with functional groups suitable for interconnecting the desired
modules in a straightforward manner. In the course of these
studies, we turned our attention to 1,3,5-dithiazines, a
potentially interesting class of S,N-heterocycles.3
Amino Acid-Based Dithiazines. Dithiazines 2a-d and
4 were obtained in good yield by treating basic aqueous
solutions of (L)-amino acids 1a-d or GABA (3) with
aqueous formaldehyde and sodium hydrosulfide, Scheme 3,
according to described procedures.9
Scheme 3
Our rationale is that the nitrogen atom at the 5-position of
the dithiazine ring is perfectly suited for linking various
functionalities and modules to the photolabile latch. It is
known that dithiazines are readily deprotonated by butyl-
lithium producing carbanions, which can add to carbonyl
compounds4 or react with other electrophiles.5 Such depro-
tonation occurs faster than in dithianes, even when it is
carried out at lower temperatures. The dithiazine ring also
hydrolyzes under much milder conditions than the dithiane
ring.6 In most reported dithiazines, nitrogen is either free of
substitution or carries a simple alkyl substituent, although
chiral dithiazines based on 1-phenylethylamine were also
synthesized.7
In view of our particular interest in biological systems,
we chose amino acids as the dithiazine building blocks. Our
long-term objective is in developing artificial photolabile
amino acids that can be incorporated into a polypeptide/
protein chain with negligible structural perturbation. The
carboxylic group can also be utilized for attaching a variety
of other potentially useful “blocks” to the photolabile latch.
As far as biocompatibility is concerned, dithiazines appear
to be quite benign compounds. They have been studied and
used in food chemistry, and there is a detailed review on
their remarkable organoleptic properties.8
Most of the synthesized dithiazines are stable white
crystalline solids except 2b, the phenylalanine-based hetero-
cycle, which is a viscous oil. Interestingly, the dithiazine
functionality can itself be considered an N-protecting group
for amino acids due to the fact that it can be hydrolyzed
under relatively mild conditions, for example, HgCl2/HgO
in wet dichloromethane.6
Benzaldehyde Adducts. The dithiazinyl addition to a
simple aldehyde, benzaldehyde, was used as a model for the
“assembly” of more complex photolabile molecular latches.
Butyllithium added in excess at -78 °C deprotonates 2a-d
and 4 in anhydrous THF within 1-2 h, whereas parent
dithianes require much higher temperatures (-20 °C) for
efficient deprotonation with BuLi.10 The observed accelera-
tion is probably due to both the electronic and chelating6
effect of nitrogen.
In this communication, we report on (i) synthesis of
N-carboxyalkyl-substituted 3,4-dihydro-1,3,5-dithiazines based
on R-amino acids and GABA (γ-aminobutyric acid), (ii)
addition of lithiated dithiazines to benzaldehyde, and (iii)
externally sensitized photofragmentation of the adducts.
The generated dithiazine anions were reacted with benz-
aldehyde at -78 °C to furnish 2-(R-hydroxybenzyl)-dithi-
azines 5a-d and 6 in moderate to good yields,11 Scheme 4.
(1) (a) McHale, W. A.; Kutateladze, A. G. J. Org. Chem. 1998, 63, 9924.
(b) Vath, P.; Falvey, D. E.; Barnhurst, L. A.; Kutateladze, A. G. J. Org.
Chem. 2001, 66, 2886.
(2) (a) Wan, Y.; Mitkin, O.; Barnhurst, L.; Kurchan, A.; Kutateladze,
A. Org. Lett. 2000, 2, 3817. (b) Mitkin, O. D.; Kurchan, A. N.; Wan, Y.;
Schiwal, B. F.; Kutateladze, A. G. Org. Lett. 2001, 3, 1841. (c) Mitkin, O.;
Wan, Y.; Kurchan, A.; Kutateladze, A. Synthesis 2001, 1133. (d) Barnhurst,
L. A.; Kutateladze, A. G. Org. Lett. 2001, 3, 2633. (e) Wan, Y.; Angleson,
J. K.; Kutateladze, A. G. J. Am. Chem. Soc. 2002, 124, 5610.
(3) First synthesized: Braithwaite, E. R.; Graymore, J. J. Chem. Soc.
1953, 143.
Scheme 4
(4) (a) Bauermeister, H.; Riechers, H.; Schomberg, D.; Washausen, P.;
Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1991, 30, 191. (b) Redlich,
H.; Lenfers, J. B. Liebigs Ann. Chem. 1988, 597. (c) Flores-Parra, A.;
Khuong-Huu, F. Tetrahedron 1986, 42, 5925. (d) Paulsen, H.; Mielke, B.;
Von Deyn, W. Liebigs Ann. Chem. 1987, 439 (e) Brown, C. A.; Chapa,
O.; Yamaichi, A. Heterocycles 1982, 18, 187.
(5) (a) Kumar, A.; Coe, P. L.; Jones, A. S.; Walker, R. T.; Balzarini, J.;
De Clercq, Eric. J. Med. Chem. 1990, 33, 2368. (b) Juaristi, E.; Gonzalez,
E. A.; Pinto, B. M.; Johnston, B. D.; Nagelkerke, R. J. Am. Chem. Soc.
1989, 111, 6745.
(6) Balanson, R. D.; Kobal, V. M.; Schumaker, R. R. J. Org. Chem.
1977, 42, 393.
(7) Cadenas-Pliego, G.; de Jesus Rosales-Hoz, M.; Contreras, R.; Flores-
Parra, A. Tetrahedron: Asymmetry 1994, 5, 633.
(8) Werkhoff, P.; Guentert, M.; Hopp, R. Food ReV. Int. 1992, 8, 391.
4130
Org. Lett., Vol. 4, No. 23, 2002