Stable chiral spirocyclic [5,5]-ammonium ylides using a metallo carbenoid approach

Article abstract of DOI:10.1016/j.tet.2005.11.020

Enantiomerically pure spiro[5,5]-ammonium ylides were obtained by Rh(II)-catalyzed decomposition of α-diazo-β-carbonylesters. In the crude decomposition mixtures, variable quantities of enamino-α,β-keto esters were detected as secondary products.

Full text of DOI:10.1016/j.tet.2005.11.020

Tetrahedron 62 (2006) 1459–1466
Stable chiral spirocyclic [5,5]-ammonium ylides using
a metallo carbenoid approach
b
Daniele Muroni,a Antonio Sabaa, and Nicola Culeddu
*
a
`
`
Dipartimento di Chimica, Facolta di Scienze, Universita di Sassari, Via Vienna 2, 07100 Sassari, Italy
bCNR Istituto di Chimica Biomolecolare Sez. di Sassari, Via La Crucca, Baldinca- Li Punti (Sassari) 07040, Italy
Received 14 September 2005; revised 21 October 2005; accepted 10 November 2005
Available online 2 December 2005
Abstract—Enantiomerically pure spiro[5,5]-ammonium ylides were obtained by Rh(II)-catalyzed decomposition of a-diazo-b-
carbonylesters. In the crude decomposition mixtures, variable quantities of enamino-a,b-keto esters were detected as secondary products.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
non-isolable ylide intermediates, a high degree of chirality
transfer from the ammonium N atom was previously
observed.2
Recently, we prepared enantiopure indolizidinone alkaloids
2 by a carbenoid/spiro[5,5]-ammonium ylide/Stevens [1,2]-
shift with ring-expansion tandem sequence1 (Scheme 1).
In this contest, isolation and characterization of ylide
intermediates 1 in a stable and enantiopure form, enabled us,
by studying their reactivity, to probe unambiguously the
complete reaction cascade pathway previously proposed for
similar processes, including the stereochemical reaction
course.2 We proved high chirality transfer from the original
proline template to a second temporary spirocyclic
ammonium nitrogen through its stereoselective quaternari-
zation. The second one permitted the preservation of the
original stereocenter during its [1,2]-shift to the newly
formed neighbour quaternary indolizidinone stereocenter, a
synthetic application of the SRS (self-regeneration of
stereocenters) Seebach principle.3
This stereoselectivity is in line with the extensive
investigations of Ollis that demonstrate a solvent caged
radical pair Stevens [1,2]-rearrangement reaction
mechanism4 or with an alternative recently proposed ion
pair mediated mechanism.5
Concerning the Stevens [1,2]-rearrangement, notwithstand-
ing the considerable examples performed in related studies,
there are few synthetic applications. One limitation of this
methodology is the need for activating groups on the
migrating carbons, such as allyl, aryl, carbonyl6 and silyl;2c
consequently, no examples of a primary carbon migration
have been reported, except for a few cases.7
In view of the mild conditions, the carbenoid route seems
most suitable for intramolecular ylide trapping, and given
the rarity of stable spirocyclic ammonium ylides obtained
In some related studies involving metallo carbenoid
generation and Stevens [1,2]-rearrangement of similar
R
CO2Et
O
R
[1,2]
N
R
CO2Et
N
H
N
O
2
R=COOR'
1
Scheme 1.
Keywords: Diazocompounds; Catalytic decomposition; Cascade process; Rearrangement.
*
Corresponding author. Tel.: C39 079 229538; fax: C39 079 229559; e-mail: saba@uniss.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.020

1460
D. Muroni et al. / Tetrahedron 62 (2006) 1459–1466
by this protocol,8 we were interested in increasing their
number and in studying their reactivity, including rearrange-
ment and cycloaddition reactions.
rearrangement of the corresponding ylide 5d; to our
knowledge, no examples of tertiary carbon Stevens-type
migration are reported.
For our purposes, the synthesis of diazoketones 4a, 4b, 4c,
4d and 4e was planned (Figs. 1 and 2). Due to the proper
diazo group position on the chain tethered to pyrrolidine or
isoindoline nitrogen atom, [5,5]-spirocyclic ammonium
ylides 5a, 5b, 5c, 5d and 5e (Fig. 3) were expected to
form predominantly as intermediates, by nitrogen trapping
of the metallocarbene precursors, over competitive C–H
insertion processes.
2. Results and discussion
All the diazoketoesters 4a–e, were conveniently prepared in
two steps. First step was the conjugate addition of
isoindoline 3a to (K)-menthyl-3-keto-pent-4-enoate,9 and
3,4-bis-methoxymethoxy-pyrrolidine 3b,10 1,4-dideoxy-
2,3,5,6-O-isopropylidene-1,4-imino-D-talitol 3c,11 2-meth-
oxymethyl-2-methyl-pyrrolidine 3d,12 and 1,4-dideoxy-2,3-
di-O-isopropylidene-1,4-imino-5-O-trityl-L-lyxitol 3e13 to
ethyl-3-keto-pent-4-enoate.14 Then the N-alkyl-isoindoline
and the N-alkyl-pyrrolidines obtained were submitted to
diazo-transfer reaction with tosylazide.
Moreover, for evaluating the enantioselectivity in
generating quaternary ammonium stereocenters, the chiral
diazo-substrates 4b, 4c and 4e were prepared as single
enantiomers.
1H NMR analysis of diazoketoesters 4b and 4c and 4e
indicated their enantiomeric purity.
Finally, the diazocompound 4d synthesis was suggested by
our interest in evaluating the possibility of the Stevens [1,2]-
O
O
O
O
O
O
O
O
O
H
N
Ph
Ph
O
O
N
H
N
H
N
H
N
H
O
O
Ph
O
3a
3b
3c
3d
3e
Figure 1.
O
O
O
O
O
O
O
O
O
H
Ph
Ph
O
N
O
O
O
N
N
N
N
Ph
O
O
O
O
O
OEt
O
O(-)Ment
O
OEt
O
OEt
O
OEt
N+
N–
N+
N–
N+
N–
N+
N–
N+
N–
4b
4a
4c
4e
4d
Figure 2.
O
O
O
O
O
O
O
Ph
Ph
Ph
O
O
O
H
O
N
O
N
O
O
O
O
N
N
N
O
OEt
OMent
O
OEt
OEt
OEt
O
O
O
O
5b
5c
5d
5a
5e
Figure 3.

D. Muroni et al. / Tetrahedron 62 (2006) 1459–1466
1461
Table 1.
R
N
R
R
N
O
OR
N
diazodecomposition
N2
O
+
O
Rh2(OAc)4 / CH2Cl2 / rfx
OR
O
O
OR
O
4
5
6
Substrate
Yield (%)a
5:6b
4a
4b
4c
4d
4e
92
89
76
87
81
80:20
75:25
100:—
70:30
—:100
a Isolated yield after column chromatography.
b Reflects percent conversion (measured by 1H NMR of crude mixture after removal of solvents).
When the diazocompounds 4a, 4b, 4c and 4d were refluxed
in CH2Cl2 solution, in the presence of rhodium(II) acetate,
the corresponding ylides 5a, 5b, 5c and 5d were obtained15
(Fig. 3 and Table 1).
Ylide 5d was obtained as a 44:56 diastereomeric mixture. In
the crude decomposition mixtures, variable quantities of
enamino-a,b-keto esters 6a, 6b and 6c were detected as
secondary products (Fig. 4). No detectable amount of ylide
O
O
O
O
O
O
O
Ph
Ph
N
O
O
O
N
O
N
O
N
O
Ph
O
O
O
OEt
OMent
OEt
OEt
6a
6b
6d
6e
Figure 4.
R
N
R
R
EtO
O
EtO
O
EtO
O
N
N
hydride
shift
O
O
O
H
Rh2Ln
Rh2Ln
7
8
R
R
R
EtO
O
EtO
O
N
N
O
N
O
O
proton
exchange
O
OEt
8
9
Scheme 2.

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D. Muroni et al. / Tetrahedron 62 (2006) 1459–1466
Figure 5. ORTEP view of compound 5a.
MentO2C
MentO2C
O
O
Cu(acac)2
toluene, rfx
4a
+
5a
N
toluene, rfx
N
10a
10'a
Scheme 3.
was found in the crude reaction mixture of the dirhodium
tetraacetate decomposition of diazoketone 4e in boiling
CH2Cl2 solution. In this case, ketopentenoic ester 6e was
obtained as the exclusive product in 81% isolated yield.
without catalyst, the same diastereomeric mixture was
obtained (Scheme 3).
No Stevens rearrangement products but undetectable
decomposition mixtures were obtained by heating of
ylides 5b and 5c and 5d under the above reaction
conditions.
The formation of unsaturated compounds can be rational-
ized by a mechanism (Scheme 2), which involves an initial
intramolecular metal–carbene hydride-abstraction,16 to give
a transient zwitterion intermediate 7, which then produces
the zwitterion enolate/ketone 8. This seemingly undergoes
proton exchange17 with an adjacent a-hydrogen to give a
new zwitterionic intermediate 9. A subsequent dissipation
of the charges then occurs to furnish enamine 6 with trans
configuration (1H NMR spectroscopy).
3. Conclusion
These preliminary studies have shown that stable
ammonium ylides may also be obtained using the mild
and concise metallo carbenoid protocol. The ready isolation
of these intermediates could be attributed to the stabilizing
effect exerted on the charged ylide carbon atom by the
presence of both carbonyl and ester groups. The lack of
ylide formation in the catalytic decomposition of diazo-
compound 4e can be rationalized in terms of steric factors.
Isolation of ylide 5a crystals enabled the single crystal
X-ray analysis18 to be performed (Fig. 5).
The absolute configuration of ylide 5c was deduced from 2D
NOESY correlation studies. Thus, the NOESY trace of ethyl
ester methylene protons shows a positive NOE effect for the
acetonide methylene protons.
Moreover, the thermal decomposition of ylide 5a, affording
the same mixture of alkaloids 10a and 100a as obtained by
catalytic decomposition of the starting diazoketone 4a,
provides a further clear confirmation of a carbenoid/
spiro[5,5]-ammonium ylide/Stevens [1,2]-shift with ring-
expansion tandem sequence. In this case, the [1,2]-shift is
assisted by the presence of the aryl group on the migrating
carbon.
1
The H NMR analysis of ylides 5b and 5c indicated their
enantiomeric purity.
Decomposition of the diazocompound 4a in boiling
toluene in the presence of Cu(acac)2 provided an
inseparable 1:1 diastereomeric mixture of indolizidinone
alkaloids 10a and 100a; surprisingly no enantioselection
was obtained. By heating of ylide 5a in toluene at reflux,
No Stevens-type rearrangement products were detected in
the crude reaction mixtures of the attempted thermal

D. Muroni et al. / Tetrahedron 62 (2006) 1459–1466
1463
decomposition of ylides 5b and 5c: this is presumably due to
the absence of activating groups on the potential migrating
carbons.
(ethyl acetate/Et2O, 10:1), mp 185–187 8C; [a]2D5 K45 (c
0.4, CHCl3); 1H NMR: d 0.76 (d, 3H, JZ6.9 Hz), 0.88 (two
overlapping doublets, 6H, JZ6.9 Hz), 1.02–1.06 (m, 1H),
1.07–1.25 (m, 1H), 1.36–1.65 (m. 4H), 2.06–2.24 (m, 3H),
2.45–2.73 (m, 2H), 3.65–3.69 (m, 2H), 4.27–4.50 (m, 2H),
4.74 (dt, 1H, d: JZ4.5 Hz, t: JZ10.8 Hz), 5.74–5.86 (m,
2H), 7.26–7.41 (m, 4H); 13C NMR (CDCl3): d 16.1, 20.9,
22.1, 23.3, 25.7, 32.6, 32.8, 34.3, 41.5, 46.8, 63.3, 68.6,
72.9, 123.0, 128.9, 133.8, 163.2, 178.3; IR (Nujol): 2924,
2854, 1640, 1606, 1460, 1413, 1376, 1200, 1112, 1013, 973,
767and 723 cmK1. Anal. Calcd for C23H31NO3: C, 74.46;
H, 8.46; N, 3.79. Found: C, 74.20; H, 8.76; N, 3.55.
No rearrangement products were also observed by heating
of ylide 5d; in our opinion, this result rules out the radical
pair reaction mechanism. Due to its stability, a putative
migrating tertiary radical intermediate would favour the
rearrangement process.
4. Experimental
4.1. General
3-Oxo-5-[1,3dihydroisoindol-yl]-pent-3,4-enoic acid (K)-
menthyl ester 6a, brown oil; [a]2D5 K34 (c 0.11, CHCl3); 1H
NMR: d 0.76 (d, 3H, JZ6.9 Hz), 0.86–0.91 (m, 6H),
0.98–1.10 (m, 2H), 1.25 (s, 2H), 1.32–1.51 (m, 2H),
1.63–1.70 (m, 3H), 1.83–2.06 (m, 2H), 3.42 (s, 2H), 4.75
(dt, 1H, d: JZ4.5 Hz, t: JZ10.8 Hz), 4.87 (s, 2H), 5.21 (d,
1H, JZ12.6 Hz), 7.26–7.34 (m, 4H), 7.90 (d, 1H, JZ
12.6 Hz); 13C NMR (CDCl3): d 16.2, 20.7, 22.0, 23.2, 26.0,
29.7, 31.4, 34.2, 40.7, 46.8, 53.3, 57.1, 74.9, 122.5, 122.7,
127.9, 128.0, 135.7, 149.1, 168.5, 188.7; IR (neat): 2955,
2869, 1715, 1650, 1571, 1463, 1361, 1271, 1143, 1097, 989
and 741 cmK1. Anal. Calcd for C23H31NO3: C, 74.46; H,
8.46; N, 3.79. Found: C, 74.54; H, 8.31; N, 3.40.
1H (300 MHz) and 13C NMR (75 MHz) spectra were recorded
on a Varian VXR-300 spectrometer with TMS as internal
standard. COSY, NOESY, HSQC and USQC-TOSCY spectra
were recorded with a Bruker Avance 600 NMR spectrometer
equipped with inverse detection probe. Infrared (IR) spectra
were performed on a FT/IR-480plus JASKO spectropho-
tometer. The optical rotations were measured by a polarimeter
P-1010 JASKO in a 1 dm tube. All reagents and solvents
employed were reagent grade materials purified by standard
methods and redistilled before use.
4.1.1. 2-Diazo-3-oxo-5-[1,3-dihydroisoindol-yl]-pentanoic
acid (K)-menthyl ester 4a. To a stirred solution of
isoindoline 3a (0.5 g, 0.0042 mol) and 3-oxo-pent-4-enoic
acid (K)-menthyl ester (1.1 g, 0.004 mol) in CH2Cl2
(15 mL), a solution of Et3N (0.76 mL, 0.0055 mol) in
CH2Cl2 (10 mL) was added dropwise and stirred for
30 min. To the reaction mixture, tosyl azide (1.1 g,
0.0055 mol) and a solution of Et3N (1.1 mL, 0.015 mol) in
CH2Cl2 (10 mL) were added dropwise at 0 8C. After the
addition was complete, the solution was stirred at room
temperature overnight. The solvent was evaporated and the
residue was purified by flash chromatography (petroleum
ether/Et2O, 8:2) affording the title compound 4a (0.995 g,
60% yield) as a yellow-brown oil: [a]2D5 K53 (c 0.7, CHCl3);
1H NMR: d 0.80 (d, 3H, JZ6.9 Hz), 0.92 (two overlapping
doublets, 6H, JZ6.9 Hz), 0.99–1.12 (m, 2H), 1.39–1.53 (m,
2H), 1.69–1.73 (m, 3H), 1.80–1.90 (m, 1H), 2.04–2.17 (m,
1H), 3.07–3.20 (m, 4H), 3.98 (s, 4H), 4.84 (dt, 1H, d: JZ
4.5 Hz, t: JZ10.8 Hz), 7.18 (s, 4H); 13C NMR (CDCl3): d
16.4, 20.6, 21.9, 23.5, 26.5, 31.4, 34.0, 39.1, 41.0, 46.9, 50.6,
58.9, 75.7, 76.5, 122.2, 126.7, 139.8, 160.9, 191.4; IR (neat):
2955, 2870, 2765, 2368, 2131, 1710, 1656, 1455, 1368, 1209,
1039, 1014, 913, 873 and 742 cmK1. Anal. Calcd for
C23H31N3O3: C, 69.49; H, 7.86; N, 10.57. Found: C, 69.61;
H, 7.58; N, 10.75.
4.1.3. (10aR,S)-1-Oxo-2,3,4,5,10-tetrahydro-1H-pyr-
rolo[1,2-b]-isoquinoline-10a-carboxylic acid (K)-
menthyl esters 10a and 100a. A solution of diazoketoester
4a (0.44 g, 0.00110 mol) in toluene (5 mL) was refluxed for
30 min in the presence of Cu(acac)2 (0.005 g, 2 mol%). The
solvent was evaporated and the residue gave, after flash
chromatography (petroleum ether/ethyl acetate, 9:1) the title
compounds 10a and 100a as a 1:1 mixture of diastereo-
isomers (0.21 g, 52% yield). 1H NMR: d 0.62 (0.41) (d, 3H,
JZ6.9 Hz), 0.76–0.92 (m, 9H), 1.19–1.37 (m, 5H),
1.56–1.74 (m, 4H), 2.48–2.67 (m, 2H), 2.87 (2.82) (d, 1H,
JZ15.6 Hz), 3.24–3.38 (m, 2H), 3.52 (q, 1H, JZ7.8 Hz),
4.02–4.23 (m, 2H), 4.60 (4.56) (dt, 1H, d: JZ4.5 Hz, t: JZ
10.8 Hz), 7.07–7.17 (m, 4H). Anal. Calcd for C23H31NO3:
C, 74.46; H, 8.46; N, 3.79. Found: C, 74.31; H, 8.18; N,
3.98.
4.1.4. 5-[(3S,4S)-3,4-Bis(methoxymethoxy)pyrrolidin-1-
yl]-2-diazo-3-oxo-pentanoic acid ethyl ester 4b. To a
stirred solution of 3,4-bis-methoxymethoxy-pyrrolidine 3b
(1.6 g, 0.008 mol) in CH2Cl2 (15 mL) a solution of 3-oxo-
pent-4-enoic acid ethyl ester (1.1 g, 0.008 mol) in CH2Cl2
(10 mL) was added dropwise and stirred for 30 min. To the
reaction mixture tosyl azide (1.6 g, 0.008 mol) and a
solution of Et3N (2.8 mL, 0.02 mol) in CH2Cl2 (10 mL)
were added dropwise at 0 8C. After the addition was
complete, the solution was warmed to room temperature and
stirred overnight. The solvent was evaporated and the
residue was purified by flash chromatography (Et2O/
petroleum ether/Et3N, 8:2:0.1) to give the title compound
4b (1.8 g, 70% yield) as a yellow oil; [a]2D5 C3 (c 0.6,
CHCl3); 1H NMR (CDCl3): d 1.33 (t, 3H, JZ7.2 Hz), 2.58
(dd, 2H, JZ4.2, 10.5 Hz); 2.70–2.90 (m, 2H), (dd, 2H, JZ
6.0, 9.9 Hz), 3.09 (dd, 2H, JZ6.9, 8.1 Hz), 3.37 (s, 6H),
4.13 (dd, 2H, JZ4.2, 5.1 Hz), 4.29 (q, 2H, JZ7.2 Hz), 4.67
(AB system, 4H); 13C NMR (CDCl3): d 14.2, 38.6. 50.4,
4.1.2. Diazo-decomposition of 4a. A solution of diazoke-
toester 4a (0.5 g, 0.00126 mol) in CH2Cl2 (5 mL) was
refluxed for 30 min in the presence of Rh2(OAc)4 (0.007 g,
2 mol%). The solvent was evaporated and the residue gave a
80:20 mixture of 5a and 6a. After flash chromatography
(Et2O/MeOH/Et3N, 5:5:0.1) 5a was obtained as a white
solid (0.336 g, 74% yield) and 6a as impure brown oil
(0.081 g, 18% yield).
20-[(K)-Menthoxycarbonyl]-30-oxo-1,3-dihydrospiro [iso-
indole-2,10-pyrrolidine]-20-ylide 5a colourless needles

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D. Muroni et al. / Tetrahedron 62 (2006) 1459–1466
55.3, 58.6, 61.2, 76.0, 81.1, 95.4, 161.0, 191.1; IR (neat):
2945, 2822, 2136, 1718 and 1655 cmK1. Anal. Calcd for
C15H25N3O7: C, 50.13; H, 7.01; N, 11.69. Found C, 50.24;
H, 7.03; N, 11.65.
25.1, 26.3, 27.1, 38.5, 49.5, 58.9, 61.2, 66.1, 70.6, 76.0,
78.6, 81.8, 109.3, 112.7, 161.1, 191.5; IR (neat): 2985, 2936,
2134, 1715, 1654, 1455, 1372, 1300, 1211, 1078, 1159,
1053, 856 and 747 cmK1. Anal. Calcd for C19H29N3O7: C,
55.46; H, 7.10; N, 10.21. Found: C, 55.71; H, 6.96; N, 10.44.
4.1.5. Diazo-decomposition of 4b. To a refluxing solution
of Rh2(OAc)4 (0.013 g, 3 mol%) in 30 mL of dry CH2Cl2, a
solution of 4b (0.360 g, 0.001 mol) in dry CH2Cl2 (20 mL)
was added dropwise over 30 min. After stirring for another
30 min at reflux, the reaction mixture was cooled and
evaporated to give a 75:25 mixture of 5b and 6b.
Purification by flash chromatography (Et2O/ethyl acetate/
Et3N, 5:5:0.1; Et2O/MeOH/Et3N, 5:5:0.1) gave 0.22 g (67%
yield) of 5b as a yellow amorphous solid and 0.074 g (22%
yield) of 6b as yellow oil.
4.1.7. (6R,7S,8S)-1-Ethoxy carbonyl-6a-[(6aS)-2,2-
dimethyl-1,3-dioxolan-6a-yl]-2,2-dimethyl tetrahydro-
7H-[1,3]-dioxolo 2-oxo-5-azonia-spiro[4,4]nonane-1-
ylide 5c. A solution of the diazoketoester 4c (0.517 g,
0.00126 mol) in CH2Cl2 (10 mL) was refluxed for 30’ in the
presence of Rh2(OAc)4 (0.015 g, 3 mol%). The solvent was
evaporated and the residue gave, after flash chromatography
(Et2O/MeOH/Et3N, 5:5:0.1) the title compound 5c as
amorphous grey solid (0.365 g, 76% yield). [a]2D5 K47 (c
1
0.37, CHCl3); H NMR: d 1.32 (s, 3H), 1.34 (t, 3H, JZ
6.9 Hz), 1.35 (s, 3H), 1.42 (s, 3H), 1.56 (s, 3H), 2.05–2.60
(m, 1H), 2.86 (quintet, 1H, JZ4 Hz), 3.61 (t, 1H, JZ
7.8 Hz), 3.83 (dt, 1H, JZ2.4, 8.7 Hz), 3.94–4.37 (m, 7H),
4.41 (dd, 1H, JZ7.2, 12.8 Hz), 4.96 (t, 1H, JZ6.6 Hz), 5.09
(dt, 1H, JZ0.6, 6.6 Hz); 13C NMR (CDCl3): d 14.6, 24.8,
26.6, 27.3, 33.4, 59.3, 65.2, 68.6, 76.7, 77.9, 80.8, 86.5,
105.8, 110.4, 113.7, 163.4, 179.4; IR (neat): 2926, 2854,
1652, 1607, 1460, 1419, 1376, 1263, 1210, 1078, 1055,
861and 844 cmK1. Anal. Calcd for C19H29NO7: C, 59.52;
H, 7.62; N, 3.65. Found: C, 59.40; H, 7.83; N, 3.43.
(7S,8S)-1-Ethoxycarbonyl-7,8-bis-methoxymethoxy-2-oxo-
5-azonia-spiro[4.4] nonane-1-ylide 5b [a]2D5 K3 (c 0.15,
CHCl3); 1H NMR: d 1.35 (t, 3H, JZ7.2 Hz), 2.60 (t, 2H, JZ
7.8 Hz), 3.25 (d, 1H, JZ12.9 Hz), 3.39 (d, 6H, JZ6.6 Hz),
3.55–3.64 (m, 2H), 3.70–3.90 (m, 1H), 4.26 (q, 2H, JZ
7.2 Hz), 4.37–4.58 (m, 3H), 4.68 (dd, 2H, JZ6.9, 10.2 Hz),
4.75 (dd, 2H, JZ3.3, 6.9 Hz), 4.88 (dd, 1H, JZ6.9,
12.9 Hz); 13C NMR (CDCl3): d 14.7, 32.8, 55.9, 59.0,
63.3, 66.0, 80.0, 80.2, 96.3, 96.4, 102.3, 162.3, 178.3; IR
(neat): 2933, 2826, 1735, 1653, 1609 and 1567 cmK1. Anal.
Calcd for C15H25NO7: C, 54.37; H, 7.60; N, 4.23. Found: C,
54.17; H, 7.58; N, 4.21.
4.1.8. rac-2-Diazo-5-(2-methoxymethyl-2-methyl-pyrro-
lidin-1-yl)-3-oxo-pentanoic acid ethyl ester 4d. TFA
(0.48 mL, 0.006 mol) was added dropwise under nitrogen
atmosphere to rac-N-Boc-2-methoxymethyl-2-methyl-pyr-
rolidine 3d (0.31 g, 0.0016 mol) at 0 8C. The mixture was
stirred at room temperature until the disappearance of the
substrate (1H NMR) and formation of trifluoroacetate of the
amine (about 1 h) and then the excess of TFA was
evaporated in vacuum at room temperature. To a stirred
solution of the residue and 3-oxo-pent-4-enoic acid ethyl
ester (0.35 g, 0.0025 mol) in CH2Cl2 (10 mL), a solution of
Et3N (0.35 mL, 0.0025 mol) in CH2Cl2 (10 mL) was added
dropwise and stirred for 30 min. To the reaction mixture,
tosyl azide (0.36 g, 0.0025 mol) and a solution of Et3N
(1.0 mL, 0.0075 mol) in CH2Cl2 (10 mL) were added
dropwise at 0 8C. After the addition was complete, the
solution was stirred at room temperature overnight. The
solvent was evaporated and the residue was purified by flash
chromatography (Et2O/petroleum ether/Et3N, 6:4:0.1) to
give the title compound 4d (0.30 g, 70% yield) as a yellow
(4E)-5-[(3S,4S)-3,4-bis(Methoxymethoxy)pyrrolidin-1-yl]-
3-oxo-pentenoic acid ethyl ester 6b [a]2D5 C5 (c 0.10,
CHCl3); 1H NMR: d 1.27 (t, 3H, JZ7.1 Hz), 3.23 (d, 1H, JZ
12.6 Hz), 3.36 (s, 6H), 3.38 (s, 2H), 3.44 (d, 1H, JZ11.8 Hz),
3.53 (d, 1H, JZ11.7 Hz), 4.14–4.21 (m, 1H), 4.17 (q, 2H, JZ
7.1 Hz), 4.26 (broad s, 1H), 4.60–4.75 (m, 4H), 5.09 (d, 1H,
JZ12.6 Hz), 7.74 (d, 1H, JZ12.6 Hz); 13C NMR (CDCl3): d
14.13, 48.2, 51.5, 55.6, 55.7, 60.9, 78.3, 78.7, 95.8, 96.4,
149.5, 168.9, 188.3; IR (neat): 3031, 2948, 2853, 2829, 1730,
1655 and 1593 cmK1. Anal. Calcd for C15H25NO7: C, 54.37;
H, 7.60; N, 4.23. Found: C, 54.25; H, 7.63; N, 4.24.
4.1.6. 2-Diazo-5-[(3aS,4aS,6aR)-4-[(4S)-2,2-dimethyl-
1,3-dioxolan-4-yl]-2,2-dimethyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyrrol-5-yl]-3-oxo-pentanoic acid ethyl
ester 4c. To a stirred solution of 1,4-dideoxy-2,3,5,
6-O-isopropylidene-1,4-imino-D-talitol 3c (0.679 g,
0.00279 mol) and 3-oxo-pent-4-enoic acid ethyl ester
(0.397 g, 0.00279 mol), in CH2Cl2 (15 mL), a solution of
Et3N (0.60 mL, 0.0042 mol) in CH2Cl2 (10 mL) was added
dropwise and stirred for 30 min. Tosyl azide (0.840 g,
0.0042 mol) and a solution of Et3N (0.60 mL, 0.0042 mol)
in CH2Cl2 (10 mL) were then added dropwise at 0 8C. After
the addition was complete, the solution was stirred at room
temperature overnight. The solvent was evaporated and the
residue gave, after flash chromatography (petroleum ether/
Et2O, 8:2), the title compound 4c (0.580 g, 84% yield) as a
yellow-brown oil: [a]2D5 C81.6 (c 0.32, CHCl3); 1H NMR: d
1.29 (s, 3H); 1.33 (t, 3H, JZ6.6 Hz), 1.34 (s, 3H), 1.42 (s,
3H), 1.50 (s, 3H), 2.58 (dd, 1H, JZ5.7, 10.2 Hz), 2.83–2.89
(m, 2H), 2.95–3.13 (m, 2H), 3.30–3.39 (m, 2H), 3.76 (dd,
1H, JZ1.2, 8.1 Hz), 4.01 (dd, 1H, JZ1.8, 8.1 Hz), 4.20 (q,
1H, JZ6.6 Hz), 4.31 (AB system, 2H), 4.36 (dd, 1H, JZ
3.9, 6.9 Hz), 4.57–4.63 (m, 1H); 13C NMR (CDCl3): d 24.8,
1
oil: H NMR (CDCl3): d 0.96 (s, 3H), 1.33 (t, 3H, JZ
7.2 Hz), 1.48–1.59 (m, 1H), 1.74 (quintet, 2H, JZ7.2 Hz),
1.84–1.96 (m, 2H), 2.61 (q, 1H, JZ7.8 Hz), 2.67–2.77 (m,
1H), 2.93–3.07 (m, 2H), 3.20 (s, 3H), 3.33 (s, 3H), 4.30 (q,
2H, JZ7.2 Hz); 13C NMR (CDCl3): d 14.3, 17.9, 21.2, 35.9,
40.3, 44.3, 51.6, 59.2, 61.3, 62.8, 76.1, 78.7, 161.3, 192.0;
IR (neat): 2965, 2928, 2132, 1718 and 1656 cmK1. Anal.
Calcd for C14H23N3O4: C, 56.55; H, 7.80; N, 14.13. Found:
C, 56.73; H, 7.77; N, 14.05.
4.1.9. Diazo-decomposition of 4d. To a refluxing solution
of Rh2(OAc)4 (0.013 g, 3 mol%) in 30 mL of dry CH2Cl2, a
solution of 4d (0.297 g, 0.001 mol) in dry CH2Cl2 (20 mL)
was added dropwise over 30 min. After stirring for another
30 min at reflux, the reaction mixture was cooled and
concentrated to give a 69:31 mixture of 5d and 6d (1H

D. Muroni et al. / Tetrahedron 62 (2006) 1459–1466
1465
NMR). Purification by flash chromatography (Et2O/ethyl
acetate/Et3N, 5:5:0.1; MeOH) gave 0.081 g of 6d as a
yellow oil and 0.180 g of inseparable mixture of ylides 5d in
the ratio of 44:56 (1H NMR).
60.8, 62.6, 63.9, 77.6, 79.0, 87.5, 112.7, 127.2, 127.8, 128.5,
143.4, 149.7, 168.7, 188.7; IR (neat): 3057, 3032, 2984,
2938, 1731, 1659, 1556, 1490, 1448, 1372, 1211, 1155,
1082, 982, 861, 764, 748, 706 and 648 cmK1. Anal. Calcd
for C34H37NO6: C, 73.49; H, 6.71; N, 2.52. Found: C, 73.22;
H, 6.50; N, 2.51.
(4E)-5-(2-Methoxymethyl-2-methyl-pyrrolidin-1-yl)-3-
oxo-pent-4-enoic acid ethyl ester 6d H NMR (CDCl3): d
1
1.27 (t, 3H, JZ7.2 Hz), 1.29 (s, 3H), 1.66–1.78 (m, 1H),
1.87–2.01 (m, 2H), 2.01–2.15 (m, 1H), 3.22–3.34 (m, 4H),
3.34 (s, 3H), 3.39 (s, 2H), 2.61 (q, 1H, JZ7.8 Hz),
2.67–2.77 (m, 1H), 2.93–3.07 (m, 2H), 3.20 (s, 3H),
3.33 (s, 3H), 4.18 (q, 2H, JZ7.2 Hz) 5.06 (d, 1H, JZ
12.6 Hz), 7.78 (d, 1H, JZ12.6 Hz); 13C NMR (CDCl3): d
14.2, 21.7. 23.7, 35.9, 48.6, 48.7, 59.4, 60.9, 65.1, 78.3,
98.0, 146.9, 169.1, 188.0; IR (neat): 2977, 2934, 2874,
1735, 1651, 1600 and 1556 cmK1. Anal. Calcd for
C14H23NO4: C, 62.43; H, 8.61; N, 5.20. Found: C,
62.51; H, 8.60; N, 5.18.
Acknowledgements
This work was supported by M.I.U.R. and Regione
Autonoma della Sardegna. Thanks are due to Mr Mauro
Mucedda for experimental assistence.
References and notes
1. Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry
2004, 15, 2609.
2. (a) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994, 116,
8420. (b) Naidu, B. N.; West, F. G. Tetrahedron 1997, 53,
16565. (c) Vanecko, J. A.; West, F. G. Org. Lett. 2002, 4, 2813.
(d) Padwa, A.; Beall, L. S.; Eidell, C. K.; Worsencroft, K. J.
J. Org. Chem. 2001, 66, 2414. (e) Clark, J. S.; Hodgson, P. B.
Tetrahedron Lett. 1995, 36, 2519. (f) Chelucci, G.; Saba, A.;
Valenti, R.; Bacchi, A. Tetrahedron: Asymmetry 2000, 11,
3449. (g) Saba, A. Tetrahedron Lett. 2003, 44, 2895. (h)
Wright, D. L.; Wekly, R. M.; Groff, R.; Mc Mills, M. C.
Tetrahedron Lett. 1996, 37, 2165. (i) Zaragoza, F. Synlett
1995, 237. (j) West, F. G.; Glaeske, K. W.; Naidu, B. N.
Tetrahedron: Asymmetry 2003, 14, 917.
4.1.10. 2-Diazo-5-[(3aR,4S,6aS)-(2,2-dimethyl-4-trityloxy-
methyl-tetrahydro[1,3] dioxolo[4,5-c]-pyrrol-5-yl)]-3-oxo-
pentanoic acid ethyl ester 4e. To a stirred solution of 1,4-
dideoxy-2,3-di-O-isopropylidene-1,4-imino-5-O-trityl-L-lyx-
itol3e(2.57 g,0.0062 mol), and3-oxo-pent-4-enoicacidethyl
ester (0.88 g, 0.0062 mol), in CH2Cl2 (15 mL), a solution of
Et3N (1.35 mL, 0.0096 mol) in CH2Cl2 (10 mL) was added
dropwise and stirred for 30 min. The solvent was evaporated
and to the residue a solution tosyl azide (1.21 g, 0.0062 mol)
and Et3N (1.35. mL, 0.0096 mol) in CH3CN (15 mL) were
added dropwise at 0 8C. After the addition was complete, the
solution was stirred at room temperature overnight. The
solvent was evaporated and the residue gave, after flash
chromatography (petroleum ether/Et2O, 8:2), the title
compound 4e (1.83 g, 50% yield) as a yellow oil: [a]D25
C52.2 (c 0.52, CHCl3); 1H NMR: d 1.27 (s, 3H), 1.28 (t, 3H,
JZ7.2 Hz), 1.29 (s, 3H), 2.07 (dd, 1H, JZ4.5, 10.8 Hz), 2.30
(q, 1H, JZ5.4 Hz), 2.40 (AB system, 1H), 2.92–2.99 (m, 2H),
3.13–3.22 (m, 2H), 3.26 (dd, 1H, JZ3.9, 9.9 Hz), 3.56 (dd,
1H, JZ3.9, 9.9 Hz), 4.22 (dq, 2H, JZ1.2, 7.2 Hz), 4.58 (dt,
2H, JZ9.1,10.8 Hz),7.21–7.48(m, 15H);13CNMR(CDCl3):
d 14.2, 25.5, 25.9, 37.9, 48.4, 59.4, 61.3, 62.3, 67.5, 75.9, 78.0,
80.8, 86.9, 110.9, 126.8, 127.6, 128.8, 144.2, 161.2, 191.5; IR
(neat): 3085, 3057, 2982, 2936, 2800, 2132, 1714, 1654, 1490,
1448, 1371, 1299, 1209, 1172, 1152, 1117, 1068, 862, 763,
747, 706 and 633 cmK1. Anal. Calcd for C34H37N3O6: C,
69.96; H, 6.39; N, 7.20. Found: C, 70.11; H, 6.25; N, 7.17.
3. Review: Seebach, D.; Sting, A. R.; Hoffmann Angew. Chem.,
Int. Ed. 1996, 35, 2709.
4. Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc., Perkin
Trans. 1 1983, 1009. Heard, G. L.; Yates, B. F. Aust. J. Chem.
1998, 48, 1413.
5. Hanessian, S.; Mauduit, M. Angew. Chem., Int. Ed. 2001, 40,
3810.
6. For a general review of the Stevens rearrangement, see (a)
`
Marko, I. E. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3,
pp 913–973. (b) West, F. G.; Clark, J. S. In Nitrogen, Oxygen
and Sulfur Ylide Chemistry; Clark, J. S., Ed.; Oxford
University Press: Oxford, 2002. (c) See also: Stevens, T. S.;
Creighton, E. M.; Gordon, A. B.; Macincol, M. T. J. Chem.
Soc. 1928, 3193.
7. Hata, Y.; Watanabe, M. Tetrahedron Lett. 1972, 13, 4659.
8. For reviews of ammonium ylides generated by diazo
compounds, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with
Diazo-Compounds; Wiley: New York, 1997. (b) West, F. G.;
Naidu, B. N. J. Am. Chem. Soc. 1993, 116, 1177. (c)
Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263. (d)
Padwa, A.; Beall, L. S.; Advances in Nitrogen Heterocycles;
JAI: Stamford, CT, 1998; Vol. 3, pp 117–158.
4.1.11. Diazo-decomposition of 4e. A solution of the
diazoketoester 4e (1.105 g, 0.00110 mol) in CH2Cl2
(10 mL) was refluxed for 30 min in the presence of
Rh2(OAc)4 (0.015 g, 3 mol%). The solvent was evaporated
and the residue gave, after flash chromatography (petroleum
ether/Et2O, 8:2), the unsaturated compound (4E)-5-
[(3aR,4S,6aS)-(2,2-dimethyl-4-trityloxymethyl-tetrahydro-
[1,3]dioxolo[4,5-c]pyrrol-5-yl)]-3-oxo-pent-4-enoic acid
ethyl ester 6e (0.852 g, 81% yield), brown oil. [a]D25
9. Muroni, D.; Saba, A.; Culeddu, N., Heterocycles 2006, 68,
No. 1.
1
C47.2 (c 0.25, CHCl3); H NMR: d 1.19 (s, 3H), 1.22 (t,
10. McCaig, A. E.; Meldrum, P.; Wightman, R. H. Tetrahedron
1998, 54, 9429.
3H, JZ7.2 Hz), 1.24 (s, 3H), 3.23–3.42 (m, 5H), (dd, 1H,
JZ3.9, 10.8 Hz), 3.70–3.78 (m, 1H), 4.13 (q, 1H, JZ
7.2 Hz), 4.69 (t, 1H, JZ6.3 Hz), 4.75 (dt, 1H, JZ2.4,
6.3 Hz), 5.01 (d, 1H, JZ13.2 Hz), 7.20–7.45 (m, 15H), 7.91
(d, 1H, JZ13.2 Hz); 13C NMR (CDCl3): d 14.0, 24.7, 25.8,
11. Fleet, G. W. J.; Son, J. C.; Green, D. S. C.; Cenci di Bello, I.;
Winchester, B. Tetrahedron 1988, 44, 2655.
12. Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.
J. Am. Chem. Soc. 1988, 110, 7828.

1466
D. Muroni et al. / Tetrahedron 62 (2006) 1459–1466
˚
13. Thompson, D. K.; Hubert, C. N.; Wightman, R. H.
Tetrahedron 1993, 49, 3827.
cZ12.104(1) A; aZ908, bZ90.46(1)8, gZ908; VZ
3
1039.63(18) A , ZZ2, DcalcdZ1.180 Mg/m3, F (000)Z400,
˚
14. Zibuck, R.; Streiber, J. M. J. Org. Chem. 1989, 54, 4717.
15. The isolation without characterization of a similar stable ylide
has been reported by Padwa, see: Ref..2d
TZ295(2) K, crystal size 0.33!0.27!0.010 mm3, qZ
1.85–25.368, limiting indicesZK12!Zh!Z13, K9!Z
k!Z9, K15!Zl!Z14, reflections collectedZ11503, inde-
pendent reflectionsZ3602 [RintZ0.0244], completness to qZ
25.368: 97%, max. and min. transmission: 0.9923 and 0.9750,
refinement method: full-matrix least-squares on F2, dataZ3602,
restrainsZ32, parametersZ369, goodness-of-fit on F2Z1.075,
final R indices [IO2s(I)]: R1Z0.0348, wR2Z0.0774, R
indices (all data): R1Z0.0504, wR2Z0.0846, absolute struc-
ture parameterZK1.0(3), extinction coefficientZ0.018(3),
16. (a) Chelucci, G.; Saba, A.; Culeddu, N.; Valenti, R.
Tetrahedron Lett. 1999, 40, 8269. (b) Doyle, M. P.;
Autry, C. L. J. Chem. Soc., Perkin Trans. 1 1995, 619.
(c) Zaragoza, F.; Zahn, G. J. Prakt. Chem./Chem. Ztg. 1995,
337, 292.
17. Padwa, A.; Hasegawa, T.; Liu, B.; Zhang, Z. J. Org. Chem.
2000, 65, 7124.
K3
˚
18. Crystal data and structure refinement for ylide 5a: single crystals
were obtained by recrystallization from ethyl acetate/Et2O, 10:1.
The substance (C23H31NO3, MrZ369.49) crystallized in the
largest diff. peak and holeZ0.109 and K0.116 e A
.
Crystallografic data have been deposited with the Cambridge
Crystallografic Data Center (Deposition number: CCDC
279550).
˚
˚
monoclinic space group P21, aZ11.022(1) A, bZ7.793(1) A,