An asymmetric synthesis of optically pure α,α-disubstituted amino aldehydes, α,α-disubstituted amino acids, and sterically demanding dipeptides

Article abstract of DOI:10.1021/ja9823518

Optically pure α-methyl-α-alkyl amino aldehydes were efficiently synthesized from the cyclohexylimine of propanal bearing an α-4(R),5(S)- diphenyl-2-oxazolidinone by asymmetric alkylation of the imine anion. α- Methylphenylalanine and α-methylleucine were

Full text of DOI:10.1021/ja9823518

12468
J. Am. Chem. Soc. 1998, 120, 12468-12473
An Asymmetric Synthesis of Optically Pure R,R-Disubstituted Amino
Aldehydes, R,R-Disubstituted Amino Acids, and Sterically
Demanding Dipeptides
Steve Wenglowsky and Louis S. Hegedus*
Contribution from the Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
ReceiVed July 6, 1998
Abstract: Optically pure R-methyl-R-alkyl amino aldehydes were efficiently synthesized from the cyclohexyl-
imine of propanal bearing an R-4(R),5(S)-diphenyl-2-oxazolidinone by asymmetric alkylation of the imine
anion. R-Methylphenylalanine and R-methylleucine were synthesized in two steps from the corresponding
amino aldehydes. Utilizing an oxaziridine rearrangement, amino aldehydes were converted to dipeptides in
which both the amino and carboxy components were R,R-disubstituted.
Introduction
Optically active R-amino aldehydes have been used in many
synthetic applications.1 Manipulation of the aldehyde functional
group provides easy access to amino alcohols,1a,b unusual amino
acids,1a amino sugars,1a natural products,1b,c heterocycles,1c
dipeptide isosteres,1a,2 and vicinal 1,2-diamines.3 Optically
active R-amino aldehydes were originally obtained from natu-
rally occurring amino acids, which limited their availability.1a,2a,4
Recently, the number of new chemical syntheses that have
appeared are testimony to the growing interest in these
compounds.5 In most of these syntheses, the chiral center is
generated by nucleophilic addition of an organometallic reagent
to a protected glyoxaldehyde imine, and the process is therefore
limited to the synthesis of monosubstituted R-amino aldehydes.
One exception is a recent report of a synthesis of optically active
R-methyl-R-amino aldehydes that requires 11 steps.6 A shorter,
more practical synthesis would expand the scope of amino
aldehyde chemistry. Herein we report an efficient, five-step
synthesis of optically pure R-methyl-R-alkyl amino aldehydes,
featuring an asymmetric alkylation of R-amino imine 1 (eq 1).
This methodology is applied to the synthesis of R-methyl-R-
amino acids and, via an oxaziridine rearrangement, dipeptides
consisting of two quaternary amino acids.
Results/Discussion
Preparation of r-Amino Imine 1. 2-Oxazolidinones have
been widely used as chiral auxiliaries.7 In particular, 4,5-
diphenyl-2-oxazolidinone has been successfully applied in these
laboratories as the chiral auxiliary in several diastereoselective
processes, including photochemical [2 + 2] cycloadditions of
N-vinyl oxazolidinones with chromium carbene complexes,8
copper-catalyzed conjugate additions of Grignard reagents to
acetamidoacrylates,9 and alkylation of â-lactams that lead to
R-methyl-R-amino acids.10 Thus, the approach to 1 started with
the nucleophilic addition of diphenyl oxazolidinone 3 to allylic
carbamate 4 to provide allylic oxazolidinone 5. Subsequent
ozonolysis and imine formation would lead to 1 (eq 2).
Pd(0)-catalyzed allylic amination was utilized for the synthesis
of 5 since direct nucleophilic displacement of substituted allylic
bromides was unsuccessful. Interestingly, some consideration
of the reaction conditions was necessary to successfully effect
this transformation.11 The standard catalyst, bis(dibenzylide-
(1) Reviews: (a) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989, 89, 149.
(b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531. (c) Sardina,
F. J.; Rapoport, H. Chem. ReV. 1996, 96, 1825.
(2) For examples, see the following. (a) Hydroxyethylamine isostere:
Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61, 3635. (b) Double bond,
epoxide, dimethylene, diol, hydroxy double bond, trihydroxy, hydroxyeth-
ylene, methyleneamino, and methylenehydroxyamino isosteres: Kalten-
bronn, J. S.; Hudspeth, J. P.; Lunney, E. A.; Michniewicz, B. M.; Nicolaides,
E. D.; Repine, J. T.; Roark, W. H.; Stier, M. A.; Tinney, F. J.; Woo, P. K.
W.; Essenburg, A. D. J. Med. Chem. 1990, 33, 838.
(7) (a) For a general review on chiral oxazolidinones in asymmetric
synthesis, see: Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta,
1997, 30, 3. (b) Akiba, T.; Tanura, O.; Terashima, S. Org. Synth. 1997, 75,
45.
(3) Reetz, M. T.; Jaeger, R.; Drewlies, R.; Hu¨bel, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 103.
(8) Hegedus, L. S. Tetrahedron 1997, 53, 4105.
(4) Fehrents, J. A.; Castro, B. Synthesis 1983, 676.
(9) Lander, P. A.; Hegedus, L. S. J. Am. Chem. Soc. 1994, 116, 8126
and references therein.
(5) (a) Enders, D.; Funk, R.; Klatt, M.; Raabe, G.; Hovestreydt, E. R.
Angew. Chem., Int. Ed. Engl. 1993, 32, 418. (b) Denmark, S. E.; Nicaise,
O. Synlett 1993, 359. (c) Muralidharan, K. R.; Mokhallalati, M. K.; Pridgen,
L. N. Tetrahedron Lett. 1994, 35, 7489. (d) Alexakis, A.; Lensen, N.;
Tranchier, J.-P.; Mangeney, P.; Feneau-Dupont, J.; Declercq, J. P. Synthesis
1995, 1038.
(10) Colson, P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918.
(11) To the best of our knowledge, an intermolecular Pd-catalyzed allylic
amination with a carbamate anion nucleophile has not been reported. For
an intramolecular example, see: Tamaru, Y.; Bando, T.; Kawamura, Y.;
Okamura, K.; Yoshida, Z.; Shiro, M.; J. Chem. Soc., Chem. Commun. 1992,
1498.
(6) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379.
10.1021/ja9823518 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/20/1998

Optically Pure R,R-Disubstituted Amino Aldehydes
J. Am. Chem. Soc., Vol. 120, No. 48, 1998 12469
Scheme 1
A method for inhibiting formation of byproduct 3 was
discovered by running a series of low-temperature control
alkylations. It was found that, at -45 °C, alkylation of imine
1 with benzyl bromide was complete within minutes, while the
rate of decomposition to oxazolidinone 3 was very low.
Decomposition to oxazolidinone 3 must be favorable over
alkylation only at higher temperatures. The conditions for
alkylation were thus established as follows: an excess (2.2
equiv) of KHMDS was added to a solution of imine 1 and BnBr
at -78 °C in THF. The reaction was stirred for 15 min, warmed
to -45 °C for 15 min, and quenched with MeOH. Under these
conditions, imine 1 was alkylated with BnBr, accompanied by
e5% of oxazolidinone 3. Subsequent hydrolysis to the aldehyde
was easily accomplished with 1 N HCl(aq)/THF.
Additives had deleterious effects on the alkylation, so
KHMDS generated from KH and HMDS in THF16 was used
as base. By using commercial KHMDS (1.0 M in toluene),
the excess required for alkylation introduced a significant
cosolvent in the reaction. The negative effect of this nonpolar
additive was demonstrated in a control alkylation for which
toluene alone was used as solvent. The major products in this
reaction were urea 6 (∼50%) and oxazolidinone 3 (∼30%).
Alkylation occurred in only minor amounts (∼20% total) and
with little diastereoselectivity. When the polar additive HMPA
was used as cosolvent with THF, a small increase in diaste-
reoselectivity was observed. However, the alkylation was
contaminated with >10% of oxazolidinone 3.
Synthesis of r-Methyl-r-Amino Aldehydes. With a pro-
cedure for alkylating R-amino imine 1 established, a series of
electrophiles was examined to determine the reaction scope
(Table 1). In general, R-methyl-R-amino aldehydes were
synthesized in the highest yields when ozonolysis, amine
condensation, alkylation, and hydrolysis were performed as a
four-step sequence without purification of intermediates. In each
case, the major diastereomer could be isolated by column
chromatography. The diastereoselectivity of alkylation was
good (g9:1), as were the overall yields over four steps (47-
75%). Activated bromides were the most reactive electrophiles
(entries 1-3); only 1 or 2 equiv was necessary for clean
alkylation of 1. Alkyl iodides were also satisfactory electro-
philes (entries 4-6) but were required in an excess (10 equiv)
to inhibit formation of urea 6. Of note was alkylation with the
secondary iodide, 2-iodopropane (entry 5). This bulky elec-
trophile gave the respective amino aldehyde in good yield and
in excellent diastereoselectivity. The main limitation of the
methodology was the requirement that the electrophile be present
upon imine anion formation. Electrophiles that are susceptible
to nucleophilic attack or deprotonation by KHMDS (methoxy-
methyl chloride, iodomethylphthalimide, methyl bromoacetate,
chloroformates) were incompatible with the reaction conditions.
Synthesis of r-Methyl-r-Amino Acids and Proof of the
Stereochemical Course of Alkylation. An obvious application
of R-methyl-R-amino aldehydes 2a-f is the synthesis of
R-methyl-R-amino acids, an important class of nonproteinogenic
amino acids which has remained a synthetic challenge for
years.17 Two of these amino acids, R-methylphenylalanine 96
and R-methylleucine 10,18 were synthesized as an application
of the methodology, as a demonstration of optical purity, and,
neacetone)palladium (Pd(dba)2), was unreactive with either
triphenylphosphine or diphenylphosphinoethane (dppe) as the
added
ligand.
Tetrakis(triphenylphosphine)palladium
(Pd(PPh3)4) was an active catalyst but was limited to conversions
of 50%, even with loadings as high as 10 mol %. The stabilizing
effect of an additional equivalent (to the catalyst) of tri-
phenylphosphine (PPh3) increased the conversion to 83%. The
chelating ligand dppe was most effective in this regard; the
catalyst system of 2.5 mol % Pd(PPh3)4/3.8 mol % dppe
achieved conversions of g95% and provided 5 routinely in 89-
95% yield as a 3:1 mixture of diastereomers on a 5 g (21 mmol)
reaction scale. Purification was easily accomplished by oxi-
dization of the phosphorus ligands with hydrogen peroxide and
filtering the crude material through a plug of silical gel.
Ozonolysis and condensation with cyclohexylamine proceeded
uneventfully in quantitative yield to form R-amino imine 1 as
a stable white solid which turned yellow upon standing. Imine
1 was used in the alkylation studies without further purification.
Alkylation of r-Amino Imine 1. Direct R-alkylation of
aldehydes is problematic because of competing aldol reactions.
Alkylation of their imine derivatives obviates this problem and
has become a well-established prodecure in organic synthesis.12
For the alkylation of imine 1, however, this methodology was
not straightforward. Ultimately, the oxazolidinone at the
R-position became the source of a number of decomposition
products unless the reaction conditions were carefully controlled.
Attempted R-alkylation by generation of the anion of imine
1 with base followed by addition of an electrophile was
unsuccessful. In a control reaction, exposure to KHMDS13 in
the absence of an electrophile converted imine 1 to two products,
urea 6 and oxazolidinone 3,14 in a ∼2:1 ratio (Scheme 1). The
presence of urea 6 implied that the imine anion indeed formed,
that the (Z)-configuration was predominant,15 and that intramo-
lecular attack of the imine anion nitrogen on the oxazolidinone
carbonyl was rather facile. To inhibit formation of 6, the imine
anion needs to be trapped as formed, requiring the presence of
an electrophile upon deprotonation. In the event, when an
excess of KHMDS was added to a solution of 1 and benzyl
bromide in THF at -78 °C, followed by warming to room
temperature, alkylation occurred smoothly, accompanied by only
a trace amount of urea 6. However, decompostition of imine 1
to oxazolidinone 3 was still a competitive process. Under the
reaction conditions, oxazolidinone 3 was benzylated, and this
decomposition product was formed in a ∼1:1 ratio to the desired
alkylation product (eq 3).
(12) For a review, see: Whitesell, J. K.; Whitesell, M. A. Synthesis 1983,
517.
(13) A number of bases were screened, including LDA, LiHMDS,
LiTMP, KH, and KOtBu. KHMDS was most effective in completely
converting imine 1 without degradation.
(14) It has not been determined exactly how imine 1 decomposes to
oxazolidinone 3 in the presence of a strong base.
(15) Unbranched aldehyde and ketone imines are reported to favor (E)-
isomer formation upon kinetic deprotonation: Knorr, R.; Low, P J. Am.
Chem. Soc. 1980, 102, 3241. However, the R-branched heteroatom
substituent of imine 1 will likely alter the (E)/(Z) selectivity.
(16) Brown, C. A. J. Org. Chem. 1974, 39, 3913.

12470 J. Am. Chem. Soc., Vol. 120, No. 48, 1998
Wenglowsky and Hegedus
Table 1. Diastereoselective Synthesis of Aldehydes 2a-f from
Allylic Oxazolidinone 5
Gas chromatographic analysis of their Mosher amide deriva-
tives indicated that amino acids 9 and 10 were optically pure
within the limits of detection. The stereochemistry and optical
purity of amino aldehydes 2a and 2f were thus established and
inferred for the rest of amino aldehydes 2.
Synthesis of Sterically Demanding Dipeptides via a Pho-
tolytic Oxaziridine Rearrangement. Imines can be converted
to substituted amides by oxidation to an oxaziridine followed
by thermal or photochemical rearrangement20 (eq 5). This
methodology has been used to form the peptide bond of
aspartame, for which the imine was synthesized from phenyl-
alanine methyl ester and the R-amino aldehyde of aspartic acid
protected as the â-lactam.21 The availability of R,R-disubstituted
amino aldehydes could extend this methodology to the synthesis
of sterically demanding dipeptides. Of particular interest was
the synthesis of dipeptides for which both the amino and carboxy
coupling components were R,R-disubstituted, compounds dif-
ficult to synthesize by standard peptide coupling methods.22
Condensation of amino aldehydes 2a and 2f with benzyl
2-aminoisobutyrate in benzene at reflux cleanly formed imines
11 and 12 (eq 6). The crude imines were oxidized with mCPBA
a Diastereoselectivity measured by gas chromatography. b Isolated
yield of major diastereomer in four steps from 3. c Diastereoselectivity
1
measured by H NMR integration.
Figure 1. Proposed conformation.
by comparison of the sign of optical rotations to the literature
values, as a proof of the stereochemical course of alkylation.
Oxidation of amino aldehydes 2a and 2d to amino acid
derivatives 7 and 8 with buffered sodium chlorite and depro-
tection by catalytic hydrogenolysis with Pearlman’s catalyst
provided the amino acids R-methylphenylalanine 9 and R-me-
thylleucine 10 in good overall yield (eq 4). A comparison of
to a ∼1:1 mixture of diastereomeric oxaziridines 13 and 14,
which were used directly in the photolytic rearrangement. As
shown in eq 5, either substituent on the ring carbon may migrate
to nitrogen. Both theoretical studies23 and mechanistic evi-
dence24 indicate that the substituent anti to the nitrogen lone
pair rearranges selectively.25 As the oxidation products of trans
imines 11 and 12, substituted oxaziridines 13 and 14 are
presumed to be trans substituted as well. Hydrogen should,
therefore, be anti to the nitrogen lone pair and migrate
selectively. Unfortunately, the photolytic oxaziridine rearrange-
ment produced these protected dipeptides 15 and 16 in poor
yields (35 and 37% overall). Numerous byproducts were
detected that, upon preliminary examination, seemed to be
formed by migration of the syn alkyl group followed by
decomposition. Rearrangement under thermal conditions led
to even greater decomposition. A detailed examination of the
the signs of rotation for amino acids 9 and 10 with those from
the literature indicated that the new stereocenter generated by
the alkylation was (R) when 4(R),5(S)-diphenyl-2-oxazolidinone
was used as chiral auxiliary. From this fact, and the observation
that the imine anion is in the (Z)-configuration (Scheme 1), a
model can be proposed to explain the stereochemistry of
alkylation. With no strong counterion to bind the imine nitrogen
to the oxazolidinone carbonyl,19 the oxazolidinone ring may
adopt a conformation to minimize dipole interaction (Figure 1).
In this conformation, the bulky phenyl substituents on the
oxazolidinone ring will block the si face of the imine anion
double bond, resulting in alkylation on the opposite, or re, face.
(20) Aube´, J. Chem. Soc. ReV. 1997, 26, 269.
(21) Duhamel, P.; Goument, B.; Plaquevent, J.-C. Tetrahedron. Lett.
1987, 28, 2595.
(22) Humphrey, J. M.; Chamberlin, A. R. Chem. ReV. 1997, 97, 2243.
(23) Oliveros, E.; Rivie`re, M.; Malrieu, J. P.; Teichteil, C. J. Am. Chem.
Soc. 1979, 101, 318.
(24) Lattes, A.; Oliveros, E.; Rivie`re, M.; Belzecki, C.; Mostowicz, D.;
Abramskj, W.; Piccinni-Leopardi, C.; Germain, G.; Van Meerssche, M. J.
Am. Chem. Soc. 1982, 104, 3929.
(17) (a) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Baldwin, J. E., Magnus, P. D., Eds.; Organic Shemistry Series 7; Pergamon
Press: Oxford, 1989. (b) Heimgartner, H. Angew. Chem., Int. Ed. Engl.
1991, 30, 238. (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (d) Myers,
A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997,
119, 656. (e) Wirth, T. Angew. Chem. Int. Ed. Engl. 1997, 36, 225.
(18) Kruizinga, W. H.; Bolster, J.; Kellogg, R. M. J. Org. Chem. 1988,
53, 1826.
(19) This chelation model was invoked to explain the selectivity of
Grignard addition in ref 9.
(25) The barrier to inversion of an oxazirine is g30 kcal/mol. See ref
23.

Optically Pure R,R-Disubstituted Amino Aldehydes
J. Am. Chem. Soc., Vol. 120, No. 48, 1998 12471
rotary evaporation to yield a diastereomeric mixture of imines as a
white solid which was used immediately for alkylation.
oxaziridine rearrangement on this type of system is in progress
and will be reported in due course.
General Procedure for the Preparation of r-Amino Aldehydes.
To a solution of amino imine 1 and 1.1-10.0 equiv of alkyl halide in
THF at -78 °C was added 2.8 equiv of 1.10 M KHMDS/THF dropwise
over 1 min. The reaction was stirred for 15 min, warmed to -45 °C
(Dry Ice/CH3CN), and stirred for another 15 min, quenched with 5
equiv of MeOH, and warmed to room temperature. EtOAc was added,
and the solution was washed with H2O (3×) and brine (1×) and dried
over Na2SO4. Removal of the solvent by rotary evaporation gave the
crude amino imine as a yellow oil. The amino imine was dissolved in
2:1 THF/1 N HCl, and the solution was stirred for 1 h. EtOAc was
added, and the solution was washed with H2O (3×) and brine (1×)
and dried over Na2SO4. Removal of the solvent by rotary evaporation
gave the diastereomeric mixture of amino aldehydes as a yellow oil or
yellow solid. Column or radial chromatography provided the indicated
products as white solids.
Conclusion
An efficient five-step synthesis of optically pure, R-methyl-
R-alkyl amino aldehydes was achieved featuring a diastereo-
selective alkylation of an R-amino imine. The amino aldehydes
served as common precursors in the synthesis of R-methyl-R-
amino acids and dipeptides consisting of two quaternary amino
acids, compounds difficult to synthesize by other methods.
Further studies of R-methyl-R-alkyl amino aldehydes as chiral
synthetic intermediates are underway.
Experimental Section
General Methods. THF was distilled from sodium-benzophenone
ketyl, and CH2Cl2, DMF, t-BuOH, and benzene were distilled from
2a. According to the general procedure, R-amino imine 1 was
prepared from 500 mg (1.63 mmol) of allylic oxazolidinone 5, 1.63
mL of Me2S (1 mL/mmol 5), and 0.21 mL (1.79 mmol) of cyclohexyl-
amine. Imine 1 was alkylated with 0.21 mL (1.79 mmol) of benzyl
bromide in 10.0 mL of THF and 3.60 mL (3.96 mmol) of 1.10 M
KHMDS. The imine was hydrolyzed with 60.0 mL of 2:1 THF/1 N
HCl, and the diastereomeric amino aldehydes were isolated by column
chromatography (SiO2/4:2:1 hexanes/CH2Cl2/Et2O), giving 390 mg
(62%) of the major diastereomeric amino aldehyde 2a and 48.0 mg
(8%) of the minor.
2a: mp 157-159 °C (EtOAc/hexanes); [R]20D +34.3 (c 1, CH2Cl2);
IR (film, cm-1) 1750 (s); 1H NMR δ 9.65 (s, 1H), 7.24-7.26 (m, 3H),
6.92-7.12 (m, 10H), 6.74 (d, J ) 9.0 Hz, 1H), 5.83 (d, J ) 8.4 Hz,
1H), 5.09 (d, J ) 8.4 Hz, 1H), 3.32 (d, J ) 6.0 Hz, 1H), 3.28 (d, J )
6.0 Hz, 1H), 1.30 (s, 3H); 13C NMR δ 198.7, 158.1, 136.3, 134.8, 134.1,
130.9, 128.3, 128.2, 128.1, 127.9, 127.7, 127.4, 127.1, 126.0, 80.6,
66.8, 64.5, 39.9, 19.3. Anal. Calcd for C25H23NO3: C, 77.90; H, 6.01;
N, 3.63. Found: C, 77.83; H, 6.13; N, 3.53. Minor diastereomer: IR
(CH2Cl2, cm-1) 1744 (s); 1H NMR δ 9.84 (s, 1H), 7.42-7.45 (m, 3H),
7.30-7.32 (m, 3H), 7.01-7.04 (m, 7H), 6.85-6.87 (m, 2H), 5.61 (d,
J ) 8.0 Hz, 1H), 4.08 (d, J ) 8.0 Hz, 1H), 3.60 (d, J ) 13.8 Hz, 1H),
3.00 (d, J ) 13.8 Hz, 1H), 0.97 (s, 3H); 13C NMR δ 199.5, 157.9,
136.8, 135.8, 133.5, 130.5, 128.6, 128.4, 128.2, 128.0, 127.9, 127.8,
127.4, 127.0, 126.9, 125.9, 81.0, 65.9, 63.6, 38.5, 19.3.
1
CaH2. 300-MHz H NMR and 75-MHz 13C NMR were recorded in
CDCl3, D2O, or D2O/CD3OD, and chemical shifts are given in ppm
1
relative to Me4Si (0 ppm, H), CDCl3 (77.0 ppm, 13C), and CD3OD
(49.0 ppm, 13C). Photolyses were performed in a Rayonet photochemi-
cal reactor, which was equipped with eight RPR 2537-Å lamps.
Column chromatography was performed with ICN 32-63 nm, 60 Å
silica gel using flash column techniques. Elemental analyses were
performed by M-H-W Laboratories, Phoenix, AZ. All reactions were
performed under an atmosphere of Ar unless otherwise noted.
Preparation of Allylic Oxazolidinone 5. In a 250-mL Airless flask,
402 mg (10.0 mmol) of NaH (60% dispersion in mineral oil) was
washed 2× with hexanes. A 250-mL addition funnel was attached,
and a solution of 4(R),5(S)-2-oxazolidinone 4 (2.00 g, 8.37 mmol) in
60.0 mL of dry DMF was added. The flask was cooled to 0 °C, and
the solution of 4 in DMF was added dropwise to the NaH with stirring.
The apparatus was rinsed with an additional 20.0 mL of DMF, and the
solution was allowed to warm to room temperature and stir for 45 min.
To this mixture were added 150 mg of dppe (0.38 mmol), 290 mg of
Pd(PPh3)4 (0.25 mmol), and 1.50 mL of carbonate 3 (10.0 mmol). After
the mixture was stirred for 12 h, 0.94 mL of 30% H2O2 was added and
stirred for 10 min, and then 30.0 mL of Na2S2O3 was added and stirred
for 10 min. The solution was partitioned between EtOAc and H2O.
The aqueous layer was extracted 1× with EtOAc, and the combined
organics were washed with H2O (3×) and brine (1×) and dried over
Na2SO4. The solvent was removed by rotary evaporation, and the
resulting oil was filtered through a plug of SiO2 with the aid of 4:1
hexanes/EtOAc. The solvent was removed by rotary evaporation,
giving 2.43 g of 5 (95%) as a white solid. Analysis by gas
chromatography revealed a 3:1 mixture of diastereomers, 99% pure:
IR (film, cm-1) 1747 (s); 1H NMR (major diastereomer) δ 7.05-7.07
(m, 6H), 6.97-7.00, (m, 2H), 6.80-6.93 (m, 2H), 5.80 (d, J ) 8.3
Hz, 1H), 5.51-5.67 (m, 2H), 4.98 (d, J ) 8.3 Hz, 1H), 4.40-4.49 (m,
1H), 1.73 (d, J ) 5.1 Hz, 1H), 0.99 (d, J ) 6.9 Hz, 1H) [peaks for
minor diastereomer, 6.80-7.07 (m), 5.13-5.77 (m), 5.02 (d J ) 8.2
Hz), 4.67-4.77 (m), 3.99-4.08 (m), 1.61 (dd, J ) 1.5, 6.8 Hz), 1.43-
1.49 (m), 1.03 (d J ) 7.0 Hz)]; 13C NMR (asterisk denotes minor
diastereomer) δ 157.5, 157.4*, 136.3, 135.5*, 134.8*, 134.6, 130.1*,
129.9, 128.0, 127.9, 127.8, 127.7, 127.6, 125.9, 79.9, 79.4*, 64.1*,
63.1, 52.5*, 51.8, 18.6, 18.4*, 17.6, 17.3*. Anal. Calcd for C20H21-
NO2: C, 78.15; H, 6.89; N, 4.56. Found: C, 78.26; H, 7.00; N, 4.53.
2b. According to the general procedure, R-amino imine 1 was
prepared from 250 mg (0.81 mmol) of allylic oxazolidinone 5, 0.81
mL of Me2S (1 mL/5 mmol), and 0.10 mL (0.89 mmol) of cyclohexyl-
amine. Imine 1 was alkylated with 206 mg (0.89 mmol) of 3,4-
dimethoxybenzyl bromide in 5.00 mL of THF and 1.80 mL (1.98 mmol)
of 1.10 M KHMDS. The imine was hydrolyzed with 30.0 mL of 2:1
THF/1 N HCl, and the diastereomeric amino aldehydes were isolated
by radial chromatography (SiO2, 2 mm plate/2:1:1 hexanes/CH2Cl2/
Et2O), giving 16 mg (5%) of the minor diastereomeric amino aldehyde.
The fractions containing the major amino aldehyde were recrystallized
from toluene to give 170 mg (47%) of 2b: mp 126-128 °C (toluene);
[R]20D +40.7 (c 1, CH2Cl2); IR (film, cm-1) 1745 (s); 1H NMR δ 9.64
(s, 1H), 6.92-7.07 (m, 8H), 6.74-6.78 (m, 3H), 6.61-6.64 (m, 2H),
5.85 (d, J ) 8.1 Hz, 1H), 5.08 (d, J ) 8.1 Hz, 1H), 3.86 (s, 3H), 3.84
(s, 3H), 3.30 (d, J ) 13.1 Hz, 1H), 3.20 (d, J ) 13.1 Hz, 1H), 1.32 (s,
3H); 13C NMR δ 198.8, 158.0, 148.6, 148.1, 136.2, 134.0, 128.1, 127.8,
127.5, 127.3, 125.9, 123.1, 114.0, 110.9, 80.6, 66.8, 64.4, 55.8, 39.5,
19.4. Anal. Calcd for C27H27NO5: C, 72.79; H, 6.11; N, 3.14.
Found: C, 72.63; H, 6.05; N, 3.12. Minor diastereomer: IR (film,
cm-1) 1745 (s); 1H NMR δ 9.86 (s, 1H), 6.81-7.05 (m, 13H), 5.62 (d,
J ) 8.0 Hz, 1H), 4.21 (d, J ) 8.0 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H),
General Procedure for the Preparation of 1. In a round-bottom
flask, a 0.04 M solution of 5 in CH2Cl2 was cooled to -78 °C. Ozone
was bubbled through until a faint blue color persisted. Oxygen was
bubbled through until the blue color disappeared, and Me2S (1.0 mL/
mmol) was added by syringe. The reaction was allowed to warm to
room temperature and was stirred for 4 h. The solution was washed
with H2O (3×) and brine (1×) and dried over Na2SO4. The solvent
was removed by rotary evaporation to yield the aldehyde as a clear
oil. This oil was dissolved in CH2Cl2 (0.16 M solution), and MgSO4
was added followed by cyclohexylamine (1.1 equiv). The solvent was
removed by rotary evaporation to yield a white solid which was filtered
through Celite with the aid of CH2Cl2. The solvent was removed by
3.58 (d, J ) 14.0 Hz, 1H), 2.94 (d, J ) 14.0 Hz, 1H), 0.99 (s, 3H); 13
C
NMR δ 199.8, 158.0, 148.9, 148.4, 136.9, 133.6, 128.4, 128.3, 128.1,
128.0, 127.8, 125.9, 122.6, 113.7, 111.2, 81.0, 66.0, 63.7, 56.0, 38.1,
19.4.
2c. According to the general procedure, R-amino imine 1 was
prepared from 250 mg (0.81 mmol) of allylic oxazolidinone 5, 0.81
mL of Me2S (1 mL/5 mmol), and 0.10 mL (0.89 mmol) of cyclohexyl-
amine. Imine 1 was alkylated with 0.14 mL (0.89 mmol) of allyl
bromide in 5 mL of THF and 1.80 mL (1.98 mmol) of 1.10 M KHMDS.

12472 J. Am. Chem. Soc., Vol. 120, No. 48, 1998
Wenglowsky and Hegedus
The imine was hydrolyzed with 30.0 mL of 2:1 THF/1 N HCl, and the
diastereomeric amino aldehydes were isolated by radial chromatography
(SiO2, 2 mm plate/4:1:1 hexanes/CH2Cl2/Et2O), giving 168 mg (62%)
of the major diastereomeric amino aldehyde 2c and 19 mg (7%) of the
minor.
(m, 3H); 13C NMR δ 198.3, 157.8, 136.5, 133.8, 128.2, 128.1, 127.7,
127.6, 125.7, 80.9, 66.1, 63.0, 33.8, 25.3, 22.6, 18.6, 13.4. Anal. Calcd
for C22H25NO3: C, 75.19; H, 7.17; N, 3.99. Found: C, 74.96; H, 7.03;
1
N, 4.10. Minor diastereomer: IR (CH2Cl2, cm-1) 1747 (s); H NMR
δ 9.67 (s, 1H), 7.06-7.11 (m, 10H), 6.00 (d, J ) 7.6 Hz, 1H), 5.07 (d,
J ) 7.6 Hz, 1H), 1.87-1.97 (m, 1H), 1.71-1.81 (m, 1H), 1.34-1.36
(m, 4H), 1.09 (s, 3H), 0.91-0.95 (m, 3H); 13C NMR δ 199.5, 157.6,
136.1, 133.6, 128.5, 128.3, 127.9, 127.5, 125.8, 81.1, 65.6, 64.0, 34.0,
25.3, 22.9, 18.7, 13.8.
6: IR (CH2Cl2, cm-1) 3323 (m), 1660 (s), 1633 (s); 1H NMR δ 7.12-
7.26 (m, 7H), 6.98-7.01 (m, 2H), 6.91-6.92 (m, 1H), 5.96 (s, 1H),
5.68 (s, 1H), 4.86 (d, J ) 2.4 Hz, 1H), 4.00-4.07 (m, 1H), 1.66-1.97
(m, 8H), 1.81 (s, 3H) 1.48-1.66 (m, 4H), 1.11-1.20 (m, 1H); 13C
NMR δ 152.9, 141.3, 135.8, 128.5, 127.5, 127.3, 127.2, 127.0, 126.3,
118.9, 104.1, 73.9, 66.8, 51.6, 32.4, 32.3, 25.3, 25.1, 10.6; HRMS m/z
377.2221 (M+ + 1) (calcd for C24H28N2O2 377.2229).
2c: mp 127-129 °C (EtOAc/hexanes); IR (CH2Cl2, cm-1) 1749 (s);
1H NMR δ 9.66 (s, 1H), 7.04-7.10 (m, 10H), 6.01 (d, J ) 8.1 Hz,
1H), 5.63 (dddd, J ) 7.2, 7.2, 9.9, 17.1 Hz, 1H), 5.20 (d, J ) 7.8 Hz,
1H), 5.04 (d, J ) 9.9 Hz, 1H), 4.95 (d, J ) 17.1 Hz, 1H), 2.44 (d, J
) 7.2 Hz, 2H), 1.40 (s, 3H); 13C NMR δ 198.3, 157.7, 136.1, 133.8,
131.3, 128.3, 128.2, 127.7, 127.6, 125.8, 119.5, 80.9, 65.5, 63.3, 38.4,
18.8. Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18.
Found: C, 75.38; H, 6.47; N, 4.07. Minor diastereomer: IR (CH2Cl2,
1
cm-1) 1748 (s); H NMR δ 9.75 (s, 1H), 7.00-7.11 (m, 10H), 5.84-
6.01 (m, 1H), 5.93 (d, J ) 7.8 Hz, 1H), 5.31 (d, J ) 9.3 Hz, 1H), 5.30
(d, J ) 18.3 Hz, 1H), 5.03 (d, J ) 7.8 Hz, 1H), 2.86 (dd, J ) 7.8, 14.1
Hz, 1H), 2.55 (dd, J ) 7.2, 14.1 Hz, 1H), 1.05 (s, 3H); 13C NMR δ
199.1, 157.8, 136.5, 133.6, 131.6, 128.4, 128.3, 128.1, 128.0, 127.9,
127.3, 125.9, 120.5, 81.1, 65.4, 63.9, 38.3, 19.0.
11. Benzyl 2-aminoisobutyrate‚HCl (92 mg, 0.4 mmol) was
dissolved in 10% NaHCO3 and extracted with CH2Cl2 (3×). The
solvent was removed by rotary evaporation. The resulting oil and 2a
(96 mg, 0.25 mmol) were dissolved in 6 mL of benzene, 4-Å molecular
seives were added, and the mixture was heated to reflux for 26 h. The
solution was filtered through Celite, and the solvent was removed by
rotary evaporation to give 11 as a clear oil which was used in the next
step without further purification: IR (film, cm-1) 1745 (s), 1729 (s),
2d. According to the general procedure, R-amino imine 1 was
prepared from 1.00 g (3.25 mmol) of allylic oxazolidinone 5, 3.25 mL
of Me2S (1 mL/5 mmol), and 0.41 mL (0.89 mmol) of cyclohexylamine.
Imine 1 was alkylated with 3.74 mL (0.89 mmol) of 1-iodo-2-
methylpropane in 20.0 mL of THF and 1.80 mL (1.98 mmol) of 1.10
M KHMDS. The imine was hydrolyzed with 120 mL of 2:1 THF/1 N
HCl, and the diastereomeric amino aldehydes were isolated by column
chromatography (SiO2/4:1:1 hexanes/CH2Cl2/Et2O), giving 709 mg
(62%) of the major diastereomeric amino aldehyde 2d and 68 mg (6%)
of the minor.
1
1668 (m); H NMR δ 7.61 (s, 1H), 7.24-7.35 (m, 11H), 6.80-7.00
(m, 7H), 6.60 (bs, 2H), 5.49 (d, J ) 8.2 Hz, 1H), 5.13 (s, 1H), 4.70 (d,
J ) 8.2 Hz, 1H), 3.63 (d, J ) 13.4 Hz, 1H), 3.36 (d, J ) 13.4 Hz,
1H), 1.37 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H); 13C NMR δ 173.9, 162.1,
158.1, 137.0, 136.6, 135.9, 134.5, 131.1, 128.5, 128.3, 128.2, 128.1,
128.0, 127.8, 127.6, 127.5, 127.3, 126.7, 126.1, 79.8, 66.6, 65.1, 65.0,
63.5, 41.5, 25.9, 24.9, 23.1.
2d: mp 127-129 °C (Et2O/hexanes); [R]20 -73.6 (c 1, CH2Cl2);
D
1
IR (CH2Cl2, cm-1) 1747 (s); H NMR δ 9.64 (s, 1H), 7.08-7.11 (m,
7H), 7.01-7.03 (m, 3H), 5.94 (d, J ) 7.8 Hz, 1H), 5.14 (d, J ) 7.8
Hz, 1H), 1.53-1.68 (m 3H), 1.44 (s, 3H), 0.86 (d, J ) 6.0 Hz, 3H),
0.70 (d, J ) 6.0 Hz, 3H); 13C NMR δ 198.8, 157.8, 136.5, 133.9, 128.4,
128.3, 127.8, 127.6, 125.9, 81.1, 66.5, 63.5, 43.0, 24.4, 24.2, 23.6, 19.4.
Anal. Calcd for C22H25NO3: C, 75.19; H, 7.17; N, 3.99. Found: C,
74.92; H, 7.20; N, 4.01. Minor diastereomer: IR (CH2Cl2, cm-1) 1746
(s); 1H NMR δ 9.72 (s, 1H), 7.03-7.12 (m, 10H), 5.98 (d, J ) 7.4 Hz,
1H), 5.07 (d, J ) 7.4 Hz, 1H), 1.74-1.91 (m, 3H), 1.11 (s, 3H), 1.02
(d, J ) 6.0 Hz, 1H), 0.98 (d, J ) 6.0 Hz, 1H); 13C NMR δ 199.7,
157.6, 136.1, 133.6, 128.6, 128.4, 128.0, 127.9, 127.8, 125.9, 81.0,
66.0, 64.4, 43.0, 24.8, 24.4, 23.5, 19.3.
12. As described above for 11, 88 mg of 2f (0.25 mmol) gave imine
1
12 as a clear oil: IR (film, cm-1) 1747 (s), 1732 (s), 1668 (m); H
NMR δ 7.61 (s, 1H), 7.33 (s, 5H), 6.94-7.01 (m, 10H). 5.82 (d, J )
7.8 Hz, 1H), 5.14 (s, 2H), 4.97 (d, J ) 7.8 Hz, 1H), 2.05-2.12 (m,
1H), 1.78-1.85 (m, 1H), 1.14 (s, 3H), 1.23-1.41 (m, 4H), 1.36 (s,
3H), 1.20 (s, 3H), 0.82-0.86 (m, 3H); 13C NMR δ 174.0, 162.8, 157.5,
137.1, 135.8, 134.4, 128.4, 128.1, 128.0, 127.8, 127.7, 127.5, 127.4,
125.9, 79.9, 66.4, 64.7, 64.3, 62.7, 35.9, 25.8, 25.6, 24.9, 22.7, 21.8,
13.8.
15. A slurry of m-CPBA (94 mg, ∼0.38 mmol) in 10% NaHCO3
was extracted with CH2Cl2 (3×), and the solvent was removed by rotary
evaporation. The resulting white solid was dissolved in 2.00 mL of
toluene and cooled to -78 °C. To this solution was added a solution
of imine 11 in 2.00 mL of toluene under air. The reaction was stirred
at -78 °C for 30 min and warmed to room temperature for 15 min.
The reaction was washed with 10% Na2S2O3 (1×), NaHCO3 (1×), and
brine (1×) and dried over Na2SO4. The solvent was removed by rotary
evaporation, giving a 1:1 mixture of diastereomeric oxazolidinones 13
as a clear oil. In a quartz tube, this oil was dissolved in 4.00 mL of
benzene and degassed for 45 min by bubbling argon through the
solution. The quartz tube containing the oxaziridine was photolyzed
at 254 nm for 2.5 h. The solvent was removed by rotary evaporation,
and purification by radial chromatography (10:1:1 hexanes/CH2Cl2/
Et2O) gave 50 mg (35%) of 15 as a white solid: mp 157-158 °C;
[R]20D +35.0 (c 1, CH2Cl2); IR (film, cm-1) 3383 (w), 1737 (s), 1667
2e. According to the general procedure, R-amino imine 1 was
prepared from 250 mg (0.81 mmol) of allylic oxazolidinone 5, 0.81
mL of Me2S (1 mL/5 mmol), and 0.10 mL (0.89 mmol) of cyclohexyl-
amine. Imine 1 was alkylated with 0.81 mL (8.13 mmol) of
2-iodopropane in 5.00 mL of THF and 1.80 mL (1.98 mmol) of 1.10
M KHMDS. The imine was hydrolyzed with 30.0 mL of 2:1 THF/1
N HCl, and the diastereomeric amino aldehydes were isolated by radial
chromatography (SiO2, 2 mm plate/4:1:1 hexanes/CH2Cl2/Et2O), giving
132 mg (48%) of the major diastereomeric amino aldehyde 2e: mp
133-140 °C (EtOAc/hexanes); [R]20 -48.8 (c 1, CH2Cl2); IR (film,
D
cm-1) 1743 (s); 1H NMR δ 9.63 (s, 1H), 7.01-7.09 (m, 10H), 5.94 (d,
J ) 8.1 Hz, 1H), 5.10 (d, J ) 8.1 Hz, 1H), 2.68 (m, 1H), 1.34 (s, 3H),
0.97 (d, J ) 6.9 Hz, 3H), 0.84 (d, J ) 6.9 Hz, 3H); 13C NMR δ 199.0,
158.0, 136.3, 134.0, 128.3, 128.1, 127.9, 127.8, 127.7, 125.8, 80.6,
69.5, 64.0, 31.1, 17.6, 17.5, 15.6. Anal. Calcd for C21H23NO3: C,
74.75; H, 6.87; N, 4.15. Found: C, 74.61; H, 6.92; N, 4.15.
1
(m); H NMR δ 7.33-7.38 (m, 5H), 7.21-7.26 (m, 5H), 7.06 (bs,
1H), 7.00-7.04 (m, 3H), 6.78-6.94 (m, 4H), 6.43 (d, J ) 6.0 Hz,
2H), 5.72 (d, J ) 8.3 Hz, 1H), 5.23 (d, J ) 6.6 Hz, 1H), 5.21 (d, J )
8.3 Hz, 1H), 5.19 (d, J ) 6.6 Hz, 1H), 3.90 (d, J ) 13.2 Hz, 1H), 3.20
(d, J ) 13.2 Hz, 1H), 1.62 (s, 3H), 1.61 (s, 3H), 1.20 (s, 3H); 13C
NMR δ 174.3, 172.2, 159.2, 136.8, 135.7, 134.5, 131.1, 128.5, 128.3,
128.1, 127.8, 127.6, 127.5, 127.4, 127.2, 126.9, 126.1, 80.1, 67.2, 65.1,
64.8, 57.0, 41.6, 24.6, 24.4, 22.6. Anal. Calcd for C36H36N2O5: C,
74.98; H, 6.29; N, 4.86. Found: C, 74.87; H, 6.33; N, 4.98.
2f. According to the general procedure, R-amino imine 1 was
prepared from 500 mg (1.63 mmol) allylic oxazolidinone 5, 1.63 mL
Me2S (1 mL/5 mmol), and 0.21 mL (1.79 mmol) cyclohexylamine.
Imine 1 was alkylated with 1.85 mL (1.79 mmol) 1-iodobutane in 10.0
mL THF and 3.60 mL (3.96 mmol) 1.10 M KHMDS. The imine was
hydrolyzed with 60.0 mL of 2:1 THF:1 N HCl and the diastereomeric
amino aldehydes were isolated by column chromatography (SiO2/4:
2:1 hexanes:CH2Cl2:Et2O) giving 369 mg (73%) of the major diaster-
eomeric amino aldehyde 2f and 38 mg (9%) of the minor.
16. As described above for 15, imine 12 was oxidized with 94 mg
(∼0.38 mmol) of m-CPBA to give 14 as a clear oil. Photolysis at 254
nm for 6 h and purification by radial chromatography (SiO2, 2 mm
plate/6:1:1 hexanes/CH2Cl2/Et2O) gave 50 mg (37%) of 16 as a clear
oil: [R]20D -39.2 (c 2.2, CH2Cl2); IR (film, cm-1) 3350 (w), 1739 (s),
2f: mp 116.5-118.5 °C; [R]20 -62.7 (c 1, CH2Cl2); IR (CH2Cl2-
D
CH2Cl2, cm-1) 1749 (s); 1H NMR δ 9.61 (s, 1H), 7.02-7.10 (m, 10H),
5.98 (d, J ) 8.1 Hz, 1H), 5.14 (d, J ) 8.1 Hz, 1H), 1.57-1.72 (m,
1H), 1.40-1.49 (m, 1H), 1.49 (s, 3H), 0.99-1.25 (m, 4H), 0.71-0.76
1
1673 (m); H NMR δ 7.35-7.37 (m, 5H), 7.23 (bs, 1H), 7.04-7.08

Optically Pure R,R-Disubstituted Amino Aldehydes
J. Am. Chem. Soc., Vol. 120, No. 48, 1998 12473
(m, 6H), 6.93-6.96 (m, 4H), 5.76 (d, J ) 7.9 Hz, 1H), 5.24 (d, J )
12.3 Hz, 1H), 5.14 (d, J ) 12.3 Hz, 1H), 5.05 (d, J ) 7.9 Hz, 1H),
1.93-2.09 (m, 2H), 1.59 (s, 3H), 1.58 (s, 3H), 1.34 (s, 3H), 1.08-
1.38 (m, 4H), 0.83 (t, J ) 7.0 Hz, 3H); 13C NMR δ 174.1, 171.7, 158.1,
136.9, 135.7, 134.0, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.6,
127.4, 125.9, 80.4, 67.0, 64.6, 64.3, 56.6, 36.4, 26.3, 25.0, 24.3, 22.9,
21.5, 13.9. Anal. Calcd for C33H38N2O5: C, 73.04; H, 7.06; N, 5.16.
Found: C, 73.10; H, 7.16; N, 4.98.
by the National Institutes of Health shared instrumentation grant
GM49631. Predoctoral fellowships were kindly provided by
the Department of Education and Boehringer-Ingelheim Phar-
maceuticals.
Supporting Information Available: Experimental proce-
dures and compound characterization for compounds 7-10 (3
pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
Acknowledgment. Support for this research by National
Science Foundation Grant CHE-9224489 is gratefully acknowl-
edged. Mass spectra were obtained on instruments supported
JA9823518