Synthesis and biological evaluation of gephyronic acid derivatives: Initial steps towards the identification of the biological target of polyketide inhibitors of eukaryotic protein synthesis

Article abstract of DOI:10.1002/ejoc.201101129

Coupled to the development of a total synthesis of gephyronic acid, a series of diastereomeric analogues and their precursors have been prepared by employing complementary aldol strategies for the key coupling step of fragments 4 and 5. A biological evalu

Full text of DOI:10.1002/ejoc.201101129

FULL PAPER
DOI: 10.1002/ejoc.201101129
Synthesis and Biological Evaluation of Gephyronic Acid Derivatives: Initial
Steps towards the Identification of the Biological Target of Polyketide
Inhibitors of Eukaryotic Protein Synthesis
Timo Anderl,[a] Lionel Nicolas,[b] Johanna Münkemer,[a] Yazh Muthukumar,[c]
Angelika Baro,[a] Wolfgang Frey,[a] Florenz Sasse,[c] Richard E. Taylor,*[b] and
Sabine Laschat*[a]
Keywords: Aldol reactions / Biological activity / Cytotoxicity / Polyketides / Structure–activity relationships
Coupled to the development of a total synthesis of gephy-
cell lines. Moreover, variation of the configuration of the C3–
ronic acid, a series of diastereomeric analogues and their pre- C5 stereotriad and the C1 carboxylic acid were found to be
cursors have been prepared by employing complementary
aldol strategies for the key coupling step of fragments 4 and
5. A biological evaluation revealed the importance of the ep-
oxide for the cytotoxicity against L-929 (mouse fibroblast)
and KB-3-1 (HeLa clone, human cervix carcinoma derived)
important features. Improved activities compared with the
natural product were observed when the carboxy terminus at
C1 was replaced by a methyl ester or PMB-protected alcohol.
Surprisingly, the derivatives (8R)-17d and (8S)-16a showed
antibacterial activity against Pseudomonas aeruginosa.
phyra strain Ar 3895 derived gephyronic acid[9] (3;
Scheme 1) are promising bioactive compounds that have
been found to be potent and selective eukaryotic protein
synthesis inhibitors. Very recently, new tedanolide ana-
logues, candidaspongiolide A and B from the sponge genus
Candidaspongia, have been reported to inhibit melanoma
cell growth.[10] Detailed structural information, synthetic
approaches, and the general mode of action of tedanolides
1 and myriaporones 3/4 2 are already known.[11–13] Struc-
ture–activity relationship (SAR) studies have identified the
60S large ribosomal subunit of Saccharomyces cerevisiae as
Introduction
Complex natural products derived from marine or terres-
trial organisms are interesting from both chemical and bio-
logical perspectives. For chemists, they provide challenging
targets for total synthesis, which often require new synthetic
methods or the novel orchestration of known procedures.[1]
Furthermore, the chemical synthesis plays a decisive role in
the elucidation of relative and absolute configurations when
an X-ray crystal structure analysis is not possible.[2] For
biologists, natural products or derivatives thereof are useful
tools for the elucidation of biological mechanisms such as
signal transduction or protein–protein interactions. In ad-
dition, natural products can serve as pharmacological lead
structures for the development of new drug candidates.[3]
Prominent examples are taxol,[4] epothilones,[5] and ecteina-
scidin-743.[6]
The structurally related polyketide natural products ted-
anolide (1a) and myriaporone 3/4 (2a,b) isolated from ma-
rine sources[7,8] and the myxobacterium Archangium ge-
[a] Institut für Organische Chemie der Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: +49-711-685-64285
E-mail: sabine.laschat@oc.uni-stuttgart.de
[b] Department of Chemistry & Biochemistry, University of Notre
Dame,
251 Nieuwland Science Hall, Notre Dame, IN 46556-5670,
USA
E-mail: taylor.61@nd.edu
[c] Department of Chemical Biology, Helmholtz Centre for Infec-
tion Research,
Scheme 1. Structurally related polyketide natural products tedanol-
ide (1a), 13-deoxytedanolide (1b), myriaporone 3/4 (2a,b), and ge-
phyronic acid (3).
Inhoffenstr. 7, 38124 Braunschweig, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101129.
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Gephyronic Acid Derivatives
the 13-deoxytedanolide (1b) target[14] and myriaporone 3/4 azolidinone (R)-7 in 10 steps and 40% overall yield by
2 may potentially have the same mode of action.[15] In con- Evans syn aldol[21] and Mukaiyama aldol reactions.[22]
trast, little is known about gephyronic acid (3), which shares
parts of the southern hemisphere of the tedanolide family
(Scheme 1). Recently, polyketide 3 was discussed as a phar-
macophoric link to compounds 1 and 2 based on its pro-
posed relative configuration.[16] A detailed NMR study re-
sulted in a revision of the structure of 3, including a full
assignment of the relative and absolute stereochemistry,[17]
which was finally confirmed by a convergent total synthe-
sis.[18] Although the biological activity of gephyronic acid
(3) is known, the specific target remains unidentified.
Therefore we were interested in various diastereomers of
gephyronic acid (3), which could serve as valuable tools for
elucidating structure–property relationships. This should ul-
timately pave the way to identifying the target protein of 3.
Herein we report the synthetic routes to the diastereomers
of gephyronic acid and its derivatives and discuss the results
of the first SAR study.
Scheme 2. Key building blocks 4 and 5 of gephyronic acid (3); the
numbering used for the NMR assignment is indicated.
The aldol coupling reaction between building blocks 4
and 5 turned out to be a critical step providing four possible
Results and Discussion
diastereoisomers, the Felkin products (8S,9S)- and (8R,9S)-
Synthesis of Gephyronic Acid Derivatives and Its Precursors
9a,b and the anti-Felkin products (8S,9R)- and (8R,9R)-
To gain access to diastereomers of gephyronic acid (3), 9c,d, as shown in Scheme 3. Moreover, the product ratio
we followed our previously established retrosynthetic strat- could be controlled by using different coupling conditions.
egy (Scheme 2).[18] Gephyronic acid (3) was traced back to Under Mukaiyama conditions (method A), that is, treat-
building blocks 4 and 5, which should be coupled by aldol ment of ketone 5 with LDA followed by addition of
reaction followed by deoxygenation and subsequent epoxid- TMSOTf to generate the enol-silane of 5 and subsequent
ation as the key steps. Fragment 4 was obtained from Roche addition of aldehyde 4 in the presence of BF3·OEt2,[23] the
ester (R)-6 and (S)-benzyloxazolidinone (S)-7 in 13 steps Felkin/anti-Felkin selectivity was Ͼ95:5, yielding selectively
and 34% overall yield by employing Evans anti aldol reac- the syn,anti diastereomer (8S,9S)-9a in 61% yield (dr Ͼ
tion[19] and two sequential Wittig reactions.[20] Fragment 5 95:5).[18,24] Upon generating the lithium enolate of 5 with
was prepared from propane-1,3-diol (8) and (R)-benzylox- LDA in THF followed by addition of HMPA and aldehyde
Scheme 3. Coupling of fragments 4 and 5 by aldol reaction to yield the possible diastereoisomers 9. Reagents and conditions: Method A:
(1) 5 (3 equiv.), LDA, THF, –50 °C; (2) HMPA; (3) TMSOTf, – 78 °C; (4) 4 (1 equiv.), CaH2 (1 equiv.), BF3·OEt2 (3.3 equiv.), CH2Cl2,
–95 °C; Method B: (1) 5 (1 equiv.), LDA, THF, –50 °C; (2) HMPA (3 equiv.), –95 °C, 4 (1.1 equiv.); Method C: 5 (3 equiv.), TiCl4
(2.9 equiv.), NEt3, CH2Cl2, –78 °C, 4 (1 equiv.), –78 °C.
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4 (method B), the formation of anti-Felkin products domi- a potential explanation for the selectivity of the anti Mukai-
nated (Felkin/anti-Felkin, Ͻ1:99) with (8S,9R)-9c as the yama aldol. Orientations C and E are disfavored due to the
major product (9c/9d = 89:11), albeit with a poor yield of parallel dipole–dipole interactions of the aldehyde and the
12%. Alternatively, treatment of ketone 5 with TiCl4 in the carbon–oxygen bond. C is further disfavored due to the ste-
presence of NEt3 followed by reaction with aldehyde 4 ric interactions between the two fragments represented by
(method C) resulted in a similar Felkin/anti-Felkin selectiv- C6 and C11 as in projection D. The synclinal transition
ity (6:94) but a reversed 9c/9d ratio of 16:84 (Scheme 3). state F can also be eliminated due to the steric interaction
The diastereomers (8S,9R)-9c and (8R,9R)-9d were isolated between the gem-dimethyl moiety at C6 and the methyl
in 8 and 61% yields, respectively. Thus, precursors 9a,c and C23. The remaining orientations A and B both lead to the
9d with anti and syn orientation at C8–C10 were accessible syn,anti product 9a, however, preference is given to the syn-
depending on the method.
clinal B due to the antiperiplanar position of the side-chains
However, the anti selectivity was surprising for a Mukai- and the unfavorable syn-pentane interaction between
yama aldol reaction.[25] Comparison of the coupling con- methyl groups C22 and C23 in A. To summarize, an alter-
3
3
stants, J(8-H,9-H) = 9.8 Hz and J(9-H,10-H) = 1.4 Hz, with native representation of the proposed transition state is
structurally related compounds revealed the anti configura- shown in Scheme 4c.
tion at C8/C9.[23] The monodentate Lewis acid BF3·OEt2
The necessary deoxygenation of the C9 secondary
rules out a chelation model. The resulting more positively alcohol in 9 under Barton–McCombie conditions[18,26]
charged transition state (see Scheme 4a) increases the di- yielded derivatives (8S)-10a and (8R)-10b (Scheme 5).
polar moment and this should explain the better selectivity
Although precursors (8S,9S)-9a and (8S,9R)-9c gave the
that is obtained compared with lithium enolate. From the same deoxygenation product (8S)-10a, the two-step reac-
anti aldehyde 4, facial selectivity is dictated by a merged tion of 9a occurred without any problems to provide 10a in
1,2- and 1,3-asymmetric induction. The anti relationship 85% yield,[18] whereas the deoxygenation of 9c was ac-
between the methyl C23 and the TBS-protected ether rein- companied by a competitive retro-aldol reaction, decreasing
forces the selectivity of the nucleophilic attack, as depicted the yield of the intermediate xanthogenate. Subsequent rad-
in Scheme 4a. The C11 substituent is oriented anti to the ical fragmentation gave selectively 10a (55% total yield).
C10–C=O bond and the polarized C11–OTBS and the car- Partial retro-aldolization was also observed for (8R,9R)-9d,
bonyl have opposed dipoles. The methyl C23 is placed syn which was deoxygenated to (8R)-10b in 60% yield over two
to the carbonyl moiety to give the Felkin product 9a as steps. In this case, traces of a potential cyclopentane prod-
shown in Scheme 4.
uct, stemming from the formation of the radical intermedi-
ate and cyclization of the C12/C13 internal olefin, were
found. The cyclization turned out to be faster yielding a
65:35 mixture of the deoxypropionate 10b and the cyclo-
pentane product when 1.5 equiv. of HSnBu3 were used (see
the Supporting Information). The formation of this by-
product was reduced by increasing the amount of tri-n-bu-
tyltin hydride up to 7 equiv.
Removal of the TBS groups in 10 was found to be rather
capricious. Both under acidic (MeCN/48% HF 20:1) and
neutral conditions (TASF in DMF) only a complex product
mixture was obtained. The desilylation with 3HF·NEt3 and
NEt3 in MeCN failed completely and after reaction for 7 d,
starting reagent 10 was reisolated almost quantitatively. Fi-
nally, the use of TBAF and 4 Å molecular sieves in THF
at room temperature yielded the desilylated products 11a,b,
albeit as a chromatographically inseparable 15:85 mixture
of diastereomers (8S)-11a and (8R)-11b, regardless of the
starting material (8S)-10a or (8R)-10b (Scheme 5). Presum-
ably, epimerization at C8 occurred under the reaction con-
ditions with the unnaturally configured diastereomer (8R)-
11b as the main product.
The epoxidation of 11a/b (15:85) with mCPBA under the
conditions reported for tedanolides 1[11,20a] and myriapo-
rones 2[13a] resulted in a mixture of oxidation products,
whereas no conversion was observed in the classic Sharpless
asymmetric epoxidation with diethyl d-(–)-tartrate [(–)-
DET]. Presumably the 1,4-syn-allylic alcohol 11 in combi-
Scheme 4. Proposed transition states for coupling by the Mukai-
yama aldol reaction.
The staggered Newman projections for the reaction with nation with (–)-DET represents a mismatched case. How-
the Z-silyl enol ether are summarized in Scheme 4b to give ever, under identical conditions without DET the mixture
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Gephyronic Acid Derivatives
Scheme 5. Deoxygenation of coupling products 9[18] followed by desilylation and epoxidation of diol 11.
of 11a/b was epoxidized chemo- and regioselectively to de- (8S)-15a[18] or (8R)-15b were isolated in yields of 77 and 68%
rivatives 12 in 87% yield. The diastereomers were separated together with the C3 monodeprotected derivatives 16a and
to give (8S)-12a and (8R)-12b in yields of 5 and 34% to- 16b. The latter could be separated and converted under these
gether with (8S)-12c and (8R)-12d in yields of 6 and 42%, conditions into diols 15, thus increasing their total yield (e.g.,
respectively (Scheme 5).
89% for 15a). Applying the epoxidation conditions described
The 1,3-syn relationship of the methyl groups at C8 and for 11a,b, diol (8S)-15a afforded the desired epoxide (8S)-17a
C10 in 11b was confirmed by the NMR coupling constants and diastereomer (8S)-17c in 88% yield (dr = 44:56).[18]
of the bicyclic acetal 13b, which was obtained from 11b by Thus, the stereogenic centers at C11 and C14 do not exert
acid-catalyzed acetalization and subsequent oxidative re- any control on the incoming electrophile. Under the same
moval of the PMB group (Scheme 6).[27]
conditions, compound (8R)-15b was epoxidized to the re-
spective derivatives (8R)-17b and (8R)-17d in 91% yield with
a diastereomeric ratio of 55:45 (Scheme 7).
Following this synthetic strategy, additional diastereoiso-
mers of gephyronic acid (3) were accessible (Scheme 8).
The coupling of aldehyde 4 and ketone ent-5, which was
obtained from 8 and (S)-benzyloxazolidinone (S)-7 as pre-
viously published,[18,21a,28] under the conditions of
method C (TiCl4, NEt3) yielded the anti-Felkin products
ent-(8S,9R)-9c and ent-(8R,9R)-9d. According to the pro-
cedures described above, derivatives ent-9c,d were converted
into the methyl esters ent-17a,c and ent-17b,d in yields of
88 and 89%, respectively.
Scheme 6. Acid-catalyzed acetalization of diol (8R)-11b.
Cleavage of the PMB ether in 12 and subsequent oxi-
dation should accomplish the synthesis of gephyronic acid
(3). However, oxidative PMB ether cleavage led to acetal
formation instead of the required primary alcohol. To over-
come this problem and to avoid undesired epimerization
Biological Studies of Gephyronic Acid Derivatives
The ability of a set of 19 derivatives to inhibit the prolif-
during the desilylation of derivatives 10, the order of the eration of mammalian tumor cell lines was investigated in
sequence was changed (Scheme 7).
an MTT assay.[29] The assay measures the metabolic activity
As previously described,[18] deprotection of compounds of cells grown in a 96-well plate after 5 days and allows
10a and 10b with DDQ followed by successive Swern and IC50 values to be determined from concentration-dependent
Pinnick oxidation as well as esterification gave the methyl activity curves. The results are summarized in Table 1. Sur-
esters (8S)-14a[18] and (8R)-14b in yields of 87 and 70%, prisingly, (8S)-17a and (8S)-12a exhibited the highest ac-
respectively. Again, desilylation caused some problems. In tivity with IC50 values of 1.4–6.3 ngmL–1 and are 5- to 15-
contrast to precursors 10, which were desilylated with TBAF, fold more potent than the naturally occurring gephyronic
the removal of the TBS groups in 14 was achieved by em- acid (3) in this assay, which demonstrates the influence of
ploying 3HF·NEt3 in the presence of NEt3 in MeCN at room functionalization at the C1 terminus (Table 1, Entries 1, 8,
temperature.[20a] After reaction for 7 d, the desired products and 9). Variation at C12–C13 in diastereomer (8R)-11b with
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Scheme 7. Synthesis of derivatives 17 in analogy to ref.[18] Reagents and conditions: (a) (COCl)2 (2 equiv.), DMSO (3 equiv.), NEt3
(6 equiv.), CH2Cl2, –78 °C Ǟ r.t.; (b) (1) NaClO2 (2.5 equiv.), KH2PO4 (7 equiv.), 2-methyl-2-butene (4.5 equiv.), tBuOH/H2O (3:1), r.t.,
1 h; (2) TMSCHN2 (2 equiv.), CH2Cl2/MeOH (4:1), r.t., 1 h; (c) 3HF·NEt3, NEt3, MeCN, r.t., 7 d.
Scheme 8. Synthesis of diastereomers ent-17a–d.
a C=C bond instead of an epoxide led to reduced potency a significant loss of activity, as can be seen for 12a,c and
against the L-929 cell line compared with its congener (8R)- 17a,c. Both PMB ether (8S)-12a and methyl ester (8S)-17a
12b (Table 1, Entries 4 and 14). The least active (IC50 with “natural” (12R,13R)-epoxide were approximately
Ͼ 40 μgmL–1) in the series of C12–C13 unsaturated ana- 1000-fold more potent against the tumor cell lines than
logues in this assay were products 9, 10b, and 14b with TBS- their counterparts (8S)-12c and (8S)-17c (Table 1, En-
protecting groups on the secondary alcohols at C3 and C11 tries 8–11). The antitumor activities of the diastereomers
(Table 1, Entries 2, 3, and 5). The correct absolute and rela- (8R)-12b and (8R)-17b with an inverse configuration at C8
tive stereochemistry turned out to be crucial for antitumor relative to 12a and 17a were lower by 1000 orders of magni-
activity. Inversion of the configuration at C12–C13 causes tude (Table 1, Entries 14 and 15).
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Gephyronic Acid Derivatives
Table 1. Cytotoxicity of gephyronic acid (3) and its analogues against L-929 (mouse fibroblast) and KB-3-1 (HeLa clone, human cervix
carcinoma derived) cell lines.
Entry
Compd.
Configuration
IC50 [μgmL–1][a]
C8
C12–C13
L-929
KB-3-1
1
2
3
4
5
6
7
8
3
9
S
–
R,R
–
–
–
–
–
–
R,R
R,R
S,S
S,S
R,R
S,S
R,R
R,R
S,S
S,S
R,R
S,S
0.051Ϯ0.003[b]
Ͼ40
0.0074Ϯ0.006[b]
Ͼ40
10b
R
R
R
R
R
S
S
S
S
S
Ͼ40
3.0Ϯ0.3
Ͼ40
Ͼ40
1.5Ϯ0.1
Ͼ40
11b
14b
15b
4.7Ϯ0.5
8.0Ϯ0.1
0.0033Ϯ0.0006
0.0063Ϯ0.0006
1.7Ϯ0.1
4.8Ϯ0.2
1.9Ϯ0.1
Ͼ40
5.0Ϯ0.1
7.0Ϯ0.1
0.0034Ϯ0.0001
0.0014Ϯ0.0004
2.3Ϯ0.5
2.8Ϯ0.7
2.0Ϯ0.1
32Ϯ8
16b
12a
9
17a
10
11
12
13
14
15
16
17
18
19
12c
17c
ent-17a
ent-17c
12b
S
R
R
R
R
R
R
0.8Ϯ0.14
4.8Ϯ0.2
2.0Ϯ0.4
Ͼ40
5.8Ϯ0.4
16Ϯ3
1.2Ϯ0.2
7.1Ϯ0.1
0.49Ϯ0.2
37Ϯ0.1
11Ϯ1
17b
12d
17d
ent-17b
ent-17d
21Ϯ3
[a] Cell proliferation was measured by an MTT assay. The data are mean valuesϮstandard deviation of two assays performed in parallel.
[b] Values for natural product 3.
A further loss of activity by one order of magnitude was assays. In this assay the inhibitory effect on the growth of
observed for product (8R)-17d with inverse stereochemistry different indicator organisms was investigated. The dia-
at both C12–C13 and C8 compared with its analogue (8S)- meters of the resulting inhibition zones were taken as a
17c (Table 1, Entries 11 and 17). Our results are consistent measure of antibiotic activity. No growth inhibition with E.
with SAR studies of myriaporone 2, revealing the necessity coli tolC, Klebsiella pneumoniae, and Staphylococcus aureus
of the epoxide for biological activity.[15]
was found. But surprisingly, derivative (8R)-17d with the
Furthermore, the results in Table 1 demonstrate the in- “unnatural” stereochemistry at C12–C13 and C8 as well as
fluence of the C3–C5 stereotriad on cytotoxicity. In general, precursor (8S)-16a showed activities against Pseudomonas
methyl esters ent-17a and ent-17b were less potent than aeruginosa. In agar diffusion assays with 20 μg/paper disc,
their counterparts 17a,b, reaching IC50 values of only 2– inhibition zones of 24 and 27 mm, respectively, were ob-
11 μgmL–1 (Table 1, Entries 12 and 18). Interestingly, com- served. Additional experiments to delineate the unique anti-
pound ent-17d with the “unnatural” R configuration at C8 bacterial activities of 17d and 16a are currently being pur-
revealed slightly increased antitumor activity in comparison sued and will be presented separately.
with its 8S-configured congener ent-17c (Table 1, Entries 13
and 19). For diastereomers 17c,d the opposite effect was
observed.
Conclusions
Furthermore, the antibacterial activities of the com-
Complementary aldol strategies for the coupling of frag-
pounds in Table 1 were determined by using agar diffusion ments 4 and 5 or ent-5 gave access to a variety of dia-
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(ddq, J = 8.4, 7.2, 7.0 Hz, 1 H, 10-H), 1.77–1.91 (m, 3 H, 2-Ha, 2-
Hb, 4-H), 3.18 (qd, J = 6.8, 2.3 Hz, 1 H, 8-H), 3.21 (s, 3 H, 19-H),
3.23 (ddq, J = 9.1, 8.8, 6.7 Hz, 1 H, 14-H), 3.44–3.47 (m, 2 H, 1-
Ha, 1-Hb), 3.52 (d, J = 3.5 Hz, 1 H, 5-H), 3.69–3.72 (m, 2 H, 3-H,
9-H), 3.74 (d, J = 1.7 Hz, 1 H, OH), 3.80 (s, 3 H, ArOCH3), 4.10
(dd, J = 7.2, 0.7 Hz, 1 H, 11-H), 4.39 (d, J = 11.4 Hz, 1 H, OCHaH-
bAr), 4.42 (d, J = 11.4 Hz, 1 H, OCHaHbAr), 4.94 (dqq, J = 8.8,
1.3, 1.3 Hz, 1 H, 15-H), 5.18 (dqd, J = 9.2, 1.3, 0.7 Hz, 1 H, 13-
H), 6.85–6.88 (m, 2 H, m-H), 7.22–7.25 (m, 2 H, o-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = –4.9 (SiCH3), –4.23 (SiCH3), –4.15
(SiCH3), –3.4 (SiCH3), 9.21 (C-18), 9.21 (C-22), 12.4 (C-24), 13.0
(C-23), 18.1 (C-26), 18.27 [SiC(CH3)3], 18.29 [SiC(CH3)3], 18.6 (C-
20), 21.3 (C-25), 23.5 (C-21), 25.8 (C-17), 26.0 [SiC(CH3)3], 26.2
[SiC(CH3)3], 31.6 (C-14), 35.1 (C-2), 38.2 (C-4), 41.0 (C-10), 43.8
(C-8), 53.8 (C-6), 55.4 (ArOCH3), 60.0 (C-19), 67.1 (C-1), 72.7
(OCH2Ar), 73.3 (C-9), 73.4 (C-3), 82.7 (C-11), 86.2 (C-5), 113.9
(C-m), 129.3 (C-o), 129.5 (C-15), 129.9 (C-12), 130.7 (C-i), 132.8
(C-16), 134.1 (C-13), 159.3 (C-p), 218.7 (C-7) ppm. FTIR (ATR):
stereomeric gephyronic acid derivatives. The structure–ac-
tivity relationship (SAR) studies of these compounds have
provided evidence for the epoxide in the western part of
gephyronic acid (3) as well as the C3–C5 stereotriad and
the C1 moiety in the eastern part to be the pharmacophoric
subunits for the observed cytotoxicity. These results provide
the basis for labeling experiments to identify the biological
target protein(s) of gephyronic acid (3). Studies towards this
goal are underway in our laboratories.
Experimental Section
1
General: H and 13C{1H} NMR spectra (125 MHz) were recorded
with a Bruker Avance 500 spectrometer. IR spectra were recorded
with a Bruker Vektor22 FTIR spectrometer with the MKII Golden
Gate Single Reflection Diamant system. Specific rotations were re-
corded with a Perkin–Elmer 241 polarimeter. Mass spectra were
recorded with a Finnigan MAT 95 (CI) or Varian MAT 711 (EI,
70 eV) spectrometer. ESI-MS were measured with a Bruker Dalton-
ics microTOF-Q spectrometer. Flash chromatography was per-
formed on silica gel 60 (Fluka; 40–63 μm). Thin-layer chromatog-
raphy (TLC) was conducted on Merck silica gel 60 F254 plates.
Preparative HPLC was performed with a Shimadzu apparatus with
a DGU-20A5 Prominence Degasser, LC-20AT Prominence Liquid
Chromatograph and SPD-M20A Prominence Diode Array Detec-
tor using a Knauer Kromasil 100 Sil 5 μm column (250ϫ 20 mm).
All reactions were performed in dried glassware.
ν = 2954 (m), 2929 (m), 2856 (m), 1613 (w), 1514 (m), 1471 (m),
˜
1361 (w), 1248 (s), 1080 (s), 1039 (s), 1003 (s), 833 (vs), 773
(vs) cm–1. MS (ESI): m/z = 828 [M + Na]+, 695, 531, 503, 447, 403.
+
HRMS (ESI): calcd. for C46H84NaO7Si2 [M + Na]+ 827.5648;
found 827.5639.
9d: Rf = 0.14 (n-hexane/EtOAc, 6:1); Rt (HPLC) = 49.55 min (n-
hexane/EtOAc, 96:4, Kromasil, flow 1.0 mLmin–1). [α]2D0 = +4.8 (c
1
= 0.42, CH2Cl2). H NMR (500 MHz, CDCl3): δ = –0.03 (s, 3 H,
SiCH3), 0.05 (s, 3 H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H,
SiCH3), 0.87 (d, J = 7.2 Hz, 3 H, 18-H), 0.887 [s, 9 H, SiC(CH3)
3], 0.889 [s, 9 H, SiC(CH3)3], 0.96 (d, J = 7.1 Hz, 3 H, 23-H), 0.97
(s, 3 H, 21-H), 1.05 (d, J = 6.7 Hz, 3 H, 25-H), 1.13 (d, J = 6.9 Hz,
3 H, 22-H), 1.18 (s, 3 H, 20-H), 1.57 (dd, J = 1.3, 0.7 Hz, 3 H, 24-
H), 1.60 (qdd, J = 7.1, 3.4, 1.3 Hz, 1 H, 10-H), 1.62 (d, J = 1.3 Hz,
3 H, 26-H), 1.66 (d, J = 1.3 Hz, 3 H, 17-H), 1.74 (qdd, J = 7.2,
3.9, 3.5 Hz, 1 H, 4-H), 1.82 (dddd, J = 14.1, 7.0, 7.0, 5.1 Hz, 1 H,
2-Ha), 1.86 (dddd, J = 14.1, 7.6, 6.5, 6.5 Hz, 1 H, 2-Hb), 3.06 (dq,
J = 9.3, 6.9 Hz, 1 H, 8-H), 3.19 (s, 3 H, 19-H), 3.26 (d, J = 1.1 Hz,
1 H, OH), 3.31 (ddq, J = 9.2, 8.8, 6.7 Hz, 1 H, 14-H), 3.41–3.43
(m, 2 H, 1-H), 3.50 (d, J = 3.5 Hz, 1 H, 5-H), 3.70 (ddd, J = 7.6,
5.1, 3.9 Hz, 1 H, 3-H), 3.80 (s, 3 H, ArOCH3), 3.93 (ddd, J = 3.4,
1.3, 0.7 Hz, 1 H, 11-H), 4.13 (ddd, J = 9.3, 1.3, 0.7 Hz, 1 H, 9-H),
4.38 (d, J = 11.5 Hz, 1 H, OCHaHbAr), 4.40 (d, J = 11.5 Hz, 1 H,
OCHaHbAr), 5.00 (dqq, J = 8.8, 1.3, 1.3 Hz, 1 H, 15-H), 5.35 (dqd,
J = 9.2, 1.3, 1.3 Hz, 1 H, 13-H), 6.84–6.87 (m, 2 H, m-H), 7.21–
7.24 (m, 2 H, o-H) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.1
(SiCH3), –4.5 (SiCH3), –4.2 (SiCH3), –3.4 (SiCH3), 8.7 (C-18), 11.6
(C-23), 13.8 (C-24), 16.0 (C-22), 18.1 (C-26), 18.29 [SiC(CH3)3],
18.31 [SiC(CH3)3], 18.7 (C-20), 21.8 (C-25), 23.7 (C-21), 25.8 (C-
17), 26.1 [SiC(CH3)3], 26.2 [SiC(CH3)3], 31.7 (C-14), 35.3 (C-2),
36.6 (C-10), 38.2 (C-4), 45.4 (C-8), 53.7 (C-6), 55.4 (ArOCH3), 59.6
(C-19), 67.1 (C-1), 71.4 (C-9), 72.8 (OCH2Ar), 73.6 (C-3), 82.4 (C-
11), 85.5 (C-5), 113.9 (C-m), 129.3 (C-o), 129.7 (C-12), 130.0 (C-
15), 130.7 (C-i), 131.2 (C-16), 132.1 (C-13), 159.3 (C-p), 219.4 (C-
(5S,6S,7S,10S,11R,12S,13S)-11-Hydroxy-7-methoxy-5-{2-[(4-meth-
oxybenzyl)oxy]ethyl}-2,2,3,3,6,8,8,10,12,15,15,16,16-tridecamethyl-
13-[(1E,3S)-1,3,5-trimethylhexa-1,4-dienyl]-4,14-dioxa-3,15-disila-
heptadecan-9-one (9c, Method B): In analogy to ref.[30], a freshly
prepared 1 m solution of LDA in THF (1010 μL, 1.01 mmol,
1.05 equiv.) was added dropwise over 5 min to a solution of 5
(462 mg, 0.96 mmol, 1.00 equiv.) in abs. THF (7.0 mL) at –78 °C
under N2. The reaction mixture was warmed to –50 °C within
15 min and stirred at –50 °C for 30 min. After recooling to –78 °C,
HMPA (501 μL, 2.88 mmol, 3.00 equiv.) was added dropwise and
the reaction mixture was stirred for 30 min. Then it was cooled
to –95 °C, a solution of freshly prepared 4[18] (344 mg, 1.06 mmol,
1.10 equiv.) in abs. THF (1.0 mL) was added dropwise over 10 min,
and the mixture was stirred for a further 10 min. A solution of
AcOH (82 μL, 1.44 mmol, 1.5 equiv.) in THF (1.0 mL) was care-
fully added and the reaction mixture warmed to room temperature.
After dilution with Et2O (10 mL), H2O (10 mL) was added. The
aqueous layer was separated and extracted with CH2Cl2 (3 ϫ
10 mL). The combined organic layers were washed with brine
(10 mL), dried (MgSO4), and concentrated. The crude product (dr
= 89:11 by 1H NMR) was purified by chromatography on SiO2
(hexanes/EtOAc, 20:1 Ǟ 5:1) to give 9c (93 mg, 0.12 mmol, 12%)
and 9d (16 mg, 0.02 mmol, 2%) as colorless oils (Ͼ95% purity each
by 1H NMR) together with reisolated 5 (370 mg, 0.77 mmol, 80%).
7) ppm. FTIR (ATR): ν = 3520 (w), 2955 (m), 2929 (m), 2856 (m),
˜
1694 (w), 1514 (m), 1471 (m), 1462 (m), 1362 (m), 1248 (s), 1081
(s), 1039 (s), 1021 (s), 834 (vs), 773 (vs) cm–1. MS (ESI): m/z =
828 [M + Na]+, 531, 503, 447, 403, 347. HRMS (ESI): calcd. for
9c: Rf = 0.61 (n-hexane/EtOAc, 4:1); Rt (HPLC) = 18.64 min (n-
hexane/EtOAc, 96:4, Kromasil, flow 1.0 mLmin–1). [α]2D0 = +38.2
(c = 1.00, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 0.01 (s, 3 H,
SiCH3), 0.066 (s, 3 H, SiCH3), 0.074 (s, 3 H, SiCH3), 0.10 (s, 3 H,
+
C46H84NaO7Si2 [M + Na]+ 827.5648; found 827.5639.
(5S,6S,7S,10R,11R,12S,13S)-11-Hydroxy-7-methoxy-5-{2-[(4-meth-
SiCH3), 0.74 (d, J = 7.0 Hz, 3 H, 23-H), 0.86 (d, J = 7.2 Hz, 3 H, oxybenzyl)oxy]ethyl}-2,2,3,3,6,8,8,10,12,15,15,16,16-tridecamethyl-
18-H), 0.88 [s, 9 H, SiC(CH3)3], 0.89 [s, 9 H, SiC(CH3)3], 0.97 (d, 13-[(1E,3S)-1,3,5 trimethylhexa-1,4-dienyl]-4,14-dioxa-3,15-disila-
J = 6.7 Hz, 3 H, 25-H), 1.01 (s, 3 H, 21-H), 1.03 (d, J = 6.8 Hz, 3
H, 22-H), 1.20 (s, 3 H, 20-H), 1.59 (d, J = 1.3 Hz, 3 H, 24-H), 1.60
(d, J = 1.3 Hz, 3 H, 26-H), 1.64 (d, J = 1.3 Hz, 3 H, 17-H), 1.73
heptadecan-9-one (9d, Method C): In analogy to ref.[31], a 1 m solu-
tion of TiCl4 in CH2Cl2 (374 μL, 374.1 μmol, 2.90 equiv.) and NEt3
(53 μL, 380.6 μmol, 2.95 equiv.) were successively added dropwise
7300
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7294–7307

Gephyronic Acid Derivatives
to a solution of 5 (186.1 mg, 387.0 μmol, 3.00 equiv.) in abs.
CH2Cl2 (4.0 mL) at –78 °C under N2 and the reaction mixture was
stirred for 1 h. Then a freshly prepared solution of 4 (41.9 mg,
129.0 μmol, 1.00 equiv.) in CH2Cl2 (1.0 mL) was added dropwise
and the reaction mixture was warmed to 0 °C over 3 h and stirred
for a further 30 min. After dilution with CH2Cl2 (5 mL), the reac-
tion was quenched by the addition of a sat. NaHCO3 solution
(5 mL) and the mixture was warmed to room temperature. The
aqueous layer was separated and extracted with CH2Cl2
(3ϫ5 mL). The combined organic extracts were washed with brine
(10 mL), dried (MgSO4), and concentrated. The residue (240 mg,
ratio 5/9c/9d = 8:15:77 by HPLC) was purified by chromatography
on SiO2 (hexanes/EtOAc, 20:1 Ǟ 5:1) to give 9d (63.4 mg,
H), 1.66 (d, J = 1.4 Hz, 3 H, 17-H), 1.74–1.91 (m, 3 H, 2-Ha, 2-
Hb, 4-H), 3.07 (dq, J = 8.8, 6.8 Hz, 1 H, 8-H), 3.20 (s, 3 H, 19-H),
3.21 (br. d, J = 1.3 Hz, 1 H, OH), 3.31 (ddq, J = 9.2, 8.8, 6.8 Hz,
1 H, 14-H), 3.44–3.48 (m, 2 H, 1-Ha, 1-Hb), 3.53 (d, J = 3.6 Hz, 1
H, 5-H), 3.67 (ddd, J = 6.7, 5.7, 4.1 Hz, 1 H, 3-H), 3.80 (s, 3 H,
ArOCH3), 3.92 (dd, J = 3.7, 1.2 Hz, 1 H, 11-H), 4.09 (ddd, J =
8.8, 1.3, 1.3 Hz, 1 H, 9-H), 4.39 (d, J = 11.5 Hz, 1 H, OCHaHbAr),
4.42 (d, J = 11.5 Hz, 1 H, OCHaHbAr), 4.99 (dqq, J = 8.8, 1.4,
1.4 Hz, 1 H, 15-H), 5.34 (dqd, J = 9.2, 1.3, 1.2 Hz, 1 H, 13-H),
6.85–6.88 (m, 2 H, m-H), 7.22–7.26 (m, 2 H, o-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –5.1 (SiCH3), –4.5 (SiCH3), –4.2 (SiCH3),
–3.5 (SiCH3), 9.7 (C-18), 11.7 (C-23), 13.6 (C-24), 14.2 (C-22), 18.1
[SiC(CH3)3], 18.28 (C-26), 18.29 [SiC(CH3)3], 18.9 (C-20), 21.7 (C-
78.7 μmol, 61%) and 9c (8.3 mg, 10.3 μmol, 8%) as colorless oils 25), 23.6 (C-21), 25.8 (C-17), 26.1 [SiC(CH3)3], 26.2 [SiC(CH3)3],
1
(Ͼ95% purity each by H NMR).
31.6 (C-14), 35.0 (C-2), 37.2 (C-10), 38.2 (C-4), 45.0 (C-8), 53.7 (C-
6), 55.4 (ArOCH3), 60.1 (C-19), 67.2 (C-1), 71.6 (C-9), 72.8
(OCH2Ar), 73.3 (C-3), 82.1 (C-11), 84.7 (C-5), 113.9 (C-m), 129.4
(C-o), 129.7 (C-12), 129.9 (C-15), 130.7 (C-i), 131.4 (C-13), 132.0
(5R,6R,7R,10S,11R,12S,13S)-11-Hydroxy-7-methoxy-5-{2-[(4-meth-
oxybenzyl)oxy]ethyl}-2,2,3,3,6,8,8,10,12,15,15,16,16-tridecamethyl-
13-[(1E,3S)-1,3,5-trimethylhexa-1,4-dienyl]-4,14-dioxa-3,15-disila-
heptadecan-9-one (ent-9c): Following method C, from ent-5 (1.05 g,
2.18 mmol) in abs. CH2Cl2 (25 mL), a 1 m solution of TiCl4 in
CH2Cl2 (2.11 mL, 2.11 mmol), NEt3 (0.30 mL, 2.14 mmol), and 4
(0.24 g, 0.73 mmol) in CH2Cl2 (5 mL). Yield: 0.36 g (0.45 mmol,
62%) ent-9c and 0.09 mg (0.12 mmol, 16%) ent-9d as colorless oils
(C-16), 159.3 (C-p), 218.6 (C-7) ppm. FTIR (ATR): ν = 2955 (m),
˜
2930 (m), 2857 (m), 1695 (w), 1514 (m), 1471 (m), 1463 (m), 1362
(m), 1248 (s), 1082 (s), 1039 (s), 1004 (m), 834 (vs), 773 (vs) cm–1.
MS (ESI): m/z = 827 [M + Na]+, 531, 503, 447, 403, 347. HRMS
(ESI): calcd. for C46H84NaO7Si2 [M + Na]+ 827.5648; found
+
827.5644.
1
(Ͼ95% purity each by H NMR).
(5S,6S,7S,10R,12S,13S)-7-Methoxy-5-{2-[(4-methoxybenz-
yl)oxy]ethyl}-2,2,3,3,6,8,8,10,12,15,15,16,16-tridecamethyl-13-
[(1E,3S)-1,3,5-trimethylhexa-1,4-dienyl]-4,14-dioxa-3,15-disilahep-
tadecan-9-one (10b)
ent-9c: Rf = 0.65 (n-hexane/EtOAc, 4:1). [α]2D0 = +17.3 (c = 1.00,
CH2Cl2). H NMR (500 MHz, CDCl3): δ = 0.00 (s, 3 H, SiCH3),
1
0.06 (s, 3 H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3),
0.73 (d, J = 7.0 Hz, 3 H, 23-H), 0.85 (d, J = 7.2 Hz, 3 H, 18-H),
0.88 [s, 9 H, SiC(CH3)3], 0.89 [s, 9 H, SiC(CH3)3], 0.97 (d, J =
6.8 Hz, 3 H, 25-H), 1.01 (d, J = 6.8 Hz, 3 H, 22-H), 1.04 (s, 3 H,
21-H), 1.14 (s, 3 H, 20-H), 1.59 (d, J = 1.3 Hz, 3 H, 24-H), 1.60
(d, J = 1.3 Hz, 3 H, 26-H), 1.63 (d, J = 1.3 Hz, 3 H, 17-H), 1.71–
1.78 (m, 1 H, 10-H), 1.78–1.90 (m, 2 H, 2-Ha, 2-Hb), 3.17 (qd, J =
6.8, 1.9 Hz, 1 H, 8-H), 3.22 (ddq, J = 9.0, 8.9, 6.8 Hz, 1 H, 14-H),
3.25 (s, 3 H, 19-H), 3.42–3.44 (m, 2 H, 1-Ha, 1-Hb), 3.51 (d, J =
3.5 Hz, 1 H, 5-H), 3.65–3.71 (m, 2 H, 3-H, 9-H), 3.80 (s, 3 H,
ArOCH3), 4.15 (d, J = 6.6 Hz, 1 H, 11-H), 4.39 (d, J = 11.8 Hz, 1
H, OCHaHbAr), 4.41 (d, J = 11.8 Hz, 1 H, OCHaHbAr), 4.93 (dqq,
J = 8.9, 1.3, 1.3 Hz, 1 H, 15-H), 5.19 (dq, J = 9.0, 1.3 Hz, 1 H, 13-
H), 6.85–6.88 (m, 2 H, m-H), 7.22–7.25 (m, 2 H, o-H) ppm. 13C
Method 1: In analogy to ref.[18,26a], a 2 m solution of NaHMDS in
THF (55 μL, 0.11 mmol, 1.4 equiv.) was added dropwise to a solu-
tion of 9d (63.0 mg, 78.2 μmol, 1.0 equiv.) in abs. CS2 (20 mL) at
–78 °C under N2 and the reaction mixture was stirred for 1 h. After
addition of MeI (73 μL, 1.17 mmol, 15.0 equiv.), the reaction mix-
ture was warmed to 0 °C over 3 h and stirred for a further 3 h. The
reaction was quenched by the addition of a sat. NaHCO3 solution
(15 mL). The aqueous layer was separated and extracted with
EtOAc (3ϫ 15 mL). The combined organic extracts were washed
with brine (20 mL), dried (MgSO4), and concentrated. The residue
was purified by chromatography on SiO2 (hexanes/EtOAc, 40:1 Ǟ
20:1) to give the xanthogenate (51.3 mg, 57.1 μmol, 73%) as a col-
1
NMR (125 MHz, CDCl3): δ = –4.9 (SiCH3), –4.3 (SiCH3), –4.2 orless oil (Ͼ95% purity by H NMR).
(SiCH3), –3.4 (SiCH3), 9.0 (C-18), 9.4 (C-22), 12.5 (C-24), 12.7 (C-
Method 2: In analogy to ref.[18,26b], HSnBu3 (101.9 mg, 0.35 mmol,
23), 18.1 [SiC(CH3)3], 18.27 (C-26), 18.29 [SiC(CH3)3], 20.0 (C-20),
21.4 (C-25), 22.9 (C-21), 25.8 (C-17), 26.1 [SiC(CH3)3], 26.2
[SiC(CH3)3], 31.6 (C-14), 35.0 (C-2), 38.7 (C-10), 41.1 (C-4), 42.9
(C-8), 54.3 (C-6), 55.4 (ArOCH3), 60.2 (C-19), 67.2 (C-1), 72.8
(OCH2Ar), 72.9 (C-3), 73.3 (C-9), 81.7 (C-11), 85.3 (C-5), 113.9
(C-m), 129.3 (C-o), 129.6 (C-15), 129.7 (C-12), 130.7 (C-i), 132.8
(C-16), 134.0 (C-13), 159.2 (C-p), 219.2 (C-7) ppm. FTIR (ATR):
7.0 equiv.) was quickly added to a solution of the xanthogenate
(45.0 mg, 50.3 μmol, 1.0 equiv.) in abs. toluene (10 mL) followed by
the dropwise addition of a 1 m solution of Et3B in hexane (60.4 μL,
60.4 μmol, 1.2 equiv.) at room temperature under N2. After stirring
for 1 h, KF (44 mg, 0.75 mmol, 15.0 equiv.) and H2O (10 mL) were
added. The aqueous layer was separated and extracted with EtOAc
(3ϫ 10 mL). The combined organic layers were washed with brine
(15 mL), dried (MgSO4), and concentrated. The residue was puri-
fied by chromatography on SiO2 (hexanes/EtOAc, 100:0 Ǟ 20:1)
to give 10b (32.5 mg, 41.2 μmol, 82%) as a colorless oil (Ͼ95%
purity by 1H NMR). Rf = 0.40 (n-hexane/EtOAc, 6:1). [α]2D0 = +2.5
ν = 2955 (m), 2929 (m), 2856 (m), 1683 (w), 1514 (m), 1471 (m),
˜
1248 (s), 1079 (s), 1040 (s), 1022 (s), 1003 (s), 834 (vs), 773
(vs) cm–1. MS (ESI): m/z = 827 [M + Na]+, 531, 503, 447, 403, 347.
HRMS (ESI): calcd. for C46H84NaO7Si2 [M + Na]+ 827.5648;
+
found 827.5645.
1
(c = 1.00, CH2Cl2). H NMR (500 MHz, CDCl3): δ = –0.05 (s, 3
ent-9d: Rf = 0.42 (n-hexane/EtOAc, 4:1). [α]2D0 = –13.9 (c = 1.00,
H, SiCH3), 0.02 (s, 3 H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H,
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ = –0.03 (s, 3 H, SiCH3), SiCH3), 0.72 (d, J = 6.8 Hz, 3 H, 23-H), 0.75 (ddd, J = 13.6, 10.1,
0.04 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3),
0.86 (d, J = 7.2 Hz, 3 H, 18-H), 0.89 [s, 9 H, SiC(CH3)3], 0.90 (s,
3 H, 21-H), 0.91 [s, 9 H, SiC(CH3)3], 0.96 (d, J = 7.1 Hz, 3 H, 23-
H), 1.05 (d, J = 6.8 Hz, 3 H, 25-H), 1.12 (d, J = 6.8 Hz, 3 H, 22-
H), 1.19 (s, 3 H, 20-H), 1.51 (qdd, J = 7.1, 3.6, 1.4 Hz, 1 H, 10-
H), 1.53 (d, J = 1.3 Hz, 3 H, 24-H), 1.62 (d, J = 1.4 Hz, 3 H, 26-
4.6 Hz, 1 H, 9-Ha), 0.86 (d, J = 7.2 Hz, 3 H, 18-H), 0.89 [s, 9 H,
SiC(CH3)3], 0.90 [s, 9 H, SiC(CH3)3], 0.98 (d, J = 6.7 Hz, 3 H, 25-
H), 1.009 (s, 3 H, 21-H), 1.012 (d, J = 6.8 Hz, 3 H, 22-H), 1.15 (s,
3 H, 20-H), 1.46 (ddqd, J = 10.1, 7.1, 6.8, 3.2 Hz, 1 H, 10-H), 1.52
(d, J = 1.4 Hz, 3 H, 24-H), 1.60 (d, J = 1.4 Hz, 3 H, 26-H), 1.65
(d, J = 1.4 Hz, 3 H, 17-H), 1.74 (qdd, J = 7.2, 3.9, 3.5 Hz, 1 H, 4-
Eur. J. Org. Chem. 2011, 7294–7307
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7301

R. E. Taylor, S. Laschat et al.
FULL PAPER
H), 1.80 (dddd, J = 14.0, 6.8, 6.8, 5.3 Hz, 1 H, 2-Ha), 1.88 (dddd,
J = 14.0, 7.4, 6.8, 6.8 Hz, 1 H, 2-Hb), 2.15 (ddd, J = 13.6, 8.5,
3.2 Hz, 1 H, 9-Hb), 3.01 (dqd, J = 8.5, 6.8, 4.6 Hz, 1 H, 8-H), 3.22
(C-16), 159.4 (C-p), 220.9 (C-7) ppm. FTIR (ATR): ν = 3463 (w),
˜
2963 (m), 2926 (m), 2869 (m), 1695 (m), 1513 (s), 1455 (m), 1366
(m), 1248 (vs), 1097 (vs), 1036 (s) cm–1. MS (ESI): m/z = 583 [M +
(ddq, J = 9.1, 8.7, 6.8 Hz, 1 H, 14-H), 3.23 (s, 3 H, 19-H), 3.41– Na]+, 317, 289, 275, 233, 217, 169. HRMS (ESI): calcd. for
+
3.45 (m, 2 H, 1-Ha, 1-Hb), 3.50 (dd, J = 7.1, 0.7 Hz, 1 H, 11-H),
3.53 (d, J = 3.5 Hz, 1 H, 5-H), 3.72 (ddd, J = 7.4, 5.2, 3.9 Hz, 1
H, 3-H), 3.80 (s, 3 H, ArOCH3), 4.39 (d, J = 11.7 Hz, 1 H, OCH-
aHbAr), 4.41 (d, J = 11.7 Hz, 1 H, OCHaHbAr), 4.96 (dqq, J =
8.7, 1.4, 1.4 Hz, 1 H, 15-H), 5.09 (dq, J = 9.1, 1.4, 0.7 Hz, 1 H, 13-
H), 6.85–6.87 (m, 2 H, m-H), 7.22–7.25 (m, 2 H, o-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = –4.9 (SiCH3), –4.2 (SiCH3), –4.1
(SiCH3), –3.4 (SiCH3), 9.0 (C-18), 12.0 (C-24), 16.9 (C-23), 18.1
[SiC(CH3)3], 18.3 (C-26), 18.4 [SiC(CH3)3], 19.3 (C-20), 20.0 (C-
22), 21.5 (C-25), 23.0 (C-21), 25.8 (C-17), 26.1 [SiC(CH3)3], 26.2
[SiC(CH3)3], 31.5 (C-14), 35.2 (C-2), 35.4 (C-10), 37.1 (C-9), 38.6
(C-4), 39.2 (C-8), 53.6 (C-6), 55.4 (ArOCH3), 60.0 (C-19), 67.2 (C-
1), 72.8 (OCH2Ar), 73.5 (C-3), 83.5 (C-11), 85.2 (C-5), 113.9 (C-
m), 129.3 (C-o), 129.7 (C-12), 130.0 (C-15), 130.8 (C-i), 132.4 (C-
C34H56NaO6 [M + Na]+ 583.3969; found 583.3979.
(2S,3R,4S,6R,8S,9S,11R)-4-Methoxy-2-{2-[(4-methoxybenzyl)-
oxy]ethyl}-3,5,5,9,11-pentamethyl-8-[(1E,3S)-1,3,5-trimethylhexa-
1,4-dienyl]-1,7-dioxaspiro[5.5]undecane (13a): A solution of PPTS
(1.2 mg, 4.8 μmol, 0.3 equiv.) in abs. MeOH (0.2 mL) was added
dropwise to a solution of 11a/11b (dr = 15:85, 9.0 mg, 16.0 μmol,
1.0 equiv.) in abs. MeOH (2.0 mL) under N2 at room temperature
and the reaction mixture was stirred for 24 h. Then it was diluted
with Et2O (5 mL) and the reaction was quenched by the addition
of a sat. NaHCO3 solution (5 mL). The aqueous layer was sepa-
rated and extracted with Et2O (3ϫ 5 mL). The combined organic
extracts were washed with brine (10 mL), dried (MgSO4), and con-
centrated. The remaining colorless oil (10 mg) was purified by flash
chromatography on SiO2 (hexanes/EtOAc/Et3N, 95:4:1) to give 13a
(7.1 mg, 12.6 μmol, 79%) as a colorless solid (dr Ͼ 99:1, 99% pu-
rity by GC). Rf = 0.57 (n-hexane/EtOAc, 2:1). [α]2D0 = +20.8 (c =
0.27, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 0.58 (d, J =
6.4 Hz, 3 H, 23-H), 0.92 (d, J = 7.0 Hz, 3 H, 18-H), 0.94 (d, J =
6.7 Hz, 3 H, 25-H), 0.95 (d, J = 6.5 Hz, 3 H, 22-H), 0.98 (s, 3 H,
20-H), 1.08 (s, 3 H, 21-H), 1.13 (ddd, J = 13.5, 12.5, 11.9 Hz, 1 H,
9-Ha), 1.41–1.48 (m, 2 H, 9-Hb, 10-H), 1.55 (d, J = 1.3 Hz, 3 H,
24-H), 1.61 (d, J = 1.3 Hz, 3 H, 26-H), 1.66 (d, J = 1.3 Hz, 3 H,
17-H), 1.71 (dddd, J = 14.1, 7.9, 7.9, 2.5 Hz, 1 H, 2-Ha), 1.89 (dqd,
J = 12.5, 6.3, 4.6 Hz, 1 H, 8-H), 1.94 (dddd, J = 14.2, 11.1, 5.7,
5.0 Hz, 1 H, 2-Hb), 2.10 (ddq, J = 10.2, 7.2, 7.0 Hz, 1 H, 4-H),
3.20 (d, J = 10.2 Hz, 1 H, 5-H), 3.23 (ddq, J = 9.1, 8.7, 6.7 Hz, 1
H, 14-H), 3.30 (d, J = 9.8 Hz, 1 H, 11-H), 3.43 (s, 3 H, 19-H),
3.64–3.70 (m, 2 H, 1-Ha, 1-Hb), 3.80 (s, 3 H, ArOCH3), 4.02 (ddd,
J = 11.1, 7.2, 2.5 Hz, 1 H, 3-H), 4.46 (d, J = 11.5 Hz, 1 H, OCHaH-
bAr), 4.49 (d, J = 11.5 Hz, 1 H, OCHaHbAr), 4.91 (dqq, J = 8.7,
1.3, 1.3 Hz, 1 H, 15-H), 5.09 (dq, J = 9.0, 1.3 Hz, 1 H, 13-H),
6.86–6.90 (m, 2 H, m-H), 7.27–7.31 (m, 2 H, o-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 11.5 (C-24), 15.0 (C-18), 17.8 (C-23), 18.1
(C-26), 19.5 (C-20), 19.7 (C-22), 21.7 (C-25), 23.3 (C-21), 25.8 (C-
17), 30.1 (C-2), 31.4 (C-14), 32.2 (C-10), 34.1 (C-8), 35.9 (C-4),
40.5 (C-9), 45.8 (C-6), 55.4 (ArOCH3), 61.4 (C-19), 69.1 (C-1), 72.9
(OCH2Ar), 73.7 (C-3), 83.3 (C-11), 84.6 (C-5), 104.0 (C-7), 113.9
(C-m), 129.5 (C-o), 129.6 (C-12), 129.9 (C-15), 131.0 (C-i), 131.7
13), 133.8 (C-16), 159.3 (C-p), 219.4 (C-7) ppm. FTIR (ATR): ν =
˜
2956 (m), 2928 (m), 2856 (m), 1699 (m), 1513 (m), 1462 (m), 1361
(w), 1248 (s), 1078 (s), 1041 (s), 833 (vs), 772 (vs) cm–1. MS (ESI):
m/z = 812 [M + Na]+, 680, 431, 403, 271. HRMS (ESI): calcd. for
C46H84NaO6Si2 [M + Na]+ 811.5699; found 811.5693.
+
(3S,4R,5S,8R,10S,11S,12E,14S)-3,11-Dihydroxy-5-methoxy-1-[(4-
methoxybenzyl)oxy]-4,6,6,8,10,12,14,16-octamethylheptadeca-
12,15-dien-7-one (11a/11b): In analogy to ref.[32], an anhydrous
solution of tetrabutylammonium fluoride, prepared according to
ref.[33] from tetrabutylammonium fluoride trihydrate (120 mg,
380 μmol, 10.0 equiv.) and 4 Å molecular sieves (50 mg) in THF
(1 mL), was added dropwise to a solution of 10b (30 mg, 38 μmol,
1.0 equiv.) in abs. THF (2.0 mL) at 0 °C under N2. Then the reac-
tion mixture was warmed to room temperature, stirred for a further
2 h, and diluted with Et2O (5 mL). The reaction was quenched by
addition of a pH 7 buffer solution (5 mL). The aqueous layer was
separated and extracted with CH2Cl2 (3ϫ 5 mL). The combined
organic extracts were washed with brine (10 mL), dried (MgSO4),
and concentrated. The residue was purified by flash chromatog-
raphy on SiO2 (hexanes/EtOAc/Et3N, 75:24:1 Ǟ 50:49:1) to give
the product (18 mg, 32 μmol, 84%) as a colorless oil in a C8 epi-
1
meric ratio 11b/11a = 85:15 (Ͼ95% purity by H NMR). The epi-
mers could not be separated by chromatography. Rf = 0.23 (n-hex-
ane/EtOAc, 2:1). [α]2D0 = +14.1 (c = 0.33, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 0.74 (d, J = 6.8 Hz, 3 H, 23-H), 0.91–0.94
(m, 1 H, 9-Ha), 0.94 (d, J = 7.0 Hz, 3 H, 18-H), 0.99 (d, J = 6.8 Hz,
3 H, 25-H), 1.04 (d, J = 6.8 Hz, 3 H, 22-H), 1.11 (s, 3 H, 20-H),
1.19 (s, 3 H, 21-H), 1.39 (ddqd, J = 8.7, 7.9, 6.8, 3.5 Hz, 1 H, 10-
H), 1.53–1.57 (m, 1 H, 4-H), 1.56 (d, J = 1.3 Hz, 3 H, 24-H), 1.61
(d, J = 1.4 Hz, 3 H, 26-H), 1.62–1.66 (m, 1 H, 2-Ha), 1.65 (d, J =
1.4 Hz, 3 H, 17-H), 1.77–1.84 (m, 1 H, 2-Hb), 1.81 (d, J = 3.6 Hz,
1 H, OH), 2.08 (ddd, J = 13.8, 8.8, 3.5 Hz, 1 H, 9-Hb), 2.94 (d, J
= 3.0 Hz, 1 H, OH), 3.15 (dqd, J = 8.8, 6.8, 5.2 Hz, 1 H, 8-H),
3.24 (ddq, J = 8.9, 8.8, 6.8 Hz, 1 H, 14-H), 3.37 (s, 3 H, 19-H),
3.55 (ddd, J = 7.9, 3.6, 0.7 Hz, 1 H, 11-H), 3.55–3.68 (m, 2 H, 1-
Ha, 1-Hb), 3.59 (d, J = 4.4 Hz, 1 H, 5-H), 3.60–3.65 (m, 1 H, 3-H),
3.80 (s, 3 H, ArOCH3), 4.42 (s, 2 H, OCH2Ar), 4.95 (dqq, J = 8.8,
1.4, 1.3 Hz, 1 H, 15-H), 5.18 (dqd, J = 8.9, 1.4, 0.7 Hz, 1 H, 13-
H), 6.86–6.89 (m, 2 H, m-H), 7.22–7.25 (m, 2 H, o-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 9.2 (C-18), 11.6 (C-24), 17.7 (C-23),
18.1 (C-26), 19.4 (C-22), 20.5 (C-20), 21.5 (C-21), 21.8 (C-25), 25.8
(C-17), 31.6 (C-14), 34.5 (C-10), 34.7 (C-2), 37.9 (C-9), 39.8 (C-8),
41.2 (C-4), 53.8 (C-6), 55.4 (ArOCH3), 60.8 (C-19), 69.1 (C-1), 73.0
(C-16), 134.0 (C-13), 159.2 (C-p) ppm. FTIR (ATR): ν = 2953 (s),
˜
2922 (vs), 2852 (s), 1613 (w), 1513 (m), 1455 (m), 1377 (m), 1247
(s), 1082 (vs), 1038 (s), 1023 (s) 974 (m), 820 (w) cm–1. MS (ESI):
m/z = 543 [M + H]+, 511, 493, 335, 235, 121 [CH2C6H4OMe]+.
HRMS (ESI): calcd. for C34H54O5 [M + H]+ 543.4044; found
+
543.4039.
General Procedure for the Removal of the PMB Group: In analogy
to ref.[27], a solution of DDQ (1.3 equiv.) in CH2Cl2 (0.6 mL) was
added dropwise to a solution of 10 or 13a (1.0 equiv.) in CH2Cl2/
pH 7 buffer (8:1, 5.4 mL) at 0 °C under N2. The reaction mixture
was warmed to room temperature and stirred for a further 1 h.
After dilution with CH2Cl2, the reaction was quenched by the ad-
dition of a sat. NaHCO3 solution (10 mL). The aqueous layer was
separated and extracted with EtOAc (3ϫ 10 mL). The combined
extracts were washed with brine (20 mL), dried (MgSO4), and con-
centrated. The residue was purified by chromatography on SiO2
with hexanes/EtOAc (15:1 or 10:1 for 13b) to give the alcohol as a
colorless oil.
(C-3), 73.1 (OCH2Ar), 83.5 (C-11), 86.3 (C-5), 114.0 (C-m), 129.5 (5S,6S,7S,10R,12S,13S)-7-Methoxy-5-(2-hydroxyethyl)-
(C-o), 129.7 (C-15), 129.8 (C-12), 130.3 (C-i), 133.3 (C-13), 133.9 2,2,3,3,6,8,8,10,12,15,15,16,16-tridecamethyl-13-[(1E,3S)-1,3,5-tri-
7302
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7294–7307

Gephyronic Acid Derivatives
methylhexa-1,4-dienyl]-4,14-dioxa-3,15-disilaheptadecan-9-one
(2.0 equiv.) in CH2Cl2 (6 mL) under N2 at –78 °C and the reaction
mixture stirred for 30 min. Then a solution of the respective alcohol
(41 or 236 μmol, 1.0 equiv.) in CH2Cl2 (1 mL) was added dropwise
(10bЈ): From 10b (47.1 mg, 59.7 μmol): yield: 30.4 mg (45.3 μmol,
76%). Rf = 0.15 (n-hexane/EtOAc, 6:1). [α]2D0 = –0.8 (c = 0.39,
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ = –0.06 (s, 3 H, SiCH3), over 2 min and the reaction mixture was stirred for a further
0.01 (s, 3 H, SiCH3), 0.11 (s, 3 H, SiCH3), 0.13 (s, 3 H, SiCH3),
0.71 (d, J = 6.8 Hz, 3 H, 23-H), 0.75 (ddd, J = 13.6, 10.1, 4.3 Hz,
1 H, 9-Ha), 0.87 (d, J = 7.2 Hz, 3 H, 18-H), 0.89 [s, 9 H, SiC-
(CH3)3], 0.91 [s, 9 H, SiC(CH3)3], 0.98 (d, J = 6.7 Hz, 3 H, 25-H),
30 min. After dropwise addition of NEt3 (6.0 equiv.), the reaction
mixture was warmed to room temperature. The reaction was
quenched by the addition of H2O and the aqueous layer was sepa-
rated and extracted with Et2O (3ϫ 5 mL). The combined organic
1.02 (d, J = 6.8 Hz, 3 H, 22-H), 1.10 (s, 3 H, 21-H), 1.16 (s, 3 H, extracts were washed with brine (10 mL), dried (MgSO4), and con-
20-H), 1.39 (ddqd, J = 10.1, 7.2, 6.8, 3.0 Hz, 1 H, 10-H), 1.51 (d, centrated to give the intermediate aldehyde as a colorless oil, which
J = 1.3 Hz, 3 H, 24-H), 1.59 (d, J = 1.3 Hz, 3 H, 26-H), 1.64 (d, J was treated without further purification.
= 1.3 Hz, 3 H, 17-H), 1.72 (qdd, J = 7.2, 4.7, 2.7 Hz, 1 H, 4-H),
Analogous to ref.[18,34], 2-methyl-2-butene (4.5 equiv.) and KH2PO4
1.81–1.85 (m, 2 H, 2-Ha, 2-Hb), 1.98 (m, 1 H, OH), 2.18 (ddd, J =
13.6, 9.0, 3.0 Hz, 1 H, 9-Hb), 3.03 (dqd, J = 9.0, 6.7, 4.4 Hz, 1 H,
8-H), 3.22 (ddq, J = 9.1, 8.7, 6.7 Hz, 1 H, 14-H), 3.29 (s, 3 H, 19-
H), 3.47 (d, J = 7.2 Hz, 1 H, 11-H), 3.50 (d, J = 2.7 Hz, 1 H, 5-
H), 3.56–3.62 (m, 1 H, 1-Ha), 3.66–3.72 (m, 1 H, 1-Hb), 3.89 (ddd,
J = 5.9, 5.9, 4.7 Hz, 1 H, 3-H), 4.95 (dqq, J = 8.7, 1.3, 1.3 Hz, 1
H, 15-H), 5.08 (dq, J = 9.1, 1.3 Hz, 1 H, 13-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –4.9 (SiCH3), –4.2 (SiCH3), –4.0 (SiCH3),
–3.6 (SiCH3), 9.6 (C-18), 11.9 (C-24), 16.9 (C-23), 18.1 (C-26), 18.3
[SiC(CH3)3], 18.4 [SiC(CH3)3], 19.8 (C-22), 20.8 (C-20), 21.47 (C-
25), 21.53 (C-21), 25.8 (C-17), 26.1 [SiC(CH3)3], 26.2 [SiC(CH3)3],
31.5 (C-14), 35.4 (C-10), 37.17 (C-9), 37.19 (C-2), 38.8 (C-4), 39.1
(C-8), 54.2 (C-6), 60.0 (C-1), 60.4 (C-19), 74.0 (C-3), 83.5 (C-11),
85.2 (C-5), 129.7 (C-12), 129.9 (C-15), 132.5 (C-13), 133.7 (C-16),
(7.0 equiv.) were added to a solution of the freshly prepared alde-
hyde (1.0 equiv.) in tBuOH/H2O (4:1, 6 mL) at room temperature
followed by the dropwise addition of a solution of NaClO2
(2.5 equiv.) in H2O (0.4 mL) and the reaction mixture was stirred
for 1 h. The reaction was quenched by the addition of a sat. NH4Cl
solution (5 mL) and the aqueous layer was separated and extracted
with CH2Cl2 (5ϫ 5 mL). The combined organic extracts were dried
(MgSO4) and concentrated to give the intermediate carboxylic acid,
which was treated without further purification.
Analogous to ref.[18,35], a 2 m solution of TMSCHN2 in hexane
(2.0 equiv.) was added dropwise to a solution of the carboxylic acid
(1.0 equiv.) in CH2Cl2/MeOH (4:1, 5 mL) under N2 at room tem-
perature and the reaction mixture was stirred for 1 h. The solvent
was removed and the crude product purified by chromatography
on SiO2 (hexanes/EtOAc, 50:1).
220.1 (C-7) ppm. FTIR (ATR): ν = 2956 (m), 2929 (m), 2857 (m),
˜
1698 (m), 1472 (m), 1386 (m), 1252 (m), 1105 (m), 1066 (s), 1004
(s), 863 (m), 833 (vs), 772 (vs) cm–1. MS (ESI): m/z = 692 [M +
Methyl (3S,4S,5S,8R,10S,11S,12E,14S)-3,11-Bis{[tert-butyl(di-
methyl)silyl]oxy}-5-methoxy-4,6,6,8,10,12,14,16-octamethyl-7-oxo-
heptadeca-12,15-dienoate [(8R)-14b]: From the respective alcohol
(27.5 mg, 41.1 μmol); yield: 26.3 mg (37.8 μmol, 92%), colorless oil.
Rf = 0.43 (n-hexane/EtOAc, 6:1). [α]2D0 = –6.2 (c = 1.00, CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = –0.06 (s, 3 H, SiCH3), 0.01 (s, 3
H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.13 (s, 3 H, SiCH3), 0.71 (d, J =
6.8 Hz, 3 H, 23-H), 0.75 (ddd, J = 13.6, 10.2, 4.6 Hz, 1 H, 9-Ha),
0.887 [s, 9 H, SiC(CH3)3], 0.890 (d, J = 7.2 Hz, 3 H, 18-H), 0.892
[s, 9 H, SiC(CH3)3], 0.98 (d, J = 6.8 Hz, 3 H, 25-H), 1.02 (d, J =
6.8 Hz, 3 H, 22-H), 1.05 (s, 3 H, 21-H), 1.17 (s, 3 H, 20-H), 1.45
(ddqd, J = 10.2, 7.1, 6.6, 3.2 Hz, 1 H, 10-H), 1.52 (d, J = 1.4 Hz,
3 H, 24-H), 1.60 (d, J = 1.4 Hz, 3 H, 26-H), 1.65 (d, J = 1.4 Hz, 3
H, 17-H), 1.80 (qdd, J = 7.2, 4.3, 3.3 Hz, 1 H, 4-H), 2.16 (ddd, J
= 13.6, 8.6, 3.2 Hz, 1 H, 9-Hb), 2.48 (dd, J = 15.2, 5.6 Hz, 1 H, 2-
Ha), 2.63 (dd, J = 15.2, 7.2 Hz, 1 H, 2-Hb), 3.02 (dqd, J = 8.6, 6.7,
4.6 Hz, 1 H, 8-H), 3.22 (ddq, J = 9.3, 8.7, 6.7 Hz, 1 H, 14-H), 3.24
(s, 3 H, 19-H), 3.49 (d, J = 7.1 Hz, 1 H, 11-H), 3.54 (d, J = 3.3 Hz,
1 H, 5-H), 3.66 (s, 3 H, CO2CH3), 4.05 (ddd, J = 7.2, 5.6, 4.3 Hz,
1 H, 3-H), 4.95 (dqq, J = 8.7, 1.4, 1.4 Hz, 1 H, 15-H), 5.08 (dq, J
= 9.3, 1.4 Hz, 1 H, 13-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
–4.9 (SiCH3), –4.5 (SiCH3), –4.2 (SiCH3), –3.7 (SiCH3), 9.2 (C-
18), 11.9 (C-24), 16.9 (C-23), 18.1 [SiC(CH3)3], 18.2 (C-18), 18.4
[SiC(CH3)3], 19.3 (C-20), 20.0 (C-22), 21.5 (C-25), 23.0 (C-21), 25.8
(C-17), 26.09 [SiC(CH3)3], 26.11 [SiC(CH3)3], 31.5 (C-14), 35.4 (C-
10), 37.1 (C-9), 39.1 (C-8), 39.4 (C-4), 40.7 (C-2), 51.7 (CO2CH3),
53.5 (C-6), 60.1 (C-19), 72.8 (C-3), 83.6 (C-11), 84.7 (C-5), 129.7
(C-12), 129.9 (C-15), 132.4 (C-13), 133.7 (C-16), 172.3 (C-1), 219.3
Na]+, 559, 431. HRMS (ESI): calcd. for C38H76NaO5Si2 [M +
+
Na]+ 691.5123; found 691.5133.
2-{(2S,3R,4S,6R,8S,9S,11R)-4-Methoxy-3,5,5,9,11-pentamethyl-8-
[(1E,3S)-1,3,5-trimethylhexa-1,4-dienyl]-1,7-dioxaspiro[5.5]undecan-
2-yl}ethanol (13b): From 13a (7.0 mg, 12.9 μmol); yield: 4.5 mg
1
(10.6 μmol, 82%), colorless oil (Ͼ95% purity by H NMR). Rf =
0.43 (n-hexane/EtOAc, 2:1). [α]2D0 = +50.0 (c = 0.23, CH2Cl2). H
1
NMR (500 MHz, CDCl3): δ = 0.62 (d, J = 6.5 Hz, 3 H, 23-H), 0.96
(d, J = 7.0 Hz, 3 H, 18-H), 0.97 (d, J = 6.5 Hz, 3 H, 22-H), 0.98
(d, J = 6.7 Hz, 3 H, 25-H), 1.03 (s, 3 H, 20-H), 1.10 (s, 3 H, 21-
H), 1.15 (ddd, J = 13.0, 12.6, 11.3 Hz, 1 H, 9-Ha), 1.48–1.52 (m, 1
H, 9-Hb), 1.50–1.53 (m, 1 H, 10-H), 1.52–1.57 (m, 1 H, 2-Ha), 1.58
(d, J = 1.4 Hz, 3 H, 24-H), 1.62 (d, J = 1.3 Hz, 3 H, 26-H), 1.65
(d, J = 1.3 Hz, 3 H, 17-H), 1.95 (dqd, J = 12.6, 6.5, 4.7 Hz, 1 H,
8-H), 1.98–2.04 (m, 1 H, 2-Hb), 2.05 (dqd, J = 8.6, 7.0, 6.6 Hz, 1
H, 4-H), 2.11 (br. s, 1 H, OH), 3.17 (d, J = 8.6 Hz, 1 H, 5-H), 3.25
(ddq, J = 9.0, 8.7, 6.7 Hz, 1 H, 14-H), 3.42 (s, 3 H, 19-H), 3.50 (d,
J = 10.0 Hz, 1 H, 11-H), 3.85–3.89 (m, 2 H, 1-Ha, 1-Hb), 4.16 (ddd,
J = 11.2, 6.6, 2.0 Hz, 1 H, 3-H), 4.94 (dqq, J = 8.7, 1.3, 1.3 Hz, 1
H, 15-H), 5.12 (dq, J = 9.0, 1.4 Hz, 1 H, 13-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 11.5 (C-24), 15.5 (C-18), 17.6 (C-23), 18.1
(C-26), 19.58 (C-22), 19.62 (C-20), 21.8 (C-25), 23.7 (C-21), 25.8
(C-17), 31.4 (C-14), 32.2 (C-10), 32.8 (C-2), 34.1 (C-8), 36.6 (C-4),
40.5 (C-9), 45.4 (C-6), 60.7 (C-19), 62.7 (C-1), 75.3 (C-3), 83.1 (C-
11), 85.1 (C-5), 104.1 (C-7), 129.7 (C-15), 129.8 (C-12), 131.7 (C-
16), 134.1 (C-13) ppm. FTIR (ATR): ν = 3390 (w), 2964 (s), 2923
˜
(vs), 1454 (m), 1378 (m), 1082 (vs), 1068 (vs), 975 (m) cm–1. MS
(CI): m/z (%) = 423 (20) [M + H]+, 391 (13), 251 (15), 228 (100),
164 (29), 121 (38) [CH2C6H4OMe]+, 86 (24). HRMS (ESI): calcd.
(C-7) ppm. FTIR (ATR): ν = 2956 (m), 2929 (m), 2857 (m), 1741
˜
(m), 1699 (m), 1472 (m), 1462 (m), 1387 (w), 1253 (m), 1098 (m),
1067 (s), 1020 (m), 835 (vs), 773 (vs) cm–1. MS (ESI): m/z = 720
[M + Na]+, 565, 433, 289, 157, 115. HRMS (ESI): calcd. for
+
for C26H46NaO4 [M + Na]+ 445.3288; found 445.3292.
General Procedure for the Synthesis of Methyl 3,11-Bis{[tert-butyl-
(dimethyl)silyl]oxy}-5-methoxy-4,6,6,8,10,12,14,16-octamethyl-7-
oxoheptadeca-12,15-dienoates (14): Analogous to ref.[18], DMSO
(3.0 equiv.) was added dropwise to a solution of oxalyl chloride
+
C39H76NaO6Si2 [M + Na]+ 719.5073; found 719.5055.
General Procedure for the Synthesis of Methyl 3,11-Dihydroxy-5-
methoxy-4,6,6,8,10,12,14,16-octamethyl-7-oxoheptadeca-12,15-dien-
Eur. J. Org. Chem. 2011, 7294–7307
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7303

R. E. Taylor, S. Laschat et al.
FULL PAPER
oates (15): NEt3 (3.60 mL) and 3HF·NEt3 (3.30 mL) were added
to a solution of 14 (1.0 equiv.) in abs. MeCN (7.5 mL) at room
temperature under N2 in a Teflon vessel and the reaction mixture
was stirred for 7 d. Then it was poured into a sat. solution of
NaHCO3 (40 mL). The aqueous layer was separated and extracted
with CH2Cl2 (4 ϫ 25 mL). The combined organic extracts were
dried (MgSO4), concentrated, and the residue purified by flash
chromatography on SiO2 (hexanes/EtOAc/Et3N, 80:19:1) to give 15
and mono-deprotected product 16, which was treated under the
same conditions to give 15.
37.9 μmol, 34%), and 12d (26.9 mg, 46.8 μmol, 42%) as colorless
oils (ca. 95% purity by H NMR).
1
(8S)-12a: Rf = 0.33 (n-hexane/EtOAc, 1:1). [α]2D0 = +36.1 (c = 0.18,
1
CH2Cl2). H NMR (500 MHz, CD3OD): δ = 0.81 (d, J = 6.8 Hz,
3 H, 23-H), 0.88 (d, J = 7.2 Hz, 3 H, 18-H), 0.98 (d, J = 6.6 Hz, 3
H, 22-H), 1.06 (d, J = 6.6 Hz, 3 H, 25-H), 1.07 (s, 3 H, 21-H), 1.13
(ddd, J = 13.7, 10.0, 3.5 Hz, 1 H, 9-Ha), 1.17 (s, 3 H, 20-H), 1.23
(s, 3 H, 24-H), 1.53 (ddqd, J = 10.0, 9.4, 6.6, 3.1 Hz, 1 H, 10-H),
1.65–1.72 (m, 2 H, 2-Ha, 4-H), 1.65 (d, J = 1.4 Hz, 3 H, 26-H),
1.69 (d, J = 1.4 Hz, 3 H, 17-H), 1.74 (ddd, J = 13.7, 10.7, 3.0 Hz,
1 H, 9-Hb), 1.76–1.82 (m, 1 H, 2-Hb), 2.34 (ddq, J = 10.0, 9.2,
6.6 Hz, 1 H, 14-H), 2.58 (d, J = 9.2 Hz, 1 H, 13-H), 2.63 (d, J =
Methyl (3S,4R,5S,8R,10S,11S,12E,14S)-3,11-Dihydroxy-5-meth-
oxy-4,6,6,8,10,12,14,16-octamethyl-7-oxoheptadeca-12,15-dienoate
[(8R)-15b]: From (8R)-14b (22.8 mg, 32.7 μmol); yield: 10.4 mg 9.4 Hz, 1 H, 11-H), 3.18 (dqd, J = 10.3, 6.7, 3.6 Hz, 1 H, 8-H),
(22.2 μmol, 68%), colorless oil. Rf = 0.30 (n-hexane/EtOAc, 1:1).
3.29 (s, 3 H, 19-H), 3.48 (d, J = 3.0 Hz, 1 H, 5-H), 3.57–3.62 (m,
2 H, 1-Ha, 1-Hb), 3.64 (ddd, J = 8.9, 4.0, 3.9 Hz, 1 H, 3-H), 3.78
(s, 3 H, ArOCH3), 4.43 (s, 2 H, OCH2Ar), 4.99 (dqq, J = 10.0, 1.4,
1
[α]2D0 = +4.6 (c = 0.35, CH2Cl2). H NMR (500 MHz, CDCl3): δ =
0.75 (d, J = 6.8 Hz, 3 H, 23-H), 0.95 (d, J = 7.1 Hz, 3 H, 18-H),
0.96 (ddd, J = 13.6, 8.6, 5.1 Hz, 1 H, 9-Ha), 0.99 (d, J = 6.7 Hz, 3 1.4 Hz, 1 H, 15-H), 6.87–6.90 (m, 2 H, m-H), 7.25–7.28 (m, 2 H,
H, 25-H), 1.09 (d, J = 6.8 Hz, 3 H, 22-H), 1.15 (s, 3 H, 20-H), 1.19
(s, 3 H, 21-H), 1.38 (ddqd, J = 8.6, 8.2, 6.8, 3.4 Hz, 1 H, 10-H),
1.559 (qdd, J = 7.2, 4.3, 3.3 Hz, 1 H, 4-H), 1.563 (d, J = 1.4 Hz, 3
H, 24-H), 1.61 (d, J = 1.4 Hz, 3 H, 26-H), 1.65 (d, J = 1.4 Hz, 3
H, 17-H), 1.74 (d, J = 3.2 Hz, 1 H, OH), 2.10 (ddd, J = 13.6, 9.0,
3.4 Hz, 1 H, 9-Hb), 2.44 (dd, J = 16.0, 3.7 Hz, 1 H, 2-Ha), 2.53
(dd, J = 16.0, 9.2 Hz, 1 H, 2-Hb), 3.02 (d, J = 3.6 Hz, 1 H, OH),
3.18 (dqd, J = 9.0, 6.9, 5.1 Hz, 1 H, 8-H), 3.24 (ddq, J = 9.0, 8.9,
6.7 Hz, 1 H, 14-H), 3.39 (s, 3 H, 19-H), 3.56 (dd, J = 8.2, 3.2 Hz,
o-H) ppm. 13C NMR (125 MHz, CD3OD): δ = 9.0 (C-18), 11.9 (C-
24), 16.1 (C-23), 16.7 (C-22), 18.5 (C-26), 19.1 (C-25), 20.3 (C-20),
22.0 (C-21), 26.0 (C-17), 33.7 (C-14), 35.2 (C-10), 36.2 (C-2), 38.4
(C-9), 39.3 (C-8), 41.2 (C-4), 55.4 (C-6), 55.8 (ArOCH3), 60.5 (C-
19), 65.4 (C-12), 68.8 (C-1), 68.9 (C-13), 73.4 (C-3), 73.8
(OCH2Ar), 83.4 (C-11), 88.2 (C-5), 114.8 (C-m), 126.6 (C-15), 130.5
(C-o), 131.8 (C-i), 133.2 (C-16), 160.8 (C-p), 222.2 (C-7) ppm.
FTIR (ATR): ν = 3465 (w), 2965 (m), 2926 (s), 2856 (m), 1695 (m),
˜
1613 (m), 1513 (s), 1456 (s), 1384 (m), 1247 (vs), 1096 (vs), 1033
1 H, 11-H), 3.58 (d, J = 4.3 Hz, 1 H, 5-H), 3.69 (s, 3 H, CO2CH3), (vs), 995 (m), 821 (m) cm–1. MS (APCI): m/z (%) = 559 (100) [M –
3.91 (dddd, J = 9.2, 3.7, 3.6, 3.3 Hz, 1 H, 3-H), 4.95 (dqq, J = 8.9,
1.4, 1.4 Hz, 1 H, 15-H), 5.19 (dq, J = 9.0, 1.4 Hz, 1 H, 13-H) ppm.
OH]+, 541 (21), 527 (11), 447 (13), 413 (9), 389 (41). HRMS
(APCI): calcd. for C34H54O6 [M – OH]+ 559.3993; found
+
13C NMR (125 MHz, CDCl3): δ = 9.1 (C-18), 11.6 (C-24), 17.7 (C- 559.3986.
23), 18.1 (C-26), 19.5 (C-22), 20.0 (C-20), 21.76 (C-21), 21.79 (C-
(8S)-12c: Rf = 0.46 (n-hexane/EtOAc, 1:1). [α]2D0 = +14.4 (c = 0.17,
CH2Cl2). H NMR (500 MHz, CD3OD): δ = 0.89 (d, J = 7.2 Hz,
25), 25.8 (C-17), 31.6 (C-14), 34.5 (C-10), 37.8 (C-9), 39.4 (C-2),
39.7 (C-8), 40.6 (C-4), 51.9 (CO2CH3), 53.9 (C-6), 60.9 (C-19), 70.2
(C-3), 83.5 (C-11), 86.0 (C-5), 129.6 (C-15), 129.9 (C-12), 133.3 (C-
1
3 H, 18-H), 0.99 (d, J = 6.7 Hz, 3 H, 22-H), 1.00 (d, J = 6.8 Hz, 3
H, 23-H), 1.01 (d, J = 7.1 Hz, 3 H, 25-H), 1.07 (s, 3 H, 21-H), 1.17
(s, 3 H, 20-H), 1.25 (ddd, J = 13.6, 11.0, 2.9 Hz, 1 H, 9-Ha), 1.31
(s, 3 H, 24-H), 1.53 (ddd, J = 13.6, 11.1, 3.0 Hz, 1 H, 9-Hb), 1.63
(d, J = 1.4 Hz, 3 H, 26-H), 1.64–1.73 (m, 2 H, 2-Ha, 4-H), 1.71 (d,
J = 1.4 Hz, 3 H, 17-H), 1.75–1.80 (m, 1 H, 2-Hb), 1.83 (dqdd, J =
11.0, 6.6, 6.0, 3.0 Hz, 1 H, 10-H), 2.36 (ddq, J = 9.1, 9.1, 6.8 Hz,
1 H, 14-H), 2.69 (d, J = 9.1 Hz, 1 H, 13-H), 3.06 (d, J = 6.0 Hz, 1
H, 11-H), 3.15 (dqd, J = 11.1, 6.6, 3.1 Hz, 1 H, 8-H), 3.31 (s, 3 H,
19-H), 3.47 (d, J = 3.0 Hz, 1 H, 5-H), 3.58–3.62 (m, 2 H, 1-Ha, 1-
Hb), 3.64 (ddd, J = 9.1, 3.9, 3.9 Hz, 1 H, 3-H), 3.78 (s, 3 H, Ar-
OCH3), 4.44 (s, 2 H, OCH2Ar), 5.08 (dqq, J = 9.1, 1.4, 1.4 Hz, 1
H, 15-H), 6.87–6.90 (m, 2 H, m-H), 7.25–7.28 (m, 2 H, o-H) ppm.
13C NMR (125 MHz, CD3OD): δ = 9.0 (C-18), 13.8 (C-24), 16.3
(C-23), 16.5 (C-22), 17.8 (C-25), 18.3 (C-26), 20.2 (C-20), 22.0 (C-
21), 26.0 (C-17), 33.4 (C-14), 33.7 (C-10), 36.1 (C-9), 36.2 (C-2),
39.0 (C-8), 41.2 (C-4), 55.3 (C-6), 55.7 (ArOCH3), 60.5 (C-19), 63.7
(C-12), 66.4 (C-13), 68.8 (C-1), 73.3 (C-3), 73.8 (OCH2Ar), 80.1
(C-11), 88.2 (C-5), 114.8 (C-m), 128.6 (C-15), 130.5 (C-o), 131.7
13), 133.8 (C-16), 173.4 (C-1), 220.9 (C-7) ppm. FTIR (ATR): ν =
˜
3467 (w), 2966 (s), 2927 (s), 2875 (m), 1737 (s), 1696 (s), 1439 (s),
1376 (m), 1170 (s), 1098 (s), 990 (vs) cm–1. MS (ESI): m/z = 491
[M + Na]+ , 451, 433, 157, 102. HRMS (ESI): calcd. for
+
C27H48NaO6 [M + Na]+ 491.3343; found 491.3349.
General Procedure for the Preparation of Epoxides 12 and 17: In
analogy to ref.[36], a 5.5 m solution of tBuOOH in nonane
(1.5 equiv.) was added dropwise under N2 to a solution of Ti-
(OiPr)4 (0.2 equiv.) in abs. CH2Cl2 (4.0 mL) and 4 Å mol. sieves
(10 pellets) at –20 °C and the reaction mixture was stirred for
30 min. Then a solution of 11a/11b or the respective 15 (1.0 equiv.)
in CH2Cl2 (1.0 mL) was added dropwise and the reaction mixture
stirred for a further 14 h. After the addition of a sat. FeSO4 solu-
tion (5 mL), the reaction mixture was warmed to room tempera-
ture. The aqueous layer was separated and extracted with CH2Cl2
(4ϫ 5 mL). The combined organic extracts were washed with brine
(10 mL), dried (MgSO4), and concentrated. The diastereomeric
mixture of 12a/12c/12b/12d (7:8:38:47, by 1H NMR) was separated
by preparative HPLC (Kromasil, 100 Sil 5 μm, n-hexane/EtOAc/
(C-i), 133.4 (C-16), 160.8 (C-p), 222.0 (C-7) ppm. FTIR (ATR): ν
˜
= 3486 (w), 2964 (m), 2930 (m), 2873 (m), 1696 (m), 1613 (m), 1513
Et3N, 95:4:1, flow 10 mLmin–1). The crude diastereomeric epoxides (m), 1456 (m), 1384 (m), 1247 (vs), 1095 (vs), 1035 (s), 987 (m),
17 were purified by chromatography on SiO2 (hexanes/EtOAc/
Et3N, 75:24:1 Ǟ 50:49:1).
821 (m) cm–1. MS (APCI): m/z (%) = 559 (100) [M – OH]+, 541
(26), 527 (9), 389 (16), 361 (9). HRMS (APCI): calcd. for
C34H54O6 [M – OH]+ 559.3993; found 559.3984.
+
(1S,2S,7S,8R,9S)-1,9-Dihydroxy-7-methoxy-11-[(4-methoxybenzyl)-
oxy]-2,4,6,6,8-pentamethyl-1-{2-methyl-3-[(S)-4-methylpent-3-en-2-
yl]oxiran-2-yl}undecan-5-one (12): From 11a/11b (dr = 15:85,
62.5 mg, 111.4 μmol), tBuOOH in nonane (30.0 μL, 167.2 μmol),
and Ti(OiPr)4 (9.9 μL, 33.4 μmol) was obtained 12a (3.2 mg,
5.6 μmol, 5 %), 12c (3.8 mg, 6.7 μmol, 6 %), 12b (21.8 mg,
(8R)-12b: Rf = 0.34 (n-hexane/EtOAc, 1:1). [α]2D0 = +19.4 (c = 0.57,
1
CH2Cl2). H NMR (500 MHz, CD3OD): δ = 0.81 (d, J = 6.8 Hz,
3 H, 23-H), 0.89 (d, J = 7.2 Hz, 3 H, 18-H), 0.92 (ddd, J = 13.7,
8.4, 5.8 Hz, 1 H, 9-Ha), 1.03 (d, J = 6.8 Hz, 3 H, 22-H), 1.062 (s,
3 H, 21-H), 1.063 (d, J = 6.6 Hz, 3 H, 25-H), 1.18 (s, 3 H, 20-H),
7304
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7294–7307

Gephyronic Acid Derivatives
1.22 (s, 3 H, 24-H), 1.43 (ddqd, J = 9.2, 8.4, 6.7, 4.1 Hz, 1 H, 10-
H), 1.63 (d, J = 1.4 Hz, 3 H, 26-H), 1.67 (qdd, J = 7.2, 3.9, 3.0 Hz,
1 H, 4-H), 1.69 (d, J = 1.4 Hz, 3 H, 17-H), 1.69 (dddd, J = 14.1,
9.0, 5.6, 5.6 Hz, 1 H, 2-Ha), 1.79 (dddd, J = 14.1, 7.6, 6.3, 4.0 Hz,
1 H, 2-Hb), 2.11 (ddd, J = 13.7, 8.0, 4.1 Hz, 1 H, 9-Hb), 2.34 (ddq,
J = 10.0, 9.3, 6.6 Hz, 1 H, 14-H), 2.60 (d, J = 9.3 Hz, 1 H, 13-H),
2.67 (d, J = 9.2 Hz, 1 H, 11-H), 3.26 (dqd, J = 8.0, 6.8, 5.8 Hz, 1
J = 10.0, 9.2, 6.6 Hz, 1 H, 14-H), 2.48 (dd, J = 15.1, 8.8 Hz, 1 H,
2-Ha), 2.55 (dd, J = 15.1, 4.8 Hz, 1 H, 2-Hb), 2.61 (d, J = 9.2 Hz,
1 H, 13-H), 2.68 (d, J = 9.2 Hz, 1 H, 11-H), 3.28 (dqd, J = 8.0,
6.8, 5.9 Hz, 1 H, 8-H), 3.30 (s, 3 H, 19-H), 3.54 (d, J = 2.8 Hz, 1
H, 5-H), 3.68 (s, 3 H, CO2CH3), 3.98 (ddd, J = 8.8, 4.8, 3.9 Hz, 1
H, 3-H), 5.01 (dqq, J = 10.0, 1.4, 1.3 Hz, 1 H, 15-H) ppm. 13C
NMR (125 MHz, CD3OD): δ = 8.8 (C-18), 12.0 (C-24), 17.2 (C-
H, 8-H), 3.29 (s, 3 H, 19-H), 3.55 (d, J = 3.0 Hz, 1 H, 5-H), 3.57– 23), 18.4 (C-26), 19.0 (C-25), 19.5 (C-22), 19.9 (C-20), 22.0 (C-21),
3.62 (m, 2 H, 1-Ha, 1-Hb), 3.64 (ddd, J = 9.0, 4.0, 3.9 Hz, 1 H, 3- 25.9 (C-17), 33.7 (C-14), 35.5 (C-10), 39.7 (C-9), 40.2 (C-8), 40.9
H), 3.78 (s, 3 H, ArOCH3), 4.43 (s, 2 H, OCH2Ar), 5.00 (dqq, J =
10.0, 1.4, 1.4 Hz, 1 H, 15-H), 6.88–6.91 (m, 2 H, m-H), 7.25–7.28 12), 68.8 (C-13), 72.7 (C-3), 83.9 (C-11), 87.7 (C-5), 126.6 (C-15),
(m, 2 H, o-H) ppm. 13C NMR (125 MHz, CD3OD): δ = 8.9 (C-
133.1 (C-16), 174.1 (C-1), 222.0 (C-7) ppm. FTIR (ATR): ν = 3490
(C-4), 41.3 (C-2), 52.1 (CO2CH3), 55.0 (C-6), 60.3 (C-19), 65.3 (C-
˜
18), 12.1 (C-24), 17.2 (C-23), 18.5 (C-26), 19.1 (C-25), 19.5 (C-22), (w), 2969 (m), 2930 (m), 1734 (m), 1696 (m), 1456 (s), 1385 (m),
19.9 (C-20), 22.3 (C-21), 26.0 (C-17), 33.7 (C-14), 35.5 (C-10), 36.2 1251 (m), 1170 (m), 1096 (s), 1047 (s), 989 (vs) cm–1. MS (ESI):
(C-2), 39.7 (C-9), 40.2 (C-8), 41.2 (C-4), 55.0 (C-6), 55.8 (ArOCH3),
m/z = 507 [M + Na]+, 467, 102. HRMS (ESI): calcd. for
60.3 (C-19), 65.4 (C-12), 68.8 (C-13), 68.9 (C-1), 73.3 (C-3), 73.8 C27H48NaO7 [M + Na]+ 507.3292; found 507.3296.
+
(OCH2Ar), 83.9 (C-11), 87.9 (C-5), 114.8 (C-m), 126.5 (C-15), 130.6
(8R)-17d: Yield: 3.0 mg (6.2 μmol, 41%), colorless oil. Rf = 0.42 (n-
(C-o), 131.7 (C-i), 133.1 (C-16), 160.8 (C-p), 222.4 (C-7) ppm.
hexane/EtOAc, 1:1). [α]2D0 = +4.2 (c = 0.12, MeOH). 1H NMR
FTIR (ATR): ν = 3471 (w), 2969 (m), 2931 (s), 2871 (m), 1695 (m),
˜
(500 MHz, CD3OD): δ = 0.91 (d, J = 7.2 Hz, 3 H, 18-H), 0.97–
1.01 (m, 1 H, 9-Ha), 1.00 (d, J = 6.8 Hz, 3 H, 23-H), 1.03 (d, J =
6.8 Hz, 3 H, 22-H), 1.101 (s, 3 H, 20-H), 1.103 (d, J = 6.8 Hz, 3
H, 25-H), 1.21 (s, 3 H, 21-H), 1.32 (s, 3 H, 24-H), 1.52–1.61 (m, 1
H, 10-H), 1.65 (d, J = 1.3 Hz, 3 H, 26-H), 1.69 (qdd, J = 7.2, 3.9,
2.9 Hz, 1 H, 4-H), 1.72 (d, J = 1.3 Hz, 3 H, 17-H), 2.02 (ddd, J =
13.3, 10.3, 2.9 Hz, 1 H, 9-Hb), 2.42 (ddq, J = 9.2, 9.1, 6.9 Hz, 1 H,
14-H), 2.48 (dd, J = 15.1, 8.6 Hz, 1 H, 2-Ha), 2.56 (dd, J = 15.1,
1613 (m), 1513 (s), 1456 (s), 1385 (m), 1246 (vs), 1096 (vs), 1034
(vs), 994 (m), 821 (m), 736 (m) cm–1. MS (APCI): m/z (%) = 594
(11) [M + NH4]+, 559 (100) [M – OH]+, 541 (22), 527 (36), 447
(13), 423 (11), 389 (100), 371 (22). HRMS (APCI): calcd. for
+
C34H54O6 [M – OH]+ 559.3993; found 559.3987.
(8R)-12d: Rf = 0.58 (n-hexane/EtOAc, 1:1). [α]2D0 = +11.3 (c = 0.34,
1
CH2Cl2). H NMR (500 MHz, CD3OD): δ = 0.90 (d, J = 7.2 Hz,
3 H, 18-H), 0.95–1.03 (m, 1 H, 9-Ha), 0.99 (d, J = 6.8 Hz, 3 H, 23- 4.8 Hz, 1 H, 2-Hb), 2.83 (d, J = 9.1 Hz, 1 H, 13-H), 3.15–3.22 (m,
H), 1.01 (d, J = 6.8 Hz, 3 H, 22-H), 1.07 (s, 3 H, 21-H), 1.08 (d, J
= 6.9 Hz, 3 H, 25-H), 1.20 (s, 3 H, 20-H), 1.31 (s, 3 H, 24-H), 1.56
(dqdd, J = 10.5, 6.8, 4.8, 3.0 Hz, 1 H, 10-H), 1.64 (d, J = 1.3 Hz,
3 H, 26-H), 1.62–1.67 (m, 1 H, 4-H), 1.71 (d, J = 1.3 Hz, 3 H, 17-
H), 1.67–1.72 (m, 1 H, 2-Ha), 1.79 (dddd, J = 14.0, 6.9, 6.9, 4.0 Hz,
1 H, 2-Hb), 2.01 (ddd, J = 13.5, 10.2, 3.0 Hz, 1 H, 9-Hb), 2.40 (ddq,
J = 9.2, 9.1, 6.9 Hz, 1 H, 14-H), 2.82 (d, J = 9.2 Hz, 1 H, 13-H),
3.170 (dqd, J = 9.5, 6.8, 4.3 Hz, 1 H, 8-H), 3.171 (d, J = 4.8 Hz, 1
H, 11-H), 3.30 (s, 3 H, 19-H), 3.56 (d, J = 2.9 Hz, 1 H, 5-H), 3.54–
1 H, 8-H), 3.18 (d, J = 4.8 Hz, 1 H, 11-H), 3.31 (s, 3 H, 19-H),
3.55 (d, J = 2.9 Hz, 1 H, 5-H), 3.68 (s, 3 H, CO2CH3), 3.98 (ddd,
J = 8.6, 4.8, 3.9 Hz, 1 H, 3-H), 5.12 (dqq, J = 9.2, 1.3, 1.3 Hz, 1
H, 15-H) ppm. 13C NMR (125 MHz, CD3OD): δ = 8.8 (C-18), 14.5
(C-24), 17.5 (C-23), 17.7 (C-25), 18.4 (C-26), 20.0 (C-20), 20.2 (C-
22), 22.1 (C-21), 26.0 (C-17), 33.6 (C-14), 34.0 (C-10), 36.6 (C-9),
40.0 (C-8), 41.0 (C-4), 41.3 (C-2), 52.1 (CO2CH3), 54.8 (C-6), 60.3
(C-19), 64.1 (C-12), 65.9 (C-13), 72.7 (C-3), 79.7 (C-11), 87.9 (C-
5), 128.8 (C-15), 133.3 (C-16), 174.1 (C-1), 222.0 (C-7) ppm. FTIR
3.61 (m, 2 H, 1-Ha, 1-Hb), 3.65 (ddd, J = 8.9, 3.9, 3.9 Hz, 1 H, 3- (ATR): ν = 3461 (w), 2921 (s), 2851 (s), 1737 (s), 1694 (s), 1459
˜
H), 3.78 (s, 3 H, ArOCH3), 4.43 (s, 2 H, OCH2Ar), 5.11 (dqq, J =
(m), 1385 (m), 1163 (m), 1099 (s), 988 (s) cm–1. MS (ESI): m/z =
9.1, 1.3, 1.3 Hz, 1 H, 15-H), 6.87–6.90 (m, 2 H, m-H), 7.24–7.27 507 [M + Na]+, 467, 242, 193, 157, 118, 102. HRMS (ESI): calcd.
(m, 2 H, o-H) ppm. 13C NMR (125 MHz, CD3OD): δ = 8.9 (C-
18), 14.5 (C-24), 17.5 (C-23), 17.7 (C-25), 18.4 (C-26), 20.0 (C-20),
20.2 (C-22), 22.2 (C-21), 26.0 (C-17), 33.6 (C-14), 34.0 (C-10), 36.2
(C-2), 36.6 (C-9), 40.0 (C-8), 41.3 (C-4), 54.8 (C-6), 55.7 (ArOCH3),
60.3 (C-19), 64.1 (C-12), 65.9 (C-13), 68.7 (C-1), 73.3 (C-3), 73.7
(OCH2Ar), 79.7 (C-11), 88.0 (C-5), 114.8 (C-m), 128.8 (C-15), 130.5
(C-o), 131.7 (C-i), 133.3 (C-6), 160.8 (C-p), 222.1 (C-7) ppm. FTIR
for C27H48NaO7 [M + Na]+ 507.3292; found 507.3287.
+
Methyl (3R,4S,5R,8R,10S,11S)-3,11-Dihydroxy-5-methoxy-
4,6,6,8,10-pentamethyl-11-{(2R,3R)-2-methyl-3-[(S)-4-methylpent-
3-en-2-yl]oxiran-2-yl}-7-oxoundecanoate (ent-17b): From ent-15b
(4.5 mg, 9.6 μmol); yield: 2.2 mg (4.5 μmol, 47%), colorless oil. Rf
1
= 0.30 (n-hexane/EtOAc, 1:1). [α]2D0 = –27.3 (c = 0.15, MeOH). H
NMR (500 MHz, CD3OD): δ = 0.83 (d, J = 6.8 Hz, 3 H, 23-H),
0.89 (d, J = 7.2 Hz, 3 H, 18-H), 0.95 (ddd, J = 13.5, 7.8, 6.6 Hz, 1
H, 9-Ha), 1.04 (d, J = 6.7 Hz, 3 H, 22-H), 1.06 (s, 3 H, 21-H), 1.07
(d, J = 6.6 Hz, 3 H, 25-H), 1.20 (s, 3 H, 20-H), 1.22 (s, 3 H, 24-
H), 1.35–1.42 (m, 1 H, 10-H), 1.64 (d, J = 1.3, Hz, 3 H, 26-H),
1.69 (d, J = 1.3 Hz, 3 H, 17-H), 1.73 (qdd, J = 7.2, 3.6, 2.8 Hz, 1
H, 4-H), 2.05 (ddd, J = 13.5, 7.4, 4.3 Hz, 1 H, 9-Hb), 2.34 (ddq, J
= 10.1, 9.2, 6.6 Hz, 1 H, 14-H), 2.48 (dd, J = 15.2, 8.7 Hz, 1 H, 2-
Ha), 2.55 (dd, J = 15.2, 4.6 Hz, 1 H, 2-Hb), 2.61 (d, J = 9.2 Hz, 1
H, 13-H), 2.68 (d, J = 9.2 Hz, 1 H, 11-H), 3.28 (dqd, J = 7.4, 6.7,
6.6 Hz, 1 H, 8-H), 3.31 (s, 3 H, 19-H), 3.52 (d, J = 2.8 Hz, 1 H, 5-
(ATR): ν = 3479 (w), 2966 (s), 2928 (s), 2873 (m), 1694 (m), 1613
˜
(w), 1513 (s), 1457 (s), 1384 (m), 1247 (vs), 1096 (vs), 1035 (s), 997
(s), 820 (m) cm–1. MS (ESI): m/z = 599 [M + Na]+, 487, 459, 333,
+
245, 121 [CH2C6H4OMe]+. HRMS (ESI): calcd. for C34H56NaO7
[M + Na]+ 599.3918; found 599.3922.
Methyl (3S,4R,5S,8R,10S,11S)-3,11-Dihydroxy-5-methoxy-
4,6,6,8,10-pentamethyl-11-{(2R,3R)-2-methyl-3-[(S)-4-methylpent-
3-en-2-yl]oxiran-2-yl}-7-oxoundecanoate [(8R)-17b]: From 15b
(7.1 mg, 15.1 μmol); yield: 3.7 mg (7.6 μmol, 50%), colorless oil. Rf
1
= 0.26 (n-hexane/EtOAc, 1:1). [α]2D0 = +18.4 (c = 0.14, MeOH). H
NMR (500 MHz, CD3OD): δ = 0.82 (d, J = 6.8 Hz, 3 H, 23-H), H), 3.69 (s, 3 H, CO2CH3), 3.98 (ddd, J = 8.7, 4.6, 3.6 Hz, 1 H, 3-
0.90 (d, J = 7.2 Hz, 3 H, 18-H), 0.93 (ddd, J = 13.6, 8.4, 5.9 Hz, 1
H, 9-Ha), 1.05 (d, J = 6.8 Hz, 3 H, 22-H), 1.07 (d, J = 6.6 Hz, 3
H), 5.01 (dqq, J = 10.1, 1.3, 1.3 Hz, 1 H, 15-H) ppm. 13C NMR
(125 MHz, CD3OD): δ = 8.9 (C-18), 11.9 (C-24), 17.5 (C-23), 18.4
H, 25-H), 1.09 (s, 3 H, 21-H), 1.19 (s, 3 H, 20-H), 1.23 (s, 3 H, 24- (C-26), 18.9 (C-22), 19.0 (C-25), 20.2 (C-20), 21.8 (C-21), 25.9 (C-
H), 1.43 (ddqd, J = 9.2, 8.4, 6.8, 4.0 Hz, 1 H, 10-H), 1.64 (d, J =
1.3 Hz, 3 H, 26-H), 1.66–1.73 (m, 1 H, 4-H), 1.70 (d, J = 1.4 Hz,
3 H, 17-H), 2.12 (ddd, J = 13.6, 8.0, 4.0 Hz, 1 H, 9-Hb), 2.34 (ddq,
17), 33.7 (C-14), 35.8 (C-10), 39.7 (C-9), 40.2 (C-8), 40.9 (C-4), 41.2
(C-2), 52.1 (CO2CH3), 55.1 (C-6), 60.4 (C-19), 65.3 (C-12), 68.8 (C-
13), 72.8 (C-3), 83.7 (C-11), 87.5 (C-5), 126.5 (C-15), 133.1 (C-16),
Eur. J. Org. Chem. 2011, 7294–7307
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7305

R. E. Taylor, S. Laschat et al.
FULL PAPER
174.2 (C-1), 222.2 (C-7) ppm. FTIR (ATR): ν = 3323 (w), 2978 J = 6.7 Hz, 3 H, 23-H), 1.007 (d, J = 6.7 Hz, 3 H, 22-H), 1.02 (d,
˜
(m), 2938 (m), 1713 (s), 1377 (m), 1258 (m), 1121 (s), 1083 (s), 1044 J = 6.9 Hz, 3 H, 25-H), 1.11 (s, 3 H, 20-H), 1.15 (s, 3 H, 21-H),
(vs), 880 (m), 845 (m) cm–1. MS (ESI): m/z = 507 [M + Na]+, 118,
1.27 (ddd, J = 13.6, 11.2, 3.0 Hz, 1 H, 9-Ha), 1.32 (s, 3 H, 24-H),
+
102. HRMS (ESI): calcd. for C27H48NaO7 [M + Na]+ 507.3292; 1.57 (ddd, J = 13.6, 11.0, 2.8 Hz, 1 H, 9-Hb), 1.64 (d, J = 1.3 Hz,
found 507.3297.
3 H, 26-H), 1.71 (d, J = 1.3 Hz, 3 H, 17-H), 1.73 (qdd, J = 7.2,
3.7, 2.9 Hz, 1 H, 4-H), 1.83 (dqdd, J = 11.2, 6.7, 6.1, 2.8 Hz, 1 H,
10-H), 2.37 (ddq, J = 9.1, 9.1, 6.9 Hz, 1 H, 14-H), 2.49 (dd, J =
15.2, 8.7 Hz, 1 H, 2-Ha), 2.55 (dd, J = 15.2, 4.9 Hz, 1 H, 2-Hb),
2.70 (d, J = 9.1 Hz, 1 H, 13-H), 3.05 (d, J = 6.1 Hz, 1 H, 11-H),
3.16 (dqd, J = 10.8, 6.7, 3.0 Hz, 1 H, 8-H), 3.34 (s, 3 H, 19-H),
3.50 (d, J = 2.9 Hz, 1 H, 5-H), 3.68 (s, 3 H, CO2CH3), 3.96 (ddd,
J = 8.7, 4.9, 3.7 Hz, 1 H, 3-H), 5.09 (dqq, J = 9.1, 1.3, 1.3 Hz, 1
H, 15-H) ppm. 13C NMR (125 MHz, CD3OD): δ = 8.8 (C-18), 13.7
(C-24), 16.47 (C-22), 16.49 (C-23), 17.8 (C-25), 18.3 (C-26), 20.2
(C-20), 21.9 (C-21), 26.0 (C-17), 33.5 (C-14), 33.8 (C-10), 36.3 (C-
9), 38.7 (C-8), 40.9 (C-4), 41.2 (C-2), 52.1 (CO2CH3), 55.3 (C-6),
60.5 (C-19), 63.8 (C-12), 66.4 (C-13), 72.7 (C-3), 80.2 (C-11), 87.6
(C-5), 128.6 (C-15), 133.4 (C-16), 174.1 (C-1), 221.6 (C-7) ppm.
ent-17d: Yield: 2.0 mg (4.0 μmol, 42%), colorless oil. Rf = 0.46 (n-
hexane/EtOAc, 1:1). [α]2D0 = –11.8 (c = 0.17, MeOH). 1H NMR
(500 MHz, CD3OD): δ = 0.90 (d, J = 7.2 Hz, 3 H, 18-H), 1.00 (d,
J = 6.7 Hz, 3 H, 23-H), 1.02 (ddd, J = 13.5, 10.0, 3.9 Hz, 1 H, 9-
Ha), 1.03 (d, J = 6.8 Hz, 3 H, 22-H), 1.05 (s, 3 H, 21-H), 1.10 (d,
J = 6.9 Hz, 3 H, 25-H), 1.23 (s, 3 H, 20-H), 1.30 (s, 3 H, 24-H),
1.50 (dqdd, J = 10.0, 6.7, 4.9, 3.0 Hz, 1 H, 10-H), 1.65 (d, J =
1.3 Hz, 3 H, 26-H), 1.72 (d, J = 1.4 Hz, 3 H, 17-H), 1.73 (qdd, J
= 7.2, 3.8, 2.9 Hz, 1 H, 4-H), 1.98 (ddd, J = 13.5, 10.1, 3.0 Hz, 1
H, 9-Hb), 2.41 (ddq, J = 9.2, 9.1, 6.9 Hz, 1 H, 14-H), 2.49 (dd, J
= 15.2, 8.7 Hz, 1 H, 2-Ha), 2.54 (dd, J = 15.2, 4.7 Hz, 1 H, 2-Hb),
2.81 (d, J = 9.2 Hz, 1 H, 13-H), 3.16 (d, J = 4.9 Hz, 1 H, 11-H),
3.19 (dqd, J = 10.1, 6.9, 3.9 Hz, 1 H, 8-H), 3.30 (s, 3 H, 19-H),
3.55 (d, J = 2.9 Hz, 1 H, 5-H), 3.69 (s, 3 H, CO2CH3), 3.98 (ddd,
J = 8.7, 4.7, 3.8 Hz, 1 H, 3-H), 5.11 (dqq, J = 9.1, 1.4, 1.3 Hz, 1
H, 15-H) ppm. 13C NMR (125 MHz, CD3OD): δ = 9.0 (C-18), 14.3
(C-24), 17.67 (C-23), 17.67 (C-25), 18.4 (C-26), 19.5 (C-22), 20.2
(C-20), 21.9 (C-21), 26.0 (C-17), 33.5 (C-14), 34.4 (C-10), 36.8 (C-
FTIR (ATR): ν = 3493 (w), 2967 (s), 2933 (s), 2877 (m), 1735 (s),
˜
1697 (s), 1455 (m), 1384 (m), 1168 (m), 1098 (s), 989 (s), 781
(s) cm–1. MS (ESI): m/z = 507 [M + Na]+, 395, 367, 333, 197.
HRMS (ESI): calcd. for C27H48NaO7+ [M + Na]+ 507.3292; found
507.3288.
9), 39.9 (C-8), 40.9 (C-4), 41.2 (C-2), 52.1 (CO2CH3), 54.9 (C-6), Cell Proliferation Assay: L-929 mouse fibroblast and KB-3-1 cervix
60.4 (C-19), 64.0 (C-12), 66.0 (C-13), 72.8 (C-3), 79.6 (C-11), 87.4 carcinoma cell lines were obtained from the German Collection of
(C-5), 128.8 (C-15), 133.3 (C-16), 174.2 (C-1), 221.7 (C-7) ppm. Microorganisms and Cell Cultures (DSMZ) and cultivated at 37 °C
FTIR (ATR): ν = 3330 (m), 2978 (m), 2937 (m), 1713 (s), 1446 (w),
and 10% CO2 in DME medium (high glucose) supplemented with
˜
1337 (s), 1259 (m), 1122 (s), 1082 (vs), 1044 (vs), 880 (m), 845 10% fetal calf serum. Cell culture reagents came from Life Technol-
(m) cm–1. MS (ESI): m/z = 507 [M + Na]+, 102. HRMS (ESI):
ogies Inc. (GIBCO BRL). Growth inhibition was measured in 96-
well plates. Serial dilutions (60 μL) of the test compounds were
added to aliquots (120 μL) of the suspended cells (50000 mL–1).
After 5 d, the metabolic activity in each well was determined
through an MTT assay.[29] The values were related to control cells
and IC50 values were determined from the resulting concentration-
dependent activity curves. The data are meansϮstandard deviation
of two assays performed in parallel.
+
calcd. for C27H48NaO7 [M + Na]+ 507.3292; found 507.3295.
Methyl (3R,4S,5R,8S,10S,11S)-3,11-Dihydroxy-5-methoxy-
4,6,6,8,10-pentamethyl-11-{(2R,3R)-2-methyl-3-[(S)-4-methylpent-
3-en-2-yl]oxiran-2-yl}-7-oxoundecanoate (ent-17a): From ent-15a
(16.3 mg, 34.8 μmol); yield: 6.1 mg (12.5 μmol, 36%), colorless oil.
Rf = 0.29 (n-hexane/EtOAc, 1:1). [α]2D0 = +15.3 (c = 0.40, MeOH).
1H NMR (500 MHz, CD3OD): δ = 0.84 (d, J = 6.7 Hz, 3 H, 23-
H), 0.89 (d, J = 7.2 Hz, 3 H, 18-H), 0.99 (d, J = 6.6 Hz, 3 H, 22-
H), 1.07 (d, J = 6.6 Hz, 3 H, 25-H), 1.11 (s, 3 H, 21-H), 1.158 (s,
3 H, 20-H), 1.160 (ddd, J = 13.5, 10.3, 3.5 Hz, 1 H, 9-Ha), 1.25 (s,
3 H, 24-H), 1.55 (ddqd, J = 10.3, 9.4, 6.7, 3.0 Hz, 1 H, 10-H), 1.65
(d, J = 1.3, Hz, 3 H, 26-H), 1.70 (d, J = 1.3 Hz, 3 H, 17-H), 1.71
(qdd, J = 7.2, 3.7, 2.9 Hz, 1 H, 4-H), 1.77 (ddd, J = 13.5, 10.5,
3.0 Hz, 1 H, 9-Hb), 2.36 (ddq, J = 10.0, 9.3, 6.6 Hz, 1 H, 14-H),
Antibacterial Assay: Antibacterial activities were determined by
agar diffusion assays using paper discs of 6 mm diameter soaked
with 20 μL of a methanolic solution of the test compound
(1 mgmL–1). The organisms were grown on standard medium and
seeded into a liquid agar medium to a final optical density of 0.01.
Plates were incubated at 30 °C and bacterial growth was observed
after 1 d. The diameter of resulting inhibition zones were taken as
2.49 (dd, J = 15.2, 8.6 Hz, 1 H, 2-Ha), 2.54 (dd, J = 15.2, 5.0 Hz, a measure of the antibiotic activity.
1 H, 2-Hb), 2.62 (d, J = 9.3 Hz, 1 H, 13-H), 2.66 (d, J = 9.4 Hz, 1
Supporting Information (see footnote on the first page of this arti-
H, 11-H), 3.18 (dqd, J = 10.3, 6.6, 3.6 Hz, 1 H, 8-H), 3.33 (s, 3 H,
19-H), 3.50 (d, J = 2.9 Hz, 1 H, 5-H), 3.69 (s, 3 H, CO2CH3), 3.97
(ddd, J = 8.6, 5.0, 3.7 Hz, 1 H, 3-H), 5.02 (dqq, J = 10.0, 1.3,
1.3 Hz, 1 H, 15-H) ppm. 13C NMR (125 MHz, CD3OD): δ = 8.8
(C-18), 11.9 (C-24), 16.0 (C-23), 16.8 (C-22), 18.4 (C-26), 19.0 (C-
25), 20.3 (C-20), 21.8 (C-21), 25.9 (C-17), 33.7 (C-14), 35.2 (C-10),
38.4 (C-9), 39.1 (C-8), 40.9 (C-4), 41.2 (C-2), 52.1 (CO2CH3), 55.4
(C-6), 60.5 (C-19), 65.4 (C-12), 68.9 (C-13), 72.7 (C-3), 83.4 (C-11),
87.6 (C-5), 126.5 (C-15), 133.2 (C-16), 174.1 (C-1), 221.7 (C-
cle): Stereochemistry at C8 by comparison of proton shifts; synthe-
sis and characterization of xanthogenates, compounds 10 and
alcohols thereof, and derivatives ent-14–ent-16; byproduct forma-
tion under deoxygenation and acetalization reactions; example
curves of MTT assays and some IC50 values.
Acknowledgments
7) ppm. FTIR (ATR): ν = 3495 (w), 2969 (m), 2928 (m), 1736 (m),
˜
Generous financial support by the National Science Foundation,
the Deutsche Forschungsgemeinschaft (CHE-0924351 for R. E. T.
and F. S.), the Deutsche Akademische Austauschdienst (fellowship
for T. A.), the Ministerium für Wissenschaft, Forschung und Kunst
des Landes Baden-Württemberg (Landesgraduierten fellowship for
T. A.), and the Fonds der Chemischen Industrie is gratefully ac-
knowledged. We would like to thank Tobias Holl and Wera Collisi
for skilful technical assistance.
1696 (m), 1455 (m), 1385 (m), 1171 (m), 1098 (s), 1047 (m), 991
(m), 780 (s) cm–1. MS (ESI): m/z = 507 [M + Na]+, 395, 367, 333,
197. HRMS (ESI): calcd. for C27H48NaO7 [M + Na]+ 507.3292;
+
found 507.3287.
ent-17c: Yield: 8.8 mg (18.1 μmol, 52%), colorless oil. Rf = 0.40 (n-
hexane/EtOAc, 1:1). [α]2D0 = –10.9 (c = 0.50, MeOH). 1H NMR
(500 MHz, CD3OD): δ = 0.89 (d, J = 7.2 Hz, 3 H, 18-H), 1.007 (d,
7306
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7294–7307

Gephyronic Acid Derivatives
454; b) S. Nishimura, S. Matsunaga, S. Yoshida, Y. Nakao, H.
Hirota, N. Fusetani, Bioorg. Med. Chem. 2005, 13, 455–462.
J. Hines, M. Roy, H. Cheng, C. M. Agapakis, R. Taylor, C. M.
Crews, Mol. Biosyst. 2006, 2, 371–379.
R. E. Taylor, Nat. Prod. Rep. 2008, 25, 854–861.
L. Nicolas, T. Anderl, F. Sasse, H. Steinmetz, R. Jansen, G.
Höfle, S. Laschat, R. E. Taylor, Angew. Chem. 2011, 123, 968–
971; Angew. Chem. Int. Ed. 2011, 50, 938–941.
T. Anderl, L. Nicolas, J. Münkemer, A. Baro, F. Sasse, H. Stein-
metz, R. Jansen, G. Höfle, R. E. Taylor, S. Laschat, Angew.
Chem. 2011, 123, 972–975; Angew. Chem. Int. Ed. 2011, 50,
942–945.
a) D. A. Evans, J. S. Tedrow, J. T. Shaw, C. W. Downey, J. Am.
Chem. Soc. 2002, 124, 392–393; b) M. J. Schnermann, F. A.
Romero, I. Hwang, E. Nakamaru-Ogiso, T. Yagi, D. L. Boger,
J. Am. Chem. Soc. 2006, 128, 11799–11807.
a) G. Ehrlich, J. Hassfeld, U. Eggert, M. Kalesse, Chem. Eur.
J. 2008, 14, 2232–2247; b) J. R. Dunetz, W. R. Roush, Org.
Lett. 2008, 10, 2059–2062.
a) D. A. Evans, J. V. Nelson, E. Vogel, T. R. Taber, J. Am.
Chem. Soc. 1981, 103, 3099–3111; b) V. K. Nyavanandi, S.
Nanduri, R. Vasu Dev, A. Naidu, J. Iqbal, Tetrahedron Lett.
2006, 47, 6667–6672.
a) D. A. Evans, M. J. Dart, J. L. Duffy, M. G. Yang, J. Am.
Chem. Soc. 1996, 118, 4322–4343; b) S. Kiyooka, M. Shiinoki,
K. Nakata, F. Goto, Tetrahedron Lett. 2002, 43, 5377–5380.
D. A. Evans, M. G. Yang, M. J. Dart, J. L. Duffy, A. S. Kim,
J. Am. Chem. Soc. 1995, 117, 9598–9599.
[1] For reviews, see: a) K. C. Nicolaou, J. S. Chen, S. M. Dalby,
Bioorg. Med. Chem. 2009, 17, 2290–2303; b) K. C. Nicolaou,
J. Org. Chem. 2009, 74, 951–972; c) K. C. Nicolaou, S. A. Sny-
der, Proc. Natl. Acad. Sci. USA 2004, 101, 11929–11936; d)
K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis II:
Targets, Strategies, Methods, Wiley-VCH, Weinheim, 2003; e)
K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis,
Wiley-VCH, Weinheim, 1995.
[2] K. C. Nicolaou, S. A. Snyder, Angew. Chem. 2005, 117, 1036–
1069; Angew. Chem. Int. Ed. 2005, 44, 1012–1044.
[3] For reviews, see: a) K. Kumar, H. Waldmann, Angew. Chem.
2009, 121, 3272–3290; Angew. Chem. Int. Ed. 2009, 48, 3224–
3242; b) K. Hübel, T. Leßmann, H. Waldmann, Chem. Soc.
Rev. 2008, 37, 1361–1374.
[4] a) S. L. Mooberry, Methods Mol. Med. 2007, 137, 289–302; b)
D. G. I. Kingston, Phytochemistry 2007, 68, 1844–1854; c) H.
Shigemori, J. Kobayashi, J. Nat. Prod. 2004, 67, 245–256.
[5] a) F. Feyen, F. Cachoux, J. Gertsch, M. Wartmann, K.-H.
Altmann, Acc. Chem. Res. 2008, 41, 21–31; b) K.-H. Altmann,
B. Pfeiffer, S. Arseniyadis, B. A. Pratt, K. C. Nicolaou, Chem-
MedChem 2007, 2, 396–423; c) E. B. Watkins, A. G. Chitti-
boyina, M. A. Avery, Eur. J. Org. Chem. 2006, 4071–4084.
[6] a) J. Fayette, I. Ray Coquard, L. Alberti, D. Ranchère, H.
Boyle, J.-Y. Blay, Oncologist 2005, 10, 827–832; b) G. J. Aune,
T. Furuta, Y. Pommier, Anti-Cancer Drugs 2002, 13, 545–555;
c) R. Henriquez, G. Faircloth, C. Cuevas in Anticancer Agents
from Natural Products (Eds.: G. M. Cragg, D. G. I. Kingston,
D. J. Newman), CRC Press LLC, Boca Raton, FL, 2005, pp.
215–240.
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
The NMR spectra of the crude product did not reveal any trace
of the second syn,syn-diastereomer 9b.
[7] a) F. J. Schmitz, S. P. Gunasekera, G. Yalamanchili, M. B. Hos-
sain, D. van der Helm, J. Am. Chem. Soc. 1984, 106, 7251–
7252; b) D. O’Hagan, Nat. Prod. Rep. 1993, 10, 593–624.
[8] K. L. Rinehart, K. Tachibana, J. Nat. Prod. 1995, 58, 344–358.
[9] F. Sasse, H. Steinmetz, G. Höfle, H. Reichenbach, J. Antibiot.
1995, 48, 21–25.
[25]
[26]
M. E. Jung, T. Zhang, Org. Lett. 2008, 10, 137–140.
a) H. Fujioka, Y. Ohba, K. Nakahara, M. Takatsuji, K. Murai,
M. Ito, Y. Kita, Org. Lett. 2007, 9, 5605–5608; b) K. Nozaki,
K. Oshima, K. Utimoto, Bull. Chem. Soc. Jpn. 1990, 63, 2578–
2583; c) K. Nozaki, K. Oshima, K. Utimoto, Tetrahedron Lett.
1988, 29, 6125–6126.
J.-H. Yang, J. Liu, R. P. Hsung, Org. Lett. 2008, 10, 2525–2528.
a) P. Phukan, S. Sasmal, M. E. Maier, Eur. J. Org. Chem. 2003,
1733–1740; b) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48,
4155–4156; c) A. B. Smith III, T. J. Beauchamp, M. J. LaMar-
che, M. D. Kaufman, Y. Qiu, H. Arimoto, D. R. Jones, K. Ko-
bayashi, J. Am. Chem. Soc. 2000, 122, 8654–8664; d) D. A.
Evans, A. M. Ratz, B. E. Huff, G. S. Sheppard, J. Am. Chem.
Soc. 1995, 117, 3448–3467; e) J. Mulzer, A. Mantoulidis, E.
Öhler, J. Org. Chem. 2000, 65, 7456–7467; f) M. Demuth, Helv.
Chim. Acta 1978, 61, 3136–3138.
T. Mosman, J. Immunol. Methods 1983, 65, 55–63.
K. C. Nicolaou, K. Namoto, A. Ritzén, T. Ulven, M. Shoji, J.
Li, G. DЈAmico, D. Liotta, C. T. French, M. Wartmann, K.-
H. Altmann, P. Giannakakou, J. Am. Chem. Soc. 2001, 123,
9313–9323.
G. Koch, O. Loiseleur, D. Fuentes, A. Jantsch, K.-H. Altmann,
Org. Lett. 2002, 4, 3811–3814.
E. J. Corey, A. Venkateswarlu, J. Am. Chem. Soc. 1972, 94,
6190–6191.
G. Majetich, R. W. Desmond, J. J. Soria, J. Org. Chem. 1986,
51, 1753–1769.
B. S. Bal, W. E. Childers, H. W. Pinnick, Tetrahedron 1981, 37,
2091–2096.
G. E. Keck, D. S. Welch, P. K. Vivian, Org. Lett. 2006, 8, 3667–
3670.
a) T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102,
5976–5978; b) Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko,
H. Masamune, K. B. Sharpless, J. Am. Chem. Soc. 1987, 109,
5765–5780.
[10] E. L. Whitson, K. M. Pluchino, M. D. Hall, J. B. McMahon,
T. C. McKee, Org. Lett. 2011, 13, 3518–3521.
[27]
[28]
[11] a) L. D. Julian, J. S. Newcom, W. R. Roush, J. Am. Chem. Soc.
2005, 127, 6186–6187; b) A. B. Smith III, C. M. Adams, S. A.
Lodise Barbosa, A. P. Degnan, Proc. Natl. Acad. Sci. USA
2004, 101, 12042–12047; c) W. R. Roush, J. S. Newcom, Org.
Lett. 2002, 4, 4739–4742; d) J. Hassfeld, M. Kalesse, Synlett
2002, 2007–2010; e) K. Matsui, B.-Z. Zheng, S. Kusaka, M.
Kuroda, K. Yoshimoto, H. Yamada, O. Yonemitsu, Eur. J. Org.
Chem. 2001, 3615–3624; f) T.-P. Loh, L.-C. Feng, Tetrahedron
Lett. 2001, 42, 3223–3226; g) T. Matsushima, N. Nakajima, B.-
Z. Zheng, O. Yonemitsu, Chem. Pharm. Bull. 2000, 48, 855–
860; h) M. E. Jung, R. Marquez, Org. Lett. 2000, 2, 1669–1672;
i) W. R. Roush, G. C. Lane, Org. Lett. 1999, 1, 95–98; j) R. E.
Taylor, J. P. Ciavarri, B. R. Hearn, Tetrahedron Lett. 1998, 39,
9361–9364; k) J.-F. Liu, A. Abiko, Z. Pei, D. C. Buske, S. Masa-
mune, Tetrahedron Lett. 1998, 39, 1873–1876; l) T. Matsu-
shima, K. Horita, N. Nakajima, O. Yonemitsu, Tetrahedron
Lett. 1996, 37, 385–388.
[12] a) For the total synthesis of 1a, see: G. Ehrlich, J. Hassfeld, U.
Eggert, M. Kalesse, J. Am. Chem. Soc. 2006, 128, 14038–14039;
b) for the total synthesis of 1b, see: A. B. Smith III, C. M.
Adams, S. A. Lodise Barbosa, A. P. Degnan, J. Am. Chem. Soc.
2003, 125, 350–351.
[13] For the total synthesis of 2, see: a) K. N. Fleming, R. E. Taylor,
Angew. Chem. 2004, 116, 1760–1762; Angew. Chem. Int. Ed.
2004, 43, 1728–1730; b) M. Pérez, C. del Pozo, F. Reyes, A.
Rodríguez, A. Francesch, A. M. Echavarren, C. Cuevas, An-
gew. Chem. 2004, 116, 1756–1759; Angew. Chem. Int. Ed. 2004,
43, 1724–1727.
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[14] a) S. Nishimura, S. Matsunaga, M. Yoshida, H. Hirota, S.
Yokoyama, N. Fusetani, Bioorg. Med. Chem. 2005, 13, 449–
Received: August 1, 2011
Published Online: October 28, 2011
Eur. J. Org. Chem. 2011, 7294–7307
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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