole (392 mg, 5.75 mmol) and TBDPS-
Cl (0.65 mL, 2.53 mmol) successively at room temperature. Stirring
was continued for 12 h at room temperature. The mixture was di-
luted with H2O (10 mL), stirred for 0.5 h, and then extracted with
diethyl ether (3ϫ15 mL). The combined organic layers were
washed with 1  HCl (10 mL), saturated aqueous NaHCO3 (360 mg, 72% yield) as a colorless gel; Rf = 0.45 (ethyl acetate/
(10 mL), and saturated aqueous NaCl (15 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo to provide the crude silyl ether,
which was purified by flash chromatography (ethyl acetate/petro-
leum ether, 5:95), yielding the mono-protected alcohol 9 (870 mg,
97% yield) as a viscous oil. Rf = 0.24 (ethyl acetate/petroleum ether,
petroleum ether, 1:3). [α]2D0 = 4.3 (c = 1.13, CH Cl ). IR (film): ν =
˜
2 2
3448, 2966, 2879, 1718, 1629, 1439, 1377, 1195, 1159, 1103, 1053
cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.94 (d, J = 6.8 Hz, 3
H, CH3CHCH2O), 1.04 (s, 9 H, tBu), 1.09 (d, J = 7.1 Hz, 3 H,
CH3CHCO), 1.56 (s, 3 H, CH3), 2.02 (dd, J = 13.4, 8.1 Hz,
2784
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2779–2790

Synthesis and Conformational Analysis of Geodiamolide Analogues
CH2CO2), 2.37 (dd, J = 13.3, 6.7 Hz, CH2CO2), 2.54–2.63 (m, 2 tert-Butyl (2S,4E,6S)-7-({N-[(9H-Fluoren-9-ylmethoxy) carbonyl]-
FULL PAPER
L-
H, CH, CH), 3.41–3.49 (m, 2 H, CH2OH), 4.99 (d, J = 9.1 Hz, 1
H, alkene H), 7.36–7.43 (m, 6 H, aromatic H), 7.82 (d, J = 6.8 Hz,
4 H, aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.8
(CH3), 16.2 (CH3CHCO), 17.3 (CH3CHCH2O), 19.2 [(CH3)3CSi],
26.8 (3 C, tBu), 35.4 (CHCO2), 37.8 (CHCH2O), 43.8 (CH2CO),
68.5 (CH2O), 127.6, 129.5 (aromatic), 130.8 (C-5), 132.0 (aromatic),
134.0 (C-4), 135.6 (aromatic), 182.8 (CO2H) ppm. HRMS (ESI):
calcd. for C26H36O3Si [M + Na]+ 447.23259; found 447.23264.
valyl}oxy)-2,4,6-trimethylhept-4-enoate (14): To a solution of hy-
droxy ester 13 (100 mg, 0.41 mmol), Fmoc--valine (140 mg,
0.41 mmol), and DMAP (25 mg, 0.20 mmol) in dry CH2Cl2 (4 mL)
was added a solution of DCC (110 mg, 0.53 mmol) in dry CH2Cl2
(0.6 mL) dropwise at 0 °C. Stirring was continued for 0.5 h at 0 °C
and for 10 h at room temperature. The reaction mixture was diluted
with diethyl ether (10 mL), filtered to remove the cyclohexyl urea,
and the precipitate was washed twice with diethyl ether (5 mL).
After concentration of the filtrate in vacuo, the crude product was
purified by flash chromatography (ethyl acetate/petroleum ether,
1:4) to give the pure product 14 (205 mg, 87% yield) as a colorless
gel. Rf = 0.30 (ethyl acetate/petroleum ether, 1:4). [α]2D0 = –5.86 (c
tert-Butyl (2S,4E,6S)-7-{[tert-Butyl(diphenyl)silyl]oxy}-2,4,6-tri-
methylhept-4-enoate (12): To a stirred solution of acid 11 (300 mg,
0.71 mmol), DMAP (1.23 g, 10.61 mmol), Et3N (1.0 mL,
7.10 mmol), and tBuOH (0.4 mL, 0.36 mmol) in dry toluene
(70 mL) was added 2,4,6-trichlorobenzoyl chloride (1.1 mL,
7.10 mmol) at –78 °C. After stirring for 30 min at –78 °C, the cool-
ing bath was removed, and the mixture was stirred for 12 h at room
temperature. The mixture was treated with saturated aqueous
NaHCO3 (25 mL). After separation of the layers, the aqueous layer
was extracted with ethyl acetate (3ϫ15 mL). The combined or-
ganic layers were washed with aqueous NaCl (25 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (ethyl acetate/petroleum
ether, 5:95), resulting in pure ester 12 (330 mg, 97% yield). Rf =
0.22 (ethyl acetate/petroleum ether, 5:95). [α]2D0 = 7.7 (c = 0.71,
= 0.87, CH Cl ). IR (film): ν = 3351, 2969, 2904, 1724, 1677, 1454,
˜
2
2
1369, 1153 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.90 (d, J =
6.8 Hz, 3 H, CH3CH2O), 0.97 (d, J = 6.3 Hz, 6 H, Val CH3), 1.03
(d, J = 6.8 Hz, 3 H, CH3CHCO), 1.41 (s, 9 H, tBu), 1.62 (s, 3 H,
CH3C=CH), 1.96 (dd, J = 13.6, 7.3 Hz, 1 H, CH2CHCO), 2.13–
2.20 (m, 1 H, CHNH), 2.32 (dd, J = 13.3, 8.2 Hz, 1 H,
CH2CHCO), 2.43–2.51 (m, 1 H, CHCH2O), 2.71–2.79 (m, 1 H,
CHCO), 3.88–3.98 (m, 2 H, Val CH, CH2O), 4.11 (dd, J = 10.2,
8.2 Hz, 1 H, CH2O), 4.22 (t, J = 7.0 Hz, 1 H, Fmoc CH), 4.30 (dd,
J = 9.0, 4.7 Hz, 1 H, Fmoc CH2), 4.34–4.43 (m, 1 H, Fmoc CH2),
4.94 (d, J = 9.1 Hz, 1 H, alkene H), 5.34 (d, J = 9.1 Hz, 1 H, NH),
7.30 (t, J = 7.3 Hz, 2 H, Fmoc aromatic), 7.39 (t, J = 7.3 Hz, 2 H,
Fmoc aromatic), 7.60 (d, J = 5.6 Hz, 2 H, Fmoc aromatic), 7.75
(d, J = 7.7 Hz, 2 H, Fmoc aromatic) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.0 (CH3C=CH), 16.8 (CH3CH2O), 17.5 (2 C, Val
CH3), 18.9 (CH3CHCO), 28.0 (3 C, tBu), 31.4 (CHCH2O), 32.0
(Val CH), 38.6 (CHCO), 43.8 (CH2C=CH), 47.1 (Fmoc CH), 59.0
(CHNH), 67.0 (Fmoc CH2), 69.5 (CH2O), 79.8 (Boc quaternary),
119.9, 125.1, 127.0, 127.7 (Fmoc aromatic), 128.1 (alkene CH),
134.5 (alkene), 141.3, 143.7, 143.9 (Fmoc aromatic), 156.2
(NHCO), 172.1 (Val CO), 175.7 (CO2tBu) ppm. HRMS (ESI):
calcd. for C34H45NO6 [M + Na]+ 586.3139; found 586.3140.
CH Cl ). IR (KBr): ν = 3066, 2962, 2931, 2861, 1727, 1461, 1369,
˜
2
2
1153, 1110 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.97 (d, J =
6.8 Hz, 3 H, CH3CH2O), 1.03 (d, J = 8.1 Hz, 3 H, CH3CO), 1.04
[s, 9 H, (CH3)3CSi], 1.41 (s, 9 H, tBu), 1.54 (s, 3 H, CH3C=C), 1.95
(dd, J = 13.6, 7.3 Hz, 1 H, CH2CO), 2.30 (dd, J = 13.4, 7.3 Hz, 1
H, CH2CO), 2.41–2.50 (m, 1 H, CHCO), 2.54–2.61 (m, 1 H,
CHCH2O), 3.39 (dd, J = 16.2, 6.8 Hz, 1 H, CH2O), 3.45–3.49 (m,
1 H, CH2O), 4.95 (d, J = 9.1 Hz, 1 H, alkene H), 7.35–7.41 (m, 6
H, aromatic H), 7.66 (d, J = 6.8 Hz, 4 H, aromatic H) ppm. 13C
NMR (100 MHz, CDCl3 ): δ = 15. 9 (CH3 C=CH), 16.9
(CH3CH2O), 17.4 (CH3CHCO), 19.2 [(CH3)3CSi], 26.8 [3 C,
(CH3)3CSi], 28.1 (3 C, tBu), 35.4 (CHCH2O), 38.7 (CHCO), 44.1
(CH2C=CH), 68.6 (CH2O), 79.7 (Boc quaternary), 127.5, 129.5
(aromatic), 129.8 (alkene CH), 132.8 (aromatic), 133.9 (alkene),
135.6 (aromatic), 175.9 (CO2tBu) ppm. HRMS (ESI): calcd. for
C30H44O3Si [M + Na]+ 503.2952; found 503.2950.
tert-Butyl (2S,4E,6S)-2,4,6-Trimethyl-7-(L-valyloxy)hept-4-enoate
(15): Et2NH (7 mL) was added to a precooled solution (0 °C) of
Fmoc-protected valine ester 14 (150 mg, 0.27 mmol) in dry THF
(7 mL). Stirring was continued for 15 min at 0 °C and then at room
temperature for 3 h. The solution was concentrated in vacuo, and
the resulting oil was purified by flash chromatography (MeOH/
CH2Cl2, 5:95) to provide pure amine 15 (80 mg, 88% yield) as a
tert-Butyl (2S,4E,6S)-7-Hydroxy-2,4,6-trimethylhept-4-enoate (13):
To a solution of ω-silyloxy ester 12 (300 mg, 0.63 mmol) in THF
(5 mL) was added TBAF (1 M solution in THF containing 5%
H2O, 0.75 mL, 0.75 mmol) at 0 °C. Stirring was continued until
TLC showed complete consumption of the reactant (4–5 h). The
mixture was concentrated in vacuo, and the residue was purified
by flash chromatography (ethyl acetate/petroleum ether, 1:3), pro-
viding pure hydroxy ester 13 (135 mg, 88% yield) as a colorless gel.
Rf = 0.35 (ethyl acetate/petroleum ether, 1:3). [α]2D0 = –15.7 (c =
slightly yellow oil. R = 0.25 (MeOH/CH Cl , 5:95). IR (film): ν =
˜
f
2
2
3351, 2969, 2904, 1724, 1677, 1454, 1369, 1153 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.88 (d, J = 6.8 Hz, 3 H, Val CH3), 0.96
(d, J = 6.8 Hz, 6 H, Val CH3, CH3CH2O), 1.03 (d, J = 7.1 Hz, 3
H, CH3CHCO),1.41 (s, 9 H, tBu), 1.62 (s, 3 H, CH3C=CH), 1.93–
2.03 (m, 2 H, CH2CHCO, Val CH), 2.32 (dd, J = 13.3, 8.2 Hz, 1
H, CH2CHCO), 2.41–2.50 (m, 1 H, CHCH2O), 2.69–2.78 (m, 1 H,
CHCO), 3.26 (d, J = 4.8 Hz, 1 H, CHNH2), 3.89 (ddd, J = 18.1,
10.8, 6.9 Hz, 2 H, CH2O), 4.94 (d, J = 8.8 Hz, 1 H, alkene H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 16.0 (CH3C=CH), 16.8
(CH3CH2O), 17.1, 17.5 (2 C, Val CH3), 19.3 (CH3CHCO), 28.1 (3
C, tBu), 32.0 (2 C, CHCH2O, Val CH), 38.6 (CHCO), 43.9
(CH2C=CH), 47.1 (Fmoc CH), 59.9 (CHNH), 69.1 (CH2O), 79.9
(Boc quaternary), 128.4 (alkene CH), 134.2 (alkene C), 175.5 (Val
CO), 175.7 (CO2tBu) ppm. HRMS (ESI): calcd. for C19H35NO4
[M + H]+ 342.2639; found 342.2639.
0.77, CH Cl ). IR (film): ν = 3384, 2973, 2930, 2872, 1729, 1457,
˜
2
2
1367, 1151 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.90 (d, J =
6.6 Hz, 3 H, CH3CH2O), 1.06 (d, J = 7.1 Hz, 3 H, CH3CHCO),
1.41 (s, 9 H, tBu), 1.65 (s, 3 H, CH3C=CH), 2.05–2.07 (m, 1 H,
CH2CHCO), 2.32 (dd, J = 13.3, 8.2 Hz, 1 H, CH2CHCO), 2.46–
2.55 (m, 1 H, CHCO), 2.56–2.65 (m, 1 H, CHCH2O), 3.29 (dd, J
= 10.2, 8.2 Hz, 1 H, CH2O), 3.44 (dd, J = 10.4, 5.8 Hz, 1 H,
CH2O), 4.90 (d, J = 9.4 Hz, 1 H, alkene H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.6 (CH3C=CH), 16.9 (CH3CH2O), 17.1 (4S)-4-Benzyl-3-((2S,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-di-
(CH3CHCO), 28.1 (3 C, tBu), 35.5 (CHCH2O), 39.0 (CHCO), 43.8 methylpent-4-enoyl)-1,3-oxazolidin-2-one (16): To a solution of al-
(CH2C=CH), 67.8 (CH2O), 80.0 (Boc quaternary), 129.1 (alkene
CH), 135.3 (alkene C), 175.8 (CO2tBu) ppm. HRMS (ESI): calcd.
for C34H45NO6 [M + Na]+ 265.1774; found 265.1775.
dol product[22] 7 (1.06 g, 3.50 mmol) in dry CH2Cl2 (25 mL) was
added 2,6-lutidine (1.02 mL, 8.75 mmol) at room temperature. The
resulting solution was stirred for 5 min before TBDMSOTf
Eur. J. Org. Chem. 2007, 2779–2790
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2785

S. Marimganti, R. Wieneke, A. Geyer, M. E. Maier
FULL PAPER
(1.05 mL, 4.54 mmol) was added. The reaction mixture was stirred (ethyl acetate/petroleum ether, 1:1). [α]2D0 = –4.5 (c = 1.18, CH2Cl2).
1
for 5 h at room temperature. It was then diluted with H2O (30 mL)
and stirred for an additional 30 min. After separation of the layers,
the aqueous layer was extracted with CH2Cl2 (2 ϫ25 mL). The
combined CH2Cl2 layers were washed with saturated aqueous
NaHCO3 (30 mL), 1 N HCl (30 mL), and saturated aqueous NaCl
(30 mL). After drying (Na2SO4) and filtration, the organic layer
was concentrated in vacuo. The crude product was purified by flash
chromatography (ethyl acetate/petroleum ether, 1:9) to provide the
protected aldol product 16 (1.36 g, 95% yield) as a colorless solid.
Rf = 0.32 (ethyl acetate/petroleum ether, 1:9). 1H NMR (400 MHz,
CDCl3): δ = 0.01, 0.03 [2 s, 6 H, Si(CH3)2], 0.93 [s, 9 H, (CH3)3-
CSi], 1.23 (d, J = 6.6 Hz, 3 H, CH3CH), 1.74 (s, 3 H, CH3C=C),
2.78 (dd, J = 13.4, 9.9 Hz, 1 H, PhCH2), 3.30 (dd, J = 13.3, 2.9 Hz,
1 H, PhCH2), 4.01–4.08 (m, 1 H, CHCH3), 4.13–4.21 (m, 2 H,
OCH2), 4.37 (d, J = 6.6 Hz, 1 H, CHOTBS), 4.59 (ddd, J = 12.9,
6.6, 3.0 Hz, 1 H, CHN), 4.86 (s, 1 H, alkene H), 4.96 (s, 1 H,
alkene H), 7.23–7.37 (m, 5 H, aromatic) ppm. 13C NMR (100 MHz,
CDCl3): δ = –5.4, –4.8 [Si(CH3)2], 12.3 (CH3CH), 17.8 (CH3C=C),
18.2 [(CH3)3CSi], 25.8 [(CH3)3CSi], 37.7 (PhCH2), 42.4 (CHCH3),
55.7 (CHN), 66.0 (OCH2), 76.9 (CHOH), 112.6 (alkene CH2),
127.3, 128.9, 129.4, 135.1 (aromatic), 145.7 (alkene C), 153.1
(NCO), 174.8 (CO) ppm.
IR (film): ν = 3340, 3193, 2935, 2892, 1662, 1461, 1072 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = –0.03 [s, 3 H, (CH3)2Si], 0.02 [s, 3
H, (CH3)2Si], 0.86 (s, 9 H, tBu), 1.07 (d, J = 7.1 Hz, 3 H, CH3CH),
1.66 (s, 3 H, CH3C=C), 2.40–2.46 (m, 1 H, CHCO), 4.21 (d, J =
5.8 Hz, 1 H, CHOTBS), 4.84 (s, 1 H, alkene H), 4.91 (s, 1 H, alkene
H), 5.91, 6.13 (2s, br. , 2 H, NH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = –5.4, –4.8 [(CH3)2Si], 12.5 (CH3CH), 18.0 (CH3C=C),
18.1 [(CH3)3CSi], 25.8 (tBu), 45.4 (CHCO), 77.8 (CHOTBS), 113.2
(alkene CH2), 144.7 (alkene C), 177.2 (CONH2) ppm. HRMS
(ESI): calcd. for C13H27NO2Si [M + Na]+ 280.1703; found
280.1702.
tert-Butyl (2R,3S)-3-Hydroxy-2,4-dimethylpent-4-enylcarbamate
(19): To a solution of amide 18 (275 mg, 1.07 mmol) in dry THF
(5 mL) was added LiAlH4 (1  solution in ether, 4.0 mL, 4.0 mmol)
at 0 °C. The mixture was stirred for 0.5 h at 0 °C, brought to room
temperature by removing the ice bath, and finally heated at reflux
for 2 h. After cooling, the reaction was worked up by the dropwise
and sequential addition of H2O (0.15 mL), 15% aqueous NaOH
(0.15 mL) and additional H2O (0.5 mL, Fieser quench). The mix-
ture was filtered through celite, and the celite bed was washed thor-
oughly with diethyl ether (6ϫ10 mL). The combined filtrates were
dried (MgSO4), filtered, and concentrated in vacuo to give crude
aminol, which was used for the next step (Boc protection) without
any further purification.
(2S,3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-2,4-dimethylpent-4-enoic
Acid (17): H2O2 (1.2 mL of a 30 wt-% solution, 9.6 mmol) was
added at 0 °C to a solution of the protected aldol product 16
(1.00 g, 2.4 mmol) in THF (25 mL), and LiOH·H2O (200 mg,
4.80 mmol), dissolved in H2O (12 mL), was added. The solution
was stirred at 0 °C for 5 h. Subsequently, saturated aqueous
Na2SO3 (10 mL) and saturated aqueous NaHCO3 (10 mL) were
added at 0 °C. The whole mixture was partially concentrated in
vacuo and diluted with H2O (10 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3ϫ25 mL) to recover the auxiliary. The aque-
ous layer was then acidified at 0 °C to pH3 by the addition of
1 N HCl and then extracted with ethyl acetate (4ϫ25 mL). The
combined organic layers were dried (MgSO4), filtered, and concen-
trated in vacuo to give an oily residue. Purification of the residue
by flash chromatography (ethyl acetate/petroleum ether, 1:3) gave
the pure acid. Further acid could be obtained by flash chromatog-
raphy of the concentrated CH2Cl2 layers. Yield 480 mg (77%) of a
To the foregoing crude aminol in dry CH2Cl2 (5 mL) were added
NEt3 (0.27 mL, 2.00 mmol) and Boc anhydride (270 mg,
1.25 mmol) at room temperature. After being stirring for 12 h, the
reaction mixture was acidified to pH 3 with 5% aqueous KHSO4
before it was extracted with CH2Cl2 (3ϫ5 mL).The combined or-
ganic layers were washed with saturated aqueous NaHCO3 (5 mL)
and saturated aqueous NaCl (5 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (ethyl acetate/petroleum ether, 1:3) to give pure
alcohol 19 (145 mg, 58% yield over two steps) as a colorless gel;
Rf = 0.35 (ethyl acetate/petroleum ether, 1:3). [α]2D0 = –4.9 (c = 1.00,
CH Cl ). IR (film): ν = 3363, 2973, 2931, 1689, 1523, 1072 cm–1.
˜
2
2
1H NMR (400 MHz, CDCl3): δ = 0.76 (d, J = 6.8 Hz, 3 H,
CH3CH), 1.42 (s, 9 H, tBu), 1.67 (s, 3 H, CH3C=C), 1.75–1.80 (m,
1 H, CHCH3), 2.91–2.98 (m, 2 H, CH2NH, OH), 3.24–3.31 (m, 1
H, CH2NH), 4.02 (br. s, 1 H, CHOH), 4.90 (br. s, 2 H, NH, alkene
H), 5.03 (s, 1 H, alkene H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 10.6 (CHCH3), 19.5 (CH3C=C), 28.4 (tBu), 36.3 (CHCH3), 43.8
(CH2NH), 74.1 (CHOH), 79.6 (Boc quaternary), 110.5 (alkene
CH2), 145.7 (alkene), 157.1 (C=O) ppm. HRMS (ESI): calcd. for
C12H23NO3 [M + Na]+ 252.15701; found 252.15697.
colorless oil. Rf = 0.35 (ethyl acetate/petroleum ether, 1:3). [α]2D0
–11.4 (c = 1.10, CH Cl ). IR (film): ν = 3100, 2938, 2892, 2618,
=
˜
2
2
1
1708, 1461, 1079 cm–1. H NMR (400 MHz, CDCl3): δ = –0.01 [s,
3 H, (CH3)2Si], 0.02 [s, 3 H, (CH3)2Si], 0.87 (s, 9 H, tBu), 1.11 (d,
J = 7.1 Hz, 3 H, CH3CH), 1.69 (s, 3 H, CH3C=C), 2.59–2.65 (m,
1 H, CHCO), 4.32 (d, J = 5.8 Hz, 1 H, CHO), 4.86 (s, 1 H, alkene
H), 4.95 (s, 1 H, alkene H), 11.42 (br. s, CO2H). 13C NMR
(100 MHz, CDCl3): δ = –5.4, –4.7 [(CH3)2Si], 11.3 (CH3CH), 17.7
(CH3C=C), 18.1 [(CH3)3CSi], 25.7 (tBu), 44.3 (CHCO), 77.3
(CHOTBS), 113.2 (alkene CH2), 144.7 (alkene C), 180.8 (CO2H)
ppm. HRMS (ESI): for C13H26O3Si [M + Na]+ 281.1543; found
281.1542.
(1S)-1-{(1R)-2-[(tert-Butoxycarbonyl)amino]-1-methylethyl}-2-meth-
ylprop-2-enyl Propionate (20): To a solution of alcohol 19 (130 mg,
0.57 mmol) in dry CH2Cl2 (5 mL) was added pyridine (0.09 mL,
1.14 mmol) and n-propionyl chloride (0.07 mL, 0.79 mmol) at 0 °C.
The cooling bath was removed, and the mixture was stirred for 12 h
at room temperature. The mixture was diluted with CH2Cl2 (4 mL),
(2S,3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-2,4-dimethylpent-4-en- washed with saturated aqueous NaCl, dried (Na2SO4), filtered and
amide (18): To a solution of acid 17 (400 mg, 1.54 mmol) in dry concentrated in vacuo. The crude product was purified by flash
CHCl3 (10 mL) were added NH4HCO3 (360 mg, 4.50 mmol) and chromatography (ethyl acetate/petroleum ether, 1:9) to provide the
EEDQ (410 mg, 1.66 mmol) at room temperature. The mixture was
stirred for 48 h at room temperature and then diluted with CH2Cl2
(15 mL) and washed with H2O (10 mL) and saturated aqueous
NaCl (10 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (ethyl acetate/petroleum ether, 1:1) to furnish the
pure amide 18 (300 mg, 75% yield) as a colorless gel; Rf = 0.40
propionate 20 (145 mg, 90% yield) as a colorless oil. Rf = 0.40
(ethyl acetate/petroleum ether, 1:9). [α]2D0 = –15.6 (c = 0.95,
CH Cl ). IR (film): ν = 3374, 2974, 2935, 1712, 1511, 1172 cm–1.
˜
2
2
1H NMR (400 MHz, CDCl3): δ = 0.84 (d, J = 6.8 Hz, 3 H,
CH3CH), 1.15 (t, J = 7.6 Hz, 3 H, CH2CH3), 1.42 (s, 9 H, tBu),
1.69 (s, 3 H, CH3C=C), 2.01–2.04 (m, 1 H, CHCH3), 2.37 (q, J =
7.6 Hz, 2 H, CH2CH3), 2.78–2.85 (m, 1 H, CH2NH), 3.08–3.15 (m,
2786
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2779–2790

Synthesis and Conformational Analysis of Geodiamolide Analogues
FULL PAPER
1 H, CH2NH), 4.90 (br. s, 3 H, NH, alkene H), 5.19 (br. s, 1 H,
CHOR) ppm. 13C NMR (100 MHz, CDCl3): δ = 9.2 (CH2CH3),
CH2Cl2 (5 mL) at 0 °C was added iPr2NEt (0.8 mL, 4.70 mmol),
and the mixture was allowed to stir for 3 h at room temperature.
11.8 (CH3CH), 19.3 (CH3C=C), 27.7 (CH2CH3), 28.4 (tBu), 35.1 The solvent was removed in vacuo, and the residue was purified by
(CHCH3), 43.2 (CH2NH), 76.4 (CHOH), 79.2 (Boc quaternary),
112.1 (alkene CH2), 141.9 (alkene), 156.0 (Boc C=O), 174.0 (CO2R)
ppm. HRMS (ESI): calcd. for C15H27NO4 [M + Na]+ 308.1832;
found 308.1834.
flash chromatography (ethyl acetate/petroleum ether, 1:3) to give
the dipeptide 25 (403 mg, 55% yield) as a colorless gel. Rf = 0.45
1
(ethyl acetate/petroleum ether, 1:3). H NMR (400 MHz, CDCl3):
δ = 0.13 [s, 6 H, (CH3)2Si], 0.84 (d, J = 6.8 Hz, 3 H, Ala CH3),
0.94 [s, 9 H, (CH3)3CSi], 1.41 (s, 9 H, Boc tBu), 2.80 (s, 3 H,
NCH3), 2.95 (dd, J = 14.5, 11.8 Hz, 1 H, Tyr CH2), 3.33 (dd, J =
14.8, 4.9 Hz, 1 H, Tyr CH2), 4.43–4.50 (m, 1 H, Ala CH), 5.12–
5.20 (m, 2 H, CH2Ph), 5.26–5.30 (m, 1 H, Tyr CH), 5.44 (d, J =
7.8 Hz, 1 H, Ala NH), 6.71 (d, J = 8.6 Hz, 2 H, aromatic H), 6.99
(d, J = 8.6 Hz, 2 H, aromatic H), 7.31–7.34 (5 H, aromatic CO2Bn)
ppm. 13C NMR (100 MHz, CDCl3): δ = –4.5 [2 C, (CH3)2Si], 18.1
(Ala CH3), 18.4 [(CH3)3CSi], 25.6 [(CH3)3CSi], 28.3 (Boc tBu), 32.5
(NCH3), 33.9 (Tyr CH2), 46.4 (Ala CH), 58.4 (Tyr CH), 67.0
(OCH2), 79.5 (Boc C), 120.1, 128.2, 128.6, 129.0, 129.6, 135.6 (aro-
matic), 154.5 (Boc CO), 155.0 (phenolic), 170.3 (Ala CO), 173.6
(Tyr CO) ppm.
(2S,4E,6S)-7-[(tert-Butoxycarbonyl)amino]-2,4,6-trimethylhept-4-en-
oic Acid (21): To solution of propionate 20 (140 mg, 0.49 mmol) in
THF/HMPA (1.1 mL/0.4 mL) was added NaN(SiMe3)2 (2  in
THF, 1.5 mL, 3.0 mmol) at –78 °C. After being stirred for 45 min
at –78 °C, TMS-Cl (0.5 mL, 4.00 mmol) and Et3N (0.20 mL,
1.50 mmol) were added simultaneously. After an additional 15 min
at –78 °C, the cooling bath was removed, and the reaction mixture
was allowed to reach room temperature within 1 h. The mixture
was then heated to 60 °C for 5 h. After the mixture was cooled,
saturated aqueous NH4Cl (2 mL) and 1 N HCl (2 mL) were added,
and the mixture was extracted with ethyl acetate (3ϫ5 mL). The
combined organic layers were washed with saturated aqueous NaCl
(4 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (ethyl acetate/petro-
leum ether, 1:1) to give the pure amino acid 21 (90 mg, 64% yield)
as a slightly yellow oil. Rf = 0.45 (ethyl acetate/petroleum ether,
N-(tert-Butoxycarbonyl)-O-[tert-butyl(dimethyl)silyl]-D-tyrosine
(28): To a solution of N-Boc--tyrosine 26 (1.00 g, 3.55 mmol) in
dry DMF (15 mL), imidazole (725 mg, 10.66 mmol) and
TBDMSCl (1.10 g, 7.80 mmol) were added successively at room
temperature. The resulting solution was stirred overnight at room
temperature. The reaction mixture was then treated with H2O
1:1). [α]2D0 = –34.6 (c = 0.62, CH Cl ). IR (film): ν = 3361, 2974,
˜
2
2
1
2930, 1735, 1712, 1511, 1172 cm–1. H NMR (400 MHz, CDCl3):
δ = 0.89 (d, J = 6.6 Hz, 3 H, 6-CH3), 1.12 (d, J = 6.8 Hz, 3 H, 2- (15 mL) and stirred for 30 min. The mixture was extracted with
CH3), 1.42 (s, 9 H, tBu), 1.62 (s, 3 H, CH3C=C), 2.03–2.10 (m, 1
H, 3-H), 2.34–2.39 (m, 1 H, 3-H), 2.56–2.67 (m, 2 H, 2-H, 6-H),
diethyl ether (3ϫ30 mL). The combined ether layers were success-
ively washed with 1 N HCl (20 mL), saturated aqueous NaHCO3
2.76–2.78 (m, 1 H, 7-H), 3.11–3.14 (m, 1 H, 7-H), 4.55 (br. s, 1 H, (20 mL), and saturated aqueous NaCl (20 mL). The dried
NH), 4.91 (d, J = 9.4 Hz, 1 H, alkene H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.2 (CH3C=C), 16.3 (2-CH3), 18.2 (6-
CH3), 28.4 (tBu), 33.0 (C-6), 37.9 (C-2), 43.6 (C-3), 46.4 (CH2NH),
79.1 (Boc quaternary), 130.8 (alkene CH), 133.4 (alkene), 156.0
(Boc C=O), 181.7 (CO2H) ppm. HRMS (ESI): calcd. for
C15H27NO4 [M + Na]+ 308.18323; found 308.18317.
(Na2SO4) organic layers were filtered and concentrated in vacuo to
give the crude silyl ester 27 as a colorless oil.
The crude ester 27 was dissolved in THF (10 mL) and treated with
K2CO3 solution (1 , 10 mL), and the mixture was stirred at room
temperature for 1 h. The mixture was acidified to pH 3 by adding
1  HCl and then extracted with ethyl acetate (3ϫ30 mL). The
Benzyl N-(tert-Butoxycarbonyl)-O-[tert-butyl(dimethyl)silyl]-N- combined ethyl acetate layers were dried with Na2SO4, filtered, and
methyl-
D
-tyrosinate (24): To a solution of acid 29 (700 mg,
concentrated in vacuo. The residue was purified by flash
chromatography (ethyl acetate/petroleum ether, 1:3) to provide the
1.71 mmol), benzyl alcohol (0.53 mL, 5.13 mmol), and DMAP
(104 mg, 0.86 mmol) in dry CH2Cl2 (15 mL) was added at 0 °C a pure acid 28 (1.20 g, 86% yield) as a colorless oil. Rf = 0.44 (ethyl
solution of DCC (460 mg, 2.22 mmol) in CH2Cl2 (2.5 mL). The
solution was stirred for 0.5 h at 0 °C and then for 12 h at room
temperature. The dicyclohexyl urea was filtered off, and the precipi-
tate was washed with diethyl ether (3ϫ5 mL). The filtrate was con-
centrated in vacuo to provide the crude product, which was purified
by flash chromatography (ethyl acetate/petroleum ether, 1:9) to fur-
nish the benzyl ester 24 (760 mg, 89% yield) as a colorless oil. Rf
= 0.52 (ethyl acetate/petroleum ether, 1:9). [α]2D0 = 71.8 (c = 1.70,
acetate/petroleum ether, 1:3). 1H NMR (400 MHz, CDCl3): δ =
0.21 [s, 6 H, Si(CH3)2], 1.03 [s, 9 H, (CH3)3CSi], 1.34 (s, 9 H, Boc
tBu), 2.71–2.79 (m, 1 H, CH2), 3.21 (br. s, 1 H, CH2), 4.31 (br. s,
1 H, CH), 6.74 (d, J = 6.6 Hz, 2 H, aromatic H), 7.10 (d, J =
4.8 Hz, 2 H, Tyr) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.5 [s,
(CH3)2Si], 18.1 [(CH3)3CSi], 25.6 [(CH3)3CSi], 28.2 (Boc tBu), 37.0
(CH2), 56.8 (CH), 79.1 (Boc quaternary), 119.6, 125.2, 130.2 (aro-
matic), 153.9 (phenolic), 156.4 (Boc CO), 179.1 (CO2H) ppm.
1
MeOH). H NMR (400 MHz, CDCl3): δ = 0.16 [s, 6 H, Si(CH3)2],
N-(tert-Butoxycarbonyl)-O-[tert-butyl(dimethyl)silyl]-N-methyl-D-
0.96 [s, 9 H, (CH3)3CSi], 1.32, 1.37 (2s, 9 H, tBu Boc), 2.65, 2.70
(2s, NCH3), 2.93–3.00 (m, 1 H, Tyr CH2), 3.19–3.28 (m, 1 H, Tyr
CH2), 4.51, 4.86 (2 dd, J = 10.6, 4.6 Hz, J = 10.5, 5.4 Hz, 1 H, Tyr
CH), 5.11–5.20 (m, 2 H, OCH2Ph), 6.74 (d, J = 8.1 Hz, 2 H, Tyr),
7.00–7.05 (m, 2 H, Tyr), 7.34 (s, 5 H, Bn aromatic) ppm.
tyrosine (29): To a solution of N-Boc amino acid 28 (1.04 g,
2.64 mmol) in dry THF (12 mL) was added tBuLi (1.5  solution
in pentane, 4.40 mL, 6.60 mmol) dropwise at –78 °C. The mixture
was stirred for 10 min, and then methyl iodide (0.57 mL,
10.6 mmol) was added to the reaction mixture at –78 °C. Stirring
was continued for 12 h with simultaneous warming of the reaction
mixture to room temperature. The reaction mixture was diluted
with saturated aqueous NH4Cl (3 mL), and the resulting mixture
was extracted with ethyl acetate (3ϫ20 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, and concentrated in
vacuo to give the crude product, which was purified by flash
chromatography (ethyl acetate/petroleum ether, 1:3) to afford the
N-methylated acid 29 (820 mg, 76% yield) as a colorless solid. Rf
= 0.52 (ethyl acetate/petroleum ether, 1:3). 1H NMR (400 MHz,
Benzyl N-(tert-Butoxycarbonyl)-
L-alanyl-O-[tert-butyl(dimethyl)-
silyl]-N-methyl- -tyrosinate (25): To a solution of -tyrosine benzyl
D
ester derivative 24 (650 mg, 1.30 mmol) in CH2Cl2 (10 mL) was
added TFA (1.0 mL, 13.0 mmol), and the mixture was stirred at
room temperature for 1 h. The solvent was removed in vacuo, and
the residue was dried by azeotropic removal of H2O with toluene.
The crude material was subjected to the next reaction without fur-
ther purification. To a stirred solution of crude amine, N-Boc--
alanine (240 mg, 1.30 mmol), and PyBroP (635 mg, 1.30 mmol) in
Eur. J. Org. Chem. 2007, 2779–2790
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2787

S. Marimganti, R. Wieneke, A. Geyer, M. E. Maier
FULL PAPER
CDCl3): δ = 0.15 [s, 6 H, Si(CH3)2], 0.95 [s, 9 H, (CH3)3CSi], 1.34,
1.37 (2s, 9 H, Boc tBu), 2.65, 2.71 (2s, NCH3), 2.92–3.03 (m, 1 H,
CH2), 3.17–3.27 (m, 1 H, CH2), 4.49, 4.79 (2 dd, J = 10.9, 4.1 Hz,
J = 11.0, 4.9 Hz, 1 H, CH), 6.74 (d, J = 8.3 Hz, 2 H, aromatic),
7.01 (d, J = 8.3 Hz, 1 H, aromatic), 7.04 (d, J = 8.3 Hz, 2 H, aro-
matic) ppm.
tBu), 120.0, 128.1, 129.4 (aromatic), 129.7 (alkene CH), 134.4 (al-
kene), 154.4 (Boc C=O), 155.3 (phenolic), 170.1 (Tyr CO), 171.7
(Val CO), 174.5 (Ala CO), 175.7 (CO2tBu) ppm. HRMS (ESI):
calcd. for C43H73N3O9Si [M + Na]+ 826.50083; found 826.50078.
(3S,6R,9S,12R,16R)-6-(4-Hydroxybenzyl)-3-isopropyl-7,9,12,14,16-
pentamethyl-1-oxa-4,7,10-triazacycloheptadec-14-ene-2,5,8,11-
tetrone (32): To a solution of linear depsipeptide 31 (40 mg,
0.05 mmol) in CH2Cl2 (0.5 mL) was added TFA (0.08 mL,
0.99 mmol) at 0 °C. Stirring was continued for 2 h; at this time TLC
showed the complete consumption of reactant 31. The solvent was
removed in vacuo, and the residue was dried by the azeotropic re-
N-(tert-Butoxycarbonyl)-
L-alanyl-O-[tert-butyl(dimethyl)silyl]-N-
methyl- -tyrosine (30): To a solution of dipeptide 25 (400 mg,
D
0.70 mmol) in ethanol (5 mL) was added 10% Pd/C (80 mg). The
reaction mixture was connected to a hydrogenation machine (Parr
apparatus) and shaken for 16 h under a hydrogen atmosphere of
about 2 bar (30 psi) at room temperature. The reaction mixture was moval of H2O with toluene. The crude material was used in the
filtered through a bed of celite, and the celite bed was washed with
ethyl acetate (2ϫ5 mL). The filtrate was concentrated in vacuo to
afford the crude acid 30 (98% yield), which was used without fur-
ther purification. 1H NMR (400 MHz, CDCl3): δ = 0.13 [s, 6 H,
(CH3)2Si], 0.86 (d, J = 7.6 Hz, 3 H, Ala CH3), 0.94 [s, 9 H,
(CH3)3CSi], 1.40, (s, 9 H, Boc tBu), 2.85 (s, 3 H, NCH3), 2.93–3.03
(m, 1 H, Tyr CH2), 3.34 (dd, J = 14.7, 4.3 Hz, 1 H, Tyr CH2), 4.47–
4.53 (m, 1 H, Ala CH), 5.28 (dd, J = 11.2, 3.9 Hz, 1 H, Tyr CH),
5.56 (d, J = 8.1 Hz, 1 H, Ala NH), 6.72 (d, J = 8.3 Hz, 2 H, aro-
matic H) 7.00 (d, J = 8.3 Hz, 2 H, aromatic H) ppm. 13C NMR
(100 MHz, CDCl3): δ = –4.5 [2 C, (CH3)2Si], 14.1, 18.2 (Ala CH3),
18.2 [(CH3)3CSi], 25.6 [(CH3)3CSi], 28.3 (Boc tBu), 32.6 (NCH3),
33.7 (Tyr CH2), 46.5 (Ala CH), 58.4 (Tyr CH), 79.8 (Boc quater-
nary C), 120.1, 129.1, 129.6 (aromatic), 154.5 (Boc C=O), 155.3
(phenolic), 173.6 (Ala CO), 174.2 (Tyr CO) ppm.
next step without further purification. To a solution of crude amine
salt in dry DMF (50 mL) were added iPr2NEt (0.04 mL,
0.20 mmol), HOBt (20 mg, 0.15 mmol), and TBTU (48 mg,
0.15 mmol) successively at room temperature. The solution was
stirred at room temperature for 18 h and then partitioned between
ethyl acetate and H2O. The aqueous layer was extracted with ethyl
acetate (3ϫ30 mL). The combined ethyl acetate layers were washed
successively with 5 % aqueous KHSO4, H2O, 50% aqueous
NaHCO3, and saturated aqueous NaCl, dried (MgSO4), filtered,
and concentrated in vacuo to give the crude product, which was
purified by flash chromatography (ethyl acetate/petroleum ether,
1:1), providing the pure cyclic depsipeptide (12 mg, 39% yield) as
a colorless oil. To this TBS-protected cyclic depsipeptide (12 mg,
0.02 mmol) in THF (0.2 mL) was added TBAF containing 5% H2O
(1  solution in THF, 0.04 mL, 0.04 mmol) at 0 °C, and stirring
was continued for 3 h at 0 °C. The mixture was concentrated in
vacuo, and the crude macrocycle was purified by flash chromatog-
raphy (ethyl acetate/petroleum ether, 7:3), yielding the pure cyclic
depsipeptide 32 (8 mg, 80% yield) as a colorless oil. Rf = 0.22 (ethyl
acetate/petroleum ether, 7:3). [α]2D0 = +11.6 (c = 0.70, CH2Cl2). IR
(2S,3E,6S)-7-tert-Butoxy-2,4,6-trimethyl-7-oxohept-3-enyl N-(tert-
Butoxycarbonyl)-
L-alanyl-O-[tert-butyl(dimethyl)silyl]-N-methyl-D-
tyrosyl- -valinate (31): To a solution of acid 30 (70 mg, 0.15 mmol),
L
and amine 15 (50 mg, 0.15 mmol) in dry DMF (1.5 mL) were
added iPr2NEt (0.07 mL, 0.44 mmol), HOBt (20 mg, 0.15 mmol),
and TBTU (47 mg, 0.15 mmol) at room temperature. The reaction
mixture was stirred for 5 h at room temperature before it was
treated with H2O (2 mL) and stirred for a further 5 min and then
extracted with ethyl acetate (3ϫ4 mL). The combined ethyl acetate
layers were washed with 1  HCl (3 mL), saturated aqueous
NaHCO3 (3 mL), and saturated aqueous NaCl , dried (Na2SO4),
filtered, and concentrated in vacuo to give the crude product, which
was purified by flash chromatography (ethyl acetate/petroleum
ether, 15:85), providing the linear depsipeptide 31 (60 mg, 51%
yield) as a colorless oil. Rf = 0.37 (ethyl acetate/petroleum ether,
(film): ν = 3361, 2974, 2930, 1735, 1712, 1511, 1172 cm–1. 1H NMR
˜
(600 MHz, [D6]DMSO): δ = 0.86 (CH3CHCH2O), 0.87 (Val CH3),
0.93 (d, J = 6.7 Hz, 3 H, Val CH3), 0.95 (d, J = 6.6 Hz, 3 H, Ala
CH3), 1.01 (d, J = 6.9 Hz, 3 H, CH3CHCO), 1.56 (s, 3 H,
CH3C=C), 1.83 (d, J = 14.9 Hz, 1 H, CH2hCHCO), 2.02 (pseudo-
sext, J = 6.7 Hz, 1 H, Val CH), 2.25 (dd, J = 15.1, 11.1 Hz, 1
t
H, CH2 CHCO), 2.36–2.43 (m, 1 H, CHCO), 2.56–2.63 (m, 1 H,
CHCH2O), 2.66 (dd, J = 14.3, 8.1 Hz, 1 H, Tyr CH2h), 2.79 (s, 3
t
H, NMe), 3.00 (dd, J = 14.3, 6.4 Hz, 1 H, Tyr CH2 ), 3.70 (dd, J
= 10.8, 2.5 Hz CH2hO), 4.04 (pseudo-t, J = 7.7 Hz, Val CH), 4.18
t
(dd, J = 10.9, 5.4 Hz, 1 H, CH2 O), 4.52 (quint, J = 6.9 Hz, 1 H,
15:85). [α]2D0 = 28.0 (c = 0.50, CH Cl ). IR (film): ν = 3361, 2974,
˜
2
2
1
Ala CH), 5.05 (d, J = 8.0 Hz, alkene), 5.24 (dd, J = 8.7, 6.5 Hz, 1
H, Tyr CH), 6.61 (d, J = 8.5 Hz, 2 H, TyrArHmeta), 6.98 (d, J =
8.5 Hz, 2 H, TyrArHortho), 7.43 (d, J = 7.7 Hz, 1 H, Val NH), 8.05
(d, J = 7.8 Hz, 1 H, Ala NH), 9.05 (s, Tyr-OH) ppm. 13C NMR
(600 MHz, [D6]DMSO): δ = 16.9 (Ala CH3), 17.8 (CH3C=C), 18.8
(Val CH3), 19.5 (CH3CHCO), 29.1 (Val CH), 29.8 (NCH3), 31.3
(CHCH2O), 32.4 (Tyr CH2), 38.5 (CHCO), 40.6 (CH2CHCO), 44.0
(Ala CH), 56.3 (Tyr CH), 58.8 (Val CH), 68.1 (CH2O), 114.4 (Tyr-
Armeta), 125.2 (alkene CH), 127.7 (CipsoAr), 129.5 (TyrArortho),
133.8 (alkene C), 155.3 (C-OH Ar), 169.8 (Tyr CO), 170.2 (Val
CO), 171.5 (Ala CO), 174.1 (CH2CHCO) ppm. HRMS (ESI):
calcd. for C28H41N3O6Si [M + Na]+ 538.2888; found 538.2891.
2930, 1735, 1712, 1511, 1172 cm–1. H NMR (400 MHz, CDCl3):
δ = 0.12 [s, 6 H, (CH3)2Si], 0.85 (d, J = 6.1 Hz, 3 H, Val CH3), 0.87
(d, J = 6.1 Hz, 3 H, Val CH3 ), 0.89 (d, J = 6.8 Hz, 3 H,
CH3CHCH2O), 0.93–0.95 [m, 12 H, (CH3)3CSiBu, CH3CHCO],
1.02 (d, J = 6.8 Hz, 3 H, Ala CH3), 1.38, 1.40 (2 s, 18 H, tBu, Boc
tBu), 1.60 (s, 3 H, CH3C=C), 1.91–1.97 (m, 1 H, Val CH), 2.10–
2.18 (m, 1 H, CH2CHCO), 2.28–2.34 (m, 1 H, CH2CHCO), 2.42–
2.48 (m, 1 H, CHCO), 2.70–2.75 (m, 1 H, CHCH2O), 2.84–2.88
(m, 1 H, Tyr CH2), 2.91 (s, 3 H, NCH3), 3.29 (dd, J = 14.9, 5.8 Hz,
1 H, Tyr CH2), 3.84–3.92 (m, 1 H, CH2O), 4.39–4.45 (m, 1 H, Ala
CH), 4.92 (d, J = 8.8 Hz, alkene H), 5.25 (d, J = 7.1 Hz, Val CH),
5.28 (br. s, 1 H, Ala NH), 5.49 (dd, J = 10.4, 5.8 Hz, 1 H, Tyr CH),
6.59 (d, J = 8.8 Hz, 1 H, Val NH), 6.69 (d, J = 8.1 Hz, 2 H, aro-
Methyl N-(tert-Butoxycarbonyl)-
L-alanyl-O-[tert-butyl(dimethyl)-
matic H), 7.01 (d, J = 8.3 Hz, 2 H, aromatic H) ppm. 13C NMR silyl]-N-methyl-
D
-tyrosyl- -valinate (33): To a solution of dipeptide
L
(100 MHz, CDCl3): δ = –4.5 [2 C, (CH3)2Si], 16.0 (CH3C=C), 16.8 acid 30 (200 mg, 0.42 mmol) and -valine methyl ester hydrochlo-
(CH3CHCO), 17.5 (Val CH3), 17.7 (Val CH3, CH3CH2CHO), 18.2 ride (70 mg, 0.42 mmol) in dry DMF (4 mL) were added iPr2NEt
[(CH3)3CSiBu], 19.1 (Ala CH3), 25.6 [(CH3)3CSiBu], 28.1, 28.3 (6 (0.18 mL, 1.05 mmol), HOBt (58 mg, 0.42 mmol), and TBTU
C, tBu, Boc tBu), 30.6 (CHCH2O), 30.8 (Val CH), 31.8 (NCH3),
34.3 (Tyr CH2), 38.6 (CHCO), 43.9 (CH2CHO), 46.6 (Ala CH), was stirred for 3 h at room temperature. Thereafter, it was treated
57.2 (Val CH), 57.4 (Tyr CH), 69.5 (CH2O), 79.6, 79.9 (2 C, Boc, with H2O (5 mL), stirred for 5 min, and extracted with ethyl acetate
(135 mg, 0.42 mmol) at room temperature. The resulting mixture
2788
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2779–2790

Synthesis and Conformational Analysis of Geodiamolide Analogues
FULL PAPER
(3ϫ10 mL). The combined ethyl acetate layers were washed with
1  HCl (5 mL), saturated aqueous NaHCO3 (5 mL), and saturated
aqueous NaCl (5 mL), dried (Na2SO4), filtered, and concentrated
in vacuo to furnish the crude product, which was purified by flash
chromatography (ethyl acetate/petroleum ether, 1:3), yielding the
pure tripeptide 33 (177 mg, 71% yield) as a colorless gel. Rf = 0.44
(ethyl acetate/petroleum ether, 1:3). [α]2D0 = 45.4 (c = 1.01, CH2Cl2).
(CH3CHCH2NH), 25.6 [(CH3)3CSi], 28.4 (Boc tBu), 30.4 (NCH3),
30.8 (CHCH2NH), 32.8 (Val CH), 33.0 (Tyr CH2), 39.2 (CHCO)
43.8 (CH2CHCO), 45.5 (CH2NH), 46.5 (Ala CH), 52.1 (OCH3),
57.1 (Tyr CH)), 57.7 (Val CH), 77.9 (quaternary C Boc), 120.1,
129.3 (aromatic), 129.7 (alkene CH), 130.5 (alkene C), 154.4 (phe-
nolic), 156.1 (Boc C=O), 170.1 (Ala CO), 172.3 (Tyr CO), 174.3
(Val CO), 175.7 (CO2Me) ppm. HRMS (ESI): calcd. for
C40H68N4O8Si [M + Na]+ 783.4699; found 783.4704.
IR (film): ν = 3336, 2962, 2930, 1739, 1685, 1511, 1172, 1052 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 0.11 [s, 6 H, (CH3)2Si], 0.85 (d,
J = 6.1 Hz, 3 H, Val CH3), 0.87 (d, J = 6.1 Hz, 3 H, Val CH3),
0.89 (d, J = 7.6 Hz, 3 H, Ala CH3), 0.92 [s, 9 H, (CH3)3CSi], 1.37
(s, 9 H, Boc tBu), 2.10–2.18 (m, 1 H, Val CH), 2.84–2.87 (m, 1 H,
Tyr CH2), 2.91 (s, 3 H, NCH3), 3.28 (dd, J = 14.8, 5.4 Hz, 1 H,
Tyr CH2), 3.68 (s, 3 H, OCH3), 4.39–4.42 (m, 2 H, Ala CH, Val
CH), 5.26 (d, J = 6.3 Hz, 1 H, Ala NH), 5.49 (dd, J = 9.9, 5.9 Hz,
1 H, Tyr CH), 6.61 (d, J = 8.3 Hz, 1 H, Val NH), 6.69 (d, J =
7.8 Hz, 2 H, aromatic H), 7.00 (d, J = 7.6 Hz, 2 H, aromatic H)
ppm. 13C NMR (100 MHz, CDCl3): δ = –4.6 [2 C, (CH3)2Si], 17.5
(Val CH3), 17.8 (Val CH3), 18.1 [(CH3)3CSi], 19.0 (Ala CH3), 25.6
[(CH3)3CSi], 28.2 (Boc tBu), 30.4 (NCH3), 30.8 (Val CH), 32.7 (Tyr
CH2), 46.6 (Ala CH), 52.0 (OCH3), 57.1 (Val CH), 57.5 (Tyr CH),
79.6 (quaternary C), 120.0, 129.3, 129.7 (aromatic), 154.4 (Boc
CO), 155.3 (phenolic), 170.2 (Tyr CO), 172.0 (Ala CO), 174.8 (Val
CO) ppm. HRMS (ESI): calcd. for C30H51N3O7Si [M + Na]+
616.3389; found 616.3396.
(3S,6R,9S,12R,16R)-6-(4-Hydroxybenzyl)-3-isopropyl-7,9,12,14,16-
pentamethyl-1,4,7,10-tetraazacycloheptadec-14-ene-2,5,8,11-tetrone
(35): An aqueous solution of LiOH·H2O (0.4 N 0.08 mL,
0.03 mmol) was added dropwise to a stirred solution of linear tetra-
peptide 34 (20 mg, 0027 mmol) in THF (0.5 mL). The reaction mix-
ture was stirred for 2 h at room temperature before it was acidified
to pH 3 with 1 N HCl and extracted with ethyl acetate (3ϫ2 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated in vacuo to furnish the TBS-deprotected free acid in
quantitative yield. This acid was used in the next step without fur-
ther purification. To a solution of the N-Boc-protected free acid
(17 mg, 0.027 mmol) in CH2Cl2 (0.3 mL) was added TFA (0.02 mL,
0.99 mmol) at 0 °C, and the mixture was stirred for 2 h. The solvent
was removed in vacuo, and the residue was dried by the azeotropic
removal of H2O with toluene. The crude material was used in the
next reaction without further purification. To a solution of crude
amine salt in dry DMF (20 mL) were added iPr2NEt (0.01 mL,
0.08 mmol), HOBt (8 mg, 0.06 mmol), and TBTU (19 mg,
0.06 mmol) successively at room temperature. The solution was
stirred at room temperature for 18 h and then partitioned between
ethyl acetate and H2O. The aqueous layer was extracted with ethyl
acetate (3ϫ30 mL). The combined ethyl acetate layers were washed
successively with 5 % aqueous KHSO4, H2O, 50% aqueous
NaHCO3, and saturated aqueous NaCl, dried (MgSO4), filtered,
and concentrated in vacuo to give the crude product, which was
purified by flash chromatography (ethyl acetate) to deliver the
macrolactam 35 (6 mg, 45% yield) as a colorless oil. Rf = 0.55
Methyl N-{(2S,4E,6S)-7-[(tert-Butoxycarbonyl)amino]-2,4,6-tri-
methylhept-4-enoyl}-L-alanyl-O-[tert-butyl(dimethyl)silyl]-N-methyl-
D
-tyrosyl- -valinate (34): To solution of tripeptide 33 (30 mg,
L
0.05 mmol) in CH2Cl2 (0.5 mL) was added TFA (0.03 mL,
0.5 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C.
The solvent was removed in vacuo, and the residue was dried by
the azeotropic removal of H2O with toluene. The crude material
was used in the next reaction without further purification. To a
solution of crude amine salt and amino acid 21 (15 mg, 0.05 mmol)
in dry DMF (1 mL) were added iPr2NEt (0.02 mL, 0.25 mmol),
HOBt (7 mg, 0.05 mmol), and TBTU (16 mg, 0.05 mmol) success-
ively. The reaction mixture was stirred for 2 h before it was diluted
with H2O (2 mL), stirred for 5 min, and then extracted with ethyl
acetate (3ϫ4 mL). The combined organic layers were washed with
1 N HCl (2 mL), saturated aqueous NaHCO3 (2 mL), and satu-
rated aqueous NaCl (2 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. The crude product was purified by flash
chromatography (ethyl acetate/petroleum ether, 1:1), producing
pure tetrapeptide 34 (20 mg, 53% yield) as a colorless gel. Rf =
0.52 (ethyl acetate/petroleum ether, 1:1). [α]2D0 = 16.6 (c = 0.84,
(ethyl acetate). [α]2D0 = –72.0 (c = 0.40, CH Cl ). IR (film): ν = 3361,
˜
2
2
2974, 2930, 1735, 1712, 1511, 1172 cm–1. 1H NMR (600 MHz, [D6]-
DMSO): δ = 0.66 (dd, J = 3.7, 3.6 Hz, 6 H, Val CH3), 0.84 (d, J
= 7.0 Hz, 3 H, CH3CHCH2NH), 0.98 (d, J = 6.9 Hz, 3 H,
CH3CHCO), 1.04 (d, J = 7.0 Hz, 3 H, Ala CH3), 1.46 (s, 3 H,
CH3C=C), 1.76 (d, J = 15.9 Hz, 1 H, CH2hCHCO), 2.20 (m, 2 H,
t
Val CH, CH2 CHCO), 2.53 (m, 1 H, CHCO), 2.54–2.58 (m, 1 H,
t
CHCH2NH), 2.83 (ddd, J = 12.9, 5.6, 2.6 Hz, 1 H, CH2 NH), 2.91
(d, J = 8.2 Hz, 2 H, Tyr CH2), 3.06 (s, 3 H, NMe), 3.14 (ddd, J =
13.1, 9.1, 6.0 Hz, 1 H, CH2hNH), 4.06 (dd, J = 9.6, 4.9 Hz, Val
CH), 4.59 (quint, J = 6.9 Hz, 1 H, Ala CH), 4.96 (d, J = 8.0 Hz,
alkene H), 5.01 (t, J = 8.2 Hz, 1 H, Tyr CH), 6.64 (d, J = 8.5 Hz,
2 H, TyrArHmeta), 7.03 (d, J = 8.5 Hz, 2 H, TyrArHortho), 7.43 (t,
J = 5.8 Hz, 1 H, CH2NH), 7.87 (d, J = 9.7 Hz, 1 H, Val NH), 8.00
(d, J = 7.0 Hz, 1 H, Ala NH), 9.10 (s, Tyr-OH) ppm. 13C NMR
(600 MHz, [D6]DMSO): δ = 16.7 (Val CH3), 16.9 (Ala CH3), 17.8
(CH3C=C), 18.8 (CH3CHCH2NH), 18.9 (Val CH3), 19.5
(CH3CHCO), 28.1 (Val CH), 30.7 (NCH3), 31.6 (CHCH2NH), 32.9
(Tyr CH2), 36.7 (CHCO), 41.1 (CH2CHCO), 44.3 (Ala CH), 45.7
(CH2NH), 56.7 (Val CH), 57.6 (Tyr CH), 114.6 (TyrArmeta), 126.7
(alkene CH), 126.8 (CipsoAr), 129.2 (TyrArortho), 133.6 (alkene C),
155.5 (C-OH Ar), 170.4 (Val CO), 170.9 (Tyr CO), 174.4
(CH2CHCO), 174.8 (Ala CO) ppm. HRMS (ESI): calcd. for
C28H42N4O5Si [M + Na]+ 537.3047; found 537.3044.
CH Cl ). IR (film): ν = 3361, 2974, 2930, 1735, 1712, 1511, 1172
˜
2
2
cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.13 [s, 6 H, (CH3)2Si],
0.87 (d, J = 6.8 Hz, 3 H, Val CH3), 0.88 (d, J = 6.8 Hz, 3 H, Val
CH3), 0.89 (d, J = 7.6 Hz, 3 H, CH3CHCH2O), 0.91–0.94 [m, 12
H, (CH3)3CSi, CH3CHCO], 1.04 (d, J = 6.8 Hz, 3 H, Ala CH3),
1.41 (s, 9 H, Boc tBu), 1.56 (s, 3 H, CH3C=C), 1.97–2.03 (m, 1 H,
Val CH), 2.13–2.21 (m, 1 H, CHCH2NH), 2.27 (dd, J = 13.8,
6.7 Hz, 1 H, CH2CHCO), 2.33–2.40 (m, 1 H, CH2CHCO), 2.53–
2.56 (m, 1 H, CHCO), 2.75–2.81 (m, 1 H, CH2NH), 2.85–2.89 (m,
1 H, CH2NH), 2.93 (s, 3 H, NCH3), 3.08–3.12 (m, 1 H, Tyr CH2),
3.29 (dd, J = 14.9, 6.1 Hz, 1 H, Tyr CH2), 3.69 (s, 3 H, OCH3),
4.41 (dd, J = 8.5, 5.8 Hz, 1 H, Val CH), 4.61–4.68 (m, 1 H, Ala
CH), 4.75 (br. s, 1 H, NHBoc), 4.89 (d, J = 9.1 Hz, alkene H), 5.48
(dd, J = 10.6, 6.1 Hz, 1 H, Tyr CH), 6.37 (d, J = 5.8 Hz, 1 H, Val
NH), 6.70 (d, J = 8.3 Hz, 2 H, aromatic), 7.02 (d, J = 8.3 Hz, 2 H,
aromatic) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.5 [2 C,
Supporting Information (see also the footnote on the first page of
(CH3)2Si], 16.4 (CH3C=C), 16.9 (CH3CHCO), 17.4 (Ala CH3), this article): Copies of H and 13C NMR spectra of the described
1
17.9 (Val CH3 ), 18.2 [(CH3 )3 CSi], 18.2 (Val CH3 ), 19.0
compounds.
Eur. J. Org. Chem. 2007, 2779–2790
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2789

S. Marimganti, R. Wieneke, A. Geyer, M. E. Maier
FULL PAPER
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Received: January 12, 2007
Published Online: April 10, 2007
2790
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2779–2790