Stereoselective synthesis of quaternary center bearing azetines and their β-amino acid derivatives

Article abstract of DOI:10.1021/jo7018202

(Chemical Equation Presented) We describe here the use of a stable, four-membered azetine heterocycle for the preparation of highly substituted β-amino acid derivatives. Imidazolidinone chiral auxiliaries were found to eliminate a competitive reaction pathway that had been present under previously reported conditions for azetine synthesis. The ephedrine derived imidazolidin-2-one 21 was allowed to react as its chlorotitanium enolate with O-methyl or -benzyl oximes under optimized conditions to gain improved access to azetines at the gram scale. The azetines were further found to undergo alkylation with complete diastereocontrol, affording the creation of a quaternary center. Subsequent ring opening with benzoyl chloride and auxiliary cleavage provided the corresponding β^2,2,3-amino carbonyl derivatives in good yields.

Full text of DOI:10.1021/jo7018202

Stereoselective Synthesis of Quaternary Center Bearing Azetines
and Their â-Amino Acid Derivatives
Christopher J. MacNevin, Rhonda L. Moore, and Dennis C. Liotta*
Department of Chemistry, Emory UniVersity, 1521 Dickey DriVe, Atlanta, Georgia 30322
dliotta@emory.edu
ReceiVed September 4, 2007
We describe here the use of a stable, four-membered azetine heterocycle for the preparation of highly
substituted â-amino acid derivatives. Imidazolidinone chiral auxiliaries were found to eliminate a
competitive reaction pathway that had been present under previously reported conditions for azetine
synthesis. The ephedrine derived imidazolidin-2-one 21 was allowed to react as its chlorotitanium enolate
with O-methyl or -benzyl oximes under optimized conditions to gain improved access to azetines at the
gram scale. The azetines were further found to undergo alkylation with complete diastereocontrol, affording
the creation of a quaternary center. Subsequent ring opening with benzoyl chloride and auxiliary cleavage
provided the corresponding â2,2,3-amino carbonyl derivatives in good yields.
Introduction
secondary structures and may serve as useful tools in facilitating
the design of synthetic biopolymers with novel biological and
catalytic properties.8 While several methodologies are available
for the creation of monosubstituted â-amino acids, either at the
â2 or â3 positions (Figure 1),9 relatively few approaches exist
for preparing geminally disubstituted species,10 as this requires
the synthetically challenging formation of a quaternary center.11
The stereoselective synthesis of â-amino acids has attracted
increased attention in recent years. Compounds containing such
moieties often show potent biological activity and have been
found to exhibit such diverse properties as HIV protease
inhibition,1 angiotensin-converting enzyme inhibition,2 antifun-
gal activity,3 antibiotic activity (both in peptidic form4 and as
precursors to the â-lactam antibiotics5), and cytotoxic activity,
as seen in the potent antitumor agents paclitaxel (Taxol)6 and
docetaxel (Taxotere).7 Also, oligomers of the â-amino acids,
the â-peptides, have been shown to form unusually stable
* Corresponding author. Fax: (404) 712-8679.
(1) Ettmaher, P.; Hubner, M.; Billich, A.; Rosenwirth, B.; Gstach, H.
Bioorg. Med. Chem. Lett. 1994, 4, 2851.
FIGURE 1. Designation of representative amino acids.
(2) Iizuka, K.; Kamijo, T.; Kubota, T.; Akahane, K.; Umeyama, H.; Kiso,
Y. J. Med. Chem. 1988, 31, 701.
(3) Zabriskie, T. M.; Klocke, J. A.; Ireland, C. M.; Marcus, A. H.;
Molinski, T. F.; Faulkner, D. J.; Xu, C.; Clardy, J. C. J. Am. Chem. Soc.
1986, 108, 3123.
(4) Hamada, M.; Takeuchi, T.; Kondo, S.; Ikeda, Y.; Naganawa, H.;
Maeda, K.; Umezawa, H. J. Antibiot. 1970, 23, 170.
(5) For reviews, see: (a) Georg, G. I. The Organic Chemistry of
â-Lactams; VCH: New York, 1993. (b) Page, M. I. The Chemistry of
â-Lactams; Blackie Academic and Professional: London, 1992.
(6) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J. Am. Chem. Soc. 1971, 93, 2325.
Previous work within our laboratory revealed that the reaction
of N-acyl thiazolidinethione enolates with O-alkyl oximes as
(8) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219.
(9) For reviews, see: (a) Juaristi, E. EnantioselectiVe Synthesis of
â-Amino Acids, 2nd ed.; John Wiley and Sons: New York, 2005. (b) Sibi,
M. P.; Liu, M. Tetrahedron 2002, 58, 7991. (c) Seewald, N. Angew. Chem.,
Int. Ed. 2003, 42, 5794.
(10) Seebach, D.; Abele, S. Eur. J. Org. Chem. 2000, 1.
(11) (a) Overman, L. E.; Douglas, C. J. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed.
2001, 40, 4591.
(7) Guenard, D.; Gueritte-Voegelein, F.; Potier, P. Acc. Chem. Res. 1993,
26, 160.
10.1021/jo7018202 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/11/2008
1264
J. Org. Chem. 2008, 73, 1264-1269

Synthesis of Quaternary Center Bearing Azetines
SCHEME 1. Azetine Formation and Hydrolytic Ring
Opening to â2-Amino Carbonyl Derivative
imine equivalents resulted in the formation of a trans-substituted
azetine ring (3, Scheme 1) that can be subsequently opened with
benzoyl chloride to afford the corresponding â-amino carbonyl
derivative (4).12 We believed that an azetine such as 3, with
the auxiliary still intact, had further potential to serve as a useful
template for stereoselective functionalization of its enolate,
thereby creating a quaternary center at what would become the
â2 position of the ring opened, â-amino carbonyl derivative.
FIGURE 2. Competitive reaction pathways leading to the formation
of either azetine (3) or pyrimidinone (5) products.
Results and Discussion
The methodology as envisioned was limited, however, by low
isolable yields at gram scale of the azetine substrates themselves
(Table 1). The azetine was recovered along with a pyrimidinone
side product in up to a 1:1 ratio (5, Figure 2), depending on the
type of auxiliary employed. The pyrimidinone is the result of a
competitive cyclization pathway thought to involve nucleophilic
attack of the transient nitrogen anion to the auxiliary, rather
than acyl, carbonyl (Figure 2). Pyrimidinone formation was also
observed to be increasingly favored with increasing reaction
scale. The origins of this trend are not fully understood, but it
is believed that the heterogeneity of the reaction mixture may
play an important role. We therefore sought to develop a
scaleable method for improved azetine access through an
approach aimed toward elimination of the pyrimidinone reaction
pathway.
Imidazolidin-2-one based chiral auxiliaries are not as widely
used as their oxazolidinone or thiazolidinethione counterparts,
but they have nevertheless been shown to exhibit high selectivity
over a range of asymmetric synthesis applications.13 There are
also distinct advantages present among the imidazolidinones,
including their crystallinity, N bifunctionality,14 and resistance
to nucleophilic ring opening.15 We believed that an auxiliary
such as (S)-5-isopropyl-1-propionyl-imidazolidin-2-one (13,
Scheme 2) could be particularly useful for our desired applica-
tion in that deprotonation of the free N-H would render the
adjacent carbonyl carbon much less electrophilic, thereby
strongly disfavoring formation of the pyrimidinone side product.
Preparation of substrate 13 proved to be challenging due to
difficulties associated with both diamine synthesis and regiose-
lective acylation. Initial access was afforded through the Michael
TABLE 1. Azetine/Pyrimidinone Product Distribution and Yield
Relative to Auxiliary Type
auxiliary: oxime 2:
entry
X
R1
azetine 3 substitution 3 yield % ratio 3/5a
1
2
1a: S
1b: O
Ph
Ph
3a
3b
trans
cis
20-25
20-25
2:1
1:1
a Ratios based on isolated product yields obtained at gram scale.
addition of (S)-4-phenyl-oxazolidin-2-one 6 to 3-methyl-1-
nitrobutene 7, followed by reduction, cyclization, and benzylic
cleavage to the free imidazolidinone 11.16 Di-acylation and
finally regioselective de-acylation with potassium t-butoxide
provided 13 in an overall yield of 21% (six steps). Once in
hand, reaction of 13 with benzaldehyde O-methyl oxime under
our standard azetine forming conditions (4 equiv of TiCl4, (-)-
sparteine, CH2Cl2, 0 °C, 12 h) with an additional equivalent of
base for deprotonation of the free N-H afforded no desired
azetine product. Alteration of reaction variables, including the
use of lithium amide bases, different solvents, and higher
temperatures, did not achieve any measurable improvements.
We next considered the possibility that deprotonation of the
free N-H was not necessary to deactivate the auxiliary carbonyl
toward nucleophilic attack if in fact the resonance delocalization
provided by a substituted nitrogen lone pair, relative to that of
sulfur or oxygen, was sufficiently enhanced. An efficient route
to such auxiliaries was found in the addition of L-valinol 14 to
isocyanates, followed by base promoted cyclization (Scheme
3).17 This method provided the additional benefit of eliminating
the need for regiochemical acylation in the subsequent step.
When the phenyl-substituted auxiliary 17a was allowed to react
with benzaldehyde O-methyl oxime under standard conditions,
no pyrimidinone product was evident in the product mixture.
The major products were instead a combination of cis- and
trans-azetines 18a, separable by conventional chromatography
(12) (a) Ambhaikar, N. B.; Snyder, J. P.; Liotta, D. C. J. Am. Chem.
Soc. 2003, 125, 3690. (b) Ferstl, E. M.; Venkatesan, H.; Ambhaikar, N. B.;
Snyder, J. P.; Liotta, D. C. Synthesis 2002, 14, 2075. (c) Ambhaikar, N.
B.; Herold, M.; Liotta, D. C. Heterocycles 2004, 62, 217. (d) Herold, M.;
Liotta, D. C. Can. J. Chem. 2006, 84, 1696.
(13) (a) Caddick, S.; Parr, N. J.; Pritchard, M. C. Tetrahedron 2001, 57,
6615. (b) For review, see: Roos, Gregory H. P. S. African J. Chem. 1998,
51, 7.
(14) Davies, S. G.; Mortlock, A. A. Tetrahedron Lett. 1991, 32, 4787.
(15) (a) Taguchi, T.; Shibuya, A.; Sasaki, H.; Endo, J.; Morikawa, T.;
Shiro, M. Tetrahedron: Asymmetry 1994, 5, 1423. (b) Drewes, S. E.;
Malissar, G. S.; Roos, G. H. P. Chem. Ber. 1993, 126, 2663.
(16) Lucet, D.; Toupet, L.; Le Gall, T.; Mioskowski, C. J. Org. Chem.
1997, 62, 2682.
(17) (a) Kim, T. H.; Lee, G.-J. Tetrahedron Lett. 2000, 41, 1505. (b)
Kim, T. H; Lee, G.-J. J. Org. Chem. 1999, 64, 2941.
J. Org. Chem, Vol. 73, No. 4, 2008 1265

MacNevin et al.
SCHEME 4. Synthesis of Ephedrine Derived Chiral
SCHEME 2. Synthesis of
(S)-5-Isopropyl-1-propionyl-imidazolidin-2-one Auxiliary (13)
Auxiliary
of preparation, low cost, and the availability of either enanti-
omer.18 The fusion cyclization of (1R,2S)-(-)-ephedrine hy-
drochloride 19 with urea provided solid (4R,5S)-1,5-dimethyl-
4-phenyl-imidazolidin-2-one 20 that could be crystallized in
large quantities and subsequently acylated in high yield (21,
Scheme 4).19 Once again, benzaldehyde O-methyl oxime was
chosen as the test substrate and allowed to react with the acylated
auxiliary under standard azetine reaction conditions. Initial
experiments at the 1 mmol scale returned a 1.6:1 mixture of
cis-/trans-azetines (22a) in 60% total yield. The reaction was
subsequently optimized for both yield and diastereoselectivity
responses using a randomized 3 factor/2 level design evaluating
possible time, temperature, and concentration effects (Figure
3). None of these factors was shown to affect the diastereomeric
and recovered in 61% total yield in a 1:1.7 (cis/trans) diaster-
eomeric ratio.
Several differentially substituted imidazolidinones were then
prepared to investigate the potential effect of the N substituent
on the yield and diastereomeric ratio (Table 2). Urea formation
proceeded rapidly in all cases, generating solid products that
were recrystallized or simply filtered, washed, and carried on
to the next step without additional purification. Cyclization
yields were found to be highly substrate dependent and varied
from a low of 19% for the N-phenyl imidazolidinone 17a to a
high of 90% for the N-benzyl 17b. Only the N-phenyl (17a)
and N-p-tolyl (17e) isocyanate derived auxiliaries were suc-
cessfully carried forward to generate azetines. Total azetine
yields were uniformly improved relative to that obtained from
either the thiazolidinethione or the oxazolidinone auxiliaries.
However, no significant effects on yield or stereoselectivity due
to N substitution were observed among the reactive substrates.
Ephedrine derived imidazolidinone auxiliaries were thought
to provide a number of potential benefits, including their ease
SCHEME 3. Isocyanate Route to Imidazolidin-2-one
Auxiliaries
FIGURE 3. Randomized 3 factor/2 level optimization study results:
response surface plot for total azetine yield.
ratio, but both time and concentration proved to be significant
with respect to overall yield.20 These results translated to an
experimentally manageable concentration of 0.03 M and an
increased reaction time of at least 24 h (Scheme 5). The reaction
mixtures were also now allowed to warm to ambient temperature
after initial oxime addition, thus eliminating the need for
prolonged temperature management.
These conditions were applied at the gram scale across a range
of both enolizable and non-enolizable oximes to afford azetine
products in good yields (Table 3). We were, however, surprised
to find a mixture of cis/trans selectivity among the different
cases. The auxiliary 21 was hydrogenated to afford the more
hindered cyclohexyl derivative, but no appreciable effect on
selectivity was found when it was allowed to react under
otherwise standard azetine reaction conditions. Neither the
choice of O-Me or O-Bn oxime nor the E/Z ratio of the oxime
mixture was shown to have any influence on selectivity. Further
optimization aimed at improving diastereoselectivity remains
an area of active investigation.
TABLE 2. Azetine Yield and Selectivity Data for Variably
Substituted Imidazolidinones
18: total
cis/
entry R-NdCdO
product: yield %
yield % trans 18
1
2
3
4
5
6
Ph
Bn
t-Bu
p-MeOPh
p-Tol
Et
15a: 79 16a: 19 17a: 87 18a: 61
15b: 75 16b: 90 17b: 51 nia
15c: 99b 16c: 38 17c: 41 ni
15d: 90 16d: 60 17d: 40 ni
15e: 99b 16e: 23 17e: 84 18e: 65
1:1.7
1:1.9
15f: 72
16f: 88 17f: 46 ni
(18) Clark, W. M.; Bender, C. J. Org. Chem. 1998, 63, 6732.
(19) Close, W. J. J. Org. Chem. 1950, 15, 1131.
(20) Model F value: 11.71; concentration p ) 0.029 and time p ) 0.01.
a ni ) not isolated. b Product carried forward without recrystallization.
1266 J. Org. Chem., Vol. 73, No. 4, 2008

Synthesis of Quaternary Center Bearing Azetines
TABLE 4. Alkylation of r-Substituted Azetines and Hydrolysis to
â-Amino Acid Derivatives
SCHEME 5. Preparation of O-Methyl and O-Benzyl Oximes
and Their Reaction with 21 under Optimized Conditions
23 yield % diastereomeric
entry
R-X
product (two steps)
ratio
1
2
3
4
5
6
benzyl bromide
iodoethane
iodopropane
iodobutane
allyl iodide
23a
23b
23c
23d
23e
23f
69
63
70
51
71
66
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
1-iodo-2-methylpropane
within a chelated transition state (Figure 4). The developed
alkylation/ring opening conditions were also applied to the trans-
substituted azetine 22a, but the reaction proceeded with only
modest yield and selectivity (28%, diastereomeric ratio 2:1 for
the benzyl bromide adduct). This result may be attributable to
the now mutually opposing phenyl directing groups present
within the hypothesized transition state. Removal of the chiral
auxiliary was demonstrated for compound 23a, from which both
the methyl ester 24 and the acid 25 were obtained in good yield.
TABLE 3. Gram Scale Additions of Oximes to Ephedrine Derived
Auxiliary 21
a Diastereomeric ratios determined from 1H NMR spectra for crude
reaction mixtures.
SCHEME 6. Azetine Alkylation, Hydrolytic Ring Opening,
and Auxiliary Cleavage to Access â2,2,3-Amino Acid
Derivatives
FIGURE 4. Substituent directed approach of electrophile to hypoth-
esized azetine transition state.
In summary, we have found imidazolidin-2-one based chiral
auxiliaries to be effective in eliminating the appearance of the
pyrimidinone side product as encountered under previously
reported conditions for azetine formation. Specific use of the
ephedrine derived imidazolidinone auxiliary 21, in combination
with optimized reaction conditions, resulted in improved ac-
cessibility to the azetine substrates at gram scale. The further
utility of cis-substituted azetine 22a as a substrate for stereo-
selective alkylation demonstrates what we believe to be a
uniquely practical method for the diastereoselective synthesis
of â2,2,3-amino acid derivatives with a potentially wide ranging
scope and application.
It remained to be seen as to whether the imidazolidinone
auxiliary bearing azetines could be successfully functionalized
as originally intended. Initial alkylation experiments using cis-
substituted azetine 22a revealed lithium hexamethyldisilazide
(4 equiv) to be the optimum base for azetine enolate formation.
Reactions were carried out in THF at 0 °C with 1.5-5 equiv of
alkyl halide and quenched with aqueous 1 N HCl after 1 h.
Although the reactions appeared to be nearing completion as
determined by TLC, isolated yields were lower than expected
following chromatographic purification. The crude product from
the alkylation step was therefore carried on to subsequent
hydrolytic ring opening of the azetine without intermediate
purification (Scheme 6). Treatment with excess benzoyl chloride,
followed by aqueous workup, afforded access to a number of
geminally disubstituted â2,2,3-amino carbonyl derivatives in good
yield (Table 4). Analysis of the 1H NMR spectra revealed that
all products were formed as a single diastereomer. The absolute
configuration at the quaternary center of the addition product
23f was determined from its X-ray crystal structure. The
observed stereochemistry was consistent with attack of the
electrophile as directed by the mutually reinforcing orientation
of azetine phenyl and auxiliary phenyl groups assumed to exist
Experimental Section
General Procedure for the Preparation of Oximes. Repre-
sentative example for 2a: methoxylamine hydrochloride (4.09 g,
48.0 mmol, 1.20 equiv) was suspended in 30 mL of absolute
ethanol, and 12.9 mL (160 mmol, 4.00 equiv) of anhydrous pyridine
was added quickly dropwise. A 4.06 mL (40.0 mmol) volume of
benzaldehyde was added, and the reaction was stirred at room
temperature for 4 h. The ethanol was removed to reveal a white
solid and clear liquid that was redissolved in dichloromethane and
extracted with 5% citric acid. The citric acid washes were combined
and extracted with dichloromethane. The organic layers were
combined and washed with brine, dried with MgSO4, filtered, and
concentrated to give a clear oil. The oil was distilled under vacuum
(0.18 mbar, 30-32 °C) to give 4.52 g (84%) of clear oil.
J. Org. Chem, Vol. 73, No. 4, 2008 1267

MacNevin et al.
Benzaldehyde O-Methyl-oxime (2a). Rf ) 0.60 (4:1 hexanes/
amber oil that was loaded neat onto a silica column and eluted
with a 1-10% isopropanol in hexanes gradient. The first main peak
fractions were combined and concentrated to give 0.602 g of white
solid (cis-azetine). The second main product was isolated as 0.334
g of white solid (trans isomer). Total yield was 69% with a ratio
of 1.8:1 cis/trans products as determined by analysis of the crude
1H NMR spectrum and confirmed in final isolated yields.
1
EtOAc); 25:1 mixture of isomers; H NMR (400 MHz, CDCl3)
major isomer: δ 8.04 (s, 1H), 7.55 (d, 2H, J ) 3.6 Hz), 7.37-
7.34 (m, 3H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) major
isomer: δ 148.72, 132.38, 130.00, 128.85, 127.18, 62.17; IR
(neat): 2937, 2898, 2817, 1462, 1447, 1211, 1049, 946, 916, 844,
753, 690 cm-1; HRMS-ESI m/z 136.0756 ([M + H]+, C8H10NO
requires 136.0757).
(4R,5S)-1,5-Dimethyl-3-((3S,4S)-3-methyl-4-phenyl-3,4-dihy-
dro-azet-2-yl)-4-phenyl-imidazolidin-2-one (22a). cis-Azetine:
(S)-4-Isopropyl-1,3-dipropionyl-imidazolidin-2-one (12). 4-Iso-
propyl-imidazolidinone (1.28 g, 10.0 mmol) was added with 25
mL of anhydrous THF to an oven dried flask under argon, and the
solution was chilled in an ice bath. A 25.0 mL (25.0 mmol, 2.50
equiv) volume of 1.0 M lithium hexamethyldisilazide in THF was
added quickly dropwise. A 2.17 mL (25.0 mmol, 2.50 equiv)
volume of propionyl chloride was added, and the reaction was
allowed to gradually equilibrate to room temperature. The solution
was quenched after 16 h with saturated aqueous ammonium chloride
and transferred to a separatory flask with a water and diethyl ether
rinse. The aqueous phase was washed with additional ether. The
organic layers were then washed with brine, dried with MgSO4,
filtered, and concentrated to give a pale amber oil. The oil was
loaded onto a silica column and eluted with 98:2 CH2Cl2/MeOH.
The main product was collected as a white waxy solid of mass
white solid; Rf ) 0.25 (95:5 CH2Cl2/MeOH); mp 162-165 °C;
1
[R]23 +214.2 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ
D
7.38-7.18 (m, 10H), 5.31 (d, 1H, J ) 8.0 Hz), 4.80 (d, 1H, J )
4.4 Hz), 4.08-4.01 (m, 2H), 2.82 (s, 3H), 0.95 (d, 3H, J ) 7.6
Hz), 0.83 (d, 3H, J ) 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ
171.1, 156.4, 140.1, 136.0, 128.8, 128.4, 127.9, 127.5, 127.3, 127.0,
65.5, 58.6, 55.9, 45.0, 28.2, 15.0, 12.8; IR (film): 3030, 2976, 2934,
1718, 1602, 1459, 1397, 1285, 969, 907, 703 cm-1; HRMS-ESI
m/z 334.1914 ([M + H]+, C21H24N3O requires 334.1914); Anal.
calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60; O, 4.80. Found
C, 75.36; H, 7.12; N, 12.55; O, 4.86. trans-Azetine: white solid;
Rf ) 0.33 (95:5 CH2Cl2/MeOH); mp 144-146 °C; [R]23 +32.7
D
1
(c 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 7.42-7.33 (m,
3H), 7.27-7.24 (m, 2H), 7.15-7.13 (m, 3H), 6.88-6.84 (m, 2H),
5.26 (d, 1H, J ) 8.4 Hz), 4.31 (d, 1H, J ) 1.6 Hz), 4.09-4.02 (m,
1H), 3.30 (dq, 1H, J ) 7.2, 1.6 Hz), 2.84 (s, 3H), 1.61 (d, 3H, J )
8.4 Hz), 0.89 (d, 3H, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ
171.5, 156.3, 141.7, 136.0, 128.7, 128.3, 128.2, 127.5, 127.0, 125.9,
69.9, 59.0, 55.6, 50.8, 28.2, 16.1, 15.1; IR (film): 2960, 2933, 1721,
1598, 1426, 1397, 1293, 1181, 957, 783, 747, 706 cm-1; HRMS-
ESI m/z 334.1913 ([M + H]+, C21H24N3O requires 334.1914); Anal.
calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60; O, 4.80. Found
C, 75.53; H, 6.92; N, 12.58; O, 4.81.
2.21 g (92%). Rf ) 0.79 (95:5 CH2Cl2/MeOH); [R]23 +59.1 (c
D
1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.31-4.27 (m, 1 H),
3.74 (dd, 1 H, J ) 12.0, 2.8 Hz), 3.60 (dd, 1H, J ) 12.0, 9.2 Hz),
3.02-2.83 (m, 4H), 2.38-2.30 (m, 1H), 1.16 (t, 6H, J ) 7.2 Hz),
0.92 (d, 3H, J ) 6.8 Hz), 0.76 (d, 3H, J ) 6.8 Hz); 13C NMR (100
MHz, CDCl3) δ 174.9, 174.7, 152.5, 54.7, 40.2, 30.2, 29.9, 29.0,
18.2, 14.4, 8.7, 8.6; IR (film): 2964, 1750, 1693, 1362, 1251, 1199,
864, 806 cm-1; HRMS-ESI m/z 241.1543 ([M + H]+, C12H21N2O3
requires 241.1547).
General Procedure for the Alkylation of Azetines. Representa-
tive example for 23a: a solution of 0.133 g (0.400 mmol) of cis-
azetine 22a in anhydrous THF (4 mL) was chilled to 0 °C under
argon. Lithium hexamethyldisilazide (1.60 mL of 1.0 M solution
in THF, 1.60 mmol, 4.00 equiv) was added dropwise. After 45
min, benzyl bromide (0.0714 mL, 0.600 mmol, 1.50 equiv) was
added, and the solution was stirred for 30 min. The reaction was
quenched with 1 N HCl, and ethyl acetate was added. The organic
layer was washed with 1 N HCl. The aqueous layers were combined
and extracted with ethyl acetate. The aqueous layer was basified
to pH > 9 with 4 N NaOH and extracted with dichloromethane.
The organic layers were combined and dried with anhydrous K2-
CO3. The solution was filtered and concentrated to give a brown
oil that was carried on to the next step without further purification.
General Procedure for Hydrolytic Ring Opening of Azetines
to â2,2,3-Amino Carbonyl Derivatives. Representative example for
23a: to a solution of azetine alkylation crude sample in dichlo-
romethane (5 mL) was added 0.0837 mL (0.600 mmol, 1.20 equiv)
of triethylamine and 0.232 mL (2.00 mmol, 5.00 equiv) of benzoyl
chloride at room temperature. The solution was stirred for 1 h and
quenched with half saturated aqueous ammonium chloride. The
aqueous layer was extracted with dichloromethane. The organic
layers were washed with aqueous saturated sodium bicarbonate and
brine, dried with anhydrous K2CO3, filtered, and concentrated.
Column chromatography on silica with 10-20% ethyl acetate in
hexanes provided the product 23a as an oil of mass 0.150 g (69%
from 22a).
(S)-5-Isopropyl-1-propionyl-imidazolidin-2-one (13). Com-
pound 12 (2.90 g, 12.1 mmol) in 30.0 mL of THF (0.40 M) was
chilled to -78 °C, and 12.1 mL (12.1 mmol, 1.00 equiv) of 1.00
M potassium t-butoxide in THF was added dropwise over the course
of 10 min. The reaction was stirred at -78 °C for a total of 4 h.
The solution was transferred dropwise by cannula to a second flask
containing 50 mL of stirring water at room temperature. The
aqueous phase was extracted with ethyl acetate and ether. The
organic layers were combined, washed with brine, dried with
MgSO4, filtered, and concentrated to give a crude oil of 2.6 g. The
oil was prepared as a silica cake, loaded onto a silica column, and
eluted with 99:1 CH2Cl2/MeOH. Main product containing fractions
were combined and submitted to preparative HPLC in 3-10%
isopropanol in hexane over 90 min at a 25 mL/min flow rate. Main
peak fractions were combined to give a clear oil of mass 0.873 of
90-95% purity as determined by 1H NMR (37% yield). Rf ) 0.30
(95:5 CH2Cl2/MeOH); 1H NMR (400 MHz, CDCl3) δ 6.00 (s, 1H),
4.39 (dt, 1H, J ) 9.2, 3.6 Hz), 3.42 (t, 1H, J ) 9.2 Hz), 3.24-3.21
(m, 1H), 3.00-2.83 (m, 2H), 2.43-2.35 (m, 1H), 1.13 (t, 3H, J )
7.2 Hz), 0.88 (d, 3H, J ) 6.8 Hz), 0.83 (d, 3H, J ) 6.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 174.7, 157.7, 58.4, 37.7, 29.4, 28.9,
18.2, 14.7, 8.99; IR (film): 3309, 2962, 1729, 1683, 1375, 1295,
1247, 807 cm-1; HRMS-ESI m/z 185.1285 ([M + H]+, C9H17N2O2
requires 185.1285).
General Procedure for Gram Scale Preparation of Azetines.
Representative example for 22a: a solution of 1.00 g (4.06 mmol)
of 21 in anhydrous dichloromethane (150 mL, 0.027 M) was chilled
to 0 °C under argon. Titanium tetrachloride (1.78 mL, 16.2 mmol,
4.00 equiv) was added, followed after 5 min by dropwise addition
of (-)-sparteine (2.33 mL, 10.2 mmol, 2.50 equiv). The solution
was stirred for 30 min, and oxime 2a (1.65 g, 12.2 mmol, 3.00
equiv) was added. The solution was allowed to equilibrate to room
temperature and was stirred for 24 h. The reaction mixture was
quenched with half saturated aqueous ammonium chloride, and the
aqueous phase was extracted with dichloromethane. The organic
layers were washed with saturated aqueous sodium bicarbonate and
brine, dried with MgSO4, filtered, and concentrated to give a dark
N-[(1R,2R)-2-Benzyl-3-((4S,5R)-3,4-dimethyl-2-oxo-5-phenyl-
imidazolidin-1-yl)-2-methyl-3-oxo-1-phenyl-propyl]-benza-
mide (23a). Rf ) 0.60 (95:5 CH2Cl2/MeOH); [R]23D +30.2 (c 1.00,
CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.38-6.88 (m, 20H), 6.44
(bs, 1H), 5.07 (d, 1H, J ) 8.4 Hz), 4.18 (d, 1H, J ) 13.8 Hz),
3.75-3.70 (m, 1H), 2.82 (s, 3H), 2.36 (d, 1H, J ) 13.2 Hz), 1.18
(s, 3H), 0.67 (d, 3H, J ) 6.6 Hz); 13C NMR (150 MHz, CDCl3) δ
175.4, 166.2, 155.5, 139.6, 137.9, 136.9, 135.0, 131.2, 130.6, 129.3,
128.5, 128.4, 128.3, 128.1, 127.8, 127.5, 127.3, 127.1, 126.7, 62.5,
57.1, 54.3, 54.1, 39.9, 28.6, 19.9, 15.1; IR (neat): 3439, 3316, 3034,
1268 J. Org. Chem., Vol. 73, No. 4, 2008

Synthesis of Quaternary Center Bearing Azetines
2984, 1725, 1664, 1513, 1424, 1247, 1073, 911, 703 cm-1; HRMS-
ESI m/z 546.2748 ([M + H]+, C35H36N3O3 requires 546.2751).
(2R,3R)-3-Benzoylamino-2-benzyl-2-methyl-3-phenyl-propi-
onic Acid Methyl Ester (24). Compound 23a (0.050 g, 0.092
mmol) was dissolved in 1.5 mL of anhydrous MeOH and chilled
to 0 °C, and sodium methoxide (0.200 mL of 0.5 M in MeOH,
0.10 mmol, 1.10 equiv) was added. The solution was allowed to
warm to room temperature and refluxed for 16 h. Water was added,
and the methanol was removed by evaporation. The aqueous layer
was extracted with dichloromethane, acidified with saturated
ammonium chloride, and further extracted with dichloromethane.
The organic layers were combined, washed with brine, dried with
MgSO4, filtered, and concentrated. Column chromatography on
silica and elution with a 0-50% ethyl acetate in hexanes gradient
16 h. Sodium sulfite (0.7 mmol in 1 mL of deionized water) was
added, and the THF was removed by evaporation. The aqueous
phase was extracted with dichloromethane. The aqueous phase was
then cooled in an ice bath, acidified to pH 1 with 10% HCl, and
extracted with ethyl acetate. The ethyl acetate layers were combined,
dried with MgSO4, filtered, and concentrated to give 0.055 g (80%)
of compound 25 as a clear oil. Rf ) 0.20 (1:1 hexanes/EtOAc);
[R]23D +73.1 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 11.01
(bs, 1H), 8.47 (d, 1H, J ) 9.2 Hz), 7.88-7.84 (m, 2H), 7.55-7.16
(m, 13H), 5.26 (d, 1H, J ) 9.2 Hz), 3.46 (d, 1H, J ) 13.2 Hz),
2.93 (d, 1H, J ) 13.2 Hz), 1.05 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 181.3, 166.9, 139.1, 136.2, 134.3, 132.0, 130.4, 128.9,
128.7, 128.6, 128.1(2C), 127.3, 127.2, 60.2, 51.2, 44.2, 19.8; IR
(solid): 3030, 1626, 1519, 1485, 1203, 908, 698, 585 cm-1; HRMS-
ESI m/z 374.1745 ([M + H]+, C24H24NO3 requires 374.1751).
gave compound 24 as 0.029 g (82%) of clear oil. Rf ) 0.53 (1:1
1
hexanes/EtOAc); [R]23 +72.3 (c 1.00, CHCl3); H NMR (400
D
MHz, CDCl3) δ 8.63 (d, 1H, J ) 9.2 Hz), 7.95-7.92 (m, 2H),
7.54-7.47 (m, 3H), 7.33-7.21 (m, 8H), 7.13-7.10 (m, 2H), 5.17
(d, 1H, J ) 9.2 Hz), 3.62 (s, 3H), 3.49 (d, 1H, J ) 13.2 Hz), 2.84
(d, 1H, J ) 13.2 Hz), 1.00 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 177.5, 166.4, 139.5, 136.6, 134.5, 131.8, 130.3, 128.8, 128.6,
128.5, 128.0, 127.9, 127.2, 127.1, 60.6, 52.3, 51.4, 44.5, 19.6; IR
(solid): 1728, 1645, 1514, 1485, 1201, 1104, 701 cm-1; HRMS-
ESI m/z 388.1905 ([M + H]+, C25H26NO3 requires 388.1907).
(2R,3R)-3-Benzoylamino-2-benzyl-2-methyl-3-phenyl-propi-
onic Acid (25). Compound 23a (0.100 g, 0.183 mmol) was
dissolved in 1.5 mL of 4:1 THF/H2O and chilled to 0 °C. A 0.075
mL volume of 30% aqueous hydrogen peroxide (0.73 mmol, 4.0
equiv) was added dropwise, followed by lithium hydroxide (0.0070
g in 0.5 mL of deionized water, 0.29 mmol, 1.6 equiv). The reaction
was allowed to equilibrate to room temperature and was stirred for
Acknowledgment. We thank Dr. Kenneth Hardcastle and
Xikui Fang of the Emory X-ray Crystallography Laboratory for
structural determinations, as well as Dr. Pahk Thepchatri for
his assistance in developing 3-D renderings for the cis- and
trans-azetines.
Supporting Information Available: Experimental procedures
and characterization for all prepared compounds described in this
work, as well as 1H and 13C spectra for all new compounds reported,
crystallographic data for cis- and trans-azetines 18a and addition
product 23f, and input data and statistical analysis for the optimiza-
tion study. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO7018202
J. Org. Chem, Vol. 73, No. 4, 2008 1269