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We present the crystal and molecular structures of 2,3,6,7,8,8a-hexahydro-6,8-methano-7,7,8a-trimethyl-3-(1-methyl-2-oxopropylidene)-5H-1,4-benzoxazin-2-one, C16H21NO3, (III), and 2,3,6,7,8,8a-hexahydro-3-(2-hydroxy-1-methylpropyl)-6,8-methano-7,7,8a-trimethyl-5H-1,4-benzoxazin-2-one, C16H25NO3, (V). These compounds are two of the four key intermediates in our synthetic route to (2R,3R,4R)-4-hydroxyisoleucine. The two structures provide a full understanding of the stereochemistry in successive steps. This synthesis was based on a new optically pure chiral oxazinone auxiliary derived from (1R,2R,5R)-2-hydroxypinan-3-one.
Supporting information
CCDC references: 179265; 179266
The enantioselective condensation of butan-2,3-dione with the
(1'R,2'R,5'R)-oxazinone, (I), resulted in the alcohol,
(II). After a dehydration step, a stereoselective hydrogenation of the double
bond of compound (III) gave the second optically pure intermediate, (IV).
After a reduction step, the final cleavage of the chiral auxiliary produced
one pure isomer of 4-hydroxyisoleucine. Crystals of (III) (m.p. 375–377 K)
and (V) (m.p. 382–384 K) suitable for single-crystal X-ray diffraction were
grown from solutions in diethyl ether.
For both structures, the H atoms were introduced at calculated positions and
refined as riding (O—H = 0.82 Å, and C—H = 0.96, 0.97 and 0.98 Å),
with a displacement parameter equal to 1.2 (OH, CH and CH2) or 1.5 (CH3)
times that of the parent atom.
For both compounds, data collection: KappaCCD Reference Manual (Nonius, 1998); data reduction: DENZO and SCALEPAK (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: maXus (Mackay et al., 1999).
(III) 2,3,5,6,7,8-Hexahydro-6,8-methano-7,7,8a-trimethyl-3-(1-methyl-2-
oxopropylidene)-5
H-1,4-benzoxazin-2-one
top
Crystal data top
C16H21NO3 | Dx = 1.200 Mg m−3 |
Mr = 275.34 | Mo Kα radiation, λ = 0.71073 Å |
Orthorhombic, P212121 | Cell parameters from 10878 reflections |
a = 8.4160 (3) Å | θ = 1.0–26.4° |
b = 12.3127 (5) Å | µ = 0.08 mm−1 |
c = 14.7039 (4) Å | T = 293 K |
V = 1523.72 (9) Å3 | Prism, colourless |
Z = 4 | 0.4 × 0.3 × 0.2 mm |
F(000) = 592 | |
Data collection top
Nonius KappaCCD area-detector diffractometer | Rint = 0.033 |
Radiation source: X-ray tube | θmax = 26.4°, θmin = 3.3° |
ϕ–scan | h = −10→10 |
10878 measured reflections | k = −15→15 |
1775 independent reflections | l = −17→17 |
1668 reflections with I > 2σ(I) | |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.038 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.100 | H-atom parameters constrained |
S = 1.06 | w = 1/[σ2(Fo2) + (0.0551P)2 + 0.1091P] where P = (Fo2 + 2Fc2)/3 |
1775 reflections | (Δ/σ)max < 0.001 |
181 parameters | Δρmax = 0.13 e Å−3 |
0 restraints | Δρmin = −0.16 e Å−3 |
Crystal data top
C16H21NO3 | V = 1523.72 (9) Å3 |
Mr = 275.34 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 8.4160 (3) Å | µ = 0.08 mm−1 |
b = 12.3127 (5) Å | T = 293 K |
c = 14.7039 (4) Å | 0.4 × 0.3 × 0.2 mm |
Data collection top
Nonius KappaCCD area-detector diffractometer | 1668 reflections with I > 2σ(I) |
10878 measured reflections | Rint = 0.033 |
1775 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.038 | 0 restraints |
wR(F2) = 0.100 | H-atom parameters constrained |
S = 1.06 | Δρmax = 0.13 e Å−3 |
1775 reflections | Δρmin = −0.16 e Å−3 |
181 parameters | |
Special details top
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor
wR and goodness of fit S are based on F2, conventional
R-factors R are based on F, with F set to zero for
negative F2. The threshold expression of F2 >
σ(F2) is used only for calculating R-factors(gt) etc.
and is not relevant to the choice of reflections for refinement.
R-factors based on F2 are statistically about twice as large
as those based on F, and R- factors based on ALL data will be
even larger. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1 | −0.0355 (2) | 0.61400 (17) | 0.53152 (14) | 0.0809 (6) | |
O2 | 0.1157 (2) | 0.54369 (11) | 0.71948 (10) | 0.0560 (4) | |
O3 | 0.16674 (16) | 0.36925 (9) | 0.73540 (8) | 0.0442 (3) | |
N1 | 0.3561 (2) | 0.37272 (13) | 0.58021 (11) | 0.0495 (4) | |
C1 | 0.1678 (2) | 0.46121 (14) | 0.68663 (12) | 0.0408 (4) | |
C2 | 0.2433 (2) | 0.45510 (15) | 0.59522 (12) | 0.0427 (4) | |
C3 | 0.2174 (3) | 0.53378 (16) | 0.53378 (13) | 0.0489 (5) | |
C4 | 0.1034 (3) | 0.62506 (17) | 0.54936 (14) | 0.0530 (5) | |
C5 | 0.1713 (4) | 0.73112 (18) | 0.5795 (2) | 0.0805 (8) | |
C6 | 0.2937 (4) | 0.5352 (2) | 0.44169 (17) | 0.0825 (9) | |
C7 | 0.1963 (2) | 0.26619 (14) | 0.68705 (12) | 0.0384 (4) | |
C8 | 0.3392 (2) | 0.28487 (15) | 0.62532 (13) | 0.0445 (4) | |
C9 | 0.4713 (3) | 0.2018 (2) | 0.62734 (18) | 0.0622 (6) | |
C10 | 0.4679 (3) | 0.1384 (2) | 0.71647 (18) | 0.0621 (6) | |
C11 | 0.4121 (3) | 0.2148 (2) | 0.79336 (16) | 0.0607 (6) | |
C12 | 0.2411 (2) | 0.18707 (15) | 0.76226 (14) | 0.0463 (4) | |
C13 | 0.3078 (3) | 0.07631 (17) | 0.72646 (17) | 0.0586 (5) | |
C14 | 0.2422 (4) | 0.0191 (2) | 0.6446 (2) | 0.0829 (8) | |
C15 | 0.3131 (4) | −0.0056 (2) | 0.8054 (2) | 0.0939 (10) | |
C16 | 0.0437 (3) | 0.24001 (18) | 0.63723 (16) | 0.0539 (5) | |
H5A | 0.0874 | 0.7835 | 0.5856 | 0.121* | |
H5B | 0.2467 | 0.7562 | 0.5353 | 0.121* | |
H5C | 0.2235 | 0.7219 | 0.6371 | 0.121* | |
H6A | 0.3272 | 0.6077 | 0.4275 | 0.124* | |
H6B | 0.2187 | 0.5109 | 0.3969 | 0.124* | |
H6C | 0.3843 | 0.4878 | 0.4417 | 0.124* | |
H9A | 0.5730 | 0.2381 | 0.6210 | 0.075* | |
H9B | 0.4592 | 0.1521 | 0.5767 | 0.075* | |
H10 | 0.5636 | 0.0958 | 0.7298 | 0.074* | |
H11A | 0.4416 | 0.2903 | 0.7849 | 0.073* | |
H11B | 0.4380 | 0.1897 | 0.8541 | 0.073* | |
H12 | 0.1632 | 0.1809 | 0.8115 | 0.056* | |
H14A | 0.3052 | −0.0441 | 0.6319 | 0.124* | |
H14B | 0.2449 | 0.0672 | 0.5932 | 0.124* | |
H14C | 0.1345 | −0.0023 | 0.6563 | 0.124* | |
H15A | 0.2071 | −0.0286 | 0.8198 | 0.141* | |
H15B | 0.3601 | 0.0281 | 0.8577 | 0.141* | |
H15C | 0.3754 | −0.0674 | 0.7879 | 0.141* | |
H16A | −0.0371 | 0.2208 | 0.6804 | 0.081* | |
H16B | 0.0614 | 0.1802 | 0.5966 | 0.081* | |
H16C | 0.0100 | 0.3024 | 0.6031 | 0.081* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0615 (10) | 0.0981 (14) | 0.0831 (12) | 0.0083 (10) | −0.0161 (9) | 0.0013 (11) |
O2 | 0.0765 (10) | 0.0421 (7) | 0.0492 (7) | 0.0106 (7) | 0.0077 (7) | −0.0055 (6) |
O3 | 0.0580 (7) | 0.0392 (6) | 0.0354 (6) | 0.0053 (6) | 0.0070 (6) | −0.0019 (5) |
N1 | 0.0530 (9) | 0.0465 (9) | 0.0490 (8) | 0.0020 (8) | 0.0135 (7) | −0.0002 (7) |
C1 | 0.0470 (9) | 0.0372 (8) | 0.0384 (8) | 0.0024 (8) | 0.0011 (8) | −0.0030 (7) |
C2 | 0.0467 (9) | 0.0405 (9) | 0.0411 (9) | −0.0024 (8) | 0.0056 (8) | −0.0018 (8) |
C3 | 0.0554 (12) | 0.0461 (10) | 0.0452 (10) | −0.0052 (9) | 0.0075 (9) | 0.0043 (8) |
C4 | 0.0584 (12) | 0.0536 (11) | 0.0471 (10) | 0.0000 (10) | 0.0012 (9) | 0.0117 (10) |
C5 | 0.0801 (17) | 0.0432 (11) | 0.118 (2) | −0.0022 (13) | 0.0139 (18) | 0.0081 (13) |
C6 | 0.105 (2) | 0.0812 (17) | 0.0609 (13) | 0.0109 (17) | 0.0342 (15) | 0.0196 (13) |
C7 | 0.0415 (9) | 0.0353 (8) | 0.0385 (8) | 0.0018 (7) | 0.0009 (7) | −0.0034 (7) |
C8 | 0.0458 (10) | 0.0448 (9) | 0.0428 (9) | 0.0029 (9) | 0.0066 (8) | −0.0055 (8) |
C9 | 0.0535 (11) | 0.0584 (12) | 0.0748 (15) | 0.0131 (11) | 0.0189 (11) | 0.0003 (12) |
C10 | 0.0479 (11) | 0.0607 (12) | 0.0775 (14) | 0.0160 (10) | 0.0005 (10) | 0.0075 (12) |
C11 | 0.0539 (12) | 0.0691 (14) | 0.0589 (12) | 0.0057 (11) | −0.0118 (10) | 0.0043 (12) |
C12 | 0.0463 (9) | 0.0454 (10) | 0.0473 (10) | 0.0047 (8) | 0.0018 (9) | 0.0069 (8) |
C13 | 0.0546 (11) | 0.0430 (10) | 0.0783 (14) | 0.0118 (9) | 0.0050 (12) | 0.0065 (10) |
C14 | 0.0798 (16) | 0.0510 (13) | 0.118 (2) | 0.0071 (13) | 0.0027 (18) | −0.0262 (14) |
C15 | 0.0873 (19) | 0.0661 (15) | 0.128 (3) | 0.0293 (16) | 0.016 (2) | 0.0414 (17) |
C16 | 0.0510 (11) | 0.0519 (11) | 0.0589 (12) | −0.0025 (10) | −0.0103 (10) | 0.0019 (10) |
Geometric parameters (Å, º) top
O1—C4 | 1.205 (3) | C5—H5A | 0.9600 |
O2—C1 | 1.207 (2) | C5—H5B | 0.9600 |
O3—C1 | 1.340 (2) | C5—H5C | 0.9600 |
O3—C7 | 1.476 (2) | C6—H6A | 0.9600 |
N1—C8 | 1.277 (2) | C6—H6B | 0.9600 |
N1—C2 | 1.407 (2) | C6—H6C | 0.9600 |
C1—C2 | 1.488 (2) | C10—H10 | 0.9800 |
C2—C3 | 1.342 (3) | C9—H9A | 0.9700 |
C3—C4 | 1.495 (3) | C9—H9B | 0.9700 |
C3—C6 | 1.499 (3) | C11—H11A | 0.9700 |
C4—C5 | 1.493 (3) | C11—H11B | 0.9700 |
C7—C8 | 1.524 (3) | C12—H12 | 0.9800 |
C8—C9 | 1.511 (3) | C14—H14A | 0.9600 |
C9—C10 | 1.526 (4) | C14—H14B | 0.9600 |
C7—C16 | 1.513 (3) | C14—H14C | 0.9600 |
C7—C12 | 1.521 (3) | C15—H15A | 0.9600 |
C10—C11 | 1.544 (3) | C15—H15B | 0.9600 |
C10—C13 | 1.556 (3) | C15—H15C | 0.9600 |
C11—C12 | 1.547 (3) | C16—H16A | 0.9600 |
C12—C13 | 1.566 (3) | C16—H16B | 0.9600 |
C13—C14 | 1.500 (4) | C16—H16C | 0.9600 |
C13—C15 | 1.538 (3) | | |
| | | |
C1—O3—C7 | 117.87 (12) | H5B—C5—H5C | 109.5 |
C8—N1—C2 | 117.02 (15) | C3—C6—H6A | 109.5 |
O2—C1—O3 | 119.63 (15) | C3—C6—H6B | 109.5 |
O2—C1—C2 | 123.97 (17) | H6A—C6—H6B | 109.5 |
O3—C1—C2 | 116.31 (15) | C3—C6—H6C | 109.5 |
C3—C2—N1 | 121.62 (17) | H6A—C6—H6C | 109.5 |
C3—C2—C1 | 120.13 (17) | H6B—C6—H6C | 109.5 |
N1—C2—C1 | 117.79 (16) | C8—C9—H9A | 109.6 |
C2—C3—C4 | 122.92 (17) | C10—C9—H9A | 109.6 |
C2—C3—C6 | 123.1 (2) | C8—C9—H9B | 109.6 |
C4—C3—C6 | 113.88 (19) | C10—C9—H9B | 109.6 |
O1—C4—C5 | 122.3 (2) | H9A—C9—H9B | 108.1 |
O1—C4—C3 | 120.2 (2) | C9—C10—H10 | 115.4 |
C5—C4—C3 | 117.2 (2) | C11—C10—H10 | 115.4 |
O3—C7—C16 | 105.88 (15) | C13—C10—H10 | 115.4 |
O3—C7—C12 | 104.02 (13) | C11—C12—H12 | 114.9 |
C16—C7—C12 | 115.22 (16) | C13—C12—H12 | 114.9 |
O3—C7—C8 | 106.86 (14) | C10—C11—H11A | 114.3 |
C16—C7—C8 | 114.43 (16) | C12—C11—H11A | 114.3 |
C12—C7—C8 | 109.48 (15) | C10—C11—H11B | 114.3 |
N1—C8—C9 | 120.11 (18) | C12—C11—H11B | 114.3 |
N1—C8—C7 | 121.67 (16) | H11A—C11—H11B | 111.4 |
C9—C8—C7 | 117.83 (16) | C7—C12—H12 | 114.9 |
C8—C9—C10 | 110.45 (18) | C13—C14—H14A | 109.5 |
C9—C10—C11 | 108.82 (18) | C13—C14—H14B | 109.5 |
C9—C10—C13 | 110.4 (2) | H14A—C14—H14B | 109.5 |
C11—C10—C13 | 88.08 (18) | C13—C14—H14C | 109.5 |
C10—C11—C12 | 86.11 (16) | H14A—C14—H14C | 109.5 |
C7—C12—C11 | 107.71 (17) | H14B—C14—H14C | 109.5 |
C7—C12—C13 | 113.73 (17) | C13—C15—H15A | 109.5 |
C11—C12—C13 | 87.61 (16) | C13—C15—H15B | 109.5 |
C14—C13—C15 | 107.9 (2) | H15A—C15—H15B | 109.5 |
C14—C13—C10 | 118.3 (2) | C13—C15—H15C | 109.5 |
C15—C13—C10 | 111.6 (2) | H15A—C15—H15C | 109.5 |
C14—C13—C12 | 123.1 (2) | H15B—C15—H15C | 109.5 |
C15—C13—C12 | 109.1 (2) | C7—C16—H16A | 109.5 |
C10—C13—C12 | 85.10 (16) | C7—C16—H16B | 109.5 |
C4—C5—H5A | 109.5 | H16A—C16—H16B | 109.5 |
C4—C5—H5B | 109.5 | C7—C16—H16C | 109.5 |
H5A—C5—H5B | 109.5 | H16A—C16—H16C | 109.5 |
C4—C5—H5C | 109.5 | H16B—C16—H16C | 109.5 |
H5A—C5—H5C | 109.5 | | |
| | | |
C7—O3—C1—O2 | 166.26 (18) | N1—C8—C9—C10 | 150.7 (2) |
C7—O3—C1—C2 | −17.0 (2) | C7—C8—C9—C10 | −22.3 (3) |
C8—N1—C2—C3 | −158.28 (19) | C8—C9—C10—C11 | −34.0 (3) |
C8—N1—C2—C1 | 29.6 (3) | C8—C9—C10—C13 | 61.1 (2) |
O2—C1—C2—C3 | −19.2 (3) | C9—C10—C11—C12 | 83.8 (2) |
O3—C1—C2—C3 | 164.23 (18) | C13—C10—C11—C12 | −27.10 (16) |
O2—C1—C2—N1 | 153.1 (2) | O3—C7—C12—C11 | −74.35 (18) |
O3—C1—C2—N1 | −23.5 (2) | C16—C7—C12—C11 | 170.23 (17) |
N1—C2—C3—C4 | −177.34 (19) | C8—C7—C12—C11 | 39.6 (2) |
C1—C2—C3—C4 | −5.4 (3) | O3—C7—C12—C13 | −169.66 (15) |
N1—C2—C3—C6 | 5.8 (3) | C16—C7—C12—C13 | 74.9 (2) |
C1—C2—C3—C6 | 177.8 (2) | C8—C7—C12—C13 | −55.7 (2) |
C2—C3—C4—O1 | −85.9 (3) | C10—C11—C12—C7 | −87.25 (18) |
C6—C3—C4—O1 | 91.2 (3) | C10—C11—C12—C13 | 26.92 (17) |
C2—C3—C4—C5 | 99.3 (3) | C9—C10—C13—C14 | 42.6 (3) |
C6—C3—C4—C5 | −83.6 (3) | C11—C10—C13—C14 | 152.0 (2) |
C1—O3—C7—C16 | −76.3 (2) | C9—C10—C13—C15 | 168.8 (2) |
C1—O3—C7—C12 | 161.85 (16) | C11—C10—C13—C15 | −81.9 (2) |
C1—O3—C7—C8 | 46.1 (2) | C9—C10—C13—C12 | −82.6 (2) |
C2—N1—C8—C9 | −167.9 (2) | C11—C10—C13—C12 | 26.79 (16) |
C2—N1—C8—C7 | 4.7 (3) | C7—C12—C13—C14 | −39.2 (3) |
O3—C7—C8—N1 | −41.3 (2) | C11—C12—C13—C14 | −147.5 (2) |
C16—C7—C8—N1 | 75.5 (2) | C7—C12—C13—C15 | −167.2 (2) |
C12—C7—C8—N1 | −153.39 (18) | C11—C12—C13—C15 | 84.4 (2) |
O3—C7—C8—C9 | 131.52 (18) | C7—C12—C13—C10 | 81.6 (2) |
C16—C7—C8—C9 | −111.6 (2) | C11—C12—C13—C10 | −26.74 (17) |
C12—C7—C8—C9 | 19.5 (2) | | |
(V) 2,3,5,6,7,8-Hexahydro-3-(2-hydroxy-1-methylpropyl)-6,8-methano-7,7,8a-
trimethyl-5
H-1,4-benzoxazin-2-one
top
Crystal data top
C16H25NO3 | Dx = 1.182 Mg m−3 |
Mr = 279.37 | Mo Kα radiation, λ = 0.71073 Å |
Orthorhombic, P212121 | Cell parameters from 11088 reflections |
a = 10.2905 (3) Å | θ = 1.0–26.3° |
b = 11.8864 (5) Å | µ = 0.08 mm−1 |
c = 12.8317 (5) Å | T = 293 K |
V = 1569.50 (10) Å3 | Prism, colourless |
Z = 4 | 0.4 × 0.3 × 0.2 mm |
F(000) = 608 | |
Data collection top
Nonius KappaCCD area-detector diffractometer | Rint = 0.036 |
Radiation source: X-ray tube | θmax = 26.3°, θmin = 3.1° |
ϕ–scan | h = −12→12 |
11088 measured reflections | k = −14→14 |
1791 independent reflections | l = −16→16 |
1638 reflections with I > 2σ(I) | |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.038 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.100 | H-atom parameters constrained |
S = 1.06 | w = 1/[σ2(Fo2) + (0.0677P)2 + 0.1278P] where P = (Fo2 + 2Fc2)/3 |
1791 reflections | (Δ/σ)max < 0.001 |
181 parameters | Δρmax = 0.13 e Å−3 |
0 restraints | Δρmin = −0.12 e Å−3 |
Crystal data top
C16H25NO3 | V = 1569.50 (10) Å3 |
Mr = 279.37 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 10.2905 (3) Å | µ = 0.08 mm−1 |
b = 11.8864 (5) Å | T = 293 K |
c = 12.8317 (5) Å | 0.4 × 0.3 × 0.2 mm |
Data collection top
Nonius KappaCCD area-detector diffractometer | 1638 reflections with I > 2σ(I) |
11088 measured reflections | Rint = 0.036 |
1791 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.038 | 0 restraints |
wR(F2) = 0.100 | H-atom parameters constrained |
S = 1.06 | Δρmax = 0.13 e Å−3 |
1791 reflections | Δρmin = −0.12 e Å−3 |
181 parameters | |
Special details top
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor
wR and goodness of fit S are based on F2, conventional
R-factors R are based on F, with F set to zero for
negative F2. The threshold expression of F2 >
σ(F2) is used only for calculating R-factors(gt) etc.
and is not relevant to the choice of reflections for refinement.
R-factors based on F2 are statistically about twice as large
as those based on F, and R- factors based on ALL data will be
even larger. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1 | 0.42623 (16) | 0.73053 (16) | 0.57239 (13) | 0.0716 (5) | |
O2 | 0.72659 (16) | 1.05251 (14) | 0.44797 (14) | 0.0734 (5) | |
O3 | 0.63837 (14) | 1.00686 (11) | 0.29869 (11) | 0.0556 (4) | |
N1 | 0.50368 (15) | 0.82874 (13) | 0.38796 (13) | 0.0496 (4) | |
C1 | 0.66693 (18) | 0.98389 (17) | 0.39881 (17) | 0.0533 (5) | |
C2 | 0.61678 (16) | 0.87394 (15) | 0.44380 (15) | 0.0464 (4) | |
C3 | 0.58141 (17) | 0.88756 (16) | 0.56013 (15) | 0.0485 (4) | |
C4 | 0.54706 (19) | 0.77388 (18) | 0.60934 (17) | 0.0549 (5) | |
C5 | 0.5371 (3) | 0.7795 (3) | 0.72699 (18) | 0.0731 (7) | |
C6 | 0.4750 (2) | 0.9749 (2) | 0.57512 (19) | 0.0690 (6) | |
C7 | 0.59405 (18) | 0.91485 (15) | 0.23041 (15) | 0.0471 (4) | |
C8 | 0.49354 (17) | 0.84735 (14) | 0.29143 (15) | 0.0463 (4) | |
C9 | 0.3705 (2) | 0.8141 (2) | 0.23492 (17) | 0.0597 (5) | |
C10 | 0.3425 (2) | 0.89586 (19) | 0.14670 (19) | 0.0628 (5) | |
C11 | 0.3903 (2) | 1.0134 (2) | 0.1794 (2) | 0.0685 (6) | |
C12 | 0.5264 (2) | 0.97498 (17) | 0.14047 (16) | 0.0535 (5) | |
C13 | 0.4521 (2) | 0.89393 (18) | 0.06422 (16) | 0.0572 (5) | |
C14 | 0.4139 (3) | 0.9582 (2) | −0.0349 (2) | 0.0837 (8) | |
C15 | 0.5060 (3) | 0.78096 (19) | 0.0297 (2) | 0.0701 (6) | |
C16 | 0.71463 (19) | 0.8475 (2) | 0.20144 (18) | 0.0631 (6) | |
H1 | 0.4199 | 0.7424 | 0.5097 | 0.086* | |
H2 | 0.6869 | 0.8184 | 0.4389 | 0.056* | |
H3 | 0.6591 | 0.9156 | 0.5959 | 0.058* | |
H4 | 0.6156 | 0.7200 | 0.5913 | 0.066* | |
H5A | 0.5288 | 0.7048 | 0.7546 | 0.110* | |
H5B | 0.4623 | 0.8231 | 0.7462 | 0.110* | |
H5C | 0.6139 | 0.8142 | 0.7548 | 0.110* | |
H6A | 0.5027 | 1.0454 | 0.5462 | 0.103* | |
H6B | 0.4577 | 0.9840 | 0.6482 | 0.103* | |
H6C | 0.3973 | 0.9504 | 0.5404 | 0.103* | |
H9A | 0.2982 | 0.8138 | 0.2835 | 0.072* | |
H9B | 0.3799 | 0.7387 | 0.2070 | 0.072* | |
H10 | 0.2539 | 0.8931 | 0.1188 | 0.075* | |
H11A | 0.3857 | 1.0276 | 0.2538 | 0.082* | |
H11B | 0.3527 | 1.0747 | 0.1397 | 0.082* | |
H12 | 0.5781 | 1.0337 | 0.1064 | 0.064* | |
H14A | 0.3798 | 1.0306 | −0.0163 | 0.126* | |
H14B | 0.3489 | 0.9164 | −0.0721 | 0.126* | |
H14C | 0.4890 | 0.9677 | −0.0784 | 0.126* | |
H15A | 0.5203 | 0.7343 | 0.0897 | 0.105* | |
H15B | 0.5868 | 0.7922 | −0.0062 | 0.105* | |
H15C | 0.4451 | 0.7450 | −0.0161 | 0.105* | |
H16A | 0.7663 | 0.8899 | 0.1531 | 0.095* | |
H16B | 0.6890 | 0.7777 | 0.1699 | 0.095* | |
H16C | 0.7646 | 0.8325 | 0.2631 | 0.095* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0648 (9) | 0.0831 (11) | 0.0669 (9) | −0.0289 (8) | −0.0023 (8) | 0.0110 (9) |
O2 | 0.0752 (10) | 0.0718 (10) | 0.0732 (9) | −0.0331 (9) | −0.0081 (9) | −0.0056 (8) |
O3 | 0.0578 (7) | 0.0476 (7) | 0.0616 (8) | −0.0177 (6) | −0.0058 (7) | 0.0016 (6) |
N1 | 0.0448 (8) | 0.0478 (8) | 0.0562 (9) | −0.0100 (7) | 0.0022 (8) | −0.0039 (7) |
C1 | 0.0444 (9) | 0.0532 (10) | 0.0623 (11) | −0.0107 (8) | −0.0006 (9) | −0.0017 (9) |
C2 | 0.0371 (8) | 0.0455 (9) | 0.0565 (10) | −0.0028 (7) | 0.0004 (8) | −0.0020 (8) |
C3 | 0.0394 (8) | 0.0512 (10) | 0.0549 (10) | −0.0011 (8) | 0.0010 (8) | −0.0061 (9) |
C4 | 0.0458 (9) | 0.0584 (11) | 0.0604 (11) | −0.0003 (8) | 0.0011 (9) | 0.0029 (10) |
C5 | 0.0593 (12) | 0.0986 (18) | 0.0613 (13) | −0.0017 (13) | 0.0014 (10) | 0.0125 (13) |
C6 | 0.0661 (13) | 0.0616 (12) | 0.0792 (14) | 0.0123 (11) | 0.0132 (12) | −0.0049 (11) |
C7 | 0.0419 (9) | 0.0438 (9) | 0.0555 (10) | −0.0061 (7) | 0.0007 (8) | 0.0002 (8) |
C8 | 0.0411 (8) | 0.0415 (8) | 0.0562 (10) | −0.0056 (8) | 0.0042 (9) | −0.0039 (8) |
C9 | 0.0479 (10) | 0.0710 (13) | 0.0603 (11) | −0.0180 (10) | −0.0012 (9) | −0.0036 (10) |
C10 | 0.0453 (10) | 0.0701 (13) | 0.0728 (13) | −0.0013 (10) | −0.0100 (10) | −0.0025 (11) |
C11 | 0.0629 (13) | 0.0602 (12) | 0.0823 (15) | 0.0133 (11) | −0.0123 (12) | −0.0040 (11) |
C12 | 0.0546 (10) | 0.0446 (9) | 0.0613 (11) | −0.0043 (8) | −0.0047 (9) | 0.0053 (8) |
C13 | 0.0616 (11) | 0.0529 (10) | 0.0572 (11) | −0.0055 (9) | −0.0076 (10) | 0.0036 (9) |
C14 | 0.0999 (19) | 0.0812 (17) | 0.0699 (14) | −0.0087 (15) | −0.0241 (14) | 0.0142 (13) |
C15 | 0.0826 (15) | 0.0623 (12) | 0.0653 (13) | −0.0079 (13) | 0.0013 (13) | −0.0092 (10) |
C16 | 0.0459 (10) | 0.0770 (14) | 0.0663 (12) | 0.0066 (10) | 0.0097 (10) | 0.0065 (11) |
Geometric parameters (Å, º) top
O1—C4 | 1.427 (2) | C3—H3 | 0.9800 |
O2—C1 | 1.200 (2) | C4—H4 | 0.9800 |
O3—C1 | 1.346 (3) | C5—H5A | 0.9600 |
O3—C7 | 1.474 (2) | C5—H5B | 0.9600 |
N1—C8 | 1.262 (2) | C5—H5C | 0.9600 |
N1—C2 | 1.468 (2) | C6—H6A | 0.9600 |
C1—C2 | 1.519 (3) | C6—H6B | 0.9600 |
C2—C3 | 1.545 (3) | C6—H6C | 0.9600 |
C3—C6 | 1.521 (3) | C9—H9A | 0.9700 |
C3—C4 | 1.533 (3) | C9—H9B | 0.9700 |
C4—C5 | 1.515 (3) | C10—H10 | 0.9800 |
C7—C16 | 1.522 (3) | C11—H11A | 0.9700 |
C7—C8 | 1.525 (2) | C11—H11B | 0.9700 |
C7—C12 | 1.526 (3) | C12—H12 | 0.9800 |
C8—C9 | 1.512 (3) | C14—H14A | 0.9600 |
C9—C10 | 1.520 (3) | C14—H14B | 0.9600 |
C10—C11 | 1.539 (3) | C14—H14C | 0.9600 |
C10—C13 | 1.547 (3) | C15—H15A | 0.9600 |
C11—C12 | 1.555 (3) | C15—H15B | 0.9600 |
C12—C13 | 1.571 (3) | C15—H15C | 0.9600 |
C13—C15 | 1.519 (3) | C16—H16A | 0.9600 |
C13—C14 | 1.535 (3) | C16—H16B | 0.9600 |
O1—H1 | 0.8200 | C16—H16C | 0.9600 |
C2—H2 | 0.9800 | | |
| | | |
C1—O3—C7 | 118.99 (15) | C4—C5—H5A | 109.5 |
C8—N1—C2 | 118.69 (16) | C4—C5—H5B | 109.5 |
O2—C1—O3 | 118.40 (18) | H5A—C5—H5B | 109.5 |
O2—C1—C2 | 123.97 (19) | C4—C5—H5C | 109.5 |
O3—C1—C2 | 117.58 (16) | H5A—C5—H5C | 109.5 |
N1—C2—C1 | 113.49 (16) | H5B—C5—H5C | 109.5 |
N1—C2—C3 | 108.85 (14) | C3—C6—H6A | 109.5 |
C1—C2—C3 | 110.92 (16) | C3—C6—H6B | 109.5 |
C6—C3—C4 | 112.55 (16) | H6A—C6—H6B | 109.5 |
C6—C3—C2 | 111.30 (17) | C3—C6—H6C | 109.5 |
C4—C3—C2 | 111.10 (16) | H6A—C6—H6C | 109.5 |
O1—C4—C5 | 106.75 (19) | H6B—C6—H6C | 109.5 |
O1—C4—C3 | 112.48 (17) | C8—C9—H9A | 109.6 |
C5—C4—C3 | 112.8 (2) | C10—C9—H9A | 109.6 |
O3—C7—C16 | 106.44 (16) | C8—C9—H9B | 109.6 |
O3—C7—C8 | 107.15 (15) | C10—C9—H9B | 109.6 |
C16—C7—C8 | 113.67 (16) | H9A—C9—H9B | 108.1 |
O3—C7—C12 | 104.09 (14) | C9—C10—H10 | 115.3 |
C16—C7—C12 | 115.68 (17) | C11—C10—H10 | 115.3 |
C8—C7—C12 | 108.99 (16) | C13—C10—H10 | 115.3 |
N1—C8—C9 | 119.60 (17) | C10—C11—H11A | 114.3 |
N1—C8—C7 | 122.67 (17) | C12—C11—H11A | 114.3 |
C9—C8—C7 | 117.34 (17) | C10—C11—H11B | 114.3 |
C8—C9—C10 | 110.42 (17) | C12—C11—H11B | 114.3 |
C9—C10—C11 | 108.45 (19) | H11A—C11—H11B | 111.4 |
C9—C10—C13 | 111.21 (18) | C7—C12—H12 | 115.0 |
C11—C10—C13 | 88.08 (18) | C11—C12—H12 | 115.0 |
C10—C11—C12 | 86.24 (16) | C13—C12—H12 | 115.0 |
C7—C12—C11 | 107.77 (18) | C13—C14—H14A | 109.5 |
C7—C12—C13 | 113.94 (16) | C13—C14—H14B | 109.5 |
C11—C12—C13 | 86.68 (16) | H14A—C14—H14B | 109.5 |
C15—C13—C14 | 107.0 (2) | C13—C14—H14C | 109.5 |
C15—C13—C10 | 118.61 (19) | H14A—C14—H14C | 109.5 |
C14—C13—C10 | 111.9 (2) | H14B—C14—H14C | 109.5 |
C15—C13—C12 | 123.07 (18) | C13—C15—H15A | 109.5 |
C14—C13—C12 | 109.62 (18) | C13—C15—H15B | 109.5 |
C10—C13—C12 | 85.40 (16) | H15A—C15—H15B | 109.5 |
C4—O1—H1 | 109.5 | C13—C15—H15C | 109.5 |
N1—C2—H2 | 107.8 | H15A—C15—H15C | 109.5 |
C1—C2—H2 | 107.8 | H15B—C15—H15C | 109.5 |
C3—C2—H2 | 107.8 | C7—C16—H16A | 109.5 |
C6—C3—H3 | 107.2 | C7—C16—H16B | 109.5 |
C4—C3—H3 | 107.2 | H16A—C16—H16B | 109.5 |
C2—C3—H3 | 107.2 | C7—C16—H16C | 109.5 |
O1—C4—H4 | 108.2 | H16A—C16—H16C | 109.5 |
C5—C4—H4 | 108.2 | H16B—C16—H16C | 109.5 |
C3—C4—H4 | 108.2 | | |
| | | |
C7—O3—C1—O2 | 165.45 (18) | N1—C8—C9—C10 | 147.37 (19) |
C7—O3—C1—C2 | −16.8 (2) | C7—C8—C9—C10 | −25.6 (3) |
C8—N1—C2—C1 | 31.4 (2) | C8—C9—C10—C11 | −32.9 (2) |
C8—N1—C2—C3 | 155.42 (17) | C8—C9—C10—C13 | 62.4 (2) |
O2—C1—C2—N1 | 154.7 (2) | C9—C10—C11—C12 | 84.0 (2) |
O3—C1—C2—N1 | −22.8 (2) | C13—C10—C11—C12 | −27.69 (16) |
O2—C1—C2—C3 | 31.8 (3) | O3—C7—C12—C11 | −77.21 (18) |
O3—C1—C2—C3 | −145.74 (17) | C16—C7—C12—C11 | 166.40 (17) |
N1—C2—C3—C6 | −64.7 (2) | C8—C7—C12—C11 | 36.9 (2) |
C1—C2—C3—C6 | 60.8 (2) | O3—C7—C12—C13 | −171.55 (16) |
N1—C2—C3—C4 | 61.6 (2) | C16—C7—C12—C13 | 72.1 (2) |
C1—C2—C3—C4 | −172.90 (15) | C8—C7—C12—C13 | −57.5 (2) |
C6—C3—C4—O1 | 55.3 (2) | C10—C11—C12—C7 | −86.83 (18) |
C2—C3—C4—O1 | −70.2 (2) | C10—C11—C12—C13 | 27.27 (16) |
C6—C3—C4—C5 | −65.5 (3) | C9—C10—C13—C15 | 43.8 (3) |
C2—C3—C4—C5 | 168.94 (18) | C11—C10—C13—C15 | 152.8 (2) |
C1—O3—C7—C16 | −77.0 (2) | C9—C10—C13—C14 | 169.05 (19) |
C1—O3—C7—C8 | 44.9 (2) | C11—C10—C13—C14 | −81.9 (2) |
C1—O3—C7—C12 | 160.32 (16) | C9—C10—C13—C12 | −81.65 (18) |
C2—N1—C8—C9 | −172.59 (17) | C11—C10—C13—C12 | 27.41 (15) |
C2—N1—C8—C7 | 0.0 (3) | C7—C12—C13—C15 | −40.6 (3) |
O3—C7—C8—N1 | −37.5 (2) | C11—C12—C13—C15 | −148.5 (2) |
C16—C7—C8—N1 | 79.8 (2) | C7—C12—C13—C14 | −167.6 (2) |
C12—C7—C8—N1 | −149.57 (19) | C11—C12—C13—C14 | 84.4 (2) |
O3—C7—C8—C9 | 135.27 (17) | C7—C12—C13—C10 | 80.83 (19) |
C16—C7—C8—C9 | −107.4 (2) | C11—C12—C13—C10 | −27.15 (16) |
C12—C7—C8—C9 | 23.2 (2) | | |
Experimental details
| (III) | (V) |
Crystal data |
Chemical formula | C16H21NO3 | C16H25NO3 |
Mr | 275.34 | 279.37 |
Crystal system, space group | Orthorhombic, P212121 | Orthorhombic, P212121 |
Temperature (K) | 293 | 293 |
a, b, c (Å) | 8.4160 (3), 12.3127 (5), 14.7039 (4) | 10.2905 (3), 11.8864 (5), 12.8317 (5) |
V (Å3) | 1523.72 (9) | 1569.50 (10) |
Z | 4 | 4 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 0.08 | 0.08 |
Crystal size (mm) | 0.4 × 0.3 × 0.2 | 0.4 × 0.3 × 0.2 |
|
Data collection |
Diffractometer | Nonius KappaCCD area-detector diffractometer | Nonius KappaCCD area-detector diffractometer |
Absorption correction | – | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 10878, 1775, 1668 | 11088, 1791, 1638 |
Rint | 0.033 | 0.036 |
(sin θ/λ)max (Å−1) | 0.626 | 0.624 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.038, 0.100, 1.06 | 0.038, 0.100, 1.06 |
No. of reflections | 1775 | 1791 |
No. of parameters | 181 | 181 |
H-atom treatment | H-atom parameters constrained | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.13, −0.16 | 0.13, −0.12 |
Selected geometric parameters (Å, º) for (III) topO1—C4 | 1.205 (3) | C1—C2 | 1.488 (2) |
O2—C1 | 1.207 (2) | C2—C3 | 1.342 (3) |
O3—C1 | 1.340 (2) | C3—C4 | 1.495 (3) |
O3—C7 | 1.476 (2) | C3—C6 | 1.499 (3) |
N1—C8 | 1.277 (2) | C4—C5 | 1.493 (3) |
N1—C2 | 1.407 (2) | C7—C8 | 1.524 (3) |
| | | |
C1—O3—C7 | 117.87 (12) | C2—C3—C4 | 122.92 (17) |
C8—N1—C2 | 117.02 (15) | C2—C3—C6 | 123.1 (2) |
O2—C1—O3 | 119.63 (15) | C4—C3—C6 | 113.88 (19) |
O2—C1—C2 | 123.97 (17) | O1—C4—C5 | 122.3 (2) |
O3—C1—C2 | 116.31 (15) | O1—C4—C3 | 120.2 (2) |
C3—C2—N1 | 121.62 (17) | C5—C4—C3 | 117.2 (2) |
C3—C2—C1 | 120.13 (17) | O3—C7—C8 | 106.86 (14) |
N1—C2—C1 | 117.79 (16) | N1—C8—C7 | 121.67 (16) |
| | | |
C8—N1—C2—C3 | −158.28 (19) | C2—C3—C4—O1 | −85.9 (3) |
O3—C1—C2—C3 | 164.23 (18) | C2—C3—C4—C5 | 99.3 (3) |
C1—C2—C3—C4 | −5.4 (3) | | |
Selected geometric parameters (Å, º) for (V) topO1—C4 | 1.427 (2) | C1—C2 | 1.519 (3) |
O2—C1 | 1.200 (2) | C2—C3 | 1.545 (3) |
O3—C1 | 1.346 (3) | C3—C6 | 1.521 (3) |
O3—C7 | 1.474 (2) | C3—C4 | 1.533 (3) |
N1—C8 | 1.262 (2) | C4—C5 | 1.515 (3) |
N1—C2 | 1.468 (2) | C7—C8 | 1.525 (2) |
| | | |
C1—O3—C7 | 118.99 (15) | C6—C3—C4 | 112.55 (16) |
C8—N1—C2 | 118.69 (16) | C6—C3—C2 | 111.30 (17) |
O2—C1—O3 | 118.40 (18) | C4—C3—C2 | 111.10 (16) |
O2—C1—C2 | 123.97 (19) | O1—C4—C5 | 106.75 (19) |
O3—C1—C2 | 117.58 (16) | O1—C4—C3 | 112.48 (17) |
N1—C2—C1 | 113.49 (16) | C5—C4—C3 | 112.8 (2) |
N1—C2—C3 | 108.85 (14) | O3—C7—C8 | 107.15 (15) |
C1—C2—C3 | 110.92 (16) | N1—C8—C7 | 122.67 (17) |
| | | |
C8—N1—C2—C3 | 155.42 (17) | C2—C3—C4—O1 | −70.2 (2) |
O3—C1—C2—C3 | −145.74 (17) | C2—C3—C4—C5 | 168.94 (18) |
C1—C2—C3—C4 | −172.90 (15) | | |
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For the synthesis of γ-hydroxy-α-aminoacids (Jacob et al., 1997), and in particular of 4-hydroxyisoleucine, we have explored a new strategy using the oxazinone (El Achkar et al., 1988) derived from (1R,2R,5R)-2-hydroxypinan-3-one as the starting material. By this route, enantiomerically pure isomers of (2R,3R,4R)-4-hydroxyisoleucine have been prepared (Kassem et al., 2001). The strategy used is outlined in the reaction scheme below. We have recently described the molecular structures of compounds (II) and (IV) (Kassem et al., 2000). At that time, we did not possess crystals of compounds (III) and (V) of sufficient quality to be able to determine their structure and stereochemistry, and without this information it is difficult to obtain a full stereochemical understanding of the different steps in the synthetic route; a particular requirement is the structure of the key didehydro intermediate, (III). \sch
During the enantioselective synthesis of 4-hydroxyisoleucine from the oxazinone, (I), three stereogenic centres were created, the key intermediate being the chiral didehydro amino-acid derivative, (III), where hydrogenation of the double bond would allow control of the configurations of the C atoms C2 and C3. The configuration of atom C3 controls the stereochemistry of atom C4 after reduction of the ketone. Hence, it was necessary to determine the geometry of the double bond of (III) and the configuration of C4 in compound (IV).
For these intermediates, we found the R configuration for C2 and S for C3 in compound (II), and the R configuration for both C2 and C3 in compound (IV). To determine the stereochemistry unambiguously during the dehydration step from (II) to (III), and the reduction step between (IV) and (V), the structures of two key intermediates, (III) and (V), were determined and their structures are presented here.
The C2═C3 double bond was found to have the E configuration in compound (III). From the known R configuration of C7, C10 and C12, coresponding to the chiral auxiliary oxazinone, we found the R configuration for C2, C3 and C4 in compound (V).
Compounds (III) and (V) have different structures. The carbonyl group on C4 and the C2═C3 double bond in compound (III) were reduced in two steps, producing three asymmetric C atoms, C2, C3 and C4, in compound (V). The six-membered C1—C2—N1—C8—C7—O3 ring of the oxazinone shares one side (C7—C8) with the bicyclo system of the (1R,2R,5R)-2-hydroxypinan-3-one. On atom C2 is found the future amino-acid side chain (C3—C4—C5).
The C1—C2—N1—C8—C7—O3 ring can be described as having a boat conformation, with slight distortion differences between (III) and (V). Atoms C2 and C7 are 0.2915 (17) and 0.5533 (17) Å, respectively, above the mean plane of the other four atoms (r.m.s. deviation 0.065 Å) in (III). However, in (V), atoms C2 and C7 are 0.3347 (17) and 0.5163 (18) Å, respectively, out of the same mean plane (r.m.s. deviation 0.066 Å). This difference is better indicated by the C8—N1—C2—C3 torsion angle, which is -158.28 (19)° in (III) and 155.44 (17)° in (V). In compound (III), a partial conjugation of the C2═C3 double bond with C8═N1 can be observed, but not with the carbonyl group of the ketone.
The bicyclo system, including the six-membered C7—C8—C9—C10—C11—C12 ring, is bridged by atom C13 between C12 and C10.