Hydroxylamine oxygen as nucleophile in palladium(0)- and palladium(II)-catalyzed allylic alkylation: A novel access to isoxazolidines

Article abstract of DOI:10.1055/s-2007-973868

In search for novel heterocyclization processes, the intramolecular Pd-mediated allylic alkylation of homoallyl hydroxylamines is described. Depending on both the reaction conditions and the substrates, cis- or trans-3-substituted-5-vinyl isoxazolidines a

Full text of DOI:10.1055/s-2007-973868

944
LETTER
Hydroxylamine Oxygen as Nucleophile in Palladium(0)- and Palladium(II)-
Catalyzed Allylic Alkylation: A Novel Access to Isoxazolidines
I
soxazolidines
e
via Palladi
d
um-Catalyz
e
r
d
A
llylic
o
A
lkylations Merino,*a Tomas Tejero,a Vanni Mannucci,a,b Guillaume Prestat,b David Madec,b Giovanni Poli*b
a
Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon,
Universidad de Zaragoza, CSIC, 50009 Zaragoza, Aragon, Spain
Fax +34(976)762075; E-mail: pmerino@unizar.es
b
Université Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie Moléculaire
(FR 2769), Case 183, 4 Place Jussieu, 75252 Paris Cedex 05, France
Fax +33(1)44277567; E-mail: giovanni.poli@upmc.fr
Received 16 January 2007
R1
R1
R1
[Pd]
[Ru]
Abstract: In search for novel heterocyclization processes, the in-
tramolecular Pd-mediated allylic alkylation of homoallyl hydroxyl-
amines is described. Depending on both the reaction conditions and
the substrates, cis- or trans-3-substituted-5-vinyl isoxazolidines are
preferentially obtained. The corresponding starting materials for the
cyclization step are readily obtained through cross-metathesis of the
easily accessible unsubstituted homoallyl hydroxylamines.
N
O
N
LG
N
OH
R2
OH
R2
R2
1
2
3
Scheme 1
Key words: palladium, ring closure, hydroxylamines, allyl com-
plexes, isoxazolidines
based on an intramolecular 5-exo Pd-catalyzed allylic
substitution of hydroxylamines 2 (Scheme 1).9 We also
show here that the cross-metathesis of homoallyl hydrox-
ylamines 3, in turn easily accessible via nucleophilic ally-
lation of nitrones,10 provides a useful method to prepare
the desired allylically substituted hydroxylamines 2.
The use of transition-metal-catalyzed cyclizations in the
synthesis of heterocycles has expanded rapidly in recent
years thanks to the possibility of achieving multiple and
often stereoselective transformations.1 In this context, al-
though the nucleophilic addition of heteronucleophiles to
several types of p-olefin2 and h3-allyl palladium
complexes3 has been amply described, the employ of sim-
ilar catalytic reactions to add heteroatom-linked oxygen
nucleophiles has only very recently been reported. This is
the case of oximes4 and hydroxylamines5 in which either
one of the two heteroatoms can act as the nucleophile.
We first prepared the homoallyl hydroxylamines 3
through the direct nucleophilic addition of allyl metals to
the corresponding nitrones (Scheme 2).10a
Although it is possible to prepare substituted compounds
by this method11 the requirement of a leaving group at the
distal allylic position in 2 prompted us to consider a cross-
metathesis as the best choice to properly elongate the un-
substituted homoallyl hydroxylamine 3.
Isoxazolidines have also attracted considerable attention.
For example, these useful intermediates can be converted
into 1,3-amino alcohols without loss of stereochemistry.6
Moreover, the presence of additional functionalities in the
ring increases their synthetic value as it allows the obtain-
ment of more elaborated target molecules. In general,
isoxazolidines are readily prepared via 1,3-dipolar cy-
cloaddition between nitrones and alkenes.7 However, in
some instances such a general approach cannot be applied
owing to functional group incompatibility. This is the
case, for instance, of vinyl isoxazolidines 1, which should
be formally prepared through a cycloaddition reaction be-
tween a nitrone and a specific double bond of a 1,3-diene.
As a consequence, the development of alternative synthet-
ic approaches toward such heterocycles is highly desir-
able.8
R1
O
R1
M
N
N
ref. 10a
R2
R2
OH
3a–e
TBSOTf,
lutidine,
CH2Cl2
–40 °C
to r.t.
AcO
OAc
R1
5
N
Hoveyda–Grubbs cat.
CH2Cl2, reflux
R2
OTBS
4a–e
R1
R2
R1
R2
Bn
R1
OAc
In this communication we report the synthesis of 5-vinyl
isoxazolidines 1 through a hitherto unknown approach
a
Ph
Ph
i-Pr
Ph
Bn
Bn
O
N
d, e
OTBS
R2
O
b
c
6a–e
d = syn, e = anti
SYNLETT 2007, No. 6, pp 0944–0948
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973868; Art ID: G00807ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

LETTER
Isoxazolidines via Palladium-Catalyzed Allylic Alkylations
945
Pd(0)
or
Pd(II)
First attempt of direct cross-metathesis between the free
hydroxylamine 3a and alkene 512 in the presence of the
second generation phosphine-free Hoveyda–Grubbs cata-
lyst [Cl2Ru(H2IMes)(2-i-PrOC7H5)]13 failed, the corre-
sponding N-phenyl homoallyl amine being obtained as the
only product. An identical result was obtained with
Grubbs’ I and II catalysts and in a Ti(Oi-Pr)4-assisted re-
action.14 Treatment of 3a with excess tert-butyldimethyl-
silyltriflate (3.0 equiv) in the presence of lutidine readily
gave the corresponding O-silylated hydroxylamine 4a in
81% yield.15
N
O
N
O
N
OAc
OR
Bn
Bn
Bn
8a
8b
AcOH
TBAF
6c R = TBS
7 R = H
8a:8b yield (%)
Pd(0): Pd(OAc)2, dppe, DMF
Pd(II): Pd(OAc)2, LiCl, DMF
55:45
93:7
86
90
Scheme 3
Treatment of the silylated hydroxylamine 4a with 1,4-di-
acetoxy-but-2-ene (5) in the presence of 5 mol% of the
above-mentioned Hoveyda–Grubbs catalyst in CH2Cl2 at
reflux for 4 hours, and then at room temperature for 12
hours, gave the expected metathesis E-adduct 6a16 in 90%
yield (Table 1, entry 1). We next examined the generality
of the reaction with the more synthetically useful N-ben-
zyl derivatives 4b and 4c (Table 1, entries 2 and 3) and the
enantiopure homoallyl hydroxylamines 4d and 4e
(Table 1, entries 4 and 5). The metathesis reactions pro-
ceeded in good yield to afford the corresponding E-com-
pounds 6 as the only products.
be separated by silica gel chromatography. No 1,2-ox-
azepane coming from a 7-endo cyclization was detected.
Pd(II) catalysis was then tested by treatment of 7 with
Pd(OAc)2 (5 mol%) and LiCl (1.0 equiv).21 This gave the
same products in a 93:7 trans:cis ratio and a 90% yield.22
The different stereochemical result between the Pd(II)-
and the Pd(0)-catalyzed cyclization of 7 is not surprising,
as the two protocols involve fundamentally different reac-
tion mechanisms. Indeed, in the former protocol addition
of the hydroxylamine hydroxyl takes place anti to the
Pd(II)-activated alkene. Deacetoxypalladation of the
newly formed s-alkyl palladium complex affords the final
product and regenerates Pd(II) [Scheme 4, Pd(II) cycle].18
On the other hand, when dppe is added to Pd(OAc)2 be-
fore the addition of the substrate, Pd(0) is rapidly generat-
ed.23 Following oxidative addition of the latter gives a
transient electrophilic h3-allyl palladium complex which
is in turn intramolecularly intercepted by the hydroxyl-
amine oxygen atom. This affords the final product and
Pd(0)/dppe, which can reenter the catalytic cycle
[Scheme 4, Pd(0) cycle].
Table 1 Cross-Metathesis between Hydroxylamines 4 and 5a
Entry
R1
R2
Hydroxylamine Yield (%)
1
2
3
4
5
Ph
Ph
Bn
Bn
Bn
Bn
6a
6b
6c
6d
6e
90
Ph
90
i-Pr
83
syn-DMDOc
anti-DMDOc
85b
86d
Having demonstrated the feasibility of the Pd-mediated
cyclization of homoallyl hydroxylamines, the prospects of
a All the reactions were carried out in CH2Cl2 (reflux 4 h, then r.t. 12
h).
b The syn (S,R) isomer.
c DMDO: 2,2-dimethyl-4-dioxolanyl.
d The anti (S,S) isomer.
Bn
R
N
OH
AcO
H
Since initial attempts of in situ desilylation prior to the cy-
clization step were unsuccessful, compounds 6a–c were
first desilylated by TBAF in THF. Under these conditions,
aromatic derivatives 6a and 6b proved to be unstable. On
the other hand, compound 6c afforded free hydroxylamine
7 in 99% yield. The planned palladium-catalyzed intramo-
lecular cyclization was next tackled by choosing 7 as the
model substrate for a preliminary study (Scheme 3). Since
such a compound could theoretically undergo cyclization
activated by Pd(0)17 catalysis but also by nonoxidative
Pd(II),18 we decided to undertake a comparative study of
both conditions.19
H
H
Pd
Pd(0) cycle
P
P
Bn
N
– AcOH
Bn
N
R
[Pd(0)]dppe
OH
R
O
OAc
PdX2
LiCl
H
– HX
Bn
X = AcO, Cl
Pd(II) cycle
R
N
OH
Pd(0) conditions were first tested by treatment of the pre-
cursor 7 with Pd(OAc)2 (10 mol%) in the presence of dppe
(0.1 equiv).20 These conditions gave rise to an almost
equimolar mixture of the desired trans and cis 5-exo-cy-
clization adducts 8a and 8b in 86% yield, which could not
OAc
H
Pd(II)X2
Scheme 4
Synlett 2007, No. 6, 944–948 © Thieme Stuttgart · New York

946
P. Merino et al.
LETTER
Table 2 Intramolecular Allylic Alkylation of 9 and 11 to 10 and 12a
O
O
Entry Hydroxylamine
Additive Isoxazolidine
Yield
(%)
O
Pd(II) or Pd(0)
see Table 2
O
(cis:trans)
N
N
OAc
OR
O
1
2
9
9
Pd(II)
Pd(II)
Pd(II)
Pd(II)
Pd(II)
Pd(II)
Pd(0)
Pd(0)
Pd(0)
Pd(0)
–
10 (10:90)
10 (<5:95)
10 (6:94)
66
92
Bn
Bn
6d R = TBS
9 R = H
LiCl
LiBr
–
10
TBAF
3
9
90
O
O
4
11
11
11
9
12 (89:11)
12 (92:8)
70
O
Pd(II) or Pd(0)
see Table 2
O
5
LiCl
LiBr
dppe
dppeb
dppe
dppeb
90
N
N
OAc
O
OR
Bn
Bn
6
12 (90:10)
10 (10:90)
10 (12:88)
12 (>95:5)
12 (>95:5)
88
6e R = TBS
11 R = H
12
TBAF
7
96
8
9
>99
92
Scheme 5
9
11
11
this reaction were next explored in the case of the enan-
tiopure derivatives 9 and 11, arising from desilylation of
6d (85%) and 6e (86%, Scheme 5).
10
90
a All the reactions have been carried out at 80 °C in DMF for 3 h and
using Pd(OAc)2 as the palladium source.
Pd(II)-catalyzed tests were conducted both in the absence
of any additive (Table 2, entries 1 and 4) and in the pres-
ence of lithium halides (Table 2, entries 2, 3, 5 and 6).24
Pd(0)-catalyzed reactions were carried out in the presence
of dppe under base-free conditions (Table 2, entries 7 and
9), or using NaH as the base (Table 2, entries 8 and 10).
Tiny differences in the respective diastereoselectivities
were observed depending on both the substrate and the re-
agent.
b Previous treatment of 9 with NaH.
Pd(0) gave rise, via different and alternative mechanistic
paths, to the target 5-vinyl-substituted isoxazolidines.
These novel allylic alkylations demonstrate that hydroxyl-
amines, even lacking an N-bound electron-withdrawing
group,5 can act as efficient oxygen nucleophiles toward
transiently generated p-olefin palladium complexes or h3-
allyl palladium complexes. Since homoallyl hydroxy-
lamines are readily prepared from commercially available
reagents, the present strategy provides a novel, useful and
straightforward method for constructing complex organic
molecules. Further use of this synthetic approach is under
study in our laboratories.
Interestingly, Pd(OAc)2/LiCl turned out to be the most se-
lective Pd(II)-based catalytic system for both the sub-
strates, giving exclusively the trans isomer 1025 from the
syn precursor 9 (Table 2, entry 2), and a 92:8 cis:trans ra-
tio from the anti isomer 11 (Table 2, entry 5). On the other
hand, when the Pd(OAc)2/dppe system was applied [Pd(0)
catalysis], the syn isomer 9 showed a 10:90 cis:trans pref-
erence (Table 2, entry 7), while the anti precursor 11 af-
forded exclusively the cis isomer 1226 (Table 2, entry 9).
It should be noted that, in contrast to what previously ob-
served with 7, the selectivity of cyclization of 9 and 11
turned out to be independent of the cyclization mecha-
nism, indicating that 9 and 11 are intrinsically biased to
favor trans and cis patterns, respectively.
Acknowledgment
This study was supported by the Ministerio de Educacion y Ciencia
(MEC) and FEDER Program (Madrid, Spain, project CTQ2004-
0421/BQU) and the Gobierno de Aragón (Zaragoza, Spain). V.M.
thanks MEC for a FPU predoctoral grant. We also thank A. Mon-
comble and P. Bonnes for exploratory work.
The ensemble of these results suggests that when studying
diastereoselectivity in palladium-catalyzed O-allylations,
both Pd(0)- and Pd(II)-catalyzed protocols are worthy to
be tested, as different, and sometimes opposite stereo-
chemical results may be obtained. Furthermore, switching
from one protocol to the other simply requires replace-
ment of the phosphine for LiCl.
References and Notes
(1) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004,
104, 3079. (b) Nakamura, I.; Yamamoto, Y. Chem. Rev.
2004, 104, 2127.
(2) (a) Hosokawa, T.; Murahashi, S.-I. Intramolecular
Oxypalladation, In Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 2; Negishi, E.-I., Ed.;
John Wiley and Sons: New York, 2002, 2169. (b) Zeni, G.;
Larock, R. C. Chem. Rev. 2004, 104, 2285.
(3) For reviews, see: (a) Tsuji, J. In Handbook of
Organopalladium Chemistry for Organic Synthesis, Vol. 1;
Negishi, E.-I., Ed.; John Wiley and Sons: New York, 2002,
1669. (b) Trost, B. M.; Vranken, D. L. V. Chem. Rev. 1996,
96, 395. (c) Hegedus, L. S. Transition Metals in the
Synthesis of Complex Organic Molecules; University
Science Book: Mill Valley, 1994.
In conclusion, we have reported a versatile method for the
synthesis of functionalized isoxazolidines, otherwise in-
accessible via conventional methods such as 1,3-dipolar
cycloadditions. The methodology successfully exploited a
cross-metathesis reaction to initially provide the allylical-
ly substituted homoallyl hydroxylamines. Cyclization of
the latter intermediates by the action of catalytic Pd(II) or
Synlett 2007, No. 6, 944–948 © Thieme Stuttgart · New York

LETTER
Isoxazolidines via Palladium-Catalyzed Allylic Alkylations
947
(4) Miyabe, H.; Yoshida, K.; Reddy, V. K.; Matsumura, A.;
Takemoto, Y. J. Org. Chem. 2005, 70, 5630.
(5) Miyabe, H.; Yoshida, K.; Yamauchi, M.; Takemoto, Y. J.
Org. Chem. 2005, 70, 2148.
(6) Frederickson, M. Tetrahedron 1997, 53, 403.
(7) Merino, P. In Science of Synthesis, Vol. 27; Padwa, A., Ed.;
Georg Thieme Verlag: New York, 2004, 511.
(8) Merino, P. In Targets in Heterocyclic Systems: Chemistry
and Properties, Vol. 7; Attanasi, O. A.; Spinelli, D., Eds.;
Italian Society of Chemistry: Rome, 2003, 140.
Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Org. Lett. 2000, 2,
2427. (e) Ferber, B.; Prestat, G.; Vogel, S.; Madec, D.; Poli,
G. Synlett 2006, 2133.
(19) We recently reported a related comparative study of Pd(0)
vs. nonoxidative Pd(II) catalysis for intramolecular allylic
amination, see ref. 18e and: Ferber, B.; Lemaire, S.; Mader,
M. M.; Prestat, G.; Poli, G. Tetrahedron Lett. 2003, 44,
4213.
(20) General Procedure for the Pd(0)-Mediated
Intramolecular Allylic Alkylation
(9) To the best of our knowledge, the only precedent so far
reported (see ref. 5) deals with intermolecular reactions,
using carbonates as leaving groups, and necessitating an
electron-withdrawing group on the hydroxylamine nitrogen
atom.
(10) (a) Merino, P.; Delso, I.; Mannucci, V.; Tejero, T.
Tetrahedron Lett. 2006, 47, 3311. (b) Laskar, D. D.;
Prajapati, D.; Sandhu, J. S. Tetrahedron Lett. 2001, 42,
7883. (c) Kumar, H. M. S.; Anjaneyulu, S.; Reddy, E. J.;
Yadav, J. S. Tetrahedron Lett. 2000, 41, 9311.
The proper homoallylhydroxylamine (1 mmol) and (if
needed) NaH (60% dispersion in a mineral oil, 1 mmol) were
dissolved in DMF (20 mL) under an argon atmosphere and
the resulting mixture was cooled to 0 °C. In a separate flask,
Pd(OAc)2 (5 mol%) and dppe (10 mol%) were mixed in
DMF (5 mL) and stirred for ca 5 min. After having carefully
verified that the initially brown solution turned into a paler
brown suspension, the thus formed Pd(0) catalyst was added
into the solution of hydroxylamine. The resulting mixture
was stirred at r.t. for 30 min, then heated at 80 °C for 3 h.
After cooling to r.t., the solution was poured into Et2O (125
mL) and H2O (50 mL) was added. The organic layer was
separated and the aqueous layer was extracted with Et2O.
The combined organic extracts were washed with brine,
dried over MgSO4, filtered and evaporated under reduced
pressure to give a residue which was purified by radial
chromatography.
(11) Merino, P.; Mannucci, V.; Tejero, T. Tetrahedron 2005, 61,
3335.
(12) Alkene 5 has been successfully used in ruthenium-catalyzed
cross-metathesis reactions. For representative examples,
see: (a) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.;
Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 58. (b) Chatterjee, A. K.; Sanders, D.
P.; Grubbs, R. H. Org. Lett. 2002, 11, 1939. (c) Chatterjee,
A. K.; Toste, F. D.; Choi, T.-L.; Grubbs, R. H. Adv. Synth.
Catal. 2002, 344, 634. (d) Chatterjee, A. K.; Choi, T.-L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125,
11360. (e) Cluzeau, J.; Capdevielle, P.; Cossy, J.
Tetrahedron Lett. 2005, 40, 6945.
(13) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791.
(b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 8168. (c) Grubbs, R. H.;
Trnka, T. M. In Ruthenium in Organic Synthesis;
Murahashi, S.-I., Ed.; Wiley-VCH: New York, 2004, 153–
177.
(21) General Procedure for the Pd(II)-Mediated
Intramolecular Allylic Alkylation
The corresponding homoallylhydroxylamine (1 mmol),
Pd(OAc)2 (10 mol%) and lithium halide (5 mmol; if needed)
were dissolved in DMF (20 mL) under an argon atmosphere.
The resulting mixture was stirred at r.t. for 30 min, then
heated at 80 °C for 3 h. After cooling to r.t., the solution was
poured into Et2O (125 mL) and H2O (50 mL) was added. The
organic layer was separated and the aqueous layer was
extracted with Et2O. The combined organic extracts were
washed with brine, dried over MgSO4, filtered and
evaporated under reduced pressure to give a residue which
was purified by radial chromatography.
(14) It has been recently described that the use of Lewis acids can
prevent undesired coordination of N-atom to the ruthenium
carbene intermediate in metathesis reactions: (a) Yang, Q.;
Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871. (b) See also:
Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130.
(15) Use of tert-butyldimethylsilyl chloride in the presence of
several tertiary amines failed to give the corresponding
protected hydroxylamine.
(22) The relative stereochemical assignment of compound 8a
was based on ROESY experiments.
(23) In situ preformation of Pd(0) from Pd(OAc)2/phosphine is
amply documented. See for example: (a) Amatore, C.;
Carre, E.; Jutand, A.; M’Barke, M. A. Organometallics
1995, 14, 1818. (b) Amatore, C.; Jutand, A.; Thuilliez, A.
Organometallics 2001, 20, 3241. (c) Shimizu, I.; Tsuji, J.
J. Am. Chem. Soc. 1982, 104, 5844.
(24) Submission of compounds 9 and 11 to the same reaction
conditions as in entries 3 and 6 of Table 2, but in the absence
of Pd(OAc)2, gave only starting material, thereby ruling out
the possibility of a noncatalytic cyclization passing through
the corresponding allylic bromide.
(16) Data for 6a: (90%). Rf = 0.55 (hexane–EtOAc, 4:1); oil. 1H
NMR (400 MHz, CDCl3, 25 °C, mixture of conformers): d =
7.27–7.22 (m, 3 H), 7.21–7.13 (m, 4 H), 7.04–6.98 (m, 3 H),
5.61–5.55 (m, 1.6 H), 5.54–5.43 (m, 0.4 H), 4.58–4.50 (m,
0.4 H), 4.41–4.37 (m, 1.6 H), 4.20 (t, 1 H, J = 7.5 Hz), 2.79
(t, 2 H, J = 6.7 Hz), 2.06 (br, 0.6 H), 2.02 (br, 2.4 H), 0.3 (br,
9 H), –0.07 (br, 3 H), –0.31 (br, 0.6 H), –0.34 (br, 2.4 H).
13C NMR (100 MHz, CDCl3, 25 °C, selected signals for the
major conformer): d = 170.7, 152,5, 137.8, 133.3, 131.9,
127.9, 127.5, 127.4, 125.8, 123.7, 121.2, 74.3, 65.0, 32.9,
26.1, 21.0, 18.0, –4.7, –5.5. Anal Calcd for C25H35NO3Si: C,
70.55; H, 8.29; N, 3.29. Found: C, 70.59; H, 8.45; N, 3.22.
(17) Hyland, C. Tetrahedron 2005, 61, 3457.
(25) Data for 10: Rf = 0.36 (hexane–EtOAc, 4:1); [a]D20 +92 (c
0.16, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): d = 7.45–
7.40 (m, 2 H), 7.37–7.31 (m, 2 H), 7.30–7.24 (m, 1 H), 5.85
(ddd, 1 H, J = 17.2, 10.3, 7.1 Hz), 5.29 (d, 1 H, J = 17.2 Hz),
5.18 (d, 1 H, J = 10.3 Hz), 4.47 (dt, 1 H, J = 7.6, 7.1 Hz),
4.34 (d, 1 H, J = 14.0 Hz), 4.15 (dt, 1 H, J = 7.1, 6.5 Hz),
4.04 (dd, 1 H, J = 8.3, 6.5 Hz), 4.00 (d, 1 H, J = 14.0 Hz),
3.74 (dd, 1 H, J = 8.3, 7.1 Hz), 3.13 (dt, 1 H, J = 8.2, 7.1 Hz),
2.21–2.04 (m, 2 H), 1.44 (s, 3 H), 1.36 (s, 3 H). 13C NMR
(100 MHz, CDCl3, 25 °C): d = 137.6, 137.2, 129.2, 128.2,
127.2, 117.5, 109.8, 78.4, 77.2, 67.2, 66.9, 62.2, 37.5, 26.7,
25.4. Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84.
Found: C, 70.47; H, 8.13; N, 4.76.
(18) (a) Lu, X.; Zhang, Q. J. Am. Chem. Soc. 2000, 122, 7604.
(b) Lei, A.; Liu, G.; Lu, X. J. Org. Chem. 2002, 67, 974.
(c) Miyazawa, M.; Hirose, Y.; Narantsetseg, M.; Yokoyama,
H.; Yamaguchi, S.; Hirai, Y. Tetrahedron Lett. 2004, 45,
2883. (d) Yokoyama, H.; Otaya, K.; Kobayashi, H.;
Synlett 2007, No. 6, 944–948 © Thieme Stuttgart · New York

948
P. Merino et al.
LETTER
(26) Data for 12: Rf = 0.42 (hexane–EtOAc, 4:1); [a]D20 +21 (c
1.38, CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): d = 7.31–
7.17 (m, 5 H), 5.89–5.79 (ddd, 1 H, J = 17.1, 10.2, 7.4 Hz),
5.20 (dt, 1 H, J = 17.1, 1.2 Hz), 5.10 (dt, 1 H, J = 10.2, 1.2
Hz), 4.50 (q, 1 H, J = 7.4 Hz), 4.04 (d, 1 H, J = 12.8 Hz),
3.98–3.92 (m, 2 H), 3.77 (d, 1 H, J = 12.8 Hz), 3.47–3.40 (m,
1 H), 3.16–3.10 (t, 1 H, J = 6.9 Hz), 2.48 (dddd, 1 H,
J = 12.8, 9.2, 7.4, 1.6 Hz), 2.15 (ddd, 1 H, J = 12.8, 9.2, 7.4
Hz), 1.27 (s, 3 H), 1.24 (s, 3 H). 13C NMR (100 MHz, CDCl3,
25 °C): d = 138.2, 137.0, 129.3, 128.5, 127.6, 117.3, 109.3,
80.4, 75.7, 68.0, 67.4, 63.6, 36.1, 26.8, 25.3. Anal. Calcd for
C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.70; H,
7.88; N, 5.01.
Synlett 2007, No. 6, 944–948 © Thieme Stuttgart · New York

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