Diastereodivergent Access to Syn and Anti 3,4-Substituted β-Fluoropyrrolidines: Enhancing or Reversing Substrate Preference

Article abstract of DOI:10.1021/acs.orglett.6b00293

A practical diastereodivergent access to β-fluoropyrrolidines with two adjacent stereocenters has been demonstrated, by either enhancing or completely reversing the substrate control, in the diastereoselective fluorination of a series of diverse pyrrolidi

Full text of DOI:10.1021/acs.orglett.6b00293

Letter
pubs.acs.org/OrgLett
Diastereodivergent Access to Syn and Anti 3,4-Substituted
β‑Fluoropyrrolidines: Enhancing or Reversing Substrate Preference
Kasper Fjelbye,†,‡ Mauro Marigo,† Rasmus Prætorius Clausen,‡ and Karsten Juhl*,†
†Discovery Chemistry and DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
‡Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen,
Universitetsparken 2, 2100 Copenhagen, Denmark
S
* Supporting Information
ABSTRACT: A practical diastereodivergent access to β-fluoropyrrolidines with two adjacent stereocenters has been
demonstrated, by either enhancing or completely reversing the substrate control, in the diastereoselective fluorination of a
series of diverse pyrrolidinyl carbaldehydes using organocatalysis. Furthermore, enamine catalysis has been successfully utilized
for kinetic resolution, obtaining a fluorinated β-prolinol analogue with two adjacent tetrasubstituted chiral centers in 95% ee from
a racemic substrate.
exploring the strategy for the diastereodivergent fluorination of
pyrrolidines as presented in Figure 1.
he incorporation of fluorine as a substitute for hydrogen
Thas had a significant impact on molecule design in drug
discovery, providing medicinal chemists with a broad collection
of scaffolds with attractive properties, and the possibility of fine-
tuning existing scaffolds.1−6 In particular, fluorine placed in close
proximity to an amine functionality can alter the electron density
and pKa and thereby influence the pharmacokinetic profile of a
compound.7 However, the synthetic challenge of introducing
fluorine in more advanced structures still limits the full
exploitation of this unique element from a medicinal chemistry
point of view.8,9 The pyrrolidine scaffold is a widely occurring
motif in biologically active compounds, and fluorinated
analogues are emerging that exploits the physicochemical
impact of H/F replacement.10,11 Introduction of fluorine at the
β-position of the pyrrolidine scaffold has a noticeable effect on
the pKa. However, chiral β-fluoropyrrolidines have previously
mostly been prepared from relatively expensive fluorine
containing starting materials, where the stereochemical course
of the synthesis is controlled by the substrate.12−14 The
importance of controlling both the relative and absolute
configurations is supported by the very different biological
properties of 3,4-substituted pyrrolidines; e.g., cis-3,4-pyrroli-
dines are reported as selective serotonin inhibitors, whereas the
trans-diastereomers had little or no activity.15 In contrast, trans-
3,4-substituted pyrrolidines have been developed as renin
inhibitors.16 Although it is possible to introduce fluorine on
chiral polysubstituted (i.e., 3,4-substituted) pyrrolidines, there
are no examples reported where this is done with high control of
the stereochemical outcome. We were therefore interested in
Figure 1. Diastereodivergent fluorination of chiral polysubstituted
pyrrolidines. [F+] = Achiral electrophilic fluorine source. FG =
functional group (e.g., ester, aldehyde, amide or cyano group). The
circles represent differently sized substituents.
Based on the well-established methodology of organocatalytic
α-functionalization of aldehydes,17 we envisioned that the
aldehyde functionality would serve as an ideal handle, allowing
diastereodifferentiation through enamine formation with a chiral
amine. In addition, the resulting product would allow rapid
chemical access to a variety of fluorinated derivatives, due to the
synthetic versatility of aldehydes.18 While the fluorination of
aldehydes has been studied extensively for α-monosubstituted
aldehydes,19 the formation of tetrasubstituted fluorinated
Received: January 28, 2016
© XXXX American Chemical Society
A
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Letter
stereocenters is more synthetically challenging. The enantiose-
lective fluorination of α-branched aldehydes, using primary
amine catalysis, was recently demonstrated for a series of
substrates with one chiral center,20 whereas the diastereodiver-
gent fluorination of aldehydes bearing two stereogenic centers
remains unprecedented. Herein, the practical application of two
different organocatalysts for the construction of tetrasubstituted
fluorinated stereocenters, adjacent to a chiral center, is presented.
A series of optically pure pyrrolidines 1a−g were synthesized
from α,β-unsaturated esters that underwent [3 + 2] cyclo-
addition with an azomethine ylide to provide the trans-3,4-
substituted pyrrolidine ring system. Subsequent reduction
followed by chiral supercritical fluid chromatographic (SFC)
separation, N-debenzylation, N-Boc-protection, and oxidation
afforded the aldehydes 1a−g.21a The catalyst screening began by
examining the effect of pyrrolidine catalysis on the enantio-
merically pure aldehyde 1a, using commercially available
N-fluorobenzenesulfonimide (NFSI) as the fluorinating
agent.21b The reaction provided a mixture of the corresponding
fluorinated aldehydes 2a and 3a in 60% yield, with an 18:82 dr,
where the only chiral information directing the stereochemical
outcome was present in the substrate (Scheme 1, cat. 4). Thus,
increased from rt to 40 °C to ensure full conversion of 1a.19a,c For
each chiral catalyst 5−9, both enantiomers were examined.
When a methyl group was introduced in the catalyst ((S)-5
and (R)-5), a chiral match/mismatch behavior was observed,
leading to a modest improvement of selectivity for (R)-5.
Encouragingly, the reversal of the stereochemical outcome of the
reaction obtained by (R)-6, now favoring 2a, occurred as a
consequence of catalyst control. This behavior was further
enhanced with the prolinol derived catalyst (R)-7 that proved to
catalyze the formation of the desired synthetically more
challenging syn product 2a in both high yield and dr.22 However,
the (S)-7 enantiomer also favored the formation of 2a albeit in
low yield. We found it surprising that both enantiomers of
catalyst 7 were selective toward the same nonsubstrate preferred
product, an effect we propose could be a consequence of different
enamine rotational isomers reacting with the fluorinating agent.
The best catalyst for enhancing the anti-selectivity, to favor 3a,
was found to be the imidazolidinone (S)-8. The ability of
secondary amine catalysts to direct the geometry of the iminium
bond being formed in enamine reactions has been supported
computationally.23 We qualitatively use the ability of such
catalyst-induced diastereofacial discrimination to rationalize the
observed diastereodivergence (Figure 2a and b).
a
Scheme 1. Screening of Organocatalysts
Figure 2. Iminium-enamine rotational isomers used to rationalize
the observed outcome of asymmetric induction based on a presumed
preference for the enamine double bond to adopt the (Z)-
configuration.
These complementing properties of the two catalysts (R)-7
and (S)-8 allowed for a high control of the stereochemical
outcome in the fluorination of 1a. The substrate scope was
subsequently examined, and as can be seen in Table 1, these two
catalysts allowed the successful and stereochemically controlled
fluorination of a variety of pyrrolidinyl carbaldehydes 1a−g
(Table 1) featuring aliphatic, aromatic, and heteroaromatic
substituents, and also a case of vicinal tetrasubstituted stereo-
centers (Table 1, 2b and 3b). The aldehydes 1a−g were initially
fluorinated using 4 to quantify the intrinsic diastereocontrol of
the substrate. When applying the diastereodivergent fluorination
protocol for an N-benzyl protected analogue of 1d, no significant
formation of the desired product was observed. However, by
employing the N-Boc-protecting group instead, the syntheses
of 2d and 3d proceeded in good yields and with excellent
diastereoselectivities. For 1c, having only a methyl substituent on
the 4-position and thus being the substrate with the least steric
bulk, it was possible to both significantly enhance substrate
a
The reactions were performed using 0.1 mmol of 1a at 40 °C with
reaction times in parentheses. Methyl-tert-butylether (MTBE) was
used as solvent for all of the reactions except for 5 and 8, where a 9:1
mixture of THF/i-PrOH was used. Ar = 3,5-(F3C)2C6H3, DCA = 2,2-
dichloroacetic acid. Yields reported after silica gel chromatography.
The dr was determined by LCMS analysis of the crude reaction
mixture after reduction to the corresponding alcohols. A 20 mol %
loading was used for 4 and 8.
the anti-product 3a was formed in majority, as a result of fluorine
approaching the least hindered enamine face. The choice of
solvent, fluorinating agent, and catalyst loading for the screening
(Scheme 1) was based on previously successful fluorination
reactions reported in literature, although the temperature was
B
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a
Table 1. Diastereodivergent Fluorination of Pyrrolidinyl Carbaldehydes Featuring Vicinal Stereocenters
a
b
c
RS = H or Me, RL = Ph, Me, Bn, 2-Pyr, 3-Pyr, 2-Thienyl. Determined by 1H NMR analysis after silica gel chromatography. Determined by LCMS
d
analysis of the crude reaction mixture after reduction to the corresponding alcohols on an analytical scale. Isolated yields; reaction times in
e
parentheses. The absolute configurations of 1a−g were assigned by comparison with data reported in the literature and by analogy; see the
f
Supporting Information for further details. The ee of 1a−g were >98%. The relative configurations of 2a−g and 3a−g were assigned using
g
h
heteronuclear NOESY analysis; by analogy, see the Supporting Information for details. 20 mol % catalyst loading was used. 10 mol % catalyst
loading was used.
control and also reverse the diastereoselectivity using (S)-8 and
(R)-7, respectively. Even in the case of 1b, where the intrinsic dr
from pyrrolidine catalysis was as high as 13:87, it was possible to
reverse the selectivity using (R)-7 in 74% yield.
C
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(3) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308−319.
For racemic 1b (rac-1b), we also examined the use of (R)-7 for
kinetic resolution. This was achieved using a substoichiometric
amount of NFSI, preferentially allowing fluorination of the most
reactive enamine enantiomer formed after condensation with the
organocatalyst (Figure 3). The fluorination provided 11b in
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anti-product was removed by silica gel chromatography (96:4 dr), and
the yields reported are after purification.
95% ee, affirming a highly selective and thus practically useful
discovery.24 In addition, the resolved starting material was
recovered in 79% ee as the corresponding alcohol 12. There is to
our knowledge no examples in literature of enamine catalysis
applied for chiral resolution of α-branched aldehydes bearing
more than one stereocenter.25
In conclusion, we have demonstrated the preparation of a
series of β-fluorinated pyrrolidines that are interesting scaffolds
from a medicinal chemistry point of view. This was achieved
starting from advanced α-branched aldehydes, and the products
were obtained in both high yields and excellent diastereose-
lectivities. Furthermore, we have employed organocatalysis for
kinetic resolution of a racemic substrate, furnishing a fluorinated
prolinol 11b with vicinal stereogenic centers in 95% ee.
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WO/2006/066896, Jun 29, 2006.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00293.
The full experimental details, the protocols for synthesis of
substrates, characterization data for new compounds, and
NMR spectra (PDF)
(20) For initial findings with up to 90% ee and moderate yields, see
(a) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.; Jørgensen,
K. A. Chem. - Eur. J. 2006, 12, 6039−6052. For recent results, see
(b) Shibatomi, K.; Kitahara, K.; Okimi, T.; Abe, Y.; Iwasa, S. Chem. Sci.
2016, 7, 1388−1392. (c) Witten, M. R.; Jacobsen, E. N. Org. Lett. 2015,
17, 2772−2775.
(21) (a) Detailed synthetic protocols for the synthesis of substrates
1a−g can be found in the Supporting Information. (b) Additional
results from the screening of organocatalysts can be found in the
Supporting Information.
(22) For a recent review, see: Donslund, B. S.; Johansen, T. K.;
Poulsen, P. H.; Halskov, K. S.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2015, 54, 13860−13874.
(23) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
11273−11283. (b) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2004, 43, 6722−6724.
(24) Kinetic resolution using catalyst 8 on rac-1b provided the
expected anti diastereomer 13b in 34% yield with no ee; see the
Supporting Information.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: KAJU@lundbeck.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financially supported by The Danish Agency for
Science, Technology and Innovation and H. Lundbeck A/S. We
thank Jessica Giacoboni, M.Sc. (H. Lundbeck A/S) for providing
a chiral starting material. Furthermore, a special thanks to Henrik
Pedersen Ph.D. and Peter Brøsen (H. Lundbeck A/S) for crucial
SFC separation of some of the starting materials.
(25) For kinetic resolution of racemic α-alkyl-α-chloroaldehydes with
one chiral center, yielding the corresponding chlorofluoroaldehydes
selectively, see: Shibatomi, K.; Okimi, T.; Abe, Y.; Narayama, A.;
Nakamura, N.; Iwasa, S. Beilstein J. Org. Chem. 2014, 10, 323−331.
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DOI: 10.1021/acs.orglett.6b00293
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