Stereoselective synthesis of a bicyclic isoxazolidine related to the pyrinodemin family of alkaloids via an intramolecular asymmetric [2+3] cycloaddition

Article abstract of DOI:10.1055/s-2004-836049

Bicyclic isoxazolidine 21, a synthetic intermediate for pyrinodemins, was synthesized in six steps using an asymmetric intramolecular [2+3] cycloaddition of a new phenylglycinol-derived oxazoline N-oxide.

Full text of DOI:10.1055/s-2004-836049

LETTER
103
Stereoselective Synthesis of a Bicyclic Isoxazolidine Related to the
Pyrinodemin Family of Alkaloids via an Intramolecular Asymmetric
[2+3] Cycloaddition
Intramolecular
D
ip
n
olar Cycload
e
dition for
P
l
yrinodeminS
F
ynthesis lorès Amado, Cyrille Kouklovsky,* Yves Langlois
Laboratoire de Synthèse des Substances Naturelles (UMR CNRS n° 8615), Institut de Chimie Moléculaire et des Matériaux d’Orsay,
Université de Paris-Sud, F-91405 Orsay, France
Fax 33 (1) 69154679; E-mail: cykouklo@icmo.u-psud.fr
Received 10 September 2004
All pyrinodemins show cytotoxic activity against murine
leukemia L210 and epidermoid carcinoma KB, pyrino-
demin A being the most active compound (IC50 = 0.058
mg mL–1, and 0.5 mg mL–1, respectively). Due to this bio-
logical activity and unusual structure, pyrinodemin A (1)
has been the subject of several synthetic studies.3,4
Abstract: Bicyclic isoxazolidine 21, a synthetic intermediate for
pyrinodemins, was synthesized in six steps using an asymmetric in-
tramolecular [2+3] cycloaddition of a new phenylglycinol-derived
oxazoline N-oxide
Key words: asymmetric synthesis, alkaloids, pyrinodemin, cyclo-
additions, dipolar
Synthesis of the bicyclic core of the molecule involves an
intramolecular [2+3] cycloaddition of a nitrone (or nitrone
equivalent) with a Z double bond (Scheme 1). This strate-
gy was applied by Snider3a and Baldwin3b in their racemic
synthesis of 1, and by Baldwin4a and Morimoto4b in their
enantioselective synthesis. In the latter case, an additional
function (e.g. a protected hydroxyl group) creating a ste-
reogenic center was used to induce diastereoselectivity in
the cycloaddition.
The pyrinodemins are a new family of marine alkaloids
that have been extracted from the sponge Amphimedon
Sp. Pyrinodemin A (1) was reported by Kobayashi and co-
workers in 1999.1 Later, three other pyrinodemins B, C
and D (2–4) were also isolated from the same sponge in
lower yields2 (Figure 1). All these natural products con-
tain a cis-cyclopent[c]isoxazolidine ring system substitut-
ed with two fatty chains terminated with a 3-pyridyl
moiety; they differ by the nature of the side chain on the
nitrogen atom. However, the exact structure of pyrino-
demin A (1) has been the subject of some controversy, and
the accurate position of the cis double bond as well as the
absolute configuration were recently determined by total
synthesis.3,4
R2
R1
N
N
O
7
5
7
N
∆
[2+3]
H
R2
H
N
R
O
R1
H
*
H
N
H
N
N
O
R =
R=
R=
N
N
N
7
5
7
*
*
H
7
13
5
N
R1, R2 = H: ref 3
Pyrinodemin A
1
(revised structure)
Pyrinodemin B
R1 = H, R2 = TBSO: ref 4a
R1 = MOMO, R2 = H: ref: 4b
2
Scheme 1
R =
N
*
3
12
8
Our strategy for the synthesis of pyrinodemins involves a
flexible approach in which the bicyclic core of pyrino-
demins would first be synthesized in an enantioselective
fashion, followed by the appendage of the side chains; this
approach would allow the preparation of all the pyrino-
demins 1–4 from a common intermediate.
Pyrinodemin C
Pyrinodemin D
3
4
Figure 1
SYNLETT 2005, No. 1, pp 0103–0106
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-836049; Art ID: D27504ST
© Georg Thieme Verlag Stuttgart · New York
0
5.
0
1.
2
0
0
5
In the recent years, our laboratory has investigated the
scope and synthetic applications of asymmetric [2+3]
cycloadditions of chiral, camphor-derived oxazoline N-

104
A. F. Amado et al.
LETTER
oxides with electron-deficient olefins.5 These cycloaddi- anticipated that a chiral auxiliary with a benzylic nitrogen
tions occur in a highly regio- and stereoselective fashion, atom could be cleaved after cycloaddition using reductive
a single isomer of cycloadducts 7 being often obtained. and hydrogenolytic conditions. Consequently, the hy-
The chiral dipole 6 is prepared in situ by condensation of droxyaminoalcohol hydrochloride 11 derived from (R)-
the 1,2-hydroxyaminoalcohol hydrochloride 5 with a tri- phenylglycinol was prepared from the known8 chiral aux-
methyl orthoester (Scheme 2). Removal of the chiral aux- iliary 10 (Equation 1).
iliary involves cleavage of the N–O bond under oxidative
Ph
Ph
conditions, followed by acidic hydrolysis. b-Hydroxycar-
bonyl derivatives 8 are obtained, together with the oxime
9. In this synthetic sequence, the dipole 6 is equivalent to
a chiral nitrile oxide.
NHOH
NHOH·HCl
HCl, Et2O, 0 °C
85%
OH
OH
10
11
Equation 1
RC(OMe)3, base
CH2Cl2 or PhMe, 45 °C
O
NHOH·HCl
OH
N
The preparation of the unsaturated trimethylorthoester 15
with a Z double bond is reported in Scheme 4: protection
of 3-butyn-1-ol (12) as its PMB ester gave the alkyne 13
which was deprotonated (2.5 M BuLi, THF–HMPA) and
condensed to the commercially available (Aldrich) tri-
methyl 4-bromoorthobutyrate. The highly labile ortho-
ester 14 was immediately submitted to hydrogenation
over Lindlar catalyst in methanol–pyridine to give the
crude orthoester 15, which was used without purification
in the cycloaddition reaction.7
R
O
5
6
EWG
45–80 °C
R1
R1
O
R
N
O
EWG
7
m-CPBA, Et2O,
then 2 N HCl
O
OH
N
OH
+
R
R1
OH
EWG
R = H, alkyl
R1 = Alkyl, aryl
8
9
b
MeO
MeO
MeO
OPMB
EWG = CO2Et, NO2, CN
OR
14
12 R = H
Scheme 2
a
13 R = PMB
Since any orthoester can be condensed with the chiral
auxiliary 5, the possibility of condensing unsaturated
orthoesters in order to perform intramolecular cycloaddi-
tions looked like a promising method for the stereoselec-
tive synthesis of functionalized carbocyclic structures
(Scheme 3).6 In this communication we wish to report the
application of asymmetric intramolecular [2+3] cyclo-
addition of chiral oxazoline N-oxides to the synthesis of
the bicyclic structure of pyrinodemins.
MeO
MeO
OPMB
c
MeO
15
Scheme 4 a) NaH, PMBBr, THF, DMF, 91%; b) n-BuLi (2.5 M),
THF, HMPA, –78 °C, then (MeO)3C(CH2)2CH2Br, –78 °C to 25 °C;
c) H2 (1 atm), Pd/BaSO4, MeOH, pyridine; 25 °C (82% crude overall
yield).
Condensation of orthoester 15 with the chiral auxiliary 11
(1.7 equiv) at 45 °C in toluene gave the intermediate ox-
azoline N-oxide 16; after addition of triethylamine (to
neutralize hydrochloric acid) and raising the temperature
to 75 °C, the reaction gave after 18 hours the cycloadduct
17 as a single compound in 56% yield (Scheme 5). The re-
action was highly stereoselective since only one stereoiso-
R
MeO
3
MeO
MeO
NHOH·HCl
O
base, 45 °C
R
X*
N
OH
X*
1
O
mer was detected by H NMR (400 MHz) of the crude
O
mixture.
R
[2+3]
N
This asymmetric intramolecular [2+3] cycloaddition
therefore allows the formation of three stereogenic centers
in a single operation, and with complete control of the ste-
reoselectivity. For better characterization, the para-meth-
oxybenzyl group was removed under standard conditions
(DDQ, CH2Cl2) and the corresponding free alcohol 18
was submitted to extensive 1H NMR and 13C NMR analy-
sis.7 From 2D NOESY data, it appeared that the configu-
rations of the newly created stereogenic centers were 2S,
3R, 3aS, which correspond to those of the natural product.
X*
O
R = alkyl, aryl
X* = chiral auxiliary
Scheme 3
In order to use the asymmetric intramolecular cycloaddi-
tion as the key step for pyrinodemin synthesis, it was nec-
essary to remove the chiral auxiliary without cleaving the
N–O bond. Thus, it appeared that camphor-derived chiral
auxiliary 5 was not appropriate for such a process. We
Synlett 2005, No. 1, 103–106 © Thieme Stuttgart · New York

LETTER
Intramolecular Dipolar Cycloaddition for Pyrinodemin Synthesis
105
PMBO
O
O
O
OPMB
OPMB
a
Ph
N
N
+
N
11
15
O
O
Ph
Ph
O
16
exo transition state
endo transition state
OPMB
O
Ph
b
N
O
H
H
17
H
O
PMBO
O
H
Scheme 5 a) 45 °C, PhMe, then Et3N; b) 75 °C, 18 h, 56%.
OPMB
N
N
O
O
O
Ph
O
Ph
H
OH
OPMB
O
H
H
O
2
3
Ph
H
DDQ, CH2Cl2,
H2O, 0 °C
N
Ph
H
N
O
3a
H
H
OPMB
OPMB
O
84%
Ph
Ph
N
N
O
H
H
17
18
O
Equation 2
17
only product
not observed
The most representative NOE correlations are shown in
Equation 2.9
Scheme 6
Cycloadduct 17 comes from an exo transition state in
which the dipolarophile approaches the dipole from the
face opposite to the phenyl substituent on the oxazoline
ring (Si face, Scheme 6). The endo transition state is de-
stabilized by torsion of the chain and steric repulsions be-
tween the OPMB group and the oxazoline ring hydrogens;
this explains the exclusive formation of the cycloadduct
17. Hence, the phenylglycinol-derived chiral auxiliary 11
shows remarkable efficiency in directing the facial selec-
tivity of the intramolecular [2+3] cycloaddition, the sense
of asymmetric induction being identical to the one ob-
tained using (+)-camphor-derived chiral auxiliary 5.10
H
H
OPMB
a
OPMB
OPMB
O
O
Ph
Ph
N
N
H
H
H
O
HO
17
19
H
H
OPMB
O
O
Ph
c
b
N
HN
H
H
H
H
MsO
20
21
The use of phenylglycinol-derived oxazoline N-oxide as a
nitrone equivalent was illustrated by the synthesis of bicy-
clic isoxazoline 21 (Scheme 7): chemo- and stereoselec-
tive reduction of the aminoacetal using zinc borohydride
in diethyl ether11 afforded the N-substituted isoxazolidine
19 as a single isomer. Removal of the chiral auxiliary was
performed using slight modification of the Agami–Couty
method:12 mesylation of the primary alcohol 19 (MsCl,
Et3N) followed by treatment of the crude mesylate 20 with
potassium cyanide in DMSO with subsequent b-elimina-
tion gave the target compound 21;13 the use of microwave
activation in the second step strongly reduced reaction
time and increased both yield and selectivity.14
Scheme 7 a) Zn(BH4)2, Et2O, –10 °C to 0 °C, 84%; b) MsCl, Et3N,
CH2Cl2, 0 °C, 98%; c) KCN, DMSO, 120 °C, microwave, 55%.
wards the total synthesis of pyrinodemins, as well as the
development of new nitrone-type chiral cycloaddition
with chiral auxiliary 11 are currently underway.
Acknowledgment
This research was supported by CNRS and Université Paris-
Sud; the CONACYT program foundation (Mexico) is gratefully
acknowledged for providing a doctoral grant to A.F.A.
In conclusion, we have prepared an advanced intermedi-
ate in pyrinodemin synthesis in 6 steps and in 19% overall
yield from 3-butyn-1-ol; the key step for the synthesis is
an asymmetric intramolecular [2+3] cycloaddition of a
chiral oxazoline N-oxide, for which we have developed a
new and highly selective chiral auxiliary. Progress to-
References
(1) Tsuda, M.; Hirano, K.; Kubota, T.; Kobayashi, J.
Tetrahedron Lett. 1999, 40, 4819.
(2) Hirano, K.; Kubota, T.; Tsuda, M.; Mikami, Y.; Kobayashi,
J. Chem. Pharm. Bull. 2000, 48, 974.
Synlett 2005, No. 1, 103–106 © Thieme Stuttgart · New York

106
A. F. Amado et al.
LETTER
1266, 1200, 1052 cm–1. MS (ES): m/z = 298.2 [M + Na],
276.2 [M + 1]. HRMS: m/z calcd for C16H22NO3 [M + 1]:
276.15997; found: 276.16029. [a]D20 –174.4 (c 2, CHCl3).
(10) Condensation of camphor-derived chiral auxiliary 5 with
orthoester 15 resulted in the formation of a cycloadduct as a
single isomer, albeit in lower yield.
(3) (a) Snider, B. B.; Shi, B. Tetrahedron Lett. 2001, 42, 1639.
(b) Baldwin, J. E.; Romeril, S. P.; Lee, V.; Claridge, T. D.
Org. Lett. 2001, 3, 1145.
(4) (a) Romeril, S. P.; Lee, V.; Baldwin, J. E.; Claridge, T. D.;
Odell, B. Tetrahedron Lett. 2003, 44, 7757. (b) Morimoto,
Y.; Kitao, S.; Okita, T.; Shoji, T. Org. Lett. 2003, 5, 2611.
(5) For a review, see: Dirat, O.; Kouklovsky, C.; Langlois, Y.;
Mauduit, M. Pure Appl. Chem. 2000, 72, 1721.
(11) Berrien, J.-F.; Royer, J.; Husson, H.-P. J. Org. Chem. 1994,
59, 3769.
(6) Preliminary work on intramolecular cycloaddition of
oxazoline N-oxides: Kobayakawa, M.; Langlois, Y.
Tetrahedron Lett. 1992, 33, 2353.
(7) The crude product consists in essentialy pure orthoester 15
with a trace of pyridine. All attempts to purify the crude
product by chromatography resulted in partial hydrolysis of
the orthoester to the corresponding methyl ester.
(8) Tamura, O.; Gotanda, K.; Yoshino, J.; Morita, Y.;
Terashima, R.; Kikuchi, M.; Miyawaki, T.; Mita, N.;
Yamashita, M.; Ishibashi, H.; Sakamoto, M. J. Org. Chem.
2000, 65, 8544.
(12) Agami, C.; Couty, F.; Evano, G. Tetrahedron Lett. 1999, 40,
3709.
(13) Data for compound 21 (clear oil): 1H NMR (400 MHz,
CDCl3): d = 7.25 (2 H, d, J = 9.0 Hz), 6.85 (2 H, d, J = 9.0
Hz), 4.40 (2 H, s), 3.90 (1 H, m), 3.78 (3 H, s), 3.68 (1 H, dd,
J = 7.6 and 7.0 Hz), 3.55 (2 H, dt, J = 7.6 and 3.6 Hz), 2.75
(1 H, m), 1.85 (3 H, m), 1.79–1.40 (4 H, m), 1.35 (1 H, m)
ppm. 13C NMR (100 MHz, CDCl3): d = 159.1, 130.4, 129.2,
113.7, 83.6, 72.7, 67.7, 66.5, 55.2, 50.1, 34.9, 29.0, 26.9,
26.5 ppm. IR (liquid film): n = 3428, 2955–2864, 1613,
1513, 1248, 1091 cm–1. MS (ES): m/z = 300.2 [M + Na],
278.2 [M + 1]. HRMS: m/z calcd for C16H23NaNO3 [M +
Na]: 300.15756; found: 300.15727. [a]D20 +36.4 (c 1,
CHCl3).
(9) Data for compound 18: 1H NMR (400 MHz, CDCl3): d =
7.49–7.14 (5 H, br s), 4.45 (1 H, m, C2-H), 4.45 (1 H, t, J = 7
Hz), 4.30 (1 H, dd, J = 7 and 2 Hz), 3.73 (3 H, m), 2.75 (1 H,
m, C3-H), 2.18 (1 H, m), 1.85–1.62 (7 H, m) ppm. 13C NMR
(100 MHz, CDCl3): d = 138.6, 128.4–127.1, 116.0, 77.6,
71.9, 69.7, 60.7, 56.4, 37.0, 31.8, 25.4, 24.6 ppm. IR (liquid
film): n = 3423, 3057, 2959, 1495, 1467, 1452, 1438, 1311,
(14) Product arising from elimination of the mesylate was also
observed in the crude product. Using microwave activation
results in decrease of elimination from 15% to 5%.
Synlett 2005, No. 1, 103–106 © Thieme Stuttgart · New York