Synthesis of pyrrolidine based natural or unnatural product derivatives (1): Application of efficient asymmetric induction of C-2 position in polysubstituted pyrrolidines

Article abstract of DOI:10.1002/jhet.5570390525

A novel method for synthesis of polysubstituted pyrrolidines, which possess a C-2 stereocenter, was developed. The strategy involves Grignard addition to the succinimide, derived from L-tartaric acid, followed by stereocontrolled triethylsilane promoted reduction of the resulting cyclic amidols.

Full text of DOI:10.1002/jhet.5570390525

Sep-Oct 2002
Synthesis of Pyrrolidine Based Natural or Unnatural Product
Derivatives (1): Application of Efficient Asymmetric
Induction of C-2 Position in Polysubstituted Pyrrolidines
Hyung Jae Jeong, Ju Man Lee, Min Kyu Kim and Sang-Gyeong Lee*
1019
*Department of Chemistry and Research Institute of Natural Science, Gyeongsang National University, Jinju 660-701, Korea
Received January 8, 2002
A novel method for synthesis of polysubstituted pyrrolidines, which possess a C-2 stereocenter, was
developed. The strategy involves Grignard addition to the succinimide, derived from L-tartaric acid,
followed by stereocontrolled triethylsilane promoted reduction of the resulting cyclic amidols.
J. Heterocyclic Chem., 39, 1019 (2002).
Much recent interest has focussed on the chemistry and
epimers (tlc R -value differences of ca. 0.1), while 3c is
f
biological activity of polysubstituted natural and unnatural
pyrrolidines. Members of this N-heterocycle family are
known to have powerful biological activities. Examples of
this are found in the pyrrolidines (-)-anisomycin, which
has been used clinically for the treatment of amebic dysen-
tery and trichomonas vaginitis [1], and (+)-preussin, which
possesses significant broad-spectrum antibiotic activity
against both filamentous fungi and yeasts [2].
isolated as a single diastereomer. The low stereoselectivity
observed in these Grignard addition reactions might be a
result of competition between two different modes of
chelation control (α and β) and steric effects [11]. In the
case of isopropylmagnesium chloride addition, steric
effects are more pronounced and, consequently, one
diastereomer of 3c is produced (presumably 5R).
Our recent interest in the chemistry and biological activ-
ity of polysubstituted natural and unnatural pyrrolidines
has led to the development of new methods to prepare
polysubstituted-pyrrolidines and -piperidines [3,4]. Our
continuing studies in this area required us to devise proce-
dures to prepare a variety of highly functionalized, C-2
substituted pyrrolidines for the purpose of biological eval-
uation. Specific targets of this effort were trans-3,4-dihy-
droxylated pyrrolidine derivatives, which possess various
C-2 substituents. Below, we describe the novel and versa-
tile method we have developed to synthesize these targets.
Reagents and conditions: a) BnNH , TBSCl, imidazole, 70%; b) RMgX,
2
THF, -78 °C to 0 °C. TBS = tert-Butyldimethylsilyl.
The strategy involves Grignard addition [5-9] to the
succinimide, derived from L-tartaric acid, coupled with
stereocontrolled triethylsilane promoted reductive
removal of the C-5 hydroxyl group in the cyclic amidol
products.
The methodology we have devised for preparation of
these targets begins with the conversion of L-tartaric acid
(1) to the bis-OTBS blocked N-benzyl-succinimide 2. This
is accomplished by treatment of acid 1 with benzylamine
followed by diol protection with t-butyldimethylsilyl
chloride [10] (Scheme 1). Reactions of tartarimide 2 with
Grignard reagents afford the corresponding alcohols 3 in
moderate to high yields (76 - 91%). The alcohols 3a, 3b
and 3d are obtained as ca. 1:1 mixtures of separable C-5
Removal of the C-5 hydroxyl group was first attempted
by using zinc and acetic acidic or the Barton's stannyl-
hydride procedure [12]. However, under these conditions
mixtures of diastereomeric products are produced. To
overcome this problem, we resorted to the use of the silane
reduction procedure [13], since we reasoned that complex-
ation of an oxophilic silane reagent to the C-4 ether oxygen
might guide diastereo-controlled hydride delivery to the
intermediate N-acyliminium ion. Accordingly, addition of
triethylsilane to a CH Cl solution of 3a (mixture of
2
2
diastereomers) at -78 °C and borontrifluoride etherate
(BF •OEt ), leads to formation of the reduction product 5a
3
2

1020
H. J. Jeong, J. M. Lee, M. K. Kim and S.-G. Lee
Vol. 39
as a single diastereomer. In addition, reductive
dehydroxylation of the cyclic amidols 3b-c, by using this
same procedure, occurs stereoselectively to yield 5b-d in
85 - 90% yields (Scheme 2). As anticipated [13], the high -
trans-selectivity associated with these reactions most
likely results from chelation of the silane to the C-4
oxygen (Figure 1). Consequently, hydride delivery occurs
selectively from the top-face at C-5 in the iminium ion to
give only trans 5.
THF for 6 hours. Excess reducing agent is quenched prior
to work-up by the careful addition of EtOH (5 mL) at
-5 °C. With this process pyrrolidines 6 are obtained in
moderate yields. The t-butyldimethylsilyl blocking group
in 6 is removed by treatment with tetrabutylammonium
fluoride in THF at room temperature, giving the N-benzyl-
pyrrolidines 7. Finally, hydrogenolytic N-benzyl removal,
by using Pd(OH) and H (1 atm) in methanol at room
2
2
temperature, affords the target 2-substituted 3,4-
dihydroxypyrrolidines 8 in good yields.
Further studies probing the mechanism of the reductive
dehydroxylation reaction and the biological properties of
the target pyrrolidines are in progress.
EXPERIMENTAL
All non-aqueous reactions were carried out under nitrogen.
THF was distilled from Na/benzophenone; methanol was
distilled from Mg; methylene chloride was distilled from CaH .
2
NMR spectra were measured on a Bruker ARX-300 (500 MHz)
spectrometer in CDCl solution used as an internal standard
3
unless otherwise noted (value in ppm); coupling constants are
reported in Hz. Ir spectra were taken on a Hitachi 270-50 FT/IR
-1
spctrophotometer (λ , cm ). Optical rotations were measured
max
on a JASCO DIP -1000 digital polarimeter in a 1-dm cell. The
elemental analyses were performed with LECO Micro Carbon
Hydrogen Determinator (CHN-800). Mass spectra were obtained
by using JEOL JMS-700 spectrophotometer. TLC was run on
Merck precoated silica gel plates. Merck silica gel 60
(230-400 mesh) was used for column chromatography. All
organic extracts were dried over MgSO .
4
(3R,4R)-3,4-bis[(tert-Butyldimethylsiloxy]-1-benzylsuccinimide
(2).
Reagents and conditions: a) BF •OEt , CH Cl , -78 °C to 0 °C; b)
3
2
2
2
A solution of L-tartaric acid (9.0 g, 60.0 mmol) and benzy-
lamine (8.05 mL, 78.0 mmol) in xylene (150 mL) was stirred at
reflux for 15 hours, cooled to 0 °C and the precipitated solid was
collected by filtration. The precipitate was dried in vacuo and
then used in the next reaction. A solution of the solid (3.0 g,
13.5 mmol) in DMF (15.0 mL) containing imidazole (4.8 g,
68.0 mmol) and t-butyldimethylsilyl chloride (6.3 g, 40.0 mmol)
was stirred for 12 hours at 25 °C, diluted with water and extracted
Et SiH, CH Cl , -78 °C to 0 °C, 88%; c) (i) (CH ) S•BH , THF, rt.
3
2
2
3 2
3
TBS = tert-Butyldimethylsilyl.
The existence of oxygen linked, pentavalent organo-
silicon species, like that shown in Figure 1, is well
documented [14].
with CH Cl . The CH Cl extracts were washed with water,
2
2
2
2
dried over MgSO and concentrated in vacuo giving a residue
4
that was subjected to flash column chromatography (silica gel,
hexane/EtOAc, 30/1, v/v) to afford 2 (5.01 g, 83%) as colorless
oil. The spectral data and mp of this substance are identical to
those previously reported [8].
Figure 1. The reaction pathway to the enantioselective hydride attack in
iminium ion 4.
Grignard Addition to Succinimide 2: Synthesis of 5-Substituted
3,4-bis[(tert-butyldimethylsiloxy]-5-hydroxy -2-pyrrolidinones (3).
A solution of the appropriate Grignard reagent (3.0 M , THF,
11.1 mmol, 5 equivalents) in THF was added dropwise to a THF
(40 mL) solution of pyrrolidinedione 2 (2.2 mmol) at -78 °C.
After stirring at 0 °C for 6 hours, saturated aqueous ammonium
The 5-substituted 2-pyrrolidinones 5, prepared by the
methodology described above, are converted to
2-substituted 3,4-dihydroxypyrrolidines 8 by the sequence
shown in Scheme 2. Removal of the C-2 carbonyl func-
tional group is performed by treatment of 5 with the
borane-methyl sulfide complex at room temperature in
chloride was added and the mixture was extracted with CH Cl .
2
2
The CH Cl extracts were dried (MgSO ), filtered and
2
2
4
concentrated in vacuo giving a residue which was subjected to
flash column chromatography (Hexane/EtOAc = 10/1, v/v) to

Sep-Oct 2002
Synthesis of Pyrrolidine Based Natural or Unnatural Product Derivatives
1021
give the corresponding adducts 3 as oils. Yields, 3a: 81.7%
(0.89 g), 3b: 76.1% (0.91 g), 3c: 75.1% (0.82 g), 3d: 91%
Anal. Calcd for C H NO Si : C, 63.24; H, 9.59; N, 2.84.
26 47 4 2
Found: C, 63.27; H, 9.57; N, 2.86.
(1.00 g). R values, 3a-1: 0.22 (Hexane/EtOAc = 10/1, v/v), 3a-2:
Compound 3d-1 has IR (KRS-5): 3530, 3130, 2950, 2860,
f
1
0.16 (Hexane/EtOAc = 10/1, v/v), 3b-1: 0.42 (Hexane/EtOAc =
10/1, v/v), 3b-2: 0.26 (Hexane/EtOAc = 10/1, v/v), 3c: 0.42
(Hexane/EtOAc = 10/1, v/v), 3d-1: 0.26 (Hexane/EtOAc = 10/1,
v/v), 3d-2: 0.13 (Hexane/EtOAc = 10/1, v/v).
1710; H NMR (500 MHz, CDCl ): δ = 6.99 - 7.15 (m, 10H),
3
4.51 (d, 1H, J = 15.0 Hz), 3.89 (d, 1H, J = 2.7 Hz), 3.71 (d, 1H,
J = 15.0 Hz), 3.67 (d, 1H, J = 2.7 Hz), 3.01 (s, OH), 0.70 (s, 9H),
0.49 (s, 9H), -0.01 (s, 3H), -0.20 (s, 3H), -0.36 (s, 3H), -0.54
13
Compound 3a-1 has IR (KRS-5): 3520, 3130, 2930, 2860,
(s, 3H); C NMR (125 MHz, CDCl ): δ = 172.9, 138.0, 136.1,
3
1
1720; H NMR (500 MHz, CDCl ): δ = 7.03 - 7.12 (m, 5H), 4.38
128.6, 128.4, 128.3, 128.2, 127.9, 127.8, 127.1, 95.1, 81.2, 76.8,
44.2, 25.6, 18.0, -4.5, -5.0, -5.2, -5.4.
3
(d, 1H, J = 15.5 Hz), 4.28 (d, 1H, J = 15.5 Hz), 3.95 (d, 1H, J =
2.80 Hz), 3.62 (d, 1H, J = 2.80 Hz), 3.29 (s, OH), 1.18 (s, 3H),
Anal. Calcd for C
H NO Si : C, 61.89; H, 9.31; N, 3.01.
30 47 4 2
0.75 (s, 9H), 0.73 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H), -0.01 (s, 3H),
Found: C, 61.49; H, 9.51; N, 3.21.
13
-0.03 (s, 3H); C NMR (125 MHz, CDCl ): δ = 170.9, 138.5,
Compound 3d-2 has IR (KRS-5): 3510, 3120, 2930, 2860,
3
1
128.4, 127.5, 127.0, 88.0, 79.1, 76.3, 42.2, 25.7, 25.6, 24.8, 18.1,
18.0, -4.2, -4.3, -4.8, -4.9.
1720; H NMR (500 MHz, CDCl ): δ = 6.91 - 7.26 (m, 10H),
3
4.41 (d, 1H, J = 14.9 Hz), 4.18 (d, 1H, J = 5.5 Hz), 3.97 (d, 1H,
J = 5.5 Hz), 3.82 (s, OH), 3.74 (d, 1H, J = 14.9 Hz), 0.77 (s, 9H),
Anal. Calcd for C
H NO Si : C, 61.89; H, 9.31; N, 3.01.
24 43 4 2
Found: C, 61.49; H, 9.51; N, 3.21.
0.64 (s, 9H), -0.11 (s, 3H), -0.00 (s, 3H), -0.12 (s, 3H), -0.61
13
Compound 3a-2 has IR (KRS-5): 3510, 3130, 2950, 2850,
(s, 3H); C NMR (125 MHz, CDCl ): δ = 171.9, 139.9, 137.8,
3
1
1710; H NMR (500 MHz, CDCl ): δ = 7.05 - 7.07 (m, 5H), 4.46
128.6, 128.4, 128.1, 127.2, 127.0, 89.4, 82.2, 76.1, 44.3, 25.8,
25.6, 18.3, 17.8, -4.0, -4.4, -4.8, -5.4.
3
(d, 1H, J = 15.7 Hz), 4.16 (d, 1H, J = 15.7 Hz), 3.78 (d, 1H, J =
2.80 Hz), 3.60 (d, 1H, J = 2.80 Hz), 2.81 (s, OH), 1.03 (s, 3H),
Anal. Calcd for C
H NO Si : C, 61.89; H, 9.31; N, 3.01.
30 47 4 2
0.72 (s, 9H), 0.68 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H), -0.08 (s, 3H),
Found: C, 61.48; H, 9.49; N, 3.19.
13
-0.11 (s, 3H); C NMR (125 MHz, CDCl ): δ = 171.9, 138.2,
3
Reaction of Alcohol 3 with Boron Trifluoride Diethyl Etherate
and Triethylsilane Reagents: Synthesis of (3R,4R,5S)-3,4-
Bis[(tert-butyldimethylsilyl)oxy]-5-(alkyl or -aryl)-1-benzyl-2-
pyrrolidinone (5).
128.4, 127.3, 127.0, 92.1, 79.7, 76.3, 42.0, 25.7, 25.6, 20.1, 18.1,
17.9, -4.51, -4.53, -4.8, -5.0.
Anal. Calcd for C
H NO Si : C, 61.89; H, 9.31; N, 3.01.
24 43 4 2
Found: C, 61.45; H, 9.50; N, 3.19.
Compound 3b-1 has IR (KRS-5): 3490, 3030, 2930, 2860,
To a solution of the diasteremeric mixture alcohol
1
1710; H NMR (500 MHz, CDCl ): δ = 7.27 -7.41 (m, 10H),
(3, 2.14 mmol) in CH Cl (30 ml), a solution of BF •OEt
3
2
2
3
2
4.57 (d, 1H, J = 2.3 Hz), 4.11 (s, 1H), 4.01 (s, 1H), 3.59 (d, 1H,
J = 1.68 Hz), 3.27 (d, 1H, J = 13.7 Hz), 2.85 (d, 1H, J = 13.7 Hz),
1.08 (s, 9H), 0.83 (s, 9H), 0.35 (s, 3H), -0.33 (s, 3H), 0.00 (s, 3H),
(0.39 ml, 3.22 mmol, 1.5 equivalent) and Et SiH (3.53 ml. 21.4
3
mmol) was added under N , and the reaction mixture was kept at
2
-78 °C for 6 hours then the temperature was slowly increased to
0 °C. After that, the reaction mixture was stirred for 12 hours at
13
-0.19 (s, 3H); C NMR (125 MHz, CDCl ): δ = 170.6, 138.7,
3
135.9, 131.1, 128.4, 128.0, 127.4, 127.0, 126.7, 90.9, 74.7, 43.7,
0 °C and the excess BF •OEt and Et SiH were quenched with
3
2
3
42.2, 25.8, 25.5, 18.2, 17.9, -4.4, -5.0, -5.1, -5.8; EIMS (m/e):
saturated NaHCO (4 ml) at 0 °C, extracted with CH Cl (40 ml
3
2
2
+
(M ) Calcd for C
H NO Si , 541.8; found, 541.0; MS m/e.
x 4), washed with water (30 ml x 3), dried over MgSO and
30 47 4 2
4
523.8(M-H O, 6), 484(60), 466(100), 450(27), 219(68), 91(90).
filtered through a glass filter. After the solvent was evaporated
under reduced pressure, the residue was purified by flash column
chromatography (n-hexane/EtOAc = 30/1) to give the
corresponding 5 as oils. Yields, 5a: 88.0% (0. 85 g), 5b: 83%
(0.93 g), 5c: 88% (0.90 g), 5d: 87% (0.95 g).
2
Anal. Calcd for C
H NO Si : C, 66.50; H, 8.74; N, 2.58.
30 47 4 2
Found: C, 66.48; H, 8.76; N, 2.60.
Compound 3b-2 has IR (KRS-5): 3390, 3030, 2930, 2860,
1
1690; H NMR (500 MHz, CDCl ): δ = 7.22 -7.33 (m, 10H),
3
4.69 (d, 1H, J = 15.1 Hz), 4.17 (d, 1H, J = 15.1 Hz), 3.90 (d, 1H,
J = 6.5 Hz), 3.49 (d, 1H, J = 6.5 Hz), 3.13 (d, 1H, J = 14.0 Hz),
3.02 (d, 1H, J = 14.0 Hz), 2.51(s, OH), 0.98 (s, 9H), 0.84 (s, 9H),
Compound 5a has the following physical and spectral
23
properties: [α]
-1.09° (c 2.7, CHCl ); IR (KRS-5): 3020,
D
3
1
2950, 2860, 1710; H NMR (500 MHz, CDCl ): δ = 7.11 - 7.11
3
13
0.12 (s, 3H), 0.08 (s, 3H), 0.03 (s, 3H), 0.00 (s, 3H); C NMR
(m, 5H), 4.92 (d, 1H, J = 15.3 Hz), 4.01 (d, 1H, J = 4.2 Hz), 3.87
(d, 1H, J = 15.3 Hz), 3.63 (t, 1H, J = 4.2 Hz), 3.09 - 3.11 (m, 1H),
1.11 (d, 1H, J = 6.6 Hz), 0.85 (s, 9H), 0.75 (s, 9H), 0.11 (s, 3H),
(125 MHz, CDCl ): δ = 170.6, 138.6, 134.7, 131.1, 128.6, 128.1,
3
128.0, 127.2, 127.1, 92.0, 83.4, 775.0, 43.1, 39.4, 26.0, 25.8,
18.2, 18.1, -4.2, -4.4, -4.5, -4.8.
13
0.08 (s, 3H), 0.07 (s, 3H), -0.91 (s, 3H); C NMR (125 MHz,
Anal. Calcd for C
H NO Si : C, 66.50; H, 8.74; N, 2.58.
CDCl ): δ = 171.7, 136.5, 128.6, 127.8, 127.4, 79.8, 78.1, 58.4,
30 47 4 2
3
Found: C, 66.49; H, 8.79; N, 2.58.
43.5, 25.9, 25.8, 25.7, 18.2, 17.8, 16.9, -4.1, -4.3, -4.5, -4.7.
Compound 3c has IR (KRS-5): 3480, 3020, 2950, 2860,
Anal. Calcd for C
Found: C, 63.97; H, 9.61; N, 3.21.
H NO Si : C, 64.09; H, 9.64; N, 3.11.
24 43 3 2
1
1700; H NMR (500 MHz, CDCl ): δ = 7.20 - 7.02 (m, 10H),
3
4.28 (s, 1H), 3.85 (d, 1H, J = 0.8 Hz), 3.78 (d, 1H, J = 0.8 Hz),
3.73 (s, OH), 1.98 (m, 1H). 0.79 (d, 3H, J = 6.85 Hz), 0.71
(s, 9H), 0.72 (s, 9H), 0.49 (d, 3H, J = 7.05 Hz), 0.02 (s, 3H),
Compound 5b has the following physical and spectral
23
properties: [α]
6.30° (c 1.3, CHCl ); IR (KRS-5): 3020,
D
3
1
2950, 2860, 1710; H NMR (500 MHz, CDCl ): δ = 7.32 - 7.57
3
13
0.01 (s, 3H), 0.00 (s, 3H), -0.02 (s, 3H); C NMR (125 MHz,
(m, 10H), 5.36 (d, 1H, J = 15.3 Hz), 4.23 (s, 1H), 4.19 (d, 1H, J =
14.9 Hz), 4.07 (s, 1H), 3.59 (dd, 1H, J = 4.9 Hz, J = 4.9 Hz), 3.29
(dd, 1H, J = 4.9 Hz, J = 4.9 Hz), 3.00 (1H, dd, J = 13.4 Hz, J =
13.4 Hz), 1.25 (s, 9H), 0.96 (s, 9H), 0.49 (d, 6H, J = 5.1 Hz),
CDCl ): δ = 170.9, 138.3, 128.6, 127.0, 92.7, 77.7, 74.4, 43.2,
3
34.0, 25.8, 25.6, 18.1, 17.9, 17.3, 16.6, -4.0, -4.1, -5.1, -5.3;
+
EIMS (m/e): (M ) Calcd for C
H NO Si , 493.83; found,
26 47 4 2
13
493.0; MS m/e: 478(M-H O, 5), 436(100), 418(71), 304(30),
-0.01 (s, 3H), -0.20 (s, 3H); C NMR (125 MHz, CDCl ): δ =
2
3
171(82), 91(76).
172.5, 137.6, 136.2, 129.3, 128.7, 128.5, 128.1, 127.4, 126.7,

1022
H. J. Jeong, J. M. Lee, M. K. Kim and S.-G. Lee
Vol. 39
78.4, 77.2, 74.0, 67.4, 44.2, 37.7, 28.5, 18.1, 17.6, -4.4, -5.1,
Anal. Calcd for C H NO Si : C, 66.15; H, 10.41; N, 3.21.
24 45 2 2
Found: C, 66.16; H, 10.43; N, 3.24.
+
-5.4, -5.5. EIMS (m/e): (M ) Calcd for C
H
NO Si , 525.87;
30 47
3
2
found, 525.0; MS m/e: 510(6), 468(100), 406(15), 91(29).
Anal. Calcd for C NO Si : C, 68.52; H, 9.01; N, 2.66.
Found: C, 68.53; H, 9.03; N, 2.68.
Compound 6b has the following physical and spectral proper-
23
H
ties: [α]
3.67° (c 2.60, CHCl ); IR (KRS-5): 3020, 2950,
30 47
3
2
D
3
1
2850, 1460; H NMR (500 MHz, CDCl ): δ = 7.07 - 7.29
3
Compound 5c has the following physical and spectral
(m, 10H), 3.86 (d, 1H, J = 4.2 Hz), 3.80 (d, 1H, J = 13.4Hz), 3.76
(s, 1H), 3.47 (d, 1H, J = 13.4Hz), 2.73 - 2.82 (m, 4H), 2.66 (dd,
1H, J = 4.3Hz, J = 10.0 Hz), 0.87 (s, 9H), 0.73 (s, 9H), 0.00
23
properties: [α]
7.37° (c 0.8, CHCl ); IR (KRS-5); 3020, 2920,
D
3
1
2850, 1700; H NMR (500 MHz, CDCl ): δ = 7.02 - 6.99 (m, 5H),
3
13
4.92 (d, 1H, J = 15.3 Hz), 3.83 ( d, 1H, J = 0.9Hz), 3.73 (d, 1H, J =
15.3Hz), 3.65 (s, 1H), 2.91 ( d, 1H, J = 4.7 Hz), 0.82 (s, 1H), 0.73
(d, 3H, J = 7.1 Hz), 0.62 (d, 3H, J = 7.0 Hz), 0.62 (d, 3H, J = 6.95
(s, 3H), -0.04 (s, 3H), -0.22 (s, 3H), -0.34 (s, 3H); C NMR (125
MHz, CDCl ): δ = 140.4, 140.2, 129.6, 129.4, 128.7, 128.3,
3
128.1, 128.0, 126.6, 125.8, 125.7, 81.7, 78.6, 73.9, 39.6, 26.0,
25.9, 25.7, 18.0, 17.7, 0.0, -4.6, -4.7, -4.9, -5.1.
Hz), 0.71 (s, 9H), 0.63 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H), -0.01
13
(s, 3H), -0.20 (s, 3H); C NMR (125 MHz, CDCl ): δ = 140.8,
Anal. Calcd for C H NO Si : C, 70.39; H, 9.65; N, 2.74.
3
30 49 2 2
128.2, 128.0, 126.5, 80.6, 78.9, 78.3, 60.2, 59.9, 29.2, 25.8, 25.7,
20.2, 18.8, 17.9, 17.8, -4.1, -4.5, -4.7, -4.8; EIMS (m/e): (M )
Found: C, 70.37; H, 9.61; N, 2.71.
+
Compound 6c has the following physical and spectral proper-
23
Calcd for C H NO Si , 477.83; found, 477.0; MS m/e: 462(6),
ties: [α]
5.73° (c 0.30, CHCl ); IR (KRS-5): 3020, 2940,
26 47
3
2
D
3
1
420(100), 288(8), 199(39), 91(31), 73(21).
Anal. Calcd for C NO Si : C, 65.35; H, 9.91; N, 2.93.
2860, 1450; H NMR (500 MHz, CDCl ): δ = 7.18 - 7.37
3
H
(m, 5H), 4.05 (d, 1H, J = 13.8 Hz), 3.88 (s, 1H), 3.83 (d, 1H, J =
3.9 Hz), 3.33 (d, 1H, J = 13.8 Hz), 2.75 (d, 1H, J = 10.2 Hz), 2.45
(dd, 1H, J = 4.1 Hz, J = 9.9 Hz), 2.31 (dd, 1H, J = 2.4 Hz, J = 5.9
Hz), 1.94 - 1.95 (m, 1H), 1.01 (d, 3H, J = 6.8 Hz), 0.97 (d, 3H, J =
26 47
3
2
Found: C, 65.37; H, 9.93; N, 2.96.
Compound 5d has the following physical and spectral proper-
23
ties: [α]
2.13° (c 1.67, CHCl ); IR (KRS-5) 3050, 2930,
D
3
1
2860, 1710; H NMR (500 MHz, CDCl ): δ = 6.81 - 7.17
6.8 Hz), 0.88 (s, 9H), 0.85 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.00
3
13
(m, 10H), 4.89 (d, 1H, J = 14.8 Hz), 4.05 (d, 1H, J = 5.4 Hz), 3.87
(t, 1H, J = 5.1 Hz), 3.83 (d, 1H, J = 5.1 Hz), 3.27 (d, 1H, J = 14.8
(s, 3H), 0.06 (s, 3H); C NMR (125 MHz, CDCl ): δ = 140.8,
3
128.2, 128.0, 126.5, 80.6, 78.9, 78.3, 60.2, 59.9, 29.2, 25.8, 25.7,
20.2, 18.8, 17.9, 17.8, -4.1, -4.5, -4.7, -4.8.
Hz), 0.76 (s, 9H0, 0.59 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H), -0.24
13
(s, 3H), -0.61 (s, 3H); C NMR (125 MHz, CDCl ): δ = 172.1,
Anal. Calcd for C H NO Si : C, 67.32; H, 10.65; N, 3.02.
3
26 49 2 2
137.3, 136.4, 129.2, 129.0, 128.9, 128.8, 127.9, 82.3, 777.2, 66.6,
44.4, 26.3, 26.2, 26.0, 25.9, 18.7, 18.1, -3.6, -4.0, -4.2, -4.9.
Found: C, 67.37; H, 10.35; N, 3.05.
Compound 6d has the following physical and spectral proper-
23
Anal. Calcd for C
H
NO Si : C, 68.05; H, 8.86; N, 2.74.
ties: [α]
12.19° (c 2.87, CHCl ); IR (KRS-5): 3060, 3020,
29 45
3
2
D
3
1
Found: C, 68.37; H, 8.61; N, 2.51.
2930, 2850, 1460; H NMR (500 MHz, CDCl ): δ = 7.17 - 7.49
3
(m, 10H), 3.93 - 4.05 (m, 1H), 3.93 (dd, 1H, J = 3.7 Hz, J = 6.7
Hz), 3.76 (d, 1H, J = 13.7 Hz), 3.28 (d, 1H, J = 6.7 Hz), 3.06
(d, 1H, J = 13.7 Hz), 2.91 (dd, 1H, J = 2.5 Hz, J = 10.3 Hz), 2.60
(dd, 1H, J = 6.9 Hz, J = 10.2 Hz), 0.86 (s, 9H), 0.86 (s, 9H), 0.01
Reduction of Lactam 5 with Borane-methyl Sulfide Complex:
Synthesis of (2S,3R,4R)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-2-
(alkyl or -aryl)1-benzylpyrrolidine (6).
13
(s, 3H), -0.04 (s, 3H), -0.15 (s, 3H), -0.45 (s, 3H); C NMR (125
A solution of Me S•BH (2 M in THF, 3.3 ml, 3.22 mmol) was
2
3
MHz, CDCl ): δ = 141.0, 139.2, 128.6, 128.3, 128.2, 128.0,
added under N to a solution of the lactam 5 (1.9 mmol) in THF
3
2
127.4, 126.6, 87.6, 77.8, 75.6, 59.3, 57.6, 25.9, 25.8, 17.9, 17.8,
-4.4, -4.5, -4.5, -5.3.
(30 ml). The reaction mixture was kept at room temperature for
2 hours and refluxed for 1 hour. The excess Me S·BH was
2
3
Anal. Calcd for C
Found: C, 69.97; H, 9.53; N, 2.84.
H NO Si : C, 69.96; H, 9.52; N, 2.81.
quenched with EtOH (2 ml) at -5 °C. After the solvent was
evaporated under reduced pressure, the residue was dissolved in
EtOH (20 ml) and heated at reflux for 2 hours. The reaction
mixture was cooled to room temperature and treated with
29 47 2 2
Deprotection of the TBDMS Group of 6 with Tetrabutyl-
ammonium Fluoride: Synthesis of (2S,3R,4R)-3,4-Dihydroxy-2-
(alkyl or aryl)-1-benzylpyrrolidine (7).
saturated NaHCO , extracted with CH Cl (30 ml x 3). The
3
2
2
collected CH Cl was washed with water, dried over MgSO and
2
2
4
concentrated under reduced pressure. The residue was purified by
flash column chromatography (n-hexane/EtOAc = 30/1) to give
corresponding compounds 6 as oils. Yields, 6a: 88.0% (0. 58 g),
6b: 73% (0.71 g), 6c: 82.8% (0.48 g), 6d: 80% (0.76 g).
To a solution of the O-TBDMS (tert-butyldimethylsilyl)
protected 6 (2.0 mmol) in THF (20 ml) was added TBAF
(tetrabutylammonium fluoride) (1.0 mol in THF, 4 ml) at
room temperature and stirred for 1 hour. The reaction was
quenched with water (10 ml) and extracted with EtOAc (30 ml
x 3). The collected EtOAc was washed with water, dried over
Compound 6a has the following physical and spectral
23
properties: [α]
13.55° (c 2.67, CHCl ); IR (KRS-5): 3020,
D
3
1
2950, 2850, 1460; H NMR (500 MHz, CDCl ): δ = 7.13 - 7.23
MgSO , and concentrated under reduced pressure. The residue
3
4
(m, 5H), 3.88 (d, 1H, J = 13.8 Hz), 3.85 (dd, 1H, J = 3.1 Hz,
J = 6.9 Hz), 3.61 (dd, 1H, J = 3.4 Hz, J = 6.4 Hz), 3.12 (d, 1H,
J = 13.48 Hz), 2.64 (dd, 1H, J = 2.5 Hz, J = 10.4 Hz), 2.43 (dd,
1H, J = 6.8 Hz, J = 10.35 Hz), 2.64 - 2.66 (m, 1H), 1.10 (d, 1H,
J = 6.3 Hz), 0.81 (s, 9H), 0.77 (s, 9H), 0.00 (s, 6H), -0.08 (s, 3H),
was purified by flash column chromatography
(n-hexane/EtOAc = 3/1) to give corresponding compounds
7 as oils. Yields, 7a: 93.0% (0. 39 g), 7b: 70% (0.39 g), 7c:
86% (0.21 g), 7d: 77% (0.40 g).
Compound 7a has the following physical and spectral
13
23
-0.14 (s, 3H); C NMR (125 MHz, CDCl ): δ = 139.1, 128.7,
properties: [α]
20.62° (c 0.20, CHCl ); IR (KRS-5): 3370,
3
D
3
1
128.0, 126.7, 86.3, 77.8, 76.8, 65.3, 59.9, 57.7, 25.9, 17.9, 16.8,
3230, 3020, 2960, 2860, 2800, 1630, 1450; H NMR (500 MHz,
+
-4.1, -4.3, -4.4, -4.6; EIMS (m/e): (M ) Calcd for C
H NO Si ,
acetone-d ): δ = 7.13 - 7.49 (m, 5H), 3.98 (d, 1H, J = 13.2 Hz),
30 47 3 2
6
435.79; found, 435.0; MS m/e: 420(50), 401(5), 378(15),
147(100), 91(53), 73(35).
3.89 - 3.91 (m, 1H), 3.59 - 3.61 (m, 1H), 3.10 (d, 1H, J = 13.2
Hz), 2.71 (dd, 1H, J = 1.9 Hz, J = 10.3 Hz), 2.47 (dd, 1H, J = 6.9

Sep-Oct 2002
Synthesis of Pyrrolidine Based Natural or Unnatural Product Derivatives
1023
Hz, J = 10.32 Hz), 2.27 - 2.30 (m, 1H), 2.04 - 2.08 (m, 1H), 1.23
J = 6.3 Hz, J = 12.5 Hz), 2.81 (t, 1H, J = 6.5 Hz), 2.74 (dd, 1H, J =
13
13
(d, 3H, J = 6.0 Hz): C NMR (125 MHz, acetone-d ): δ = 140.4,
3.5 Hz, J = 12.5 Hz), 1.15 (d, 3H, J = 6.6 Hz); C NMR (125
6
+
129.5, 128.9, 127.5, 86.4, 77.1, 66.8, 61.0, 58.5, 17.3.
MHz, D O): δ = 83.7, 77.7, 59.9, 50.8, 17.4; EIMS (m/e): (M )
2
Anal. Calcd for C
H
NO : C, 69.54; H, 8.27; N, 6.76.
Calcd for C H NO , 117.15; found, 117.15; MS m/e: 99(16),
12 17
2
14 21 2
Found: C, 69.58; H, 8.29; N, 6.73.
82(7), 71(8), 57(100), 56(33).
Anal. Calcd for C H NO : C, 51.26; H, 9.46; N, 11.96.
Found: C, 51.28; H, 9.47; N, 11.97.
Compound 7b has the following physical and spectral
5
11
2
23
properties: [α]
7.64° (c 0.07, CHCl ). IR (KRS-5): 3360,
D
3
1
3060, 3020, 2920, 2810, 1490; H NMR (500 MHz, acetone-d ):
Compound 8b has the following physical and spectral
6
23
1
δ = 7.16 - 7.35 (m, 10H), 4.02 (d, 1H, J = 13.2 Hz), 3.90 - 3.91
(m, 2H), 3.83 - 3.84 (m, 1H), 3.45 - 3.73 (broad s, 1H), 3.28
(d, 1H, J = 13.2 Hz), 2.96 - 2.98 (m, 2H), 2.74 - 2.76 (m, 2H),
properties: [α]
45.48° (c 0.35, H O); H NMR (500 MHz,
D
2
D O): δ = 7.12 - 7.24 (m, 5H), 4.01 - 4.03 (m, 1H), 3.72 (dd, 1H,
2
J = 5.2 Hz, J = 5.2 Hz), 3.14 - 3.16 (m, 1H), 3.04 (dd, 1H, J = 5.7
Hz, J = 5.7 Hz), 2.94 (dd, 1H, J = 6.3 Hz, J = 6.3 Hz), 2.83
13
2.59 (dd, 1H, J = 6.0 Hz, J = 10.2 Hz); C NMR (125 MHz,
acetone-d ): δ = 206.8, 206.6, 206.5, 141.2, 141.1, 131.0, 129.9,
6
(dd, 1H, J = 3.1 Hz, J = 8.0 Hz), 2.71 (dd, 1H, J = 8.7 Hz, J = 8.7
129.3, 129.2, 127.9, 127.1, 82.9, 77.7, 73.5, 60.7, 60.1, 39.5.
13
Hz); C NMR (125 MHz, D O): δ = 138.24, 129.8, 129.5,
2
Anal. Calcd for C
H NO : C, 76.29; H, 7.47; N, 4.94.
18 21 2
129.3, 129.1, 127.4, 80.9, 76.9, 66.2, 50.8, 38.1; EIMS (m/e):
Found: C, 76.28; H, 7.49; N, 4.99.
+
(M ) Calcd. for C
H NO , 193.11; found, 191.0(M-2); MS
14 15 2
Compound 7c has the following physical and spectral
m/e: 148(10), 132(13), 102(M-Bz, 100), 91(tropylium, 38),
77(14).
23
properties: [α]
14.60° (c 1.67, CHCl ); IR (KRS-5): 3390,
D
3
1
3020, 2950, 2790, 1450; H NMR (500MHz, CDCl ): δ = 7.22
3
Anal. Calcd for C
H NO : C, 68.37; H, 7.82; N, 7.25.
11 15 2
-7.32 (m, 10H), 4.01 (d, 1H, J = 13.2 Hz), 3.91 (d, 1H, J = 4.1
Hz), 3.76 (d, 1H, J = 3.9 Hz), 3.19 (d, 1H, J = 10.3 Hz), 2.47
(dd, 1H, J = 4.0 Hz, J = 10.3 Hz), 2.38 (broad s, 2OH), 2.22
Found: C, 68.47; H, 7.83; N, 7.19.
Compound 8c has the following physical and spectral proper-
23
1
ties: [α]
6.03° (c 0.20, H O); H NMR (500 MHz, D O): δ =
D
2
2
(t, 1H, J = 4.2 Hz), 2.03 - 2.11 (m, 1H), 1.05 (d, 3H, J = 6.7 Hz),
4.08 - 4.10 (m, 1H), 3.82 - 3.83 (m, 1H), 2.98 (dd, 1H, J = 4.8 Hz,
J = 12.5 Hz), 2.87 (dd, 1H, J = 2.4 Hz, J = 12.5 Hz), 2.53 (dd, 1H,
13
0.09 (d, 3H, J = 6.8 Hz); C NMR (125MHz, CDCl ): δ = 138.8,
3
128.7, 128.3, 127.0, 78.6, 76.6, 76.5, 59.0, 57.6, 26.8, 19.8, 16.5;
J = 5.3 Hz, J = 8.1 Hz), 1.72 - 1.76 (m, 1H), 0.98 (d, 3H, J = 6.7
+
EIMS (m/e): (M ) Calcd. for C
H NO , 235.16; found, 235.0;
14 21 2
13
Hz), 0.95 (d, 3H, J = 6.7 Hz); C NMR (125 MHz, D O): δ =
2
MS m/e: 204(9), 192(75), 160(5), 91(100), 65(12).
Anal. Calcd for C NO : C, 71.46; H, 8.99; N, 5.95.
+
81.1, 78.5, 51.2, 31.2, 19.6, 19.3; EIMS (m/e): (M ) Calcd for
H
14 21
2
C H NO 145.11; found, 145.0; MS m/e: 145(45) 128(52),
Found: C, 71.48; H, 8.97; N, 5.97.
7
15
2,
116(38), 102(80), 72(100), 56(64).
Compound 7d has the following physical and spectral
23
Anal. Calcd for C H NO : C, 57.90; H, 10.41; N, 9.65.
properties: [α]
11.70° (c 0.20, CHCl ); IR (KRS-5): 3410,
7
15
2
D
3
1
Found: C, 57.92; H, 10.43; N, 9.67.
3030, 2950, 2820, 1450; H NMR (500 MHz, acetone-d ): δ =
6
Compound 8d has the following physical and spectral proper-
7.19 - 7.55 (m, 10H), 5.21 (broad s, 1 OH), 4.04 - 4.05 (m, 1H),
3.89 - 3.91 (m, 1H), 3.75 (d, 1H, J = 6.8 Hz), 3.29 (d, 1H, J = 13.4
Hz), 3.06 (d, 1H, J = 13.4 Hz), 2.93 (d, 1H, J = 10.3 Hz), 2.91
23
1
ties: [α]
-2.25° (c 0.10, H O); H NMR (500 MHz, D O):
D
2
2
δ = 7.27 - 7.39 (m, 5H), 3.82 - 3.86 (m, 1H), 3.53 - 3.56 (m, 1H),
13
13
-2.99 (s, OH), 2.63 (dd, 1H, J = 6.8 Hz, J = 10.3 Hz); C NMR
2.90 (dd, 1H, J = 4.8 Hz, J = 4.8 Hz), 2.73 - 2.83 (m, 3H);
C
(125 MHz, acetone-d ): δ = 206.3, 206.2, 142.7, 140.1, 130.2,
129.3, 129.2, 129.1, 128.9, 128.8, 128.7, 128.1, 127.6, 87.9, 77.5,
77.3, 60.5, 58.5.
NMR (125 MHz, D O): δ = 139.0, 129.8, 129.0, 126.9, 73.9,
73.7, 43.3, 39.1; EIMS (m/e): (M ) Calcd. for
6
2
+
C
H NO ,193.24; found, 193.0; MS m/e: 163(10), 134(17),
14 21 2
Anal. Calcd for C
H NO : C, 75.81; H, 7.11; N, 5.20.
17 19 2
103(23), 91(100), 65(23).
Anal. Calcd for C
Found: C, 75.77; H, 7.23; N, 5.31.
H
NO : C, 67.02; H, 7.31; N, 7.82.
2
10 13
Found: C, 67.04; H, 7.34; N, 7.83.
Deprotection of the Benzyl group of 7 with Palladium
Hydroxide/Hydrogen: Synthesis of (2S,3R,4R)-3,4-Dihydroxy-2-
(alkyl or aryl)-pyrrolidine (8).
Acknowledgement.
Financial support for this work provided by a grant from Korea
Research Foundation (KRF- 2000-015-DP0252), Korea.
To a solution of the N-benzyl protected 7 (1.1 mmol) in MeOH
was added Pd(OH) (0.1 g) under H pressure (1 atm) at room
2
2
temperature. After 12 hours, the inorganic salt was filtered
through a Celite fitted glass filter and rinsed with MeOH. The
MeOH solution was acidfied with HCl (2 N) at 0 °C. The solvents
were evaporated under reduced pressure, and the residue was
dissolved in MeOH. To the MeOH solution, to absorb the product,
was added Dowex 50W-X8 (0.3 g) and was stirred for 30 minutes.
The solvents were evaporated, and the mixture of Dowex 50W-X8
and product were subjected to column chromatography and
purified by elution with ammonia water to give corresponding
compounds 8 as solids. Yields, 8a: 64% (82 mg), 8b: 95.0%
(200 mg), 8c: 90% (140 mg), 8d: 90% (240 mg).
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23
1
properties: [α]
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D O): δ = 4.04 - 4.71 (m, 1H), 3.53 - 3.55 (m, 1H), 3.02 (dd, 1H,
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