Diastereoselective synthesis of β-heteroaryl syn -α-methyl- β-amino acid derivatives via a double chiral auxiliary approach

Article abstract of DOI:10.1021/ol3033785

The addition of the SuperQuat enolate to five- and six-membered heterocyclic tert-butyl sulfinimines led to a high syn-selectivity of up to 99:1 in good to excellent yields. The reaction is tentatively proposed to proceed through an open-chain transition

Full text of DOI:10.1021/ol3033785

ORGANIC
LETTERS
2013
Vol. 15, No. 3
562–565
Diastereoselective Synthesis of β‑Heteroaryl
syn-r-Methyl-β-Amino Acid Derivatives
via a Double Chiral Auxiliary Approach
Jianwei Bian,* David Blakemore, Joseph S. Warmus, Jianmin Sun, Matthew Corbett,
Colin R. Rose, and Bruce M. Bechle
Neusentis Chemistry, Pfizer Worldwide Research and Development, Eastern Point
Road, Groton, Connecticut 06340, United States, and The Portway Building,
Granta Park, Cambridge, CB21 6GS, U.K.
jianwei.bian@pfizer.com
Received December 10, 2012
ABSTRACT
The addition of the SuperQuat enolate to five- and six-membered heterocyclic tert-butyl sulfinimines led to a high syn-selectivity of up to 99:1 in good
toexcellent yields. Thereactionistentativelyproposedtoproceedthroughan open-chain transitionstatewith the presence of anR-heteroatomon the
sulfinimine leading to high diastereoselectivities. The adducts were derivatized to β-amino esters and amides in a facile manner.
β-Amino acids are present as key building blocks in
bioactive natural products such as taxol and cocaine as
well as in naturally occurring peptides such as bestatin
and pepstatin.1 Their derivatives, β-lactams, are prevalent
structural motifs in antibiotics.2 The presence of β-amino
acids in polypeptides can potentially enhance their biolog-
ical activities and physical properties.3
In recent years, asymmetric syntheses of β-amino acid
derivatives have received much attention from the synthetic
community and various methods have been developed
to access different substitution patterns.4 In the context
of supporting our internal medicinal chemistry programs,
we were particularly interested in the stereoselective synthe-
sis of β-heteroaryl R-substituted-β-amino acid derivatives.
Several asymmetric synthetic methods for the preparation
of R,β-disubstituted β-amino acid derivatives are known in
the literature; for example, ArndtÀEistert homologation
through asymmetric Wolff rearrangement on the R-alkyl-
R-diazoketone leads to moderate to good diastereose-
lectivities.5 Davies6 and Hawkins7 independently reported
an asymmetric method relying on the Michael addition of
chiral amines to β-substituted acrylate derivatives followed
by diastereoselective alkylation. Ring opening of R,β-di-
substituted β-lactams with predefined stereochemistry
provides an alternative approach.8 Of particular relevance
to us is the pseudoephedrine acetamide based enolate addition
to prochiral imines from Badıa9 and the seminal work from
Ellman10 and Davis11 employing a diastereoselective enolate
addition to chiral N-sulfinyl imines. These two approaches
(1) (a) Barrett, G. C., Ed. Chemistry and Biochemistry of the Amino
Acids; Chapman and Hall: London, 1985. (b) Hecht, S. M. Acc. Chem. Res.
1986, 19, 383. (c) Morita, H.; Nagashima, S.; Takeya, K.; Itokava, H.
Chem. Pharm. Bull. 1993, 41, 992.
(2) (a) Kiers, D.; Moffat, D.; Tomanek, R. J. Chem. Soc., Perkin
Trans. 1 1991, 1041. (b) Mayachim, N.; Shibasaki, M. J. Org. Chem.
1990, 55, 1975. (c) Kim, S.; Lee, P. H.; Lee, T. A. J. Chem. Soc., Chem.
Commun. 1988, 1242. (d) Tanner, D.; Somfai, P. Tetrahedron 1988, 44,
613. (e) Kunieda, T.; Nagamatsu, T.; Kiguchi, T.; Hirobe, M. Tetra-
hedron Lett. 1988, 29, 2203.
(5) Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts,
E. Org. Lett. 2000, 2, 2177–2179.
(6) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.
Tetrahedron: Asymmetry 2012, 23, 1111À1153 and references cited therein.
(7) Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1994, 59, 649–652.
(8) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Synlett
2001, 12, 1813–1826.
(9) Vicario, J. L.; Badia, D.; Carrillo, L. Org. Lett. 2001, 3, 773.
(10) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819.
(3) Spatola, A. F. In Chemistry and Biochemistry of Amino Acids,
Peptides and Proteins; Weinstein, B., Ed.; Marcel Dekker: New York, 1983;
Vol. 7, pp 331À333 and references cited therein.
(4) (a) Enantioselective Synthesis of β-Amino Acids; Juaristi, E., Ed.;
Wiley-VCH: New York, 1997. (b) Cardillo, G.; Tomasini, C. Chem. Soc.
Rev. 1996, 117. (c) Cole, D. C. Tetrahedron 1994, 50, 9517.
r
10.1021/ol3033785
Published on Web 01/23/2013
2013 American Chemical Society

represent a direct and convergent method to construct a CÀC
bond with good to excellent diastereoselectivities. Among all
the approaches, it was noticed that β-substituents were gen-
erally limited to alkyl and phenyl groups, and incorporation
of nitrogen-containing 2-heteroaryl groups such as 2-pyridyl
to the adducts was very rare.12
Table 1. Optimization of the Enolate Addition Reactionsa
We initiated our investigation following Ellman’s enolate
addition10 of simple achiral esters to the 2-benzimidazolyl
tert-butyl sulfinimine (R)-1r. Surprisingly, low diastereo-
selectivity (dr <2:1) was observed even in the presence of
3 equiv of ClTi(OiPr)3 (entry 1, Table 1). Screening of
different esters gave similarly low diastereoselectivities
(entries 2À5). The enolate of 2d, albeit locked in the
Z-geometry, did not improve the dr. The observed reversal
of facial selectivity from that expected by the chairlike
transition state proposed by Ellman10 and others9,11 sug-
gests that the presence of an R-heteroatom disrupts such
transition states. Such disruption could come from compe-
titive chelation from the R-heteroatom. This chelation
effect has been seen in the reversal of stereoselectivity in
the Grignard addition to 2-pyridyl13 and R-alkoxy14 tert-
butyl sulfinimines. In our case, it seemed clear that in order
to achieve a higherdr, extra stereocontrolling elements were
required. We envisioned a second chiral auxiliary from the
enolate may enable stereocontrol for the R-center and thus
improve the dr. Gratifyingly, a combination of (S)-1r and
Evans’ auxiliary15 (S)-2e improved the dr to 6:1 (entries 8
and 9). As a comparison, the prochiral p-tosylimine 1x and
(S)-2e (entry 6) gave a lower dr (1:1).16 This indicated that
the stereoselectivity could be modulated by double asym-
metric induction.17 At this stage, we tested out the more
sterically demanding Davies’ SuperQuat18 (S)-2f which
has shown certain advantages over Evans’ auxiliary. Even
in the mismatched case (entry 10), the dr was improved to
10:1 compared to the matched case use of Evans’ auxiliary.
A matched combination between (R)-1rand (S)-2f (entry 11)
dramatically enhanced the dr to 99:1. Notably in both cases,
the stereochemical outcome for the major diastereomers
(3r and 3y, Scheme 1) was equal as proven by the fact that
removal of the sulfinyl group led to the identical product 4
yield
(%)
entry
imine
enolate
base/additive
drd
1
(R)-1r
(R)-1r
(R)-1r
(R)-1r
(R)-1r
1x
2a
LDA/ClTi(OiPr)3
LDA
1.9:1
1.5:1
1.6:1
1.3:1
1.2:1
1:1
75b
79b
88b
62b
85b
77b
69b
37c
56c
76c
89c
2
2a
3
2b
NaHMDS
LDA
4
2c
5
2d
LDA
6
(S)-2e
(S)-2e
(S)-2e
(S)-2e
(S)-2f
(S)-2f
LDA
7
(R)-1r
(S)-1r
(S)-1r
(S)-1r
(R)-1r
LDA
2:1
8
LDA
6:1
9
LDA/LiCl
NaHMDS
NaHMDS
6:1
10
11
10:1
99:1
a All reactions run with 2 equiv of esters/amides in THF at À78 °C for
1À3 h. b Combined isolated yield for the mixture of diastereomers.
c Isolated yield for the major diastereomer. d Diastereomeric ratio was
determined by 1H NMR analysis of the crude reaction mixture and/or
by HPLC.
Scheme 1. Deprotection
(11) (a) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413. (b) Davis,
F. A.; Theddu, N. J. Org. Chem. 2010, 75, 3814.
(12) (a) Grigg, R.; Blacker, J.; Kilner, C.; McCaffrey, S.; Savic, V.;
Sridharan, V. Tetrahedron 2008, 64, 8177. (b) Wang, Y.; He, Q.-F.;
Wang, H.-W.; Zhou, X.; Huang, Z.-Y.; Qin, Y. J. Org. Chem. 2006, 71,
1588.
(13) Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng, C.; Bock,
M. G. Tetrahedron Lett. 2004, 45, 6641–6643.
(14) (a) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051–2054. (b) Evans,
J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948. (c) Davis, F. A.;
McCoull, W. J. Org. Chem. 1999, 64, 3396–3397.
(15) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757.
(16) For chiral enolate addition to prochiral aryl or alkyl imines, see: (a)
Ma, Z.;Zhao, Y.;Nan, J.;Jin, X.;Wang, J. Tetrahedron Lett. 2002, 43, 3209–
3212. (b) Pilli, R. A.; Alves, C.; de, F.; Bockelmann, M. A.; Mascarrenhas,
Y. P.; Nery, J. G.; Vencato, I. Tetrahedron Lett. 1999, 40, 2891.
(17) Masamme, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1–30.
(Scheme 1). This illustrated that the SuperQuat is the major
controlling element in the addition process.19 Furthermore,
the matched pairing of Evans’ auxiliary (S)-2e and Super-
Quat (S)-2f to the opposite enantiomer (S)-1r and (R)-1r
(18) (a) Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry 1995,
6, 671–674. (b) Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J.
J. Chem. Soc., Perkin Trans. 1 1999, 387. (c) Bull, S. D.; Davies, S. G.;
Garner, A. C.; Kruchinin, D.; Key, M.-S.; Roberts, P. M.; Savory, E. D.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2006, 4, 2945.
(19) For similar cases, see: (a) Guerrini, A.; Varchi, G.; Daniele, R.;
Samori, C.; Battaglia, A. Tetrahedron 2007, 63, 7949–7969. (b) Davies,
S. G.; Nicholson, R. L.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 3385–
3400.
Org. Lett., Vol. 15, No. 3, 2013
563

Table 2. Substrate Scope of the SuperQuat Enolate Addition to the Heterocyclic N-tert-Butanesulfinyl Aldiminesa,b
a All reactions run at 0.2 M in THF at 0.3 mmol scale. b If not specified, yields refer to the major diastereomer isolated over silica gel. Diastereomeric
ratio was determined by 1H NMR analysis of the crude reaction mixture and/or by HPLC. c Combined isolated yields of diastereomers.
suggests that the Evans and SuperQuat enolates proceed
through a different favored transition state.19a
groups at the 6-position of the pyridine ring (1b vs 1c)
significantly affect the electron density of the nitrogen,21
both substrates gave excellent dr’s and good yields. For
the 5-substituted pyridines, less electron-withdrawing
groups (1d vs 1e) provided slightly improved dr’s and
yields. For the 3-substituted pyridines (1hÀ1j), the in-
creased size of the substituent degraded both the diaster-
eoselectivity and the yield. The small F group substituent
did, however, give acceptable results. Similarly, the electron-
rich poor pyridine substrate (1g) may partly result from the
steric effect with the fused bulky saturated ring. For the
pyrimidines, both 2- and 4-pyrimidinyl substrates (1m and
1n) afforded excellent dr and yields. Compared with 1g, the
2-pyrimidine counterpart (1m) provided decent results
probably benefiting from a double R-heteroatom effect
(i.e., less steric interactions and/or increased reactivity).
Quinolines, pyridazines, and pyrazines all furnished ad-
ducts with excellent dr’s and good to excellent yields in the
absence of ortho-substituents. Remarkably, 8-quinolinyl
sulfinimine 1l also provided high stereoselectivity due to
the properly oriented β-nitrogen. For the five-membered
heterocycles, two R-heteroatoms are required to achieve
good dr’s and yields. As shown in Table 2, 1s, 1v, and
1w have proven to be good substrates due to a double
The success of the addition to the first substrate (R)-1r
prompted an investigation into the breadth of this reac-
tion. Further optimization revealed that bases (LDA,
LiHMDS, and NaHMDS) did not have a noticeable effect
on the dr and yields, suggesting that the potential for
chelation control of the reaction was diminished. A slight
excess of the SuperQuat (1.2 equiv) was sufficient to drive
the reaction to completion within 3 h at À78 °C. Notably,
the presence of the R-heteroatom of the aromatic was
crucial for achieving excellent dr’s and yields. For example,
while the addition to the 2-pyridyl substrates provided
satisfactory results, the 3-pyridyl counterpart resulted in a
low dr (3:1) and yield (41%). Similarly, the SuperQuat
enolate addition to phenyl and 4-nitrophenyl tert-butyl
sulfinimines gave poor dr’s (<2:1) and yields (<40%).20
It was gratifying to find that the conditions discovered
for the high syn-selective enolate addition reaction trans-
lated into the successful addition to a range of five- and six-
membered heterocycles. The substrate scope is highlighted
in Table 2. For the six-membered heterocycles, pyridines,
quinolines, pyrazines, pyridazines, and pyrimidines were
investigated. Although the electron-donating and -withdrawing
(20) The possible chairlike transition state involving the SuperQuat
Z-enolate is sterically unfavorable. See model D in Figure 2.
(21) Katritzky, A. R.; Pozharski, A. F. Handbook of Heterocyclic
Chemistry, 2nd ed.; Pergamon/Elsevier: 2000; p 178.
564
Org. Lett., Vol. 15, No. 3, 2013

R-heteroatom effect, whereas 1t and 1u were less successful
in terms of both dr’s and yields. This suggests that subtle
changes in the steric19a or electronic22 component around
the sulfinimine disrupt the optimal orientation, thus
diminishing the selectivity.
The X-ray crystal structure of the addition product 3p
confirmed the absolute configuration of the adduct and
allowed correlation of the syn-stereochemistry of the re-
lated products (Figure 1).
R-heteroatom lone pair is important in giving selectivity.
Model C suffers from the steric repulsion between the
heteroaryl and the SuperQuat. The chairlike model D is
ruled out because it is sterically encumbered and it also leads
to the anti products. Model E explains the mismatched case
when (S)-N-tert-butanesulfinyl imine is applied.
With a general method for the stereoselective generation
of adducts 3aÀ3w in hand, attention was turned toward
synthesizing β-amino acid derivatives. Owing to the intrinsic
benefits offered by the SuperQuat,23 facile alcoholysis and
aminolysis occurred predominantly in the exocyclic mode
without losing stereochemical integrity. Treatment of 4 and
3s with a 2 N solution of NH3 in MeOH cleanly afforded
β-amino methyl ester 5 and 6 after 4 h at rt (Scheme 2).
Similarly, β-amino amide 7 was generated slowly with
saturated NH3(g) in DMF. Of further note, the N-tert-
butanesulfinyl group and the SuperQuat can be orthogon-
ally removed, which allows the adducts 3aÀ3w to be
versatile building blocks for peptide syntheses.
Figure 1. X-ray structure of the pyrazine adduct 3p.
Scheme 2. Derivatizations of the Adducts
In summary, an efficient double chiral auxiliary approach
was developed to access β-heteroaryl syn-R-methyl-β-amino
acid derivatives. The enolate addition was tentatively pro-
posed to proceed through an open chain transition state.
The current work will enhance options for the asymmetric
synthesis of β-amino acids. Future work will involve
examining the scope of R-substituents and epimerizing the
R-center to access anti-β-amino acid derivatives and will be
reported in due course.
Figure 2. Proposed models.
The absolute stereochemistry could be rationalized by
model A in Figure 2. The chelation between the two N’s and
the chelation among the three O’s stabilized the conforma-
tion to minimize the interaction between the bulky tert-
butyl group and the benzyl group, thus reinforcing the
stereoselectivity. However, it is hard to explain how chela-
tion could be the controlling element with sodium as the
counterion. It may therefore be that the chelation between
the two N’s is unnecessary and high stereoselectivity simply
resulted from an open chain model B. The increased
diastereoselectivity that the R-heteroatom brings may be
due to the diminished steric impact from removal of an
R CÀH. An electronic component to the effect cannot
be discounted, and it may be that a repulsion of the
Acknowledgment. We thank Alan D. Brown for his
advice and support of our research. We also thank Brian
Samas for X-ray crystallography determination.
Supporting Information Available. Experimental pro-
cedures, compound characterization data, NMR spectra,
and crystallographic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(22) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303.
(23) Davies, S. G.; Sanganee, H. J.; Szolcsanyi, P. Tetrahedron 1999,
55, 3337.
The authors declare no competing financial interest.
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