Stereoselective additions of thiyl radicals to terminal ynamides

Article abstract of DOI:10.1021/ol1008679

Two complementary sets of conditions for radical additions of thiols to terminal ynamides are described. The use of 1 equiv of thiol affords the cis-β-thioenamide adducts in rapid fashion (10 min) and good dr, whereas employing excess thiol and longer rea

Full text of DOI:10.1021/ol1008679

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2650-2652
Stereoselective Additions of Thiyl
Radicals to Terminal Ynamides
Biplab Banerjee, Dmitry N. Litvinov, Junghoon Kang, Jennifer D. Bettale, and
Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602
scastle@chem.byu.edu
Received April 15, 2010
ABSTRACT
Two complementary sets of conditions for radical additions of thiols to terminal ynamides are described. The use of 1 equiv of thiol affords
the cis-ꢀ-thioenamide adducts in rapid fashion (10 min) and good dr, whereas employing excess thiol and longer reaction times favors the
trans products.
Ynamides are a class of compounds that have gained
prominence in recent years.1 They are electron-rich
alkynes,2 although their nucleophilicity can be tuned by
varying the nature of the N-acyl group. Malacria has
demonstrated the utility of ynamides as radical accep-
tors.3,4 We reasoned that they should react readily with thiyl
radicals, which are electrophilic in nature.5 A recent report
by Yorimitsu and Oshima detailing radical additions of
arenethiols to internal tosylynamides6 lent support to this
hypothesis.
The addition of a thiyl radical to an ynamide produces a
ꢀ-thioenamide. This moiety is present in unusual cyclic peptides
such as thioviridamide7 (Figure 1) and the lantibiotics.8 Inspired
(1) (a) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.;
Wei, L.-L. Tetrahedron 2001, 57, 7575. (b) Mulder, J. A.; Kurtz, K. C. M.;
Hsung, R. P. Synlett 2003, 1379. (c) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840.
Figure 1. Thioviridamide (ꢀ-thioenamide highlighted in red).
(2) (a) Mulder, J. A.; Hsung, R. P.; Frederick, M. O.; Tracey, M. R.;
Zificsak, C. A. Org. Lett. 2002, 4, 1383. (b) Al-Rashid, Z. F.; Hsung, R. P.
Org. Lett. 2008, 10, 661.
by the striking architecture of these natural products, we
investigated additions of thiyl radicals to terminal ynamides.
Herein, we report the initial results of our study, which
demonstrate that both cis- and trans-ꢀ-thioenamides can be
obtained selectively by simply varying the reaction conditions.
(3) (a) Marion, F.; Courillon, C.; Malacria, M. Org. Lett. 2003, 5, 5095.
(b) Marion, F.; Coulomb, J.; Servais, A.; Courillon, C.; Fensterbank, L.;
Malacria, M. Tetrahedron 2006, 62, 3856
.
(4) For allenamides as radical acceptors, see: (a) Shen, L.; Hsung, R. P.
Org. Lett. 2005, 7, 775. For N-acylcyanamides as radical acceptors, see:
(b) Servais, A.; Azzouz, M.; Lopes, D.; Courillon, C.; Malacria, M. Angew.
Chem., Int. Ed. 2007, 46, 576. (c) Beaume, A.; Courillon, C.; Derat, E.;
Malacria, M. Chem.sEur. J. 2008, 14, 1238. (d) Larraufie, M.-H.; Ollivier,
C.; Fensterbank, L.; Malacria, M.; Lacoˆte, E. Angew. Chem., Int. Ed. 2010,
49, 2178. (e) Larraufie, M.-H.; Courillon, C.; Ollivier, C.; Lacoˆte, E.;
(7) (a) Hayakawa, Y.; Sasaki, K.; Adachi, H.; Furihata, K.; Nagai, K.;
Shin-ya, K. J. Antibiot. 2006, 59, 1. (b) Hayakawa, Y.; Sasaki, K.; Nagai,
K.; Shin-ya, K.; Furihata, K. J. Antibiot. 2006, 59, 6.
(8) (a) Chatterjee, C.; Paul, M.; Xie, L.; van der Donk, W. A. Chem.
ReV. 2005, 105, 633. (b) van der Donk, W. A. J. Org. Chem. 2006, 71,
9561.
Malacria, M.; Fensterbank, L. J. Am. Chem. Soc. 2010, 132, 4381
.
(5) (a) Ito, O.; Matsuda, M. J. Am. Chem. Soc. 1979, 101, 5732. (b) Ito,
O.; Fleming, M. D. C. M. J. Chem. Soc., Perkin Trans. 2 1989, 689.
(6) Sato, A.; Yorimitsu, H.; Oshima, K. Synlett 2009, 28.
10.1021/ol1008679  2010 American Chemical Society
Published on Web 05/03/2010

The proposed reaction is shown in Figure 2. Regioselective
addition of a thiyl radical to the terminal carbon of ynamide
contrast, employing 1 equiv of thiol and 0.5 equiv of AIBN
led to Z-3a in good yield (76%, 1:11 E/Z) after only 10 min.
Similar trends were observed with thiophenol, although
greater quantities of the E isomer were obtained under both
sets of conditions. When the radical addition of tert-butyl
thiol to 1 was performed under the Z-selective conditions,
no reaction was observed. Subjection of this bulky thiol to
the typically E-selective conditions afforded a sluggish
reaction, and a modest yield (41%) of Z-3c was obtained
after 6 h. Longer reaction times led to decomposition, and
E-3c was never observed. There are two possible mechanisms
for the formation of E-ꢀ-thioenamides: hydrogen atom
abstraction from the thiol by vinyl radical isomer B (see
Figure 2) and addition-elimination of thiyl radical to
Z-adduct D. Both of these processes would be slowed
significantly by the use of bulky thiols.
Figure 2. Proposed radical addition.
Thiyl radical additions to cyclic carbamate-derived yna-
mide 215 showed similar trends to reactions involving acyclic
ynamide 1. However, the stereoselectivities of most reactions
with this acceptor were attenuated, and slightly higher
amounts of the minor isomers were produced under both E-
and Z-selective conditions. For example, addition of tert-
butyl thiol to 2 under the conditions that produced Z-3c
exclusively (4 equiv of thiol, 2 equiv of AIBN, 6 h) provided
a small amount of E-4c (1:5.2 E/Z). Importantly, E- and Z-ꢀ-
thioenamides 3 and 4 were stable to SiO2 and separable via
chromatography in all cases. The acyclic ꢀ-thioenamides 3
exhibited line broadening of the enamide signals in both the
1H and 13C NMR spectra, suggesting that the adducts exist
in solution as a pair of slowly interconverting conformational
isomers. In contrast, the corresponding signals in the spectra
of cyclic adducts 4 were sharp.
The protocol developed by Yorimitsu and Oshima for
radical additions of arenethiols to internal ynamides utilizes
low-temperature initiation (Et3B, -78 °C).6 We wondered
if the selectivity for the kinetic products Z-3 and Z-4 would
improve under these conditions. Surprisingly, when the
addition of thiophenol to terminal ynamide 2 was conducted
in this manner, decreased selectivity for Z-4b was observed
(Scheme 1, eq 1; compare to 1:5.1 E/Z, Table 1). The reasons
for this result are unclear but may be related to the difference
in solvent (CH2Cl2 vs t-BuOH) or to the fact that Et3B is a
Lewis acid as well as a radical initiator.
A would provide vinyl radicals B and/or C. These intermedi-
ates would rapidly equilibrate, and hydrogen atom abstraction
from the thiol by the less hindered radical C, according to
the precedent of Montevecchi and co-workers,9 should afford
cis-ꢀ-thioenamide D as the kinetic product. In contrast,
known methods of ꢀ-thioenamide construction based on
imine acylation10 or Pummerer rearrangement11 chemistry
deliver predominantly the trans isomers. We also recognized
that the presence of excess thiol in the reaction mixture would
permit isomerization of D to the thermodynamically more
stable trans isomer via a radical addition-ꢀ-thiyl radical
elimination pathway.12 Accordingly, we pursued a stereo-
selective synthesis of both cis- and trans-ꢀ-thioenamides by
seeking two complementary sets of reaction conditions.
We began by studying the additions of commercially
available thiols to simple ynamides. Our results are collected
in Table 1. Addition of excess n-butyl thiol (4 equiv) to
Table 1. Additions of Simple Thiols to Ynamides 1 and 2
RSH (equiv) AIBN (equiv)
time
3 h
10 min
5 h
10 min
6 h
3 h
10 min
5 h
10 min
6 h
product % yielda (E/Z)b
n-BuSH (4)
n-BuSH (1)
PhSH (4)
2
0.5
2
3a
3a
3b
3b
3c
4a
4a
4b
4b
4c
72 (15:1)
76 (1:11)
97 (33:1)
33 (1:4.3)
41 (Z only)c
73 (8.4:1)
72 (1:6.0)
73 (8.5:1)
74 (1:5.1)
72 (1:5.2)
1
In the reactions described above, the Z adduct predomi-
nates under kinetically controlled conditions (1 equiv of thiol,
short reaction times), whereas the E adduct emerges under
thermodynamically controlled conditions (excess thiol, long
PhSH (1)
0.5
2
2
0.5
2
t-BuSH (4)
n-BuSH (4)
n-BuSH (1)
PhSH (4)
(9) (a) Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin
Trans. 1 1991, 2103. (b) Melandri, D.; Montevecchi, P. C.; Navacchia,
M. L. Tetrahedron 1999, 55, 12227.
PhSH (1)
t-BuSH (4)
0.5
2
(10) Ishibashi, H.; Kameoka, C.; Iriyama, H.; Kodama, K.; Sato, T.;
Ikeda, M. J. Org. Chem. 1995, 60, 1276.
(11) (a) Magnus, P.; Sear, N. L.; Kim, C. S.; Vicker, N. J. Org. Chem.
1992, 57, 70. (b) Ishibashi, H.; Inomata, M.; Ohba, M.; Ikeda, M.
Tetrahedron Lett. 1999, 40, 1149. (c) Ishibashi, H.; Kato, I.; Takeda, Y.;
Kogure, M.; Tamura, O. Chem. Commun. 2000, 1527.
(12) Chatgilialoglu, C.; Ferreri, C. Acc. Chem. Res. 2005, 38, 441.
(13) Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. 1998, 37, 489.
(14) Majumdar, K. C.; Maji, P. K.; Ray, K.; Debnath, P. Tetrahedron
Lett. 2007, 48, 9124.
a Isolated yield of the major isomer. Determined via H NMR of the
b
crude reaction mixture. c The E isomer was not detected.
acyclic amide-derived ynamide 113 in refluxing t-BuOH with
AIBN as initiator14 afforded ꢀ-thioenamide E-3a as the major
product of a separable mixture (72%, 15:1 E/Z) after 3 h. In
(15) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833.
Org. Lett., Vol. 12, No. 11, 2010
2651

Scheme 1
Table 2. Addition of Cys-Derived Thiol to Ynamides 1 and 2
equiv of 5 equiv of AIBN
time
3 h
10 min
2.5 h
10 min
b
product % yielda (E/Z)b
2
1
2
1
2
0.5
1
6
6
7
7
68 (8.5:1)
67 (1:6.1)
71 (10:1)
60 (1:2.9)
0.5
reaction times). To confirm our suspicions that the Z adducts
isomerize to the more stable E adducts under the thermo-
dynamic conditions, we exposed enriched Z-3a to the radical
addition conditions (Scheme 1, eq 2). As anticipated, we
obtained a sample enriched in the E isomer in good yield.
Having established the viability of radical additions of
simple thiols to ynamides 1 and 2, we wished to examine
the use of a thiol that would be more relevant to the
construction of peptide-based ꢀ-thioenamides. Thus, we
employed N-Cbz cysteine methyl ester (5) as the thiol
component. Pleasingly, the E-isomer of ꢀ-thioenamide 6 was
favored by using excess 5 and longer reaction times, while
Z-6 was the major product with 1 equiv of 5 and shorter
reaction times (Table 2). In an effort to conserve the thiol,
we found that 2 equiv of 5 was sufficient to promote Z-to-E
isomerization. The relatively low ratio in favor of Z-7 (1:
2.9 E/Z) under kinetic conditions was surprising. Either the
difference in the relative rates of formation of Z-7 and E-7
is slight or the rate of isomerization of Z-7 is rapid enough
to compete with radical addition of 5 to 2.
a Isolated yield of the major isomer. Determined via H NMR of the
crude reaction mixture.
1
form via SiO2 chromatography, and the yields are good (ca.
60-80% in most cases). By enabling the selective production
of either alkene isomer via selection of the appropriate
conditions, this reaction provides an advantage over previ-
ously developed methods that afford trans-ꢀ-thioenamides
predominantly.10,11 Thiyl radical additions to amino-acid-
derived ynamides would provide access to complex peptide
natural products such as thioviridamide (Figure 1). Studies
directed toward this aim are currently in progress and will
be the subject of future reports.
Acknowledgment. We thank the National Institutes of
Health (GM70483) and Brigham Young University (Cancer
Research Center Fellowship to J.K., CHIRP award to S.L.C.)
for support.
In summary, we have discovered two complementary
protocols for the stereoselective radical addition of thiols to
terminal ynamides. Under kinetically controlled conditions,
the cis-ꢀ-thioenamides are obtained in good dr (g2.9:1,
typically >5:1). In contrast, thermodynamically controlled
conditions allow equilibration to the more stable trans
adducts (>8:1 dr). The major isomers can be isolated in pure
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL1008679
2652
Org. Lett., Vol. 12, No. 11, 2010