δ-Amino β-keto Esters, a designed polyfunctionalized chiral building block for alkaloid synthesis. Asymmetric synthesis of (R)-(+)-2-phenylpiperidine and (-)-SS20846A

Article abstract of DOI:10.1021/ol005580j

δ-Amino β-keto esters 3 and 11 are designed polyfunctionalized chiral building blocks for alkaloid synthesis and are prepared in one step from the corresponding sulfinimine (N-sulfinyl imine). Concise highly enantioselective four-step syntheses of 2-phenylpiperidine (7) and SS20846A (14) from 3 and 11, respectively, are described.

Full text of DOI:10.1021/ol005580j

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1041-1043
δ-Amino â-Keto Esters, a Designed
Polyfunctionalized Chiral Building Block
for Alkaloid Synthesis. Asymmetric
Synthesis of (R)-(+)-2-Phenylpiperidine
and (−)-SS20846A
Franklin A. Davis,* Bin Chao, Tianan Fang, and Joanna M. Szewczyk
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@astro.ocis.temple.edu
Received January 24, 2000
ABSTRACT
δ-Amino â-keto esters 3 and 11 are designed polyfunctionalized chiral building blocks for alkaloid synthesis and are prepared in one step
from the corresponding sulfinimine (N-sulfinyl imine). Concise highly enantioselective four-step syntheses of 2-phenylpiperidine (7) and SS20846A
(14) from 3 and 11, respectively, are described.
Polyfuctionalized chiral building blocks, which we define
as molecules having at least one stereogenic center and more
than one chemically differentiated functional group, have
played significant roles in asymmetric synthesis and the
synthesis of biologically and pharmacologically active
molecules.1 Examples include carbohydrates, amino acids,
hydroxy acids, and terpenes.1a Since they are derived from
the “chiral pool”, they usually require extensive manipulation
and protecting group chemistry to transform them into the
desired target. Furthermore, access to both enantiomers is
usually limited. More recently, designed polyfunctionalized
chiral building blocks (DPFCB’s) have been developed to
overcome these limitations. DPFCB’s are generally easily
prepared in both enantiomeric forms and require a minimum
of manipulation and protecting group chemistry because they
are designed for a specific purpose. Examples include
Johnson’s enones,2 Ojima’s â-lactams,3 Meyers’ bicyclic
lactams,4 and sulfinimines (N-sulfinyl imines).5 In this regard,
the piperidine ring system, found in many alkaloids,6
combined with the challenge of devising efficient strategies
for the synthesis of polysubstituted examples has resulted
in Comins’ 1-acylpyridinium salts7 and Husson’s R-cya-
nomethyloxazolidines.8 As part of a program aimed at the
design and synthesis of polyfunctionalized chiral building
blocks, we introduce N-sulfinyl δ-amino â-keto esters for
(4) Meyers, A. I.; Brengel, G. P. J. Chem. Soc., Chem. Commun. 1997,
1.
(5) For reviews on sulfinimines, see: (a) Zhou, P.; Chen, B.-C.; Davis,
F. A. In AdVances in Sulfur Chemistry; Rayner, C. M., Ed.; JAL Press
Inc.: 2000; Vol. 2, pp 249-282. (b) Hua, D. H.; Chen, Y.; Millward, G.
S. Sulfur Rep. 1999, 21, 211. (c) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem.
Soc. ReV. 1998, 27, 13.
(6) For reviews on the synthesis of substitute piperidines, see: (a) Bailey,
P. D.; Millwood, P. A. Smith, P. D. J. Chem. Soc., Chem. Commun. 1998,
633. (b) Leclercq, S.; Daloze, D.; Braekman, J.-C. Org. Prep. Procd. Int.
1996, 28, 499. (c) Wang, C.-L. J.; Wuonola, M. A. Org. Prep. Procd. Int.
1992, 28, 585.
(1) (a) Hanessian, S. Total Synthesis of Natural Products: the ′Chiron′
Approach; Pergamon: Oxford 1983. (b) Banfi, L.; Guanti, G. Synthesis
1993, 1029.
(2) (a) Johnson, C. R. Acc. Chem. Res. 1998, 31, 333. (b) Murphy, S.
T.; Bencsik, J. R.; Johnson, C. R. Org. Lett. 1999, 1, 1483.
(3) Ojima, I. Acc. Chem. Res. 1995, 28, 383.
(7) Comins, D. L.; Joseph, S. P. In AdVances in Nitrogen Heterocycles;
Moody, C. J., Ed.; JAL Press Inc.: 1996; Vol. 2, pp 251-294.
(8) Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28, 383.
10.1021/ol005580j CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

the asymmetric synthesis of alkaloids.9 The utility of these
new building blocks is illustrated in concise four-step
enantioselective syntheses of (R)-(+)-2-phenylpiperidine (7)
and (-)-SS20846A (14).
To illustrate the utility of (+)-3, (R)-(+)-2-phenylpiperi-
dine (7) was prepared in four steps from (SS,R)-(+)-3
(Scheme 2). Removal of the N-sulfinyl in 3 with 5 equiv of
Earlier we reported that (S)-(+)-N-benzylidene-p-toluene-
sulfinamide (1) reacts with the sodium enolate of methyl
acetate in ether at -78 °C to give N-sulfinyl â-phenylalanine
2 in 84% yield and >97% de (Scheme 1).10 Subsequent
Scheme 2
Scheme 1
TFA in MeOH/CH2Cl2 gave the amine (not shown), which
was passed through a short pad of silica gel to remove methyl
p-toluenesulfinate, prior to reaction with saturated NaHCO3
in CH2Cl2 to give (R)-(+)-6-phenylpiperidine-2,4-dione (4)
as a solid in 90% yield.11 Dione 4 was treated with 10 equiv
of ethanedithiol and 2.5 equiv of BF3‚OEt2 at rt in CH2Cl2
for 8 h to give the thioketal (R)-(+)-5, which was isolated
in 85% yield by chromatography. Next, (+)-5 was subjected
to W2 Raney nickel desulfurization in EtOH to give (R)-
(+)-6-phenylpiperidin-2-one (6) in 75% isolated yield.
Reduction with LAH at rt for 8 h gave an 82% yield of the
volatile (R)-(+)-6-phenylpiperidine (7), which was purified
by chromatography.12 The enantiomeric purity was deter-
treatment of 2 with 4 equiv of the sodium enolate of methyl
acetate, prepared from NaHMDS and methyl acetate, affords
(SS,R)-(+)-methyl 3-oxo-N-(p-toluenesulfinyl)-5-amino-5-
phenylpentanoate (3) in 93% yield following flash chroma-
tography. The de was >97%. About 10-15% of â-keto ester
3 exists as the enol form in solution. Significantly, (+)-3
can be prepared in one step, in 89% yield, by treating the
sulfinimine 1 with 5 equiv of the enolate generated from 5
equiv of methyl acetate and 6 equiv of NaHMDS. The de
was the same, i.e., >97%. Although the one-step method is
more concise, the two-step procedure could be advantageous
if the initial enolate addition was not highly diastereoselec-
tive. In this case, up-grading the diastereomeric purity of
the â-amino ester could be performed prior to formation of
the δ-amino â-keto ester.
mined to be >98% ee by comparison of its rotation, [R]20
D
50.0 (c 0.31, CH2Cl2), with literature values, [R]23 48.4 (c
D
0.31, CH2Cl2), for 98% ee.12b
2-Substituted-4-piperidones represent an important class
of building blocks for the synthesis of substituted piperidine
derivatives13 and other biologically active materials.14 In this
context the application of δ-amino â-keto esters to the
synthesis of these chiral building blocks was demonstrated
in the asymmetric synthesis of (-)-(2S,4S)-SS20846 A (14).
SS20846 A (14) was isolated from Steptomyces sp. S2084615
and is a proposed intermediate in the biosynthesis of the
potent antimicrobial agent streptazolin.16 It is also reported
(9) For references to δ-amino â-keto esters, see: (a) Li, B.; Franck, R.
W. Bioorg. Med. Chem. Lett. 1999, 9, 2629. (b) Werner, R. M.; Shokek,
O. Davis, J. T. J. Org. Chem. 1997, 62, 8243.
(10) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995,
60, 7037.
(15) Komoto, T.; Yano, K.; Ono, J.; Okawa, J.; Nakajima, T. Jpn. Kokai
35788(20/02/1986); Chem. Abstr. 1986, 105, 132137w.
(16) (a) Mayer, M.; Thiericke, R. J. Org. Chem. 1993, 58, 3486. (b)
Grabley, S.; Hammann, P.; Kluge, H.; Wink, J.; Kricke, P.; Zeeck, A. J.
Antibiot. 1991, 44, 797.
(17) Davis, F. A.; Zhang, Y. Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1043.
(11) For a racemic synthesis of 4, see: Ashton, M. J.; Hills, S. J.; Newton,
C. G.; Taylor, J. B.; Tondu, S. C. D. Heterocycles 1989, 28, 1015.
(12) For earlier asymmetric syntheses of 7, see: (a) Davis, F. A.;
Szewczyk, J. M. Tetrahedron Lett. 1998, 39, 5951. (b) Willoughby, C. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8952. (c) Deziel, R.;
Malenfant, E. J. J. Org. Chem. 1995, 60, 4660.
(13) See, for example: (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine
Structure, Preparation, ReactiVity and Synthetic Applications of Piperidine
and its DeriVatiVes; Elsevier: Amsterdam, 1991. (b) Rubiralta, M.; Diez,
A.; Vila, C.; Troin, Y.; Feliz, M. J. Org. Chem. 1991, 56, 6292. (c) Comins,
D. L.; LaMunyon, D. H. J. Org. Chem. 1992, 57, 5807. (d) Diez, A.; Mavel,
S.; Teulade, J. C.; Chavignon, O.; Sinibaldi, M. E.; Troin, Y.; Rubiralta,
M. Heterocycles 1993, 36, 2451.
(18) For leading references to sulfinimines (N-sulfinyl imines) chemistry,
see: Davis, F. A.; Andemichael, Y. W. J. Org. Chem. 1999, 64, 8627.
1
(19) The cis alkene isomer was not detected by H NMR.
(20) Kathawala, F. G.; Prager, B.; Prasad, K.; Repic, O.; Shapiro, M. J.;
Stabler, R. S.; Widler, L. HelV. Chim. Acta 1986, 69, 803.
(21) For earlier syntheses of 14, see: (a) Ripoche, I.; Canet, J.-L.; Aboab,
B.; Gelas, J.; Troin, Y. J. Chem. Soc., Perkin Trans. 1 1998, 3485. (b)
Yokoyama, H.; Otaya, K.; Yamaguchi, S.; Hirai, Y. Tetrahedron Lett. 1998,
39, 5971. (c) Takemoto, Y.; Ueda, S.; Takeuchi, J.; Baba, Y.; Iwata, C.
Chem. Pharm. Bull. 1997, 45, 1906. (d) Takemoto, Y.; Ueda, S.; Takeuchi,
J.; Nakamoto, T.; Iwata, C. Tetrahedron Lett. 1994, 35, 8821.
(14) For leading references, see: Kudzma, L. V.; Severnak, S. A.;
Benvenga, M. J.; Ezell, E. F.; Ossipov, M. H.; Knight, V. V.; Rudo, F. G.;
Spencer, H. K.; Spaulding, T. C. J. Med. Chem. 1989, 32, 2534.
1042
Org. Lett., Vol. 2, No. 8, 2000

to have a restrictive action on the digestive system.15,16b
Condensation of (R)-(-)-p-toluenesulfinamide (8) with sorbic
aldehyde in the presence of 5 equiv of Ti(OEt)4, as previously
described,17,18 gave a 95% yield of sulfinimine (R)-(-)-9
(Scheme 3). Since this aldehyde contained about 10% of the
step, impure 9 was condensed with the sodium enolate of
methyl acetate to give â-amino acid (RS,S)-(-)-10 in 87%
yield and >97% de. With 4 equiv of the enolate, (-)-10
gave δ-amino â-keto ester (RS,S)-(-)-11 in 81% isolated
yield.19 The one-step procedure, starting from sulfinimine
(R)-(+)-9, afforded (-)-11 in 81%. To obtained the correct
epimer of 14, it was necessary to reduce the 3-oxo group
with syn selectivity, achieved using metal chelation control.20
The best ratio (76:24, syn:anti) was obtained with Zn(BH4)2
at -78 °C in THF, affording the desired syn isomer
(RS,3R,5S)-12 in 61% isolated yield following chromatog-
raphy. Other reducing agents such as NaBH4, LAH, and
L-Selectride either failed to react or gave nearly equal
amounts of the alcohols. Removal of the N-sulfinyl group
and cyclization, as before, gave the trans 4-hydroxy-2-
piperidone 13 in 94% yield. Reduction with LAH afforded
(2S,4S)-(-)-SS20646A-(14) in 71% yield.21 The enantio-
meric purity was >97% as determined by comparison with
literature values.21
Scheme 3
In summary, the one-step asymmetric sulfinimine-mediated
synthesis of δ-amino â-keto esters, a designed polyfunc-
tionalized chiral building block (DPFCB) for alkaloid
synthesis, is reported. The utility of this building block was
illustrated in four-step asymmetric syntheses of piperidines
(R)-(+)-7 and (2S,4S)-(-)-14. These procedures, which
required no protecting group chemistry, represent some of
the most concise enantioselective preparations of these
alkaloids reported to date.12,21,22
Acknowledgment. This work was supported by the
National Institutes of Health (GM51982). We thank Professor
David Dalton, Temple University, for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1-13. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL005580J
(22) Selected properties: (SS,R)-(+)-3, colorless oil; [R]20D 73.60 (c 1.63,
CHCl3); (R)-(+)-4, mp 166-168 °C [lit.5 mp 167-169 °C for (()-4]; [R]20
D
124.3 (c 0.37, CHCl3); (R)-5, colorless oil; [R]20 61.9 (c 0.42, CHCl3);
D
(R)-(+)-6, mp 119-120 °C.; [R]20 72.8 (c 1.2, CHCl3); (R)-(-)-9, mp
cis isomer, it resulted in 10% of the cis sulfinimine being
formed. Crystallization from hexanes reduced the cis isomer
to about 4%. Since it was expected that the cis isomer would
be eliminated in subsequent steps, borne out in the second
D
89-90 °C.; [R]20D -1009 (c 1.2, CHCl3); (RS,S)-(-)-10, oil, [R]20D -133.9
(c 1.2, CHCl3); (RS,S)-(-)-11, colorless oil; [R]20 -78.9 (c 1.5, CHCl3);
D
syn-(-)-12, colorless oil; [R]20D -57.7 (c 1.3, CHCl3); trans-(+)-13, white
gum; [R]20D 90.9 (c 1.5, MeOH); (-)-14, oil; [R]20D -15.7 (c 0.51, CHCl3).
Org. Lett., Vol. 2, No. 8, 2000
1043