Supporting Information

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1 Supporting Information Remote Stereoinductive Intramolecular Nitrile Oxide Cycloaddition: Asymmetric Total Synthesis and Structure Revision of ( )-11 -Hydroxycurvularin Hyeonjeong Choe, Thuy Trang Pham, Joo Yun Lee, Muhammad Latif, Haeil Park, Young Kee Kang* and Jongkook Lee* College of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon, Gangwon-do , Korea Contents 1. Details for DFT calculations X-ray crystal data for isoxazoline Characterization data for -hydroxyketone Copies of the 1 H & 13 C NMR spectra of all new compounds, ( )-11- hydroxycurvularin (1a) and ( )-11- -hydroxycurvularin (1b), and copies of the NOESY and HMBC spectra of 4b

2 1. Details for DFT calculations 1.1 Systematic searching for local minima of macrolactones 4a-d Conformational analysis of macrolactones 4a-d with -OMe groups replacing the -OBn groups was carried out using DFT methods to understand the conformational effects on INOC reactions in CH2Cl2. All DFT calculations were carried out using the Gaussian 03 program. 1 GaussView 2 was used in editing the structures. To obtain feasible structures for macrolactones 4a-d, the initial structures for 4b and 4d were generated from the extended structure s1, whereas those for 4a and 4c were generated from the extended structure s2 (Figure S1). The 196 and 204 initial structures, respectively, were generated from these extended s1 and s2 structures with i = 0, ±60, ±120, and 180 (i = 1 3) using the systematic search module from the Discovery Studio package 3 using the CHARMm force field, with the maximum systematic conformations = 1000 and the energy threshold = 20 kcal mol 1. Among these initial structures, 44, 36, 43, and 25 structures were selected as being likely to form cyclic compounds 4a -d, and were cyclized using GaussView. First, these initial structures were optimized at the HF/3-21G(d) level of theory and we obtained six, six, eight, and five local minima for 4a -d, respectively. Then, these were reoptimized at the B3LYP/6-31G(d) level of theory, followed by further optimization at the B3LYP/6-31+G(d) level of theory with replacement of the -OH groups with -OMe groups, from which we obtained all feasible local minima for 4a-d. Vibrational frequencies were calculated for all local minima at the B3LYP/6-31+G(d) level of theory at 25 C and 1 atm. A scaling factor of was chosen to reproduce the experimental frequency for the amide I band of N-methylacetamide in Ar and N2 matrixes. 4 Zero-point energy and thermal energy corrections were employed in calculating the Gibbs free energy of each conformation. Here, the ideal gas, rigid rotor, and harmonic oscillator approximations were used for the translational, rotational, and vibrational contributions to the Gibbs free energy, 2

3 respectively. 5 Single-point energies were calculated at the B3LYP/ G(d,p) level of theory for all local minima located at the B3LYP/6-31+G(d) level of theory. The solvation free energy ( Gs) of each local minimum was calculated using the conductor-like polarizable continuum model (CPCM) with the UAKS cavities 6 at the B3LYP/6-31+G(d) level of theory in CH2Cl2. The relative electronic energy ( Ee), the relative enthalpy ( H), and the relative Gibbs free energy ( G) of each of the local minima in CH2Cl2 were calculated from the sum of their values at the B3LYP/ G(d,p)//B3LYP/6-31+G(d) level of theory in the gas phase and the corresponding Gs value. The population of each local minimum was calculated using its G value in CH2Cl2 at 25 C. The torsion angles and thermodynamic properties of the feasible local minima of macrolactones 4a-d obtained in CH2Cl2 are listed in Table S1. The structures for all local minima of 4a-d optimized at the B3LYP/6-31+G(d) level of theory are shown in Figure S Exploring the paths for INOC reactions Each initial structure of transition states (TSs) for INOC reactions was generated from the most preferred products of 4b-1, 4a-1, 4c-1, and 4d-1 optimized at the B3LYP/6-31+G(d) level of theory, and this was followed by the TS optimization at the same level of theory. Each transition state was confirmed by checking whether it had one imaginary frequency following frequency calculations at the same level of theory. In addition, each transition state was checked using the intrinsic reaction coordinate (IRC) method 7 to determine whether it connects the reactants and products. However, as in most cases, the IRC calculation did not step all the way to the minimum on either side of the path. 8 Further optimizations were carried out starting from the reactants and products obtained by the IRC method to reach the two minima connected by the transition state. Single-point energies and solvation free energies of reactant, TS, and product of each INOC reaction were calculated at the same level of theory in CH2Cl2 as for local minima. The torsion angles and thermodynamic properties of reactant, TS, and product of each INOC reaction obtained in CH2Cl2 are listed in Table S2. Their structures optimized at the B3LYP/6-31+G(d) level of theory are shown in Figure S3. The free energy profiles for INOC reactions are depicted in Figure S4. Absolute energies of reactant, transition state, and product of each INOC reaction at the B3LYP/ G(d,p)//B3LYP/6-31+G(d) and CPCM B3LYP/6-31+G(d) levels of theory are presented in Table S3. Cartesian coordinates of reactant, transition state, and product of each INOC reaction optimized at the B3LYP/6-31+G(d) level of theory are listed in the following pages. 3

4 1.3 References (1) Frisch, M. J. et al., Gaussian 03, Revision C.02, Gaussian, Inc., Wallingford, (2) Frisch, A.; Hratchian, H. P.; Dennington II, R. D.; Keith, T. A.; Millam, J. GaussView, Version 5.0, Gaussian, Inc., Wallingford, (3) Discovery Studio, Accelrys Software, Inc., San Diego, (4) Kang, Y. K. J. Mol. Struct. (Theochem) 2001, 546, 183. (5) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital Theory, Wiley, New York, 1986, pp (6) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, (7) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154.(b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, (8) Foresman, J. B.; Frisch, A. Exploring Chemistry with Electronic Structure Methods, 2nd ed., Gaussian, Inc., Pittsburgh, 1996, Chapter 8. 4

5 + s1 4b 4d + s2 4a 4c Figure S1. Generation of the initial structures for 4a -d. The initial structures for 4b and 4d were generated from the extended structure s1, whereas those for 4a and 4c were generated from the extended structure s2. The 196 and 204 initial structures, respectively, were generated from these extended s1 and s2 structures with i = 0, ±60, ±120, and 180 (i = 1 3) using the systematic search module from the Discovery Studio package. 3 The torsion angles 1, 2, and 3 in s1 and s2 are defined for the sequences of C1 O17 C15 C14, O17 C15 C14 C13, and C15 C14 C13 C12, respectively. The definition of torsion angles 1 4 in 4b was also applied to those for 4a, 4c, and 4d. 5

6 Table S1. Calculated torsion angles and thermodynamic properties of macrolactones 4a-d in CH2Cl2 at 25 C a Torsion angles b Thermodynamic properties Conformers Ee c H c G c P d 4b b b b b b a a a a a a c c c c c c c c d d d d d a Calculated at the B3LYP/ G(d,p)//B3LYP/6-31+G(d) level of theory with solvation free energies at the CPCM B3LYP/6-31+G(d) level of theory. b Torsion angles ( ) are defined in Figure S1. c Ee, H, and G are relative electronic energies, relative enthalpies, and relative Gibbs free energies in kcal mol 1, respectively. d Populations (%) were calculated using G values at 25 C. 6

7 a) 4b-1 4b-2 4b-3 4b-4 4b-5 4b-6 b) 4a-1 4a-2 4a-3 4a-4 4a-5 4a-6 7

8 c) 4c-1 4c-2 4c-3 4c-4 d) 4c-5 4c-6 4c-7 4c-8 4d-1 4d-2 4d-3 4d-4 4d-5 Figure S2. The local minima for 4a-d optimized at the B3LYP/6-31+G(d) level of theory in the gas phase: a) 4b, b) 4a, c) 4c, d) 4d. 8

9 Table S2. Calculated torsion angles and thermodynamic properties of reactant, transition state, and product of each INOC reaction in CH2Cl2 at 25 C a Torsion angles b Thermodynamic properties Conformers Ee c H c G c R b-1 TS P a-1 4c-1 R TS P R TS P R d-1 TS P a Calculated at the B3LYP/ G(d,p)//B3LYP/6-31+G(d) level of theory with solvation free energies at the CPCM B3LYP/6-31+G(d) level of theory. b Torsion angles ( ) are defined in Figure S1. c Ee, H, and G are relative electronic energies, relative enthalpies, and relative Gibbs free energies to the corresponding values of reactant of 4d-1, respectively; in units of kcal mol 1. The values for TS correspond to Ee, H, and G of the barrier. 9

10 a) 4b-1-TS 4b-1-R 4b-1-P b) 4a-1-TS 4a-1-R 4a-1-P 10

11 c) 4c-1-TS d) 4c-1-R 4c-1-P 4d-1-TS 4d-1-R 4d-1-P Figure S3. The structures of reactant (R), transition state (TS), and product (P) of each INOC reaction optimized at the B3LYP/6-31+G(d) level of theory in the gas phase: a) 4b-1, b) 4a-1, c) 4c-1, d) 4d-1. 11

12 Figure S4. The free energy profiles for INOC reactions relative to the Gibbs free energy of the reactant 4d-1. 12

13 Table S3. Absolute energies of reactant, transition state, and product of each INOC reaction at the B3LYP/ G(d,p)//B3LYP/6-31+G(d) and CPCM B3LYP/6-31+G(d) levels of theory in CH2Cl2 at 25 C a Conformers B3LYP/6-31+G(d) B3LYP/ G(d,p) b CPCM B3LYP/6-31+G(d) c Ee H G Ee Ee R b-1 TS P R a-1 TS P R c-1 TS P R d-1 TS P a Energies in Hartees. b Single-point energies for optimized structures at the B3LYP/6-31+G(d) level of theory. c Singlepoint solvation free energies calculated using the CPCM method in CH2Cl2 for optimized structures at the B3LYP/6-31+G(d) level of theory. 13

14 1.4 Cartesian coordinates of reactant, transition state, and product of each INOC reaction optimized at the B3LYP/6-31+G(d) level of theory (1) 4b-1 (a) reactant R E e = Hartrees C C C C C C C C C C C C C C C C O O O O O N H H H H H H H H H H H H H H H H H C

15 H H H C H H H (b) transition state TS E e = Hartrees C C C C C C C C C C C C C C C C O O O O O N H H H H H H H H H H H H H H

16 H H H C H H H C H H H (c) product P E e = Hartrees C C C C C C C C C C C C C C C C O O O O O N H H H H H H H H H H

17 H H H H H H H C H H H C H H H (2) 4a-1 (a) reactant R E e = Hartrees C C C C C C C C C C C C C C C C O O O O O N H H H H

18 H H H H H H H H H H H H H C H H H C H H H (b) transition state TS E e = Hartrees C C C C C C C C C C C C C C C C O O O O O N

19 H H H H H H H H H H H H H H H H H C H H H C H H H (c) product P E e = Hartrees C C C C C C C C C C C C C C C C O O

20 O O O N H H H H H H H H H H H H H H H H H C H H H C H H H (3) 4c-1 (a) reactant R E e = Hartrees C C C C C C C C C C C C

21 C C C C O O O O O N H H H H H H H H H H H H H H H H H C H H H C H H H (b) transition state TS E e = Hartrees C C C C C C C C

22 C C C C C C C C O O O O O N H H H H H H H H H H H H H H H H H C H H H C H H H (c) product P E e = Hartrees C C C C

23 C C C C C C C C C C C C O O O O O N H H H H H H H H H H H H H H H H H C H H H C H H H

24 (4) 4d-1 (a) reactant R E e = Hartrees C C C C C C C C C C C C C C C C O O O O O N H H H H H H H H H H H H H H H H H C H H H

25 C H H H (b) transition state TS E e = Hartrees C C C C C C C C C C C C C C C C O O O O O N H H H H H H H H H H H H H H H H H

26 C H H H C H H H (c) product P E e = Hartrees C C C C C C C C C C C C C C C C O O O O O N H H H H H H H H H H H H H

27 H H H H C H H H C H H H

28 2. Crystal data for isoxazoline 10. Figure S5. X-ray crystal structure of isoxazoline 10 with atom numbers (The thermal ellipsoids are set at a 25% probability level). 28

29 Table S4. Crystal data and structure refinement for isoxazoline 10 Identification code lt_0m Empirical formula C16 H19 N O5 Formula weight Temperature 100(1) K Wavelength Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = (2) Å = 90 b = (2) Å = (2) c = (3) Å = 90 Volume (3) Å 3 Z 2 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 324 Crystal size 0.20 x 0.14 x 0.10 mm 3 Theta range for data collection 1.49 to Index ranges -9<=h<=9, -9<=k<=9, -16<=l<=18 Reflections collected Independent reflections 3632 [R(int) = ] Completeness to theta = % Absorption correction Multi-scan Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 3632 / 1 / 199 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter 0.2(8) Largest diff. peak and hole and e.å -3 29

30 Table S5. Atomic coordinates ( 10 4 ) and equivalent isotropic displacement parameters (Å ) for isoxazoline 10. U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) C(1) 1086(2) 3100(2) 7004(1) 17(1) C(2) 26(2) 1930(2) 6276(1) 17(1) C(3) 1149(2) 1417(2) 5408(1) 16(1) C(4) 475(2) 1912(2) 4486(1) 16(1) C(5) 1510(2) 1605(2) 3660(1) 16(1) C(6) 3247(2) 817(2) 3762(1) 18(1) C(7) 3929(2) 317(2) 4686(1) 17(1) C(8) 2876(2) 550(2) 5525(1) 15(1) C(9) 3619(2) -24(2) 6498(1) 15(1) C(10) 5546(2) 316(2) 6904(1) 18(1) C(11) 5443(2) -410(2) 7951(1) 19(1) C(12) 5857(2) 973(2) 8761(1) 22(1) C(13) 4718(2) 2727(2) 8712(1) 21(1) C(14) 2813(2) 2569(2) 9165(1) 21(1) C(15) 1378(2) 3889(2) 8724(1) 20(1) C(16) -134(2) 4396(2) 9413(1) 24(1) O(17) 428(2) 2934(2) 7898(1) 19(1) O(18) 2368(1) 4093(2) 6812(1) 19(1) O(19) 872(2) 2122(2) 2749(1) 19(1) O(20) 5632(2) -424(2) 4828(1) 22(1) O(21) 3556(2) -1124(2) 8011(1) 20(1) N(22) 2581(2) -827(2) 7110(1) 18(1) 30

31 Table S6. Bond lengths [Å ] and angles [ ] for isoxazoline 10 C(1)-O(18) (19) C(1)-O(17) (19) C(1)-C(2) 1.505(2) C(2)-C(3) 1.511(2) C(2)-H(2A) C(2)-H(2B) C(3)-C(4) 1.382(2) C(3)-C(8) 1.409(2) C(4)-C(5) 1.396(2) C(4)-H(4A) C(5)-O(19) (19) C(5)-C(6) 1.388(2) C(6)-C(7) 1.390(2) C(6)-H(6A) C(7)-O(20) (18) C(7)-C(8) 1.409(2) C(8)-C(9) 1.477(2) C(9)-N(22) 1.287(2) C(9)-C(10) 1.506(2) C(10)-C(11) 1.531(2) C(10)-H(10A) C(10)-H(10B) C(11)-O(21) (18) C(11)-C(12) 1.525(2) C(11)-H(11A) C(12)-C(13) 1.531(2) C(12)-H(12A) C(12)-H(12B) C(13)-C(14) 1.537(2) C(13)-H(13A) C(13)-H(13B) C(14)-C(15) 1.530(2) C(14)-H(14A) C(14)-H(14B)

32 C(15)-O(17) (18) C(15)-C(16) 1.516(2) C(15)-H(15A) C(16)-H(16A) C(16)-H(16B) C(16)-H(16C) O(19)-H(19A) O(20)-H(20A) O(21)-N(22) (17) O(18)-C(1)-O(17) (14) O(18)-C(1)-C(2) (14) O(17)-C(1)-C(2) (13) C(1)-C(2)-C(3) (12) C(1)-C(2)-H(2A) C(3)-C(2)-H(2A) C(1)-C(2)-H(2B) C(3)-C(2)-H(2B) H(2A)-C(2)-H(2B) C(4)-C(3)-C(8) (14) C(4)-C(3)-C(2) (13) C(8)-C(3)-C(2) (14) C(3)-C(4)-C(5) (14) C(3)-C(4)-H(4A) C(5)-C(4)-H(4A) O(19)-C(5)-C(6) (14) O(19)-C(5)-C(4) (14) C(6)-C(5)-C(4) (14) C(5)-C(6)-C(7) (14) C(5)-C(6)-H(6A) C(7)-C(6)-H(6A) O(20)-C(7)-C(6) (14) O(20)-C(7)-C(8) (14) C(6)-C(7)-C(8) (14) C(3)-C(8)-C(7) (14) C(3)-C(8)-C(9) (13) 32

33 C(7)-C(8)-C(9) (13) N(22)-C(9)-C(8) (13) N(22)-C(9)-C(10) (13) C(8)-C(9)-C(10) (13) C(9)-C(10)-C(11) (12) C(9)-C(10)-H(10A) C(11)-C(10)-H(10A) C(9)-C(10)-H(10B) C(11)-C(10)-H(10B) H(10A)-C(10)-H(10B) O(21)-C(11)-C(12) (13) O(21)-C(11)-C(10) (12) C(12)-C(11)-C(10) (13) O(21)-C(11)-H(11A) C(12)-C(11)-H(11A) C(10)-C(11)-H(11A) C(11)-C(12)-C(13) (13) C(11)-C(12)-H(12A) C(13)-C(12)-H(12A) C(11)-C(12)-H(12B) C(13)-C(12)-H(12B) H(12A)-C(12)-H(12B) C(12)-C(13)-C(14) (14) C(12)-C(13)-H(13A) C(14)-C(13)-H(13A) C(12)-C(13)-H(13B) C(14)-C(13)-H(13B) H(13A)-C(13)-H(13B) C(15)-C(14)-C(13) (13) C(15)-C(14)-H(14A) C(13)-C(14)-H(14A) C(15)-C(14)-H(14B) C(13)-C(14)-H(14B) H(14A)-C(14)-H(14B) O(17)-C(15)-C(16) (12) O(17)-C(15)-C(14) (12) 33

34 C(16)-C(15)-C(14) (14) O(17)-C(15)-H(15A) C(16)-C(15)-H(15A) C(14)-C(15)-H(15A) C(15)-C(16)-H(16A) C(15)-C(16)-H(16B) H(16A)-C(16)-H(16B) C(15)-C(16)-H(16C) H(16A)-C(16)-H(16C) H(16B)-C(16)-H(16C) C(1)-O(17)-C(15) (12) C(5)-O(19)-H(19A) C(7)-O(20)-H(20A) N(22)-O(21)-C(11) (10) C(9)-N(22)-O(21) (12) 34

35 Table S7. Anisotropic displacement parameters (Å ) for isoxazoline 10. The anisotropic displacement factor exponent takes the form: -2 2 [ h 2 a* 2 U h k a* b* U 12 ]. U 11 U 22 U 33 U 23 U 13 U 12 C(1) 14(1) 14(1) 23(1) 0(1) 3(1) 3(1) C(2) 10(1) 18(1) 23(1) -2(1) 3(1) 1(1) C(3) 12(1) 12(1) 23(1) -2(1) 2(1) -2(1) C(4) 12(1) 14(1) 24(1) 0(1) 0(1) 1(1) C(5) 16(1) 12(1) 22(1) 1(1) 0(1) -3(1) C(6) 16(1) 16(1) 21(1) -2(1) 3(1) -1(1) C(7) 12(1) 13(1) 25(1) 0(1) 2(1) 0(1) C(8) 14(1) 11(1) 20(1) 0(1) 1(1) 0(1) C(9) 13(1) 12(1) 22(1) -3(1) 2(1) 2(1) C(10) 12(1) 20(1) 22(1) -1(1) 1(1) 0(1) C(11) 13(1) 20(1) 24(1) 2(1) 0(1) 0(1) C(12) 16(1) 26(1) 24(1) 0(1) -2(1) -1(1) C(13) 16(1) 21(1) 27(1) -2(1) 1(1) -2(1) C(14) 17(1) 22(1) 24(1) -1(1) 2(1) -2(1) C(15) 17(1) 20(1) 22(1) -4(1) 1(1) -3(1) C(16) 21(1) 26(1) 27(1) -7(1) 3(1) 2(1) O(17) 17(1) 21(1) 20(1) -3(1) 4(1) -3(1) O(18) 14(1) 20(1) 25(1) 1(1) 3(1) -3(1) O(19) 16(1) 21(1) 20(1) 2(1) -2(1) -2(1) O(20) 17(1) 28(1) 24(1) 2(1) 6(1) 10(1) O(21) 17(1) 22(1) 21(1) 3(1) -1(1) -2(1) N(22) 17(1) 16(1) 21(1) 0(1) -1(1) 0(1) 35

36 Table S8. Hydrogen coordinates ( 10 4 ) and isotropic displacement parameters (Å ) for isoxazoline 10 x y z U(eq) H(2A) H(2B) H(4A) H(6A) H(10A) H(10B) H(11A) H(12A) H(12B) H(13A) H(13B) H(14A) H(14B) H(15A) H(16A) H(16B) H(16C) H(19A) H(20A)

37 Table S9. Torsion angles [ ] for isoxazoline 10 O(18)-C(1)-C(2)-C(3) 26.0(2) O(17)-C(1)-C(2)-C(3) (13) C(1)-C(2)-C(3)-C(4) (15) C(1)-C(2)-C(3)-C(8) 55.09(18) C(8)-C(3)-C(4)-C(5) -1.7(2) C(2)-C(3)-C(4)-C(5) (13) C(3)-C(4)-C(5)-O(19) (13) C(3)-C(4)-C(5)-C(6) -0.9(2) O(19)-C(5)-C(6)-C(7) (14) C(4)-C(5)-C(6)-C(7) 0.9(2) C(5)-C(6)-C(7)-O(20) (14) C(5)-C(6)-C(7)-C(8) 1.6(2) C(4)-C(3)-C(8)-C(7) 4.0(2) C(2)-C(3)-C(8)-C(7) (13) C(4)-C(3)-C(8)-C(9) (13) C(2)-C(3)-C(8)-C(9) 4.5(2) O(20)-C(7)-C(8)-C(3) (13) C(6)-C(7)-C(8)-C(3) -4.0(2) O(20)-C(7)-C(8)-C(9) -0.9(2) C(6)-C(7)-C(8)-C(9) (14) C(3)-C(8)-C(9)-N(22) 44.1(2) C(7)-C(8)-C(9)-N(22) (15) C(3)-C(8)-C(9)-C(10) (15) C(7)-C(8)-C(9)-C(10) 44.3(2) N(22)-C(9)-C(10)-C(11) -2.26(17) C(8)-C(9)-C(10)-C(11) (13) C(9)-C(10)-C(11)-O(21) 2.08(15) C(9)-C(10)-C(11)-C(12) (14) O(21)-C(11)-C(12)-C(13) (17) C(10)-C(11)-C(12)-C(13) 53.83(19) C(11)-C(12)-C(13)-C(14) 83.37(18) C(12)-C(13)-C(14)-C(15) (14) C(13)-C(14)-C(15)-O(17) 90.87(15) C(13)-C(14)-C(15)-C(16) (14) 37

38 O(18)-C(1)-O(17)-C(15) -4.8(2) C(2)-C(1)-O(17)-C(15) (12) C(16)-C(15)-O(17)-C(1) (13) C(14)-C(15)-O(17)-C(1) (15) C(12)-C(11)-O(21)-N(22) (13) C(10)-C(11)-O(21)-N(22) -1.46(15) C(8)-C(9)-N(22)-O(21) (12) C(10)-C(9)-N(22)-O(21) 1.44(17) C(11)-O(21)-N(22)-C(9) 0.07(16) Table S10. Hydrogen bonds for isoxazoline 10 [Å and ] D-H...A d(d-h) d(h...a) d(d...a) <(DHA) O(19)-H(19A)...O(18)# (16) O(20)-H(20A)...O(18)# (15) Symmetry transformations used to generate equivalent atoms: #1 -x,y-1/2,-z+1 #2 -x+1,y-1/2,-z+1 38

39 3. Characterization data for -hydroxyketone 11 To a solution of oxazoline 4a,c [4a/4c (or 4d), 3.7:1, 56.0 mg] in EtOH/ THF/H2O (5:5:1, ml) was added freshly activated Raney-Ni (2 scoop of spatula). The mixture was stirred 1 d at room temperature under a hydrogen atmosphere. To the mixture was added catalytic amount of Pd/C (5%, 10 mg). The mixture was stirred for 5 h at room temperature under a hydrogen atmosphere and filtered through a pad of Celite. The filtrate was concentrated and the resulting residue was purified by flash column chromatography on silica gel to give (-)-11 -hydroxycurvularin (1a) (15.4 mg) in 43% (55%, calculated from 4a) yield and alcohol 11 (3.6 mg) in 10% [46%, calculated from 4c (or 4d)] yield. 11: [ ] 20 D = (c 1.00, EtOH); 1 H NMR (acetone-d 6, 500 MHz) δ 6.34 (d, J = 1.6 Hz, 1H), 6.32 (s, 1H), (m, 1H), 4.14 (d, J = 17.1 Hz, 1H), 3.93 (t, J = 9.2 Hz, 1H), 3.74 (dd, J = 9.5, 5.6 Hz, 1H), (m, 1H), 3.43 (d, J = 17.1 Hz, 1H), (m, 6H), 1.12 (d, J = 6.0 Hz, 3H); 13 C NMR (acetone-d 6, 75 MHz) δ 210.7, 169.9, 161.4, 159.4, 137.3, 121.9, 112.4, 103.6, 70.6, 65.8, 53.8, 41.9, 33.6, 27.6, 24.1, 21.2; IR (neat) 3240, 2968, 2930, 1700, 1602, 1586, 1260, 1160, 1042; HRMS: (EI, magnetic sector) m/z calcd for C16H20O6 (M + ) , found

40 4. Copies of the 1 H & 13 C NMR spectra of all new compounds, ( )-11- -hydroxycurvularin (1a) and ( )-11- -hydroxycurvularin (1b) ), and a copy of NOESY spectrum of 4b. 40

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