Organocatalytic Enantioselective Synthesis of α-Fluoro-β-amino Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b03297

Asymmetric cyclocondensation of N-sulfonylimines with fluoroacetic acid promoted by isothiourea catalyst HBTM-2 generates 3-fluoro-β-lactams with high enantio- and diastereoselectivity. These reactive compounds are opened with alcohols or amines to produce the corresponding α-fluoro-β-amino acid derivatives in moderate yields.

Full text of DOI:10.1021/acs.orglett.8b03297

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organocatalytic Enantioselective Synthesis of α‑Fluoro-β-amino
Acid Derivatives
Matthew R. Straub and Vladimir B. Birman*
Department of Chemistry, Washington University, Campus Box 1134, One Brookings Drive, St. Louis, Missouri 63130, United
States
S
* Supporting Information
ABSTRACT: Asymmetric cyclocondensation of N-sulfonyli-
mines with fluoroacetic acid promoted by isothiourea catalyst
HBTM-2 generates 3-fluoro-β-lactams with high enantio- and
diastereoselectivity. These reactive compounds are opened
with alcohols or amines to produce the corresponding α-
fluoro-β-amino acid derivatives in moderate yields.
luorinated analogues of amino acids have received
considerable attention due to their potential in preparing
found only three examples of 3-halogenated β-lactams prepared
in this manner.8,11
F
bioactive molecules with unique characteristics.1 Among these,
enantioenriched α-fluoro-β-amino acids have been synthesized
via enzymatic resolution,2 using chiral pool3 and chiral auxiliary
approaches,4 and catalytically via asymmetric aminofluorination
(Figure 1, eq 1),5 Mannich reaction (eq 2),6 and hydrosilylation
We began our study by developing a reaction protocol relying
on in situ activation of fluoroacetic acid. Treatment of
fluoroacetic acid with tosyl chloride12 and excess triethylamine
followed by addition of N-tosyl benzaldimine 8a produced the
expected β-lactam 9a in the absence of any additional catalyst,
indicating that this base would not be suitable for developing an
asymmetric version of this reaction (Table 1, entry 1). No
reaction took place in the presence of DBU or Hu
alone (entries 2 and 3). Adding 20 mol % of DHPB 11a13 led to
rapid product formation in the presence of Hunig’s base but not
̈
nig’s base
̈
DBU (entries 4 and 5), which determined our choice of base for
the remainder of this study.
Analysis of crude reaction mixtures by 19F NMR revealed
several byproducts, suggesting that fluoroacetic acid was
consumed via unproductive pathways, which confirmed the
need to use it in excess. The choice of tosyl chloride proved to be
critical, as other activating agents, such as pivaloyl chloride14 and
2,4,6-trichlorobenzoyl chloride (TCBC),15 were completely
ineffective (entries 6 and 7). Other achiral Lewis base catalysts
were examined briefly. Both electron-poor (11b)16 and
electron-rich (11c)17 derivatives of DHPB produced lower
conversion (entries 8 and 9). DMAP 12 was slightly more
effective than DHPB 11a (entry 10). No reaction was observed
in the presence of triazolium salt 13 (entry 11).
The enantioselective variant of the new reaction was
examined next. BTM 1418a and HBTM-2.1 15a19 produced
excellent enantioselectivity, although the reactions stalled
without reaching completion (Table 2, entries 1 and 2), similar
to the achiral catalyst DHPB 11a (Table 1, entry 5). Pleasingly,
HBTM 15b18b and HBTM-2 15c18c,20 brought the reaction to
completion (Table 2, entries 3 and 4). Although high
Figure 1. Catalytic approaches to α-fluoro-β-amino acids.
(eq 3).7 In this letter, we disclose an alternative approach to
these important compounds that has heretofore remained
unexplored (eq 4).
Although the formal [2 + 2] cycloaddition between
zwitterionic enolates and electron-deficient imines (sometimes
referred to as the Umpolung Staudinger reaction)8 has received
considerable attention over the last two decades,9,10 we have
1
conversions were observed by H NMR, β-lactam 9a was
isolated in only low yields (ca. 40%), presumably due to
Received: October 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03297
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
its relative and absolute stereochemistry (Figure 2). Analysis of
crude mixtures by 19F NMR revealed that both the intermediate
Table 1. Optimization of Reaction Conditions
entry
catalyst
activator
base
NEt3
DBU
i-Pr2NEt
DBU
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
9a/8a
a
1
2
3
4
5
6
7
8
9
none
none
none
11a
11a
11a
11a
11b
11c
12
TsCl
TsCl
TsCl
TsCl
TsCl
PivCl
TCBC
TsCl
TsCl
TsCl
TsCl
94:6
Figure 2. X-ray crystal structure of 10a-OMe. The absolute
configuration was determined from the Flack parameters.23
NR
NR
NR
66:34
NR
β-lactam 9a and the benzyl ester 10a-OBn were produced with
ca. 15:1 diastereoselectivity, which indicated that no epimeriza-
tion was taking place during the ring opening.21 Comparable
yields were observed on a larger scale (2.64 mmol, entry 8) and
at lower catalyst loadings (entries 9 and 10). To illustrate the
practical utility of the new reaction, we demonstrated that the
tosyl group can be replaced with the more convenient Boc
protecting group using a known protocol22 (Scheme 1). The
NR
22:78
57:43
72:28
NR
10
11
13
a
After 24 h.
Scheme 1. Protecting Group Exchange
Table 2. Optimization of the Enantioselective Variant
detosylation step carried out in methanol was accompanied by
clean transesterification of the benzyl ester. However, no
evidence of defluorination or epimerization was observed during
this transformation.
With these results in hand, we proceeded to investigate the
substrate scope of the reaction. Arylsulfonyl groups with a para-
methoxy or para-bromo substituent produced yields lower than
those of the tosyl group (Table 3, entries 2 and 3). N-Nosyl
benzaldimine reacted rapidly, as expected, but produced mostly
byproducts (entry 4). Variation of the C-substituent on the
aldimine, on the other hand, indicated that, whereas electron-
withdrawing and mildly donating groups on the benzene ring
were tolerated (entries 5−11), a para-methoxy group led to
complex mixtures of products (entry 12). Likewise, N-tosyl
furaldimine underwent mostly side reactions (entry 13).
Surprisingly, no reaction was observed with N-tosyl cinnamaldi-
mine (entry 14). An alicyclic substituent with an α-proton
underwent enolization and gave the corresponding N-
fluoroacetyl-N-tosylenamine instead of the desired product
(entry 15). Excellent enantioselectivities and moderate to high
syn-diastereoselectivities were observed in most cases (except
entries 9 and 11).
b
entry
catalyst (mol %)
9a/8a
% yield
NuH
% ee
1
2
3
4
5
6
7
14 (20)
73:27
68:32
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
50
38
45
60
61
53
55
58
55
54
BnOH
BnOH
BnOH
BnOH
MeOH
BnNH2
Et2NH
BnOH
BnOH
BnOH
99
−99
−99
>99
96
ent-15a (20)
ent-15b (20)
15c (20)
15c (20)
15c (20)
15c (20)
15c (20)
15c (10)
15c (5)
98
>99
>99
99
c
8
d
9
d
10
98
a
General conditions: FCH2CO2H (0.5 mmol), TsCl (0.75 mmol), i-
Pr2NEt (0.75 mmol), CDCl3, 0 °C, then catalyst, i-Pr2NEt (0.75
mmol), 8a (0.25 mmol), 0 °C, 18 h, then NuH (1.2 equiv of BnOH
b
or 10 equiv of MeOH, BnNH2, or Et2NH), rt, 4 h. Isolated yields of
c
the pure major diastereomer. Perfomed on 10× scale (2.64 mmol
substrate). Reaction times extended to 28 h.
d
Whereas the syn-selectivity observed above is consistent with
Lectka’s study employing cinchona-based catalysts,8 it stands in
contrast to the stereochemical outcome observed by Smith et
al.24 in the [2 + 2] cyclocondensation of N-tosylaldimines with
aryl-, arylthio-, and alkenylacetic acids (18a−c, Scheme 2). This
is noteworthy because we employed essentially the same
decomposition during aqueous workup and chromatography.
Therefore, we chose to convert it in situ into stable esters and
amides, which were isolated in moderate overall yields (entries
4−7) as crystalline solids. The methyl ester (10a-OMe)
produced X-ray quality crystals, which allowed us to confirm
B
DOI: 10.1021/acs.orglett.8b03297
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Substrate Scope
Experimental procedures, X-ray crystallographic data,
NMR spectra, and HPLC data (PDF)
Accession Codes
CCDC 1873414 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
entry
1
2
R
Ar2
% yield
dr
% ee
b
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeOC6H4
4-BrC6H4
60
14.9:1
12.6:1
11.5:1
ND
13.8:1
7.5:1
>20:1
>20:1
1.1:1
18.8:1
9.1:1
ND
>99
>99
95
ND
>99
>99
98
>99
99
99
a
50
38
<5
3
4
5
6
7
8
d
AUTHOR INFORMATION
4-O2NC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
■
4-O2NC6H4
4-O2NC6H4
4-BrC6H4
4-ClC6H4
2-ClC6H4
2-MeC6H4
1-naphthyl
4-MeOC6H4
2-furyl
32
48
Corresponding Author
*E-mail: birman@wustl.edu.
ORCID
b
52
b
53
a
9
38
43
39
<5
<5
Vladimir B. Birman: 0000-0003-0299-358X
Notes
a
10
a
11
74
The authors declare no competing financial interest.
d
12
13
14
ND
ND
ND
ND
d
ND
ND
ND
ACKNOWLEDGMENTS
■
styryl
0
0
a
c
We thank the National Science Foundation for the continued
support of our studies (CHE 1566588). We also thank Dr.
Nigam Rath (University of Missouri-Saint Louis) for providing
crystallographic data for 10a-OMe.
15
cyclohexyl
4-MeC6H4
a
b
Reactions performed at rt. Yield of the major diastereomer only.
N-Fluoroacetyl-N-tosylenamine was produced instead in 68% yield.
Complex reaction mixture.
c
d
REFERENCES
Scheme 2. Substrate-Dependent Diastereoselectivities
■
(1) (a) Mikami, K.; Fustero, S.; Sanchez-Rosello, M.; Acena, J. L.;
Soloshonok, V.; Sorochinsky, A. Synthesis 2011, 2011, 3045−3079.
(b) Qiu, X.-L.; Qing, F.-L. Eur. J. Org. Chem. 2011, 2011, 3261−3278.
(2) Li, X.-G.; Laehitie, M.; Paeivioe, M.; Kanerva, L. T. Tetrahedron:
Asymmetry 2007, 18, 1567−1573.
(3) Peddie, V.; Abell, A. D. Helv. Chim. Acta 2012, 95, 2460−2473.
(4) (a) Duggan, P. J.; Johnston, M.; March, T. L. J. Org. Chem. 2010,
75, 7365−7372. (b) Shang, H.; Li, Y.; Li, X.; Ren, X. J. Org. Chem. 2015,
80, 8739−8747.
(5) Appayee, C.; Brenner-Moyer, S. E. Org. Lett. 2010, 12, 3356−
3359.
(6) (a) Pan, Y.; Zhao, Y.; Ma, T.; Yang, Y.; Liu, H.; Jiang, Z.; Tan, C.-
H. Chem. - Eur. J. 2010, 16, 779−782. See also: (b) Wang, H.-Y.;
Zhang, K.; Zheng, C.-W.; Chai, Z.; Cao, D.-D.; Zhang, J.-X.; Zhao, G.
Angew. Chem., Int. Ed. 2015, 54, 1775−1779.
(7) (a) Zhang, P.; Wang, C.; Zhou, L.; Sun, J. Chin. J. Chem. 2012, 30,
2636−2640. (b) During preparation of this paper, an analogous
asymmetric hydrogenation was reported to produce excellent
enantioselectivities: Han, Z.; Guan, Y.-Q.; Liu, G.; Wang, R.; Yin, X.;
Zhao, Q.; Cong, H.; Dong, X.-Q.; Zhang, X. Org. Lett. 2018, 20, 6349−
6353.
(8) (a) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.;
Lectka, T. J. Am. Chem. Soc. 2002, 124, 6626−6635. (b) France, S.;
Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37, 592−
600. (c) France, S.; Shah, M. H.; Weatherwax, A.; Wack, H.; Roth, J. P.;
Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206−1215.
(9) For seminal work in this area, see: (a) Taggi, A. E.; Hafez, A. M.;
Wack, H.; Young, B.; Drury, W. J., III; Lectka, T. J. Am. Chem. Soc. 2000,
122, 7831−7832. (b) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 1578−1579.
(10) For recent advances in the synthesis of β-lactams via Staudinger
reaction and other methods, see: (a) Pitts, C. R.; Lectka, T. Chem. Rev.
2014, 114, 7930−7953. (b) Hosseyni, S.; Jarrahpour, A. Org. Biomol.
Chem. 2018, 16, 6840−6852.
(11) Tato, F.; Reboul, V.; Metzner, P. J. Org. Chem. 2008, 73, 7837−
7840.
conditions and amidine-based catalysts as Smith, which means
the diastereoselectivity must be substrate-dependent. The
absolute configuration at C3 is the same in both studies,
which suggests the same catalyst-controlled facial selectivity
with respect to the intermediate zwitterionic Z-enolates.
Therefore, the opposite stereochemistry at C4 points to the
change in the orientation of the N-tosylaldimine in the transition
state (cf. transition state models 19 and 20). In contrast, Lectka
et al. observed syn-selectivity in all cases examined.8,25
In conclusion, we have developed a new asymmetric catalytic
approach to esters and amides of α-fluoro-β-amino acids by way
of 3-fluoro-β-lactams. The substrate-dependent stereoselectivity
of the formal [2 + 2] cycloaddition of zwitterionic enolates
generated from amidine-based catalysts is intriguing and merits
further exploration. Studies in this direction will be reported in
due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
(12) (a) Liu, G.; Shirley, M. E.; Romo, D. J. Org. Chem. 2012, 77,
2496−2500. (b) Smith, S. R.; Douglas, J.; Prevet, H.; Shapland, P.;
Slawin, A. M. Z.; Smith, A. D. J. Org. Chem. 2014, 79, 1626−1639.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03297.
C
DOI: 10.1021/acs.orglett.8b03297
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(13) Kobayashi, M.; Okamoto, S. Tetrahedron Lett. 2006, 47, 4347−
4350.
(14) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith,
A. D. J. Am. Chem. Soc. 2011, 133, 2714−20.
(15) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989−93.
(16) Okamoto, S.; Sakai, Y.; Watanabe, S.; Nishi, S.; Yoneyama, A.;
Katsumata, H.; Kosaki, Y.; Sato, R.; Shiratori, M.; Shibuno, M.;
Shishido, T. Tetrahedron Lett. 2014, 55, 1909−1912.
(17) Ahlemeyer, N. A.; Streff, E. V.; Muthupandi, P.; Birman, V. B.
Org. Lett. 2017, 19, 6486−6489.
(18) (a) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351. (b) Birman, V.
B.; Li, X. Org. Lett. 2008, 10, 1115. (c) Zhang, Y.; Birman, V. B. Adv.
Synth. Catal. 2009, 351, 2525.
(19) Belmessieri, D.; Joannesse, C.; Woods, P. A.; MacGregor, C.;
Jones, C.; Campbell, C. D.; Johnston, C. P.; Duguet, N.; Concellon, C.;
Bragg, R. A.; Smith, A. D. Org. Biomol. Chem. 2011, 9, 559.
(20) For reviews of applications of these and other amidine-based
catalysts, see: (a) Birman, V. B. Aldrichimica Acta 2016, 49, 23.
(b) Merad, J.; Pons, J.-M.; Chuzel, O.; Bressy, C. Eur. J. Org. Chem.
2016, 2016, 5589.
(21) Epimerization has been observed in a structurally similar case:
Kant, J.; Huang, S.; Wong, H.; Fairchild, C.; Vyas, D.; Farina, V. Bioorg.
Med. Chem. Lett. 1993, 3, 2471−2474.
(22) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997,
1017−1018.
(23) Flack, H. D.; Bernardinelli, G. Chirality 2008, 20, 681−690.
(24) (a) Smith, S. R.; Douglas, J.; Prevet, H.; Shapland, P.; Slawin, A.
M. Z.; Smith, A. D. J. Org. Chem. 2014, 79, 1626−1639. (b) Morrill, L.
C.; Smith, S. M.; Slawin, A. M. Z.; Smith, A. D. J. Org. Chem. 2014, 79,
1640−1655.
(25) For previous examples of the reversal of diastereoselectivity in the
[2 + 2] cycloaddition of N-sulfonylaldimines and zwitterionic enolates,
see: (a) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 11586−11587. (b) Weatherwax, A.; Abraham, C.
J.; Lectka, T. Org. Lett. 2005, 7, 3461−3463.
D
DOI: 10.1021/acs.orglett.8b03297
Org. Lett. XXXX, XXX, XXX−XXX