Facile conversion of 2-azetidinones to 2-piperidones: Application to a formal synthesis of Prosopis and Cassia alkaloids

Article abstract of DOI:10.1016/S0040-4020(03)01063-9

Nonracemic 5,6-disubstituted 2-piperidones were prepared from readily accessible 3,4-disubstituted-2-azetidinones having pre-installed substituents by reductive ring opening of 2-azetidinones followed by stereoselective installation of Z-α,β-unsaturated ester and lactam formation. For the synthetic application to the naturally occurring piperidine alkaloids, such as Prosopis and Cassia alkaloids, 5-hydroxy-2-piperidones (+)-13 and (-)-24 were prepared from 2-azetidinones (-)-6b and (+)-18 via two-carbon ring homologation.

Full text of DOI:10.1016/S0040-4020(03)01063-9

Tetrahedron 59 (2003) 6445–6454
Facile conversion of 2-azetidinones to 2-piperidones: application
to a formal synthesis of Prosopis and Cassia alkaloids
*
Hyeon Kyu Lee, Jong Soo Chun and Chwang Siek Pak
*
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yusung, Taejon 305-606, South Korea
Received 17 May 2003; revised 4 July 2003; accepted 7 July 2003
Abstract—Nonracemic 5,6-disubstituted 2-piperidones were prepared from readily accessible 3,4-disubstituted-2-azetidinones having pre-
installed substituents by reductive ring opening of 2-azetidinones followed by stereoselective installation of Z-a,b-unsaturated ester and
lactam formation. For the synthetic application to the naturally occurring piperidine alkaloids, such as Prosopis and Cassia alkaloids,
5-hydroxy-2-piperidones (þ)-13 and (2)-24 were prepared from 2-azetidinones (2)-6b and (þ)-18 via two-carbon ring homologation.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
been developed.9 There are also many applications of
2-azetidinones as useful chiral building blocks for other
classes of molecules.10 For example, 2-azetidinones were
converted to nonproteogenic amino acids and peptides,10e
and their ring expansion by the action of internal or external
nucleophiles to 2-pyrrolidinones10d were reported. A recent
application include a facile synthesis of sphingosine and
phytosphingosine.10c
A large number of functionalized piperidine alkaloids have
been found in nature and many of them have shown valuable
biological and pharmacological properties.1 For example,
naturally occurring 3-piperidinols with long aliphatic
appendage such as Prosopis (A, B) and Cassia (C, D)
alkaloids (Fig. 1) received increasing attention as medicinal
agents due to a variety of phamacological properties.2
Consequently, the development of efficient synthetic
methods for these alkaloids has been an active area of
research.3–7
We recently reported a new method for preparing
2-piperidones that may serve as versatile intermediates for
asymmetric syntheses of various piperidine and indolizidine
alkaloids starting with readily accessible 2-azetidinones.11
A 2-azetidinone (b-lactam) skeleton is well established as
the key pharmacophore of b-lactam antibiotics, the most
widely employed class of antibacterial agents.8 As a result,
diverse practical methods for preparing 2-azetidinones have
We herein report a full details of the asymmetric synthesis
of nonracemic 2-piperidones and subsequent application to
an efficient formal synthesis of Prosopis and Cassia
alkaloids starting with readily available 2-azetidinones.
Our construction of 2-piperidone involves reductive ring
opening of a 2-azetidinone followed by stereoselective
installation of Z-a,b-unsaturated ester and subsequent
lactam formation (Scheme 1).
Scheme 1.
Figure 1.
2. Results and discussion
Keywords: 2-azetidinone; 2-piperidone; ring homologation; piperidine
alkaloid.
Previous syntheses of the Prosopis alkaloids4a,c,6l,m such as,
(þ)-prosophylline (A) or (þ)-prosopinine (B), utilized
(5S,6R)-5,6-disubstituted-2-piperidinone V as a key
*
Corresponding authors. Tel.: þ82-428-607-016; fax: þ82-428-610-307;
e-mail: leehk@krict.re.kr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01063-9

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H. K. Lee et al. / Tetrahedron 59 (2003) 6445–6454
Scheme 2.
Scheme 4. (a) LiAlH4, THF, 08C, 10 min, (7a: 87%, 7b: 95%); (b) IBX,
DMSO, room temperature, 3 h, (8a: 93%, 8b: 95%); (c) Ph3PvCHCO2Me,
MeOH, room temperature, 12 h, (9a: 87%, E:Z¼1:7, 9b: 81%, E:Z¼1:4);
(d) TMSOTf, 2,6-lutidine, CH2Cl2, 08C, 1 h, then cat. DMAP, toluene,
reflux, 1 h, (10a: 95%, 10b: 89%).
intermediate, whereas (5S,6S)-5,6-disubstituted-2-piperidi-
none VI was used as a key building block for the synthesis
of Cassia alkaloids4a,c such as, (þ)-spectaline (C) and
(2)-prosafrinine (D). We envisaged that these key inter-
mediates 2-piperidinone V and VI could be derived from the
corresponding 3,4-disubstituted 2-azetidinones VII and
VIII via two-carbon ring homologation as shown in Scheme
2. The substitutents and stereochemistry of C-3 and C-4 in
2-azetidinones VII and VIII correspond to C-5 and C-6
substitutents of 2-piperidones.
MeOH16,17 and treated with methyl (triphenylphosphoranyl-
idene)acetate at room temperature to give a 7:1 mixture
of the Z-a,b-unsaturated ester 9a and its E-isomer in
81% overall yield from 7a. These two isomers were
separated by flash chromatography. Finally, removal of
N-Boc protection group of 9a was achieved under mild
conditions (TMSOTf, 2,6-lutidine, CH2Cl2, 08C, 1 h)18
and subsequent cyclization in the presence of catalytic
DMAP in toluene gave 5,6-cis-disubstituted-2-piperi-
done 10a in 95% yield from 9a. Similarly, 5,6-trans-
disubstituted-2-piperidone 10b was also prepared from
the 3,4-trans-N-Boc-2-azetidinone 6b.22
We chose enantiomerically pure 4-formyl-2-azetidinone
2a12,13 as starting material for the preparation of 2-
piperidones V and VI. 4-Formyl-2-azetidinone 2a was
first converted to 4a by reduction of the 4-formyl group and
protection of the resulting alcohol with t-butyldiphenylsilyl
chloride (Scheme 3). Removal of the PMP group in 4a with
CAN and subsequent treatment with (Boc)2O furnished 3,4-
cis-N-Boc-2-azetidinone 6a.
With 2-piperidone (þ)-10b in hand, (þ)-13 was readily
prepared from reduction of the double bond and simple
manipulation of protecting groups: hydrogenation of the
double bond, followed by subsequent desilylation of 10b
with (n-Bu)4NF and benzylation provided tribenzylated
2-piperidinone (þ)-13, a key common intermediate for the
chiral synthesis of Prosopis alkaloids Scheme 5. The
conversion of (^)-13 to (^)-prosopinine was already
elaborated by Stille6l,m and the conversion of (2)-13 to
(2)-prosophylline and (2)-prosopinine was reported by
Momose group.4a,c Thus our synthesis of (þ)-13 constitutes
formal synthesis of (þ)-prosophylline (A) and (þ)-proso-
pinine (B).
Scheme 3. (a) NaBH4, THF-H2O, 08C, 2 h; TBDPSCl, Imidazole, DMF,
room temperature, 24 h; (4a: 90%, 4b: 81%); (b) CAN, CH3CN–H2O, 08C,
30 min; (Boc)2O, cat. DMAP, CH3CN, 4 h (6a: 82%, 6b: 66%); (c) 40%
aq.(CH3)2NH, benzene, room temperature, 48 h, (96%).
3,4-trans-N-Boc-2-Azetidinone (2)-6b was prepared from
the corresponding 3,4-trans-N-PMP-4-formyl-2-azetidi-
none 2b that is prepared by the known, dimethylamine-
induced epimerization14 of 3,4-cis-N-PMP-4-formyl-2-
azetidinone 2a.
Scheme 5. (a) (i) H2, Pd/C, EtOAc, (92%); (ii) (n-Bu)4NF, THF, 08C, 1 h,
(87%); (iii) NaH, BnBr, cat. (n-Bu)4NI, THF, 08C, 2 h, (87%); (b) Refs. 4a,
c,6l,m.
For the synthesis of Cassia alkaloids such as spectaline (C)
and prosafrinine (D), the methyl group in the C-2 position
of the piperidine-3-ol skeleton was required in place of
the hydroxymethyl group as in Prosopis alkaloids. Thus,
N-Boc-4-methyl-2-azetidinone 18 was easily prepared from
the 4-hydroxymethyl-2-azetidinone (þ)-3a as depicted in
Scheme 6. Conversion of the hydroxy group of 3a to iodide
15, followed by hydrogenolysis afforded N-PMP-4-methyl-
2-azetidinone 16. Removal of the PMP protecting group in
16 with CAN and subsequent treatment with (Boc)2O
The cis-N-Boc-2-azetidinone (þ)-6a was next converted to
2-piperidone 10a via two-carbon homologation as shown in
Scheme 4. Thus, treatment of 6a with LiAlH4 in THF at 08C
afforded 3-N-Boc-amino alcohol 7a in 87% yield. Oxidation
of 7a by IBX (2-iodoxybenzoic acid)15 in DMSO at room
temperature cleanly produced pure 3-N-Boc-amino alde-
hyde 8a, which was used for the next step without
further purification. The aldehyde 8a was dissolved in dry

H. K. Lee et al. / Tetrahedron 59 (2003) 6445–6454
6447
3. Experimental
Flash column chromatography was performed on silica gel
(230–400 mesh). THF and Et2O were refluxed over sodium
in the presence of benzophenone and distilled prior to use.
CH2Cl2 was distilled from calcium hydride. DMF, benzene,
CH3CN, MeOH, toluene were dried, distilled, and stored
under nitrogen. All other reagent grade chemicals obtained
from commercial sources were used as received.
Scheme 6. (a) MsCl, Et3N, cat. DMAP, CH2Cl2, 08C, (quant.); (b) NaI,
NaHCO3, DMF, 60–708C, 6 h, (68%); (c) H2, Pd/C, NaHCO3, EtOH, 24 h,
(92%); (d) CAN, CH3CN–H2O, 08C, 30 min (76%); (e) (Boc)2O, cat.
DMAP, CH3CN, 4 h (93%)
3.1. (3R,4S)-1-(4-Methoxyphenyl)-3-benzyloxy-4-
formyl-2-azetidinone (2b)14
furnished N-Boc-4-methyl-2-azetidinone (þ)-18 in good
yield.
A mixture of 2a13 (4.98 g, 16 mmol) and dimethylamine
(40% aq, 40 mL) in benzene (200 mL) was stirred at room
temperature for 48 h. The organic layer was separated and
washed with saturated NaHCO3 (50 mL), brine (50 mL),
and dried with MgSO4 followed by filtration and evapor-
ation of the solvent under reduced pressure afforded crude
product. The crude products were difficult to purify and
directly subjected to NaBH4 reduction in next step without
further purification. Crude yield: 4.77 g (96%); (cis:trans¼
5:95 judged from the cis:trans ratio of reduced alcohols
cis-3a:trans-3b ratio) in next step which were easily
separated by flash chromatography).
N-Boc-4-methyl-2-azetidinone (þ)-18 was then trans-
formed to the corresponding (5S,6S)-5-benzyloxy-6-
methyl-2-piperidone (þ)-22 by the essentially identical
procedure for 6a to 10a. Thus, reduction of the (þ)-18 with
LiAlH4, oxidation of the resulting alcohol by IBX in DMSO
and subsequent treatment of the 3-N-Boc-amino aldehyde
20 with Ph3PvCHCO2Me in dry MeOH produced a 3.5:1
mixture of a,b-unsaturated esters Z- and E-21. After
purification of Z-21 by flash chromatography, removal of
the N-Boc protecting group of Z-21 by TMSOTf and
subsequent cyclization by catalytic DMAP in toluene
afforded the 5-benzyloxy-6-methyl-2-piperidone 22 in
good yield Scheme 7.22
3.2. (1)-(3R,4S)-1-(4-Methoxyphenyl)-3-benzyloxy-4-
hydroxymethyl-2-azetidinone (3a)
To a stirred solution of 2a13 (20.0 g, 64 mmol) in THF–H2O
(9:1, 600 mL) at 08C was added NaBH4 (7.3 g, 190 mmol)
in small portions. The solution was stirred for 2 h at room
temperature before the reaction was quenched by cautious
addition of acetone and saturated NH4Cl solution. THF was
evaporated in vacuo and CH2Cl2 (200 mL) was added and
washed with saturated NaHCO3 (100 mL), brine (100 mL)
and dried (MgSO4). After filtration and evaporation of
solvent in vacuo, the crude product was purified by flash
chromatography (from 1:1 to 1:3 hexane–EtOAc) to afford
the product as a white solid. Yield 18.63 g (93%); mp 112–
1148C; [a]2D1¼þ113.08 (c¼0.5, CH2Cl2); IR (KBr) n 3539,
1725, 1252, 1043 cm21; 1H NMR (300 MHz, CDCl3) d 7.40
(m, 7H), 6.88 (d, 2H, J¼9.15 Hz), 5.03 (d, 1H, J¼11.5 Hz),
4.87 (d, 1H, J¼ 5.1 Hz), 4.78 (d, 1H, J¼11.5 Hz), 4.25 (m,
1H), 4.02 (m, 2H), 3.79 (s, 3H), 2.38 (dd, 1H, J¼5.3,
8.3 Hz); 13C NMR (125 MHz, CDCl3) d 164.06, 156.53,
136.41, 130.47, 128.69, 128.44, 128.21, 118.79, 114.48,
80.88, 73.69, 59.43, 57.67, 55.48; MS m/z 313 (Mþ), 256,
149, 134, 91; HRMS (EI) calcd for C18H19NO4 313.1314,
found 313.1309.
Scheme 7. (a) (i) LiAlH4, THF, 08C, 10 min, (87%), (ii) IBX, DMSO, room
temperature, 3 h, (95%); (b) Ph3PvCHCO2Me, MeOH, room temperature,
12 h, (98%, E:Z¼1:3.5); (c) TMSOTf, 2,6-lutidine, CH2Cl2, 08C, 1 h, then
cat. DMAP, toluene, reflux, 1 h, (85%); (d) (i) BnBr, NaH (87%); (ii) H2-
Pd/C, EtOAc, room temperature, (99%); (e) Ref. 4a.
Finally, reduction of the double bond and N-benzylation at
nitrogen of 22 provided (2)-24, a key intermediate for the
chiral synthesis of Cassia alkaloids. The spectroscopic data
of (2)-24 were identical in every respect to the literature
values.4a Since (2)-24 was previously converted to (þ)-
spectaline and (þ)-prosafrinine by Momose,4a the present
work represents formal syntheses of (þ)-spectaline (C) and
(þ)-prosafrinine (D).
3.3. (2)-(3R,4R)-1-(4-Methoxyphenyl)-3-benzyloxy-4-
hydroxymethyl-2-azetidinone (3b)
Since the enantiomers of 2-azetidinones (2)-6b and (þ)-3a
are available by literature methods,20,21 2-piperidones
(2)-13 and (þ)-24 can be prepared from 2-azetidinones
(þ)-6b and (2)-3a by the same procedure of the present
work for the synthesis of antipodal Prosopis and Cassia
alkaloids.
Crude 2b was subjected to NaBH4 reduction in THF–H2O
(9:1) via essentially the same procedure for 3a affording a
mixture of cis-3a and trans-3b alcohols which were
separated by flash chromatography (4:1 hexane–EtOAc).
Yield 90%, cis-3a:trans-3b¼5:95); [a]2D2¼22.88 (c¼1.56,
In summary, we have developed a convenient method for
the conversion of 2-azetidinones to 2-piperidones via two-
carbon ring homologation. This methodology was success-
fully applied to the synthesis of naturally occurring Prosopis
and Cassia alkaloids.
CHCl3); IR (NaCl) n 3441, 1753, 1249, 1032 cm21; H
1
NMR (300 MHz, CDCl3) d 7.39 (m, 5H), 7.33 (d, 2H,
J¼8.94 Hz), 6.87 (d, 2H, J¼8.95 Hz), 4.92 (d, 1H, J¼
11.8 Hz), 4.76 (d, 1H, J¼1.6 Hz), 4.67 (d, 1H, J¼11.8 Hz),

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H. K. Lee et al. / Tetrahedron 59 (2003) 6445–6454
4.01 (dd, 1H, J¼1.6, 2.8 Hz), 3.93 (d, 1H, J¼3.6 Hz), 3.79
(d, 1H, J¼1.6 Hz), 3.78 (s, 3H), 3.74 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 196.67, 163.99, 161.92, 156.56,
136.97, 130.06, 128.78, 128.52, 128.42, 119.40, 119.21,
118.36, 114.51, 114.47, 83.075, 82.74, 72.77, 66.00, 61.62,
59.08, 55.39; MS m/z 313 (Mþ), 254, 164, 149, 134, 123;
HRMS (EI) calcd for C18H19NO4 313.1314, found
313.1310.
extracted again with EtOAc (100 mL), and all organic layers
were combined and washed with 10% NaHSO3
(3£300 mL), NaHCO3 (100 mL), brine (100 mL), and
dried over MgSO4. After filtration and evaporation of
solvents in vacuo, the crude product was purified by flash
chromatography (from 3:1 to 1:2 hexane–EtOAc) to afford
the product as a yellow oil. Yield 10.0 g (86%);
[a]2D2¼220.08 (c¼0.23, CHCl3); IR (NaCl) n 3270,
1
1765 cm21; H NMR (300 MHz, CDCl3) d 7.65 (m, 5H),
3.4. (1)-(3R,4S)-1-(4-Methoxyphenyl)-3-benzyloxy-4-
(t-butyldiphenylsilyloxymethyl)-2-azetidinone (4a)
7.40 (m, 10H), 5.98 (br s, 1H), 4.76 (d, 1H, J¼11.8 Hz),
4.69 (d, 1H, J¼2.2 Hz), 4.63 (d, 1H, J¼11.8 Hz), 3.83 (m,
3H), 1.05 (s, 9H); 13C NMR (125 MHz, CDCl3) d 168.29,
136.85, 135.51, 133.12, 133.09, 129.90, 129.85, 128.42,
128.00, 127.95, 127.83, 127.79, 82.10, 73.16, 63.57, 60.39,
55.63, 26.80, 21.04, 19.16, 14.18; MS m/z 360 (Mþ285),
192, 177, 162, 135, 91; HRMS (CI, methane) calcd for
C27H31NO3Si 446.2151 (MHþ), found 446.2149.
A mixture of 3a (5.2 g, 16.6 mmol), imidazole (3.4 g,
49.8 mmol), TBDPS-Cl (5.18 mL, 19.92 mmol), and
DMAP (0.2 g, 1.6 mmol) in dry DMF (30 mL) was stirred
at room temperature for 24 h. The reaction mixture was
quenched by addition of water (100 mL) and extracted with
Et2O (2£100 mL). Combined organic layer was washed
with water, saturated NaHCO3, and brine. After drying
(MgSO4), filtration, and evaporation of solvent the crude
product was purified by flash column chromatography (from
10:1 to 5:1 hexane–EtOAc) to afford the product as white
solid. Yield 8.9 g (97%); mp 62–638C; [a]2D2¼þ22.58
(c¼1.12, CHCl3); IR (NaCl) n 1770, 1382 cm21; 1H NMR
(300 MHz, CDCl3) d 7.63 (m, 5H), 7.39 (m, 10H), 7.24 (d,
2H, J¼9.05 Hz), 6.74 (d, 2H, J¼9.15 Hz), 4.80 (m, 3H),
4.23 (dd, 1H, J¼4.9, 10.3 Hz), 4.09 (dd, 1H, J¼5.5,
11.4 Hz), 3.94 (dd, 1H, J¼4.9, 11.5 Hz), 3.76 (s, 3H),
1.05 (s, 9H); 13C NMR (125 MHz, CDCl3) d 164.29,
156.18, 136.94, 135.66, 135.55, 132.87, 132.69, 130.74,
129.85, 129.80, 128.40, 127.97, 127.95, 127.79, 127.77,
118.75, 114.16, 80.55, 73.23, 60.86, 59.25, 55.42, 26.72,
19.05, 14.16; MS m/z 551 (Mþ), 466, 346, 177, 135, 91;
HRMS (EI) calcd for C34H37NO4Si 551.2491, found
551.2484.
3.7. (1)-(3R,4R)-3-Benzyloxy-4-(t-butyldiphenyl-
silyloxymethyl)-2-azetidinone (5b)
Prepared from 4b and (NH4)2Ce(NO3)6 in CH3CN–H2O via
essentially the same procedure for 5a. Yield: 72%; mp 106–
1088C; [a]2D1¼ þ36.438 (c¼1.01, CHCl3); IR (KBr) n 3270,
1
1765 cm21; H NMR (300 MHz, CDCl3) d 7.56 (m, 5H),
7.32 (m, 10H), 5.76 (br s, 1H), 4.80 (d, 1H, J¼11.6 Hz),
4.59 (d, 1H, J¼ 11.6 Hz), 4.53 (t, 1H, J¼1.63 Hz), 3.64 (m,
3H), 1.04 (s, 9H); 13C NMR (125 MHz, CDCl3) d 167.04,
136.89, 135.52, 132.83, 129.99, 128.48, 128.11, 127.85,
83.69, 72.55, 63.35, 57.87, 26.76, 19.16; MS m/z 359
(Mþ286), 289, 259, 180, 162, 135; HRMS (CI, methane)
calcd for C27H31NO3Si 446.2151 (MHþ), found 446.2144.
3.8. (1)-(3R,4S)-1-(t-Butyloxycarbonyl)-3-benzyloxy-4-
(t-butyldiphenylsilyloxymethyl)-2-azetidinone (6a)
3.5. (2)-(3R,4R)-1-(4-Methoxyphenyl)-3-benzyloxy-4-
(t-butyldiphenylsilyloxymethyl)-2-azetidinone (4b)
To a solution of 5a (2.1 g, 4.71 mmol) and di-tert-butyl
dicarbonate (1.13 g, 5.18 mmol) in dry CH3CN (20 mL)
was added DMAP (0.03 g, 0.24 mmol) and stirred at room
temperature for 4 h. After completion of the reaction
CH3CN was evaporated in vacuo and CH2Cl2 (20 mL)
was added and washed with saturated NaHCO3 (10 mL),
brine (10 mL) and dried (MgSO4). After filtration and
evaporation of solvent, the crude product was purified by
flash chromatography (7:1 hexane–EtOAc) to afford the
product as a colorless oil. Yield 2.44 g (95%); [a]2D2¼
þ13.18 (c¼0.55, CHCl3); IR (NaCl) n 1722, 1369,
Prepared from 3b, TBDPS-Cl, and imidazole with catalytic
DMAP in dry DMF via essentially the same procedure for
4a. Yield 90%; [a]2D1¼25.28 (c¼0.62, CHCl3); IR (NaCl) n
1753, 1392, 1248 cm21; 1H NMR (300 MHz, CDCl3) d 7.52
(m, 2H), 7.36 (m, 15H), 6.83 (d, 2H, J¼9.13 Hz), 4.89 (d,
1H, J¼11.6 Hz), 4.84 (m, 1H), 4.67 (d, 1H, J¼11.6 Hz),
3.97 (m, 2H), 3.80 (s, 3H), 3.70 (m, 1H), 0.96 (s, 9H); 13C
NMR (125 MHz, CDCl3) d 163.71, 156.42, 137.06, 135.48,
132.69, 132.15, 130.18, 129.88, 128.52, 128.25, 128.16,
127.80, 127.63, 119.31, 114.38, 82.44, 72.81, 61.38, 59.73,
55.48, 26.60, 19.06; MS m/z 551 (Mþ), 466, 346, 177, 135;
HRMS (EI) calcd for C34H37NO4Si 551.2491, found
551.2489.
1
1153 cm21; H NMR (300 MHz, CDCl3) d 7.64 (m, 5H),
7.32 (m, 10H), 4.87 (d, 1H, J¼11.6 Hz), 4.75 (d, 1H, J¼
11.8 Hz), 4.73 (d, 1H, J¼4.9 Hz), 4.14 (m, 2H), 3.94 (m,
1H), 1.44 (s, 9H), 1.03 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 165.26, 147.98, 136.62, 135.68, 135.54, 132.97,
132.83, 129.61, 128.42, 128.23, 128.07, 127.60, 127.56,
127.15, 83.24, 80.21, 73.59, 60.34, 58.55, 57.86, 27.90,
26.55, 21.00, 19.10, 14.15; MS m/z 545 (Mþ), 508, 490,
462, 404, 388, 282, 236, 177, 91; HRMS (CI, methane)
calcd for C32H39NO5Si 546.2675 (MHþ), found 546.2673.
3.6. (2)-(3R,4S)-3-Benzyloxy-4-(t-butyldiphenyl-
silyloxymethyl)-2-azetidinone (5a)
A solution of (NH4)2Ce(NO3)6 (42.9 g, 78.2 mmol) in water
(250 mL) was added dropwise to a solution of 4a (14.4 g,
26.1 mmol) in CH3CN (240 mL) at 08C. The mixture was
stirred at this temperature for 30 min. Then, water (400 mL)
was added, and this mixture was extracted with EtOAc
(3£200 mL) and washed with a saturated solution of
NaHCO3 (350 mL). The aqueous layer of NaHCO3 was
3.9. (2)-(3R,4R)-1-(t-Butyloxycarbonyl)-3-benzyloxy-4-
(t-butyldiphenylsilyloxymethyl)-2-azetidinone (6b)
Prepared from 5b and di-tert-butyl dicarbonate with
catalytic DMAP in dry CH3CN via essentially the same

H. K. Lee et al. / Tetrahedron 59 (2003) 6445–6454
6449
procedure for 6a. Yield 92%; [a]2D2¼218.58 (c¼0.54,
extrcacted with Et2O (3£30 mL). The combined organic
layers were washed with saturated NaHCO3 and brine, and
dried (MgSO4) and evaporated in vacuo. The crude
aldehyde was pure enough to used in next step without
further purification. Yield 2.49 g (93%); IR (NaCl) n 3441,
CHCl3); IR (NaCl) n 1723, 1149 cm21
;
1H NMR
(300 MHz, CDCl3) d 7.54 (m, 5H), 7.32 (m, 10H), 4.84
(d, 1H, J¼11.6 Hz), 4.76 (d, 1H, J¼2.2 Hz), 4.60 (d, 1H,
J¼11.6 Hz), 4.04 (dd, 1H, J¼3.6, 11.3 Hz), 3.86 (dd, 1H,
J¼1.02, 2.2 Hz), 3.69 (tt, 1H, J¼1.02, 11.2 Hz), 1.46 (s,
9H), 1.05 (s, 9H); 13C NMR (125 MHz, CDCl3) d 171.14,
164.40, 148.12, 136.58, 135.49, 132.75, 129.92, 128.54,
128.22, 127.83, 83.39, 81.88, 72.91, 60.79, 59.72, 27.92,
26.70, 21.02, 19.24; MS m/z 433 (Mþ2112), 404, 345, 282,
177; HRMS (CI, methane) calcd for C32H39NO5Si 546.2675
(MHþ), found 546.2682.
1
2858, 1720, 1378 cm21; H NMR (300 MHz, CDCl3) d
9.77 (s, 1H), 7.64 (m, 5H), 7.35 (m, 10H), 4.94 (d, 1H,
J¼9.16 Hz), 4.74 (d, 1H, J¼11.4 Hz), 4.51 (d, 1H, J¼
11.4 Hz), 4.25 (m, 2H), 3.85 (dd, 1H, J¼4.17, 9.56 Hz),
3.65 (m, 1H), 1.39 (s, 9H), 1.04 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 202.01, 155.38, 135.52, 134.77,
129.86, 129.75, 128.49, 127.81, 81.74, 79.83, 61.87,
28.25, 26.67, 19.16; MS m/z 474 (Mþ273), 434, 342,
240, 199, 162, 135, 91, 57; HRMS (CI, methane) calcd for
C32H41NO5Si 548.2832 (MHþ), found 548.2839.
3.10. (2)-(2R,3S)-2-Benzyloxy-3-(t-butyloxycarbonyl)-
amino-4-(t-butyldiphenylsilyloxymethyl)butan-1-ol (7a)
To a suspension of LiAlH4 (0.15 g, 4.09 mmol) in THF
(10 mL) was added dropwise a solution of 6a (2.23 g,
4.09 mmol) in THF (10 mL) at 08C. After stirring at that
temperature for 20 min, ice-water (20 mL) and Rochelle salt
(20 mL) was added and the reaction mixture was stirred for
additional 1 h. The reaction mixture was extracted with
CH2Cl2 (3£30 mL) and washed with NaHCO3 and brine
and dried (MgSO4). After filtration and evaporation of
solvent in vacuo, the crude product was purified by flash
column chromatograph (from 7:1 to 2:1 hexane–EtOAc) to
afford the product as colorless oil. Yield 1.96 g (87%);
[a]2D2¼215.88 (c¼0.82, CHCl3); IR (NaCl) n 3444, 1366,
3.13. (2R,3R)-2-Benzyloxy-3-(t-butyloxycarbonyl)-
amino-4-(t-butyldiphenylsilyloxymethyl)butanal (8b)
Prepared from 7b and 2-iodoxybenzoic acid in DMSO via
essentially the same procedure for 8a. Yield 95%; IR (NaCl)
;
n 3446, 2858, 1715, 1113 cm21 1H NMR (300 MHz,
CDCl3) d 9.70 (s, 1H), 7.61 (m, 5H), 7.33 (m, 10H), 4.78 (m,
1H), 4.75 (d, 1H, J¼11.4 Hz), 4.53 (d, 1H, J¼11.4 Hz), 4.16
(br s, 1H), 3.92 (dd, 1H, J¼2.2 Hz), 3.74 (m, 2H), 1.39 (s,
9H), 1.04 (s, 9H); 13C NMR (125 MHz, CDCl3) d 200.97,
155.00, 135.57, 132.58, 129.83, 128.55, 128.17, 128.02,
127.81, 127.77, 83.39, 73.28, 61.84, 52.19, 40.96, 28.24,
26.77, 19.13; MS m/z 547 (Mþ), 492, 474, 434, 342, 204;
HRMS (CI, methane) calcd for C32H41NO5Si 548.2832
(MHþ), found 548.2864.
1
1112, 1056 cm21; H NMR (300 MHz, CDCl3) d 7.65 (m,
5H), 7.39 (m, 10H), 4.59 (d, 1H), 4.57 (d, 1H, J¼11.4 Hz),
4.46 (d, 1H, J¼11.4 Hz), 4.05 (m, 1H), 3.75 (m, 4H), 3.51
(m, 1H), 3.23 (m, 1H), 1.41 (s, 9H), 1.06 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 171.15, 156.98, 138.02, 135.60, 135.57,
133.16, 133.00, 129.83, 129.80, 128.40, 127.82, 127.79,
127.76, 102.19, 79.95, 77.54, 73.07, 62.76, 60.61, 60.38,
52.01, 28.25, 26.83, 19.18, 14.18; MS m/z 436 (Mþ2113),
314, 240, 199, 162, 135, 105; HRMS (CI, methane) calcd for
C32H43NO5Si 550.2988 (MHþ), found 550.3017.
3.14. Methyl (4S,5S)-4-benzyloxy-5-(t-butyloxycarbonyl)-
amino-6-(t-butyldiphenylsilyloxy)-2-hexenoate (E and
Z-9a)
To a solution of 8a (2.37 g, 4.33 mmol) in dry methanol
(40 mL) was added Ph3PvCHCO2Me (1.74 g, 5.19 mmol)
and stirred for 12 h at room temperature. After the reaction
mixture was evaporated in vacuo, crude reaction product
was separated to pure E and Z isomers by flash
chromatography (from 15:1 to 7:1 hexane–EtOAc). Yield
2.27 g (87%, E:Z¼1:7).
3.11. (1)-(2R,3R)-2-Benzyloxy-3-(t-butyloxycarbonyl)-
amino-4-(t-butyldiphenylsilyloxymethyl)butan-1-ol (7b)
Prepared from 6b and LiAlH4 in dry THF via essentially the
same procedure for 6a as colorless oil. Yield 95%;
[a]2D2¼þ6.58 (c¼1.5, CHCl3); IR (NaCl) n 3444, 1366,
E-isomer (E-9a): [a]2D2¼23.98 (c¼0.96, CHCl3); IR (NaCl)
1
1113, 1064 cm21; H NMR (300 MHz, CDCl3) d 7.61 (m,
n 3447, 1723, 1366, 1112 cm21 1H NMR (300 MHz,
;
5H), 7.27 (m, 10H), 5.03 (d, 1H, J¼8.95 Hz), 4.70 (d, 1H,
J¼11.6 Hz), 4.51 (d, 1H, J¼11.4 Hz), 4.11 (m, 1H), 3.81
(m, 3H), 3.65 (m, 1H), 3.54 (m, 1H), 3.34 (m, 1H), 1.44 (s,
9H), 1.08 (s, 9H); 13C NMR (125 MHz, CDCl3) d 156.63,
138.04, 135.55, 132.83, 129.92, 128.34, 127.84, 127.61,
108.14, 80.11, 78.04, 71.53, 62.75, 59.75, 51.12, 28.31,
26.94, 19.31; MS m/z 540 (Mþ29), 476, 436, 314; HRMS
(CI, methane) calcd for C32H43NO5Si 550.2988 (MHþ),
found 550.2995.
CDCl3) d 7.62 (m, 5H), 7.32 (m, 10H), 6.96 (dd, 1H, J¼5.1,
15.8 Hz), 6.08 (dd, 1H, J¼1.2, 15.8 Hz), 4.74 (d, 1H, J¼
9.7 Hz), 4.56 (d, 1H, J¼11.4 Hz), 4.44 (m, 1H), 4.34 (d, 1H,
J¼11.4 Hz), 3.93 (m, 1H), 3.74 (s, 3H), 3.68 (m, 2H), 1.38
(s, 9H), 1.04 (s, 9H); 13C NMR (125 MHz, CDCl3) d 166.21,
155.35, 145.55, 135.44, 133.07, 129.71, 128.31, 127.70,
122.74, 79.36, 71.75, 62.19, 54.42, 51.53, 28.16, 26.74,
19.10, 14.10; MS m/z 604 (Mþþ1), 530, 504, 490, 446, 368,
342, 264, 240; HRMS (CI, methane) calcd for C35H45NO6Si
604.3094 (MHþ), found 604.3079.
3.12. (2R,3S)-2-Benzyloxy-3-(t-butyloxycarbonyl)amino-
4-(t-butyldiphenylsilyloxymethyl)butanal (8a)
Z-isomer (Z-9a): [a]2D1¼þ6.58 (c¼1.23, CHCl3); IR (NaCl)
n 3448, 1722, 1365, 1112 cm21 1H NMR (300 MHz,
;
2-Iodoxybenzoic acid (IBX, 2.05 g, 7.33 mmol) was added
to a solution of 7a (2.69 g, 4.88 mmol) in DMSO (20 mL).
After stirring at room temperature for 3 h, the reaction
mixture was diluted with water (40 mL), filtered, and
CDCl3) d 7.67 (m, 5H), 7.32 (m, 10H), 6.28 (dd, 1H, J¼8.9,
11.8 Hz), 5.99 (dd, 1H, J¼1.0, 11.8 Hz), 5.45 (dd, 1H,
J¼ 8.7, 10.1 Hz), 4.82 (d, 1H, J¼9.9 Hz), 4.52 (d, 1H,
J¼ 11.4 Hz), 4.39 (d, 1H, J¼11.4 Hz), 4.06 (m, 1H), 3.79

6450
H. K. Lee et al. / Tetrahedron 59 (2003) 6445–6454
(m, 2H), 3.70 (s, 3H),1.39 (s, 9H), 1.06 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 165.78, 155.41, 147.11, 138.07,
135.55, 133.33, 133.29, 129.56, 128.20, 127.94, 127.60,
127.56, 122.44, 79.07, 72.77, 71.42, 62.92, 60.28, 55.25,
51.32, 28.28, 28.13, 26.74, 20.95, 19.18, 14.12; MS m/z 604
(Mþþ1), 504, 490, 342, 240, 194, 162; HRMS (CI, methane)
calcd for C35H45NO6Si 604.3094 (MHþ), found 604.3095.
J¼4.49, 9.97 Hz), 6.06 (dd, 1H, J¼2.2, 10.0 Hz), 5.91 (br s,
1H), 4.50 (d, 1H, J¼11.7 Hz), 4.40 (d, 1H, J¼11.7 Hz), 4.07
(t, 1H, J¼4.56 Hz), 3.95 (t, 1H, J¼9.61 Hz), 3.85 (dd, 1H,
J¼4.26, 10.33 Hz), 3.75 (m, 1H), 1.08 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 164.54, 138.73, 137.28, 135.41,
132.77, 129.83, 128.33, 127.78, 127.53, 127.06, 70.84,
68.06, 62.50, 60.26, 55.81, 26.71, 19.05, 14.09; MS m/z 471
(Mþ), 414, 306, 246, 218, 91; HRMS (CI, methane) calcd
for C29H33NO3Si 472.2307 (MHþ), found 472.2331.
3.15. Methyl (4S,5R)-4-benzyloxy-5-(t-butyloxycarbonyl)-
amino-6-(t-butyldiphenylsilyloxy)-2-hexenoate (E and
Z-9b)
3.17. (1)-(5S,6R)-5-Benzyloxy-6-(t-butyldiphenyl-
silyloxymethyl)-1,2,5,6-tetrahydro-2-pyridinone (10b)
Prepared from 8b and Ph3PvCHCO2Me in dry methanol
via essentially the same procedure for 9a. Yield 81%,
E:Z¼1:4.
Prepared from Z-9b, TMSOTf and 2,6-lutidine in CH2Cl2
and subsequent DMAP catalyzed cyclization in refluxing
toluene via essentially the same procedure for 10a. Yield
89%; [a]2D2¼þ34.78 (c¼1.13, CHCl3); IR (NaCl) n 3213,
1686, 1620, 1112 cm21; 1H NMR (300 MHz, CDCl3) d 7.60
(m, 5H), 7.26 (m, 10H), 6.57 (dd, 1H, J¼2.8, 10.2 Hz), 5.95
(dd, 1H, J¼1.6, 9.9 Hz), 5.74 (br s, 1H), 4.58 (d, 1H, J¼
11.8 Hz), 4.43 (d, 1H, J¼11.6 Hz), 4.09 (m, 1H), 3.76 (m,
2H), 3.72 (d, 1H, J¼4.5 Hz), 1.05 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 164.47, 145.72, 140.09, 137.07,
135.52, 132.62, 130.14, 128.50, 127.88, 127.78, 127.71,
124.94, 71.16, 70.79, 56.09, 26.82, 19.14; MS m/z 472
(Mþþ1), 414, 380, 368, 298, 278; HRMS (CI, methane)
calcd for C29H33NO3Si 472.2307 (MHþ), found 472.2314.
E-isomer (E-9b): [a]2D2¼24.98 (c¼0.9, CHCl3); IR (NaCl) n
3449, 1722, 1383, 1112 cm21; 1H NMR (300 MHz, CDCl3)
d 7.60 (m, 5H), 7.25 (m, 10H), 6.90 (dd, 1H, J¼6.7,
15.8 Hz), 6.05 (d, 1H, J¼15.8 Hz), 4.77 (d, 1H, J¼9.16 Hz),
4.58 (d, 1H, J¼11.4 Hz), 4.35 (d, 1H, J¼11.4 Hz), 4.20 (d,
1H, J¼6.10 Hz), 3.92 (m, 1H), 3.73 (s, 3H), 3.69 (m, 1H),
1.40 (s, 9H), 1.05 (s, 9H); 13C NMR (125 MHz, CDCl3) d
166.12, 155.23, 145.63, 137.59, 135.55, 132.96, 129.81,
128.38, 127.77, 127.63, 123.60, 79.45, 78.23, 71.60, 62.60,
60.39, 54.47, 51.59, 28.26, 26.86, 19.24; MS m/z 604
(Mþþ1), 548, 504, 490, 342; HRMS (CI, methane) calcd for
C35H45NO6Si 604.3094 (MHþ), found 604.3092.
3.18. (1)-(5S,6R)-5-(Benzyloxy)-6-(t-butyldiphenylsilyl-
oxymethyl)-2-piperidinone (11)
Z-isomer (Z-9b): [a]2D1¼þ3.18 (c¼1.34, CHCl3); IR (NaCl)
n 3447, 1745, 1366, 1112 cm21 1H NMR (300 MHz,
;
CDCl3) d 7.65 (m, 5H), 7.25 (m, 10H), 6.24 (dd, 1H, J¼8.9,
11.6 Hz), 6.02 (d, 1H, J¼11.8 Hz), 5.36 (t, 1H, J¼8.9 Hz),
5.19 (d, 1H, J¼9.97 Hz), 4.55 (d, 1H, J¼11.4 Hz), 4.43 (d,
1H, J¼11.4 Hz), 4.05 (br s, 1H), 3.80 (m, 2H), 3.75 (s,
3H),1.39 (s, 9H), 1.09 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 166.64, 155.58, 148.83, 138.01, 135.62, 133.31, 129.64,
128.30, 127.67, 127.59, 123.04, 108.26, 78.99, 73.88, 71.93,
62.60, 54.74, 51.45, 28.35, 26.87, 19.38; MS m/z 604
(Mþþ1), 530, 504, 490, 342, 240; HRMS (CI, methane)
calcd for C35H45NO6Si 604.3094 (MHþ), found 604.3099.
A mixture of 10b (472 mg, 1 mmol) and 10% palladium on
carbon (10% w/w) in EtOAc (10 mL) was stirred under an
atmosphere of H2 for 1 h. After filtration over Celite and
concentration in vacuo, the crude product was purified by
silica gel column chromatography. Yield: 436 mg (92%); Rf
0.1 (hexane–EtOAc 1:1); [a]2D0¼þ20.758 (c¼0.54, CHCl3);
1H NMR (500 MHz, CDCl3) d 7.61 (m, 4H), 7.45 (m, 2H),
7.40 (m, 4H), 7.27 (m, 3H), 7.17 (m, 2H), 5.9 (broad-s, 1H),
4.56 (d, 1H, J¼11.8 Hz), 4.38 (d, 1H, J¼11.8 Hz), 3.75 (dd,
1H, J¼4, 9.95 Hz), 3.56 (m, 1H), 3.49 (m, 2H), 2.54 (m, 1H),
2.27 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.04 (s, 9H); 13C
NMR (125 MHz, CDCl3) d 171.12, 137.65, 135.55, 135.49,
132.74, 132.65, 129.98, 129.94, 128.43, 127.88, 127.86,
127.80, 127.48, 71.90, 70.67, 65.46, 58.38, 28.16, 26.80,
23.96, 19.14; MS m/z 418, 416, 248, 199, 135; HRMS (EI)
calcd for C29H33NO3Si 473.2386, found 473.2383.
IR (KBr) n 3209, 3070, 2931, 2858, 1669, 1428, 1113 cm21
;
3.16. (1)-(5S,6S)-5-Benzyloxy-6-(t-butyldiphenyl-
silyloxymethyl)-1,2,5,6-tetrahydro-2-pyridinone (10a)
To a solution of Z-9a (1.83 g, 2.95 mmol) and 2,6-lutidine
(0.63 g, 5.95 mmol) in CH2Cl2 (30 mL) was added
TMSOTf (0.82 mL, 4.43 mmol) dropwise at 08C and stirred
for 1 h. The reaction mixture was quenched by addition of
saturated NaHCO3 solution (30 mL) and the organic layer
was separated and dried over MgSO4. After filtration and
evaporation of the solvent in vacuo, the resulting oil was
dissolved in toluene (20 mL) and DMAP (0.01 g,
0.09 mmol) was added, and the reaction mixture was
refluxed for 1 h. The reaction mixture was cooled to room
temperature and washed with 1N HCl solution, saturated
NaHCO3 (20 mL), and brine (20 mL) successively. After
drying (MgSO4) and evaporation of the solvent in vacuo the
crude product was purified by flash chromatography (from
3:1 to 1:1 hexane–EtOAc) to give the product as a colorless
oil. Yield 1.32 g (95%); [a]2D2¼þ109.28 (c¼1.31, CHCl3);
IR (NaCl) n 3220, 1684, 1618, 1112 cm21 1H NMR
;
3.19. (1)-(5S,6R)-1-Benzyl-5-(benzyloxy)-6-(benzyloxy-
methyl)hexahydro-2-pyridinone (13)
To a solution of 11 (362 mg, 0.77 mmol) in THF (5 mL) was
added (n-Bu)4NF (1.14 mL of 1 M solution in THF,
1.15 mmol) at 08C. The reaction mixture was stirred for
1 h at room temperature, quenched with aqueous NaHCO3,
and extracted with EtOAc (3£5 mL). The combined organic
layers were washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane–
EtOAc 1:3) to give (5S,6R)-5-(benzyloxy)-6-(hydroxy-
methyl)-2-piperidinone (12) as a colorless oil. [Yield:
158 mg (87%); Rf 0.2 (hexane–EtOAc 1:3)] To a slurry
(300 MHz, CDCl3) d 7.65–7.16 (m, 15H), 6.61 (dd, 1H,

H. K. Lee et al. / Tetrahedron 59 (2003) 6445–6454
6451
of 60% NaH (110 mg, 2.75 mmol) in THF (5 mL) was
added a solution of 12 (158 mg, 0.68 mmol) in THF (5 mL)
at 08C. After stirring for 10 min at this temperature, benzyl
bromide (0.32 mL, 2.75 mmol) and (n-Bu)4NI (10 mg,
0.027 mmol) was added. The reaction mixture was stirred
for 2 h at room temperature and quenched with saturated
NH4Cl (10 mL) at 08C. The aqueous layer was extracted
with EtOAc (3£10 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by column chromatog-
raphy on silica gel (from 1:1 to 1:2 hexane–EtOAc) to give
13 as a colorless oil. Yield 245 mg (87%); Rf 0.1 (hexane–
EtOAc 1:1). [a]D20¼þ45.88 (c¼0.85, CHCl3) [lit.19
[a]2D0¼þ48.68 (c¼1.2, CHCl3), lit.4a [a]2D6¼246.78
(c¼3.32, CHCl3) for (2)-13]; IR (NaCl) n 3062, 3030,
temperature. Et2O (20 mL) was added. The layers were
washed with water and brine, dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (7:1 hexane–EtOAc) to give 15 as
a colorless oil. Yield 228 mg (68%); Rf 0.67 (hexane–
EtOAc 2:1). [a]2D1¼ þ107.88 (c¼3.68, CHCl3); IR (NaCl) n
1754, 1511, 1384, 1247, 1124, 1031 cm21 1H NMR
;
(500 MHz, CDCl3) d 7.47–7.29 (m, 7H), 6.88–6.86 (m,
2H), 4.91 (s, 2H), 4.80 (d, 1H, J¼4.8 Hz), 4.52 (ddd, 1H,
J¼2.7, 4.8, 10.1 Hz), 3.77 (s, 3H), 3.49 (dd, 1H, J¼2.7,
10.1 Hz), 3.40 (t, 1H, J¼ 10.1 Hz); 13C NMR (125 MHz,
CDCl3) d 163.91, 156.68, 136.86, 129.61, 128.46, 128.06,
127.90, 118.70, 114.60, 80.89, 74.14, 59.04, 55.48; MS m/z
423 (Mþ), 366, 268, 239, 177, 149, 133, 117, 91; HRMS
(EI) calcd for C18H18NO3I 423.0331, found 423.0329.
1
2926, 1641, 1452 cm21; H NMR (500 MHz, CDCl3) d
7.37–7.18 (m, 15H), 5.36 (d, 1H, J¼14.0 Hz), 4.44 (d, 1H,
J¼12.0 Hz), 4.40 (d, 1H, J¼11.75 Hz), 4.37 (d, 1H,
J¼11.75 Hz), 4.29 (d, 1H, J¼11.75 Hz), 4.01 (d, 1H,
J¼15.3 Hz), 3.86 (q, 1H, J¼3.25 Hz), 3.66 (q, 1H, J¼
3.2 Hz), 3.55 (dd, 1H, J¼4.0, 9.9 Hz), 3.42 (dd, 1H, J¼7.1,
9.9 Hz), 2.69 (ddd, 1H, J¼9.5, 10.2, 18.05 Hz), 2.41 (ddd,
1H, J¼3.95, 5.9, 17.85 Hz), 2.03–1.98 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 170.21, 138.03, 137.52, 137.22,
128.48, 128.43, 128.27, 127.88, 127.77, 127.59, 127.51,
127.29, 127.09, 73.26, 71.97, 70.00, 69.34, 58.55, 47.89,
27.41, 22.38; MS m/z 415 (Mþ), 324, 294, 181, 105, 91, 65;
HRMS (EI) calcd for C27H29NO3 415.2147, found
415.2143.
3.22. (1)-(3R,4S)-1-(p-Anisyl)-4-methyl-3-(benzyloxy)-2-
azetidinone (16)
A mixture of 15 (54 mg, 0.127 mmol), 10% palladium on
carbon (27 mg, 50% w/w), and NaHCO3 (162 mg,
1.91 mmol) in EtOH (6 mL) was shaken for 2 h under
50 psi hydrogen pressure using Parr hydrogenator. The
mixture was filtered over Celite, and the filtrate was
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane–
EtOAc 7:1) to give 16 as a white solid. Yield 105 mg (92%);
Rf 0.28 (hexane–EtOAc 5:1); mp 110–1118C; [a]2D1¼
þ116.88 (c¼1.61, CHCl3); IR (KBr) n 1743, 1517, 1394,
1
1251, 1143, 1033 cm21; H NMR (300 MHz, CDCl3) d
3.20. (1)-(3R,4S)-1-(p-Anisyl)-4-(methanesulfonyl-
oxymethyl)-3-(benzyloxy)-2-azetidinone (14)
7.41–7.31 (m, 7H), 6.88–6.85 (m, 2H), 4.88 (d, 1H,
J¼11.8 Hz), 4.76–4.73 (m, 1H), 4.71 (d, 1H, J¼11.8 Hz),
4.26 (quintet-like, 1H, J¼6.0 Hz), 3.78 (s, 3H), 1.41 (d, 3H,
J¼6.3 Hz); 13C NMR (125 MHz, CDCl3) d 164.16, 156.19,
137.07, 130.44, 128.43, 127.99, 127.94, 118.53, 114.40,
80.92, 73.03, 55.44, 53.85, 12.96; MS m/z 297 (Mþ), 240,
178, 149, 134, 106, 91; HRMS (EI) calcd for C18H19NO3
297.1364, found 297.1376.
To a stirred solution of 3a (300 mg, 0.957 mmol) and
DMAP (12 mg, 0.096 mmol) in CH2Cl2 (10 mL) were
added Et3N (0.4 mL, 2.872 mmol) and methanesulfonyl
chloride (0.11 mL, 1.435 mmol) at 08C. The reaction
mixture was stirred for 6 h at room temperature, quenched
with saturated NaHCO3 (7 mL) at 08C, extracted with
CH2Cl2 (3£10 mL), and washed with brine. The combined
organic layers were dried (MgSO4), filtered, and concen-
trated under reduced pressure. The residue was purified by
column chromatography on silica gel (3:1 hexane–EtOAc)
to give 14 as a colorless oil. Yield 375 mg (100%); Rf 0.37
(hexane–EtOAc 2:1); [a]2D1¼þ84.8 (c¼2.43, CHCl3); IR
3.23. (1)-(3R,4S)-4-Methyl-3-(benzyloxy)-2-azetidinone
(17)
Prepared from 16 via essentially the same procedure for 5a.
Yield 76%; white solid. Rf 0.13 (hexane–EtOAc 2:1); mp
82–838C; [a]2D1¼þ66.08 (c¼1.4, CHCl3); IR (KBr) n 3189,
1710, 1446, 1340, 1211, 1159, 1062, 1000 cm21; 1H NMR
(300 MHz, CDCl3) d 7.38–7.30 (m, 5H), 6.36 (br s, 1H),
4.81 (d, 1H, J¼11.8 Hz), 4.67–4.63 (m, 1H), 4.65 (d, 1H,
J¼11.8 Hz), 3.92–3.80 (m, 1H), 1.28 (d, 3H, J¼6.3 Hz);
13C NMR (125 MHz, CDCl3) d 168.68, 137.09, 128.39,
127.98, 127.85, 82.44, 72.69, 50.57, 15.60; MS m/z 192
(Mþþ1), 148, 119, 91, 77, 65, 44; HRMS (CI, methane)
calcd for C11H13NO2 192.1024 (MHþ), found 192.1021.
(NaCl) n 1754, 1513, 1456, 1359, 1249, 1176, 1124 cm21
;
1H NMR (500 MHz, CDCl3) d 7.41–7.35 (m, 7H), 6.89–
6.87 (m, 2H), 4.91 (d, 1H, J¼11.5 Hz), 4.90 (d, 1H,
J¼4.6 Hz), 4.75 (d, 1H, J¼ 11.5 Hz), 4.57–4.48 (m, 3H),
3.79 (s, 3H), 2.88 (s, 9H); 13C NMR (125 MHz, CDCl3) d
163.77, 156.74, 136.35, 129.94, 128.62, 128.38, 128.17,
118.80, 114.48, 80.48, 73.62, 66.86, 55.92, 55.45, 37.21;
MS m/z 391 (Mþ), 334, 244, 176, 160, 149, 133, 117, 105,
91; HRMS (EI) calcd for C19H21NO6S 391.1089, found
391.1084.
3.24. (1)-(3R,4S)-1-(t-Butyloxycarbonyl)-4-methyl-3-
(benzyloxy)-2-azetidin-one (18)
3.21. (1)-(3R,4R)-1-(p-Anisyl)-4-iodomethyl-3-
(benzyloxy)-2-azetidinone (15)
Prepared from 17 via essentially the same procedure for 6a.
Yield 93%; colorless oil. Rf 0.72 (hexane–EtOAc 2:1);
[a]2D1¼þ85.08 (c¼3.12, CHCl3); IR (NaCl) n 1806, 1722,
1334, 1259, 1157, 1025 cm21; 1H NMR (300 MHz, CDCl3)
d 7.38–7.30 (m, 5H), 4.84 (d, 1H, J¼11.8 Hz), 4.66 (d, 1H,
J¼11.8 Hz), 4.65–4.62 (m, 1H), 4.15 (quintet-like, 1H,
To a stirred solution of 14 (309 mg, 0.79 mmol) in DMF
(9 mL) were slowly added NaI (237 mg, 1.58 mmol) and
NaHCO3 (200 mg, 2.37 mmol). The reaction mixture was
heated to 60–708C for 6 h and then cooled to room

6452
H. K. Lee et al. / Tetrahedron 59 (2003) 6445–6454
J¼6.3 Hz), 1.51 (s, 9H), 1.38 (d, 3H, J¼6.3 Hz); 13C NMR
(125 MHz, CDCl3) d 165.07, 147.99, 136.65, 128.46,
128.12, 127.97, 83.30, 80.63, 73.08, 53.96, 27.98, 13.09;
MS m/z 292 (Mþþ1), 236, 208, 181, 148, 119, 91; HRMS
(CI, methane) calcd for C16H22NO4 292.1548 (MHþ), found
292.1549.
Z-isomer: [a]2D1¼þ22.88 (c¼2.54, CHCl3); IR (NaCl) n
3382, 1722, 1498, 1454, 1367, 1228, 1176, 1062 cm21; 1H
NMR (300 MHz, CDCl3) d 7.38–7.32 (m, 5H), 6.26 (dd,
1H, J¼8.6, 11.7 Hz), 5.97 (dd, 1H, J¼1.1, 11.7 Hz), 4.99 (d,
1H, J¼7.3 Hz), 4.86 (d, 1H, J¼7.3 Hz), 4.56 (d, 1H, J¼
11.5 Hz), 4.40 (d, 1H, J¼11.5 Hz), 3.91 (br s, 1H), 3.71 (s,
3H), 1.42 (s, 9H), 1.26 (d, 3H, J¼6.7 Hz); 13C NMR
(125 MHz, CDCl3) d 166.11, 155.47, 148.72, 138.01,
128.30, 127.81, 127.73, 122.20, 79.65, 76.96, 71.68,
51.40, 50.21, 28.35, 18.64; MS m/z 350 (Mþþ1), 294,
276, 262, 250, 232, 206, 144, 115, 91, 57, 44; HRMS (CI,
methane) calcd for C19H27NO5 350.1967 (MHþ), found
350.1964.
3.25. (2)-(2R,3S)-3-(t-Butyloxycarbonyl)amino-2-
(benzyloxy)butan-1-ol (19)
To a slurry of LiAlH4 (38 mg, 1 mmol) in THF (5 mL) at
08C was added slowly a solution of 18 (290 mg, 1 mmol) in
THF (3 mL). The resulting mixture was stirred for 10 min at
this temperature, and a few drops of water were added
slowly until no more hydrogen gas evolved. The resulting
mixture was dried (MgSO4), filtered over Celite, concen-
trated under reduced pressure, and purified by silica gel
column chromatography. Yield 257 mg (87%); colorless oil.
Rf 0.25 (hexane–EtOAc 3:1); [a]2D1¼255.98 (c¼2.22,
CHCl3); IR (NaCl) n 3434, 1689, 1504, 1454, 1367, 1249,
1168, 1062 cm21; 1H NMR (300 MHz, CDCl3) d 7.38–7.30
(m, 5H), 4.70 (d, 1H, J¼9.0 Hz), 4.62 (d, 1H, J¼11.6 Hz),
4.52 (d, 1H, J¼ 11.6 Hz), 4.02 (t, 1H, J¼7.7 Hz), 3.70 (dd,
1H, J¼5.4, 8.8 Hz), 3.61–3.39 (m, 3H), 1.44 (s, 9H), 1.20
(d, 3H, J¼6.9 Hz); 13C NMR (125 MHz, CDCl3) d 156.96,
138.05, 128.47, 128.05, 127.98, 81.38, 79.95, 73.39, 60.63,
45.84, 28.31, 17.75; MS m/z 296 (Mþþ1), 286, 265, 240,
221, 178, 134, 118, 91, 57, 44; HRMS (CI, methane) calcd
for C16H25NO4 296.1861 (MHþ), found 296.1857.
3.28. (1)-(5S,6S)-5-(Benzyloxy)-6-methyl-1,2,5,6-
tetrahydro-2-pyridinone (22)
Prepared from 21 via essentially the same procedure for
10a. Yield 85%; white solid; Rf 0.06 (hexane–EtOAc 1:1);
mp 78–798C; [a]2D1¼þ116.08 (c¼ 2.12, CHCl3); IR (KBr) n
3185, 1693, 1606, 1425, 1334, 1062 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.38–7.30 (m, 5H), 6.63 (dd, 1H,
J¼4.0, 10.0 Hz), 6.08 (br s, 1H), 6.00 (dd, 1H, J¼2.2,
10.0 Hz), 4.61 (d, 1H, J¼11.8 Hz), 4.57 (d, 1H, J¼11.8 Hz),
4.07 (t, 1H, J¼4.5 Hz), 3.78–3.73 (m, 1H), 1.31 (d, 3H,
J¼6.7 Hz); 13C NMR (125 MHz, CDCl3) d 165.09, 139.97,
137.62, 128.50, 127.98, 127.71, 125.92, 71.11, 70.85, 49.94,
15.52; MS m/z 217 (Mþ), 174, 145, 126, 111, 91; HRMS
(EI) calcd for C13H15NO2 217.1102, found 217.1105.
3.26. (2R,3S)-3-(t-Butyloxycarbonyl)amino-2-
(benzyloxy)butanal (20)
3.29. (1)-(5S,6S)-1-Benzyl-5-(benzyloxy)-6-methyl-
1,2,5,6-tetrahydro-2-pyridinone (23)
Prepared from 19 via essentially the same procedure for 8a.
Crude yield 95%. Yellow oil. IR (NaCl) n 3411, 1710, 1500,
To a slurry of 60% NaH (165 mg, 4.12 mmol) in THF
(8 mL) was added a solution of 22 (448 mg, 2.06 mmol) in
THF (13 mL) at 08C. After stirring for 10 min at this
temperature, benzyl bromide (0.5 mL, 4.12 mmol) and
tetra-n-butylammonium iodide (30 mg, 0.08 mmol) was
added. The reaction mixture was stirred for 2 h at room
temperature and quenched with saturated NH4Cl (20 mL) at
08C. The aqueous layer was extracted with EtOAc
(3£15 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on
silica gel (from 7:1 to 5:1 hexane–EtOAc) to give 23 as a
colorless oil. Yield 550 mg (87%); Rf 0.65 (hexane–EtOAc
1:1). [a]2D1¼þ24.78 (c¼2.12, CHCl3); IR (NaCl) n 1666,
1
1454, 1367, 1247, 1168, 1066 cm21; H NMR (300 MHz,
CDCl3) d 9.66 (s, 1H), 7.37–7.32 (m, 5H), 4.90–4.88 (m,
1H), 4.79 (d, 1H, J¼11.6 Hz), 4.54 (d, 1H, J¼11.6 Hz),
4.26–4.24 (m, 1H), 3.80 (br s, 1H), 1.41 (s, 9H), 1.21 (d, 3H,
J¼6.9 Hz); 13C NMR (125 MHz, CDCl3) d 201.84, 155.12,
136.92, 129.73, 128.47, 128.18, 85.16, 79.69, 73.00, 46.42,
28.24, 17.83; MS m/z 293 (Mþþ1), 220, 208, 144, 118, 91,
57, 44; HRMS (CI, methane) calcd for C16H23NO4
294.1705 (MHþ), found 294.1702.
3.27. Methyl (4S,5S)-5-(t-butyloxycarbonyl)amino-4-
(benzyloxy)-2-hexeno-ate (E and Z-21)
1
1614, 1450, 1257, 1118, 1076 cm21; H NMR (500 MHz,
Prepared from 20 via essentially the same procedure for 9a.
Yield 98% (E:Z¼1:3.5); colorless oil.
CDCl3) d 7.33–7.20 (m, 10H), 6.38 (tt, 1H, J¼1.7,
10.0 Hz), 5.92 (dd, 1H, J¼2.5, 10.0 Hz), 5.30 (d, 1H,
J¼15.0 Hz), 4.47 (d, 1H, J¼11.7 Hz), 4.43 (d, 1H, J¼
11.7 Hz), 4.42–4.40 (m, 1H), 3.87 (d, 1H, J¼15.0 Hz),
3.62–3.57 (m, 1H), 1.18 (d, 3H, J¼6.6 Hz); 13C NMR
(125 MHz, CDCl3) d 163.13, 140.27, 137.82, 137.06,
128.64, 128.48, 127.98, 127.83, 127.66, 127.42, 123.87,
74.03, 71.17, 52.88, 47.43, 10.93; MS m/z 307 (Mþ), 216,
201, 186, 174, 134, 106, 91; HRMS (EI) calcd for
C20H21NO2 307.1572, found 307.1565.
E-isomer: [a]2D1¼212.78 (c¼2.04, CHCl3); IR (NaCl) n
3363, 1712, 1500, 1454, 1365, 1251, 1170 cm21; 1H NMR
(300 MHz, CDCl3) d 7.38–7.30 (m, 5H), 6.88 (dd, 1H,
J¼5.9, 15.9 Hz), 6.07 (dd, 1H, J¼1.5, 15.9 Hz), 4.65 (m,
1H), 4.62 (d, 1H, J¼11.6 Hz), 4.39 (d, 1H, J¼11.6 Hz), 4.00
(br s, 1H), 3.90–3.77 (m, 1H), 3.75 (s, 3H), 1.42 (s, 9H),
1.16 (d, 3H, J¼6.7 Hz); 13C NMR (125 MHz, CDCl3) d
166.32, 155.30, 145.22, 137.57, 128.42, 127.87, 127.83,
123.09, 79.95, 71.60, 60.37, 51.64, 48.94, 28.32, 17.40; MS
m/z 294 (Mþ255), 276, 262, 250, 232, 206, 144, 115, 91,
57, 44; HRMS (CI, methane) calcd for C19H27NO5
350.1967 (MHþ), found 350.1967.
3.30. (2)-(5S,6S)-1-Benzyl-5-(benzyloxy)-6-
methylhexahydro-2-pyridinone (24)
A mixture of 23 (103 mg, 0.34 mmol) and 10% palladium

H. K. Lee et al. / Tetrahedron 59 (2003) 6445–6454
6453
Org. Lett. 2000, 2, 2427. (f) Williams, S. J.; Hoos, R.; Winters,
S. G. J. Am. Chem. Soc. 2000, 122, 2223. (g) Laschat, S.;
Dickner, T. Synthesis 2000, 1781. (h) Davis, F. A.; Chao, B.;
Fang, T.; Szewczyk, J. M. Org. Lett. 2000, 2, 1041. (i) Comins,
D. L.; Kuethe, J. T.; Hong, H.; Lakner, F. J.; Concolino, T. E.;
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(j) Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.;
Naito, T. Tetrahedron 1998, 54, 15589. (k) Pahl, A.;
Wartchow, R.; Meyer, H. H. Tetrahedron Lett. 1998, 39,
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(o) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
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on carbon (30% w/w) in EtOAc (10 mL) was stirred under
an atmosphere of H2 for 1 h. After filtration over Celite and
concentration in vacuo, the crude product was purified by
silica gel column chromatography. Yield 104 mg (99%);
colorless oil; Rf 0.14 (hexane–EtOAc 2:1); [a]2D1¼260.78
(c¼2.33, CHCl3) [lit.4a [a]D26¼260.98 (c¼2.24, CHCl3)]; IR
(NaCl) n 1641, 1452, 1068 cm21 1H NMR (500 MHz,
;
CDCl3) d 7.32–7.20 (m, 10H), 5.32 (d, 1H, J¼15.0 Hz),
4.47 (d, 1H, J¼ 12.0 Hz), 4.43 (d, 1H, J¼12.0 Hz), 3.94 (d,
1H, J¼15.0 Hz), 3.66–3.63 (m, 1H), 3.56–3.54 (m, 1H),
2.64–2.60 (ddd, 1H, J¼3.7, 7.5, 18.4 Hz), 2.53–2.46 (ddd,
1H, J¼8.0, 9.5, 17.7 Hz), 2.03–1.94 (m, 2H), 1.22 (d, 3H,
J¼6.5 Hz); 13C NMR (125 MHz, CDCl3) d 169.18, 137.76,
137.34, 128.59, 128.40, 127.73, 127.50, 127.30, 73.98,
70.65, 52.75, 47.77, 29.14, 22.02, 13.49; MS m/z 309 (Mþ),
218, 203, 174, 134, 112, 91; HRMS (EI) calcd for
C20H23NO2 309.1728, found 309.1724.
4. (a) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T. J. Org.
Chem. 1999, 64, 4914. (b) Momose, T.; Toyooka, N.; Jin, M.
J. Chem. Soc., Perkin Trans. 1 1997, 2005. (c) Toyooka, N.;
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(d) Momose, T.; Toyooka, N. Tetrahedron Lett. 1993, 34,
5785. (e) Momose, T.; Toyooka, N.; Jin, M. Tetrahedron Lett.
1992, 33, 5389.
Acknowledgements
This work was supported by the Ministry of Science and
Technology of Korea. We thank to Dr Jin K. Cha for his
kind reading of the manuscript.
5. For synthesis of prosophylline and/or desoxoprosophylline,
see: (a) Jourdant, A.; Zhu, J. Tetrahedron Lett. 2001, 42, 3431.
(b) Koulocheri, S. D.; Magiatis, P.; Haroutounian, S. A. J. Org.
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nian, S. A. Synthesis 1999, 1889. (g) Herdeis, C.; Telser, J.
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3592. (l) Takao, K.; Nigawara, Y.; Nishio, E.; Takagi, I.;
Maeda, K.; Tadano, K.; Ogawa, S. Tetrahedron 1994, 50,
5681. (m) Tadano, K.; Takao, K.; Nigawara, Y.; Nishio, E.;
Takagi, I.; Maeda, K.; Ogawa, S. Synlett 1993, 565.
(n) Natume, M.; Ogawa, M. Heterocycles 1981, 16, 973.
(o) Saitoh, Y.; Moriyama, Y.; Hirota, H.; Takahashi, T.;
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(p) Saitoh, Y.; Moriyama, Y.; Takahashi, T.; Khuong-Huu,
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