Synthesis of unnatural selenocystines and β-aminodiselenides via regioselective ring-opening of sulfamidates using a sequential, one-pot, multistep strategy

Article abstract of DOI:10.1021/jo1001388

A variety of N-alkyl-β-aminodiselenides have been synthesized in high yield from sulfamidates under mild reaction conditions using potassium selenocyanate and benzyltriethylammonium tetrathiomolybdate ([BnNEt ₃]₂MoS₄) in a sequential, one-pot, multistep reaction. The tolerance of multifarious protecting groups under the reaction conditions is discussed. The methodology was successfully extended to the synthesis of selenocystine, 3,3′-dialkylselenocystine, and 3,3′-diphenylisoselenocystine and their direct incorporation into peptides.

Full text of DOI:10.1021/jo1001388

pubs.acs.org/joc
Synthesis of Unnatural Selenocystines and β-Aminodiselenides via
Regioselective Ring-Opening of Sulfamidates Using a Sequential,
One-Pot, Multistep Strategy
Nasir Baig Rashid Baig, R. N. Chandrakala, V. Sai Sudhir, and
Srinivasan Chandrasekaran*,†
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, Karnataka, India.
†Honorary Professor, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
scn@orgchem.iisc.ernet.in
Received January 31, 2010
A variety of N-alkyl-β-aminodiselenides have been synthesized in high yield from sulfamidates under
mild reaction conditions using potassium selenocyanate and benzyltriethylammonium tetrathiomo-
lybdate ([BnNEt3]2MoS4) in a sequential, one-pot, multistep reaction. The tolerance of multifarious
protecting groups under the reaction conditions is discussed. The methodology was successfully
extended to the synthesis of selenocystine, 3,30-dialkylselenocystine, and 3,30-diphenylisoselenocys-
tine and their direct incorporation into peptides.
Introduction
Recent advances in the synthesis of organoselenium com-
pounds have been propelled by the interesting reactivities2
and their potential pharmaceutical significance.3 Although
several methods are available for the synthesis of organo-
seleniumcompounds,4 therestillexistchallengesanddemands
to develop new versatile selenating reagents which can per-
form regio- and stereocontrolled selenium-transfer reac-
tions. These challenges arise partly because of the relative
instability of the existing selenating reagents even at room
temperature. Conventional selenating reagents generally
yield monoselenides and triselenides as byproducts.5 Among
the many classes of organoselenium compounds, the chiral
diselenides have received special attention due to their higher
stability and ease of handling relative to the parent selenols.
They have been used in the stereoselective ring-opening of
epoxides6 and in the electrophilic selenenylation of alkenes.7
Most importantly, chiral diselenides have been employed as
Organoselenium chemistry has led to the emergence of an
exceptional class of structures in recent years due to its
pivotal role in the synthesis of a large number of biologically
active compounds and their importance in therapeutics.1
(1) (a) Mugesh, G.; Du Mont, W. W.; Sies, H. Chem. Rev. 2001, 101,
2125–2179. (b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004,
104, 6255–6285. (c) Klayman, D. L.; G€unter, W. H. H. In Organoselenium
Compounds: Their Chemistry and Biology; Wiley-Interscience: New York,
1973. (d) Nicolaou, K. C.; Petasis, N. A. In Selenium in Natural Products
Synthesis; CIS, Inc.: PA, 1984; and references therein.
(2) (a) Paulmier, C. Selenium Reagents and Intermediates in Organic
Synthesis; Pergamon: Oxford, U.K., 1986. (b) Krief, A.; Hevesi, L. Organo-
selenium Chemistry I; Springer: Berlin, 1988. (c) Comasseto, J. V.; Ling, L. W.;
Petragnani, N.; Stefani, H. A. Synthesis 1997, 373–403. (d) Braga, A. L.;
Reckziegel, A.; Silveira, C. C.; Comasseto, J. V. Synth. Commun. 1994, 24,
1165–1170. (e) Organoselenium Chemistry: A Practical Approach; Back, T. G.,
Ed.; Oxford University Press: U.K., 1999.
(3) (a) Kumar, Y.; Green, R.; Borysko, K. Z.; Wise, D. S.; Wotring, L. L.;
Townsend, L. B. J. Med. Chem. 1993, 36, 3843–3848. (b) Soriano-Garcia, M.
Curr. Med. Chem. 2004, 11, 1657–1669. (c) De Silva, V.; Woznichak, M. M.;
Burns, K. L.; Grant, K. B.; May, S. W. J. Am. Chem. Soc. 2004, 126,
2409–2413.
(4) (a) Klayman, D. L.; Griffin, T. S. J. Am. Chem. Soc. 1973, 95, 197–
199. (b) Gladysz, J. A.; Hornby, J. L.; Garbe, J. E. J. Org. Chem. 1978, 43,
1204–1208. (c) Thomson, D. P.; Boudjouk, P. J. Org. Chem. 1988, 53, 2109–
2112. (d) Copeland, C. M.; Ghosh, J.; McAdam, D. P.; Skelton, B. W.; Stick,
R. V.; White, A. H. Aust. J. Chem. 1988, 41, 549–561. (e) Li, G. M.; Zingaro,
R. A. J. Chem. Soc., Perkin Trans. 1 1998, 647–650. (f) Ishihara, H.; Koketsu,
M.; Fukuta, Y.; Nada, F. J. Am. Chem. Soc. 2001, 123, 8408–8409.
(5) (a) Topics in Current Chemistry: Organoselenium Chemistry, Modern
Developments in Organic Synthesis; Wirth, T., Ed.; Springer: Berlin, Germany,
2000. (b) Krief, A.; Wemmel, T, V.; Redon, M.; Dumont, W; Delmotte, C. Angew.
Chem., Int. Ed. 1999, 38, 2245–2248. (c) Wirth, T. Angew. Chem., Int. Ed. 2000,
39, 3740–3749. and references cited therein.
(6) (a) Fukuzawa, S.; Takahashi, K.; Kato, H.; Yamazaki, H. J. Org.
Chem. 1997, 62, 7711–7716. (b) Tomoda, S.; Iwaoka, M. J. Chem. Soc.,
Chem. Commun. 1988, 1283–1284. (c) Nishibayashi, Y.; Singh, J. D.;
Fukuzawa, S.-I.; Uemura, S. J. Chem. Soc., Perkin Trans. 1 1995, 2871–2876.
2910 J. Org. Chem. 2010, 75, 2910–2921
Published on Web 04/14/2010
DOI: 10.1021/jo1001388
r
2010 American Chemical Society

Rashid Baig et al.
JOCArticle
SCHEME 1
useful ligands and catalysts in various asymmetric transfor-
mations such as diethylzinc addition to aldehydes,8 asym-
metric hydrosilylation,9 and 1,4 addition of Grignard
reagents to enones.10
withLi2Se2.14,17 This reactiontakes moretime, gives moderate
yields, and is limited to the synthesis of N-carbamato-β-
aminodiselenides. In addition, Li2Se2 has to be prepared in
situ for each reaction and leads to monoselenides and trisele-
nides as by products which are very difficult to purify. In our
laboratory, we have developed an efficient method for the
synthesis of N-tosyl β-aminodiselenides, selenocystine, and
their higher homologues using tetraethylammonium tetrase-
lenotungstate, [Et4N]2WSe4.18 Our efforts to extend the same
methodology for the synthesis of 3,30-dimethylselenocystine
were unsuccessful. The bromo or tosyl derivatives of dipro-
tected threonine were found to be inert to the reaction with
tetraselenotungstate, and longer reaction time led to the
formation of the corresponding dehydroamino acids. The
reaction of aziridine carboxylates 2 with tetraselenotungstate
gave inseparable mixture of products (Scheme 1).
The synthesis of peptides containing selenocysteine is
gaining interest with the discovery of an increasing number
of proteins containing this amino acid.11,12 Selenocysteine
derivatives can also serve as convenient precursors to dehydro-
amino acids,13 which are useful electrophilic handles for the
chemoselective preparation of peptide conjugates.14 Seleno-
cystine has also been used in protein ligation to incorporate
selenocysteine in the active site of a metalloprotein.15 To the
best of our knowledge, only very few methods are reported
for the synthesis β-aminodiselenides and selenocystine.
Braga et al. reported the synthesis of β-amino diselenides
from N-Boc-aziridines and N-Boc-2-oxazolidinone using
Li2Se2 as a selenating reagent,8c,16 whereas selenocystine
was synthesized by the reaction of β-L-bromo or iodoalanine
(7) (a) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.;
Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2000, 11, 4645–4650.
(b) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.; Bagnoli,
L.; Temperini, A. Tetrahedron: Asymmetry 2001, 12, 3053–3059. (c) Back,
T. G.; Moussa, Z.; Parvez, M. J. Org. Chem. 2002, 67, 499–509.
(8) (a) Wirth, T. Tetrahedron Lett. 1995, 36, 7849–7852. (b) Wirth, T.;
Kulieke, K. J.; Fragale, G. Helv. Chim. Acta 1996, 79, 1957–1966. (c) Santi,
C.; Wirth, T. Tetrahedron: Asymmetry 1999, 10, 1019–1023. (d) Braga, A. L.;
Paixao, M. W.; Ludtke, D. S.; Silveira, C. C.; Rodrigues, O. E. D. Org. Lett.
2003, 5, 2635–2638.
(9) (a) Nishibayashi, Y.; Singh, J. D.; Segawa, K.; Fukuzawa, S. I.;
Uemura, S. J. Chem. Soc., Chem. Commun. 1994, 11, 1375–1376.
(b) Nishibayashi, Y.; Segawa, K.; Singh, J. D.; Fukuzawa, S. I.; Ohe, K.;
Uemura, S. Organometallics 1996, 15, 370–379.
(10) Braga, A. L.; Silva, S. J. N.; Ludtke, D. S.; Drekener, R. L.; Silveira,
C. C.; Rocha, J. B. T.; Wessjohann, L. A. Tetrahedron Lett. 2002, 43, 7329–
7331.
(11) (a) Rotruck, J. T.; Pope, A. L.; Ganther, H. E.; Swanson, A. B.;
Hafeman, D. G.; Hoekstra, W. G. Science 1973, 179, 588–590. (b) Leonard,
J. L.; Visser, T. J. Biochemistry of Deiodination. In Thyroid Hormone Metabo-
lism; Hennemann, G., Ed.; Marcel Dekker: New York, 1986; pp 189-220.
(c) Berry, M. J.; Banu, L.; Larsen, P. R. Nature 1991, 349, 438–440. (d) Leonard,
J. L.; Kohrle, J.Intracellular Pathways of Iodothyronine Metabolism. In
The Thyroid; Braverman, L. E., Utiger, R. D., Eds.; Lippincott-Raven:
Philadelphia, 1996; pp 144-189. (e) St Germain, D. L.; Galton, V. A. Thyroid
1997, 7, 655–668.
FIGURE 1. Regioselectivity in the ring-opening of sulfamidates
over the aziridines with nucleophiles.
Sulfamidates are emerging as important intermediates in
organic synthesis19 and considered as a synthetic equivalent
to aziridines. They have certain advantages over the azir-
idines: (a) they have only one site for nucleophilic attack, i.e.,
C1, which renders the reactivity independent of the nature of
R1 and R2 in contrast to the regioselectivity problem asso-
ciated with aziridines (Figure 1); (b) the reactivity of sulfa-
midates is independent of the nature of R3, while aziridines
themselves are classified as activated and nonactivated azir-
idines based on the nature of R3.
(12) (a) Stadtman, T. C. Annu. Rev. Biochem. 1996, 65, 83–100. (b) Kohrle,
J.; Brigelius-Flohe, R.; Bock, A.; Gartner, R.; Meyer, O.; Flohe, L. Biol. Chem.
2000, 381, 849–864. (c) Arner, E. S. J.; Holmgren, A. Eur.J. Biochem. 2000, 267,
6102–6109. (d) May, J. M.; Cobb, C. E.; Mendiratta, S.; Hill, K. E.; Burk, R. F.
J. Biol. Chem. 1998, 273, 23039–23045. (e) Arteel, G. E.; Briviba, K.; Sies, H.
Chem. Res. Toxicol. 1999, 12, 264–269. (f) Becker, K.; Gromer, S.; Schirmer,
R. H.; Uller, S. M. Eur. J. Biochem. 2000, 267, 6118–6125. (g) Mustacich, D.;
Powis, G. Biochem. J. 2000, 346, 1–8.
(13) (a) Okeley, N. M.; Zhu, Y.; Van der Donk, W. A. Org. Lett. 2000, 2,
3603–3606. (b) Hashimoto, K.; Sakai, M.; Okuno, T.; Shirahama, H. Chem.
Commun. 1996, 1139–1140. (c) Sakai, M.; Hashimoto, K.; Shirahama, H.
Heterocycles 1997, 44, 319–324.
(14) Zhu, Y.; Van der donk, W. A. Org. Lett. 2001, 3, 1331–1334.
(15) Berry, S. M.; Gieselman, M. D.; Nilges, M. J.; van der Donk, W. A.;
Lu, Y. J. Am. Chem. Soc. 2002, 124, 2084–2085.
(16) Sehenem, J. A.; Vargas, F.; Milani, P.; Nascimento, V.; Braga, A. L.
Synthesis 2008, 8, 1262–1268.
(17) Stocking, E. M.; Schwarz, J. N.; Senn, H.; Salzmann, M.; Silks, L. A.
J. Chem. Soc., Perkin Trans. 1. 1997, 2443–2447.
(18) (a)Sureshkumar, D.;Gunasundari, T.;Saravanan,V.;Chandrasekaran,
S. Tetrahedron Lett. 2007, 48, 623–626. (b) Bhat, R. G.; Porhiel, E.; Saravanan,
V.; Chandrasekaran, S. Tetrahedron Lett. 2003, 44, 5251–5253.
(19) (a) Cohen, S. C.; Halcomb, R. L. J. Am. Chem. Soc. 2002, 124, 2534–
2543. (b) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 143–
150. (c) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 4901–4912.
(d) Avenoza, A.; Busto, J. H.; Jimenez-Oses, G.; Peregrina, J. M. Org. Lett.
2006, 8, 2855–2858. (e) Bower, J. F.; Chakthong, S.; Svenda, J.; Williams, A. J.;
Lawrence., R. M.; Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2006, 4, 1868–
1877. (f) Bower, J. F.; Svenda, J.; Williams, A. J.; Charmant., J. P. H.;
Lawrence., R. M.; Szeto, P.; Gallagher, T. Org. Lett. 2004, 6, 4727–4730.
(g) Avenoza, A.; Busto, J. H.; Corzana, F.; Jimenez-Oses, G.; Peregrina, J. M.
Chem. Commun. 2004, 980–981. (h) Attani, M.; Wei, L.; Lubell, W. D. Org.
Lett. 2001, 3, 2965–2968.
J. Org. Chem. Vol. 75, No. 9, 2010 2911

Rashid Baig et al.
JOCArticle
SCHEME 2. Synthesis of N-Benzyl-β-aminodiselenide
Recently, we have demonstrated the use of benzyltriethyl-
ammonium tetrathiomolybdate [BnNEt3]2MoS4, 1, as a
useful sulfur-transfer reagent for the synthesis of β-amino
disulfides20 and β-sulfonamidodisulfides21 as well as a re-
agent that can mediate reductive dimerization of alkyl
azides,22 organic thiocyanates,23 and organic selenocya-
nates.24 In exploring further the utility of induced internal
redox reactions23-25 of tetrathiomolybdate 1 in organic
synthesis, it appeared quite attractive to study the sequential
nucleophilic ring-opening of sulfamidates with potassium
selenocyanate followed by reductive dimerization in one pot.
Herein, we present the results of such an investigation.
followed by hydrolysis to give the corresponding N-benzyl-
β-amino diselenides 6a-h.The results of this investigation
are summarized in Table 1. From the Table 1, it is clear that
this method is general, and all the reactions proceed
smoothly under mild reaction conditions to afford the
desired N-benzyl-β-amino diselenides in very good yields.
The reactivity of the sulfamidate with KSeCN was found to
be substrate dependent; the sulfamidates 3a-g took 2 h for
the reaction to reach completion, whereas substituted sulfa-
midate 3h derived from (1S,2R)-1-amino-2,3-dihydro-1H-
inden-2-ol did not react completely even after refluxing for
48 h with excess of KSeCN. However, reductive dimerization
and hydrolysis for all the substrates were equally efficient.
The milder conditions and excellent yields obtained in
this process encouraged us to study the scope and generality
of this methodology with various protecting groups used for
the protection of amino groups in sulfamidates. With this
objective, we synthesized the sulfamidates 3i-l starting from
(S)-2-aminobutanol. The reaction of these sulfamidates 3i-l
with KSeCN followed by reductive dimerization with 1 and
hydrolysis gave the corresponding β-aminodiselenides 6i-l
in good to excellent yields (Table 1).
Results and Discussion
We began our investigation with the reaction of sulfami-
date 3a20(1.0 equiv) with KSeCN (2.0 equiv, reflux, 2 h),
which undergoes regioselective ring-opening to afford the
N-benzyl-β-amino selenocyanate 4a in the form of a salt.
Our attempts to hydrolyze 4a and isolate the corresponding
N-benzyl-β-amino selenocyanate before proceeding to re-
ductive dimerization were unsuccessful as the selenocyanate
decomposes during hydrolysis with dilute HCl. To overcome
this problem, we changed our strategy and subjected the salt
4a to reductive dimerization by treatment with tetrathiomo-
lybdate 124 (1.2 equiv, CH3CN, 28 °C, 8 h), which gave the
N-benzyl-β-aminodiselenide 6a after hydrolysis in 85% yield
(Scheme 2). In order to demonstrate the general utility of this
methodology, we prepared a number of N-benzylsulfami-
dates 3a-h.20 They were then subjected to a one-pot, multi-
step process involving the regioselective ring-opening with
KSeCN, reductive dimerization using tetrathiomolybdate 1,
It is reasonable to visualize the nucleophilic attack of
KSeCN exclusively at the C-O bond of 3 in a highly
stereospecific (SN2) manner to give 4 followed by the attack
2-
of MoS4 on the selenium of selenocyanate 4 leading to
mononuclear molybdenum species of the type X1. The
second stage of the reaction can be represented as an induced
internal electron-transfer from a sulfur ligand to Mo(VI) to
produce Mo(IV) species X2. The reaction of X2 with 1 results
in the formation of alkyl diselenide 5 and Mo2S82-. The
intermediate 5 on hydrolysis gives β-aminodiselenide 6. This
mechanistic rationale is based on our earlier work23,24 and
that of Steifel25a (Scheme 3).
In order to demonstrate further the scope of this metho-
dology, we synthesized various chiral diols 7m-q starting
from the corresponding L-amino acids.26 The reaction of
diols 7m-q with Burgess reagent (Et3NSO2NCOOMe) gave
sulfamidates 3m-q (Scheme 4) in excellent yields.27 These
sulfamidates 3m-q when subjected to the reaction with
KSeCN and 1 followed by hydrolysis gave the corresponding
(20) Nasir Baig, R. B; Kanimozhi, C.; Sai Sudhir, V.; Chandrasekaran, S.
Synlett 2009, 8, 1227–1232.
(21) (a) Sureshkumar, D.; Koutha, S.; Chandrasekaran, S. J. Am. Chem.
Soc. 2005, 127, 12760–12761. (b) Sureshkumar, D.; Gunasundari, T.;
Ganesh, V.; Chandrasekaran, S. J. Org. Chem. 2007, 72, 2106–2117.
(22) Ramesha, A. R.; Bhat, S; Chandrasekaran, S. J. Org. Chem. 1995, 60,
7682–7683.
(23) (a) Prabhu, K. R.; Ramesha, A. R; Chandrasekaran, S. J. Org. Chem.
1995, 60, 7142–7143. (b) Nasir Baig, R. B.; Sai Sudhir, V; Chandrasekaran, S.
Tetrahedron: Asymmetry 2008, 19, 1424–1428.
(24) Prabhu, K. R.; Chandrasekaran, S. Chem. Commun. 1997, 11, 1021–
1022.
(25) (a) Coyle, E. L.; Harmer, M. H.; George, G. N.; Daage, M; Steifel,
E. I. Inorg. Chem. 1990, 29, 14–19. (b) Posakony, J. J.; Grierson, J. R.;
Tewson, T. J. J. Org. Chem. 2002, 67, 5164–5169.
(26) Hughes, A. B.; Sleeb, M. M. J. Org. Chem. 2005, 70, 3079–3088.
(27) Nicollaou, K. C.; Synder, S. A.; Longbotton, D. A.; Nalbandian,
A. Z.; Huang, X. Chem.;Eur. J. 2004, 10, 5581–5606.
2912 J. Org. Chem. Vol. 75, No. 9, 2010

Rashid Baig et al.
JOCArticle
TABLE 1. Synthesis of N-Benzyl-β-aminodiselenides
aTime required for the formation of selenocyanate and its reductive dimerization. bReaction conditions: (i) KSeCN, acetone, reflux, 2 h;
(ii) [BnEt3N]2MoS4, CH3CN, rt, 8 h; (iii) 2 N HCl, rt, 12 h. cReaction conditions: isolated yield after 24 h of reflux with KSeCN followed by reaction
with [BnEt3N]2MoS4. dReaction conditions: (i) KSeCN, acetone, reflux, 2 h; (ii) [BnEt3N]2MoS4, CH3CN, rt, 8 h; (iii) satd citric acid, 2 h.
substituted β-aminodiselenides 6m-q in quantitative yields.
Since the sulfamidate 3q is derived from a racemic diol,
it gave 1:1 diastereomeric mixture of the corresponding
β-aminodiselenide 6q1 and 6q2 as deduced from the proton
NMR spectra (Table 2).
Synthesis of Selenocystines. In order to elaborate this
methodology for the synthesis of selenoamino acids, we
synthesized sulfamidates 9 by treating the diprotected serine
and their 3-alkyl derivative 8 with SOCl2 followed by oxida-
tion with NaIO4 (Scheme 5).
The sulfamidates 9a-g were treated with KSeCN to
give the corresponding selenocyanates which on reductive
dimerization with tetrathiomolybdate 1 followed by hydro-
lysis gave the corresponding selenocystine derivatives 10
(Scheme 6) in very good yields. The reactivity of sulfamidates
with KSeCN was found to be dependent on the substituents
J. Org. Chem. Vol. 75, No. 9, 2010 2913

Rashid Baig et al.
JOCArticle
SCHEME 3. Tentative Mechanism for the Formation of β-Aminodiselenide 6 from 3
SCHEME 4. Synthesis of Sulfamidates 3m-q from Diols Using
Burgess Reagent
TABLE 2. Synthesis of β-Aminodiselenides by the Reaction of
Sulfamidate Derived from Diols
SCHEME 5. Synthesis of Sulfamidate 9a-g
present at the β-position. Serine-derived sulfamidate 9a
took 2 h to react with KSeCN in acetone under reflux,
whereas methyl-substituted sulfamidates 9b-f required 5 h
to react with KSeCN. The sulfamidate derived from (()
3-phenyl serine 9g took only 2 h to react with KSeCN in
refluxing acetone. This may be due to the electron with-
drawing nature of the phenyl group which enhances the
reactivity of sulfamidate 9g toward the incoming nucleo-
phile. The reductive dimerization and hydrolysis for all the
selenocyanate intermediates were found to be equally effi-
cient to give the corresponding selenocystine derivatives
10a-g.29 From Table 3 it can be seen that this method is
general and could be utilized for the synthesis of orthogon-
ally protected selenocystine and N-alkyl selenocystine deri-
vatives like 10e.
aReaction conditions: (i) KSeCN, acetone, reflux, 4 h; (ii) [BnEt3N]2-
MoS4, CH3CN, rt, 8 h; (iii) satd citric acid, rt, 2 h. bTime required for the
formation of selenocyanate and its reductive dimerization.
11 with amino acid methyl ester 12a-d (Scheme 7). The
sulfamidates 13a-d were treated with KSeCN followed by
reductive dimerization with tetrathiomolybdate 1 and hydro-
lysis to give the peptide-containing 3,30-dimethylselenocystine
14a-d in very good yields (Table 4).
Direct Incorporation of 3,30-Dimethyl Selenocystine into
Peptides. In order to demonstrate the scope of this methodo-
logy for the direct incorporation of selenocystine and its
derivatives into peptides, we synthesized the peptide derived
sulfamidates 13a-d by DCC-mediated coupling of sulfamidate
Synthesis of 3,30-Diphenylisoselenocystine. After synthesiz-
ing a variety of selenocystine derivatives, we decided to
extend this methodology to the synthesis of isoselenocystine.
With this objective in mind, we prepared the chiral diol 16
by Sharpless asymmetric dihydroxlation of ethyl cinnamate
2914 J. Org. Chem. Vol. 75, No. 9, 2010

Rashid Baig et al.
JOCArticle
SCHEME 6. Synthesis of Selenocystine Derivatives 10 from Sulfamidates 9
TABLE 3. Synthesis of Selenocystine Derivatives
SCHEME 7. Synthesis of Peptide Sulfamidates 13a-d
Synthesis of 3,30-Dimethylselenocystine-Derived Peptides.
The peptides 20a-d were synthesized from 3,30-dimethyl-
selenocystine derivative 10b by coupling with N-Cbz-protected
amino acids 19a-d using a conventional peptide coupling
reaction (scheme 9). The peptide 20c was crystallized, and its
X-ray crystal structure is shown in Figure 2.
Conclusion
We have demonstrated that a variety of N-alkyl-β-amino-
diselenides can be synthesized in high yield from sulfamidates
under mild reaction conditions using potassium seleno-
cyanate and tetrathiomolybdate 1 in a sequential, one-pot,
multistep reaction. The tolerance of a variety of protecting
groups under the reaction conditions has been discussed. The
methodology was successfully extended to the synthesis of
selenocystines and their direct incorporation into peptides.
Experimental Section
General Methods. All the reactions were performed in oven-
dried apparatus and were stirred magnetically. Melting points
and optical rotation values (recorded at 25 °C) reported
are uncorrected. Infrared spectra were recorded using an
FTIR instrument, the frequencies are reported in wavenum-
bers (cm-1), and intensities of the peak are denoted as s (strong),
aTime required for the formation of selenocyanate and its reductive
dimerization. bReaction condition: (i) KSeCN, acetone, reflux, 2-5 h;
(ii) [BnEt3N]2MoS4, CH3CN, rt, 8 h; (iii) satd citric acid, rt, 2 h.
cReaction conditions: (i) KSeCN, acetone, reflux, 5 h; (ii) [BnEt3N]2-
MoS4, CH3CN, rt, 8 h; (iii) 2 N HCl, rt, 12 h.
1
w (weak), m (medium), broad (br). H and 13C spectra were
recorded at 300/400 MHz and 75/100 MHz NMR instruments,
respectively. Chemical shifts are reported in parts per million
downfield from the internal reference, tetramethylsilane
(TMS). Multiplicity is indicated using the following abbrevia-
tions: s (singlet), d (doublet), dd (double doublet), t (triplet), m
(multiplet), bs (broad singlet). Diphenyl diselenide has been
used as an internal standard for 77Se NMR. Mass spectra were
recorded on a Q-TOF instrument. References for the compound
reported previously are indicated against each of them along
with the characterization data.
General Procedure for the Synthesis of Sulfamidates from
Diols. Synthesis of Sulfamidate 3m. The diol 7m (0.076 g,
0.5 mmol, 1.0 equiv) was dissolved in anhydrous THF (5 mL),
and methoxycarbonylsulfamoyltriethylammonium hydroxide
(0.293 g, 1.25 mmol, 2.5 equiv, 25 °C) was added in a single por-
tion. The resultant solution was immediately warmed to reflux
(using a preheated oil bath) and stirred for 2 h. After completion
of the reaction, the reaction mixture was cooled to 25 °C, poured
into saturated aqueous NH4Cl (25 mL), and extracted with
CH2Cl2 (3 ꢀ 20 mL). The combined organic layer was then
washed with water (50 mL) and dried over anhydrous sodium
15 using (DHQ)2PHAL as the chiral ligand.28 Refluxing
the chiral diol 16 with Burgess reagent (Et3NSO2NCOOMe)
in anhydrous THF gave sulfamidate 17 in 95% yield.
The reaction of sulfamidate 17 with KSeCN followed by
reductive dimerization with 1 gave 3,30-diphenylisoseleno-
cystine derivative 18 in very good yield (Scheme 8).
(28) Sharpless, K, B.; Amberg, W.; Bennani, Y, L.; Crispino, G, A.;
Hortung, J.; Jeong, K, S.; Known, H, L; Morikawa, K.; Wang, Z, M.; Xu, D.;
Zhang, X, L. J. Org. Chem. 1992, 57, 2768–2771.
(29) The HPLC analysis for a representative compound 10b has been
recorded using a reversed-phase C-18 column with a gradient flow of 50%
MeOH, 50% H2O (1% TFA). The diastereomeric ratio of 10b was found to
be 92:8. When the HPLC analysis was carried out using a chiral reversed-
phase C-18 column, we observed >99% ee of the major diastereomer. See the
Supporting Information for further details.
J. Org. Chem. Vol. 75, No. 9, 2010 2915

Rashid Baig et al.
JOCArticle
TABLE 4. Direct Incorporation of 3,30-Dimethylselenocystine into Peptides
aTime required for the formation of selenocyanate and its reductive dimerization. bReaction conditions: (i) KSeCN, acetone, reflux, 7 h;
(ii) [BnEt3N]2MoS4, CH3CN, rt, 8 h; (iii) sat citric acid, rt, 2 h.
SCHEME 8. Synthesis of 3,30-Diphenylisoselenocystine
sulfate (Na2SO4), and the filtrate was concentrated. The crude
product was purified by silica gel (100-200 mesh) column
chromatography (eluted with petroleum ether and ethyl acetate)
to obtain the compound 3m as a white solid: yield 90% (0.121 g);
mp 78 °C; [R]25D þ7.39 (c = 1, CHCl3); IR (neat) 2962 (m), 2876
(w), 1747 (s), 1444 (m), 1377 (s), 1335 (s), 1195 (s), 1158 (w), 918
J = 8 Hz, J = 16 Hz), 3.05 (1H, dd, J = 8 Hz, J = 16 Hz); 13
C
NMR (100 MHz, CDCl3) δ 150.8, 133.6, 129.7, 129.5, 128.3,
80.2, 55.2, 50.7, 38.8; HRMS calcd for C11H13NO5S [M þ Na]þ
294.0412, found 294.0422.
Compound 3n: yield 88% (0.104 g); white solid; mp 42 °C;
[R]25D þ13.79 (c = 1, CHCl3); IR (neat) 2968 (m), 2939 (w), 2883
(w), 1747 (s), 1443 (m), 1377 (s), 1334 (s), 1195 (s), 865 (m), 762
(m), 634 (w) cm-1; 1H NMR (400 MHz, CDCl3) δ 4.96 (1H, m),
4.15 (1H, dd, J = 8 Hz, J = 12 Hz), 3.9 (3H, s), 3.71 (1H, t, J =
(w), 859 (m), 807 (w) cm-1 1H NMR (400 MHz, CDCl3)
;
δ 7.38-7.21 (5H, m), 5.05 (1H, m), 4.02 (1H, dd, J = 8 Hz,
J = 16 Hz), 3.88 (3H, s), 3.81 (1H, t, J = 12 Hz), 3.30 (1H, dd,
2916 J. Org. Chem. Vol. 75, No. 9, 2010

Rashid Baig et al.
JOCArticle
SCHEME 9. Synthesis of 3,30-Dimethylselenocystine-Containing Peptides
31.2, 28.5, 24.3, 22.2, 13.8; HRMS calcd for C10H19NO5S
[M þ Na]þ 288.0882, found 288.0887.
Compound 17: yield 95% (0.156 g); gummy solid; [R]25D þ23.50
(c = 1, CHCl3); IR (neat) 2969 (w), 2930 (w), 1749 (s), 1442 (m),
1388 (s), 1315 (s), 1194 (s), 1043 (s), 836 (s), 701 (s) cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.46-7.36 (5H, m), 5.56 (1H, d, J = 6.3 Hz),
5.53 (1H, d, J = 6.3 Hz), 3.97-3.83 (5H, m), 0.93 (3H, t, J =
7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 162.1, 149.5, 132.9,
129.6, 128.7, 127.6, 77.4, 63.0, 62.5, 54.7, 13.4; HRMS calcd for
C13H15NO7S [M þ Na]þ 352.0467, found 352.0461.
General Procedure for the Synthesis of N-Boc-, N-Cbz-, and N-
Fmoc-Protected Sulfamidates. Compound 9a. Step I. A solu-
tion of SOCl2 (0.47 mL, 6.5 mmol) in dry CH3CN (15 mL)
under nitrogen was cooled to -40 °C, and then Boc-Threo-OMe
(1.05 g, 5 mmol) in dry CH3CN (10 mL) was added drop-
wise over 10 min and stirring continued for a further 45 min at
the same temperature. Dry pyridine (1.9 mL, 25 mmol) was then
added. The reaction mixture was further stirred for 1 h and then
allowed to warm to room temperature. The reaction mix-
ture was quenched with water and extracted with ethyl acetate
(20 mL ꢀ 3). The combined organic extract was washed with
water, dried over anhydrous sodium sulfate (Na2SO4), and
concentrated in vacuum to afford the crude sulfamidite. This
was used without further purification in the next step.
FIGURE 2. ORTEP diagram for compound 20c.
Step II. To a cooled (ice bath) solution of crude (step I)
sulfamidite (5 mmol) in MeCN (30 mL) was added ruthenium-
(III) chloride (20 mg) followed by NaIO4 (1.60 g, 7.50 mmol)
and then water (30 mL). The mixture was stirred at 0 °C for 2 h
and diluted with ether, and the phases were separated. The
aqueous phase was extracted with ether. The combined organic
portions were washed with NaHCO3 solution and then brine.
The solution was dried over anhydrous (Na2SO4) and concen-
trated. The crude product was purified by silica gel (100-200
mesh) column chromatography: yield 76% (1.06 g); white
solid; mp 71 °C; [R]25D -39.38 (c = 1, CHCl3); IR (neat) 2984
(m), 1746 (s), 1459 (m), 1440 (w), 1385 (s), 1334 (s), 1194 (m),
12 Hz), 1.95-1.77 (2H, m), 1.62-1.54 (1H, m), 0.99 (6H, d, J =
8 Hz); 13C NMR (100 MHz, CDCl3) δ 150.3, 79.0, 54.5, 51.0,
41.0, 24.5, 22.5, 21.9; HRMS calcd for C8H15NO5S [M þ Na]þ
260.0569, found 260.0556.
Compound 3o: yield 94% (0.104 g); white solid; mp 60 °C;
[R]25D þ33.20 (c = 1, CHCl3); IR (neat) 2269 (m), 2883 (w), 1746
(s), 1443 (m), 1376 (s), 1330 (s), 1223 (w), 1194 (s), 996 (w), 955
1
(w), 853 (m) cm-1; H NMR (400 MHz, CDCl3) δ 4.57-4.51
(1H, m), 4.07 (1H, dd, J = 5.6 Hz, J = 10 Hz), 3.89 (3H, s), 3.76
(1H, t, J = 10 Hz), 2.11-2.02 (1H, m), 1.08 (3H, d, J = 6.8 Hz),
0.98 (3H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 150.4,
84.2, 54.6, 49.1, 31.0, 18.2, 16.6; HRMS calcd for C7H13NO5S
[M þ Na]þ 246.0412, found 246.0414.
1
1150 (m), 1024 (m), 977 (m), 830 (s), 786 (s) cm-1; H NMR
(300 MHz, CDCl3) δ 4.84-4.68 (3H, m), 3.86 (3H, s), 1.55
(9H, s); 13C NMR (75 MHz, CDCl3) δ 167.4, 147.9, 86.1, 67.4,
57.3, 53.4, 27.7; HRMS calcd for C9H15NO7S [M þ Na]þ
304.0467, found 304.0540.
Compound 3p: yield 95% (0.112 g); white solid; mp 53 °C;
[R]25D þ30.38 (c = 1, CHCl3); IR (neat) 2261 (m), 1747 (s), 1443
Compound 9b: yield 85% (1.25 g); gummy solid; [R]25D -20.12
(c = 1, CHCl3); IR (neat) 2985 (m), 1741 (s), 1441 (w), 1376 (m),
1326 (w), 1151(s), 1012 (s), 890 (w), 828 (m), 780 (w) cm-1; 1H
NMR (300 MHz, CDCl3) δ 4.87 (1H, m), 4.50 (1H, d, J = 6 Hz),
3.85 (3H, s), 1.71 (3H, d, J = 8 Hz), 1.55 (9H, s); 13C NMR
(75 MHz, CDCl3) δ 167.4, 148.9, 86.7, 64.1, 54.0, 28.3, 19.4;
HRMS calcd for C10H17NO7S [M þ Na]þ 318.0623, found
318.0613.
(m), 1378 (s), 1333 (s), 995 (w), 859 (m), 745 (m), 702 (m) cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.65 (1H, m), 4.07 (1H, dd, J =
5.6 Hz, J = 10 Hz), 3.91 (3H, s), 3.77 (1H, t, J = 10.4 Hz), 1.91
(1H, m), 1.67 (1H, m), 1.29 (1H, m), 0.96 (6H, m); 13C NMR
(100 MHz, CDCl3) δ 150.4, 83.0, 54.5, 49.1, 37.0, 24.8, 12.8,
10.4; HRMS calcd for C8H15NO5S [M þ Na]þ 260.0569, found
260.0568.
Compound 3q: yield 85% (0.112 g); gummy solid; IR (neat)
2956 (m), 2932 (s), 2860 (m), 1747 (s), 1444 (s), 1379 (s), 1334 (s),
1195 (s), 1157 (w), 919 (w), 855 (m), 762 (m) cm-1; 1H NMR (400
MHz, CDCl3) δ 4.90-4.82 (1H, m) δ 4.12 (1H, dd, J = 5.7, J =
9 Hz), 3.90 (3H, s), 3.73 (1H, t, J = 9.6), 2.01-1.88 (1H, m),
1.83-1.72 (1H, m), 1.52-1.30 (8H, m), 0.89 (3H, t, J = 6.9 Hz);
13C NMR (100 MHz, CDCl3) δ 150.3, 80.2, 54.4, 50.6, 32.2,
Coumpound 9c: 87% (1.43 g); gummy solid; [R]25 -30.51
D
(c = 1, CHCl3); IR (neat) 2983 (w), 1739 (s), 1440 (w), 1384 (s),
1326 (s), 1192 (s), 1074 (m), 1018 (w), 751 (w) cm-1; 1H NMR (300
MHz, CDCl3) δ 7.61 (5H, m), 5.37 (1H, d, J = 12 Hz), 5.35-5.25
(1H, m), 4.95-.4.87 (1H, m), 4.55 (1H, d, J = 6 Hz), 3.75 (3H, s),
1.70 (3H, d, J= 6 Hz);13C NMR (75 MHz, CDCl3) δ166.5, 149.3,
J. Org. Chem. Vol. 75, No. 9, 2010 2917

Rashid Baig et al.
JOCArticle
134.1, 128.6, 128.5, 127.9, 77.8, 69.6, 63.7, 53.7, 18.8; HRMS calcd
18.9, 15.3, 11.4; HRMS calcd for C16H28N2O8S [M þ Na]þ
431.1464, found 431.1475.
for C13H15NO7S [M þ Na]þ 352.0467, found 352.0454.
Compound 9d: 79% (1.64 g); gummy solid; [R]25 -17.28
(c = 1, CHCl3); IR (neat) 3066 (s), 3038 (w), 2957 (w), 1749 (s),
1451 (s), 1390 (s), 1316 (s), 1200 (s), 969 (m), 820 (m), 758 (s), 741
Compound 13d: yield 56% (0.846 g); white solid; mp 117 °C;
[R]25D -19.3 (c = 1, CHCl3); IR (neat) 3315 (br), 2980 (m), 2931
(m), 2856 (w), 1740 (s), 1702 (s), 1539 (m), 1371 (m), 1195 (m),
1158 (m), 1053 (w), 886 (w), 875 (w) cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.22 (1H, d, J = 7.5 Hz), 5.06-4.98 (1H, m), 4.77-
4.70 (1H, m), 4.46 (1H, d, J = 4.8 Hz), 3.76 (3H, s), 2.51 (3H, t,
J = 7.2 Hz), 2.26-1.98 (2H, m), 2.11 (3H, s), 1.72 (3H, d, J = 6
Hz), 1.57 (9H, s); 13C NMR (75 MHz, CDCl3) δ 171.3, 165.9,
148.5, 86.7, 78.9, 64.7, 52.6, 51.8, 33.8, 29.6, 27.7, 18.8,15.3;
HRMS calcd for C15H26N2O8S2 [M þ Na]þ 449.1028, found
449.1022.
D
1
(s) cm-1; H NMR (300 MHz, CDCl3) δ 7.76-7.68 (4H, m),
7.43-7.24 (4H, m), 4.97 (1H, m), 4.61-4.46 (3H, m); 4.33 (1H, t,
J = 7.2 Hz), 3.80 (3H, s), 1.73 (3H, d, J = 6.3); 13C NMR
(75 MHz, CDCl3) δ 166.5, 149.5, 142.8, 141.2, 127.9, 127.2,
125.2, 119.9, 78.1, 70.5, 63.7, 53.5, 46.4, 19.0; HRMS calcd for
C20H19NO7S [M þ Na]þ 440.0780, found 440.0770.
Compound 9f: 85% (1.57 g); gummy solid; [R]25 -26.52
D
(c = 1, CHCl3); IR (neat) 2983 (w), 1737 (s), 1455 (w), 1325
(m), 1325 (m), 1190 (s), 1151 (m), 826 (w) cm-1; 1H NMR (300
MHz, CDCl3) δ 7.36 (5H, s), 5.31 (1H, d, J = 12 Hz), 5.20 (1H,
d, J = 12 Hz), 4.87-4.79 (1H, m), 4.51 (1H, d, J = 6 Hz), 1.67
(3H, d, J = 6 Hz), 1.48 (9H, s); 13C NMR (75 MHz, CDCl3) δ
166.3, 148.1, 134.4, 128.7, 128.7, 128.3, 86.1, 77.2, 68.3, 63.7,
27.7, 18.9; HRMS calcd for C16H21NO7S [M þ Na]þ 394.0936
found 394.0941.
General Procedure for the Synthesis of β-Aminodiselenides.
Synthesis of 6a. To a solution of sulfamidate 3a (0.151 g,
0.5 mmol) in acetone (5 mL) was added KSeCN (0.144, 2 equiv,
1 mmol), and the reaction mixture was refluxed for 2 h. The
reaction mixture was allowed to come to room temperature, and
the volume was reduced to 1 mL. To this solution was added
acetonitrile (4 mL) followed by [BnEt3N]2MoS4 (1.5 equiv), and
stirring was continued for a further 8 h. After the completion of
dimerization, the salt was hydrolyzed with 2 N HCl (12 h) or
saturated citric acid solution (2 h).The reaction mixture was
neutralized with NH4OH and extracted with ethyl acetate (3 ꢀ
25 mL). The combined organic portions were washed with brine.
The solution was dried over anhydrous sodium sulfate (Na2SO4)
and concentrated. The crude product was purified by silica gel
(100-200 mesh) column chromatography (eluted with petro-
leum ether and ethyl acetate) to obtain compound 6a as a
Compound 9g((): 79% (1.41 g); white solid; mp 175 °C; (neat)
2893 (w), 1743 (s), 1459 (s), 1388 (s), 1321 (m), 1197 (s), 1147 (s),
1
881 (m), 825 (m), 761 (m) cm-1; H NMR (300 MHz, CDCl3)
δ 7.47 (5H, s), 5.68 (1H, d, J = 6 Hz), 4.85 (1H, d, J = 6 Hz), 3.82
(3H, s), 1.55 (9H, s); 13C NMR (75 MHz, CDCl3) δ 166.6, 147.9,
132.5, 130.5, 129.2, 126.6, 86.3, 80.8, 64.1, 53.4, 27.7; HRMS
calcd for C15H19NO7S [M þ Na]þ 380.0780, found 380.0791.
Synthesis of Peptide Sulfamidates. Synthesis of 13a. A solu-
tion of 11 (1.0 g, 3.55 mmol), HCl NH2-Phe-OMe 12a (0.765 g,
3
gummy solid: 85%; [R]25 þ39.62 (c = 1, CHCl3); IR (neat)
4.2 mmol, 1.2 equiv), and N-methylmorpholine (1.16 mL,
10.6 mmol, 3 equiv) in ethyl acetate (50 mL) was cooled to
0 °C, and DCC (1.09 g, 5.32 mmol, 1.5 equiv) was added in small
portions. The reaction mixture was brought to room tempera-
ture (28 °C) and stirred for 12 h. The reaction mixture was
cooled and filtered. The filtrate was washed with saturated citric
acid solution (25 mL), saturated Na2CO3 (25 mL), and brine
solution (25 mL). Ethyl acetate was removed under vacuum, and
the sulfamidate peptide 13a was purified by silica gel (100-200
mesh) column chromatography: yield 55% (0.863 g); gummy
solid; [R]25D þ2.90 (c = 1, CHCl3); 3064 (w), 2982 (w), 2934 (m),
2556 (w), 1743 (s), 1701 (s), 1684 (s), 1541 (m), 1455 (w), 1372
(m), 1327 (m), 1196 (m), 1149 (m), 1051 (w), 828 (w), 702 (w)
D
3428 (br), 3026 (w), 2926 (m), 2856 (m), 1578 (w), 1458 (m), 1117
(m), 744 (m), 698 (s) cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.30-7.12 (10H, m), 3.81 (1H, d, J = 12 Hz), 3.74 (1H, d, J = 12
Hz), 3.15-2.94 (3H, m), 2.87-2.74 (2H, m), 1.25 (1H, s); 13C
NMR (75 MHz, CDCl3) δ 140.0, 138.4, 129.3, 128.4, 128.3,
128.1, 126.9, 126.3, 58.4, 51.0, 40.4, 36.2; 77Se NMR (76 MHz,
CDCl3) δ 265.94; HRMS calcd for C32H36N2Se2 [M þ H]þ
609.1287, found 609.1305.
Compound 6b: 72%; yellow gummy solid; [R]25 þ158.75
D
(c = 1, CHCl3); IR (neat) 3305 (br), 2962 (m), 2920 (m), 1453
(s), 733 (s), 697 (s) cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.32-7.21 (5H, m), 3.82 (1H, d, J = 12 Hz), 3.74 (1H, d, J =
12 Hz), 3.12-2.90 (3H. m), 1.73 (1H, bs), 1.17 (3H, d, J = 6 Hz);
13C NMR (75 MHz, CDCl3) δ 140.2, 128.3, 128.0, 126.9, 52.4,
51.1, 38.7, 20.3; 77Se NMR (76 MHz, CDCl3) δ 268.66; HRMS
calcd for C20H28N2Se2 [M þ H]þ 457.0661, found 457.0667.
cm-1 1H NMR (300 MHz, CDCl3) δ 7.35-7.16 (3H, m),
;
7.16-7.13 (2H, m), 6.81 (1H, d. J = 8.1 Hz), 4.93-4.86 (1H,
m), 4.68-4.60 (1H, m), 4.35 (1H, d, J = 4.8 Hz), 3.74 (3H, s),
3.21 (1H, dd, J = 5.4 Hz, J = 15 Hz), 3.01 (1H, dd, J = 7.2 Hz,
J = 12 Hz), 1.61 (3H, d, J = 6 Hz), 1.51 (9H, s); 13C NMR (75
MHz, CDCl3) δ 170.9, 165.6, 148.3, 135.2, 129.2, 128.6, 127.1,
86.6, 78.6, 64.5, 53.1, 52.4, 37.8, 27.6; HRMS calcd for
C19H26N2O8S [M þ Na]þ 465.1308, found 465.1319.
Compound 6c: 75%; yellow gummy solid; [R]25 -45.69
D
(c = 1, CHCl3); IR (neat) 3335 (br), 2959 (m), 2942 (m), 867
1
(w), 1452 (s), 1200 (m), 733 (m), 697 (s) cm-1; H NMR (300
MHz, CDCl3) δ 7.35-7.23 (5H, m), 3.78 (2H, s), 3.18 (1H, dd,
J = 6 Hz, J = 12 Hz), 3.04 (1H, dd, J = 6 Hz, J = 12 Hz), 2.75
(1H, m), 1.63-1.52 (3H, m), 0.91 (3H, t, J = 6 Hz); 13C NMR
(75 MHz, CDCl3) δ 140.4, 128.3, 128.1, 126.9, 58.4, 50.9, 36.5,
26.6, 10.0; 77Se NMR (76 MHz, CDCl3) δ 264.80; HRMS calcd
for C22H32N2Se2 [M þ H]þ 485.0974, found 485.0994.
Compound 13b: yield 60% (0.869 g); white solid; mp 117 °C;
[R]25 -19.33 (c = 1, CHCl3); IR (neat) 3373 (br), 2959 (m),
1744 (s), 1708 (s), 1549 (w), 1390 (m), 1326 (m), 1197 (m), 1151
D
1
(m), 1052 (w), 885 (w), 831 (m) cm-1; H NMR (300 MHz,
CDCl3) δ 6.81 (1H, d, J = 7.8 Hz), 5.06-4.98 (1H, m), 4.66-4.6
1 (1H, m), 3.73 (3H, s), 1.72-1.45 (15H, m), 0.93 (3H, d, J = 6
Hz); 13C NMR (75 MHz, CDCl3) δ 172.4, 165.8, 148.6, 86.7,
78.8, 64.6, 52.3, 51.0, 41.1, 27.7, 24.7, 22.7, 21.6, 18.9; HRMS
calcd for C16H28N2O8S [M þ Na]þ 431.1464, found 431.1446.
Compound 13c: yield 53% (0.767 g); white solid; mp 102 °C;
[R]25D -8.53 (c = 1, CHCl3); IR (neat) 2968 (w), 2936 (m), 2879
(w), 1742 (s), 1700 (s), 1544 (m), 1372 (s), 1327 (s), 1196 (m), 1148
Compound 6d: 80%; yellow gummy solid; [R]25 þ15.13
D
(c = 1, CHCl3); IR (neat) 3315 (br), 3060 (m), 3026 (w), 2954
(s), 2919 (s), 2868 (s), 1493 (w), 1262 (m), 1454 (m), 737 (m), 698
(m) cm-1; H NMR (300 MHz, CDCl3) δ 7.33-7.23 (5H, m),
1
3.81 (1H, d, J = 12 Hz), 3.74 (1H, d, J = 12 Hz), 3.24 (1H, dd,
J = 6 Hz, J = 12 Hz), 3.06 (1H, dd, J = 6 Hz, J = 12 Hz), 2.86,
(1H, m), 1.77 (1H, bs), 1.69 (1H, m), 1.49-1.25 (2H, m), 0.88
(3H, t, J = 6 Hz); 13C NMR (75 MHz, CDCl3) δ 140.3, 128.3,
128.2, 126.9, 55.1, 50.8, 43.7, 37.5, 24.9, 22.8; 77Se NMR
(76 MHz, CDCl3) δ 264.83; HRMS calcd for C26H40N2Se2
[M þ H]þ 541.1600, found 541.1632.
1
(m), 886 (w), 856 (w) cm-1; H NMR (300 MHz, CDCl3) δ
7.0(1H, bs), 5.05 (1H, m), 4.59 (1H, dd, J = 4.8 Hz, J = 9 Hz),
4.49 (1H, d, J = 4.5 Hz), 3.74 (3H, s), 1.99-1.90 (1H, m), 1.72
(3H, d, J = 6 Hz), 1.57 (9H, s), 1.47-1.33 (1H, m), 1.31-1.14
(1H, m), 0.94-0.89 (6H, m); 13C NMR (75 MHz, CDCl3) δ
171.3, 165.9, 148.5, 86.6, 78.9, 64.5, 56.7, 52.1, 37.7, 27.6, 24.7,
Compound 6e: 84%; yellow gummy solid; [R]25 þ49.27
D
(c = 1, CHCl3); IR (neat) 3305 (br), 3024 (m), 2954 (s), 2920
2918 J. Org. Chem. Vol. 75, No. 9, 2010

Rashid Baig et al.
JOCArticle
(s), 2862 (m), 1460 (m), 1081 (w), 738 (m), 697 (m) cm-1; H
NMR (300 MHz, CDCl3) δ 7.36-7.20 (5H, m), 3.78 (2H, s), 3.15
(1H, dd, J = 6 Hz, J = 12 Hz), 3.04 (1H, dd, J = 6 Hz, J =
12 Hz), 2.63 (1H, m), 1.95 (1H, m), 1.73 (1H, bs), 0.91 (3H, d,
J = 3 Hz), 0.89 (3H, d, J = 3 Hz); 13C NMR (75 MHz, CDCl3)
δ 148.4, 128.2, 128.1, 126.8, 62.6, 51.4, 33.8, 29.8, 18.7, 17.9; 77Se
757(m), 737(m) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.73 (4H,
d, J = 8 Hz), 7.56 (4H, d, J = 8 Hz), 7.39-7.25 (8H, m), 5.09
(2H, bs), 4.38 (4H, bd, J = 8 Hz), 4.19 (2H, bs), 3.12 (4H, bm),
1.6-1.4 (4H, m), 0.92 (6H, bs); 13C NMR (75 MHz, CDCl3) δ
156.0, 143.9, 141.3, 127.6, 126.9, 125.0, 119.9, 66.52, 53.3,
47.2, 35.9, 27.2, 10.3; 77Se NMR (76 MHz, CDCl3) δ 288.48;
HRMS calcd for C38H40N2O4Se2 [M þ Na]þ 771.1216, found
771.1254.
1
NMR (76 MHz, CDCl3)
δ 271.13; HRMS calcd for
C24H36N2Se2 [M þ H]þ 513.1287, found 513.1287.
Compound 6f. 85%; yellow gummy solid; [R]25 þ20.63
Compound 6m: 99%; yellow gummy solid; [R]25 þ88.49
D
D
(c = 1, CHCl3); IR (neat) 3365 (br), 3027 (w), 2926 (s), 2870
(c = 1, CHCl3); IR (neat) 3332 (br), 2960 (s), 2930 (m), 2874
(m), 1457 (s), 1050 (w), 736 (m), 697 (s) cm-1 ; H NMR (300
(m), 1704 (s), 1533 (s), 1260 (s), 1057 (w), 777 (m) cm-1; H
1
1
MHz, CDCl3) δ 7.36-7.22 (5H, m), 3.80 (1H, d, J = 12 Hz),
3.73 (1H, d, J = 12 Hz), 3.10 (1H, dd, J = 4.5 Hz, J = 12 Hz),
2.97 (1H, dd, J = 3.6 Hz, J = 12 Hz), 2.75 (1H, m), 1.74 (2H, bs),
1.43 (1H, m), 1.21 (1H, m), 0.90 (6H, m); 13C NMR (75 MHz,
CDCl3) δ 140.5, 128.3, 128.2, 126.8, 61.2, 51.3, 36.4, 33,5, 26.0,
14.0, 12.0; 77Se NMR (76 MHz, CDCl3) δ 270.44; HRMS calcd
for C26H40N2Se2 [M þ H]þ 541.1600, found 541.1605.
NMR (300 MHz, CDCl3) δ 7.32-7.13 (5H, m), 5.25 (1H, bs),
3.66 (3H, s), 3.43-3.26 (3H, m), 2.96-2.78 (2H, m); 13C NMR
(75 MHz, CDCl3) δ 157.0, 138.6, 129.0, 128.5, 126.6, 25.2, 47.0,
45.5, 39.7; 77Se NMR (76 MHz, CDCl3) δ 310.40; HRMS calcd
for C22H28N2O4Se2 [M þ Na]þ 567.0277, found 567.0275.
Compound 6n: 98%; yellow gummy solid; [R]25 þ54.28
D
(c = 1, CHCl3); IR (neat) 3337 (br), 2955 (s), 2926 (s), 2856
(s), 1713 (s), 1537 (s), 1435 (s), 1257 (m), 1193 (w), 854 (w), 777
Compound 6g: 87%; yellow gummy solid; [R]25 -19.38
D
1
(c = 1, CHCl3); IR (neat) 3432 (br), 2923 (w), 1642 (m), 1453
(m), 737 (m), 699 (m) cm-1
(m) cm-1; H NMR (300 MHz, CDCl3) δ 5.39 (1H, bs), 3.68
;
1H NMR (300 MHz, CDCl3)
(3H, s), 3.50-3.31 (2H, m), 3.25-3.05 (1H, m), 1.88-1.76 (1H,
m), 1.53-1.37 (2H, m), 0.93 (3H, d, J = 6 Hz), 0.90 (3H, d, J = 6
Hz); 13C NMR (75 MHz, CDCl3) δ 157.0, 52.1, 46.1, 43.5, 42.3,
26.2. 22.7, 21.9; 77Se NMR (76 MHz, CDCl3) δ 294.90; HRMS
calcd for C16H32N2O4Se2 [M þ Na]þ 499.0599, found 499.0580.
δ 7.34-7.20 (10H, m), 3.86 (1H, m), 3.68 (1H, dd, J = 6 Hz,
J = 15 Hz), 3.50 (1H, dd, J = 6 Hz, J = 15 Hz), 3.15-3.07
(2H, m), 2.07 (1H, bs); 13C NMR (75 MHz, CDCl3) δ 140.4,
140.1, 128.6, 128.3, 128.1, 127.5, 127.2, 126.9, 61.8, 51.3, 38.9;
77SeNMR (76 MHz, CDCl3) δ 282.47; HRMS calcd for
C30H32N2Se2 [M þ H]þ 581.0974, found 581.0977.
Compound 6o: 98%; yellow gummy solid; [R]25 þ86.50
D
(c = 1, CHCl3); IR (neat) 3335 (br), 2959 (s), 2930 (m), 2872
(m), 1713 (s), 1537 (s), 1531 (s), 1368 (m), 1260 (m), 1021 (w), 777
Compound 6h. 30%; yellow gummy solid; [R]25D -2.40 (c = 1,
CHCl3); IR (neat) 3404 (br), 2953 (m), 2923 (s), 2853 (m), 1605
1
(m) cm-1; H NMR (300 MHz, CDCl3) δ 5.24 (1H, bs), 3.68
1
(m), 1457 (m), 1320 (w), 747 (m) cm-1; H NMR (300 MHz,
(3H, s), 3.63-3.59 (1H, m), 3.43-3.34 (1H, m), 3.06 (1H, dd,
J = 6 Hz, J = 12 Hz), 1.98-1.88 (1H, m), 1.07 (3H, d, J = 6
Hz), 0.99 (3H, d, J = 6 Hz); 13C NMR (75 MHz, CDCl3) δ
156.9, 56.7, 52.1, 44.1, 30.9, 20.8, 19.8; 77Se NMR (76 MHz,
CDCl3) δ 295.88; HRMS calcd for C14H28N2O4Se2 [M þ Na]þ
471.0277, found 471.0278.
CDCl3) δ 7.36-7.22 (10H, m), 4.38 (1H, d, J = 6 Hz), 3.89
(2H, s), 3.86-3.77 (2H, m), 3.46 (1H, dd, J = 7.5 Hz, J = 16.8
Hz), 3.03 (1H, dd, J = 5.4 Hz, J = 16.8 Hz); 13C NMR (75
MHz, CDCl3) δ 143.21, 141.42, 140.41, 128.39, 128.13, 128.01,
126.99, 124.74, 70.12, 50.75, 46.19, 39.17; 77Se NMR (76 MHz,
CDCl3) δ 386.80; HRMS calcd for C32H32N2Se2 [M þ Na]þ
627.0794, found 627.0797.
Compound 6p: 98%; yellow gummy solid; [R]25 þ103.2
D
(c = 1, CHCl3); IR (neat) 3334 (br), 2925 (m), 2853 (w), 1704
(s), 1531 (m), 1257 (s), 1193 (w), 1147 (w), 777 (w), 747 (w), 700
Compound 6i: 77%; yellow gummy solid; [R]25 -56.68
D
1
(c = 1, CHCl3); IR (neat) 3335 (br), 2920 (m), 2862 (w), 1610
(w), 1509 (s), 1457 (m), 1244 (s), 1171 (w), 1032 (m), 823 (m), 705
(w) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.24 (2H, d, J = 9 Hz),
6.84 (2H, d, J = 9 Hz), 3.78 (3H, s), 3.72 (2H, s), 3.18 (1H, dd,
J = 6 Hz, J = 12 Hz), 3.03 m (1H, dd, J = 6 Hz, J = 12 Hz), 2.75
(m) cm-1; H NMR (300 MHz, CDCl3) δ 5.33 (1H, bs), 3.68
(3H, s), 3.63-3.54 (1H, m), 3.48-3.39 (1H, m), 0.95-0.89
(6H, m); 13C NMR (75 MHz, CDCl3) δ 157.0, 55.5, 52.1, 44.6,
37.4, 27.8, 16.2, 11.6; 77Se NMR (76 MHz, CDCl3) δ 296.74;
HRMS calcd for C16H32N2O4Se2 [M þ Na]þ 499.0890, found
499.0581
(1H, m), 2.09 (1H, bs), 1.57 (2H, m), 0.97 (3H, t, J = 6 Hz); 13
C
NMR (75 MHz, CDCl3) δ 158.6, 132.37, 129.3, 113.8, 58.3,
55.2, 50.3, 36.3, 26.5, 10.0; HRMS calcd for C24H36N2O2Se2
[M þ H]þ 545.1185, found 545.1185.
Compounds 6q1 and 6q2: (1:1 dr) 99%; yellow gummy solid; IR
(neat) 3334 (br), 2955 (m), 2926 (s), 2855 (m), 1704 (s), 1530 (s),
1463 (m), 1257 (s), 1194 (m), 1016 (w), 777 (w) cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.34 (1H, bs), 5.26 (1H, bs), 3.64 (6H,s),
3.47-3.24 (4H, m), 3.03 (2H, bm), 1.67-1.36(2H, m), 0.84 (6H, t,
J = 6 Hz); 13C NMR (75 MHz, CDCl3) δ 157.0, 52.1, 50.2, 46.6,
45.9, 45.8, 45.63, 33.1, 31.8, 31.5, 28.9, 28.8, 27.7, 27.7, 27.6, 22.5,
13.9, 77SeNMR (76 MHz, CDCl3) δ 302.89, 294.11; HRMS calcd
for C20H40N2O4Se2 [M þ Na]þ 555.1216, found 555.1210.
Compound 10b: yield 95% (0.140 g); yellow gummy solid;
Compound 6j: 79%; yellow gummy solid; [R]25 þ47.40
D
(c = 1, CHCl3); IR (neat) 3337 (br), 2969 (m), 2930 (m), 1694
(s), 1510 (m), 1366 (m), 1279 (w), 1170 (s), 1098 (w), 987 (w),
cm-1; 1H NMR (300 MHz, CDCl3) δ 4.88 (1H, bs), 3.72 (1H,
bs), 3.20-3.08 (2H, m), 1.67 (1H, m), 1.45 (10H, s), 0.95 (3H, t,
J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 155.56, 79.29, 52.59,
36.45, 28.46, 27.09, 10.43; 77Se NMR (76 MHz, CDCl3) δ 283.96;
HRMS calcd for C18H36N2O4Se2 [M þ Na]þ 527.0903, found
527.0927.
[R]25 þ43.19 (c = 1, CHCl3); IR (neat) 3368 (br), 2977 (w),
D
1739 (m), 1713 (s), 1502 (m), 1367 (w), 1162 (m), 1078 (w), 1017
(w), 735 (w) cm-1; 1H NMR (300 MHz, CDCl3) δ 5.25 (1H,d,
J = 9 Hz), 4.62 (1H, dd, J = 3.6 Hz, J = 9 Hz), 3.76 (3H, s),
3.64-3.51 (1H, m), 1.45 (9H, s), 1.43 (3H, d, J = 6 Hz); 13C
NMR (75 MHz, CDCl3) δ 171.5, 155.7, 80.7, 58.3, 53.0, 41.5,
28.7, 18.4; 77Se NMR (76 MHz, CDCl3) δ 374.05; HRMS calcd
for C20H36N2O8Se2 [M þ Na]þ 615.0700, found 615.0719.
Compound 10c. yield 93% (0.153 g); yellow gummy solid;
Compound 6k: 85%; yellow gummy solid; [R]25D -1.8 (c = 1,
CHCl3); IR (neat) 3320 (br), 2964 (m), 2930 (w), 1695 (s), 1532
1
(m), 1274 (m), 1239 (m), 1101 (m), 737 (m), 696 (m) cm-1; H
NMR (300 MHz, CDCl3) δ 3.74-3.25 (5H, m), 5.19-5.06 (3H,
m), 3.78 (1H, bm), 3.16-3.02 (2H, m), 1.65-1.42 (2H, m), 0.92
(3H, t, J = 6 Hz), 13C NMR (75 MHz, CDCl3) δ 156.0, 136.5,
128.4, 127.9, 66.5, 53.2, 36.1, 27.1, 10.3; 77Se NMR (76 MHz,
CDCl3) δ 289.34; HRMS calcd for C24H32N2O4Se2 [M þ Na]þ
595.0590, found 595.0593.
[R]25 þ10.00 (c = 1, CHCl3); IR (neat) 3347 (br), 2952 (w),
D
1721 (s), 1520 (m), 1213 (s), 1055 (w), 1024 (w), 698 (w) cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.37-3.26 (5H, m), 5.48 (1H, d, J =
8.7 Hz), 5.11 (2H, s), 4.70 (1H, dd, J = 4.2 Hz, J = 9 Hz), 3.7
(3H, s), 3.64-3.55 (1H, m), 1.41 (3H, d, J = 6 Hz); 13C NMR (75
Compound 6l: 88%; yellow gummy solid; [R]25 -11.24
D
(c = 1, CHCl3); IR (neat) 3328 (br), 2962 (m), 2925 (m), 1693
(s). 1531 (m), 1447 (m), 1274 (s), 1241 (m), 1106 (m), 1080 (m),
J. Org. Chem. Vol. 75, No. 9, 2010 2919

Rashid Baig et al.
JOCArticle
MHz, CDCl3) δ 170.7, 155.9, 136.0, 128.5, 128.2, 128.1, 67.2,
58.4, 52.5, 41.0, 17.9; 77Se NMR (76 MHz, CDCl3) δ 375.01;
HRMS calcd for C26H32N2O8Se2 [M þ Na]þ 683.0387, found
683.0409.
(s), 1716 (s), 1505 (s), 1497 (s), 1367 (m), 1245 (m), 1208 (m), 1163
(s), 1055 (w), 700 (m) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.76
(1H, d, J = 8.1 Hz), 5.63 (1H, d, J = 10.2 Hz), 4.91 (1H, dd, J =
3.9 Hz, J = 9 Hz), 4.66-4.59 (1H, m), 3.73-3.65 (1H, m), 3.69
(3H, s), 1.75-1.53 (3H, m), 1.46 (9H, s), 1.28 (3H, d, J = 6 Hz),
0.91 (3H, d, J = 3 Hz), 0.89 (3H, d, J = 3 Hz); 13C NMR (75
MHz, CDCl3) δ 172.8, 169.6, 155.8, 79.9, 58.2, 52.0, 50.8, 48.4,
40.2, 28.3, 24.9, 22.5, 21.7, 16.8; 77Se NMR (76 MHz, CDCl3) δ
390.41; HRMS calcd for C32H58N4O10Se2 [M þ Na]þ 841.2381,
found 841.2353.
Compound 10d: yield 95% (0.198 g); yellow solid; mp 112 °C;
D
[R]25 þ19.58 (c = 1, CHCl3); IR (neat); 3334 (w), 3054 (w),
2951 (w), 1722 (s), 1449 (m), 1509 (m), 1212 (s), 1085 (w), 1027
(w), 758 (w), 739 (s) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.75
(2H, d, J = 7.2 Hz), 7.59 (2H, d, J = 7.2 Hz), 3.41-7.28 (4H, m),
5.52 (1H, d, J = 9 Hz) 4.72 (1H, dd, J = 4.2 Hz, J = 9 Hz), 4.38
(2H, m), 4.23 (1H, t, J = 6.6 Hz), 3.76 (3H, s), 3.66-3.59 (1H,
m), 1.45 (3H, d, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ
170.7, 155.8, 143.7, 141.2, 127.7, 127.0, 125.07, 119.9, 67.3, 58.3,
52.6, 47.1, 40.9, 18.0; 77Se NMR (76 MHz, CDCl3) δ 373.88;
HRMS calcd for C40H40N2O8Se2 [M þ Na]þ 859.1013, found
859.1096.
Compound 14d: yield 80% (0.170 g); yellow solid; mp 201 °C;
D
[R]25 þ100.75 (c = 1, CHCl3); IR (neat) 3315 (br), 2975 (m),
2926 (m), 1745 (s), 1662 (s), 1516 (s), 1447 (m), 1367 (m), 1271
(m), 1166 (s), 1015 (w) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.83
(1H, d, J = 8.1 Hz), 5.62 (1H, d, J = 9.9 Hz), 4.90 (1H, dd, J =
3.6 Hz, J = 9.9 Hz), 4.78-4.71 (1H, m), 3.71 (3H, s), 3.71-3.62
(1H, m), 2.56-2.46 (2H, m), 2.20 (3H, s), 1.96-1.90 (1H, m),
1.80-1.66 (1H, m), 1.46 (3H, d, J = 6.3, Hz), 1.46 (9H, s); 13C
NMR (75 MHz, CDCl3) δ 171.9, 169.8, 155.9, 80.1, 58.8,
52.3, 51.4, 33.9, 31.0, 30.6, 28.3, 16.9, 15.4; 77Se NMR (76
MHz, CDCl3) δ 406.59; HRMScalcd for C30H54N4O10S2Se2
[M þ Na]þ 877.1509, found 877.1529.
Compound 10e: yield 97% (0.138 g); yellow gummy solid;
[R]25 þ47.47 (c = 1, CHCl3); IR (neat) 3332 (bs), 3028 (w),
D
2952 (m), 1734 (s), 1455 (m), 1201 (m), 1178 (m), 1152 (m), 986
(w), 742 (w), 698 (w) cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.37-7.24 (5H, m), 3.88 (1H, d, J = 12.9 Hz), 3.71 (3H, s), 3.65
(1H, d, J = 12 Hz), 3.57 (1H, d, J = 5.1 Hz), 3.51-3.41 (1H, m),
2.03 (1H, bs), 1.41 (3H, d, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 173.4, 139.4, 128.34, 128.31, 127.1, 64.8, 52.5, 51.8,
43.6, 18.1; 77Se NMR (76 MHz, CDCl3) δ 391.25; HRMS calcd
for C24H32N2O4Se2 [M þ H]þ 573.0770, found 573.0795.
Compound 10f: yield 96% (0.178 g); yellow gummy solid;
Compound 18: yield 92% (0.151 g); yellow color solid; mp
110 °C; [R]25D -365.04 (c = 1, CHCl3); IR (neat) 3338 (br), 2981
(m), 2955 (m), 2853 (w), 1728 (s), 1535 (s), 1288 (s), 1255 (s), 1175
1
(m), 1025 (m), 701 (m) cm-1; H NMR (300 MHz, CDCl3) δ
7.40-7.26, (5H, m), 6.1 (1H, bs), 5.11 (1H, dd, J = 9 Hz, J = 15
Hz), 4.05-3.98 (3H, m), 3.69 (3H, s), 1.05 (3H, t, J = 6.9 Hz);
13C NMR (75 MHz, CDCl3) δ 170.8, 156.3, 139.3, 128.6, 128.1,
127.2, 61.5, 56.2, 52.3, 49.7, 13.7; 77Se NMR (76 MHz, CDCl3) δ
433.12; HRMS calcd for C26H32N2O8Se2 [M þ Na]þ 683.0387,
found 683.0374.
[R]25 þ16.25 (c = 1, CHCl3); IR (neat) 3366 (br), 2977 (m),
D
2926 (w), 1718 (s), 1498 (m), 1455 (w), 1367 (m), 1159 (s), 1063
(w), 752 (w), 698 (m) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.34
(5H, s), 5.24-5.16 (3H, m), 4.60 (1H, bs), 1.43 ((9H, s), 1.36 (3H,
d, J = 6 Hz);); 13C NMR (75 MHz, CDCl3) δ 170.3, 155.1,
135.1, 128.5, 128.44, 128.41, 80.2, 67.3, 58.0, 41.2, 28.2, 17.9;
77Se NMR (76 MHz, CDCl3) δ 377.06; HRMS calcd for
C32H44N2O8Se2 [M þ Na]þ 769.1326, found 769.1346.
General Procedure for the Synthesis of 3,30-Dimethylseleno-
cystine Peptides (20a-d). Boc-protected 3,30-dimethylseleno-
cystine derivative 10b (0.5 mmol) was dissolved in dichloro-
methane (4 mL), and TFA (1 mL) was added. The reaction
mixture was stirred at 0 °C for 3 h. Dichloromethane and TFA
were removed under vacuum, and the crude trifluoroacetate salt
was used directly for peptide coupling without purification.
The trifluoroacetate salt (0.5 mmol, obtained as above),
N-Cbz-amino acid (1.2 mmol), and HOBt (1.2 mmol) were
dissolved in acetonitrile (8 mL). The solution was cooled to
0 °C, and N-methylmorpholine (1.5 mmol, 3 equiv) was added
dropwise. EDC (1.5 mmol, 3 equiv) was added to the reaction
mixture, which was allowed to come to rt (28 °C), and stirring
was continued for 8 h. The solvent was removed under vacuum,
and the residue was extracted with ethyl acetate (25 mLꢀ3).
The combined ethyl acetate layers were washed with saturated
citric acid solution, saturated Na2CO3 solution, and finally with
brine. The crude solution of the peptide was dried over anhy-
drous Na2SO4 and concentrated. The peptides (20a-d) were
purified by silica gel (100-200 mesh) column chromatography.
Compound 10g((): yield 97% (0.172 g); yellow solid; mp
115 °C; IR (neat) 3320 (m), 2959 (s), 2930 (m), 1747 (s), 1700
(s), 1540 (s), 1522 (s), 1367 (m), 1250 (m), 1165 (s), 1017 (m)
cm-1 1H NMR (300 MHz, CDCl3) δ 7.31-7.20 (3H, m),
;
7.19-7.13 (2H, m), 4.98-4.87 (2H, m), 4.20 (1H, m), 3.66-
3.65 (3H, 2s), 1.40-1.39 (9H, 2s); 77Se NMR (76 MHz, CDCl3) δ
407.92; HRMS calcd for C30H40N2O8Se2 [M þ Na]þ 739.1013,
found 739.1038.
Compound 14a: yield 85% (0.188 g); yellow solid; mp 147 °C;
[R]25D þ66.9 (c = 1, CHCl3); IR (neat) 3317 (br), 3063 (w), 2976
(w), 2930 (m), 1745 (s), 1662 (s), 1519 (s), 1367 (m), 1166 (s), 1078
(w), 739 (w), 700 (w) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.85
(1H, d, J = 7.5 Hz), 7.26-7.14 (5H, m), 5.50 (1H, d, J = 9 Hz),
4.89-4.81 (2H, m). 3.70-3.58 (1H, m), 3.65 (3H, s), 3.20 (1H,
dd, J = 6 Hz, J = 15 Hz), 3.01 (1H, dd, J = 6 Hz, 12 Hz), 1.44
(9H, s), 1.27 (3H, d, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ
171.6, 169.5, 155.7, 136.3, 129.0, 128.4, 126.8, 80.0, 58.5, 53.6,
522.1, 37.7, 33.9, 28.3, 17.0; 77Se NMR (76 MHz, CDCl3) δ
402.54; HRMS calcd for C38H54N4O10Se2 [M þ Na]þ 907.2068,
found 907.2097.
Compound 20a: yield 80% (0.177 g); yellow gummy solid; [R]25
D
þ47.5 (c = 1, CHCl3); IR (neat) 3309 (br), 3032 (m), 2963 (s), 2932
(s), 1744 (s), 1666 (s), 1533 (s), 1455 (m), 1216 (s), 1027 (m) 756 (s)
1
Compound 14b: yield 85% (0.173 g); yellow solid; mp 115 °C;
D
cm-1; H NMR (300 MHz, CDCl3) δ 7.70 (1H, d, J = 9 Hz),
[R]25 þ33.87 (c = 1, CHCl3); IR (neat) 3318 (br), 2966 (m),
7.34-7.26 (5H, m), 5.63 (1H, d, J = 9 Hz), 5.20 (1H, d, J = 12.6
Hz), 5.08 (1H, d, J = 12.6 Hz), 5.01 (1H, dd, J = 3 Hz, J = 5,4
Hz), 4.45 (1H, t, J = 9 Hz), 3.70 (3H, s), 3.63-3.53 (1H, m),
1.80-1.72 (1H, m), 1.61-1.52 (1H, m), 1.38 (3H, d, J = 6 Hz),
1.20-1.05 (1H, m), 0.94 (3H, d, J = 6.6 Hz), 0.86 (3H, t, J = 7.5
Hz); 13C NMR (75 MHz, CDCl3) δ 172.2, 170.0, 156.7, 136.4,
128.4, 127.9, 127.7, 66.9, 59.0, 57.4, 52.3, 38.6, 37.3, 24.6, 18.3, 15.2,
10.8; 77Se NMR (76 MHz, CDCl3) δ 379.31; HRMS calcd for
C38H54N4O10Se2 [M þ Na]þ 909.2068 found 909.2136.
2930 (m), 2875 (w), 1744 (s), 1662 (s), 1522 (s), 1457 (w), 1367
1
(m), 1165 (m), 1015 (w) cm-1; H NMR (300 MHz, CDCl3) δ
7.43 (1H, d, J = 6.6 Hz), 5.53 (1H, d, J = 9 Hz), 4.64 (1H, bs),
4.53 (1H, dd, J = 6 Hz, J = 8.4 Hz), 3.71 (3H, s), 3.66-3.61 (1H,
m) 1.95-1.86 (1H, m), 1.43 (9H, s), 1.42-1.10 (5H, m), 0.92-
0.85 (6H, m); 13C NMR (75 MHz, CDCl3) δ 171.8, 169.9, 155.7,
80.1, 58.6, 56.8, 51.9, 37.0, 28.2, 25.2, 17.7, 15.4, 11.1; 77Se NMR
(76 MHz, CDCl3) δ 390.41; HRMS calcd for C32H58N4O10Se2
[M þ Na]þ 841.2381, found 841.2383.
Compound 20b: yield 83% (0.166 g); yellow gummy solid;
[R]25D þ54.00 (c = 1, CHCl3); IR (neat) 3314 (br), 3032 (w), 2955
(m), 2977 (m), 1738 (s), 1672 (s), 1530 (s), 1454 (m), 1258 (m),
Compound 14c: yield 83% (0.169 g); yellow gummy solid;
[R]25D -2.09 (c = 1, CHCl3); IR (neat) 3367 (br), 2978 (m), 1745
2920 J. Org. Chem. Vol. 75, No. 9, 2010

Rashid Baig et al.
JOCArticle
1215 (m), 1027 (m), 753 (m), 698 (w); cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.41-7.27 (6H, m), 5.87 (1H, d, J = 9 Hz), 5.15 (2H,
2d, J = 12 Hz), 4.93 (1H, bm), 4.52-4.43 (1H, m), 3.72(3H, s),
3.58-3.50 (1H, m), 1.39 (3H, d, J = 7.5 Hz), 1.37 (3H, d, J = 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 172.7, 170.2, 156.3,
136.1, 128.4, 128.0, 127.9, 66.9, 57.1, 52.5, 50.2, 39.8, 18.3,
18.0; 77Se NMR (76 MHz, CDCl3) δ 379.57; HRMS calcd for
C32H42N4O10Se2 [M þ Na]þ 825.1129, found 825.1164.
(m), 2919 (m), 1740 (s), 1704 (s), 1668 (s), 1531 (s), 1437 (m), 1256
(m), 1216 (s), 1050 (m), 753 (m); 1H NMR (300 MHz, CDCl3) δ
7.48 (1H. bs), 7.32 (5H, s), 5.96 (1H, bs), 5.11 (2H, 2d, J = 12
Hz), 4.94 (1H, bs), 4.01 (1H, bm), 3.72 (3H, s), 3.60-3.51
(1H, m), 2.58 (2H, t, J = 12 Hz), 2.10-1.91 (5H, m), 1.38
(3H, d, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 171.8, 170.0,
156.4, 136.1, 128.4, 128.8, 127.9, 67.0, 57.2, 53.7, 52.4, 39.2,
31.6,29.5, 18.2, 15.1; 77Se NMR (76 MHz, CDCl3) δ 379.23;
HRMS calcd for C36H50N4O10S2Se2 [M þ Na]þ 945.1196,
found 945.1277.
Compound 20c: yield 87% (0.207 g); yellow solid; mp 144 °C;
[R]25 þ43.50 (c = 1, CHCl3); IR (neat) 3305 (br), 3061 (w),
D
2929 (w), 1742 (s), 1662 (s), 1536 (s), 1262 (m), 1025 (m), 737(m),
698(s) cm-1 1H NMR (300 MHz, CDCl3) δ 7.41-7.14
;
Acknowledgment. N.B.R.B. thanks the Council of Scien-
tific and Industrial research, New Delhi, for a senior research
fellowship, and S.C. thanks the Department of Science
and Technology, New Delhi, for the JC Bose National
Fellowship.
(11H, m), 5.72 (1H, d, J = 8.4 Hz), 5.12-4.92 (3H, m), 4.83-
4.74 (1H, bm), 3.67 (3H, s), 3.52-3.42 (1H, m), 3.08 (1H. dd,
J = 6 Hz, J = 15 Hz), 2.93 (1H, dd, J = 6 Hz, J = 15 Hz), 1.34 d,
J = 6 Hz), 13C NMR (75 MHz, CDCl3) δ 171.5, 169.9, 156.3,
136.4, 136.2, 129.3, 128.6, 128.4, 128.0, 127.7, 126.7, 66.9, 57.3,
55.8, 52.4, 38.5, 33.8, 18.3; 77Se NMR (76 MHz, CDCl3) δ
379.69; HRMS calcd for C44H50N4O10Se2 [M þ Na]þ 977.1755,
found 977.1761.
Supporting Information Available: Experimental proce-
dures, characterization of all new compounds, and crystallo-
graphic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
Compound 20d: yield 78% (0.179 g); yellow gummy solid;
[R]25D þ45.2 (c = 1, CHCl3); IR (neat) 3311 (br), 3033 (w), 2953
J. Org. Chem. Vol. 75, No. 9, 2010 2921