Asymmetric synthesis of (2R,3R,4R)-3-hydroxy-4-methyl-propline via chromium(II) chloride-mediated coupling reactions of (S)-garner aldehyde with crotyl bromide

Article abstract of DOI:10.3987/COM-05-10500

Efficient synthesis of (2R,4R,4R)-3-hydroxy-4-methylproline (1a), which is an antipode of the component of potent antifungal echinocandins, from (S)-Garner aldehyde (2a) has been established. The key step is chromium(II) chloride-mediated coupling reactio

Full text of DOI:10.3987/COM-05-10500

HETEROCYCLES, Vol. 65, No. 11, 2005
2657
HETEROCYCLES, Vol. 65, No. 11, 2005, pp. 2657 - 2665
Received, 1st July, 2005, Accepted, 2nd September, 2005, Published online, 2nd September, 2005
ASYMMETRIC SYNTHESIS OF (2R,3R,4R)-3-HYDROXY-4- METHYL-
PROPLINE VIA CHROMIUM(II) CHLORIDE-MEDIATED COUPLING
REACTIONS OF (S)-GARNER ALDEHYDE WITH CROTYL BROMIDE
Haruko Inaba, Yukiko Hiraiwa, Satoshi Yoshida, Mina Tamura, Asako Kuroda,
Aki Ogawa, Yutaka Aoyagi , Akihiro Ohta, and Koichi Takeya*
School of Pharmacy, Tokyo University of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Abstract–Efficient synthesis of (2R,4R,4R)-3-hydroxy-4-methylproline (1a), which is an
antipode of the component of potent antifungal echinocandins, from (S)-Garner aldehyde
(2a) has been established. The key step is chromium(II) chloride-mediated coupling
reactions with crotyl bromide giving homoallyl alcohols (4a) and (4a’) in a ratio of 83:17.
INTRODUCTION
Compounds containing pyrrolidine or proline derivatives in the molecule found in nature are attracting attention
today. Some polyhydroxylated pyrrolidine alkaloids from plants and micro-organisms were found to be potential
therapeutic agents i.e. anticancer, immuneostimulating, antidiabetic, and antiviral agents.1 Some peptide antibiotics
containing proline derivatives in the molecule,2
Me
OH
R1
R1
H
such as echinocandins from Aspergillus ruglosus,
are known to have a potent antifungal activity,3
and LY303366, which is a semisynthetic
N
OH
N
O
OH
OH
Me
Me
Me
O
O
O
NHCOR3
Me
OH
OH
NH
R2
N
N
O
O
HN
N
H
H
O
N
H
(2S,3S,4S)-1b
(2R,3R,4R)-1a
analogue of echinocandin B, to be a potential
therapeutic agent for serious systemic Candida or
Aspergillus infecton (Figure 1).4 In these
OH
OH
HO
O
HO
R1 = R2 = OH, R3 = C17H31
Echinocandin B
C
D
R1 = OH, R2 = H, R3 = C17H31
R1 = R2 = H, R3 = C17H31
R1 = R2 = OH, R3 =
LY303366
compounds, pyrrolidine moiety is considered to
be responsible for the activity. Hence, a number
OC5H11
Figure 1
of papers on stereoselective syntheses of polysubstituted pyrrolidines5 have been published including our reports.6

2658
HETEROCYCLES, Vol. 65, No. 11, 2005
In the active echinocandins, (2S,3S,4S)-3-hydroxy-4-methylproline (1b) is the common constituent and is
considered to be the most likely component which is related to the activity. For the elucidation of the definite
structure-activity relationships and for the preparation of the analogues of these peptide antibiotics, it is essential,
therefore, to establish an efficient method for the synthesis of 1. A number of papers reported chiral synthesis of
(2S,3S,4S)-3-hydroxy-4-methylproline (1b).7, 8 Chiral synthesis of 1a, the antipode of 1b is also reported.9 To study
the effect of the segment of 1a on the echinocandin activity, it may be significant to prepare 1a. In the present
paper, we performed chiral synthesis of (2R,3R,4R)-3-hydroxy-4-methylproline (1a) from (S)-Garner aldehyde
(2a),10 which can be easily derived from L-serine. Briefly, the method comprises the chromium(II) chloride-
mediated coupling reaction of Garner aldehyde with allyl bromide and the conversion of its coupling product,
homoallylic alcohol, to the target compound (1a). The
Me
OH
Me
HO
3
Me
O
Me
4
Me
3
4
O
2
HO
chromium(II) chloride-mediated cross couplings of
aldehydes with allyl halides are known to proceed chemo-
and stereoselectively under mild reaction conditions to
give coupling products in moderate to good yields.6c, 11
The retrosynthetic analysis of 1a is depicted in Scheme 1.
The target amino acid (1a) was obtained via deprotection
O
Me
Me
5
5
N
N
2
O
H
O
NHR
R
A
B
(2R,3R,4R)-1a
HO
O
H
Me
L
-serine
O
NR
Me
C
O
NR
Me
2a
Me
Me
Scheme 1 Retrosynthetic analysis of 1a.
of the pyrrolidine derivative (A). The cleavage of the C5-N bond gave the intermediate (B). In turn, B should lead
us back to the homoallylic alcohol (C), which can be prepared via the stereoselective chromium(II) chloride-
mediated coupling reactions of the (S)-Garner aldehyde (2a) with (E)-crotyl bromide (3).
RESULTS AND DISCUSSION
In our previous paper,6c we reported that the chromium(II) chloride-mediated coupling reaction of (S)-Garner
aldehyde (2a) with 3 gave, of the 4 possible diastereomers, only two homoallylalcohol diastereomers (4a) and (4a’)
in a ratio of 83:17. Silica gel chromatography separated 4a and 4a’, which were converted to acetonides (5a) and
(5a’), respectively. The spectral data of 5a’ was identical with those in the literature.12 In the 1H NMR spectra of 5a,
the coupling constant (J4,5) between the protons at C4 and C5 was 8.9 Hz, implying that the relative configuration
between C4 and C5 was anti. The Nozaki-Hiyama reaction13 or the reaction to produce 4a and 4a’ is to proceed via
a six-membered transition intermediate (D) (Figure 2) and the substituents attached to the α-position to the formyl
group in 2 are considered to be arranged as in the Houk models.14 Thus, the relative configuration between the

HETEROCYCLES, Vol. 65, No. 11, 2005
2659
hydroxy group at C4 and the methyl group at C1’ in 5a should be also anti. However, at this stage, the
stereochemistry of C1’ on the side chain is not known and hence its absolute stereochemistry can not be defined,
which is to be assigned later.
O
HO
HO
NtBoc
H
i)
+
Transformation of 5a to a proline
derivative (12a) was performed as
shown in Scheme 2. By ozonolysis
followed by sodium borohydride
reduction, 5a gave an alcohol (6) in
97 % yield. Tosylation of 6 and
subsequent treatment of the tosylate
(7) with sodium hydride gave 8, and
the removal of the acetonide in 8
gave the corresponding diol (9) in
98 % yield. A series of reactions,
including protection of the primary
Me
Br
Me
NtBoc
4a
+
Me
O
NHtBoc
80 %
(83 : 17)
3
O
O
Me
Me
4a'
Me
Me
Me
Me
(S)-Garner aldehyde 2a
ii)
52 %
ii) 53 %
Me
Me
1'
4
1'
O
5
O
Me
Me
Me
Me
4
5
O
O
NHtBoc
J4,5 = 2.0 Hz 5a'11
NHtBoc
iii)
J4,5 = 8.9 Hz
97 %
5a
OTs
Me
OH
Me
Me
Me
HO
HO
1'
4
Me
Me
O
1'
4
O
Me
v)
89 %
O
Me
vi)
91 %
i)
98 %
Me
iv)
98 %
Me
5
O
O
5
6
NHtBoc
O
N
NHtBoc
N
tBoc
tBoc
9
8
7
Me
HO
Me
Me
HO
TBSO
PhCOO
TBSO
Me
PhCOO
HO
ref 9)
vii)
93 %
viii)
90 %
HO
N
N
N
N
H
tBoc
tBoc
O
tBoc
11
10
12a
1a
Reagents and conditions: i) CrCl2, THF, rt; ii) a) p-TsOH·H2O, MeOH, rt, b) 2,2-dimethoxy-
propane, p-TsOH·H2O; iii) O3 then NaBH4; iv) TsCl; v) NaH; vi) TBSCl, imidazole, DMF;
vii) PhCOCl, Et3N, DMAP; viii) TBAF
Scheme 2 Formal synthesis of 1a.
hydroxyl group in 9 with the t-butyldimethylsilyl (TBS) group, esterification of the 3-hydroxyl group in the
resulting 10 with benzoic acid, and deprotection of the TBS group in 11, gave a proline derivative (12a). The
spectral data and physical properties of 12a including the specific rotation were
identical with those in the literature.8 Accordingly, the absolute configuration of C1’
Me
H
Me
O
Cr
O
H
Me
in 5a and 4a was determined to be R. The transformation of thus prepared 12a is
reported to give the target compound [(2R,3R,4R)-1a] in 88 %.9 If (R)-Garner
aldehyde (2b)10 is employed as the starting material, the present method should give
a very efficient method for the preparation of (2S,3S,4S)-1b. Because our present
N
O
O
Me
Me Me
D
Figure 2
stereoselective synthesis of the target proline (1a) has the following advantageous features; it involves fewer steps
(12 steps from the commercially available Garner aldehyde) than the procedures9, 15 reported by Raghavan et al. (15
steps from the commercially available oxazolidinone) and gives final product, 12a in a better overall yield (22 %)
than that of the Raghavan’s procedure (6 %), and the key step, the facile chromium(II) chloride-mediated
stereoselective coupling reaction of the Garner aldehyde with crotyl bromide, produces, of the 4 possible

2660
HETEROCYCLES, Vol. 65, No. 11, 2005
diastereomers, the aimed compound as the major product acompanied with a small amount of another diastereomer.
EXPERIMENTAL
General Methods. Melting points were measured on a Yanagimoto micro melting point apparatus and are recorded
uncorrected. 1H (300 and 400 MHz) and 13C (75 and 100 MHz) NMR spectra were obtained on a Varian Gemini
A-300 and a Brucker DPX-400 instruments. Chemical shifts are reported in parts per million downfield from the
internal standard. IR spectra (λmax in cm-1) were recorded on a Japan Spectroscopic Co. A-100 and MS spectra on a
Fisons VG Auto Spec instrument. Flash chromatography and MPLC were performed with Merck silica gel
Kieselgel 60 (230-400 mesh), and preparative thin layer chromatography (PTLC) with Merck Kieselgel 60 F254
precoated glass plates (0.25 or 0.50 mm). All solvents were of commercial grade and were distilled and dried as
specified below before use: tetrahydrofuran (THF) with sodium benzophenone ketyl; CH2Cl2 with CaH2. Garner
aldehydes were prepared according to the procedures described by Garner et al.10 Chromium(II) chloride was
purchased from Aldrich Chemical Co. and used without further purification.
Preparation of compounds (4a) and (4a’).
A THF solution (5 mL) containing 2a (0.23 g, 1 mmol) and 3 (0.27 g, 2 mmol) was added uropwise to a suspension
of CrCl2 (0.61 g, 6.0 mmol) in dry THF (10 mL). After stirring for 2.5 h at rt, sat. aq. NaHCO3 solution (10 mL)
was added to the mixture and the organic layer was separated. The aqueous solution was then extracted with AcOEt
(2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered, and evaporated in vacuo to give a
residue, which was separated by silica gel flash chromatography (hexanes:AcOEt = 6:1) to give 4a and 4a’.
Compound (4a): Yield 0.19 g (66 %). Colorless oil, [α]D -30.6° (CHCl3, c = 1.04,). IR (neat): 3500 (OH), 1700
(C=O) cm-1; 1H NMR (C6D6, 300 MHz, 333K): 6.00 (1H, ddd, J = 18.0, 11.2, and 6.9 Hz), 5.03 (1H, ddd, J = 18.0,
1.9, and 1.0 Hz), 5.02 (1H, ddd, J = 11.2, 1.9, and 1.0 Hz), 4.09 (1H, dd, J = 8.9 and 2.5 Hz), 3.94 (2H, m), 3.67
(1H, dd, J = 8.9 and 6.9 Hz), 2.25 (1H, m), 1.90 (1H, bs), 1.71 (3H, s), 1.54 (3H, s), 1.44 (9H, s), 1.05 (3H, d, J =
6.9 Hz); MS (EI): 270 (M+-Me). HRMS calcd for C14H24NO4 (M+-Me): m/z 70.1725, Found: m/z 270.1705.
Compound (4a’): Yield 0.04 g (14 %).Colorless solid, mp 65°C, [α]D -25.2° (CHCl3, c = 1.0,). Anal. Calcd for
C15H27NO4: C, 63.13; H, 9.54; N, 4.91. Found: C, 63.23; H, 9.48; N, 4.89. The physical and spectral data were
identical with those reported.10
Preparation of compound (5a).
A mixture of MeOH (20 mL), 4a (0.66 g, 2.3 mmol), and p-TsOH·H2O (0.08 g, 0.4 mmol) was stirred for 2 h at rt.

HETEROCYCLES, Vol. 65, No. 11, 2005
2661
After evaporation of the solvent in vacuo, sat. NaHCO3-H2O (1:1) solution (30 mL) was added to the residue. The
aqueous solution was extracted with AcOEt (30 mL x 3), and the combined organic layer was, after washing with
sat. NaCl (40 mL x 3), dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica gel
flash chromatography (hexanes-AcOEt) to give a diol (0.42 g, 75 % yield) as a colorless oil. A mixture of the diol
(0.35 g, 1.4 mmoL), DMP (10 mL), and p-TsOH·H2O (0.02 g, 0.1 mmol) was stirred at rt for 2 h. To the reaction
mixture, 5 % aq. NaHCO3 solution (30 mL) was added. The aqueous phase was then extracted with AcOEt (3 x 30
mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The
residue was purified by silica gel flash chromatography (hexanes:AcOEt = 15:1) to give 5a (0.35 g, 53 %).
Compound (5a): Colorless solid, mp 81°C (CH2Cl2), [α]D +15.6° (CHCl3, c = 0.90). IR (neat): 1680 (C=O) cm-1;
1H NMR (Pyridine-d5, 400 MHz, 300 K): 6.12 (1H, ddd, J = 17.0, 10.3 and 8.2 Hz), 5.26 (1H, d, J = 17.0 Hz), 5.17
(1H, dd, J = 10.3 and 2.1 Hz), 4.09 (1H, dd, J = 11.8 and 2.0 Hz), 3.96 (1H, dd, J = 11.8 and 1.9 Hz), 3.91 (1H, m),
3.78 (1H, dd, J = 9.6 and 2.0 Hz), 2.75 (1H, m), 1.52 (9H, s), 1.47 (6H, s), 1.19 (3H, d, J = 6.9 Hz); MS (EI): m/z
270 (M+-CH3); MS (CI): m/z 286 (M++1); Anal. Calcd for C15H27NO4: C, 63.13; H, 9.54; N, 4.91. Found: C, 62.95;
H, 9.60; N, 4.90.
Preparation of compound (5a’).
According to the procedures described above, 5a’ was obtained in 52 % from 4a’.
Compound (5a’): Colorless oil, [α]D -7.72° (CHCl3, c = 1.01). Physical and spectral data of 5a’ were identical with
those reported in the literature.10
Preparation of compound (6).
A solution of 5a (0.86 g, 3 mmol) in dry MeOH (30 mL) was treated with O3 at -78 °C until the color of the
solution turned blue (ca. 3 h). After the reaction mixture was purged with Ar gas, NaBH4 (0.57 g, 15 mmol) was
carefully added at the same temperature. Then the reaction mixture was stirred at rt overnight. The solvent was
evaporated under reduced pressure and H2O (30 mL) was added to the residue. The mixture was extracted with
Et2O (3 x 30 mL), and the organic layer was successively washed with H2O (1 x 40 mL) and sat. aq. NaCl solution
(1 x 40 mL), dried over MgSO4, filtered, and evaporated in vacuo to give an oily residue, which was purified by
flash column chromatography (hexanes:AcOEt = 4:1) to give 6 as a coloress oil (0.80 g, 97 %). Compound (6):
[α]D +20.8° (CHCl3, c = 0.15). IR (neat): 3440 (OH), 3350 (NH), 1685 (C=O) cm-1; 1H NMR (CDCl3, 400 MHz,
300 K): 4.53 (1H, br s), 3.93 (1H, dd, J = 11.3 and 5.1 Hz), 3.83 (2H, m), 3.62 (1H, m), 3.56 (1H, dd, J = 9.3 and

2662
HETEROCYCLES, Vol. 65, No. 11, 2005
3.6 Hz), 3.53 (1H, dd, J = 11.3 and 7.0 Hz), 2.62 (1H, br s), 1.93 (1H, m), 1.43 (9H, s), 1.41 (3H, s), 1.38 (3H, s),
1.05 (3H, d, J = 7.0 Hz); 13C NMR (CDCl3, 75 MHz, 300 K): 155.2, 99.3, 77.2, 64.7, 63.7, 47.9, 36.3, 28.3, 27.5,
20.1, 14.2; MS (EI): m/z 290 (M++H). Anal. Calcd for C14H27NO5: C, 58.11; H, 9.41; N, 4.84. Found: C, 57.97; H,
9.55; N, 4.77.
Preparation of compound (7).
p-TsCl (0.83 g, 4.4 mmol) was added to a solutions of 6 (0.80 g, 2.9 mmol), Et3N (1.63 mL, 11.7 mmol), and
DMAP (0.07 g, 0.58 mmol) in CH2Cl2 (3 mL) at 0 °C and the mixture was then stirred at rt for 2.5 h. After dilution
with CHCl3 (30 mL), the organic phase was washed with H2O (3 x 30 mL), dried over MgSO4, filtered, and
evaporated in vacuo to give an oily residue, which was purified by flash column chromatography (hexanes:AcOEt
= 3:1) to give 7 as a colorless oil (1.28 g, 98 %). Compound (7): [α]D +26.7° (CHCl3, c = 0.32). IR (neat): 3400
(NH), 1690 (C=O) cm-1; 1H NMR (CDCl3, 300 MHz, 300 K): 7.47 (2H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz),
4.57 (1H, br d), 4.11-3.97 (2H, m), 3.84 (1H, dd, J = 11.5 and 4.8 Hz), 3.71-3.44 (3H, m), 2.44 (3H, s), 2.08 (1H,
m), 1.42 (9H, s), 1.33 (3H, s), 1.27 (3H, s). 1.0 (3H, d, J = 6.9 Hz); MS (EI): m/z 428 (M+-CH3). Anal. Calcd for
C21H33NO7S: C, 56.86; H, 7.50; N, 3.16. Found: C, 56.56; H, 7.57; N, 2.96.
Preparation of compound (8).
A solution of 7 (0.36 g, 0.81 mmol) in dry THF (1 mL) was added to a suspension of 60 % NaH in mineral oil
(0.11 g, 2.8 mmol) at 0 °C. After stirring at rt for 15 h, the resulting mixture was poured into ice-water (10 mL) and
the whole was treated with Et2O (3 x 20 mL). The organic phase was washed with sat. aq. NaCl solution (3 x 20
mL), dried over MgSO4, filtered, and evaporated in vacuo to give an oily residue, which was purified by flash
column chromatography (hexanes:AcOEt = 4:1) to give 8 as a colorless oil (0.20 g, 89 %). Compound (8): [α]D
+118° (CHCl3, c = 0.13). IR (neat): 1695 (C=O) cm-1; 1H NMR (CDCl3, 400 MHz, 300 K): 3.75 (1H, dd, J = 10.5
and 6.4 Hz), 3.94-3.63 (2H, m), 3.50 (1H, dd, J = 10.5 and 6.4 Hz), 3.23 (1H, br s), 3.14 (1H, br d), 2.46-2.39 (1H,
m), 1.48, 1.46 (6H, 2 x s), 1.451, 1.446 (9H, 2 x s), 1.06, 1.01 (3H, 2 x d, J = 7.0 Hz); MS (EI): m/z 271 (M+). Anal.
Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C, 61.70; H, 9.11; N, 5.20.
Preparation of compound (9).
A mixture of 8 (0.20 g, 0.72 mmol), p-TsOH·H2O (0.04 g, 0.21 mmol), and MeOH (5 mL) was stirred at rt for 2 h.
To this reaction mixture, 5 % aq. NaHCO3 solution (30 mL) was added. The aqueous phase was then extracted with
AcOEt (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in

HETEROCYCLES, Vol. 65, No. 11, 2005
2663
vacuo. The residue was subjected to silica gel flash chromatography (hexanes:AcOEt = 1:2) to give 9 as a colorless
oil (0.17 g, 98 %). Compound (9): [α]D +34.8° (CHCl3, c = 0.41). IR (neat): 3400 (OH), 1665 (C=O) cm-1; 1H
NMR (CDCl3, 400 MHz, 300 K): 4.12-3.64 (4H, m), 3.47 (1H, br m), 3.15 (1H, br m), 2.31, 2.14 (1H, 2 x br s),
1.70 (2H, s), 1.46 (9H, 2 x s), 1.06 (3H, d, J = 6.9 Hz); 13C NMR (CDCl3, 75 MHz, 300 K): (CO not visible) 80.1,
75.0, 68.4, 64.8, 51.4, 36.2, 28.4, 11.0; MS (EI): m/z 231 (M+), 200 (M+-CH2OH). HRMS calcd for C11H21NO4
(M+): m/z 231.1471, Found: m/z 231.1471.
Preparation of compound (10).
TBSCl (1.02 g, 6.72 mmol) was added in one portion to a solution of 9 (0.52 g, 2.24 mmol), Et3N (0.91 g, 8.96
mmol), and DMAP (0.05 g, 0.45 mmol) in CH2Cl2 (16 mL) at 0 °C. The mixture was stirred at rt for 3 h. After
dilution with CHCl3 (30 mL), the organic layer was washed with H2O (3 x 15 mL), dried over anhydrous Na2SO4,
filtered, and evaporated in vacuo. The residue was subjected to silica gel flash chromatography (hexanes:AcOEt =
6:1) to give monosilylated pyrrolidine (10) as a colorless oil (0.702 g, 91 %). Compound (10): [α]D +40.4° (CHCl3,
c = 0.26). IR (neat): 3430 (OH), 1670 (C=O) cm-1; 1H NMR (CDCl3, 400 MHz, 300 K): 4.16 (1H, m), 3.86-3.83
(1H, m), 3.77-3.43 (3H, m), 3.15, 3.08 (1H, 2 x t, J = 10.1 Hz), 2.39 (1H, m), 1.58 (1H, d, J = 2.0 Hz), 1.39 (9H, s),
1.06 (3H, m), 0.89 (9H, s), 0.07 (6H, s); MS (EI): m/z 288 (M+-t-Bu). Anal. Calcd for C17H35NO4Si: C, 59.09; H,
10.21; N, 4.05. Found: C, 59.19; H, 10.02; N, 4.12.
Preparation of compound (11).
BzCl (0.089 g, 0.63 mmol) was added to a solution of 10 (0.086 g, 0.25 mmol), Et3N (0.101 g, 1.0 mmol), and
DMAP (0.006 g, 0.05 mmol) in CH2Cl2 (2.5 mL) at 0 °C with stirring. The mixture was stirred at rt for 4 h and then
refluxed for 5 h. After dilution with H2O (10 mL), the aqueous phase was extraced with CHCl3 (3 x 10 mL). The
combined organic layer was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was
purified by silica gel flash chromatography (hexanes:AcOEt = 10:1) to give 11 as a colorless oil (0.101 g, 93 %).
Compound (11): [α]D +20.7° (CHCl3, c = 0.37). IR (neat): 1710, 1690 (C=O) cm-1; 1H NMR (CDCl3, 400 MHz,
300 K): 8.04 (2H, dd, J = 6.2 and 6.2 Hz), 7.57 (1H, m), 7.16 (2H, m), 5.45 (1H, dd, J = 11.9 and 4.3 Hz),
3.99-3.73 (3H, m), 3.67-3.55 (1H, m), 3.25, 3.16 (1H, 2 x t, J = 10.5 Hz), 2.76-2.69 (1H, m), 1.47, 1.46 (9H, 2 x s),
1.08 (3H, t, J = 7.3 Hz), 0.902, 0.896 (9H, 2 x s), 0.07, 0.065 (overlapped), 0.05 (6H, 4 x s); 13C NMR (CDCl3, 100
MHz, 300 K):166.0, 154.3, 133.1, 133.0, 130.22, 130.15, 129.6, 128.43, 128.36, 79.7, 79.5, 79.4, 79.1, 65.9, 62.5,
61.9, 52.4, 51.9, 35.7, 34.7, 28.5, 25.9, 18.2, 11.5, -5.5; MS (EI): m/z 450 (M++H). Anal. Calcd for C24H39NO5Si: C,

2664
HETEROCYCLES, Vol. 65, No. 11, 2005
64.10; H, 8.75; N, 3.12. Found: C, 63.82; H, 8.69; N, 3.27.
Preparation of compound (12a).
A 1.0 M TBAF solution in THF (0.44 mL, 0.44 mmol) was added to a solution of 11 (0.101 g, 0.22 mmol) in THF
(0.25 mL) at 0 °C. The mixture was stirred at rt for 48 h. After the addition of sat. aq. NaHCO3 solution (30 mL) to
the reaction mixture, the aqueous phase was extracted with AcOEt (3 x 30 mL). The combined organic layer was
dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was subjected to silica gel flash
chromatography (hexanes:AcOEt = 3:1) to give 12a as a colorless oil (0.067 g, 90 %). Compound (12a): [α]D
+31.4° (CHCl3, c = 1.31) [[α]D -30.4° (CHCl3, c = 1.34)].8 IR (neat): 3420 (OH), 1715, 1692 (C=O) cm-1; 1H NMR
(CDCl3, 400 MHz, 300 K): 8.04 (2H, d, J = 7.3 Hz), 7.59 (1H, m), 7.46 (2H, dd, J = 7.3 and 7.3 Hz), 5.36, 5.21
(1H, 2 x m), 4.10 (1H, m), 3.92-3.62 (4H, m), 3.25 (1H, m), 2.59 (1H, br s), 1.47 (9H, s), 1.10 (3H, d, J = 6.3 Hz)
[lit.,8 1H NMR (CDCl3, 300 MHz, 300 K): 8.05 (2H, d), 7.60 (1H, dd), 7.47 (2H, dd), 5.36, 5.21 (1H, 2m), 4.10 (1H,
m), 3.85 (masked m), 3.90, 3.75 (OCH2), 3.66 (1H, m), 3.26 (1H, m), 2.60 (1H, m),1.47 (9H, s), 1.10 (3H, d, J =
6)]; 13C NMR (CDCl3, 75 MHz, 300 K): (CO not visible) 133.3, 129.8, 129.6, 128.5, 80.5, 77.8, 66.2, 64.7, 52.3,
35.5, 28.4, 11.4 [lit.,8 13C NMR (CDCl3, 75 MHz, 300 K) (CO not visible) 133.36, 129.95, 129.74, 128.56, 80.57,
78.01, 66.33, 64.66, 52.35, 35.65, 28.50, 11.48]; MS (CI): m/z 336 (M++H). Anal. Calcd for C18H25NO5: C, 64.46;
H, 7.51; N, 4.18. Found: C, 64.30; H, 7.53; N, 4.20.
ACKNOWLEDGEMENTS
This work was supported by the Ministry of Education, Science, Sports and Culture, Grant-in-Aid for Scientific
Research (C). The authors are grateful to Prof. Dr. Nicole Langlois for kindly giving us the spectral and physical
data of compound (10).
REFERENCES
1. A. A. Watson, G. W. J. Fleet, N. Asano, R. J. Molyneux, and R. J. Nash, Phytochemistry, 2001, 56, 265.
2. D. J. Faulkner, Nat. Prod. Rep., 2001, 18, 1 and the references cited therein.
3. F. Benz, F. Knüsel, J. Nüesch, H. Treichler, W. Voser, R. Nyfeler, and W. Keller-Schirerlin,
Helv. Chim. Acta, 1974, 57, 2459.
4. U. E. Udodong, W. W. Turner, B. A. Astleford, F. Brown Jr., M. T. Clayton, S. E. Dunlap, S. A. Frank, J. L.
Grutsch, L. M. LaGrandeur, D. E. Verral, and J. A. Werner, Tetrahedron Lett., 1998, 39, 6115.

HETEROCYCLES, Vol. 65, No. 11, 2005
2665
5. D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435 and the references cited therein.
6. a) M. Maeda, F. Okazaki, M. Murayama, Y. Tachibana, Y. Aoyagi, and A. Ohta, Chem. Pharm. Bull., 1997,
45, 962. b) Y. Aoyagi and R. M. Williams, Tetrahedron, 1998, 54, 13045. c) Y. Aoyagi, H. Inaba,Y.
Hiraiwa, A. Kuroda, and A. Ohta, J. Chem. Soc., Perkin Trans. 1, 1998, 3975.
7. a) J. Mulzer, R. Becker, and E. Brunner, J. Am. Chem. Soc., 1989, 111, 7500. b) N. Kurokawa and Y. Ohfune,
J. Am. Chem. Soc., 1986, 108, 6041. c) N. Kurokawa and Y. Ohfune, Tetrahedron, 1993, 49, 6195. d) D. A.
Evans and A. E. Weber, J. Am. Chem. Soc., 1987, 109, 7151. e) W. –H. Meng, T. –J. Wu, H. –K. Zhang, and
P. –Q. Huang, Tetrahedron: Asymmetry, 2004, 15, 3899.
8. (a) N. Langlois, Tetrahedron: Asymmetry, 1998, 9, 1333. (b) N. Langlois and F. Rakotondradany,
Tetrahedron, 2000, 56, 2437.
9. S. Raghavan and S. R. Reddy, Tetrahedron Lett., 2003, 44, 7459.
10. (a) O. Garner and J. M. Park, J. Org. Chem., 1987, 52, 2361. (b) O. Garner and J. M. Park, Org. Synth., 1991,
70, 18. The both enantiomers of Garner's aldehyde can be purchased from Aldrich Co., Ltd. (S-form: 462063,
R-form: 432741).
11. a) M. D. Lewis and Kishi, Tetrahedron Lett., 1982, 23, 2343. b) H. Nagaoka and Y. Kishi, Tetrahedron, 1981,
37, 3873.
12. A. Hafner, R. O. Duthaler, R. Marti, G. Rihs, P. Rothe-Streit, and F. Schwarzenbach, J. Am. Chem. Soc., 1992,
114, 2321.
13. a) T. Hiyama, Y. Okude, K. Kimura, and H. Nozaki, Bull. Chem. Soc. Jpn., 1982, 55, 561. b) M. D. Lewis
and Y. Kish, Tetrahedron Lett., 1982, 23, 2343. (c) P. Cintas, Synthesis, 1992, 248 and the references cited
therein.
14. M. N. Paddon-Row, N. G. Rondan, and K. N. Houk, J. Am. Chem. Soc., 1982, 104, 7162.
15. S. Raghavan and K. A. Tony, J. Org. Chem., 2003, 68, 5002.