ORGANIC
LETTERS
Organocatalytic Mannich-Type Reactions
of Trifluoroethyl Thioesters
2008
Vol. 10, No. 16
3405-3408
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 β-amino
acids. A variety of thioesters were found to be reactive with different imines under mild conditions to provide β-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 β-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
(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)
10.1021/ol801207x CCC: $40.75
Published on Web 07/16/2008
 2008 American Chemical Society
using enamine-based mechanisms and toward solving the
stereochemical challenges of direct organocatalytic enantioselective 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 reactions that utilize donors in the ester oxidation state and are
either diastereoselective or both diastereo- and enantioselective. 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 Mannichtype reactions that utilize thioester donors.
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.
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 Mannichtype reactions with preformed imines with the hope of
developing a diastereoselective transformation en route to
an enantioselective one (Scheme 1). We initially studied the
Scheme 1. Thioester Enolization and Addition to an Imine
reaction of thioester 1a with the N-Boc-imine of benzaldehyde,2a,usingacatalyticamountof1,8-diazabicyclo[5.4.0]undec7-ene (DBU) (Table 1).
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 diastereoselectivity, slightly favoring the syn-product 3a (entries 1-4).
The protic solvent methanol provided the product with slight
(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.
(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
Table 1. Catalyst and Solvent Screening for the Mannich
Reaction of Thioester with N-Boc-iminea
entry
catalyst
solvent
yieldb (%)
syn/antic
1
DBU
DMF
96
57/43
2d
DBU
DMF
78
57/43
3
DBU
CH2Cl2
89
50/50
4
DBU
THF
86
57/43
5e
DBU
MeOH
17
(19)
41/59
6
DBU
CH3CN
85
80/20
7f
DBU
hexane
quant
88/12
quant
89/11
8f
DBU
Et2O
9f
DBU
toluene
94
83/17
toluene
quant
41/59
10f
KOtBu
11
Et3N
toluene
22
(73)
50/50
iPr EtN
12
toluene
18
(80)
47/53
2
13
K2CO3
toluene
13
(87)
44/56
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 conditions, 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 diastereoselective (entry 10). Reactions using the other three bases tested
(Et3N, iPr2EtN, K2CO3) gave reduced product yield and diastereoselectivity after 2 h relative to reactions in DBU. Most of
thioester 1a was recovered intact following reactions using Et3N,
i
Pr2EtN, 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 diastereoselectivity 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 hypothesis, we studied both longer and shorter reaction times and
reductions in reaction temperature. No significant change in
Org. Lett., Vol. 10, No. 16, 2008
Table 2. Effect of Temperature and Reaction Time on the
Reaction of Thioester with N-Boc-iminea
entry
solvent
T (°C)
time (h)
yieldb (%)
syn/antic
1
toluene
25
2
89
83/17
2
toluene
25
6
89
83/17
3
toluene
4
5 min
98
75/25
4
toluene
4
2
96
92/8
5
toluene
-15
4
quant
91/9
6
toluene
-40
2
93
29/71
7
toluene
-78
2
8
(83)
50/50
8
Et2O
25
2
quant
89/11
9
Et2O
4
2
91
89/11
10
Et2O
-15
4
quant
89/11
11
hexane
25
2
quant
88/12
12
hexane
4
2
quant
88/12
13
hexane
-15
4
quant
75/25
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.
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 temperature 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) diastereoselection (entries 8-10). Reactions in hexane did not provide
diastereoselectivities exceeding ∼7:1 (entries 11-13).
These data are consistent with our hypothesis that synselectivity 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
Table 3. Selectivities when Products Were Isolated Using
Extraction vs Filtrationa
entry
workup method
time (min)
yieldb (%)
syn/antic
extractiond
5
98
75/25
filtratione
5
70
83/17
extractiond
120
96
92/8
e
filtration
120
65
96/4
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.
1
2
3
4
As final evidence for a dynamic thermodynamic mechanism, 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
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 precipitation 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 diastereoselectivity. 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, chlorosubstitution 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
3407
Table 4. Scope of Diastereoselective Mannich-Type Reaction of Thioestersa
entry
R1
R2
R3
product
time (h)
yieldb (%)
syn/antic
1d
4-ClC6H4
Ph
Boc
3a
2
93
92/8
2d,e,f
4-ClC6H4
Ph
Ts
3b
30
88
92/8
g
3
4-MeOC6H4
4-ClC6H4
CO2Et
3c
4
65
75/25h
4d
4-CF3C6H4
Ph
Boc
3d
2
88
92/8
5d
4-NO2C6H4
Ph
Boc
3e
72
90
94/6
6d
Ph
Ph
Boc
3f
2
87
89/11
d,i
7
Ph
Ph
Ts
3g
4
78
92/8
8d
4-MeOC6H4
Ph
Boc
3h
2
94
19/1
9g
2-ClC6H4
Ph
Boc
3i
2
quant
33/67
10g
1-Naphtyl
Ph
Boc
3j
2
98
40/60
d
11
2-Thienyl
Ph
Boc
3k
17
94
22/78
12g
Cl
Ph
Boc
3l
2
39
55/45h
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 Synstereochemistry of other products was assigned if they demonstrated strong 1H NMR spectral correlations with 3f.
Scheme 3. Determination of Relative Stereochemistry
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-Bocimine 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-
Scheme 4. Enantioselective Mannich Reaction of a Thioester
ingly, this reaction (performed at -45 °C) was modestly antiselective, 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.
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 β-amino acids. These syn-selective direct Mannichtype 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 Mannich reactions.
Acknowledgment. This study was supported by The
Skaggs Institute for Chemical Biology.
Supporting Information Available: Experimental procedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL801207X
(7) The major product was found to have the syn relative stereochemistry
as determined by 1H 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
Supporting Information
Organocatalytic Mannich-type Reactions of Trifluoroethyl Thioesters
Naoto Utsumi, Shinji Kitagaki, Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and
Molecular Biology, The Scripps Reserach Institute, 10550 North Torrey Pines Road, La
Jolla, California 92037
General: For thin layer chromatography (TLC), silica gel plates VWR GL60 F254 were used and
compounds were visualized by irradiation with UV light and/or by treatment with a solution of
phosphomolybdic acid (25 g), Ce(SO4 )2・H2O (10 g), and conc. H2SO4 (60 mL) in H2O (940 mL)
followed by heating or treatment with a solution of KMnO4 (1.5 g), K2CO3 (10g), and 10% NaOH
(1.25 mL) in H2O (200 mL). Flash column chromatography was performed using Bodman silica gel
32-63, 60 Å. 1H NMR and
13
C NMR spectra were recorded on INOVA-400, AV-400, DRX-500 or
DRX-600. Proton chemical shifts are given in δ value to tetramethylsilane (δ 0.00 ppm) in CDCl3.
Carbon chemical shifts were internally referenced to the deuterated solvent signals in CDCl3 (δ
77.00 ppm). High-resolution mass spectra were recorded on an Agilent ESI-TOF mass spectrometer.
Enantiomeric excesses were determined by chiral-phase HPLC using a Hitachi instrument.
THIOESTER PREPARATION
General procedure for the preparation of thioester. To a solution of carboxylic acid (5 mmol) in
CH2Cl2 (25 mL) was added HOBt (5.25 mmol) at 0 °C, and the resulting solution was stirred for 10
min at that temperature. EDC·HCl (5.25 mmol) was added at 0 °C and the mixture was stirred for 30
min at that temperature. Finally, 2,2,2-trifluoroethanethiol was added at 0 °C, and the mixture was
allowed to warm to room temperature. After being stirred overnight, the reaction mixture was diluted
with CH2Cl2 and water was added. Aqueous layer was extracted with CH2Cl2, and the extract was
washed with water and brine, dried over Na2SO4, and concentrated in vacuo. Chromatography
(hexane/EtOAc = 4/1) gave thioester.
1 / 53
S-2,2,2-Trifluoroethyl 4-chlorophenylthioacetate (1a).
1
3.57 (q, J = 9.8 Hz, 2H, CH2CF3), 3.87 (s,
H NMR (500 MHz, CDCl3):
2H, CH2C=O), 7.20-7.24 (m, 2H, ArH), 7.31-7.35 (m, 2H, ArH).
NMR (150 MHz, CDCl3):
Cl
O
13
C
F3C
30.8 (q, J = 34.3 Hz), 49.2, 124.5 (q, J =
S
275.8 Hz), 129.0, 130.7, 131.0, 133.9, 193.3. HRMS: calcd. for C10H8ClF3OS ([M-H]-) 266.9864,
found 266.9861.
S-2,2,2-Trifluoroethyl 4-trifluoromethylphenylthioacetate (1b).
1
H NMR (500 MHz, CDCl3): 3.58 (q, J = 10.0 Hz, 2H, CH2CF3), 3.95
CF3
O
(s, 2H, CH2C=O), 7.39 (d, J = 8.0 Hz, 2H, ArH), 7.60 (d, J = 8.0 Hz, 2H,
S
F3C
ArH). 13C NMR (125 MHz, CDCl3): 30.9 (q, J = 34.5 Hz), 49.5, 124.0
(q, J = 272.0 Hz), 124.6 (q, J = 275.7 Hz), 125.7 (q, J = 3.8 Hz), 129.9, 130.2 (q, J = 32.6 Hz), 136.4,
192.7. GCMS: 302 (M+).
S-2,2,2-Trifluoroethyl 4-nitrophenylthioacetate (1c).
1
H NMR (500 MHz, CDCl3): 3.63 (q, J = 10.0 Hz, 2H, CH2CF3), 4.07
(s, 2H, CH2C=O), 7.48 (d, J = 8.5 Hz, 2H, ArH), 8.17 (d, J = 8.5 Hz,
2H, ArH). 13C NMR (125 MHz, CDCl3):
30.5 (q, J = 34.3 Hz), 48.9,
NO2
O
F3C
S
123.6, 124.4 (q, J = 275.8 Hz), 130.3, 139.7, 147.2, 192.0. HRMS: calcd for C10H8F3NO3S [(M-H)-]
278.0104, found 278.0099.
S-2,2,2-Trifluoroethyl phenylthioacetate (1d).
1
H NMR (400 MHz, CDCl3):
3.54 (q, J = 9.9 Hz, 2H, CH2CF3), 3.88 (s,
2H, CH2C=O), 7.25-7.37 (m, 5H, ArH).
O
13
C NMR (100 MHz, CDCl3):
F3C
S
30.8 (q, J = 34.1 Hz), 50.0, 124.6 (q, J = 275.8 Hz), 127.8, 128.8, 129.6,
132.4, 193.7. HRMS: calcd. for C10H9F3OS (MH+) 235.0399, found 235.0390.
S-2,2,2-Trifluoroethyl 4-methoxyphenylthioacetate (1e).
1
H NMR (500 MHz, CDCl3):
3.52 (q, J = 10.0 Hz, 2H, CH2CF3),
7.15-7.18 (m, 2H, ArH). 13C NMR (125 MHz, CDCl3):
30.7 (q, J =
OCH3
O
3.76 (s, 3H, CH3), 3.79 (s, 2H, CH2C=O), 6.85-6.88 (m, 2H, ArH),
F3C
S
34.1 Hz), 49.0, 55.0, 114.1, 124.2, 124.7 (q, J = 275.7 Hz), 130.8, 159.3, 194.2. HRMS: calcd for
C11H11F3O2S (MH+) 265.0505, found 265.0510.
S-2,2,2-Trifluoroethyl 2-chlorophenylthioacetate (1f).
1
H NMR (500 MHz, CDCl3):
3.54 (q, J = 10.0 Hz, 2H, CH2CF3), 4.00 (s,
O
F3C
S
Cl
2 / 53
2H, CH2C=O), 7.20-7.28 (m, 3H, ArH), 7.35-7.37 (m, 1H, ArH). 13C NMR (125 MHz, CDCl3):
30.6 (q, J = 34.2 Hz), 47.5, 124.6 (q, J = 275.8 Hz), 127.0, 129.4, 129.6, 130.7, 131.9, 134.8, 192.7.
HRMS: calcd for C10H8ClF3OS (MH+) 269.0009, found 269.0012.
S-2,2,2-Trifluoroethyl 1-naphthylthioacetate (1g).
1
H NMR (500 MHz, CDCl3):
3.41 (q, J = 10.0 Hz, 2H, CH2CF3), 4.20 (s,
13
2H, CH2C=O), 7.31-7.47 (m, 4H, ArH), 7.74-7.82 (m, 3H, ArH). C NMR
O
F3C
S
(125 MHz, CDCl3): 30.6 (q, J = 34.1 Hz), 47.6, 123.4, 124.6 (q, J = 275.8
Hz), 125.3, 126.0, 126.7, 128.7, 128.8, 128.9, 129.0, 132.0, 133.8, 194.0. HRMS: calcd for
C14H11F3OS (MH+) 285.0555, found 285.0555.
S-2,2,2-Trifluoroethyl 2-thienylthioacetate (1h).
1
H NMR (500 MHz, CDCl3):
3.53 (q, J = 10.0 Hz, 2H, CH2CF3), 4.04 (s,
O
2H, CH2C=O), 6.95-6.97 (m, 2H, ArH), 7.22-7.24 (m, 1H, ArH). 13C NMR F3C
S
S
(125 MHz, CDCl3): 30.7 (q, J = 34.2 Hz), 43.4, 124.6 (q, J = 275.8 Hz), 126.0, 127.1, 128.2, 133.0,
192.8. HRMS: calcd for C8H7F3OS2 (MH+) 240.9963, found 240.9966.
S-2,2,2-Trifluoroethyl 2-thienylthioacetate (1i).
O
1
H NMR (400 MHz, CDCl3): 3.65 (q, J = 9.8 Hz, 2H, CH2CF3), 4.28 (s, 2H,
CH2C=O). 13C NMR (125 MHz, CDCl3): 31.1 (q, J = 34.5 Hz), 41.7, 124.4
F3C
S
Cl
(q, J = 276.0 Hz), 191.4.
DIASTEREOSELECTIVE MANNICH REACTION OF THIOESTERS
General Procedure for the Diastereoselective Mannich Reaction of Thioesters:
To a cooled solution of thioester (0.1 mmol) in toluene (0.5 M) at 0 oC, was added imine (0.12
mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.01 mmol). After stirring at 4 oC for
2-72 h, brine was added and extracted with EtOAc (3 times). Organic layers were combined, washed
with brine, dried by Na2SO4, concentrated in vacuo and purified by flash chromatography
(hexane/EtOAc mixture ) to afford Mannich reaction product.
S-2,2,2-Trifluoroethyl
3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-3-phenylpropanethioate (3a).
Major diastereomer (syn): 1H NMR (500 MHz, CDCl3):
1.26 (s, 9H,
C(CH3)3), 3.31-3.47 (m, 2H, CH2CF3), 4.13-4.29 (m, 1H, CHC=O), F C
3
4.65-4.85 (m, 1H, NH), 6.26-6.46 (m, 1H, CHNH), 7.23-7.36 (m, 9H,
3 / 53
O HN
S
Cl
Boc
ArH). 13C NMR (150 MHz, CDCl3):
28.1, 30.7 (q, J = 34.5 Hz), 56.6, 65.4, 80.0, 124.3 (q, J =
276.1 Hz), 127.1, 128.1 128.7, 128.9, 130.5, 132.4, 134.5, 139.3, 154.5, 193.9. HRMS: calcd for
C22H23ClF3NO3S (MH+) 474.1118, found 474.1114.
Minor diastereomer (anti): 1H NMR (400 MHz, CDCl3): 1.35 (s, 9H, C(CH3)3), 3.40-3.60 (m, 2H,
CH2CF3), 4.20-4.40 (m, 1H, CHC=O), 5.15-5.30 (m, 1H, NH), 5.40-5.70
O HN
(m, 1H, CHNH), 7.20-7.40 (m, 9H, ArH). 13C NMR (150 MHz, CDCl3):
F3C
Boc
S
28.2, 30.9 (q, J = 34.5 Hz), 57.6, 64.2, 80.0, 124.4 (q, J = 275.9 Hz), 126.6,
127.7, 128.6, 129.0, 130.0, 132.6, 134.3, 139.2, 154.8, 193.9. HRMS:
calcd for C22H23ClF3NO3S (MH+) 474.1118, found 474.1106.
Cl
S-2,2,2-trifluoroethyl
2-(4-chlorophenyl)-3-(4-methylphenylsulfonamido)-3-phenylpropanethioate (3b).
Major diastereomer (syn): 1H NMR (600 MHz, CDCl3):
2.38 (s, 3H, CH3),
3.23-3.38 (m, 2H, CH2CF3), 4.04 (d, J = 10.0 Hz, 1H, CHC=O), 4.72 (d, J =
O HN
F3C
Ts
S
6.8 Hz, 1H, NH), 4.91 (dd, J = 6.8, 10.0 Hz, 1H, CHNH), 7.06 (d, J = 8.1 Hz,
2H, ArH), 7.08-7.24 (m, 9H, ArH), 7.29 (d, J = .8.1 Hz, 2H, ArH). 13C NMR
(150 MHz, CDCl3):
Cl
21.5, 30.7 (q, J = 34.5 Hz), 59.8, 66.5, 124.1 (q, J =
276.0 Hz), 127.0, 127.5, 128.2, 128.5, 129.3, 129.3, 130.1, 131.4, 135.1, 136.6, 137.5, 143.3, 193.5.
HRMS: calcd for C24H21ClF3NO3S2 (MH+) 528.0676, found 528.0680.
Ethyl
3-(4-chlorophenyl)-2-(4-methoxyphenylamino)-4-oxo-4-(2,2,2-trifluoroethylthio)butanoate (3c).
1
H NMR (400 MHz, CDCl3): major/minor = 3/1: *denotes minor isomer,
OMe
0.95 (t, J = 7.1 Hz, 3H x 3/4, CH2CH3), 1.21 (t, J = 7.1 Hz, 3H* x 1/4,
CH2CH3), 3.45-3.70 (m, 2H, CH2CF3 and 1H* x 1/4), 3.73 (s, 3H* x 1/4,
O HN
F3C
CO2 Et
S
OCH3), 3.73 (s, 3H x 3/4, OCH3), 3.92 (q, J = 7.1 Hz, 2H x 3/4, CH2CH3),
4.01 (br. s, 1H x 3/4), 41.5 (q, J = 7.1 Hz, 2H* x 1/4, CH2CH3), 4.18 (d, J =
Cl
8.6 Hz, 1H x 3/4), 4.33 (d, J = 6.8 Hz, 1H* x 1/4), 4.56 (br. d, J = 8.6 Hz,
1H x 3/4), 4.70 (br. d, J = 6.8 Hz, 1H* x 1/4), 6.62-6.78 (m, 4H, ArH), 7.24-7.37 (m, 4H, ArH).
NMR (150 MHz, CDCl3): major/minor = 3/1, *denotes minor isomer,
13
C
13.8, 14.1*, 31.0 (q, J =
34.3 Hz), 31.0* (q, J = 34.4 Hz), 55.6, 55.6*, 60.7*, 61.3*, 61.4, 61.9*, 62.1, 62.3, 114.7*, 114.7,
116.6*, 116.8, 124.4 (q, J = 276.0 Hz), 124.4 (q, J = 276.0 Hz), 129.0, 129.1*, 130.5, 131.0*, 131.4*,
131.5, 134.9, 135.0*, 140.1*, 140.1, 153.5*, 153.7, 171.7, 171.7*, 194.1, 194.5*. HRMS: calcd for
C21H21ClF3NO4S (MH+) 476.0905, found 476.0910.
S-2,2,2-Trifluoroethyl
4 / 53
3-(tert-butoxycarbonylamino)-2-(4-trifluoromethylphenyl)-3-phenylpropanethioate (3d).
Major diastereomer (syn): 1H NMR (500 MHz, CDCl3):
1.31 (s, 9H,
O HN
C(CH3)3), 3.30-3.50 (m, 2H, CH2CF3), 4.39 (br. s, 1H, CHC=O), 4.82 (br. s,
1H, NH), 5.50 (br. s, 1H, CHNH), 6.85-6.90 (m, 2H, ArH), 7.24-7.40 (m, 5H,
ArH), 7.52 (d, J = 8.2 Hz, 2H, ArH), 7.61 (d, J = 8.2 Hz, 2H, ArH).
NMR (150 MHz, CDCl3):
F3C
Boc
S
13
C
28.0, 30.8 (q, J = 34.5 Hz), 55.8, 65.9, 80.1,
CF3
123.9 (q, J = 272.1 Hz), 124.2 (q, J = 276.0), 125.6, 127.1, 128.2, 128.8,
129.6, 130.6 (q, J = 130.6 Hz), 137.9, 139.1, 154.3, 193.6. HRMS: calcd for C23H23F6NO3S (MH+)
508.1376, found 508.1375.
S-2,2,2-Trifluoroethyl
3-(tert-butoxycarbonylamino)-2-(4-nitrolphenyl)-3-phenylpropanethioate (3e).
Major diastereomer (syn): 1H NMR (600 MHz, CDCl3):
1.24 (s, 9H,
O
C(CH3)3), 3.30-3.50 (m, 2H, CH2CF3), 4.43 (br. s, 1H, CHC=O), 4.86 (br. s,
1H, NH), 5.42 (br. s, 1H, CHNH), 7.20-7.40 (m, 5H, ArH), 7.60 (d, J = 8.6
Hz, 2H, ArH), 8.20 (d, J = 8.6 Hz, 2H, ArH).
CDCl3):
F3C
HN
Boc
S
13
C NMR (150 MHz,
28.0, 30.8 (q, J = 34.5 Hz), 57.0, 65.6, 80.2, 124.1 (q, J = 276.0
NO2
Hz), 123.7, 127.1, 128.4, 128.9, 130.1, 138.6, 141.3, 147.8, 154.4, 193.3.
HRMS: calcd for C22H23F3N2O5S (MNa+) 507.1172, found 507.1171.
S-2,2,2-Trifluoroethyl 3-(tert-butoxycarbonylamino)-2,3-diphenylpropanethioate (3f).
Major diastereomer (syn): 1H NMR (500 MHz, CDCl3):
1.24 (s, 9H,
C(CH3)3), 3.28-3.48 (m, 2H, CH2CF3), 4.20 (br. s, 1H, CHC=O), 4.80 (d, J
= 8.6 Hz, 1H, NH), 5.40 (br. s, 1H, CHNH), 7.22-7.38 (m, 9H, ArH).
NMR (125 MHz, CDCl3):
13
C
O HN
F3C
Boc
S
28.1, 30.7 (q, J = 34.4 Hz), 56.6, 66.2, 79.8,
124.3 (q, J = 275.8 Hz), 127.1, 127.9, 128.4, 128.6, 128.8, 129.1, 133.8,
139.8, 154.5, 194.1. HRMS: calcd for C22H24F3NO3S (MNa+) 440.1502, found 440.1494.
S-2,2,2-trifluoroethyl 3-(4-methylphenylsulfonamido)-2,3-diphenylpropanethioate (3g).
Major diastereomer (syn): 1H NMR (600 MHz, CDCl3):
2.36 (s, 3H,
O HN
CH3), 3.20-3.40 (m, 2H, CH2CF3), 4.04 (d, J = 10.0 Hz, 1H, CHC=O),
4.74 (d, J = 5.3 Hz, 1H, NH), 4.92 (dd, J = 5.3, 10.0 Hz, 1H, CHNH),
F3C
Ts
S
6.90-7.40 (m, 14H, ArH). 13C NMR (150 MHz, CDCl3): 21.5, 30.7 (q, J
= 34.5 Hz), 59.6, 66.4, 124.1 (q, J = 276.0 Hz), 127.2, 127.7, 128.1, 128.3,
128.9, 129.0, 129.2, 129.3, 132.6, 136.4, 137.4, 143.1, 193.7. HRMS: calcd for C24H22F3NO3S2
(MH+) 494.1066, found 494.1063.
5 / 53
S-2,2,2-Trifluoroethyl
3-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)-3-phenylpropanethioate (3h).
Major diastereomer (syn): 1H NMR (500 MHz, CDCl3):
1.26 (s, 9H,
O HN
C(CH3)3), 3.29-3.48 (m, 2H, CH2CF3), 3.80 (s, 3H, CH3), 4.13 (br. s, 1H,
CHC=O), 4.78 (br. s, 1H, NH), 5.34 (br. s, 1H, CHNH), 6.85-6.90 (m, 2H,
ArH), 7.22-7.35 (m, 7H, ArH). 13C NMR (150 MHz, CDCl3):
F3C
Boc
S
28.1, 30.7
(q, J = 34.4 Hz), 55.3, 56.5, 65.3, 79.8, 114.2, 124.4 (q, J = 276.0 Hz),
OMe
125.7, 127.1, 127.8, 128.5, 130.3, 139.9, 154.6, 159.7, 194.3. HRMS:
calcd for C23H26F3NO4S (MH+) 470.1607, found 470.1607.
S-2,2,2-Trifluoroethyl
3-(tert-butoxycarbonylamino)-2-(2-chlorophenyl)-3-phenylpropanethioate (3i).
1
H NMR (500 MHz, CDCl3): syn/anti = 1/2: *denotes syn isomer,
1.20 (s,
O HN
9H* x 1/3, C(CH3)3), 1.31 (s, 9H x 2/3, C(CH3)3), 3.30-3.45 (m, 2H* x 1/3,
CH2CF3), 3.45-3.60 (m, 2H x 2/3, CH2CF3), 4.85 (br. s, 1H* x 1/3), 4.96 (br.
F3C
Boc
S
Cl
d, J = 11.1 Hz, 1H* x 1/3), 5.02 (br. d, J = 4.3 Hz, 1H x 2/3), 5.34 (br. s, 1H
x 2/3), 5.48 (br. s, 1H* x 1/3), 5.79 (br. s, 1H x 2/3), 7.18-7.46 (m, 9H, ArH).
13
C NMR (150 MHz, CDCl3): syn/anti = 1/2, *denotes syn isomer,
28.0*, 28.2, 30.6*, 30.8, 56.1,
56.5*, 60.2, 60.9*, 79.7, 124.3* (q, J = 276.0 Hz), 124.3 (q, J = 276.0 Hz), 126.4, 127.0*, 127.1,
127.4*, 127.6, 128.1, 128.5, 128.7, 129.2*, 129.4, 129.4*, 129.5*, 129.7*, 130.0*, 131.8*, 131.9,
134.2, 134.8*, 139.5, 139.7*, 154.3, 154.8*, 193.5, 195.5*. HRMS: calcd for C22H23ClF3NO3S
(MNa+) 496.0931, found 496.0931.
S-2,2,2-Trifluoroethyl
3-(tert-butoxycarbonylamino)-2-(1-naphthyl)-3-phenylpropanethioate
(3j).
1
H NMR (600 MHz, CDCl3): syn/anti = 2/3: *denotes syn isomer,
1.17 (s,
9H* x 2/5, C(CH3)3), 1.31 (s, 9H x 3/5, C(CH3)3), 3.28-3.45 (m, 2H* x 2/5,
CH2CF3), 3.45-3.58 (m, 2H x 3/5, CH2CF3), 4.85 (br. s, 1H* x 2/5), 5.20 (br. s,
O HN
F3C
S
Boc
Ph
1H* x 2/5), 5.29 (br. d, J = 5.6 Hz, 1H x 3/5), 5.44 (br. s, 1H x 3/5, NH), 5.61
(br. s, 1H* x 2/5), 5.86 (br. s, 1H x 3/5), 7.15-7.65 (m, 9H, ArH), 7.75-7.92 (m,
2H, ArH), .8.05-8.18 (m, 1H, ArH).
13
both syn and anti isomers were shown,
C NMR (150 MHz, CDCl3): syn/anti = 2/3, signals due to
28.0, 28.2, 30.7, 30.8, 56.8, 57.5, 59.2, 60.1, 79.6, 121.9,
122.3, 124.3 (q, J = 276.0 Hz), 124.4 (q, J = 275.9 Hz), 125.1, 125.5, 125.8, 125.9, 126.4, 126.5,
127.0, 127.0, 127.3, 127.5, 127.9, 128.5, 128.5, 129.0, 129.0, 129.3, 129.4, 129.6, 129.7, 131.2,
132.0, 134.0, 134.1, 13.9.8, 140.0, 154.6, 154.9, 194.3, 196.0. HRMS: calcd for C26H26F3NO3S
6 / 53
(MNa+) 490.1658, found 490.1660.
S-2,2,2-trifluoroethyl 3-(tert-butoxycarbonylamino)-3-phenyl-2-(thiophen-2-yl)propanethioate
(3k).
1
H NMR (600 MHz, CDCl3): syn/anti = 1/2: *denotes syn isomer,
1.33 (s,
O HN
9H* x 1/3, C(CH3)3), 1.39 (s, 9H x 2/3, C(CH3)3), 3.38-3.48 (m, 2H* x 1/3,
F3C
CH2CF3), 3.44-3.62 (m, 2H x 2/3, CH2CF3), 4.52 (br. s, 1H* x 1/3), 4.61 (br. s,
S
Boc
Ph
S
1H x 2/3), 5.02 (br. s, 1H* x 1/3), 5.29 (br. s, 1H x 2/3), 5.32 (br. s, 1H* x 1/3),
5.77 (br. s, 1H x 2/3), 6.90-7.00 (m, 2H, ArH), 7.18-7.34 (m, 6H, ArH).
13
C NMR (150 MHz,
CDCl3): major isomer (anti), 28.3, 31.0 (q, J = 34.5 Hz), 57.9, 59.6, 80.0, 124.33 (q, J = 276.0 Hz),
126.3, 126.5, 127.6, 127.8, 128.5, 128.6, 135.5, 139.1, 154.9, 195.2.
HRMS: calcd for
+
C20H22F3NO3S2 (MH ) 446.1066, found 446.1066.
S-2,2,2-Trifluoroethyl 3-(tert-butoxycarbonylamino)-2-chloro-3-phenylpropanethioate (3l).
1
H NMR (500 MHz, CDCl3): major/minor = 6/5: *denotes minor isomer,
1.42 (s, 9H* x 5/11, C(CH3)3), 1.44 (s, 9H x 6/11, C(CH3)3), 3.42-3.55 (m,
2H x 6/11,, CH2CF3), 3.55-3.70 (m, 2H* x 5/11, CH2CF3), 4.83 (br. s, 1H* x
O HN
F3C
Boc
S
Cl
5/11), 5.02 (br. s, 1H* x 5/11), 5.42 (br. s, 1H* x 5/11 and 2H x 6/11), 5.57
(br. s, 1H* x 5/11), 7.24-7.40 (m, 5H, ArH).
peaks of mixture of diastereomer were shown,
13
C NMR (150 MHz, CDCl3): major/minor = 6/5, all
28.2, 28.3, 31.4 (q, J = 34.4 Hz), 31.8 (q, J = 34.3
Hz), 56.5, 57.2, 67.0, 69.3, 80.5, 80.5, 124.3 (q, J = 276.2 hz), 124.4 (q, J = 276.2 Hz), 126.6, 127.5,
128.3, 128.6, 128.7, 128.7, 135.6, 137.3, 154.5, 154.7, 193.1, 193.1. HRMS: calcd for
C16H19ClF3NO3S (MNa+) 420.0618, found 420.0615.
DETERMINATION OF RELATIVE STEREOCHEMISTRY
O HN
F3C
S
Boc
Ph
2) CF3CO2H, CH2Cl2, 20 min
Ph
3f
NH2
1) LiAlH4, THF, 0 oC, 30min
HO
Ph
Ph
4
dr = 12/1
syn diastereomer
59% yield
Relative stereochemistry of the Mannich product 3f was determined as follows. Mannich product of
phenylthioacetate
3f
(dr
=
12/1)
was
converted
to
known
aminoalcohol,
3-amino-2,3-diphenylpropan-1-ol, via LAH reduction and subsequent Boc removal. Major Mannich
7 / 53
adduct was found to be syn compound by analysis of coupling constants of 1H NMR [(1) Fodor, G.;
Reavill, R. E.; Stefanovsky, J.; Kurtev, B. Tetrahedron, 1966, 22, 235. (2) Kunz, H.; Burgard, A.;
Schanzenbach, D. Angew. Chem. Int. Ed. Engl. 1997, 36, 386.]. The relative stereochemistry of the
other Mannich products having very strong 1H NMR spectra correlation with 3f was also determined
by the analogy of 3f.
ENANTIOSELECTIVE THIOESTER MANNICH REACTION
A mixture of thioester 1a (0.1 mmol) and tert-butyl phenyl(phenylsulfonyl)methylcarbamate (2b)
(0.1 mmol) in toluene (1 mL) was cooled to -45 oC, and added (8S,9R)-(−)-N-benzylcinchonidium
chloride (5) (0.01 mmol) and powdered KOH (5 equiv). After stirring for 6 h at -45 oC, the reaction
mixture was quenched with 5% aq. NaHCO3 and extracted with CH2Cl2 for three times. Organic
layers were combined, dried by Na2SO4 and evaporated. The residue was purified by flash
chromatography to afford Mannich adduct 3a as a colorless solid (79% yield, syn/anti = 18/82). The
ee was determined by HPLC analysis. (Daicel Chiralpak AD, hexane/iPrOH = 90/10, flow rate 1.0
mL/min,
= 254 nm): tR (anti major enantiomer) = 33.8 min, tR (anti minor enantiomer) = 8.1 min,
tR (syn major enantiomer) = 12.2 min, tR (syn minor enantiomer) = 16.1 min. 45% ee for anti.
8 / 53
0.000000
1.537
3.598
3.578
3.559
3.539
3.870
7.259
7.226
7.222
7.217
7.208
7.204
7.345
7.340
7.336
7.327
7.323
nu3-211-1
Date:
1 Feb 2008
Document's Title:
nu3-211-1
Spectrum Title:
O
F3C
Cl
S
1a
2.24
2.03
2.07
2.03
10.0
ppm (t1)
Frequency (MHz):
(f 1) 500.133
Original Points Count:
(f 1) 16384
Actual Points Count:
(f 1) 32768
Acquisition Time (sec):
(f 1) 2.7263
Spectral Width (ppm):
(f 1) 12.016
Pulse Program:
ZG30
Temperature:
299.16
Number of Scans:
8
Acq. Date:
Tue Nov 13 05:49:20 PM
5.0
0.0
9 / 53
Date:
1 Feb 2008
Document's Title:
nu3-211-1
31.1
30.9
30.7
30.5
49.2
77.2
77.0
76.8
121.8
123.6
125.4
127.2
129.0
131.0
130.7
133.9
193.3
nu3-211-1
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O
F3C
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
289
Number of Scans:
22
Acq. Date:
Thu Jan 31 10:20:43 AM
Cl
S
1a
200
150
100
50
ppm (t1)
10 / 53
0
3.574
3.554
3.534
3.514
4.003
7.277
7.272
7.269
7.264
7.258
7.251
7.246
7.236
7.230
7.224
7.216
7.212
7.201
7.372
7.368
7.360
7.357
7.354
Date:
4 Mar 2008
Document's Title:
da158H
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
8
Acq. Date:
Tue Jan 29 06:02:27 PM
O
F3C
S
Cl
1b
7.0
6.0
5.0
4.0
2.08
8.0
2.09
3.03
1.00
9.0
3.0
2.0
ppm (t1)
11 / 53
1.0
0.0
30.969
30.698
30.425
30.154
47.472
77.255
77.000
76.745
121.318
123.511
125.704
127.896
127.038
129.590
129.443
130.735
134.799
131.938
192.678
Date:
4 Mar 2008
Document's Title:
da158C
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
299.16
Number of Scans:
160
Acq. Date:
Tue Jan 29 06:00:11 PM
O
F3C
S
Cl
1b
200
150
100
50
ppm (t1)
12 / 53
0
0.0000000
3.606
3.586
3.566
3.547
3.952
7.612
7.596
7.402
7.386
Date:
4 Mar 2008
Document's Title:
da159H
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
CF3
O
F3C
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
299.16
Number of Scans:
8
Acq. Date:
Mon Jan 28 06:08:34 PM
S
1c
8.0
7.0
6.0
5.0
4.0
2.03
9.0
2.07
1.99
2.00
10.0
ppm (t1)
3.0
2.0
13 / 53
1.0
0.0
31.278
31.004
30.730
30.457
49.489
121.271
120.766
77.255
77.000
76.746
123.464
122.929
125.763
125.733
125.704
125.657
125.093
127.848
127.255
136.409
130.563
130.303
130.044
129.946
129.785
192.675
Date:
4 Mar 2008
Document's Title:
da159C
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
O
F3C
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
299.16
Number of Scans:
200
Acq. Date:
Mon Jan 28 06:06:44 PM
CF3
S
1c
200
ppm (t1)
150
100
50
14 / 53
0
3.660
3.640
3.620
3.601
4.069
7.492
7.475
8.176
8.173
8.159
8.154
Date:
4 Mar 2008
Document's Title:
sk044H
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
NO2
O
F 3C
S
1d
7.0
6.0
5.0
4.0
2.00
8.0
2.02
9.0
2.00
1.98
10.0
ppm (t1)
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
299.16
Number of Scans:
8
Acq. Date:
Thu Jan 31 10:41:12 AM
3.0
2.0
15 / 53
1.0
0.0
30.944
30.671
30.398
30.126
48.927
77.255
77.000
76.744
121.105
123.568
123.300
125.492
127.685
130.329
139.728
147.239
192.038
Date:
4 Mar 2008
Document's Title:
SK044C
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
O
F 3C
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
299.16
Number of Scans:
120
Acq. Date:
Thu Jan 31 10:39:03 AM
NO2
S
1d
200
ppm (t1)
150
100
50
16 / 53
0
0.0000000
3.580
3.555
3.531
3.506
3.883
7.279
7.274
7.269
7.264
7.259
7.255
7.229
7.370
7.364
7.354
7.351
7.348
7.344
7.342
7.334
7.330
7.328
7.324
7.319
7.314
7.308
nu3-250-1
Date:
1 Feb 2008
Document's Title:
nu3-250-1
Spectrum Title:
H-1 Routine 1D experiment. BBO Probe, 9-13-2007
Frequency (MHz):
(f1) 400.122
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.4166
Spectral Width (ppm):
(f1) 11.985
Pulse Program:
ZG30
Temperature:
297.6
Number of Scans:
16
Acq. Date:
Wed Dec 05 04:32:38 PM
O
F3C
S
1e
1.99
2.00
4.77
10.0
ppm (t1)
5.0
0.0
17 / 53
Date:
1 Feb 2008
Document's Title:
nu3-250-1
31.3
31.0
30.6
30.3
50.0
77.3
77.0
76.7
123.3
120.5
126.0
127.8
128.8
132.4
129.6
193.7
nu3-250-1
Spectrum Title:
C-13 Routine 1D experiment. BBO Probe, 9-13-2007
Frequency (MHz):
(f 1) 100.620
Original Points Count:
(f 1) 16384
Actual Points Count:
(f 1) 32768
Acquisition Time (sec):
(f 1) 0.6816
Spectral Width (ppm):
(f 1) 238.903
Pulse Program:
ZGPG30
Temperature:
298.8
Number of Scans:
122
Acq. Date:
Tue Dec 11 08:14:04 PM
O
F3C
S
1e
200
ppm (f1)
150
100
50
18 / 53
0
3.546
3.526
3.506
3.486
3.794
3.759
6.876
6.870
6.866
6.857
6.853
6.847
7.179
7.173
7.169
7.160
7.156
7.150
Date:
4 Mar 2008
Document's Title:
da157H
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
O
F3C
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
299.16
Number of Scans:
8
Acq. Date:
Mon Jan 28 05:49:35 PM
OCH3
S
1f
9.0
8.0
7.0
2.06
5.19
2.00
2.00
10.0
ppm (t1)
6.0
5.0
4.0
3.0
2.0
19 / 53
1.0
0.0
31.076
30.805
30.534
30.263
48.997
55.036
77.254
77.000
76.745
114.145
121.365
124.234
123.557
125.750
127.942
130.780
159.262
194.186
Date:
4 Mar 2008
Document's Title:
da157C
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
O
F3C
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
299.16
Number of Scans:
200
Acq. Date:
Mon Jan 28 05:44:20 PM
OCH3
S
1f
200
150
100
50
ppm (t1)
20 / 53
0
4.195
3.444
3.424
3.404
3.384
7.473
7.471
7.460
7.457
7.454
7.443
7.440
7.431
7.428
7.415
7.413
7.401
7.399
7.367
7.353
7.337
7.328
7.325
7.314
7.311
7.805
7.787
7.771
7.769
7.753
7.737
Date:
4 Mar 2008
Document's Title:
da155H
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
299.16
Number of Scans:
8
Acq. Date:
Thu Jan 31 10:26:07 AM
O
F3C
S
1g
8.0
7.0
6.0
5.0
4.0
2.00
9.0
1.98
1.92
2.00
3.00
10.0
ppm (t1)
3.0
2.0
21 / 53
1.0
0.0
-1.0
31.008
30.737
30.465
30.195
47.645
77.254
77.000
76.746
121.339
123.531
123.403
126.660
125.986
125.725
125.345
131.976
129.008
128.864
128.784
128.700
127.918
133.778
193.954
Date:
4 Mar 2008
Document's Title:
da155C
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
299.16
Number of Scans:
120
Acq. Date:
Thu Jan 31 10:24:04 AM
O
F3C
S
1g
200
ppm (t1)
150
100
50
22 / 53
0
4.035
3.560
3.540
3.520
3.501
6.968
6.961
6.957
6.952
7.235
7.231
7.227
7.223
Date:
4 Mar 2008
Document's Title:
da156H
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
8
Acq. Date:
Tue Jan 29 05:44:27 PM
O
F3C
S
S
1h
8.0
7.0
6.0
5.0
4.0
2.19
9.0
2.21
2.07
1.00
10.0
ppm (t1)
3.0
2.0
23 / 53
1.0
0.0
43.444
31.081
30.810
30.537
30.265
77.255
77.000
76.746
121.271
123.465
126.024
125.658
128.228
127.851
127.103
132.977
192.824
Date:
4 Mar 2008
Document's Title:
da156C
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
299.16
Number of Scans:
160
Acq. Date:
Tue Jan 29 05:41:46 PM
O
F3C
200
ppm (t1)
S
1h
S
150
100
50
24 / 53
0
0.0000000
3.686
3.662
3.637
3.613
4.282
nu3-299-1
O
F3C
Cl
S
Date:
7 Mar 2008
Document's Title:
nu3-299-1
Spectrum Title:
H-1 Routine 1D experiment. BBO Probe, 9-13-2007
1i
Frequency (MHz):
(f1) 400.122
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.4166
Spectral Width (ppm):
(f1) 11.985
Pulse Program:
ZG30
Temperature:
297.4
Number of Scans:
8
Acq. Date:
Fri Feb 15 04:43:21 PM
2.00
1.93
10.0
ppm (t1)
5.0
0.0
25 / 53
Date:
7 Mar 2008
Document's Title:
nu3-299-1
31.487
31.212
30.938
30.664
47.713
77.254
77.000
76.745
127.707
125.514
123.319
121.125
191.356
nu3-299-1
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
298.16
Number of Scans:
296
Acq. Date:
Fri Feb 15 05:47:32 PM
O
F3C
Cl
S
1i
200
150
100
50
ppm (t1)
26 / 53
0
O
F3C
HN
-0.000000
1.263
1.345
3.420
3.401
3.386
3.367
4.745
4.743
4.741
4.211
4.210
4.206
4.205
4.200
5.359
7.259
7.317
7.306
nu4-15-1
Date:
7 Mar 2008
Document's Title:
nu4-15-1
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
Boc
S
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
16
Acq. Date:
Mon Mar 03 10:40:58 AM
syn-3a
Cl
9.09
0.40
2.10
0.13
1.06
1.00
1.03
0.05
10.36
10.0
ppm (t1)
5.0
0.0
27 / 53
Date:
7 Mar 2008
Document's Title:
nu3-55-4
28.1
56.6
31.1
30.9
30.6
30.4
65.4
77.2
77.0
76.8
123.3
80.0
125.2
127.1
128.9
128.7
128.1
130.5
132.4
134.5
139.3
154.5
193.9
nu3-55-4
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O HN
F3C
Boc
S
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
300
Number of Scans:
256
Acq. Date:
Thu Jun 14 08:12:22 AM
syn-3a
Cl
200
150
100
50
ppm (t1)
28 / 53
0
-0.000000
1.345
3.492
3.530
3.516
3.555
4.307
4.304
4.299
4.296
4.293
5.249
5.553
5.548
5.546
5.544
5.540
7.145
7.188
7.166
7.261
7.242
7.228
7.211
7.315
7.308
nu3-55-2
Date:
13 Feb 2008
Document's Title:
nu3-55-2_01.fid
Spectrum Title:
Std proton
O
F3C
HN
Boc
Frequency (MHz):
(f1) 399.735
Original Points Count:
(f1) 9827
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.0487
Spectral Width (ppm):
(f1) 12.000
Pulse Program:
Unknown
Temperature:
25
S
anti-3a
Cl
Number of Scans:
32
Acq. Date:
Jun 13 2007
9.04
2.12
1.02
1.07
1.00
11.99
10.0
ppm (t1)
5.0
0.0
29 / 53
Date:
13 Feb 2008
Document's Title:
nu3-55-2
28.2
31.3
31.0
30.8
30.6
77.2
77.0
76.8
64.2
57.6
123.5
80.0
125.3
126.6
129.0
128.6
127.7
130.0
132.6
134.3
154.8
139.2
193.9
nu3-55-2
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O
F3C
HN
Boc
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
300
Number of Scans:
256
Acq. Date:
Thu Jun 14 08:33:46 AM
S
anti-3a
Cl
200
150
100
50
ppm (t1)
30 / 53
0
Date:
6 Mar 2008
Document's Title:
nu4-13-2
2.378
3.329
3.313
3.298
3.282
4.044
4.027
4.724
4.713
4.922
4.910
4.905
4.894
7.062
7.049
7.219
7.205
7.194
7.182
7.142
7.128
7.114
7.103
7.297
7.283
7.263
7.262
nu4-13-2
Spectrum Title:
H-1 Routine 1D, DCH CryoProbe, 1-13-2006
O HN
F3C
Ts
Frequency (MHz):
(f1) 600.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.2807
Spectral Width (ppm):
(f1) 11.971
Pulse Program:
ZG30
Temperature:
297
Number of Scans:
32
Acq. Date:
Tue Mar 04 05:14:50 PM
S
syn-3b
Cl
3.02
1.98
1.01
1.00
1.02
2.10
4.21
5.14
7.49
10.0
ppm (t1)
5.0
0.0
31 / 53
Date:
6 Mar 2008
Document's Title:
nu4-13-2
30.827
30.598
21.486
59.806
77.211
77.000
76.788
65.529
123.142
124.971
130.133
129.311
129.255
128.521
128.246
127.458
126.987
131.387
135.051
136.556
137.487
143.313
193.533
nu4-13-2
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O HN
F3C
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
297
Number of Scans:
1024
Acq. Date:
Tue Mar 04 05:18:11 PM
Ts
S
syn-3b
Cl
200
150
100
50
ppm (t1)
32 / 53
0
3.560
3.544
3.535
3.519
1.226
1.214
1.202
0.964
0.952
0.940
3.646
3.637
3.629
3.621
3.605
3.729
3.726
3.927
3.915
4.709
4.698
4.567
4.553
4.333
4.321
4.189
4.175
4.164
4.152
4.140
4.128
6.646
6.641
6.631
6.753
6.739
7.259
7.326
nu4-3-1
Date:
6 Mar 2008
Document's Title:
nu4-3-1
Spectrum Title:
H-1 Routine 1D, DCH CryoProbe, 1-13-2006
OMe
O HN
F3C
S
Frequency (MHz):
(f 1) 600.133
Original Points Count:
(f 1) 16384
Actual Points Count:
(f 1) 32768
Acquisition Time (sec):
(f 1) 2.2807
Spectral Width (ppm):
(f 1) 11.971
Pulse Program:
ZG30
Temperature:
297
Number of Scans:
8
Acq. Date:
Thu Feb 21 11:35:14 AM
CO2Et
3c
Cl
5.0
3.02
1.18
3.20
4.10
2.07
0.93
1.75
0.36
1.00
0.36
5.52
5.86
10.0
ppm (t1)
0.0
33 / 53
55.588
31.369
31.321
31.141
31.093
30.913
30.866
30.685
30.638
13.756
14.070
62.311
62.063
61.855
61.418
61.276
60.758
114.699
114.664
77.212
77.000
76.788
121.712
121.645
116.762
116.593
123.540
123.473
125.368
125.302
127.197
127.130
129.126
129.044
131.532
131.430
131.011
130.527
194.520
194.054
171.736
171.682
153.696
153.528
140.097
140.054
134.961
134.874
nu4-3-1
Date:
6 Mar 2008
Document's Title:
nu4-3-1
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
OMe
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
297
Number of Scans:
464
Acq. Date:
Thu Feb 21 11:38:21 AM
O HN
F3C
S
CO2Et
3c
Cl
200
150
100
50
ppm (t1)
34 / 53
0
Date:
5 Mar 2008
Document's Title:
nu3-240-1
1.328
1.224
3.428
3.409
3.386
3.366
4.737
4.311
4.309
4.307
4.304
4.301
4.299
4.297
4.296
5.423
5.420
7.282
7.279
7.266
7.259
7.342
7.328
7.530
7.514
7.601
nu3-240-1
Spectrum Title:
H-1 Routine 1D experiment. BBO Probe, 9-13-2007
O
F3C
HN
Boc
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
299.16
Number of Scans:
16
Acq. Date:
Thu Nov 29 05:13:32 PM
S
syn-3d
CF3
9.17
0.67
2.00
0.16
0.98
0.97
1.07
6.78
4.08
10.0
ppm (t1)
5.0
0.0
35 / 53
28.0
31.1
30.9
30.7
30.4
56.8
65.9
77.2
77.0
76.8
80.1
121.5
121.2
123.3
123.0
125.6
125.1
124.8
127.1
126.9
126.6
130.7
130.5
130.3
129.6
128.8
128.2
137.9
139.1
154.3
193.6
nu3-240-1
Date:
5 Mar 2008
Document's Title:
nu3-240-1
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O
F3C
HN
Boc
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
300
Number of Scans:
735
Acq. Date:
Tue Dec 11 08:26:30 PM
S
syn-3d
CF3
200
150
100
50
ppm (t1)
36 / 53
0
0.0000
1.348
1.240
3.419
3.403
3.387
4.859
4.858
4.433
5.425
7.282
7.271
7.264
7.605
7.591
7.348
7.336
7.324
8.208
8.193
nu4-16-1
Date:
5 Mar 2008
Document's Title:
nu4-16-1
Spectrum Title:
H-1 Routine 1D, DCH CryoProbe, 1-13-2006
O
F3C
HN
Boc
Frequency (MHz):
(f1) 600.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.2807
Spectral Width (ppm):
(f1) 11.971
Pulse Program:
ZG30
Temperature:
297
Number of Scans:
8
Acq. Date:
Tue Mar 04 12:02:02 AM
S
syn-3e
NO2
9.94
0.69
2.08
0.12
1.08
0.95
1.20
0.07
5.71
2.08
0.11
1.99
10.0
ppm (t1)
5.0
0.0
37 / 53
Date:
5 Mar 2008
Document's Title:
nu4-16-1
31.1
30.9
30.7
30.4
28.0
57.0
77.2
77.0
76.8
65.6
80.2
121.4
123.7
123.2
125.0
127.1
126.9
128.9
128.4
130.1
154.4
147.8
141.3
138.6
193.3
nu4-16-1
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O HN
F3C
Boc
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
297
Number of Scans:
206
Acq. Date:
Tue Mar 04 12:06:00 AM
S
syn-3e
200
NO2
150
100
50
ppm (t1)
38 / 53
0
Date:
6 Mar 2008
Document's Title:
sk085
1.243
1.332
3.359
3.340
4.202
4.200
4.198
3.421
3.401
4.812
4.795
5.400
5.398
7.353
7.343
7.331
7.327
7.314
7.312
7.298
7.275
7.268
7.263
7.261
7.259
7.254
s k 085
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
O HN
F3C
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
16
Acq. Date:
Thu Mar 06 12:09:24 AM
Boc
S
syn-3f
8.86
0.52
2.09
0.08
0.97
0.07
1.00
1.01
0.05
10.54
10.0
ppm (t1)
5.0
0.0
39 / 53
Date:
6 Mar 2008
Document's Title:
sk085
28.093
31.119
30.846
30.573
30.299
66.178
56.647
79.785
77.254
77.000
76.745
121.039
123.235
125.427
133.809
129.124
128.818
128.571
128.413
127.858
127.622
127.132
139.847
154.538
194.060
s k 085
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
O HN
F3C
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
299.16
Number of Scans:
352
Acq. Date:
Thu Mar 06 12:13:28 AM
Boc
S
syn-3f
200
150
100
50
ppm (t1)
40 / 53
0
0.0000000
2.315
2.361
3.330
3.314
3.275
3.259
4.048
4.031
4.748
4.739
4.932
4.923
4.916
4.907
7.051
7.212
7.200
7.168
7.156
7.121
7.118
7.293
7.288
7.275
7.260
nu4-10-1
Date:
7 Mar 2008
Document's Title:
nu4-10-1
Spectrum Title:
H-1 Routine 1D, DCH CryoProbe, 1-13-2006
O
F3C
HN
S
syn-3g
Ts
Frequency (MHz):
(f1) 600.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.2807
Spectral Width (ppm):
(f1) 11.971
Pulse Program:
ZG30
Temperature:
297
Number of Scans:
8
Acq. Date:
Tue Feb 26 11:37:11 AM
Ph
Ph
0.30
2.91
2.00
0.16
1.00
0.08
1.01
1.07
0.08
16.18
10.0
ppm (t1)
5.0
0.0
41 / 53
Date:
7 Mar 2008
Document's Title:
nu4-10-1
31.0
30.8
30.6
30.3
21.5
59.6
66.4
121.4
123.2
125.0
129.3
129.2
129.0
128.9
128.3
128.1
127.7
127.2
126.9
132.6
136.4
137.4
143.1
193.7
nu4-10-1
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O
F3C
S
syn-3g
200
HN
Ts
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
297
Number of Scans:
343
Acq. Date:
Tue Feb 26 11:19:06 AM
Ph
Ph
150
100
50
ppm (t1)
42 / 53
0
-0.000000
1.263
3.452
3.433
3.423
3.403
3.383
3.371
3.352
3.341
3.322
4.775
4.774
4.140
4.138
4.136
4.134
4.132
4.129
4.127
3.798
6.881
6.877
6.868
6.864
5.342
5.340
5.327
7.323
7.309
7.295
7.273
7.271
7.257
7.254
7.249
7.245
7.241
7.235
nu3-239-1
Date:
5 Mar 2008
Document's Title:
nu3-239-1
Spectrum Title:
H-1 Routine 1D experiment. BBO Probe, 9-13-2007
O HN
F3C
S
Boc
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
299.16
Number of Scans:
16
Acq. Date:
Thu Nov 29 05:08:43 PM
Ph
syn-3h
OMe
8.68
0.44
2.00
0.09
2.84
0.94
0.97
1.10
0.09
1.84
7.28
10.0
ppm (t1)
5.0
0.0
43 / 53
Date:
5 Mar 2008
Document's Title:
nu3-239-1
31.034
30.806
30.579
30.351
28.121
55.274
56.520
79.782
77.212
77.000
76.788
65.324
114.244
121.620
123.448
125.661
125.276
128.537
127.798
127.131
126.677
130.302
139.941
154.591
159.711
194.348
nu3-239-1
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O HN
F3C
S
Boc
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
300
Number of Scans:
195
Acq. Date:
Thu Nov 29 05:30:45 PM
Ph
syn-3h
OMe
200
150
100
50
ppm (t1)
44 / 53
0
-0.000000
3.401
3.381
3.361
1.309
1.202
3.514
3.494
3.475
4.847
4.845
4.841
4.841
4.966
4.946
5.485
5.483
5.479
5.478
5.341
5.338
5.336
5.022
5.014
5.793
5.790
5.788
7.233
7.225
7.335
7.300
7.292
nu4-17-1
Date:
5 Mar 2008
Document's Title:
nu4-17-1
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
O
F3C
HN
Boc
S
Cl
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
16
Acq. Date:
Mon Mar 03 10:51:51 AM
3i
9.83
16.01
2.18
3.63
1.01
2.83
1.92
1.00
1.84
25.34
1.11
10.0
ppm (t1)
5.0
0.0
45 / 53
28.2
28.0
31.1
31.0
30.9
30.7
30.6
30.5
30.4
30.3
56.5
56.1
60.9
60.2
79.7
121.6
121.5
123.4
123.3
125.3
125.2
130.0
129.7
129.5
129.4
129.4
129.2
128.7
128.5
128.1
127.6
127.4
127.1
127.0
126.4
139.7
139.5
134.8
134.2
131.9
131.8
193.5
154.8
154.3
195.5
nu4-17-1
Date:
5 Mar 2008
Document's Title:
nu4-17-1
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O
F3C
HN
Boc
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
297
Number of Scans:
337
Acq. Date:
Mon Mar 03 12:18:46 AM
S
Cl
3i
200
150
100
50
ppm (t1)
46 / 53
0
-0.000000
3.356
3.340
3.332
3.315
1.309
1.169
3.428
3.412
4.849
3.507
3.492
5.206
5.205
5.203
5.293
5.283
5.443
5.612
5.611
5.863
7.248
7.463
7.460
7.452
7.316
7.306
7.528
7.516
7.849
7.835
7.607
7.604
7.597
7.909
7.895
8.137
8.123
8.107
8.092
s k 078-2
Date:
6 Mar 2008
Document's Title:
sk078-2
Spectrum Title:
H-1 Routine 1D, DCH CryoProbe, 1-13-2006
O HN
F3C
S
Boc
Ph
Frequency (MHz):
(f1) 600.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.2807
Spectral Width (ppm):
(f1) 11.971
Pulse Program:
ZG30
Temperature:
297
Number of Scans:
16
Acq. Date:
Thu Mar 06 09:08:26 PM
3j
9.17
13.17
1.02
0.93
3.16
1.00
0.89
1.67
1.58
0.94
1.48
23.64
5.21
2.49
10.0
ppm (f1)
5.0
0.0
47 / 53
57.5
56.8
31.2
31.1
30.9
30.8
30.7
30.6
30.5
30.4
28.2
28.0
79.6
60.1
59.2
122.3
121.9
121.7
121.6
123.5
123.4
129.7
129.6
129.4
129.3
129.0
129.0
128.5
128.5
127.9
127.5
127.3
127.2
127.1
127.0
127.0
126.5
126.4
125.9
125.8
125.5
125.3
125.3
125.1
132.0
131.2
134.1
134.0
140.0
139.8
154.9
154.6
194.3
196.0
s k 078-2
Date:
6 Mar 2008
Document's Title:
sk078-2
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O HN
F3C
S
Boc
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
297
Number of Scans:
760
Acq. Date:
Thu Mar 06 09:11:41 PM
Ph
3j
200
150
100
50
ppm (f1)
48 / 53
0
Date:
7 Mar 2008
Document's Title:
sk084-2
1.329
1.392
3.469
3.449
4.519
3.569
3.560
3.544
4.613
5.027
5.025
5.023
5.020
5.018
5.015
5.291
6.946
6.930
6.922
5.765
7.289
7.276
7.258
7.239
7.233
7.211
7.200
s k 084-2
Spectrum Title:
H-1 Routine 1D, DCH CryoProbe, 1-13-2006
O HN
F3C
S
3k
Boc
Frequency (MHz):
(f1) 600.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.2807
Spectral Width (ppm):
(f1) 11.971
Pulse Program:
ZG30
Temperature:
297
Number of Scans:
16
Acq. Date:
Fri Mar 07 10:34:59 AM
Ph
S
9.04
21.31
6.66
1.00
2.22
0.87
3.31
2.24
6.33
20.73
10.0
ppm (f1)
5.0
0.0
49 / 53
31.3
31.1
30.8
30.6
28.3
57.9
59.6
80.0
121.6
123.4
125.2
135.5
128.6
128.5
127.8
127.6
127.0
126.5
126.3
154.9
139.1
195.2
Date:
7 Mar 2008
Document's Title:
sk084-2
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O HN
F3C
S
3k
200
Boc
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
297
Number of Scans:
394
Acq. Date:
Fri Mar 07 10:09:12 AM
Ph
S
150
100
50
ppm (f1)
50 / 53
0
Date:
7 Mar 2008
Document's Title:
nu4-7-2
1.443
1.424
3.509
3.493
3.479
3.622
3.608
4.833
5.029
5.429
5.578
7.376
7.363
7.341
7.329
7.310
7.297
7.270
7.262
nu4-7-2
Spectrum Title:
H-1 Routine 1D, DCH CryoProbe, 1-13-2006
O HN
F3C
Boc
Frequency (MHz):
(f1) 600.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.2807
Spectral Width (ppm):
(f1) 11.971
Pulse Program:
ZG30
Temperature:
297
Number of Scans:
16
Acq. Date:
Thu Mar 06 05:16:19 PM
S
3l
Cl
20.95
2.61
1.95
1.00
1.09
3.16
0.96
12.76
10.0
ppm (f1)
5.0
0.0
51 / 53
Date:
7 Mar 2008
Document's Title:
nu4-7-2
32.129
31.902
31.674
31.474
31.246
31.018
28.254
28.179
57.232
56.483
69.290
67.043
80.532
80.507
121.522
123.477
123.351
125.307
125.182
127.516
127.137
127.011
126.632
135.555
128.713
128.665
128.625
128.336
154.683
154.545
137.251
193.309
193.075
nu4-7-2
Spectrum Title:
C-13 Routine 1D, DCH CryoProbe, 10-26-2006
O
F3C
HN
Boc
Frequency (MHz):
(f1) 150.918
Original Points Count:
(f1) 32768
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 0.8716
Spectral Width (ppm):
(f1) 249.102
Pulse Program:
ZGPG45
Temperature:
297
Number of Scans:
608
Acq. Date:
Thu Mar 06 05:20:43 PM
S
3l
200
Cl
150
100
50
ppm (f1)
52 / 53
0
3.140
3.127
3.113
3.100
0.0000000
2.086
3.769
3.757
3.747
3.741
3.734
3.728
3.719
3.706
4.358
4.352
4.335
4.320
7.184
7.181
7.168
7.340
7.331
7.327
7.324
7.317
7.312
7.302
7.298
7.295
7.292
7.281
7.276
7.273
7.266
7.258
Date:
7 Mar 2008
Document's Title:
SK089-4
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
NH2
HO
Ph
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
297.16
Number of Scans:
32
Acq. Date:
Tue Mar 04 09:01:54 PM
Ph
1.00
2.07
1.16
4.15
8.73
10.0
ppm (t1)
5.0
0.0
53 / 53