Additions of Carbohydrate-Derived Alkoxyallenes to Imines and Subsequent Reactions to Enantiopure 2,5-Dihydropyrrole Derivatives

Article abstract of DOI:10.1055/s-0037-1609942

The additions of six alkoxyallenes bearing carbohydrate-derived chiral auxiliaries to imines were systematically studied. The reactions of three lithiated 1-alkoxypropa-1,2-dienes with an N-tosyl imine revealed that the diacetone fructose-derived auxiliary provided the highest diastereoselectivity of 91:9. The preferred absolute configuration of the newly formed stereogenic center was determined by subsequent ozonolysis of the allene moiety, transesterification and comparison with literature data. The analogous reactions of three axially chiral 3-nonyl-substituted 1-alkoxyallenes with these auxiliaries confirm these results and also prove that the configuration of the generated stereogenic center was only steered by the auxiliaries, whereas the chiral axis has essentially no influence. In general, four diastereomers were obtained in various portions, depending on the ratio of the two precursor allene diastereomers and on the auxiliary employed. The obtained dia?-stereomeric allenyl amines were cyclized under different conditions. As expected, under basic conditions, a stereospecific cyclization occurred, whereas under silver nitrate catalysis partial isomerization at the allene stage was observed. Under both conditions the 2,5-cis-disubstituted dihydropyrroles were formed faster than the trans-isomers. Several of the 2-substituted or 2,5-disubstituted dihydropyrrole derivatives could be isolated in diastereomerically pure form and were subsequently converted into the expected pyrrolidin-3-ones by removal of the carbohydrate-derived auxiliary under acidic conditions. The desired products were obtained in good yield and with high enantiopurity. They are suitable starting materials for the synthesis of enantiopure pyrrolidine natural products.

Full text of DOI:10.1055/s-0037-1609942

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–N
paper
A
en
A. Hausherr et al.
Paper
Synthesis
Additions of Carbohydrate-Derived Alkoxyallenes to Imines and
Subsequent Reactions to Enantiopure 2,5-Dihydropyrrole Deriva-
tives
ODAF1
Arndt Hausherr
ODAF1
Li
H
H
ODAF1
Reinhold Zimmer
Hans-Ulrich Reissig*
•
•
R2
R1
R2
R1
R1
N
HN
Tos
+
Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Tos
O
O
O
R2
hans.reissig@chemie.fu-berlin.de
O
R1 = H, Non
R
2 = Ph, CH2Ph
R2
O
R1
= ODAF1
N
N
O
Tos
O
Tos
Received: 28.07.2018
Accepted after revision: 10.08.2018
Published online: 04.09.2018
and also reported on their addition to imines,4 which pro-
vided allenyl amines (Scheme 1). Unfortunately, the diaste-
reoselectivities of the addition reactions studied were low.
DOI: 10.1055/s-0037-1609942; Art ID: ss-2018-e0507-op
OMe
Abstract The additions of six alkoxyallenes bearing carbohydrate-de-
rived chiral auxiliaries to imines were systematically studied. The reac-
tions of three lithiated 1-alkoxypropa-1,2-dienes with an N-tosyl imine
revealed that the diacetone fructose-derived auxiliary provided the
highest diastereoselectivity of 91:9. The preferred absolute configura-
tion of the newly formed stereogenic center was determined by subse-
quent ozonolysis of the allene moiety, transesterification and compari-
son with literature data. The analogous reactions of three axially chiral
3-nonyl-substituted 1-alkoxyallenes with these auxiliaries confirm these
results and also prove that the configuration of the generated stereo-
genic center was only steered by the auxiliaries, whereas the chiral axis
has essentially no influence. In general, four diastereomers were ob-
tained in various portions, depending on the ratio of the two precursor
allene diastereomers and on the auxiliary employed. The obtained dia-
stereomeric allenyl amines were cyclized under different conditions. As
expected, under basic conditions, a stereospecific cyclization occurred,
whereas under silver nitrate catalysis partial isomerization at the allene
stage was observed. Under both conditions the 2,5-cis-disubstituted di-
hydropyrroles were formed faster than the trans-isomers. Several of the
2-substituted or 2,5-disubstituted dihydropyrrole derivatives could be
isolated in diastereomerically pure form and were subsequently con-
verted into the expected pyrrolidin-3-ones by removal of the carbohy-
drate-derived auxiliary under acidic conditions. The desired products
were obtained in good yield and with high enantiopurity. They are suit-
able starting materials for the synthesis of enantiopure pyrrolidine nat-
ural products.
OMe
OMe
•
R1
R2
•
R2
R1
N
R3
R1
HN
A
R3
+
+
•
+
OMe
OMe
R2
R3
H
N
R2
R1
R1
R2
N
R3
HN
R3
OR*
OR*
•
•
R1
C
B
OR* = Chiral Carbohydrate-Derived Auxiliary
Scheme 1 Synthesis of 2,5-disubstituted dihydropyrroles starting from
3-alkyl-substituted methoxyallenes A and general structure of alkoxyal-
lenes B and C, bearing chiral auxiliaries
The prepared allenyl amines undergo a 5-endo-trig cy-
clization under appropriate conditions and delivered 2,5-
dihydropyrrole derivatives. These heterocycles are suitable
intermediates for further synthetic elaboration and for the
synthesis of natural products with a pyrrolidine substruc-
ture.5 Alkoxyallenes B, bearing carbohydrate-derived auxil-
iaries, are known and have been employed in hetero-Diels–
Alder reactions6 or, after lithiation, in additions to electro-
philes.7 We also described methods to prepare similar 3-al-
kyl-substituted alkoxyallenes C.8 In this report, we present
our results on the additions of lithiated B and C to imines
followed by cyclization and other transformations. The in-
fluence of the axial chirality and of the carbohydrate auxil-
iary on the diastereoselectivity of addition was of particular
interest. Experiments were also performed to set up an en-
antioselective synthesis of the natural product preussin and
analogues thereof.9
Key words alkoxyallenes, axial chirality, carbohydrate derivatives,
imines, lithiation, nitrogen heterocycles, pyrrolidines
Axially chiral 1,3-disubstituted alkoxyallenes such as A
have rarely been studied in organic synthesis.1 Considering
the preparative potential2 of simple alkoxyallenes such as
methoxyallene, a broad variety of compounds should be
available if additional substituents are installed at the C-3
terminus of these cumulenes. We recently described the
synthesis of racemic 3-alkyl-substituted alkoxyallenes A3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

B
A. Hausherr et al.
Paper
Synthesis
The preparation of alkoxyallenes 1–3 has been pub-
lished.8 The selectively protected carbohydrate-derived
auxiliaries were efficiently alkylated at their free hydroxyl
group by propargyl bromide and the subsequent base-cata-
lyzed isomerizations furnished the corresponding allenes
connected to the oxygen of the auxiliaries (at C-3 for diace-
tone glucose derivative 1 and diacetone fructose derivative
2, and at C-1 for the regioisomeric diacetone fructose deriv-
ative 3, see Scheme 2). The lithiation of the three alkoxyal-
lenes with n-butyllithium in tetrahydrofuran under stan-
dard conditions and subsequent treatment with N-tosyl
imine 4 provided, after aqueous work-up, the allenyl imines
5–7 in moderate to good yields and with differing diastereo-
selectivities (Table 1). Whereas the diacetone glucose de-
rived alkoxyallene gave a 70:30 ratio of the two diastereo-
meric allenyl imines 5 (entry 1), this ratio was enhanced to
very good 91:9 for 6, when diacetone fructose derivative 2
was used as precursor (entry 2). The isomeric diacetone
fructose-derived allene 3 gave only a 40:60 ratio of the two
diastereomers of 7, but with inverted preference.
For the determination of the predominating absolute
configuration at the newly formed stereogenic center, we
converted allenyl imines 6 and 7 into the corresponding es-
ters 8 and 9 and finally into the known protected phenyl-
glycine derivative 10 (Scheme 3). Ozonolysis of allenyl alco-
hols and amines has been employed earlier in our group to
convert these into the corresponding ester.10 This oxidative
removal of two carbon atoms proves that lithiated alkoxyal-
lenes are also synthetic equivalents of acyl anions and some
years ago we used this capacity in a synthesis of neuraminic
acid.11 Under standard conditions of ozonolysis, the esters 8
and 9, still containing the carbohydrate-derived auxiliaries,
were obtained in moderate yields, but with essentially un-
changed diastereomeric ratios. An acid-catalyzed transes-
terification was then performed to convert the two inter-
mediates into a compound with known absolute configura-
tion. Although the yields under fairly harsh conditions were
only moderate, the stereogenic center was not touched
since 8 provided (R)-10 with an ee of 80%, whereas 9 fur-
nished (S)-10 with a lower ee of 27%. These values were cal-
culated from the observed optical rotations and from the
reported value of enantiopure (R)-10.12 More importantly,
the shown sequences reveal that the two carbohydrate-de-
rived auxiliaries used induce opposite directions of asym-
metry, as indicated in Table 1.
1. nBuLi, THF, –50 °C
OR*
H
OR*
OR*
30 min
•
•
•
+
Ph
Tos
Ph
Tos
2.
Ph
–50 °C
HN
HN
1-3
to –20 °C
3 h
N
Tos
Given the number of stereogenic centers and the large
number of oxygen atoms as potential coordination partners
for the lithium cation,13 it is not possible to propose a seri-
ous mechanistic model for the observed diastereoselectivi-
ties. We can just state that diacetone fructose-derived sub-
stituent DAF1 is a reasonably good, though not perfect, aux-
iliary attached to alkoxyallenes. As an additional benefit,
the very low cost and simple methodology for the synthesis
of alkoxyallene 2 should be emphasized here.
5-7
4
O
O
O
O
O
O
OR* = ODAF1
=
O
O
OR* = ODAG =
O
O
O
O
O
O
O
OR* = ODAF2
=
O
O
O
OR*
OR*
OMe
O3
HCl, MeOH
Scheme 2 Synthesis of allenyl amines 5–7 by lithiation of alkoxyallenes
1–3 and additions to N-tosyl imine 4 (for details see Table 1)
•
O
O
Ph
Tos
Ph
Ph
CH2Cl2
–78 °C
HN
HN
HN
Tos
Tos
OR* = ODAF1
OR* = ODAF2
(R)-10
8
41%
34%
(ee 80%)a
6
Table 1 Additions of Alkoxyallenes 1–3, Bearing Carbohydrate-De-
rived O-Substituents, to N-Tosyl Imine 4 Leading to Allenyl Amines 5–7
(d.r. 91:9)
(d.r. 90:10)
7
9
57%
(S)-10 43%
OR*a
Imine
Product d.r.b (R/S)c Yield (%)d
(d.r. 40:60)
(ee 27%)a
(d.r. 40:60)
Entry
Allene
Scheme 3 Ozonolysis of allenyl amines 6 and 7 to esters 8 and 9 fol-
lowed by transesterification to give (R)-10 and (S)-10, respectively (for
substituents OR* see Scheme 2). a Calculated by comparison of the op-
tical rotation with literature data.
1
1
2
3
ODAG
ODAF1
ODAF2
4
4
4
5
6
7
70:30
91:9
69
85
44f
2e
3
40:60
a For definition of OR* see Scheme 2.
b Ratio determined by HPLC or NMR analysis of the crude product.
c Assignment by subsequent reactions.
Two additional reactions were performed with lithiated
alkoxyallene 2 to gain information for the planned synthe-
sis of preussin. Given that a benzyl group has to be installed
at C-2 of the pyrrolidine skeleton of this natural product, we
studied additions of lithiated 2 to phenylethanal (11) and to
its N-tosyl imine congener 14 (Scheme 4). From 2 and 11
we obtained the expected allenyl alcohol 12 in good yield
d Yield of purified product.
e Slight modification: addition of imine 4 at –80 °C (30 min), then warmed
to –30 °C within 3 h and stirring at this temperature for 12 h.
f Precursor 3 (30%) was reisolated.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

C
A. Hausherr et al.
Paper
Synthesis
as a 65:35 mixture of diastereomers (Equation 1). The cor-
responding imine 14 is not stable due to its easy tautomeri-
zation to the corresponding N-tosyl-substituted enamine.
Fortunately, the C,N-ditosyl amine 13 is an excellent alter-
native because it easily undergoes elimination to 14 by
treatment with base (Equation 2), which is efficiently
trapped by a suitable nucleophile to give the corresponding
addition products.14 Hence, we examined this option to
generate imine 14 by adding two equivalents of lithiated
alkoxyallene 2 to its precursor 13; gratifyingly, we obtained
the expected allenyl amine 15 in good yield (Equation 3).
The diastereoselectivity of ca. 80:20 lies between the ratio
observed in additions of lithiated 2 to imine 4 and to alde-
hyde 11, respectively.
tuted congener 17 provided the highest R/S-selectivity (en-
try 2). On the other hand, alkoxyallene 18 furnished a prod-
uct mixture with the S-configured allenyl amines in slight
excess (entry 3).
1. nBuLi, THF
–50 °C, 30 min
OR*
H
OR*
OR*
•
•
•
+
Ph
Ph
Tos
Non
Non
Non
2.
Ph
–80 °C
to –30 °C
10–17 h
HN
HN
16-18
N
Tos
Tos
19-21
4
Scheme 5 Synthesis of allenyl amines 19–21 by addition of lithiated
alkoxyallenes 16–18 to N-tosyl imine 4 (for details see Table 2, for sub-
stituents OR* see Scheme 2)
Table 2 Additions of 3-Nonyl-Substituted Alkoxyallenes 16–18, Bear-
ing Carbohydrate-Derived O-Substituents, to N-Tosyl Imine 4 Leading to
Allenyl Amines 19–21
1. nBuLi, THF, –40 °C
ODAF1
H
ODAF1
30 min
(1)
•
•
2.
Ph
O
Ph
2
HO
Product d.r.a
R,aR/R,aS/S,aR/S,aSb
Yield
(%)c
11
Entry Allene
OR*
12
R:aS
–80 °C to –20 °C
3.5 h
64% (d.r. 65:35)
1
2
3
16
50:50
ODAG
19
20
21
37:37:13:13
(R/S = 74:26;
aR/aS = 50:50)
88d
99e
76
Ph
Ph
Tos
base
(2)
17
75:25
ODAF1
ODAF2
69:21:6:4
(R/S = 90:10;
aR/aS = 75:25)
NH
N
Tos
Tos
13
14
18
55:45
20:14:35:31f
(R/S = 34:66;
aR/aS = 55:45)g
ODAF1
•
ODAF1
1. 2 equiv. nBuLi, THF
–40 °C, 30 min
•
(3)
a Determined by HPLC analysis of the crude product.
H
Ph
–80 °C
to –30 °C
16 h
HN
b Assignment of the configurations by subsequent reactions (see text).
c Yield of purified product.
2.
13
2 equiv.
Tos
2
15
d Major fraction (66%, R,aR/R,aS = 50:50), minor fraction (22%,
S,aR/S,aS = 50:50).
72% (d.r. 80:20)
e All four diastereomers; after HPLC separation: major fraction (68%,
R,aR/S,aR/S,aS = 87:9:4), minor fraction (23%, R,aS).
f No assignment possible.
Scheme 4 Additions of lithiated alkoxyallene 2 to aldehyde 11 and to
imine 14 leading to allenyl alcohol 12 and allenyl amine 15 (for substit-
uent ODAF1 see Scheme 2)
g Assignments and ratios assuming that axial chirality of 18 has no influ-
ence on the newly formed stereogenic center.
We then investigated the axially chiral 3-nonyl-substi-
tuted alkoxyallenes 16–18, which — depending on the
method applied for their synthesis — are available in differ-
ing diastereomeric ratios.8 We already knew from the mod-
el reactions with racemic compounds that the chirality of
the allene axis has almost no influence on the (relative)
configuration of the newly formed stereogenic center.4 This
was fully confirmed by the results obtained with 16–18 and
N-tosyl imine 4 as model electrophile (Scheme 5, Table 2).
Starting with the DAG-substituted alkoxyallene 16 (d.r.
50:50), we could confirm that this auxiliary induces only
moderate diastereoselectivity (entry 1). The four diastereo-
mers of allenyl amine 19 were obtained in a ratio of
37:37:13:13 and were assigned to the configurations as de-
picted, assuming that the axial chirality has no influence on
the selectivity. This hypothesis was substantiated by con-
verting diastereomers into subsequent products with
known configuration (see below). As expected from the re-
actions of alkoxyallene 2, the addition of its 3-nonyl-substi-
The isolated major fraction of allenyl amine 19 was also
subjected to the ozonolysis/transesterification sequence,
which provided phenylglycine derivative (R)-10 in 27%
overall yield and with an ee of 86%. This confirms that in
this fraction both diastereomers have identical R-configura-
tion at the stereogenic center, but that the chiral axis has
different configurations. It also shows that the diacetone
glucose-derived auxiliary DAG, like the fructose-derived
auxiliary DAF1 (Scheme 3), preferentially induces R-config-
uration at the newly formed stereogenic center, but with
considerably lower selectivity. The assignments given for
entries 2 and 3 of Table 2 are based on this experiment and
on subsequent cyclization reactions of allenyl amines 20
and 21.
As an alternative, we also examined a method based on
a study of the Brandsma group.15 Nonyl-substituted propar-
gyl ether 22 with DAF2 as auxiliary was deprotonated and
potassium tert-butoxide and hexamethylphosphoramide
(HMPA) were added. The reaction of the in situ generated
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

D
A. Hausherr et al.
Paper
Synthesis
metallated allene to imine 4 was unselective and afforded
24% of allene 18 (d.r. 60:40) and 69% of all four diastereo-
mers of 21 (d.r. 35:25:20:20) (Scheme 6). Given this moder-
ate selectivity, we did not study this method in additional
cases.
ciently adds to 14 and furnished allenyl amine 23 in 81%
and 85% yield, respectively, after chromatographic purifica-
tion. The ratios of the four diastereomers were determined
by HPLC analysis of the crude product. These ratios agree
well with the calculated ratios if it is assumed that the dias-
tereoselectivity is identical to that observed in the addition
of allene 2 to 14 (80:20, see Scheme 4) and that the chirality
of the allene axis has negligible influence. This last assump-
tion is based on our reported reactions with racemic model
compounds.4
1. nBuLi, THF
–50 °C, 30 min
2. KOtBu, HMPA
–85 °C, 30 min
ODAF2
ODAF2
Ph
Tos
ODAF2
•
•
Non
+
Ph
Non
Non
3.
Ph
HN
HN
22
–85 °C
N
Tos
to –30 °C
16 h
Table 3 Synthesis of Allenyl Amine 23 by Addition of Lithiated
3-Nonyl-Substituted Alkoxyallene 17 to N-Tosyl Imine 14
Tos
21
4
69% (d.r. 35:25:20:20)
Entry
1
Allene 17
aR/aS
Allenyl Amine 23
R,aR/R,aS/S,aR,S/S,aS
Yield
(%)a
Scheme 6 Synthesis of allenyl amines 21 starting from propargyl ether
22 (for substituent ODAF2 see Scheme 2)
15:85
11:68:0:21b
81
(R/S = 79:21; aR/aS = 11:89)
For the synthesis of preussin, we planned to combine a
3-nonyl-substituted alkoxyallene with N-tosyl imine (14).
As auxiliary we selected the DAF1 group, which provided
the highest diastereoselectivities in the model reactions
presented above, and as a reliable imine source we again
employed the bis-tosylated compound 13. The precursor al-
lene 17 was available with different ratios of diastereomers3
and hence two cases are presented (Scheme 7, Table 3). In
entry 1, 17 with an aR/aS ratio of 15:85 was combined with
in situ generated 14, whereas in entry 2 a 75:25 mixture
was used. In both cases, two equivalents of the lithiated al-
lene were employed because one equivalent is lost by the
conversion of 13 into 14; the excess of 17 could be partially
regained. For reisolated alkoxyallene 17 of entry 1 (69%
yield) a diastereomeric ratio of 15:85 was determined,
which was identical to that of the starting material. This ob-
servation suggests that the intermediate lithiated 17 is con-
figurationally stable under the reaction conditions em-
ployed. The second equivalent of lithiated allene 17 effi-
(12:68:3:17)c
2
75:25
54:22:21:3b
85
(R/S = 76:24; aR/aS = 75:25)
(60:20:15:5)c
a Yield of purified product.
b Determined by HPLC analysis.
c Calculated ratios (see text).
After these addition reactions and the (partial) configu-
rational assignments, we studied the cyclizations of the al-
lenyl amines.16 Treatment with ca. 0.2 equiv of potassium
tert-butoxide in dimethyl sulfoxide at 50 °C converted alle-
nyl amines 5–7 into the dihydropyrrole derivatives 24–26
(Scheme 8, Table 4). The yields of purified products were in
general very good and, in the case of (R/S)-26 (entry 3), we
separated the two diastereomers by HPLC. Most important-
ly, the three entries show that the diastereomeric ratios did
not change under the basic reaction conditions applied.
ODAF1
H
ODAF1
H
•
•
+
H
H
Non
Non
(aR)-17
(2 equiv.)
(aS)-17
2.
1. 2 equiv. nBuLi
THF, –40 °C, 30 min
13
–80 °C
to –30 °C
16 h
Ph
N
Tos
14
ODAF1
ODAF1
•
ODAF1
ODAF1
•
•
•
+
+
+
Non
Non
Non
Non
Ph
Ph
Ph
Ph
HN
HN
HN
HN
Tos
Tos
Tos
Tos
(R,aR)-23
(R,aS)-23
(S,aR)-23
(S,aS)-23
Scheme 7 Synthesis of allenyl amine 23 by addition of lithiated alkoxyallene 17 to N-tosyl imine 14 generated in situ from 13 (for details see Table 3,
for substituent ODAF1 see Scheme 2)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

E
A. Hausherr et al.
Paper
Synthesis
methylene)-d-camphorate] and no splitting of the signals
was observed. A control experiment with racemic 2916a,c re-
vealed that already 3% of the shift reagent was sufficient to
induce signal splitting. We can therefore assume that our
sample of (R)-29 has an enantiomeric purity of >95:5 and
that even the harsh hydrolysis conditions did not induce ra-
cemization at the C–H acidic position C-2 of the compound.
The absolute configuration of (R)-29 and its precursor (R)-
26 is based on the ozonolysis and transesterification exper-
iments with its precursor 7 (see Scheme 3). A similar ap-
proach to enantiopure 2-substituted pyrrolidin-3-one de-
rivatives has been reported by Liu.7e
OR*
OR*
0.15-0.20 equiv.
OR*
KOtBu
•
+
Ph
Ph
DMSO
50 °C, 1–2 h
N
Ph
N
Tos
HN
Tos
Tos
(R)-24-26
(S)-24-26
(R/S)-5-7
Scheme 8 Cyclizations of allenyl amines (R/S)-5–7 under basic condi-
tions to dihydropyrrole derivatives (R/S)-24–26 (for details see Table 4,
for substituents OR* see Scheme 2)
Table 4 Potassium tert-Butoxide-Promoted Cyclizations of Allenyl
Amines (R/S)-5–7 to Dihydropyrrole Derivatives (R/S)-24–26
ODAF2
O
Entry
Allenyl amine, R/S
OR*
Product, R/Sa
Yield (%)b
20% H2SO4/H2O
THF, , 2.5 h
59%
1
2
3
5, 70:30
6, 91:9
ODAG
ODAF1
ODAF2
24, 70:30
25, 90:10
26, 40:60
68
75
84c
Ph
Ph
N
N
Tos
Tos
7, 40:60
(R)-26
(R)-29
a Determined by 1H NMR spectroscopy.
b Yield of purified product.
Scheme 10 Hydrolysis of minor diastereomer (R)-26 to enantiopure
pyrrolidin-3-one (R)-29 with sulfuric acid (for substituent ODAF2 see
Scheme 2)
c The two isomers were separated by HPLC to provide 31% of (R)-26 and
53% of (S)-26.
The cyclization results of allenyl amines with 3-nonyl
substituents such as 19, 20 or 23 are more complex due to
existence of four diastereomers caused by the chiral axis.
When a 50:50 mixture of DAG-substituted (R,aR/R,aS)-19
was cyclized under the approved basic conditions with po-
tassium tert-butoxide, longer reaction times were required
(Scheme 11). The 3-alkyl substituent considerably retards
the cyclization, as already observed with the model com-
pounds.4 Hence, 19 was heated in total for 44 h to achieve
full conversion into (2R,5S)-cis-30 and (2R,5R)-trans-30.
The cyclization under basic conditions is stereospecific and
therefore the two compounds were formed as a 50:50 mix-
ture. The second pair of diastereomers (S,aR/S,aS)-19 af-
forded the two diastereomers (2S,5R)-cis-30 and (2S,5S)-
trans-30 in 64% yield, proving that no cross-over to the oth-
er diastereomers occurred. Since the base-promoted cy-
clization was already stopped after 14 h, 12% of the precur-
sor (S,aR)-19 were re-isolated and (2S,5R)-cis-30 was
formed in excess. This confirms our results in the racemic
series where the pro-trans-precursors cyclized consider-
ably slower than pro-cis-diastereomers.
As an alternative to the basic cyclization conditions, we
also examined the known silver nitrate catalysis.17,18 The al-
lenyl alcohols (R/S)-12 furnished the dihydrofuran deriva-
tives (R)-27 and (S)-27 in low yield and unchanged diaste-
reomeric ratio (Scheme 9). This method also converted the
analogous allenyl amines (R/S)-15 into the expected dihy-
dropyrrole derivative (R)-28 and (S)-28, isolated after sepa-
ration in 66% and 20% yield, respectively.
ODAF1
ODAF1
ODAF1
0.22 equiv. AgNO3
•
+
acetone
r.t., 12 h
O
O
Ph
Ph
HO
Ph
(R)-27
(S)-27
ODAF1
12 (d.r. 65:35)
(d.r. 65:35)
38%
ODAF1
ODAF1
0.22 equiv. AgNO3
+
•
N
N
acetone
r.t., 12 h
Ph
Ph
Ph
Tos
Tos
HN
Tos
15 (d.r. 80:20)
(R)-28 66%
(S)-28 20%
Similar results were observed with the DAF1-substituted
allenyl amine 20 under basic conditions (Scheme 12). Start-
ing with a 87:4:9 mixture of three diastereomers, the ex-
pected cyclization products (2R,5S)-cis-31 and (2S,5R)-cis-
31 were formed and separated from the crude product mix-
ture. The third diastereomer (2S,5S)-trans-31 was isolated
only as a minor component in a mixture together with pyr-
role 32, which was apparently generated by oxidation of the
dihydropyrroles. In addition, 18% of the precursor (R,aR)-
and (S,aR)-20 was re-isolated as a 65:35) mixture, again
showing the slowness of the cyclization.
Scheme 9 Silver nitrate-catalyzed cyclizations of (R/S)-12 and (R/S)-15
providing dihydrofuran and dihydropyrrole derivatives (R/S)-27 and
(R/S)-28, respectively (for substituent ODAF1 see Scheme 2)
Removal of the chiral auxiliary of diastereomerically
pure dihydropyrrole derivative (R)-26 by hydrolysis of the
enol ether moiety under strongly acidic conditions gave the
2-phenyl-substituted pyrrolidin-3-one (R)-29 in 59% yield
1
(Scheme 10). This compound was carefully analyzed by H
NMR spectroscopy in the presence of the chiral shift
reagent europium(III) tris[3-(heptafluoropropylhydroxy-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

F
A. Hausherr et al.
Paper
Synthesis
ODAG
Ph
ODAG
Ph
1. 0.2 equiv. KOtBu
ODAG
•
DMSO, 50 °C, 32 h
+
Non
Non
N
N
Ph
2. 0.4 equiv. KOtBu
Non
Tos
Tos
DMSO, 50 °C, 12 h
HN
Tos
(2R,5S)-cis-30
(2R,5R)-trans-30
19
63%
(50:50)
(R,aR:R,aS = 50:50)
ODAG
ODAG
ODAG
•
0.2 equiv. KOtBu
DMSO, 50 °C, 14 h
64%
+
Ph
Ph
Non
Non
N
N
Ph
Non
Tos
Tos
HN
Tos
(2S,5R)-cis-30
(2S,5S)-trans-30
19
(S,aR:S,aS = 50:50)
(70:30)
(+ 12% of (S,aR)-19)
Scheme 11 Cyclizations of diastereomers of 19 under basic conditions to dihydropyrrole derivatives 30 (for substituent ODAG see Scheme 2)
ODAF1
Ph
ODAF1
Ph
ODAF1
Ph
•
•
•
+
+
Non
Non
Non
HN
HN
HN
Tos
Tos
Tos
20
(R,aR:S,aS:S,aR = 87:4:9)
0.3 equiv. KOtBu
DMSO, 50 °C, 14 h
ODAF1
Ph
ODAF1
Ph
ODAF1
ODAF1
+
+
+
Ph
Ph
Non
Non
Non
Non
N
N
N
N
Tos
Tos
Tos
Tos
32
(2R,5S)-cis-31
(2S,5R)-cis-31
(2S,5S)-trans-31
4% (15:85)
2%
53%
(+ 18% of (R,aR/S,aR)-20 = 65:35)
Scheme 12 Base-promoted cyclization of allenyl amine 20 to dihydropyrrole derivative 31 (for substituent ODAF1 see Scheme 2)
With diastereomerically pure (R,aS)-20, the silver ni-
trate-catalyzed cyclization was examined. After 3 h the ma-
jority of the precursor was recovered unchanged and
(2R,5R)-trans-31 was isolated together with (2R,5S)-cis-31
(Scheme 13). This experiment again shows that cyclizations
in the presence of silver nitrate are not stereospecific due to
partial isomerization of the chiral axis at the allenyl amine
stage.4 Again, the formation of cis-compounds is kinetically
favored, hence leading to a slight excess of (2R,5S)-cis-31.
With the DAF2-substituted allenyl amines 21 very similar
results were obtained, confirming the stereospecificity of
the cyclization under basic conditions.9a
The diastereomers of allenyl amine 23 were prepared as
potential precursors of preussin and its stereoisomers.
Hence their cyclizations to dihydropyrroles 33 were sys-
tematically investigated employing methods A–C (Scheme
14, Table 5). In entry 1, a 12:68:3:17 mixture was used in a
silver nitrate-promoted cyclization (method A) and the four
conceivable dihydropyrroles 33 were formed in
a
68:12:3:17 ratio as analyzed by HPLC of the crude product
ODAF1
Ph
ODAF1
Ph
ODAF1
0.25 equiv. AgNO3
•
+
Non
Non
N
N
acetone, r.t., 3 h
Ph
Non
Tos
Tos
HN
Tos
(2R,5R)-trans-31
(2R,5S)-cis-31
(R,aS)-20
11%
18%
(+ 71% of (R,aS)-20)
Scheme 13 Partial silver nitrate-promoted cyclization of (R,aS)-20 to dihydropyrrole 31 (for substituent ODAF1 see Scheme 2)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

G
A. Hausherr et al.
Paper
Synthesis
ODAF1
ODAF1
ODAF1
ODAF1
•
•
•
•
+
+
+
Non
Non
Non
Non
Ph
Ph
Ph
Ph
HN
HN
HN
HN
Tos
Tos
Tos
Tos
(R,aR)-23
(R,aS)-23
(S,aS)-23
(S,aR)-23
Method A–C
ODAF1
Ph
ODAF1
ODAF1
Ph
ODAF1
Ph
+
+
Non
+
Non
Non
Non
N
N
N
N
Ph
Tos
Tos
Tos
Tos
(2R,5S)-cis-33
(2R,5R)-trans-33
(2S,5S)-trans-33
(2S,5R)-cis-33
Scheme 14 Cyclizations of allenyl amine 23 to dihydropyrrole derivative 33 under different conditions (for details see Table 5, for substituent ODAF1
see Scheme 2)
mixture. Three fractions were obtained by preparative
Table 5 Cyclizations of Allenyl Amine 23 with Silver Nitrate (Methods
HPLC consisting of (2R,5S)-cis-33 together with (2S,5S)-
A or B) or with Potassium tert-Butoxide (Method C) Leading to Diaste-
reomers of Dihydropyrrole 33 (see Scheme 14)
trans-33 (49% yield, ratio 95:5), (2R,5R)-trans-33 (11%) and
(2S,5R)-cis-33 (14% yield). The shifted ratio of products
again shows that the silver nitrate-promoted cyclization is
accompanied by an isomerization of the allene axis and
that the formation of cis-configured products is generally
favored. This result was confirmed by the data shown in en-
try 2, where a 54:22:21:3 mixture was employed under
slightly modified19 silver nitrate catalysis (method B). In en-
try 3 the approved basic conditions were used (method C)
to convert a 54:22:21:3 mixture of allenyl amines 23 into
the two dihydropyrroles (2R,5S)-cis-33 and (2S,5R)-cis-33
in 61% yield (ratio 90:10); the two allenyl amine diastereo-
mers (R,aS)-23 and (S,aR)-23, that would have led to the
trans-configured products, were isolated unchanged in this
experiment in 33% yield. This result again demonstrates the
stereospecificity of the base-promoted cyclization and the
lower reactivity of pro-trans allenyl amines such as (R,aS)-
23 and (S,aR)-23.4
Entry Allenyl Amine 23
R,aR/R,aS/S,aR/S,aSa
Methodb Dihydropyrrole 33
2R,5S/2R,5R/2S,5S/2S,5Rc
(yields of separated diastereomers)
1
2
3
12:68:3:17
54:22:21:3
54:22:21:3
A
B
C
68:12:3:17
(47%,d 11%, 2%,d 14%)
54:24:14:8
(38%, 18%, 8%, 8%)
90:0:0:10e
(61%)
a Ratio determined by HPLC analysis (Table 3), in the case of entry 1 the
calculated ratio is listed.
b Method A: AgNO3 (0.2 equiv), acetone, r.t., 16 h; Method B: AgNO3 (0.2
equiv), K2CO3 (2.2 equiv), acetonitrile, r.t., 14 h; Method C: KOtBu (0.1
equiv), DMSO, 50 °C, 12 h.
c Ratio of diastereomers in the crude product determined by HPLC.
d Obtained as 95:5 mixture of (2R,5S)- and (2S,5S)-diastereomers.
e Ratio determined by 1H NMR analysis of the purified products; in addi-
tion, 33% of a mixture of (R,aS)-23 and (S,aR)-23 were recovered.
Gore et al.20 reported the addition of simple lithiated
alkoxyallenes to hydrazones, including SAMP- or RAMP-de-
rived hydrazones.21 The primary addition products cyclized
under the reaction conditions to furnish the expected dihy-
dropyrrole derivatives with the chiral auxiliaries linked to
the pyrrole nitrogen. Given that this method provided ex-
cellent diastereoselectivities, we also briefly investigated
the addition of racemic 3-nonyl-substituted methoxyallene
to the benzaldehyde derived SAMP-hydrazone. The lithiated
allene provided the two expected diastereomeric dihydro-
pyrroles in 22% and 3% yield.9a Although in this unopti-
mized reaction the yield was low, it demonstrated the po-
tential of this method. However, the corresponding pheny-
lethanal-derived RAMP-hydrazone, required to approach
preussin, did not furnish the expected addition and cycliza-
tion products. Apparently, this electrophile is not suitable
for lithiated alkoxyallene additions.22
With diastereomerically highly enriched or pure sam-
ples of 33 in hand, the removal of the auxiliary was exam-
ined (Scheme 15). Hydrolysis of the enol ether moiety of a
(2R,5S)-cis/(2S,5S)-trans-33 mixture (95:5) furnished the
two pyrrolidin-3-ones (2R,5S)-cis-34 and (2S,5S)-trans-34,
which could be separated by column chromatography and
were isolated in 79% and 4%, respectively. Diastereomerical-
ly pure (2S,5R)-cis-33 analogously provided the corre-
sponding pyrrolidinone (2S,5R)-cis-34 in good yield. The
samples of the two enantiomers (2R,5S)-cis-34 and (2S,5R)-
cis-34 showed optical rotations [α]D20 of –39.4 and of +41.5,
respectively. This already indicates that our assignments are
correct and that these pyrrolidinones are enantiomerically
pure as already shown above for compound (R)-29. An un-
equivocal confirmation of the high enantiopurity and the
assigned absolute configuration of (2R,5S)-cis-34 was ob-
tained by its conversion into the unnatural enantiomer of
preussin.9 The recorded optical rotation of the final product
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

H
A. Hausherr et al.
Paper
Synthesis
O
Non
N
Ph
Tos
ODAF1
ODAF1
(2R,5S)-cis-34
79%
20% H2SO4/H2O
THF, , 3 h
+
+
Non
Non
N
O
N
Ph
Ph
Tos
Tos
Non
(95:5) (2S,5S)-trans-33
N
(2R,5S)-cis-33
Ph
Tos
4%
(2S,5S)-trans-34
ODAF1
O
20% H2SO4/H2O
THF, , 4 h
68%
Non
N
Non
N
Ph
Ph
Tos
Tos
(2S,5R)-cis-34
(2S,5R)-cis-33
Scheme 15 Removal of the auxiliary DAF1 by acidic hydrolysis converting the dihydropyrrole derivatives 33 into pyrrolidin-3-one derivatives 34 (for
substituent ODAF1 see Scheme 2)
nicely matched the reported literature data. The syntheses
of racemic preussin, enantiopure (–)-preussin and ana-
logues thereof as well as their biological evaluation will be
reported in a subsequent publication.9b
butoxide was freshly sublimed in vacuo before use. Products were pu-
rified by flash chromatography on neutral aluminum oxide (6% water,
activity III, Merck-Schuchardt or Fluka) or on silica gel (32–63 μm,
Merck-Schuchardt or Fluka). HPLC was performed with nucleosil
50–5 columns (dimensions: analytical, 4 × 245 mm; preparative,
16 × 244 mm or 32 × 237 mm). Detection by Knauer variable UV de-
tector (λ = 255 nm) and Knauer refractometer. Unless otherwise stat-
ed, yields refer to analytically pure samples.
1H NMR [CHCl3 (δ = 7.26 ppm), TMS (δ = 0.00 ppm) as internal stan-
dard] and 13C NMR spectra [CDCl3 (δ = 77.0 ppm) as internal standard]
were recorded with Bruker AC 250, WH 270, AC 300 and DRX 500 in-
struments in CDCl3 solutions. Integrals are in accordance with assign-
ments; coupling constants are given in Hz. The signals of the carbohy-
drate auxiliaries are very similar and are given only once for com-
pounds 5–7. A complete data set can be obtained from the authors.9a
1H/13C-correlated spectra (HSQC, HMBC) and 1H/1H-correlated spectra
(COSY, NOESY) were recorded for assignments. IR spectra were mea-
sured with Nicolet 5 SXC FTIR or Nicolet 205 FTIR spectrometers. Op-
tical rotations ([α]D) were measured with a Perkin Elmer 241 po-
larimeter in a 1 mL microcuvette at the temperature given. MS analy-
ses were performed with MAT 711, MAT 112 S and with HP 5890 II
instruments. The elemental analyses were recorded with ‘Elemental-
Analyzers’ (Perkin–Elmer or Carlo Erba). Melting points were mea-
sured with a Reichert apparatus (Thermovar) or a Gallenkamp appa-
ratus (MPD 350) and are uncorrected.
In conclusion, we could demonstrate that the diacetone
fructose-derived auxiliary DAF1 steers the additions of the
corresponding lithiated alkoxyallenes to imines with rea-
sonably good selectivities.23 The primarily obtained allenyl
amines 6, 15, 20 and 23 were formed with preferential R-
configuration at the newly formed stereogenic center (d.r.
76:24 to 91:9). Addition of the axially chiral 3-nonyl-substi-
tuted alkoxyallene 17 showed that the chirality of the axis
has no influence on the diastereoselectivity of the reaction.
Hence, four diastereomeric allenyl imines were isolated, the
proportion of which depends on the ratio of the two pre-
cursor alkoxyallene stereoisomers. The obtained allenyl
amines were cyclized under basic conditions to stereospe-
cifically furnish dihydropyrrole derivatives, whereas the
silver nitrate-promoted cyclizations proceed with partial
stereochemical cross-over as observed earlier.4 Dihydropyr-
role derivatives such as (R)-26 or (2R,5S)-cis-33 were con-
verted into the expected 2-substituted or 2,5-disubstituted
pyrrolidin-3-one derivatives (R)-29 or (2R,5S)-cis-34 with-
out racemization or epimerization. The enol ether moiety
of dihydropyrroles such as 26 or 33 should also allow the
introduction of other functional groups at C-4, for example
by electrophilic halogenation or hydroboration. Overall, the
sequence of reactions developed in the current study shows
the potential of auxiliary-derived enantiopure alkoxyal-
lenes as key C3-building blocks in stereoselective synthesis.
Alkoxyallenes 1,8 2,8 3,8 16,8 17,8,3 188 and propargyl ether 223 were
prepared according to the cited literature procedures. Imine 2a24 and
imine precursor 1314 are known compounds.
Addition of Lithiated Alkoxyallenes to Imines; General Procedure
GP1
For generation of lithiated alkoxyallene, the corresponding alkoxyal-
lene was dissolved in THF and n-butyllithium (ca. 2.4 M in hexanes)
was added at –50 °C or at –40 °C. After 30 min, a solution of the corre-
sponding imine (dissolved in a small amount of THF) was added with-
in 5 min. The mixture was allowed to warm to –20 °C or to –30 °C for
the time given. After quenching with saturated aqueous NaHCO3 solu-
tion, the organic phase was separated and the aqueous phase was ex-
tracted with EtOAc (3 × 15 mL/mmol of alkoxyallene). The combined
Reactions were generally performed under argon in flame-dried
flasks, and the components were added by using a syringe. Reagents
were purchased and used without further purification. Potassium t-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

I
A. Hausherr et al.
Paper
Synthesis
organic phases were dried (Na2SO4), filtered and evaporated in vacuo
to provide the crude product, which was purified by column chroma-
tography on aluminum oxide (activity III). The given yields refer to
the amount of imine used.
1,2:4,5-Di-O-isopropylidene-3-O-[2-phenyl-2-(p-toluenesulfon-
amido)acetyl]-β-D-fructopyranose (8)
According to GP2, allenyl amine 6 (0.520 g, 0.93 mmol, d.r. 91:9) in
dichloromethane (10 mL) provided crude 8 (0.500 g) as a light-yellow
oil. Purification by column chromatography (silica gel, hexanes/EtOAc
1:1) provided pure 8 (0.210 g, 41%, d.r. 90:10) as colorless crystals
(m.p. 172–174 °C). The diastereomers were not separated.
1,2:4,5-Di-O-isopropylidene-3-O-[1-phenyl-1-(p-toluenesulfon-
amido)buta-2,3-dien-2-yl]-β-D-fructopyranose (6)
[α]D20 = –155.1 (c = 0.5, CHCl3).
According to GP1, alkoxyallene 2 (0.500 g, 1.68 mmol) was treated
with n-butyllithium (0.70 mL, 1.68 mmol of 2.27 M in hexanes) in
THF (35 mL). After 30 min the mixture was cooled to –80 °C and
imine 4 (0.413 g, 1.59 mmol) was added. After stirring at this tem-
perature for 1 h the mixture was allowed to warm to –30 °C within 3
h and stirred at this temperature for 12 h. Crude product 6 (d.r. 91:9)
was purified by column chromatography (alumina III, hexanes/EtOAc
2:1) to afford pure allene 2 (0.060 g, 12%) and pure 6 (0.757 g, 85%,
d.r. 91:9) as viscous colorless oils. A separation of the diastereomers
was not possible at this stage. Subsequent reactions show that the
major diastereomer is R-configured.
1H NMR (CDCl3, 270 MHz): δ = 2.40 (s, 3 H, Tos-Me), 5.07 (d, J = 8.3 Hz,
1 H, 2-H), 5.66 (d, J = 8.3 Hz, 1 H, NH), 7.21–7.30 (m, 7 H, Ph, Tos), 7.69
(d, J = 8.3 Hz, 2 H, Tos); signal of the minor diastereomer: δ = 2.43 (s,
3 H, Tos-Me).
13C NMR (CDCl3, 67.9 MHz): δ = 21.5 (q, Tos-Me), 59.2 (d, C-2), 127.2,
127.3, 128.5, 128.7, 129.7 (5 d, Ph, Tos), 135.0, 137.1, 143.7 (3 s, Ph,
Tos), 170.0 (s, C-1); due to the low content of the minor diastereomer
no signals could be detected.
IR (KBr): 3430 (N–H), 2990, 2935 (C–H), 1760 (C = O), 1335, 1160
(TosN) cm–1
.
[α]D20 = –73.9 (c = 1.2, CHCl3).
MS (EI, 80 eV): m/z (%) = 547 (0.1) [M+], 532 (2) [M+ – Me], 260 (100)
1H NMR (CDCl3, 270 MHz): δ = 2.41 (s, 3 H, Tos-Me), 5.04 (d, J = 7.8 Hz,
1 H, 1-H), 5.25, 5.34 (AB system, JAB = 8.5 Hz, 2 H, 4-H), 5.57 (d,
J = 7.8 Hz, 1 H, NH), 7.18–7.30 (m, 5 H, Ph, Tos), 7.37 (d, J = 7.3 Hz, 2 H,
Ph), 7.70 (d, J = 8.3 Hz, 2 H, Tos); DAF1-auxiliary: δ = 1.02, 1.35, 1.40,
1.44 (4 s, 3 H each, Me), 3.59, 3.74 (AB system, JAB = 8.8 Hz, 2 H, 1-H),
3.74 (d, J = 7.5 Hz, 1 H, 3-H), 3.93, 4.02 (AB part of ABX system,
JAB = 13.3 Hz, JA,5 = 2.2 Hz, 2 H, 6-H), 4.08–4.16 (m, 1 H, 5-H), 4.20 (dd,
J = 7.5 Hz, J = 5.4 Hz, 1 H, 4-H); distinguishable signals of the minor
isomer, allene part: δ = 5.70 (d, J = 7.8 Hz, 1 H, NH); DAF1-auxiliary:
δ = 3.50 (d, J = 9.3 Hz, 1 H, 1-H), 3.81 (d, J = 7.8 Hz, 1 H, 3-H), 5.13 (d,
J = 7.8 Hz, 1 H, 1-H).
13C NMR (CDCl3, 67.9 MHz): δ = 21.5 (q, Tos-Me), 58.4 (d, C-1), 93.8 (t,
C-4), 127.1, 127.4, 127.6, 128.2, 129.3 (5 d, Ph, Tos), 133.1 (s, C-2),
137.5, 138.1, 143.0 (3 s, Tos, Ph), 196.7 (s, C-3); DAF1-auxiliary:
δ = 25.5, 26.2, 26.7, 27.8 (4 q, Me), 60.3 (t, C-6), 71.3 (t, C-1), 73.7,
75.4, 76.1 (3 d, C-3, C-4, C-5), 103.6 (s, C-2), 109.1, 112.0 (2 s, CMe2);
minor diastereomer, allene part: δ = 21.0 (q, Tos-Me), 58.8 (d, C-1),
93.5 (t, C-4), 127.1, 127.4, 127.6, 128.2, 129.3 (5 d, Ph, Tos), 133.1 (s,
C-2), 137.5, 138.1, 143.0 (3 s, Tos, Ph), 196.7 (s, C-3); DAF1-auxiliary:
δ = 25.5, 25.9, 26.5, 27.3 (4 q, Me), 60.7 (t, C-6), 71.4 (t, C-1), 72.6,
75.7, 76.7 (3 d, C-3, C-4, C-5), 103.6 (s, C-2), 109.0, 111.9 (2 s, CMe2).
[C12H20O6+].
HRMS (EI, 80 eV): m/z [M+ – Me] calcd for C26H30NO9S: 532.1641;
found: 532.1644.
Transesterification; General Procedure GP3
The corresponding ester bearing the auxiliary was dissolved in anhy-
drous MeOH (4 mL) and a saturated solution of HCl in MeOH (1 mL)
was added at r.t. The mixture was heated to reflux for 1.5 h, cooled to
r.t., and neutralized with solid potassium carbonate. The solid was fil-
tered off and the solvent was removed in vacuo. The crude product
was purified either by recrystallization or by HPLC.
Methyl (R)-N-(p-Tosyl)-2-phenylglycinate (10)
According to GP3, DAF1-ester 8 (0.152 g, 0.28 mmol, d.r. 90:10) in
MeOH (4 mL) provided crude 10 (0.070 g) as a brownish oil. Purifica-
tion by column chromatography (silica gel, hexanes/EtOAc 1:1) and
HPLC (hexanes/EtOAc 4:1) provided pure 10 (0.030 g, 34%) as color-
less crystals (m.p. 127–130 °C, reported value for racemic 10 m.p.
111 °C25). By comparison with literature12 the predominating config-
uration at C-2 was determined to be R.
IR (film): 3285 (N–H), 2985, 2935 (C–H), 1965 (C=C=C), 1375, 1160
20
20
[α]D
=
–90.0 (c = 1.2, CHCl3); reported value: [α]D
= –113.6
(TosN) cm–1
.
(c = 2.33, CHCl3).12 Enantiomeric excess of the sample according to
MS (EI, 80 eV): m/z (%) = 557 (8) [M+], 542 (2) [M+ – Me], 402 (4) [M+ –
Tos], 260 (100) [C12H20O6], 185 (50).
HRMS (EI, 80 eV): m/z [M]+ calcd for C29H35NO8S: 557.2083; found:
557.2082.
these values: 80%.
1H NMR (CDCl3, 270 MHz): δ = 2.37 (s, 3 H, Tos-Me), 3.55 (s, 3 H,
OMe), 5.06 (d, J = 8.1 Hz, 1 H, 2-H), 5.88 (d, J = 8.1 Hz, 1 H, NH), 7.10–
7.35 (m, 7 H, Ph, Tos), 7.62 (d, J = 8.3 Hz, 2 H, Tos); these data agree
with those of the literature.26
Ozonolysis of Allenyl Amines; General Procedure GP2
13C NMR (CDCl3, 67.9 MHz): δ = 21.4 (q, Tos-Me), 52.9 (q, OMe), 59.3
(d, C-2), 127.0, 127.1, 128.5, 128.7, 129.4 (5 d, Ph, Tos), 135.1, 136.8,
143.5 (3 s, Tos, Ph), 170.5 (s, C-1); no literature data available.
The corresponding allenyl amine was dissolved in anhydrous di-
chloromethane and cooled to –78 °C and the solution was saturated
with oxygen. Ozone was bubbled through the solution until the blue
color remained (ca. 1 h). The mixture was allowed to warm to r.t. and
quenched with saturated aqueous NaHCO3 solution. The organic
phase was separated and the aqueous phase was extracted with di-
chloromethane (3 × 10 mL). The combined organic phases were dried
(Na2SO4), filtered and evaporated in vacuo to provide the crude prod-
uct, which was purified either by recrystallization from hexanes/di-
chloromethane or by column chromatography.
1,2:4,5-Di-O-isopropylidene-3-O-[1-phenyl-2-(p-toluenesulfon-
amido)penta-3,4-dien-3-yl]-β-D-fructopyranose (15)
According to GP1, alkoxyallene 2 (0.260 g, 0.87 mmol), n-butyllithium
(0.36 mL, 0.87 mmol of 2.42 M in hexanes) in THF (35 mL) and 13
(0.188 g, 0.44 mmol) provided, after 1 h at –80 °C and warm-up to
–30 °C within 3 h and stirring at –30 °C for 12 h, the crude product
mixture (0.470 g) as a light-yellow oil. Purification by column chro-
matography (alumina III, hexanes/EtOAc 3:1) afforded allene 2 (0.110
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

J
A. Hausherr et al.
Paper
Synthesis
g, 42%) as yellow oil and 15 (0.180 g, 72%, d.r. 80:20) as light-yellow
oil. A separation of the diastereomers was not possible at this stage.
Preferred R-configuration is assumed by analogy.
H), 5.56 (t, J = 6.3 Hz, 1 H, 4-H), 5.67 (d, J = 7.4 Hz, 1 H, NH), 7.16–7.26
(m, 5 H, Ph, Tos), 7.35 (d, J = 6.6 Hz, 2 H, Ph), 7.69 (d, J = 8.1 Hz, 2 H,
Tos).
[α]D20 = –45.4 (c = 0.5, CHCl3).
13C NMR (CDCl3, 67.9 MHz): δ [(R,aR)-20] = 14.0 (q, Me), 21.4 (q, Tos-
Me), 22.6, 28.6, 29.1, 29.2, 29.3, 29.4, 31.3, 31.8 (8 t, CH2), 58.4 (d, C-
1), 111.7 (d, C-4), 127.2, 127.3, 127.5, 128.0, 129.3 (5 d, Ph, Tos), 132.7
(s, C-2), 137.7, 138.5, 142.9 (3 s, Ph, Tos), 188.6 (s, C-3); δ [(S,aR)-20] =
14.0 (q, Me), 21.4 (q, Tos-Me), 22.6, 28.8, 29.1, 29.2, 29.3, 29.4, 31.3,
31.8 (8 t, CH2), 59.5 (d, C-1), 111.7 (d, C-4), 127.2, 127.3, 127.5, 128.0,
129.3 (5 d, Ph, Tos), 132.7 (s, C-2), 137.7, 138.6, 142.9 (3 s, Ph, Tos),
188.6 (s, C-3); δ [(R,aS)-20] = 14.1 (q, Me), 21.5 (q, Tos-Me), 22.6, 28.7,
29.2, 29.3, 29.4, 29.5, 31.3, 31.8 (8 t, CH2), 59.2 (d, C-1), 110.2 (d, C-4),
127.0, 127.3, 127.4, 128.1, 129.3 (5 d, Ph, Tos), 132.1 (s, C-2), 137.6,
138.4, 142.9 (3 s, Ph, Tos), 188.5 (s, C-3).
1H NMR (CDCl3, 270 MHz): δ = 2.38 (s, 3 H, Tos-Me), 3.02, 3.09 (AB
part of ABX system, JAB = 13.8 Hz, JAX = 6.5 Hz, JBX = 5.2 Hz, 2 H, 1-H),
4.02–4.15 (m, 1 H, 2-H), 4.69 (d, J = 9.6 Hz, 1 H, NH), 5.03, 5.06 (AB
system, JAB = 11.8 Hz, JA,CH = 2.1 Hz, JB,CH = 2.1 Hz, 2 H, 5-H), 7.15–7.25
(m, 7 H, Ph, Tos), 7.64 (d, J = 8.3 Hz, 2 H, Tos); minor diastereomer:
δ = 2.38 (s, 3 H, Tos-Me), 2.98, 3.10 (AB part of ABX system,
JAB = 13.2 Hz, JAX = 5.9 Hz, JBX = 8.1 Hz, 2 H, 1-H), 4.02–4.15 (m, 1 H, 2-
H), 5.01 (s, 2 H, 5-H), 5.39 (d, J = 8.7 Hz, 1 H, NH), 7.15–7.25 (m, 7 H,
Ph, Tos), 7.66 (d, J = 8.3 Hz, 2 H, Tos).
13C NMR (CDCl3, 67.9 MHz): δ = 20.9 (q, Tos-Me), 39.4 (t, C-1), 54.8 (d,
C-2), 94.5 (t, C-5), 126.6, 127.1, 127.9, 129.4, 130.2 (5 d, Ph, Tos), 133.5
(s, C-3), 135.7, 137.6, 143.1 (3 s, Ph, Tos), 196.6 (s, C-4); minor diaste-
reomer: δ = 20.9 (q, Tos-Me), 40.5 (t, C-1), 57.9 (d, C-2), 92.4 (t, C-5),
126.3, 127.2, 127.9, 129.2, 129.7 (5 d, Ph, Tos), 131.1 (s, C-3), 135.7,
137.0, 143.1 (3 s, Ph, Tos), 196.2 (s, C-4).
Although (S,aS)-20 could not be detected unambiguously in the major
fraction by 1H- and 13C NMR spectroscopy, its presence was proven by
the subsequent base-catalyzed cyclization to (2S,2R)-cis-31 of this
mixture (see below).
1,2:4,5-Di-O-isopropylidene-3-O-[1-phenyl-2-(p-toluenesulfon-
amido)tetradeca-3,4-dien-3-yl]-β-D-fructopyranose (23)
IR (film): 3430 (N–H), 3030, 2990, 2935 (C–H), 1965 (C=C=C), 1385,
1160 (TosN) cm–1
.
According to GP1, alkoxyallene 17 (0.960 g, 3.20 mmol, d.r. 15:85), n-
butyllithium (1.37 mL, 3.20 mmol of 2.34 M in hexanes) in THF (60
mL) and 13 (0.688 g, 1.60 mmol) provided (after 1 h at –80 °C, warm-
up to –30 °C within 3 h and stirring at –30 °C for 12 h) the crude
product mixture. Purification by column chromatography (alumina
III, hexanes/EtOAc 3:1) afforded allene 17 (0.666 g, 69%, d.r. 15:85) as
a yellow oil and 23 (0.907 g, 81%, d.r. 11:68:0:21) as a light-yellow oil.
The ratio of diastereomers was determined by analytical HPLC.
[α]D20 = –45.4 (c = 0.5, CHCl3).
MS (EI, 80 eV): m/z (%) = 571 (0.8) [M+], 570 (2) [M+ – H], 479 (5) [M+ –
H – Bn], 326 (9), [M+ – Bn – Tos], 155 (31) [Tos+], 91 (100) [Bn+].
1,2:4,5-Di-O-isopropylidene-3-O-[1-(p-toluenesulfonamido)-1-
phenyltrideca-2,3-dien-2-yl]-β-D-fructopyranose (20)
According to GP1, alkoxyallene 17 (0.930 g, 2.19 mmol, d.r. 75:25), n-
butyllithium (0.86 mL, 2.08 mmol of 2.42 M in hexanes) in THF (40
mL) and 4 (0.511 g, 1.97 mmol) provided, after 1 h at –80 °C and
warm-up to –30 °C within 1.5 h and stirring at –30 °C for 8 h, the
crude product mixture (1.84 g, d.r. 69:21:6:4) as a light-yellow oil. Pu-
rification by column chromatography (alumina III, hexanes/EtOAc
4.5:1) afforded allene 17 (0.087 g, 9%) as colorless oil and 20 (1.35 g,
99%, all four diastereomers) as a light-yellow oil.
According to GP1, alkoxyallene 17 (1.40 g, 3.30 mmol, d.r. 75:25), n-
butyllithium (1.36 mL, 3.30 mmol of 2.43 M in hexanes) in THF (60
mL) and 13 (0.708 g, 1.65 mmol) provided (after 1 h at –80 °C and
warm-up to –30 °C within 3 h and stirring at –30 °C for 12 h) the
crude product mixture. Purification by column chromatography (alu-
mina III, hexanes/EtOAc 3:1) afforded allene 17 (0.768 g, 55%) as a yel-
low oil and 23 (0.972 g, 85%, d.r. 54:22:21:3) as a light-yellow oil. The
ratio of diastereomers was determined by analytical HPLC.
1H NMR (CDCl3, 270 MHz): δ [(R,aS)-23] = 0.89 (t, J = 6.6 Hz, 3 H, Me),
0.95–1.60 (m, 16 H, CH2), 2.40 (s, 3 H, Tos-Me), 3.02–3.10 (m, 2 H, 1-
H), 3.95–4.10 (m, 1 H, 2-H), 5.07 (d, J = 8.6 Hz, 1 H, NH), 5.40 (td,
J = 6.7 Hz, J = 0.8 Hz, 1 H, 5-H), 7.15–7.25 (m, 7 H, Ph, Tos), 7.70 (d,
J = 8.3 Hz, 2 H, Tos); distinguishable signals of the other isomers,
δ [(S,aR)-23] = 5.24 (t, J = 6.6 Hz, 1 H, 5-H), 5.56 (d, J = 8.8 Hz, 1 H,
NH), δ [(R,aR)-23] = 2.38 (s, 3 H, Tos-Me), 4.41 (d, J = 9.6 Hz, 1 H, NH),
5.32 (t, J = 6.7 Hz, 1 H, 5-H), 7.64, 7.69 (2 d, J = 8.4 Hz, 2 H each, Tos);
the signals of (S,aS)-23 are hidden by those of the other diastereo-
mers.
13C NMR (CDCl3, 67.9 MHz): δ [(R,aS)-23] = 14.1 (q, Me), 21.4 (q, Tos-
Me), 22.6, 29.2, 29.3, 29.5, 30.9, 31.0, 31.1, 31.8 (8 t, CH2), 40.1 (t, C-1),
56.9 (d, C-2), 110.1 (d, C-5), 126.4, 127.0, 127.9, 129.4, 129.9 (5 d, Ph,
Tos), 131.3 (s, C-3), 136.6, 137.9, 142.9 (3 s, Ph, Tos), 188.6 (s, C-4);
distinguishable signals of the other isomers, δ [(R,aR)-23] = 39.1 (t,
C-1), 53.9 (d, C-2), 111.5 (d, C-5), 126.8, 127.1, 129.2, 129.6, 130.5 (5
d, Ph, Tos), 132.1 (s, C-3), 135.3, 137.4, 142.6 (3 s, Ph, Tos), 187.8 (s,
C-4); δ [(S,aR)-23 and (S,aS)-23] = 40.1, 40.6 (2 t, C-1), 111.1, 111.3 (2
d, C-5).
Data obtained from this mixture:
IR (film): 3280 (N–H), 3030–2855 (C–H), 1965 (C=C=C) cm–1
.
MS (EI, 80 eV): m/z (%) = 683 (3) [M+], 668 (10) [M+ – Me], 556 (16)
[M+ – C9H19], 260 (46) [C12H20O6+], 185 (74), 91 (100) [Bn+].
HRMS (EI, 80 eV): m/z [M+] calcd for C38H53NO8S: 683.3492; found:
683.3447.
The four diastereomers of 20 were partially separated by HPLC (hex-
anes/EtOAc 4:1).
Fraction 1: (R,aR/S,aR/S,aS)-20 (0.922 g, 68%, d.r. 87:9:4, determined
by HPLC) as a colorless oil.
Optical rotation: [α]D20 = –72.4 (c = 0.9, CHCl3).
Fraction 2: (R,aS)-20 (0.308 g, 23%) as a light-yellow oil.
Optical rotation: [α]D20 = –42.7 (c = 1.2, CHCl3).
1H NMR (CDCl3, 270 MHz): δ [(R,aR)-20] = 0.90 (t, J = 6.4 Hz, 3 H, Me),
1.15–1.40, 1.80–1.90 (2 m, 14 H, 2 H, CH2), 2.39 (s, 3 H, Tos-Me), 5.02
(d, J = 7.7 Hz, 1 H, 1-H), 5.61 (d, J = 7.7 Hz, 1 H, NH), 5.73 (dt,
J = 6.6 Hz, J = 1.0 Hz, 1 H, 4-H), 7.18–7.26, 7.32–7.38 (2 m, 7 H, Ph,
Tos), 7.69 (d, J = 8.1 Hz, 2 H, Tos); δ [(S,aR)-20] = 0.90 (t, J = 6.4 Hz, 3 H,
Me), 1.15–1.40, 1.80–1.90 (2 m, 14 H, 2 H, CH2), 2.41 (s, 3 H, Tos-Me),
5.07 (d, J = 7.5 Hz, 1 H, 1-H), 5.59 (t, J = 6.6 Hz, 1 H, 4-H), 5.83 (d,
J = 7.5 Hz, 1 H, NH), 7.16–7.43 (m, 7 H, Ph, Tos), 7.68 (d, J = 8.3 Hz, 2 H,
Tos); δ [(R,aS)-20] = 0.88 (t, J = 6.6 Hz, 3 H, Me), 1.15–1.40, 1.90–2.00
(2 m, 14 H, 2 H, CH2), 2.40 (s, 3 H, Tos-Me), 5.00 (d, J = 7.4 Hz, 1 H, 1-
IR (film): 3285 (N–H), 3060–2855 (C–H), 1965 (C=C=C), 1380, 1160
(TosN) cm–1
.
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K
A. Hausherr et al.
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Synthesis
MS (EI, 80 eV): m/z (%) = 697 (4) [M+], 696 (4) [M+ – H], 682 (4) [M+ –
Me], 606 (32) [M+ – Bn], 548 (16), 274 (53), 243 (100), 185 (65), 91
(93) [Bn+].
chromatography (alumina III, hexanes/EtOAc 2:1) and separation by
HPLC (hexanes/EtOAc 2:1) afforded (R)-28 (0.100 g, 66%) and (S)-28
(0.030 g, 20%) as colorless oils.
HRMS (EI, 80 eV): m/z [M+] calcd for C39H55NO8S: 697.3648; found:
Data for (R)-28
697.3682.
[α]D20 = –139.0 (c = 0.4, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 2.40 (s, 3 H, Tos-Me), 3.07, 3.20 (AB
part of ABX system, JAB = 13.5 Hz, JAX = 2.2 Hz, JBX = 5.3 Hz, 2 H,
PhCH2), 3.25 (dd, J = 13.8 Hz, J = 4.0 Hz, 1 H, 5-H), 3.79 (dd, J = 13.8 Hz,
J = 1.8 Hz, 1 H, 5-H), 4.20 (sbr, 1 H, 4-H), 4.40–4.44 (m, 1 H, 2-H), 7.15–
7.24 (m, 3 H, Ph), 7.28 (d, J = 8.2 Hz, 2 H, Tos), 7.41 (d, J = 7.3 Hz, 2 H,
Ph), 7.68 (d, J = 8.2 Hz, 2 H, Tos).
13C NMR (CDCl3, 125.8 MHz): δ = 21.4 (q, Tos-Me), 39.0 (t, PhCH2),
52.3 (t, C-5), 64.9 (d, C-2), 91.6 (d, C-4), 126.2, 127.0, 127.4, 129.7,
131.0 (5 d, Ph, Tos), 134.1, 135.7, 143.7 (3 s, Ph, Tos), 154.1 (s, C-3).
Potassium tert-Butoxide Promoted Cyclization; General Procedure
GP4
The corresponding allenyl amine was dissolved in anhydrous dimeth-
yl sulfoxide and, under a stream of argon, at 50 °C sublimed potassi-
um tert-butoxide was added via a funnel. The mixture was stirred at
this temperature for the time given in the individual experiments. Af-
ter cooling to r.t., the mixture was hydrolyzed with saturated aqueous
NaHCO3 solution (20 mL) and the aqueous phase was extracted with
EtOAc (2 × 20 mL). The combined organic phases were washed with
aqueous NaHCO3 solution (2 × 20 mL) to remove DMSO, dried with
Na2SO4, filtered and concentrated in vacuo. The crude product was
purified by column chromatography.
IR (film): 3030, 2985, 2930, 2875 (C–H), 1665 (C=C), 1385, 1165
(TosN) cm–1
.
MS (EI, 80 eV): m/z (%) = 571 (4) [M+], 556 (9) [M+ – Me], 480 (100)
[M+ – Bn], 155 (40) [Tos+], 91 (75) [Bn+].
HRMS (EI, 80 eV): m/z [M+] calcd for C30H37NO8S: 571.2240; found:
571.2288; m/z [M+ – Me] calcd for C29H34NO8S: 556.2005; found:
556.2036.
3-O-(2-Phenyl-1-tosyl-2,5-dihydro-1H-pyrrol-3-yl)-1,2:4,5-di-O-
isopropylidene-β-D-fructopyranose (25)
According to GP4, allenyl amine 6 (0.120 g, 0.22 mmol, R/S 91:9) and
KOtBu (5 mg, 0.05 mmol) in DMSO (5 mL) gave, after 2 h heating to
50 °C, the crude product (0.200 g) as a yellow oil. Purification by col-
umn chromatography (alumina III, hexanes/EtOAc 3:1) afforded 25
(0.091 g, 75%, R/S 90:10) as a light-yellow oil. The ratio of diastereo-
mers was determined by 1H NMR spectroscopy.
Anal. calcd. for C30H37NO8S (571.7): C 63.03, H 6.52, N 2.45; found: C
63.01, H 6.35, N 2.20.
Data for (S)-28
[α]D20 = –41.6 (c = 0.4, CHCl3).
1H NMR (CDCl3, 270 MHz): δ = 2.42 (s, 3 H, Tos-Me), 3.02, 3.31 (AB
part of ABX system, JAB = 13.9 Hz, JAX = 2.6 Hz, JBX = 4.6 Hz, 2 H,
PhCH2), 3.48 (ddd, J = 13.3 Hz, J = 5.1 Hz, J = 2.4 Hz, 1 H, 5-H), 3.82
(ddd, J = 13.3 Hz, J = 2.6 Hz, J = 1.4 Hz, 1 H, 5-H), 4.32 (sbr, 1 H, 4-H),
4.57–4.65 (m, 1 H, 2-H), 7.18–7.25 (m, 3 H, Ph), 7.30 (d, J = 8.3 Hz, 2 H,
Tos), 7.38 (dd, J = 8.0 Hz, J = 1.6 Hz, 2 H, Ph), 7.72 (d, J = 8.3 Hz, 2 H,
Tos).
13C NMR (CDCl3, 67.9 MHz): δ = 21.5 (q, Tos-Me), 38.7 (t, PhCH2), 52.2
(t, C-5), 65.0 (d, C-2), 93.5 (d, C-4), 126.3, 127.4, 127.7, 129.6, 130.6 (5
d, Ph, Tos), 134.7, 136.3, 143.2 (3 s, Ph, Tos), 154.5 (s, C-3).
[α]D20 = –124.5 (c = 0.8, CHCl3).
1H NMR (CDCl3, 270 MHz): δ [(R)-25] = 2.37 (s, 3 H, Tos-Me), 3.85–
4.05 (m, 1 H, 5-H), 4.83 (sbr, 1 H, 4-H), 5.27 (sbr, 1 H, 2-H), 7.18 (d,
J = 8.3 Hz, 2 H, Tos), 7.20–7.36 (m, 5 H, Ph), 7.50 (d, J = 8.3 Hz, 2 H,
Tos); distinguishable signals of (S)-25: δ = 4.86 (s, 1 H, 4-H), 7.43 (d,
J = 8.3 Hz, 2 H, Tos).
13C NMR (CDCl3, 67.9 MHz): δ [(R)-25] = 21.3 (q, Tos-Me), 51.8 (t, C-5),
67.2 (d, C-2), 92.8 (d, C-4), 127.1, 127.7, 128.1, 128.8, 129.3 (5 d, Tos,
Ph), 135.2, 138.5, 143.1 (3 s, Tos, Ph), 154.9 (s, C-3); distinguishable
signals of (S)-25: δ = 155.4 (s, C-3).
IR (film): 3030, 2990, 2930, 2875 (C–H), 1665 (C=C), 1385, 1165
IR (film): 3065–2880 (C–H), 1665 (C=C), 1385, 1160 (TosN) cm–1
.
(TosN) cm–1
.
MS (EI, 80 eV): m/z (%) = 557 (2) [M+], 542 (4) [M+ – Me], 402 (15)
MS (EI, 80 eV): m/z (%) = 571 (2) [M+], 556 (6) [M+ – Me], 480 (58) [M+
[M+ – Tos], 260 (5) [C12H20O6+], 243 (70), 185 (100).
– Bn], 155 (47) [Tos+], 91 (100) [Bn+].
HRMS (EI, 80 eV): m/z [M+ – Me] calcd for C28H32NO8S: 542.1849;
found: 542.1874.
HRMS (EI, 80 eV): m/z [M+] calcd for C30H37NO8S: 571.2240; found:
571.2266; m/z [M+ – Me] calcd for C29H34NO8S: 556.2005; found:
556.2037.
Anal. Calcd. for C29H35NO8S (557.7): C 62.46, H 6.33, N 2.51; found: C
62.83, H 6.44, N 2.25.
Anal. Calcd. for C30H37NO8S (571.7): C 63.03, H 6.52, N 2.45; found: C
63.00, H 6.41, N 2.25.
Silver Nitrate-Promoted Cyclization; General Procedure GP5
To a solution of the corresponding allenyl alcohol or amine in anhy-
drous acetone was added silver nitrate under a stream of argon via a
funnel. The resulting mixture was stirred at r.t. under light exclusion
for 3–16 h and then evaporated in vacuo. EtOAc (ca. 5 mL) was added
to the residue and the mixture was filtered through a pad of Celite
(elution with EtOAc). After removal of the solvents in vacuo, the crude
product was purified as indicated in the individual experiments.
3-O-(2,5-Dihydro-5-nonyl-2-phenyl-1-tosyl-1H-pyrrol-3-yl)-
1,2:4,5-di-O-isopropylidene-β-D-fructopyranose (31)
According to GP4, allenyl amine 20 (0.894 g, 1.31 mmol,
R,aR/S,aR/S,aS = 87:9:4) and KOtBu (47 mg, 0.42 mmol) in DMSO (20
mL) gave after 14 h heating to 50 °C the crude product (0.980 g) as
brown oil. Purification by column chromatography (alumina III, hex-
anes/EtOAc 9:2) afforded 31 (0.627 g, 70%) as a light-yellow oil and
allenyl amine 20 (0.165 g, 18%, R,aR/S,aR = 65:35) as a light-yellow oil.
Product 31 was separated by HPLC (hexanes/EtOAc 6:1) to provide a
mixture of (2S,5S)-trans-31 and pyrrole 32 (0.030 g, 4%, 15:85),
(2R,5S)-cis-31 (0.470 g, 53%) as colorless crystals (m.p. 85 °C) and
(2S,5R)-cis-31 (0.018 g, 2%) as a light-yellow oil.
3-O-(2-Benzyl-1-tosyl-2,5-dihydro-1H-pyrrol-3-yl)-1,2:4,5-di-O-
isopropylidene-β-D-fructopyranose (28)
According to GP5, allenyl amine 15 (0.151 g, 0.26 mmol, R/S 80:20)
and AgNO3 (10 mg, 0.06 mmol) in acetone (10 mL) gave, after 12 h,
the crude product (0.300 g) as a brown oil. Purification by column
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

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A. Hausherr et al.
Paper
Synthesis
Data for (2R,5S)-cis-31
[α]D20 = –109.0 (c = 1.8, CHCl3).
13C NMR (CDCl3, 67.9 MHz): δ = 14.1 (q, Me), 21.3 (q, Tos-Me), 22.3,
27.9, 29.3, 29.6,* 29.8, 31.9, 36.0 (7 t, CH2), 64.8 (d, C-5), 68.8 (d, C-2),
98.8 (d, C-4), 126.6, 127.8, 127.9, 128.7, 129.3 (5 d, Ph, Tos), 136.6,
140.0, 141.9 (3 s, Ph, Tos), 154.5 (s, C-3); * higher intensity.
MS (EI, 80 eV): m/z (%) = 683 (0.05) [M+], 668 (2) [M+ – Me], 667 (3)
[M+ – H – Me], 556 (51) [M+ – C9H19], 555 (72) [M+ – H – C9H19], 313
(47), 243 (51), 185 (41), 57 (100).
1H NMR (CDCl3, 500 MHz): δ = 0.89 (t, J = 6.8 Hz, 3 H, Me), 1.21–1.35,
1.52–1.59, 1.84–1.92 (3 m, 14 H, 1 H each, CH2), 2.40 (s, 3 H, Tos-Me),
4.37–4.42 (m, 1 H, 5-H), 4.81 (s, 1 H, 4-H), 5.23 (s, 1 H, 2-H), 7.25–7.35
(m, 5 H, Ph, Tos), 7.49 (d, J = 7.1 Hz, 2 H, Ph), 7.65 (d, J = 8.3 Hz, 2 H,
Tos).
13C NMR (CDCl3, 125.8 MHz): δ = 14.1 (q, Me), 21.4 (q, Tos-Me), 22.7,
29.2, 29.3, 29.4, 29.5, 31.5, 31.8, 38.3 (8 t, CH2), 65.0 (d, C-5), 67.2 (d,
C-2), 97.2 (d, C-4), 127.4, 127.7, 127.8, 128.1, 129.5 (5 d, Ph, Tos),
134.8, 139.0, 143.5 (3 s, Ph, Tos), 154.3 (s, C-3).
HRMS (EI, 80 eV): m/z [M+ – Me] calcd for C37H50NO8S: 668.3257;
found: 668.3275.
3-O-(2,5-Dihydro-2-benzyl-5-nonyl-1-tosyl-1H-pyrrol-3-yl)-
1,2:4,5-di-O-isopropylidene-β-D-fructopyranose (33)
IR (KBr): 3030–2855 (C–H), 1665 (C=C), 1350, 1165 cm–1 (TosN).
Method A: According to GP5, allenyl amine 23 (0.960 g, 1.30 mmol,
R,aR/R,aS/S,aR/S,aS = 12:68:3:17) and AgNO3 (44 mg, 0.26 mmol) in
acetone (35 mL) gave, after 16 h, the crude product mixture, which
was pre-purified by column chromatography (alumina III, hex-
anes/EtOAc 6:1). The obtained product mixture (0.970 g) was separat-
ed by HPLC (hexanes/EtOAc 9:1) to afford (2R,5R)-trans-33 (0.099 g,
11%) as colorless crystals (m.p. 103–106 °C), (2R,5S)-cis-33 (0.445 g,
49%, containing ca. 5% of (2S,5S)-trans-33) as a colorless foam and
(2S,5R)-cis-33 (0.130 g, 14%) as colorless crystals (m.p. 96–99 °C).
MS (EI, 80 eV): m/z (%) = 683 (0.2) [M+], 668 (6) [M+ – Me], 556 (100)
[M+ – C9H19], 314 (39), 243 (30), 185 (14).
HRMS (EI, 80 eV): m/z [M+ – Me] calcd for C37H50NO8S: 668.3257;
found: 668.3279.
Anal. Calcd. for C38H53NO8S (683.3): C 66.74, H 7.81, N 2.05; found: C
66.68, H 7.74, N 2.21.
Data for (2S,5R)-cis-31
[α]D20 = –4.8 (c = 0.5, CHCl3).
Data for (2R,5R)-trans-33
[α]D20 = –127.1 (c = 0.4, CHCl3).
1H NMR (CDCl3, 270 MHz): δ = 0.89 (t, J = 6.8 Hz, 3 H, Me), 1.20–1.70,
2.05–2.25 (2 m, 14 H, 2 H, CH2), 2.39 (s, 3 H, Tos-Me), 4.48–4.57 (m,
1 H, 5-H), 4.95 (s, 1 H, 4-H), 5.29 (s, 1 H, 2-H), 7.17 (d, J = 8.3 Hz, 2 H,
Tos), 7.21–7.35 (m, 5 H, Ph), 7.54 (d, J = 8.3 Hz, 2 H, Tos).
13C NMR (CDCl3, 67.9 MHz): δ = 14.1 (q, Me), 21.4 (q, Tos-Me), 22.7,
26.1, 29.3, 29.5, 29.6,* 31.9, 38.7 (7 t, CH2), 64.6 (d, C-5), 68.4 (d, C-2),
96.5 (d, C-4), 127.6, 127.9, 128.0, 128.4, 129.4 (5 d, Ph, Tos), 135.9,
139.7, 143.1 (3 s, Ph, Tos), 154.6 (s, C-3); * higher intensity.
1H NMR (CDCl3, 500 MHz): δ = 0.87 (t, J = 7.2 Hz, 3 H, Me), 0.90–1.30,
1.75–1.85 (2 m, 15 H, 1 H, CH2), 2.41 (s, 3 H, Tos-Me), 3.15, 3.55 (AB
part of ABX system, JAB = 13.7 Hz, JAX = 1.5 Hz, JBX = 5.2 Hz, 2 H,
PhCH2), 3.88–3.94 (m, 1 H, 5-H), 4.49 (sbr, 1 H, 4-H), 4.69–4.74 (m,
1 H, 2-H), 7.17–7.28 (m, 5 H, Ph, Tos), 7.48 (d, J = 7.0 Hz, 2 H, Ph), 7.71
(d, J = 8.3 Hz, 2 H, Tos).
13C NMR (CDCl3, 125.8 MHz): δ = 14.1 (q, Me), 21.4 (q, Tos-Me), 22.6,
25.1, 29.2, 29.3, 29.4, 29.5, 31.8, 33.8 (8 t, CH2), 38.6 (t, PhCH2), 65.1
(d, C-5), 66.3 (d, C-2), 96.8 (d, C-4), 126.2, 126.5, 127.6, 129.4, 131.0 (5
d, Ph, Tos), 136.2, 140.3, 142.7 (3 s, Ph, Tos), 153.2 (s, C-3).
IR (film): 3035–2855 (C–H), 1665 (C=C), 1350, 1165 (TosN) cm–1
.
MS (EI, 80 eV): m/z (%) = 683 (0.2) [M+], 668 (3) [M+ – Me], 556 (100)
[M+ – C9H19], 314 (71), 243 (86), 185 (63).
HRMS (EI, 80 eV): m/z [M+ – Me] calcd for C37H50NO8S: 668.3257;
found: 668.3289.
IR (KBr): 3060–2855 (C–H), 1670 (C=C), 1380, 1160 (TosN) cm–1
.
MS (EI, 80 eV): m/z (%) = 697 (1.4) [M+], 683 (4.4) [M+ – Me], 606 (100)
Data for 32 and (2S,5S)-cis-31
[M+ – Bn], 570 (8) [M+ – C9H19], 364 (67), 91 (76) [Bn+].
1H NMR (CDCl3, 270 MHz): δ (32) = 0.88 (t, J = 7.0 Hz, 3 H, Me), 1.10–
1.35, 1.65–1.82 (2 m, 14 H, 2 H, CH2), 2.38 (s, 3 H, Tos-Me), 5.95 (d,
J = 1.7 Hz, 1 H, 4-H), 7.17 (d, J = 8.2 Hz, 2 H, Tos), 7.32–7.38, 7.40–7.45
(2 m, 5 H, Ph), 7.55 (d, J = 8.2 Hz, 2 H, Tos); the following signals could
be assigned to (2S,5S)-31: δ = 2.32 (s, 3 H, Tos-Me), 4.66 –4.75 (m, 1 H,
5-H), 4.80 (s, 1 H, 4-H), 5.37 (d, J = 5.2 Hz, 1 H, 2-H).
HRMS (EI, 80 eV): m/z [M+] calcd for C39H55NO8S: 697.3648; found:
697.3684.
Anal. Calcd for C39H55NO8S (697.4): C 67.12, H 7.94, N 2.01; found: C
67.42, H 7.80, N 1.76.
(2R,5S)-cis-33
[α]D20 = –55.4 (c = 0.4, CHCl3).
Due to the very low amount available no further characterization was
possible.
1H NMR (CDCl3, 270 MHz): δ = 0.89 (t, J = 6.8 Hz, 3 H, Me), 0.75–1.40
(m, 16 H, CH2), 2.41 (s, 3 H, Tos-Me), 3.08–3.15 (m, 2 H, PhCH2), 3.92–
4.05 (m, 1 H, 5-H), 4.20–4.30 (m, 2 H, 2-H, 4-H), 7.15–7.32 (m, 5 H, Ph,
Tos), 7.35 (d, J = 7.6 Hz, 2 H, Ph), 7.68 (d, J = 8.2 Hz, 2 H, Tos).
13C NMR (CDCl3, 67.9 MHz): δ = 14.0 (q, Me), 21.3 (q, Tos-Me), 22.5,
25.5, 29.1, 29.2,* 29.3, 31.7, 37.2, 38.9 (8 t, PhCH2, CH2), 65.0, 65.3 (2 d,
C-2, C-5), 95.4 (d, C-4), 126.2, 127.2, 127.4, 129.5, 131.3 (5 d, Ph, Tos),
133.8, 136.1, 143.5 (3 s, Ph, Tos), 153.5 (s, C-3); * higher intensity.
According to GP5, diastereomerically pure allenyl amine (R,aS)-20
(0.170 g, 0.25 mmol) and AgNO3 (10 mg, 0.06 mmol) in acetone (8
mL) gave, after 3 h, the crude product (0.300 g) as a brown oil. Purifi-
cation and separation by column chromatography (alumina III, hex-
anes/EtOAc 2:1) afforded (2R,5R)-trans-31 (0.019 g, 11%) and (2R,5S)-
cis-31 (0.030 g, 18%) as colorless oils and (R,aS)-20 (0.120 g, 71%) as a
light-yellow oil.
Data for (2R,5R)-trans-31
[α]D20 = –116.5 (c = 0.9, CHCl3).
IR (film): 3060, 3030, 2985, 2925, 2855 (C–H), 1665 (C=C), 1380, 1165
(TosN) cm–1
.
MS (EI, 80 eV): m/z (%) = 697 (0.9) [M+], 682 (7) [M+ – Me], 606 (100)
1H NMR (CDCl3, 270 MHz): δ = 0.89 (t, J = 6.6 Hz, 3 H, Me), 1.20–1.43,
1.93–2.06 (2 m, 14 H, 2 H, CH2), 2.31 (s, 3 H, Tos-Me), 4.64–4.71 (m,
1 H, 5-H), 4.97 (s, 1 H, 4-H), 5.39 (d, J = 5.1 Hz, 1 H, 2-H), 6.91, 6.98 (2
d, J = 8.8 Hz, 2 H each, Tos), 7.05–7.30 (m, 5 H, Ph).
[M+ – Bn], 364 (65), 155 (23) [Tos+], 91 (48) [Bn+].
HRMS (EI, 80 eV): m/z [M+] calcd for C39H55NO8S: 697.3648; found:
697.3673.
Data for (2S,5S)-trans-33
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

M
A. Hausherr et al.
Paper
Synthesis
The compound was isolated as mixture with (2R,5S)-cis-33.
Data of (2R,5S)-cis-34
1H NMR (CDCl3, 500 MHz): δ = 0.88 (t, J = 6.9 Hz, 3 H, Me), 0.90–1.30,
1.79–1.87 (2 m, 15 H, 1 H, CH2), 2.40 (s, 3 H, Tos-Me), 3.06 (dd,
J = 14.4 Hz, J = 2.0 Hz, 1 H, PhCH2), 3.71 (dd, J = 14.4 Hz, J = 4.8 Hz, 1 H,
PhCH2), 4.06–4.11 (m, 1 H, 5-H), 4.52 (s, 1 H, 4-H), 4.76 (sbr, 1 H, 2-H),
7.17–7.28 (m, 5 H, Ph, Tos), 7.45 (d, J = 7.2 Hz, 2 H, Ph), 7.69 (d,
J = 8.3 Hz, 2 H, Tos).
13C NMR (CDCl3, 125.8 MHz): δ = 14.1 (q, Me), 21.4 (q, Tos-Me), 22.6,
29.2, 29.3, 29.5, 29.7, 31.5, 31.8, 34.0 (8 t, CH2), 37.9 (t, PhCH2), 65.4,
66.0 (2 d, C-2, C-5), 98.4 (d, C-4), 126.2, 126.7, 127.8, 129.3, 130.5 (5 d,
Ph, Tos), 136.8, 140.0, 142.6 (3 s, Ph, Tos), 153.3 (s, C-3).
[α]D20 = –39.4 (c = 0.3, CHCl3).
1H NMR (CDCl3, 270 MHz): δ = 0.90 (t, J = 6.7 Hz, 3 H, Me), 0.90–1.40
(m, 16 H, CH2), 1.76, 2.14 (AB part of ABX system, JAB = 18.2 Hz,
JAX = 3.0 Hz, JBX = 9.3 Hz, JA,CH = 1.3 Hz, 2 H, 4-H), 2.43 (s, 3 H, Tos-Me),
3.22, 3.27, 3.93 (ABX system, JAB = 13.5 Hz, JAX = 5.7 Hz, JBX = 4.0 Hz,
1 H each, PhCH2, 2-H), 3.77–3.88 (m, 1 H, 5-H), 7.20–7.30 (m, 5 H, Ph),
7.33, 7.73 (2 d, J = 8.3 Hz, 2 H each, Tos).
13C NMR (CDCl3, 67.9 MHz): δ = 14.1 (q, Me), 21.5 (q, Tos-Me), 22.6,
25.8, 29.0, 29.2, 29.3, 29.4, 31.8, 37.0, 37.9, 42.2 (10 t, CH2, PhCH2,
C-4), 56.8, 65.4 (2 d, C-2, C-5), 126.9, 127.5, 128.2, 130.0, 130.9 (5 d,
Ph, Tos), 134.1, 136.2, 144.1 (3 s, Ph, Tos), 211.3 (s, C-3).
(2S,5R)-cis-33
[α]D20 = –81.3 (c = 0.5, CHCl3).
IR (film): 3060, 3030, 2925, 2855 (C–H), 1760 (C=O), 1355, 1155
(TosN) cm–1
.
1H NMR (CDCl3, 270 MHz): δ = 0.87 (t, J = 7.2 Hz, 3 H, Me), 0.80–1.40
(m, 16 H, CH2), 2.39 (s, 3 H, Tos-Me), 3.05, 3.19 (AB part of ABX sys-
tem, JAB = 13.6 Hz, JAX = 2.8 Hz, JBX = 5.2 Hz, 2 H, PhCH2), 4.39 (sbr, 1 H,
4-H), 4.48–4.53 (m, 1 H, 2-H), 7.10–7.36 (m, 7 H, Ph, Tos), 7.69 (d,
J = 8.2 Hz, 2 H, Tos); signal of 5-H is hidden by those of the auxiliary.
MS (EI, 80 eV): m/z (%) = 455 (1.5) [M+], 364 (100) [M+ – Bn], 155 (89)
[Tos+], 91 (91) [Bn+].
HRMS (EI, 80 eV): m/z [M+] calcd for C27H37NO3S: 455.2494; found:
455.2473.
13C NMR (CDCl3, 125.8 MHz): δ = 14.0 (q, Me), 21.4 (q, Tos-Me), 22.6,
25.7, 29.2, 29.3, 29.4, 31.5, 31.8, 37.6, 38.7 (9 t, PhCH2, CH2), 64.9, 65.7
(2 d, C-2, C-5), 97.5 (d, C-4), 126.3, 127.6*, 129.5, 131.1 (4 d, Ph, Tos),
134.5, 136.3, 143.0 (3 s, Ph, Tos), 154.1 (s, C-3); * signal with double
intensity.
Anal. Calcd. for C27H37NO3S (455.6): C 71.17, H 8.18, N 3.07; found: C
71.19, H 7.96, N 2.95.
Data of (2S,5S)-trans-34
1H NMR (CDCl3, 270 MHz): δ = 0.87 (t, J = 6.8 Hz, 3 H, Me), 0.90–1.35,
1.60–1.70 (2 m, 15 H, 1 H, CH2), 1.65, 1.99 (AB system, JAB = 17.2 Hz,
JA,5 = 9.0 Hz, JB,5 = 1.0 Hz, 2 H, 4-H), 2.44 (s, 3 H, Tos-Me), 3.12 (dd,
J = 13.7 Hz, J = 3.2 Hz, 1 H, PhCH2), 3.64 (dd, J = 13.7 Hz, J = 5.1 Hz, 1 H,
PhCH2), 3.94 (dd, J = 5.1 Hz, J = 3.2 Hz, 1 H, 2-H), 4.00–4.10 (m, 1 H, 5-
H), 7.20–7.30 (m, 7 H, Ph, Tos), 7.77 (d, J = 8.3 Hz, 2 H, Tos).
13C NMR (CDCl3, 67.9 MHz): δ = 14.1 (q, Me), 21.5 (q, Tos-Me), 22.6,
24.6, 27.4, 29.3*, 29.4, 31.8, 33.2, 37.9, 42.8 (9 t, CH2, PhCH2, C-4), 57.6,
64.8 (2 d, C-2, C-5), 127.0, 127.2, 128.3, 129.7, 130.6 (5 d, Ph, Tos),
135.3, 137.8, 143.6 (3 s, Ph, Tos), 210.9 (s, C-3); * double intensity.
IR (KBr): 3060, 3030, 2990, 2925, 2855 (C–H), 1665 (C=C), 1380, 1165
(TosN) cm–1
.
MS (EI, 80 eV): m/z (%) = 697 (1.3) [M+], 682 (7) [M+ – Me], 606 (99)
[M+ – Bn], 364 (77), 155 (44) [Tos+], 91 (100) [Bn+].
HRMS (EI, 80 eV): m/z [M+ – Me] calcd for C38H52NO8S: 682.3414;
found: 682.3456.
Method B: Analogously to GP5, allenyl amine 23 (0.311 g, 0.45 mmol,
R,aR/R,aS/S,aR/aS,S = 54:22:21:3) and AgNO3 (17 mg, 0.10 mmol),
K2CO3 (0.135 g, 0.98 mmol) in acetonitrile (10 mL) gave, after 14 h, the
crude product mixture, which was pre-purified by column chroma-
tography (alumina III, hexanes/EtOAc 7:1). The obtained product mix-
ture (0.270 g) was separated by HPLC (hexanes/EtOAc 9:1) to afford
(2R,5R)-trans-33 (0.060 g, 18%), (2S,5S)-trans-33 (0.027 g, 8%),
(2R,5S)-cis-33 (0.130 g, 38%) and (2S,5R)-cis-32 (0.026 g, 8%) as color-
less oils.
Due to the low amount available, further characterization was not
possible.
(2S,5R)-2-Benzyl-5-nonyl-1-tosylpyrrolidin-3-one (cis-34)
A solution of (2S,5R)-cis-33 (0.045 g, 0.065 mmol) in THF (5 mL) and
20% aqueous sulfuric acid (4 mL) was heated to reflux for 4 h. After
cooling to r.t., the mixture was cautiously neutralized with saturated
aqueous NaHCO3 solution and the organic phase was separated. The
aqueous phase was extracted with diethyl ether (2 × 10 mL), the com-
bined organic phases were dried (Na2SO4), filtered and evaporated in
vacuo. The crude product was purified by column chromatography
(silica gel, hexanes/EtOAc 5:1) to give pure (2S,5R)-cis-34 (0.020 g,
68%) as a colorless wax (m.p. 30–31 °C).
Method C: According to GP4, allenyl amine 23 (0.972 g, 1.39 mmol,
R,aR/R,aS/S,aR/S,aS = 54:22:21:3) and KOtBu (32 mg, 0.14 mmol) in
DMSO (20 mL) gave, after 12 h heating to 50 °C, the crude product.
Purification by column chromatography (alumina III, hexanes/EtOAc
5:1) afforded a mixture of (2R,5S)-cis-33 and (2S,5R)-cis-33 (0.634 g,
61%, d.r. 90:10) as a colorless yellow oil and allenyl amine 23 (0.343 g,
33%, R,aS/S,aR = 55:45) as a light-yellow oil.
Data of (2S,5R)-cis-34
[α]D20 = +41.5 (c = 1.1, CHCl3).
(2R,5S)- and (2S,5S)-2-Benzyl-5-nonyl-1-tosylpyrrolidin-3-one
(34)
The NMR data agree with those of enantiomer (2R,5S)-cis-34.
IR (film): 3060–2855 (C–H), 1760 (C=O), 1355, 1165 (TosN) cm–1
.
A solution of 33 (0.320 g, 0.46 mmol, 2R,5S/2S,5S = 95:5) in THF (20
mL) and 20% aqueous sulfuric acid (12 mL) was heated to reflux for 3
h. After cooling to r.t., the mixture was cautiously neutralized with
saturated aqueous NaHCO3 solution and the organic phase was sepa-
rated. The aqueous phase was extracted with diethyl ether (2 × 15
mL), the combined organic phases were dried (Na2SO4), filtered and
evaporated in vacuo. The crude product was purified by column chro-
matography (silica gel, hexanes/EtOAc 5:1) to give pure (2R,5S)-cis-34
(0.165 g, 79%) as a colorless wax (m.p. 32–33 °C) and (2S,5S)-trans-34
(8 mg, 4%) as colorless crystals (m.p. 76–78 °C).
Anal. Calcd. for C27H37NO3S (455.6): C 71.17, H 8.18, N 3.07; found: C
71.20, H 8.11, N 2.94.
Funding Information
This work was generously supported by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie.
)(
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

N
A. Hausherr et al.
Paper
Synthesis
Acknowledgment
Reissig, H.-U. Synlett 2008, 2046. (e) Prisyazhnyuk, V.; Jachan,
M.; Brüdgam, I.; Zimmer, R.; Reissig, H.-U. Collect. Czech. Chem.
Commun. 2009, 74, 1069.
We thank the Fonds der Chemischen Industrie (Kekulé fellowship for
Arndt Hausherr) and the Schering AG for supply of materials. We ac-
knowledge the assistance of Christiane Groneberg und Winfried
Münch in analytic work.
(11) Bressel, B.; Reissig, H.-U. Org. Lett. 2009, 11, 527.
(12) Kobayashi, K.; Okamoto, T.; Oida, T.; Tanimoto, S. Chem. Lett.
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(13) For gas-phase and solution studies of lithiated methoxyallene
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Pratt, L. M. J. Org. Chem. 2009, 74, 5881. (b) Pratt, L. M.; Dixon, D.
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(15) Verkruijsse, H. D.; Verboom, W.; Van Rijn, P. E.; Brandsma, L.
J. Organomet. Chem. 1982, 232, C1.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609942.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(16) For cyclizations of allenyl amines under basic conditions, see:
(a) ref. 5a. (b) Flögel, O.; Reissig, H.-U. Synlett 2004, 895.
(c) Okala Amombo, M. G.; Flögel, O.; Kord Daoroun Kalai, S.;
Schoder, S.; Warzok, U.; Reissig, H.-U. Eur. J. Org. Chem. 2017,
1965. (d) For a theoretical study of this reaction, see: Cumine,
F.; Young, A.; Reissig, H.-U.; Tuttle, T.; Murphy, J. A. Eur. J. Org.
Chem. 2017, 6867.
(17) For silver nitrate-promoted reactions of allenyl alcohols and
amines, see: (a) Leandri, G.; Monti, M.; Bertrand, M. Tetrahedron
1974, 30, 289. (b) Olsson, L.-I.; Claesson, A. Synthesis 1979, 743.
(c) Claesson, A.; Sahlberg, S.; Luthman, K. Acta Chem. Scand., Ser.
B 1979, 33, 309. (d) Arseniyadis, S.; Goré, J. Tetrahedron Lett.
1983, 24, 3997. (e) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett.
1988, 29, 4253. (f) Shaw, R. W.; Lathbury, D.; Gallagher, T.
Synlett 1993, 710. (g) Schierle, K.; Vahle, R.; Steckhan, E. Eur. J.
Org. Chem. 1998, 509; see also refs. 16a–c.
(18) The presented investigations were performed (ref. 9a) before
gold compounds were discovered to be superior catalysts for
many cyclization reactions: For selected examples, see:
(a) Hashmi, A. S. K.; Schwarz, I.; Choi, J.-H.; Frost, T. M. Angew.
Chem. Int. Ed. 2000, 39, 2285; Angew. Chem. 2000, 112, 2382.
(b) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485. (c) Tao, S.;
Deutsch, C.; Krause, N. Org. Biomol. Chem. 2012, 10, 5965. For
reviews on gold-catalyzed allene cyclizations, see: (d) Krause,
N.; Winter, C. Chem. Rev. 2011, 111, 1994. (e) Alcaide, B.;
Almendros, P. Acc. Chem. Res. 2014, 47, 939. For our results
employing gold catalysis in allenyl amine cyclizations, see ref.
16c.
(19) Flögel, O.; Reissig, H.-U. Eur. J. Org. Chem. 2004, 2797.
(20) (a) Breuil-Desvergnes, V.; Compain, P.; Vatèle, J.-M.; Goré, J. Tet-
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Tetrahedron 2001, 57, 1951.
(21) For a review, see: Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.;
Enders, D. Tetrahedron 2002, 58, 2253.
(22) We assume that the relatively high acidity of the benzylic posi-
tion of this hydrazone is responsible for a protonation of the
fairly basic lithiated allenes.
(23) For reviews on the use of carbohydrate derivatives as auxiliaries
in organic synthesis, see: (a) Reissig, H.-U. Angew. Chem. Int. Ed.
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(e) Lehnert, T.; Özüduru, G.; Grugel, H.; Albrecht, F.; Telligmann,
S. M.; Boysen, M. M. K. Synthesis 2011, 2685.
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(7) (a) Rochet, P.; Vatèle, J.-M.; Goré, J. Synthesis 1994, 795.
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diastereoselective additions of lithiated alkoxyallenes bearing
carbohydrate-derived auxiliaries to N-tosyl imines was pub-
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N