Synthesis of Optically Active N -(4-Hydroxynon-2-enyl)pyrrolidines: Key Building Blocks in the Total Synthesis of Streptomyces coelicolor Butanolide 5 (SCB-5) and Virginiae Butanolide A (VB-A)

Article abstract of DOI:10.1055/s-0037-1610770

Starting from 5-methylhexanal and (S)-configured N -propargylprolinol ethers, coupling delivered N -(4-hydroxynon-2-ynyl)prolinol derivatives as mixtures of C4 diastereomers. Resolution of the epimers succeeded after introduction of an (R)-mandelic ester derivative and subsequent HPLC separation. Alternatively, suitable oxidation gave the corresponding alkynyl ketone. Midland reagent controlled diastereoselective reduction afforded a defined configured propargyl alcohol with high selectivity. LiAlH ₄reduction and Mosher analyses of the allyl alcohols enabled structure elucidation. The suitably protected products are used as key intermediates in enantioselective Streptomyces γ-butyrolactone signaling molecule total syntheses.

Full text of DOI:10.1055/s-0037-1610770

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–K
paper
A
en
J. Donges et al.
Paper
Synthesis
Synthesis of Optically Active N-(4-Hydroxynon-2-enyl)pyrrolidines:
Key Building Blocks in the Total Synthesis of Streptomyces coelicolor
Butanolide 5 (SCB-5) and Virginiae Butanolide A (VB-A)
Jonas Dongesa
O
AcO
Sandra Hofmannb
Johannes C. Walterc
Julia Reichertzd
Moritz Brüggemanne
Andrea Franka
N
O
Ph
N
PhO
1. HPLC
OH
4
4
*
N
PhO
( )3
( )3
+
4R + 4S
(R)-O-acetyl-
mandelic acid
4S
isoheptanal
PhO
LiAlH
2.
4
Udo Nubbemeyer*a
HO
OH
4
N
4
MnO2
N
a Organische Chemie/Johannes Gutenberg-Universität Mainz,
Duesbergweg 10-14, 55128 Mainz, Germany
nubbemey@uni-mainz.de
( )3
( )3
O
PhO
N
4R/S
4
4R
PhO
1.
Midland
( )3
b Konrad-Adenauer-Gymnasium, Wörthstr. 16, 56457 Wester-
burg, Germany
PhO
2. LiAlH4
c Otto-Schott-Gymnasium, An Schneiders Mühle 1, 55122
Mainz, Germany
d Maria-Ward-Schule, Ballplatz 3, 55116 Mainz, Germany
e Shimadzu Deutschland GmbH, Im Leuschnerpark 4, 64347
Griesheim, Germany
Corresponding Author
Received: 02.03.2021
Accepted after revision: 24.03.2021
Published online: 15.04.2021
Focusing on the bioactivity of the -butyrolactones
(GBL, Figure 1), the substitution pattern of the C2-bound
(1′-hydroxyalkyl) side chain and the relative and the abso-
lute configuration of the stereogenic centers (stereotriad
2,3,1′) play a crucial role.6 Because of the limited pool of ac-
cessible defined GBL’s, most investigations have been run
using compounds isolated from natural sources and biosyn-
thesis using genetically modified Streptomyces strains. Until
now, total syntheses of defined optically active VB- and
SCB/IM-2-type natural products and diastereomers/enan-
tiomers are sparsely reported.7
DOI: 10.1055/s-0037-1610770; Art ID: ss-2021-f0100-op
Abstract Starting from 5-methylhexanal and (S)-configured N-prop-
argylprolinol ethers, coupling delivered N-(4-hydroxynon-2-ynyl)proli-
nol derivatives as mixtures of C4 diastereomers. Resolution of the epi-
mers succeeded after introduction of an (R)-mandelic ester derivative
and subsequent HPLC separation. Alternatively, suitable oxidation gave
the corresponding alkynyl ketone. Midland reagent controlled diastere-
oselective reduction afforded a defined configured propargyl alcohol
with high selectivity. LiAlH4 reduction and Mosher analyses of the allyl
alcohols enabled structure elucidation. The suitably protected products
are used as key intermediates in enantioselective Streptomyces -buty-
rolactone signaling molecule total syntheses.
OH
(–)-SCB-5
OH
OH
OH
H
H
(+)-SCB-5
R
S
( )3
R
( )3
S
S
R
Key words propargyl alcohols, allyl alcohols, N-allylprolinol deriva-
tives, O-acetylmandelic acid, enantioselective reduction, Mosher analy-
sis
O
O
OH
O
O
OH
H
(1'R)-syn-anti
(1'S)-syn-anti
1'
R
3
2
OH
OH
OH
H
OH
H
O
O
Antibiotic production in Streptomyces sp. such as S. vir-
giniae and S. coelicolor is triggered by small molecule hor-
mones.1 A widely distributed and well-characterized series
of signaling molecules are the trans-(2-substituted 3-hy-
droxymethyl)--butyrolactones.2 After the first discovery of
the so-called A-factor (the only 2-acyl--butyrolactone of
this series known so far) by Khokhlov and co-workers,3 16
further species displaying a 2-(1′-hydroxyalkyl) side chain
have been isolated. The Virginiae butanolide (VB)/Gräfe VB-
Factor family displays (1′S) configuration,4 the Streptomyces
coelicolor butanolide (SCB)/IM-2/Gräfe SCB-Factor 1 family
(1′R) configuration.5
GBL
S
R
( )3
( )3
S
R
S
R
O
O
O
O
(–)-VB-A
(+)-VB-A
(1'S)-anti-anti
(1'R)-anti-anti
Figure 1 Absolute and relative configurations of Virginiae butanolide A
type -butyrolactone stereotriads [R = iPr(CH2)3]: (–)-SCB-5 (2R,3R,1′R
= 1′R-syn-anti), (+)-SCB-5 (1′S-syn-anti), (–)-VB-A/Gräfe VB-Factor I
(2R,3R,1′S = 1′S-anti-anti), (+)-VB-A/Gräfe VB-Factor I (1′R-anti-anti)
The convergent total syntheses of GBL’s A published so
far involved aldol reactions and Claisen condensation/-
keto ester reduction sequences coupling the side-chain
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Donges et al.
Paper
Synthesis
fragments C and paraconyl alcohol derivatives B completing
the stereotriad within the last step with varying selectivi-
ties (Scheme 1).7–9 In this connection, Bibb, Takano and co-
workers succeeded in synthesizing both enantiomers of
SCB-1/Gräfe Factor 1 and Gräfe VB-Factor II.7f The genera-
tion of six representative VB and SCB substitution pattern
compounds by Mori and Chiba in 1990 should be men-
tioned as pioneering work.8 However, assignment of the
configurations of the stereogenic centers had to be correct-
ed by Sakuda and Yamada in 1991.9
An alternative attempt should build up the stereotriad
with high diastereoselectivity prior to the completion of the
substitution pattern of the GBL’s. For a first total synthesis
of the VB-A (Gräfe VB-Factor I)/SCB-5 substitution pattern,
a more linear strategy was chosen (Figure 1, Scheme 1).
An alternative retrosynthesis involves a separation of
generation of the stereogenic centers and the complete as-
sembly of the -hydroxy lactone moiety (Scheme 1). In this
connection, the target lactone A was traced back via few
steps to a ,-unsaturated amide D. The N-acylpyrrolidine D
is the product of a diastereoselective zwitterionic aza-
Claisen rearrangement of 4-phenylbutenoic acid fluoride E
and N-allylpyrrolidine F.10 Intending to run the key rear-
rangement likewise as an auxiliary-controlled and a sub-
strate-controlled process, both defined allyl alcohol config-
uration and defined (protected) 2-(hydroxyalkyl)pyrroli-
dine moieties had to be installed. Thus, a coupling of a
metalated alkene G (X′ = metal) and a metalated alkyne (+
reduction) to isoheptanal C (R = 4-MeC5H10) was envisaged.
N-Allylprolinol derivatives G (X′ = H, halide, SnBu3) and the
corresponding N-propargyl building blocks should serve as
reactants, which had to be synthesized from L-(–)-proline
(I), propargyl bromide and suitable allyl halides H following
literature procedures.
The syntheses of allylamines F (compounds 21, 22)
commenced by assembling the building blocks C (com-
pounds 2, 3) and G (compounds 9, 14).
Commercially available 5-methylhexanoic acid (1) was
converted into the Weinreb amide 2 following a procedure
reported by Gosh and Gong (Scheme 2).11 DIBAL-H reduc-
tion gave 5-methylhexanal (3) in >83% yield over two steps.
Alternatively, LiAlH4 reduction of acid 1 to carbinol 4 and
subsequent TEMPO oxidation delivered aldehyde 3 in opti-
mized 96% yield (two steps).12 Alternatively, a four-step se-
quence according to literature procedures was started from
monoethyl malonate (5) and 3-methylbutanal (6). Knoeve-
nagel–Doebner condensation, subsequent DIBAL-H reduc-
tion and double bond hydrogenation delivered alcohol 4
(61%, 3 steps).13 In contrast to the TEMPO version as men-
tioned above (97%), a final Swern oxidation afforded alde-
hyde 3 in 75% yield only.12c,13d
O
O
HO2C
CO2Et
+
H
OH
6
5
1
2
iv
i
iii
O
OH
N
4
OMe
ii
v
O
H
3
Scheme 2 Synthesis of 5-methylhexanal (3). Reagents and conditions:
(i) DCC, DMAP, [MeO(Me)NH2]+Cl–, Et3N, CH2Cl2, 23 °C, 24 h, 99%; (ii)
DIBAL-H, CH2Cl2, –78 °C, 2 h, 84%; (iii) LiAlH4, THF, 23 °C, 24 h, >99%;
(iv) (a) pyridine, piperidine, 23 °C to 80 °C, 77 h, 85%; (b) DIBAL-H,
CH2Cl2, –78 °C to 23 °C, 24 h, 76%; (c) H2, Pd/C, EtOH, K2CO3, 23 °C, 16
h, 94%; (v) version 1 (Swern oxidation): DMSO, C2Cl2O2, Et3N, CH2Cl2,
–78 °C to 23 °C, 8 h, 75%; version 2: TEMPO, KBr, NaHCO3, NaOCl,
CH2Cl2, H2O, 0 °C, 1 h, 97%. For details, see refs. 11–13 and the Sup-
porting Information.
OH
OPG
OH
*
see refs.
7, 8, 9
H
*
O
R
*
*
+
The optically active pyrrolidines 7b and 7c were synthe-
sized according to literature procedures, starting from the
corresponding amino acids L-(–)-proline and trans-4-hy-
droxy-L-(–)-proline, respectively (Scheme 3).10g,14 N-Allyla-
tion employing allyl halides 8 gave the corresponding 3-
functionalized N-allylpyrrolidines 9 in 66–89% yield (Table
1).15 Furthermore, tin–iodine exchange succeeded via stan-
dard procedures. Treatment of pyrrolidines 9b and 9e with
I2 afforded the vinyl iodides 9c and 9f in 66% and >99% yield,
respectively.16 All attempts to couple 5-methylhexanal (3)
and the N-allylpyrrolidines 9 via Grignard-type procedures
gave disappointing results despite wide variation of the re-
action conditions. Vinyllithium derivatives from (chloroal-
lyl)pyrrolidine 9a (LiDtBB) and the corresponding stannane
9b (nBuLi) gave some racemic allyl alcohol 10 (R1 = R2 = H)
in 14% and 58% yield, but the processes proved to be not ro-
bust (Table 1; entries 1, 2).15b,17 If anything, most runs (9e–9g;
R
H
O
O
O
O
A
B
C
Ph
OPG1
Ph
C(O)F
OPG1
E
N
N
*
*
R
*
*
*
R
*
O
PG2O
PG2O
D
F
X'
X'
X
O
H
HN
N
*
HO
PG2O
+
R
H
*
O
I
G
C
Scheme 1 Retrosynthesis of -butyrolactone natural products A.
R = 4-MeC5H10: SCB-5/VB-A (Gräfe VB-Factor I) [for comparison:
R = 5-MeC6H12: SCB-1 (Gräfe SCB-Factor 1)/Gräfe VB-Factor II]
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

C
J. Donges et al.
Paper
Synthesis
philic building blocks for coupling with aldehyde 3 (Scheme
4). The assembly of the N-propargylprolinol derivatives
started from L-(–)-proline methyl ester hydrochloride
(12).18 After N-substitution with propargyl bromide and
subsequent DIBAL-H reduction, the N-propargylprolinol 13
was protected as TBS ether 14a in 52% yield (3 steps). The
generation of phenyl ether 14b required intermediate pro-
tection of the nitrogen for avoiding side reactions. N-Ben-
zylation and LiAlH4 reduction gave N-benzylprolinol (15;
88% yield, 2 steps).18c,19 For phenyl ether introduction, the
Mitsunobu reaction or O-mesylation with mesyl chlo-
ride/Williamson ether formation gave disappointing re-
sults.20 In contrast, treatment of prolinol 15 with phenyl io-
OtBu
Cl
Cl
Br
Br
8a
Br
HN
HN
HN
8b
8c
CH2OTBS
CH2OPh
Bu3Sn
7a
7b
7c
R2
R2
i
X'
X
HN
X'
N
N
+
ii
R1
R1
8
7
9
iii
R2
R2
OH
21
dide and CuI/Cs2CO3 afforded the corresponding phenyl
+
N
H
ether 16 in 97% yield. Finally, hydrogenolysis of the benzyl-
amine and subsequent treatment with propargyl bromide
gave the desired N-propargylprolinol derivative 14b in 87%
yield (2 steps).22
R1
for details see Table 1
R1
H
H
10
11
Scheme 3 Synthesis of N-allylpyrrolidines 9 and allyl alcohol 10. Re-
agents and conditions: (i) variation A: THF, 23 °C, 12–20 h, 86% (9a), 89%
(9b); variation B: Et3N, PhMe, 65 °C, 67% (9d); variation C: iPr2NEt, THF,
23 °C, 16–60 h, 76% (9e), 80% (9g, Z/E = 1:6); (ii) I2, CH2Cl2, 23 °C, 2.5–
3 h, 66% (9c from 9b), >99% (9f from 9e); (iii) variation A: Li, DtBB (di-
tert-butylbiphenyl), THF, 0 °C, 3 h, then 3, THF, –78 °C to 23 °C, 12 h,
14% (10 from 9a); variation B: nBuLi, THF, –78 °C, then 3, THF, –78 °C to
23 °C, 12 h, 58% (10 from 9b); variation C: nBuLi, PhMe, –78 °C, then 3,
PhMe, –78 °C to 23 °C, 12 h, 40% (11 from 9f), 66% (11 from 9g). For
further details, see Table 1 and the Supporting Information.
i
ii
Cl–
N+
H
N
N
H
CO2Me
HO
TBSO
12
13
14a
iii
iv
v
N
N
N
Bn
Bn
HO
PhO
PhO
15
16
14b
Table 1, entries 5–7) delivered some N-allylpyrrolidine 11
(R1 = CH2OPh, R2 = OtBu) which indicated a rapid competing
proton transfer from aldehyde 3 to lithiated 9, thus enforc-
ing us to abandon this sequence. Obviously, the Brønsted
basicity of the metalated vinyl system dominates and steric
reasons might have suppressed any addition.
Scheme 4 Synthesis of N-propargylamines 14. Reagents and conditions:
(i) (a) propargyl bromide, Et3N, MgSO4, PhMe, 65 °C, 4 h, 75%; (b)
DIBAL-H, THF, –78 °C, 12 h, then –15 °C, 4 h, 83%; (ii) TBSCl, imidazole,
THF, 0 °C to 23 °C, 16 h, 84%; (iii) (a) BnBr, Et3N, CH2Cl2, 23 °C, 3 d, 91%;
(b) LiAlH4, THF, 0 °C to 23 °C, 21 h, 97%; (iv) PhI, CuI, Cs2CO3, phenanth-
roline, PhMe, reflux, 9 d, 97%; (v) (a) H2, Pd/C, MeOH, 23 °C, 7 d, >99%;
(b) propargyl bromide, Et3N, THF, 23 °C, 3 d, 88%. For further details,
see the Supporting Information.
Switching to N-propargylpyrrolidine derivatives 14
promised the use of less sterically congested, more nucleo-
Table 1 Synthesis of N-Allylpyrrolidines
Entry Amine 7
Olefin 8
Allylamine 9 X′
R1
R2
Yield (%)
Remarks
9
10
(a) 14
11
n.d.a
1
2
3
4
5
6
7
7a
7a
–
8a
8c
–
9a
9b
9c
9d
9e
9f
Cl
H
H
86
89
varying yields
varying yields
Bu3Sn
H
H
H
H
(a) 58
n.d.a
I
H
66b
67
–
–
–
–
–
n.d.a
7b
7c
–
8b
8c
–
Br
CH2OTBS
CH2OPh
CH2OPh
CH2OPh
impure
(c) <40
(c) 40
(c) 66
Bu3Sn
OtBu
OtBu
OtBu
76
competing aldol-type processes
competing aldol-type processes
competing aldol-type processes
I
>99c
7c
8a
9g
Cl
80 (1:6)d
a Not detected because of low boiling point, removed via Rotavapor.
b From 9b.
c From 9e.
d (Z/E).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

D
J. Donges et al.
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Synthesis
Starting from alkynes 14 and aldehyde 3, additions were
performed under standard conditions (Scheme 5).23 Over-
all, the less Brønsted basic alkynyl anion effected no com-
peting proton transfers and the reduced steric congestion
enabled smooth additions. 5-Methylhexanal (3) was treated
with lithiated alkynes 14a and 14b (nBuLi/THF) affording
propargyl alcohols 17a in 62% and 17b in 91% yield, respec-
tively, as mixtures of C4 diastereomers (about 1:1 and 4:5
R/S). In contrast to silyl ether 17a (inseparable diastereo-
mers under widely varied conditions), the phenyl ether 17b
diastereomers were separated via laborious preparative
HPLC. Intending to facilitate the resolution of the diastereo-
mers (4R/S)-17b, several ester derivatives 18 were generat-
ed. Formation of benzoate (4R/S)-18a and 4-nitrobenzoate
(4R/S)-18b succeeded under standard conditions,24 in near-
ly quantitative yields. Analysis of the 1H NMR data revealed
a perfect overlapping for all signals in connection with ben-
zoates (4R/S)-18a and (4R/S)-18b. The 13C NMR data of es-
ters (4R/S)-18a and (4R/S)-18b displayed some separated
peaks for (4R)- and (4S)-18a and (4R)- and (4S)-18b. Unfor-
tunately, HPLC separation of the diastereomers of 18a and
18b failed.
Obviously, the long distance between the stereogenic
centers of the diastereomers (rigid alkyne moiety) had to be
considered. Therefore, introduction of an ester function in-
corporating a defined remote stereogenic center was rec-
ommended. Upon treatment of carbinol (4R/S)-17b with
(R)-O-acetylmandelic acid chloride,25 the esterification suc-
ceeded in 87% yield delivering a mixture of four diastereo-
mers 18c (Scheme 5). Apparently, the original (R)-config-
ured stereocenter of the mandelic acid moiety suffered
from some (S/R) epimerization under the applied reaction
conditions.25b,c Separation and structure elucidation re-
quired laborious HPLC techniques. In contrast, reaction of
(4R/S)-17b with (R)-O-acetylmandelic acid under Steglich
conditions (DCC/DMAP)26 avoided accompanying epi-
merization, and the mandelic ester (4R/S)-18c was isolated
in 92% yield. Preparative HPLC separation gave (4R)-18c
(42% yield) and (4S)-18c (50% yield). Finally, ester formation us-
ing (S)-2-(6-methoxynaphthalenyl)propanoic acid/DCC/DMAP
gave the corresponding esters 18d in 78% yield and a d.r. of
36.5:63.5, which were separated via preparative HPLC.27 In
comparison to the mandelic acid derivatives 18c, an incipi-
ent kinetic resolution of the diastereomers 18d in combina-
tion with a somewhat lower yield recommended prioritiz-
ing the 18c series. Regeneration of diastereomerically pure
carbinols 17b succeeded applying Zemplén conditions
(K2CO3, MeOH).28 Carbinol (4S)-17b was obtained from es-
ter (4S)-18c (97% yield) and from (4S)-18d (90% yield). Car-
binol (4R)-17b was generated from (4R)-18c (99% yield)
and from (4R)-18d (88% yield).
Weinreb amide 2, treatment with lithiated propargylamine
14a gave ketone 19a in 34% yield only. The analogous reac-
tion using alkyne 14b delivered ketone 19b in 51% yield.
Side reactions such as aza-Michael addition of the hydrox-
ylamine to the alkynyl ketone could not be completely sup-
pressed.29 Alternatively, Dess–Martin oxidation30 of propar-
gyl alcohol 17a was tested, and the corresponding ketone
19a was isolated in 83% yield. Furthermore, MnO2 oxida-
tion31 of carbinol 17b gave ketone 19b in 80% yield. Com-
parison of the sequences acid 1 to ketone 19b, the four-step
N
O
O
OMe
( )3
R1O
N
( )3
H
14
v
i
Me
2
3
vi
vii
O
HO
( )3
N
N
N
4
*
( )3
R1O
R1O
19
17
ii
HO
( )3
HO
( )3
N
4
4
+
PhO
PhO
(4R)-17b
iii iv
(4S)-17b
iii iv
O
O
R2
O
R2
O
N
N
4
4
+
( )3
( )3
PhO
PhO
(4R)-18
(4S)-18
MeO
R
R
1 = TBS: 14a, 17a, 19a
1 = Ph: 14b, 17b, 19b
R
R
2 = Ph: 18a
2 = 4-O2NC6H4: 18b
OAc
(18c)
(18d)
Scheme 5 Synthesis and separation of propargyl alcohols (4R)-17 and
(4S)-17. Reagents and conditions: (i) nBuLi, Et2O or THF, –78 °C to 23 °C,
3 h, then 3, Et2O or THF, –78 °C to 23 °C, 16 h–2 d, 62% (17a, d.r. 1:1,
inseparable via HPLC), 91% (17b, d.r. 4:5, separable via HPLC); (ii) HPLC
separation [Nucleosil OH (Diol), hexane/EtOAc 85:15 + 1% Et3N]; (iii) (a)
BzCl, Et3N, CH2Cl2, 23 °C, 24 h, >99% (18a, d.r. ~57:43, inseparable via
HPLC) or (b) 4-O2NC6H4C(O)Cl, Et3N, CH2Cl2, 23 °C, 24 h, >99% (18b,
d.r. ~55:45, inseparable via HPLC) or (c) (R)-O-acetylmandelic acid chlo-
ride, Et3N, CH2Cl2, 23 °C, 22 h, 87% (18c, mixture of 4 diastereomers,
partly separable via HPLC) or (d) (R)-O-acetylmandelic acid, DCC, DMAP,
CH2Cl2, 23 °C, 2 d, 92% [18c, d.r. (4R/4S) 46:54, separable via HPLC] or
(e) (S)-2-(6-methoxynaphthalenyl)propanoic acid, DCC, DMAP, CH2Cl2,
23 °C, 2 d, 78% [18d, d.r. (4R/4S) 36.5:63.5, separable via HPLC]; (iv)
K2CO3, MeOH, 23 °C, 24 h, 99% [(4R)-17b from (4R)-18c], 97% [(4S)-
17b from (4S)-18c], 88% [(4R)-17b from (4R)-18d], 90% [(4S)-17b from
(4S)-18d]; (v) nBuLi, THF, –78 °C to 23 °C, 3 h, then 2, THF, –78 °C to 23
°C, 16 h, 34% (19a), 51% (19b); (vi) (a) Dess–Martin reagent, CH2Cl2, 23
°C, 5 h, 83% (19a from 17a) or (b) MnO2, CH2Cl2, 23 °C, 6 d, 80% (19b
from 17b); (vii) R-Alpine-Borane (B-isopinocampheyl-9-borabicyclo-
[3.3.1]nonane), THF, 23 °C, 3 d, 69% [17b from 19b, d.r. (4R)-17b/(4S)-
17b 95:5]. For details, see the Supporting Information.
A stereoselective access to likewise (4R)- and (4S)-carbi-
nols 17b should avoid any laborious separation problems
(Scheme 5). In this connection, a reagent-controlled reduc-
tion of an alkyl alkynyl ketone 19 was chosen. Starting from
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

E
J. Donges et al.
Paper
Synthesis
sequence via alcohol 4 and aldehyde 3 gave about 70% yield
overall, the two-step sequence including the costly Weinreb
amide 2 afforded significantly lower 50% yield (Scheme 2,
Scheme 5).
HO
( )3
HO
( )3
N
N
4
4
PhO
PhO
(4R)-17b
(4S)-17b
For a reagent-controlled diastereoselective propargyl
ketone 19 reduction (Scheme 5), Midland’s reagent (R-Al-
pine-Borane) gave a convincing result.32 Reduction of ke-
tone 19b afforded carbinol (4R)-17b in 69% yield and a d.r.
of about 95:5 [(4R)-17b/(4S)-17b] according to direct HPLC
analysis and HPLC separation after mandelic ester 18c for-
mation.
i, iii or iv
i, iii or iv
OR
OR
N
N
( )3
( )3
PhO
PhO
(4R)-20 (R = H)
(4R)-21 (R = TBS)
(4S)-20 (R = H)
(4S)-21 (R = TBS)
After assembly of propargyl alcohol (4R/S)-17b (mix-
ture of diastereomers) and the diastereomerically pure
propargyl alcohols (4R)- and (4S)-17b, as well as the corre-
sponding esters (4R)- and (4S)-18c, LiAlH4 reduction33 en-
abled selective trans-olefin 20 formation (Scheme 6). The
reaction of carbinol 17b (mixture of diastereomers) gave al-
lyl alcohol 20 (mixture of diastereomers, d.r. ~46:54) in 85%
yield. Again, resolution of the diastereomers (4R)- and (4S)-
20 required laborious preparative HPLC. Treatment of man-
delic esters (4R)- and (4S)-18c with LiAlH4 allowed ester re-
moval and alkyne reduction in a single step.34 Allyl alcohol
(4S)-20 was obtained from ester (4S)-18c in >99% yield, the
analogous conversion using (4R)-18c gave (4R)-20 in 99%
yield. Focusing on workup and purification of the carbinols
(4R)- and (4S)-20, reduction of the neat propargyl alcohols
(4R)- and (4S)-17b proved to be the best method. Finally,
protection of the OH function as a silyl ether was carried
out under standard conditions.35 Reaction of (4R)-20 with
TBSOTf/2,6-lutidine delivered the corresponding silyl ether
(4R)-21 in 90% yield, (4S)-21 was generated from carbinol
(4S)-20 in 83% yield.
(4R)-22a (R = R-MTPA)
(4R)-22b (R = S-MTPA)
(4S)-23a (R = R-MTPA)
(4S)-23b (R = S-MTPA)
ii, iii or iv
O
ii, iii or iv
O
AcO
Ph
AcO
Ph
O
O
4
N
N
4
( )3
( )3
PhO
PhO
(4R)-18c
(4S)-18c
O
O
R = R-MTPA
in 22a, 23a
R = S-MTPA
in 22b, 23b
MeO CF3
MeO CF3
Scheme 6 Synthesis of defined configured, protected allyl alcohols
(4R)-21 and (4S)-21. Reagents and conditions: (i) LiAlH4, THF, 0 °C to 23
°C, 2 d, 39% (4R)-20 + 46% (4S)-20 [from (4R/S)-17b]; (ii) LiAlH4, THF,
23 °C, 19 h, 99% [(4R)-20 from (4R)-18c], >99% [(4S)-20 from (4S)-18c];
(iii) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to 23 °C, 20 h, 90% [(4R)-21 from
(4R)-20], 83% [(4S)-21 from (4S)-20]; (iv) R- or S-MTPA-OH, DCC,
DMAP, CH2Cl2, 23 °C, 4 d, 63% [(4R)-22a from R-MTPA-OH and (4R)-20],
80% [(4R)-22b from S-MTPA-OH and (4R)-20], 87% [(4S)-23a from R-
MTPA-OH and (4S)-20], 70% [(4S)-23b from S-MTPA-OH and (4S)-20];
MTPA-OH = 2-methoxy-2-(trifluoromethyl)phenylacetic acid. For fur-
ther information, including an alternative seven-step synthesis of race-
mic N-(4-benzyloxy-8-methylnon-2-en-1-yl)pyrrolidine, see the
Supporting Information.
Since none of the amino alcohol intermediates 17–21
crystallized, structure elucidation was carried out via modi-
fied Mosher analysis (Scheme 6).36 Most convincing results
were found starting from allyl alcohols 20. Reaction of car-
binol (4R)-20 with (R)- and (S)-Mosher acid (MTPA-OH,
DCC/DMAP), respectively, gave the corresponding esters
(4R)-22a/b in 63%/80% yield. Reaction of carbinol (4S)-20
with (R)- and (S)-Mosher acid (MTPA-OH, DCC/DMAP) af-
forded esters (4S)-23a/b in 87%/70% yield. Comparison of
tures of diastereomers. Separation succeeded after O-pro-
tection as mandelic esters 18c via preparative HPLC [(4R)-
18c: 42% yield, (4S)-18c: 50% yield]. Alternatively, Braun-
stein oxidation delivered the alkynyl ketones 19; ketone
19b was then treated with Midland’s reagent delivering the
product propargyl alcohol moiety (4R)-17b with defined
configuration (52% yield, 2 steps). Finally, LiAlH4 reduction
and subsequent allyl alcohol protection delivered the de-
sired key building blocks (4R)-21 in 89% yield and (4S)-21 in
82% yield. Always, structure elucidation of the allyl alcohols
20 was performed via careful Mosher analyses.
Overall, starting from known reactants (S)-prolinol phe-
nyl ether, propargyl bromide and 5-methylhexanal (3),
propargyl alcohol 17b was synthesized via two steps in 80%
yield. The generation of single diastereomer protected allyl
alcohols (4R)-21 and (4S)-21 was achieved via three further
steps via an O-acetylmandelic acid ester sequence (HPLC
separation of the diastereomers) delivering (4R)-21 in >37%
yield and (4S)-21 in 41% yield. Alternatively, a diastereo-
1
the H NMR data unequivocally enabled assignment of the
absolute configuration at the C4 allyl alcohol centers.
The stereoselective synthesis of enantiopure Virginiae
butanolide and Streptomyces coelicolor butanolide hor-
mones required efficient access to the optically active
(2,3,1′) stereotriads characterizing the key fragments of this
series of natural products. Since zwitterionic aza-Claisen
rearrangements developed earlier proved to serve as reli-
able tools to generate such stereotriads with high selectivi-
ties, the syntheses of suitably substituted allylamines 20
and 21 were required. The reaction of 5-methylhexanal (3)
with N-propargylprolinol derivatives 14 delivered N-(4-hy-
droxyalk-2-ynyl)pyrrolidines 17 in up to 91% yield as mix-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

F
J. Donges et al.
Paper
Synthesis
selective four-step sequence (Midland reduction) gave (4R)-
21 in >46% yield overall. The optically active allylamines are
used as key fragments in an SCB-5 and a VB-A/Gräfe VB-
Factor I total synthesis.
2.71–2.63 (m, 1 H, H-5b), 2.31 (s, 1 H, H-20), 2.06–1.95 (m, 1 H, H-3a),
1.90–1.69 (m, 3 H, H-3b, H-4), 1.68–1.58 (m, 2 H, H-15), 1.57–1.49 (m,
1 H, H-18), 1.48–1.38 (m, 2 H, H-16), 1.23–1.13 (m, 2 H, H-17), 0.87
(d, 3J = 6.6 Hz, 6 H, H-19, H-19′).
13C NMR (101 MHz, CDCl3):  = 159.0 (C-7), 129.5 (C-9), 120.8 (C-10),
114.6 (C-8), 86.3 (C-12), 80.2 (C-13), 70.9 (C-6), 62.7 (C-14), 60.1 (C-
2), 53.7 (C-5), 42.4 (C-11), 38.7 (C-17), 38.4 (C-15), 28.7 (C-3), 28.0 (C-
18), 23.2 (C-4, C-16), 22.7 (C-19), 22.7 (C-19′).
Thin-film IR spectra were recorded with a Jasco FT/IR-4100 spectro-
photometer with single reflection horizontal ATR (ZnSe window). Op-
tical rotations were recorded with an MC 241 polarimeter (Perkin-
Elmer). 1H NMR, 13C NMR and 2D NMR (COSY, HSQC, HMBC, NOESY)
spectra were recorded at room temperature with a Bruker Avance III
HD 300, Avance II 400 or Avance III HD 400 spectrometer, in CDCl3 us-
ing the signal of residual CHCl3 (1H: 7.26 ppm; 13C: 77.16 ppm) as in-
ternal standard. FD mass spectra were obtained using a Finnigan MAT
95 system and ESI mass spectra were measured using a Waters Micro-
mass QTOF Ultima 3 spectrometer. HRMS ESI spectra were recorded
using an Agilent G6545A Q-ToF spectrometer. Column chromatogra-
phy was performed on MN silica gel 60M (Macherey-Nagel GmbH &
Co. KG) with a grain size of 0.040–0.063 nm. An analytical HPLC sys-
tem was used to analyze the products: Knauer HPLC Pump 64 con-
nected to a HPLC column (see the Supporting Information), Knauer
Variable Wavelength Monitor ( = 254 or 220 nm) and Knauer Differ-
ential Refractometer. Preparative HPLC system: Knauer WellChrom
Preparative Pump K-1800 connected to a HPLC column, Knauer Vari-
able Wavelength Monitor ( = 254 or 220 nm) and Bischoff RI detector
8100. A selection of experimental procedures is given in the follow-
ing. For all procedures and the numbering used in the 1H and 13C NMR
spectra, see the Supporting Information.
MS (ESI): m/z (%) = 330.25 (100) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H32NO2+: 330.2433; found:
330.2432.
(4S)-17b
22
[]D –96.6 (c 1.00, CH2Cl2); Rf = 0.20 (EtOAc/petroleum ether, 1:3;
vanillin, UV).
HPLC: t0 = 1.44 min, k = 7.67 [Nucleosil OH (Diol), EtOAc/hexane 15:85
+ 1% Et3N, 2 mL/min, 52 bar].
IR (thin film): 3383 (m, br), 2951 (m), 2868 (m), 1600 (s), 1587 (m),
1496 (s), 1467 (m), 1385 (w), 1366 (w), 1327 (w), 1301 (w), 1241 (s),
1172 (m), 1138 (m), 1079 (m), 1039 (s), 912 (w), 881 (w), 752 (s), 690
(s), 614 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.32–7.22 (m, 2 H, H-9), 6.96–6.88 (m,
3
5
3 H, H-8, H-10), 4.37 (tt, J = 6.6 Hz, J = 1.8 Hz, 1 H, H-14), 3.98 (dd,
2J = 9.4 Hz, 3J = 5.8 Hz, 1 H, H-6a), 3.90 (dd, 2J = 9.4 Hz, 3J = 5.6 Hz, 1 H,
H-6b), 3.67 (d, J = 1.8 Hz, 2 H, H-11), 3.16–3.03 (m, 2 H, H-2, H-5a),
5
2.73–2.62 (m, 1 H, H-5b), 2.07–1.94 (m, 1 H, H-3a), 1.92–1.70 (m, 3 H,
H-3b, H-4), 1.69–1.58 (m, 2 H, H-15), 1.58–1.49 (m, 1 H, H-18), 1.49–
1.38 (m, 2 H, H-16), 1.24–1.14 (m, 2 H, H-17), 0.87 (d, 3J = 6.6 Hz, 6 H,
H-19, H-19′).
13C NMR (101 MHz, CDCl3):  = 159.0 (C-7), 129.5 (C-9), 120.9 (C-10),
114.6 (C-8), 86.3 (C-12), 80.3 (C-13), 70.9 (C-6), 62.7 (C-14), 60.2 (C-
2), 53.7 (C-5), 42.4 (C-11), 38.7 (C-17), 38.4 (C-15), 28.7 (C-18), 28.1
(C-3), 23.2 (C-4, C-16), 22.7 (C-19), 22.7 (C-19′).
(R)-8-Methyl-1-((S)-2-(phenoxymethyl)pyrrolidin-1-yl)non-2-yn-
4-ol [(4R)-17b] and (S)-8-Methyl-1-((S)-2-(phenoxymethyl)pyrro-
lidin-1-yl)non-2-yn-4-ol [(4S)-17b]
nBuLi (1.12 mL, 3.03 mmol, 1.5 equiv, 2.7 M in PhMe) was added
dropwise to a solution of pyrrolidine 14b (434.9 mg, 2.02 mmol, 1.0
equiv) in Et2O (15 mL) at –78 °C and the mixture was stirred for 2.5 h
at this temperature. 5-Methylhexanal (3; 739.7 mg, 6.478 mmol, 3.2
equiv) in Et2O (10 mL) was added and stirring was continued for 23 h
with warming to room temperature. The organic layer was washed
with brine (15 mL). The aqueous phase was extracted with Et2O (3 ×
10 mL) and the combined organic layers were washed with brine (3 ×
100 mL) and dried (MgSO4). The solvent was removed in vacuo and
the residue was purified via column chromatography (EtOAc/petro-
leum ether, 1:5 to 1:1) to afford a diastereomeric mixture of alcohols
(4R)-17b and (4S)-17b (602.5 mg, 1.829 mmol, 91%) as a yellow oil.
The diastereomers (d.r. 4:5) were separated in an analytical amount
by HPLC [Nucleosil OH (Diol), EtOAc/hexane 15:85 + 1% Et3N, 30
mL/min, 34 bar] for characterization.
MS (ESI): m/z (%) = 330.25 (100) [M + H]+, 352.24 (19) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H31NNaO2+: 352.2252; found:
352.2245.
(R)-8-Methyl-1-((S)-2-(phenoxymethyl)pyrrolidin-1-yl)non-2-yn-
4-yl (R)-2-Acetoxy-2-phenylacetate [(4R)-18c] and (S)-8-Methyl-1-
((S)-2-(phenoxymethyl)pyrrolidin-1-yl)non-2-yn-4-yl (R)-2-Ace-
toxy-2-phenylacetate [(4S)-18c]
N,N′-Dicyclohexylcarbodiimide (46.0 mg, 0.223 mmol, 2.1 equiv), 4-
(dimethylamino)pyridine (12.8 mg, 0.104 mmol, 1.0 equiv) and (R)-
O-acetylmandelic acid (42.3 mg, 0.218 mmol, 2.1 equiv) were added
to the diastereomeric mixture of (4R/S)-alcohols 17b (34.4 mg, 0.104
mmol, 1.0 equiv) in CH2Cl2 (6 mL). The mixture was stirred for 2 d at
room temperature. After dilution with CH2Cl2 (10 mL) and washing
with aqueous NaHCO3 (10 mL), the aqueous layer was extracted with
CH2Cl2 (3 × 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, 1:4) to afford a di-
astereomeric mixture of esters (4R)-18c and (4S)-18c (48.6 mg, 96.0
mol, 92%) as a yellow oil. Purification via HPLC (Nucleosil 50-5, EtO-
Ac/hexane 1:4, 60 mL/min, 63 bar) afforded (4R)-18c (22.1 mg, 43.7
mol, 42%) and (4S)-18c (26.5 mg, 52.3 mol, 50%).
(4R)-17b
22
[]D –91.1 (c 1.00, CH2Cl2); Rf = 0.20 (EtOAc/petroleum ether, 1:3;
vanillin, UV).
HPLC: t0 = 1.44 min, k = 7.00 [Nucleosil OH (Diol), EtOAc/hexane 15:85
+ 1% Et3N, 2 mL/min, 52 bar].
IR (thin film): 3389 (m, br), 2952 (m), 2867 (m), 1600 (s), 1587 (m),
1496 (s), 1467 (m), 1366 (w), 1301 (w), 1241 (s), 1172 (m), 1079 (m),
1039 (s), 913 (w), 882 (w), 752 (s), 691 (s), 610 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.30–7.23 (m, 2 H, H-9), 6.96–6.87 (m,
3
5
3 H, H-8, H-10), 4.36 (tt, J = 6.6 Hz, J = 1.8 Hz, 1 H, H-14), 3.97 (dd,
(4R)-18c
2J = 9.4 Hz, 3J = 5.7 Hz, 1 H, H-6a), 3.89 (dd, 2J = 9.4 Hz, 3J = 5.7 Hz, 1 H,
H-6b), 3.66 (d, J = 1.8 Hz, 2 H, H-11), 3.16–3.03 (m, 2 H, H-2, H-5a),
23
[]D –52.3 (c 1.00, CH2Cl2); Rf = 0.18 (EtOAc/petroleum ether, 1:4;
5
ninhydrin, UV).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

G
J. Donges et al.
Paper
Synthesis
HPLC: t0 = 1.28 min, k = 5.25 (Nucleosil 50-5, EtOAc/hexane 1:4, 2
8-Methyl-1-((S)-(2-phenoxymethyl)pyrrolidin-1-yl)non-2-yn-4-
mL/min, 109 bar).
one (19b)
MnO2 (296.8 mg, 3.414 mmol, 10.0 equiv) was added to the diastereo-
meric mixture of (R/S)-alcohols (4R)-17b and (4S)-17b (112.3 mg,
0.341 mmol, 1.0 equiv) in CH2Cl2 (3 mL). The reaction mixture was
stirred for 3 d at room temperature. Then, another portion of MnO2
(297.4 mg, 3.421 mmol, 10.0 equiv) was added and stirring was con-
tinued for a further 3 d. The solids were removed by filtration through
a silica pad and the solid residues were rinsed with EtOAc (100 mL).
The combined organic layers were dried (MgSO4) to afford ketone 19b
(89.7 mg, 0.274 mmol, 80%) as a yellow oil.
IR (thin film): 3035 (w), 2954 (m), 2869 (m), 1751 (s), 1601 (m), 1587
(w), 1497 (m), 1457 (m), 1371 (m), 1327 (w), 1233 (vs), 1206 (s),
1174 (s), 1082 (m), 1052 (m), 967 (w), 913 (w), 753 (s), 693 (m), 657
(w), 628 (w), 618 (w), 602 (w), 584 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.50–7.46 (m, 2 H, H-26), 7.40–7.33
(m, 3 H, H-25, H-27), 7.30–7.23 (m, 2 H, H-9), 6.93 (tt, 3J = 7.4 Hz, 4J =
1.1 Hz, 1 H, H-10), 6.90–6.86 (m, 2 H, H-8), 5.91 (s, 1 H, H-21), 5.41 (tt,
3J = 6.6 Hz, 5J = 1.8 Hz, 1 H, H-14), 3.86 (dd, 2J = 9.3 Hz, 3J = 5.7 Hz, 1 H,
H-6a), 3.81 (dd, 2J = 9.3 Hz, 3J = 5.6 Hz, 1 H, H-6b), 3.56 (dd, 2J = 2.6 Hz,
5J = 1.8 Hz, 2 H, H-11), 3.02–2.93 (m, 1 H, H-2), 2.88 (ddd, 2J = 9.0 Hz,
3J = 7.0 Hz, 3J = 2.3 Hz, 1 H, H-5a), 2.50 (ddd, 2J = 9.0 Hz, 3J = 6.9 Hz, 3J =
6.9 Hz, 1 H, H-5b), 2.20 (s, 3 H, H-23), 1.95–1.83 (m, 1 H, H-3a), 1.82–
1.61 (m, 5 H, H-3b, H-4, H-15), 1.59–1.47 (m, 1 H, H-18), 1.47–1.37
(m, 2 H, H-16), 1.23–1.14 (m, 2 H, H-17), 0.87 (d, 3J = 6.7 Hz, 6 H, H-19,
H-19′).
13C NMR (101 MHz, CDCl3):  = 170.4 (C-22), 168.0 (C-20), 159.1 (C-7),
133.5 (C-24), 129.5 (C-9), 129.3 (C-27), 128.8 (C-25), 127.8 (C-26),
120.8 (C-10), 114.6 (C-8), 81.7 (C-12), 81.4 (C-13), 74.6 (C-21), 70.9
(C-6), 65.9 (C-14), 59.7 (C-2), 53.3 (C-5), 42.0 (C-11), 38.4 (C-17), 35.0
(C-15), 28.7 (C-3), 27.9 (C-18), 23.3 (C-4), 22.9 (C-16), 22.6 (C-19),
22.6 (C-19′), 20.8 (C-23).
22
[]D –96.5 (c 1.00, CH2Cl2); Rf = 0.41 (EtOAc/petroleum ether, 1:4;
ninhydrin, UV).
HPLC: t0 = 2.60 min, k = 4.00 (Nucleosil 50-5, iPrOH/hexane 1:99, 2
mL/min, 41 bar).
IR (thin film): 2954 (m), 2871 (m), 2210 (m), 1675 (s), 1600 (m), 1587
(m), 1498 (s), 1468 (m), 1366 (w), 1301 (w), 1243 (vs), 1153 (m),
1039 (m), 754 (s), 691 (m), 618 (w), 605 (w), 587 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.30–7.24 (m, 2 H, H-9), 6.94 (tt, 3J =
7.3 Hz, 4J = 1.1 Hz, 1 H, H-10), 6.92–6.87 (m, 2 H, H-8), 3.92 (d, 3J = 5.6
Hz, 2 H, H-6), 3.84 (d, 2J = 9.2 Hz, 2 H, H-11), 3.17–3.11 (m, 1 H, H-2),
3.08 (ddd, 2J = 9.3 Hz, 3J = 6.7 Hz, 3J = 2.8 Hz, 1 H, H-5a), 2.74–2.66 (m,
1 H, H-5b), 2.51 (dd, 3J = 7.9 Hz, 3J = 7.0 Hz, 2 H, H-15), 2.08–1.97 (m, 1
H, H-3a), 1.91–1.77 (m, 2 H, H-4), 1.76–1.70 (m, 1 H, H-3b), 1.70–1.61
(m, 2 H, H-16), 1.60–1.48 (m, 1 H, H-18), 1.23–1.15 (m, 2 H, H-17),
0.88 (d, 3J = 6.6 Hz, 6 H, H-19, H-19′).
HRMS (ESI): m/z [M + H]+ calcd for C31H40NO5+: 506.2901; found:
506.2898.
(4S)-18c
13C NMR (101 MHz, CDCl3):  = 188.1 (C-14), 158.9 (C-7), 129.6 (C-8),
121.0 (C-10), 114.6 (C-9), 88.8 (C-12), 84.6 (C-13), 71.2 (C-6), 60.1 (C-
2), 53.9 (C-5), 45.9 (C-15), 42.4 (C-11), 38.3 (C-17), 28.5 (C-3), 27.9 (C-
18), 23.3 (C-4), 22.6 (C-19, C-19′), 22.1 (C-16).
HRMS (ESI): m/z [M + H]+ calcd for C21H30NO2+: 328.2276; found:
328.2268.
22
[]D –123.1 (c 1.00, CH2Cl2); Rf = 0.18 (EtOAc/petroleum ether, 1:4;
ninhydrin, UV).
HPLC: t0 = 1.28 min, k = 7.10 (Nucleosil 50-5, EtOAc/hexane 1:4, 2
mL/min, 109 bar); t0 = 1.68 min, k = 6.67 (S,S-Whelk-O 1, iPrOH/hex-
ane 2:98, 2 mL/min, 29 bar).
IR (thin film): 3064 (w), 3038 (w), 2953 (m), 2870 (m), 1747 (s), 1600
(m), 1497 (m), 1456 (w), 1371 (m), 1336 (m), 1291 (w), 1228 (vs),
1172 (s), 1110 (w), 1081 (w), 1041 (s), 964 (w), 925 (w), 753 (s), 693
(R)-8-Methyl-1-((S)-2-(phenoxymethyl)pyrrolidin-1-yl)non-2-yn-
4-ol [(4R)-17b]
(s), 654 (w), 626 (w), 612 (w), 598 (w), 586 (w) cm–1
.
R-Alpine-Borane (142 mg, 0.550 mmol, 2.0 equiv, 0.5 M in THF) was
added to neat ketone 19b (90.1 mg, 0.275 mmol, 1.0 equiv). The mix-
ture was stirred for 3 d at room temperature. After cooling to 0 °C, 2 M
aqueous NaOH (0.35 mL) was added dropwise. After stirring for 5 min,
aqueous H2O2 solution (0.23 mL, 35%) was added dropwise and stir-
ring was continued for 5 min. The cooling bath was removed and the
reaction mixture was heated to 40 °C for 4 h. After cooling to room
temperature and dilution with Et2O (10 mL), 2 M aqueous NaOH (4
mL) was added and the layers were separated. The aqueous layer was
extracted with Et2O (3 × 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, 1:1) to
afford a diastereomeric mixture of alcohols (4R)-17b and (4S)-17b
(62.4 mg, 0.19 mmol, 69%) as a yellow oil. The diastereomers were
separated by HPLC [Nucleosil OH (Diol), EtOAc/hexane 15:85 + 1%
Et3N, 60 mL/min, 105 bar] to afford (4R)-17b (56.9 mg, 0.173 mmol,
63%) and a remaining 2:3 mixture of the diastereomeric alcohols
(4R)-17b and (4S)-17b (5.5 mg, 0.017 mmol, 6%). Overall, a diastereo-
meric ratio of 95:5 of major (4R)-17b (59.1 mg, 0.18 mmol, 65.3%)
and minor (4S)-17b (3.3 mg, 0.010 mmol, 3.7%) was found. For spec-
troscopic data, see above.
1H NMR (400 MHz, CDCl3):  = 7.50–7.44 (m, 2 H, H-26), 7.41–7.33
(m, 3 H, H-25, H-27), 7.31–7.23 (m, 2 H, H-9), 6.96–6.88 (m, 3 H, H-8,
H-10), 5.94 (s, 1 H, H-21), 5.39 (tt, 3J = 6.6 Hz, 5J = 1.8 Hz, 1 H, H-14),
3.94 (dd, 2J = 9.4 Hz, 3J = 5.7 Hz, 1 H, H-6a), 3.87 (dd, 2J = 9.4 Hz, 3J = 5.5
Hz, 1 H, H-6b), 3.67 (dd, 5J = 1.8 Hz, 2J = 1.6 Hz, 2 H, H-11), 3.14–2.99
(m, 2 H, H-2, H-5a), 2.67 (ddd, 2J = 9.3 Hz, 3J = 9.3 Hz, 3J = 7.2 Hz, 1 H,
H-5b), 2.19 (s, 3 H, H-23), 2.03–1.91 (m, 1 H, H-3a), 1.90–1.66 (m, 3 H,
H-3b, H-4), 1.65–1.56 (m, 2 H, H-15), 1.45–1.33 (m, 1 H, H-18), 1.28–
1.09 (m, 2 H, H-16), 1.09–0.98 (m, 2 H, H-17), 0.78 (d, 3J = 6.6 Hz, 3 H,
H-19), 0.78 (d, 3J = 6.6 Hz, 3 H, H-19′).
13C NMR (101 MHz, CDCl3):  = 170.2 (C-22), 168.0 (C-20), 159.1 (C-7),
133.9 (C-24), 129.5 (C-9), 129.4 (C-27), 128.9 (C-25), 127.8 (C-26),
120.8 (C-10), 114.6 (C-8), 81.9 (C-12), 81.7 (C-13), 74.6 (C-21), 70.8
(C-6), 65.7 (C-14), 60.0 (C-2), 53.5 (C-5), 42.3 (C-11), 38.2 (C-17), 35.0
(C-15), 28.6 (C-3), 27.9 (C-18), 23.3 (C-4), 22.6 (C-16), 22.6 (C-19),
22.5 (C-19′), 20.8 (C-23).
HRMS (ESI): m/z [M + H]+ calcd for C31H40NO5+: 506.2901; found:
506.2908.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

H
J. Donges et al.
Paper
Synthesis
(R,E)-8-Methyl-1-((S)-2-(phenoxymethyl)pyrrolidin-1-yl)non-2-
en-4-ol [(4R)-20]
13C NMR (101 MHz, CDCl3):  = 159.0 (C-7), 136.5 (C-12), 129.5 (C-9),
128.0 (C-13), 120.8 (C-10), 114.6 (C-8), 72.6 (C-14), 71.0 (C-6), 62.3
(C-2), 56.9 (C-11), 54.6 (C-5), 39.0 (C-17), 37.6 (C-15), 28.8 (C-3), 28.0
(C-18), 23.3 (C-16), 23.1 (C-4), 22.7 (C-19), 22.7 (C-19′).
HRMS (ESI): m/z [M + H]+ calcd for C21H34NO2+: 332.2590; found:
332.2598.
LiAlH4 (12.6 mg, 0.332 mmol, 11.3 equiv) was added to alkyne (4R)-
18c (14.8 mg, (0.029 mmol, 1.0 equiv) in THF (3 mL) at 0 °C. The reac-
tion mixture was warmed to room temperature and stirred for 19 h.
At 0 °C, water (0.1 mL), 3 M aqueous NaOH (0.1 mL) and water (0.3
mL) were successively added dropwise. The mixture was warmed to
room temperature and stirred for 30 min. Then, MgSO4 was added.
After stirring for 30 min, the mixture was filtered through a pad of
Celite and rinsed with Et2O (50 mL). The organic layer was washed
with water (10 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were dried (MgSO4). The solvent
was removed in vacuo to afford (R)-alcohol (4R)-20 (9.6 mg, 0.029
mmol, 99%) as a yellow oil.
(S)-1-((R,E)-4-(tert-Butyldimethylsilyloxy)-8-methylnon-2-en-1-
yl)-2-(phenoxymethyl)pyrrolidine [(4R)-21]
2,6-Lutidine (0.16 mL, 0.15 g, 1.4 mmol, 2.2 equiv) and TBSOTf (0.30
mL, 0.35 g, 1.3 mmol, 2.1 equiv) were added dropwise to (R)-alcohol
(4R)-20 (210.5 mg, 0.635 mmol, 1.0 equiv) in CH2Cl2 (20 mL) at 0 °C.
The reaction mixture was stirred for 20 h at room temperature. After
dilution with CH2Cl2 (20 mL) and washing with aqueous NaHCO3 (40
mL), the remaining aqueous layer was extracted with CH2Cl2 (5 × 20
mL) and the combined organic layers were dried (MgSO4). The solvent
was removed in vacuo and the residue was purified via column chro-
matography (EtOAc/petroleum ether, 1:10) to afford silyl ether (4R)-
21 (254.9 mg, 0.572 mmol, 90%) as a yellow oil.
29
[]D –58.4 (c 1.01, CH2Cl2); Rf = 0.11 (EtOAc/petroleum ether, 2:3;
vanillin, UV).
HPLC: t0 = 1.17 min, k = 10.64. (Remark: preparative column.)
IR (thin film): 3366 (m, br), 2952 (s), 2927 (s), 2868 (m), 1600 (s),
1496 (s), 1468 (m), 1365 (w), 1300 (w), 1242 (s), 1172 (w), 1078 (s),
1039 (s), 974 (m), 912 (w), 883 (w), 753 (s), 691 (s), 640 (w), 617 (w),
31
[]D –43.5 (c 0.99, CH2Cl2); Rf = 0.53 (EtOAc/petroleum ether, 1:5;
606 (w) cm–1
.
ninhydrin, UV).
1H NMR (400 MHz, CDCl3):  = 7.32–7.22 (m, 2 H, H-9), 6.96–6.87 (m,
3 H, H-8, H-10), 5.82–5.73 (m, 1 H, H-13), 5.69–5.61 (m, 1 H, H-12),
4.11–4.04 (m, 1 H, H-14), 4.00 (dd, 2J = 9.3 Hz, 3J = 5.3 Hz, 1 H, H-6a),
3.85 (dd, 2J = 9.3 Hz, 3J = 6.3 Hz, 1 H, H-6b), 3.57 (dd, 2J = 13.3 Hz, 3J =
5.8 Hz, 1 H, H-11a), 3.15–3.02 (m, 2 H, H-11b, H-5a), 2.95–2.87 (m, 1
H, H-2), 2.38–2.29 (m, 1 H, H-5b), 2.07–1.95 (m, 1 H, H-3a), 1.85–1.71
(m, 3 H, H-3b, H-4), 1.57–1.40 (m, 3 H, H-15, H-18), 1.40–1.24 (m, 2
H, H-16), 1.20–1.14 (m, 2 H, H-17), 0.86 (d, J = 6.6 Hz, 6 H, H-19, H-
19′).
13C NMR (101 MHz, CDCl3):  = 159.0 (C-7), 136.4 (C-12), 129.5 (C-9),
128.3 (C-13), 120.8 (C-10), 114.6 (C-8), 72.7 (C-14), 71.1 (C-6), 62.4
(C-2), 57.0 (C-11), 54.6 (C-5), 38.9 (C-17), 37.5 (C-15), 28.7 (C-3), 28.0
(C-18), 23.4 (C-16), 23.1 (C-4), 22.7 (C-19), 22.7 (C-19′).
HPLC: t0 = 1.00 min, k = 4.00 (Nucleosil 50-5, EtOAc/hexane 1:4, 2
mL/min, 103 bar).
IR (thin film): 2953 (s), 2929 (s), 2857 (m), 2791 (w), 1692 (w), 1601
(m), 1587 (m), 1496 (m), 1469 (m), 1362 (w), 1300 (w), 1245 (s),
1171 (w), 1079 (m), 1039 (m), 1007 (w), 973 (m), 937 (w), 835 (s),
775 (s), 752 (s), 690 (m), 616 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.31–7.22 (m, 2 H, H-9), 6.96–6.88 (m,
3 H, H-8, H-10), 5.73–5.57 (m, 2 H, H-12, H-13), 4.11–4.05 (m, 1 H, H-
14), 4.04–3.96 (m, 1 H, H-6a), 3.83 (dd, 2J = 9.2 Hz, 3J = 6.7 Hz, 1 H, H-
6b), 3.54 (dd, 2J = 13.3 Hz, 3J = 5.3 Hz, 1 H, H-11a), 3.15–3.03 (m, 2 H,
H-11b, H-5a), 2.96–2.86 (m, 1 H, H-2), 2.41–2.30 (m, 1 H, H-5b), 2.06–
1.95 (m, 1 H, H-3a), 1.86–1.71 (m, 3 H, H-3b, H-4), 1.58–1.49 (m, 1 H,
H-18), 1.48–1.37 (m, 2 H, H-15), 1.37–1.17 (m, 2 H, H-16), 1.17–1.08
3
3
HRMS (ESI): m/z [M + H]+ calcd for C21H34NO2+: 332.2590; found:
(m, 2 H, H-17), 0.88 (s, 9 H, H-22), 0.84 (d, J = 6.6 Hz, 6 H, H-19, H-
19′), 0.04 (s, 3 H, H-20), 0.02 (s, 3 H, H-20′).
332.2597.
13C NMR (101 MHz, CDCl3):  = 159.1 (C-7), 137.0 (C-12), 129.5 (C-9),
126.8 (C-13), 120.7 (C-10), 114.6 (C-8), 73.3 (C-14), 71.2 (C-6), 61.9
(C-2), 57.0 (C-11), 54.4 (C-5), 39.0 (C-17), 38.7 (C-15), 28.9 (C-3), 28.1
(C-18), 26.1 (C-22), 23.3 (C-16), 23.2 (C-4), 22.7 (C-19), 22.7 (C-19′),
18.4 (C-21), –4.1 (C-20), –4.6 (C-20′).
HRMS (ESI): m/z [M + H]+ calcd for C27H48NO2Si+: 446.3449; found:
446.3455.
(S,E)-8-Methyl-1-((S)-2-(phenoxymethyl)pyrrolidin-1-yl)non-2-
en-4-ol [(4S)-20]
Alkyne (4S)-18c (21.7 mg, 0.0429 mmol, 1.0 equiv) was reduced with
LiAlH4 (18.6 mg, 0.490 mmol, 11.4 equiv) according to the procedure
described above to afford (S)-alcohol (4S)-20 (14.2 mg (0.043 mmol,
>99%) as a yellow oil.
29
[]D –58.1 (c 1.02, CH2Cl2); Rf = 0.13 (EtOAc/petroleum ether, 3:2;
vanillin, UV).
(S)-1-((S,E)-4-(tert-Butyldimethylsilyloxy)-8-methylnon-2-en-1-
yl)-2-(phenoxymethyl)pyrrolidine [(4S)-21]
HPLC: t0 = 1.17 min, k = 14.18. (Remark: preparative column.)
2,6-Lutidine (0.69 mL, 0.64 g, 6.0 mmol, 2.2 equiv) and TBSOTf (1.25
mL, 1.43 g, 5.4 mmol, 2.0 equiv) were added dropwise to (S)-alcohol
(4S)-20 (899.4 mg, 2.713 mmol, 1.0 equiv) in CH2Cl2 (30 mL) at 0 °C.
The reaction mixture was stirred for 20 h at room temperature. After
dilution with CH2Cl2 (20 mL) and washing with aqueous NaHCO3 (40
mL), the resulting aqueous layer was extracted with CH2Cl2 (3 × 20
mL) and the combined organic layers were dried (MgSO4). The solvent
was removed in vacuo and the residue was purified via column chro-
matography (EtOAc/petroleum ether, 1:10) to afford silyl ether (4S)-
21 (1.007 g, 2.259 mmol, 83%) as a yellow oil.
IR (thin film): 3354 (m, br), 2951 (s), 2927 (s), 2868 (m), 1600 (s),
1496 (s), 1467 (m), 1384 (w), 1300 (w), 1243 (s), 1172 (w), 882 (w),
753 (s), 691 (s), 652 (w), 633 (w), 616 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.30–7.23 (m, 2 H, H-9), 6.96–6.87 (m,
3
3 H, H-8, H-10), 5.84–5.74 (m, 1 H, H-13), 5.68 (ddt, J = 15.4 Hz, 3J =
6.5 Hz, 4J = 1.1 Hz, 1 H, H-12), 4.13–4.05 (m, 1 H, H-14), 4.00 (dd, 2J =
9.5 Hz, 3J = 5.3 Hz, 1 H, H-6a), 3.84 (dd, 2J = 9.3 Hz, 3J = 6.4 Hz, 1 H, H-
6b), 3.55 (dd, 2J = 13.4 Hz, 3J = 5.9 Hz, 1 H, H-11a), 3.18–3.06 (m, 2 H,
H-11b, H-5a), 2.99–2.88 (m, 1 H, H-2), 2.41–2.31 (m, 1 H, H-5b), 2.07–
1.94 (m, 1 H, H-3a), 1.87–1.69 (m, 3 H, H-3b, H-4), 1.57–1.41 (m, 3 H,
H-15, H-18), 1.41–1.21 (m, 2 H, H-16), 1.20–1.09 (m, 2 H, H-17), 0.85
(d, 3J = 6.7 Hz, 6 H, H-19, H-19′).
30
[]D –52.7 (c 1.02, CH2Cl2); Rf = 0.47 (EtOAc/petroleum ether, 1:5;
ninhydrin, UV).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

I
J. Donges et al.
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Synthesis
HPLC: t0 = 1.00 min, k = 4.50 (Nucleosil 50-5, EtOAc/hexane 1:4, 2
mL/min, 103 bar).
(4) VB Factors: (a) Georgousaki, K.; Tsafantakis, N.; Gumeni, S.;
Gonzalez, I.; Mackenzie, T. A.; Reyes, F.; Lambert, C.; Trougakos,
I. P.; Genilloud, O.; Fokialakis, N. Bioorg. Med. Chem. Lett. 2020,
30, 126952. (b) Kondo, K.; Higuchi, Y.; Sakuda, S.; Nihira, T.;
Yamada, Y. J. Antibiot. 1989, 42, 1873. (c) Yamada, Y.; Sugamura,
K.; Kondo, K.; Yanagimoto, M.; Okada, H. J. Antibiot. 1987, 40,
496. (d) Gräfe, U.; Reinhardt, G.; Schade, W.; Eritt, I.; Fleck, W.
F.; Radics, L. Biotechnol. Lett. 1983, 5, 591.
(5) SCB Factors: (a) Sidda, J. D.; Poon, V.; Song, L.; Wang, W.; Yang,
K.; Corre, C. Org. Biomol. Chem. 2016, 14, 6390. (b) Sato, K.;
Nihira, T.; Sakuda, S.; Yanagimoto, M.; Yamada, Y. J. Ferment.
Bioeng. 1989, 68, 170. (c) Gräfe, U.; Schade, W.; Eritt, I.; Fleck,
W. F.; Radics, L. J. Antibiot. 1982, 35, 1722. For further SCB-1
derivatives displaying additional hydroxyl groups within the
side chain, see: (d) Mu, Y.; Yu, X.; Zheng, Z.; Liu, W.; Li, G.; Liu, J.;
Jiang, Y.; Han, L.; Huang, X. Magn. Reson. Chem. 2019, 57, 1150.
(6) SAR: (a) Hsiao, N.-H.; Nakayama, S.; Merlo, M. E.; de Vries, M.;
Bunet, R.; Kitani, S.; Nihira, T.; Takano, E. Chem. Biol. 2009, 16,
951. (b) Nihira, T.; Shimizu, Y.; Kim, H. S.; Yamada, Y. J. Antibiot.
1988, 41, 1828.
(7) Syntheses. A-factor: (a) Morin, J. B.; Adams, K. L.; Sello, J. K. Org.
Biomol. Chem. 2012, 10, 1517. (b) Crawforth, J. M.; Fawcett, J.;
Rawlings, B. J. J. Chem. Soc., Perkin Trans. 1 1998, 1721. (c) Mori,
K.; Yamane, K. Tetrahedron 1982, 38, 2919. (d) Parsons, P. J.;
Lacrouts, P.; Buss, A. D. J. Chem. Soc., Chem. Commun. 1995, 437.
(e) Posner, G. H.; Weitzberg, M.; Jew, S.-S. Synth. Commun. 1987,
17, 611. SCB-1: (f) Takano, E.; Nihira, T.; Hara, Y.; Jones, J. J.;
Gershater, C. J. L.; Yamada, Y.; Bibb, M. J. Biol. Chem. 2000, 275,
11010. SCB-2: (g) Sarkale, A. M.; Kumar, A.; Appayee, C. J. Org.
Chem. 2018, 83, 4167. IM-2: (h) Mizuno, K.; Sakuda, S.; Nihira,
T.; Yamada, Y. Tetrahedron 1994, 50, 10849. VB-D: (i) Elsner, P.;
Jiang, H.; Nielsen, J. B.; Pasi, F.; Jørgensen, K. A. Chem. Commun.
2008, 5827. VB-C: (j) Takabe, K.; Mase, N.; Matsumura, H.;
Hasegawa, T.; Iida, Y.; Kuribayashi, H.; Adachi, K.; Yoda, H.; Ao,
M. Bioorg. Med. Chem. Lett. 2002, 12, 2295.
IR (thin film): 2954 (s), 2927 (s), 2858 (m), 2794 (w), 1746 (w), 1601
(m), 1497 (m), 1469 (m), 1388 (w), 1362 (w), 1300 (w), 1245 (s), 1171
(w), 1081 (m), 1039 (m), 974 (m), 835 (s), 775 (s), 752 (s), 690 (m),
664 (w) cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.31–7.22 (m, 2 H, H-9), 6.96–6.88 (m,
3 H, H-8, H-10), 5.73–5.57 (m, 2 H, H-12, H-13), 4.11–4.05 (m, 1 H, H-
14), 4.04–3.96 (m, 1 H, H-6a), 3.83 (dd, 2J = 9.2 Hz, 3J = 6.7 Hz, 1 H, H-
6b), 3.54 (dd, 2J = 13.3 Hz, 3J = 5.3 Hz, 1 H, H-11a), 3.15–3.03 (m, 2 H,
H-11b, H-5a), 2.96–2.86 (m, 1 H, H-2), 2.41–2.30 (m, 1 H, H-5b), 2.06–
1.95 (m, 1 H, H-3a), 1.86–1.71 (m, 3 H, H-3b, H-4), 1.58–1.49 (m, 1 H,
H-18), 1.48–1.37 (m, 2 H, H-15), 1.37–1.17 (m, 2 H, H-16), 1.17–1.08
(m, 2 H, H-17), 0.88 (s, 9 H, H-22), 0.84 (d, 3J = 6.6 Hz, 6 H, H-19, H-
19′), 0.04 (s, 3 H, H-20), 0.02 (s, 3 H, H-20′).
13C NMR (101 MHz, CDCl3):  = 159.1 (C-7), 137.0 (C-12), 129.5 (C-9),
126.9 (C-13), 120.8 (C-10), 114.6 (C-8), 73.4 (C-14), 71.1 (C-6), 62.2
(C-2), 57.1 (C-11), 54.5 (C-5), 39.0 (C-17), 38.7 (C-15), 28.9 (C-3), 28.1
(C-18), 26.1 (C-22), 23.2 (C-4, C-16), 22.8 (C-19), 22.7 (C-19′), 18.4 (C-
21), –4.1 (C-20), –4.6 (C-20′).
HRMS (ESI): m/z [M + H]+ calcd for C27H48NO2Si+: 446.3449; found:
446.3447.
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
The authors are grateful to the Naturstoffzentrum Rheinland-Pfalz for
helpful discussions and financial aid.
(8) Mori, K.; Chiba, N. Liebigs Ann. Chem. 1990, 31.
Supporting Information
(9) Sakuda, S.; Yamada, Y. Tetrahedron Lett. 1991, 32, 1817.
(10) The zwitterionic aza-Claisen rearrangement is described as a
two-step process. After addition of a tertiary allylamine to an
intermediately formed Lewis acid activated ketene, a zwitteri-
onic N-acylammonium enolate is generated, which then under-
goes a Claisen-type rearrangement with charge neutralization
and high stereoselectivities. For a review, see: (a) Nubbemeyer,
U. Synthesis 2003, 961. Substrate control: (b) Nubbemeyer, U.
J. Org. Chem. 1995, 60, 3773. (c) Nubbemeyer, U. J. Org. Chem.
1996, 61, 3677. (d) Heescher, C.; Schollmeyer, D.; Nubbemeyer,
U. Eur. J. Org. Chem. 2013, 4399. Auxiliary control: (e) Laabs, S.;
Münch, W.; Nubbemeyer, U.; Bats, J.-W. Tetrahedron 2002, 58,
1317. (f) Zhang, N.; Nubbemeyer, U. Synthesis 2002, 242.
(g) Friedemann, N. M.; Härter, A.; Brandes, S.; Groß, S.; Gerlach,
D.; Münch, W.; Schollmeyer, D.; Nubbemeyer, U. Eur. J. Org.
Chem. 2012, 2346.
(11) (a) Gosh, A. K.; Gong, G. Org. Lett. 2007, 9, 1437. (b) Frost, J. R.;
Cheong, C. B.; Akhtar, W. M.; Caputo, D. F.; Stevenson, N. G.;
Donohoe, T. J. J. Am. Chem. Soc. 2015, 137, 15664.
(12) (a) Kanegusuku, A. L.; Castanheiro, T.; Ayer, S. K.; Roizen, J. L.
Org. Lett. 2019, 21, 6089. (b) Tate, D. J.; Anemian, R.; Bushby, R.
J.; Nanan, S.; Warriner, S. L.; Whitaker, B. J. Beilstein J. Org. Chem.
2012, 8, 120. (c) Zhang, X.; Da, S.; Zhang, C.; Xie, Z.; Li, Y. Tetra-
hedron Lett. 2006, 47, 507.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610770. Su
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

K
J. Donges et al.
Paper
Synthesis
(36) The diastereomerically pure alcohols (4R)-20 and (4S)-20 with
unknown absolute configuration were converted into the corre-
sponding esters with (R)- and (S)-Mosher acid. The anisotropic
shielding effect of the aryl group causes a more intensive
upfield shift of adjacent protons upon comparison of the 1H
NMR spectra of both esters. Adopting favorable conformations
of the carbon backbone (zigzag chain with minimized repulsive
interactions), the Newman projections presented in the Sup-
porting Information indicate the proximity of R1 and R2 of the
carbinol and the Mosher ester substituents Ph and OMe. For
details, see the Supporting Information. Also see: (a) Hoye, T. R.;
Jeffrey, C. S.; Sao, F. Nat. Protoc. 2007, 2, 2451. (b) Dale, J. A.;
Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (c) Sullivan, G. G.;
Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K