Studies towards the Synthesis of (-)-Pulvomycin: Construction of the C12-C40 Segment by a Stereoselective Aldol Reaction

Article abstract of DOI:10.1055/a-1464-2576

A convergent strategy was developed for the synthesis of the C12 C40 segment of ( )-pulvomycin. Key step was a diastereoselective aldol reaction between a chiral ethyl ketone representing the C24 C40 fragment and a chiral aldehyde representing the C12 C23

Full text of DOI:10.1055/a-1464-2576

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
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021, 53, A–Q
special topic
A
Dedicated to Prof. Sarah Reisman, recipient
Synthesis
S. Wienhold et al.
Special Topic
Studies towards the Synthesis of (–)-Pulvomycin: Construction of
the C12–C40 Segment by a Stereoselective Aldol Reaction
Sebastian Wienhold
Lukas Fritz
aldol Julia–Kocie n´ ski
reaction olefination
OTBDPS TBSO
Tatjana Judt
24
2
3
OTBDPS
MeO 40
Sabrina Hackl
O
12
O
SiEt
3
O
OH OTES
Thomas Neubauer
Bastian Sauerer
TBDPSO
OTES
OMe Stille cross-
aldol
reaction
coupling
Thorsten Bach*
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0
0
0
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0
0
0
2
-
1
3
4
2
-
0
2
0
2
Department Chemie and Catalysis Research Center (CRC), Technische
Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
thorsten.bach@ch.tum.de
Published as part of the Special Issue
dedicated to Prof. Sarah Reisman, recipient of the 2019 Dr. Margaret Faul Women in Chemistry Award
Corresponding Author
Received: 19.03.2021
Accepted: 25.03.2021
Published online: 25.03.2021
DOI: 10.1055/a-1464-2576; Art ID: ss-2021-m0156-st
OH
23
21
OH
MeO
HO
40
32
O
O
O
OH
O
O
O
1
12
OMe
Abstract A convergent strategy was developed for the synthesis of
the C12–C40 segment of (–)-pulvomycin. Key step was a diastereose-
lective aldol reaction between a chiral ethyl ketone representing the
C24–C40 fragment and a chiral aldehyde representing the C12–C23
fragment. Both compounds were prepared from enantiomerically pure
building blocks in a convergent fashion. The longest linear sequence
commenced with a known D-fucose-derived glycosyl donor and en-
tailed a total number of 16 steps. The desired anti-aldol product was ob-
tained in a total yield of 5% over these steps and contains 12 out of 13
stereogenic centers present in the natural product.
(
−)-pulvomycin (1)
5
OH
OTBDPS
26
MeO
TBDPSO
24
O
27
O
O
2
OMe
O
OTBPDS
OTES
Key words aldol reaction, alkenes, diastereoselectivity, natural prod-
ucts, polyketides, total synthesis
23
OTES
3
12
Scheme 1 Retrosynthetic disconnection of (–)-pulvomycin at the
indicated positions leading to putative building blocks 2 (C24–C40
fragment) and 3 (C12–C23 fragment) for the natural product
The natural product (–)-pulvomycin (1) was isolated in
957 by Zief et al. from an unidentified Streptomyces strain
1
and its antibiotic activity towards gram positive bacteria
was described. In 1963, Akita et al. isolated a compound
from Streptomyces albosporeus var. labilomyceticus which
1
6
and Groeger. In 2004, Parmeggiani and co-workers identi-
7
fied the binding site of pulvomycin at EF-Tu and, two years
they named labilomycin and which was later shown to be
identical to pulvomycin. Akita et al. managed to decipher
later, they solved the crystal structure of the natural prod-
2
uct in concert with EF-Tu and 5′-guanylyl imidodiphos-
8
the structure of some subunits of the natural product in-
cluding the carbohydrate (labilose) fragment but a complete
structure assignment was impossible.3 In 1978, it was
shown that the antibiotic activity of pulvomycin was due to
its binding to the bacterial elongation factor EF-Tu but the
phate (GDPNP). Although it is undisputable that the unique
binding mode of pulvomycin and its high potency against
many bacteria make the compound a promising target for
biological studies, its synthesis has remained elusive. Based
on our interest in the chemistry of EF-Tu inhibitors9 we
have some time ago embarked on a total synthesis of pulvo-
mycin. In an initial disconnection (Scheme 1) we identified
three bonds, the retrosynthetic cleavage of which led to
building blocks for the C1–C11 (not depicted), the C12–C23,
and the C24–C40 segment. The C24–C40 segment 2 was
4
mode of binding remained unknown. The complete struc-
ture of the compound except for the configuration at car-
bon atoms C32 and C33 was established in 1985 by thor-
5
ough mass spectrometry and NMR analysis. The biosyn-
thesis of the polyketide was unraveled in 1995 by Priestley
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synthesis
S. Wienhold et al.
Special Topic
previously described10 and it was meant to undergo an al-
dol reaction with aldehyde 3 as one of the key steps. How-
ever, it turned out that trienone 2 was not only unstable
upon storage but it also resisted the desired aldol reaction
in extensive test experiments with simple aldehydes. In ad-
dition, we became concerned that the facial diastereoselec-
tivity induced by the stereogenic centers of compound 3
might be insufficient to guarantee a high selectivity in the
key aldol reaction. In this paper, we describe the prepara-
tion of aldehyde 3 and its successful aldol reaction with a
C24–C40 building block which serves as a useful surrogate
of compound 2. Our synthetic efforts culminated in the ste-
reoselective synthesis of the C12–C40 segment of pulvomy-
cin.
center in the natural product. A syn-stereospecific Peterson
2
0
elimination was considered to be a viable pathway to re-
lease the double bond C26/C27 in the desired (E)-configura-
tion. To this end, it was required that the silyl group at car-
bon atom C27 was oriented syn to the TBSO group at the
1
2a
adjacent carbon atom. Based on these considerations, ke-
tone 4 (Figure 2) appeared to be a suitable building block
which promised a higher stability than 2, a clean formation
of the required (O)-E enolate, and a diastereoselective aldol
reaction. Since the western part of the compound was un-
changed as compared to 2, it was envisaged that an access
to the compound could be accomplished by a stereospecific
2
1
Stille cross-coupling that merges the respective olefin
building blocks to the desired 1,3-diene.
When searching for potential alternative compounds to
substitute trienone 2 as the C24–C40 fragment, we were
guided by the desire (a) to introduce a stereogenic center at
position C26 that induces a high diastereoselectivity in the
aldol reaction step11 and (b) to mask the double bond at
C26/C27 by an entity that would at a later stage allow its dia-
stereoselective formation.12 There was literature prece-
dence for anti-selective aldol reactions to occur from (O)-E
OTBDPS TBSO
MeO 40
24
•
•
bench stable
O
defined enolate
O
SiEt3 O
TBDPSO
Stille cross-
coupling
• stereocontrol
OMe
4
Figure 2 Ketone 4 as a surrogate for trienone 2 in a putative aldol reac-
tion with aldehyde 3
1
3
enolates which in turn were generated by treatment of
ethyl ketones with a combination of a boron reagent (e.g.
The synthesis of the C25–C29 segment of compound 4
commenced with the known epoxide 5 which was obtained
1
4
15
chlorodicyclohexylborane, Cy BCl) and an amine base or
2
2
2
a magnesium base, such as 2,2,6,6-tetramethylpiperidin-1-
ylmagnesium bromide (TMPMgBr).16 If the substituent in
the -position to the ketone carbonyl group was a protect-
ed hydroxy group, diastereofacial control was achieved via a
by Sharpless epoxidation from the respective (E)-config-
23
ured allylic alcohol (Scheme 2). Stereospecific S 2-type
N
ring opening of the epoxide required protection at the ter-
minal hydroxy group. Two protective group strategies
turned out to be viable, either employing the triethylsilyl
(TES) group, as shown, or the tetrahydropyranyl (THP)
group, as outlined in the Supporting Information (SI). TES
protection proceeded smoothly employing triethylamine as
stoichiometric base and 4-(dimethylamino)pyridine
17
preferred Zimmerman–Traxler-type transition state in
2
which the bulky R group points away from the aldehyde
1
5a,16a
(
1
Figure 1).
The enolate conformation is dictated by the
,3-allylic strain18 exerted by the enolate methyl group on
the -stereogenic center. The diastereofacial preference
matches the less pronounced Felkin–Anh preference exert-
ed by an -methyl-substituted aldehyde.19
2
4
(DMAP) as catalyst. Epoxide 6 was opened with an alumi-
num acetylide derived from trimethylsilyl (TMS) acetylene
in the presence of boron trifluoride.
2
5
R2
OTBS
R
TBSO
H
H
2
TBSO
Cy
TESCl, NEt3
O
26
Cy
Cy
O
R226
H
H
26
5 mol% DMAP
B
B
O
OH
OTES
O
Et
3
Si
5 (95% ee)
3
Et Si
O
2 R1
Cy
O
O
2 2
r.t. (CH Cl )
2
R1
R1
H
22
H
O
6
9
9%
(
O)-E enolate
preferred
TMS
0
, BuLi, AlMe
3
Figure 1 Control of the facial and simple diastereoselectivity in the re-
action of an -chiral aldehyde and an (O)-E enolate with an -tert-bu-
°C → r.t. (Et O);
2
TMS
Bu
OH
20 mol% AgNO
3
tyldimethylsilyloxy (TBSO) substituent (see refs1
5a,16a
then BF
3
2
·OEt , −78 °C
OTES r.t. (acetone/H
2
O, 4:1)
)
SiEt
3
78%
8
3%
7
3
SnH
Adapted to our situation, it was desirable for the enolate
component to display an -stereogenic center with (R)-con-
figuration at carbon atom C26. The stereogenic center
would force an attack at the prostereogenic carbonyl group
of the aldehyde to occur from the Re face. The configuration
at carbon atom C22 in the aldehyde part could not be freely
chosen but was determined by the configuration of this
10 mol% Pd
2 3
dba
OH
OH
2
9 mol% PCy
3
OH
i
Bu3Sn
OH
2
9 mol% Pr
2
NEt
0
°C (CH Cl )
2
2
SiEt
3
SiEt
3
8
9
5
9%
Scheme 2 Synthesis of alkenylstannane 9 from epoxide 5, which is
readily available by Sharpless epoxidation22
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

C
Synthesis
S. Wienhold et al.
Special Topic
The release of the TMS group and the cleavage of the
TES group in the presence of the elimination prone -si-
lylated alcohol 7 required careful optimization. Eventually,
catalytic quantities of silver nitrate26 in a 4:1 (v/v) mixture
of acetone and water turned out to be ideal and delivered
the desired diol 8 in 78% yield. An (E)-selective hydrostan-
nylation of the free alkyne was accomplished with tributyl-
stannane in the presence of catalytic quantities of
tris(dibenzylideneacetone)dipalladium (Pd dba ) and tricy-
Table 1 Optimization of the Stille Cross-Coupling between Alkenyl
Iodide 10 and Stannane 9
OTBDPS
1.50 equiv 9
MeO
30
I
catalyst, r.t. (solvent)
O
O
TBDPSO
1
0
OMe
OTBDPS
OH
OH
25
MeO
TBDPSO
2
3
O
O
SiEt3
2
7
clohexylphosphane (PCy3).
The sterically encumbered
11
OMe
phosphane ligand increases the regioselectivity by avoiding
a stannylation at the internal carbon atom.28 If palladium
with a less bulky substituent, e.g. Pd(PPh ) , was employed,
Entrya
Yield [%]b
Catalyst
t [h]
Solvent
3
4
1
2
20 mol% PdCl
2
(dppf)
16
21
DMF
DMF
62c
–c
the total yield decreased notably. Product 9 was free from
any diastereoisomers and was to be coupled in the next
step with an appropriate (E)-alkenyl iodide representing
the western half of building block 4. Previous studies had
shown that iodide 10 can be readily obtained from an (S)-
lactate-derived aldehyde and a D-fucose-derived glycosyl
donor in nine steps.10 By modifying the final two steps of
the sequence (hydrostannylation and iodo-de-stannylation)
an overall yield of 18% was achieved for the complete se-
quence. Optimization of the Stille cross-coupling between
iodide 10 and stannane 9 commenced by using [1,1′-bis(di-
10 mol% Pd
2
dba
3
3
3
3
4
0 mol% P(2-furyl)
3
3
4
5
6
10 mol% Pd
2
dba
16
17
21
DMF
DMF
DMF
69c
–c
4
0 mol% PCy
3
10 mol% Pd
2
dba
2
0 mol% dppe
10 mol% Pd dba
20 mol% dppp
2
55c
–c
20 mol% PdCl
2
2
(dppf)
(dppf)
16
16
dioxane
MeCN
7
20 mol% PdCl
88
a
The reaction was performed under exclusion of light by stirring the reac-
phenylphosphino)ferrocene]dichloropalladium [PdCl (dp-
2
tion mixture for the indicated period of time t at ambient temperature.
pf)] as the catalyst in DMF as the solvent29 (Table 1, entry 1).
The desired cross-coupling (62% yield) was accompanied by
a notable Peterson elimination. Applying conditions de-
b
Yield of isolated product after column chromatography.
For additional information, see the narrative.
c
3
0
OTBDPS
PGO
scribed by Farina and Krishnan did not facilitate a signifi-
cant conversion (entry 2). A variation of the ligand in DMF
as the solvent led to a successful cross-coupling in all cases
TESCl
26
OTES
25
MeO
2,6-lutidine
78 °C (CH2Cl2)
O
−
O
SiEt3
TBDPSO
1
1
OMe
12 PG = H
13 PG = TBS
(
entries 3–5) but Peterson elimination was inevitable with
9
2%
PCy and 1,2-bis(diphenylphosphino)ethane (dppe) as the
TBSOTf, py
0 °C → r.t. (CH Cl )
3
3
1
ligand. In the latter case (entry 4), the elimination went to
completion (94% yield of the respective triene) and the de-
sired product 11 was not observed. With 1,3-bis(diphenyl-
phosphino)propane (dppp), diene 11 was obtained in 55%
yield (entry 5). Eventually, a solvent variation helped to
overcome the elimination issue.32 While the use of Pd-
2
2
9
3%
(COCl)2
DMSO, NEt3
78 °C → r.t.
OTBDPS TBSO
EtMgBr
CeCl3
−
O
MeO
(
CH2Cl2)
0 °C (THF)
O
O
SiEt3
TBDPSO
1
4
84%
84%
OMe
Cl (dppf) in dioxane gave no product (entry 6), acetonitrile
2
OTBDPS TBSO
2 3
(COCl) , DMSO, NEt
turned out to be the solvent of choice (entry 7) delivering
reproducibly high yields of the desired (E,E)-1,3-diene 11.
The conversion of diol 11 into fragment 4 commenced
with a selective protection of the primary hydroxy group at
the terminal carbon atom C25 (Scheme 3).33 Treatment
with TESCl in the presence of 2,6-lutidine furnished pro-
tected intermediate 12 which was taken into the second si-
lyl protection step (PG = protecting group), now at carbon
atom C26. The TBS group was installed by treatment with
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf)
25
MeO
−78 °C → r.t. (CH2Cl2)
O
4
O
SiEt3 OH
87%
TBDPSO
1
5
OMe
Scheme 3 Conversion of Stille cross-coupling product 11 into chiral
ketone 4 (C24–C40 fragment)
pound36 and the sequence was completed by another Swern
oxidation (15 → 4).
The synthesis of the C12–C23 building block 3 followed
a convergent synthesis strategy according to which the
C19–C23 fragment was to be coupled with a C12–C18 alde-
hyde by an (E)-selective Julia–Kocieński olefination.37 The
two stereogenic centers were introduced by the Evans aldol
3
4
in the presence of pyridine. The known lability of the TES
group under Swern oxidation conditions35 allowed to con-
vert compound 13 directly into aldehyde 14. The ethyl
group was favorably introduced via the ethyl cerium com-
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

D
Synthesis
S. Wienhold et al.
Special Topic
reaction38 of N-propionyloxazolidinone 16 with 3-(benzyl-
plished with diisobutylaluminum hydride (DIBAL-H) in di-
chloromethane. The terminal hydroxy group was temporar-
3
9
oxy)propanal. The required (O)-Z enolate was generated
by treatment of the CH-acidic fragment with dibutylboron
triflate and Hünig’s base.40 Upon addition of the aldehyde
the mixture was warmed to room temperature and the de-
sired syn-aldol product 17 was obtained with perfect ste-
reocontrol. After TES protection of the free hydroxy group
51
ily protected with an acetyl group before releasing the
52
acetonide group from intermediate 29. The resulting diol
30 was selectively TES-protected at the primary position by
3
3
treatment with TESCl and 2,6-lutidine. In a subsequent
step, the more robust TBDPS group was introduced to pro-
tect the free secondary alcohol 31. The temporary acetyl
protecting group at the C18 alcohol was released by reduc-
tion of the acetate 32 with DIBAL-H and the resulting alco-
hol 33 was oxidized to aldehyde 34 with manganese diox-
41
at C21 the chiral auxiliary was reductively removed from
3
9e
compound 18. Alcohol 19 was isolated in 84% yield and
the chiral oxazolidinone was recovered in 91% yield
(
Scheme 4).
53
ide. With this building block in hand the Julia–Kocieński
i
37a
Bu2BOTf, Pr2NEt, 0 °C;
olefination
was performed employing potassium hexa-
O
O
O
O
O
O
then
OBn
methyldisilazanide (KHMDS) as the base. Deprotonation of
the sulfone 24 was accomplished at –78 °C in THF as the
solvent. After warming the reaction mixture to –40 °C, the
aldehyde 34 was added as a solution in THF. The desired
triene 35 was isolated as a mixture of diastereoisomers
with the desired (E,E,E)-diastereoisomer prevailing. The dia-
stereomeric ratio (d.r.) of 35 relative to its diastereoisomers
was d.r. ≅ 90:10. In order to generate the aldehyde group at
C18 of 3 for the key aldol reaction, the pivaloyl group was
removed by reduction and the resulting alcohol 36 was oxi-
2
1
OHC
N
OBn
N
22
−
78 °C → r.t. (CH2Cl2)
Bn
Bn
OPG
1
6
97%
TESCl
imidazole
r.t. (DMF)
1
1
7 PG = H
8 PG = TES
NaBH4, r.t.
93%
PGO
OBn
(
THF/H2O)
PivCl, pyridine
10 mol% DMAP
r.t. (CH2Cl2)
1
2
9 PG = H
0 PG = Piv
OTES
8
4%
quant.
Ph
N
H2 (1 bar)
Pd(OH)2/C
r.t. (EtOAc)
PPh3, DIAD, HS
°C (THF)
PivO
OH
0
N
54
2
2
N
dized with the Dess–Martin periodinane (DMP) in di-
N
OTES
21
chloromethane (Scheme 5).
8
6%
91%
Attempts to generate the enolate from ketone 4 with a
boron reagent and a weak amine base remained unsuccess-
mCPBA
NaHCO3
Ph
O
S
O
Ph
PivO
S
PivO
N
N
r.t. (CH2Cl2)
ful. Further deprotonation and optimization experiments
N
23
19
N
OTES
N
OTES
N
16b,c,55
N
85%
N
were mainly performed with a TMP base.
Table 2
2
3
24
shows a selection of the results and additional results are
summarized in the Supporting Information. In the optimi-
zation experiments, both the aldol product and its O-bory-
Scheme 4 Synthesis of 5-sulfonyltetrazole 24 from chiral, enantiomer-
ically pure N-propionyloxazolidinone 16
56
lated derivative were isolated. The combined yield for the
two products is given. Attempts to release the free aldol
product from the borylated intermediate are described in
the next paragraph. While the initial experiment to involve
the resulting magnesium enolate directly in an aldol reac-
Since the outcome of the Evans aldol reaction is highly
3
8
predictable and has been extensively verified the absolute
and relative configuration of alcohol 19 was not proven. In-
stead, the free primary hydroxy group was protected as
pivalate 20. The pivaloyl (Piv) protecting group was chosen
to attain orthogonality with the other protecting groups of
5
7
tion led to a mixture of diastereomeric aldol products
combined with other impurities (entry 1), the reaction
showed more promise if a transmetalation to boron was
performed. The reaction with dibutylboron triflate already
led to a major diastereoisomer but the d.r. was unsatisfacto-
ry (entry 2). Transmetalation to the bulkier dicyclohexylbo-
4
2
the molecule. The removal of the benzyl group was per-
formed by hydrogenolysis in the presence of Pearlman’s
catalyst and delivered alcohol 21.4 The subsequent trans-
formation to the 5-sulfonyltetrazole 24 included a Mitsuno-
3
4
4
bu reaction with thiol 22 and an oxidation of intermediate
ron (Cy B) group gave mainly two diastereomeric products
2
2
3 with meta-chloroperbenzoic acid (mCPBA).45 Oxidation
in a ratio of 78:22 (entry 3). The yield improved when the
reaction was performed at 0 °C (entry 4) and a variation of
the stoichiometry (entry 5) resulted in an acceptable yield
of the aldol product. It was found that the base TMPMgBr
which had to be freshly prepared in every reaction could be
substituted by the commercially available TMPMgCl·LiCl
complex (entry 6). In order to increase the diastereoselec-
tivity of the aldol reaction a chiral boron fragment was in-
stalled at the enolate oxygen atom. (–)-Chlorodiisopino-
46
attempts with H O and ammonium molybdate induced
2
2
an undesired cleavage of the TES ether at carbon atom
4
7
C21.
The assembly of the C12–C18 fragment required the in-
troduction of the stereogenic center at C13 with (S)-config-
uration. Protected glyceraldehyde 26 was selected as a
building block which is readily available from the chiral
4
8
pool. A vinylogous Horner–Wadsworth–Emmons reaction
14c,58
with phosphonate 25 delivered the known ,,,-unsatu-
campheylborane [(–)-Ipc BCl]
turned out to be the re-
2
4
9
50
rated ester 27. Reduction to alcohol 28 was accom-
agent of choice and delivered, to our delight, a single aldol
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

E
Synthesis
S. Wienhold et al.
Special Topic
LDA
78 °C → r.t.
DIBAL-H
−78 °C
O
−
70 °C
O
O
O
O
(THF)
O
O
(CH2Cl2)
O
O
(HOAc/H O, 4:1)
+
O
O 18
PGO
2
PO(OEt)2
65%
12
quant.
2
5
26
27
2
2
8 PG = H
9 PG = Ac
Ac2O, NEt3, 10 mol% DMAP
0 °C → r.t. (CH2Cl2)
TESCl
,6-lutidine
9
5%.
2
TBDPSCl
−
78 °C → r.t
CH2Cl2)
NEt3, DMAP
0 °C → r.t. (DMF)
18
DIBAL-H, −78 °C
OH
OH
(
OH
OTBDPS
OTES
(CH2Cl2)
AcO
AcO
AcO
6
3% (2 steps)
98%
96%
3
0
31
OTES
32
2
4, KHMDS
DIBAL-H, −78 °C
MnO2, r.t.
CH2Cl2)
−78 °C (THF)
then 34, −40 °C PivO
(
CH2Cl2/PhMe)
(
OTBDPS
OTES
OTBDPS
OTBDPS
OTES
HO
HO
O
23
9
4%
91%
OTES
92%
3
3
34
OTES
35
1
. DMP, NaHCO3
OTBDPS TBSO
r.t. (CH2Cl2)
23
21
OTBDPS
OTES
OTBDPS
OTES
MeO 40
24
2
. see Table 2
O
OTES
O
SiEt3 O
OH OTES
TBDPSO
3
6
OMe
37
Scheme 5 Synthesis of aldehyde 3 starting from phosphonate 25 and protected glyceraldehyde 26, and the product 37 of its aldol reaction with
ketone 4
product albeit in low yield (entry 7). The yield was im-
proved when the reaction was warmed to room tempera-
ture once the addition of aldehyde was complete (entry 8).
A decrease of the relative quantities for base, borane, and al-
dehyde 3 led to a decrease in yield (entry 9) but was more
economical regarding the used aldehyde.
yield based on conversion reached an acceptable value of
63%. The C12–C23 fragment was not recovered as aldehyde
3 but as alcohol 36 which can be explained by the known5
8a
reductive properties of (–)-Ipc BCl. The recovery yield of
2
the alcohol was 67% which compensated at least in part for
the fact that the aldehyde was used in excess.
Several methods were probed to release the boron frag-
ment from the product and it turned out that the use of 8-
The relative configuration of product 37 was elucidated
in two steps. In the first step, the relative configuration be-
tween the newly formed stereogenic centers at C23 and
C24 was established. In the second step, the known abso-
lute configuration at C21 was used as a handle to decipher
the configuration at C23. Based on the assumption that ke-
tone 4 forms the (O)-E enolate, the Zimmerman–Traxler
5
9
hydroxyquinoline in dichloromethane/methanol
was
most efficient. No loss of aldol product was observed and it
was possible (conditions of entry 9) to reproducibly isolate
4
0% of aldol product 37. In addition, it was possible to re-
isolate ketone 4 in 37% yield which in turn means that the
Table 2 Optimization of the Aldol Reaction between Chiral Ketone 4 and Aldehyde 3 (see Scheme 5)
b
d.r.c
n.d.d
Entry
3 (equiv)
Base (equiv)
Borane (equiv)
–
Tempa
Yield [%]
1
2
3
4
5
6
7
8
2.2
1.6
2.5
2.0
1.8
1.8
3.0
3.0
2.5
TMPMgBr (2.2)
0 °C
40
30
27
43
49
38
35
55
40
TMPMgBr (1.6)
Bu
2
BOTf (1.6)
BCl (4.0)
BCl (3.0)
BCl (2.5)
BCl (2.6)
0 °C → r.t.
–30 °C → 0 °C
0 °C
65:19:16
78:22
89:11
86:14
88:12
>95:5
TMPMgBr (2.5)
Cy
Cy
Cy
Cy
2
2
2
2
TMPMgBr (2.0)
TMPMgBr (2.4)
0 °C
TMPMgCl·LiCl (2.0)
TMPMgCl·LiCl (1.8)
TMPMgCl·LiCl (2.5)
TMPMgCl·LiCl (2.0)
0 °C
(–)-Ipc
(–)-Ipc
(–)-Ipc
2
2
2
BCl (2.0)
BCl (2.5)
BCl (2.0)
0 °C
0 °C → r.t.
0 °C → r.t.
>95:5
9
>95:5
a
Temperature for enolization and addition of borane and aldehyde 3. If the reaction mixture was warmed subsequently, the final temperature is given. All reac-
tions were performed in THF as the solvent. For further details, see the Supporting Information.
b
Yield as sum of free and O-borylated aldol product. For recovered ketone 4 and further details, see the Supporting Information.
The diastereomeric ratio was determined by H NMR analysis.
n.d. = not determined.
c
1
d
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

F
Synthesis
S. Wienhold et al.
Special Topic
transition state17 (Figure 1) suggests formation of the anti-
aldol product. The hydrogen bond between the -hydroxy
and the keto group of the aldol induces a preferred confor-
mation in which the hydrogen atoms at the - and -carbon
The carbon atoms of the two methyl groups in the 1,3-
dioxane ring (marked as •) resonate at distinctly different
6
5
field if the dioxane is derived from a syn-1,3-diol. The two
1
equatorial groups R and R stabilize a preferred ring con-
atoms are antiperiplanar for anti-aldol and synclinal for
former and avoid a change of position from axial to equato-
rial for the methyl group. In stark contrast, the dioxane ring
derived from an anti-1,3-diol is conformationally flexible
and the two methyl groups do not significant differ in their
3
syn-aldol products. As a result, J coupling constants be-
HH
tween these hydrogen atoms are large in anti- and small in
syn-aldol products.60 A second indication is the C NMR
chemical shift of the methyl group at the -carbon atom
13
1
3
C NMR resonance. For compound 38, it was found that the
6
1
13
which is larger in anti-aldol than in syn-aldol products.
axial methyl group displayed a C NMR chemical shift of 1
6
2
Typical values from literature reports are provided in Fig-
ure 3. In aldol product 37 the 3JHH coupling constant be-
tween - and -hydrogen atoms of the aldol subunit, corre-
= 19.4 and the equatorial methyl group resonated at  =
2
29.9. The results support the assumed absolute and relative
configuration of aldol product 37 which bears twelve (out
of 13) stereogenic centers required for the natural product.
In summary, a C12–C40 segment of (–)-pulvomycin has
been assembled in a convergent and stereoselective fashion.
The masked double bond at C26–C27 renders the com-
pound stable towards degradation and isomerization. The
envisaged Peterson elimination has been attempted with
ketone 4 (tetrabutylammonium fluoride in THF) and deliv-
sponding to the hydrogen atoms in positions C24 and C23,
3
was J = 9.7 Hz. The methyl group at C24 resonated at  =
HH
1
3.8 in the 13C NMR spectrum. Both values are in perfect
agreement with an anti-relationship of the methyl group at
C23 and the hydroxy group at C24 substantiating the ex-
pected outcome of the aldol reaction, at least regarding the
relative product configuration.
1
0
ered cleanly (E,E,E)-trienone 2 in 81% yield. The comple-
tion of the total synthesis requires to attach a C1–C11 frag-
ment at carbon atom C12 prior to macrocyclization. The
proper handling of the protective groups will be of pivotal
importance for a successful completion of the synthesis.
3JHH = 9.7 Hz
3JHH = 6–9 Hz
3JHH = 1–3 Hz
vs.
TBSO
PGO
PGO
H
H
H
O
H
H
O
H
2
1
R1
R1
R
R
SiEt3 O
OH OTES
OH
OH
δ = 13.8 ppm (13C)
δ = 13.4–14.8 ppm (13C) δ = 7.9–9.3 ppm (13C)
anti aldol syn aldol
3
7
Thin-layer chromatography (TLC) was performed on silica-coated
glass plates (silica gel 60 F254) with detection by UV ( = 254 nm).
Flash column chromatography (FCC) was performed on silica gel 60
(Merck, 230–400 mesh) with the indicated eluent. Common solvents
Figure 3 Proof of the relative configuration at the aldol bond C23 and
C24 by NMR analysis. The product exhibits an anti configuration of the
methyl group at C24 and the hydroxy group at C23.
for chromatography (pentane, Et O, EtOAc) were distilled prior to use.
2
Solutions refer to saturated aqueous solutions unless otherwise stat-
ed. All melting points were determined using a Büchi M 565 melting
point apparatus, with a range quoted to the nearest integer. IR spectra
were recorded on a JASCO IR-4100 instrument (ATR). HRMS measure-
ments were performed on a Thermo Scientific LTQ-FT Ultra or a high-
resolution Thermo Scientific Exactive Plus Orbitrap mass spectrome-
The structure proof for the correct relative configura-
tion of the newly formed stereogenic centers to the existing
stereogenic centers was based on the known NMR data of
1
,3-dioxanes that are obtained from 1,3-diols. Successive
6
3
treatment of aldol product 37 with HF-pyridine to release
1
13
19
ter (ESI). H, C, and F NMR spectra were recorded at 303 K either
on a Bruker AVHD 300, AVHD 400, or AVHD 500 spectrometer. NMR
spectra were calibrated to the respective residual solvent signals of
the TES group and with 2-methoxypropene to generate the
6
4
dioxane ring delivered product 38. The C12 hydroxy group
of 38 was protected as an acetone acetal and the dioxane
ring was established between the two hydroxy groups at
C21 and C23 (Figure 4).
1
13
CDCl [ ( H) = 7.26,  ( C) = 77.16]. Apparent multiplets that occur as
3
a result of the accidental equality of coupling constants to those of
magnetically non-equivalent protons are marked as virtual (virt.). As-
signments are based on COSY and HMBC experiments.
OTBPDS TBSO
2
3
21
H
H
R
H
OTBPDS
OMe
H
O
MeO
H
O
R1
O
vs.
R1
O
R
O
SiEt3 O
O
O
12
H
TBPDSO
O
O
syn
anti
OMe
3
8
δ1 = 19.4 ppm
δ2 = 29.9 ppm
δ1 = 18.5–20.0 ppm
δ2 = 29.6–30.4 ppm
δ1 ≈ δ2 = 23.8–25.6 ppm
Figure 4 Proof of the relative configuration at carbon atoms C21 and C23. Dioxane 38 displays two magnetically non-equivalent methyl groups at the
acetal carbon atom the 1 C NMR chemical shifts of which are significantly different. The chemical shift difference in turn stems from the stable chair
conformation expected for an acetal derived from a 1,3-syn-diol.65
3
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

G
Synthesis
S. Wienhold et al.
Special Topic
Silyl-Protected Epoxy Alcohol 6
Pentyne-1,2-diol 8
To a solution of epoxide 5 (1.00 g, 5.31 mmol, 1.00 equiv) in CH Cl2
The reaction was carried out in a brown glass flask. To a solution of
2
(
23 mL) were added NEt (1.10 mL, 806 mg, 7.96 mmol, 1.50 equiv),
alkyne 7 (10.3 g, 25.7 mmol, 1.00 equiv) in acetone (200 mL) was add-
3
DMAP (32.5 mg, 265 mol, 5 mol%) and TESCl (1.07 mL, 960 mg, 6.37
ed a solution of AgNO (873 mg, 5.14 mmol, 0.20 equiv) in water (46
3
mmol, 1.20 equiv). After stirring at r.t. for 3 h, sat. aq NH Cl solution
mL). The suspension was stirred for 18 h at r.t. and was then poured
into sat. aq NaCl solution (70 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (4 × 25 mL). The organic lay-
ers were combined, dried (Na SO ), and filtered. The solvent was re-
4
(20 mL) was added. The layers were separated and the aqueous layer
was extracted with CH Cl (2 × 20 mL). The organic layers were com-
2
2
bined, dried (Na SO ), and filtered. The solvent was removed under
2
4
2
4
reduced pressure. Following flash column chromatography (silica,
moved under reduced pressure. Following flash column chromatogra-
pentane/Et O, 100:1), silyl-protected alcohol 6 was obtained as a col-
phy (silica, pentane/Et O 2:1 → 1:1), diol 8 was obtained as a colorless
2
2
orless oil (1.59 g, 99%).
oil (4.29 g, 78%).
R = 0.82 (pentane/Et O, 20:1) [UV, KMnO ].
R = 0.45 (pentane/Et O, 1:2) [KMnO ].
f
2
4
f
2
4
IR (ATR): 2954 (s), 2912 (m), 2877 (s, Csp3–H), 1459 (w, C–H), 1094
(
IR (ATR): 3372 (br s), 3313 (vs, O–H), 2953 (vs), 2912 (s), 2876 (vs,
vs), 1006 cm–1 (vs, C–O).
Csp3–H), 2099 (w, C≡C), 1458 (m), 1416 (m, O–H), 1239 (m), 1017 (vs,
–
1
1
C–O), 720 cm (vs).
H NMR (300 MHz, CDCl ):  = 0.57–0.66 [m, 12 H, Si(CH CH ) ,
3
2
3
3 3
3
1
OSi(CH CH ) ], 0.96 [t, J = 7.9 Hz, 9 H, OSi(CH CH ) ], 0.98 [t, J = 7.9
H NMR (400 MHz, CDCl ):  = 0.68–0.77 [m, 6 H, Si(CH CH ) ], 1.00 [t,
2
3
3
2
3
3
3
2
3 3
3
3
4
Hz, 9 H, Si(CH CH ) ], 2.13 (d, J = 3.6 Hz, 1 H, CH-27), 2.99 (virt. dt,
J = 7.7 Hz, 9 H, Si(CH CH ) ], 2.06 (d, J = 2.9 Hz, 1 H, CH-29), 2.10–
2
3
3
2 3 3
3
3
3
2
3
3
J = 5.4 Hz, J ≅ J = 3.5 Hz, 1 H, CH-26), 3.60 (dd, J = 11.6 Hz, J = 5.4
2.15 (m, 2 H, CH-27, CH-26–OH), 2.44 (d, J = 6.1 Hz, 1 H, CH -25–OH),
2
2
3
Hz, 1 H, CHH-25), 3.84 (dd, J = 11.6 Hz, J = 3.3 Hz, 1 H, CHH-25).
13C
NMR (75 MHz, CDCl ): 2.0 [t, Si(CH CH ) ], 4.6 [t,
OSi(CH CH ) ], 6.9 [q, OSi(CH CH ) ], 7.4 [q, Si(CH CH ) ], 47.0 (d, CH-
3.66–3.74 (m, 1 H, CHH-25), 3.81–3.89 (m, 2 H, CHH-25, CH-26).

=
13C NMR (101 MHz, CDCl ):
 = 3.3 [t, Si(CH CH ) ], 7.6 [q,
3
2
3
3
3
2
3
3
Si(CH CH ) ], 21.8 (d, CH-27), 66.5 (t, CH -25), 71.3 (d, CH-29), 72.1
2
3
3
2
3
3
2
3
3
2
3
3
2
2
7), 56.0 (d, CH-26), 65.9 (t, CH -25).
(d, CH-26), 83.0 (s, C-28).
HRMS-ESI: m/z [C11H22O Si – H O] calcd: 196.1294; found: 196.1279.
2
HRMS-ESI: m/z [C15H34O Si + MeCN + H]+ calcd: 344.2435; found:
+
2
2
2
2
344.2435.
Stannylated Pentene-1,2-diol 9
TMS-Protected Alkynol 7
To a solution of trimethylsilylacetylene (19.2 mL, 13.2 g, 117 mmol,
.00 equiv) in Et O (240 mL) were added BuLi (56.2 mL, 2.4 M in hex-
The reaction was carried out in a brown glass flask. To a solution of
Pd dba ·CHCl (2.75 g, 2.66 mmol, 0.10 equiv) in CH Cl2 (200 mL)
2
3
3
2
i
3
were added PCy ·HBF4 (2.87 g, 7.78 mmol, 0.29 equiv) and Pr NEt
2
3
2
ane, 135 mmol, 3.00 equiv) and AlMe (65.2 mL, 2.0 M in hexane, 130
(2.65 mL, 2.01 g, 15.6 mmol, 0.58 equiv). The red solution was stirred
for 1 h at r.t. A solution of alkynediol 8 (5.70 g, 26.6 mmol, 1.00 equiv)
in CH Cl (40 mL) was added and the reaction was cooled to 0 °C. Sub-
3
mmol, 2.90 equiv) at 0 °C. The reaction was warmed to r.t. and stirred
for 1 h before epoxide 6 (13.6 g, 45.0 mmol, 2.00 equiv) was added as
a solution in Et O (50 mL). After cooling to –78 °C, BF ·OEt (11.4 mL,
2
2
sequently, Bu SnH (9.86 mL, 10.8 g, 37.2 mmol, 1.40 equiv) was added
2
3
2
3
12.8 g, 89.9 mmol, 2.00 equiv) was added and the mixture was stirred
and the reaction was stirred for another 15 h at 0 °C. The reaction was
for 16 h at –78 °C. MeOH was added (138 mL) and the reaction was
stirred at 0 °C for 1 h. Subsequently, aq pH 10 buffer (240 mL) was
added, and stirring at 0 °C was continued for an additional 1 h. The
quenched by the addition of sat. aq NH Cl solution (300 mL) and the
4
layers were separated. The aqueous layer was extracted with CH Cl
2
2
(4 × 250 mL). The organic layers were combined, dried (Na SO ), and
2
4
layers were separated and the aqueous layer was extracted with Et O
filtered. The solvent was removed under reduced pressure. Following
2
(
2 × 250 mL). The organic layers were combined, dried (Na SO ), and
flash column chromatography (silica, pentane/Et O 5:1), stannane 9
2
4
2
filtered. The solvent was removed under reduced pressure. Following
was obtained as a colorless oil (7.93 g, 59%).
flash column chromatography (silica, pentane/Et O, 100:1 → 50:1),
2
R = 0.57 (pentane/Et O, 1:1) [UV, KMnO ].
f
2
4
alkyne 7 was obtained as a colorless oil (15.0 g, 83%).
R = 0.73 (pentane/Et O, 20:1) [KMnO ].
IR (ATR): 3364 (br m, O–H), 2954 (vs), 2925 (vs), 2873 (s, Csp3–H),
1584 (w, C=C), 1458 (m, Csp3–H), 1417 (w, O–H), 1376 (w, Csp3–H),
1239 (w, C–O), 1089 (m), 1017 cm–1 (m, C–O).
f
2
4
IR (ATR): 3549 (w), 2954 (vs), 2912 (s), 2877 (vs, Csp3–H), 1459 (w, C–
–
1
H), 1094 (vs), 1006 cm (vs, C–O).
1
3
H NMR (500 MHz, CDCl ):  = 0.63 [q, J = 7.9 Hz, 6 H, Si(CH CH ) ],
3
2
3 3
1
3
H NMR (400 MHz, CDCl ):  = 0.11 [s, 9 H, Si(CH ) ], 0.57–0.68 [m, 6
0.84–0.87 {m, 6 H, Sn[CH (CH ) CH ] }, 0.89 {t, J = 7.3 Hz, 9 H,
3
3
3
2 2 2 3 3
3
3
H, OSi(CH CH ) ], 0.69–0.77 [m, 6 H, Si(CH CH ) ], 0.95–1.03 [m, 18 H,
Sn[(CH ) CH ] }, 0.96 [t, 9 H, J = 7.9 Hz, Si(CH CH ) ], 1.30 {virt. h, J ≅
2 3 3 3 2 3 3
2
3
3
2
3
3
3
3
Si(CH CH ) , OSi(CH CH ) ], 2.06 (d, J = 9.5 Hz, 1 H, CH-27), 2.57 (d,
J
=
7.3 Hz,
6 H, Sn[(CH ) CH CH ] }, 1.45–1.51 [m, 6 H,
2
3
3
2
3
3
2 2 2 3 3
3
2
3
J = 4.6 Hz, 1 H, OH), 3.61 (dd, J = 9.8 Hz, J = 6.7 Hz, 1 H, CHH-25),
.74–3.83 (m, 1 H, CH-26), 3.90 (dd, J = 9.8 Hz, J = 2.9 Hz, 1 H, CHH-
Sn(CH CH CH CH ) ], 1.85 (br s, 1 H, CH -25–OH), 2.01 (br s, 1 H, CH-
2
2
2
3
3
2
2
3
3
3
2
3
26–OH), 2.06 (virt. t, J ≅ J = 9.0 Hz, 1 H, CH-27), 3.45 (ddd, J = 11.0
Hz, J = 7.8, 4.5 Hz, 1 H, CHH-25), 3.72 (ddd, J = 11.0 Hz, J = 7.2, 2.9
Hz, 1 H, CHH-25), 3.90 (dddd, J = 9.0 Hz, 7.8, 6.2, 2.9 Hz, 1 H, CH-26),
3
2
3
25).
3
1
3
C NMR (101 MHz, CDCl ):  = 0.3 [q, Si(CH ) ], 3.5 [t, Si(CH CH ) ],
3
3
3
2
3 3
5
.74–5.84 (m, 2 H, CH-28, CH-29).
13C NMR (101 MHz, CDCl ):
 = 3.5 [t, Si(CH CH ) ], 7.8 [q,
2 3 3
4
.6 [t, OSi(CH CH ) ], 6.9 [q, OSi(CH CH ) ], 7.7 [q, Si(CH CH ) ], 22.3
2 3 3 2 3 3 2 3 3
(
d, CH-27), 66.8 (t, CH -25), 72.3 (d, CH-26), 86.7 (s, C-29), 106.3 (s, C-
2
3
28).
Si(CH CH ) ], 9.7 {t, Sn[CH (CH ) CH ] }, 13.9 {q, Sn[(CH ) CH ]}, 27.4
2 3 3 2 2 2 3 3 2 3 3
+
{t, Sn[(CH
) CH CH ] }, 29.4 [t, Sn(CH CH CH CH ) ], 42.6 (d, CH-27),
2 2 2 3 3 2 2 2 3 3
HRMS-ESI: m/z [C20H44O Si + H] calcd: 401.2722; found: 401.2721.
2
3
6
7.1 (t, CH -25), 72.8 (d, CH-26), 128.9 (d, CH-29), 146.0 (d, CH-28).
2
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

H
Synthesis
S. Wienhold et al.
Special Topic
3
3
Glycoside Diol Fragment 11
Hz, 1 H, CH-38), 2.87 (q, J = 6.4 Hz, 1 H, CH-39), 3.11 (dd, J = 9.6, 7.7
2
3
Hz, 1 H, CH-36), 3.17 (s, 3 H, CH-36–OCH ), 3.30 (dd, J = 9.9 Hz, J =
.4 Hz, 1 H, CHH-25), 3.39 (s, 3 H, CH-38–OCH ), 3.43–3.52 (m, 3 H,
CH-33, CH-35, CH-37), 3.63 (dd, J = 9.9 Hz, J = 2.9 Hz, 1 H, CHH-25),
.75–3.80 (m, 1 H, CH-26), 4.25–4.27 (m, 1 H, CH-32), 5.36 (dd, J =
The reaction was carried out in a brown glass flask. To a solution of
3
7
PdCl (dppf) (392 mg, 535 mol, 0.20 equiv) in MeCN (10 mL) was
3
2
2
3
added a solution of stannane 9 (2.03 g, 4.01 mmol, 1.50 equiv) in
MeCN (15 mL). Vinyl iodide 10 (2.35 g, 2.68 mmol, 1.00 equiv) was
added and the reaction was stirred at r.t. for 16 h. The solvent was re-
moved under reduced pressure and the residue was purified by col-
3
3
1
3
5.0, 10.3 Hz, 1 H, CH-28), 5.55 (dd, J = 15.2, 6.3 Hz, 1 H, CH-31), 5.85
(
dd, 3J = 15.0, 10.4 Hz, 1 H, CH-29), 6.00 (dd, 3J = 15.2, 10.4 Hz, 1 H,
CH-30), 7.27–7.45 (m, 12 H, CHAr), 7.60–7.65 (m, 4 H, CHAr), 7.72–7.75
umn chromatography (silica, pentane/Et O 2:1 → 1:1), to afford diol
2
(
m, 4 H, CHAr).
1
1 as a yellowish oil (2.27 g, 88%).
1
3
C NMR (101 MHz, CDCl ):  = 3.6 [t, CHSi(CH CH ) ], 4.5 [t,
OSi(CH CH ) ], 6.9 [q, OSi(CH CH ) ], 7.8 [q, CHSi(CH CH ) ], 15.6 (q,
CH -34), 16.7 (q, CH -40), 19.4 [s, C(CH ) ], 19.6 [s, C(CH ) ], 27.2 [q,
C(CH ) ], 35.6 (d, CH-27), 60.4 (q, CH-36–OCH ), 62.1 (q, CH-38–
OCH ), 67.2 (t, CH -25), 69.7 (d, CH-39), 72.9 (d, CH-26), 74.3 (d, CH-
32), 76.3 (d, CH-37), 77.6 (d, CH-33), 80.9 (d, CH-36), 82.1 (d, CH-38),
103.0 (d, CH-35), 127.4 (d, CH ), 127.5 (d, CH ), 127.6 (d, CH ), 127.6
R = 0.27 (pentane/Et O, 1:1) [UV, KMnO ].
3
2
3 3
f
2
4
2
3
3
2
3
3
2
3 3
IR (ATR): 3436 (br w, O–H), 3071 (w), 3049 (w, CAr–H), 2956 (s), 2931
3
3
3
3
3 3
(vs), 2875 (s), 2857 (s, Csp3–H), 1734 (w), 1652 (w), 1589 (w, C=C),
–
1
3
3
3
1
461 (m, C =C ), 1426 (m, O–H), 1109 (vs), 1059 cm (s, C–O).
Ar Ar
3
2
1
3
H NMR (300 MHz, CDCl ):  = 0.63 [q, J = 7.7 Hz, 6 H, Si(CH CH ) ],
.98 [t, J = 7.7 Hz, 9 H, Si(CH CH ) ], 1.03 (d, J = 6.5 Hz, 3 H, CH -40),
3
2
3
3
3
3
0
2
3
3
3
Ar
Ar
Ar
3
1
.05 [s, 9 H, C(CH ) ], 1.08 [s, 9 H, C(CH ) ], 1.11 (d, J = 6.4 Hz, 3 H,
3
3
3
3
(d, CH ), 128.0 (d, CH-31), 129.5 (d, CH-29), 129.5 (d, CH ), 129.6 (d,
A
r
A
r
3
CH -34), 1.81 (br s, 1 H, CH -25–OH), 1.97 (dd, J = 10.7, 9.1 Hz, 1 H,
3
2
CH ), 129.7 (d, CH ), 129.7 (d, CH ), 132.0 (d, CH-28), 132.5 (d, CH-
Ar Ar Ar
3
CH-27), 2.08 (br s, 1 H, CH-26–OH), 2.68 (d, J = 3.0 Hz, 1 H, CH-38),
3
0), 134.1 (s, C ), 134.2 (s, C ), 134.4 (s, C ), 134.6 (s, C ), 136.1 (d,
Ar Ar Ar Ar
3
3
2
.89 (q, J = 6.5 Hz, 1 H, CH-39), 3.12 (dd, J = 9.7, 7.7 Hz, 1 H, CH-36),
CH ), 136.1 (d, CH ), 136.2 (d, CH ), 136.3 (d, CH ).
Ar
Ar
Ar
Ar
3
.16 (s, 3 H, CH-36–OCH ), 3.36–3.43 (m, 1 H, CHH-25), 3.40 (s, 3 H,
3
NH ]+ calcd: 1098.6521; found:
+
4
HRMS-ESI: m/z [C62H96O Si4
2
8
CH-38–OCH ), 3.45–3.53 (m, 3 H, CH-33, CH-35, CH-37), 3.66 (dd, J =
3
1
098.6532.
1
0.9 Hz, 3J = 2.9 Hz, 1 H, CHH-25), 3.81–3.86 (m, 1 H, CH-26), 4.25–
3
4
.28 (m, 1 H, CH-32), 5.34 (dd, J = 14.4, 10.7 Hz, 1 H, CH-28), 5.57 (dd,
3
3
TBS-Protected Glycoside Fragment 13
J = 15.0, 6.1 Hz, 1 H, CH-31), 5.88 (dd, J = 14.4, 10.4 Hz, 1 H, CH-29),
6
.00 (dd, 3J = 15.0, 10.4 Hz, 1 H, CH-30), 7.27–7.46 (m, 12 H, CHAr),
A solution of alcohol 12 (2.29 g, 2.12 mmol, 1.00 equiv) in CH Cl (23
2 2
7
13C
.58–7.64 (m, 4 H, CH ), 7.71–7.75 (m, 4 H, CHAr).
mL) was cooled to –78 °C. Pyridine (2.05 mL 2.01 g, 25.4 mmol, 12.0
equiv) and TBSOTf (2.92 mL, 3.36 g, 12.7 mmol, 6.00 equiv) were add-
ed successively. The reaction was stirred for 22 h while warming up to
Ar
NMR (101 MHz, CDCl ):
 = 3.5 [t, Si(CH CH ) ], 7.7 [q,
2 3 3
3
Si(CH CH ) ], 15.7 (q, CH -34), 16.7 (q, CH -40), 19.5 [s, C(CH ) ], 19.6
2
3
3
3
3
3 3
r.t. Subsequently, sat. aq NH Cl solution (70 mL) was added and the
4
[s, C(CH ) ], 27.2 [q, C(CH ) ], 36.4 (d, CH-27), 60.4 (q, CH-36–OCH ),
3
3
3
3
3
layers were separated. The aqueous layer was extracted with CH Cl
2
2
6
2
8
1
2.1 (q, CH-38–OCH ), 67.0 (t, CH -25), 69.8 (d, CH-39), 73.2 (d, CH-
6), 74.3 (d, CH-32), 76.3 (d, CH-37), 77.8 (d, CH-33), 81.0 (d, CH-36),
2.1 (d, CH-38), 103.2 (d, CH-35), 127.4 (d, CH ), 127.5 (d, CH ),
3
2
(
3 × 150 mL). The organic layers were combined, dried (Na SO ), and
2 4
filtered. The solvent was removed under reduced pressure. Following
Ar
Ar
flash column chromatography (silica, pentane/Et O 20:1), silyl-pro-
2
27.6 (d, CH ), 127.7 (d, CH ), 128.9 (d, CH-31), 129.5 (d, CHAr), 129.6
Ar
Ar
tected diol 13 was obtained as a colorless oil (2.36 g, 93%).
(d, CH ), 129.7 (d, CH ), 129.8 (d, CHAr), 130.5 (d, CH-29), 130.8 (d,
Ar Ar
CH-28), 132.0 (d, CH-30), 134.1 (s, CAr), 134.3 (s, C ), 134.3 (s, C ),
R
f
= 0.74 (pentane/Et
O, 5:1), [UV, KMnO ].
2 4
Ar
Ar
1
34.5 (s, C ), 136.1 (d, CH ), 136.1 (d, CH ), 136.2 (d, CH ), 136.3 (d,
Ar Ar Ar Ar
IR (ATR): 3073 (w), 3048 (w, CAr–H), 2954 (s), 2929 (vs), 2878 (s),
2856 (s, Csp3–H), 1463 (m, C =C ), 1254 (w), 1113 (vs), 1063 cm (s,
Ar Ar
C–O).
CH ).
–1
Ar
HRMS-ESI: m/z [C56H82O Si
+
NH ]+ calcd: 984.5656; found:
8
3
4
9
84.5662.
1
H NMR (300 MHz, CDCl ):  = 0.03 [s, 3 H, Si(CH )], 0.04 [s, 3 H,
3
3
3
3
Si(CH )], 0.58 [q, J = 7.9 Hz, 6 H, OSi(CH CH ) *], 0.60 [q, J = 7.9 Hz, 6
H, CHSi(CH CH ) *], 0.86 [s, 9 H, C(CH ) ], 0.95 [t, J = 7.9 Hz, 9 H,
OSi(CH CH ) *], 0.95 [t, J = 7.9 Hz, 9 H, CHSi(CH CH ) *], 1.01 (d, J =
6
(
2
3
2
3 3
3
TES-Protected Glycoside Fragment 12
2 3 3 3 3
3
3
A solution of diol 11 (2.22 g, 2.30 mmol, 1.00 equiv) in CH Cl (35 mL)
2
3
3
2
3 3
2
2
.3 Hz, 3 H, CH -40), 1.05 [s, 9 H, C(CH ) ], 1.07 [s, 9 H, C(CH ) ], 1.10
was cooled to –78 °C. 2,6-Lutidine (1.07 mL, 986 mg, 9.20 mmol, 4.00
equiv) and TESCl (771 L, 693 mg, 4.60 mmol, 2.00 equiv) were add-
ed. After stirring for 17 h, the reaction was quenched by addition of
sat. aq NH Cl solution (90 mL) and the layers were separated. The
aqueous layer was extracted with CH Cl (4 × 100 mL). The organic
layers were combined, dried (Na SO ), and filtered. The solvent was
removed under reduced pressure. Following flash column chromatog-
raphy (silica, pentane/Et O 20:1 → 5:1), silyl-protected alcohol 12
was obtained as a colorless oil (2.29 g, 92%).
3 3 3 3 3
3
3
d, J = 6.5 Hz, 3 H, CH -34), 2.08 (dd, J = 11.0, 3.6 Hz, 1 H, CH-27),
3
3
3
.65 (d, J = 3.0 Hz, 1 H, CH-38), 2.85 (q, J = 6.3 Hz, 1 H, CH-39), 3.10
3
(
dd, J = 9.6, 7.7 Hz, 1 H, CH-36), 3.18 (s, 3 H, CH-36–OCH ), 3.38 (s, 3
3
4
H, CH-38–OCH ), 3.40–3.45 (m, 2 H, CH-33, CH-35), 3.46–3.53 (m, 3
H, CH -25, CH-37), 3.83–3.88 (m, 1 H, CH-26), 4.23–4.25 (m, 1 H, CH-
3
2
Hz, 1 H, CH-30), 7.27–7.45 (m, 12 H, CH ), 7.60–7.65 (m, 4 H, CH ),
7
3
2
2
2
2
4
3
2), 5.54 (dd, J = 15.3, 11.5 Hz, 1 H, CH-31), 5.52–5.59 (m, 1 H, CH-
3
3
8), 5.84 (dd, J = 14.9, 10.5 Hz, 1 H, CH-29), 6.05 (dd, J = 15.3, 10.5
2
Ar
Ar
.71–7.74 (m, 4 H, CH ); * interchangeable assignment.
Ar
R = 0.54 (pentane/Et O, 5:1) [UV, KMnO ].
f
2
4
1
3
C NMR (101 MHz, CDCl ):  = –4.2 [q, Si(CH )], –4.2 [q, Si(CH )], 3.7
3
3
3
IR (ATR): 3567 (w, O–H), 3069 (w), 3052 (w, CAr–H), 2954 (s), 2932 (s),
910 (m), 2875 (m), 2857 (m, C –H), 1461 (m, C =C ), 1427 (m, O–
[t, CHSi(CH CH ) ], 4.5 [t, OSi(CH CH ) ], 7.0 [q, OSi(CH CH ) ], 7.9 [q,
2 3 3 2 3 3 2 3 3
2
sp3
Ar
Ar
CHSi(CH CH ) ], 15.7 (q, CH -34), 16.7 (q, CH -40), 18.4 [s, C(CH ) ],
1
37.1 (d, CH-27), 60.5 (q, CH-36–OCH ), 62.1 (q, CH-38–OCH ), 66.6 (t,
CH -25), 69.7 (d, CH-39), 74.3 (d, CH-32), 76.3 (d, CH-37), 76.4 (d, CH-
26), 77.6 (d, CH-33), 80.9 (d, CH-36), 82.1 (d, CH-38), 103.0 (d, CH-
35), 127.4 (d, CH *), 127.5 (d, CH *), 127.6 (d, CH , CH-31*), 129.5
–
1
2
3
3
3
3
3 3
H), 1369 (m), 1112 cm (vs, C–O).
9.4 [s, C(CH ) ], 19.6 [s, C(CH ) ], 26.2 [q, C(CH ) ], 27.2 [q, C(CH ) ],
3 3 3 3 3 3 3 3
1
H NMR (300 MHz, CDCl ):  = 0.57–0.67 [m, 12 H, Si(CH CH ) ], 0.95
3
2
3
3
3
3
3
3
[t, J = 8.0 Hz, 9 H, OSi(CH CH ) ], 0.98 [t, J = 8.0 Hz, 9 H, CH-
2 3 3
2
3
Si(CH CH ) ], 1.03 (d, J = 6.4 Hz, 3 H, CH -40), 1.06 [s, 9 H, C(CH ) ],
2
3
3
3
3
3
3
3
1
.08 [s, 9 H, C(CH ) ], 1.12 (d, J = 6.4 Hz, 3 H, CH -34), 1.93 (virt. t, J ≅
3
3
3
Ar
Ar
Ar
3
3
3
J = 10.3 Hz, 1 H, CH-27), 2.60 (d, J = 3.8 Hz, 1 H, OH), 2.67 (d, J = 2.9
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

I
Synthesis
S. Wienhold et al.
Special Topic
(
d, CH *), 129.6 (d, CH-29*), 129.6 (d, CHAr*), 129.7 (d, CHAr*), 129.7
rated. The aqueous layer was extracted with Et O (3 × 50 mL). The or-
Ar
2
(
d, CH *), 132.8 (d, CH-30), 133.4 (d, CH-28), 134.1 (s, CAr), 134.2 (s,
ganic layers were combined, dried (Na SO ), and filtered. The solvent
Ar
2
4
C ), 134.4 (s, C ), 134.6 (s, C ), 136.1 (d, CH ), 136.1 (d, CH ), 136.2
was removed under reduced pressure. Following flash column chro-
Ar
Ar
Ar
Ar
Ar
(
d, CH ), 136.3 (d, CH ); * interchangeable assignment.
matography (silica, pentane/Et O 10:1 → 5:1), alcohol 15 was ob-
Ar
Ar
2
NH ]+ calcd: 1212.7385; found:
tained as a colorless oil (1.15 g, 84%).
HRMS-ESI: m/z [C68H110O Si
+
8
5
4
1212.7413.
d.r. [15 (A)/epi-15 (B)] ≈ 5:1.
R = 0.36 (pentane/Et O, 5:1), [UV, KMnO ].
f
2
4

-Silyloxyaldehyde 14
IR (ATR): 3069 (w), 3048 (w, CAr–H), 2953 (m), 2931 (s), 2876 (m),
Oxalyl chloride (746 L, 1.10 g, 8.69 mmol, 4.40 equiv) was added
dropwise to a cold solution (–78 °C) of DMSO (1.24 mL, 1.36 g, 17.4
mmol, 8.80 equiv) in CH Cl (10 mL). After 50 min, a solution of TES-
2
857 (m, Csp3–H), 1731 (w), 1666 (w, C=C), 1459 (m), 1427 (m,
–1
C =C ), 1112 (vs), 1061 (s, C–O), 740 cm (s).
Ar
Ar
2
2
1
H NMR (500 MHz, CDCl ):  = 0.07 [s, 3 H, Si(CH )], 0.09 [s, 3 H,
3
3
protected alcohol 13 (2.36 g 1.98 mmol, 1.00 equiv) in CH Cl (10 mL)
2
2
3
Si(CH )], 0.63 [q, J = 7.9 Hz, 6 H, Si(CH CH ) ], 0.89 [s, 9 H, C(CH ) ],
3
2
3
3
3 3
was added slowly over the course of 10 min. The solution was
warmed to –30 °C and stirred for 1.5 h. Subsequently, the reaction
.93 (dd, 3J = 11.2, 7.6 Hz, 3 H, CH -45), 0.96 [t, J = 7.9 Hz, 9 H,
3
0
3
3
Si(CH CH ) ], 1.03 (d, J = 6.5 Hz, 3 H, CH -40), 1.05 [s, 9 H, C(CH ) ],
1
Hz, 2.55 H, CH -34 ), 1.32–1.38 (m, 1 H, CHH-24), 1.54–1.59 (m, 1 H,
CHH-24), 1.67 (d, J = 4.5 Hz, 1 H, OH), 2.19 (dd, J = 10.8, 4.5 Hz, 0.85
H, CH-27 ), 2.24–2.28 (m, 0.15 H, CH-27 ), 2.65 (d, J = 2.9 Hz, 0.15 H,
CH-38 ), 2.68 (d, J = 3.0 Hz, 0.85 H, CH-38 ), 2.82–2.86 (m, 0.15 H,
CH-39 ), 2.88 (q, J = 6.5 Hz, 0.85 H, CH-39 ), 3.11 (dd, J = 9.6, 7.7 Hz,
1
OCH3-B), 3.37–3.41 (m, 0.3 H, CH-33 , CH-35 ), 3.39 (s, 0.45 H, CH-38–
OCH3-B), 3.40 (s, 2.55 H, CH-38–OCH ), 3.46–3.51 (m, 3.7 H, CH-25,
3-A
CH-33
(dd, J = 6.3, 3.7 Hz, 0.85 H, CH-32
H, CH-32
2
3
3
3
3 3
was cooled back to –78 °C and NEt (4.11 mL, 3.00 g, 29.6 mmol, 15.0
3
3
.07 [s, 9 H, C(CH ) ], 1.07–1.09 (m, 0.45 H, CH -34 ), 1.12 (d, J = 6.4
3
3
3
B
equiv) was added. The mixture was warmed up to r.t. over the course
3
A
of 1 h and then poured into sat. aq NH Cl solution (220 mL). The lay-
4
3
3
ers were separated and the aqueous layer was extracted with CH Cl2
2
3
A
B
(
3 × 200 mL). The organic layers were combined, dried (Na SO ), and
2 4
3
B
A
filtered. The solvent was removed under reduced pressure. Following
3
3
B
A
flash column chromatography (silica, pentane/Et O 15:1 → 5:1), alde-
2
H, CH-36), 3.16 (s, 2.55 H, CH-36–OCH3-A), 3.20 (s, 0.45 H, CH-36–
hyde 14 was obtained as a colorless oil (1.76 g, 84%).
B
B
R = 0.53 (pentane/Et O, 5:1), [UV, KMnO ].
f
2
4
3
3
IR (ATR): 3069 (w), 3048 (w, CAr–H), 2955 (s), 2929 (vs), 2858 (s, Csp3–
A
, CH-35
A
, CH-37), 3.81 (virt. t, J ≅ J = 4.5 Hz, 1 H, CH-26), 4.25
–
1
3
3
3
H), 1735 (m, C=O), 1463 (m, CAr=C ), 1112 (vs), 1065 cm (s, C–O).
A
), 4.36 (virt. t, J ≅ J = 4.7 Hz, 0.15
), 5.51–5.54 (m, 1.15 H, CH-28
Ar
3
1
B
B
, CH-31), 5.57 (dd, J = 14.9,
H NMR (500 MHz, CDCl ):  = 0.06 [s, 3 H, Si(CH )], 0.06 [s, 3 H,
3
3
3
3
10.8 Hz, 0.85 H, CH-28 ), 5.83 (dd, J = 14.9, 10.4 Hz, 1 H, CH-29), 6.02
A
Si(CH )], 0.59 [q, J = 8.0 Hz, 6 H, Si(CH CH ) ], 0.92 [s, 9 H, C(CH ) ],
0
1
CH -34), 2.22 (dd, J = 10.7, 4.7 Hz, 1 H, CH-27), 2.66 (d, J = 3.0 Hz, 1
H, CH-38), 2.87 (q, J = 6.4 Hz, 1 H, CH-39), 3.11 (dd, J = 9.6, 7.7 Hz, 1
H, CH-36), 3.18 (s, 3 H, CH-36–OCH ), 3.39 (s, 3 H, CH-38–OCH ),
3
2
3
3
3
3 3
(dd, 3J = 15.3, 10.4 Hz, 1 H, CH-30), 7.28–7.45 (m, 12 H, CHAr), 7.59–
3
.95 [t, J = 8.0 Hz, 9 H, Si(CH CH ) ], 1.02 (d, J = 6.4 Hz, 3 H, CH -40),
.05 [s, 9 H, C(CH ) ], 1.08 [s, 9 H, C(CH ) ], 1.10 (d, J = 6.4 Hz, 3 H,
2
3
3
3
3
7.65 (m, 4 H, CHAr), 7.71–7.75 (m, 4 H, CHAr).
3
3
3
3 3
3
13C NMR (101 MHz, CDCl
[t, Si(CH CH 3-A], 4.2 [t, Si(CH
Si(CH CH 3-A], 10.5 (q, CH -45), 15.7 (q, CH
18.4 [s, C(CH ], 19.4 [s, C(CH
26.3 (t, CH -24), 27.2 [q, C(CH
OCH ), 62.1 (q, CH-38–OCH
CH-37), 76.6 (d, CH-25), 77.4 (d, CH-33), 78.0 (d, CH-26), 80.9 (d, CH-
36), 82.1 (d, CH-38), 103.0 (d, CH-35), 127.4 (d, CHAr*), 127.5 (d,
CHAr*), 127.6 (d, CHAr*), 127.6 (d, CHAr*), 127.8 (d, CH-31*), 129.5 (d,
):  = –4.3 [q, Si(CH
CH 3-B], 7.7 [q, Si(CH
-34), 16.7 (q, CH
], 19.6 [s, C(CH ], 26.2 [q, C(CH
], 36.2 (d, CH-27), 60.4 (q, CH-36–
)], –3.4 [q, Si(CH
CH 3-B], 8.0 [q,
-40),
],
)], 3.9
3
3
3
3
3
3
)
)
)
3
2
3
2
3
2
)
3
3
2
3
3
3
3
3
.41–3.44 (m, 2 H, CH-33, CH-35), 3.47–3.51 (m, 1 H, CH-37), 4.12
3
)
3
3
)
3
3
)
3
)
3 3
3
(
dd, J = 4.7, 1.8 Hz, 1 H, CH-26), 4.24–4.27 (m, 1 H, CH-32), 5.51 (dd,
J = 15.0, 10.7 Hz, 1 H, CH-28), 5.59 (dd, J = 15.2, 6.0 Hz, 1 H, CH-31),
2
3
)
3
3
3
), 69.8 (d, CH-39), 74.4 (d, CH-32), 76.3 (d,
3
3
3
3
5.91 (dd, J = 15.0, 10.5 Hz, 1 H, CH-29), 6.05 (dd, J = 15.2, 10.5 Hz, 1
H, CH-30), 7.28–7.45 (m, 12 H, CH ), 7.59–7.64 (m, 4 H, CH ), 7.71–
Ar
Ar
3
7
.74 (m, 4 H, CH ), 9.55 (d, J = 1.8 Hz, 1 H, CH-25).
Ar
#
#
#
#
1
3
CHAr ), 129.6 (d, CHAr ), 129.7 (d, CHAr ), 129.7 (d, CHAr ), 129.8 (d,
CH-29 ), 132.8 (d, CH-30), 133.3 (d, CH-28), 134.2 (s, CAr), 134.3 (s,
C ), 134.4 (s, C ), 134.6 (s, C ), 136.1 (d, CH ), 136.1 (d, CHAr), 136.2
C NMR (101 MHz, CDCl ):  = –4.4 [q, Si(CH )], –4.3 [q, Si(CH )], 3.6
3
3
3
#
[
t, Si(CH CH ) ], 7.7 [q, Si(CH CH ) ], 15.8 (q, CH -34), 16.7 (q, CH -
2 3 3 2 3 3 3 3
Ar
Ar
Ar
Ar
4
0), 18.4 [s, C(CH ) ], 19.5 [s, C(CH ) ], 19.6 [s, C(CH ) ], 26.1 [q,
3 3 3 3 3 3
#
(
d, CH ), 136.3 (d, CH ); *, interchangeable assignments.
Ar
Ar
C(CH ) ], 27.2 [q, C(CH ) ], 27.2 [q, C(CH ) ], 36.0 (d, CH-27), 60.5 (q,
3
3
3
3
3 3
HRMS-ESI: m/z [C64
H
O Si + NH
]+ calcd: 1126.6834; found:
CH-36–OCH ), 62.1 (q, CH-38–OCH ), 69.7 (d, CH-39), 74.2 (d, CH-32),
100
8 4 4
3
3
76.3 (d, CH-37), 77.7 (d, CH-33), 80.7 (d, CH-26), 80.9 (d, CH-36), 82.1
1126.6846.
(
d, CH-38), 103.2 (d, CH-35), 127.4 (d, CH ), 127.5 (d, CH ), 127.6 (d,
Ar
Ar
CH ), 127.6 (d, CH ), 129.2 (d, CH-31), 129.5 (d, CH ), 129.6 (d,
-Siloxy Ketone 4
Ar
Ar
Ar
CH ), 129.7 (d, CH ), 129.8 (d, CH ), 130.3 (d, CH-29), 131.2 (d, CH-
Ar
Ar
Ar
Oxalyl chloride (49.1 L, 72.7 mg, 572 mol, 4.40 equiv) was added
dropwise to a cold solution (–78 °C) of DMSO (81.4 L, 89.5 mg, 1.15
mmol, 8.80 equiv) in CH Cl (600 L). After 30 min, a solution of alco-
2
8), 132.0 (d, CH-30), 134.0 (s, CAr), 134.2 (s, C ), 134.4 (s, C ), 134.5
Ar Ar
(
s, C ), 136.1 (d, CH ), 136.1 (d, CH ), 136.2 (d, CH ), 136.3 (d, CH ),
Ar
Ar
Ar
Ar
Ar
2
2
203.6 (d, CH-25).
hol 15 (144 mg, 1.98 mmol, 1.00 equiv) in CH Cl (1.0 mL) was added
2
2
HRMS-ESI: m/z [C62H94O Si
+
NH ]+ calcd: 1096.6364; found:
and the mixture was stirred for 1 h. Subsequently, NEt (217 L, 198
8
4
4
3
1096.6380.
mg, 1.95 mmol, 15.0 equiv) was added and the reaction was warmed
up to r.t. The mixture was poured into sat. aq NH Cl solution (5 mL)
4
and the layers were separated. The aqueous layer was extracted with
CH Cl (3 × 5 mL). The organic layers were combined, dried (Na SO ),
and filtered. The solvent was removed under reduced pressure. Fol-
Dienyl Alcohol 15
2
2
2
4
CeCl (609 mg, 2.47 mmol, 2.00 equiv) was added to a solution of al-
3
dehyde 14 (1.33 g, 1.24 mmol, 1.00 equiv) in THF (25 mL) and cooled
to 0 °C. EtMgBr solution (9.88 mL, 1.0 M in THF, 9.88 mmol, 8.00
equiv) was added over the course of 40 min and the mixture was
stirred for 1.5 h at 0 °C. Subsequently, the reaction was quenched by
lowing flash column chromatography (silica, pentane/Et O 15:1), ke-
2
tone 4 was obtained as a colorless oil (125 mg, 87%).
R = 0.57 (pentane/Et O, 5:1), [UV, KMnO ].
f 2 4
addition of sat. aq NH Cl solution (50 mL) and the layers were sepa-
4
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

J
Synthesis
S. Wienhold et al.
Special Topic
1
3
IR (ATR): 3073 (w), 3048 (w, C –H), 2953 (s), 2931 (s), 2876 (m), 2857
C NMR (101 MHz, CDCl ):  = 11.3 (q, CH -44), 33.9 (t, CH -20), 38.0
Ar
3
3
2
(
1
s, Csp3–H), 1713 (m, C=O), 1472 (m), 1463 (m), 1427 (m, C =C ),
112 (vs), 1083 (vs), 1065 cm (s, C–O).
(t, CHCH Ar), 42.7 (d, CH-22), 55.4 (d, CHN), 66.3 (t, CH -19), 68.5 (t,
CH OCO), 70.6 (d, CH-21), 73.4 (t, OCH Ar), 127.5 (d, CH ), 127.8 (d,
2 2 Ar
Ar
Ar
2
2
–
1
1
CHAr), 127.8 (d, CHAr), 128.6 (d, CHAr), 129.1 (d, CHAr), 129.6 (d, CHAr),
135.3 (s, CAr), 138.2 (s, CAr), 153.2 (s, OCO), 176.8 (s, C-23).
The analytical data matched those reported in the literature.[66]
H NMR (500 MHz, CDCl ):  = 0.01 [s, 3 H, Si(CH )], 0.05 [s, 3 H,
3
3
3
Si(CH )], 0.61 [q, J = 8.0 Hz, 6 H, Si(CH CH ) ], 0.91 [s, 9 H, C(CH ) ],
0
3
2
3
3
3 3
3
.95 [t, J = 8.0 Hz, 9 H, Si(CH CH ) ], 0.95–0.99 (m, 3 H, CH -45), 1.02
2
3
3
3
3
(d, J = 6.4 Hz, 3 H, CH -40), 1.05 [s, 9 H, C(CH ) ], 1.08 [s, 9 H,
3
3
3
3
3
C(CH ) ], 1.11 (d, J = 6.4 Hz, 3 H, CH -34), 2.09 (dd, J = 11.1, 5.8 Hz, 1
3
3
3
TES-Protected Aldol Product 18
2
3
H, CH-27), 2.43 (dd, J = 18.6 Hz, J = 7.3 Hz, 1 H, CHH-24), 2.49 (dd,
To a solution of alcohol 17 (10.0 g, 25.2 mmol, 1.00 equiv) in DMF (40
mL) were added imidazole (15.4 g, 226 mmol, 9.00 equiv), DMAP (307
mg, 2.52 mmol, 0.10 equiv), and TESCl (10.6 mL, 9.48 g, 62.9 mmol,
2
3
3
J = 18.6 Hz, J = 7.3 Hz, 1 H, CHH-24), 2.66 (d, J = 3.0 Hz, 1 H, CH-38),
3
3
2
3
.87 (q, J = 6.4 Hz, 1 H, CH-39), 3.11 (dd, J = 9.6, 7.7 Hz, 1 H, CH-36),
.17 (s, 3 H, CH-36–OCH ), 3.39 (s, 3 H, CH-38–OCH ), 3.42 (d, J = 7.7
3
3
3
2
.50 equiv) successively. The solution was stirred for 24 h at r.t. and
3
Hz, 1 H, CH-35), 3.42–3.46 (m, 1 H, CH-33), 3.49 (dd, J = 9.6, 3.0 Hz, 1
H, CH-37), 4.19 (d, J = 5.8 Hz, 1 H, CH-26), 4.22–4.25 (m, 1 H, CH-32),
then quenched by addition of sat. aq NH Cl solution (40 mL). The lay-
4
3
ers were separated and the aqueous layer was extracted with Et O (3
2
3
3
5
.32 (dd, J = 14.9, 11.1 Hz, 1 H, CH-28), 5.56 (dd, J = 15.3, 6.2 Hz, 1 H,
×
45 mL). The combined organic layers were washed with sat. aq NaCl
CH-31), 5.85 (dd, J = 14.9, 10.5 Hz, 1 H, CH-29), 6.01 (dd, 3J = 15.3,
3
solution, dried (Na SO ), and filtered. The solvent was removed under
2
4
1
0.5 Hz, 1 H, CH-30), 7.27–7.47 (m, 12 H, CHAr), 7.58–7.64 (m, 4 H,
reduced pressure and the residue was purified with flash column
CH ), 7.71–7.74 (m, 4 H, CH ).
1
Ar
Ar
chromatography (silica, pentane/Et O 10:1 → 5:1), to afford silyl
2
3
C NMR (126 MHz, CDCl ):  = –4.6 [q, Si(CH )], –4.4 [q, Si(CH )], 3.3
ether 18 as a colorless oil (11.9 g, 93%).
R = 0.29 (pentane/Et O, 5:1) [UV, KMnO ].
3
3
3
[t, Si(CH CH ) ], 7.4 (q, CH -45), 7.8 [q, Si(CH CH ) ], 15.7 (q, CH -34),
2 3 3 3 2 3 3 3
f
2
4
1
2
3
6.7 (q, CH -40), 18.3 [s, C(CH ) ], 19.4 [s, C(CH ) ], 19.6 [s, C(CH ) ],
3 3 3 3 3 3 3
IR (ATR): 3086 (w), 3063 (w), 3033 (w, CAr–H), 2978 (m), 2954 (m),
6.0 [q, C(CH ) ], 27.2 [q, C(CH ) ], 27.2 [q, C(CH ) ], 31.5 (t, CH -24),
3
3
3
3
3
3
2
2
(
937 (m), 2912 (m), 2875 (m, Csp3–H), 1780 (vs), 1695 (s, C=O), 1455
8.4 (d, CH-27), 60.5 (q, CH-36–OCH ), 62.1 (q, CH-38–OCH ), 69.7 (d,
3
3
m), 1383 (m), 1208 (s), 1106 (vs, C–O), 741 (vs), 699 cm–1 (s).
CH-39), 74.2 (d, CH-32), 76.2 (d, CH-37), 77.6 (d, CH-33), 80.4 (d, CH-
2
1
1
3
6), 80.9 (d, CH-36), 82.1 (d, CH-38), 103.0 (d, CH-35), 127.4 (d, CHAr),
27.5 (d, CH ), 127.6 (d, CH ), 127.6 (d, CHAr), 128.7 (d, CH-31), 129.5
H NMR (400 MHz, CDCl ):  = 0.59 [q, J = 7.9 Hz, 6 H, OSi(CH ) ], 0.95
3
2 3
3
3
[t, J = 7.9 Hz, 9 H, OSi(CH CH ) ], 1.25 (d, J = 6.9 Hz, 3 H, CH -44),
1.84–1.98 (m, 2 H, CH -20), 2.73 (dd, J = 13.3 Hz, J = 9.6 Hz, 1 H, CH-
Ar
Ar
2
3
3
3
2
3
(d, CH ), 129.6 (d, CH ), 129.7 (d, CH ), 129.7 (d, CH ), 130.5 (d, CH-
Ar
Ar
Ar
Ar
2
2
3
2
1
9), 130.8 (d, CH-28), 132.2 (d, CH-30), 134.0 (s, CAr), 134.2 (s, CAr),
34.3 (s, C ), 134.5 (s, C ), 136.1 (d, CH ), 136.1 (d, CH ), 136.2 (d,
CHHAr), 3.23 (dd, J = 13.3 Hz, J = 3.2 Hz, 1 H, CHCHHAr), 3.52 (ddd,
2
3
2
3
J = 9.4 Hz, J = 6.6, 5.6 Hz, 1 H, CHH-19), 3.63 (virt. dt, J = 9.4 Hz, J ≅
Ar
Ar
Ar
Ar
3
3
3
CH ), 136.3 (d, CH ), 213.8 (s, C-25).
J = 6.2 Hz, 1 H, CHH-19), 3.78 (virt. t, J ≅ J = 8.3 Hz, 1 H, CHHOCO),
Ar
Ar
3
3
3
3
NH ]+ calcd: 1124.6677; found:
+
4
3.89 (virt. p, J ≅ J = 6.9 Hz, 1 H, CH-22), 4.03 (dd, J = 9.0 Hz, J = 2.1
Hz, 1 H, CHHOCO), 4.15 (dt, J = 6.8, 5.1 Hz, 1 H, CH-21), 4.43 (d, J =
1
HRMS-ESI: m/z [C64H98O Si
1
8
4
3
2
124.6690.
2
1.8 Hz, 1 H, OCHHAr), 4.48 (d, J = 11.8 Hz, 1 H, OCHHAr), 4.50–4.55
(
m, 1 H, CHN), 7.18–7.34 (m, 10 H, CHAr).
13C
NMR (101 MHz, CDCl ): 5.2 [t, OSi(CH ) ], 7.1 [q,
OSi(CH CH ) ], 13.8 (q, CH -44), 35.4 (t, CH -20), 37.9 (t, CHCH Ar),
Evans Aldol Product 17

=
3
2 3
A solution of oxazolidinone 16 (40.8 g, 175 mmol, 1.00 equiv) in
2
3
3
3
2
2
CH Cl2 (700 mL) was cooled to 0 °C and Bu BOTf (210 mL, 1.0 M in
2
2
4
3.4 (d, CH-22), 55.6 (d, CHN), 66.0 (t, CH OCO), 66.5 (t, CH -19), 71.3
2
2
CH Cl , 210 mmol, 1.20 equiv) was added over the course of 30 min.
2
2
i
(d, CH-21), 73.1 (t, OCH Ar), 127.4 (d, CHAr), 127.6 (d, CHAr), 127.8 (d,
CH ), 128.4 (d, CH ), 129.0 (d, CH ), 129.6 (d, CH ), 135.6 (s, C ),
1
2
Subsequently, Pr NEt (41.6 mL, 31.6 g, 245 mmol, 1.40 equiv) was
2
Ar
Ar
Ar
Ar
Ar
added over the course of 10 min. The solution was stirred a further 10
min and then cooled to –78 °C. A solution of 3-(benzyloxy)propanal
38.7 (s, C ), 153.0 (s, OCO), 175.7 (s, C-23).
Ar
+
(33.6 g, 205 mmol, 1.17 equiv) in CH Cl (70 mL) was added over the
HRMS-ESI: m/z [C29
H41NO
5
Si + H] calcd: 512.2827; found: 512.2829.
2
2
course of 10 min and the reaction was stirred for 2 h at –78 °C and 1.5
h at 0 °C. Subsequently, the reaction was quenched by addition of aq
pH 7 buffer (225 mL) and MeOH (325 mL). After stirring for 30 min,
MeOH (450 mL) and H O (30%, 225 mL) were added and stirring was
TES/Benzyl-Protected Pentanol 19
Silyl ether 18 (78.8 g, 154 mmol, 1.00 equiv) was dissolved in THF
2
2
(3.45 L) and a solution of NaBH (29.1 g, 770 mmol, 5.00 equiv) in wa-
4
continued for 30 min at r.t. The layers were separated and the aque-
ous layer was extracted with CH Cl (3 × 250 mL). The organic layers
ter (950 mL) was slowly added at 0 °C. The reaction was stirred for 20
h at r.t. and then quenched by careful addition of sat. aq NH Cl solu-
2
2
4
were combined, washed with sat. aq NaHCO solution (280 mL) and
3
tion (1.0 L). The layers were separated and the aqueous layer was ex-
tracted with EtOAc (6 × 600 mL). The organic layers were combined,
dried (Na SO ), and filtered. The solvent was removed under reduced
sat. aq NaCl solution (390 mL), and dried (Na SO ). The solvent was
2
4
removed under reduced pressure and the residue was purified with
2
4
flash column chromatography (silica, pentane/Et O 1:1 → 0:1), to af-
2
pressure. Following flash column chromatography (silica, pen-
ford alcohol 17 as a colorless oil (67.2 g, 97%).
tane/Et O 20:1 → 1:1 → EtOAc), alcohol 19 was obtained as a colorless
2
R = 0.10 (pentane/Et O, 1:1) [UV, KMnO ].
oil (43.6 g, 84%). Additionally, oxazolidinone (24.9 g, 140 mmol, 91%)
was re-isolated.
f
2
4
1
3
H NMR (500 MHz, CDCl ):  = 1.29 (d, J = 7.0 Hz, 3 H, CH -44), 1.75
3
3
2
3
2
(dddd, J = 14.3 Hz, J = 6.6, 4.7, 3.0 Hz, 1 H, CHH-20), 1.88 (dddd, J =
R = 0.32 (pentane/Et O, 2:1) [UV, KMnO ].
f
2
4
3
2
3
1
9
4.3 Hz, J = 9.4, 7.3, 4.8 Hz, 1 H, CHH-20), 2.78 (dd, J = 13.4 Hz, J =
.5 Hz, 1 H, CHCHHAr), 3.26 (dd, J = 13.4 Hz, J = 3.4 Hz, 1 H, CHCH-
IR (ATR): 3430 (br m, O–H), 2955 (vs), 2912 (s), 2875 (vs, Csp3–H),
2
3
1
455 (m), 1413 (w, C–H), 1363 (w), 1239 (w), 1092 (vs), 1048 (vs),
3
HAr), 3.31 (d, J = 2.4 Hz, 1 H, OH), 3.59–3.73 (m, 2 H, CH OCO), 3.80–
–1
2
1017 (vs, C–O), 733 cm (vs).
3
.87 (m, 1 H, CH-22), 4.16–4.21 (m, 3 H, CH -19, CH-21), 4.52 (s, 2 H,
2
3
OCH Ar), 4.68 (ddt, J = 9.5, 6.8, 3.4 Hz, 1 H, CHN), 7.19–7.21 (m, 2 H,
2
CH ), 7.26–7.36 (m, 8 H, CH ).
Ar
Ar
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

K
Synthesis
S. Wienhold et al.
Special Topic
1
3
1.91–1.99 (m, 1 H, CH-22), 3.7–3.8 (m, 2 H, CH -19), 3.93 (ddd, 3J =
H NMR (500 MHz, CDCl ):  = 0.61 [q, J = 7.9 Hz, 6 H, OSi(CH ) ], 0.82
3
2
3
2
3
3
7.5, 4.9, 4.0 Hz, 1 H, CH-21), 3.97 (dd, J = 10.8 Hz, 3J = 6.9 Hz, 1 H,
2
(d, J = 7.0 Hz, 3 H, CH -44), 0.96 [t, J = 7.9 Hz, 9 H, OSi(CH CH ) ],
3
2
3
3
3
2
3
1
.74–1.86 (m, 2 H, CH -20), 1.97 (dqdd, J = 8.5, 7.0, 4.9, 3.6 Hz, 1 H,
CHH-23), 4.06 (dd, J = 10.8 Hz, J = 5.8 Hz, 1 H, CHH-23).
13C NMR (101 MHz, CDCl ):
5.2 [t, OSi(CH ) ], 7.0 [q,
2
CH-22), 2.76 (br s, 1 H, OH), 3.50–3.58 (m, 3 H, CH -19, CHH-23), 3.70
2
 =
3
2 3
2
3
3
(ddd, J = 11.3 Hz, J = 8.5, 2.9 Hz, 1 H, CHH-23), 3.98 (dt, J = 7.9, 3.6
OSi(CH CH ) ], 12.3 (q, CH -44), 27.4 [q, C(CH ) ], 36.1 (t, CH -20),
2
3
3
3
3
3
2
2
2
Hz, 1 H, CH-21), 4.48 (d, J = 12.0 Hz, 1 H, OCHHAr), 4.52 (d, J = 12.0
Hz, 1 H, OCHHAr), 7.26–7.37 (m, 5 H, CHAr).
3
8.2 (d, CH-22), 39.0 [s, C(CH ) ], 60.5 (t, CH -19), 66.2 (t, CH -23),
3 3 2 2
71.8 (d, CH-21), 178.7 (s, COO).
13C
OSi(CH CH ) ], 12.5 (q, CH -44), 32.6 (t, CH -20), 40.1 (d, CH-22), 66.1
NMR (101 MHz, CDCl ):

=
5.2 [t, OSi(CH ) ], 7.0 [q,
3
2
3
HRMS-ESI: m/z [C17H36O Si + H] calcd: 333.2456; found: 333.2456.
+
4
2
3
3
3
2
(
t, CH -23), 67.3 (t, CH -19), 73.2 (t, OCH Ar), 73.3 (d, CH-21), 127.7
2
2
2
Piv/TES-Protected Thioether 23
(d, CH ), 127.8 (d, CH ), 128.5 (d, CH ), 138.6 (s, C ).
Ar
Ar
Ar
Ar
To a cold solution (0 °C) of alcohol 21 (3.74 g, 11.2 mmol, 1.00 equiv)
in THF (130 mL) were added 1-phenyl-1H-tetrazole-5-thiol (22; 3.02
g, 16.9 mmol, 1.51 equiv), DIAD (3.41 g, 16.9 mmol, 1.50 equiv), and
PPh3 (4.42 g, 16.9 mmol, 1.50 equiv). After stirring for 3 h, the reac-
tion was quenched by addition of sat. aq NaHCO3 solution (150 mL)
and the layers were separated. The aqueous layer was extracted with
+
HRMS-ESI: m/z [C19H34O Si + H] calcd: 339.2350; found: 339.2351.
3
Piv/TES/Benzyl-Protected Pentanol 20
To a solution of alcohol 19 (43.6 g, 129 mmol, 1.00 equiv) in CH Cl2
2
(
436 mL) was added pyridine (31.2 mL, 30.5 g, 386 mmol, 3.00 equiv),
DMAP (1.57 g, 12.9 mmol, 0.10 equiv), and pivaloyl chloride (23.8 mL,
3.3 g, 193 mmol, 1.50 equiv). The reaction was stirred for 16.5 h at
Et O (3 × 150 mL) and the combined organic layers were dried
2
2
(Na SO ) and filtered. The solvent was removed under reduced pres-
2
4
r.t. and then quenched by addition of sat. aq NH Cl solution (200 mL).
sure and the residue was purified with flash column chromatography
4
The layers were separated and the aqueous layer was extracted with
CH Cl (3 × 200 mL). The combined organic layers were dried (Na SO )
(silica, pentane/Et O 10:1 → 5:1), to afford thioether 23 as a colorless
oil (5.04 g, 91%).
2
2
2
2
4
and filtered. The solvent was removed under reduced pressure and
the residue was purified with flash column chromatography (silica,
R = 0.75 (pentane/Et O, 1:1) [UV, KMnO ].
f
2
4
IR (ATR): 2958 (vs), 2911 (s), 2877 (s, Csp3–H), 1728 (vs, C=O), 1501
pentane/Et O 30:1 → 10:1), to afford pivalate 20 as a colorless oil
2
(
m, C–H), 1283 (s), 1156 (vs, C–O), 744 cm–1 (vs).
(11.9 g, quant.).
1
3
H NMR (500 MHz, CDCl ):  = 0.59 [q, J = 7.9 Hz, 6 H, OSi(CH ) ], 0.91
3
2 3
R = 0.43 (pentane/Et O, 10:1) [UV, KMnO ].
f
2
4
3
3
(
d, J = 7.9 Hz, 3 H, CH -44), 0.94 [t, J = 7.9 Hz, 9 H, OSi(CH CH ) ],
3
2
3
3
IR (ATR): 3033 (w, C –H), 2957 (vs), 2912 (m), 2876 (s, Csp3–H), 1730
Ar
1.17 [s, 9 H, C(CH ) ], 1.90–1.98 (m, 2 H, CHH-20, CH-22), 2.04 (dddd,
3
3
(
1
vs, C=O), 1481 (m), 1456 (m, C–H), 1283 (m), 1155 (vs), 1101 (s),
051 (m, C–O), 735 cm (vs).
2
3
J = 14.0 Hz, J = 8.6, 6.6, 5.4 Hz, 1 H, CHH-20), 3.35–3.44 (m, 2 H, CH -
9), 3.89 (ddd, J = 7.2, 5.4, 3.4 Hz, 1 H, CH-21), 3.97 (dd, J = 10.8 Hz,
J = 6.6 Hz, 1 H, CHH-23), 4.06 (dd, J = 10.8 Hz, J = 6.4 Hz, 1 H, CHH-
2
–
1
3
2
1
1
3
3
2
3
H NMR (500 MHz, CDCl ):  = 0.59 [q, J = 8.0 Hz, 6 H, OSi(CH ) ], 0.89
3
2 3
3
3
(d, J = 6.9 Hz, 3 H, CH -44), 0.94 [t, J = 8.0 Hz, 9 H, OSi(CH CH ) ],
23), 7.51–7.59 (m, 5 H, CHAr).
3
2
3 3
1
.19 [s, 9 H, C(CH ) ], 1.70–1.77 (m, 1 H, CHH-20), 1.78–1.84 (m, 1 H,
13C NMR (101 MHz, CDCl ):
3 3
 = 5.3 [t, OSi(CH ) ], 7.1 [q,
3
2
3
3
3
3
3
CHH-20), 1.89 (virt. qd, J ≅ J = 6.8, J = 3.2 Hz, 1 H, CH-22), 3.50 (t, J =
.6 Hz, 2 H, CH -19), 3.93–3.96 (m, 1 H, CH-21), 3.97–4.04 (m, 2 H,
OSi(CH CH ) ], 11.6 (q, CH -44), 27.3 [q, C(CH ) ], 30.1 (t, CH -19),
2
3
3
3
3
3
2
6
2
33.5 (t, CH -20), 37.8 (d, CH-22), 38.9 [s, C(CH ) ], 66.0 (t, CH -23),
2
3
3
2
2
2
CH -23), 4.47 (d, J = 11.9 Hz, 1 H, OCHHAr), 4.50 (d, J = 11.9 Hz, 1 H,
OCHHAr), 7.27–7.29 (m, 1 H, CH ), 7.31–7.36 (m, 4 H, CH ).
13C
2
71.6 (d, CH-21), 124.0 (d, CH ), 129.9 (d, CH ), 130.2 (d, CH ), 133.9
Ar
Ar
Ar
Ar
Ar
(s, C ), 154.2 (s, OCNN), 178.7 (s, COO).
Ar
NMR (101 MHz, CDCl ):

=
5.3 [t, OSi(CH ) ], 7.1 [q,
H]+ calcd: 493.2663; found:
HRMS-ESI: m/z [C24H40N O SSi +
4 3
493.2666.
3
2
3
OSi(CH CH ) ], 11.3 (q, CH -44), 27.4 [q, C(CH ) ], 34.5 (t, CH -20),
2
3
3
3
3
3
2
3
6
1
8.0 (d, CH-22), 38.9 [s, C(CH ) ], 66.5 (t, CH -23), 67.3 (t, CH -19),
9.9 (d, CH-21), 73.1 (t, OCH Ar), 127.6 (d, CH ), 127.7 (d, CH ),
28.5 (d, CH ), 138.6 (s, C ), 178.7 (s, COO).
3 3 2 2
2
Ar
Ar
Piv/TES-Protected Sulfone 24
To a solution of thioether 23 (36.5 g, 74.2 mmol, 1.00 equiv) in CH Cl
Ar
Ar
2
2
+
HRMS-ESI: m/z [C24H42O Si + H] calcd: 423.2925; found: 423.2929.
4
(
(
1.4 L) were added NaHCO (62.3 g, 742 mmol, 10.0 equiv) and mCPBA
77 wt%, 99.7 g, 445 mmol, 6.00 equiv). The colorless suspension was
3
Piv/TES-Protected Pentanol 21
stirred for 24 h at r.t., before sat. aq sodium sulfite solution (1 M, 145
mL) was added. After separation of the layers, the aqueous layer was
Pd(OH) /C (686 mg, 20 wt%) was added to a solution of pivalate 20
2
(5.50 g, 13.0 mmol, 1.00 equiv) in EtOAc (91 mL). The reaction flask
extracted with CH Cl2 (3 × 250 mL). The organic layers were com-
2
was flushed with argon and then exchanged for a H2 atmosphere (1
atm). After stirring for 23.5 h at r.t. the reaction flask was again
flushed with argon and the mixture was filtered over Celite. The sol-
vent was removed under reduced pressure and the residue was puri-
fied with flash column chromatography (silica, pentane/EtOAc 5:1),
to afford alcohol 21 as a colorless oil (3.74 g, 86%).
bined, dried (Na SO ), and filtered. The solvent was removed under
reduced pressure. Following flash column chromatography (silica,
2
4
pentane/Et O 10:1 → 3:1), alcohol 24 was obtained as a colorless oil
2
(33.0 g, 85%).
R = 0.24 (pentane/Et O, 5:1), 0.74 (CH Cl /THF, 80:1) [UV, KMnO ].
f
2
2
2
4
IR (ATR): 2959 (vs), 2912 (s), 2878 (s, Csp3–H), 1728 (vs, C=O), 1346 (s),
R = 0.73 (pentane/EtOAc, 2:1) [KMnO ].
–1
f
4
1154 (vs, C–O), 770 cm (vs).
IR (ATR): 3447 (br m, O–H), 2957 (vs), 2913 (s), 2878 (s, Csp3–H), 1732
1
3
H NMR (500 MHz, CDCl ):  = 0.62 [q, J = 8.0 Hz, 6 H, OSi(CH ) ],
3
2 3
(
(
1
vs), 1713 (s, C=O), 1481 (m), 1460 (m, C–H), 1285 (s), 1159 (vs), 1035
3
0
1
.94–0.98 (m, 3 H, CH -44), 0.96 [t, J = 8.0 Hz, 9 H, OSi(CH CH ) ],
3
2
3
3
–
1
s), 1008 (s, C–O), 742 cm (vs).
H NMR (500 MHz, CDCl ):  = 0.62 [q, J = 7.9 Hz, 6 H, OSi(CH ) ], 0.93
3
3
3
.19 [s, 9 H, C(CH ) ], 1.93 (virt. qd, J ≅ J = 6.5 Hz, J = 4.1 Hz, 1 H, CH-
3
3
3
2
3
22), 2.06–2.18 (m, 2 H, CH -20), 3.74 (ddd, J = 14.4 Hz, J = 10.5, 5.4
Hz, 1 H, CHH-19), 3.82 (ddd, J = 14.4 Hz, J = 10.6, 5.7 Hz, 1 H, CHH-
3
2
3
2
3
3
2
3
(
d, J = 6.9 Hz, 3 H, CH -44), 0.96 [t, J = 7.9 Hz, 9 H, OSi(CH CH ) ],
3
2
3 3
1
.20 [s, 9 H, C(CH ) ], 1.66–1.80 (m, 2 H, CH -20), 1.84 (br s, 1 H, OH),
3
3
2
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

L
Synthesis
S. Wienhold et al.
Special Topic
3
2
3
13
1
9), 3.90 (dt, J = 7.3, 4.6 Hz, 1 H, CH-21), 3.98 (dd, J = 11.0 Hz, J = 6.2
C NMR (101 MHz, CDCl ):  = 26.0 (q, CCH ), 26.8 (q, CCH ), 63.3 (t,
3
3
3
2
3
Hz, 1 H, CHH-23), 4.05 (dd, J = 11.0 Hz, J = 6.0 Hz, 1 H, CHH-23),
.59–7.64 (m, 3 H, CH ), 7.69–7.71 (m, 2 H, CHAr).
CH -18), 69.6 (t, CH -12), 76.1 (d, CH-13), 109.5 (s, C(CH ) ), 130.1 (d,
CH-15), 130.6 (d, CH-14), 132.7 (d, CH-17), 133.5 (d, CH-16).
2
2
3
2
7
Ar
13C
The analytical data matched those reported in the literature.50
NMR (126 MHz, CDCl ):
 = 5.2 [t, OSi(CH ) ], 7.1 [q,
2 3
3
OSi(CH CH ) ], 12.1 (q, CH -44), 26.6 (t, CH -20), 27.3 [q, C(CH ) ],
2
3
3
3
2
3 3
3
8.1 (d, CH-22), 39.0 [s, C(CH ) ], 53.3 (t, CH -19), 65.5 (t, CH -23),
3 3 2 2
Acetal-Protected Pentadienyl Acetate 29
71.4 (d, CH-21), 125.1 (d, CH ), 129.9 (d, CH ), 131.6 (d, CH ), 133.1
Ar
Ar
Ar
To a cold (0 °C) solution of alcohol 28 (12.5 g, 68.0 mmol, 1.00 equiv)
(s, C ), 153.5 (s, OCNN), 178.5 (s, COO).
Ar
in CH Cl2 (81 mL) was added NEt3 (18.8 mL, 13.8 g, 136 mmol, 2.00
2
HRMS-ESI: m/z [C24H40N O SSi
+
H]+ calcd: 525.2561; found:
equiv), Ac O (7.71 mL, 8.33 g, 81.6 mmol, 1.20 equiv), and DMAP
4
5
2
525.2564.
(1.25 g, 10.2 mmol, 0.15 equiv) successively. After stirring for 15 min
at 0 °C, the reaction was warmed to r.t. and stirring was continued for
Methyl Dienoate 27
16 h. The reaction was quenched by the addition of sat. aq NH Cl solu-
4
i
tion (160 mL) and the layers were separated. The aqueous layer was
extracted with CH Cl (3 × 200 mL) and the combined organic layers
A solution of Pr NH (18.8 mL, 13.6 g, 134 mmol, 1.10 equiv) in THF
(
2
540 mL) was cooled to –78 °C and BuLi (53.6 mL, 2.5 M in hexane,
34 mmol, 1.10 equiv) was added dropwise. After stirring for 30 min
at 0 °C, the solution was cooled back to –78 °C and phosphonate 25
28.8 g, 122 mmol, 1.00 equiv) was added as a solution in THF (20
mL). Stirring was continued for 20 min, before a solution of aldehyde
6 (22.2 g, 170 mmol, 1.40 equiv) in THF (20 mL) was added. The re-
2
2
were dried (Na SO ) and filtered. The solvent was removed under re-
1
2
4
[
67]
duced pressure and the residue was purified with flash column chro-
matography (silica, pentane/Et O 2:1), to afford acetate 29 as a color-
(
2
less oil (14.6 g, 95%).
2
R = 0.65 (pentane/Et O, 1:1) [UV, KMnO ].
f
2
4
action was slowly warmed to 0 °C over the course of 15 h and then
IR (ATR): 2987 (w), 2515 (m), 2159 (m), 2160 (m), 2026 (w), 1738 (s),
1222 (s), 1056 cm (s, C–O).
quenched by the addition of sat. aq NH Cl solution (250 mL). After
–1
4
separation of the layers, the aqueous layer was extracted with Et O (3
2
1
H NMR (400 MHz, CDCl ):  = 1.39 (s, 3 H, CCH ), 1.43 (s, 3 H, CCH ),
3
3
3
×
200 mL). The organic layers were combined, dried (Na SO ), and fil-
2 4
2
2
.07 (s, 3 H, CH CO), 3.59 (virt. t, J ≅ 3J = 7.9 Hz, 1 H, CHH-12), 4.09
3
tered. The solvent was removed under reduced pressure. Following
2
3
3
3
(
dd, J = 8.2 Hz, J = 6.2 Hz, 1 H, CHH-12), 4.54 (virt. q, J ≅ J = 7.2 Hz, 1
flash column chromatography (silica, pentane/Et O 10:1 → 5:1), di-
2
H, CH-13), 4.59 (d, J = 6.0 Hz, 2 H, CH -18), 5.67–5.72 (m, 1 H, CH-17),
2
enoate 27 was obtained as a colorless oil (16.8 g, 65%).
5
.75–5.82 (m, 1 H, CH-14), 6.24–6.33 (m, 2 H, CH-15, CH-16).
R = 0.66 (pentane/Et O, 1:1) [UV, KMnO ].
f
2
4
1
3
C NMR (101 MHz, CDCl ):  = 21.1 (q, CH CO), 26.0 (q, CCH ), 26.8 (q,
3
3
3
1
H NMR (500 MHz, CDCl ):  = 1.40 (s, 3 H, CCH ), 1.44 (s, 3 H, CCH ),
3
3
3
CCH ), 64.6 (t, CH -18), 69.6 (t, CH -12), 76.7 (d, CH-13), 109.6 (s,
3
2
2
2
3
3
.63 (dd, J = 8.2 Hz, J = 7.4 Hz, 1 H, CHH-12), 3.75 (s, 3 H, OCH ), 4.14
3
C(CH ) ), 128.0 (d, CH-17), 131.9 (d, CH-15), 132.1 (d, CH-14), 133.0
3 2
2
3
(dd, J = 8.2 Hz, J = 6.4 Hz, 1 H, CHH-12), 4.58–4.63 (m, 1 H, CH-13),
(
d, CH-16), 170.8 (s, CO).
HRMS-ESI: m/z [C12H O + H] calcd: 226.1200; found: 226.1196.
18 4
3
3
3
5
.91 (d, J = 15.4 Hz, 1 H, CH-17), 6.06 (virt. ddt, J = 15.3 Hz, J = 6.9
+
4
4
3
3
Hz, J ≅ J = 0.8 Hz, 1 H, CH-14), 6.42 (virt. ddt, J = 15.2 Hz, J = 11.1
Hz, J ≅ J = 0.9 Hz, 1 H, CH-15), 7.27 (ddd, J = 15.4, 11.0 Hz, J = 0.7
4
4
3
4
Acetyl-Protected Heptadienol 30
Hz, 1 H, CH-16).
1
3
Acetate 29 (14.6 g, 64.6 mmol, 1.00 equiv) was dissolved in a mixture
of HOAc (55.8 mL) and water (15.4 mL) and heated on the rotary evap-
orator at 480 mbar and 70 °C for 4 h. Subsequently, the solvents were
removed under reduced pressure. In order to remove traces of water
and HOAc, the residue was dissolved in toluene (150 mL) and the sol-
vent was again removed under reduced pressure. The diol 30 was
used without further purification in the next step.
C NMR (101 MHz, CDCl ):  = 26.0 (q, CCH ), 26.7 (q, CCH ), 51.8 (q,
3
3
3
OCH ), 69.4 (t, CH -12), 76.1 (d, CH-13), 110.0 (s, C(CH ) ), 122.2 (d,
CH-17), 130.1 (d, CH-15), 139.2 (d, CH-14), 143.5 (d, CH-16), 167.3 (s,
C-18).
3
2
3 2
The analytical data obtained matched those reported in the litera-
ture.
[
49]
Acetal-Protected Pentadienol 28
Acetyl/TES-Protected Heptadienol 31
DIBAL-H (150 mL, 1.0 M in CH Cl , 150 mmol, 2.20 equiv) was slowly
2
2
Crude diol 30 was dissolved in CH Cl (500 mL) and 2,6-lutidine (14.9
2
2
added to a cold (–78 °C) solution of ester 27 (14.4 g, 68.0 mmol, 1.00
mL, 13.8 g, 129 mmol, 2.00 equiv) and TESCl (11.9 mL, 10.7 g, 71.1
mmol, 1.10 equiv) were added at –78 °C. The solution was stirred for
equiv) in CH Cl (141 mL) over the course of 10 min. After stirring for
2
2
16 h, sat. aq potassium sodium tartrate solution (400 mL) was added
1
9 h while warming up to r.t. After addition of sat. aq NH Cl solution
4
and the mixture was warmed to r.t. while stirring. Water (200 mL)
was added and the layers were separated. The aqueous layer was ex-
tracted with EtOAc (3 × 200 mL) and the combined organic layers
were dried (Na SO ) and filtered. After removal of the solvent under
(
400 mL) the layers were separated and the aqueous layer was ex-
tracted with CH Cl (3 × 200 mL). The organic layers were combined,
2
2
dried (Na SO ), and filtered. The solvent was removed under reduced
2
4
2
4
pressure. Following flash column chromatography (silica, pen-
reduced pressure, alcohol 28 was obtained as a colorless oil (12.5 g,
quant.) and used without further purification.
tane/Et O 5:1 → 1:1), alcohol 31 was obtained as a colorless oil (12.1
2
g, 63%, 2 steps).
R = 0.32 (pentane/Et O, 1:1) [UV, KMnO ].
f
2
4
R = 0.20 (pentane/Et O, 4:1) [UV, KMnO ].
f
2
4
1
H NMR (400 MHz, CDCl ):  = 1.39 (s, 3 H, CCH ), 1.43 (s, 3 H, CCH ),
3
3
3
IR (ATR): 3453 (w, O–H), 3408 (w, O–H), 2953 (s, Csp3–H), 2911 (m,
Csp3–H), 2876 (m, Csp2–H), 1739 (s, C=O), 1227 (m), 990 (m), 727 cm
2
3
2
3
3
.59 (virt. t, J ≅ J = 8.0 Hz, 1 H, CHH-12), 4.09 (dd, J = 8.1 Hz, J = 6.0
–1
3
3
Hz, 1 H, CHH-12), 4.19 (virt. t, J ≅ J = 5.4 Hz, 2 H, CH -18), 4.54 (ddd,
2
(
m).
3
3
3
3
J = 8.0, 7.1, 6.0 Hz, 1 H, CH-13), 5.65 (virt. dd, J = 14.3 Hz, J ≅ J = 7.5
1
3
3
3
3
H NMR (500 MHz, CDCl
3
):  = 0.61 [q, J = 7.9 Hz, 6 H, OSi(CH
2
)
3
], 0.96
Hz, 1 H, CH-17), 5.87 (virt. dt, J = 14.7 Hz, J ≅ J = 5.8 Hz, 1 H, CH-14),
.22–6.35 (m, 2 H, CH-15, CH-16).
3
[t, J = 7.9 Hz, 9 H, OSi(CH CH ) ], 2.06 (s, 3 H, CH CO), 2.66 (br s, 1 H,
6
2
3
3
3
2
3
2
OH), 3.42 (dd, J = 10.0 Hz, J = 7.9 Hz, 1 H, CHH-12), 3.64 (dd, J = 10.0
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

M
Synthesis
S. Wienhold et al.
Special Topic
3
3
3
3
3
Hz, J = 3.7 Hz, 1 H, CHH-12), 4.22 (virt. t, J ≅ J = 16.8 Hz, 1 H, CH-13),
H, CH -18), 4.22 (virt. q, J ≅ J = 6.2 Hz, 1 H, CH-13), 5.67–5.74 (m, 2
2
3
3
3
4
1
1
.59 (d, J = 6.4 Hz, 2 H, CH -18), 5.69 (dd, J = 14.7, 6.0 Hz, 1 H, CH-
4), 5.76 (dt, J = 14.6, 6.4 Hz, 1 H, CH-17), 6.27 (dd, J = 14.6, 10.6 Hz,
H, CH-16), 6.33 (dd, J = 14.7, 10.6 Hz, 1 H, CH-15).
H, CH-14, CH-17), 6.05 (dd, J = 15.4, 10.5 Hz, 1 H, CH-16), 6.17 (dd,
J = 15.2, 10.5 Hz, 1 H, CH-15), 7.32–7.43 (m, 6 H, CHAr), 7.63–7.65 (m,
2 H, CH ), 7.68–7.70 (m, 2 H, CH ).
2
3
3
3
3
Ar
Ar
13C
OSi(CH CH ) ], 21.1 (q, CH CO), 64.7 (t, CH -18), 66.8 (t, CH -12), 72.5
NMR (101 MHz, CDCl ):

=
4.5 [t, OSi(CH ) ], 6.8 [q,
13C NMR (101 MHz, CDCl ):

=
4.4 [t, OSi(CH ) ], 6.8 [q,
3
2
3
3
2 3
OSi(CH CH ) ], 19.5 [s, OSiC(CH ) ], 27.2 [q, OSiC(CH ) ], 63.6 (t, CH -
2
3
3
3
2
2
2
3
3
3
3
3
3
2
(d, CH-13), 127.2 (d, CH-17), 130.7 (d, CH-15), 133.0 (d, CH-14), 133.7
12), 67.3 (t, CH -18), 74.4 (d, CH-13), 127.6 (d, CHAr), 127.6 (d, CHAr),
2
(d, CH-16), 170.9 (s, CO).
129.7 (d, CH ), 129.7 (d, CH ), 130.1 (d, CH-16), 131.3 (d, CH-15),
Ar
Ar
+
131.6 (d, CH-14), 134.1 (s, CAr), 134.4 (s, CAr), 134.6 (d, CH-17), 136.1
d, CH ), 136.1 (d, CH ).
HRMS-ESI: m/z [C15H28O Si + Na] calcd: 323.1655; found: 323.1649.
4
(
Ar
Ar
+
HRMS-ESI: m/z [C29H44O Si + Na] calcd: 519.2721; found: 519.2723.
Acetyl/TES/TBDPS-Protected Heptadienol 32
3
2
To a cold solution (0 °C) of alcohol 31 (15.7 g, 52.4 mmol, 1.00 equiv)
in DMF (120 mL) were added TBDPSCl (20.4 mL, 21.6 g, 78.6 mmol,
Heptadienal 34
1
.50 equiv), NEt (14.5 mL, 10.6 g, 105 mmol, 2.00 equiv), and DMAP
MnO (21.3 g, 246 mmol, 20.0 equiv) was added to a solution of alco-
3
2
(6.40 g, 52.4 mmol, 1.00 equiv). After warming to r.t., the reaction was
hol 33 (6.10 g, 12.3 mmol, 1.00 equiv) in CH Cl (140 mL) at r.t. After
2
2
stirred for 17 h and then quenched by addition of sat. aq NH Cl solu-
tion (280 mL). After separation of the layers, the aqueous layer was
stirring for 24 h, the black suspension was filtered over Celite and the
solvent was removed under reduced pressure to afford aldehyde 34 as
a colorless oil (5.69 g, 94%).
4
extracted with Et O (3 × 200 mL). The organic layers were combined,
2
dried (Na SO ), and filtered. The solvent was removed under reduced
pressure. Following flash column chromatography (silica, pen-
2
4
R = 0.60 (pentane/Et O, 4:1) [UV, KMnO ].
f
2
4
IR (ATR): 2954 (s, Csp3–H), 2876 (s, Csp2–H), 1684 (s, C=O), 1104 (w),
tane/Et O 20:1), diene 32 was obtained as a colorless oil (27.7 g, 98%).
2
1
007 (w), 958 (w), 700 cm–1 (s).
R = 0.67 (pentane/Et O, 4:1) [UV, KMnO ].
f
2
4
1
3
H NMR (400 MHz, CDCl ):  = 0.46 [q, J = 7.9 Hz, 6 H, OSi(CH ) ], 0.85
3
2 3
IR (ATR): 2954 (s, Csp3–H), 2876 (s, Csp2–H), 2665 (w), 1739 (s, C=O),
3
3
[t, J = 7.9 Hz, 9 H, OSi(CH CH ) ], 1.09 [s, 9 H, OSiC(CH ) ], 1.26 (t, J =
5
2
3
3
3 3
–
1
1
057 (w), 1016 (w), 990 (m), 727 (m), 671 cm (w).
2
3
.9 Hz, 1 H, OH), 3.43 (dd, J = 9.7 Hz, J = 7.5 Hz, 1 H, CHH-12), 3.58
1
3
2
3
3
3
H NMR (400 MHz, CDCl ):  = 0.45 [q, J = 7.9 Hz, 6 H, OSi(CH ) ], 0.84
(dd, J = 9.7 Hz, J = 5.6 Hz, 1 H, CHH-12), 4.32 (virt. dt, J = 7.3 Hz, J ≅
3
2 3
3
3
3
[t, J = 7.9 Hz, 9 H, OSi(CH CH ) ], 1.07 [s, 9 H, C(CH ) -TBDPS], 2.07 (s,
J = 5.4 Hz, 1 H, CH-13), 5.03 (dd, J = 15.3, 8.0 Hz, 1 H, CH-17), 6.27
2
3
3
3 3
2
3
3
3
3
H, CH CO), 3.38 (dd, J = 9.8 Hz, J = 7.0 Hz, 1 H, CHH-12), 3.51–3.54
(dd, J = 15.4, 5.0 Hz, 1 H, CH-14), 6.36 (dd, J = 15.4, 10.3 Hz, 1 H, CH-
15), 7.02 (dd, J = 15.3, 10.3 Hz, 1 H, CH-16), 7.32–7.44 (m, 6 H, CHAr),
3
3
3
3
(
m, 1 H, CHH-12), 4.22 (virt. q, J ≅ J = 6.2 Hz, 1 H, CH-13), 4.57 (dd,
3
3
3
3
J = 6.5 Hz, J = 1.2 Hz, 2 H, CH -18), 5.62 (dd, J = 15.1, 6.5 Hz, 1 H, CH-
4), 5.76 (dt, J = 15.3, 5.9 Hz, 1 H, CH-17), 6.06 (dd, J = 15.3, 10.6 Hz,
H, CH-16), 6.20 (dd, J = 15.1, 10.6 Hz, 1 H, CH-15), 7.32–7.44 (m, 6
7.61–7.63 (m, 2 H, CH ), 7.67–7.69 (m, 2 H, CH ), 9.50 (d, J = 8.0 Hz,
2
Ar
Ar
3
3
1
1
1 H, CH-18).
3
13C
NMR (101 MHz, CDCl ):

=
4.4 [t, OSi(CH ) ], 6.8 [q,
3
2 3
H, CH ), 7.62–7.73 (m, 4 H, CHAr).
Ar
OSi(CH CH ) ], 19.5 [s, OSiC(CH ) ], 27.1 [q, OSiC(CH ) ], 66.7 (t, CH -
2 3 3 3 3 3 3 2
13C
OSi(CH CH ) ], 19.5 [s, C(CH ) -TBDPS], 21.1 (q, CH CO), 27.2 [q,
NMR (101 MHz, CDCl ):

=
4.4 [t, OSi(CH ) ], 6.8 [q,
12), 73.9 (d, CH-13), 127.8 (d, CH ), 128.3 (d, CH-15), 130.0 (d, CHAr),
3
2
3
Ar
130.0 (d, CH ), 131.7 (d, CH-17), 133.6 (s, C ), 133.8 (s, C ), 136.0 (d,
2
3
3
3
3
3
Ar
Ar
Ar
C(CH ) -TBDPS], 64.9 (t, CH -18), 67.2 (t, CH -12), 74.3 (d, CH-13),
CH ), 145.7 (d, CH-14), 151.9 (d, CH-16), 194.0 (d, CH-18).
3
3
2
2
Ar
1
1
1
26.1 (d, CH-14), 127.6 (d, CHAr), 129.6 (d, CH *), 129.7 (d, CH *),
+
Ar
Ar
HRMS-ESI: m/z [C29H42O Si + Na] calcd: 517.2565; found: 517.2565.
3
2
29.7 (d, CH *), 129.8 (d, CH-16*), 134.0 (s, C ), 134.2 (d, CH-15),
Ar
Ar
34.3 (s, C ), 135.7 (d, CH-17), 136.1 (d, CH ), 136.1 (d, CH ), 170.9
Ar
Ar
Ar
Protected Triene 35
(s, CO); * interchangeable assignment.
Sulfone 24 (3.57 g, 6.80 mmol, 1.16 equiv) was dissolved in THF (100
mL), cooled to –78 °C and KHMDS (21.1 mL, 0.5 M solution in toluene,
+
HRMS-ESI: m/z [C31H46O Si + Na] calcd: 561.2827; found: 561.2830.
4
2
1
0.6 mmol, 1.80 equiv) was added slowly. After 30 min, the solution
TES/TBDPS-Protected Heptadienol 33
was warmed to –40 °C and a solution of aldehyde 34 (2.90 g, 5.86
To a cold (–78 °C) solution of acetate 32 (23.7 g, 44.0 mmol, 1.00
mmol, 1.00 equiv) in THF (30 mL) was added. The reaction was stirred
equiv) in CH Cl (600 mL) was added DIBAL-H (74.8 mL, 1.0 M solu-
for 19 h and then quenched by addition of sat. aq NH Cl solution (150
2
2
4
tion in CH Cl , 74.8 mmol, 1.70 equiv). After stirring for 16 h, the reac-
mL). After warming to r.t., the layers were separated and the aqueous
2
2
tion was quenched by addition of sat. aq potassium sodium tartrate
solution (500 mL). After warming up to r.t., the layers were separated
and the aqueous layer was extracted with CH Cl (1 × 200 mL) and
layer was extracted with Et O (3 × 150 mL). The organic layers were
2
combined, dried (Na SO ), and filtered. The solvent was removed un-
2
4
der reduced pressure. Following double flash column chromatography
2
2
Et O (3 × 250 mL). The organic layers were combined, dried (Na SO ),
(1. silica, pentane/Et O 100:1, 2. silica, pentane/CHCl3 1:1), triene 35
2
2
4
2
and filtered. The solvent was removed under reduced pressure. Fol-
was obtained as a colorless oil (4.23 g, 91%).
lowing flash column chromatography (silica, pentane/Et O 9:1 →
2
R = 0.85 (pentane/Et O, 4:1) [UV, KMnO , CAM]
f
2
4
3:1), alcohol 33 was obtained as a colorless oil (21.0 g, 96%).
IR (ATR): 2956 (vs), 2935 (s), 2911 (s), 2877 (s, Csp3–H), 2859 (m),
1731 (vs, C=O), 1460 (m, C=C), 1112 (vs, C–O), 997 cm (vs).
R = 0.59 (pentane/Et O, 1:1) [UV, KMnO ].
–1
f
2
4
IR (ATR): 3349 (br s, O–H), 2954 (s, Csp3–H), 2876 (s, Csp2–H), 2535 (w),
1
1
3
H NMR (500 MHz, CDCl ):  = 0.45 [q, J = 8.0 Hz, 6 H, OSi(CH ) -12],
3
2 3
078 (w), 987 cm–1 (m).
.58 [q, 3J = 7.8 Hz, 6 H, OSi(CH ) -21], 0.84 [t, J = 8.0 Hz, 9 H,
3
0
2
3
1
3
3
3
H NMR (500 MHz, CDCl ):  = 0.46 [q, J = 8.0 Hz, 6 H, OSi(CH ) ], 0.85
OSi(CH CH ) -12], 0.89 (d, J = 6.9 Hz, 3 H, CH -44), 0.95 [t, J = 7.8 Hz,
3
2
3
2
3
3
3
3
3
[t, J = 8.0 Hz, 9 H, OSi(CH CH ) ], 1.07 [s, 9 H, OSiC(CH ) ], 1.26 (t, J =
9 H, OSi(CH CH ) -21], 1.06 [s, 9 H, OSiC(CH ) ], 1.20 [s, 9 H,
2 3 3 3 3
2
3
3
3
3
2
3
COC(CH ) ], 1.87 (virt. qd, J ≅ 3J = 6.8 Hz, J = 3.0 Hz, 1 H, CH-22),
3
3
5
.9 Hz, 1 H, OH), 3.40 (dd, J = 9.8 Hz, J = 7.0 Hz, 1 H, CHH-12), 3.54
3 3
2
3
3
3
2
3
(dd, J = 9.8 Hz, J = 5.8 Hz, 1 H, CHH-12), 4.16 (virt. t, J ≅ J = 5.5 Hz, 2
2.23–2.33 (m, 2 H, CH -20), 3.40 (dd, J = 9.8 Hz, J = 6.9 Hz, 1 H, CHH-
2
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

N
Synthesis
S. Wienhold et al.
Special Topic
2
3
3
1
2), 3.54 (dd, J = 9.8 Hz, J = 5.9 Hz, 1 H, CHH-12), 3.79 (td, J = 6.6, 3.0
Trienal 3
To a solution of alcohol 36 (2.45 g, 3.45 mmol, 1.00 equiv) in CH Cl
3
3
Hz, 1 H, CH-21), 3.93–4.00 (m, 2 H, CH -23), 4.21 (virt. q, J ≅ J = 6.3
2
2
2
3
3
Hz, 1 H, CH-13), 5.58 (dt, J = 14.8, 7.3 Hz, 1 H, CH-19), 5.67 (dd, J =
4.7, 6.6 Hz, 1 H, CH-14), 5.98–6.09 (m, 4 H, CH-15, CH-16, CH-17,
CH-18), 7.31–7.43 (m, 6 H, CH ), 7.63–7.65 (m, 2 H, CH ), 7.68–7.70
(
100 mL) was added NaHCO3 (1.16 g, 13.8 mmol, 4.00 equiv) and
1
Dess–Martin periodinane (2.93 g, 6.91 mmol, 2.00 equiv). The sus-
pension was stirred for 1.5 h at r.t. and then diluted with pentane
(100 mL). After filtration over Celite, the organic layer was washed
Ar
Ar
(
m, 2 H, CHAr).
1
3
C NMR (126 MHz, CDCl ):  = 4.4 [t, OSi(CH ) -12], 5.2 [t, OSi(CH ) -
1], 6.9 [q, OSi(CH CH ) -12], 7.1 [q, OSi(CH CH ) -21], 10.6 (q, CH -
4), 19.5 [s, OSiC(CH ) ], 27.2 [q, OSiC(CH ) ], 27.4 [q, COC(CH ) ], 37.2
d, CH-22), 38.6 (t, CH -20), 38.9 [s, COC(CH ) ], 66.7 (t, CH -23), 67.3
t, CH -12), 72.2 (d, CH-21), 74.6 (d, CH-13), 127.5 (d, CHAr), 127.6 (d,
CH ), 129.6 (d, CH ), 129.7 (d, CH ), 130.6 (d, CH-19), 131.1 (d, CH-
twice with a mixture of NaHCO
tion (40 mL). The combined aqueous layers were extracted with a
mixture of pentane/Et O (10:1, 50 mL). The organic layers were com-
bined, dried (Na SO ), and filtered. The solvent was removed under
reduced pressure. Following flash column chromatography (silica,
pentane/Et O 30:1 → 15:1), aldehyde 3 was obtained as a colorless oil
3
solution (40 mL) and Na S O solu-
2
2
3
3
2
3
2 3
2
4
(
(
2 3 3 2 3 3 3
3
3
3
3
3 3
2
2
3
3
2
2
4
2
Ar
Ar
Ar
2
15), 131.2 (d, CH-16*), 132.5 (d, CH-18), 132.8 (d, CH-17*), 133.8 (d,
(2.22 g, 91%).
CH-14), 134.1 (s, C ), 134.4 (s, C ), 136.1 (d, CH ), 136.1 (d, CH ),
Ar
Ar
Ar
Ar
R = 0.81 (pentane/Et O, 4:1) [UV, KMnO , CAM].
f
2
4
178.6 (s, CO); * interchangeable assignment.
IR (ATR): 2955 (vs), 2932 (vs), 2912 (s), 2876 (s), 2858 (s, Csp3–H),
+
HRMS-ESI: m/z [C46H76O Si + Na] calcd: 815.4893; found: 815.4884.
–1
5
3
1729 (s, C=O), 1428 (m, C=C), 1106 (vs), 998 cm (vs, C–O).
1
3
H NMR (500 MHz, CDCl ):  = 0.45 [q, J = 7.9 Hz, 6 H, OSi(CH ) -12],
3
2 3
Trienol 36
.58 [q, 3J = 7.8 Hz, 6 H, OSi(CH ) -21], 0.85 [t, J = 7.9 Hz, 9 H,
3
0
2
3
3
To a cold (–78 °C) solution of triene 35 (1.38 g, 1.73 mmol, 1.00 equiv)
OSi(CH CH ) -12], 0.94 [t, J = 7.8 Hz, 9 H, OSi(CH CH ) -21], 1.07 [s, 9
H, OSiC(CH ) ], 1.09 (d, J = 7.0 Hz, 3 H, CH -44), 2.33 (virt. t, J ≅ J =
3 3 3
2
3
3
2
3
3
3
3
3
in CH Cl (58 mL) and toluene (58 mL) was added DIBAL-H (8.67 mL,
2
2
2
1
.0 M in CH Cl , 8.67 mmol, 5.00 equiv). After 2 h, the reaction was
7.1 Hz, 2 H, CH -20), 2.42–2.47 (m, 1 H, CH-22), 3.40 (dd, J = 9.8 Hz,
2
2
2
3
2
3
quenched by addition of sat. aq potassium sodium tartrate solution
75 mL). After warming up to r.t., the layers were separated and the
J = 6.9 Hz, 1 H, CHH-12), 3.54 (dd, J = 9.8 Hz, J = 5.8 Hz, 1 H, CHH-
3
(
12), 4.19–4.23 (m, 2 H, CH-13, CH-21), 5.58 (dd, J = 15.1, 7.5 Hz, 1 H,
CH-19), 5.69 (dd, J = 14.9, 6.2 Hz, 1 H, CH-14), 5.99–6.06 (m, 3 H, CH-
3
aqueous layer was extracted with EtOAc (3 × 200 mL). The organic lay-
ers were combined, washed with sat. aq NaCl solution (1 × 100 mL),
dried (Na SO ), and filtered. The solvent was removed under reduced
15, CH-16, CH-17), 6.07–6.13 (m, 1 H, CH-18), 7.31–7.43 (m, 6 H,
3
2
4
CH ), 7.63–7.65 (m, 2 H, CH ), 7.68–7.70 (m, 2 H, CH ), 9.74 (d, J =
Ar
Ar
Ar
pressure. Following flash column chromatography (silica, pen-
1.0 Hz, 1 H, CH-23).
tane/Et O 10:1 → 5:1), alcohol 36 was obtained as a colorless oil (1.13
g, 92%).
13
2
C NMR (101 MHz, CDCl ):  = 4.4 [t, OSi(CH ) -12], 5.2 [t, OSi(CH ) -
3
2
3
2 3
2
1], 6.8 [q, OSi(CH CH ) -12], 7.0 [q, OSi(CH CH ) -21], 7.7 (q, CH -
2 3 3 2 3 3 3
R = 0.31 (pentane/Et O, 4:1) [UV, KMnO , CAM].
44), 19.5 [s, OSiC(CH ) ], 27.2 [q, OSiC(CH ) ], 38.8 (t, CH -20), 51.3 (d,
f
2
4
3 3 3 3 2
CH-22), 67.3 (t, CH -12), 71.9 (d, CH-21), 74.6 (d, CH-13), 127.6 (d,
IR (ATR): 3435 (br m, O–H), 2955 (vs), 2933 (vs), 2877 (s), 2858 (s,
2
Csp3–H), 1740 (m), 1693 (s), 1415 (s, C=C), 1113 (vs), 998 cm–1 (vs, C–
O).
CH ), 127.6 (d, CH ), 129.4 (d, CH-19), 129.6 (d, CH ), 129.7 (d,
A
r
A
r
A
r
CH ), 131.1 (d, CH-15*), 131.7 (d, CH-16*), 132.1 (d, CH-17*), 133.7
Ar
(
d, CH-18), 134.2 (d, CH-14), 134.2 (s, CAr), 134.2 (s, C ), 136.1 (d,
1
3
Ar
H NMR (500 MHz, CDCl ):  = 0.46 [q, J = 8.0 Hz, 6 H, OSi(CH ) -12],
3
2 3
CH ), 136.1 (d, CH ), 205.1 (d, CH-23); * interchangeable assignment.
.61 [q, 3J = 7.9 Hz, 6 H, OSi(CH ) -21], 0.85 [t, J = 8.0 Hz, 9 H,
3
Ar
Ar
0
2
3
+
3
3
HRMS-ESI: m/z [C41H66O Si + H] calcd: 707.4342; found: 707.4340.
4 3
OSi(CH CH ) -12], 0.85 (d, J = 7.0 Hz, 3 H, CH -44), 0.96 [t, J = 7.9 Hz,
2
3
3
3
9
H, OSi(CH CH ) -21], 1.07 [s, 9 H, OSiC(CH ) ], 1.89–1.96 (m, 1 H,
2
3
3
3
3
3
3
3
CH-22), 2.31 (virt. t, J ≅ J = 6.9 Hz, 2 H, CH -20), 2.51 (dd, J = 6.0, 4.3
Hz, 1 H, OH), 3.41 (dd, J = 9.8 Hz, J = 6.9 Hz, 1 H, CHH-12), 3.53–3.57
Aldol Product 37
2
2
3
To a cold (0 °C) solution of ketone 4 (890 mg, 803 mol, 1.00 equiv) in
THF (5.5 mL) was added TMPMgCl·LiCl (2.11 mL, 0.76 M solution in
THF/toluene, 1.61 mmol, 2.00 equiv) over the course of 6 min. The or-
ange solution was stirred for 2.5 h and then (–)-B-chlorodiisopino-
campheylborane (1.15 mL, 50–65% in heptane, 1.61 mmol, 2.00
equiv) was added. After stirring for 2 h, a solution of aldehyde 3 (1.42
g, 2.01 mmol, 2.50 equiv) in THF (5.5 mL) was added. The solution was
stirred for 17 h while warming up to r.t. and then sat. aq potassium
sodium tartrate solution (50 mL) was added. The layers were separat-
ed and the aqueous layer was extracted with EtOAc (5 × 50 mL). The
combined organic layers were washed with sat. aq NaCl solution (1 ×
50 mL) and the aqueous layer was again extracted with EtOAc (1 × 50
2
3
(m, 2 H, CHH-12, CHH-23), 3.68 (ddd, J = 10.6 Hz, J = 8.1, 4.3 Hz, 1 H,
3
3
3
CHH-23), 3.86 (td, J = 6.5, 3.1 Hz, 1 H, CH-21), 4.21 (virt. q, J ≅ J = 6.4
3
3
Hz, 1 H, CH-13), 5.61 (dd, J = 14.9, 7.5 Hz, 1 H, CH-19), 5.67 (dd, J =
4.9, 6.4 Hz, 1 H, CH-14), 5.98–6.08 (m, 4 H, CH-15, CH-16, CH-17,
CH-18), 7.31–7.42 (m, 6 H, CH ), 7.63–7.65 (m, 2 H, CH ), 7.68–7.70
1
Ar
Ar
(
1
m, 2 H, CHAr).
3
C NMR (101 MHz, CDCl ):  = 4.4 [t, OSi(CH ) -12], 5.2 [t, OSi(CH ) -
3
2
3
2 3
2
4
1], 6.8 [q, OSi(CH CH ) -12], 7.0 [q, OSi(CH CH ) -21], 11.7 (q, CH -
4), 19.5 [s, OSiC(CH ) ], 27.2 [q, OSiC(CH ) ], 37.0 (t, CH -20), 39.8 (d,
2 3 3 2 3 3 3
3
3
3
3
2
CH-22), 66.3 (t, CH -23), 67.3 (t, CH -12), 74.7 (d, CH-13), 75.6 (d, CH-
2
2
2
1
1
1
1), 127.5 (d, CH ), 127.6 (d, CH ), 129.6 (d, CH ), 129.7 (d, CH ),
Ar Ar Ar Ar
31.0 (d, CH-19), 131.1 (d, CH-15*), 131.3 (d, CH-16*), 132.4 (d, CH-
7*), 132.9 (d, CH-18*), 133.8 (d, CH-14), 134.2 (s, CAr), 134.9 (s, CAr),
36.1 (d, CH ), 136.2 (d, CH ); * interchangeable assignment.
mL). All organic layers were combined, dried (Na
The solvent was removed under reduced pressure. Following flash
column chromatography (silica, pentane/Et O 30:1 → 5:1), a mixture
2 4
SO ), and filtered.
Ar
Ar
2
NH ]+ calcd: 726.4764; found:
+
4
of aldol 37, diisopinocampheylboron aldol adduct, ketone 4, and alco-
hol 36 was isolated as a colorless oil.
HRMS-ESI: m/z [C41H68O Si
4
3
726.4762.
The mixture was dissolved in CH Cl (25 mL) and MeOH (25 mL) and
2
2
8
-hydroxyquinoline (350 mg, 2.41 mmol, 3.00 equiv) was added. Af-
ter stirring at r.t. for 2.5 h, a further 350 mg 8-hydroxyquinoline (2.41
mmol, 3.00 equiv) and CH Cl (25 mL) were added, and stirring at r.t.
2
2
was continued for 20 h. Subsequently, sat. aq NH Cl solution (25 mL)
4
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

O
Synthesis
S. Wienhold et al.
Special Topic
was added, and the layers were separated. The aqueous layer was ex-
tracted with CH Cl (4 × 25 mL) and Et O (1 × 25 mL). The combined
mol, 4.00 equiv) and HF-pyridine (70 wt%/30 wt%, 10.4 L, 11.4 mg,
44.0 mol, 2.00 equiv) were added. The reaction was warmed to r.t.
and stirred for an additional 1 h and then quenched by addition of sat.
2
2
2
organic layers were dried (Na SO ) and filtered. After removal of the
2
4
solvent under reduced pressure, the residue was purified with flash
aq NaHCO solution (3 mL). The layers were separated and the aque-
3
column chromatography (silica, pentane/Et O 25:1 → 1:5), to afford
aldol 37 as a colorless foam (679 mg, 40%). Ketone 4 (331 mg, 37%)
and alcohol 36 (953 mg, 67%) were re-isolated.
ous layer was extracted with EtOAc (3 × 20 mL). The combined organ-
ic layers were washed with sat. aq NaCl solution, dried (Na SO ), and
filtered. The solvent was removed under reduced pressure. Following
2
2
4
flash column chromatography (silica, pentane/Et O 3:1), the desired
triol was obtained as a colorless oil (25.6 mg, 73%).
R = 0.45 (pentane/Et O, 7:1), [UV, KMnO , CAM].
2
f
2
4
IR (ATR): 3510 (br w, O–H), 3072 (w), 3049 (w, CAr–H), 2955 (s), 2931
The triol was dissolved in acetone (500 L) and PPTS (4.2 mg, 16.8
mol, 1.00 equiv) and 2-methoxypropene (18.1 mg, 251 mol, 15.0
equiv) were added. The solution was stirred for 1.5 h at r.t. and then
(
(
1
s), 2876 (m), 2858 (m, Csp3–H), 1725 (w, C=O), 1462 (m, C=C), 1112
vs), 1080 (vs), 998 (s, C–O), 822 cm (s).
–
1
H NMR (500 MHz, CDCl ):  = 0.04 [s, 3 H, OSi(CH )], 0.10 [s, 3 H,
3
3
quenched by the addition of sat. aq NaHCO solution (2 mL). The lay-
3
3
OSi(CH )], 0.45 [q, J = 8.0 Hz, 6 H, CH -12–OSi(CH CH ) ], 0.59–0.66
3
2
2
3 3
ers were separated and the aqueous layer was extracted with CH Cl
2
2
[
m, 12 H, CH-21–OSi(CH CH ) , CH-27–Si(CH CH ) ], 0.82–0.83 (m, 3
2 3 3 2 3 3
(
3 × 10 mL). The combined organic layers were dried (Na SO ) and fil-
2 4
3
H, CH -45), 0.84 [t, J = 8.0 Hz, 9 H, CH -12–OSi(CH CH ) ], 0.87–0.88
3
2
2
3 3
3
tered. After removal of the solvent under reduced pressure, the resi-
due was purified with flash column chromatography (silica, pen-
(
m, 3 H, CH -44), 0.91 [s, 9 H, OSiC(CH ) -TBS], 0.93 [t, J = 8.0 Hz, 9 H,
3
3
3
3
CH-27–Si(CH CH ) ], 0.96 [t, J = 8.0 Hz, 9 H, CH-21–OSi(CH CH ) ],
1
2
3
3
2
3 3
tane/Et O 10:1 → 7:1), to afford acetal-protected aldol product 38 as a
2
3
.02 (d, J = 6.5 Hz, 3 H, CH -40), 1.04 [s, 9 H, OSiC(CH ) -TBDPS], 1.06
3
3
3
colorless oil (17.4 mg, 64%). The methoxy acetal at C12 turned out to
be labile upon column chromatography.
[
s, 9 H, OSiC(CH ) -TBDPS], 1.07 [s, 9 H, OSiC(CH ) -TBDPS], 1.11 (d,
3
3
3
3
3
J = 6.6 Hz, 3 H, CH -34), 1.62–1.64 (m, 1 H, CH-22), 2.32–2.38 (m, 3 H,
3
3
3
R = 0.54 (pentane/Et O, 3:1), [UV, KMnO , CAM].
f 2 4
CH -20, CH-27), 2.65 (d, J = 3.0 Hz, 1 H, CH-38), 2.86 (q, J = 6.5 Hz, 1
2
H, CH-39), 3.04 (br s, 1 H, OH), 3.04–3.08 (m, 1 H, CH-24), 3.10 (dd,
IR (ATR): 2956 (m), 2927 (s), 2856 (m, Csp3–H), 1724 (m, C=O), 1260
(s), 1111 cm (vs, C–O).
3
–1
J = 9.7, 7.6 Hz, 1 H, CH-36), 3.17 (s, 3 H, CH-36–OCH ), 3.38 (s, 3 H,
3
3
CH-38–OCH ), 3.38–3.41 (m, 1 H, CHH-12), 3.43 (d, J = 7.6 Hz, 1 H,
1
3
H NMR (500 MHz, CDCl ):  = 0.07 [s, 3 H, OSi(CH )], 0.12 [s, 3 H,
3
3
3
CH-35), 3.44–3.46 (m, 1 H, CH-33), 3.49 (dd, J = 9.7, 3.0 Hz, 1 H, CH-
7), 3.53 (dd, J = 9.7 Hz, J = 5.9 Hz, 1 H, CHH-12), 3.91–3.95 (m, 2 H,
CH-21, CH-23), 4.19–4.24 (m, 2 H, CH-13, CH-32), 4.34 (d, J = 2.8 Hz,
H, CH-26), 5.52–5.58 (m, 3 H, CH-19, CH-28, CH-31), 5.68 (dd, J =
4.7, 6.3 Hz, 1 H, CH-14), 5.87 (dd, J = 15.0, 10.5 Hz, 1 H, CH-29),
.99–6.11 (m, 5 H, CH-15, CH-16, CH-17, CH-18, CH-30), 7.26–7.45
3
3
OSi(CH )], 0.63 [virt. qd, J = 7.9, 3.4 Hz, 6 H, Si(CH CH ) ], 0.81 (d, J =
7
OSiC(CH ) -TBS], 0.96 [t, J = 7.9 Hz, 9 H, Si(CH CH ) ], 1.02 (d, J = 6.4
3
2
3 3
2
3
3
3
.0 Hz, 3 H, CH -45), 0.84 (d, J = 6.8 Hz, 3 H, CH -44), 0.90 [s, 9 H,
3
3
3
3
3
3
3
2
3 3
3
1
1
5
Hz, 3 H, CH -40), 1.04 [s, 9 H, OSiC(CH ) -TBDPS], 1.07 [s, 18 H, 2
3
3 3
3
3
OSiC(CH ) -TBDPS], 1.11 (d, J = 6.5 Hz, 3 H, CH -34), 1.18 [s, 3 H,
3
3
3
O(CH )C(CH )OMe], 1.20 [s, 3 H, O(CH )C(CH )OMe], 1.31 [s, 3 H,
3
3
3
3
(
m, 18 H, CH ), 7.59–7.64 (m, 6 H, CH ), 7.68–7.74 (m, 6 H, CH ).
Ar Ar Ar
O(CH )C(CH )O], 1.34 [s, 3 H, O(CH )C(CH )O], 1.40–1.43 (m, 1 H, CH-
3
3
3
3
1
3
C NMR (101 MHz, CDCl ):  = –4.6 [q, OSi(CH )], –4.2 [q, OSi(CH )],
22), 2.15–2.21 (m, 2 H, CHH-20, CH-27), 2.31–2.37 (m, 1 H, CHH-20),
3
3
3
3
3
3
.3 [t, CH-27–Si(CH CH ) ], 4.4 [t, CH -12–OSi(CH CH ) ], 5.4 [t, CH-
2.66 (d, J = 3.0 Hz, 1 H, CH-38), 2.86 (q, J = 6.4 Hz, 1 H, CH-39), 3.02
2
3
3
2
2
3 3
3
2
1–OSi(CH CH ) ], 6.9 [q, CH -12–OSi(CH CH ) ], 7.0 [q, CH-21–
(s, 3 H, OCMe OCH ), 3.09 (dd, J = 9.7, 7.7 Hz, 1 H, CH-36), 3.15 (s, 3 H,
2
3
3
2
2
3
3
2
3
CH-36–OCH ), 3.19 (virt. dd, J ≅ 3J = 10.2, 7.1 Hz, 1 H, CH-24), 3.23
3
OSi(CH CH ) ], 8.0 [q, CH-27–Si(CH CH ) ], 13.8 (q, CH -45), 14.3 (q,
2
3
3
2
3
3
3
3
3
3
CH -44), 15.6 (q, CH -34), 16.7 (q, CH -40), 18.4 [s, OSiC(CH ) -TBS],
(dd, J = 9.4, 5.9 Hz, 1 H, CHH-12), 3.34 (dd, J = 9.4, 6.4 Hz, 1 H, CHH-
12), 3.38 (s, 3 H, CH-38–OCH ), 3.44 (d, J = 7.7 Hz, 1 H, CH-35), 3.46–
3.48 (m, 1 H, CH-33), 3.49 (dd, J = 9.7, 3.0 Hz, 1 H, CH-37), 3.91 (td,
J = 7.1, 2.1 Hz, 1 H, CH-21), 4.06 (dd, J = 10.2, 2.1 Hz, 1 H, CH-23),
4.21–4.23 (m, 1 H, CH-32), 4.24 (d, J = 3.4 Hz, 1 H, CH-26), 4.31 (virt.
q, J ≅ J = 6.2 Hz, 1 H, CH-13), 5.48 (dd, J = 14.9, 10.4 Hz, 1 H, CH-28),
5.52 (dd, J = 15.2, 6.5 Hz, 1 H, CH-31), 5.60 (virt. dd, J = 13.8 Hz, J ≅
3
3
3
3 3
3
1
9.4 [s, OSiC(CH ) -TBDPS], 19.5 [s, OSiC(CH ) -TBDPS], 19.6 [s,
3
3
3
3
3
3
OSiC(CH ) -TBDPS], 26.1 [q, OSiC(CH ) -TBS], 27.2 [q, OSiC(CH ) -TB-
3
3
3
3
3 3
3
3
DPS], 27.2 [q, OSiC(CH ) -TBDPS], 27.2 [q, OSiC(CH ) -TBDPS], 36.5 (d,
3
3
3 3
3
CH-27), 36.6 (d, CH-22), 38.8 (t, CH -20), 44.5 (d, CH-24), 60.5 (q, CH-
2
3
3
3
3
6–OCH ), 62.1 (q, CH-38–OCH ), 67.3 (t, CH -12), 69.7 (d, CH-39),
3
3
2
a
3
3
3
74.3 (d, CH-32), 74.5 (d, CH-13), 76.2 (d, CH-37), 77.4 (d, CH-21 ), 77.6
a
a
3
3
(d, CH-23 ), 77.8 (d, CH-33 ), 80.9 (d, CH-36), 81.1 (d, CH-26), 82.1 (d,
J = 7.2 Hz, 1 H, CH-19), 5.67 (dd, J = 14.9, 6.2 Hz, 1 H, CH-14), 5.85
CH-38), 102.9 (d, CH-35), 127.4 (d, CHAr), 127.5 (d, CH ), 127.5 (d,
(dd, 3J = 14.9, 10.5 Hz, 1 H, CH-29), 5.99 (dd, 3J = 15.2, 10.5 Hz, 1 H,
Ar
CH ), 127.6 (d, CH ), 127.6 (d, CH ), 127.6 (d, CH ), 127.9 (d, CH-
CH-30), 6.02–6.08 (m, 3 H, CH-15, CH-16, CH-17), 6.09–6.14 (m, 1 H,
Ar
Ar
Ar
Ar
b
b
3
1), 129.4 (d, CH-19 ), 129.5 (d, CH-29 ), 129.6 (d, CH ), 129.6 (d,
CH-18), 7.27–7.45 (m, 18 H, CH ), 7.59–7.66 (m, 6 H, CHAr), 7.70–7.74
Ar
Ar
CH ), 129.7 (d, CH ), 129.7 (d, CH ), 129.7 (d, CH ), 129.7 (d, CH ),
(m, 6 H, CHAr).
Ar
Ar
Ar
cd
Ar
Ar
c
d
1
31.1 (d, CH-15 ), 131.3 (d, CH-16 ), 132.3 (d, CH-17 ), 132.8 (d, CH-
13
C NMR (126 MHz, CDCl ):  = –4.7 [q, OSi(CH )], –4.1 [q, OSi(CH )],
3
3
3
d
d
e
e
18 ), 133.2 (d, CH-30 ), 133.9 (d, CH-14 ), 133.9 (d, CH-28 ), 133.9 (s,
3
.7 [t, Si(CH CH ) ], 4.8 (q, CH -44), 8.0 [q, Si(CH CH ) ], 12.1 (q, CH -
2 3 3 3 2 3 3 3
e
CAr ), 134.0 (s, C ), 134.1 (s, C ), 134.1 (s, C ), 134.4 (s, C ), 134.5 (s,
Ar
Ar
Ar
Ar
45), 15.5 (q, CH -34), 16.7 (q, CH -40), 18.3 [s, OSiC(CH ) -TBS], 19.4
[q, O(CH )C(CH )O], 19.5 [s, OSiC(CH ) -TBDPS], 19.5 [s, OSiC(CH ) -
3 3 3 3 3 3
TBDPS], 19.6 [s, OSiC(CH ) -TBDPS], 24.4 [q, O(CH )C(CH )OMe], 24.4
3
3
3
3
C ), 136.1 (d, CH ), 136.1 (d, CH ), 136.1 (d, CH ), 136.1 (d, CH ),
Ar
Ar
Ar
Ar
Ar
a–e
1
36.2 (d, CH ), 136.3 (d, CH ), 214.7 (s, C-25);
interchangeable as-
Ar
Ar
3
3
3
3
signments.
[
q, O(CH )C(CH )OMe], 26.0 [q, OSiC(CH ) -TBS], 27.2 [q, 2 OSiC(CH ) -
3 3 3 3 3 3
HRMS-ESI: m/z [C105H164O12Si7 + NH ]+ calcd: 1831.0946; found:
TBDPS], 27.2 [q, OSiC(CH ) -TBDPS], 29.9 [q, O(CH )C(CH )O], 31.7 (d,
4
3
3
3
3
1831.1003.
CH-22), 36.5 (t, CH -20), 36.9 (d, CH-27), 41.9 (d, CH-24), 48.5 (q, OC-
2
Me OCH ), 60.5 (q, CH-36–OCH ), 62.1 (q, CH-38–OCH ), 65.5 (t, CH -
2
3
3
3
2
1
7
2), 69.7 (d, CH-39), 73.1 (d, CH-21), 73.2 (d, CH-13), 74.3 (d, CH-32),
5.9 (d, CH-23), 76.2 (d, CH-37), 77.4 (d, CH-33), 80.9 (d, CH-26), 80.9
Acetal-Protected Aldol Product 38
To a cold (0 °C) solution of aldol product 37 (40.0 mg, 22.0 mol, 1.00
equiv) in THF (700 L) were added pyridine (7.0 L, 7.0 mg, 44 mol,
(
d, CH-36), 82.1 (d, CH-38), 99.0 (s, OCMe O), 100.0 (s, OCMe OMe),
2
2
1
02.7 (d, CH-35), 127.4 (d, CHAr), 127.4 (d, CH ), 127.5 (d, CH ), 127.5
Ar Ar
4.00 equiv) and HF-pyridine (70 wt%/30 wt%, 10.4 L, 11.4 mg, 44.0
(
d, CH ), 127.6 (d, CH ), 127.7 (d, CHAr), 127.7 (d, CH-31), 129.5 (d,
Ar Ar
mol, 2.00 equiv). After 3 and 5 h, further pyridine (7.0 L, 7.0 mg, 44
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, A–Q

P
Synthesis
S. Wienhold et al.
Special Topic
CH ), 129.6 (d, CH ), 129.6 (d, CH ), 129.6 (d, CH ), 129.7 (d, CH ),
J. 2008, 14, 2322. (d) Gross, S.; Nguyen, F.; Bierschenk, M.;
Sohmen, D.; Menzel, T.; Antes, I.; Wilson, D. N.; Bach, T.
ChemMedChem 2013, 8, 1954.
Ar
Ar
Ar
Ar
Ar
b
a
a
1
1
3
1
1
2
29.8 (d, CH ), 130.0 (d, CH-19 ), 130.0 (d, CH-29 ), 131.0 (d, CH-15 ),
Ar
bc
bc
c
31.0 (d, CH-16 ), 132.7 (d, CH-17 ), 132.8 (d, CH-18 ), 133.0 (d, CH-
0), 133.3 (d, CH-28), 133.6 (d, CH-14), 134.1 (s, CAr), 134.1 (s, CAr),
34.1 (s, C ), 134.4 (s, C ), 134.4 (s, C ), 134.5 (s, C ), 136.1 (d, CH ),
(10) Börding, S.; Bach, T. Chem. Commun. 2014, 50, 4901.
(11) (a) Evans, D. A.; Ng, H. P.; Clark, S. J.; Rieger, D. L. Tetrahedron
1992, 48, 2127. (b) Paterson, I.; Steadman neé Doughty, V. A.;
McLeod, M. D.; Trieselmann, T. Tetrahedron 2011, 67, 10119.
(12) (a) Kishi, N.; Maeda, T.; Mikami, K.; Nakai, T. Tetrahedron 1992,
Ar
Ar
Ar
Ar
Ar
36.1 (d, 2 C, 2 CH ), 136.2 (d, 2 C, 2 CH ), 136.3 (d, CH ), 213.8 (s, C-
Ar
Ar
Ar
a–c
5);
interchangeable assignments.
HRMS-ESI: m/z [C100H148O13Si5 + NH ]+ calcd: 1642.9529; found:
4
4
1
8, 4087. (b) Pohnert, G.; Boland, W. Tetrahedron 1994, 50,
0235. (c) Neubauer, T.; Kammerer-Pentier, C.; Bach, T. Chem.
1642.9554.
Commun. 2012, 48, 11629.
(
13) Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101,
Conflict of Interest
6120.
The authors declare no conflict of interest.
(14) (a) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.;
Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441. (b) Brown, H. C.;
Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org. Chem. 1992, 57, 499.
(c) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535.
Funding Information
Financial support by the Deutsche Forschungsgemeinschaft (Ba
(
15) (a) Galobardes, M.; Gascón, M.; Mena, M.; Romea, P.; Urpí, F.;
Vilarrasa, J. Org. Lett. 2000, 2, 2599. (b) Crossman, J. S.; Perkins,
M. V. J. Org. Chem. 2006, 71, 117.
1372/18) is gratefully acknowledged. S.W. was supported by a Ph.D.
fellowship of the Fonds der Chemischen Industrie, T.N. was the recipi-
ent of a Ph.D. scholarship by the Studienstiftung des Deutschen Vol-
(
16) (a) van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.;
Heathcock, C. H. J. Org. Chem. 1991, 56, 2499. (b) Evans, D. A.;
Yang, M. G.; Dart, M. J.; Duffy, J. L. Tetrahedron Lett. 1996, 37,
kes.
D
e
u
tsch
e
F
orsch
u
n
gsgem
e
inschaft(B
a
1
3
7
2
/18)Fo
n
ds
d
er
C
he
m
icshen In
d
ustri
e
()Studienstiftu
n
g
d
es
D
eutsch
e
n
V
o
l
k
es()
1
957. (c) Paterson, I.; Chen, D. Y. K.; Coster, M. J.; Aceña, J. L.;
Supporting Information
Bach, J.; Wallace, D. J. Org. Biomol. Chem. 2005, 3, 2431.
(
(
17) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
Supporting information for this article is available online at
1920.
https://doi.org/10.1055/a-1464-2576. Su
p
p
orting Inform atio
n
Su
p
p
orting Inform atio
n
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Chem. Rev. 1989, 89, 1841. (c) Winbush, S. M.; Mergott, D. J.;
Roush, W. R. J. Org. Chem. 2008, 73, 1818.
Primary Data
(19) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc.
1
995, 117, 9073.
Primary data for this article are available online at https://zeno-
do.org/record/4637081 and can be cited using the following DOI:
(
20) (a) Peterson, D. J. J. Org. Chem. 1968, 33, 780. (b) Ager, D. J. Syn-
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©
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