Highly diastereoselective and general synthesis of primary β-fluoroamines

Article abstract of DOI:10.1021/ol202415j

A short, high yielding protocol has been developed for the highly diastereoselective (dr >20:1) and general synthesis of primary β-fluoroamines by the enantioselective α-fluorination of aldehydes, conversion into the N-sulfinyl aldimine, nucleophilic addi

Full text of DOI:10.1021/ol202415j

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5684–5687
Highly Diastereoselective and General
Synthesis of Primary β-Fluoroamines
Michael L. Schulte and Craig W. Lindsley*
Departments of Chemistry and Pharmacology, Vanderbilt University, Nashville,
Tennessee 37232, United States
craig.lindsley@vanderbilt.edu
Received September 6, 2011
ABSTRACT
A short, high yielding protocol has been developed for the highly diastereoselective (dr >20:1) and general synthesis of primary β-fluoroamines by
the enantioselective R-fluorination of aldehydes, conversion into the N-sulfinyl aldimine, nucleophilic addition of various organometallic species,
and 1° amine liberation.
β-Fluoroamines are common moieties in drug candi-
dates as the β-fluorine atom can lower pKa (diminish
ancillary pharmacology), enhance binding interactions,
improve metabolic stability, and increase CNS penetration.1ꢀ6
Despite their value, few methods exist for the general and
stereoselective synthesis of primary β-fluoroamines out-
side of the classical DAST approaches which are plagued
with rearranged and dehydrated products.7ꢀ10 Alternate
routes have emerged based on the diastereoselective reduction
of R-fluoroimines, hydrofluorination of epoxides with further
manipulation to provide β-fluoroamines, or tandem conjugate
additionꢀfluorination sequences; however, all of these routes
lack generality (inability to incorporate diversity) or display
preference for either the anti or syn products.11ꢀ14
Recently, we reported a one-pot protocol to provide
pharmaceutically relevant chiral β-fluoroamines via orga-
nocatalysis (Figure 1, eq 1).15 In this Letter, we describe a
novel methodology for the general synthesis of primary
β-fluoroamines in high yield and diasteroselectivity employ-
ing organocatalytic R-fluorination of aldehydes,16 Ellman
N-sulfinyl aldimine technology,17ꢀ21 nucleophilic addition
of organometallic species,22ꢀ25 and 1° amine liberation
(1) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369.
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Figure 1. Organocatalytic approach to chiral β-fluoroamines
and envisioned route to chiral primary β-fluoroamines.
r
10.1021/ol202415j
Published on Web 09/26/2011
2011 American Chemical Society

(Figure 1, eq 2). This methodology affords complete con-
trol of the two contiguous stereogenic centers based on the
chirality of the organocatalyst and sulfimine employed as
well as on the transiton state (metal-chelate versus nonmetal
chelate transition states, MCTS and NMCTS, respec-
tively) that the organometallic species adopts.
With R-fluoro-N-sulfinylaldimine 4 in hand, we exam-
ined the addition of a number of organometallic nucleo-
philes to add unprecendented diversity to the primary
β-fluoroamine scaffold and access derivatives previously
unavailable. We first explored Grignard reagents (Scheme 2)
and found a wide range of diverse R groups were tolerated
affording the sulfinamide-protected primary β-fluoroa-
mines 8aꢀc in good isolated yields (72ꢀ92%) and >20:1
dr (as determined by 19F NMR).22 The anti-diastereomer
of the β-fluoroamine formed predominantly as expected
due to the known metal-chelated transition state (see inset
under arrow) for 8a and 8b. The syn-diastereomer was
formed in the case of 8c, as a result of additional coordina-
tion to the acetal oxygen, in accordance with the work of
Ellman.23
Key to the success of this approach is the ability to trap
the incipient chiral R-fluoroaldehyde with the Ellman tert-
butanesulfonamide toformthe correspondingR-fluoro-N-
sulfinylaldimine in high diastereomeric ratio (dr). A number
of conditions were surveyed (time, desiccant, equivalents
of NFSI) for the conversion of hydrocinnamaldehyde 1 to
β-fluoro-N-sulfinylaldimine 4 (Scheme 1). Ultimately, we
found that 5.0 equiv of NFSI, 20 mol % (R)-2, Ti(OEt)4 as
desiccant with (R)-tert-butanesulfinamide 3, and a 5 h
reaction time were optimial to deliver 4 in >20:1 dr (as
judged by 19F NMR). With these conditions, a variety of
diverse aldehydes could be converted into their corre-
sponding β-fluoro-N-sulfinylaldimines 5ꢀ7 in good iso-
lated yield (67ꢀ75%) for the two steps and with up to
>20:1 dr (Figure 1). Here, substrates with handles for
further elaboration were tolerated, such as the phthalimide
congener 5, a progenitor for basic amine analogues, the
olefin in 6 for subsequent manipulations, and a benzyl
protected alcohol congener 7.
Scheme 2. Scope of Grignard Addition to 4 To Deliver Sulfi-
namide-Protected Primary β-Fluoroamines 8aꢀc
Scheme 1. Optimization of R-Fluoro-N-sulfinyl Aldimine 4
Formation and Substrate Scope
a With 0.5 mmol of 4.
Due to the extensive diversity and availability of func-
tionalized boronic acids, we next explored boronic acid
additions. Under Batey’s mild Rh(I) catalysis protocol,24
a
diverse group of aryl boronic acids (electron-rich, biaryl,
and heterocyclic congeners) smoothly afforded the target
adducts 9aꢀc in 65ꢀ91% yield and once again in >20:1 dr
(Scheme 3). In this instance, the syn-diastereomers of the
β-fluoroamines are formed based on the known addition
of the aryl rhodium species through a nonmetal chelated
transition state.24
a Diastereomeric ratio (dr) determined by 19F NMR.
Lin and co-workers previously demonstrated that in-
dium-mediated allylations (In(0), allyl bromide in aqueous
NaBr) of (R)-N-tert-butanesulfinylimines provide the (S)-
adducts as confirmed by single X-ray crystallography.25
(12) Duggan, P. J.; Johnston, M.; March, T. L. J. Org. Chem. 2010,
75, 7365–7372.
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127, 8826–8828.
(21) Brak, K.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 3850–3851.
(22) Brinner, K. M.; Ellman, J. A. Org. Biomol. Chem. 2005, 3, 2109–
2113.
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8904.
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J. Org. Chem. 1999, 64, 1278–1284.
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(24) Bolshan, Y.; Batey, R. A. Org. Lett. 2005, 7, 1481–1484.
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1259–1262.
Org. Lett., Vol. 13, No. 20, 2011
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the SmI2-induced reductive aldehyde cross-coupling with
our β-fluoro-N-sulfinylaldimine 4 (Scheme 5) produced
the target sulfinamide-protected primary β-fluoro-β0-ami-
no alcohols 11aꢀc in excellent yields (80ꢀ87%) and once
again with high dr (>20:1).
Scheme 3. Scope of Boronic Acid Addition to 4 To Deliver
Sulfinamide-Protected Primary β-Fluoroamines 9aꢀe
Scheme 5. Scope of SmI2-Induced Reductive Aldehyde Cou-
pling of 4 To Deliver Sulfinamide-Protected Primary β-Fluoro-
β0-Amino Alcohols 11aꢀc
a With 0.5 mmol of 4.
To further add structural diversity to the primary β-fluoroa-
mine scaffolds accessible through this approach, we employed
Lin’s protocol with our β-fluoro-N-sulfinylaldimine 4(Scheme
4). As expected, anti-diastereomers of the sulfinamide-pro-
tected β-fluoroamine products 10 were produced in good
yields (66ꢀ90%) and up to 9:1 dr. Here, we could install
additional stereogenic centers (10b) and allene moieties (10c).
a With 0.5 mmol of 4.
An attractive feature of the Ellman sulfinamide-
protected primary amines is the generality and ease
of deprotection.17ꢀ26 Treatment of a representative exam-
ple 8b with HCl in dioxane at room temperature smoothly
affords the desired primary β-fluoroamine congener 12 in
greater than 90% yield and without loss of stereochemical
integrity (Scheme 6). In our drug discovery efforts, we have
deprotected numerous congeners of 8b and have never
observed issues with stereochemical integrity or clean
deprotections.
Scheme 4. Scope of In-Mediated Allylation of 4 To Deliver
Sulfinamide-Protected Primary β-Fluoroamines 10aꢀc
Scheme 6. Deprotection To Afford 1° β-Fluoroamine 12
Finally, we wanted to apply this methodology to cyclic
primary β-fluoroamines, as this pharmacophore has pro-
ven to be an important component of therapeutics, such as
BACE inhibitors.27,28 Classically, cyclic, racemic trans-
primary β-fluoroamines (()-13 are prepared by the ring
opening of aziridines with nucleophilic fluoride, followed
by deprotection (Figure 2, eq 3).8,27,28 Cyclic, racemic cis-
primary β-fluoroamines (()-14 are prepared by fluorination
a With 0.5 mmol of 4.
We also hoped to expand this protocol to include
β-amino alcohols. Following the work of Xu and Lin,26
(27) Merck & Co: WO011810, 2007.
(28) Merck & Co: WO011833, 2007.
(26) Zhong, Y.-W.; Dong, Y.-Z.; Fang, K.; Izumi, K.; Xu, M.-H.;
Lin, G.-Q. J. Am. Chem. Soc. 2005, 127, 11956–11957.
5686
Org. Lett., Vol. 13, No. 20, 2011

Scheme 7. Access to Chiral, Cyclic 1° β-Fluoroamine 18
Figure 2. Standard synthetic route to trans- and cis-racemic and
enantiopure cyclic primary β-fluoroamines.
lation with previously reported 19F NMR shifts for cis-
(ꢀ197 ppm) and trans-cyclic β-fluoroamines (ꢀ180
ppm), wherein 18 displayed a singlet at ꢀ198 ppm.29
In summary, we have developed a highly diastereose-
lective and general synthesis of primary β-fluoroamines
using a combination of organocatalysis and Ellman
N-sulfinylaldimine technology to enable the preparation
of all possible stereoisomers in high isolated yields.
Importantly, this methodology provides access to pri-
mary β-fluoramine chemotypes that are generally not
accessible, or difficult to prepare, through current che-
mistries, as well as providing a significant improvement
for the synthesis of cyclic primary β-fluoroamines.
Further refinements are in progess and will be reported
in due course.
of a silyl enol ether, followed by reductive amination and
deprotection (Figure 2, eq 4).27,28 Overall, yields are modest
to low (average 12% overall) for the racemic, cyclic primary
β-fluoroamines and require several steps. In order to access
enantiopure derivatives, heroic chiral chromatography is
performed on either the free amine or, more likely, a
protected form that introduces a chromophore, followed
by chiral chromatography and deprotection. Ultimately,
pure enantiomers of trans-13 and cis-14 are arrived at in
typically less than 3% overall yield. In contrast, our metho-
dology can provide rapid, high yielding access to either cis- or
trans-cyclic primary β-fluoroamines with high enantios-
electivity based on the chirality of the organocatalyst
and the sulfinylamine employed. For example (Scheme
7), an indium-mediated allylation of 6 with allyl bro-
mide gives 15 in 90% yield and 9:1 dr (if allyl Grignard
employed, comparable yield, but >20:1 dr). Ring clos-
ing metathesis with Grubbs II affords cyclohexene 16 in
85% yield. Hydrogenation and standard acid-mediated
deprotection provide chiral cyclic primary β-fluoroa-
mine 18 in 70% overall yield for the four-step sequence,
a notable improvement over the classical route. The
relative stereochemistry of 18 was confirmed by corre-
Acknowledgment. This work was supported, in part, by
the Department of Pharmacology and Vanderbilt Univer-
sity. Funding for the NMR instrumentation was provided
in part by a grant from the NIH (S10 RR019022).
Supporting Information Available. Experimental pro-
cedures; characterization data; chiral HPLC traces; and
1H, 13C, and 19F NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(29) Toulgui, Ch.; Chaabouni, M. M.; Baklouti, K. J. Fluorine Chem.
1990, 46, 385–391.
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