Flexible synthesis of planar chiral azoninones and optically active indolizidinones

Article abstract of DOI:10.1002/ejoc.201402720

The flexible synthesis of defined substituted optically active indolizidinones starting from chiral pool (S)-proline and trans 4-hydroxy-(S)-proline is described. Several defined 2-vinylpyrrolidines were generated in short sequences. The aza-Claisen rearr

Full text of DOI:10.1002/ejoc.201402720

FULL PAPER
DOI: 10.1002/ejoc.201402720
Flexible Synthesis of Planar Chiral Azoninones and Optically Active
Indolizidinones
Frank Bohland,[a] Irina Erlin,[a] Lukas Platte,[a] Maike Schröder,[a] Dieter Schollmeyer,[a]
and Udo Nubbemeyer*[a]
Dedicated to Professor Dr. Johann Mulzer on the occasion of his 70th birthday
Keywords: Nitrogen heterocycles / Allylic compounds / Sigmatropic rearrangement / Ring expansion / Medium-ring
compounds / Ring contraction
The flexible synthesis of defined substituted optically active
trophile iodine induced diastereoselective transannular ring
indolizidinones starting from chiral pool (S)-proline and trans contractions. Here, the planar chiral arrangement of the
4-hydroxy-(S)-proline is described. Several defined 2-vinyl- azoninone double bond predetermined the bridgehead con-
pyrrolidines were generated in short sequences. The aza-
Claisen rearrangement using chloro and phenylketene ine starting materials could be used to gain access to either
equivalents delivered nine-membered-ring lactams with up one of the two antipodal series of indolizidinone products.
to three stereogenic centres and pS-arranged E olefins. De- The indolizidinone scaffolds should serve as versatile key in-
figuration of the product indolizidinones. Thus, the (S)-prol-
pending on the substitution pattern, certain azoninones had
a flexible conformation and showed pS/pR double-bond flip-
ping. Treatment of the unsaturated lactams with the soft elec-
termediates in the synthesis of natural products and pharma-
ceutically important molecules.
Introduction
The synthesis of optically active indolizidine alkaloids
and their analogues delivers various biologically active and
structurally challenging compounds.[1] New natural prod-
ucts are still isolated from natural sources, and total synthe-
sis helps to allow their chemical and biological investiga-
tion.[2]
A long-term research program in our group focusses on
flexible access to defined substituted indolizidinone scaf-
folds as key intermediates for the synthesis of enantiomer-
ically pure natural products and drugs.[3] This strategy has
been used successfully in several examples. Starting from
vinylpyrrolidine I, trihydroxyindolizidinones II and III were
generated as useful precursors for the synthesis of castano-
spermine analogues.[4] Simple enantiopure 2-vinylpyrrol-
idine IV was converted into hydroxyindolizidinone V, and
further steps allowed the completion of a total synthesis of
pumiliotoxin 251D.[5] Furthermore, ester VI could be con-
verted into lactam VII, which served as a key intermediate
in the synthesis of dendroprimines (Figure 1).[6]
Figure 1. Syntheses using optically active indolizidinones as key in-
termediates; TBS = tert-butyldimethylsilyl.
Analysis of the reaction cascade that converts vinyl-
pyrrolidines into indolizidinones reveals that stereochemical
aspects need careful consideration. Starting from stereo-
chemically defined 2-vinylpyrrolidine derivatives VIII and
acid halides IX, a ring expansion by means of a zwitterionic
aza-Claisen rearrangement gave unsaturated nine-mem-
bered ring lactams X, and a complete chirality transfer led
[a] Institute of Organic Chemistry, Johannes Gutenberg University
Mainz,
Duesbergweg 10–14, 55128 Mainz
E-mail: nubbemey@uni-mainz.de
http://www.chemie.uni-mainz.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402720.
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Synthesis of Azoninones and Indolizidinones
to a defined planar chiral arrangement of the 5,6 double literature procedures.[5a,11] The OH group of hydroxy ester
bond (pS-X and pR-X). A complete 1,4 chirality transfer 3 could be protected as a TBS ether (to give 4b) or as a
was found for vinylpyrrolidines VIII (R1 ϶ H, R2 = H) and MOM (methoxymethyl) ether (to give 4d), as described ear-
acid halides IX (X = Cl, F),[3a–3c,4] a complete 1,3 chirality lier.[12] Phenyl ether 4c was obtained in 38% yield by Buch-
transfer was observed for substrates VIII (R2 ϶ H) and acid wald coupling with PhI using catalytic amounts of CuI/
chlorides IX (X = Cl),[3d,3e] and the same results were found 1,10-phenanthroline in the presence of Cs2CO3.[13] The in-
in preliminary experiments involving less reactive acid version of the 4-OH configuration was achieved under Mit-
fluorides IX (X = F).[3c] A smooth formation of defined sunobu conditions. Treatment of hydroxy ester 3 with
stereogenic centres in the rearrangement delivered lactams DIAD, PPh3, and PhOH led to 2,4-cis phenyl ether 5c in
X. Subsequent transformation of the double bond moiety 56% yield.[14] Mitsunobu inversion according a publication
allowed the planar chiral properties to be used for the dia- by Cossy using DEAD, PPh3, and benzoic acid, and subse-
stereoselective synthesis of bicyclic systems. Running the quent Zemplén transesterification with K2CO3 in MeOH
olefin conversion as a transannular ring contraction, the delivered the cis 4-hydroxy proline ester derivative. A final
configuration of the bridgehead carbon of the product silyl ether protection with TBSCl and imidazole gave cis
indolizidinones could be chosen to be R or S (in XI and silyl ether 5b in 41% yield (over three steps).[15]
XII, respectively; Figure 2).[3–7]
The introduction of the olefin moieties always followed
a three-step sequence. After initial DIBAL-H reduction of
esters 4 and 5, and subsequent Swern oxidation,[16] the re-
sulting aldehydes were immediately subjected to Horner
olefinations to avoid any epimerisation of the 2-position un-
der the basic reaction conditions. Typical Horner ole-
finations using trimethylphosphonoacetate and ethyl di-
methylphosphonoacetate delivered predominantly E α,β-
unsaturated γ-amino esters E-6 and E-7 in 48–87% yield
(E/Z = 5–13:1).[17] Z isomers Z-6 and Z-7 were isolated as
minor products. In contrast, Ando olefination using ethyl-
diphenylphosphonoacetate gave Z-6 and Z-7 Z/E ratios of
5:2 to Ͼ10:1, and yields of 48–90% (for details, see Table 1
and Scheme 1).[18]
Table 1. Results of Horner and Ando olefinations.[a]
Entry Olefin
Method
R1
Yield [%] Ratio E/Z
1
2
3
4
5
6
7
8
9
E-6a
Horner
Ando
Horner
Horner
Ando
H
H
55
48
79
58
54
50
48
70
87
90
10:1
1:10
9:1
Figure 2. Concept: diastereoselective synthesis of optically active
indolizidinones.
Z-6a*
E-6b
OTBS
OPh
OPh
OMOM
OTBS
OPh
OPh
OPh
E-6c
5:1
To gain deeper insight into the scope and limitations of
this strategy, the interactions between the different stereo-
chemical components (e.g., the relative configuration of R1
and the vinyl group, and the olefin geometry in VIII) had
to be investigated systematically. In this paper, we report
the synthesis of protected cis and trans 4-hydroxy-2-vinyl-
pyrrolidines with defined olefin geometries. Subsequent
aza-Claisen rearrangements delivered the corresponding
azoninones with several combinations of defined stereo-
genic centres and planar chiral arranged E olefins.[8] Next,
anti addition across the double bond of an external soft
electrophile and the intramolecular lactam nitrogen gave,
after von Braun removal of the benzyl moiety, a set of tar-
get indolizidinones.[9] These indolizidinone scaffolds should
serve as key intermediates for further synthetic applications.
Z-6c*
Z-6d*
E-7b
1:10
1:10
6:1
13:1
10:1
25:65
Ando
Horner
Horner
Horner
Ando
E-7c
E-7c*
Z-7c*
10
[a] Standard: methyl ester (R2 = Me); * ethyl ester (R2 = Et).
With a set of defined amino esters in hand, the zwitter-
ionic aza-Claisen rearrangement[3–6] to induce ring expan-
sion was investigated using chloroacetyl fluoride and phen-
ylacetyl fluoride as the standard ketene sources.[19,20] Gen-
erally, allylamines 6 and 7 and an excess of acid fluoride
were dissolved in dry dichloromethane in the presence of
solid potassium carbonate, and trimethylaluminum was
added at 23 °C. In most runs, the conversion was found to
be complete after 12–16 h of stirring. After hydrolysis,
product azoninones 8–21 could be isolated in 49–94% yield.
Separation of the diastereomers (if necessary) was achieved
Results and Discussion
Starting from commercially available trans-4-hydroxy-l- by careful preparative HPLC. The temperatures at every
(–)-proline (1) and l-(–)-proline (2), ester formation with stage of the process were kept at 23 °C or below to avoid
AcCl and MeOH,[10] and N-benzylation with BnCl and any rotation of the olefin moiety within the ring and main-
Et3N gave amino esters 3 and 4a, respectively, according to tain the kinetic pS arrangement of azoninones pS-8–pS-21.
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Scheme 1. Synthesis of 2-vinylpyrrolidines. Conditions: i) 1. AcCl, MeOH, reflux, 12 h; 2. BnCl, Et3N, CH2Cl2, 23 °C, 12 h, yield 3: 72%,
4a: 53%; ii) TBSCl, imidazole, CH2Cl2, 23 °C, 12 h, 4b: 88%; iii) PhI, CuI, 1,10-phenanthroline, K2CO3, solvent, 23 °C, 4c: 38%;
iv) MOMCl, EtN(iPr)2, CH2Cl2, 23 °C, 12 h, 4d: ca. 70%; v) DIAD, PPh3, PhOH, CH2Cl2, 23 °C, 12 h, 5c: 56%; vi) 1. DEAD, PPh3,
BzOH, CH2Cl2, 23 °C, 12 h; 2. K2CO3, MeOH, 23 °C, 12 h; 3. TBSCl, imidazole, CH2Cl2, 23 °C, 12 h, 5b: 41% (3 steps); vii) 1. DIBAL-
H, THF, 0 °C, 12 h; 2. (COCl)2, DMSO, Et3N, CH2Cl2, –70 °C to 0 °C, 3 h; 3. (MeO)2P(O)CH2CO2Me/NaH, THF, 0 °C, 12 h (Horner,
procedure A); or (PhO)2P(O)CH2CO2Et/NaH, THF, 0 °C, 12 h (Ando, procedure B), yield E-6a: 35% (E/Z = 10:1), Z-6a: 30% (ethyl
ester E/Z = 1:10), E-6b: 54% (E/Z = 9:1), E-6c: 58% (E/Z = 5:1), Z-6c: 54% (E/Z = 1:10), Z-6d: ca. 40% (ethyl ester, E/Z = 1:10), E-
7b: 32% (E/Z = 6:1), E-7c: 49% (E/Z = 13:1, R2 = Me), E-7c: 87% (E/Z = 10:1, R2 = Et), Z-7c: 90% (E/Z = 25:65), (always: three steps,
for details concerning olefination see Table 1).
Furthermore, selected reactions were conducted in the ab- olefin 6a proceeded with complete 1,3 chirality transfer, but
sence of K2CO3 to avoid any base-promoted epimerisation the diastereoselectivity at the C-3 position was low (2:1 to
of the α-chloro and α-phenyl substituents at the C-3 posi- 1:2), irrespective of whether any base was present, indicat-
tion. Details are given in Table 2 and Scheme 2.
ing an unselective reaction. It is unlikely that significant C-
3 epimerisation of azoninones 8a/9a and 10a/11a oc-
curred.[21] In contrast, the ring expansion of cis 2-vinylpyr-
rolidine Z-6a (Table 2, entries 7 and 8) succeeded, with
complete 1,3 chirality transfer and high diastereoselectivity,
to give trans azoninones 12a and 14a in 77 and 92% yield,
respectively. None of the 3,4-cis lactams (i.e., 13a and 15a)
were found.
For all of the 4-substituted vinylpyrrolidines (i.e., E/Z-
6b–6d and E/Z-7b–7c), the C-4 configuration and the olefin
geometry had a crucial influence on the diastereoselectivity
of the aza-Claisen rearrangement.
Starting from 2,4-trans-configured allylamines E- and Z-
6 (with an α-C-4 substituent), all the reactions proceeded
with complete 1,3 chirality transfer and a high diastereo-
selectivity to give the C-3 chloride and phenyl groups in the
β position (β:α, Ͼ10:1). Azoninones 8b, 8c, 10b, 12b–12d,
and 14b–14c were isolated in 57–92% yield, and none of
the 3α-chloride (i.e., 9 and 13) or 3α-phenyl (i.e., 11 and 15)
configured diastereomers could be detected (Table 2, en-
tries 4–6, 9–14). Some of the phenyl-derived compounds
underwent partial facile flipping of the double bond to give
Table 2. Results of the aza-Claisen rearrangement.
Entry Olefin Method Products R2
Yield [%] Ratio
1
2
3*
4
5
E-6a
E-6a
E-6a
E-6b
E-6c
E-6c
Z-6a
Z-6a
Z-6b
Z-6b
Z-6b
Z-6c
Z-6c
Z-6d
E-7b
E-7b
E-7c
E-7c
E-7c
E-7c
Z-7c
C
D
C
C
C
D
C
D
C
C
C
C
D
C
C
D
C
D
C
D
C
8a/9a
Cl
Cl
Ph
Cl
Cl
Ph
Cl
Ph
Cl
Cl
Ph
Cl
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Ph
Cl
83
84
79
68
64
70
77
92
58
69
81
57
70
77
56
94
68
89
49
63
78
2:1[a]
8a/9a
1.3:1
10a/11a
8b/9b
8c/9c
1:2[a]
Ͼ10:1
Ͼ10:1
Ͼ10:1[b]
Ͼ10:1
Ͼ10:1[c]
Ͼ10:1
Ͼ10:1
Ͼ10:1[c]
Ͼ10:1
Ͼ10:1
Ͼ10:1
1:1.3
1:6
2:1
1:10
1:1
1:10
68:10
6
10c/11c
12a/13a
14a/15a
12b/13b
12b/13b
14b/15b
12c/13c
14c/15c
12d/13d
16b/17b
16b/17b
16c/17c
16c/17c
16c/17c
18c/19c
20c/21c
7*
8*
9
10*
11*
12*
13*
14*
15
16
17
18
19*
20
21*
[a] For details see ref.[3b] [b] 17:6 mixture of pS and pR dia- mixtures of planar chiral diastereomers (Table 2, entries 6,
stereomers. [c] Mixture (potential equilibrium) of pS and pR dia-
8, and 11; pS/pR-10c, pS/pR-14b, and pS/pR-14c). Initial
stereomers. Standard: methyl ester (R2 = Me); * ethyl ester (R2 =
rearrangements starting from 2,4-cis amino esters E-7 (β-
Et).
C-4 substituent) in the presence of K2CO3 delivered mix-
The first rearrangements using monosubstituted 2-vinyl- tures of diastereomers 16/17 (Table 2, entries 15, 17, and
pyrrolidine E-6a (Table 2, entries 1–3) gave high yields (79– 19). Although complete 1,3 chirality transfer occurred, the
84%) of azoninones 8a/9a and 10a/11a. The reactions of E diastereoselectivity 16/17 was low (β:α, 1:1–2:1), and the
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Synthesis of Azoninones and Indolizidinones
Scheme 2. Aza-Claisen rearrangement to synthesise azoninones. Conditions: ia) (procedure C) ClCH2C(O)F, Me3Al, K2CO3, CH2Cl2,
23 °C, 12 h, yield 8a/9a: 83% (2:1), 8b/9b: 68% (Ͼ10:1), 8c/9c: 64% (Ͼ10:1), 12a/13a: 77% (Ͼ10:1), 12b/13b: 58% (Ͼ10:1), 12b/13b: 69%
(Ͼ10:1, R2 = Et), 12c/13c: 57% (Ͼ10:1), 12d/13d: 77% (Ͼ10:1), 16b/17b: 56% (1:1.3), 16c/17c: 68% (2:1, R2 = Me), 49% (1:1, R2 = Et),
20c/21c: 78% (7:1); ib) (procedure C) PhCH2C(O)F, Me3Al, K2CO3, CH2Cl2, 23 °C, 12 h, yield 10a/11a: 79% (2:1), 14b/15b: 81% (Ͼ10:1);
iia) (procedure D) ClCH2C(O)F, Me3Al, CH2Cl2, 23 °C, 12 h, 8a/9a: 84% (1.3:1), 16b/17b: 94% (1:6), 16c/17c: 89% (1:10); iib) (procedure
D) PhCH2C(O)F, Me3Al, CH2Cl2, 23 °C, 12 h, 10c/11c: 70% (Ͼ10:1), mixture pS/pR 17:6, 14a/15a: 92% (Ͼ10:1), 14c/15c: 70% (1:Ͼ10),
18c/19c: 63% (1:Ͼ10), see Table 2.
yields varied from 49 to 68%. When the ring-expansion re- B was found for lactams pS-12, pS-14, and pS-20.[22] X-ray
actions were run without K2CO3, the outcome changed analysis of lactam pS-8b supported the findings of the
(Table 2, entries 16, 18, and 20). The formation of 3α-chlor- NMR spectra (Figure 3).[23] Lactams pS-9a, pS-17, and
ides 17 and 3α-phenyl derivative 19 predominated. Lactam pS-19 adopted a single conformation A in which all the
17b was isolated in 94% yield with a dr of 6:1, lactam 17c substituents were arranged in quasi-equatorial positions.
was obtained in 89% yield with a dr of Ͼ10:1, and lactam Additionally, pS-21c adopted a conformation A with a
19c was formed in 63% yield with a dr of Ͼ10:1. A first quasi-axial positioned ester group. For detailed infor-
rearrangement of 2,4-cis amino ester Z-7c (β-C-4 substitu- mation, see Figure 6 and NOE data.[22]
ent) preferentially delivered 3β-chloride 20c with a com-
The stability of the pS arrangement of the double bond
bined yield of 20c and 21c of 78%, and a dr of nearly 7:1 in the presence of the defined stereogenic centres was cru-
(Table 2, entry 21).
cial for the planned diastereoselective transannular ring
The structural determination of all the azononinones was contractions.[3,4] With this in mind, selected azoninones pS-
achieved unequivocally by H and 13C NMR spectroscopic 8–pS-21 directly obtained from the rearrangement were
1
analysis. NOESY spectra gave decisive information about heated to 40–65 °C, and the potential transformation from
the relative configuration of the lactams. Most of the prod- pS into pR arranged compounds was investigated using
ucts (i.e., pS-8, pS-10, and pS-16) adopted a preferred con- TLC and HPLC analysis as well as NMR spectroscopy.
formation A (Figure 5) in which the lactam oxygen and the Heating 3,4-trans azoninone pS-9a gave no new conformer,
benzyl group were arranged anti with respect to the C-5 even after prolonged heating to 65 °C, indicating a thermo-
olefin proton. A second minor conformation B (Figure 5) dynamic stability (Table 3, entry 3). In contrast, 3,4-trans
1
was detected in the H NMR spectra of pS-8b (ratio 1:2) azoninones pS-12a and pS-14a underwent a nearly com-
and pS-8c (ratio 1:4) in which the lactam oxygen and the plete double-bond flip to give pR-12a and pR-14a as more
benzyl group were arranged syn with respect to the C-5 ole- stable planar chiral diastereomers (Table 3, entries 5–10).
fin proton. In contrast, a high preference for conformation Furthermore, all the 4β/8α-configured pS azoninones (i.e.,
Eur. J. Org. Chem. 2014, 6272–6284
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U. Nubbemeyer et al.
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Heating 4α/8α-configured lactams pS-12 and pS-14 re-
sulted in almost complete flipping of the double bond to
give the pR diastereomers as stable products. After 12 h of
heating, pS-12b gave a 1:3 mixture of pS-12b and pR-12b,
which could be separated by preparative HPLC (Table 3,
entry 6). Prolonged heating resulted in complete flipping of
the double bond. Heating of azoninone pS-12d for a short
time resulted in a nearly complete isomerisation to give pR-
12d (Table 3, entry 8). Finally, 3-phenyllactam pS-14b
underwent a complete double-bond flip from pS to pR
within 6 h (Table 3, entry 10). In contrast, 4β/8β lactams
pS-17b/c and pS-19c showed no significant isomerisation,
indicating the thermodynamic stability of the starting
planar diastereomer (Table 3, entries 11–13).[24] Lactam pS-
21c underwent partial pS/pR flipping upon heating. After
12 h, a ratio of 1:1.6 of the two compounds was found
(Table 3, entry 14). Separation was achieved by preparative
HPLC. The structures of all the pR azoninones were deter-
mined by 1H and 13C NMR spectroscopy and NOESY
analysis. For detailed information, see Table 3 and
Scheme 3.[22]
Figure 3. X-ray analysis of lactam pS-8b (lactam oxygen and benzyl
group anti with respect to the C-5 olefin proton).
pS-8 and pS-10) underwent at least a partial double-bond
rotation from pS to pR with respect to the ring (Table 3,
entries 1, 2, and 4). The heating of pS-8b to 65 °C for 12 h
led to the formation of a 1.5:1 mixture of pS-8b and pR-8b,
and this ratio remained the same even after prolonged heat-
ing (Table 3, entry 1). These diastereomers (i.e., pS-8b and
pR-8b) were separated by preparative HPLC. Heating pS-
8c to 65 °C for 12 h led to the formation of a 2:1 mixture
of pS-8c and pR-8c, which could be separated by prepara-
tive HPLC (Table 3, entry 2). 3-Phenyllactam 10c under-
went pS/pR isomerisation at room temperature. Even
though the diastereomers could be separated by preparative
HPLC, a nearly 3:1 mixture of pS/pR-10c always regener-
ated from either isomer upon standing. Structural elucida-
tion was achieved by analysing the spectra of the mixture
(Table 3, entry 4).
Table 3. pS/pR epimerisation of selected azoninones.
Entry
Reactant R3
Product
Ratio
pS/pR
Time
1
2
3
4
5*
6
7*
8*
9*
10*
11
12
13*
14*
pS-8b
Cl
Cl
Cl
Ph
Cl
Cl
Cl
Cl
Ph
Ph
Cl
Cl
Ph
Cl
pR-8b
1.5:1
2:1
Ͼ10:1
3:1
1:Ͼ10
1:3
1:Ͻ5
1:Ͼ10
1:Ͼ10
1:Ͼ10
Ͼ10:1
Ͼ10:1
5:1
12 h to 5 d
12 h
pS-8c
pR-8c
Scheme 3. Epimerisation of selected azoninones. Conditions:
CHCl3, 65 °C, 12 h, quantitative yield, see Table 3.
pS-9a
pR-9a
12 h
pS-10c
pS-12a
pS-12b
pS-12b
pS-12d
pS-14a
pS-14b
pS-17b
pS-17c
pS-19c
pS-21c
pR-10c
pR-12a
pR-12b
pR-12b
pR-12d
pR-14a
pR-14b
pR-17b
pR-17c
pR-19c
pR-21c
12 h[a]
24 h
To investigate transannular ring contractions, iodocycli-
sation was chosen. According to literature procedures,[3–7]
azoninones 8–20 were treated portionwise with iodine in
CH2Cl2 at 23 °C until the colour of unreacted iodine re-
mained. After destruction of the excess iodine and removal
of the benzyl iodide by-product, indolizidinones 22–32
(along with 33 and 34) were isolated in 40–93% yield. The
products were subjected to careful NMR spectroscopic
analysis to determine the relative configurations of the new
stereogenic centres.[22] Consistently with the literature, pS
lactams 8–20 gave the corresponding indolizidinones with
12 h
12 h[c]
6 h
6 h[a]
6 h[a]
12 h
12 h
12 h[b]
12 h
1:1.6
[a] Rapid induction of epimerisation at 20 °C. [b] Inseparable mix-
ture. [c] With some decomposition. Standard: methyl ester (R2
Me); * ethyl ester (R2 = Et).
=
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Synthesis of Azoninones and Indolizidinones
α bridgehead C–H and α C–I configurations, indicating
highly regioselective and diastereoselective conversions
(Table 4, entries 1, 2, 4, 6, 9, and 12–21, Schemes 4 and 5).
The relative and absolute configurations of iodolactams 22b
were unambiguously proved by X-ray analysis (Figure 4).[25]
Table 4. Iodocyclisation of selected pS/pR azoninones to form
indolizidinones.[a]
Entry Reactant
Product
R3
Yield [%]
Ratio
1
2
3
4
5
6
7
8
pS-8a
22a
Cl
Cl
Cl
Cl
Cl
Cl
Ph
Ph
Cl
Cl
Cl
Cl
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Ph
Cl
60
68
93
52
51
51
75
71
83
67
65
65
54
40
68
62
68
49
65
73
62
Ͼ20:1
Ͼ20:1
42:51
Ͼ20:1
37:14
Ͼ20:1
67:8
38:33
pS-8b
22b
pR-8b
pS-8c
22b/33b
22c
22c/34
30a
pS/pR-8c (2:1)
pS-9a
pS/pR-10c (3:1) 24/25c
pR-10c
pS-12b
pS/pR-12b (1:3) 26b/27b
pR-12b
pS-12c
pS-14c
pS-16b
pS-16c
pS-16c
pS-17b
pS-17c
pS-17c
pS-19c
pS-20c
24/25c
26b
9
Ͼ20:1
15:52
10
11
12*
13*
14
15
16*
17
18
19*
20
21*
27b
26c
28c
29b
29c
29c
30b
30c
30c
31c
32c
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
[a] Standard: methyl ester (R2 = Me); * ethyl ester (R2 = Et).
Scheme 4. Transannular ring contraction to synthesise indolizidin-
ones. Conditions: i) I2, CH2Cl2, 23 °C, yield 22a: 60%, 22b: 68%,
22b/33b: 93% (42:51), 22c: 52%, 22c/34: 51% (37:14 from pS/pR-
8c 2:1), 24c/25c: 75% (67:8), 24c/25c: 71% (38:33 from pR-10c),
26b: 83%, 26b/27b: 67% (15:52 from pS/pR-12b, 1:3), 26c: 65%,
27b: 65%, 28c: 54% see Table 4.
Surprisingly, the iodocyclisations starting from selected
pR azoninones gave a somewhat different outcome (Table 4,
entries 3, 5, 7, 8, 10, and 11). The reaction of azoninone
pR-8b gave a 42:51 mixture of indolizidinones 22b and 33b
in 93% yield (Table 4, entry 3). No lactam 25b was detected,
indicating that after its formation, it must have undergone
rapid dehydroiodination to form the unsaturated ester moi-
ety in 33b. In contrast, 3-phenyllactam pR-10c delivered
iodoindolizidinones 24c and 25c in 71% yield with a ratio
of 38:33, and no HI elimination could be detected (Table 4,
entry 8). Furthermore, transannular ring contractions start-
ing from mixtures of pS/pR-8c (2:1) and pS/pR-10c (3:1)
resulted in the formation of bicycles 22c/34 (51% yield,
37:14 ratio, complete dehydrohalogenation in 34) and 24c/
25c (75% yield, 67:8 ratio), respectively (Table 4, entries 5
and 7). Despite the lower percentage of the pS lactam in
the reactant mixtures, the proportion of the corresponding
bicycles 22c/24c in the product mixtures from the ring con-
traction were found to increase. Obviously, pS/pR flipping
of the double bond and iodocyclisation could be assumed
to be competing processes under the reaction conditions,
and this could explain the formation of the observed dia-
stereomeric mixture of indolizidinones (Scheme 4).
In contrast, ring contraction of a 1:3 mixture of azon-
inones pS/pR-12b delivered a 52:15 mixture of bicycles 27b
and 26b in 67% yield, and no accompanying dehydroiodin-
ation could be observed (Table 4, entry 10). However, pure
Scheme 5. Transannular ring contraction to synthesise indolizidin-
ones. Conditions: i) I2, CH2Cl2, 23 °C, yield: 29b: 40%, 29c: 68%,
62% (R2 = Et), 30a: 51%, 30b: 68%, 30c: 49%, 65% (R2 = Et),
azoninone pR-12b underwent transannular ring contraction 31c: 73%, 32c: 62% see Table 4.
Eur. J. Org. Chem. 2014, 6272–6284
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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U. Nubbemeyer et al.
FULL PAPER
Figure 4. X-ray analysis of indolizidinone 22b.
to give indolizidinone 27b diastereoselectively in 65% yield
(Table 4, entry 11). The pS/pR arrangements of the azon-
inone double bonds in the pS/pR-12b lactams were stable
under the iodolactamization reaction conditions. Conse-
quently, the ratio of the pS/pR-12b mixture was retained in
the ratio of indolizidinone products 26b and 27b (Table 4,
entry 10), and neat pR-12b was converted into indolizid-
inone 27b. For detailed information, see Table 4 and
Scheme 4.
Mechanistic Conclusions
The reaction mechanism and stereochemical outcome of
the substrate-controlled zwitterionic aza-Claisen rearrange-
ment have been rationalised (Figures 5 and 6). Initially,
chloroacetyl fluoride or phenylacetyl fluoride and trimeth-
ylaluminium formed a Lewis-acid-activated ketene 35.[26]
The evolution of methane was always observed. Then,
ketene 35 added to the nitrogen of N-benzylpyrrolidines 6
and 7, respectively, to generate intermediate acylammonium
enolates with complete selectivity for the Z enolate geome-
try.[27] All of the rearrangements were characterised by com-
plete 1,3 chirality transfer to generate an E olefin in a pS
arrangement.
Figure 5. Mechanistic conclusions on the aza-Claisen rearrange-
ment starting from E olefins E-6 and E-7.
Analysing the transformations of E alkenes E-6 and E-
7, the configuration of the R1-substituted carbon (C-4) di-
rected the diastereoselectivity of the acylation. The C-4-α- and the pS-E-olefin moiety, with repulsive interactions.[28]
configured E-6 delivered the 1,2-syn ketene adduct, which Furthermore, heating to about 60 °C for 12 h in an inert
then rearranged via a boat-like conformation with mini- solvent induced a partial reversible flipping of the double
mised 1,3 repulsive interactions to form azoninones 8 and bond to form pR-E diastereomers pR-8/10.[29] In contrast,
10, with β-configured C–Cl and C–Ph groups, respec- the NMR spectra of lactams pS-17/19 showed a single
tively.[3a,4] In contrast, the 1,2-anti acylammonium enolate lactam conformation AЈ with a pS arrangement of the
derived from C-4-β-configured E-7 went via a favoured double bond, and further heating to 60 °C caused no pS-
chair-like conformation to give lactams 17 and 19 with α- into-pR flipping of the olefin moiety.[24] Surprisingly, lact-
configured C–Cl and C–Ph groups.[3d] Simple E-configured ams pS-17b and pS-17c were sensitive to basic conditions.
2-vinylpyrrolidine E-6a underwent a nearly equal ketene ad- Obviously, if the C-3 C–Cl bond of lactams pS-17 suffered
dition from either side to give both 1,2-syn and 1,2-anti from some epimerisation in the presence of potassium carb-
zwitterions.[5a] Consequently, both pathways were active, onate, the resulting pS-16 diastereomers might be character-
and a product mixture of pS-8a/10a and pS-9a/11a was ised by a decreased 3,4-gauche repulsive interaction within
formed (Figure 5). The NMR spectra of lactams pS-8/10 the nine-membered ring. When the rearrangement was run
revealed that most of these products showed an equilibrium in the absence of potassium carbonate, the initially formed
of at least two interconverting conformations A and B, indi- α-chlorides (i.e., pS-17) and α-phenyl derivative (i.e., pS-19)
cating a non-ideal arrangement of the stereogenic centres remained almost unchanged (Figure 5).
6278
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Eur. J. Org. Chem. 2014, 6272–6284

Synthesis of Azoninones and Indolizidinones
cally stable conformation A.[30] Ring enlargement of 2,4-
cis disubstituted vinylpyrrolidines Z-7c (R1b = OPh) should
suffer from mismatched stereodirecting substituents (β-R1
vs. Z olefin). A plausible mechanism to account for the pre-
ferred formation of lactam pS-20c involves 1,2-syn addition
directed by the Z olefin, and subsequent rearrangement via
a boat-shaped transition state to form conformer B. How-
ever, β-R1-directed 1,2-anti addition, a subsequent re-
arrangement via a chair-shaped transition state to form
conformer AЈ, and an efficient C-3 C–Cl epimerisation to
form conformer B cannot be excluded (Figure 6).
In contrast to earlier experiments that generated 3,8-di-
substituted azoninones, kinetically obtained 3,4,8-trisubsti-
tuted pS lactams pS-8–21 are not characterised by a general
instability with respect to the planar chiral arrangement of
the double bond moiety.[3a,4] In fact, the entire substitution
pattern had to be considered. In summary, kinetically ob-
tained lactams pS-9/16/17 remained stable, lactams pS-8/10
were characterised by a reversible partial flipping pS↔pR,
and lactams pS-12/14/21 underwent complete pSǞpR
transformation.[31]
When azoninones 8–20 were subjectd to iodocyclisation,
indolizidinones 22–34 were generated with selective anti ad-
ditions to the planar chiral olefin moiety. Starting from pS
azoninones, the iodine attacked the unshielded Re face of
the double bond to form an intermediate iodonium ion.
After transannular ring closure by the nitrogen lone pair of
the amide functionality, the so-formed intermediate acyl-
ammonium salt underwent immediate degradation. Finally,
benzyl iodide was removed in an SN2 reaction to give lact-
ams 22, 24, 26, and 28–32, respectively, with an α-config-
ured bridgehead proton and an adjacent C–I bond. All
other stereogenic centres remained untouched (Figure 7).
In contrast, pR lactam pR-12b suffered Si face attack by
the iodine. Transannular ring contraction and SN2 removal
Figure 6. Mechanistic conclusions on the aza-Claisen rearrange-
ment starting from Z olefins Z-6 and Z-7.
In the transformations of Z alkenes Z-6 and Z-7, the of benzyl iodide gave lactam 27b, with a β-configured
olefin geometry was more important for the diastereoselec- bridgehead proton and an adjacent C–I bond. When a mix-
tivity of the ring enlargement. In contrast to the corre- ture of pR-12b/pS-12b (ratio 52:15) was subjected to the
sponding E series, the reaction of amino ester Z-6a deliv- ring-contraction conditions, a mixture of indolizidinones
ered lactam pS-12a diastereoselectively. Obviously, the 27b/26b (ratio 52:15) was obtained with complete transfer
minimisation of the 1,3-allylic strain caused an efficient of planar chirality to central chirality.
shielding of the α face of the pyrrolidine ring by the Z-
Surprisingly, the conversion of pure azoninone pR-8b led
configured double bond.[28] So amine acylation delivered to a mixture of indolizidinones 22b/33b (via intermediate
the 1,2-syn adduct to give lactams pS-12a/14a (R1a/b = H, 23b) (ratio 1.2:1), and pR-10c gave a mixture of indolizid-
R2 = CO2Et). In addition, 2,4-trans disubstituted vinyl- inones 24c/25c (ratio 2.3:2). Furthermore, mixtures of pS/
pyrrolidines 6 (R1a ϶ H, R1b = H) with matched stereodi- pR-8c (2:1) and pS/pR-10c (3:1) resulted in indolizidinone
recting substituents (α-R1 and Z olefin) also underwent 1,2- mixtures 22c/34 (via intermediate 23c) and 24c/25c, respec-
syn ketene addition. Rearrangement via the boat-like transi- tively, showing an increased proportion of the pS-derived
tion state resulted in the generation of lactams pS-12/14 bicycles with an α-configured bridgehead proton. Such an
with β-configured C–Cl and C–Ph groups. In most cases, outcome could be rationalised by assuming comparable
the NMR spectra of these products showed an equilibrium (slower) rates of pS↔pR flipping of the olefin moiety and
of at least two interconverting conformations. The predomi- of the transannular ring contraction of the pR diastereomer
nant form B indicated a non-ideal arrangement of ste- under the reaction conditions, and a faster transannular
reogenic centres and the pS-E olefin moiety, with repulsive ring closure of the pS azoninone. Consequently, ring con-
interactions/allylic strain.[29] Consequently, heating to about traction of lactam pS-8b led to indolizidinone 22b dia-
30–40 °C (C–Ph) or 60 °C (C–Cl) induced flipping of the stereoselectively, the conversion of lactam pR-8b gave a
double bond to form the pR-E diastereomers, with signifi- mixture of indolizidinones 22b and 23b. Furthermore, the
cant relaxation of the steric repulsions in thermodynami- anti relationship of the iodide and the C-4 proton in lact-
Eur. J. Org. Chem. 2014, 6272–6284
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6279

U. Nubbemeyer et al.
FULL PAPER
Z-2-vinylpyrrolidines and 2,4-trans-disubstituted 2-vinyl-
pyrrolidines E/Z-6 and Z-7 gave β-C–Cl- and β-C–Ph-con-
figured azoninones 8–14 stereoselectively. Upon heating,
the pS arranged olefin in azoninones 8 and 10 underwent
partial flipping to generate the pR form, and azoninones
12/14 underwent complete pS-to-pR isomerisation. In con-
trast, the rearrangements starting from 2,4-trans disubsti-
tuted 2-vinylpyrrolidines E-7 gave α-C–Cl- and α-C–Ph-
configured azoninones 17 and 19 with high selectivity. Epi-
merisation of the C–Cl functionality could be induced un-
der basic conditions. Even upon heating, azoninones pS-
16, 17, and 19 had a stable pS olefin arrangement. As an
exception, the reaction of monosubstituted E-2-vinyl-
pyrrolidine 6a delivered azoninones 8a and 9a with low dia-
stereoselectivity. Finally, indolizidinones 22–34 were synthe-
sised by subjecting the azoninones to transannular iodo-
cyclisation. Generally, the anti-additions meant that the
planar chiral information of the double bond generated
α-configured C–H bridgehead groups from pS reactants
and β-C–H groups from pR azoninones, respectively.
Azoninones pR-8b/c and pR-10c delivered a mixture of
both indolizidinone series 22/23 (33/34) and 24/25, indicat-
ing that the ring contraction and pR/pS olefin flipping have
similar activation barriers.
Overall, the two-step generation of indolizidinones bear-
ing up to five stereogenic centres from simple 2-vinylpyrrol-
idines (one or two stereogenic centres) is a major advantage
of this sequence. In addition, the generation of the two
indolizidinone series with each of the two bridgehead con-
figurations starting from the same chiral pool starting mate-
rial (i.e., S-proline) recommends the strategy for further ap-
plications in the total synthesis of natural products and
drug molecules.
Figure 7. Mechanistic conclusions on the transannular ring con-
traction by iodocyclisation.
ams 23b and 23c allowed a facile (partial) dehydrohalogen-
ation to generate unsaturated lactams 33b (via indolizidi-
none 23b as an intermediate) and 34 (via indolizidinones
23c and 33c as intermediates).
In summary, the activation energy for the pS↔pR flip-
ping of the olefin moiety in most azoninones proved to be
much higher than that for the transannular ring contrac-
tion. The planar chiral olefin moiety could be used to gen-
erate indolizidinones with complete chirality transfer. In
contrast, the pR-8/10 series was characterised by a low
pS↔pR flipping activation barrier at room temperature
that enabled both competing double bond rotation and
iodocyclisation under the conditions used. Consequently, a
mixture of diastereomers was generated (Figure 7).
Experimental Section
General Remarks: When necessary, reaction solvents were dried fol-
lowing standard procedures before use. All reactions involving
moisture- or air-sensitive reagents were carried out under an argon
atmosphere. 1H , 13C, and 2D (COSY, HSQC, HMBC, NOESY)
NMR spectra were recorded at room temperature with Bruker AM
300, ARX400, AV400, AC 250, AM 270, and AMX 500 spectrome-
ters in CDCl3 using the signal of residual CHCl3 as internal stan-
dard. IR spectra were recorded with a Jasco FTIR 400 plus spec-
trometer, a Perkin–Elmer IR 257 or IR 580B spectrometer, or a
Nicolet 5SXC, 55C or AVATAR 320 FTIR spectrometer. High-
resolution mass spectra (HRMS) were recorded with a Waters Q-
Tof Ultima 3 Micromass spectrometer, or a Varian-MAT MAT 711
or MAT 112S instrument. Optical rotations were recorded with a
Perkin–Elmer P241 polarimeter, or a IBZ Messtechnik Polar-LμP
polarimeter. Column chromatography was carried out on MN sil-
ica gel 60M from Macherey–Nagel (grain size: 0.040–0.063 mm).
The progress of reactions was monitored by thin-layer chromatog-
raphy (TLC) on aluminum sheets pre-coated with 60F254 silica gel
from Merck. PE = petroleum ether, Hept = heptane, Hex = hexane,
tR = HPLC peak retention time.
Conclusions
A set of 2-vinylpyrrolidines with defined substitution
patterns and with defined configurations of stereogenic
centres and double bonds has been synthesised starting
from S-proline and 4-trans-hydroxy-S-proline. Zwitterionic
aza-Claisen rearrangements allowed the conversion of the
unsaturated amino esters into azoninones with complete 1,3
chirality transfer and the formation of a pS arranged olefin
moiety. The simple diastereoselectivity directing the config-
uration of the C–Cl or C–Ph bond (C-3) depended on the
2S,4R-(N-Benzyl)-4-phenoxyproline Methyl Ester (4c): Iodobenzene
(0.19 mL, 1.70 mmol), CuI (20.0 mg, 0.09 mmol), Cs2CO3 (0.55 g,
substitution pattern of the allylamine starting materials: 1.70 mmol), and 1,10-phenanthroline (31.0 mg, 0.17 mmol) were
6280 Eur. J. Org. Chem. 2014, 6272–6284
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Synthesis of Azoninones and Indolizidinones
3
3
3
added to a solution of N-benzyl-trans-4-hydroxy-(S)-proline methyl
ester (3; 0.20 g, 0.85 mmol) in dry toluene (5 mL). The mixture was
heated at 125 °C for 24 h, then it was cooled to room temperature.
The mixture was filtered through silica gel, which was then washed
with EtOAc (20 mL). The filtrate was concentrated, and the re-
sulting residue was purified by flash chromatography (PE/EtOAc,
6:1) to give phenyl ether 4c (38%) as a colourless oil. Rf = 0.17
(PE/EtOAc, 10:1). 1H NMR (400 MHz, CDCl3): δ = 2.30–2.44 (m,
= 9.2, J = 8.3, J = 7.9 Hz, 1 H, 4-H), 5.88 (d, J = 11.6 Hz, 1 H,
16-H), 6.21 (dd, J = 11.5, J = 8.6 Hz, 1 H, 15-H), 6.80 (t, 3J =
7.5 Hz, 2 H, 13-H), 6.86–6.91 (m, 1 H, 14-H), 7.22–7.31 (m, 7 H,
8-H, 9-H, 10-H, 12-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
38.6 (C-3), 51.3 (C-18), 58.3 (C-6), 59.7 (C-5), 64.2 (C-2), 75.0 (C-
4), 115.2 (C-12), 120.6 (C-14), 122.2 (C-16), 127.1 (C-10), 128.2 (C-
8), 128.7 (C-9), 129.4 (C-13), 138.5 (C-7), 157.5 (C-11), 166.3 (C-
3
4
17) ppm. IR: ν = 3027, 2948, 1723, 1599, 1495, 1455, 1373, 1240,
˜
2
3
2 H, 3-H), 2.66 (dd, J = 10.5, J = 4.0 Hz, 1 H, 5a-H), 3.52 (dd,
1169, 1085, 884, 754, 700, 669 cm–1. HRMS (ESI): calcd. for
C21H24NO3 [M]+ 338.1756; found 338.1763. [α]D = –67 (c = 1.20,
CH2Cl2).
3
3
2J = 10.5, J = 6.1 Hz, 1 H, 5b-H), 3.62 (t, J = 7.9 Hz, 1 H, 2-H),
2
2
3.63 (d, J = 12.8 Hz, 1 H, 8a-H), 3.68 (s, 3 H, 7-H), 3.95 (d, J =
12.9 Hz, 1 H, 8b-H), 4.88 (ddd, J = 10.2, J = 6.9, J = 3.7 Hz, 1
3
3
3
Standard Procedure B: Ando Reaction: Ethyl(diphenylphosphono)
acetate (24 mmol) in dry THF (130 mL) was slowly added to a
suspension of NaH (80% dispersion in mineral oil; 36 mmol) in
dry THF (130 mL) at –78 °C with stirring. After 0.5 h, a freshly
prepared solution of the aldehyde (26 mmol) in dry THF (50 mL)
was added. The reaction mixture was stirred for 12 h, during which
time it was allowed to warm up to room temperature. The reaction
was then stopped by the addition of saturated aqueous NH4Cl
(170 mL), and the mixture was extracted with diethyl ether (3ϫ).
The combined organic phases were washed with saturated aqueous
NaHCO3 and brine, dried (MgSO4), and concentrated under vac-
uum. The crude unsaturated ester was purified by flash chromatog-
raphy (formation of the ethyl ester!).
3
4
3
H, 4-H), 6.81 (dd, J = 8.7, J = 0.9 Hz, 2 H, 14-H), 6.93 (t, J =
7.4 Hz, 1 H, 16-H), 7.24–7.35 (m, 7 H, 10-H, 11-H, 12-H, 15-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 36.9 (C-3), 51.9 (C-7), 58.6
(C-8), 58.9 (C-5), 64.2 (C-2), 75.0 (C-4), 115.2 (C-14), 120.9 (C-16),
127.3 (C-12), 128.3 (C-10), 129.1 (C-11), 129.5 (C-15), 137.8 (C-9),
157.3 (C-13), 173.6 (C-6) ppm. IR: ν = 3027, 2947, 1737, 1599,
˜
1495, 1455, 1374, 1241, 1173, 1087, 913, 750, 692, 667 cm–1. HRMS
(ESI): calcd. for C19H22NO3 [M]+ 312.1600; found 312.1595. [α]D
= –58 (c = 1.00, CH2Cl2).
Standard Procedure A for Horner Olefination: Trimethylphos-
phonoacetate (11 mmol) in dry CH2Cl2 (5 mL) was slowly added
to a suspension of NaH (60% dispersion in mineral oil; 11 mmol)
in dry THF (50 mL) at 0 °C with stirring. After 1 h, a freshly pre-
pared solution of the aldehyde (5 mmol) in dry THF (10 mL) was
added. The reaction mixture was stirred for 12 h, during which time
it was allowed to warm up to room temperature. The reaction was
then stopped by the addition of water (70 mL), and the mixture
was extracted with diethyl ether (3ϫ). The combined organic
phases were washed with brine (2ϫ), dried (MgSO4), and concen-
trated under vacuum. The crude unsaturated ester was purified by
flash chromatography.
2S,4S-(N-Benzyl)-2-(E-ethoxycarbonylethenyl)-4-phenoxy-pyrrol-
idine (E-7c Ethyl Ester) and 2S,4S-(N-Benzyl)-2-(Z-ethoxycarbonyl-
ethenyl)-4-phenoxypyrrolidine (Z-7c Ethyl Ester): Reaction between
aldehyde 5cЈЈ (6.0 g, 21.0 mmol) and ethyldiphenylphosphonoacet-
ate (9.0 g, 28.0 mmol) following standard procedure B. Purification
by column chromatography (PE/EtOAc, 5:1) gave a mixture (25:65)
of E-7c/Z-7c ethyl esters (90%). The mixture was separated by
HPLC [Nucleosil 50–5 (ID 32 ϫ 238 mm), (Hex/EtOAc, 5.7:1),
100 mL/min, 16.2 MPa, tR = 0.9 min (Z-7c ethyl ester), tR
=
1.4 min (E-7c ethyl ester)] to give Z-7c ethyl ester (65 %) as a
colourless solid.
2S,4R-(N-Benzyl)-2-(E-methoxycarbonyl-ethenyl)-4-phenoxypyrrol-
idine (E-6c) and 2S,4R-(N-Benzyl)-2-(Z-methoxycarbonyl-ethenyl)-
4-phenoxypyrrolidine (Z-6c): Reaction between N-benzyl-trans-
4-phenoxy-(S)-prolinal (0.28 g, 1.00 mmol) and trimethylphos-
phonoacetate (0.30 mL, 2.09 mmol) following standard procedure
A. Ratio E-6c/Z-6c about 5:1. Separation and purification by col-
umn chromatography (PE/EtOAc, 6:1) gave E-6c (41%) as a yellow
Data for Z-7c ethyl ester: Rf = 0.5 (PE/EtOAc, 5:1), m.p. 104 °C.
3
1H NMR (400 MHz, CDCl3): δ = 1.31 (t, J = 7.1 Hz, 3 H, 19-H),
1.79–1.87 (m, 1 H, 3a-H), 2.53–2.60 (m, 1 H, 5a-H), 2.70–2.79 (m,
1 H, 3b-H), 3.20 (d, 3J = 10.9 Hz, 1 H, 5b-H), 3.34 (d, 2J = 13.0 Hz,
1 H, 6a-H), 3.94 (d, 2J = 13.3 Hz, 1 H, 6b-H), 4.19 (q, 3J = 7.1 Hz,
3
3
1
2 H, 18-H), 4.24 (m, 1 H, 2-H), 4.79 (dd, J = 10.3, J = 6.4 Hz, 1
H, 4-H), 5.86 (dd, 3J = 11.6, 4J = 0.9 Hz, 1 H, 16-H), 6.36–6.43
(m, 1 H, 15-H), 6.81 (d, 3J = 7.8 Hz, 1 H, 12-H), 6.91 (t, 3J =
7.4 Hz, 1 H, 14-H), 7.19–7.36 (m, 7 H, 8-H, 9-H, 10-H, 13-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.4 (C-19), 39.0 (C-3), 58.7 (C-
6), 59.6 (C-5), 60.3 (C-18), 61.5 (C-2), 75.5 (C-4), 115.4 (C-12),
120.7 (C-14), 121.4 (C-16), 127.2 (C-10), 128.4 (C-8), 129.1 (C-9),
129.5 (C-13), 138.5 (C-7), 151.6 (C-15), 157.8 (C-11), 166.3 (C-17)
oil. Rf = 0.37 (PE/EtOAc, 6:1). H NMR (400 MHz, CDCl3): δ =
2.08 (ddd, 2J = 13.7, 3J = 10.0, 3J = 7.1 Hz, 1 H, 3a-H), 2.21 (ddd,
3
3
2
2J = 13.5, J = 6.4, J = 1.9 Hz, 1 H, 3b-H), 2.45 (dd, J = 10.7,
3J = 4.3 Hz, 1 H, 5a-H), 3.29 (d, 2J = 13.1 Hz, 1 H, 6a-H), 3.46
(dd, 3J = 13.1, 3J = 5.7 Hz, 1 H, 2-H), 3.51 (dd, 2J = 10.8, 3J =
6.3 Hz, 1 H, 5b-H), 3.76 (s, 3 H, 18-H), 3.98 (d, 2J = 13.1 Hz, 1 H,
3
3
3
6b-H), 4.80 (tdd, J = 6.4, J = 4.3, J = 1.8 Hz, 1 H, 4-H), 6.08
(dd, 3J = 15.7, 4J = 0.6 Hz, 1 H, 16-H), 6.79 (dd, 3J = 8.7, 4J =
3
3
ppm. IR: ν = 2979, 2794, 1716, 1647, 1600, 1494, 1372, 1240, 1192,
˜
0.9 Hz, 2 H, 12-H), 6.90 (dd, J = 16.3, J = 8.5 Hz, 1 H, 15-H),
1027, 825, 981, 753, 694 cm–1. HRMS (ESI): calcd. for C22H26NO3
3
6.93 (t, J = 7.4 Hz, 1 H, 14-H), 7.24–7.31 (m, 7 H, 8-H, 9-H, 10-
[M + H]+ 352.1913; found 352.1901. [α]D = –72 (c = 1.0, CH2Cl2).
H, 13-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 39.4 (C-3), 51.6
(C-18), 58.3 (C-6), 59.7 (C-5), 64.2 (C-2), 74.8 (C-4), 115.1 (C-12),
120.8 (C-14), 122.5 (C-16), 127.1 (C-10), 128.3 (C-8), 128.7 (C-9),
Standard Procedure C for an Aza-Claisen Rearrangement: K2CO3
(40 mmol) was suspended in dry CH2Cl2 (100 mL), and allylamine
6/7 (10 mmol) and a solution of freshly prepared chloroacetyl
fluoride (50 mmol) in dry CH2Cl2 (75 mL) were added at 0 °C.
Then, trimethylaluminium (2 m in heptane; 50 mmol) was added
dropwise, with stirring. Methane was evolved, and the mixture was
stirred for 12 h, during which time the temperature slowly reached
23 °C. The reaction was stopped by the careful dropwise addition
of water until the remaining trimethylaluminium was hydrolysed.
129.5 (C-13), 138.5 (C-7), 157.3 (C-11), 166.7 (C-17) ppm. IR: ν =
˜
3025, 2946, 1724, 1599, 1495, 1454, 1362, 1240, 1169, 1085, 889,
770, 775, 693, 668 cm–1. HRMS (ESI): calcd. for C21H24NO3 [M]+
338.1756; found 338.1759. [α]D = –72 (c = 1.10, CH2Cl2).
And Z-6c (8%) as a yellow oil. Rf = 0.27 (PE/EtOAc, 6:1). 1H
NMR (400 MHz, CDCl3): δ = 1.94–2.02 (m, 1 H, 3a-H), 2.18–2.24
2
(m, 1 H, 3b-H), 2.42–2.49 (m, 1 H, 5a-H), 3.35 (d, J = 13.0 Hz, 1
H, 6a-H), 3.45–3.52 (m, 1 H, 5b-H), 3.73 (s, 3 H, 18-H), 3.92 (d, The resulting suspension was dried (MgSO4), and then filtered
2J = 13.0 Hz, 1 H, 6b-H), 4.77–4.82 (m, 1 H, 2-H), 4.88 (ddd, 3J through MgSO4. The filtrate was washed with saturated aqueous
Eur. J. Org. Chem. 2014, 6272–6284
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6281

U. Nubbemeyer et al.
FULL PAPER
NaHCO3 (2 ϫ) and brine (1 ϫ). The combined aqueous phases
were reextracted with diethyl ether (3ϫ). The combined organic
phases were dried (MgSO4) and concentrated under vacuum. The
crude azoninone 8–13 was purified by flash chromatography.
(C-4), 49.5 (C-10), 49.9 (C-9), 55.2 (C-3), 61.2 (C-20), 71.8 (C-8),
115.8 (C-23), 121.6 (C-25), 129.4 (C-6), 127.7 (C-14), 127.9 (C-18),
128.1 (C-12), 128.4 (C-13), 128.6 (C-17), 128.9 (C-24), 129.2 (C-
16), 132.2 (C-5), 137.2 (C-11), 137.7 (C-15), 157.0 (C-21), 171.0 (C-
19), 173.2 (C-2) ppm. IR: ν = 3029 (w), 2933 (w), 1729 (s), 1637
˜
(pS) E-3R,4S,8R-N-Benzyl-3-chloro-4-methoxycarbonyl-8-(phen-
oxy)-2,3,4,7,8,9-hexahydro-1H-azonin-2-one (pS-8c): Reaction be-
tween allylamine E-6c (0.11 g, 0.33 mmol) and chloroacetyl fluor-
ide (0.12 mL, 1.63 mmol) following standard procedure C. Purifica-
tion by column chromatography (PE/EtOAc, 6:1) gave pS-8c (64%)
as a yellow oil. Rf = 0.38 (PE/EtOAc, 4:1). 1H NMR (400 MHz,
CDCl3, amide conformation A): δ = 2.51 (dd, 2J = 11.4, 3J =
(s), 1597 (m), 1451 (m), 1225 (s), 1157 (s), 1033 (m), 942 (w), 752
(s), 695 cm–1. HRMS (ESI): calcd. for C30H31NO4Na [M + Na]+
492.2151; found 492.2163. [α]D = –115 (c = 1.03, CH2Cl2).
(pS) E-3S,4R,8S-N-Benzyl-3-chloro-4-ethoxycarbonyl-8-(phenoxy)-
2,3,4,7,8,9-hexahydro-1H-azonin-2-one (pS-20c) and (pS) E-
3R,4R,8S-N-Benzyl-4-ethoxycarbonyl-8-(phenoxy)-3-phenyl-
2,3,4,7,8,9-hexahydro-1H-azonin-2-one (pS-21c): Reaction between
allylamine Z-7c (4.0 g, 11.38 mmol) and chloroacetyl fluoride
(4.8 mL, 79.6 mmol) following standard procedure C. Purification
by column chromatography (PE/EtOAc, 8:1) gave pS-20c (68%) as
a pale yellow oil, and pS-21c (10%) as a pale yellow oil.
2
3
6.0 Hz, 1 H, 7a-H), 2.77 (dd, J = 13.5, J = 4.1 Hz, 1 H, 7b-H),
2
3
3.59 (dd, J = 15.4, J = 5.0 Hz, 1 H, 9a-H), 3.81 (s, 3 H, 20-H),
3
3
2
3.89 (dd, J = 9.5, J = 2.3 Hz, 1 H, 4-H), 4.50 (d, J = 15.4 Hz, 1
2
3
H, 10a-H), 4.69 (d, J = 15.4 Hz, 1 H, 9b-H), 4.88 (t, J = 5.3 Hz,
1 H, 8-H), 5.43 (d, J = 2.5 Hz, 1 H, 3-H), 5.46 (d, J = 15.6 Hz,
3
2
3
3
3
1
1 H, 10b-H), 5.99 (ddd, J = 15.8, J = 11.2, J = 4.2 Hz, 1 H, 6-
Data for pS-20c. Rf = 0.3 (PE/EtOAc, 5:1). H NMR (400 MHz,
H), 6.15 (dd, 3J = 16.0, 3J = 9.6 Hz, 1 H, 5-H), 6.90 (d, 3J = 7.9 Hz,
3
CDCl3): δ = 1.31 (t, J = 7.1 Hz, 3 H, 21-H), 2.31–2.42 (m, 1 H,
3
3
2
3
7-Hβ), 3.07 (dd, J = 13.2, J = 7.6 Hz, 1 H, 7-Hα), 3.57–3.62 (m,
2 H, 16-H), 7.01 (t, J = 7.4 Hz, 1 H, 18-H), 7.13 (d, J = 7.0 Hz,
2 H, 17-H), 7.28–7.35 (m, 5 H, 12-H, 13-H, 14-H); (amide confor-
mation B): 2.32–2.33 (m, 1 H, 7a-H), 2.47 (dd, 2J = 11.4, 3J =
6.2 Hz, 1 H, 7b-H), 3.38 (dd, J = 15.2, J = 4.1 Hz, 1 H, 9a-H),
3.79–3.80 (m, 1 H, 9b-H), 3.83–3.85 (m, 1 H, 4-H), 3.85 (s, 3 H,
20-H), 4.45 (d, 2J = 14.6 Hz, 1 H, 10a-H), 4.61–4.65 (m, 1 H, 8-
1 H, 4-H), 3.65 (d, J = 16.2 Hz, 1 H, 9-Hβ), 3.81–3.95 (m, 2 H, 9-
2
Hα), 4.20–4.33 (m, 2 H, 20-H), 4.38 (d, J = 14.2 Hz, 1 H, 10a-H),
2
2
3
3
4.63–4.70 (m, 1 H, 8-H), 5.14 (d, J = 9.8 Hz, 1 H, 3-H), 5.60 (dd,
2J = 14.2, J = 1.1 Hz, 1 H, 10b-H), 5.78–5.91 (m, 2 H, 5-H, 6-H),
4
3
3
6.92 (d, J = 7.8 Hz, 2 H, 16-H), 7.01 (t, J = 7.4 Hz, 1 H, 18-H),
7.21–7.27 (m, 5 H, 12-H, 13-H, 14-H), 7.28–7.34 (m, 2 H, 17-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2 (C-21), 36.2 (C-7), 48.8
(C-9), 49.7 (C-10), 50.4 (C-4), 57.0 (C-3), 61.9 (C-20), 74.4 (C-8),
115.8 (C-16), 122.0 (C-18), 127.6 (C-14), 128.6 (C-13), 129.0 (C-
12), 129.4 (C-5 or C-6), 129.9 (C-17), 130.2 (C-5 or C-6), 136.8 (C-
2
3
H), 4.94 (d, J = 15.1 Hz, 1 H, 10b-H), 5.08 (d, J = 7.9 Hz, 1 H,
3-H), 5.87–5.90 (m, 2 H, 5-H, 6-H), 6.76 (d, J = 7.9 Hz, 2 H, 16-
3
3
3
H), 6.99 (t, J = 7.1 Hz, 1 H, 18-H), 7.22 (d, J = 7.1 Hz, 2 H, 17-
H), 7.29–7.32 (m, 5 H, 12-H, 13-H, 14-H) ppm. 13C NMR
(100 MHz, CDCl3, amide conformation A): δ = 38.0 (C-7), 48.2
(C-9), 50.0 (C-4), 52.7 (C-20), 53.4 (C-10), 66.5 (C-3), 79.4 (C-8),
115.6 (C-16), 121.6 (C-18), 127.2 (C-17), 128.3 (C-13), 128.5 (C-5),
129.5 (C-12), 129.5 (C-14), 133.3 (C-6), 137.4 (C-11), 156.5 (C-15),
169.3 (C-2), 169.7 (C-19); (amide conformation B): 34.1 (C-7), 50.1
(C-10), 50.5 (C-4), 50.6 (C-9), 52.3 (C-20), 56.1 (C-3), 71.9 (C-8),
115.8 (C-16), 121.8 (C-18), 127.0 (C-17), 127.9 (C-13), 128.7 (C-
12), 128.8 (C-14), 129.4 (C-5), 131.5(C-6), 136.8 (C-11), 156.5 (C-
11), 156.7 (C-15), 169.0 (C-2), 170.0 (C-19) ppm. IR: ν = 3030,
˜
2935, 1732, 1647, 1597, 1492, 1422, 1374, 1222, 1172, 1063, 1013,
753, 695 cm–1. HRMS (ESI): calcd. for C24H26NO4ClNa [M +
Na]+ 450.1448; found 450.1450. [α]D = 19.0 (c = 1.0, CH2Cl2).
1
Data for pS-21c. Rf = 0.2 (PE/EtOAc, 5:1). H NMR (400 MHz,
3
2
CDCl3): δ = 1.34 (t, J = 7.1 Hz, 3 H, 21-H), 2.18 (td, J = 11.8,
3J = 9.2 Hz, 1 H, 7-Hβ), 3.07–3.15 (m, 1 H, 7-Hα), 3.28 (d, 2J =
14.4 Hz, 1 H, 9-Hα), 3.70–3.80 (m, 2 H, 4-H, 9-Hβ), 4.19–4.38 (m,
3 H, 10a-H, 20-H), 4.56 (dd, 3J = 16.4, 3J = 8.5 Hz, 1 H, 8-H),
15), 166.7 (C-2), 168.9 (C-19) ppm. IR: ν = 3031, 2953, 1739, 1657,
˜
1621, 1597, 1494, 1231, 1169, 1028, 913, 750, 695, 640 cm–1. HRMS
(ESI): calcd. for C23H24NO4NaCl [M + Na]+ 436.1292; found
436.1290. [α]D = –45 (c = 0.85, CH2Cl2).
3
2
4.82 (d, J = 3.6 Hz, 1 H, 3-H), 5.03 (d, J = 14.7 Hz, 1 H, 10b-
H), 5.75 (dd, 3J = 16.1, 3J = 6.2 Hz, 1 H, 5-H), 6.31 (ddd, 3J =
16.1, 3J = 12.2, 3J = 3.7 Hz, 1 H, 6-H), 6.85 (dd, 3J = 8.7, 4J =
0.9 Hz, 2 H, 16-H), 7.02–7.08 (m, 1 H, 18-H), 7.09–7.11 (m, 2 H,
13-H), 7.21–7.28 (m, 3 H, 12-H, 14-H), 7.28–7.34 (m, 2 H, 17-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4 (C-21), 39.8 (C-7), 50.5
(C-10), 51.1 (C-4), 52.4 (C-9), 57.5 (C-3), 61.5 (C-20), 75.2 (C-8),
117.3 (C-16), 122.6 (C-18), 127.7 (C-5), 128.5 (C-12), 128.6 (C-13),
128.8 (C-14), 130.0 (C-17), 132.5 (C-6), 137.1 (C-11), 157.1 (C-15),
Standard Procedure D: Same procedure as described for Standard
Procedure C, but without K2CO3.
(pS) E-3S,4S,8R-N-Benzyl-4-ethoxycarbonyl-8-(phenoxy)-3-phenyl-
2,3,4,7,8,9-hexahydro-1H-azonin-2-one (pS-14c): Reaction between
allylamine Z-6c (ethyl ester; 300 mg, 0.85 mmol) and phenylacetyl
fluoride (648 mg, 4.69 mmol) following standard procedure D. Pu-
rification by column chromatography (PE/EtOAc, 5:1) and HPLC
[Nucleosil 50–5 (ID 32ϫ250 mm), (Hex/EtOAc, 17:3), 64 mL/min,
68 bar, tR = 4.56 min] gave pS-19c (70%) as a yellow solid. Rf =
165.9 (C-2), 168.1 (C-19) ppm. IR: ν = 3029, 2930, 1736, 1650,
˜
1597, 1492, 1415, 1222, 1179, 1043, 753, 695 cm–1. HRMS (ESI):
calcd. for C24H27NO4Cl [M + H]+ 428.1629; found 428.1636. [α]D
= 107.0 (c = 0.5, CH2Cl2).
1
0.3 (PE/EtOAc, 5:1), m.p. 113 °C. H NMR (400 MHz, CDCl3): δ
3
2
3
= 1.11 (t, J = 7.1 Hz, 3 H, 21-H), 2.11 (ddd, J = 13.8, J = 11.8,
Standard Procedure E for a Transannular Ring Contraction: A solu-
tion of azoninone 8–20 (1.0 mmol) in dry CH2Cl2 (20 mL) was
treated dropwise with a solution of iodine (1.1 mmol) in dry
CH2Cl2 until the colour of unreacted iodine remained. The mixture
was stirred for a further 15 min at 23 °C to achieve complete con-
version. Then, the excess iodine was destroyed by adding saturated
aqueous Na2S2O3. The organic phase was dried (MgSO4), and con-
centrated under vacuum. The residue was purified by flash
chromatography.
3J = 5.9 Hz, 1 H, 7β-H), 2.58 (dd, J = 13.8, J = 3.4 Hz, 1 H, 7α-
2
3
H), 3.46 (dd, 2J = 14.9, 3J = 4.7 Hz, 1 H, 9β-H), 3.83 (dd, 3J =
3
3
3
10.7, J = 7.3 Hz, 1 H, 4-H), 4.13 (td, J = 7.2, J = 3.4 Hz, 2 H,
2
3
2
20-H), 4.35 (dd, J = 14.9, J = 10.0 Hz, 1 H, 9α-H), 4.52 (d, J =
14.7 Hz, 1 H, 10α-H), 4.67–4.74 (m, 1 H, 8-H) 4.71 (d, 3J =
2
10.7 Hz, 1 H, 3-H), 4.84 (d, J = 14.7 Hz, 1 H, 10β-H), 5.86 (dd,
3J = 16.4, J = 7.3 Hz, 1 H, 5-H), 6.18–6.28 (m, 1 H, 6-H), 6.75
3
3
3
(d, J = 7.8 Hz, 2 H, 23-H), 6.96 (t, J = 6.1 Hz, 1 H, 25-H), 7.19
(d, J = 2.1 Hz, 2 H, 14-H, 18-H), 7.19–7.23 (m, 2 H, 12-H), 7.21–
3
3
7.36 (m, 6 H, 13-H, 17-H, 24-H), 7.48 (d, J = 7.1 Hz, 2 H, 16-H) 2R,6R,7S,8R,8aS-6-Chloro-8-iodo-7-methoxycarbonyl-2-phenoxy-
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (C-21), 34.6 (C-7), 48.7 indolizidin-5-one (22c): Reaction between azoninone pS-8c
6282
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6272–6284

Synthesis of Azoninones and Indolizidinones
25–28; c) A. Sudau, U. Nubbemeyer, Angew. Chem. Int. Ed.
1998, 37, 1140–1143; Angew. Chem. 1998, 110, 1178–1181; d)
M. Diederich, U. Nubbemeyer, Chem. Eur. J. 1996, 2, 894–900;
e) M. Diederich, U. Nubbemeyer, Angew. Chem. Int. Ed. Engl.
1995, 34, 1026–1028; Angew. Chem. 1995, 107, 1095–1098.
A. Sudau, W. Münch, U. Nubbemeyer, J.-W. Bats, Chem. Eur.
J. 2001, 7, 611–621.
a) A. Sudau, W. Münch, U. Nubbemeyer, J.-W. Bats, Eur. J.
Org. Chem. 2002, 3304–3314; b) A. Sudau, W. Münch, U. Nub-
bemeyer, J.-W. Bats, Eur. J. Org. Chem. 2002, 3315–3325.
(75.0 mg, 0.18 mmol) and iodine (47.0 mg, 0.20 mmol) following
standard procedure E. Purification by column chromatography
(PE/EtOAc, 2:1) gave indolizidinone 22c (52%) as a white solid. Rf
= 0.16 (PE/EtOAc, 3:1), m.p. 175 °C; 1H NMR (400 MHz, CDCl3):
2
3
3
δ = 1.94 (ddd, J = 13.3, J = 11.3, J = 4.9 Hz, 1 H, 7a-H), 2.84
[4]
[5]
2
3
3
3
(dd, J = 13.2, J = 4.5 Hz, 1 H, 7b-H), 3.64 (dd, J = 11.3, J =
2
4.9 Hz, 1 H, 4-H), 3.82 (s, 3 H, 15-H), 3.85 (d, J = 14.2 Hz, 1 H,
2
3
3
9a-H), 4.13 (dd, J = 13.5, J = 7.9 Hz, 1 H, 9b-H), 4.18 (t, J =
11.1 Hz, 1 H, 5-H), 4.26 (td, 3J = 11.1, 3J = 4.5 Hz, 1 H, 6-H),
4.57 (d, 3J = 4.9 Hz, 1 H, 3-H), 4.94 (t, 3J = 5.0 Hz, 1 H, 8-H),
6.84 (dd, J = 8.7, J = 0.9 Hz, 2 H, 11-H), 7.00 (t, J = 7.0 Hz, 1
H, 13-H), 7.30 (dd, 3J = 8.6, 3J = 7.4 Hz, 2 H, 12-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 17.6 (C-5), 40.8 (C-7), 52.9 (C-15),
53.9 (C-9), 54.3 (C-3), 54. (C-4), 64.0 (C-6), 71.8 (C-8), 115.5 (C-
11), 121.9 (C-13), 129.9 (C-12), 156.5 (C-10), 162.8 (C-2), 167.9 (C-
[6]
[7]
M. Diederich, U. Nubbemeyer, Synthesis 1999, 286–289.
a) E. D. Edstrom, J. Am. Chem. Soc. 1991, 113, 6690–6692; b)
E. D. Edstrom, Tetrahedron Lett. 1991, 32, 5709–5712.
3
4
3
[8]
a) E. A. Ilardi, C. E. Stivala, A. Zakarian, Chem. Soc. Rev.
2009, 38, 3133–3148; b) U. Nubbemeyer, in: The Claisen Rear-
rangment (Eds.: M. Hiersemann, U. Nubbemeyer), Wiley-
VCH, Weinheim, Germany, 2007, p. 461–515; c) U. Nubbeme-
yer, Synthesis 2003, 961–1008; d) U. Nubbemeyer, in: Topics in
Current Chemistry, vol. 216: Stereoselective Heterocyclic Syn-
thesis III (Ed.: P. Metz), Springer, Berlin/Heidelberg, 2001, p.
125–196.
14) ppm. IR: ν = 3083, 2978, 1742, 1664, 1488, 1289, 1230, 1099,
˜
913, 751, 689, 652 cm–1. HRMS (ESI): calcd. for C16H17NO4NaClI
[M + Na]+ 338.1756; found 471.9789. [α]D = 68 (c = 0.80, CH2Cl2).
2R,6S,7S,8R,8aS-8-Iodo-7-methoxycarbonyl-2-phenoxy-6-phenyl-
indolizidin-5-one (28c): Reaction between azoninone pS-14c
(141 mg, 0.30 mmol) and iodine (85.0 mg, 0.33 mmol) following
standard procedure E. Purification by column chromatography
(PE/EtOAc, 1:1) gave 28c (54%) as a colourless oil. Rf = 0.16 (PE/
EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 1.34 (t, 2J = 7.1 Hz,
[9]
[10]
J. H. Cooley, E. J. Evain, Synthesis 1989, 1–7.
a) T. Sato, T. Mori, T. Sugiyama, H. Ishibashi, M. Ikeda, Het-
erocycles 1994, 37, 245–248; b) A. G. M. Barett, D. Pilipauskas,
J. Org. Chem. 1990, 55, 5194–5196.
[11]
3: a) T. Rosen, S. W. Fesik, D. T. W. Chu, A. G. Pernet, Synthe-
sis 1988, 40–44; b) T. Rosen, D. T. W. Chu, I. M. Lico, P. B.
Fernandez, K. Marsh, L. Shen, V. G. Cepa, A. G. Pernet, J.
Med. Chem. 1988, 31, 1598–1611; c) C. Concellon, T. Gal-
lagher, D. Gray, J. Org. Chem. 2004, 69, 4849–4851; d) E. Alza,
S. Sayalero, P. Kasaplar, D. Almasi, M. A. Pericas, Chem. Eur.
J. 2011, 17, 11585–11595; e) A. Cochi, D. G. Pardo, J. Cossy,
Eur. J. Org. Chem. 2012, 2023–2040. 4a: f) C. B. von Bucher,
A. Linden, H. Heimgartner, Helv. Chim. Acta 1995, 78, 935–
946; g) M. T. Rispens, O. J. Gelling, A. H. M. de Vries, A.
Meetsma, F. van Bolhuis, B. L. Feringa, Tetrahedron 1996, 52,
3521–3546; h) W. A. J. Starmans, R. W. A. Walgers, L. Thijs,
R. de Gelder, J. M. M. Smits, B. Zwanenburg, Tetrahedron
1998, 54, 4991–5004.
a) TBS: E. Vedejs, N. Lee, J. Am. Chem. Soc. 1995, 117, 891–
900; b) R. Roudeau, D. G. Pardo, J. Cossy, Tetrahedron 2006,
62, 2388–2394; c) MOM: R. Tamura, K. Watabe, N. Ono, Y.
Yamamoto, J. Org. Chem. 1992, 57, 4895–4903.
a) M. Wolter, G. Nordmann, G. E. Job, S. L. Buchwald, Org.
Lett. 2002, 4, 973–976; b) M. Toumi, V. Rincheval, A. Young,
D. Gergeres, E. Turos, F. Couty, B. Mignotte, G. Evano, Eur.
J. Org. Chem. 2009, 3368–3386.
a) H. Nakano, K. Takahashi, Y. Okuyama, C. Senoo, N. Tsu-
gawa, Y. Suzuki, R. Fujita, K. Sasaki, C. Kabuto, J. Org.
Chem. 2004, 69, 7092–7100; b) J. A. Comez-Vidal, R. B. Sil-
verman, Org. Lett. 2001, 3, 2481–2484; c) B. Bellier, I. McCort-
Tranchepain, B. Ducos, S. Danascimento, H. Meudal, J. Med.
Chem. 1997, 40, 3947–3956; d) K. G. Rajeev, G. J. Sanjayan,
K. N. Ganesh, J. Org. Chem. 1997, 62, 5169–5173; e) D. J. Raw-
son, D. Brugier, A. Harrison, J. Hough, J. Newman, J. Otter-
burn, G. N. Maw, J. Price, L. R. Thompson, P. Turnpenny,
A. N. Warren, Bioorg. Med. Chem. Lett. 2011, 21, 3767–3770.
a) A. Cochi, D. Gomez Pardo, J. Cossy, Org. Lett. 2011, 13,
4442–4445; b) H. Marusawa, H. Setoi, A. Sawada, A. Kuroda,
J. Seki, M. Yukio, H. Tanaka, Bioorg. Med. Chem. 2002, 10,
1399–1416.
2
3
3
3 H, 16-H), 1.86 (ddd, J = 13.2, J = 11.6, J = 5.1 Hz, 1 H, 7β-
H), 2.75 (dd, 2J = 13.1, 3J = 4.8 Hz, 1 H, 7α-H), 3.90 (d, 2J =
14.1 Hz, 1 H, 9α-H), 3.33 (dd, 3J = 4.8, 3J = 2.1 Hz, 1 H, 4-H),
2
3
4.12 (q, J = 7.1 Hz, 2 H, 15-H), 4.05 (t, J = 5.5 Hz, 1 H, 5-H),
3
3
2
3
4.28 (dd, J = 7.2, J = 1.9 Hz, 1 H, 3-H), 4.31 (dd, J = 5.4, J =
1.6 Hz, 1 H, 9β-H), 4.68 (td, 3J = 11.3, 3J = 4.8 Hz, 1 H, 6-H),
3
3
4.98 (t, J = 5.3 Hz, 1 H, 8-H), 6.88 (d, J = 7.6 Hz, 2 H, 18-H),
3
3
6.99 (t, J = 7.4 Hz, 1 H, 20-H), 7.13 (d, J = 5.3 Hz, 2 H, 11-H),
7.28–7.37 (m, 5 H, 12-H, 13-H, 19-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.4 (C-16), 41.8 (C-7), 50.9 (C-5), 53.4 (C-9), 55.6
(C-4), 60.2 (C-6), 60.5 (C-15), 61.8 (C-3), 72.0 (C-8), 115.6 (C-18),
121.6 (C-20), 127.7 (C-13), 128.1 (C-11), 129.2 (C-12), 129.8 (C-
19), 139.8 (C-10), 156.8 (C-17), 166.5 (C-2), 171.1 (C-14) ppm. IR:
[12]
[13]
[14]
ν = 2951, 1738, 1630, 1490, 1290, 1228, 1096, 905, 760, 696 cm–1.
˜
HRMS (ESI): calcd. for C23H24NO4I [M + H]+ 506.0826; found
506.0892. [α]D = –15 (1.04, CH2Cl2).
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data, NOE data and copies of 1H and 13C NMR
spectra for new compounds.
Acknowledgments
This work was supported by the Naturstoffzentrum Rheinland-
Pfalz, University of Mainz, Germany. The authors are grateful for
helpful discussions and financial aid.
[1] a) J. P. Michael, Nat. Prod. Rep. 2008, 25, 139–165; b) J. P.
Michael, Nat. Prod. Rep. 2007, 24, 191–222 and previous arti-
cles in this series; c) S. V. Pronin, M. G. Tabor, D. J. Jansen,
R. A. Shenvi, J. Am. Chem. Soc. 2012, 134, 2012–2015; d) S. P.
Marsden, A. D. McElhinney, Beilstein J. Org. Chem. 2008, 4,
No. 8, DOI: 10.1186/1860–5397–4–8.
[2] a) J. W. Daly, T. F. Spande, H. M. Garraffo, J. Nat. Prod. 2005,
68, 1556–1575; b) P. L. Katavic, D. A. Venables, P. I. Forster,
G. Guymer, A. R. Carroll, J. Nat. Prod. 2006, 69, 1295–1299;
c) P. A. Evans, A. B. Holmes, Tetrahedron 1991, 47, 9131–9166.
[3] a) A. Sudau, W. Münch, U. Nubbemeyer, J.-W. Bats, J. Org.
Chem. 2000, 65, 1710–1720; b) S. Laabs, A. Scherrmann, A.
Sudau, M. Diederich, C. Kierig, U. Nubbemeyer, Synlett 1999,
[15]
[16]
a) E. Winterfeldt, Synthesis 1975, 617–630; b) K. Thai, L.
Wang, M. Gravel, T. Dudding, F. Bilodeau, Org. Lett. 2010,
12, 5708–5711. For additional references, and data concerning
the intermediate carbinols and aldehydes, see the Supporting
Information.
[17]
a) G. H. Fülep, C. E. Hoesl, G. Höfner, K. T. Wanner, Eur. J.
Med. Chem. 2006, 41, 809–827; b) A. Mishra, S. Batra, Eur. J.
Org. Chem. 2010, 4832–4840, and ref.[3]
.
Eur. J. Org. Chem. 2014, 6272–6284
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6283

U. Nubbemeyer et al.
FULL PAPER
[18] a) H. Kogen, T. Nishi, J. Chem. Soc., Chem. Commun. 1987,
311–312; b) H. Kogen, H. Kadokawa, M. Kurabayashi, J.
Chem. Soc., Chem. Commun. 1990, 1240–1241; c) C. Grison,
S. Geneve, E. Halbin, P. Coutrot, Tetrahedron 2001, 57, 4903–
4924; d) K. Ando, J. Org. Chem. 1997, 62, 1934–1939.
[19] a) G. A. Olah, S. Kuhn, S. Beke, Chem. Ber. 1956, 89, 862–864;
b) S. Groß, S. Laabs, A. Scherrmann, A. Sudau, N. Zhang, U.
Nubbemeyer, J. Prakt. Chem. 2000, 342, 711–714. The use of
acid fluorides suppressed any competing von Braun degrada-
tion. However, as a result of the lower reactivity of the acid
fluorides, the ring enlargement had to be run at 23 °C.
[20] The use of the corresponding acid chlorides induced rapid von
Braun degradation as a major competing process. In the earlier
reported ring enlargement of N-benzyl-substituted E-2-vinyl-
pyrrolidines, acid chlorides were used, and the reactions were
run at 0 °C. In all cases, von Braun degradation competed ef-
fectively with the desired reaction, and the azoninones were
formed in low to moderate yields. For more detailed infor-
mation, see ref.[3,4,5,9]
[26] It is known from the literature that tertiary amines and acid
fluorides do not react spontaneously, see: a) D. Granitza, M.
Beyermann, H. Wenschuh, H. Haber, L. A. Carpino, G. A.
Truran, M. Bienert, J. Chem. Soc., Chem. Commun. 1995,
2223–2224; b) L. A. Carpino, E.-S. M. E. Mansour, A. El-
Faham, J. Org. Chem. 1993, 58, 4162–4164.
[27] a) D. A. Evans, J. Bartoli, T. L. Shih, J. Am. Chem. Soc. 1981,
103, 2127–2129; b) W. Richter, W. Sucrow, Chem. Ber. 1971,
104, 3679–3682.
[28] For a related example, see: N. M. Friedemann, A. Härter, S.
Brandes, S. Groß, D. Gerlach, W. Münch, D. Schollmeyer, U.
Nubbemeyer, Eur. J. Org. Chem. 2012, 2346–2358.
[29] For the conformational flexibility of azonanones, see: a) G. L.
Olson, M. E. Voss, D. E. Hill, M. Kahn, V. S. Madison, C. M.
Cook, J. Am. Chem. Soc. 1990, 112, 323–333; b) for terpenes,
see: G. Guella, G. Chiasera, I. D_Diaye, F. Pietra, Helv. Chim.
Acta 1994, 77, 1203–1221; c) A. J. Minnaard, J. B. P. A.
Wijnberg, A. de Groot, J. Org. Chem. 1997, 62, 7346–7350; d)
for indolizidines, see: W. H. Pearson, E. J. Hembre, J. Org.
Chem. 1996, 61, 5546–5556.
[30] a) A. C. Cope, B. A. Pawson, J. Am. Chem. Soc. 1965, 87,
3649–3651; b) A. C. Cope, K. Banholzer, H. Keller, B. A. Paw-
son, J. J. Wang, H. J. S. Winkler, J. Am. Chem. Soc. 1965, 87,
3644–3649; c) G. Binsch, J. Am. Chem. Soc. 1965, 87, 5157–
5162; d) D. M. Pawar, S. D. Miggins, S. V. Smith, E. A. Noe, J.
Org. Chem. 1999, 64, 2418–2421.
[31] For further syntheses of unsaturated medium-sized ring lact-
ams, including some transannular reactions, see: a) P. A. Evans,
A. B. Holmes, R. P. McGeary, A. Nadin, K. Russell, P. J.
O’Hanlon, N. D. Pearson, J. Chem. Soc. Perkin Trans. 1 1996,
123–138; b) P. A. Evans, A. B. Holmes, I. Collins, P. R.
Raithby, K. Russell, J. Chem. Soc., Chem. Commun. 1995,
2325–2326; c) P. A. Evans, A. B. Holmes, K. Russell, Tetrahe-
dron Lett. 1992, 33, 6857–6858; d) P. A. Evans, I. Collins, P.
Hamley, A. B. Holmes, P. R. Raithby, K. Russell, Tetrahedron
Lett. 1992, 33, 6859–6862; e) P. Wipf, W. Li, J. Org. Chem.
1999, 64, 4576–4577.
[21] A diastereoselective ring expansion, as reported earlier for an
small-scale experiment (ref.[3b]
)
and using acid chlorides
(ref.[3d]), was not reproduced in the larger scale experiments
described here.
[22] For detailed NOESY data, see the Supporting Information.
[23] CCDC-985005 contains supplementary crystallographic data
of pS-8b for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
[24] The H NMR spectrum of the mixture of lactams 19c showed
chemical shifts typical of the olefin protons for a pS arrange-
ment (major) and a pR arrangement (minor). All attempts to
induce complete isomerisation and to separate the potential
planar diastereomers failed. The unambiguous assignment of
the minor component structure failed because of (partial) over-
lap of crucial peaks in the NMR spectra.
[25] CCDC-985006 contains supplementary crystallographic data
of 22b for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: June 8, 2014
Published Online: August 21, 2014
6284
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6272–6284