Bu3SnH-mediated 5-exo selective radical cyclization of N-vinyl-α,β-unsaturated amides leading to γ-lactams

Article abstract of DOI:10.1016/j.tet.2005.06.116

Treatment of N-vinyl-α,β-unsaturated amides 1a-h with Bu ₃SnH and a catalytic amount of AIBN in boiling benzene caused 5-exo cyclization of allylic O-stannyl ketyl radicals generated by addition of Bu ₃Sn· on the amide-oxygen atoms t

Full text of DOI:10.1016/j.tet.2005.06.116

Tetrahedron 61 (2005) 9180–9187
Bu3SnH-mediated 5-exo selective radical cyclization of N-vinyl-
a,b-unsaturated amides leading to g-lactams
*
Takashi Okitsu, Miho Saito, Osamu Tamura and Hiroyuki Ishibashi
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kanazawa 920-1192, Japan
Received 26 May 2005; accepted 23 June 2005
Abstract—Treatment of N-vinyl-a,b-unsaturated amides 1a–h with Bu3SnH and a catalytic amount of AIBN in boiling benzene caused
5-exo cyclization of allylic O-stannyl ketyl radicals generated by addition of Bu3Sn$ on the amide-oxygen atoms to provide g-lactams 2a–h
after acidic workup. When enamide 1d was treated with Bu3SnH in the presence of AIBN followed by aldehydes 3a–d, sequential radical
cyclization and aldol reactions occurred to afford anti-adducts 4a–d and syn-adducts 5a,b.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Bu3SnH-mediated reductive radical cyclizations of u-halo-
alkenes are widely used in organic synthesis.1 However, one
of the drawbacks of these radical cyclizations is the loss of
halogen functionalities. From this point of view, cycliza-
tions of allylic O-stannyl ketyl radicals [Bu3-
SnOC(R)]CH–CHR0 radicals] generated from a,b-
Scheme 1.
unsaturated ketones having activated olefin moieties under
standard Bu3SnH-mediated radical conditions appear to be
attractive due to without the use of halogen atoms.2–4
(Scheme 2). Enamide 1e having non-substituted N-vinyl
group was synthesized from crotonic acid by three step;
condensation with N-benzyl-N-(2-phenylthioethyl)amine,
oxidation of phenylthio group to phenylsulfinyl group and
b-elimination of the phenylsulfinyl group.
´
Recently, Lesniak et al. reported that treatment of N-(1-
substituted ethenyl)cinnamamides 1 (R2ZR4ZH, R3Z
mainly Ph or RS, R5ZPh) with Bu3SnH and AIBN
produced allylic O-stannyl ketyl radicals to give 6-endo
radical cyclization products, d-lactams.5 We have now
found that Bu3SnH-mediated cyclization of enamides 1
(R3ZH) gave 5-exo radical cyclization products, g-lactams
2, via allylic O-stannyl ketyl radicals (Scheme 1).6 The aldol
reaction of intermediary tin(IV) enolates is also described.
Our investigation on radical cyclization of 1 began with
reaction of enamide 1a–d bearing 2,2-diphenylethenyl
group known as a good radical acceptor (Table 1).7
Treatment of acrylamide 1a with Bu3SnH (2 equiv) in the
presence of AIBN (0.2 equiv) in boiling benzene for 8 h
gave g-lactam 2a in 10% yield after workup with 10% HCl
(entry 1). Compound 1a was not recovered and the 6-endo
cyclization product was not detected. The formation of
lactam 2a may involve cyclization of allylic O-stannyl
radical A (Scheme 3). Bu3Sn$ attacks the carbonyl oxygen
atom of amide 1a to generate radical A, which undergoes
5-exo cyclization to give radical B stabilized by two phenyl
groups. Radical B is trapped with Bu3SnH to give tin(IV)
enolate C, whose hydrolysis by acidic workup affords
g-lactam 2a. The radical reaction of 1a might suffer from
addition of Bu3Sn$ at the b-position of amide 1a,8 giving
radical D, which is likely to cause side reactions.
2. Results and discussion
The starting enamides 1a–d and 1f–h (for structures of
enamides 1, see Tables 1 and 2) were readily prepared by
direct acylation of imines derived from aldehydes and
benzylamine with acyl chlorides in the presence of Et3N
Keywords: N-Vinyl-a,b-unsaturated amides; Radical cyclization; Allylic
O-stannyl ketyl radical; Aldol reaction; Tin(IV) enolate.
*
Corresponding author. Tel.: C81 76 234 4474; fax: C81 76 234 4476;
e-mail: isibasi@p.kanazawa-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.116

T. Okitsu et al. / Tetrahedron 61 (2005) 9180–9187
Table 1. Radical cyclization of N-(2,2-diphenylethenyl)amides
9181
Entry
1
Enamide
Product (time, yield)
1a
1b
2a (8 h, 10%)
2
trans-2b
cis-2b
Scheme 2.
(7 h,91%; trans:cisZ1.4:1)
3
4
1c
2c (9 h, 97%)
1d
2d (1.5 h, 93%)
Scheme 3.
Table 2. Radical cyclization of varius N-vinylamides
Introduction of a substituent at the b-position of a,b-
unsaturated amide 1 might prevent undesired b-addition of
Bu3Sn$ due to steric reason and/or stabilize the allyic
O-stannyl ketyl radical intermediate and result in improve-
ment of the yield of cyclization product 2. Indeed, reaction
of crotonamide 1b gave a mixture of cyclization products
trans-2b and cis-2b in dramatically improved yield (91%)
(entry 2). Under conditions similar to those for 1a and 1b,
3,3-dimethylacrylamide 1c and cinnamoylamide 1d
afforded excellent yields of g-lactams 2c (97%) and 2d
(93%), respectively (entries 3 and 4).
Entry
1
Enamide
Product (time, yield)
1e
2e (8.5 h, 26%) 3:1
2
3
4
2f (12 h, 44%) 2:1
1f
The stereostructures of trans-2b and cis-2b were deduced
by means of NOE and coupling constants in their 1H NMR
spectra (Fig. 1). Compound trans-2b exhibited an NOE
between methyl group and C5–H and very a small coupling
constant J4,5 (w0 Hz) whereas cis-2b showed a relatively
large coupling constant (J4,5Z6.6 Hz) (Fig. 1). The
stereostructure of compound 2d was also deduced to be
1g
2g (3.5 h, 64%)
2h (10 h, 71%)
trans on the basis of the small coupling constant (J4,5
1.0 Hz).
Z
1h
2f0
Figure 1.

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T. Okitsu et al. / Tetrahedron 61 (2005) 9180–9187
aliphatic aldehydes 3c and 3d appear to have good
selectivities (entries 3 and 4). Although aldol reaction of
heptanal (3c) with enolate E took a long time, exclusive
formation of adduct 4c resulted in 45% yield along with 2d
(53%). The reaction with cyclohexylcarboaldehyde (3d)
required the use of high boiling toluene as a solvent, and
therefore, the radical cyclization of 1d was performed in
toluene in the presence of ACN having a long half-life
period. These conditions gave adduct 4d in 27% yield along
with cyclization product 2d (47%).
In principle, four stereoisomers are possible for the aldol
reaction. C4-Phenyl group, however, effectively shields
b-face, hence aldehydes 3a–d may approach from a-face to
Scheme 4.
Table 3. Radical cyclization and aldol reaction of enamide 1d
Entry
Aldehyde (R)
Reaction time (h)
Yield (%)
4
5
2d
1
2
3a (Ph)
12
10
25
24
42
54
45
27
33
15
3b (PhCH]CH–)
3c (n-hexyl)
3d (cyclohexyl)
20
53
47
3
4a
a The reaction was carried out by using toluene and ACN (1,10-azobis(cyclohexane-1-carbonitrile).
We next examined the effect of the substituent(s) at the
terminus of N-vinyl-moieties of 1 (Table 2). In contrast to
the reaction of amide 1b (Table 1, entry 2), reaction of
amide 1e having a non-substituted N-vinyl group with
Bu3SnH (3 equiv) and AIBN (2.5 equiv) gave an insepar-
able 3:1 diastereomeric mixture of g-lactams 2e in only
26% yield (Table 2, entry 1). This result suggests that a
radical stabilizing group at the terminus of the N-vinyl
group would be required for efficient cyclization. Treatment
of amide 1f bearing an N-2,2-bis(phenylthio)ethenyl group
with a large excess of Bu3SnH (8 equiv) and AIBN afforded
lactam 2f as an inseparable mixture of diastereomers in a
moderate yield (44%) probably via desulfurization of the
initial cyclization product 2f0 (entry 2). Partial desulfuriza-
tion of 2f0 giving 2f may be explained by assuming that the
radical intermediate formed by an attack of tin radical on the
sulfur atom is highly stabilized by an adjacent phenylthio
group. N-2,2-Dimethylethenyl and N-2-phenylethenyl
groups also appear to be efficient as radical acceptors for
the present cyclization. The reactions of amides 1g and 1h
gave g-lactams 2g and 2h in 64 and 71% yields, respectively
(compare to Table 1, entry 3).
give C3–C4 trans-adducts 4 and 5 (Fig. 2). The C3–C4
trans-relationship of 4b was supported by an NOE as
illustrated in Figure 2. Stereostructures of C3–C10positions
for adducts 3a–d and 4a,b were deducted on the basis of
1
their H NMR spectra. In general, the b-proton referred to
the carbonyl group of an anti-aldol resonates in upper field
and exhibits a larger J-value than does the corresponding
syn-aldol.10 In fact, HB of anti-aldol 6a related to 4a shows
the signal at d 4.71 (JABZ9.0 Hz), whereas HB of syn-aldol
6b does at d 5.30 (JABZ2.9 Hz) (Fig. 3).11 The tendencies
of NMR data for adducts 4a–d and 5a,b listed in Table 4
Figure 2.
Enholm et al. reported aldol reaction of tin(IV) enolates
generated from a,b-unsaturated ketones with Bu3SnH.9
Since tin(IV) enolates should be also generated in the
present reactions, radical cyclization–aldol reaction
sequence of 1d was next examined (Scheme 4 and
Table 3). Enamide 1d was treated with Bu3SnH and
AIBN in refluxing benzene for 45 min to form tin(IV)
enolate E, to which benzaldehyde (3a) was added. Further
heating the resulting mixture caused aldol reaction of
enolate E with aldehyde 3a to afford anti-adduct 4a and syn-
adduct 5a in 42 and 33% yields, respectively (entry 1). In a
similar manner, reaction of trans-cinnamaldehyde (3b) gave
adduct 4b in 54% yield along with 5b (15%) and simple
cyclization product 2d (20%) (entry 2). Compared to
aromatic aldehyde 3a or a,b-unsaturated aldehyde 3b,
Figure 3.
Table 4
d C10–H
0
J1 3 (Hz)
4a
5a
4b
5b
4c
4d
4.17
5.33
3.79
4.75
4.30
3.00
9.2
3.3
8.5
3.5
8.6
9.2

T. Okitsu et al. / Tetrahedron 61 (2005) 9180–9187
9183
well accord with those for 6a and 6b. The predominant
formation of the anti adducts 4 by the aldol reaction of E
with aldehydes 3a–d (RCHO) may be explained by
considering the six-membered transition state in which R
is equatorial.
(639 mL, 6.00 mmol). Chromatography on silica gel
(hexane/AcOEt 20:1) gave 1b (1.25 g, 88%) as a colorless
1
oil. IR (CHCl3) 1665, 1610 cmK1; H NMR (270 MHz,
CDCl3) d 1.80 (3H, dd, JZ6.9, 1.7 Hz), 4.48 (2H, s), 6.36
(1H, dd, JZ15.2, 1.7 Hz), 6.49 (1H, s), 6.87 (1H, dq, JZ15.2,
6.9 Hz), 7.08–7.40 (15H, m); 13C NMR (68 MHz, CDCl3) d
18.6, 49.8, 123.5, 126.1, 127.7, 128.6, 128.7, 128.8, 129.0,
130.0, 138.0, 138.3, 139.7, 141.0, 143.0, 166.9; HRMS calcd
for C25H23NO 353.1780, found 353.1777.
3. Conclusion
We have explored 5-exo selective Bu3SnH-mediated radical
cyclization of N-vinyl a,b-unsaturated amides leading to
g-lactams. Sequential radical cyclization and aldol reaction
of an intermediary tin(IV) enolate have been also
demonstrated. Further studies on cascade-type cyclization12
are in progress.
4.1.3. N-Benzyl-N-(2,2-diphenylvinyl)-3-methylbut-2-
enamide, 1c. Using a procedure similar to that for the
preparation of 1a, the crude material was obtained from
diphenylacetaldehyde (366 mL, 2.00 mmol), BnNH2
(223 mL, 2.00 mmol), Et3N (509 mL, 3.60 mmol) and 3,3-
dimethylacryloyl chloride (344 mL, 3.00 mmol). Chroma-
tography on silica gel (hexane/AcOEt 20:1) gave 1c
(651 mg, 89%) as a colorless oil. IR (CHCl3) 1650,
4. Experimental
4.1. General
1
1610 cmK1; H NMR (270 MHz, CDCl3) d 1.75 (3H, s),
1.91 (3H, s), 4.50 (2H, s), 5.99 (1H, s), 6.45 (1H, s), 7.05–
7.37 (15H, m); 13C NMR (68 MHz, CDCl3) d 20.1, 27.1,
48.9, 118.1, 126.0, 127.2, 127.9, 128.2, 128.3, 128.4, 128.5,
129.5, 137.8, 138.1, 138.4, 140.8, 151.8, 167.3; HRMS
calcd for C26H25NO 367.1936, found 367.1937.
Melting points are uncorrected. IR spectra were recorded
with a Shimadzu FTIR-8100 spectrophotometer for
solutions in CHCl3. 1H and 13C NMR spectra were
measured on JEOL JNM-EX 270 and JEOL JNM-GSX
500 spectrometers. d values quoted are relative to TMS
(tetramethylsilane). High resolution mass spectra (HRMS)
were obtained with a JEOL JMS-SX 102A instrument. All
new compounds determined to be O95% pure by
microanalyses or 1H NMR spectra. Column chromato-
graphy was performed on Silica gel 60 PF254 under pressure.
2-(Phenylthio)ethylamine,13 and bis(phenylthio)acetalde-
hyde14 were prepared by reported methods.
4.1.4. N-Benzyl-N-(2,2-diphenylvinyl)cinnamamide, 1d.
Using a procedure similar to that for the preparation of 1a,
the crude material was obtained from diphenylacetaldehyde
(366 mL, 2.00 mmol), BnNH2 (223 mL, 2.00 mmol), Et3N
(509 mL, 3.60 mmol) and cinnamoyl chloride (526 mg,
3.00 mmol). Chromatography on silica gel (hexane/AcOEt
15:1) gave 1d (705 mg, 85%) as yellow crystals: mp 93–
1
95 8C (hexane). IR (CHCl3) 1650, 1605 cmK1; H NMR
(270 MHz, CDCl3) d 4.59 (2H, s), 6.58 (1H, s), 6.93 (1H, d,
JZ15.5 Hz), 7.08–7.45 (20H, m), 7.59 (1H, d, JZ15.5 Hz);
13C NMR (68 MHz, CDCl3) d: 49.9, 118.6, 125.3, 127.4,
127.9, 128.2, 128.3, 128.4, 128.6, 128.7, 128.8, 129.5,
129.7, 135.1, 137.4, 137.7, 140.0, 140.4, 143.0, 166.3. Anal.
Calcd for C30H25NO: C, 86.71; H, 6.06; N, 3.37. Found: C,
86.47; H, 6.09; N, 3.21.
4.1.1. N-Benzyl-N-(2,2-diphenylvinyl)acrylamide, 1a. A
solution of diphenylacetaldehyde (366 mL, 2.00 mmol) and
BnNH2 (223 mL, 2.00 mmol) in benzene (7 mL) was heated
at reflux for 1 h, and then the mixture was cooled to 0 8C. To
the mixture were successively added a solution of Et3N
(509 mL, 3.60 mmol) in benzene (5 mL) and a solution of
acryloyl chloride (255 mL, 3.00 mmol) in benzene (5 mL) at
the same temperature, then the mixture was stirred at room
temperature for 30 min. The mixture was washed with a
saturated aqueous NH4Cl, and the aqueous phase was
further extracted with CHCl3. The organic phases were
combined, washed successively with a saturated aqueous
NaHCO3 and brine, dried (MgSO4), and concentrated under
reduced pressure. The crude material was chromatographed
on silica gel with (hexane/AcOEt 15:1) to give 1a (414 mg,
4.1.5. (2E)-N-Benzyl-N-vinylbut-2-enamide, 1e. To a
stirred solution of trans-crotonic acid (522 mg,
6.00 mmol) and N-benzyl-N-(phenylthio)ethylamine
(1.53 g, 6.30 mmol) in CH2Cl2 (30 mL) was added 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC) (1.76 g, 9.00 mmol) and DMAP (147 mg,
1.20 mmol) at 0 8C and the mixture was further stirred at
room temperature for 1 h. The mixture was washed with a
saturated aqueous solution of NH4Cl, and the aqueous phase
was further extracted with CHCl3. The organic phases were
combined, washed successively with a saturated aqueous
solution of NaHCO3 and brine, dried (MgSO4) and
concentrated under reduced pressure to give crude (2E)-N-
1
61%) as a colorless oil. IR (CHCl3) 1655, 1610 cmK1; H
NMR (270 MHz, CDCl3) d 4.51 (2H, s), 5.59 (1H, dd, JZ
10.2, 2.0 Hz), 6.31 (1H, dd, JZ16.8, 2.0 Hz), 6.48 (1H, s),
6.67 (1H, dd, JZ16.8, 10.2 Hz), 7.07–7.39 (15H, m); 13C
NMR (68 MHz, CDCl3) d 50.1, 125.6, 127.9, 128.7, 128.8,
128.9, 129.1, 129.2, 130.0, 137.7, 138.0, 140.6, 140.8,
166.5; HRMS calcd for C24H21NO 339.1623, found
339.1620.
benzyl-N-[2-(phenylthio)ethyl]but-2-enamide.
This
material was dissolved in CH2Cl2 (250 mL) and cooled to
0 8C. To this solution was added a solution of mCPBA
(1.36 g, 6.30 mmol) in CH2Cl2 (100 mL) at the same
temperature over 1 h and the resulting mixture was further
stirred for 30 min. A 10% aqueous solution of Na2S2O3
(20 mL) was added to the mixture and the resulting mixture
was vigorously stirred for 30 min. The organic phase was
separated, washed successively with a saturated aqueous
4.1.2. (2E)-N-Benzyl-N-(2,2-diphenylvinyl)but-2-enamide,
1b. Using a procedure similar to that for the preparation of
1a, the crude material was obtained from diphenylacetalde-
hyde (732 mL, 4.00 mmol), BnNH2 (446 mL, 4.00 mmol),
Et3N (1.02 mL, 7.20 mmol) and trans-crotonyl chloride

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T. Okitsu et al. / Tetrahedron 61 (2005) 9180–9187
solution of NaHCO3 and brine, dried (MgSO4) and
concentrated under reduced pressure to give crude (2E)-N-
benzyl-N-[2-(phenylsulfinyl)ethyl]but-2-enamide. A mixture
of this crude sulfoxide and NaHCO3 (1.01 g, 12.0 mmol) in
xylene (150 mL) was heated at reflux for 18 h. After cooling,
the mixture was filtered, and then the filtrate was washed
successively with water and brine, dried (MgSO4) and
concentrated under reduced pressure. The crude material
was cromatographed on silica gel (hexane/AcOEt 10:1) to
give 1e (808 mg, 67%) as a colorless oil. IR (CHCl3) 1665,
1620 cmK1; The 1H and 13C NMR spectra of 1e showed the
presence of two rotamers; 1H NMR (270 MHz, CDCl3) d 1.91
(3H, br), 4.27–4.47 (2H, br), 4.90 (2H, br s), 6.08–6.51 (1H,
br), 6.88–7.10 (1HC1H!3/5, br), 7.10–7.40 (5H, m), 7.64
(1H!2/5H, br s); 13C NMR (68 MHz, CDCl3) d: 15.5, 18.3,
36.3, 46.1, 48.3, 94.8, 65.7, 121.6, 122.2, 125.6, 126.8, 126.9,
128.5, 132.2, 132.8, 133.4, 136.4, 136.9, 137.9, 144.3, 144.5,
165.8;HRMScalcdfor C13H15NO201.1154, found 201.1156.
4.1.8. N-Benzyl-N-[(1E)-2-phenylvinyl]-3-methylbut-2-
enamide, 1h. Using a procedure similar to that for the
preparation of 1a, the crude material was obtained from
phenylacetaldehyde (248 mL, 2.00 mmol), BnNH2 (223 mL,
2.00 mmol), Et3N (509 mL, 3.60 mmol) and 3,3-dimethyl-
acryloyl chloride (344 mL, 3.00 mmol). Chromatography on
silica gel (hexane/AcOEt 20:1) gave 1h (121 mg, 21%) as
colorless crystals: mp 87.5–88.5 8C (hexane). IR (CHCl3)
1660; 1635 cmK1; 1H NMR (270 MHz, CDCl3) d 1.83–2.08
(6H, br), 4.98 (2H, br), 5.78–6.10 (2H, br), 7.16 (10HC
1H!2/3, m), 8.23 (1H!1/3, br). Anal. Calcd for
C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.08;
H, 7.27; N, 4.81.
4.1.9. 5-Benzhydryl-1-benzylpyrrolidin-2-one, 2a:
general procedure for radical reaction of enamides 1.
A mixture of 1a (136 mg, 0.400 mmol), Bu3SnH (219 mL,
0.800 mmol) and AIBN (6.7 mg, 0.040 mmol) in benzene
(4 mL) was heated at reflux for 5 h. Since the reaction was
not completed, a solution of AIBN (6.7 mg, 0.040 mmol) in
benzene (1 mL) was added, then the mixture was further
refluxed for 3 h. After cooling the mixture was concentrated
to give a residue, which was partitioned between 10% HCl
and AcOEt, and the aqueous phase was extracted with
AcOEt. The organic phases were combined, stirred
vigorously with an 8% aqueous KF overnight. After
filtration to remove precipitates, the organic phase was
separated and the aqueous phase was further extracted with
AcOEt. The combined organic phase was washed with
brine, dried (MgSO4), and concentrated under reduced
pressure. The crude material was chromatographed on silica
gel (hexane/AcOEt 4:1/3:1) to give 2a (9.6 mg, 10%) as a
colorless oil. IR (CHCl3) 1675 cmK1; 1H NMR (270 MHz,
CDCl3) d 1.86–2.26 (4H, m), 3.28 (1H, d of a pair of ABq,
JZ15.2 Hz), 4.18–4.27 (2H, m), 5.06 (1H, d of a pair of
ABq, JZ15.2 Hz), 6.99–7.35 (15H, m); 13C NMR
(68 MHz, CDCl3) d 24.1, 29.8, 45.2, 54.1, 60.0, 127.4,
127.5, 127.9, 128.3, 128.9, 129.0, 129.1, 129.2, 131.7,
141.6, 141.9, 176.2; HRMS calcd for C24H23NO 341.1780,
found 341.1781.
4.1.6. (2E)-N-Benzyl-N-[2,2-bis(phenylthio)vinyl]but-2-
enamide, 1f. A solution of bis(phenylthio)acetaldehyde
(521 mg, 2.00 mmol) and BnNH2 (223 mL, 2.00 mmol) in
benzene (12 mL) was heated at reflux for 1.5 h. To the
mixture were added Et3N (509 mL, 3.60 mmol) and a
solution of trans-crotonyl chloride (319 mL, 3.00 mmol) in
benezene (5 mL), then the mixture was further refluxed for
1.5 h. Since the reaction was not completed, additional Et3N
(509 mL, 3.60 mmol) and a solution of trans-crotonyl
chloride (319 mL, 3.00 mmol) in benezene (5 mL), were
added to the mixture, then the mixture was further refluxed
for 1 h. Workup similar to that for the preparation of 1a gave
a crude material, which was chromatographed on silica gel
(hexane/AcOEt 20:1/15:1/10:1) to give 1f (622 mg,
79%) as colorless crystals: mp 73–74 8C (hexane). IR
1
(CHCl3) 1665, 1630 cmK1; H NMR (270 MHz, CDCl3) d
1.89 (3H, dd, JZ6.9, 1.7 Hz), 4.88 (2H, s), 6.17 (1H, dd,
JZ15.2, 1.7 Hz), 6.81–7.33 (17H, m); 13C NMR (68 MHz,
CDCl3) d 18.3, 49.9, 122.7, 127.5, 127.8, 128.5, 128.5,
128.8, 131.1, 132.0, 132.5, 133.7, 134.1, 137.0, 143.3,
166.1. Anal. Calcd for C25H23NOS: C, 71.91; H, 5.55; N,
3.35. Found: C, 71.88; H, 5.58; N, 3.36.
4.1.10. (4R*,5R*)-5-Benzhydryl-1-benzyl-4-methylpyr-
rolidin-2-one, trans-2b and its (4R*,5S*)-isomer, cis-2b.
Following the general procedure, the crude material was
obtained from 1b (141 mg, 0.400 mmol), Bu3SnH (219 mL,
0.800 mmol) and AIBN (6.7 mg, 0.040 mmol). Chromato-
graphy on silica gel (hexane/AcOEt 4:1) gave a 1.4:1
mixture of trans-2b and cis-2b (129 mg, 91%). Analytical
samples of trans-2b and cis-2b were obtained by further
chromatography on silica gel (hexane/AcOEt 6:1). trans-2b:
IR (CHCl3) 1675 cmK1; 1H NMR (270 MHz, CDCl3) d 0.88
(3H, d, JZ6.9 Hz), 1.80 (1H, d, JZ15.8 Hz), 2.13–2.27
(2H, m), 2.95 (1H, d of a pair of ABq, JZ14.8 Hz), 3.69
(1H, d, JZ7.9 Hz), 4.11 (1H, d, JZ7.9 Hz), 5.04 (1H, d of a
pair of ABq, JZ14.8 Hz), 7.01–7.37 (15H, m); 13C NMR
(125 MHz, CDCl3) d 20.6, 30.5, 37.5, 44.7, 54.5, 67.1,
126.9, 127.0, 127.4, 128.2, 128.4, 128.6, 128.7, 128.8,
136.5, 141.4, 141.6, 174.9; HRMS calcd for C25H25NO
4.1.7. N-Benzyl-N-(2,2-dimethylvinyl)-3-methylbut-2-
enamide, 1g. To a stirred mixture of BnNH2 (223 mL,
2.00 mmol) and MgSO4 (300 mg) in Et2O (2 mL) was
added isobutyraldehyde (335 mL, 3.69 mmol) at 0 8C, then
the mixture was stirred at the same temperature for 1.5 h.
The mixture was filtered, and filtrate was concentrated to
give a residue, which was dissolved in benzene (3 mL). To
the solution were added Et3N (509 mL, 3.6 mmol) and 3,3-
dimethylacryloyl chloride (344 mL, 3.00 mmol) at 0 8C and
the mixture was stirred at the same temperature for 2 h.
Workup similar to that for the preparation of 1a gave a crude
material, which was chromatographed on silica gel (hexane/
AcOEt 20:1) to give 1g (193 mg, 40%) as a colorless oil. IR
1
(CHCl3) 1650, 1615 cmK1; H NMR (270 MHz, CDCl3) d
1.36 (3H, d, JZ1.3 Hz), 1.67 (3H, d, JZ1.3 Hz), 1.81 (3H,
d, JZ1.0 Hz), 2.13 (3H, d, JZ1.0 Hz), 4.62 (2H, s), 5.74
(1H, t, JZ1.3 Hz), 5.85 (1H, t, JZ1.3 Hz), 7.21–7.28 (5H,
m); 13C NMR (68 MHz, CDCl3) d 17.5, 20.0, 21.9, 27.2,
50.1, 117.7, 123.3, 126.9, 128.1, 128.5, 135.3, 137.7, 150.0,
167.1; HRMS calcd for C16H21NO 243.1623, found
243.1629.
355.1936, found 355.1932. cis-2b: IR (CHCl3) 1675 cmK1
;
1H NMR (270 MHz, CDCl3) d 0.85 (3H, d, JZ6.9 Hz), 2.09
(1H, dd, JZ15.8, 10.2 Hz), 2.38 (1H, dd, JZ15.8, 7.3 Hz),
2.42–2.56 (1H, m), 2.71 (1H, d of a pair of ABq, JZ
15.2 Hz), 4.14 (1H, d, JZ8.3 Hz), 4.23 (1H, dd, JZ8.3,

T. Okitsu et al. / Tetrahedron 61 (2005) 9180–9187
9185
6.6 Hz), 4.78 (1H, d of a pair of ABq, JZ15.2 Hz), 6.77–
6.80 (2H, m), 7.17–7.33 (13H, m); 13C NMR (125 MHz,
CDCl3) d 15.4, 34.2, 38.0, 45.1, 51.4, 63.1, 126.5, 127.0,
127.1, 127.6, 128.1, 128.3, 128.6, 128.8, 129.4, 136.9,
140.9, 142.2, 175.5; HRMS calcd for C25H25NO 355.1936,
found 355.1938.
(major), 60.0 (minor), 127.3 (both isomers), 127.8 (major),
128.0 (minor), 128.6 (both isomers), 136.8 (minor), 137.0
(major), 174.3 (major), 174.4 (minor); HRMS calcd for
C13H17NO 203.1310, found 203.1305.
4.1.14. 1-Benzyl-4-methyl-5-(phenylthiomethyl)pyrroli-
din-2-one, 2f. Following the general procedure, the crude
material was obtained from 1f (167 mg, 0.400 mmol),
Bu3SnH (438 mL, 1.60 mmol) and AIBN (13.4 mg,
0.080 mmol). Chromatography on silica gel (hexane/
AcOEt 5:1/4:1) gave 2f (54.3 mg, 44%) as an inseparable
4.1.11. 5-Benzhydryl-1-benzyl-4,4-dimethylpyrrolidin-2-
one, 2c. Following the general procedure, the crude material
was obtained from 1c (147 mg, 0.400 mmol), Bu3SnH
(219 mL, 0.800 mmol) and AIBN (6.7 mg, 0.040 mmol).
Chromatography on silica gel (hexane/AcOEt 4:1) gave 2c
(144 mg, 97%) as colorless crystals: mp 84–86 8C (hexane).
IR (CHCl3) 1675 cmK1; 1H NMR (270 MHz, CDCl3) d 0.76
(3H, s), 0.86 (3H, s), 1.90 (1H, d of a pair of ABq, JZ
16.2 Hz), 2.24 (1H, d of a pair of ABq, JZ16.2 Hz), 2.42
(1H, d of a pair of ABq, JZ14.5 Hz), 3.68 (1H, d, JZ
7.6 Hz), 4.21 (1H, d, JZ7.6 Hz), 4.90 (1H, d of a pair of
ABq, JZ14.5 Hz), 6.88–6.92 (2H, m), 7.19–7.38 (13H, m);
13C NMR (68 MHz, CDCl3) d 24.1, 29.3, 38.2, 44.6, 45.2,
52.7, 69.2, 126.5, 127.1, 127.4, 128.2, 128.3, 128.6, 128.7,
129.1, 130.0, 136.2, 140.4, 142.4, 174.5; HRMS calcd for
C26H27NO 369.2093, found 369.2095.
ca. 2:1 mixture of diastereomers. IR (CHCl3) 1675 cmK1
;
1H NMR (270 MHz, CDCl3) d 0.98 (3H!2/3, d, JZ
6.9 Hz), 1.11 (3H!1/3, d, JZ6.6 Hz), 2.03 (1H!2/3, dd,
JZ17.0, 3.8 Hz), 2.27–2.37 (1H, m), 2.47–2.56 (2H!1/3,
m), 2.77 (1H!2/3, dd, JZ17.3, 8.9 Hz), 2.85 (1H!2/3, dd,
JZ13.9, 8.2 Hz), 2.99 (1H!1/3, dd, JZ13.5, 7.6 Hz),
3.07–3.15 (2H!2/3C1H!1/3, m), 3.61 (1H!1/3, td, JZ
7.3, 3.6 Hz), 3.81 (1H!1/3, d of a pair of ABq, JZ
15.2 Hz), 3.83 (1H!2/3, d of a pair of ABq, JZ15.2 Hz),
4.95 (1H!2/3, d of a pair of ABq, JZ15.2 Hz), 4.97 (1H!
1/3, d of a pair of ABq, JZ15.2 Hz), 7.12–7.30 (5H, m); 13C
NMR (68 MHz, CDCl3) d 14.7, 20.5, 29.6, 30.5, 30.7, 33.3,
36.6, 38.1, 38.6, 44.3, 44.4, 58.8, 63.3, 126.6, 126.7, 127.4,
127.5, 127.8, 128.1, 128.6, 128.8, 129.0, 129.8, 130.0,
135.3, 135.6, 136.3, 136.5, 174.2, 174.7; HRMS calcd for
C19H21NOS 311.1344, found 311.1342.
4.1.12. (4R*,5S*)-5-Benzhydryl-1-benzyl-4-phenylpyr-
rolidin-2-one, 2d. Following the general procedure, the
crude material was obtained from 1d (166 mg,
0.400 mmol), Bu3SnH (219 mL, 0.800 mmol) and AIBN
(6.7 mg, 0.040 mmol). Chromatography on silica gel
(hexane/AcOEt 5:1/4:1) gave 2d (155 mg, 93%) as
colorless crystals: mp 148–150 8C (AcOEt). IR (CHCl3)
4.1.15. 1-Benzyl-5-isopropyl-4,4-dimethylpyrrolidin-2-
one, 2g. Following the general procedure, the crude material
was obtained from 1g (97.3 mg, 0.400 mmol), Bu3SnH
(219 mL, 0.800 mmol) and AIBN (6.7 mg, 0.040 mmol).
Chromatography on silica gel (hexane/AcOEt 4:1) gave 2g
1
1675 cmK1; H NMR (270 MHz, CDCl3) d 2.25 (1H, dd,
JZ17.5, 1.7 Hz), 2.48 (1H, dd, JZ17.5, 8.6 Hz), 3.14 (1H,
d of a pair of ABq, JZ14.5 Hz), 3.23 (1H, d, JZ8.9 Hz),
4.19 (1H, dd, JZ7.3, 1.0 Hz), 4.29 (1H, d, JZ7.5 Hz), 5.07
(1H, d of a pair of ABq, JZ14.5 Hz), 6.74–6.77 (2H, m),
7.01–7.35 (18H, m); 13C NMR (68 MHz, CDCl3) d 37.7,
41.0, 45.2, 55.2, 67.7, 126.4, 126.7, 127.1, 127.5, 128.3,
128.6, 128.7, 128.8, 128.9, 136.0, 141.0, 144.3, 174.7. Anal.
Calcd for C30H27NO: C, 86.30; H, 6.52; N, 3.35. Found: C,
86.32; H, 6.56; N, 3.39.
(63.2 mg, 64%) as a colorless oil. IR (CHCl3) 1665 cmK1
;
1H NMR (270 MHz, CDCl3) d 0.88 (3H, s), 0.95 (3H, d, JZ
6.9 Hz), 1.09 (3H, d, JZ7.3 Hz), 1.09 (3H, s), 2.03 (1H, d of
a pair of ABq, JZ16.5 Hz), 2.02–2.11 (1H, m), 2.41 (1H, d
of a pair of ABq, JZ16.5 Hz), 2.84 (1H, d, JZ2.0 Hz), 3.86
(1H, dd, JZ14.9, 1.0 Hz), 5.31 (1H, d, JZ14.9 Hz), 7.25–
7.36 (5H, m); 13C NMR (68 MHz, CDCl3) d 17.3, 22.1,
23.5, 29.8, 31.0, 36.6, 45.6, 45.8, 70.7, 127.4, 128.4, 128.7,
136.4, 174.5.
4.1.13. 1-Benzyl-4,5-dimethylpyrrolidin-2-one, 2e.
Following the general procedure, the crude material was
obtained from 1e (80.5 mg, 0.400 mmol), Bu3SnH (219 mL,
0.800 mmol) and AIBN (6.7 mg, 0.040 mmol). Chromato-
graphy on silica gel (hexane/AcOEt 20:1) gave 2e (20.8 mg,
26%) as an inseparable ca. 3:1 mixture of diastereomers. IR
4.1.16. 1,5-Dibenzyl-4,4-dimethylpyrrolidin-2-one, 2h.
Following the general precedure, the crude material was
obtained from 1h (117 mg, 0.400 mmol), Bu3SnH (219 mL,
0.800 mmol) and AIBN (6.7 mg, 0.040 mmol). Chromato-
graphy on silica gel (hexane/AcOEt 5:1) gave 2h (83.8 mg,
71%) as colorless crystals: mp 74–75 8C (hexane). IR
1
(CHCl3) 1670 cmK1; H NMR (270 MHz, CDCl3) d 0.99
1
(CHCl3) 1675 cmK1; H NMR (270 MHz, CDCl3) d 0.82
(3H!3/4, d, JZ6.6 Hz), 1.02 (3H!3/4, d, JZ6.9 Hz),
1.04 (3H!1/4, d, JZ6.9 Hz), 1.15 (3H!1/4, d, JZ
6.3 Hz), 1.92 (1H!1/4, br sep, JZ7.6 Hz), 2.06 (1H!1/
4, dd, JZ16.5, 7.6 Hz), 2.14 (1H!3/4, ddd, JZ15.0, 7.3,
1.0 Hz), 2.41 (1H!3/4, br sep, JZ7.3 Hz), 2.50 (1H!3/4,
dd, JZ16.5, 8.3 Hz), 2.64 (1H!1/4, ddd, JZ16.5, 8.3,
1.0 Hz), 3.03 (1H!1/4, qd, JZ6.3, 5.9 Hz), 3.49 (1H!3/4,
qd, JZ6.9, 6.6 Hz), 3.93 (1H!3/4, d of a pair of ABq, JZ
15.2 Hz), 3.96 (1H!1/4, d of a pair of ABq, JZ15.2 Hz),
4.97 (1H!1/4, d of a pair of ABq, JZ15.2 Hz), 4.99 (1H!
3/4, d of a pair of ABq, JZ15.2 Hz), 7.21–7.35 (5H, m); 13C
NMR (68 MHz, CDCl3) d 13.0 (major), 14.7 (major), 18.2
(minor), 18.5 (minor), 31.0 (major), 35.0 (minor), 38.0
(major), 38.7 (minor), 43.9 (minor), 44.0 (major), 55.7
(3H, s), 1.07 (3H, s), 2.12 (1H, d of a pair of ABq, JZ
16.3 Hz), 2.38 (1H, d of a pair of ABq, JZ16.3 Hz), 2.81
(2H, m), 3.30 (1H, dd, JZ7.9, 6.3 Hz), 3.34 (1H, d of a pair
of ABq, JZ14.8 Hz), 4.95 (1H, d of a pair of ABq, JZ
14.8 Hz), 6.96–6.99 (2H, m), 7.11–7.14 (2H, m), 7.23–7.33
(6H, m); 13C NMR (68 MHz, CDCl3) d 23.3, 28.0, 36.3,
36.9, 44.9, 45.3, 67.0, 126.5, 127.3, 128.4, 128.6, 129.1,
136.5, 138.5, 174.1. Anal. Calcd for C20H23NO: C, 81.81;
H, 7.90; N, 4.77. Found: C, 81.83; H, 8.03; N, 4.65.
4.1.17. (3R*,4R*,5S*)-5-Benzhydryl-1-benzyl-3-[(S*)-
hydroxy(phenyl)methyl]-4-phenylpyrrolidin-2-one, 4a
and its 3-[(R*)-hydroxy(phenyl)methyl] isomer, 5a:

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T. Okitsu et al. / Tetrahedron 61 (2005) 9180–9187
general procedure for sequential radical cyclization and
aldol reaction. A solution of enamide 1d (200 mg,
0.48 mmol), Bu3SnH (0.26 mL, 0.96 mmol) and AIBN
(7.7 mg, 0.048 mmol) in benzene (5 mL) was heated at
reflux for 45 min. After cooling, a solution of aldehyde 3a
(0.195 mL, 0.192 mmol) in benzene was added to the
mixture and the resulting mixture was refluxed for 12 h and
allowed to cool to room temperature. According to
Enholm’s procedure for workup, the mixture was concen-
trated under reduced pressure and diluted with Et2O. To the
mixture were added DBU (0.32 mL) followed a solution of
iodine in Et2O until the iodine color persisted. The mixture
was filtered through a pad of silica gel and the filtrate was
concentrated under reduced pressure. The crude material
was chromatographed (hexane/AcOEt 7:1/5:1/3:1) to
give 4a (108 mg, 43%) and 5a (84 mg, 33%). Compound
which was dissolved in THF (1 mL). To the solution was
added a 1 M solution of TBAF in THF (0.3 mL, 0.3 mmol)
at room temperature, and the mixture was stirred for two
days. The mixture was diluted with water, and whole was
extracted with AcOEt, washed successively with water and
brine, dried (MgSO4), and concentrated under reduced
pressure. The residue was chromatographed on silica gel
(hexane/AcOEt 7:1) to give 4b. Compound 4b: IR (CHCl3)
3450, 1660 cmK1; 1H NMR (270 MHz, CDCl3) d 2.63 (1H,
dd, JZ8.5, 5.4 Hz), 2.91 (1H, dd, JZ5.4, 4.0 Hz), 3.51 (1H,
d, JZ14.6 Hz), 3.79 (1H, t, JZ8.5 Hz), 4.26, (1H, d, JZ
6.3 Hz), 4.33 (1H, dd, JZ6.3, 4.0 Hz), 4.47 (1H, br s), 5.19
(1H, d, JZ14.6 Hz), 5.82, (1H, dd, JZ15.8, 8.5 Hz), 6.35
(1H, d, JZ15.8 Hz), 6.60–7.59 (25H, m); 13C NMR
(68 MHz, CDCl3) d 44.7, 45.7, 56.2, 56.3, 67.7, 74.7,
126.6, 126.7, 127.1, 127.3, 127.8, 128.4, 128.6, 128.7,
128.8, 129.0, 129.1, 132.9, 135.8, 136.3, 140.2, 140.7,
144.4, 176.1; HRMS calcd for C39H35NO2 549.2668, found
549.2668. Compound 5b: IR (CHCl3) 3400, 1665 cmK1; 1H
NMR (270 MHz, CDCl3) d 2.88 (1H, dd, JZ5.6, 3.5 Hz),
3.06 (1H, dd, JZ5.6, 4.0 Hz), 3.16 (1H, d, JZ14.9 Hz),
3.42 (1H, br), 4.26 (1H, d, JZ9.2 Hz), 4.33 (1H, dd, JZ9.2,
4.0 Hz), 4.75 (1H, br), 5.02 (1H, d, JZ14.9 Hz), 6.08 (1H,
dd, JZ15.8, 6.3 Hz), 6.64 (1H, d, JZ15.8 Hz), 6.90–7.34
(25H, m, Ph); 13C NMR (68 MHz, CDCl3) d 43.8, 45.9,
57.3, 58.0, 67.5, 71.4, 126.4, 126.5, 127.0, 127.2, 127.5,
127.7, 128.1, 128.4, 128.6, 128.7, 128.9, 129.3, 131.5,
136.6, 141.9, 144.9, 175.5. Anal. Calcd for C39H35NO2: C,
85.21; H, 6.42; N, 2.55. Found: C, 84.99; H, 6.44; N, 2.53.
4a: mp 188–190 8C (hexane/AcOEt). IR(CHCl3) 1660 cmK1
;
1H NMR (270 MHz, CDCl3) d 2.67 (1H, dd, JZ4.9,
3.3 Hz), 2.73 (1H, dd, JZ9.2, 4.9 Hz), 3.42 (1H, d of a pair
of ABq, JZ14.5 Hz), 4.06 (1H, d, JZ6.6 Hz), 4.17 (1H, d,
JZ9.2 Hz), 4.29 (1H, dd, JZ6.6, 3.3 Hz), 4.75 (1H, s), 5.21
(1H, d of a pair of ABq, JZ14.5 Hz), 6.11 (2H, br d, JZ
7.3 Hz), 6.87–7.35 (23H, m); 13C NMR (68 MHz, CDCl3) d
44.0, 45.7, 56.5, 57.9, 67.6, 75.6, 126.3, 126.6, 127.0, 127.4,
127.8, 128.0, 128.1, 128.4, 128.5, 128.6, 128.7, 129.0,
129.2, 135.8, 140.0, 140.2, 140.7, 144.4, 176.4. Anal. Calcd
for C37H33NO2: C, 84.86; H, 6.35; N, 2.67. Found: C, 84.80;
H, 6.49; N, 2.61. Compound 5a: mp 179–180 8C (hexane/
AcOEt). IR (CHCl3) 1665 cmK1 1H NMR (270 MHz,
;
CDCl3) d 2.88 (1H, dd, JZ4.6, 3.0 Hz), 2.89 (1H, d of a pair
of ABq, JZ14.9 Hz), 2.96 (1H, dd, JZ4.6, 3.3 Hz), 4.09
(1H, d, JZ9.9 Hz), 4.24 (1H, dd, JZ9.9, 3.0 Hz), 4.35 (1H,
br s), 4.98 (1H, d of a pair of ABq, JZ14.9 Hz), 5.33 (1H, d,
JZ3.3 Hz), 6.07 (2H, br d, JZ7.3 Hz), 6.83–7.28 (23H, m);
13C NMR (68 MHz, CDCl3) d 43.2, 45.9, 58.2, 59.5, 67.5,
72.1, 126.0, 126.1, 126.4, 126.6, 127.0, 127.3, 127.5, 128.1,
128.2, 128.3, 128.4, 128.5, 128.6, 128.9, 136.5, 141.6,
141.7, 142.5, 145.6, 175.7. Anal. Calcd for C37H33NO2: C,
84.86; H, 6.35; N, 2.67. Found: C, 84.56; H, 6.46; N, 2.60.
4.1.19. (3R*,4R*,5S*)-5-Benzhydryl-1-benzyl-3-[(R*)-1-
hydroxyheptyl]-4-phenylpyrrolidin-2-one, 4c. Following
general procedure, the crude material was obtained from 1d
(200 mg, 0.48 mmol), Bu3SnH (0.26 mL, 0.96 mmol),
AIBN (7.7 mg, 0.048 mmol), and 3c (231 mg, 1.92 mmol)
and. After workup, the crude product was chromatographed
(hexane/AcOEt 7:1/3:1) to give 4c (114 mg, 45%) and 2d
(107 mg, 53%). Compound 4c: IR (CHCl3) 3450,
1660 cmK1 1H NMR (270 MHz, CDCl3) d 0.80–1.38
;
(13H, m), 2.51 (1H, dd, JZ8.6, 5.3 Hz), 2.85 (1H, dd, JZ
5.3, 4.0 Hz), 3.29 (1H, br), 3.49 (1H, d, JZ14.9 Hz), 4.21
(1H, d, JZ6.9 Hz), 4.29 (1H, dd, JZ6.9, 4.0 Hz), 5.12 (1H,
d, JZ14.9 Hz), 6.67–7.33 (20H, m); 13C NMR (68 MHz,
CDCl3) d 14.0, 22.5, 24.5, 29.1, 31.7, 34.6, 45.6, 55.3, 56.8,
67.9, 72.7, 126.7, 127.0, 127.1, 127.3, 127.6, 128.5, 128.7,
128.8, 129.0, 136.0, 140.4, 176.8; HRMS calcd for
C37H41NO2 531.3137, found 531.3109.
4.1.18. (3R*,4R*,5S*)-5-Benzhydryl-1-benzyl-3-[(R*,E)-
1-hydroxy-3-phenylallyl]-4-phenylpyrrolidin-2-one, 4b
and its 3-[(S*,E)-1-hydroxy-3-phenylallyl] isomer, 5b.
Following general procedure, the crude material was
obtained from 1d (200 mg, 0.48 mmol), Bu3SnH (262 mL,
0.96 mmol), AIBN (7.7 mg, 0.048 mmol) and 3b (259 mg,
1.92 mmol). The crude product was chromatographed
(hexane/AcOEt 7:1). The first fraction gave a 2.6:1
inseparable mixture (183 mg) of 4b and 2d on the basis of
intensities of signals, d 5.07 (d, JZ14.9 Hz, one of benzylic
H, 4b) and 5.19 (d, JZ14.9 Hz, 2d), in the 1H NMR
spectrum of the mixture. The yields of 4b and 2d were
calculated to be 54 and 20%, respectively. The second
fraction gave 5b (58 mg, 15%). To obtain analytical sample,
4b was silylated. The mixture of 4b and 2d was dissolved in
DMF (0.5 mL), and TBDPSCl (0.062 mL, 0.24 mmol) and
imidazole (33 mg, 0.48 mmol) were added to the mixture at
room temperature. After being stirred for 3 h, the mixture
was diluted with water, and the whole was extracted with
AcOEt. The organic phase was washed successively with
water and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed on
silica gel (hexane/AcOEt 7:1/3:1) to give silylated 4b,
4.1.20. (3R*,4R*,5S*)-5-Benzhydryl-1-benzyl-3-[(R*)-
cyclohexyl(hydroxy)methyl]-4-phenylpyrrolidin-2-one,
4d. Following general procedure, the reaction was carried
out by using 1d (200 mg, 0.48 mmol), Bu3SnH (0.26 mL,
0.96 mmol), ACN (12 mg, 0.048 mmol) and 3d (0.24 mL,
1.9 mmol) in toluene (5 mL). The crude product was
chromatographed (hexane/AcOEt 7:1/3:1) to give 4d
(49.9 mg, 20%) and 2d (150 mg, 75%). Compound 4d: mp
1
144–145 8C (hexane). IR (CHCl3) 3450, 1660 cmK1; H
NMR (270 MHz, CDCl3) d 0.66–1.77 (11H, m), 2.63 (1H,
dd, JZ9.2, 5.6 Hz), 2.87 (1H, dd, JZ5.6, 4.3 Hz), 2.98 (1H,
d, JZ9.2 Hz), 3.46 (1H, d, JZ14.9 Hz), 4.25 (1H, JZ
6.6 Hz), 4.31 (1H, dd, JZ6.6, 4.3 Hz), 5.13 (1H, d, JZ
14.9 Hz), 6.68–7.32 (20H, m); 13C NMR (68 MHz, CDCl3)
d 24.9, 25.7, 26.2, 30.0, 40.0, 45.2, 45.5, 52.6, 56.3, 67.8,

T. Okitsu et al. / Tetrahedron 61 (2005) 9180–9187
9187
´ ´
5. Flisinska-Łuczak, J.; Lesniak, S.; Nazarski, R. B. Tetrahedron
76.6, 126.7, 127.0, 127.2, 127.6, 128.1, 128.4, 128.6, 128.7,
128.8, 128.9, 129.0, 135.9, 140.4, 140.8, 144.3, 177.4. Anal.
Calcd for C37H39NO2: C, 83.89; H, 7.42; N, 2.64. Found: C,
83.86; H, 7.50; N, 2.66.
´
2004, 60, 8181–8188. See also: Lesniak, S.; Flisinska, J.
´
Synthesis 2001, 135–139.
6. For recent our researches on radical cyclization onto enamides,
see: (a) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.;
Tamura, O. Chem. Commun. 2000, 1527–1528. (b) Ishibashi,
H.; Kato, I.; Takeda, Y.; Tamura, O. Tetrahedron Lett. 2001,
42, 931–933. (c) Ishibashi, H.; Ishita, A.; Tamura, O.
Tetrahedron Lett. 2002, 43, 473–475. (d) Kato, I.;
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