A practical improvement of crystallization-induced asymmetric transformation of allene-1,3-dicarboxylates

Article abstract of DOI:10.1016/j.tetasy.2006.11.004

Enantiomerically pure allene-1,3-dicarboxylates were easily synthesized by using epimerization-crystallization of dissymmetric allene compounds, which were prepared from acetone-1,3-dicarboxylates and naturally abundant chiral alcohols, that is, (-)- and

Full text of DOI:10.1016/j.tetasy.2006.11.004

Tetrahedron: Asymmetry 17 (2006) 2943–2951
A practical improvement of crystallization-induced
asymmetric transformation of allene-1,3-dicarboxylates
Takahiro Katoh, Chie Noguchi, Hiroyuki Kimura, Toshio Fujiwara, Shogo Ichihashi,
Kiyoharu Nishide, Tetsuya Kajimoto and Manabu Node*
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University,
1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
Received 13 October 2006; accepted 1 November 2006
Abstract—Enantiomerically pure allene-1,3-dicarboxylates were easily synthesized by using epimerization–crystallization of dissym-
metric allene compounds, which were prepared from acetone-1,3-dicarboxylates and naturally abundant chiral alcohols, that is, (ꢀ)-
and (+)-menthols, borneol, and isoborneol. After scrutinizing the crystallization of several allene-1,3-dicarboxylates in the presence
of triethylamine, it was found that allene-1,3-dicarboxylate carrying bornyl groups was the most easily prepared as a single isomer
because of it having suitable solubility to be crystallized in hexane at 0 °C to room temperature. Diels–Alder reaction of the enantio-
merically pure allene-1,3-dicarboxylates and cyclic dienes, such as N-Boc-pyrrole and cyclopentadiene, afforded endo-adducts having
the same configurations at two newly generated stereogenic centers.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Cl
H
RO2C
R'
N
X
R'
N
Allene-1,3-dicarboxylates 1 are useful dienophiles for the
Diels–Alder reaction and excellent acceptors in the Michael
addition;1 however, practical methods to prepare optically
active allene-1,3-dicarboxylates 1 have not been published
except for a few reports. For example, one example has
been reported by Kanematsu, who employed resolutional
crystallization of a mixture of di-(ꢀ)-L-menthyl allene-
1,3-dicarboxylates,2 while another was developed by
Naruse, who attained the enantiomerically enriched equi-
librium of allene-1,3-dicarboxylates with a chiral organo-
europium reagent.3 However, the former method does
not afford satisfactory yields (<25%), while the latter
requires equimolar amounts of expensive Eu(hfc)3 as well
as long reaction times with accompanying partial decom-
position of the substrate.
C
CO2R
H
1
2
3a: X = NBoc
3b: X = CH2
Figure 1.
Herein, we report a new strategy and details of the crystal-
lization-induced asymmetric transformation of allene-1,
3-dicarboxylates and its application to the Diels–Alder
reaction with cyclic dienes, such as N-Boc-pyrrole 3a and
cyclopentadiene 3b, since the reaction is applicable to the
synthesis of many naturally occurring compounds, for
example, a- and b-santalols,6 as well as epibatidine 2
(Fig. 1).
We have recently encountered the first example of epimer-
ization-crystallization in dissymmetric allene-1,3-dicarb-
oxylates during a synthetic study of (ꢀ)-epibatidine 2,4
an excellent candidate for non-opioidal anesthesia, and
its derivatives.5
2. Results and discussion
We started by establishing a new method for the synthesis
of allene-1,3-dicarboxylates. At first, dimethyl 1,3-acetone-
dicarboxylate 4a was chosen as a starting material to pre-
pare racemic allene-1,3-dicarboxylates 1 on a large scale
*
Corresponding author. Tel.: +81 75 595 4639; fax: +81 75 595 4775;
e-mail: node@mb.kyoto-phu.ac.jp
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.004

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T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 2943–2951
in advance of preparing optically active ones. Initially, we
attempted the reaction of 4a with 2-chloro-1,3-dimethyl-
imidazolinium chloride (DMC) 5a in the presence of an
equimolar amount of triethylamine; this afforded vinyl
chloride 6a as the sole product in moderate yield (Table
1, entry 1).7 Since the elimination of hydrogen chloride
from 6a should provide dimethyl allene-1,3-dicarboxylate
1a, the reaction was performed with two equimolar
amounts of triethylamine to afford a better result (Table
1, entry 2) and the best result was obtained by reaction
in the presence of three equimolar amounts of triethyl-
amine (Table 1, entry 3). Moreover, the use of 2-chloro-
1,3-dimethylimidazolinium hexafluorophosphate (CIP) 5b
developed by Kiso for peptide synthesis was effective to
avoid the production of 6a, since pentafluorophosphide is
less nucleophilic than chloride to the sp-carbon of 1a
(Table 1, entries 8, 9, and 10). The reaction condition was also
effective to prepare 1b–e from 4b–e (Table 1, entries 11–14).
Expecting that chiral induction might occur during the
transformation from acetone dicarboxylates to allene-1,3-
dicarboxylates, dimenthyl 1,3-acetonedicarboxylate 4f pre-
pared by the ester exchange of 4a with (ꢀ)-menthol was
transformed to allene-1,3-dicarboxylate 1f by treatment
with 1,3-dimethylimidazolium salt 5a or 5b in the presence
of triethylamine; however, it only afforded a mixture of (S)-
and (R)-(diastereomeric ratio = 5:4) (Table 2, entries 1
and 2).
Since allene-1,3-dicarboxylate diesters are excellent
Michael acceptors, we searched for the possibility of epi-
merization induced by the addition–elimination reaction
with bases (Scheme 1). The epimerization of the (R)-isomer
of 1f in the presence of a catalytic amount of triethylamine
was easily monitored by nuclear magnetic resonance
(NMR) spectroscopy and it was observed that the epimer-
ization between the (R)- and (S)-isomers of the allene
moiety can reach an equilibrium within 30 min at room
temperature. On the basis of this fact, a mixture of the
(R)- and (S)-epimers was crystallized in pentane, the most
non-polar solvent among the ones available, with a cata-
lytic amount of triethylamine (0.01 equiv) at low tempera-
ture (ꢀ20 °C) to afford the pure (R)-isomer as a single
crystal. Repeating the same procedure three times gave 1f
with an (R)-configuration in 90% total yield. However,
the process was too tedious in order to afford high repro-
ducibility because the crystals of 1f were easily dissolved
Alternative amines were next employed in place of triethyl-
amine to investigate the effects of bases in the reaction from
4a to 1a; however, neither the reactions with diisopropyl-
ethylamine nor with pyridine gave more favorable results
than the reaction with triethylamine (Table 1, entries 4
and 5). The reactions with optically active amines, for
example, (S)-2-methoxymethylpyrrolidine and (ꢀ)-sparte-
ine, did not afford optically active 1a at all but instead a
racemic mixture (Table 1, entries 6 and 7).
Table 1.
O
R1O2C
Cl
R2
R1O2C
CO2R1
.
R1O2C
CO2R1
+
CO2R1
R2 R2
R2
R2 R2
4
1
6
Entry
Reactant
R1
R2
Reagent
Base (equiv)
Time (h)
Products (%)
1
6
1
2
3
4
5
4a
4a
4a
4a
4a
Me
Me
Me
Me
Me
H
H
H
H
H
5a
5a
5a
5a
5a
Et3N (1)
Et3N (2)
Et3N (3)
(i-Pr)2NEt
Pyridine
24
22
1
1.5
15
—
6a (44)
6a (21)
—
1a (72)
1a (90)
1a (84)
6a (8)
No reaction
6
7
4a
4a
Me
Me
H
H
5a
5a
0.5
1a (61)
1a (78)
6a (23)
N
OMe
N
Me
H
H
N
1
—
H
H
8
9
4a
4a
4a
4b
4c
4d
4e
Me
Me
Me
Me
Et
H
H
H
Me
H
5b
5b
5b
5a
5a
5a
5a
Et3N (1)
Et3N (2)
Et3N (3)
Et3N (3)
Et3N (3)
Et3N (3)
Et3N (3)
1.5
1.5
1.5
2
0.5
2.5
0.5
1a (32)
1a (80)
1a (88)
1b (73)
1c (92)
1d (70)
1e (71)
6a (3)
—
—
—
—
10
11
12
13
14
Bn
t-Bu
H
H
—
—
5a: X = Cl (DMC)
5b: X = PF6 (CIP)
N
CH3
X-
H3C
N
+
Cl

T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 2943–2951
2945
Table 2.
RO2C
H
RO2C
H
O
CO2R
H
H
4 or 6
·
·
+
CO2R
RO2C
CO2R
4f-i
(R)-1f-i
(S)-1f-i
Entry
Starting material
R
Reagent (1.2 equiv)
Et3N
Time (h)
Product (%)
1
2
3
4
5
6
7
8
4f
(ꢀ)-Menthyl
5a
5b
5a
5b
5a
5b
5a
5b
3
2
3
2
3
2
3
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1f (86)
1f (93)
1g (75)
1g (80)
1h (78)
1h (77)
1i (83)
1i (86)
4g
4h
4i
(+)-Menthyl
(ꢀ)-Bornyl
(ꢀ)-Isobornyl
-O
RO2C
RO2C
+ Et3N
OR
RO2C
H
- Et3N
CO2R
H
·
·
·
H
CO2R
- Et3N
H
H
H
+ Et3N
(R)-1f-i
(S)-1f-i
NEt3
+
crystallisation
Scheme 1.
in the organic solvent during filtration, unless the glass
ware was well chilled. Furthermore, it was almost impossi-
ble to collect crystals once the temperature of the solution
rose above 0 °C.
while the procedure repeated three times at room tempera-
ture afforded a slightly higher yield (92%) (Table 3, entries
1–4). Interestingly, the crystallization of 1i at 0 °C only
gave a mixture of (R)- and (S)-1,3-dicarboxylate with a
maximum ratio of 9:1. The procedure repeated twice at
room temperature gave enantiomerically pure (R)-1i in
total 89% yield (Table 3, entry 5), which was as good a
result as that of 1h in spite of the disadvantage that isobor-
neol is not commercially available. The absolute configura-
tion of allene-1,3-dicarboxylates 1h and 1i obtained was
determined to be (R) by means of X-ray crystallography
(Fig. 2).
Therefore, we synthesized (ꢀ)-bornyl allene-1,3-dicarboxy-
late 1h and (ꢀ)-isobornyl allene-1,3-dicarboxylate 1i (Table
2, entries 3–8) and attempted the crystallization-induced
asymmetric transformation, based on the speculation that
bicyclic terpenes, such as borneol and isoborneol, could
form more rigid lattice structures than menthol and this
tendency would not change even if the bicyclic moieties
of the monoterpenes are involved as a partial structure in
the linear derivatives of allene (Table 3).
Finally, Diels–Alder reactions of allene-1,3-dicarboxylates
1h and 1i with N-Boc-pyrrole 3a and cyclopentadiene 3b
were carried out under the same conditions as the reaction
of 1f and 3a.5 As a result, the reaction, respectively,
afforded 7-azabicyclo[2.2.1]heptane as a single isomer of
The crystallization-induced asymmetric transformation of
1h afforded (ꢀ)-bornyl (R)-allene-1,3-dicarboxylate 1h at
0 °C in 85% yield by repeating the procedure four times,
Table 3. Improved crystallization-induced asymmetric transformation
RO2C
RO2C
H
Et3N (cat.)
solvent
H
CO2R
H
·
·
CO2R
H
single diastereomer
Condition
Entry
Substrate
R
Yield (%)
Abs. config
Solvent
Times
Temperature
1
2
3
4
5
1f
1h
(ꢀ)-Menthyl
(ꢀ)-Bornyl
Pentane
Pentane
Hexane
Hexane
Hexane
3
4
2
3
2
ꢀ20 °C
90
85
89
92
89
(R)
(R)
(R)
(R)
(R)
0 °C
rt
rt
rt
1i
(ꢀ)-Isobornyl

2946
T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 2943–2951
Figure 2. ORTEPs of chiral allene-1,3-dicarboxylates 1h (CCDC No. 626803) and li (CCDC No. 626802).
endo-adducts 7a–c in excellent yields. In addition, the ste-
reochemistry of 7a and 7c was confirmed by X-ray crystal-
lography, and the absolute configurations of the newly
generated stereogenic centers were revealed to be identical
in 7a and 7b by comparison of all physical data including
[a]D values of each acetate 8a and 8b, which was, respec-
tively, derived by reduction of 7a and 7b with LiAlH4
followed by conventional acetylation (Scheme 2).
enantiomerically pure allene-1,3-dicarboxylate on a gram-
scale. Moreover, it was found that the Diels–Alder adducts
7a and 7b obtained from 1h, 1i, and 3a had the same abso-
lute configuration at the two newly generated stereogenic
centers as the adduct from 1f and 3a.5
4. Experimental
4.1. General
3. Conclusion
Infrared (IR) spectra were recorded on a Shimadzu FTIR-
8300 diffraction grating infrared spectrophotometer and 1H
NMR spectra were obtained on a JEOL JNM-AL 300, a
Varian Unity INOVA-400, a JEOL JNM-LA 500 spec-
trometer with tetramethylsilane as an internal standard.
13C NMR spectra were obtained on a JEOL JNM-AL
In conclusion, we were able to establish a practical method
to synthesize chiral allene-1,3-dicarboxylate. Namely, when
a bornyl or an isobornyl ester 1h was employed as the start-
ing material, a crystallization-induced asymmetric transfor-
mation was attainable at room temperature to afford

T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 2943–2951
2947
Scheme 2. ORTEPs of adducts 7a (CCDC No. 626804) and 7c (CCDC No. 626801).
300, a Varian Unity INOVA-400 spectrometer with CDCl3
as an internal standard. Mass spectra (MS) were deter-
mined on a JEOL JMS-SX 102A QQ or a JEOL JMS-
GC-mate mass spectrometer. Specific rotations were
recorded on a Horiba SEPA-200 automatic digital polar-
imeter. Wakogel C-200 (silica gel) (100–200 mesh, Wako)
was used for open column chromatography. Flash column
chromatography was performed by using Silica Gel 60N
(Kanto Chemical Co., Inc.) as a solid support of immobile
phase. Kieselgel 60 F-254 plates (Merck) were used for thin
layer chromatography (TLC). Preparative TLC (PTLC)
was conducted with Kieselgel 60 F-254 plate (0.25 mm,
Merck) or Silica gel 60 F-254 plate (0.5 mm, Merk). Unless
purification with silica gel gave a compound pure enough,
the compounds were treated further with a recycle HPLC
(JAI LC-908) on GPC column (JAIGEL 1H and 2H).
When possible, diastereomeric mixtures were also sepa-
rated by a recycle HPLC (JAI LC-908) on a silica gel col-
umn (Kusano Si-10) after the purification procedure
mentioned above.
4.2. Dimethyl 2,3-pentadienedioate 1a
Dimethyl 1,3-acetonedicarboxylate 4a (5.00 g, 28.7 mmol)
and triethylamine (11.6 g, 115 mmol) were successively
added to a solution of 2-chloro-1,3-dimethylimidazolinium

2948
T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 2943–2951
chloride (DMC; 5.80 g, 34.5 mmol) in absolute dichloro-
methane (100 ml) at 0 °C. After stirring the reaction mix-
ture for 1 h at room temperature, the reaction mixture
was directly charged on silica gel column chromatography
263.1250, found: 263.1239. Anal. Calcd for C13H20O4: C,
64.98, H, 8.39. Found: C, 64.70, H, 8.16.
1
4.7. Dimethyl 3-chloro-2-pentene-1,5-dioate 6a
(hexane/AcOEt = 2:1) to afford 1a as a pale yellow oil. H
NMR (300 MHz, CDCl3): d 3.76 (s, 6H), 6.03 (s, 2H); 13C
NMR (75 MHz, CDCl3): d 52.3 (2C), 91.9 (2C), 163.5 (2C),
219.5; IR (CHCl3): 3036, 2955, 2359, 1967, 1720, 1439,
1269 cmꢀ1; MS (70 eV) m/z: 156 (M+, 7), 128 (100), 112
(23), 98 (3); HRMS calcd for C7H8O4: 156.0422, found:
156.0420. Anal. Calcd for C7H8O4: C, 53.85, H, 5.16.
Found: C, 53.68, H, 5.04.
Dimethyl 1,3-acetonedicarboxylate 4a (100 mg, 0.57 mmol)
and triethylamine (63 mg, 0.63 mmol) were successively
added to a solution of 2-chloro-1,3-dimethylimidazolinium
chloride (DMC; 146 mg, 0.86 mmol) in absolute dichloro-
methane (5 ml) at 0 °C. After stirring the reaction mixture
for 1 h at room temperature, the reaction mixture was
poured into a saturated aqueous solution of NH4Cl and
extracted with diethyl ether. The organic layer was dried
over sodium sulfate and condensed in vacuo, and the resi-
due was purified by PTLC (hexane/ethyl acetate = 2:1) to
afford 6a (49 mg, 44%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3): d 3.73 (s, 3H), 3.74 (s, 3H), 4.11 (s,
2H), 6.27 (s, 1H); 13C NMR (75 MHz, CDCl3): d 41.0,
51.5, 52.1, 121.4, 146.9, 164.3, 168.0; IR (CHCl3): 3034,
2954, 1720, 1641, 1437, 1321, 1167, 1015 cmꢀ1; MS
FAB(+) m/z: 193 [M+H]+; HRMS calcd for C7H10O435Cl
[M+H]+: 193.0267, found: 193.0250. Anal. Calcd for
C7H9ClO4: C, 43.65, H, 4.71. Found: C, 43.53, H, 4.65.
4.3. Dimethyl 2,4-dimethyl-2,3-pentadienedioate 1b
Dimethyl 1,3-dimethyl-1,3-acetonedicarboxylate 4b (150 mg,
0.74 mmol) was treated as 4a in the above reaction to
1
afford 1b (100 mg, 73%) as a pale yellow oil. H NMR
(300 MHz, CDCl3): d 1.95 (s, 6H), 3.75 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 14.4 (2C), 52.2 (2C), 98.0
(2C), 166.3 (2C), 216.4; IR (CHCl3): 2955, 1771, 1456,
1263, 1151, 1092 cmꢀ1; MS FAB(+) m/z: 185 [M++H];
HRMS calcd for C9H13O4 [M++H]: 185.0814, found:
185.0843. Anal. Calcd for C9H12O4: C, 58.69, H, 6.57.
Found: C, 58.39, H, 6.38.
4.8. (ꢀ)-[Bis-(1R,2S,5R)-(ꢀ)-menthyl] 1,3-acetonedicarb-
4.4. Diethyl 2,3-pentadienedioate 1c
oxylate 4f
Diethyl 1,3-acetonedicarboxylate 4c (100 mg, 0.50 mmol)
was treated as 4a in the above reaction to afford 1c
(84 mg, 92%) as a pale yellow oil. H NMR (300 MHz,
(1R,2S,5R)-(ꢀ)-Menthol (31.9 g, 0.20 mol) and DMAP
(998 mg, 8.17 mmol) were added to a solution of dimethyl
1,3-acetonedicarboxylate 4a (14.2 g, 81.7 mmol) in toluene
(100 ml), and the reaction mixture was refluxed. After 6 h,
the resultant mixture was concentrated in vacuo. The resi-
due was purified by silica gel column chromatography
(hexane/ethyl acetate = 12:1) to afford 4f (32.6 g, 95%) as
a pale yellow oil. ½aꢁD ¼ ꢀ84:4 (c 1.0, CHCl3); H NMR
(300 MHz, CDCl3): d 0.75–1.59 (m, 28H), 1.65–1.70 (m,
4H), 1.84–1.89 (m, 2H), 1.99–2.05 (m, 2H), 3.58 (d,
J = 5.9 Hz, 4H), 4.68–4.80 (m, 2H); IR (CHCl3): 2961,
2930, 1724, 1653, 1456, 1244, 1180 cmꢀ1; MS FAB(+)
m/z: 423 [M++H]; HRMS calcd for C25H43O5: 423.3110,
found: 423.3119.
1
CDCl3): d 1.29 (t, J = 7.1 Hz, 6H), 4.23 (q, J = 7.1 Hz,
4H), 6.04 (s, 2H); 13C NMR (75 MHz, CDCl3): d 13.6
(2C), 61.3 (2C), 92.2 (2C), 163.1 (2C), 219.2; IR (CHCl3):
3032, 2986, 1967, 1716, 1265, 1149 cmꢀ1; MS (70 eV)
m/z: 184 (M+, 11), 157 (3), 156 (31), 128 (24), 112 (100);
HRMS calcd for C9H12O4 (M+): 184.0735, found:
184.0721. Anal. Calcd for C9H12O4: C, 58.69, H, 6.57.
Found: C, 58.67, H, 6.44.
25
1
4.5. Dibenzyl 2,3-pentadienedioate 1d
Dibenzyl 1,3-acetonedicarboxylate (4d) (50 mg, 0.15 mmol)
was treated as 4a in the above reaction to afford 1d (32 mg,
1
70%) as a pale yellow oil. H NMR (300 MHz, CDCl3): d
4.9. (+)-[Bis-(1S,2R,5S)-(+)-menthyl] 1,3-acetonedicarb-
oxylate 4g
5.18 (s, 4H), 6.07 (s, 2H), 7.29–7.32 (m, 10H); 13C NMR
(75 MHz, CDCl3): d 67.1 (2C), 92.4 (2C), 128.1 (4C),
128.3 (2C), 128.5 (4C), 135.3 (2C), 163.0 (2C), 219.8: IR
Dimethyl 1,3-acetonedicarboxylate 4a (5.00 g, 28.7 mmol)
and (1S,2R,5S)-(+)-menthol (5.00 g, 28.7 mmol) were trea-
ted as 4f in the above reaction and the residue was purified
by silica gel column chromatography (hexane/ethyl ace-
(CHCl3): 3069, 1967, 1720, 1288, 1263, 1142, 1003 cmꢀ1
;
MS FAB(+) m/z: 331 [M++Na]; HRMS calcd for
C19H16O4Na [M+Na]+: 331.0947, found: 331.0962.
tate = 10:1) to afford 4g (8.71 g, 72%) as a pale yellow
25
4.6. Di-tert-butyl 2,3-pentadienedioate 1e
oil. ½aꢁD ¼ þ83:0 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): d 0.76 (d, J = 7.0 Hz, 6H), 0.89 (d, J = 7.1 Hz,
6H), 0.91 (d, J = 6.6 Hz, 6H), 0.85–0.92 (m, 5H), 0.95–
1.01 (m, 4H), 1.35–1.55 (m, 4H), 1.65–1.71 (m, 4H),
1.84–1.89 (m, 2H), 2.00–2.05 (m, 2H), 3.20 (s, 0.5H), 3.57
(d, J = 15.7 Hz, 1.5H), 3.59 (d, J = 15.7 Hz, 1.5H), 4.73
(dt, J = 13.2, 4.3 Hz, 2H), 5.10 (s, 0.25H), 12.18 (s,
0.25H); IR (CHCl3): 2960, 2930, 2872, 1724, 1653, 1456,
1317, 1244 cmꢀ1; MS FAB(+) m/z: 423 [M+H]+; HRMS
calcd for C25H43O5 (M++H): 423.3110, found: 423.3106.
Di-tert-butyl 1,3-acetonedicarboxylate 4e (100 mg,
0.39 mmol) was treated as 4a in the above reaction to
afford 1e (66 mg, 71%) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3): d 1.48 (s, 18H), 5.89 (s, 2H); 13C
NMR (75 MHz, CDCl3): d 27.9 (6C), 81.8 (2C), 93.5
(2C), 162.6 (2C), 218.8; IR (CHCl3): 2981, 1963, 1701,
1369, 1302, 1136, 966 cmꢀ1; MS FAB(+) m/z: 263
[M++Na]; HRMS calcd for C13H20ONa [M++Na]:

T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 2943–2951
2949
4.10. (ꢀ)-[Bis-(1S)-(ꢀ)-bornyl] 1,3-acetonedicarboxylate 4h
CDCl3): d 0.78, 0.89, 0.91 (each d, J = 7.0 Hz, 6H), 0.83–
1.11 (m, 6H), 1.36–1.54 (m, 4H), 1.66–1.71 (m, 4H),
1.82–1.90 (m, 2H), 2.00–2.05 (m, 2H), 4.74 (dt, J = 10.8,
4.5 Hz, 2H), 5.99 (s, 1.97H), 6.01 (s, 0.03H); IR (CHCl3)
3028, 2959, 2928, 1965, 1699, 1456, 1290, 1263,
1146 cmꢀ1; MS FAB(+) m/z: 427 (M++Na); HRMS calcd
for C25H40O4Na (M++Na): 427.2824, found: 427.2832.
Dimethyl 1,3-acetonedicarboxylate 4a (2.01 g, 11.5 mmol)
and (1S)-(ꢀ)-borneol (4.45 g, 28.9 mmol) were treated as
4f in the above reaction and the residue was purified by
silica gel column chromatography (hexane/ethyl acetate =
24
7:1) to afford 4h (3.65 g, 75%) as a pale yellow oil. ½aꢁD
¼
ꢀ43:1 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3): d
0.85, 0.88, 0.90 (each s, 6H), 0.99–1.05 (m, 2H), 1.20–1.56
(m, 4H), 1.68–1.95 (m, 6H), 2.33–2.41 (m, 2H), 3.24 (s,
0.5H), 3.63 (s, 3H), 4.92–4.98 (m, 2H), 5.20 (s, 0.25H),
12.14 (s, 0.25H); IR (CHCl3): 3013, 2959, 1728, 1655,
1454, 1327, 1240 cmꢀ1; MS FAB(+) m/z: 419 (M++H);
HRMS calcd for C25H39O5 (M++H): 419.2797, found:
419.2801.
4.14. (R)-(ꢀ)-[Bis-(1S)-(ꢀ)-bornyl] 2,3-pentadienedioate 1i
A catalytic amount of triethylamine was added to a solu-
tion of a diastereomeric mixture of 4h (4.72 g, 11.8 mmol)
in a minimum amount of hexane, and the crystallization
was attained at room temperature. Crystallization was
repeated three times to afford one diastereomer (4.34 g,
26
92%) as colorless crystals. Mp: 146 °C (hexane); ½aꢁD
¼
1
4.11. (ꢀ)-[Bis-(1R)-(ꢀ)-isobornyl] 1,3-acetonedicarboxylate
(ꢀ)-4i
ꢀ206:8 (c 0.98, CHCl3); H NMR (400 MHz, CDCl3): d
0.85, 0.88, 0.91 (each s, 6H), 1.01 (dd, J = 13.8, 3.4 Hz,
2H), 1.17–1.23 (m, 2H), 1.25–1.33 (m, 2H), 1.68–1.79 (m,
4H), 1.88–1.94 (m, 2H), 2.35–2.43 (m, 2H), 4.93 (ddd,
J = 9.9, 3.3, 2.2 Hz, 2H), 6.03 (s, 2H); 13C NMR
(100 MHz, CDCl3): d 13.5 (2C), 18.8 (2C), 19.7 (2C),
26.9 (2C), 28.0 (2C), 36.8 (2C), 44.9 (2C), 47.8 (2C), 49.0
(2C), 81.2 (2C), 92.5 (2C), 163.8 (2C), 219.9; IR (CHCl3):
3032, 3007, 2957, 2880, 1963, 1701, 1454, 1391, 1377,
1366, 1302, 1288, 1261, 1238, 1204, 1151, 1194,
1024 cmꢀ1; MS FAB(+) m/z: 423 (M++Na); HRMS calcd
for C25H36ONa (M++Na): 423.2514, found: 423.2508.
Anal. Calcd for C25H36O4: C, 74.96, H, 9.06. Found: C,
75.17, H, 8.99.
Dimethyl 1,3-acetonedicarboxylate 4a (1.31 g, 7.52 mmol)
and (1R)-(ꢀ)-isoborneol (2.90 g, 18.8 mmol) were treated
as 4f in the above reaction and the residue was purified
by silica gel column chromatography (hexane/ethyl ace-
tate = 7:1) to afford 4i (2.41 g, 76%) as a pale yellow oil.
24
½aꢁD ¼ ꢀ65:3 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d 0.83, 0.85, 0.96 (each s, 6H), 1.12 (m, 4H), 1.52–1.56 (m,
2H), 1.66–1.85 (m, 8H), 3.18 (s, 0.6H), 3.57 (s, 3H), 4.70
(dd, J = 7.3, 4.0 Hz, 2H), 5.09 (s, 0.2H), 12.11 (s, 0.2H);
IR (CHCl3): 3013, 2957, 1728, 1655, 1327, 1219 cmꢀ1
;
MS FAB(+) m/z: 441 (M++Na); HRMS calcd for
C25H38O5Na (M++Na): 441.2617, found: 441.2624.
4.15. (R)-(ꢀ)-Bis[(1R)-(ꢀ)-isobornyl] 2,3-pentadienedioate
4.12. (R)-(ꢀ)-[Bis-(1R,2S,5R)-(ꢀ)-menthyl] 2,3-pentadiene-
1i
dioate 1f
A catalytic amount of triethylamine was added to a solu-
tion of a diastereomeric mixture of 4i (784 mg, 1.96 mmol)
in a minimum amount of hexane, and the crystallization
was attained at room temperature. Crystallization was
Triethylamine (5.0 mg, 0.05 mmol) was added to a solution
of a diastereomeric mixture of 4f (2.00 g, 4.95 mmol) in
pentane (5 ml), and the solution was chilled at ꢀ20 °C to
afford crystals. Crystallization was repeated three times to
afford 1f (1.8 g, 90%) as colorless crystals. Mp: 83 °C
(pentane); ½aꢁD ¼ ꢀ244:2 (c 1.1, CHCl3); H NMR (300
MHz, CDCl3): d 0.78, 0.77 (each d, J = 6.9 Hz, 3H),
0.91–1.18 (m, 16H), 1.34–1.63 (m, 6H), 1.63–1.77 (m,
4H), 1.84, 1.87 (each dq, J = 6.9, 2.6 Hz, 1H), 2.03 (br d,
J = 11.9 Hz, 2H), 4.75 (dt, J = 10.8, 4.4 Hz, 2H), 5.99 (s,
2H); 13C NMR (75 MHz, CDCl3): d 16.5 (2C), 20.1 (2C),
21.9 (2C), 23.6 (2C), 26.4 (2C), 31.3 (2C), 34.1 (2C), 40.7
(2C), 46.9 (2C), 75.5 (2C), 92.6 (2C), 162.9 (2C), 219.5;
IR (CHCl3): 1945, 1685 cmꢀ1; MS FAB(+) m/z: 405
[M++H]; HRMS calcd for C25H41O4: 405.3005, found:
405.3013.
repeated twice to afford one diastereomer (698 mg, 89%)
21
as colorless crystals. Mp: 151 °C (hexane); ½aꢁD ¼ ꢀ263:8
26
(c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3): d 0.83,
0.84, 0.92 (each s, 6H), 1.04–1.18 (m, 4H), 1.52–1.59 (m,
2H), 1.65–1.85 (m, 8H), 4.71 (dd, J = 7.7, 3.3 Hz, 2H),
5.95 (s, 2H); 13C NMR (100 MHz, CDCl3): d 11.4 (2C),
19.8 (2C), 20.0 (2C), 27.0 (2C), 33.5 (2C), 38.6 (2C), 45.0
(2C), 47.2 (2C), 48.9 (2C), 82.2 (2C), 92.4 (2C), 162.9
(2C), 220.2; IR (CHCl3): 3026, 3013, 2957, 2880, 1962,
1699, 1477, 1454, 1404, 1391, 1371, 1312, 1261, 1244,
1217, 1200, 1163, 1051, 1009 cmꢀ1; MS FAB(+) m/z: 401
(M++H); HRMS calcd for C25H37O4 (M++H): 401.2692,
found: 401.2683 Anal. Calcd for C25H36O4: C, 74.96; H,
9.06. Found: C, 74.92; H, 9.13.
1
4.13. (S)-(+)-[Bis-(1S,2R,5S)-(+)-menthyl] 2,3-pentane-
dienedioate 1g
4.16. (1S,2R,3E,4R)-(+)-[(1S)-(ꢀ)-Bornyl] 3-[2-(ꢀ)-bornyl-
oxy-2-oxoethylidene]-7-tert-butoxycarbonyl-7-azabicyclo-
[2.2.1]hept-5-ene-2-carboxylate 7a
A catalytic amount of triethylamine was added to a solu-
tion of a diastereomeric mixture of 4g (917 mg, 2.27 mmol)
in a minimum amount of pentane, and the solution was
chilled at ꢀ20 °C to afford crystals. Crystallization was
repeated three times to afford one diastereomer (825 mg,
90%) as colorless crystals. Mp: 87 °C (pentane);
[a]D = +243.3 (c 0.54, CHCl3); 1H NMR (400 MHz,
Aluminum chloride (199 mg, 1.50 mmol) was added to a
solution of 1h (500 mg, 1.25 mmol) in dichloromethane
(20 ml) and the mixture was stirred for 30 min at ꢀ78 °C.
A solution of 3a (2.09 g, 12.5 mmol) in dichloromethane
(5 ml) was added to the reaction mixture, which was stirred

2950
T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 2943–2951
for 48 h while keeping the temperature at ꢀ78 °C. The
reaction mixture was poured into water and extracted with
chloroform. The organic layer was washed with a saturated
aqueous solution of sodium chloride, dried over sodium
sulfate, and evaporated. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 10:1)
diethyl ether and the reaction was quenched by adding
saturated aqueous solution of sodium sulfate. Magnesium
sulfate was directly added to the mixture, and the filtrate
was evaporated. The residue was purified by silica gel
column chromatography (chloroform/methanol = 15:1) to
afford (1S,2R,3E,4R)-7-tert-butoxycarbonyl-2-(20-hydroxy-
ethylidene)-3-hydroxymethyl-7-azabicyclo[2.2.1]heptane (63
mg), which was treated with acetic anhydride and pyridine.
After stirring the mixture for 1 h at room temperature,
methanol was added and the organic solvents were
removed in vacuo. The residue was purified by silica gel
to afford 7a (669 mg, 94%) as colorless crystals. Mp:
31
138 °C (methanol); ½aꢁD ¼ þ19:3 (c 0.64, CHCl3); 1H
NMR (400 MHz, CDCl3, 55 °C): d 0.81, 0.82, 0.86 (each
s, 3H), 0.88 (s, 6H), 0.90 (s, 3H), 0.93 (dd, J = 13.9,
3.5 Hz, 1H), 0.96 (dd, J = 13.6, 3.6 Hz, 1H), 1.11–1.17
(m, 1H), 1.21–1.34 (m, 3H), 1.43 (s, 9H), 1.63–1.68 (m,
2H), 1.70–1.85 (m, 3H), 1.91–1.97 (m, 1H), 2.24–2.37 (m,
2H), 4.10 (dd, J = 4.3, 1.9 Hz, 1H), 4.78 (ddd, J = 3.8,
5.7, 9.9 Hz, 1H), 4.92 (br m, 1H), 5.03 (br m, 1H), 6.12
(d, J = 2.2 Hz, 1H), 6.33 (dd, J = 5.7, 2.1 Hz, 1H), 6.41
(dd, J = 5.7, 2.6 Hz, 1H); IR (CHCl3): 3028, 2959, 2880,
1707, 1369, 1352, 1273, 1236, 1205, 1196 cmꢀ1; MS
FAB(+) m/z: 590 (M++Na); HRMS calcd for C34H49-
NO6 (M++Na): 590.3457, found: 590.3463. Anal. Calcd
for C34H49NO6: C, 71.93; H, 8.70; N, 2.47. Found: C,
71.84; H, 8.69; N, 2.57.
column chromatography (hexane/ethyl acetate = 3:1) to
27
afford 8a (63 mg, 53%) as a colorless oil. ½aꢁD ¼ þ73:6
(c 0.64, CHCl3); 13C NMR (CDCl3): d 20.7, 20.8, 20.9,
28.06, 28.14, 61.7, 63.0, 65.4, 65.7, 80.1, 80.6, 170.5,
170.6, 170.7, 171.0. 8b was treated as the same way as 7a:
24
½aꢁD ¼ þ73:3 (c 0.83, CHCl3).
4.19. (1S,2R,3E,4R)-(ꢀ)-[(1S)-(ꢀ)-Bornyl] 3-[2-(ꢀ)-bornyl-
oxy-2-oxoethylidene]bicyclo[2.2.1]hept-5-ene-2-carboxylate
7c
Aluminum chloride (88 mg, 0.66 mmol) was added to a
solution of 1h (220 mg, 0.55 mmol) in dichloromethane
(6 ml) and the mixture was stirred for 30 min at ꢀ78 °C.
A solution of 3b (726 mg, 5.49 mmol) in dichloromethane
(4 ml) was added to the reaction mixture, which was stirred
for 48 h while keeping the temperature at ꢀ78 °C. The
reaction mixture was poured into water and extracted with
chloroform. The organic layer was washed with a saturated
aqueous solution of sodium chloride, dried over sodium
sulfate, and evaporated. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 15:1)
to afford 7c (244 mg, 95%) as colorless crystals. Mp:
115 °C (diethyl ether); ½aꢁD ¼ ꢀ31:5 (c 0.64, CHCl3); H
NMR (400 MHz, CDCl3): d 0.79 (s, 6H), 0.83 (s, 3H),
0.86 (s, 6H), 0.88 (s, 3H), 0.89–0.95 (m, 1H), 0.98 (d,
J = 3.7 Hz, 1H), 1.05–1.12 (m, 1H), 1.16–1.33 (m, 3H),
1.50–1.81 (m, 7H), 1.92–1.99 (m, 1H), 2.21–2.39 (m, 2H),
3.39 (m, 1H), 3.44 (m, 1H), 3.90 (dd, J = 3.6, 2.1 Hz,
1H), 4.73 (ddd, J = 5.5, 3.4, 2.2 Hz, 1H), 4.86 (ddd,
J = 5.6, 3.5, 2.1 Hz, 1H), 6.06 (dd, J = 2.2, 0.5 Hz, 1H),
6.14–6.19 (m, 2H); MS FAB(+) m/z: 467 (M++H); HRMS
calcd for C30H42O4 (M++H): 467.3161, found: 467.3169.
Anal. Calcd for C30H42O4: C, 77.21; H, 9.07. Found: C,
76.80; H, 9.10.
4.17. (1S,2R,3E,4R)-(ꢀ)-[(1R)-(ꢀ)-Isobornyl] 3-[2-(ꢀ)-iso-
bornyloxy-2-oxoethylidene]-7-tert-butoxycarbonyl-7-azabi-
cyclo[2.2.1]hept-5-ene-2-carboxylate 7b
Aluminum chloride (21 mg, 0.16 mmol) was added to a
solution of 1i (52 mg, 0.13 mmol) in dichloromethane
(3 ml) and the mixture was stirred for 30 min at ꢀ78 °C.
A solution of 3a (217 mg, 1.30 mmol) in dichloromethane
(2 ml) was added to the reaction mixture, which was stirred
for 48 h while keeping the temperature at ꢀ78 °C. The
reaction mixture was poured into water and extracted with
chloroform. The organic layer was washed with a saturated
aqueous solution of sodium chloride, dried over sodium
sulfate, and evaporated. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 10:1)
26
1
to afford 7b (68 mg, 92%) as colorless crystals. Mp:
27
157 °C (methanol); ½aꢁD ¼ ꢀ16:7 (c 2.5, CHCl3); 1H
NMR (400 MHz, CDCl3, 55 °C): d 0.81, 0.82, 0.83, 0.84,
0.85, 0.98 (each s, 3H), 1.16–1.12 (m, 2H), 1.41 (s, 9H),
1.47–1.81 (m, 12H), 4.03 (dd, J = 3.9, 2.1 Hz, 1H), 4.60
(ddd, J = 11.3, 7.7, 3.4 Hz, 2H), 4.92 (br s, 1H), 4.97 (br
m, 1H), 6.01 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 5.8,
2.2 Hz, 1H), 6.73 (dd, J = 5.8, 2.5 Hz, 1H); IR (CHCl3):
3034, 2957, 1707, 1369, 1352, 1275, 1256, 1186, 1167
cmꢀ1; MS FAB(+) m/z: 590 (M++Na); HRMS calcd for
C34H49NO6 (M++Na): 590.3457, found: 590.3463. Anal.
Calcd for C34H49NO6: C, 71.93; H, 8.70; N, 2.47. Found:
C, 71.78; H, 8.81; N, 2.59.
Acknowledgments
This research was financially supported in part by Frontier
Research Program and the 21st Century Center of Excel-
lence Program ‘Development of Drug Discovery Frontier
Integrated from Tradition to Proteome’ of the Ministry
of Education, Culture, Science, Sports and Technology,
Japan.
4.18. (1S,2R,3E,4R)-(+)-7-tert-Butoxycarbonyl-2-(20-acet-
oxyethylidene)-3-acetoxymethyl-7-azabicyclo[2.2.1]heptane
8a and 8b
A solution of 7a (200 mg, 0.35 mmol) in tetrahydrofuran
(5 ml) was added to a suspension of lithium aluminum
hydride (33 mg, 0.88 mmol) and tetrahydrofuran (10 ml)
at 0 °C and the mixture was stirred for 1 h while keeping
the temperature the same and then for another 48 h at
room temperature. The reaction mixture was diluted with
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