II. Enantioselective Synthesis of β-Amino-α-Fluoronitroalkanes via the Aza-Henry
2.7 Target Molecule Synthesis and Future Directions
While these β-amino fluoronitroalkanes may be an inherently valuable in their own right, the ability to transform to enantioenriched β-fluoroamines is especially noteworthy. The derivatization reactions highlighted in the previous section demonstrate the ability of the nitro group to function as a synthetic handle, allowing for the incorporation of additional functional groups in a site-specific manner generating substituted β-fluoroamines.
β-Fluoroamines are known to have dramatic biological influences on small molecules in biological systems. This class of organofluorine compounds displays remarkable CNS- penetrant properties through several key features: lipophilicity is often increased (although not
118 Ono, N. The Nitro Group in Organic Synthesis. Wiley-VCH. New York, New York. 2001.
119 Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem. 1987, 52, 5061. Takeuchi, Y.; Nagata, K.; Koizumi, T. J.
Org. Chem. 1989, 54, 5453.
Figure 28. Derivatized compounds from enantioenriched β-amino fluoronitroalkanes.
F HN
Boc Cl
3º β-fluoroamine 184 H HN
Boc Cl
F
2º β-fluoroamine 183 H H
N Boc Cl
F
2º β-fluoroamine 182 H
96% ee 2:1 dr
96% ee
> 10:1 dr 94% ee
~1:1 dr
H H
always), enhancing passive transport into the cell and greater overall bioavailability. Perturbation of pKa of proximal functional groups allows for improved bioavailability and target binding.
And finally, molecular conformational changes are often observed upon fluorine substitutions.64 This is perhaps most pronounced with 1,2-difluoroethane, preferring to adopt a gauche conformation instead of the common anti conformation (termed gauche effect, Figure 29). The electronegative fluorine anti-bonding orbitals are stabilized through hyperconjugation of the C–H bond, thus adopting a gauche arrangement.
In an effort to illustrate the value of accessing these β-fluoroamine motifs, we sought to prepare β-fluorinated analogues of lanicemine (186, AZD6765) – a potent, low-trapping NMDA receptor antagonist containing a chiral phenethylamine motif. Lanicemine entered the clinic in 2006 (PhI-PhIIB, 2006-2010) for the treatment of major depressive disorder (MDD), exhibiting more desirable characteristics than the dissociative anesthetic drug, ketamine (185), including limited psychotomimetic and dissociative side effects (Figure 30).120 Ketamine is also infamously non-selective, hitting other targets including opioid receptors and monoamine transporters.121 It is for these reasons a number of pharmaceutical companies continue to pursue more efficacious and selective CNS-penetrant agents targeting depression.
120 Sanacora, G.; Smith, M. A.; Pathak, S.; Su, H. L.; Boeijinga, P. H.; McCarthy, D. J.; Quirk, M. C. Molecular Psychiatry 2014, 19, 978.
121 Kohrs, R.; Durieux, M. E. Anesth Analg 1998, 87, 1186.
Figure 29. Conformational preference of 1,2-difluoroethane.
H
H F
F
H H
F
H H
F
H H
0 kcal/mol 1.8 kcal/mol
gauche anti
relative energies H
H F F H H
1,2-difluoroethane
≈
An optimized process patent122 from AstraZeneca reports a one step synthesis (using LiHMDS to generate the TMS-imine from 187 in situ) and chiral resolution using (S)-malic acid, yielding the single enantiomer of lanicemine (186) in 36% yield over the two steps (Scheme 53).
While β-fluoroamines are known to have dramatic influences on blood-brain barrier penetrant small molecules, there is no concrete way to predict the conformational effects of a F-
lanicemine derivative from the outset, especially considering the gauche conformational influence of β-fluoroamines when protonated at physiological pH (Figure 31).
122 Giles. M.E. et al. U.S. patent WO00/63175 US006518432B1, 2003
Figure 30. NMDA receptor antagonists: Ketamine, used in the treatment of depression, among a variety of ailments. Lanicemine 186 is a low-trapping antagonist.
NH2 N
low-trapping NMDA antagonist Lanicemine (AZD6765) NMDA antagonist (non-selective)
Ketamine HN
Me
Cl O
185 186
Scheme 53. Synthesis of lanicemine 186 reported in a patent from AstraZeneca.
THF, 20-40 ºC i. LiHMDS H
O
N CH3 ii. (S)-malic acid, EtOH
NH2 N
(36%) 186
147 187
Using our developed methodology, we envisioned preparing then screening all four stereoisomers of F-lanicemine (187a-d, Figure 32) in NMDA-based assays prepared by David Weaver here at Vanderbilt University to assess activity and viability. As proven in our substrate scope, pyridines are well tolerated under the optimized conditions, a necessary aspect in order to prepare the four stereoisomers. Retrosynthetically, using both antipodes of
6,7(MeO)2PBAM•HNTf2 organocatalyst, from the (R,R) and (S,S) cyclohexane diamine
Figure 31. Potential conformational changes upon of the installation of fluorine in F-lanicemine ((R,S)-F- lanicemine pictured), as compared to lanicemine.
H Ph NH3
F
Ar H
H Ph NH3
Ph
H F
does the gauche effect play a role in F-lanicemine?
H
Ph NH3
H
F Ar
H
Ph NH3
H
Ar H
Lanicemine - preferred conformation
Figure 32. All four stereoisomers of F-lanicemine targeted for synthesis.
NH2
F N
NH2
F N
NH2
F N
NH2
F N 187d 187b (S,R) F-lanicemine (R,R) F-lanicemine
(R,S) F-lanicemine (S,S) F-lanicemine
187c 187a
Scheme 54. Retrosynthesis of F-lanicemine stereoisomers.
NH2
F N
NH2
F N
NH
F N Boc
NO2
187d 187b 141
NH2
F N
NH2
F N
NH
F N Boc
NO2
187c 187a ent-141
backbone, both enantiomers of the fluoropyridyl aza-Henry products 141 could be obtained in high ee. Reductive denitration (non-selective) followed by Boc-deprotection should arrive at all four stereoisomers of F-lanicemine (Scheme 54).
In the forward sense, aza-Henry adduct 141 with R-configuration at the benzylic amine stereocenter was prepared in good yield and enantioselection (81% yield, 2.5:1 dr, 95% ee).
Following the four-step synthesis of the (S,S)-6,7(MeO)2PBAM•HNTf2 catalyst, the enantiomer ent-141 was prepared in 94% yield (2.3:1 dr, 96% ee, Scheme 55). Fortunately, high dr of this material is not critical considering the subsequent steps.
Scheme 55. Synthesis of all four F-lanicemine stereoisomers from the enantioenriched β-amino fluoronitroalkanes.
N NO2 N Boc F
(R,R)-6,7(MeO)2PBAM•HNTf2 toluene, 0 °C
Boc NH
24 h
95/94% ee 2.5:1 dr NOF2
N
(81%) 10 mol %
188 149
N NO2 N Boc F
(S,S)-6,7(MeO)2PBAM•HNTf2 toluene, 0 °C
Boc NH
24 h
96/95% ee 2.3:1 dr NOF2
N
(94%) 10 mol %
188 149
141
ent-141
Boc NH
NO2 F N
NH2
F N
NH2
F N NH2
F N
NH2
F N
2.5:1 dr, 95% ee
ca. 90% yield (2 steps) 2.3:1 dr, 96% ee
Boc NH
NO2 N F
141 ent-141
187d 187b
187c 187a
94% yield (2 steps)
i, ii
i, ii i, ii
i, ii
•TFA
•TFA
•TFA
•TFA
i) HSnBu3 (5 equiv.), AIBN, benzene, 80 ºC, 4 h; ii) TFA (40 equiv.), DCM, 2 h, separated by reverse phase prep HPLC
Reductive denitration went smoothly to afford the Boc-protected 2º β-fluoroamines in good yields (see Experimental for additional details). Several silica gel purifications were attempted at this stage in order to separate diastereomers, but clean separations were never obtained and the material was carried forward as a ~2:1 mixture of diastereomers. In the final step, trivial Boc-deprotections with trifluoroacetic acid (TFA) afforded the desired F-lanicemine TFA salts. While the crude material from the deprotection step afforded clean 187, these TFA adducts could be readily separated via reverse phase preparatory HPLC. Thus, all four F- lanicemine stereoisomers were isolated and characterized as their TFA salts. Notably, these β- fluoroamines salts can be converted to the stable free amines – no aziridine formation was observed by 1H and 19F NMR.)
In sum, the organocatalyzed, asymmetric Mannich reaction employing fluoronitroalkanes developed in this work was readily extended to the synthesis of β-fluoroamine containing F- lanicemine derivatives in two additional steps. While synthesizing all four stereoisomers does not require the implementation of a highly enantioselective organocatalyst, we have set the stage
Scheme 56. Proposed retrosynthesis to 190 (en route F-morphine 189) implementing the enantioselective aza- Henry reaction with the corresponding aryl fluoronitromethane.
F
MeO RO
MeO
N Boc
LG NO2
MeO
MeO
NH Boc
LG RO
MeO
MeO
N Boc (Me) RO
(S)–F-reticuline 190
NO2 F
direct precursor to morphine analogous to Rice intermediate
RO RO RO
F organocatalyzed, enantioselective aza-Henry reaction
HO HO
O
N CH3 F H H
F-morphine 189
H
for an efficient asymmetric synthesis should a single enantiomer be highly potent as a novel NMDA antagonist. While this document was under preparation, biological data on the four molecules submitted was not yet available.
Additional projects are underway in the group utilizing fluoronitromethanes in the aza- Henry reaction. Since this work has proven β-fluoroamines are readily accessible, F-morphine (189) has been targeted for formal (total) synthesis, featuring the aza-Henry reaction as the key enantiodetermining step to access the reticuline-type intermediate (190) targeted by Kenner Rice123 in his original elegant synthesis (Scheme 56). Morphine, one the most widely prescribed opioid painkillers, is a highly effective analgesic, yet can be highly addictive along with many opioids in this class. For various reasons, it would be worthwhile to investigate the effects of a β- fluoroamine analogue of morphine from an activity and pharmacological perspective.
123 Rice, K. C. J. Org. Chem. 1980, 45, 3135.
Chapter III