Enantioselective Diels-Alder reaction of α-(acylthio)acroleins: A new entry to sulfur-containing chiral quaternary carbons

Article abstract of DOI:10.1021/ol300921f

A catalytic and enantioselective Diels-Alder reaction of α-(carbamoylthio)acroleins induced by an organoammonium salt of chiral triamine is described. α-(Carbamoylthio)acroleins are designed and synthesized as new sulfur-containing dienophiles for the fir

Full text of DOI:10.1021/ol300921f

ORGANIC
LETTERS
2012
Vol. 14, No. 12
2972–2975
Enantioselective DielsꢀAlder Reaction
of r-(Acylthio)acroleins: A New Entry
to Sulfur-Containing Chiral Quaternary
Carbons
Akira Sakakura,† Hiroki Yamada,‡ and Kazuaki Ishihara*,‡,§
EcoTopia Science Institute, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603,
Japan, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya
464-8603, Japan, and JST, CREST, Furo-cho, Chikusa, Nagoya 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
Received April 10, 2012
ABSTRACT
A catalytic and enantioselective DielsꢀAlder reaction of R-(carbamoylthio)acroleins induced by an organoammonium salt of chiral triamine is
described. R-(Carbamoylthio)acroleins are designed and synthesized as new sulfur-containing dienophiles for the first time. The DielsꢀAlder
reaction affords chiral tertiary thiol precursors with up to 91% ee.
The DielsꢀAlder reaction is one of the most powerful
carbonꢀcarbonbond-formingreactionsandiswidelyused
for the synthesis of various bioactive natural compounds.1
We previously reported the catalytic enantioselective
DielsꢀAlder reaction and [2 þ 2] cycloaddition reac-
tion of R-(acyloxy)acroleins and R-(phthalimido)acroleins
induced by organoammonium salts of chiral triamine 1 with
C6F5SO3H or Tf2NH (Scheme 1).2 R-(Acyloxy)acroleins
and R-(phthalimido)acroleins are useful dienophiles for
the synthesis of chiral R-quaternary R-hydroxy or R-amino
acid equivalents. In this context, R-(acylthio)acroleins
would also be useful dienophiles for the construction of
sulfur-containing quaternary carbons. The corresponding
adducts are potential chiral intermediates for the synthesis
of sulfur-containing bioactive natural products.3 For ex-
ample, the DielsꢀAlder adduct of an R-(acylthio)acrolein
† EcoTopia Science Institute.
(3) For representative examples of bioactive compounds bearing
sulfur-containing quaternary carbons, see: (a) Hofmeister, H.; Hoyer,
G.-A.; Cleve, G.; Laurent, H.; Wiechert, R. Chem. Ber. 1976, 109, 185.
(b) Costa, M. d. C.; Teixeira, S. G.; Rodrigues, C. B.; Ryberg Figueiredo, P.;
Marcelo Curto, M. J. Tetrahedron 2005, 61, 4403. (c) Asthana, R. K.;
Srivastava, A.; Singh, A. P.; Deepali; Singh, S. P.; Nath, G.; Srivastava, R.;
Srivastave, B. S. J. Appl. Phycol. 2006, 18, 33. (d) Sawant, S.; Youssef, D.;
Mayer, A.; Sylvester, P.; Wali, V.; Arant, M.; El Sayed, K. A. Chem. Pharm.
‡ Graduate School of Engineering.
§ CREST.
(1) (a) Ishihara, K.; Sakakura, A. In Stereoselective Synthesis; Evans,
P. A., Ed.; Georg Thieme Verlag KG: Stuttgart, 2011; Vol. 3, pp 67ꢀ123.
(b) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100. (c) Nicolaou,
K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew.
Chem., Int. Ed. 2002, 41, 1668. (d) Oppolzer, W. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 5, pp 315ꢀ399.
€
Bull. 2006, 54, 1119. (e) Dormann, K. L.; Bruckner, R. Angew. Chem., Int.
Ed. 2007, 46, 1160.
(4) Pattenden, G.; Shuker, A. J. Tetrahedron Lett. 1991, 32, 6625.
(5) (a) Aggarwal, V. K.; Jones, D. E.; Martin-Castro, A. M. Eur. J.
Org. Chem. 2000, 2939. (b) Sobhani, S.; Fielenbach, D.; Marigo, M.;
Wabnitz, T. C.; Jørgensen, K. A. Chem.;Eur. J. 2005, 11, 5689.
(c) Jereb, M.; Togni, A. Org. Lett. 2005, 7, 4041. (d) Lu, H.; Zhang, F.;
Meng, X.; Duan, S.; Xiao, W. Org. Lett. 2009, 11, 3946. (e) Fujiwara, Y.;
Fu, G. C. J. Am. Chem. Soc. 2011, 133, 12293.
(2) (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127,
10504; correction 2005, 127, 13079. (b) Sakakura, A.; Suzuki, K.;
Nakano, K.; Ishihara, K. Org. Lett. 2006, 8, 2229. (c) Sakakura, A.;
Suzuki, K.; Ishihara, K. Adv. Synth. Catal. 2006, 348, 2457. (d) Ishihara,
K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930. (e) Ishihara, K.;
Nakano, K.; Akakura, M. Org. Lett. 2008, 10, 2893. (f) Sakakura, A.;
Ishihara, K. Bull. Chem. Soc. Jpn. 2010, 83, 313.
r
10.1021/ol300921f
Published on Web 05/25/2012
2012 American Chemical Society

with isoprene would be readily converted to a key synthetic
intermediate of leinamycin4 (Scheme 2). Although some
methods for the synthesis of sulfur-containing quaternary
stereogenic centers have been reported,5 most of these
methods produce chiral thioethers and only a few can give
tertiary thiols.5b,e We report here the catalytic and enantio-
selective DielsꢀAlder reaction of R-(acylthio)acroleins to
give optically active tertiary thiol precursors.
0 °C (Table 1). As a result, the enantioselectivities of the
corresponding adducts 3 highly depended on the benzoyl
groups. The introduction of an electron-donating dialkyl-
amino group at the 4-position increased the enantioselec-
tivity, and dienophile 2d bearing a pyrrolidinyl group gave
the highest enantioselectivity (entry 4). However, the en-
antioselectivity of 2d (72% ee) was still lower than those of
R-(4-methoxybenzoyloxy)acrolein (92% yield, 92% ee)2a
and R-(phthalimido)acrolein (82% yield, 96% ee)2e in the
1 2.75C6F5SO3H-catalyzed DielsꢀAlder reaction of 2,3-
3
dimethylbutadiene. It is conceivable that the formation of
stronger hydrogen bonding between the acyl group and an
ammonium proton of the catalyst might stabilize the con-
formation of the transition state to increase the enantio-
selectivity (Figure 1). The lower basicity of thioesters
compared to esters and imides resulted in the lower
enantioselectivity of R-(benzoylthio)acroleins 2aꢀd than
R-(4-methoxybenzoyloxy)acrolein and R-(phthalimido)-
acrolein. In addition, although the R-benzoylacroleins
2c and 2d gave good enantioselectivities, the yields of
the corresponding adducts 3c and 3d were low (entries 3
and 4). The low yields were mainly attributed to the low
solubilities of 2c and 2d in EtNO2. Therefore, both the
solubility and the basicity of the acyl group of 2 had to be
improved to achieve high yield and enantioselectivity.
Scheme 1. Enantioselective DielsꢀAlder Reaction of
R-(Acyloxy)acroleins and R-(Phthalimido)acroleins2
Table 1. Enantioselective DielsꢀAlder Reaction of
R-(Benzoylthio)acroleins 2a
Scheme 2. DielsꢀAlder Reaction of R-(Acylthio)acroleins for
the Synthesis of Sulfur-Containing Quaternary Carbons
entry
2 [Ar]
3, yield (%)
eeb (%)
1
2
3
4
2a [Ph]
3a, 58
3b, 53
3c, 28
3d, 30
43
44
68
72
2b [4-(MeO)C6H4]
2c [4-(Me2N)C6H4]
2d [4-[(CH2)4N]C6H4]
a Reaction of 2 (0.1 mmol) with 2,3-dimethylbutadiene (4 equiv) was
conducted in the presence of 1 2.75C6F5SO3H (10 mol %) in EtNO2 at
3
0 °C for 36 h. b Determined by HPLC analysis.
On the basis of our previousresults, benzoylgroups were
considered to be promising candidates as protecting groups
for the R-mercapto group. We first synthesized β-unsubsti-
tuted R-(benzoylthio)acroleins 2 based on the acylation6 of
2-(diethoxymethyl)thiirane.7,8 The DielsꢀAlder reaction of
2aꢀd with 2,3-dimethylbutadiene (4 equiv) was conducted
in the presence of 1 2.75C6F5SO3H (10 mol %) in EtNO2 at
3
(6) (a) Sander, M. Chem. Rev. 1966, 66, 297. (b) Silvestri, M. G.;
Wong, C.-H. J. Org. Chem. 2001, 66, 910.
(7) Pederson, R. L.; Liu, K. K.-C.; Rutan, J. F.; Chen, L.; Wong,
C.-H. J. Org. Chem. 1990, 55, 4897.
(8) See the Supporting Information for details.
(9) Barany, G.; Schroll, A. L.; Mott, A. W.; Halsrud, D. A. J. Org.
Chem. 1983, 48, 4750.
Figure 1. Proposed transition-state assembly.
Org. Lett., Vol. 14, No. 12, 2012
2973

Thus, we next designed R-(carbamoylthio)acroleins
11aꢀd (R1 = H, Scheme 3) as new R-sulfur-substituted
acroleins to overcome the above problems. The carbamoyl
groups were expected to have a stronger electron-donating
ability than the benzoyl groups. However, it would be very
difficult to promote the carbamoylation of 2-(diethoxy-
methyl)thiirane with dialkylcarbamoyl chlorides, since the
dialkylcarbamoyl chlorides were much less electrophilic
than the carboxylic chlorides. Thus, we developed a new
synthetic route for 11 based on the umpolung strategy:
CꢀS bond formation between a “carbamoylthio cation
R2NCOSþ” and a “vinyl anion RCHdCꢀCHO” (Scheme 3).
According to this strategy, bis(carbamoyl)disulfides 10, syn-
thetic equivalents of a carbamoylthio cation, were prepared
from bis(chlorocarbonyl)disulfide9 and secondary amines.
Lithiation10 of R-bromoacrolein diethylacetals 411 generated
the corresponding vinyl anion. The reaction of the vinyl anion
with 10 followed by acid hydrolysis of the acetal moiety gave
11aꢀd in yields of 30ꢀ50%.
Scheme 3. Synthesis of R-(Carbamoylthio)acroleins 11ꢀ16
As expected, R-(carbamoylthio)acroleins 11aꢀd were
readily soluble in EtNO2 under the reaction conditions,
and showed high reactivities and enantioselectivity in the
1 2.75C6F5SO3H-catalyzed DielsꢀAlder reaction with
3
2,3-dimethylbutadiene (entries 1ꢀ4, Table 2). Although
11b bearing a pyrrolidinecarbonylthio group gave the
highest enantioselectivity (76% ee), the yield of the corre-
sponding adduct 17b was low (20%) because 11b was labile
under the reaction conditions (entry 2). Dienophile 11a
bearing an N,N-diisopropylaminocarbonylthio group was
Table 2. Enantioselective DielsꢀAlder Reaction of R-(Carbamoylthio)acroleins 11ꢀ16a
a Reactions of 11ꢀ16 (0.1 mmol) with a diene (4 equiv) were conducted in the presence of 1 2.75C6F5SO3H (10 mol %) in EtNO2 at 0 °C for 1.5 days
3
(for 11) or 3 days (for 12ꢀ16). b Determined by 1H NMR analysis. c Determined by HPLC analysis.
2974
Org. Lett., Vol. 14, No. 12, 2012

ities (entries 9ꢀ13). In particular, β-aryl-substituted die-
nophiles 14aꢀ16a showed more than 90% ee (entries
11ꢀ13). The absolute configuration of the major diaster-
eomer of the adduct 26 was determined to be (2R,3R) by
X-ray crystallographic analysis (Figure 2).8 The stereo-
chemical outcome of exo-26 was consistent with those of
the DielsꢀAlder adducts of R-(acyloxy)acroleins and R-
phthalimidoacroleins.2
The carbamoyl group in the DielsꢀAlder adducts could
be removed by reductive cleavage. For example, the treat-
ment of 22 with LiAlH4 (6 equiv) and ZnCl2 (3 equiv)13
followed by acetylation of the resultant hydroxyl group
and mercapto group gave 27 in 71% yield (Scheme 4).
Figure 2. X-ray single-crystal structure of exo-26 with thermal
ellipsoids drawn at a 50% probability level. C = black, H =
white, N = blue, O = red, S = yellow, F = green.
Scheme 4. Derivatization of 22
stable and gave the adduct 17a in 65% yield with 74% ee
(entry 1). With the optimized dienophile 11a in hand, we
next examined the enantioselective DielsꢀAlder reaction
with representative dienes (entries 5ꢀ8). 2-Alkyl-substi-
tuted dienes such as isoprene, myrcene, and (E)-β-farne-
sene smoothly reacted with 11a to give the corresponding
4-alkyl-substituted adducts 18ꢀ20 with >99% regioselec-
tivity and 67ꢀ81% ee. In contrast, the reaction of 11a with
cyclopentadiene gave the corresponding adduct 21 in
racemic form (entry 8).
According to the synthetic method for 11 desribed in
Scheme 3, β-substituted R-(carbamoylthio)acroleins 12aꢀ
16a (R1 ¼ H) were synthesized in 41ꢀ60% yields. In this
reaction sequence, the bromination of β-substituted acro-
leins followed by acetalization selectively afforded cis-β-
substituted R-bromoacrolein diethylacetals 5ꢀ9 despite
the fact that the starting β-substituted acroleins were iso-
meric mixtures.12
In conclusion, we have developed an organocatalytic
and enantioselective DielsꢀAlder reaction of R-(carba-
moylthio)acroleins to provide chiral tertiary thiol precur-
sors for the first time. β-Unsubstituted or β-substituted
R-(carbamoylthio)acroleins 11ꢀ16 were designed and
synthesized as new sulfur-containing dienophiles.
Acknowledgment. Financial support for this project was
provided by JSPS.KAKENHI (20245022 and 23350039).
H.Y. thanks ‘‘the Nagoya University IGER Program in
Green Natural Sciences for Leading Graduate Schools from
MEXT’’ for a research fellowship.
The DielsꢀAlder reactions of β-substituted R-(carba-
moylthio)acroleins 12aꢀ16a with cyclopentadiene were
Supporting Information Available. Experimental de-
tails and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
also catalyzed by 1 C6F5SO3H (10 mol %) and gave the
corresponding adducts 22ꢀ26 with high enantioselectiv-
3
(10) Takahashi, T.; Yokoyama, H.; Haino, T.; Yamada, H. J. Org.
Chem. 1992, 57, 3521.
(11) Barlow, A. j.; Compton, B. J.; Weavers, R. T. J. Org. Chem.
(13) Marr, F.; Hoppe, D. Org. Lett. 2002, 4, 4217.
2005, 70, 2470.
(12) (a) Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem.
1982, 47, 5088. (b) Gilly, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett.
2007, 9, 3631.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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