Synthesis and application of novel proline-derived chiral piperazinones and sulfamide-amine alcohols

Article abstract of DOI:10.1080/00397910701392400

Several novel chiral piperazinone and sulfamide-amine alcohols were synthesized starting from inexpensive and readily available L-proline and trans-4-hydroxy-L-proline. The catalytic activity of the sulfamide-amine alcohols for the asymmetric addition of diethylzinc to benzaldehyde were evaluated preliminarily. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701392400

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Synthesis and Application of
Novel Proline-Derived Chiral
Piperazinones and Sulfamide-
Amine Alcohols
Y.-Q. Fu a , L.-N. Ding a , L.-G. Wang a & J.-C. Tao a
a Department of Chemistry, New Drug Research
and Development Center , Zhengzhou University ,
Zhengzhou, China
Published online: 09 Sep 2008.
To cite this article: Y.-Q. Fu , L.-N. Ding , L.-G. Wang & J.-C. Tao (2008)
Synthesis and Application of Novel Proline-Derived Chiral Piperazinones and
Sulfamide-Amine Alcohols, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:15, 2672-2683, DOI:
10.1080/00397910701392400
To link to this article: http://dx.doi.org/10.1080/00397910701392400
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Synthetic Communications1, 38: 2672–2683, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701392400
Synthesis and Application of Novel
Proline-Derived Chiral Piperazinones and
Sulfamide-Amine Alcohols
Y.-Q. Fu, L.-N. Ding, L.-G. Wang, and J.-C. Tao
Department of Chemistry, New Drug Research and Development Center,
Zhengzhou University, Zhengzhou, China
Abstract: Several novel chiral piperazinone and sulfamide-amine alcohols were
synthesized starting from inexpensive and readily available L-proline and trans-4-
hydroxy-L-proline. The catalytic activity of the sulfamide-amine alcohols for the
asymmetric addition of diethylzinc to benzaldehyde were evaluated preliminarily.
Keywords: Catalysis, piperazinone, proline derivatives, synthesis, sulfamide-
amine alcohol
Proline and proline derivatives have attracted much attention from
chemists in recent years because of their special biological functions
and extensive application in asymmetric synthesis. For example, cyclodi-
peptides derived from L-proline and 4-hydroxy-L-proline are plant
growth regulators,[1–3] and some proline derivatives have been used as
highly efficient chiral auxiliaries,[4] chiral ligands,[5–7] or organocata-
lysts[8,9] in asymmetric synthesis.
The piperazinone ring and chiral b-amino alcohol moiety are widely
used structures in medicinal chemistry. Because of the similarity of piper-
azinone (Fig. 1) to a conformationally constrained cyclodipeptide, it
serves as an effective and versatile template for the construction of biolo-
gically active molecules[10,11] (e.g., some substituted piperazinone anolo-
gues have been demonstrated as inhibitors of farnesyltransferase,[12]
growth hormone secretagogue,[13] etc). Chiral b-amino alcohol moieties
Received in the U.S.A. September 22, 2006
Address correspondence to J.-C. Tao, Department of Chemistry, New Drug
Research and Development Center, Zhengzhou University, Zhengzhou 450052,
China. E-mail: jctao@zzu.edu.cn
2672

Chiral Piperazinones and Sulfamide-Amine Alcohols
2673
Figure 1. Substituted piperazinone.
are critical structural segments of some natural or synthesized biologi-
cally active compounds such as adrenergic agonists or antagonists,[14,15]
inhibitors for HIV protease,[16] and anticancer agents.[17] Moreover, some
chiral b-amino alcohols have been successfully used as chiral ligands in
asymmetric synthesis (e.g., asymmetric alkylation,[5–7] reductions,[18–20]
and epoxylation.)[21–23]
In this report, we prepared two piperazinone derivatives 5a,b and five
sulfamide-amine alcohols 6a-e (Scheme 1) via simple methods using com-
mercially available, inexpensive L-proline and trans-4-hydroxyl-L-proline
as main materials.
Scheme 1. Reagents and conditions: i) TsCl, dry pyridine, ꢀ 10 ꢁC to rt, 12 h; ii)
Na2CO3, CH3CN, 80 ꢁC, 36 h; iii) 40% HBr, HOAc, phenol, reflux, 2–4 h; iv)
NaBH4, CH3OH, t-BuOH, reflux, 3 h; v) RMgBr, THF, 0 ꢁC to rt, 0.5–2 h.

2674
Y.-Q. Fu et al.
Figure 2. Single crystal structure of compound 6b.
Compound 1 is an intermediate of the synthetic veterinary drug
danofloxacin mesylate, derived from trans-4-hydroxyl-L-proline.[24] The
primary hydroxyl group could be selectively transformed into sulfonate
2 in good yield at ꢀ10 ꢁC to room temperature. The sulfonate group
of compound 2 was substituted conveniently by methyl L-prolinate 3a
or methyl 4-hydroxyl-L-prollinate 3b in the presence of excess Na2CO3
to give compounds 4a and 4b respectively. In this step, the use of an
inorganic base instead of organic base made the reaction easily treated
after reaction and environmentally green. By the action of HBr=
HOAc=phenol,[25] 4a,b detosylated and cyclized in one step to furnish
chiral 1,3,4,6-tetrasubstitued tricycle piperazinone derivatives 5a,b. By
reduction of 4a with NaBH4 in t-butyl alcohol and methanol[26] or rou-
tine Grignard reagent addition of alkyl magnesium bromide to 4a, com-
pounds 6a-e were obtained. The single crystals of compound 6b suitable
for X-ray analysis were obtained by recrystallization from ethanol at
room temperature. From the single-crystal structure of 6b, we can see
that the three chiral centers keep their original configurations (C(4)ꢀS,
C(2)ꢀR, and C(9)ꢀS) in trans-4-hydroxyl-L-proline and L-proline
(Fig. 2) because the configuration of C (2) could not change.
Many prolinol analogues have been demonstrated as highly efficient
catalysts for various kinds of asymmetric transformations.[5–7] The cata-
lytic functions of these compounds are mainly attributed to the unique
structure of the strained five-membered pyrrolidine ring, the chirality,
and the coordinative capabilities of N, O atoms. Cho and Chun found
that the zinc complexes chirally modified by b-sulfonamidoalchohol
alone without the use of Ti(OiPr)4 are effective as chiral catalysts for
the addition of diethylzinc to aldehydes to afford secondary alcohols
with moderate enantioselectivity.[27] Recently, Wan and coworkers[28]

Chiral Piperazinones and Sulfamide-Amine Alcohols
2675
Figure 3. Proposed trivalent binding modes of the Zn with the sulfamide-amino
alcohols derived from L-proline.[29]
synthesized a series of proline-derived sulfamide-amine alcohols to
promote the addition of diethylzinc to aldehyde with high enantioselec-
tivities. From the experimental results, they reasoned that the nitrogen
atom from the sulfonamide served as another weakly coordinative site
besides the coordination of the nitrogen and oxygen atoms from the
prolinol moiety (Fig. 3). Considering that compounds 6a-e have struc-
tures similar to Wan’s catalyst, we presumed that they should be
potential catalysts to promote the reaction of alkylation of aldehyde.
Therefore, the catalytic activity of 6a-e for the addition of diethylzinc
to benzaldehyde was first evaluated at room temperature, and the results
are summarized in Table 1. When 5 mol% of catalyst were used to pro-
mote the reaction for 3 days at room temperature, the products were
furnished in moderate yields with poor enantioselectivity. The activity
Table 1. Addition of diethylzinc to benzaldehyde catalyzed by 6a-e
Entry
Cat.
Cat. loading (mol%)
Yield (%)a
Ee (%)b
Config.c
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6e
6e
5
5
5
5
5
Trace
26
32
31
63
—
6
—
S
R
R
S
27
11
27
26
26
10
20
62
60
S
S
aIsolated yields.
bDetermined by chiral high performance liquid chromatography (HPLC) on
chiralcel OD-H column.
cDetermined by comparison with literature.[29]

2676
Y.-Q. Fu et al.
of 6e (R ¼ Ph) was higher than that of others (entry 5). The configuration
of the major product depended on the substituent group R of the catalyst.
When R ¼ ꢀðCH Þ (6c) or n-Bu (6d), R-enantiomer was excess (entries
4ꢀ
ꢀ2
3 and 4), whereas when R ¼ Et (6b) or Ph (6e), S-enantiomer was the
major product (entries 2 and 5). Increasing the catalyst loading did not
improve the activity and enantioselectivity (entries 6 and 7).
In conclusion, the present work describes the synthesis of several
novel L-proline derivatives—two chiral piperazinones and five sulfa-
mide-amine alcohols—and provides candidate compounds for the screen-
ing of new drug. Primary investigation demonstrated that 6b-e could
catalyze the asymmetric addition of diethylzinc to benzaldehyde with
moderate yield. Other applications of these compounds, such as asym-
metric catalysis in other reactions and biological activity, are now in
progress in our laboratory.
EXPERIMENTAL
General
Tetrahydrofuran (THF) was distilled from sodium-benzophenone immedi-
ately prior to use. All other chemicals were used as received unless otherwise
1
noted. H NMR spectra were collected on a Bruker DPX (400 MHz)
with TMS as an internal stantard. IR spectra were recorded on a Thermo
Nicolet IR200 unit. High-resolution mass spectra (HRMS) were carried
out on a Waters Micromass Q-Tof MicroTM instrument using the electro-
spray ionization (ESI) technique. Melting points were determined using
an XT5A apparatus and are uncorrected. Specific rotatory power was
determined on a Perkin Elmer 341 polarimeter. The single-crystal struc-
ture was determined on a Rigaku R-AXIS-IV image area detector.
Synthesis of Compound 2
A solution of compound 1 (8.140 g, 30 mmol) in anhydrous pyridine
(50 mL) was added p-TsCl (6.100 g, 32 mmol) portion wise at ꢀ10 ꢁC.
The mixture was stirred for 12 h, during which the temperature was
allowed to rise to room temperature. Then the mixture was poured into
50 mL of cool water. The aqueous phase was extracted with CHCl3
(3 ꢂ 30 mL), and the organic layer was washed with 2 M aq. HCl, satu-
rated aq. Na2CO3, and water, then dried over anhydrous Na2SO4,
filtered, and evaporated in vacuo. The crude product was purified
through column chromatography on silica gel (eluent: ethyl acetate=
petroleum ether ¼ 1:2, v=v) to give 2 as a white solid.

Chiral Piperazinones and Sulfamide-Amine Alcohols
2677
(2S, 4R)-4-Hydroxyl-1-tosyl-2-p-tosyloxymethyl-pyrrolidine 2
20
Yield: 86%, mp 103–105 ꢁC; ½aꢃD ¼ ꢀ87:9 (c 1.80, EtOH); IR (KBr
1
disc) cmꢀ1: 3514, 3089, 1597, 1362, 818; H NMR (400 MHz, CDCl3) d:
1.95 (m, 1H), 2.02 (m, 1H), 2.43 (s, 3H), 2.45 (s, 3H), 3.23 (dd,
J ¼ 11.6 Hz, 1H), 3.48 (dd, J ¼ 11.6 Hz, 1H), 3.94 (m, 1H), 4.13 (dd,
ꢁ
J ¼ 10.4, 6.4 Hz, H), 4.33 (dd, J ¼ 10.4, 2. Hz, 2H), 7.30 (d, J ¼ 8.0 Hz,
2H), 7.39 (d, J ¼ 8.0 Hz, 2H), 7.67 (d, J ¼ 8.0 Hz, 2H), 7.81 (d, J ¼
8.0 Hz, 2H).
Synthesis of Compound 4a,b
General Procedures for Preparation of 4a and 4b
To the stirring mixture of methyl prolinate hydrochloride 3a.
(1.507 g, 9 mmol), Na2CO3 (5.774 g, 54 mmol), and anhydrous CH3CN
(50 mL), compound 2 (7.765 g, 1 ꢁmmol) was added. After stirring at
80 ꢁC for 36 h and filtering off the solid, the filtrate was evaporated in
vacuo. By column chromatography on silica gel (ethyl acetate as eluent),
compound 4a was obtained as a slabby, and the excess 2 was recovered
also. A similar procedure afforded 4b as a sllaby.
(2S,20S,40R)-Methyl 1-[ (10-p-Tosyl-40-hydroxypyrolidin-20-yl)methyl]
pyrrolidine-2-carboxylate 4a
20
Yield: 78%, ½aꢃD ¼ ꢀ126:0 (c 1.20, CHCl3), IR (KBr disc) cmꢀ1:
1
3513, 1741, 1598, 1494, 817; H NMR (400 MHz, CDCl3) d: 1.84 (m,
4H), 2.16 (m, 2H), 2.41 (s, 3H), 2.45 (m, 2H), 2.77 (m, 1H), 2.90 (dd,
J ¼ 12.0, 3.6 Hz, 1H), 3.17 (dd, J ¼ 11.2, 3.2 Hz, 2H), 3.26 (m, 1H),
3.50 (dd, J ¼ 11.2, 4.4 Hz, 1H), 3.70 (s, 3H), 3.75 (m, 1H), 4.32 (t,
J ¼ 4.4 Hz, 1H), 7.30 (d, J ¼ 8.0 Hz, 2H), 7.71 (d, J ¼ 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d: 23.0, 24.8, 30.4, 40.4, 53.2, 55.0, 57.7, 59.3,
61.8, 67.7, 70.8, 129.1 (2Ar-C), 131.0 (2Ar-C), 135.5, 145.0, 176.1. MS
(ESI) m=z: 383 (M þ Hþ ), 405 (M þ Naþ ); HRMS (ESI) m=z: calcd.
for C18H27N2O5S (M þ H)þ 383.1640, found 383.1654.
(2S,20S,40R,40R)-Methyl 4-Hydroxy-1-[(10-p-tosyl-40-hydroxypyroli-
din-20-yl)methyl] pyrrolidine-2-carboxylate 4b
20
Yield 47%, ½aꢃD ¼ ꢀ100:0 (c 1.30, acetone); IR (KBr, cmꢀ1): 3461,
1
3064, 2951, 1734, 1598, 817; H NMR (400 MHz, CDCl3) d 1.77 (m,

2678
Y.-Q. Fu et al.
1H), 2.04ꢀ2.12 (m, 3H), 2.40 (s, 3H), 2.59 (dd, J ¼ 10.0, 2.8, 1H), 2.75
(dd, J ¼ 12.0, 9.6, 1H), 2.98 (dd, J ¼ 12.0, 4.0, 1H), 3.14 (dd, J ¼ 11.2,
4.0, 1H), 3.39 (dd, J ¼ 10.0, 5.2, 1H), 3.49 (dd, J ¼ 10.0, 4.8, 1H), 3.64
(t, J ¼ 8.0, 1H), 3.71 (s, 3H), 3.76 (m, 1H), 4.33 (m, 1H), 4.42 (m, 1H),
7.30 (d, J ¼ 8.0, 2H), 7.70 (d, J ¼ 8.0, 2H); 13C NMR (100 MHz, CDCl3)
d: 21.3, 38.4, 38.6, 51.6, 55.9, 57.7, 59.7, 61.5, 64.5, 69.0, 70.1, 127.4
=
(2Ar-C), 129.4 (2Ar-C), 133.9 (Ar-C), 143.4 (Ar-C), 174.2 (C O); MS
(ESI) m=z: 399 (M þ Hþ ), 421 (M þ Naþ ), 437 (M þ Kþ ); HRMS
(ESI) m=z: calcd for C18-27N2O6S (M þ H)þ 399.1590, found 399.1592.
Synthesis of 5a,b
General Procedures for Preparation of 5a and 5b
The mixture of 4a (382 mg, 1 mmol), phenol (113 mg, 1.2 mmol),
acetic acid (0.13 mL, 2.4 mmol), and 40% HBr (1 mL) was refluxed for
2–4 h, then extracted with ethyl ether to remove most of the phenol.
The aqueous phase was evaporated, and the solid was extracted with
acetone to give 153 mg of 5a (hydrobromide) as a white solid.
(3S,9S,11R,)-11-Hydroxy-1,7-diaza-2-oxo-tricyclo[7.3.0.03,7]dodecane 5a
(Hydrobromide)
20
Yield 55%, mp 245 ꢁC (decompose); ½aꢃD ¼ ꢀ50:5 (c 1.09, H2O); IR
1
(KBr disc) cmꢀ1: 3507 (br), 2956, 2808, 1641; H NMR (400 MHz, D2O)
d: 1.85 (td, J ¼ 12.8, 4.0, 1H), 2.08 (m, 1H), 2.16ꢀ2.27 (m, 3H), 2.52 (m,
1H,), 3.14 (m, 1H), 3.38 (m, 1H), 3.45 (d, J ¼ 13.6, 1H), 3.75 (dd,
J ¼ 13.6, 4.8, 1H), 3.87 (m, 1H), 3.92 (dd, J ¼ 12.4, 2.8, 1H), 4.20 (m,
1H), 4.44 (t, J ¼ 9.6, 1H), 4.51 (t, J ¼ 4.0, 1H); 13C NMR (100 MHz,
D2O) d: 22.0, 27.4, 37.7, 52.2, 53.2, 54.2, 57.1, 62.1, 67.8, 165.2; MS
(ESI) m=e: 197 (M þ Hþ ); HRMS (ESI) m=z: calcd. for C10H17N2O2S
(M þ H)þ 213.1239, found 213.1239.
(3S, 5R, 9S, 11R)ꢀ5,11-Dihydroxy-1,7-diaza-2-oxo-tricyclo[7.3.0.03,7
dodecane 5b (Hydrobromide)
]
20
Yield 51%, mp 205ꢀ207 ꢁC; ½aꢃD ¼ ꢀ35:5 (c 1.36, H2O); IR (KBr
1
disc) cmꢀ1: 3372, 3007, 2950, 2933, 2815, 2672, 2631, 1650; H NMR
(400 MHz, D2O) d: 1.76ꢀ1.84 (m, 1H), 2.20 (dd, J ¼ 13.5, 5.6, 1H),
2.34–2.48 (m, 2H), 3.04 (m, 1H), 3.40 (dd, J ¼ 12.8, 3.6, 1H), 3.44 (d,
J ¼ 12.4, 1H), 3.67 (dd, J ¼ 13.4, 4.3, 1H), 3.82 (dd, J ¼ 12.8, 1.2, 1H),
3.98 (dd, J ¼ 12.2, 2.6, 1H), 4.16 (m, 1H), 4.55–4.59 (m, 2H), 4.66–4.71

Chiral Piperazinones and Sulfamide-Amine Alcohols
2679
(m, 1H); 13C NMR (100 MHz, D2O) d: 36.1, 37.7, 53.4, 53.4, 54.3, 60.4,
64.3, 68.1, 68.2, 165.3; MS (ESI) m=e: M þ Hþ (213); HRMS: (ESI)
m=z: calcd. for C10H17N2O3S (M þ H)þ 197.1291, found 197.1279.
Synthesis of 6a
To the mixture of 4a (0.661 g, 1.7 mmol), NaBH4 (0.772 g, 20 mmol), and
t-BuOH (10 mL), MeOH (7 mL) was added over 7.5 h at 80 ꢁC. The
reaction mixture was stirred overnight at this temperature. Then most
of the solvent was evaporated and extracted with n-BuOH, dried over
Na2SO4, filtered, and evaporated in vacuo. The residue was purified
through column chromatography on silica gel to give compound 6a
as a white solid (chloroform=methanol ¼ 7:1, v=v).
(2S,20S,40R)-2-Hydroxylmethyl-1-[(10-p-tosyl-40-hydroxypyrolidin-20-
yl) methyl] pyrrolidine (6a)
20
Yield: 56%, mp 114–116 ꢁC, ½aꢃD ¼ ꢀ123:0 (c 0.60, EtOH); IR (KBr
1
disc) cmꢀ1: 3412, 1596, 817; H NMR (400 MHz, DMSO) d: 1.46–1.50
(m, 2H), 1.61–1.67 (m, 2H), 1.76–1.79 (m, 1H), 1.88–1.92 (m, 1H), 2.18
(m, 1H), 2.40 (s, 3H), 2.50 (m, 1H), 2.70–2.74 (m, 2H), 2.91 (dd,
J ¼ 10.0, 5.2 Hz, 1H), 3.21 (m, 1H), 3.37 (m, 1H), 3.41–3.45 (m, 2H),
3.55 (m, 1H), 4.16–4.21 (m, 1H), 4.38 (s, 1H), 4.78 (d, J ¼ 3.8Hz, 1H),
7.42 (d, J ¼ 8.0 Hz, 2H), 7.67 (d, J ¼ 8.0 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) d: 20.9, 22.7, 27.6, 38.2, 54.0, 55.9, 57.5,
60.6, 64.2, 65.5, 67.4, 127.5 (2 ꢂ C), 129.5 (2 x C), 133.7, 143.0;
HRMS (ESI) m=z: calcd. for C17H27N2O4S (M þ H)þ 355.1691, found
355.1676.
Synthesis of 6b-e
General Procedure for Preparation of Sulfamide-Amine alcohols 6b-e
Under an argon atmosphere, a solution of alkyl bromide (16 mmol)
and 1,4-dibromobutane (ꢁmmol) was used to prepare 6c in THF
(10 mL). It was added slowly to a three-necked flask containing magnes-
ium scraps (16 mmol). The reaction mixture was stirred for another
20 min at room temperature, then cooled to 0 ꢁC, and a solution of com-
pound 4a (2 mmol) in THF (6 mL) was added dropwise. After stirring the
mixture for 0.5–2 h, it was acidified with 2 M aq. HCl and extracted with
EtOAc. The organic layer was successively washed with saturated

2680
Y.-Q. Fu et al.
Na2CO3, water, and brine, then dried over Na2SO4, filtrated, and
evaporated in vacuo. The crude product was purified through column
chromatography to furnish sulfamide amino alcohols 6b-e.
(2S,20S,40R)-2-(100 0-Hydroxy-1000-ethylpropyl)-1-[(10-p-tosyl-40-hydroxy-
pyrolidin-20-yl)methyl]pyrrolidine 6b
20
Colorless crystal, yield 91%, mp 220–222 ꢁC, ½aꢃD ¼ ꢀ95:6 (c 1.30,
ethanol); IR (KBr, cmꢀ1): 3423, 3336, 1598, 1456, 816; 1H NMR
(400 MHz, D2O) d: 0.79 (t, J ¼ 7.2 Hz, 3H), 0.85 (t, J ¼ 7.2 Hz, 3H),
1.43–1.59 (m, 4H), 1.75–2.12 (m, 6H), 2.32 (s, 3H), 3.24 (m, 1H), 3.38
(m, 1H), 3.42–3.54 (m, 4H), 3.75 (m, 1H), 4.19 (m, 2H), 7.36 (d,
J ¼ 8.0 Hz, 2H), 7.68 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 Hz, D2O) d:
6.3, 6.3, 20.5, 23.1, 25.6, 26.2, 28.1, 37.8, 55.8, 55.9, 58.2, 63.0, 68.8,
74.9, 77.8, 127.7 (2Ar-C), 129.8 (2Ar-C), 131.3, 145.8; HRMS (ESI)
m=z: calcd for C21H35N2O4S (M þ H)þ 411.2317, found 411.2321.
(2S,20S,40R)-2-(100-Hydroxy-cyclopenta-100-yl)-1-[(10-p-tosyl-40-hydroxy-
pyrolidin-20-yl)methyl] pyrrolidine 6c
White solid, yield: 75%, mp 128.9–130.8 ꢁC, [a]D ¼ ꢀ116.5 (c 0.54,
20
EtOH); IR (KBr disc) cmꢀ1: 3383, 1597, 816; 1H NMR (400 MHz, CDCl3)
d: 1.45–1.68 (m, 5H), 1.75–1.92 (m, 7H), 2.02 (dd, J ¼ 6.4, 5.2 Hz, 2H), 2.43
(s, 3H), 2.73 (m, 1H), 2.85 (m, 1H), 2.98 (t, J ¼ 11.2 Hz, 1H), 3.19 (dd,
J ¼ 11.2, 3.6 Hz, 1H), 3.29 (dd, J ¼ 12.0, 3.2 Hz, 1H), 3.34 (m, 1H), 3.53
(dd, J ¼ 11.2,4.4 Hz, 1H), 3.86–3.89 (m, 4H), 4.32 (m, 1H), 7.33 (d,
J ¼ 8.0 Hz, 2H), 7.73 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d: 21.5, 23.0, 24.1, 24.5, 24.7, 36.8, 39.5, 40.5, 54.9, 56.1, 57.4, 62.9, 69.3,
74.2, 82.1, 127.8 (2þC), 129.7 (2 C), 133.8, 143.8; HRMS (ESI) m=z: calcd.
for C21H33N2O4S (M þ H)þ 409.2161, found 409.2152.
(2S,20S,40R)-2-(100-Hydroxy-100-butylpentyl)-1-[(10-p-tosyl-40-hydroxy-
pyrolidin-20-yl)methyl] pyrrolidine 6d
White solid, yield: 72%, mp 155–156 ꢁC, [a]D ¼ ꢀ100.6 (c 1.67,
20
EtOH); IR (KBr disc) cmꢀ1: 3436, 3335, 1599, 812; 1H NMR
(400 MHz, CDCl3) d: 0.91 (t, J ¼ 6.8, 3H, CH3), 0.94 (t, J ¼ 7.2, 3H,
CH3), 1.07 (m, 1H, CHH), 1.21–1.70 (m, 11H, CHH, 5CH2), 1.92–2.33
(m, 8H, 4CH2), 2.44 (s, 3H, Ar-CH3), 2.91 (br, 1H, OH), 3.26 (m, 2H,
CH2), 3.38–3.52 (m, 3H, CHH, CH2), 3.83–3.95 (m, 2H, CHH, CH),
4.05 (m, 1H, CH), 4.32 (m, 1H, CH), 7.34 (d, J ¼ 8.0, 2H, Ar-H), 7.70
(d, J ¼ 8.0, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) d14.0, 14.1, 21.6,

Chiral Piperazinones and Sulfamide-Amine Alcohols
2681
23.1, 23.1, 24.1, 25.3, 25.6, 26.1, 35.0, 35.9, 42.6, 55.5, 55.9, 56.2, 65.1,
69.3, 74.4, 79.9, 128.0, 129.9, 132.8, 144.5; HRMS (ESI) m=z: calcd. for
C25H43N2O4S (M þ H)þ 467.2943, found 467.2943.
(2S,20S,40R)-2-(100-Hydroxy-100-phenylbenzyl)-1-[(10-p-tosyl-40-hydro-
xypyrolidin-20-yl)methyl]pyrrolidine 6e
White solid, yield: 70%, mp 214–216 ꢁC, [a]D ¼ ꢀ52.8 (c
20
0.5, CHCl3); IR (KBr disc) cmꢀ1: 3496, 3420, 1598, 814; 1H NMR
(400 MHz, CDCl3) d: 1.38–1.46 (m, 3H CH2CHH), 1.63–1.73 (m,
3H, CH2CHH), 1.87 (m, 1H), 2.01 (t, J ¼ 11.6 Hz, 1H), 2.41 (s,
3H, CH3), 2.57 (m, 1H), 2.82 (dd, J ¼ 11.6, 4.0 Hz, 1H), 2.91
(dd, J ¼ 10.8, 4.8 Hz, 1H), 3.11 (dd, J ¼ 10.8, 4.8 Hz, 1H), 3.19 (m, 1H),
3.58 (m, 1H), 3.98 (dd, J ¼ 8.8, 4.8 Hz, 1H), 4.53 (s, 1H), 7.14 (m, 2H,
Ar-H), 7.25–7.30 (m, 6H, Ar-H), 7.52 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.65
(m, 4H, Ar-H); 13C NMR (100 MHz, CDCl3) d21.6, 24.8, 29.1, 37.9,
55.2, 55.6, 62.3, 69.4, 71.5, 77.9, 125.2 (2 C), 126.0 (2 C), 126.3 (2 C),
127.6 (2 C), 128.1 (4 C), 129.7 (2 C), 134.1, 143.7, 146.2, 147.9; HRMS:
(ESI) m=z: calcd. for C29H35N2O4S (M þ H)þ 507.2314, found 507.2317.
General Procedure for the Addition of Diethylzinc to Benzaldehyde and
Conditions for the Analysis of Chiral Secondary Alcohol
Under a dry argon atmosphere, chiral ligand (0.05 mmol) in dry toluene
(1 mL) was cooled to 0 ꢁC, and a solution of Et2Zn (0.9 M in hexane,
1.1 mL, 1.0 mmol) was added. After the mixture was stirred for 30 min
at 0 ꢁC, freshly distilled aldehyde (0.5 mmol) was added, and the reaction
was stirred for 3 days at room temperature. The reaction mixture was
quenched with saturated aqueous NH4Cl. The aqueous phase was
extracted with ether (3 ꢂ 8 mL). The combined organic phase was washed
with brine, dried with Na2SO4, filtered, and concentrated. The residue
was purified by thin-layer chromatography on silica gel (petroleum
ether=ethyl acetate ¼ 6:1) to give the carbinol. The enantiomeric purity
of the product was determined by HPLC. The absolute configuration
of the product was assigned by comparison to literature values.[29]
Chiral HPLC: Chiralcel OD-H, UV 216 nm, i-PrOH=hexane ¼ 2=100,
flow rate 1.0 mL=min, tR 12.4 min (R-isomer), tR 14.7 min (S-isomer).
ACKNOWLEDGMENT
We are grateful for financial support from the National Natural Science
Foundation of China (Grant 20372059). We also thank Jian-Xun Kang
and Wei-Guo Zhu for the NMR data and Shao-Min Wang for HRMS.

2682
Y.-Q. Fu et al.
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