Synthetic studies towards oxazinins. An expedient first total synthesis and proof of the absolute stereochemistry of oxazinin-3

Article abstract of DOI:10.1016/j.tetlet.2004.08.054

A synthetic strategy, based on intramolecular addition of an appropriate hydroxyl substituent to a 3-methyleneindolenine, towards the naturally occurring marine toxins oxazinin-1, -2 and -3 is presented. The expedient first total synthesis of oxazinin-3, thus accomplished, demonstrated the efficiency of the approach and established the absolute stereochemistry of oxazinin-3 as 2S,5S.

Full text of DOI:10.1016/j.tetlet.2004.08.054

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7779–7781
Synthetic studies towards oxazinins. An expedient first
total synthesis and proof of the absolute stereochemistry of
oxazinin-3
b
b
Elias A. Couladouros,a,b, Vassilios I. Moutsos and Emmanuel N. Pitsinos
*
aChemistry Laboratories, Agricultural University of Athens, Iera Odos 75, GR 11855 Athens, Greece
bNatural Product Synthesis and Bioorganic Chemistry Laboratory, Institute of Physical Chemistry,
NCSR ÔDemokritosÕ, PO Box 60228, GR 153 10 Ag. Paraskevi, Greece
Received 18 May 2004; revised 28 July 2004; accepted 6 August 2004
Abstract—A synthetic strategy, based on intramolecular addition of an appropriate hydroxyl substituent to a 3-methyleneindole-
nine, towards the naturally occurring marine toxins oxazinin-1, -2 and -3 is presented. The expedient first total synthesis of oxaz-
inin-3, thus accomplished, demonstrated the efficiency of the approach and established the absolute stereochemistry of oxazinin-3 as
2S,5S.
Ó 2004 Elsevier Ltd. All rights reserved.
Notwithstanding the serious threat that harmful algal
blooms (red tides) pose to both human health and coastal
economic activities, they constitute a rich source of
novel bioactive natural products of which brevetoxins,
saxitoxin, domoic and ocadaic acid are just a few illus-
trative examples.1 Oxazinin-1, -2 and -3 (1, 2 and 3,
respectively, Fig. 1), isolated from edible mussels from
the North Adriatic Sea during such an incident, are
but a recent addition to the list.2,3 A central morphol-
inone ring containing two or three substituents, includ-
ing an indole and a phenol ring, dominates their
structure. This structural motif, while being reminiscent
of the well-known pharmacophoric structure of morph-
oline, is unprecedented in natural products and can be
viewed as a promising scaffold for new bioactive mole-
cule prospecting through combinatorial chemistry.4 This
possibility prompted us to develop and report herein an
expedient and efficient synthetic strategy towards this
class of compounds exemplified by the first total synthe-
sis of oxazinin-3.
The key retrosynthetic disconnection of our strategy
involves the C(2)–O(1) bond. It was based on the
hypothesis that the central morpholinone ring of the
oxazinines might be formed through intramolecular dia-
stereoselective addition of an appropriate hydroxyl sub-
stituent to a 3-methyleneindolenine (4a or 4b, Fig. 1).
However, since 3-methyleneindolenines are reactive spe-
cies, postulated as intermediates either in the oxidation
of 3-alkyl-indoles5 or the reduction of 3-hydroxymethyl-
indoles,6 diols 5a and 5b were designed as convenient
progenitors. Finally, further disconnection at the
amide bond revealed 3-indoleglyoxylic acid 67 and
tyrosine derivatives 7a8 and 7b as appropriate building
blocks.
The diol 5b required to test our hypothesis was easily
obtained upon coupling of 3-indoleglyoxylic acid 6 with
tyrosine methyl ester 7b and subsequent concomitant
reduction of the keto and ester functionalities of 8
(Scheme 1). Both diastereomers of diol 5b upon treat-
ment with PPTS in refluxing acetonitrile furnished mor-
pholinone 3, as a 1:1 mixture of diastereomers. The two
isomers were easily separated by flash column chroma-
tography (8:2 CH2Cl2:acetone, silica gel). One of
them had an identical 1H NMR spectrum to that
reported for oxazinin-3 3 and was thus assigned as the
cis-isomer. The undesired diastereomer could be equili-
brated with the desired one upon exposure to the
Keywords: Total synthesis; Oxazinins; Morpholinone; 3-Methyl-
eneindolenine.
*
Corresponding author. Tel.: +302106530789; fax: +30210
6777849; e-mail: ecoula@chem.demokritos.gr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.054

7780
E. A. Couladouros et al. / Tetrahedron Letters 45 (2004) 7779–7781
OH
H
H
O
N
O
N
3
3
6
1
1
6
O
O
OH
HN
OR
HN
3
1: R = CH2CH2CN
2: R = H
OR
H
H
N
O
O
N
HO
OH
HO
4a
4b
N
N
OH
OH
OH
OR
OH
H
N
H
N
O
O
N
OH
N
H
OH
OH
OH
H
5a
5b
OR
O
OH
+
+
O
COOMe
NH2
N
H
HO
OR
NH2
7a
6
7b
Figure 1. Synthetic strategy towards oxazinin-1 1, -2 2 and -3 3.
O
OH
O
H
N
OH
+
a
O
O
8
N
H
N
H
O
OMe
OH
OH
OH
6
7b
COOMe
NH2
b
OH
H
H
N
O
N
c
O
5b
O
OH
N
H
(2R,S)-3
HN
HN
d
c
H
N
H
N
O
O
(R)
O
(2R)-3
(S)
O
(2S)-3
OH
OH
HN
Scheme 1. Preparation of oxazinin-3. Reagents and conditions: (a) EDC, HOBt, N,N-diisopropylethylamine, CH2Cl2:DMF 20:1, 0°C!2h, rt!22h,
95%; (b) LiBH4, MeOH:Et2O 1:2, rt, 12h 96%; (c) PPTS, CH3CN, reflux, 1h, 67%; (d) flash column chromatography (8:2 CH2Cl2:acetone, silica gel).
reaction conditions of its formation. Thus, after two
cycles, oxazinin-3 could be obtained in three steps and
61% overall chemical yield.
ously assigned,3 the same was not possible in the case
of oxazinin-3 due to the very small amount of material
isolated.2 Thus, the above synthesis established, by com-
parison of the specific optical rotations of synthetic and
natural material, the absolute stereochemistry of oxazi-
nin-3 as 2S,5S.9
At this point it should be noted that, although the abso-
lute stereochemistry of oxazinin-1 has been unambigu-

E. A. Couladouros et al. / Tetrahedron Letters 45 (2004) 7779–7781
6. Leete, E. J. Am. Chem. Soc. 1959, 81, 6023–6026.
7781
The observed lack of diastereoselectivity of the anula-
tion reaction may be attributed to the low stereochemi-
cal demand of the primary hydroxyl involved and the
distant 1,4-arrangement of the ring substituents.
Whether addition of a more sterically demanding sec-
ondary hydroxyl to 3-methyleneindolenine 4a in con-
junction with a more intimate substituent arrangement
around the morpholinone ring of oxazinin-1 and -2
would lead to higher diastereoselectivity remains to be
investigated. In this context, preparation of oxazinin-1
and -2 as well as of a library of related analogues is
underway.
7. Shaw, K. N. F.; McMillan, A.; Gudmundson, A. G.;
Armstrong, M. D. J. Org. Chem. 1958, 23, 1171–1178.
8. Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29,
5177–5180.
9. Selected spectroscopic data:
25
Compound 8: ½aꢀD ꢁ18 (c = 0.65 in MeOH). 1H NMR (250
MHz, acetone-d6): d 11.32 (br s, 1H), 8.99 (s, 1H), 8.52–8.09
(m, 2H), 7.57 (m, 1H), 7.29 (m, 2H), 7.12 (d, J = 8.4Hz,
2H), 6.80(d, J = 8.4Hz, 2H), 4.95–4.75 (m, 1H), 3.72 (s,
3H), 3.30–3.10 (m, 2H). 13C NMR (62.5MHz, acetone-d6)
d: 182.0, 173.1, 164.1, 158.1, 140.6, 138.2, 132.1, 129.0,
128.5, 125.5, 124.6, 123.6, 117.1, 114.0, 55.5, 53.5, 38.1.
Mass: ESI pos. m/z: 367.2 [(M+H)+].
Compound 5b (1:1 mixture of diastereomers): 1H NMR
(500MHz, MeOH-d4): d 7.73/7.48 (two d, J = 8.2/7.8Hz, 1/
1 H; ArH), 7.39/7.35 (two d, J = 8.1/9.3Hz, 1/1H; ArH),
7.22–6.95 (m, 5+5H; ArH), 6.75/6.70(two d, J = 8.5/8.2Hz,
2/2H; ArH), 5.35/5.33 (two s, 1/1H; CHOH), 4.25–4.13 (m,
1+1H; NHCH), 3.62/3.60(two br d, J = 3.4/4.8Hz, 2/2H;
CH2OH), 2.94/2.84 (two dd, J = 13.9/13.8, 6.1/6.5Hz, 1/1H;
ArCHH), 2.79–2.72 (m, 1+1H; ArCHH). 13C NMR
(125MHz, MeOH-d4) d: 175.7, 175.6, 156.9, 156.8, 138.2,
138.1, 131.4, 130.4, 130.1, 127.2, 125.3, 122.7, 122.7, 120.3,
116.4, 116.2, 115.2, 115.0, 112.4, 112.3, 69.6, 69.4, 64.1,
63.7, 54.1, 53.9, 49.4, 49.2, 49.0, 48.9, 48.7, 37.1, 37.0. Mass:
ESI pos. m/z: 341.3 [(M+H)+].
Acknowledgements
This work was supported in part by a joint Greek–
Italian research and technology program co-funded by
the General Secretariat for Research and Technology
of the Greek Ministry of Development and the Euro-
pean Community. We would like to thank Prof. Ernesto
Fattorusso and Prof. Patrizia Cimimiello for kindly pro-
viding us with NMR spectra of natural oxazinin-3.
Thanks are expressed to Dr. L. Leondiadis for the ESI
mass spectral analysis performed at the ÔMass Spectro-
metry and Dioxin Analysis LabÕ, NCSR ÔDemokritosÕ.
25
1
Compound (2R)-3: ½aꢀ ꢁ23 (c 0.65 in MeOH). H NMR
(500MHz, CD3CN): dD9.35 (br s, 1H), 7.63 (d, J = 7.9Hz,
1H), 7.40(d, J = 8.3Hz, 1H), 7.17–7.01 (m, 4H), 6.73 (d,
J = 8.4Hz, 2H), 6.62 (br s, 1H), 5.36 (s, 1H), 3.76 (dd,
J = 13.4, 5.4Hz 1H), 3.71–3.67 (m, 2H), 2.87 (d, J = 6.5Hz,
2H). 13C NMR (125MHz, CD3CN) d: 170.4, 156.6, 131.5,
129.3, 126.3, 122.8, 120.4, 120.2, 116.2, 112.5, 74.4, 64.7,
54.2, 39.5. Mass: ESI pos. m/z: 323.3 [(M+H)+].
References and notes
1. Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897–
1909.
2. Ciminiello, P.; DellÕAversano, C.; Fattorusso, E.; Forino,
M.; Magno, S.; Ianaro, A.; Di Rosa, M. Eur. J. Org. Chem.
2001, 1, 49–53.
3. Ciminiello, P.; DellÕAversano, C.; Fattorusso, C.; Fat-
torusso, E.; Forino, M.; Magno, S. Tetrahedron 2001, 57,
8189–8192.
4. Nilsson, J. W.; Kvarnstro¨m, I.; Musil, D.; Nilsson, I.;
Samulesson, B. J. Med. Chem. 2003, 46, 3985–4001.
5. (a) Bergman, J.; Bergman, S.; Lindstro¨m, J.-O. Tetrahedron
Lett. 1989, 30, 5337–5340; (b) Oikawa, Y.; Toshioka, T.;
Mohri, K.; Yonemitsu, O. Heterocycles 1979, 12, 1457–
1462.
25
Compound (2S)-3: ½aꢀD +40( c 0.66 in MeOH). 1H
NMR (500MHz, CD3CN): d 9.27 (br s, 1H), 7.58 (br d,
J = 7.7Hz, 1H), 7.39 (br d, J = 8.2Hz, 1H), 7.23 (d,
J = 2.6Hz, 1H), 7.13 (ddd, J = 8.2, 7.2, 1.0Hz, 1H), 7.09
(d, J = 8.4Hz, 2H), 7.04 (ddd, J = 7.7, 7.2, 0.9Hz, 1H), 6.92
(br s, 1 H), 6.76 (d, J = 8.4Hz, 2H), 6.45 (br s, 1H), 5.30
(s, 1H), 3.91–3.83 (m, 3H), 3.52 (dd, J = 11.3, 6.7Hz, 1H),
2.78 (d,J = 6.9Hz, 2H). 13C NMR (125MHz, CD3CN)
d: 156.6, 137.4, 131.3, 129.2, 126.1, 122.7, 120.2, 116.3,
112.4, 74.5, 66.2, 54.3, 39.0. Mass: ESI pos. m/z: 323.3
[(M+H)+].