Efficient synthesis of enantiomerically pure trans-2,5-bis(arylethynyl)pyrrolidines. A new entry into C2-symmetric chiral secondary amines

Article abstract of DOI:10.1016/S0957-4166(99)00303-1

A new class of C₂-symmetric pyrrolidine derivatives bearing arylethynyl groups at the 2,5-positions has been synthesized in enantiomerically pure form from 1,7-octadiyne-3,6-diol in five steps. Some notable features of the synthesis are: (i) the formation of a separable diastereomeric mixture of pyrrolidine carbamates using a newly prepared chiral chloroformate; and (ii) the development of a new method for the deprotection of the carbamate via a novel SmI₂-promoted electron transfer process.

Full text of DOI:10.1016/S0957-4166(99)00303-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2951–2959
Efficient synthesis of enantiomerically pure
trans-2,5-bis(arylethynyl)pyrrolidines. A new entry into
C2-symmetric chiral secondary amines
Takeshi Hanamoto,† Nami Shimomoto, Takashi Kikukawa and Junji Inanaga ∗
Institute for Fundamental Research of Organic Chemistry (IFOC), Kyushu University, Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
Received 17 June 1999; accepted 14 July 1999
Abstract
A new class of C2-symmetric pyrrolidine derivatives bearing arylethynyl groups at the 2,5-positions has been
synthesized in enantiomerically pure form from 1,7-octadiyne-3,6-diol in five steps. Some notable features of the
synthesis are: (i) the formation of a separable diastereomeric mixture of pyrrolidine carbamates using a newly
prepared chiral chloroformate; and (ii) the development of a new method for the deprotection of the carbamate via
a novel SmI2-promoted electron transfer process. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The development of asymmetric synthesis is one of the major expanding fields in organic chemistry.
A number of chiral auxiliaries have so far been devised for this purpose. Among them, 2,5-disubstituted
pyrrolidines bearing a C2 axis of symmetry constitute an important class1,2 since Whitesell and Felman
first reported trans-2,5-dimethylpyrrolidine as a useful chiral auxiliary for the enantioselective alkylation
of enamines derived from it.3 However, there are no examples where the side chains at the 2,5-positions
on the pyrrolidine rings are composed of sp carbons. With the expectation that the introduction of an
arylethynyl group as a side chain would effectively extend the original chirality on the pyrrolidine ring
to remote positions without affording serious steric hindrance around the pyrrolidine nitrogen, we have
synthesized trans-(2R,5R)-bis(arylethynyl)pyrrolidines 1a and 1b in enantiomerically pure forms.
∗
†
Corresponding author. E-mail: inanaga@ms.ifoc.kyushu-u.ac.jp
Present address: Department of Chemistry, Saga University, Saga 840-8502, Japan.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00303-1

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2. Results and discussion
The synthetic route is shown in Scheme 1. A diastereomeric mixture of 1,7-octadiyne-3,6-diol 2 was
prepared from succinaldehyde and monolithium acetylide according to the literature.4 These isomeric
diols could not be separated by column chromatography. Fortunately, however, the dl-rich (dl:meso=9:1)
diol 2 was conveniently obtained by filtration because the meso-diol selectively solidified out from the
oily mixture upon being allowed to stand at room temperature. Mesylation of the dl-rich diol 2 proceeded
smoothly under the standard conditions to give the desired dimesylate 3 in 82% yield. Cyclization of 3
with an excess of 4-methoxybenzylamine was initially performed in CH2Cl2 at 0°C and then at 40°C to
afford a diastereomeric mixture of N-protected 2,5-diethynylpyrrolidines 4 in high yields. At this stage,
the N-protected trans-2,5-diethynylpyrrolidine dl-4 was completely separated from the corresponding
cis-isomer by column chromatography on silica gel to give the pure trans-isomer in 77% isolated
yield. Introduction of an aryl group to the terminal acetylenic moiety on the pyrrolidine ring of dl-4
was performed by Sonogashira’s protocol5 using aryl bromide in the presence of a catalytic amount of
PdCl2(PPh3)2 and CuI (10 mol%) in triethylamine. The 2-naphthyl derivative dl-5a and the 4-biphenylyl
derivative dl-5b were obtained in 91 and 71% yields, respectively. For the debenzylation of dl-5a and
dl-5b, Olofson’s protocol6 was successfully applied: the N-acylation with α-chloroethyl chloroformate
was followed by the methanolysis of the resulting carbamates. The acetylenic moieties were intact under
these conditions and the desired trans 2,5-bis(arylethynyl)pyrrolidines were obtained in high yields (dl-
1a, 81%; dl-1b, 96%).
Scheme 1.
Since many attempts to resolve dl-1a using conventional chiral non-racemic acids ended in failure, dl-
1a was converted to a diastereomeric mixture of the carbamates with (1R,2S,5R)-menthyl chloroformate
(Scheme 2). Fractional recrystallization of the mixture using a hexane/ether/CH2Cl2 solvent system affor-
ded one diastereomer 6a, the absolute configuration of which was determined by X-ray crystallographic
analysis to have the (2S,5S) configuration with respect to the pyrrolidine ring. The ORTEP drawing of 6a
is shown in Fig. 1.

T. Hanamoto et al. / Tetrahedron: Asymmetry 10 (1999) 2951–2959
2953
Scheme 2.
Figure 1. The ORTEP drawing of the compound 6a
With enantiomerically pure carbamate 6a in hand, we next tried to remove the N-carbomenthoxy
group. Unfortunately, however, all efforts to cleave the N-acyl bond using literature protocols were
unsuccessful mainly because of the nucleophile-susceptible propargylic amine structure of 6a.7 In order
to circumvent this problem, we developed a different type of chiral chloroformate 7, the α-oxy ester
structure of which was expected to become, in the later stage, a good trigger for the cleavage of the
N-acyl bond of the corresponding carbamate (e.g. 8).
The requisite chloroformate, isopropyl (R)-(chloroformyloxy)phenylacetate 7, was prepared from (R)-
mandelic acid in two steps: (1) esterification under acidic conditions; and (2) chloroformylation8 of the re-
sulting (R)-isopropyl mandelate9 with triphosgene. The reaction of the racemic pyrrolidine dl-1a with the
chiral chloroformate 7 afforded the corresponding carbamates (R,R)-8a and (S,S)-8a in 97% yield as a 1:1
diastereomeric mixture (Scheme 3). Alternatively, they could directly be prepared from the N-protected
amine dl-5a in 74% yield (91% based on the recovered starting material) by treating it with excess
chloroformate 7 in the presence of a catalytic amount of 1,8-bis(dimethylamino)naphthalene in refluxing
1,2-dichloroethane. Fractional recrystallization of the diastereomeric mixture from hexane/ether/CH2Cl2
gave one diastereomer as transparent crystals in 30% yield (maximum 50% in theory). This crystal was,
however, found not to be suitable for X-ray structural analysis. Therefore, removal of the N-protective
group of the crystalline carbamate 8a was investigated. As we had already found that α-oxy esters
were successfully deoxygenated by the use of SmI2 under mild conditions,10 we applied this protocol
to the above deprotection step. As expected, the SmI2-promoted electron transfer reaction proceeded
very smoothly at room temperature to give the desired free amine (R,R)-1a in high yield (92%). The
enantiomeric excess of this compound was determined to be >99% by HPLC using Chiralpak AD eluted
with a hexane–i-PrOH mixture, and the (R,R) configuration was confirmed, after converting the amine to
the corresponding menthyl carbamate with (1R,2S,5R)-menthyl chloroformate, by the comparison of its
1
rotation and H NMR spectrum with those of the authentic one whose absolute configuration had been
determined by X-ray crystallographic analysis.
As shown in Scheme 4, the deprotection reaction seems to involve the successive two-electron
transfer process: (1) one electron reduction of the ester carbonyl; and (2) second electron transfer

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T. Hanamoto et al. / Tetrahedron: Asymmetry 10 (1999) 2951–2959
Scheme 3.
to give the β-oxycarbanion species from which β-elimination of the N-carboxylate anion would take
place. The resulting carbamic acid carboxylate would then release carbon dioxide to give the free
amine. As the present electron transfer-based deprotection method using SmI2 is so mild and unique,
the mandelyloxycarbonyl (Moc) group may be registered as a useful chiral N-protective group. Other
carbamates having a similar α-oxy ester structure should also be effective as N-protective groups.
Scheme 4.
In a similar manner, the biphenylyl derivatives, (R,R)-8b and (R,R)-1b, were prepared from dl-1b in
good yields, although their absolute configurations were tentatively assigned based on the spectroscopic
(1H NMR) and optical (CD) similarities to the corresponding 2-naphthyl derivatives (R,R)-8a and (R,R)-
1a, respectively. The strategy presented here possesses considerable flexibility for the introduction of a
variety of substituents at the terminal positions of the acetylenic moieties. The potential of the chiral
pyrrolidines 1a and 1b as well as their derivatives as a chiral controller in asymmetric synthesis is
currently underway in our laboratory.

T. Hanamoto et al. / Tetrahedron: Asymmetry 10 (1999) 2951–2959
2955
3. Experimental
Melting points were measured with a Yanagimoto MP-S3 micro melting point apparatus and are
1
uncorrected. Infrared (IR) spectra were recorded on a Jeol SP170011-0055 spectrometer. H NMR and
13C NMR spectra were measured using a Jeol JNM-EX 400. Chemical shifts are given by δ relative
to that of internal Me4Si (TMS). Mass spectra were obtained using a Shimadzu GCMS QP-5000. Fast
atom bombardment mass spectra (FABMS) were obtained with a Jeol JMS-HX110A. Rotations were
measured using a Horiba SEPA-300. Circular dichroism (CD) spectra were recorded on a Jeol J-720W
instrument. Enantiomeric excesses were determined by chiral HPLC using Chiralpak AD. Elemental
analyses were performed on a Yanagimoto MT3 CHN instrument or were accomplished at the service
center for the elementary analysis of organic compounds, Kyushu University. Analytical thin layer
chromatography (TLC) was performed on a silica gel plate (Merck, Kieselgel 60 F254, 20×20 cm, 0.25
mm). All solvents were purified before use; ether and tetrahydrofuran (THF) were dried over sodium
benzophenone ketyl radical while dichloromethane (CH2Cl2) and 1,2-dichloroethane (ClCH2CH2Cl)
were distilled from calcium hydride (CaH2). All reactions were carried out under an atmosphere of argon
or nitrogen. Commercially available compounds were purchased and used without further purification.
3.1. (R*,R*)-3,6-Bis(methanesulfonyloxy)-1,7-octadiyne 3
To a solution of 1,7-octadiyne-3,6-diol4 (2, dl:meso=9:1, 1.1 g, 8.0 mmol) in CH2Cl2 (20 mL) at
0°C was slowly added methanesulfonyl chloride (1.36 mL, 17.6 mmol). Triethylamine (2.68 mL, 19.2
mmol) was added dropwise with vigorous stirring while the temperature was maintained at 0°C. After the
addition was complete, the mixture was allowed to warm to room temperature and then quenched with 1N
HCl. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were washed with saturated (NH4)2SO4, saturated NaCl, dried over MgSO4, filtered, and
concentrated. The crude oil was separated by column chromatography (silica gel, hexane:EtOAc=1:1) to
give the corresponding bis(methanesulfonate) (3, dl:meso=ca. 9:1, 1.93 g, 82%) as a pale yellow solid.
1
Mp 96.2–110.6°C; IR (KBr) 3276, 3033, 2942, 2123, 1357, 1328, 1170, 944, 858, 688, 518 cm−1; H
NMR (dl-3, 400 MHz, CDCl3) δ 2.13–2.19 (m, 4H), 2.76 (s, 2H), 3.14 (s, 6H), 5.27 (t, 2H). Anal. calcd
for C10H14O6S2: C, 40.81; H, 4.79%. Found: C, 40.64; H, 4.78%.
3.2. (2R*,5R*)-N-40-Methoxybenzyl-2,5-diethynylpyrrolidine dl-4
To a solution of (R*,R*)-3,6-bis(methanesulfonyloxy)-1,7-octadiyne (2.04 g, 6.93 mmol) in CH2Cl2
(14 mL) at 0°C was added 4-methoxybenzylamine (3.17 mL, 24.3 mmol). The mixture was stirred at
room temperature for 3 h, then heated at 40°C for 12 h with stirring. After cooling, the reaction mixture
was treated with 1N NaOH, then extracted with hexane:ether=1:1. The combined organic layer was
washed with saturated NaCl, and dried over MgSO4. After removal of the solvent, the remaining oil
was separated by column chromatography (silica gel, hexane:EtOAc=20:1) to give the corresponding
(2R*,5R*)-N-40-methoxybenzyl-2,5-diethynylpyrrolidine (1.29 g, 5.39 mmol, 77%) as a colorless oil.
1
IR (neat) 3290, 2954, 2832, 1612, 1513, 1247, 1172, 1035, 646 cm−1; H NMR (400 MHz, CDCl3) δ
1.89–2.04 (m, 2H), 2.15–2.29 (m, 2H), 2.35 (s, 1H), 2.36 (s, 1H), 3.18 (s, 3H), 3.49 (d, 1H, J=12.4 Hz),
3.54 (s, 2H), 4.14 (d, 1H, J=12.4 Hz), 6.84 (d, 2H, J=8.8 Hz), 7.33 (d, 2H, J=8.8 Hz); MS (FAB) m/z (rel.
intensity) 240 (M++1; 29), 239 (18), 238 (26), 121 (100). HRMS (FAB) calcd for C16H18NO: 240.1388.
Found: 240.1389 (M++1). Anal. calcd for C16H17NO: C, 80.29; H, 7.16; N, 5,86%. Found: C, 80.13; H,
7.17; N, 5.81%.

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3.3. (2R*,5R*)-N-400-Methoxybenzyl-2,5-bis(20 -naphthylethynyl)pyrrolidine dl-5a
To a mixture of 2-bromonaphthalene (3.9 g, 18.9 mmol), CuI (164 mg, 0.86 mmol), and PdCl2(PPh3)2
(603 mg, 0.86 mmol) in triethylamine (20 mL) was added a solution of (2R*,5R*)-N-40-methoxybenzyl-
2,5-diethynylpyrrolidine (2.05 g, 8.57 mmol) in triethylamine (23 mL). The mixture was heated to 50°C
and stirred for 12 h. After removal of the excess of triethylamine by distillation, the residue was diluted
with ether. The mixture was passed through a short Celite column, and the eluate was concentrated.
The remaining residue was separated by column chromatography (silica gel, hexane:EtOAc=15:1 then
10:1) to give the corresponding (2R*,5R*)-N-400-methoxybenzyl-2,5-bis(20 -naphthylethynyl)pyrrolidine
(3.82 g, 91%) as a colorless solid. Mp 139.5–140.5°C (colorless needles after recrystallization from
hexane/EtOAc); IR (KBr) 3052, 2987, 2952, 2915, 2827, 2790, 1610, 1511, 1351, 1301, 1247, 1174,
1
1039, 862, 819 cm−1; H NMR (400 MHz, CDCl3) δ 2.12–2.16 (m, 2H), 2.36–2.41 (m, 2H), 3.76 (d,
1H, J=12.5 Hz), 3.77 (s, 3H), 3.95 (s, 2H), 4.34 (d, 1H, J=12.5 Hz), 6.88 (d, 2H, J=8.8 Hz), 7.46 (d,
2H, J=5.3 Hz), 7.47 (dd, 2H, J=3.9, 5.3 Hz), 7.50 (d, 2H, J=4.3 Hz), 7.51 (dd, 2H, J=3.9, 5.4 Hz), 7.77
(d, 2H, J=8.8 Hz), 7.78 (d, 2H, J=5.3 Hz), 7.79 (d, 2H, J=4.3 Hz), 7.98 (s, 2H); MS (FAB) m/z (rel.
intensity) 493 (M++1; 20), 492 (54), 491 (27), 490 (27), 340 (13), 154 (15), 121 (100). HRMS (FAB)
calcd for C36H30NO: 492.2328. Found: 492.2327 (M++1). Anal. calcd for C36H29NO: C, 87.95; H, 5.95;
N, 2.85%. Found: C, 87.82; H, 5.96; N, 2.96%.
3.4. (2R*,5R*)-N-400-Methoxybenzyl-2,5-bis(40 -biphenylylethynyl)pyrrolidine dl-5b
Yield: 71%. Mp 141.0–142.0°C (colorless needles after recrystallization from hexane/EtOAc); IR
(KBr) 3448, 2782, 1612, 1511, 1484, 1349 1317, 1299, 1243, 1170, 1108, 1031, 840, 817, 765, 725,
1
698; H NMR (400 MHz, CDCl3) δ 2.08–2.12 (m, 2H), 2.32–2.38 (m, 2H), 3.69 (d, 1H, J=12.7 Hz),
3.80 (s, 3H), 3.84–3.89 (m, 2H), 4.28 (d, 1H, J=12.7 Hz), 6.88 (d, 2H, J=8.8 Hz), 7.34–7.61 (m, 20H);
13C NMR (CDCl3) δ 30.32, 52.78, 53.45, 55.34, 85.49, 89.28, 113.71, 122.25, 126.79, 128.95, 130.63,
131.16, 132.24, 140.49, 140.91, 158.79; MS (FAB) m/z (rel. intensity) 544 (M++1; 16), 154 (100), 121
(22), 108 (9). HRMS (FAB) calcd for C40H34NO: 544.2640. Found: 544.2645 (M++1). Anal. calcd for
C40H33NO: C, 88.36; H, 6.12; N, 2.58%. Found: C, 88.52; H, 6.13; N, 2.62%.
3.5. (2R*,5R*)-2,5-Bis(20-naphthylethynyl)pyrrolidine dl-1a
To a solution of (2R*,5R*)-N-400-methoxybenzyl-2,5-bis(20 -naphthylethynyl)pyrrolidine (dl-5a, 1.5
g, 3.05 mmol) and a catalytic amount of 1,8-bis(dimethylamino)naphthalene in 1,2-dichloroethane
(15 mL) at 0°C was added α-chloroethyl chloroformate (1.7 mL, 15.25 mmol). The mixture was
allowed to warm to room temperature, then refluxed for 18 h. After removal of the solvent, the residue
was separated by column chromatography (silica gel, hexane:EtOAc=15:1) to give the corresponding
carbamate as a mixture of two diastereomers (1.35 g, 2.81 mmol, 92%) as a white solid. This compound
was used directly without further separation. The carbamate (923 mg, 1.93 mmol) was dissolved in
MeOH (38 mL), then refluxed for 1.5 h. After removal of the solvent, the residue was separated by
column chromatography (silica gel, hexane:EtOAc:triethylamine=700:100:0.5) to give the corresponding
(2R*,5R*)-2,5-bis(20-naphthylethynyl)pyrrolidine (dl-1a, 700 mg, 1.87 mmol, 97%) as a pale yellow
solid, recrystallization of which from hexane/AcOEt afforded a colorless solid. Mp 131.5–132.0°C; IR
(KBr) 3284, 3052, 2962, 1592, 1498, 1346, 1272, 1220, 1078, 962, 948, 900, 867, 819, 740, 478, 468
cm−1; 1H NMR (400 MHz, CDCl3) δ 1.6 (br s, 1H), 2.04–2.12 (m, 2H), 2.39–2.46 (m, 2H), 4.45 (t, 2H,
J=5.4 Hz), 7.46–7.94 (m, 14H); CIMS (2-methylpropane) m/z (rel. intensity) 372 (M++1; 100), 370 (13),

T. Hanamoto et al. / Tetrahedron: Asymmetry 10 (1999) 2951–2959
2957
344 (12), 343 (35), 220 (40), 219 (12). Anal. calcd for C28H21N: C, 90.57; H, 5.76; N, 3.72%. Found: C,
90.53; H, 5.70; N, 3.77%.
3.6. (2R*,5R*)-2,5-Bis(40-biphenylylethynyl)pyrrolidine dl-1b
Yield 96%. Mp 175.2–176.4°C (a pale yellow solid after recrystallization from hexane/EtOAc); IR
(KBr) 3353, 3050, 3033, 2987, 2946, 1594, 1484, 1448, 1403, 1330, 1153, 1004, 840, 763, 719, 690,
1
559; H NMR (400 MHz, CDCl3) δ 1.60 (br s, 1H), 2.01–2.07 (m, 2H), 2.17–2.42 (m, 2H), 4.39–4.41
(m, 2H), 7.33–7.56 (m, 18H); 13C NMR (CDCl3) δ 32.42, 48.58, 82.79, 91.79, 122.09, 127.01, 127.08,
127.67, 128.91, 132.13, 140.43, 140.87; MS (FAB) m/z (rel. intensity) 424 (M++1; 52), 154 (100). Anal.
calcd for C32H25N: C, 90.74; H, 5.95; N, 3.31%. Found: C, 90.52; H, 5.93; N, 3.37%.
3.7. (1R,2S,5R)-Menthyl [(20R,500R)-20,50-bis(200-naphthylethynyl)pyrrolidinyl]carbamate 6a
To a solution of (2R*,5R*)-N-400-methoxybenzyl-2,5-bis(20 -naphthylethynyl)pyrrolidine (dl-1a, 260.1
mg, 0.70 mmol) and (1R,2S,5R)-menthyl chloroformate (180 µL, 0.84 mmol) in THF (7 mL) at 0°C
was slowly added pyridine (125 mL, 1.54 mmol). The mixture was stirred at room temperature for
30 min. The addition of ether to the mixture produced a precipitate. The entire mixture was passed
through a short silica gel column. The eluate was concentrated and the residue was separated by
column chromatography (silica gel, hexane:EtOAc=40:1) to give the corresponding (1R,2S,5R)-menthyl
[(20R*,50R*)-20,50-bis(200-naphthylethynyl)pyrrolidinylcarbamate (382.1 mg, 99%). Recrystallization of
the above carbamate from hexane/ether/CH2Cl2 afforded one diastereomer 6a, which was later found to
have the (20R,50R) configuration, as a white solid. Mp 171.0–172.5°C; [α]D18.0=−256 (c 1.0, CHCl3);
IR (KBr) 3446, 2923, 1691, 1596, 1396, 1326, 1265, 1176, 1112, 892, 860, 819, 769, 754, 476 cm−1;
1H NMR (400 MHz, CDCl3) δ 0.84–2.60 (m, 22H), 4.75 (dt, 1H, J=4.4, 10.7 Hz), 4.89–4.99 (m, 2H),
7.46–7.93 (m, 14H). Anal. calcd for C39H39NO2: C, 84.58; H, 7.10; N, 2.53%. Found: C, 84.34; H,
7.10; N, 2.50%. X-Ray crystallographic analysis. C39H39NO2, M=553.74, monoclinic, space group P21,
a=13.269(1), b=14.403(1), c=17.846(1) Å, β=108.826(5)°, V=3228.2(4) Å3, Z=4, Dcalc=1.139 g cm−3,
graphite monochromated radiation λ(CuKα)=1.54178 Å, µ=5.35 cm−1, T=23.0°C. Data collected on a
Rigaku AFC7R diffractometer. The structure was solved by direct methods. Final agreement statistics
are: R=0.044, Rw=0.039. The authors have deposited the atomic coordinates for this structure with the
Cambridge Crystallographic Data Centre. The coordinates can be obtained on request from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
3.8. Isopropyl (R)-(chloroformyloxy)phenylacetate 7
To a solution of isopropyl (R)-mandelate8 (2.8 g, 14.4 mmol) in a mixed solvent of toluene (10 mL)
and CH2Cl2 (5 mL) at 0°C was successively added triphosgene (2.14 g, 10.8 mmol) and quinoline (1.9
mL, 16 mmol). The mixture was stirred for 12 h at room temperature, cooled to 0°C, and quenched with
10% HCl. After the organic layer was separated, the aqueous layer was extracted with ether (twice). The
combined organic layers were washed with saturated NaCl, dried over MgSO4, and concentrated. The
brown residue was separated by column chromatography (silica gel, hexane:EtOAc=50:1) to give the
corresponding isopropyl (R)-(chloroformyloxy)phenylacetate (7, 2.96 g, 11.5 mmol, 80%) as a colorless
oil. [α]D19.7=−93.1 (c 1.73, CHCl3); IR (neat) 1778, 1749, 1220, 1147, 1103, 821, 676 cm−1; 1H NMR
(400 MHz, CDCl3) δ 1.15 (d, 3H, J=6.4 Hz), 1.28 (d, 3H, J=6.4 Hz), 5.09 (sep, 1H, J=6.4 Hz), 5.91 (s,
1H), 7.39–7.47 (m, 5H). Anal. calcd for C12H13ClO4: C, 56.24; H, 5.12%. Found: C, 56.33; H, 5.17%.

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3.9. Isopropyl (R)-[(20R,50R)-20,50-bis(200-naphthylethynyl)pyrrolidinylcarbonyloxy]phenylacetate 8a
Preparation from dl-1a: To a solution of dl-1a (645 mg, 1.73 mmol) and 7 (535 mg, 2.08 mmol) in
dry THF (17 mL) was added pyridine (308 mL, 3.8 µmol) at 0°C, and then the mixture was stirred
for 5 h at room temperature. Ether (ca. 20 mL) was added and the entire mixture was passed through
a short column of silica gel. After evaporation of the solvents, the crude product was subjected to
column chromatography (SiO2, hexane:EtOAc=12:1) to give isopropyl (R)-[(20R*,50R*)-20,50-bis(200-
naphthylethynyl)pyrrolidinylcarbonyloxy]phenylacetate (994 mg, 97%) as a mixture of diastereomers.
Preparation from dl-5a: A mixture of dl-5a (533 mg, 1.08 mmol), 7 (1.39 g, 5.4 mmol), and a catalytic
amount of 1,8-bis(dimethylamino)naphthalene was gently refluxed in 1,2-dichloroethane (5.4 mL) for
16 h. After removal of the solvent, the residue was separated by column chromatography to give the
corresponding carbamate (476 mg, 74%) as a mixture of diastereomers along with the starting material
(97.7 mg, 18%).
Fractional recrystallization of the above carbamate (476 mg) from hexane/ether/CH2Cl2 afforded one
diastereomer (8a, 141 mg, 30%) as a white solid. Mp 172.9–173.3°C; [α]D24.9=+207 (c 1.0, CHCl3); IR
(KBr) 2987, 1749, 1712, 1496, 1396, 1103, 748 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.09 (d, 3H, J=6.4
Hz), 1.20 (d, 3H, J=6.4 Hz), 2.27–2.35 (m, 2H), 2.64–2.69 (m, 2H), 4.99–5.05 (m, 3H), 5.89 (s, 1H),
7.31–7.34 (m, 3H), 7.43–7.49 (m, 5H), 7.59–7.65 (m, 3H), 7.72–7.82 (m, 6H), 7.93 (br s, 1H), 8.08 (br s,
1H); MS (FAB) m/z (rel. intensity) 592 (M++1; 30), 591 (12), 590 (19), 550 (25), 440 (29), 415 (22), 414
(58), 398 (41), 396 (42), 370 (29), 354 (28), 264 (30), 220 (76), 218 (31), 178 (48), 165 (42), 155 (40),
154 (36), 152 (20), 136 (39), 135 (100), 107 (56), 91 (93), 79 (24). HRMS (FAB) calcd for C40H34NO4:
592.2488. Found: 592.2484 (M++1). Anal. calcd for C40H33NO4: C, 81.20; H, 5.62; N, 2.37%. Found:
C, 81.11; H, 5.63; N, 2.09%.
3.10. Isopropyl (R)-[20,50-bis(400-biphenylylethynyl)pyrrolidinylcarbonyloxy]phenylacetate 8b
The (20R,50R)-configuration is tentatively assigned. Mp 224.9–225.6°C (colorless needles);
[α]D23.7=+212 (c 0.341, CH2Cl2); IR (KBr) 3029, 2977, 2933, 2873, 1747, 1720, 1484, 1446, 1403,
1
1375, 1332, 1263, 1220, 1174, 1126, 1066, 844, 765, 732, 696; H NMR (400 MHz, CDCl3) δ 1.09
(d, 3H, J=6.34 Hz), 1.21 (d, 3H, J=5.86 Hz), 2.23–2.30 (m, 2H), 2.59–2.62 (m, 3H), 4.95–5.04 (m,
3H), 5.87 (s, 1H), 7.34–7.63 (m, 23H); 13C NMR (CDCl3) δ 21.49, 21.78, 32.17, 32.90, 49.34, 49.69,
69.05, 76.0, 82.40, 82.81, 89.15, 89.39, 121.80, 122.07, 126.88, 126.99, 127.08, 127.50, 127.65, 128.62,
128.91, 132.35, 140.43, 140.49, 140.94, 153.12, 168.69; MS (FAB) m/z (rel. intensity) 644 (M++1; 19),
466 (16), 422 (8), 289 (17), 154 (100). HRMS (FAB) calcd for C44H38NO4: 644.2800. Found: 644.2803
(M++1). Anal. calcd for C44H37NO4: C, 82.09; H, 5.79; N, 2.18%. Found: C, 81.83; H, 5.79; N, 2.20%.
3.11. (2R,5R)-2,5-Bis(20-naphthylethynyl)pyrrolidine 1a
To a solution of isopropyl (R)-[(20R,5R)-20,50-bis(200-naphthylethynyl)pyrrolidinylcarbonyloxy]-
phenylacetate (8a, 90 mg, 0.152 mmol) and MeOH (18 µL, 0.456 mmol) in THF (2.5 mL) was
added an SmI2–THF solution (0.1 mol dm−3, 4.5 mL, 0.45 mmol). The mixture was stirred for 90
min at room temperature, then quenched with oxygen. The resulting yellow solution was added
to diethylene glycol (43 µL, 0,76 mmol), and then filtered through a short silica gel column
with THF as the eluent. The eluate was concentrated, and the residue was separated by column
chromatography (silica gel, hexane:EtOAc:triethylamine=700:100:0.5) to give the corresponding
(2R,5R)-2,5-bis(20-naphthylethynyl)pyrrolidine [1a, 51.7 mg, 0.139 mmol, 92%, >99% ee (Chiralpak

T. Hanamoto et al. / Tetrahedron: Asymmetry 10 (1999) 2951–2959
2959
AD, hexane:i-PrOH=9:1, retention time: 48.8 min, cf. 43.5 min for the opposite enantiomer)]. Mp
117.5–118.5°C; [α]D24.0=+268 (c 1.0, CHCl3). CD (CH2Cl2) λext 252 nm (+). H NMR (400 MHz,
1
CDCl3) δ 1.6 (br s, 1H), 2.04–2.12 (m, 2H), 2.39–2.46 (m, 2H), 4.45 (br t, 2H), 7.46–7.94 (m, 14H).
HRMS (FAB) calcd for C28H22N: 372.1752. Found: 372.1703 (M++1).
3.12. 2,5-Bis(40-biphenylylethynyl)pyrrolidine 1b
The (2R,5R)-configuration is tentatively assigned. Yield: 80% [>99% ee (Chiralpak AD, hexane:i-
PrOH=9:1, retention time: 35.7 min, cf. 18.7 min for the opposite enantiomer)]. Mp 184.7–186.0°C (a
pale yellow solid); [α]D26.8=+154 (c 0.075, CHCl3). CD (CH2Cl2) λext 238 nm (+). 1H NMR (400 MHz,
CDCl3) δ 1.60 (br s, 1H), 2.01–2.07 (m, 2H), 2.17–2.42 (m, 2H), 4.39–4.41 (m, 2H), 7.33–7.56 (m,
18H). HRMS (FAB) calcd for C32H26N: 424.2065. Found: 424.2018 (M++1).
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan.
References
1. For reviews, see: (a) Whitesell, J. K. Chem. Rev. 1989, 89, 1581–1590. (b) Seyden-Penne, J. Chiral Auxiliaries and Ligands
in Asymmetric Synthesis; John Wiley & Sons: New York, 1995.
2. (a) Kawanami, T.; Ito, Y.; Kitagawa, T.; Taniguchi, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1984, 25, 857–860.
(b) Gawley, R. E.; Chemburker, S. R.; Smith, A. L.; Anklekar, T. V. J. Org. Chem. 1988, 53, 5381–5383. (c) Whitesell, J.
K.; Minton, M. A. Chen, K.-M. J. Org. Chem. 1988, 53, 5383–5384. (d) Shing, T. K. M. Tetrahedron 1988, 44, 7261–7264.
(e) Short, R. P.; Kennedy, R. M.; Masamune, S. J. Org. Chem. 1989, 54, 1755–1756. (f) Marzi, M.; Misiti, D. Tetrahedron
Lett. 1989, 30, 6075–6076. (g) Najdi, S.; Kurth, M. Tetrahedron Lett. 1990, 31, 3279–3282. (h) Marzi, M.; Minetti, P.;
Misiti, D. Tetrahedron 1992, 48, 10127–10132. (i) Zwaagstra, M. E.; Meetsma, A.; Feringa, B. L. Tetrahedron: Asymmetry
1993, 4, 2163–2172. (j) Chong, J. M.; Clarke, I. S.; Koch, I.; Olbach, P. C.; Taylor, N. J. Tetrahedron: Asymmetry 1995, 6,
409–418. (k) Review: Pichon, M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927–964. (l) Kozmin, S. A.; Rawal, V.
H. J. Am. Chem. Soc. 1997, 119, 7165–7166.
3. Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1977, 42, 1663–1664.
4. Chiarino, D.; Fantucci, M. J. Heterocycl. Chem. 1991, 28, 1705–1708.
5. Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627–630.
6. (a) Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T. J. Org. Chem. 1984, 49, 2081–2082. (b) Yang, B. V.;
O’Rourke, D.; Li, J. Synlett 1993, 195–196.
7. (a) Carpino, L. A. Chem. Commun. 1966, 858–859. (b) Greene, W. T.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; John Wiley & Sons, 1991; pp. 315–348. (c) Kocienski, P. J. Protecting Groups; Georg Thieme Verlag: Stuttgart,
1994; pp. 186–209.
8. Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894–895.
9. Ralf, F.; Siavosh, M.; Klaus, N.; Peter, S.; Karl, B. Helv. Chim. Acta 1990, 73, 439–454.
10. Kusuda, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1989, 30, 2945–2948.