Amino acid-based dithiazines: Synthesis and photofragmentation of their benzaldehyde adducts

Article abstract of DOI:10.1021/ol0268790

(formula presented) α-Amino acids and GABA are functionalized with dithiazine rings via reaction with sodium hydrosulfide in aqueous formaldehyde. The resulting dithiazines are lithiated at -78°C and reacted with benzaldehyde furnishing amino acid-based 2,5-bis-substituted dithiazines. These adducts undergo externally sensitized photofragmentation with quantum efficiency comparable to that of the parent dithiane adducts, thus offering a novel approach to amino acid-based photolabile tethers.

Full text of DOI:10.1021/ol0268790

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4129-4131
Amino Acid-Based Dithiazines:
Synthesis and Photofragmentation of
Their Benzaldehyde Adducts
Alexei N. Kurchan and Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, UniVersity of DenVer,
DenVer, Colorado 80208-2436
akutatel@du.edu
Received September 10, 2002
ABSTRACT
r-Amino acids and GABA are functionalized with dithiazine rings via reaction with sodium hydrosulfide in aqueous formaldehyde. The resulting
dithiazines are lithiated at −78 °C and reacted with benzaldehyde furnishing amino acid-based 2,5-bis-substituted dithiazines. These adducts
undergo externally sensitized photofragmentation with quantum efficiency comparable to that of the parent dithiane adducts, thus offering a
novel approach to amino acid-based photolabile tethers.
We are developing a general strategy for assembly and
photoinduced disassembly of modular photolabile molecular
objects, designed for applications in chemical biology. At
the core of this approach is the recently discovered photo-
fragmentation in dithiane- or trithiane-carbonyl adducts,
which is initiated by photoinduced electron transfer followed
by mesolytic C-C bond scission in the generated cation-
radical, Scheme 1.1
This approach was utilized to link calixarenes,2a,c crown
ethers,2c,d carbohydrates,2c hydrophobic tails and hydrophilic
headgroups of photolabile amphiphiles,2e and even the blocks
equipped with hydrogen bond-based elements of molecular
recognition, for example ureas or aminopyridines.2b
Successful implementation of this methodology requires
a systematic search for photolabile tethers capable of
photoinduced fragmentation and at the same time outfitted
Scheme 2
Scheme 1
We use such adducts as photolabile “latches” that can hold
together various molecular blocks and at the same time are
capable of releasing them upon photoirradiation (Scheme 2).
10.1021/ol0268790 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/19/2002

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.
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Org. Lett., Vol. 4, No. 23, 2002

Chiral dithiazines 2b-d (based on R-amino acids) were
expected to produce diastereomeric adducts 5b-d. Given
the considerable spatial separation of the two stereogenic
centers, which are five bonds apart, we did not expect the
diastereomers to exhibit large differences in their NMR
spectra. In fact, it was only adduct 5b (phenylalanine-based
dithiazine) that clearly showed an approximately 0.006 ppm
difference in chemical shifts of the benzylic Ph-CH-OH
protons. Both adducts 5c (valine-based) and 5d (leucine-
based) have this doublet broadened but not resolved into two
doublets. Presented in Figure 1 is the expansion of the
doublets of these benzylic protons in 5b and 5c for
comparison.
Photoinduced Fragmentation. Synthesized adducts 5 and
6 were then irradiated in acetonitrile with a medium-pressure
mercury lamp using a Pyrex filter (∼300 nm cutoff) in the
presence of benzophenone. The photoinduced C-C bond
cleavage was followed by proton NMR monitoring of the
release of benzaldehyde. It is not possible to follow the
release of the dithiazine fragment due to its degradation in
secondary photoprocesses in the presence of benzophenone.
In all the cases studied, the cleavage occurred with an
efficiency similar to that of the parent di- or trithiane-based
system.
As a representative example, the quantum yield of photo-
cleavage in 6 was determined in a carousel Rayonet-type
photoreactor using the standard benzophenone-benzhydrol
actinometer system at conversions below 10-15% and found
to be 0.078. This value is similar to the quantum efficiency
of the cleavage of benzaldehyde-trithiane adduct (0.069) and
slightly smaller than that of the benzaldehyde-dithiane adduct
(0.119), Figure 2.2b
1
Figure 1. Expanded portion of H NMR spectra of 5b and 5c
showing resonances of benzylic (Ph-CH-OH) protons.
Figure 2. Quantum efficiencies of the photoinduced cleavage of
benzaldehyde adducts of dithiane, trithiane, and dithiazine 4 (adduct
6), sensitized by benzophenone.
The ratio of diastereomers 5b determined by NMR is
approximately 2:1. The line width derived from the left
spectrum is about 1.8 Hz. We suggest that the 0.4 Hz
broadening in 5c is due to the presence of the second
diastereomer.
In conclusion: we synthesized novel amino acid-based
dithiazines that can potentially be utilized as linkers in
photolabile molecular systems. Specifically, we have shown
that carboxylate functionality does not interfere with dithi-
azines’ deprotonation by butyllithium and their addition to
benzaldehyde. Externally sensitized irradiation of the benz-
aldehyde adducts triggers a photofragmentation reaction,
similar to that of the parent tri- and dithiane-aldehyde
adducts. Benzaldehyde adducts 5 and 6 represent a model
system designed to prove the concept. Work is in progress
in our laboratories to synthesize photolabile tethers via
addition of lithiated dithiazines 2 and 4 to aldimines or
substituted aldehydes possessing auxiliary functionalities
suitable for anchoring useful molecular blocks.
(9) General Procedure. Amino acid (20 mmol) was dissolved upon
stirring in 50 mL of 0.4 M aqueous KOH. The solution was cooled to 0
°C, and 6.3 mL of 38% formalin was added dropwise. The resulting solution
was stirred at 0 °C for 1.5 h, and then 25 mL of 2 M aqueous NaHS was
added dropwise. The reaction mixture was stirred for an additional 2 h at
0 °C and then allowed to warm overnight. Workup included addition of 1
mL of concentrated HCl and extraction with 20 mL of CHCl3. The first
organic extract was discarded, and the aqueous layer was further acidified
to pH ) 6 by adding more concentrated HCl. The water phase was extracted
again with chloroform (3 × 40 mL); organic layers were combined and
dried over MgSO4, and the solvent was removed under reduced pressure.
Resulting products were purified by recrystallization or flash chromatog-
raphy (for further details and spectra, see Supporting Information; this
procedure is a modification of the N-methyldithiazine synthesis described
in ref 5b).
(10) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
(11) General Procedure. To a solution of dithiazine (2 mmol) in 25
mL of anhydrous THF at -78 °C was added 3.1 mL of 1.6 M BuLi in
hexane (5 mmol) under nitrogen. The reaction mixture was stirred for 2 h
at -78 °C, and a solution of benzaldehyde (3 mmol) in 10 mL of anhydrous
THF was added dropwise. The resulting solution was stirred at -78 °C for
1 h and then allowed to warm to room temperature. The reaction mixture
was washed with a solution prepared from 30 mL of saturated ammonium
chloride and 10 mL of 3% HCl. The aqueous layer was extracted twice
with 20 mL of ethyl acetate. The organic extracts were combined and dried
over MgSO4. The solvent was removed under reduced pressure, and the
product was purified by flash chromatography using chloroform as an eluent.
(For further details and spectra, see Supporting Information.)
Acknowledgment. Support of this research by the
National Science Foundation (Career Award CHE-9876389)
is gratefully acknowledged.
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0268790
Org. Lett., Vol. 4, No. 23, 2002
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