A - And B -fluorinated aminophosphonates-Synthesis and properties

Article abstract of DOI:10.1080/10426507.2015.1091832

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-monofluo

Full text of DOI:10.1080/10426507.2015.1091832

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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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 SN2-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 SN1 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 SN2'-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 SNi mechanism. In addition triple
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bond migration via SN2' 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 SN2 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 CH2Cl2 at -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 (JC-P = 153-155 ppm) for (16a-e) to 57-60 ppm (JC-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)13 olefination 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/CH2Cl2 protocol.
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
13
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 CDCl3 as an internal standard (δ = 77.0). Chemical shifts of 19F NMR were
expressed in parts per million upfiled from CFCl3 as an internal standard (δ = 0) in
31
CDCl3. Chemical shifts of P NMR were expressed in parts per million downfield from
1
13
85% H3PO4 as 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 CuKα
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 SIR9221 and refined with the full-matrix least-squares
procedure on F2 by 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 Ueq value 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,
NCHAHBPh), 3.75 (d, J = 13.6 Hz, 2H, NCHAHBPh), 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,
NCHAHBPh), 3.59 (d, J = 14.1 Hz, 2H, NCHAHBPh), 3.38 (dddd, J = 14.3, 9.3, 5.4, 2.0
Hz, 1H, PhCHAHBCH), 3.11-3.04 (m, 2H, PhCHAHBCH, PhCHAHBCH), 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,
NCHAHBPh), 3.87 (d, J = 13.5 Hz, 2H NCHAHBPh), 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, NCHAHBPh),
3.76 (d, J = 13.5 Hz, 2H, NCHAHBPh), 3.34 (ddd, J = 14.4, 11.9, 4.3 Hz, 1H,
PhCHACHB), 3.21 (ddd, J = 23.9, 15.2, 4.2 Hz, 1H, PhCHACHB), 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, PhCHAHB),
2.82 (dd, J = 13.8, 7.0 Hz, 1H, PhCHAHB), 2.24 -- 2.06 (m, 1H, CHAHBCHF), 2.04 -- 1.84
(m, 1H, CHAHBCHF), 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, CHAHBCHNH), 40.77 CHAHBPh, 34.08
(d, J = 20.2 Hz, CHAHBCHNH), 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, CHAHBCHF), 2.02 -- 1.86 (m, 1H, CHAHBCHF), 1.43 (s, 9H, C(CH3)3), 1.38 -- 1.31
13
(m, 9H, 2x OCH2CH3, CH3CHNHt-Boc), 1.21 (d, J = 6.7 Hz, 3H, CH3CHNH). C NMR
(151 MHz, CDCl3) δ 172.37 C = O, 155.46 (CH3)3 CC = O, 85.88 (dd, J = 180.8, 171.3
Hz, CHFP), 79.87 (CH3)3 CC = 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,
CHAHBCHNH), 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.
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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, CHAHBCHF, (CH3)2CH), 2.00 -- 1.86 (m, 1H, CHAHBCHF), 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,
CHAHBCHNH), 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, CHAHBCHF), 1.95 -- 1.87 (m, 1H, CHAHBCHF), 1.87 -- 1.79
(m, 1H, CH3CHCHNHt-Boc), 1.50 -- 1.46 (CH3CHAHB), 1.41 (s, 9H, C(CH3)3), 1.33 (td, J
15
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= 7.1, 2.8 Hz, 6H, 2x OCH2CH3), 1.20 (d, J = 6.6 Hz, 3H, CH3CH), 1.16 -- 1.02 (m, 1H,
CH3CHAHB), 0.91 (d, J = 6.7 Hz, 3H, CH3CHCHNHt-Boc), 0.87 (t, J = 7.4 Hz, 3H,
CH3CHAHB). 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, CHAHBCHNH), 28.20 C(CH3)3, 24.56 CH3CHAHB, 20.81
CH3CHNH, 16.35(d, J = 5.9 Hz, OCH2CH3), 16.31 (d, J = 6.0 Hz, OCH2CH3), 15.55,
CH3CH, 11.27, CH3CHAHB. 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 NaHCO3 was 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
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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,
PhCHAHB), 2.73 (dd, J = 13.7, 9.0 Hz, 1H, PhCHAHB), 2.09 (dtdt, J = 15.3, 11.4, 7.5, 4.0
Hz, 1H, CHAHBCHF), 2.03 -- 1.88 (m, 1H, CHAHBCHF), 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, CHAHBCHNH), 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,
PhCHAHB), 2.70 (dd, J = 13.8, 9.0 Hz, 1H, PhCHAHB), 2.04 (dddq, J = 15.0, 11.1, 7.2,
3.5 Hz, 1H, CHACHBCHF), 1.89 -- 1.75 (m, 1H, CHACHBCHF), 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)2CHCHAHB), 1.28 (td,
17
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J = 7.0, 4.1 Hz, 6H, 2x OCH2CH3), 1.24 (td, J = 8.6, 4.3 Hz, 1H, (CH3)2CHCHAHB), 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, CHAHBCHNH), 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,
PhCHAHB), 2.68 (dd, J = 13.7, 9.0 Hz, 1H, PhCHAHB), 2.09 -- 1.95 (m, 1H,
CHACHBCHF), 1.86 -- 1.59 (m, 1H, CHACHBCHF), 1.56 -- 1.45 (m, 1H, CH3CH), 1.44 --
1.33 (m, 1H, CH3CHAHB), 1.32 -- 1.25 (m, 6H, 2x OCH2CH3), 1.11 -- 0.96 (m, 1H,
CH3CHAHB), 0.85 (t, J = 7.4 Hz, 3H, CH3CHAHB), 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),
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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,
CHAHBCHNH), 25.15 CH3CHAHB, 16.43 (t, J = 5.7 Hz, 2x OCH2CH3), 15.01 CH3CH,
11.59 CH3CHAHB. 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, CDCl3`) 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, PhCHAHBCHNH2), 2.84 (dd, J = 7.0, 2.5 Hz, 2H, CH2Ph), 2.45 (dd, J =
13.8, 9.2 Hz, 1H, PhCHAHBCHNH2), 2.17 (tddd, J = 14.9, 11.1, 7.6, 3.3 Hz, 1H,
CHAHBCHF), 2.01 -- 1.85 (m, 1H, CHAHBCHF), 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, CHAHBCHNH), 40.98 CHAHBPh, 40.58
CH2Ph, 34.68 (d, J = 20.3 Hz, CHAHBCHNH), 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
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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, PhCHAHB), 2.85 (dd, J = 13.9, 7.6 Hz, 1H, PhCHAHB), 2.26 --
2.11 (m, 1H, CHAHBCHF), 2.04 -- 1.89 (m, 1H, CHAHBCHF), 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, CHAHBCHNH), 41.00 CHAHBPh,
34.74 (d, J = 20.0 Hz, CHAHBCHNH), 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
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(m, 4H, 2x OCH2CH3), 3.48 (q, J = 6.9 Hz, 1H, CHNH2), 2.19 -- 2.05 (m, 1H,
CHAHBCHF), 2.06 -- 1.88 (m, 1H, CHAHBCHF), 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, CHAHBCHNH),
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, CHAHBCHF), 2.06 -- 1.89 (m, 1H, CHAHBCHF), 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, CHAHBCHNH), 30.79 (CH3)2CH, 21.21
21
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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,
CHAHBCHF), 2.05 -- 1.89 (m, 2H, CHAHBCHF, CH3CHCHNH2), 1.64 (m, 1H,
CH3CHAHB), 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, CH3CHAHB), 0.96 (d, J = 7.0 Hz, 3H,
CH3CHCHNH2), 0.90 (t, J = 7.4 Hz, 3H, CH3CHAHB). 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, CHAHBCHNH), 23.58 CH3CHAHB, 21.16 CH3CHNH,
16.41 (d, J = 5.6 Hz, OCH2CH3), 16.36 (d, J = 5.7 Hz, OCH2CH3), 16.14 CH3CH, 11.87
CH3CHAHB. 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
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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)
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References:
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Berkowitz, D. B.; Bose, M.; Pfannenstiel, T. J.; Doukov, T. J. Org. Chem. 2000,
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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
48a
53a
44a
50a
48a
80:20
75:25
90:10
85:15
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
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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, JP-F = 19.7)
27.18
25.56
(d, JP-F = 7.9)
26.19
17a
17b
17c
17d
17e
CH3
85 : 15
95:5
CH(CH3)2
CH2CH(CH3)2
CH2Ph
(d, JP-F = 14.6),
26.48
(d, JP-F = 7.4)
25.65
95 : 5
90 : 10
90 : 10
(d, JP-F = 14.7)
25.75
(d, JP-F = 9.6)
24.50
(d, JP-F = 15.5)
25.70
(d, JP-F = 9.4)
24.44
(ent.) CH2Ph
(d, JP-F = 15.8)
(JP-F = 9.4 Hz)
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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
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
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)
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Figure 1
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