Zinc carbenoid-mediated chain extension: Preparation of α,β-unsaturated-γ-keto esters and amides

Article abstract of DOI:10.1021/jo026299g

An efficient one-pot preparation of α,β-unsaturated-ω-keto esters and amides has been developed. A zinc carbenoid-mediated chain extension of a β-dicarbonyl substrate provides access to an intermediate zinc enolate, which is treated sequentially with a halogen and amine base. This method has been applied to a variety of ester and amide starting materials, as well as to amino acid-derived substrates and to a formal synthesis of (R,R)-(-)-pyrenophorin.

Full text of DOI:10.1021/jo026299g

SCHEME 1
Zin c Ca r ben oid -Med ia ted Ch a in Exten sion :
P r ep a r a tion of r,â-Un sa tu r a ted -γ-k eto
Ester s a n d Am id es
Matthew D. Ronsheim and Charles K. Zercher*
Department of Chemistry, University of New Hampshire,
Durham, New Hampshire 03824
ckz@christa.unh.edu
Received August 9, 2002
Abstr a ct: An efficient one-pot preparation of R,â-unsatur-
ated-γ-keto esters and amides has been developed. A zinc
carbenoid-mediated chain extension of a â-dicarbonyl sub-
strate provides access to an intermediate zinc enolate, which
is treated sequentially with a halogen and amine base. This
method has been applied to a variety of ester and amide
starting materials, as well as to amino acid-derived sub-
strates and to a formal synthesis of (R,R)-(-)-pyrenophorin.
The appearance of R,â-unsaturated-γ-keto ester func-
tionalities in a variety of natural products1 coupled with
the rich reactivity of this functional group have stimu-
lated interest in the preparation of this functionality.
Methods reported for the preparation of R,â-unsaturated-
γ-keto esters include the conversion of γ-keto esters to
the R,â-unsaturated systems via selenium dioxide oxida-
tion,2 bromination of γ-keto esters, followed by elimina-
tion with base,3 Horner-Emmons chemistry between
R-formyl esters and â-keto phosphonates,4 oxidation of
furan skeletons,5 and laborious multistep syntheses.6
Herein we present a rapid one-pot conversion of readily
available â-keto carbonyl compounds to the corresponding
R,â-unsaturated-γ-keto carbonyl systems utilizing a one-
pot chain extension followed by halogenation and elimi-
nation.
well as amides and phosphonates, to a mixture of diethyl
zinc and methylene iodide facilitates chain extension of
the system in which an intermediate zinc enolate (2) is
generated.10 Addition of a proton completes the chain
extension process in which the new methylene is incor-
porated adjacent to the ketone functionality. A variety
of alternative electrophiles have been used to trap this
intermediate enolate, namely aldehydes,10 ketones,11
iminium ions,11 and carbenoids.12 We envisioned a modi-
fication of this procedure in which the intermediate zinc
enolate (2) is trapped with an electrophile that could be
subsequently eliminated to form an R,â-unsaturated-γ-
dicarbonyl 6 (Scheme 1). Herein we report the results of
a study in which halogens were used to quench the
intermediate zinc enolate and the resulting halide elimi-
nated through treatment with base. Rapid and efficient
diastereoselective formation of an unsaturated system
results.
Initial attempts to capture the zinc enolate intermedi-
ate (2) utilized bromine as the electrophile and triethy-
lamine as the base. Formation of the R-bromo-γ-keto
carbonyl (4) was assumed and in situ elimination of the
halide provided the unsaturated system (6); however, the
yield of the olefin-containing compound was poor and a
product (5) resulting from iodination at the R-carbon and
incomplete elimination was observed. The source of the
iodine is likely the zinc iodide salts13 that are byproducts
of carbenoid formation and reaction; however, the details
of iodination are unclear. The ratio of products formed
The facile conversion of readily available â-keto esters
(1),7 amides,8 and phosphonates9 to the corresponding
γ-keto carbonyl system (3) through application of a zinc
carbenoid has been a recent focus of our research efforts.
We demonstrated that exposure of â-keto esters (1), as
(1) (a) Rothweiler, W.; Tamm, C. Helv. Chim. Acta 1970, 696-724.
(b) Grove, J . F. J . Chem. Soc. C 1971, 2261-2263. (c) Massias, M.;
Molho, L.; Rebuffat, S.; Cesario, M.; Guilhen, J . Phytochemistry 1989,
28, 1491-1494. (d) Sekiguchi, J .; Kuroda, H.; Yamada, Y.; Okada, H.
Tetrahedron Lett. 1985, 26, 2341-2342. (e) Proksa, B.; Fuska, J .
Pharmazie 1995, 50, 215-216. (f) Grove, J . F. J . Chem. Soc. C 1971,
2261-2263.
(2) Raymond, T. J . Am. Chem. Soc. 1950, 72, 3296-3297.
(3) McMurry, J . E.; Blaszczak, L. C. J . Org. Chem. 1974, 39, 2217-
2222.
(4) Schuda, P. F.; Ebner, C. B.; Potlock, S. J . Synthesis 1987, 12,
1055-1057.
(5) Antonioletti, R.; D’Auria, M.; Mico, A. De; Piancatelli, G.; Scettri,
A. Synthesis 1984, 3, 280-281.
(6) Hoffman, R. V.; Patonay, T.; Nayyar, N. K.; Tao, J . Tetrahedron
Lett. 1996, 37, 2381-2384.
(7) (a) Brogan, J . B.; Zercher, C. K. J . Org. Chem. 1997, 62, 6444-
6446. (b) Ronsheim, M. D.; Hilgenkamp, R.; Zercher, C. K. Org. Synth.
2002, 79, 146-153.
(10) Lai, S.; Zercher, C. K.; J asinski, J . P.; Reid, S. N.; Staples, R.
J . Org. Lett. 2001, 3, 4169-4171.
(11) Hanson, K. J . B.A. Thesis, 2001, University of New Hampshire.
(12) Hilgenkamp, R.; Zercher, C. K. Org. Lett. 2001, 3, 3037-3040.
(13) Stanko, V. I.; Okhlobystin, O. Yu.; Anorova, G. A.; Beletskaya,
I. P. Zh. Obs. Khim. 1970, 40, 2767.
(8) Hilgenkamp, R.; Zercher, C. K. Tetrahedron 2001, 57, 8793-
8800.
(9) Verbicky, C. A.; Zercher, C. K. J . Org. Chem. 2000, 65, 5615-
5622.
10.1021/jo026299g CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/23/2003
J . Org. Chem. 2003, 68, 4535-4538
4535

TABLE 1. Ch a in Exten sion -Oxid a tion -Elim in a tion of
Ester s a n d Am id es
TABLE 2. Ch a in Exten sion -Oxid a tion -Elim in a tion of
Am in o Acid s Su bstr a tes
SM
R
R′
OCH3
OC(CH3)3
OCH3
OCH2CH3
OCH2C6H5
OCH2CH3
CH2CHdCH2
N(C6H5)CH3
prod
yield, %
7
9
C(CH3)3
CH3
CH3
CH3
CH3
C6H5
CH3
CH3
8
86
73
67
70
73
59
71
63
10
12
14
16
18
20
22
11
13
15
17
19
21
under this initial set of reaction conditions was incon-
sistent and suitable yields of the desired R,â-unsaturated-
γ-keto ester were not obtained. Further attempts to form
the bromide intermediate 4 with N-bromosuccinimide
(NBS) or 1,2-dibromoethane were unsuccessful and re-
sulted in the formation of the saturated γ-keto ester 3.
To ensure that a single intermediate is being formed
in the halogenation reaction, molecular iodine was uti-
lized as the electrophile. Efficient, reproducible, and
exclusive iodination of the intermediate zinc enolate
resulted. All subsequent reactions were performed with
a 5-fold excess of iodine. Destruction of excess iodine with
saturated aqueous Na2S2O3, followed by treatment with
triethylamine provided mixtures of the R-iodo ester (5)
and the desired unsaturated ester (6). However, efficient
elimination was facilitated by treatment with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 10 equiv) and re-
sulted in the formation of the R,â-unsaturated-γ-keto
ester (6) or amide in good yield (Table 1). Isolation of the
intermediate iodide (5) is possible when DBU is not added
to the reaction; however, chromatographic purification
of the iodinated species is challenging and typically
results in partial elimination and the formation of several
products.
tives14 and aromatic and aliphatic cuprates.15 Although
the simple chain extension of monoprotected amino acid
derivatives proceeds smoothly,9,16 we found that exposure
of amino acid derivatives 23 and 24 to the chain exten-
sion-oxidation-elimination reaction resulted in a very
complex reaction mixture and afforded the desired prod-
uct in very low yield. However, simple benzyl protection
of the nitrogen was sufficient to provide the desired
iodinated species, which is readily eliminated to the R,â-
unsaturated system (Table 2). HPLC analysis with a
chiral stationary phase revealed that complete racem-
ization of the amino acids occurred under the elimination
reaction conditions. Since loss of stereochemical integrity
is not observed in the simple chain extension of amino
acid-derived â-keto esters,17 the epimerization is appar-
ently occurring in the elimination step. We have recently
reported18 a procedure in which an intermediate iodide
is isolated and, without purification, subjected to 1.2
equiv of DBU in cold diethyl ether to facilitate a kineti-
cally controlled elimination. A similar avoidance of excess
DBU in the reaction of amino acid-derived â-keto esters
would be expected to minimize potential epimerization
in the elimination reaction. Efforts are presently under-
way to develop conditions in which the stereochemical
integrity of the amino acid-derived substrates is main-
tained.
The formation of the R,â-unsaturated compounds pro-
ceeds efficiently with complete E selectivity in the forma-
tion of the new alkene. No evidence of Z-olefin formation
was observed in any of the reactions. In addition, we have
demonstrated that oxidation of the enolate is efficient
even in the presence of reactive olefins. For example,
conversion of 19 to 20 proceeds cleanly, without cyclo-
propanation or halogenation of the olefin.
In addition to performing this transformation on
simple â-keto carbonyl compounds, we have also applied
this methodology to the formation of amino acid-derived
R,â-unsaturated-γ-keto carbonyl systems. These conju-
gated olefins have been used in the preparation of keto-
methylene isosteric replacements for peptide bonds
through conjugate addition of malonate anion deriva-
We have further demonstrated the utility of this
transformation in a two-pot formal synthesis of the 16-
(14) Deziel, R.; Plante, R.; Caron, V.; Grenier, L.; Llinas-Brunet, M.
J . Org. Chem. 1996, 61, 2901-2903.
(15) Captain, L. F.; Xia, X.; Liotta, D. C. Tetrahedron Lett. 1996,
37, 4293-4296.
4536 J . Org. Chem., Vol. 68, No. 11, 2003

was added and the resulting white suspension was stirred for
10 min. Methyl pivaloylacetate (7) (0.16 mL, 1.0 mmol) was
added rapidly by syringe and allowed to stir at 0 °C for 30 min.
Iodine (1.27 g, 5 mmol) was added to the reaction mixture in a
single portion and the solution was allowed to stir until a pink
color persisted for 30 s. Saturated aqueous sodium thiosulfate
(10 mL) was added and the biphasic mixture was stirred until
the pink color had disappeared. 1,8-Diazabicyclo[5.4.0]undec-7-
ene (DBU) (1.5 mL, 10 mmol) was added and the mixture was
stirred vigorously for 1 min. Saturated aqueous ammonium
chloride was added and the solution was extracted three times
with diethyl ether. The combined organic layers were dried with
anhydrous sodium sulfate and concentrated in vacuo. The
residue was chromatographed on silica (15:1, hexanes/ethyl
acetate; Rf 0.23) to yield 147 mg (86%) of 8 as a yellow oil.
Spectroscopic data were identical with those reported in the
literature.18 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H, J ) 15.6
Hz), 6.75 (d, 1H, J ) 15.6 Hz), 3.79 (s, 3H), 1.74 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 203.8, 166.3, 135.8, 131.1, 52.4, 43.8,
25.9.
SCHEME 2
1,1-Dim eth yleth yl E-4-Oxo-p en t-2-en oa te23 (10). Chro-
matography on silica (20:1, hexanes/EtOAc; Rf 0.20) yielded 170
mg (73%) of a yellow oil that possessed spectroscopic data
identical with that reported in the literature. 1H NMR (400 MHz,
CDCl3) δ 6.92 (d, 1H, J ) 16.4 Hz), 6.58 (d, 1H, J ) 16.4 Hz),
2.35 (s, 3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 198.2,
164.9, 139.4, 133.9, 82.3, 28.2, 28.1.
Meth yl E-4-Oxo-p en t-2-en oa te24 (12). Chromatography on
silica (10:1, hexanes/EtOAc; Rf 0.25) yielded 86 mg (67%) of a
white solid that possessed spectroscopic data identical with that
reported in the literature. Mp 58.5-60.0 °C (lit.25 mp 59-60 °C);
1H NMR (400 MHz, CDCl3) δ 7.03, (d, 1H, J ) 16.4 Hz), 6.66 (d,
1H, J ) 16.4 Hz), 3.83 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.7, 166.1, 140.3, 131.3, 52.6, 28.4.
membered dilactone natural product pyrenophorin 31.19
Reaction of the dianion of methyl acetoacetate (11) with
R-propylene oxide (32) followed by capture of the result-
ing alkoxide with TBDPSCl produced the hydroxy-
protected â-keto ester 33 in 47% yield.20 Exposure of 33
to the chain extension/iodination/elimination reaction
conditions produced the desired R,â-unsaturated-γ-keto
ester 34 in 64% yield (Scheme 2). The enantiomer of 34
has been reported as a synthetic intermediate in the total
synthesis of (R,R)-(-)-pyrenophorin 31.21
We have developed an efficient method for the forma-
tion of R,â-unsaturated-γ-keto esters and amides from
readily available â-keto esters and amides. In addition,
we applied this methodology to the synthesis of amino
acid-derived compounds that offer potential utility as
precursors to ketomethylene isosteres. A short formal
synthesis of optically active pyrenophorin 31 was ac-
complished.
Eth yl E-4-Oxo-p en t-2-en oa te26 (14). Chromatography on
silica (10:1, hexanes/EtOAc; Rf 0.25) yielded 100 mg (70%) of a
yellow oil that possessed spectroscopic data identical with that
reported in the literature. 1H NMR (500 MHz, CDCl3) δ 7.04 (d,
1H, J ) 16.0 Hz), 6.65 (d, 1H, J ) 16.0 Hz), 4.28 (q, 2H, J ) 7.0
Hz), 2.36 (s, 3H), 1.33 (t, 3H, J ) 7.0 Hz); 13C NMR (125 MHz,
CDCl3) δ 197.9, 185.7, 140.2, 131.8, 61.7, 28.3, 14.3.
P h en ylm eth yl E-4-Oxo-p en t-2-en oa te2 (16). Chromatog-
raphy on silica (15:1, hexanes/EtOAc; Rf 0.19) yielded 148 mg
(73%) of a yellow oil that possessed spectroscopic data identical
with that reported in the literature. 1H NMR (400 MHz, CDCl3)
δ 7.39-7.36 (m, 5H), 7.05 (d, 1H, J ) 16.0 Hz), 6.69 (d, 1H, J )
16.4 Hz), 5.25 (s, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 197.7, 165.5, 140.6, 135.4, 131.4, 128.9, 128.8, 128.6, 67.4, 28.3.
Eth yl E-4-Oxo-4-p h en yl-bu t-2-en oa te18 (18). Chromatog-
raphy on silica (15:1, hexanes/EtOAc; Rf 0.21) yielded 120 mg
(59%) of a yellow oil that possessed spectroscopic data identical
with that reported in the literature. 1H NMR (400 MHz, CDCl3)
δ 8.01-7.99 (m, 2H), 7.91 (d, 1H, J ) 15.6 Hz), 7.63-7.60 (m,
1H), 7.53-7.49 (m, 2H), 6.89 (d, 1H, J ) 15.6 Hz), 4.30 (t, 2H,
J ) 7.2 Hz), 1.35 (q, 3H, J ) 7.2 Hz); 13C NMR (100 MHz, CDCl3)
δ 189.8, 165.8, 136.8, 136.6, 134.0, 132.8, 129.1, 129.0, 61.6, 14.4.
P r op -2-en yl E-4-Oxo-p en t-2-en oa te (20). Chromatography
on silica (10:1, hexanes/EtOAc; Rf 0.23) yielded 110 mg (71%) of
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were run in oven-dried
glassware under a nitrogen atmosphere. Methylene chloride was
distilled from phosphorus pentoxide (P2O5). The reactions were
monitored by thin-layer chromatography (TLC) on EM Science
F254 glass plates that were visualized by short-wavelength UV
and anisaldehyde stain. Column chromatography was performed
on Baker 40 µm silica gel, using the indicated mobile phase. The
Rf value refers to the use of the identical mobile phase in TLC
analysis. Starting materials were purchased from commercial
sources and used as received. HPLC analysis was performed
through use of a Diacel Chiralpak AD-RH reverse-phase column.
Gen er a l P r oced u r e: Meth yl E-5,5-Dim eth yl-4-oxo-h ex-
2-en oa te22 (8). A 100-mL round-bottom flask was equipped with
a stir bar and charged with 15 mL of methylene chloride and
diethyl zinc (1.0 M in hexanes, 5.0 mL, 5.0 mmol) under an
atmosphere of N2 at 0 °C. Methylene iodide (0.42 mL, 5.2 mmol)
1
a yellow oil. H NMR (500 MHz, CDCl3) δ 7.05 (d, 1H, J ) 16.1
Hz), 6.70 (d, 1H, J ) 16.1 Hz), 5.94 (tdd, 1H, J ) 5.9, 10.7, 16.1
Hz), 5.39-5.28 (m, 2H), 4.71 (td, 2H, J ) 1.5, 5.9), 2.37 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 194.2, 161.8, 136.9, 128.1, 127.9,
115.7, 62.7, 24.8.
N-Meth yl-N-p h en yl E-4-Oxo-p en t-2-en oa m id e (22). Chro-
matography on silica (3:1, hexanes/EtOAc; Rf 0.20) yielded 104
mg (60%) of a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.47-
7.27 (m, 3H), 7.18-7.17 (m, 2H), 7.07 (d, 1H, J ) 15.5 Hz), 6.64
(d, 1H, J ) 15.5 Hz), 3.40 (s, 3H), 2.19 (s, 3H); 13C NMR (125
(16) Theberge, C. T. Ph.D. Dissertation, 2002, University of New
Hampshire.
(17) Theberge, C. R.; Zercher, C. K. Tetrahedron 2003, 59, 1521-
1527.
(18) Ronsheim, M. D.; Zercher, C. K. J . Org. Chem. 2003, 68,
(19) Nozoe, S.; Hirai, K.; Tsuda, K.; Ishibashi, K.; Shirasaka, M.
Tetrahedron Lett. 1965, 4675-4677.
(20) Hoffman, R. V.; Patonay, T.; Nayyar, N. K.; Tao, J . Tetrahedron
Lett. 1996, 37, 2381-2384.
(23) Lerche, H. Chem. Ber. 1974, 107, 1509-1517.
(24) Hase, T. A.; Ourila, A.; Holmberg, C. J . Org. Chem. 1981, 46,
3137-3139.
(25) Raymond, T. J . Am. Chem. Soc. 1950, 72, 4304-4306.
(26) Bonete, P.; Najera, C. Tetrahedron 1995, 51, 2763-2776.
(21) Machinaga, N.; Kibayashi, C. Tetrahedron Lett. 1993, 34, 841-
844.
(22) Bonete, P.; Najera, C. J . Org. Chem. 1994, 59, 3202-3209.
J . Org. Chem, Vol. 68, No. 11, 2003 4537

MHz, CDCl3) δ 197.7, 164.5, 142.7, 137.2, 131.9, 129.9, 128.2,
127.0, 37.7, 28.8.
combined organic extracts were dried over Na2SO4 and concen-
trated in vacuo. Chromatography on silica (15:1, hexanes/EtOAc;
Rf 0.18) yielded 823 mg (48%) of 33 as a clear oil. H NMR (500
1
P h en ylm eth yl E-4-(1-Ben zoyl-p yr r olid in -2-yl)-4-oxo-bu t-
2-en oa te (26). Chromatography on silica (2:1, hexanes/EtOAc;
Rf 0.21) yielded 65 mg (62%) of a yellow oil. 1H NMR (500 MHz,
CDCl3) δ 7.60-7.22 (m, 11H), 6.90 (d, 1H, J ) 16.1 Hz), 5.24 (s,
2H), 4.96 (dd, 1H, J ) 6.4, 8.8 Hz), 3.70-3.56 (m, 2H), 2.34-
2.25 (m, 1H), 2.05-1.88 (m, 3H); 13C NMR (125 MHz, CDCl3) δ
197.3, 169.8, 165.4, 137.3, 135.9, 135.5, 131.9, 130.6, 128.9, 128.7,
128.6, 128.5, 127.6, 67.4, 64.5, 50.4, 28.6, 25.7. HRMS (CI, NH3)
[M + H]+ calcd for C22H22NO4 364.1544, found 364.1546.
Meth yl E-5-[N-Ben zyl-N-(ben zyloxyca r bon yl)a m in o]-4-
oxo-h ex-2-en oa te (28). Chromatography on silica (2:1, hexanes/
EtOAc; Rf 0.21) yielded a yellow oil (65 mg, 62%) as a mixture
(55:45) of rotomers. 1H NMR (500 MHz, CDCl3) δ 7.40-7.15 (m,
10H), 7.08 (d, 0.55H, J ) 15.6 Hz), 6.90 (d, 0.45H, J ) 15.6 Hz),
6.65 (d, 0.55H, J ) 15.6 Hz), 6.41 (d, 0.45H, J ) 15.6 Hz), 5.25-
5.09 (m, 2H), 4.76 (d, 0.45H, J ) 13.0 Hz), 4.68 (d, 0.55H, J )
13.0 Hz), 4.46-4.31 (m, 1.55H), 4.02 (m, 0.45H), 3.75 (s, 3H),
1.33-1.21 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 196.8, 196.4,
166.0, 165.8, 156.2, 137.6, 137.4, 136.7, 136.3, 135.9, 130.8, 128.9,
128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 68.2, 61.3, 60.9, 52.4,
51.6, 49.9, 13.8, 13.3. HRMS (CI, NH3) [M + NH4]+ calcd for
C22H27N2O5 399.1914, found 399.1898.
MHz, CDCl3) δ 7.70-7.67 (m, 3H), 7.46-7.38 (m, 7H), 3.96-
3.90 (m, 1H), 3.72 (s, 3H), 3.38 (d, 1H, J ) 15.6 Hz), 3.35 (d, 1H,
J ) 15.6 Hz), 2.59 (ddd, 2H, J ) 5.9, 9.3, 15.1 Hz), 1.82-1.69
(m, 2H), 1.10-1.07 (m, 12H); 13C NMR (125 MHz, CDCl3) δ
202.5, 167.6, 135.8, 135.8, 134.8, 129.6, 129.5, 127.6, 127.5, 68.4,
52.2, 48.9, 38.7, 32.5, 27.0, 23.1, 19.2. [R]20 +10.25 (c 0.0122
D
g/mL, benzene).
Meth yl 7R-(ter t-Bu tyl-d ip h en yl-sila n yloxy)-4-oxo-oct-2-
en oa te18 (34). A 100-mL round-bottom flask was equipped with
a stir bar and charged with 15 mL of methylene chloride and
diethyl zinc (1.0 M in hexanes, 1.95 mL, 1.95 mmol) under an
atmosphere of N2 at 0 °C. Methylene iodide (0.16 mL, 2.03 mmol)
was added and the resulting white suspension was stirred for
10 min. Compound 33 (146 mg, 0.39 mmol) was added rapidly
by syringe and allowed to stir at 0 °C for 30 min. Iodine (516
mg, 2.03 mmol) was added in a single portion to the reaction
mixture and allowed to stir until a pink color persisted for 30 s.
Saturated aqueous sodium thiosulfate (10 mL) was added and
the biphasic mixture was stirred until the pink color had
disappeared. DBU (0.58 mL, 3.9 mmol) was added and the
mixture was stirred vigorously for 1 min. Saturated aqueous
ammonium chloride was added and the solution was extracted
three times with diethyl ether. The combined organic layers were
dried with anhydrous sodium sulfate and concentrated in vacuo.
The residue was chromatographed on silica (15:1, hexanes/ethyl
Met h yl E-2-[Ben zyl(4-oxo-p en t -2-en oyl)a m in o]p r op i-
on a te (30). Chromatography on silica (2:1, hexanes/EtOAc; Rf
1
0.18) yielded 120 mg (74%) of a yellow oil. H NMR (400 MHz,
CDCl3) δ 7.39-7.26 (m, 5H), 7.15 (d, 1H, J ) 15.2 Hz), 7.08 (d,
1H, J ) 15.6), 4.79-4.59 (m, 3H), 3.70 (s, 2.5H), 3.56 (s, 0.50H),
2.36 (s, 052H), 2.24 (s, 2.4H), 1.45-1.39 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 197.6, 171.9, 166.2, 138.8, 136.9, 131.4, 129.2,
128.2, 126.6, 54.8, 52.6, 50.6, 29.2, 15.0. HRMS (CI, NH3) [M +
H]+ calcd for C16H20NO4 290.1387, found 290.1395.
1
acetate; Rf 0.19) to yield 96 mg (64%) of 34 as a colorless oil. H
NMR (500 MHz, CDCl3) δ 7.65-7.62 (m, 3H), 7.43-7.36 (m, 7H),
6.98 (d, 1H, J ) 16.1 Hz), 6.58 (d, 1H, J ) 16.1 Hz), 3.96-3.90
(m, 1H), 3.82 (s, 3H), 2.64 (ddd, 2H, J ) 5.9, 9.3, 15.1 Hz), 1.82-
1.69 (m, 2H), 1.08 (d, 3H, J ) 8.3 Hz), 1.05 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 199.5, 166.0, 139.5, 135.9, 135.8, 134.8,
130.1, 129.7, 129.6, 127.6, 127.5, 68.7, 52.5, 37.5, 33.0, 27.3, 23.5,
Meth yl 6R-(ter t-Bu tyldiph en ylsilyloxy)-3-oxo-h eptan oate
(33). Into a 100-mL round-bottom flask containing a 60%
suspension of sodium hydride in mineral oil (221 mg, 5.5 mmol)
under an atmosphere of N2 was added THF (20 mL). The
resulting gray suspension was brought to 0 °C and methyl
acetoacetate (11) (0.54 mL, 5 mmol) was added slowly. The
resulting yellow solution was allowed to stir at this temperature
for 0.5 h. The temperature of the yellow solution was lowered
to -15 °C and a 2.5 M solution of n-BuLi (2.2 mL, 5.5 mL) was
added. The resulting red solution was allowed to stir for 15 min
and R-propylene oxide (32) (0.39 mL, 5.5 mmol) was added. The
solution was then stirred for 4 h at this temperature and
TBDPSCl (1.17 mL, 5 mmol) was added. The solution was
allowed to slowly warm to room temperature and stirred for an
additional 8 h. The reaction was quenched with NH4Cl (25 mL),
and the solution was extracted with ether (3 × 25 mL). The
19.5; [R]25 +19.1 (c 0.0045 g/mL, methanol).18 Optical purity
D
was assessed to be >95% by HPLC, using a chiral stationary
phase.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (R15 GM060967-01) and the University
of New Hampshire for their financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 8, 10, 12, 14, 16, 18, 20, 22, 26, 28, 30, 33, and 34.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O026299G
4538 J . Org. Chem., Vol. 68, No. 11, 2003