Synthesis of optically active selenium-containing isotryptophan, homoisotryptophan, and homotryptophan

Article abstract of DOI:10.1002/ejoc.201300352

Selenoisotryptophan and its higher homologues were synthesized by Sonogashira coupling of iodophenyl methyl selenide and alkynyloxazolidines followed by iodocyclization as the key step. Sonogashira coupling of 3-iodobenzoselenophene with ethynyloxazolidin

Full text of DOI:10.1002/ejoc.201300352

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300352
Synthesis of Optically Active Selenium-Containing Isotryptophan,
Homoisotryptophan, and Homotryptophan
Koushik Goswami,[a] Amrita Chakraborty,[a] and Surajit Sinha*[a]
Keywords: Amino acids / Chiral pool / Selenium / Cross-coupling / Cyclization
Selenoisotryptophan and its higher homologues were syn-
thesized by Sonogashira coupling of iodophenyl methyl sel-
enide and alkynyloxazolidines followed by iodocyclization as
the key step. Sonogashira coupling of 3-iodobenzoseleno-
phene with ethynyloxazolidine allowed the synthesis of sel-
enohomotryptophan.
blocks for the introduction of a chiral center to the amino
acids. We anticipated that selenoisotryptophan 5a and its
higher homologue 5b could possibly be synthesized by
iodocyclization[3] of intermediate 4, which could be ob-
tained by Sonogashira coupling[4] of iodophenyl methyl sel-
enide (2)[3a,3b] with alkynyloxazolidines 3a and 3b[5a–5d]
(retrosynthesis A, Scheme 1). The synthesis of selenohomo-
tryptophan 9 could be achieved from intermediate 8, which
in turn could be synthesized by Sonogashira coupling of
3-iodobenzoselenophene (6)[3a] and ethynyloxazolidine 7[6]
(retrosynthesis B, Scheme 1).
Introduction
Selenium-containing unnatural amino acids are well
known to reduce phase problems in protein crystallogra-
phy.[1a,1b] In the last decade, selenium analogues of trypto-
phan (i.e., 1a and 1b; Figure 1) are found to be used in this
direction.[1c] Besides crystallography, amino acids bearing
radioactive selenium are used for imaging purpose. In this
area, different selenium-substituted aromatic or heterocyclic
α-amino acids (e.g., 1d, 1e)[2a] have been synthesized as
model compounds. Radioactive Se75 labeled tryptophan 1c
is in clinical trials as a pancreatic scanning agent.[2b]
Figure 1. Important selenotryptophan analogues.
As part of our ongoing research toward the synthesis of
tryptophan analogues, we decided to prepare new Se ana-
logues in optically active form. Herein we report the synthe-
sis of selenium-containing isotryptophan 5a, homoisotryp-
tophan 5b and homotryptophan 9 by using a chiral pool
approach.
Scheme 1. Retrosynthetic pathway.
Results and Discussion
Our retrosynthetic route is depicted in Scheme 1; suitably
substituted alkynyloxazolidines were used as building
The synthesis of tryptophan analogues was previously re-
ported by Rutjes et al.[7] by using Sonogashira coupling as
the key step; however, a similar synthesis of the Se ana-
logues has not been attempted. Moreover, the starting
acetylene-containing α-amino acids were prepared by a
chemoenzymatic method, as these compounds are very ex-
pensive commercially. Recently, we developed a strategy to
prepare indole/benzofuran-containing amino acids through
the palladium-catalyzed coupling of alkynyloxazolid-
[a] Department of Organic Chemistry, Indian Association for the
Cultivation of Science,
2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032,
India
Fax: +91-33-24732805
E-mail: ocss5@iacs.res.in
Homepage: http://www.iacs.res.in/ochem/ocss5/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300352.
Eur. J. Org. Chem. 2013, 3645–3647
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. Goswami, A. Chakraborty, S. Sinha
SHORT COMMUNICATION
ines.[5d,5e] At the onset of the synthesis, we prepared iodo- following the reaction sequence shown in Scheme 2. Chiral
phenyl methyl selenide 2[3a,3b] from commercially available acetylenes 3a and 3b were synthesized from naturally occur-
2-iodoaniline. This was then coupled with acetylene 3a to ring l-aspartic acid and l-glutamic acid according to a lit-
form adduct 4a. Upon treatment with iodine in dichloro- erature procedure.[5a–5d]
methane at room temperature, compound 4a gave desired
Synthesis of selenohomotryptophan 9 commenced with
10a in 60% yield along with amino alcohol 11a as a result the preparation of 3-iodobenzoselenophene (6)[3a] from
of the Lewis acidic behavior of molecular iodine. Deiodin- iodophenyl methyl selenide (2). Compound 6 was then cou-
ation[8] of 10a by using tributyltin hydride (TBTH) in the pled with ethynyloxazolidine 7[6] under Sonogashira[4] con-
presence of 2,2Ј-azobisisobutyronitrile (AIBN) afforded ditions to obtain coupling product 8. Ethynyloxazolidine
12a, which after acetonide removal under acidic conditions 7 was made from Garner’s aldehyde,[6] which in turn was
provided deiodinated amino alcohol 13a. Sequential oxi- prepared from naturally occurring l-serine. Application of
dation[9] and esterification afforded selenoisotryptophan 5a standard hydrogenation[10] conditions to reduce the triple
from 13a. Repetition of the same sequence with 11a led to bond of 8 resulted in a mixture of half-saturated product
the formation of 3-iodoselenoisotryptophan derivative 14a. 17, completely saturated product 18, and starting material
Similarly, higher homologue 5b and iodo derivative 14b 8, in which 17 was the major species (Scheme 3). Hydrogen-
were prepared from butynyloxazolidine 3b and selenide 2 by ation at high (Ͼ80 psi) pressure[10] provided a parallel out-
come (Scheme 3).
Scheme 3. Synthesis of selenohomotryptophan derivative from
iodophenyl methyl selenide (TBAF = tetrabutylammonium fluor-
ide, DIPA = diisopropylamine, PTSA = p-toluenesulfonic acid).
After purification, semisaturated compound 17 was sub-
jected to hydrogenation under several conditions[10]
(Table 1, entries 1–6) but none of these provided 18 in more
than 7% yield.
However, overnight hydrogenation in a Parr hydro-
genator (Ͼ80 psi) afforded desired product 18 in moderate
yield (Table 1, entry 7). Unreacted starting material 17 was
recovered in every case (Scheme 3). At this juncture, aceton-
ide deprotection of 18 resulted in amino alcohol 19, which
upon oxidation[9] and esterification afforded selenohomo-
Scheme 2. Synthesis of selenoisotryptophan and selenohomoiso-
tryptophan derivatives (PTSA = p-toluenesulfonic acid).
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tryptophan derivative 9 (Scheme 3).
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Eur. J. Org. Chem. 2013, 3645–3647

Synthesis of Optically Active Selenoisotryptophan and Derivatives
Table 1. Conditions for the reduction of the double bond to a single
bond.[a]
Acknowledgments
S. S. thanks the Department of Science and Technology (DST),
New Delhi for financial support by a grant. K. G. is thankful to
the Indian Association for the Cultivation of Science (IACS), and
A. C. is thankful to the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for their fellowships.
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[a] Reagents and conditions: Reactions were performed with 17
(0.05 mmol) in methanol (1 mL, entries 1 to 5) and AcOH (1 mL,
entry 6). Reaction was performed with 17 (0.26 mmol) in methanol
(20 mL, entry 7). 1 psi = 6.89 kPa; 1 atm = 101.32 kPa. [b] Isolated
yield. [c] Et3SiH (10 equiv.). [d] NaBH4 (1.5 equiv.). [e] No reaction.
Conclusions
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In summary, the synthesis of optically active new seleno-
tryptophan analogues was reported from alkynyloxazolid-
ines by using a chiral pool approach. Though the yield in
the reduction step was moderate, the synthesis of seleno-
homotryptophan is reported for the first time. During their
synthesis, we prepared 3-iodosusbtituted analogues that can
be further derivatized by standard coupling reactions to af-
ford several other analogues.
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data, 1H NMR
spectra of all new compounds and 13C NMR spectra of compounds
3a, 3b, 4a, 4b, 5a, 5b, 8, 9, 12a, 12b, 13a, 13b, 14a, 14b, 17, 18, and
19.
Received: March 8, 2013
Published Online: May 7, 2013
Eur. J. Org. Chem. 2013, 3645–3647
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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