SG1 based alkoxyamines as radical initiators for the synthesis of lactones and lactames

Article abstract of DOI:10.1016/j.tet.2005.06.100

Recently, it has been shown that alkoxyamines can be used as radical initiators in tin-free radical chemistry. Thus, it prompted us to develop the preparation of highly valuable alkoxyamines via ionic chemistry and the radical cyclization was triggered by thermal initiation. Following that procedure, bicyclic, spiro and eight-membered lactones were easily prepared in good yields with very high stereoselectivity.

Full text of DOI:10.1016/j.tet.2005.06.100

Tetrahedron 61 (2005) 8752–8761
SG1 based alkoxyamines as radical initiators for the synthesis
of lactones and lactames
*
Denis Bertin, Didier Gigmes, Sylvain R.A. Marque and Paul Tordo
´
UMR 6517 case 542, Universites d’Aix-Marseille I, II et III-CNRS, Av. Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Received 11 February 2005; revised 18 April 2005; accepted 8 June 2005
Available online 20 July 2005
Abstract—Recently, it has been shown that alkoxyamines can be used as radical initiators in tin-free radical chemistry. Thus, it prompted us
to develop the preparation of highly valuable alkoxyamines via ionic chemistry and the radical cyclization was triggered by thermal
initiation. Following that procedure, bicyclic, spiro and eight-membered lactones were easily prepared in good yields with very high
stereoselectivity.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
For decades, research has been actively carried out to find
new monocomponent initiators for free radical reactions.1
Such initiators have to fulfill several requirements: they
have to be easy to handle and to store, highly selective and
not hazardous. At the same time, a number of research
teams has developed new hydrogen donors2,3 to replace the
Scheme 2.
tin derivatives, as they have several drawbacks: they are
Three solutions have been found to this problem:
toxic, environmental harmful, not easily removable and they
(i) protection of the carbonyl function (Scheme 2),8,9
generate waste.4 Meanwhile, they are always based on
(ii) work above 80 8C and addition of H-donor by small
bicomponent systems. In addition, over the past decade, a
fractions to keep its concentration low (Scheme 3),10
major challenge has been the preparation of lactone by free
(iii) use of a degenerative process based on iodine transfer
radical cyclization from alkoxycarbonylethylene 1 pre-
(Scheme 4).11,12
cursors.5–7 In fact, when 1 was heated below 80 8C in the
presence of a H-donor and radical initator (AIBN), only a
small amount of the targeted lactone 3 could be obtained
while the main product was the reduced radical 2
(Scheme 1).
Scheme 3.
Scheme 1.
Keywords: Ueno–Stork reaction; Alkoxyamines; Radical cyclization.
*
Corresponding author. Fax: C33 4 91 28 87 58;
e-mail: didier.gigmes@up.univ-mrs.fr
Scheme 4.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.100

D. Bertin et al. / Tetrahedron 61 (2005) 8752–8761
8753
chemistry. Using TEMPO alkoxyamines 18 (Scheme 8), the
corresponding cyclic compounds 19 were obtained in good
yields (O80%).21
The same methodology was applied to the synthesis of
triquinane 21 (Scheme 9).21 However, such TEMPO
alkoxyamines are not suitable to prepare lactones or
lactams.21 Even with new technology based on microwave
process, the preparation of lactones and lactames from
TEMPO alkoxyamines remains still difficult, leading to
low yield.22 Improvements could be achieved in presence
of acid additives.
Scheme 5.
Most of the solutions (bicomponent system) involve the
presence of tin compounds either as H-donors or as
transferring agents. Then, many works have been devoted
to develop tin free Ueno–Stork reaction13 as, for example,
the works of the Renaud14 (Scheme 5) and Oshima15
(Scheme 6) groups on the iodine atom transfer reaction, and
as, for example, the search for less toxical hydrogen donor
agents such as Ph2SiH2.16 Beside the development of the
Ueno–Stork reaction, the preparation of g-lactames by
radical cyclization interests also many groups.17 The
halogen atom transfer in the presence of metal salts is
probably the most suitable approach as exemplified by the
work of Clark et al. (Scheme 7).18
Scheme 9.
For several years, our research team has been developing
with success new nitroxide (SG1 leader) and derivative
alkoxyamines as initiators/controllers for nitroxide
mediated polymerization (NMP).23,24 Many improvements
were obtained compared to TEMPO such as lower
temperature polymerization, application to various
monomers, heterogenous systems.25,26 And recently,
Ciufolini et al.27 have shown that SG1 alkoxyamines are
good radical initiators for conjunctive reactions (Scheme
10) and have applied that reaction model to the preparation
of isoindoline (Scheme 11).28 We present hereafter a
versatile approach using SG1-alkoxyamines which allows
us to overcome the drawbacks mentioned above. The
valuable alkoxyamines were prepared by condensation
reaction between the easily accessible29 alkoxyamine 37
and valuable alcohols or amine. It was first applied to the
Scheme 6.
Scheme 7.
However, all these synthetic ways rest on the preparation of
halogenated homologues, and often require the presence of
catalytic amount of metal salt. Thus, developing new radical
cyclization processes free of the drawbacks mentioned
above is of high interest. With the introduction, by
Rizzardo,19 of nitroxide in radical chemistry to prepare
alkoxyamines by radical addition onto olefins, a new
concept was developed. Main of efforts20 were done on
radical polymerization to achieve a controlled process with
a living character up to Studer,21 who showed, five years
ago, that alkoxyamines could fulfil almost all the
requirements for their applications in free radical organic
Scheme 10.
Scheme 8.
Scheme 11.

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D. Bertin et al. / Tetrahedron 61 (2005) 8752–8761
purified by chromatography (60 Silicagel, 70–230 mesh,
Merck), eluent: ethyl acetate/pentane 3:1.
2.1. General procedure 1 (GP1)
In a typical experiment, a solution of 38 (4.0 g, 11.0 mmol)
in CH2Cl2 was degassed by nitrogen bubbling for 10 min.
Then, 3 equiv of SOCl2 (2.4 mL, 33.0 mmol) were added
under nitrogen atmosphere. The mixture was stirred for
45 min at rt and the excess of SOCl2 was removed under
vacuum (0.1 mbar) to yield alkoxyamine 39. Under nitrogen
atmosphere, crude 39 was diluted in ether, and then a 20 mL
ether solution of alcohol (2 equiv), Et3N (1 equiv, 1.5 mL,
11 mmol) and DMAP (0.4 equiv, 0.3 g, 2.4 mmol) was
added. A white solid precipitated and the mixture was
stirred for 16 h at rt. The white solid was filtered off and the
solvent removed to yield oil. The oil was dissolved in 30 mL
of ether, washed three times with 15 mL of an aqueous
solution of NH4Cl 5%, three times with 15 mL of a saturated
sodium carbonate aqueous solution, and then with water to
reach a neutral pH. The organic layer was dried over MgSO4
and the solvent removed to yield oil, which was purified by
chromatography to afford alkoxyamines 28a,b and 30a–c.
Scheme 12.
preparation of the simple lactone 29a and lactame 29b
(Scheme 12). It was then used to prepare the bicyclic-, spiro-
and eight-membered ring lactones 31, 32, and 33 with good
yields and moderate to good stereoselectivity, starting
from SG1 alkoxyamines 30a–c, respectively, without the
presence of any tin compounds or other reactants.
(Scheme 13).
2.2. General procedure 2 (GP2)
A 0.025 M solution of alkoxyamine 28 and 30 in degassed
tert-BuOH was heated in a Schlenk flask at 110 8C for 12 h.
The solvent was removed and the residue was purified by
column chromatography to afford the cyclic lactone or
lactame aimed at.
2.2.1. Alkoxyamine 28a. Alkoxyamine 28a was prepared
according to GP1 (40% yields). 31P NMR (121.59 MHz,
CDCl3, d, ppm): 23.23 (s, Dia I, 80%). 22.61 (s, Dia II,
20%). 1H NMR (300 MHz, CDCl3, d, ppm): 5.96–5.87 (m,
2H, dia ICII), 5.37–5.23 (m, 4H, dia ICII), 4.64–4.58 (m,
6H, dia ICII), 4.25–3.93 (m, 8H, dia ICII), 3.37 (d, JZ
27 Hz, 1H, dia II), 3.27 (d, 1H, JZ24 Hz, dia I), 1.53 (d, JZ
9 Hz, 3H, dia I), 1.50 (d, JZ6 Hz, 3H, dia II), 1.36–1.27 (m,
12H, dia ICII), 1.17 (s, 9H, dia II), 1.16 (s, 9H, dia I), 1.14
(s, 9H, dia II), 1.11 (s, 9H, dia I). 13C NMR (75.54 MHz,
CDCl3, d, ppm): Dia I. 173.4 (s, CO), 131.7 (s, CH]CH2),
118.5 (s, CH]CH2), 82.5 (s, CH–ON), 69.5 (d, JZ
139.75 Hz, CH–P), 64.9 (s, O–CH2–CH), 61.7 (d, JZ
6.04 Hz, CH2), 61.5 (s, N–C(CH3)3), 58.7 (d, JZ7.55 Hz,
CH2), 35.5 (d, JZ5.28 Hz, CH–C(CH3)3), 29.5 (d, JZ
5.28 Hz, CH–C(CH3)3), 27.8 (s, N–C(CH3)3), 19.2 (s, CH–
CH3), 16.4 (d, JZ5.29 Hz, CH2CH3), 16.1 (d, JZ6.8 Hz,
CH2CH3). Dia II. 172.0 (s, CO), 132.1 (s, CH]CH2), 118.0
(s, CH]CH2), 82.5 (s, CH–ON),69.2 (d, JZ139.75 Hz,
CH–P), 64.8 (s, O–CH2–CH), 61.8 (d, JZ8.3 Hz, CH2),
61.3 (s, N–C(CH3)3), 58.8 (d, JZ6.8 Hz, CH2), 35.1 (d,
JZ5.28 Hz, CH–C(CH3)3), 30.2 (d, JZ6.04 Hz, CH–
C(CH3)3), 27.9 (s, N–C(CH3)3), 17.7 (s, CH–CH3), 15.8
(d, JZ6.8 Hz, CH2CH3), 15.8 (d, JZ6.8 Hz, CH2CH3).
Scheme 13.
2. Experimental
Solvents, triethylamine, dimethylamino 4-pyridine
(DMAP), thionyl chloride (SOCl2), homoallylic alcohol
and amine, and alcohols 34, 35 and 36 (Scheme 14) were
purchased from Aldrich and used as received. Alkoxyamine
37 (MONAMS) was provided by ARKEMA. Alkoxyamine
38 was prepared as previously described.30 NMR experi-
ments were performed on 300 Avance Bruker spectrometer
(1H 300 MHz, 13C 75.48 MHz and 31P 121.59 MHz).
Chemical shifts were relative to TMS (internal reference)
1
for H NMR, to CDCl3 (internal reference) for 13C NMR
and to H3PO4 85% (external reference) for 31P NMR.
Elemental analyses were performed in the ‘Service
´
Commun de Micro Analyse Universite d’Aix-Marseille 3’.
Reactions were monitored by TLC (60 F 240 Silicagel
plates, eluent: ethyl acetate/pentane 1:1), using UV and
phosphomolybdic acid as indicators. Alkoxyamines were
2.2.2. Alkoxyamine 28b. Alkoxyamine 28b was prepared
according to GP1 (50% yields). 31P NMR (121.59 MHz,
CDCl3, d, ppm): 27.42 (s, Dia I, 35%). 27.05 (s, Dia II,
65%). 1H NMR (300 MHz, CDCl3, d, ppm): Dia I. 8.61 (b,
NH, 1H), 5.96–5.83 (m, 1H), 5.19 (dq, JHHZ1.5, 18 Hz,
1H), 5.08 (dq, JHHZ1.5, 9 Hz, 1H), 4.48 (q, JZ6 Hz, 1H),
Scheme 14.

D. Bertin et al. / Tetrahedron 61 (2005) 8752–8761
8755
4.29–3.97 (m, 5H), 3.67 (m, 1H), 3.35 (d, JZ27 Hz, 1H),
1.51 (d, JZ6 Hz, 3H), 1.35–1.28 (m, 6H), 1.21 (s, 9H), 1.08
(s, 9H). Dia II. 7.74 (b, NH, 1H), 5.96–5.83 (m, 1H), 5.21
(d, JZ18 Hz, 1H), 205.11 (d, JZ9 Hz, 1H), 4.51 (q, JZ
9 Hz, 1H), 4.20–3.95 (m, 5H), 3.88 (t, JZ7.5 Hz, 1H), 3.28
(d, JZ24 Hz, 1H), 1.63 (d, JZ6 Hz, 3H), 1.36–1.28 (m,
6H), 1.25 (s, 9H), 1.24 (s, 9H). 13C NMR (75.54 MHz,
CDCl3, d, ppm): Dia I. 173.6 (s, CO), 134.4 (s, CH]CH2),
115.2 (s, CH]CH2), 81.7 (s, CH–ON), 68.6 (d, JZ
137.48 Hz, CH–P), 62.2 (s, N–C(CH3)3), 61.6 (d, JZ
6.04 Hz, CH2), 59.6 (d, JZ7.55 Hz, CH2), 41.1 (s, N–CH2),
35.4 (d, JZ5.28 Hz, CH–C(CH3)3), 29.7 (d, JZ6.04 Hz,
CH–C(CH3)3), 28.2 (s, N–C(CH3)3), 19.2 (s, CH–CH3),
16.3 (d, JZ6.04 Hz, CH2CH3), 15.9 (d, JZ6.8 Hz,
CH2CH3). Dia II. 173.4 (s, CO), 134.3 (s, CH]CH2),
116.3 (s, CH]CH2), 83.1 (s, CH–ON), 69.3 (d, JZ
137.48 Hz, CH–P), 62.9 (s, N–C(CH3)3), 61.6 (d, JZ
6.04 Hz, CH2), 60.0 (d, JZ7.55 Hz, CH2), 41.5 (s, N–CH2),
35.3 (d, JZ5.28 Hz, CH–C(CH3)3), 30.1 (d, JZ5.28 Hz,
CH–C(CH3)3), 28.4 (s, N–C(CH3)3), 19.6 (s, CH–CH3),
16.6 (d, JZ6.80 Hz, CH2CH3), 16.3 (d, JZ6.8 Hz,
CH2CH3).
6.0 Hz, CH2CH3), 16.1 (d, JZ6.8 Hz, CH2CH3, dia IIIC
IV), 14.3 (s, CH3CH), 14.1 (s, CH3CH).
2.2.4. Alkoxyamine 29b. Alkoxyamine 29b was isolated
(70% yield) according to GP2. 31P NMR (121.59 MHz,
CDCl3, d, ppm): mixture of 4 diastereoisomers 23.24 (16%),
23.00 (16%), 22.93 (34%), 22.79 (34%). 13C NMR
(75.54 MHz, CDCl3, d, ppm): mixture of 4 diastereoisomers
180.9, 180.4, 180.2, 180.0 (4 s, 4 CO), 77.4, 77.1, 74.3, 73.9
(4 s, 4 CH–ON), 68.7 (d, JZ142.0 Hz, 2 CH–P), 68.5
(d, JZ139.0 Hz, 2 CH–P); 61.6 (s, 2 N–C(CH3)3), 61.6 (s, 2
N–C(CH3)3), 60.8–60.7 (m, 4 O–CH2CH3), 59.1–58.7 (m, 4
O–CH2CH3), 44.6, 44.4, 43.8, 43.7 (4s, 4 CH2NH), 42.3,
42.1 (2 s, 2 CH–CH3), 39.0 (s, 2 CH–CH3), 38.4, 37.9, 37.8
(4 s, 4 NO–CH2–CH), 34.9–35.1 (m, CH–C(CH3)3), 29.9–
29.6 (m, CH–C(CH3)3), 27.7, 27.6 (2 s, 2 N–C(CH3)3), 27.5
(s, 2 N–C(CH3)3), 16.3–15.9 (m, CH2CH3), 14.9, 14.7, 10.4,
9.9 (4 s, 4 CH3CH).
2.2.5. Alkoxyamines 30a. Alkoxyamines 30a were pre-
pared according to GP1 (50% yields). Calcd for
C22H42NO6P (447.55 g molK1): C, 59.04; H, 9.46; N,
3.13. Found: C, 58.70; H, 9.49; N, 3.11. 31P NMR
(121.59 MHz, CDCl3, d, ppm): 24.77 (s, Dia 1C2, 60%),
2.2.3. Alkoxyamine 29a. Alkoxyamine 29a was isolated
(70% yield) according to GP2. 31P NMR (121.59 MHz,
CDCl3, d, ppm): 4 diastereoisomers 23.11 (s, Dia I, 12%).
22.68 (s, Dia II, 38%), 22.61 (s, Dia III, 12%), 22.49 (s, Dia
1
24.23 (s, Dia 3, 20%), 24.12 (s, dia 4, 20%). H NMR
(300 MHz, CDCl3, d, ppm): 6.00–5.66 (m, 8H), 5.27
(m, 4H), 4.71–4.52 (m, 2H), 4.29–3.89 (m, 2H), 3.35
(d, dia 1Cdia 2, JZ24.0 Hz, 2H), 3.26 (d, dia 3Cdia 4,
JZ27.0 Hz, 2H), 2.13–1.12 (m, 148H). 13C NMR
(75.54 MHz, CDCl3, d, ppm), for diastereoisomers 1 and
2: 173.7 (C), 173.7 (C), 133.0 (CH), 132.8 (CH), 125.3
(CH), 125.1 (CH), 83.2 (CH), 83.1 (CH), 69.7 (d, JZ
140.4 Hz, 2 CH), 68.1 (2 CH), 61.9 (d, JZ6.0 Hz, CH2),
61.6 (2 C), 58.7 (d, JZ8.3 Hz, CH2), 35.6 (d, JZ6.0 Hz, 2
C), 29.5 (d, JZ6.0 Hz, 2 CH3), 28.0 (2 CH3), 24.8 (CH2),
24.8 (CH2), 19.5 (CH3), 19.5 (CH3), 18.7 (CH2), 18.6 (CH2),
16.5 (d, JZ6.0 Hz, CH3), 16.2 (d, JZ7.5 Hz, CH3); for
diastereoisomers 3 and 4: 172.2 (C), 172.2 (C), 133.0 (CH),
132.8 (CH), 125.7 (CH), 125.6 (CH), 76.9 (CH), 76.8 (CH),
69.4 (d, JZ138.9 Hz, 2CH), 68.3 (CH), 68.1 (CH), 62.0 (d,
JZ7.54 Hz, CH2), 61.5 (C), 61.4 (C), 59.5 (d, JZ6.8 Hz,
CH2), 35.3 (d, JZ4.5 Hz, C), 35.3 (d, JZ4.5 Hz, C), 30.3
(d, JZ4.5 Hz, CH3), 30.2 (d, JZ5.3 Hz, CH3), 28.2 (CH2),
28.1 (CH2), 28.0 (2 CH3), 18.9 (CH2), 18.8 (CH2), 17.9
(CH3), 16.5 (d, JZ6.0 Hz, CH3), 16.2 (d, JZ7.5 Hz, CH3).
1
IV, 38). H NMR (300 MHz, CDCl3, d, ppm): Dia I.4.46–
3.95 (m, 7H), 3.55 (m, 1H), 3.18 (d, JZ24.0 Hz, 1H), 2.88–
2.77 (m, 1H), 2.45–2.31 (m, 1H), 1.31 (t, JZ6.0 Hz, 6H),
1.18 (d, JZ6 Hz, 3H), 1.15–1.13 (m, 18H). Dia II. 4.33–
3.86 (m, 7H), 3.58 (t, JZ12.0 Hz, 1H), 3.26 (d, JZ27.0 Hz,
1H), 3.00–2.94 (m, 1H), 2.72 (quint, JZ9.0 Hz, 1H), 1.31
(td, JHHZ6.0 Hz, JHPZ3.0 Hz, 6H), 1.18 (d, JZ6.0 Hz,
3H), 1.15 (s, 9H), 1.14 (s, 9H). Mixture of Dia IIICIV (1/1)
d 4.41–3.7 (m, 16H, IIICIV), 3.37 (d, JZ27.0 Hz, 1H, III/
IV), 3.27 (d, 1H, JZ27.0 Hz, III/IV), 2.63–2.30 (m, 4H,
IIICIV), 1.37–1.26 (m, 18H, IIICIV), 1.15–1.14 (m, 36 H,
dia IIICIV). 13C NMR (75.54 MHz, CDCl3, d, ppm): Dia I.
179.7 (s, CO), 73.0 (s, CH–ON), 69.5 (s, CH2O), 69.1
(d, JZ137.48 Hz, CH–P), 62.1 (s, N–C(CH3)3), 61.0 (d, JZ
5.3 Hz, O–CH2CH3), 59.6 (d, JZ7.6 Hz, O–CH2CH3), 38.2
(s, CH–CH3), 36.5 (s, NO–CH2–CH), 35.4 (d, JZ5.3 Hz,
CH–C(CH3)3), 30.0 (d, JZ6.0 Hz, CH–C(CH3)3), 28.0 (s,
N–C(CH3)3), 16.6 (d, JZ6.0 Hz, CH2CH3), 16.3 (d, JZ
6.8 Hz, CH2CH3), 10.3 (s, CH3CH). Dia II. 179.5 (s, CO),
72.7 (s, CH–ON), 69.0 (s, CH2O), 69.0 (d, JZ139.74 Hz,
CH–P), 62.0 (s, N–C(CH3)3), 61.0 (d, JZ7.6 Hz,
O–CH2CH3), 59.3 (d, JZ8.3 Hz, O–CH2CH3), 38.3 (s,
CH–CH3), 36.4 (s, NO–CH2–CH), 35.3 (d, JZ5.3 Hz,
CH–C(CH3)3), 30.1 (d, JZ6.0 Hz, CH–C(CH3)3), 27.8
(s, N–C(CH3)3), 16.6 (d, JZ5.3 Hz, CH2CH3), 16.3 (d, JZ
6.8 Hz, CH2CH3), 9.9 (s, CH3CH). Dia IIICIV. 179.1
(s, CO), 179.1 (s, CO), 75.7 (s, CH–ON), 75.5 (s, CH–ON),
69.9 (s, CH2O), 69.8 (s, CH2O), 68.7 (d, JZ139.0 Hz,
CH–P), 68.6 (d, JZ139.8 Hz, CH–P), 61.9 (s, N–C(CH3)3),
61.9 (s, N–C(CH3)3), 60.9–60.8 (m, O–CH2CH3, dia IIIC
IV), 59.5 (d, JZ6.8 Hz, O–CH2CH3, dia IIICIV), 42.9
(s, CH–CH3), 42.9 (s, CH–CH3), 37.1 (s, NO–CH2–CH),
36.6 (s, NO–CH2–CH), 35.1 (d, JZ5.3 Hz, CH–C(CH3)3),
35.1 (d, JZ5.3 Hz, CH–C(CH3)3), 30.1 (d, JZ6.0 Hz,
CH–C(CH3)3, dia IIICIV), 27.7 (s, N–C(CH3)3), 27.6
(s, N–C(CH3)3), 16.4 (d, JZ5.3 Hz, CH2CH3), 16.4 (d, JZ
2.2.6. Alkoxyamines 30b. Alkoxyamines 30b were pre-
pared according to GP1 (48% yields). Calcd for
C23H44NO6P (461.57 g molK1): C, 59.85; H, 9.61; N,
3.03. Found: C, 59.93; H, 9.57; N, 3.07. 31P NMR
(121.59 MHz, CDCl3, d, ppm): 24.69 (s, Dia 1, 50%).
24.03 (s, Dia 2, 50%). 1H NMR (300 MHz, CDCl3, d, ppm):
5.77–5.72 (m, dia 1Cdia 2, 2H), 4.69 (q, JZ6.0 Hz, dia 1,
1H), 4.58 (q, JZ6.0 Hz, dia 2, 1 H), 4.53–4.44 (m, dia 1C
dia 2, 2 H), 4.25–3.91 (m, dia 1Cdia 2, 8 H), 3.36 (d, JZ
24.0 Hz, dia1, 1 H), 3.26 (d, JZ24.0 Hz, dia 2, 1 H), 2.07–
1.92 (m, dia 1Cdia 2, 8 H), 1.70–1.65 (m, diaCdia 2, 8 H),
1.53 (t, JZ6.0 Hz, dia 1Cdia 2, 6 H), 1.27–1.36 (m, dia 1C
dia 2, 12 H), 1.17 (s, 9 H), 1.15 (s, 9 H), 1.14 (s, 9 H),
1.10 (s, 9 H). For diastereoisomers 1 and 2, 13C NMR
(75.54 MHz, CDCl3, d, ppm): 173.7 (C), 172.2 (C), 132.6
(C), 132.3 (C), 127.0 (CH), 125.9 (CH), 82.8 (CH), 76.5
(CH), 69.5 (d, JZ129.7 Hz, CH), 69.2 (d, JZ129.7 Hz,

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D. Bertin et al. / Tetrahedron 61 (2005) 8752–8761
CH), 68.8 (CH2), 68.4 (CH2), 61.7 (d, JZ7.6 Hz, CH2), 61.7
(d, JZ6.8 Hz, CH2), 61.5 (C), 61.2 (C), 58.8 (d, JZ8.3 Hz,
CH2), 58.5 (d, JZ8.3 Hz, CH2), 35.4 (d, JZ5.3 Hz, C), 35.0
(d, JZ4.5 Hz, C), 30.1 (d, JZ6.0 Hz, CH3), 29.3 (d, JZ
5.3 Hz, CH3), 27.8 (CH3), 27.7 (CH3), 25.8 (CH2), 25.6
(CH2), 22.2 (2 CH2), 21.9 (CH2), 21.9 (CH2), 19.3 (CH3),
17.6 (CH3), 16.3 (d, JZ6.0 Hz, CH3), 16.0 (d, JZ6.0 Hz,
CH3).
Calcd for C22H42NO6P (447.55 g molK1): C, 59.04; H,
9.46; N, 3.13. Found: C, 59.15; H, 9.48; N, 3.23.
2.2.10. Alkoxyamine 31c,d. Alkoxyamines 31c,d were
isolated (10% yield) according to GP2 as a mixture 1:1.
Calcd for C23H44NO6P (461.57 g molK1): C, 59.85; H,
9.61; N, 3.03. Found: C, 59.93; H, 9.56; N, 3.07. 31P NMR
(121.59 MHz, CDCl3, d, ppm): 24.69 (54%), 24.03 (46%).
1H NMR (300 MHz, CDCl3, d, ppm): 5.77–5.72 (m, c or d,
2H), 4.69 (q, c or d, JZ6.0 Hz, 1H), 4.59 (q, c or d, JZ
6.0 Hz, 1H), 4.54–4.40 (m, cCd, 4H), 4.29–3.91 (m, cCd,
8H), 3.36 (d, c or d, JZ24.0 Hz, 1H), 3.26 (d, c or d, JZ
24.0 Hz, 1H), 2.05–1.95 (m, cCd, 8H), 1.65–1.49 (m, cCd,
14H) 1.36–1.27 (m, cCd, 12H) 1.19 (s, c or d, 9H), 1.17 (s,
c or d, 9H), 1.15 (s, c or d, 9H), 1.10 (s, c or d, 9H). 13C
NMR (75.54 MHz, CDCl3, d, ppm): 31c or 31d: 173.7 (C),
132.6 (C), 127.0 (CH), 82.8 (CH), 69.5 (d, JZ138.9 Hz,
CH), 68.8 (CH2), 61.7 (d, JZ6.0 Hz, CH2), 61.5 (C), 58.5
(d, JZ6.0 Hz, CH2), 35.4 (d, JZ5.3 Hz, C), 29.3 (d, JZ
5.3 Hz, 3 CH3), 27.7 (3 CH3), 25.8 (CH2), 24.8 (CH2), 22.2
(CH2), 22.0 (CH2), 19.3 (CH3), 16.3 (d, JZ6.0 Hz, CH3),
16.0 (d, JZ6.0 Hz, CH3). 31c or 31d: 172.2 (C), 132.3 (C),
125.9 (CH), 76.5 (CH), 69.2 (d, JZ139.6 Hz, CH), 68.4
(CH2), 61.8 (d, JZ7.5 Hz, CH2), 61.2 (C), 58.8 (d, JZ
7.5.0 Hz, CH2), 35.0 (d, JZ4.5 Hz, C), 30.1 (d, JZ6.0 Hz,
3CH3), 27.8 (3 CH3), 25.6 (CH2), 24.8 (CH2), 22.1 (CH2),
21.9 (CH2), 17.6 (CH3), 16.3 (d, JZ6.0 Hz, CH3), 16.0 (d,
JZ6.0 Hz, CH3).
2.2.7. Alkoxyamines 30c. Alkoxyamines 30c were prepared
according to GP1 (45% yields). Calcd for C21H42NO6P
(435.27 g molK1): C, 57.61; H, 9.72; N, 3.22. Found: C,
58.26; H, 9.83; N, 3.30. 31P NMR (121.59 MHz, CDCl3, d,
ppm): 25.72 (s, Dia 1, 60%), 25.16 (s, Dia 2, 40%). 1H NMR
(300 MHz, CDCl3, d, ppm): 5.90–5.70 (m, 1H), 5.08–4.98
(m, 1H), 4.66 (q, dia 2, JZ6.0 Hz, 1H), 4.58 (q, dia 1, JZ
6 Hz, 1H), 4.27–3.93 (m, dia 1 and 2, 12H), 3.36 (d, JZ
26.0 Hz, dia 2, 1H), 3.27 (d, JZ24.0 Hz, dia 2, 1H), 2.19–
2.10 (m, dia 1C2, 4H), 1.85–1.69 (m, dia 1C2, 4H), 1.52
(d, JZ26.0 Hz, dia 1, 3H), 1.49 (d, JZ26.0 Hz, dia 2, 3H),
1.33–1.26 (m, dia 1C2, 14H), 1.17 (s, dia 1, 9H), 1.16
(s, dia 1, 9H), 1.14 (s, dia 2, 9H), 1.11 (s, dia 2, 9H). 13C
NMR (75.54 MHz, CDCl3, d, ppm), for diasteroisomer 1:
173.9 (C), 137.1 (CH), 115.4 (CH2), 82.7 (CH), 69.6 (d, JZ
139.4 Hz, CH), 63.7 (CH2), 61.8 (d, JZ6.0 Hz, CH2), 61.6
(C), 58.7 (d, JZ7.5 Hz, CH2), 35.5 (d, JZ5.5 Hz, C), 29.5
(d, JZ6.0 Hz, CH3), 27.9 (CH3), 27.7 (CH2), 19.3 (CH3),
16.5 (d, JZ5.5 Hz, CH3), 16.1 (d, JZ7.0 Hz, CH3); for
diasteroisomer 2: 172.5 (C), 137.4 (CH), 115.1 (CH2), 77.0
(CH), 69.3 (d, JZ139.4 Hz, CH), 63.7 (CH2), 61.8 (d, JZ
6.54, CH2), 61.4 (C), 58.9 (d, JZ7.5 Hz, CH2), 35.2 (d, JZ
5.0 Hz, C), 30.2 (d, JZ6.5 Hz, CH3), 29.9 (CH2), 28.0
(CH3), 19.3 (CH3), 17.8 (d, JZ5.5 Hz, CH3), 16.1 (d, JZ
7.0 Hz, CH3).
2.2.11. Alkoxyamine 32a. Alkoxyamines 32a, were
isolated according to GP2. Calcd for C23H44NO6P
(461.57 g molK1): C, 59.85; H, 9.61; N, 3.03. Found: C,
59.94; H, 9.75; N, 3.05. 31P NMR (121.59 MHz, CDCl3, d,
1
ppm): 24.39 (78%). H NMR (300 MHz, CDCl3, d, ppm):
4.89 (bd, JZ9.0 Hz, 1H), 4.16–3.94 (m, 5H), 3.71 (dd, JZ
12.0, 3.0 Hz, 1H), 3.30 (d, JZ27.0 Hz, 1H), 2.44 (b, 1H),
1.82–1.10 (m, 35H). 13C NMR (75.54 MHz, CDCl3, d,
ppm): 180.2 (C), 81.7 (CH), 68.2 (d, JZ139.6 Hz, CH),
69.0 (CH2), 62.8 (C), 60.9 (d, JZ7.5 Hz, CH2), 60.5 (d, JZ
6.8 Hz, CH2), 47.3 (C), 37.8 (CH), 35.4 (d, JZ4.5 Hz, C),
30.6 (d, JZ5.3 Hz, 3CH3), 29.0 (CH2), 28.4 (3CH3), 28.0
(CH2), 24.3 (CH2), 21.3 (CH2), 16.5–16.1 (m, CH3), 9.1
(CH3).
2.2.8. Alkoxyamine 31a. Alkoxyamine 31a was isolated
(31% yield) according to GP2. 31P NMR (121.59 MHz,
CDCl3, d, ppm): 24.70. 1H (300 MHz, CDCl3, d, ppm): 4.76
(q, JZ6.0 Hz, 1H), 4.27–3.98 (m, 5H), 3.38 (d, JZ27.0 Hz,
1 H), 2.92 (m, 1H), 2.01–1.40 (m, 7H), 1.35–1.28 (m, 9H),
1.15 (s, 9H), 1.13 (s, 9H). 13C NMR (75.54 MHz, CDCl3, d,
ppm): 179.9 (C), 78.2 (CH), 76.9 (CH), 69.0 (d, JZ
137.4 Hz, CH), 61.4 (C), 61.2 (d, JZ6.0 Hz, CH2), 60.0 (d,
JZ7.6 Hz, CH2), 46.7 (CH), 38.4 (CH), 35.4 (d, JZ4.5 Hz,
C), 30.6 (d, JZ6.0 Hz, 3CH3), 28.5 (3CH3), 28.3 (CH2),
26.5 (CH2), 17.9 (CH2), 16.5 (d, JZ6.0 Hz, CH3), 16.3 (d,
JZ3.4 Hz, CH3), 14.1 (CH3). Calcd for C22H42NO6P
(447.55 g molK1): C, 59.04; H, 9.46; N, 3.13. Found: C,
59.23; H, 9.49; N, 3.17.
2.2.12. Alkoxyamine 32b,c,d. Alkoxyamines 32b,c,d were
isolated according to GP2 as a mixture. Calcd for
C21H42NO6P (435.27 g molK1): C, 57.91; H, 9.72; N,
3.22. Found: C, 58.25; H, 9.82; N, 3.30. 31P NMR
(121.59 MHz, CDCl3, d, ppm): 25.72, 25.16, 23.99. 1H
NMR (300 MHz, CDCl3, d, ppm): 5.90–5.70 (m, dia cCd,
2H), 5.12–4.94 (m, dia cCd, 4H), 4.71–4.43 (m, dia bCcC
d, 3H), 4.32–3.88 (m, dia bCcCd, 12H), 3.36 (d, dia bCd,
JZ26.0 Hz, 2H), 3.27 (d, dia c, JZ24.0 Hz, 1H), 2.19–2.07
(m, dia cCd, 2H), 1.84–1.11 (m, 105H). 13C NMR
(75.54 MHz, CDCl3, d, ppm): 32b: 181.0 (C), 77.5 (CH),
68.8 (d, JZ135.9 Hz, CH), 68.8 (CH2), 61.7 (C), 61.3 (d,
JZ7.5 Hz, CH2), 60.6 (d, JZ6.8 Hz, CH2), 47.8 (C), 37.9
(CH), 35.6 (d, JZ6.8 Hz, C), 30.1 (d, JZ6.0 Hz, 3CH3),
29.1 (CH2), 28.8 (3CH3), 27.5 (CH2), 24.0 (CH2), 21.8
(CH2), 16.5–16.1 (CH3), 9.3 (CH3); 32c: 173.9 (C),
137.1 (CH), 115.4 (CH2), 82.7 (CH), 69.6 (d, JZ
139.4 Hz, CH), 63.7 (CH2), 61.8 (d, JZ6.0 Hz, CH2),
61.7 (C), 58.7 (d, JZ7.5 Hz, CH2), 35.4 (d, JZ5.5 Hz, C),
2.2.9. Alkoxyamine 31b. Alkoxyamine 31b was isolated
(31% yield) according to GP2. 31P NMR (121.59 MHz,
CDCl3, d, ppm): 22.96. 1H NMR (300 MHz, CDCl3, d,
ppm): 4.76–4.65 (m, 1H), 4.20–3.96 (m, 5H), 3.44 (d, JZ
27.0 Hz, 1H), 2.87–2.80 (m, 1H), 2.58–2.48 (m, 1H), 2.23–
2.17 (m, 1H), 2.10–2.03 (m, 1H), 1.73–1.39 (m, 4H), 1.36–
1.28 (m, 9H), 1.18 (s, 9H), 1.15 (s, 9H). 13C NMR
(75.54 MHz, CDCl3, d, ppm): 179.0 (C), 77.4 (CH), 76.5
(CH), 68.8 (d, JZ139.6 Hz, CH), 61.4 (C), 61.2 (d, JZ
6.0 Hz, CH2), 59.4 (d, JZ6.8 Hz, CH2), 43.9 (CH), 37.1
(CH), 35.1 (d, JZ3.8 Hz, C), 31.1 (d, JZ6.0 Hz, 3 CH3),
29.0 (CH2), 27.9 (3 CH3), 26.1 (CH2), 17.3 (CH2), 16.4 (d,
JZ6.8 Hz, CH3), 16.3 (d, JZ6.0 Hz, CH3), 14.5 (CH3).

D. Bertin et al. / Tetrahedron 61 (2005) 8752–8761
8757
29.9 (CH2), 29.5 (d, JZ5.3 Hz, 3 CH3), 27.9 (3 CH3), 27.6
(CH2), 19.3 (CH3), 16.5 (d, JZ5.5 Hz, CH3), 16.1 (d, JZ
7.0 Hz, CH3); 32d: 172.5 (C), 137.4 (CH), 115.1 (CH2),
77.0 (CH), 69.3 (d, JZ139.4 Hz, CH), 63.7 (CH2), 61.8
(d, JZ6.5 Hz, CH2), 61.4 (C), 58.7 (d, JZ7.5 Hz, CH2),
35.2 (d, JZ5.0 Hz, C), 30.2 (d, JZ6.5 Hz, 3CH3), 29.9
(CH2), 28.0 (3 CH3), 27.6 (CH2), 17.8 (CH3), 16.5 (d, JZ
5.5 Hz, CH3), 16.1 (d, JZ7.0 Hz, CH3).
(d, JZ5.3 Hz, 3 CH3), 28.9 (CH2), 28.1 (3CH3), 17.5 (CH3),
16.6 (d, JZ6.0 Hz, CH3), 16.3 (d, JZ6.8 Hz, CH3). Dia 4:
178.0 (C), 80.0 (CH), 69.3 (d, JZ138.9 Hz, CH), 69.4
(CH2), 61.4 (d, JZ6.8 Hz, CH2), 61.1 (C), 59.2 (d, JZ
8.3 Hz, CH2), 41.6 (CH2), 35.2 (d, JZ5.3 Hz, C), 33.3
(CH2), 30.9 (d, JZ6.0 Hz, 3 CH3), 30.9 (CH), 29.1 (CH2),
28.1 (3 CH3), 17.8 (CH3), 16.5 (d, JZ6.0 Hz, CH3), 16.3 (d,
JZ6.8 Hz, CH3).
2.2.13. Alkoxyamine 33. Alkoxyamines 33 were isolated
(70% yield) according to GP2 as a mixture of 2 unseparable
diastereoisomers and 2 pure diastereoisomers in the ratio
1:1:1:1. Calcd for C21H42NO6P (435.27 g molK1): C, 57.91;
H, 9.72; N, 3.22. Found: C, 57.56; H, 9.85; N, 3.13. 31P
NMR (121.59 MHz, CDCl3, d, ppm): 24.28 (dia 1), 24.15
3. Results and discussion
As mentioned above, TEMPO-alkoxyamines are not
suitable for the preparation of lactones and lactames
because the TEMPO nitroxyl radical abstracts readily the
H-atom from the alkoxycarbonylethyl-type radical
(Scheme 1) and because the intramolecular H-tranfer is
facilitated in stable alkoxyamines such as TEMPO-tBu and
TEMPO-EEst (Scheme 15).31
1
(dia 2), 22.83 (dia 3), 24.88 (dia 4). H NMR (300 MHz,
CDCl3, d, ppm): dia 3: 4.33–3.93 (m, 7H), 3.35 (d, JZ
27.0 Hz, 1H), 3.05–2.93 (m, 1H), 2.66–2.59 (b, 1H), 2.19–
2.10 (m, 1H), 1.95–1.78 (m, 4H), 1.30 (t, JZ9.0 Hz, 3H),
1.29 (t, JZ9.0 Hz, 3H), 1.24 (d, JZ6.0 Hz, 3H), 1.13 (s,
9H), 1.11 (s, 9H). Dia 4: 4.42–3.89 (m, 7H), 3.37 (d, JZ
30.0 Hz, 1H), 3.07–2.95 (m, 1H), 2.39–2.31 (m, 1H), 2.27–
2.17 (m, 1H), 1.84–1.49 (m, 4H), 1.28 (t, JZ6.0 Hz, 6H),
1.26 (d, JZ6.0 Hz, 3H), 1.14 (s, 9H), 1.11 (s, 9H). 13C NMR
(75.54 MHz, CDCl3, d, ppm): Dia 1. 179.6 (C), 80.1 (CH),
68.7 (d, JZ139.6 Hz, CH), 65.9 (CH2), 61.0 (d, dia 1Cdia
2, JZ6.8 Hz, CH2), 60.8 (C), 58.6 (d, JZ6.8 Hz, CH2), 42.9
(CH2), 36.5 (CH), 34.8 (d, dia 1Cdia 2, JZ4.5 Hz, C), 32.0
(CH2), 30.5 (d, JZ5.3 Hz, 3 CH3), 28.0 (CH2), 27.5 (dia 1, 3
CH3), 16.8 (CH3), 16.2 (d, JZ6.0 Hz, CH3), 15.9 (d, JZ
6.8 Hz, CH3). Dia 2: 179.2 (C), 81.2 (CH), 68.8 (d, JZ
140.4 Hz, CH), 65.4 (CH2), 61.0 (d, dia 1Cdia 2, JZ
6.8 Hz, CH2), 60.9 (C), 58.8 (d, JZ7.5 Hz, CH2), 43.6
(CH2), 34.9 (CH), 34.8 (d, dia 1Cdia 2, JZ4.5 Hz, C), 30.3
(d, JZ6.0 Hz, CH3), 28.5 (CH2), 28.0 (CH2), 27.5 (dia 2, 3
CH3), 17.5 (CH3), 16.1 (d, JZ6.0 Hz, CH3), 15.9 (d, JZ
6.0 Hz, CH3). Dia 3: 1H NMR (300 MHz, CDCl3, d, ppm):
4.33–3.93 (m, 7H), 3.35 (d, JZ27.0 Hz, 1H), 3.05–2.93 (m,
1H), 2.66–2.59 (b, 1H), 2.19–2.10 (m, 1H), 1.95–1.78 (m,
4H), 1.30 (t, JZ9.0 Hz, 3H), 1.29 (t, JZ9.0 Hz, 3H), 1.24
(d, JZ6.0 Hz, 3H), 1.13 (s, 9H), 1.11 (s, 9H). Dia 3: 178.4
(C), 79.4 (CH), 69.3 (d, JZ137.4 Hz, CH), 69.0 (CH2),
61.5 (d, JZ6.0 Hz, CH2), 61.4 (C), 59.7 (d, JZ7.5 Hz,
CH2), 41.2 (CH2), 35.5 (b, CH2), 35.2 (C), 31.3 (CH), 30.8
On the other hand, it has been shown in the case of SG1-
alkoxyamines that neither the H-abstraction by the SG1
nitroxyl radical from the alkyl radical nor the intramolecular
H-transfer occurred.32 Consequently, SG1-alkoxyamines
look as if they are the most suitable alkoxyamines to carry
out radical cyclization with high yields. In general,
alkoxyamines are prepared with the Atom Transfer Radical
Addition (ATRA) method, which is today the easiest
method. However, this method requires the presence of a
copper catalyst for the alkyl radical to be generated and a
big amount of metal wastes is produced. Furthermore, the
metal residues have to be removed since the synthesis of
drugs requires a high level of purity.They are difficult to get
rid of, except when highly valuable alkoxyamines are
prepared as displayed in Scheme 16. To validate our
approach lactone 29a and lactame 29b were prepared
starting from alkoxyamine MONAMS (37). It was firstly
hydrolyzed into 38, then the acid function was transformed
into acyl chloride (39 was not isolated) and homoallylic
alcohol or amine was added to yield (z50%) alkoxyamines
28a or 28b, respectively (Scheme 16).
Heating a solution of 0.025 M of 29a or 29b, at 120 8C
under nitrogen atmosphere for 12 h in a Schlenk flask,
afforded lactone 28a or lactame 28b in 70% isolated yields
(100% conversion, more than 95% of the targeted
alkoxyamines by 31P NMR). Alkoxyamines 28a and 28b
1
were identified by H, 13C and 31P NMR and Elemental
analysis. Alkoxyamine 29a was obtained as a mixture of
four diastereoisomers in the ratio 12, 12, 38 and 38%. Such
ratio is expected from the two possible transition states13,33
and the unselective scavenging34 of the primary alkyl
radical by the nitroxyl radical SG1. Similarly, alkoxyamine
Scheme 15.
Scheme 16.

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D. Bertin et al. / Tetrahedron 61 (2005) 8752–8761
29b was obtained as a mixture of four diastereoisomers in
the ratio 16, 16, 34 and 34%. To highlight the potentiality of
that approach alkoxyamines 31–33 were prepared (Scheme
13). Alkoxyamines 30a–c were prepared beforehand (50%
yields) as depicted in Scheme 16. Structures were
rules,36 the 5-exo-trig cyclization is favored over the
6-endo-trig.37,38 Due to exclusive cis ring junction the
stereochemistry of C5 controls the stereochemistry of C6
(Scheme 13).33 The C2 stereochemistry is controlled by a
late transition state (TS) where the TS1 is favored over TS2,
which is more sterically hindered (Scheme 18).12 As
expected from the work of Hannessian et al.10 a high
stereoselectivity (90%, see Scheme 13) in favor of the trans
methyl group is observed (intermediate A, Scheme 18) and
one can assume that the 10% left correspond to the
diastereoisomer with the cis methyl group (TS2 leads to
intermediate B, see Scheme 18).
1
determined by H, 13C and 31P NMR. All the cyclizations
were carried out to total conversion, and alkoxyamines
31–33 were isolated with moderate to good yields (70, 60
and 70%, respectively) as racemics. Good to moderate
stereoselectivity is observed (see Scheme 13) since three
stereocenters in 30a were replaced by five stereocenters in
31 but only four diastereoisomers were observed, and two
stereocenters in 30b were replaced by four stereocenters in
31 but only four diastereoisomers were again observed. The
relative configurations of diastereoisomers 31a and 31b,
and 32a were determined by X-ray crystallography
(Scheme 17).35
For lactone 31, in agreement with the Beckwith–Baldwin
Scheme 19.
Then, both radicals A and B are stereoselectively scavenged
by the SG1 via the less sterically hindered face to provide
32a,b and 32c,d, respectively (Scheme 19). Diastereo-
isomers 31a and 31b differ only by the chiral carbon on the
SG1 moiety. Unfortunately, despite several attempts, it was
not possible to isolate 31c or 31d sufficiently pure to confirm
the stereochemistry given in Scheme 20.
Scheme 17. X-ray structure for alkoxyamines 31a,b, and 32a.
Scheme 20.
The synthesis of 32 is also highly selective because two new
chiral centers are generated in the course of the reaction and
the final molecule exhibits four assymetric carbons but only
four diastereoisomers are observed (Scheme 13). And by
analogy to 31a,b, and because 32b was obtained in the same
amount as 32a (Scheme 13), one can honestly assume that
32b differs from 32a only by the chiral carbon of the
nitroxyl moiety.
For lactone 32, in agreement with the Beckwith–Baldwin
rules,36 the 5-exo-trig cyclization was favored over the
Scheme 18.

D. Bertin et al. / Tetrahedron 61 (2005) 8752–8761
8759
membered ring in TS4 (Scheme 22). The scavenging of the
alkyl radical C by SG1 to afford 32 occurred through the
sterically less hindered face.
However, the conformer E should be more stable than the
conformer F, which exhibit more syn-1,3 interactions
(Scheme 23). Then, the formation of 32a,b can occur either
by the attack of the SG1 onto the more hindered face of the
conformer E (route b) or by the attack of the SG1 on the
more accessible face of the less stable conformer F to yield
the strongly hindered conformer I, which exchange fastly
into the most stable conformers 32a,b.
Scheme 21.
6-endo-trig (no overlap between the odd electron and the
double bond, Scheme 21).12,37,38 Like for lactone 31, the
a-ester alkyl radical was made up of two conformers Z and
E in equilibrium and in roughly comparable amount.39,40
However, TS3 was strongly preferred over TS4 because of
strong steric strain between the methyl group and the six
The upper face of the conformer F is too sterically hindered
to allow the approach of the SG1. Whereas the attack of
the SG1 on the less sterically hindered upper face of the
conformer E (route a, Scheme 23) should afford the
probable minor compounds 32c,d because of strong
destabilizing syn-1,3 interactions. Unfortunately, it was
not possible to confirm the structure of 32c,d because all the
attempts to separate 32c or 32d of 32a,b were unsuccessful.
Eight-membered ring lactones are often difficult to
prepare.41 But Lee et al.42 have shown that such lactones
can be easily prepared via selective 8-endo radical
cyclization. However, with unsubstituted precursors yields
are generally low (!60%), for example, preparation of
hydrogenated C8 of 33 has been done with 13% yields.42
That challenge has been readily overcome thanks to the
Persistent Radical Effect,43–45 which governs the reactivity
of alkoxyamines.46 Therefore, the synthesis of lactone 33
afforded quantitatively four diastereoisomers (three
assymetric carbons in the final alkoxyamine) via 8-endo
ring closure as expected from the work of Beckwith et al.38
Scheme 22.
Scheme 23.

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D. Bertin et al. / Tetrahedron 61 (2005) 8752–8761
and Lee et al.42 The diastereoisomers were not separated but
the 31P NMR shifts lay in the alkoxyamine zone and were
different from those of the starting materials (see Section 2).
The 1:1:1:1 diaseteroisomer ratio delineates unhindered
both cyclization and scavenging TSs.33,34 The 13C NMR
analyses showed that the four C8 carbons are bound to the
SG1 fragment, which rules out any 7-exo cyclization that
would have involved a methylene (C9) bound to the SG1
fragment (Scheme 13). Although 100% conversion was
observed by 31P NMR with at least 95% of the expected
compounds 33, only 70% was recovered after chromato-
graphy. The success of the total conversion of 30c in 33
leads us to expect that this radical generation approach via
alkoxyamines would be very efficient to prepare large ring
lactones with high yields.
10. Hanessian, S.; Di Fabio, R.; Marcoux, J.-F.; Prud’homme, M.
J. Org. Chem. 1990, 55, 3436–3438.
11. Curran, D. P.; Chang, C.-T. Tetrahedron Lett. 1987, 28,
2477–2480.
12. Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54,
3140–3157.
´ `
13. Salom-Roig, X. J.; Denes, F.; Renaud, P. Synthesis 2004,
1903–1928 and references cited therein.
14. Ollivier, C.; Bark, T.; Renaud, P. Synthesis 2000, 1598–1602.
15. Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K.
J. Org. Chem. 1998, 63, 8604–8605.
16. Chuang, C.-P.; Jiang, V. J. J. Chin. Chem. Soc. 1989, 36, 177.
17. Clark, A. J. Chem. Soc. Rev. 2002, 31, 1–11 and references
cited therein.
18. Clark, A. J.; De Campo, F.; Deeth, R. J.; Filik, R. P.; Gatard,
´
`
S.; Hunt, N. A.; Lastecoueres, D.; Thomas, G. H.; Verlhac,
J.-B.; Wongtap, H. J. Chem. Soc., Perkin Trans 1 2000, 671.
19. Rizzardo, E.; Solomon, D.H.; Cacioli, P. U.S. Patent 4,581,
429, 1986.
4. Conclusion
20. Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer,
G. K. Macromolecules 1993, 26, 2987–2988.
In conclusion, this monocomponent system using SG1-
based alkoxyamines as radical reaction initiators is very
efficient for preparing heterocyclic compounds with good
yields (O60%) and high stereoselectivity, that is, four
diasteroisomers out of the 16 or 8 expected for lactones 31
and 32, respectively. Furthermore, the experiments did not
take too much time (less than 12 h) at not too high
temperatures (110 8C). These syntheses highlight the
powerfulness of the Persistent Radical Effect and of the
SG1-based alkoxyamines applied to radical synthetic
chemistry.
21. Studer, A. Angew. Chem., Int. Ed. 2000, 39, 1108–1111.
22. Wetter, C.; Studer, A. Chem. Commun. 2004, 174–175.
23. Grimaldi, S.; Le Moigne, F.; Finet, J.-P.; Tordo, P.; Nicol, P.;
Plechot, M. International Patent WO 96,24620. 15 August
1996.
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Acknowledgements
27. Leroi, C.; Fenet, B.; Couturier, J.-L.; Guerret, O.; Ciufolini,
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The authors thank M. Giorgi for performing X-ray
´
experiments. S. M. is grateful to Pr M. Bertrand (Universite
d’Aix-Marseille 3) for helpful discussions and advices. The
´
authors thank Universite de Provence, CNRS and Arkema
for their financial support.
28. Leroi, C.; Fenet, B.; Couturier, J.-L.; Guerret, O.; Ciufolini,
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29. The nitroxyl radical SG1 or the alkoxyamine 37 can be
purchased to Arkema group.
30. Bertin, D.; Gigmes, D.; Marque, S.; Maurin, R.; Tordo, P.
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