Highly diastereoselective mannich-type reactions of chiral N-acylhydrazones

Article abstract of DOI:10.1021/jo0358170

The Lewis acid-mediated addition of silyl enolates to easily accessible homochiral N-acylhydrazones derived from 3-amino-2-oxazolidinones proceeded in yields up to 71% and diastereomeric ratios of 99:1. In most cases, optimal reaction conditions entailed the simple use of ZnCl₂ in acetonitrile at room temperature. Hydrazones derived from phenyl-, isopropyl-, and benzyl-substituted 2-oxazolidinones were examined in the reaction in terms of yield and diastereoselectivity. The facile SmI₂-mediated N-N bond cleavage of the formed hydrazines was demonstrated yielding a β-amino acid derivative. Hence, the overall reaction sequence constitutes an efficient asymmetric Mannich-type reaction. The sense of diastereoselectivity was explained by a preferential attack on the less shielded Si face of the chiral hydrazones and confirmed by means of X-ray crystallography.

Full text of DOI:10.1021/jo0358170

High ly Dia ster eoselective Ma n n ich -Typ e Rea ction s of Ch ir a l
N-Acylh yd r a zon es
Mikkel F. J acobsen, Liviu Ionita, and Troels Skrydstrup*
Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
Received December 15, 2003
The Lewis acid-mediated addition of silyl enolates to easily accessible homochiral N-acylhydrazones
derived from 3-amino-2-oxazolidinones proceeded in yields up to 71% and diastereomeric ratios of
99:1. In most cases, optimal reaction conditions entailed the simple use of ZnCl2 in acetonitrile at
room temperature. Hydrazones derived from phenyl-, isopropyl-, and benzyl-substituted 2-oxazo-
lidinones were examined in the reaction in terms of yield and diastereoselectivity. The facile SmI2-
mediated N-N bond cleavage of the formed hydrazines was demonstrated yielding a â-amino acid
derivative. Hence, the overall reaction sequence constitutes an efficient asymmetric Mannich-type
reaction. The sense of diastereoselectivity was explained by a preferential attack on the less shielded
Si face of the chiral hydrazones and confirmed by means of X-ray crystallography.
In tr od u ction
â-lactam precursors.4 In our pursuit of simple and novel
methods for the asymmetric synthesis of such C4-
functionalized precursors, we have recently reported on
the asymmetric Mannich-type reaction of ketene acetals
4 and sulfinimines of the structure 3 derived from chiral
N-tert-butanesulfinamide.5 These sulfinimines are stable
imine equivalents. The aspartic acid derivatives 2 ob-
tained are excellent precursors for the access to â-lactams
1 (Scheme 1).
Another stable class of imine equivalents is repre-
sented by the hydrazones since a variety of protocols exist
for efficient N-N cleavage of hydrazones.6 On the other
hand, their lack of reactivity toward nucleophiles has
resulted in few reports on addition reactions compared
to imines,6b-f,7 except those involving organometallic
reagents.8 While the use of basic organometallic reagents
for C-C bond formation limits the functional group
tolerance and can result in competitive metalloenamine
formation,9 the Lewis acid-mediated Mannich-type reac-
tions of silyl enolates are usually highly chemoselective
and can be performed under relatively mild conditions.
The Lewis acid-mediated reactions of imines with silyl
enolates are among the most efficient for the synthesis
of â-amino acids. The unique conformational and biologi-
cal properties of â-amino acids in â-peptides1 incorporat-
ing such monomers and their use as building blocks for
many nitrogen-containing biological compounds2 has
prompted a tremendous amount of effort in the develop-
ment of asymmetric variants.3 However, many imines
tend to be unstable during purification by chromatogra-
phy, distillation, or prolonged storage, especially aliphatic
imines. Our previous work on the SmI2-mediated dias-
tereoselective construction of highly functionalized pro-
line derivatives demonstrated that key stereocontrol in
the reaction could be traced to the C4-stereocenter of the
(1) (a) J uaristi, E., Ed. Enantioselective Synthesis of â-amino acids,
1st ed.; Wiley-VCH: New York, 1997. (b) Hamuro, Y.; Schneider, J .
P.; DeGrado, W. F. J . Am. Chem. Soc. 1999, 121, 12200. (c) Wang, X.;
Espinosa, J . F.; Geillman, S. H. J . Am. Chem. Soc. 2000, 122, 4821.
(d) Appella, D. H.; Barchi, J . J ., J r.; Durell, S. R.; Gellman, S. H. J .
Am. Chem. Soc. 1999, 121, 2309.
(2) For some leading references, see: (a) Bai, R. L.; Verdier-Pinard,
P.; Gangwar, S.; Stessman, C. C.; McClure, K. J .; Sausville, E. A.;
Pettit, G. R.; Bates, R. B.; Hamel, E. Mol. Pharmacol. 2001, 59, 462.
(b) J efferson, E. A.; Swayze, E. E. Tetrahedron Lett. 1999, 40, 7757.
(c) Iijima, K.; Katada, J .; Hayashi, Y. Bioorg. Med. Chem. Lett. 1999,
9, 413.
(3) For representative examples, see: (a) Kobayashi, S.; Matsubara,
R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J . Am. Chem. Soc. 2003,
125, 2507. (b) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett.
2002, 1, 143. (c) J uhl, K.; Gathergood, N.; J ørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 2995. (d) Kobayashi, S.; Ishitani, H. Chem.
Rev. 1999, 99, 1069 and references therein. (e) Ferraris, D.; Young,
B.; Coz, C.; Dudding, T.; Drury, W. J ., III; Ryzhkov, L.; Taggi, A. E.;
Lectka, T. J . Am. Chem. Soc. 2002, 124, 67. (f) Kawecki, R. J . Org.
Chem. 1999, 64, 8724. (g) Higashiyama, K.; Kyo, H.; Takahashi, H.
Synlett 1998, 489. (h) Hagiwara, E.; Fujii, A.; Sodeoka, M. J . Am.
Chem. Soc. 1998, 120, 2474. (i) Corey, E. J .; Decicco, C. P.; Newbold,
R. C. Tetrahedron Lett. 1991, 32, 5287. (j) Ishihara, K.; Miyata, M.;
Hattori, K.; Tada, T.; Yamamoto, H. J . J . Am. Chem. Soc. 1994, 116,
10520. (k) Shimizu, M.; Kume, K.; Fujisawa, T. Tetrahedron Lett. 1995,
36, 5227.
(4) J acobsen, M. F.; Turks, M.; Hazell, R.; Skrydstrup, T. J . Org.
Chem. 2002, 67, 2411.
(5) J acobsen, M. F.; Skrydstrup, T. J . Org. Chem. 2003, 68, 7112.
(6) For some examples, see: (a) Sturino, C. F.; Fallis, A. G. J . Am.
Chem. Soc. 1994, 116, 7447. (b) Burk, M. J .; Feaster, J . E. J . Am. Chem.
Soc. 1992, 114, 6266. (c) Kadota, J .; Park, J .-Y.; Yamamoto, Y. J . Chem.
Soc., Chem. Commun. 1996, 841. (d) Claremon, D. A.; Lumma, P. K.;
Philips, B. T. J . Am. Chem. Soc. 1986, 108, 8265. (e) Takahashi, H.;
Suzuki, Y. Chem. Pharm. Bull. 1983, 31, 4295. (f) Enders, D.; Bettray,
W.; Raabe, G.; Runsink, J . Synthesis 1994, 1322. (g) Solladio-Cavallo,
A.; Bonne, F. Tetrahedron: Asymmetry 1996, 7, 171. (h) Choi, J . Y.;
Kim, Y. H. Tetrahedron Lett. 1996, 37, 7795. (i) Leblanc, Y.; Bou-
dreault, N. J . Org. Chem. 1995, 60, 4268. (j) J uhl, K.; J ørgensen, K.
A. J . Am. Chem. Soc. 2002, 124, 2420.
(7) For Lewis acid-mediated nucleophilic additions to hydrazones,
see: (a) Kobayashi, S.; Hamada, T.; Manabe, K. J . Am. Chem. Soc.
2002, 124, 5640 and references therein. (b) Manabe, K.; Oyamada, H.;
Sugita, K.; Kobayashi, S. J . Org. Chem. 1999, 64, 8054. (c) Friestad,
G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 40, 4491.
(8) For recent reviews, see: (a) Bloch, R. Chem. Rev. 1998, 98, 1407.
(b) Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895.
10.1021/jo0358170 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/15/2004
4792
J . Org. Chem. 2004, 69, 4792-4796

Mannich-Type Reactions of Chiral N-Acylhydrazones
SCHEME 1
TABLE 1. Su r vey of Lew is Acid s for P r om otion of
Ad d ition to Hyd r a zon e 3a a ,b
Recently, Friestad introduced N-acylhydrazones de-
rived from N-amino 2-oxazolidinones in asymmetric
synthesis, most prominently in stereoselective allylation
and radical addition reactions.7c,10 We envisioned that the
right choice of Lewis acid and aldehyde precursor of the
hydrazone would yield a sufficiently potent species
capable of reacting with many different silyl enolates.
Thus, glyoxylates emerged as obvious aldehyde candi-
dates for the condensation with N-amino 2-oxazolidino-
nes. The neighboring ester functionality should increase
the reactivity toward nucleophiles by lowering the LUMO
of the CdN bond.
entry
Lewis acid (mol %)
yield (%)c
drd
1
2e
3
4
5
In(OTf)3 (130%)
In(OTf)3 (130%)
Yb(OTf)3 (10%)
CeCl3 (110%)
Cu(OTf)2 (100%)
Sc(OTf)3 (5%)
0
0
trace
trace
0
Resu lts a n d Discu ssion
6
53
99:1
99:1
98:2
83:17
79:21
7
8
9
10
11f
12
13
14
Sc(OTf)3 (10%)
Sc(OTf)3 (20%)
Zn(OTf)2 (100%)
51
46
66
71
Deprotonation of chiral 2-oxazolidinones 5a -c with
+
NaH in dioxane and subjection to the effective NH2
equivalent O-(p-nitrobenzoyl)hydroxylamine (NbzONH2)
furnished crude N-amino 2-oxazolidinones, which were
condensed with ethyl glyoxylate in toluene to give the
N-acylhydrazones 3a -c in moderate to good yields (34-
78%).11
Our initial studies examined the influence of different
Lewis acids on the outcome of the reaction of chiral
hydrazone 3a with ketene acetal 4a (Table 1).
Indium(III) trifluoromethanesulfonate has proven ef-
ficient in the allylations of similar hydrazones with
allylsilanes,7c but no reaction was observed in either CH2-
Cl2 or CH3CN (entry 1 and 2). This was surprising since
ketene acetals are usually considered more reactive than
allylsilanes as nucleophiles. The lanthanide salts Yb-
(OTf)3 and CeCl3 did not prove successful either, since
only a trace of product could be observed.12
The use of Sc(OTf)3 in catalytic quantities for the
activation of hydrazones has been reported before,7b,13 and
indeed the product 2a was obtained in a promising 53%
yield with almost complete stereocontrol (entry 6). Chang-
ing the amount of Sc(OTf)3 seemed to have little influ-
ence. Minor amounts (∼5%) of product resulting from the
attack of 4a on the ester moiety of 3a were also detected
by 1H NMR and MS in the case of Sc(OTf)3 (entries 6-8).
Zn(OTf)2 (130%)
ZnF2 (130%)
ZnI2 (130%)
ZnCl2 (130%)
ZnCl2 (250%)
trace
60
98:2
64 (54)g
60
97:3 (>99:1)g
97:3
a
Reaction time was 24 h except for entries 1, 10, 11, and 13
b
where reaction time was 44 h. The absolute configuration of the
major diastereomer of 2a shown was confirmed by X-ray crystal-
lographic analysis; see the text. c Isolated yields of purified dia-
d
stereomeric mixtures after chromatography. Determined by 1H
NMR (400 MHz) analysis of crude product. e Reaction was per-
formed in CH2Cl2. f Very low solubility of ZnF2 in CH3CN. Iso-
g
lated yield after direct recrystallization of crude product from Et2O/
pentanes.
More clean reactions ensued by using Zn2+ Lewis acids,
and analytically pure samples of virtually complete
enantiopurity could be obtained in greater than 50% yield
by a single recrystallization of the crude product (entry
13).14 The optimal conditions involved the use of a slight
excess of either ZnI2 or ZnCl2 in CH3CN. A larger excess
did not improve the yield (entry 14).
Next, we examined the effect of changing the substitu-
tion on the 2-oxazolidinones (Table 2). However, little
change in yield and diastereoselectivity was observed
with the isopropyl derivative 3b and ketene acetal 4a
compared to 3a and 4a . The yields were lowered consid-
erably when other silyl enolates 4b and 4c were employed
(entry 3 and 4), although high dr values were still
attained. Interestingly, extensive formation of byproducts
was observed in the reaction of 3b with 4b (entry 3, see
discussion below). The phenyl derivative 3c showed
similar tendencies as 3a , but furnished lower dr values
(entries 5-6) and yields (entries 6 and 7). Notably, the
yield and diastereoselectivity eroded compared to the
results for 3b when ZnCl2 was used.
(9) (a) Enders, D.; Diez, R.; Fernandez, R.; Martin-Zamora, E.;
Munoz, J . M.; Pappalardo, R. R.; Lassaleta, J . M. J . Org. Chem. 1999,
64, 6329. (b) Stork, G.; Dowd, S. R. J . Am. Chem. Soc. 1963, 85, 2178.
(10) (a) Friestad, G. K.; Shen, Y.; Ruggles, E. L. Angew. Chem., Int.
Ed. 2003, 42, 5061. (b) Friestad. G. K.; Qin. J . J . Am. Chem. Soc. 2001,
123, 9922. (c) Friestad. G. K.; Qin. J . J . Am. Chem. Soc. 2000, 122,
8329.
(11) Shen, Y.; Friestad, G. K. J . Org. Chem. 2002, 67, 6236.
(12) Catalytic amounts of Yb(OTf)3 have been efficient in the
activation of imines. For examples, see: (a) Annunziata, R.; Cinquini,
M.; Cozzi, F.; Molteni, V.; Schupp, O. J . Org. Chem. 1996, 61, 8293.
(b) Kobayashi, S.; Araki, M.; Ishitani, H.; Nagayama, S.; Hachiya, I.
Synlett 1995, 233. (c) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron
Lett. 1995, 36, 5773.
The generally poorer performance of 3b and 3c com-
pared to 3a and the more efficient synthesis of 3a then
(13) (a) Okitsu, O.; Oyamada, H.; Furuta, T.; Kobayashi, S. Hetero-
cycles 2000, 52, 1143. (b) Oyamada, H.; Kobayashi, S. Synlett 1998,
249. (c) Kobayashi, S.; Furuta, T.; Sugita, K.; Oyemada, H. Synlett
1998, 1019. (d) Kobayashi, S.; Hasegawa, Y.; Ishitani, H. Chem. Lett.
1998, 1131.
(14) Zn2+ Lewis acids have also been employed in the catalytic
asymmetric Mannich-type reactions of N-acylhydrazones, see ref 7a.
J . Org. Chem, Vol. 69, No. 14, 2004 4793

J acobsen et al.
TABLE 2. Effect of Differ en t Ch ir a l 2-Oxa zolid in on es on th e Ad d ition to Hyd r a zon es 3b-ca ,b
entry
R1
R2, Y
Lewis acid (mol %)
product
% yieldc
drd
1
i-Pr (3b)
i-Pr (3b)
i-Pr (3b)
i-Pr (3b)
Ph (3c)
Me, OEt (4a )
Me, OEt (4a )
H, OEt (4b)
H, SPh (4c)
Me, OEt (4a )
Me, OEt (4a )
Me, OEt (4a )
Zn(OTf)2 (130%)
ZnCl2 (130%)
ZnCl2 (130%)
ZnCl2 (130%)
Zn(OTf)2 (130%)
ZnCl2 (130%)
Sc(OTf)3 (20%)
2b
2b
2c
2d
2e
2e
2e
64
64
17
27
64
35
36
86:14
98:2
97:3
2
3e
4
98:2
5
6
7
65:35
80:20
99:1
Ph (3c)
Ph (3c)
a
b
Reaction time was 24 h. Configurations of 2b-e shown are assigned by analogy with 2a ; see the text. c Isolated yields of purified
diastereomeric mixtures after chromatography. Determined by 1H NMR (400 MHz) analysis of crude product. e The formation of major
d
amounts of byproducts was observed.
TABLE 3. Ma n n ich -Typ e Rea ction s of Hyd r a zon e 3a
w ith Differ en t Keten e Aceta ls 4b-ea
F IGURE 1. A model explaining the stereochemical outcome
of the Mannich-type reactions with hydrazones 3a -c.
entry
R, Y
Lewis acid (mol %) product % yieldb
drc
SCHEME 2
1
2
3
4
5e
6
7
8
H, OEt (4b)
H, OEt (4b)
H, OEt (4b)
H, SPh (4c)
H, SPh (4c)
H, SPh (4c)
H, SEt (4d )
H, Ot-Bu (4e)
Sc(OTf)3 (10%)
Zn(OTf)2 (130%)
ZnCl2 (130%)
Sc(OTf)3 (10%)
ZnCl2 (130%)
ZnCl2 (130%)
ZnCl2 (130%)
ZnCl2 (130%)
2f
2f
2f
2g
2g
2g
2h
2i
<5d
trace
61
27
50
62
30
56
70:30
98:2
77:23
87:13
96:4
95:5
97:3
a
Configurations of 2f-i shown are assigned by analogy with
b
2a ; see the text. Isolated yields of purified diastereomeric
mixtures after chromatography. c Determined by 1H NMR (400
SCHEME 3
MHz) analysis of crude product. NMR yield. e The solvent was
d
CH2Cl2.
prompted us to use the latter for further investigations
of reactions with other silyl enolates (Table 3).
Fortunately, the behavior of the 3a -ZnCl2 system
proved different than that of 3b-ZnCl2, as silyl enolates
4b-e reacted almost equally well, with the exception of
4d where the yield was 30%. Again, other Lewis acids
tested were overall less efficient than ZnCl2. Surprisingly,
almost no reaction with 4b could be detected by 1H NMR
when Sc(OTf)3 or Zn(OTf)2 was employed, contrary to the
reaction of 4a .
The cleavage of the N-N bond of hydrazines is
sometimes troublesome, and epimerization is often likely
to occur with some hydrogenation protocols, e.g. Raney
nickel/H2.8 It was pleasing to find though that the
published procedure for the mild cleavage of N-N bonds
with SmI2 was efficient.6b First, 2a was subjected to
careful benzoylation with n-BuLi and BzCl (Scheme 3).
The crude product was then reacted with excess freshly
prepared SmI2 in THF-MeOH to afford the desired
product 6 in good yield (65%, two steps). Furthermore,
the 2-oxazolidinone 5a could be isolated for recycling.
The sense of diastereoselection in the above Mannich-
type reactions was confirmed by single-crystal X-ray
crystallography of 2a .15 Stereoregularity was thereafter
inferred for 2b-i. This facial selectivity can be explained
by the blocking of the Re face of the CdN bond in 2a -i
by the substituent R, hence, the attack is directed to the
Si face (Figure 1). Similar selectivity was seen in the
radical addition and allylations reactions of other N-
acylhydrazones derived from N-amino 2-oxazolidinones.7c,10
However, the portrayed bidentate chelation of the
Lewis acid may not be the only possible binding mode
(Scheme 4, 7). The chelation of the Lewis acid to the ester
moiety and nitrogen atom as in 8 cannot be ruled out. In
(15) See the Supporting Information.
4794 J . Org. Chem., Vol. 69, No. 14, 2004

Mannich-Type Reactions of Chiral N-Acylhydrazones
SCHEME 4
the 2-oxazolidinone chiral auxiliary with SmI2. Consis-
tently high diastereoselectivities were observed in these
clean room-temperature reactions with ZnCl2, and mod-
erate to good yields of the products were obtained.
Exp er im en ta l Section
Gen er a l P r oced u r e for Ma n n ich -Typ e Rea ction s of
N-Acylh yd r a zon es 3a -c. To a solution of the hydrazone in
CH3CN (0.1 M) was added the Lewis acid at room temperature.
The resulting solution was stirred for 15 min, after which the
ketene acetal or ketene thioacetal (2.0 equiv) was added. The
reaction mixture was stirred for the time indicated (Tables 1
and 2) or until no further progress could be detected by TLC
(Table 3). Saturated aqueous NH4Cl solution (0.3 mL/mL of
reaction mixture) was added, and the organic phase was
diluted with CH2Cl2. The aqueous phase was extracted several
times with CH2Cl2. The combined organic phases were dried
over MgSO4 and evaporated to dryness in vacuo. Diastereo-
selectivity was determined by NMR integration of the crude
product (Tables 1-3). Flash chromatography (pentanes/EtOAc,
gradient elution) on silica gel afforded the products.
support of this, the isolation of minor amounts (∼5%) of
byproduct resulting from the attack of 4a on the ester
moiety of hydrazones 3a and 3b in the case of Sc(OTf)3
could be the result of an enhanced activation of the ester
as in 8 (Table 1, entries 6-8 and Table 2, entry 6). The
catalytic use of rare earth triflates has been rationalized
by the equilibrium of the coordination of the Lewis acids
to the nitrogen of the CdN bond.13a,16 Therefore, one could
speculate that an equilibrium between differently che-
lated species exists, which is responsible for the decreased
regioselectivity in the reactions with Sc(OTf)3 (Scheme
4). Such regioisomers were not detected in the clean
reactions with stoichiometric amounts of Zn2+ Lewis
acids, indicating that chelation of the ester moiety as in
8 may not be of importance, or that the reactivity
difference between the two Zn-coordinated species is
sufficiently large.
An unexpected and interesting feature of the ZnCl2-
mediated reaction of 3b with 4b (Table 2, entry 3) was
the isolation of major amounts of 2-oxazolidinone 5c and
the unsaturated ester 9.17,18 Obviously, this must be the
result of N-N bond cleavage. A possible explanation for
this observation is outlined below (Scheme 5). Initially,
the intermediate 10 is formed from addition to the
chelated hydrazone 7. If silylation of the basic zinc amide
moiety in 10 is sufficiently slow, intermolecular depro-
tonation of 11 can occur, although the reasons for this
slow silylation step are not fully understood. This creates
the zinc carbanion 12 which in turn can undergo â-elim-
ination to yield the N-silylated imine 13 and 14. Upon
aqueous workup 5c and 9 ensue.
(S)-Dieth yl 3-((S)-4-Ben zyl-2-oxooxazolidin -3-ylam in o)-
2,2-d im eth ylsu ccin a te (2a ). Data for major diastereomer:
1
Mp 93-94 °C (CH2Cl2/pentanes); H NMR (400 MHz, CDCl3)
δ 1.27 (s, 3H), 1.29 (t, J ) 7.2 Hz, 3H), 1.30 (t, J ) 6.8 Hz,
3H), 1.36 (s, 3H), 2.60 (dd, J ) 10.0, 13.6 Hz, 1H), 3.40 (dd, J
) 2.8, 13.6 Hz, 1H), 3.94 (t, J ) 7.2 Hz, 2H), 3.98 (t, J ) 6.4
Hz, 1H), 4.05 (t, J ) 8.0 Hz, 1H), 4.15-4.23 (m, 2H), 4.23 (q,
J ) 7.2 Hz, 2H), 4.81 (d, J ) 6.8 Hz, 1H), 7.16-7.34 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 14.2, 14.3, 21.3, 22.8, 37.5, 45.2,
59.6, 61.3, 61.5, 66.5, 69.1, 127.2, 129.1 (4C), 135.9, 171.6,
175.5; MS (electrospray) m/z 415.2 (M + Na); HRMS m/e calcd
for C20H28N2NaO6 (M + Na) 415.1845, found 415.1843.
(S)-Dieth yl 3-((S)-4-Isop r op yl-2-oxooxa zolid in -3-yla m i-
n o)-2,2-d im eth ylsu ccin a te (2b). Data for major diastere-
omer: 1H NMR (400 MHz, CDCl3) δ 0.86 (d, J ) 7.2 Hz, 3H),
0.87 (d, J ) 6.8 Hz, 3H), 1.20 (s, 3H), 1.25 (t, J ) 7.2 Hz, 3H),
1.26 (t, J ) 7.2 Hz, 3H), 1.29 (s, 3H), 2.18-2.30 (m, 1H), 3.68
(ddd, J ) 3.2, 5.6, 8.8 Hz, 1H), 3.86 (br s, 1H), 4.00 (dd, J )
6.0, 8.8 Hz, 1H), 4.11-4.19 (m, 5H), 4.62 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 14.2, 14.8, 18.0, 21.3, 22.5, 26.9, 45.0,
61.2, 61.3, 61.9, 62.5, 68.3, 158.6, 171.5, 175, 4; MS (electro-
spray) m/z 367.2 (M + Na); HRMS m/e calcd for C16H28N2NaO6
(M + Na) 367.1845, found 367.1852.
Con clu sion s
(S)-Dieth yl 2-((S)-4-Isop r op yl-2-oxooxa zolid in -3-yla m i-
n o)su ccin a te (2c). Data for major diastereomer: 1H NMR
(400 MHz, CDCl3) δ 0.86 (d, J ) 6.9 Hz, 3H), 0.90 (d, J ) 7.1
Hz, 3H), 1.26 (t, J ) 7.6 Hz, 3H), 1.28 (t, J ) 7.2 Hz, 3H),
2.20-2.32 (m, 1H), 2.72 (dd, J ) 7.2, 16.4 Hz, 1H), 2.80 (dd, J
In summary, a simple and useful methodology has
been devised for the synthesis of â-amino acid derivatives
via Mannich-type reactions of chiral N-acylhydrazones
and silyl enolates followed by a subsequent removal of
SCHEME 5
J . Org. Chem, Vol. 69, No. 14, 2004 4795

J acobsen et al.
) 5.6, 16.4 Hz, 1H), 3.76-3.80 (m, 1H), 4.04-4.09 (m, 2H),
4.13-4.23 (m, 5H), 4.62 (br s, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.2 (2C), 15.0, 18.0, 27.3, 36.1, 58.8, 61.2, 61.6, 61.7, 62.9,
158.9, 170.6, 171.3; MS (electrospray) m/z 339.2 (M + Na);
HRMS m/e calcd for C14H24N2NaO6 (M + Na) 339.1532, found
339.1537.
(S)-Eth yl 2-((S)-4-Isopr opyl-2-oxooxazolidin -3-ylam in o)-
4-oxo-4-(p h en ylth io)bu ta n oa te (2d ). Data for major dias-
tereomer: 1H NMR (400 MHz, CDCl3) δ 0.85 (d, J ) 7.2 Hz,
3H), 0.89 (d, J ) 7.2 Hz, 3H), 1.29 (t, J ) 6.8 Hz, 3H), 2.21-
2.30 (m, 1H), 3.08 (dd, J ) 7.2, 16.0 Hz, 1H), 3.15 (dd, J )
5.2, 16.0 Hz, 1H), 3.72-3.76 (m, 1H), 4.04 (dd, J ) 4.4, 8.8
Hz, 1H), 4.09-4.24 (m, 4H), 4.62 (br s, 1H), 7.39-7.42 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 14.2, 15.0, 17.9, 27.2, 44.5, 58.7,
61.1, 61.2, 62.9, 127.2, 129.4 (2C), 129.8 (2C), 134.6, 158.8,
170.8, 194.8; MS (electrospray) m/z 403.2 (M + Na); HRMS
m/e calcd for C18H24N2NaO5S (M + Na) 403.1304, found
403.1303.
J ) 5.5, 16.4 Hz, 1H), 3.36 (dd, J ) 3.2, 16.4 Hz, 1H), 3.96-
4.03 (m, 2H), 4.07-4.12 (m, 1H), 4.18-4.28 (m, 3H), 4.76 (d,
J ) 5.5 Hz, 1H), 7.16-7.34 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 14.2, 14.8, 23.8, 44.7, 59.2, 59.3, 61.8, 66.5, 127.2,
129.1 (2C), 129.2 (2C), 135.9, 158.7, 171.1, 196.3; MS (elec-
trospray) m/z 403.2 (M + Na); HRMS m/e calcd for C18H24N2-
NaO5S (M + Na) 403.1304, found 403.1304.
(S)-Eth yl 2-((S)-4-Ben zyl-2-oxooxa zolid in -3-yla m in o)-
5,5-d im eth yl-4-oxoh exa n oa te (2i). Data for major diaste-
reomer: 1H NMR (400 MHz, CDCl3) δ 1.30 (t, J ) 7.1 Hz, 3H),
1.47 (s, 9H), 2.58-2.64 (m, 1H), 2.71 (dd, J ) 4.0, 16.4 Hz,
1H), 2.76 (dd, J ) 6.0, 16.4 Hz, 1H), 3.38 (dd, J ) 3.2, 13.2
Hz, 1H), 3.99-4.06 (m, 2H), 4.07-4.14 (m, 2H), 4.19-4.29 (m,
2H), 4.79 (d, J ) 4.4 Hz, 1H), 7.17-7.34 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 14.3, 28.2 (3C), 37.1, 37.2, 59.0, 59.4, 61.6,
66.5, 81.7, 127.2, 129.0 (2C), 129.2 (2C), 135.9, 158.8, 169.7,
171.3; MS (electrospray) m/z 415.2 (M + Na); HRMS m/e calcd
for C20H28N2NaO6 (M + Na) 415.1845, found 415.1832.
(S)-Dieth yl 2,2-Dim eth yl-3-((S)-2-oxo-4-p h en yloxa zo-
lid in -3-yla m in o)su ccin a te (2e). Data for diastereomeric
mixture: 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H, minor
diastereomer), 1.02 (s, 3H, minor diastereomer), 1.07 (s, 3H,
major diastereomer), 1.15 (s, 3H, major diastereomer), 1.19
(t, J ) 7.2 Hz, 3H, major diastereomer), 1.20 (t, J ) 7.2 Hz,
3H, minor diastereomer), 1.25 (t, J ) 7.2 Hz, 3H, minor
diastereomer), 1.26 (t, J ) 7.2 Hz, 3H, major diastereomer),
3.47 (d, J ) 7.6 Hz, 1H, minor diastereomer), 3.85 (s, 1H, major
diastereomer), 3.99-4.09 (m, 4H), 4.11-4.19 (m, 6H), 4.53 (t,
J ) 8.8 Hz, 1H, minor diastereomer), 4.59 (t, J ) 8.4 Hz, 1H,
major diastereomer), 4.72-4.84 (m, 4H), 7.24-7.27 (m, 2H),
7.34-7.45 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 14.1, 14.2,
20.9, 21.8, 22.1, 22.3, 46.2, 60.9, 61.0, 61.4, 61.5, 62.9, 68.4,
68.9 (2C), 69.3, 127.1 (2C), 127.9 (2C), 128.9, 129.1 (2C), 129.2
(2C), 129.4, 136.8, 138.1, 157.9, 158.3, 171.7 (2C), 175.3, 175.8;
MS (electrospray) m/z 401.2 (M + Na); HRMS m/e calcd for
(S)-Dieth yl 3-Ben za m id o-2,2-d im eth ylsu ccin a te (6). To
a solution of the hydrazine 2a (91 mg, 0.23 mmol) in THF (2.0
mL) was added dropwise n-BuLi (158 µL, 1.6 M in hexanes,
0.25 mmol) at -78 °C. The resulting mixture was stirred for
40 min at -78 °C. Benzoyl chloride (35 µL, 0.30 mmol) was
added dropwise and the reaction mixture was allowed to warm
to room temperature. Saturated aqueous NH4Cl (2.0 mL) was
added and the aqueous phase was extracted several times with
CH2Cl2. The combined organics were dried over MgSO4 and
evaporated to dryness in vacuo. The crude product was
redissolved in MeOH (2.5 mL) and SmI2 solution was added
dropwise (6.0 mL, 0.60 mmol, 0.1 M in THF) at room temper-
ature. The resulting solution was stirred for 5 min and
saturated aqueous NH4Cl (2.0 mL) was added. The organic
solvents were removed by evaporation in vacuo and the
aqueous phase was extracted with CH2Cl2. The combined
organic phases were dried over MgSO4 and evaporated to
dryness in vacuo. The residue was subjected to column
chromatography (pentanes/EtOAc, gradient elution) on silica
gel. This afforded 35 mg (65%) of 6, followed by 29 mg (70%)
of 5a .19 Data for 6: 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J )
6.8 Hz, 3H), 1.31 (t, J ) 7.2 Hz, 3H), 1.37 (s, 6H), 4.16-4.26
(m, 4H), 5.04 (d, J ) 9.2 Hz, 1H), 7.23 (d, J ) 9.2 Hz, 1H),
C
19H26N2NaO6 (M + Na) 401.1689, found 401.1688.
(S)-Dieth yl 2-((S)-4-Ben zyl-2-oxooxa zolid in -3-yla m in o-
)su ccin a te (2f). Data for major diastereomer: 1H NMR (400
MHz, CDCl3) δ 1.27 (t, J ) 7.0 Hz, 3H), 1.30 (t, J ) 7.0 Hz,
3H), 2.61 (dd, J ) 9.4, 13.3 Hz, 1H), 2.78 (dd, J ) 7.0, 16.4
Hz, 1H), 2.84 (dd, J ) 5.5, 16.4 Hz, 1H), 3.37 (dd, J ) 3.6,
12.5 Hz, 1H), 3.97-4.05 (m, 2H), 4.08-4.30 (m, 6H), 4.80 (d,
J ) 3.9 Hz, 1H), 7.16-7.34 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 14.2, 14.3, 36.0, 37.3, 59.0, 59.4, 61.2, 61.7, 66.6,
127.2, 129.1 (2C), 129.2 (2C), 135.9, 158.8, 170.6, 171.2; MS
(electrospray) m/z 387.2 (M + Na); HRMS m/e calcd for
7.44-7.48 (m, 2H), 7.51-7.55 (m, 1H), 7.82-7.84 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 14.2, 22.9, 23.2, 45.5, 58.5, 61.4,
61.8, 127.2 (2C), 128.8 (2C), 132.0, 134.1, 167.3, 170.6, 175.8;
MS (electrospray) m/z 344.2 (M + Na); HRMS m/e calcd for
C
18H24N2NaO6 (M + Na) 387.1532, found 387.1527.
(S)-Eth yl 2-((S)-4-Ben zyl-2-oxooxa zolid in -3-yla m in o)-
C
17H23NNaO5 (M + Na) 344.1474, found 344.1469.
4-oxo-4-(p h en ylth io)bu ta n oa te (2g). Data for major dias-
tereomer: 1H NMR (400 MHz, CDCl3) δ 1.31 (t, J ) 7.0 Hz,
3H), 2.61 (dd, J ) 9.4, 13.3 Hz, 1H), 3.11 (dd, J ) 7.0, 16.4
Hz, 1H), 3.18 (dd, J ) 5.5, 16.4 Hz, 1H), 3.35 (dd, J ) 3.1,
13.3 Hz, 1H), 3.94-4.11 (m, 3H), 4.18-4.31 (m, 3H), 4.77 (d,
J ) 4.7 Hz, 1H), 7.15-7.33 (m, 5H), 7.39-7.43 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 14.2, 37.2, 44.4, 59.0, 59.0, 61.9,
66.5, 127.2 (2C), 129.1 (2C), 129.2 (2C), 129.5 (2C), 129.8 (2C),
134.6, 135.8, 158.7, 170.8, 194.7; MS (electrospray) m/z 451.2
(M + Na); HRMS m/e calcd for C22H24N2NaO5S (M + Na)
451.1304, found 451.1307.
(S)-Eth yl 2-((S)-4-Ben zyl-2-oxooxa zolid in -3-yla m in o)-
4-(eth ylth io)-4-oxobu ta n oa te (2h ). Data for major diaste-
reomer: 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J ) 7.0 Hz, 3H),
1.30 (t, J ) 7.0 Hz, 3H), 2.61 (dd, J ) 10.2, 13.3 Hz, 1H), 2.92
(q, J ) 7.0 Hz, 2H), 3.00 (dd, J ) 7.0, 16.4 Hz, 1H), 3.06 (dd,
Ack n ow led gm en t. We thank Dr. Rita Hazell for
X-ray analysis. We are indebted to the Danish National
Science Research Council, the University of Aarhus, and
the LEO Pharma Research Foundation for generous
financial support.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal methods, spectroscopic data for 3a -c, copies of H NMR
and 13C NMR spectra for compounds 2a -i and 6, and single-
crystal X-ray structure and crystallographic data for 2a . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0358170
(16) (a) Kobayashi, S.; Manabe, K. Tetrahedron Lett. 1999, 40, 3773.
(b) Kobayashi, S.; Busujima, T.; Nagayama, S. Synlett 1999, 545.
(17) Minor amounts of the 2-oxazolidinone and the corresponding
unsaturated ester were also detected (1H NMR) in the case of the ZnCl2-
mediated reaction of 4b and 3a (Table 3, entry 3). The exact reasons
for this apparent deviation of 4b from the other silyl enolates are
unknown.
(18) For spectroscopic data for 2-hydroxybut-2-enedioic acid diethyl
ester (9), see: Chrystal, E. J . T.; Couper, L.; Robins, D. J . Tetrahedron
1995, 37, 10241.
(19) Wu, Y.; Shen, X. Tetrahedron: Asymmetry 2000, 11, 4359.
4796 J . Org. Chem., Vol. 69, No. 14, 2004