Advances and Setbacks in the Total Synthesis of the Fungal Metabolite Curvicollide C: Synthesis and Elaboration of Non-Aldol Stereotriads from Gosteli-Type Allyl Vinyl Ethers

Article abstract of DOI:10.1055/s-0035-1561614

Advances and setbacks are reported in regard to the asymmetric total synthesis of the fungal metabolite curvicollide C relying on a synthetic strategy that exploits non-aldol stereotriads as chiral building blocks. A catalytic asymmetric Gosteli-Claisen rearrangement, a two-step aldehyde-to-alkyne-homologation, and a Julia-Kocienski olefination served as key C/C-connecting transformations.

Full text of DOI:10.1055/s-0035-1561614

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–Q
paper
A
M. Körner, M. Hiersemann
Paper
Synthesis
Advances and Setbacks in the Total Synthesis of the Fungal
Metabolite Curvicollide C: Synthesis and Elaboration of Non-Aldol
Stereotriads from Gosteli-Type Allyl Vinyl Ethers
Marleen Körner
O
OH
20
8
Martin Hiersemann*
14
1
O
Fakultät für Chemie und Chemische Biologie,
Technische Universität Dortmund,
44227 Dortmund, Germany
O
curvicollide C:
fungal metabolite; abs. and rel. config. unknown; unique constitution
building block synthesis:
martin.hiersemann@tu-dortmund.de
20
8
7
14
R1O
OR4
central-eastern
central
OR3
OR3
R2O
R2O
Received: 16.01.2016
Accepted after revision: 11.03.2016
Published online: 10.05.2016
were not tested by Gloer et al. The interpretation of the re-
sults of NMR experiments revealed the molecular constitu-
tion of 1a–c and, in part, the relative configuration of 1a
(Figure 1). The relative configuration of the γ-lactone moi-
ety in 1b and 1c was only assigned in analogy. The constitu-
tion of the γ-lactone structural element of 1a–c deviates
from the regular polyketide architecture. Gloer and collabo-
rators suggested the condensation of two polyketide units
by carbon–carbon bond formation in order to explain the
curvicollide architecture. A biosynthetic pathway involving
a Favorski-type rearrangement of regular linear polyketide
precursors could also account for the formation of the
unique γ-lactone structural element featuring a non-aldol
stereotriad.9
DOI: 10.1055/s-0035-1561614; Art ID: ss-2016-t0036-op
Abstract Advances and setbacks are reported in regard to the asym-
metric total synthesis of the fungal metabolite curvicollide C relying on
a synthetic strategy that exploits non-aldol stereotriads as chiral build-
ing blocks. A catalytic asymmetric Gosteli–Claisen rearrangement, a
two-step aldehyde-to-alkyne-homologation, and a Julia–Kocienski olefi-
nation served as key C/C-connecting transformations.
Key words antifungal agents, total synthesis, Claisen rearrangement,
Michael addition, chiral auxiliaries, ozonolysis
Fungicides are chemical entities that are used for the
management of fungal infections of humans, animals, and
plants. Invasive fungal infections are life-threatening for
critically ill or immunocompromised patients. The limited
number of antifungal agents in concert with the emergence
and spread of drug-resistant Candida and Aspergillus strains
constitute the need for the development of fungicides with
new modes of action.1–5 However, fungal-selective eukary-
otic cellular targets are more challenging to identify com-
pared to prokaryotes or viruses.6 The development of new
classes of antifungal metabolites from natural sources could
provide new opportunities for the therapeutic treatment of
fungal infections.7
R2
20
1
O
HO
R1
R1
CH2OH
CH3
R2
H
OH
H
curvicollide
(−)-A (1a)
(−)-B (1b)
(−)-C (1c)
CH3
O
O
Figure 1 Reported structures of the fungal metabolites curvicollide A–
C (Podospora curvicolla)
In 2004, Gloer and collaborators reported antifungal ac-
tivity of an extract of fermentation cultures of Podospora
curvicolla against Aspergillus flavus and Fusarium verticilli-
oides.8 From the fungicidal crude extract (3.3 g), the linear
polyketides curvicollide A (1a, 6.5 mg), B (1b, 2.1 mg), and C
(1c, 3.0 mg) were isolated. Curvicollide A (1a) demonstrated
antifungal activity against A. flavus and F. verticilloides in
disk assays. Because of the limited availability of curvicol-
lide B (1b) and C (1c), their respective antifungal activities
The mycoparasite Podospora curvicolla was initially col-
lected from a sclerotium of an Aspergillus flavus species
found in Illinois (USA).
The unprecedented molecular architecture of the curvi-
collides 1a–c could give rise to a creative process-like inter-
action between method development and target-oriented
synthesis. Furthermore, an asymmetric total synthesis
would enable the completion of the structural assignment,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

B
M. Körner, M. Hiersemann
Paper
Synthesis
20
[Cu{(S,S)-t-Bu-box}(H2O)2](SbF6)2
[(S,S)-3]
1
MeO
(0.075 equiv)
O
O
CH2Cl2−CF3CH2OH (1:1)
r.t., 16 h
CO2Me
O
HO
BnO
O
14
6
98%
dr >95:5 (NMR)
99% ee (HPLC)
BnO
syn-4
(Z,Z)-2
(−)-curvicollide C
fungal metabolite
abs. and rel.
20
3 steps
O
config. unknown
unique constitution
O
OBn
OBn
12 steps
11
8
O
12
15
20
1
OTBS
5a
14
OTBS
TBSO
7
O
6
R1O
OR3
various conditions
R2O
6
OH
central-eastern
(this article)
lateral
(western)
11
8
12
15
20
OTBS
TBSO
20
14
7a
8
Scheme 2 Previous effort aimed at the total synthesis of (–)-curvicol-
lide A
OR3
R2O
15
(+)- or (−)-central
(+)- or (−)-lateral
building blocks as well as their coupling. We will further
outline initial advances and ultimate setbacks in the elabo-
ration of the central eastern building block.
(non-aldol stereotriad)
(eastern)
12
12
8
8
We previously reported the synthesis of the α-keto ester
syn-4 by catalytic asymmetric Claisen rearrangement of the
Gosteli-type allyl vinyl ether (Z,Z)-2 (Scheme 2).11 Post-
rearrangement transformations delivered aldehyde 5a that
was converted into the C8–C20 building block 6. In execut-
ing the projected sequence from 6 to curvicollide C (1c), a
major obstacle was anticipated in the chemoselective cleav-
age of the benzyl-protecting group in the presence of the
diene moiety. Hence, we avoided reductive conditions and
turned our attention to the application of Lewis acids or ox-
idants. However, Lewis acids (e.g., BCl3·SMe2,12 BCl3,13 FeCl3-
14) triggered cleavage of both silyl ethers whereas subject-
ing compound 6 to DDQ-induced cleavage15 of the allylic si-
lyl ether at C11.
Notwithstanding this setback, we continued to favor the
convergent central-to-lateral approach, wherein the lateral
aldol segment would be connected to a larger central-east-
ern segment at a late stage of the synthetic sequence. To-
ward this end, and intending to circumvent the previously
experienced hurdle, we set out to switch the critical pro-
tecting group at C8. Hence, the known enyne 8a11a was re-
CO2R4
CO2R4
R2O
or
O
O
R2O
diastereomeric and quasi-enantiomeric
α-keto esters
Scheme 1 Modular central-to-lateral synthetic strategy to curvicollide
C. The curvicollide numbering system is used for all fragments and
building blocks throughout the article.
and drive the further evaluation of the antifungal proper-
ties. Thus, we have initiated a research project aimed at the
total synthesis of (–)-curvicollide C (1c).
Aiming to elucidate the absolute configuration of (–)-
curvicollide C (1c) by total synthesis, we decided to pursue
a modular central-to-lateral strategy (Scheme 1). Thus, a
suitably elaborated central building block was required in
order to assemble from the central to the lateral in a con-
vergent manner. We felt comfortable implementing this
modular strategy because it enables redeployment of the
required stereodiverse synthesis to the smaller lateral
building blocks. In further developing the central-to-lateral
strategy toward (–)-curvicollide C (1c), we recognized the
opportunity to access central building blocks that are char-
acterized by the non-aldol type stereotriad starting from
β,γ-branched δ,ε-unsaturated α-keto esters.10
acted
with
2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ) in a mixture of CH2Cl2 and aqueous buffer to yield
the primary alcohol 8b in moderate yield (61% isolated
yield, 0.18 g isolated mass, Scheme 3). Subsequent silyl
ether formation proceeded uneventful and delivered the
enyne 8c (92%). Synthesis of the desired non-aldol stereo-
triad was completed by chemoselective ozonolysis of the
In this article, our efforts to implement the central-to-
lateral synthetic strategy are described. We will delineate
the successful asymmetric synthesis of central and lateral
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

C
M. Körner, M. Hiersemann
Paper
Synthesis
the E-configured allylic alcohol 11a. Toward this end, termi-
nal alkyne 9b was treated with LDA and isopropyl chloro-
formate to give the alkynoate 10a in good yield (85%). Expo-
sure of 10a to a large excess of freshly prepared copper(I)
bromide dimethyl sulfide complex and methylmagnesium
bromide in THF at –78 °C delivered upon warming to 0 °C
the corresponding alkenoate.17,18 Subsequent reduction of
the alkenoate with an excess of diisobutylaluminum hy-
dride (DIBAL-H) in THF at low temperature provided the al-
lylic alcohol 11a (44% from 10a, E/Z = 95:5). Having com-
pleted the assembling of the central building block 11a, ef-
forts were directed to couple the central with the eastern
lateral building block by installation of the C14/C15 double
bond. Hence, the allylic alcohol 11a was oxidized with
manganese dioxide at elevated temperature.19 Subsequent
Julia–Kocienski olefination20 using a large excess of the
known sulfone (R)-1211a and potassium bis(trimethylsi-
lyl)amide in THF yielded the E,E-configured diene 7b (79%
from 11a, E/Z = 95:5). Selective cleavage of the primary TBS
ether21 at C8 in the presence of the primary TPS ether at C9′
and the secondary TBS ether at C11 was then required in
order to afford the desired alcohol 7c. To our dismay, how-
ever, none of the conditions probed enabled the differentia-
tion of the primary and the secondary TBS ether. Exposure
of the tris-silyl ether 7b to ammonium fluoride in methanol
at ambient temperature led to no conversion (Scheme 3, en-
try 1). Using hydrogen fluoride pyridine in dichlorometh-
ane at 0 °C triggered rapid cleavage of all silyl ethers (entry
2). Subjecting compound 7b to tetra-n-butylammonium
fluoride in THF at room temperature or to Oxone in metha-
nol22 at 0 °C resulted in the cleavage of the primary as well
as the allylic secondary TBS ethers (entries 3 and 4). This
outcome again illustrates the pronounced susceptibility of
the allylic silyl ether for cleavage under various conditions,
and evaluation of alternative protecting group patterns was
inevitable.
An alternative route to non-adol-type building blocks
embarked from the known Gosteli-type allyl vinyl ether
(E,Z)-2 (Scheme 4).11 Catalytic asymmetric Gosteli–Claisen
rearrangement (CAGC) of (E,Z)-2 using the Evans-type cop-
per(II) bis(oxazoline) Lewis acid (S,S)-3 delivered the α-keto
ester anti-4 in high yield and stereoselectivity on gram
scale (98%, dr = 95:5, 95% ee). Importantly, a faster turn-
over was observed when the catalyzed rearrangement was
run in an equal volume mixture of CH2Cl2 and 2,2,2-trifluo-
roethanol instead of pure CH2Cl2 as reported previously.23
Notably, CAGC of Gosteli-type allyl vinyl ethers analogous
to (E,Z)-2 but equipped with different silyl protecting
groups were less diastereoselective (t-BuPh2Si: dr = 83:17;
t-BuMe2Si: dr = 80:20); the presence of a PMB instead of the
Bn protecting group turned out to be incompatible with the
Lewis acidity of the catalyst 3. Highly diastereoselective re-
duction of the α-keto ester (+)-anti-4 with K-Selectride de-
livered the α-hydroxy ester 13a as a single diastereomer
(92%).24 Hydrogenolysis, hydrogenation, and lactonization
DDQ (1.8 equiv)
CH2Cl2−pH 7 buffer (10:1)
OBn
OH
r.t., 22 h
61% (0.18 g)
OTBS
8a
OTBS
8b
TBSCl (1.1 equiv), imidazole (1.5 equiv) 92%
DMAP (0.1 equiv), CH2Cl2, 0 °C, 1 h
(0.24 g)
O3, Sudan Red
MeOH−CH2Cl2 (3:1), −78 °C
PPh3 (3 equiv), −78 °C, 1 h
NaBH4 (3 equiv), −78 °C to r.t.
OTBS
OTBS
8
9'
OTBS
75% (0.61 g)
OTBS
8c
HO
9a
97%
(0.94 g)
TPSCl (1.2 equiv), imidazole (2 equiv)
DMAP (0.1 equiv), CH2Cl2, 0 °C, 2 h
LDA (1.3 equiv), THF, −78 °C, 30 min
ClCO2i-Pr (1.3 equiv)
TBSO
TPSO
−78 °C, 30 min; 0 °C, 2 h
OTBS
85% (0.68 g)
9b
1. CuBr·SMe2 (10 equiv)
MeMgBr (10 equiv), THF, −78 °C to 0 °C
2. DIBAL-H (2.3 equiv)
TBSO
TPSO
CO2i-Pr
CH2Cl2, −100 °C, 1 h
OTBS
10a
44% (54 mg)
E/Z = 95:5
O
O
TBSO
S
N
N
OH
N
N
OTBS
Ph
(R)-12
TPSO
11a
1. MnO2 (11 equiv), CH2Cl2, 40 °C, 3 h
2. (R)-12 (7 equiv), THF, KHMDS (7 equiv), toluene
−78 °C, 30 min
73% (139 mg)
E/Z = 95:5
aldehyde (1 equiv), THF, −78 °C to r.t.
8
11
TBSO
OTBS
9'
TPSO
7b
R1O
conditions
OR3
R2O
desired: 7c (R1 = H, R2 = TPS, R3 = TBS)
R1 R2
TBS TPS
R3
TBS
H
H
H
Entry
Conditions
NH4F (100 equiv), MeOH, r.t., 24 h
HF-pyridine, CH2Cl2, 0 °C, 1 h
TBAF (1.1. equiv), THF, r.t., 16 h
Oxone (1.1 equiv), MeOH, 0 °C, 4 h
Yield
99%
79%
72%
60%
1
2
3
4
H
H
H
H
TPS
TPS
Scheme 3 Successful synthesis of the building block 7b and failed at-
tempts to access the alcohol 7c by selective cleavage of the TBS pro-
tecting group at C8
double bond with reductive workup and in situ reduction
to deliver the alcohol 9a (75%). In order to allow for chemi-
cal differentiation between the primary hydroxyl groups at
C8 and C9′ at a later stage of the synthesis, we decided to
introduce
a
tert-butyldiphenylsilyl (TPS)-protecting
group.16 Thus, subjecting the alcohol 9a to standard condi-
tions for silyl ether formation afforded the tris-silyl ether
9b (97%). We next concentrated our efforts on synthesizing
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

D
M. Körner, M. Hiersemann
Paper
Synthesis
in a single operation delivered the δ-lactone 14 (99%); NOE
studies on 14 support the assignment of the relative config-
uration of the non-aldol stereotriad of 15a. Subsequent TBS
protection of the secondary hydroxyl group (94%), reduc-
tion of the ester to the alcohol with diisobutylaluminum
hydride (82%), and oxidation using the Dess–Martin perio-
dinane (DMP)25 (91%) all proceeded uneventful to yield the
aldehyde 5b. Aldehyde-to-alkyne homologation was ac-
complished by a two-step procedure. Exposure of 5b to
[Cu{(S,S)-t-Bu-box}(H2O)2](SbF6)2
[(S,S)-3]
(0.05 equiv)
CH2Cl2−CF3CH2OH (1:1)
r.t., 12 h
MeO
O
CO2Me
O
BnO
95% (3.8 g)
dr = 95:5 (NMR)
99% ee (HPLC)
O
BnO
(+)-anti-4
(E,Z)-2
K[s-Bu3BH] (1.2 equiv)
THF, −100 °C, 10 min
Pd/C, H2
92% (3.7 g)
dr > 95:5 (NMR)
NOE
H
OH
O
triphenylphosphinechloromethylene,
prepared
from
DMF, r.t., 1 h
H
O
H
CO2Me
H
chloromethyltriphenylphosphonium chloride and n-BuLi,
delivered the corresponding vinylic chloride.26 Subsequent
treatment of the vinylic chloride with lithium diisopropyl-
amide triggered β-elimination to yield the desired alkyne
8d (88%).27 Attempted dibromomethylenation of 5b accord-
ing to Corey and Fuchs trigged cleavage of the TBS ether and
partial epimerization.28 Application of the Ohira–Bestmann
protocol led to decomposition of 5b.29
The setbacks delineated in Scheme 2 prompted us to
consider alternatives for the benzyl-protecting group at C9′
of the enyne 8d. After some optimization, conditions for the
oxidative removal of the benzyl-protecting group using a
two-fold excess of DDQ in a 11:1 mixture of CH2Cl2 and
aqueous pH 7 buffer served to prepare the alcohol 8e in
moderate yield (67%). Exposure of 8e to 2-(4-methoxyben-
zyloxy)-3-nitropyridine (PMBONPy) according to Mukaiyama
using copper(II) triflate instead of trimethylsilyl triflate de-
livered the p-methoxybenzyl ether 8f in good yield (87%).30
Ozonolysis of compounds 8d,f with reductive workup and
in situ reduction provided the alcohols 9c,d (80%, 75%), re-
spectively.
With the non-aldol stereotriad building blocks 9c,d in
hand, we turned our attention to the construction of the
trisubstituted C12/C13 double bond (Scheme 5). The re-
quired chemistry had been established for the purpose of
the synthesis of the E-configured allylic alcohol 11a from
the alkyne 9b (Scheme 3). Thus, formation of the bis-TBS
ether delivered the tris-protected alkynes 9e,f (95%, 98%).
Subsequent lithiation and isopropoxycarbonylation yielded
the alkynoates 10b,c (87%, 78%), and methyl cupration fi-
nally provided the E-configured enoates 16a,b (99%, 70%).
The synthesis of the allylic alcohols 11b,c was completed by
DIBAL-H reduction of 16a,b. Notably, compounds 11a as
well as 11b,c represent differently protected enantiomeric
building blocks that were synthesized from the diastereo-
meric α-keto esters syn- and anti-4.
Relying on the procedures used for the synthesis of 7b,
we next turned to the coupling of 11b,c with both enantio-
mers of the eastern building block 12 (Scheme 6). Hence,
MnO2-mediated oxidation of the allylic alcohols 11b,c was
followed by Julia–Kocienski olefination with S- or R-config-
ured sulfones 12 to deliver the E,E-dienes 7d–f in fair yields
(58–75%).
H
99% (15.8 mg)
dr > 95:5
OH
NOE
NOE
BnO
13a
96%
(4.6 g)
14
TBSCl (2 equiv), imidazole (3 equiv)
DMAP (0.1 equiv), DMF−CH2Cl2 (1:1), r.t., 3 d
DIBAL-H (3 equiv)
CO2Me
CH2Cl2, −78 °C, 1 h
OH
OTBS
OTBS
13b
82% (3.5 g)
BnO
BnO
15
DMP (1.5 equiv)
pyridine−CH2Cl2 (2:1), r.t., 2 h
91%
(3.3 g)
1. Ph3P=CHCl (2 equiv)
THF, 0 °C, 5 min
2. LDA (2.5 equiv)
THF, −78 °C, 5 min
O
OTBS
OTBS
9'
BnO
BnO
89% (2.9 g)
5b
NO2
8d
DDQ (2 equiv)
CH2Cl2−aq pH 7 buffer (11:1), r.t., 39 h (0.2 g)
67%
N
OPMB
PMBONPy (1.5 equiv)
Cu(OTf)2 (0.1 equiv)
toluene, r.t., 18 h
PMBONPy
87% (0.58 g)
OTBS
OTBS
PMBO
HO
8f
8e
O3, Sudan Red
MeOH−CH2Cl2 (3:1), −78 °C
PPh3 (3 equiv), −78 °C, 2 h
NaBH4 (3 equiv), −78 °C to r.t.
HO
8d or 8f
OTBS
9c: 78% (2.3 g)
9d: 76% (0.54 g)
PgO
9c: Pg = Bn
9d: Pg = PMB
Scheme 4 Asymmetric synthesis of non-aldol stereotriad building
blocks 9c,d based on catalytic asymmetric Claisen rearrangement of
Gosteli-type allyl vinyl ether (E,Z)-2
The asymmetric synthesis of the sulfone (S)-12 is de-
picted in Scheme 7.31 (S)-3-Hexanoyl-4-isopropyloxazoli-
din-2-one (17) was subjected to sodium hexamethyldisi-
lazide and methyl iodide to yield (S)-4-isopropyl-3-[(S)-2-
methylhexanoyl]oxazolidin-2-one (18) in very good yield
and with excellent diastereoselectivity (93%, dr >95:5).32
Reductive cleavage and recovery of the auxiliary (91%) de-
livered the alcohol (–)-(S)-1933 that was purified by distilla-
tion in very good yield (90%). The absolute configuration of
the alcohol was assigned in accordance with the excepted
empirical model for the stereochemical course of alkyla-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

E
M. Körner, M. Hiersemann
Paper
Synthesis
fide 21. Oxidation of compound 21 with H2O2 in the pres-
ence of catalytic amounts of ammonium heptamolybdate37
finally afforded the desired eastern building block (S)-12.
TBSCl (1.5 equiv)
OH
13
OTBS
imidazole (3 equiv)
DMAP (0.1 equiv)
CH2Cl2, r.t.
12
OTBS
OTBS
PgO
PgO
9e: 95% (1.5 g)
9f: 97% (0.63 g)
NaHMDS (1.2 equiv)
9c: Pg = Bn
9d: Pg = PMB
9e: Pg = Bn
9f: Pg = PMB
THF, −78 °C, 1 h
CH3I (2.5 equiv)
−78 °C to −20 °C
O
O
O
O
O
N
O
N
LDA (1.2 equiv), THF, −78 °C, 15 min 10b: 87% (0.35 g)
ClCO2i-Pr (1.3 equiv), −78 °C, 30 min; 0 °C, 15 min
10c: 78% (0.42 g)
93% (11.4 g)
dr > 95:5
CO2i-Pr
CuBr•SMe2 (10 equiv)
MeMgBr (10 equiv)
THF, −78 °C to 0 °C
17
18
TBSO
PgO
LiBH4 (3 equiv), MeOH (3 equiv)
Et2O, r.t., 1.5 h (0.79 g)
(R)-MTPA (3 equiv)
90%
OTBS
16a: 99% (0.88 g)
16b: 70% (0.3 g)
E/Z > 95:5
10b: Pg = Bn
10c: Pg = PMB
DMAP (0.5 equiv)
DCC (3.75 equiv)
CH2Cl2, r.t., 3 h
F3C OCH3
O
HO
Ph
O
DIBAL-H (3 equiv)
CH2Cl2, −100 °C, 1 h
99% (57 mg)
dr > 95:5
CO2i-Pr
19
TBSO
PgO
20
OTBS
11b: 99% (0.45 g)
11c: 95% (0.26 g)
PTSH (1.5 equiv), PPh3 (1.2 equiv)
DIAD (1.3 equiv), THF, 0 °C, 1 h
99%
(2.4 g)
16a: Pg = Bn
16b: Pg = PMB
SH
N
S
N
12
N
PTSH:
TBSO
OH
N
13
N
N
N
11b: Pg = Bn
11c: Pg = PMB
Ph
N
OTBS
Ph
PgO
21
Scheme 5 Elaboration of the non-aldol stereotriad building blocks
11b,c. Detailed conditions refer to Pg = Bn and may vary for Pg = PMB;
see experimental section for details.
(NH4)6Mo7O24·4H2O (0.01 equiv)
H2O2 (30% m/v in H2O, 9 equiv)
EtOH, r.t., 15 h
O
O
S
N
N
N
N
Ph
94% (2.3 g)
(S)-12
tions controlled by Evans-type auxiliaries.34 Mosher ester
analysis35 confirmed the high enantiomeric excess expect-
ed for (–)-(S)-2-methylhexan-1-ol (19). The synthesis of the
sulfone (S)-12 was completed by Mitsunobu reaction36 of
(–)-(S)-19 with phenyltetrazole-5-thiol to deliver the sul-
Scheme 7 Asymmetric synthesis of the sulfone (S)-12
With compounds 7e,f in hand, their elaboration to cen-
tral eastern building blocks according to our initial planning
was explored (Scheme 8). In order to attach the missing
carbon atoms C7 and C7′ by alkynylation of a C8 aldehyde
functionality, chemoselective cleavage of the primary silyl
ether at C8 in the presence of the secondary but allylic silyl
ether at C11 was required. Previous efforts including the
use of HF-pyridine in CH2Cl2 had been futile (Scheme 3).
However, adding pyridine afforded a distinct mixture of HF-
pyridine, ‘extra’ pyridine, and CH2Cl2 that affected the de-
sired cleavage of the primary silyl ether in very good yield
(95%) for 7g (Pg = Bn) and still acceptable yield (79%) for 7h
(Pg = PMB).38 Subsequent alkynylation of the primary alco-
hols 7g,h proceeded uneventful and was achieved by a se-
quence consisting of Dess–Martin oxidation,25 chlorometh-
ylenation, and base-mediated elimination to deliver the
alkynes 22a,b in moderate overall yield (54%, 45%) and
without notable epimerization at C9. The presence of the
terminal alkyne functionality then allowed for the intro-
duction of the C7′ methyl group.39 Thus, upon treatment of
compounds 22a,b with an excess of lithium diisopropyl-
amide and methyl iodide the dienynes 23a,b were isolated
in very good yields (87%, 90%).
TBSO
PgO
OH
11b: Pg = Bn
11c: Pg = PMB
OTBS
O
O R2 R1
1. MnO2 (12 equiv)
S
CH2Cl2, 40 °C, 3 h
N
N
2. 12 (1.8 equiv), THF, −78 °C
KHMDS (1.8 equiv), 30 min
then aldehyde (1 equiv)
from step 1, THF
N
N
Ph
R1 = Me, R2 = H: (S)-12
R1 = H, R2 = Me: (R)-12
−78 °C to r.t.
R2 R1
TBSO
OTBS
PgO
R1 = Me, R2 = H, Pg = Bn: 7d, 75% (0.17 g) E/Z = 95:5
R1 = H, R2 = Me, Pg = Bn: 7e, 75% (0.26 g), E/Z = 95:5
R1 = H, R2 = Me, Pg = PMB: 7f, 58% (0.17 g), E/Z = 95:5
Scheme 6 Coupling of the central and eastern building by Julia–
Kocienski olefination; conditions refer to Pg = Bn and may vary for Pg =
PMB; see experimental section for details.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

F
M. Körner, M. Hiersemann
Paper
Synthesis
Using catalytic amounts of bis(triphenylphosphine)palladi-
um(II) dichloride and stoichiometric amounts of tri-n-but-
yltin hydride in different solvents and at different tempera-
tures led to no conversion. At this point, we turned to the
PMB-protected building block 23b with the intent to con-
struct the central lactone – or lactol – upstream to the fur-
ther functionalization of the C7/C8 triple bond. However,
and although expected otherwise,42 the primary PMB ether
at C9′ could not be cleaved using DDQ in buffered or non-
buffered aqueous solutions. Once again, the allylic TBS
ether at C11 was found to be very susceptible to different
conditions for oxidative ether cleavage.15 This constitutes a
problem that, at that time, could not be solved in our hands.
8
20
11
7e: Pg = Bn
7f: Pg =PMB
TBSO
OTBS
PgO
7g: 95% (200 mg)
7h: 79% (91 mg)
HF-pyridine−pyridine−THF (0.9:1.4:4)
0 °C; r.t., 12 h
7g: Pg = Bn
7h: Pg = PMB
HO
OTBS
PgO
1. DMP (3 equiv), CH2Cl2−pyridine (10:1)
0 °C; r.t., 3 h
2. ClCH2PPh3Cl (6 equiv), n-BuLi (5 equiv)
THF, 0 °C, 5 min
22a: 54% (119 mg)
22b: 45% ( 41 mg)
3. LDA (3.5 equiv), THF, −78 °C, 0.5 h; 0 °C, 1 h
23a
22a: Pg = Bn
t
T2
n/a
0 °C
−78 °C
Equiv
3
10
T1
Entry
22b: Pg = PMB
Cp2ZrHCl (equiv)
THF, T1, t
T2, I2, CH2Cl2
OTBS
4 h
2 h
24 h
40 °C
40 °C
r.t.
1
2
3
PgO
LDA (3 equiv)
CH3I (6 equiv)
THF, −78 °C to −30 °C
10
23a: 87% (100 mg)
23b: 90% ( 38 mg)
I
7'
20
7
OTBS
23a: Pg = Bn
23b: Pg = PMB
8
BnO
OTBS
PgO
23b
Scheme 8 Synthesis of the C7–C20 building blocks 23a,b by chemose-
lective silyl ether cleavage and aldehyde-to-alkyne homologation
DDQ (1.2 equiv)
CH2Cl2, H2O, 0 °C, 3 h
With the dienyne 23a in hand, we proceeded to com-
plete the synthesis of a central eastern building block. Our
initial tactic for fragment coupling considered cross-cou-
pling or Heck-type reaction for C7–C6 bond formation.
Thus, we sought to convert the alkyne 23a to the corre-
sponding vinyl iodide using chloridobis(η5-cyclopentadie-
nyl)hydridozirconium according to Schwartz (Scheme 9).40
However, no conversion was detected by TLC when subject-
ing compound 23a to a small excess (3 equiv) of Cp2ZrHCl in
CH2Cl2 at 40 °C for 4 hours. Using a large excess (10 equiv)
of the Schwartz reagent at 40 °C triggered consumption of
the starting material. Subsequent addition of iodine afford-
ed an inseparable product mixture. NMR analysis of this
mixture led us to conclude that the conversion of 23a to the
desired vinyl iodide was complicated by the competitive
formation of two isomeric vinyl iodides as well as protode-
zirconation of the intermediate vinyl zirconium species.
OH
PMBO
24 (57%) + 23b (32%)
Scheme 9 Attempted hydrozirconation-iodination of 23a and unex-
pected protecting group chemistry of 23b
In conclusion, we have reported the asymmetric syn-
thesis of various building blocks for the crucial non-aldol
stereotriad that uniquely characterizes the curvicollides A–
C. One key feature of our investigation includes the use of
the catalytic asymmetric Gosteli–Claisen rearrangement for
the synthesis of β,γ-branched δ,ε-unsaturated α-keto esters
that serve as valuable chiral building blocks. A series of
post-rearrangement transformations enabled multifaceted
structural elaboration of these α-keto esters. In addition, E-
diastereoselective alkynoate methyl cupration in combina-
tion with an E-diastereoselective Julia–Kocienski olefina-
tion enabled building block coupling and 1,3-diene forma-
tion. Finally, our studies revealed challenges associated with
protecting group chemistry and functional group intercon-
version that currently are being addressed.
1
Two sets of characteristic vinylic H NMR multiplets indi-
cated the intactness of the C12–C14 diene moiety. Some at-
tempts were undertaken to bias the positional selectivity of
the hydrozirconation. For instance, subjecting the dienyne
23a to a large excess (10 equiv) of Schwartz’s reagent in
THF at ambient temperature required 24 hours for com-
plete consumption of the starting material according to TLC
analysis. Subsequent cooling to –78 °C and addition of io-
dine again delivered an inseparable product mixture. As an
alternative to hydrozirconation, we briefly studied the pal-
ladium-catalyzed hydrostannation of the dienyne 23a.41
Unless otherwise stated, commercially available reagents, catalysts,
and solvents were used as purchased. THF, CH2Cl2, MeCN, and Et2O
were dried by using a commercially available solvent purification sys-
tem. Et3N was dried over KOH followed by distillation from CaH2 and
stored under an atmosphere of argon. All moisture-sensitive reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

G
M. Körner, M. Hiersemann
Paper
Synthesis
tions were performed in flame-dried septum-sealed glassware under
an atmosphere of argon. Reagents were transferred by means of sy-
ringe. Solids were introduced under a counter-flow of argon. The con-
centration of commercially available n-BuLi solutions was confirmed
by titration against diphenylacetic acid.43
13C NMR (101 MHz, CDCl3): δ = –4.8, –4.2, 11.8, 18.5, 26.1, 41.6, 48.6,
63.1, 66.2, 74.2, 83.5, 118.3, 139.0.
Anal. Calcd for C15H28O2Si: C, 67.11; H, 10.51. Found: C, 67.2; H, 10.2.
Bis-Silyl Ether 8c (Scheme 3)
Analytical TLC was performed using precoated silica gel foils (4 cm).
Visualization was achieved using 254 nm ultraviolet irradiation fol-
lowed by staining with the Kägi–Miescher reagent (p-anisaldehyde
2.53% v/v, AcOH 0.96% v/v, EtOH 93.06% v/v, concd H2SO4 3.45% v/v) or
the KMnO4 reagent [KMnO4 (3 g), K2CO3 (20 g), NaOH (0.25 g in 5 mL
H2O), H2O (300 mL)].44 Unless otherwise specified, chromatographic
purification45 was performed on silica gel (particle size 0.040–0.063
mm. Mixtures of cyclohexane and EtOAc or n-pentane and Et2O were
used as eluents.
To an ice-cooled solution of the alcohol 8b (C15H28O2Si, 268.47 g/mol,
184 mg, 0.685 mmol, 1 equiv) in CH2Cl2 (0.7 mL) were successively
added imidazole (68.08 g/mol, 70 mg, 1.03 mmol, 1.5 equiv), DMAP
(122.17 g/mol, 8 mg, 0.065 mmol, 0.1 equiv), and TBSCl (150.72
g/mol, 113 mg, 0.75 mmol, 1.1 equiv). The mixture was stirred at 0 °C
for 1 h and then diluted by the addition of sat. aq NH4Cl (1 mL). The
biphasic mixture was partitioned in a separatory funnel and the
aqueous layer was extracted with CH2Cl2 (3 × 2 mL). The combined
organic phases were dried (MgSO4) and concentrated. The residue
was purified by chromatography (hexanes–EtOAc, 100:1) to afford
the bis-TBS protected (2R,3S,4S)-3-methyl-2-vinylhex-5-yne-1,4-diol
8c (C21H42O2Si2, 382.74 g/mol, 240 mg, 0.63 mmol, 92%) as a colorless
oil; Rf = 0.66 (hexanes–EtOAc, 20:1); [α]D25 +24.0 (c 1.1, CHCl3).
1H NMR spectra were recorded at 400 or 500 MHz. Chemical shifts (δ)
are reported in ppm relative to CHCl3 (7.26 ppm).46 Standard abbrevi-
ations were used to denote signal splitting patterns. Coupling con-
stants (Hz) are given as reported by the NMR processing and analysis
software. 13C NMR spectra were recorded at 101 or 126 MHz. Unless
otherwise reported, all 13C NMR spectra were obtained with broad-
band proton decoupling. Chemical shifts are reported in ppm relative
to CDCl3 (77.16 ppm); the total number of reported 13C atom signals
may fall short of the expected number because of coincidental chem-
ical shifts, even for constitutopic or diastereotopic carbon atoms. The
NMR peak assignment as well as the assignment of the relative con-
IR (film): 3000–2860, 1470, 1250, 1090, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 3 H), 0.01 (s, 3 H), 0.06 (s, 3 H),
0.09 (s, 3 H), 0.86 (s, 9 H), 0.87 (s, 9 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.75–
1.84 (m, 1 H), 2.08–2.14 (m, 1 H), 2.31 (d, J = 2.0 Hz, 1 H), 3.62 (dd, J =
9.8, 3.8 Hz, 1 H), 3.67 (dd, J = 9.8, 5.3 Hz, 1 H), 4.42 (dd, J = 4.6, 2.0 Hz,
1 H), 5.03–5.08 (m, 2 H), 5.74 (ddd, J = 17.1, 10.5, 9.3 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = –5.5, –5.2, –4.7, 11.0, 18.2, 25.7, 40.0,
48.3, 64.0, 65.4, 73.0, 83.3, 116.0, 139.3.
1
1
figuration rests on the interpretation of H1H COSY, H13C HSQC, and
1H1H NOESY experiments. Atom numbering is based on the curvicol-
lide numbering system (Figure 1) or as stated in the experimental
procedure.
Anal. Calcd for C21H42O2Si2: C, 65.90; H, 11.06. Found: C, 66.0; H, 11.2.
Unless stated otherwise, IR spectra were recorded as a thin film on a
Alcohol 9a by Ozonolysis of Enyne 8c (Scheme 3)
KBr disk. IR absorptions are reported in reciprocal wavelength (cm–1
)
Using a commercially available ozonizer, an oxygen–ozone mixture
was passed through a solution of the enyne 8c (C21H42O2Si2, 382.74
g/mol, 0.8 g, 2.09 mmol, 1 equiv) and Sudan Red B (one crystal) in
MeOH (12 mL) and CH2Cl2 (4 mL) at –78 °C until the raspberry-like
color had disappeared. For reductive workup, PPh3 (262.29 g/mol, 1.6
g, 6.1 mmol, 3 equiv) was immediately added and the mixture was
stirred at –78 °C for 1 h. For in situ reduction, NaBH4 (37.83 g/mol,
0.24 g, 6.34 mmol, 3 equiv) was added and the mixture was allowed
to warm to r.t. overnight. The solvents were evaporated at reduced
pressure and the residue was purified by chromatography (hexanes–
EtOAc, 50:1 to 20:1 to 10:1) to deliver the bis-TBS protected
and are adjusted downward or upward to 0 or 5 cm–1. Relative inten-
sities are indicated as they appeared using standard abbreviations.
High-resolution mass spectra were recorded on a LTQ Orbitrap mass
spectrometer using electrospray ionization (ESI).
Molecular formula assignment was confirmed by combustion ele-
mental analysis using the elemental analyzers Leco CHNS-932 or Ele-
mentar Vario Micro Cube. Melting points are uncorrected and were
recorded on a Büchi B-540 melting point apparatus.
Alcohol 8b by Benzyl Ether Cleavage (Scheme 3)
(2S,3S,4S)-2-(hydroxymethyl)-3-methylhex-5-yne-1,4-diol
9a
To an ice-cooled solution of the benzyl ether 8a11 (C22H34O2Si, 358.60
g/mol, 0.4 g, 1.115 mmol, 1 equiv) in CH2Cl2 (9 mL) and aq pH 7 buffer
(0.9 mL) was added DDQ (227.0 g/mol, 0.46 g, 2.03 mmol, 1.8 equiv).
The mixture was stirred at r.t. for 22 h and then diluted by the addi-
tion of H2O (16 mL). The biphasic mixture was partitioned in a sepa-
ratory funnel and the aqueous layer was extracted with CH2Cl2 (3 × 15
mL). The combined organic phases were dried (MgSO4) and concen-
trated. The residue was purified by chromatography (hexanes−EtOAc,
100:1 to 20:1) to afford the monoprotected (2R,3S,4S)-3-methyl-2-vi-
nylhex-5-yne-1,4-diol 8b (C15H28O2Si, 268.47 g/mol, 184 mg, 0.685
(C20H42O3Si2, 386.72 g/mol, 0.61 g, 1.577 mmol, 75%) as a colorless oil;
Rf = 0.5 (hexanes–EtOAc, 5:1); [α]D25 –17.2 (c 1.3, CHCl3).
IR (film): 3500–3100, 3000–2860, 1470, 1250, 1080, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.08 (s, 3 H),
0.12 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.98 (d, J = 6.8 Hz, 3 H), 1.79–
1.86 (m, 1 H), 1.91–1.98 (m, 1 H), 2.35 (d, J = 2.3 Hz, 1 H), 2.95 (t, J =
5.7 Hz, 1 H), 3.71–3.84 (m, 3 H), 3.92 (dd, J = 9.9, 3.6 Hz, 1 H), 4.49 (dd,
J = 4.9, 2.1 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = –5.8, –5.7, –5.3, –4.7, 11.9, 18.1, 25.7,
37.7, 43.2, 65.2, 65.3, 65.7, 73.2, 83.7.
25
mmol, 61%) as light yellow oil; Rf = 0.43 (hexanes–EtOAc, 2:1); [α]D
+1.5 (c 0.9, CHCl3).
Anal. Calcd for C20H42O3Si: C, 62.12; H, 10.95. Found: C, 62.3; H, 10.8.
IR (film): 3500–3100, 3000–2860, 1470, 1250, 1080, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.10 (s, 3 H), 0.14 (s, 3 H), 0.90 (s, 9 H),
1.03 (d, J = 6.9 Hz, 3 H), 1.76–1.82 (m, 1 H), 2.07 (br s, 1 H), 2.40 (d, J =
1.9 Hz, 1 H), 2.43–2.49 (m, 1 H), 3.49 (dd, J = 10.9, 7.5 Hz, 1 H), 3.73
(dd, J = 10.9, 5.6 Hz, 1 H), 4.42 (dd, J = 4.6, 1.9 Hz, 1 H), 5.15–5.20 (m, 2
H), 5.68 (ddd, J = 17.1, 10.4, 9.1 Hz, 1 H).
Tris-Silyl Ether 9b (Scheme 3)
To an ice-cooled solution of the alcohol 9a (C20H42O3Si2, 386.72 g/mol,
0.6 g, 1.552 mmol, 1 equiv) in CH2Cl2 (1.5 mL) were successively add-
ed imidazole (68.08 g/mol, 210 mg, 3.085 mmol, 2 equiv), DMAP
(122.17 g/mol, 19 mg, 0.156 mmol, 0.1 equiv), and TPSCl (t-BuPh2SiCl,
274.86 g/mol, 1.057 g/mL, 0.49 mL, 518 mg, 1.885 mmol, 1.2 equiv).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

H
M. Körner, M. Hiersemann
Paper
Synthesis
After stirring at 0 °C for 2 h, the mixture was diluted by the addition
of sat. aq NH4Cl (1 mL). The biphasic mixture was partitioned in a
separatory funnel and the aqueous layer was extracted with CH2Cl2 (3
× 2 mL). The combined organic phases were dried (MgSO4) and con-
centrated. The residue was purified by chromatography (hex-
anes−EtOAc, 100:1) to afford the tris-protected (2R,3S,4S)-2-(hy-
droxymethyl)-3-methylhex-5-yne-1,4-diol 9b (C36H60O3Si3, 625.13
g/mol, 0.94 g, 1.504 mmol, 97%) as a colorless oil; Rf = 0.54 (hexanes–
EtOAc, 50:1); [α]D25 –9.7 (c 1.1, CHCl3).
The biphasic mixture was partitioned in a separatory funnel and the
aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The combined
organic phases were dried (MgSO4) and concentrated. The residue
was purified by chromatography (hexanes–EtOAc, 100:1) to afford
the enoate and the ynoate 10a as an inseparable mixture (0.6 g); Rf =
0.57 (hexanes−EtOAc, 20:1).
DIBAL-H Reduction: To a solution of the product from the 1,4-addition
(86 mg, assumed to be pure C41H70O5Si3, 727.26 g/mol, 0.1825 mmol,
1 equiv) in CH2Cl2 (1.2 mL) at –100 °C was slowly added DIBAL-H (1 M
in CH2Cl2, 0.42 mL, 0.42 mmol, 2.3 equiv). After stirring at –100 °C for
1 h, the reaction mixture was diluted by the addition of sat. aq Na/K
tartrate (1.2 mL) and stirred at 0 °C for 1 h. The biphasic mixture was
partitioned in a separatory funnel and the aqueous layer was extract-
ed times with CH2Cl2 (3 × 3 mL). The combined organic phases were
dried (MgSO4) and concentrated. The residue was purified by chro-
matography (hexanes–EtOAc, 20:1 to 10:1) to afford the tris-protect-
IR (film): 3000–2860, 1470, 1250, 1080, 837 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.03 (s, 3 H), –0.02 (s, 3 H), 0.03 (s, 3
H), 0.08 (s, 3 H), 0.81 (s, 9 H), 0.85 (s, 9 H), 0.96 (d, J = 6.5 Hz, 3 H), 1.02
(s, 9 H), 1.92–1.97 (m, 2 H), 2.31 (d, J = 2.0 Hz, 1 H), 3.58 (dd, J = 9.8,
6.8 Hz, 1 H), 3.66 (dd, J = 9.9, 5.4 Hz, 1 H), 3.76 (dd, J = 9.9, 5.1 Hz, 1 H),
3.83 (dd, J = 10.0, 3.8 Hz, 1 H), 4.40 (m, 1 H), 7.32–7.38 (m, 6 H), 7.62–
7.65 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.6, 11.4, 18.0, 18.1,
19.2, 25.7, 25.8, 26.8, 38.4, 44.0, 60.4, 62.8, 65.8, 73.1, 84.3, 127.5,
129.3, 133.8, 133.9, 135.4, 135.5.
ed
(4S,5S,6R,E)-6-(hydroxymethyl)-3,5-dimethylhept-2-ene-1,4,7-
triol (C38H66O4Si3, 671.20 g/mol, 54 mg, 0.0805 mmol, 44%) 11a as a
colorless oil, but contaminated with NMR visible but inseparable im-
purities; Rf = 0.33 (hexanes–EtOAc, 5:1); [α]D25 –5.6 (c 1.0, CHCl3).
Anal. Calcd for C36H60O3Si3: C, 69.17; H, 9.67. Found: C, 69.2; H, 9.5.
IR (film): 3000–2860, 1470, 1260, 1100, 840 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.06 (s, 3 H), –0.05 (s, 3 H), 0.04 (s, 3
H), 0.03 (s, 3 H), 0.61 (d, J = 7.3 Hz, 3 H), 0.80 (s, 9 H), 0.88 (s, 9 H), 1.02
(s, 9 H), 1.57 (s, 3 H), 2.00–2.07 (m, 1 H), 2.27–2.30 (m, 1 H), 3.43 (dd,
J = 9.9, 7.9 Hz, 1 H), 3.53 (dd, J = 9.8, 8.5 Hz, 1 H), 3.67 (dd, J = 10.0, 5.0
Hz, 1 H), 3.80 (dd, J = 9.8, 5.3 Hz, 1 H), 3.89 (d, J = 8.5 Hz, 1 H), 4.15–
4.18 (m, 2 H), 5.51 (t, J = 6.7 Hz, 1 H), 7.31–7.40 (m, 6 H), 7.62–7.65
(m, 4 H); no OH signal was detected.
13C NMR (101 MHz, CDCl3): δ = –5.7, –5.6, –5.2, –4.4, 11.2, 11.6, 18.0,
18.1, 19.2, 25.7, 25.8, 26.7, 34.9, 41.4, 59.1, 60.4, 63.8, 80.8, 125.6,
127.4, 129.3, 133.9, 135.4, 135.5, 140.4.
Ynoate 10a by Nucleophilic Isopropoxycarbonylation (Scheme 3)
To a solution of LDA, prepared from i-Pr2NH (101.19 g/mol, 0.722
g/mL, 0.2 mL, 144.4 mg, 1.427 mmol, 1.3 equiv) and n-BuLi (2.2 M in
n-hexane, 0.7 mL, 1.54 mmol, 1.4 equiv) in THF (2 mL) at –78 °C was
added a cooled (–78 °C) solution of the alkyne 9b (C36H60O3Si3, 625.13
g/mol, 0.7 g, 1.12 mmol, 1 equiv) in THF (4 mL). The mixture was
stirred for 30 min at –78 °C and isopropyl chloroformate (1 M in tolu-
ene, 1.5 mL, 1.3 mmol, 1.3 equiv) was slowly added. After stirring at
–78 °C for 30 min and at 0 °C for 2 h, the reaction mixture was diluted
by the addition of sat. aq NH4Cl (4 mL). The biphasic mixture was par-
titioned in a separatory funnel and the aqueous phase was extracted
with CH2Cl2 (3 × 10 mL). The combined organic phases were dried
(MgSO4) and concentrated. The residue was purified by chromatogra-
phy (hexanes–EtOAc, 100:1) to yield the tris-protected isopropyl
(4S,5S,6R)-4,7-dihydroxy-6-(hydroxymethyl)-5-methylhept-2-ynoate
10a (C40H66O5Si3, 711.22 g/mol, 0.68 g, 0.956 mmol, 85%) as a colorless
oil; Rf = 0.33 (hexanes–EtOAc, 20:1); [α]D25 –6.1 (c 1.1, CHCl3).
Diene 7b by Julia–Kocienski Olefination (Scheme 3)
MnO2 Oxidation: To a solution of the allylic alcohol 11a (C38H66O4Si3,
671.20 g/mol, 0.17 g, 0.253 mmol, 1 equiv) in CH2Cl2 (5 mL) was add-
ed MnO2 (86.94 g/mol, 0.25 g, 2.76 mmol, 11 equiv) and the mixture
was stirred in the dark at 40 °C for 3 h. The mixture was then filtered
through Celite and the filter cake was rinsed with CH2Cl2. The com-
bined filtrates were concentrated in vacuo to afford the correspond-
ing crude enal (0.17 g) as a light yellow oil that was used immediately
and without further purification; Rf = 0.66 (hexanes–EtOAc, 5:1).
Julia–Kocienski Olefination: To a solution of (R)-1211a (C14H20N4O2S,
308.40 g/mol, 0.53 g, 1.719 mmol, 7 equiv) in THF (2.5 mL) at –78 °C
was added KHMDS (0.5 M in toluene, 3.5 mL, 1.75 mmol, 7 equiv). Af-
ter stirring at –78 °C for 30 min, a solution of the crude enal (assumed
to be pure C38H64O4Si3, 669.18 g/mol, 0.17 g, 0.254 mmol, 1 equiv) in
THF (2.5 mL) was added and the mixture was allowed to warm to r.t.
overnight. The reaction mixture was then diluted by the addition of
sat. aq NH4Cl (5 mL). The biphasic mixture was partitioned in a sepa-
ratory funnel and the aqueous layer was extracted with CH2Cl2 (3 × 20
mL). The combined organic phases were dried (MgSO4) and concen-
trated. The residue was purified by chromatography (hexanes–EtOAc,
100:1) to afford the tris-silyl protected (2R,3S,4S,5E,7E,9R)-2-(hy-
IR (film): 3000–2860, 1710, 1470, 1260, 1100, 840 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.03 (s, 3 H), –0.02 (s, 3 H), 0.05 (s, 3
H), 0.11 (s, 3 H), 0.81 (s, 9 H), 0.87 (s, 9 H), 0.97 (d, J = 7.0 Hz, 3 H), 1.02
(s, 9 H), 1.25 (d, J = 6.3 Hz, 6 H), 1.93–2.05 (m, 2 H), 3.56 (dd, J = 10.0,
6.8 Hz, 1 H), 3.62 (dd, J = 10.0, 6.0 Hz, 1 H), 3.73–3.81 (m, 2 H), 4.54 (d,
J = 5.8 Hz, 1 H), 5.05 (sept, J = 5.8 Hz, 1 H), 7.33–7.39 (m, 6 H), 7.62–
7.65 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.6, 11.5, 18.0, 18.1,
19.2, 21.5, 25.6, 25.7, 26.8, 38.7, 43.7, 60.6, 63.0, 65.9, 69.6, 77.7, 87.3,
127.5, 129.4, 133.7, 135.4, 135.5, 153.0.
Anal. Calcd for C40H66O5Si3: C, 67.55; H, 9.35. Found: C, 67.8; H, 9.2.
Allylic Alcohol 11a from Ynoate 10a (Scheme 3)
1,4-Addition: To an ice-cooled solution of CuBr·SMe2 (205.58 g/mol, 2
g, 9.728 mmol, 10 equiv) in THF (20 mL) was added MeMgBr (1 M in
THF, 9.8 mL, 9.8 mmol, 10 equiv). After stirring at 0 °C for 1 h, the
solution of the reagent was chilled to –78 °C and a cooled (–78 °C)
solution of the ynoate 11a (C40H66O5Si3, 711.22 g/mol, 0.7 g, 0.984
mmol, 1 equiv) in THF (20 mL) was added. The reaction mixture was
allowed to warm to r.t. overnight and then cooled to 0 °C. Sat. aq
NH4Cl (10 mL) and H2O (10 mL) were carefully added (gas evolution!).
droxymethyl)-3,5,9-trimethyltrideca-5,7-diene-1,4-diol
7b
(C45H78O3Si3, 751.37 g/mol, 0.139 g, 0.185 mmol, 73% from 11a, E/Z =
95:5) as a colorless oil, but contaminated with NMR visible impurities
that are difficult to separate because of the low polarity of the tris-
silyl ether; Rf = 0.57 (hexanes–EtOAc, 20:1); [α]D25 –2.2 (c 1.1, CHCl3).
IR (film): 3000–2850, 1470, 1260, 1110, 910 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

I
M. Körner, M. Hiersemann
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = –0.06 (s, 3 H), –0.05 (s, 3 H), –0.03 (s, 3
H), 0.03 (s, 3 H), 0.62 (d, J = 7.3 Hz, 3 H), 0.81 (s, 9 H), 0.88 (m, 12 H),
0.99 (d, J = 6.5 Hz, 3 H), 1.03 (s, 9 H), 1.18–1.27 (m, 6 H), 1.63 (s, 3 H),
2.06–2.12 (m, 1 H), 2.13–2.17 (m, 1 H), 2.29–2.34 (m, 1 H), 3.44 (dd,
J = 9.8, 8.3 Hz, 1 H), 3.55 (dd, J = 9.2, 9.2 Hz, 1 H), 3.70 (dd, J = 9.9, 4.9
Hz, 1 H), 3.83 (dd, J = 9.8, 5.3 Hz, 1 H), 3.88 (d, J = 8.5 Hz, 1 H), 5.47
(dd, J = 15.1, 8.0 Hz, 1 H), 5.87 (d, J = 10.8 Hz, 1 H), 6.16 (dd, J = 15.1,
10.8 Hz, 1 H), 7.32–7.38 (m, 6 H), 7.64–7.66 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.6, 11.5, 11.6, 14.0,
18.0, 18.1, 19.2, 20.5, 22.7, 25.7, 25.8, 26.8, 29.5, 35.2, 36.8, 37.0, 41.6,
60.4, 63.8, 81.3, 124.0, 126.9, 127.4, 129.3, 134.0, 134.2, 135.5, 136.6,
140.0.
13C NMR (76 MHz, CDCl3): δ = 12.4, 38.0, 44.4, 52.1, 71.5, 72.9, 74.4,
117.8, 127.5, 128.3, 135.6, 136.7, 138.2, 175.1.
Anal. Calcd for C16H22O4: C, 69.04; H, 7.97. Found: C, 69.0; H, 8.1.
δ-Lactone 14) (Scheme 4)
To a solution of the α-hydroxy ester 13a (C16H22O4, 278.35 g/mol, 28
mg, 0.1 mmol, 1 equiv) in DMF (1 mL) was added Pd/C (40.4 mg, 10%
w/w Pd, 4.04 mg Pd, 106.42 g/mol, 0.038 mmol, 0.38 equiv). The flask
was twice evacuated (100 mbar, 1 min) and vented with H2 (balloon).
The reaction mixture was then stirred for about 1 h and until TLC in-
dicated complete conversion. The mixture was filtered through Celite
and the filter cake was rinsed with CH2Cl2. The solvents were re-
moved at reduced pressure and the residue was purified by Kugelrohr
distillation (70 °C/1 mbar) to afford (3R,4R,5R)-5-ethyl-3-hydroxy-4-
methyl-tetrahydropyran-2-one (14) (C8H14O3, 158,20 g/mol, 15.8 mg,
0.10 mmol, dr = 95:5, 99%) as a white solid; mp 91 °C; Rf = 0.54
(hexanes–EtOAc, 1:1); [α]D25 −120.9 (c 0.69, CHCl3).
Anal. Calcd for C45H78O3Si3: C, 71.93; H, 10.46. Found: C, 72.0; H, 10.1.
α-Keto Ester (+)-anti-4 by Catalytic Asymmetric Gosteli–Claisen
Rearrangement in CH2Cl2−CF3CH2OH (1:1) (Scheme 4)
A
solution of [Cu{(S,S)-tert-butyl-box}(H2O)2](SbF6)2 [(S,S)-3;
C
17H34CuF12N2O4Sb2, 865.52 g/mol, 0.63 g, 0.728 mmol, 0.05 equiv) in
IR (film): 3700–3100, 3080–2870, 1750 cm–1
.
CF3CH2OH (15 mL) was stirred for 5 min at r.t. To the turquoise blue
solution of (S,S)- 3 in CF3CH2OH was added a solution of (E,Z)-2
(C16H20O4, 276.33 g/mol, 4 g, 14.475 mmol, 1 equiv) in CH2Cl2 (15 mL).
The reaction mixture was stirred for about 12 h at r.t. (TLC monitor-
ing). The solvents were subsequently removed at reduced pressure
and the residue was purified by chromatography (cyclohexane–
EtOAc, 50:1) to provide the α-keto ester 4 (C16H20O4, 276.33 g/mol, 3.8
g, 13.75 mmol, 95%, dr >95:5, 99% ee) as a colorless oil. The ee was
determined by HPLC: Chiralpak IA, 4.6 × 250 mm, n-heptane–EtOAc,
99:1, 1 mL/min; (3R,4R)-4, tR = 12.8 min, (3S,4S)-4, tR = 15.0 min; Rf =
0.6 (cyclohexane–EtOAc, 3:1); [α]D25 +39.7 (c 0.89, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 0.96 (d, J = 7.2 Hz, 3 H), 0.97 (t, J = 7.4
Hz, 3 H), 1.43 (m, 2 H), 1.66–1.72 (m, 1 H), 2.21 (m, 1 H), 3.12 (s, 1 H),
3.96 (dd, J = 11.6, 11.6 Hz, 1 H), 4.32 (dd, J = 11.6, 6.2 Hz, 1 H), 4.45 (d,
J = 7.7 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 11.4, 16.5, 25.0, 36.2, 42.3, 67.9, 69.6,
175.9.
HRMS (ESI): m/z [M + H]+ calcd for C8H15O3: 159.1056; found:
159.1014.
Silyl Ether 13b (Scheme 4)
IR (film): 1730 (s), 1455 (s), 1260 (s), 1100 (s), 1050 (s) cm–1
.
To an ice-cooled solution of the α-hydroxy ester 13a (C16H22O4,
278.35 g/mol, 3.4 g, 12.21 mmol, 1 equiv) in CH2Cl2 (3 mL) and DMF (3
mL) were successively added imidazole (68.08 g/mol, 2.5 g, 36.72
mmol, 3 equiv), DMAP (137.21 g/mol, 0.15 g, 1.09 mmol, 0.1 equiv),
and tert-butyldimethylsilyl chloride (TBSCl, C6H15ClSi, 150.72 g/mol,
3.7 g, 24.55 mmol, 2 equiv). The cooling bath was removed and the
mixture was stirred at r.t. for 3 d. Sat. aq NH4Cl was added and the
resulting biphasic mixture was partitioned in a separatory funnel.
The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic phases were dried (MgSO4) and concentrated. The resi-
due was purified by chromatography (hexanes–EtOAc, 100:1) to pro-
vide the silyl ether 13b (C22H36O4Si, 392.61 g/mol, 4.6 g, 11.72 mmol,
96%) as a colorless oil; Rf = 0.42 (hexanes–EtOAc, 10:1); [α]D25 +34.0 (c
2.68, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.08 (d, J = 6.9 Hz, 3 H), 2.83 (qd, J = 9.4,
4.9 Hz, 1 H), 3.31–3.39 (m, 2 H), 3.45 (dd, J = 9.6, 4.9 Hz, 1 H), 3.62 (s,
3 H), 4.33 (d, J = 12.0 Hz, 1 H), 4.37 (d, J = 12.0 Hz, 1 H), 5.12–5.13 (m,
2 H), 5.52 (ddd, J = 17.6, 9.4, 9.4 Hz, 1 H), 7.22–7.34 (m, 5 H).
13C NMR (101 MHz, CDCl3): δ = 14.4, 43.1, 48.4, 52.5, 72.4, 72.7, 118.7,
127.6, 128.3, 135.3, 137.5, 161.5, 184.2.
Anal. Calcd for C16H24O4: C, 69.54; H, 7.30. Found: C, 69.3; H, 7.4.
α-Hydroxy Ester 13a by K-Selectride Reduction (Scheme 4)
Four of the following procedures were run in parallel and were com-
bined for workup. To a solution of the α-keto ester (+)-anti-4
(C16H20O4, 276.33 g/mol, 1 g, 3.619 mmol, 1 equiv) in THF (20 mL) at
–100 °C was slowly added K-Selectride (1 M in THF, 4.3 mL, 4.3 mmol,
1.2 equiv). After stirring for 10 min at –100 °C, the reaction mixture
was first diluted by the addition of sat. aq NH4Cl (15 mL) and then
warmed to r.t. The four biphasic mixtures were combined in a separa-
tory funnel and the layers were separated. The aqueous layer was ex-
tracted with CH2Cl2 (3 ×). The combined organic phases were dried
(MgSO4) and concentrated. The residue was purified by chromatogra-
phy (hexanes–EtOAc, 20:1) to afford the α-hydroxy ester 13a
(C16H22O4, 278.35 g/mol, 3.7 g, 13.292 mmol, 92% combined yield, dr
IR (film): 3030–2850, 1745 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 3 H), 0.02 (s, 3 H), 0.78 (d, J =
7.1 Hz, 3 H), 0.89 (s, 9 H), 2.11–2.17 (m, 1 H), 2.69–2.80 (m, 1 H), 3.43
(dd, J = 9.4, 6.6 Hz, 1 H), 3.48 (dd, J = 9.5, 6.6 Hz, 1 H), 3.65 (s, 3 H),
4.00 (d, J = 7.2 Hz, 1 H), 4.43 (d, J = 12.1 Hz, 1 H), 4.52 (d, J = 12.2 Hz, 1
H), 5.03–5.14 (m, 2 H), 5.70 (ddd, J = 17.2, 10.4, 8.9 Hz, 1 H), 7.26–7.31
(m, 5 H).
13C NMR (101 MHz, CDCl3): δ = –5.4, –5.1, 11.7, 18.1, 25.6, 37.8, 43.0,
51.4, 71.5, 72.5, 75.2, 117.3, 127.3, 127.4, 128.2, 136.4, 138.4, 173.8.
25
>95:5) as a colorless oil; Rf = 0.37 (cyclohexane–EtOAc, 3:1); [α]D
Anal. Calcd for C22H36O4Si: C, 67.30; H, 9.24. Found: C, 67.5; H, 9.3.
+14.9 (c 0.4, CHCl3).
IR (film): 3600, 3050, 3000, 2850, 1735 cm–1
.
Alcohol 15 by DIBAL-H Reduction (Scheme 4)
1H NMR (300 MHz, CDCl3): δ = 0.91 (d, J = 7.1 Hz, 3 H), 2.12–2.23 (m, 1
H), 2.61–2.70 (m, 1 H), 3.44 (d, J = 6.7 Hz, 2 H), 3.74 (s, 3 H), 4.06 (d, J =
5.8 Hz, 1 H), 4.46 (d, J = 12.1 Hz, 1 H), 4.51 (d, J = 12.1 Hz, 1 H), 5.11–
5.17 (m, 2 H), 5.73 (ddd, J = 17.8, 11.5, 9.4 Hz, 1 H), 7.27–7.36 (m, 5
H); no OH signal was detected.
To a solution of the ester 13b (C22H36O4Si, 392.61 g/mol, 4.6 g, 11.71
mmol, 1 equiv) in CH2Cl2 (4 mL) at –78 °C was slowly added DIBAL-H
(1 M in CH2Cl2, 35 mL, 35 mmol, 3 equiv). The mixture was stirred at
–78 °C for 1 h and then diluted at 0 °C by the careful addition of aq pH
7 buffer (24 mL) and sat. aq Na/K tartrate (48 mL). Stirring was contin-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

J
M. Körner, M. Hiersemann
Paper
Synthesis
ued for 1 h at 0 °C. The aqueous layer was extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were dried (MgSO4) and concen-
trated. Purification of the residue by chromatography (cyclohexane–
EtOAc, 50:1 to 20:1) yielded the bis-protected (2R,3R,4R)-3-methyl-4-
vinylpentane-1,2,5-triol 15 (C21H36O3Si, 364.60 g/mol, 3.5 g, 9.6
chloride (assumed 9.1 mmol, 1 equiv) in THF (45 mL). After stirring at
–78 °C for 5 min, the mixture was diluted by the addition of sat. aq
NH4Cl (50 mL). The biphasic mixture was partitioned in a separatory
funnel and the aqueous layer was extracted with CH2Cl2 (3 × 40 mL).
The combined organic phases were dried (MgSO4) and concentrated.
The residue was purified by chromatography (hexanes–EtOAc, 100:1)
to afford the bis-protected (2R,3R,4R)-3-methyl-2-vinylhex-5-yne-
1,4-diol 8d (C22H34O2Si, 358.60 g/mol, 2.9 g, 8.09 mmol, 89%) as a col-
25
mmol, 82%) as a colorless oil; Rf = 0.50 (hexanes–EtOAc, 3:1); [α]D
+16.5 (c 0.51, CHCl3).
IR (film): 3650–3200, 3070−2860 cm–1
.
25
orless oil; Rf = 0.65 (hexanes–EtOAc, 10:1); [α]D +12.5 (c 1.34, CH-
Cl3).
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 6 H), 0.75 (d, J = 7.2 Hz, 3 H),
0.83 (s, 9 H), 1.93–2.00 (m, 2 H), 2.46–2.55 (m, 1 H), 3.42 (dd, J = 9.2,
7.4 Hz, 1 H), 3.47 (dd, J = 9.2, 6.2 Hz, 1 H), 3.51–3.61 (m, 1 H), 3.67–
3.71 (m, 1 H), 4.39 (d, J = 12.0 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.95–
5.03 (m, 2 H), 5.63 (ddd, J = 17.0, 10.6, 8.7 Hz, 1 H), 7.18–7.29 (m, 5
H); no OH signal detected.
IR (film): 3070–2860, 1080 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.07 (s, 3 H), 0.12 (s, 3 H), 0.88 (s, 9 H),
0.90 (d, J = 7.0 Hz, 3 H), 1.90–1.93 (m, 1 H), 2.36 (d, J = 2.0 Hz, 1 H),
2.68–2.74 (m, 1 H), 3.47–3.52 (m, 2 H), 4.27 (dd, J = 7.2, 2.1 Hz, 1 H),
4.45 (d, J = 12.1 Hz, 1 H), 4.52 (d, J = 12.1 Hz, 1 H), 5.05–5.10 (m, 2 H),
5.70 (ddd, J = 17.0, 10.4, 9.2 Hz, 1 H), 7.25–7.31 (m, 5 H).
13C NMR (101 MHz, CDCl3): δ = –5.1, –4.4, 11.3, 18.1, 25.8, 40.1, 43.8,
65.2, 71.8, 72.6, 73.4, 84.4, 117.1, 127.4, 128.2, 136.9, 138.4.
13C NMR (101 MHz, CDCl3): δ = –4.5, –4.3, 11.4, 18.1, 25.9, 36.6, 44.1,
63.6, 72.4, 72.9, 75.0, 116.7, 127.5, 127.6, 128.3, 137.5, 138.4.
Anal. Calcd for C21H36O3Si: C, 69.18; H, 9.97. Found: C, 69.2; H, 10.0.
Anal. Calcd for C22H34O2Si: C, 73.69; H, 9.56. Found: C, 73.9; H, 9.3.
Aldehyde 5b by Dess–Martin Oxidation (Scheme 4)
To an ice-cooled solution of the alcohol 15 (C21H36O3Si, 364.60 g/mol,
3.5 g, 9.6 mmol, 1 equiv) in CH2Cl2 (20 mL) and pyridine (10 mL) was
added the Dess–Martin periodinane (424.14 g/mol, 6 g, 14.15 mmol,
1.5 equiv). The cooling bath was removed and the mixture was stirred
for 2 h at r.t. The reaction mixture was subsequently diluted by the
addition of sat. aq NH4Cl (15 mL). The phases were separated and the
aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were dried (MgSO4) and concentrated. Purification of
the residue by chromatography (hexanes–EtOAc, 50:1) afforded the
Alcohol 8e by Benzyl Ether Cleavage (Scheme 4)
To an ice-cooled solution of the benzyl ether 8d (C22H34O2Si, 358.60
g/mol, 0.4 g, 1.115 mmol, 1 equiv) in CH2Cl2 (9 mL) and aq pH 7 buffer
(0.8 mL) was added DDQ (227.00 g/mol, 0.3 g, 1.32 mmol, 1.2 equiv).
After stirring 15 h at r.t., additional DDQ (0.2 g, 0.88 mmol, 0.8 equiv)
was added and stirring was continued for 24 h. The mixture was di-
luted by the addition of H2O (16 mL) and the resulting biphasic mix-
ture was partitioned in a separatory funnel. The aqueous layer was
extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were
dried (MgSO4) and concentrated. The residue was purified by chro-
matography (hexanes–EtOAc, 100:1 to 20:1) to provide the monopro-
tected (2R,3R,4R)-3-methyl-2-vinylhex-5-yne-1,4-diol 8e (C15H28O2Si,
268.47 g/mol, 200 mg, 0.745 mmol, 67%) as a colorless oil; Rf = 0.57
(hexanes–EtOAc, 2:1); [α]D25 +35.9 (c 1.0, CHCl3).
bis-protected
(2R,3R,4R)-2-hydroxy-4-(hydroxymethyl)-3-methyl-
hex-5-enal 5b (C21H34O3Si, 362.59 g/mol, 3.3 g, 9.1 mmol, 95%) as a
25
colorless oil; Rf = 0.78 (hexanes–EtOAc, 3:1); [α]D +37.6 (c 0.36,
CHCl3).
IR (film): 3070–2850, 1735 cm–1
.
1H NMR (300 MHz, CDCl3): δ = –0.01 (s, 3 H), 0.00 (s, 3 H), 0.83 (d, J =
7.2 Hz, 3 H), 0.88 (s, 9 H), 2.15 (m, 1 H), 2.59 (dddd, J = 9.0, 5.9, 5.9, 5.9
Hz, 1 H), 3.37 (dd, J = 9.5, 6.5 Hz, 1 H), 3.44 (dd, J = 9.5, 5.9 Hz, 1 H),
3.80 (dd, J = 6.0, 2.4 Hz, 1 H), 4.36 (d, J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0
Hz, 1 H), 4.99–5.08 (m, 2 H), 5.68 (ddd, J = 17.1, 10.5, 8.9 Hz, 1 H),
7.24–7.37 (m, 5 H), 9.48 (d, J = 2.4 Hz, 1 H).
IR (film): 3500–3100, 3000–2860, 1470, 1250, 1080, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.08 (s, 3 H), 0.13 (s, 3 H), 0.88 (s, 9 H),
0.94 (d, J = 7.0 Hz, 3 H), 1.40–1.43 (m, 1 H), 1.77–1.86 (m, 1 H), 2.38
(d, J = 2.3 Hz, 1 H), 2.50–2.57 (m, 1 H), 3.55 (ddd, J = 10.7, 8.2, 4.1 Hz, 1
H), 3.62 (ddd, J = 10.6, 8.2, 5.5 Hz, 1 H), 4.24 (dd, J = 6.7, 2.3 Hz, 1 H),
5.11–5.21 (m, 2 H), 5.65 (ddd, J = 17.2, 10.2, 9.4 Hz, 1 H).
13C NMR (76 MHz, CDCl3): δ = –5.0, –4.4, 12.7, 18.2, 25.7, 36.1, 43.7,
71.6, 72.7, 80.4, 117.2, 127.5, 127.6, 128.3, 137.1, 138.4, 203.7.
13C NMR (101 MHz, CDCl3): δ = –5.2, –4.5, 12.0, 18.0, 25.7, 40.7, 47.4,
63.9, 65.2, 73.6, 84.1, 118.6, 136.7.
Anal. Calcd for C21H34O3Si: C, 69.56; H, 9.45. Found: C, 69.5; H, 9.4.
Anal. Calcd for C15H28O2Si: C, 67.11; H, 10.51. Found: C, 67.2; H, 10.4.
Alkyne 8d by Two-Step Homologation (Scheme 4)
PMB Ether 8f from Alcohol 8e (Scheme 4)
Chloromethylenation: To an ice-cooled suspension of ClCH2PPh3Cl
(347.22 g/mol, 8.7 g, 25.06 mmol, 2.8 equiv) in THF (50 mL) was slow-
ly added n-BuLi (2.3 M in n-hexane, 8.3 mL, 19.09 mmol, 2.1 equiv).
The cooling bath was removed and the stirring was continued for 2 h.
The mixture was cooled to 0 °C and a solution of the aldehyde 5b
(C21H34O3Si, 362.59 g/mol, 3.3 g, 9.1 mmol, 1 equiv) in THF (25 mL)
was added. After stirring for 5 min at 0 °C, the reaction mixture was
diluted by the addition pentane (300 mL) and filtered through a plug
of silica gel. The filter cake was thoroughly washed with pentane and
the combined filtrates were concentrated at reduced pressure. The
crude vinyl chloride was used without further purification.
To a solution of the alcohol 8e (C15H28O2Si, 268.47 g/mol, 0.46 g, 1.71
mmol, 1 equiv) in toluene (17 mL) at r.t. was added 2-[(4-methoxy-
benzyl)oxy]-3-nitropyridine (PMBONPy, C13H12N2O4, 260.25 g/mol,
0.67 g, 2.57 mmol, 1.5 equiv) and Cu(OTf)2 (361.67 g/mol, 62 mg,
0.171 mmol, 0.1 equiv). After stirring for 18 h at r.t., the mixture was
diluted by the addition of sat. aq NH4Cl (10 mL). The biphasic mixture
was partitioned in a separatory funnel. The aqueous layer was ex-
tracted with CH2Cl2 (3 × 15 mL). The combined organic phases were
dried (MgSO4) and concentrated at reduced pressure. The residue was
purified by chromatography (hexanes–EtOAc, 100:1) to yield the bis-
protected
(2R,3R,4R)-3-methyl-2-vinylhex-5-yne-1,4-diol
8f
β-Elimination: To a solution of LDA, prepared from i-Pr2NH (101.19
g/mol, 0.722 g/mL, 3.4 mL, 2.455 g, 24.26 mmol, 2.7 equiv) and n-BuLi
(2.3 M in n-hexane, 10.3 mL, 23.69 mmol, 2.5 equiv), in THF (36 mL)
at –78 °C was added a cooled (–78 °C) solution of the crude vinyl
(C23H36O3Si, 388.62 g/mol, 0.58 g, 1.493 mmol, 87%); Rf = 0.5 (hex-
anes−EtOAc, 10:1); [α]D25 +36.5 (c 1.05, CHCl3).
IR (film): 3070–2860, 1610, 1515, 1250, 1080, 835 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

K
M. Körner, M. Hiersemann
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 0.07 (s, 3 H), 0.11 (s, 3 H), 0.87–0.89
(m, 12 H), 1.90–1.95 (m, 1 H), 2.35 (d, J = 2.3 Hz, 1 H), 2.65–2.72 (m, 1
H), 3.41 (dd, J = 9.7, 6.4 Hz, 1 H), 3.45 (dd, J = 9.4, 6.4 Hz, 1 H), 3.78 (s,
3 H), 4.26 (dd, J = 7.2, 2.3 Hz, 1 H), 4.38 (d, J = 11.5 Hz, 1 H), 4.44 (d, J =
11.5 Hz, 1 H), 5.03–5.09 (m, 2 H), 5.68 (ddd, J = 17.1, 10.3, 8.9 Hz, 1 H),
6.80 (d, J = 8.5 Hz, 2 H), 7.25–7.21 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = –5.1, –4.4, 11.3, 18.1, 25.8, 40.0, 43.8,
55.1, 65.2, 71.5, 72.2, 73.4, 84.4, 113.6, 117.0, 129.0, 130.5, 136.9,
158.9.
added and the resulting biphasic mixture was partitioned in a separa-
tory funnel. The aqueous layer was extracted with CH2Cl2 (3 × 15 mL).
The combined organic phases were dried (MgSO4) and concentrated.
The residue was purified by chromatography (hexanes–EtOAc, 50:1)
to provide the tris-protected (2R,3R,4R)-2-(hydroxymethyl)-3-meth-
ylhex-5-yne-1,4-diol 9e (C27H48O3Si2, 476.85 g/mol, 1.5 g, 3.146
25
mmol, 95%) as a colorless oil; Rf = 0.37 (hexanes–EtOAc, 20:1); [α]D
+14.3 (c 1.23, CHCl3).
IR (film): 3000–2800, 1085, 835 cm–1
.
Anal. Calcd for C22H34O2Si: C, 71.08; H, 9.34. Found: C, 71.5; H, 9.0.
1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 6 H), 0.07 (s, 3 H), 0.11 (s, 3 H),
0.86 (s, 9 H), 0.88 (s, 9 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.88–1.94 (m, 1 H),
1.95–2.00 (m, 1 H), 2.35 (d, J = 2.3 Hz, 1 H), 3.55–3.61 (m, 3 H), 3.79
(dd, J = 9.9, 4.1 Hz, 1 H), 4.43–4.51 (m, 3 H), 7.24–7.32 (m, 5 H).
Alcohol 9c by Ozonolysis of Enyne 8d (Scheme 4)
Using a commercially available ozonizer, an ozone–oxygen mixture
was passed through a solution of the enyne 8d (C22H34O2Si, 358.60
g/mol, 2.9 g, 8.09 mmol, 1 equiv) and Sudan Red B (one crystal) in
MeOH (48 mL) and CH2Cl2 (16 mL) at –78 °C until the raspberry-like
color had disappeared. PPh3 (262.29 g/mol, 6.3 g, 24.02 mmol, 3
equiv) was immediately added and the mixture was stirred at –78 °C
for 2 h. NaBH4 (37.83 g/mol, 0.91 g, 24.06 mmol, 3 equiv) was added
and the mixture was allowed to warm to r.t. overnight. The solvents
were evaporated at reduced pressure and the residue was purified by
chromatography (hexanes–EtOAc, 50:1 to 20:1) to deliver the bis-pro-
tected (3R,4R)-2-(hydroxymethyl)-3-methylhex-5-yne-1,4-diol 9c
(C21H34O3Si, 362.59 g/mol, 2.3 g, 6.34 mmol, 78%) as a colorless oil;
Rf = 0.37 (hexanes–EtOAc, 5:1); [α]D25 +12.9 (c 1.18, CHCl3).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.7, 11.6, 18.0, 18.1,
25.7, 25.8, 38.6, 41.9, 60.9, 65.5, 69.1, 72.8, 73.0, 84.2, 127.3, 127.4,
128.2, 138.6.
Anal. Calcd for C27H48O3Si2: C, 68.01; H, 10.15. Found: C, 67.8; H, 9.9.
Silyl Ether 9f from Alcohol 9d (Scheme 5)
Following the procedure for the preparation of 9e from 9c, 9d
(C22H36O4Si, 392.61 g/mol, 0.5 g, 1.274 mmol, 1 equiv) in CH2Cl2 (1.4
mL) was reacted with imidazole (68.08 g/mol, 0.28 g, 4.11 mmol, 3
equiv), DMAP (137.21 g/mol, 17 mg, 0.124 mmol, 0.1 equiv), and
TBSCl (C6H15ClSi, 150.72 g/mol, 0.31 g, 2.06 mmol, 1.5 equiv) to yield
9f (C28H50O4Si2, 506.87 g/mol, 0.63 g, 1.243 mmol, 97%) as a colorless
oil; Rf = 0.46 (hexanes–EtOAc, 20:1); [α]D25 +13.1 (c 1.13, CHCl3).
IR (film): 3600–3350, 3300, 3000–2800, 1380, 1080 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.09 (s, 3 H), 0.14 (s, 3 H), 0.89 (s, 9 H),
0.98 (d, J = 7.0 Hz, 3 H), 1.97–2.04 (m, 1 H), 2.21–2.28 (m, 1 H), 2.41
(d, J = 2.0 Hz, 1 H), 3.11 (dd, J = 7.4, 4.1 Hz, 1 H), 3.51 (dd, J = 9.4, 5.4
Hz, 1 H), 3.57 (dd, J = 9.5, 6.5 Hz, 1 H), 3.60–3.66 (m, 1 H), 3.68–3.74
(m, 1 H), 4.40 (dd, J = 4.5, 2.0 Hz, 1 H), 4.48 (d, J = 12.1 Hz, 1 H), 4.51
(d, J = 12.1 Hz, 1 H), 7.28–7.32 (m, 5 H).
IR (film): 3000–2800, 1515, 1250, 1085, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 6 H), 0.05 (s, 3 H), 0.09 (s, 3 H),
0.85 (s, 9 H), 0.87 (s, 9 H), 0.98 (d, J = 6.8 Hz, 3 H), 1.88–1.92 (m, 1 H),
1.92–2.00 (m, 1 H), 2.33 (d, J = 2.0 Hz, 1 H), 3.50–3.52 (m, 2 H), 3.54–
3.58 (m, 1 H), 3.74–3.76 (m, 1 H), 3.78 (s, 3 H), 4.36 (d, J = 11.5 Hz, 1
H), 4.41 (d, J = 11.5 Hz, 1 H), 4.46 (dd, J = 5.3 Hz, 2.3 Hz, 1 H), 6.84 (d,
J = 8.5 Hz, 2 H), 7.23 (d, J = 7.8 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.7, 11.6, 18.0, 18.1,
25.7, 25.8, 38.6, 41.8, 55.2, 60.9, 65.5, 68.8, 72.4, 73.0, 84.2, 113.5,
129.1, 130.8, 158.0.
13C NMR (101 MHz, CDCl3): δ = –5.3, –4.8, 11.8, 18.1, 25.6, 38.4, 41.3,
62.4, 66.0, 72.0, 73.1, 73.8, 83.5, 127.5, 127.6, 128.3, 137.9.
Anal. Calcd for C21H34O3Si: C, 69.56; H, 9.45. Found: C, 69.2; H, 9.2.
Alcohol 9d by Ozonolysis of Enyne 8f (Scheme 4)
HRMS (ESI): m/z [M + Na]+ calcd for C28H50O4Si2Na: 529.3140; found:
Following the procedure reported for enyne 8d, the ozonolysis of 8f
(C23H36O3Si, 388.62 g/mol, 0.7 g, 1.8 mmol, 1 equiv) in MeOH (48 mL)
and CH2Cl2 (16 mL) with subsequent addition of PPh3 (262.29 g/mol,
1.4 g, 5.34 mmol, 3 equiv) and NaBH4 (37.83 g/mol, 0.21 g, 5.55 mmol,
3 equiv) delivered 9d (C22H36O4Si, 392.61 g/mol, 0.54 g, 1.375 mmol,
76%) as a colorless oil; Rf = 0.33 (hexanes–EtOAc, 5:1). Characteriza-
tion of 9d rests on 1H NMR data only.
1H NMR (400 MHz, CDCl3): δ = 0.09 (s, 3 H), 0.13 (s, 3 H), 0.89 (s, 9 H),
0.97 (d, J = 7.0 Hz, 3 H), 1.95–2.03 (m, 1 H), 2.18–2.25 (m, 1 H), 2.40
(d, J = 2.3 Hz, 1 H), 3.12 (dd, J = 7.4, 4.4 Hz, 1 H), 3.48 (dd, J = 9.3, 5.3
Hz, 1 H), 3.53 (dd, J = 9.5, 6.5 Hz, 1 H), 3.59–3.64 (m, 1 H), 3.67–3.72
(m, 1 H), 3.78 (s, 3 H), 4.39 (dd, J = 4.6, 1.9 Hz, 1 H), 4.40 (d, J = 11.3 Hz,
1 H), 4.44 (d, J = 12.1 Hz, 1 H), 6.85 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.5
Hz, 2 H).
529.3144.
Ynoate 10b from Alkyne 9e (Scheme 5)
To a solution of LDA, prepared from i-Pr2NH (101.19 g/mol, 0.722
g/mL, 0.12 mL, 86.6 mg, 0.856 mmol, 1.2 equiv) and n-BuLi (2.3 M in
n-hexane, 0.37 mL, 0.851 mmol, 1.2 equiv) in THF (1.5 mL) at –78 °C
was added a cooled (–78 °C) solution of the alkyne 9e (C27H48O3Si2,
476.85 g/mol, 0.34 g, 0.713 mmol, 1 equiv) in THF (3 mL). The mixture
was stirred for 15 min at –78 °C and isopropyl chloroformate (1 M in
toluene, 0.9 mL, 0.92 mmol, 1.3 equiv) was slowly added. After stir-
ring at –78 °C for 30 min and at 0 °C for 15 min, the reaction mixture
was diluted by the addition of sat. aq NH4Cl (4 mL). The biphasic mix-
ture was partitioned in a separatory funnel and the aqueous phase
was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases
were dried (MgSO4) and concentrated. The residue was purified by
chromatography (hexanes–EtOAc, 100:1) to yield the tris-protected
Silyl Ether 9e from Alcohol 9c (Scheme 5)
isopropyl
(4R,5R,6R)-4,7-dihydroxy-6-(hydroxymethyl)-5-methyl-
To an ice-cooled solution of the alcohol 9c (C21H34O3Si, 362.59 g/mol,
1.2 g, 3.31 mmol, 1 equiv) in CH2Cl2 (3 mL) were successively added
imidazole (68.08 g/mol, 0.66 g, 9.69 mmol, 3 equiv), DMAP (137.21
g/mol, 40 mg, 0.292 mmol, 0.1 equiv), and TBSCl (C6H15ClSi, 150.72
g/mol, 0.74 g, 4.91 mmol, 1.5 equiv). The cooling bath was removed
and the mixture was stirred at r.t. for 2 h. Sat. aq NH4Cl (2 mL) was
hept-2-ynoate 10b (C31H54O5Si2, 562.94 g/mol, 0.35 g, 0.622 mmol,
87%) as a colorless oil; Rf = 0.56 (hexanes–EtOAc, 20:1); [α]D25 +5.5 (c
0.69, CHCl3).
IR (film): 3000–2850, 1710, 1630, 1250, 1100, 835 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

L
M. Körner, M. Hiersemann
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 6 H), 0.06 (s, 3 H), 0.11 (s, 3 H),
0.85 (s, 9 H), 0.87 (s, 9 H), 1.00 (d, J = 6.5 Hz, 3 H), 1.24 (d, J = 6.3 Hz, 6
H), 1.94–1.97 (m, 2 H), 3.54 (d, J = 4.8 Hz, 2 H), 3.57–3.61 (m, 1 H),
3.76 (dd, J = 9.9, 3.9 Hz, 1 H), 4.43 (d, J = 12.1 Hz, 1 H), 4.48 (d, J = 11.8
Hz, 1 H), 4.59 (d, J = 5.3 Hz, 1 H), 5.05 (sept, J = 6.3 Hz, 1 H), 7.23–7.31
(m, 5 H).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.7, 11.8, 18.0, 21.5,
25.6, 25.8, 38.8, 41.6, 60.9, 65.6, 69.1, 69.6, 72.8, 77.5, 87.2, 127.3,
127.5, 128.2, 138.5, 153.0.
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.2, –4.6, 12.2, 14.2, 18.0,
18.1, 21.9, 25.7, 25.8, 35.8, 38.9, 60.6, 66.7, 70.3, 72.5, 81.1, 117.3,
127.2, 127.4, 128.1, 138.7, 159.3, 166.1.
Anal. Calcd for C32H58O5Si2: C, 66.38; H, 10.10. Found: C, 66.5; H, 10.1.
Enoate 16b by 1,4-Addition (Scheme 5)
According to the procedure for the preparation of 16a from 10b, 10c
(C32H56O6Si2, 592.96 g/mol, 0.42 g, 0.708 mmol, 1 equiv) in THF (14
mL) was treated with the reagent prepared from CuBr·SMe2 (205.58
g/mol, 1.5 g, 7.296 mmol, 10 equiv) in THF (14 mL) and MeMgBr (1 M
in THF, 7.0 mL, 7 mmol, 10 equiv) to afford 16b (C33H60O6Si2, 609.01
g/mol, 0.3 g, 0.493 mmol, 70%, E/Z = 95:5) as a colorless oil; Rf = 0.56
(hexanes–EtOAc, 20:1); [α]D25 not determined.
Anal. Calcd for C31H54O5Si2: C, 66.14; H, 9.67. Found: C, 66.3; H, 9.5.
Ynoate 10c from Alkyne 9f (Scheme 5)
Following the procedure for the synthesis of 10b from 9e, a solution
of LDA, prepared from i-Pr2NH (101.19 g/mol, 0.722 g/mL, 0.26 mL,
187.7 mg, 1.855 mmol, 2 equiv) and n-BuLi (2.1 M in n-hexane, 0.9
mL, 1.89 mmol, 2 equiv) in THF (4 mL) was reacted with 9f (C28H50O4Si2,
506.87 g/mol, 0.46 g, 0.908 mmol, 1 equiv) in THF (4 mL) and isopro-
pyl chloroformate (1 M in toluene, 1.8 mL, 1.8 mmol, 2 equiv) to af-
ford 10c (C32H56O6Si2, 592.96 g/mol, 0.42 g, 0.708 mmol, 78%) as a col-
orless oil; Rf = 0.33 (hexanes–EtOAc, 10:1).
IR (film): 3000–2850, 1715, 1110, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.05 (s, 3 H), –0.01 (s, 3 H), 0.00 (s, 3
H), 0.03 (s, 3 H), 0.71 (d, J = 7.3 Hz, 3 H), 0.84 (s, 9 H), 0.87 (s, 9 H), 1.22
(d, J = 6.0 Hz, 6 H), 1.95–2.00 (m, 1 H), 2.03 (s, 3 H), 2.19–2.25 (m, 1
H), 3.39 (dd, J = 9.5, 8.0 Hz, 1 H), 3.47 (dd, J = 9.9, 7.7 Hz, 1 H), 3.53 (dd,
J = 9.7, 5.4 Hz, 1 H), 3.71 (dd, J = 10.0, 5.0 Hz, 1 H), 3.77 (s, 3 H), 3.95
(m, 1 H), 4.32 (d, J = 11.5 Hz, 1 H), 4.43 (d, J = 11.5 Hz, 1 H), 5.00 (sept,
J = 6.3 Hz, 1 H), 5.75 (s, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 7.22 (d, J = 8.8 Hz,
2 H).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.2, –4.6, 12.1, 14.2, 18.0,
18.1, 21.8, 25.7, 25.8, 35.7, 38.8, 55.1, 60.6, 66.6, 69.9, 72.0, 81.0,
113.5, 117.3, 128.9, 130.1, 158.9, 159.3, 166.0.
HRMS (ESI): m/z [M + H]+ calcd for C33H61O6Si2: 609.4001; found:
609.4002.
IR (film): 3000–2850, 1710, 1250, 1090, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 3 H), 0.01 (s, 3 H), 0.05 (s, 3 H),
0.10 (s, 3 H), 0.85 (s, 9 H), 0.87 (s, 9 H), 1.00 (d, J = 6.5 Hz, 3 H), 1.25 (d,
J = 6.3 Hz, 6 H), 1.92–1.97 (m, 2 H), 3.49–3.50 (m, 2 H), 3.56 (dd, J =
10.0, 6.5 Hz, 1 H), 3.74 (dd, J = 10.0, 3.8 Hz, 1 H), 3.78 (s, 3 H), 4.36 (d,
J = 11.8 Hz, 1 H), 4.41 (d, J = 11.3 Hz, 1 H), 4.58 (d, J = 5.3 Hz, 1 H), 5.04
(sept, J = 6.3 Hz, 1 H), 6.84 (d, J = 8.5 Hz, 2 H), 7.22 (d, J = 9.5 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.7, 11.8, 18.0, 18.1,
21.5, 25.6, 25.8, 38.8, 41.5, 55.1, 61.0, 65.6, 68.8, 69.6, 72.5, 77.5, 87.2,
113.6, 129.0, 130.6, 153.0, 158.9.
Allylic Alcohol 11b by DIBAL-H Reduction (Scheme 5)
To a solution of the enoate 16a (C32H58O5Si2, 578.98 g/mol, 0.49 g,
0.846 mmol, 1 equiv) in CH2Cl2 (8 mL) at –100 °C was slowly added a
solution of DIBAL-H in CH2Cl2 (1 M, 2.5 mL, 2.5 mmol, 3 equiv). After
stirring at –100 °C for 1 h, the mixture was diluted by the addition of
aq pH 7 buffer (3 mL) and sat. aq Na/K tartrate (8 mL) and stirring was
continued for 1 h at 0 °C. The biphasic mixture was partitioned in a
separatory funnel and the aqueous layer was extracted with CH2Cl2 (3
× 15 mL). The combined organic phases were dried (MgSO4) and con-
centrated. The residue was purified by chromatography (hexanes–
EtOAc, 20:1 to 10:1) to afford the tris-protected (4R,5R,6R,E)-6-(hy-
droxymethyl)-3,5-dimethylhept-2-ene-1,4,7-triol 11b (C29H54O4Si2,
522.92 g/mol, 0.45 g, 0.861 mmol, 99%) as a colorless oil; Rf = 0.40 (cy-
clohexane–EtOAc, 5:1); [α]D22 +12.9 (c 0.99, CHCl3).
HRMS (ESI): m/z [M + H]+ calcd for C32H57O6Si2: 593.3688; found:
593.3689.
Enoate 16a by 1,4-Addition (Scheme 5)
To an ice-cooled solution of CuBr·SMe2 (205.58 g/mol, 3.1 g, 15.08
mmol, 10 equiv) in THF (68 mL) was added MeMgBr (1 M in THF, 15.3
mL, 15.3 mmol, 10 equiv). After stirring at 0 °C for 1 h, the solution of
the reagent was chilled to –78 °C and a cooled (–78 °C) solution of the
ynoate 10b (C31H54O5Si2, 562.94 g/mol, 0.86 g, 1.528 mmol, 1 equiv) in
THF (45 mL) was added. The reaction mixture was allowed to warm
to r.t. overnight and then cooled to 0 °C. Sat. aq NH4Cl (20 mL) and
H2O (20 mL) were carefully added (gas evolution!). The biphasic mix-
ture was partitioned in a separatory funnel and the aqueous layer was
extracted with CH2Cl2 (3 × 40 mL). The combined organic phases were
dried (MgSO4) and concentrated. The residue was purified by chro-
matography (hexanes–EtOAc, 100:1) to afford the tris-protected iso-
propyl (4R,5R,6R,E)-4,7-dihydroxy-6-(hydroxymethyl)-3,5-dimethyl-
hept-2-enoate 16a (C32H58O5Si2, 578.98 g/mol, 0.88 g, 1.52 mmol, 99%,
IR (film): 3400–3000, 3000–2850, 1470, 1255, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.04 (s, 3 H), 0.00 (s, 3 H), 0.01 (s, 3
H), 0.04 (s, 3 H), 0.68 (d, J = 7.3 Hz, 3 H), 0.86 (s, 9 H), 0.87 (s, 9 H), 1.57
(s, 3 H), 1.88–1.92 (m, 1 H), 2.29–2.32 (m, 1 H), 3.45 (dd, J = 9.5, 8.0
Hz, 1 H), 3.50 (dd, J = 9.8, 7.5 Hz, 1 H), 3.58 (dd, J = 9.5, 5.5 Hz, 1 H),
3.71 (dd, J = 9.8, 4.9 Hz, 1 H), 3.89 (d, J = 8.5 Hz, 1 H), 4.16–4.17 (m, 2
H), 4.41 (d, J = 11.8 Hz, 1 H), 4.52 (d, J = 12.1 Hz, 1 H), 5.52 (t, J = 6.4
Hz, 1 H), 7.24–7.31 (m, 5 H); no OH signal detected.
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.2, –4.4, 11.3, 12.0, 18.0,
18.1, 25.8, 35.6, 38.8, 59.1, 60.6, 70.6, 72.4, 81.0, 125.8, 127.2, 127.4,
128.2, 138.8, 140.2.
25
E/Z >95:5) as a colorless oil; Rf = 0.51 (hexanes–EtOAc, 20:1); [α]D
+14.2 (c 1.02, CHCl3).
IR (film): 3000–2850, 1710, 1250, 1090, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.04 (s, 3 H), –0.01 (s, 3 H), 0.00 (s, 3
H), 0.04 (s, 3 H), 0.72 (d, J = 7.3 Hz, 3 H), 0.84 (s, 9 H), 0.88 (s, 9 H), 1.22
(d, J = 6.3 Hz, 6 H), 1.98–2.01 (m, 1 H), 2.04 (s, 3 H), 2.21–2.24 (m, 1
H), 3.43 (dd, J = 9.5, 8.4 Hz, 1 H), 3.48 (dd, J = 9.8, 7.8 Hz, 1 H), 3.57 (dd,
J = 9.5, 5.3 Hz, 1 H), 3.70 (m, 1 H), 3.94 (d, J = 7.5 Hz, 1 H), 4.40 (d, J =
12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 5.00 (sept, J = 6.3 Hz, 1 H), 5.76
(s, 1 H), 7.23–7.30 (m, 5 H).
Anal. Calcd for C29H54O4Si2: C, 66.61; H, 10.41. Found: C, 66.9; H, 10.2.
Allylic Alcohol 11c by DIBAL-H Reduction (Scheme 5)
Following the procedure for the preparation of 11b from 16a, 16b
(C33H60O6Si2, 609.01 g/mol, 0.3 g, 0.493 mmol, 1 equiv) in CH2Cl2 (5
mL) was treated with DIBAL-H (1 M in CH2Cl2, 1.5 mL, 1.5 mmol, 3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

M
M. Körner, M. Hiersemann
Paper
Synthesis
equiv) to deliver the allylic alcohol 11c (C30H56O5Si2, 552.94 g/mol,
0.26 g, 0.47 mmol, 95%) as a colorless oil; Rf = 0.57 (hexanes–EtOAc,
2:1); [α]D25 not determined.
J = 9.8, 4.8 Hz, 1 H), 3.66 (d, J = 8.3 Hz, 1 H), 4.41 (d, J = 12.1 Hz, 1 H),
4.52 (d, J = 12.0 Hz, 1 H), 5.47 (dd, J = 15.1, 7.8 Hz, 1 H), 5.86 (d, J = 11.0
Hz, 1 H), 6.13 (dd, J = 15.1, 11.0 Hz, 1 H), 7.26–7.31 (m, 5 H).
IR (film): 3000–2850, 1515, 1250, 835 cm–1
.
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.6, 11.8, 12.0, 14.0,
18.0, 18.1, 20.4, 22.8, 25.8, 25.9, 29.5, 35.9, 36.7, 36.8, 39.0, 60.6, 70.6,
72.4, 81.4, 123.9, 127.0, 127.2, 127.4, 128.1, 136.3, 138.9, 140.1.
1H NMR (400 MHz, CDCl3): δ = −0.04 (s, 3 H), 0.00 (s, 3 H), 0.01 (s, 3
H), 0.04 (s, 3 H), 0.66 (d, J = 7.3 Hz, 3 H), 0.85 (s, 9 H), 0.86 (s, 9 H), 1.56
(s, 3 H), 1.85–1.90 (m, 1 H), 2.27−2.30 (m, 1 H), 3.40 (dd, J = 9.4, 7.9
Hz, 1 H), 3.49 (dd, J = 9.9, 7.4 Hz, 1 H), 3.54 (dd, J = 9.7, 5.7 Hz, 1 H),
3.69 (dd, J = 9.9, 4.9 Hz, 1 H), 3.78 (s, 3 H), 3.88 (d, J = 8.3 Hz, 1 H), 4.16
(dd, J = 6.5, 2.3 Hz, 2 H), 4.33 (d, J = 11.5 Hz, 1 H), 4.44 (d, J = 11.5 Hz, 1
H), 5.51 (t, J = 6.7 Hz, 1 H), 6.84 (d, J = 8.5 Hz, 2 H), 7.22 (d, J = 7.8 Hz, 2
H); no OH signal detected.
Anal. Calcd for C36H66O3Si2: C, 71.70; H, 11.03. Found: C, 71.6; H, 10.7.
Diene 7d by Julia–Kocienski Olefination (Scheme 6)
MnO2 Oxidation: According to the procedure reported for the prepara-
tion of 7e, the allylic alcohol 11b (C29H54O4Si2, 522.92 g/mol, 0.2 g,
0.383 mmol, 1 equiv) in CH2Cl2 (12 mL) was treated with MnO2 (86.94
g/mol, 0.39 g, 4.49 mmol, 12 equiv) to yield the corresponding enal as
a light yellow oil that was used immediately and without further pu-
rification; Rf = 0.51 (hexanes–EtOAc, 10:1).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.2, –4.4, 11.3, 12.0, 18.0,
18.1, 25.8, 35.6, 38.7, 55.1, 59.0, 60.6, 70.2, 72.0, 81.0, 113.5, 125.8,
129.0, 130.9, 140.2, 158.9.
HRMS (ESI): m/z [M + Na]+ calcd for C30H56O5Si2Na: 575.3559; found:
For NMR data of the enal, see above.
575.3549.
Julia–Kocienski Olefination: Following the procedure outlined for the
synthesis of 7e, (S)-12 (C14H20N4O2S, 308.40 g/mol, 0.2 g, 0.649 mmol,
1.8 equiv) in THF (4 mL) was treated with KHMDS (0.5 M in toluene,
1.3 mL, 0.65 mmol, 1.8 equiv) and a solution of the above crude enal
(0.37 mmol) in THF (8 mL) to afford 7d (C36H66O3Si2, 603.09 g/mol,
174 mg, 0.289 mmol, 75%, E/Z >95:5) as a colorless oil; Rf = 0.57 (hex-
anes–EtOAc, 20:1); [α]D25 +8.8 (c 1.18, CHCl3).
Diene 7e by Julia–Kocienski Olefination of 11b (Scheme 6)
MnO2 Oxidation: To a solution of the allylic alcohol 11b (C29H54O4Si2,
522.92 g/mol, 0.3 g, 0.574 mmol, 1 equiv) in CH2Cl2 (12 mL) was add-
ed MnO2 (86.94 g/mol, 0.59 g, 6.78 mmol, 12 equiv) and the mixture
was stirred in the dark at 40 °C for 3 h. The mixture was then filtered
through Celite and the filter cake was rinsed with CH2Cl2. The com-
bined filtrates were concentrated in vacuo to afford the correspond-
ing enal that was used immediately and without further purification;
Rf = 0.51 (hexanes–EtOAc, 10:1).
1H NMR (400 MHz, CDCl3): δ = –0.05 (s, 3 H), 0.00 (s, 6 H), 0.05 (s, 3
H), 0.75 (d, J = 7.3 Hz, 3 H), 0.84 (s, 9 H), 0.89 (s, 9 H), 2.00–2.05 (m, 1
H), 2.08 (s, 3 H), 2.19–2.22 (m, 1 H), 3.41 (dd, J = 8.8, 8.8 Hz, 1 H), 3.50
(dd, J = 9.9, 7.7 Hz, 1 H), 3.54 (dd, J = 9.5, 5.3 Hz, 1 H), 3.71 (dd, J = 9.9,
5.3 Hz, 1 H), 4.05 (d, J = 7.3 Hz, 1 H), 4.41 (d, J = 12.0 Hz, 1 H), 4.50 (d,
J = 12.0 Hz, 1 H), 5.98 (d, J = 8.0 Hz, 1 H), 7.24–7.31 (m, 5 H), 10.00 (d,
J = 8.0 Hz, 1 H).
IR (film): 3000–2850, 1470, 1255, 1090, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.07 (s, 3 H), –0.01 (s, 3 H), 0.00 (s, 3
H), 0.02 (s, 3 H), 0.66 (d, J = 7.3 Hz, 3 H), 0.84 (s, 9 H), 0.84–0.87 (m, 12
H), 0.97 (d, J = 6.5 Hz, 3 H), 1.20–1.30 (m, 6 H), 1.61 (s, 3 H), 1.90–1.96
(m, 1 H), 2.10–2.15 (m, 1 H), 2.30–2.33 (m, 1 H), 3.45 (dd, J = 8.8, 8.0
Hz, 1 H), 3.49 (dd, J = 9.8, 7.5 Hz, 1 H), 3.58 (dd, J = 9.8, 5.5 Hz, 1 H),
3.71 (dd, J = 9.8, 4.8 Hz, 1 H), 3.86 (d, J = 8.5 Hz, 1 H), 4.41 (d, J = 12.1
Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 5.46 (dd, J = 14.8, 7.8 Hz, 1 H), 5.85
(d, J = 10.8 Hz, 1 H), 6.14 (dd, J = 14.9, 10.7 Hz, 1 H), 7.26–7.31 (m, 5
H).
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.3, –4.6, 11.6, 12.0, 14.0,
18.0, 18.1, 20.5, 22.7, 25.8, 25.9, 29.5, 35.8, 36.3, 36.7, 36.9, 60.6, 70.5,
72.4, 81.4, 124.0, 127.0, 127.2, 127.4, 128.1, 136.4, 138.9, 140.1.
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.2, –4.6, 12.1, 12.9, 18.0,
18.1, 25.7, 25.8, 35.8, 39.0, 60.7, 70.3, 72.6, 80.7, 127.3, 127.4, 127.5,
128.2, 138.6, 163.8, 191.3.
HRMS (ESI): m/z [M + Na]+ calcd for C36H66O3Si2Na: 625.4443; found:
Julia–Kocienski Olefination: To a solution of (R)-12 (C14H20N4O2S,
308.40 g/mol, 0.321 g, 1.041 mmol, 1.8 equiv) in THF (6 mL) at –78 °C
was added KHMDS (0.5 M in toluene, 2.1 mL, 1.05 mmol, 1.8 equiv).
After stirring at –78 °C for 30 min, a solution of the above crude enal
(0.58 mmol) in THF (12 mL) was added and the mixture was allowed
to warm to r.t. overnight. The reaction mixture was then diluted by
the addition of sat. aq NH4Cl (15 mL), The biphasic mixture was parti-
tioned in a separatory funnel and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic phases were dried
(MgSO4) and concentrated. The residue was purified by chromatogra-
phy (hexanes–EtOAc, 100:1) to afford the tris-protected
(2R,3R,4R,5E,7E,9R)-2-(hydroxymethyl)-3,5,9-trimethyltrideca-5,7-
diene-1,4-diol 7e (C36H66O3Si2, 603.09 g/mol, 0.26 g, 0.431 mmol, 75%,
625.4438.
Anal. Calcd for C36H66O3Si2: C, 71.70; H, 11.03. Found: C, 71.0; H, 10.6.
Diene 7e by Julia–Kocienski Olefination (Scheme 6)
MnO2 Oxidation: According to the procedure reported for the prepara-
tion of 7d, the allylic alcohol 11c (C30H56O5Si2, 552.94 g/mol, 0.26 g,
0.47 mmol, 1 equiv) in CH2Cl2 (mL) was treated with MnO2 (86.94
g/mol, 0.48 g, 5.52 mmol, 12 equiv) to yield the corresponding enal as
a light yellow oil that was used immediately and without further pu-
rification; Rf = 0.66 (hexanes–EtOAc, 5:1).
Julia–Kocienski Olefination: Following the procedure outlined for the
synthesis of 7d, (R)-12 (C14H20N4O2S, 308.40 g/mol, 0.24 g, 0.778
mmol, 1.8 equiv) in THF (8 mL) was treated with KHMDS (0.5 M in
toluene, 1.5 mL, 0.75 mmol, 1.8 equiv) and a solution of the above
crude enal (0.43 mmol) in THF (4 mL) to afford 7e (C37H68O4Si2, 633.12
g/mol, 173 mg, 0.273 mmol, 58%, E/Z = 95:5) as a colorless oil; Rf =
0.36 (hexanes–EtOAc, 20:1); [α]D25 not determined.
25
E/Z >95:5) as a colorless oil; Rf = 0.6 (hexanes–EtOAc, 20:1); [α]D
–11.8 (c 1.08, CHCl3).
IR (film): 3000–2850, 1470, 1255, 1090, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.07 (s, 3 H), 0.01 (s, 3 H), 0.00 (s, 3
H), 0.02 (s, 3 H), 0.67 (d, J = 7.3 Hz, 3 H), 0.85 (s, 9 H), 0.86 (m, 12 H),
0.98 (d, J = 6.5 Hz, 3 H), 1.23–1.27 (m, 6 H), 1.62 (s, 3 H), 1.90–1.94 (m,
1 H), 2.11–2.15 (m, 1 H), 2.31–2.33 (m, 1 H), 3.45 (dd, J = 9.2, 7.9 Hz, 1
H), 3.49 (dd, J = 9.5, 7.5 Hz, 1 H), 3.59 (dd, J = 9.5, 5.5 Hz, 1 H), 3.72 (dd,
IR (film): 3000–2850, 1515, 1250, 1090, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.07 (s, 3 H), 0.00 (s, 3 H), 0.01 (s, 3
H), 0.02 (s, 3 H), 0.65 (d, J = 7.3 Hz, 3 H), 0.83 (s, 9 H), 0.84–0.87 (m, 12
H), 0.98 (d, J = 6.8 Hz, 3 H), 1.24–1.28 (m, 6 H), 1.61 (s, 3 H), 1.89–1.93
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

N
M. Körner, M. Hiersemann
Paper
Synthesis
(m, 1 H), 2.10–2.15 (m, 1 H), 2.28–2.32 (m, 1 H), 3.41 (dd, J = 9.5, 8.0
Hz, 1 H), 3.48 (dd, J = 9.8, 7.5 Hz, 1 H), 3.56 (dd, J = 9.7, 5.7 Hz, 1 H),
3.71 (dd, J = 9.9, 4.6 Hz, 1 H), 3.78 (s, 3 H), 3.86 (d, J = 8.3 Hz, 1 H), 4.33
(d, J = 11.5 Hz, 1 H), 4.41 (d, J = 11.5 Hz, 1 H), 5.48 (dd, J = 15.1, 7.8 Hz,
1 H), 5.85 (d, J = 10.5 Hz, 1 H), 6.13 (dd, J = 15.1, 10.5 Hz, 1 H), 6.84 (d,
J = 8.5 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3 H), 0.89 (d, J = 6.5
Hz, 3 H), 1.04–1.12 (m, 1 H), 1.19–1.40 (m, 6 H), 1.53–1.62 (m, 1 H),
3.39 (dd, J = 10.5, 6.5 Hz, 1 H), 3.48 (dd, J = 10.5, 5.8 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 14.0, 16.5, 22.9, 29.1, 32.7, 35.6, 68.3.
HRMS (EI): m/z calcd for [C7H16O]+: 116.1196; found: 116.1177.
13C NMR (101 MHz, CDCl3): δ = –5.6, –5.5, –5.2, –4.5, 11.7, 11.9, 14.0,
18.0, 18.1, 20.4, 22.7, 25.8, 25.9, 29.4, 35.8, 36.7, 36.8, 38.8, 55.1, 60.6,
70.2, 71.9, 81.4, 113.5, 123.9, 127.0, 129.0, 131.0, 136.3, 140.1, 158.8.
HRMS (ESI): m/z [M + Na]+ calcd for C37H68O3Si2Na: 655.4548; found:
655.4544.
(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (20) by Esteri-
fication of (S)-2-Methylhexan-1-ol (19) (Scheme 7)
To a solution of (S)-2-methylhexan-1-ol (19; C7H16O, 116.20 g/mol, 20
mg, 0.172 mmol, 1 equiv) in CH2Cl2 (3 mL) at r.t. was added (R)-3,3,3-
trifluoro-2-methoxy-2-phenylpropanoic acid (C10H9F3O3, 234.17
g/mol, 121 mg, 0.517 mmol, 3 equiv), DMAP (122.17 g/mol, 10 mg,
0.082 mmol, 0.5 equiv), and DCC (C13H22N2, 206.33 g/mol, 133 mg,
0.645 mmol, 3.75 equiv). After stirring at r.t. for 3 h, the mixture was
diluted by the addition of brine (1 mL). The biphasic mixture was par-
titioned in a separatory funnel and the aqueous layer was extracted
with CH2Cl2 (3 × 3 mL). The combined organic phases were dried (Mg-
SO4) and concentrated. The residue was purified by chromatography
(hexanes–EtOAc, 200:1 to 100:1) to yield the ester 20 (C17H23F3O3,
332.36 g/mol, 57 mg, 0.172 mmol, 99%, dr >95:5) as a colorless oil;
Rf = 0.60 (hexanes–EtOAc, 20:1). The characterization rests on NMR
spectroscopy only.
1H NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.2 Hz, 3 H), 0.89 (d, J = 6.8
Hz, 3 H), 1.10–1.31 (m, 6 H), 1.79–1.84 (m, 1 H), 3.53 (s, 3 H), 4.13 (d,
J = 5.8 Hz, 2 H), 7.37–7.39 (m, 3 H), 7.48–7.50 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 13.9, 16.7, 22.7, 28.8, 32.3, 32.6, 55.3,
71.1, 84.7 (d, JC,F = 28.2 Hz), 121.8, 124.7, 127.4, 128.3, 129.5, 132.2,
166.6.
(S)-4-Isopropyl-3-[(S)-2-methylhexanoyl]oxazolidin-2-one (18)
(Scheme 7)
To a solution of (S)-3-hexanoyl-4-isopropyloxazolidin-2-one (17;
C
12H21NO3, 227.30 g/mol, 11.6 g, 51.03 mmol, 1 equiv) in THF (100
mL) at –78 °C was added NaHMDS (2 M in toluene, 31 mL, 62 mmol,
1.2 equiv). The mixture was stirred at –78 °C for 1 h. MeI (141.94
g/mol, 2.27 g/mol, 8 mL, 18.16 g, 127.9 mmol, 2.5 equiv) was added at
–78 °C and the reaction mixture was allowed to warm to –20 °C over
a period of about 3 h. The reaction mixture was then diluted by the
addition of sat. aq NH4Cl (50 mL). The biphasic mixture was parti-
tioned in a separatory funnel and the aqueous layer was extracted
with CH2Cl2 (3 × 100 mL). The combined organic phases were dried
(MgSO4) and concentrated. The residue was purified by chromatogra-
phy (hexanes–EtOAc, 20:1) to yield 18 (C13H23NO3, 241.33 g/mol, 11.4
g, 47.24 mmol, 93%, dr >95:5) as a colorless oil; Rf = 0.5 (hexanes–
EtOAc, 10:1); [α]D +96.4 (c 1.0, CHCl3) {Lit.32 [α]D +79.0 (c 1.0,
CHCl3). The assignment of the absolute configuration rests on the ac-
cepted stereochemical model.
25
25
(S)-5-[(2-Methylhexyl)thio]-1-phenyl-1H-tetrazole (21) by
Mitsunobu Reaction (Scheme 7)
IR (film): 3000–2870, 1780, 1700, 1385, 1200 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.84–0.90 (m, 9 H), 1.17 (d, J = 6.8 Hz, 3
H), 1.20–1.40 (m, 5 H), 1.65–1.74 (m, 1 H), 2.29–2.37 (m, 1 H), 3.66–
3.74 (m, 1 H), 4.17 (dd, J = 9.0, 3.0 Hz, 1 H), 4.24 (dd, J = 9.0, 9.0 Hz, 1
H), 4.41–4.45 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 14.0, 14.7, 17.9, 22.7, 28.4, 29.5, 32.8,
37.7, 58.4, 63.2, 153.7, 177.3.
To an ice-cooled solution of (S)-2-methylhexan-1-ol (19; C7H16O,
116.20 g/mol, 1 g, 8.605 mmol, 1 equiv) in THF (9 mL) were succes-
sively added PPh3 (262.29 g/mol, 2.73 g, 10.41 mmol, 1.2 equiv), 1-
phenyl-1H-tetrazole-5-thiol (178.21 g/mol, 2.31 g, 12.96 mmol, 1.5
equiv), and diisopropyl azodicarboxylate (202.21 g/mol, 1.027 g/mL,
2.2 mL, 2.26 g, 11.176 mmol, 1.3 equiv). After stirring at 0 °C for 1 h,
the mixture was diluted by the addition of sat. aq NaHCO3 (5 mL). The
biphasic mixture was partitioned in a separatory funnel and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined
organic phases were dried (MgSO4) and concentrated. The residue
was purified by chromatography (hexanes–EtOAc, 50:1) to provide
the sulfide 21 (C14H20N4S, 276.40 g/mol, 2.4 g, 8.683 mmol, 99%) as a
Anal. Calcd for C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C, 64.9; H,
9.5; N, 5.5.
(–)-(S)-2-Methylhexan-1-ol (19) (Scheme 7)
To an ice-cooled solution of the 3-(2-methylhexanoyl)oxazolidin-2-
one (18; C13H23NO3, 241.33 g/mol, 1.82 g, 7.54 mmol, 1 equiv) and
MeOH (32.04 g/mol, 0.79 g/mL, 0.9 mL, 711 mg, 22.19 mmol, 3 equiv)
in Et2O (75 mL) was added LiBH4 (21.78 g/mol, 0.49 g, 22.6 mmol, 3
equiv). The cooling bath was removed and the mixture was stirred at
r.t. for 1.5 h. The reaction mixture was diluted by the addition of sat.
aq Na/K tartrate (40 mL) and subsequently stirred at r.t. for 30 min.
The biphasic mixture was then partitioned in a separatory funnel and
the aqueous layer was extracted with Et2O (4 × 30 mL). The combined
organic phases were dried (MgSO4) and carefully concentrated at re-
duced pressure (40 °C/700 mbar). The residue was purified by
Kugelrohr distillation (100 °C/20 mbar) to yield, as the distillate, the
colorless liquid alcohol 19 (C7H16O, 116.20 g/mol, 0.79 g, 6.8 mmol,
90%) and residual (S)-4-isopropyloxazolidin-2-one (C6H11NO2, 129.16
25
light yellow oil; Rf = 0.26 (hexanes–EtOAc, 10:1); [α]D +3.4 (c 1.75,
CHCl3).
IR (film): 3000–2850, 1500, 1385 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 6.8 Hz, 3 H), 1.01 (d, J = 6.8
Hz, 3 H), 1.21–1.33 (m, 5 H), 1.42–1.51 (m, 1 H), 1.88–1.95 (m, 1 H),
3.24 (dd, J = 12.6, 7.5 Hz, 1 H), 3.44 (dd, J = 12.6, 5.8 Hz, 1 H), 7.51–
7.58 (m, 5 H).
13C NMR (101 MHz, CDCl3): δ = 13.9, 19.0, 22.7, 28.9, 32.8, 35.5, 40.4,
123.7, 129.7, 130.0, 133.6, 154.7.
HRMS (ESI): m/z calcd for [C14H21N4S]+: 277.1482; found: 277.1476.
g/mol, 0.89 g, 6.89 mmol, 91%); Rf = 0.31 (hexanes−EtOAc, 5:1); [α]25
(S)-5-[(2-Methylhexyl)sulfonyl)-1-phenyl-1H-tetrazole [(S)-12] by
Oxidation (Scheme 7)
D
19
–13.1 (c 1.0, CHCl3) {Lit.47 [α]D25 –14.2 (c 0.31, MeOH), Lit.48 [α]D
–11.6 (c 7.59, Et2O)}.
IR (film): 3700–3100, 3000–2850, 1465, 1260 cm–1
To an ice-cooled solution of the sulfide 21 (C14H20N4S, 276.40 g/mol,
2.2 g, 7.959 mmol, 1 equiv) in EtOH (78 mL) was added a solution of
(NH4)6Mo7O24·4H2O (1235.99 g/mol, 100 mg, 0.0809 mmol, 0.01
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

O
M. Körner, M. Hiersemann
Paper
Synthesis
equiv) in H2O2 (34.02 g/mol, 7.6 mL of a 30% m/v H2O, 1.11 g/mL, 2.53
g, 74.37 mmol, 9 equiv). The cooling bath was removed and the mix-
ture was stirred at r.t. for 15 h. The reaction mixture was then diluted
by the addition of brine (10 mL). The biphasic mixture was parti-
tioned in a separatory funnel and the aqueous layer was extracted
with CH2Cl2 (3 × 40 mL). The combined organic phases were dried
(MgSO4) and concentrated. The residue was purified by chromatogra-
phy (hexanes–EtOAc, 100:1 to 50:1) to deliver the sulfone (S)-12
(C14H20N4O2S, 308.40 g/mol, 2.3 g, 7.458 mmol, 94%) as a light yellow
oil; Rf = 0.66 (hexanes–EtOAc, 5:1); [α]D25 –2.1 (c 1.01, CHCl3).
Hz, 1 H), 4.37 (d, J = 11.8 Hz, 1 H), 4.41 (d, J = 11.8 Hz, 1 H), 5.50 (dd,
J = 15.1, 7.8 Hz, 1 H), 5.90 (d, J = 11.0 Hz, 1 H), 6.12 (dd, J = 15.1, 11.0
Hz, 1 H), 6.84 (d, J = 6.8 Hz, 2 H), 7.20 (d, J = 6.8 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = –5.3, –4.7, 12.7, 12.8, 14.0, 18.2, 20.4,
22.7, 25.7, 29.5, 36.3, 36.7, 36.9, 39.1, 55.2, 61.9, 72.5, 73.0, 81.1,
113.6, 123.6, 127.1, 129.2, 130.1, 134.8, 140.7, 159.0.
HRMS (ESI): m/z [M + Na]+ calcd for C31H54O4SiNa: 541.3684; found:
541.3683.
Alkyne 22a by Alcohol to Alkyne Homologation (Scheme 8)
IR (film): 3000–2900, 2360–2340, 1500, 1340, 1150, 760 cm–1
.
Dess–Martin Oxidation: To an ice-cooled solution of the alcohol 7g
(C30H52O3Si, 488.83 g/mol,0.21 g, 0.430 mmol, 1 equiv) in CH2Cl2 (9
mL) and pyridine (0.9 mL) was added the Dess–Martin periodinane
(424.14 g/mol, 0.55 g, 1.297 mmol, 3 equiv). The cooling bath was re-
moved and the mixture was stirred for 3 h at r.t. The reaction mixture
was then diluted by the addition of sat. aq Na2S2O3 (4 mL). The bipha-
sic mixture was partitioned in a separatory funnel and the aqueous
layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic
phases were dried (MgSO4) and concentrated. The residue was puri-
fied by chromatography (hexanes–EtOAc, 50:1) to provide the corre-
sponding aldehyde as colorless oil. The aldehyde was used immedi-
ately and without further purification; Rf = 0.66 (hexanes–EtOAc, 5:1).
1H NMR (400 MHz, CDCl3): δ = –0.07 (s, 3 H), –0.01 (s, 3 H), 0.85 (m,
15 H), 0.98 (d, J = 6.5 Hz, 3 H), 1.23–1.31 (m, 6 H), 1.61 (s, 3 H), 2.10–
2.15 (m, 1 H), 2.18–2.45 (m, 1 H), 2.81–2.92 (m, 1 H), 3.54 (dd, J = 9.5,
6.3 Hz, 1 H), 3.83 (dd, J = 9.5, 7.8 Hz, 1 H), 3.88 (d, J = 6.8 Hz, 1 H), 4.46
(d, J = 12.3 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 5.50 (dd, J = 14.9, 7.7 Hz,
1 H), 5.94 (d, J = 10.8 Hz, 1 H), 6.12 (dd, J = 14.8, 10.8 Hz, 1 H), 7.25–
7.34 (m, 5 H), 9.78 (d, J = 1.3 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 7.2 Hz, 3 H), 1.14 (d, J = 6.8
Hz, 3 H), 1.22–1.38 (m, 5 H), 1.50–1.56 (m, 1 H), 2.27–2.35 (m, 1 H),
3.56 (dd, J = 14.4, 7.9 Hz, 1 H), 3.79 (dd, J = 14.4, 4.8 Hz, 1 H), 7.57–
7.68 (m, 5 H).
13C NMR (101 MHz, CDCl3): δ = 13.9, 19.7, 22.5, 28.2, 28.4, 36.2, 61.8,
125.1, 129.6, 131.4, 133.1, 154.0.
HRMS (ESI): m/z calcd for [C14H21N4SO2]+: 309.1380; found: 309.1377.
Alcohol 7g by Regioselective Silyl Ether Cleavage (Scheme 8)
To a solution of 7e (C36H66O3Si2, 603.09 g/mol, 0.26 g, 0.431 mmol, 1
equiv) in THF (4 mL) at 0 °C was slowly added a solution of commer-
cially available HF-pyridine (0.9 mL), pyridine (1.4 mL), and THF (4
mL). The cooling bath was removed and the mixture was stirred at r.t.
overnight. The reaction mixture was then diluted by the addition of
sat. aq NaHCO3 (6 mL), The biphasic mixture was partitioned in a sep-
aratory funnel and the aqueous layer was extracted with CH2Cl2 (3 ×
20 mL). The combined organic phases were dried (MgSO4) and con-
centrated. The residue was purified by chromatography (hexanes–
EtOAc, 50:1 to 20:1) to deliver the alcohol 7g (C30H52O3Si, 488.83
g/mol, 200 mg, 0.409 mmol, 95%) as a colorless oil; Rf = 0.49 (hex-
anes–EtOAc, 5:1); [α]D25 –23.9 (c 0.99, CHCl3).
Chloromethylenation: To an ice-cooled suspension of ClCH2PPh3Cl
(347.22 g/mol, 0.91 g, 2.621 mmol, 6 equiv) in THF (4 mL) was added
n-BuLi (2.2 M in n-hexane, 1 mL, 2.2 mmol, 5 equiv). The cooling bath
was removed and the red-brown mixture was stirred at r.t. for 2 h.
The mixture was chilled to 0 °C and a solution of the above crude al-
dehyde (C30H50O3Si, 486.81 g/mol, 214 mg, 0.44 mmol, 1 equiv) in THF
(4 mL) was added. After stirring at 0 °C for 5 min, the reaction mixture
was diluted by the addition of pentane (18 mL) and the solids were
removed by filtration through a plug of silica gel. The filter cake was
thoroughly rinsed with pentane and the combined filtrates were con-
centrated in vacuo to yield a residue that was used without further
purification; Rf = 0.66 (hexanes–EtOAc, 20:1).
IR (film): 3000–2850, 1455, 1250, 1050, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.03 (s, 3 H), 0.06 (s, 3 H), 0.77 (d, J =
7.3 Hz, 3 H), 0.85 (t, J = 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.98 (d, J = 6.8 Hz, 3
H), 1.20–1.30 (m, 6 H), 1.61 (s, 3 H), 1.86–1.91 (m, 1 H), 2.11–2.15 (m,
1 H), 2.31–2.35 (m, 1 H), 3.38–3.63 (m, 4 H), 3.87 (d, J = 6.5 Hz, 1 H),
4.44 (d, J = 12.1 Hz, 1 H), 4.48 (d, J = 12.1 Hz, 1 H), 5.50 (dd, J = 15.1, 7.8
Hz, 1 H), 5.92 (d, J = 10.8 Hz, 1 H), 6.13 (dd, J = 15.1, 10.8 Hz, 1 H),
7.26–7.34 (m, 5 H); no OH signal detected.
13C NMR (101 MHz, CDCl3): δ = –5.3, –4.7, 12.7, 12.8, 14.0, 18.2, 20.4,
22.7, 25.8, 29.5, 36.3, 36.7, 36.9, 39.2, 61.8, 72.8, 73.2, 81.1, 123.6,
127.1, 127.4, 127.5, 128.3, 134.9, 138.1, 140.7.
β-Elimination: To a solution of LDA, prepared from i-Pr2NH (101.19
g/mol, 0.722 g/mL, 0.22 mL, 158.8 mg, 1.569 mmol, 3.6 equiv) and n-
BuLi (2.2 M in n-hexane, 0.7 mL, 1.54 mmol, 3.5 equiv), in THF (4 mL)
at –78 °C was added a cooled (–78 °C) solution of the above vinyl
chloride (assumed 0.44 mmol, 1 equiv) in THF (4 mL). After stirring at
–78 °C for 0.5 h and at 0 °C for 1 h, the reaction mixture was diluted
by the addition of sat. aq NH4Cl (4 mL). The biphasic mixture was par-
titioned in a separatory funnel and the aqueous layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic phases were dried
(MgSO4) and concentrated. The residue was purified by chromatogra-
phy (hexanes–EtOAc, 100:1) to yield the bis-protected
(2S,3R,4R,5E,7E,9R)-2-ethynyl-3,5,9-trimethyltrideca-5,7-diene-1,4-
diol 22a (C31H50O2Si, 482.82 g/mol, 119 mg, 0.247 mmol, 54%) as a
colorless oil; Rf = 0.46 (hexanes–EtOAc, 20:1); [α]D25 –26.9 (c 0.92, CH-
Cl3).
HRMS (ESI): m/z [M + Na]+ calcd for C30H52O3SiNa: 511.3578; found:
511.3571.
Alcohol 7h by Regioselective Silyl Ether Cleavage (Scheme 8)
In analogy to the procedure reported for the preparation of 7g from
7e, 7f (C37H68O4Si2, 633.12 g/mol, 140 mg, 0.221 mmol, 1 equiv) in
THF (4.5 mL) was subjected to commercially available HF-pyridine
(0.44 mL), pyridine (0.7 mL), and THF (4.5 mL) to deliver the alcohol
7h (C31H54O4Si, 518.85 g/mol, 91 mg, 0.175 mmol, 79%) as a colorless
oil; Rf = 0.43 (hexanes–EtOAc, 5:1); [α]D25 –25.0 (c 1.4, CHCl3).
IR (film): 3000–2850, 1513, 1250, 1050, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.03 (s, 3 H), 0.05 (s, 3 H), 0.75 (d, J =
7.3 Hz, 3 H), 0.85 (t, J = 6.7 Hz, 3 H), 0.89 (s, 9 H), 0.97 (d, J = 6.8 Hz, 3
H), 1.23–1.27 (m, 6 H), 1.60 (s, 3 H), 1.84–1.87 (m, 1 H), 2.09–2.16 (m,
1 H), 2.29–2.32 (m, 1 H), 3.37 (dd, J = 9.3, 6.0 Hz, 1 H), 3.41–3.49 (m, 2
H), 3.50–3.54 (m, 1 H), 3.56–3.61 (m, 1 H), 3.78 (s, 3 H), 3.85 (d, J = 6.5
IR (film): 3000–2850, 1640, 1055, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = –0.05 (s, 3 H), 0.06 (s, 3 H), 0.65 (d, J =
6.8 Hz, 3 H), 0.83–0.86 (m, 12 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.23–1.27
(m, 6 H), 1.61 (s, 3 H), 1.84–1.89 (m, 1 H), 2.02 (d, J = 2.3 Hz, 1 H),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

P
M. Körner, M. Hiersemann
Paper
Synthesis
2.10–2.15 (m, 1 H), 3.32–3.36 (m, 1 H), 3.47 (dd, J = 9.2, 9.2 Hz, 1 H),
3.58 (dd, J = 9.2, 6.9 Hz, 1 H), 3.83 (d, J = 9.8 Hz, 1 H), 4.47 (d, J = 12.1
Hz, 1 H), 4.58 (d, J = 12.3 Hz, 1 H), 5.51 (dd, J = 15.2, 7.9 Hz, 1 H), 5.84
(d, J = 10.8 Hz, 1 H), 6.12 (dd, J = 14.9, 10.7 Hz, 1 H), 7.25–7.32 (m, 5
H).
13C NMR (101 MHz, CDCl3): δ = –5.3, –4.8, 10.6, 11.0, 14.0, 18.1, 20.4,
22.7, 25.8, 29.4, 32.2, 36.1, 36.7, 36.8, 70.9, 71.2, 72.4, 81.3, 82.8,
123.8, 127.5, 127.6, 128.1, 128.3, 135.6, 138.2, 140.7.
tioned in a separatory funnel and the aqueous layer was extracted
with CH2Cl2 (3 × 5 mL). The combined organic phases were dried
(MgSO4) and concentrated. The residue was purified by chromatogra-
phy (hexanes–EtOAc, 100:1) to yield the bis-protected
(2S,3R,4R,5E,7E,9R)-3,5,9-trimethyl-2-(prop-1-yn-1-yl)trideca-5,7-di-
ene-1,4-diol 23a (C32H52O2Si, 496.85 g/mol, 100 mg, 0.201 mmol,
87%) as a colorless oil; Rf = 0.63 (hexanes–EtOAc, 20:1); [α]D25 –33.6 (c
1.07, CHCl3).
IR (film): 3000–2850, 1640, 1055, 835 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C31H50O2SiNa: 505.3472; found:
505.3467.
1H NMR (400 MHz, CDCl3): δ = –0.05 (s, 3 H), 0.06 (s, 3 H), 0.60 (d, J =
7.0 Hz, 3 H), 0.83–0.86 (m, 12 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.23–1.27
(m, 6 H), 1.61 (s, 3 H), 1.78 (d, J = 2.3 Hz, 3 H), 1.80–1.86 (m, 1 H),
2.10–2.17 (m, 1 H), 3.25–3.30 (m, 1 H), 3.41 (dd, J = 9.4, 9.4 Hz, 1 H),
3.51 (dd, J = 9.4, 6.5 Hz, 1 H), 3.81 (d, J = 9.8 Hz, 1 H), 4.45 (d, J = 12.3
Hz, 1 H), 4.56 (d, J = 12.3 Hz, 1 H), 5.49 (dd, J = 15.2, 7.8 Hz, 1 H), 5.84
(d, J = 10.3 Hz, 1 H), 6.13 (dd, J = 15.2, 10.3 Hz, 1 H), 7.25–7.32 (m, 5
H).
13C NMR (101 MHz, CDCl3): δ = –5.3, –4.8, 3.5, 10.7, 11.0, 14.0, 18.1,
20.4, 22.8, 25.8, 29.4, 32.2, 36.2, 36.7, 36.8, 71.2, 72.3, 78.4, 81.5, 81.8,
123.9, 127.4, 127.6, 127.9, 128.2, 136.0, 138.4, 140.7.
HRMS (ESI): m/z calcd for [C32H53O2SiNa]+: 519.3629; found:
519.3623.
Alkyne 22b by Alcohol to Alkyne Homologation (Scheme 8)
Dess–Martin Oxidation: Following the procedure reported for the oxi-
dation of 7g, 7h (C31H54O4Si, 518.85 g/mol, 93 mg, 0.179 mmol, 1
equiv) in CH2Cl2 (4 mL) and pyridine (0.4 mL) was treated with the
Dess–Martin periodinane (424.14 g/mol, 0.23 g, 0.542 mmol, 3 equiv)
to provide the corresponding enal as a colorless oil (80 mg) that was
used immediately and without further purification; Rf = 0.71 (hex-
anes–EtOAc, 5:1).
Chloromethylenation: According to the procedure used for the prepa-
ration of the alkyne 23a, the above crude aldehyde (assumed 0.155
mmol, 1 equiv) from the Dess–Martin oxidation in THF (4 mL) was
treated with the reagent prepared from ClCH2PPh3Cl (347.22 g/mol,
0.37 g, 1.066 mmol, 7 equiv) in THF (4 mL) and n-BuLi (2.3 M in n-
hexane, 0.4 mL, 0.92 mmol, 6 equiv) to deliver a residue that was used
without further purification; Rf = 0.41 (hexanes–EtOAc, 20:1).
Alkyne 23b by Methylation (Scheme 8)
Following the procedure for the preparation of 23a from 22a, 22b
(C32H52O3Si, 512.85 g/mol, 41 mg, 0.08 mmol, 1 equiv) in THF (1.6 mL)
was subjected to a solution of LDA in THF (0.8 mL), prepared from
i-Pr2NH (101.19 g/mol, 0.722 g/mL, 0.04 mL, 28.9 mg, 0.286 mmol,
3.6 equiv) and n-BuLi (2.2 M in n-hexane, 0.1 mL, 0.22 mmol, 2.75
equiv), and MeI (141.94 g/mol, 2.27 g/mol, 0.03 mL, 68.1 mg, 0.48
mmol, 6 equiv) to yield 23b (C33H54O3Si, 526.88 g/mol, 38 mg, 0.072
β-Elimination: Using the procedure reported for the preparation of
alkyne 22a, the crude vinyl chloride (assumed 0.155 mmol, 1 equiv)
from the chloromethylenation in THF (1.6 mL) was treated with LDA,
prepared from i-Pr2NH (101.19 g/mol, 0.722 g/mL, 0.07 mL, 50.54 mg,
0.499 mmol, 3.2 equiv) and n-BuLi (2.2 M in n-hexane, 0.21 mL, 0.462
mmol, 3.0 equiv), in THF (1.6 mL) to deliver the alkyne 22b (C32H52O3Si,
512.85 g/mol, 41 mg, 0.08 mmol, 45%) as a colorless oil; Rf = 0.41
(hexanes–EtOAc, 20:1); [α]D25 –20.5 (c 1.07, CHCl3).
25
mmol, 90%) as a colorless oil; Rf = 0.53 (hexanes–EtOAc, 20:1); [α]D
–31.0 (c 0.93, CHCl3).
IR (film): 3000–2850, 1630 cm–1
.
IR (film): 3000–2850, 1615, 1515, 1260, 1055, 835 cm–1
.
1H NMR (400 MHz, CDCl3): δ = −0.05 (s, 3 H), 0.06 (s, 3 H), 0.60 (d, J =
6.8 Hz, 3 H), 0.83–0.86 (m, 12 H), 0.98 (d, J = 6.8 Hz, 3 H), 1.24–1.28
(m, 6 H), 1.62 (s, 3 H), 1.78 (d, J = 2.3 Hz, 3 H), 1.80–1.84 (m, 1 H),
2.10–2.16 (m, 1 H), 3.26–3.28 (m, 1 H), 3.38 (dd, J = 9.4, 9.4 Hz, 1 H),
3.48 (dd, J = 9.4, 6.5 Hz, 1 H), 3.78 (s, 3 H), 3.81 (d, J = 9.8 Hz, 1 H), 4.38
(d, J = 11.8 Hz, 1 H), 4.50 (d, J = 11.8 Hz, 1 H), 5.50 (dd, J = 15.1, 7.5 Hz,
1 H), 5.84 (d, J = 11.0 Hz, 1 H), 6.13 (dd, J = 15.1, 11.0 Hz, 1 H), 6.85 (d,
J = 8.5 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = –5.4, –4.8, 3.5, 10.6, 11.1, 14.0, 18.1,
20.4, 22.7, 25.8, 29.4, 32.1, 36.1, 36.7, 36.8, 55.1, 70.9, 71.9, 77.1, 78.3,
81.5, 113.6, 123.9, 127.9, 129.2, 130.4, 136.0, 140.3, 159.0.
HRMS (ESI): m/z calcd for [C33H54O3SiNa]+: 549.3734; found:
549.3723.
1H NMR (400 MHz, CDCl3): δ = –0.05 (s, 3 H), 0.07 (s, 3 H), 0.65 (d, J =
6.8 Hz, 3 H), 0.83–0.86 (m, 12 H), 0.98 (d, J = 6.5 Hz, 3 H), 1.24–1.28
(m, 6 H), 1.62 (s, 3 H), 1.83–1.88 (m, 1 H), 2.02 (d, J = 2.5 Hz, 1 H),
2.10–2.15 (m, 1 H), 3.31–3.36 (m, 1 H), 3.44 (dd, J = 9.4, 9.4 Hz, 1 H),
3.55 (dd, J = 9.5, 6.8 Hz, 1 H), 3.78 (s, 3 H), 3.84 (d, J = 10.0 Hz, 1 H),
4.40 (d, J = 11.8 Hz, 1 H), 4.51 (d, J = 11.8 Hz, 1 H), 5.51 (dd, J = 15.2, 7.7
Hz, 1 H), 5.84 (d, J = 10.5 Hz, 1 H), 6.13 (dd, J = 15.2, 10.5 Hz, 1 H), 6.85
(d, J = 8.8 Hz, 2 H), 7.25 (d, J = 8.8 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = –5.3, –4.7, 10.6, 11.0, 14.0, 18.1, 20.4,
22.7, 25.8, 29.4, 32.1, 36.0, 36.7, 36.8, 55.1, 70.5, 71.2, 72.0, 81.3, 82.8,
113.6, 123.8, 128.1, 129.2, 130.2, 135.6, 140.6, 159.0.
HRMS (ESI): m/z [M + Na]+ calcd for C32H52O3SiNa: 535.3578; found:
535.3574.
Alkyne 23a by Methylation (Scheme 8)
Acknowledgment
To a solution of LDA, prepared from i-Pr2NH (101.19 g/mol, 0.722
g/mL, 0.1 mL, 72.2 mg, 0.722 mmol, 3.1 equiv) and n-BuLi (2.3 M in n-
hexane, 0.3 mL, 0.69 mmol, 3 equiv), in THF (2 mL) at –78 °C was add-
ed a cooled (–78 °C) solution of the alkyne 22a (C31H50O2Si, 482.82
g/mol, 111 mg, 0.23 mmol, 1 equiv) in THF (4 mL). After stirring for 30
min at –78 °C, MeI (141.94 g/mol, 2.27 g/mol, 0.09 mL, 204.3 mg,
1.439 mmol, 6 equiv) was added and the reaction mixture was al-
lowed to warm to –30 °C. The reaction mixture was then diluted by
the addition of sat. aq NH4Cl (2 mL). The biphasic mixture was parti-
Financial support by the DFG (HI628/12-1) is gratefully acknowl-
edged.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561614.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q

Q
M. Körner, M. Hiersemann
Paper
Synthesis
References
(19) Gritter, R. J.; Wallace, T. J. J. Org. Chem. 1959, 24, 1051.
(20) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
(1) Pouliot, M.; Jeanmart, S. J. Med. Chem. 2016, 59, 497.
(2) Wong, S. S. W.; Samaranayake, L. P.; Seneviratne, C. J. Drug Dis-
covery Today 2014, 19, 1721.
(3) Paulussen, C.; Boulet, G. A. V.; Cos, P.; Delputte, P.; Maes, L. J. R.
M. Drug Discovery Today 2014, 19, 1380.
(4) Morace, G.; Perdoni, F.; Borghi, E. J. Glob. Antimicrob. Resist.
2014, 2, 254.
(5) Favre-Godal, Q.; Dorsaz, S.; Queiroz, E. F.; Marcourt, L.;
Ebrahimi, S. N.; Allard, P.-M.; Voinesco, F.; Hamburger, M.;
Gupta, M. P.; Gindro, K.; Sanglard, D.; Wolfender, J.-L. J. Nat.
Prod. 2015, 78, 2994.
(21) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(22) Sabitha, G.; Syamala, M.; Yadav, J. S. Org. Lett. 1999, 1, 1701.
(23) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem.
Int. Ed. 2001, 40, 4700. (b) Abraham, L.; Körner, M.; Schwab, P.;
Hiersemann, M. Adv. Synth. Catal. 2004, 346, 1281. (c) Abraham,
L.; Körner, M.; Hiersemann, M. Tetrahedron Lett. 2004, 45. 3647.
(24) Yield and diastereoselectivity were significantly affected by the
scale of the reduction. Thus, the reduction was run in four sepa-
rated reaction vessels in parallel and then combined for workup.
See the experimental section for details.
(6) Myung, K.; Klittich, C. J. R. Drug Discovery Today 2015, 20, 7.
(7) Vengurlekar, S.; Sharma, R.; Trivedi, P. Pharmacogn. Rev. 2012, 6,
91.
(25) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(26) Seyferth, D.; Grim, S. O.; Read, T. O. J. Am. Chem. Soc. 1961, 83,
1617.
(8) Che, Y.; Gloer, J. B.; Wicklow, D. T. Org. Lett. 2004, 6, 49.
(9) Ferreira, E. L. F.; Williams, D. E.; Ioca, L. P.; Morais-Urano, R. P.;
Santos, M. F. C.; Patrick, B. O.; Elias, L. M.; Lira, S. P.; Ferreira, A.
G.; Passarini, M. R. Z.; Sette, L. D.; Andersen, R. J.; Berlinck, R. G.
S. Org. Lett. 2015, 17, 5152.
(10) For application of β,γ-branched δ,ε-unsaturated α-keto esters in
target-oriented synthesis, see: (a) Pollex, A.; Hiersemann, M.
Org. Lett. 2005, 7, 5705. (b) Stiasni, N.; Hiersemann, M. Synlett
2009, 2133. (c) Gille, A.; Hiersemann, M. Org. Lett. 2010, 12,
5258. (d) Becker, J.; Butt, L.; von Kiedrowski, V.; Mischler, E.;
Quentin, F.; Hiersemann, M. Org. Lett. 2013, 15, 5982.
(e) Becker, J.; Butt, L.; von Kiedrowski, V.; Mischler, E.; Quentin,
F.; Hiersemann, M. J. Org. Chem. 2014, 79, 3040.
(27) Usage of n-BuLi instead of LDA led to a product mixture.
(28) (a) Desai, N. B.; McKelvie, N.; Ramirez, F. J. Am. Chem. Soc. 1962,
84, 1745. (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13,
3769.
(29) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Müller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(30) Nakano, M.; Kikuchi, W.; Matsuo, J.-i.; Mukaiyama, T. Chem.
Lett. 2001, 30, 424.
(31) For the synthesis of (R)-12, see ref. 12a.
(32) Nagai, K.; Doi, T.; Sekiguchi, T.; Namatame, I.; Sunazuka, T.;
Tomoda, H.; Ōmura, S.; Takahashi, T. J. Comb. Chem. 2006, 8, 103.
(33) Fuganti, C.; Grasselli, P.; Servi, S.; Zirotti, C. Tetrahedron Lett.
1982, 23, 4269.
(34) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(11) (a) Körner, M.; Hiersemann, M. Org. Lett. 2007, 9, 4979.
(b) Körner, M.; Hiersemann, M. Synlett 2006, 121.
(12) (a) Paterson, I.; Lyothier, I. Org. Lett. 2004, 6, 4933. (b) Izzo, I.;
Scioscia, M.; Del Gaudio, P.; De Riccardis, F. Tetrahedron Lett.
2001, 42, 5421.
(13) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465.
(14) (a) Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. Tetrahedron
Lett. 1996, 37, 5477. (b) Park, M. H.; Takeda, R.; Nakanishi, K.
Tetrahedron Lett. 1987, 28, 3823.
(35) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
(36) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
(37) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963, 28,
1140.
(38) Panek, J. S.; Jain, N. F. J. Org. Chem. 1998, 63, 4572.
(39) One-pot procedure consisting of LDA-mediated elimination and
methylation resulted in incomplete conversion.
(15) (a) Tanaka, T.; Oikawa, Y.; Hamada, T.; Yonemitsu, O. Tetrahe-
dron Lett. 1986, 27, 3651. (b) Oikawa, Y.; Tanaka, T.; Horita, K.;
Yonemitsu, O. Tetrahedron Lett. 1984, 25, 5397. (c) Oikawa, Y.;
Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
(d) For selective silyl ether cleavage using NaIO4 in THF–H2O
(4:1), see: Li, J.; Menche, D. Synthesis 2009, 1904. (e) For the
DDQ-mediated oxidative cleavage of allylic silyl ethers to enals
and enones, see: Paterson, I.; Cowden, C. J.; Rahn, V. S.;
Woodrow, M. D. A. Synlett 1998, 915.
(40) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679.
(41) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. Rev. 2000, 100,
3257.
(42) For chemoselective DDQ-mediated PMB ether cleavage in the
presence of allylic silyl ethers, see: (a) Das, S.; Abraham, S.;
Sinha, S. C. Org. Lett. 2007, 9, 2273. (b) Lowe, J. T.; Wrona, I. E.;
Panek, J. S. Org. Lett. 2006, 9, 327. (c) Williams, D. R.; Walsh, M.
J.; Miller, N. A. J. Am. Chem. Soc. 2009, 131, 9038.
(16) Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975.
(17) We found that the E/Z selectivity heavily depends on the nature
of the reagent and the conditions. For instance, subjecting the
ynoate to a reagent prepared from MeLi (6 equiv) and CuI (3
equiv) in Et2O or THF at –78 °C and then at 0 °C led to the forma-
tion of the Z-configured enoate. Furthermore, using reagents
prepared from MeMgBr (3 equiv) and CuBr·SMe2 (4 equiv) or
MeMgBr (4 equiv) and CuI (3 equiv) led to inferior yields and E/Z
selectivities.
(43) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.
(44) (a) Miescher, K. Helv. Chim. Acta 1946, 29, 743. (b) Miescher, K.;
Kägi, H. Helv. Chim. Acta 1949, 32, 761. (c) Stahl, E.; Kaltenbach,
U. J. Chromatogr. 1961, 5, 351.
(45) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(46) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62,
7512.
(47) Decicco, C. P.; Grover, P. J. Org. Chem. 1996, 61, 3534.
(48) Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem. 1990, 55, 4986.
(18) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3,
2721.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Q