Asymmetric Reduction of Lactam-Based β-Aminoacrylates. Synthesis of Heterocyclic β2-Amino Acids

Article abstract of DOI:10.1021/acs.orglett.6b02074

The ability to affect asymmetric reduction of heterocyclic β-aminoacrylates 1 (n = 1-3) has been assessed with pyrrolidine and piperidone variants generating the corresponding N-heterocyclic β²-amino acids 3b and 5b with high enantioselectivity

Full text of DOI:10.1021/acs.orglett.6b02074

Letter
pubs.acs.org/OrgLett
Asymmetric Reduction of Lactam-Based β‑Aminoacrylates. Synthesis
of Heterocyclic β2‑Amino Acids
Hugo Rego Campello,† Jeremy Parker,‡ Matthew Perry,§ Per Ryberg,∥,⊥ and Timothy Gallagher*,†
†School of Chemistry, University of Bristol, Bristol BS8 1TS U.K.
‡AstraZeneca, Pharmaceutical Development, Silk Road Business Park, Macclesfield SK10 2NA U.K.
§AstraZeneca, Innovative Medicines, R&I Chemistry, AstraZeneca R&D Molndal, Peparedsleden, SE-431 83 Molndal, Sweden
̈
̈
∥AstraZeneca, PR&D Sodertalje, S-151 85 Sodertalje, Sweden
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: The ability to affect asymmetric reduction of
heterocyclic β-aminoacrylates 1 (n = 1−3) has been assessed
with pyrrolidine and piperidone variants generating the
corresponding N-heterocyclic β2-amino acids 3b and 5b with
high enantioselectivity (≥97% ee) using a Rh/WALPHOS
catalyst combination. The use of the carboxylic acid substrate
was essential; the corresponding esters do undergo reduction
but led to racemic products. The seven-ring azepanone variant (as the carboxylic acid 9b) underwent reduction, but only a
minimal level of asymmetric induction was observed.
unctionalized and chiral N-heterocycles represent widely
exploited and valuable synthetic units, where an ability to
Scheme 1
F
gain access to either enantiomer of the target heterocycle is
often an important issue.1 Asymmetric alkene reduction
methods2 are especially attractive in this area since other
functional groups present in the alkene substrate, e.g., a
carbonyl moiety often serves to direct the catalytic reduction
step; such functionality can then also be of value in terms of the
synthetic flexibility inherent within the reduction product.
In terms of general CC reduction, high enantioselectivity
has been reported for a range of functionalized alkenyl
substrates, such as acrylates3 and, relevant here, α- and β-
amino/amidoacrylates.4 Similarly, cyclic enamines are effective
substrates for asymmetric reduction leading to substituted five-,
six-, and seven-ring N-heterocycles.5
Our interest in this area has focused on reduction of an
unusual class of β-amidoacrylates (i.e., lactams) of general
structure 1 (n = 1−3). The potential of these systems is
exemplified by lactam 2 (1, n = 2); reduction of the readily
available ester 2a6 provides piperidone 3a (a β2-amino acid
derivative) which has served as a key intermediate in the
synthesis of cytisine as well as of a series of cytisine variants
(Scheme 1).7
In previous work, we developed an asymmetric approach to
cytisine by exploiting an ability to carry out a kinetic resolution
of methyl ester 3a using α-chymotrypsin (α-CHY).8 This
provided acid (S)-3b (>64% ee; 48% yield) and (unreacted)
ester (R)-(+)-3a (>98% ee; 42% yield). While useful, such
resolution processes are, however, inherently inefficient.
Catalytic asymmetric reduction of 2a/b, which is a more
attractive option, had been explored using standard methods
reported previously for acrylates. However, these efforts
enjoyed limited success; we obtained low enantioselectivities
and poor conversions.9 One factor affecting the levels of
asymmetric induction observed may link to the relative spatial
disposition of the lactam carbonyl (as a potential ligand and
directing group) with respect to either or both of the CC or
carboxylate functions.10
Given these limitations, the value and attractiveness of
enantiomerically pure piperidinone 3a/b in other contexts,11
and the opportunity to develop a methodology applicable to a
wider range of substrates, we undertook a more extensive
screening program to assess the potential for the asymmetric
reduction of methyl ester 2a and carboxylic acid 2b. A wide
range of metal catalysts, ligands, and reaction conditions were
Received: July 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02074
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
evaluated within AstraZeneca. Having screened a range of
parameters, effective reaction conditions were identified, which
are shown in Scheme 2, and asymmetric reduction of acid 2b
was achieved to product (S)-(−)-3b in over 97% ee with Rh
catalysis in combination with (S,Sp)-WALPHOS 4 as ligand.12
Scheme 3. Synthesis of 6a and 6b: Asymmetric Reduction of
6b
Scheme 2. Asymmetric Reduction of 2b To Give (S)-3b
High selectivity was observed only with carboxylic acid 2b;
methyl ester 2a did undergo reduction but with a negligible
level of enantiomeric induction under all of the different
conditions evaluated. Further, the isolated (after purification)
yield (65%) of (S)-3b is likely a result of the high pressures
involved necessary to achieve reasonable conversion under
which N-debenzylation appeared to begin to compete.
The stereochemical outcome of this asymmetric reduction
process (in terms of generating (S)-(−)-3b) was established by
comparison to the piperidinone products obtained from
enzymatic kinetic resolution. In this previous work, we had
obtained as the unreacted enantiomer ester (R)-(+)-3a in high
enantiomeric excess, which we had then converted to
(unnatural) (+)-cytisine.
We have further explored the scope of this reduction
methodology and examined the viability of the corresponding
pyrrolidine and azepane-based lactams 1 (n = 0 and 2,
respectively) given that, alongside piperidone 2, these would
provide a homologous series of enantiomerically enriched,
functionalized, and synthetically versatile N-heterocyclic units.
In the case of the pyrrolidine variant, the enzymatic kinetic
resolution of ( )-5a (to provide access to enriched ester (R)-
(−)-5a and acid (S)-(+)-5b) has been reported.13 This earlier
work provided us with the basis for a later structural
assignment, but two potential reduction substrates needed to
be considered: the β-aminoacrylates 6a/b14 (the Δ4,5-lactam,
analogous to 2a/b) and the corresponding Δ3,4-isomer
(incorporating a fumarate subunit), previously reported as the
methyl ester 7.15
cyclization of which was best carried out under strongly basic
conditions. Given our experience in the piperidinone series, we
focused attention on the use of the corresponding carboxylic
acid 6b as the reduction substrate, but the conversion of ester
6a to acid 6b proved to be surprisingly difficult; product
degradation under standard conditions appeared to be facile.16
Optimal conditions developed are shown in Scheme 3, and
once isolated, acid 6b is crystalline, stable, and easily handled.
Reduction of acid 6b followed a very similar course to that of
2b, and the (S)-(+)-carboxylic acid 5b was isolated in 75% yield
and in 97% ee. The configuration of 5b was established by
comparison with optical rotation data reported for this
compound derived by enzymatic resolution,13 and clearly, 2b
and 6b undergo asymmetric reduction in the same sense as one
another under these Rh/WALPHOS conditions.
We were interested in the behavior of the isomeric lactam 7
under reduction conditions, recognizing that CC isomer-
ization could be involved in the reduction of β-aminoacrylates
such as 6b. However, our attempts to reproduce the route
reported to 7 failed to give the product claimed;15 see the
Supporting Information. In our hands, the only product
obtained under these conditions was methyl ester 6c (i.e., the
Δ4,5-lactam isomer), which was isolated in 70% yield.
The azepane variant 9 was prepared using a nitrone-based
Beckmann rearrangement (Scheme 4), which was based on the
previous work of both Barton17a and Ward.17b To avoid a
problematic separation of isomeric lactam products, it was
critical to isolate the individual nitrone isomers 8 (isolated as a
3:1 mixture of E/Z isomers) prior to rearrangement. In this way
azepene 9a was obtained in 40% yield and converted efficiently
to the corresponding acid 9b.
Reduction of 9b, under the conditions applied to 1b and 5b,
provided the azepane 10 but in 10% ee, and the absolute
configuration of the predominant product was not established.
This was a surprising result given the relatively small structural
modification involved, and further work will be needed to
probe the mechanism by which this set of substrates interacts
with the Rh/ligand complex.18
Given that both pyrrolidinone 5a and piperidone 3a are
viable substrates for kinetic resolution using α-chymotrypsin
(α-CHY), we have evaluated methyl ester 11 under these
The synthesis of β-aminoacrylate 6a/b we have developed is
shown in Scheme 3 and is based on formylation of diethyl
succinate followed by enamine formation (using benzylamine),
B
DOI: 10.1021/acs.orglett.6b02074
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
Scheme 4. Synthesis of 9a and 9b: Asymmetric Reduction of
9b
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Mairi Haddow and Dr. Hazel Sparkes for
crystallographic determination of 3b, the University of Bristol
for a postgraduate fellowship (to H.R.C.), and AstraZeneca for
partial financial support and access to catalyst screening/
optimization facilities.
REFERENCES
■
(1) The ability to access selectively either enantiomer of a target (e.g.,
bioactive) molecule is widely appreciated, and methods of “measuring”
different complexity descriptors, including chirality, have been
reported: (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem.
2009, 52, 6752. (b) Lovering, F. MedChemComm 2013, 4, 515.
(c) Zayit, A.; Pinsky, M.; Elgavi, H.; Dryzun, C.; Avnir, D. Chirality
2011, 23, 17.
(2) For reviews of asymmetric alkene reduction, see: (a) Chi, Y.-X.;
Tang, W.-J.; Zhang, X. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 1−31.
(b) Genet, J. P. In Modern Reduction Methods; Andersson, P. G.,
Munslow, I. J., Eds.; Wiley-VCH: Weinheim, 2008; pp 3−38.
(c) Hartwig, J. In Organotransition Metal Chemistry, 1st ed.; University
Science Books: Sausalito, 2010; Chapter 15, pp 575−665.
conditions (Scheme 5). Ester 11 was obtained in 85% yield by
hydrogenation of 9a (see the Supporting Information).
Scheme 5. Enzymatic Kinetic Resolution of ( )-11
(3) High selectivity has been reported for the asymmetric reduction
of acrylates: (a) Ohta, T.; Takaya, H.; Noyori, R. Tetrahedron Lett.
1990, 31, 7189. (b) Yamada, I.; Yamaguchi, M.; Yamagishi, T.
Tetrahedron: Asymmetry 1996, 7, 3339. (c) Uemura, T.; Zhang, X. Y.;
Matsumura, K.; Sayo, N.; Kumobayashi, H.; Ohta, T.; Nozaki, K.;
Takaya, H. J. Org. Chem. 1996, 61, 5510. (d) Yamada, I.; Ohkouchi,
M.; Yamaguchi, M.; Yamagishi, T. J. Chem. Soc., Perkin Trans. 1 1997,
1869. (e) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard, A. J.;
Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de Vries,
J. G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 4209.
(f) Khumsubdee, S.; Burgess, K. ACS Catal. 2013, 3, 237. (g) Song,
S.; Zhu, S.-F.; Li, Y.; Zhou, Q.-L. Org. Lett. 2013, 15, 3722.
At pH 7.4, racemic 11 underwent selective hydrolysis, and
the corresponding acid 10 was isolated in 31% yield and 78% ee
and the unreacted ester 11 was recovered in 46% yield and 97%
ee (as assessed by chiral HPLC).19 We have not assigned the
absolute configurations of these products and this process has
not been optimized further in terms of yields and enantiomeric
purities.
(4) The synthesis of β-amino acids (including via reduction methods
to provide β2-derivatives) has been reviewed; see: Seebach, D.; Beck,
̌
A. K.; Capone, S.; Deniau, G.; Groselj, U.; Zass, E. Synthesis 2009,
In summary, we have shown that an unusual but synthetically
useful class of heterocyclic β-aminoacrylates undergo efficient
asymmetric reduction with a Rh-WALPHOS catalyst combina-
tion. This process works efficiently for the pyrrolidinone and
piperidinone carboxylic acid substrates 6b and 2b, respectively,
but the level of enantiomeric selectivity dramatically diminished
in the case of the seven-ring azepine substrate 9b.
2009, 1. Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.;
Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656. Rh-mediated
asymmetric hydrogenation of acrylates, β-amino acrylates, and β2-
dehydroamino esters has been reported: (a) Rocha Gonsalves, A.;
Bayon, J. C.; Pereira, M. M.; Serra, M. E. S.; Pereira, J. P. R. J.
Organomet. Chem. 1998, 553, 199. (b) Deng, J.; Hu, X.-P.; Huang, J.-
D.; Yu, S.-B.; Wang, D.-Y.; Duan, Z.-C.; Zheng, Z. J. Org. Chem. 2008,
73, 2015. (c) Yasutake, M.; Gridnev, I. D.; Higashi, N.; Imamoto, T.
Org. Lett. 2001, 3, 1701. (d) Elaridi, J.; Thaqi, A.; Prosser, A.; Jackson,
W. R.; Robinson, A. J. Tetrahedron: Asymmetry 2005, 16, 1309.
(e) Hoen, R.; Tiemersma-Wegman, T.; Procuranti, B.; Lefort, L.; de
Vries, J. G.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2007, 5,
267. (f) Qiu, L.; Prashad, M.; Hu, B.; Prasad, K.; Repic, O.; Blacklock,
T. J.; Kwong, F. Y.; Kok, S. H. L.; Lee, H. W.; Chan, A. S. C. Proc. Natl.
Acad. Sci. U. S. A. 2007, 104, 16787. (g) Bisset, A. A.; Shiibashi, A.;
Desmond, J. L.; Dishington, A.; Jones, T.; Clarkson, G. J.; Ikariya, T.;
Wills, M. Chem. Commun. 2012, 48, 11978. More recently, the Rh-
and Ru-mediated asymmetric hydrogenation of N-acyl β-aminoacrylic
acids (the acyclic variant of the systems described here) to provide β2-
(arylated)amino acids has been reported: Remarchuk, T.; Babu, S.;
Stults, J.; Zanotti-Gerosa, A.; Roseblade, S.; Yang, S.; Huang, P.; Sha,
C.; Wang, Y. Org. Process Res. Dev. 2014, 18, 135.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02074.
Experimental procedures and spectroscopic data for all
new compounds and the X-ray crystallographic structure
determination of (S)-3b (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: t.gallagher@bristol.ac.uk.
Present Address
(5) For a review of the asymmetric hydrogenation of enamines, see:
Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713. Studies
have reported high selectivity for the asymmetric hydrogenation of
enamines and cyclic enamines: (a) Hou, G.-H.; Xie, J.-H.; Yan, P.-C.;
Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366. (b) Zhou, Q.-L.; Xie,
⊥Ferring Pharmaceuticals, Kay Fiskers Plads 11, 2300
Copenhagen S, Denmark.
C
DOI: 10.1021/acs.orglett.6b02074
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
J.-H. In Stereoselective Formation of Amines; Li, W., Zhang, X., Eds.;
Springer-Verlag: Berlin, 2013; pp 75−101.
(6) Ester 2a is available on a multigram scale: Cook, G. R.; Beholz, L.
G.; Stille, J. R. J. Org. Chem. 1994, 59, 3575. Subsequent conversion of
ester 2a to acid 2b was carried out in essentially quantitative yield
using NaOH/H2O/THF.
give α-amino esters) where the opposite trend i.e. increasing
enantioselectivity with increasing ring size was observed. However, it
is probable that these substrates involve a chelated metal complex
involving the N-acyl moiety which is not possible with the substrates
we report here. Nicolaou, K. C.; Shi, G.-Q.; Namoto, K.; Bernal, F.
Chem. Commun. 1998, 1757.
(19) Enantiomeric purities reported were determined by chiral
HPLC using racemates as standards.
(7) (a) Botuha, C.; Galley, M. S. C.; Gallagher, T. Org. Biomol. Chem.
2004, 2, 1825. (b) Hirschhauser, C.; Haseler, C. A.; Gallagher, T.
̈
Angew. Chem., Int. Ed. 2011, 50, 5162. For a different approach to a
structurally related piperidinone, see: (c) Struth, F. R.; Hirschhauser,
̈
C. Eur. J. Org. Chem. 2016, 2016, 958. (d) Khong, D. T.; Pamarthy, V.
S.; Gallagher, T.; Judeh, Z. M. A. Eur. J. Org. Chem. 2016, 2016, 3084.
(8) Gray, D.; Gallagher, T. Angew. Chem., Int. Ed. 2006, 45, 2419.
(9) We utilized Ru-based methods based on BINAP and Me-Duphos
(MeOH, 20−50 °C) under both hydrogenation and transfer
hydrogenation conditions. The enantioselectivities observed for
reduction of ester 2a and acid 2b using Ru[(R,R)-Me-Duphos]
COD))BF4 were, respectively, 24% and 10% ee, but chemical
conversions were only of the order of 25%. Ester reduction of ester
2a was also carried out to assess the potential of the corresponding
allylic alcohol as a substrate under asymmetric hydrogenation
conditions. This alcohol was extremely labile, and over-reduction to
form the corresponding 5-methyl lactam was observed: Botuha, C.;
Gallagher, T. Unpublished work.
(10) For asymmetric reduction of heterocyclic enamines carrying an
N-Boc moiety (i.e., a carbonyl director on the periphery rather than
integral to the heterocycle), see: Wilkinson, T. J.; Stehle, N. W.; Beak,
P. Org. Lett. 2000, 2, 155. Lim, S. H.; Ma, S.; Beak, P. J. Org. Chem.
2001, 66, 9056.
(11) Lactams 3 and 5 provide multipoint, spiro-fused heterocyclic
scaffolds: Hirschhauser, C.; Parker, J. S.; Perry, M. W. D.; Haddow, M.
̈
F.; Gallagher, T. Org. Lett. 2012, 14, 4846.
(12) We used (S)-1-{(SP)-2-[2-(dicyclohexylphosphino)phenyl]
ferrocenyl}ethylbis[3,5-bis(trifluoromethyl)phenyl]phosphine (CAS:
849925-22-0), both enantiomers of which are commercially available.
(13) The enzymatic resolution of ester 5a has been reported: Felluga,
F.; Pitacco, G.; Prodan, M.; Pricl, S.; Visintin, M.; Valentin, E.
Tetrahedron: Asymmetry 2001, 12, 3241.
(14) Pyrrolidinone 6a has been reported using a very different
approach from that shown in Scheme 3; see: Dubinina, G. G.; Chain,
W. J. Tetrahedron Lett. 2011, 52, 939.
(15) Lactam 7 (the Δ3,4-isomer) was of interest because of the
possibility that alkene isomerization (6 → 7) may occur prior to CC
reduction. The synthesis of ester 7 was reported by Amri: Besbes, R.;
́
Villieras, M.; Amri, H. Indian J. Chem. 1997, 36B, 5. However, in our
hands, this route gave only the Δ4,5-isomer isomer ester 6c; see the
Supporting Information for characterization and for references to
related structures. We suggest that the original authors misassigned the
structure of their final product as 7 rather than the β-amino acrylate
6c.
(16) Extensive decomposition of 6a occurred under standard ester
hydrolysis conditions. Optimal conditions involved use TMSOK:
Lovric, M.; Cepanec, I.; Litvic, M.; Bartolincic, A.; Vinkovicc, V. Croat.
́ ́ ̌ ́ ́ ̌
Chem. Acta 2007, 80, 109. Once isolated, acid 6b is a stable, colorless
solid.
(17) (a) Barton, D. H. R.; Day, M. J.; Hesse, R. H.; Pechet, M. M. J.
Chem. Soc., Perkin Trans. 1 1975, 1764. (b) Prager, R. H.; Raner, K. D.;
Ward, A. D. Aust. J. Chem. 1984, 37, 381. Under Beckmann
rearrangement conditions, nitrone (Z)-8 gave a complex mixture of
products within which we were unable to isolate 9a. Reaction of (E)-8
provided a much less complicated mixture of products from which 9a
was isolated in 40% yield.
(18) The steep drop off in % ee with the seven-ring substrate 9b was
surprising, but 9b has not been screened separately against a bank of
metals/ligands. Incorporating three sp3 centers, molecular models
suggest that 9b is significantly more puckered than either the five- or
six-ring variants which may affect the relative stability of the
diasteromeric substrate-metal complexes. Nicolaou has reported the
asymmetric reduction of N-acyl heterocyclic dehydroamino esters (to
D
DOI: 10.1021/acs.orglett.6b02074
Org. Lett. XXXX, XXX, XXX−XXX