organic letters organocatalytic mannich-type reactions ...in order to expand the scope of direct...
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Organocatalytic Mannich-Type Reactionsof Trifluoroethyl ThioestersNaoto Utsumi, Shinji Kitagaki, and Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry andMolecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,La Jolla, California 92037
Received May 27, 2008
ABSTRACT
Direct organocatalytic Mannich-type reactions of thioesters provide for the expedient and diastereoselective synthesis of protected �-aminoacids. 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 reactionsprovide expedient access to R- and �-amino acids, aminoalcohols and sugars, and amino carbonyl derivatives that aresynthons of import in the pharmaceutical and other industriesand have, therefore, received much attention.1–3 We havedevoted considerable effort toward addressing this reaction
using enamine-based mechanisms and toward solving thestereochemical challenges of direct organocatalytic enanti-oselective syn- or anti-selective syntheses of these types ofproducts based on the use of ketone or aldehyde donors.3 Asignificant unmet challenge in this area is the developmentof direct organocatalytic Mannich and Mannich-type reac-tions that utilize donors in the ester oxidation state and areeither diastereoselective or both diastereo- and enantiose-lective. Such reactions are not amenable to enamine-basedorganocatalytic approaches. Recently, we have described anew approach4 to direct organocatalytic ester-based reactionsthat utilizes electronic tuning of thioesters to provide esterdonor reactivity without need to resort to decarboxylativeapproaches5 for enolate generation. Herein we report theapplication of this strategy to direct asymmetric Mannich-type reactions that utilize thioester donors.
(1) For recent reviews that consider the contributions of the manylaboratories 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 concerningorganocatalytic 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. Tetrahedron2008, 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.
ORGANICLETTERS
2008Vol. 10, No. 16
3405-3408
10.1021/ol801207x CCC: $40.75 2008 American Chemical SocietyPublished on Web 07/16/2008
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In order to expand the scope of direct organocatalyticreactions of trifluoroethyl thioesters,4,6 we have evaluatedthioesters as nucleophiles in Mannich-type reactions. Ourgoal was to study their general reactivity in direct Mannich-type reactions with preformed imines with the hope ofdeveloping a diastereoselective transformation en route toan enantioselective one (Scheme 1). We initially studied the
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).
In our preliminary study of the related aldol reaction,4 wefound that DBU was an effective catalyst. As noted in entries1-9, we observed significant solvent effects on both theoverall yield of the reaction and the diastereoselectivity ofthe 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 anti-selectivity albeit in very low yield (entry 5). A significant
improvement in both yield and diastereoselectivity wasobserved 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 wereobtained and the syn/anti ratio reached ∼8:1. We alsoobserved that the reaction product 3a precipitated during thecourse of the reaction when these solvents were used butremained soluble in the polar solvents studied (entries 1-5).
We then studied the role of the catalyst under the toluenesolvent conditions. As noted in entry 10, the base KOtBu provedan effective substitute for DBU in terms of overall yield of thedesired product; however, the reaction was poorly diastereo-selective (entry 10). Reactions using the other three bases tested(Et3N, iPr2EtN, K2CO3) gave reduced product yield and dias-tereoselectivity after 2 h relative to reactions in DBU. Most ofthioester 1a was recovered intact following reactions using Et3N,iPr2EtN, and K2CO3, indicating that substrate decompositionwas not responsible for the low yields under these conditions.
Next we optimized reaction time and temperature across thethree most promising solvents (toluene, diethylether, andhexane) (Table 2). Our preliminary study of the reaction intoluene indicated that the reaction was complete in less than2 h. Given that the product was insoluble using this and theother high-yielding solvent systems and that the diastereose-lectivity of the reaction was low under solvent conditionswherein the product was soluble (polar solvents), we speculatedthat diastereoselectivity was under thermodynamic controldriven by precipitation of the syn-product. To test this hypoth-esis, we studied both longer and shorter reaction times andreductions in reaction temperature. No significant change in
(3) For studies from this laboratory concerning organocatalytic Mannichand 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.
Scheme 1. Thioester Enolization and Addition to an Imine
Table 1. Catalyst and Solvent Screening for the MannichReaction of Thioester with N-Boc-iminea
entry catalyst solvent yieldb (%) syn/antic
1 DBU DMF 96 57/432d DBU DMF 78 57/433 DBU CH2Cl2 89 50/504 DBU THF 86 57/435e DBU MeOH 17 (19) 41/596 DBU CH3CN 85 80/207f DBU hexane quant 88/128f DBU Et2O quant 89/119f DBU toluene 94 83/1710f KOtBu toluene quant 41/5911 Et3N toluene 22 (73) 50/5012 iPr2EtN toluene 18 (80) 47/5313 K2CO3 toluene 13 (87) 44/56a 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 stirredat room temperature for 2 h. b Yields were calculated from crude 1H NMRspectra using anisole as a internal standard. Recovered yield of thioester isshown in parentheses. c Determined by crude 1H NMR spectra. d MS4Awas used as an additive. e MeOH adduct of imine (69% based on imine)and methyl 4-chlorophenylacetate (39% yield) were formed. f Products wereprecipitated during the reaction.
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either yield or diastereoselectivity was noted when we increasedthe 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 yieldremained high but the diastereoselectivity was reduced (entry3). Significantly, the syn:anti ratio of the 4 °C reaction wasimproved to 92:8 (from 75:35 after 5 min) simply by extendingthe reaction time to 2 h (entry 4). Interestingly, reduction ofthe reaction temperature to -40 °C (entry 6) resulted in aslightly anti-selective reaction, whereas reduction of the tem-perature to -78 °C significantly slowed the reaction (8% yieldafter 2 h) and no selectivity was obtained (entry 7). Reactionsin 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 providediastereoselectivities exceeding ∼7:1 (entries 11-13).
These data are consistent with our hypothesis that syn-selectivity was driven by product solubility and that the synand anti isomers could interconvert under the reaction conditionswherein the syn product was less soluble than the anti product.To further test this hypothesis, we reexamined the reaction intoluene at 4 °C (Table 2, entries 3 and 4). We isolated thereaction product by extractive workup and compared the isolatedproduct with product isolated by filtration (insoluble precipitatewas formed during the reaction) (Table 3, entries 1 and 2). Wefound that the product isolated via filtration was syn-enrichedcompared to that obtained from extractive workup. However,when the reaction time was extended to 2 h, which allowedthe reaction to equilibrate, there was little difference in theselectivities of products isolated using the two methods (Table3, entries 3 and 4).
As final evidence for a dynamic thermodynamic mecha-nism, purified product 3a (Table 2, entry 6), which had asyn:anti ratio of 29:71, was incubated with fresh DBUcatalyst in toluene for 2 h at 4 °C and 3a was reisolated(Scheme 2, 3). We found that this product had a syn:anti
ratio of 86:14 indicating that epimerization of the R-positionwas facile under these conditions and that selective precipita-tion of the syn-product increased the diastereoselectivity ofthe reaction in nonpolar solvents.
The optimized reaction conditions were suitable for a rangeof thioester donors and imine acceptors (Table 4). Boc-iminesderived from benzaldehyde were substantially more reactivethan the corresponding tosyl (Ts) imines; compare entries 1 and2 to entries 6 and 7. Modest to insignificant differences indiastereoselectivites were observed between Boc- and Ts-iminereactions. The N-p-methoxyphenyl (PMP)-protected imine ofethyl glyoxylate provided product with low yield and diaste-reoselectivity. Of the eight thioesters studied, those withinsoluble products were obtained in good diastereoselectivity.Product 3h, for example, was obtained in 94% yield with 19:1syn:anti diastereoselection (entry 8). In addition to thioestersfunctionalized with an aromatic group at the R-position, chloro-substitution at this position led to generation of a reactive enolateunder these mild organocatalytic conditions (entry 12). Therelative syn-stereochemistry of product 3f was determined
Table 2. Effect of Temperature and Reaction Time on theReaction of Thioester with N-Boc-iminea
entry solvent T (°C) time (h) yieldb (%) syn/antic
1 toluene 25 2 89 83/172 toluene 25 6 89 83/173 toluene 4 5 min 98 75/254 toluene 4 2 96 92/85 toluene -15 4 quant 91/96 toluene -40 2 93 29/717 toluene -78 2 8 (83) 50/508 Et2O 25 2 quant 89/119 Et2O 4 2 91 89/1110 Et2O -15 4 quant 89/1111 hexane 25 2 quant 88/1212 hexane 4 2 quant 88/1213 hexane -15 4 quant 75/25a 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 stirredat specified temperature for the specified time. b Yield was calculated byNMR of the crude product using anisole as an internal standard. Recoveredyield of thioester is shown in parentheses. c Determined by 1H NMR ofcrude product.
Table 3. Selectivities when Products Were Isolated UsingExtraction vs Filtrationa
entry workup method time (min) yieldb (%) syn/antic
1 extractiond 5 98 75/252 filtratione 5 70 83/173 extractiond 120 96 92/84 filtratione 120 65 96/4a 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 stirrredat 4 °C for specified time. b Isolated yield. c Determined by 1H NMR spectra.d Extraction by EtOAc/brine followed by purification by flash columnchromatography. e The precipitated solid was collected by filteration andwashed using small amount of cold toluene.
Scheme 2. Syn/Anti Isomerization of Mannich Adduct 3aCatalyzed by DBU
Org. Lett., Vol. 10, No. 16, 2008 3407
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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.
We were also interested in exploring the potential of anenantioselective version of this reaction. As noted in Scheme4, we adopted phase-transfer conditions with in situ N-Boc-imine generation from the R-amido sulfone 2b.8 Using aCinchona alkaloid-based catalyst 5, good yields of 3a wereobtained with modest diastereo- and enantioselectivity. Interest-
ingly, this reaction (performed at -45 °C) was modestly anti-selective, like the DBU reaction performed at -40 °C (Table2, entry 6). Although the enantioselectivity of this reaction wasmodest, 45% ee, the reactivity of our system compares veryfavorably with direct Mannich-type reactions based on malonicacid half-thioesters that typically require reaction times of 3days.
In conclusion, we report the first direct diastereoselectiveMannich-type reactions of thioesters using the simple tertiaryamine DBU as a catalyst. This methodology provides expedientaccess 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 serveto complement the anti-selective direct Mannich-type reactionof sulfonylimidates recently described by Kobayashi et al.9
These studies provide a foundation for future development ofhighly diastereo- and enantioselective direct ester-based Man-nich reactions.
Acknowledgment. This study was supported by TheSkaggs Institute for Chemical Biology.
Supporting Information Available: Experimental pro-cedures and compound characterization data. This materialis available free of charge via the Internet at http://pubs.acs.org.
OL801207X
(7) The major product was found to have the syn relative stereochemistryas 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.
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 92/82d,e,f 4-ClC6H4 Ph Ts 3b 30 88 92/83g 4-ClC6H4 CO2Et 4-MeOC6H4 3c 4 65 75/25h4d 4-CF3C6H4 Ph Boc 3d 2 88 92/85d 4-NO2C6H4 Ph Boc 3e 72 90 94/66d Ph Ph Boc 3f 2 87 89/117d,i Ph Ph Ts 3g 4 78 92/88d 4-MeOC6H4 Ph Boc 3h 2 94 19/19g 2-ClC6H4 Ph Boc 3i 2 quant 33/6710g 1-Naphtyl Ph Boc 3j 2 98 40/6011d 2-Thienyl Ph Boc 3k 17 94 22/7812g 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 reactionwas 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 Reactionwas 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.
Scheme 3. Determination of Relative Stereochemistry
Scheme 4. Enantioselective Mannich Reaction of a Thioester
3408 Org. Lett., Vol. 10, No. 16, 2008
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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 13C 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.
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S-2,2,2-Trifluoroethyl 4-chlorophenylthioacetate (1a). 1H NMR (500 MHz, CDCl3): 3.57 (q, J = 9.8 Hz, 2H, CH2CF3), 3.87 (s,
2H, CH2C=O), 7.20-7.24 (m, 2H, ArH), 7.31-7.35 (m, 2H, ArH). 13C
NMR (150 MHz, CDCl3): 30.8 (q, J = 34.3 Hz), 49.2, 124.5 (q, J =
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). 1H NMR (500 MHz, CDCl3): 3.58 (q, J = 10.0 Hz, 2H, CH2CF3), 3.95
(s, 2H, CH2C=O), 7.39 (d, J = 8.0 Hz, 2H, ArH), 7.60 (d, J = 8.0 Hz, 2H,
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). 1H 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,
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). 1H 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). 13C NMR (100 MHz, CDCl3):
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). 1H NMR (500 MHz, CDCl3): 3.52 (q, J = 10.0 Hz, 2H, CH2CF3),
3.76 (s, 3H, CH3), 3.79 (s, 2H, CH2C=O), 6.85-6.88 (m, 2H, ArH),
7.15-7.18 (m, 2H, ArH). 13C NMR (125 MHz, CDCl3): 30.7 (q, J =
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). 1H NMR (500 MHz, CDCl3): 3.54 (q, J = 10.0 Hz, 2H, CH2CF3), 4.00 (s,
Cl
S
O
F3C
F3C S
OCF3
F3C S
ONO2
S
O
F3C
F3C S
OOCH3
F3C S
O
Cl
-
3 / 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). 1H NMR (500 MHz, CDCl3): 3.41 (q, J = 10.0 Hz, 2H, CH2CF3), 4.20 (s,
2H, CH2C=O), 7.31-7.47 (m, 4H, ArH), 7.74-7.82 (m, 3H, ArH). 13C NMR
(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). 1H NMR (500 MHz, CDCl3): 3.53 (q, J = 10.0 Hz, 2H, CH2CF3), 4.04 (s,
2H, CH2C=O), 6.95-6.97 (m, 2H, ArH), 7.22-7.24 (m, 1H, ArH). 13C NMR
(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). 1H 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
(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),
4.65-4.85 (m, 1H, NH), 6.26-6.46 (m, 1H, CHNH), 7.23-7.36 (m, 9H, F3C S
O HN
Cl
Boc
O
SF3C
O
SF3C S
F3C S
OCl
-
4 / 53
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
(m, 1H, CHNH), 7.20-7.40 (m, 9H, ArH). 13C NMR (150 MHz, CDCl3):
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.
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 =
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): 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). 1H NMR (400 MHz, CDCl3): major/minor = 3/1: *denotes minor isomer,
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,
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 =
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). 13C
NMR (150 MHz, CDCl3): major/minor = 3/1, *denotes minor isomer, 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
F3C S
O HN
Cl
Ts
S
O
F3C CO2Et
HN
Cl
OMe
F3C S
O HN
Cl
Boc
-
5 / 53
3-(tert-butoxycarbonylamino)-2-(4-trifluoromethylphenyl)-3-phenylpropanethioate (3d).
Major diastereomer (syn): 1H NMR (500 MHz, CDCl3): 1.31 (s, 9H,
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). 13C
NMR (150 MHz, CDCl3): 28.0, 30.8 (q, J = 34.5 Hz), 55.8, 65.9, 80.1,
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,
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). 13C NMR (150 MHz,
CDCl3): 28.0, 30.8 (q, J = 34.5 Hz), 57.0, 65.6, 80.2, 124.1 (q, J = 276.0
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). 13C
NMR (125 MHz, CDCl3): 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,
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),
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.
F3C S
O HN
CF3
Boc
F3C S
O HN
NO2
Boc
F3C S
O HNBoc
S
O
F3C
HNTs
-
6 / 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,
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): 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),
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). 1H NMR (500 MHz, CDCl3): syn/anti = 1/2: *denotes syn isomer, 1.20 (s,
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.
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). 13C 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). 1H 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,
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). 13C NMR (150 MHz, CDCl3): syn/anti = 2/3, signals due to
both syn and anti isomers were shown, 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
F3C S
O HN
OMe
Boc
F3C S
O HNBoc
ClF3C S
O HNBoc
Cl
S
O
F3C Ph
HNBoc
-
7 / 53
(MNa+) 490.1658, found 490.1660.
S-2,2,2-trifluoroethyl 3-(tert-butoxycarbonylamino)-3-phenyl-2-(thiophen-2-yl)propanethioate
(3k). 1H NMR (600 MHz, CDCl3): syn/anti = 1/2: *denotes syn isomer, 1.33 (s,
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,
CH2CF3), 3.44-3.62 (m, 2H x 2/3, CH2CF3), 4.52 (br. s, 1H* x 1/3), 4.61 (br. 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). 13C 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). 1H 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
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). 13C NMR (150 MHz, CDCl3): major/minor = 6/5, all
peaks of mixture of diastereomer were shown, 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
S
O
F3CPh
HN
Ph
Boc1) LiAlH4, THF, 0 oC, 30min
2) CF3CO2H, CH2Cl2, 20 minHO
Ph
NH2
Ph
dr = 12/1
59% yield
3fsyn diastereomer
4
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
F3C S
O
Cl
HNBoc
S
O
F3C Ph
HNBoc
S
-
8 / 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.
-
9 / 53
ppm (t1)0.05.010.0
7.34
57.
340
7.33
67.
327
7.32
3
7.25
97.
226
7.22
27.
217
7.20
87.
204
3.87
03.
598
3.57
83.
559
3.53
9
1.53
7
0.00
0000
2.032.07
2.03
2.24
Date:1 Feb 2008Document's Title:nu3-211-1
Spectrum Title:
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:ZG30Temperature:299.16Number of Scans:8Acq. Date:Tue Nov 13 05:49:20 PM
nu3-211-1
Cl
S
O
F3C1a
-
10 / 53
ppm (t1)050100150200
193.
3
133.
913
1.0
130.
7
129.
0
127.
2
125.
4
123.
6
121.
8
77.2
77.0
76.8
49.2
31.1
30.9
30.7
30.5
Date:1 Feb 2008Document's Title:nu3-211-1
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:289Number of Scans:22Acq. Date:Thu Jan 31 10:20:43 AM
nu3-211-1
Cl
S
O
F3C1a
-
11 / 53
ppm (t1)0.01.02.03.04.05.06.07.08.09.0
7.37
27.
368
7.36
07.
357
7.35
4
7.27
77.
272
7.26
97.
264
7.25
87.
251
7.24
67.
236
7.23
07.
224
7.21
67.
212
7.20
1
4.00
33.
574
3.55
43.
534
3.51
4
1.003.03
2.09
2.08
Date:4 Mar 2008Document'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:ZG30Temperature:298.16Number of Scans:8Acq. Date:Tue Jan 29 06:02:27 PM
F3C S
O
Cl1b
-
12 / 53
ppm (t1)050100150200
192.
678
134.
799
131.
938
130.
735
129.
590
129.
443
127.
896
127.
038
125.
704
123.
511
121.
318
77.2
5577
.000
76.7
45
47.4
72
30.9
6930
.698
30.4
2530
.154 Date:
4 Mar 2008Document'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:ZGPG45Temperature:299.16Number of Scans:160Acq. Date:Tue Jan 29 06:00:11 PM
F3C S
O
Cl1b
-
13 / 53
ppm (t1)0.01.02.03.04.05.06.07.08.09.010.0
7.61
27.
596
7.40
27.
386
3.95
23.
606
3.58
63.
566
3.54
7
0.00
0000
0
2.001.99
2.072.03
Date:4 Mar 2008Document's Title:da159H
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:ZG30Temperature:299.16Number of Scans:8Acq. Date:Mon Jan 28 06:08:34 PM
F3C S
OCF3
1c
-
14 / 53
ppm (t1)050100150200
192.
675
136.
409
130.
563
130.
303
130.
044
129.
946
129.
785
127.
848
127.
255
125.
763
125.
733
125.
704
125.
657
125.
093
123.
464
122.
929
121.
271
120.
766
77.2
5577
.000
76.7
46
49.4
89
31.2
7831
.004
30.7
3030
.457 Date:
4 Mar 2008Document's Title:da159C
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:ZGPG45Temperature:299.16Number of Scans:200Acq. Date:Mon Jan 28 06:06:44 PM
F3C S
OCF3
1c
-
15 / 53
ppm (t1)0.01.02.03.04.05.06.07.08.09.010.0
8.17
68.
173
8.15
98.
154
7.49
27.
475
4.06
9
3.66
03.
640
3.62
03.
601
1.98
2.00
2.02
2.00
Date:4 Mar 2008Document's Title:sk044H
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:ZG30Temperature:299.16Number of Scans:8Acq. Date:Thu Jan 31 10:41:12 AM
F3C S
ONO2
1d
-
16 / 53
ppm (t1)050100150200
192.
038
147.
239
139.
728
130.
329
127.
685
125.
492
123.
568
123.
300
121.
105
77.2
5577
.000
76.7
44
48.9
27
30.9
4430
.671
30.3
9830
.126 Date:
4 Mar 2008Document's Title:SK044C
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:ZGPG45Temperature:299.16Number of Scans:120Acq. Date:Thu Jan 31 10:39:03 AM
F3C S
ONO2
1d
-
17 / 53
ppm (t1)0.05.010.0
7.37
07.
364
7.35
47.
351
7.34
87.
344
7.34
27.
334
7.33
07.
328
7.32
47.
319
7.31
47.
308
7.27
97.
274
7.26
97.
264
7.25
97.
255
7.22
9
3.88
3
3.58
03.
555
3.53
13.
506
0.00
0000
0
4.77
2.00
1.99
Date:1 Feb 2008Document'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:ZG30Temperature:297.6Number of Scans:16Acq. Date:Wed Dec 05 04:32:38 PM
nu3-250-1
S
O
F3C
1e
-
18 / 53
ppm (f1)050100150200
193.
7
132.
412
9.6
128.
812
7.8
126.
012
3.3
120.
5
77.3
77.0
76.7
50.0
31.3
31.0
30.6
30.3
Date:1 Feb 2008Document's Title:nu3-250-1
Spectrum Title:C-13 Routine 1D experiment. BBO Probe, 9-13-2007
Frequency (MHz):(f1) 100.620 Original Points Count:(f1) 16384 Actual Points Count:(f1) 32768 Acquisition Time (sec):(f1) 0.6816 Spectral Width (ppm):(f1) 238.903 Pulse Program:ZGPG30Temperature:298.8Number of Scans:122Acq. Date:Tue Dec 11 08:14:04 PM
nu3-250-1
S
O
F3C
1e
-
19 / 53
ppm (t1)0.01.02.03.04.05.06.07.08.09.010.0
7.17
97.
173
7.16
97.
160
7.15
67.
150
6.87
66.
870
6.86
66.
857
6.85
36.
847
3.79
43.
759
3.54
63.
526
3.50
63.
486
2.002.00
5.192.06
Date:4 Mar 2008Document's Title:da157H
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:ZG30Temperature:299.16Number of Scans:8Acq. Date:Mon Jan 28 05:49:35 PM
F3C S
OOCH3
1f
-
20 / 53
ppm (t1)050100150200
194.
186
159.
262
130.
780
127.
942
125.
750
124.
234
123.
557
121.
365
114.
145
77.2
5477
.000
76.7
45
55.0
36
48.9
97
31.0
7630
.805
30.5
3430
.263 Date:
4 Mar 2008Document's Title:da157C
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:ZGPG45Temperature:299.16Number of Scans:200Acq. Date:Mon Jan 28 05:44:20 PM
F3C S
OOCH3
1f
-
21 / 53
ppm (t1)-1.00.01.02.03.04.05.06.07.08.09.010.0
7.80
57.
787
7.77
17.
769
7.75
37.
737
7.47
37.
471
7.46
07.
457
7.45
47.
443
7.44
07.
431
7.42
87.
415
7.41
37.
401
7.39
97.
367
7.35
37.
337
7.32
87.
325
7.31
47.
311
4.19
53.
444
3.42
43.
404
3.38
4
3.002.001.92
1.98
2.00
Date:4 Mar 2008Document'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:ZG30Temperature:299.16Number of Scans:8Acq. Date:Thu Jan 31 10:26:07 AM
O
SF3C
1g
-
22 / 53
ppm (t1)050100150200
193.
954
133.
778
131.
976
129.
008
128.
864
128.
784
128.
700
127.
918
126.
660
125.
986
125.
725
125.
345
123.
531
123.
403
121.
339
77.2
5477
.000
76.7
46
47.6
45
31.0
0830
.737
30.4
6530
.195 Date:
4 Mar 2008Document'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:ZGPG45Temperature:299.16Number of Scans:120Acq. Date:Thu Jan 31 10:24:04 AM
O
SF3C
1g
-
23 / 53
ppm (t1)0.01.02.03.04.05.06.07.08.09.010.0
7.23
57.
231
7.22
77.
223
6.96
86.
961
6.95
76.
952
4.03
53.
560
3.54
03.
520
3.50
1
1.002.07
2.21
2.19
Date:4 Mar 2008Document'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:ZG30Temperature:298.16Number of Scans:8Acq. Date:Tue Jan 29 05:44:27 PM
O
SF3C S1h
-
24 / 53
ppm (t1)050100150200
192.
824
132.
977
128.
228
127.
851
127.
103
126.
024
125.
658
123.
465
121.
271
77.2
5577
.000
76.7
46
43.4
4431
.081
30.8
1030
.537
30.2
65 Date:4 Mar 2008Document'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:ZGPG45Temperature:299.16Number of Scans:160Acq. Date:Tue Jan 29 05:41:46 PM
O
SF3C S1h
-
25 / 53
ppm (t1)0.05.010.0
4.28
2
3.68
63.
662
3.63
73.
613
0.00
0000
0
1.93
2.00
Date:7 Mar 2008Document's Title:nu3-299-1
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:ZG30Temperature:297.4Number of Scans:8Acq. Date:Fri Feb 15 04:43:21 PM
nu3-299-1
F3C S
OCl
1i
-
26 / 53
ppm (t1)050100150200
191.
356
127.
707
125.
514
123.
319
121.
125
77.2
5477
.000
76.7
45
47.7
13
31.4
8731
.212
30.9
3830
.664
Date:7 Mar 2008Document's Title: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:ZGPG45Temperature:298.16Number of Scans:296Acq. Date:Fri Feb 15 05:47:32 PM
nu3-299-1
F3C S
OCl
1i
-
27 / 53
ppm (t1)0.05.010.0
7.31
77.
306
7.25
9
5.35
9
4.74
54.
743
4.74
14.
211
4.21
04.
206
4.20
54.
200
3.42
03.
401
3.38
63.
367
1.34
5
1.26
3
-0.0
0000
0
10.36
0.05
1.03
1.00
1.06
0.132.10
0.409.09
Date:7 Mar 2008Document's Title:nu4-15-1
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:ZG30Temperature:298.16Number of Scans:16Acq. Date:Mon Mar 03 10:40:58 AM
nu4-15-1
F3C S
O HN
Cl
Boc
syn-3a
-
28 / 53
ppm (t1)050100150200
193.
9
154.
5
139.
3
134.
5
132.
4
130.
512
8.9
128.
712
8.1
127.
1
125.
2
123.
380
.0
77.2
77.0
76.8
65.4
56.6
31.1
30.9
30.6
30.4
28.1
Date:7 Mar 2008Document's Title:nu3-55-4
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:300Number of Scans:256Acq. Date:Thu Jun 14 08:12:22 AM
nu3-55-4
F3C S
O HN
Cl
Boc
syn-3a
-
29 / 53
ppm (t1)0.05.010.0
7.31
57.
308
7.26
17.
242
7.22
87.
211
7.18
87.
166
7.14
55.
553
5.54
85.
546
5.54
45.
540
5.24
9
4.30
74.
304
4.29
94.
296
4.29
3
3.55
53.
530
3.51
63.
492
1.34
5
-0.0
0000
0
11.99
1.00
1.07
1.02
2.12
9.04
Date:13 Feb 2008Document's Title:nu3-55-2_01.f id
Spectrum Title:Std proton
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:UnknownTemperature: 25
Number of Scans: 32
Acq. Date: Jun 13 2007
nu3-55-2
F3C S
O HN
Cl
Boc
anti-3a
-
30 / 53
ppm (t1)050100150200
193.
9
154.
813
9.2
134.
313
2.6
130.
012
9.0
128.
612
7.7
126.
612
5.3
123.
580
.0
77.2
77.0
76.8
64.2
57.6
31.3
31.0
30.8
30.6
28.2
Date:13 Feb 2008Document's Title:nu3-55-2
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:300Number of Scans:256Acq. Date:Thu Jun 14 08:33:46 AM
nu3-55-2
F3C S
O HN
Cl
Boc
anti-3a
-
31 / 53
ppm (t1)0.05.010.0
7.29
77.
283
7.26
37.
262
7.21
97.
205
7.19
47.
182
7.14
27.
128
7.11
47.
103
7.06
27.
049
4.92
24.
910
4.90
54.
894
4.72
44.
713
4.04
44.
027
3.32
93.
313
3.29
83.
282
2.37
8
7.495.144.212.10
1.021.00
1.01
1.98
3.02
Date:6 Mar 2008Document's Title:nu4-13-2
Spectrum Title:H-1 Routine 1D, DCH CryoProbe, 1-13-2006
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:ZG30Temperature:297Number of Scans:32Acq. Date:Tue Mar 04 05:14:50 PM
nu4-13-2
F3C S
O HN
Cl
Ts
syn-3b
-
32 / 53
ppm (t1)050100150200
193.
533
143.
313
137.
487
136.
556
135.
051
131.
387
130.
133
129.
311
129.
255
128.
521
128.
246
127.
458
126.
987
124.
971
123.
142
77.2
1177
.000
76.7
8865
.529
59.8
06
30.8
2730
.598
21.4
86
Date:6 Mar 2008Document's Title:nu4-13-2
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:297Number of Scans:1024Acq. Date:Tue Mar 04 05:18:11 PM
nu4-13-2
F3C S
O HN
Cl
Ts
syn-3b
-
33 / 53
ppm (t1)0.05.010.0
7.32
6
7.25
9
6.75
36.
739
6.64
66.
641
6.63
14.
709
4.69
84.
567
4.55
34.
333
4.32
14.
189
4.17
54.
164
4.15
24.
140
4.12
8
3.92
73.
915
3.72
93.
726
3.64
63.
637
3.62
93.
621
3.60
53.
560
3.54
43.
535
3.51
91.
226
1.21
41.
202
0.96
40.
952
0.94
0
5.86
5.52
0.361.000.361.750.932.074.103.20
1.183.02
Date:6 Mar 2008Document's Title:nu4-3-1
Spectrum Title:H-1 Routine 1D, DCH CryoProbe, 1-13-2006
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:ZG30Temperature:297Number of Scans:8Acq. Date:Thu Feb 21 11:35:14 AM
nu4-3-1
S
O
F3C CO2Et
HN
Cl
OMe
3c
-
34 / 53
ppm (t1)050100150200
194.
520
194.
054
171.
736
171.
682
153.
696
153.
528
140.
097
140.
054
134.
961
134.
874
131.
532
131.
430
131.
011
130.
527
129.
126
129.
044
127.
197
127.
130
125.
368
125.
302
123.
540
123.
473
121.
712
121.
645
116.
762
116.
593
114.
699
114.
664
77.2
1277
.000
76.7
88
62.3
1162
.063
61.8
5561
.418
61.2
7660
.758
55.5
8831
.369
31.3
2131
.141
31.0
9330
.913
30.8
6630
.685
30.6
3814
.070
13.7
56
Date:6 Mar 2008Document's Title:nu4-3-1
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:297Number of Scans:464Acq. Date:Thu Feb 21 11:38:21 AM
nu4-3-1
S
O
F3C CO2Et
HN
Cl
OMe
3c
-
35 / 53
ppm (t1)0.05.010.0
7.60
1
7.53
07.
514
7.34
27.
328
7.28
27.
279
7.26
67.
259
5.42
35.
420
4.73
74.
311
4.30
94.
307
4.30
44.
301
4.29
94.
297
4.29
63.
428
3.40
93.
386
3.36
6
1.32
81.
224
4.086.78
1.07
0.97
0.98
0.162.00
0.679.17
Date:5 Mar 2008Document's Title:nu3-240-1
Spectrum Title:H-1 Routine 1D experiment. BBO Probe, 9-13-2007
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:ZG30Temperature:299.16Number of Scans:16Acq. Date:Thu Nov 29 05:13:32 PM
nu3-240-1
F3C S
O HN
CF3
Boc
syn-3d
-
36 / 53
ppm (t1)050100150200
193.
6
154.
3
139.
113
7.9
130.
713
0.5
130.
312
9.6
128.
812
8.2
127.
112
6.9
126.
612
5.6
125.
112
4.8
123.
312
3.0
121.
512
1.2
80.1
77.2
77.0
76.8
65.9
56.8
31.1
30.9
30.7
30.4
28.0
Date:5 Mar 2008Document's Title:nu3-240-1
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:300Number of Scans:735Acq. Date:Tue Dec 11 08:26:30 PM
nu3-240-1
F3C S
O HN
CF3
Boc
syn-3d
-
37 / 53
ppm (t1)0.05.010.0
8.20
88.
193
7.60
57.
591
7.34
87.
336
7.32
47.
282
7.27
17.
264
5.42
5
4.85
94.
858
4.43
3
3.41
93.
403
3.38
7
1.34
81.
240
0.00
00
1.99
2.08
5.71
0.071.20
0.95
1.08
0.122.08
0.699.94
0.11
Date:5 Mar 2008Document's Title:nu4-16-1
Spectrum Title:H-1 Routine 1D, DCH CryoProbe, 1-13-2006
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:ZG30Temperature:297Number of Scans:8Acq. Date:Tue Mar 04 12:02:02 AM
nu4-16-1
F3C S
O HN
NO2
Boc
syn-3e
-
38 / 53
ppm (t1)050100150200
193.
3
154.
414
7.8
141.
313
8.6
130.
112
8.9
128.
412
7.1
126.
9
125.
012
3.7
123.
2
121.
4
80.2
77.2
77.0
76.8
65.6
57.0
31.1
30.9
30.7
30.4
28.0
Date:5 Mar 2008Document's Title:nu4-16-1
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:297Number of Scans:206Acq. Date:Tue Mar 04 12:06:00 AM
nu4-16-1
F3C S
O HN
NO2
Boc
syn-3e
-
39 / 53
ppm (t1)0.05.010.0
7.35
37.
343
7.33
17.
327
7.31
47.
312
7.29
87.
275
7.26
87.
263
7.26
17.
259
7.25
4
5.40
05.
398
4.81
24.
795
4.20
24.
200
4.19
83.
421
3.40
13.
359
3.34
0
1.33
2
1.24
3
10.54
0.05
1.01
1.00
0.07
0.97
0.08
2.09
0.528.86
Date:6 Mar 2008Document's Title:sk085
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:ZG30Temperature:298.16Number of Scans:16Acq. Date:Thu Mar 06 12:09:24 AM
sk085
F3C S
O HNBoc
syn-3f
-
40 / 53
ppm (t1)050100150200
194.
060
154.
538
139.
847
133.
809
129.
124
128.
818
128.
571
128.
413
127.
858
127.
622
127.
132
125.
427
123.
235
121.
039
79.7
8577
.254
77.0
0076
.745
66.1
7856
.647
31.1
1930
.846
30.5
7330
.299
28.0
93
Date:6 Mar 2008Document's Title:sk085
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:ZGPG45Temperature:299.16Number of Scans:352Acq. Date:Thu Mar 06 12:13:28 AM
sk085
F3C S
O HNBoc
syn-3f
-
41 / 53
ppm (t1)0.05.010.0
7.29
37.
288
7.27
57.
260
7.21
27.
200
7.16
87.
156
7.12
17.
118
7.05
1
4.93
24.
923
4.91
64.
907
4.74
84.
739
4.04
84.
031
3.33
03.
314
3.27
53.
259
2.36
12.
315
0.00
0000
0
16.18
0.08
1.071.01
0.081.00
0.162.00
2.910.30
Date:7 Mar 2008Document's Title:nu4-10-1
Spectrum Title:H-1 Routine 1D, DCH CryoProbe, 1-13-2006
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:ZG30Temperature:297Number of Scans:8Acq. Date:Tue Feb 26 11:37:11 AM
nu4-10-1
S
O
F3CPh
Ph
HNTs
syn-3g
-
42 / 53
ppm (t1)050100150200
193.
7
143.
113
7.4
136.
4
132.
612
9.3
129.
212
9.0
128.
912
8.3
128.
112
7.7
127.
212
6.9
125.
0
123.
2
121.
4
66.4
59.6
31.0
30.8
30.6
30.3
21.5
Date:7 Mar 2008Document's Title:nu4-10-1
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:297Number of Scans:343Acq. Date:Tue Feb 26 11:19:06 AM
nu4-10-1
S
O
F3CPh
Ph
HNTs
syn-3g
-
43 / 53
ppm (t1)0.05.010.0
7.32
37.
309
7.29
57.
273
7.27
17.
257
7.25
47.
249
7.24
57.
241
7.23
56.
881
6.87
76.
868
6.86
45.
342
5.34
05.
327
4.77
54.
774
4.14
04.
138
4.13
64.
134
4.13
24.
129
4.12
73.
798
3.45
23.
433
3.42
33.
403
3.38
33.
371
3.35
23.
341
3.32
21.
263
-0.0
0000
0
7.28
1.840.09
1.10
0.97
0.94
0.092.00
8.680.44
2.84
Date:5 Mar 2008Document's Title:nu3-239-1
Spectrum Title:H-1 Routine 1D experiment. BBO Probe, 9-13-2007
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:ZG30Temperature:299.16Number of Scans:16Acq. Date:Thu Nov 29 05:08:43 PM
nu3-239-1
S
O
F3C Ph
HNBoc
OMesyn-3h
-
44 / 53
ppm (t1)050100150200
194.
348
159.
711
154.
591
139.
941
130.
302
128.
537
127.
798
127.
131
126.
677
125.
661
125.
276
123.
448
121.
620
114.
244
79.7
8277
.212
77.0
0076
.788
65.3
24
56.5
2055
.274
31.0
3430
.806
30.5
7930
.351
28.1
21
Date:5 Mar 2008Document's Title:nu3-239-1
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:300Number of Scans:195Acq. Date:Thu Nov 29 05:30:45 PM
nu3-239-1
S
O
F3C Ph
HNBoc
OMesyn-3h
-
45 / 53
ppm (t1)0.05.010.0
7.33
57.
300
7.29
27.
233
7.22
5
5.79
35.
790
5.78
8
5.48
55.
483
5.47
95.
478
5.34
15.
338
5.33
65.
022
5.01
44.
966
4.94
6
4.84
74.
845
4.84
14.
841
3.51
43.
494
3.47
5
3.40
13.
381
3.36
11.
309
1.20
2
-0.0
0000
0
1.11
25.34
1.84
1.001.92
2.831.01
3.632.18
16.019.83
Date:5 Mar 2008Document's Title:nu4-17-1
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:ZG30Temperature:298.16Number of Scans:16Acq. Date:Mon Mar 03 10:51:51 AM
nu4-17-1
F3C S
O HNBoc
Cl3i
-
46 / 53
ppm (t1)050100150200
195.
5
193.
515
4.8
154.
3
139.
713
9.5
134.
813
4.2
131.
913
1.8
130.
012
9.7
129.
512
9.4
129.
412
9.2
128.
712
8.5
128.
112
7.6
127.
412
7.1
127.
012
6.4
125.
312
5.2
123.
412
3.3
121.
612
1.5
79.7
60.9
60.2
56.5
56.1
31.1
31.0
30.9
30.7
30.6
30.5
30.4
30.3
28.2
28.0
Date:5 Mar 2008Document's Title:nu4-17-1
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:297Number of Scans:337Acq. Date:Mon Mar 03 12:18:46 AM
nu4-17-1
F3C S
O HNBoc
Cl3i
-
47 / 53
ppm (f1)0.05.010.0
8.13
78.
123
8.10
78.
092
7.90
97.
895
7.84
97.
835
7.60
77.
604
7.59
7
7.52
87.
516
7.46
37.
460
7.45
27.
316
7.30
67.
248
5.86
35.
612
5.61
1
5.44
35.
293
5.28
3
5.20
65.
205
5.20
34.
849
3.50
73.
492
3.42
83.
412
3.35
63.
340
3.33
23.
315
1.30
91.
169
-0.0
0000
0
2.49
5.21
23.64
1.48
0.941.581.670.89
1.00
3.160.931.02
13.179.17
Date:6 Mar 2008Document's Title:sk078-2
Spectrum Title:H-1 Routine 1D, DCH CryoProbe, 1-13-2006
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:ZG30Temperature:297Number of Scans:16Acq. Date:Thu Mar 06 09:08:26 PM
s k078-2
S
O
F3C Ph
HNBoc
3j
-
48 / 53
ppm (f1)050100150200
196.
0
194.
315
4.9
154.
6
140.
013
9.8
134.
113
4.0
132.
013
1.2
129.
712
9.6
129.
412
9.3
129.
012
9.0
128.
512
8.5
127.
912
7.5
127.
312
7.2
127.
112
7.0
127.
012
6.5
126.
412
5.9
125.
812
5.5
125.
312
5.3
125.
1
123.
512
3.4
122.
312
1.9
121.
712
1.6
79.6
60.1
59.2
57.5
56.8
31.2
31.1
30.9
30.8
30.7
30.6
30.5
30.4
28.2
28.0
Date:6 Mar 2008Document's Title:sk078-2
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:297Number of Scans:760Acq. Date:Thu Mar 06 09:11:41 PM
sk078-2
S
O
F3C Ph
HNBoc
3j
-
49 / 53
ppm (f1)0.05.010.0
7.28
97.
276
7.25
87.
239
7.23
37.
211
7.20
06.
946
6.93
06.
922
5.76
55.
291
5.02
75.
025
5.02
35.
020
5.01
85.
015
4.61
3
4.51
93.
569
3.56
03.
544
3.46
93.
449
1.39
21.
329
20.73
6.33
2.24
3.31
0.87
2.221.00
6.66
21.319.04
Date:7 Mar 2008Document's Title:sk084-2
Spectrum Title:H-1 Routine 1D, DCH CryoProbe, 1-13-2006
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:ZG30Temperature:297Number of Scans:16Acq. Date:Fri Mar 07 10:34:59 AM
s k084-2
S
O
F3C Ph
HNBoc
S3k
-
50 / 53
ppm (f1)050100150200
195.
2
154.
913
9.1
135.
512
8.6
128.
512
7.8
127.
612
7.0
126.
512
6.3
125.
2
123.
4
121.
6
80.0
59.6
57.9
31.3
31.1
30.8
30.6
28.3
Date:7 Mar 2008Document's Title:sk084-2
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:297Number of Scans:394Acq. Date:Fri Mar 07 10:09:12 AM
S
O
F3C Ph
HNBoc
S3k
-
51 / 53
ppm (f1)0.05.010.0
7.37
67.
363
7.34
17.
329
7.31
07.
297
7.27
07.
262
5.57
85.
429
5.02
9
4.83
3
3.62
23.
608
3.50
93.
493
3.47
9
1.44
31.
424
12.76
0.963.16
1.091.00
1.952.61
20.95
Date:7 Mar 2008Document's Title:nu4-7-2
Spectrum Title:H-1 Routine 1D, DCH CryoProbe, 1-13-2006
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:ZG30Temperature:297Number of Scans:16Acq. Date:Thu Mar 06 05:16:19 PM
nu4-7-2
F3C S
O
Cl
HNBoc
3l
-
52 / 53
ppm (f1)050100150200
193.
309
193.
075
154.
683
154.
545
137.
251
135.
555
128.
713
128.
665
128.
625
128.
336
127.
516
127.
137
127.
011
126.
632
125.
307
125.
182
123.
477
123.
351
121.
522
80.5
3280
.507
69.2
9067
.043
57.2
3256
.483
32.1
2931
.902
31.6
7431
.474
31.2
4631
.018
28.2
5428
.179
Date:7 Mar 2008Document's Title:nu4-7-2
Spectrum Title:C-13 Routine 1D, DCH CryoProbe, 10-26-2006
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:ZGPG45Temperature:297Number of Scans:608Acq. Date:Thu Mar 06 05:20:43 PM
nu4-7-2
F3C S
O
Cl
HNBoc
3l
-
53 / 53
ppm (t1)0.05.010.0
7.34
07.
331
7.32
77.
324
7.31
77.
312
7.30
27.
298
7.29
57.
292
7.28
17.
276
7.27
37.
266
7.25
87.
184
7.18
17.
168
4.35
84.
352
4.33
54.
320
3.76
93.
757
3.74
73.
741
3.73
43.
728
3.71
93.
706
3.14
03.
127
3.11
33.
100
2.08
60.
0000
000
1.16
2.07
1.00
8.734.15
Date:7 Mar 2008Document's Title:SK089-4
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:ZG30Temperature:297.16Number of Scans:32Acq. Date:Tue Mar 04 09:01:54 PM
HOPh
NH2
Ph