Synthesis of (+) and (-)-Streptomyces coelicolor Butanolide 5 (SCB-5)

Article abstract of DOI:10.1002/ejoc.202100497

Various 1-(1-hydroxyalkyl) paraconyl alcohols are important signaling molecules within antibiotics production in Streptomyces sp. Intending developing a flexible convergent chemical synthesis of such butanolides, a zwitterionic aza-Claisen rearrangement was chosen as reliable strategy generating the central stereotriad. Reaction of enantiopure N-allyl pyrrolidines and 4-phenylbutenoic acid fluoride delivered defined configured amides displaying the 2,3,1’ stereotriads. The configuration was determined by the allyl alcohol moiety indicating a complete remote stereo control. Amide removal by iodolactonization and proceeding reductions, halocyclization and elimination gave key alkylidene tetrahydrofuran derivatives. Stepwise degradation of the olefins through ozonolysis, reductive work-up and protecting group removal delivered both enantiomers of the target Streptomyces coelicolor butanolide 5.

Full text of DOI:10.1002/ejoc.202100497

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of (+) and (-) Streptomyces coelicolor Butanolide 5
(SCB-5)
Authors: Jonas Donges, Sandra Hofmann, Moritz Brüggemann,
Andrea Frank, Dieter Schollmeyer, and Udo Nubbemeyer
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100497
Link to VoR: https://doi.org/10.1002/ejoc.202100497
01/2020

10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
Synthesis of (+) and (-) Streptomyces coelicolor Butanolide 5
(SCB-5)
Jonas Donges,[a] Sandra Hofmann,[b] Moritz Brüggemann,[c] Andrea Frank,[a] Dieter Schollmeyer[a] and
Udo Nubbemeyer*[a]
[a]
J. Donges, A. Frank, Dr. D. Schollmeyer, Prof. Dr. U. Nubbemeyer
Organische Chemie
Johannes Gutenberg-Universität Mainz
Duesbergweg 10 – 14, D-55128 Mainz
E-mail: nubbemey@uni-mainz.de
S. Hofmann
Konrad-Adenauer-Gymnasium
Wörthstr. 16, D-56457 Westerburg
Dr. M. Brüggemann
[b]
[c]
Shimadzu Deutschland GmbH
Im Leuschnerpark 4, D-64347 Griesheim
Supporting information for this article is given via a link at the end of the document.
Abstract: Various 1-(1-hydroxyalkyl) paraconyl alcohols are
important signaling molecules within antibiotics production in
Streptomyces sp. Intending developing a flexible convergent chemical
VB-Factor I) to VB-E and Gräfe VB-Factors II and III 3a – 3i.5 The
SCB-type GBL’s incorporating 2-(1’,n-dihydroxyalkyl) side chains
should be attributed to a third family 2l – 2o.6
synthesis of such butanolides,
a
zwitterionic aza-Claisen
rearrangement was chosen as reliable strategy generating the central
stereotriad. Reaction of enantiopure N-allyl pyrrolidines and 4-
phenylbutenoic acid fluoride delivered defined configured amides
displaying the 2,3,1’ stereotriads. The configuration was determined
by the allyl alcohol moiety indicating a complete remote stereo control.
Amide removal via iodolactonization and proceeding reductions,
halocyclization and elimination gave key alkylidene tetrahydrofuran
derivatives. Stepwise degradation of the olefins via ozonolysis,
reductive work-up and protecting group removal delivered both
enantiomers of the target Streptomyces coelicolor butanolide 5.
OH
O
H
R
1'
3
( )2
2
O
VB-type
(1'S)-anti-anti
SCB/IM-2-type
(1'R)-syn-anti
O
1g: (-)-A-Factor
OH
OH
OH
OH
H
H
R
R
R
S
R
R
( )2
( )2
R
R
O
O
O
O
3a: not found
3b: (-)-VB-E
3c: (-)-VB-C
2a: (-)-IM-2
2b: not found
2c: (-)-SCB-8
3d: (-)-VB-A =
Gräfe VB-Factor I
3e: (-)-VB-B
3f: (-)-VB-D
3g: (-)-Gräfe VB-Factor II
2d: (-)-SCB-5
Introduction
2e: (+)-SCB-4
2f: (-)-SCB-6
2g: (-)-SCB-1 =
Gräfe SCB-Factor 1
2h: (-)-SCB-2
2i: not found
2j: SCB-3
Small molecule hormones are known to trigger the antibiotic
production in various bacteria.1 Focusing on Streptomyces sp.,
defined 2,3 disubstituted γ-butyrolactones had been identified as
a family of compounds characterized by prominent bioactivity.2
Systematic investigation and structure elucidation had been
initiated by the pioneering work of Khokhlov et al. in 1976 isolating
and characterizing the so-termed A-factor 1g from Streptomyces
griseus (S. griseus) displaying the only 2-acyl-3-hydroxymethyl γ-
butyrolactone natural product found so far (Figure 1).3 Since then,
three series of trans 2-(1’-hydroxyalkyl)-3-hydroxymethyl γ-
butyrolactones had been isolated successively from
Streptomyces sp. such as S. viridochromogenes,4a S.
bikiniensis,5a S. cyaneofuscatus,5a S. coelicolor,4a-d S. virginiae,5c,d
S. lavendulae,4e S. badius.6a Despite of the fact, that the relative
and absolute stereochemistry of several γ-butyrolactones (GBL’s)
remain to be validated,4a,5a,7 three substitution pattern types
predominate. The Streptomyces coelicolor butanolide/IM-2 type 2
(SCB) comprises (2R, 3R, 1’R)-trans-2-(1’-hydroxyalkyl)-3-
(hydroxymethyl)-γ-butyrolactones SCB-1 (Gräfe SCB-Factor 1) to
SCB-8 and IM-2 2a – 2k.4 In contrast, the Virginiae butanolide
(VB) type 3 displays the (2R, 3R, 1’S) diastereomers VB-A (Gräfe
3h: not found
3i: (-)-Gräfe VB-Factor III
3j: not found
3k: not found
2k: SCB-7
2l, 2n, 2m, 2o: 2-(1',n-dihydroxyalkyl)
Figure 1. γ-Butyrolactones from natural sources/bioreactors: (C7)1g (-)-A-factor
(R = 3-Me-C4H8 [iC5H11]). 2 (SCB-type, increasing C2 chain length) (C4) 2a (-)-
IM-2 (R = Me). (C6) 2c (-)-SCB-8 (R = nC3H7). 2d (-)-SCB-5 (R = 2-Me-C3H6
[iC4H9]). 2e (+)-SCB-4 (R = 1-Me-C3H6 [sC4H9], 2 diastereomers), (C7) 2f (-)-
SCB-6 (R = nC4H9). 2g (-)-SCB-1, Gräfe SCB-Factor 1 (R = 3-Me-C4H8 [iC5H11]).
(C8) 2h (-)-SCB-2 (R = nC5H11), 2j SCB-3 (R = 3-Me-C5H10 [sC6H13], 2
diastereomers). (C9) 2k SCB-7 (R = nC6H13). 2-(1,n-dihydroxylalkyl) SCB-
series: (C4) 2l (R = 3-hydroxy-3-Me-C4H7). (C5) 2m (R = 3-hydroxy-4-Me-C5H9,
2 diastereomers). (C6): 2n (R = 4-hydroxy-5-Me-C6H11, 2 diastereomers). 2o (R
= 5-hydroxy-5-Me-C6H11). 3 (VB-type, increasing C2 chain length) (C5) 3b (-)-
VB-E (R = 1-Me-C2C4 [iC3H7])., (C6) 3c (-)-VB-C (R = nC3H7). 3d (-)-VB-A, (-)-
Gräfe VB-factor I, (R = 2-Me-C3H6 [iC4H9]). 3e (-)-VB-B (R = 1-Me-C3H6 [sC4H9],
2 diastereomers). (C7) 3f (-)-VB-D (R = nC4H9), 3g (-)-Gräfe VB-factor II (R = 3-
Me-C4H8 [iC5H11])., (C8) 3i (-)-Gräfe VB-factor III (R = 4-Me-C5H10 [iC6H13]).
Various defined GBL’s have been isolated from different
streptomyces strains.4,5 Obviously, a particular GBL influences
1
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10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
OPG
OPG
O
biosynthesis
pathways
depending
on
the
individual
H
CHO
bacterium.2e,4d,8 Analyzing the SCB and the VB diastereomers and
enantiomers of the SCB-1 type, Takano et al. found, that the
bioactivity of the all (R) configured (-)-SCB-1 showed by far the
highest activity within a Kanamycin bioassay in comparison to the
three analogues pointing out the importance of the defined
substituted and configured compound in connection with the
bioactivity of a special organism.4c Furthermore, investigation of a
series of GBL’s gave an optimal C2 chain length of 7 to 9 carbon
atoms, an additional methyl group at C6 (favored) and C7 (less
favored) and a 1’ (R) OH group. Generally, the corresponding
1’(S) VB diastereomers were described to be less active.4c
In contrast, VB-bioessays gave different results in respect to
bioactivity. Investigations by Y. Yamada et al. gave optimal C2
chain lengths of 6 to 8 carbon atoms,2e,8 an additional methyl
group at C5 (VB-A) and the standard 1’ (S) configured OH group.9
In contrast, additional methyl groups at C4 caused a drastic loss
of bioactivity.5d The corresponding SCB-type diastereomers were
described to be about 10-fold less active.9a Investigation of the
VB-A hyperproducing strain S. antibioticus NF-18 improved the
biosynthesis of (-)-VB-A (major) and both enantiomers of SCB-5
(minor).9d However, the bioactivity regulating role of the GBL’s
remains unclear.
R
( )2
*
*
CO2Me
O
O
O
O
B-1
B
C
Ref. 10f-i
OH
Ref. 10f
O
OH
OH
B-3
HO
HO
H
*
1'
R
3
O
2
( )2
*
*
*
X
O
O
A
O
O
B-2
Ref. 10k
NO2
O
D
O
NO2
O
O
O
R
H
G
( )2
H
F
X
R
R
Ref. 10k
( )2
( )2
*
*
+
OPG
O
O2N
OPG
O
X
E
Figure 2. Chemical syntheses of butanolides (X = O-alkyl, NH-alkyl, N-
acyl/alkyl; PG = OH, TBS, Bn, Ph, acyl, etc.). For details see Ref 10.
Results and Discussion
Despite of the fact, that modified hyperproducing Streptomyces
strains deliver (semi)preparative amounts of suitable GBL
derivatives, chemical syntheses of A-factor,10a-e SCB-type4b,10f-i
and VB-type10j-k products promised a higher flexibility upon
generating defined diastereomers and enantiomers.4b,5c,10
Chemical syntheses of GBL’s A known so far can be subdivided
in two strategies (Figure 2). Most attempts described the
generation of optically active protected paraconyl alcohol C from
paraconic acid B-1 and open chain reactants B-1/B-2,
respectively. The final steps incorporate the butanolide C2 side
chain introduction via aldol type reaction (using suitable
aldehydes, direct formation of A)10f or via Claisen condensation
(using acid derivatives) affording 2-acyl butanolides C and
subsequent reduction of the ketone moiety (→ A).10f-i Jørgensen
et al.10k started with a Michael addition of a suitable β-ketoester
(X = OR)/amide (X = NR2) derivative D and nitroalkene E to
Re-analyzing the substitution patterns of the Streptomyces
butenolides, the sequence of three continuous stereogenic
centers (2, 3, 1’) can be defined as the central segment of all
targets. The defined generation of the optically active stereotriad
independent of final ring closure and functional group
transformations promised developing flexible and reliable
syntheses of selected natural products. The retrosynthesis
concentrated on assembling the backbone including the
stereogenic centers (1’, 2, 3) using a kit of building blocks and
final functional group variations enabling completion of the
syntheses (Scheme 1).
Starting from target butanolide I, lactone and hydroxymethyl
function should originate from the corresponding olefins in II via
ozonolytic cleavage and reductive work-up without endangering
epimerization of the adjacent C2 and C3 positions. The vinyl ether
in II must be obtained from unsaturated carbinol III via haloether
formation and elimination. Carbinol III represents the reduction
product of amide IV, which should be build-up by a zwitterionic
aza-Claisen rearrangement from allylamine V and styryl acetic
acid fluoride VI.11 Acyl fluoride VI can be generated in two steps
from malonic acid and phenyl acetaldehyde via Knoevenagel
condensation and acid fluoride formation.12 Allylamine V should
be obtained from aldehyde VII and a suitable N-propargyl prolinol
derivative VIII via alkyne addition reduction and carbinol
protection.13 Prolinol derivative VIII can be generated from L-(-)-
proline via reduction/OH protection and N propargylation adapting
literature procedures.13
generate
a protected 3-nitroallyl alcohol F. Ring closure
generating the γ-lactone G, reduction of the ketone moiety and
Nef reaction of the nitro group and a final reduction delivered the
target molecules A.
Overall, all attempts incorporated a late-stage introduction of
almost two stereogenic centers requiring challenging structure
elucidations. Until 1990, the VB-type GBL’s had been described
as 2,3-cis butanolides displaying 2(S), 3(R), 1’(R) configurations
(see K. Mori et al. 1990).10h In 1991, Y. Yamada et al. published
a corrected assignment of the stereocenters of the VB-type GBL’s
as 2(R), 3(R), 1’(S).10i Obviously, the so termed “trans-VB-type”
diastereomers effectively displayed the SCB-type 2(R), 3(R),
1’(R) configuration.10h,i Consequently, synthesis strategies
separating the generation of the stereogenic centers and the
complete assembly of the β hydroxy lactone moiety occurred
advantageous meeting the stereoselectivity challenges.
2
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10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
Ph
O
Ph
5 steps
ref. 13
OPG1
OPG1
OH
OMe
OH
*
N
( )3
6
H
N
H
*
HCl
H
OPh
O
+
R
*
*
*
*
*
*
R
4
5
R
*
OH
O
O
4 steps, both diastereomers
or 5 steps, Midland's reagent
ref. 13
O
I
II
III
OTBS
OTBS
Ph
+
S
S
N
N
S
R
( )3
Ph
( )3
OPG1
*
OPG1
(4R)-8
PhO
(4S)-7
PhO
N
N
+
*
*
*
R
R
F
O
Scheme 2. Syntheses of optically active N-allylpyrrolidine diastereomers (4S)-
7 and (4R)-8 according ref. 13.
PG2O
PG2O
O
V
VI
IV
Ref. 12, 17
HO2C
Ref. 13
Ph
CHO
CO2H
+
Acid fluoride 9 was obtained from phenylacetaldehyde and
malonic acid via two steps (Scheme 3). Literature known
Knoevenagel condensation of phenylacetaldehyde and malonic
acid delivered 4-phenyl-3-butenoic acid (78% yield),17 which then
was activated with cyanuric fluoride and pyridine to give acid
fluoride 9 with quantitative yield.12c
O
H
N
N
PG2O
VIII
HO
+
R
H
VII
O
Scheme 1. Retrosynthesis of defined γ-butyrolactones. Streptomyces coelicolor
butanolide 5 (SCB-5) 2d and Virginiae butanolide A (VB-A) 3d substitution
pattern: R = 4-Me-C5H10/iC6H13
.
i
F
HO2C
CO2H
Ph
+
Ph
CHO
ref. 15, 11c
O
9
phenylacetaldehyde
malonic acid
For a first total synthesis, the SCB-5/VB-A 2d/3d substitution
pattern was chosen. (-)-VB-A is described as the most bioactive
compound of the VB family. Including the corrections of Yamada
et al.10i Mori et al. already published the syntheses of (-)-SCB-5
2d and (-)-VB-A 3d in 1990 as a mixture of diastereomers.10h,14
Therefore, diastereoselective syntheses aiming for assembling
complete data sets of these compounds have been developed in
our laboratory.
The synthesis started synthesizing the key N-allyl prolinol
diastereomers 10 and 11 (retrosynthesis compound V) as well as
acid fluoride 12 (retrosynthesis compound VI) according literature
procedures.15
For optically active pyrrolidine derivative 7 and 8 syntheses, L-(-)-
proline methyl ester 4 was used as starting material (Scheme 2).
A five-step sequence (N-benzylation, LiAlH4 reduction, Buchwald
phenyl ether formation, benzylamine hydrogenolysis and N-
propargylation) afforded N-propargyl prolinol 5 via five steps with
74% yield overall.13 Alkynyl anion coupling with aldehyde 6 (two
steps from 5-methyl hexanoic acid: LiAlH4 reduction, TEMPO
oxidation, 96%), HPLC resolution of the diastereomers of the
corresponding O-acetyl mandelic esters, LiAlH4 reduction and
allylalcohol TBS protection delivered both, N-allyl prolinol
derivative (4R)-8 with 34% yield and diastereomer (4S)-7 with
37% yield. Alternatively, a five-step sequence of alkynyl anion
(from 5) coupling with aldehyde 6, MnO2 oxidation and
subsequent Midland’s reagent controlled diastereoselective
ketone reduction, LiAlH4 reduction and TBS protection allylalcohol
moiety selectively afforded N-allyl prolinol derivative (4R)-8 with
42% yield.16
Scheme 3. Synthesis of acid fluoride 9. Conditions and yields: iv) (a) N-methyl
morpholine, 95 °C, 14 h, 78%. Ref 17. (b) C3F3N3, CH2Cl2, pyridine, 0 °C to
23 °C, 3 h, >99%. According Ref. 12c.
The aza-Claisen rearrangement using allylamine diastereomers
(4S)-7 and (4R)-8, respectively, and acid fluoride 9 served as the
key step upon generating the stereotriad displaying amides 10
and 11 (Scheme 4).11 Predictably, the reaction of TBS-ether
derived allylamine (4S)-7 and acid fluoride 9 gave product amide
10 with 93% yield as a single diastereomer (matched combination
of the stereodirecting factors, see Figure 5 below). First attempts
intending for direct reduction of the amide to the corresponding
primary alcohol failed despite of wide variation of the reaction
conditions.18 Because of unconvincing results running direct
tertiary amide cleavage processes,19
a reliable two-step
sequence was applied. Removal of the pyrrolidine auxiliary
moiety succeeded via iodo lactonization.11g,19,20 Treatment of
amide 10 with iodine in DME/H2O delivered a mixture of C4-α
iodolactone ent-α-11 and C4-β iodolactone ent-β-11 as a 0.85:1
mixture of C4-epimers with 91% yield. The relative configuration
of the new stereogenic centers (C2/C3 anti) was elucidated by
means of NOESY analyses. Furthermore, iodolactone ent-β-11
crystallized and the X-ray analysis improved absolute and relative
configurations of all stereogenic centers (Figure 3).21 Reductive
opening of the lactones ent-11 with Zn/HOAc gave the
intermediate acid (85% yield, not shown), which was treated with
diazomethane solution to afford corresponding ester ent-15 with
88% yield (75% yield over 2 steps). Furthermore, reaction of the
intermediate acid with SOCl2 in MeOH caused TBS group
removal and subsequent cyclization to give lactone ent-13 with
90% yield (77% yield over 2 steps). Careful structure elucidation
via NOESY analysis gave the cis arrangement of all γ-
butyrolactone side chains.
Surprisingly, reaction of allylamine (4R)-8 and acid fluoride 9
delivered amide 14 with 90% yield as a single diastereomer
3
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10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
Et2O, 0 °C, 5 h, yields: 75% 12 (from 11); 75% ent-12 from ent-11 (two steps
each). Remark: Since α and β characterize the relative arrangement of the
iodomethyl group within the present drawing, α-11/ent-β-11 as well as β-11/ent-
α-11 represent enantiomers.
(Scheme 4). No minor compounds had been found after careful
analyses (HPLC, NMR). Despite of the fact, that the mismatched
combination of the stereodirecting ether and pyrrolidine moieties
had been involved, one of these factors completely predominated
the diastereoselectivity of the process (see Figure 5 below). Again,
removal of the pyrrolidine via iodocyclization delivered lactones α-
11 and β-11 as a 1:1 mixture of C4-epimers (76% yield). The
relative configuration of the new stereogenic centers (C2/C3 anti)
could be elucidated by means of NOESY analyses. In analogy to
the enantiomer series mentioned above, iodolactone α-11
crystallized and the X-ray analysis improved absolute and relative
configurations of all stereogenic centers (Figure 4).21 Finally,
reductive opening of the lactones 11 with Zn/HOAc gave the
intermediate acid (81% yield, not shown), which was treated with
diazomethane solution to afford corresponding ester 12 with 92%
yield (75% yield over 2 steps). Furthermore, reaction of the
intermediate acid with SOCl2 in MeOH caused TBS group
removal and subsequent cyclization to give lactone 13 with 68%
yield (55% yield over 2 steps). Careful structure elucidation via
NOESY analysis gave the cis arrangement of all γ-butyrolactone
side chains.
Ph
Figure 3. X-ray structure of iodolactone ent-β-11 (only selected hydrogens are
shown).
OTBS
OTBS
i
S
S
N
N
S
S
( )3
( )3
O
PhO
PhO
(4S)-7
10
ii
Ph
TBSO
H
1'
2
( )3
O
3
4
*
O
I
iii, iv
H
iii, v
ent--11/
ent--11
Ph
O
O
OTBS
Ph
OMe
S
S
( )3
( )3
O
ent-13
ent-12
Ph
OTBS
OTBS
i
S
S
N
N
R
R
( )3
( )3
O
PhO
PhO
(4R)-8
14
ii
Figure 4. X-ray structure of iodolactone α-11 (only selected hydrogens are
Ph
shown).
TBSO
H
1'
2
( )3
I
O
3
Methyl esters 12 and ent-12 displaying both enantiomeric
stereotriades served as starting key intermediates for SCB/IM-2
butenolide syntheses (2R,3R,1’R) (-)-SCB-5 2d (Schemes 6, 7,
9) and (2S,3S,1’S) (+)-SCB-5 ent-2d (Schemes 5, 8).22 Reduction
of the ester functions with DIBAL-H afforded the carbinols 15 and
ent-15 with high yields (99% of 15 and 85% of ent-15,
respectively).
4
*
O
iii, iv
H
iii, v
-11/
-11
Ph
O
O
OTBS
Ph
OMe
R
R
( )3
13
( )3
O
12
A most straight forward process heading for the target butanolide
ent-2d formation was the oxidative cleavage of both double bonds
of carbinol ent-15 (Scheme 4). Ozonolysis had to generate two
aldehyde functions, five-membered ring lactol formation should
protect the C1 position. The remaining aldehyde moiety had to be
reduced selectively20 to deliver hydroxymethyl lactol ent-16.
Scheme 4. Aza-Claisen rearrangement of allylamines (4S)-7 and (4R)-8,
structure elucidation and auxiliary removal. Conditions and yields: i) 9, Me3Al,
Na2CO3, CH2Cl2, 0 °C, 4 d, yields: 93% (10), 90% (14). (ii) I2, DME, H2O, 23 °C,
4 d, yields: 38% β-11 + 38% α-11 (from 13); yields: 49% ent-β-11 + 42% ent-α-
11 (from 10), 21 h. (iii) Zn, HOAc, Et2O, 23 °C, 2 d, (iv) SOCl2, MeOH, 23 °C, 3
d, yields: 55% 13 (from 11); 77% ent-13 from ent-11 (two steps each). (v) CH2N2,
4
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10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
However, various attempts varying reagents and conditions failed
because of the rapid destruction of the material under the
oxidizing conditions or the competing reduction of the lactol
delivering triol side products (stereochemical information of C3 is
lost).
The failure of the twofold oxidative cleavage of the double bonds
in combination with proceeding chemoselective aldehyde
reduction (hydroxymethyl moiety) and oxidation (lactol moiety)
two regioisomer tetrahydrofurans 20/21 (63% yield, ratio 48:52)
and ent-20/ent-21 (84% yield, ratio 43:57) as single
diastereomers, respectively (Schemes 5, 6). After careful column
chromatography and
HPLC
separation
2-(iodomethyl)
tetrahydrofurans 21/ent-21 displayed the standard 5-exo-trig
substitution pattern in favor of the trans C1/C2 arrangement of the
side chains.26a-f The formation of the regioisomers 20/ent-20
indicated a competing 5-endo-trig reaction.26g,h Obviously, the
motivated to generate an enolether function first (Scheme 5). Now, attack of the iodo cation at the styryl double bond generated an
ozonolysis of olefin and enolether type ent-22 would have
generated a lactono aldehyde intermediate, the so formed
aldehyde function had to be selectively reduced to build-up
hydroxy lactones type ent-23.
intermediate benzyl cation, which finally underwent intramolecular
five membered ring ether formation affording the 2-phenyl-
tetrahydrofurans 20/ent-20 with trans arrangement of all side
chain substituents. Wide variation of iodo cation donor and
reaction conditions resulted no higher regioselectivity in favor of
regioisomers 21/ent-21. However, starting from iodo
tetrahydrofuran ent-20, reductive elimination using Zn and HOAc
enabled regeneration of carbinol ent-15 with nearly quantitative
yield (Scheme 5).
Then, installation of the exo enolether moiety had been
investigated (→ ent-22) (Scheme 5).27 Reactions of iodomethyl
derivative ent-21 at room temperature induced substitution
processes. AgOTf/tBuOK, pyridine replacement of iodide only
generated carbinols and pyridinium salts, respectively.28 In
contrast, long lasting subjecting of iodomethyl tetrahydrofuran
ent-21 to potassium tert-butoxide in refluxing THF gave exo
enolether ent-22 with > 99% yield after 9 days of reaction time.
Again, simultaneous oxidative cleavage of both double bonds
failed (→ ent-23). The intermediately formed lactonoaldeyde
might have suffered from proceeding condensation (β-eliminaton
of the lactone carboxyl group) and further oxidation of the nascent
acrolein moiety.
For tetrahydrofuran formation and subsequent β elimination to
generate exo enol ethers of type ent-22, a selenocyclization,24a-c
oxidation, syn-elimination cascade24d,e had been tested (Scheme
5). Treatment of carbinol ent-15 with PhSeBr and SnCl2 in CH2Cl2
smoothly delivered 2-(phenylselanylmethyl) tetrahydrofuran ent-
17 with 77% yield as a 41:36 mixture of C1 β and α-epimers.25
Subsequent oxidation with mCPBA afforded the corresponding
selenoxide ent-18 diastereomers with nearly quantitative yields
(>97%). However, in contrast to literature precedence describing
tetrahydropyran exo enolether formation from phenylselenyl
methyl precursors,24d,e no β elimination generating enolether ent-
22 could be enforced. Heating of the material induced
decomposition and competing product formation (e. g. furofuran
derivative ent-19 after silyl group removal and cyclization).
Furthermore, no exo enolether ent-22 and hydroxylactones type
ent-23 compounds were found upon running selenium oxidation,
oxidative cleavage of the olefins and aldehyde reduction as a one
pot process.
Ring closure by means of iodocyclization required careful
optimization.26 In contrast to the iodolactonizations using amides
10/14 and the selenocyclizations described above, treatment of
carbinols 15 and ent-15 with iodine in Et2O/aq. NaHCO3 afforded
Overall, the simultaneous oxidative cleavage of both olefines
failed, enforcing development of a stepwise process. In this
connection, the iodoethers 20/ent-20 and 21/ent-21 served as
appropriate starting materials.
Ph
Ph
Ph
Ph
Ph
TBSO
( )3
TBSO
( )3
OTBS
OTBS
H
H
( )3
O
H
ii
iii
OMe
i
iv
H
( )3
ent-12
( )3
ent-15
O
O
O
OH
O
PhSe
PhSe
O
ent-17
ent-18
ent-19
H
v
vi
I
Ph
Ph
Ph
OH
OH
TBSO
( )3
TBSO
H
H
TBSO
( )3
TBSO
( )3
TBSO
( )3
+
H
H
O
( )3
vii
H
O
O
O
O
O
HO
I
ent-16
ent-20
ent-21
ent-22
ent-23
Scheme 5. Synthesis of iodo tetrahydrofuranes ent-20 and ent-21: Conditions and yields: (i) DIBAL-H, CH2Cl2, -78 °C, 5 h, yield: 85% ent-15; (ii) SnCl2, PhSeBr,
CH2Cl2, 23 °C, 15 min, yield ent-17 77% overall. HPLC separation gave β (CH2SePh) ent-17: 32% (OTBS + 9% (OH), α (CH2SePh) ent-17: 26% (OTBS) + 10%
(OH). (iii) from ent-15 via crude ent-17: mCPBA, pyridine, DME, -78 °C, 30 min, 23 °C, 1.5 h, yield ent-18 (mixture of diastereomers) 97% (from ent-15). (iv) pyridine,
DME, 80 °C 4 h, yield ent-19: 19% (from ent-15). (v) I2, NaHCO3, Et2O, H2O, 23 °C, 9 h yields: 36% ent-20 and 48% ent-21 (d.r. 43:57). (vi) Zn, HOAc, Et2O, 23 °C,
22 h, yield: >99%. (vii) tBuOK, THF, 60 °C, 6 d, yield: >99% ent-22.
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
Ph
O
Ph
I
I
TBSO
( )3
TBSO
i
Ph
Ph
O
( )3
H
H
OTBS
OTBS
i
CO2H
24
20
OMe
( )3
( )3
iii
iii
ii
O
OH
12
15
ii
Ph
Ph
TBSO
( )3
I
H
TBSO
O
Ph
Ph
O
I
( )3
TBSO
( )3
TBSO
H
O
H
O
R
+
( )3
20
26
25a: R = CO2Me
25b: R = CHO
H
O
21
iv
I
OH
OH
HO
TBSO
( )3
Scheme 6. Synthesis of iodo tetrahydrofuranes 20 and 21: Conditions and
yields: (i) DIBAL-H, CH2Cl2, -78 °C, 5 h, yield: >99% 15; (ii) I2, NaHCO3, Et2O,
H2O, 23 °C, 17 h yields: 32% 21 and 31% 20 (d.r. 52:48).
H
H
v
( )3
O
23
O
O
O
2d
2-Phenyl tetrahydrofuran 20 was chosen to install the carboxyl
function first.29 Ozonolysis of iodoether 20 in MeOH and oxidative
work-up with aqueous H2O2 afforded acid 24 (Scheme 7).
Because of work-up and purification problems, a disappointing
yield of 21% was found. For facilitating chromatographic
purification and characterization, the crude acid 24 was
Scheme 7. Synthesis of (-)-SCB-5 2d. Conditions and yields: (i) O3/O2, MeOH,
-78 °C, 20 min, then: 35% aq. H2O2, MeOH, -78 °C to 23 °C, 15 h. Yield: 21%
24. (ii) CH2N2, Et2O, 0 °C, 3 h, yield 26% 25a (from 20) + 21% of the aldehyde
25b. (iii) Zn, HOAc, Et2O, 23 °C, 36 h, yields of 26: 49% (from 24), 87% (from
25a), 36% (from 20). (iv) O3/O2, MeOH/CH2Cl2, -78 °C, 1h, then: MeOH/CH2Cl2,
NaBH4, -78 °C to 23 °C, 23 h, Yield 71% of 23. (v) TBAF, HOAc, THF, 23 °C,
19 h, yield: 98% 2d, (-)-SCB-5.
immediately treated with
a solution of freshly prepared
diazomethane. Methyl ester 25a was isolated with moderate 26%
yield (3 steps). Remaining aldehyde 25b (21% yield) indicated an
incomplete second H2O2 oxidation step. Reductive ring opening
with Zn in AcOH/Et2O induced regeneration of the styrene moiety,
the intermediate hydroxy acid underwent γ-lactonization
delivering butanolide 26 with 49% yield from acid 24 and 87%
yield from ester 25a. Best results were achieved running a
cascade of oxidative degradation of the vinyl group and reductive
ring opening of the iodo tetrahydrofuran segment with final
lactonization. Stating from iodoether 20, such a sequence
enabled generation of butanolide 26 with 36% yield overall.30
Ozonolytic cleavage of the styryl double bond of lactone 26 in
MeOH/CH2Cl2 and subsequent reductive work-up using NaBH4
afforded 3-(hydroxymethyl) lactone 23 with 71% yield.31,11d Finally,
protecting group removal with buffered TBAF- solution in
THF/HOAc enabled to complete a first total synthesis of (-) SCB-
5 2d with 98% yield.32
Iodomethyl tetrahydrofuran ent-21 served as key intermediate for
a synthesis of (+)-SCB-5 ent-2d. The starting sequence focused
on introduction of the 3-(hydroxymethyl) group first (Scheme 8).
Treatment of reactant ent-21 with O3/O2 in MeOH, subsequent
reduction with NaBH4 and final protection of the carbinol delivered
TBS ether ent-27 with >76% yield (2 steps). Reductive ring
opening using Zn/HOAc afforded alkenol ent-28 with 79% yield.
For introduction of the lactone carboxyl function, two alternative
reaction paths were tested (Scheme 8). In analogy to the oxidative
degradation of the vinyl group of tetrahydrofuran 21 delivering
lactone 26 (see above, Scheme 7), hydroxyalkene ent-28 was
subjected to O3/O2 in CH2Cl2 and subsequent oxidative work-up
with 35% aq. H2O2. Surprisingly, a lactol only (82% yield, not
shown) was found indicating the failure of the final oxidation. No
lactone ent-30 was detected. Consequently, introduction of the
carboxyl function required an additional transformation. Reaction
of the intermediate lactol with PCC in dry CH2Cl2 gave the desired
TBS protected SCB-5 derivative ent-30 with moderate 34% yield.
Competing degradation products could be isolated in up to 43%
yield.33
The cumbersome oxidative cleavage of alkenol ent-28 advised
reactivation of the enol ether pathway (Scheme 8, in analogy to
the consideration to generate lactone moiety in ent-23, Scheme
5). Starting from TBS ether ent-27, H-I β-elimination succeeded
using KOtBu in THF at 50°C. After 3 d of reaction time exo enol
ether ent-29 could be isolated with 98% yield. Oxidative cleavage
of the double bond with O3/O2 in CH2Cl2 and standard work-up
with Me2S delivered the desired TBS protected SCB-5 ent-30 with
75% yield. Finally, global protective group removal with
TBAF/HOAc in THF gave the target (+)-SCB-5 derivative ent-2d
with <99% yield.32
6
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10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
Ph
Ph
OTBS
OTBS
TBSO
TBSO
TBSO
( )3
TBSO
( )3
H
H
H
H
i, ii
i, ii
iii
( )3
( )3
O
O
O
O
I
I
I
I
27
ent-27
21
ent-21
iii
v
iv
OTBS
OTBS
TBSO
OTBS
OTBS
OTBS
OH
TBSO
( )3
OTBS
28
H
H
( )3
( )3
( )3
O
O
OH
ent-28
ent-29
29
vi
v
iv
OTBS
TBSO
OH
OTBS
OH
HO
HO
TBSO
( )3
H
H
H
H
vii
vi
( )3
( )3
( )3
O
O
O
O
O
O
O
O
ent-2d
2d
ent-30
30
Scheme 8. Synthesis of (+)-SCB-5 ent-2d. Conditions and yields: (i) O3/O2,
CH2Cl2, -78 °C, 15 min, then: MeOH, NaBH4, -78 °C to 23 °C, 22 h, Yield 99%
of carbinol. (ii) TBSOTf, Et3N, CH2Cl2, 23 °C, 20 h, yield 78% silylether ent-27.
(iii) Zn, HOAc, Et2O, 23 °C, 24 h, yield 79% olefin ent-28. (iv) (a) O3/O2, CH2Cl2,
-78 °C, 15 min, then: 35% aq. H2O2, CH2Cl2, 23 °C to reflux, 2 h, yield: 82% of
lactol. (b) PCC, 3 Å molsieves, CH2Cl2, 23 °C, 1 h, Yield: 34% lactone ent-30 (+
43% of ketoformiate, see supporting information). (v) tBuOK, THF, 50 °C, 3 d,
Yield 98% of enolether ent-29. (vi) O3/O2, CH2Cl2, -78 °C, 1h, then: Me2S,
CH2Cl2, -78 °C to 23 °C, 4 h, Yield 75% of lactone ent-30. (vii) TBAF, HOAc,
THF, 23 °C, 15 h, yield: 99% of target (+)-SCB-5 ent-2d.
Scheme 9. Synthesis of (-)-SCB-5 2d. Conditions and yields: (i) O3/O2, CH2Cl2,
-78 °C, 1h, then: MeOH, NaBH4, -78 °C to 23 °C, 21 h, Yield 82% of carbinol.
(ii) TBSOTf, Et3N, CH2Cl2, 23 °C, 20 h, yield 86% silylether 27. (iii) Zn, HOAc,
Et2O, 23 °C, 21 h, yield 81% olefin 28. (iv) tBuOK, THF, 50 °C, 3 d, Yield 99%
of enolether 29. (v) O3/O2, CH2Cl2, -78 °C, 1h, then: Me2S, CH2Cl2, -78 °C to
23 °C, 3 h, Yield 63% of lactone 30. (vi) TBAF, HOAc, THF, 23 °C, 20 h, yield:
>99% of target (-)-SCB-5 2d.
Generally, the aza-Claisen rearrangement as the central key step
offers two options in respect of the stereocontrol building up
stereotriads (Figure 5) involving N-allylpyrrolidines (4S)-7 and
(4R)-8, respectively and activated intermediate ketene 9a (from
acid fluoride 9 and Me3Al, evolution of methane).11 The addition
of the lone pair of the nitrogen at the carbonyl center of the ketene
9a was the initiating step in both cases, delivering the central
zwitterionic intermediate with high diastereoselectivity. Then,
Claisen rearrangement required the passing of a chair-like
transition state. In this connection, the stereodirecting factors
need to be examined.
1) Starting from N-allyl pyrrolidines 7 and 8 bearing a defined
ether function in position 4, 1,2 asymmetric induction enables to
generate stereotriads with anti/syn substitution pattern with high
diastereoselectivity (minimized repulsive interactions because of
anti-arrangement of enolate C and bulky TBS ether).35 2) Starting
from optically active N-allyl (S)-prolinol derivatives 7 and 8,
auxiliary induced rearrangements deliver 2,3 anti-amides with 2
(R) configurations (quasi equatorial arrangement of the bulky
branched pyrrolidine moiety). The combination of both
independently directing stereoinductors in a single molecule
should affect matched and mismatched results concerning the
amide formation. The matched case is found in reactant (4S)-
7/(S)-prolinol derivative delivering the syn-anti amide 10 as an
intermediate of a (+)-SCB-5 ent-2d synthesis. In contrast, the
mismatched combination of reactant (4R)-8/(S)-prolinol derivative
resulted syn-anti amide 14 (via mismatched-s, predominating
substrate control, transition state suffering from quasi axial
arrangement of the bulky branched pyrrolidine moiety) as a (-)-
SCB-5 2d precursor. However, formation of anti-anti amide 14a
(via mismatched-a, predominating auxiliary control, transition
state suffering from repulsive interactions because of syn-
In addition, the synthesis of (-)-SCB-5 2d had been run via the
optimized route developed for (+)-SCB-5 ent-2d applying slightly
varied conditions (Scheme 9). The oxidative cleavage of the
styrene subunit starting from tetrahydrofuran 21 with O3/O2 in
CH2Cl2, subsequent reduction with NaBH4 and final protection of
the carbinol delivered TBS ether 27 with 70% yield (2 steps). Too,
reductive ring opening using Zn/HOAc enabled to generate
alkenol 28 with 81% yield. Again, the enol ether route proved
successful. Starting from TBS ether 27, H-I β-elimination was
achieved using KOtBu in THF at 50°C. After 3 d of reaction time
exo-enol ether 29 could be isolated with nearly quantitative yield.
Oxidative cleavage of the double bond with O3/O2 in CH2Cl2 and
standard work-up with Me2S delivered the desired TBS protected
SCB-5 derivative 30 with 63% yield. Finally, global protective
group removal with TBAF/HOAc in THF gave the target (-)-SCB-
5 2d with <99% yield.32
Comparison of the 1H NMR data of our (-)-SCB-5 with these
published by Mori et al. (corrected structure)10h,i gave a convincing
agreement of both sets. Especially, the lactone protons H-5 and
H-5’ were described as two dd systems at 4.41 and 3.97 ppm.
The proton attached to C-1’ was found as a m between 4.05 and
4.00 ppm. In contrast, the VB-A protons are found as dd systems
at 4.42 and 4.1 ppm, respectively, the proton attached to C-1’ was
described as a m between 4.15 and 4.10 ppm. Comparison of the
data of further SCB/VB type substitution pattern pairs of several
compounds 2/3 displayed the same tendency in connection with
the protons mentioned above. Unfortunately, no 13C NMR data of
SCB-5 have been published in the literature so far.34
7
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10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
arrangement of enolate C and bulky TBS ether) inducing a (+)-
VB-A 3d synthesis was not observed.
R2
OH
OPG1 R2
OH
H
OTBS
H
H
N+
N
C
O
H
R1
S
N
S
R1
R1
S
+
S
H
FAlMe2
S
TBSO
R1
OPh
PhO
R2
(4S)-7
9a
H
O
O
PG2O
O
H
O
10
matched
syn-anti
ent-2d
H
OPG1 R2
OH
H
N+
OH
H
H
R1
TBSO
N
R1
R1
R
S
S
R2
OPh
O
H
O
O
PG2O
O
R2
H
OTBS
14a
mismatched-a
OPh
anti-anti
ent-3d
N
R1
C
O
R
+
S
FAlMe2
OH
OPG1 R2
PhO
H
OH
(4R)-8
9a
H
H
H
N+
H
N
R1
R1
R
R2
R
R
R1
TBSO
R1 = -(CH2)3CHMe2 (i-C6H13
R2 = (E) -CH=CH-Ph
)
O
O
O
PG2O
H
O
2d
14
mismatched-s
syn-anti
Figure 5. Stereochemical outcome of the zwitterionic aza-Claisen rearrangement key-step: axial N lone pair in (4S)-7 and (4R)-8, attack at the carbonyl C of ketene
9a, passing of chair-like transition states with minimized repulsive interactions. “matched” gives syn anti 10 (→ (+)-SCB-5 ent-2d), mismatched-a auxiliary control
gives anti anti 14a (→ (+)-VB-A ent-3d), mismatched-s substrate control gives syn anti 14 (→ (-)-SCB-5 2d).
completion of the total synthesis of target (-)-2d (25% overall from
iodoether 20).
Conclusion
Starting from iodoether ent-21 enabled introduction of the
hydroxymethyl function first. Ozonolysis/reductive work-up and
silyl ether protection delivered tetrahydrofuran ent-27 (77% yield).
Since the carboxyl group introduction with regeneration of the
vinyl group (via ent-28) and subsequent oxidative degradation
gave moderate results upon generating protected (+)-SCB-5 ent-
30 (6 steps from ent-21, 17% yield), potassium tert-butoxide
induced HI elimination gave enol ether ent-29. Subsequent
ozonolysis/standard work-up of the double bond afforded lactone
ent-30 with 74% yield (2 steps). Final protecting group removal
gave (+)-SCB-5 ent-2d with nearly quantitative yield (overall: 5
steps from ent-21, 56% yield). In addition, starting from iodoether
21 enabled completion of the total synthesis of (-)-SCB-5 2d with
44% yield (5 steps from 21 applying the enol ether 28 cascade).
The data of the SCB-5 enantiomers synthesized here match with
these published by Mori.10h In contrast, a VB-A synthesis requires
a late-stage inversion of the C1’ OH group.37 Alternatively, more
The stereoselective synthesis of enantiopure Streptomyces
coelicolor butanolide hormones required efficient access to the
optically active (2,3,1’) stereotriads characterizing the key
fragments of this series of natural products. Zwitterionic aza-
Claisen rearrangements developed earlier proved to serve as
reliable tools to generate such stereotriads with high selectivity.
Starting from suitably substituted N-allylpyrrolidine (4S)-7,
reaction with 4-phenylbutenoyl fluoride 9 delivered the γ,δ-
unsaturated amide 10 as a single diastereomer with high yield
(93%, matched combination of stereochemistry inducing factors).
Despite of involving differently directing stereochemistry inducing
factors as present in pyrrolidine (4R)-8, 1,2 asymmetric induction
(remote stereocontrol) of the (4R)-TBS ether moiety
predominated delivering γ,δ-unsaturated amide 14 only with 90%
yield. Two step removal of the amide via iodocyclization, reductive
ring opening and subsequent reduction of the carboxyl function
afforded carbinols 15 (R,R,R stereotriad, 55% yield) and ent-15
(S,S,S stereotriad, 58% yield). Structure elucidation succeeded
by means of NOESY and X-ray analyses of appropriate
intermediates in both series.
Chemoselective conversion of the olefins into carboxyl and
hydroxymethyl groups required careful elaborated reaction
sequences. Despite of several attempts, the simultaneous
degradation of both double bonds failed. Iodocyclizaton of
carbinols 15/ent-15 delivered two regioisomeric iodoethers
20/ent-20 (protected styryl double bond) and 21/ent-21 (protected
vinyl group).36
Starting from iodoether 20 allowed introduction of the carboxyl
function first. Best results were achieved via ozonolysis/oxidative
work-up and reductive iodoether ring opening generating γ
lactone 26 with 36% yield. A second ozonolysis/reductive work-
up gave protected (-)-SCB-5, a final silyl ether removal enabled
attractive
auxiliary
dominated zwitterionic
aza-Claisen
rearrangement would require a sterically less encumbered C4
carbinol protection group and a suitable auxiliary substituent.
Further investigations in our laboratory aim for such Virginiae
butanolide total syntheses.
Experimental Section
General Remarks: Thin film IR spectra were recorded with a Jasco FT/IR-
4100 spectrometer with single reflection horizontal ATR (ZnSe window).
Melting points were determined with an IA 9100 apparatus, manufactured
by Electrothermal Engineering Ltd. Optical rotation was recorded with MC
241 polarimeter (Perkin-Elmer). 1H NMR, 13C NMR and 2D NMR (COSY,
HSQC, HMBC, NOESY) spectra were recorded at room temperature with
8
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10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
a Bruker Avance III HD 300, Avance II 400 or Avance III HD 400
spectrometer in CDCl3 using the signal of residual CHCl3 (1H: 7.26 ppm;
13C: 77.16 ppm) as internal standard. FD mass spectra were obtained
using a Finnigan MAT 95, ESI spectra were measured using a Waters
Micromass QTOF Ultima 3. HRMS ESI spectra were recorded using an
Agilent G6545A Q-ToF spectrometer. Column chromatography was
performed on MN silica gel 60M from Macherey-Nagel GmbH & Co. KG
with a grain size of 0.040 – 0.063 nm. The analytical HPLC system was
used to analyze the products: Knauer HPLC Pump 64 connected to a
HPLC column (see table below), a Knauer Variable Wavelength Monitor
at λ = 254 nm or 220 nm and Knauer Differential Refractometer.
Preparative HPLC system: Knauer WellChrom Preparative Pump K-1800
connected to the HPLC column, a Knauer Variable Wavelength Monitor at
λ = 254 nm or 220 nm and Bischoff RI-detector 8100. A selection of
experimental procedures is given in the following. For all procedures and
the numbering used in the 1H and 13C NMR spectra, see supporting
information.
21 h with exclusion of light. DCM (100 mL) and an aqueous Na2S2O3
(30 mL, 10%) were added. The layers were separated and the aqueous
layer was extracted with DCM (3x 100 mL). The combined organic layers
were dried (MgSO4), the solvent was removed in vacuo and the residue
was purified via column chromatography (EtOAc/petroleum ether 1:30) to
afford the iodolactones ent-β-11 and ent-α-11 (2.391 g, 4.296 mmol, 91%)
as a yellow oil, 1:0.85 mixture of diastereomers. For characterization, an
analytical amount was separated via column chromatography
(EtOAc/petroleum ether 1:30).
Analytical data of (3R,4R,5S)-4-((S)-1-(tert-butyldimethylsilyloxy)-5-
methylhexyl)-5-(iodo-methyl)-3-((E)-phenethenyl)-dihydrofuran-
2(3H)-one ent-α-11: Rf = 0.18 (EtOAc/petroleum ether 1:30, cerium
reagent, UV). HPLC: 푡0 = 1.28 min,
EtOAc/hexane 5:95, 2 mL/min, 102 bar), 푡0 = 1.60 min,
[ ]29
푘
= 4.50 (Nucleosil 50-5;
= 15.60
= +124.0°
푘
(S,S-Whelk-O1; EtOAc/hexane 8:92, 2 mL/min, 50 bar.
α
D
(CH2Cl2, c = 0.99 g/100 mL). IR (thin film): 2952 (m), 2931 (m), 2856 (w),
1779 (vs), 1496 (w), 1469 (m), 1385 (w), 1327 (w), 1254 (m), 1169 (w),
1132 (m), 1079 (s), 1006 (m), 962 (m), 888 (w), 835 (s), 805 (m), 775 (s),
745 (s), 692 (s), 614 (w), 602 (w), 586 (w). 1H NMR (CDCl3, 400 MHz): δ
[ppm] = 7.38 – 7.30 (m, 4H, H-15, H-16), 7.29 – 7.24 (m, 1H, H-17), 6.61
(d, 3J = 15.8 Hz, 1H, H-13), 6.00 (dd, 3J = 15.9 Hz, 3J = 8.0 Hz, 1H, H-12),
4.87 – 4.77 (m, 1H, H-5), 4.01 – 3.92 (m, 1H, H-6), 3.66 – 3.52 (m, 2H, H-
3, H-18a), 3.31 (dd, 2J = 11.3 Hz, 3J = 9.7 Hz, 1H, H-18b), 2.75 – 2.65 (m,
1H, H-4), 1.65 – 1.43 (m, 3H, H-7, H-10), 1.36 – 1.22 (m, 2H, H-8),
(2R,3S,4S)-4-((tert-Butyldimethylsilyloxy)-8-methyl-1-((S)-2-
(phenoxymethyl)-pyrrolidin-1-yl)-2-((E)-styryl)-3-vinylnonan-1-
one 10: Sodium carbonate (1.446 g, 13.644 mmol, 6.0 eq) was dried and
N-allyl pyrrolidine (4S)-7 (1.007 g, 2.259 mmol, 1.0 eq.) in DCM (30 mL)
was added. Acyl fluoride 9 (0.904 g, 5.507 mmol, 2.4 eq) in DCM (10 mL)
was added at 0 °C. Then, trimethylaluminum (2.75 mL, 0.40 g, 5.5 mmol,
2.4 eq, 2 M in toluene) was added dropwise over 30 min. After stirring for
4 d at 0 °C (cryostat), the mixture was warmed-up room temperature.
Water (2 mL) and saturated aqueous KNa tartrate (15 mL) were added
dropwise and the resulting mixture was stirred for 3 h. The organic layer
was washed with saturated aqueous K,Na tartrate (100 mL). The aqueous
layer was extracted with DCM (3x 100 mL) and the combined organic
layers were dried (MgSO4). The solvent was removed in vacuo and the
residue was purified via column chromatography (EtOAc/petroleum ether
1:10 to 1:4) to afford amide 10 (1.234 g, 2.091 mmol, 93%) as a yellow oil.
3
1.20 – 1.04 (m, 2H, H-9), 0.91 (s, 9H, H-21), 0.85 (d, J = 6.6 Hz, 3H, H-
11), 0.84 (d, 3J = 6.6 Hz, 3H, H-11‘), 0.11 (s, 3H, H-19), 0.10 (s, 3H, H-19').
13C NMR (CDCl3, 101 MHz): δ [ppm] = 175.7 (C-2), 136.1 (C-14), 135.8
(C-13), 128.8 (C-15), 128.3 (C-17), 126.6 (C-16), 122.9 (C-12), 80.3 (C-5),
69.8 (C-6), 49.7 (C-4), 44.4 (C-3), 39.0 (C-9), 35.5 (C-7), 28.1 (C-10), 26.0
(C-21), 23.3 (C-8), 22.7 (C-11), 22.6 (C-11‘), 18.1 (C-20), 4.3 (C-18), −3.7
(C-19), −4.4 (C-19‘). HRMS (ESI): m/z [M+H]+ calcd for C26H41INaO3Si+:
579.1759; found: 579.1762.
[ ]22
Rf = 0.29 (EtOAc/petroleum ether 1:15, ninhydrin, UV). α = –16.87°
D
(CH2Cl2, c = 1.00 g/100 mL). IR (thin film): 2953 (s), 2927 (s), 2853 (m),
Analytical data of (3R,4R,5R)-4-((S)-1-(tert-butyldimethylsilyloxy)-5-
methylhexyl)-5-(iodomethyl)-3-((E)-phenethenyl)-dihydrofuran-2(3H)-
one ent-β-11: Rf = 0.26 (EtOAc/petroleum ether 1:30, cerium reagent, UV).
HPLC: 푡0 = 1.70 min, 푘 = 3.25 (Nucleosil 50-5; EtOAc/hexane 5:95,
1727 (w), 1637 (s), 1600 (m), 1497 (s), 1469 (m), 1415 (s), 1245 (s),
1088 (m), 1038 (w), 1004 (m), 964 (w), 914 (m), 836 (s), 775 (s), 752 (vs),
691 (s), 617 (m). 1H NMR (CDCl3, 400 MHz): δ [ppm] = 7.41 – 7.16 (m, 7H,
H-17, H-22, H-23, H-24), 7.00 – 6.83 (m, 3H, H-16, H-18), 6.59 (d,
3J = 16.1 Hz, 0.2H, H-20B), 6.49 (d, 3J = 16.0 Hz, 0.8H, H-20A), 6.26 (dd,
3J = 16.0 Hz, 3J = 9.2 Hz, 0.8H, H-19A), 6.22 (dd, 3J = 16.1 Hz,
3J = 9.3 Hz, 0.2H, H-19B), 5.91 – 5.78 (m, 1H, H-25), 5.30 – 5.20 (m, 0.4H,
H-26B), 5.21 – 5.10 (m, 1.6H, H-26A), 4.42 – 4.33 (m, 1H, H-10), 4.22 (dd,
2J = 9.7 Hz, 3J = 3.2 Hz, 0.8H, H-14Aa), 4.02 (dd, 2J = 9.0 Hz, 3J = 3.8 Hz,
0.2H, H-14Ba), 3.89 (dd, 2J = 9.7 Hz, 3J = 7.6 Hz, 0.8H, H-14Ab), 3.86 –
3.79 (m, 1H, H-4), 3.78 – 3.70 (m, 0.2H, H-14Bb), 3.70 – 3.62 (m, 1H, H-
2), 3.61 – 3.43 (m, 2H, H-13), 2.85 – 2.75 (m, 0.2H, H-3B), 2.71 – 2.63 (m,
0.8H, H-3A), 2.12 – 2.04 (m, 2H, H-11a, H-12a), 1.98 – 1.88 (m, 2H, H-
11b, H-12b), 1.54 – 1.43 (m, 2H, H-5a, H-8), 1.43 – 1.32 (m, 1H, H-5b),
1.30 – 1.16 (m, 1H, H-6a), 1.15 – 1.04 (m, 3H, H-6b, H-7), 0.96 (s, 7.2H,
H-29A), 0.83 (d, 3J = 6.6 Hz, 6H, H-9, H-9'), 0.74 (s, 1.8H, H-29B), 0.06 (s,
2 mL/min, 102 bar), 푡0 = 1.49 min,
EtOAc/hexane 1:9, 2 mL/min, 50 bar).
푘
= 20.42 (S,S-Whelk-O1;
[ ]29
α
= +19.0° (CH2Cl2,
D
c = 1.00 g/100 mL). IR (thin film): 2952 (s), 2926 (s), 2854 (m), 1778 (vs),
1496 (w), 1463 (m), 1412 (w), 1362 (w), 1256 (m), 1163 (s), 1063 (m),
963 (m), 901 (w), 835 (s), 805 (m), 775 (s), 745 (s), 692 (s), 624 (w),
613 (w), 587 (w). 1H NMR (CDCl3, 400 MHz): δ [ppm] = 7.41 – 7.36 (m, 2H,
H-16), 7.36 – 7.30 (m, 2H, H-15), 7.31 – 7.22 (m, 1H, H-17), 6.59 (d,
3J = 15.8 Hz, 1H, H-13), 6.17 (dd, 3J = 15.8 Hz, 3J = 8.1 Hz, 1H, H-12),
4.37 – 4.30 (m, 1H, H-5), 3.81 – 3.77 (m, 1H, H-6), 3.65 (dd, 2J = 11.1 Hz,
3J = 4.0 Hz, 1H, H-18a), 3.42 – 3.33 (m, 2H, H-3, H-18b), 2.54 – 2.46 (m,
1H, H-4), 1.64 – 1.27 (m, 5H, H-15, H-16, H-17), 1.16 – 1.07 (m, 2H, H-9),
0.91 (s, 9H, H-21), 0.84 (d, 3J = 6.6 Hz, 3H, H-11), 0.83 (d, 3J = 6.6 Hz, 3H,
H-11‘), 0.13 (s, 3H, H-19), 0.11 (s, 3H, H-19'). 13C NMR (CDCl3, 101 MHz):
δ [ppm] = 175.3 (C-2), 136.2 (C-14), 135.1 (C-13), 128.7 (C-15), 128.2 (C-
17), 126.7 (C-16), 123.9 (C-12), 77.3 (C-5), 72.2 (C-6), 51.0 (C-4), 47.5
(C-3), 39.1 (C-9), 35.6 (C-7), 28.0 (C-10), 26.0 (C-21), 22.7 (C-11), 22.6
(C-11‘), 22.6 (C-8), 18.2 (C-20), 11.1 (C-18), −3.8 (C-19), −4.2 (C-19‘).
HRMS (ESI): m/z [M+H]+ calcd for C26H41INaO3Si+: 579.1762; found:
579.1745.
2.4H, H-27A), 0.05 (s, 2.4H, H-27A'), −0.02 (s, 1.2H, H-27B, H-27B'). 13
C
NMR (CDCl3, 101 MHz): δ [ppm] = 172.5 [171.6] (C-1), 158.8 [158.6] (C-
15), 137.0 [136.9] (C-21), 134.7 [134.7] (C-25), 132.8 [133.0] (C-20), 129.5
[129.6] (C-17), 128.7 [128.7] (C-23), 128.4 [128.2] (C-19), 127.6 [127.7]
(C-24), 126.5 [126.4] (C-22), 120.7 [121.2] (C-18), 119.1 [119.6] (C-26),
114.8 [114.4] (C-16), 71.6 [71.7] (C-4), 67.1 [68.5] (C-14), 56.0 [56.5] (C-
10), 50.5 [50.3] (C-3), 50.1 [49.7] (C-2), 47.5 [46.2] (C-13), 39.2 [39.3] (C-
7), 36.1 [36.2] (C-5), 28.0 [28.0] (C-8), 27.6 [29.0] (C-11), 26.3 [26.0] (C-
29), 24.2 [21.8] (C-12), 23.1 [23.1] (C-6), 22.8 [22.9] (C-9), 22.6 (C-9'), 18.4
[18.2] (C-28), −3.0 [−3.1] (C-27), −4.3 [−4.5] (C-27'). HRMS (ESI): m/z
[M+H]+ calcd for C37H56NO3Si+: 590.4024; found: 590.4003. Because of
the slowly reconverting amide rotamers, 1H and 13C NMR spectra display
a double set of signals (ratio 4:1). The absolute configuration of new
stereogenic centers was elucidated via X-ray analysis of iodolactones.
(2R,3S,4S)-4-((tert-Butyldimethylsilyloxy)-8-methyl-2-((E)-styryl)-3-
vinyl-nonanoic acid: Zinc powder (1.658 g) and acetic acid (10 drops)
were added to iodolactone ent-11 (43.3 mg, 0.078 mmol, 1.0 eq, mixture
of diastereomers) in Et2O (5 mL). The reaction mixture was stirred for 2 d.
After filtration through a silica gel pad and careful rinsing with DCM, the
solvent was removed in vacuo and the residue was purified via column
chromatography (EtOAc/petroleum ether 1:20 to 1:10 +0.1% AcOH) to
afford acid (28.5 mg, 66.2 µmol, 85%) as yellow oil. Rf
(EtOAc/petroleum ether 1:10 +0,1% AcOH, ninhydrin, UV). For data see
supporting information.
= 0.25
Iodolactonization: Iodine (3.607 g, 14.231 mmol, 3 eq) was added to
amide 14 (2.789 g, 4.727 mmol, 1.0 eq) in dimethoxy ethane (40 mL) and
water (10 mL). The reaction mixture was stirred at room temperature for
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
Methyl (2R,3S,4S)-4-((tert-butyldimethylsilyloxy)-8-methyl-2-((E)-2-
Iodocyclization: Iodine (997.4 mg, 3.93 mmol, 3.03 eq) was added to
alcohol ent-15 (540.9 mg, 1.298 mmol, 1.0 eq) in Et2O (10 mL) and
saturated aqueous NaHCO3 (18 mL). The reaction mixture was stirred at
room temperature for 9 h with exclusion of light. Et2O (20 mL) and an
aqueous Na2S2O3 (20 mL, 10%) were added. The layers were separated
and the aqueous layer was extracted with Et2O (3x 20 mL). The combined
organic layers were dried (MgSO4), the solvent was removed in vacuo and
the residue was filtered through a silica gel pad (careful rinsing with DCM).
The solvent was removed in vacuo and the residue was purified via HPLC
(Gemini NX C18, MeCN, 40 mL/min, 37 bar) to afford iodoether ent-21
(334.9 mg, 0.617 mmol, 48%) and iodoether ent-20 (250.5 mg,
0.462 mmol, 36%) as colorless oils. For data of minor cis alkene ent-21a
see supporting information.
phenylethenyl)-3-vinyl-nonanoate ent-12:
N-Methyl-N-nitroso
urea (139.6 mg, 1.354 mmol, 20.5 eq) was dissolved in Et2O (20 mL) and
aqueous KOH (20 mL, 40%) was added in a beaker at 0°C. After stirring
for 10 min the bright yellow color of diazomethane within the organic layer
occurred. In a second beaker the crude acid (28.5 mg, 0.066 mmol, 1.0 eq)
in Et2O (5 mL) was treated with diazomethane in ether until the yellow color
of surplus diazomethane remained. Stirring was continued at 0 °C for 5 h.
Then acetic acid (5 mL, 2 M) in Et2O was added dropwise to quench the
excess of diazomethane and stirring was continued for further 30 min. The
reaction mixture was washed with saturated aqueous NaHCO3 (50 mL)
and the aqueous layer was extracted with Et2O (3x 30 mL). The combined
organic layers were dried (MgSO4), the solvent was removed in vacuo and
the residue was purified via column chromatography (EtOAc/petroleum
ether 1:50) to afford ester ent-12 (25.8 mg, 0.058 mmol, 88%) as a
colorless oil. Rf = 0.25 (EtOAc/petroleum ether 1:50, cerium reagent, UV).
[ ]23
Analytical data of (2R,3R,4R)-3-(((1S)-tert-butyldimethylsilyloxy)-5-
methylhexyl)-2-(iodomethyl)-4-((E)-styryl)-tetrahydrofuran ent-21: Rf
= 0.19 (EtOAc/ petroleum ether 1:100, cerium reagent, UV). HPLC:
푡0 = 1.33 min, 푘 = 2.09 (Gemini NX C18, MeCN, 2 mL/min, 73 bar).
[ ]23
α
= +28.4° (CH2Cl2, c = 1.01 g/100 mL). IR (thin film): 2954 (s),
D
2931 (s), 2858 (m), 1740 (vs), 1471 (m), 1434 (m), 1363 (w), 1256 (s),
1155 (s), 1090 (s), 1002 (w), 969 (m), 919 (m), 836 (vs), 774 (s), 751 (m),
690 (m), 605 (w). 1H NMR (CDCl3, 400 MHz): δ [ppm] = 7.39 – 7.29 (m,
4H, H-13, H-14), 7.27 – 7.22 (m, 1H, H-15), 6.56 (d, 3J = 15.9 Hz, 1H, H-
11), 6.12 (dd, 3J = 15.9 Hz, 3J = 9.6 Hz, 1H, H-10), 5.85 (ddd, 3J = 17.3 Hz,
3J = 10.3 Hz, 3J = 10.1 Hz 1H, H-16), 5.13 (dd, 3J = 10.3 Hz, 2J = 2.2 Hz,
1H, H-17a), 5.07 (dd, 3J = 17.3 Hz, 2J = 2.2 Hz, 1H, H-17b), 3.76 (ddd,
3J =9.5 Hz, 3J = 4.6 Hz, 3J = 1.7 Hz, 1H, H-4), 3.62 (s, 3H, H-21), 3.49 –
3.40 (m, 1H, H-2), 2.49 (ddd, 3J = 11.0 Hz, 3J = 10.1 Hz, 3J = 1.7 Hz, 1H,
H-3), 1.55 – 1.47 (m, 1H, H-8), 1.49 – 1.25 (m, 2H, H-5), 1.25 – 1.16 (m,
1H, H-6a), 1.19 – 1.05 (m, 3H, H-6b, H-7), 0.93 (s, 9H, H-20), 0.85 (d,
3J = 6.6 Hz, 6H, H-9, H-9'), 0.03 (s, 3H, H-18), 0.02 (s, 3H, H-18'). 13C NMR
(CDCl3, 101 MHz): δ [ppm] = 173.8 (C-1), 136.8 (C-12), 135.3 (C-16),
134.0 (C-11), 128.7 (C-14), 127.8 (C-15), 126.5 (C-13), 126.4 (C-10),
118.4 (C-17), 71.2 (C-4), 52.1 (C-2), 51.7 (C-21), 50.8 (C-3), 39.2 (C-7),
36.0 (C-5), 28.0 (C-8), 26.2 (C-20), 23.1 (C-6), 22.9 (C-9), 22.6 (C-9'), 18.4
(C-19), −3.2 (C-18), −4.2 (C-18'). HRMS (ESI): m/z [M+H]+ calcd for
C27H45O3Si+: 445.3132; found: 445.3135.
α
= +12.2° (CH2Cl2, c = 0.99 g/100 mL). IR (thin film): 3027 (w),
D
2954 (s), 2929 (s), 2899 (m), 2857 (s), 1740 (m), 1600 (w), 1493 (w),
1471 (m), 1411 (w), 1385 (w), 1364 (w), 1255 (s), 1075 (s), 1051 (s),
1006 (w), 967 (s), 938 (w), 835 (vs), 807 (m), 774 (vs), 747 (s), 693 (s),
615 (w), 597 (w), 585 (w). 1H NMR (CDCl3, 400 MHz): δ [ppm] = 7.38 –
7.26 (m, 4H, H-15, H-16), 7.27 – 7.18 (m, 1H, H-17), 6.42 (d, 3J = 15.8 Hz,
1H, H-13), 6.13 (dd, 3J = 15.8 Hz, 3J = 9.1 Hz, 1H, H-12), 3.99 (dd,
2J = 8.8 Hz, 3J = 7.5 Hz, 1H, H-5a), 3.94 (ddd, 3J = 6.6 Hz, 3J = 6.4 Hz,
3J = 3.1 Hz, 1H, H-2), 3.85 – 3.75 (m, 2H, H-5b, H-6), 3.56 (dd,
2J = 10.5 Hz, 3J = 3.1 Hz, 1H, H-21a), 3.32 (dd, 2J = 10.5 Hz, 3J = 6.4 Hz,
1H, H-21b), 3.00 – 2.88 (m, 1H, H-4), 2.08 – 1.99 (m, 1H, H-3), 1.63 – 1.42
(m, 3H, H-7, H-10), 1.42 – 1.16 (m, 2H, H-8), 1.13 – 1.01 (m, 2H, H-9),
0.91 (s, 9H, H-20), 0.81 (d, 3J = 6.6 Hz, 3H, H-11), 0.79 (d, 3J = 6.6 Hz, 3H,
H-11'), 0.11 (s, 3H, H-18), 0.08 (s, 3H, H-18'). 1H NMR (C6D6, 600 MHz):
δ [ppm] = 7.26 – 7.22 (m, 2H, H-16), 7.16 – 7.10 (m, 2H, H-15), 7.08 – 7.02
(m, 1H, H-17), 6.34 (d, 3J = 15.8 Hz, 1H, H-13), 6.06 (dd, 3J = 15.8 Hz,
3J = 9.2 Hz, 1H, H-12), 4.00 – 3.94 (m, 1H, H-2), 3.89 (dd, 2J = 8.7 Hz,
3J = 7.5 Hz, 1H, H-5a), 3.78 – 3.73 (m, 1H, H-5b), 3.73 – 3.67 (m, 1H, H-
6), 3.47 (dd, 2J = 10.4 Hz, 3J = 3.4 Hz, 1H, H-21a), 3.18 (dd, 2J = 10.4 Hz,
3J = 5.9 Hz, 1H, H-21b), 2.80 – 2.72 (m, 1H, H-4), 2.08 (ddd, 3J = 7.9 Hz,
3J = 6.3 Hz, 3J = 6.3 Hz, 1H, H-3), 1.55 – 1.45 (m, 1H, H-7a), 1.47 – 1.39
(m, 1H, H-10), 1.41 – 1.31 (m, 2H, H-7b, H-8a), 1.33 – 1.23 (m, 1H, H-8b),
(2R,3S,4S)-4-((tert-Butyldimethylsilyloxy)-8-methyl-2-((E)-2-
phenylethenyl)-3-vinylnonan-1-ol
ent-15:
DIBAL-H
(0.82 mL,
0.82 mmol, 2.7 eq, 1.0 M in toluene) was added dropwise to ester ent-12
(133.1 mg, 0.299 mmol, 1.0 eq) in DCM (2 mL) at −78 °C. After stirring at
this temperature for 3 h, the reaction mixture was warmed to 0 °C.
Saturated aqueous KNa tartrate (15 mL) was added dropwise and the
resulting mixture was stirred for 1.5 h at room temperature. The layers
were separated and the aqueous phase was extracted with DCM (5x 10
mL). The combined organic layers were dried (MgSO4), the solvent was
removed in vacuo and the residue was purified via column
chromatography (EtOAc/petroleum ether 1:20) to afford alcohol ent-15
3
1.10 – 1.01 (m, 2H, H-9), 0.97 (s, 9H, H-20), 0.83 (d, J = 6.6 Hz, 3H, H-
11), 0.81 (d, 3J = 6.6 Hz, 3H, H-11'), 0.10 (s, 3H, H-18), 0.06 (s, 3H, H-
18').13C NMR (CDCl3, 101 MHz): δ [ppm] = 137.1 (C-14), 131.6 (C-13),
129.9 (C-12), 128.7 (C-15), 127.6 (C-17), 126.3 (C-16), 80.9 (C-2), 72.8
(C-6), 72.8 (C-5), 55.3 (C-3), 47.9 (C-4), 39.2 (C-9), 36.0 (C-7), 28.1 (C-
10), 26.1 (C-20), 22.7 (C-11), 22.7 (C-11'), 22.0 (C-8), 18.2 (C-19), 13.0
(C-21), −3.9 (C-18), −4.1 (C-18'). 13C NMR (C6D6, 151 MHz): δ [ppm] =
137.4 (C-14), 131.9 (C-13), 130.3 (C-12), 128.9 (C-16), 127.7(C-17), 126.5
(C-15), 81.2 (C-2), 73.4 (C-6), 72.8 (C-5), 55.7 (C-3), 48.1 (C-4), 39.5 (C-
9), 35.9 (C-7), 28.3 (C-10), 26.2 (C-20), 22.8 (C-11), 22.7 (C-11'), 22.2 (C-
8), 18.3 (C-19), 13.1 (C-21), −3.9 (C-18), −4.1 (C-18'). HRMS (ESI): m/z
[M+Na]+ calcd for C26H43INaO2Si+: 565.1969; found: 565.1970.
(106.0 mg, 0.254 mmol, 85%) as
(EtOAc/petroleum ether 1:10, vanillin, UV).
a
colorless oil. Rf
=
0.29
[ ]25
α
= +0.6° (CH2Cl2,
D
c = 0.99 g/100 mL). IR (thin film): 3393 (br, m), 2954 (s), 2929 (s),
2857 (m), 1638 (w), 1494 (m), 1471 (m), 1386 (m), 1365 (m), 1254 (m),
1089 (s), 1057 (s), 1004 (m), 970 (m), 913 (m), 834 (vs), 807 (m), 773 (s),
748 (s), 692 (s), 665 (m), 614 (w), 601 (w), 592 (w). 1H NMR (CDCl3,
400 MHz): δ [ppm] = 7.40 – 7.30 (m, 4H, H-13, H-14), 7.27 – 7.22 (m, 1H,
H-15), 6.55 (d, 3J = 16.0 Hz, 1H, H-11), 6.00 (dd, 3J = 16.0 Hz, 3J = 9.3 Hz,
1H, H-10), 5.85 (ddd, 3J = 17.4 Hz, 3J = 10.1 Hz, 3J = 10.1 Hz, 1H, H-16),
5.19 (dd, 3J = 10.1 Hz, 2J = 2.2 Hz, 1H, H-17a), 5.08 (dd, 3J = 17.4 Hz,
2J = 2.2 Hz, 1H, H-17b), 3.77 (ddd, 3J = 9.4 Hz, 3J = 4.7 Hz, 3J = 1.6 Hz,
1H, H-4), 3.74 – 3.68 (m, 1H, H-1a), 3.45 (dd, 2J = 11.0 Hz, 3J = 8.0 Hz,
1H, H-1b), 2.69 – 2.58 (m, 1H, H-2), 2.14 (ddd, 3J = 10.2 Hz, 3J = 10.1 Hz,
3J = 1.6 Hz, 1H, H-3), 1.60 (s, 1H, H-21), 1.56 – 1.43 (m, 2H, H-5a, H-8),
1.40 – 1.31 (m, 1H, H-5b), 1.29 – 1.16 (m, 1H, H-6a), 1.15 – 1.06 (m, 3H,
H-6b, H-7), 0.91 (s, 9H, H-20), 0.85 (d, 3J = 6.6 Hz, 6H, H-9, H-9'), 0.03 (s,
3H, H-18), 0.01 (s, 3H, H-18'). 13C NMR (CDCl3, 101 MHz): δ [ppm] =
137.1 (C-12), 136.9 (C-16), 133.8 (C-11), 130.9 (C-10), 128.7 (C-14),
127.6 (C-15), 126.3 (C-13), 117.8 (C-17), 72.8 (C-4), 65.1 (C-1), 50.2 (C-
3), 46.3 (C-2), 39.2 (C-7), 35.9 (C-5), 28.0 (C-8), 26.2 (C-20), 23.3 (C-6),
22.9 (C-9), 22.6 (C-9'), 18.4 (C-19), −3.3 (C-18), −4.2 (C-18'). HRMS (ESI):
m/z [M+H]+ calcd for C26H45O2Si+: 417.3184; found: 417.3184.
Analytical data of (2R,3S,4R)-4-(((2S)-tert-butyldimethylsilyloxy)-(1S)-
ethenyl-6-methylheptyl)-3-iodo-2-phenyl-tetrahydrofuran ent-20: Rf =
0.15 (EtOAc/ petroleum ether 1:100, cerium reagent, UV). HPLC:
푡0 = 1.33 min, 푘 = 3.01 (Gemini NX C18, MeCN, 2 mL/min, 73 bar).
[ ]23
α
= -43.3° (CH2Cl2, c = 0.98 g/100 mL). IR (thin film): 3068 (w),
D
2954 (s), 2929 (s), 2895 (m), 2860 (s), 1741 (m), 1636 (w), 1492 (w),
1471 (m), 1382 (w), 1365 (w), 1255 (s), 1086 (s), 1050 (s), 1027 (s),
1005 (m), 922 (m), 874 (w), 836 (vs), 807 (m), 774 (vs), 759 (s), 733 (w),
1
698 (s), 61w (w), 597 (w), 586 (w). H NMR (CDCl3, 400 MHz): δ [ppm] =
7.43 – 7.39 (m, 2H, H-15), 7.37 – 7.30 (m, 3H, H-14, H-16), 5.79 (ddd,
3J = 17.2 Hz, 3J = 10.2 Hz, 3J = 9.9 Hz, 1H, H-17), 5.26 (dd, 3J = 10.2 Hz,
2J = 2.1 Hz, 1H, H-18a), 5.14 (dd, 3J = 17.2 Hz, 2J = 2.1 Hz, 1H, H-18b),
4.96 (d, 3J = 9.0 Hz, 1H, H-2), 4.07 (dd, 2J = 8.8 Hz, 3J = 8.7 Hz, 1H, H-5a),
4.00 (dd, 2J = 8.8 Hz, 3J = 7.5 Hz, 1H, H-5b), 3.78 – 3.67 (m, 2H, H-3, H-
7), 2.81 – 2.71 (m, 1H, H-4), 2.55 (ddd, 3J = 9.9 Hz, 3J = 3.8 Hz,
3J = 3.8 Hz, 1H, H-6), 1.59 – 1.52 (m, 1H, H-11), 1.51 – 1.42 (m, 1H, H-
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
8a), 1.43 – 1.30 (m, 1H, H-8b), 1.29 – 1.18 (m, 2H, H-9), 1.18 – 1.10 (m,
2H, H-10), 0.91 (s, 9H, H-21), 0.88 (d, 3J = 6.6 Hz, 3H, H-12), 0.88 (d,
3J = 6.6 Hz, 3H, H-12'), 0.11 (s, 3H, H-19), 0.08 (s, 3H, H-19'). 1H NMR
(C6D6, 600 MHz): δ [ppm] = 7.58 – 7.54 (m, 2H, H-14), 7.19 – 7.15 (m, 2H,
H-15), 7.11 – 7.08 (m, 1H, H-16), 5.74 – 5.66 (m, 1H, H-17), 5.07 (d,
3J = 8.8 Hz, 1H, H-2), 5.06 – 4.99 (m, 2H, H-18), 4.05 – 3.98 (m, 2H, H-5),
3.89 (dd, 3J = 8.8 Hz, 3J = 8.8 Hz, 1H, H-3), 3.68 (ddd, 3J = 6.1 Hz,
3J = 6.1 Hz, 3J = 3.8 Hz, 1H, H-7), 2.86 – 2.80 (m, 1H, H-4), 2.63 (ddd,
(3S,4R)-3-((1S)-tert-butyldimethylsilyloxy-5-methylhexyl)-4-(tert-
butyldimethylsilyloxymethyl)-2-(methylene)-tetrahydrofuran ent-29:
Potassium tert-butoxide (50.0 mg, 0.446 mmol, 14.6 eq) was added to
iodoether ent-27 (17.9 mg, 30.6 µmol, 1.0 eq) in THF (10 mL). The
reaction mixture was heated for 3 d to 50 °C. Then, the solvent was
removed in vacuo. The residue was dissolved in Et2O (10 mL) and washed
with water (10 mL). The aqueous layer was extracted with Et2O (3x 10 mL).
The combined organic layers were dried (MgSO4) and the solvent was
removed in vacuo to afford olefine ent-29 (13.7 mg, 30.0 µmol, 98%) as a
3
3J = 9.8 Hz, 3J = 4.0 Hz, J = 3.8 Hz, 1H, H-6), 1.54 – 1.44 (m, 2H, H-8a,
H-11), 1.41 – 1.20 (m, 3H, H-8b, H-9), 1.17 – 1.10 (m, 2H, H-10), 1.00 (s,
9H, H-21), 0.90 (d, 3J = 6.7 Hz, 3H, H-12), 0.90 (d, 3J = 6.7 Hz, 3H, H-12'),
0.14 (s, 3H, H-19), 0.08 (s, 3H, H-19'). 13C NMR (CDCl3, 101 MHz): δ
[ppm] = 138.9 (C-13), 133.9 (C-17), 128.6 (C-14), 128.5 (C-16), 126.9 (C-
15), 120.1 (C-18), 88.0 (C-2), 75.0 (C-7), 69.0 (C-5), 51.8 (C-4), 48.6 (C-
6), 39.2 (C-10), 35.4 (C-8), 34.8 (C-3), 28.0 (C-11), 26.2 (C-21), 23.1 (C-
9), 22.8 (C-12), 22.7 (C-12'), 18.3 (C-20), −3.8 (C-19), −3.8 (C-19'). 13C
NMR (C6D6, 151 MHz): δ [ppm] = 139.6 (C-13), 134.2 (C-17), 128.6 (C-15),
128.3 (C-16), 126.9 (C-14), 119.7 (C-18), 88.2 (C-2), 74.9 (C-7), 68.7 (C-
5), 51.8 (C-4), 49.2 (C-6), 39.2 (C-10), 35.4 (C-8), 35.3 (C-3), 28.1 (C-11),
26.1 (C-21), 23.2 (C-9), 22.7 (C-12), 22.6 (C-12'), 18.2 (C-20), −3.9 (C-19),
−4.0 (C-19'). HRMS (ESI): m/z [M+H]+ calcd for C26H44IO3Si+: 543.2150;
found: 543.2156.
yellow oil. Rf
=
0.19 (EtOAc/petroleum ether 1:20, cerium
[ ]25
reagent). α = -1.4° (CH2Cl2, c = 1.00 g/100 mL). IR (thin film): 2954 (s),
D
2929 (s), 2896 (m), 2857 (m), 1732 (w), 1667 (m), 1602 (w), 1471 (m),
1386 (m),1363 (m), 1256 (s), 1092 (s), 1066 (s), 1006 (m), 939 (w),
889 (w), 837 (vs), 798 (m), 775 (vs), 713 (w), 666 (w), 625 (w), 613 (w),
605 (w), 594 (w). 1H NMR (C6D6, 400 MHz): δ [ppm]
= 4.63 (dd,
4J = 1.6 Hz, 2J = 1.5 Hz, 1H, H-19a), 4.15 (dd, 2J = 8.8 Hz, 3J = 6.9 Hz, 1H,
H-5a), 4.07 (dd, 2J = 8.8 Hz, 3J = 4.2 Hz, 1H, H-5b), 3.90 (dd, 2J = 1.5 Hz,
4J = 1.4 Hz, 1H, H-19b), 3.89 – 3.85 (m, 1H, H-6), 3.71 (dd, 2J = 9.8 Hz,
3J = 5.1 Hz, 1H, H-12a), 3.45 (dd, 2J = 9.8 Hz, 3J = 8.8 Hz, 1H, H-12b),
2.73 – 2.69 (m, 1H, H-3), 2.68 – 2.59 (m, 1H, H-4), 1.68 – 1.60 (m, 1H, H-
7a), 1.60 – 1.54 (m, 1H, H-8a), 1.54 – 1.46 (m, 1H, H-10), 1.45 – 1.34 (m,
1H, H-7b), 1.33 – 1.24 (m, 1H, H-8b), 1.24 – 1.05 (m, 2H, H-9), 0.99 (s,
9H, H-18), 0.94 (s, 9H, H-15), 0.90 (d, 3J = 6.7 Hz, 3H, H-11), 0.90 (d,
3J = 6.7 Hz, 3H, H-11'), 0.09 (s, 3H, H-16), 0.07 (s, 3H, H-16'), 0.04 (s, 6H,
H-13, H-13'). 13C NMR (C6D6, 101 MHz): δ [ppm] = 164.3 (C-2), 80.9 (C-
19), 75.1 (C-6), 73.0 (C-5), 65.7 (C-12), 51.1 (C-3), 41.9 (C-4), 39.2 (C-9),
33.2 (C-7), 28.4 (C-10), 26.1 (C-18), 26.1 (C-15), 24.9 (C-8), 22.8 (C-11),
22.8 (C-11'), 18.5 (C-14), 18.3 (C-17), −4.0 (C-16), −4.5 (C-16'), −5.3 (C-
13), −5.3 (C-13'). HRMS (ESI): m/z [M+Na]+ calcd for C25H52O3Si2Na+:
479.3347; found: 479.3359.
((2R,3R,4S)-3-((1S)-((tert-Butyldimethylsilyloxy)-5-methylhexyl)-4-
(hydroxymethyl)-2-(iodomethyl)-tetrahydrofuran:
Alkene ent-21
(85.1 mg, 0.157 mmol, 1.0 eq) in DCM (10 mL) was cooled to −78 °C.
Oxygen was bubbled through the solution for 10 min. Then, ozone was
bubbled through the solution for 1 h until the blue color of unreacted ozone
occurred. The ozone was displaced by oxygen (10 min) and argon
(15 min). Then, sodium borohydride (68.6 mg, 1.81 mmol, 11.6 eq) in
MeOH (4 mL, cooled to −78 °C) was added dropwise. The mixture was
stirred for 21 h, the temperature was allowed to warm-up to 23. After
washing with semi-saturated aqueous NH4Cl (20 mL), the aqueous layer
was extracted with DCM (4x 10 mL). The combined organic layers were
dried (MgSO4), the solvent was removed in vacuo and the residue was
purified via column chromatography (EtOAc/petroleum ether 1:6) to afford
the ent-alcohol (72.8 mg, 0.155 mmol, 99%) as a colorless oil. Rf = 0.25
(EtOAc/petroleum ether 1:5, vanillin, UV). For analytical data see
supporting information.
(3S,4R)-3-((1S)-1-((tert-Butyldimethylsilyloxy)-5-methylhexyl)-4-
((tert-butyldimethylsilyloxy)-methyl)-dihydrofuran-2(3H)-one ent-30:
Alkene ent-29 (13.7 mg, 30 µmol, 1.0 eq) was dissolved in DCM (10 mL)
and cooled to −78 °C. Then, ozone was bubbled through the solution for 1
h until the blue color of unreacted ozone occurred. The ozone was
displaced by oxygen (10 min) and argon (15 min). Dimethyl sulfide
(0.33 mL, 280.5 mg, 4.73 mmol, 145.8 eq) was added dropwise and the
reaction mixture was stirred for 2 h at −78 °C and 1 h at room temperature.
The solvent and the excess dimethyl sulfide were removed in vacuo. The
residue was purified via column chromatography (EtOAc/petroleum ether
1:50) to afford lactone ent-30 (10.3 mg, 22.5 µmol, 75%) as a colorless oil.
(2R,3R,4R)-3-((1S)-1-(tert-Butyldimethylsilyloxy)-5-methylhexyl)-4-
tert-butyldimethylsilyloxymethyl-1-(iodomethyl)-tetrahydrofuran ent-
27: Triethylamine (0.12 mL, 0.87 mmol, 7.4 eq) and TBSOTf (0.14 mL,
0.61 mmol, 5.2 eq) were added dropwise to ent-alcohol (55.3 mg,
0.118 mmol, 1.0 eq) in DCM (3 mL) at 0 °C. The mixture was stirred at
room temperature for 20 h. After dilution with DCM (10 mL) and washing
with saturated aqueous NaHCO3 (8 mL), the resulting aqueous layer was
extracted with DCM (4x 6 mL). The combined organic layers were dried
(MgSO4), the solvent was removed in vacuo and the residue was purified
via column chromatography (EtOAc/petroleum ether 1:100) to afford silyl
ether ent-27 (53.8 mg, 0.092 mmol, 78%) as a colorless oil. Rf = 0.20
[ ]23
[ ]23
Rf = 0.13 (EtOAc/petroleum ether 1:50, cerium reagent). α = +30.5°
(CH2Cl2, c = 0.21 g/100 mL). IR (thin film): 2954 (s), 2929 (s), 2902 (m),
D
2857 (s), 1775 (s), 1736 (m), 1605 (w), 1514 (w), 1471 (m), 1389 (m),
1363 (m), 1255 (s), 1172 (m), 1094 (s), 1071 (s), 1006 (m), 938 (w),
837 (vs), 776 (vs), 713 (w), 667 (w), 627 (w), 598 (w). 1H NMR (CDCl3,
600 MHz): δ [ppm] = 4.34 (dd, 2J = 9.0 Hz, 3J = 8.2 Hz, 1H, H-5a), 4.09 (dd,
2J = 9.0 Hz, 3J = 5.9 Hz, 1H, H-5b), 4.05 (ddd, 3J = 8.4 Hz, 3J = 5.2 Hz,
3J = 3.5 Hz, 1H, H-6), 3.73 (dd, 2J = 10.0 Hz, 3J = 4.6 Hz, 1H, H-12a), 3.58
(dd, 2J = 10.0 Hz, 3J = 6.5 Hz, 1H, H-12b), 2.75 – 2.69 (m, 1H, H-4), 2.61
(dd, 3J = 6.4 Hz, 3J = 3.5 Hz, 1H, H-3), 1.60 – 1.53 (m, 1H, H-7a), 1.55 –
1.49 (m, 1H, H-10), 1.49 – 1.42 (m, 1H, H-7b), 1.42 – 1.33 (m, 1H, H-8a),
1.32 – 1.26 (m, 1H, H-8b), 1.24 – 1.17 (m, 1H, H-9a), 1.17 – 1.09 (m, 1H,
H-9b), 0.88 (s, 9H, H-18), 0.88 (s, 9H, H-15), 0.86 (d, 3J = 6.6 Hz, 3H, H-
11), 0.86 (d, 3J = 6.6 Hz, 3H, H-11'), 0.09 (s, 3H, H-16), 0.07 (s, 3H, H-16'),
0.05 (s, 3H, H-13), 0.05 (s, 3H, H-13'). 1H NMR (C6D6, 600 MHz): δ [ppm]
= 4.20 (ddd, 3J = 7.9 Hz, 3J = 4.8 Hz, 3J = 2.8, 1H, H-6), 4.08 – 4.03 (m,
1H, H-5a), 3.77 (dd, 2J = 9.1 Hz, 3J = 5.6 Hz, 1H, H-5b), 3.52 – 3.48 (m,
1H, H-12a), 3.33 – 3.28 (m, 1H, H-12b), 2.59 – 2.52 (m, 2H, H-3, H-4),
1.77 – 1.69 (m, 1H, H-7a), 1.54 – 1.42 (m, 3H, H-7b, H-8a, H-10), 1.39 –
1.25 (m, 1H, H-8b), 1.21 – 1.14 (m, 1H, H-9a), 1.14 – 1.06 (m, 1H, H-9b),
0.94 (s, 9H, H-18), 0.92 (s, 9H, H-15), 0.90 (d, 3J = 6.3 Hz, 3H, H-11), 0.89
(d, 3J = 6.3 Hz, 3H, H-11'), 0.05 (s, 3H, H-16), 0.02 (s, 3H, H-16'), 0.00 (s,
3H, H-13), −0.01 (s, 3H, H-13'). 13C NMR (CDCl3, 151 MHz): δ [ppm] =
177.0 (C-2), 72.5 (C-6), 69.9 (C-5), 64.3 (C-12), 47.8 (C-3), 39.5 (C-4),
39.0 (C-9), 34.2 (C-7), 28.1 (C-10), 25.9 (C-15, C-18), 24.2 (C-8), 22.7 (C-
11), 22.6 (C-11'), 18.3 (C-14), 18.1 (C-17), −4.2 (C-16), −4.4 (C-16'), −5.4
(C-13), −5.4 (C-13'). 13C NMR (C6D6, 151 MHz): δ [ppm] = 175.7 (C-2),
(EtOAc/petroleum ether 1:50, cerium reagent).
α
= -1.2° (CH2Cl2,
D
c = 1.00 g/100 mL). IR (thin film): 2954 (s), 2929 (s), 2857 (s), 1471 (m),
1411 (w), 1386 (m), 1362 (m), 1255 (s), 1176 (w), 1093 (s), 1073 (s),
1006 (m), 938 (w), 915 (w), 835 (vs), 774 (vs), 726 (w), 666 (m), 630 (w),
1
617 (w), 607 (w), 588 (w). H NMR (C6D6, 400 MHz): δ [ppm] = 3.89 (dd,
2J = 8.9 Hz, 3J = 4.9 Hz, 1H, H-5a), 3.86 – 3.77 (m, 2H, H-2, H-5b), 3.75 –
3.69 (m, 1H, H-6), 3.64 – 3.58 (m, 2H, H-12), 3.42 (dd, 2J = 10.2 Hz,
3J = 4.6 Hz, 1H, H-19a), 3.14 (dd, 2J = 10.2 Hz, 3J = 5.3 Hz, 1H, H-19b),
2.36 – 2.26 (m, 1H, H-4), 2.01 – 1.94 (m, 1H, H-3), 1.61 – 1.48 (m, 1H, H-
10), 1.48 – 1.32 (m, 4H, H-7, H-8), 1.19 – 1.10 (m, 2H, H-9), 0.97 (s, 9H,
3
H-18), 0.96 (s, 9H, H-15), 0.92 (d, J = 6.6 Hz, 6H, H-11, H-11'), 0.11 (s,
3H, H-16), 0.08 (s, 3H, H-16'), 0.07 (s, 6H, H-13, H-13'). 13C NMR (C6D6,
101 MHz): δ [ppm] = 80.4 (C-2), 74.0 (C-6), 70.3 (C-5), 64.9 (C-12), 52.1
(C-3), 46.0 (C-4), 39.6 (C-9), 35.6 (C-7), 28.4 (C-10), 26.2 (C-15), 26.2 (C-
18), 23.3 (C-8), 22.9 (C-11), 22.8 (C-11'), 18.5 (C-17), 18.3 (C-14), 12.2
(C-19), −3.9 (C-16), −4.0 (C-16'), −5.2 (C-13), −5.2 (C-13'). HRMS (ESI):
m/z [M+H]+ calcd for C25H54IO3Si2+: 585.2651; found: 585.2654.
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100497
European Journal of Organic Chemistry
FULL PAPER
72.8 (C-6), 69.5 (C-5), 64.8 (C-12), 48.3 (C-3), 39.5 (C-4), 39.1 (C-9), 34.4
(C-7), 28.3 (C-10), 26.0 (C-18), 26.0 (C-15), 24.6 (C-8), 22.8 (C-11), 22.7
(C-11'), 18.4 (C-14), 18.2 (C-17), −4.3 (C-16), −4.5 (C-16'), −5.4 (C-13),
−5.4 (C-13'). HRMS (ESI): m/z [M+Na]+ calcd for C24H50O4Si2Na+:
481.3140; found: 481.3140.
[4]
SCB-1/Gräfe SCB-Factor 1: from S. viridochromogenes a) U. Gräfe, W.
Schade, I. Eritt, W. F. Fleck, L. Radies, J. Antibiot. 1982, 35, 1722-1723;
from S. coelicolor A3(2) (incl. syntheses SCB-1, Gräfe VB-II) b) E.
Takano, T. Nihira, Y. Hara, J. J. Jones, C. J. L. Gershater, Y. Yamada,
M. Bibb, J. Biol. Chem. 2000, 275, 11010-11016; SCB-2-3 from S.
coelicolor M145 c) N.-H. Hsiao, S. Nakayama, M. E. Merlo, M. de Vries,
R. Bunet, S. Kitani, T. Nihira, E. Takano, Chem. Biol. 2009, 16, 951-960;
SCB-1 – SCB-8 from S. M1152 d) J. D. Sidda, V. Poon, L. Song, W.
Wang, K. Yang, C. Corre, Org. Biomol. Chem. 2016, 14, 6390-6393; IM-
2 from S. sp. FRI-5 e) K. Sato, T. Nihira, S. Sakuda, M. Yanagimoto, Y.
Yamada, J. Ferment. Bioeng. 1989, 68, 170-173.
(3S,4S)-3-((S)-1-Hydroxy-5-methylhexyl)-4-(hydroxymethyl)-
dihydrofuran-2(3H)-one ent-2d (+)-SCB-5: Acetic acid (16.8 mg,
0.280 mmol, 12.5 eq) and TBAF (0.23 mL, 0.23 mmol, 10.3 eq, 1.0 M in
THF) were added dropwise to a solution of silyl ether ent-30 (10.3 mg,
22.5 µmol, 1.0 eq) in THF (4 mL). The reaction mixture was stirred at room
temperature for 20 h. After dilution with Et2O (10 mL) and washing with an
aqueous NaHCO3 (10 mL), the aqueous layer was extracted with Et2O (3x
10 mL). The combined organic layers were dried (MgSO4), the solvent was
removed in vacuo and the residue was purified via column
chromatography (EtOAc/petroleum ether 1:10 to 1:1) to afford (+)-SCB-
[5]
Gräfe-VB-Factor I-III from S. bikiniensis and S. cyaneofuscatus (III only)
a) U. Gräfe, G. Reinhardt, W. Schade, I. Eritt, W. F. Fleck, L. Radics,
Biotechnology Lett. 1983, 5, 591-596; VB-A from S. antibioticus b) H. Y.-
H. Ohashi, Zheng, Y. Yamada, J. Antibiot. 1989, 42, 1191-1195; VB-A-
C from S. virginiae (incl. synthesis VB-C) c) Y. Yamada, K. Sugamura,
K. Kondo, M. Yanagimoto, H. Okada, J. Antibiot. 1987, 40, 496-504; VB-
A-E from S. virginiae d) K. Kondo, Y. Higuchi, S. Sakuda, T. Nihira, Y.
Yamada, J. Antibiot. 1989, 42, 1873-1876; VB-C, VB-E from S. sp. CA-
129531 e) K. Georgousaki, N. Tsafantakis, S. Gumeni, I. Gonzalez, T. A.
Mackenzie, F. Reyes, C. Lambert, I. P. Trougakos, O. Genilloud, N.
Fokialakis, Bioorg. Med. Chem. Lett. 2020, 30, Art.-No. 126952.
SCB-1 derivatives displaying additional hydroxyl groups within the side
chain see from S. badius: a) Y.; Mu, X. Yu, Z. Zheng, W. Liu, G. Li, J. Liu,
Y. Jiang, L. Han, X. Huang, Magn. Res. Chem. 2019, 57, 1150-1157;
From S. sp. W5: b) G. Wei, N. Zhu, Y. Zeng, Y. Shen, P. Zhao, Ann.
Microbiol. 2010, 60, 249-253.
5 ent-2d (5.1 mg, 22 µmol, 99%) as
(EtOAc/petroleum ether 1:1, vanillin).
a
colorless oil. Rf = 0.20
[ ]19
α
= +13.5° (CH2Cl2,
D
c = 0.50 g/100 mL). IR (thin film): 3421 (s, br), 2953 (s), 2923 (s), 2869 (s),
1767 (s), 1666 (w), 1467 (m), 1388 (m), 1260 (m), 1222 (w), 1179 (s),
1132 (m), 1027 (vs), 906 (w), 846 (w), 804 (w), 680 (w), 651 (w), 625 (w),
613 (w), 597 (w), 583 (w). 1H NMR (C6D6, 600 MHz): δ [ppm] = 3.80 – 3.74
(m, 1H, H-6), 3.73 (dd, 2J = 8.6 Hz, 3J = 7.8 Hz, H-5a), 3.28 (dd,
2J = 8.6 Hz, 3J = 8.6 Hz, 1H, H-5b), 3.00 (dd, 2J = 10.6 Hz, 3J = 4.8 Hz, 1H,
H-12a), 2.90 (dd, 2J = 10.6 Hz, 3J = 6.2 Hz, 1H, H-12b), 2.81 (s, 1H, H-13),
2.16 – 2.07 (m, 2H, H-3, H-4), 1.95 (s, 1H, H-14), 1.53 – 1.45 (m, 2H, H-
8a, H-10), 1.45 – 1.39 (m, 1H, H-7a), 1.38 – 1.24 (m, 2H, H-7b, H-8b), 1.18
– 1.05 (m, 2H, H-9), 0.90 (d, 3J = 6.7 Hz, 3H, H-11), 0.90 (d, 3J = 6.7 Hz,
3H, H-11'). 13C NMR (C6D6, 151 MHz): δ [ppm] = 176.9 (C-2), 70.9 (C-6),
67.9 (C-5), 62.9 (C-12), 49.4 (C-3), 40.1 (C-4), 39.1 (C-9), 34.4 (C-7), 28.3
(C-10), 24.1 (C-8), 22.8 (C-11), 22.8 (C-11'). HRMS (ESI): m/z [M+H]+
calcd for C12H23O4+: 231.1592; found: 231.1591.
[6]
[7]
Generally, GBL’s isolated from various (modified) streptomyces strains
had been characterized via several spectroscopic methods. Until now,
the 1H NMR data of the GBL’s enable to subdivide into SCB and VB type
species. However, the determination of the absolute configuration based
on chemical synthesis of suitable enantiomers and diastereomers. Then,
activity tests elucidated the bioactivity connected with the individual
structure of the GBL’s. Actually, it cannot be excluded, that the relative
and absolute configurations of the compounds given in Figure 1 need
further correction and addenda. Further investigations are required.
SAR Ref. 2e, a) S.-U. Choi, C.-K. Lee, Y.-I. Hwang, H. Kinoshita, T.
Nihira, Arch. Microbiol. 2003, 180, 303-307; b) S. Kitani, Y. Yamada, T.
Nihira, J. Bacteriol. 2001, 183, 4357-4363; c) S. Okamoto, K. Nakamura,
T. Nihira, Y. Yamada, J. Biol. Chem. 1995, 270, 12319-12326; d) S.
Okamoto, T. Nihira, H. Kataoka, A. Suzuki, Y. Yamada, J. Biol. Chem.
1992, 267, 1093-1098; e) H. S. Kim, H. Tada, T. Nihira, Y. Yamada, J.
Antibiot. 1990, 43, 692-706.
Acknowledgements
[8]
[9]
This work was supported by the “Naturstoffzentrum Rheinland-
Pfalz”. The authors are grateful for helpful discussions and
financial aid.
Keywords: diastereoselective synthesis • bioactive γ-
butyrolactone • zwitterionic aza-Claisen rearrangement •
iodocyclization • ozonolysis
a) T. Nihira, Y. Simizu, H. S. Kim, Y. Yamada, J. Antibiot. 1988, 41, 1828-
1837; b) K. Hashimoto, T. Nihira, Y. Yamada, J. Ferment. Bioeng. 1992,
73, 61-65; c) M. Kawabuchi, Y. Hara, T. Nihira, Y. Yamada, FEMS
Microbiol. Lett. 1997, 157, 81-85; d) N. Shikura, T. Nihira, Y. Yamada,
Biochim. Biophys. Acta 2000, 1475, 329-336.
[1]
Small molecule hormones triggering antibiotics production in
Streptomyces: a) N. B. Thao, S. Kitani, H. Nitta, T. Tomioka, T. Nihira, J.
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10.1002/ejoc.202100497
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[14] In 1990, Mori et al. (ref. 10h) published 1H NMR, IR and [α] data of both
compounds 2d/3d. For VB-A 3d additional 13C NMR and MS data are
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13C-NMR, bioactivity data) are reported in the literature. Nihira et al. (ref.
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NADPH-dependent hydrogenation of racemic 1’-dehydro VB-A 1d to
give enantiopure (-)-VB-A (2R,3R,1’S) 3d as well as the minor SCB-5
analogues (-)-(2R,3R,1’R) 2d and (+)-(2S,3S,1’S) ent-2d separable via
chiral HPLC. In 2016, Corre et al. (ref 4d) reported on the SCB-5
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published. The bioactivity of both SCB-5 enantiomers 2d remains to be
investigated.
[25] Work-up and purification via column chromatography of selanides ent-17
for analytical purposes was connected with a partial cleavage of the TBS
group delivering minor amounts of the corresponding carbinols ent-17a
(Scheme 5). However, such silylether cleavage was not found after
running the selenocyclization and the subsequent oxidation. Selenoxides
ent-18 were isolated with 97 % yield.
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supporting information), aza-Claisen rearrangement, amide cleavage
and reduction delivered racemic key intermediate rac-15 analog with high
diastereoselectivity. For procedures and data see supporting information.
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yields might be achievable optimizing the intermediate aldehyde 25b
oxidation. However, such oxidation hampered from several competing
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[32] For a final removal of the TBS ether strong basic conditions should be
avoided. Any intramolecular transesterification incorporating the C3
hydroxymethyl group would have caused a C3 epimerization potentially
leading to competing 2,3 cis configured GBL side products.
[21] Deposition numbers 2076145 (ent-β-11) and 2076144 (α-11) contain
supplementary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic Data
Centre and Fachinformationszentrum Karlsruhe Access Structures
service via www.ccdc.cam.ac.uk/structures.
[33] Furthermore, a ketoformate was isolated indicating some over oxidation
within this last Cr(VI) reaction. Presumably, the lactol suffered from H2O
elimination and subsequent dihydrofuran oxidative cleavage. For details
and data see supporting information.
[22] The zwitterionic aza-Claisen rearrangement led to the syntheses of both
enantiomers of ester 12 and carbinol 15, respectively. For completion of
both, (-)-SCB-5 and (+)-SCB-5 total synthesis, several strategies had
been tested involving only one of the enantiomer series. For clarification,
all intermediates heading for (-)-SCB-5 2d, the simple molecule numbers
are used. All intermediates leading to (+)-SCB-5 ent-2d are presented
using the prefix “ent”.
[34] For details and data lists see supporting information (NMR data
measured in CDCl3 and C6D6, respectively. Mori: NMR data in CDCl3
published, ref. 10h)
[35] Furthermore, orientation of the electron rich enolate terminus in the
proximity of the empty anti bonding orbital of the C-OTBS bond, might be
rated as an attractive interaction, too.
13
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10.1002/ejoc.202100497
European Journal of Organic Chemistry
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[36] Always, starting from both iodoethers 20/21, reductive ring opening
allowed regeneration of carbinols 15 with nearly quantitative yield. Thus,
the likewise generation of iodoethers 20 and 21, respectively, could be
optimized by recycling the undesired isomer.
[37] First experiments introducing an ester group at the 1’ OH function gave
small amounts of the ester. The major product displayed an exo double
bond indicating a rapid condensation destroying the stereogenic centers
at C2 an C1’. However, OH group inversion requires the absence of the
lactone carbonyl function. For details see supporting information.
14
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Entry for the Table of Contents
OTBS
F
S
Ph
N
+
*
R
O
PhO
Ph
O
Ph
OTBS
OTBS
stereotriades
S
N
N
S
R
S
R
R
O
PhO
PhO
OH
OH
OH
OH
H
H
3
1'
1'
3
2
2
R
R
S
S
S
R
O
O
(-)-SCB-5
(+)-SCB-5
O
O
Streptomyces coelicolor Butanolide 5
A diastereoselective total synthesis of (+) and (-) Streptomyces coelicolor butanolides SCB-5 has been developed. Starting from
suitable allylamines and acyl fluorides, a zwitterionic aza-Claisen rearrangement delivered amides displaying the key stereotriades with
defined configurations. Stepwise oxidative degradation of the double bonds and subsequent regioselective cyclization afforded the
enantiopure target butanolides.
15
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