The tert-butanesulfinyl group: An ideal chiral directing group and boc- surrogate for the asymmetric synthesis and applications of β-amino acids

Full text of DOI:10.1021/jo9820824

12
J . Org. Chem. 1999, 64, 12-13
Ta ble 1. Solven t a n d Meta l Ion Effects on
Dia ster eofa cia l Selectivity of En ola te Ad d ition s to 2
(R1 ) P h , R2 ) H)
Th e ter t-Bu ta n esu lfin yl Gr ou p : An Id ea l
Ch ir a l Dir ectin g Gr ou p a n d Boc-Su r r oga te
for th e Asym m etr ic Syn th esis a n d
Ap p lica tion s of â-Am in o Acid s
metal enolate (base)
solvent
yielda (%)
drb
Li (LDA)
Li (LDA)
Na (NaHMDS)
Na (NaHMDS)
1 equiv of ClTi(O-i-Pr)3 (LDA)
2 equiv of ClTi(O-i-Pr)3 (LDA)
4 equiv of ClTi(O-i-Pr)3 (LDA)
THF
Et2O
THF
Et2O
THF
THF
THF
76
91
89
78
90
90
90
83:17
67:33
75:25
96:4
87:13
98:2
Tony P. Tang and J onathan A. Ellman*
Department of Chemistry, University of California, Berkeley,
Berkeley, California 94720
99:1
Received October 16, 1998
a
b
Isolated yields of analytically pure material. Diastereoselec-
tivity was determined by HPLC analysis of the corresponding
MTPA derivatives, prepared after sulfinyl cleavage of unpurified
product.
â-Amino acids are components of numerous natural
products and therapeutic agents.1 Recently, oligomers of
â-amino acids have received considerable attention due to
their unique structural properties.2 Although a number of
methods are available for the synthesis of â-substituted
amino acids, highly substituted derivatives are not readily
accessible.1
Sch em e 1
We have recently reported a practical, catalytic enantio-
selective synthesis of the versatile chiral ammonia synthon
tert-butanesulfinamide 1 in two steps and 71-75% overall
yield from tert-butyl disulfide.3 Sulfinamide 1 condenses
readily with aldehydes and ketones to give tert-butane-
sulfinyl imines 2 in high yields.4 Additions of Grignard
reagents or organolithiums to 2 proceed cleanly with high
diastereoselectivities. Acidic methanolysis then provides the
desired R-branched amine-hydrochloride products.5
To effect the synthesis of â-amino acids, we first explored
the effect of different metal enolate species and solvents on
yield and diastereofacial selectivity of the enolate addition
to the tert-butanesulfinyl aldimine derived from benzalde-
hyde. Additions of lithium, sodium, and titanium enolates
of methyl acetate to 2 (R1 ) Ph, R2 ) H) were carried out in
THF or Et2O (Table 1).
The stereoselectivity observed for the lithium and tita-
nium enolate addition is consistent with a proposed Zim-
merman-Traxler-type six-membered transition state TS-1
favoring approach of the enolate from the si-face of 2 (R1 )
Ph, R2 ) H) as shown in Scheme 1.7 The titanium enolate
is prepared by transmetalation of the corresponding lithium
enolate with ClTi(O-i-Pr)3 and is proposed to be in equilib-
rium with the lithium enolate and a lithium-titanium-ate
enolate complex.8 The effect of ClTi(O-i-Pr)3 stoichiometry
on diastereoselectivity was therefore evaluated. An ap-
preciable improvement in diastereoselectivity was observed
upon increasing the ClTi(O-i-Pr)3 stoichiometry from 1 to 2
equiv, but no significant improvement in stereoselectivity
was observed at higher stoichiometries.
Reaction generality was then evaluated by performing
titanium (2 equiv) enolate additions to aryl, branched alkyl,
and unbranched alkyl tert-butanesulfinyl aldimines. All of
the substrates showed high diastereoselectivities and high
yields. Even enolate additions to sulfinyl ketimines (entries
3f and 3g, Table 2) proceeded in high yields and stereo-
selectivities.9
Here, we report that tert-butanesulfinyl imines can also
serve as chiral building blocks for the asymmetric synthesis
of â-amino acids via enolate additions to 2. This method is
extremely general, providing access not only to â-substituted
â-amino acids but also to â,â- and R,â-disubstituted â-amino
acids.5,6 The latter two classes of â-amino acids cannot
readily be prepared using standard Arndt-Eistert R-amino
acid homologations, Michael addition of amines to acrylate
derivatives, or hydrogenation of 3-amino acrylates.1 Fur-
thermore, we demonstrate that the tert-butanesulfinyl moi-
ety serves not only as an imine activating and chiral
directing group but also as a versatile amine protecting
group for subsequent synthetic transformations.
(1) For a review of â-amino acid syntheses see: Cole, D. C. Tetrahedron
1994, 50, 9517-9582. For leading references on catalytic asymmetric
syntheses of â-amino acids see: (a) Kobayashi, S.; Ishitani, H.; Ueno, M. J .
Am. Chem. Soc. 1998, 120, 431-432. (b) Ishitani, H.; Ueno, M.; Kobayashi,
S. Ibid. 1997, 119, 7153-7154.
(2) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180. (b) Seebach,
D.; Matthews, J . L. Chem. Commun. 1997, 2015-2022. (c) Clark, T. D.;
Buehler, L. K.; Ghadiri, M. R. J . Am. Chem. Soc. 1998, 120, 651-656.
(3) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J .; Ellman, J . A. J . Am.
Chem. Soc. 1998, 120, 8011-8019.
We have also preliminarily evaluated the diastereoselec-
tive synthesis of R,â-disubstituted â-amino esters by reaction
of the titanium enolate of methyl propionate with 2 (R1
)
CH3, R2 ) H) to give 92% of the major diastereomer 4
(4) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J . A. J .
Org. Chem., submitted.
(5) For a review of p-toluenesulfinyl imine chemistry, see: Davis, F. A.;
Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13-18.
(6) Acetate enolate additions to p-toluenesulfinyl aldimines have been
explored by others: Davis, F. A.; Reddy, R. E.; Szewczyk, J . M. J . Org. Chem.
1995, 60, 7037-7039; Fujusawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahe-
dron Lett. 1996, 37, 3881-3884.
(7) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J . Org. Chem. 1992, 57, 6387-
6389.
(8) Siegel, C.; Thornton, E. R. J . Am. Chem. Soc. 1989, 111, 5722-5728.
(9) Only the E isomer of sulfinyl ketimines prepared from isopropyl
methyl ketone and acetophenone are observed by 1H NMR.
10.1021/jo9820824 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

Communications
J . Org. Chem., Vol. 64, No. 1, 1999 13
Sch em e 3a
Ta ble 2. Effect of Su lfin yl Im in e Su bstitu tion on Yield
a n d Dia ster eoselectivity
cmpd
R1
R2
yielda (%)
drb
3a
3b
3c
3d
3e
3f
Me
i-Pr
i-Bu
Ph
3-pyridine
i-Pr
Ph
H
H
H
H
H
Me
Me
94
85
80
90
70
85
89
99:1
98:2
98:2
98:2
95:5c
99:1
98:2
3g
a
b
Isolated yields of analytically pure material. Diastereoselec-
tivity was determined by HPLC analysis of the MTPA derivatives,
prepared after sulfinyl cleavage of unpurified product. c Diaste-
reoselectivity was determined by 1H NMR.
Sch em e 2
a
Reaction conditions: (a) LiOH, MeOH, H2O; (b) â-Ala-OEt‚HCl,
DCC, HOBt, CH2Cl2; (c) HCl, EtOH, then 4-cyanophenylisocyanate,
i-Pr2NEt, DMF; (d) HCl, EtOH, then NH4OH, NH4Cl.
reaction conditions (Scheme 3). After filtration through silica
gel, the acid was coupled to â-Ala-OEt using standard
peptide coupling conditions in 85% yield for the two-step
process. The tert-butanesulfinyl group was then cleaved by
brief treatment with HCl/EtOH at room temperature, fol-
lowed by reaction with 4-cyanophenylisocyanate to afford 7
in 92% overall yield. Conversion of the nitrile to an amidine
was accomplished by treatment with HCl/EtOH and then
NH4OH/NH4Cl to afford the literature compound 8 in 65%
yield, which can be converted to 9 by straightforward
saponification.11
In conclusion, we have demonstrated the utility of tert-
butanesulfinyl imines for the asymmetric synthesis of
â-substituted and â,â- and R,â-disubstituted â-amino acids
in high yields and diastereoselectivities. We have further
demonstrated the utility of the tert-butanesulfinyl group as
a versatile amine protecting group that is stable to basic
conditions and amide bond formations but can be cleaved
with stoichiometric acid treatment. The applicablity of
N-tert-butanesulfinyl-â-amino acids to the rapid solid-phase
synthesis of â-amino acid oligomers will be reported in due
course.
(Scheme 2). Cleavage of the tert-butanesulfinyl group fol-
lowed by acylation with benzoyl chloride provides the
benzamide product. Correlation of the spectral properties
1
to literature values for optical rotation and H and 13C NMR
spectra10 confirmed that the reaction proceeded with syn
selectivity, consistent with a Zimmerman-Traxler transition
state.
The tert-butanesulfinyl group not only is an ideal auxiliary
for the synthesis of â-amino esters but also can serve as a
versatile, low molecular weight protecting group that can
be readily removed by treatment with stoichiometric HCl.
To demonstrate the suitability of the tert-butanesulfinyl
group as a Boc-surrogate, we have prepared compound 8,
which constitutes a formal synthesis of 9, investigated by
Monsanto Co. (St. Louis) as a GPIIbIIIa antagonist and
which incorporates â-(3-pyridine)-â-amino acid.11 This â-ami-
no acid is also a key pharmacophore in a number of other
reported GPIIbIIIa antagonists.12
Hydrolysis of 3e cleanly provided acid 5, demonstrating
the stability of the tert-butanesulfinyl group toward basic
Ack n ow led gm en t . This work was supported by the
National Science Foundation, Berlex, and Abbott Labora-
tories.
(10) J uaristi, E.; Escalante, J . J . Org. Chem. 1993, 58, 2282-2285.
(11) Tjoeng, F. S.; Toth, M. V.; McMackins, D. E.; Adams, S. P. U.S.
Patent Number 5,314,902.
(12) For leading references, see: Hutchinson, J . H.; Cook, J . J .; Brashear,
K. M.; Breslin, M. J .; Glass, J . D.; Gould, R. J .; Halczenko, W.; Holahan,
M. A.; Lynch, R. J .; Sitko, G. R.; Stranieri, M. T.; Hartman, G. D. J . Med.
Chem. 1996, 39, 4583-4591.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for compounds 2e and 3-8 (10 pages).
J O9820824