Preparation of enantiopure norbornane ligands bearing both (2S,3S)-bis(phosphinomethyl) and 7-syn-oxygen functional groups and an application to rhodium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1248/cpb.52.1367

Enantiopure bicyclo[2.2.1]heptane derivatives having both (2S,3S)-bis[(diphenylphosphino)methyl] and 7-syn-oxygen functional groups were synthesized by using diastereoselective Diels-Alder reaction of di-(1R)-menthyl fumarate and 5-trimethylsilylcyclopent

Full text of DOI:10.1248/cpb.52.1367

November 2004
Notes
Chem. Pharm. Bull. 52(11) 1367—1371 (2004)
1367
Preparation of Enantiopure Norbornane Ligands Bearing Both (2S,3S)-
Bis(phosphinomethyl) and 7-syn-Oxygen Functional Groups and
an Application to Rhodium-Catalyzed Asymmetric Hydrogenation
Toshiaki MORIMOTO,* Akira YAMAZAKI, and Kazuo ACHIWA
School of Pharmaceutical Sciences, University of Shizuoka; 52–1 Yada, Shizuoka 422–8526, Japan.
Received June 18, 2004; accepted August 23, 2004
Enantiopure bicyclo[2.2.1]heptane derivatives having both (2S,3S)-bis[(diphenylphosphino)methyl] and 7-
syn-oxygen functional groups were synthesized by using diastereoselective Diels–Alder reaction of di-(1R)-men-
thyl fumarate and 5-trimethylsilylcyclopentadiene followed by silver-promoted stereospecific frame rearrange-
ment of a bromolactone intermediate. Rhodium-catalyzed asymmetric hydrogenations were carried out using the
diphosphines as a chiral ligand.
Key words chiral norbornane; diphosphine ligand; asymmetric hydrogenation; diastereoselective Diels–Alder reaction; stere-
ospecific rearrangement; rhodium
Development of efficient methods for the practical enan- (2S,3S)-norbornene-dicarboxylic acid di-(1R)-menthyl ester
tioselective synthesis of chiral compounds has been one of 3 bearing a trimethylsilyl group at the 7-exo position in a
the most important subjects in synthetic organic chemistry.1) quantitative yield with a diastereomeric excess of 97%. A
Many kinds of enantioselective syntheses employing various single recrystallization from ethanol gave optically pure di-
catalysts such as metal complexes coordinated with chiral (1R)-menthyl ester 3. Halolactonization of the norbornene di-
ligands have been reported for more than three decades,1—6) ester 3 was carried out with bromine to give a bromolactone
and several optically pure compounds prepared by enantiose- 4 (97%) with selective participation of the carbonyl group of
lective synthesis with the chiral catalysts are now commer- the 2-endo ester. The bromolactone 4 was allowed to re-
cially available (e.g. optically pure a-amino acids or alcohols arrange stereospecifically with silver nitrate in methanol
by using asymmetric hydrogenation with Rh- or Ru-chiral according to Fleming’s procedure.9,10) The corresponding
phosphine catalysts3—5); L-menthol by using Rh-BINAP-cat- (2S,3S)-norbornene dicarboxylate 5 having a 7-syn hydroxyl
alyzed asymmetric isomerization of an allylamine4)) and are group was obtained in 88% yield. The mechanism of the
used as chiral pools or auxiliaries for enantioselective syn- stereospecific frame rearrangement (Wagner–Meerwein type
theses. For the development of efficient chiral metal complex rearrangement) of 4 is depicted in Chart 2. A silver cation
catalysts, the most significant strategy is based on the prepa- extracts the bromo atom as an anion, forming a frame-re-
ration of new useful chiral ligands. Various types of di- or arranged carbocation intermediate 15 which is stabilized by a
mono-functionalized chiral ligands have been developed; for
sC–Si–p conjugate effect of the silyl atom at the b-position.
example, di- and mono-phosphines (P,P- or P-type), amino- Elimination of the silyl group as a cation forms a rearranged
phosphines (P,N-type), diamine and amine (N,N- or N-type), norbornene lactone intermediate 16, which has a strained
etc. On the other hand, tri- or multi-functionalized ligands structure and is attacked by methanol, resulting in the forma-
are much rarer. We previously reported in a preliminary com- tion of norbornene-diester 5 having a 7-syn hydroxyl group
munication the preparation of chiral norbornane derivatives stereospecifically. It was known that the silver-promoted
bearing both diphosphine moieties and another hetero func- frame rearrangement could not be induced in the absence of
tional group.7) In this article we describe in detail the synthe- the 7-silyl group in a methyl ester analog of 4.9,10) The hy-
sis of enantiomerically pure norbornane derivatives by em- droxyl group of 5 was protected with chloromethyl methyl
ploying both highly diastereoselective Diels–Alder reaction ether in the presence of ethyldiisopropylamine, yielding the
and stereospecific frame rearrangement (Wagner–Meerwein corresponding methoxymethyl (MOM) ether 6 in 99% yield.
type rearrangement) as the key steps, and an application to Reduction of the ester groups with lithium aluminum hydride
rhodium-catalyzed asymmetric hydrogenation.
(LAH) gave 2,3-dimethanol 7 (88%), and subsequent hydro-
genation of the olefinic bond with Pd on carbon gave a nor-
bornane-2,3-dimethanol 8 in 92% yield. Mesylation of the
Results and Discussion
The synthetic route to several optically pure norbornane diol 8 was carried out with methanesulfonyl (mesyl) chloride
derivatives bearing (2S)- and (3S)-substituents and an oxygen in pyridine at ꢀ35 °C to afford the dimesylate 9 in 91%
functional group at the 7-syn position is described in Chart 1. yield. Phosphination of 9 with lithium diphenylphosphide,
Yamamoto and co-workers reported an efficient Diels–Alder which was prepared in situ from diphenylphosphine and n-
reaction of cyclopentadiene with an optically pure dimenthyl butyllithium in tetrahydrofuran (THF) at ꢀ35 °C, gave the
fumarate for the preparation of optically active norbornene diphosphino compound 10 in 87% yield. The MOM group of
derivatives.8) According to Yamamoto’s and Fleming’s proce- 10 was removed by treatment with trifluoroacetic acid, and
dures,8—10) the diastereoselective Diels–Alder reaction of 5- the corresponding diphosphine 7-syn alcohol 11 was ob-
trimethylsilylcyclopentadiene 1 with di-(1R)-menthyl fuma- tained in 74% yield. (2S,3S)-Norbornane diphosphine 14
rate 2 was carried out in the presence of diethylaluminun bearing no hetero functional group at the 7-position was also
chloride in toluene at ꢀ78 °C to yield the corresponding prepared by phosphination of (2S,3S)-norbornanedimethanol
∗ To whom correspondence should be addressed. e-mail: morimtt@u-shizuoka-ken.ac.jp
© 2004 Pharmaceutical Society of Japan

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Vol. 52, No. 11
Chart 1. Synthesis of (2S,3S)-Bis[(diphenylphosphino)methyl]bicyclo[2.2.1]heptane Derivatives Having 7-syn-Oxy-Functional Groups
Chart 2. Mechanism of Silver Cation-Promoted Frame Rearrangement of Norbornane Bromolactone 4
Table 1. Asymmetric Hydrogenation of Itaconic Acid and (Z)-2-Acetami-
docinnamic Acid Catalyzed by Rhodium(I) Complexes of Ligands 10, 14
dimesylate 13 which was prepared similarly via a synthetic
intermediate reported by Yamamoto et al.8)
By using two representative norbornane diphosphines 10
and 14 as chiral ligands, preliminary asymmetric hydrogena-
tion of functionallized olefins, itaconic acid and (Z)-a-
acetamidocinnamic acid, was carried out with a cationic
rhodium complex catalyst. The results are summarized in
Table 1. In the presence of 0.1 mol% of the rhodium com-
plexes prepared in situ by mixing bis(norbornadiene)rhodi-
Ligand [Subst.]/[Rh] atm/°C/h Convn. (%)a) ee (%)b) Confign.c)
10
14
1000
1000
1/30/20
1/30/20
100
100
62
77
R
R
ꢀ
um(I) perchlorate [[Rh(nbd)2]ꢁClO4 ] with 10 and 14, the
hydrogenation of itaconic acid proceeded smoothly under 1
atm of hydrogen, yielding the hydrogenation product quanti-
tatively in 62% ee (R) and 77% ee (R), respectively. Simi-
larly, the hydrogenation of (Z)-a-acetamidocinnamic acid
was carried out with 1 mol% of the same rhodium complexes
of 10 and 14 under 20 atm of hydrogen, and the hydrogena-
tion product was obtained quantitatively in 72% ee (S) and
80% ee (S), respectively. In these hydrogenations, the 7-syn
substituent of 10 has unfortunately a negative influence on
the enantioselectivity of the parent ligand 14. We previously
Ligand [Subst.]/[Rh] atm/°C/h Convn. (%)a) ee (%)d) Confign.c)
10
14
100
100
20/50/20
20/50/20
100
100
72
80
S
S
a) Determined by 1H-NMR analysis. b) Calculated on the basis of the specific
rotation value of the pure (R)-enantiomer, [a]D20 ꢁ16.88° (cꢂ2.16, EtOH). c) Deter-
mined by the sign of the specific rotation. d) Calculated on the basis of the specific
rotation value of the pure (S)-enantiomer, [a]D20 ꢁ40.1° (cꢂ1.0, MeOH).
reported the correlation between the chirality of bidentate palladium-catalyzed asymmetric allylic alkylation. We first
ligands and the absolute configuration of the products ob- proposed a P/M chirality concept,11) where the positioning
tained by rhodium-catalyzed asymmetric hydrogenation or array of four phenyl rings of diphosphine ligands closely cor-

November 2004
1369
on a JASCO IR-810 spectrometer. Optical rotations were measured on a
JASCO DIP-140 digital polarimeter. Column chromatographic isolation was
conducted using silica gel (Kieselgel 60, 70—230 mesh, Merck). Kieselgel
60 F254 aluminum plates (Merck) were employed for TLC. In general, all
organic reagents were used as purchased. THF was distilled over sodium
metal/benzophenone ketyl and used as peroxide-free. Dichloromethane and
toluene were dried over Molecular Sieves 4A. Pyridine was dried by storing
in the presence of sodium hydroxide. For the catalytic reactions, dehydrated
methanol and ethanol were purchased and used after being degassed and
filled with argon.
[1R-(2-endo,3-exo,7-anti)]-7-Trimethylsilylbicyclo[2.2.1]hept-5-ene-
2,3-dicarboxylic Acid Di-(1R)-menthyl Ester (3) To a stirred and chilled
(ꢀ78 °C) solution of di-(1R)-menthyl fumarate 2 (12.0 g, 30.6 mmol) in
toluene (180 ml) was added dropwise a solution of diethylaluminum chloride
(0.98 M in hexane; 31 ml, 30.6 mmol). After 1 h stirring at ꢀ78 °C, 5-
(timethylsilyl)cyclopenta-1,3-diene 1 (6.0 g, 42.8 mmol) obtained by distilla-
tion was added and the mixture was stirred for another 1 h at the same tem-
perature. The reaction mixture was warmed to room temperature and satu-
rated NaHCO3 solution (180 ml) was added. The organic layer was extracted
with isopropyl ether (3ꢃ200 ml). The combined organic layers were washed
with saturated brine and dried over MgSO4. Removal of the solvents in
vacuo gave 3 (16.2 g, 100%) as a white solid. The diastereomeric excess was
determined to be 97% de by reduction of a small portion of the product with
LiAlH4 followed by ditosylation and HPLC (CHIRALCEL OD) analysis
(97% ee). The product was purified by recrystallization from EtOH, afford-
ing pure 3 (ca. 90% yield, ꢄ99% de): mp 126—127 °C, [a]D20 ꢀ9.2°
(cꢂ1.02, CHCl3). IR (KBr) cmꢀ1: 1719 (CꢂO). 1H-NMR d (CDCl3): ꢀ0.09
(9H, s, Si(CH3)3), 0.75, 0.74 (3H, 3H, each d, Jꢂ2.9 Hz, CH3ꢃ2), 1.23 (1H,
s, H-7), 0.86—0.94 (14H, m, CH(CH3)2ꢃ2), 1.05—0.86, 1.43, 1.68, 1.92,
(2H, 4H, 4H, 4H, each m, menthyl), 2.73 (1H, d, Jꢂ4.4 Hz, H-3), 3.18 (m,
1H, H-4), 3.30 (m, 1H, H-1), 3.40 (dd, 1H, Jꢂ4.4, 4 Hz, H-2), 4.58 (ddd,
1H, Jꢂ4.4, 11.2, 11.2 Hz, CO2CH), 4.71 (ddd, 1H, Jꢂ4.4, 10.8, 10.8 Hz,
CO2CH), 5.29 (dd, 1H, Jꢂ2.9, 5.4 Hz, H-6), 6.20 (dd, 1H, Jꢂ2.9, 5.4 Hz, H-
5). Anal. Calcd for C32H54O4Si: C, 72.40; H, 10.25. Found: C, 72.42; H,
10.27.
Chart 3. Correlation between the Chirality of Bidentate Ligands 10, 14
and the Absolute Configuration of the Asymmetric Hydrogenation Products
[3R-(3a,3ab,4b,5a,6b,6ab,7R*)]-6-Bromohexahydro-2-oxo-4-
(trimethylsilyl)-3,5-methano-2H-cyclopenta[b]furan-7-carboxylic Acid
(1R)-Menthyl Ester (4) To an ice-cooled solution of 3 (6.0 g, 11.3 mmol)
in dichloromethane (30 ml) was added dropwise bromine (1.16 ml,
22.6 mmol), and the mixture was stirred at room temperature for 3 d. The re-
action mixture was treated with excess sodium thiosulfate solution, washed
with saturated brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(toluene/AcOEtꢂ30/1), affording pure 4 (5.37 g, 97.4% yield): mp 88—
90 °C, [a]D23 ꢀ46.7° (cꢂ1.04, CHCl3). IR (KBr) cmꢀ1: 1799 (lactone CꢂO),
1725 (CꢂO). 1H-NMR d (CDCl3): 0.20 (9H, s, Si(CH3)3), 0.74 (3H, d,
Jꢂ6.8 Hz, CHCH3), 0.92 (6H, d, Jꢂ6.8 Hz, CH(CH3)2), 1.26 (1H, s, H-7),
0.86—1.06, 1.43, 1.70, 1.79, 1.94 (2H, 2H, 2H, 1H, 1H, each m, menthyl),
2.81 (1H, d, Jꢂ1.5 Hz, H-1), 3.15 (1H, m, H-4), 3.19 (1H, dt, Jꢂ1.5, 4.4 Hz,
H-3), 3.29 (1H, dd, Jꢂ4.4 Hz, H-2), 3.80 (1H, d, Jꢂ2.0 Hz, H-5), 4.57 (1H,
relates with the absolute configuration of products in asym-
metric hydrogenation, and later represented a more general
concept, Pr/Mr chirality,12) for showing all chiral bidentate
ligands (e.g, P,N-ligand, S,N-ligand, N,N-ligand, etc.) (Chart
3). The ligands 10, 14 showed R-selectivity and S-selectivity
in the hydrogenation of itaconic acid and (Z)-a-acetami-
docinnamic acid, respectively. The R- and S-selectivities in
both hydrogenations are the same in a stereochemical sense,
though the R and S are superficially different. (2S,3S)-2,3-O-
Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-
butane [(S,S)-DIOP] (Pr chirality) bearing
a similar
bis(phosphinomethyl) structure showed the same enantiose- ddd, 4.4, 10.7, 10.7 Hz, CO2CH), 4.95 (1H, d, Jꢂ4.9 Hz, H-6). Anal. Calcd
lectivity as 10 and 14 in both hydrogenations.11,13) The pre-
for C22H35BrO4Si: C, 56.04; H, 7.48. Found: C, 55.89; H, 7.33.
[1R-(2-endo,3-exo,7-syn)]-7-Hydroxybicyclo[2.2.1]hept-5-ene-2,3-di-
sent results on the hydrogenation with 10 and 14 also show a
carboxylic Acid Methyl (1R)-Menthyl Ester (5) To a solution of 4
good correlation between the absolute configurations of the
(5.37 g, 11.0 mmol) in methanol (250 ml) was added silver nitrate (7.5 g,
products and the chirality of the ligands (Pr chirality).
In conclusion, we have described the synthesis of enan-
tiopure norbornane diphosphine ligands bearing 7-syn-oxy-
gen functional groups or no 7-substituent, and the results on
a good correlation between the chirality of the ligands and
the absolute configuration of the products in the asymmetric
hydrogenation of some olefins. Further development of more
efficient norbornane diphosphine ligands for asymmetric hy-
drogenation may be possible by introducing other hetero-
functional groups into (or in place of) the 7-syn-oxygen
group.
44.1 mmol), and the mixture was stirred and heated under reflux for 3 d.
After cooling to room temperature, the precipitated solid was filtered and the
filtrate was concentrated in vacuo. To the residue was added water (300 ml)
and the mixture was extracted with dichloromethane (3ꢃ200 ml). The com-
bined extracts were washed with saturated brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by silica gel column chro-
matography (toluene/AcOEtꢂ4/1), affording pure 5 (3.56 g, 88% yield): mp
78—81 °C, [a]D24 ꢁ38.5° (cꢂ1.02, CHCl3). IR (KBr) cmꢀ1: 3476 (OH),
1
1713 (CꢂO). H-NMR d (CDCl3): 0.74 (3H, d, Jꢂ6.8 Hz, CHCH3), 0.90,
0.91 (3H, 3H, each d, Jꢂ6.9, 6.5 Hz, CH(CH3)2), 0.84—1.08, 1.41, 1.47,
1.68, 1.90, 2.02 (2H, 1H, 1H, 2H, 1H, 1H, each m, menthyl), 2.82 (1H, d,
Jꢂ4.6 Hz, H-3), 3.04 (1H, m, H-4), 3.12 (1H, m, H-1), 3.54 (1H, dd, Jꢂ4.6,
4 Hz, H-2), 3.71 (s, 1H, OH), 3.72 (1H, s, H-7), 3.74 (3H, s, CO2CH3), 4.62
(1H, ddd, Jꢂ4.6, 11.0, 11.0 Hz, CO2CH), 5.88 (1H, dd, Jꢂ3.2, 6.4 Hz, H-6),
6.23 (1H, dd, Jꢂ3.7, 6.4 Hz, H-5). Anal. Calcd for C20H30O5: C, 68.54; H,
8.63. Found: C, 68.10; H, 8.82.
Experimental
Melting points (mp) were determined on a micro hot-stage apparatus and
are uncorrected. 1H-NMR spectra were recorded in CDCl3 solution at
270 MHz using a JEOL JNM-EX 270 spectrometer. Chemical shift values
are expressed in ppm based on tetramethylsilane. IR spectra were measured
[1R-(2-endo,3-exo,7-syn)]-7-(Methoxymethoxy)bicyclo[2.2.1]hept-5-
ene-2,3-dicarboxylic Acid Methyl (1R)-Menthyl Ester (6) To a cooled
solution of
5 (2.96 g, 8.10 mmol) and ethyldiisopropylamine (5.6 ml,

1370
Vol. 52, No. 11
affording pure 10 (2.86 g, 81% yield): [a]D25 ꢀ3.62° (cꢂ0.97, C6H6). 1H-
NMR d (CDCl3): 0.94—1.64 (6H, m), 2.0—2.43 (6H, m), 3.17 (3H, s,
OCH3), 3.81 (1H, s, H-7), 4.50 (2H, dd, Jꢂ6.3, 6.3 Hz, OCH2O), 7.16—7.53
(20H, m, 4ꢃC6H5). Anal. Calcd for C35H38O2P2: C, 76.07; H, 6.93. Found:
C, 76.28; H, 7.13.
32.4 mmol) in dichloromethane (70 ml) was added chloromethyl methyl
ether (0.62 ml, 8.16 mmol). The mixture was stirred at room temperature for
3 d. The reaction mixture was treated with saturated NaHCO3 (50 ml) and
the organic layer was separated, washed with saturated brine, and dried over
MgSO4. Removal of volatile materials in vacuo gave pure 6 (3.3 g, 99%
yield) as an oil: [a]D25 ꢀ10.7° (cꢂ1.08, CHCl3). IR (film) cmꢀ1: 1730
(CꢂO). 1H-NMR d (CDCl3): 0.90, 0.91 (3H, 3H, each d, Jꢂ6.9, 6.4 Hz,
CH(CH3)2), 0.84—1.07, 1.41, 1.47, 1.68, 1.92, 2.03 (2H, 1H, 1H, 2H, 1H,
1H, each m, menthyl), 2.84 (1H, d, Jꢂ4.6 Hz, H-3), 3.14 (1H, m, H-4), 3.30
(1H, m, H-1), 3.35 (3H, d, Jꢂ0.9 Hz, CH2OCH3), 3.64 (1H, dd, Jꢂ4.6, 4 Hz,
H-2), 3.60 (1H, s, H-7), 3.69 (3H, s, CO2CH3), 4.46 (1H, d, Jꢂ6.9 Hz,
OCHaHbO), 4.56 (1H, d, Jꢂ6.9 Hz, OCHaHbO), 4.61(1H, ddd, Jꢂ4.6,
11.0, 11.0 Hz, CO2CH), 5.90 (1H, dd, Jꢂ3.2, 6.0 Hz, H-6), 6.22 (dd, 1H,
Jꢂ3.7, 6.0 Hz, H-5). Anal. Calcd for C22H34O6: C, 66.98; H, 8.69. Found: C,
67.15; H, 8.81.
[1R-(2-endo,3-exo,7-syn)]-[(7-Hydroxybicyclo[2.2.1]heptane-2,3-
diyl)bis(methylene)]bis[diphenylphosphine] (11) To a solution of 10
(1.0 g) in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml) at
room temperature under an argon atmosphere, and the mixture was stirred
for 20 h. The solvent and volatile materials were removed by evaporation in
vacuo. To the residue was added saturated NaHCO3 (50 ml), and the mixture
was extracted with toluene (3ꢃ30 ml). The extracts were combined, washed
with saturated brine, and concentrated in vacuo. The residue was dissolved
in THF and treated with aqueous NaOH for 5 h at room temperature under
argon. After evaporation of the solvent, toluene (100 ml) was added. The
mixture was washed with water (50 ml) and saturated brine (50 ml), and
dried over MgSO4. Evaporation of the solvent in vacuo gave almost pure 11
(0.68 g, 74% yield): [a]D20 ꢀ17.6° (cꢂ0.98, C6H6). 1H-NMR d (CDCl3):
0.87—1.55 (7H, m), 1.98—2.16 (2H, m), 2.35—2.45 (3H, m), 4.06 (1H, s,
H-7), 7.14—7.51 (20H, m, 4ꢃC6H5). Anal. Calcd for C33H34OP2: C, 77.94;
H, 6.74. Found: C, 77.92; H, 6.94.
[1S-(2-endo,3-exo)]-Bicyclo[2.2.1]heptane-2,3-dimethanol Dimethane-
sulfonate (13) Dimesylate (13) was prepared from (2S,3S)-
bicyclo[2.2.1]heptane-2,3-dimethanol (12) (946 mg, 6.57 mmol) and
methanesulfonyl chloride (3.18 g, 27.8 mmol) in a similar manner as de-
scribed for the synthesis of 9. 13 (1.85 g, 90% yield): [a]D23 ꢁ14.2° (cꢂ1.0,
CHCl3). 1H-NMR d (CDCl3): 1.31—1.35 (1H, m), 1.46—1.63 (5H, m),
1.75—1.82 (1H, m), 2.03—2.06 (1H, m), 2.35 (1H, br d, Jꢂ4.0 Hz), 2.52
(1H, br s), 3.16 (6H, s, 2ꢃCH3), 4.13 (1H, dd, Jꢂ9.6, 7.3 Hz, CHaHbO),
4.20 (1H, dd, Jꢂ9.6, 7.3 Hz, CHaHbO), 4.31 (1H, dd, Jꢂ9.6, 7.3 Hz,
CHaHbO), 4.40 (1H, dd, Jꢂ9.6, 7.3 Hz, CHaHbO). Anal. Calcd for
C11H20O6S2: C, 42.29; H, 6.45. Found: C, 42.17; H, 6.50.
[1R-(2-endo,3-exo,7-syn)]-7-(Methoxymethoxy)bicyclo[2.2.1]hept-5-
ene-2,3-dimethanol (7) To a stirred and ice-cooled solution of lithium
aluminum hydride (1.22 g, 32.2 mmol) in THF was added dropwise a solu-
tion of 6 (3.3 g, 8.05 mmol) in THF (7 ml). The mixture was stirred for 2 h
under ice-cooling and then for 1 h at room temperature. The reaction mix-
ture was cooled again with an ice-bath, and water (5 ml) was added dropwise
with caution. After stirring for 0.5 h, the mixture was filtered through a bed
of Celite, and the filter cake was extracted twice with hot THF. The filtrate
and the extracts were combined, dried over MgSO4, and concentrated in
vacuo. The residue was purified by silica gel column chromatography
(AcOEt), affording pure 7 (1.57 g, 88% yield) as an oil: [a]D24 ꢀ34.4°
1
(cꢂ0.99, CHCl3). IR (film) cmꢀ1: 3338 (OH). H-NMR d (CDCl3): 1.14—
1.44 (1H, m, H-3), 2.37—2.40 (1H, m, H-2), 2.55 (1H, m, H-4), 2.81 (1H,
m, H-1), 3.30 (2H, m, 2ꢃOH), 3.21, 3.70—3.76, 3.89 (1H, 2H, 1H, t,
Jꢂ9.6 Hz, m, t, Jꢂ9.6 Hz, 2ꢃCH2OH), 3.36 (3H, s, OCH3), 3.55 (1H, s, H-
7), 4.58 (2H, s, OCH2O), 5.87 (1H, dd, Jꢂ3.2, 6.0 Hz, H-6), 6.18 (1H, dd,
Jꢂ3.7, 6.0 Hz, H-5). Anal. Calcd for C11H18O4·2/5H2O: C, 59.66; H, 8.56.
Found: C, 59.74; H, 8.67.
[1S-(2-endo,3-exo)]-[Bicyclo[2.2.1]heptane-2,3-diylbis(methylene)]bis
[diphenylphosphine] (14) Diphosphine (14) was prepared from 13
(1.32 g, 4.2 mmol), diphenylphosphine (3.0 ml, 16.9 mmol), and n-butyl-
lithium (1.7 M in hexane, 10 ml, 16.9 mmol) in a similar manner as described
for the synthesis of 10. The product was isolated by silica gel column chro-
matography (hexane/tolueneꢂ2/1). 14 (1.67 g, 81% yield): [a]D23 ꢀ22.4°
[1R-(2-endo,3-exo,7-syn)]-7-(Methoxymethoxy)bicyclo[2.2.1]heptane-
2,3-dimethanol (8) To a solution of 7 (1.54 g, 7.08 mmol) in ethanol
(40 ml) was added 5% Pd on carbon (containing 50% water, 0.3 g), and the
mixture was stirred overnight under an atmosphere of hydrogen (1 atm).
After filtration of the catalyst, the filtrate was concentrated in vacuo, afford-
ing almost pure 8 (1.42 g, 91%) as an oil: [a]D23 ꢀ41.8° (cꢂ1.0, CHCl3). IR
(cꢂ0.64, C6H6) [lit.,14) [a]D22 ꢀ24.2° (cꢂ1.1, C6H6)]. H-NMR d (CDCl3):
1
1
(film) cmꢀ1: 3354 (OH). H-NMR d (CDCl3): 1.19—1.25, 1.43—1.51 (2H,
0.99—1.59 (8H, m), 1.87—2.35 (6H, m), 7.24—7.53 (20H, m, 4ꢃC6H5).
FAB-MS m/z: 493 ([MꢁH]ꢁ). Anal. Calcd for C33H34P2: C, 80.47; H, 6.96.
Found: C, 81.00; H, 7.19.
2H, each m, CH2CH2), 1.65—1.66 (1H, m, H-3), 1.96 (1H, d, Jꢂ4.1 Hz, H-
4), 2.24 (1H, m, H-1), 2.30—2.32 (1H, m, H-2), 3.35 (2H, m, 2ꢃOH), 3.38
(3H, s, OCH3), 3.60—3.77 (4H, m, 2ꢃCH2OH), 3.84 (1H, s, H-7), 4.62
(2H, s, OCH2O). Anal. Calcd for C11H20O4·2/5H2O: C, 59.12; H, 9.38.
Found: C, 59.20; H, 9.45.
Catalytic Asymmetric Hydrogenation of Itaconic Acid A solution of
a rhodium(I) complex catalyst was prepared in situ by mixing bis(norborna-
diene)rhodium(I) perchlorate (1.9 mg, 0.005 mmol) and a chiral ligand
(0.006 mmol) in degassed methanol (2.5 ml) was stirred at room temperature
for 0.5 h under an argon atmosphere. To a 100-ml round-bottomed flask
were placed itaconic acid (651 mg, 5 mmol), degassed methanol (7.5 ml), tri-
ethylamine (5 mmol), and a solution of the rhodium(I) complex catalyst pre-
pared above, and the hydrogenation was carried out under hydrogen (1 atm)
at 30 °C for 20 h. After evaporation of the solvent, the residue was dissolved
in aqueous 0.5 M NaOH solution (10 ml) and extracted with dichloromethane
(10 ml). The aqueous layer was separated, acidified with 6 M HCl (2 ml), and
extracted with ether (3ꢃ100 ml). The combined extracts were dried over
MgSO4, and concentrated in vacuo. The conversion rate of the substrate was
[1R-(2-endo,3-exo,7-syn)]-7-(Methoxymethoxy)bicyclo[2.2.1]heptane-
2,3-dimethanol Dimethanesulfonate (9) To a stirred and chilled solution
of 8 (1.42 g, 6.47 mmol) in pyridine (20 ml) at –35 °C was added a solution
of methanesulfonyl chloride (3.18 g, 27.8 mmol) in pyridine (4 ml), and the
mixture was stirred at the same temperature overnight. Water (30 ml) was
added with cooling in an ice bath and then 10% HCl was added until the
mixture became acidic. The mixture was extracted with AcOEt (3ꢃ50 ml),
and the combined extracts were washed with water (50 ml), saturated
NaHCO3 (50 ml), and saturated brine (50 ml). After being dried over
MgSO4, the solvent was removed in vacuo. The residue was purified by sil-
ica gel column chromatography, affording pure 9 (2.35 g, 91% yield) as an
oil: [a]D23 ꢁ4.02° (cꢂ1.08, CHCl3). 1H-NMR d (CDCl3): 1.15—1.21,
1.50—1.54, 1.62—1.66 (1H, 2H, 1H, each m, CH2CH2), 1.67—1.73 (1H, m,
H-3), 2.13 (1H, d, Jꢂ4.6 Hz, H-4), 2.37 (1H, m, H-1), 2.49 (1H, m, H-2),
3.02 (3H, s, SO2CH3), 3.05 (3H, s, SO2CH3), 3.05 (3H, s, OCH3), 3.95 (1H,
s, H-7), 4.26—4.41 (4H, m, 2ꢃCH2OSO2), 4.62 (2H, s, OCH2O). Anal.
Calcd for C13H24O8S2: C, 41.92; H, 6.50. Found: C, 41.92; H, 6.49.
[1R-(2-endo,3-exo,7-syn)]-[[7-(Methoxymethoxy)bicyclo[2.2.1]hep-
tane-2,3-diyl]bis(methylene)]bis[diphenylphosphine] (10) To a chilled
and stirred solution of diphenylphosphine (5.0 ml, 28.7 mmol) in THF
(50 ml) at ꢀ40 °C was added a solution of n-butyllithium (1.7 M in hexane,
17.0 ml, 28.7 mmol) under an argon atmosphere, and the mixture was stirred
at ꢀ35 °C for 0.5 h. To the THF solution of lithium diphenylphosphide
formed was added dropwise a solution of 9 (2.4 g, 6.4 mmol) in THF
(10 ml), and the mixture was stirred at the same temperature for 20 h. The
solvent was evaporated in vacuo and water (100 ml) was added to the
residue. The mixture was extracted with toluene (3ꢃ100 ml). The extracts
were combined, dried over MgSO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (toluene/AcOEtꢂ20/1),
1
measured by H-NMR analysis, and the optical yield and the absolute con-
figuration of the product were determined by measurement of its optical ro-
tation value in EtOH (cꢂca. 2.2) [lit. 100% ee (R): [a]D20 ꢁ16.88° (cꢂ2.16,
EtOH)].15)
Catalytic Asymmetric Hydrogenation of (Z)-a-Acetamidocinnamic
Acid A solution of a rhodium(I) complex catalyst was prepared in situ by
mixing bis(norbornadiene)rhodium(I) perchlorate (3.9 mg, 0.01 mmol) and a
chiral ligand (0.012 mmol) in degassed ethanol (2 ml) at room temperature
for 0.5 h under an argon atmosphere. In a glass tube containing a magnetic
stirring bar were placed a solution of (Z)-a-acetamidocinnamic acid
(205 mg, 1 mmol) and triethylamine (0.5 mmol) in degassed ethanol (6 ml)
and a solution of the rhodium(I) complex catalyst prepared above. The glass
tube was placed in a stainless autoclave, and after ventilation with hydrogen
(3 times) the pressure of hydrogen in the autoclave was adjusted at 20 atm.
The mixture was stirred and heated at 50 °C for 20 h. After cooling to room
temperature, the reaction solution was treated with active charcoal (0.5 g) by
stirring for 0.5 h. Filtration and concentration in vacuo gave the correspond-
ing hydrogenation product in a quantitative yield. The conversion rate of the
1
substrate was measured by H-NMR analysis, and the optical yield and the

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1371
absolute configuration of the product were determined by measurement of
its optical rotation value in MeOH (cꢂca. 1.0) [lit. 100% ee (S): [a]D20
ꢁ40.1° (cꢂ1.0 MeOH)].16)
8) Furuta K., Iwanaga K., Yamamoto H., Tetrahedron Lett., 27, 4507—
4510 (1986).
9) Fleming I., Michael J. P., J. Chem. Soc., Chem. Commun., 1978, 245—
247.
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