Synthesis, experimental and in silico studies of N-fluorenyl­methoxycarbonyl-O-tert-butyl-N-methyl­tyrosine, coupled with CSD data: a survey of inter­actions in the crystal structures of Fmoc–amino acids

Bojarska, J.; Remko, M.; Madura, I.D.; Kaczmarek, K.; Zabrocki, J.; Wolf, W.M.

doi:10.1107/S2053229620003009

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Synthesis, experimental and in silico studies of N-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

J. Bojarska, M. Remko, I. D. Madura, K. Kaczmarek, J. Zabrocki and W. M. Wolf

Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc–tyrosine or Fmoc–phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc-protected amino acid, namely, 2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}-3-{4-[(2-hydroxypropan-2-yl)oxy]phenyl}propanoic acid or N-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, Fmoc-N-Me-Tyr(t-Bu)-OH, C₂₉H₃₁NO₅, was successfully synthesized and the structure of its unsolvated form was determined by single-crystal X-ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N-Fmoc-phenylalanine [Draper et al. (2015). CrystEngComm, 42, 8047–8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H

H, C

H/H

C and O

H/H

O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogen-bonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C—H

O, C—H

π, (fluorenyl)C—H

Cl(I), C—Br

π(fluorenyl) and C—I

π(fluorenyl) interactions are observed. Basic synthons, in combination with the Long-Range Synthon Aufbau Modules, further supported by energy-framework calculations, are discussed. Furthermore, the relevance of Fmoc-based supramolecular hydrogen-bonding patterns in biocomplexes are emphasized, for the first time.

Keywords: Fmoc amino acids; supramolecular synthon; tecton; DFT; Hirshfeld surface; electrostatic molecular potential; SC-XRD; energy framework; crystal structure.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229620003009/qp3039sup1.cif Contains datablocks I, global
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229620003009/qp3039Isup2.hkl Contains datablock I
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229620003009/qp3039sup3.cml Supplementary material
	Portable Document Format (PDF) file https://doi.org/10.1107/S2053229620003009/qp3039sup4.pdf Supplementary material

CCDC reference: 1951365

Computing details top

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS (Siemens, 1996); data reduction: XSCANS (Siemens, 1996); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015b).

2-{[(9H-Fluoren-9-ylmethoxy)carbonyl](methyl)amino}-3-{4-[(2-hydroxypropan-2-yl)oxy]phenyl}propanoic acid top

Crystal data top

C₂₉H₃₁NO₅	D_x = 1.242 Mg m⁻³
M_r = 473.55	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 9925 reflections
a = 6.4917 (3) Å	θ = 2.3–28.6°
b = 17.5357 (7) Å	µ = 0.09 mm⁻¹
c = 22.2418 (8) Å	T = 296 K
V = 2531.93 (18) Å³	Plate, colourless
Z = 4	0.60 × 0.25 × 0.15 mm
F(000) = 1008

Data collection top

Siemens P3 diffractometer	5543 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.022
profile data from θ/2θ scans	θ_max = 27.5°, θ_min = 1.5°
Absorption correction: multi-scan (SADABS; Sheldrick, 2008)	h = −8→8
T_min = 0.872, T_max = 0.992	k = −22→22
58330 measured reflections	l = −28→28
5823 independent reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.032	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.091	w = 1/[σ²(F_o²) + (0.0623P)² + 0.2078P] where P = (F_o² + 2F_c²)/3
S = 0.99	(Δ/σ)_max = 0.001
5823 reflections	Δρ_max = 0.15 e Å⁻³
396 parameters	Δρ_min = −0.16 e Å⁻³
0 restraints	Absolute structure: Flack x determined using 2313 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons & Flack, 2004)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.19 (14)

Special details top

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

Refinement. The SC-XRD was performed on a Siemens P3 diffractometer using graphite monochromated Mo Kα radiation (λ = 0.71073 Å) as a source of radiation. The structure was solved with the SHELXS structure solution program and refined in the SHELXL-2014 (Sheldrick, 2015) by the full-matrix least-squares on F². All non-hydrogen atoms were initially located on E maps and refined anisotropically.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
N1	0.40982 (19)	−0.08075 (7)	0.97111 (6)	0.0360 (3)
O3	0.5064 (2)	−0.27780 (7)	0.93447 (6)	0.0530 (3)
O1	−0.0581 (2)	0.08123 (8)	0.76045 (5)	0.0557 (3)
O2	0.5219 (3)	−0.21723 (7)	1.02265 (6)	0.0582 (4)
C23	−0.2349 (3)	0.16051 (8)	1.02378 (8)	0.0395 (3)
C14	0.2537 (2)	−0.05737 (8)	1.00620 (7)	0.0346 (3)
O4	0.08814 (18)	−0.09013 (6)	1.01111 (6)	0.0467 (3)
C13	0.4813 (3)	−0.21821 (8)	0.97018 (7)	0.0394 (3)
C16	0.0909 (3)	0.11810 (9)	1.06152 (7)	0.0396 (3)
C11	0.4532 (3)	−0.14247 (10)	0.87096 (8)	0.0448 (4)
O5	0.29769 (19)	0.00778 (7)	1.03506 (6)	0.0458 (3)
C28	−0.0475 (3)	0.12640 (8)	1.00715 (7)	0.0394 (3)
C22	−0.2289 (3)	0.17649 (8)	1.08842 (8)	0.0405 (3)
C8	0.3252 (3)	−0.08382 (9)	0.83773 (7)	0.0432 (3)
C12	0.3838 (2)	−0.15093 (8)	0.93673 (7)	0.0362 (3)
C24	−0.3857 (3)	0.17599 (9)	0.98133 (8)	0.0470 (4)
C17	−0.0380 (3)	0.15294 (9)	1.11122 (7)	0.0419 (3)
C27	−0.0115 (3)	0.10738 (10)	0.94742 (8)	0.0489 (4)
C15	0.1475 (3)	0.03615 (10)	1.07729 (8)	0.0468 (4)
C1	−0.0793 (3)	0.09457 (12)	0.69571 (7)	0.0531 (4)
C19	−0.1362 (5)	0.19791 (14)	1.20822 (9)	0.0687 (6)
C25	−0.3483 (4)	0.15657 (11)	0.92150 (9)	0.0552 (4)
C5	0.0729 (3)	0.02494 (10)	0.78133 (7)	0.0457 (4)
C18	0.0089 (4)	0.16336 (12)	1.17156 (9)	0.0567 (5)
C7	0.1252 (4)	−0.10153 (12)	0.81968 (10)	0.0582 (5)
C26	−0.1640 (4)	0.12277 (11)	0.90508 (9)	0.0567 (5)
C29	0.6171 (3)	−0.04817 (11)	0.97609 (9)	0.0491 (4)
H29A	0.6116	−0.0022	0.9995	0.059*
H29B	0.6688	−0.0367	0.9367	0.059*
H29C	0.7068	−0.0842	0.9953	0.059*
C10	0.2722 (3)	0.04351 (11)	0.79854 (9)	0.0544 (4)
C9	0.3956 (3)	−0.01074 (12)	0.82630 (9)	0.0532 (4)
C6	0.0011 (3)	−0.04802 (13)	0.79183 (10)	0.0600 (5)
C21	−0.3733 (3)	0.21104 (11)	1.12580 (9)	0.0546 (4)
C20	−0.3228 (4)	0.22187 (14)	1.18594 (10)	0.0688 (6)
C2	0.1203 (5)	0.12258 (15)	0.66979 (10)	0.0692 (6)
H2A	0.1643	0.1672	0.6912	0.083*
H2B	0.1012	0.1349	0.6281	0.083*
H2C	0.2230	0.0835	0.6735	0.083*
C3	−0.1507 (5)	0.02203 (17)	0.66476 (11)	0.0802 (8)
H3A	−0.0515	−0.0177	0.6714	0.096*
H3B	−0.1644	0.0312	0.6224	0.096*
H3C	−0.2815	0.0068	0.6809	0.096*
C4	−0.2427 (5)	0.15678 (19)	0.69363 (14)	0.0886 (9)
H4A	−0.3668	0.1386	0.7122	0.106*
H4B	−0.2705	0.1700	0.6525	0.106*
H4C	−0.1939	0.2009	0.7148	0.106*
H121	0.236 (3)	−0.1625 (11)	0.9379 (8)	0.037 (5)*
H271	0.112 (4)	0.0871 (13)	0.9356 (10)	0.057 (6)*
H112	0.605 (4)	−0.1285 (12)	0.8696 (9)	0.049 (5)*
H91	0.530 (4)	0.0020 (15)	0.8349 (12)	0.069 (7)*
H151	0.032 (4)	0.0014 (12)	1.0755 (10)	0.048 (5)*
H241	−0.515 (4)	0.2013 (14)	0.9950 (10)	0.061 (6)*
H111	0.436 (4)	−0.1907 (14)	0.8531 (10)	0.059 (6)*
H181	0.137 (4)	0.1454 (15)	1.1878 (11)	0.066 (7)*
H161	0.217 (4)	0.1451 (13)	1.0553 (10)	0.053 (6)*
H61	−0.144 (4)	−0.0624 (14)	0.7784 (10)	0.063 (6)*
H101	0.325 (3)	0.0959 (13)	0.7930 (9)	0.052 (5)*
H201	−0.413 (6)	0.2460 (19)	1.2134 (15)	0.099 (10)*
H71	0.070 (4)	−0.1525 (17)	0.8276 (11)	0.072 (7)*
H221	−0.504 (4)	0.2285 (15)	1.1090 (11)	0.061 (6)*
H251	−0.459 (5)	0.1670 (15)	0.8923 (12)	0.073 (8)*
H3	0.538 (5)	−0.3189 (16)	0.9576 (12)	0.074 (7)*
H152	0.213 (4)	0.0359 (14)	1.1168 (12)	0.062 (6)*
H261	−0.137 (4)	0.1106 (15)	0.8636 (12)	0.072 (7)*
H191	−0.100 (5)	0.2089 (18)	1.2504 (15)	0.098 (10)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0294 (6)	0.0317 (6)	0.0468 (6)	0.0017 (5)	0.0004 (5)	−0.0009 (5)
O3	0.0721 (9)	0.0368 (5)	0.0502 (6)	0.0172 (6)	−0.0111 (6)	−0.0032 (5)
O1	0.0680 (8)	0.0635 (7)	0.0356 (5)	0.0254 (7)	−0.0058 (5)	0.0024 (5)
O2	0.0841 (10)	0.0466 (6)	0.0439 (6)	0.0179 (7)	−0.0119 (7)	0.0006 (5)
C23	0.0441 (8)	0.0294 (6)	0.0449 (8)	−0.0015 (6)	0.0049 (6)	−0.0002 (6)
C14	0.0313 (7)	0.0278 (6)	0.0448 (7)	0.0040 (5)	−0.0005 (6)	0.0067 (5)
O4	0.0342 (5)	0.0373 (5)	0.0686 (7)	−0.0021 (4)	0.0076 (5)	0.0011 (5)
C13	0.0417 (8)	0.0340 (6)	0.0425 (7)	0.0059 (6)	−0.0032 (6)	0.0012 (6)
C16	0.0388 (8)	0.0335 (7)	0.0464 (8)	0.0005 (6)	0.0046 (6)	−0.0029 (6)
C11	0.0506 (10)	0.0419 (8)	0.0419 (8)	0.0100 (7)	0.0004 (7)	0.0013 (6)
O5	0.0390 (6)	0.0380 (5)	0.0605 (7)	0.0006 (5)	0.0078 (5)	−0.0096 (5)
C28	0.0433 (8)	0.0304 (6)	0.0444 (8)	−0.0020 (6)	0.0061 (6)	0.0005 (5)
C22	0.0459 (8)	0.0302 (6)	0.0454 (8)	0.0006 (6)	0.0055 (7)	−0.0017 (6)
C8	0.0486 (9)	0.0433 (8)	0.0376 (7)	0.0050 (7)	−0.0035 (7)	0.0026 (6)
C12	0.0349 (7)	0.0324 (6)	0.0412 (7)	0.0043 (6)	−0.0028 (6)	0.0006 (5)
C24	0.0481 (9)	0.0381 (7)	0.0549 (9)	0.0011 (7)	−0.0003 (8)	0.0037 (7)
C17	0.0488 (9)	0.0323 (7)	0.0447 (8)	0.0018 (6)	0.0039 (7)	−0.0036 (6)
C27	0.0574 (10)	0.0438 (8)	0.0454 (8)	0.0010 (8)	0.0124 (8)	−0.0013 (6)
C15	0.0494 (9)	0.0402 (8)	0.0509 (9)	0.0105 (7)	0.0086 (8)	0.0002 (7)
C1	0.0621 (11)	0.0608 (10)	0.0363 (7)	0.0069 (9)	−0.0128 (8)	0.0042 (7)
C19	0.0937 (18)	0.0685 (13)	0.0439 (9)	0.0093 (13)	0.0037 (11)	−0.0132 (9)
C25	0.0682 (12)	0.0461 (9)	0.0513 (9)	−0.0037 (9)	−0.0101 (9)	0.0058 (7)
C5	0.0524 (10)	0.0495 (8)	0.0351 (7)	0.0127 (7)	−0.0052 (7)	0.0010 (6)
C18	0.0691 (13)	0.0530 (10)	0.0480 (9)	0.0055 (10)	−0.0070 (9)	−0.0065 (8)
C7	0.0569 (11)	0.0495 (10)	0.0682 (12)	−0.0057 (9)	−0.0133 (10)	0.0100 (8)
C26	0.0791 (14)	0.0488 (9)	0.0422 (8)	−0.0048 (9)	0.0049 (9)	0.0005 (7)
C29	0.0318 (7)	0.0515 (9)	0.0641 (10)	−0.0046 (7)	0.0042 (8)	−0.0090 (8)
C10	0.0630 (11)	0.0447 (9)	0.0553 (10)	−0.0026 (8)	−0.0147 (9)	0.0087 (8)
C9	0.0504 (10)	0.0517 (9)	0.0575 (10)	−0.0046 (8)	−0.0151 (8)	0.0100 (8)
C6	0.0485 (10)	0.0665 (12)	0.0650 (12)	−0.0031 (9)	−0.0129 (9)	0.0096 (9)
C21	0.0549 (11)	0.0488 (9)	0.0600 (10)	0.0107 (8)	0.0113 (9)	−0.0075 (8)
C20	0.0808 (15)	0.0682 (13)	0.0574 (11)	0.0162 (12)	0.0198 (11)	−0.0164 (10)
C2	0.0872 (16)	0.0677 (12)	0.0526 (10)	−0.0089 (13)	−0.0005 (11)	0.0016 (10)
C3	0.097 (2)	0.0905 (17)	0.0535 (11)	−0.0239 (16)	−0.0172 (13)	−0.0050 (11)
C4	0.0912 (19)	0.0972 (19)	0.0773 (16)	0.0346 (16)	−0.0253 (15)	0.0161 (14)

Geometric parameters (Å, º) top

N1—C14	1.3434 (19)	C15—H152	0.98 (3)
N1—C12	1.4587 (19)	C1—C2	1.501 (3)
N1—C29	1.466 (2)	C1—C3	1.519 (3)
O3—C13	1.3226 (19)	C1—C4	1.522 (3)
O3—H3	0.91 (3)	C19—C20	1.375 (4)
O1—C5	1.383 (2)	C19—C18	1.385 (3)
O1—C1	1.465 (2)	C19—H191	0.99 (3)
O2—C13	1.197 (2)	C25—C26	1.384 (3)
C23—C24	1.387 (3)	C25—H251	0.99 (3)
C23—C28	1.406 (2)	C5—C6	1.382 (3)
C23—C22	1.465 (2)	C5—C10	1.388 (3)
C14—O4	1.2233 (19)	C18—H181	0.96 (3)
C14—O5	1.3413 (19)	C7—C6	1.383 (3)
C13—C12	1.532 (2)	C7—H71	0.98 (3)
C16—C28	1.513 (2)	C26—H261	0.96 (3)
C16—C17	1.515 (2)	C29—H29A	0.9600
C16—C15	1.524 (2)	C29—H29B	0.9600
C16—H161	0.95 (2)	C29—H29C	0.9600
C11—C8	1.515 (2)	C10—C9	1.389 (3)
C11—C12	1.538 (2)	C10—H101	0.99 (2)
C11—H112	1.02 (2)	C9—H91	0.92 (3)
C11—H111	0.94 (3)	C6—H61	1.02 (3)
O5—C15	1.442 (2)	C21—C20	1.390 (3)
C28—C27	1.389 (2)	C21—H221	0.98 (3)
C22—C21	1.392 (2)	C20—H201	0.95 (4)
C22—C17	1.401 (2)	C2—H2A	0.9600
C8—C9	1.384 (3)	C2—H2B	0.9600
C8—C7	1.394 (3)	C2—H2C	0.9600
C12—H121	0.98 (2)	C3—H3A	0.9600
C24—C25	1.395 (3)	C3—H3B	0.9600
C24—H241	1.00 (3)	C3—H3C	0.9600
C17—C18	1.388 (3)	C4—H4A	0.9600
C27—C26	1.393 (3)	C4—H4B	0.9600
C27—H271	0.91 (3)	C4—H4C	0.9600
C15—H151	0.97 (2)

C14—N1—C12	118.33 (13)	O1—C1—C4	102.11 (18)
C14—N1—C29	122.00 (13)	C2—C1—C4	110.8 (2)
C12—N1—C29	118.33 (13)	C3—C1—C4	111.9 (2)
C13—O3—H3	108.2 (16)	C20—C19—C18	121.4 (2)
C5—O1—C1	120.11 (14)	C20—C19—H191	119 (2)
C24—C23—C28	121.01 (16)	C18—C19—H191	119 (2)
C24—C23—C22	130.50 (16)	C26—C25—C24	120.45 (19)
C28—C23—C22	108.45 (15)	C26—C25—H251	122.4 (16)
O4—C14—O5	122.98 (14)	C24—C25—H251	117.1 (16)
O4—C14—N1	124.85 (14)	C6—C5—O1	120.67 (18)
O5—C14—N1	112.16 (13)	C6—C5—C10	119.03 (17)
O2—C13—O3	124.75 (15)	O1—C5—C10	119.89 (17)
O2—C13—C12	123.62 (14)	C19—C18—C17	118.5 (2)
O3—C13—C12	111.57 (13)	C19—C18—H181	120.7 (15)
C28—C16—C17	102.50 (13)	C17—C18—H181	120.8 (15)
C28—C16—C15	114.68 (14)	C6—C7—C8	121.37 (19)
C17—C16—C15	110.19 (14)	C6—C7—H71	119.3 (16)
C28—C16—H161	110.1 (14)	C8—C7—H71	119.3 (16)
C17—C16—H161	112.2 (14)	C25—C26—C27	121.28 (18)
C15—C16—H161	107.2 (14)	C25—C26—H261	120.5 (17)
C8—C11—C12	111.64 (14)	C27—C26—H261	118.2 (17)
C8—C11—H112	110.8 (12)	N1—C29—H29A	109.5
C12—C11—H112	109.6 (12)	N1—C29—H29B	109.5
C8—C11—H111	109.8 (14)	H29A—C29—H29B	109.5
C12—C11—H111	106.3 (14)	N1—C29—H29C	109.5
H112—C11—H111	108.5 (19)	H29A—C29—H29C	109.5
C14—O5—C15	117.48 (13)	H29B—C29—H29C	109.5
C27—C28—C23	119.95 (17)	C5—C10—C9	119.99 (19)
C27—C28—C16	129.87 (16)	C5—C10—H101	120.4 (13)
C23—C28—C16	110.15 (14)	C9—C10—H101	119.6 (13)
C21—C22—C17	120.51 (17)	C8—C9—C10	121.68 (19)
C21—C22—C23	130.65 (18)	C8—C9—H91	120.0 (17)
C17—C22—C23	108.81 (14)	C10—C9—H91	118.2 (17)
C9—C8—C7	117.46 (16)	C5—C6—C7	120.47 (19)
C9—C8—C11	122.45 (17)	C5—C6—H61	119.5 (14)
C7—C8—C11	120.03 (16)	C7—C6—H61	120.0 (14)
N1—C12—C13	110.33 (12)	C20—C21—C22	118.4 (2)
N1—C12—C11	112.54 (13)	C20—C21—H221	122.0 (15)
C13—C12—C11	114.53 (13)	C22—C21—H221	119.6 (15)
N1—C12—H121	105.9 (11)	C19—C20—C21	120.8 (2)
C13—C12—H121	103.5 (11)	C19—C20—H201	117 (2)
C11—C12—H121	109.3 (11)	C21—C20—H201	122 (2)
C23—C24—C25	118.60 (18)	C1—C2—H2A	109.5
C23—C24—H241	118.3 (13)	C1—C2—H2B	109.5
C25—C24—H241	123.1 (13)	H2A—C2—H2B	109.5
C18—C17—C22	120.34 (17)	C1—C2—H2C	109.5
C18—C17—C16	129.59 (18)	H2A—C2—H2C	109.5
C22—C17—C16	110.07 (14)	H2B—C2—H2C	109.5
C28—C27—C26	118.70 (18)	C1—C3—H3A	109.5
C28—C27—H271	121.0 (14)	C1—C3—H3B	109.5
C26—C27—H271	120.2 (14)	H3A—C3—H3B	109.5
O5—C15—C16	109.77 (14)	C1—C3—H3C	109.5
O5—C15—H151	106.2 (13)	H3A—C3—H3C	109.5
C16—C15—H151	113.5 (13)	H3B—C3—H3C	109.5
O5—C15—H152	106.9 (15)	C1—C4—H4A	109.5
C16—C15—H152	108.4 (15)	C1—C4—H4B	109.5
H151—C15—H152	112 (2)	H4A—C4—H4B	109.5
O1—C1—C2	110.38 (17)	C1—C4—H4C	109.5
O1—C1—C3	109.91 (17)	H4A—C4—H4C	109.5
C2—C1—C3	111.3 (2)	H4B—C4—H4C	109.5

C12—N1—C14—O4	−1.0 (2)	C23—C22—C17—C16	−1.21 (18)
C29—N1—C14—O4	−167.57 (16)	C28—C16—C17—C18	−178.38 (18)
C12—N1—C14—O5	−179.84 (12)	C15—C16—C17—C18	59.1 (2)
C29—N1—C14—O5	13.6 (2)	C28—C16—C17—C22	1.36 (17)
O4—C14—O5—C15	5.2 (2)	C15—C16—C17—C22	−121.14 (16)
N1—C14—O5—C15	−175.97 (14)	C23—C28—C27—C26	0.0 (2)
C24—C23—C28—C27	−0.3 (2)	C16—C28—C27—C26	−178.33 (16)
C22—C23—C28—C27	−178.23 (15)	C14—O5—C15—C16	−125.56 (16)
C24—C23—C28—C16	178.33 (14)	C28—C16—C15—O5	74.60 (19)
C22—C23—C28—C16	0.37 (17)	C17—C16—C15—O5	−170.39 (15)
C17—C16—C28—C27	177.39 (16)	C5—O1—C1—C2	−65.0 (2)
C15—C16—C28—C27	−63.2 (2)	C5—O1—C1—C3	58.2 (3)
C17—C16—C28—C23	−1.03 (16)	C5—O1—C1—C4	177.2 (2)
C15—C16—C28—C23	118.37 (15)	C23—C24—C25—C26	−0.2 (3)
C24—C23—C22—C21	0.7 (3)	C1—O1—C5—C6	−92.0 (2)
C28—C23—C22—C21	178.41 (18)	C1—O1—C5—C10	95.5 (2)
C24—C23—C22—C17	−177.17 (16)	C20—C19—C18—C17	−0.2 (4)
C28—C23—C22—C17	0.53 (17)	C22—C17—C18—C19	−0.5 (3)
C12—C11—C8—C9	102.0 (2)	C16—C17—C18—C19	179.24 (19)
C12—C11—C8—C7	−75.2 (2)	C9—C8—C7—C6	−0.5 (3)
C14—N1—C12—C13	−96.94 (16)	C11—C8—C7—C6	176.9 (2)
C29—N1—C12—C13	70.12 (18)	C24—C25—C26—C27	−0.1 (3)
C14—N1—C12—C11	133.77 (15)	C28—C27—C26—C25	0.2 (3)
C29—N1—C12—C11	−59.17 (19)	C6—C5—C10—C9	−0.5 (3)
O2—C13—C12—N1	18.3 (2)	O1—C5—C10—C9	172.13 (18)
O3—C13—C12—N1	−164.27 (14)	C7—C8—C9—C10	0.7 (3)
O2—C13—C12—C11	146.51 (19)	C11—C8—C9—C10	−176.61 (19)
O3—C13—C12—C11	−36.1 (2)	C5—C10—C9—C8	−0.2 (3)
C8—C11—C12—N1	−62.63 (18)	O1—C5—C6—C7	−171.88 (19)
C8—C11—C12—C13	170.29 (14)	C10—C5—C6—C7	0.7 (3)
C28—C23—C24—C25	0.4 (2)	C8—C7—C6—C5	−0.2 (3)
C22—C23—C24—C25	177.83 (17)	C17—C22—C21—C20	0.3 (3)
C21—C22—C17—C18	0.4 (3)	C23—C22—C21—C20	−177.3 (2)
C23—C22—C17—C18	178.56 (16)	C18—C19—C20—C21	1.0 (4)
C21—C22—C17—C16	−179.35 (16)	C22—C21—C20—C19	−1.0 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O4ⁱ	0.91	1.77	2.666 (1)	168
C29—H29C···O4ⁱⁱ	0.96	2.50	3.240 (2)	134
C15—H151···O4	0.97	2.18	2.687 (2)	111
C26—H261···O1	0.96	2.41	3.369 (2)	178

Symmetry codes: (i) x+1/2, −y−1/2, −z+2; (ii) x+1, y, z.

Crystal data of other known Fmoc–Tyr/Phe derivatives top

CSD code	CAMLEK	OGOGIA	OGIYAG	INEJEQ	OGIXOT	VERXUO	OGIXUZ	EKEWUM	NUBPEH
	Group A				Group B
Structural formula	C₂₄H₂₁NO₆	C₂₆H₂₄N₄O₅	C₂₄H₂₁NO₅.H₂O	C₃₀H₃₃NO₆.1.5CHCl₃	C₂₄H₂₁NO₄	C₂₄H₂₁NO₄.C₂H₆OS	C₂₄H₂₁NO₄.2CH₄O	C₂₄H₂₂N₂O₄	C₃₃H₃₀N₂O₅.0.88H₂O
Crystal system	monoclinic	orthorh.	monoclinic	monoclinic	monoclinic	triclinic	monoclinic	orthorh.	monoclinic
Space group	P2₁	P2₁2₁2₁	C2	P2₁	P2₁	P1	P2₁	P2₁2₁2₁	C2
Density (Mg m^-3)	1.384	1.325	1.346	1.408	1.344	1.361	1.288	1.371	1.269
a (Å)	12.673 (3)	5.019 (0)	18.640 (16)	12.142 (1)	13.157 (1)	5.015 (4)	13.076 (6)	5.524 (4)	52.270 (50)
b (Å)	5.687 (1)	19.203 (1)	5.992 (5)	5.378 (0)	4.908 (0)	13.125 (10)	4.887 (2)	14.988 (11)	5.010 (6)
c (Å)	15.101 (4)	24.566 (2)	18.841 (15)	24.926 (2)	16.124 (1)	17.419 (14)	18.998 (9)	23.557 (18)	22.830 (30)
α (°)	90.00	90.00	90.00	90.00	90.00	96.47 (1)	90.00	90.00	90.00
β (°)	112.37 (1)	90.00	98.83 (1)	98.44 (1)	113.14 (0)	94.35 (1)	106.42 (1)	90.00	105.49 (3)
γ (°)	90.00	90.00	90.00	90.00	90.00	90.12 (1)	90.00	90.00	90.00
R1 [I > 2σ(I)]	5.35	6.67	3.70	5.31	4.55	8.71	12.69	5.17	10.27
Temperature (K)	100	173	100	160	100	100	100	173	100
KPI* (%)	69.7	67.4	69.4	55.8	70.1	71.5	68.8	71.3	67.1

	MOXSUP	DULLAZ	WATSIU01	UQOGUE	UQIYUQ	XATKEL	XATJAG	XATJEK	XATKIP
	Group C		Group D			Group E
Structural formula	C₃₁H₂₇NO₄.0.33C₆H₁₄	C₂₈H₂₉NO₄	C₂₄H₂₁N₃O₆.2CH₂Cl₂	0.7C₂₅H₂₀N₂O₄.0.3C₂₄H₂₀N₂O₆	C₂₅H₂₃NO₄	C₂₄H₂₀INO₄.0.333H₂O	C₂₄H₂₀BrNO₄.0.3H₂O	C₂₄H₂₀ClO₄	C₂₄H₂₀FO₄.C₂H₆OS
Crystal system	orthorhom.	monoclinic	monoclinic	orthorhom.	orthorhom.	cubic	cubic	monoclinic	orthorhombic
Space group	Pbca	P2₁	P2₁	P2₁2₁2₁	P2₁2₁2₁	P6₃	P6₃	P2₁	P2₁2₁2₁
Density (Mg m^-3)	1.263	1.246	1.415	1.374	1.339	1.654	1.520	1.357	1.361
a (Å)	5.379 (1)	5.444 (3)	12.362 (3)	5.747 (3)	5.675 (0)	26.878 (4)	26.744 (4)	13.168 (3)	4.920 (1)
b (Å)	25.977 (4)	38.160 (20)	10.489 (3)	15.850 (7)	15.661 (1)	26.878 (4)	26.744 (4)	4.839 (1)	13.034 (3)
c (Å)	38.081 (6)	11.382 (6)	22.958 (4)	22.201 (10)	22.411 (3)	4.999 (1)	4.997 (0)	17.400 (4)	36.789 (7)
α (°)	90.00	90.00	90.00	90.00	90.00	90.00	90.00	90.00	90.00
β (°)	90.00	90.13 (3)	103.17 (3)	90.00	90.00	90.00	90.00	111.41 (3)	90.00
γ (°)	90.00	90.00	90.00	90.00	90.00	120.00	120.00	90.00	90.00
R1 [I > 2σ(I)]	5.60	9.99	6.14	6.01	5.44	7.33	6.91	6.65	11.5
Temperature (K)	90	110	100	100	100	100	100	100	100
KPI* (%)	62.9	67.2	66.9	71.6	70.6	71	71	67.8	70.9

Note: (*) Kitaigorodsky's packing index.

Experimental and theoretically optimized relevant dihedral angles (°) of (1) and OGIXOT [Missing label and format of last entry?] top

Parameter	X-ray	DFT	DFT-CPCM	X-ray	DFT	DFT-CPCM
	(1)			OGIXOT
O5—C15—C16—C17	74.59 (15)	72.92	71.01	-71.88	-71.17	-69.93
C14—O5—C15—C16	-125.55 (16)	-174.18	176.94	175.11	-179.31	176.28
N1—C12—C11—C8	-62.60 (18)	-55.27	-63.08	-66.60	-64.17	-63.88
C12—C11—C8—C7	-75.24 (2)	-47.38	-74.18	-94.58	-75.63	-74.21
N1—C12—C13—O2	18.32 (2)	-8.10	1.41	134.27	167.89	164.11
C15—O5—C?—N1	-175.97 (14)	-177.07	-177.97	175.03	178.24	179.18
R[C26—H···O1 (Å)	2.40648 (16)	4.9518	6.5907	-	-	-

Estimated energy for main interactions in (1) and OGIXOT decomposed to electrostatic (E_ele), polarization (E_pol), dispersion (E_dis) and repulsion (E_rep) components. The total energies (E_tot) are the sum of the four energy components scaled appropriately for two benchmarked energy models included in the CrystalExplorer (Version 1.75; Wolff et al., 2012) CE_B3LYP/6-31G(d,p) and CE_HF/3-21G (data in italics) top

Interaction type	R^*	E_ele	E_pol	E_dis	E_rep	E_tot
(1)
Interactions in the large synthon along [100] direction	6.49	-10.4	-5.0	-67.2	33.7	-52.5
	-11.3	-8.0	-67.2	24.8	-57.1
O—H···O	10.65	-61.3	-15.2	-22.0	66.5	-54.2
		-66.0	-20.8	-22.0	50.7	-59.5
C—H···π (Fmoc···Fmoc)	8.89	-8.5	-2.4	-52.3	29.0	-38.4
		-9.4	-5.2	-52.3	23.0	-41.4
Secondary interactions along the [001] direction; mainly C—H···π (Fmoc···phenyl)	11.36	-6.5	-2.1	-36.2	17.4	-29.2
	-6.2	-2.9	-36.2	12.9	-30.4
	11.99	-4.0	-0.8	-23.2	7.8	-20.2
		-4.6	-1.4	-23.2	6.1	-21.7
OGIXOT
N—H···O(peptide)	4.91	-43.2	-10.1	-81.2	66.6	-82.7
		-45.1	-15.5	-81.2	49.9	-88.7
C—H···π(phenyl···phenyl)	8.45	-14.6	-2.8	-56.0	45.5	-38.2
		-15.0	-5.1	-56.0	35.4	-40.3
O—H···O	12.44	-47.2	-12.7	-7.5	69.4	-22.9
		-53.7	-18.7	-7.5	53.1	-30.7
C—H···π(Fmoc···Fmoc)	8.60	-6.3	-1.7	-34.3	19.1	-26.0
		-6.3	-2.5	-34.3	13.5	-28.0
C—H···π(phenyl···Fmoc)	13.16	-6.2	-1.3	-16.0	9.0	-15.9
		-9.4	-2.2	-16.0	6.9	-19.8

Note: (*) R is the distance between molecular centres of mass (Å)

Occurrence of supramolecular synthons in all Fmoc–AAs top

		Fmoc–Tyr/Phe derivatives	Other Fmoc-based AA derivatives
S(6)	(CH₂)···(C═O)	OGIYAG, DULLAZ, MOXSUP
S(11)	(CH_cycl)···(C═O)	EKEWUM	QOFHID (Ile)
C(4)	(CH)···(C═O)	(1), NUBPEH
	(OH)···(C═O)	OGIXOT, CAMLEK, UQIYUQ, UQOGUE, XATJAG, XATJEK, XATKEL	QOFHID (Ile)
	(NH)···(C═O)	OGIXOT, INEJEQ, OGOGIA, NUBPEH, OGIXUZ, VERXUO, XATJAG, XATJEK, XATKEL, XATKIP	CUWKOU01 (Ala), XAVYIE (Gly), EXOFAY (Orn)
C(5)	(CH₂)···(C═O)	OGIYAG, CAMLEK, DULLAZ, EKEWUM, MOXSUP, UQIYUQ, UQOGUE, XATJAG, XATKEL	VERQOB (Gly), BIZXUE (Leu), DIZNIK (Trp)
	(CH)···(C—O—C)	OGIYAG, CAMLEK, EKEWUM, UQIYUQ, UQOGUE	QOFHID (Ile), BIZXUE (Leu), MOHCIW (Ser), DIZNIK (Trp)
	(NH)···(C═O)	CAMLEK	ADAGOE (Ser)
	(NH)···(C—O—C)	EKEWUM	DIZNIK (Trp)
	(NH)···(OH)	UQIYUQ, UQOGUE	QOFHID (Ile) BIZXUE (Leu)
C(6)	(CH₂)···(C—O—C)	DULLAZ, MOXSUP
C(7)	(OH)···(C═O)	(1)	ADAGUK (Ala), VERXIC (Gly), VERXOI (Gly), BIZXUE (Leu), MOHCIW (Ser)
C(8)	(CH_cycl)···(C═O)	INEJEQ, EKEWUM	ADAGUK (Ala), VERQER (Gly), VERQIW (Gly), VERXIC (Gly), MOHCIW (Ser)
	(CH₂)···(C═O)		VERQOB (Gly), VERXIC (Gly), VERXOI (Gly), BIZXUE (Leu), MOHCIW (Ser)
C(11)	(CH₂)···(C═O)	OGOGIA	DIZNIK (Trp)
C(12)	(CH_cycl)···(C═O)	EKEWUM	ADAGUK (Ala)
	(CH_cycl)···(OH)		VERQER (Gly), VERXIC (Gly), VERXOI (Gly)
C(13)	(CH_cycl)···(OH)	XATJEK	ADAGUK (Ala)
C(14)	(CH_cycl)···(F)		VERQIW (Gly), VERQOB (Gly)
C₂¹(8)	(CH₂)···(C═O)		VERQIW (Gly), VERXIC (Gly)
C₂²(7)	(OH)···(C═O) & (OH)···(NH)	CAMLEK, UQIYUG, UQOGUE	QOFHID (Ile)
C₂²(8)	(CH)···(C–O–C) & (OH)···(C═O)		BIZXUE (Leu), MOHCIW (Ser)
C₂²(9)	(OH)···(C═O) & (OH)···(NH)	CAMLEK, UQIYUQ, UQOGUE	QOFHID (Ile)
	(C═O)···(OH) & (C═O)···(CH₂)	XATJAG	VERQIW (Gly), VERXIC (Gly), MOHCIW (Ser)
C₂²(10)	(NH)···(C═O) & (CH)···(C—O—C)	EKEWUM	BIZXUE (Leu)
	(NH)···(OH) & (CH)···(C—O—C)	UQIYUQ, UQOGUE	QOFHID (Ile)
	(CH₂)···(C═O) & (CH)···(C-O-C)	EKEWUM, UQIYUQ, UQOGUE	BIZXUE (Leu), DIZNIK (Trp)
C₂²(10)	(CH_cycl)···(C═O) & (CH_cycl)···(OH)		ADAGUK (Ala), VERQER (Gly), VERXIC (Gly)
	(CH_cycl)···(OH) & (CH₂)···(C═O)		VERQIW (Gly), VERQIW (Gly), VERXOI (Gly)
	(CH₃)···(C—O—C) & (CH_cycl)···(C═O)	INEJEQ, EKEWUM
	(CH₂)···(C═O) & (CH)···(C—O—C)	CAMLEK, OGIYAG, DULLAZ
C₂²(11)	(OH)···(C═O) & (CH)···(C═O)	(1)	VERQIW (Gly)
	(CH₂)···(C═O) & (CH₂)···(C—O—C)	DULLAZ, MOXSUP
	(CH)···(C—O—C) & (OH)···(C═O)	UQIYUQ, UQOGUE	QOFHID (Ile)
	(CH_Fmoc)···(NO₂) & (CH₂)···(NO₂)	UQOGUE
	(NH)···(C═O) & (CH₂)···(C═O)	XATJAG, XATKEL
C₂²(11)	(OH)···(C═O) & (CH_cycl)···(OH)		VERQIW (Gly), VERXIC (Gly), VERXOI (Gly)
	(OH)···(C═O) & (CH₂)···(C═O)		VERQIW (Gly), VERXIC (Gly)
C₂²(12)	(OH)···(C═O) & (NH)···(C═O)	OGIXOT, XATJAG, XATJEK, XATKEL,	BIZXUE (Leu)
	(NH)···(OH) & (CH₂)···(C═O)	CAMLEK, UQIYUQ, UQOGUE
	[(CH₂)···(C═O)]₂	CAMLEK	VERXIC (Gly)
	(NH)···(C═O) & (CH_cycl)···(C═O)	INEJEQ, EKEWUM
	(CH_cycl)···(C═O) & (CH₂)···(C═O)		VERXIC (Gly), MOHCIW (Ser)
	(OH)···(C═O) & (CH)···(C—O—C)		BIZXUE (Leu), MOHCIW (Ser)
C₂²(13)	[(CH₂)···(C═O)]₂		VERQOB (Gly), BIZXUE (Leu)
	(CH₂)···(C═O) & (CH)···(C—O—C)		BIZXUE (Leu), MOHCIW (Ser)
C₂²(14)	[(CH₂)···(C═O)]₂	DULLAZ, MOXSUP
	(CH_cycl)···(OH) & (CH₂)···(C═O)		VERQIW (Gly), VERXIC (Gly)
C₂²(15)	(OH)···(C═O) & (CH₂)···(C═O)	CAMLEK, UQOGUE	VERQIW (Gly), VERXIC (Gly), VERXOI (Gly), BIZXUE (Leu)
	(OH)···(C═O) & (CH_Fmoc)···(OH)	OGIXUZ, XATJEK
	(OH)···(C═O) & (CH_cycl)···(C═O)		ADAGUK (Ala), VERXIC (Gly)
	(NH)···(C═O) & (CH_Fmoc)···(Cl₁)	XATJEK
	(NH)···(C═O) & (CH_Fmoc)···(OH)	XATJEK
	(CH)···(Cl) & (OH)···(CH_Fmoc)	XATJEK
	(CH_cycl)···(OH) & (CH₂)···(C═O)		VERQIW (Gly), VERXIC (Gly)
	(CH_cycl)···(C═O) & (CH₂)···(C═O)		VERXIC (Gly), VERXOI (Gly), MOHCIW (Ser)
C₂²(19)	(OH)···(C═O) & (CH₂)···(C═O)	OGIYAG, UQOGUE
	(CH_cycl)···(C═O) & (OH)···(C═O)	DULLAZ	ADAGUK (Ala), QOFHID (Ile)
C₂²(19)	(OH)···(C═O) & (CH_cycl)···(OH)		VERQIW (Gly), VERXIC (Gly), VERXOI (Gly)
	(CH_Fmoc)···(NO₂) & (CH₂)···(C═O)	UQOGUE
C₂²(20)	(CH_cycl)···(C═O) & (CH_cycl)···(OH)		VERQER (Gly), VERXIC (Gly)
	(CH₂)···(C═O) & (CH_cycl)···(OH)		VERQIW (Gly), VERXIC (Gly), VERXOI (Gly)
C₄⁴(20)	(OH)···(C═O) & (CH)···(C—O—C)		BIXUE (Leu), MOHCIW (Ser)
	(CH)···(C—O—C) & (CH₂)···(C═O)		BIXUE (Leu), MOHCIW (Ser)
R₂²(8)	(NH)···(OH) & (CH)···(C—O—C)	CAMLEK, UQOGUE	QOFHID (Ile)
	(CH₂)···(C═O) & (CH)···(C—O—C)	CAMLEK, OGIYAG, EKEWUM, UQIYUQ, UQOGUE	BIZXUE (Leu), DIZNIK (Trp)
	[(OH)···(C═O)]₂	DULLAZ, MOXSUP	VERQER (Gly), VERQOB (Gly)
	(NH)···(C—O—C) & (CH)···(C—O—C)	EKEWUM	DIZNIK (Trp)
R₂²(9)	(CH₂)···(C—O—C) & (CH₂)···(C═O)	OGOGIA, MOXSUP
	[(CH₂)···(C═O)]₂	DULLAZ	VERQOB (Gly)
R₂²(9)	(OH)···(C═O) & (CH₂)···(C═O)		VERQIW (Gly), VERXIC (Gly), VERXOI (Gly), BIZXUE (Leu)
R₂²(12)	(CH₂)···(C═O) & (NH)···(C—O—C)	EKEWUM	DIZNIK (Trp)
R₂²(14)	(CH₃)···(C═O) & (NH)···(C═O)	INEJEQ, NUBPEH
	[(CH₂)···(C═O)]₂	DULLAZ, MOXSUP	XAVYIE (Gly)
R₃³(11)	(NH)···(OH) & (OH)···(C═O)	CAMLEK, UQIYUQ, UQOGUE	QOFHID (Ile)
R₃³(15)	(OH)···(C═O) & (CH)···(C—O—C)	CAMLEK, UQIYUQ, UQOGUE	QOFHID (Ile)
R₃³(19)	(OH)···(C═O) & (CH₂)···(C═O)	CAMLEK, UQIYUQ, UQOGUE
R₄⁴(16)	(OH)···(C═O) & (NH)···(OH)	UQIYUQ, UQOGUE	QOFHID (Ile)
R₄⁴(20)	(OH)···(C═O) & (CH)···(C—O—C)		BIZXUE (Leu), MOHCIW (Ser)
	(CH₂)···(C═O) & (CH)···(C—O—C)		BIZXUE (Leu), MOHCIW (Ser)

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Synthesis, experimental and in silico studies of N-fluorenyl­methoxycarbonyl-O-tert-butyl-N-methyl­tyrosine, coupled with CSD data: a survey of inter­actions in the crystal structures of Fmoc–amino acids

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Synthesis, experimental and in silico studies of N-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids