Stereoselective synthesis of highly enantioenriched 3-methyl-2-cyclohexen-1-ones possessing an asymmetric quaternary carbon as C-4 or C-6: a sugar template approach

Article abstract of DOI:10.1016/j.tetlet.2007.12.031

The 1,4-addition of the enolate generated from α-methylated acetoacetate incorporated at C-4 of methyl 6-deoxy-2,3-di-O-(tert-butyldimethylsilyl)-α-d-glucopyranoside to methyl vinyl ketone, followed by aldol condensation of the resulting 1,4-addition prod

Full text of DOI:10.1016/j.tetlet.2007.12.031

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1203–1207
Stereoselective synthesis of highly enantioenriched
3-methyl-2-cyclohexen-1-ones possessing an asymmetric
quaternary carbon as C-4 or C-6: a sugar template approach
Hiroto Kubo, Ikuko Kozawa, Ken-ichi Takao, Kin-ichi Tadano *
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Received 1 November 2007; revised 5 December 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
The 1,4-addition of the enolate generated from a-methylated acetoacetate incorporated at C-4 of methyl 6-deoxy-2,3-di-O-(tert-butyl-
dimethylsilyl)-a-D-glucopyranoside to methyl vinyl ketone, followed by aldol condensation of the resulting 1,4-addition product under
two base-mediated conditions, provided 4-O-functionalized D-glucose derivatives with high diastereoselectivity. These products install a
3-methyl-2-cyclohexen-1-one-4- (or -6-) carboxylic acid as the O-4 ester, in which C-4 or C-6 is an asymmetric quaternary carbon.
Removal of the sugar template from those aldol condensation products provided synthetically useful 3,6-dimethyl-2-cyclohexen-1-
one-6-carboxylic acid and 3,4-dimethyl-2-cyclohexen-1-one-4-carboxylic acid derivatives both in high enantioenriched forms.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Sugar template; 1,4-Addition; Aldol condensation; Intramolecular cyclization
We have studied on the diastereoselective carbon–carbon
bond-forming reactions using sugar templates as stereocon-
trolling elements.1 Through these studies, we found that a
D-glucose derivative, that is, methyl 6-deoxy-2,3-di-O-
(tert-butyldimethylsilyl)-a-D-glucopyranoside (1),2 prepared
from methyl a-D-glucopyranoside in six steps, served as an
effective chiral template for a variety of carbon–carbon
bond-forming reactions using its 4-O-propionyl (2),3 4-O-
acryloyl-(3),4 and 4-O-crotonyl esters (4)2,3a (Fig. 1).
O
O
HO
O
O
TBSO
TBSO
TBSO
TBSO
OMe
OMe
1
2
O
O
O
O
TBSO
O
O
TBSO
TBSO
TBSO
OMe
3
OMe
4
One of the highlights in current organic synthesis is the
enantioselective construction of an all-carbon asymmetric
quaternary carbon. The highly stereoselective induction
of an all-carbon quaternary center has been investigated
in a number of groups, mostly using transition-metal-cata-
lysts,5 organocatalysts,6 or chiral auxiliaries.7 Recently, we
reported the highly diastereoselective quaternization of the
a-carbon in the 4-acetoacetate 5 of 1 by a double C-alkyl-
Fig. 1. Sugar template 1 and substrates 2–4 for stereoselective carbon–
carbon bond-forming reactions.
ation strategy (5 to 7 or 8) and the transformation of the
resulting differentially a,a-dialkylated acetoacetate 8 into
a 2-cyclohexen-1-one-6-carboxylic acid ester 11, installing
an asymmetric quaternary carbon at C-6 via 9 and 10 by
an aldol condensation strategy (Scheme 1).8
As a further development of this sugar template strategy
for asymmetric access to synthetically useful chiral carbo-
cycles possessing an asymmetric quaternary carbon, we
explored the 1,4-addition of the enolate generated from
*
Corresponding author. Tel./fax: +81 45 566 1571.
E-mail address: tadano@applc.keio.ac.jp (K. Tadano).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.031

1204
H. Kubo et al. / Tetrahedron Letters 49 (2008) 1203–1207
Xc
O
O
O
O
HO
TBSO
MeI/K2CO3
Xc
Xc
O
O
TBSO
OMe
5
1
O
R
O
O
for 8
RX/NaOMe
Xc
O
7 R: -CH2Ph
8 R: -CH2-CH=CH2
6
O
O
O
O
O
O
Xc
Xc
Ac2O/pyr.
Xc
O
O
O
DBU
HO
9
10
OHC
11
Scheme 1. Highly stereoselective formation of enantioenriched 2-cyclohexen-1-one with an asymmetric quaternary carbon from 5.
O
O
Xc
1
O
6
O
O
13 (71% yield obtained
Xc
a) or b)
O
using conditions a)
6
O
O
Xc
12
O
4
1
O
14 (73% yield obtained
using conditions b);
21% recovery of 6
Scheme 2. 1,4-Addition and successive intramolecular cyclization in the reaction of 6 and methyl vinyl ketone. Reagents and conditions: (a) methyl vinyl
ketone, MeONa in MeOH, ꢀ78 °C (3 h), ꢀ18 °C (0.5 h), 0 °C (0.5 h) then rt (3 h); (b) methyl vinyl ketone, pyrrolidine/AcOH, Et2O, rt (5 d).
a-methylated acetoacetate 6 to methyl vinyl ketone
(Scheme 2). This intermediate 6 exists as a 5:2:2 mixture
of three tautomeric forms. We did not determine the struc-
ture of each tautomer. If the 1,4-addition could provide an
adduct 12 stereoselectively, as in the case of the formation
of 7 and 8, the base-mediated intramolecular aldol cycli-
zation of the resulting 1,5-diketone 12 would be expected to
simultaneously proceed to aldol-like cyclization, providing
highly enantioenriched 3,6-dimethyl-2-cyclohexen-1-one-6-
carboxylic ester 13 and/or 3,4-dimethyl-2-cyclohexen-1-
one-4-carboxylic ester 14, both attached to C-4 of 1.
We explored the 1,4-addition of the enolate generated
from 6 to vinyl methyl ketone under two conditions. As
shown in Scheme 2, we first examined MeONa as the base.
As a result, a diastereomer 13 was obtained in 71% yield in
one-pot with high stereoselectivity.9 The structure of 13
was determined by 1H NMR analysis. Previously, we
observed that the second alkylation of 6 occurred exclu-
sively from the side opposite to the bulky (tert-butyl-
dimethyl)silyl (TBS) group located at C-3.8 This result
was explainable on the basis of the steric hindrance caused
by the TBS group. Similarly, the 1,4-addition in the present
case proceeded with high diastereoselectivity to provide the
intermediary 1,4-addition product 12. The structure of 13
having an (R)-configuration for the newly introduced qua-
ternary carbon was confirmed later. On the other hand, this
sequential 1,4-addition/intramolecular condensation of 6
was carried out using pyrrolidine/acetic acid. After stirring
a solution of 6 in Et2O in the presence of pyrrolidine and
acetic acid at rt for 5 days, another cyclohexenone 14 was
obtained in 89% yield based on recovered 6.10 The struc-
ture of 14 was confirmed as depicted through experiments
described later. Some previous papers demonstrated a sim-
ilar difference of regioselectivity in the second aldol con-
densation realized by switching the activator.11
Next, we examined the detachment of the sugar moiety
from the cyclization products 13 and 14. After several
attempts, we could not find efficient procedures to remove
the sugar moiety directly from 13 and 14.12 However, this
was smoothly achieved by the ethanolysis of de-O-silylated

H. Kubo et al. / Tetrahedron Letters 49 (2008) 1203–1207
1205
O
O
O
O
O
HO
HO
+
O
OEt
b)
a)
O
HO
13
14
HO
OMe
HO
OMe
17 (96%)
16 (83%, ee=86%)
15 (quant.)
O
O
b)
c)
O
OEt
O
+
HO
17 (85%)
O
HO
O
OMe
18 (quant.)
19 (78%, ee=80%)
Scheme 3. Removal of the sugar template from 13 and 14. Reagents and conditions: (a) 6 M aq HCl/THF (1:1), rt; (b) EtONa/EtOH, rt; (c) 4 M aq HCl/
THF (1:1), rt.
derivatives 15 and 18, which were prepared quantitatively
from 13 and 14, respectively, by acid hydrolysis (Scheme
3).13 The ethanolysis of 15 provided 1614 and methyl 6-
deoxy-a-D-glucopyranoside 1715 both in good yields. By
the analogous ethanolysis of 18, another cyclohexenone
1916 was obtained together with 17. The enantiomeric
excess (ee) of 1617 and 1918 was measured by chiral HPLC
analysis to be 86% and 80%, respectively. The (R)-configu-
ration for 16 was confirmed by the comparison of its levoro-
form in 45% yield from 5. Then the methylation of the a0-
carbon of cyclohexenone 22 with iodomethane in the pres-
ence of MeONa occurred with high diastereoselectivity to
provide 23.19 Removal of the TBS groups in the sugar moi-
ety of 23 and ethanolysis of the resulting 2420 provided
25,21 the (S)-antipode of the aforementioned (R)-enantio-
mer, that is, 16. The planar and absolute configurations
of 25 were confirmed by spectral and [a]D comparisons with
those of 16. The enantiomeric excess of 25 was measured to
be 82% by chiral HPLC analysis. The useful level of the
diastereoselectivity observed in the methylation at the a0-
position of the a,b-unsaturated cyclohexenone 22 should
be emphasized in comparison to the fact that the second
methylation of other linear-chain-substituted acetoacetates
did not reveal such a high diastereoselectivity as that
observed in the case of 22.22
26
tatory property [½aꢁD ꢀ50.0 (c 0.87, CHCl3)] to that of a
known (+)-(S)-enantiomer.11c Moreover, the (R)-configu-
24
ration of 19 [½aꢁD +93.5 (c 0.23, CHCl3)] was confirmed
by the comparison of the sign of [a]D to that of a known
(ꢀ)-(S)-isomer.11c
Finally, we explored the 1,4-addition of the enolate gen-
erated from 5 to methyl vinyl ketone in the presence of
MeONa/MeOH (Scheme 4). This 1,4-addition followed a
partial intramolecular aldol cyclization to provide a mix-
ture of 1,4-adduct 20 and the cyclized aldol product 21.
Without the determination of their stereostructures, the
mixture was further treated with MeONa in MeOH at rt.
This treatment provided the aldol condensation product
22 as a ca. 7:2:1 mixture of two diastereomers and an enol
In summary, highly enantioenriched ethyl (R)-3,6-
dimethyl-2-cyclohexen-1-one-6-carboxylate
and
ethyl
(R)-3,4-dimethyl-2-cyclohexen-1-one-4-carboxylate were
efficiently synthesized via diastereoselective 1,4-addition
reaction at the methyl-branched a-carbon of the 4-O-aceto-
acetyl derivative of methyl 6-deoxy-2,3-di-O-(tert-butyl-
dimethylsilyl)-a-D-glucopyranoside with methyl vinyl
O
O
O
O
O
O
Xc
Xc
Xc
b)
a)
O
O
O
O
5
+
22 as a mixture
of two diastereomers
and enol form (45%)
OH
21
20
O
O
O
O
O
O
Xc
c)
O
e)
OEt
17 (89%)
d)
O
O
HO
+
HO
OMe
25 (83%, ee=82%)
23 (87%)
24 (qunat.)
Scheme 4. Synthesis of 25, the antipode of 16. Reagents and conditons: (a) methyl vinyl ketone, MeONa/MeOH, ꢀ78 °C (1 h), ꢀ18 °C (1 h), 0 °C (1 h), rt
(24 h); (b) MaONa/MeOH, rt (24 h ); (c) MeI, MeONa/MeOH, ꢀ78 °C (0.5 h), ꢀ18 °C (0.5 h), 0 °C (0.5 h), rt (24 h); (d) 6 M aq HCl/THF (1:1), rt (32 h);
(e) EtONa/EtOH, rt (0.5 h).

1206
H. Kubo et al. / Tetrahedron Letters 49 (2008) 1203–1207
column chromatography on silica gel (AcOEt/hexane, 1:20) to
provide 94.7 mg (73%) of 14 as a colorless oil and 24.5 mg (21%) of
recovered 6. Compound 14: TLC, Rf 0.49 (AcOEt/ hexane, 1:3); IR
ketone, followed by intramolecular aldol condensation.
Furthermore, it should be emphasized that the single sugar
template used in this study, that is, methyl 6-deoxy-2,
3-di-O-(tert-butyldimethylsilyl)-a-D-glucopyranoside, works
remarkably well as enantiodiscriminating element in the
1,4-addition step, resulting in the formation of both
enantiomers of ethyl 3,6-dimethyl-2-cyclohexen-1-one-6-
carboxylates.
26
mmax (neat) 2930, 2860, 1730, 1680 cmꢀ1; ½aꢁD +147 (c 1.21, CHCl3);
1H NMR (300 MHz) d 0.03 (s, 3H), 0.11 (s, 9H), 0.84, 0.93 (2s, each
9H), 1.06 (d, 3H, J = 6.3 Hz), 1.48 (s, 3H), 1.90–2.69 (m, 4H), 2.04 (s,
3H), 3.37 (s, 3H), 3.69 (dd, 1H, J = 8.2, 3.3 Hz), 3.71 (m, 1H), 3.93 (t,
1H, J = 8.2 Hz), 4.62 (d, 1H, J = 3.3 Hz), 4.77 (t, 1H, J = 8.2 Hz),
5.94 (s, 1H); 13C NMR (68 MHz) d ꢀ4.3, ꢀ4.2, ꢀ3.2, ꢀ2.7, 17.9, 18.1,
18.5, 21.3, 24.1, 25.9 ꢂ 3, 26.2 ꢂ 3, 33.7, 34.5, 47.1, 55.0, 65.3, 72.1,
74.3, 78.6, 99.6, 129.1, 160.7, 172.5, 198.2; HRMS calcd for
27H49O6Si2 (M+–OCH3) m/z 525.3068, found 525.3069.
References and notes
C
11. (a) Terashima, S.; Sato, S.; Koga, K. Tetrahedron Lett. 1979, 20,
3469–3472; (b) Kreiser, W.; Balow, P. Tetrahedron Lett. 1981, 22,
1. Totani, K.; Takao, K.; Tadano, K. Synlett 2004, 2066–2680.
2. Munakata, R.; Totani, K.; Takao, K.; Tadano, K. Synlett 2000, 979–
982.
´
429–432; (c) Frater, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984,
40, 1269–1277.
12. We examined the following reaction conditions for the removal of the
sugar moiety from 13 and 14. For 13: NaOEt in EtOH, rt to 50 °C, 8 h
[recovery of 13 (51%), 16 (17%), 1 (9%), C-3 to C-4 silyl migrated
sugar (28%)]. For 14: NaOEt in EtOH, rt to reflux, 5 h [recovery of 14
(39%), 19 (19%); 1 (23%), C-3 to C-4 silyl migrated sugar (37%). For
13: hydrazine hydrate in EtOH, 140 °C (sealed tube), 24 h8 [the
hydrazine adduct = a pyrazoline derivative (19%), 1 (77%), C-3 to C-4
silyl migrated sugar (17%)].
3. (a) Totani, K.; Asano, S.; Takao, K.; Tadano, K. Synlett 2001, 1772–
1776; (b) Asano, S.; Tamai, T.; Totani, K.; Takao, K.; Tadano, K.
Synlett 2003, 2252–2254; (c) Sasaki, D.; Sawamoto, D.; Takao, K.;
Tadano, K.; Okue, M.; Ajito, K. Heterocycles 2007, 72, 103–110.
4. (a) Nagatsuka, T.; Yamaguchi, S.; Totani, K.; Takao, K.; Tadano, K.
Synlett 2001, 481–484; (b) Nagatsuka, T.; Yamaguchi, S.; Totani, K.;
Takao, K.; Tadano, K. J. Carbohydr. Chem. 2001, 20, 519–535; (c)
Tamai, T.; Asano, S.; Totani, K.; Takao, K.; Tadano, K. Synlett
2003, 1865–1867.
5. Some recent prominent papers on this subject: (a) Trost, B. M.;
Pissot-Soldermann, C.; Chen, I.; Schroeder, G. M. J. Am. Chem. Soc.
2004, 126, 4480–4481; (b) Trost, B. M.; Xu, J. J. Am. Chem. Soc.
2005, 127, 2846–2847; (c) Mohr, J. T.; Behenna, D. C.; Harned, A.
M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2005, 44, 6924–6927.
6. Some recent prominent papers on this subject: (a) Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672–5673; (b)
Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 11616–11617.
13. For the acid hydrolysis of 13: To a cooled (0 °C) stirred solution of 13
(302 mg, 542 lmol) in THF (3.0 mL) was added 6 M aqueous HCl
(3.0 mL). The mixture was stirred at rt for 32 h and neutralized with
saturated aqueous NaHCO3 (20 mL). This was extracted with CH2Cl2
(10 mL ꢂ 3). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column chromato-
graphy on silica gel (AcOEt/hexane, 1:10) to provide 178 mg (quant.)
of 15 as a colorless oil: TLC, Rf 0.27 (AcOEt); IR mmax (neat) 3450,
28
2940, 1730, 1680 cmꢀ1; ½aꢁD +110 (c 1.47, CHCl3); 1H NMR
(300 MHz) d 1.18 (d, 3H, J = 6.3 Hz), 1.41 (s, 3H), 1.86–2.60 (m,
4H), 1.97 (s, 3H), 2.42 (br s, 1H), 3.22 (br s, 1H), 3.42 (s, 3H), 3.60
(dd, 1H, J = 9.2, 3.8 Hz), 3.77 (t, 1H, J = 9.2 Hz), 3.77 (m, 1H), 4.65
(t, 1H, J = 9.2 Hz), 4.74 (d, 1H, J = 3.8 Hz), 5.89 (s, 1H); 13C NMR
(68 MHz) d 17.2, 19.5, 24.2, 28.2, 32.2, 52.6, 55.3, 65.1, 72.5, 72.7,
77.0, 99.0, 124.9, 162.6, 172.5, 197.3; HRMS calcd for C16H24O7 (M+)
m/z 328.1522, found 328.1532.
7. A recent review on this subject Arya, P.; Qin, H. Tetrahedron 2000,
56, 917–947.
8. Kozawa, I.; Akashi, Y.; Takiguchi, K.; Sasaki, D.; Sawamoto, D.;
Takao, K.; Tadano, K. Synlett 2007, 399–402.
9. For the synthesis of 13, the following reaction was carried out under
Ar. To a cooled (ꢀ78 °C) stirred solution of 6 (135 mg, 267 lmol) in
MeOH (2.7 mL) was added NaOMe (1.0 M solution in MeOH,
320 lL, 320 lmol). The mixture was stirred at ꢀ78 °C for 30 min, and
methyl vinyl ketone (45 lL, 560 lmol) was added. After being stirred
at ꢀ78 °C for 3 h, at ꢀ18 °C for 0.5 h, at 0 °C for 0.5 h, and at rt for
3 h, the mixture was quenched with saturated aqueous NH4Cl (1 mL).
The mixture was diluted with AcOEt (10 mL), and washed with
saturated aqueous NH4Cl (5 mL ꢂ 3). The organic layer was dried
(Na2SO4) and concentrated in vacuo.The residue was purified by
column chromatography on silica gel (AcOEt/hexane, 1:80) to
provide 105 mg (71%) of 13 as a colorless oil: TLC, Rf 0.54
Using 4 M aqueous HCl, compound 18 was obtained from 14
analogously as above: 18 as a colorless oil: TLC, Rf 0.25 (AcOEt); IR
27
mmax (neat) 3400, 2950,1730, 1680 cmꢀ1; ½aꢁD +159 (c 1.46, CHCl3);
1H NMR (300 MHz) d 1.17 (d, 3H, J = 6.3 Hz), 1.46 (s, 3H), 1.95–
2.67 (m, 4H), 1.99 (s, 3H), 2.67 (br, 1H), 3.11 (br, 1H), 3.43 (s, 3H),
3.55 (dd, 1H, J = 9.6, 3.6 Hz), 3.73 (t, 1H, J = 9.6 Hz), 3.76 (m, 1H),
4.70 (t, 1H, J = 9.6 Hz), 4.73 (d, 1H, J = 3.6 Hz), 5.94 (s, 1H); 13C
NMR (68 MHz) d 17.4, 21.2, 22.7, 34.2, 34.6, 47.5, 55.5, 65.0, 72.5,
73.0, 76.2, 99.0, 128.5,161.0, 173.6,198.8; HRMS calcd for C16H24O7
(M+) m/z 328.1522, found 328.1527.
23
14. For the ethanolysis of 15: To a cooled (0 °C) stirred solution of 15
(27.9 mg, 75.8 lmol) in EtOH (1.0 mL) was added EtONa (1.0 M
solution in EtOH, 80 lL, 80 lmol). The mixture was stirred at rt for
30 min and Amberlite IR 120 [H+] was added for neutralization. The
resin was filtered off and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography on silica gel (AcOEt/
hexane, 1:10 then AcOEt) to provide 12.4 mg (83%) of 16 and 12.9 mg
(96%) of 17. Compound 16 was obtained as a colorless oil: TLC, Rf
(AcOEt/hexane, 1:3); ½aꢁD +68.2 (c 0.82, CHCl3); IR mmax (neat)
1
2930, 2860, 1730, 1680 cmꢀ1; H NMR (300 MHz) d 0.00, 0.07, 0.09,
0.09 (4s, each 3H), 0.82, 0.91 (2s, each 9H), 1.14 (d, 3H, J = 6.3 Hz),
1.39 (s, 3H), 1.85–2.58 (m, 4H), 1.92 (s, 3H), 3.37 (s, 3H), 3.66 (dd,
1H, J = 8.4, 3.3 Hz), 3.68 (m, 1H), 3.90 (t, 1H, J = 8.4 Hz), 4.59 (d,
1H, J = 3.3 Hz), 4.73 (t, 1H, J = 8.4 Hz), 5.86 (s, 1H); 13C NMR
(68 MHz) d ꢀ4.3, ꢀ4.2, ꢀ3.2, ꢀ2.6, 17.8, 17.9, 18.5, 20.7, 24.2,
25.9 ꢂ 3, 26.2 ꢂ 3, 28.2, 32.5, 52.5, 54.9, 65.6, 72.0, 74.5, 78.4, 99.6,
125.6, 161.7, 171.3, 195.7; HRMS calcd for C27H49O6Si2 (M+–OCH3)
m/z 525.3068, found 525.3070.
26
0.80 (AcOEt); IR mmax (neat) 2980, 2940, 1730, 1680 cmꢀ1; ½aꢁD ꢀ50.0
(c 0.87, CHCl3); 1H NMR (300 MHz) d 1.23 (t, 3H, J = 7.1 Hz), 1.37
(s, 3H), 1.82–2.52 (m, 4H), 1.95 (s, 3H), 4.16 (q, 2H J = 7.1 Hz), 5.90
(s, 1H); 13C NMR (68 MHz) d 14.1, 20.3, 24.2, 28.6, 33.1, 52.2, 61.2,
125.6, 161.4, 172.8, 196.8; HRMS calcd for C11H16O3 (M+) m/z
196.1099, found 196.1104. Compound 17 was obtained as white
crystals: TLC, Rf 0.09 (AcOEt); mp 93–96 °C; IR mmax (KBr) 3400,
10. For the synthesis of 14, the following reaction was carried out under
Ar. To a cooled (0 °C) stirred solution of 6 (118 mg, 234 lmol) in
Et2O (2.4 mL) were added methyl vinyl ketone (40 lL, 490 lmol),
pyrrolidine (20 lL, 250 lmol), and AcOH (15 lL, 200 lmol). After
being stirred at rt for 5 days, the mixture was quenched with saturated
aqueous NH4Cl (1 mL), diluted with AcOEt (10 mL) and washed with
saturated aqueous NH4Cl (5 mL ꢂ 3). The organic layer was dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
22
2940 cmꢀ1; ½aꢁD +147 (c 1.00, CHCl3); 1H NMR (300 MHz) d 1.29 (d,
3H, J = 6.3 Hz), 2.18 (br s, 1H), 3.15 (t, 1H, J = 9.2 Hz), 3.42 (s, 3H),
3.53–3.72 (m, 3H), 4.01 (br s, 1H), 4.70 (d, 1H, J = 3.3 Hz), 4.71 (br s,

H. Kubo et al. / Tetrahedron Letters 49 (2008) 1203–1207
1207
1H); 13C NMR (68 MHz) d 17.5, 55.1, 67.3, 72.4, 74.4, 75.5, 99.3;
HRMS calcd for C7H13O5 (M+–H) m/z 177.0763, found 177.0764.
15. Yamazaki, O.; Togo, H.; Matsubayashi, S.; Yokoyama, M. Tetra-
hedron 1999, 55, 3735–3747.
(neat) 2930, 2860, 1730, 1680 cmꢀ1
;
1H NMR (300 MHz) for the
major product d 0.04, 0.08, 0.10, 0.11 (4s, each 3H), 0.85, 0.92 (2s,
each 9H), 1.31 (d, 3H, J = 6.0 Hz), 1.92–2.51 (m, 4H), 1.98 (s, 3H),
3.32 (m, 1H), 3.36 (s, 3H), 3.66 (dd, 1H, J = 9.2, 3.6 Hz), 3.79 (m,
1H), 3.95 (t, 1H, J = 9.2 Hz), 4.62 (d, 1H, J = 3.6 Hz), 4.74 (t, 1H,
J = 9.2 Hz), 5.89 (s, 1H); HRMS calcd for C27H50O7Si2 (M+) m/z
542.3095, found 542.3103.
16. By the ethanolysis of 18 as described for the conversion of 15 to 16,
compound 19 was obtained as a colorless oil: TLC, Rf 0.81 (AcOEt/
24
hexane, 1:1); ½aꢁD +93.5 (c 0.23, CHCl3); IR mmax (neat) 2980, 2940,
1730, 1680 cmꢀ1; 1H NMR (300 MHz) d 1.27 (t, 3H, J = 7.2 Hz), 1.44
(s, 3H), 1.89–2.57 (m, 4H), 1.97 (s, 3H), 4.20 (q, 2H, J = 7.2 Hz), 5.92
(s, 1H); 13C NMR (68 MHz) d 14.1, 21.1, 22.3, 34.2, 34.3, 47.3, 61.4,
128.1, 161.5, 174.1, 198.3; HRMS calcd for C11H16O3 (M+) m/z
196.1099, found 196.1100.
The following reaction was carried out under Ar. To a cooled
(ꢀ78 °C) stirred solution of the mixture obtained above 22 (111 mg,
204 lmol) in MeOH (2.2 mL) was added NaOMe (1.0 M solution in
MeOH, 200 lL, 200 lmol). The mixture was stirred at ꢀ78 °C for
15 min, and then iodomethane (40 lL, 640 lmol) was added. After
being stirred at ꢀ78 °C for 0.5 h, at ꢀ18 °C for 0.5 h, at 0 °C for 0.5 h,
and at rt for 24 h, the mixture was quenched with saturated aqueous
NH4Cl (1 mL), diluted with saturated aqueous NH4Cl (10 mL), and
extracted with CH2Cl2 (5 mL ꢂ 3). The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (AcOEt/hexane, 1:80) to
provide 99.2 mg (87%) of 23 as a colorless oil. TLC, Rf 0.54 (AcOEt/
17. HPLC analysis (column, Daicel Chiralpak AD-H, 2-propanol:hex-
ane = 1:80, flow rate = 0.5 mL/min); tR (min) = 38.1 for 16, 34.2 for
(S)-16. A racemic mixture of 16 was prepared from commercial ethyl
2-methylacetoacetate y treatment with methyl vinyl ketone in MeOH
in the presence of MeONa, followed by ester exchange with EtONa in
EtOH.
18. HPLC analysis (column, Daicel Chiralpak OJ-H, MeOH:hex-
ane = 1:80, flow rate = 0.5 mL/min); tR (min) = 24.2 for 19, 21.5
for (S)-19. A racemic mixture of 19 was prepared from ethyl 2-
methylacetoacetate by treatment with methyl vinyl ketone in the
presence of pyrrolidine/AcOH.
19. For the synthesis of 23, the following reaction was carried out under
Ar. To a cooled (ꢀ78 °C) stirred solution of 5 (309 mg, 630 lmol) in
MeOH (6.2 mL) was added MeONa (1.0 M solution in MeOH,
760 lL, 760 lmol). The mixture was stirred at ꢀ78 °C for 30 min, and
then methyl vinyl ketone (200 lL, 2.52 mmol) was added. The mixture
was stirred at ꢀ78 °C for 1 h, at ꢀ18 °C for 1 h, at 0 °C for 1 h, and at
rt for 24 h. The mixture was quenched with saturated aqueous NH4Cl
(1 mL), diluted with saturated aqueous NH4Cl (10 mL), and extracted
with CH2Cl2 (5 mL ꢂ 3). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (AcOEt/hexane, 1:10) to
provide 318 mg of a mixture of 20 and 21, which was used for the
next step directly.
21
hexane, 1:3); IR mmax (neat) 2930, 2860, 1730, 1680 cmꢀ1; ½aꢁD +71.7
(c 1.12, CHCl3); 1H NMR (300 MHz) d 0.00, 0.06, 0.10, 0.10 (4s, each
3H), 0.85, 0.92 (2s, each 9H), 1.16 (d, 3H, J = 6.3 Hz), 1.41 (s, 3H),
1.84–2.59 (m, 4H), 1.95 (s, 3H), 3.36 (s, 3H), 3.66 (dd, 1H, J = 8.4,
3.3 Hz), 3.70 (m, 1H), 3.93 (t, 1H, J = 8.4 Hz), 4.60 (d, 1H,
J = 3.3 Hz), 4.74 (t, 1H, J = 8.4 Hz), 5.87 (s, 1H); 13C NMR
(68 MHz) d ꢀ4.3, ꢀ4.1, ꢀ3.2, ꢀ2.6, 17.6, 17.8, 18.5, 20.0, 24.2,
26.0 ꢂ 3, 26.2 ꢂ 3, 28.2, 32.9, 52.5, 54.9, 65.6, 71.7, 74.6, 78.2, 99.7,
125.3, 161.9, 171.8, 196.6; HRMS calcd for C27H49O6Si2 (M+–OCH3)
m/z 525.3068, found 525.3073.
20. By the analogous acid hydrolysis used for the conversion of 13 into
15, compound 23 was converted into 24 quantitatively. Compound 24
was obtained as a colorless oil.TLC, Rf 0.27 (AcOEt); IR mmax (neat)
21
3180, 2880, 1730, 1680 cmꢀ1; ½aꢁD +54.4 (c 3.42, CHCl3); 1H NMR
(300 MHz) d 1.13 (d, 3H, J = 6.0 Hz), 1.40 (s, 3H), 1.89–2.65 (m, 4H),
1.98 (s, 3H), 2.64 (br s, 1H), 3.41 (s, 3H), 3.60 (br s, 1H), 3.60–3.80 (m,
3H), 4.66 (t, 1H, J = 10.5 Hz), 4.74 (d, 1H, J = 4.1 Hz) 5.90 (s, 1H);
13C NMR (68 MHz) d 17.1 19.1, 24.2, 28.0, 32.1, 52.9, 55.3, 64.9,
72.3 ꢂ 2, 76.8, 99.0, 125.0, 162.7, 172.4, 198.3; HRMS calcd for
C16H24O7 (M+) m/z 328.1522, found 328.1525.
The following reaction was carried out under Ar. To a cooled (0 °C)
stirred solution of the mixture obtained above (318 mg) in MeOH
(6.4 mL) was added MeONa (1.0 M solution in MeOH, 570 lL,
570 lmol). After being stirred at rt for 24 h, the mixture was quenched
with saturated aqueous NH4Cl (1 mL), diluted with saturated
aqueous NH4Cl (10 mL), and extracted with CH2Cl2 (5 mL ꢂ 3).
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel (AcOEt/hexane, 1:70) to provide 154 mg (45%) of 22 as a
mixture (ca. 7:2:1) of diastereomers and an enol form. Mixture 22 was
obtained as a colorless oil:TLC, Rf 0.68 (AcOEt/hexane, 1:3); IR mmax
21
21. Compound 25 was obtained as a colorless oil: ½aꢁD +48.2 (c 1.17,
CHCl3).
22. In previous studies, we experienced that low diastereoselectivities were
observed when the sequential alkylations at the a-carbon of 5 were
executed in the order of benzylation then methylation (up to 4.5:1 in
favor of the formation of 7).8 In the case of allylation and successive
methylation, the diastereoselectivity was remarkably reduced to
ca. 1:1.