Short Synthetic Route to (Ϫ)-Acetomycin
SHORT COMMUNICATION
Pd-catalyzed diastereoselective σ-bond forming reactions, it Conclusion
is noteworthy that the face selectivity of a β-keto ester enol-
In conclusion, fully carbon-substituted consecutive qua-
ternary and tertiary carbon centers were constructed with
high regio- and stereoselectivity by a Pd catalyzed allylic
alkylation reaction. The utility of this reaction was demon-
strated by producing the shortest asymmetric synthesis of
(Ϫ)-acetomycin so far achieved. We are now investigating
the details of this reaction mechanism.
ate was highly controlled by a simple o-(diphenylphos-
phanyl)arylcarboxylic acid.
Acetomycin was isolated from Streptomyces ramulosus sp.
in 1958 by Prelog et al.[13] It is a rather small molecule (Mr
214) but possesses unique and potent anti-tumor activity.[14]
In addition, its highly oxygenated structure, having three
chiral centers located consecutively on the γ-lactone ring,
is particularly attractive for synthetic chemists. Although
several total syntheses, including ours, have been reported
so far,[15] these methods are rather tedious or lack flexibility
for the preparation of its analogues. The consecutive qua-
ternary and tertiary carbon centers of the molecule are
good synthetic targets for demonstrating the above syn-
thetic method. The synthesis is outlined in Scheme 4.
Experimental Section
Representative Experimental Procedure for Pd Catalyzed Allylic Al-
kylation Reaction: (R)-2-Acetoxy-4-phenyl-3-butene (1; 190 mg,
1.0 mmol) and ethyl 2-methylacetoacetate (2; 216 mg, 1.50 mmol)
were added to a stirred solution of 2-(diphenylphosphanyl)benzoic
acid (30.6 mg, 0.10 mmol) and Pd(OAc)2 (11.2 mg, 0.050 mmol) in
anhydrous 1,4-dioxane (7.4 mL). NaHMDS (1.40 mmol, 1.4 mL of
1.0 in THF) was slowly added dropwise at 0 °C, and the resultant
mixture allowed to warm up to room temperature over 12 h. The
standard work up and purification of the crude product by silica
gel chromatography gave 3 (237 mg) in 86% yield as a colorless oil
(R)-3: 1H NMR (400 MHz, CDCl3): δ ϭ 7.35Ϫ7.20 (m, 5 H), 6.43
(d, J ϭ 15.8 Hz, 1 H), 6.05 (dd, J ϭ 15.8, 8.6 Hz, 1 H), 4.22 (q,
J ϭ 7.1 Hz, 2 H), 3.23 (m, 1 H), 2.17 (s, 3 H), 1.35 (s, 3 H), 1.28
(t, J ϭ 7.1 Hz, 3 H), 1.13 (d, J ϭ 6.7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 204.9, 172.0, 137.2, 131.4, 130.3, 128.5,
127.4, 126.3, 63.5, 61.3, 41.1, 26.9, 16.4, 16.0, 14.1 ppm.
HRMS(EI) calcd. for C17H22O3 [Mϩ]: m/z ϭ 274.1569; found
274.1567.
1
(S)-3: H NMR (400 MHz, CDCl3): δ ϭ 7.43Ϫ7.19 (m, 5 H), 6.42
(d, J ϭ 15.8 Hz, 1 H), 6.15 (dd, J ϭ 15.8, 8.4 Hz, 1 H), 4.15 (q,
J ϭ 7.1 Hz, 2 H), 3.24 (m, 1 H), 2.19 (s, 3 H), 1.36 (s, 3 H), 1.23
(t, J ϭ 7.1 Hz, 3 H), 1.07 (d, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 205.0, 171.9, 137.3, 131.3, 130.7, 128.5,
127.3, 126.2, 63.7, 61.7, 41.0, 26.8, 15.7, 15.2, 14.1 ppm.
Scheme 4. Synthesis of (Ϫ)-acetomycin; reagents & conditions: a)
cat. Pd(OAc)2, 2-(diphenylphosphanyl)naphthoic acid, NaHMDS,
1,4-dioxane; b) cat. CSA, ethylene glycol, benzene, reflux; c)
LiSC12H25, HMPA; d) O3, CH2Cl2, then Me2S; e) MsCl, Et3N,
CH2Cl2; f) AcOK, dibenzo-18-crown-O-6, toluene, reflux; g)
TsOH, acetone
Acknowledgments
This work was financially supported in Grant-in-Aid for Scientific
Research on Priority Areas (A) in Japan.
In the first step, allylation of methyl 2-methylacetoacet-
ate[16] with (R)-1 using the ligand L-3 gave 9 in 95% yield
with a 93:7 ratio. Protection of the carbonyl group with
ethylene glycol in the presence of CSA followed by hydroly-
sis of methyl ester with odorless thiol lithium salt[17] gave
the carboxylic acid 10 in 83% yield in two steps. After ozon-
olysis of the alkenyl bond, the carboxylic acid was immedi-
ately cyclized to give lactol 11 in 95% yield. Replacement
of the anomeric hydroxy group at the β-position with an
acetoxy group was achieved with inversion of the configura-
tion via its methanesulfonate by the nucleophilic attack of
acetoxy anion activated by dibenzo-18-crown-O-6.[15b] The
desired acetate was obtained in 51% yield. Finally, depro-
tection of the acetal under acidic conditions gave (Ϫ)-aceto-
mycin in 82% yield. All of the physical and spectroscopic
data, including melting point (mp, 110Ϫ111 °C) and
specific rotation {[α]D22 ϭ Ϫ156 (c ϭ 0.43, EtOH)}, are in
good accordance with those of the natural product.[18] This
method has considerably shortened the reaction steps.[19]
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