O-Benzyl-N-tert-butoxy­carbonyl-N-methyl-L-tyrosine

The crystal structure of the title compound, alternatively called 3-[4-(benzyl­oxy)­phenyl]-2-(N-tert-butoxy­car­bonyl-N-methyl­amino)­propi­onic acid, C₂₂H₂₇NO₅, has been studied in order to ex­amine the role of N-methyl­ation as a determinant of peptide conformation. The conformation of the tert-butoxy­carbonyl group is trans–trans. The side chain has a folded conformation and the two phenyl rings are effectively perpendicular to one another. The carboxyl­ate hydroxyl group and the urethane carbonyl group form a strong intermolecular O—H...O hydrogen bond.

S1. Comment

Conformational studies of peptides and pseudopeptides (peptidomimetics) represent an ongoing project in our laboratory aimed at finding new biologically active peptide analogues and new proteases inhibitors. N-Alkylated amino acids occur in many natural compounds, like antibiotics or toxins, and they are widely used in the synthesis of peptide analogues. As an example, incorporation of N-methylglycine (sarcosine) and N-methylalanine at position 7 of oxytocin has led to new derivatives with interesting properties (Grzonka et al., 1983; Gazis et al., 1984). The well known and widely used immunosuppressive drug cyclosporin A contains seven N-methylated amino acid residues (Loosli et al., 1985). The N-alkylated peptide bond is more resistant to enzymatic cleavage. The cis–trans isomerization of N-alkyated peptide bonds is shifted towards the cis-isomer. Finally, incorporation of N-alkylamino acid residues into the polypeptide chain decreases the possibility of hydrogen-bond formation, and at the same time, increases the hydrophobicity of such peptide fragments (Spatola, 1983). The present study is a contribution to our understanding of the structural role of N-methylation in amino acids and peptide derivatives.

The molecular structure and atom-numbering scheme of the title compound, (I), is shown in Fig. 1. A selection of bond distances and angles are given in Table 1 together with some notable torsion angles. The bond lengths within the tert-butoxycarbonyl group are very similar (except for the bond C19—O4, which is lengthened by nearly 0.02 Å) to the average lengths for this blocking group compiled by Benedetti et al. (1980). There is one notable variation from these averages in the bond angles involving the urethane bond. Thus, the C18—O4—C19 angle is 2° wider than the computed averages for these urethane linkages (Table 1). The conformation of the tert-butoxycarbonyl group, characterized by the torsion angles Θ₀ (C19—O4—C18—O3) and ω₀ (O4—C18—N1—C2), is trans–trans (Table 1). This is opposite to most of the published X-ray structures of compounds containing the tert-butoxycarbonyl group at a tertiary N atom (e.g. proline or sarcosine derivatives), which usually have a cis-urethane bond (Benedetti et al., 1980). The deviation from planarity of the urethane bond is in a typical range found for tert-butoxycarbonylamino acid and peptide derivatives (Sobková et al., 1996; Banumathi et al., 1999). The backbone conformation is characterized by the torsion angles Φ (C18—N1—C2—C1) and Ψ (O1—C1—C2—N1), and the conformation of the side chain is characterized by χ₁ (N1—C2—C3—C4) and χ₂ (C2—C3—C4—C5) (Table 1). Therefore, the side chain has a folded conformation. The O5—C10 bond is roughly coplanar with the tyrosine ring [C6—C7—O5—C10 = 1.3 (4)°] but perpendicular to the benzyl ring [O5—C10—C11—C12 = -85.7 (3)°]. With the O5—C10 bond in the trans orientation [C7—O5—C10—C11 = -176.9 (2)°], the two phenyl rings are thus perpendicular to each other [interplanar angle 86.5 (5)°]. The tyrosine and benzyl rings are planar with χ² values of 43.1 and 11.1°, respectively. In the crystal packing, the tyrosine and benzyl moieties form layers with the tert-butoxycarbonyl groups located between them (Fig. 2).

The carboxylate hydroxyl and the urethane carbonyl group form a strong intermolecular O1—H1···O3 hydrogen bond [O1···O3ⁱ 2.679 (2) Å and O1—H1···O3ⁱ 170 (3)°; symmetry code: (i) -x - 1, y - 0.5, -z - 0.5] (Fig. 2). A similar hydrogen bond was also reported in the crystal structure of tert-butoxycarbonyl-phenylalanine (Bats at al., 1980).

S2. Experimental

The title compound was synthesized from tert-butoxycarbonyl-(O-benzyl)-L-tyrosine and methyl iodide in the presence of KH and crown ether (18-C-6) (Schuman et al., 1983). The tyrosine derivative t hus formed is suitable for peptide synthesis both in solution and on solid-phase via peptide-chain elongation because it has a protected amino group (Boc) and an unprotected carboxylic acid group. Single crystals of the title compound (m.p. = 400–401 K) were obtained by slow evaporation from an ethyl acetate/petroleum ether solution at room temperature.

S3. Refinement

The position and isotropic displacement parameter of the hydroxyl H atom were refined. All other H atoms were generated geometrically and treated as riding atoms (C—H = 0.93–0.98 Å). The Friedel-equivalent reflections were merged, as attempted refinement of the Flack (1983) parameter was inconclusive [refined value 0.5 (10)]. The absolute configuration was set by reference to the known configuration of L-tyrosine.

Computing details

Data collection: KM4CCD Software (Kuma Diffraction, 1995–1999); cell refinement: KM4CCD Software; data reduction: KM4CCD Software; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: Stereochemical Workstation Operation Manual (Siemens, 1989).

Figures

	Fig. 1. Displacement-ellipsoid view (50% probability level) of the title compound with the atom-numbering scheme.
	Fig. 2. The crystal packing of the title compound viewed along c.

N-t-butoxycarbonyl-N-methyl-(O-benzyl)-L-tyrosine

Crystal data

C22H27NO5	F(000) = 824
Mr = 385.45	Dx = 1.231 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 6728 reflections
a = 9.346 (2) Å	θ = 3.4–29.6°
b = 11.413 (2) Å	µ = 0.09 mm^−1
c = 19.493 (4) Å	T = 100 K
V = 2079.2 (7) Å^3	Prism, colourless
Z = 4	0.35 × 0.30 × 0.25 mm

Data collection

Kuma CCD diffractometer	2602 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.044
Graphite monochromator	θmax = 29.6°, θmin = 2.1°
ω scans	h = −12→9
11736 measured reflections	k = −15→15
3067 independent reflections	l = −26→25

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.048	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.112	H atoms treated by a mixture of independent and constrained refinement
S = 1.34	w = 1/[σ^2(Fo^2) + (0.0369P)^2 + 0.4413P] where P = (Fo^2 + 2Fc^2)/3
3067 reflections	(Δ/σ)max < 0.001
257 parameters	Δρmax = 0.36 e Å^−3
0 restraints	Δρmin = −0.34 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

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 (Ų)

	x	y	z	Uiso*/Ueq
C1	0.4823 (3)	0.0363 (2)	0.80810 (13)	0.0188 (5)
C2	0.4612 (3)	0.1673 (2)	0.82199 (13)	0.0166 (5)
H2	0.5026	0.2109	0.7835	0.020*
C3	0.5429 (3)	0.2009 (2)	0.88737 (14)	0.0200 (6)
H3A	0.6439	0.1853	0.8803	0.024*
H3B	0.5104	0.1512	0.9246	0.024*
C4	0.5248 (3)	0.3281 (2)	0.90884 (13)	0.0174 (5)
C5	0.5415 (3)	0.4196 (2)	0.86279 (14)	0.0194 (5)
H5	0.5590	0.4029	0.8168	0.023*
C6	0.5328 (3)	0.5370 (2)	0.88385 (14)	0.0204 (6)
H6	0.5424	0.5974	0.8522	0.024*
C7	0.5089 (3)	0.5615 (2)	0.95287 (13)	0.0165 (5)
C8	0.4907 (3)	0.4705 (2)	0.99939 (13)	0.0188 (5)
H8	0.4733	0.4869	1.0454	0.023*
C9	0.4980 (3)	0.3555 (2)	0.97697 (13)	0.0196 (5)
H9	0.4847	0.2952	1.0084	0.024*
C10	0.5179 (3)	0.7707 (2)	0.93510 (13)	0.0213 (5)
H10A	0.6080	0.7664	0.9105	0.026*
H10B	0.4405	0.7732	0.9020	0.026*
C11	0.5141 (3)	0.8770 (2)	0.98061 (13)	0.0195 (5)
C12	0.3840 (3)	0.9273 (2)	0.99931 (15)	0.0214 (5)
H12	0.2992	0.8981	0.9811	0.026*
C13	0.3811 (3)	1.0210 (2)	1.04485 (15)	0.0224 (6)
H13	0.2940	1.0546	1.0570	0.027*
C14	0.5075 (3)	1.0641 (2)	1.07221 (13)	0.0216 (5)
H14	0.5051	1.1266	1.1028	0.026*
C15	0.6366 (3)	1.0143 (2)	1.05368 (15)	0.0243 (6)
H15	0.7215	1.0435	1.0718	0.029*
C16	0.6402 (3)	0.9211 (2)	1.00808 (15)	0.0236 (6)
H16	0.7274	0.8876	0.9961	0.028*
C17	0.2292 (3)	0.1548 (2)	0.88562 (13)	0.0198 (5)
H17A	0.2939	0.1197	0.9179	0.024*
H17B	0.1593	0.0980	0.8716	0.024*
H17C	0.1819	0.2202	0.9067	0.024*
C18	0.2456 (3)	0.2483 (2)	0.77139 (13)	0.0165 (5)
C19	0.0050 (3)	0.3014 (2)	0.72621 (13)	0.0210 (5)
C20	0.0290 (4)	0.2414 (3)	0.65794 (15)	0.0342 (7)
H20A	0.0162	0.1584	0.6633	0.041*
H20B	−0.0383	0.2706	0.6249	0.041*
H20C	0.1246	0.2570	0.6423	0.041*
C21	−0.1406 (3)	0.2701 (3)	0.75539 (16)	0.0302 (7)
H21A	−0.1500	0.1864	0.7571	0.036*
H21B	−0.1496	0.3017	0.8008	0.036*
H21C	−0.2143	0.3021	0.7266	0.036*
C22	0.0229 (4)	0.4334 (2)	0.72242 (18)	0.0329 (7)
H22A	0.0064	0.4665	0.7670	0.040*
H22B	0.1184	0.4517	0.7078	0.040*
H22C	−0.0445	0.4656	0.6904	0.040*
O2	0.3872 (2)	−0.03413 (17)	0.80441 (11)	0.0266 (5)
O1	0.6198 (2)	0.01092 (18)	0.80018 (12)	0.0286 (5)
H1	0.630 (4)	−0.061 (3)	0.7952 (18)	0.036 (10)*
O3	0.3122 (2)	0.28603 (15)	0.72172 (9)	0.0207 (4)
O5	0.5022 (2)	0.67162 (15)	0.98023 (9)	0.0206 (4)
O4	0.1034 (2)	0.25426 (17)	0.77968 (9)	0.0212 (4)
N1	0.3088 (2)	0.19508 (18)	0.82567 (11)	0.0169 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0185 (13)	0.0213 (12)	0.0167 (11)	0.0002 (11)	0.0010 (10)	−0.0045 (10)
C2	0.0136 (12)	0.0158 (11)	0.0205 (12)	0.0000 (10)	0.0012 (10)	−0.0027 (10)
C3	0.0215 (14)	0.0158 (12)	0.0227 (13)	0.0018 (10)	−0.0023 (11)	−0.0043 (10)
C4	0.0163 (13)	0.0141 (11)	0.0216 (12)	0.0011 (10)	−0.0036 (10)	−0.0011 (10)
C5	0.0236 (14)	0.0173 (12)	0.0174 (12)	−0.0009 (10)	0.0002 (10)	−0.0007 (10)
C6	0.0245 (14)	0.0174 (12)	0.0193 (12)	0.0006 (11)	−0.0010 (11)	0.0031 (10)
C7	0.0159 (12)	0.0140 (10)	0.0194 (11)	−0.0001 (10)	−0.0002 (10)	−0.0026 (9)
C8	0.0193 (12)	0.0207 (11)	0.0163 (11)	0.0000 (11)	−0.0022 (11)	−0.0005 (10)
C9	0.0203 (13)	0.0171 (11)	0.0214 (12)	0.0003 (11)	−0.0024 (11)	0.0026 (10)
C10	0.0315 (15)	0.0148 (11)	0.0176 (11)	0.0007 (11)	0.0015 (11)	−0.0001 (10)
C11	0.0240 (14)	0.0141 (11)	0.0204 (12)	−0.0002 (11)	0.0022 (11)	0.0006 (10)
C12	0.0192 (13)	0.0205 (12)	0.0245 (13)	−0.0010 (11)	−0.0044 (12)	0.0015 (11)
C13	0.0218 (14)	0.0185 (12)	0.0270 (14)	0.0031 (11)	0.0040 (12)	0.0022 (11)
C14	0.0312 (15)	0.0137 (11)	0.0198 (12)	−0.0013 (11)	0.0023 (12)	−0.0019 (10)
C15	0.0229 (15)	0.0221 (13)	0.0280 (15)	−0.0042 (11)	−0.0019 (12)	−0.0018 (12)
C16	0.0210 (14)	0.0214 (13)	0.0284 (15)	0.0001 (11)	0.0032 (12)	−0.0003 (12)
C17	0.0202 (13)	0.0225 (13)	0.0168 (11)	0.0025 (11)	0.0014 (10)	0.0038 (11)
C18	0.0194 (12)	0.0132 (11)	0.0169 (11)	0.0000 (10)	0.0003 (10)	−0.0037 (10)
C19	0.0236 (13)	0.0209 (12)	0.0187 (11)	0.0023 (11)	−0.0057 (12)	0.0032 (10)
C20	0.0400 (18)	0.0374 (16)	0.0252 (14)	−0.0006 (15)	−0.0076 (13)	−0.0045 (13)
C21	0.0259 (16)	0.0288 (15)	0.0358 (16)	0.0045 (13)	−0.0023 (13)	0.0044 (13)
C22	0.0334 (17)	0.0208 (13)	0.0446 (18)	0.0032 (13)	−0.0052 (15)	0.0048 (14)
O2	0.0240 (10)	0.0226 (10)	0.0331 (11)	−0.0063 (8)	0.0035 (9)	−0.0075 (9)
O1	0.0208 (10)	0.0196 (10)	0.0455 (13)	0.0031 (8)	0.0024 (9)	−0.0118 (10)
O3	0.0242 (10)	0.0178 (9)	0.0200 (9)	−0.0012 (8)	0.0028 (8)	0.0036 (8)
O5	0.0296 (10)	0.0142 (8)	0.0182 (8)	−0.0004 (8)	0.0027 (9)	−0.0014 (7)
O4	0.0178 (9)	0.0264 (10)	0.0195 (9)	0.0035 (8)	−0.0006 (8)	0.0049 (8)
N1	0.0146 (10)	0.0194 (10)	0.0167 (10)	0.0001 (8)	0.0016 (8)	0.0012 (9)

Geometric parameters (Å, º)

C1—O2	1.201 (3)	C13—C14	1.386 (4)
C1—O1	1.327 (3)	C13—H13	0.9300
C1—C2	1.531 (3)	C14—C15	1.383 (4)
C2—N1	1.462 (3)	C14—H14	0.9300
C2—C3	1.534 (4)	C15—C16	1.386 (4)
C2—H2	0.9800	C15—H15	0.9300
C3—C4	1.520 (3)	C16—H16	0.9300
C3—H3A	0.9700	C17—N1	1.459 (3)
C3—H3B	0.9700	C17—H17A	0.9598
C4—C5	1.386 (4)	C17—H17B	0.9600
C4—C9	1.387 (4)	C17—H17C	0.9601
C5—C6	1.403 (4)	C18—O3	1.229 (3)
C5—H5	0.9302	C18—O4	1.340 (3)
C6—C7	1.392 (3)	C18—N1	1.356 (3)
C6—H6	0.9300	C19—O4	1.491 (3)
C7—O5	1.367 (3)	C19—C20	1.514 (4)
C7—C8	1.389 (4)	C19—C21	1.517 (4)
C8—C9	1.385 (4)	C19—C22	1.518 (4)
C8—H8	0.9300	C20—H20A	0.9600
C9—H9	0.93	C20—H20B	0.9600
C10—O5	1.440 (3)	C20—H20C	0.9600
C10—C11	1.504 (3)	C21—H21A	0.9600
C10—H10A	0.9701	C21—H21B	0.9599
C10—H10B	0.9700	C21—H21C	0.9601
C11—C16	1.389 (4)	C22—H22A	0.9599
C11—C12	1.393 (4)	C22—H22B	0.9600
C12—C13	1.390 (4)	C22—H22C	0.9600
C12—H12	0.9300	O1—H1	0.83 (4)
O2—C1—O1	124.3 (2)	C15—C14—C13	119.8 (2)
O2—C1—C2	124.7 (2)	C15—C14—H14	120.3
O1—C1—C2	111.0 (2)	C13—C14—H14	119.9
N1—C2—C1	110.2 (2)	C14—C15—C16	120.3 (3)
N1—C2—C3	112.9 (2)	C14—C15—H15	119.8
C1—C2—C3	109.1 (2)	C16—C15—H15	119.9
N1—C2—H2	108.2	C15—C16—C11	120.3 (3)
C1—C2—H2	108.1	C15—C16—H16	119.9
C3—C2—H2	108.2	C11—C16—H16	119.8
C4—C3—C2	114.3 (2)	N1—C17—H17A	109.6
C4—C3—H3A	108.8	N1—C17—H17B	109.4
C2—C3—H3A	108.7	H17A—C17—H17B	109.5
C4—C3—H3B	108.5	N1—C17—H17C	109.4
C2—C3—H3B	108.7	H17A—C17—H17C	109.5
H3A—C3—H3B	107.6	H17B—C17—H17C	109.5
C5—C4—C9	118.1 (2)	O3—C18—O4	125.4 (2)
C5—C4—C3	121.9 (2)	O3—C18—N1	123.4 (2)
C9—C4—C3	119.9 (2)	O4—C18—N1	111.1 (2)
C4—C5—C6	121.6 (2)	O4—C19—C20	111.1 (2)
C4—C5—H5	119.2	O4—C19—C21	101.9 (2)
C6—C5—H5	119.2	C20—C19—C21	110.9 (2)
C7—C6—C5	119.0 (2)	O4—C19—C22	108.9 (2)
C7—C6—H6	120.5	C20—C19—C22	113.0 (3)
C5—C6—H6	120.5	C21—C19—C22	110.6 (3)
O5—C7—C8	115.3 (2)	C19—C20—H20A	109.4
O5—C7—C6	124.7 (2)	C19—C20—H20B	109.5
C8—C7—C6	120.0 (2)	H20A—C20—H20B	109.5
C9—C8—C7	119.8 (2)	C19—C20—H20C	109.4
C9—C8—H8	120.3	H20A—C20—H20C	109.5
C7—C8—H8	120.0	H20B—C20—H20C	109.5
C8—C9—C4	121.6 (2)	C19—C21—H21A	109.2
C8—C9—H9	119.1	C19—C21—H21B	109.6
C4—C9—H9	119.3	H21A—C21—H21B	109.5
O5—C10—C11	105.71 (19)	C19—C21—H21C	109.5
O5—C10—H10A	110.5	H21A—C21—H21C	109.5
C11—C10—H10A	110.6	H21B—C21—H21C	109.5
O5—C10—H10B	110.7	C19—C22—H22A	109.2
C11—C10—H10B	110.5	C19—C22—H22B	109.5
H10A—C10—H10B	108.7	H22A—C22—H22B	109.5
C16—C11—C12	119.3 (2)	C19—C22—H22C	109.8
C16—C11—C10	120.0 (2)	H22A—C22—H22C	109.5
C12—C11—C10	120.5 (2)	H22B—C22—H22C	109.5
C13—C12—C11	120.1 (3)	C1—O1—H1	110 (3)
C13—C12—H12	120.1	C7—O5—C10	118.62 (19)
C11—C12—H12	119.8	C18—O4—C19	123.1 (2)
C14—C13—C12	120.1 (3)	C18—N1—C17	123.0 (2)
C14—C13—H13	120.1	C18—N1—C2	118.9 (2)
C12—C13—H13	119.8	C17—N1—C2	117.9 (2)
O2—C1—C2—N1	−3.6 (4)	C11—C12—C13—C14	−0.5 (4)
O1—C1—C2—N1	175.9 (2)	C12—C13—C14—C15	0.5 (4)
O2—C1—C2—C3	120.9 (3)	C13—C14—C15—C16	−0.3 (4)
O1—C1—C2—C3	−59.5 (3)	C14—C15—C16—C11	0.0 (4)
N1—C2—C3—C4	−54.3 (3)	C12—C11—C16—C15	0.0 (4)
C1—C2—C3—C4	−177.2 (2)	C10—C11—C16—C15	−175.7 (3)
C2—C3—C4—C5	−48.6 (4)	C8—C7—O5—C10	−179.1 (2)
C2—C3—C4—C9	134.8 (3)	C6—C7—O5—C10	1.3 (4)
C9—C4—C5—C6	0.4 (4)	C11—C10—O5—C7	−176.9 (2)
C3—C4—C5—C6	−176.3 (2)	O3—C18—O4—C19	4.3 (4)
C4—C5—C6—C7	1.0 (4)	N1—C18—O4—C19	−176.0 (2)
C5—C6—C7—O5	178.0 (3)	C20—C19—O4—C18	52.8 (3)
C5—C6—C7—C8	−1.6 (4)	C21—C19—O4—C18	171.0 (2)
O5—C7—C8—C9	−178.9 (2)	C22—C19—O4—C18	−72.2 (3)
C6—C7—C8—C9	0.7 (4)	O3—C18—N1—C17	177.5 (2)
C7—C8—C9—C4	0.7 (4)	O4—C18—N1—C17	−2.2 (3)
C5—C4—C9—C8	−1.2 (4)	O3—C18—N1—C2	−8.0 (4)
C3—C4—C9—C8	175.5 (2)	O4—C18—N1—C2	172.3 (2)
O5—C10—C11—C16	90.0 (3)	C1—C2—N1—C18	−103.2 (3)
O5—C10—C11—C12	−85.7 (3)	C3—C2—N1—C18	134.5 (2)
C16—C11—C12—C13	0.2 (4)	C1—C2—N1—C17	71.6 (3)
C10—C11—C12—C13	175.9 (2)	C3—C2—N1—C17	−50.7 (3)