A - And B -fluorinated aminophosphonates-Synthesis and properties

Phosphorus, Sulfur, and Silicon and the Related Elements

ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20

α- and β- fluorinated aminophosphonates –

synthesis and properties

Marcin Kaźmierczak, Maciej Kubicki & Henryk Koroniak

To cite this article: Marcin Kaźmierczak, Maciej Kubicki & Henryk Koroniak (2016): α- and β-

fluorinated aminophosphonates – synthesis and properties, Phosphorus, Sulfur, and Silicon

and the Related Elements, DOI: 10.1080/10426507.2015.1091832

To link to this article: http://dx.doi.org/10.1080/10426507.2015.1091832

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Jan 2016.

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Date: 26 February 2016, At: 10:35

ACCEPTED MANUSCRIPT

α- AND β- FLUORINATED AMINOPHOSPHONATES -- SYNTHESIS AND

PROPERTIES

Marcin Kaźmierczak*, Maciej Kubicki and Henryk Koroniak

Faculty of Chemistry, Adam Mickiewicz University in Poznan, Umultowska 89B, 61-614

Poznań, Poland

*Corresponding

author.

Tel.:

+48618291560.

E-mail

address:

marcin.kazmierczak@amu.edu.pl

In memoriam of Professor Reinhard Schmutzler.

Abstract

Interest in synthesis of fluorinated aminophosphonates has grown significantly in recent

years due to their promising applications in medicinal and bioorganic chemistry. We

report herein efficient and general methods for the synthesis of α- and β-

monofluorinated aminophosphonates. Series of β-fluoro aminophosphonates were

prepared in nucleophilic DAST-mediated fluorination of α-hydroxyphosphonates.

Horner--Wadsworth--Emmons reaction between carbonyl compounds containing an

amino group, and lithiated tetraethyl fluoromethylenediphosphonate was used in the

synthesis of α-fluorinated-γ-aminophosphonates. Futhermore, this protocol was

efficiently applied in synthesis

aminophosphonates.

of dipeptide analogues α-fluorinated-γ-

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Keywords

fluorinated aminophosphonates, nucleophilic fluorination, Horner--Wadsworth--Emmons

reaction.

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1. Introduction

Aminophosphonates and aminophosphonic acids are important substrates in the

study of biochemical processes¹. They have found a wide range of applications as

enzyme inhibitors, agrochemicals and pharmaceuticals in the areas of biological and

medicinal chemistry. Due to unique properties of fluorine atom, such as high

electronegativity and electron density², its presence in aminophosphonates' moiety can

influence chemical reactivity, biological activity, metabolic stability, chemical bonding

19

ability and solubility. Moreover, F nuclear magnetic resonance spectroscopy can be

used in investigation of the interactions between fluorinated compounds and biological

systems³. Recently, special interest has been focused on synthesis of fluorinated

aminophosphonates due to their promising applications in the fields of bioorganic

chemistry. Some of these compounds exhibit antitumor, antibacterial and antifungal

activities⁴.

2. Nucleophilic fluorination of α-hydroxyphosphonates

Nucleophilic fluorination is one of the methods to introduce a fluorine atom into

organic compounds. The most common and commercially available reagent is

diethylaminosulfur trifluoride. DAST allows direct transformation of a C--OH bond of

primary, secondary, tertiary or allylic alcohols to a C--F bond (fluoride). The mechanism

of DAST-promoted fluorination is quite simple and reasonably well understood. First

nucleophilic attack of alcohol onto sulfur atom in DAST occurs, followed by the fluoride

displacing of activated hydroxyl group in S_N2-like mechanism⁵. For most substrates the

reactions are stereoselective with an inversion of configuration. However, the

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mechanism of fluorination with DAST in case of α-hydroxyphosphonates depends on

the phosphonate system. First report showed that DAST-mediated fluorination of

benzylic α-hydroxyphosphonates (1) proceed with good yields from 40 to 84% to furnish

corresponding α-fluorides (2) (Scheme 1). Blackburn have reported that even sterically

crowded tertiary alcohols (R¹= Me, R²= H and R¹= Me, R²= p-Cl) can be used as

starting materials in a selective DAST-promoted fluorination of benzylic α-

hydroxyphosphonates⁶.

However, Shibuya et al. studies of fluorination with diethylaminosulfur trifluoride

on the single diastereoisomers of benzylic α-hydroxyphosphonate (3) derivatives have

showed that the reaction proceeds probably also via S_N1 mechanism (Scheme 2). The

fluorination on single diastereoisomer (2S,4S)-(3) or (2S,4R)-(3) provided two sets of

diastereoisomers (4) in ratios of 60:40 [yield = 87% from (2S,4S)-(3)] and 44:56 [yield =

77% from (2S,4R)-(3)]. These data may prove that phosphoryl group can stabilize

adjacent carbocation by resonance type C⁺-^P≡O⁺⁷.

In case of allylic α-hydroxyphosphonates (5) Blackburn et al. presented that

replacement of the activated hydroxyl group by fluorine proceeds via S_N2'-like

displacement or a [3,3]-sigmatropic rearrangement and gives only γ-fluorides (8)

(Scheme 3)⁶.

On the other hand, selective fluorination of propargylic α-hydroxyphosphonates

(9) affording exclusively α-fluoro-isomers (10) was reported by Hammond (Scheme 4).

Regiospecificity of this reaction is presumably related to the presence of a linear alkyne

system which prevents fluorine transfer through cyclic S_Ni mechanism. In addition triple

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bond migration via S_N2' mechanism is also difficult, because it requires formation of a

more energetically unfavorable allene intermediate⁸.

Berkowitz et al. demonstrated DAST-mediated conversion of unactivated and

non-benzylic secondary α-hydroxyphosphonates (11) to corresponding α-

fluorophosphonates (12) (Scheme 5). Transformation of diastereomeric mixture of 7(R)-

(11) and 7(S)-(11) derivatives (ratio: 1,4:1) gave mainly one diastereoisomer of α-

fluorophosphonate 7(S)-(12) (ratio 10:1). A fluorination reaction under the same

conditions was repeated with pure diastereomers. Alcohol 7(R)-(11) provided fluoride

7(S)-(12), and the absolute configuration of the alpha atom with respect to the fluorine

was confirmed by X-Ray analysis. Interestingly derivative 7(S)-(11) underwent

decomposition under the reaction conditions. Berkowitz did not explain the different

reactivity of phosphonates 7(R)-(11) and 7(S)-(11) during DAST-promoted fluorination.

However their studies clearly show that in this case the fluorination reaction mainly

proceed via S_N2 mechanism with inversion of configuration of the alpha atom with

respect to the phosphorus atom⁹.

In our studies we showed neighbouring group participation during DAST-mediated

reaction. Substrates for the fluorination reaction (16a-e) were prepared as a mixture of

diastereoisomers from amino acids (13a- L-alanine, 13b- L-valine, 13c- L-leucine, 13d-

L-phenylalanine, 13e- D-phenylalanine) (Scheme 6, Table 1).

Fluorodehydroxylation of β-amino-α-hydroxyphosphonates (16a-e) with

diethylaminosulfur trifluoride (DAST) in CH₂Cl₂at -78°C gave access to β-fluoro-α-

aminophosphonates (17a-e) in good yield (Scheme 7, Table 2)¹⁰. The reaction

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proceeded stereoselectively and regioselectively. Proposed mechanism involves

formation of an aziridinium ion (18) as the key step of the synthesis (Figure 1).

¹⁹F NMR, ³¹P NMR and ¹³C NMR data were extremely diagnostic for the

identification of β-fluoro-α-aminophosphonates (17a-e). Signals in the ¹⁹F NMR

appeared at around -180 ppm, moreover coupling constant between P and F atoms

clearly indicates that the fluorine atom is at beta position relative to the phosphorous

atom. Transformation of alcohols to fluorides resulted in significant upfield shifts of C-P

in ¹³C NMR spectra from 65-69 ppm (J_C-P= 153-155 ppm) for (16a-e) to 57-60 ppm (J_C-P

= 135-141 ppm) for (17a-e). Relative stereochemistry of the products (17a-e) was

established based on the NMR data. Phosphonates (17a-e) exist mostly as single

conformers (19) having the fluorine atom and phosphonate groups synperiplanar to

each other (Figure 2, Table 2).

After many attempts of crystallization of the fluorides, only in case of (17a) we

obtained a single crystal suitable for X-ray analysis. The analysis confirmed the

structure of the resulting compound. (17a) crystalized in the centrosymmetric space

group which means that both enantiomers are present in the crystals (Figure 3)¹¹.

Interestingly, no such effect was observed in case of fluorination β-hydroxy-γ-

aminophosphonate (21). Regioselective formation of corresponding β-fluoro analogue

(22) was accomplished using similar conditions (Scheme 8)¹².

3. Horner--Wadsworth--Emmons reaction in synthesis of α-fluorovinylphosphonates

Horner--Wadsworth--Emmons (HWE)¹³olefination reaction of aldehydes and

ketones with fluorinated phosphonate carbanions is a synthetic method to prepare α-

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fluorinated aminophosphonates via α-fluorovinylphosphonates. The first application of

HWE reaction in the synthesis of fluorinated phosphonates (26) was presented by

Blackburn (Scheme 9)¹⁴. As starting materials aliphatic, aromatic as well as α,β-

unsaturated aldehydes or ketones (24) were used. HWE reaction of carbonyl

compounds (24) with lithiated carbanion generated from (23) gave access to α-

fluorovinylphosphonates (25) in good yields and E selectivity. Due to the steric

hindrance in case of ketones, a lower product stereoselectivity was observed. (25) were

then converted to α-fluorinated phosphonates (26).

Standard HWE reaction conditions require application of an equimolar amount of

n-BuLi in an aprotic solvent (usually diethyl ether or tetrahydrofuran). Savigniac

obtained α-fluorovinylphosphonates (29a-e) in high yields and excellent stereoselectivity

(Scheme 10). The olefination reactions proceed between lithium salt of diethyl

ﬂuoromethylenebisphosphonate and aromatic or heteroaromatic aldehydes¹⁵. However,

Beier have reported that application of Cs₂CO₃(2-fold excess) instead of n-BuLi in DMF

at room temperature in some cases increases yield of α-fluorovinylphosphonates (29f-

g), but unfortunately reduces E/Z selectivity (Scheme 10)¹⁶.

Using the HWE reaction Prestwich obtained α-fluorovinylaminophosphonate (30)

in excellent yield and stereoselectivity (E:Z = 12:1)¹⁷. Compound (30) was used in

synthesis of fluorinated analogues of lysophosphatidic acid (31) and (32) (Scheme 11).

There are also a few literature reports on utility of the HWE reaction in selective

syntheses of (E)-α-fluorovinylaminophosphonates. Cox and co-workers showed

synthesis of N-blocked precursor (33) which was next transformed into the fluorinated

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analogue of aspartyl-β-phosphate (34) (Scheme 12)¹⁸. Derivative (34) is a potential

inhibitor of bacterial enzyme aspartate semialdehyde dehydrogenase.

Cui et al. showed utilization of HWE reaction in a synthesis of α-fluorinated

analogue of lysophosphatidic acid (LPA) (36), which is a potential inhibitor of autotaxin.

(E)-α-fluorovinylaminophosphonate (35) was obtained in 70% yield (Scheme 13)¹².

We

demonstrated

stereoselective

synthesis

of

(E)-α-

fluorovinylaminophosphonates (39a-e) and their conversion to α-fluorinated-γ-

aminophosphonates (41a-e)¹⁹. The structure and absolute configuration of the main

diastereoisomer of resulting amines was determined by X-Ray analysis of oxalate salts

(40a-e) (Scheme 14).

In the next step α-fluorinated-γ-aminophosphonates (41a-d) were used for

synthesis of N-Boc protected dipeptide analogues of fluorinated phosphonates (42a-h).

The final products were formed by deprotection of Boc group. Amines (43a-h) were

obtained in quantitative yields after using 3h TFA/CH₂Cl₂protocol.

4. Summary

In conclusion, we have demonstrated an approach to α- and β- fluorinated

aminophosphonates. Neighbouring group participation during DAST-mediated reaction

in synthesis of β-fluoro-α-aminophosphonates was utilized. Moreover, convenient

synthesis of α-fluorinated-γ-aminophosphonates using HWE olefination following

hydrogenation reaction was presented. The structure of resulting compounds was

confirmed by X-Ray analysis. The obtained compounds can be used as precursors for a

new class of building blocks in preparation of medicinally important analogues. As an

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example a synthesis of dipeptide analogs of α-fluorinated-γ-aminophosphonates was

presented.

Development of new methods of stereo- and regioselective synthesis of

fluorinated aminophosphonates is one of those areas that needs to be explored further

due to their promising applications. This paper also covered some synthetic

methodologies and utilization of fluorinated phosphonates.

5. Experimental

5.1. General methods

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19

31

¹H NMR, C NMR, F NMR and P NMR spectra were performed on Varian GEMINI

300 (300 MHz), Varian 400 (400 MHz), Bruker Avance 400 (400 MHz) and Bruker

1

Avance 600 (600 MHz) spectrometers. Chemical shifts of H NMR were expressed in

parts per million downfield from tetramethylsilane (TMS) as an internal standard (δ = 0)

in CDCl₃. Chemical shifts of ¹³C NMR were expressed in parts per million downfield

from CDCl₃as an internal standard (δ = 77.0). Chemical shifts of ¹⁹F NMR were

expressed in parts per million upfiled from CFCl₃as an internal standard (δ = 0) in

31

CDCl₃. Chemical shifts of P NMR were expressed in parts per million downfield from

1

13

85% H₃PO₄as an external standard (δ = 0) in H₂O. H, C NMR chemical shifts are

reported for the major diastereoisomer only. Mass spectra were recorded by electron

impact (MS-EI) techniques using AMD-402 or Bruker 320-MS spectrometer. X-ray

diffraction data were collected at room temperature by the ω-scan technique on Agilent

Technologies four-circle SuperNova (Atlas detector) with mirror-monochromatized CuK_α

radiation (λ = 1.54178Å). The data were corrected for Lorentz-polarization and

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absorption effects²⁰. Accurate unit-cell parameters were determined by a least-squares

fit of 3423 reflections of highest intensity, chosen from the whole experiment. The

structures were solved with SIR92²¹and refined with the full-matrix least-squares

procedure on F²by SHELXL97²². All non-hydrogen atoms were refined anisotropically,

hydrogen atoms involved in strong hydrogen bonds were located in difference Fourier

maps and isotropically refined, all other H atoms were placed in the calculated

positions, and refined as ‘riding model’ with the isotropic displacement parameters set at

1.2 (1.5 for methyl groups) times the U_eqvalue for appropriate non-hydrogen atom.

Reagent grade chemicals were used. Solvents were dried by refluxing with sodium

metal-benzophenone (THF), with CaCl₂(CH₂Cl₂), NaH (Et₂O) and distilled under argon

atmosphere. All moisture sensitive reactions were carried out under argon atmosphere

using oven-dried glassware. Reaction temperatures below 0°C were performed using a

cooling bath (liquid N₂/hexane or CO₂/isopropanol). TLC was performed on Merck

Kieselgel 60-F254 with EtOAc/hexane as developing systems, and products were

detected by inspection under UV light (254 nm) and with a solution of potassium

permanganate. Merck Kieselgel 60 (230--400 mesh) was used for column

chromatography. Selectfluor and DAST were obtained from Aldrich. The Supplemental

Materials contains selected ¹H, ¹³C and ¹⁹F NMR spectra of compound 17a

5.2. General procedures

5.2.1. β-Amino-α-hydroxyphosphonates (16a-e) were prepared according to previously

reported procedure¹⁰.

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16b: Yield: 53%, pale yellow oil, ¹H NMR (300 MHz, CDCl₃) δ 7.48 -- 7.19 (m, 10H, Ar-

H, 4.24 (dd, J = 11.3, 3.4 Hz, 2H), 4.17 -- 4.05 (m, 1H, CHOH), 3.86 (d, J = 13.7 Hz, 2H,

NCH_AH_BPh), 3.75 (d, J = 13.6 Hz, 2H, NCH_AH_BPh), 2.83 (ddd, J = 21.4, 8.8, 3.4 Hz, 1H,

(CH₃)₂CHCH), 2.46 -- 2.29 (m, 1H, (CH₃)₂CH), 1.27 (td, J = 7.1, 3.1 Hz, 6H, 2 x

13

OCH₂CH₃), 1.20 (d, J = 6.6 Hz, 3H, CH₃), 0.96 (d, J = 6.5 Hz, 3H, CH₃). C NMR (75

MHz, CDCl₃) δ 139.54 C-Ar, 129.12 C-Ar, 127.96 C-Ar, 126.76 C-Ar, 66.15 (d, J = 154.6

Hz, C-P), 64.48 (d, J = 4.7 Hz, CHN), 62.23 (d, J = 7.3 Hz, OCH₂CH₃), 62.00 (d, J = 7.2

Hz, OCH₂CH₃), 54.86, PhCH₂N, 27.55 (CH₃)₂CH, 21.89 (CH₃)₂CH, 21.41 (CH₃)₂CH,

31

16.25 (d, J = 3.8 Hz, OCH₂CH₃), 16.18 (d, J = 4.4 Hz, OCH₂CH₃). P{/¹H} NMR (121

MHz, CDCl₃) δ major diastereoisomer 24.85 (s, 1P), minor diastereoisomer 23.69 (s,

1P). MS (EI) m/z: 420 [M+H]⁺.

1

16e: Yield: 48%, white solid, H NMR (300 MHz, CDCl₃) δ 7.36-7.06 (m, 15H, Ar-H),

4.37- 4.28 (m, 1H, CHOH), 4.19-3.97 (m, 4H, OCH₂CH₃), 3.87 (d, J = 14.1 Hz, 2H,

NCH_AH_BPh), 3.59 (d, J = 14.1 Hz, 2H, NCH_AH_BPh), 3.38 (dddd, J = 14.3, 9.3, 5.4, 2.0

Hz, 1H, PhCH_AH_BCH), 3.11-3.04 (m, 2H, PhCH_AH_BCH, PhCH_AH_BCH), 1.65 (s, 1H, OH),

13

1.28 (t, J = 5.5 Hz, 3H, OCH₂CH₃), 1.23 (t, J = 5.4 Hz, 3H, OCH₂CH₃). C NMR (101

MHz, CDCl₃) δ 140.27 C-Ar, 139.53 C-Ar, 129.66 C-Ar, 128.58 C-Ar, 127.90 C-Ar,

127.84 C-Ar, 126.54 C-Ar, 125.68 C-Ar, 65.74 (d, J = 154.1 Hz, C-P), 62.89 (d, J = 7.1

Hz, OCH₂CH₃) 62.26 (d, J = 7.5 Hz, OCH₂CH₃), 59.34 (d, J = 6.2 Hz, CHN), 54.05

PhCH₂N, 32.24 PhCH₂CH, 16.40 OCH₂CH₃, 16.35 OCH₂CH₃. ³¹P{/¹H} (121 MHz,

CDCl₃) δ major diastereoisomer 24.28 (s, 1P), minor diastereoisomer 23.50 (s, 1P). MS

(EI) m/z: 468 [M+H]⁺.

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5.2.2 β-Fluoro-α-aminophosphonates (17a-e) were prepared according to previously

reported procedure¹⁰.

17b: Yield: 47%, pale yellow oil, ¹H NMR (300 MHz, CDCl₃) δ 7.49 -- 7.04 (m, 10H, Ar-

H), 4.67 -- 4.42 (m, 1H, CHF), 4.26 -- 4.07 (m, 4H, OCH₂CH₃), 3.99 (d, J = 13.5 Hz, 2H,

NCH_AH_BPh), 3.87 (d, J = 13.5 Hz, 2H NCH_AH_BPh), 3.27 (ddd, J = 17.8, 13.4, 7.2 Hz,

1H, (CH₃)₂CHCHFCH), 2.30 -- 2.09 (m, 1H, (CH₃)₂CH), 1.39 (t, J = 6.5 Hz, 3H,

OCH₂CH₃), 1.34 (t, J = 6.5 Hz, 3H, OCH₂CH₃), 0.87 (d, J = 7.0 Hz, 3H, CH₃), 0.46 (d, J

13

= 6.7 Hz, 3H, CH₃). C NMR (75 MHz, CDCl₃) δ 139.16 C-Ar, 129.24 C-Ar, 128.23 C-

Ar, 127.15 C-Ar, 96.42 (dd, J = 176.1, 0.8 Hz, C-F), 61.56 (d, J = 3.1 Hz, OCH₂CH₃),

61.46 (d, J = 2.8 Hz, OCH₂CH₃), 56.79 (dd, J = 136.3, 25.1 Hz, C-P), 55.62 PhCH₂N,

55.58 PhCH₂N, 28.84 (dd, J = 20.3, 5.9 Hz, (CH₃)₂CH), 19.57 (CH₃)₂CH, 19.51

19

(CH₃)₂CH, 16.61 (d, J = 5.7 Hz, OCH₂CH₃), 16.51 (d, J = 5.8 Hz, OCH₂CH₃). F NMR

(282 MHz, CDCl₃) δ minor diastereoisomer -185.17 -- -185.80 (m, 1F), major

diastereoisomer -187.26 -- -187.74 (m, 1F). ³¹P NMR (121 MHz, CDCl₃) δ minor

diastereoisomer 27.18 (d, J = 14.6 Hz, 1P), major diastereoisomer 26.19 (d, J = 7.4 Hz,

1P).

17e: Yield: 65%, pale yellow oil, ¹H NMR (300 MHz, CDCl₃) δ 7.36 -- 7.07 (m, 15H, Ar-

H), 5.17 -- 4.88 (m, 1H, PhCH₂CHF), 4.25 -- 3.92 (m, 4H, OCH₂CH₃, 2H, NCH_AH_BPh),

3.76 (d, J = 13.5 Hz, 2H, NCH_AH_BPh), 3.34 (ddd, J = 14.4, 11.9, 4.3 Hz, 1H,

PhCH_ACH_B), 3.21 (ddd, J = 23.9, 15.2, 4.2 Hz, 1H, PhCH_ACH_B), 2.79 (ddd, J = 16.2,

14.4, 8.4 Hz, 1H, PhCH₂CHFCH), 1.34 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 1.25 (t, J = 7.1

Hz, 3H, OCH₂CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 138.93 C-Ar, 137.04 (d, J = 3.9 Hz, C-

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Ar), 129.34 C-Ar, 129.14 C-Ar, 128.50 C-Ar, 128.21 C-Ar, 127.12 C-Ar, 126.58 C-Ar,

92.73 (dd, J = 176.3, 1.7 Hz, C-F), 61.61 (dd, J = 6.8, 1.0 Hz, OCH₂CH₃), 61.47 (dd, J =

7.1, 1.8 Hz, OCH₂CH₃), 58.56 (dd, J = 141.1, 24.0 Hz, C-P), 55.71 PhCH₂N, 55.67

PhCH₂N, 39.55 (dd, J = 21.6, 5.2 Hz, PhCH₂CH), 16.48 (2x dd, J = 5.5 Hz, 2x

OCH₂CH₃). ¹⁹F NMR (282 MHz, CDCl₃) δ major diastereoisomer -182.21 -- -182.70 (m,

31

1F), minor diastereoisomer -185.02 -- -185.51 (m, 1F). P NMR (121 MHz, CDCl₃) δ

minor diastereoisomer 25.70 (d, J = 15.8 Hz, 1P), major diastereoisomer 24.44 (J = 9.4

Hz, 1P). HRMS (EI) Calcd. For: C₂₇H₃₃FNO₃P [M]⁺: 469.21820; Found: 469.21677.

5.2.3. N-Boc amines (42a-h) were prepared according to previously reported

procedure¹⁹.

1

42e: Yield: 87%, white solid, H NMR (400 MHz, CDCl₃) δ 7.33 -- 7.13 (m, 5H, Ar-H),

6.48 (d, J = 9.0 Hz, 1H, NH), 5.05 (d, J = 7.3 Hz, 1H, NH), 4.82 (dddd, J = 47.2, 11.5,

3.9, 2.0 Hz, 1H, CHFP), 4.45 -- 4.33 (m, 1H, PhCH₂CH), 4.21 -- 4.12 (m, 4H, 2x

OCH₂CH₃), 4.12 -- 4.03 (m, 1H, CHNHt-Boc), 2.93 (dd, J = 13.7, 7.0 Hz, 1H, PhCH_AH_B),

2.82 (dd, J = 13.8, 7.0 Hz, 1H, PhCH_AH_B), 2.24 -- 2.06 (m, 1H, CH_AH_BCHF), 2.04 -- 1.84

(m, 1H, CH_AH_BCHF), 1.44 (s, 9H, C(CH₃)₃), 1.32 (td, J = 7.1, 5.5 Hz, 6H, 2x OCH₂CH₃),

1.28 -- 1.24 (m, 3H, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ 172.53 C = O, 155.36 CC = O,

137.26 C-Ar, 129.23 C-Ar, 128.42 C-Ar, 126.57 C-Ar, 85.61 (dd, J = 181.1, 171.0 Hz,

CFP), 79.94 CC = O, 63.36 (d, J = 6.9 Hz, OCH₂CH₃), 62.93 (d, J = 6.6 Hz, OCH₂CH₃),

50.21 CHNHt-Boc, 46.85 (dd, J = 14.4, 1.9 Hz, CH_AH_BCHNH), 40.77 CH_AH_BPh, 34.08

(d, J = 20.2 Hz, CH_AH_BCHNH), 28.24 C(CH₃)₃, 18.33 CH₃, 16.35 (d, J = 3.4 Hz,

OCH₂CH₃), 16.30 (d, J = 3.4 Hz, OCH₂CH₃). ¹⁹F NMR (376 MHz, CDCl₃) δ minor

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diastereoisomer -206.41 -- -207.25 (m, 1F), major diastereoisomer -209.75 (dtd, J =

73.8, 45.3, 14.3 Hz, 1F). ¹⁹F{/¹H} NMR (376 MHz, CDCl₃) δ minor diastereoisomer -

206.79 (d, J = 76.3 Hz, 1F), major diastereoisomer -209.75 (d, J = 73.0 Hz, 1F). ³¹P{/¹H}

(162 MHz, CDCl₃) δ major diastereoisomer 17.62 (d, J = 73.1 Hz, 1P), minor

diastereoisomer 17.19 (d, J = 76.8 Hz, 1P). HRMS (EI) Calcd. For: C₂₂H₃₆N₂O₆FP [M]⁺:

474.22949; Found: 474.22938.

42f: Yield: 81%, white solid, ¹H NMR (600 MHz, CDCl₃) δ 6.59 (s, 1H, NH), 5.20 (d, J =

7.5 Hz, 1H, NH), 4.81 (dd, J = 47.2, 11.1 Hz, 1H, CHFP), 4.28 -- 4.22 (m, 1H, CH₃CH),

4.24 -- 4.13 (m, 4H, 2x OCH₂CH₃), 4.14 -- 4.07 (m, 1H, CHNHt-Boc), 2.15 -- 2.03 (m,

1H, CH_AH_BCHF), 2.02 -- 1.86 (m, 1H, CH_AH_BCHF), 1.43 (s, 9H, C(CH₃)₃), 1.38 -- 1.31

13

(m, 9H, 2x OCH₂CH_3,CH₃CHNHt-Boc), 1.21 (d, J = 6.7 Hz, 3H, CH₃CHNH). C NMR

(151 MHz, CDCl₃) δ 172.37 C = O, 155.46 (CH₃)₃CC = O, 85.88 (dd, J = 180.8, 171.3

Hz, CHFP), 79.87 (CH₃)₃CC = O, 63.35 (d, J = 6.8 Hz, OCH₂CH₃), 62.97 (d, J = 6.7 Hz,

OCH₂CH₃), 50.05 CHNHt-Boc, 41.89 (d, J = 15.3 Hz, CH₃CHNH), 36.62 (d, J = 19.6 Hz,

CH_AH_BCHNH), 28.23 C(CH₃)₃, 20.84 CH₃CHNH, 18.36 CH₃CHNHt-Boc, 16.38 (d, J =

5.4 Hz, OCH₂CH₃), 16.33 (d, J = 5.6 Hz, OCH₂CH₃). ¹⁹F NMR (565 MHz, CDCl₃) δ

minor diastereoisomer -207.62 -- -208.11 (m, 1F), major diastereoisomer -209.23 (dtd, J

19

= 90.2, 45.1, 15.4 Hz, 1F). F{/¹H} NMR (565 MHz, CDCl₃) δ minor diastereoisomer -

207.90 (d, J = 75.0 Hz, 1F), major diastereoisomer -209.23 (d, J = 73.2 Hz, 1F). ³¹P{/¹H}

NMR (243 MHz,CDCl₃) δ major diastereoisomer 17.68 (d, J = 73.7 Hz, 1P), minor

diastereoisomer 17.37 (d, J = 77.9 Hz, 1P). HRMS (EI) Calcd. For: C₁₆H₃₂N₂O₆FP [M]⁺:

398.19821; Found: 398.19706.

14

ACCEPTED MANUSCRIPT

42g: Yield: 77%, white solid, ¹H NMR (400 MHz, CDCl₃) δ 6.29 (br. s, 1H, NH), 5.15 (br.

s, 1H, NH), 4.84 (dddd, J = 47.4, 11.4, 4.2, 2.3 Hz, 1H, CHFP), 4.32 -- 4.25 (m, 1H,

CH₃CH), 4.26 -- 4.14 (m, 4H, 2x OCH₂CH₃), 3.84 (dd, J = 8.7, 6.3 Hz, 1H, CHNHt-Boc),

2.20 -- 2.03 (m, 2H, CH_AH_BCHF, (CH₃)₂CH), 2.00 -- 1.86 (m, 1H, CH_AH_BCHF), 1.44 (s,

9H, C(CH₃)₃), 1.36 (td, J = 7.0, 2.1 Hz, 6H, 2x, OCH₂CH₃), 1.23 (d, J = 6.7 Hz, 3H,

13

CH₃CH), 0.96 (d, J = 6.8 Hz, 3H, (CH₃)₂CH), 0.91 (d, J = 6.8 Hz, 3H, (CH₃)₂CH). C

NMR (101 MHz, CDCl₃) δ 171.30 C = O, 155.91 CC = O, 85.95 (dd, J = 180.8, 171.1

Hz, CHFP), 79.80 CC = O, 63.41 (d, J = 7.0 Hz, OCH₂CH₃), 63.02 (d, J = 6.7 Hz,

OCH₂CH₃), 60.16 CHNHt-Boc, 42.13 (d, J = 15.2 Hz, CH₃CHNH), 36.50 (d, J = 19.8 Hz,

CH_AH_BCHNH), 30.64 (CH₃)₂CH, 28.25 C(CH₃)₃, 20.84 CH₃CH, 19.33 (CH₃)₂CH, 16.41

19

(d, J = 5.1 Hz, OCH₂CH₃), 16.36 (d, J = 5.0 Hz, OCH₂CH₃), 14.15 (CH₃)₂CH. F NMR

(376 MHz, CDCl₃) δ minor diastereoisomer -206.99 -- -208.29 (m, 1F), major

19

diastereoisomer -209.01 -- -209.73 (m, 1F). F{/¹H} NMR (376 MHz, CDCl₃) δ minor

diastereoisomer -207.60 (d, J = 75.0 Hz, 1F), major diastereoisomer -209.41 (dd, J =

73.2, 13.5 Hz, 1F). ³¹P{/¹H} NMR (162 MHz, CDCl₃) δ major diastereoisomer 17.62 (d, J

= 72.6 Hz, 1P), minor diastereoisomer 17.33 (d, J = 75.3 Hz, 1P). HRMS (EI) Calcd.

For: C₁₈H₃₆N₂O₆FP [M]⁺: 426.22951; Found: 426.22927.

42h: Yield: 82%, white solid, ¹H NMR (600 MHz, CDCl₃) δ 6.43 (d, J = 8.7 Hz, 1H, NH),

5.17 (d, J = 9.0 Hz, 1H, NH), 4.81 (dddd, J = 47.3, 11.5, 3.9, 1.9 Hz, 1H, CHFP), 4.26

(m, 1H, CH₃CHNH), 4.21 -- 4.14 (m, 4H, 2x OCH₂CH₃), 3.87 (t, J = 7.7 Hz, 1H, CHNHt-

Boc), 2.14 -- 1.95 (m, 1H, CH_AH_BCHF), 1.95 -- 1.87 (m, 1H, CH_AH_BCHF), 1.87 -- 1.79

(m, 1H, CH₃CHCHNHt-Boc), 1.50 -- 1.46 (CH₃CH_AH_B), 1.41 (s, 9H, C(CH₃)₃), 1.33 (td, J

15

ACCEPTED MANUSCRIPT

= 7.1, 2.8 Hz, 6H, 2x OCH₂CH₃), 1.20 (d, J = 6.6 Hz, 3H, CH₃CH), 1.16 -- 1.02 (m, 1H,

CH₃CH_AH_B), 0.91 (d, J = 6.7 Hz, 3H, CH₃CHCHNHt-Boc), 0.87 (t, J = 7.4 Hz, 3H,

CH₃CH_AH_B). ¹³C NMR (151 MHz, CDCl₃) δ 171.28 C = O, 155.78 CC = O, 85.90 (dd, J

= 181.0, 171.1 Hz, CHFP), 79.61 CC = O, 63.29 (d, J = 7.0 Hz, OCH₂CH₃), 62.89 (d, J =

6.6 Hz, OCH₂CH₃), 60.29 CHNHt-Boc, 41.96 (d, J = 15.3 Hz, CH₃CHNH), 37.03

CH₃CH, 36.50 (d, J = 19.8 Hz, CH_AH_BCHNH), 28.20 C(CH₃)₃, 24.56 CH₃CH_AH_B, 20.81

CH₃CHNH, 16.35(d, J = 5.9 Hz, OCH₂CH₃), 16.31 (d, J = 6.0 Hz, OCH₂CH₃), 15.55,

CH₃CH, 11.27, CH₃CH_AH_B. ¹⁹F NMR (565 MHz, CDCl₃) δ minor diastereoisomer -

207.64 (dddd, J = 75.1, 47.1, 38.5, 18.0 Hz, 1F), major diastereoisomer -209.56 (dtd, J

19

= 73.6, 45.7, 14.6 Hz, 1F). F{/¹H} NMR (565 MHz, CDCl₃) δ minor diastereoisomer -

207.64 (d, J = 75.9 Hz, 1F), major diastereoisomer -209.56 (d, J = 73.0 Hz, 1F). ³¹P{/¹H}

NMR (243 MHz, CDCl₃) δ major diastereoisomer 17.58 (d, J = 73.4 Hz, 1P), minor

diastereoisomer 17.34 (d, J = 75.0 Hz, 1P). HRMS (EI) Calcd. For: C₁₉H₃₈N₂O₆FP [M]⁺:

440.24515; Found: 440.24311.

5.2.4. Amines (43a-h) were prepared according to general procedure.

Derivatives 42a-h (1 equiv.) were dissolved in CH₂Cl₂/TFA 1:1 mixture (excess) and

stirred for 3 hours at room temperature. Solvent was removed by rotary evaporation and

the saturated aqueous solution of NaHCO₃was added to the resulting oil. Products

were extracted to CH₂Cl₂(310 mL), dried over MgSO₄, filtered, concentrated under

reduced pressure.

1

43a: Quant. yield, white solid, H NMR (600 MHz, CDCl₃) δ 7.32 (dd, J = 8.1, 6.9 Hz,

2H, Ar-H), 7.27 -- 7.24 (m, 1H, Ar-H), 7.23 -- 7.20 (m, 2H, Ar-H), 4.80 (dddd, J = 47.2,

16

ACCEPTED MANUSCRIPT

11.2, 3.9, 2.0 Hz, 1H, CHFP), 4.32 -- 4.24 (m, 1H, CH₃CHNH), 4.23 -- 4.15 (m, 4H, 2x

OCH₂CH₃), 3.61 (dd, J = 9.3, 4.3 Hz, 1H, NH₂CH), 3.23 (dd, J = 13.8, 4.3 Hz, 1H,

PhCH_AH_B), 2.73 (dd, J = 13.7, 9.0 Hz, 1H, PhCH_AH_B), 2.09 (dtdt, J = 15.3, 11.4, 7.5, 4.0

Hz, 1H, CH_AH_BCHF), 2.03 -- 1.88 (m, 1H, CH_AH_BCHF), 1.66 (br. s, 3H, NH₂, NH), 1.36

13

(td, J = 7.1, 2.9 Hz, 6H, 2x OCH₂CH₃), 1.20 (d, J = 6.8 Hz, 3H, CH₃). C NMR (151

MHz, CDCl₃) δ 173.69 C = O, 137.66 C-Ar, 129.25 C-Ar, 128.60 C-Ar, 126.75 C-Ar,

86.02 (dd, J = 181.0, 171.1 Hz, CHFP), 63.29 (d, J = 7.1 Hz, OCH₂CH₃), 62.95 (d, J =

6.6 Hz, OCH₂CH₃), 56.19 CNH₂, 41.64 (d, J = 15.2 Hz, CH₃CHNH), 40.78 CH₂Ph, 36.83

(d, J = 19.9 Hz, CH_AH_BCHNH), 20.99 CH₃, 16.42 (d, J = 5.6 Hz, OCH₂CH₃), 16.37 (d, J

= 6.1 Hz, OCH₂CH₃). ¹⁹F NMR (565 MHz, CDCl₃) δ minor diastereoisomer -207.84

(dddd, J = 74.8, 47.4, 38.5, 19.2 Hz, 1F), major diastereoisomer -208.67 (dddd, J =

73.3, 47.4, 43.0, 15.9 Hz, 1F). ¹⁹F{/¹H} NMR (565 MHz, CDCl₃) δ minor diastereoisomer

-207.84 (d, J = 75.0 Hz, 1F), major diastereoisomer -208.67 (d, J = 73.2 Hz, 1F).

³¹P{/¹H} (243 MHz, CDCl₃) δ major diastereoisomer 17.80 (d, J = 73.2 Hz, 1P), minor

diastereoisomer 17.40 (d, J = 74.0 Hz, 1P).

43b: Quant. yield, white solid, ¹H NMR (600 MHz, CDCl₃) δ 7.28 -- 7.21 (m, 2H, Ar-H),

7.19 -- 7.17 (m, 1H, Ar-H), 7.17 -- 7.15 (m, 2H, Ar-H), 4.77 (dddd, J = 47.0, 11.4, 3.6,

1.8 Hz, 1H, CHFP), 4.20 (qdd, J = 9.1, 5.0, 3.1 Hz, 1H, CHNH), 4.16 -- 4.08 (m, 4H, 2x

OCH₂CH₃), 3.58 (dd, J = 9.0, 4.2 Hz, 1H, NH₂CH), 3.17 (dd, J = 13.8, 4.1 Hz, 1H,

PhCH_AH_B), 2.70 (dd, J = 13.8, 9.0 Hz, 1H, PhCH_AH_B), 2.04 (dddq, J = 15.0, 11.1, 7.2,

3.5 Hz, 1H, CH_ACH_BCHF), 1.89 -- 1.75 (m, 1H, CH_ACH_BCHF), 1.47 (ddq, J = 12.9, 8.7,

6.5 Hz, 1H, (CH₃)₂CH), 1.37 (ddd, J = 14.6, 9.5, 5.5 Hz, 1H, (CH₃)₂CHCH_AH_B), 1.28 (td,

17

ACCEPTED MANUSCRIPT

J = 7.0, 4.1 Hz, 6H, 2x OCH₂CH₃), 1.24 (td, J = 8.6, 4.3 Hz, 1H, (CH₃)₂CHCH_AH_B), 1.18

13

(br. s, 1H, NH), 0.86 (d, J = 6.5 Hz, 3H, CH₃), 0.84 (d, J = 6.6 Hz, 3H, CH₃). C NMR

(151 MHz, CDCl₃) δ 173.44 C = O, 137.52 C-Ar, 129.35 C-Ar, 128.69 C-Ar, 126.85 C-

Ar, 85.89 (dd, J = 181.2, 170.4 Hz, CHFP), 63.33 (d, J = 7.0 Hz, OCH₂CH₃), 63.04 (d, J

= 6.6 Hz, OCH₂CH₃), 56.35 CNH₂, 44.37 (CH₃)₂CHCH₂, 43.72 (d, J = 14.3 Hz,

(CH₃)₂CHCH₂CH), 40.58 CH₂Ph, 36.12 (d, J = 20.0 Hz, CH_AH_BCHNH), 24.90

(CH₃)₂CHCH₂, 23.02 CH₃, 22.08 CH₃, 16.47 (d, J = 5.7 Hz, OCH₂CH₃), 16.41 (d, J = 5.8

Hz, OCH₂CH₃). ¹⁹F NMR (565 MHz, CDCl₃) δ minor diastereoisomer -206.68 (dddd, J =

75.6, 47.2, 38.8, 19.2 Hz, 1F), major diastereoisomer -208.63 (dtd, J = 72.6, 45.3, 15.1

19

Hz, 1F). F{/¹H} NMR (565 MHz, CDCl₃) δ minor diastereoisomer -206.68 (d, J = 75.6

Hz, 1F), major diastereoisomer -208.63 (d, J = 72.5 Hz, 1F). ³¹P{/¹H} (243 MHz, CDCl₃)

δ major diastereoisomer 18.08 (d, J = 73.1 Hz, 1P), δ minor diastereoisomer 17.64 (d, J

= 75.6 Hz, 1P).

1

43c: Quant. yield, white solid, H NMR (400 MHz, CDCl₃) δ 7.35 -- 7.07 (m, 5H, Ar-H),

4.69 (dddd, J = 46.9, 11.4, 3.3, 1.7 Hz, 1H, CHFP), 4.19 -- 4.06 (m, 6H, 2x OCH₂CH₃,

CHNH), 3.58 (dd, J = 9.0, 4.1 Hz, 1H, NH₂CH), 3.20 (dd, J = 13.7, 4.1 Hz, 1H,

PhCH_AH_B), 2.68 (dd, J = 13.7, 9.0 Hz, 1H, PhCH_AH_B), 2.09 -- 1.95 (m, 1H,

CH_ACH_BCHF), 1.86 -- 1.59 (m, 1H, CH_ACH_BCHF), 1.56 -- 1.45 (m, 1H, CH₃CH), 1.44 --

1.33 (m, 1H, CH₃CH_AH_B), 1.32 -- 1.25 (m, 6H, 2x OCH₂CH₃), 1.11 -- 0.96 (m, 1H,

CH₃CH_AH_B), 0.85 (t, J = 7.4 Hz, 3H, CH₃CH_AH_B), 0.79 (d, J = 6.7 Hz, 3H, CH₃CH). ¹³C

NMR (101 MHz, CDCl₃) δ 173.84 C = O, 137.63 C-Ar, 129.33 C-Ar, 128.69 C-Ar,

126.83 C-Ar, 85.82 (dd, J = 182.0, 170.5 Hz, CHFP), 63.36 (d, J = 7.0 Hz, OCH₂CH₃),

18

ACCEPTED MANUSCRIPT

63.01 (d, J = 6.6 Hz, OCH₂CH₃), 56.39 CNH₂, 48.89 (d, J = 14.4 Hz,

CH₃CH₂CH(CH₃)CH), 40.77 CH₂Ph, 38.64 CH₃CH, 32.23 (d, J = 20.4 Hz,

CH_AH_BCHNH), 25.15 CH₃CH_AH_B, 16.43 (t, J = 5.7 Hz, 2x OCH₂CH₃), 15.01 CH₃CH,

11.59 CH₃CH_AH_B. ¹⁹F NMR (376 MHz, CDCl₃) δ minor diastereoisomer -205.65 (dddd, J

= 77.2, 46.9, 37.2, 20.9 Hz, 1F), major diastereoisomer -208.64 -- -209.26 (m, 1F).

¹⁹F{/¹H} NMR (376 MHz, CDCl₃) δ minor diastereoisomer -205.64 (d, J = 76.9 Hz, 1F),

major diastereoisomer -208.94 (d, J = 72.3 Hz, 1F). ³¹P{/¹H} (162 MHz, CDCl_3`) δ major

diastereoisomer 18.17 (d, J = 72.4 Hz, 1P), minor diastereoisomer 17.55 (d, J = 76.7

Hz, 1P).

43d: Quant. yield, white solid, ¹H NMR (600 MHz, CDCl₃) δ 7.34 -- 7.09 (m, 11H, Ar-H,

NH), 4.78 (dddd, J = 47.0, 11.4, 3.7, 1.8 Hz, 1H, CHFP), 4.52 -- 4.42 (m, 1H, CHNH),

4.22 -- 4.11 (m, 4H, 2x OCH₂CH₃), 3.54 (dd, J = 9.2, 4.1 Hz, 1H, CHNH₂), 3.10 (dd, J =

13.8, 4.1 Hz, 1H, PhCH_AH_BCHNH₂), 2.84 (dd, J = 7.0, 2.5 Hz, 2H, CH₂Ph), 2.45 (dd, J =

13.8, 9.2 Hz, 1H, PhCH_AH_BCHNH₂), 2.17 (tddd, J = 14.9, 11.1, 7.6, 3.3 Hz, 1H,

CH_AH_BCHF), 2.01 -- 1.85 (m, 1H, CH_AH_BCHF), 1.33 (td, J = 7.1, 1.7 Hz, 6H, 2x

OCH₂CH₃). ¹³C NMR (151 MHz, CDCl₃) δ 174.06 C = O, 137.73 C-Ar, 137.20 C-Ar,

129.30 C-Ar, 129.21 C-Ar, 128.60 C-Ar, 128.36 C-Ar, 126.72 C-Ar, 126.58 C-Ar, 85.78

(dd, J = 181.4, 171.0 Hz, CHFP), 63.28 (d, J = 7.2 Hz, OCH₂CH₃), 62.91 (d, J = 6.5 Hz,

OCH₂CH₃), 56.20 CNH₂, 46.27 (d, J = 14.8 Hz, CH_AH_BCHNH), 40.98 CH_AH_BPh, 40.58

CH₂Ph, 34.68 (d, J = 20.3 Hz, CH_AH_BCHNH), 16.36 (d, J = 5.5 Hz, OCH₂CH₃), 16.33 (d,

19

J = 5.6 Hz, OCH₂CH₃). F NMR (565 MHz, CDCl₃) δ minor diastereoisomer -206.75

(dddd, J = 75.6, 47.1, 38.0, 19.1 Hz, 1F), major diastereoisomer -208.80 -- -209.21 (m,

19

ACCEPTED MANUSCRIPT

19

1F). F{/¹H} NMR (565 MHz, CDCl₃) δ minor diastereoisomer -206.75 (d, J = 75.3 Hz,

1F), major diastereoisomer -208.99 (d, J = 72.9 Hz, 1F). ³¹P{/¹H} NMR (243 MHz,

CDCl₃) δ major diastereoisomer 17.76 (d, J = 73.0 Hz, 1P), minor diastereoisomer

17.27 (d, J = 76.1 Hz, 1P).

1

43e: Quant. yield, white solid, H NMR (600 MHz, CDCl₃) δ 7.31 -- 7.16 (m, 5H, Ar-H,

NH), 4.82 (dddd, J = 47.1, 11.4, 3.7, 2.0 Hz, 1H, CHFP), 4.48 -- 4.36 (m, 1H,

PhCH₂CH), 4.25 -- 4.09 (m, 4H, 2x OCH₂CH₃), 3.42 (q, J = 6.9 Hz, 1H, CHNH₂), 2.89

(dd, J = 13.8, 6.5 Hz, 1H, PhCH_AH_B), 2.85 (dd, J = 13.9, 7.6 Hz, 1H, PhCH_AH_B), 2.26 --

2.11 (m, 1H, CH_AH_BCHF), 2.04 -- 1.89 (m, 1H, CH_AH_BCHF), 1.57 (br. s, 2H, NH₂), 1.33

13

(td, J = 7.0, 1.9 Hz, 6H, 2x OCH₂CH₃), 1.16 (d, J = 7.0 Hz, 3H, CH₃). C NMR (151

MHz, CDCl₃) δ 175.52 C = O, 137.29 C-Ar, 129.27 C-Ar, 128.35 C-Ar, 126.54 C-Ar,

85.84 (dd, J = 181.4, 170.9 Hz, CHFP), 63.31 (d, J = 7.0 Hz, OCH₂CH₃), 62.94 (d, J =

6.8 Hz, OCH₂CH₃), 50.59 CNH₂, 46.26 (d, J = 14.6 Hz, CH_AH_BCHNH), 41.00 CH_AH_BPh,

34.74 (d, J = 20.0 Hz, CH_AH_BCHNH), 21.46 CH₃, 16.36 (d, J = 5.6 Hz, OCH₂CH₃), 16.32

(d, J = 5.9 Hz, OCH₂CH₃). ¹⁹F NMR (565 MHz, CDCl₃) δ minor diastereoisomer -206.70

(dddd, J = 76.1, 47.1, 38.2, 19.1 Hz, 1F), major diastereoisomer -208.65 -- -209.07 (m,

19

1F). F{/¹H} NMR (565 MHz, CDCl₃) δ minor diastereoisomer -206.70 (d, J = 75.4 Hz,

1F), major diastereoisomer -208.87 (d, J = 72.9 Hz, 1F). ³¹P{/¹H} NMR (243 MHz,

CDCl₃) δ major diastereoisomer 17.77 (d, J = 73.0 Hz, 1P), minor diastereoisomer

17.29 (d, J = 76.2 Hz, 1P).

1

43f: Quant. yield, white solid, H NMR (600 MHz, CDCl₃) δ 7.26 (s, 1H, NH), 4.84

(dddd, J = 47.2, 11.1, 4.0, 2.1 Hz, 1H, CHFP), 4.32 -- 4.23 (m, 1H, CH₃CH), 4.25 -- 4.15

20

ACCEPTED MANUSCRIPT

(m, 4H, 2x OCH₂CH₃), 3.48 (q, J = 6.9 Hz, 1H, CHNH₂), 2.19 -- 2.05 (m, 1H,

CH_AH_BCHF), 2.06 -- 1.88 (m, 1H, CH_AH_BCHF), 1.73 -- 1.64 (br.s, 2H, NH₂), 1.36 (td, J =

7.1, 3.2 Hz, 6H, 2x OCH₂CH₃), 1.33 (d, J = 7.0 Hz, 3H, CH₃CHNH₂), 1.24 (d, J = 6.7 Hz,

3H, CH₃CHNH). ¹³C NMR (151 MHz, CDCl₃) δ 175.28 C = O, 86.14 (dd, J = 181.0,

171.0 Hz, CHFP), 63.35 (d, J = 7.0 Hz, OCH₂CH₃), 63.01 (d, J = 6.6 Hz, OCH₂CH₃),

50.62 CNH₂, 41.61 (d, J = 15.1 Hz, CH₃CHNH), 36.92 (d, J = 19.9 Hz, CH_AH_BCHNH),

21.66 CH₃CHNH₂, 21.01 CH₃CHNH, 16.45 (d, J = 6.1 Hz, OCH₂CH₃), 16.41 (d, J = 6.5

Hz, OCH₂CH₃). ¹⁹F NMR (565 MHz, CDCl₃) δ minor diastereoisomer -207.73 (dddd, J =

74.7, 47.4, 36.8, 21.1 Hz, 1F), major diastereoisomer -208.53 (dtd, J = 73.0, 45.7, 45.3,

19

15.9 Hz, 1F). F{/¹H} NMR (565 MHz, CDCl₃) δ minor diastereoisomer -207.73 (d, J =

31

74.9 Hz, 1F), major diastereoisomer -208.53 (d, J = 73.0 Hz, 1F). P{/¹H} NMR (243

MHz, CDCl₃) δ major diastereoisomer 17.82 (d, J = 73.3 Hz, 1P), minor diastereoisomer

17.44 (d, J = 74.9 Hz, 1P).

1

43g: Quant. yield, white solid, H NMR (600 MHz, CDCl₃) δ 7.32 (d, J = 9.0 Hz, 1H,

NH), 4.85 (dddd, J = 47.2, 11.3, 3.9, 2.0 Hz, 1H, CHFP), 4.36 -- 4.27 (m, 1H, CH₃CH),

4.26 -- 4.15 (m, 4H, 2x OCH₂CH₃), 3.23 (d, J = 3.8 Hz, 1H, CHNH₂), 2.35 -- 2.26 (m, 1H,

CH(CH₃)₂), 2.18 -- 2.06 (m, 1H, CH_AH_BCHF), 2.06 -- 1.89 (m, 1H, CH_AH_BCHF), 1.61 --

1.48 (br. s, 2H, NH₂), 1.36 (td, J = 7.1, 3.4 Hz, 6H, 2x OCH₂CH₃), 1.24 (d, J = 6.7 Hz,

3H, CH₃CH), 0.99 (d, J = 7.0 Hz, 3H, (CH₃)₂CH), 0.82 (d, J = 6.9 Hz, 3H, (CH₃)₂CH). ¹³C

NMR (151 MHz, CDCl₃) δ 173.96 C = O, 86.11 (dd, J = 180.9, 171.1 Hz, CHFP), 63.33

(d, J = 7.0 Hz, OCH₂CH₃), 62.98 (d, J = 6.7 Hz, OCH₂CH₃), 59.88 CNH₂, 41.58 (d, J =

15.7 Hz, CH₃CHNH), 36.91 (d, J = 19.9 Hz, CH_AH_BCHNH), 30.79 (CH₃)₂CH, 21.21

21

ACCEPTED MANUSCRIPT

CH₃CH, 19.66 (CH₃)₂CH, 16.45 (d, J = 5.9 Hz, OCH₂CH₃), 16.40 (d, J = 5.8 Hz,

OCH₂CH₃), 15.86 (CH₃)₂CH. ¹⁹F NMR (565 MHz, CDCl₃) δ minor diastereoisomer -

207.69 (dddd, J = 74.6, 47.1, 37.7, 19.9 Hz, 1F), major diastereoisomer -208.64 (dddd,

J = 73.1, 47.0, 43.7, 15.6 Hz, 1F). ¹⁹F{/¹H} NMR (565 MHz, CDCl₃) δ minor

diastereoisomer -207.69 (d, J = 74.9 Hz, 1F), major diastereoisomer -208.64 (d, J =

31

73.0 Hz, 1F). P{/¹H} NMR (243 MHz, CDCl₃) δ major diastereoisomer 17.82 (d, J =

73.2 Hz, 1P), minor diastereoisomer 17.44 (d, J = 74.8 Hz, 1P).

1

43h: Quant. yield, white solid, H NMR (600 MHz, CDCl₃) δ 7.35 (d, J = 9.0 Hz, NH),

4.84 (dddd, J = 47.2, 11.3, 3.9, 2.0 Hz, 1H, CHFP), 4.34 -- 4.24 (m, 1H, CH₃CHNH),

4.24 -- 4.16 (m, 4H, 2x OCH₂CH₃), 3.27 (d, J = 3.8 Hz, 1H, CHNH₂), 2.17 -- 2.05 (m, 1H,

CH_AH_BCHF), 2.05 -- 1.89 (m, 2H, CH_AH_BCHF, CH₃CHCHNH₂), 1.64 (m, 1H,

CH₃CH_AH_B), 1.53 (s, 2H, NH₂), 1.36 (td, J = 7.1, 3.4 Hz, 6H, 2x OCH₂CH₃), 1.24 (d, J =

6.7 Hz, 3H, CH₃CH), 1.16 -- 1.06 (m, 1H, CH₃CH_AH_B), 0.96 (d, J = 7.0 Hz, 3H,

CH₃CHCHNH₂), 0.90 (t, J = 7.4 Hz, 3H, CH₃CH_AH_B). ¹³C NMR (151 MHz, CDCl₃) δ

173.93 C = O, 86.08 (dd, J = 181.0, 171.1 Hz, CHFP), 63.29 (d, J = 6.9 Hz, OCH₂CH₃),

62.94 (d, J = 6.8 Hz, OCH₂CH₃), 59.60 CNH₂, 41.51 (d, J = 15.4 Hz, CH₃CHNH), 37.88

CH₃CH, 36.92 (d, J = 20.0 Hz, CH_AH_BCHNH), 23.58 CH₃CH_AH_B, 21.16 CH₃CHNH,

16.41 (d, J = 5.6 Hz, OCH₂CH₃), 16.36 (d, J = 5.7 Hz, OCH₂CH₃), 16.14 CH₃CH, 11.87

CH₃CH_AH_B. ¹⁹F NMR (565 MHz, CDCl₃) δ minor diastereoisomer -207.71 (dddd, J =

75.1, 47.1, 38.2, 19.8 Hz, 1F), major diastereoisomer -208.48 -- -208.86 (m, 1F).

¹⁹F{/¹H} (565 MHz, CDCl₃) δ minor diastereoisomer -207.71 (d, J = 75.1 Hz, 1F), major

31

diastereoisomer -208.68 (d, J = 73.0 Hz, 1F). P{/¹H} NMR (243 MHz, CDCl₃) δ major

22

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diastereoisomer 17.82 (d, J = 73.5 Hz, 1P), minor diastereoisomer 17.44 (d, J = 74.8

Hz, 1P).

Acknowledgments

The research was supported by Wroclaw Research Centre EIT+ under the project

„Biotechnologies and advanced medical technologies" -- BioMed (POIG.01.01.02-02-

003/08) financed from the European Regional Development Fund (Operational

Programme Innovative Economy, 1.1.2)

23

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2.

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65 (15), 4498-4508.

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24

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11.

Crystallographic data (excluding structure factors) for the structural analysis has

been deposited with the Cambridge Crystallographic Data Centre, No. CCDC -- 997687.

Copies of this information may be obtained free of charge from: The Director, CCDC, 12

Union Road, Cambridge, CB2 1EZ, UK. Fax: +44(1223)336-033, e-

mail:deposit@ccdc.cam.ac.uk, or www: www.ccdc.cam.ac.uk.

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Table 1: NMR data and diastereomeric ratio of compounds 16a-e.

³¹P{/¹H} NMR

yield

R

d.r.

minor

major

%

diastereoisomer diastereoisomer

48^a

53^a

44^a

50^a

48^a

80:20

75:25

90:10

85:15

16a

16b

16c

16d

16e

CH₃

23.12 (s)

23.69 (s)

23.64 (s)

23.42 (s)

23.50 (s)

23.86 (s)

24.85 (s)

24.32 (s)

24.23 (s)

24.28 (s)

CH(CH₃)₂

CH₂CH(CH₃)₂

CH₂Ph

(ent.) CH₂Ph

^alast step yield

26

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Table 2: NMR data and diastereomeric ratio of compounds 17a-e.

³¹P{/¹H} NMR

yield

R

d.r.

minor

major

%

55

47

41

60

65

diastereoisomer diastereoisomer

25.98

(d, J_P-F= 19.7)

27.18

25.56

(d, J_P-F= 7.9)

26.19

17a

17b

17c

17d

17e

CH₃

85 : 15

95:5

CH(CH₃)₂

CH₂CH(CH₃)₂

CH₂Ph

(d, J_P-F= 14.6),

26.48

(d, J_P-F= 7.4)

25.65

95 : 5

90 : 10

(d, J_P-F= 14.7)

25.75

(d, J_P-F= 9.6)

24.50

(d, J_P-F= 15.5)

25.70

(d, J_P-F= 9.4)

24.44

(ent.) CH₂Ph

(d, J_P-F= 15.8)

(J_P-F= 9.4 Hz)

27

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Table 3: NMR data and diastereomeric ratio of compounds 43a-h.

³¹P{/¹H} NMR

R

R'

d.r.

minor

major

diastereoisomer diastereoisomer

17.40 ppm

(d, J = 74.0 Hz)

17.64 ppm

17.80 ppm

(d, J = 73.2 Hz)

18.08 ppm

43a

43b

CH₃

CH₂Ph

90:10

80:20

95:5

CH₂CH(CH₃)₂

(d, J = 75.6 Hz)

17.55 ppm

(d, J = 73.1 Hz

18.17 ppm

43c CH(CH₃)CH₂CH₃

CH₂Ph

(d, J = 76.7 Hz)

17.27 ppm

(d, J = 72.4 Hz)

17.76 ppm

43d

43e

43f

CH₂Ph

CH₃

CH₂Ph

95:5

(d, J = 76.1 Hz)

17.29 ppm

(d, J = 73.0 Hz)

17.77 ppm

CH₃

85:15

90:10

85:15

75:25

(d, J = 76.2 Hz)

17.37 ppm

(d, J = 73.0 Hz)

17.68 ppm

CH₃

(d, J = 77.9 Hz)

17.44 ppm

(d, J = 73.7 Hz)

17.82 ppm

43g

43h

CH₃

CH(CH₃)₂

CH(CH₃)CH₂CH₃

(d, J = 74.8 Hz)

17.44 ppm

(d, J = 73.2 Hz)

17.82 ppm

CH₃

(d, J = 74.8 Hz)

(d, J = 73.5 Hz)

28

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Figure 1

29

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Article Doi

A - And B -fluorinated aminophosphonates-Synthesis and properties

DOI: 10.1080/10426507.2015.1091832

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Article abstract of DOI:10.1080/10426507.2015.1091832

Full text of DOI:10.1080/10426507.2015.1091832

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