Design, Synthesis and Biological Evaluation of Highly Potent Simplified Archazolids

Article abstract of DOI:10.1002/cmdc.202000154

The archazolids are potent antiproliferative compounds that have recently emerged as a novel class of promising anticancer agents. Their complex macrolide structures and scarce natural supply make the development of more readily available analogues highly important. Herein, we report the design, synthesis and biological evaluation of four simplified and partially saturated archazolid derivatives. We also reveal important structure-activity relationship data as well as insights into the pharmacophore of these complex polyketides.

Full text of DOI:10.1002/cmdc.202000154

Accepted Article
Title: Design, Synthesis and Biological Evaluation of Highly Potent
Simplified Archazolids
Authors: Dirk Menche, Solenne Rivière, Christin Vielmuth, Christiane
Ennenbach, Aliaa Abdelrahman, Carina Lemke, Michael
Gütschow, and Christa E. Müller
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.202000154
Link to VoR: https://doi.org/10.1002/cmdc.202000154
01/2020

10.1002/cmdc.202000154
ChemMedChem
FULL PAPER
Design, Synthesis and Biological Evaluation of Highly Potent
Simplified Archazolids
Solenne Rivière,[a] Christin Vielmuth,[b] Christiane Ennenbach,[b] Aliaa Abdelrahman,[b] Carina Lemke,[b] Michael
Gütschow,[b] Christa E. Müller,[b] and Dirk Menche*[a]
[a] Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Gerhard-Domagk-Str. 1, D-53121
Bonn, Germany
[b] Pharmazeutische & Medizinische Chemie, Pharmazeutisches Institut, Universität Bonn, An der Immenburg 4,
D-53121 Bonn, Germany
*e-mail: dirk.menche@uni-bonn.de
Abstract: The archazolids represent potent antiproliferative
compounds which have recently emerged as a novel class of
promising anticancer agents. Their complex macrolide structures
and scarce natural supply render the development of more readily
available analogs of high importance. Herein, we report the design,
synthesis and biological evaluation of four simplified and partially
saturated archazolid derivatives revealing important structure-
activity relationship data and insights into the pharmacophore of
these complex polyketides.
Furthermore,
elaborate
fragment
synthesis
of
2,3-
dihydroarchazolid was published by O’Neil et al.[18-20]
HO
MeO
HO
OH MeO
OH
O
O
R
O
O
Introduction
N
N
H
H
N
O
N
O
S
S
Extended polyene segments are key structural features of a broad
range of complex polyketide macrolide antibiotics. The archazolids
A (1) and B (2, Figure 1) are typical representatives which were
first reported in the 1990s by the Höfle group as a novel class of
highly potent antiproliferative agents.[1] A decade later, Sasse et al.
and Huss et al. reported V-ATPase as a molecular target inhibited
by archazolids,[2-3] and subsequently, the binding site has been
defined.[4-5] In 2011, archazolid F (3), was demonstrated to display
higher antiproliferative activity making it the most potent member
of this family.[6] In recent years, the archazolids have also been
shown to exhibit remarkable inhibitory effects of tumor growth,
and based on these studies they have emerged as a promising class
of novel anticancer drugs.[7–12] Furthermore, the G-protein-coupled
A3-adenosine receptor, the ATP-gated ion channel receptor P2X3,
and human leukocyte elastase have been discovered as further
molecular targets of archazolids, which may contribute to their
anticancer activities.[13]
The archazolids are 24-membered macrolactones carrying 8
stereocenters, 7 double bonds and a thiazole side chain. Since they
are only produced in scarce quantities by nature, there is a need for
a synthetic approach to provide sufficient amounts for studies on
their mode of action and their target selectivity. So far, one total
synthesis of archazolid A was published by us in 2007,[14] and two
total syntheses of archazolid B have been reported by the Trauner
group[15] and our group in 2007 and 2009.[16] More recently, in
2018, we have accomplished the total synthesis of archazolid F.[17]
O
O
1
2
3
: Archazolid F
: Archazolid A (R = Me)
: Archazolid B (R = H)
Figure 1. Potent members of the archazolid family.
Design of new simplified archazolid derivatives
Despite various total syntheses, only few SAR studies have been
published so far, relying on compounds obtained by chemical
derivatization of natural archazolid A[20] or on acyclic
fragments.[21-22] Initial archazolid derivatizations mainly occurred
on the two free hydroxyl groups as well as on the carbamate side
chain. In detail, modification of either hydroxyl function led to a
drop in potency,[20] while removal of the carbamate side chain had
only a minor effect on biological activity.[21] Hence, it was
proposed that the Northern part would be critical for binding, as
shown in Figure 2. This hypothesis was further supported by
docking calculations and molecular dynamics experiments.[22]
Accordingly, a novel synthetic route towards such macrolides was
developed and applied for the total synthesis of archazolid F.[17]
This strategy relied on disconnections of the C18-C19 bond, by an
aldol condensation and a ring closing metathesis along the C3-C4
bond. The synthetic methodology route was subsequently used for
the total synthesis of a first series of unnatural analogs.[13] The
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10.1002/cmdc.202000154
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substantially simplified analog 4 (Figure 2) was discovered which
still exhibited excellent antiproliferative activity towards several
mammalian cancer cell lines, even surpassing the activity of
natural archazolid F. These results confirmed our previous
hypothesis that the archazolids’ binding site is located in the
Northern, top part of the macrolactone.
HO
MeO
HO
MeO
OH
OH
(1)
(1)
O
O
O
O
Pharmacophore
5
6
(2)
(2)
HO
15
HO
MeO
HO
MeO
HO
MeO
MeO
OH
7
17
15
18
7
OH
OH
OH
19
4
6
3
5
4
20
O
3
(1)
21
(1)
Analog
Design
O
O
O
O
N
H
O
O
O
4
7
8
N
O
S
(2)
(2)
1'
archazolid F (3)
: areas of further
simplification
(this study)
O
(1) aldol condensation
(2) macrolactonization
R3O
O
OR3
Figure 2. Proposed pharmacophoric area of the archazolids leading to the
design of potent archazolog 4[6] and further simplifications addressed within
this study.
O
H
+
OR2
R1O
Based on the structure of analog 4, a further series of
derivatives was devised for this study, focusing on additional
simplifications of the Southern part. Modifications were gathered
around saturations of the three double bonds C3-C4, C5-C6 and
C20-C21 as well as the elimination of the C5 methyl group. Loss
of these double bonds would introduce more flexibility into the
macrocycle and also shorten the synthetic route. Removal of one
double bond could indicate its relevance for biological activity.
Based on this rationale, the four derivatives 5-8 (Figure 3) were
envisaged.
9
10
Figure 3. Targeted analogs of this work and their retrosynthetic analysis.
Results and Discussion
The synthesis of these derivatives utilizes
a methodology
developed during the total synthesis of archazolid F.[17] As shown
in Figure 3, the implementation of the analogs 5-8 was achieved by
the combination of two fragments, i.e. a main Northern subunit of
type 10 and various Southern segments of type 9. Following our
own precedence,[17] an aldol-condensation sequence was planned to
forge the 18,19-double bond, while a novel macrolactonization
approach was considered to close the ring.
Schemes 1, 2 and 3 show the synthesis of the main fragments
27, 28, 39 and 40 via robust and reliable routes involving aldol and
olefination reactions that have previously been established on
related systems.[21-22] As shown in Schemes 2 and 3, we first
focused on the preparation of the main fragments 27 and 28, which
were required for analogs 5 and 6. Their synthesis started with
ketone 12 which was obtained in 4 steps from commercially
available pentandiol 11 (Scheme 1). C2 homologation was initially
attempted with Wittig ylide 13a (Table 1) which was found to be
too unreactive to produce ester 14. On the contrary, HWE reagents
such as 13b and c were more appropriate. While rather low yields
and selectivities were obtained using NaH or KHMDS (Table 1),
BuLi was found to result in higher degrees of conversion but still
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10.1002/cmdc.202000154
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O
low selectivity. The presence of a bulkier R group on the
phosphonate was described to increase the selectivity.[23] However,
in our case with phosphonate 13b, the E/Z ratio was only slightly
improved from 2:1 to 3:1. The best conditions involved the use of
phosphonate 13c and the addition of DMPU in combination with
BuLi at room temperature with prolongated reaction times
overnight, resulting in a high yield (80%). At this stage, the
selectivity of 3:1 was accepted as the two isomers were easily
separated by column chromatography. Finally, the resulting enoate
14 was converted to aldehyde 15 in two steps. This route proved to
be scalable and employed inexpensive starting materials.
BzO
O
OH
O
16
BzO
OR
OTBDPS
3
3
(c-Hex)2BCl,
DMEA,
84% dr>20:1
15
17, R=TBDPS
1) TBS, lut.
2) LiBH4
3) NaIO4
78%
O
O
P
MeO
O
OCH2CF3
OCH2CF3
MeO
O
OTBS
OTBS
19
KHMDS, 18-c-6
dr
92%
> 20:1
3
3
20
OTBDPS
18
OTBDPS
1) TBDPSCl, NaH
2) (COCl)2, DMSO, NEt3
1) DIBAL-H
2) (COCl)2
DMSO
O
HO
OH
O
OTBDPS
3
3
3) MeMgBr
OTBS
11
12
4) (COCl)2, DMSO, NEt3
41% (4 steps)
PH3P
NEt3
or
19, KHMDS, 18-c-6
98% dr > 20:1
O
O
P
O
MeO
MeO
94% (2 steps)
OMe
OR
3
13a
21
OTBDPS
13b (R=tBu)
13c
See Table 1
O
(R=Me)
O
MeO
O
1) DIBAL-H
OTBDPS
MeO
OTBDPS
3
3
OTBS
2) (COCl)2, DMSO,
NEt3, 85% (2 steps)
O
OTBS
15
14
1) DIBAL-H
2) (COCl)2, DMSO, NEt3
95% (2 steps)
Scheme 1. Synthesis of aldehyde 15.
3
3
22
OTBDPS
23
OTBDPS
MeO
Table 1. Olefination reactions of ketone 12.
DMPU, BuLi
O
OTBS
1) DIBAL-H
2) (COCl)2
DMSO
Reactants
Conditions
Yielda
E/Z
O
P
O
b
/
/
/
MeO
MeO
12+13a
12+13a
DCM, reflux, 24 h
OMe
95% dr > 20:1
b
NEt3
Toluene, reflux, 24 h
/
13c
3
95%
(2 steps)
12+13c
12+13c
12+13b
12+13c
NaH, THF, r.t., 24 h
KHMDS, THF, r.t., 24 h
nBuLi, THF, r.t., o/n
16%
36%
52%
80%
2:1
2:1
3:1
3:1
24
OTBDPS
DMPU, nBuLi, THF, r.t., o/n
TBSO
O
O
aCombined yield, bNo conversion
O
OTBS
OTBS
26
As shown in Scheme 2, aldehyde 15 was then subjected to a
boron-mediated Paterson aldol reaction with the (S)-lactate-derived
ketone 16,[24] which proceeded with excellent yield and
diastereoselectivity (dr>20:1) towards β-hydroxyketone 17. After
TBS protection, LiBH4 reduction and cleavage of the diol with
NaIO4, aldehyde 18 was obtained. The Z/Z/E triene was then
generated using two consecutive Still-Gennari reactions and an
HWE olefination with excellent yield and selectivity. After
reduction and oxidation of ester 24, the required building block 27
was obtained by a syn-boron-mediated aldol reaction with diethyl
ketone 26[25] and TBS protection. For the synthesis of analog 5 (see
below), the TBDPS group had to be replaced by a TES group.
Accordingly, the primary hydroxyl group of 27 was selectively
liberated in presence of the two secondairy TBS groups using
TBAF/AcOH conditions[26] and reprotected as a TES ether towards
28.
1) (-)-Ipc2BOTf,
DIEA
2) TBSOTf, lut.
65% (2 steps)
3
3
27,
21 steps, 5%
OTBDPS
25
OTBDPS
TBSO
O
OTBS
1) TBAF, AcOH, 73%
2) TESOTf, lut., 90%
3
28,
23 steps, 4%
OTES
Scheme 2. Synthesis of main fragments 27 and 28.
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10.1002/cmdc.202000154
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1) TBDPSCl, NaH
2) (COCl)2,DMSO, NEt3
The more simplified main fragments 39 and 40 which lack the
C2-C3 and C4-C5 double bonds as well as the C5 methyl group as
required for archazologs 7 and 8 were prepared in an analogous
manner (Scheme 3). In detail, both the corresponding Paterson
aldol coupling with derived aldehyde 30, the two consecutive Still-
Gennari olefinations with aldehydes 32 and 34, as well as the
HWE-olefination with 36 and the final Ipc-mediated boron aldol
reaction of 38 proceeded with excellent selectivity, giving the
required chiral triene building block 39 in an effective and scalable
fashion. Likewise, all intermediate interconversions, mainly
involving adjustments of the required oxidation states of 31, 33, 35,
and 37 could also be carried out in reliable fashions and high yields.
The corresponding TES ether 40 was prepared again by the facile
deprotection/reprotection sequence.
With these Northern fragments in hand, efforts were directed
towards the pivotal aldol condensation sequence to access the fully
functionalized carbon skeleton of the desired analogs (Scheme 4).
The required aldehyde 41 was obtained from the corresponding
diol by mono-acetate protection and Swern oxidation, while 42 was
prepared from but-3-en-1-ol[27] by cross metathesis with acrolein
and TBS protection. Gratifyingly, a three step aldol-condensation
sequence could be implemented, which proceeded with excellent
selectivity as well as good yield. In particular, full degrees of
conversions of the starting ketones 27, 28, 39 and 40 in the initial
aldol coupling were obtained with lithium tetramethylpiperidine
(LiTMP). Indeed, it was found that LiTMP offers the double
benefit of full conversion and facile work-up in constrast to Ph2NLi
used in the total synthesis of archazolid F[17].. Acetate esterification
of the aldol products and a DBU-mediated elimination then
afforded the desired unsaturated ketones 43a/b-44a/b. Excellent E-
selectivity was obtained in the final elimination step by careful
temperature control in the initial aldol reaction. Indeed, an increase
of the temperature over -30 °C during the enolate formation
resulted in an approximately 3:1 E/Z mixture after the elimination
step to 43a and 43b.
OTBDPS
O
HO
OH
O
5
30
5
46%
29
(c-Hex)2BCl, DMEA BzO
54% dr>20:1
1) TBS, lut.
2) LiBH4
16
OH
O
O
OTBS
3) NaIO4
BzO
OTBDPS
5
5
72%
31
32
OTBDPS
1) DIBAL-H
2) (COCl)2, DMSO
NEt3
KHMDS, 18-c-6
MeO
O
O
O
OTBS
91%
(2 steps)
P(OCH2CF3)2
MeO
19
91% dr > 20:1
5
OTBDPS
33
MeO
O
O
OTBS
19
OTBS
, KHMDS, 18-c-6
5
5
87% dr > 20:1
35
OTBDPS
34
OTBDPS
1) DIBAL-H
2) (COCl)2
DMSO
O
P
O
MeO
MeO
OMe
O
OTBS
13c
NEt3
5
DMPU, BuLi
86% (2 steps)
36
OTBDPS
89% dr > 20:1
1) DIBAL-H
2) (COCl)2
DMSO
MeO
O
OTBS
90%
(2 steps)
NEt3
5
37
OTBDPS
O
1)
(-)-Ipc2BOTf
DIEA
26
O
OTBS
2) TBSOTf, lut.
63% (2 steps)
5
38
OTBDPS
TBSO
O
1) TBAF, AcOH, 93%
OTBS
2) TESOTf, lut.
90%
5
OTBDPS
39, 17 steps, 6%
OTBS
TBSO
O
5
OTES
40, 19 steps, 5%
Scheme 3. Synthesis of main fragments 39 and 40.
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10.1002/cmdc.202000154
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was less satisfying (40-50% yield). The macrocycles were then
closed using the Shiina macrolactonization method. Slow addition
of the seco acids to a highly diluted solution of MNBA and DMAP,
pretreated with 4 Å molecular sieves, led to the formation of the
macrolactones with high yield (77-86%), without side products and
the need of HPLC . Notably, these cyclizations represent the most
efficient methods for macrolide formation of the archazolids
reported so farThe reported ring closing methods for the
archazolids are so far a HWE macrocyclization (Arch A: 44%), a
Hoye RRCM (Arch B: 27%), a Heck coupling (Arch B: 60%:
diastereomeric mixture) and an RCM reaction (Arch F:
49%).Finally, global deprotection of the secondary TBS groups
successfully afforded the four targeted derivatives 5-8. Similar to
the C23 deprotection, removal of the secondary TBS groups was
difficult (25-40%) and required prolonged reaction times as well as
subsequent additions of HF.-pyr to realize full conversion.
TBSO
O
TBSO
O
OTBS
OTBS
43a
44a
AcO
OTBDPS
1) LiTMP
TBSO
OTES
O
TBSO
27 41
28 42
+
+
2) Ac2O, DMAP
3) DBU
67%
64%
42
TBSO
O
TBSO
O
OTBS
OTBS
TBSO
O
TBSO
O
39 : R1=TBDPS
40 : R1=TES
27 : R1=TBDPS
OR1
1
OTBS
: R =TES
OR1
OTBS
28
6
6
1) LiTMP
2) Ac2O, DMAP
3) DBU
5
5
O
AcO
39 + 41
61%
40 + 42
58%
41
43-48a:
43-48b:
23
1
23
1
AcO
OTBDPS
6
TBSO
OTES
5
5
6
TBSO
O
TBSO
O
43a, 43b
44a, 44b
62% (46a from 44a)
72% (46b from 44b)
OTBS
OTBS
60% (45a from 43a)
57% (45b from 43b)
1) NaBH4
2) Me3OBF4
TBSO
MeO
TBSO
OTBS MeO
OTBS
6
6
43b
44b
TBSO
AcO
OTBDPS
OTES
5
5
23
1
23
1
Scheme 4. Coupling of the main fragments by an aldol-condensation
sequence.
AcO
OTBDPS
TBSO
OTES
45a, 45b
46a, 46b
88% (47a from 45a)
82% (48a from 46a)
K2CO3
TBAF, AcOH
47b
45b
48b
46b
from )
92% (
TBSO
MeO
from
)
94% (
As shown in Scheme 5, for completion of the synthesis,
ketones 43a/b and 44a/b were selectively reduced by means of
NaBH4. This procedure was originally described by the Trauner
group[15] in their total synthesis of archazolid B and had
subsequently also been used by us in the preparations of archazolid
F[17] and related analogs.[13] Gratifyingly, this protocol again
proceeded with good selectivity (dr 10:1) and yields to give, after
methylation with Meerwein salt, the corresponding ethers 47a/b
and 48a/b. The protecting group at the C1 hydroxyl was then
selectively removed under TBAF/AcOH conditions for the TBDPS
groups of 47a and 47b and K2CO3 for the TES groups of 48a and
48b. The primary alcohols were then oxidized to the carboxylic
acids in two steps applying the Parikh-Doering and Pinnick
procedures. The C23 hydroxyl protecting groups were selectively
removed with K2CO3 for the acetate groups (left part of Scheme 5)
and HF.-pyr for the primary TBS groups (right part) affording the
corresponding alcohols 47a/b and 48a/b. Deprotection at the C1
hydroxyl group as well as the two oxidations to the carboxylic
acids proceeded smoothly while deprotection of the C23 positions
TBSO
OTBS MeO
OTBS
6
6
5
5
1
1
23
23
AcO
OH
47a, 47b
TBSO
OH
48a, 48b
1) DMSO, SO3-pyr, NEt3
2) NaClO2, KH2PO4; K2CO3
3) HF.pyr
3) K2CO3
6%
(from
48a
7%
(from
8%
(from
48b)
11%
(from
47b)
1) MNBA, DMAP
2) HF-pyr
)
1) MNBA, DMAP
2) HF-pyr
47a
)
5
7
6
8
Scheme 5. Completion of the synthesis of analogs 5-8 by macrolactonization.
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Importantly, the choice of protecting groups on the two
primary alcohols at C1 and C23 was found to be crucial for the
successful synthesis of 5 and 7. For these two analogs, carrying the
C20-C21 double bond, the C23 hydroxyl group, prone to
elimination during the aldol-condensation sequence, had to be
equipped with a carefully chosen protecting group. The C1
protecting group had to be orthogonally deprotectable with respect
to C7, C15 and C23, whereas C23 itself had to be deprotected
without affecting the protection of C7 and C15.
As shown in Table 2, several strategies were evaluated.
Primary attempts with a benzoic ester functionality (entry 1) as
protecting group led to a formation of the C18-C23 triene during
the DBU-mediated elimination. The aldol condensation sequence
with PMB as R2 (entry 2) led to the desired diene with good yield.
Deprotection occurred using DDQ however only low yields were
obtained and oxidation at C17 was also observed. Attempts to
reduce this group at a later stage of the synthesis were also carried
out but could only be realized in low yield. The other variable on
the molecule was the protecting group at C1. Removal of the
TBDPS group to directly introduce the carbonate functionality
(entry 3) led to degradation of the ketone during the aldol reaction.
Similar degradation was observed with an acetate group as R1
(entry 4). The best combination was found to be a TES group as R1
and a TBS group as R2 (entry 5). Indeed, the TBS group suppressed
further elimination along the 22,23-bond during the aldol-
condensation sequence and the TES group was selectively cleaved
in the presence of three TBS groups with high yield. After
oxidation at C1, the primary R2-TBS ether could be successfully
removed without affecting the two secondary TBS groups using a
diluted solution of HF.-pyr.
C-5 methyl group are well tolerated with almost no change in
activities in these assays. These data confirm and refine our
pharmacophore model and demonstrate that the overall structure
may be further simplified without loss of biological activity.
In contrast, the modifications addressed within this study did
influence the affinity to the A3-adenosine receptor. In detail, the
(5,6)-olefin in combination with the appending methyl group was
crucial for receptor interaction, as analogs 7 and 8 lacking this
functional pattern were inactive. In contrast, new analogs 5 and 6,
retaining these structural features were still potent and even
exhibited slightly better affinity as compared to archazolid F.
These results are in agreement with an earlier study[6]
demonstrating that also slight variations in the C2-C3 region had a
profound biological effect on this target. In summary, these results
suggest that the Eastern part of the archazolids is involved in A3-
adenosine receptor binding. Regarding human leukocyte elastase
(HLE), the new archazologs retained moderate inhibitory potency
at this enzyme, but were weaker than archazolid F.
Table 3. Biological data of novel analogs 5 - 8 in comparison to archazolid F
(3) and archazolog 4.
3
4
5
6
7
8
Growth inhibition of
1321N1 astrocytoma
cells
4.51 ±
0.51
0.757 ± 12.2 ±
19.6 ±
4.0
9.65 ±
1.48
17.4 ±
1.30
2.9
0.121
IC50 ± SEM (nM)
Human P2X3
inhibition IC50
SEM (µM)
0.438 ±
144
1.31 ±
0.19
2.46 ±
0.46
1.19 ±
0.18
1.02 ±
0.24
1.87 ±
0.03
±
Affinity for the human 859 ± 75
adenosine
690 ±39 539 ± 44 436 ±
111
> 1000 > 1000
A3 receptor
Ki ± SEM (nM)
HLE inhibition
Ki ± SEM (µM)
0.830 ±
0.134
5.85 ±
0.16
5.01 ±
0.79
13.3 ±
1.5
5.78 ±
0.65
8.18 ±
1.01
Table 2. Crucial protecting groups choice for the precursors to 5 and 7.
TBSO
15
MeO
OTBS
7
5
17
20
Conclusions
6
21
In conclusion, we have reported the design and synthesis of four
novel partially saturated archazolid derivatives and their biological
evaluation. The design of these derivatives is based on previous
SAR studies and pharmacophore analysis suggesting the
archazolids’ binding site to be located on the top part of the
macrolactone. The modifications were focused on the C3-C4, C5-
C6 and C20-C21 double bonds as well as the C5 methyl group. The
synthesis relied on a scalable and convenient approach to the
Northern part utilizing an olefination and aldol methodology as
well as a coupling with various Southern fragments using a highly
stereoselective aldol condensation sequence. We report for the first
time the implementation of a macrolactonization strategy to close
the archazolid 24-membered ring without formation of any side
product such as dimers. Further insights into the archazolids’
pharmacophore were obtained after biological assessment of these
new analogs. Indeed, derivatives 5-8 retained potent
antiproliferative activities in the nanomolar range, similar to the
23
1
R2O
OR1
Entry
Protecting groups
Aldol condensation
elimination
61%
R1/R2 deprotection
R1=TBDPS, R2=Bz
/
1
2
3
4
5
R1=TBDPS, R2=PMB
R1=CO2Me, R2=TBS
R1=Ac, R2=TBS
79%/31%
/
degradation
degradation
60%
/
R1=TES, R2=TBS
94%/42%
All four new analogs 5-8 retained antiproliferative activities
against 1321N1 astrocytoma cells in the low nanomolar range
similar to the parent natural product archazolid F (Table 3).
However, they did not reach the subnanomolar potency of
archazolog 4. Macrolactones 5-8 also showed similar human P2X3
receptor inhibition as compared to 4. Our results demonstrate that
removal of the (3,4), (5,6) and (20,21) double bonds as well as the
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10.1002/cmdc.202000154
ChemMedChem
FULL PAPER
parent natural product archazolid F but weaker than archazolog 4.
The modifications of these analogs were well tolerated by the
P2X3 receptor and HLE as demonstrated in inhibition assays
suggesting that further simplifications might be allowed. However,
the results of the A3-adenosine receptor binding assays showed that
modifications in the C3-C6 area led to a drop in potency suggesting
the crucial role of this pattern for receptor interaction. The
developed synthetic approach allowed easy access to simplified
archazolid derivatives and could be used to further develop this
promising novel class of potent anticancer drugs.
of the organic phase, the aqueous phase was extracted with DCM.
The combined organic layers were dried over MgSO4, evaporated
in vacuo and purified by column chromatography.
Ketone 17: Method A with chlorodicylohexylborane (10.1 mL,
10.1 mmol), DMEA (1.45 mL, 13.4 mmol) in Et2O (55 mL),
ketone 16 (1.43 g, 6.69 mmol) in Et2O (50 mL) and aldehyde 15
(2.86 g, 7.35 mmol) in Et2O (4 mL). Work-up MeOH (10 mL),
buffer (pH 7, 10 mL), H2O2 (5 mL) and DCM (3×50 mL).
Chromatography (SiO2, CH/EtOAc, 10:1 to 5:1) gave 17 (3.23g,
5.50 mmol, 82%, dr>20:1). Rf = 0.31 (SiO2, CH/EtOAc, 5:1);
1
ꢀꢁꢂꢄꢃꢅ= + 18.0° (c = 0.44, CHCl3); H-NMR (500 MHz, CDCl3): δ
[ppm] = 8.13 – 8.10 (m, 2H), 7.70 – 7.67 (m, 4H), 7.60 (ddt, J =
7.9, 7.0, 1.3 Hz, 1H), 7.49 – 7.37 (m, 8H), 5.48 (qd, J = 7.0, 1.6 Hz,
1H), 5.13 (dq, J = 9.3, 1.3 Hz, 1H), 4.60 (td, J = 9.0, 4.3 Hz, 1H),
3.68 (t, J = 5.9 Hz, 2H), 2.89 (dq, J = 8.6, 7.1 Hz, 1H), 2.02 (d, J =
4.3 Hz, 2H), 1.70 (d, J = 1.3 Hz, 3H), 1.59 (dd, J = 7.0, 1.2 Hz,
3H), 1.56 – 1.48 (m, 4H), 1.15 (d, J = 7.1 Hz, 3H), 1.07 (d, J = 1.5
Hz, 9H); 13C-NMR (176 MHz, CDCl3): δ [ppm] = 211.3, 165.9,
140.9, 135.6, 134.1, 133.6, 129.8, 129.6, 128.5, 127.6, 125.1, 75.0,
70.4, 63.7, 60.4, 48.9, 39.3, 32.1, 26.9, 23.9, 21.1, 19.2, 16.8, 15.6,
14.2; HRMS (ESI+) calculated for C36H46O5SiNa+ [M+Na]+:
609.3007 found: 609.3007.
Experimental Section
General procedures. All reagents were purchased from
commercial suppliers (Sigma-Aldrich, TCI, Acros, Alfa Aesar) in
the highest purity grade available and used without further
purification. Anhydrous solvents (DCM, Et2O, THF, and toluene)
were obtained from a solvent drying system MB SPS800 (MBrain)
and stored over molecular sieves (4 Å). The reactions in which dry
solvents were used were performed under an argon atmosphere in
flame-dried glassware, which had been flushed with argon unless
stated otherwise. The reagents were handled using standard
Schlenk techniques.
Ketone 31: with chlorodicylohexylborane (8.70 mL, 8.70
mmol), DMEA (1.26 mL, 11.6 mmol) in Et2O (45 mL), ketone 16
(1.20 g, 5.82 mmol) in Et2O (45 mL) and aldehyde 30 (2.63 g, 7.00
mmol) in Et2O (3.5 mL). Work-up MeOH (10 mL), buffer (pH 7,
10 mL), H2O2 (5 mL) and DCM (3×50 mL). Chromatography
(SiO2, CH/EtOAc, 10:1 to 5:1) gave 31 (1.80 g, 3.12 mmol, 54%,
dr>20:1). Rf = 0.34 (SiO2, CH/EtOAc, 4:1); ꢀꢁꢂꢄꢃꢅ = + 25.2° (c =
0.31, CHCl3); 1H-NMR (700 MHz, CDCl3): δ [ppm] = 8.13 – 8.08
(m, 2H), 7.71 – 7.66 (m, 4H), 7.63 – 7.59 (m, 1H), 7.50 – 7.38 (m,
8H), 5.46 (q, J = 7.1 Hz, 1H), 3.77 (ddd, J = 9.7, 7.0, 2.5 Hz, 1H),
3.67 (t, J = 6.5 Hz, 2H), 2.88 (p, J = 7.2 Hz, 1H), 1.59 (d, J = 7.1
Hz, 3H), 1.57-1.55 (m, 2H), 1.52 (tq, J = 7.9, 2.8, 2.3 Hz, 2H), 1.42
– 1.31 (m, 6H), 1.29 (d, J = 7.2 Hz, 3H), 1.06 (s, 9H); 13C-NMR
(176 MHz, CDCl3): δ [ppm] = 212.1, 165.9, 135.6, 134.2, 133.4,
129.8, 129.5, 129.4, 128.5, 63.9, 60.4, 48.2, 34.5, 32.5, 29.3, 26.9,
25.8, 25.5, 15.9, 14.6; HRMS (ESI+) calculated for
C35H46O5SiNa+ [M+Na]+: 597.3307, found: 597.3007.
Thin-layer chromatography monitoring was performed with
silica gel 60 F254 precoated polyester sheets (0.2 mm silica gel,
Macherey-Nagel) and visualized using UV light and staining with a
solution of CAM (1.0 g Ce(SO4)2, 2.5 g (NH4)6Mo7O24, 8 mL conc.
H2SO4 in 100 mL H2O) and subsequent heating.
Semipreparative and analytical HPLC analyses were performed
on Knauer Wissenschaftliche Gerate GmbH systems. The solvents
for HPLC were purchased in HPLC grade. The products were
detected by their UV absorption at 230 nm or 254 nm, respectively.
All NMR spectra were recorded on Bruker spectrometers with
operating frequencies of 125, 150, 500, 600, and 700 MHz in
deuterated solvents obtained from Deutero. Spectra were measured
at room temperature unless stated otherwise, and chemical shifts
are reported in parts per million relative to (Me)4Si and were
calibrated to the residual signal of undeuterated solvents.[29] For
full assignment of 1H and 13C signals of the final products, see the
supporting information section. Optical rotations were measured
with a PerkinElmer 341 polarimeter in 10 mm cuvette and are
uncorrected. High-resolution mass spectroscopy (HRMS) spectra
General method B: TBS protection, LiBH4 reduction and
glycol cleavage. To a stirred solution of β-hydroxyketone (1.00 eq)
in DCM at -78 °C was added 2,6-lutidine (2.00 eq) and TBSOTf
(1.50 eq). The reaction was stirred for 1.5 h and quenched with a
saturated solution of NaHCO3 at 0 °C. After separation of the
organic layer, the aqueous layer was extracted with DCM. The
organic layers were combined, dried over MgSO4 and evaporated
in vacuo. The crude product was purified by column
chromatography.
To a solution of protected alcohol (1.00 eq) in THF at -78 °C
was added LiBH4 (15.0 eq) in one portion. After stirring 2 h at -
78 °C, the mixture was stirred 3 days at room temperature. At 0 °C,
water was added followed by careful addition of a saturated
were recorded on
spectrometer
a Thermo LTQ Orbitrab Velos mass
.
General method A: Paterson aldol reaction. To a solution of
chlorodicyclohexylborane (1.00 eq) in Et2O at -78 °C, was added
DMEA (2.0 eq) followed by ketone 16 (1.00 eq) in Et2O. The
reaction was stirred for 2 h at 0 °C then cooled down again at -
78 °C. The aldehyde (1.10 eq) in Et2O was added. The mixture was
stirred for 1 h at -78 °C and then stored at -20 °C overnight. The
reaction was quenched at 0 °C with MeOH, pH 7 buffer and H2O2
(2:2:1) and stirred for 1.5 h at room temperature. After separation
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10.1002/cmdc.202000154
ChemMedChem
FULL PAPER
solution of NH4Cl. The mixture was poured to a mixture of water
and Et2O (1:1). After separation of the organic layer, the aqueous
layer was extracted with Et2O. The organic layers were combined,
dried MgSO4 and evaporated in vacuo. The residue was purified by
colum chromatography.
(125 MHz, CDCl3): δ [ppm] = 205.2, 135.6, 134.2, 129.5, 127.6,
73.5, 63.9, 51.1, 34.8, 32.5, 29.5, 26.9, 25.8, 24.8, 19.2, 18.1, 10.5,
-4.2, -4.7; HRMS (ESI+) calculated for C34H56O3Si2K+ [M+K]+:
579.3087, found: 579.3090.
To a solution of diol (1.00 eq) in dioxane and water (2:1) at
0 °C was added NaIO4 (2.50 eq) portionwise. The reaction mixture
was vigourously stirred overnight. The reaction was diluted with
DCM and quenched with water. After separation of the organic
layer, the aqueous layer was extracted with DCM. The organic
layers were combined, dried over MgSO4 and evaporated in vacuo.
The residue was purified by column chromatography.
General method C: Still-Gennari olefination. To a solution
of 18-c-6 (2.30 eq,) and phosphonate 19 (1.40 eq) in THF at -78 °C
was added KHMDS (1.30 eq) over 10 min. The reaction was
stirred for 30 min then the aldehyde (1.00 eq) in THF was added
dropwise and the reaction was stirred for another 2 h at -78 °C. The
reaction was quenched with a saturated solution of NaHCO3 at
0 °C. After separation of the organic layer, the aqueous layer was
extracted with DCM. The organic layers were combined, dried
over MgSO4, evaporated in vacuo and purified by column
chromatography.
Aldehyde 18: Method B with β-hydroxyketone (3.23g, 5.50
mmol), 2,6-lutidine (1.26 mL,10.9 mmol), TBSOTf (1.88 mL, 8.17
mmol) in DCM (120 mL). Work-up NaHCO3 (80 mL) and DCM
(80 mL). Chromatography (SiO2, CH/EtOAc, 10:1) gave TBS
protected alcohol (3.64 g, 94%). Protected alcohol (3.64g, 5.19
mmol), LiBH4 (1.68 g, 77.1 mmol) in THF (120 mL). Work-up
H2O (40 mL), NH4Cl (5 mL) and Et2O/H2O (1:1, 100 mL).
Chromatography (SiO2, CH/EtOAc, 4:1) gave the diol (3.01 g,
98%, dr=4:1). Diol (3.01 g, 5.09 mmol), NaIO4 (2.68 g, 12.5
mmol) in dioxane /water (120 mL). Work-up water (50 mL) and
DCM (3×100 mL). Chromatography (SiO2, CH/EtOAc, 9:1) gave
18 (2.33 g 4.22 mmol, 83%). Rf = 0.65 (SiO2, CH/EtOAc,
5:1); ꢀꢁꢂꢄꢃꢅ = - 17.4° (c = 0.39, CHCl3); 1H-NMR (700 MHz,
CD2Cl2): δ [ppm] = δ 9.73 (d, J = 2.9 Hz, 1H), 7.68 – 7.65 (m, 4H),
7.44 – 7.41 (m, 2H), 7.38 (ddt, J = 8.1, 6.7, 1.1 Hz, 4H), 5.16 (dp, J
= 9.1, 1.3 Hz, 1H), 4.58 – 4.52 (m, 1H), 3.68 (t, J = 6.0 Hz, 2H),
2.42 – 2.35 (m, 1H), 2.06 – 1.97 (m, 2H), 1.65 (d, J = 1.4 Hz, 3H),
1.60 – 1.50 (m, 7H), 1.04 (s, 9H), 0.94 (d, J = 7.0 Hz, 3H), 0.85 (d,
J = 2.7 Hz, 9H), -0.02 (s, 3H), -0.04 (s, 3H); 13C-NMR (176 MHz,
Ester 20: Method C with 18-c-6 (2.52 g, 9.55 mmol), 19 (1.93
g, 5.82 mmol), KHMDS (10.8 mL, 8.40 mmol) in THF (100 mL),
aldehyde 18 (2.30 g, 4.15 mmol) in THF (4 mL). Work-up
NaHCO3 (100 mL) and DCM (240 mL). Chromatography (SiO2,
CH/EtOAc, 9:1) gave 20 (2.38 g, 3.82 mmol, 92%, dr>20:1). Rf =
1
0.56 (SiO2, CH/EtOAc, 10:1); = + 9.1° (c = 0.32, CHCl3); H-
NMR (500 MHz, CDCl3): δ [ppm] = 7.75 – 7.66 (m, 4H), 7.49 –
7.38 (m, 6H), 5.84 (dq, J = 10.1, 1.4 Hz, 1H), 5.09 (dq, J = 9.1, 1.3
Hz, 1H), 4.21 (dd, J = 9.0, 5.9 Hz, 1H), 3.72 (s, 3H), 3.68 (t, J =
6.0 Hz, 2H), 3.26 – 3.15 (m, 1H), 1.98 (t, J = 7.3 Hz, 2H), 1.90 (d,
J = 1.4 Hz, 3H), 1.60 (d, J = 1.3 Hz, 3H), 1.58 – 1.48 (m, 4H), 1.07
(s, 9H), 0.96 (dd, J = 6.9, 2.6 Hz, 3H), 0.88 (s, 9H), -0.02 (s, 3H), -
0.04 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ [ppm] = 146.0, 135.8,
135.6, 134.1, 129.5, 127.6, 127.3, 126.4, 73.0, 63.7, 51.1, 40.8,
39.3, 32.2, 26.9, 25.8, 24.0, 21.0, 19.2, 18.1, 16.6, 16.1, -4.1, -4.9;
HRMS (ESI+) calculated for C37H58O4Si2Na+ [M+Na]+: 645.3766,
CD2Cl2): δ [ppm] = 204.7, 137.8, 135.5, 134.1, 129.5, 127.6, 126.4, found: 645.3766.
71.2, 63.7, 53.5, 39.2, 32.2, 26.6, 25.5, 23.9, 19.1, 17.9, 16.5, 10.3,
-4.2, -5.4; HRMS (ESI+) calculated for C33H52O4Si2Na+ [M+Na]+:
575.3347, found: 575.3347.
Ester 22: Method C with 18-c-6 (2.13 g, 8.14 mmol), 19 (1.64
g, 4.96 mmol), KHMDS (9.2 mL, 4.6 mmol) in THF (100 mL),
aldehyde 21 (2.12 g, 3.54 mmol) in THF (4 mL). Work-up
NaHCO3 (100 mL) and DCM (240 mL). Chromatography (SiO2,
CH/EtOAc, 9:1) gave 22 (2.17 g, 3.27 mmol, 93 %, dr>20:1). Rf =
0.56 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 28.1° (c = 0.31, CHCl3);
1H-NMR (500 MHz, CDCl3): δ [ppm] = 7.68 – 7.66 (m, 4H), 7.42
– 7.36 (m, 6H), 6.41 – 6.38 (m, 1H), 5.09 (ddt, J = 11.8, 9.0, 1.4
Hz, 2H), 4.10 (dd, J = 9.0, 5.9 Hz, 1H), 3.70 (s, 3H), 3.66 (t, J =
6.1 Hz, 2H), 2.40 (dq, J = 10.0, 6.5 Hz, 1H), 1.97 – 1.93 (m, 5H),
1.77 – 1.74 (m, 3H), 1.58 (d, J = 1.3 Hz, 3H), 1.55 – 1.43 (m, 4H),
1.04 (d, J = 1.5 Hz, 9H), 0.86 – 0.83 (m, 13H), -0.01 (s, 3H), -0.04
(s, 3H); 13C-NMR (125 MHz, CDCl3): δ [ppm] = 169.8, 135.6,
134.1, 133.5, 131.4, 129.5, 127.9, 127.6, 127.3, 73.1, 63.7, 51.4,
40.6, 39.3, 62.2, 26.9, 25.8, 24.0, 22.2, 21.2, 19.2, 18.2, 16.6, 16.0,
-4.3, -4.9; HRMS (ESI+) calculated for C40H62O4Si2Na+ [M+Na]+:
686.4079 found: 686.4097.
Aldehyde 32: Method B with β-hydroxyketone (888 mg, 1.54
mmol), 2,6-lutidine (0.36 mL,3.08 mmol), TBSOTf (0.53 mL, 2.31
mmol) in DCM (50 mL). Work-up NaHCO3 (25 mL), DCM (25
mL). Chromatography (SiO2, CH/EtOAc, 10:1) gave TBS
protected alcohol (996 mg, 85%). Protected alcohol (885 mg, 1.33
mmol), LiBH4 (340 mg, 15.7 mmol) in THF (40 mL). Work-up
H2O (15 mL), NH4Cl (2 mL) and Et2O/H2O (1:1, 40 mL).
Chromatography (SiO2, CH/EtOAc, 4:1) gave the diol (750 mg,
quant., dr=4:1). Diol (750 mg, 1.33 mmol), NaIO4 (683 gm, 3.20
mmol) in dioxane /water (30 mL). Work-up water (20 mL) and
DCM (3×20 mL). Chromatography (SiO2, CH/EtOAc, 9:1) gave
32 (583 mg, 1.07 mmol, 85%). Rf = 0.66 (SiO2, CH/EtOAc, 5:1);
1
ꢀꢁꢂꢄꢃꢅ= -22.6° (c = 0.35, CHCl3); H-NMR (500 MHz, CDCl3): δ
[ppm] = 9.74 (d, J = 2.3 Hz, 1H), 7.70 – 7.63 (m, 4H), 7.47 – 7.33
(m, 6H), 3.91 (q, J = 5.5 Hz, 1H), 3.65 (t, J = 6.4 Hz, 2H), 2.49
(ddd, J = 7.1, 4.9, 2.3 Hz, 1H), 1.59 – 1.50 (m, 6H), 1.44 (ddd, J =
15.4, 9.5, 4.2 Hz, 1H), 1.38 – 1.23 (m, 7H), 1.07 (d, J = 7.0 Hz,
3H), 1.04 (s, 9H), 0.88 (s, 9H), 0.06 (d, J = 4.0 Hz, 6H); 13C-NMR
Ester 33: Method C with 18-c-6 (674 mg, 2.55 mmol), 19 (516
mg, 1.55 mmol), KHMDS (2.9 mL, 1.44 mmol) in THF (20 mL),
aldehyde 32 (594 mg, 1.11 mmol) in THF (2 mL). Work-up
NaHCO3 (30 mL) and DCM (100 mL). Chromatography (SiO2,
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10.1002/cmdc.202000154
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FULL PAPER
CH/EtOAc, 9:1) gave 22 (610 mg, 1.00 mmol, 91%, dr>20:1). Rf =
0.66 (SiO2, CH/EtOAc, 5:1); ꢀꢆꢂꢈꢇꢉ = + 5.2° (c = 0.33, CHCl3); 1H-
NMR (700 MHz, CDCl3): δ [ppm] = 7.69 – 7.68 (m, 4H), 7.45 –
7.42 (m, 2H), 7.41 – 7.38 (m, 4H), 5.94 (dq, J = 10.1, 1.4 Hz, 1H),
3.73 (s, 3H), 3.66 (t, J = 6.5 Hz, 2H), 3.55 (td, J = 6.1, 3.6 Hz, 1H),
3.30 (dqd, J = 10.4, 6.8, 3.5 Hz, 1H), 1.93 (d, J = 1.4 Hz, 3H), 1.40
– 1.18 (m, 10H), 1.06 (s, 9H), 1.00 (d, J = 6.8 Hz, 3H), 0.92 (s,
9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C-NMR (176 MHz, CDCl3): δ
[ppm] = 168.5, 144.8, 135.6, 134.2, 129.5, 127.6, 126.6, 75.7, 64.0,
51.2, 38.0, 35.1, 32.6, 29.6, 26.9, 26.0, 25.8, 25.5, 21.1, 19.2, 18.2,
17.0, -4.2, -4.5; HRMS (ESI+) calculated for C36H58O4Si2Na+
[M+Na]+: 633.3766, found : 633.3763.
Ester 35: Method C with 18-c-6 (536 mg, 2.05 mmol), 19 (416
mg, 1.25 mmol), KHMDS (2.3 mL, 1.16 mmol) in THF (20 mL),
aldehyde 34 (520 mg, 0.96 mmol) in THF (2 mL). Work-up
NaHCO3 (30 mL) and DCM (100 mL). Chromatography (SiO2,
CH/EtOAc, 9:1) gave 22 (510 mg, .078 mmol, 87%, dr>20:1). Rf =
0.55 (SiO2, CH/EtOAc, 20:1); ꢀꢁꢂꢄꢃꢅ = + 0.9 ° (c = 0.22, CHCl3);
1H-NMR (700 MHz, CDCl3): δ [ppm] = 7.67 (dt, J = 6.7, 1.5 Hz,
4H), 7.43 – 7.36 (m, 6H), 6.38 – 6.36 (m, 1H), 5.16 (dp, J = 9.9,
1.6 Hz, 1H), 3.70 (s, 3H), 3.65 (t, J = 6.5 Hz, 2H), 3.44 (dt, J = 7.0,
4.3 Hz, 1H), 2.44 (dqd, J = 13.7, 6.8, 3.9 Hz, 1H), 1.97 (d, J = 1.6
Hz, 3H), 1.79 – 1.77 (m, 3H), 1.57 – 1.54 (m, 2H), 1.35 – 1.29 (m,
4H), 1.28 – 1.19 (m, 3H), 1.17 – 1.12 (m, 1H), 1.04 (s, 9H), 0.90 –
0.88 (m, 12H), 0.01 (d, J = 3.0 Hz, 6H); 13C-NMR (176 MHz,
CDCl3): δ [ppm] = 169.4, 136.1, 134.2, 131.9, 129.5, 128.4, 127.6,
75.8, 64.0, 51.4, 35.8, 33.6, 32.6, 29.7, 26.9, 26.0, 25.9, 22.5, 21.1,
19.2, 18.1, 15.9, -4.3, -4.5; HRMS (ESI+) calculated for
C39H62O4Si2Na+ [M+Na]+: 637.4079, found: 673.4079.
6.7 Hz, 1H), 2.02 – 1.95 (m, 2H), 1.77 (d, J = 1.4 Hz, 3H), 1.62 (d,
J = 1.3 Hz, 3H), 1.54 – 1.46 (m, 4H), 1.04 (s, 9H), 1.00 (d, J = 6.7
Hz, 3H), 0.82 (d, J = 2.6 Hz, 9H), -0.02 (s, 3H), -0.04 (s, 3H); 13C-
NMR (125 MHz, CDCl3): δ [ppm] = 192.1, 152.6, 136.0, 135.9,
135.5, 134.1, 129.5, 127.6, 127.0, 73.0, 63.6, 39.3, 38.4, 32.2, 26.9,
25.7, 23.9, 19.2, 18.1, 17.2, 16.8, 16.6, -4.1, -4.9; HRMS (ESI+)
calculated for C36H56O3Si2Na+ [M+Na]+: 615,3660 found:
615.3664.
Aldehyde 23: Method D with ester 22 (2.17g, 3.27 mmol),
DIBALH (9.81 mL, 9.81 mmol), in DCM (50 mL). Work-up DCM
(50 mL), H2O (0.40 mL), 3M NaOH (0.40 ml), H2O (1.0 mL).
Crude product and MnO2 (5.69g, 65.4 mmol) in DCM (40 mL).
Chromatography (SiO2, CH/EtOAc, 9:1) gave 21 (1.96 g, 3.09
mmol, 95 %). Rf = 0.61 (SiO2, CH/EtOAc, 20:1); ꢀꢆꢂꢈꢇꢉ = + 11.3°
(c = 0.77, CHCl3); 1H-NMR (500 MHz, CDCl3): δ [ppm] = 9.90 (s,
1H), 7.70 – 7.64 (m, 5H), 7.44 – 7.35 (m, 7H), 6.92 (dd, J = 2.3,
1.2 Hz, 1H), 5.40 (dq, J = 10.2, 1.4 Hz, 1H), 5.03 (dq, J = 9.0, 1.3
Hz, 1H), 4.09 (dd, J = 8.9, 6.2 Hz, 1H), 3.66 (t, J = 6.1 Hz, 2H),
2.35 – 2.27 (m, 1H), 1.98 – 1.94 (m, 2H), 1.88 (q, J = 2.1, 1.6 Hz,
2H), 1.81 (d, J = 1.4 Hz, 2H), 1.56 (d, J = 1.3 Hz, 2H), 1.53 – 1.45
(m, 3H), 1.05 – 1.04 (m, 9H), 0.87 – 0.83 (m, 12H) -0.01 (s, 3H), -
0.04 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ [ppm] = 193.4,
147.0, 136.2, 135.8, 135.6, 134.1, 129.5, 127.6, 127.4, 73.2, 63.7,
40.9, 39.3, 32.2, 26.9, 25.8, 25.0, 24.0, 19.2, 18.1, 16.6, 16.3, 15.9,
-4.2, -4.9; HRMS (ESI+) calculated for C39H60O3Si2Na+ [M+Na]+:
655.3973 found: 655.3973.
Aldehyde 25: Method D with ester 24 (582 mg, 0.84 mmol),
DIBALH (2.50 mL, 2.50 mmol), in DCM (10 mL). Work-up DCM
(20 mL), H2O (0.1 mL), 3M NaOH (0.1 ml), H2O (0.2 mL). Crude
product and MnO2 (1.46 g, 16.8 mmol) in DCM (6 mL).
Chromatography (SiO2, CH/EtOAc, 9:1) gave 21 (540 mg, 0.82
mmol, 98 %). Rf = 0.50 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 17.0°
(c = 0.37, CHCl3); 1H-NMR (700 MHz, CDCl3): δ [ppm] = 9.61 (d,
J = 7.9 Hz, 1H), 7.70 – 7.68 (m, 5H), 7.53 (dd, J = 15.7, 0.8 Hz,
1H), 7.45 – 7.43 (m, 2H), 7.41 – 7.38 (m, 5H), 6.29 (dd, J = 2.2,
1.2 Hz, 1H), 6.18 (ddt, J = 15.7, 7.8, 0.7 Hz, 1H), 5.32 (dt, J =
10.2, 1.5 Hz, 1H), 5.08 – 5.05 (m, 1H), 4.10 (dd, J = 8.9, 6.2 Hz,
1H), 3.68 (t, J = 6.1 Hz, 2H), 2.29 (dp, J = 10.3, 6.8 Hz, 1H), 1.97
(t, J = 7.4 Hz, 2H), 1.95 (d, J = 1.3 Hz, 3H), 1.86 – 1.85 (m, 3H),
1.59 (dd, J = 1.3, 0.7 Hz, 3H), 1.57 – 1.54 (m, 2H), 1.49 (qd, J =
7.1, 3.4 Hz, 2H), 1.06 (d, J = 0.6 Hz, 10H), 0.87 (d, J = 0.6 Hz,
12H); 13C-NMR (176 MHz, CD2Cl2): δ [ppm] = 194.0, 150.8,
139.9, 135.8, 135.5, 134.8, 134.2, 131.7, 131.2, 129.5, 128.9,
127.6, 127.3, 73.1, 63.8, 40.7, 39.3, 32.2, 26.6, 25.6, 24.1, 24.0,
19.4, 19.1, 18.0, 16.4, 15.6, -4.5, -5.2; HRMS (ESI+) calculated for
C41H62O3Si2Na+ [M+Na]+: 681.4130 found: 681.4130.
General method D: Red-Ox sequence from ester to
aldehyde. To a solution of ester (1.00 eq) in DCM at -78°C was
added DIBAL-H (3.00 eq) dropwise. The mixture was stirred for 1
h and warmed up to 0 °C for 45 min. DCM was added followed by
H2O, a 3 M aqueous solution of NaOH and H2O (1:1:2.5). After
stirring 15 min at room temperature, MgSO4 was added and the
mixture was stirred an additionnal 15 min. After filtration, the
solvent was removed in vacuo.
The crude product was directly diluted in DCM and MnO2
(20.0 eq) was added. The reaction was stirred overnight at room
temperature. The solution was filtered through celite and the
solvent was evaporated in vacuo. The residue was purified by
column chromatography.
Aldehyde 21: Method D with ester 20 (2.38 g, 3.82 mmol),
DIBAL-H (11.4 mL, 11.4 mmol), in DCM (50 mL). Work-up
DCM (50 mL), H2O (0.45 mL), 3M NaOH (0.45 ml), H2O (1.1
mL). Crude product and MnO2 (6.64 g, 76.4 mmol) in DCM (40
mL). Chromatography (SiO2, CH/EtOAc, 9:1) gave 21 (2.12 g,
3.54 mmol, 94%). Rf = 0.56 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = +
Aldehyde 34: Method D with ester 34 (620 mg, 1.01 mmol),
DIBAL-H (3.00 mL, 3.00 mmol), in DCM (10 mL). Work-up
DCM (20 mL), H2O (0.12 mL), 3M NaOH (0.12 ml), H2O (0.30
mL). Crude product and MnO2 (1.85 g, 21.3 mmol) in DCM (6
mL). Chromatography (SiO2, CH/EtOAc, 9:1) gave 34 (525 mg,
0.96 mmol, 90 %). Rf = 0.52 (SiO2, CH/EtOAc, 20:1); ꢀꢆꢂꢈꢇꢉ = +
1
11.8° (c = 0.51, CHCl3); H-NMR (500 MHz, CDCl3): δ [ppm] =
10.04 (d, J = 0.5 Hz, 1H), 7.69 – 7.63 (m, 4H), 7.45 – 7.34 (m,
6H), 6.34 (dq, J = 10.9, 1.3 Hz, 1H), 5.06 (dq, J = 9.3, 1.4 Hz, 1H),
4.19 – 4.13 (m, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.17 (dp, J = 10.7,
1
8.8° (c = 0.26, CHCl3); H-NMR (700 MHz, CDCl3): δ [ppm] =
10.08 (d, J = 0.5 Hz, 1H), 7.68 – 7.65 (m, 4H), 7.43 – 7.40 (m,
This article is protected by copyright. All rights reserved.

10.1002/cmdc.202000154
ChemMedChem
FULL PAPER
2H), 7.39 – 7.36 (m, 4H), 6.45 (dq, J = 10.8, 1.3 Hz, 1H), 3.64 (t, J
= 6.4 Hz, 2H), 3.55 (td, J = 5.7, 4.6 Hz, 1H), 3.33 – 3.27 (m, 1H),
1.79 (d, J = 1.3 Hz, 3H), 1.56 – 1.53 (m, 4H), 1.46 (ddt, J = 13.7,
10.4, 5.0 Hz, 1H), 1.40 – 1.31 (m, 3H), 1.30 – 1.21 (m, 4H), 1.06
(d, J = 6.8 Hz, 3H), 1.04 (s, 9H), 0.88 (s, 9H); 13C-NMR (176
MHz, CDCl3): δ [ppm] =191.6, 152.1, 135.6, 134.2, 129.5, 127.6,
75.6, 63.9, 35.6, 34.9, 32.5, 29.6, 26.9, 25.9, 25.8, 24.8, 19.2, 18.6,
18.1, 16.7, -4.2, -4.4; HRMS (ESI+) calculated for C35H56O3Si2Na+
[M+Na]+: 603.3660, found: 603.3663.
dried over MgSO4, evaporated in vacuo and purified by column
chromatography.
Ester 24: Method E with 13c (0.75 mL, 4.64 mmol), DMPU
(0.56 mL, 4.64 mmol, n-BuLi (2.7 mL, 4.33 mmol) and aldehyde
23 (1.96 g, 3.09 mmol) in THF (80 mL). Work-up at pH 7 (50 mL)
and Et2O (300 mL). Chromatography (SiO2, CH/EtOAc, 9:1) gave
24 (2.03 g, 2.94 mmol, 95%). Rf = 0.53 (SiO2, CH/EtOAc, 20:1);
ꢀꢆꢂꢈꢇꢉ = + 39.3° (c = 0.41, CHCl3); 1H-NMR (500 MHz, CDCl3): δ
[ppm] = 7.68 – 7.62 (m, 5H), 7.41 – 7.35 (m, 6H), 6.17 (td, J = 1.5,
0.8 Hz, 1H), 5.86 (dd, J = 15.8, 0.7 Hz, 1H), 5.23 – 5.17 (m, 1H),
5.05 (dq, J = 9.2, 1.3 Hz, 1H), 4.08 (dd, J = 9.0, 5.8 Hz, 1H), 3.74
(s, 3H), 3.66 (td, J = 6.0, 2.5 Hz, 3H), 2.30 – 2.22 (m, 1H), 1.98 –
1.93 (m, 2H), 1.89 (d, J = 1.4 Hz, 3H), 1.80 (dd, J = 1.4, 0.7 Hz,
3H), 1.57 (d, J = 1.3 Hz, 3H), 1.54 – 1.46 (m, 5H), 1.04 (d, J = 2.0
Hz, 11H), 0.88 – 0.86 (m, 3H), 0.86 – 0.82 (m, 9H), -0.06 (s, 5H);
13C-NMR (125 MHz, CDCl3): δ [ppm] = 167.8, 143.3, 138.3,
135.5, 134.5, 134.1, 131.3, 131.2, 129.5, 127.6, 127.1, 117.8, 72.9,
63.7, 51.4, 40.8, 39.3, 62.2, 26.8, 25.8, 24.5, 24.0, 19.8, 19.2, 18.1,
16.6, 15.5, -4.3, -4.9; HRMS (ESI+) calculated for C42H64O4Si2Na+
[M+Na]+: 711.4235, found : 711.4238.
Ester 37: Method E with 13c (0.16 mL, 1.00 mmol), DMPU
(0.12 mL, 1.00 mmol, n-BuLi (0.58 mL, 0.94 mmol) and aldehyde
23 (416 mg, 0.67 mmol) in THF (15 mL). Work-up at pH 7 (15
mL), Et2O (60 mL). Chromatography (SiO2, CH/EtOAc, 9:1) gave
37 (416 mg, 0.67 mmol, 89%). Rf = 0.52 (SiO2, CH/EtOAc, 20:1);
ꢀꢆꢂꢈꢇꢉ = + 40.4° (c = 0.26, CHCl3); 1H-NMR (700 MHz, CDCl3): δ
[ppm] = 7.68 – 7.65 (m, 4H), 7.61 (dd, J = 15.8, 0.7 Hz, 1H), 7.43
– 7.36 (m, 6H), 6.15 (d, J = 1.9 Hz, 1H), 5.87 (dd, J = 15.8, 0.7 Hz,
1H), 5.29 (dt, J = 10.3, 1.4 Hz, 1H), 3.74 (s, 3H), 3.64 (t, J = 6.5
Hz, 2H), 3.39 (ddd, J = 6.9, 4.8, 3.5 Hz, 1H), 2.32 (ddd, J = 10.4,
6.9, 3.7 Hz, 1H), 1.89 (d, J = 1.4 Hz, 3H), 1.81 (dd, J = 1.4, 0.7 Hz,
3H), 1.59 – 1.54 (m, 2H), 1.38 – 1.18 (m, 9H), 1.04 (d, J = 1.7 Hz,
9H), 0.92 (d, J = 6.8 Hz, 3H), 0.87 (s, 9H), -0.02 (s, 3H), -0.03 (s,
3H); 13C-NMR (176 MHz, CDCl3): δ [ppm] = 167.7, 142.2, 138.0,
135.6, 134.2, 133.3, 131.6, 129.5, 127.6, 118.0, 75.9, 64.0, 51.5,
38.5, 33.5, 32.6, 29.6, 26.9, 26.0, 25.9, 24.6, 19.6, 19.2, 18.1, 15.5,
-4.4, -4.6; HRMS (ESI+) calculated for C41H64O4Si2Na+ [M+Na]+:
699.4235, found: 699.4235.
Aldehyde 36: Method D with ester 35 (507 mg, 0.78 mmol),
DIBAL-H (2.33 mL, 2.33 mmol), in DCM (12 mL). Work-up
DCM (15 mL), H2O (0.10 mL), 3M NaOH (0.10 ml), H2O (0.20
mL). Crude product and MnO2 (1.35 g, 15.6 mmol) in DCM (10
mL). Chromatography (SiO2, CH/EtOAc, 9:1) gave 36 (416 mg,
0.67 mmol, 86 %). Rf = 0.52 (SiO2, CH/EtOAc, 20:1); ꢀꢆꢂꢈꢇꢉ = +
1
6.2° (c = 0.26, CHCl3); H-NMR (700 MHz, CDCl3): δ [ppm] =
9.89 (s, 1H), 7.68 – 7.65 (m, 4H), 7.42 – 7.36 (m, 6H), 6.94 (dd, J
= 2.5, 1.3 Hz, 1H), 5.44 (dt, J = 10.3, 1.5 Hz, 1H), 3.65 (t, J = 6.5
Hz, 2H), 3.46 – 3.38 (m, 1H), 2.40 (ddd, J = 10.5, 6.9, 3.9 Hz, 1H),
1.90 (dd, J = 1.4, 0.8 Hz, 3H), 1.83 (d, J = 1.5 Hz, 3H), 1.38 – 1.20
(m, 9H), 1.04 (s, 9H), 0.91 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), -0.00
(d, J = 7.1 Hz, 6H); 13C-NMR (176 MHz, CDCl3): δ [ppm] =
193.1, 146.8, 136.5, 135.6, 135.3, 134.2, 129.8, 129.5, 127.6, 75.8,
64.0, 38.5, 33.9, 32.6, 29.6, 25.9, 25.6, 25.1, 19.2, 18.1, 16.2, 15.8,
-4.3, -4.5; HRMS (ESI+) calculated for C38H60O3Si2Na+ [M+Na]+:
643.3973, found: 643.3973.
Aldehyde 38: Method D with ester 37 (120 mg, 0.18 mmol),
DIBAL-H (.053 mL, 0.53 mmol), in DCM (7 mL). Work-up DCM
(15 mL), H2O (0.08 mL), 3M NaOH (0.08 ml), H2O (0.15 mL).
Crude product and MnO2 (0.31 mg, 3.54 mmol) in DCM (10 mL).
Chromatography (SiO2, CH/EtOAc, 20:1) gave 36 (416 mg, 0.67
mmol, 86 %). Rf = 0.52 (SiO2, CH/EtOAc, 20:1); ꢀꢆꢂꢈꢇꢉ = + 3.3° (c
1
= 0.24, CHCl3); H-NMR (700 MHz, CDCl3): δ [ppm] = 9.61 (dd,
J = 7.8, 5.5 Hz, 1H), 7.69 – 7.64 (m, 4H), 7.50 – 7.43 (m, 1H), 7.42
– 7.34 (m, 6H), 6.27 (s, 1H), 6.16 (dd, J = 15.7, 7.8 Hz, 1H), 5.35
(dt, J = 10.2, 1.5 Hz, 1H), 3.64 (t, J = 6.4 Hz, 2H), 3.40 (dd, J =
6.4, 4.0 Hz, 1H), 2.34 (ddd, J = 10.5, 6.9, 3.8 Hz, 1H), 1.94 (d, J =
1.4 Hz, 2H), 1.87 – 1.81 (m, 2H), 1.26 (dt, J = 21.0, 11.2 Hz, 8H),
1.04 (s, 9H), 0.91 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 2.7 Hz, 9H),
0.04 – -0.06 (m, 6H); 13C-NMR (176 MHz, CDCl3): δ [ppm] =
194.2, 150.7, 139.9, 135.6, 134.2, 134.0, 132.0, 131.5, 129.5,
129.1, 127.6, 75.9, 64.0, 38.5, 33.7, 32.6, 29.6, 26.9, 25.9, 24.5,
19.6, 19.2, 18.1, 15.8, -4.3, -4.6; HRMS (ESI+) calculated for
C40H62O3Si2Na+ [M+Na]+: 669.4130, found: 669.4130.
General method F: Ipc boron mediated aldol reaction and
TBS protection. (-)-Ipc2BH (1.00 eq) was dissolved in anhydrous
hexane and cooled down at 0 °C. Triflic acid (1.00 eq) was added
dropwise and the mixture was stirred at room temperature until no
Ipc2BH crystals were seen to afford a stock solution of triflate of
1.9 M. The stock solution (1.30 eq) was diluted in DCM and
cooled down to -78 °C. DIEA (3.00 eq) was added dropwise
followed by diethylketone 26 (1.40 eq). The reaction mixture was
General method E: HWE olefination. To a solution of
trimethyl phosphonoacetate 13c (1.50 eq) and DMPU (1.50 eq) in
THF at 0 °C was added n-BuLi (1.40 eq). The mixture was stirred
for 30 min then the aldehyde (1.00 eq) in THF was added dropwise. stirred for 3 h at this temperature. Then the aldehyde (1.00 eq) in
After stirring for 2 h at 0 °C, the reaction was stirred overnight at
room temperature. The reaction was quenched with buffer pH 7
and H2O at 0 °C. After separation of the organic layer, the aqueous
layer was extracted with Et2O. The organic layers were combined,
DCM was added, the reaction was stirred for 1 h at -78 °C and
stored overnight at -20 °C. Buffer (pH 7), MeOH and H2O2 (2:2:1)
were added and the solution was stirred for 1 h at room
temperature. After separation of the organic layer, the aqueous
layer was extracted with DCM. The organic layers were combined,
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10.1002/cmdc.202000154
ChemMedChem
FULL PAPER
dried over MgSO4, evaporated in vacuo and purified by column
chromatography.
Hz, 1H), 5.17 (d, J = 9.6 Hz, 1H), 4.34 (t, J = 6.8 Hz, 1H), 3.67 (t,
J = 6.5 Hz, 2H), 3.42 (s, 1H), 2.72 (p, J = 6.8 Hz, 1H), 2.49 (dq, J
= 10.4, 7.2 Hz, 3H), 1.84 (d, J = 1.4 Hz, 3H), 1.58 (d, J = 7.4 Hz,
2H), 1.40 – 1.23 (m, 8H), 1.10 – 1.05 (m, 12H), 1.01 (t, J = 7.2 Hz,
4H), 0.89 (dd, J = 2.8, 1.3 Hz, 21H), -0.00 – -0.03 (m, 12H); 13C-
NMR (176 MHz, CDCl3): δ [ppm] = 213.3, 135.6, 134.2, 131.8,
130.7, 130.3, 129.6, 129.5, 127.6, 75.9, 75.8, 64.0, 53.0, 38.7, 36.6,
33.0, 32.6, 29.7, 26.9, 26.3, 26.0, 25.9, 24.6, 20.2, 19.2, 18.1, 15.3,
12.5, 7.2, -4.0, -4.4, -4.5, -4.9; HRMS (ESI+) calculated for
C51H86O4Si3Na+ [M+Na]+: 869.5726, found: 869.5727.
To a stirred solution of β-hydroxyketone (1.00 eq) in DCM at -
78 °C was added 2,6-lutidine (2.00 eq) and TBSOTf (1.50 eq). The
reaction was stirred for 1.5 h and quenched with a saturated
solution of NaHCO3 at 0 °C. After separation of the organic layer,
the aqueous layer was extracted with DCM. The organic layers
were combined, dried over MgSO4 and evaporated in vacuo. The
crude product was purified by column chromatography.
Ketone 27: Method F with TfOH (336 μL, 3.81 mmol),
Ipc2BH (1.09 g, 3.81 mmol) in hexane (0.88 mL). Triflate stock
solution (0.55 mL, 1.05 mmol), DIEA (360 μL, 2.10 mmol),
diethylketone 26 (100 μL, 0.98 mmol) and aldehyde 25 (460 mg,
0.70 mmol) in DCM (8 mL). Work-up at pH 7 buffer (4 mL),
MeOH (4 mL), H2O2 (2 mL) and DCM (30 mL). Chromatography
(SiO2, CH/EtOAc, 30:1) gave β-hydroxyketone (310 mg, 0.42
mmol, 61%). The β-hydroxyketone (370 mg, 0.50 mmol), 2,6-
lutidine (0.11 mL, 1.00 mmol) and TBSOTf (0.17 mL, 0.75 mmol)
in DCM (8 mL). Work-up NaHCO3 (10 mL) and DCM (30 mL).
Chromatography (SiO2, CH/EtOAc, 30:1) gave 27 (383 mg, 0.44
mmol, 90%). Rf = 0.18 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 56.2° (c
General method G: TDBPS deprotection and TES
protection. To a solution of TBAF (1.00 eq) in THF at 0 °C was
added AcOH (1.00 eq) resulting in a 41.5 mM stock solution. To
the neat alcohol (1.00 eq) was added the TBAF stock solution at
0 °C (1.10 eq). The reaction was stirred for 1 h at this temperature
then 30 h at room temperature. The reaction was diluted with Et2O
and quenched with a saturated solution of NaHCO3 at 0 °C. After
separation of the organic layer, the aqueous layer was extracted
with Et2O. The organic layers were combined, dried over MgSO4
and evaporated in vacuo. The crude product was purified by
column chromatography.
To a solution of alcohol (1.00 eq) in DCM at -78 °C was added
2,6-lutidine (2.00 eq) followed by TESOTf (1.50 eq). The reaction
mixture was stirred 1 h and quenched with water at 0 °C. After
separation of the organic layer, the aqueous layer was extracted
with DCM. The combined organic layers were dried over MgSO4
and evaporated in vacuo. The crude product was purified by
column chromatography.
1
= 0.34, CHCl3); H-NMR (700 MHz, CD2Cl2): δ [ppm] = 7.68 –
7.66 (m, 4H), 7.43 – 7.41 (m, 2H), 7.38 (ddt, J = 8.2, 6.7, 1.2 Hz,
4H), 6.44 – 6.39 (m, 1H), 5.93 – 5.91 (m, 1H), 5.60 – 5.54 (m, 1H),
5.11 (dq, J = 9.7, 1.5 Hz, 1H), 5.08 (dp, J = 9.0, 1.2 Hz, 1H), 4.35
(ddd, J = 6.9, 5.8, 1.2 Hz, 0H), 4.31 (ddd, J = 7.7, 5.9, 1.0 Hz, 1H),
4.14 – 4.10 (m, 1H), 3.68 (t, J = 6.2 Hz, 2H), 2.70 (qd, J = 6.9, 5.7
Hz, 1H), 2.53 – 2.38 (m, 2H), 2.37 – 2.31 (m, 1H), 2.00 – 1.96 (m,
2H), 1.84 – 1.81 (m, 3H), 1.78 – 1.76 (m, 3H), 1.58 (d, J = 1.4 Hz,
2H), 1.57 – 1.54 (m, 2H), 1.50 (ddd, J = 8.5, 6.7, 4.7 Hz, 2H), 1.04
– 1.02 (m, 12H), 0.95 (t, J = 7.2 Hz, 3H), 0.87 (s, 9H), 0.85 (d, J =
4.4 Hz, 12H), 0.03 (s, 3H), -0.01 (d, J = 4.4 Hz, 6H), -0.03 – -0.04
(m, 3H); 13C-NMR (176 MHz, CDCl3): δ [ppm] = 212.6, 135.5,
135.4, 134.2, 132.7, 132.1, 131.9, 130.6, 130.4, 129.7, 129.5,
127.6, 127.2, 76.0, 72.9, 63.8, 52.9, 40.5, 39.3, 36.5, 32.2, 26.6,
25.7, 25.6, 24.5, 24.0, 20.1, 19.1, 18.0, 19.7, 16.4, 15.4, 12.1, 7.2, -
4.3, -4.6, -5.1, -5.2; HRMS (ESI+) calculated for C52H88O4Si3Na+
[M+Na]+: 881.5726, found: 881.5726.
Ketone 28: Method G with TBAF (830 μL,0.84 mmol), AcOH
(48 μL, 0.84 mmol) in THF (10.6 mL).Neat alcohol (340 mg, 0.40
mmol) and stock solution (10.6 mL, 0.44 mmol). Work-up
NaHCO3 (10 mL) and Et2O (10 mL). Chromatography (SiO2,
CH/EtOAc, 20:1) gave the unprotected alcohol (180 mg, 0.29
mmol, 73%). Unprotected alcohol (102 mg, 0.16 mmol), 2,6-
lutidine (38 μL, 0.33 mmol), TESOTf (56 μL, 0.25 mmol) in DCM
(4 mL). Work-up H2O (4 mL) and DCM (15 mL). Chromatography
(SiO2, CH/EtOAc, 20:1) gave 28 (108 mg, 0.15 mmol, 90%). Rf =
0.59 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 61.0° (c = 0.29, CHCl3);
1H-NMR (700 MHz, CD2Cl2): δ [ppm] = 6.41 (d, J = 15.8 Hz, 1H),
5.92 (s, 1H), 5.59 – 5.55 (m, 1H), 5.12 – 5.07 (m, 2H), 4.32 – 4.30
(m, 1H), 4.12 (dd, J = 8.9, 5.9 Hz, 1H), 3.60 (t, J = 6.2 Hz, 4H),
2.72 – 2.68 (m, 1H), 2.53 – 2.39 (m, 2H), 2.33 (ddd, J = 16.9, 10.1,
5.0 Hz, 1H), 1.98 (t, J = 7.1 Hz, 2H), 1.83 (d, J = 1.1 Hz, 3H), 1.77
(s, 3H), 1.58 (s, 3H), 1.50 – 1.43 (m, 4H), 1.03 (d, J = 6.9 Hz, 3H),
0.96 (dt, J = 14.5, 5.2 Hz, 12H), 0.89 (s, 3H), 0.87 (d, J = 3.0 Hz,
9H), 0.85 – 0.84 (m, 9H), 0.58 (dt, J = 8.0, 5.3 Hz, 6H), 0.03 (s,
3H), -0.01 (s, 6H), -0.03 (s, 6H); 13C-NMR (700 MHz, CD2Cl2): δ
[ppm] = 212.8, 135.5, 132.7, 132.1, 131.9, 130.6, 130.4, 129.7,
127.1, 76.0, 72.9, 62.6, 52.9, 40.5, 39.4, 36.4, 32.6, 25.6, 25.6,
24.5, 24.1, 20.1, 18.0, 17.9, 16.4, 15.4, 13.8, 12.1, 7.2, 6.6, 4.4, -
4.3, -4.6, -5.2; HRMS (ESI+) calculated for C42H86O4Si3N
[M+NH4]+: 752.5859, found: 752.5859.
Ketone 39: Method F with TfOH (167 μL, 1.93 mmol),
Ipc2BH (545 mg, 1.93 mmol) in hexane (0.44 mL). Triflate
solution (0.22 mL, 0.76 mmol), DIEA (145 μL, 0.83 mmol),
diethylketone 26 (41 μL, 0.39 mmol) and aldehyde 38 (180 mg,
0.28 mmol) in DCM (4 mL).
Work-up buffer (pH 7, 2 mL), MeOH (2 mL), H2O2 (1 mL)
and DCM (30 mL). Chromatography (SiO2, CH/EtOAc, 30:1) gave
β-hydroxyketone (132 mg, 0.18 mmol, 64%). The β-hydroxyketone
(145 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and
TBSOTf (68 μL, 0.30 mmol) in DCM (3 mL). Work-up NaHCO3
(5 mL) and DCM (15 mL). Chromatography (SiO2, CH/EtOAc,
20:1) gave 39 (153 mg, 0.18 mmol, 90%). Rf = 0.54 (SiO2,
1
CH/EtOAc, 10:1); ꢀꢁꢂꢃꢄꢅ = + 23.0° (c = 0.31, CHCl3); H-NMR
(700 MHz, CDCl3): δ [ppm] = 7.73 – 7.67 (m, 4H), 7.51 – 7.36 (m,
6H), 6.39 (d, J = 15.7 Hz, 1H), 5.89 (s, 1H), 5.59 (dd, J = 15.8, 7.4
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10.1002/cmdc.202000154
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Ketone 40: Method G with TBAF (830 μL,0.84 mmol), AcOH
(48 μL, 0.84 mmol in THF (10.6 mL). Neat alcohol (340 mg, 0.40
mmol) and stock solution (10.6 mL, 0.44 mmol). Work-up
NaHCO3 (10 mL) and Et2O (10 mL). Chromatography (SiO2,
CH/EtOAc, 20:1) gave the unprotected alcohol (180 mg, 0.29
mmol, 73%). Unprotected alcohol (127 mg, 0.32 mmol), 2,6-
lutidine (48 μL, 0.42 mmol), TESOTf (78 μL, 0.31 mmol) in DCM
(4 mL). Work-up H2O (4 mL) and DCM (15 mL). Chromatography
(SiO2, CH/EtOAc, 20:1) gave 40 (140 mg, 0.19 mmol, 90%). Rf =
0.52 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 26.1° (c = 0.62, CHCl3);
1H-NMR (700 MHz, CD2Cl2): δ [ppm] = 6.39 (dt, J = 15.7, 0.9 Hz,
1H), 5.89 (d, J = 1.7 Hz, 1H), 5.60 – 5.56 (m, 1H), 5.19 – 5.16 (m,
1H), 4.33 (ddd, J = 7.2, 5.9, 1.0 Hz, 1H), 3.58 (td, J = 6.7, 1.8 Hz,
2H), 3.43 (td, J = 6.5, 6.0, 3.8 Hz, 1H), 2.69 (qd, J = 6.9, 5.7 Hz,
1H), 2.54 – 2.37 (m, 3H), 1.84 – 1.81 (m, 2H), 1.78 – 1.74 (m, 3H),
1.51 – 1.47 (m, 2H), 1.36 – 1.15 (m, 8H), 1.04 (d, J = 6.9 Hz, 3H),
0.95 (td, J = 7.6, 4.5 Hz, 12H), 0.89 – 0.88 (m, 3H), 0.88 (d, J =
2.7 Hz, 9H), 0.87 (s, 9H), 0.59 (q, J = 8.0 Hz, 6H), 0.05 (s, 3H), -
0.01 (s, 6H), -0.04 (s, 3H); 13C-NMR (700 MHz, CD2Cl2): δ [ppm]
= 212.6, 132.4, 132.4, 131.7, 130.8, 130.2, 129.4, 75.9, 75.8, 62.8,
53.8, 53.7, 53.6, 53.6, 53.5, 53.4, 53.3, 53.3, 53.1, 52.9, 38.6, 36.4,
33.1, 33.0, 29.7, 26.2, 25.9, 25.7, 25.7, 25.6, 25.6, 25.6, 24.6, 19.9,
18.0, 17.9, 15.1, 12.1, 7.2, 6.5, 4.4, -4.3, -4.7, -4.8, -5.2; HRMS
(ESI+) calculated for C41H82O4Si3Na+ [M+Na]+: 745.5413, found:
745.5410.
Ketone 43a: Method H with TMP (32 μL, 0.18 mmol), n-BuLi
(0.12 mL, 0.18 mmol) in THF (0.8 mL). Ketone 40 (40 mg, 47
μmol), LiTMP (0.50 mL, 94 μmol) in THF (1.5 mL) and aldehyde
41 (10 mg, 70 μmol) in THF (0.2 mL). Work-up NaHCO3 (2 mL)
and DCM (15 mL). Chromatography (SiO2, CH/EtOAc, 30:1 to
10:1) gave the aldol product (39 mg, 39 μmol, 83%). Directly used
with DMAP (24 mg, 0.19 mmol) and Ac2O (15 μL, 0.16 mmol) in
THF (2 mL). Work-up buffer (pH 7, 3mL) and EtOAc (9 mL).
Chromatography (SiO2, CH/EtOAc, 20:1) gave protected alcohol
(35 mg, 33 μmol, 86%). Directly used with DBU (175 μL, 1.29
mmol) in THF (2 mL). Work-up buffer (pH 7, 2 mL) and EtOAc (9
mL). Chromatography (SiO2, CH/EtOAc, 100:1) gave 43a (31 mg,
32 μmol, 94%, 67% over 3 steps). Rf = 0.48 (SiO2, CH/EtOAc,
10:1). ꢀꢆꢂꢈꢇꢉ = + 24.7° (c = 0.58, CHCl3); 1H-NMR (700 MHz,
CD2Cl2): δ [ppm] = 7.73 – 7.69 (m, 4H), 7.48 – 7.39 (m, 7H), 6.62
– 6.57 (m, 1H), 6.39 (dt, J = 15.8, 0.8 Hz, 1H), 5.95 (s, 1H), 5.60 –
5.54 (m, 1H), 5.13 (dddd, J = 10.3, 9.1, 2.8, 1.4 Hz, 2H), 4.33 –
4.24 (m, 1H), 4.16 (ddd, J = 9.0, 5.9, 1.5 Hz, 1H), 4.09 (td, J = 6.6,
5.0 Hz, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.48 – 3.37 (m, 1H), 2.46 –
2.33 (m, 1H), 2.34 – 2.25 (m, 2H), 2.05 (d, J = 2.0 Hz, 3H), 2.02 (t,
J = 7.2 Hz, 2H), 1.82 (d, J = 1.3 Hz, 2H), 1.80 (d, J = 0.6 Hz, 3H),
1.72 (q, J = 0.9 Hz, 3H), 1.71 – 1.66 (m, 2H), 1.62 (d, J = 1.4 Hz,
3H), 1.57 (s, 15H), 1.11 (dd, J = 6.8, 2.0 Hz, 3H), 1.08 (s, 8H),
0.94 – 0.89 (m, 11H), 0.89 – 0.88 (m, 9H), 0.06 (s, 3H), 0.03 (s,
3H), 0.02 (s, 3H), 0.01 (s, 3H). 13C-NMR (176 MHz, CD2Cl2): δ
[ppm] = 203.6, 170.8, 141.3, 137.9, 135.5, 135.4, 134.2, 132.8,
132.2, 132.0, 131.4, 130.1, 129.5, 129.3, 127.6, 127.2, 76.8, 72.9,
64.0, 63.8, 46.4, 40.6, 39.3, 32.2, 28.6, 28.4, 26.6, 25.6, 25.1, 24.6,
24.0, 20.7, 20.1, 19.6, 18.0, 16.4, 15.5, 14.0, 11.3, -4.2, -4.6, -5.1, -
5.2. HRMS (ESI+) calculated for C59H96O6Si3Na+ [M+Na]+:
1007.6407, found: 1007.6407.
Ketone 43b: Method H with TMP (120 μL, 0.70 mmol), n-
BuLi (0.28 mL, 0.70 mmol) in THF (2.0 mL). Ketone 39 (150 mg,
176 μmol), LiTMP stock solution (1.20 mL, 0.35 mmol) in THF
(3.0 mL) and aldehyde 41 (38 mg, 265 μmol) in THF (0.5 mL).
Work-up NaHCO3 (4 mL) and DCM (30 mL). Chromatography
(SiO2, CH/EtOAc, 30:1 to 10:1) gave the aldol product (148 mg,
149 μmol, 85%). Directly used with DMAP (91 mg, 0.75 mmol)
and Ac2O (56 μL, 0.60 mmol) in THF (5 mL). Work-up buffer (pH
7, 10 mL) and EtOAc (30 mL). Chromatography (SiO2, CH/EtOAc,
20:1) gave protected alcohol (135 mg, 130 μmol, 87%). Directly
used with DBU (0.68 mL, 4.57 mmol) in THF (8 mL). Work-up
buffer (pH 7, 10 mL) and EtOAc (30 mL). Chromatography (SiO2,
CH/EtOAc, 100:1) gave 43b (105 mg, 108 μmol, 83%, 61% over 3
steps). Rf = 0.48 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 10.9° (c =
0.35, CHCl3); 1H-NMR (700 MHz, CD2Cl2): δ [ppm] = 7.66 (dt, J
= 6.8, 1.5 Hz, 4H), 7.42 (ddt, J = 8.4, 6.5, 1.5 Hz, 2H), 7.40 – 7.36
(m, 4H), 6.59 – 6.53 (m, 1H), 6.33 (dt, J = 15.8, 0.8 Hz, 1H), 5.91
– 5.86 (m, 1H), 5.59 – 5.53 (m, 1H), 5.19 – 5.16 (m, 1H), 4.28 –
4.25 (m, 1H), 4.05 (q, J = 6.5 Hz, 2H), 3.66 (td, J = 6.5, 2.2 Hz,
2H), 3.44 (td, J = 6.6, 5.8, 3.5 Hz, 1H), 3.39 (q, J = 6.9 Hz, 1H),
2.44 – 2.37 (m, 1H), 2.30 – 2.23 (m, 2H), 2.04 – 1.99 (m, 3H), 1.79
– 1.77 (m, 3H), 1.76 (t, J = 1.1 Hz, 3H), 1.70 (p, J = 1.3 Hz, 2H),
1.68 – 1.64 (m, 2H), 1.59 – 1.55 (m, 2H), 1.37 – 1.21 (m, 8H), 1.10
General method H: Aldol condensation sequence. LiTMP
stock solution: To a solution of TMP (4.00 eq) in THF at -78 °C
was added n-BuLi (4.00 eq). The yellow solution was stirred for 15
min at this temperature and 15 min at 0 °C.
The ketone (1.00 eq) was diluted in THF and cooled down at -
78 °C. LiTMP (2.00 eq) was added dropwise. The mixture was
stirred for 30 min at -78 °C and warmed up to -50 °C for 20 min.
The enolate solution was cooled down to -78 °C and the aldehyde
(1.50 eq) was added dropwise. After 2 h, the reaction mixture was
diluted with DCM and quenched with a saturated solution of
NaHCO3 at 0 °C. After separation of the organic layer, the aqueous
layer was extracted with DCM. The organic layers were combined,
dried over MgSO4, evaporated in vacuo and purified by column
chromatography.
The mixture of diastereoisomers was directly diluted in THF,
DMAP (5.00 eq) and Ac2O (4.00 eq) were added at 0 °C. After 30
min, buffer pH 7 was added. After separation of the organic layer,
the aqueous layer was extracted with Et2O. The organic layers were
combined, dried over MgSO4, evaporated under vacuum and
purified by column chromatography.
The protected alcohol was diluted in THF and DBU (35.0 eq)
was added at room temperature. After one night, the reaction was
quenched with buffer (pH 7). After separation of the organic layer,
the aqueous layer was extracted with EtOAc. The organic layers
were combined, dried over MgSO4, evaporated under vacuum and
purified by column chromatography.
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10.1002/cmdc.202000154
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– 1.06 (m, 2H), 1.04 (s, 9H), 0.91 – 0.89 (m, 3H), 0.88 (d, J = 2.7
Hz, 9H), 0.87 (s, 8H), -0.00 – -0.03 (m, 12H); 13C-NMR (176
MHz, CD2Cl2): δ [ppm] = 203.6, 170.8, 141.3, 137.8, 135.5, 134.2,
132.5, 132.4, 131.6, 131.5, 129.9, 129.5, 129.0, 127.5, 76.6, 75.9,
64.0, 63.9, 46.4, 38.6, 33.2, 32.6, 29.6, 28.6, 28.4, 26.6, 26.2, 25.9,
25.7, 25.6, 25.1, 24.6, 20.7, 20.0, 19.1, 18.0, 15.2, 14.0, 11.4, -4.3,
-4.7, -4.8, -5.1; HRMS (ESI+) calculated for C58H100O6Si3N+
[M+NH4]+: 990.6853, found: 990.6853.
1H), 6.54 (dd, J = 15.3, 10.7 Hz, 1H), 6.36 (d, J = 15.8 Hz, 1H),
6.17 (dt, J = 14.3, 6.9 Hz, 1H), 5.91 (s, 1H), 5.63 – 5.54 (m, 1H),
5.21 (dt, J = 9.6, 1.6 Hz, 1H), 4.35 – 4.27 (m, 1H), 3.75 (t, J = 6.4
Hz, 2H), 3.62 (td, J = 6.6, 1.3 Hz, 2H), 3.51 – 3.37 (m, 2H), 2.45 (q,
J = 6.6 Hz, 3H), 1.83 (d, J = 1.1 Hz, 3H), 1.82 – 1.76 (m, 6H), 1.51
(dd, J = 10.5, 4.0 Hz, 2H), 1.33 (dd, J = 11.4, 7.3 Hz, 8H), 1.15 –
1.10 (m, 3H), 1.02 – 0.96 (m, 9H), 0.93 (s, 12H), 0.91 (t, J = 2.4
Hz, 17H), 0.62 (qd, J = 7.9, 0.8 Hz, 6H), 0.09 (s, 6H), 0.06 (s, 3H),
0.05 (s, 3H), -0.01 (s, 3H), -0.04 (s, 3H); 13C-NMR (125 MHz,
CD2Cl2): δ [ppm] = 203.6, 139.7, 138.1, 134.9, 132.5, 132.4, 131.6,
129.8, 128.9, 128.3, 76.5, 75.9, 62.8, 62.8, 62.2, 53.8, 53.6, 53.5,
53.4, 53.2, 53.1, 52.9, 46.3, 38.6, 36.8, 33.1, 32.9, 30.0, 29.7, 26.2,
25.9, 25.7, 25.6, 25.6, 25.4, 24.6, 19.9, 18.1, 18.0, 15.2, 14.1, 11.5,
6.5, 4.3, -4.3, -4.7, -4.8, -4.8, -5.1, -5.6, -5.7; HRMS (ESI+)
calculated for C52H102O5Si4Na+ [M+Na]+: 941.6679, found:
Ketone 44a: Method H with TMP (94 μL, 0.28 mmol), n-BuLi
(0.11 mL, 0.28 mmol) in THF (2.0 mL). Ketone 28 (104 mg, 140
μmol), LiTMP stock solution (1.1 mL, 0.28 mmol) in THF (3.0
mL) and aldehyde 42 (45 mg, 211 μmol) in THF (0.5 mL). Work-
up NaHCO3 (4 mL) and DCM (30 mL). Chromatography (SiO2,
CH/EtOAc, 100:1 to 20:1) gave the aldol product (117 mg, 123
μmol, 88%). Directly used with DMAP (75 mg, 0.62 mmol) and
Ac2O (47 μL, 0.49 mmol) in THF (4 mL). Work-up buffer (pH 7, 5
mL) and EtOAc (20 mL). Chromatography (SiO2, CH/EtOAc,
30:1) gave protected alcohol (111 mg, 112 μmol, 91%). Directly
used with DBU (0.58 mL, 3.92 mmol) in THF (6 mL). Work-up
buffer (pH 7, 10 mL) and EtOAc (30 mL). Chromatography (SiO2,
CH/EtOAc, 100:1) gave 44a (84 mg, 90 μmol, 80%, 64% over 3
steps). Rf = 0.67 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = - 14.7° (c =
0.32, CHCl3); 1H-NMR (700 MHz, CD2Cl2): δ [ppm] = 7.03 – 6.98
(m, 1H), 6.53 – 6.47 (m, 1H), 6.37 – 6.33 (d, 1H), 6.17 – 6.11 (m,
1H), 5.90 (dd, J = 11.8, 6.9 Hz, 1H), 5.56 – 5.52 (m, 1H), 5.11 –
5.06 (m, 1H), 4.26 – 4.22 (m, 1H), 4.14 – 4.10 (m, 1H), 3.72 – 3.70
(m, 2H), 3.60 (t, J = 6.2 Hz, 2H), 3.42 (dd, J = 13.8, 6.9 Hz, 1H),
2.41 (q, J = 6.5 Hz, 2H), 2.32 (ddd, J = 15.6, 9.5, 4.6 Hz, 1H), 2.00
– 1.96 (m, 2H), 1.78 (s, 3H), 1.78 – 1.76 (m, 6H), 1.58 (d, J = 1.1
Hz, 3H), 1.49 – 1.44 (m, 4H), 1.09 (d, J = 6.8 Hz, 1H), 0.96 – 0.94
(m, 9H), 0.90 – 0.89 (m, 12H), 0.87 – 0.86 (m, 9H), 0.85 (d, J =
1.2 Hz, 9H), 0.60 – 0.57 (m, 6H), 0.06 (d, J = 2.2 Hz, 6H), 0.02 (d,
J = 1.4 Hz, 3H), -0.01 – -0.02 (m, 3H), -0.02 – -0.03 (m, 3H), -0.04
(d, J = 1.4 Hz, 3H); 13C-NMR (176 MHz, CD2Cl2): δ [ppm] =
203.6, 147.7, 139.8, 138.0, 135.6, 135.2, 132.6, 132.3, 131.9,
131.4, 130.1, 129.2, 128.4, 127.2, 76.8, 73.0, 62.6, 62.2, 46.3, 40.6,
39.6, 36.9, 32.7, 25.6, 24.6, 24.3, 20.3, 18.2, 17.7, 16.5, 15.5, 14.2,
11.5, 6.5, 4.3, -4.2, -4.6, -5.1, -5.2, -5.6; HRMS (ESI+) calculated
for C53H102O5Si4Na+ [M+Na]+: 953:6697, found: 953.6697.
941.6679
.
General method I: Reduction and methylation at C18
position. To a solution of ketone (1.00 eq) in MeOH and THF at
0 °C was added NaBH4 (4.00 eq) and the solution was warmed up
to room temperature. After 3 h, the reaction was diluted with
EtOAc and quenched carefully with a saturated solution of NH4Cl
at 0 °C. After separation of the organic layer, the aqueous layer
was extracted with EtOAc. The organic layers were combined,
dried over MgSO4 and evaporated in vacuo. The crude product was
purified by column chromatography.
To a solution of alcohol (1.00 eq) in DCM at 0 °C was added
proton sponge (5.50 eq) followed by Me3OBF4 (5.00 eq). The
reaction was stirred for 3 to 5 h at 0 °C. After this time, a saturated
solution of NaHCO3 was added at 0 °C. After separation of the
organic layer, the aqueous layer was extracted with DCM. The
organic layers were combined, dried over MgSO4, evaporated in
vacuo and purified by column chromatography.
Methyl ether 45a: Method I with ketone 43a (65 mg, 66
μmol) and NaBH4 (5 mg, 132 μmol) in MeOH (3 mL) and THF (1
mL). Work-up with NH4Cl (4 mL) and EtOAc (35 mL).
Chromatography (SiO2, CH/EtOAc, 60:1 to 30:1) gave the alcohol
(44 mg, 45 μmol, 67%, dr=10:1). The alcohol (42 mg, 42 μmol)
was used with proton sponge (46 mg, 0.23 mmol) and Me3OBF4
(31 mg, 0.21 mmol) in DCM (3 mL). Work-up NaHCO3 (3 mL)
and DCM (20 mL). Chromatography (SiO2, CH/EtOAc, 60:1) gave
45a (37 mg, 37 μmol, 89%, 60% over 2 steps). Rf = 0.46 (SiO2,
CH/EtOAc, 10:1); ꢀꢆꢂꢇꢈꢉ = + 29.8° (c = 0.48, CHCl3); 1H-NMR
(700 MHz, CD2Cl2): δ [ppm] = 7.71 – 7.70 (m, 4H), 7.47 – 7.44
(m, 2H), 7.43 – 7.41 (m, 4H), 6.46 (dt, J = 15.9, 0.9 Hz, 1H), 5.75
(ddd, J = 15.9, 6.9, 0.7 Hz, 1H), 5.35 – 5.33 (m, 1H), 5.12 (dddq, J
= 9.7, 4.3, 3.0, 1.4 Hz, 2H), 4.72 (dt, J = 7.0, 1.5 Hz, 1H), 4.16 (dd,
J = 9.0, 5.8 Hz, 1H), 4.07 (t, J = 6.7 Hz, 2H), 3.71 (t, J = 6.2 Hz,
2H), 3.34 (d, J = 10.0 Hz, 1H), 3.13 (s, 3H), 2.44 – 2.38 (m, 1H),
2.18 – 2.09 (m, 2H), 2.04 (s, 4H), 2.03 – 1.99 (m, 2H), 1.88 (d, J =
1.4 Hz, 3H), 1.82 (dt, J = 2.8, 1.4 Hz, 2H), 1.70 – 1.64 (m, 3H),
1.62 – 1.57 (m, 7H), 1.50 – 1.44 (m, 6H), 1.07 (s, 9H), 0.95 (s,
9H), 0.93 – 0.92 (m, 3H), 0.88 (d, J = 2.7 Hz, 10H), 0.67 (dd, J =
Ketone 44b: Method H with TMP (134 μL, 0.40 mmol), n-
BuLi (0.30 mL, 0.40 mmol) in THF (2.0 mL). Ketone 40 (145 mg,
200 μmol), LiTMP stock solution (1.3 mL, 0.40 mmol) in THF
(3.0 mL) and aldehyde 42 (65 mg, 300 μmol) in THF (0.5 mL).
Work-up NaHCO3 (4 mL) and DCM (30 mL). Chromatography
(SiO2, CH/EtOAc, 100:1 to 50:1) gave the aldol product (148 mg,
157 μmol, 78%). Directly used with DMAP (96 mg, 0.78 mmol)
and Ac2O (59 μL, 0.63 mmol) in THF (5 mL). Work-up buffer (pH
7, 5 mL) and EtOAc (20 mL). Chromatography (SiO2, CH/EtOAc,
50:1) gave protected alcohol (130 mg, 133 μmol, 85%). Directly
used with DBU (0.69 mL, 4.64 mmol) in THF (5 mL). Work-up
buffer (pH 7, 10 mL) and EtOAc (30 mL). Chromatography (SiO2,
CH/EtOAc, 100:1) gave 44b (108 mg, 117 μmol, 88%, 58% over 3
steps). Rf = 0.67 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = - 29.6° (c = 0.23,
1
CHCl3); H-NMR (500 MHz, CD2Cl2): δ [ppm] = 7.07 – 6.99 (m,
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6.9, 2.4 Hz, 3H), 0.08 (d, J = 4.3 Hz, 3H), 0.02 (s, 6H), 0.01 (s,
3H); 13C-NMR (176 MHz, CD2Cl2): δ [ppm] = 170.9, 135.5, 135.4,
134.2, 134.0, 133.5, 132.6, 132.5, 132.2, 130.2, 129.5, 129.1,
127.7, 127.6, 127.1, 88.3, 72.8, 71.8, 64.3, 63.8, 55.1, 42.4, 40.5,
32.2, 28.3, 27.1, 16.6, 25.9, 25.7, 25.6, 24.5, 24.0, 20.7, 20.2, 19.1,
18.1, 18.0, 16.3, 15.1, 9.8, 8.9, -4.1, -4.6, -5.2, -5.4; HRMS (ESI+)
calculated for C60H100O6Si3Na [M+Na]+: 1023.6720, found:
1023.6720.
132.1, 130.7, 129.6, 129.1, 127.7, 126.9, 88.1, 72.8, 71.7, 62.8,
62.5, 55.3, 42.6, 40.4, 39.3, 36.5, 32.5, 25.7, 25.6, 25.6, 24.5, 24.1,
20.1, 18.1, 18.0, 17.9, 16.4, 15.1, 10.3, 8.7, 6.5, 4.3, -4.1, -4.7, -5.3,
-5.4, -5.6; HRMS (ESI+) calculated for C54H110O5Si3N+
[M+NH4]+: 964.7456, found: 964.7456.
Methyl ether 46b: Method I with ketone 44b (78 mg, 85
μmol) and NaBH4 (13 mg, 340 μmol) in MeOH (4 mL) and THF (1
mL). Work-up with NH4Cl (4 mL) and EtOAc (35 mL).
Chromatography (SiO2, CH/EtOAc, 50:1) gave the alcohol (67 mg,
73 μmol, 86%, dr=10:1). Directly used with proton sponge (86 mg,
0.40 mmol) and Me3OBF4 (54 mg, 0.36 mmol) in DCM (4 mL).
Work-up NaHCO3 (3 mL) and DCM (20 mL). Chromatography
(SiO2, CH/EtOAc, 80:1) gave 46b (57 mg, 61 μmol, 84%, 72%
over 2 steps). Rf = 0.69 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = - 7.2° (c
Methyl ether 45b: Method I with ketone 43b (105 mg, 108
μmol) and NaBH4 (8 mg, 216 μmol) in MeOH (5 mL) and THF (2
mL). Work-up with NH4Cl (8 mL) and EtOAc (40 mL).
Chromatography (SiO2, CH/EtOAc, 60:1 to 30:1) gave the alcohol
(73 mg, 75 μmol, 70%, dr=10:1). Directly used with proton sponge
(88 mg, 0.41 mmol) and Me3OBF4 (55 mg, 0.37 mmol) in DCM (4
mL). Work-up NaHCO3 (5 mL) and DCM (30 mL).
Chromatography (SiO2, CH/EtOAc, 60:1) gave 45b (60 mg, 61
μmol, 82%, 57% over 2 steps). Rf = 0.44 (SiO2, CH/EtOAc, 10:1);
1
= 0.25, CHCl3); H-NMR (700 MHz, CDCl3): δ [ppm] = 6.41 –
6.37 (m, 1H), 6.33 (ddt, J = 15.0, 10.6, 1.3 Hz, 1H), 5.92 – 5.88
(m, 1H), 5.80 (s, 1H), 5.71 – 5.64 (m, 2H), 5.13 – 5.10 (m, 1H),
4.69 (dt, J = 6.9, 1.6 Hz, 1H), 3.67 (t, J = 6.7 Hz, 2H), 3.59 (t, J =
6.8 Hz, 3H), 3.40 (td, J = 8.7, 7.9, 4.7 Hz, 1H), 3.34 (d, J = 10.0
Hz, 1H), 3.13 (d, J = 9.8 Hz, 3H), 2.40 (tt, J = 10.8, 6.5 Hz, 1H),
2.36 – 2.32 (m, 2H), 1.83 (d, J = 1.4 Hz, 3H), 1.78 (q, J = 1.8, 1.1
Hz, 3H), 1.60 (s, 1H), 1.59 – 1.57 (m, 3H), 1.53 – 1.49 (m, 3H),
1.34 – 1.27 (m, 7H), 1.15 (tt, J = 9.8, 5.8 Hz, 1H), 0.96 (t, J = 7.9
Hz, 12H), 0.92 (d, J = 6.4 Hz, 9H), 0.89 (d, J = 2.9 Hz, 13H), 0.87
– 0.86 (m, 9H), 0.63 (d, J = 6.9 Hz, 2H), 0.60 (t, J = 8.0 Hz, 6H),
0.05 (s, 6H), 0.04 (s, 3H), -0.01 (s, 3H), --0.02 (s, 3H), -0.03 (s,
3H); 13C-NMR (176 MHz, CDCl3): δ [ppm] = 134.2, 134.2, 132.8,
132.6, 131.7, 130.6, 129.7, 129.0, 127.9, 127.5, 88.3, 77.2, 77.2,
77.0, 76.8, 75.8, 71.6, 63.0, 62.9, 55.6, 42.7, 38.7, 36.6, 33.0, 32.7,
29.7, 29.7, 26.3, 26.0, 26.0, 26.0, 26.0, 25.9, 25.9, 24.9, 20.4, 18.4,
18.2, 18.1, 14.8, 10.5, 9.0, 6.8, 4.5, -3.8, -4.5, -4.6, -5.1, -5.2, -5.2;
HRMS (ESI+) calculated for C53H106O5Si4Na+ [M+Na]+: 934.7117,
found: 934.7117.
1
ꢀꢆꢂꢈꢇꢉ = + 4.5° (c = 0.33, CHCl3); H-NMR (500 MHz, CD2Cl2): δ
[ppm] = 7.68 – 7.65 (m, 4H), 7.43 – 7.35 (m, 6H), 6.39 (d, J = 15.9
Hz, 1H), 5.80 (s, 1H), 5.69 (dd, J = 15.9, 6.8 Hz, 1H), 5.29 (t, J =
6.6 Hz, 1H), 5.13 – 5.10 (m, 1H), 4.68 (d, J = 6.8 Hz, 1H), 4.07 (t,
J = 6.6 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 3.41 – 3.37 (m, 1H), 3.30
(d, J = 10.0 Hz, 1H), 3.11 (s, 3H), 2.42 – 2.38 (m, 1H), 2.09 (dt, J
= 13.9, 6.9 Hz, 2H), 2.05 (s, 3H), 1.83 (d, J = 1.2 Hz, 3H), 1.78 (s,
3H), 1.64 (dt, J = 14.7, 6.6 Hz, 2H), 1.59-1.55 (m, 2H), 1.47 – 1.42
(m, 5H), 1.36-1.20 (m, 8H) 1.04 (s, 9H), 0.92 – 0.90 (s, 9H), 0.89 –
0.87 (m, 3H), 0.87 – 0.86 (m, 9H), 0.64 – 0.61 (d, J = 6.9 Hz 2H),
0.03 (d, J = 2.5 Hz, 3H), -0.01-(-0.02) (s, 6H), -0.03 (s, 3H); 13C-
NMR (125 MHz, CD2Cl2): δ [ppm] = 171.2, 135.6, 134.3, 134.2,
133.5, 132.8, 132.6, 131.7, 130.1, 129.5, 128.9, 127.6, 127.5, 88.4,
75.8, 71.6, 64.4, 64.0, 55.4, 42.4, 38.6, 32.7, 32.6, 29.7, 28.3, 27.2,
26.9, 26.3, 25.9, 24.9, 21.0, 20.4, 19.3, 18.2, 18.1, 14.8, 10.0, 9.1, -
3.8, -4.5, -4.6, -5.1; HRMS (ESI+) calculated for C59H104O6Si3N+
[M+NH4]+: 1006.7166 found: 1006.7166.
Methyl ether 46a: Method I with ketone 44a (84 mg, 90
μmol) and NaBH4 (14 mg, 360 μmol) in MeOH (3 mL) and THF (1
mL). Work-up with NH4Cl (4 mL) and EtOAc (35 mL).
Chromatography (SiO2, CH/EtOAc, 50:1) gave the alcohol (67 mg,
73 μmol, 86%, dr=8:1). Directly used with proton sponge (86 mg,
0.40 mmol) and Me3OBF4 (54 mg, 0.36 mmol) in DCM (4 mL).
Work-up NaHCO3 (3 mL) and DCM (20 mL). Chromatography
(SiO2, CH/EtOAc, 80:1) gave 46a (50 mg, 53 μmol, 72%, 62%
over 2 steps). Rf = 0.69 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 15.6°
General method J: Deprotection at the C1 position. J1:
TBDPS group. To a solution of TBAF (1.00 eq) in THF at 0 °C
was added AcOH (1.00 eq) resulting in a 41.5 mM solution stock
solution. To the neat TBDPS protected alcohol (1.00 eq) was
added the stock solution at 0 °C (1.10 eq). The reaction was stirred
for 1 h at this temperature and 44 h at room temperature. The
reaction was diluted with Et2O and quenched with a saturated
solution of NaHCO3 at 0 °C. After separation of the organic layer,
the aqueous layer was extracted with Et2O. The organic layers were
combined, dried over MgSO4 and evaporated in vacuo. The crude
product was purified by column chromatography.
1
(c = 0.41, CHCl3); H-NMR (700 MHz, CDCl3): δ [ppm] = 6.45 –
6.41 (m, 1H), 6.38 – 6.32 (m, 1H), 5.92 (t, J = 8.1 Hz, 2H), 5.86 (s,
1H), 5.73 – 5.62 (m, 2H), 5.08 (ddd, J = 8.3, 5.1, 1.3 Hz, 2H), 4.69
(d, J = 7.0 Hz, 1H), 4.15 – 4.10 (m, 2H), 3.66 (t, J = 6.6 Hz, 2H),
3.60 (t, J = 6.1 Hz, 2H), 3.34 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.39
– 2.29 (m, 3H), 1.98 (t, J = 7.2 Hz, 2H), 1.85 – 1.84 (m, 3H), 1.79
(s, 3H), 1.57 (d, J = 1.4 Hz, 6H), 1.50 – 1.43 (m, 4H), 0.95 (dd, J =
10.3, 5.5 Hz, 9H), 0.92 (s, 9H), 0.89 (s, 12H), 0.86 – 0.86 (m, 3H),
0.64 – 0.62 (m, 3H), 0.59 (q, J = 8.0 Hz, 6H), 0.05 (d, J = 1.3 Hz,
3H), 0.05 (s, 6H), -0.01 (s, 3H), -0.01 (s, 3H), -0.04 (s, 3H). 13C-
NMR (176 MHz, CDCl3): δ [ppm] = 135.4, 134.2, 133.9, 132.5,
Alcohol 47a: Method J1 with TBAF (415 μL, 0.42 mmol) and
AcOH (24 μL, 0.42 mmol) in THF (9.6 mL). Alcohol 45a (40 mg,
40 μmol) and TBAF stock solution (1.0 mL, 44 μmol). Work-up
NaHCO3 (2 mL) and Et2O (20 mL). Chromatography (SiO2,
CH/EtOAc, 10:1 to 5:1) gave 47a (27 mg, 36 μmol, 88%). Rf =
0.16 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 34.8° (c = 0.33, CHCl3, 20
°C); 1H-NMR (700 MHz, CD2Cl2): δ [ppm] = 6.46 – 6.40 (m, 1H),
5.86 (s, 1H), 5.71 (dddd, J = 16.0, 7.0, 3.6, 0.7 Hz, 1H), 5.31 –
This article is protected by copyright. All rights reserved.

10.1002/cmdc.202000154
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5.28 (m, 1H), 5.14 – 5.05 (m, 2H), 4.71 – 4.65 (m, 1H), 4.14 – 4.09
(m, 1H), 4.03 (t, J = 6.7 Hz, 2H), 3.62 – 3.57 (m, 2H), 3.30 (d, J =
10.0 Hz, 1H), 3.10 (d, J = 2.0 Hz, 3H), 2.36 (dqd, J = 12.6, 6.7,
6.3, 3.6 Hz, 1H), 2.09 (dp, J = 18.4, 7.3 Hz, 2H), 2.00 (d, J = 3.3
Hz, 6H), 1.85 – 1.83 (m, 3H), 1.82 – 1.77 (m, 3H), 1.64 – 1.61 (m,
2H), 1.59 – 1.57 (m, 3H), 1.47 – 1.40 (m, 8H), 0.91 (s, 9H), 0.90 –
0.88 (m, 3H), 0.85 (s, 9H), 0.64 (dd, J = 6.9, 4.4 Hz, 3H), 0.04 (s,,
3H), -0.01 (s, 6H), -0.03 – -0.05 (s, 3H); 13C-NMR (176 MHz,
CD2Cl2): δ [ppm] = 170.9, 135.2, 134.1, 133.5, 132.6, 132.5,
132.2, 130.2, 129.0, 127.7, 127.2, 88.3, 72.8, 71.8, 64.3, 62.6, 55.1,
42.4, 40.5, 39.3, 32.5, 28.3, 27.1, 25.9, 25.7, 25.6, 24.5, 23.9, 20.7,
20.2, 18.1, 18.0, 16.4, 15.2, 9.8, 8.9, -4.1, -4.7, -5.2, -5.4; HRMS
(ESI+) calculated for C44H82O6Si2Na+ [M+Na]+: 785.5548, found:
785.5544.
Alcohol 47b: Method J1 with TBAF (415 μL, 0.42 mmol) and
AcOH (24 μL, 0.42 mmol) in THF (9.6 mL). Alcohol 45b (58 mg,
59 μmol) and TBAF stock solution (1.6 mL, 65 μmol). Work-up
NaHCO3 (2 mL) and Et2O (20 mL). Chromatography (SiO2,
CH/EtOAc, 20:1 to 10:1) gave 47b (41 mg, 54 μmol, 92%). Rf =
0.13 (SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = - 0.7° (c = 0.22, CHCl3); 1H-
NMR (700 MHz, CD2Cl2): δ [ppm] = 6.46 – 6.40 (m, 1H), 5.86 (s,
1H), 5.71 (dddd, J = 16.0, 7.0, 3.6, 0.7 Hz, 1H), 5.31 – 5.28 (m,
1H), 5.14 – 5.05 (m, 2H), 4.71 – 4.65 (m, 1H), 4.14 – 4.09 (m, 1H),
4.03 (t, J = 6.7 Hz, 2H), 3.62 – 3.57 (m, 2H), 3.30 (d, J = 10.0 Hz,
1H), 3.10 (d, J = 2.0 Hz, 3H), 2.36 (dqd, J = 12.6, 6.7, 6.3, 3.6 Hz,
1H), 2.09 (dp, J = 18.4, 7.3 Hz, 2H), 2.00 (d, J = 3.3 Hz, 6H), 1.85
– 1.83 (m, 3H), 1.82 – 1.77 (m, 3H), 1.64 – 1.61 (m, 2H), 1.59 –
1.57 (m, 3H), 1.44 (d, J = 0.8 Hz, 9H), 0.91 (s, 9H), 0.90 – 0.88
(m, 3H), 0.85 (s, 9H), 0.64 (dd, J = 6.9, 4.4 Hz, 3H), 0.05 (s, 3H), -
0.01 (s, 6H), -0.04 (s, 3H); 13C-NMR (176 MHz, CDCl3): δ [ppm]
= 170.9, 134.4, 133.5, 132.8, 132.7, 131.6, 130.2, 128.9, 127.4,
88.3, 75.8, 71.7, 64.3, 62.8, 55.1, 42.5, 38.6, 32.9, 32.6, 29.6, 28.3,
27.1, 26.3, 25.9, 25.8, 25.7, 25.6, 25.4, 20.7, 20.0, 18.1, 17.9, 14.6,
9.7, 8.9, -4.1, -4.8, -4.9, -5.3; HRMS (ESI+) calculated for
C43H82O6Si2Na+ [M+Na]+: 773.5542, found: 773.5542.
= 7.0 Hz, 1H), 4.16 – 4.10 (m, 1H), 3.66 (t, J = 6.6 Hz, 2H), 3.60
(t, J = 11.8 Hz, 2H), 3.34 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.39 –
2.35 (m, 1H), 2.32 (dd, J = 13.4, 6.7 Hz, 2H), 2.02 – 1.98 (m, 2H),
1.85 (d, J = 1.2 Hz, 3H), 1.79 (s, 3H), 1.58 (dd, J = 5.0, 3.8 Hz,
6H), 1.50 – 1.43 (m, 4H), 0.92 (s, 9H), 0.88 (d, J = 1.9 Hz, 9H),
0.86 (d, J = 3.2 Hz, 3H), 0.85 (s, 9H), 0.64 – 0.62 (m, 3H), 0.05 (d,
J = 1.5 Hz, 3H), 0.05 (s, 6H), -0.01 (s, 3H), -0.01 (s, 3H), -0.04 (s,
3H). 13C-NMR (126 MHz, CDCl3): δ [ppm] = 137.1, 136.2, 135.9,
134.5, 134.4, 134.1, 132.6, 131.6, 131.5, 131.0, 129.7, 129.1, 90.1,
74.7, 73.7, 64.7, 64.5, 57.2, 44.6, 42.3, 41.2, 38.4, 34.6, 27.7, 27.6,
27.6, 27.5, 26.4, 25.8, 22.1, 20.1, 18.3, 17.0, 12.3, 10.7, -2.2, -2.8, -
3.3, -3.5, -3.7. HRMS (ESI+) calculated for C48H92O5Si3Na+
[M+Na]+: 855.6145, found: 855.6145.
Alcohol 48b: Method J2 with alcohol 46b (60 mg, 64 μmol)
and K2CO3 (226 mg, 190 μmol) in MeOH (10 mL). Work-up
NaHCO3 (10 mL) and EtOAc (40 mL). Chromatography (SiO2,
CH/EtOAc, 10:1) gave 48b (50 mg, 61 μmol, 94%). Rf = 0.10
1
(SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = - 11.6° (c = 0.32, CHCl3); H-
NMR (700 MHz, CD2Cl2): δ [ppm] = 6.40 – 6.36 (m, 1H), 6.36 –
6.32 (m, 1H), 5.94 – 5.90 (m, 1H), 5.81 (s, 1H), 5.74 – 5.65 (m,
2H), 5.16 – 5.12 (m, 1H), 4.70 (dt, J = 6.9, 1.5 Hz, 1H), 3.66 (t, J =
6.6 Hz, 2H), 3.58 (td, J = 6.7, 5.3 Hz, 2H), 3.43 (ddd, J = 9.8, 7.4,
4.3 Hz, 1H), 3.34 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.41 (dqd, J =
10.6, 6.8, 3.7 Hz, 1H), 2.34 – 2.29 (m, 2H), 1.84 (d, J = 1.4 Hz,
3H), 1.80 – 1.77 (m, 3H), 1.60 – 1.58 (m, 1H), 1.58 – 1.56 (m, 3H),
1.52 – 1.49 (m, 2H), 1.34 – 1.27 (m, 8H), 0.92 (d, J = 6.5 Hz, 9H),
0.89 (d, J = 4.0 Hz, 12H), 0.86 (s, 9H), 0.63 – 0.61 (m, 3H), 0.06
(s, 3H), 0.05 (s, 6H), -0.01 (s, 3H), -0.01 (s, 3H), -0.02 (s, 3H); 13C-
NMR (176 MHz, CD2Cl2): δ [ppm] = 134.3, 134.2, 132.8, 132.7,
131.6, 130.7, 129.6, 128.9, 127.8, 127.5, 88.2, 75.8, 71.7, 62.8,
62.8, 62.8, 55.3, 53.8, 53.7, 53.6, 53.6, 53.5, 53.4, 53.3, 53.1, 42.7,
38.6, 36.5, 32.9, 32.6, 29.7, 29.6, 26.3, 25.8, 25.8, 25.8, 25.7, 25.7,
25.7, 25.7, 25.7, 25.7, 24.5, 20.0, 18.2, 18.1, 18.0, 18.0, 14.5, 10.3,
8.8, -4.1, -4.8, -4.9, -5.3, -5.6, -5.6; HRMS (ESI+) calculated for
C47H96O5Si3N+ [M+NH4]+: 838.6591, found: 838.6591.
General method J: Deprotection at the C1 position. J2: TES
group. To a solution of TES protected alcohol (1.00 eq) in MeOH
was added K2CO3 (30.0 eq) at 0 °C. The solution was warmed up
to room temperature and stirred overnight. The reaction was
quenched with a saturated solution of NaHCO3 and diluted with
EtOAc. After separation of the organic layer, the aqueous layer
was extracted with EtOAc. The combined organic layers were
dried over MgSO4 and evaporated in vacuo. The crude product was
purified by column chromatography.
General method K: C1 Oxidations to carboxylic acid, C23
deprotection, macrolactonization and global deprotection. To a
solution of DMSO (10.0 eq), sulfur trioxide pyridine complex
(3.00 eq) and DIEA (4.00 eq) in DCM at 0 °C was added alcohol
(1.00 eq) diluted in DCM. The solution was stirred at 0 °C for 1.5 h.
After this time the reaction was quenched with aqueous saturated
solution of NaHCO3 and diluted with DCM. After separation of the
organic layer, the aqueous layer was extracted with DCM. The
organic layers were combined, dried over MgSO4 and evaporated
in vacuo until 200 mbar. The crude product was then directly used
in the next reaction.
The crude aldehyde was diluted in tert-butanol and 2-
methylbut-2-ene (10:1) and cooled at 0 °C. A solution of NaClO2
(3.20 eq), KH2PO4 (4.00 eq) in H2O was added to the reaction
mixture. The reaction was stirred for 1 h at room temperature.
Saturated aqueous solution of NaCl was added and DCM. After
separation of the organic layer, the aqueous layer was extracted
Alcohol 48a: Method J2 with alcohol 46a (48 mg, 51 μmol)
and K2CO3 (210 mg, 1.53 μmol) in MeOH (7 mL). Work-up
NaHCO3 (10 mL) and EtOAc (40 mL). Chromatography (SiO2,
CH/EtOAc, 10:1) gave 48a (35 mg, 42 μmol, 82%). Rf = 0.22
1
(SiO2, CH/EtOAc, 10:1); ꢀꢆꢂꢈꢇꢉ = + 10.4° (c = 0.25, CHCl3); H-
NMR (500 MHz, CDCl3): δ [ppm] = 6.43 (d, J = 15.9 Hz, 1H),
6.35 (dd, J = 15.1, 10.8 Hz, 1H), 5.91 (d, J = 11.2 Hz, 1H), 5.86 (s,
1H), 5.73 – 5.63 (m, 2H), 5.09 (dd, J = 12.8, 5.3 Hz, 2H), 4.69 (d, J
This article is protected by copyright. All rights reserved.

10.1002/cmdc.202000154
ChemMedChem
FULL PAPER
with DCM. The organic layers were combined, dried over MgSO4
and evaporated under vacuum.
THF (0.3 mL) and pyridine (0.3 mL). Work-up buffer (pH 7, 5
mL) and EtOAC (20 mL). Chromatography (SiO2, CH/EtOAc, 5:1)
gave 5 (1.2 mg, 3.4 μmol, 35%, 6% over 5 steps).
K1: C23=Ac. The crude carboxylic acid was diluted in MeOH
and K2CO3 was added (3.00 eq). The reaction was stirred for 3 h at
room temperature. The reaction was quenched with NaHCO3 and
diluted with DCM. After separation of the organic layer, the
aqueous layer was extracted with DCM. The combined organic
layers were washed with brine, dried over MgSO4 and evaporated
in vacuo. The crude product was purified by column
chromatography.
K2:C23=TBS: To a solution of THF and pyridine at 0 °C was
added HF-pPyr (70 % HF) resulting in a stock solution. To a
solution of carboxylic acid (1.00 eq) in THF at 0 °C was added the
HF-pyr stock solution. The reaction was stirred for 6 h at 0 °C. The
reaction was quenched with a saturated solution of NaHCO3 and
diluted with DCM. After separation of the organic layer, the
aqueous layer was extracted with DCM. The combined organic
layers were washed with brine, dried over MgSO4 and evaporated
in vacuo. The crude product was purified by column
chromatography.
MNBA (5.00 eq), DMAP (7.00 eq) and 4 Å MS were dried for
1 h under high vacuum before DCM was added. The seco acid was
diluted in DCM and added to the solution over 20h at room
temperature. Two hours after completion of the addition, the
reaction was quenched at 0 °C with buffer (pH 7). After separation
of the organic layer, the aqueous layer was extracted with DCM.
The combined organic layers were washed with brine, dried over
MgSO4 and evaporated in vacuo. The crude product was purified
by column chromatography.
The macrolactone (1.00 eq) was then diluted in THF and
cooled down at 0 °C. Pyridine was added followed by HF-pyr
(70 % HF). After 1 day, the reaction was quenched at 0 °C with
buffer (pH 7). After separation of the organic layer, the aqueous
layer was extracted with EtOAc. The organic layers were washed
with a saturated solution of NaHCO3, combined, dried over MgSO4
and evaporated in vacuo. The crude product was purified by
column chromatography.
Rf = 0.45 (SiO2, CH/EtOAc, 3:1); ꢀꢆꢂꢈꢇꢉ = - 33.4° (c = 0.12,
CHCl3); 1H-NMR (700 MHz, CD2Cl2): δ [ppm] = 6.53 (d, J = 16.0
Hz, 1H), 6.32 (dd, J = 15.1, 10.9 Hz, 1H), 5.93 (d, J = 10.7 Hz,
1H), 5.67 (dd, J = 16.0, 4.8 Hz, 1H), 5.63 (s, 1H), 5.60 – 5.56 (m,
1H), 5.20 – 5.17 (m, 1H), 5.01 (dd, J = 9.0, 1.1 Hz, 1H), 4.40 (d, J
= 4.5 Hz, 1H), 4.39 – 4.37 (m, 1H), 4.01 – 3.97 (m, 1H), 3.95 (d, J
= 9.4 Hz, 1H), 3.50 (d, J = 9.0 Hz, 1H), 3.19 (s, 3H), 2.44 (dt, J =
12.0, 3.9 Hz, 2H), 2.24 (ddd, J = 9.9, 8.7, 5.4 Hz, 1H), 2.21 – 2.19
(m, 2H), 1.95 (td, J = 9.8, 5.8 Hz, 2H), 1.89 (d, J = 2.3 Hz, 3H),
1.82 (ddd, J = 9.1, 7.3, 2.0 Hz, 1H), 1.77 (s, 3H), 1.71 (dd, J = 6.3,
2.9 Hz, 2H), 1.67 (d, J = 1.2 Hz, 3H), 1.63 (s, 3H), 0.71 (d, J = 6.7
Hz, 3H), 0.57 (d, J = 7.2 Hz, 3H); 13C-NMR (176 MHz, CDCl3): δ
[ppm] = 173.3, 139.2, 134.6, 133.7, 132.6, 132.0, 131.1, 130.8,
128.9, 128.5, 128.0, 127.9, 126.8, 89.3, 72.9, 72.8, 62.6, 55.9, 40.9,
40.3, 39.2, 34.5, 32.7, 24.3, 23.8, 19.8, 17.1, 16.5, 11.8, 10.6;
HRMS (ESI+) calculated for C30H46O5Na+ [M+Na]+: 509.3237,
found: 509.3237.
.
Analog 6: Method K1 with DMSO (25 μL, 354 mmol), SO3 -
pyr (17 mg, 106 μmol), DIEA (25 μL, 141 μmol) and alcohol 47a
(27 mg, 35 μmol) in DCM (3 mL). Work-up NaHCO3 (3 mL) and
DCM (20 mL). Crude aldehyde in tert-butanol (2 mL) and 2-
methylbut-2-ene (0.2 mL) with NaClO2 (10 mg, 113 μmol) and
KH2PO4 (19 mg, 141 μmol) in H2O (2 mL). Work-up NaCl (4 mL)
and DCM (20 mL). Crude carboxylic acid with K2CO3 (15 mg, 106
μmol) in MeOH (2.5 mL). Work-up NaHCO3 (5 mL) and DCM
(20 mL). Chromatography (SiO2, CH/EtOAc, 3:2) gave seco acid
(5 mg, 7 μmol, 20% over 3 steps). Directly used with MNBA (11
mg, 31 μmol) and DMAP (5.2 mg, 43 μmol) in DCM (3 mL). Seco
acid diluted in DCM (4 mL). Work-up buffer (pH 7, 3 mL) and
DCM (15 mL). Chromatography (SiO2, CH/EtOAc, 50:1) gave the
macrolactone (4.3 mg, 6 μmol, 86%). Directly used with HF-.pyr
(0.2 mL) in THF (0.3 mL) and pyridine (0.3 mL). Work-up buffer
(pH 7, 5 mL) and EtOAC (20 mL). Chromatography (SiO2,
CH/EtOAc, 10:1 to 5:1) gave 6 (1.2 mg, 2.5 μmol, 41%, 7% over 5
steps). Rf = 0.37 (SiO2, CH/EtOAc, 2:1); ꢀꢆꢂꢈꢇꢉ = - 10.4° (c = 0.1,
CHCl3, 20 °C); 1H-NMR (700 MHz, CD2Cl2): δ [ppm] = 6.51 (d, J
= 15.9 Hz, 1H), 5.71 – 5.67 (m, 1H), 5.66 (s, 1H), 5.38 – 5.35 (m,
1H), 5.18 (d, J = 1.2 Hz, 1H), 4.99 (dd, J = 9.1, 1.2 Hz, 1H), 4.32
(s, 1H), 4.09 – 4.05 (m, 1H), 3.99 – 3.93 (m, 2H), 3.43 (d, J = 9.9
Hz, 1H), 3.17 (s, 3H), 2.27 – 2.18 (m, 5H), 2.07 – 2.03 (m, 2H),
2.01 – 1.97 (m, 2H), 1.91 (d, J = 1.4 Hz, 3H), 1.77 (dd, J = 1.4, 0.8
Hz, 3H), 1.72 – 1.68 (m, 2H), 1.65 (d, J = 1.4 Hz, 3H), 1.59 – 1.55
(m, 2H), 1.51 (t, J = 1.2 Hz, 3H), 1.45 (ddd, J = 10.5, 4.4, 2.9 Hz,
2H), 0.73 (d, J = 6.7 Hz, 3H), 0.60 (d, J = 7.1 Hz, 3H); 13C-NMR
(176 MHz, CD2Cl2): δ [ppm] = 173.3, 138.4, 135.0, 132.9, 132.2,
131.9, 130.9, 130.6, 128.8, 18.7, 126.7, 90.1, 73.0, 71.7, 64.1, 55.4,
40.7, 40.4, 38.8, 34.1, 27.8, 26.6, 25.9, 24.3, 23.0, 19.7, 17.0, 16.7,
12.1, 9.8; HRMS (ESI+) calculated for C30H48O5Na+ [M+Na]+:
511.3394, found: 511.3394.
Analog 5: Method K2 with DMSO (30 μL, 420 mmol), SO3-
pyr (20 mg, 126 μmol), DIEA (29 μL, 168 μmol) and alcohol 48a
(35 mg, 42 μmol) in DCM (3 mL). Work-up NaHCO3 (3 mL) and
DCM (20 mL). Crude aldehyde diluted in tert-butanol (2 mL) and
2-methylbut-2-ene (0.2 mL) with NaClO2 (12 mg, 134 μmol) and
KH2PO4 (23 mg, 168 μmol) in H2O (2 mL). Work-up NaCl (4 mL)
and DCM (20 mL). Crude carboxylic acid and HF.-pyr stock
solution (0.34 mL, out of a solution of THF (1.3 mL), pyridine
(0.75 mL), HF.-pyr (0.25 mL, 75% HF)) in THF (0.8 mL). Work-
up NaHCO3 (10 mL) and DCM (20 mL). Chromatography (SiO2,
CH/EtOAc, 3:2) gave seco acid (6.3 mg, 8.6 μmol, 32% over 3
steps). Directly used with MNBA (15 mg, 43 μmol) and DMAP
(7.3 mg, 60 μmol) in DCM (4 mL). Seco acid diluted in DCM (5
mL). Work-up buffer (pH 7, 7 mL) and DCM (15 mL).
Chromatography (SiO2, CH/EtOAc, 50:1) gave the macrolactone
(5.1 mg, 7.1 μmol, 83%). Directly used with HF.-pyr (0.3 mL) in
.
Analog 7: Method K2 with DMSO (41 μL, 523 mmol), SO3 -
pyr (25 mg, 157 μmol), DIEA (37 μL, 209 μmol) and alcohol 48b
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10.1002/cmdc.202000154
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(43 mg, 52 μmol) in DCM (3 mL). Work-up NaHCO3 (3 mL) and
DCM (20 mL). Crude aldehyde in tert-butanol (2 mL) and 2-
methylbut-2-ene (0.2 mL) with NaClO2 (15 mg, 167 μmol) and
KH2PO4 (29 mg, 209 μmol) in H2O (2 mL). Work-up NaCl (4 mL)
and DCM (20 mL). Crude carboxylic acid and HF.-pyr stock
solution (0.50 mL, out of a solution of THF (1.3 mL), pyridine
(0.75 mL), HF.-pyr (0.25 mL, 75% HF)) in THF (1.0 mL). Work-
up NaHCO3 (10 mL) and DCM (20 mL). Chromatography (SiO2,
CH/EtOAc, 3:2) gave seco acid (12 mg, 17 μmol, 42% over 3
steps). Directly used with MNBA (29 mg, 84 μmol) and DMAP
(14 mg, 117 μmol) in DCM (6 mL). Seco acid diluted in DCM (8
mL). Work-up buffer (pH 7, 10 mL) and DCM (25 mL).
Chromatography (SiO2, CH/EtOAc, 50:1) gave the macrolactone
(9.8 mg, 14 μmol, 83%). Directly used with HF.-pyr (0.5 mL) in
THF (0.5 mL) and pyridine (0.5 mL). Work-up buffer (pH 7, 5
mL) and EtOAC (20 mL). Chromatography (SiO2, CH/EtOAc,
10:1 to 5:1) gave 7 (1.6 mg, 3.4 μmol, 24%, 8% over 5 steps). Rf =
0.28 (SiO2, CH/EtOAc, 2:1); ꢀꢆꢂꢈꢇꢉ = - 24.7° (c = 0.15, CHCl3); 1H-
NMR (700 MHz, CD2Cl2): δ [ppm] = 6.53 (dd, J = 16.0, 4.0 Hz,
1H), 6.35 (dd, J = 15.3, 10.7 Hz, 1H), 5.93 (d, J = 10.8 Hz, 1H),
5.69 (dd, J = 16.0, 4.9 Hz, 1H), 5.64 (s, 1H), 5.60 (ddd, J = 13.8,
9.6, 5.3 Hz, 1H), 5.16 (d, J = 9.9 Hz, 1H), 4.39 (s, 1H), 4.28 (ddd,
J = 10.8, 8.7, 4.4 Hz, 1H), 4.04 (ddd, J = 10.1, 6.8, 4.6 Hz, 1H),
3.53 (d, J = 9.2 Hz, 1H), 3.24 (td, J = 8.9, 2.4 Hz, 1H), 3.18 (s,
3H), 2.48 – 2.43 (m, 2H), 2.26 – 2.15 (m, 3H), 1.89 (d, J = 2.7 Hz,
3H), 1.87 – 1.84 (m, 1H), 1.76 (d, J = 3.1 Hz, 3H), 1.64 (d, J = 2.9
Hz, 3H), 1.51 – 1.42 (m, 4H), 1.25 – 1.13 (m, 4H), 0.80 (d, J = 6.7
Hz, 3H), 0.55 (d, J = 7.2 Hz, 3H); 13C-NMR (176 MHz, CD2Cl2): δ
[ppm] = δ 173.6, 134.4, 133.8, 132.3, 132.0, 131.4, 130.9, 129.2,
128.5, 128.1, 128.0, 89.3, 76.3,73.2, 62.9, 55.9, 40.9, 40.2, 35.2,
33.8, 32.3, 29.9, 26.1, 25.5, 24.5, 19.8, 17.3,11.4, 10.5; HRMS
(ESI+) calculated for C29H46O5Na+ [M+Na]+: 497.3237, found:
497.3237.
(s, 1H), 4.11 (dt, J = 10.8, 6.0 Hz, 1H), 3.99 – 3.95 (m, 1H), 3.42
(d, J = 10.0 Hz, 1H), 3.24 (td, J = 8.8, 8.3, 2.2 Hz, 1H), 3.16 (s,
3H), 2.30 (dt, J = 14.6, 6.8 Hz, 1H), 2.24 – 2.18 (m, 3H), 2.05
(dtdd, J = 14.1, 6.4, 5.1, 1.3 Hz, 1H), 1.89 (d, J = 1.4 Hz, 3H), 1.87
– 1.83 (m, 1H), 1.76 (dd, J = 1.5, 0.8 Hz, 3H), 1.62 – 1.56 (m, 4H),
1.51 (t, J = 1.2 Hz, 3H), 1.27 – 1.18 (m, 8H), 0.81 (d, J = 6.7 Hz,
3H), 0.57 (d, J = 7.1 Hz, 3H); 13C-NMR (176 MHz, CD2Cl2): δ
[ppm] = 173.3, 134.3, 132.9, 132.6, 132.0, 131.4, 130.6, 128.4,
127.9, 89.6, 76.7, 72.8, 64.0, 55.4, 40.5, 39.9, 35.1, 34.0, 29.6, 28.1,
26.9, 26.8, 26.0, 25.5, 24.4, 19.7, 17.5, 11.1, 9.7; HRMS (ESI+)
calculated for C29H48O5Na+ [M+Na]+: 499.3394, found: 499.3394.
MTT assays: The test compounds were investigated at human
1321N1 astrocytoma cells using the 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (MTT) assay in order to assess
their cytotoxic effects. Assays were performed as previously
described by Baqi et al.[30] In brief, cells were detached from the
175 cm2 culture flasks in which they were grown and subsequently
counted using a Neubauer haemocytometer. Then, they were
resuspended in the growth medium. An aliquot of the cell
suspension (180 μL) was added into each well of a 96-well plate to
obtain 1000 cells per well and incubated for 24 h at 37 °C, 5%
CO2, and 95% humidity. The outer wells of the 96-well plate were
filled with 200 μL of phosphate-buffered saline (PBS) to prevent
evaporation of the fluid. After 24 h, stock solutions (10 mM) of the
test compounds (archazolids) were prepared in DMSO and diluted
with cell culture medium to give 10-fold of the final
concentrations. Then, test compound solution (20 μL) was added to
each well. The final DMSO concentration was 1%. The cells were
incubated in the presence of the appropriate drug for 71 h. Then, 40
μL from a freshly made stock solution of MTT in water (5 mg/mL)
was added to each well, and the cells were incubated for 1 h at 37
°C, 5% CO2. After the incubation time, the medium containing
MTT was removed, and 100 μL of DMSO was added to each well
in order to dissolve the crystals that were formed. The
spectrophotometric absorbance was subsequently measured at 570
nm using a FlexStation (3 multimode plate reader, molecular
devices) with a filter of 690 nm. The data were analyzed using
Microsoft Excel and GraphPad Prism 5. Results were evaluated by
comparing the absorbance of the wells containing compound-
treated cells with the absorbance of wells containing 1% DMSO
without any drug (=100% viability). All experiments were
performed in duplicates in at least three separate experiments.
.
Analog 8: Method K1 with DMSO (20 μL, 208 mmol), SO3 -
pyr (13 mg, 84 μmol), DIEA (20 μL, 112 μmol) and alcohol 47b
(21 mg, 28 μmol) in DCM (3 mL). Work-up NaHCO3 (3 mL) and
DCM (20 mL). Crude aldehyde in tert-butanol (2 mL) and 2-
methylbut-2-ene (0.2 mL) with NaClO2 (8 mg, 89 μmol) and
KH2PO4 (15 mg, 111 μmol) in H2O (2 mL). Work-up NaCl (4 mL)
and DCM (20 mL). Crude carboxylic acid with K2CO3 (11 mg, 84
μmol) in MeOH (2.0 mL). Work-up NaHCO3 (2 mL) and DCM
(15 mL). Chromatography (SiO2, CH/EtOAc, 3:2) gave seco acid
(9.5 mg, 13 μmol, 46% over 3 steps). Directly used with MNBA
(23 mg, 66 μmol) and DMAP (11 mg, 92 μmol) in DCM (5 mL).
Seco acid diluted in DCM (7 mL). Work-up buffer (pH 7, 3 mL)
and DCM (15 mL). Chromatography (SiO2, CH/EtOAc, 50:1) gave
the macrolactone (7.1 mg, 10 μmol, 77%). Directly used with HF.-
pyr (0.3 mL) in THF (0.5 mL) and pyridine (0.5 mL). Work-up
buffer (pH 7, 5 mL) and EtOAC (20 mL). Chromatography (SiO2,
CH/EtOAc, 10:1 to 5:1) gave 6 (2.1 mg, 4.4 μmol, 31%, 11% over
5 steps). Rf = 0.44 (SiO2, CH/EtOAc, 2:1); ꢀꢆꢂꢈꢇꢉ = - 8.0° (c = 0.20,
CHCl3); 1H-NMR (700 MHz, CD2Cl2): δ [ppm] = 6.59 (d, J = 16.0
Hz, 1H)., 5.71 (ddd, J = 15.9, 4.6, 0.7 Hz, 1H), 5.64 (s, 1H), 5.37
(ddd, J = 9.3, 5.4, 1.6 Hz, 1H), 5.18 (dq, J = 9.9, 1.3 Hz, 1H), 4.46
P2X3 Receptor Assay. 1321N1 astrocytoma cell lines stably
expressing the human P2X3 receptor were utilized to determine the
compounds’ inhibition of ATP-induced calcium influx as
previously described.[13,31] The agonist concentration used
corresponded to ∼80% of its maximal effect. Full
concentration−inhibition curves were determined, and IC50 values
were calculated using GraphPad Prism. Data are means from at
least 3 separate experiments, each performed in duplicates.
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10.1002/cmdc.202000154
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FULL PAPER
acknowledged. We thank Andreas J. Schneider (University of
Bonn) for excellent HPLC-support.
A3 Adenosine Receptor Radioligand Binding Assay.
Membrane preparations of Chinese hamster ovary (CHO) cells
expressing human A3ARs were obtained as described before.[32]
[3H]Phenyl-8-ethyl-4-methyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo-
[2,1-i]purine-5-one ([3H]PSB-11, 53 Ci/mmol) was used as a
radioligand (0.5 nM).[33] Nonspecific binding was determined in
the presence of 100 μM (R)-N6-phenylisopropyladenosine (R-PIA).
The competition assays were performed in a total volume of 400
μL in assay buffer (50 mM Tris-HCl, pH 7.4). Stock solutions of
the test compounds were prepared in DMSO; the final DMSO
concentration was 1%. The membrane preparations were
preincubated for 20 min with adenosine deaminase 2 U/mL per mg
of protein. Incubation was carried out for 60 min at 23 °C. The
incubation was terminated by filtration through GF/B glass-fiber
filters using a 48-channel cell harvester, and filters were washed
three times with ice-cold Tris-HCl buffer (50 mM, pH 7.4). The
filters were transferred into scintillation vials and incubated for 6 h
with 2.5 mL of scintillation cocktail (Beckman-Coulter).
Radioactivity was counted in a liquid scintillation counter. At least
three separate experiments were performed. Data were analyzed
using Graph Pad Prism version 5 (San Diego, CA, USA). For the
calculation of Ki values by nonlinear regression analysis, the
Cheng−Prusoff equation and a KD value of 4.9 nM for [3H]PSB-11
were used.
Keywords: Polyketides, polyenes, macrolactonization, macrolides,
anticancer
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Entry for the Table of Contents
FULL PAPER
Polyene Macrolides*
Solenne Rivière, Christin Vielmuth,
Christiane Ennenbach, Aliaa
Abdelrahman, Carina Lemke, Michael
Gütschow, Christa E. Müller and Dirk
Menche
Novel
retaining
simplified
powerful
archazolids
biological
potencies were efficiently obtained
by an aldol condensation and
macrolactonization sequence.
Design, Synthesis and Biological
Evaluation
of
Highly
Potent
Simplified Archazolids
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