Synthesis of chiral helical 1,3-oxazines

Article abstract of DOI:10.1021/ol301267r

A series of novel 1,3-oxazines were prepared to construct a helical framework. The 1,3-oxazine attached to the phenanthrene unit showed a small bite angle θ (～12°), while the units attached to [4]helicene showed a larger θ (～35°) and exhibited helical isomers at ambient conditions. The diastereomers of the third type of helicene-like bis-oxazine attached to binaphthyl were easily separable and showed good thermal stability. All four diastereomers of bis-helicene were synthesized, and their absolute configuration was established.

Full text of DOI:10.1021/ol301267r

ORGANIC
LETTERS
Synthesis of Chiral Helical 1,3-Oxazines§
Harish R. Talele,† Sibaprasad Sahoo,‡ and Ashutosh V. Bedekar*,†
2012
Vol. 14, No. 12
3166–3169
Department of Chemistry, Faculty of Science, M.S. University of Baroda,
Vadodara 390 002, India, and Sun Pharma Advance Research Centre, Tandalja,
Vadodara 390 020, India
avbedekar@yahoo.co.in
Received May 8, 2012
ABSTRACT
A series of novel 1,3-oxazines were prepared to construct a helical framework. The 1,3-oxazine attached to the phenanthrene unit showed a small
bite angle θ (∼12°), while the units attached to [4]helicene showed a larger θ (∼35°) and exhibited helical isomers at ambient conditions. The
diastereomers of the third type of helicene-like bis-oxazine attached to binaphthyl were easily separable and showed good thermal stability.
All four diastereomers of bis-helicene were synthesized, and their absolute configuration was established.
A search for new chiral molecules with different shape,
size, and functional group is an extremely crucial aspect of
modern organic chemistry. This is particularly vital in the
fields of molecular recognition, supramolecular and me-
dicinal chemistry, asymmetric synthesis and enantioselec-
tive catalysis, material chemistry, etc. Among this class of
compounds, helically chiral molecules find a unique place
because of their special chiroptical properties. Since the
pioneering work on helicene by Newman in 1956,1 the area
has presented a number of other helical molecules with a
wide range of applications.2ꢀ5
Primarily the helically shaped molecules are of two
types: carbohelicenes and helicenes with heteroatoms
or heterohelicenes.6,7 The heterohelicenes possessing a
1,3-oxazine unit in the framework are not reported in the
§ Dedicated to Professor B.V. Kamath on his 62nd birthday.
† M.S. University of Baroda.
‡ Sun Pharma Advance Research Centre.
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Oudman, D.; Wynberg, H. J. Am. Chem. Soc. 1973, 95, 3692. (b)
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r
10.1021/ol301267r
Published on Web 06/06/2012
2012 American Chemical Society

literature, except for one system,7d although this hetero-
cyclic moiety is present in a few biologically active
molecules.8 In this paper, we present the synthesis, char-
acterization, and determination of absolute configuration
of three types of novel helical 1,3-oxazines.
The synthetic strategy is based on a well-known conver-
sion of 2-naphthol to angularly fused 1,3-oxazine when
treated with a primary amine and excess of formaldehyde
by an aromatic Mannich reaction (Scheme 1).9
Scheme 1. General Synthesis of 1,3-Oxazines from 2-Naphthol
Figure 1. ORTEP diagram of compound 2 (type A).
The design of helically shaped 1,3-oxazine is based on
the construction of the heterocyclic ring on the ortho fused
aromatic ring system. Initially, phenanthrene was chosen
for this purpose, and the oxazine of type A was synthesized
from its hydroxyl derivative 1 (Scheme 2). Two derivatives
2 and 3 were sythesized from benzyl amine and (S)-R-
methylbenzyl amine, respectively. The molecules prepared
were fully characterized by usual spectral and analytical
techniques.
be stable and free from conformational isomerization. In
an effort to prepare a more rigid helical shape, the second
set is designed with[4]helicene asthe aromatic system. Two
derivatives of type B were synthesized from hydroxy-
[4]helicene 4 under similar reaction conditions (Scheme 3).
Scheme 3. Synthesis of Oxazine of Type B
Scheme 2. Synthesis of Oxazine of Type A
The 1H NMR analysis of 5 showed two sets of dd for the
protons of the oxazine ring against the two s for compound
2. Further confirmation of the helical shape was obtained
from the single-crystal analysis of 5 (Figure 2), where a
considerable bite angle θ (∼35°) was observed between the
two terminal rings of the helicene system.
The third type of helical oxazine was planned where
two oxazine rings are attached to the central helical
unit. Accordingly, type C is synthesized from the 7,70-
dihydroxy-2,20-binaphthol 710 via atropisomeric inter-
mediates 8a and 8b (Scheme 4). The intermediates were
at first purified from the reaction mixture, and subse-
quently, one of them (8a) was isolated by recrystallization.
The separated pure diastereomer 8a was then transformed
to the methylene-bridged compound 9a by reaction with
diiodomethane and Cs2CO3.7c
The presence of bromine helped its crystal quality, and
single crystal analysis indicated a small bite angle θ (∼12°)
between the planes of the two terminal rings of the
phenanthrene system in 2 (Figure 1). However, chiral-
phase HPLC analysis showed only one peak confirming
the absence of isomers in solution at ambient conditions.
The helical molecules with substantial bite angle show
special chiroptical properties and high optical rotation.
For practical applications, the helical shape also needs to
ꢀ
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(8) (a) Urbanski, T. Nature 1951, 168, 562. (b) Chylinska, J. B.;
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Urbanski, T.; Mordarski, M. J. Med. Chem. 1963, 6, 484. (c) Chylinska,
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Mathew, B. P.; Kumar, A.; Sharma, S.; Shukla, P. K.; Nath, M. Eur. J.
Med. Chem. 2010, 45, 1502.
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Longman: Essex, 1991; p 1053.
Org. Lett., Vol. 14, No. 12, 2012
3167

Figure 3. ORTEP diagram of compound 8a, clearly establishing
the (P) configuration (or S) at the chiral axis.
Figure 2. ORTEP diagram of compound 5 (type B).
Scheme 4. Synthesis of Helical Bis-oxazines of Type C
molecular OR ([Φ]D þ5487), while the open structure 8a
showed specific rotation of only þ204. This enhancement
of the degree of optical rotation when the atropisomeric
open structure is converted to a rigid form by introducing
the bridge is in accordance with recent observations.7c The
cyclized form with the methylene bridge also provides
stability to the helical shape, and a solution of 9a was
refluxed in toluene for over 12 h without any visible
thermal isomerization.
A similar synthetic process followed for the preparation
of all four diastereoisomers of the helically chiral bis-
oxazines (Figure 4). Isomer 9b was prepared from 8b,
while the other two isomers 11a and 11b were prepared
from the corresponding two diastereomers of 10a and 10b
obtained from 7 and (S)-R-methylbenzylamine.
The single-crystal X-ray analysis confirmed the absolute
configuration of the chiral axis to be P for the crystallized
isomer 8a (Figure 3).11 Since the methylene bridge forma-
tion will retain the stereochemistry of the axis of 8a, the
absolute configuration of the methylene-bridged com-
pound 9a was accepted to be RPR. Helical compound 9a
has a large specific optical rotation ([R]D þ884) and
Figure 4. Four diastereoisomers of the bis-oxazines of type C.
Org. Lett., Vol. 14, No. 12, 2012
(11) The crystal of 9a could not be satisfactorily solved by X-ray
diffraction analysis.
3168

Scheme 5. Synthesis of N-Me-bis-oxazine of Type C
Figure 5. Chiral HPLC analysis of 5 (left) and 12 (right).
The synthesis of the isomers of type C is quite straight-
forward and can be carried out on a multigram scale for
further applications and study.
Another derivative of 1,3-oxazine of type C with a single
helical chiral unit was synthesized by selecting methyl-
amine in place of optically active amine (Scheme 5). The
molecule 12 was isolated as a racemate of two helical
enantiomers.
Chiral-phase HPLC analysis of the compound 5 and 12
was performed in order to establish the stability of isomers
in solution at ambient conditions (Figure 5). The first
molecule attached with four ortho fused aromatic rings 5
did show the presence of two helical isomers, but the
separation was never up to the baseline, probably indicat-
ing their dynamic behavior. At the same time, the two
helical isomers of 12 were clearly separated to the baseline
indicating their stability.
Helical oxazines show typical UV and CD spectral
features (Figure 6).12 The presence of two opposite
bisignate couplets, a positive one at around 270 nm and
a negative at 292 nm, are attributed to the P configuration
(9a). As expected, the two enantiomers of the pair 9a and
11a show identical but opposite CD curves.
Figure 6. CD spectra of bis-oxazine enantiomer pair RPR-9a
(red) and SMS-11a (black) (c 0.5 ꢁ 10ꢀ7 mol in acetonitrile).
Acknowledgment. This work was supported by a
SERC project of Department of Science and Technology,
New Delhi (SR/SI/OC-42/2006). We thank the DST and
CSIR (SRF) for the fellowship to H.R.T. and Prof. B. V.
Kamath, Head, Department of Chemistry, for the facilities
and encouragement.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, CD spectra, and X-ray crys-
tal data of the reported compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
In conclusion, a series of new helical oxazines were
synthesized which showed high degree of optical rotation
and particularly the bis-oxazines of type C had consider-
able thermal stability.
(12) Blackemore, P. R.; Kilner, C.; Milicevic, S. D. J. Org. Chem.
2006, 71, 8212.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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