Synthetic studies toward the total synthesis of tautomycetin

Article abstract of DOI:10.1021/acs.joc.9b01712

The studies culminating in the synthesis of two large subunits of tautomycetin are described. The first one, fragment C1-C12 that has an anti-1,3-dimethyl system and a terminal diene unit, was accomplished in 10 linear steps in 7.4% overall yield. The second one, fragment C13-C25 which bears the sensitive anhydride framework and the majority of the stereogenic centers, was prepared in 13 linear steps (longest sequence) in 8% overall yield. Among the key transformations used, a regioselective epoxide opening, a Pd-catalyzed addition of terminal alkyne to acceptor alkyne, a Mukaiyama aldol reaction, a Yamaguchi esterification, and a homemade mild di-esterification can be cited. The chosen strategies allowed good yields, stereoselectivity, reproducibility, and scalability for several important intermediates.

Full text of DOI:10.1021/acs.joc.9b01712

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Article
Synthetic Studies toward the Total Synthesis of Tautomycetin
Danilo Pereira de Sant’Ana, Celso de Oliveira Rezende Júnior, Jean-
Marc Campagne, Luiz Carlos Dias, and Renata Marcia de Figueiredo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01712 • Publication Date (Web): 03 Sep 2019
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Synthetic Studies toward the Total Synthesis of Tautomycetin
Danilo Pereira de Sant’Ana,†§‡ Celso de Oliveira Rezende Júnior,†‡ Jean-Marc Campagne,*§ Luiz Car-
los Dias,*† and Renata Marcia de Figueiredo*§
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† Institute of Chemistry, University of Campinas, Campinas/São Paulo - 13083-970, Brazil.
§ Institut Charles Gerhardt, UMR 5253, Univ Montpellier, CNRS, ENSCM, 240 Avenue du Professeur Emile Jeanbrau,
34296 Montpellier Cedex 5, France.
ABSTRACT: The studies culminating in the synthesis of two large subunits of tautomycetin are described. The first one, fragment
C1-C12 that has an anti-1,3-dimethyl system and a terminal diene unit, was accomplished in 10 linear steps in 7.4% overall yield.
The second one, fragment C13-C25 which bears the sensitive anhydride framework and the majority of the stereogenic centers, was
prepared in 13 linear steps (longest sequence) in 8% overall yield. Among the key transformations used, a regioselective epoxide
opening, a Pd-catalyzed addition of terminal alkyne to acceptor alkyne, a Mukaiyama aldol reaction, a Yamaguchi esterification
and a homemade mild di-esterification can be cited. The chosen strategies allowed good yields, stereoselectivity, reproducibility
and scalability for several important intermediates.
1. INTRODUCTION
Tautomycetin (TTN, 1, Figure 1) is a natural linear polyketide
isolated by Isono and co-workers in 1989 from extracts of
Streptomyces griseochromogenes during a screening of soil
microorganisms.1-3 Initially recognized as an antifungal antibi-
otic able to induce morphological changes on human erythroid
leukemia cell K562 in the late 1980s,4 follow-up studies re-
vealed its inhibitory activity toward protein phosphatases type
1 and 2 (PP1 and PP2). Compared to other natural products
that share this biological activity [i.e. tautomycin (2), okadaic
acid (3), forstriecin (4) and cantharidin (5), (Figure 1)],5 TTN
proved to be very specific toward PP1.6 More recently, the
potential of TTN against colorectal7 and breast8 cancer cells
growth as well as its activity as immunosuppressor in organ
transplantation,9,10 have also been highlighted.11
Besides the impressive biological potential of TTN, this natu-
ral product has a unique and original chemical structure em-
bedding eight stereogenic centers,12 a terminal diene motif, an
anti-1,3-dimethyl system and an anhydride moiety that exists
as an equilibrium mixture with its open diacid form in a 4:6
ratio in methanol-buffer solution.1,13
Figure 1. Tautomycetin (1) and selected examples of natural
products that inhibit PP1 and PP2.
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Scheme 1. Retrosynthesis of TTN. R1, R2, R3, R4 = protecting groups.
Due to the unique biological properties and structural com-
plexity of TTN, we embarked into a program aimed at its total
synthesis. Despite efforts devoted to this end by Oikawa and
co-workers,14,15 a total synthesis of TTN has not yet been
achieved. Herein, we report the synthesis of two fragments
(C1-C12 and C13-C25) and our synthetic efforts toward the
assembly of the entire backbone of TTN.
Synthesis of Fragment C1-C12
On the basis of Negishi’s work,18 known alcohol 15 was pre-
pared in three steps from (S)-(-)-citronellal (6) in 30% overall
yield (Scheme 2). Thanks to a Zr-catalyzed asymmetric car-
boalumination of alkene 14 (ZACA reaction), the anti-
dimethyl system could be satisfactorily addressed. However,
in our hands, this strategy appeared difficult to be reproduced
on a multigram scale preserving the same outcomes in terms
of both yield and selectivity. Therefore, a fallback method was
envisaged.
The retrosynthetic strategy that we envisaged for accessing 1
is outlined in scheme 1. A disconnection on C12-C13 bond
gives two fragments of more or less the same size. The linear
backbone of TTN would be thus obtained through a boron
mediated aldolisation. At last, a final general deprotection step
would afford the synthetic TTN. We anticipated that C1-C12
moiety, which bears an anti-dimethyl system, would be
formed via acylation of an organolithium derivative in order to
form C5-C6 bond. The regio- and stereocontrolled introduc-
tion of the methyl group in C7 could derive either from a
strategy based on the ZACA reaction or via a regioselective
ring opening of an epoxide. The terminal diene system was to
be formed by means of palladium-catalyzed addition of termi-
nal alkyne to acceptor alkyne developed by Trost and co-
workers.16 Elaboration of C13-C25 challenging segment, that
bears the anhydride moiety, would be achieved by a sequence
of reactions including a Mukaiyama aldol addition (C15-C16
bond) and an esterification in the conditions of Yamaguchi
(O19-C20 bond). The strategy pictured to reach the puzzling
diester form of the dialkylmaleic anhydride moiety (segment
11) was envisaged from an original step of di-esterification,
under very mild conditions, previously developed in our la-
boratories.17
Scheme 2. Synthesis of the anti-1,3-dimethyl system via the
ZACA reaction.18a
The intermediate 15 could also be synthesized following the
strategy described in scheme 3. The Horner-Wadsworth-
Emmons (HWE) reaction on 6 followed by the ester reduction
to the corresponding alcohol (DIBAL-H at -78 °C), afforded
the allylic alcohol 16 in 88% yield. Asymmetric epoxidation
2. RESULTS AND DISCUSSION
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of 16 under Sharpless conditions19 [(+)-DIPT, Ti(OiPr)4,
tBuOOH, 4Å MS, -35 to -20 °C] gave the epoxy alcohol 17
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in 74% yield with a good diastereomeric ratio (d.r.) of 16:1. It
might be mentioned that when the epoxidation was realized in
the presence of less encumbered chiral ligand (+)-DEPT a
better yield was observed (81%) however with lower diastere-
oselectivity (d.r 4.5:1). With epoxy alcohol 17 in hands, the
regio- and diastereoselective ring opening studies were thus
undertaken. The goal here was to favor the formation of the
1,2-diol 18, that bears the 1,3-anti dimethyl system, instead of
the 1,3 regioisomer. Within this purpose, this step was tried
with trimethylaluminium in different solvents. Indeed, in our
hands, this key step showed to be quite sensitive to the solvent
used on the reaction. While the reaction fails when CH2Cl2
was used, which is a quite common solvent for this kind of
transformation,20 toluene gave moderate yield (55%) and d.r.
(6:1). Interestingly, changing toluene by pentane allowed us to
improve both yield and diastereoselectivity (82%, d.r. 13:1).
Subsequent oxidative cleavage (NaIO4) and reduction
(NaBH4) afforded the alcohol 15 in 79% yield. Following this
strategy, 15 was obtained in five steps with improved overall
yield (42% vs 30%)21 and better scalability than the one de-
scribed on scheme 2.22 Finally, iodide 7 was prepared by using
the conditions devised by Garegg-Samuelsson (PPh3, I2, and
Imidazole) in 84% yield.23
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Scheme 4. Synthesis of amide 10 bearing the terminal diene
system.
The stage was then set for the assembly of the backbone of the
eastern fragment C1-C12 by the key acylation step via organo-
lithium 21 (derived from tBuLi addition into iodide 7) addition
to the Weinreb amide 10.24 The transformation proceeded
smoothly when conducted in Et2O at -78 °C and the required
coupling adduct 22 was obtained in 58% yield (Scheme 5).25
Next, the regio- and chemoselective oxidative cleavage of the
more enriched double bond on the triene 22 afforded the frag-
ment C1-12 in 36% yield for the two steps. The synthesis of
subunit C1-C12, that embedded two among the eight stereo-
centers present in TTN and the dimethyl 1,3-anti system, was
thus achieved in 10 linear steps from commercially available
(S)-(-)-citronellal in 7.4% overall yield.26
Scheme 3. Synthesis of the 1,3-dimethyl system via the epoxida-
tion strategy.
Concerning the terminal diene moiety, a palladium-catalyzed
addition of terminal alkyne 9 to the acceptor alkyne 8
[Pd(OAc)2, tris(2,6-dimethoxyphenyl)phosphine (TDMPP),
THF] developed by Trost and co-workers16 enabled the isola-
tion of adduct 19 in good yield (85%) and excellent E/Z ratio
(>95:5) (Scheme 4). The E geometry could be established by
NOESY experiments after the reduction of the ester into the
corresponding alcohol. Saponification of the ester function
(LiOH, THF/MeOH/H2O 5:1:1) and Weinreb amide for-
mation (MeONHOMe∙HCl, DCC, DMAP, CH2Cl2) allowed
the access to the ene-yne intermediate 20 that afforded the
diene-amide 10 (31% overall yield for four steps) after reduc-
tion of the triple bond with the Lindlar catalyst.
Scheme 5. Accomplishment of the synthesis of fragment C1-C12.
Synthesis of Fragment C13-C25
We have next initiated the studies toward the western frag-
ment C13-C15 that bears the six other stereocenters and also
the challenging anhydride moiety. Even though the prepara-
tion of the anhydride derivative seems to be straightforward,
examples of syntheses reported in the literature showed that
this is not the case due to the equilibrium between the anhy-
dride and its opened diacid form (Scheme 6a). This point was
indeed demonstrated during studies toward the total synthesis
of tautomycin 2, a structural analog of TTN (see figure 1), that
bears the same tricky 2,3-disubstituted maleic anhydride seg-
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ment. Isono and co-workers reported in 1993 the synthesis of
the segment 26 (16% overall yield, 11 steps from 23 and 24)
(Scheme 6b),27 and two years later, Oikawa, Ichiara and co-
workers described the synthesis of compound 28 (13% overall
yield, 13 steps from 27) (Scheme 6c).13a
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Scheme 7. Synthesis of C20-C25 moiety.
Scheme 6. a) Chemical behavior in aqueous media: equilibrium
between anhydride and diacid forms. b) Synthesis of the dial-
kylmaleic anhydride 26 by Isono and co-workers. c) Synthesis of
the dialkylmaleic anhydride 28 by Oikawa, Ichiara and co-
workers. DEIPS = Diethylisopropylsilyl.
Aware of the difficulties encountered on precedent works
toward the anhydride moiety synthesis,13a,27 we have anticipat-
ed that the key for a robust strategy lies on an easy ester
deprotection at the end of the synthesis. Therefore, a great deal
of efforts and work were devoted to find a practical and mild
methodology to form the strategic dialkylmaleic anhydride
intermediate 34. Indeed, among the weaknesses highlighted on
previous strategies, the need for harsh conditions that are not
always compatible with the polyfunctionalized structure of
TTN or difficulties to find orthogonal protecting groups for
the diester intermediate synthesis hamper the accomplishment
of the total synthesis of 1.14,15 Thus, to overcome all this poten-
tial future complications, we relied on a mild and practical
procedure for the esterification of free carboxylic acids with β-
(trimethylsilyl)ethoxymethyl chloride developed in our labora-
tories.17 Accordingly, an anhydride intermediate was formed
through the saponification of 33 (LiOH, THF/H2O, rt), then
sequential bis-esterification (DCA, MeOH at 0 °C then
SEMCl) led to di-ester 34 in 67% yield (2 steps). The use of
such silyl/alkyl-ester derivative 34 has the advantage to allow
a single late deprotection step of all silyl-protecting groups in
the molecule under mild conditions avoiding strong basic
conditions. Then, 34 was transformed into acid 11 by oxida-
tive cleavage of the double bond [OsO4, NMO, acetone/H2O
then PhI(OAc)2 in CH2Cl2] followed by oxidation under
Pinnick’s conditions (80% over 3 steps).32
Considering this behavior, and keeping in mind the possible
synthetic problems that this equilibrium can accommodate, we
therefore envisaged a synthetic strategy where the anhydride
was to be formed only in the last step of the synthesis [i.e.
during the final deprotection of all protecting groups once the
entire carbon backbone of the TTN has been built (see scheme
1)]. We envisioned the synthesis of the dialkylmaleic anhy-
dride intermediate 11 starting from the commercially available
dimethyl 2-butynedioate 29 (Scheme 7). By using the stere-
oselective addition of an organocopper reagent (MeCu-
LiCN),28 followed by the trapping of the transiently formed b-
disubstituted-a-carbethoxyvinyl)cuprate with 30,13b the un-
saturated ketone intermediate 31 was isolated in 58% yield in
several grams scale. With 31 in hands, we undertook studies
toward the enantioselective reduction of the ketone function.
For this purpose, we first chose the Corey-Bakshi-Shibata
(CBS) conditions which are broadly used in total syntheses.29
Under these conditions (CBS catalyst, BH3∙BMS in THF at 0
°C) the expected alcohol could be isolated in a moderate yield
of 40% and a disappointing enantiomeric ratio (e.r. 60:40). We
were able to improve both yield and enantioselectivity by
simply moving to (+)-Ipc2BCl at -20 °C for which alcohol 32
could be isolated in 70% yield with an e.r. of 86:14.30 The
configuration of the newly generated C22 stereogenic center
was confirmed via Mosher ester analysis (see supporting in-
formation for details).31 Silylation of 32 (TBSOTf, 2,6-
lutidine, 0 °C) gave rise to the silylether 33 in 94% yield.
The synthesis of alcohol 12 commenced with the protection of
(S)-Roche ester (35) in the presence of 4-methoxybenzyl tri-
chloroacetimidate to form the p-methoxybenzyl (PMB) ether
36 (Scheme 8). DIBAL-H mediated reduction into alcohol 37
followed by Swern oxidation33 provided aldehyde 38 in 71%
yield for these three steps. In order to avoid both decomposi-
tion and C17 racemization, alcohol 37 was oxidized into alde-
hyde 38 prior to the step of methylation and directly used
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without further purification. Then, treatment of 38 with Gil- none 46 in 41% yield) in the presence of BF3∙Et2O in Et2O at
man’s reagent34 (Me2CuLi) in Et2O at low temperature af-
forded the secondary alcohol 12 in good yield (75%) and
diastereomeric ratio (12:1). The stereochemistry of the newly
formed hydroxy group was established on the basis of NOE
interactions between vicinal protons of the corresponding p-
metoxybenzylidene acetal derivative 39.35 The sequence pro-
posed to reach 12 works finely; it can be scaled up easily and
all intermediates are very stable (with the exception of alde-
hyde 38).
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-78 °C furnished the aldol adduct 47 in 42% yield (two steps;
oxidation/aldolisation) and a diastereomeric ratio of 4:1. The
relative configuration of the newly formed stereocenter was
established by conversion of 47 into ketal 48, under Ba(OH)2
treatment, and NOESY experiment. We could thus define a
trans relative stereochemistry for C18, C17 and C16 for ketal
48. Accordingly, the relative configuration of C17 and C16 on
47 is syn, and as the absolute stereochemistry of C17 is known
(S), the one from the newly formed stereocenter is (R). Alt-
hough we expected a better selectivity, this result is consistent
with a Felkin/1,3-anti aldol adduct as an anti-relationship
between the a- and b-substituents influences the facial bias of
the carbonyl moiety under non-chelating conditions.37
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On the basis of these encouraging model studies, the aldol
condensation was thus investigated on our real substrate
(Scheme 11). For this purpose, the oxidation of alcohol 42
(Scheme 7) furnished the required aldehyde 49. Then, we were
delighted to obtain the expected aldol adduct 50 in 50% yield
(two steps; Swern oxidation and aldolisation) and a similar 4:1
diastereomeric ratio. Next, we proceeded with the TBS protec-
tion step of alcohol 50. Although this transformation generally
works well, in our case it proved to be more difficult than
anticipated. Indeed, under the classical conditions (TBSOTf
and 2,6-lutidine) the protection failed. By tuning the amounts
of reagents (excess of TBSOTf) resulted extensive degradation
of 50. We believe that the reluctance of this substrate toward
TBS protection might be due to the easy dehydration on C15-
C16 under mild basic conditions as observed by Isono and co-
workers.2 Moving to milder conditions (TBSCl and imidazole
in DMF) only provided the unchanged substrate 50. To cir-
cumvent this problem, we decided to add a less encumbered
TMS protecting group. Gratefully, the TMS protection works
finely in the presence of N-trimethylsilylimidazole in CH2Cl2
at room temperature (quantitative yield). This step concluded
thus a sequence of 13 linear steps to provide the western C13-
C25 fragment of TTN in 8% overall yield.
Scheme 8. Synthesis of secondary alcohol 12.
Having synthesized the acid 11 and the secondary alcohol 12,
the coupling step was investigated (Scheme 9). Of the various
esterification protocols that were examined, Yamaguchi’s
reagent (2,4,6-trichlorobenzoyl chloride 40) proved the most
fruitful, giving ester 41 in excellent 91% yield.36 Removal of
the PMB group from 41 using DDQ furnished the primary
alcohol 42 in 85% yield.
Scheme 9. Synthesis of primary alcohol 42.
Prior to the oxidation of 42 into aldehyde and its use in the
Mukaiyama aldol reaction with 13, we studied this transfor-
mation on the model compound 45. Starting from alcohol 12
(see scheme 8), model aldehyde 45 was synthesized in three
steps via O-benzoylation (92%), PMB removal (83%) fol-
lowed by Swern oxidation (Scheme 10). Exposure of 45 to 2-
(trimethylsilyloxy)-1-butene 13 (easily prepared from buta-
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Scheme 10. Survey of the aldol reaction on the model aldehyde
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Scheme 11. Assembly of the carbon backbone of the protected
fragment C13-C25 via Mukaiyama’s aldolisation. TMSI = N-
Trimethylsilylimidazole.
Endgame strategy toward the TTN synthesis
Scheme 12. Studies toward the completion of the TTN total syn-
thesis.
With main fragments C1-C12 and C13-C25 of TTN synthe-
tized, we were ready to proceed with their attachment in order
to build the entire backbone of TTN. To remind, the endgame
steps of our proposed strategy (see Scheme 1) relied on a key
boron-mediated aldolisation to forge and control the relative
stereochemistry of C12-C13 bond38 followed by a final re-
moval of all protecting groups. Knowing that 1,2-anti adducts
are mostly like to be obtained via E-boron enolates,39 we tried
the condensation by pre-mixing fragment C13-C25 with
(cHex)2BCl (which favors E-enolate formation) in the pres-
ence of Et3N in Et2O at -30 °C followed by the addition of
aldehyde C1-C12 at -78 °C (Scheme 12). The usually recom-
mended oxidative quench was avoided due to the presence of
double bonds on both fragments which are prone to oxidation.
Then, the crude material of the aldol reaction was engaged in
the final deprotection step in the presence of HF in CH3CN.
Even though we got some evidence concerning the formation
of TTN (a mass spectra of the crude material and an HPLC
profile, see supporting information),40 to our greatest regret,
we were unable to purify and isolate the natural product. We
probably encountered problems associated with the high insta-
bility of the natural product as described in the original papers
(i.e. sites both prone to reduction and oxidation, the possible
degradation via retro-aldol reactions and the quite unpredicta-
ble behavior of the anhydride moiety).
3. CONCLUSION
We have described the synthesis of two advanced fragments of
tautomycetin (TTN, 1): the eastern one (C1-C12 segment, 10
linear steps; 7.4% yield) which bears both the terminal conju-
gated diene and the anti-1,3-dimethyl system and the western
one (C13-C25 segment, 13 linear steps; 8% overall yield) that
includes four from the eight stereogenic centers present in the
molecule and the tricky anhydride framework. Besides the
remarkable and vast biological properties of this natural linear
polyketide, its unique chemical structure displays a real chal-
lenge for chemical synthesis. Likewise, the very sensitive
chemical nature of TTN in addition to its low natural availabil-
ity were responsible for a late complete stereochemistry char-
acterization.12 Thus, to the best of our knowledge, no total
synthesis of this natural product has been described so far.
During our work on the endgame strategy to conclude the total
synthesis, indications concerning the formation of TTN were
obtained; regrettably, all attempts to purify and isolate the
natural product failed in our hands. The difficulties faced
might be related to the chemical instability previously ob-
served for this compound.12 Nonetheless, the synthesis of two
large subunits of TTN was accomplished in good overall
yields and stereocontrols. The strategies used allowed high
reproducibility and easy scale-up of key intermediates and the
challenging dialkylmaleic anhydride moiety could be efficient-
ly prepared through a homemade method.
4. EXPERIMENTAL SECTION
4.1. General Method. Unless otherwise specified (see paragraph
below), all commercial products and reagents were used as pur-
chased, without further purification. Reactions were carried out in
round-bottom flasks, and Schlenk tubes were equipped with a
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flash chromatography using 80:20 hexane:EtOAc as eluent to
magnetic stirring bar under argon atmosphere. All reactions were
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carried out under an atmosphere of argon with dry solvents under
anhydrous conditions unless otherwise stated. Analytical thin-
layer chromatography (TLC) of all reactions was performed on
silica gel 60 F254 TLC plates. Visualization of the developed
chromatogram was performed by UV absorbance (254 nm), using
p-anisaldehyde, KMnO4, vanillin or phosphomolybdic acid stains.
Flash chromatography was carried out on silica gel 60 Å (35−70
nm). FT-IR spectra were recorded with a PerkinElmer Spectrum
provide 1.13 g of 15 in 66% yield and 6:1 d.r.
1.10 g of this material (6.02 mmol) was solubilized in CH2Cl2
(20.0 mL). Then, Amano Lipase PS (180 mg, 30.0 mg/mmol) and
vinyl acetate (2.80 mL, 30.1 mmol) were added. The reaction was
stirred for 3 h. The mixture was filtered on Celite®, the solvent
was evaporated and the crude was purified by flash chromatog-
raphy on silica gel eluting with hexane:EtOAc 80:20 to give 684
mg of 15 in 44% yield from 14 and d.r. 22:1.
1
Rf = 0.57 (hexane:EtOAc 80:20). [a]!#" = +23.0 (c 1.3, CHCl3).
1000; absorptions are given in wave numbers (cm−1). H (250,
400, 500 and 600 MHz) and 13C (62.5, 100, 125 and 150 MHz)
NMR spectra were recorded with a Bruker 250, 400, 500 and
Ultra Shield 400 Plus. 1H chemical shifts are reported in delta (δ)
units in parts per million (ppm) relative to the singlet at 7.26 ppm
for chloroform-d (residual CHCl3). 13C chemical shifts are report-
ed in ppm relative to the central line of the triplet at 77.0 ppm for
chloroform-d. Splitting patterns are designated as s, singlet; d,
doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; l, large;
and combinations thereof. All coupling constants (J values) are
reported in hertz (Hz). Data are reported as follows: chemical shift
(δ in ppm), multiplicity, coupling constants (Hz), integration, and
attribution. Optical rotations were measured with a Bellingham +
Stanley ADP 440 polarimeter or a PerkinElmer polarimeter with a
sodium lamp at 589 nm. Low resolution mass spectra were rec-
orded on a Waters QTof-I and LTQ FT (Thermo Scientific, Bre-
men, Germany), spectrometer using electrospray ionization and
electron ionization. High-resolution mass spectra were obtained
using the mass spectrometers operated by the “Laboratoire de
Mesures Physiques of the University of Montpellier” and Uni-
camp. THF was dried by distillation over sodium metal and ben-
zophenone under argon. Dichloromethane (CH2Cl2), triethylamine
(Et3N), 2,6-lutidine, toluene and diethyl ether (Et2O) were dried
by distillation over CaH2 under argon. Methanol (MeOH) was
distilled from Mg(OMe)2.
1H NMR (500 MHz, CDCl3) d 5.09 (t, J 7.0 Hz, 1H), 3.47 (dd, J
10.4, 5.8 Hz, 1H), 3.39 (dd, J 10.4, 6.6 Hz, 1H), 2.0 – 1.9 (m, 2H),
1.78 – 1.63 (m, 4H), 1.60 (s, 3H), 1.56 – 1.43 (m, 2H), 1.37 – 1.00
(m, 4H), 0.88 (d, J 6.7 Hz, 3H), 0.85 (d, J 6.5 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3) d 131.1, 124.9, 69.1, 40.5, 38.0, 33.2,
29.6, 25.7, 25.5, 19.3, 17.7, 16.3. IR (Film) 3340 (broad), 2962,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
1
2914, 2874, 2872, 2853, 1454, 1377 cm .
4.1.3. (S,E)-5,9-Dimethyldeca-2,8-dien-1-ol (16)
4.1.3.a. To a suspension of NaH (60% mass/mass) (1.58 g, 39.6
mmol) in THF (112 mL) was added triethyl phosphonoacetate
(8.00 mL, 39.6 mmol) dropwise at 0° C. The suspension was
stirred for 30 min at this temperature. A solution of (S)-citronellal
(4.70 g, 30.5 mmol) in THF (51.0 mL) was added dropwise and
the mixture was stirred at this temperature for 1 h. The tempera-
ture was allowed to reach room temperature and the reaction was
stirred for an additional 18 h. A saturated aqueous solution of
NH4Cl was added (100 mL), the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2 x 50.0 mL). The
organic extract was dried with Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by flash chro-
matography, eluting with 95:5 hexane:EtOAc to give 6.20 g of
ethyl ester, 90% yield.
Rf = 0.50 (hexane:EtOAc 95:5). [a]!#" = -2.0 (c 1.3; CHCl3). H
1
4.1.1. (S)-4,8-Dimethylnona-1,7-diene (14):18a To a solution of
methyltriphenylphosphine bromide (22.1 g, 64.3 mmol) in THF
(81.0 mL) was added 1.6 M nBuLi (40.2 mL, 64.3 mmol) at 0° C.
After 30 min at 0 °C, a solution of (S)-citronellal (5.00 g, 32.7
mmol) in THF (50.0 mL) was added. The reaction mixture was
stirred for 3.5 h at 0° C and quenched by a saturated aqueous
solution of NH4Cl (50.0 mL). This mixture was extracted with
Et2O (3 x 25.0 mL). The combined organic extract were dried
over MgSO4, filtered and concentrated under reduced pressure.
The crude was purified by flash chromatography, eluting with
95:5 hexane:Et2O to give 3.12 g of 14 (72% yield).
NMR (250 MHz, CDCl3) d 6.93 (dt, J 15.4, 7.5 Hz, 1H), 5.8 (d, J
15.4 Hz, 1H), 5.07 (m, 1H), 4.17 (q, J 7.2 Hz, 2H), 2.21 (m, 1H),
2.00 (m, 3H), 1.67 (s, 3H), 1.60 (m, 1H), 1.59 (s, 3H), 1.37 (m,
1H), 1.29 (t, J 7.2 Hz, 3H), 1.17 (m, 1H), 0.89 (d, J 6.7 Hz, 3H).
13C{1H} NMR (62.5 MHz, CDCl3) d 166.6, 148.1, 131.4, 124.4,
122.4, 60.0, 39.6, 36.6, 32.0, 25.6, 25.4, 19.4, 17.6, 14.2. IR
-
1
(Film) 2964, 2915, 2874, 2854, 1722 cm . HRMS (ESI+) m/z
calculated for C14H25O2 [M+H]+ 225.1855, found 225.1964.
4.1.3.b.41 To a solution of the ethyl ester intermediate (6.12 g,
27.3 mmol) in CH2Cl2 (270 mL) was added 1 M DIBAL-H (65.0
mL, 65.0 mmol) dropwise at -78° C (DIBAL-H solution was
prepared immediately before use). After stirring at -78 °C for 2 h,
MeOH (50.0 mL) and a solution of potassium tartrate (220 mL)
were added and the mixture was stirred for 18 h. The layers were
separated and the aqueous layer was extracted with EtOAc (3 x
50.0 mL). The organic layer was dried with Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography using hexane:EtOAc 70:30 as eluent to
provide 4.90 g of 16, 98% yield.
Rf = 0.88 (hexane:Et2O 99:1). [a]!" = -2.0 (c 1.2, CHCl3). H
1
#
NMR (250 MHz, CDCl3) d 5.79 (m, 1H), 5.15 – 5.05 (m, 1H),
5.01 (dd, J 5.4, 1.2 Hz, 1H), 4.96 (s, 1H), 2.15 – 1.81 (m, 4H),
1.68 (s, 3H), 1.61 (s, 3H), 1.53 – 1.47 (m, 1H), 1.42 – 1.25 (m,
1H), 1.23 – 1.06 (m, 1H), 0.88 (d, J 6.6 Hz, 3H). 13C{1H} NMR
(62.5 MHz, CDCl3) d 137.7, 131.1, 124.9, 115.5, 41.4, 36.6,
32.4, 25.7, 25.6, 19.3, 17.6. IR (Film) 3076, 2966, 2914, 2874,
-
1
2854, 1641 cm .
Rf = 0.45 (hexane:EtOAc 80:20). 1H NMR (250 MHz, CDCl3) d
5.71 – 5.61 (m, 2H), 5.09 (dd, J 7.7, 6.5 Hz, 1H), 4.09 (d, J 4.3
Hz, 2H), 2.14 – 1.80 (m, 4H), 1.68 (s, 3H), 1.60 (s, 3H), 1.54 –
1.44 (m, 1H), 1.41 – 1.24 (m, 2H), 1.23 – 1.05 (m, 1H), 0.88 (d, J
6.6 Hz, 3H). 13C{1H} NMR (62.5 MHz, CDCl3) d 131.9, 131.2,
130.1, 124.7, 63.8, 39.6, 36.6, 32.5, 25.7, 25.5, 19.3, 17.6. IR
(Film) 3377 (broad), 3016, 2964, 2914, 2874, 2856, 1456, 1439,
4.1.2. (2R,4S)-2,4,8-Trimethylnon-7-en-1-ol (15) (method
scheme 2):18a To a solution of AlMe3 (1.80 mL, 18.6 mmol) and
(-)-bis[(1-neomenthyl)indenyl]zirconium dichloride (250 mg,
0.37 mmol) in CH2Cl2 (18.0 mL) was added a solution of the
olefin 14 (1.42 g, 9.30 mmol) in CH2Cl2 at room temperature. The
reaction was stirred for 18 h at this temperature. Then, the mixture
was cooled to 0° C and an intense flow of O2 was bubbled into the
solution for 1.5 h. The reaction was maintained under an O2 at-
mosphere at room temperature for 5 h and quenched by the addi-
tion of a solution of HCl (0.5 M, 15.0 mL). The layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (2 x 10.0
mL). The organic extract was dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by
-
1
1377, 1215 cm .
4.1.4. ((2S,3S)-3-((S)-2,6-Dimethylep-5-enyl)
oxiran-2-yl)
methanol (17): To a suspension of L-(+)-DIPT (3.90 mL, 19.0
mmol), MS 4Å (3.50 g) in CH2Cl2 (60.0 mL) was added Ti(iOPr)4
(6.04 mL, 20.0 mmol) at -35° C and the mixture was stirred for
20 min. tBuOOH (8.40 mL, 41.8 mmol) was added and the sus-
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Page 8 of 15
purification, 2.64 g of 15 was isolated in 87% yield for the two
pension was stirred for another 40 min at -35 °C. A solution of
1
2
3
4
5
6
7
8
steps.
alcohol 16 (3.47 g, 19.0 mmol) in CH2Cl2 (35.0 mL) was added
dropwise. The suspension was left in the freezer at approximately
-20° C for 18 h. Then, the mixture was filtered on Celite® and
eluted with CH2Cl2. To this solution was added a solution of
potassium sodium tartrate (100 mL) and the mixture was stirred
for 18 h. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 x 100 mL). The organic extract was
dried with Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica
gel, eluting with hexane:EtOAc (70:30) to provide 2.79 g of 17,
74% yield.
Rf = 0.57 (hexane:EtOAc 80:20). [a]!#" = +23.0 (c 1.3, CHCl3).
1H NMR (500 MHz, CDCl3) d 5.09 (t, J 7.0 Hz, 1H), 3.47 (dd, J
10.4, 5.8 Hz, 1H), 3.39 (dd, J 10.4, 6.6 Hz, 1H), 2.0 – 1.9 (m, 2H),
1.78 – 1.63 (m, 4H), 1.60 (s, 3H), 1.56 – 1.43 (m, 2H), 1.37 – 1.00
(m, 4H), 0.88 (d, J 6.7 Hz, 3H), 0.85 (d, J 6.5 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3) d 131.1, 124.9, 69.1, 40.5, 38.0, 33.2,
29.6, 25.7, 25.5, 19.3, 17.7, 16.3. IR (Film) 3340 (broad), 2962,
-
1
2914, 2874, 2872, 2853, 1454, 1377 cm .
9
4.1.7. (6S,8R)-9-Iodo-2,6,8-trimethylnon-2-ene (7): To a sus-
pension of PPh3 (2.70 g, 10.3 mmol) and imidazole (0.76 g, 11.2
mmol) in CH2Cl2 (10.0 mL) was added I2 (2.62 g, 10.3 mmol) at
0° C. After 10 min stirring the suspension became dark red, then a
solution of alcohol 15 (1.60 g, 8.60 mmol) in CH2Cl2 (7.00 mL)
was added and the reaction was stirred for 18 h at the room tem-
perature. The reaction was concentrated under reduced pressure
and the residue purified by flash chromatography using 99:1
hexane:Et2O as the eluent. After purification, 2.38 g of 7 was
obtained, 94% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rf = 0.54 (hexane:EtOAc, 60:40). [a]!#" = -19.0 (c 1.3, CHCl3).
1H NMR (250 MHz, CDCl3) d 5.14 – 4.97 (m, 1H), 3.90 (d, J
12.4 Hz, 1H), 3.70 – 3.50 (m, 1H), 3.01 – 2.92 (m, 1H), 2.89 –
2.85 (m, 1H), 2.06 – 1.92 (m, 3H), 1.67 (s, 4H), 1.59 (s, 3H), 1.56
– 1.30 (m, 3H), 1.26 – 1.15 (m, 1H), 0.97 (d, J 6.5 Hz, 3H).
13C{1H} NMR (62.5 MHz, CDCl3) d 131.4, 124.4, 61.6, 58.4,
54.8, 38.8, 36.8, 31.0, 25.7, 25.4, 19.9, 17.6. IR (Film) 3418
-
1
(broad), 2964, 2918, 2872, 2856, 1454, 1379 cm . HRMS
(ESI+) m/z calculated for C12H23O2 [M+H]+ 199.1698, found
199.1699.
[a]!#" = +10.0 (c 0.8, CHCl3). H NMR (250 MHz, CDCl3) d
1
5.09 (t, J 7.0 Hz, 1H), 3.21 (dd, J 9.5, 4.9 Hz, 1H), 3.12 (dd, J 9.5,
6.2 Hz, 1H), 1.98 (dt, J 12.9, 6.3 Hz, 2H), 1.69 (s, 3H), 1.61 (s,
3H), 1.56-1.42 (m, 2H), 1.36 – 1.10 (m, 4H), 0.95 (d, J 6.5 Hz,
3H), 0.87 (d, J 6.5 Hz, 3H). 13C{1H} NMR (62.5 MHz, CDCl3) d
131.2, 124.7, 44.0, 37.5, 32.4, 29.8, 25.7, 25.4, 20.3, 19.5, 18.5,
4.1.5. (2R,3R,5S)-3,5,9-Trimethyldec-8-ene-1,2-diol (18): To a
solution of the epoxide 17 (3.90 g, 19.7 mmol) in hexane (100
mL) was added dropwise a freshly prepared solution of AlMe3
(5.66 mL, 59.0 mmol) in hexane (30.0 mL) at -40° C. The reac-
tion was stirred for 1 h at -40° C, then a saturated aqueous solu-
tion of NH4Cl (10.0 mL) was added. The cold bath was removed,
and a concentrated solution of sodium potassium tartrate was
added (50.0 mL). The obtained mixture was stirred for 4 h. The
layers were separated, and the organic extract was washed with a
saturated aqueous NaCl solution (100 mL). The organic layer was
thus extracted with EtOAc (3 x 50.0 mL). The organic extract was
dried with Na2SO4, filtered and concentrated under reduced pres-
sure. The resulting residue was purified by flash chromatography,
eluting with hexane:EtOAc (70:30). After purification, 3.65 g of
18 was obtained, 86% yield.
17.7. IR (Film) 2960, 2913, 2869, 2850, 1455, 1377, 817 cm-
1
.
HRMS (ESI+) m/z calculated for C12H24I [M+H]+ 295.0879,
found 295.0908.
4.1.8. (E)-Ethyl 3-ethyl-5-(trimethylsilyl)pent-2-en-4-ynoate
(19): A mixture of Pd(AcO)2 (337 mg, 1.50 mmol) and tris-(2,6-
dimethoxyphenyl)-phosphine (664 mg, 1.50 mmol) in THF (50.0
mL) was stirred for 30 min. Then, 8 (6.60 mL, 50.0 mmol) was
added and the mixture was stirred for another 10 minutes. After
this time, 9 (7.00 mL, 50.0 mmol) was added and the reaction was
stirred for 18 h. Thus, the solvent was removed and the residue
was purified by flash chromatography, eluting with pen-
tane:EtOAc 90:10 to provide 9.36 g of 19, 85% yield.
Rf= 0.46 (hexane:EtOAc 60:40). [a]!#" = +20 (c 0.86, CHCl3). 1H
1
Rf = 0.72 (hexane:EtOAc 95:5). H NMR (400 MHz, CDCl3)
NMR (600 MHz, CDCl3) d 5.12-5.10 (m, 1H), 3.73 (dd, J 10.9,
2.2 Hz, 1H), 3.57 (dd, J 10.8, 8.4 Hz, 1H), 3.54 – 3.48 (m, 1H),
2.90 (s, 1H), 2.82 (s, 1H), 2.04-1.96 (m, 2H), 1.73 – 1.66 (m, 4H),
1.62 (s, 3H), 1.55 – 1.47 (m, 1H), 1.34 – 1.13 (m, 4H), 0.95 – 0.84
(m, 6H). 13C{1H} NMR (62.5 MHz, CDCl3) d 131.1, 124.8, 76.8,
64.5, 39.6, 38.3, 33.6, 29.6, 25.7, 25.6, 18.9, 17.6, 15.1. IR (ATR)
d 6.06 (t, J 1.0 Hz, 1H), 4.16 (q, J 7.1 Hz, 2H), 2.74 (qd, J 7.6, 1.0
Hz, 2H), 1.28 (t, J 7.1 Hz, 3H), 1.15 (t, J 7.6 Hz, 3H), 0.2 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3) d 165.7, 143.9, 124.2, 105.2,
100.1, 60.0, 25.4, 14.2, 12.8, 0.3 (3C). IR (Film) 2996, 2932,
-
1
2878, 2147, 1718, 1612 cm . HRMS (ESI+) m/z calculated for
C12H21O2Si [M+H]+ 225.1311, found 225.1329.
-
1
3362 (broad), 2960, 2813, 2874, 1672, 1454, 1377, 1216 cm .
HRMS (ESI+) m/z calculated for C13H27O2 [M+H]+ 215.2011,
found 215.1998.
4.1.9. (E)-3-Ethyl-N-methoxy-N-methylpent-2-en-4-ynamide
(20)
4.1.9.a. To a solution of 19 (3.00 g, 13.4 mmol) in THF (111 mL)
and MeOH /H2O 1:1 (22.2 mL) was added LiOH (6.40 g, 267
mmol). The reaction was stirred at reflux for 18 h. Then the mix-
ture was poured into an Et2O/H2O 1:1 mixture (100 mL) and
acidified with 1N HCl (pH 1.0). The layers were separated and the
aqueous layer was extracted with Et2O (4 x 25.0 mL). The organic
layer was washed with a saturated aqueous NaCl solution (25.0
mL), dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography using
hexane:EtOAc 60:40 as eluent to afford 1.38 g of the respective
carboxylic acid intermediate, 83% yield.
4.1.6. (2R,4S)-2,4,8-Trimethylnon-7-en-1-ol (15) (method
scheme 3): To a solution of the diol 18 (3.50 g, 16.4 mmol) in
THF (131 mL) and water (32.8 mL) at room temperature was
added NaIO4 (21.0 g, 98.0 mmol) in a single portion. The reaction
was stirred for 5 h and quenched by the addition of a saturated
aqueous NaCl solution (150 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 x 60.0 mL). The
organic layer was dried with Na2SO4, filtered and concentrated
under reduced pressure. The resulting residue was used in the next
step without further purification.
The material from the previous step was solubilized in methanol
(164 mL) and cooled to 0° C. To this solution was added NaBH4
(0.93 g, 24.5 mmol) in small portions over 5 minutes. The reac-
tion was stirred for 15 min when a 0.5 M solution of citric acid
(100 mL) and CH2Cl2 (50.0 mL) was added. The layers were
separated and the aqueous layer extracted with CH2Cl2 (3 x 50.0
mL). The organic layer was dried with Na2SO4, filtered and con-
centrated under reduced pressure. The crude was purified by flash
chromatography using hexane:EtOAc (80:20) as eluent. After
1
Rf = 0.15 (hexane:EtOAc 80:20). MP 80-82 °C. H NMR (250
MHz, CDCl3) d 6.13 (s, 1H), 3.29 (s, 1H), 2.77 (q, J 7.0 Hz, 2H),
1.17 (t, J 7.0 Hz, 3H). 13C{1H} NMR (62.5 MHz, CDCl3) d
171.1, 145.9, 124.4, 83.7, 83.4, 25.8, 12.7. IR (ATR) 3295, 2969,
-
1
2936, 2878, 2095, 1686, 1606 cm . HRMS (ESI+) m/z calcula-
ted for C7H7O2 [M-H]- 123.0452, found 123.0456.
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The Journal of Organic Chemistry
4.1.12.a. To a solution of polyene 22 (92.0 mg, 0.33 mmol) in
4.1.9.b. To a solution of this carboxylic acid (1.96 g, 15.8 mmol)
1
2
3
4
5
6
7
8
tBuOH (1.70 mL) and H2O (1.70 mL) were added K3Fe(CN)6
(329 mg, 1.00 mmol), K2CO3 (138 mg, 1.00 mmol), MeSO4NH2
(31.7 mg, 0.33 mmol), (DHQ)2PHAL (13.0 mg, 0.02 mmol) and
K2OsO4×2H2O (1.20 mg, 3.30 µmol). The reaction was stirred for
20 h at 0 °C. After this time, Na2SO3 (460 mg) and H2O (10.0
mL) were added to the reaction mixture. The layers were separat-
ed and the aqueous layer extracted with EtOAc (5 x 10.0 mL).
The organic extracts combined were dried over MgSO4, filtered
and concentrated under reduced pressure. The resulting residue
was purified by flash chromatography using hexane:EtOAc 60:40
as eluent. After purification 41.0 mg of the diol intermediate was
obtained.
4.1.12.b. To a solution of this diol (41.0 mg, 0.13 mmol) in H2O
(260 µL) and THF (1.06 mL) was added NaIO4 (151 mg, 0.79
mmol) and the reaction was stirred for 2 h. After this time, the
reaction was quenched by the addition of a saturated aqueous
NaCl solution (0.50 mL). The layers were separated and the aque-
ous layer was extracted with CH2Cl2 (3 x 0.50 mL). The organic
extracts combined were dried over MgSO4, filtered and concen-
trated under reduced pressure. The resulting residue was purified
by flash chromatography using hexane:EtOAc 90:10 as eluent.
After purification, 30.0 mg of the fragment C1-C12 was obtained,
36% yield (2 steps).
and MeON(Me)H×HCl (3.08 g, 31.6 mmol) in CH2Cl2 (78.9 mL),
were added DMAP (386 mg, 16.0 mmol) and DCC (6.52 g, 31.6
mmol). Then, Et3N (4.40 mL, 31.6 mmol) was added dropwise.
The reaction was stirred for 18 h at room temperature. The mix-
ture was washed with H2O (30.0 mL) and 1M HCl solution (2 x
15.0 mL). The organic layer was dried over MgSO4, filtered and
carefully concentrated (the product is volatile). The residue was
purified by flash chromatography, eluting with hexane:EtOAc
80:20, to provide 1.60 g of the amide 20, 60% yield. Note: A high
vacuum pump was not used to remove residual solvents; they
were removed by co-evaporation with CHCl3.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rf = 0.28 (hexane:EtOAc 80:20). 1H NMR (250 MHz, CDCl3) d
6.57 (s, 1H), 3.68 (s, 3H), 3.21 (s, 3H), 3.11 (s, 1H), 2.70 (q, J 7.5
Hz, 2H), 1.16 (t, J 7.5 Hz, 3H). 13C{1H} NMR (62.5 MHz,
CDCl3) d 166.2, 139.8, 123.9, 84.5, 80.3, 61.6, 32.1, 25.5, 12.8.
IR (ATR) 3287, 3238, 2971, 2938, 2878, 2838, 2091, 1643, 1607
-
1
cm . HRMS (ESI+) m/z calculated for C9H14NO2 [M+H]+
168.1024, found 168.1054.
4.1.10. (E)-3-Ethyl-N-methoxy-N-methylpent-2,4-dienamide
(10): To a solution of acetylene 20 (806 mg, 4.82 mmol) in ben-
zene (24.1 mL), were added quinoline (0.14 mL, 0.96 mmol) and
Lindlar's catalyst (718 mg, 0.24 mmol). The reaction was stirred
under H2 atmosphere for 30 min. The reaction mixture was fil-
tered under Celite® and eluted with CH2Cl2. The solvent was
carefully evaporated (the product is volatile). The residue was
purified by flash chromatography using CH2Cl2:hexane 60:40 as
eluent to provide 600 mg of the diene 10, 72% yield. Note: A high
vacuum pump was not used to remove residual solvents; they
were removed by co-evaporation with CHCl3.
1H NMR (500 MHz, CDCl3) d 9.77 (t, J 1.8 Hz, 1H), 6.27 (dd, J
17.4, 10.8 Hz, 1H), 6.07 (s, 1H), 5.69 (d, J 17.4 Hz, 1H), 5.45 (d,
J 10.7 Hz, 1H), 2.73 (q, J 7.6, 2H), 2.42 (m, 3H), 2.30 (m, 1H),
2.13 (m, 1H), 1.63 (m, 1H), 1.48 (m, 2H), 1.13 (m, 2H), 1.09 (t, J
7.6 Hz, 3H), 0.89 (d, J 3.5 Hz, 3H), 0.87 (d, J 3.7 Hz, 3H).
13C{1H} NMR (125 MHz, CDCl3) d 202.8, 201.0, 156.4, 139.2,
126.2, 120.2, 52.9, 44.2, 41.7, 29.8, 29.6, 27.1, 20.5, 19.6, 19.0,
14.0.
1
Rf = 0.28 (hexane:EtOAc 80:20). H NMR (250 MHz, CDCl3)
d 6.29 (dd, J 17.5, 10.7 Hz, 1H), 6.15 (s, 1H), 5.4 (d, J 17.4 Hz,
1H), 5.27 (d, J 10.7 Hz, 1H), 3.62 (s, 3H), 3.17 (s, 3H), 2.71 (q, J
7.5 Hz, 2H), 1.7 (t, J 7.5 Hz, 3H). 13C{1H} NMR (62.5 MHz,
CDCl3) d 167.5, 155.5, 139.2, 117.8, 117.5, 61.4, 32.2, 20.4,
14.0. IR (film) 3093, 2970, 2937, 2877, 2819, 2091, 1651, 1619,
4.1.13. (E)-Pent-3-enoyl chloride (30):13b Freshly distilled oxalyl
chloride (15.6 mL, 182 mmol) was slowly added to a solution of
(E)-pent-3-enoic acid (9.24 mL, 91.0 mmol) at 45 °C. The reac-
tion was stirred for 3 h, warmed up to 70 °C and stirred for 30
minutes. Excess of oxalyl chloride was removed under reduced
pressure and the crude material was purified by distillation to
provide 4.60 g of 30, 42% yield.
-
1
1599 cm . HRMS (ESI+) m/z calculated for C9H16NO2 [M+H]+
170.1181, found 170.1162.
4.1.11.
(7R,9S,E)-3-Ethyl-7,9,13-trimethyltetradeca-1,3,12-
1H NMR (250 MHz, CDCl3) d 5.70 (m, 1H), 5.52 (m, 1H), 3.54
(dt, J 6.6, 1.1 Hz, 2H), 1.73 (dd, J 6.0, 1.2 Hz, 3H).
trien-5-one (22):25 To a solution of the iodide 7 (1.09 g, 3.72
mmol) in Et2O (12.0 mL) at -78 °C was added dropwise a 1.7 M
solution of tBuLi (4.37 mL, 7.44 mmol). The reaction was stirred
at this temperature for 30 min. The temperature was thus allowed
to reach room temperature for 2 h. After this time, the mixture
was cooled again to -78 °C and a solution of the amide 10 (538
mg, 3.18 mmol) in Et2O (3.90 mL) was added dropwise. The
reaction was stirred for 1 h at this temperature. The cold bath was
removed, and the temperature was allowed to reach room temper-
ature. Then, NH4Cl (15.0 mL) was added, the layers were separat-
ed, and the aqueous layer was extracted with Et2O (3 x 10.0 mL).
The organic extracts were combined, washed with saturated aque-
ous NaHCO3 (10.0 mL), dried over MgSO4, filtered and concen-
trated under reduced pressure. The residue obtained was purified
by flash chromatography, eluting with 95:5 hexane:EtOAc to
afford 510 mg of triene 22, 58% yield.
4.1.14. Dimethyl 2-methyl-3-(E)-pent-3-enoylmaleate (31):
MeLi 1.6 M (20.1 mL, 32.2 mmol) was added dropwise to a
mixture of CuCN (2.80 g, 32.2 mmol) in THF (117 mL) at -40
°C, after 30 minutes the mixture was cooled down to -78 °C and
commercially available diester 29 (3.59 mL, 29.2 mmol) was
added for 5 minutes. After 2.5 h, 30 (6.75 g, 43.9 mmol) was
added at once and the reaction was stirred for 2 h. The reaction
was warmed up to 0 °C and quenched by the addition of H2O
(14.0 mL). The mixture was filtered under Celite® and eluted
with Et2O. The mixture was washed with saturated aqueous solu-
tion of NaCl (70.0 mL). The layers were separated, and the aque-
ous layer was extracted with Et2O (2 x 50.0 mL). The combined
organic layers were dried over MgSO4, filtrated and concentrated
under reduced pressure. The crude material was purified by flash
chromatography, eluted with hexane:AcOEt 85:15 to provide 4.10
g of 31, 58% yield.
1H NMR (500 MHz, CDCl3) d 6.29 (dd, J 17.5, 10.8 Hz, 1H),
6.09 (s, 1H), 5.70 (d, J 17.4 Hz, 1H), 5.46 (d, J 10.7 Hz, 1H), 5.11
(t, J 7.1 Hz, 1H), 2.81 – 2.72 (m, 2H), 2.43 (dd, J 15.1, 5.8 Hz,
1H), 2.30 (dd, J 15.2, 7.9 Hz, 1H), 2.16-2.11 (m, 1H), 2.01-1.95
(m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 1.56 – 1.47 (m, 1H), 1.33 –
1.26 (m, 1H), 1.20 – 1.14 (m, 2H), 1.14 – 1.07 (m, 4H), 0.89 (d, J
4.0 Hz, 3H), 0.90 (d, J 4.0 Hz, 3H). 13C{1H} NMR (125 MHz,
CDCl3) d 201.3, 156.2, 139.2, 131.1, 126.3, 124.9, 120.0, 53.0,
44.5, 37.8, 29.7, 29.2, 27.3, 25.7, 25.5, 20.5, 19.3, 17.7, 13.9.
Rf = 0.36 (hexane:AcOEt 80:20). 1H NMR (250 MHz, CDCl3) d
5.63 – 5.41 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.39 – 3.28 (m,
2H), 2.01 (s, 3H), 1.70 (d, J 4.9 Hz, 3H). 13C{1H} NMR (62.5
MHz, CDCl3) d 199.2, 168.3, 164.1, 142.3, 134.8, 130.6, 121.3,
-
1
52.4, 52.4, 46.3, 17.8, 17.0. IR (film) 2955, 1704, 1729 cm .
HRMS (ESI+) m/z calculated for C12H16O5Na [M+Na]+
263.0895, found 263.0884.
4.1.15.
Dimethyl
2-((R,E)-1-hydroxypent-3-enyl)-3-
4.1.12.
(4S,6R,E)-10-Ethyl-4,6-dimethyl-8-oxododeca-9,11-
dienal (Fragment C1-C12)26
methylmaleate (32): (+)-DIPCl (11.0 mL, 19.8 mmol) was added
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Page 10 of 15
to a solution of 31 (3.17 g, 13.2 mmol) in freshly distilled THF
(66.0 mL) at -78 °C. The reaction was warmed up to -20 °C and
stirred for 3 days at that temperature. Then, the reaction was
warmed up to 0 °C. The reaction was quenched by the addition of
a solution of H2O2 30% (1.70 mL), and MeOH (30.0 mL), and the
mixture obtained was stirred for 2 h. Thus, the organic solvent
was removed under reduced pressure and the aqueous layer was
extracted with Et2O (3 x 10.0 mL). The combined organic layers
were dried over MgSO4, filtrated and concentrated under reduced
pressure. The crude material was purified by flash chromatog-
raphy, eluted with hexane:AcOEt 3:1 to provide 2.20 g of 32,
70% yield.
mmol) was added. The reaction was stirred for 1 h at 0 °C. After
1
2
3
4
5
6
7
8
this time, the reaction was washed with H2O (3 x 2.00 mL), and
the organic layer was dried over MgSO4, filtrated and concentrat-
ed under reduced pressure. The crude material was purified by
flash chromatography, eluted with hexane:AcOEt 80:20 to pro-
vide 642 mg of 34, 67% yield (2 steps).
Rf = 0.43 (hexane:AcOEt 80:20). [a]!#" = -6.0 (c 1.14, CHCl3).
1H NMR (250 MHz, CDCl3) d 5.62 – 5.22 (m, 4H), 4.62 – 4.47
(m, 1H), 3.83 – 3.63 (m, 5H), 2.60 – 2.45 (m, 1H), 2.43 – 2.25 (m,
1H), 1.93 (s, 3H), 1.64 (d, J 5.8 Hz, 3H), 1.01 – 0.91 (m, 2H),
0.86 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 9H). 13C{1H}
NMR (125 MHz, CDCl3) d 168.1, 167.3, 144.4, 128.6, 126.9,
90.1, 71.5, 68.1, 52.2, 40.1, 32.0, 29.7, 25.7 (3C), 18.1, 18.0, 14.7,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rf = 0.33 (hexane:AcOEt 3:2). [a]!#" = -17.0 (c 1.1, CHCl3). H
1
-
1
NMR (250 MHz, CDCl3) d 5.63-5.58 (m, 1H), 5.47 – 5.30 (m,
1H), 4.53 (s, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 2.71 (s, 1H), 2.55 –
2.37 (m, 1H), 2.37 – 2.22 (m, 1H), 1.91 (s, 3H), 1.64 (d, J 6.1 Hz,
3H). 13C{1H} NMR (62.5 MHz, CDCl3) d 168.3, 168.0, 141.9,
130.5, 129.5, 125.8, 69.5, 52.3, 52.1, 39.1, 17.9, 14.6. IR (Film)
-1.4 (3C), -4.9, -5.1. IR (film) 2954, 2927, 1730 cm . HRMS
(ESI+) m/z calculated for C23H44NaO6Si2 [M+Na]+ 495.2574,
found 495.2581.
4.1.18.
(R,Z)-3-((tert-Butyldimethylsilyloxy)-4-
(methoxycarbonyl)-5-methyl-6-oxo-6-((2-(trimethylsilyl)
ethoxy) methoxy)hex-4-enoic acid and (R,Z)-3-((tert-
butyldimethylsilyloxy)-4-(methoxycarbonyl)-5-methyl-6-oxo-
6-((2-(trimethylsilyl)ethoxy)methoxy)hex-4-enoic acid (11)
4.1.18.a. NMO (219 mg, 1.87 mmol) and OsO4 4% (0.24 mL,
0.04 mmol) were added to a solution of 34 in acetone (11.3 mL)
and H2O (1.13 mL). The reaction was stirred for 2 h and then
quenched by the addition of a saturated aqueous solution of
Na2S2O4 (30.0 mL). The mixture was extracted with AcOEt (3 x
50.0 mL). The combined organic layers were dried over MgSO4,
filtrated and concentrated under reduced pressure. The residue
was used in the next step without further purification.
4.1.18.b. PIDA (441 mg, 1.37 mmol) was added to a solution of
the previously synthesized residue in CH2Cl2 (12.4 mL). The
reaction was stirred for 2 h, and then filtered through a plug of
silica gel and eluted with CH2Cl2. The solvent was removed under
reduced pressure and engaged in the next step without further
purification.
-
1
3477 (br), 3026, 3001, 2953, 2919, 2857 cm . HRMS (ESI+)
m/z calculated for C12H18O5Na [M+Na]+ 265.1052, found
265.1021. e.r. 86:14; S-32 Retention Time 11 minutes and R-32
Retention Time: 9 minutes (Chiralpak IC®, hexane:iPrOH 8:2,
1.0 mL/min, 254 nm).
4.1.16. Dimethyl 2-((R,E)-1-((tert-butyldimethylsilyl)oxy) pent-
3-en-1-il)-3-methylmaleate (33): 2,6-lutidine (1.45 mL, 12.4
mmol) and TBSOTf (1.78 mL, 8.30 mmol) were added slowly to
a solution of 32 (1.00 g, 4.15 mmol) in CH2Cl2 (41.5 mL) at 0 °C.
The reaction was stirred for 1 h, after which the reaction was
quenched by the addition of a saturated aqueous solution of Na-
HCO3 (15.0 mL). The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (2 x 30.0 mL). The combined
organic layers were dried over MgSO4, filtrated and concentrated
under reduced pressure. The crude material was purified by flash
chromatography, eluted with hexane:AcOEt 90:10 to provide 1.39
g of 33, 94% yield.
Rf = 0.29 (hexane:AcOEt 90:10). [a]!#" = -7.0 (c 1.1, CHCl3). 1H
4.1.18.c. NaH2PO4 (383 mg, 3.19 mmol), 2-methyl-2-butene (0.51
mL, 4.79 mmol) and NaClO2 (125 mg, 1.38 mmol) were added to
a solution of the previously synthesized residue in tBuOH (12.1
mL) and H2O (12.1 mL). The reaction was stirred for 18 h and
then quenched by the addition of a saturated aqueous solution of
NaCl (15.0 mL). The mixture was extracted with AcOEt (4 x 15.0
mL). The combined organic layers were dried over MgSO4, fil-
trated and concentrated under reduced pressure. The crude materi-
al was purified by flash chromatography, eluted with hex-
ane:AcOEt:formic acid 75:24:1 to provide 474 mg of 11, 80%
yield.
NMR (250 MHz, CDCl3) d 5.55-5.44 (m, 1H), 5.43 – 5.28 (m,
1H), 4.51 (dd, J 8.1, 5.7 Hz, 1H), 3.71 (d, J 3.8 Hz, 6H), 2.58 –
2.42 (m, 1H), 2.41 – 2.24 (m, 1H), 1.90 (s, 3H), 1.62 (d, J 6.2 Hz,
3H), 0.84 (s, 9H), 0.01 (d, J 6.5 Hz, 6H). 13C{1H} NMR (62.5
MHz, CDCl3) d 168.2, 167.9, 145.1, 128.5, 127.3, 126.8, 71.4,
52.2, 51.7, 40.0, 25.6 (3C), 18.1, 17.9, 14.4, -5.0, -5.2. IR (film)
-
1
3025, 2952, 2930, 2857, 1731 cm . HRMS (ESI+) m/z calculated
for C18H33O5Si [M+H]+ 357.2097, found 357.2094.
4.1.17. Methyl 1-((2-(trimethylsilyl)ethoxy)methyl) 2-((R,E)-1-
((tert-butyldimethylsilyl)oxy)pent-3-en-1-il)-3-metylmaleate
and Methyl 4-((2-trimethylsilyl)ethoxy)methyl) 2-((R,E)-1-
((tert-butyldimethylsilyl)oxy)pent-3-en-1-yl)-3-methylmaleate
(34)
Rf = 0.37 (hexane:AcOEt:formic acid 75:24:1). [a]!#" = +2.0 (c
1
1.4, CHCl3). H NMR (500 MHz, CDCl3) d 5.47-5.35 (m, 2H),
5.16 (dd, J 9.1, 3.9 Hz, 1H), 3.77 (s, 3H), 3.75 (m, 2H), 3.08-3.02
(m, 1H), 2.73-2.67 (m, 1H), 2.07 (d, J 2.9 Hz, 3H), 1.05 – 0.98
(m, 2H), 0.88 (m, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.05 (s, 9H).
13C{1H} NMR (125 MHz, CDCl3) d 175.8, 168.1, 167.6, 167.0,
167.0, 142.8, 141.6, 130.8, 130.8, 90.3, 68.3, 67.4, 52.4, 52.1,
41.7, 29.7, 25.6 (3C), 18.1, 18.0, 14.9, 14.6, -1.44 (3C), -4.87,
4.1.17.a. LiOH (757 mg, 31.6 mmol) was added to a solution of
33 (751 mg, 2.11 mmol) in THF (15.8 mL) and H2O (5.30 mL) at
0 °C. The reaction was warmed up to room temperature and
stirred for 18 h, at which time HCl 1M (29.0 mL) was added (pH
= 3.0). Then, the reaction was heated up to 60 °C until the appear-
ance of a spot on the TLC (Rf = 0.3, hexane:AcOEt 80:20) with
concomitant disappearance of the spot observed on the baseline of
the TLC (i.e. dicarboxylic acid intermediate). The THF was re-
moved under reduced pressure and aqueous layer was extracted
with AcOEt (5 x 20.0 mL). The combined organic layers were
dried over MgSO4, filtrated and concentrated under reduced pres-
sure. The crude compound was then engaged in the next step
without further purification.
-
1
-5.44. IR (film) 3446, 2954, 2929, 2907, 2857, 1738, 1715 cm .
HRMS (ESI+) m/z calculated for C21H40O8NaSi2 [M+Na]+
499.2159, found 499.2149.
4.1.19.
(2S)-Methyl
3-(4-methoxybenzyloxy)-2-
methylpropionate (36):42 To a solution of the (S)-Roche ester
(2.60 g, 22.1 mmol) in CH2Cl2 (50.0 mL) was added p-
methoxybenzyl trichloroacetimidate (9.36 g, 33.2 mmol) and
camphorsulfonic acid (0.50 g, 1.14 mmol). The reaction mixture
was stirred at room temperature for 18 h. Thus, the mixture was
diluted with Et2O (200 mL) and washed with a saturated aqueous
NaHCO3 solution (2 x 45.0 mL) and NaCl (45.0 mL), followed by
H2O (2 x 45.0 mL). The organic extract was dried over MgSO4,
4.1.17.b. Dried MeOH (0.20 mL, 5.05 mmol) was added into a
solution containing the residue of the previous step in CH2Cl2
(4.20 mL) dropwise at 0 °C. The, DIPA (0.83 mL, 5.79 mmol)
was added dropwise. After 50 minutes, SEMCl (0.56 mL, 3.16
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The Journal of Organic Chemistry
75.1, 72.9, 72.4, 55.1, 39.9, 20.9, 13.5. IR (film) 3432 (br), 2966,
filtered and concentrated under reduced pressure. The crude was
-
1
1
2
3
purified by flash chromatography, eluting with pentane:EtOAc
2932, 2902, 2876, 2837 cm . HRMS (ESI+) m/z calculated for
C13H20O3Na [M+Na]+ 247.1310; found 247.1303.
90:10 to provide 5.90 g of protected ester 36, 98% yield.
[a]!#" = +11.0 (c 1.1, CHCl3). H NMR (250 MHz, CDCl3) d
1
4.1.22. (4R,5S)-2-(4-Methoxyphenyl)-4,5-dimethyl-1,3-dioxane
(39): DDQ (82.0 mg, 0.36 mmol) was added to a solution of
alcohol 12 (54.0 mg, 0.24 mmol) in CH2Cl2 (2.00 mL) and phos-
phate buffer pH 7.0 (0.40 mL). The reaction was stirred for 1 h in
an open flask, after which the reaction was quenched by the addi-
tion of a saturated aqueous solution of NaHCO3 (2.00 mL). The
mixture was filtered through a plug of Celite®, a plug of silica gel
and eluted with CH2Cl2. The layers were separated, and the organ-
ic one was dried over MgSO4, filtered and concentrated under
reduced pressure. The crude material was purified by flash chro-
matography, eluted with hexane:AcOEt 90:10 to provide 24.0 mg
of 39, 45% yield.
7.23 (d, J 8.5 Hz, 2H), 6.87 (d, J 8.6 Hz, 2H), 4.45 (s, 2H), 3.80
(s, 3H), 3.70 (s, 3H), 3.69 – 3.57 (m, 1H), 3.46 (dd, J 9.1, 5.9 Hz,
1H), 2.85 – 2.69 (m, 1H), 1.17 (d, J 7.1 Hz, 3H). 13C{1H} NMR
(62.5 MHz, CDCl3) d 175.3, 159.2, 130.2, 129.2 (2C), 113.7
(2C), 72.7, 71.6, 55.2, 51.7, 40.2, 14.0. IR (film) 3054, 2953,
4
5
6
7
8
9
-
1
2862, 1736 cm .
4.1.20.
(2R)-3-(4-Methoxybenzyloxy)-2-methylpropan-1-ol
(37):42 A solution of 1M DIBAL-H (61.0 mL, 61.0 mmol) was
added into a solution of ester 36 (5.80 g, 24.4 mmol) in CH2Cl2
(190 mL) at -78 °C. The reaction was stirred for 1 h at this tem-
perature. Then, MeOH (40.0 mL) was added followed by the
addition of H2O (24.0 mL) and an aqueous saturated solution of
sodium and potassium tartrate (160 mL). The mixture was stirred
until complete homogenization of the organic phase. Thus, the
layers were separated, and the aqueous one was extracted with
CH2Cl2 (2 x 50.0 mL). The combined organic extracts were dried
over MgSO4, filtered and concentrated under educed pressure.
The crude material was purified by flash chromatography, eluted
with pentane:AcOEt 80:20 to provide 4.92 g of 37, 96% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rf = 0.39 (hexane:AcOEt 80:20). [a]!#"
= 10.0 (c 1.0, CHCl3).
-
1H NMR (400 MHz, CDCl3) d 7.46 (d, J 8.6 Hz, 2H), 6.92 (d, J
8.8 Hz, 2H), 5.49 (s, 1H), 4.12 (dd, J 11.3, 4.7 Hz, 1H), 3.83 (s,
3H), 3.57 (dd, J 9.7, 6.2 Hz, 1H), 3.51 (t, J 11.3 Hz, 1H), 1.89 –
1.76 (m, 1H), 1.35 (d, J 6.2 Hz, 3H), 0.83 (d, J 6.7 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) d 159.9, 131.3, 127.4 (2C),
113.6 (2C), 101.2, 79.5, 73.0, 55.3, 35.9, 19.1, 12.5. IR (Film)
-
1
2962, 2917, 2849, 1614, 1518, 1250 cm . HRMS (ESI+) m/z
calculated for C13H19O3 [M+H]+ 223.1334, found 223.1364.
4.1.23. 1-((2R,3S)-4-((4-methoxybenzyl)oxy)-3-methylbutan-2-
yl) 4-methyl 3-((2-(trimethylsilyl)ethoxy)methyl) (R,Z)-2-((tert-
butyldimethylsilyl)oxy)pent-3-ene-1,3,4-tricarboxylate and 1-
[a]!#" = +14.8 (c 1.15, CHCl3). H NMR (250 MHz, CDCl3) d
1
7.24 (d, J 8.7 Hz, 2H), 6.87 (d, J 8.7 Hz, 2H), 4.43 (s, 2H), 3.78
(s, 3H), 3.57 (d, J 6.3 Hz, 2H), 3.49-3.35 (m, 2H), 2.72 (sl, 1H),
2.13 – 1.91 (m, 1H), 0.87 (d, J 7.0 Hz, 3H). 13C{1H} NMR (62.5
MHz, CDCl3) d 159.2, 130.2, 129.2 (2C), 113.8 (2C), 74.8, 73.0,
67.4, 55.2, 35.6, 13.5. IR (film). 3455 (br), 3016, 2960, 2864
((2R,3S)-4-((4-methoxybenzyl)oxy)-3-methylbutan-2-yl)
methyl 4-((2-(trimethylsilyl)ethoxy)methyl) (R,Z)-2-((tert-
butyldimethylsilyl)oxy)pent-3-ene-1,3,4-tricarboxylate (41):
3-
-
1
cm .
Acid 11 (141 mg, 0.63 mmol) in toluene (9.00 mL), 2,4,6-
trichlorobenzoyl chloride (0.11 mL, 0.69 mmol) and DMAP (230
mg, 1.88 mmol) were added to a solution of secondary alcohol 12
(329 mg, 0.69 mmol) in toluene (22.4 mL). Then, Et3N (0.26 mL,
1.88 mmol) was added dropwise. The reaction was stirred for 4 h
at room temperature. Thus, the reaction was quenched by the
addition of a saturated aqueous solution of NaHCO3 (28.0 mL)
and extraction was performed with CH2Cl2 (3 x 20.0 mL). The
combined organic layers were dried over MgSO4, filtrated and
concentrated under reduced pressure. The crude material was
purified by flash chromatography, eluted with hexane:AcOEt
80:20 to provide 390 mg of ester 41, 91% yield.
4.1.21. (2R,3S)-4-(4-Methoxybenzyloxy)-3-methylbutan-2-ol
(12)14
4.1.21.a. A solution of oxalyl chloride (3.92 mL, 46.3 mmol) in
CH2Cl2 (100 mL) was slowly added to a solution of DMSO (4.80
mL, 68.8 mmol) in CH2Cl2 (10.0 mL) at -78 °C. The mixture was
stirred for 10 minutes. Thus, a solution of alcohol 37 (4.80 g, 22.8
mmol) in CH2Cl2 (48.0 mL) was slowly added to above men-
tioned mixture. After 1 h at -78 °C, Et3N (15.8 mL, 114 mmol)
was added dropwise. The reaction was quenched by addition of a
saturated aqueous solution of NH4Cl (70.0 mL). Then, the mixture
was allowed to warm up to room temperature. The layers were
separated, and the aqueous one was extracted with Et2O (3 x 50.0
mL). The combined organic extracts were washed with brine
(50.0 mL), dried over MgSO4, filtered and concentrated under
reduced pressure to provide the aldehyde intermediate 38 which
was used for the next step without further purification.
Rf = 0.36 (hexane:AcOEt: 4:1). [a]!#" = -2.0 (c 1.4, CHCl3). H
1
NMR (500 MHz, CDCl3) d 7.26 (d, J 8.0 Hz, 2H), 6.89 (d, J 8.5
Hz, 2H), 5.49 – 5.30 (m, 2H), 5.17 (ddd, J 9.8, 6.4, 3.8 Hz, 1H),
5.00 (quint, J 6.2 Hz, 1H), 4.42 (d, J 1.5 Hz, 2H), 3.82 (s, 3H),
3.80 – 3.72 (m, 5H), 3.41 (ddd, J 8.7, 5.9, 2.4 Hz, 1H), 3.35 –
3.23 (m, 1H), 2.94 (ddd, J 16.0, 8.8, 7.3 Hz, 1H), 2.57 (td, J 16.3,
3.7 Hz, 1H), 2.05 (s, 4H), 1.22 – 1.15 (m, 3H), 1.02-0.94 (m, 5H),
0.87 (d, J 3.8 Hz, 9H), 0.11 (s, 3H), 0.08 (s, 3H), 0.05 (s, 9H).
13C{1H} NMR (125 MHz, CDCl3) d 170.4, 170.3, 168.0, 167.7,
167.0, 166.9, 159.1, 143.6, 142.5, 130.6, 129.2 (2C), 113.7 (2C),
90.1, 72.7, 72.5, 71.7, 68.2, 67.5, 67.4, 55.3, 52.3, 51.9, 42.1,
42.0, 37.9, 25.6 (3C), 18.0, 16.4, 14.8, 14.6, 12.8, -1.40 (3C),
4.1.21.b. MeLi 1.6 M (54.1 mL, 86.6 mmol) was added to a solu-
tion of CuI (8.24 g, 43.4 mmol) in Et2O (24.0 mL) at -20 °C for
15 minutes. Thus, the solution was cooled to -78 °C, and a solu-
tion of the above-mentioned aldehyde 38 in Et2O (32.0 mL) was
added dropwise. The reaction was stirred for 12 h, and quenched
by the addition of a saturated aqueous solution of NH4Cl (30.0
mL) and warmed up to room temperature. The layers were sepa-
rated, and the aqueous one was extracted with Et2O (2 x 30.0 mL).
The combined organic extracts were washed with brine (20.0
mL), dried over MgSO4, filtered and concentrated under reduced
pressure. The crude material was purified by flash chromatog-
raphy, eluted with pentane:AcOEt 3:1 to provide 3.80 g of alcohol
12 (d.r. 12:1), 75% yield (2 steps).
-
1
-4.9, -5.3. IR (film) 2953, 2942, 2898, 2857, 1738, 1732 cm .
+
HRMS (ESI+) m/z calculated for C34H58O10NaSi2 [M+Na]
705.3466, found 705.3466.
4.1.24. 1-((2R,3S)-4-hydroxy-3-methylbutan-2-yl) 4-methyl 3-
((2-(trimethylsilyl)ethoxy)methyl)
(R,Z)-2-((tert-
Rf = 0.13 (hexane:AcOEt 80:20). [a]!#" = +18.0 (c 0.9, CHCl3).
butyldimethylsilyl)oxy)pent-3-ene-1,3,4-tricarboxylate and 1-
((2R,3S)-4-hydroxy-3-methylbutan-2-yl)
(trimethylsilyl)ethoxy)methyl)
butyldimethylsilyl)oxy)pent-3-ene-1,3,4-tricarboxylate
3-methyl
(R,Z)-2-((tert-
(42):
4-((2-
1H NMR (400 MHz, CDCl3) d 7.25 (d, J 8.6 Hz, 2H), 6.89 (d, J
8.7 Hz, 2H), 4.47 (s, 2H), 3.81 (s, 3H), 3.67 (m, 1H), 3.57 (dd, J
9.2, 4.2 Hz, 1H), 3.42 (dd, J 9.3, 8.3 Hz, 1H), 2.93 (sl, 1H), 1.78
(m, 1H), 1.17 (d, J 6.1 Hz, 3H), 0.85 (d, J 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) d 159.1, 129.7, 129.2 (2C), 113.7 (2C),
DDQ (84.0 mg, 0.37 mmol) was added to a solution of 41 (126
mg, 0.18 mmol) in CH2Cl2 (1.60 mL) and phosphate buffer pH
7.0 (0.18 mL) at 0 °C. The reaction was stirred for 4 h, and then
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The Journal of Organic Chemistry
Page 12 of 15
quenched by the addition of a saturated aqueous solution of Na- saturated aqueous solution of NaHCO3 (10.0 mL) was performed.
1
2
3
4
5
6
7
8
HCO3 (2.00 mL). The mixture was filtered through a plug of
Celite® and eluted with CH2Cl2. The crude material obtained was
purified by flash chromatography, eluted with hexane:AcOEt 3:1
to provide 88.0 mg of alcohol 42, 85% yield.
The mixture was extracted with CH2Cl2 (2 x 20.0 mL). The com-
bined organic layers were filtered through silica gel and eluted
with hexane:AcOEt 80:20. The crude aldehyde 45 obtained was
used in the next step without further purification.
4.1.28. (But-1-en-2-yloxy)trimethylsilane (13):43 nBuLi (72.1
mL, 180 mL mmol) was slowly added to a solution of DIPA (29.6
mL, 208 mmol) in THF (154 mL) at 0 °C. After which the mix-
ture was cooled down to - 78 °C and TMSCl (35.5 mL, 277
mmol) was added. Thus, butanone (12.4 mL, 139 mmol) was
added to the reaction and the mixture was stirred for 15 minutes.
After, Et3N (38.7 mL, 277 mmol) was added and the reaction was
stirred for additional 30 minutes. The reaction was warmed up to
room temperature and quenched by the addition of a saturated
aqueous solution of NaHCO3 (20.0 mL). The layers were separat-
ed, and the aqueous one was extracted with pentane (3 x 60.0
mL). The combined organic layers were washed with a saturated
aqueous solution of CuSO4 (2 x 30.0 mL) and concentrated
through vigreux column distillation (20.0 cm). The crude material
was purified by distillation under reduced pressure to provide 8.30
g of 13, 41% yield.
Rf = 0.3 (hexane:AcOEt: 70:30). [a]!#" = +2.0 (c 0.7, CHCl3). 1H
NMR (500 MHz, CDCl3) d 5.44-5.19 (m, 2H), 5.18 (dd, J 8.3,
5.0 Hz, 1H), 4.97-4.91 (m, 1H), 3.81 – 3.71 (m, 2H), 3.77 (s, 3H),
3.54 (qd, J 11.2, 4.6 Hz, 2H), 2.95 (dd, J = 15.6, 8.4 Hz, 1H), 2.73
(dd, J 15.7, 4.9 Hz, 1H), 2.06 (s, 3H), 1.82-1.77 (m, 1H), 1.25 (d,
J 6.4 Hz, 3H), 1.02 – 0.97 (m, 5H), 0.87 (s, 9H), 0.11 (s, 3H), 0.08
(s, 3H), 0.05 (s, 9H). 13C{1H} NMR major regioisomer (125
MHz, CDCl3) d 170.9, 168.3, 166.9, 141.7, 130.8, 90.2, 72.6,
68.2, 67.3, 64.2, 52.0, 42.0, 40.6, 25.6 (3C), 18.0, 17.9, 17.6, 15.0,
13.2, -1.4 (3C), -5.0, -5.3. IR (film) 3486 (br), 3018, 2954,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
1
2925, 2852, 1731, 1644 cm . HRMS (ESI+) m/z calculated for
C26H50O9NaSi2 [M+Na]+ 585.2891, found 585.2892.
4.1.25. (2R,3S)-4-((4-Methoxylbenzyl)oxy)-3-methylbutan-2-yl
benzoate (43): Bz2O (1.09 g, 4.81 mmol), DIPEA (1.12 mL, 6.42
mmol) and DMAP (39.2 mg, 0.32 mmol) were added to a solution
of 12 (360 mg, 1.61 mmol) in CH2Cl2 (10.4 mL). The reaction
was stirred for 18 h, after which ethylenediamine (1.80 mL) and
H2O (5.00 mL) were added. The layers were separated, and the
aqueous one was extracted with CH2Cl2 (2 x 15.0 mL) and Et2O
(15.0 mL). The combined organic layers were dried over MgSO4,
filtrated and concentrated under reduced pressure. The crude
material was purified by flash chromatography, eluted with hex-
ane:AcOEt 80:20 to provide 485 mg of 43, 92% yield.
1H NMR (250 MHz, CDCl3) d 4.04 (d, J 3.9 Hz, 2H), 2.01 (q, J
8.0 Hz, 2H), 1.03 (t, J 8.0 Hz, 3H), 0.2 (s, 9H).
4.1.29. (2R,3S,4R)-4-Hydroxy-3-methyl-6-oxooctan-2-yl ben-
zoate (47): BF3×OEt2 (72.0 µL, 0.57 mmol) was slowly added to a
solution of the crude aldehyde 45 and enol silyl ether derivative
13 (0.14 mL, 0.78 mmol) in CH2Cl2 (6.50 mL) at -78 °C. The
reaction was stirred for 1 h and then quenched by addition of a
saturated aqueous solution of NaHCO3 (8.00 mL). The layers
were separated, and the aqueous layer was extracted with CH2Cl2
(3 x 8.00 mL). The combined organic layers were dried over
MgSO4, filtrated and concentrated under reduced pressure. The
crude material was purified by flash chromatography, eluted with
hexane:AcOEt 70:30 to provide 60.0 mg of 47 (d.r. 4:1), 42%
yield.
Rf = 0.53 (hexane:AcOEt 80:20). [a]D= -32.0 (c 1.4, CHCl3). 1H
NMR (250 MHz, CDCl3) d 8.03 (d, J 7.3 Hz, 2H), 7.55 (t, J 7.3
Hz, 1H), 7.43 (t, J 7.5 Hz, 2H), 7.25 (d, J 8.5 Hz, 2H), 6.85 (d, J
8.5 Hz, 2H), 5.23 (quint, J 6.3 Hz, 1H), 4.44 (s, 2H), 3.78 (s, 3H),
3.52 (dd, J 9.2, 5.7 Hz, 1H), 3.40 (dd, J 9.2, 6.4 Hz, 1H), 2.20 (dt,
J 12.9, 6.5 Hz, 1H), 1.33 (d, J 6.4 Hz, 3H), 1.06 (d, J 6.9 Hz, 3H).
13C{1H} NMR (62.5 MHz, CDCl3) d 165.7, 158.9, 132.5 (2C),
130.6, 130.3, 129.3 (2C), 129.0, 128.1 (2C), 113.5 (2C), 72.5,
72.5, 71.5, 55.0, 38.1, 16.5, 12.9. IR (ATR) 3063, 3033, 2972,
Rf = 0.37 (hexane:AcOEt 70:30). [a]!#" = -15.0 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3) major diastereomer d 8.06 (dd, J
7.2, 6.0 Hz, 2H), 7.59 (t, J 7.4 Hz, 1H), 7.47 (t, J 7.7 Hz, 2H),
5.22 (dq, J 13.0, 6.4 Hz, 1H), 4.28 (dt, J 9.4, 3.0 Hz, 1H), 3.06 (s,
1H), 2.74 (dd, J 16.9, 9.4 Hz, 1H), 2.51-2.47 (m, 3H), 1.84 – 1.76
(m, 1H), 1.40 (d, J 6.4 Hz, 3H), 1.07 (t, J 7.1 Hz, 3H), 1.03 (d, J
7.0 Hz, 3H). 13C{1H) NMR (125 MHz, CDCl3) major diastereo-
mer d 211.6, 166.5, 133.0, 130.6, 129.6 (2C), 128.3 (2C), 73.0,
66.5, 46.7, 42.9, 36.8, 17.8, 9.3, 7.5. IR (film) 3505, 2979, 2938,
-
1
2935, 2855, 1712, 1613 cm . HRMS (ESI+) m/z calculated for
C20H24O4Na [M+Na]+ 351.1572, found 351.1564.
4.1.26. (2R,3S)-4-Hydroxy-3-methylbutan-2-yl benzoate (44):
DDQ (522 mg, 2.30 mmol) was added to a solution of 43 (464
mg, 1.41 mmol) in CH2Cl2 (13.8 mL) and phosphate buffer pH
7.0 (1.53 mL) at 0 °C. The reaction was stirred for 3.5 h, and then
quenched by the addition of a saturated aqueous solution of Na-
HCO3 (7.90 mL). The mixture was filtered through a plug of
Celite® and eluted with CH2Cl2. The crude material was purified
by flash chromatography, eluted with hexane:AcOEt 70:30 to
provide 250 mg of 44, 83% yield.
-
1
1713, 1602, 1585 cm . HRMS (ESI+) m/z calculated for
C16H22O4Na [M+Na]+ 301.1416, found 301.1409.
4.1.30. (2S,4R,5S,6R)-2-Ethyl-2-methoxy-5,6-dimethyltetra
hydro-2H-pyran-4-ol (48): Ba(OH)2×8H2O (431 mg, 1.36 mmol)
was added to a solution of 47 (38.0 mg, 0.14 mmol) in MeOH
(19.5 mL) at room temperature. The reaction was stirred for 30
minutes. Thus, the mixture was filtered through silica gel and
eluted with pure AcOEt to provide 14.0 mg of 48, 55% yield.
Rf = 0.32 (hexane:AcOEt 70:30). [a]!#" = -22.0 (c 0.8, CHCl3).
1H NMR (250 MHz, CDCl3) d 8.04 (d, J 7.1 Hz, 2H), 7.57 (t, J
7.4 Hz, 1H), 7.45 (t, J 7.4 Hz, 2H), 5.27 – 5.12 (m, 1H), 3.61 (d, J
4.7 Hz, 2H), 2.04-1.90 (m, 1H), 1.62 (sl, 1H), 1.37 (d, J 6.4 Hz,
3H), 1.07 (d, J 7.0 Hz, 3H). 13C{1H} NMR (62.5 MHz, CDCl3) d
166.6, 133.0, 130.4, 129.6 (2C), 128.4 (2C), 72.8, 64.3, 40.8,
17.5, 13.2. IR (ATR) 3437 (br), 2978, 2935, 2882, 1715, 1698,
Rf = 0.45 (hexane:AcOEt 70:30). [a]!#" = -3.0 (c 0.3, CHCl3). 1H
NMR (500 MHz, CDCl3) d 3.68 (dq, J 10.1, 6.3 Hz, 1H), 3.37 (s,
3H), 3.28 – 3.20 (m, 1H), 2.23 (dd, J 12.5, 4.7 Hz, 1H), 1.82 (s,
1H), 1.66 (qd, J 7.5, 2.7 Hz, 2H), 1.27-1.22 (m, 2H), 1.18 (d, J 6.3
Hz, 3H), 0.97 (d, J 6.5 Hz, 3H), 0.99 (t, J 7.6 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3) d 98.4, 79.0, 70.5, 56.5, 43.7, 37.0,
36.1, 19.3, 13.0, 7.5. IR (film) 3590, 3412, 3012, 3005, 2971,
-
1
1602, 1585 cm . HRMS (ESI+) m/z calculated for C12H16O3Na
[M+Na]+ 231.0997, found 231.0991.
4.1.27. (2R,3R)-3-Methyl-4-oxobutan-2-yl benzoate (45): Ox-
alyl chloride (68.0 µL, 0.78 mmol) was added dropwise to a
solution of DMSO (74.0 µL, 1.04 mmol) in CH2Cl2 (4.00 mL)
at -78 °C. The mixture was stirred for 15 minutes. Thus, a solu-
tion of 44 (108 mg, 0.52 mmol) in CH2Cl2 (2.00 mL) was slowly
added. The reaction was stirred for 1 h and Et3N (0.29 mL, 2.07
mmol) was added dropwise. The reaction was allowed to warm up
to 0 °C. After reaching this temperature, quench by addition of a
-
1
2929, 2851 cm . HRMS (ESI+) m/z calculated for C10H20O3Na
[M+Na]+ 211.1310, found 211.1305.
4.1.31. 1-((2R,3S,4R)-4-Hydroxy-3-methyl-6-oxooctan-2-yl) 3-
methyl 4-((2-(trimethylsilyl)ethoxy)methyl) (R,Z)-2-((tert-
butyldimethylsilyl)oxy)pent-3-ene-1,3,4-tricarboxy
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The Journal of Organic Chemistry
-
1
late and 1-((2R,3S,4R)-4-hydroxy-3-methyl-6-oxooctan-2-yl) 4-
methyl 3-((2-(trimethylsilyl)ethoxy)methyl) (R,Z)-2-((tert-
butyldimethylsilyl)oxy)pent-3-ene-1,3,4-tricarbo
2858, 1731, 1644 cm . HRMS (ESI+) m/z calculated for
C33H64O10NaSi3 [M+Na]+ 727.3705, found 727.3700.
1
2
3
xylate (50)
4.1.31.a. Oxalyl chloride (84.0 µL, 0.97 mmol) was slowly added
to a solution of DMSO (80.0 µL, 1.13 mmol) in CH2Cl2 (2.00
mL) at -78 °C. The mixture was stirred for 15 minutes and a
solution of alcohol 42 (181 mg, 0.32 mmol) in CH2Cl2 (1.20 mL)
was added dropwise. The reaction was stirred for 1 h and then
Et3N (0.27 mL, 1.93 mmol) was added dropwise. The reaction
was allowed to warm up to 0 °C and thus quenched by the addi-
tion of a saturated aqueous solution of NaHCO3 (5.00 mL). The
mixture was extracted with CH2Cl2 (2 x 10.0 mL). The combined
organic layers were filtered through silica gel and eluted with
hexane:AcOEt 80:20. The crude aldehyde 49 obtained was used
in the next step without further purification.
ASSOCIATED CONTENT
Supporting Information
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5
6
7
8
9
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
1H, 13C, NOESY NMR, Mosher ester studies, IR, MS spectra, and
HPLC profile (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: renata.marcia_de_figueiredo@enscm.fr
*E-mail: ldias@unicamp.br
*E-mail: jean-marc.campagne@enscm.fr
4.1.31.b. BF3×OEt2 (30.0 µL, 0.25 mmol), was slowly added to a
solution of the aldehyde previously synthesized and enol silyl
ether derivative 13 (86.0 µL, 0.47 mmol) in CH2Cl2 (2.79 mL) at
-78 °C. The reaction was stirred for 1 h and then it was quenched
by the addition of a saturated aqueous solution of NaHCO3 (8.00
mL). The layers were separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3 x 8.00 mL). The combined organic layers
were dried over MgSO4, filtrated and concentrated under reduced
pressure. The crude material was purified by flash chromatog-
raphy, eluted with hexane:AcOEt 75:25 to provide 102 mg of
intermediate 50, 50% yield (2 steps).
ORCID
Celso de Oliveira Rezende Júnior: 0000-0003-1402-2035
Jean-Marc Campagne: 0000-0002-4943-047X
Luiz Carlos Dias: 0000-0003-0628-9928
Renata Marcia de Figueiredo: 0000-0001-5336-6071
Present Addresses
Rf = 0.29 (hexane:AcOEt 70:30). [a]!#" = +9.0 (c 0.8, CHCl3). 1H
‡ (D.P.S.) Eurofarma - 3.565, Presidente Castelo Branco Highway
- Itaqui, Itapevi - São Paulo, 06696-000, Brazil. (C.O.R.J.) Insti-
tute of Chemistry, Federal University of Uberlândia, 38400-902,
Uberlândia, Minas Gerais, Brazil.
NMR (500 MHz, CDCl3) major diastereomer d 5.39 – 5.32 (m,
2H), 5.17 (dd, J 8.7, 4.3 Hz, 1H), 5.01 – 4.89 (m, 1H), 4.20 (dd, J
6.7, 2.7 Hz, 1H), 3.81 – 3.70 (m, 5H), 2.98 (dd, J 15.8, 8.7 Hz,
2H), 2.72 – 2.64 (m, 2H), 2.49 (q, J 7.2 Hz, 3H), 2.05 (s, 3H),
1.68 – 1.58 (m, 1H), 1.28 – 1.23 (m, 3H), 1.07 (t, J 7.3 Hz, 3H),
0.97 (dd, J 20.8, 12.6 Hz, 4H), 0.86 (d, J 6.6 Hz, 9H), 0.10 (s,
3H), 0.06 (s, 3H), 0.04 (s, 9H). 13C{1H} NMR (125 MHz,
CDCl3) major diastereomer d 211.7, 170.7, 168.2, 166.9, 141.8,
127.6, 90.2, 72.8, 68.1, 67.3, 66.2, 52.3, 46.8, 42.6, 42.0, 36.8,
25.6 (3C), 18.0, 18.0, 17.9, 14.9, 9.1, 7.5, -1.4
(3C), -4.9, -5.4. IR (film) 3528, 2954, 2930, 2858, 1732, 1644
Author Contributions
All authors have given approval to the final version of the manu-
script.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
cm- . HRMS (ESI+) m/z calculated for C30H56O10NaSi2 [M+Na]+
1
The authors are grateful to ENSCM, CNRS and UNICAMP-
Campinas/SP. We also thank the CAPES-FAPESP (PhD grant of
D.P.S., project FAPESP 2012/11220-9) and CNPq-FAPESP for
post-doctoral fellowship of C.O.R.J. (projects: FAPESP
655.3310, found 655.3310.
4.1.32.
4-Methyl
1-((2R,3R,4R)-3-methyl-6-oxo-4-
((trimethylsilyl)oxy)octan-2-yl) 3-((2-(trimethylsilyl)
ethoxy)methyl) (R,Z)-2-((tert-butyldimethylsilyl)oxy)
pent-3-ene-1,3,4-tricarboxylate and 3-methyl 1-((2R,3R,4R)-3-
14/50249-8
and
15/08541-6,
CNPq
303154/2015-2,
573.564/2008-6 and 158926/2014-5).
methyl-6-oxo-4-((trimethylsilyl)oxy)octan-2-yl)
4-((2-
(trimethylsilyl)ethoxy)methyl)
(R,Z)-2-((tert-
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mL) at room temperature. The reaction was stirred for 2 h and
then filtered through silica gel and eluted with hexane:AcOEt
90:10 to provide 29.0 mg of the C13-C25 fragment, 100% yield.
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Rf = 0.26 (hexane:AcOEt 90:10). [a]!#" = +6.0 (c 0.5, CHCl3). 1H
NMR (500 MHz, CDCl3) major diastereomer d 5.40 – 5.33 (m,
2H), 5.19 (dd, J 9.2, 3.1 Hz, 1H), 4.82 – 4.75 (m, 1H), 4.39 – 4.33
(m, 1H), 3.81 – 3.72 (m, 5H), 3.02 (dd, J 16.3, 9.2 Hz, 1H), 2.70
(dd, J 16.1, 7.6 Hz, 1H), 2.58 (dd, J 16.2, 3.2 Hz, 1H), 2.51 – 2.41
(m, 3H), 2.05 (s, 3H), 1.22 (d, J 6.3 Hz, 3H), 1.08 (t, J 7.3 Hz,
3H), 1.02 – 0.97 (m, 2H), 0.91 – 0.85 (m, 12H), 0.14 – 0.03 (m,
25H). 13C{1H} NMR (125 MHz, CDCl3) major diastereomer
d 209.6, 170.5, 167.6, 167.0, 143.6, 128.9, 90.1, 72.6, 68.1, 68.0,
67.4, 51.9, 48.4, 43.3, 42.1, 37.3, 25.6 (3C), 18.0, 17.9, 17.5, 14.6,
9.5, 7.5, 0.2 (3C), -1,4 (3C), -5.0, -5.3. IR (film) 2954, 2930,
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