Approach to the Core Structure of 15- epi -Exiguolide

Article abstract of DOI:10.1055/s-0037-1610821

The synthesis of seco acid 41 of the macrolactone part of 15- epi -exiguolide, containing a bis-pyran subunit and a trans double bond, is described. Key features of the synthetic strategy include a Feringa-Minnaard asymmetric organocuprate addition to uns

Full text of DOI:10.1055/s-0037-1610821

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–N
feature
A
en
A. Riefert, M. E. Maier
Feature
Synthesis
Approach to the Core Structure of 15-epi-Exiguolide
thermolysis of b-lactone
Alexander Riefert
TIPS
a) LAu+
b) PPTS
Martin E. Maier*
0
0
0
0
0-
0
0
2
3-
5
7
0
4-
9
4
3
TBSO
19
OTBS
13
OH
9
19
15
Institut für Organische Chemie, Eberhard Karls Universität
Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
martin.e.maier@uni-tuebingen.de
OTBS
O
c) TBSOTf
(75%)
TIPS
13
O
9
C
7
7
6
O
7
H
Meyer-Schuster rearrangement
and oxa-Michael
19
O
15
OH
6 steps
13
O
1
O
HO2C
7
41
OTBS
Received: 08.06.2018
Accepted: 15.06.2018
Published online: 16.07.2018
DOI: 10.1055/s-0037-1610821; Art ID: ss-2018-z0394-fa
was later shown that exiguolide has antiproliferative activi-
ty against some human cancer cell lines with IC50 values in
the low micromolar range.3,4
Abstract The synthesis of seco acid 41 of the macrolactone part of
15-epi-exiguolide, containing a bis-pyran subunit and a trans double
bond, is described. Key features of the synthetic strategy include a Fer-
inga–Minnaard asymmetric organocuprate addition to unsaturated es-
ter 17 to set the stereocenter at C15. The derived acid 8 (C9–C16 frag-
ment) was ideally suited for combination with aldehyde 9 (C17–C21
fragment) via an aldol strategy leading to β-lactone 25 which upon
thermal decarboxylation provided alkene 26. Chain extension led to
propargylic alcohol 7. Treatment of 7 with a LAu+ catalyst promoted a
Meyer–Schuster rearrangement to enone 30 that led to cis-tetrahydro-
pyran 31 via intramolecular oxa-Michael reaction. The second pyran
ring was prepared from alkoxy ketone 5 by reductive cyclization. The
further steps toward macrolactone 43 were hampered by the epimeric
mixture at C5.
O
CO2Me
O
OH
19
C
19
16
CO2Me
O
1
O
O
OH
HO
O
1
O
13
O
O
O
O
A
B
5
B
MeO2C
A
7
9
MeO2C
13
OAc
HO
(–)-exiguolide (1)
bryostatin 1 (2)
Figure 1 Structures of (–)-exiguolide (1) and bryostatin 1 (2)
In 2008 a paper by Cossy pointed out the structural sim-
ilarity to the bryostatins.5 These polyketides feature three
tetrahydropyran rings, one double bond in the macrolac-
tone and several stereocenters. They elicit a range of biolog-
ical activities, but most important is their ability to modu-
late the activity of protein kinase C.6 However, the total syn-
thesis of bryostatins requires too many steps, making
access to these compounds difficult.7 Efforts by the Wender
group generated much simpler bryostatin analogues, some
of which show comparable activities as the natural lead
compound.8 If the Cossy hypothesis would be true, even
more simple bryostatin analogues might be discovered.
However, this seems questionable since the lower regions
of these macrolides are quasi-enantiomeric so binding to
the same protein targets seems unlikely.
Key words exiguolide, β-lactone, Meyer–Schuster rearrangement,
tetrahydropyrans, alkenes, Mulzer–Adam olefination
Polyketide-based macrolactones commonly feature sub-
stituents or transannular ether bridges to restrict the con-
formational freedom and to provide defined local confor-
mations. Biosynthetic considerations make it understand-
able that tetrahydropyran rings are frequently seen in
macrocyclic polyketides.1 A few natural products, for exam-
ple (–)-exiguolide (1) and the bryostatins (Figure 1), even
contain two or more tetrahydropyran rings. Exiguolide (1)
is a 20-membered macrolactone known since 2006.2 It was
isolated from the marine sponge Geodia exigua. Key struc-
tural features include two cis-2,6-disubstituted tetrahydro-
pyran rings, one of them carrying an exocyclic enoate, one
trans double bond within the macrocyclic ring, and a
triene-containing side chain extending from C19. The C16–
C17 double bond is flanked by two methyl-bearing stereo-
centers that might impede olefination reactions. Originally
reported to inhibit the fertilization of sea urchin gametes, it
So far, six total syntheses of exiguolide have been re-
ported.3,4,9 Three syntheses rely on a ring-closing metathe-
sis (rcm) with formation of the C16–C17 double bond. In
this context, the type of functional group extending from
C19 seems to be crucial. Thus, the rcm on substrates with a
vinyl iodide side chain gives low yields of the corresponding
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

B
A. Riefert, M. E. Maier
Feature
Synthesis
macrolactone. In two of the total syntheses, macrolacton-
ization strategies came into use. In the synthesis by the
Scheidt group,3 an intramolecular Prins cyclization led to
the macrolactone. The shortest synthesis so far requires 19
steps in the longest linear sequence with an overall yield of
16.8%.9b Here, the two pyran rings were constructed by
Prins cyclizations. Regarding the synthesis of exiguolide an-
alogues, major contributions have come from the Fuwa
group.4,10 This work led to the SAR findings shown in Figure
2. Thus, the 15-CH3 is not essential, whereas the exocyclic
enoate seems to be crucial. The C20–C23 E,Z-diene, the cor-
rect length of the side chain and a heteroatom at C27 are
also required for the antiproliferative activity. Tests on the
A549 cell line showed that exiguolide arrests the cell cycle
at the G1 phase. It seems that exiguolide inhibits phosphor-
ylation and therefore activity of the retinoblastoma protein,
a tumor suppressor protein.11 However, it is still not known
with certainty whether (–)-exiguolide really represents a
simplified bryostatin. Accordingly, further analogues would
be desirable.
chosing 15-epi-exiguolide as target, we hoped to modulate
the activity or even redirect the analogue to another pro-
tein target.13
H
OP
19
5
O
1
1
15
1 /
O
O
OP
OH
13
15-epi-1
9
O
OP
O
O
9
19
5
13
HO
16
3
TIPS
4
Meyer–Schuster
rearrangement
+ oxa-Michael
PMBO
OP
O
9
5
O
OP
1
PO
O
13
19
9
O
OP
TIPS
6
5
13
15
TIPS
OH
OP
OP
methyl group and double bond not essential
18-CH3 probably essential
9
13
19
15
6
TIPS
E-configuration essential
7
19
O
OP
16
OP
OP
27
O
O
1
15-CH3 not essential
+
MeO
9
19
13
15
17
H
O
TIPS
CO2H
heteroatom at C27 essential
MeO2C
13
8
9
O
O
A
B
5
Scheme 1 Retrosynthetic plan for the synthesis of (–)-exiguolide and
congeners; P = tert-butyldimethylsilyl (TBS)
9
methoxycarbonyl group
essential
(–)-exiguolide (1)
Figure 2 Key structure–activity findings by the Fuwa group10
We started the synthesis with the preparation of the
C9–C16 fragment 8, which carries two stereocenters. Thus,
monoprotection of pentane-1,5-diol (10) with tert-butyldi-
methylsilyl chloride to alcohol 11 was followed by oxidation
to pentanal derivative 12 using Swern conditions (Scheme
2).12,14 Next, a Brown allylation15 using (–)-Ipc2BH16 as the
boron source established the stereocenter at C13, furnish-
ing homoallyl alcohol17 13 in 86% yield and 95% ee. Subse-
quent protection of the alcohol function of 13 as tert-bu-
tyldimethylsilyl (TBS) ether 14 and ozonolysis of the double
bond provided aldehyde 15 in good yield. Aldehyde 15 was
used for chain extension with the stabilized ylide18 16 re-
sulting in enethioate 17. The methyl-bearing stereocenter
at C15 was established using a Feringa–Minnaard asym-
metric conjugate addition to unsaturated thioester 17.19,20
As we planned to prepare C15-epi-exiguolide, (S)-Tol-BINAP
was used as a chiral ligand. Thus, enethioate 17 was reacted
with MeMgBr (5 equiv) in the presence of (S)-Tol-BINAP (ca.
0.75 mol%) and CuI (1 mol%) in t-BuOMe at –75 °C to give
thioester 18 in 83% yield (20 g scale). A final hydrolysis of
the thioester function of 18 furnished carboxylic acid 8.
Our interest in exiguolide was triggered by its appealing
structure, its biology and the fact that we recently had
found a method based on a Meyer–Schuster rearrangement
for the synthesis of 2,6-cis-tetrahydropyrans.12 In this
transformation a substrate with a 6-heptyne-1,5-diol sub-
structure (compound 7) undergoes a gold(I)-catalyzed rear-
rangement to a 7-hydroxy enone that can cyclize to a tetra-
hydropyran (compound 6) via an intramolecular oxa-Mi-
chael reaction. For the methyl-bearing stereocenter at C15,
we opted for a Feringa–Minnaard asymmetric methyl cu-
prate addition to an enoate derivative, giving an acid of type
8. We also hoped to utilize the 3-methyl carboxylic acid de-
rivative for a subsequent olefination reaction (Scheme 1).
The second tetrahydropyran ring would be constructed by
chain extension of methyl ketone 6 and ionic reduction of a
derived hemiacetal 4. The exocyclic enoate extending from
C5 would be installed by an asymmetric Horner–Wad-
sworth–Emmons reaction after macrolactonization. By
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

C
A. Riefert, M. E. Maier
Feature
Synthesis
has never been reported. The aldol reaction between acid 8
and aldehyde 9 turned out to be nontrivial. Thus, formation
of the dilithium enolate of acid 8 with 2 equivalents of
either n-BuLi, N-naphthalenide or NaN(SiMe3)2 in THF at
–75 °C for 1 hour led to decomposition of the acid. This was
detected after quenching of the enolate solution with pH 7
buffer solution. With LDA and t-BuLi at –75 to 0 °C for 1
hour, enolate formation was successful and did not lead to
decomposition of the acid. In the aldol reaction, best results
were obtained with t-BuLi, deprotonation at –75 to –10 °C,
followed by addition of aldehyde 9 at –75 °C and stirring of
the mixture at this temperature for 14 hours. Under these
conditions, 57% of hydroxy acid 24 was obtained. Due to
OTBS
O
(COCl)2, DMSO, Et3N
(+)-Ipc2B(allyl)
OR
OH
H
H
CH2Cl2, –60 °C (76%)
Et2O, –75 °C
(86%)
10 R = H
12
NaH, THF
TBSCl (75%)
11 R = TBS
O
16
SEt
CH2Cl2, reflux
(80%)
Ph3P
OTBS
OR
O3, CH2Cl2
OTBS TBSO
13
O
–78 °C (78%)
9
15
15
13 R = H
14 R = TBS
OTBS
TBSCl, imid.
DMF (98%)
MeMgBr
OTBS
O
OTBS TBSO
(S)-Tol-BINAP
SEt
CuI, t-BuOMe
–75 °C
17
18
1
(83%)
O
SEt
signal overlap in the H NMR spectrum of 24, we were not
OTBS TBSO
LiOH, H2O2
sure about the stereochemistry and the presence of iso-
mers. The structure was tentatively assigned based on the
chair-like transition state model A (Scheme 4) similar to at-
tack of an E-enolate to an aldehyde with an α-methyl sub-
stituent.24 Formation of the β-lactone was achieved by stir-
ring hydroxy acid 24 with benzenesulfonyl chloride in pyri-
dine. Lactone 25 essentially showed only one set of signals
in the 13C NMR spectrum indicating its isomeric purity. The
thermal fragmentation of β-lactone 25 to alkene 26 was
best performed neat at an oil bath temperature of 190 °C.
This way, a 87% yield of trans-alkene 26 could be obtained.
CO2H
9
13
15
THF, H2O (92%)
8
Scheme 2 Synthesis of carboxylic acid 8 (C9–C16 fragment). The allyl-
borane reagent was prepared from (+)-α-pinene.
We next focused on the preparation of an aldehyde frag-
ment 9 which would be combined with acid 8 in a Mulzer–
Adam-type olefination reaction.21 The synthesis of building
block 9 began with an Evans aldol reaction between oxazo-
lidinone22 19 and propynal derivative23 20 (Scheme 3). Clas-
sical conditions using the boron enolate of 19 and running
the aldol reaction in CH2Cl2 at –65 °C provided an 85% yield
of syn-aldol product 21. Thereafter routine functional
group manipulations, namely protection of the alcohol
function as the TBS ether to give 22, reductive removal of
the chiral auxiliary and Dess–Martin periodinane (DMP)
oxidation of alcohol 23, furnished aldehyde 9.
1
In the H NMR spectrum of 26, the coupling constant J =
15.4 Hz between the olefinic protons indicated formation of
the trans double bond. We also tried to form β-lactone 25
from the corresponding 2-pyridyl thioester in a domino
Mukaiyama aldol reaction/lactonization (LiTMP, THF, TESCl,
–78 °C, 2 h, addition of ZnCl2, r.t., 2 h, then addition of 9,
50 °C, 3 d);25 however, the expected 25 was not formed.
Continuing with the synthesis, the primary alcohol func-
tion was deprotected by acid-catalyzed transetherification
to give alcohol 27. Its oxidation with Dess–Martin perio-
dinane (DMP) led to aldehyde 28. The propynyllithium spe-
cies for addition to aldehyde 28 was generated from 1-bro-
moprop-1-ene using n-BuLi (1.5 equiv). This gave propar-
a) n-Bu2BOTf, Et3N
CH2Cl2, –30 °C
O
O
O
O
OR
NaBH4
O
N
O
N
b) –65 °C, addition of
O
THF/H2O
(94%)
TIPS
Bn
Bn
TIPS
19
21 R = H
22 R = TBS
nonsignificant mixture26 of
20
H
TBSOTf, 2,6-lutidine
CH2Cl2 (93%)
gylic alcohol
7
as
a
(85%)
diastereomers. The key Meyer–Schuster rearrangement of 7
with the Echavarren catalyst27 29 was highly dependent on
the catalyst loading. Here, the intermediate enone 30 typi-
cally was not isolated but rather treated in the same pot
with p-TsOH to induce the intramolecular oxa-Michael ad-
dition to tetrahydropyran derivative 31. Whereas 10 mol%
of 29 gave methyl ketone 31 in 46% yield, 15 mol% of 29 led
to ketone 31 in acceptable 82% yield. Reprotection of the
19-OH function as the TBS ether delivered key fragment 6.
In the NOESY spectrum, 9-H (δ = 3.68 ppm) and 13-H (δ =
3.28 ppm) showed a very strong cross-peak, indicating
their cis configuration at the tetrahydropyran ring.
OH OTBS
O
OTBS
DMP, NaHCO3
CH2Cl2 (85%)
H
17
19
21
TIPS
TIPS
23
9
Scheme 3 Synthesis of pent-4-ynal derivative 9 (C17–C21 fragment)
via an aldol strategy
With both fragments 8 and 9 in hand, we could then fo-
cus on their combination (Scheme 4). As far as we know,
formation of an alkene of the size of 26, with methine
groups flanking the alkene, via an intermediate β-lactone
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

D
A. Riefert, M. E. Maier
Feature
Synthesis
etherification (64%). For conversion of the terminal double
bond into the aldehyde 36 we relied on a dihydroxylation
reaction followed by oxidative cleavage of the intermediate
diol.
via:
H
Li
R1
a) t-BuLi, THF
–75 to –10°C, 30 min
b) –75 °C, addition of
O
OTBS TBSO
Li
H
R2
O
9
13
15
O
Me
O
OTBS
CO2H
8
A
H
H
(–)-Ipc2B(allyl), Et2O
–90 °C to r.t. , 4 h
DMP, NaHCO3
CH2Cl2, 0 °C to r.t.
TIPS
(57%)
9
TBSO
O
TBSO
OH
OTBS TBSO
OH OTBS
PhSO2Cl, pyridine
0 °C to r.t. (70%)
H
then NaOOH, r.t., 10 h
1 h (64%)
32
33
24
HO2C
TIPS
a) K2OsO4•2H2O, K3Fe(CN)6
K2CO3, t-BuOH/H2O, 0 °C
TBSO
OR
TBSO
OR
O
TIPS
1
3
5
H
b) NaIO4, MeCN/H2O, 0 °C
(44%)
190 °C
neat (87%)
OTBS TBSO
36 R = PMB
34 R = H
PMBO(C=NH)CCl3
CH2Cl2, r.t.
OTBS
OTBS
35 R = PMB
12 h (64%)
O
25
O
Scheme 5 Synthesis of aldehyde 36 (C1–C5 fragment)
OR
TBSO
DMP, NaHCO3
CH2Cl2 (82%)
TIPS
Next, we focused on the combination of aldehyde 36
with methyl ketone 6 to a C1–C21 fragment. Thus, reaction
of the lithium enolate of 6, prepared from ketone 6 and LDA,
with aldehyde 36 gave hydroxy ketone 37 as a 3:1 mixture
of diastereomers at C5 (Scheme 6).31 Since this alcohol
function would be oxidized at a later stage, the mixture was
used as such for the further steps. After protection of the al-
cohol function as TBS ether 5, the crucial pyran formation
was investigated. Initial attempts at oxidative cleavage of
the PMB ether using DDQ in MeOH/CH2Cl2 resulted in de-
composition; using water instead of MeOH gave an inter-
mediate hemiacetal in 48% yield. Ceric ammonium nitrate
in acetone/H2O led to decomposition as well. The best over-
all results were obtained with Et3SiH in the presence of
BF3·Et2O. In this case, a one-step reductive removal of the
PMB ether and ionic reduction of the hemiacetal took place,
leading to bis-tetrahydropyran 38 in 61% yield. In the next
step, selective cleavage of the silyl ether at C1 was per-
formed using acid-catalyzed transetherification in a mix-
ture of MeOH/CH2Cl2. The resulting primary alcohol 39 was
then oxidized to acid 40 using Stark conditions,32 where tet-
rapropylammonium perruthenate was used as catalyst to-
gether with N-methylmorpholine N-oxide (NMO) as oxi-
dant. The NOESY spectrum of acid 40 showed the expected
correlation for 3-H/7-H as well as 9-H/13-H indicating the
cis configuration in the respective tetrahydropyran rings. In
preparation for the crucial macrolactonization, acid 40 was
treated with tetra-n-butylammonium fluoride hydrate
which gave seco acid 41. Surprisingly, the equatorial-posi-
tioned silyl ether at C5 was retained. We tried the macrolac-
tonization with the Shiina method, which utilizes 2-meth-
yl-6-nitrobenzoic anhydride (MNBA, 42) to convert the acid
function of ω-hydroxy acid 41 into a reactive mixed anhy-
dride that undergoes the lactonization.33 While the macro-
lactone formation could be realized (~60%), the compound
was not 100% clean. Moreover, we were not able to cleave
26 R = TBS
27 R = H
PPTS
MeOH/CH2Cl2
(64%)
Br
O
TBSO
OTBS
n-BuLi, THF
9
13
15
19
H
21
–75 °C (92%)
TIPS
28
OH
O
TBSO
OTBS
TIPS
cat. 29 (15 mol%)
CH2Cl2
7
TIPS
7
19
p-TsOH·H2O
OR
OR
OTBS
13
CH2Cl2 (82%)
13
O
TIPS
30 (R = TBS)
t-Bu
7
31 R = H
TBSOTf
2,6-lutidine, CH2Cl2
(91%)
O
t-Bu
P
6 R = TBS
–
Au+NCMe SbF6
29
Scheme 4 Synthesis of alkene 26, Meyer–Schuster rearrangement of
alkynol 7 and formation of tetrahydropyran 6 (C6–C21 fragment)
We then could turn to the synthesis of aldehyde 36
which corresponds to the C1–C5 fragment. The require-
ment for formation of the pyran ring A was a protected al-
cohol at C3 that could be liberated in a selective manner to
form a hemiacetal with the keto function at C7. Therefore,
we opted for a PMB protecting group for the 3-OH. Thus,
known monoprotected propanediol28 32 was oxidized to al-
dehyde29 33 and then subjected to a Brown allylation15 with
(–)-B-allyldiisopinocampheylborane, prepared from (+)-α-
pinene, leading to homoallyl alcohol 34 (Scheme 5). The en-
antiomeric excess was 91%, as determined by chiral GC.
Since protection of alcohol 34 to give PMB ether 35 under
basic conditions (NaH, PMBCl, DMF, 0 °C) proceeded only in
a moderate yield of 40%, we used the PMB imidate30 for this
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

E
A. Riefert, M. E. Maier
Feature
Synthesis
the remaining silyl ether of lactone 43, neither under acidic
conditions (AcOH, CSA) nor under conditions that utilize
fluoride (TBAF, HF·py).
Chain extension of the methyl ketone via aldol reaction
eventually led to hydroxy ketone 5 which was cyclized
through ionic reduction to deliver bis-tetrahydropyran 38.
Functional group manipulations gave seco acid 41 which
was converted into macrolactone 43 (impure) using the
Shiina method.
TIPS
TIPS
19
LDA, Et2O, –75 °C
OTBS
OTBS
13
1 h, then add 36
(69%)
O
O
O
Reactions were generally run under nitrogen atmosphere in oven-
dried glassware. Progress of the reactions was followed using POLY-
GRAM SIL G/UV254 TLC plates, and petroleum ether/Et2O mixtures of
them as an eluent. Anhydrous Et2O and THF were distilled from sodi-
um and benzophenone, whereas anhydrous CH2Cl2 and MeOH were
distilled from CaH2. Distilled petroleum ether with a boiling range of
40–60 °C was used. Ozonolysis: ozone generator Fischer OZ 502, ap-
plied oxygen pressure: 1.2 bar, operating pressure: 0.5 bar, flow: 50
L·h–1, conversion was set to 100% which corresponds to 1.6 mol O3/h.
1H NMR and 13C NMR spectra were measured on a Bruker Avance 400
spectrometer using CDCl3 as solvent at r.t. High-resolution mass spec-
tra (HRMS) were recorded on a Bruker maXis 4G spectrometer with
electrospray ionization (ESI). Optical rotations: Perkin Elmer polarim-
eter model 341, sodium D line (589 nm), c = g/100 mL. Chiral GC was
performed with a 6-tert-butyl-2,3-di-O-ethyl-β-cyclodextrin column
(Mega s.n.c., Italy; 25 m, 0.25 mm i.d.).
TBSO
5
1
7
PMBO
OR
6
O
37 R = H
TBSOTf
2,6-lutidine, CH2Cl2
(75%)
5 R = TBS
TIPS
19
15
TPAP, NMO·H2O
BF3•Et2O, Et3SiH
OTBS
13
MeCN (74%)
CH2Cl2, –75 °C (61%)
O
9
RO
O
3
7
38 R = TBS
39 R = H
PPTS
CH2Cl2/MeOH
(76%)
OTBS
H
R2
5-((tert-Butyldimethylsilyl)oxy)pentan-1-ol (11)14
19
To a suspension of NaH (5.04 g, 0.21 mol) in anhydrous THF (300 mL)
was added pentane-1,5-diol (10; 20.83 g, 0.20 mol) at 0 °C in a drop-
wise fashion. After complete addition, stirring was continued at 0 °C
for 15 min. The cooling bath was removed and the mixture stirred for
an additional 1 h before a solution of TBSCl (30.14 g, 0.20 mol) in an-
hydrous THF (100 mL) was slowly added in a dropwise fashion. The
yellow suspension was stirred for 12 h at r.t. and then carefully treat-
ed with H2O (100 mL). The layers were separated and the aqueous
layer was extracted with Et2O (3 × 100 mL). The combined organic
layers were washed with saturated NaCl solution, dried with MgSO4,
filtered and concentrated in vacuo. The residue was purified by flash
chromatography (petroleum ether/Et2O, 2:3) to yield 32.9 g (75%) of
silyl ether 11 as a colorless oil.
16
OR1
O
1
MNBA (42), DMAP
O
CH2Cl2, 8 h
(61%)
O
O
3
13
O
O
A
B
HO2C
5
7
9
TBSO
43 (impure)
Me Me
OTBS
R1
R2
TIPS
O
TBS
40
TBAF•3H2O
THF (39%)
NO2
O
O
NO2
H
H
41
MNBA (42)
Scheme 6 Combination of methyl ketone 6 with aldehyde 36 via aldol
reaction to give the C1–C21 fragment 5, subsequent formation of the
second tetrahydropyran, and ring closure to macrolactone 43. For C5,
the stereochemistry of the major isomer is depicted.
Rf = 0.61 (petroleum ether/Et2O, 2:3).
1H NMR (400 MHz, CDCl3): δ = 0.01 (s, 6 H, Si(CH3)2), 0.86 (s, 9 H,
SiC(CH3)3), 1.32–1.39 (m, 2 H, 3-H), 1.48–1.59 (m, 4 H, 2-H, 4-H),
3.56–3.61 (m, 4 H, 1-H, 5-H).
13C NMR (100 MHz, CDCl3): δ = –5.4 (Si(CH3)2), 18.3 (SiC(CH3)3), 22.0
(C-3), 25.9 (SiC(CH3)3), 32.4 (C-2, C-4), 62.7 (C-1), 63.1 (C-5).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H26O2Si: 219.177483;
In conclusion, we have described a novel strategy to the
core structure of the macrolactone exiguolide, exemplified
with the synthesis of seco acid 41 that would lead to 15-
epi-exiguolide. For the construction of the C9–C21 building
block 28 we used a Feringa–Minnaard asymmetric methyl
cuprate addition to set the methyl-bearing stereocenter at
C15. The C16–C17 trans double bond was created by com-
bining carboxylic acid 8 with aldehyde 9, leading to β-lac-
tone 25. Thermal decarboxylation of 25 provided the de-
sired alkene 26. This is probably the most complex com-
pound prepared using this Mulzer–Adam olefination
strategy. Another key transformation was a domino Meyer–
Schuster rearrangement of propargylic alcohol 7 to an
enone followed by an intramolecular oxa-Michael addition
providing the cis-configured tetrahydropyran derivative 31.
found: 219.177347.
5-((tert-Butyldimethylsilyl)oxy)pentanal (12)14
To a solution of DMSO (120 mL, 132 g, 1.69 mol) in CH2Cl2 (140 mL) at
–75 °C, a solution of oxalyl chloride (75 mL, 111 g, 0.87 mol) in CH2Cl2
(550 mL) was slowly added dropwise while keeping the temperature
of the solution below –60 °C. After complete addition, the mixture
was stirred for 10 min at –75 °C, followed by dropwise addition of al-
cohol 11 (149.23 g, 0.683 mol). The reaction mixture was stirred for 1
h at this temperature, then treated dropwise with Et3N (448 mL, 327
g, 3.23 mol), brought to r.t. and stirred for 1 h. The resulting white
suspension was treated with H2O (300 mL), the layers were separated
and the aqueous phase was extracted with Et2O (3 × 150 mL). The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

F
A. Riefert, M. E. Maier
Feature
Synthesis
combined organic layers were washed with saturated NaCl solution,
dried over MgSO4, filtered and concentrated in vacuo. The crude
product was purified by flash chromatography (petroleum
ether/Et2O, 4:1) giving 112.3 g (76%) of aldehyde 12 as a colorless oil.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H30O2Si: 281.190728;
found: 281.190740.
GC (75 kP; 80 °C, 3 min, 5 °C/min to 190 °C, 10 min): tR = 18.38 (minor
enantiomer), 18.55 (major enantiomer) min.
Rf = 0.73 (petroleum ether/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = –0.04 (s, 6 H, Si(CH3)2), 0.81 (s, 9 H,
SiC(CH3)3), 1.46 (q, J = 6.7 Hz, 2 H, 3-H), 1.62 (q, J = 7.3 Hz, 2 H, 4-H),
2.37 (td, J = 7.3, 1.8 Hz, 2 H, 2-H), 3.54 (t, J = 6.3 Hz, 2 H, 5-H), 9.68 (t,
J = 1.6 Hz, 1 H, 1-H).
13C NMR (100 MHz, CDCl3): δ = –5.5 (Si(CH3)2), 18.1 (SiC(CH3)3), 18.5
(C-3), 25.0 (SiC(CH3)3), 32.0 (C-4), 43.4 (C-2), 62.9 (C-5), 202.2 (C-1).
(R)-4,8-Bis((tert-butyldimethylsilyl)oxy)oct-1-ene (14)
A solution of alcohol 13 (500 mg, 1.93 mmol) in anhydrous DMF (23
mL) was treated with imidazole (1.3 g, 19.1 mmol) and DMAP (70 mg,
0.57 mmol). The reaction mixture was stirred for 20 min at r.t. before
TBSCl (310 mg, 2.06 mmol) was added. Stirring was continued at r.t.
for 12 h. Thereafter, the reaction was quenched with H2O (50 mL). The
layers were separated and the aqueous layer was extracted with Et2O
(3 × 20 mL). The combined organic layers were washed with saturated
NaCl solution, dried over MgSO4, filtered and concentrated in vacuo.
The crude silyl ether was purified by flash chromatography (petro-
leum ether/Et2O, 20:1) resulting in 705 mg (98%) of ether 14 as a col-
orless oil.
HRMS (ESI-TOF): m/z [M + Na + MeOH]+ calcd for C11H24O2Si:
271.169992; found: 271.169913.
(R)-8-((tert-Butyldimethylsilyl)oxy)oct-1-en-4-ol (13)
(–)-B-Methoxydiisopinocampheylborane15
To a solution of (–)-Ipc2BH16 (12.8 g, 44.7 mmol) in anhydrous THF
(70 mL) at 0 °C was added anhydrous MeOH (4.0 mL, 3.16 g, 99 mmol)
dropwise, which was accompanied by vigorous gas evolution. After
complete addition, the reaction mixture was stirred at r.t. for 3 h and
then concentrated for 10 h under reduced pressure (oil pump) at
40 °C using a cold trap. The product (10.9 g, 77%) was obtained as a
white waxy solid.
[α]D20 +4.92 (c 2.1, CH2Cl2); Rf = 0.72 (petroleum ether/Et2O, 20:1).
1H NMR (400 MHz, CDCl3): δ = 0.04 (s, 12 H, Si(CH3)2), 0.88 (s, 9 H,
SiC(CH3)3), 0.89 (s, 9 H, SiC(CH3)3), 1.26–1.53 (m, 6 H, 5-H, 6-H, 7-H),
2.20 (m, 2 H, 3-H), 3.59 (t, J = 6.3 Hz, 2 H, 8-H), 3.68 (q, J = 5.6 Hz, 1 H,
4-H), 4.99 (s, 1 H, 1-H), 5.02 (d, J = 6.3 Hz, 1 H, 1-H), 5.75–5.85 (m, 1 H,
2-H).
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –4.5 (Si(CH3)2), –4.4
(Si(CH3)2), 18.1 (SiC(CH3)3), 18.4 (SiC(CH3)3), 21.8 (C-6), 25.9
(SiC(CH3)3), 26.0 (SiC(CH3)3), 33.0 (C-7), 36.6 (C-5), 42.0 (C-3), 63.2 (C-
8), 72.0 (C-4), 116.6 (C-1), 135.4 (C-2).
(–)-B-Allyldiisopinocampheylborane15
To a solution of (–)-B-methoxydiisopinocampheylborane obtained as
above (1.8 g, 5.70 mmol) in anhydrous Et2O (10 mL) was added at
–80 °C a freshly prepared solution of allylmagnesium bromide34 (0.6
M in Et2O, 9.6 mL, 5.75 mmol) dropwise followed by stirring of the
mixture for 15 min. The suspension formed was allowed to warm to
r.t. within 30 min and then stirred at r.t. for 1 h. The white suspension
obtained was immediately used for the subsequent Brown allylation
reaction.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H44O2Si2: 395.277205;
found: 395.277073.
(R)-3,7-Bis((tert-butyldimethylsilyl)oxy)heptanal (15)
Through a solution of alkene 14 (5.0 g, 13.41 mmol) in anhydrous
CH2Cl2 (250 mL), cooled to –78 °C, was passed ozone via a glass tube
until the starting material was consumed (TLC, about 60 min) and the
color of the solution had changed to blue. Subsequently, the reaction
mixture was purged with nitrogen for 20 min and then quenched by
the dropwise addition of Me2S (15 mL). The mixture was stirred for
12 h at r.t., then refluxed for 10 h before it was concentrated in vacuo.
The oily residue was purified by flash chromatography (petroleum
ether/Et2O, 20:1) to give 3.9 g (78%) of aldehyde 15 as a colorless oil.
(R)-8-((tert-Butyldimethylsilyl)oxy)oct-1-en-4-ol (13)
To a freshly prepared suspension of (–)-B-allyldiisopinocampheylbo-
rane (1.88 g, 5.70 mmol) in anhydrous Et2O (20 mL) was added alde-
hyde 12 (1.0 g, 4.6 mmol), dissolved in Et2O (10 mL), dropwise very
slowly at –90 °C followed by stirring of the mixture at –75 °C for 1.5 h.
Then, the reaction mixture was brought to r.t. within 1 h and stirred
for 1 h at r.t., before it was cooled to 0 °C and slowly treated with 3 M
NaOH (6 mL), H2O2 (30%, 2.5 mL) and saturated NaHCO3 solution (8
mL). The reaction mixture was stirred at r.t. for 10 h and extracted
with Et2O (3 × 20 mL). The combined organic layers were washed with
saturated NaCl solution, dried over MgSO4, filtered and concentrated
in vacuo. The crude alcohol was purified by flash chromatography
(petroleum ether/Et2O, 2:1) resulting in 1.03 g (86%) of homoallyl al-
cohol 13 as a colorless oil; 95.3% ee.
[α]D20 +3.75 (c 1.0, CH2Cl2) {Lit.17a [α]D20 +4.6 (c 1.0, CHCl3); Lit.17b [α]D
+4.5 (c 0.3, CHCl3)}; Rf = 0.48 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.01 (s, 6 H, Si(CH3)2), 0.85 (s, 9 H,
SiC(CH3)3), 1.31–1.53 (m, 6 H, 5-H, 6-H, 7-H), 2.07–2.14 (m, 1 H, 3-H),
2.22–2.28 (m, 1 H, 3-H), 3.58 (t, J = 6.3 Hz, 2 H, 8-H), 3.60–3.63 (m, 1
H, 4-H), 5.06 (s, 1 H, 1-H), 5.09 (d, J = 4.0 Hz, 1 H, 1-H), 5.74–5.84 (m, 1
H, 2-H).
[α]D20 +1.70 (c 1.0, CH2Cl2); Rf = 0.21 (petroleum ether/Et2O, 20:1).
1H NMR (400 MHz, CDCl3): δ = –0.01 (s, 6 H, Si(CH3)2), 0.02, 0.03 (2 s, 3
H each, Si(CH3)2), 0.82 (s, 9 H, SiC(CH3)3), 0.84 (s, 9 H, SiC(CH3)3), 1.32
(q, J = 7.1 Hz, 2 H, 5-H), 1.43–1.57 (m, 4 H, 4-H, 6-H), 2.45 (dd, J = 3.3,
2.5 Hz, 2 H, 2-H), 3.55 (t, J = 6.3 Hz, 2 H, 7-H), 4.14 (q, J = 5.8 Hz, 1 H, 3-
H), 9.75 (t, J = 2.5 Hz, 1 H, 1-H).
13C NMR (100 MHz, CDCl3): δ = –5.4 (Si(CH3)2), –4.8 (Si(CH3)2), –4.5
(Si(CH3)2), 17.9 (SiC(CH3)3), 18.2 (SiC(CH3)3), 21.5 (C-5), 25.7
(SiC(CH3)3), 25.9 (SiC(CH3)3), 32.7 (C-4), 37.6 (C-6), 50.8 (C-2), 62.8 (C-
7), 68.1 (C-3), 202.0 (C-1).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H42O3Si2: 397.256469;
found: 397.256703.
S-Ethyl (R,E)-5,9-Bis((tert-butyldimethylsilyl)oxy)non-2-enethio-
ate (17)
To a solution of aldehyde 15 (6.90 g, 18.41 mmol) in anhydrous CH2Cl2
(350 mL) was added ylide18 16 (13.41 g, 36.80 mmol). Then, the reac-
tion mixture was stirred for 12 h at reflux temperature. After being
cooled to r.t., most of the volatiles were removed under reduced pres-
13C NMR (100 MHz, CDCl3): δ = –5.4 (Si(CH3)2), 18.3 (SiC(CH3)3), 21.9
(C-6), 25.9 (SiC(CH3)3), 32.7 (C-7), 36.4 (C-5), 41.9 (C-3), 63.0 (C-8),
70.5 (C-4), 117.8 (C-1), 134.8 (C-2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

G
A. Riefert, M. E. Maier
Feature
Synthesis
sure. The residue was washed with petroleum ether, the filtrate was
concentrated in vacuo and the resulting crude product, obtained as a
yellow oil, was purified by flash chromatography (petroleum
ether/Et2O, 20:1). The enethioate 17 (6.80 g, 80%) was obtained as a
colorless oil.
concentrated in vacuo. The oily residue was purified by flash chroma-
tography (petroleum ether/Et2O, 2:1) to give acid 8 (108.5 mg, 92%) as
a colorless oil.
[α]D20 –4.06 (c 1.0, CH2Cl2); Rf = 0.36 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.03 (s, 12 H, Si(CH3)2), 0.87 (s, 9 H,
SiC(CH3)3), 0.88 (s, 9 H, SiC(CH3)3), 0.95 (d, J = 6.3 Hz, 3 H, 3-CH3),
1.19–1.52 (m, 8 H, 4-H, 6-H, 7-H, 8-H), 2.07–2.14 (m, 1 H, 3-H), 2.16
(d, J = 7.8 Hz, 1 H, 2-H), 2.32 (m, 1 H, 2-H), 3.59 (t, J = 6.6 Hz, 2 H, 9-H),
3.67–3.73 (m, 1 H, 5-H).
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –4.5 (Si(CH3)2), –4.2
(Si(CH3)2), 18.1 (SiC(CH3)3), 18.4 (SiC(CH3)3), 19.8 (3-CH3), 21.3 (C-7),
25.9 (SiC(CH3)3), 26.0 (SiC(CH3)3), 26.8 (C-3), 33.0 (C-8), 37.6 (C-6),
42.2 (C-2), 43.9 (C-4), 63.2 (C-9), 70.2 (C-5), 179.2 (C-1).
[α]D20 +4.39 (c 1.0, CH2Cl2); Rf = 0.31 (petroleum ether/Et2O, 20:1).
1H NMR (400 MHz, CDCl3): δ = 0.01 (s, 12 H, Si(CH3)2), 0.85 (s, 9 H,
SiC(CH3)3), 0.86 (s, 9 H, SiC(CH3)3), 1.24 (t, J = 7.6 Hz, 3 H, SCH2CH3),
1.27–1.50 (m, 6 H, 6-H, 7-H, 8-H), 2.23–2.36 (m, 2 H, 4-H), 2.90 (q,
J = 7.3 Hz, 2 H, SCH2CH3), 3.57 (t, J = 6.5 Hz, 2 H, 9-H), 3.75 (q, J = 5.6
Hz, 1 H, 5-H), 6.06 (d, J = 15.4 Hz, 1 H, 2-H), 6.82–6.89 (m, 1 H, 3-H).
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –4.6 (Si(CH3)2), 14.8
(SCH2CH3), 18.0 (SiC(CH3)3), 18.3 (SiC(CH3)3), 21.6 (SCH2CH3), 23.0 (C-
7), 25.8 (SiC(CH3)3), 25.9 (SiC(CH3)3), 32.8 (C-8), 37.1 (C-6), 40.1 (C-4),
63.0 (C-9), 71.2 (C-5), 130.6 (C-2), 142.0 (C-3), 189.8 (C-1).
HRMS (ESI-TOF): m/z [M + H]– calcd for C22H48O4Si2: 431.30184;
found: 431.30268.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H48O3Si2S: 483.275490;
found: 483.275363.
(R)-4-Benzyl-3-((2R,3R)-3-hydroxy-2-methyl-5-(triisopropylsi-
lyl)pent-4-ynoyl)oxazolidin-2-one (21)
Under an inert atmosphere a solution of propionyloxazolidinone22 19
(100 mg, 0.43 mmol) in anhydrous CH2Cl2 (1 mL), that had been
cooled to –30 °C, was treated dropwise with n-Bu2BOTf (1 M in CH2-
Cl2, 0.5 mL, 0.50 mmol), and then with Et3N (63 μL, 50 mg, 0.50
mmol). This solution was stirred for 30 min at 0 °C, then cooled to –
65 °C before aldehyde23 20 (98.8 mg, 0.47 mmol), dissolved in CH2Cl2
(1 mL), was added dropwise. The reaction mixture was stirred for 30
min at –65 °C and for 1 h at 0 °C. It was quenched with pH 7 buffer
(0.5 mL), MeOH (1.4 mL) and a MeOH/H2O2 (30% in H2O) solution (2:1,
2.35 mL). The layers were separated and the aqueous layer was ex-
tracted with Et2O (3 × 3 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo. The oily residue was
purified by flash chromatography (petroleum ether/Et2O, 3:2) result-
ing in aldol product 21 (161 mg, 85%) as a colorless oil.
S-Ethyl (3S,5R)-5,9-Bis((tert-butyldimethylsilyl)oxy)-3-methyl-
nonanethioate (18)
Under inert conditions, CuI (97.0 mg, 0.51 mmol) and (S)-Tol-BINAP
(0.26 g, 0.383 mmol) were dissolved in t-BuOMe (400 mL) and the
mixture was stirred for 1 h at r.t. Thereafter, it was cooled to –75 °C,
and treated dropwise with MeMgBr (3 M in Et2O, 85.8 mL, 257.4
mmol) and stirred for 15 min before enethioate 17 (23.72 g, 51.47
mmol), dissolved in t-BuOMe (118 mL), was added dropwise over a
period of 2 h. The reaction mixture was stirred at –75 °C for another 2
h, then treated with MeOH (25 mL) and saturated NH4Cl solution (50
mL). The mixture was brought to r.t., the layers were separated and
the aqueous layer was extracted with Et2O (3 × 40 mL). The combined
organic layers were washed with saturated NaCl solution, dried over
MgSO4 and concentrated in vacuo. The oily residue was purified by
flash chromatography (petroleum ether/Et2O, 20:1) to give thioester
18 (20.4 g, 83%) as a colorless oil.
[α]D20 –42.21 (c 1.0, CH2Cl2); Rf = 0.73 (petroleum ether/Et2O, 3:2).
1H NMR (400 MHz, CDCl3): δ = 0.99 (s, 21 H, Si(CH(CH3)2)3), 1.35 (d,
J = 6.8 Hz, 3 H, 2′-CH3), 2.73 (dd, J = 13.4, 9.3 Hz, 1 H, CH2Ph), 3.14 (dd,
J = 13.4, 3.0 Hz, 1 H, CH2Ph), 3.88–3.94 (m, 1 H, 2′-H), 4.09–4.16 (m, 2
H, 5-H), 4.58–4.64 (m, 1 H, 4-H), 4.65 (d, J = 5.1 Hz, 1 H, 3′-H), 7.11–
7.28 (m, 5 H, Haromat).
13C NMR (100 MHz, CDCl3): δ = 11.0 (SiCH(CH3)2), 12.4 (2′-CH3), 18.5
(SiCH(CH3)2), 37.7 (CH2Ph), 44.3 (C-2′), 55.0 (C-4), 63.7 (C-5), 66.2 (C-
3′), 86.6 (C-5′), 105.9 (C-4′), 127.4, 128.9, 129.4, 134.9 (Caromat), 152.8
(C-2), 175.1 (C-1′).
[α]D20 –11.92 (c 1.0, CH2Cl2); Rf = 0.42 (petroleum ether/Et2O, 20:1).
1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 12 H, Si(CH3)2), 0.86 (s, 9 H,
SiC(CH3)3), 0.87 (s, 9 H, SiC(CH3)3), 0.90 (d, J = 6.6 Hz, 3 H, 3-CH3), 1.22
(t, J = 7.3 Hz, 3 H, SCH2CH3), 1.27–1.51 (m, 8 H, 4-H, 6-H, 7-H, 8-H),
2.12–2.21 (m, 1 H, 3-H), 2.32 (dd, J = 8.3, 6.1 Hz, 1 H, 2-H), 2.48 (dd,
J = 8.3, 6.1 Hz, 1 H, 2-H), 2.83 (q, J = 7.3 Hz, 2 H, SCH2CH3), 3.57 (t,
J = 6.6 Hz, 2 H, 9-H), 3.65–3.71 (m, 1 H, 5-H).
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –4.5 (Si(CH3)2), –4.2
(Si(CH3)2), 14.8 (SCH2CH3), 18.1 (SiC(CH3)3), 18.3 (SiC(CH3)3), 19.7 (3-
CH3), 21.3 (SCH2CH3), 23.2 (C-7), 25.9 (SiC(CH3)3), 26.0 (SiC(CH3)3),
27.7 (C-3), 33.1 (C-8), 37.6 (C-6), 43.9 (C-4), 52.0 (C-2), 63.1 (C-9),
70.0 (C-5), 198.8 (C-1).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C25H37NO4Si: 466.238406;
found: 466.238156.
(R)-4-Benzyl-3-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-meth-
yl-5-(triisopropylsilyl)pent-4-ynoyl)oxazolidin-2-one (22)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C24H52O3Si2S: 499.306790;
found: 499.306575.
A solution of alcohol 21 (1.0 g, 2.25 mmol) in anhydrous CH2Cl2 (30
mL) was treated at 0 °C dropwise with 2,6-lutidine (653 μL, 603 mg,
5.63 mmol). The reaction mixture was stirred for 10 min before TB-
SOTf35 (0.778 mL, 895 mg, 3.38 mmol) was added dropwise. Stirring
was continued for 1 h at r.t. before the mixture was treated with satu-
rated NH4Cl solution (5 mL). The layers were separated and the aque-
ous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated in vacuo. The
oily residue was purified by flash chromatography (petroleum
ether/Et2O, 3:2) to give silyl ether 22 (1.167 g, 93%) as a colorless oil.
(3S,5R)-5,9-Bis((tert-butyldimethylsilyl)oxy)-3-methylnonanoic
Acid (8)
To a solution of thioester 18 (130 mg, 0.27 mmol) in THF (4 mL), an
aqueous solution of LiOH (2 mL, 27.2 mg, 1.136 mmol) and H2O2 (0.07
mL, 30% in H2O) were dropped at r.t. The reaction mixture was stirred
for 12 h at r.t., then adjusted to pH 3 with 1 N HCl. The layers were
separated and the aqueous layer was extracted with Et2O (3 × 2 mL).
The combined organic layers were dried over MgSO4, filtered and
[α]D20 –19.05 (c 1.0, CH2Cl2); Rf = 0.64 (petroleum ether/Et2O, 3:2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

H
A. Riefert, M. E. Maier
Feature
Synthesis
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 3 H, Si(CH3)2), 0.04 (s, 3 H,
Si(CH3)2), 0.78 (s, 9 H, SiC(CH3)3), 0.92 (s, 21 H, Si(CH(CH3)2)3), 1.19 (d,
J = 6.8 Hz, 3 H, 2′-CH3), 2.67 (dd, J = 13.4, 9.3 Hz, 1 H, CH2Ph), 3.12 (dd,
J = 13.1, 2.8 Hz, 1 H, CH2Ph), 3.95–4.06 (m, 3 H, 2′-H, 5-H), 4.44–4.48
(m, 1 H, 4-H), 4.51 (d, J = 7.8 Hz, 1 H, 3′-H), 7.07–7.22 (m, 5 H, Haromat).
13C NMR (100 MHz, CDCl3): δ = –5.24 (Si(CH3)2), –4.66 (Si(CH3)2), 11.1
(SiCH(CH3)2), 13.8 (2′-CH3), 18.1 (SiC(CH3)3), 18.5 (SiCH(CH3)2), 25.6
(SiC(CH3)3), 37.7 (CH2Ph), 45.7 (C-2′), 55.4 (C-4), 64.5 (C-5), 66.0 (C-
3′), 85.4 (C-5′), 107.7 (C-4′), 127.3, 128.9, 129.4, 135.2 (Caromat), 152.8
(C-2), 173.9 (C-1′).
(2S,3S,5R)-5,9-Bis((tert-butyldimethylsilyl)oxy)-2-((1S,2S,3R)-3-
((tert-butyldimethylsilyl)oxy)-1-hydroxy-2-methyl-5-(triisopro-
pylsilyl)pent-4-yn-1-yl)-3-methylnonanoic Acid (24)
To a solution of acid 8 (100 mg, 0.231 mmol) in anhydrous Et2O (2 mL)
was added t-BuLi (1.7 M in hexane, 0.3 mL, 0.51 mmol) at –75 °C. The
reaction mixture was stirred for 1 h at –75 °C and 1 h at –10 °C.
Thereafter, the resulting yellow solution was cooled to –75 °C before
aldehyde 9 (107.9 mg, 0.282 mmol), dissolved in anhydrous THF (5
mL), was added dropwise followed by stirring of the reaction mixture
for 14 h at –75 °C. The reaction mixture was treated with pH 7 buffer
(10 mL, KH2PO4/Na2HPO4). The layers were separated and the aque-
ous layer was extracted with Et2O (3 × 5 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated in vacuo. The
oily residue obtained was purified by flash chromatography (petro-
leum ether/Et2O, 2:1) to give β-hydroxy acid 24 (87.3 mg, 57%) as a
colorless oil.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C31H51NO4Si2: 580.324883;
found: 580.324526.
(2S,3R)-3-((tert-Butyldimethylsilyl)oxy)-2-methyl-5-(triisopropyl-
silyl)pent-4-yn-1-ol (23)
To a solution of acid derivative 22 (130 mg, 0.233 mmol) in THF (10
mL), a solution of NaBH4 (53 mg, 1.40 mmol) in H2O (2 mL) was added
dropwise at 0 °C followed by stirring of the reaction mixture at r.t.
overnight. Then, saturated NH4Cl solution (2 mL) was added and the
mixture stirred for 1 h. The layers were separated and the aqueous
layer was extracted with Et2O (3 × 2 mL). The combined organic layers
were dried over MgSO4, filtered and concentrated in vacuo. The oily
residue was purified by flash chromatography (petroleum ether/Et2O,
3:2) providing alcohol 23 (84 mg, 94%) as a colorless oil.
[α]D20 +4.8 (c 1.0, CH2Cl2); Rf = 0.21 (petroleum ether/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 12 H, Si(CH3)2), 0.11 (s, 3 H,
Si(CH3)2), 0.15 (s, 3 H, Si(CH3)2), 0.84 (s, 9 H, SiC(CH3)3), 0.87 (s, 18 H,
SiC(CH3)3), 0.99 (d, J = 6.8 Hz, 3 H, 3-CH3), 1.02 (d, J = 6.9 Hz, 3 H, 2′-
CH3), 1.04 (s, 21 H, Si(CH(CH3)2)3), 1.23–1.30 (m, 3 H, 4-H, 7-H), 1.40–
1.51 (m, 5 H, 4-H, 6-H, 8-H), 1.83–1.94 (m, 1 H, 2′-H), 2.01–2.12 (m,
1 H, 3-H), 2.48 (t, J = 6.1 Hz, 1 H, 2-H), 3.57 (t, J = 6.6 Hz, 2 H, 9-H),
3.63–3.70 (m, 1 H, 5-H), 4.33 (dd, J = 7.3, 3.3 Hz, 1 H, 1′-H), 4.43 (d,
J = 5.6 Hz, 1 H, 3′-H).
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –5.1 (Si(CH3)2), –4.6
(Si(CH3)2), –4.4 (Si(CH3)2), 9.1 (2’-CH3), 11.2 (SiCH(CH3)2), 17.9 (3-
CH3), 18.0 (SiC(CH3)3), 18.1 (SiC(CH3)3), 18.3 (SiC(CH3)3), 18.6
(SiCH(CH3)2), 21.4 (C-7), 25.8 (SiC(CH3)3), 25.9 (SiC(CH3)3), 26.0
(SiC(CH3)3), 28.2 (C-3), 33.1 (C-6), 38.4 (C-8), 39.4 (C-4), 41.7 (C-2′),
55.0 (C-2), 63.1 (C-9), 66.7 (C-3′), 69.9 (C-5), 70.9 (C-1′), 87.2 (C-5′),
107.6 (C-4′), 179.2 (C-1).
[α]D20 +41.00 (c 1.0, CH2Cl2); Rf = 0.51 (petroleum ether/Et2O, 3:2).
1H NMR (400 MHz, CDCl3): δ = 0.13 (s, 3 H, Si(CH3)2), 0.16 (s, 3 H,
Si(CH3)2), 0.89 (s, 9 H, SiC(CH3)3), 0.91 (d, J = 7.1 Hz, 3 H, 2-CH3), 1.06
(s, 21 H, Si(CH(CH3)2)3), 2.01–2.10 (m, 1 H, 2-H), 3.54 (dd, J = 7.3, 3.8
Hz, 1 H, 1-H), 3.88 (dd, J = 11.1, 8.6 Hz, 1 H, 1-H), 4.51 (d, J = 4.3 Hz,
1 H, 3-H).
13C NMR (100 MHz, CDCl3): δ = –5.4 (Si(CH3)2), –4.6 (Si(CH3)2), 11.2
(SiCH(CH3)2), 12.7 (2-CH3), 18.1 (SiC(CH3)3), 18.6 (SiCH(CH3)2), 25.7
(SiC(CH3)3), 41.3 (C-2), 65.8 (C-1), 68.1 (C-3), 87.1 (C-5), 106.4 (C-4).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C43H90O6Si4: 837.57067;
found: 837.57090.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H44O2Si2: 407.277205;
found: 407.277285.
(3S,4S)-3-((2S,4R)-4,8-Bis((tert-butyldimethylsilyl)oxy)octan-2-
yl)-4-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-5-(triisopropylsi-
lyl)pent-4-yn-2-yl)oxetan-2-one (25)
(2R,3R)-3-((tert-Butyldimethylsilyl)oxy)-2-methyl-5-(triisopro-
pylsilyl)pent-4-ynal (9)
A solution of hydroxy acid 24 (100 mg, 0.122 mmol) in anhydrous
pyridine (1 mL) was treated dropwise at 0 °C with benzenesulfonyl
chloride (64.5 mg, 0.366 mmol), followed by stirring of the mixture at
r.t. for 12 h. The reaction mixture was quenched with ice–water (2
mL) and diluted with Et2O (3 mL). The layers were separated and the
aqueous layer was extracted with Et2O (3 × 2 mL). The combined or-
ganic layers were dried over MgSO4, filtered and concentrated in vac-
uo. The oily residue was purified by flash chromatography (petro-
leum ether/Et2O, 10:1) yielding β-lactone 25 (68 mg, 70%) as a color-
less oil.
A solution of alcohol 23 (580 mg, 1.51 mmol) in anhydrous CH2Cl2 (12
mL) was treated at 0 °C with NaHCO3 (421 mg, 5.0 mmol) and Dess–
Martin periodinane (836 mg, 1.97 mmol). The reaction mixture was
brought to r.t. and stirred for 2 h. The mixture was then washed with
saturated Na2S2O3 solution (3 mL) and saturated NaHCO3 solution (2
mL). The layers were separated and the aqueous layer was extracted
with Et2O (3 × 2 mL). The combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. The oily residue was puri-
fied by flash chromatography (petroleum ether/Et2O, 10:1) to give al-
dehyde 9 (492 mg, 85%) as a colorless oil.
[α]D20 +36.3 (c 1.0, CH2Cl2); Rf = 0.61 (petroleum ether/Et2O, 10:1).
[α]D20 +3.8 (c 1.0, CH2Cl2); Rf = 0.41 (petroleum ether/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 0.11 (s, 3 H, Si(CH3)2), 0.15 (s, 3 H,
Si(CH3)2), 0.86 (s, 9 H, SiC(CH3)3), 1.05 (s, 21 H, Si(CH(CH3)2)3), 1.18 (d,
J = 7.1 Hz, 3 H, 2-CH3), 2.51–2.57 (m, 1 H, 2-H), 4.70 (d, J = 4.6 Hz, 1 H,
3-H), 9.81 (d, J = 1.5 Hz, 1 H, 1-H).
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –4.5 (Si(CH3)2), 9.3 (2-
CH3), 11.1 (SiCH(CH3)2), 18.1 (SiC(CH3)3), 18.5 (SiCH(CH3)2), 25.6
(SiC(CH3)3), 52.6 (C-2), 63.8 (C-3), 87.6 (C-5), 106.2 (C-4), 203.6 (C-1).
1H NMR (400 MHz, CDCl3): δ = 0.02, 0.03 (2 s, 12 H, Si(CH3)2), 0.12,
0.14 (2 s, 6 H, Si(CH3)2), 0.85 (s, 9 H, SiC(CH3)3), 0.88 (s, 9 H, SiC(CH3)3),
0.89 (s, 9 H, SiC(CH3)3), 1.03 (d, J = 6.8 Hz, 3 H, 1′′-H), 1.06 (s, 21 H,
Si(CH(CH3)2)3), 1.11 (d, J = 6.8 Hz, 3 H, 1′-H), 1.18–1.33 (m, 3 H, 3′-H,
6′-H), 1.41–1.51 (m, 4 H, 5′-H, 7′-H), 1.83–1.94 (ddd, J = 9.4, 6.4, 3.8
Hz, 1 H, 3′-H), 1.96–2.04 (m, 1 H, 2′′-H), 2.13–2.22 (m, 1 H, 2′-H), 3.37
(dd, J = 8.3, 3.8 Hz, 1 H, 3-H), 3.58 (t, J = 6.6 Hz, 2 H, 8′-H), 3.72–3.78
(m, 1 H, 4′-H), 4.42 (d, J = 5.1 Hz, 1 H, 3′′-H), 4.48 (dd, J = 7.1, 3.8 Hz, 1
H, 4-H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H42O2Si2: 405.261555;
found: 405.261924.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

I
A. Riefert, M. E. Maier
Feature
Synthesis
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –5.2 (Si(CH3)2), –4.6
(Si(CH3)2), –4.4 (Si(CH3)2), –4.0 (Si(CH3)2), 11.2 (SiCH(CH3)2), 11.4 (C-
1′′), 17.5 (C-1′), 18.0 (SiC(CH3)3), 18.2 (SiC(CH3)3), 18.3 (SiC(CH3)3),
18.6 (SiCH(CH3)2), 21.3 (C-6′), 25.8 (SiC(CH3)3), 25.9 (SiC(CH3)3), 26.0
(SiC(CH3)3), 29.1 (C-2′), 33.1 (C-7′), 38.0 (C-5′), 40.6 (C-3′), 44.3 (C-2′′),
60.9 (C-3), 63.1 (C-8′), 65.5 (C-3′′), 69.6 (C-4′), 77.3 (C-4), 87.6 (C-5′′),
106.1 (C-4′′), 171.3 (C-2).
3), 25.7 (SiC(CH3)3), 25.9 (SiC(CH3)3), 33.0 (C-2), 33.2 (C-7), 36.7 (C-4),
44.0 (C-10), 44.5 (C-6), 62.9 (C-1), 67.7 (C-11), 70.0 (C-5), 85.0 (C-13),
108.6 (C-12), 130.1 (C-9), 136.8 (C-8).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C36H74O3Si3: 661.483797;
found: 661.484030.
(5R,7S,10S,11R,E)-5,11-Bis((tert-butyldimethylsilyl)oxy)-7,10-di-
methyl-13-(triisopropylsilyl)tridec-8-en-12-ynal (28)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C43H88O5Si4: 819.56010;
found: 819.56112.
To a solution of alcohol 27 (160 mg, 0.25 mmol) in anhydrous CH2Cl2
(12 mL) were added at 0 °C NaHCO3 (40 mg, 0.476 mmol) and Dess–
Martin periodinane (150 mg, 0.353 mmol). The reaction mixture was
stirred at r.t. for 2 h, then quenched with saturated Na2S2O3 solution
(2 mL) and saturated NaHCO3 solution (2 mL), and stirred for 1 h. The
layers were separated and the aqueous layer was extracted with CH2-
Cl2 (3 × 3 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated in vacuo. The oily residue was purified by
flash chromatography (petroleum ether/Et2O, 10:1) to give aldehyde
28 (130 mg, 82%) as a colorless oil.
(5R,7S,10S,11R,E)-1,5,11-Tris((tert-butyldimethylsilyl)oxy)-7,10-
dimethyl-13-(triisopropylsilyl)tridec-8-en-12-yne (26)
Lactone 25 (7.2 g, 9.03 mmol), kept neat in a round-bottom flask, was
heated with an oil bath for 4 h at 190 °C. After the flask was cooled to
r.t., the residue was purified by flash chromatography (petroleum
ether/Et2O, 10:1) to give alkene 26 (5.9 g, 87%) as a colorless oil.
[α]D20 +21.5 (c 1.0, CH2Cl2); Rf = 0.73 (petroleum ether/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 6 H, (SiCH3)2), 0.04 (s, 6 H,
(SiCH3)2), 0.08 (s, 3 H, (SiCH3)2), 0.12 (s, 3 H, (SiCH3)2), 0.87 (s, 9 H,
SiC(CH3)3), 0.89 (s, 18 H, SiC(CH3)3), 0.92 (d, J = 6.6 Hz, 3 H, 7-CH3),
1.06 (s, 24 H, Si(CH(CH3)2)3, 10-CH3), 1.26–1.53 (m, 8 H, 2-H, 3-H, 4-H,
6-H), 2.17 (ddd, J = 13.6, 7.1, 6.8 Hz, 1 H, 7-H), 2.31 (dd, J = 6.8, 6.3 Hz,
1 H, 10-H), 3.59 (t, J = 6.6 Hz, 2 H, 1-H), 3.62–3.68 (m, 1 H, 5-H), 4.15
(d, J = 5.3 Hz, 1 H, 11-H), 5.32 (dd, J = 15.4, 7.3 Hz, 1 H, 8-H), 5.40 (dd,
J = 15.7, 7.6 Hz, 1 H, 9-H).
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –5.1 (Si(CH3)2), –4.5
(Si(CH3)2), –4.4 (Si(CH3)2), –4.3 (Si(CH3)2), 11.2 (SiCH(CH3)2), 16.0 (10-
CH3), 18.1 (SiC(CH3)3), 18.2 (SiC(CH3)3), 18.4 (SiC(CH3)3), 18.6
(SiCH(CH3)2), 20.6 (7-CH3), 21.3 (C-3), 25.7 (SiC(CH3)3), 25.9
(SiC(CH3)3), 26.0 (SiC(CH3)3), 33.2 (C-2, C-7), 37.0 (C-4), 44.0 (C-10),
44.6 (C-6), 63.2 (C-1), 67.8 (C-11), 70.2 (C-5), 85.0 (C-13), 108.6 (C-
12), 130.1 (C-9), 136.9 (C-8).
[α]D20 +25.5 (c 1.0, CH2Cl2); Rf = 0.82 (petroleum ether/Et2O, 6:1).
1H NMR (400 MHz, CDCl3): δ = 0.02, 0.02, 0.04, 0.05 (4 s, 3 H each,
Si(CH3)2), 0.86 (s, 9 H, SiC(CH3)3), 0.88 (s, 9 H, SiC(CH3)3), 0.93 (d,
J = 6.6 Hz, 3 H, 7-CH3), 1.05 (s, 24 H, Si(CH(CH3)2)3, 10-CH3), 1.24–1.34
(m, 1 H, 6-H), 1.36–1.51 (m, 3 H, 4-H, 6-H), 1.58–1.73 (m, 2 H, 3-H),
2.14 (ddd, J = 14.1, 7.1, 6.8 Hz, 1 H, 7-H), 2.31 (dd, J = 6.8, 6.3 Hz, 1 H,
10-H), 2.39 (dd, J = 7.3, 1.8 Hz, 2 H, 2-H), 3.64–3.70 (m, 1 H, 5-H), 4.14
(d, J = 5.6 Hz, 1 H, 11-H), 5.30 (dd, J = 15.4, 7.6 Hz, 1 H, 8-H), 5.41 (dd,
J = 15.4, 7.6 Hz, 1 H, 9-H), 9.74 (t, J = 1.8 Hz, 1 H, 1-H).
13C NMR (100 MHz, CDCl3): δ = –5.1 (Si(CH3)2), –4.5 (Si(CH3)2), –4.4
(Si(CH3)2), –4.4 (Si(CH3)2), 11.2 (SiCH(CH3)2), 16.0 (10-CH3), 17.6 (C-3),
18.1 (SiC(CH3)3), 18.2 (SiC(CH3)3), 18.6 (SiCH(CH3)2), 20.8 (7-CH3), 25.7
(SiC(CH3)3), 25.9 (SiC(CH3)3), 33.3 (C-7), 36.2 (C-4), 44.0 (C-10), 44.0
(C-2), 44.4 (C-6), 67.7 (C-11), 69.9 (C-5), 85.0 (C-13), 108.6 (C-12),
130.3 (C-9), 136.6 (C-8), 202.4 (C-1).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C42H88O3Si4: 775.57027;
found: 775.57091.
HRMS (ESI-TOF): m/z [M + Na + MeOH]+ calcd for C36H72O3Si3:
691.494362; found: 691.494713.
(5R,7S,10S,11R,E)-5,11-Bis((tert-butyldimethylsilyl)oxy)-7,10-di-
methyl-13-(triisopropylsilyl)tridec-8-en-12-yn-1-ol (27)
(8R,10S,13S,14R,E)-8,14-Bis((tert-butyldimethylsilyl)oxy)-10,13-
dimethyl-16-(triisopropylsilyl)hexadeca-11-ene-2,15-diyn-4-ol
(7)
A solution of silyl ether 26 (310 mg, 0.41 mmol) in anhydrous
MeOH/CH2Cl2 (1:1, 8 mL) was treated at 0 °C with PPTS (10.3 mg,
0.041 mmol). The reaction mixture was stirred at r.t. for 5 h, then
quenched with Et3N (0.1 mL), and treated with H2O (5 mL) and CH2Cl2
(5 mL). The layers were separated and the aqueous layer was extract-
ed with CH2Cl2 (3 × 3 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo. The oily residue was
purified by flash chromatography (petroleum ether/Et2O, 2:1) to give
primary alcohol 27 (144 mg, 64%, brsm) as a colorless oil. In addition,
some starting material (44 mg) was recovered.
To a solution of 1-bromoprop-1-ene (2.2 mL, 3.12 g, 25.7 mmol) in
anhydrous THF (80 mL), cooled to –75 °C, was added dropwise n-BuLi
(2.5 M in hexane, 15.2 mL, 38.02 mmol) followed by stirring of the
mixture for 2 h at –75 °C. Subsequently, aldehyde 28 (10.46 g, 16.41
mmol), dissolved in anhydrous THF (20 mL), was added dropwise. Af-
ter being stirred for 2 h at –75 °C, the mixture was slowly warmed to
r.t., stirred for 1 h at r.t. and then treated with saturated NH4Cl solu-
tion (40 mL). The layers were separated and the aqueous layer was ex-
tracted with Et2O (3 × 20 mL). The combined organic layers were
dried over MgSO4, filtered and concentrated in vacuo. The oily residue
was purified by flash chromatography (petroleum ether/Et2O, 6:1)
yielding propargylic alcohol 7 (10.24 g, 92%) as a colorless oil.
[α]D20 +27.1 (c 1.0, CH2Cl2); Rf = 0.45 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 6 H, Si(CH3)2), 0.03, 0.04 (2 s, 3
H each, Si(CH3)2), 0.86 (s, 9 H, SiC(CH3)3), 0.88 (s, 9 H, SiC(CH3)3), 0.92
(d, J = 6.8 Hz, 3 H, 7-CH3), 1.05 (s, 24 H, Si(CH(CH3)2)3, 10-CH3), 1.24–
1.48 (m, 6 H, 3-H, 4-H, 6-H), 1.50–1.57 (m, 2 H, 2-H), 2.16 (ddd,
J = 13.9, 7.1, 6.8 Hz, 1 H, 7-H), 2.30 (dd, J = 6.6, 6.3 Hz, 1 H, 10-H), 3.61
(t, J = 6.8 Hz, 2 H, 1-H), 3.63–3.69 (m, 1 H, 5-H), 4.14 (d, J = 5.6 Hz, 1 H,
11-H), 5.31 (dd, J = 15.7, 7.3 Hz, 1 H, 8-H), 5.40 (dd, J = 15.4, 7.6 Hz, 1
H, 9-H).
[α]D20 +20.7 (c 1.0, CH2Cl2); Rf = 0.21 (petroleum ether/Et2O, 6:1).
1H NMR (400 MHz, CDCl3): δ = 0.03 (s, 6 H, Si(CH3)2), 0.07, 0.11 (2 s, 3
H each, Si(CH3)2), 0.87 (s, 9 H, SiC(CH3)3), 0.88 (s, 9 H, SiC(CH3)3), 0.92
(d, J = 6.6 Hz, 3 H, 10-CH3), 1.05 (s, 24 H, Si(CH(CH3)2)3, 13-CH3), 1.24–
1.33 (m, 1 H, 7-H), 1.38–1.50 (m, 5 H, 7-H, 6-H, 9-H), 1.58–1.65 (m, 2
H, 5-H), 1.82 (d, J = 2.0 Hz, 3 H, 1-H), 2.17 (ddd, J = 13.9, 7.1, 6.8 Hz, 1
H, 10-H), 2.31 (dd, J = 6.8, 6.1 Hz, 1 H, 13-H), 3.67–3.73 (m, 1 H, 8-H),
4.14 (d, J = 5.6 Hz, 1 H, 14-H), 4.27–4.35 (m, 1 H, 4-H), 5.32 (dd,
J = 15.4, 7.3 Hz, 1 H, 11-H), 5.40 (dd, J = 15.4, 7.6 Hz, 1 H, 12-H).
13C NMR (100 MHz, CDCl3): δ = –5.1 (Si(CH3)2), –4.5 (Si(CH3)2), –4.4
(Si(CH3)2), –4.3 (Si(CH3)2), 11.2 (SiCH(CH3)2), 16.0 (10-CH3), 18.1
(SiC(CH3)3), 18.2 (SiC(CH3)3), 18.6 (SiCH(CH3)2), 20.6 (7-CH3), 21.1 (C-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

J
A. Riefert, M. E. Maier
Feature
Synthesis
13C NMR (100 MHz, CDCl3): δ = –5.1 (Si(CH3)2), –4.5 (Si(CH3)2), –4.4
(Si(CH3)2), –4.3 (Si(CH3)2), 3.5 (C-1), 11.2 (SiCH(CH3)2), 16.0 (13-CH3),
18.1 (SiC(CH3)3), 18.2 (SiC(CH3)3), 18.6 (SiCH(CH3)2), 20.6 (10-CH3),
20.7 (C-6), 25.7 (SiC(CH3)3), 25.9 (SiC(CH3)3), 33.2 (C-10), 36.7 (C-7),
38.4 (C-5), 44.0 (C-13), 44.5 (C-9), 62.7 (C-4), 67.7 (C-14), 70.0 (C-8),
80.4 (C-2), 81.0 (C-3), 85.0 (C-16), 108.6 (C-15), 130.1 (C-12), 136.8
(C-11).
1-((2S,6R)-6-((2S,5S,6R,E)-6-((tert-Butyldimethylsilyl)oxy)-2,5-di-
methyl-8-(triisopropylsilyl)oct-3-en-7-yn-1-yl)tetrahydro-2H-
pyran-2-yl)propan-2-one (6)
A solution of alcohol 31 (330 mg, 0.74 mmol) in anhydrous CH2Cl2 (10
mL) was treated dropwise with 2,6-lutidine (180 μL, 166.6 mg, 1.55
mmol) at 0 °C. The reaction mixture was stirred for 10 min at this
temperature before TBSOTf (245 mg, 0.93 mmol) was added drop-
wise. The mixture was stirred for 1 h at r.t. and then treated with sat-
urated NH4Cl solution (3 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 × 3 mL). The combined
organic layers were dried over MgSO4, filtered and concentrated in
vacuo. The oily residue was purified by flash chromatography (petro-
leum ether/Et2O, 2:1) to give silyl ether 6 (377 mg, 91%) as a colorless
oil.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C39H76O3Si3: 699.499447;
found: 699.500080.
1-((2S,6R)-6-((2S,5S,6R,E)-6-Hydroxy-2,5-dimethyl-8-(triisopro-
pylsilyl)oct-3-en-7-yn-1-yl)tetrahydro-2H-pyran-2-yl)propan-2-
one (31)
To a solution of propargylic alcohol 7 (600 mg, 0.89 mmol) in CH2Cl2
(50 mL) was added gold catalyst 29 (103 mg, 0.133 mmol). The reac-
tion mixture was warmed to r.t. and stirred for 3 h. After all the start-
ing material had been converted into enone 30, p-TsOH·H2O (338 mg,
1.78 mmol) was added and the mixture stirred for another 8 h at r.t.
Then, the mixture was washed with saturated NaHCO3 solution (10
mL). The layers were separated and the aqueous layer was extracted
with Et2O (3 × 5 mL). The combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. The oily residue obtained
was purified by flash chromatography (petroleum ether/Et2O, 2:1) to
give pyran derivative 31 (327 mg, 82%) as a colorless oil.
[α]D20 +25.3 (c 1.0, CH2Cl2); Rf = 0.71 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.05, 0.09 (2 s, 3 H each, Si(CH3)2), 0.86
(s, 9 H, SiC(CH3)3), 0.90 (d, J = 6.8 Hz, 3 H, 2′′-CH3), 1.05 (s, 24 H,
Si(CH(CH3)2)3, 5′′-CH3), 1.09–1.23 (m, 3 H, 1′′-H, 3′-H, 5′-H), 1.42–1.57
(m, 4 H, 1′′-H, 3′-H, 4′-H, 5′-H), 1.74–1.82 (m, 1 H, 4′-H), 2.14 (s, 3 H,
3-H), 2.19–2.32 (m, 2 H, 2′′-H, 5′′-H), 2.37 (dd, J = 15.2, 4.8 Hz, 1 H, 1-
H), 2.62 (dd, J = 14.9, 8.1 Hz, 1 H, 1-H), 3.26–3.32 (m, 1 H, 6′-H), 3.66–
3.72 (m, 1 H, 2′-H), 4.20 (d, J = 4.6 Hz, 1 H, 6′′-H), 5.33 (dd, J = 15.6, 6.6
Hz, 1 H, 4′′-H), 5.38 (dd, J = 15.7, 6.8 Hz, 1 H, 3′′-H).
13C NMR (100 MHz, CDCl3): δ = –5.2 (Si(CH3)2), –4.5 (Si(CH3)2), 11.2
(SiCH(CH3)2), 15.8 (5′′-CH3), 18.2 (SiC(CH3)3), 18.6 (SiCH(CH3)2), 19.7
(2′′-CH3), 23.5 (C-4′), 25.7 (SiC(CH3)3), 31.1 (C-3), 31.3 (C-3′ or C-5′),
31.5 (C-3′ or C-5′), 32.4 (C-2′′), 43.4 (C-1′′), 43.9 (C-5′′), 50.3 (C-1),
67.4 (C-6′′), 74.5 (C-2′), 75.5 (C-6′), 84.9 (C-8′′), 108.6 (C-7′′), 129.7 (C-
3′′), 136.6 (C-4′′), 207.8 (C-2).
[α]D20 +30.6 (c 1.0, CH2Cl2); Rf = 0.23 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.96 (d, J = 6.6 Hz, 3 H, 2′′-CH3), 1.05 (s,
24 H, Si(CH(CH3)2)3, 5′′-CH3), 1.10–1.29 (m, 3 H, 1′′-H, 3′-H, 5′-H),
1.47–1.59 (m, 4 H, 1′′-H, 3′-H, 4′-H, 5′-H), 1.78–1.84 (m, 1 H, 4′-H),
2.16 (s, 3 H, 3-H), 2.30 (dd, J = 7.1, 6.8 Hz, 1 H, 2′′-H), 2.35 (m, 1 H, 5′′-
H), 2.39 (dd, J = 10.7, 4.8 Hz, 1 H, 1-H), 2.66 (dd, J = 8.1, 7.4 Hz, 1 H, 1-
H), 3.30–3.36 (m, 1 H, 6′-H), 3.70–3.76 (m, 1 H, 2′-H), 4.20 (d, J = 4.6
Hz, 1 H, 6′′-H), 5.39 (dd, J = 16.4, 8.3 Hz, 1 H, 4′′-H), 5.53 (dd, J = 15.6,
7.1 Hz, 1 H, 3′′-H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C33H62O3Si2: 585.41297;
found: 585.41300.
3-((tert-Butyldimethylsilyl)oxy)propanal (33)29
13C NMR (100 MHz, CDCl3): δ = 11.1 (SiCH(CH3)2), 16.7 (5′′-CH3), 18.6
(SiCH(CH3)2), 19.8 (2′′-CH3), 23.5 (C-4′), 31.0 (C-3), 31.5 (C-3′, C-5′),
32.5 (C-2′′), 43.4 (C-5′′, C-1′′), 50.3 (C-1), 66.6 (C-6′′), 74.4 (C-2′), 75.7
(C-6′), 86.2 (C-8′′), 107.0 (C-7′′), 127.7 (C-4′′), 140.0 (C-3′′), 207.7 (C-
2).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C27H48O3Si: 471.326493;
found: 471.326944.
To a solution of DMSO (33.2 mL, 36.52 g, 0.47 mol) in CH2Cl2 (40 mL)
cooled to –75 °C was added dropwise a solution of oxalyl chloride
(20.8 mL, 30.8 g, 0.24 mol) in CH2Cl2 (100 mL) keeping the tempera-
ture of the solution below –60 °C. After complete addition, the mix-
ture was stirred for 10 min at –75 °C, followed by the dropwise addi-
tion of alcohol28 32 (38.6 g, 0.203 mol) in CH2Cl2 (40 mL). The reaction
mixture was stirred for 1 h at –75 °C before Et3N (66 mL, 48.18 g,
0.476 mol) was added dropwise. The mixture was brought to r.t. and
stirred for 1 h. The resulting white suspension was treated with H2O
(100 mL), the layers were separated and the aqueous layer was ex-
tracted with Et2O (3 × 50 mL). The combined organic layers were
washed with saturated NaCl solution, dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by flash chro-
matography (petroleum ether/Et2O, 4:1) to give aldehyde 33 (24.3 g,
64%) as a colorless oil.
NMR Data for Enone 30
1H NMR (400 MHz, CDCl3): δ = 0.01, 0.02, 0.07, 0.11 (4 s, 3 H each,
Si(CH3)2), 0.87, 0.87 (2 s, 9 H each, SiC(CH3)3), 0.93 (d, J = 6.8 Hz, 10-
CH3), 1.05 (s, 24 H, 13-CH3, Si(CH(CH3)2)3), 1.28 (ddd (app quin),
J = 13.4, 6.8, 6.8 Hz, 1 H, 9-H), 1.35–1.52 (m, 5 H, 6-H, 7-H, 9-H), 2.11–
2.22 (m, 3 H, 5-H, 10-H), 2.22 (s, 3 H, 1-H), 2.32 (q, J = 6.6 Hz, 1 H, 13-
H), 3.63–3.70 (m, 1 H, 8-H), 4.15 (d, J = 5.3 Hz, 1 H, 14-H), 5.30 (dd, J =
15.7, 7.6 Hz, 1 H, 11-H), 5.41 (d, J = 15.4, 7.3 Hz, 1 H, 12-H), 6.05 (d, J =
15.9 Hz, 1 H, 3-H), 6.77 (dd, J = 15.9, 6.8 Hz, 1 H, 4-H).
13C NMR (100 MHz, CDCl3): δ = –5.1, –4.5, –4.4, –4.3 (Si(CH3)2), 11.2
(SiCH(CH3)2), 16.0 (13-CH3), 18.1, 18.2 (SiC(CH3)3), 18.6 (SiCH(CH3)2),
20.7 (10-CH3), 23.5 (C-6), 32.7 (C-10), 33.3 (C-5), 36.5 (C-7), 43.9 (C-
13), 44.5 (C-9), 67.7 (C-14), 69.8 (C-8), 85.0 (C-16), 108.5 (C-15),
130.3 (C-12), 131.4 (C-3), 136.6 (C-11), 148.3 (C-4), 198.6 (C-2).
Rf = 0.67 (petroleum ether/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = –0.01 (s, 6 H, Si(CH3)2), 0.84 (s, 9 H,
SiC(CH3)3), 2.51 (dt, J = 6.1, 2.0 Hz, 2 H, 2-H), 3.92 (t, J = 6.1 Hz, 2 H, 3-
H), 9.72 (t, J = 2.0 Hz, 1 H, 1-H).
13C NMR (100 MHz, CDCl3): δ = –5.6 (Si(CH3)2), 18.1 (SiC(CH3)3), 25.7
(SiC(CH3)3), 46.4 (C-2), 57.3 (C-3), 201.7 (C-1).
(S)-1-((tert-Butyldimethylsilyl)oxy)hex-5-en-3-ol (34)36
To a freshly prepared suspension of (–)-B-allyldiisopinocampheylbo-
rane (1.88 g, 5.75 mmol) (see procedure for compound 13) in anhy-
drous Et2O (20 mL) was added dropwise very slowly aldehyde 33 (1.0
g, 5.3 mmol), dissolved in anhydrous Et2O (10 mL), at –90 °C. After
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

K
A. Riefert, M. E. Maier
Feature
Synthesis
complete addition, the reaction mixture was stirred for 1.5 h at
–75 °C. Then, it was brought to r.t. within 1 h, stirred for 1 h at r.t.,
then cooled to 0 °C, and slowly treated with aqueous 3 M NaOH (6
mL), then with H2O2 (30%, 2.5 mL), and finally with saturated NaHCO3
(8 mL). The reaction mixture was stirred at r.t. for 10 h, then extracted
with Et2O (3 × 20 mL). The combined organic layers were washed with
saturated NaCl solution, dried over MgSO4, filtered and concentrated
in vacuo. The crude product was purified by flash chromatography
(petroleum ether/Et2O, 2:1) providing homoallyl alcohol 34 (860 mg,
70%) as a colorless oil; 91.3% ee.
dried over MgSO4, filtered and concentrated in vacuo. The crude
product was immediately dissolved in MeCN/H2O (3:2, 35 mL) and
treated with NaIO4 (644 mg, 3.01 mmol). This mixture was stirred for
1 h at 0 °C before it was diluted with H2O (10 mL) and Et2O (10 mL).
The layers were separated and the aqueous layer was extracted with
Et2O (3 × 20 mL). The combined organic layers were washed with sat-
urated NaCl solution, dried over MgSO4, filtered and concentrated in
vacuo. The product was purified by flash chromatography (petroleum
ether/Et2O, 20:1) providing aldehyde 36 (240 mg, 44%) as a colorless
oil.
20
20
[α]D –6.3 (c 1.0, CH2Cl2) {Lit.36b [α]D –5.95 (c 2.20, CHCl3); Lit.36c
[α]D20 +4.5 (c 1.0, CH2Cl2); Rf = 0.43 (petroleum ether/Et2O, 2:1).
[α]D25 –4.2 (c 0.66, CHCl3)}; Rf = 0.44 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.04 (s, 6 H, Si(CH3)2), 0.87 (s, 9 H,
SiC(CH3)3), 1.68–1.76 (m, 1 H, 4-H), 1.80–1.88 (m, 1 H, 4-H), 2.58–2.60
(m, 2 H, 2-H), 3.66–3.72 (m, 2 H, 5-H), 3.73 (s, 3 H, OCH3), 4.07–4.14
(m, 1 H, 3-H), 4.47 (d, J = 2.5 Hz, 2 H, OCH2Ar), 6.85 (d, J = 8.6 Hz, 2 H,
1H NMR (400 MHz, CDCl3): δ = 0.05 (s, 6 H, Si(CH3)2), 0.87 (s, 9 H,
SiC(CH3)3), 1.61–1.66 (m, 2 H, 2-H), 2.16–2.26 (m, 2 H, 4-H), 3.75–3.80
(m, 1 H, 3-H), 3.82–3.89 (m, 2 H, 1-H), 5.03–5.10 (m, 2 H, 6-H), 5.80
(dd, J = 10.1, 7.1 Hz, 1 H, 5-H).
H
aromat), 7.22 (d, J = 8.8 Hz, 2 H, Haromat), 9.75 (t, J = 2.5 Hz, 1 H, 1-H).
13C NMR (100 MHz, CDCl3): δ = –5.6 (Si(CH3)2), 18.1 (SiC(CH3)3), 25.8
(SiC(CH3)3), 37.7 (C-2), 41.9 (C-4), 62.5 (C-1), 71.1 (C-3), 117.2 (C-6),
135.0 (C-5).
13C NMR (100 MHz, CDCl3): δ = –5.5 (Si(CH3)2), 18.2 (SiC(CH3)3), 25.8
(SiC(CH3)3), 37.3 (C-4), 48.6 (C-2), 55.2 (OCH3), 59.1 (C-5), 71.1
(OCH2Ar), 71.4 (C-3), 113.8, 129.3, 130.2, 159.2 (4 Caromat), 201.6 (C-1).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H26O2Si: 253.15943;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H32O4Si: 375.19621;
found: 253.15963.
found: 375.19632.
GC (75 kP; 80 °C, 3 min, 10 °C/min to 190 °C, 10 min): tR = 9.14 (minor
enantiomer), 9.26 (major enantiomer) min.
(6R)-8-((tert-Butyldimethylsilyl)oxy)-1-((2S,6R)-6-((2S,5S,6R,E)-6-
((tert-butyldimethylsilyl)oxy)-2,5-dimethyl-8-(triisopropylsi-
lyl)oct-3-en-7-yn-1-yl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-6-
((4-methoxybenzyl)oxy)octan-2-one (37)
(S)-1-((tert-Butyldimethylsilyl)oxy)-3-((4-methoxyben-
zyl)oxy)hex-5-ene (35)36c,37
Under an inert atmosphere, a solution of ketone 6 (347 mg, 0.62
mmol) in anhydrous Et2O (2 mL) was added dropwise to a solution of
LDA (1 M in THF, 0.65 mL, 0.65 mmol) at –75 °C. The mixture was
stirred for 1 h at –75 °C before aldehyde 36 (239 mg, 0.68 mmol), dis-
solved in Et2O (1 mL), was added dropwise. After complete addition,
the reaction mixture was stirred for 1 h and then quenched with pH 7
buffer (2 mL). The layers were separated and the aqueous layer was
extracted with Et2O (3 × 2 mL). The combined organic layers were
washed with saturated NaCl solution, dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by flash chro-
matography (petroleum ether/Et2O, 2:1) to provide aldol product 37
(391 mg, 69%) as a colorless oil (dr = 3:1).
A solution of alcohol 34 (100 mg, 0.43 mmol) and 4-methoxybenzyl-
2,2,2-trichloroacetimidate30 (182 mg, 0.645 mmol) in anhydrous CH2-
Cl2 (3 mL) was treated with CSA (1 mg, 0.0043 mmol). The reaction
mixture was stirred at r.t. for 12 h and then quenched with H2O (2
mL). The layers were separated and the aqueous layer was extracted
with Et2O (3 × 2 mL). The combined organic layers were washed with
saturated NaCl solution, dried over MgSO4, filtered and concentrated
in vacuo. The crude ether was purified by flash chromatography (pe-
troleum ether/Et2O, 2:1) to give pure 35 (98 mg, 64%) as a colorless
oil.
[α]D20 +8.5 (c 1.0, CH2Cl2); Rf = 0.81 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 6 H, Si(CH3)2), 0.85 (s, 9 H,
SiC(CH3)3), 1.60–1.76 (m, 2 H, 2-H), 2.13–2.22 (m, 1 H, 4-H), 2.28 (t,
J = 5.9 Hz, 1 H, 4-H), 3.44–3.48 (m, 1 H, 3-H), 3.55–3.69 (m, 2 H, 1-H),
3.73 (s, 3 H, OCH3), 4.38 (d, J = 10.9 Hz, 1 H, OCH2Ar), 4.39 (d, J = 10.9
Hz, 1 H, OCH2Ar), 4.96–5.06 (m, 2 H, 6-H), 5.71–5.85 (m, 1 H, 5-H),
6.81 (dd, J = 6.6, 2.3 Hz, 2 H, Haromat), 7.20 (dd, J = 8.6, 3.3 Hz, 2 H, Haro-
mat).
13C NMR (100 MHz, CDCl3): δ = –5.4 (Si(CH3)2), 18.2 (SiC(CH3)3), 25.9
(SiC(CH3)3), 37.2 (C-2), 38.5 (C-4), 55.1 (OCH3), 59.6 (C-1), 70.8
(OCH2Ar), 75.1 (C-3), 113.7 (Caromat), 116.9 (C-6), 129.2 (Caromat), 130.9
(Caromat), 134.9 (C-5), 159.0 (Caromat).
[α]D20 +14.1 (c 1.0, CH2Cl2); Rf = 0.19 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.02, 0.03, 0.06, 0.10 (4 s, 3 H each,
Si(CH3)2), 0.87 (s, 18 H, SiC(CH3)3), 0.91 (d, J = 6.6 Hz, 3 H, 2′′-CH3),
1.04 (s, 24 H, SiCH(CH3)2, 5′′-CH3), 1.44–1.58 (m, 6 H, 1′′-H, 5′-H, 4′-H),
1.61–1.86 (m, 6 H, 5-H, 7-H, 3′-H), 2.15–2.38 (m, 3 H, 5′′-H, 2′′-H, 1-
H), 2.53–2.66 (m, 3 H, 3-H, 1-H), 3.23–3.32 (m, 1 H, 6′-H), 3.62–3.72
(m, 3 H, 6-H, 8-H), 3.74 (s, 3 H, OCH3), 3.79–3.86 (m, 1 H, 2′-H), 4.14
(d, J = 5.6 Hz, 1 H, 6′′-H), 4.26–4.34 (m, 1 H, 4-H), 4.34–4.54 (m, 2 H,
OCH2Ar), 5.32 (ddd, J = 8.6, 6.8, 2.8 Hz, 1 H, 4′′-H), 5.38 (dd, J = 15.7,
7.1 Hz, 1 H, 3′′-H), 6.80–6.83 (m, 2 H, Haromat), 7.22 (t, J = 8.3 Hz, 2 H,
H
aromat).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H34O3Si: 373.21694;
found: 373.21735.
13C NMR (100 MHz, CDCl3): δ = –5.5 (Si(CH3)2), –5.2 (Si(CH3)2), –4.6
(Si(CH3)2), 11.1 (SiCH(CH3)2), 15.7 (5′′-CH3), 18.1 (SiC(CH3)3), 18.5
(SiCH(CH3)2), 19.8 (SiC(CH3)3), 19.9 (2′′-CH3), 23.3 (C-4′), 25.6
(SiC(CH3)3), 25.8 (SiC(CH3)3), 31.1, 31.4 (C-3′, C-5′), 32.3 (C-2′′), 37.3
(C-7), 40.8 (C-5), 43.2 (C-1′′), 43.8 (C-5′′), 49.8 (C-1), 51.1 (C-3), 55.0
(OCH3), 59.3 (C-8), 67.6 (C-6′′), 70.4 (C-4), 71.3 (OCH2Ar), 73.2 (C-4
isomer), 74.1, 74.2 (C-2′), 75.0 (C-6), 75.5, 75.6 (C-6′), 84.8 (C-8′′),
108.5 (C-7′′), 113.7 (Caromat), 129.4 (Caromat), 129.8 (Caromat), 130.5 (C-
3′′), 136.3 (C-4′′), 159.1 (Caromat), 209.7 (C-2).
(R)-5-((tert-Butyldimethylsilyl)oxy)-3-((4-methoxyben-
zyl)oxy)pentanal (36)
A solution of alkene 35 (543 mg, 1.55 mmol) in H2O/t-BuOH (1:1, 27
mL) was treated at 0 °C with K3Fe(CN)6 (1.56 g, 4.74 mmol), K2CO3
(652 mg, 4.72 mmol) and K2OsO4·2 H2O (6.8 mg, 0.018 mmol). The re-
action mixture was stirred at r.t. for 8 h, then diluted with H2O (4 mL)
and Et2O (5 mL). The layers were separated and the aqueous layer was
extracted with Et2O (3 × 10 mL). The combined organic layers were
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C52H94O7Si3: 937.61996;
found: 937.62065.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

L
A. Riefert, M. E. Maier
Feature
Synthesis
(6R)-4,8-Bis((tert-butyldimethylsilyl)oxy)-1-((2S,6R)-6-
((2S,5S,6R,E)-6-((tert-butyldimethylsilyl)oxy)-2,5-dimethyl-8-(tri-
isopropylsilyl)oct-3-en-7-yn-1-yl)tetrahydro-2H-pyran-2-yl)-6-
((4-methoxybenzyl)oxy)octan-2-one (5)
[α]D20 +20.3 (c 1.0, CH2Cl2); Rf = 0.82 (petroleum ether/Et2O, 4:1).
1H NMR (400 MHz, CDCl3): δ = 0.02, 0.03, 0.04, 0.05, 0.08, 0.11 (6 s, 18
H, Si(CH3)2), 0.87 (s, 18 H, SiC(CH3)3), 0.88 (s, 9 H, SiC(CH3)3), 0.93 (d,
J = 6.6 Hz, 3 H, 15-CH3), 1.03 (d, J = 4.3 Hz, 3 H, 18-CH3), 1.05 (s, 21 H,
SiCH(CH3)2), 1.14–1.27 (m, 5 H, 6-H, 8-H, 10-H, 12-H, 14-H), 1.32–
1.42 (m, 1 H, 4-H), 1.45–1.65 (m, 6 H, 2-H, 10-H, 11-H, 12-H, 14-H),
1.74–1.84 (m, 4 H, 4-H, 6-H, 8-H, 11-H), 2.20–2.35 (m, 2 H, 15-H, 18-
H), 3.22–3.30 (m, 1 H, 13-H), 3.33–3.44 (m, 2 H, 5-H, 9-H), 3.64–3.77
(m, 3 H, 1-H, 7-H), 3.85–3.93 (m, 1 H, 3-H), 4.16 (d, J = 5.6 Hz, 1 H, 19-
H), 5.35 (dd, J = 15.4, 6.8 Hz, 1 H, 17-H), 5.41 (dd, J = 15.4, 8.1 Hz, 1 H,
16-H).
13C NMR (100 MHz, CDCl3): δ = –5.3 (Si(CH3)2), –5.1 (Si(CH3)2), –4.5
(Si(CH3)2), –4.5 (Si(CH3)2), 11.2 (SiCH(CH3)2), 15.9 (18-CH3), 18.1
(SiC(CH3)3), 18.2 (SiC(CH3)3), 18.3 (SiC(CH3)3), 18.6 (SiCH(CH3)2), 19.7
(15-CH3), 23.8 (C-11), 25.8 (SiC(CH3)3), 25.9 (SiC(CH3)3), 26.0
(SiC(CH3)3), 31.5 (C-10, C-12), 33.7 (C-12), 32.3 (C-15), 39.3 (C-2), 41.4
(C-14), 42.0 (C-4), 42.6 (C-8), 43.6 (C-6), 44.0 (C-18), 59.7 (C-1), 67.8
(C-5), 69.0 (C-9), 72.1 (C-7), 72.2 (C-13), 74.3 (C-3), 75.3 (C-19), 84.9
(C-21), 108.7 (C-20), 129.7 (C-16), 136.8 (C-17).
To a solution of alcohol 37 (4.4 g, 4.8 mmol) in anhydrous CH2Cl2 (75
mL) was added dropwise 2,6-lutidine (1.4 mL, 1.29 g, 12.0 mmol) at
0 °C. The reaction mixture was stirred for 20 min before TBSOTf (2.5
g, 9.5 mmol) was added dropwise at 0 °C. The solution was brought to
r.t. and stirred for 1 h. Thereafter, it was treated with saturated NH4Cl
solution (20 mL). The layers were separated and the aqueous layer
was extracted with Et2O (3 × 20 mL). The combined organic layers
were washed with saturated NaCl solution, dried over MgSO4, filtered
and concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/Et2O, 2:1) providing silyl ether 5
(3.71 g, 75%) as a colorless oil.
[α]D20 +11.6 (c 1.0, CH2Cl2); Rf = 0.77 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.01, 0.02, 0.03, 0.04, 0.05, 0.07, 0.12 (s,
18 H, Si(CH3)2), 0.85 (s, 9 H, SiC(CH3)3), 0.88 (s, 18 H, SiC(CH3)3), 0.93
(d, J = 6.1 Hz, 3 H, 2′′-CH3), 1.05 (s, 21 H, SiCH(CH3)2), 1.05 (d, J = 4.8
Hz, 3 H, 5′′-CH3), 1.10–1.25 (m, 3 H, 3′-H, 5′-H, 1′′-H), 1.42–1.64 (m, 5
H, 5-H, 3′-H, 4′-H, 5′-H, 1′′-H), 1.67–1.80 (m, 4 H, 5-H, 7-H, 4′-H),
2.23–2.38 (m, 3 H, 1-H, 2′′-H, 5′′-H), 2.54–2.66 (m, 3 H, 1-H, 3-H),
3.25–3.33 (m, 1 H, 6′-H), 3.60–3.73 (m, 4 H, 6-H, 8-H, 2′-H), 3.75 (s, 3
H, OCH3), 4.15 (d, J = 4.3 Hz, 1 H, 6′′-H), 4.28–4.35 (m, 1 H, 4-H), 4.37–
4.48 (m, 2 H, OCH2Ar), 5.34 (dd, J = 15.4, 6.6 Hz, 1 H, 4′′-H), 5.40 (dd,
J = 15.4, 6.6 Hz, 1 H, 3′′-H), 6.84 (dd, J = 8.6, 2.8 Hz, 2 H, Haromat), 7.24
(dd, J = 8.6, 3.5 Hz, 2 H, Haromat).
13C NMR (100 MHz, CDCl3): δ = –5.4, –5.2, –4.6, –4.5, –4.5 (Si(CH3)2),
11.1 (SiCH(CH3)2), 15.8 (5′′-CH3), 17.8, 17.9, 18.1, 18.2 (SiC(CH3)3),
18.5 (SiCH(CH3)2), 19.9 (2′′-CH3), 23.4 (C-4′), 25.7, 25.8, 25.9
(SiC(CH3)3), 31.2, 31.5 (C-3′, C-5′), 32.3 (C-2′′), 37.5, 37.7 (C-7), 43.1
(C-5), 43.4 (C-1′′), 43.9 (C-5′′), 50.8 (C-1), 52.1 (C-3), 55.0 (OCH3), 59.4
(C-8), 66.3 (C-4), 67.7 (C-6′′), 70.4 (OCH2Ar), 72.4, 72.9 (C-6), 73.9 (C-
2′), 75.5 (C-6′), 84.8 (C-8′′), 108.6 (C-7′′), 113.6 (Caromat), 129.0 (Caromat),
129.3 (Caromat), 129.7 (C-3′′), 136.3 (C-4′′), 159.0 (Caromat), 207.4, 207.7
(C-2).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C50H100O5Si4: 915.65400;
found: 915.65248.
Alcohol 39
A solution of bis-tetrahydropyran 38 (609 mg, 0.681 mmol) in anhy-
drous CH2Cl2/MeOH (1:1, 40 mL) was treated at 0 °C with PPTS (18.4
mg, 0.073 mmol). The reaction mixture was stirred at r.t. for 4 h and
then treated with saturated NaHCO3 solution (10 mL). The layers were
separated and the aqueous layer was extracted with Et2O (3 × 5 mL).
The combined organic layers were washed with saturated NaCl solu-
tion, dried over MgSO4, filtered and concentrated in vacuo. The crude
product was purified by flash chromatography (petroleum ether/Et2O,
2:1) providing primary alcohol 39 (406 mg, 76%) as a colorless oil.
[α]D20 +31.2 (c 1.0, CH2Cl2); Rf = 0.38 (petroleum ether/Et2O, 2:1).
1H NMR (400 MHz, CDCl3): δ = 0.03 (s, 6 H, Si(CH3)2), 0.07 (d, J = 15.4
Hz, 6 H, Si(CH3)2), 0.86 (s, 9 H, SiC(CH3)3), 0.87 (s, 9 H, SiC(CH3)3), 0.92
(d, J = 6.6 Hz, 3 H, 15-CH3), 1.05 (s, 24 H, SiCH(CH3)2, 18-CH3), 1.13–
1.26 (m, 4 H, 4-H, 11-H), 1.37–1.67 (m, 8 H, 6-H, 10-H, 12-H, 14-H),
1.70–1.89 (m, 4 H, 2-H, 8-H), 2.22–2.34 (m, 2 H, 15-H, 18-H), 3.21–
3.29 (m, 1 H, 13-H), 3.29–3.39 (m, 1 H, 7-H), 3.48–3.56 (m, 1 H, 3-H),
3.69–3.81 (m, 3 H, 1-H, 5-H), 3.95–4.03 (m, 1 H, 9-H), 4.14 (d, J = 5.5
Hz, 1 H, 19-H), 5.29–5.38 (m, 1 H, 17-H), 5.41 (dd, J = 15.5, 6.6 Hz, 1 H,
16-H).
13C NMR (100 MHz, CDCl3): δ = –5.1 (Si(CH3)2), –4.6 (Si(CH3)2), –4.5
(Si(CH3)2), 11.2 (SiCH(CH3)2), 15.8 (18-CH3), 18.0 (SiC(CH3)3), 18.2
(SiC(CH3)3), 18.6 (SiCH(CH3)2), 19.5 (15-CH3), 23.7 (C-11), 25.7
(SiC(CH3)3), 25.8 (SiC(CH3)3), 31.7 (C-15), 32.2 (C-12), 32.5 (C-10), 37.8
(C-2), 40.8 (C-14), 41.7 (C-4), 42.4 (C-8), 43.5 (C-6), 44.0 (C-18), 61.5
(C-1), 67.8 (C-5), 68.5 (C-9), 72.8 (C-7), 74.2 (C-13), 75.3 (C-3), 76.2
(C-19), 84.9 (C-21), 108.7 (C-20), 129.7 (C-16), 136.7 (C-17).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C58H108O7Si4: 1051.70643;
found: 1051.70640.
Bis-tetrahydropyran 38
To a solution of ketone 5 (1.77 g, 1.72 mmol) in Et3SiH/CH2Cl2 (1:3, 85
mL) was added slowly at –75 °C BF3·Et2O (1.02 mL, 1.173 g, 8.26
mmol). The stirred reaction mixture was allowed to warm to –20 °C
within 1 h and stirred for 1 h at this temperature. The reaction was
quenched with Et3N (5 mL) and saturated NaHCO3 solution (10 mL).
The layers were separated and the aqueous layer was extracted with
Et2O (3 × 10 mL). The combined organic layers were washed with sat-
urated NaCl solution, dried over MgSO4, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography (pe-
troleum ether/Et2O, 4:1) to give bis-pyran 38 (937 mg, 61%) as a color-
less oil.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C44H86O5Si3: 801.56753;
found: 801.56785.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

M
A. Riefert, M. E. Maier
Feature
Synthesis
Carboxylic Acid 40
Macrolactone 43
A solution of bis-tetrahydropyranyl alcohol 39 (320 mg, 0.411 mmol)
in MeCN/petroleum ether (2:1, 15 mL) was treated at 0 °C with
NMO·H2O (576 mg, 4.26 mmol) and TPAP (13.8 mg, 0.039 mmol). The
reaction mixture was stirred at r.t. for 3 h. After completion of the re-
action (TLC), the volatiles were removed under reduced pressure and
the residue was purified by flash chromatography (petroleum
ether/Et2O, 3:2). Acid 40 (240 mg, 74%) was obtained as a colorless
oil.
To a solution of MNBA (42; 9.7 mg, 0.028 mmol) and DMAP (5.6 mg,
0.46 mmol) in anhydrous CH2Cl2 (2 mL) was added bis-tetrahydropy-
ranyl hydroxy acid 41 (10 mg, 0.019 mmol), dissolved in anhydrous
CH2Cl2 (20 mL), dropwise via syringe pump over a period of 7 h at r.t.
The reaction mixture was stirred for an additional 1 h and quenched
with saturated NaHCO3 solution (5 mL). The layers were separated
and the aqueous layer was extracted with Et2O (3 × 3 mL). The com-
bined organic layers were washed with saturated NaCl solution, dried
over MgSO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography (petroleum ether/Et2O, 10:1)
to give macrolactone 43 (5.9 mg, 61%) as a colorless oil.
[α]D20 +10.5 (c 1.0, CH2Cl2); Rf = 0.78 (petroleum ether/Et2O, 3:2).
1H NMR (400 MHz, CDCl3): δ = 0.03, 0.04, 0.07, 0.11 (4 s, 3 H each,
Si(CH3)2), 0.87 (s, 9 H, SiC(CH3)3), 0.88 (s, 9 H, SiC(CH3)3), 0.93 (d,
J = 6.7 Hz, 3 H, 15-CH3), 1.03 (d, J = 6.7 Hz, 3 H, 18-CH3), 1.05 (s, 21 H,
SiCH(CH3)2), 1.13–1.28 (m, 5 H, 4-H, 6-H, 10-H, 12-H, 14-H), 1.37–
1.67 (m, 6 H, 6-H, 8-H, 10-H, 11-H, 12-H, 14-H), 1.70–1.89 (m, 3 H, 4-
H, 6-H, 8-H, 11-H), 2.22–2.35 (m, 2 H, 15-H, 18-H), 2.48 (dd, J = 11.3,
8.9 Hz, 1 H, 2-H), 2.56 (dd, J = 15.9, 8.1 Hz, 1 H, 2-H), 3.22–3.30 (m, 1
H, 13-H), 3.33–3.40 (m, 1 H, 9-H), 3.54–3.63 (m, 1 H, 7-H), 3.67–3.81
(m, 2 H, 3-H, 5-H), 4.14 (d, J = 5.5 Hz, 1 H, 19-H), 5.29–5.45 (m, 2 H,
16-H, 17-H).
13C NMR (100 MHz, CDCl3): δ = –5.1 (Si(CH3)2), –4.6 (Si(CH3)2), –4.5
(Si(CH3)2), 11.2 (SiCH(CH3)2), 15.9 (18-CH3), 18.0 (SiC(CH3)3), 18.2
(SiC(CH3)3), 18.6 (SiCH(CH3)2), 19.7 (15-CH3), 23.6 (C-11), 25.8
(SiC(CH3)3), 25.8 (SiC(CH3)3), 31.7 (C-10, C-12), 32.3 (C-15), 40.7 (C-2),
41.1 (C-4), 42.1 (C-8), 43.4 (C-6, C-14), 44.0 (C-18), 67.8 (C-19), 68.2
(C-5), 71.8 (C-3), 73.2 (C-7), 74.2 (C-9), 75.4 (C-13), 84.9 (C-21), 108.7
(C-20), 129.8 (C-16), 136.7 (C-17), 173.9 (C-1).
[α]D20 –17.4 (c 1.0, CH2Cl2); Rf = 0.17 (petroleum ether/Et2O, 10:1).
1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 3 H, Si(CH3)2), 0.03 (s, 3 H,
Si(CH3)2), 0.88 (s, 9 H, SiC(CH3)3), 1.07 (d, J = 7.1 Hz, 3 H, 15-CH3), 1.19
(d, J = 6.8 Hz, 3 H, 18-CH3), 1.21–1.31 (m, 5 H, 4-H, 6-H, 8-H, 10 H, 12
H), 1.39–1.62 (m, 9 H, 4-H, 6-H, 8 H, 10-H, 11-H (2 x), 12-H, 14-H (2
x)), 2.27–2.38 (m, 2 H, 15-H, 18-H), 2.42 (d, J = 2.1 Hz, 1 H, 21-H),
2.45–2.56 (m, 2 H, 2-H), 3.18–3.23 (m, 1 H, 13-H), 3.26–3.30 (m, 1 H,
9-H), 3.62–3.68 (m, 1 H, 7-H), 4.14–4.19 (m, 1 H, 5-H), 4.24–4.31 (m,
1 H, 3-H), 5.30 (t, J = 2.2 Hz, 1 H, 19-H), 5.46 (dd, J = 7.6, 6.7 Hz, 1 H,
17-H), 5.58 (dd, J = 15.8, 5.1 Hz, 1 H, 16-H).
13C NMR (100 MHz, CDCl3): δ = –4.9 (Si(CH3)2), 14.6 (18-CH3), 18.1
(SiC(CH3)3), 20.5 (15-CH3), 23.6 (C-11), 25.6 (SiC(CH3)3), 31.6 (C-10, C-
12) 32.9 (C-15), 40.6 (C-4, C-6), 40.8 (C-2), 41.5 (C-8), 42.2 (C-18),
43.9 (C-14), 65.1 (C-5), 68.1 (C-19), 68.7 (C-3), 69.8 (C-7), 72.2 (C-7,
minor), 73.6 (C-21), 75.9 (C-9), 76.5 (C-13), 80.9 (C-20), 128.4 (C-16),
135.9 (C-17), 171.2 (C-1).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C44H84O6Si3: 815.54679;
found: 815.54679.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C29H48O5Si: 527.31632;
found: 527.31672.
Hydroxy Acid 41
To a solution of bis-tetrahydropyranyl carboxylic acid 40 (7.4 mg,
0.0093 mmol) in anhydrous THF (1 mL) was added at 0 °C TBAF·3 H2O
(17.6 mg, 0.056 mmol). The reaction mixture was stirred at r.t. for 4 h.
After completion of the reaction (TLC), the volatiles were removed
under reduced pressure and the residue was purified by flash chro-
matography (petroleum ether/Et2O, 3:2). Seco acid 41 (1.9 mg, 39%)
was obtained as a colorless oil.
Acknowledgment
Financial support by the state of Baden-Württemberg is gratefully ac-
knowledged. The authors appreciate networking contribution by the
COST Action CM1407 ‘Challenging organic syntheses inspired by na-
ture – from natural products chemistry to drug discovery’.
[α]D20 –9.8 (c 1.0, CH2Cl2); Rf = 0.19 (petroleum ether/Et2O, 3:2).
1H NMR (400 MHz, CDCl3): δ = 0.03 (d, J = 5.3 Hz, 6 H, Si(CH3)2), 0.87
(d, J = 5.6 Hz, 9 H, SiC(CH3)3), 0.97 (d, J = 6.7 Hz, 3 H, 15-CH3), 1.07 (d,
J = 7.0 Hz, 3 H, 18-CH3), 1.21–1.31 (m, 4 H, 6-H, 11-H), 1.39–1.62 (m, 8
H, 4-H, 10-H, 12-H, 14-H), 1.79–1.88 (m, 2 H, 8-H), 2.28–2.40 (m, 2 H,
15-H, 18-H), 2.43 (t, J = 2.3 Hz, 1 H, 21-H), 2.45–2.50 (m, 1 H, 2-H),
2.56 (dd, J = 15.7, 8.4 Hz, 1 H, 2-H), 3.25–3.31 (m, 1 H, 13-H), 3.35–
3.41 (m, 1 H, 7-H), 3.53–3.59 (m, 1 H, 9-H), 3.69–3.81 (m, 1 H, 5-H),
4.15–4.19 (m, 1 H, 3-H), 4.22 (d, J = 4.9 Hz, 1 H, 19-H), 5.39 (dd, J = 8.0,
3.7 Hz, 1 H, 17-H), 5.41 (dd, J = 15.4, 7.6 Hz, 1 H, 16-H).
13C NMR (100 MHz, CDCl3): δ = –4.9 (Si(CH3)2), –4.6 (Si(CH3)2), 16.0
(18-CH3), 18.0 (SiC(CH3)3), 20.1 (15-CH3), 23.6 (C-11), 25.6
(SiC(CH3)3), 31.6 (C-10, C-12), 32.9 (C-15), 40.7 (C-2), 40.9 (C-4), 42.9
(C-18), 43.4 (C-6, C-14), 66.0 (C-19), 68.1 (C-5), 71.9 (C-3), 73.4 (C-7),
73.7 (C-21), 74.5 (C-9), 77.8 (C-21), 83.2 (C-20), 127.7 (C-16), 139.7
(C-17), 177.7 (C-1).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609551.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N