Organocatalytic Mannich-type reactions of trifluoroethyl thioesters

Article abstract of DOI:10.1021/ol801207x

(Chemical Equation Presented) Direct organocatalytic Mannich-type reactions of thioesters provide for the expedient and diastereoselective synthesis of protected β-amino acids. A variety of thioesters were found to be reactive with different lmines under mild conditions to provide β-amino acids in good yields. This chemistry was extended to a diastereo- and enantioselective variant.

Full text of DOI:10.1021/ol801207x

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3405-3408
Organocatalytic Mannich-Type Reactions
of Trifluoroethyl Thioesters
Naoto Utsumi, Shinji Kitagaki, and Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and
Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
carlos@scripps.edu
Received May 27, 2008
ABSTRACT
Direct organocatalytic Mannich-type reactions of thioesters provide for the expedient and diastereoselective synthesis of protected ꢀ-amino
acids. A variety of thioesters were found to be reactive with different imines under mild conditions to provide ꢀ-amino acids in good yields.
This chemistry was extended to a diastereo- and enantioselective variant.
Direct organocatalytic Mannich and Mannich-type reactions
provide expedient access to R- and ꢀ-amino acids, amino
alcohols and sugars, and amino carbonyl derivatives that are
synthons of import in the pharmaceutical and other industries
and have, therefore, received much attention.1–3 We have
devoted considerable effort toward addressing this reaction
using enamine-based mechanisms and toward solving the
stereochemical challenges of direct organocatalytic enanti-
oselective syn- or anti-selective syntheses of these types of
products based on the use of ketone or aldehyde donors.3 A
significant unmet challenge in this area is the development
of direct organocatalytic Mannich and Mannich-type reac-
tions that utilize donors in the ester oxidation state and are
either diastereoselective or both diastereo- and enantiose-
lective. Such reactions are not amenable to enamine-based
organocatalytic approaches. Recently, we have described a
new approach4 to direct organocatalytic ester-based reactions
that utilizes electronic tuning of thioesters to provide ester
donor reactivity without need to resort to decarboxylative
approaches5 for enolate generation. Herein we report the
application of this strategy to direct asymmetric Mannich-
type reactions that utilize thioester donors.
(1) For recent reviews that consider the contributions of the many
laboratories that have studied the organocatalytic Mannich reaction, see:
(a) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797. (b) Dondoni,
A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638
.
(2) For recent leading references from other laboratories concerning
organocatalytic Mannich and Mannich-type reactions, see: (a) Wang, W.;
Wang, J.; Li, H. Tetrahedron Lett. 2004, 45, 7243. (b) Westermann, B.;
Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077. (c) Fustero, S.; Jimenez,
D.; Sanz-Cervera, J. F.; Sanchez-Rosello, M.; Esteban, E.; Simon-Fuentes,
A. Org. Lett. 2005, 7, 3433. (d) Cobb, A. J. A.; Shaw, D. M.; Longbottom,
D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. (e) Kano,
T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005,
127, 16408. (f) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (g)
Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A. Angew.
Chem. 2005, 117, 2956; Angew. Chem., Int. Ed. 2005, 44, 2896. (h) Enders,
D.; Grondal, C.; Vrettou, M. Synthesis 2006, 3597. (i) Kano, T.; Hato, Y.;
Maruoka, K. Tetrahedron Lett. 2006, 47, 8467. (j) Janey, J. M.; Hsiao, Y.;
Armstrong, J. D., III. J. Org. Chem. 2006, 71, 390. (k) Chi, Y.; Gellman,
S. H. J. Am. Chem. Soc. 2006, 128, 6804. (l) Song, J.; Wang, Y.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 6048. (m) Ting, A.; Lou, S.; Schaus, S. E.
Org. Lett. 2006, 8, 2003. (n) Song, J.; Shih, H. W.; Deng, L. Org. Lett.
2007, 9, 603. (o) Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72,
9998. (p) Chi, Y.; English, E. P.; Pomerantz, W. C.; Horne, W. S.; Joyce,
L. A.; Alexander, L. R.; Fleming, W. S.; Hopkins, E. A.; Gellman, S. H.
J. Am. Chem. Soc. 2007, 129, 6050. (q) Cheng, L. L.; Han, X.; Huang,
H. M.; Wong, M. W.; Lu, Y. X. Chem. Commun. 2007, 40, 4143. (r)
Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054. (s) Yang,
J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609. (t)
Marianacci, O.; Micheletti, G.; Bernardi, L.; Fini, F.; Fochi, M.; Pettersen,
D.; Sgarzani, V.; Ricci, A. Chem. Eur. J. 2007, 13, 8338. (u) Guo, Q.-X.;
Liu, H.; Guo, C.; Luo, S.-W.; Gu, Y.; Gong, L.-Z. J. Am. Chem. Soc. 2007,
129, 3790. (v) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5,
1018. (w) Kano, T.; Hato, Y.; Yamamoto, A.; Maruoka, K. Tetrahedron
2008, 64, 1197. (x) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.;
List, B. Nature 2008, 452, 453. (y) Hayashi, Y.; Urushima, T.; Aratake,
S.; Okano, T; Obi, K. Org. Lett. 2008, 10, 21. (z) Zhang, Y.; Liu, Y.-K.;
Kang, T.-R.; Hu, Z.-K.; Chen, Y. -C. J. Am. Chem. Soc. 2008, 130, 2456
.
10.1021/ol801207x CCC: $40.75
Published on Web 07/16/2008
2008 American Chemical Society

In order to expand the scope of direct organocatalytic
reactions of trifluoroethyl thioesters,4,6 we have evaluated
thioesters as nucleophiles in Mannich-type reactions. Our
goal was to study their general reactivity in direct Mannich-
type reactions with preformed imines with the hope of
developing a diastereoselective transformation en route to
an enantioselective one (Scheme 1). We initially studied the
Table 1. Catalyst and Solvent Screening for the Mannich
Reaction of Thioester with N-Boc-iminea
entry
catalyst
solvent
yieldb (%)
syn/antic
Scheme 1. Thioester Enolization and Addition to an Imine
1
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
KOtBu
Et3N
iPr2EtN
K2CO3
DMF
96
78
89
86
57/43
57/43
50/50
57/43
41/59
80/20
88/12
89/11
83/17
41/59
50/50
47/53
44/56
2d
3
DMF
CH2Cl2
THF
MeOH
CH3CN
hexane
Et2O
toluene
toluene
toluene
toluene
toluene
4
5e
6
17
(19)
85
7f
8f
9f
10f
11
12
13
quant
quant
94
reaction of thioester 1a with the N-Boc-imine of benzalde-
hyde,2a,usingacatalyticamountof1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (Table 1).
quant
22
18
13
(73)
(80)
(87)
In our preliminary study of the related aldol reaction,4 we
found that DBU was an effective catalyst. As noted in entries
1-9, we observed significant solvent effects on both the
overall yield of the reaction and the diastereoselectivity of
the reaction. Polar aprotic solvents such as DMF, CH2Cl2,
and THF provided the product in good yield after 2 h;
however, the reaction demonstrated only modest diastereo-
selectivity, slightly favoring the syn-product 3a (entries 1-4).
The protic solvent methanol provided the product with slight
a Catalyst (0.01 mmol) was added to a mixture of thioester 1a (0.1 mmol)
with imine 2a (0.12 mmol) in solvent (0.2 mL), and the reaction was stirred
at room temperature for 2 h. b Yields were calculated from crude 1H NMR
spectra using anisole as a internal standard. Recovered yield of thioester is
shown in parentheses. c Determined by crude 1H NMR spectra. d MS4A
was used as an additive. e MeOH adduct of imine (69% based on imine)
and methyl 4-chlorophenylacetate (39% yield) were formed. f Products were
precipitated during the reaction.
anti-selectivity albeit in very low yield (entry 5). A significant
improvement in both yield and diastereoselectivity was
observed for reactions in nonpolar solvents such as hexane,
diethyl ether, and toluene (entries 7-9). Under these condi-
tions, quantitative or near-quantitative yields of 3a were
obtained and the syn/anti ratio reached ∼8:1. We also
observed that the reaction product 3a precipitated during the
course of the reaction when these solvents were used but
remained soluble in the polar solvents studied (entries 1-5).
We then studied the role of the catalyst under the toluene
solvent conditions. As noted in entry 10, the base KOtBu proved
an effective substitute for DBU in terms of overall yield of the
desired product; however, the reaction was poorly diastereo-
selective (entry 10). Reactions using the other three bases tested
(3) For studies from this laboratory concerning organocatalytic Mannich
and Mannich-type reactions, see: (a) Notz, W.; Sakthivel, K.; Bui, T.;
Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 199. (b) Sakthivel, K.; Notz,
W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (c)
Cordova, A.; Notz, W.; Zhong, G.; Betancort, J.; Barbas, C. F., III. J. Am.
Chem. Soc. 2002, 124, 1842. (d) Cordova, A.; Watanabe, S.; Tanaka, F.;
Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866. (e) Cordova,
A.; Barbas, C. F., III. Tetrahedron. Lett. 2002, 43, 7749. (f) Watanabe, S.;
Cordova, A.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2002, 4, 4519. (g)
Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.;
Thayumanuvan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624. (h)
Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Synlett 2003, 1906.
(i) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2003, 44, 1923. (j)
Notz, W.; Watanabe, S.; Chowdari, N. S.; G.; Zhong, Betancort, J. M.;
Tanaka, F.; Barbas, C. F., III. AdV. Synth. Catal 2004, 346, 1131. (k)
Chowdari, N. S.; Suri, J.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507. (l)
Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580.
(m) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas,
C. F., III. Org. Lett. 2006, 8, 2839. (n) Cheong, P. H.-Y.; Zhang, H.;
Thayamanavan, R.; Tanaka, F.; Houk, K. N.; Barbas, C. F., III. Org. Lett.
2006, 8, 811. (o) Mitsumori, S.; Zhang, H.; Cheong, P. H. Y.; Houk, K. N.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1040. (p) Zhang,
H. L.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006,
128, 9630. (q) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2007, 129, 288. (r) Zhang, H.; Ramasastry, S. S. V.;
Tanaka, F.; Barbas, C. F., III. AdV. Synth. Catal. 2008, 350, 791. (s) Zhang,
H. L.; Mitsumori, S.; Utsumi, N.; Imai, M.; Garcia-Delgado, N.; Mifsud,
M.; Albertshofer, K.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas,
C. F., III. J. Am. Chem. Soc. 2008, 130, 875.
i
(Et3N, Pr2EtN, K2CO3) gave reduced product yield and dias-
tereoselectivity after 2 h relative to reactions in DBU. Most of
thioester 1a was recovered intact following reactions using Et3N,
iPr2EtN, and K2CO3, indicating that substrate decomposition
was not responsible for the low yields under these conditions.
Next we optimized reaction time and temperature across the
three most promising solvents (toluene, diethylether, and
hexane) (Table 2). Our preliminary study of the reaction in
toluene indicated that the reaction was complete in less than
2 h. Given that the product was insoluble using this and the
other high-yielding solvent systems and that the diastereose-
lectivity of the reaction was low under solvent conditions
wherein the product was soluble (polar solvents), we speculated
that diastereoselectivity was under thermodynamic control
driven by precipitation of the syn-product. To test this hypoth-
esis, we studied both longer and shorter reaction times and
reductions in reaction temperature. No significant change in
(4) Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2008, 47, 4588.
(5) (a) Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.;
Shair, M. D. J. Am. Chem. Soc. 2005, 127, 7284. (b) Lalic, G.; Aloise,
A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125, 2852. (c) Orlandi, S.;
Benaglia, M.; Cozzi, F. Tetrahedron Lett. 2004, 45, 1747. (d) Yost, J. M.;
Zhou, G.; Coltart, D. M. Org. Lett. 2006, 8, 1503. (e) Ricci, A.; Pettersen,
D.; Bernardi, L.; Fini, F.; Fochi, M.; Perez Herrera, R.; Sgarzani, V. AdV.
Synth. Catal. 2007, 349, 1037. (f) Lubkoll, J.; Wennemers, H. Angew. Chem.
2007, 119, 6965; Angew. Chem., Int. Ed. 2007, 46, 6841.
(6) Um, P. -J.; Drueckhammer, D. G. J. Am. Chem. Soc. 1998, 120,
5605.
3406
Org. Lett., Vol. 10, No. 16, 2008

Table 2. Effect of Temperature and Reaction Time on the
Reaction of Thioester with N-Boc-iminea
Table 3. Selectivities when Products Were Isolated Using
Extraction vs Filtrationa
entry
solvent
T (°C)
time (h)
yieldb (%)
syn/antic
entry
workup method
time (min)
yieldb (%)
syn/antic
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
25
25
2
89
83/17
83/17
75/25
92/8
1
2
3
4
extractiond
filtratione
extractiond
filtratione
5
5
120
120
98
70
96
65
75/25
83/17
92/8
2
6
89
3
4
5 min
98
96
quant
93
8
quant
91
quant
quant
quant
quant
4
4
2
4
2
2
2
2
4
2
2
4
96/4
5
-15
-40
-78
25
91/9
a DBU (0.1 equiv) was added to a mixture of thioester 1a (1 equiv)
with imine 2a (1.2 equiv) in toluene (0.5 M), and the reaction was stirrred
at 4 °C for specified time. b Isolated yield. c Determined by 1H NMR spectra.
d Extraction by EtOAc/brine followed by purification by flash column
chromatography. e The precipitated solid was collected by filteration and
washed using small amount of cold toluene.
6
29/71
50/50
89/11
89/11
89/11
88/12
88/12
75/25
7
(83)
8
9
Et2O
4
-15
25
4
-15
10
11
12
13
Et2O
hexane
hexane
hexane
a Catalyst (0.01 mmol) was added to a mixture of thioester 1a (0.1 mmol)
with imine 2a (0.12 mmol) in a solvent (0.2 mL). The reaction was stirred
at specified temperature for the specified time. b Yield was calculated by
NMR of the crude product using anisole as an internal standard. Recovered
yield of thioester is shown in parentheses. c Determined by 1H NMR of
crude product.
As final evidence for a dynamic thermodynamic mecha-
nism, purified product 3a (Table 2, entry 6), which had a
syn:anti ratio of 29:71, was incubated with fresh DBU
catalyst in toluene for 2 h at 4 °C and 3a was reisolated
(Scheme 2, 3). We found that this product had a syn:anti
either yield or diastereoselectivity was noted when we increased
the reaction time from 2 to 6 h (entries 1 and 2). However,
when we slowed the reaction by lowering the temperature to 4
°C and worked up the reaction after just 5 min, the yield
remained high but the diastereoselectivity was reduced (entry
3). Significantly, the syn:anti ratio of the 4 °C reaction was
improved to 92:8 (from 75:35 after 5 min) simply by extending
the reaction time to 2 h (entry 4). Interestingly, reduction of
the reaction temperature to -40 °C (entry 6) resulted in a
slightly anti-selective reaction, whereas reduction of the tem-
perature to -78 °C significantly slowed the reaction (8% yield
after 2 h) and no selectivity was obtained (entry 7). Reactions
in diethyl ether were high yielding over the +4 to -15 °C range,
providing the syn-product with ∼8:1 (syn:anti) diastereoselec-
tion (entries 8-10). Reactions in hexane did not provide
diastereoselectivities exceeding ∼7:1 (entries 11-13).
Scheme 2
.
Syn/Anti Isomerization of Mannich Adduct 3a
Catalyzed by DBU
ratio of 86:14 indicating that epimerization of the R-position
was facile under these conditions and that selective precipita-
tion of the syn-product increased the diastereoselectivity of
the reaction in nonpolar solvents.
The optimized reaction conditions were suitable for a range
of thioester donors and imine acceptors (Table 4). Boc-imines
derived from benzaldehyde were substantially more reactive
than the corresponding tosyl (Ts) imines; compare entries 1 and
2 to entries 6 and 7. Modest to insignificant differences in
diastereoselectivites were observed between Boc- and Ts-imine
reactions. The N-p-methoxyphenyl (PMP)-protected imine of
ethyl glyoxylate provided product with low yield and diaste-
reoselectivity. Of the eight thioesters studied, those with
insoluble products were obtained in good diastereoselectivity.
Product 3h, for example, was obtained in 94% yield with 19:1
syn:anti diastereoselection (entry 8). In addition to thioesters
functionalized with an aromatic group at the R-position, chloro-
substitution at this position led to generation of a reactive enolate
under these mild organocatalytic conditions (entry 12). The
relative syn-stereochemistry of product 3f was determined
These data are consistent with our hypothesis that syn-
selectivity was driven by product solubility and that the syn
and anti isomers could interconvert under the reaction conditions
wherein the syn product was less soluble than the anti product.
To further test this hypothesis, we reexamined the reaction in
toluene at 4 °C (Table 2, entries 3 and 4). We isolated the
reaction product by extractive workup and compared the isolated
product with product isolated by filtration (insoluble precipitate
was formed during the reaction) (Table 3, entries 1 and 2). We
found that the product isolated via filtration was syn-enriched
compared to that obtained from extractive workup. However,
when the reaction time was extended to 2 h, which allowed
the reaction to equilibrate, there was little difference in the
selectivities of products isolated using the two methods (Table
3, entries 3 and 4).
Org. Lett., Vol. 10, No. 16, 2008
3407

Table 4. Scope of Diastereoselective Mannich-Type Reaction of Thioestersa
entry
R1
R2
R3
product
time (h)
yieldb (%)
syn/antic
1d
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CF3C6H4
4-NO2C6H4
Ph
Ph
Boc
Ts
3a
3b
3c
3d
3e
3f
3g
3h
3i
2
30
4
93
88
92/8
2d,e,f
3g
Ph
92/8
CO2Et
Ph
4-MeOC6H4
Boc
65
75/25h
92/8
94/6
89/11
92/8
19/1
33/67
40/60
22/78
55/45h
4d
2
88
5d
Ph
Boc
72
2
90
6d
Ph
Boc
87
7d,i
8d
Ph
Ph
Ts
4
78
4-MeOC6H4
2-ClC6H4
1-Naphtyl
2-Thienyl
Cl
Ph
Boc
2
94
9g
Ph
Boc
2
quant
98
10g
11d
12g
Ph
Boc
3j
3k
3l
2
Ph
Boc
17
2
94
39
Ph
Boc
a Unless specified, DBU (0.01 mmol) was added to a mixture of thioester (0.1 mmol) with a imine (0.12 mmol) in toluene (0.2 mL), and the reaction
was stirred at 4 °C for specified time. b Isolated yield. c Determined by 1H NMR of crude product. d Products were precipitated during the reaction. e Reaction
was performed in 0.25 M concentration. f Thioester (1.2 equiv) and imine (1 equiv) were used. g Product did not precipitate during the reaction. h Major/minor
(syn/anti was not asssigned). i Reaction was performed at 0.16 M concentration.
following conversion to the known amino alcohol 4.7 Syn-
stereochemistry of other products was assigned if they dem-
onstrated strong 1H NMR spectral correlations with 3f.
ingly, this reaction (performed at -45 °C) was modestly anti-
selective, like the DBU reaction performed at -40 °C (Table
2, entry 6). Although the enantioselectivity of this reaction was
modest, 45% ee, the reactivity of our system compares very
favorably with direct Mannich-type reactions based on malonic
acid half-thioesters that typically require reaction times of 3
days.
Scheme 3. Determination of Relative Stereochemistry
In conclusion, we report the first direct diastereoselective
Mannich-type reactions of thioesters using the simple tertiary
amine DBU as a catalyst. This methodology provides expedient
access to ꢀ-amino acids. These syn-selective direct Mannich-
type reactions are the first of their kind involving thioesters.
The reactions described here compare favorably with and serve
to complement the anti-selective direct Mannich-type reaction
of sulfonylimidates recently described by Kobayashi et al.9
These studies provide a foundation for future development of
highly diastereo- and enantioselective direct ester-based Man-
nich reactions.
We were also interested in exploring the potential of an
enantioselective version of this reaction. As noted in Scheme
4, we adopted phase-transfer conditions with in situ N-Boc-
imine generation from the R-amido sulfone 2b.8 Using a
Cinchona alkaloid-based catalyst 5, good yields of 3a were
obtained with modest diastereo- and enantioselectivity. Interest-
Acknowledgment. This study was supported by The
Skaggs Institute for Chemical Biology.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 4. Enantioselective Mannich Reaction of a Thioester
OL801207X
(7) The major product was found to have the syn relative stereochemistry
1
as determined by H NMR coupling constant analysis; see:(a) Fodor, G.;
Reavill, R. E.; Stefanovsky, J.; Kurtev, B. Tetrahedron 1966, 22, 235. (b)
Kunz, H.; Burgard, A.; Schanzenbach, D. Angew. Chem. 1997, 109, 394;
Angew Chem., Int. Ed. 1997, 36, 386.
(8) (a) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi,
L.; Ricci, A. Angew. Chem. 2005, 117, 8189; Angew Chem., Int. Ed. 2005,
44, 7975.
(9) Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc. 2008,
130, 1804.
3408
Org. Lett., Vol. 10, No. 16, 2008