organic letters organocatalytic mannich-type reactions ...in order to expand the scope of direct...

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

[email protected]

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

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.

3406 Org. Lett., Vol. 10, No. 16, 2008

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

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.

2 / 53

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.


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).


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.


3-(tert-butoxycarbonylamino)-2-(4-nitrolphenyl)-3-phenylpropanethioate (3e).


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).


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).


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


3-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)-3-phenylpropanethioate (3h).


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.


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


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


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



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:



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


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


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


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


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



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:



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



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:



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



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


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


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



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



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



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



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


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



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



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



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



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



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



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



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


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


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



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



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

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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



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

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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



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

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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



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



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


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



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



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

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F3C Ph

HNBoc

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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



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



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



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


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

organic letters organocatalytic mannich-type reactions ...in order to expand the scope of direct...

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