Synthesis of a pseudoenantiomer of β-isocupreidine (β-ICD), a chiral amine catalyst for asymmetric baylis-hillman reactions

Article abstract of DOI:10.3987/COM-05-S(K)38

-(3S,8S,9R)-3,9-Epoxy-6′-hydroxy-11-norcinconane (23), a pseudoenantiomer of β-isocupreidine (β-ICD), was synthesized starting with a fragmentation reaction of 10-bromo-10,11-dihydroquinine, prepared from quinine. Baylis-Hillman reaction of benzaldehyde w

Full text of DOI:10.3987/COM-05-S(K)38

HETEROCYCLES, Vol. 66, 2005
371
HETEROCYCLES, Vol. 66, 2005, pp. 371 – 383. © The Japan Institute of Heterocyclic Chemistry
Received, 30th August, 2005, Accepted, 28th October, 2005, Published online, 1st November, 2005. COM-05-S(K)38
SYNTHESIS OF A PSEUDOENANTIOMER OF β-ISOCUPREIDINE
(
β-ICD), A CHIRAL AMINE CATALYST FOR ASYMMETRIC
†
BAYLIS-HILLMAN REACTIONS
Ayako Nakano, Keisuke Takahashi, Jun Ishihara, and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki
8
52-8521, Japan: susumi@net.nagasaki-u.ac.jp
Abstract
–
(3S,8S,9R)-3,9-Epoxy-6’-hydroxy-11-norcinconane
(23),
a
pseudoenantiomer of β-isocupreidine (β-ICD), was synthesized starting with a
fragmentation reaction of 10-bromo-10,11-dihydroquinine, prepared from quinine.
Baylis-Hillman reaction of benzaldehyde with 1,1,1,3,3,3-hexafluoroisopropyl
acrylate (HFIPA) using 23 as a chiral amine catalyst gave the corresponding
S-enriched adduct in high optical purity (93% ee) in contrast to the β-ICD-
catalyzed reaction which affords R-enriched adducts.
INTRODUCTION
The Morita-Baylis-Hillman reaction, an organocatalytic three component reaction leading to coupling of
aldehydes or imines with activated alkenes, has attracted considerable interest due to the atom economical
efficacy and the promising utility of the multifunctional products. However, the major problems
associated with this reaction are its slow reaction rate and difficulty in realization of a high level of
asymmetric induction. This situation has brought about recent great progress in rate accelerationas well
1
as asymmetric induction based on various imaginative ideas. Recently, we have developed a highly
2
3
enantioselective asymmetric Baylis-Hillman reaction of aldehydes as well as imines by use of
4
,5
β-isocupreidine (β-ICD) as a chiral amine catalyst and 1,1,1,3,3,3-hexafluoroisopropyl acrylate
(
HFIPA) as an activated alkene. In addition, we have successfully demonstrated the synthetic utility of
6
this reaction via syntheses of biologically intriguing natural products. This β-ICD-HFIPA method has
remarkable advantages in terms of the high enantionselectivity, the broad applicability, and the
availability of both β-ICD and HFIPA. However, one serious drawback is that this method cannot be
†
Dedicated to the memory of the late Professor Kenji Koga.

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HETEROCYCLES, Vol. 66, 2005
applied to the synthesis of the products with opposite absolute configuration because the required
7
enantiomer of β-ICD is not easily available. As one solution to this problem, we investigated the
8
synthesis of an enantio-complementary catalyst of β-ICD.
OH
N
OH
O
CF3
CF3
HFIPA, !-ICD
O
RCHO
R
R
O
DMF, –55 ˚C
N
>
90% ee
!
-ICD
Ph P(O)HN
O
CF3
CF3
2
NP(O)Ph2
O
CF
3
HFIPA, !-ICD
Ar
S
O
Ar
H
O
CF
3
DMF, –55 ˚C
then
recrystallization
>
90% ee
HFIPA
Scheme 1. β-ICD-HFIPA method
2
β-ICD can be prepared in one step from quinidine by treatment with aqueous KBr-H PO at 100 °C. In
3
4
this process, together with demethylation, acid-induced cycloisomerization of quinidine takes place via
9
carbocations (1) and (2) as reported by Hoffmann et al. (Scheme 2)
OMe
N
OMe
N
H
OMe
N
+
OH
+
OH
OH
KBr-H PO
1,2-hydrogen
shift
3
4
N
N
N
100 °C
2
quinidine
1
OH
O
cyclization
demethylation
N
N
!
-ICD
Scheme 2. Cycloisomerization of quinidine leading to β-ICD
This transformation suggests that if carbocation (5) is accessible from quinine, a pseudoenantiomer of
quinidine, then the synthesis of 6, a pseudoenantiomer of β-ICD, would also become possible. Thus, we
envisaged alkene (4) as a precursor of carbocation (5) and postulated that this intermediate could be
accessed via cyclization of piperidine (3), accessible from quinine via cleavage of the C2-C3 bridge by

HETEROCYCLES, Vol. 66, 2005
373
1
0
taking advantage of the fragmentation reaction developed by Thiel at al. and a suitable functionalization
of the resulting C4-substituent involving epimerization. (Scheme 3)
CHR
OH
CHR
OH
OMe
N
OMe
N
OMe
N
5
X
Thiel's
fragmentation
6
OH
4
4
3
5
N
N
N
2
6
epimerization (C4)
H
quinine
3
4
R
OH
N
R
OMe
+
O
KBr-H PO4
cyclization
3
OH
N
N
demethylation
6
N
5
J. Thiel et al.
OH
OH
Ar
+
H
N
H
N
+
N
Ar
Ar
Ar
H
N
X
H
OH
O
Scheme 3. Strategy for the synthesis of a pseudoenantiomer of β-ICD
RESULTS AND DISCUSSION
Following the strategy mentioned above, the synthesis of a psudoenantiomer of β-ICD started from
cleavage of the C2-C3 bridge of quinine by Thiel’s fragmentation reaction (Scheme 4). Thus, treatment of
1
1
1
0-bromo-10,11-dihydroquinine (7), prepared as a 3:1 epimeric mixture by the reaction of quinine with
hydrogen bromide, with aqueous NaHCO in boiling dioxane caused fragmentation reaction to give
3
alkene (8) as a 2:1 Z- and E-mixtures. Hydrolysis of the N,O-acetal of 8 followed by protection of 9 as its
cyclic carbamate afforded carbamate (10). To invert the C4 stereocenter, carbamate (10) was successively
1
1
subjected to dihydroxylation, NaIO -oxidation, and base-catalyzed epimerization to give a 1:7
4
equilibrium mixture of aldehydes (12) and (13). Without separation, this mixture was converted to
piperidine (15) via 14 by a four-step sequence involving Wittig reaction employing
1
2
methoxymethylenetriphenylphosphorane,
acidic hydrolysis,
Mannich reaction
employing
1
3
14
Eschenmoser’s salt, and Luche reduction. Alkaline hydrolysis of 15 produced quantitatively amino

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HETEROCYCLES, Vol. 66, 2005
diol (16), intramolecular N-alkylation of which was then investigated to obtain quinuclidine (17).
1
5
However, all attempts including the Stork’s procedure employed in the synthesis of quinine were
unsuccessful.
OMe
OH
N
HBr
NaHCO
3
H
(COOH)
2
(
–)-quinine
N
4
8% aq. HBr 10
67% aq. dioxane
reflux
N
96% aq. EtOH
reflux
H
0
°C
Br
N
O
7
8
OMe
1
0S:10R = 3:1
Z:E = 2:1
OH
HO
1
2
) ClCO Me
2
Et N, THF
cat. OsO4
N
3
N
N
H
H
H
) NaH, THF
60 °C
K [Fe(CN) ]
3 6
aq. t-BuOH
N
H
N
N
H
H
O
H
OH
O
O
O
98%
9
10
5% from quinine
11
OMe
N
OMe
OMe
4
Cl–
CHO
H
+
CHO
N
CHO
1
) Ph PCH OMe
3
2
n-BuLi
THF, –78 °C
N
N
NaIO4
NaOMe
MeOH
H
H
N
N
H O
2) 5 M HCl
THF
2
H
H
H
CH Cl
2
2
O
O
O
O
O
O
1
2
13
2:13 = 1:7
14
9
3%
OMe
OMe
OMe
OMe
1
OH
H
OH
I–
+
1
)Me N CH
2 2
N
N
OH
Et N, CH Cl
2 M NaOH
80 °C
3
2
2
H
N
2
) NaBH4
CeCl ·7H O
N
N
H
H
H
O
3
2
OH
N
MeOH
O
17
OMe
16
OMe
15
5
3% from 12
Scheme 4. Attempt to synthesize the key intermediate
The above-mentioned failure of the quinuclidine ring formation is attributed possibly to severe strain
caused by the existence of the exo-methylene. Therefore, we alternatively examined the route shown in
Scheme 5. Thus, compound (15) was converted to 18 by alkaline hydrolysis followed by
tert-butoxycarbonylation. Successive hydroboration of 18, oxidation of the resulting alkylborane using
1
6
NaBO , and decomplexation of the corresponding quinoline-borane complex with ethylenediamine
4
afforded triol (19) quantitatively. Triol (19) was then converted to dimesylate (20) by mesylation

HETEROCYCLES, Vol. 66, 2005
375
followed by acetylation. The tert-butoxycarbonyl group of 20 was removed cleanly by the reaction with
1
7
in situ generated trimethylsilyl iodide to give the corresponding amino dimesylate, which underwent
cyclization smoothly in boiling acetonitrile to produce quinuclidine (21) as an inseparable epimeric
mixture. Without purification, 21 was directly treated with DBU and tetra-n-butylanmonium iodide in
2
boiling xylene to give alkene (22) cleanly. Finaly, 22 was directly exposed to the conditions employed
for the synthesis of β-ICD to furnish compound (23), a pseudoenantiomer of β-ICD.
OH
H
HO
OH
H
2
M NaOH
0 °C
BH3, THF
N
8
N
15
then Boc O
then NaBO ·4H O
2
N
Boc
4
2
N
Boc
H
OH
H
OH
then NH (CH ) NH
2
2 2
2
74%
quant.
18
OMe
19
OMe
OMe
MsO
OMs
H
MsO
MsCl
pyridine, 0 °C
1) NaI, TMSCl
MeCN
OAc
N
N
then Ac O
2) MeCN
reflux
2
N
Boc
H
OAc
N
77%
21
2
0
OMe
OMe
OH
N
+
—
OAc
O
Bu N I , DBU
KBr, 85% H3PO4
100 °C
4
N
N
xylene, reflux
N
69%
2
2
23
58% from 20
Scheme 5. Synthesis of a pseudoenantiomer of β-ICD
In order to evaluate the ability of 23 as a chiral amine catalyst complementary to β-ICD, we examined the
Baylis-Hillman reaction of benzaldehyde with HFIPA using 23 as a catalyst. As a result, compound (23)
catalyzed Baylis-Hillman reaction as effectively as β-ICD and resulted in opposite enantioselectivity.
2
3 or !-ICD (0.1 equiv.)
OH
Ph *
O
CF3
HFIPA (1.3 equiv.)
PhCHO
O
CF3
DMF, –55 ˚C
23 (24 h): 64%, S (93% ee)
-ICD (48 h): 75%, R (97% ee)
!
24
Scheme 6. Baylis-Hillman reaction of benzaldehyde using 23 and β-ICD

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HETEROCYCLES, Vol. 66, 2005
In conclusion, we have synthesized chiral amine (23) starting from quinine and proved that it behaves as
an enantio-complementary catalyst to β-ICD in the asymmetric Baylis-Hillman reaction of aldehydes
with HFIPA. Efforts toward improving the synthetic route are now underway in this laboratory.
EXPERIMENTAL
Where appropriate, reactions were performed in flame-dried glassware under an argon atmosphere. All
extracts were dried over K CO and concentrated by rotary evaporation below 30 °C at ca. 25 Torr unless
2
3
otherwise noted. TLC was performed with Merck F-254 TLC plates. Column chromatography was
performed employing silica gel 60 (230-400 mesh ASTM, Merk). Commercial reagents and solvents
including anhydrous tetrahydrofuran (THF) (stabilizer free) were used as supplied with the following
exceptions. Dichloromethane (CH Cl ), N,N-dimethyformamide (DMF), acetonitrile (MeCN),
2
2
triethylamine, pyridine, and xylene were distilled from CaH . All melting points were taken on a
2
Yanagimoto micro melting point apparatus and are uncorrected. Optical rotations were recorded on a
JASCO DIP-370 polarimeter at ambient temperature. IR spectra were measured on a JASCO FT/IR-230
1
13
spectrophotometer. H and C NMR spectra were measured on a Varian Gemini 300, JEOL JNM-AL 400,
or a Varian Unity plus 500 spectrometer. Chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane (TMS) in δ units and coupling constants are given in hertz. TMS was
1
defined as 0 ppm for H NMR spectra and the center of the triplet of CDCl was also defined as 77.10
3
1
3
ppm for C NMR spectra. HRMS (EI) spectra were measured on a JEOL JMS-DX303 or a JEOL
JMS-700N.
(
1R,7S,8aS)-Tetrahydro-1-(6-methoxyquinolin-4-yl)-7-prop-1-enyl-1H-oxazolo[3,4-a]pyridin-3(5H)-
one (10) (2:1 Z- and E-mixture). HBr gas, generated by the addition of Br (45 mL) to tetraline (48 mL),
2
was passed slowly through an ice-cooled solution of quinine (11.1 g, 34.3 mmol) in 48% HBr (22 mL)
over 3 h. The reaction mixture was basified with 10 M NaOH (130 mL), extracted with Et O, washed
2
with brine, dried, concentrated to give bromide 7 (11.5 g) as a yellow amorphous solid, which was used
for the next reaction without purification. The ratio of the 10S and 10R-isomer was determined to be 3:1
1
11
by H NMR spectrum of 7 which was identical with that reported.
A mixture of crude bromide 7 (11.5 g) and NaHCO (5.79 g, 68.7 mmol) in 33% aqueous 1,4-dioxane
3
(
807 mL) was heated at 120 ˚C for 6 h. The reaction mixture was concentrated, extracted with CHCl3,
washed with brine, dried, and concentrated to give 8 (8.60 g) as a yellow amorphous solid, which was
1
used for the next reaction without purification. The Z/E-ratio was determined to be 2:1 by H NMR
1
0
spectrum of 8 which was identical with that reported.
A solution of crude 8 (8.60 g) and oxalic acid (3.10 g, 34.4 mmol) in 96% EtOH (550 mL) was refluxed
for 3 h. The reaction mixture was basified with 10% K CO with cooling in an ice bath, extracted with
2
3

HETEROCYCLES, Vol. 66, 2005
377
1
CHCl , washed with brine, dried, and concentrated to give 9 (10.3 g), the H NMR spectrum of which was
3
1
0
identical with that reported.
To a stirred solution of crude 9 (10.3 g) in THF (200 mL) at rt were added triethylamine (6.74 mL, 48.0
mmol) and methyl chloroformate (3.18 mL, 41.2 mmol). After being stirred at rt for 15 h, H O (4 mL)
2
was added and the reaction mixture was concentrated. The residue was extracted with AcOEt, and the
extract was washed with brine, dried, and concentrated to give the corresponding carbamate (10.1 g).
To an ice-cooled solution of crude carbamate (10.1 g) in THF (120 mL) was added NaH (60% in mineral
oil, 1.60 g, 40.0 mmol) and the mixture was heated at 60 °C for 1.5 h. The reaction was quenched with
H O (10 mL) with cooling in an ice bath and most of the THF was removed by evaporation. The residue
2
was extracted with Et O, washed with brine, dried, concentrated, and chromatographed (SiO , CHCl ) to
2
2
3
2
4
1
give 10 (5.18 g, 45% from quinine) as a colorless amorphous solid: [α]D –250.0° (c 1.008, CHCl ); H
3
NMR (300 MHz, CDCl ) δ 8.83 (d, J = 4.5 Hz, 1H), 8.10 (d, J = 9.6 Hz, 0.67H), 8.09 (d, J = 9.6 Hz,
3
0
0
3
1
0
0
1
5
1
.33H), 7.62 (d, J = 4.5 Hz, 1H), 7.45-7.39 (m, 1H), 6.86 (d, J = 2.7 Hz, 0.67H), 6.83 (d, J = 2.7 Hz,
.33H), 6.19 (d, J = 8.1 Hz, 0.33H), 6.16 (d, J = 7.8 Hz, 0.67H), 5.71-5.35 (m, 2H), 4.54-4.45 (m, 1H),
.95 (s, 2H), 3.93 (s, 1H), 3.89-3.82 (m, 1H), 3.31-3.19 (m, 1H), 2.81 (br s, 0.33H), 2.49 (br s, 0.67H),
.69 (d, J = 1.5 Hz, 2H), 1.68 (d, J = 1.5 Hz, 1H), 1.64 (br d, J = 4.5 Hz, 1H), 1.49 (br d, J = 15.3 Hz,
.33H), 1.44 (dd, J = 1.5, 6.6 Hz, 0.67H), 1.26 (t, J = 7.2 Hz, 0.33H), 1.14 (dt, J = 4.2, 12.9 Hz, 0.67H),
13
.93 (br d, J = 14.1 Hz, 0.67H), 0.81 (br d, J = 11.7 Hz, 0.33H); C NMR (75 MHz, CDCl ) δ 158.3,
3
56.3, 148.0, 144.0, 139.1, 132.3, 130.6, 128.5, 126.8, 126.5, 125.8, 121.7, 118.3, 100.3, 100.2, 74.4, 55.7,
5.6, 53.8, 53.6, 38.0, 32.7, 30.8, 30.3, 28.7, 28.4, 28.3, 18.2, 13.0; FT-IR (neat) 2935, 1757, 1622, 1508,
-
1
+
427, 1238, 1061, 970, 860, 725 cm ; HRMS (EI) calcd for C H N O (M ): 338.1630, found 338.1631.
20
22
2
3
(
1R,7S,8aS)-Tetrahydro-7-(1,2-dihydroxypropyl)-1-(6-methoxyquinolin-4-yl)-1H-oxazolo[3,4-a]-
pyridin-3(5H)-one (11) (diastereoisomeric mixture). To a stirred solution of 10 (1.20 g, 3.53 mmol) in
0% aqueous tert-BuOH (36 mL) at rt were added K CO (1.37 g, 9.90 mmol), K [Fe(CN) ] (3.26 g, 9.90
5
2
3
3
6
mmol), and an aqueous solution of OsO (0.15 M, 0.48 mL, 0.072 mmol). After 13 h, saturated Na S O
3
4
2
2
(
7 mL) was added and the mixture was stirred at rt for 10 min. The reaction mixture was basified with
0% K CO , extracted with CHCl , and the extract was washed with brine, dried, concentrated, and
1
2
3
3
chromatographed (SiO , CHCl /MeOH = 30/1) to give 11 (1.29 g, 98%) as a colorless amorphous solid:
2
3
2
4
1
[
α]D –205.9° (c 1.195, CHCl ); H NMR (300 MHz, CDCl ) δ 8.81-8.67 (m, 1H), 8.12-7.98 (m, 1H),
3 3
7
4
2
.65-7.54 (m, 1H), 7.46-7.34 (m, 1H), 6.94-6.82 (m, 1H), 6.22-6.10 (m, 1H), 4.85-4.70 (m, 0.8H),
.70-4.60 (m, 0.13H), 4.57-4.47 (m, 0.07H), 4.01-3.15 (m, 4H), 3.95, 3.94 (s x 2, 3H), 2.96-2.50 (m, 1H),
1
3
.30 (br s, 1H), 2.05-1.38 (m, 3H), 1.30-0.84 (m, 2H), 1.16, 1.14, 1.06, 0.99 (d, J = 6.3 Hz, 3H); C NMR
(
75 MHz, CDCl ) δ 158.3, 158.3, 156.6, 156.5, 156.5, 147.5, 147.4, 143.5, 139.6, 139.5, 139.4, 132.0,
3
1
31.8, 131.5, 125.9, 125.8, 122.1, 122.0, 121.9, 121.7, 118.3, 118.2, 118.1, 100.5, 100.4, 100.3, 75.5, 74.7,

378
HETEROCYCLES, Vol. 66, 2005
7
2
1
4.7, 74.6, 74.4, 72.5, 72.3, 68.4, 68.2, 68.0, 67.9, 55.7, 54.2, 53.9, 53.8, 39.2, 38.5, 38.3, 38.2, 33.1, 32.3,
9.3, 27.8, 26.8, 26.6, 26.4, 25.7, 24.4, 23.8, 20.5, 20.2, 16.3, 15.8; FT-IR (neat) 3417, 2931, 1751, 1624,
-
1
+
510, 1435, 1240, 1065 cm ; HRMS (EI) calcd for C H N O (M ): 372.1685, found 372.1674.
2
0
24
2
5
(
1R,7S,8aS)-Hexahydro-1-(6-methoxyquinolin-4-yl)-3-oxo-1H-oxazolo[3,4-a]pyridine-7-carb-
aldehyde (12). To a solution of the above-mentioned diol (978.7 mg, 2.63 mmol) in CH Cl (30 mL)
2
2
were added H O (3 mL) and NaIO (731.5 mg, 3.42 mmol), and the mixture was stirred at rt for 1 h. The
2
4
reaction mixture was basified with saturated NaHCO (10 mL) and filterd through a pad of Celite. The
3
pad was washed with CH Cl , and the filtrate was washed with brine, dried, concentrated, and
2
2
chromatographed (SiO , CHCl /MeOH = 50/1) to give 12 (795.1 mg, 93%) as a yellow amorphous solid:
2
3
2
3
1
[
α]D –283.7° (c 1.055, CHCl ); H NMR (500 MHz, CDCl ) δ 9.71 (d, J = 1.0 Hz, 1H), 8.83 (d, J = 4.0
3 3
Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 4.5 Hz, 1H), 7.43 (dd, J = 2.5, 9.0 Hz, 1H), 6.90 (d, J = 2.5
Hz, 1H), 6.17 (d, J = 8.5 Hz, 1H), 4.53 (ddd, J = 4.0, 8.5, 12.5 Hz, 1H), 4.03 (s, 3H), 3.98 (dd, J = 5.5,
1
6.5 Hz, 1H), 2.99 (ddd, J = 3.5, 13.5, 13.5 Hz, 1H), 2.68-2.64 (m, 1H), 2.16-2.10 (m, 1H), 1.83 (dddd, J
1
3
=
6.0, 6.0, 14.0, 14.0 Hz, 1H), 1.49-1.43 (m, 1H), 1.10 (ddd, J = 5.5, 13.0, 13.0 Hz, 1H); C NMR (75
MHz, CDCl ); δ 202.5, 158.3, 155.7, 147.6, 143.8, 138.4, 132.0, 125.4, 122.0, 118.0, 99.8, 74.3, 55.5,
3
-
1
5
3.9, 44.0, 38.7, 24.1, 22.4; FT-IR (neat); 2935, 1757, 1620, 1510, 1427, 1238, 1063 cm ; HRMS (EI)
+
calcd for C H N O (M ); 326.1267, found 326.1252.
18
18
2
4
(
[
1R,7R,8aS)-Tetrahydro-7-(1-hydroxyprop-2-en-2-yl)-1-(6-methoxyquinolin-4-yl)-1H-oxazolo-
3,4-a]pyridin-3(5H)-one (15). To a solution of 12 (192.1 mg, 0.589 mmol) in MeOH (3.9 mL) was
added NaOMe (6.4 mg, 0.118 mmol), and the mixture was stirred at rt for 1.5 h. The reaction mixture was
diluted with CHCl , washed with brine, dried, and concentrated to give 13 (223.3 mg), a yellow
3
1
amorphous solid, as a 7:1 epimeric mixture: H NMR (300 MHz, CDCl ) δ 9.71 (s, 0.1H), 9.38 (s, 0.7H),
3
8
6
.83 (d, J = 4.5 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 4.2 Hz, 1H), 7.45 (dd, J = 2.7, 9.3 Hz, 1H),
.90 (d, J = 2.7 Hz, 1H), 6.25 (d, J = 8.1 Hz, 0.88H), 6.23-6.15 (m, 0.12H), 4.59-4.47 (m, 0.12H), 4.29
(
ddd, J = 3.6, 7.8, 12.3 Hz, 0.88H), 4.18 (br dd, J = 4.5, 13.2 Hz, 0.88H), 4.03 (s, 0.36H), 4.02-3.88 (m,
0
2
1
.12H), 3.97 (s, 2.64H), 3.08 (ddd, J = 3.6, 13.2, 13.2 Hz, 0.88H), 2.99 (br dd, J = 13.5, 13.5 Hz, 0.12H),
.67 (m, 0.12H), 2.46-2.32 (m, 0.88H), 2.18-2.09 (m, 0.12H), 2.02-1.91 (m, 0.88H), 1.90-1.75 (m, 0.12H),
.51-1.30 (m, 1H), 1.18 (br d, J = 13.5 Hz, 0.88H), 1.12-0.95 (m, 0.12H), 0.87 (ddd, J = 12.6, 12.6, 12.6
Hz, 0.88H).
To a stirred suspension of methoxymethyltriphenylphosphonium chloride (427.6 mg, 1.25 mmol), dried at
8
0
0 ˚C under vacuum for 5 h, in THF (4.2 mL) at –78 ˚C was added n-butyllithium (1.54 M in hexane,
.77 mL, 1.18 mmol). After the mixture was stirred at 0 ˚C for 0.5 h and cooled to –78 ˚C, a solution of
crude 13 (223.3 mg) in THF (5.0 mL), pre-cooled at –78 ˚C, was added via cannula, and the mixture was
gradually allowed to warm to –40 ˚C. After being stirred at –40 °C for 1 h, at –20 °C for 1 h, and at rt for

HETEROCYCLES, Vol. 66, 2005
379
1
2 h, the reaction mixture was diluted with AcOEt, washed with H O and saturated NaHCO , dried, and
2 3
concentrated. The residue was dissolved in CHCl and filtered through SiO pad and the filter pad was
3
2
thoroughly washed with 100:1 CHCl -MeOH. Concentration of the filtrate and washings gave the
3
corresponding enol ether (500.2 mg) as a yellow viscous oil.
To a solution of the crude enol ether (500.2 mg) in THF (2.6 mL) was added 5 M HCl (1.3 mL), and the
mixture was stirred at rt for 2 h. The reaction mixture was diluted with H O (10 mL) and washed with
2
Et O thoroughly. The aqueous layer was basified with NaHCO , extracted with CHCl , washed with brine,
2
3
3
1
dried, and concentrated to give 14 (230.4 mg) as a white solid: H NMR (300 MHz, CDCl ) δ 9.58 (s, 1H),
3
8
6
3
0
.82 (d, J = 4.5 Hz, 1H), 8.09 (d, J = 9.3 Hz, 1H), 7.58 (d, J = 4.2 Hz, 1H), 7.43 (dd, J = 2.4, 9.3 Hz, 1H),
.89 (d, J = 2.7 Hz, 1H), 6.20 (d, J = 8.1 Hz, 1H), 4.28 (m, 1H), 4.11-3.98 (m, 1H), 4.00 (s, 3H),
.11-2.98 (m, 1H), 2.33-2.02 (m, 3H), 1.69 (br d, J = 15.3 Hz, 1H), 1.20-1.04 (m, 1H), 0.94-0.83 (m, 1H),
.69-0.54 (m, 1H).
To a stirred solution of crude 14 (230.4 mg) in CH Cl (2.0 mL) at rt was added a solution of
2
2
N,N-dimethylmethyleneiminium iodide (Eschenmoser’s salt) (490.3 mg, 2.65 mmol) and triethylamine
0.74 mL, 5.30 mmol) in CH Cl (3.0 mL). After 4 h, an additional Eschenmoser’s salt (109.0 mg, 0.59
(
2
2
mmol) was added and the mixture was stirred at rt for 1 h. The reaction mixture was diluted with CH Cl ,
2
2
washed with H O, saturated NaHCO , and brine, dried, and concentrated to give the corresponding
2
3
methylenated aldehyde (378.5 mg) as a yellow amorphous solid.
To an ice-cooled solution of the crude methylenated aldehyde (378.5 mg) and CeCl ·7H O (658.3 mg,
3
2
1
0
.767 mmol) in MeOH (12 mL) was added NaBH (200 mg, 5.29 mmol), and the mixture was stirred at
4
°C for 3h. H O (5 mL) was added and the mixture was stirred at rt for 10 min. After most of the MeOH
2
was evaporated, the residue was basified with NaHCO , diluted with CHCl , and filtered through a pad of
3
3
Celite. The filtrate was washed with brine, dried, concentrated, and chromatographed (SiO2,
2
3
CHCl /MeOH = 50/1) to give 15 (110.8 mg, 53% from 12) as a white solid: [α]D –373.6° (c 0.720,
3
1
MeOH); mp 147-150 ˚C (toluene); H NMR (300 MHz, CDCl ) δ 8.80 (d, J = 4.8 Hz, 1H), 8.09 (d, J =
3
9
7
1
1
1
3
.3 Hz, 1H), 7.63 (d, J = 4.5 Hz, 1H), 7.44 (dd, J = 2.7, 9.0 Hz, 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.23 (d, J =
.8 Hz, 1H), 4.91 (s, 1H), 4.59 (s, 1H), 4.27 (ddd, J = 3.9, 7.8, 11.7 Hz, 1H), 4.10 (dd, J = 3.6, 13.2 Hz,
H), 3.97 (s, 3H), 3.89 (s, 2H), 3.06 (ddd, J = 3.6, 13.2, 13.2 Hz, 1H), 2.23-2.15 (m, 1H), 2.10 (br s, 1H),
1
3
.37 (dddd, J = 12.6, 12.6, 12.6, 4.8 Hz, 1H), 0.96-0.78 (m, 2H); C NMR (75 MHz, CDCl ) δ 158.4,
3
56.2, 150.9, 147.8, 143.8, 138.8, 132.2, 125.8, 121.5, 118.3, 110.3, 100.6, 74.1, 64.5, 57.9, 55.5, 42.0,
-1
7.2, 31.3, 29.7; FT-IR (neat) 3379, 2937, 1749, 1622, 1514, 1431, 1236, 1028 cm ; HRMS (EI) calcd
+
for C H N O (M ): 354.1580, found 354.1570.
20
22
2
4
(
2S,4R)-N-tert-Butoxycarbonyl-2-[(R)-hydroxy(6-methoxyquinolin-4-yl)methyl]-4-(1-hydroxyprop-
-en-2-yl)piperidine (18). A mixture of 15 (215.7 mg, 0.609 mmol) and 2 M NaOH (1.5 mL) in MeOH
2

380
HETEROCYCLES, Vol. 66, 2005
(
(
1.5 mL) was heated at 80 ˚C for 3 h. After most of the MeOH was evaporated, H O (1.5 mL) and THF
2
1.5 mL) were added to the residue. To this mixture at 0 °C was added di-tert-butyl dicarbonate (0.49 mL,
2
.13 mmol) and the mixture was stirred at rt for 7 h. The reaction mixture was diluted with CHCl3,
washed with brine, dried, concentrated, and chromatographed (SiO , Hex/AcOEt = 2/1) to give 18 (258.5
2
2
4
1
mg, 74%) as a colorless amorphous solid: [α]D –91.5° (c 1.060, CHCl ); H NMR (300 MHz, CDCl ) δ
3
3
8
.47 (d, J = 4.8 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.26
(
dd, J = 2.7, 9.0 Hz, 1H), 5.79 (s, 1H), 5.00 (s, 1H), 4.79 (s, 1H), 4.07-3.78 (m, 3H), 4.01 (s, 3H),
3
1
1
1
.67-3.51 (m, 2H), 2.13-2.00 (m, 1H), 2.00-1.72 (m, 4H), 1.50 (s, 9H), 1.50-1.31 (m, 1H), 1.31-1.23 (m,
1
3
H); C NMR (75 MHz, CDCl ); δ 157.9, 156.0, 152.9, 146.9, 143.5, 130.5, 126.7, 122.0, 118.4, 108.5,
3
02.2, 80.0, 70.7, 64.5, 58.9, 55.9, 41.4, 34.9, 29.4, 28.5, 24.8; FT-IR (neat); 2927, 1676, 1419, 1244,
-
1
+
149, 1036 cm ; HRMS (EI) calcd for C H N O (M ); 428.2312, found 428.2299.
2
4
3 2
2
5
(
2S,4R)-N-tert-Butoxycarbonyl-2-[(R)-hydroxy(6-methoxyquinolin-4-yl)methyl]-4-(1,3-dihydroxy-
propan-2-yl)piperidine (19). To an ice-cooled solution of 18 (71.6 mg, 0.167 mmol) in THF (0.84 mL)
was added BH ·THF complex (1.0 M in THF, 1.0 mL, 1.00 mmol), and the mixture was stirred at rt for 1
3
h. H O (1.8 mL) and NaBO ·4H O (30.8 mg, 0.200 mmol) were added with cooling in an ice bath and the
2
4
2
mixture was stirred at rt for 1 h. The reaction mixture was diluted with CHCl , washed with saturated
3
Na S O and saturated NaHCO , dried, and concentrated. The residue was dissolved in ethylenediamine
2
2
3
3
(
0.56 mL) and the mixture was stirred at rt for 3 h. The reaction mixture was concentrated and
chromatographed (SiO , CHCl /MeOH = 50/1) to give 19 (77.7 mg, 100%) as a colorless amorphous
2
3
2
4
1
solid: [α]D –29.5° (c 1.330, CHCl ); H NMR (300 MHz, CDCl ) δ 8.59 (br s, 1H), 7.94 (br d, J = 8.7
3
3
Hz, 1H), 7.76 (br d, J = 2.7 Hz, 1H), 7.53 (br s, 1H), 7.32 (br d, J = 9.0 Hz, 1H), 5.83 (br s, 1H), 4.01 (s,
3
1
1
1
4
H), 4.01-3.92 (m, 1H), 3.79-3.63 (m, 5H), 3.50-3.40 (m, 2H), 1.90-1.75 (m, 2H), 1.68-1.41 (m, 12H),
13
.31-1.17 (m, 3H); C NMR (75 MHz, CDCl ) δ 158.0, 156.0, 146.9, 146.8, 143.3, 130.3, 126.8, 122.2,
3
18.4, 102.3, 80.0, 70.7, 63.9, 58.8, 56.0, 46.8, 41.2, 29.9, 28.5, 27.5, 23.0; FT-IR (neat) 3375, 2933,
-
1
+
670, 1419, 1363, 1242, 1153, 1032 cm ; HRMS (EI) calcd for C H N O (M ): 446.2417, found
2
4
34
2
6
46.2439.
2S,4R)-N-tert-Butoxycarbonyl-2-[(R)-Acetoxy(6-methoxyquinolin-4-yl)methyl]-4-(1,3-dimethane-
(
sulfonyloxypropan-2-yl)piperidine (20). To an ice-cooled solution of 19 (44.5 mg, 0.100 mmol) in
pyridine (2.0 mL) was added methanesulfonyl chloride (0.04 mL, 0.500 mmol), and the mixture was
stirred at 0 °C for 1 h. The reaction mixture was diluted with AcOEt, washed with H O and brine, dried,
2
concentrated. The residue was dissolved in pyridine (2.0 mL) and acetic anhydride (0.25 mL, 2.650
mmol) was added to the mixture with cooling in an ice bath. After being stirred at rt for 7 h, the reaction
mixture was quenched with MeOH (0.1 mL), extracted with AcOEt, washed with brine, dried,
concentrated, and chromatographed (SiO , CHCl /MeOH = 50/1) to give 20 (49.5 mg, 77%) as a yellow
2
3

HETEROCYCLES, Vol. 66, 2005
381
2
3
1
amorphous solid: [α]D +2.6° (c 1.030, CHCl ); H NMR (300 MHz, CDCl ) δ 8.73 (d, J = 4.5 Hz, 1H),
3
3
8
6
.10 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.39 (dd, J = 2.7, 9.3 Hz, 1H), 7.29 (d, J = 4.5 Hz, 1H),
.93 (d, J = 2.1 Hz, 1H), 4.38 (ddd, J = 2.4, 6.6, 11.4 Hz, 1H), 4.29 (dd, J = 4.2, 10.5 Hz, 1H), 4.24-4.15
(
m, 2H), 4.12-4.06 (m, 2H), 4.10 (s, 3H), 3.98 (dd, J = 7.4, 13.8 Hz, 1H), 3.17 (ddd, J = 6.6, 11.4, 14.1 Hz,
1
H), 2.96 (s, 3H), 2.87 (s, 3H), 2.26 (s, 3H), 2.08-1.94 (m, 1H), 1.87-1.56 (m, 3H), 1.48 (s, 9H), 1.42-1.33
13
(
m, 1H), 1.26-1.20 (m, 1H); C NMR (75 MHz, CDCl ) δ 169.6, 158.5, 155.3, 147.1, 144.4, 141.8, 131.2,
3
1
2
26.5, 122.8, 117.4, 102.3, 80.5, 73.0, 66.7, 66.4, 56.2, 55.4, 42.9, 38.5, 37.4, 37.3, 29.5, 28.4, 26.7, 23.2,
-1
1.2; FT-IR (neat) 2974, 1745, 1678, 1624, 1412, 1354, 1236, 1169 cm ; HRMS (EI) calcd for
+
C H N O S (M ): 644.2073, found 644.2070.
2
8
40
2
11
2
(
2S,4R)-2-[(R)-Acetoxy(6-methoxyquinolin-4-yl)methyl]-5-methylenequinuclidine (22). To an
ice-cooled solution of 20 (42.3 mg, 0.066 mmol) in MeCN (1.3 mL) were added NaI (29.7 mg, 0.198
mmol) and chlorotrimethylsilane (0.03 mL, 0.198 mmol). After being stirred at rt for 1 h, the reaction
mixture was diluted with CHCl , washed with 10% Na CO and brine, dried, and concentrated to give the
3
2
3
1
corresponding amine (38.9 mg) as a yellow amorphous solid: H NMR (300 MHz, CDCl ) δ 8.75 (d, J =
3
4
3
5
.2 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.47-7.37 (m, 3H), 6.33 (d, J = 6.0 Hz, 1H), 4.41-4.20 (m, 4H),
.99 (s, 3H), 3.23-3.09 (m, 2H), 3.03 (s, 3H), 3.01 (s, 3H), 2.65-2.53 (m, 1H), 2.19 (s, 3H), 2.05-1.58 (m,
H), 1.39-1.16 (m, 2H).
A solution of the crude amine (38.9 mg) in MeCN (5.0 mL) was refluxed for 6 h. After cooling, the
reaction mixture was diluted with CHCl , washed with 10% Na CO and brine, dried, concentrated to give
3
2
3
1
2
4
0
3
1 (32.0 mg), a yellow viscous oil, as a 7:3 epimeric mixture: H NMR (300 MHz, CDCl ) δ 8.73 (d, J =
3
.5 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.42-7.27 (m, 3H), 6.55 (d, J = 6.3 Hz, 0.3H), 6.52 (d, J = 6.3 Hz,
.7H), 4.34 (dd, J = 3.9, 8.1 Hz, 0.6H), 4.19 (dd, J = 6.0, 7.8 Hz, 1.4H), 3.96 (s, 3H), 3.45-3.25 (m, 2H),
.07 (s, 0.9H), 3.03 (s, 2.1H), 3.01-2.49 (m, 3H), 2.36-1.12 (m, 6H), 2.18 (s, 0.9H), 2.16 (s, 2.1H).
A mixture of crude 21 (32.0 mg), tetra-n-butylammonium iodide (27.0 mg, 0.073 mmol) and DBU (0.04
mL, 0.264 mmol) in xylene (6.0 mL) was refluxed for 9 h. The reaction mixture was concentrated and
purified with preparative TLC (CHCl /MeOH = 10/1) to give 22 (13.4 mg, 58% from 20) as a colorless
3
2
4
1
viscous oil: [α]D –12.8° (c 0.670, CHCl ); H NMR (300 MHz, CDCl ) δ 8.74 (d, J = 4.5 Hz, 1H), 8.02
3
3
(
(
d, J = 9.3 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 2.4, 9.3 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 6.51
d, J = 6.9 Hz, 1H), 4.83 (s, 1H), 4.70 (s, 1H), 3.97 (s, 3H), 3.77 (br dd, J = 1.8, 16.8 Hz, 1H), 3.43 (ddd,
J = 8.1, 8.1, 8.1 Hz, 1H), 3.30 (br d, J = 17.7 Hz, 1H), 2.87-2.71 (m, 2H), 3.51 (br t, J = 3.0 Hz, 1H), 2.12
13
(
s, 3H), 1.84 (br dd, J = 3.0, 8.7 Hz, 2H), 1.69-1.63 (m, 2H); C NMR (75 MHz, CDCl ) δ 170.0, 158.0,
3
1
2
51.4, 147.5, 144.8, 143.7, 131.9, 127.0, 121.9, 118.8, 103.9, 101.5, 73.8, 58.8, 55.7, 51.2, 50.7, 33.1,
-
1
9.8, 27.2, 21.1; FT-IR (neat) 2940, 1741, 1622, 1508, 1466, 1367, 1230, 1078, 1028 cm ; HRMS (EI)
+
calcd for C H N O (M ): 352.1787, found 352.1784.
21
24
2
3

382
HETEROCYCLES, Vol. 66, 2005
(
3S,8S,9R)-3,9-Epoxy-6’-hydroxy-11-norcinconane (23). A solution of crude 22 (28.2 mg, 0.080 mmol)
and KBr (428.4 mg, 3.600 mmol) in 85 % aqueous H PO (2.7 mL) was heated at 100 ˚C for 12 days. The
3
4
reaction mixture was basified to pH 9 with 4 M KOH, extracted with CHCl , washed with brine, dried,
3
concentrated, and chromatographed (SiO , CHCl /MeOH = 50/1) to give 23 (16.4 mg, 69%) as a colorless
2
3
2
2
1
amorphous solid: [α]D +19.5° (c 0.195, MeOH); H NMR (300 MHz, CDCl ) δ 8.73 (d, J = 4.5 Hz, 1H),
3
8
.16 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.67 (d, J = 4.5 Hz, 1H), 7.23 (dd, J = 2.4, 9.0 Hz, 1H),
.08 (s, 1H), 3.73 (d, J = 13.5 Hz, 1H), 3.48 (d, J = 6.3 Hz, 1H), 3.25 (dd, J = 12.6, 8.4 Hz, 1H),
.17-3.04 (m, 1H), 2.81 (d, J = 13.5 Hz, 1H), 2.16 (m, 1H), 1.97-1.87 (m, 1H), 1.87-1.72 (m, 1H),
6
3
1
3
1
.72-1.60 (m, 1H), 1.36 (s, 3H), 1.31-1.20 (m, 1H); C NMR (75 MHz, CDCl ) δ 156.4, 146.9, 143.2,
3
1
41.8, 131.2, 127.3, 122.1, 119.0, 106.8, 75.0, 73.0, 66.0, 56.4, 55.6, 46.7, 35.0, 23.4, 21.0; FT-IR (neat)
-
1
+
3
600-3200, 2958, 1620, 1506, 1238, 1138, 1014 cm ; HRMS (EI) calcd for C H N O (M ): 296.1525,
18 20 2 2
found 296.1527.
1
,1,1,3,3,3-Hexafluoroisopropyl (S)-3-Hydroxy-2-methylene-3-phenylpropanoate (24). To a solution
of benzaldehyde (23.7 mg, 0.223 mmol) and 23 (6.6 mg, 0.022 mmol) in DMF (0.45 mL) at –55 °C was
added HFIPA (48 µL, 0.290 mmol). After stirring at –55 °C for 24 h, the reaction was quenched by the
addition of 0.1 M HCl (0.5 mL). The reaction mixture was extracted with AcOEt, washed with saturated
NaHCO and brine, dried over MgSO , concentrated, and chromatographed (SiO , AcOEt/hexane) to give
3
4
2
1
13
2
4 (46.9 mg, 64%) as a colorless oil. The spectral data ( H and C NMR, IR, HRMS) were identical with
2
those reported. The optical purity and absolute configuration of 24 were determined by HPLC analysis
28
using a chiral column of the corresponding methyl ester, a colorless oil (93% ee): [α]D +105.6° (c 1.29,
MeOH); Daicel Chiralcel OJ, 2-propanol:hexane = 1:5 (0.5 mL/min), t = 26.4 min (R) and 32.4 min (S).
R
ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid for Scientific Research on Priority Areas (16073213) from The
Ministry of Education,Culture, Sports, Science and Technology (MEXT).
REFERENCES AND NOTES
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3
2
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HETEROCYCLES, Vol. 66, 2005
383
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4
5
.
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9
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