Synthesis of the Aglycon of the Antibiotic Disciformycin

Article abstract of DOI:10.1002/ejoc.201701639

The synthesis of the aglycon of disciformycin, a new secondary metabolite from Pyxidicoccus fallax, is reported. The disciformycins are highly potent antibiotics including inhibitory activity towards methicillin- and vancomycin-resistant Staphylococcus au

Full text of DOI:10.1002/ejoc.201701639

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Accepted Article
Title: Synthesis of the aglycon of the antibiotic disciformycin
Authors: Andreas Kirschning and Michael Wolling
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10.1002/ejoc.201701639
European Journal of Organic Chemistry
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Synthesis of the aglycon of the antibiotic disciformycin
Michael Wolling and Andreas Kirschning*[a]
Abstract: The synthesis of the aglycon of disciformycin, a new
secondary metabolite from Pyxidicoccus fallax, is reported. The
disciformycins are highly potent antibiotics including inhibitory
human cells were encountered for all four natural products.
Structurally, these four polyketides only differ in the region at
C2-C4 and the missing isovaleric ester on C6 in gulmirecin B
(4). Due to their novel scaffold they provide a starting point for a
total synthesis program, which will provide further insight into
their structure–activity relationship.
We suggest that the four polyketides are biosynthetically linked
to each other as depicted in Scheme 1. The last ACP-bound
polyketide synthase intermediate cyclizes under the catalytic
influence of the thioesterase to furnish macrolactone 5. Then,
two tailoring steps (Cyp450-based oxidation at C6 and
glycosylation at C7 leads to gulmirecin B (4). Next, oxidation at
C3 and esterification at C6 provides gulmirecin A (3). Elimination
of the hydroxyl group at C3 can either lead to disciformycin A (1)
and B (2), respectively. At this stage it is not clear whether both
disciformycins are interconvertible, either enzymatically or
chemically.
activity
towards
methicillin-
and
vancomycin-resistant
Staphylococcus aureus. The stereocontrolled installation of the
olefinic double bonds at C2-C3/C3-C4 and C12-C13, respectively,
as well the orthogonal differentiation of the oxy functionalities turned
out to be key challenges of our approach.
Introduction
Recently, a group of macrocyclic polyketides was independently
reported by the groups of Müller and Nett.[1,2] Disciformycins A
(1) and B (2) were isolated from Pyxidicoccus fallax AndGT8.
Both disciformycins inhibit growth of methicillin- and
vancomycin-resistant Staphylococcus aureus, with disciformycin
B (2) bearing stronger inhibiting activity.
Figure 1. Structures of the disciformycins A (1) and B (2) and the gulmirecins
A (3) and B (4).
Nett and coworkers disclosed the structures of gulmirecins A (3)
and B (4), that were isolated from the predatory bacterium
Pyxidicoccus fallax HKI 727. The gulmirecins also exhibit strong
activity against staphylococci, including methicillin-resistant
Scheme 1. Proposed biosynthetic relationship between gulmirecins and
diciformycins starting from the last ACP-bound polyketide synthase
intermediate (ACP= acyl carrier protein, TE= thioesterase).
Staphylococcus aureus, with gulmirecin
B
(4) showing
significantly less activity than A (3). No cytotoxic effects on
Synthetically, the disciformycins bear several challenges, which
are: a) A well-orchestrated protecting group strategy has to be
developed for differentiating differently functionalized oxygen-
bearing functionalities, b) stereo- and position control of the
double bond at C3-C4 in disciformycin A (1) and C2-C3 in
disciformycin B (2) has to be achieved, c) stereocontrol of the
trisubstituted alkene at C12-C13 has to be achieved.
[a]
M. Wolling, Prof. Dr. A. Kirschning
Gottfried Wilhelm Leibniz Universität Hannover
Institut für Organische Chemie
Schneiderberg 1 B, 30167 Hannover (Germany)
E-mail: andreas.kirschning@oci.uni-hannover.de;
http://www.kirschning-group.com/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701639
European Journal of Organic Chemistry
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Results and Discussion
Initially the introduction of the correctly (Z)-configured olefinic
double bond at C12-C13 was planned to occur at the beginning
of the synthesis. (Z)-2-Methyl-but-2-enal (12) was coupled with
the Nagao building block 11 to yield the aldol product[5] which
was silyl-protected (Scheme 4). The resulting silyl ether 13 was
collected in good diastereomeric ratio. Nevertherless, we had to
abandon this approach, because reductive removal of the
auxiliary and Wittig olefination[6] led to almost complete loss of a
defined stereochemistry on the trisubstituted double bond in
ester 14.
Disciformycin A (1) was chosen as the synthetic target, since
computer modeling of the ground state energy of the
disciformycins A (1), B (2) and 2-epi-disciformycin B (2-epi-2) (in
H2O as well as CHCl3) suggests, that it might be possible to
convert disciformycin A (1) to disciformycin B (2) under
thermodynamically controlled reaction conditions, allowing direct
access to the respective other natural product. The structurally
closely related disciformycins B (2) and 2-epi-B (2-epi-2) might
lead to a mixture of both compounds during this isomerization
process.
Scheme 4. Isomerization of the (Z)-olefine motif at C12-C13 (disciformycin
numbering) (DIPEA= diisopropylethyl amine; Dibal-H= diisobutylaluminium
hydride; tBu= tert-butyl; TBS= tert-butyldimethylsilyl).
Reagents and conditions: a. TiCl4, DIPEA, CH2Cl2, -95°C, 50 min; b. TBSOTf,
2,6 lutidine, CH2Cl2, (78% for 2 steps); c. Dibal-H, toluene, -78 °C, 1 h; d.
Ph3PC(Me)CO2Et 8, CH2Cl2, 50°C, 60 h.
Scheme 2. Interconversion of discifomrycins A (1) and B (2) and calculated
ground state energies of the disciformycins A, B, and 2-epi-B (for details see
SI).
Consequently, we had to alter the synthesis and decided to
introduce the alkene at a late stage of the total synthesis. The
synthesis towards the linear precursor started from methyl (R)-
lactate (6) (Scheme 5). This was converted into alkene 15 after
O-protection[7], reduction to the aldehyde followed by a chelation
controlled Hosomi-Sakurai allylation[8-9], and O-silylation. Next,
ozonolysis provided the aldehyde[9] which was subjected to
Wittig olefination conditions[6] to yield ethyl ester 16 with
excellent stereocontrol (>10:1).
The retrosynthetic plan depicted in Scheme 3 is the result of
several synthetic efforts to synthetically access the aglycons of
the disciformycins (1/2).[4] Basically, the macrolactone is stripped
off all elements attached to hydroxyl groups (isobutyric acid,
D-arabinose) and the alkene unit at C11. We were aware of the
fact, that isomerization of Z-configured-α,β-unsaturated acids
can occur during macrolactonization.[4] Therefore, we chose the
E-configured macrocycle 5 as synthetic target and isomerization
was planned to be initiated towards the end of the the total
synthesis. The macrolactone 5 is planned to be formed by
macrolactonization and the precursor seco-acid is dissected into
building blocks 6-10. Several aldol reactions and allylations as
well as olefinations were chosen to create the carbon backbone.
Scheme 5. Preparation of linear precursor 18 (PMB= p-methoxybenzyl; CSA=
camphorsulfonic
acid;
TF=
trifluoromethylsulfonyl;
SEM=
trimethylsilylethoxymethyl; DMAP= p-dimethylamino pyridine).
Reagents and conditions: a) (CCl3)CNH(OPMB), CSA, CH2Cl2, rt, 18 h (95 %);
b) Dibal-H, CH2Cl2, -78 °C, 1 h; c) SnCl4, 7, CH2Cl2, -78 °C, 100 min; d)
TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 40 min (69 % for 3 steps), d.r.= 7:1; e)
O3, PPh3, CH2Cl2/MeOH, -78 °C, 5 min; f) 8, CH2Cl2, 40 °C, 18 h (87 % for 2
steps); g) LiAlH4, THF, 0 °C, 20 min; h) MnO2, CH2Cl2, rt, 5 h; i) 9, Bu2BOTf,
NEt3, PhMe, -78 °C, 16 h (61 % for 3 steps, d.r.= >10:1); j) Dibal-H in
cyclohexane, Me(MeO)NH·HCl, -30 °C, 2 h (90%); k) SEMCl, DIPEA, DMAP,
40 °C, 18 h, 100 %.
The ester was transformed into the corresponding aldehyde,
which was subjected to an Evans aldol protocol using
functionalized Evans auxiliary 9.[10] The aldol product 17 was
obtained with good diastereocontrol (>10:1) and could
straightforwardly be transformed into Weinreb amide 18 by
Scheme 3. Retrosynthetic considerations and planning.
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10.1002/ejoc.201701639
European Journal of Organic Chemistry
FULL PAPER
direct transamidation[11] followed by protection of the free alcohol
with the SEM-group.[12] With respect to yields, this sequence
turned out to be superior to the one with reversed timing of
protection and amide formation. Weinreb amide 18 was further
elaborated towards macrolactone formation by first nucleophilic
allylation[13] followed by diastereocontrolled reduction of the
intermediate ketone using the CBS-reagent and BH3·SMe2
(Scheme 6).[14] The resulting (S)-configured alcohol 19 was
obtained with excellent stereocontrol. The configuration of the
newly formed stereogenic center was determined using the
Mosher-ester method.[15] It is worth mentioning that this reaction
proceeds with strong substrate control, furnishing the same
product with both CBS-enantiomers. Surprisingly, reduction
using Zn(BH4)2 gave the other epimer in 63 % yield. Reduction
with NaBH4 led to a 1:1 mixture of diastereoisomers.
The alternative sequence, reduction to the aldehyde followed by
diastereoselective allylation failed to deliver satisfying results.
Next, the allyl alcohol 19 was transformed into the ester 21
bearing the complete carbon backbone required for
macrocyclization. The synthetic sequence consisted of
dihydroxylation and periodate cleavage[16], Wittig olefination[6]
and provided -unsaturated ester 20 which was followed by
protection of the free alcohol as SEM-acetal[12] and final removal
of the TBS group at C11.[17] This set the stage for lactone
formation. First ester hydrolysis provided the seco acid
derivative which was smoothly cyclized under Yamaguchi
conditions[18] to yield the macrolactones 22, surprisingly
deconjugated with respect to the olefinic double bond (C2-
C3→C3-C4). As a consequence a new stereogenic center is
formed at C2 so that macrolactone 22 was isolated as an
unseparable mixture (4:1) of diastereomers.
turned out to lack chemoselectivity with respect to the olefinic
double bond. For achieving best yields on a multigram scale, it
was also important to carry out the Wittig olefination under mild
conditions.
As pointed out, migration of the olefinic double bond occurred
during macrocyclization. Several efforts to isomerize the double
bond in 22a,b back to the conjugated system were pursued,
however, different acidic as well as basic conditions did not
affect this isomerization. To understand these unexpected
results, the ground state energies of the possible isomers were
calculated by molecular modeling (figure 2). With these data in
hand, one can conclude that compared to macrocycles 22a,b
the E-configured macrocycle 23b is less stable and hence its
formation is not observed. These results explain the observation
that macrolactone 22 was formed under the macrolactonization
conditions as mixture of diastereoisomers. It also provides a
rationale of why the Z-configured macrocycle 23a was not
formed through an isomerization process under thermodynamic
conditions.
Figure 2. Calculated ground state energies of isomers 22a,b and 23a,b.
Scheme 6. Synthesis of macrolacton 22.
Next, the installation of the Z-configured alkene was pursued
and finally achieved by first removing the PMB-protection in
macrolactones 22,[21] oxidation of the resulting alcohol[22] and
Wittig olefination.[23] A reaction temperature of -50°C was the key
to successfully obtain the desired Z-alkene 24. Furthermore, it
was important to add the ketone to an excess of the Wittig ylide
and conduct the olefination in a mixture of DME and HMPA.
Scheme 7. Final steps of the synthesis.
Reagents and conditions: a) Allyl-MgBr, THF, -78 °C, 15 min; b) (R)-CBS,
BH3·SMe2, THF, -78 °C, 1 h, -50 °C, 15 h (95 % for 2 steps), d.r.> 10:1; c) AD-
mix-β, tBuOH/H2O (1:1), rt, 21 h; d) NaIO4, THF/H2O (1:1), rt, 2 h; e) 8, CH2Cl2,
0 °C, 4 h, then rt, 16 h (56 % over 3 steps); f) SEMCl, DIPEA, DMF, 40 °C,
18 h (80 %); g) HF·pyr, pyr, THF (1:3:5) (0.04 M) rt, 3 d (74 %); h) LiOH (1 M),
THF, MeOH (1:1:1), 40 °C, 25 h; i) 2,4,6-trichlorobenzoyl chloride, DIPEA,
90 min, then slow addition over a period of 17 h to DMAP, PhMe (0.01 M),
80 °C (69% over 2 steps) d.r.= 4:1.
Reagents and conditions: a) DDQ, CH2Cl2:pH7-buffer 10:1, 0 °C, 3 h; b) Dess-
Martin periodinane, NaHCO3, CH2Cl2, rt, 75 min, (55 % over 2 steps, d.r.=
6:1); c) EtPPh3·Br, KHMDS, DME:HMPA 10:1, -50 °C, 20 min, (70 %, d.r.=
6:1); d) DDQ, CH2Cl2/pH7-buffer 10:1, 35 °C, 20 h; e) isovaleric anhydride,
DIPEA, DMAP, CH2Cl2, rt, 3 d, (68 % over 2 steps, d.r.= 10:1); f) ZnCl2·OEt2,
Et2O, EtSH, 0 °C, 1 h, (69 %, d.r.= 10:1).
Several additional aspects of this synthetic sequence are worth
discussing. An alternative approach based on cross metathesis
for introducing the ester[19] was not successful, whereas
[20]
dihydroxylation using OsO4
instead of the AD-mix mixture
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10.1002/ejoc.201701639
European Journal of Organic Chemistry
FULL PAPER
a Micromass LCT via loop-mode injection from a Waters (Alliance 2695)
HPLC system or via a Micromass Q-TOF in combination with a Waters
Aquity Ultraperformance LC system. Ionization is achieved by ESI. All
reactions were performed under an argon atmosphere unless otherwise
stated. Glassware was dried by heating under vacuum followed by
flushing with argon gas prior to use. Dry solvents were obtained after
filtration through drying columns on a M. BRAUN solvent purification
system or purchased from commercial providers. Wittig reagent 8 was
was prepared according to reference [27]. Evans building block 9 was
prepared according to reference [28].
The configuration of the olefinic double bond was confirmed by a
1H-NMR NOESY experiment. Conditions for the manipulation of
the three hydroxyl groups were tested. Introduction of the ester
side chain at C6 was possible using DDQ at elevated
[24]
temperatures for removal of the benzyl group.
However, it
was not possible to remove the SEM groups from the resulting
ester 25 without substantial decomposition or acyl migration, but
it is possible to cleave both SEM groups in benzyl ether 24
furnishing diol 26.[25]
Synthesis of homoallyl alcohol 15 from methyl lactate 6: To a
solution of methyl (R)-2-[(4-methoxybenzyl)oxy]propanoate (8.71 g,
38.9 mmol, 1.0 eq.; obtained according to reference [7]) in CH2Cl2
(390 ml) at -78 °C was added a solution of DiBAl-H (1M in PhMe, 42.8 ml,
42.8 mmol, 1.1 eq.) dropwise over 15 min. The solution was stirred for
1 h at -78 °C, before an aqueous saturated solution of potassium sodium
tartrate was added. It was stirred for 3 h at rt and the aqueous phase was
extracted with CH2Cl2 (3x). The combined organic phases were dried
(Na2SO4), filtered and concentrated in vacuo. The aldehyde was added
dropwise to a solution of SnCl4 (4.53 ml, 38.9 mmol, 1 eq.) in CH2Cl2
(180 ml) at -78 °C and the red solution was stirred for 15 min.
Allyltrimethylsilane (6.78 ml, 42.8 mmol, 1.1 eq.) was added and it was
stirred for 100 min at -78 °C. The reaction was terminated by addition of
H2O (90 ml). The aqueous phase was extracted with CH2Cl2 (3x) the
combined organic phases were dried (Na2SO4), filtered and concentrated
under reduced pressure to a volume of about 100 ml. The resulting
solution was cooled to -78 °C and 2,6-lutidine (18.1 ml, 155 mmol,
4.0 eq.) and TBSOTf (14.1 ml, 77.7 mmol, 2 eq.) were added
sequentially. After stirring at room temperature for 40 min, the reaction
was terminated by addition of a saturated NH4Cl solution. The aqueous
phase was extracted with CH2Cl2, the combined organic phases were
dried (Na2SO4), filtered and concentrated under reduced pressure.
Purification by flash chromatography (10:1) afforded the title compound
15 (9.39 g, 26.8 mmol, 69 % over 3 steps) as a colorless oil. 1H-NMR-
spectroscopic data and the optical rotation are in accordance with those
published in the literature.[9]
Conclusions
In essence, we developed the first total synthesis of the aglycon
of disciformycin B. It unravels the principal synthetic challenges
of these macrolactones. Key issues to be solved are associated
with the stereochemistry and position of the two olefinic double
bonds at C2-C3/C3-C4 and C12-C13 and with the orthogonal
differentiation of the oxy-functionalities. This work allows to
successfully access the disciformycins and the structurally
related gulmirecins and subsequently paves the way to develop
a medicinal chemistry programme for these highly active
antibacterial polyketides.
Experimental Section
General information: 1H-NMR spectra were recorded at 400 MHz or 500
MHz, respectively, and 13C-NMR spectra were recorded at 100 MHz or
125 MHz, respectively, with a Bruker Avance 400, DPX 400 or DRX 500.
Chemical shift values of NMR data are reported as values in ppm relative
to (residual undeuterated) solvent signal as internal standard.
Multiplicities for 1H-NMR signals are described using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet; where appropriate with the addition of b = broad. The residual
undeuterated solvent signals were used as an internal standard for the
1H-NMR spectra; the carbon signal was used for the 13C spectra.[26]
Chemical shifts δ are given in ppm, coupling constants J in Hertz (Hz).
Multiplicities for 1H-NMR signals are described using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad. The multiplicity of the 13C-NMR signals is given as:
p = primary, s = secondary, t = tertiary, q = quaternary. Assignment of the
benzyl and PMB protecting groups is presented: for aromatic rings= Ar,
for benzylic positions= Bn and for methoxy groups in PMB= ArOMe.
Mass spectra were obtained with a type LCT (ESI) (Micromass) equipped
with a lockspray dual ion source in combination with a Waters Alliance
2695 LC system, or with a type QTOF premier (Micromass) spectrometer
(ESI mode) in combination with a WATERS Acquity UPLC system
equipped with a Waters BEH C18 1.7 μm (SN 01473711315545) column
(solvent A: water + 0.1%(v/v) formic acid, solvent B: MeOH + 0.1 % (v/v)
formic acid; flow rate = 0.4 mL/min; gradient (t [min]/solvent B [%]): (0:5)
(2.5:95) (6.5:95) (6.6:5) (8:5)). Ion mass signals (m/z) are reported as
values in atomic mass units. Melting points were measured using a SRS
OptiMelt apparatus.Optical rotations were measured on a Perkin-Elmer
polarimeter type 341 or 241 in a quartz glass cuvette at l = 589 nm (Na
D-line). The optical rotation is given in [° ml·g-1·dm-1] with c= 1
corresponding to 10 mg ml-1. Flash chromatography was performed using
silica gel with a particle size of 40 to 63 μm as the stationary phase
(Machery-Nagel); mixtures of petroleum ether (PE) and ethyl acetate
(EA) as mobile phase. High resolution mass spectra were obtained with
[α]D24= +0.42° (c= 2.16, CHCl3; ref.: +0.40° [c= 2.4, CHCl3]); 1H-NMR
(400 MHz, CDCl3) : 7.28-7.24 (2H, m, HAr), 6.89-6.85 (2H, m, HAr),
5.88-5.77 (1H, ddt, J= 17.1, 10.3, 7.2 Hz, H-2), 5.07-5.00 (2H, m, H-1),
4.52 (1H, d, J= 11.6, HBn), 4.44 (1H, d, J= 11.6 Hz, HBn), 3.80 (3H, s,
HArOMe), 3.72 (1H, ddd, J= 8.0, 4.7, 3.6 Hz, H-4), 3.47 (1H, dq, J= 4.7,
6.4 Hz, H-5), 2.41-2.33 (1H, m, H-3), 2.15-2.08 (1H, m, H-3), 1.12 (3H, d,
J= 6.4 Hz, H-6), 0.87 (9H, s, HTBS), 0.01 (3H, s, HTBS), -0.02 (3H, s, HTBS
)
ppm.
Synthesis of ethyl hept-2-enoate 16: A solution of homoallyl alcohol 15
(9.39 g, 26.8 mmol, 1.0 eq.) in a 5:1 mixture of CH2Cl2/MeOH (54 ml)
was cooled to -78 °C. Ozone was passed through the solution until the
blue color persisted. Then oxygen gas was lead through the solution until
the blue color had disappeared and PPh3 (21.1 g, 80.5 mmol, 3.0 eq.)
was added. The solution was warmed to room temperature and stirred
for an additional hour and the solvent was removed under reduced
pressure. The residue was dissolved in CH2Cl2 (40 ml) and Wittig reagent
8 (5.15 g, 14.2 mmol, 3.0 eq.) was added. The solution was stirred for
18 h at 40 °C. Silica gel was added and the solvent was removed under
reduced pressure. Flash chromatography of the loaded silica gel sample
(20:1) afforded the title compound 16 (10.2 g, 23.3 mmol, 87 %) as a
colorless oil.
[α]D26= +2.70° (c= 1.11, CH2Cl2); 1H-NMR (400 MHz, CDCl3) : 7.26-7.22
(2H, m, HAr), 6.89-6.85 (2H, m, HAr), 6.85-6.81 (1H, m, H-3), 4.53 (1H, d,
J= 11.6 Hz, HBn), 4.43 (1H, d, J= 11.6 Hz, HBn), 4.18 (1H, q, J= 7.2 Hz,
HEt), 3.84-3.81 (1H, m, H-5), 3.80 (3H, s, HArOMe), 3.50 (1H, dq, J= 4.8,
6.5 Hz, H-6), 2.46 (1H, m, H-4), 2.31-2.23 (1H, m, H-4), 1-84 (3H, d,
J= 1.2 Hz, H-8), 1.28 (3H, t, J= 7.2 Hz, HEt), 1.14 (3H, d, J= 6.5 Hz), 0.85
(9H, s, HTBS), 0.00 (3H, s, HTBS), -0.03 (3H, s, HTBS) ppm; 13C-NMR (100
MHz, CDCl3) : 168.2 (q, C-1), 159.3 (q, CAr), 140.1 (t, C-3), 131.0 (q,
CAr), 129.2 (t, CAr), 128.8 (q, C-2), 113,9 (t, CAr), 77.0 (t, C-6), 73.0 (t,
C-5), 70.8 (s, CBn), 60.4 (s, CEt), 55.4 (p, CArOMe), 30.8 (s, C-4), 25.9 (p,
CTBS), 18.1 (q, CTBS), 14.4 (p, CEt), 13.8 (p, C-7), 12.7 (p, C-8), -4.5 (p,
CTBS), -4.6 (p, CTBS) ppm; HRMS (ESI): m/z calcd for C24H40O5SiNa
[M + Na]+: 459.2543, found: 459.2546.
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10.1002/ejoc.201701639
European Journal of Organic Chemistry
FULL PAPER
Synthesis of amide 17: Ester 16 (9.49 g, 21.7 mmol, 1.0 eq.) was
dissolved in Et2O (200 ml) at 0 °C. After addition of lithium aluminium
hydride (2.48 g, 65.1 mmol, 3.0 eq.) the suspension was stirred for
20 min at 0 °C. The reaction was terminated by cautious addition of H2O
(2.50 ml), an aqueous 15 % NaOH solution (2.50 ml) und a second
portion of H2O (7.50 ml). After 15 minutes MgSO4 was added and stirring
was continued for additional 15 min. The mixture was filtered and the
filter cake was washed with CH2Cl2. The combined extracts were
removed under reduced pressure. The resulting alcohol (8.34 g,
21.1 mmol, 97 %) was obtained as a colorless oil and was directly used
in the next step without further purification. This alcohol (8.07 g,
20.4 mmol, 1.0 eq.) was dissolved in CH2Cl2 (50 ml) and the solution was
stirred for 4.5 h after addition of MnO2 (53.3 g, 613 mmol, 30 eq.). After
filtration through a pad of CeliteTM, the solvent was removed under
reduced pressure. The resulting aldehyde was used in the following step
without further purification. To a solution of Evans building block 9 (8.36 g,
25.7 mmol, 1.2 eq.) and NEt3 (4.77 ml, 34.3 mmol, 1.6 eq.) in PhMe
(64 ml) at -78 °C was added Bu2BOTf (1 M solution in CH2Cl2, 30.0 ml,
30.0 mmol, 1.4 eq.). The mixture was stirred for 2 h at 0 °C, the solution
was cooled to -78 °C and the aldehyde (7.64 g, 19.4 mmol, 1.0 eq.)
dissolved in toluene (15 ml) was added dropwise. The mixture was
stirred for 16 h at -78 °C and then warmed up to 0 °C and stirred for
further 30 minutes The reaction was quenched by addition of aqueous
pH 7-buffer (20 ml). A mixture of aqueous 30 % H2O2 solution (20 ml) and
MeOH (60 ml) was added dropwise over 30 minutes and stirring was
continued for 1 h at room temperature. The aqueous phase was
extracted five times with CH2Cl2, the combined organic phases were
dried (Na2SO4), filtered and concentrated under reduced pressure. The
title compound 17 (9.62 g, 13.4 mmol, 66 % over 2 steps) was obtained
by purification using flash chromatography (4:1) as a 1.5:1 mixture along
with the Evans building block 9.
(1H, d, J= 11.7 Hz, HBn), 4.66 (1H, d, J= 6.8 Hz, HSEM), 4.59 (d, J= 6.8 Hz,
HSEM), 4.51 (1H, d, J= 11.7 Hz, HBn), 4.50 (1H, d, J= 11.5, HBn), 4.44-4.38
(2H, m, H-2,3), 4.42 (1H, d, J= 11.5 Hz, HBn), 3.79 (3H, s, HArOMe), 3.77-
3.67 (2H, m, H-7, HSEM), 3.53-3.41 (5H, m, H-8, HSEM, HN-OMe), 3.12 (3H,
s, HNMe), 2.46-2.39 (1H, m, H-6), 2.08-2.01 (1H, m, H-6), 1.60 (3H, s, H-
10), 1.09 (3H, d, J= 6.5 Hz, H-9), 0.92-0.86 (2H, m, HSEM), 0.86 (9H, s,
HTBS), 0.03 (3H, s, HTBS), -0.01 (3H, s, HTBS), -0.02 (9H, s, HSEM) ppm;
13C-NMR (100 MHz, CDCl3) : 159.1 (q, CAr), 138.0 (q, CAr), 132.5 (q, C-
4), 131.22 (q, CAr), 129.2 (t, CAr), 128.4 (t, CAr), 128.0 (t, CAr), 127.7 (t, C-
5), 127.2 (t, CAr), 113.8 (t, CAr), 92.4 (s, CSEM), 81.0 (t, C-2/C-3), 79.2 (t,
C-2/C-3), 76.9 (t, C-8), 74.1 (t, C-7), 72.4 (s, CBn), 70.8 (s, CBn), 65.3 (s,
CSEM), 61.2 (p, CN-OMe), 55.4 (p, CArOMe), 35.5 (p, CNMe), 30.4 (s, C-6),
26.0 (p, CTBS), 18.2 (q, CTBS), 18.1 (q, CSEM), 14.4 (p, C-9), 13.1 (p,
C-10), -1.3 (p, CSEM), -4.4 (p, CTBS), -4.5 (p, CTBS) ppm; HRMS (ESI): m/z
calcd for C39H66NO8Si2 [M + H]+: 732.4327, found 732.4330.
Synthesis of allyl alcohol 19: To a solution of Weinreb amide 18
(9.65 g, 13.2 mmol, 1.0 eq.) in THF (100 ml) at -78 °C was slowly added
AllylMgBr (1 M in Et2O, 40.0 ml, 40.0 mmol, 3.0 eq.). The mixture was
stirred for 15 min at -78 °C, then warmed up to 0 °C and stirring was
continued for 15 min until the reaction was terminated by addition of an
aqueous saturated solution of NH4Cl. The aqueous layer was extracted
with CH2Cl2 (3x), the combined organic phases were dried (MgSO4),
filtered and concentrated under reduced pressure. The crude product
was used in the next step without further purification. To a solution of the
resulting ketone (9.65 g, 13.2 mmol, 1.0 eq.) in THF (130 ml) at -78 °C
was added (R)-(+)-2-methyl-CBS-oxazaborolidine (1 M solution in PhMe,
40 ml, 40.0 mmol, 3.0 eq.) and the reaction mixture was stirred for 90 min.
After addition of BH3·SMe2 (12.5 ml, 132 mmol, 10 eq.) the solution was
stirred for 1 h at -78 °C and then for additional 15 h at -50 °C. The
reaction was terminated by careful addition of MeOH (20 ml) and the
resulting mixture was slowly warmed up to room temperature and H2O
was added. The aqueous layer was extracted with CH2Cl2 (3x), the
combined organic phases were dried (Na2SO4), filtered and concentrated
under reduced pressure. The residue was purified by flash
chromatography (PE:EA= 10:1) to afford the title compound 19 (8.98 g,
12.6 mmol, 95 % over 2 steps) as a colorless oil.
HRMS (ESI): m/z calcd for C41H55NO8SiNa [M + Na]+: 740.3589, found
740.3467.
Synthesis of Weinreb amide 18: To
a suspension of N,O-
dimethylhydroxylamine·HCl (20.0 g, 206 mmol, 15 eq.) in THF (70 ml) at
0 °C DiBAl-H (1 M in hexane, 206 ml, 206 mmol, 15 eq.) was slowly
added. The reaction mixture was stirred at room temperature until a clear
solution was obtained (30 min). The solution was cooled to -30 °C, amide
17 (9.86 g, 13.8 mmol, 1.0 eq.) in THF (40 ml) was added and stirring
was continued for 3 h. The solution was added to a mixture of an
aqueous saturated solution of potassium sodium tartrate (120 ml) and
CH2Cl2 (120 ml) at 0 °C. The reaction mixture was stirred for 18 h at
room temperature. The aqueous layer was extracted with CH2Cl2 (3x),
the combined organic phases were dried (MgSO4), filtered and
concentrated under reduced pressure. The residue was purified by flash
chromatography (PE:EA= 1:1) to afford the aldol product (7.46 g,
12.4 mmol, 90 %) as an oil.
1
[α]D25= -31.4° (c= 1.00, CH2Cl2); H-NMR (400 MHz, CDCl3) : 7.37-7.24
(7H, m, HAr), 6.87-6.85 (2H, m, HAr), 5.73 (1H, dddd, J= 17.1, 8.7, 7.0,
5.1 Hz, H-2), 5.64 (1H, t, J= 6.8 Hz, H-8), 5.05-4.99 (2H, m, H-1), 4.96
(1H, d, J= 11.2 Hz, HBn), 4.61 (2H, s, HSEM), 4.60 (1H, d, J= 11.2 Hz, HBn),
4.51 (1H, d, J= 11.6 Hz, HBn), 4.42 (1H, d, J= 11.6 Hz, HBn), 4.26 (1H, d,
J= 7.5 Hz, H-6), 3.80 (3H, s, HArOMe), 3.76-3.70 (2H, m, H-10, HSEM),
3.57-3.43 (4H, m, H-4,5,11, HSEM), 2.46-2.40 (1H, m, H-9), 2.33-2.10 (3H,
m, H-3,9), 1.60 (3H, s, H-13), 1.11 (3H, d, J= 6.5 Hz, H-12), 0.92-0.88
(2H, m, HSEM), 0.87 (9H, s, HTBS), 0.04 (3H, s, HTBS), -0.01 (3H, s,
HTBS), -0.04 (9H, s, HSEM) ppm; 13C-NMR (100 MHz, CDCl3) : 159.2 (q,
CAr), 138.7 (q, CAr), 135.0 (t, C-2), 132.6 (q, C-7), 131.2 (q, CAr), 129.3 (t,
CAr), 128.5 (t, CAr), 128.3 (t, CAr), 128.2 (t, C-8), 127.8 (t, CAr), 117.5 (s,
C-1), 113.9 (t, CAr), 92.2 (s, CSEM), 83.2 (t, C-6), 81.0 (t, C-5), 76.9 (t,
C-11), 75.4 (s, CBn), 74.1 (t, C-10), 70.8 (s, CBn), 70.4 (t, C-4), 65.5 (s,
CSEM), 55.4 (p, CPMB), 39.2 (s, C-3), 30.6 (s, C-9), 26.0 (p, CTBS), 18.2 (q,
CTBS), 18.2 (s, CSEM), 14.3 (p, C-12), 12.7 (p, C-13), -1.3 (p, CSEM), -4.4 (p,
CTBS), -4.4 (p, CTBS) ppm; HRMS (ESI): m/z calcd for C40H66O7Si2Na
[M + Na]+: 737.4245, found 737.4243.
1
[α]D22= -15.9° (c= 0.97, CH2Cl2); H-NMR (400 MHz, CDCl3) : 7.36-7.26
(7H, m, HAr), 6.90-6.87 (2H, m, HAr), 5.56 (1H, t, J= 7.5 Hz, H-5), 4.75
(1H, d, J= 11.6 Hz, HBn), 4.52 (1H, d, J= 11.6 Hz, HBn), 4.48 (1H, d,
J= 11.6 Hz, HBn), 4.46 (1H, d, J= 11.6 Hz, HBn), 4.38 (1H, d, J= 4.6 Hz,
H-2), 4.31 (1H, t, J= 4.6 Hz, H-3), 3.79 (3H, s, HArOMe), 3.74-3.70 (1H, m,
H-7), 3.52 (3H, s, HN-OMe), 3.51-3.45 (1H, m, H-8), 3.16 (3H, s, HNMe),
2.87 (1H, d, J= 4.6 Hz, HOH), 2.46-2.40 (1H, m, H-6), 2.11-2-04 (1H, m,
H-6), 1.62 (3H, s, H-10), 1.13 (3H, d, J= 6.5 Hz, H-9), 0.88 (9H, s, HTBS) ,
0.03 (3H, s, HTBS), 0.00 (3H, s, HTBS) ppm; 13C-NMR (100 MHz, CDCl3) :
159.2 (q, CAr), 137.3 (q, CAr), 133.9 (q, C-4), 131.2 (q, CAr), 129.2 (t, CAr),
128.6 (t, CAr), 128.3 (t, CAr), 128.1 (t, CAr), 125.3 (t, C-5), 113.8 (t, CAr),
77.0 (C-8), 76.9 (s, C-2,3), 73.8 (t, C-7), 72.2 (s, CBn), 70.79 (s, CBn), 61.2
(p, CN-OMe), 55.4 (p, CArOMe), 32.6 (p, CNMe), 30.0 (s, C-6), 26.0 (p, CTBS),
Preparation of diastereomeric Mosher esters derived from alcohol
19: To a solution of the alcohol 19 (1.0 eq.) in CH2Cl2 (0.1 M) were added
DMAP (cat.), DIPEA (3.0 eq.) and either of the two enantiomers of
Mosher acid chloride (1.0 eq.). After stirring for 18 h at room temperature
the reaction was terminated by addition of H2O. The aqueous phase was
extracted with CH2Cl2, the combined organic phases were dried
(Na2SO4), filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography (PE:EA= 10:1) to afford the
corresponding esters.
18.1 (q, CTBS), 14.2 (p, C-9), 12.8 (p, C-10), -4.4 (p, CTBS), -4.4 (p, CTBS
)
ppm; The signal for C-1 could not be detected; HRMS (ESI): m/z calcd
for C33H51NO7SiNa [M + Na]+: 624.3333, found 624.3329.
To a solution of this aldol product (7.95 g, 13.2 mmol, 1.0 eq.) in DMF
(130 ml) were added DIPEA (13.3 ml, 78.5 mmol, 6.0 eq.), SEMCl
(4.65 ml, 26.2 mmol, 2.0 eq.) and DMAP (cat.). The mixture was stirred
for 18 h at 40 °C. The red solution was terminated by addition of H2O.
The aqueous layer was extracted with CH2Cl2 (3x), the combined organic
phases were dried (MgSO4), filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography (PE:EA=
4:1) to afford the title compound 18 (9.65 g, 13.2 mmol, 100 %) as a
colorless oil.
[α]D23= -36.2° (c= 0.81, CH2Cl2); 1H-NMR (400 MHz, CDCl3) : 7.34-7.23
(7H, m, HAr), 6.87-6.84 (2H, m, HAr), 5.58 (1H, t, J= 6.8 Hz, H-5), 4.73
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701639
European Journal of Organic Chemistry
FULL PAPER
167.9 (q, C-1), 159.2 (q, CAr), 138.7 (q, CAr), 138.2 (t, C-3), 132.8 (q, C-8),
131.2 (q, CAr), 129.5 (q, C-2), 129.2 (t, CAr), 128.4 (t, CAr), 128.4 (t, CAr),
127.6 (t, C-9), 113.8 (t, CAr), 96.3 (s, CSEM), 92.4 (s, CSEM), 82.2 (t, C-7),
81.4 (t, C-6), 78.3 (t, C-5), 76.9 (t, C-12), 75.2 (s, CBn), 74.1 (t, C-11),
70.8 (s, CBn), 65.8 (s, CSEM), 65.5 (s, CSEM), 60.5 (s, CEt), 55.4 (p, CArOMe),
31.6 (t, C-4), 30.5 (t, 10), 26.0 (p, CTBS), 18.2 (q, CSEM), 18.1 (s, CTBS),
18.1 (s, CSEM), 14.5 (p, CEt), 14.3 (p, C-13), 12.9 (p, C-14), 12.9 (p, C-
15), -1.3 (p, CSEM), -1.3 (p, CSEM), -4.4 (p, CTBS), -4.4 (p, CTBS) ppm;
HRMS (ESI): m/z calcd for C50H86O10Si3Na [M + Na]+: 953.5427, found
953.5424.
Δ  SR=  (S) –  (R)
(ppm)
 (S)-ester
 (R)-ester
(ppm)
(ppm)
1a
1b
2
3a
3b
6
5.0688
5.0346
5.6566
2.5981
2.4377
4.1871
5.5440
2.4493
2.0799
1.0842
1.5410
5.1042
5.0705
5.7060
2.6268
2.5115
4.1384
5.5346
2.4284
2.0649
1.1004
1.5027
-0.0354
-0.0359
-0.0494
-0.0287
-0.0738
0.0487
0.0094
0.0209
0.0150
-0.0162
0.0383
8
9a
9b
12
13
The SEM-ether described above (2.45 g, 2.64 mmol, 1.0 eq.) was divided
and inserted into two plastic vessels at 0 °C. A solution of HF·Py (6.6 ml
HF·Py, 19.2 ml pyridine) in THF (33.6 ml) was added to both vessels.
The mixture was stirred for 72 h and the reaction was terminated by
addition of an aqueous saturated solution of NaHCO3. Then, also solid
NaHCO3 was carefully added, until gas evolution stopped. The aqueous
phase was extracted with CH2Cl2 (3x), the combined organic phases
were dried (Na2SO4), filtered and concentrated under reduced pressure
to yield the title compound 21 (1.59 g, 1.95 mmol, 74 %) as a colorless oil
which was directly employed in the next reaction.
Missing signals could not be assigned with sufficient accuracy.
Synthesis of -unsaturated ester 20: To a solution of allyl alcohol 19
(4.20 g, 5.87 mmol, 1.0 eq.) in a mixture of t-BuOH (30 ml) and H2O
(30 ml) at 0 °C was added AD-mix-α (8.80 g, 1.5 g/mmol) and it was
stirred for 21 h at room temperature. The product was collected after
direct flash chromatography (PE:EA= 1:1) of the solution as a colorless
oil. The resulting triol was dissolved in THF (30 ml) and H2O (30 ml) and
NaIO4 (1.88 g, 8.80 mmol, 1.5 eq.) was added. The reaction mixture was
stirred for 2 h. The product was obtained after direct flash
chromatography (PE:EA= 1:1) of the solution as a colorless oil after
removal of the eluent. Then, a solution of the resulting aldehyde in
CH2Cl2 (60 ml) at 0 °C was added Wittig ylid 8 (5.31 g, 14.7 mmol,
2.5 eq.). The mixture was stirred for 72 h at room temperature. Silica gel
was added and the solvent was removed under reduced pressure. Flash
chromatography of the loaded silica gel (4:1) afforded the Horner-
Wadsworth-Emmons product (2.63 g, 3.29 mmol, 56 % over 3 steps) as
a colorless oil.
Synthesis of macrolactone 22: To the -unsaturated ester 21 (1.59 g,
1.95 mmol, 1.0 eq.) in THF/MeOH (10 ml each) was added an aqueous
1 M LiOH solution (19.5 ml, 19.5 mmol, 10 eq.). The reaction mixture was
stirred for 25 h at 40 °C and the reaction was terminated by addition of an
aqueous saturated solution of NH4Cl. The aqueous phase was extracted
with Et2O (3x), the combined organic phases were dried (Na2SO4),
filtered and concentrated under reduced pressure to afford the seco acid.
It was dissolved in THF (20 ml) and DIPEA (2.08 ml, 11.7 mmol, 6.0 eq.)
and 2,4,6-trichloro benzoylchloride (0.91 ml, 5.84 mmol, 3.0 eq.) were
added. After stirring for 2 h, the mixture was filtered through a pad of
CeliteTM and the solvent was removed under reduced pressure. The
residue was dissolved in toluene (1.25 l). The solution was divided into
three portions, each of which was added over a period of 5.5 h to a
solution of DMAP (each 793 mg, 6.50 mmol, 10 eq.) in toluene (each
70 ml volume) at 80 °C. After cooling to room temperature, the reaction
was terminated by addition of an aqueous saturated solution of NaHCO3.
The aqueous phase was extracted with Et2O (3x), the combined organic
phases were dried (MgSO4), filtered and concentrated under reduces
pressure. The residue was purified by flash chromatography (PE:EA=
4:1) to afford the macrolactone 22 (1.03 g, 1.34 mmol, 69 % over 2 steps,
d.r.= 4:1), as a yellowish oil.
[α]D22= -33.0° (c= 1.00, CH2Cl2); H-NMR (400 MHz, CDCl3) : 7.35-7.23
1
(7H, m, HAr), 6.87-6.85 (2H, m, HAr), 6.72 (1H, t, J= 6.7 Hz, H-3), 5.65
(1H, t, J= 6.8 Hz, H-9), 4.98 (1H, d, J= 11.3 Hz, HBn), 4.61 (2H, s, HSEM),
4.58 (1H, d, J= 11.3 Hz, HBn), 4.51 (1H, d, J= 11.7 Hz, HBn), 4.41 (1H, d,
J= 11.7 Hz, HBn), 4.27 (1H, d, J= 7.5 Hz, H-7), 4.15 (2H, q, J= 7.0 Hz,
HEt), 3.79 (3H, s, HArOMe), 3.79-3.70 (2H, m, H-11, HSEM), 3.64-3.61 (1H,
m, H-5), 3.54-3.40 (3H, m, H-6,12, HSEM), 2.47-2.33 (2H, m, H-4,10),
2.26-2.11 (2H, m, H-4,10), 1.77 (3H, s, H-14), 1.60 (3H, s, H-15), 1.26
(3H, t, J= 7.0 Hz, HEt), 1.11 (3H, d, J= 6.3 Hz, H-13), 0.92-0.86 (2H, m,
HSEM), 0.86 (9H, s, HTBS), 0.03 (3H, s, HTBS), -0.02 (3H, s, HTBS), 0.03 (9H,
s, HSEM) ppm; 13C-NMR (100 MHz, CDCl3) : 167.9 (q, C-1), 159.2 (q,
CAr), 138.5 (q, CAr), 138.1 (t, C-3), 132.4 (t, C-9), 131.2 (t, CAr), 129.7 (q,
C-2), 129.3 (q, CAr), 128.7 (q, C-8), 128.6 (t, CAr), 128.2 (t, CAr), 127.9 (t,
CAr), 113.8 (t, CAr), 92.2 (s, CSEM), 83.3 (t, C-7), 81.4 (t, C-6), 76.9 (t, C-
12), 75.4 (s, CBn), 74.0 (t, C-11), 70.8 (s, CBn), 70.1 (t, C-5), 65.5 (s,
CSEM), 60.6 (s, CEt), 55.4 (p, CArOMe), 34.2 (s, C-4), 30.6 (s, C-10), 26.0 (p,
CTBS), 18.2 (s, CSEM), 18.2 (q, CTBS), 14.4 (p, CEt), 14.2 (p, C-13), 12.8 (p,
C-14), 12.5 (p, C-15), -1.3 (p, CSEM), -4.4 (p, CTBS), -4.4 (p, CTBS) ppm;
HRMS (ESI): m/z calcd for C44H72O9Si2Na [M + Na]+: 823.4613, found
823.4614.
1
[α]D24= -13.9° (c= 0.64, CH2Cl2); H-NMR (400 MHz, CDCl3) : 7.37-7.22
(7H, m, HAr), 6.89-6.86 (2H, m, HAr), 5.54 (1H, dd, J= 15.5, 7.3 Hz, H-3),
5.38 (1H, ddd, J= 15.5, 8.0, 0.8 Hz, H-4), 5.22-5.19 (1H, m, H-9), 5.02
(1H, ddd, J= 11.9, 4.3, 2.9 Hz, H-11), 4.88 (1H, d, J= 10.8 Hz, HBn), 4.72
(1H, d, J= 10.8 Hz, HBn), 4.67 (1H, d, J= 6.8 Hz, HSEM), 4.65 (1H, d,
J= 6.8 Hz, HSEM), 4.60 (1H, d, J= 6.6 Hz, HSEM), 4.59 (1H, d, J= 11.5 Hz,
HBn), 4.58 (1H, d, J= 6.6 Hz, HSEM), 4.45 (1H, d, J= 11.5 Hz, HBn), 4.00
(1H, dd, J= 8.0, 8.0 Hz, H-5), 3.86 (1H, d, J= 9.8 Hz, H-7), 3.80 (3H, s,
HArOMe), 3.67-3.37 (6H, m, H-6,12, HSEM), 3.16 (1H, qd, J= 7.3, 6.6 Hz, H-
2), 2.79-2.70 (1H, m, H-10), 2.07-2.03 (1H, m, H-10), 1.62 (3H, s, H-15),
1.19 (3H, d, J= 6.6 Hz, H-14), 1.16 (3H, d, J= 6.4 Hz, H-13), 0.88-0.81
(4H, m, HSEM), -0.08 (18H, s, HSEM) ppm; 13C-NMR (100 MHz, CDCl3) :
174.5 (q, C-1), 159.4 (q, CAr), 139.5 (q, CAr), 134.7 (q, C-8), 134.0 (t, C-3),
130.6 (q, CAr), 129.5 (t, CAr), 128.5 (t, C-9), 128.4 (t, C-4), 128.3 (t, CAr),
127.7 (t, CAr), 127.3 (t, CAr), 113.9 (t, CAr), 92.9 (s, CSEM), 91.6 (s, CSEM),
82.7 (t, C-7), 82.5 (t, C-6), 79.5 (t, C-5), 75.7 (s, CBn), 74.7 (t, C-12), 73.6
(t, C-11), 70.9 (s, CBn), 65.4 (s, CSEM), 65.1 (s, CSEM), 55.4 (p, CArOMe),
42.9 (t, C-2), 29.1 (s, C-10), 18.1 (s, CSEM), 18.1 (s, CSEM), 16.2 (p, C-14),
15.6 (p, C-13), 12.6 (p, C-15),-1.3 (p, CSEM, p, CSEM) ppm; HRMS (ESI):
m/z calcd for C42H66O9Si2Na [M + Na]+: 793.4143; found 793.4144.
Synthesis of alcohol 21: To a solution of Horner-Wadsworth-Emmons
product 20 (2.63 g, 3.29 mmol, 1.0 eq.) in DMF (33 ml) were added
DIPEA (3.35 ml, 19.7 mmol, 6.0 eq.), DMAP (cat.) and SEMCl (1.17 ml,
6.58 mmol, 2.0 eq.). The reaction mixture was stirred for 18 h at 40 °C
and terminated by addition of H2O. After stirring for 10 min at room
temperature the aqueous phase was extracted with EtOAc (3x), the
combined organic phases were dried (Na2SO4), filtered and
concentrated under reduced pressure. The crude product was purified by
flash chromatography (PE:EA= 20:1) to afford the SEM-ether (2.45 g,
2.64 mmol, 80 %) as a colorless oil.
[α]D22= -41.9° (c= 0.87, CH2Cl2); H-NMR (400 MHz, CDCl3) : 7.35-7.22
1
(7H, m, HAr), 6.87-6.85 (2H, m, HAr), 6.72 (1H, tq, J= 7.1, 1.3 Hz, H-3),
5.57 (1H, t, J= 7.2 Hz, H-9), 4.78 (1H, d, J= 11.4 Hz, HBn), 4.70 (1H, d,
J= 7.0 Hz, HSEM), 4.67 (1H, d, J= 7.0 Hz, HSEM), 4.62 (1H, d, J= 11.4 Hz,
HBn), 4.61 (1H, d, J= 6.7 Hz, HSEM), 4.58 (1H, d, J= 6.7 Hz, HSEM), 4.50
(1H, d, J= 11.6 Hz, HBn), 4.41 (1H, d, J= 11.6 Hz, HBn), 4.20-4.14 (3H, m,
H-7, HEt), 3.80 (3H, s, HArOMe), 3.78-3.67 (4H, m, H-5,11, HSEM), 3.54-3.42
(4H, m, H-6,12, HSEM), 2.55 (2H, t, J= 6.6 Hz, H-4), 2.47-2.41 (1H, m, H-
10), 2.10-2.03 (1H, m, H-10), 1.80 (3H, d, J= 1.3 Hz, H-14), 1.55 (3H, s,
H-15), 1.28 (3H, t, J= 7.2 Hz, HEt), 1.10 (3H, d, J= 6.4 Hz, H-13), 0.92-
0.85 (4H, m, HSEM), 0.86 (9H, s, HTBS), 0.03 (3H, s, HTBS), -0.02 (12H, s,
HSEM, HTBS), -0.02 (9H, s, HSEM) ppm; 13C-NMR (100 MHz, CDCl3) :
Synthesis of alkene 24: To a solution of macrolactone 21 (285 mg,
0.37 mmol, 1.0 eq.) in a mixture composed of CH2Cl2 and a pH 7-buffer
(10:1, 4.0 ml) at 0 °C was slowly added DDQ (252 mg, 1.11 mmol,
3.0 eq.). After stirring for 2 h at 0 °C the alcohol was collected as a
colorless oil after flash chromatography (PE:EA= 1:1, traces of NEt3).
The resulting alcohol was dissolved in CH2Cl2 (4.0 ml) and the solution
was stirred after addition of NaHCO3 (621 mg, 7.40 mmol, 20 eq.) and
Dess-Martin periodinane (785 mg, 1.85 mmol, 5.0 eq.) for 90 min at room
temperature. The reaction was terminated by addition of an aqueous,
saturated solution of NaHCO3 followed by a Na2S2O3 solution. The
aqueous phase was extracted with Et2O (3x), the combined organic
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10.1002/ejoc.201701639
European Journal of Organic Chemistry
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[α]D24 = -29.2° (c= 0.12, CH2Cl2); 1H-NMR (400 MHz, CDCl3) : 5.68 (1H,
dd, J= 11.7, 2.9 Hz, H-11), 5.58 (1H, dd, J= 15.5, 7.6 Hz, H-3), 5.40-5.30
(4H, m, H-4,6,9,13), 4.64 (1H, d, J= 6.8 Hz, HSEM), 4.56 (1H, d, J= 1.7 Hz,
HSEM), 4.54 (1H, d, J= 1.7 Hz, HSEM), 4.46 (1H, d, J= 6.8 Hz, HSEM), 4.03
(1H, t, J= 8.7 Hz, H-5), 3.87 (1H, d, J= 10.2 Hz, H-7), 3.73-3.65 (2H, m,
HSEM), 3.46 (1H, dt, J= 7.4, 9.5 Hz, HSEM), 3.39 (1H, dt, J= 6.7, 9.9 Hz,
HSEM), 3.15 (1H, dq, J= 7.6, 7.1 Hz, H-2), 2.82 (1H, dt, J= 14.3, 11.7 Hz,
H-10), 2.22-2.14 (3H, m, H-2‘,3‘), 1.98-1.94 (1H, m, H-10), 1.72-1.69 (6H,
m, H-14,17), 1.68 (3H, s, H-16), 1.18 (3H, d, J= 7.1 Hz, H-15), 0.97 (6H,
d, J= 6.1 Hz, H-4‘), 0.94-0.83 (4H, m, HSEM), 0.03 (9H, s, HSEM), 0.02 (9H,
s, HSEM) ppm; 13C-NMR (100 MHz, CDCl3) : 173.7 (q, C-1), 172.5 (q,
C-1‘), 136.1 (t, C-3), 133.7 (q, C-8), 133.5 (q, C-12), 130.2 (t, C-9), 127.2
(t, C-4), 123.4 (t, C-13), 91.4 (s, CSEM), 90.3 (s, CSEM), 79.3 (t, C-7), 76.5
(t, C-5), 73.0 (t, C-6), 70.8 (t, C-11), 65.4 (s, CSEM), 65.1 (s, CSEM), 43.7 (s,
C-2‘), 43.2 (t, C-2), 31.9 (s, C-10), 25.5 (p, C-3‘), 22.6 (p, C-4‘), 22.6 (p,
C-4‘), 18.3 (C-17), 18.2 (s, CSEM), 18.2 (s, CSEM), 16.0 (p, C-15), 13.1 (p,
C-14), 12.4 (p, C-16), -1.1 (p, CSEM), -1.2 (p, CSEM) ppm; HRMS (ESI):
m/z calcd for C34H62O8Si2Na [M + Na]+: 677.3881, found 671.3876.
phases were dried (MgSO4), filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography (PE:EA=
10:1 to 4:1) to afford the ketone (131 mg, 0.20 mmol, 55 % over 2 steps)
as a mixture of diastereoisomers (6:1), as a colorless oil.
[α]D25= +21.3° (c= 0.30, CH2Cl2); 1H-NMR (400 MHz, CDCl3) : 7.37-7.21
(5H, m, HAr), 5.55 (1H, dd, J= 15.6, 7.9 Hz, H-3), 5.41 (1H, ddd, J= 15.6,
7.9, 0.7 Hz, H-4), 5.25-5.21 (1H, m, H-9), 5.15 (1H, dd, J= 12.0, 3.4 Hz,
H-11), 4.87 (1H, d, J= 11.1 Hz, HBn), 4.74 (1H, d, J= 11.1 Hz, HBn), 4.68
(1H, d, J= 6.8 Hz, HSEM), 4.66 (1H, d, J= 6.8 Hz, HSEM), 4.60 (2H, s, HSEM),
4.01 (1H, dd, J= 8.1, 7.9 Hz, H-5), 3.89 (1H, d, J= 9.8 Hz, H-7), 3.66-3.38
(4H, m, HSEM), 3.64 (1H, dd, J= 9.9, 7.9 Hz, H-6), 3.27 (1H, dq, J= 7.2,
7.0 Hz, H-2), 2.70-2.61 (1H, m, H-10), 2.52-2.47 (1H, m, H-10), 2.19 (3H,
s, H-13), 1.63 (3H, s, H-15), 1.23 (3H, d, J= 6.8 Hz, H-14), 0.87-0.81 (4H,
m, HSEM), -0.07 (9H, s, HSEM), -0.07 (9H, s, HSEM) ppm; 13C-NMR (125
MHz, CDCl3) : 205.3 (q, C-12), 173.8 (q, C-1), 139.3 (q, CAr), 136.4 (q,
C-8), 133.4 (t, C-3), 128.8 (t, C-4), 128.3 (t, CAr), 127.7 (t, CAr), 127.3 (t,
CAr), 126.6 (t, C-9), 92.9 (s, CSEM), 91.7 (s, CSEM), 82.7 (t, C-7), 82.7 (t, C-
6), 79.0 (t, C-5), 76.3 (t, C-11), 75.9 (s, CBn), 65.5 (s, CSEM), 65.2 (s,
CSEM), 42.6 (t, C-2), 29.8 (s, C-10), 26.4 (p, C-13), 18.1 (s, CSEM), 18.1 (s,
CSEM), 16.0 (p, C-14), 12.8 (p, C-15), -1.3 (p, CSEM), -1.3 (p, CSEM) ppm;
HRMS (ESI): m/z for C34H56O8Si2Na [M + Na]+: 671.3411; found
671.3410.
Thionylchloride (2.0 ml) was added to ZnCl2 (29.3 mg, 0.22 mmol) and
the mixture was heated under refluxing conditions for 2 h. After removal
of thionylchloride under reduced pressure, the residue was dissolved in
Et2O (2.0 ml) and EtSH (0.3 ml). This solution was cooled to 0 °C and
compound 24 in Et2O (2x 0.5 ml) (71.1 mg, 108 μmol, 1.0 eq.) was added
dropwise. The mixture was terminated after stirring for 35 min at 0 °C, by
addition of an aqueous, saturated NaHCO3 solution. The aqueous layer
was extracted with EtOAc, the combined organic phases were dried
(Na2SO4), filtered and evaporated under reduced pressure. The residue
was purified by flash chromatography (4:1 to 1:1) to give product 26
(35.6 mg, 89 μmol, 83 %) as a mixture of diastereoisomers (10:1), in form
of a colorless oil.
Ethyltriphenylphosphonium bromide (453 mg, 1.22 mmol, 6.0 eq.) was
dissolved in a mixture of 1,2-dimethoxyethane and HMPA (10:1, 2.0 ml)
and KHDMS (0.5 m solution in toluene, 2.03 ml, 5.0 eq.) was slowly
added. The dark red solution was stirred for 10 min at room temperature,
then it was cooled to -50 °C and stirring was continued for additional
5 min. The ketone described above (131 mg, 0.20 mmol, 1.0 eq.)
dissolved in 1,2-dimethoxyethane (0.4 ml) was slowly added to the
solution. The reaction was terminated after 20 min at room temperature
by addition of pH 7-buffer. The aqueous phase was extracted with Et2O
(3x), the combined organic phases were dried (MgSO4), filtered and
concentrated under reduced pressure. The residue was purified by flash
chromatography (PE:EA= 10:1 to 4:1) to afford the alkene 24 (93.6 mg,
0.14 mmol, 70 %) as a mixture of diastereoisomers (6:1) as a colorless
oil.
[α]D21 = -13.2° (c= 0.19, CH2Cl2); 1H-NMR (400 MHz, CDCl3) : 7.37-7.36
(2H, m, HAr), 7.30-7.21 (3H, m, HAr), 5.69 (1H, dd, J= 12.1, 2.9 Hz, H-11)
5.55 (1H, dd, J= 15.6, 7.8 Hz, H-3), 5.41 (1H, ddd, J= 15.6, 8.0, 0.7 Hz,
H-4), 5.39-5.36 (1H, m, H-13), 5.32-5.28 (1H, m, H-9), 4.89 (1H, d,
J= 10.9 Hz, HBn), 4.75 (1H, d, J= 10.9 Hz, HBn), 4.69 (1H, d, J= 6.7 Hz,
HSEM), 4.67 (1H, d, J= 6.7 Hz, HSEM), 4.63 (1H, d, J= 6.7 Hz, HSEM), 4.60
(1H, d, J= 6.7 Hz, HSEM), 4.01 (1H, dd, J= 8.0, 8.0 Hz, H-5), 3.90 (1H, d,
J= 9.9 Hz, H-7), 3.67-3.58 (2H, m, H-6, HSEM), 3.66 (1H, d, J= 9.9, 8.0 Hz,
H-6), 3.54-3.48 (1H, m, HSEM), 3.44-3.39 (1H, m, HSEM), 3.13 (1H, dq,
J=7.8, 6.6 Hz, H-2), 2.81 (1H, dt, J= 14.3, 11.5 Hz, H-10), 1.96-1.93 (1H,
m, H-10), 1.71 (3H, dq, J= 8.4, 1.4 Hz, H-14), 1.71 (3H, dq, J= 1.6,
1.4 Hz, H-17), 1.65 (3H, s, H-16), 1.17 (3H, d, J= 6.6 Hz, H-15),
0.87-0.82 (4H, m, HSEM), -0.07 (18H, s, HSEM) ppm; NOESY interactions
between H-11 and H-14 can only be explained by a (Z)-configuration of
the olefin double bond; 13C-NMR (100 MHz, CDCl3) : 173.9 (s, C-1),
139.5 (q, CAr), 134.8 (q, C-8), 133.9 (t, C-3), 133.7 (q, C-12), 128.7 (t,
C-9), 128.3 (t, CAr), 128.2 (C-4), 127.7 (t, CAr), 127.3 (t, CAr), 123.3 (t,
C-13), 93.0 (s, CSEM), 91.5 (s, CSEM), 82.9 (t, C-6), 82.9 (t, C-7), 79.3 (t,
C-5), 75.9 (s, CBn), 70.8 (t, C-11), 65.5 (s, CSEM), 65.1 (s, CSEM), 42.9 (t,
C-2), 31.9 (s, C-10), 18.3 (p, C-17), 18.2 (s, CSEM), 18.1 (s, CSEM), 16.1 (p,
C-15), 13.1 (p, C-14), 12.6 (p, C-16), -1.3 (p, CSEM), -1.3 (p, CSEM) ppm;
HRMS (ESI): m/z calcd for C36H60O7Si2Na [M + Na]+: 683.3775, found
683.3774.
[α]D24= -2.4° (c= 0.25, CH2Cl2); 1H-NMR (400 MHz, CDCl3) : 7.40-7.33
(5H, m, HAr), 5.72 (1H, dd, J= 12.0, 3.1 Hz, H-11), 5.61 (1H, dd, J= 15.6,
7.3 Hz, H-3), 5.50 (1H, dd, J= 15.6, 7.5 Hz, H-4), 5.40-5.33 (2H, m,
H-9,13), 4.90 (1H, d, J= 10.9 Hz, HBn), 4.85 (1H, d, J= 10.9 Hz, HBn), 4.04
(1H, dd, J= 8.6, 7.5 Hz, H-5), 3.86 (1H, d, J= 9.5 Hz, H-7), 3.49 (1H, dd,
J= 9.5, 8.6 Hz, H-6), 3.12 (1H, dq, J= 7.3, 6.9 Hz, H-2), 2.85-2.76 (1H,
ddd, J= 14.5, 12.0, 11.1, H-10), 2.80 (1H, br, HOH), 2.28 (1H, br, HOH),
2.01-1.91 (1H, m, H-10), 1.73-1.69 (9H, m, H-14,16,17), 1.18 (3H, d,
J= 6.9 Hz, H-15) ppm; 13C-NMR (100 MHz, CDCl3) : 173.8 (q, C-1),
137.6 (q, CAr), 136.4 (q, C-8), 133.9 (t, C-3), 133.4 (q, C-12), 129.9 (t,
C-4), 128.8 (t, CAr), 128.5 (t, CAr), 128.3 (t, C-9), 128.1 (t, CAr), 123.3 (t,
C-13), 84.0 (t, C-6), 78.1 (t, C-7), 76.1 (s, CBn), 75.3 (t, C-5), 70.8 (t,
C-11), 43.0 (t, C-2), 31.9 (s, C-10), 18.2 (p, C-17), 15.8 (p, C-15), 13.0 (p,
C-14), 12.0 (p, C-16) ppm; HRMS (ESI): m/z calcd for C24H32O5Na
[M + Na]+: 423.2147, found 423.2156.
Keywords: Antibiotics • Disciformycin • Natural product
synthesis • Polyketides
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Entry for the Table of Contents
FULL PAPER
Challenging alkenes: The synthesis
of the aglycon of disciformycin, a new
secondary metabolite from
M. Wolling, A. Kirschning*
Page No. – Page No.
Pyxidicoccus fallax, with high
Synthesis of the aglycon of the
antibiotic disciformycin
antibacterial potency is reported. The
stereocontrolled installation of the
olefinic double bonds at C2-C3/C3-C4
and C12-C13, respectively, as well the
orthogonal differentiation of the oxy
functionalities unexpectedly were
found to be key challenges of the
project.
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