Zwitterionic aza-Claisen rearrangements controlled by pyrrolidine auxiliaries-useful key steps in convergent enantioselective syntheses

Article abstract of DOI:10.1002/ejoc.201200073

Chiral pyrrolidine substituents served as efficient auxiliaries in diastereoselective zwitterionic ketene aza-Claisen rearrangements. Palladium-catalysed N-allylation starting from optically active proline and prolinol derivatives, as well as from (2S,5S)-2,5-dimethoxymethylpyrrolidine, gave various allylamines bearing trisubstituted olefin moieties. Treatment with complex carboxylic acid fluorides in the presence of trimethylaluminium induced activated ketene addition to the nitrogen and subsequent [3,3] sigmatropic rearrangement to give γ,δ-unsaturated amides with excellent simple diastereoselectivities and up to 11:1 auxiliary-induced diastereomeric ratios. Cleavage of the pyrrolidine amide was achieved through iodolactonization, with the option for recovery of the auxiliary pyrrolidine. The stereochemical outcomes of the rearrangements and the iodocyclizations were established by X-ray and NOEDS analyses of suitable amides and lactones. Overall, both enantiomers were accessible selectively. The optically active amides and lactones of defined configurations formed in this way should be useful as key intermediates in convergent steroidal natural and pharmaceutically important product synthesis. Enantiopure N-allylpyrrolidines and 4-arylbut-3-enoyl fluorides underwent zwitterionic aza-Claisen rearrangements in high yields, as well as with high simple and up to 11:1 auxiliary-induced diastereoselectivities. After selective olefin hydrogenation, iodocyclization and pyrrolidine removal enabled synthesis of the lactones. Both enantiomers of target molecules could be achieved selectively.

Full text of DOI:10.1002/ejoc.201200073

FULL PAPER
DOI: 10.1002/ejoc.201200073
Zwitterionic Aza-Claisen Rearrangements Controlled by Pyrrolidine
Auxiliaries – Useful Key Steps in Convergent Enantioselective Syntheses
Nora M. Friedemann,[a] Alice Härter,[b] Sebastian Brandes,[c] Steffen Groß,[d]
Dorothea Gerlach,[a] Winfried Münch,[a] Dieter Schollmeyer,[a] and Udo Nubbemeyer*[a]
Dedicated to Professor Ekkehard Winterfeldt on the occasion of his 80th birthday
Keywords: Rearrangement / Asymmetric synthesis / Chiral auxiliaries / Steroids
Chiral pyrrolidine substituents served as efficient auxiliaries
in diastereoselective zwitterionic ketene aza-Claisen re-
arrangements. Palladium-catalysed N-allylation starting
from optically active proline and prolinol derivatives, as well
as from (2S,5S)-2,5-dimethoxymethylpyrrolidine, gave vari-
stereomeric ratios. Cleavage of the pyrrolidine amide was
achieved through iodolactonization, with the option for re-
covery of the auxiliary pyrrolidine. The stereochemical out-
comes of the rearrangements and the iodocyclizations were
established by X-ray and NOEDS analyses of suitable
ous allylamines bearing trisubstituted olefin moieties. Treat- amides and lactones. Overall, both enantiomers were access-
ment with complex carboxylic acid fluorides in the presence
of trimethylaluminium induced activated ketene addition to
the nitrogen and subsequent [3,3] sigmatropic rearrange-
ment to give γ,δ-unsaturated amides with excellent simple
diastereoselectivities and up to 11:1 auxiliary-induced dia-
ible selectively. The optically active amides and lactones of
defined configurations formed in this way should be useful
as key intermediates in convergent steroidal natural and
pharmaceutically important product synthesis.
states. In particular, variants with use of low reaction tem-
peratures potentially permit optimisation of stereoselecti-
vity.
Introduction
Syntheses of optically active complex natural products
require versatile and powerful reactions to generate the core
fragments of molecules incorporating defined stereogenic
centres.[1] In this respect, sigmatropic rearrangements are
well-established transformations that enable access to vari-
ous demanding key structures from simple starting reac-
tants.[2] Claisen rearrangements are often used in stereose-
lective syntheses of optically active target molecules.[3] To
introduce the chiral information, several variants of this sig-
matropic rearrangement use appropriate auxiliaries and/or
catalysts to achieve high levels of asymmetric induction.[4,5]
Claisen rearrangements are generally characterized by mild
reaction conditions and highly ordered defined transition
The zwitterionic ketene aza-Claisen rearrangement has
been developed as a reliable transformation for the con-
struction of optically active α-amino acid derivatives of type
III (Figure 1) by a strategy based on the use of chiral auxil-
iaries. The reactions between N-protected glycine fluorides
I and N-allylpyrrolidines II, containing stereogenic centres
in their five-membered rings, gave C-allyl glycine amides III
with high asymmetric induction. Subsequent transforma-
tions, including removal of the auxiliary pyrrolidine sys-
tems, enabled 3-arylproline derivatives IV and isoquino-
lones V to be synthesized with high optical purities.[6]
The high levels of asymmetric induction and the high
yields achieved in the α-amino acid syntheses motivated us
to test the scope and limitations of the zwitterionic ketene
aza-Claisen rearrangement. Our aim is to incorporate such
reactions as key steps in convergent stereoselective total
synthesis.
A long-term program in our group focuses on the synthe-
ses of steroids containing C/D-cis ring junctions.[7] A brief
retrosynthesis of estradiol derivative VI is outlined in Fig-
ure 2:[8] Estradiol VI should be accessible from tetralone
VII through introduction of C11 and C/D ring closure by
use of radical cascade cyclization. Tetralone VII should be
obtainable from amide VIII by intramolecular Grignard re-
[a] Institute of Organic Chemistry,
Johannes Gutenberg-University Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
Fax: +49-6131-3924533
E-mail: nubbemey@uni-mainz.de
[b] Keim-Additec Surface GmbH,
Hugo-Wagner-Str. 9, 55481 Kirchberg/Hunsrück, Germany
[c] H. Lundbeck A/S
Ottiliavej 9, 2500 Valby, Denmark
[d] BASF AG,
67056 Ludwigshafen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200073.
2346
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Auxiliary-Controlled Zwitterionic Aza-Claisen Rearrangements
Results and Discussion
The syntheses of the starting allyl alcohol 2 (Scheme 1),
pyrrolidines 3 and carboxylic acid fluorides 6 and 7 were
achieved by application of literature procedures.
Figure 1. Synthesis of optically active 3-arylprolines and isoquino-
lones.
action (X = Br) and Vilsmeier cyclization. Amide VIII is
the product of an auxiliary-directed zwitterionic ketene aza-
Claisen rearrangement starting from (unsaturated) 4-aryl-
butyric acid fluoride IX (A/B ring fragment) and N-allyl-
pyrrolidine X (C/D ring fragment), incorporating a trisub-
stituted olefin moiety. Allylamine X should be obtainable
from pyrrolidines XII and allyl alcohol derivatives XI by
Pd-catalysed regioselective amination. 4-Arylbutyric acids,
allyl alcohols and pyrrolidines can be synthesized by short
reaction sequences, enabling investigation of the stereodi-
recting power in the aza-Claisen rearrangement key step on
a broad basis.
Scheme 1. Synthesis of allylamines 4: Reagents and conditions:
i) 1. MsCl, iPr2EtN, MeCN, –15 °C, 2. 3, Pd2(dba)3(CHCl3),
iPr2EtN, PPh3, MeCN, 23 °C (4a: R1 = H, R2 = CO2Me: 81%; 4b:
R1 = OH, R2 = CO2Me: 83%; 4h: R1 = OMe, R2 = CH2OMe:
88%; 4i: R1 = OMe, R2 = CH2OtBu: 99%; 4j: R1 = OtBu, R2 =
CH2OMe: 82%; 4k = R1 = OtBu, R2 = CH2OtBu: 35%, 4l: R1 =
OtBu, R2 = CH2OPh: 84%; 4m 37%); ii) 4e: R1 = H, R2
=
CH2OTBS: 1. DIBAL-H, THF, 100%, 2. TBSCl, NEt3, DMF,
23 °C, 74%; iii) 4c: R1 = OTPS, R2 = CO2Me: TPSCl, imidazole,
THF/CH2Cl2, 66 °C 41%; iv) 1. MOMCl, iPr2NEt, DMAP,
CH2Cl2, 73%, 2. DIBAL-H, THF, 0 °C, 100%, 4f: R1 = OMOM,
R2 = CH2OTPS: 3. TPSCl, imidazole, CH2Cl2, 91% or 4g: R1
=
OMOM, R2 = CH2OMOM: 3. MOMCl, iPr2Net, DMAP, CH2Cl2
46%.
Butane-1,4-diol (1) could be converted into allyl alcohol
2 by mono-OH protection with TPS-Cl, TEMPO oxidation
of the remaining alcohol and addition of prop-2-enylmag-
nesium bromide to the thus-formed aldehyde.[9] A one-pot
sequence of OH group activation as the mesylate and subse-
quent palladium(0)-catalysed amination with allyl inversion
then afforded the product amines 4 with 80–99% yields.[10]
In contrast, the bis-tert-butyl-substituted amine 3k and the
(2S,5S)-2,5-dimethoxymethyl-derived system 3m gave lower
yields (35–37%), presumably because of more efficient ste-
ric shielding of the nitrogen centre.[11] However, in most
attempts a convergent sequence using a suitably substituted
pyrrolidine 3 was preferred.[12] Generally, the alternative re-
Figure 2. Synthesis of steroids – retrosynthesis (planned).
Here we describe the synthesis of various optically active actions with proline esters 3a and 3b gave the amines 4a
N-allylamines with defined configurations. Their reactions and 4b with Ͼ80% yields. The OH group of pyrrolidine 4b
with 4-arylbutyric acid fluorides allowed the development was protected both as the TPS ether and as the MOM
of the reaction conditions and investigation of the stereo- ether. Finally, DIBAH reduction[13] of the ester moieties of
chemical influences of the auxiliary moieties in the genera- 4a and 4d gave the corresponding alcohols, which then were
tion of the rearrangement product amides. The configura- converted into the corresponding silyl ethers 4e and 4f and
tions of the newly formed stereogenic centres in the major MOM ether 4g.[14] The substitution patterns of the allyl-
diastereomers have been verified in each case. Finally, auxil- amines used in the zwitterionic aza-Claisen rearrangements
iary cleavage through iodolactonization was developed.
are detailed in Figure 3.
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U. Nubbemeyer et al.
FULL PAPER
rolidine 4h with butanoyl fluorides 6a and 6b and trimeth-
ylaluminium in the presence of solid sodium carbonate
failed, however.[18] Despite wide variation of the reaction
conditions no product amides 17–20 were found. Only some
reactant allylamine 4 and some carboxylic acid (from 6)
were recovered.
Figure 3. Allylamines involved in ketene aza-Claisen rearrange-
ments.
Wittig olefination of m-anisaldehydes 5 (X = H and X =
Br, Scheme 2) with (2-carboxyethyl)triphenylphosphonium
chloride gave mixtures of 3-arylbutenoic acids that could be
separated by column chromatography and HPLC, respec-
tively. Hydrogenation of the mixtures with H2/Pd/C gave allylamines 4. Reagents and conditions: i) 7 (or 6), AlMe3, Na2CO3,
the corresponding saturated acid (X = H) with Ͼ90% yield.
Scheme 3. Aza-Claisen rearrangements of acid fluorides 6/7 and
CH2Cl2 (Table 1). ii) H2, Pd/C, EtOAc (Table 1). iii) 1. TBAF,
THF/HOAc, 2. p-(O2N)C6H4C(O)Cl, DMAP, pyridine, CH2Cl2,
Then, bromination succeeded to give the saturated acid (X
23 °C, 88%.
= Br).[15,16] Finally, fluorination with cyanuric fluoride and
pyridine gave the butanoyl fluorides 6a and 6b and butenoyl
In contrast, all reactions between the unsaturated
fluorides 7a and 7b with Ͼ80% yields by literature pro-
carboxylic acid fluorides 7 and the N-allylpyrrolidines 4
cedures (Scheme 2).[17]
smoothly delivered the product β,γ-unsaturated amides 8–
11 (X = H) and 12–15 (X = Br) with yields of Ͼ70% up to
100% (except for 4g: 44.7%). The reaction temperatures
could be varied between 0 °C down to –50 °C, but at the
latter temperature the rates were slower and complete con-
sumption of the reactant allylamines 4 was hardly ac-
complishable. At –78 °C no rearrangement could be de-
tected any longer. The NMR spectra of the products 8–15
always displayed at least double sets of peaks because of
the slowly interconverting amide mesomers. In instances of
low diastereoselectivities upon rearrangement the NMR
spectra of the mixtures were characterized by complex peak
patterns, making determination of selectivities difficult. In
Scheme 2. Synthesis of acid fluorides 6 and 7.
most cases HPLC analyses allowed light to be shed on the
Aza-Claisen rearrangements of N-allylpyrrolidines 4 outcomes of the reactions. Preparative column chromatog-
(Scheme 3) were first investigated with Lewis-acid-activated raphy and preparative HPLC enabled the diastereomers to
ketenes –formed in situ – bearing saturated 2-arylethyl side be separated and reliable information relating to the dia-
chains. Treatment of N-allylproline methyl ester 4a and pyr- stereomeric ratios to be obtained. As expected, the forma-
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Auxiliary-Controlled Zwitterionic Aza-Claisen Rearrangements
tion of the anti-2,3 diastereomers 8/9 or 12/13 (with respect ment with the C2-symmetric auxiliary derived from allyl-
to the newly formed stereogenic centres) predominated, amine 4m to afford 8m/9m; dr values range from 7.7:1 up
with the dr values found always being Ͼ90:10 up to 99:1, in to 11:1.
improvements on already high simple diastereoselectivities
(internal asymmetric induction).
The temperature dependency with respect to the dia-
stereoselectivity was found to be of moderate importance.
Detailed information analysing the efficiency of the aux- Generally, use of a lower reaction temperature produced a
iliary-directed asymmetric induction is given in Table 1. slightly higher selectivity but the rate of the rearrangement
Simple proline and prolinol substituents (4a and 4e) led to decreased. At –50 °C, incomplete conversion was found af-
the formation of 1:1 to Ͼ2:1 mixtures of products 8 and 9, ter 24 h. The rearrangement of 4j to give the major amides
indicating low external asymmetric induction. With em- 8j/9j displayed smooth reactions at 0 °C and –20 °C, with
ployment of (2R,4S)-4-hydroxyproline derivative 4c or pro- 99% and 92.5% chemical yields and dr values of 5.3:1 and
linol derivatives 4f–4l the substitution patterns (R1/R2) on 5.6:1, respectively. When the process was run at –50 °C the
the auxiliary fragments were found to be crucial. Small R1 dr increased to about 6:1, but the yield decreased to about
and R2 groups, as present in 4g and 4h, led to dia- 68% despite use of a longer reaction time. Reaction tem-
stereomeric ratios of 2.8:1 to 3.8:1 in the rearrangements, peratures of –20 °C (or 0 °C) have so far been found to be
yielding 8h/9h, 12h/13h and 12g/13g. The presence of a the best compromise in terms of rate, yield and diastereo-
bulky substituent for R2 and a small one for R1 (4f, 4i) selectivity.
decreased the selectivities to 1.5:1 (12f/13f) or 3.7:1 (8i/9i).
Structure determination by X-ray analysis succeeded in
In contrast, a bulky R1 group and a small R2 group (4c, two instances. The minor anti-bromoamide 13g crystallized
4j) enabled the auxiliary-induced diastereoselectivities to be without any further derivatization and displayed the (2S,3S)
increased from 4.5:1 (8c/9c) up to about 6:1 (8j/9j). This configuration in the newly formed stereogenic centres (Fig-
diastereoselectivity could be enhanced to 7.5:1 with a bulky ure 4).[19] In contrast, none of the amides 8–11 gave suitable
R1 group and an aromatic R2 residue (4l), giving 8l/9l. The crystals. The side-chain silyl ether of the minor product
presence of two bulky substituents (4k) caused a rather anti-9j was thus cleaved with TBAF in THF/HOAc, and
lower selectivity of about 4:1 (8k/9k). The best levels of in- subsequent esterification with p-nitrobenzoyl chloride in the
duction, however, were obtained by running the rearrange- presence of DMAP and pyridine gave the corresponding
Table 1. Results of the zwitterionic aza-Claisen rearrangement (n.d.: not detected).
Entry
Allylamines
Acyl
fluorides T [°C]
Rearrangement
Diastereoselectivity (dr)
Hydrogenation yield [%]
17 18
(from 8) (from 9)
Yield [%] syn/anti 8+9/10+11 anti/anti 8/9
8
12
9
13
10
14
11
15
(12+13/14+15)
12/13
1
2
3
4
5
6
7
8
4a
4g
4a
4e
4c
4f
4g
4h
4h
4h
4i
4i
4j
4j
4j
4k
4k
4l
4l
4m
4m
6a
6b
7a
7a
7a
7b
7b
7b
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
23
23
0
0
0
0
0
0
0
–20
0
–20
0
–20
–50
0
–20
0
0
0
–
–
–
–
–
–
50
67
81.8
60
–
–
50
33
18.2
40
–
–
–
–
–
–
–
–
100
–
–
0
0
–
61
97
Ͼ90:10
Ͼ90:10
Ͼ90:10
Ͼ90:10
Ͼ90:10
95:5
96:4
98:2
93:7
94:6
95:5
98:2
Ͼ99:1
95:5
96:4
97:3
98:2
Ͼ98:2
Ͼ98:2
1:1
Ͼ2:1
4.5:1
1.5:1
2.8:1
3.2:1
3:1
3.8:1
2.9:1
3.7:1
5.3:1
5.6:1
6.0:1
3.9:1
4.0:1
4.8:1
7.5:1
1:7.7
1:11.2
n. d. n. d. 100
n. d. n. d. 63
n. d. n. d. 59
n. d. n. d.
n. d. n. d.
1.9
2.4
1.5
3.8
3.3
2.4
1.1
63[a]
100
95
45
100
86
80
85
86
99
0
0
0
72
74.0
72.8
71.9
77.5
68.9
74.0
80.2
83.0
85.7
75.4
77.0
80.4
86.8
11.3
8.1
26.0
22.7
24.1
20.4
23.9
20.5
15.2
15.4
14.3
19.3
19.1
16.5
11.6
87.3
90.5
2.6
1.6
0.6
3.4
2.2
2.1
0.5
9
10
11
12
13
14
15
16
17
18
19
20
21
82
55
71
52
92
68[b]
n. d. n. d.
96
96
88
92
67
71
2.7
1.9
2.0
1.2
n. d. 1.4
n. d. 1.5
2.7
2.0
1.1
0.4
99
96
–
–
68
82
–20
0
–20
[a] Yield for pure diastereomer 8e. [b] Based on recovered starting material.
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U. Nubbemeyer et al.
FULL PAPER
benzoate with 88% yield over two steps. Derivate 16j af- Clearly, the o-bromide groups caused severe steric shielding
forded suitable crystals for X-ray analysis. Again, the newly of the olefins adjacent to the aromatic rings, preventing any
formed stereogenic centres showed the (2S,3S) configura- selective reduction to form amides 19 and 20. More drastic
tion (Figure 5).[20]
reaction conditions resulted in debromination together with
additional hydrogenation of the γ,δ double bond
(Scheme 3).
The X-ray analysis of ester 16j was pivotal for the struc-
ture determination of the major diastereomers. Generally,
cleavage of the auxiliary allowed all amides 17/18 to be con-
verted into constitutionally identical products. Such a strat-
egy allowed improvement of the asymmetric induction orig-
inating from the set of auxiliaries involved. Because the al-
ready known absolute configurations of the core centres de-
duced from ester 16j remain unaffected during the course
of the transformation, complete structure elucidation could
be achieved for the major diastereomers 8/9, 17/18 and 21/
22.
Cleavage of the amides 17/18 under acidic and basic con-
ditions, respectively, gave unsatisfying results.[21] In con-
trast, iodolactonizations are well-known procedures en-
abling γ,δ-unsaturated N,N-dialkyl amides to be cleaved un-
der mild conditions. The 5-exo-trig cyclisations (Scheme 4)
always led to the corresponding γ-butyrolactones, with the
aid of iodine, ICl, IBr and NIS as suitable reagents. Gen-
erally, the amine components can be recycled after aqueous
workup.[22] In our case, iodine was found to afford the best
results in terms of level of conversion and protecting group
stability. In most runs some cleavage of the TPS ether, in-
ducing lower yields of the product lactones 21/22, was ob-
served.[23]
Figure 4. X-ray structure of amide 16j (only important hydrogen
atoms are shown; the newly formed stereogenic centres are labelled
as 2, 3).
Figure 5. X-ray structure of amide 13g (only important hydrogen
atoms are shown; the newly formed stereogenic centres are labelled
as 2, 3).
Because direct rearrangement to produce the amides 17/
18 and 19/20 from allylamines 4 and butanoyl fluorides 6
had failed, the chemoselective removal of the double bonds
adjacent to the aryl rings in the β,γ-unsaturated amides 8/9
and 12/13 was necessary. Hydrogenation (H2/Pd/C in ethyl
acetate) of the amides 8 and 9 (X = H) delivered the corre-
sponding saturated systems 17 and 18 (X = H) in 50 to
100% yields. The hydrogenation reaction rates depended on
the substitution patterns of the materials. In most runs, the
reaction of the major diastereomer 8 was faster than that
Scheme 4. Iodolactonization with cleavage of the auxiliaries
(Table 2). Reagents and conditions: i) I2 (3 equiv.), THF/MeOH/
H2O, HCl (2.5 equiv.).
Upon treatment of the γ,δ-unsaturated amides 17 with
of the minor diastereomer 9. In contrast, chemoselective iodine, iodocyclisation gave mixtures of the diastereomeric
hydrogenation with the β,γ-unsaturated amides 12 and 13 iodolactones 21 and 22 in 39 to 72% yields. Aqueous
(X = Br) failed despite wide variation of the conditions. workup allowed cleaving of the intermediately formed imin-
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Auxiliary-Controlled Zwitterionic Aza-Claisen Rearrangements
ium salts. In several runs the auxiliary pyrrolidines 3 were
recycled from the aqueous phase in 60–89% yields. The
product iodolactones 21 and 22 were separated by prepara-
tive HPLC. NOEDS analyses of the diastereomers 21/22
exclusively indicated the trans configuration of the α and β
carbon centres, confirming high simple diastereoselectivity
during the aza-Claisen rearrangement. The γ-position cre-
ated during iodocyclization was formed with low diastereo-
selectivity – the iodolactones 21 and 22 were always both
isolated from each transformation in nearly equal amounts.
NOEDS (Figure 6) and an X-ray analysis of lactone 22
(Figure 7)[24] unequivocally confirmed the structures. The
optical rotation was always characterized by a positive sign.
Figure 8. Crystal structure of the iodolactone ent-22 obtained from
rearrangement product 9i (hydrogenation product 18i; only impor-
tant hydrogen atoms are shown.).
Overall, the (2S,4R)-4-alkoxyprolinol auxiliaries in 4c–l
predominantly led to the formation of (2R,3R)-amides 8/
12. In contrast, the C2-symmetrical (2S,5S)-2,5-bis(meth-
oxymethyl)pyrrolidine 4m preferentially delivered the dia-
stereomer (2S,3S)-products 9m/(13m). Detailed information
is given in Table 2.[26]
Table 2. Iodolactonization.
Entry
Reactant Yield [%]
dr (21/22) [α]D (22) [α]D (21)
1
2
3
4
5
6
7
8
9
17h
18h
17i
72
67
48
63
65
93
39
68
54
54
1:1.0
1:1.0
1:1.2
1:1.0
1:1.3
2.5:1
1:1.1
1:1.2
1:1.2
1.6:1
+42.9
–43.1
+43.4
–44.0
+39.5
–39.4
+45.8
+42.4
–43.2
–44.0
+2.0
–2.0
+2.8
–2.3
+3.0
–1.9
+4.4
+3.6
+3.2
–2.2
Figure 6. NOESY analysis of the iodocyclization products.
18i
17j
18j
17k
17l
18l
18m
10
Mechanistic Conclusions
The reaction pathway and stereochemical outcome were
interpreted by analysis of the auxiliary-controlled zwitter-
ionic aza-Claisen rearrangement (Figure 9). Initially, acid
fluorides 6/7 and trimethylaluminium could form Lewis-
acid-activated ketenes 23.[27] Evolution of methane was al-
ways observed. The ketenes 23 could then add to nitrogen
in the N-allylpyrrolidines 4 to generate intermediate acyl-
ammonium enolates with complete Z enolate geometry.[28]
With the proline- and 4-hydroxyproline-derived allylamines
4a–l the intermediate acylammonium enolates containing
Figure 7. Crystal structure of the iodolactone 22 obtained from
rearrangement product 8l (hydrogenation product 17l; only impor-
tant hydrogen atoms are shown).
In contrast, the iodocyclizations of amides 18 (Scheme 4) asymmetric nitrogen centres could be formed. At low reac-
delivered the iodolactones ent-21 and ent-22 with 41 to 67% tion temperatures, and especially with bulky R1 substitu-
yields (with low diastereoselectivities). The spectroscopic ents, conformation 4–1 should represent the most favour-
data for these compounds were identical with those for 21 able arrangement. The acylation of the quasiaxial nitrogen
and 22, respectively, the only differences being the negative lone pair of this conformation would result in the 1,2-syn
signs of the optical rotations, indicating the formation of adduct. Smooth addition at the lone pair could be dis-
the enantiomers in this series. As expected, NOEDS analy- turbed by the 1,3-syn-periplanar positioned methyl group
ses (Figure 6) and X-ray analysis of ent-22 (Figure 8)[25] of the double bond. Furthermore, a too bulky R2 substitu-
confirmed the structures.
ent in a gauche position could amplify this shielding. Some
Eur. J. Org. Chem. 2012, 2346–2358
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2351

U. Nubbemeyer et al.
FULL PAPER
conformational flexibility could thus enable adoption of the
As expected, the formation of the syn amides 10/14 and
(still reactive) conformations 4–2 and 4–3 as well. Here, 11/15 was less significant. Passing through boat-like transi-
acylation of the nitrogen lone pair could cause the forma- tion states would generally require higher activation ener-
tion of the 1,2-anti adduct. Then, the sigmatropic re- gies. The stereo-directing impacts of the auxiliaries would
arrangements could proceed with complete 1,3 chirality be less pronounced (as shown for b-syn) resulting in the
transfer (NǞC). The charge neutralization should serve as formation of both diastereomers 10/14 and 11/15 in nearly
a highly efficient driving force. Generally, the chair-like equal amounts (Figure 9).
transition state is known to be predominantly passed
Until now, the C2-symmetric auxiliary as present in N-
through in an open-chain Claisen rearrangement.[29] Conse- allylpyrrolidine 4m has given the best diastereoselectivity.
quentially, the syn adducts could react via c-syn with the Because of the chiral homotopic setting of the nitrogen the
branched R2 substituted carbons arranged in a quasiequ- N-acylation afforded a single acylammonium enolate. With
atorial orientation to give anti amides 8/12 with (2R,3R) the adoption of the chair-like transition states, passing
configuration. The anti adducts could pass through c-anti through c-2 should be favoured because of minimized repul-
to afford anti amides 9/13 with (2S,3S) configuration. In sive interactions whereas c-1 should be disfavoured because
summary, allylamines 4c, 4j and 4l (bulky R1, small R2) of the proximity of the methyl group and R2, as shown in
gave the best selectivities. The somewhat lower selectivities Figure 10.[30] Consequentially, a diastereomeric ratio of 1:7
obtained in the other experiments could be explained in to 1:11 (8m/9m) could be achieved in the ketene aza-Claisen
terms of less selective acylation because of smaller R1 rearrangement (Figure 10).
groups (4a, 4e, 4f, 4g, 4h, 4i) and too bulky R2 groups (4f,
4i, 4k), respectively (Figure 9).
Figure 10. Proposed mechanisms of the aza-Claisen rearrange-
ments induced by C2-symmetric auxiliaries.
Conclusions
A short convergent sequence for the synthesis of op-
tically active defined α,β-disubstituted γ,δ-unsaturated
amides from simple starting materials had been developed.
After activation of the starting allyl alcohol 2 as the mesyl-
ate, palladium(0)-catalysed aminations with various
enantiopure pyrrolidine derivatives 3 enabled the generation
of N-allylpyrrolidines 4, each incorporating a defined tri-
substituted olefin. Zwitterionic aza-Claisen rearrangements
with 4-arylbut-3-enoyl fluorides 7 then delivered the prod-
uct amides with high simple diastereoselectivities; the 2,3-
anti/2,3-syn ratios were always found to be Ͼ90:10 (up to
98:2). Furthermore, a suitable substitution pattern in the
pyrrolidine moiety enabled moderate to high auxiliary-di-
rected asymmetric induction to be achieved. The best re-
sults were obtained with N-allyl pyrrolidines 4j and 4l, with
bulky 4-tert-butoxy and small 2-methoxmethyl and phen-
oxymethyl substituents, respectively. The major anti-
(2R,3R)-amides 8j and 8l were isolated in 4–7.5 ratios in
relation to the minor anti-(2S,3S)-amides 9j and 9l. In con-
trast, the reaction of C2-symmetric allylamine 4m predomi-
Figure 9. Proposed mechanisms of the aza-Claisen rearrangements
with proline- and 4-hydroxyproline-derived auxiliaries.
2352
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2346–2358

Auxiliary-Controlled Zwitterionic Aza-Claisen Rearrangements
fication: column chromatography (EA/PE 1:2); yield 7.83 g
(15.79 mmol, 88.3%) as a clear, colourless oil. Rf = 0.40 (EA/PE
1:2). [α]2D3 = –26.5 (c = 0.86, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 1.06 (s, 9 H, 13-H), 1.61 (m, 2 H, 5-H), 1.63 (s, 3 H,
7-H), 1.86 (dt, 3JH,H = 7.6, 2JH,H = 13.3 Hz, 1 H, 16-H), 1.94 (ddd,
nantly delivered the corresponding anti-(2S,3S)-amide 9m
(8m/9m = 1:11). The olefin moieties adjacent to the aryl
substituents were then chemoselectively removed by cata-
lytic hydrogenation (50–100% yields). Finally, the auxiliary
pyrrolidine components could be removed through iodolac-
tonization (50–70% yield). Overall, the trans-(2R,3R)-lac-
tones 21 and 22 were synthesized via the allylamines 4j and
4l, whereas the trans-(2S,3S)-lactone enantiomers ent-21
and ent-22 were generated by use of allylamine 4m. The
3
2
3JH,H = 4.0, JH,H = 7.7, JH,H = 13.1 Hz, 1 H, 16-H), 2.09 (q,
3
2
3JH,H = 7.5 Hz, 1 H, 4-H), 2.16 (dd, JH,H = 5.6, JH,H = 10.1 Hz,
2
1 H, 18-H), 2.75 (d, JH,H = 12.4 Hz, 1 H, 1-H), 2.77 (m, 1 H, 15-
H), 3.23 (dd, 3JH,H = 4.0, 2JH,H = 9.9 Hz, 1 H, 18-H), 3.27 (s, 3 H,
2
19-H), 3.33 (br. d, JH,H = 12.2 Hz, 1 H, 14-H), 3.34 (s, 3 H, 19-
absolute configurations of the new stereogenic centres both H), 3.39 (dd, 3JH,H = 4.4, 2JH,H = 9.6 Hz, 1 H, 14-H), 3.66 (t, 3JH,H
3
= 6.4 Hz, 2 H, 6-H), 3.86 (m, 1 H, 17-H), 5.28 (t, JH,H = 7.2 Hz,
1 H, 3-H), 7.35–7.47 (m, 6 H, 10-H, 11-H), 7.65–7.67 (m, 4 H, 9-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.99 (C-7), 19.18 (C-
12), 24.02 (C-4), 26.82 (C-13), 32.46 (C-5), 35.42 (C-16), 56.64 (C-
19), 59.08 (C-19), 59.63 (C-18), 61.96 (C-15), 63.38 (C-6), 64.31 (C-
1), 75.66 (C-14), 78.82 (C-17), 126.56 (C-3), 127.53 (C-10), 129.45
in amides 8–18 and in lactones 21/22 were unequivocally
verified by X-ray analyses of suitable intermediates and
products. Optimization of the sequences incorporating the
best auxiliaries (especially in the m series) is still required,
however. Further investigations with subjection of amides
and lactones to ring-closing processes to generate enantio-
merically pure tetralone derivatives for continuing steroid
syntheses are in progress.
(C-11), 133.95 (C-2), 134.02 (C-8), 135.51 (C-9) ppm. IR: ν = 2929
˜
(m), 2857 (m), 2360 (w), 1471 (w), 1428 (w), 1324 (m), 1175 (w),
1105 (s), 823 (w), 740 (m), 701 (s), 613 (m) cm–1. HRMS (ESI):
calcd. for C30H46NO3Si: 496.3247; found 496.3258.
General Procedure for Aza-Claisen Rearrangements: A solution of
an allylamine 4 (1.0 equiv.) in CH2Cl2 (0.08 m) and a solution of
an acid fluoride 7 (1.5 equiv.) in CH2Cl2 (0.10 m) were combined
over Na2CO3 (5 equiv.). The reaction mixture was cooled to the
desired temperature. AlMe3 (2 equiv., 2 m in toluene) was then
added over 15 min by syringe. After the mixture had been stirred
for 6 h at the reaction temperature the hydrolysis was started by
injection of 3 drops of water at room temperature and stirring for
another 15 min. The hydrolysis was complete after cessation of the
gas evolution. The mixture was then diluted with diethyl ether and
filtered through MgSO4 and silica gel. The crude product was puri-
fied by column chromatography or preparative HPLC.
Experimental Section
General Remarks: Reaction solvents were dried by standard pro-
cedures prior to use when necessary. All reactions involving moist-
ure- or air-sensitive reagents were carried out under argon. 1H
NMR, 13C NMR and 2D (COSY, HSQC, HMBC, NOESY) spec-
tra were recorded at room temperature with Bruker ARX 400 or
AV 400 spectrometers in CDCl3 with use of the signal of residual
CHCl3 as internal standard. The additional signals from the
amide’s rotation isomers are given in square brackets. IR spectra
were recorded with a Jasco FT/IR-400 plus spectrometer. The high-
resolution mass spectra (HRMS) were recorded with a Waters
Q Tof Ultima 3 Micromasses spectrometer. Optical rotations were
For yields and data relating to 8–15a to 8–15g and 8–15i to 8–15m,
see the Supporting Information.
recorded with
a Perkin–Elmer P 241 polarimeter. Column
chromatography was performed on MN silica gel (60M) from Ma-
cherey–Nagel (grain size: 0.040–0.063 mm). Progress of reactions
was monitored by thin layer chromatography (TLC) performed on
aluminium sheets pre-coated with silica gel (60 F254, Merck). EA
= ethyl acetate, PE = petroleum ether, HPLC: tR = peak retention
time, k = retention factor = (tR – t0)/t0.
anti/syn-2R/S,3R/S-3-(3-tert-Butyldiphenylsilyloxypropyl)-1-[(2S,4R)-
4-methoxy-2-(methoxymethyl)pyrrolidin-1-yl]-2-[(E)-2-(3-methoxy-
phenyl)ethenyl]-4-methylpent-4-en-1-one (8h–11h): At a reaction
temperature of –20 °C: the reaction was carried out with allylamine
4h (10.10 g, 20.37 mmol), acid fluoride 7a (5.94 g, 30.56 mmol,
1.5 equiv.) and AlMe3 (20.4 mL, 40.74 mmol, 2 equiv., 2 m in tolu-
ene) by the standard procedure; yield 12.49 g [18.64 mmol, 91.5%
(–20 °C)]. At a reaction temperature of 0 °C: the reaction was car-
ried out with allylamine 4h (476 mg, 0.99 mmol), acid fluoride 7a
(267 mg, 1.38 mmol, 1.4 equiv.) and AlMe3 (0.96 mL, 1.92 mmol,
2 equiv., 2 m in toluene) by the standard procedure; yield 554 mg
[0.82 mmol, 86.2% (0 °C)] as a clear, colourless oil. Purification:
preparative HPLC (Nucleosil 50–5, ID 32ϫ238 mm): (1): propan-
2-ol/hexane (3:97); (2): EA/hexane (1:4), 98 mLmin–1, 97 bar; dr
values for 8h/9h/10h/11h: 71.9:24.1:2.4:1.6 (0 °C), 77.5:20.4:1.5:0.6
(–20 °C). The absolute configurations of the minor 2,3-syn-1 and
2,3-syn-2 diastereomers 10h and 11h with respect to the auxiliary
stereogenic centres were determined by α-epimerization of 10h.[31]
General Procedure for Pd-Catalysed Amination: Diisopropylethyl-
amine (5.2 equiv.) was added to a solution of allyl alcohol 2
(1.0 equiv.) in acetonitrile (0.06 m) and the mixture was cooled to
–15 °C. Methanesulfonyl chloride (1.2 equiv.) was slowly added by
syringe and the reaction mixture was stirred for 3 h at room tem-
perature. In another flask the pyrrolidine (3h–3m, 1.3 equiv.) was
dissolved in acetonitrile (0.08 m) and diisopropylethylamine was
added (3 equiv.). The mesylation reaction mixture was then added
from a funnel, with subsequent addition of Pd2(dba)3CHCl3
(0.025 equiv.) and PPh3 (0.1 equiv.). After the system had been
stirred at room temperature for a further 20 h, aq. Na2CO3 (satd.)
was added and the aqueous phase was extracted with diethyl ether
(4ϫ). The combined organic phases were dried (MgSO4) and the
solvents were removed. The crude product can be purified by col-
umn chromatography.
Major (2,3-anti): (2R,3R)-3-(3-tert-Butyldiphenylsilyloxypropyl)-1-
[(2S,4R)-4-methoxy-2-(methoxymethyl)pyrrolidin-1-yl]-2-[(E)-2-(3-
methoxyphenyl)ethenyl]-4-methylpent-4-en-1-one (8h): HPLC (1):
k(8h) = 7.3, tR = 12.5 min; HPLC (2): k(8h) = 2.0 tR = 23 min; Rf
= 0.18 (EA/PE 1:2). [α]2D4 = +28.9 (c = 1.01, CH2Cl2). 1H NMR
(400 MHz, CDCl3, COSY): δ = 0.97 (s, 9 H, 24-H), 1.41 [1.52] (m,
2 H, 4-H), 1.30 [1.65] (m, 2 H, 5-H), 1.70 [1.74] (s, 3 H, 17-H), 1.91
For yields and data relating to 4a–4g and 4i–4m, see the Supporting
Information.
(2S,4R)-1-[(E)-6-(tert-Butyldiphenylsilyloxy)-2-methylhex-2-enyl]-4-
methoxy-2-(methoxymethyl)pyrrolidine (4h): The reaction was car-
ried out with allyl alcohol 2 (6.60 g, 17.89 mmol) and pyrrolidine
3h (4.22 g, 23.25 mmol, 1.3 equiv.) by the standard procedure. Puri-
3
3
2
[2.02] (ddd, JH,H = 6.6, JH,H = 8.7, JH,H = 12.8 Hz, 1 H, 27-H),
3
3
2
2.19 [2.09] (ddd, JH,H = 3.6, JH,H = 6.3, JH,H = 12.9 Hz, 1 H,
Eur. J. Org. Chem. 2012, 2346–2358
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2353

U. Nubbemeyer et al.
FULL PAPER
27-H), 2.67 [2.75] (td, 3JH,H = 3.4, 3JH,H = 10.7 Hz, 1 H, 3-H), 3.22
[3.25] (s, 3 H, 30-H or 31-H), 3.25 (t, JH,H = 9.9 Hz, 1 H, 2-H),
(400 MHz, CDCl3, COSY): δ = 1.04 (s, 9 H, 24-H), 1.35–1.54 (m,
3
3
4 H, 5-H, 6-H), 1.58 [1.62] (s, 3 H, 17-H), 1.98 [2.07] (ddd, JH,H
3
2
3.33 [3.36] (s, 3 H, 30-H or 31-H), 3.42–3.46 (m, 2 H, 29-H, 25-H), = 6.1, JH,H = 8.6, JH,H = 13.0 Hz, 1 H, 27-H), 2.20 [2.07] (ddd,
3
2
3
2
3.53 (dd, JH,H = 5.2, JH,H = 9.7 Hz, 1 H, 29-H), 3.59 (m, 2 H, 6-
3JH,H = 4.2, JH,H = 6.0, JH,H = 12.9 Hz, 1 H, 27-H), 2.73 (td,
3
2
3
3
H), 3.75 [3.82] (dd, JH,H = 6.3, JH,H = 10.3 Hz, 1 H, 25-H), 3.79
(s, 3 H, 15-H), 4.08 [4.02] (m, 1 H, 26-H), 4.29 [4.22] (m, 1 H, 28- H, 2-H), 3.24 [3.32] (s, 3 H, 30-H or 31-H), 3.31 [3.28] (s, 3 H, 30-
3JH,H = 2.5, JH,H = 10.7 Hz, 1 H, 3-H), 3.17 (t, JH,H = 9.7 Hz, 1
3
2
H), 4.76 [4.82] (br. s, 1 H, 18-H), 4.84 [4.86] (br. s, 1 H, 18-H), 6.14 H or 31-H), 3.46 [3.35] (dd, JH,H = 2.8, JH,H = 9.7 Hz, 1 H, 29-
3
3
3
(dd, JH,H = 9.4, JH,H = 15.9 Hz, 1 H, 7-H), 6.43 [6.43] (d, JH,H H), 3.55–3.60 (m, 2 H, 29-H, 25-H), 3.58–3.69 (m, 2 H, 6-H), 3.76
3
4
3
2
= 15.9 Hz, 1 H, 8-H), 6.78 (dd, JH,H = 8.2, JH,H = 2.5 Hz, 1 H, [3.91] (dd, JH,H = 6.1, JH,H = 10.4 Hz, 1 H, 25-H), 3.79 (s, 3 H,
12-H), 6.89 (t, JH,H = 2.0 Hz, 1 H, 10-H), 6.93 (br. d, JH,H
7.70 Hz, 1 H, 14-H), 7.21 [7.20] (t, JH,H = 7.9 Hz, 1 H, 13-H),
7.30–7.40 (m, 6 H, 21-H, 22-H), 7.60–7.62 (m, 4 H, 20-H) ppm.
13C NMR (100 MHz, CDCl3, HSQC): δ = 19.1 (C-23), 20.9 [21.1]
4
3
=
15-H), 4.11 [4.03] (m, 1 H, 26-H), 4.35 [4.27] (m, 1 H, 28-H), 4.79
(br. s, 1 H, 18-H), 4.79 [4.82] (br. s, 1 H, 18-H), 6.10 [6.07] (dd,
3
3
3
3JH,H = 8.9, JH,H = 15.9 Hz, 1 H, 7-H), 6.32 [6.33] (d, JH,H
=
15.9 Hz, 1 H, 8-H), 6.76 (dd, 3JH,H = 2.5, JH,H = 8.2 Hz, 1 H, 12-
4
3
(C-17), 26.8 [27.1] (C-24), 26.9 (C-4) 30.0 [30.1] (C-5), 33.4 (C-27), H), 6.86 (m, 1 H, 10-H), 6.91 [6.90] (br. d, JH,H = 7.7 Hz, 1 H,
48.4 [48.3] (C-3), 52.1 (C-25), 53.3 (C-2), 55.2 (C-15), 55.9 (C-28),
57.0 [56.8] (C-30 or C-31), 59.2 (C-30 or C-31), 63.9 [64.0] (C-6),
72.4 (C-29), 78.7 (C-26), 111.3 [111.2] (C-10), 112.6 (C-18), 113.4
[113.5] (C-12), 119.1 (C-14), 127.5 (C-21), 128.3 (C-7), 129.4 (C-
14-H), 7.20 [7.19] (t, 3JH,H = 7.9 Hz, 1 H, 13-H), 7.35–7.43 (m, 6 H,
21-H, 22-H), 7.64–7.68 (m, 4 H, 20-H) ppm. 13C NMR (100 MHz,
CDCl3, HSQC): δ = 18.26 (C-17), 19.14 (C-23), 26.81 (C-24), 27.17
(C-4), 30.60 [30.74] (C-5), 33.37 [35.33] (C-27), 49.58 (C-3), 51.97
22), 129.5 (C-13), 132.6 (C-8), 134.0 [133.9] (C-19), 135.5 (C-20), (C-25 or C-2), 52.24 (C-2 or C-25), 55.13 (C-15), 55.98 (C-28),
138.3 (C-9), 145.9 (C-16), 159.8 (C-11) 171.5 (C-1) ppm. IR: ν = 56.81 [56.74] (C-30 or C-31), 59.2 [59.06] (C-30 or C-31), 63.82
˜
3058 (w), 2930 (br.), 2845 (m), 1635 (br.), 1596 (m), 1471 (s), 1427
[63.95] (C-6), 72.36 [75.81] (C-29), 78.65 [77.47] (C-26), 111.34
(s), 1289 (m), 1262 (m), 1187 (w), 1160 (w), 1110 (br.), 1053 (m), [111.28] (C-10), 112.95 [113.05] (C-12), 114.51 (C-18), 118.95 (C-
972 (w), 903 (w), 840 (w), 778 (m), 743 (m), 703 (s), 615 (m) cm–1. 14), 127.50 (C-21), 128.63 (C-7), 129.36 (C-13), 129.40 (C-22),
HRMS (ESI): calcd. for C41H56NO5Si: 670.3928; found 670.3934.
130.57 [130.50] (C-8), 133.97 (C-19), 135.50 [135.47] (C-20), 138.56
(C-9), 143.82 [144.03] (C-16), 159.65 (C-11), 171.48 (C-1) ppm. IR:
Minor (2,3-anti): (2S,3S)-3-(3-tert-Butyldiphenylsilyloxypropyl)-1-
[(2S,4R)-4-methoxy-2-(methoxymethyl)pyrrolidin-1-yl]-2-[(E)-2-(3-
methoxyphenyl)ethenyl]-4-methylpent-4-en-1-one (9h): HPLC (1):
k(9h) = 11.0, tR = 18 min. Rf = 0.18 (EA/PE 1:2). [α]2D3 = –18.4 (c
= 1.09, CH2Cl2). 1H NMR (400 MHz, CDCl3, COSY): δ = 0.97
[0.96] (s, 9 H, 24-H), 1.40 [1.52] (m, 2 H, 4-H), 1.27 [1.64] (m, 2 H,
5-H), 1.68 [1.70] (s, 3 H, 17-H), 1.94 (ddd, 3JH,H = 5.5, 3JH,H = 8.6,
ν = 3058 (w), 2924 (br.), 2855 (m), 1733 (w), 1636 (s), 1599 (w),
˜
1480 (w), 1462 (s) 1428 (s), 1364 (w), 1262 (m), 1194 (w), 1156 (w),
1108 (br.), 1045 (w), 970 (w), 893 (w), 823 (w), 782 (m), 742 (m),
703 (s), 688 (m), 612 (m) cm–1 . HRMS (ESI): calcd. for
C41H56NO5Si: 670.3928; found 670.3925.
(2,3-syn-2): (2S,3R)-3-(3-tert-Butyldiphenylsilyloxypropyl)-1-
[(2S,4R)-4-methoxy-2-(methoxymethyl)pyrrolidin-1-yl]-2-[(E)-2-(3-
methoxyphenyl)ethenyl]-4-methylpent-4-en-1-one (11h): HPLC (1):
k(11h) = 7.0, tR = 12 min; HPLC (2): k(11h) = 1.4 tR = 18 min. Rf
= 0.24 (EA/PE 1:2). [α]2D2 = –19.5 (c = 1.02, CH2Cl2). 1H NMR
(400 MHz, CDCl3, COSY): δ = 1.05 [1.04] (s, 9 H, 24-H), 1.37–
1.43 (m, 2 H, 4-H), 1.43–1.56 (m, 2 H, 5-H), 1.58 (s, 3 H, 17-H),
3
3
2JH,H = 13.5 Hz, 1 H, 27-H), 2.16 (ddd, JH,H = 4.6, JH,H = 5.9,
2JH,H = 13.0 Hz, 1 H, 27-H), 2.67 [2.60] (td, JH,H = 3.4, JH,H
11.0 Hz, 1 H, 3-H), 3.21 (t, JH,H = 9.9 Hz, 1 H, 2-H), 3.25 [3.29]
=
3
3
3
(s, 3 H, 30-H or 31-H), 3.30 [3.28] (s, 3 H, 30-H or 31-H), 3.41 (dd,
2
3
3JH,H = 2.5, JH,H = 9.3 Hz, 1 H, 29-H), 3.48 (dd, JH,H = 4.6,
2JH,H = 9.5 Hz, 1 H, 29-H), 3.58 (m, 1 H, 25-H), 3.60 (m, 2 H, 6-
H), 3.65 [3.72] (dd, JH,H = 5.8, JH,H = 10.4 Hz, 1 H, 25-H), 3.78
(s, 3 H, 15-H), 4.09 [4.00] (m, 1 H, 26-H), 4.34 [4.18] (m, 1 H, 28-
H), 4.79 [4.80] (br. s, 1 H, 18-H), 4.82 [4.85] (br. s, 1 H, 18-H), 6.17
3
2
3
3
2
1.96 (ddd, JH,H = 5.4, JH,H = 8.8, JH,H = 13.0 Hz, 1 H, 27-H),
3
3
2
2.17 (ddd, JH,H = 5.0, JH,H = 10.7, JH,H = 13.0 Hz, 1 H, 27-H),
3
3
2.72 [2.63] (td, JH,H = 4.3, JH,H = 10.3 Hz, 1 H, 3-H), 3.14 (t,
3JH,H = 9.7 Hz, 1 H, 2-H), 3.19 [3.30] (s, 3 H, 30-H), 3.26 [3.20] (s,
3 H, 31-H), 3.42 (dd, 3JH,H = 2.7, 2JH,H = 9.4 Hz, 1 H, 29-H), 3.55–
3.68 (m, 4 H, 6-H, 25-H, 29-H), 3.71 [3.91] (dd, JH,H = 5.8, JH,H
= 10.4 Hz, 1 H, 25-H), 3.79 [3.79] (s, 3 H, 15-H), 4.10 [3.98] (m, 1
H, 26-H), 4.35 [4.27] (m, 1 H, 28-H), 4.78 (br. s, 1 H, 18-H), 4.80
(br. s, 1 H, 18-H), 6.11 (dd, JH,H = 9.1, JH,H = 16.0 Hz, 1 H, 7-
H), 6.31 [6.30] (d, JH,H = 16.0 Hz, 1 H, 8-H), 6.75 (dd, JH,H
2.2, JH,H = 7.9 Hz, 1 H, 12-H), 6.86 [6.88] (m, 1 H, 10-H), 6.90
[6.91] (br. d, JH,H = 7.7 Hz, 1 H, 14-H), 7.18 [7.19] (t, JH,H
3
3
[6.32] (dd, JH,H = 9.8, JH,H = 15.9 Hz, 1 H, 7-H), 6.43 [6.40] (d,
3JH,H = 15.9 Hz, 1 H, 8-H), 6.77 (dd, JH,H = 2.4, JH,H = 8.2 Hz,
3
4
4
3
1 H, 12-H), 6.89 (t, JH,H = 1.9 Hz, 1 H, 10-H), 6.93 (br. d, JH,H
= 7.70 Hz, 1 H, 14-H), 7.19 [7.20] (t, JH,H = 7.9 Hz, 1 H, 13-H),
3
2
3
7.30–7.40 (m, 6 H, 21-H, 22-H), 7.60–7.63 (m, 4 H, 20-H) ppm.
13C NMR (100 MHz, CDCl3, HSQC): δ = 19.1 (C-23), 20.1 [20.5]
(C-17), 26.7 [26.9] (C-24), 26.8 (C-4) 30.0 [30.1] (C-5), 33.3 (C-27),
48.5 (C-3), 51.9 (C-25), 53.4 (C-2), 55.2 (C-15), 55.7 (C-28), 56.6
[56.7] (C-30 or C-31), 58.8 [59.3] (C-30 or C-31), 63.8 [63.7] (C-6),
72.8 (C-29), 78.8 [78.7] (C-26), 111.0 [110.9] (C-10), 113.0 [113.1]
(C-18), 113.6 [113.4] (C-12), 119.2 [119.0] (C-14), 127.5 (C-21),
128.1 (C-7), 129.4 (C-22), 129.5 (C-13), 132.6 (C-8), 134.0 [133.9]
(C-19), 135.5 (C-20), 138.2 [138.3] (C-9), 145.1 [145.2] (C-16), 159.7
3
3
3
4
=
3
3
3
=
7.9 Hz, 1 H, 13-H), 7.35–7.44 (m, 6 H, 21-H, 22-H), 7.64–7.68 (m,
4 H, 20-H) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 18.32
(C-17), 19.16 (C-23), 26.82 (C-4, C-24), 30.51 [30.61] (C-5), 33.49
[35.61] (C-27), 50.21 (C-3), 52.04 (C-25), 52.20 (C-2), 55.14 (C-15),
55.98 (C-28), 56.67 (C-31), 58.84 (C-30), 64.08 [63.90] (C-6), 72.51
(C-29), 78.61 (C-26), 111.27 [111.20] (C-10), 113.08 [112.95] (C-12),
114.52 [114.59] (C-18), 119.03 (C-14), 127.52 (C-21 or C-22), 128.29
(C-7), 129.31 (C-13), 129.44 (C-21 or C-22), 130.81 (C-8), 133.93
[134.02] (C-19), 135.48 (C-20), 138.50 (C-9), 143.76 (C-16), 159.62
(C-11), 172.4 (C-1) ppm. IR: ν = 3076 (w), 2929 (br.), 2862 (m),
˜
1634 (s), 1604 (m), 1471 (br.), 1427 (s), 1261 (m), 1194 (w), 1156
(w), 1108 (br.), 1045 (m), 971 (w), 893 (w), 823 (w), 801 (m) 742
(m), 703 (s), 688 (w), 614 (m) cm–1. HRMS (ESI): calcd. for
C41H56NO5Si: 670.3928; found 670.3915.
(2,3-syn-1): (2R,3S)-3-(3-tert-Butyldiphenylsilyloxypropyl)-1- (C-11), 171.43 (C-1) ppm. IR: ν = 3076 (w), 2926 (br.), 2862 (m),
˜
[(2S,4R)-4-methoxy-2-(methoxymethyl)pyrrolidin-1-yl]-2-[(E)-2-(3-
methoxyphenyl)ethenyl]-4-methylpent-4-en-1-one (10h): HPLC (1):
k(10h) = 5.7, tR = 10 min; HPLC (2): k(10h) = 1.1 tR = 16 min. Rf
= 0.24 (EA/PE 1:2). [α]2D2 = –1.3 (c = 1.03, CH2Cl2). 1H NMR
1733 (w), 1685 (m), 1635 (s), 1599 (m), 1480 (w), 1462 (s) 1427 (s),
1373 (m), 1262 (m), 1155 (w), 1109 (br.), 1053 (w), 968 (w), 892
(w), 823 (w), 779 (m), 742 (m), 703 (s), 688 (m), 614 (m) cm–1.
HRMS (ESI): calcd. for C41H56NO5Si: 670.3928; found 670.3925.
2354
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2346–2358

Auxiliary-Controlled Zwitterionic Aza-Claisen Rearrangements
General Procedure for Catalytic Hydrogenation: The rearrangement
product 8 or 9 (1 equiv.) was dissolved in ethyl acetate (0.01–0.08 m)
18-H), 4.81 [4.88] (br. s, 1 H, 18-H), 6.74 (m, 2 H, 10-H, 12-H),
3
3
6.79 (br. d, JH,H = 7.6 Hz, 1 H, 14-H), 7.19 [7.20] (t, JH,H
=
and Pd/C (10%, 0.025–0.05 equiv.) was added. The mixture was 7.7 Hz, 1 H, 13-H), 7.34–7.55 (m, 6 H, 21-H, 22-H), 7.66–7.72 (m,
stirred under hydrogen for 24 h (or until completion). The catalyst
was separated by filtration through MgSO4 and the crude product
was purified by preparative HPLC.
4 H, 20-H) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 19.09
(C-23), 20.39 (C-17), 25.66 (C-4), 26.76 (C-24), 30.31 (C-5), 31.40
(C-7), 33.09 (C-27), 33.63 (C-8), 46.75 (C-2), 49.06 (C-3), 52.45 (C-
25), 54.95 (C-15), 55.25 (C-28), 56.50 (C-30), 58.67 (C-31), 63.86
(C-6), 72.72 (C-29), 78.93 (C-26), 111.30 (C-10), 112.76 (C-18),
113.70 (C-12), 120.61 (C-14), 127.47 (C-21), 129.14 (C-13), 129.39
(C-22), 133.8 (C-19), 135.42 (C-20), 143.69 (C-9), 145.08 (C-16),
For yields and data relating to 17/18a to 17/18g and 17/18i to 17/
18m, see the Supporting Information.
(2R,3R)-3-(3-tert-Butyldiphenylsilyloxypropyl)-1-[(2S,4R)-4-meth-
oxy-2-(methoxymethyl)pyrrolidin-1-yl]-2-[2-(3-methoxyphenyl)-
ethyl]-4-methylpent-4-en-1-one (17h): The reaction was carried out
with amide 8h (1.10 g, 1.64 mmol) by the standard procedure. Puri-
fication: preparative HPLC: Nucleosil 50–5 (ID 32ϫ238 mm, pro-
159.50 (C-11), 173.37 (C-1) ppm. IR: ν = 3071 (w), 2931 (s), 2858
˜
(s), 1632 (s), 1478 (w), 1455 (m), 1428 (m), 1259 (s), 1191 (w), 1152
(w), 1105 (b), 1044 (m), 908 (m), 823 (m), 777 (m), 729 (s), 701 (s),
612 (m) cm–1. HRMS (ESI): calcd. for C41H57NO523NaSi:
694.3904; found 694.3938.
pan-2-ol/hexane 5:95, 60 mLmin–1, 63 bar), k(17h) = 2.6, tR
=
8 min; yield 794 mg (1.18 mmol, 72.0%) as a clear, colourless oil.
General Procedure for Iodocyclization: An amide 17 or 18 (1 equiv.)
was dissolved in THF/methanol/water (8:1:1, 0.01 m) and hydro-
chloric acid (1 m, 2.5 equiv.). Iodine (3 equiv.) was added and the
reaction mixture was stirred for 24 h at room temperature. The mix-
ture was then diluted with an excess of ether and the organic phase
was washed twice with a mixture of aq. Na2S2O3 (10%) and brine/
citric acid (pH 2–3) to remove the cleaved pyrrolidine 3 moiety. The
organic phase was dried (MgSO4) and the solvents were removed.
The diastereomers can be separated by preparative HPLC.
1
Rf = 0.21 (EA/PE 1:2). [α]2D4 = +3.5 (c = 1.26, CH2Cl2). H NMR
(400 MHz, CDCl3, COSY): δ = 1.04 (s, 9 H, 24-H), 1.34 (m, 2 H,
5-H, 4-H), 1.54 (m, 1 H, 5-H), 1.64 (s, 3 H, 17-H), 1.70 (m, 1 H,
4-H), 1.92 (m, 3 H, 7-H, 27-H), 2.19 (ddd, 3JH,H = 4.3, JH,H = 6.0,
2JH,H = 12.9 Hz, 1 H, 27-H) 2.36 (m, 1 H, 3-H), 2.40 (m, 1 H, 8-
3
2
H), 2.47 (dt, JH,H = 4.0, JH,H = 9.9 Hz, 1 H, 2-H), 2.69 (ddd,
3JH,H = 5.0, JH,H = 9.5, JH,H = 14.2 Hz, 1 H, 8-H), 3.31 (m, 1 H,
25-H), 3.30 (s, 3 H, 31-H), 3.34 (s, 3 H, 30-H), 3.43 (dd, JH,H
2.5, JH,H = 9.4 Hz, 1 H, 29-H), 3.46 (dd, JH,H = 6.0, JH,H
10.3 Hz, 1 H, 25-H), 3.64 (m, 2 H, 6-H), 3.78 (dd, JH,H = 3.6,
2JH,H = 5.6 Hz, 1 H, 29-H), 3.79 (s, 3 H, 15-H), 4.05 (m, 1 H, 26-
H), 4.33 (m, 1 H, 28-H), 4.71 [4.78] (br. s, 1 H, 18-H), 4.80 [4.84]
(br. s, 1 H, 18-H), 6.73 (m, 1 H, 12-H), 6.74 (m, 1 H, 10-H), 6.77
2
3
=
=
2
3
2
Auxiliary Recycling: The combined aqueous layers were treated
with aq. Na2CO3 (satd.) until pH 12 was reached. After extensive
extraction with diethyl ether (8–10ϫ) the combined organic layers
were washed with brine and dried (MgSO4) and the solvent was
removed to give the crude pyrrolidine 3 (hydrate), which was pure
enough (NMR analysis) for further applications; yield about 60–
90%, containing varying amounts of water.
3
3
3
3
(br. d, JH,H = 7.6 Hz, 1 H, 14-H), 7.20 (dd, JH,H = 7.6, JH,H
=
8.9 Hz, 1 H, 13-H), 7.34–7.42 (m, 6 H, 21-H, 22-H), 7.64–7.67 (m,
4 H, 20-H) ppm. 13C NMR (100 MHz, CDCl3, HSQC, HMBC): δ
= 19.19 (C-23), 21.15 (C-17), 25.55 (C-4), 26.84 (C-24), 30.27 (C-
5), 31.85(C-7), 33.10 (C-8), 33.54 (C-27), 46.70 (C-2), 47.84 (C-3),
52.25 (C-25), 55.06 (C-15), 55.71 (C-28), 56.85 (C-31), 58.90 (C-
30), 63.97 (C-6),72.51 (C-29), 78.62 (C-26), 111.12 (C-12), 112.51
(C-18), 114.06 (C-10), 120.69 (C-14), 127.53 (C-21), 129.23 (C-13),
129.44 (C-22), 134.02 (C-19), 135.51 (C-20), 143.72 (C-9), 145.95
For reactions with 17/18a to 17/18g and 17/18i to 17/18m, see the
Supporting Information.
Iodocyclization of Amide 17h: The reaction was carried out with
amide 17h (9.89 g, 14.72 mmol) by the standard procedure. The
diastereomers can be separated by preparative HPLC: Nucleo-
sil 50–5 (ID 32ϫ238 mm), 70 mLmin–1, 82 bar (EA/hexane 15:85);
yield 7.08 g (10.56 mmol, 71.7%), dr 21/22 = 1:1.0.
(C-16), 159.62 (C-11), 173.64 (C-1) ppm. IR: ν = 3076 (m), 2931
˜
(s), 2858 (s), 1638 (b), 1581 (m), 1491 (m), 1427 (s), 1361 (w), 1259
(s), 1194 (m), 1110 (b), 1046 (s), 894 (m), 823 (m), 778 (m), 741
(s), 702 (s), 615 (m) cm–1. HRMS (ESI): calcd. for: C41H58NO5Si:
672.4084; found 672.4094.
(3R,4R,5R)-4-(3-tert-Butyldiphenylsilyloxypropyl)-5-(iodomethyl)-3-
(3-methoxyphenethyl)-5-methyl-2(3H)-furanone (21): Clear, colour-
less oil. HPLC: k(21) = 1.3, tR = 4.6 min. Rf = 0.37 (EA/PE 1:4).
[α]2D3 = +2.0 (c = 1.02, CH2Cl2). 1H NMR (400 MHz, CDCl3,
(2S,3S)-3-(3-tert-Butyldiphenylsilyloxypropyl)-1-[(2S,4R)-4-meth- COSY): δ = 1.06 (s, 9 H, 24-H), 1.39 (s, 3 H, 17-H), 1.53 (m, 4 H,
oxy-2-(methoxymethyl)pyrrolidin-1-yl]-2-[2-(3-methoxyphenyl)- 4-H, 5-H), 1.98 (m, 2 H, 7-H), 2.30 (m, 1 H, 3-H), 2.39 (ddd, 3JH,H
3
3
3
ethyl]-4-methylpent-4-en-1-one (18h): The reaction was carried out
with amide 9h (305 mg, 0.46 mmol) by the standard procedure. Pu-
rification: preparative HPLC: Nucleosil 50–5 (ID 32ϫ238 mm,
= 4.5, JH,H = 6.4, JH,H = 11.1 Hz, 1 H, 2-H), 2.71 (ddd, JH,H =
7.2, 3JH,H = 9.6, 2JH,H = 13.7 Hz, 1 H, 8-H), 2.90 (ddd, 3JH,H = 6.4,
JH,H = 9.3, 2JH,H = 13.8 Hz, 1 H, 8-H), 3.29 (d, 2JH,H = 11.3 Hz, 1
H, 18-H), 3.50 (d, JH,H = 11.3 Hz, 1 H, 18-H), 3.66 (m, 2 H, 6-
2
propan-2-ol/hexane 2:98), 70 mLmin–1, 72 bar, k(18h) = 27.9 tR
=
50 min; yield 185 mg (0.28 mmol, 60.5%) as a clear, colourless oil.
H), 3.78 (s, 3 H, 15-H), 6.73 (m, 1 H, 12-H) 6.75 (s, 1 H, 10-H),
6.79 (br. d, JH,H = 7.7 Hz, 1 H, 14-H), 7.19 (t, JH,H = 7.6 Hz, 1
3
3
Rf = 0.10 (EA/PE 1:4). [α]2D2 = –12.49 (c = 1.04, CH2Cl2). 1H NMR
(400 MHz, CDCl3, COSY): δ = 1.06 (s, 9 H, 24-H), 1.35 (m, 1 H, H, 13-H), 7.36–7.46 (m, 6 H, 21-H, 22-H), 7.64–7.65 (m, 4 H, 20-
4-H), 1.41 (m, 1 H, 5-H), 1.57 (m, 1 H, 5-H), 1.65 (s, 3 H, 17-H),
H) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 16.00 (C-18),
1.69 (m, 1 H, 4-H), 1.85 (m, 1 H, 7-H), 1.97 (m, 1 H, 7-H), 2.02 19.18 (C-23), 20.62 (C-17), 26.21 (C-4), 26.87 (C-24), 30.98 (C-7 or
3
3
2
(ddd, JH,H = 4.9, JH,H = 8.4, JH,H = 13.2 Hz, 1 H, 27-H), 2.16
C-5), 30.91 (C-7 or C-5), 32.49 (C-8), 45.45 (C-2), 47.15 (C-3),
55.16 (C-15), 63.33 (C-6), 82.70 (C-16), 111.53 (C-12), 114.11 (C-
10), 120.78 (C-14), 127.71 (C-21), 129.43 (C-13), 129.76 (C-22),
133.59 (C-19), 135.52 (C-20), 142.91 (C-9), 159.69 (C-11), 176.09
3
2
(dt, JH,H = 5.5, JH,H = 13.1 Hz, 1 H, 27-H), 2.34 (m, 1 H, 3-H),
2.46 (ddd, JH,H = 6.3, JH,H = 10.7, JH,H = 13.6 Hz, 1 H, 8-H),
3
3
2
3
2
3
2.53 (td, JH,H = 3.4, JH,H = 10.5 Hz, 1 H, 2-H), 2.68 (ddd, JH,H
3
2
= 4.8, JH,H = 10.8, JH,H = 15.5 Hz, 1 H, 8-H), 3.30 (s, 6 H, 30-
(C-1) ppm. IR: ν = 2931 (s), 2858 (s), 1771 (b), 1601 (m), 1585 (m),
˜
3
2
H, 31-H), 3.45 (dd, JH,H = 2.8, JH,H = 9.3 Hz, 1 H, 29-H), 3.49 1489 (m), 1456 (m), 1428 (m), 1385 (w), 1262 (s), 1154 (m), 1110
3
2
(dd, JH,H = 6.4, JH,H = 9.0 Hz, 1 H, 25-H), 3.51 (m, 1 H, 29-H),
3.53 (m, 1 H, 25-H), 3.65 (m, 2 H, 6-H), 3.78 (s, 3 H, 15-H), 4.04
(m, 1 H, 26-H), 4.43 [4.17] (m, 1 H, 28-H), 4.75 [4.78] (br. s, 1 H,
(b), 1052 (s), 958 (w), 823 (w), 784 (w), 741 (s), 702 (s), 614
(m) cm–1. HRMS (ESI): calcd. for C34H43O423NaSi127I: 693.1873;
found 693.1884.
Eur. J. Org. Chem. 2012, 2346–2358
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2355

U. Nubbemeyer et al.
FULL PAPER
(3R,4R,5S)-4-(3-tert-Butyldiphenylsilyloxypropyl)-5-(iodomethyl)-3-
(3-methoxyphenethyl)-5-methyl-2(3H)-furanone (22): White crystals;
m.p. 93.5 °C. HPLC: k(22) = 1.0, tR = 4 min. Rf = 0.42 (EA/PE
1:4). [α]2D3 = +42.9 (c = 0.58, CH2Cl2). 1H NMR (400 MHz, CDCl3,
COSY): δ = 1.04 (s, 9 H, 24-H), 1.50 (s, 3 H, 17-H), 1.55 (m, 4 H,
(m, 6 H, 21-H, 22-H), 7.65–7.67 (m, 4 H, 20-H) ppm. 13C NMR
(70 MHz, CDCl3): δ = 10.12 (C-18), 19.13 (C-23), 25.41 (C-4),
26.87 (C-24), 28.64 (C-17), 31.34 (C-7, C-5), 32.44 (C-8), 45.28 (C-
2), 49.32 (C-3), 55.11 (C-15), 63.29 (C-6), 82.54 (C-16), 111.52 (C-
12), 114.10 (C-10), 120.75 (C-14), 127.70 (C-21), 129.42 (C-13),
4-H, 5-H), 1.90 (m, 2 H, 7-H), 2.12 (m, 1 H, 3-H), 2.53 (ddd, 3JH,H 129.75 (C-22), 133.56 (C-19), 135.50 (C-20), 142.80 (C-9), 159.69
3
3
= 4.9, JH,H = 6.7, JH,H = 11.7 Hz, 1 H, 2-H), 2.68 (ddd, JH,H
=
(C-11), 176.55 (C-1) ppm. IR: ν = 3048 (w), 2927 (s), 2855 (s), 1770
˜
7.2, JH,H = 9.2, 2JH,H = 13.6 Hz, 1 H, 8-H), 2.87 (ddd, 3JH,H = 6.8,
JH,H = 8.8, JH,H = 13.7 Hz, 1 H, 8-H), 3.20 (d, JH,H = 11.2 Hz,
(b), 1601 (m), 1585 (m), 1489 (m), 1456 (m), 1427 (m), 1382 (w),
1260 (s), 1151 (m), 1108 (b), 1043 (m), 951 (w), 823 (w), 782 (w),
740 (s), 700 (s), 613 (m) cm–1. HRMS (ESI): calcd. for
2
2
2
1 H, 18-H), 3.24 (d, JH,H = 11.2 Hz, 1 H, 18-H), 3.65 (m, 2 H, 6-
H), 3.76 (s, 3 H, 15-H), 6.72 (m, 2 H, 10-H, 12-H), 6.75 (br. d, C34H43O423NaSi127I: 693.1873; found 693.1867.
3JH,H = 7.7 Hz, 1 H, 14-H), 7.17 (m, 1 H, 13-H), 7.34–7.44 (m, 6 H,
21-H, 22-H), 7.61–7.71 (m, 4 H, 20-H) ppm. 13C NMR (100 MHz, Supporting Information (see footnote on the first page of this arti-
CDCl3, HSQC): δ = 10.12 (C-18), 19.17 (C-23), 25.44 (C-4), 26.89
(C-24), 28.67 (C-17), 31.37 (C-7, C-5), 32.47 (C-8), 45.31 (C-2),
49.34 (C-3), 55.15 (C-15), 63.30 (C-6), 82.59 (C-16), 111.54 (C-12),
114.12 (C-10), 120.77 (C-14), 127.73 (C-21), 129.45 (C-13), 129.78
cle): Procedures, alternative attempts and data for all new com-
1
pounds mentioned in this paper, H NMR, 13C NMR, COSY and
HSQC spectra of compounds 3l, 4h, 4i, 4j, 4k, 4l, 4m, 8h, 8i, 8j,
8k, 8l, 8m, 9h, 9i, 9j, 9k, 9l, 9m, 10h/11h, 10h/11h, 10i/11i, 10i/11i,
(C-22), 133.57 (C-19), 135.53 (C-20), 142.82 (C-9), 159.69 (C-11), 10j/11j, 10j/11j, 10k/11k, 10k/11k, 10l/11l, 10l/11l, 10m/11m, 12h,
176.61 (C-1) ppm. IR: ν = 2930 (s), 2857 (s), 1771 (b), 1601 (m),
13h, 14h/15h, 14h/15h, 16j, 17h, 17i, 17j, 17k, 17l, 18h, 18i, 18j, 18l,
˜
1581 (m), 1489 (m), 1457 (m), 1428 (m), 1382 (w), 1261 (s), 1151 18m, 21, 22, ent-21, ent-22, IV, XI.
(m), 1110 (b), 1044 (m), 952 (w), 823 (w), 783 (w), 741 (s), 702 (s),
612 (m) cm–1. HRMS (ESI): calcd. for C34H43O4Na23SiI127
693.1873; found 693.1880.
:
Acknowledgments
Iodocyclization of Amide 18h: The reaction was carried out with
amide 18h (172 mg, 0.241 mmol) by the standard procedure. The
diastereomers can be separated by preparative HPLC: Nucleo-
sil 50–5 (ID 32ϫ238 mm), 70 mLmin–1, 81 bar (EA/hexane 15:85);
yield 102 mg (0.15 mmol, 63.3%), dr ent-21/ent-22 = 1.01:1.
We are grateful to the Deutsche Forschungsgemeinschaft (DFG)
for support of this work.
[1] Stereoselective synthesis: Classics in Stereoselective Synthesis,
E. M. Carreira, L. Kvaerno, Wiley-VCH, Weinheim, Germany,
2008.
(3S,4S,5S)-4-(3-tert-Butyldiphenylsilyloxypropyl)-5-(iodomethyl)-3-
(3-methoxyphenethyl)-5-methyl-2(3H)-furanone (ent-21): Clear,
colourless oil. HPLC: k(ent-21) = 1.3, tR = 4.6 min. Rf = 0.37 (EA/
[2] E. A. Ilardi, C. E. Stivala, A. Zakarian, Chem. Soc. Rev. 2009,
PE 1:4). [α]2D2 = –2.3 (c = 1.01). H NMR (400 MHz, CDCl3): δ =
38, 3133–3148.
1
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1.07 (s, 9 H, 24-H), 1.40 (s, 3 H, 17-H), 1.53 (m, 4 H, 4-H, 5-H),
3
2.00 (m, 2 H, 7-H), 2.32 (m, 1 H, 3-H), 2.40 (ddd, JH,H = 4.6,
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3
JH,H = 6.4, JH,H = 11.1 Hz, 1 H, 2-H), 2.73 (m, 1 H, 8-H), 2.92
3
2
(ddd, JH,H = 6.5, JH,H = 9.3, JH,H = 13.9 Hz, 1 H, 8-H), 3.31 (d,
2JH,H = 11.3 Hz, 1 H, 18-H), 3.51 (d, JH,H = 11.3 Hz, 1 H, 18-H),
2
3.69 (m, 2 H, 6-H), 3.79 (s, 3 H, 15-H), 6.74 (m, 1 H, 12-H), 6.77
3
(s, 1 H, 10-H), 6.80 (br. d, JH,H = 7.7 Hz, 1 H, 14-H), 7.20 (t,
3JH,H = 7.7 Hz, 1 H, 13-H), 7.38–7.47 (m, 6 H, 21-H, 22-H), 7.65–
7.67 (m, 4 H, 20-H) ppm. 13C NMR (70 MHz, CDCl3): δ = 15.98
(C-18), 19.15 (C-23), 20.59 (C-17), 26.18 (C-4), 26.85 (C-24), 30.88
(C-7 or C-5), 30.95 (C-7 or C-5), 32.47 (C-8), 45.42 (C-2), 47.14
(C-3), 55.12 (C-15), 63.32 (C-6), 82.67 (C-16), 111.51 (C-12), 114.11
(C-10), 120.76 (C-14), 127.70 (C-21), 129.41 (C-13), 129.74 (C-22),
133.58 (C-19), 135.50 (C-20), 142.89 (C-9), 159.69 (C-11), 176.04
(C-1) ppm. IR: ν = 3069 (w), 2927 (s), 2855 (s), 1770 (b), 1600 (m),
˜
1584 (m), 1489 (m), 1456 (m), 1427 (m), 1385 (w), 1261 (s), 1153
(m), 1109 (b), 1052 (m), 956 (w), 823 (w), 784 (w), 739 (s), 700 (s),
613 (m) cm–1. HRMS (ESI): calcd. for C34H43O423NaSi127I:
693.1873; found 693.1905.
(3S,4S,5R)-4-(3-tert-Butyldiphenylsilyloxypropyl)-5-(iodomethyl)-3-
(3-methoxyphenethyl)-5-methyl-2(3H)-furanone (ent-22): White
crystals; m.p. 96.5 °C. HPLC: k(ent-22) = 1.0, tR = 4 min. Rf = 0.42
(EA/PE 1:4). [α]2D2 = –44.03 (c = 0.89). 1H NMR (400 MHz,
CDCl3): δ = 1.08 (s, 9 H, 24-H), 1.53 (s, 3 H, 17-H), 1.59 (m, 4 H,
4-H, 5-H), 1.94 (m, 2 H, 7-H), 2.16 (m, 1 H, 3-H), 2.57 (ddd, 3JH,H
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3
= 5.2, JH,H = 6.6, JH,H = 11.7 Hz, 1 H, 2-H), 2.71 (m, 1 H, 8-H),
2
2.90 (m, 1 H, 8-H), 3.24 (d, JH,H = 11.2 Hz, 1 H, 18-H), 3.27 (d,
2JH,H = 11.2 Hz, 1 H, 18-H), 3.69 (m, 2 H, 6-H), 3.78 (s, 3 H, 15-
3
H), 6.75 (m, 2 H, 10-H, 12-H), 6.78 (br. d, JH,H = 7.7 Hz, 1 H,
14-H), 7.20 (dd, 3JH,H = 7.6, 3JH,H = 8.9 Hz, 1 H, 13-H), 7.38–7.47
2356
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Eur. J. Org. Chem. 2012, 2346–2358

Auxiliary-Controlled Zwitterionic Aza-Claisen Rearrangements
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overall yield after the final ester cleavage. For experimental de-
tails and data see the Supporting Information.
S. Groß, S. Laabs, A. Scherrmann, A. Sudau, N. Zhang, U.
Nubbemeyer, J. Prakt. Chem. 2000, 342, 711–714.
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[18]
The use of the corresponding acid chlorides induced rapid
von Braun degradation as the major competing process. For
more detailed information, see: a) A. Sudau, U. Nubbemeyer,
Angew. Chem. 1998, 110, 1178–1181; Angew. Chem. Int. Ed.
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611–621; d) J. H. Cooley, E. J. Evain, Synthesis 1989, 1–7.
CCDC-854400 (for 13g) contains supplementary crystallo-
graphic data 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.
CCDC-854399 (for 16j) contains supplementary crystallo-
graphic data 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.
Cleavage with dry HCl (from MeOH and AcCl) gave 3,4-trans-
disubstituted 5,5-dimethyl-(3H)furanones after addition of the
intermediately formed acid to the γ,δ double bond. Further-
more, the TPS protecting group was removed. Workup and pu-
rification were found to be difficult and the yields were vari-
able. Cleavage with hydroxide/hydroperoxide and related rea-
gents required harsh conditions affording low yields and some
equilibration of the stereogenic centre in the α-position. Expla-
nation of the stereochemical outcome thus turned to be diffi-
cult.
a) M. S. Oberinde, H. N. Hunter, S. W. Bremner, M. G. Organ,
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TPS cleavage always led to polar side products, which could be
separated by column chromatography and HPLC. Amides of
type 17/18 with terminal OH groups and lactones of type 21/
22 with side chain OH groups were recycled by treatment with
TPSCl and imidazole to deliver the starting materials 17/18
and the products 21/22, respectively, without affecting the ste-
reogenic centres. Overall, the disposition of Ͼ90% of the mate-
rial subjected to the iodocyclization was ensured. The yields
outlined in Table 2 relate only to the original iodolactonization.
Optimization including the recycling processes was not consid-
ered.
[19]
[20]
[21]
[8]
[9]
Lumiestrone is a well-known compound originally synthesized
in one single step from estrone: A. Butenandt, A. Wolff, P.
Karlson, Ber. Dtsch. Chem. Ges. 1941, 74, 1318–1312. We plan
to generate lumiestrone/estradiol as a model to elaborate the
strategy and to apply these findings to synthesize biologically
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experimental details and spectroscopic data see the Supporting
Information.
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Reactions with sterically encumbered pyrrolidines (3k, 3m, for
instance) gave incomplete conversion and some substitution
without allyl inversion as side products. For the initial aza-
Claisen rearrangement tests the N-allylation of 3k and 3m was
not optimized.
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[13]
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Protection: a) MOM: R. Tamura, K. Watabe, N. Ono, Y. Yam-
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details and data see the Supporting Information.
[24]
[25]
[26]
CCDC-855461 (for 22) contains supplementary crystallo-
graphic data 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.
CCDC-854401 (for ent-22) contains supplementary crystallo-
graphic data 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.
Furthermore, a mixture of amides 17a and 18a was subjected
to iodolactonization, resulting in the racemic mixtures of 21
and 22. The iodolactonization of an analytical sample of 17c
confirmed the findings of NMR analyses of the reaction mix-
ture.
As known in the literature, tertiary amines and acid fluorides
do not react spontaneously: a) D. Granitza, M. Beyermann,
H. Wenschuh, H. Haber, L. A. Carpino, G. A. Truran, M. Bi-
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[16]
Alternatively, a four-step sequence of homoenolate addition,
thiocarbonate activation, Barton–McCombie reduction and es-
ter cleavage gave the saturated acid (X = H) with 81% yield
overall. Through replacement of the reduction by a thermoly-
sis, the butenoic acid (X = H) could be synthesized in 80%
[27]
Eur. J. Org. Chem. 2012, 2346–2358
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2357

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Received: January 23, 2012
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Published Online: March 12, 2012
2358
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2346–2358