Radical Functionalization of Unsaturated Amino Acids: Synthesis of Side-Chain-Fluorinated, Azido-Substituted, and Hydroxylated Amino Acids

Philip A P Reeve; Urszula Grabowska; Lourdes Salvador Oden; Daniel Wiktelius; Fredrik Wångsell; Richard F W Jackson

doi:10.1021/acsomega.9b01509

. 2019 Jun 21;4(6):10854–10865. doi: 10.1021/acsomega.9b01509

Radical Functionalization of Unsaturated Amino Acids: Synthesis of Side-Chain-Fluorinated, Azido-Substituted, and Hydroxylated Amino Acids

Philip A P Reeve ^†, Urszula Grabowska ^‡, Lourdes Salvador Oden ^‡, Daniel Wiktelius ^‡, Fredrik Wångsell ^‡, Richard F W Jackson ^†,^*

PMCID: PMC6648964 PMID: 31460183

Abstract

A range of enantiomerically pure protected side-chain-fluorinated amino acids has been prepared (13 examples) by treatment of protected amino acids containing unsaturated side chains with a combination of Fe(III)/NaBH₄ and Selectfluor. The modification of the conditions by replacement of Selectfluor with NaN₃ allowed the preparation of side-chain azido-substituted amino acids (five examples), which upon catalytic hydrogenation gave the corresponding amines, isolated as lactams (four examples). Radical hydration of the unsaturated side chains leading to side-chain-hydroxylated protected amino acids has also been demonstrated.

Introduction

The synthesis of enantiomerically pure amino acids continues to attract substantial attention, and the development of new methods for the preparation of side-chain-functionalized amino acids is the focus of much effort.¹ In particular, the synthesis of amino acids with side-chain fluorine substitution has been widely studied,² specifically in the context of the preparation of (S)-γ-fluoroleucine, a component of the Merck Cathepsin K inhibitor odanacatib.³ An early approach to (S)-γ-fluoroleucine ethyl ester relied on the use of the Schöllkopf bis-lactim ether.⁴ The synthetic routes that have been developed more recently include the use of aspartic acid as a chiral pool starting material,⁵ a titanium-catalyzed asymmetric ene-reaction,⁶ use of glycine-Schiff base alkylation followed by enzymatic resolution,⁷ and more recently direct photochemical fluorination of leucine itself.⁸ This followed an earlier indirect method which employed photochemical bromination of leucine, followed by treatment with AgF.⁹ The latter two approaches rely on the selective radical cleavage of the tertiary C–H bond of leucine for their success. A complementary method makes use of AgF/tetra-n-butylammonium fluoride as the fluorine source, in conjunction with a manganese porphyrin catalyst.¹⁰ In previous work, we have reported a single example of the synthesis of the γ-fluorinated cyclopentylalanine derivative 2a using the ionic addition of hydrogen fluoride (HF) (using HF-pyridine) to an unsaturated amino acid 1a (Scheme 1).¹¹ This compound was a key component of a Cathepsin S inhibitor. Although this synthetic approach was rather inefficient, largely due to the in situ tert-butoxycarbonyl (Boc)-deprotection of the substrate under the conditions of the reaction, it was nevertheless a very considerable improvement over the previous method used for making this protected amino acid.¹²

The report by Barker and Boger on the new radical addition of HF to unactivated alkenes, using Fe(III)/NaBH₄, with Selectfluor as the fluorine source,¹³ prompted us to revisit our general strategy. Indeed, after we had completed the majority of the work reported in this paper, another group reported the application of the Barker and Boger method to the synthesis of Fmoc-(S)-γ-fluoroleucine 4 (in presumed 94% enantiomeric excess (ee), based on the ee of the starting material), using the 2-propenylalanine derivative 3.¹⁴ We now report an in-depth study of this reaction, to assess its generality and scope for the preparation of side-chain-fluorinated amino acids as well as a possible extension by trapping the intermediate alkyl radicals to allow the introduction of other functional groups into the amino acid side chains, by exploring the use of subsequently reported variants of the Boger process.¹⁵

Results and Discussion

Preparation of Unsaturated Amino Acids

The initial goal was to prepare a representative selection of protected enantiomerically pure unsaturated amino acids, with double bonds at both the γ- and δ-positions. A range of cycloalkenylalanine derivatives was prepared by room-temperature Negishi cross-coupling of cycloalkenyl triflates (5a–d, 6, and 7) with the serine-derived zinc reagent 8, according to our previously reported methods from the protected iodoalanine derivative 9 (Scheme 2, Table 1).¹⁶ It was established that extending the reaction times for the cross-coupling generally resulted in higher isolated yields of the desired products (1a–d) than we had previously observed.^11,16 In addition, two more functionalized vinyl triflates 6 and 7 were successfully coupled, giving the corresponding protected amino acids 10 and 11.

Table 1. Negishi Coupling of Zinc Reagent 8 with Cycloalkenyl Triflates.

entry	substrate	X	n	product	yield (%)
1	5a	CH₂	0	1a	83 (70)^a
2	5b	CH₂	1	1b	92 (70)^a
3	5c	CH₂	2	1c	81 (62)^a
4	5d	CH₂	3	1d	61 (63)^a
5	6	O	1	10	52
6	7	CF₂	1	11	90

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Yield obtained under previous conditions.¹¹

Although there is less precedent for the use of vinyl bromides in the Negishi cross-coupling with zinc reagent 8, a range of vinyl bromides (12–15) was successfully coupled under the same conditions that we had employed for coupling the vinyl triflates to give the expected unsaturated amino acids (16–19) (Scheme 3, Table 2). The cross-coupling reactions of (E)- and (Z)-2-bromo-2-butene with zinc reagent 8 were stereospecific, leading to the isomeric products (E)-18 and (Z)-18, respectively. Interestingly, the use of an excess of the commercially available isomeric mixture of 2-bromo-2-butene (E/Z, 1.9:1, as determined by ¹H NMR, with both isomers used in excess relative to zinc reagent 8) in the cross-coupling resulted in the formation of a mixture of the products 18 that was substantially enriched in the (E)-isomer (E/Z, 7:1) (Table 2, entry 5), indicating that the Negishi cross-coupling of the zinc reagent 8 with (E)-2-bromo-2-butene (E)-14 was faster than with (Z)-isomer 2-bromo-2-butene (Z)-14 (by a factor of 3.5). This most likely reflects a faster rate of oxidative addition of the less hindered (E)-isomer of compound 14 to Pd. The most notable example was the successful cross-coupling of zinc reagent 8 with 1-bromocyclobutene 15 leading to the cyclobutenyl alanine derivative 19, which is a rare example of the use of 1-bromocyclobutene in the Negishi cross-coupling.

Table 2. Negishi Coupling of Zinc Reagent 8 with Vinyl Bromides.

entry	substrate	R¹	R²	R³	product	yield (%)
1	12	Me	H	H	16	84
2	13	H	Me	Me	17	95
3	(E)-14	Me	Me	H	(E)-18	68
4	(Z)-14	Me	H	Me	(Z)-18	72
5	(E,Z)-14	Me	Me/H		(E,Z)-18	88
6	15	(CH₂)₂		H	19	79

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A small selection of unsaturated amino acid substrates 20–22 was prepared by our previously reported method using copper-catalyzed allylation of the zinc reagent 8 (Scheme 4).¹⁷ Again, we observed that extended reaction times at room temperature resulted, in most cases, in improved yields over those we had previously observed.

Radical Addition of HF to Unsaturated Amino Acids

Barker and Boger’s original report contained examples of the radical HF-addition to terminal alkenes containing an ester or a protected amine as well as a dipeptide in which the terminal alkene was incorporated into a tyrosine residue.¹³ Therefore, it was reasonable that unsaturated amino acid substrates would also undergo the reaction. In the event, the application of the conditions reported by Barker and Boger to the cyclopentenylalanine derivative 1a resulted in the formation of 2a, identical to the material we had previously prepared,¹¹ but in substantially higher yield (64%) and without unproductive protecting group removal and using less toxic reagents (Scheme 5). The structure of compound 2a was confirmed by X-ray analysis and showed a hydrogen bond from the carbamate N–H to the carbamate carbonyl of the neighboring molecule as well as a very distinct alignment of the C–F bond with the C–F bond of the closest neighbor.

We were pleased to find that with the exception of the 4,4-difluorocyclohexen-1-yl alanine derivative 11 (vide infra), the procedure proved applicable to the other substrates that we had prepared, giving the desired HF-addition products in good to excellent yields (Table 3). To establish whether or not the reaction proceeded without racemization, both enantiomers of the 3-methyl-3-butenylglycine derivatives 16 and ent-16 were each separately subjected to the radical HF-addition conditions; the products 25 and ent-25 were obtained with high ee (99 and 98%, respectively, as determined by chiral phase high-performance liquid chromatography (HPLC)), thus establishing that the reaction did indeed proceed without racemization. When the two isomeric alkene substrates 17 and 21 were separately subjected to the radical HF-addition conditions, the same tert-fluoride 26 was obtained, with a slightly higher yield from the starting material 17 with the more substituted double bond (cf. entries 9 and 13, Table 3). When the radical HF-addition was attempted on the 4,4-difluorocyclohexen-1-yl alanine derivative 11, the conversion was incomplete and purification difficult. We, therefore, modified the procedure by increasing the amounts of Fe(III) and Selectfluor and by the dropwise addition of a solution of NaBH₄ (in 0.1 M NaOH) over a period of 6 h, which resulted in the isolation of the desired product 24 in comparable yield to that obtained with the other substrates. This modified procedure may be successful with other more challenging substrates. The X-ray crystal structure of compound 24 was obtained, confirming the structure and showing similar intermolecular interactions in the solid state to those observed in the X-ray structure of 2a.

Table 3. Radical Hydrofluorination of Unsaturated Substrates.

entry	substrate	product	yield (%)
1	1a	2a	64
2	1b	2b	64
3	1c	2c	70
4	1d	2d	65
5	10	23	54
6	11	24	0 (64)^a
7	16	25	84
8	ent-16	ent-25	88
9	17	26	75
10	18	27	63
11	19	28	81
12	20	29	73
13	21	26	62
14	22	30	91

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Reaction carried out by increasing the molar equivalents of Fe(III) and Selectfluor and by the dropwise addition of a solution of NaBH₄ (in 0.1 M NaOH).

The addition of HF to the substrates 18 and 20 resulted in the formation of products 27 and 29 each with a new stereogenic center. In each case, the removal of the Boc-protecting group with trifluoroacetic acid (TFA) to give the corresponding trifluoroacetate salts, 31 and 32, followed by analysis by NMR methods established that, in each case, the new stereogenic center had been formed with very low diastereomeric excess (de) (specifically less than 5% de), entirely consistent with the results of Barker and Boger.¹³

Radical Addition of HN₃ to Unsaturated Amino Acids

Given the efficiency of the radical addition of HF to unsaturated amino acids and the precedent from Leggans et al. that a combination of Fe(III)/NaBH₄ and NaN₃ as the azide source promoted the efficient radical addition of HN₃ to alkenes,¹⁵ we have explored the application of this method to the functionalization of unsaturated amino acids. The formation of amino acids with side-chain nitrogen functionality is of interest, since the compounds are analogues of lysine. Direct application of the literature protocol for the hydroazidation of citronellol¹⁵ to unsaturated amino acid 16 resulted in the incomplete conversion of the starting materials. However, a minor modification, in which the excess of reagents was increased, resulted in a very efficient conversion of 16 to the corresponding tertiary azide 33. The application of this modified method to a representative selection of unsaturated amino acids resulted, in each case, in the formation of the expected tertiary azide in good to excellent yields (Scheme 6, Table 4). The two isomeric alkenes 17 and 21 gave the same tertiary azide 36, with a slightly higher yield being observed when using the more substituted alkene 17 (Scheme 7), as already observed during the HF-addition to the same substrates.

Table 4. Radical Hydroazidation of Unsaturated Substrates.

entry	substrate	R¹	R²	product	yield (%)
1	16	Me	H	33	88
2	1a	(CH₂)₃		34	88
3	1b	(CH₂)₄		35	71
4	(E)-18	Me	Me	37	63

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Each of the azides 33–36 was reduced by catalytic hydrogenation to give the corresponding free amines, which underwent spontaneous cyclization to give the corresponding lactams 38–41, which were each isolated in high yields (Scheme 8, Table 5). The structure of the lactam 40 was confirmed by single-crystal X-ray structure analysis.

Table 5. Hydrogenation of Azides.

entry	substrate	R¹	R²	n	product	yield (%)
1	33	Me	Me	1	38	99
2	34	(CH₂)₄		1	39	93
3	35	(CH₂)₅		1	40	91
4	36	Me	Me	2	41	98

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Radical Alkene Hydration

The final transformation that we briefly investigated was the radical hydration of unsaturated amino acids using the combination of Fe(III)/NaBH₄ and air as a radical trap.¹⁵ Such a process would lead to amino acids with a side-chain hydroxyl group. The optimization of this particular radical addition process proved challenging and appeared to be critically dependent on the means by which the air was introduced into the reaction mixture. Most reliable results were obtained when the air was introduced using a sintered gas inlet, and in two cases (using 16 and 17 as substrates), moderate yields of the corresponding hydroxylated amino acids were obtained, albeit isolated as the corresponding lactone 42 in one case (Scheme 9).

Conclusions

In conclusion, the generality and scope of the radical HF-addition to unsaturated amino acid substrates have been established, further demonstrating the functional group tolerance of the Boger radical hydrofluorination process. In combination with our previously reported methods for the preparation of unsaturated amino acids (extended to the Negishi cross-coupling with vinyl bromides in this paper), this constitutes an effective and direct method for the preparation of important side-chain-fluorinated amino acid derivatives. Furthermore, radical hydroazidation of unsaturated amino acid substrates has been demonstrated, allowing the synthesis of side-chain amino-substituted amino acids. Finally, radical hydration of unsaturated amino acid substrates has been demonstrated, but further work is required to establish the full scope of this transformation.

Experimental Section

High-resolution mass spectrometry (HRMS) measurements were carried out using electrospray (ES) ionization, with a time-of-flight mass analyzer. IR spectra were recorded as thin films or using attenuated total reflection. The synthesis of N-Boc-β-I-Ala-OMe was accomplished by the literature methods.¹⁸ For the preparation of zinc reagent 8 and general procedures A, B, and F, flame-dried glassware was used. Cycloalkenyl triflates 5a–d were prepared by general literature methods¹⁹ from the corresponding ketones and used without purification. Triflates 6,²⁰7²¹ and 1-cyclobutenyl bromide 15(22) were each prepared by literature methods.

Preparation of Zinc Reagent 8

Zinc powder (3 equiv) was suspended in dry dimethylformamide (DMF) (3 mL) under nitrogen, and iodine (nine crystals) was added immediately. A change in color from colorless to dark brown and colorless again was observed. N-Boc-β-I-Ala-OMe 9 (1 equiv) was added followed immediately by iodine (three crystals), the aforementioned color change was observed once more, and the insertion process was allowed to proceed for 30–60 min.

General Procedure A, Coupling of 8 to Vinyl Triflates and Halides

Immediately after the preparation of 8, Pd₂(dba)₃ (2.5 mol %) and SPhos (5.0 mol %) were added to the reaction vessel along with an excess vinyl halide/triflate (≈1.6 equiv), as indicated in the individual procedures below. The reaction mixture was stirred under a gentle flow of nitrogen for 72 h. The reaction mixture was then filtered through a silica plug eluting with EtOAc. The organic phase was washed with water (2 × 50 mL) and brine (50 mL). The organic phase was dried with Na₂SO₄, filtered, and the solvent removed under reduced pressure. Purification was carried out by flash column chromatography (EtOAc in petroleum ether (40–60) mixtures over silica).

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclopent-1-en-1-yl)propanoate 1a

Synthesis was achieved by general procedure A using zinc dust (0.217 g, 3.32 mmol), iodine (2 crystals, then 1 crystal), 9 (0.325 g, 0.99 mmol), Pd₂(dba)₃ (0.024 g, 0.03 mmol), SPhos (0.023 g, 0.06 mmol), and 5a (0.375 g, 1.73 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 1a as a light orange oil (0.220 g, 0.82 mmol, 83%); [α]_D²⁵ +17.0 (c 2.00, CHCl₃), [lit. [α]_D²² +13.9 (c 2.09, CHCl₃)];¹⁶ ν_max(ATR)/cm^–1 3371, 2974, 2951, 2932, 2848, 1744, 1713, 1501, 1436, 1392, 1365, 1248, 1211, 1160, 1056, 1020, 860, 778, and 759; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.47 (s, 1H), 4.98 (d, J = 7.8 Hz, 1H), 4.41 (m, 1H), 3.73 (s, 3H), 2.59 (dd, J = 14.2 Hz, 4.8 Hz, 1H), 2.49 (dd, J = 14.4 Hz, 7.5 Hz, 1H), 2.33–2.16 (m, 4H), 1.86 (apparent quin, J = 7.4 Hz, 2H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.2, 155.2, 139.0, 128.3, 79.8, 52.2, 52.1, 34.7, 34.2, 32.5, 28.3, 23.6; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₄H₂₃NO₄Na 292.1519; found 292.1523.

The characterization data was consistent with that reported in the literature.¹⁶

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclohex-1-en-1-yl)propanoate 1b

Synthesis was achieved by general procedure A using zinc dust (0.606 g, 9.27 mmol), iodine (6 crystals, then 4 crystals), 9 (1.013 g, 3.08 mmol), Pd₂(dba)₃ (0.068 g, 0.07 mmol), SPhos (0.069 g, 0.17 mmol), and 5b (1.283 g, 5.57 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 1b as a light orange oil (0.798 g, 2.82 mmol, 92%); [α]_D²⁴ +14.1 (c 0.99, CHCl₃), [lit. [α]_D²² +14.5 (c 1.68, CHCl₃)];¹⁶ ν_max(ATR)/cm^–1 3355, 2976, 2929, 2859, 2838, 1744, 1713, 1504, 1437, 1391, 1365, 1275, 1258, 1215, 1161, 1084, 1048, 1020, 920 and 863; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.48 (s, 1H), 4.92 (d, J = 7.6 Hz, 1H), 4.39 (m, 1H), 3.74 (s, 3H), 2.43 (dd, J = 13.5 Hz, 5.2 Hz, 1H), 2.26 (dd, J = 13.5 Hz, 8.6 Hz, 1H), 2.00–1.88 (m, 4H), 1.68–1.52 (m, 4H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.4, 155.2, 132.7, 125.7, 79.8, 52.1, 51.9, 41.4, 28.3, 27.8, 25.3, 22.7, 22.1; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₅H₂₅NO₄Na 306.1681; found 306.1676.

The characterization data was consistent with that reported in the literature.¹⁶

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclohept-1-en-1-yl)propanoate 1c

Synthesis was achieved by general procedure A using zinc dust (0.791 g, 12.10 mmol), iodine (12 crystals, then 5 crystals), 9 (1.330 g, 4.04 mmol), Pd₂(dba)₃ (0.094 g, 0.10 mmol), SPhos (0.112 g, 0.27 mmol), and 5c (1.609 g, 6.59 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 1c as a light orange oil (0.981 g, 3.30 mmol, 82%); [α]_D²⁴ +8.4 (c 1.08, CHCl₃), [lit. [α]_D²² +7.8 (c 1.15, CHCl₃)];¹⁶ ν_max(ATR)/cm^–1 3367, 2975, 2919, 2846, 1744, 1712, 1498, 1438, 1389, 1365, 1248, 1212, 1159, 1050, 1022, 994 and 852; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.62 (t, J = 6.2 Hz, 1H), 4.93 (d, J = 7.1 Hz, 1H), 4.34 (m, 1H), 3.73 (s, 3H), 2.46 (dd, J = 13.2 Hz, 5.6 Hz, 1H), 2.27 (dd, J = 13.3 Hz, 8.3 Hz, 1H), 2.14–2.06 (m, 4H), 1.76–1.70 (m, 2H), 1.44–1.35 (m, 13H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.4, 155.2, 139.3, 131.0, 79.8, 52.1, 52.0, 43.4, 32.4, 32.3, 28.5, 28.3, 27.0, 26.5; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₆H₂₇NO₄Na 320.1838; found 320.1833.

The characterization data was consistent with that reported in the literature.¹⁶

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclooct-1-en-1-yl)propanoate 1d

Synthesis was achieved by general procedure A using zinc dust (0.596 g, 9.11 mmol), iodine (9 crystals, then 5 crystals), 9 (0.990 g, 3.01 mmol), Pd₂(dba)₃ (0.074 g, 0.08 mmol), SPhos (0.066 g, 0.16 mmol), and 5d (1.311 g, 5.08 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 1d as a light orange oil (0.572 g, 1.84 mmol, 61%); [α]_D²⁴ +7.8 (c 1.15, CHCl₃), [lit. [α]_D²² +9.5 (c 0.53, CHCl₃)];¹⁶ ν_max(ATR)/cm^–1 3365, 2977, 2923, 2851, 1745, 1714, 1501, 1469, 1436, 1391, 1365, 1248, 1216, 1160, 1057, 1023, 894, and 861; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.42 (t, J = 8.0 Hz, 1H), 4.90 (d, J = 7.2 Hz, 1H), 4.35 (m, 1H), 3.73 (s, 3H), 2.50 (dd, J = 13.8 Hz, 4.9 Hz, 1H), 2.26 (dd, J = 13.7 Hz, 9.1 Hz, 1H), 2.15–2.08 (m, 4H), 1.54–1.47 (m, 8H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.4, 155.2, 135.6, 128.7, 79.8, 52.1, 52.0, 40.3, 29.7, 28.5, 28.3, 26.4, 26.3, 26.2; HRMS (ES) m/z: [M + H]⁺ calcd for C₁₇H₃₀NO₄ 312.2175; found 312.2183.

The characterization data was consistent with that reported in the literature,¹⁶ with the exception of the ¹³C NMR shifts. In the previous report, a signal at δ_C 22.8 was assigned to the compound, but this was not observed in our purified sample, and is, therefore, due to an impurity; heteronuclear single quantum coherence analysis established that the true signal was, in fact, obscured by the tert-butyl methyl signal.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(3,6-dihydro-2H-pyran-4-yl)propanoate 10

Synthesis was achieved by general procedure A using zinc dust (1.484 g, 22.69 mmol), iodine (12 crystals, then 6 crystals), 9 (2.507 g, 7.62 mmol), Pd₂(dba)₃ (0.168 g, 0.18 mmol), SPhos (0.153 g, 0.37 mmol), and 6 (2.620 g, 11.28 mmol). Purification by flash column chromatography (25% EtOAc in petroleum ether (40–60), over silica) gave 10 as a colorless oil (1.132 g, 3.97 mmol, 52%); [α]_D²⁵ +18.6 (c 1.02, CHCl₃); ν_max(ATR)/cm^–1 3340, 3003, 2977, 2930, 2853, 1743, 1709, 1511, 1436, 1391, 1365, 1249, 1215, 1160, 1126, 1054, 1024, 1000, 849 and 752; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.52 (m, 1H), 5.00 (d, J = 7.7 Hz, 1H), 4.42 (m, 1H), 4.11 (m, 2H), 3.77 (m, 5H), 2.50 (dd, J = 13.9 Hz, 4.6 Hz, 1H), 2.32 (dd, J = 14 Hz, 8.5 Hz, 1H), 2.08 (m, 2H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.1, 155.2, 130.9, 124.1, 80.0, 65.4, 64.3, 52.3, 51.7, 40.44, 28.3, 27.9; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₄H₂₃NO₅Na 308.1474; found 308.1485.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(4,4-difluorocyclohex-1-en-1-yl)propanoate 11

Synthesis was achieved by general procedure A using zinc dust (0.615 g, 9.41 mmol), iodine (10 crystals, then 3 crystals), 9 (1.046 g, 3.18 mmol), Pd₂(dba)₃ (0.066 g, 0.07 mmol), SPhos (0.075 g, 0.18 mmol), and 7 (1.313 g, 4.93 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 11 as a colorless oil (0.914 g, 2.86 mmol, 90%); [α]_D²⁴ +25.6 (c 1.02, CHCl₃); ν_max(ATR)/cm^–1 3353, 2980, 1744, 1711, 1504, 1437, 1365, 1264, 1250, 1216, 1160, 1108, 1069, 1014, 971, 889, 860, and 777; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.36 (m, 1H), 4.97 (br d, J = 7.9 Hz, 1H), 4.46 (m, 1H), 3.75 (s, 3H), 2.51 (m, 3H), 2.38–2.25 (m, 3H), 2.09–1.98 (m, 2H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 172.9, 155.1, 132.7, 122.7 (t, J = 240 Hz), 120.4, 80.0, 52.3, 51.8, 40.6, 34.7 (t, J = 27 Hz), 30.3 (t, J = 24 Hz), 28.3, 26.1 (t, J = 5 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −95.7 (d, J = 235 Hz, 1 F), −97.3 (d, J = 235 Hz, 1 F); HRMS (ES) m/z: [M + H]⁺ calcd for C₁₅H₂₄F₂NO₄ 320.1673; found 320.1679.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylpent-4-enoate 16

Synthesis was achieved by general procedure A using zinc dust (1.966 g, 30.07 mmol), iodine (15 crystals, then 6 crystals), 9 (3.292 g, 10.00 mmol), Pd₂(dba)₃ (0.229 g, 0.25 mmol), SPhos (0.211 g, 0.51 mmol), and 2-bromopropene 12 (0.9 mL, 1.226 g, 10.13 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 16 as a light orange oil (2.051 g, 8.43 mmol, 84%); [α]_D²⁴ +10.5 (c 1.05, CHCl₃); ν_max(ATR)/cm^–1 3379, 2977, 2956, 2932, 1744, 1713, 1500, 1437, 1365, 1247, 1215, 1160, 1046, 1020, 895, 861, 779 and 759; ¹H NMR (CDCl₃, 400 MHz) δ_H 4.96 (d, J = 6.6 Hz, 1H), 4.86 (s, 1H), 4.76 (s, 1H), 4.41 (m, 1H), 3.73 (s, 3H), 2.52 (dd, J = 13.8 Hz, 5.4 Hz, 1H), 2.37 (dd, J = 13.8 Hz, 8.3 Hz, 1H), 1.74 (s, 3H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.1, 155.3, 140.5, 114.5, 79.9, 52.2, 51.8, 40.7, 28.3, 21.8; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₂H₂₁NO₄Na 266.1363; found 266.1365.

Methyl (2R)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylpent-4-enoate ent-16

Synthesis was achieved by general procedure A using zinc dust (0.607 g, 9.28 mmol), iodine (9 crystals, then 3 crystals), (S)-N-Boc-β-I-Ala-OMe ent-9 (1.027 g, 3.12 mmol), Pd₂(dba)₃ (0.076 g, 0.08 mmol), SPhos (0.067 g, 0.16 mmol), and 2-bromopropene 12 (0.45 mL, 0.613 g, 5.07 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave ent-16 as a light orange oil (0.729 g, 3.00 mmol, 96%); [α]_D²⁴ −10.1 (c 1.48, CHCl₃).

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-5-methylhex-4-enoate 17

Synthesis was achieved by general procedure A using zinc dust (0.594 g, 9.08 mmol), iodine (6 crystals, then 3 crystals), 9 (1.006 g, 3.06 mmol), Pd₂(dba)₃ (0.070 g, 0.08 mmol), SPhos (0.065 g, 0.16 mmol), and 1-bromo-2-methyl-1-propene 13 (0.614 g, 4.55 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 17 as a light orange oil (0.748 g, 2.91 mmol, 95%); [α]_D²⁴ +28.6 (c 1.05, CHCl₃); ν_max(ATR)/cm^–1 3358, 2976, 2918, 1744, 1702, 1498, 1437, 1366, 1352, 1273, 1248, 1208, 1162, 1111, 1059, 1023, 860 and 754; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.02 (m, 2H), 4.34 (m, 1H), 3.72 (s, 3H), 2.53 (m, 1H), 2.41 (m, 1H), 1.70 (d, J = 0.8 Hz, 3H), 1.6 (s, 3H), 1.43 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 172.9, 155.3, 136.3, 117.6, 79.8, 53.3, 52.2, 30.9, 28.3, 25.9, 17.8; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₃NO₄Na 280.1519; found 280.1524.

This reaction was also carried out on a larger scale using 9 (3.292 g, 10.00 mmol) and analogous equivalents of reagents, giving 17 (2.310 g, 8.98 mmol, 90%).

Methyl (2S,4E)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylhex-4-enoate (E)-18

Synthesis was achieved by general procedure A using zinc dust (0.233 g, 3.56 mmol), iodine (4 crystals, then 2 crystals), 9 (0.339 g, 1.03 mmol), Pd₂(dba)₃ (0.026 g, 0.03 mmol), SPhos (0.023 g, 0.06 mmol), and (E)-2-bromo-2-butene 14 (0.12 mL, 0.159 g, 1.18 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave (E)-18 as a light orange oil (0.181 g, 0.70 mmol, 68%); [α]_D²⁴ +10.0 (c 1.20, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3443, 3372, 2978, 2930, 2862, 1747, 1718, 1503, 1438, 1366, 1250, 1218, 1170, 1060 and 1019; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.26 (q, J = 6.0 Hz, 1H), 4.91 (d, J = 7.4 Hz, 1H), 4.34 (m, 1H), 3.70 (s, 3H), 2.45 (dd, J = 13.4 Hz, 5.3 Hz, 1H), 2.27 (dd, J = 13.4 Hz, 8.5 Hz, 1H), 1.6 (m, 3H), 1.57 (d, J = 6.7 Hz, 3H), 1.41 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.3, 155.2, 130.7, 123.2, 79.7, 52.1, 52.0, 42.7, 28.3, 15.3, 13.5; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₃NO₄Na 280.1519; found 280.1521.

Methyl (2S,4E)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylhex-4-enoate (Z)-18

Synthesis was achieved by general procedure A using zinc dust (0.623 g, 9.53 mmol), iodine (10 crystals, then 3 crystals), 9 (1.000 g, 3.04 mmol), Pd₂(dba)₃ (0.072 g, 0.08 mmol), SPhos (0.068 g, 0.17 mmol), and (Z)-2-bromo-2-butene 14 (0.50 mL, 0.666 g, 4.93 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave (Z)-18 as a light orange oil (0.564 g, 2.19 mmol, 72%); [α]_D²³ +13.7 (c 1.38, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3445, 3373, 2977, 2930, 2865, 1747, 1717, 1505, 1453, 1438, 1367, 1278, 1251, 1208, 1169, 1086, 1052, 1021, 861 and 779; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.39 (q, J = 6.6 Hz, 1H), 4.97 (d, J = 7.7 Hz, 1H), 4.40 (m, 1H), 3.72 (s, 3H), 2.52 (dd, J = 13.6 Hz, 6.2 Hz, 1H), 2.42 (dd, J = 13.2 Hz, 7.8 Hz, 1H), 1.68 (m, 3H), 1.56 (d, J = 6.6 Hz, 3H), 1.42 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.3, 155.2, 130.5, 123.5, 79.8, 52.2, 52.0, 34.3, 28.3, 23.3, 13.4; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₃NO₄Na 280.1519; found 280.1520.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclobut-1-en-1-yl)propanoate 19

Synthesis was achieved by general procedure A using zinc dust (0.592 g, 9.06 mmol), iodine (9 crystals, then 6 crystals), 9 (0.988 g, 3.00 mmol), Pd₂(dba)₃ (0.070 g, 0.08 mmol), SPhos (0.063 g, 0.17 mmol), and 1-bromo-1-cyclobutene 15 (2.6 M in tetrahydrofuran, 0.38 mL, 0.99 mmol). Purification by flash column chromatography (8% EtOAc in petroleum ether (40–60), over silica) initially gave the product and N-Boc-Ala-OMe as a mixture. Further purification by flash column chromatography (CH₂Cl₂, over silica) gave 19 as a colorless oil (0.201 g, 0.79 mmol, 80%); [α]_D²⁴ +20.2 (c 1.19, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3362, 2978, 2953, 2929, 1745, 1716, 1512, 1438, 1392, 1367, 1250, 1219, 1166, 1052, 1024, and 858; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.82 (s, 1H), 5.08 (d, J = 7.8 Hz, 1H), 4.42 (m, 1H), 3.75 (s, 3H), 2.54–2.36 (br, m, 6H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 172.9, 155.2, 144.5, 131.6, 79.9, 52.3, 51.9, 34.0, 31.5, 28.3, 27.1; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₁NO₄Na 278.1363; found 278.1363.

General Procedure B, Reaction of 8 with Allyl Chlorides

A flask containing CuBr·DMS (10 mol %) was placed under vacuum and heated vigorously until the gray CuBr·DMS became light green/yellow. The flask was then placed under a flow of nitrogen and allowed to cool to room temperature. This was repeated once more, and the flask was allowed to cool to room temperature. A prepared solution of 8 in DMF was transferred to the flask containing CuBr·DMS. Allylic chloride (1.5 equiv) was added, and the reaction stirred for 72 h at room temperature. The reaction mixture was then filtered through a silica plug eluting with EtOAc. The organic phase was washed with water (2 × 50 mL) and brine (50 mL). The organic phase was dried with Na₂SO₄, filtered, and the solvent removed under reduced pressure. The product was purified by flash column chromatography (EtOAc in petroleum ether (40–60) over silica).

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}hex-5-enoate 20

Synthesis was achieved by general procedure B using zinc dust (0.993 g, 15.19 mmol), iodine (11 crystals, then 5 crystals), 9 (1.665 g, 5.06 mmol), CuBr·DMS (0.064 g, 0.31 mmol), and allyl chloride (0.5 mL, 0.470 g, 6.14 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 20 as a colorless oil (1.030 g, 4.23 mmol, 84%); [α]_D²⁴ +20.0 (c 1.05, CHCl₃); ν_max(ATR)/cm^–1 3352, 2978, 2953, 2930, 1742, 1697, 1504, 1437, 1392, 1366, 1247, 1214, 1159, 1049, 1023, 994, 913, 858 and 778; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.80 (m, 1H), 5.04 (m, 3H), 4.34 (m, 1H), 3.75 (s, 3H), 2.12 (m, 2H), 1.92 (m, 1H), 1.73 (m, 1H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.3, 155.3, 136.9, 115.7, 79.9, 53.0, 52.3, 32.0, 29.5, 28.3; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₂H₂₁NO₄Na 266.1363; found 266.1369.

This characterization data is consistent with that previously reported.²³

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-5-methylhex-5-enoate 21

Synthesis was achieved by general procedure B using zinc dust (1.033 g, 15.80 mmol), iodine (15 crystals, then 6 crystals), 9 (1.648 g, 5.00 mmol), CuBr·DMS (0.105 g, 0.51 mmol), and 3-chloro-2-methyl-1-propene (1.038 g, 11.46 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 21 as a colorless oil (1.009 g, 3.92 mmol, 78%); [α]_D²⁴ +21.6 (c 1.11, CHCl₃); ν_max(ATR)/cm^–1 3358, 2978, 2160, 1978, 1743, 1713, 1506, 1450, 1365, 1276, 1258, 1212, 1163, 1051, 1023 and 888; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.07 (d, J = 7.9 Hz, 1H), 4.75 (br s, 1H), 4.70 (br s, 1H), 4.33 (m, 1H), 3.75 (s, 3H), 2.09–1.88 (br m, 3H), 1.79–1.72 (br m, 4H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.3, 155.3, 144.3, 110.7, 79.9, 53.2, 52.2, 33.3, 30.7, 28.3, 22.5; HRMS (ES) m/z: [M + H]⁺ calcd for C₁₃H₂₄NO₄ 258.1705; found 258.1710.

1,9-Dimethyl (2S,8S)-2,8-Bis({[(tert-butoxy)carbonyl]amino})-5-methylidenenonanedioate 22

Synthesis was achieved by general procedure B using zinc dust (0.495 g, 7.57 mmol), iodine (10 crystals, then 5 crystals), 9 (0.828 g, 2.52 mmol), CuBr·DMS (0.058 g, 0.28 mmol), and 3-chloro-2-chloromethyl-1-propene (0.125 mL, 0.116 g, 0.93 mmol). Purification by flash column chromatography (25% EtOAc in petroleum ether (40–60), over silica) gave 22 as a colorless oil (0.393 g, 0.86 mmol, 92%); [α]_D²² +27.5 (c 1.09, CHCl₃); ν_max(ATR)/cm^–1 3358, 2976, 2933, 1739, 1694, 1647, 1513, 1452, 1437, 1392, 1365, 1273, 1248, 1213, 1160, 1049, 1025, 892, and 864; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.08 (d, J = 8.0, 2H), 4.77 (s, 2H), 4.31–4.26 (m, 2H), 3.72 (s, 6H), 2.07–1.90 (m, 6H), 1.76–1.67 (m, 2H), 1.43 (s, 18H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.2, 155.3, 146.5, 110.6, 79.9, 53.1, 52.2, 31.6, 30.8, 28.3; HRMS (ES) m/z: [M + H]⁺ calcd for C₂₂H₃₉N₂O₈ 459.2706; found 459.2690.

General Procedure C, Radical Fluorination

The protected amino acid (1 equiv) was dissolved in MeCN (20 mL) and placed under nitrogen. The solution was cooled to 0 °C. Fe₂(ox)₃ (15 wt % solution) and deionized water (18 mL) were added. Selectfluor was then added followed by NaBH₄, which was added in two portions with ≈2 min between each addition. The reaction was stirred for 45 min at 0 °C. Conc. NH₄OH solution (4 mL) was added. The reaction mixture was stirred for 1 min. The aqueous layer was extracted with CH₂Cl₂ (3 × 50 mL), the combined organic layers were dried with Na₂SO₄, filtered, and the solvent removed under reduced pressure. The product was isolated by column chromatography (EtOAc in petroleum ether (40–60) mixtures over silica).

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocyclopentyl)propanoate 2a

Synthesis was achieved by general procedure C using 1a (0.128 g, 0.48 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.283 g, 1.02 mmol), Selectfluor (0.367 g, 1.04 mmol), and NaBH₄ (0.069 g, 1.82 mmol; 0.066 g, 1.74 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 2a as a colorless oil (0.088 g, 0.30 mmol, 63%); crystals were obtained by dissolving in hot pentane and leaving the solution to slowly evaporate; mp 43–46 °C; [α]_D²³ +5.0 (c 1.20, CHCl₃); ν_max(ATR)/cm^–1 3355, 2972, 1752, 1685, 1531, 1438, 1391, 1366, 1337, 1318, 1289, 1205, 1161, 1130, 1055, 1028, 996, 960, 866, 792, 778, and 761; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.26 (d, J = 6.0 Hz, 1H), 4.44 (m, 1H), 3.73 (s, 3H), 2.32–1.96 (br m, 4H), 1.79 (m, 2H), 1.69–1.52 (br m, 4H), 1.43 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.1, 155.2, 105.9 (d, J = 173 Hz), 79.9, 52.3, 51.3, 39.9 (d, J = 23 Hz), 37.8 (d, J = 24 Hz), 37.7 (d, J = 24 Hz), 28.3, 23.6, 23.5; ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −142.8 (s); HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₄H₂₄FNO₄Na 312.1582; found 312.1573.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocyclohexyl)propanoate 2b

Synthesis was achieved by general procedure C using 1b (0.155 g, 0.55 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.318 g, 1.03 mmol), Selectfluor (0.365 g, 1.03 mmol), and NaBH₄ (0.066 g, 1.74 mmol; 0.070 g, 1.85 mmol). Purification by flash column chromatography (8% EtOAc in petroleum ether (40–60), over silica) gave 2b as a colorless oil (0.107 g, 0.35 mmol, 64%); [α]_D²⁴ +2.0 (c 1.13, CHCl₃); ν_max(ATR)/cm^–1 3367, 2936, 2866, 1746, 1710, 1504, 1437, 1392, 1366, 1276, 1257, 1212, 1160, 1114, 1049, 1023, 965, 946, 917, 865, and 827; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.20 (d, J = 4.6 Hz, 1H), 4.43 (m, 1H), 3.74 (s, 3H), 2.16–1.87 (br m, 4H), 1.64–1.24 (m, 17H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.3, 155.3, 95.7 (d, J = 170 Hz), 79.9, 52.4, 50.2, 41.4 (d, J = 22 Hz), 35.6 (d, J = 22 Hz), 34.7 (d, J = 22 Hz), 28.3, 25.1, 21.8; ¹⁹F NMR (CDCl₃, 377 MHz) δ_F −153.7 (br s); HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₅H₂₆FNO₄Na 326.1744; found 326.1736.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocycloheptyl)propanoate 2c

Synthesis was achieved by general procedure C using 1c (0.148 g, 0.50 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.236 g, 1.00 mmol), Selectfluor (0.368 g, 1.04 mmol), and NaBH₄ (0.061 g, 1.61 mmol; 0.063 g, 1.67 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 2c as a colorless oil (0.112 g, 0.35 mmol, 70%); [α]_D²⁴ +1.8 (c 1.14, CHCl₃); ν_max(ATR)/cm^–1 3362, 2931, 2858, 1744, 1712, 1502, 1458, 1438, 1389, 1365, 1252, 1204, 1159, 1050, 1022, 961, 861, and 836; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.21 (m, 1H), 4.41 (m, 1H), 3.75 (s, 3H), 1.72 (br m, 23H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.3, 155.3, 100.1 (d, J = 169 Hz), 80.0, 52.4, 50.6, 42.4 (d, J = 22 Hz), 39.2 (d, J = 24 Hz), 38.0 (d, J = 24 Hz), 29.55, 29.51, 28.3, 22.1 (d, J = 7 Hz), 22.0 (d, J = 5 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −137.7; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₆H₂₈FNO₄Na 340.1900; found 340.1913.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocyclooctyl)propanoate 2d

Synthesis was achieved by general procedure C using 1d (0.171 g, 0.55 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.320 g, 1.03 mmol), Selectfluor (0.367 g, 1.04 mmol), and NaBH₄ (0.070 g, 1.85 mmol; 0.065 g, 1.72 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 2d as a colorless oil (0.120 g, 0.36 mmol, 65%); [α]_D²⁵ +3.8 (c 1.58, CHCl₃); ν_max(ATR)/cm^–1 3363, 2921, 2857, 1747, 1713, 1504, 1475, 1436, 1391, 1366, 1276, 1248, 1213, 1160, 1048, 1026, 917, 864, and 829; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.24 (d, J = 4.2 Hz, 1H), 4.40 (m, 1H), 3.74 (s, 3H), 1.71 (br m, 25H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.3, 155.3, 99.8 (d, J = 167 Hz), 79.9, 52.4, 50.6, 40.3 (d, J = 21 Hz), 34.7 (d, J = 24 Hz), 33.2 (d, J = 24 Hz), 28.3, 28.0, 27.8, 24.9, 21.9 (d, J = 8 Hz), 21.8 (d, J = 8 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −137.2; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₇H₃₀FNO₄Na 354.2057; found 354.2067.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(4-fluorooxan-4-yl)propanoate 23

Synthesis was achieved by general procedure C using 10 (0.144 g, 0.50 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.247 g, 1.01 mmol), Selectfluor (0.355 g, 1.00 mmol), and NaBH₄ (0.061 g, 1.61 mmol; 0.067 g, 1.77 mmol). Purification by flash column chromatography (15–25% EtOAc in petroleum ether (40–60), over silica) gave 23 as a colorless oil (0.090 g, 0.29 mmol, 58%); [α]_D²⁴ +7.0 (c 1.42, CHCl₃); ν_max(ATR)/cm^–1 3347, 2958, 2930, 2867, 1747, 1710, 1513, 1436, 1392, 1366, 1280, 1249, 1214, 1160, 1102, 1048, 1014, 985, 838, 780, and 758; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.17 (d, J = 6.7 Hz, 1H), 4.50 (m, 1H), 3.65–3.69 (m, 7H), 2.23–1.62 (m, 6H), 1.46 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.0, 155.2, 92.7 (d, J = 172 Hz), 80.1, 63.4, 52.5, 49.7, 41.9 (d, J = 21 Hz), 35.6 (d, J = 22 Hz), 35.1 (d, J = 22 Hz), 28.3; ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −159.8; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₄H₂₄FNO₅Na 328.1536; found 328.1551.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1,4,4-trifluorocyclohexyl)propanoate 24

Synthesis was achieved by general procedure C with the modifications discussed in the Results and Discussion section using 11 (0.161 g, 0.50 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.289 g, 1.02 mmol), Selectfluor (0.905 g, 2.55 mmol), and NaBH₄ (0.305 g, 8.06 mmol) in 0.1 M NaOH solution (30 mL) added over 6 h. Purification by flash column chromatography (13% EtOAc in petroleum ether (40–60), over silica) gave the product as a colorless oil that solidified on standing to give 24 as a white solid. Recrystallized from hot pentane (0.110 g, 0.32 mmol, 64%); mp 67–69 °C; [α]_D²⁴ +1.9 (c 1.03, CHCl₃); ν_max(ATR)/cm^–1 3378, 3010, 2970, 2936, 2862, 2339, 1763, 1689, 1530, 1442, 1389, 1367, 1343, 1316, 1270, 1256, 1221, 1162, 1122, 1095, 1053, 1022, 992, 963, 913, 893, 865, and 844; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.16 (d, J = 7.5 Hz, 1H), 4.48 (m, 1H), 3.76 (s, 3H), 2.20–2.00 (br m, 8H), 1.82–1.65 (br m, 2H), 1.45 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 172.9, 155.2, 122.6 (dd, J = 243 Hz, 238 Hz), 93.5 (d, J = 173 Hz), 80.2, 52.6, 50.1, 41.3 (d, J = 21 Hz), 31.8 (dd, J = 10 Hz, 10 Hz), 31.5 (dd, J = 10 Hz, 10 Hz), 29.2 (apparent t, J = 25 Hz), 28.3; ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −93.4 (d, J = 238 Hz, 1 F), −105.0 (d, J = 238 Hz, 1 F), −162.6 (s, 1 F); HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₅H₂₄F₃NO₄Na 362.1555; found 362.1541.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-4-fluoro-4-methylpentanoate 25

Synthesis was achieved by general procedure C using 16 (0.119 g, 0.49 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.247 g, 1.01 mmol), Selectfluor (0.357 g, 1.01 mmol), and NaBH₄ (0.066 g, 1.74 mmol; 0.059 g, 1.56 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 25 as a colorless oil, which solidified on standing (0.107 g, 0.41 mmol, 84%); mp 37–40 °C; [α]_D²⁴ −2.5 (c 1.18, CHCl₃); ν_max(ATR)/cm^–1 3373, 2980, 2957, 2917, 2849, 1746, 1712, 1505, 1438, 1390, 1366, 1249, 1206, 1161, 1049, 1027, 990, 889, 866, 849, 797, and 781; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.20 (d, J = 6.2 Hz, 1H), 4.41 (m, 1H), 3.73 (s, 3H), 2.17–1.94 (br m, 2H), 1.43 (s, 9H), 1.41 (d, J = 21.5 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.1, 155.3, 95.0 (d, J = 166 Hz), 80.0, 52.4, 50.8, 42.6 (d, J = 22 Hz), 28.3, 27.1 (d, J = 25 Hz), 26.5 (d, J = 25 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −136.6 (s); HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₂H₂₂FNO₄Na 286.1425; found 286.1427.

Methyl (2R)-2-{[(tert-Butoxy)carbonyl]amino}-4-fluoro-4-methylpentanoate ent-25

Synthesis was achieved by general procedure C using ent-16 (0.124 g, 0.51 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.330 g, 1.03 mmol), Selectfluor (0.379 g, 1.07 mmol), and NaBH₄ (0.058 g, 1.54 mmol; 0.064 g, 1.69 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave ent-25 as a colorless oil, which solidified on standing (0.118 g, 0.45 mmol, 88%); mp 38–40 °C; [α]_D²⁴ +3.1 (c 1.31, CHCl₃).

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-5-fluoro-5-methylhexanoate 26

Synthesis was achieved by general procedure C using 17 (0.130 g, 0.51 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.109 g, 0.96 mmol), Selectfluor (0.368 g, 1.04 mmol), and NaBH₄ (0.064 g, 1.70 mmol; 0.061 g, 1.60 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 26 as a colorless oil (0.104 g, 0.38 mmol, 75%); [α]_D²⁴ +14.0 (c 1.07, CHCl₃); ν_max(ATR)/cm^–1 3358, 3004, 2980, 2933, 1743, 1712, 1512, 1454, 1438, 1389, 1366, 1276, 1260, 1210, 1160, 1053, 1027, and 875; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.08 (d, J = 8.0 Hz, 1H), 4.30 (m, 1H), 3.75 (s, 3H), 2.00–1.91 (br m, 1H), 1.78–1.59 (br m, 3H), 1.43 (s, 9H), 1.34 (d, J = 21.3 Hz, 6H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.1, 155.4, 94.9 (d, J = 166 Hz), 79.9, 53.3, 52.3, 36.78 (d, J = 23 Hz), 28.3, 27.14 (d, J = 5 Hz), 26.7 (d, J = 24 Hz), 26.5 (d, J = 24 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −139.5 (s); HRMS (ES) m/z: [M + H]⁺ calcd for C₁₃H₂₄FNO₄ 278.1768; found 278.1756.

Synthesis of 26 was also achieved by general procedure C using 21 (0.133 g, 0.52 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.285 g, 1.02 mmol), Selectfluor (0.358 g, 1.01 mmol), and NaBH₄ (0.067 g, 1.77 mmol; 0.067 g, 1.77 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 26 as a colorless oil (0.090 g, 0.32 mmol, 62%), identical to that isolated above.

Methyl (2S,4RS)-2-{[(tert-Butoxy)carbonyl]amino}-4-fluoro-4-methylhexanoate 27

Synthesis was achieved by general procedure C using (E/Z)-18 (7:1, E/Z) (0.132 g, 0.51 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.460 g, 1.07 mmol), Selectfluor (0.358 g, 1.01 mmol), and NaBH₄ (0.062 g, 1.64 mmol; 0.061 g, 1.61 mmol). Purification by flash column chromatography (8% EtOAc in petroleum ether (40–60), over silica) gave 27 as a colorless oil as a mixture of diastereomers (0.114 g, 0.41 mmol, 80%); ν_max(thin film, NaCl plates)/cm^–1 3371, 2979, 2937, 2889, 1750, 1716, 1513, 1456, 1438, 1386, 1367, 1280, 1249, 1208, 1167, 1056, 1026, 865, and 781; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.19 (m, 1H), 4.40 (m, 1H), 3.73 (s, 3H), 2.01 (m, 2H), 1.66 (m, 2H), 1.43 (s, 9H), 1.36 (d, J = 21.9 Hz, 3H), 0.93 (td, J = 7.5 Hz, 1.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.2, 155.3, 97.2 (d, J = 168 Hz), 97.1 (d, J = 168 Hz), 79.9, 52.4, 50.6 (d, J = 24 Hz), 40.8 (d, J = 22 Hz), 40.3 (d, J = 22 Hz), 33.1 (d, J = 23 Hz), 32.3 (d, J = 23 Hz), 28.3, 23.7 (d, J = 25 Hz), 23.2 (d, J = 25 Hz), 8.0 (d, J = 7 Hz), 7.8 (d, J = 7 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −144.3 (s), −144.6 (s); HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₄FNO₄Na 300.1582; found 300.1586.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocyclobutyl)propanoate 28

Synthesis was achieved by general procedure C using 19 (0.135 g, 0.53 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.289 g, 1.02 mmol), Selectfluor (0.378 g, 1.07 mmol), and NaBH₄ (0.068 g, 1.80 mmol; 0.066 g, 1.74 mmol). Purification by flash column chromatography (8% EtOAc in petroleum ether (40–60), over silica) gave 28 as a colorless oil, which solidifies on standing (0.118 g, 0.43 mmol, 81%); mp 52–54 °C; [α]_D²⁵ +7.6 (c 1.19, CHCl₃); ν_max(ATR)/cm^–1 3362, 2982, 2941, 1755, 1686, 1510, 1457, 1440, 1393, 1365, 1291, 1250, 1219, 1158, 1124, 1093, 1048, 1021, 980, 949, 909, 862, 874, 790, 777, and 758; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.22 (d, J = 7.0 Hz, 1H), 4.43 (m, 1H), 3.73 (s, 3H), 2.39–2.13 (m, 6H), 1.91–1.82 (m, 1H), 1.60–1.52 (m, 1H), 1.43 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.0, 155.2, 96.8 (d, J = 210 Hz), 79.9, 52.4, 50.5, 38.7 (d, J = 22 Hz), 33.9 (d, J = 22 Hz), 33.7 (d, J = 22 Hz), 28.3, 12.1 (d, J = 12 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −132.3 (s); HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₂FNO₄Na 298.1425; found 298.1425.

Methyl (2S,5RS)-2-{[(tert-Butoxy)carbonyl]amino}-5-fluorohexanoate 29

Synthesis was achieved by general procedure C using 20 (0.123 g, 0.51 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.253 g, 1.01 mmol), Selectfluor (0.363 g, 1.02 mmol), and NaBH₄ (0.064 g, 1.69 mmol; 0.061 g, 1.61 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 29 as a colorless oil as a mixture of diastereomers (0.097 g, 0.37 mmol, 73%); [α]_D²⁴ +10.0 (c 1.75, CHCl₃); ν_max(ATR)/cm^–1 3346, 2978, 2933, 1743, 1705, 1508, 1451, 1391, 1366, 1296, 1247, 1214, 1159, 1049, 1020, 923, 838, and 780; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.09 (d, J = 6.6 Hz, 1H), 4.76–4.54 (br m, 1H), 4.32 (m, 1H), 3.74 (s, 3H), 2.07–1.51 (br, m, 4H), 1.44 (s, 9H), 1.32 (dd, J = 23.9 Hz, 6.2 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.1, 155.4, 90.0 (d, J = 165 Hz), 90.3 (d, J = 166 Hz), 79.9, 53.2, 52.9, 52.33, 52.31, 32.7 (d, J = 21 Hz), 32.6 (d, J = 21 Hz), 28.4 (d, J = 4 Hz) 28.3, 21.0 (d, J = 23 Hz), 20.9 (d, J = 23 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −173.7 (s), −174.1 (s); HRMS (ES) m/z: [M + H]⁺ calcd for C₁₂H₂₃FNO₄ 264.1611; found 264.1621.

1,9-Dimethyl (2S,8S)-2,8-Bis({[(tert-butoxy)carbonyl]amino})-5-fluoro-5-methylnonane-dioate 30

Synthesis was achieved by general procedure C using 22 (0.251 g, 0.55 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (3.231 g, 1.00 mmol), Selectfluor (0.361 g, 1.02 mmol), and NaBH₄ (0.065 g, 1.72 mmol; 0.064 g, 1.69 mmol). Purification by flash column chromatography (20% EtOAc in petroleum ether (40–60), over silica) gave 30 as a colorless oil (0.237 g, 0.50 mmol, 91%); [α]_D²⁵ +17.8 (c 1.01, CHCl₃); ν_max(ATR)/cm^–1 3358, 2978, 2937, 2159, 2031, 1978, 1740, 1694, 1514, 1454, 1438, 1392, 1365, 1276, 1255, 1211, 1158, 1049, 1024, 881, and 856; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.10 (d, J = 8.1 Hz, 2H), 4.29 (m, 2H), 3.74 (s, 6H), 1.91 (br m, 2H), 1.63 (br m, 6H), 1.44 (s, 18H), 1.27 (d, J = 21.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.0, 155.4, 95.9 (d, J = 170 Hz), 80.0, 53.3, 52.4, 35.2 (d, J = 23 Hz), 35.0 (d, J = 23 Hz), 28.3, 26.82 (d, J = 6 Hz), 26.76 (d, J = 6 Hz), 23.9 (d, J = 25 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −147.1 (s); HRMS (ES) m/z: [M + H]⁺ calcd for C₂₂H₄₀FN₂O₈ 479.2769; found 479.2774.

General Procedure D, NHBoc Deprotection

The Boc-protected amino acid was dissolved in CH₂Cl₂ (3 mL), TFA (3 mL) was added, and the solution was stirred overnight. The mixture was concentrated under reduced pressure and the residue redissolved in 1:1 toluene/MeOH (6 mL), which was removed under reduced pressure; this process was repeated twice more to afford the product as the TFA salt without further purification.

Methyl (2S,4RS)-2-Ammonium-4-fluoro-4-methylhexanoate Trifluoroacetate 31

Synthesis was achieved by general procedure D using 27 (0.030 g, 0.11 mmol), CH₂Cl₂/TFA (1:1, 6 mL) and isolated without further purification gave 31 as a colorless oil as a mixture of diastereomers (0.031 g, 0.11 mmol, >99%); ν_max(thin film, NaCl plates)/cm^–1 3445, 2962, 2666, 1751, 1675, 1631, 1533, 1441, 1384, 1240, 1203, 1138, 1034, 927, 838, and 800; ¹H NMR (CDCl₃, 400 MHz) δ_H 8.42 (br s, 3H), 4.78–4.58 (br m, 1H), 4.07–4.00 (br m, 1H), 3.82 (s, 3H), 2.19–1.68 (br m, 4H), 1.34 (dd, J = 24.0 Hz, 5.6 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 169.9, 162.3 (q, J = 36.8 Hz), 90.2 (d, J = 165.6 Hz), 89.9 (d, J = 165.7 Hz), 53.3, 52.9, 52.7, 32.0 (d, J = 21.3 Hz), 31.6 (d, J = 21.1 Hz), 26.4 (d, J = 3.8 Hz), 26.1 (d, J = 3.8 Hz), 20.6 (d, J = 22.4 Hz), 20.5 (d, J = 22.4 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −76.0 (s, 3 F), −174.6 (s, 0.46 F), −175.0 (s, 0.49 F); ¹⁹F NMR (CDCl₃, 377 MHz) δ_F −76.0 (s, 3 F), −174.7 (m, 0.98 F); HRMS (ES) m/z: [M + H]⁺ calcd for C₇H₁₅FNO₂ 164.1081; found 164.1081.

Methyl (2S,5RS)-2-Ammonium-5-fluorohexanoate Trifluoroacetate 32

Synthesis was achieved by general procedure D using 29 (0.019 g, 0.07 mmol), CH₂Cl₂/TFA (1:1, 6 mL) and isolated without further purification gave 32 as a colorless oil as a mixture of diastereomers (0.020 g, 0.07 mmol, 96%); ν_max(thin film, NaCl plates)/cm^–1 3423, 2980, 1754, 1678, 1533, 1442, 1385, 1299, 1237, 1204, 1137, 1055, 997, 949, 886, 838, and 801; ¹H NMR (CDCl₃, 400 MHz) δ_H 7.39 (br m, 3H), 4.26 (m, 1H), 3.81 (s, 3H), 2.44–2.14 (m, 2H), 1.84–1.59 (m, 2H), 1.42 (d, J = 22.0 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 169.9, 169.7, 97.9 (d, J = 166.6 Hz), 97.6 (d, J = 166.8 Hz), 53.5, 53.4, 50.0, 49.8, 38.9 (d, J = 20.8 Hz), 38.8 (d, J = 20.5 Hz), 33.2 (d, J = 23.0 Hz), 31.6 (d, J = 23.4 Hz), 23.6 (d, J = 24.2 Hz), 22.5 (d, J = 24.8 Hz), 7.8 (d, J = 7.9 Hz), 7.6 (d, J = 7.3 Hz); ¹⁹F{¹H} NMR (CDCl₃, 377 MHz) δ_F −75.8 (s, 3 F), −146.0 (s, 0.5 F), −147.4 (s, 0.48 F); ¹⁹F NMR (CDCl₃, 377 MHz) δ_F −75.8 (s, 3 F), −146.1 (m, 0.49 F), −147.4 (m, 0.47 F); HRMS (ES) m/z: [M + H]⁺ calcd for C₈H₁₆FNO₂ 178.1238; found 178.1240.

General Procedure E, Radical Hydroazidation

The protected unsaturated amino acid was dissolved in MeCN (20 mL), and the solution was cooled to 0 °C. Fe₂(ox)₃·6H₂O (15 wt % solution) was added followed by deionized water (18 mL), NaN₃ was then added followed by NaBH₄, which was added in eight portions with ≈2 min between each addition. The reaction was stirred for 45 min at 0 °C. Conc. NH₄OH solution (30 mL) was added. The reaction mixture was stirred for 1 min. The aqueous phase was extracted with CH₂Cl₂ (3 × 50 mL), the combined organic layers were dried with Na₂SO₄, filtered, and the solvent removed under reduced pressure. The product was purified by flash column chromatography (EtOAc in petroleum ether (40–60) mixtures over silica).

Methyl (2S)-4-Azido-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanoate 33

Synthesis was achieved by general procedure E using 16 (0.127 g, 0.52 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (7.698 g, 2.39 mmol), NaN₃ (0.125 g, 1.92 mmol), and NaBH₄ (0.066 g, 1.74 mmol; 0.078 g, 2.06 mmol; 0.067 g, 1.77 mmol; 0.073 g, 1.93 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 33 as a colorless oil (0.133 g, 0.46 mmol, 88%); [α]_D²⁴ +11.6 (c 0.86, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3364, 2978, 2932, 2851, 2100, 1747, 1716, 1512, 1456, 1438, 1392, 1368, 1252, 1218, 1167, 1051, 1028, 994, 863, and 760; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.21 (d, J = 7.7 Hz, 1H), 4.40 (m, 1H), 3.74 (s, 3H), 1.97 (dd, J = 14.5 Hz, 4.4 Hz, 1H), 1.78 (dd, J = 14.5 Hz, 8.4 Hz, 1H), 1.43 (s, 9H), 1.36 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.1, 155.2, 80.1, 60.3, 52.4, 50.9, 43.0, 28.3, 26.3, 26.0; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₂H₂₂N₄O₄Na 309.1533; found 309.1536.

Methyl (2S)-3-(1-Azidocyclopentyl)-2-{[(tert-butoxy)carbonyl]amino}propanoate 34

Synthesis was achieved by general procedure E using 1a (0.141 g, 0.52 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (7.371 g, 2.37 mmol), NaN₃ (0.109 g, 1.68 mmol), and NaBH₄ (0.071 g, 1.77 mmol; 0.065 g, 1.72 mmol; 0.066 g, 1.74 mmol, 0.071 g, 1.88 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 34 as a colorless oil (0.107 g, 0.34 mmol, 65%); [α]_D²⁵ +15.1 (c 1.33, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3364, 2968, 2919, 2880, 2102, 1748, 1717, 1513, 1451, 1438, 1393, 1367, 1254, 1208, 1166, 1055, 1023, 864, and 779; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.21 (d, J = 7.6 Hz, 1H), 4.44 (m, 1H), 3.75 (s, 3H), 2.18 (dd, J = 14.6 Hz, 4.9 Hz, 1H), 1.98 (dd, J = 14.3, J = 7.2 Hz, 1H), 1.92 (m, 2H), 1.82–1.66 (br m, 4H), 1.65–1.54 (br m, 2H), 1.44 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.1, 155.1, 80.0, 71.7, 52.5, 51.5, 40.8, 37.3, 37.2, 28.3, 23.4, 23.3; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₄H₂₄N₄O₄Na 335.1690; found 335.1688.

Methyl (2S)-3-(1-Azidocyclohexyl)-2-{[(tert-butoxy)carbonyl]amino}propanoate 35

Synthesis was achieved by general procedure E using 1b (0.142 g, 0.50 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (7.371 g, 2.29 mmol), NaN₃ (0.145 g, 2.23 mmol), and NaBH₄ (0.068 g, 1.80 mmol; 0.059 g, 1.56 mmol; 0.075 g, 1.98 mmol, 0.070 g, 1.85 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 35 as a colorless oil (0.116 g, 0.36 mmol, 72%); [α]_D²⁴ +4.4 (c 1.59, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3363, 2977, 2934, 2861, 2103, 1747, 1717, 1513, 1450, 1438, 1390, 1367, 1254, 1211, 1164, 1051, 1024, 864, and 779; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.18 (d, J = 7.8 Hz, 1H), 4.42 (m, 1H), 3.74 (s, 3H), 2.06 (dd, J = 14.8 Hz, 4.5 Hz, 1H), 1.83 (dd, J = 14.8 Hz, 8.1 Hz, 1H), 1.72 (m, 2H), 1.59–1.24 (br m, 17H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.2, 155.1, 80.0, 62.8, 52.5, 50.2, 41.5, 34.8, 34.3, 28.3, 25.1, 22.0; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₅H₂₆N₄O₄Na 349.1846; found 349.1851.

Methyl (2S)-5-Azido-2-{[(tert-butoxy)carbonyl]amino}-5-methylhexanoate 36

Synthesis was achieved by general procedure E using 21 (0.134 g, 0.52 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (7.585 g, 2.35 mmol), NaN₃ (0.130 g, 2.00 mmol), and NaBH₄ (0.061 g, 1.61 mmol; 0.074 g, 1.96 mmol; 0.066 g, 1.74 mmol; 0.076 g, 2.01 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave the product 36 as a colorless oil (0.108 g, 0.36 mmol, 69%); [α]_D²⁴ +17.4 (c 1.09, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3359, 2977, 2935, 2098, 1745, 1718, 1512, 1454, 1440, 1392, 1368, 1255, 1209, 1166, 1056, 1029, 867, 853, and 780; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.11 (d, J = 7.9 Hz, 1H), 4.29 (m, 1H), 3.74 (s, 3H), 1.91 (br m, 1H), 1.68 (br m, 1H), 1.53 (br m, 2H), 1.43 (s, 9H), 1.25 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.0, 155.3, 79.9, 61.0, 53.3, 52.4, 36.8, 28.3, 27.5, 26.0, 25.8; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₄N₄O₄Na 323.1690; found 323.1692.

Synthesis of 36 was also achieved by general procedure E using 17 (0.128 g, 0.50 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (6.733 g, 2.09 mmol), NaN₃ (0.125 g, 1.92 mmol), and NaBH₄ (0.066 g, 1.74 mmol; 0.058 g, 1.53 mmol; 0.060 g, 1.59 mmol; 0.066 g, 1.74 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 36 as a colorless oil (0.130 g, 0.43 mmol, 86%), identical to that isolated above.

Methyl (2S,4RS)-4-Azido-2-{[(tert-butoxy)carbonyl]amino}-4-methylhexanoate 37

Synthesis was achieved by general procedure E using (E/Z)-18 (7:1, E/Z) (0.131 g, 0.51 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (7.627 g, 2.37 mmol), NaN₃ (0.126 g, 1.94 mmol), and NaBH₄ (0.060 g, 1.59 mmol; 0.074 g, 1.96 mmol; 0.075 g, 1.98 mmol; 0.078 g, 2.06 mmol). Purification by flash column chromatography (10% EtOAc in petroleum ether (40–60), over silica) gave 37 as a colorless oil, which is a mixture of diastereomers (0.096 g, 0.32 mmol, 63%); ν_max(thin film, NaCl plates)/cm^–1 3361, 2977, 2935, 2883, 2105, 1748, 1716, 1514, 1458, 1437, 1390, 1367, 1255, 1205, 1166, 1056, 1025, 862, and 779; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.20 (d, J = 7.8 Hz, 1H), 4.39 (m, 1H), 3.75 (s, 3H), 1.95 (m, 1H), 1.76 (m, 1H), 1.65 (m, 2H), 1.44 (s, 9H), 1.33 (s, 3H), 0.95 (t, J = 7.4 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.2, 155.2, 80.1, 63.1, 52.5, 50.7, 50.6, 41.0, 40.5, 32.8, 32.4, 28.3, 22.6, 22.4, 8.4, 8.3; HRMS (ES) m/z: [M + H]⁺ calcd for C₁₃H₂₅N₄O₄ 301.1870; found 301.1872.

General Procedure F, Azide Reduction

The azido amino acid was dissolved in EtOAc, 10 wt % Pd on carbon was added (≈20 wt %), and the mixture was stirred overnight under an atmosphere of hydrogen. The product was purified by flash column chromatography (EtOAc in petroleum ether (40–60) mixtures over silica).

tert-Butyl N-[(3S)-5,5-Dimethyl-2-oxopyrrolidin-3-yl]carbamate 38

Synthesis was achieved by general procedure F using 33 (0.138 g, 0.48 mmol), EtOAc (4 mL), Pd/C 10 wt % (0.037 g, ≈20 wt %). Purification by flash column chromatography (50% EtOAc in petroleum ether (40–60), over silica) gave 38 as a white solid (0.109 g, 0.48 mmol, >99%); mp 121–123 °C; [α]_D²⁵ +27.4 (c 1.09, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3284, 2975, 2933, 2883, 1705, 1528, 1455, 1420, 1392, 1368, 1327, 1292, 1247, 1169, 1056, 1028, 1001, 979, 885, 835, and 755; ¹H NMR (CDCl₃, 400 MHz) δ_H 7.11 (br s, 1H), 5.24 (br d, J = 4.3 Hz, 1H), 4.35 (br m, 1H), 2.54 (br t, J = 8.3 Hz, 1H), 1.75 (br t, J = 11.1 Hz, 1H), 1.43 (s, 9H), 1.31 (s, 3H), 1.27 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 174.2, 155.9, 79.8, 53.9, 52.1, 44.2, 29.9, 28.5, 28.3; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₁H₂₀N₂O₃Na 251.1366; found 251.1366.

tert-Butyl N-[(3S)-2-Oxo-1-azaspiro[4.4]nonan-3-yl]carbamate 39

Synthesis was achieved by general procedure F using 34 (0.161 g, 0.52 mmol), EtOAc (4 mL), Pd/C 10 wt % (0.038 g, ≈20 wt %). Purification by flash column chromatography (50% EtOAc in petroleum ether (40–60), over silica) gave 39 as a colorless oil (0.121 g, 0.48 mmol, 92%); [α]_D²⁵ +13.9 (c 1.22, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3276, 2967, 2874, 1702, 1523, 1454, 1391, 1366, 1323, 1285, 1248, 1168, 1062, 1028, 1007, 839, and 753; ¹H NMR (CDCl₃, 400 MHz) δ_H 7.57 (br s, 1H), 5.28 (br s, 1H), 4.29 (m, 1H), 2.61 (br t, J = 9.4 Hz, 1H), 1.86–1.63 (br m, 9H), 1.42 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 174.6, 160.0, 79.7, 64.0, 52.2, 42.8, 39.4, 38.4, 28.3, 23.5, 22.7; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₂N₂O₃Na 277.1523; found 277.1525.

tert-Butyl N-[(3S)-2-Oxo-1-azaspiro[4.5]decan-3-yl]carbamate 40

Synthesis was achieved by general procedure F using 35 (0.106 g, 0.32 mmol), EtOAc (5 mL), Pd/C 10 wt % (0.023 g, ≈20 wt %). Purification by flash column chromatography (40% EtOAc in petroleum ether (40–60), over silica) gave a colorless oil that solidified on standing. Recrystallization from hot Et₂O/pentane (1:1) gave compound 40 (0.079 g, 0.29 mmol, 91%); mp 160–163 °C; [α]_D²⁴ +24.1 (c 1.14, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3231, 3029, 3006, 2978, 2932, 2857, 1702, 1501, 1453, 1391, 1366, 1332, 1293, 1280, 1246, 1170, 1064, 973, 854, and 760; ¹H NMR (CDCl₃, 400 MHz) δ_H 7.49 (br s, 1H), 5.24 (br s, 1H), 4.29 (br m, 1H), 2.67 (br t, J = 9.7 Hz, 1H), 1.62–1.49 (br m, 11H), 1.43 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 174.3, 156.0, 79.8, 56.8, 51.5, 41.7, 39.4, 37.3, 28.3, 25.0, 23.0, 22.7; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₄H₂₄N₂O₃Na 291.1679; found 291.1679.

tert-Butyl N-[(3S)-6,6-Dimethyl-2-oxopiperidin-3-yl]carbamate 41

Synthesis was achieved by general procedure F using 36 (0.180 g, 0.60 mmol), EtOAc (3 mL), Pd/C 10 wt % (0.037 g, ≈20 wt %). Purification by flash column chromatography (50% EtOAc in petroleum ether (40–60), over silica) gave compound 41 as a white solid (0.144 g, 0.59 mmol, 98%); mp 124–127 °C; [α]_D²⁵ +47.8 (c 1.36, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3285, 3230, 2974, 2935, 1705, 1665, 1490, 1459, 1416, 1367, 1344, 1312, 1249, 1164, 1076, 1054, 1024, 971, 831, and 756; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.82 (br s, 1H), 5.46 (br s, 1H), 3.96 (m, 1H), 2.40 (m, 1H), 1.75 (m, 3H), 1.46 (s, 9H), 1.29 (s, 3H), 1.27 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 170.8, 156.0, 79.4, 53.1, 51.4, 34.4, 31.6, 29.7, 28.3, 25.3; HRMS (ES) m/z: [M + H]⁺ calcd for C₁₂H₂₃N₂O₃ 243.1705; found 243.1703.

General Procedure G, Radical Hydroxylation

The amino acid was dissolved in MeCN (20 mL), and Fe₂(ox)₃ (15 wt % solution) and deionized water (18 mL) were added. The mixture was stirred, and a flow of air passed through the solution. NaBH₄ was added in eight portions with ≈2 min between each addition. The reaction mixture was then stirred for 45 min. Conc. NH₄OH solution (4 mL) was added, and the reaction mixture stirred for 1 min. The aqueous phase was extracted with 5% MeOH in CH₂Cl₂ (3 × 50 mL). The combined organic phases were dried with Na₂SO₄, filtered, and concentrated under reduced pressure. The product was purified by flash column chromatography (EtOAc in petroleum ether (40–60) mixtures over silica).

tert-Butyl N-[(3S)-5,5-Dimethyl-2-oxooxolan-3-yl]carbamate 42

Synthesis was achieved by general procedure G using 16 (0.133 g, 0.55 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (7.701 g, 2.39 mmol), and NaBH₄ (0.027 g, 0.71 mmol; 0.0306 g, 0.81 mmol; 0.0228 g, 0.60 mmol; 0.039 g, 1.03 mmol; 0.031 g, 0.82 mmol; 0.036 g, 0.95 mmol; 0.025 g, 0.66 mmol; 0.037 g, 0.98 mmol). Purification by flash column chromatography (15–30% EtOAc in petroleum ether (40–60), over silica) gave 42 as a white solid (0.055 g, 0.24 mmol, 44%); mp 110–113 °C; [α]_D²⁴ +20.0 (c 0.95, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3317, 2981, 2937, 1759, 1708, 1531, 1453, 1375, 1368, 1307, 1272, 1249, 1207, 1158, 1109, 1001, 973, 952, 923, 885, and 809; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.12 (br s, 1H), 4.57 (br m, 1H), 2.67 (apparent t, J = 10.2 Hz, 1H), 1.97 (apparent t, J = 11.9 Hz, 1H), 1.50 (s, 3H), 1.46 (s, 9H), 1.43 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 174.6, 155.5, 82.4, 80.5, 51.3, 42.6, 29.0, 28.3, 26.9; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₁H₁₉NO₄Na 252.1206; found 252.1209.

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-5-hydroxy-5-methylhexanoate 43

Synthesis was achieved by general procedure G using 17 (0.149 g, 0.58 mmol), Fe₂(ox)₃·6H₂O (15 wt % solution) (7.117 g, 2.21 mmol), and NaBH₄ (0.031 g, 0.82 mmol; 0.035 g, 0.93 mmol; 0.031 g, 0.82 mmol; 0.032 g, 0.85 mmol; 0.032 g, 0.85 mmol; 0.039 g, 1.03 mmol; 0.038 g, 1.00 mmol; 0.027 g, 0.71 mmol). Purification by flash column chromatography (30–100% EtOAc in petroleum ether (40–60), over silica) gave 43 as a colorless oil (0.099 g, 0.36 mmol, 62%); [α]_D²⁴ +10.1 (c 1.09, CHCl₃); ν_max(thin film, NaCl plates)/cm^–1 3439, 3373, 2975, 2934, 1738, 1712, 1521, 1455, 1437, 1392, 1367, 1273, 1252, 1208, 1165, 1054, 1028, 914, and 858; ¹H NMR (CDCl₃, 400 MHz) δ_H 5.20 (br m, 1H), 4.32 (br m, 1H), 3.74 (s, 3H), 1.98–1.67 (br m, 3H), 1.55–1.44 (br m, 11H), 1.21 (s, 6H); ¹³C NMR (CDCl₃, 100 MHz), δ_C 173.4, 155.4, 79.9, 70.4, 53.6, 52.3, 38.8, 29.4, 29.2, 28.3, 27.6; HRMS (ES) m/z: [M + Na]⁺ calcd for C₁₃H₂₅NO₅Na 298.1625; found 298.1626.

Acknowledgments

We thank Medivir for partial support of a Ph.D. studentship (P.A.P.R.) and Harry Adams and Craig Robertson for carrying out the X-ray crystal structure analyses.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b01509.

Details for the X-ray structure determinations of compounds 2a, 24, and 40; ¹H and ¹³C NMR spectra for all compounds; ¹⁹F NMR spectra for compounds containing fluorine; chiral HPLC traces for compounds 25 and ent-25 (PDF)
Crystallographic data file (CIF)

Author Present Address

^⊥ Research Institutes of Sweden, RISE Bioscience and Materials/Chemistry and Materials, Brinellgatan, SE-504 64 Borås, Sweden (F.W.).

Author Present Address

^∥ Swedish Defence Research Agency, FOI, CBRN Defence and Security, Cementvägen 20, 90182 Umeå, Sweden (D.W.).

Author Present Address

^§ F-star Biotechnology Limited, Eddeva B920, Babraham Research Campus, Cambridge CB22 3AT, U.K. (U.G.).

The authors declare no competing financial interest.

Supplementary Material

ao9b01509_si_001.pdf^{(8.9MB, pdf)}

ao9b01509_si_002.cif^{(1.6MB, cif)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao9b01509_si_001.pdf^{(8.9MB, pdf)}

ao9b01509_si_002.cif^{(1.6MB, cif)}

[ref1] Blaskovich M. A.Handbook on Syntheses of Amino Acids: General Routes for the Syntheses of Amino Acids; Oxford University Press: Oxford, 2010. [Google Scholar]

[ref2] a Welch J. T.; Eswarakrishnan S.. Fluorine in Bioorganic Chemistry; John Wiley & Sons: Chichester, 1991. [Google Scholar]; b Salwiczek M.; Nyakatura E. K.; Gerling U. I. M.; Ye S. J.; Koksch B. Fluorinated Amino Acids: Compatibility with Native Protein Structures and Effects on Protein-protein Interactions. Chem. Soc. Rev. 2012, 41, 2135–2171. 10.1039/C1CS15241F. [DOI] [PubMed] [Google Scholar]

[ref3] Gauthier J. Y.; Chauret N.; Cromlish W.; Desmarais S.; Duong L. T.; Falgueyret J. P.; Kimmel D. B.; Lamontagne S.; Leger S.; LeRiche T.; Li C. S.; Masse F.; Mckay D. J.; Nicoll-Griffith D. A.; Oballa R. A.; Palmer J. T.; Percival M. D.; Riendeau D.; Robichaud J.; Rodan G. A.; Rodan S. B.; Seto C.; Therien M.; Truong V. L.; Venuti M. C.; Wesolowski G.; Young R. N.; Zamboni R.; Black W. C. The Discovery of Odanacatib (MK-0822), a Selective Inhibitor of Cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18, 923–928. 10.1016/j.bmcl.2007.12.047. [DOI] [PubMed] [Google Scholar]

[ref4] Papageorgiou C.; Borer X.; French R. R. Calcineurin Has a Very Tight-Binding Pocket for the Side-Chain of Residue-4 of Cyclosporine. Bioorg. Med. Chem. Lett. 1994, 4, 267–272. 10.1016/S0960-894X(01)80127-X. [DOI] [Google Scholar]

[ref5] Truong V. L.; Gauthier J. Y.; Boyd M.; Roy B.; Scheigetz J. Practical and Efficient Route to (S)-gamma-Fluoroleucine. Synlett 2005, 1279–1280. 10.1055/s-2005-868494. [DOI] [Google Scholar]

[ref6] Nadeau C.; Gosselin F. S.; O’Shea P. D.; Davies I. W.; Volante R. P. A Concise Synthesis of (S)-gamma-Fluoroleucine Ethyl Ester. Synlett 2006, 291–295. 10.1055/s-2005-923593. [DOI] [Google Scholar]

[ref7] Limanto J.; Shafiee A.; Devine P. N.; Upadhyay V.; Desmond R. A.; Foster B. R.; Gauthier D. R.; Reamer R. A.; Volante R. P. An Efficient Chemoenzymatic Approach to (S)-gamma-Fluoroleucine Ethyl Ester. J. Org. Chem. 2005, 70, 2372–2375. 10.1021/jo047918j. [DOI] [PubMed] [Google Scholar]

[ref8] a Halperin S. D.; Fan H.; Chang S.; Martin R. E.; Britton R. A Convenient Photocatalytic Fluorination of Unactivated C-H Bonds. Angew. Chem., Int. Ed. 2014, 53, 4690–4693. 10.1002/anie.201400420. [DOI] [PubMed] [Google Scholar]; b Halperin S. D.; Kwon D.; Holmes M.; Regalado E. L.; Campeau L. C.; DiRocco D. A.; Britton R. Development of a Direct Photocatalytic C-H Fluorination for the Preparative Synthesis of Odanacatib. Org. Lett. 2015, 17, 5200–5203. 10.1021/acs.orglett.5b02532. [DOI] [PubMed] [Google Scholar]

[ref9] Padmakshan D.; Bennett S. A.; Otting G.; Easton C. J. Stereocontrolled Synthesis of (S)-gamma-Fluoroleucine. Synlett 2007, 1083–1084. 10.1055/s-2007-977420. [DOI] [Google Scholar]

[ref10] Liu W.; Huang X.; Placzek M. S.; Krska S. W.; McQuade P.; Hooker J. M.; Groves J. T. Site-selective 18F Fluorination of Unactivated C–H Bonds Mediated by a Manganese Porphyrin. Chem. Sci. 2018, 9, 1168–1172. 10.1039/C7SC04545J. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref11] Wuttke C.; Ford R.; Lilley M.; Grabowska U.; Wiktelius D.; Jackson R. F. W. New Routes to Lipophilic Amino Acids: Synthesis of Alkynyl and Fluoro-Containing Alanine Derivatives. Synlett 2012, 243–246. 10.1055/s-0031-1290123. [DOI] [Google Scholar]

[ref12] Ayesa S.; Ersmark K.; Grabowska U.; Hewitt E.; Jönsson D.; Kahnberg P.; Klasson B.; Lind P.; Lundgren S.; Odén L.; Parkes K.; Wiktelius D.. Cysteine Protease Inhibitors. WO2011070539, 2011.

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PERMALINK

Radical Functionalization of Unsaturated Amino Acids: Synthesis of Side-Chain-Fluorinated, Azido-Substituted, and Hydroxylated Amino Acids

Philip A P Reeve

Urszula Grabowska

Lourdes Salvador Oden

Daniel Wiktelius

Fredrik Wångsell

Richard F W Jackson

Abstract

Introduction

Scheme 1. Original Ionic Method for the Preparation of tert-Fluoride 2a.

Results and Discussion

Preparation of Unsaturated Amino Acids

Scheme 2. Negishi Cross-Coupling with Cycloalkenyl Triflates.

Table 1. Negishi Coupling of Zinc Reagent 8 with Cycloalkenyl Triflates.

Scheme 3. Negishi Cross-Coupling with Vinyl Bromides.

Table 2. Negishi Coupling of Zinc Reagent 8 with Vinyl Bromides.

Scheme 4. Cu(I)-Catalyzed Allylation of Zinc Reagent 8.

Radical Addition of HF to Unsaturated Amino Acids

Scheme 5. Radical Hydrofluorination of Cyclopentenylalanine 1a.

Table 3. Radical Hydrofluorination of Unsaturated Substrates.

Radical Addition of HN3 to Unsaturated Amino Acids

Scheme 6. Radical Hydroazidation of Unsaturated Substrates.

Table 4. Radical Hydroazidation of Unsaturated Substrates.

Scheme 7. Alternative Approaches to Tertiary Azide 36.

Scheme 8. Hydrogenation of Azido Amino Acids.

Table 5. Hydrogenation of Azides.

Radical Alkene Hydration

Scheme 9. Radical Hydration of Unsaturated Amino Acids.

Conclusions

Experimental Section

Preparation of Zinc Reagent 8

General Procedure A, Coupling of 8 to Vinyl Triflates and Halides

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclopent-1-en-1-yl)propanoate 1a

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclohex-1-en-1-yl)propanoate 1b

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclohept-1-en-1-yl)propanoate 1c

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclooct-1-en-1-yl)propanoate 1d

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(3,6-dihydro-2H-pyran-4-yl)propanoate 10

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(4,4-difluorocyclohex-1-en-1-yl)propanoate 11

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylpent-4-enoate 16

Methyl (2R)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylpent-4-enoate ent-16

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-5-methylhex-4-enoate 17

Methyl (2S,4E)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylhex-4-enoate (E)-18

Methyl (2S,4E)-2-{[(tert-Butoxy)carbonyl]amino}-4-methylhex-4-enoate (Z)-18

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(cyclobut-1-en-1-yl)propanoate 19

General Procedure B, Reaction of 8 with Allyl Chlorides

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}hex-5-enoate 20

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-5-methylhex-5-enoate 21

1,9-Dimethyl (2S,8S)-2,8-Bis({[(tert-butoxy)carbonyl]amino})-5-methylidenenonanedioate 22

General Procedure C, Radical Fluorination

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocyclopentyl)propanoate 2a

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocyclohexyl)propanoate 2b

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocycloheptyl)propanoate 2c

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocyclooctyl)propanoate 2d

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(4-fluorooxan-4-yl)propanoate 23

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1,4,4-trifluorocyclohexyl)propanoate 24

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-4-fluoro-4-methylpentanoate 25

Methyl (2R)-2-{[(tert-Butoxy)carbonyl]amino}-4-fluoro-4-methylpentanoate ent-25

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-5-fluoro-5-methylhexanoate 26

Methyl (2S,4RS)-2-{[(tert-Butoxy)carbonyl]amino}-4-fluoro-4-methylhexanoate 27

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-3-(1-fluorocyclobutyl)propanoate 28

Methyl (2S,5RS)-2-{[(tert-Butoxy)carbonyl]amino}-5-fluorohexanoate 29

1,9-Dimethyl (2S,8S)-2,8-Bis({[(tert-butoxy)carbonyl]amino})-5-fluoro-5-methylnonane-dioate 30

General Procedure D, NHBoc Deprotection

Methyl (2S,4RS)-2-Ammonium-4-fluoro-4-methylhexanoate Trifluoroacetate 31

Methyl (2S,5RS)-2-Ammonium-5-fluorohexanoate Trifluoroacetate 32

General Procedure E, Radical Hydroazidation

Methyl (2S)-4-Azido-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanoate 33

Methyl (2S)-3-(1-Azidocyclopentyl)-2-{[(tert-butoxy)carbonyl]amino}propanoate 34

Methyl (2S)-3-(1-Azidocyclohexyl)-2-{[(tert-butoxy)carbonyl]amino}propanoate 35

Methyl (2S)-5-Azido-2-{[(tert-butoxy)carbonyl]amino}-5-methylhexanoate 36

Methyl (2S,4RS)-4-Azido-2-{[(tert-butoxy)carbonyl]amino}-4-methylhexanoate 37

General Procedure F, Azide Reduction

tert-Butyl N-[(3S)-5,5-Dimethyl-2-oxopyrrolidin-3-yl]carbamate 38

tert-Butyl N-[(3S)-2-Oxo-1-azaspiro[4.4]nonan-3-yl]carbamate 39

tert-Butyl N-[(3S)-2-Oxo-1-azaspiro[4.5]decan-3-yl]carbamate 40

tert-Butyl N-[(3S)-6,6-Dimethyl-2-oxopiperidin-3-yl]carbamate 41

General Procedure G, Radical Hydroxylation

tert-Butyl N-[(3S)-5,5-Dimethyl-2-oxooxolan-3-yl]carbamate 42

Methyl (2S)-2-{[(tert-Butoxy)carbonyl]amino}-5-hydroxy-5-methylhexanoate 43

Radical Addition of HN₃ to Unsaturated Amino Acids