Highly diastereoselective synthesis of enantioenriched: Anti -α-allyl-β-fluoroamines

Article abstract of DOI:10.1039/c9cc02765c

A highly diastereoselective synthesis of anti-α-allyl-β-fluoroamines has been developed involving enantioselective α-fluorination of aldehydes followed by a diastereoselective Petasis allyl borono-Mannich reaction. The products are obtained generally in g

Full text of DOI:10.1039/c9cc02765c

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DOI: 10.1039/C9CC02765C.
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DOI: 10.1039/C9CC02765C
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Highly diastereoselective synthesis of enantioenriched anti--
allyl--fluoroamines
Received 00th January 20xx,
Philip J. Chervis, ‡a Sirilak Wangngae, ‡a,b Thanaphat Thaima,a Anthony W. Carroll,a Anthony C.
Accepted 00th January 20xx
Willis,c Mookda Pattarawarapanb and Stephen G. Pyne*a
DOI: 10.1039/x0xx00000x
A
highly diastereoselective synthesis of anti--allyl--
(a) Fluorinated -fluoroamine drugs
fluoroamines has been developed involving enantioselective -
fluorination of aldehydes followed by a diastereoselective Petasis
allyl borono-Mannich reaction. The products are obtained
generally in good overall yields for the two steps and with drs of
97:3–99:1 and ees of 86-92%. Selected products were converted to
3-, 5- and 6-membered ring heterocycles, the latter two types
incorporating an exo-cyclic fluorine.
Br
Br
N
N
N
N
HN
N
N
N
O
F
X
MeO
NH
N
HN
Me
OMe
Fluorine plays an important role in the development of
pharmaceutical drugs, chiral ligands and organocatalysts1 as it
can modulate the electronic and conformational properties of
molecules without imposing severe steric effects. The
inductive effect of fluorine results in reduced basicity of
neighbouring amines, which often leads to more desirable
pharmacokinetic (PK) properties in amine based drugs,
including increased bioavailability, enhanced metabolic
stability, and desirable drug lipophilicity. In the case of PF-
06459988 (Fig. 1 (a)), an irreversible and selective inhibitor of
oncogenic EGFR mutants, the inductive effect of the fluoro
substituent is essential for the enhanced reactivity of the
acrylamide “warhead” moiety.2 The neuroprotective agent
P7C3-A20 (X = F) was significantly more potent than its
hydroxy (X = OH) analogue (Fig. 1 (a)), with the F-substituent
leading to reduced toxicity and better PK properties.3 A recent
survey of clinical candidates published in the Journal of
Medicinal Chemistry (2016-2017) indicated that 43 out of 65
had at least one heterocyclic nitrogen while 20 had at least
one fluorine atom.4 Thus new methods to prepare cyclic and
acyclic fluoro-substituted amines, are of significant importance
in pharmaceutical drug development, including -
PF-06747775
P7C3-A20 [X = F]
(b) Known borono-Mannich reaction
NR2R3
O
H
R1
HO
R1
HO
R4B(OR)2
+
N
+
R2
R3
R4
I
(R4 = aryl,vinyl, alkynyl,
allenyl)
(c) Proposed chemistry in this study
NR2R3
R4
O
H
R1
R1
R4B(OR)2
+
N
+
R2
R3
F
F
II
Fig. 1 (a) Structures of -fluoroamine drugs. (b) Known borono-
Mannich reaction. (c) Proposed chemistry in this study.
catalysts and nucleophilic5 and electrophilic6 fluorine regents,
the Mannich7 and aza-Henry reactions,8 the hydrogenation of
-fluoro-enamines and enamides,9 and the aminofluorination
of alkenes.10
We report here a straightforward method of preparing -
allyl--fluoroamines (II, R4
diastereoselectivities (dr 97:3–99:1) and high enantiomeric
purities (ee 84−92%) using the three component Petasis
borono-Mannich reaction (BMR) of chiral -fluoroaldehydes,
primary amines and pinacol allylboronate (Fig. 1 (b) and (c)).
The products have been converted to novel, 3-, 5- and 6-
membered ring heterocycles.
fluoroamines, as exemplified in the drug structures in Fig. 1 (a).
Several methods have been developed to prepare these
compounds in enantioenriched form using chiral substrates or
= allyl) with excellent anti-
a. School of Chemistry and Molecular Biosciences, University of Wollongong,
Wollongong, New South Wales, 2522, Australia
b. Department of Chemistry and Center of Excellence for Innovation in Chemistry,
Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
c. Research School of Chemistry, Australian National University, Canberra ACT 0200,
Australia.
† Electronic Supplementary Information (ESI) available: [Experimental procedures,
copies of NMR spectra and ORTEP plots for 3 (CCDC 1904599) and 5 (CCDC
1904600)]. See DOI: 10.1039/x0xx00000x
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benzylamine failed to produce the desired product 2b. Other
View Article Online
Table 1 Scope of the boronate and amine componentsa
solvents (dichloromethane, or acetoniDtrOilIe: )10.w10e3r9e/C9eCxCa0m27in6e5Cd
___________________________________________________ however these proved to be unsuccessful. The more reactive
pinacol allylboronate13 however, smoothly provided the
desired -fluoroamine 2c in 73% yield as a 97:3 mixture of anti
and syn diastereomers, respectively from 19F NMR analysis (SI)
(Table 1, entry 1).14 Surprisingly, the BMR of 1 (R = n-Hex),
pinacol allylboronate and secondary amines (Bn2NH, Me2NH
and morpholine) or the hindered primary amine Ph2CHNH2
were unsuccessful in producing their respective products 2d.
An almost identical yield and dr of 2c was obtained using
potassium allyltrifluoroborateboronate. Lesser amounts (1.0 or
1.5 equiv) of either the amine or organoboron reagent or both
resulted in reduced yields of product 2c. The reaction involving
pinacol allenylboronate15 and benzylamine produced the
propargyl product 2e in modest yield (33%) but with high
NFSI,
(S)-catalyst
R2R3NH
F
F
R4B(OR)2
O
R1
R4
O
R1
R1
t-BuOMe,
rt, 24 h
MeOH/pentane
(1:1)
H
R1 = n-Hex
NR2R3
H
rt, 24 h
1
2
_________________________________________________
OMe
F
F
Ph
n-Hex
n-Hex
NR2R2
NHBn
2b
0% yield
2a
0% yield
R2 = H, R3 = Bn; R2 = R3 = Bn
F
F
F
n-Hex
-Hex
n
n-Hex
NR2R2
NHBn
NHBn
regiochemistry and diastereoselectivity (dr
= 97:3). The
2c
2e
2d
enantiomeric purities of the anti-products of 2c and 2e were
determined as 90% and 86%, respectively from 1H and 19F
NMR analysis of their corresponding (1S)-camphorsulfonamide
derivatives (SI).16 This analysis method was validated for 2c,
and the latter compounds 2h, 2i, 2k, 2l, 2m and 2o, from the
synthesis and NMR analysis of their corresponding
enantiomeric compounds (e.g. ent-2c, Table 3) and their
diastereomeric (1S)-camphorsulfonamide derivatives. The ee
values of anti-2c and 2e were slightly less than the reported
96% ee of (S)--fluorooctanal,12 determined on its more stable
alcohol derivative, indicating some erosion of the
stereochemical integrity of 1 (R = n-Hex) had occurred. The
major diastereomer of the (1S)-camphorsulfonamide
derivative 3 of 2e provided suitable crystals for X-ray structure
determination which identified its absolute configuration and
the anti-stereochemical relationship of the vicinal
heteroatoms (Fig. 2).17
73% yield (97/3 dr)
90% ee
33% yield (97/3 dr)
86% ee
0% yield
R2 = R3 = Bn; R2 = R3 = Me;
R2/R3 = (CH2)2O(CH2)2;
R2 = H, R3 = CHPh2
a
Reaction conditions; Step 1: octanal (1.5 equiv), NFSI (1.0 equiv), (S)-α,α-
bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether
(0.001 equiv). Step 2: amine (2 equiv), organoboron reagent (2 equiv).
___________________________________________________
The BMR works most efficiently on substrates having a
proximal hydroxy group (e.g. -hydroxyaldehydes) which can
activate the boron component by coordination.11 Based on the
strong inductive effect of fluorine we reasoned that -
fluoroaldehydes should also be productive components in the
BMR. The report by Lindsley6(a) on the reductive amination of
chiral -fluoroaldehydes to give -substituted--fluoroamines
in high enantiomeric purities provide strong evidence for the
stereochemical integrity and stability of the intermediate -
fluoroimines which would be
a requirement for their
successful BMRs to give enantioenriched ,-disubstituted--
fluoroamines (II) .
F
In this study we used the method of Jørgensen12 to prepare
n-Hex
(S)--fluorooctanal
bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol
1 (R = n-Hex) using (S)-α,α-bis[3,5-
NBn
SO2
O
trimethylsilyl ether as the chiral organocatalyst, and N-
fluorobenzenesulfonimide (NFSI) as the fluorinating agent. We
initially encountered isolation problems because of the
volatility of this fluorinated product. To circumvent this, the
reaction mixtures were diluted with pentane to precipitate
unwanted by products and the solution was filtered then
diluted with methanol (1:1) and treated directly with a primary
or secondary amine (2.0 equiv, based on the amount of NFSI
used) and a boronic acid, boronate ester or potassium
trifluoroborateboronate (2.0 equiv) at ambient temperature.
Those reactions using benzylamine and -styrenylboronic acid,
pinacol -styrenylboronate or potassium -styrenyl
trifluoroborateboronate were unsuccessful and none of the
desired BMR product 2a (R2 =H, R3 = Bn) could be isolated
(Table 1). The combination of dibenzylamine and -styrenyl
boronic acid was also ineffective at producing 2a (R2 =Bn, R3 =
Bn). The combination of 4-methoxyphenylboronic acid and
3
Fig. 2 ORTEP plot of (1S)-camphorsulfonamide derivative 3 of 2e.
___________________________________________________
The generality of this diastereoselective allylation reaction
with pinacol allylboronate, non-hindered primary amines and
other (S)- (1) and (R)--aldehydes (ent-1) was further
examined and the results are presented in Tables 2 and 3,
respectively. Similar yields and diastereomeric ratios to 2c
were obtained for the products 2f-2m starting with straight
chain aldehydes and using benzylamine, allylamine or p-
methoxybenzylamine (Table 2). Diastereomeric ratios were
generally high (dr 97:3−99:1).14 The enantiomeric purities (ee
86−92%) of the products derived from these aldehydes were
similar, but slightly lower than those reported for the parent
(S)--fluoroaldehydes (ee 91-96%).12
2 | J. Name., 2012, 00, 1-3
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Table 2 Synthesis of (4R,5S) β-fluoroamines 2 and their (4S, 5R)-
enantiomers (ent-2)a
___________________________________________________
The former aldehyde gave 2n in a lower diastereoselectivity
(2n:2p = 93:7) than obtained for its diastereomer 2p (2p:2n =
View Article Online
DOI: 10.1039/C9CC02765C
98:2, Table 3) using the enantiomeric (R)-organocatalyst, likely
reflecting a minor mismatching of catalyst and substrate in the
asymmetric fluorination step in the former case. The latter,
more hindered substrate, gave a relatively low yield of 2o as a
63:37 mixture of diastereomers. An enantiomeric series of -
allyl--fluoroamines (ent-2) could be formed from (R)--
fluoroaldehydes ent-1 which, as expected, were formed in
similar yields with comparable drs and ees (Table 2).
R2NH2
NFSI,
(S)-catalyst
F
F
O
R1
PinB
O
R1
R1
t-BuOMe,
rt, 24 h
MeOH/pentane
(1:1)
H
NHR2
H
2
rt, 24 h
1
___________________________________________________
F
F
F
n-Hex
n
-Hex
n-Hex
To demonstrate the potential utility of these anti--allyl-β-
fluoroamine products, compound 2k was treated with KOH in
EtOH/H2O under refluxing conditions.18 This gave the expected
trans-aziridine 4 as a 1:1 mixture of N-invertomers.19 A ring-
closing metathesis reaction of the N-tosyl derivative of 2h gave
the unsaturated piperidine 5 bearing a fluorinated side chain
at C-2. The structure of this compound was secured by a
single-crystal X-ray diffraction analysis (SI).17 While cyclization
NHBn
ent
-2c
HN
2f
NHBn
2c
77% yield (98/2 dr)
86% ee
73% yield (97/3 dr)
90% ee
73% yield (97/3 dr)
92% ee
F
F
F
Bn
Bn
n-Hex
HN
NHPMB
HN
20
2g
2h
ent-2h
46% yield (97/3 dr)
88% ee
of 2i using Hg(OAc)2 gave the analogous pyrrolidine
derivative 6 in an unoptimized yield of 23%.
69% yield (98/2 dr)
86%ee
60% yield (99/1 dr)
88% ee
F
F
F
F
Bn
KOH, EtOH
reflux, 48 h
(44%)
N
Bn
Bn
Bn
n-Bu
NHBn
NHBn
NHPMB
n
-Bu
NHBn
4
2i
-2i
2j
ent
2k
47% yield (99/1 dr)
92% ee
60% yield (97/3 dr)
92% ee
60% yield (98/2 dr)
92% ee
Bn
N
F
F
F
n-Bu
n-Bu
n-Bu
n-Pr
NHBn
-2k
72% yield (98/2 dr)
88% ee
NHBn
NHBn
F
F
1. TsCl, DMAP, Et3N
CH2Cl2, rt, 24 h (44%)
2k
ent
2l
50% yield (98/2 dr)
86% ee
60% yield (98/2 dr)
90% ee
Bn
Bn
2. Grubbs II (10 mol%)
CH2Cl2, reflux, 2 h (72%)
HN
2h
TsN
5 [X-ray]
F
F
F
F
n-Pr
n
-Pr
n-Pr
1. Hg(OAc)2 (2 eq),
THF/H2O (1:1), 24 h
F
NHPMB
NHBn
NHPMB
Bn
2. NaBH4, 24 h (23%)
ent
-2l
2m
ent-2m
53% yield (99/1 dr)
92% ee
Bn
BnN
41% yield (98/2 dr)
86% ee
50% yield (98/2 dr)
92% ee
NHBn
6
2i
F
H3C
F
Scheme 1. Synthesis of 3-, 5- and 6-membered heterocycles
H3C
NHBn
2o
CH3
CH3 NHBn
The success of only pinacol allylboronate and
allenylboronate and primary amines, and the anti-
diastereoselective outcomes in these BMRs can be readily
rationalized by invoking the reactive imine intermediate A,
involving B-N coordination (Scheme 2). Such coordination and
activation of allenyl boronic acid and pinacol allenyl boronate
has been suggested previously to explain the formation of
propargyl products from their BMR reactions with -
hydroxyaldehydes and primary amines.15 Intermediate A (R1 =
n-Hex) can reactive to give the allylic or propargylic products
2c or 2d via a favourable six-membered ring transition state
involving a polar Felkin-Ahn model.21 Clearly, an analogous
intermediate for the unsuccessful -styrenyl organoboron
reagents and 4-methoxyphenylboronic acid (Table 1) would
require a highly unfavourable four-membered ring transition
2n
51% yield (2n:2p = 93/7)
17% yield (63/37 dr)
F
H3C
F
H3C
NHBn
ent-2o
CH3
CH3 NHBn
2p
11% yield (70/30 dr)
53% yield (2n:2p = 98/2)
___________________________________________________
aSee Table 1 for general conditions. Yields based on NFSI as the limiting reagent.
Ent-2 compounds were prepared using the (R)-organocatalyst.
These reactions were also successful for the more hindered
aldehydes, (S)-(-)-citronellal and racemic 2-phenylpropanal.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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4
5
D. G. Brown and J. Boström, J. Med. Chem. 2018, 61, 9442.
(a) B. Duthion, D. G. Pardo and J. CosDsyO,I:O10rg.1.0L3Ve9i/teCtw.9A2Crt0Cic10le02O7,n61l5in2Ce,
4620. (b) J. A. Kalow, D. E. Schmitt and A. G. Doyle, J. Org.
Chem. 2012, 77, 4177. (c) H.-T. Huang, T. C. Lacy, B. Błachut,
G. X. Ortiz and Q. Wang, Org. Lett. 2013, 15, 1818. (e) J. A.
Kalow and A. G. Doyle, Tetrahedron 2013, 69, 5702. (f) M. K.
Nielsen, C. R. Ugaz, W. Li and A. G. Doyle, J. Am. Chem. Soc.
2015, 137, 9571. (g) M. Nonn, L. Kiss, M. Haukka, S. Fustero
and F. Fulop, Org. Lett. 2015, 17, 1074. (h) S. Hajra, A. Hazra
and P. Mandal, Org. Lett. 2018, 20, 6471. (i) J. C. Mixdorf, A.
M. Sorlin, Q. Zhang and H. M. Nguyen, ACS Catal. 2018, 8,
790. (j) K. M. Mennie, S. M. Banik, E. C. Reichert and E. N.
Jacobsen, J. Am. Chem. Soc. 2018, 140, 4797.
state. Interestingly, this stereochemical outcome is opposite to
that found in the BMR of an -hydroxy aldehyde with pinacol
allylboronate which resulted in exclusive formation of the syn
1,2-amino alcohol product,13 and not the expected anti one
when aryl,- allenyl- or aryl-organoboron reagents are used.11,15
Pin
BPin
R1
B
RN
RN
H
R1
F
F
H
H
H
A
6
7
(a) O. O. Fadeyi and C. W. Lindsley, Org. Lett. 2009, 11, 943
(b) R. J. Phipps, K. Hiramatsu and F. D. Toste, J. Am. Chem.
Soc. 2012, 134, 8376 (c) J. Wu, Y. M. Wang, A. Drljevic, V.
Rauniyar, R. J. Phipps and F. D. Toste, Proc. Natl. Acad. Sci. U.
S. A. 2013, 110, 13729. (d) M. C. O’Reilly and C. W. Lindsley,
Tetrahedron Lett. 2013, 54, 3627. W. Huang, Y. Yao, Y.-J. Xu
and C.-D. Lu, J. Org. Chem. 2018, 83, 14777.
V. Vaithiyanathan, M. J. Kim, Y. Liu, H. Yan and C. E. Choong,
Chem. Eur. J. 2017, 23, 1268. F. Zhong, W.-J. Yue, H.-J. Zhang,
C.-Y. Zhang and L. Yin, J. Am. Chem. Soc. 2018, 140, 15170.
B. A. Vara and J. N. Johnston, J. Am. Chem. Soc. 2016, 138,
13794.
Scheme 2. Possible reactive intermediate A
In contrast, the analogous -chloroaldehyde to 1 (R1 = n-Bu,
see SI for Scheme), gave, under similar BMR conditions using
benzylamine, followed by treatment with KOH/EtOH/H2O, a
separable mixture of 4 (32%) and its cis-aziridine isomer (10%),
thus indicating significantly poorer diatereoselectivity in the
BMR than its fluoro counterpart.
In conclusion, we have developed a direct method for
8
9
preparing
anti--allyl--fluoroamines
in
two
easily
Y.-Q. Guan, Z. Han, X. Li, C. You, X. Tan, H. Lv and X. Zhang,
Chem. Sci. 2019, 10, 252.
manipulated steps from aldehydes with excellent
diastereoselectives (dr = 97:3–99:1) and high enantiomeric
purities (ee 86-92%). These compounds would be difficult to
prepare using many of the existing methods due to
incompatibly of the allyl substituent to hydrogenation,9 or
electrophilic fluorine reagents,6 or regioselectivity issues when
using ring-opening of 2-allyl-3-alkyl aziridines with nucleophilic
10 W. Kong, P. Feige, T. de Haro and C. Nevado, Angew. Chem.
Int. Ed. 2013, 52, 2469.
11 (a) N. A. Petasis and I. A. Zavialov, J. Am. Chem. Soc. 1998,
120, 11798. (b) C. W. G. Au and S. G. Pyne, J. Org. Chem.
2006, 71, 7097.
12 M. Marigo, D. Fielenbach, A. Brainton, A. Kjærsgaard and K.
A. Jørgensen, Angew. Chem. Int. Ed. 2005, 44, 3703.
13 M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc.
2004, 126, 7182.
fluorine,18 or would otherwise require
a more lengthy
synthesis. Thus, this work offers a complementary and
practical method towards these important compounds.
We thank the University of Wollongong for supporting this
project. S. W. thanks the Thailand Research Fund through the
Royal Golden Jubilee PhD Program (Grant no. PHD/0206/2556)
14 The major anti-diastereomers typically showed a 19F NMR
(CDCl3) resonance at ca δF −125, while the minor syn-
diastereomers at ca δF −130.
15 (a) T. Thaima and S. G. Pyne Org. Lett. 2015, 17, 778. (b) F.
Liepouri, G. Bernasconi and N. A. Petasis, Org. Lett. 2015, 17,
1628.
16 The ee values of the anti--fluoroamines 2 and ent-2 were
calculated from the dr of their resulting (1S)-
camphorsulfonamide derivatives which were determined by
1H and 19F NMR analysis. Typically, the diastereotopic
methylene protons next to the SO2 group showed well
resolved 1H NMR doublet resonances unique to each
diastereomer. For NBn and NPMB derivatives the
diastereotopic benzylic methylene resonances could also be
used to calculate dr values. In each case, the ratios
calculated from 1H and 19F NMR analysis were identical
within experimental error. In contrast, the resonances for
the (1S)-camphorsulfonamide derivatives of the minor syn-
isomers were relatively minor; with the minor diastereomer
usually not detected.
17 CCDC deposit numbers for compounds 3 and 5 are 1904599
and 1904600, respectively.
18 G. M. Alvernhe, C. M. Ennakoua, S. M. Lacombe and A. J.
Laurent, J. Org. Chem. 1981, 46, 4938.
19 R. Mansueto, L. Degennaro, J.-François Brière, K. Griffin, M.
Shipman, S. Florio and R. Luisi Org. Biomol. Chem., 2014,12,
8505.
20 D. D. Dhavale and S. M. Jachak, Molecules, 2005, 10, 893.
21 (a) N.T. Anh and O. Eisenstein, Nouv. J. Chim. 1977, 1, 61. (b)
S. S. Wong and M. N. Paddon-Row, J. Chem. Soc. Chem.
Commun. 1990, 456.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
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