Asymmetric synthesis of syn-α-substituted β-amino ketones by using sulfinimines and prochiral weinreb amide enolates

Article abstract of DOI:10.1021/ol0708166

syn-α-Substituted β-amino Weinreb amides are new chiral building blocks for asymmetric synthesis of syn-α-substituted β-amino acids, aldehydes, and ketones and are prepared by addition of prochiral lithium enolates of Weinreb amides to sulfinimines (N-sul

Full text of DOI:10.1021/ol0708166

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2413-2416
Asymmetric Synthesis of
syn- -Substituted -Amino Ketones by
Using Sulfinimines and Prochiral
Weinreb Amide Enolates
r
â
Franklin A. Davis* and Minsoo Song
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received April 5, 2007
ABSTRACT
syn-r-Substituted â-amino Weinreb amides are new chiral building blocks for asymmetric synthesis of syn-r-substituted â-amino acids,
aldehydes, and ketones and are prepared by addition of prochiral lithium enolates of Weinreb amides to sulfinimines (N-sulfinyl imines).
â-Amino aldehydes and ketones are important chiral building
blocks for the asymmetric synthesis of nitrogen-containing
biologically active molecules.1,2 For example, they have been
employed in the synthesis of â-amino acids3 and 1,3-amino
alcohols.4-6 They undergo Wittig-type condensations3,4,7 to
give homoallylic amines which were employed in the
asymmetric synthesis of (-)-197B, a trans-2,5-disubstituted
pyrrolidine.8 The intramolecular Mannich cyclization of
â-amino ketones with aldehydes is a particularly useful
protocol for the asymmetric synthesis of stereodefined ring
functionalized piperidines,9 indolizidines,10 and other alka-
loids.11 However, there are few methods reported for the
synthesis of enantiopure â-amino aldehydes and ketones, and
most of these are of limited scope.12 We recently disclosed
a general procedure for the asymmetric synthesis of â-amino
aldehydes and ketones via the addition of organometallic
reagents to N-sulfinyl â-amino Weinreb amides.13 The
(9) For leading references see: Davis, F. A.; Santhanaraman, M. J. Org.
Chem. 2006, 71, 4222.
(10) (a) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011. (b) Davis, F.
A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398. (c) Reference 9e.
(11) (a) Schultz, A. G.; Dai, M. Tetrahedron Lett. 1999, 40, 645. (b)
Chan, C.; Zheng, S.; Zhou, B.; Guo, J.; Heid, R. M.; Wright, B. J. D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2006, 45, 1749.
(12) Asymmetric syntheses of â-amino aldehydes and ketones: (a)
Reduction of â-amino esters, or nitriles, see ref 5 of this article and: Davis,
F. A.; Szewczyk, J. M. Tetrahedron Lett. 1998, 39, 5951. (b) Addition of
methyl ketone enolates to sulfinimines, see ref 10a. (c) Oxidation of γ-amino
alcohols, see: Davies, S. B.; McKervey, M. A. Tetrahedron Lett. 1999,
40, 1229. (d) Arndt-Eistert reaction: (i) Rodriguez, M.; Aumelas, A.;
Martinez, J. Tetrahedron Lett. 1990, 31, 5153. (ii) Rodriguez, M.; Heitz,
A.; Martinez, J. Tetrahedron Lett. 1990, 31, 7319. (iii) Limal, D.; Quesnel,
A.; Briand, J.-P. Tetrahedron Lett. 1998, 39, 4239. (e) Hydrolysis of 1,3-
oxazines, see: Gizecki, P.; Dhal, R.; Toupet, L.; Dujardin, G. Org. Lett.
2000, 2, 585. (f) Rearrangement of 2,3-aziridinio alcohols, see: Wang, B.
M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Shi, Y. Org. Lett. 2002, 4, 363.
(13) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.;
Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184.
(1) (a) Tramontini, M. Synthesis 1973, 703. (b) Tramontini, M.; Angiolini,
L. Tetrahedron 1990, 46, 1791. (c) Kleinman, E. F. In ComprehensiVe
Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press: Oxford, UK,
1991; Vol. 2, Chapter 4, p 893.
(2) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044.
(3) For recent reviews on the asymmetric synthesis of â-amino acids
see: (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (b) Cole, D. C.
Tetrahedron 1994, 50, 9517.
(4) For a review see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58,
5957.
(5) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 2911.
(6) Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5,
925.
(7) For leading references see: Ishimaru, K.; Kojima, T. J. Org. Chem.
2000, 65, 8395.
(8) Davis, F. A.; Song, M.; Augustine, A. J. Org. Chem. 2006, 71, 2779.
10.1021/ol0708166 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/11/2007

Weinreb amides were prepared in good to excellent yields
and high de values by addition of the potassium enolate of
N-methoxy-N-methylacetamide to sulfinimines (N-sulfinyl
imines) or reaction of lithium N,O-dimethylhydroxylamine
with N-sulfinyl â-amino esters.13
Scheme 2
Methods for the asymmetric synthesis of R-substituted
â-amino ketones that are required for the synthesis of
architecturally complex piperidine alkaloids via the Mannich
cyclization protocol are limited. Several racemic syntheses
of R-substituted â-amino ketones14 and a number of asym-
metric syntheses of R-substituted â-amino esters have been
reported.15 To the best of our knowledge, the only asym-
metric synthesis of an R-substituted â-amino ketone is our
highly diastereoselective addition of the E-lithium enolate
of 4-heptanone 2 to sulfinimine (S)-(+)-1.10b A 12:1 separable
mixture of â-amino ketones syn-3 and anit-4 was obtained
(Scheme 1). A limitation of this procedure is that the ketone
the addition of prochiral enolate and carbanion species to
sulfinimines18 exist where the formation of four diastereo-
isomers is possible.19 The chemistry of prochiral Weinreb
amide enolates has not been described.20,21
The prochiral Weinreb amide enolate of N-methoxy-N-
methylpropylamide (8) was generated at -78 °C by addition
of 1 equiv of the appropriate base at -78 °C (Scheme 2).
After 2 h 0.5 equiv of sulfinimine (S)-4 (Z ) 4-MePh) was
added to the preformed enolate and TLC monitored the
progress for completion (typically 30 min). Products were
isolated by chromatography and are recorded in Table 1.
These results reveal that good levels of stereoinduction were
observed for formation of the syn-R-methyl â-amino Weinreb
amides, syn-9 and syn-10, regardless of the base (Table 1,
entries 1-4 and 6). Optimum results were noted for LiHMDS
in THF (Table 1, entries 1 and 6). However, all four
diastereoisomers were detected and they were not separable
by conventional chromatography. This phenomenon has
occasionally been observed for the addition of carbanion
species to sulfinimines and can usually be overcome by
changing the N-sulfinyl group.22 Diverse N-sulfinyl imines
Scheme 1
needs to be symmetrical. A more general way of preparing
R-substituted â-amino ketones would be the reaction of
organometallic reagents with a sulfinimine-derived R-sub-
stituted â-amino Weinreb amide. We describe here a study
of the asymmetric synthesis of R-substituted â-amino Wein-
reb amides and their conversion into R-substituted â-amino
acids, aldehydes, and unsymmetrical R-substituted â-amino
ketones.
(17) For reviews on Weinreb amides see: (a) Sibi, M. P. Org. Prep.
Proced. Int. 1993, 25, 15. (b) Khlestkin, V. K.; Mazhukin, D. G. Current
Org. Chem. 2003, 7, 967.
(18) For recent reviews on the chemistry of sulfinimines see: (a) Morton,
D.; Stockman, R. A. Tetrahedron 2006, 62, 8869. (b) Senanayake, C. H.;
Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichim. Acta 2005,
38, 93. (c) Reference 9. (d) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc.
Chem. Res. 2002, 35, 984.
(19) (a) Garcia Ruano, J. L.; Fernandez, I.; Del Prado Catalina, M.;
Hermoso, J. A.; Sanz-Aparicio, J.; Martinez-Ripoll, M. J. Org. Chem. 1998,
63, 7157. (b) Garcia Ruano, J. L.; Alcudia, A.; Del Prado, M.; Barros, D.;
Maestro, M. C.; Fernandez, I. J. Org. Chem. 2000, 65, 2856. (c) Tang, T.
P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819. (d) Garcia Ruano, J. L.;
Aleman, J.; Del Prado, M.; Fernandez, I. J. Org. Chem. 2004, 69, 4454.
(e) Davis, F. A.; Deng, J. Org. Lett. 2004, 6, 2789. (f) Davis, F. A.; Deng,
J. Org. Lett. 2005, 7, 621. (g) Reference 10b. (h) Wang, Y.; He, Q.-F.;
Wang, H.-W.; Zhou, X,; Huang, Z.-Y.; Qin, Y. J. Org. Chem. 2006, 71,
1588. (i) Davis, F. A.; Zhang, Y.; Qui, H. Org. Lett. 2007, 9, 833.
(20) The aldol reaction with R-isocyano Weinreb amide has been
reported. Sawamura, M.; Nakayama, Y.; Kato, T.; Ito, Y. J. Org. Chem.
1995, 60, 1727.
(21) For reports of aldol reactions with isoxazolidines chiral auxiliaries
see: (a) Abiko, A.; Liu, J. F.; Wang, G. Q.; Masamune, S. Tetrahedron
Lett. 1997, 38, 3261. (b) Farr, R. N. Tetrahedron Lett. 1998, 39, 195. (c)
Sharma, G. V. M.; Reddy, I. S.; Reddy, V. G.; Rao, A. V. R. Tetrahedron:
Asymmetry 1999, 10, 229.
(22) (a) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem.
2000, 65, 8704. (b) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67,
1290. (c) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J.
Org. Chem. 2003, 68, 2410. (d) Davis, F. A.; Melamed, J. Y.; Sharik, S. S.
J. Org. Chem. 2006, 71, 8761.
Conceptually the most direct way for preparing R-substi-
tuted â-amino Weinreb amides is the addition of a prochiral
Weinreb amide enolate to a sulfinimine (Scheme 2). Weinreb
amides, introduced by Nahm and Weinreb in 1981,16 are
valuable carbonyl equivalents and are widely used for the
synthesis of carbonyl compounds.17 Only a few studies on
(14) (a) Loh, T.-P.; Wei, L.-L Tetrahedron Lett. 1998, 39, 323. (b) Zarghi,
A.; Naimi-Jamal, M. R.; Webb, S. A.; Balalaie, S.; Saidi, M. R.; Ipaktschi,
J. Eur. J. Org. Chem. 1998, 197. (c) Kobayashi, S.; Busujima, T.; Nagayama,
S. Synlett 1999, 545. (d) Loh, T.-P.; Liung, S. B. K. W.; Tan, K.-L.; Wei,
L.-L. Tetrahedron 2000, 56, 3227. (e) Miura, K.; Tamaki, K.; Nakagawa,
T.; Hosomi, A. Angew. Chem., Int. Ed. 2000, 39, 1958. (f) Schunk, S.;
Enders, D. Org. Lett. 2001, 3, 3177. (g) Wabnitz, T. C.; Spencer, J. B.
Tetrahedron Lett. 2002, 43, 3891. (h) Ma, Z.; Zhao, Y.; Jiang, N.; Jin, X.;
Wang, J. Tetrahedron Lett. 2002, 43, 3209.
(15) For reviews see: (a) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102.
(b) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005,
16, 2833. (c) Reference 3a.
(16) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
2414
Org. Lett., Vol. 9, No. 12, 2007

Scheme 3
Table 1. Synthesis of R-Substituted â-Amino Weinreb Amides
at -78 °C
% yieldb
(dr syn:anti)c
entry
Z
R
basea
solvent
1
2
4a Ph LiHMDS THF
99 (87:13:<1:trace)
LiHMDS THF:Et2O (1:1) 35 (93:7:trace)
3
4
5
NaHMDS THF
Et2O
KHMDS THF
67 (91:6:3:0)
99 (73:17:9:1)
NR
6
7
4b Et LiHMDS THF
67 (75:11:10:4)
NR
5
Ph LiHMDS THF
8
9
10
6a Ph LiHMDS THF
6b Et LiHMDS THF
7a Ph LiHMDS THF
99 (96:4:0:0)
72 (80:17:3:0)
74 (92:5:3:0)
[syn-13, 68%]d
95 (4:1:0:0)
[syn-14,76%],
[anti-14,19%]d
11
7b Et LiHMDS THF
a Ratio of base to 8. b Combined yield of diastereoisomers that were not
1
separable unless otherwise noted. c Determined by H NMR on the crude
reaction mixture. d Isolated yields.
can be prepared with use of the N-sulfonyl-1,2,3-oxathia-
zolidine-2-oxide chiral auxiliary introduced by Senanayake
and co-workers.23 These workers also reported that for
the addition of Grignards to sulfinimines the stereo-
induction improves as the steric size of the N-sulfinyl moiety
increases.23b
conversion to products of known stereochemistry as outlined
in Scheme 3. Selective removal of the N-sulfinyl groups in
(+)-13 and (+)-14 gave amines (-)-15a and (+)-15b in
excellent yield, which when treated with TsCl/Et3N gave the
corresponding N-tosyl â-amino Weinreb amides (+)-16a and
(+)-16b in 68% and 76% isolated yields, respectively.
Hydrolysis of (+)-16a with aqueous KOH gave the known
acid (2R,3R)-(+)-17 in 99% yield.25 When (+)-16b was
subjected to DIBAL-H reduction, aldehyde (-)-18 was
obtained in 71% yield and reduction of the aldehyde with
Super hydride gave the known 1,3-amino alcohol (2R,3S)-
(-)-19 in quantitative yield.23 Both amino acid (+)-17 and
amino alcohol (-)-19 have properties identical with those
of authentic samples. These results establish that the major
diastereoisomer formed in the addition of the prochiral
lithium enolate of 8 to sulfinimines has the syn stereochem-
istry. Importantly these R-substituted â-amino Weinreb
amides exhibit high configuration stability under the chemical
transformations shown in Scheme 3.
The stereochemistry of the minor product isolated in the
addition of the enolate of 8 to (S)-7b is shown to be anti as
shown in Scheme 4. Weinreb amide (SS,2S,3S)-(+)-14 was
converted to the N-tosyl derivative (-)-20, which was
hydrolyzed to the â-amino acid (-)-21. Treatment of the
acid with DCC/cat. 4-pyrrolidinopyridine afforded the â-lac-
tam (-)-22 in 67% yield. The proton J3.4 coupling constant
in (-)-22 of 6.4 Hz is suggestive of a cis-relationship for
these protons.26 However, the large NOE (4.5%) for the C-3
proton and C-4 methyl group indicates that they have the
expected anti-relationship.
To improve the separation of the diastereoisomers and to
explore the effect of the sulfinimine N-sulfinyl moiety on
the stereoselectivity, the prochiral enolate of 8 was added to
sulfinimines (S)-5, (S)-6, and (S)-7 where the N-sulfinyl
group was tert-butyl (TB), 2,4,6-mesityl (TMP), and 2,4,6-
triisopropylphenyl (TIPP), respectively. These sulfinimines
were prepared by condensation of the corresponding enan-
tiopure sulfinamides (Z-S(O)NH2)23 with the appropriate
aldehydes, using Ti(OEt)4 as previously described.24
Unexpectedly, addition of the lithium enolate of 8 to
N-tert-butanesulfinyl imine (S)-5 resulted in no reaction and
recovery of starting material (Table 1, entry 7). The reason
for this result may be related to the larger size of the tert-
butyl moiety that inhibits addition of the bulky amide enolate.
Both the less bulky N-(2,4,6-mesitylsulfinyl) and the N-(2,4,6-
triisopropylphenylsulfinyl) imines, (S)-6 and (S)-7, gave
results similar to those of (S)-4 with the syn-isomers
predominating (Table 1, entries 8-11). Importantly, both the
N-(2,4,6-triisopropylphenylsulfinyl)amides, syn-13 and syn-
14, could be isolated in 68% and 76% yield, respectively
(Table 1, entries 10 and 11). The minor anti-14 isomer was
obtained in 19% yield (Table 1, entry 11).
The absolute configurations of the R-substituted â-amino
Weinreb amides (+)-13 and (+)-14 were determined by
(23) (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Su, X.;
Wilkinson, H. S.; Lu, Z.-H.; Magiera, D.; Senanayake, C. H. Tetrahedron
2005, 61, 6386. (b) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.;
Pflum, D. A.; Senanayake, C. H. Tetrahedron Lett. 2003, 44, 4195.
(24) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
(25) Davis, F. A.; Reddy, G. V.; Liang, C.-H. Tetrahedron Lett. 1997,
38, 5139.
(26) Abrahams, I.; Motevalli, M.; Robinson, A. J.; Wyatt, P. B.
Tetrahedron 1994, 50, 12755.
Org. Lett., Vol. 9, No. 12, 2007
2415

rationalized as involving addition of the E-enolate species
to the sulfinimine via the usual six-membered chairlike
transition states. A similar transition state TS-1 explains the
formation of the major syn product observed in the addition
of lithium Weinreb amide enolates to sulfinimines (Figure
1). However, lithium enolates of amides are known to have
Scheme 4
Figure 1. Transition state for enolate addition.
Reaction of 5 equiv of n-butyl and phenylmagnesium
chloride with (SS,2R,3S)-(+)-14 gave the corresponding
unsymmetrical R-methyl â-amino ketones (+)-23a and (+)-
23b in 83% and 72% yields, respectively (Scheme 5).
the Z-geometry, because A1,3 interactions are thought to be
lower than in the E-form.28 This dichotomy is not easily
explained and attempts to determine the geometry of the
lithium enolate of 8 have failed. Perhaps because a Weinreb
amide enolate is likely to exist in an intramolecular chelated
form, the A1,3 interactions in E-26 are not as important as
they would be in a nonchelated amide.29
Scheme 5
In summary, of four possible diastereoisomers the syn-R-
substituted â-amino Weinreb amide is the major product
observed in the addition of lithium prochiral Weinreb amide
enolates to sulfinimines. These new sulfinimine-derived
chiral building blocks are important precursors of syn-R-
substituted â-amino acids, aldehydes, and ketones on hy-
drolysis, reduction, and reaction with Grignard reagents,
respectively.
Acknowledgment. We thank Dr. Rodrigo Andrade
(Temple University) and Dr. Chris Senanayake (Boehringer
Ingelheim) for helpful discussions and for providing the (+)-
and (-)-1-amino-2-indanol and (-)-4-methyl-5-phenyl-3-
tosyl-1,2,3-oxathiazolidine-2-oxide auxiliaries. We also thank
Dr. Charles DeBrosse, Director of Temple NMR facilities,
for aid with the NOE experiments. This work was supported
by NIGMS (GM 51982 and 57870) and Boehringer Ingel-
heim Pharmaceuticals, Inc.
R-Ethyl â-amino ketone syn-(+)-3 was obtained in 93% yield
by treating (+)-25 with n-propylmagnesium chloride. This
Weinreb amide was prepared by reaction of the lithium
enolate of N-methoxy-N-methylbutrylamide with sulfinimine
(S)-(+)-1 and isolated in 52% yield from the diastereomeric
mixture of isomers.
Addition of the prochiral enolates of esters,19c glycine
esters,19e,f R-bromoesters,27 ketones,10b and O-Boc-R-hydroxy
esters19h to sulfinimines gives syn-2,3-disubstituted â-amino
carbonyl derivatives as the major product. These results are
Supporting Information Available: Experimental details
1
and H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0708166
(28) (a) Evans, D. A.; McGee, L. R. Tetrahedron Lett. 1980, 21, 3975.
(b) Murphy, P. J.; Procter, G.; Russell, A. T. Tetrahedron Lett. 1987, 28,
2037.
(27) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y.
J. Org. Chem. 1999, 64, 7559.
(29) Qu, B.; Collum, D. B. J. Org. Chem. 2006, 71, 7117.
2416
Org. Lett., Vol. 9, No. 12, 2007