Diastereoselective borono-Mannich reactions on cyclic N-acyliminium ions

Article abstract of DOI:10.1016/j.tet.2007.11.046

The addition of boronic acids to five- and six-membered ring N-acyliminium ions has been employed to prepare 5- and 6-substituted 4-hydroxypyrrolidin-2-ones and 5-hydroxypiperidin-2-ones, respectively, in a diastereoselective fashion. Crown Copyright

Full text of DOI:10.1016/j.tet.2007.11.046

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1409e1419
www.elsevier.com/locate/tet
Diastereoselective borono-Mannich reactions on cyclic
N-acyliminium ions
*
Ian R. Morgan, Arife Yazici, Stephen G. Pyne
Department of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
Received 23 August 2007; received in revised form 31 October 2007; accepted 15 November 2007
Available online 19 November 2007
Abstract
The addition of boronic acids to five- and six-membered ring N-acyliminium ions has been employed to prepare 5- and 6-substituted 4-hy-
droxypyrrolidin-2-ones and 5-hydroxypiperidin-2-ones, respectively, in a diastereoselective fashion.
Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
R1O
HO
R1O
R3
1. Introduction
( )n
R3SnR4
or
( )n
N
3
O
O
N
R3SiR4
As part of a project aimed at the synthesis of bioactive poly-
hydroxylated pyrrolidine, piperidine, indolizidine and pyrro-
lizidine alkaloids and their analogues,1 we have examined
the addition of organoboronic acids to five- and six-membered
ring N-acyliminium ions. The synthesis of trans 5-substituted-
4-hydroxypyrrolidin-2-ones and 6-substituted-5-hydroxy-
piperidin-2-ones is relatively easily achieved from the addition
of tin or silicon based nucleophiles to five- and six-membered
ring N-acyliminium ions (Scheme 1).2e7 cis-Diastereoselec-
tive additions to N-acyliminium ions have been reported by
Batey.5 He has shown that the racemic hemi-aminal deriva-
tives, rac-1 (n¼1 or 2), having an exo-cyclic N-acyl group, re-
act with 2-substituted vinyl- and arylboronate ethylene glycol
esters, in the presence of BF3$Et2O, to give products rac-2 in
a highly diastereoselective manner (Scheme 1).5 This work,
however, has not been extended to enantiomerically enriched
cyclic hemi-aminals of the type A (n¼1, 2) having an endo-
cyclic N-acyl group. Here we report our work on the borono-
Mannich reactions of the cyclic N-acyliminium ions generated
in situ from the enantiomerically enriched cyclic hemi-aminals
A (n¼1, 2).
3
R2
A
R2
Lewis acid
B
(trans/cis mixture)
R
O
B
O
HO
( )n
HO
(1.4 equiv)
( )n
R
BF3·Et2O (4 equiv)
HO
N
N
Cbz
rac-2
CH2Cl2
-78 °C to rt
( n = 1 , 2)
Cbz
rac-1
dr > 98 : < 2
yields 77-99%
Scheme 1.
2. Results and discussion
The six-membered ring hemi-aminal (5S )-3 (dr¼3:1) was
prepared from the known N-PMB-(3S )-hydroxyglutarimi-
de2m,6 by NaBH4 reduction. Under the conditions described
by Batey5 the diol (5S )-3 when treated with (E )-2-styrylboro-
nic acid 4 (X¼OH, n¼2), in the presence of BF3$Et2O, failed
to produce the desired product, even at elevated temperatures.
However, when the more polar solvent MeCN was used this
modification gave rise to the desired cis-adduct 5 in a yield
of 77% and with high diastereoselectivity (>98:<2) as deter-
* Corresponding author.
E-mail address: spyne@uow.edu.au (S.G. Pyne).
1
mined by H NMR analysis at 500 MHz (Scheme 2). The
0040-4020/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.046

1410
I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
Table 1
Products from the reactions of RB(OH)2 with (4S )-18
cis isomers. The J5,6 values for all the major diastereomers
of these compounds were 5.1e6.0 Hz, and is consistent with
that of the known cis-6-phenyl analogue of these compounds,
which had J5,6¼5.2 Hz.7
Entry
R
Product
Yield (%)
dr (trans/cis)
1
2
3
4
5
6
7
8
a
(E )-PhCH]CH
(E )-PhCH]CHa
2-Furyl
19a
19a
19b
19c
19d
19e
19f
47
59
79
55
72
0
91:9
92:8
The stereochemical outcomes of the major products in
Scheme 2 are consistent with the formation of an initial boro-
nate complex C (Scheme 2) to the 5-hydroxy group of (5S )-3
followed by the intramolecular delivery of the sp2 hybridised
boron ligand to the same face of the iminium ion intermediate.
A similar mechanism has been proposed for the borono-Man-
nich reaction involving acyclic iminium ions.1e,8 Further sup-
port for such boronate intermediates being responsible for the
high cis-diastereoselectivity came from the result of treating 9,
the O-methyl derivative of (5S )-3, with potassium (E )-2-styryl-
trifluoroborate in the presence of BF3$Et2O. This reaction was
high yielding (96%) but poorly diastereoselective in favour of
the cis-adduct 10 (Scheme 4).9
71:29
89:11
38:62
d
2-Benzofuranyl
2-Thienyl
Phenyl
4-MeOC6H4
3,4-(MeO)2C6H3
48
74
72:28
74:26
19g
The corresponding RBF3K was used.
corresponding potassium trifluoroborate 4 (X¼F, n¼3) also
provided the cis-adduct 5 but with a reduced yield (72%)
and a lower, but good diastereoselectivity (dr¼92:8). We
have examined the reactions of (5S )-3 with other boronic
acids and boronates as shown in Table 1. Only the electron-
rich boronic acids, 2-furylboronic acid and 2-benzofuranylboro-
nic acid, gave the desired adducts, 6 and 7, respectively
(Scheme 2). The other boronic acids and boronates did not re-
act or gave mixtures that were not readily characterised. The
use of MeNO2 as an alternative, less nucleophilic solvent to
MeCN did not provide increased yields of the desired
products.
BF3K
Ph
MeO
HO
MeO
BF3·OEt2
MeCN, 0 °C - rt
18 h
N
PMB
9
O
Ph
N
O
PMB
10
dr = 65 : 35
[96%, cis : trans = 65 : 35]
Scheme 4.
B(X)n
(3 equiv)
HO
HO
HO
Ph
4
Similarly, (4S )-1110,11 was also unreactive under Batey’s
conditions but, in contrast to (5S )-3, treatment of (4S )-11
with (E )-2-styrylboronic acid 4 (X¼OH, n¼2) and BF3$Et2O
in MeCN, under similar reaction conditions to that of (5S )-3,
did not result in the desired product 14. Instead this reaction
resulted in formation of the cyclic boronate ester 12 that
was readily isolated (73% yield) and characterised. Repeating
this reaction with heating at reflux temperature gave rise to the
epoxide 13 (Scheme 5). Attempts to purify this epoxide by
column chromatography were unsuccessful due to its instabil-
ity on silica gel.11b While further treatment of this epoxide mix-
ture in MeCN at reflux with fresh 4 (X¼OH, n¼2 or X¼F,
n¼3, as the Kþ salt) and BF3$Et2O gave none of the desired
product 14. When MeNO2 was used as solvent in the reaction
of (4S )-11 then the desired adduct cis-14 was isolated in 20%
yield using either (E )-2-styrylboronic acid 4 (X¼OH, n¼2) or
its ethylene glycol boronate ester 4 (n¼2, X¼OCH2CH2O).
The 4,5-cis-stereochemistry of 14 was based on the magnitude
of J4,5 (6.0 Hz) for this compound.2a,b In related literature ex-
amples, J4,5 is typically 0e2.5 Hz for trans isomers and 6.0e
7.5 Hz for the corresponding cis isomers.2a,b Under similar re-
action conditions and using MeNO2 as solvent, the electron-
rich boronic acids, 2-furyl-, 2-benzofuranyl- and 3,4-dime-
thoxyphenylboronic acid, also reacted with (4S )-11, furnish-
ing the adducts 15e17, respectively, (Scheme 5) and in
higher yields than 14. Interestingly, both adducts 15 and 17
favoured formation of the 4,5-trans-adduct, while the 2-benzo-
furanyl-adduct 16 favoured the 4,5-cis-diastereomer in high
diastereoselectivity (dr¼92:8). The stereochemical outcomes
of 14 and 16 are consistent with the formation of an initial bor-
onate complex similar to C (Scheme 2). While that of 15 and
N
O
N
O
Ph
BF3·Et2O (5 equiv)
MeCN
0 °C to rt, 12 h
PMB
PMB
5
(5S)-3
(dr = 3 : 1)
[4; X = OH, 77%,
dr = > 98 : < 2]
[4; X = F, 72%,
dr = 92 : 8]
X
X
O
B
R
N
O
PMB
C
HO
O
HO
N
O
N
O
PMB
6
PMB
7
O
[49%, dr = 80 : 20]
[70%, dr = > 98 : < 2]
Scheme 2.
To determine the stereochemistry of 5, the alcohol was oxi-
dised using the DesseMartin periodinane reagent to its corre-
sponding ketone 8, which upon sodium borohydride reduction
gave the carbinol 5 as the major isomer in an 81:19 mixture of
two carbinol isomeric products (Scheme 3). From literature
precedence7 the major isomer from reduction of 8 was ex-
pected to be the cis-isomer 5, thus we have assigned the major
isomers of 5e7, prepared according to Scheme 2, as the 5,6-
NaBH4
MeOH
Dess-
Martin
O
5 + 5-epi-5
5
43% overall
oxidation
N
O
Ph
PMB
8
[dr = 81 : 19]
Scheme 3.

I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
1411
HO
HO
acids (entries 3e5) gave the adducts 19b and 19c in which
the major diastereoisomers had the trans stereochemistry,
while the 2-thienyl adduct 19e favoured the unexpected cis-ad-
duct. The reaction of (4S )-18 with furan itself in the presence
of BF3$Et2O also gave 19b (40% yield) as a 55:45 mixture of
trans and cis isomers, respectively. In contrast, phenylboronic
acid was unreactive (entry 6), while its more electron-rich an-
alogues, 4-methoxyphenylboronic acid and 3,4-dimethoxyphe-
nylboronic, acid gave their respective adducts 19f and 19g, in
yields (48 and 74%, respectively) that reflected their electron-
richness and associated nucleophilicities. The latter two reac-
tions favoured formation of the trans isomer (entries 7 and 8).
The stereochemistry of these adducts 19 was readily deter-
mined from examination of the coupling constant J4,5, which
was typically 0e2.5 Hz for the trans isomers and 6.0e
7.5 Hz for the corresponding cis isomers, consistent with liter-
ature examples.2a,b Furthermore, O-debenzylation of 19a with
BBr3 gave trans-14 (Scheme 6), identical to the minor isomer
formed from the reaction of (4S )-11 and (E )-2-styrylboronic
acid (Scheme 5).
Ph
O
(1.4 equiv)
B(X)n
4
N
Bn
BF3·Et2O (4 equiv)
MeCN or MeNO2
rt to reflux, 16 h
(4S)-11
Ph
O
B
O
O
O
O
N
Bn
12
N
Bn
13
[4; X = OH, 73%]
HO
Ph
O
N
Bn
cis-14
[4; X = OH or OCH2CH2O, 20%, dr = 91 : 9]
HO
HO
O
O
O
O
N
N
Bn
16
Bn
15
In an attempt to prepare the compound 19a in higher yield
and diastereoselectivity via an alternative route, the succinimide
2011 was treated with 2-phenylvinylmagnesium bromide14
to give a diastereomeric mixture of tertiary carbinols 21
(Scheme 7). Reduction of this mixture with Et3SiH/BF3$Et2O
gave the trans-5-(2-phenylethyl)-2-pyrrolidinone 22 in 83%
yield (dr¼91:9). A plausible mechanism for this transformation
is shown in Scheme 7. The intermediate iminium ion D un-
dergoes 1,4-addition of hydride to give the N-acyl enamine
E, which upon protonolysis gives the iminium ion F that is fur-
ther reduced to the trans-product 22. The reduction of alkenes
with Et3SiH/BF3$Et2O in the absence of a transition metal
catalyst has precedence15 as also does the formation of 4,5-
[65%, dr = 77 : 23 ]
HO
[56%, dr = 92 : 8 ]
O
N
Bn
MeO
MeO
17
[44%, dr = 72 : 28]
Scheme 5.
17 suggest that direct addition of the arylboronic acid to the
cyclic iminium ion intermediate had occurred.
The results of the reactions of (4S )-18,12 the 4-O-benzyl
ether of (4S )-11, with boronic acids and trifluoroboronates13
are shown in Scheme 6 and Table 1. In contrast to the reaction
of (4S )-11, these reactions were successful under Batey’s
conditions (CH2Cl2 solution) but at a slightly elevated temper-
ature (rt).
BnO
HO
BnO
O
MgBr
Ph
Ph
O
O
THF
45%
BnO
N
N
Bn
21
Bn
20
BnO
R
BnO
HO
Et3SiH
RB(OH)2 (3 equiv)
BF3·Et2O (4 equiv)
Et3SiH
Ph
O
O
O
N
Bn
(4S)-18
N
BF3·Et2O
N
Bn
D
Bn
19
CH2Cl2
0 °C to rt, 16 h
BnO
BnO
H+
HO
BBr3, CH2Cl2
0 °C, 10 min
Ph
Ph
O
O
N
N
19a
Bn
E
Bn
F
Ph
O
N
90%
Bn
trans-14
BnO
Et3SiH
Scheme 6.
Ph
dr = 91 : 9
O
83%
N
Bn
22
The reaction of (4S )-18 with (E )-2-styrylboronic acid 4
(X¼OH, n¼2) in CH2Cl2 at rt gave the 5-(2-styryl)-adduct
19a in 47% yield and as a 91:9 mixture of the trans and cis
isomers, respectively (Table 1, entry 1). This product 19a
was obtained in a slightly higher yield (59%) and diastereose-
lectivity (92:8) when potassium (E )-2-styryltrifluoroborate
was used (entry 2). The electron-rich heteroaromatic boronic
HO
PdCl2
PdCl2
Ph
22
19a
O
H2
76%
H2
67%
N
Bn
23
Scheme 7.

1412
I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
trans-pyrrolidinones from the reduction of hemi-aminals
related to 21.2r
(1H, d, J¼14.6 Hz, CHHPMP), 3.87 (1H, m, 5-H), 3.79 (3H,
s, OMe), 2.64 (1H, ddd, J¼18.0, 6.0, 4.2 Hz, 3-CHH),
2.40e2.48 (1H, m, 3-CHH ), 2.07e2.14 (1H, m, 4-CHH),
1.82e1.87 (1H, m, 4-CHH ); dC (CD3OD) 171.1, 160.4, 132.4,
129.8, 114.9, 72.7, 62.8, 55.7, 43.1, 32.4, 29.3; MS (ESIꢁ) m/z
285.8 (MþCl)ꢁ 100%; HRMS (ESIþ) calcd for C13H18NO4
(MþH)þ: 252.1236, found: 252.1246.
To prove the stereochemistry of 22, it was converted to the
alcohol 23 by hydrogenolysis over PdCl2. The same com-
pound 23 was obtained from 19a after treatment under similar
reductive conditions, thus indicating the trans stereochemistry
of 22 (Scheme 7).
In conclusion, we have demonstrated that boronic acids and
boronates add to five- and six-membered ring N-acyliminium
ions having an endo-cyclic N-acyl group to provide 5- and 6-
substituted 4-hydroxypyrrolidin-2-ones and 5-hydroxypiperi-
din-2-ones, respectively, in a diastereoselective fashion. The
six-membered rings adducts can be obtained with good to
high cis-diastereoselectivities but are limited to reactive, elec-
tron-rich, boronic acids. Nevertheless, such 5,6-cis-substituted
compounds are difficult to access using current methods.2c
3.1.2. (5S,6S )-1-(4-Methoxybenzyl)-5-hydroxy-
6-styrylpiperidin-2-one (5)
To a suspension of the diol 3 (0.150 g, 0.597 mmol) and (E )-
2-styrylboronic acid (0.265 g, 1.791 mmol) in anhydrous
MeCN (10 mL) at 0 ꢀC was added BF3$OEt2 (0.375 mL,
2.985 mmol) and the resulting solution was stirred at rt over-
night (ca. 15 h). The reaction was quenched by careful addition
of saturated NaHCO3 solution (5 mL), brine (5 mL) and diluted
with EtOAc (20 mL). The organic layer was separated and the
aqueous portion was further extracted with EtOAc (2ꢂ20 mL).
The combined organics were washed with brine (60 mL), dried
and the solvent removed. Column chromatography (EtOAc to
1% MeOH/EtOAc) of the crude residue yielded the olefin
5 (0.156 g, 0.463 mmol, 77%, Rf¼0.51, 1% MeOH/EtOAc)
essentially, as a single diastereoisomer. [a]2D3 þ12.4 (c 1.93,
CHCl3); nmax/cmꢁ1 3360, 2925, 2848, 1612, 1512, 1455,
1245, 1173, 1025, 749; dH 7.28e7.41 (5H, m), 7.16 (2H, d,
J¼8.6 Hz), 6.84 (2H, d, J¼8.6 Hz), 6.53 (1H, d, J¼16.0 Hz),
6.19 (1H, dd, J¼16.0, 7.4 Hz), 5.40 (1H, d, J¼14.6 Hz), 4.04
(1H, dd, J ca. 7, 6 Hz), 3.98 (1H, app dt, J¼10.0, 5.2 Hz), 3.79
(3H, s), 3.73 (1H, d, J¼14.6 Hz), 2.69 (1H, ddd, J¼18.3, 6.1,
4.1 Hz), 2.55 (1H, ddd, J¼18.3, 8.2, 9.6 Hz), 1.90e1.97 (2H,
m). dC 168.8, 158.8, 135.8, 134.4, 129.3, 128.8, 128.5, 128.0,
126.5, 124.4, 113.4, 67.7, 61.8, 55.2, 47.3, 29.3, 26.0; MS
(ESIꢁ) m/z 371.9 (MþCl)ꢁ 100%; HRMS (ESIþ) calcd for
C21H24NO3 (MþH)þ, 338.1756, found: 338.1766.
3. Experimental
3.1. General
Unless stated, CDCl3 was used as a solvent for all 1H NMR
(500 MHz) and 13C NMR (125 MHz) measurements. All IR
spectra were determined as neat samples. All solutions were
dried over anhydrous MgSO4. Petrol refers to the hydrocarbon
fraction of boiling point 40e60 ꢀC.
3.1.1. (5S )-1-(4-Methoxybenzyl)-5,6-dihydroxypiperidin-
2-one (3)
To a solution of (5S )-1-(4-methoxybenzyl)-6-hydroxypipe-
ridin-2,6-dione2m,6 (2.00 g, 8.02 mmol) in MeOH/CH2Cl2
(80:40 mL) at ꢁ15 ꢀC was added NaBH4 (1.52 g, 40.12 mmol)
and the reaction was monitored by TLC. After 40 min the reac-
tion was carefully quenched with acetone (30 mL). Saturated
NaHCO3 solution (30 mL) and then brine (30 mL) were added
and the volatiles were removed in vacuo. The crude residue
was taken up in EtOAc (150 mL) and washed with brine (1ꢂ
100 mL). The aqueous portions were then combined and re-ex-
tracted with EtOAc (1ꢂ50 mL) and then the combined organic
extracts were dried and concentrated to yield the crude diol as
a colourless solid. The crude product was purified by column
chromatography (10% MeOH/EtOAc) yielding the diol 3
(0.972 g, 3.87 mmol, 48%, Rf¼0.30 EtOAc) as a colourless solid
and as a mixture of diastereoisomers (3:1) showing: mp 120e
122 ꢀC;nmax/cmꢁ1 3263, 2935, 1614, 1562, 1244, 1029, 964,818.
Major isomer: dH 7.25 (2H, app, d, J¼8.6 Hz, 2-, 6-ArCH),
6.86 (2H, app d, J¼8.6 Hz, 3-, 5-ArCH), 4.89 (1H, d,
J¼14.7 Hz, CHHPMP), 4.73 (1H, dd, J¼4.9, 4.4 Hz, 6-CH),
4.45 (1H, d, J¼14.7 Hz, CHHPMP), 3.93 (1H, m, 5-H), 3.79
(3H, s, OMe), 2.68 (1H, ddd, J¼17.9, 9.8, 6.7 Hz, 3-CHH ),
2.47 (1H, ddd, J¼17.9, 6.5, 4.7 Hz, 3-CHH), 2.40 (1H, d,
J¼5.9 Hz, OH), 2.15e2.17 (1H, m, 4-CHH ), 1.82e1.86 (1H,
m, 4-CHH); dC (CD3OD) 172.3, 160.6, 130.5, 130.4, 115.0,
80.7, 68.4, 55.7, 47.5, 30.7, 24.1.
3.1.3. (5S,6R)-1-(4-Methoxybenzyl)-6-(furan-2-yl)-
5-hydroxypiperidin-2-one (6 and 6-epi-6)
Prepared in a similar fashion to 5 above, from the diol 3
(150 mg, 0.597 mmol), 2-furanboronic acid (100 mg,
0.894 mmol) and BF3$OEt2 (375 mL, 2.985 mmol) with stir-
ring at rt overnight. Column chromatography (EtOAc) of the
crude residue furnished trans-6 (7 mg, 0.023 mmol, 4%,
Rf¼0.42), cis-6 (63 mg, 0.209 mmol, 35%, Rf¼0.36) and
a cis/trans-mixture (19 mg, 0.063 mmol, 10%) as pale yellow
oils (cis/trans 80:20). The trans isomer: [a]2D4 þ13.1 (c 0.265,
CHCl3); nmax/cmꢁ1 3345, 2935, 2827, 1609, 1516, 1465, 1245,
1173; dH 7.39 (1H, br, 5-Ar0CH), 7.13 (2H, app d, J¼8.3 Hz,
2-, 6-ArCH), 6.83 (2H, app d, J¼8.3 Hz, 3-, 5-ArCH), 6.37
(1H, dd, J¼3.1, 1.8 Hz, 4-Ar0CH), 6.22 (1H, d, J¼3.1 Hz, 3-
Ar0CH), 5.51 (1H, d, J¼14.8 Hz, CHHePMP), 4.38 (1H, d,
J¼3.2 Hz, 6-H), 4.17e4.20 (1H, m, 5-H), 3.79 (3H, s, OMe),
3.46 (1H, d, J¼14.8 Hz, CHHePMP), 2.75 (1H, ddd, J¼18.0,
10.2, 7.1 Hz, 3-CHH), 2.54 (1H, ddd, J¼18.0, 6.6, 4.0 Hz, 3-
CHH ), 2.05e2.13 (1H, m, 4-CHH), 1.80e1.87 (1H, m, 4-
CHH ); dC 142.8 (2-Ar0CH), 129.4 (2-, 6-ArCH), 128.8 (ArC),
114.1 (3-, 5-ArC), 110.4 and 108.6 (3-, 4-Ar0CH), 67.3 (5-C),
60.7 (6-C), 55.2 (OMe), 46.9 (CH2ePMP), 27.3 (3-CH2), 24.8
Minor isomer: dH 7.26 (2H, app, d, J¼8.6 Hz, 2-, 6-ArCH),
6.87 (2H, app d, J¼8.6 Hz, 3-, 5-ArCH), 5.00 (1H, d, J¼
14.6 Hz, CHHPMP), 4.80 (1H, dd, J¼5.4, 2.9 Hz, 6-H), 4.29

I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
1413
(4-CH2); m/z (ESIꢁ) 299.8 (MꢁH)ꢁ 75%; HRMS (ESIþ)
calcd for C17H20NO4 (MþH)þ: 302.1392, found: 302.1384.
The cis isomer: [a]2D3 ꢁ10.4 (c 2.16, CHCl3); nmax/cmꢁ1
3309, 2919, 2848, 1610, 1513, 1475, 1246, 1177, 747; dH
7.46 (1H, dd, J¼1.6, 0.6 Hz, 5-Ar0CH), 7.09 (2H, app d,
J¼8.6 Hz, 2-Ar0CH), 6.83 (2H, app d, J¼8.6 Hz, 3-, 5-
ArCH), 6.42 (2H, dd, J¼3.2, 1.8 Hz, 4-Ar0CH), 6.32 (2H, d,
J¼3.2 Hz, 3-Ar0CH), 5.40 (1H, d, J¼14.6 Hz, CHHePMP),
4.49 (1H, d, J¼5.2 Hz, 6-CH), 3.98e4.04 (1H, m, 5-CH),
3.80 (3H, s, OMe), 3.42 (1H, d, J¼14.6 Hz, CHHePMP),
2.75 (1H, ddd, J¼18.2, 6.4, 3.2 Hz, 3-CHH), 2.57 (1H, ddd,
J¼18.2, 10.0, 8.0 Hz, 3-CHH ), 1.94e1.97 (2H, m, 4-CH2);
dC 169.4 (C]O), 159.0 (ArC), 149.7 (5-Ar0CH), 143.3 (2-
Ar0CH), 129.6 (2-, 6-ArCH), 128.6 (ArC), 114.0 (3-, 5-ArCH),
110.9, 110.5 (3-, 4-Ar0CH), 67.2 (5-CH), 57.7 (6-CH), 55.2
(OMe), 47.4 (CH2ePMP), 29.6 (3-CH2), 26.1 (4-CH2); m/z
(ESIꢁ) 299.8 (Mꢁ1)ꢁ 70%; HRMS (ESIþ) calcd for
C17H20NO4 (MþH)þ: 302.1392, found: 302.1393.
(3ꢂ25 mL) and the combined organic extracts were washed
with brine (50 mL) and the solvent evaporated to yield the ke-
tone 8 as pale yellow oil, which was used without any further
purification. dH 7.28e7.35 (5H, m), 7.19 (2H, d, J¼8.6 Hz),
6.85 (2H, d, J¼8.6 Hz), 6.50 (1H, dd, J¼16.0, 1.7 Hz), 6.05
(1H, dd, J¼16.0, 5.6 Hz), 5.41 (1H, d, J¼14.6 Hz), 4.42
(1H, dd, J¼5.6, 1.7 Hz), 3.85 (1H, d, J¼14.6 Hz), 3.79 (3H,
s), 2.77e2.85 (2H, m), 2.69e2.74 (2H, m); dC 203.3, 170.5,
159.0, 136.3, 135.1, 127.9, 129.7, 129.6, 128.6, 128.4,
126.6, 114.2, 67.1, 55.2, 47.4, 35.0, 28.8. To a solution of
the crude ketone 8 (assumed quantitative yield, 0.505 mmol)
in MeOH (3 mL) at 0 ꢀC was added NaBH4 (57.3 mg,
1.515 mmol) and the reaction mixture was stirred for 45 min
at which time TLC analysis indicated that the reaction was
complete. The reaction was quenched with saturated NaHCO3
solution (2 mL) and then the MeOH was removed in vacuo.
The crude residue was diluted with EtOAc (50 mL), washed
with saturated K2CO3 (10 mL), brine (20 mL), dried, concen-
trated and finally subjected to column chromatography yield-
ing a mixture of 5 and 5-epi-5 (74 mg, 0.219 mmol, 43%,
Rf¼0.1, 90:10 Et2O/EtOAc, 5/5-epi-5, 81:19), with the major
isomer showing analytical data in full accordance with an
analytically pure sample of compound 5.
3.1.4. (5S,6R)-1-(4-Methoxybenzyl)-6-(benzofuran-2-yl)-
5-hydroxypiperidin-2-one (7)
Prepared in a similar fashion to 5 above, from the diol 3
(150 mg, 0.597 mmol), 2-benzofuranboronic acid (193 mg,
1.194 mmol) and BF3$OEt2 (375 mL, 2.985 mmol) with stir-
ring at rt overnight. Column chromatography (EtOAc, Rf¼
0.5) of the crude residue furnished 7 (146 mg, 0.415 mmol,
70%) as a pale yellow oil. [a]2D3 þ21.6 (c 1.11, CHCl3);
nmax/cmꢁ1 3365, 2960, 1614, 1512, 1454, 1248, 1175, 1030,
820, 752; dH 7.58 (1H, d, J¼7.4 Hz, 4-Ar0CH), 7.49 (1H, d,
J¼8.2 Hz, 7-Ar0CH), 7.32 (1H, ddd, J¼8.2, 7.9, 1.3 Hz, 6-
Ar0CH), 7.25e7.29 (1H, m, 5-Ar0CH), 7.11 (2H, app d,
J¼8.5 Hz, 2-, 6-ArCH), 6.82 (2H, app d, J¼8.5 Hz, 3-, 5-
ArCH), 6.70 (1H, s, 3-Ar0CH), 5.46 (1H, d, J¼14.7 Hz,
CHHePMP), 4.63 (1H, d, J¼5.1 Hz, 6-CH), 4.08e4.15 (1H,
m, 5-CH), 3.78 (3H, s, OMe), 3.52 (1H, d, J¼14.7 Hz, CHHe
PMP), 2.83 (1H, ddd, J¼18.3, 6.7, 2.7 Hz, 3-CHH ), 2.63 (1H,
ddd, J¼18.3, 10.6, 7.7 Hz, 3-CHH), 2.00e2.10 (1H, m, 4-
CHH ), 1.94e2.00 (1H, m, 4-CHH), 1.76 (1H, d, J¼7.9 Hz,
OH); dC 169.6 (C]O), 159.0 (ArC), 155.1 (2-Ar0C), 152.6
(3-Ar0CH), 129.5 (2-, 6-ArCH), 128.4 (ArC), 127.7 (Ar0C),
124.5 (6-Ar0CH), 123.0 (5-Ar0CH), 120.9 (4-Ar0CH), 114.0
(3-, 5-ArCH), 111.3 (7-Ar0CH), 107.5 (3-Ar0CH), 67.1 (5-
CH), 58.1 (6-CH), 55.1 (OMe), 47.6 (CH2ePMP), 29.6 (3-
CH2), 26.0 (4-CH2); m/z (ESIꢁ) 299.8 (MꢁH)ꢁ 70%; HRMS
(ESIþ) calcd for C21H21NO4Na (MþNa)þ: 374.1368, found:
374.1379.
3.1.6. (S )-1-(4-Methoxybenzyl)-6-hydroxy-
5-methoxypiperidin-2-one (9)
Step 1: into an oven-dried flask under an atmosphere of dry
nitrogen were added (5S )-1-(4-methoxybenzyl)-6-hydroxy-
piperidin-2,6-dione2m,6 (0.75 g, 3.01 mmol), silver oxide
˚
(2.09 g, 9.03 mmol), anhydrous EtOAc (4 A molecular sieve
dried, 20 mL), methyl iodide (0.56 mL, 9.03 mmol) and then
the resulting heterogeneous mixture was stirred at rt overnight.
The methyl iodide was quenched by slow addition of triethyl-
amine (10 mL) and the mixture was allowed to stir for 30 min
at rt. The solids were removed by filtration through a short
plug of silica (ca. 5 cmꢂ5 cm) using ethyl acetate as the eluent
and then the solvent was removed yielding the crude product.
Subsequent column chromatography (20:80 petrol/EtOAc,
Rf¼0.54) afforded (5S )-6-methoxy-1-(4-methoxybenzyl)pi-
peridin-2,6-dione (0.629 g, 2.39 mmol, 79%) as a colourless
oil. [a]2D2 þ13.0 (c 1.56, CHCl3); dH 7.32 (2H, app d, J¼
8.4 Hz, 2-, 6-ArCH), 6.81 (2H, app d, J¼8.4 Hz, 3-, 5-
ArCH), 4.87 (2H, br s, CH2PMP), 3.89 (1H, dd, J¼7.0,
4.1 Hz, 3-CH), 3.77 (3H, s, OMe), 3.50 (3H, s, OMe), 2.89
(1H, ddd, J¼17.7, 8.2, 5.6 Hz, 5-CHH), 2.60 (1H, app dt,
J¼17.7, 6.2 Hz, 5-CHH ), 2.04e2.10 (2H, m, 4-CH2); dC
171.5 (C]O), 171.2 (C]O), 158.9 (ArCOMe), 103.3 (2-,
6-ArCH), 129.2 (ArC), 113.7 (3-, 5-ArCH), 76.4 (3-CH),
58.5 (OMe), 55.2 (OMe), 42.3 (CH2PMP), 29.1 (5-CH2),
23.6 (4-CH2); m/z (ESIꢁ) 279.8 (Mþ17)ꢁ 100%; HRMS
(ESIþ) calcd for C14H18NO4 (MþH)þ: 264.1236, found:
264.1246.
3.1.5. Synthesis of (5S,6S )-1-(4-methoxybenzyl)-5-hydroxy-
6-styrylpiperidin-2-one (5) from (6S )-1-(4-methoxybenzyl)-
6-styrylpiperidin-2,5-dione (8)
To a solution of the olefin 5 (170 mg, 0.505 mmol) in anhy-
drous CH2Cl2 (15 mL) was added DesseMartin periodinane
(0.30 g, 0.707 mmol) and the mixture was stirred at rt. After
1 h TLC analysis indicated a complete reaction and the excess
oxidant was quenched with saturated sodium thiosulfate
(10 mL) then this mixture was allowed to stir vigorously for
30 min. The resulting mixture was extracted with EtOAc
Step 2: the title compound was prepared from (5S )-6-
methoxy-1-(4-methoxybenzyl)piperidin-2,6-dione (0.600 g,
2.28 mmol) in a similar fashion to 3 above using sodium
borohydride (0.26 g, 6.84 mmol) at ꢁ20 ꢀC to ꢁ5 ꢀC for
1 h. Column chromatography (30:70 petrol/EtOAc to 100%

1414
I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
EtOAc) yielded the title alcohol 9 (0.448 g, 1.69 mmol, 74%
Rf¼0.24 EtOAc) as a colourless oil and as a mixture of diaste-
reoisomers (trans/cis 65:35); nmax/cmꢁ1 3309, 2935, 2827,
1614, 1513, 1245, 1175, 1107, 1065, 1032.
(2ꢂArCH), 127.8 (ArCH), 126.4 (2ꢂArCH), 124.6 (b-CH),
76.7 (6-CH), 59.3 (5-CH), 56.4 (OMe), 55.0 (OMe), 47.2
(CH2PMP), 29.0 (3-CH2), 22.2 (4-CH2); m/z (ESIþ) 351.9
(MþH)þ 100%; HRMS (ESIþ) calcd for C22H26NO3
(MþH)þ: 352.1907, found: 352.1905.
The major trans alcohol: dH 7.23 (2H, app d, J¼8.6 Hz, 3-,
5-ArCH), 6.85 (2H, d, J¼8.6 Hz, 2-, 6-ArCH), 4.89 (1H, d,
J¼14.8 Hz, CHHPMP), 4.84e4.86 (1H, m, 6-CH), 4.42 (1H,
d, J¼14.8 Hz, CHHPMP), 3.78 (3H, s, ArOMe), 3.45e3.48
(1H, m, 5-CH), 3.27 (3H, s, OMe), 2.55e2.64 (1H, m, 1ꢂ
CHH), 2.34e2.43 (1H, m, 1ꢂCHH ), 2.08e2.19 (1H, m, 1ꢂ
CHH), 1.78 (1H, m, 1ꢂCHH ); dC 170.5 (C]O), 158.6 (ArC),
129.1 (ArC), 129.0 (2ꢂArCH), 113.7 (2ꢂArCH), 79.0 (6-CH),
76.2 (5-CH), 56.2 (OMe), 55.0 (OMe), 46.1 (CH2PMP), 27.1
(3-CH2), 19.7 (4-CH2).
The minor cis alcohol: dH 7.24 (2H, d, J¼8.8 Hz, 3-, 5-
ArCH), 6.84 (2H, d, J¼8.8 Hz, 2-, 6-ArCH), 5.13 (1H, d,
J¼14.5 Hz, CHHPMP), 4.82 (1H, dd, J¼5.8, 3.6 Hz, 6-CH),
4.18 (1H, d, J¼14.5 Hz, CHHPMP), 3.79 (3H, ArOMe),
3.45e3.48 (1H, m, 5-CH), 3.39 (3H, s, OMe), 2.55e2.64 (1H,
m, 1ꢂCHH), 2.34e2.43 (1H, m, 1ꢂCHH ), 2.08e2.19 (1H, m,
1ꢂCHH), 1.91e1.97 (1H, m, 1ꢂCHH ); dC 169.9 (C]O),
129.2 (ArC), 129.2 (2ꢂArCH), 113.8 (2ꢂArCH), 77.7 (6-
CH), 75.4 (5-CH), 56.4 (OMe), 55.1 (OMe), 45.9 (CH2PMP),
28.6 (3-CH2), 19.9 (4-CH2); m/z (ESIꢁ) 263.8 (Mꢁ1)ꢁ 100%;
HRMS (ESIþ) calcd for C14H20NO4 (MþH)þ: 266.1392,
found: 266.1396.
3.1.8. (4S )-1-Benzyl-4,5-dihydroxypyrrolidin-2-one (11)
(S )-1-Benzyl-3-hydroxypyrrolidin-2,5-dione10
(1.0 g,
4.87 mmol) was dissolved in a mixture of EtOH and CH2Cl2
(40 mL, 1:1), and the solution cooled to ꢁ20 ꢀC. NaBH4
(0.92 g, 24.3 mmol) was added portionwise and the resulting
suspension was stirred at ꢁ20 ꢀC for 30 min. The mixture
was poured into a saturated aqueous solution of NaHCO3
(30 mL) and was extracted with CH2Cl2 (3ꢂ50 mL). The
combined organic layers were dried and concentrated in va-
cuo. The crude product was purified by flash column chroma-
tography (increasing polarity from 1:1, EtOAc/petrol as eluent
to EtOAc) to give the title compound (0.725 g, 72%) as a white
solid. Rf: 0.22 (1:1, EtOAc/petrol); Mp 109e111 ꢀC; nmax
/
cmꢁ1 3477, 1644, 1449, 1332, 1178, 1081; dH (CD3OD)
7.32e7.24 (5H, m), 4.85 (1H, d, J¼15.5 Hz, H10), 4.76 (1H,
br d, J¼1.0 Hz, H5), 4.12 (1H, dd, J¼1.5, 6.5 Hz, H4), 4.08
(1H, d, J¼15.5 Hz, H10), 2.86 (1H, dd, J¼6.5, 17.0 Hz),
2.22 (1H, dd, J¼1.5, 17.0 Hz); dC (CD3OD) 175.7, 137.6,
129.6, 129.6, 128.9, 128.4, 90.1, 72.3, 43.9, 39.3; MS (EI)
ꢃ
m/z 207 (100%); HRMS (EI) calcd for C11H13NO3 (Mþ ):
207.0895, found: 207.0902.
3.1.7. (S )-1-(4-Methoxybenzyl)-5-methoxy-
6-styrylpiperidin-2-one (10)
3.1.9. (3aS,6aS,E )-1-Benzyl-5-styryl-hexahydroborolo-
[3,4-b]pyrrol-2(1H )-one (12)
Prepared in a similar fashion to 5 above, using 9 (0.118 g,
0.445 mmol), potassium trans-styryltrifluoroborate (0.286 g,
1.36 mmol), acetonitrile (8 mL) and BF3$OEt2 (0.279 mL,
2.225 mmol) with stirring at rt overnight. Column chromatog-
raphy (EtOAc/petrol, 70:30e100:0) of the crude residue
yielded the adduct 10 (0.150 g, 0.427 mmol, 96%, Rf¼0.56,
EtOAc) as a mixture of diastereoisomers (cis/trans, 65:35).
nmax/cmꢁ1 2925, 1638, 1512, 1460, 1245, 1175, 1105, 1032,
751; dH 7.14e7.44 (14H, 14ꢂArCH), 6.85e6.87 (4H, m,
2ꢂ3-, 5-ArCH), 6.49 (1H, d, J¼16.0 Hz, a-CH trans), 6.43
(1H, d, J¼16.0 Hz, a-CH cis), 6.21 (1H, dd, J¼16.0, 6.5 Hz,
b-CH cis), 6.01 (1H, dd, J¼15.0, 6.8 Hz, b-CH trans), 5.53
(1H, d, J¼14.9 Hz, CHHPMP trans), 5.45 (1H, d, J¼
14.6 Hz, CHHPMP cis), 4.12e4.18 (2H, m, 6-CH cis and
trans), 3.80 (3H, s, OMe cis), 3.79 (3H, s, OMe trans), 3.72
(1H, d, J¼14.8 Hz, CHHPMP cis), 3.69 (1H, d, J¼14.9 Hz,
CHHPMP trans), 3.49e3.54 (1H, m, 5-CH cis), 3.45e3.48
(1H, m, 5-CH trans), 3.32 (3H, s, OMe cis), 3.18 (3H, s,
OMe trans), 2.63e2.72 (2H, m, 2ꢂ3-CHH), 2.42e2.56 (2H,
m, 2ꢂ3-CHH ), 1.89e2.02 (4H, m, 2ꢂ4-CH2).
To a solution of 11 (0.10 g, 0.482 mmol) and trans-styryl-
boronic acid (0.214 g, 1.45 mmol) in dry MeCN (5.0 mL) at
0 ꢀC under N2 was added dropwise BF3$OEt2 (0.273 g,
1.927 mmol). The reaction mixture was warmed to rt and
stirred for 16 h. Saturated NaHCO3 solution (15 mL) was
added and the aqueous layer was extracted with CH2Cl2
(3ꢂ15 mL). The combined extracts were dried (MgSO4), fil-
tered and concentrated in vacuo. The title product was ob-
tained without further purification (0.113 g, 73%). nmax/cmꢁ1
1685, 1449, 1367, 1065. dH 7.42 (1H, d, J¼18.5 Hz, H20),
7.35e7.20 (10H, m, ArH), 6.14 (1H, d, J¼18.5 Hz, H10),
5.59 (1H, d, J¼6.0 Hz, H5), 5.02 (1H, d, J¼14.5 Hz, H30),
4.93 (1H, dd, J¼6.0, 7.0 Hz, H4), 4.15 (1H, d, J¼14.5 Hz,
H30), 2.83 (1H, dd, J¼7.0, 18.0 Hz, H3), 2.71 (1H, d,
J¼18.0 Hz, H3); dC 171.2 (C2), 151.5 (ArC), 136.9 (ArC),
135.6 (ArC), 129.4 (C20), 128.7 (ArC), 128.7 (ArC), 128.6
(ArC), 128.4 (ArC), 128.3 (ArC), 127.8 (ArC), 127.2 (C10),
89.4 (C5), 73.1 (C4), 43.9 (C30), 38.1 (C3); MS (EI) m/z
ꢃ
319 (100%); HRMS (EI) calcd for C19H18BNO3 (Mþ ):
The trans isomer: dC 169.7 (C]O), 158.7 (ArCOMe),
135.7 (ArC), 132.9 (a-CH), 129.1 (2ꢂArCH), 129.0 (ArC),
128.5 (2ꢂArCH), 128.0 (ArCH), 126.6 (b-CH), 126.3 (2ꢂ
ArCH), 113.7 (3-, 5-ArCH), 76.1 (5-CH), 60.0 (6-CH), 55.8
(OMe), 55.0 (OMe), 46.7 (CH2PMP), 27.0 (3-CH2), 21.3
(4-CH2).
319.1379, found: 319.1376.
3.1.10. (1S,5S )-2-Benzyl-6-oxa-2-aza-bicyclo[3.1.0]-
hexan-3-one (13)
To a solution of 11 (0.10 g, 0.482 mmol) in nitromethane
(5 mL) at 0 ꢀC was added BF3$OEt2 (0.273 g, 1.93 mmol).
The mixture was stirred at 80 ꢀC for 5 h. A saturated solution
of NaHCO3 (5 mL) was added, and aqueous layer was
The cis isomer: dC 169.7 (C]O), 158.8 (ArCOMe), 136.0
(ArC), 133.0 (a-CH), 129.3 (2ꢂArCH), 128.9 (ArC), 128.4

I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
1415
extracted with dichloromethane (3ꢂ10 mL). The combined
extracts were dried (MgSO4) and concentrated in vacuo. The
title compound was unstable to silica gel and was obtained
as an oil without further purification (0.071 g, 78%). Rf: 0.31
(EtOAc); nmax/cmꢁ1 1690, 1449, 1362, 1214, 1081, 1019; dH
7.33e7.22 (5H, m, ArH), 5.41 (1H, d, J¼7.0 Hz, H5), 5.03
(1H, d, J¼14.5 Hz, H10), 4.89 (1H, dd, J¼7.0, 8.0 Hz, H4),
4.07 (1H, d, J¼14.5 Hz, H10), 2.85 (1H, dd, J¼8.0, 18.5 Hz,
H3), 2.68 (1H, d, J¼18.5 Hz, H3); dC 171.1 (C2), 136.2
(ArC), 128.9 (ArC), 128.8 (ArC), 128.7 (ArC), 128.6 (ArC),
128.4 (ArC), 128.1 (ArC), 83.5 (C5), 75.0 (C4), 44.7 (C10),
37.7 (C3); MS (EI) m/z 189 (75%); HRMS (EI) calcd for
(C2), 150.1 (ArC), 143.1 (ArC), 135.8 (ArC), 128.7 (ArC),
128.6 (ArC), 128.5 (ArC), 128.3 (ArC), 128.1 (ArC), 128.0
(ArC), 127.4 (C50), 110.3 (C40), 109.0 (C30), 69.5 (C4), 63.9
(C5), 44.2 (C60), 39.8 (C3). Minor cis isomer: dH 7.46 (1H,
d, J¼1.5 Hz, H50), 7.30e7.17 (5H, m, ArH), 6.42 (1H, dd,
J¼1.5, 3.0 Hz, H40), 6.17 (1H, d, J¼3.0 Hz, H30), 4.98 (1H,
d, J¼15.0 Hz, H60), 4.57 (1H, d, J¼7.0 Hz, H5), 4.53 (1H,
ddd, J¼7.5, 7.0, 2.5 Hz, H4), 3.60 (1H, d, J¼15.0 Hz, H60),
2.70 (1H, dd, J¼7.5, 17.0 Hz, H3), 2.65 (1H, dd, J¼2.5,
17.0 Hz, H3); dC 172.5 (C2), 148.3 (ArC), 143.6 (ArC),
135.7 (ArC), 128.7 (ArC), 128.7 (ArC), 128.5 (ArC), 128.1
(ArC), 128.0 (ArC), 127.6 (C50), 111.1 (C40), 110.5 (C30), 66.9
(C4), 59.8 (C5), 44.6 (C60), 39.1 (C3).
ꢃ
C11H11NO2 (Mþ ) 189.0789, found: 189.0783.
3.1.11. (4S,5S,E )-1-Benzyl-4-hydroxy-5-styrylpyrrolidin-
2-one (14)
3.1.13. (4S,5R)-5-(Benzofuran-2-yl)-1-benzyl-
4-hydroxypyrrolidin-2-one (16)
To a solution of 11 (0.10 g, 0.482 mmol) in anhydrous
MeNO2 (5 mL), at 0 ꢀC was added trans-styrylboronic acid
(0.214 g, 1.4 mmol) and then BF3$OEt2 (0.273 g, 1.93 mmol).
The mixture was stirred at 80 ꢀC for 5 h. A saturated aqueous
solution of NaHCO3 (5 mL) was added, and aqueous layer was
extracted with CH2Cl2 (3ꢂ10 mL). The combined extracts
were dried and concentrated in vacuo. The crude product
was purified by column chromatography (1:1, EtOAc/petrol as
eluent) to give the title compound (0.027 g, 20%, dr¼91:9) as
a white solid. Rf: 0.32 (1:1, EtOAc/petrol); mp 128e130 ꢀC;
nmax/cmꢁ1 3334, 1669, 1444, 1426, 1262, 1176, 1071; dH (ma-
jor isomer): 7.35e7.18 (10H, m, ArH), 6.51 (1H, d,
J¼16.5 Hz, H20), 6.15 (1H, dd, J¼16.5, 8.5 Hz, H10), 4.93
(1H, d, J¼15.5 Hz, H30), 4.43 (1H, ddd, J¼3.5, 6.0, 7.0 Hz,
H4), 4.10 (1H, dd, J¼6.0, 8.5 Hz, H5), 3.96 (1H, d, J¼
15.5 Hz, H30), 2.73 (1H, dd, J¼7.0, 17.5 Hz, H3), 2.54 (1H,
dd, J¼3.5, 17.5 Hz, H3), 2.45 (1H, br s, OH); dC 172.9
(C2), 136.5 (ArC), 136.3 (C20), 135.7 (ArC), 128.6 (ArC),
128.6 (ArC), 128.4 (ArC), 128.3 (ArC), 127.4 (ArC), 126.6
(ArC), 123.3 (C10), 67.5 (C4), 65.2 (C5), 44.3 (C30), 39.9
(C3); MS (EI) m/z 293 (100%); HRMS (EI) calcd for
Prepared in a similar fashion to 15 above, from 11 (0.05 g,
0.241 mmol), 2-benzofuranboronic acid (0.117 g, 0.724 mmol),
MeNO2 (3.0 mL) and BF3$OEt2 (0.137 g, 0.966 mmol). The
crude product was purified by flash column chromatography
(Et2O as eluent) to give the title compound (0.041 g, 56%,
dr¼92:8) as an oil. Rf: 0.47 (Et2O); MS (EI) m/z 307
ꢃ
(100%); HRMS (EI) calcd for C19H17NO3 (Mþ ): 307.1208,
found: 307.1207; nmax/cmꢁ1 3308, 1670, 1454, 1417, 1355,
1306, 1255, 1167, 1108, 1086.
Major cis isomer: dH 7.51 (1H, d, J¼8.0 Hz, ArH), 7.41
(1H, d, J¼8.0 Hz, ArH), 7.24 (6H, m, ArH), 7.08 (1H, d,
J¼8.0 Hz, ArH), 6.64 (1H, s, H10), 5.06 (1H, d, J¼15.0 Hz,
H20), 4.64 (1H, d, J¼7.0 Hz, H5), 4.57 (1H, app br q, J ca.
7 Hz, H4), 3.61 (1H, d, J¼15.0 Hz, H20), 2.74 (2H, m, H3);
dC 172.5 (C2), 155.3 (ArC), 151.3 (ArC), 135.7 (ArC), 128.4
(ArC), 128.2 (ArC), 127.7 (ArC), 127.6 (ArC), 124.8 (ArC),
123.1 (ArC), 121.2 (ArC), 111.5 (ArC), 108.1 (ArC), 107.7
(C10), 67.0 (C4), 60.2 (C5), 44.5 (C20), 39.1 (C3).
Minor trans isomer: dH 7.54 (1H, d, J¼8.0 Hz, ArH), 7.42
(1H, d, J¼8.0 Hz, ArH), 7.25 (7H, m, ArH), 6.58 (1H, s, H10),
5.12 (1H, d, J¼15.0 Hz, H20), 4.57 (1H, br dd, J¼7.0, 2.5 Hz,
H4), 4.48 (1H, s, H5), 3.71 (1H, d, J¼15.0 Hz, H20), 3.07 (1H,
dd, J¼7.0, 17.5 Hz, H3), 2.52 (1H, dd, J¼2.5, 17.5 Hz, H3);
dC 172.8 (C2), 155.2 (ArC), 152.6 (ArC), 135.7 (ArC), 128.6
(ArC), 128.1 (ArC), 127.6 (ArC), 125.5 (ArC), 124.8 (ArC),
123.1 (ArC), 121.1 (ArC), 111.4 (ArC), 105.9 (C10), 69.6
(C4), 64.3 (C5), 44.4 (C20), 39.9 (C3).
ꢃ
C19H19NO2 (Mþ ): 293.1417, found: 293.1415.
3.1.12. (4S,5S )-1-Benzyl-5-(furan-2-yl)-
4-hydroxypyrrolidin-2-one (15)
Prepared in a similar fashion to 14 above, from 11 (0.150 g,
0.725 mmol), 2-furanboronic acid (0.243 g, 2.17 mmol),
MeNO2 (5.0 mL) and BF3$OEt2 (0.411 g, 2.90 mmol), except
that the reaction mixture was warmed to rt and stirred for 16 h.
The crude product was purified by flash column chromatogra-
phy (1:1, EtOAc/petrol as eluent) to give the title compound
(0.126 g, 65%, dr¼77:23) as an oil. Rf: 0.53 (1:1, EtOAc/pet-
rol); MS (EI) m/z 257 (100%); HRMS (EI) calcd for
3.1.14. (4S,5R)-1-Benzyl-5-(3,4-dimethoxyphenyl)-
4-hydroxypyrrolidin-2-one (17)
Prepared in a similar fashion to 15 above, from 11 (0.05 g,
0.241 mmol), 3,4-dimethoxyphenylboronic acid (0.132 g,
0.724 mmol) and BF3$OEt2 (0.137 g, 0.966 mmol). The
desired product (0.035 g, 44%, dr¼72:28) was obtained as
an oil after purification by column chromatography (EtOAc as
eluent). Rf: 0.23 (EtOAc); MS (EI) m/z 327 (100%); HRMS
ꢃ
C15H15NO3 (Mþ ): 257.1049, found: 257.1049; nmax/cmꢁ1
3365, 1669, 1447, 1253, 1149, 1070, 1012.
Major trans isomer: dH 7.38 (1H, d, J¼1.5 Hz, H50), 7.30e
7.17 (5H, m, ArH), 6.34 (1H, dd, J¼1.5, 3.0 Hz, H40), 6.21
(1H, d, J¼3.0 Hz, H30), 4.92 (1H, d, J¼15.5 Hz, H60), 4.42
(1H, ddd, J¼2.0, 2.5, 6.0 Hz, H4), 4.31 (1H, d, J¼2.0 Hz,
H5), 3.58 (1H, d, J¼15.5 Hz, H60), 3.00 (1H, dd, J¼6.5,
17.0 Hz, H3), 2.48 (1H, dd, J¼2.5, 17.0 Hz, H3); dC 172.9
ꢃ
(EI) calcd for C19H21NO4 (Mþ ): 327.1470, found: 327.1468;
nmax/cmꢁ1 3352, 1699, 1505, 1463, 1272, 1257, 1149, 1016.
Major trans isomer: dH 7.28e7.21 (5H, m, ArH), 7.02 (1H,
s, ArH), 6.89 (1H, d, J¼8.0 Hz, ArH), 6.72 (1H, d, J¼8.0 Hz,
ArH), 4.88 (1H, d, J¼2.5 Hz, H5), 4.82 (1H, d, J¼14.5 Hz,

1416
I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
H10), 4.23 (1H, br dd, J¼6.5, 2.5 Hz, H4), 4.10 (1H, d,
J¼14.5 Hz, H10), 3.89 (3H, s, OMe), 3.80 (3H, s, OMe),
2.58 (1H, dd, J¼6.5, 17.0 Hz, H3), 2.46 (1H, d, J¼17.0 Hz,
H3); dC 172.4 (C2), 149.3 (ArC), 136.0 (ArC), 128.6 (ArC),
128.5 (ArC), 128.5 (ArC), 128.4 (ArC), 128.2 (ArC), 127.9
(ArC), 127.6 (ArC), 127.5 (ArC), 127.4 (ArC), 125.2 (ArC),
121.0 (ArC), 111.6 (ArC), 111.2 (ArC), 81.8 (C4), 65.13
(C5), 55.8 (OMe), 43.2 (C10), 38.3 (C3).
Minor cis isomer: dH 7.28e7.21 (5H, m, ArH), 6.99 (1H, s,
ArH), 6.86 (1H, d, J¼8.0 Hz, ArH), 6.70 (1H, d, J¼8.0 Hz,
ArH), 5.06 (1H, d, J¼14.5 Hz, H10), 4.47 (1H, d, J¼5.5 Hz,
H5), 4.43e4.45 (1H, br m H4), 3.87 (3H, s, OMe), 3.77
(3H, s, OMe), 3.63 (1H, d, J¼14.5 Hz, H10), 2.70 (1H, dd,
J¼6.5, 17.0 Hz, H3), 2.54 (1H, d, J¼17.0 Hz, H3); dC 174.1
(C2), 149.2 (ArC), 135.7 (ArC), 128.6 (ArC), 128.5 (ArC),
128.5 (ArC), 128.4 (ArC), 128.2 (ArC), 127.9 (ArC), 127.6
(ArC), 127.5 (ArC), 127.4 (ArC), 125.2 (ArC), 121.0 (ArC),
111.6 (ArC), 66.7 (C5), 66.3 (C4), 55.9 (OMe), 44.6 (C10),
39.5 (C3).
1.00 mmol) and then BF3$OEt2 (0.168 g, 1.34 mmol). The re-
action mixture was stirred at rt for 2 h. Saturated aqueous
NaHCO3 solution (5 mL) was added and aqueous layer was
extracted with CH2Cl2 (3ꢂ10 mL). The combined extracts
were dried (MgSO4), filtered, and concentrated in vacuo.
The desired product (0.045 g, 40%, dr¼55:45) was obtained
as an oil after purification by column chromatography (1:3,
EtOAc/petrol. as eluent). Rf: 0.44 (1:3, EtOAc/petrol); MS
ꢃ
(EI) m/z 347 (100%); HRMS (EI) calcd for C22H21NO3 (Mþ ):
347.4078, found: 347.4079; nmax/cmꢁ1 1673, 1452, 1263,
1154, 1072, 1027.
Major trans isomer: dH 7.35 (1H, d, J¼1.2 Hz, H50), 7.29e
7.05 (10H, m, ArH), 6.32 (1H, dd, J¼1.2, 3.2 Hz, H40), 6.16
(1H, d, J¼3.2 Hz, H30), 5.07 (1H, d, J¼15.0 Hz, H60), 4.51
(1H, d, J¼1.5 Hz, H5), 4.45 (2H, s, H70), 4.24e4.20 (1H, m,
H4), 3.64 (1H, d, J¼15.0 Hz, H60), 2.93 (1H, dd, J¼7.0,
17.5 Hz, H3), 2.59 (1H, dd, J¼2.5, 17.5 Hz, H3); dC 172.4
(C2), 150.3 (C20), 143.0 (C50), 137.1 (ArC), 135.7 (ArC),
128.4 (ArC), 128.2 (ArC), 128.2 (ArC), 127.8 (ArC), 127.7
(ArC), 127.6 (ArC), 127.5 (ArC), 127.4 (ArC), 127.3 (ArC),
110.2 (C30), 108.6 (C40), 76.1 (C4), 71.0 (C70), 60.85 (C5),
44.0 (C60), 37.3 (C3).
3.1.15. (4S,5R,E )-1-Benzyl-4-(benzyloxy)-
5-styrylpyrrolidin-2-one (19a)
To a solution of 1811 (0.150 g, 0.504 mmol) and potassium
(E )-2-styryltrifluoroborate (0.315 g, 1.49 mmol) in dry
CH2Cl2 (5 mL) at 0 ꢀC under N2 was added dropwise
BF3$OEt2 (0.286 g, 2.06 mmol). The reaction mixture was
warmed to rt and stirred for 16 h. Saturated NaHCO3 solution
(5 mL) was added and the aqueous layer was extracted with
CH2Cl2 (3ꢂ10 mL). The combined extracts were dried, fil-
tered and concentrated in vacuo. The crude product was puri-
fied by flash column chromatography (1:4, EtOAc/petrol as
eluent) to give the title compound (0.113 g, 59%, dr¼92:8)
as an oil. Rf: 0.32 (1:2, EtOAc/petrol); MS (EI) m/z 383
Minor cis isomer: dH 7.45 (1H, d, J¼1.2 Hz, H50), 7.29e
7.05 (10H, m, ArH), 6.38 (1H, dd, J¼1.2, 3.0 Hz, H40), 6.29
(1H, d, J¼3.0 Hz, H30), 5.07 (1H, d, J¼14.7 Hz, H60), 4.67
(1H, d, J¼7.5 Hz, H5), 4.32 (2H, s, H70), 4.30e4.28 (1H, m,
H4), 3.58 (1H, d, J¼14.7 Hz, H60), 2.84 (1H, dd, J¼8.5,
16.5 Hz, H3), 2.71 (1H, dd, J¼8.5, 16.5 Hz); dC 171.8 (C2),
148.8 (C20), 143.0 (C50), 137.0 (ArC), 135.9 (ArC), 128.4
(ArC), 128.2 (ArC), 128.2 (ArC), 127.8 (ArC), 127.7 (ArC),
127.6 (ArC), 127.5 (ArC), 127.4 (ArC), 127.3 (ArC), 110.3
(C30), 110.2 (C40), 73.2 (C4), 71.4 (C70), 57.8 (C5), 44.3
(C60), 36.6 (C3).
ꢃ
(80%); HRMS (EI) calcd for C26H25NO2 (Mþ ): 383.1881,
found: 383.1885; nmax/cmꢁ1 1692, 1495, 1451, 1261, 1096,
1071, 1028.
3.1.17. (4S, 5R)-5-(Benzofuran-2-yl)-1-benzyl-4-(benzyloxy)-
pyrrolidin-2-one (19c)
dH (major isomer) 7.58e7.15 (15H, m, ArH), 6.45 (1H, d,
J¼15.7 Hz, H20), 5.91 (1H, dd, J¼15.7, 8.0 Hz, H10), 5.07
(1H, d, J¼14.7 Hz, H30), 4.50 (2H, s, H40), 4.10 (1H, d,
J¼7.2 Hz, H4), 3.99 (1H, d, J¼8.0 Hz, H5), 3.91 (1H, d,
J¼14.7 Hz, H30), 2.82 (1H, dd, J¼7.2, 17.5 Hz, H3), 2.58
(1H, d, J¼17.5 Hz, H3); dC (major isomer) 172.4 (C2),
137.3 (ArC), 136.2 (ArC), 135.7 (ArC), 133.9 (C7), 128.7
(ArC), 128.6 (ArC), 128.4 (ArC), 128.3 (ArC), 128.1 (ArC),
127.8 (ArC), 127.6 (ArC), 127.4 (ArC), 126.5 (ArC), 125.6
(C6), 77.0 (C4), 71.2 (C8), 65.9 (C5), 44.0 (C9), 37.2 (C3).
Prepared in a similar fashion to 19a above, from 18 (0.10 g,
0.336 mmol), benzofuranboronic acid (0.163 g, 1.0 mmol),
BF3$OEt2 (0.190 g, 1.34 mmol) and CH2Cl2 (5 mL). The de-
sired product (0.110 g, 55%, dr¼89:11) was obtained as an
oil after purification by column chromatography (1:3, EtOAc/
petrol as eluent). Rf: 0.47 (1:2, EtOAc/petrol); MS (EI) m/z:
ꢃ
397 (75%); HRMS (EI) calcd for C26H23NO3 (Mþ ):
397.1676, found: 397.1677; nmax/cmꢁ1 1684, 1454, 1417,
1253, 1109, 1093.
Major trans isomer: dH 7.53 (1H, d, J¼8.0 Hz, ArH), 7.42
(1H, d, J¼8.0 Hz, ArH), 7.28e7.18 (12H, m, ArH), 6.55 (1H,
s, H10), 5.15 (1H, d, J¼15.2 Hz, H20), 4.63 (1H, d, J¼2.0 Hz,
H5), 4.49 (2H, s, H30), 4.30e4.28 (1H, m, H4), 3.71 (1H, d,
J¼15.2 Hz, H20), 3.01 (1H, dd, J¼7.0, 17.2 Hz, H3), 2.65
(1H, dd, J¼2.5, 17.2 Hz, H3); dC 172.6 (C2), 155.1
(ArC), 152.9 (ArC), 137.0 (ArC), 135.6 (ArC), 128.5 (ArC),
128.3 (ArC), 127.9 (ArC), 127.8 (ArC), 127.5 (ArC), 127.4
(ArC), 124.7 (ArC), 123.0 (ArC), 121.0 (ArC), 111.3 (ArC),
105.4 (C10), 76.1 (C4), 71.2 (C30), 61.3 (C5), 44.2 (C20),
37.4 (C3).
3.1.16. (4S,5R)-1-Benzyl-4-(benzyloxy)-5-(furan-2-yl)-
pyrrolidin-2-one (19b)
Method A: prepared in a similar fashion to 19a above, from
18 (0.150 g, 0.504 mmol), 2-furanboronic acid (0.169 g,
1.51 mmol), BF3$OEt2 (0.286 g, 2.06 mmol) and CH2Cl2
(5 mL). The desired product (0.140 g, 79%, dr¼71:29) was
obtained as an oil after purification by column chromatogra-
phy (1:3, EtOAc/petrol as eluent). Rf: 0.44 (1:3, EtOAc/petrol).
Method B: to a solution of 18 (0.10 g, 0.336 mmol) in
CH2Cl2 (5 mL) at 0 ꢀC under N2 was added furan (0.068 g,

I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
1417
Minor cis isomer: dH 7.56 (1H, d, J¼8.0 Hz, ArH), 7.48
(1H, d, J¼8.0 Hz, ArH), 7.29e7.02 (12H, m, ArH), 6.67
(1H, s, H10), 5.16 (1H, d, J¼15.0 Hz, H20), 4.78 (1H, d,
J¼7.5 Hz, H5), 4.49 (1H, d, J¼12.0 Hz, H30), 4.43e4.39
(1H, m, H4), 4.39 (1H, d, J¼12.0 Hz, H30), 3.65 (1H, d,
J¼15.0 Hz, H20), 2.93 (1H, dd, J¼8.0, 16.5 Hz, H3), 2.76
(1H, dd, J¼8.0, 16.5 Hz, H3); dC 172.0 (C2), 155.3 (ArC),
152.0 (ArC), 137.0 (ArC), 135.9 (ArC), 128.7 (ArC), 128.3
(ArC), 127.8 (ArC), 127.7 (ArC), 127.5 (ArC), 124.5 (ArC),
122.9 (ArC), 120.9 (ArC), 111.5 (ArC), 107.1 (C10), 73.4
(C4), 71.8 (C30), 58.3 (C5), 44.5 (C20), 36.6 (C3).
Major trans isomer: dH 7.29e7.12 (10H, m, ArH), 7.00
(2H, d, J¼8.0 Hz, ArH), 6.89 (2H, d, J¼8.0 Hz, ArH), 5.10
(1H, d, J¼15.0 Hz, H10), 4.37 (2H, s, H20), 4.34 (1H, d,
J¼2.5 Hz, H5), 3.90e3.87 (1H, m, H4), 3.74 (3H, s, OMe),
3.44 (1H, d, J¼15.0 Hz, H10), 2.87 (1H, dd, J¼6.5, 17.0 Hz,
H3), 2.60 (1H, dd, J¼2.5, 17.0 Hz, H3); dC 172.9 (C2),
159.5 (ArC), 137.3 (ArC), 135.8 (ArC), 130.0 (ArC), 128.5
(ArC), 128.4 (ArC), 128.3 (ArC), 128.1 (ArC), 128.0 (ArC),
127.8 (ArC), 127.7 (ArC), 127.5 (ArC), 127.4 (ArC), 127.3
(ArC), 127.1 (ArC), 114.4 (ArC), 79.4 (C4), 71.1 (C5), 67.0
(C20), 55.2 (OMe), 43.9 (C10), 37.2 (C3). Minor cis isomer:
dH 7.28e7.12 (14H, m, ArH), 7.10 (2H, d, J¼8.5 Hz, ArH),
6.93 (2H, d, J¼8.5 Hz, ArH), 5.15 (1H, d, J¼14.5 Hz, H10),
4.53 (1H, d, J¼6.5 Hz, H5), 4.25e4.23 (1H, m, H4), 4.17
(1H, d, J¼12.0 Hz, H20), 4.12 (1H, d, J¼12.0 Hz, H20), 3.76
(3H, s, OMe), 3.48 (1H, d, J¼14.5 Hz, H10), 2.73 (2H, m,
H3); dC 172.6 (C2), 159.6 (ArC), 137.2 (ArC), 136.0 (ArC),
129.6 (ArC), 128.5 (ArC), 128.4 (ArC), 128.3 (ArC),
128.1 (ArC), 128.0 (ArC), 127.8 (ArC), 127.7 (ArC), 127.5
(ArC), 127.4 (ArC), 127.3 (ArC), 127.1 (ArC), 113.8 (ArC),
73.5 (C4), 71.6 (C5), 64.4 (C20), 55.2 (OMe), 44.1 (C10),
37.6 (C3).
3.1.18. (4S,5R)-1-Benzyl-4-(benzyloxy)-5-(2-thienyl)-
pyrrolidin-2-one (19d)
Prepared in a similar fashion to 19a above, from 18 (0.10 g,
0.336 mmol), 2-thiopheneboronic acid (0.127 g, 1.0 mmol),
BF3$OEt2 (0.190 g, 1.34 mmol) and CH2Cl2 (5 mL). The de-
sired product (0.088 g, 72%, dr¼62:38) was obtained as an
oil after purification by column chromatography (1:4, EtOAc/
petrol as eluent). Rf: 0.33 (1:3, EtOAc/petrol); MS (EI) m/z
ꢃ
363 (100%); HRMS (EI) calcd for C22H21NO2S (Mþ ):
363.1296, found: 363.1293; nmax/cmꢁ1 1685, 1451, 1434,
1269, 1111, 1072.
Minor trans isomer: dH 7.39e7.12 (10H, m, ArH), 7.03
(1H, m, H50), 6.98 (1H, dd, J¼3.2, 4.7 Hz, H40), 6.84 (1H,
d, J¼3.2 Hz, H30), 5.17 (1H, d, J¼15.5 Hz, H60), 4.72 (1H,
d, J¼2.0 Hz, H5), 4.47 (2H, s, H70), 4.11e4.07 (1H, m, H4),
3.65 (1H, d, J¼15.5 Hz, H60), 2.93 (1H, dd, J¼7.0, 17.5 Hz,
H3), 2.59 (1H, dd, J¼2.5, 17.5 Hz, H3); dC 172.3 (C2),
141.6 (C20), 137.1 (ArC), 135.7 (ArC), 128.6 (ArC), 128.4
(ArC), 128.2 (ArC), 128.1 (ArC), 127.8 (ArC), 127.5 (ArC),
127.4 (ArC), 127.1 (C50), 125.9 (C40), 125.7 (C30), 79.5
(C4), 71.3 (C60), 63.0 (C5), 44.0 (C70), 37.0 (C3).
3.1.20. (4S,5R)-1-Benzyl-4-(benzyloxy)-5-(3,4-dimethoxy-
phenyl)pyrrolidin-2-one (19g)
Prepared in a similar fashion to 19a above, from 18 (0.10 g,
0.336 mmol), 3,4-dimethoxyphenylboronic acid (0.182 g,
1.0 mmol), BF3$OEt2 (0.190 g, 1.34 mmol), and CH2Cl2
(5 mL). The desired product (0.103 g, 74%, dr¼74:26) was
obtained as an oil after purification by column chromatogra-
phy (1:2, EtOAc/petrol as eluent). Rf: 0.47 (1:3, EtOAc/pet-
rol); MS (EI) m/z 417 (80%); HRMS (EI) calcd for
ꢃ
C26H27NO4 (Mþ ): 417.1941, found: 417.1940; nmax/cmꢁ1
Major cis isomer: dH 7.29e7.22 (9H, m, ArH), 7.13 (1H, d,
J¼7.0 Hz, ArH), 7.03 (2H, m, H50, H40), 6.95 (1H, d, J¼
3.5 Hz, H30), 5.13 (1H, d, J¼15.0 Hz, H60), 4.89 (1H, d, J¼
7.0 Hz, H5), 4.33 (1H, d, J¼12.0 Hz, H70), 4.33e4.29 (1H,
m, H4), 4.28 (1H, d, J¼12.0 Hz, H70), 3.58 (1H, d,
J¼15.0 Hz, H60), 2.79 (1H, dd, J¼7.5, 17.5 Hz, H3), 2.72
(1H, dd, J¼7.5, 17.5 Hz, H3); dC 171.1 (C2), 137.7 (C20),
136.0 (ArC), 128.6 (ArC), 128.6 (ArC), 128.4 (ArC), 128.2
(ArC), 128.0 (ArC), 128.0 (ArC), 127.7 (ArC), 127.6 (ArC),
127.4 (C50), 126.8 (C40), 126.4 (C30), 73.3 (C4), 71.7 (C60),
60.2 (C5), 44.1 (C70), 36.8 (C3).
1689, 1515, 1453, 1413, 1260, 1237, 1139, 1072, 1026.
Major trans isomer: dH 7.28e7.12 (10H, m, ArH), 6.85
(1H, d, J¼8.0 Hz, ArH), 6.66 (1H, dd, J¼2.0, 7.7 Hz, ArH),
6.48 (1H, d, J¼2.0 Hz, ArH), 5.14 (1H, d, J¼15.5 Hz, H10),
4.45 (2H, s, H20), 4.40 (1H, d, J¼2.5 Hz, H5), 4.00e3.97
(1H, m, H4), 3.88 (3H, s, OMe), 3.79 (3H, s, OMe), 3.58
(1H, d, J¼15.5 Hz, H10), 2.88 (1H, dd, J¼7.0, 17.0 Hz, H3),
2.60 (1H, dd, J¼3.5, 17.0 Hz, H3); dC 172.7 (C2), 149.4
(ArC), 148.8 (ArC), 137.2 (ArC), 135.8 (ArC), 128.3 (ArC),
128.2 (ArC), 128.0 (ArC), 128.0 (ArC), 127.4 (ArC), 127.4
(ArC), 118.9 (ArC), 111.3 (ArC), 109.3 (ArC), 79.1 (C4),
71.0 (C20), 67.3 (C5), 55.7 (OMe), 43.9 (C10), 37.0 (C3).
Minor cis isomer: dH 7.28e7.12 (10H, m, ArH), 6.87 (1H,
d, J¼8.0 Hz, ArH), 6.72 (1H, d, J¼8.0 Hz, ArH), 6.71 (1H, s,
ArH), 5.10 (1H, d, J¼15.0 Hz, H10), 4.51(1H, d, J¼7.0 Hz,
H5), 4.22e4.20 (1H, m, H4), 4.19 (1H, d, J¼11.5 Hz, H20),
4.08 (1H, d, J¼11.5 Hz, H20), 3.91 (3H, s, OMe), 3.78 (1H,
d, J¼15.0 Hz, H10), 3.73 (3H, s, OMe), 2.73 (2H, m, H3);
dC 172.8 (C2), 149.5 (ArC), 148.9 (ArC), 137.3 (ArC),
136.0 (ArC), 128.3 (ArC), 128.2 (ArC), 128.0 (ArC), 127.6
(ArC), 127.3 (ArC), 127.2 (ArC), 127.1 (ArC), 126.6 (ArC),
121.2 (ArC), 111.9 (ArC), 110.6 (ArC), 73.6 (C4), 71.5
(C20), 64.9 (C5), 55.6 (OMe), 44.1 (C10), 37.7 (C3).
3.1.19. (4S,5R)-1-Benzyl-4-(benzyloxy)-5-(4-methoxy-
phenyl)pyrrolidin-2-one (19f)
Prepared in a similar fashion to 19a above, from 18
(0.10 g, 0.336 mmol), p-methoxyphenylboronic acid (0.214 g,
1.00 mmol), BF3$OEt2 (0.190 g, 1.34 mmol) and CH2Cl2
(5 mL). The desired product (0.063 g, 48%, dr¼72:28) was
obtained as an oil after purification by column chromatogra-
phy (1:3, EtOAc/petrol. as eluent). Rf: 0.42 (1:3, EtOAc/
petrol); MS (EI) m/z 387 (100%); HRMS (EI) calcd for
ꢃ
C25H25NO3 (Mþ ): 387.1833, found: 387.1834; nmax/cmꢁ1
1690, 1512, 1442, 1408, 1248, 1175, 1072.

1418
I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
3.1.21. (4S,5R,E )-1-Benzyl-4-hydroxy-5-styrylpyrrolidin-
2-one (trans-14)
4.57e4.49 (3H, m, H40, H30), 4.31 (1H, d, J¼15.0 Hz, H30),
3.99e3.96 (1H, m, H4), 2.87 (1H, dd, J¼6.5, 17.5 Hz, H3),
2.52 (1H, dd, J¼3.0, 17.5 Hz, H3); dC 173.1 (C2), 138.1
(ArC), 137.3 (ArC), 135.7 (C20), 128.5 (ArC), 128.5 (ArC),
128.5 (ArC), 128.3 (ArC), 128.3 (ArC), 128.2 (ArC), 128.1
(ArC), 127.8 (ArC), 127.7 (ArC), 127.5 (ArC), 127.4 (ArC),
127.3 (ArC), 126.8 (C10), 93.7 (C5), 81.7 (C4), 72.1 (C40),
42.8 (C30), 36.6 (C3).
To a solution of 19a (0.080 g, 0.208 mmol) in CH2Cl2
(10 mL) at 0 ꢀC under N2 was added dropwise BBr3
(0.209 g, 0.835 mmol). The mixture was stirred for 10 min,
and then water (15 mL) and saturated aqueous NaHCO3 solu-
tion (5 mL) were added. The aqueous layer was extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic extracts were
dried, filtered and concentrated in vacuo. The crude product
was purified by flash column chromatography (increasing po-
larity from 1:1, EtOAc/petrol to EtOAc as eluent) to give the
title compound (0.055 g, 90%) as an oil. Rf: 0.62 (EtOAc);
nmax/cmꢁ1 3334, 1664, 1511, 1449, 1253, 1058; dH 7.32e
7.21 (10H, m, ArH), 6.47 (1H, d, J¼15.5 Hz, H20), 5.90 (1H,
dd, J¼8.5, 15.5 Hz, H10), 4.90 (1H, d, J¼15.0 Hz, H30), 4.23
(1H, br dd, J¼6.5, 2.5 Hz, H4), 3.94 (1H, d, J¼15.0 Hz,
H30), 3.92 (1H, d, J¼8.5 Hz, H5), 2.84 (1H, dd, J¼6.5,
17.0 Hz, H3), 2.63 (1H, br s., OH), 2.45 (1H, dd, J¼2.5,
17.0 Hz, H3); dC 172.6 (C2), 136.2 (ArC), 135.6 (C20),
134.2 (ArC), 128.7 (ArC), 128.6 (ArC), 128.3 (ArC), 128.1
(ArC), 127.5 (ArC), 126.5 (ArC), 125.09 (C10), 70.6 (C4),
68.9 (C5), 44.2(C30), 39.4 (C3); MS (EI) m/z 293 (100%);
3.1.23. (4S,5R)-1-Benzyl-4-(benzyloxy)-
5-phenethylpyrrolidin-2-one (22)
To a solution of 21 (0.98 g, 2.45 mmol) in CH2Cl2 (7 mL)
at ꢁ78 ꢀC was added dropwise Et3SiH (1.42 g, 12.25 mmol)
and then BF3$OEt2 (1.03 g, 7.35 mmol). The mixture was
stirred at ꢁ78 ꢀC for 6 h and then allowed to warm slowly
to rt and stirred overnight. Saturated aqueous NaHCO3 solu-
tion (10 mL) was added, and the aqueous layer was extracted
with CH2Cl2 (3ꢂ10 mL). The combined organic extracts were
washed with brine, dried (anhydrous Na2SO4), filtered and
concentrated in vacuo. The residue was purified by column
chromatography (increasing polarity from 1:1, EtOAc/petrol
to EtOAc as eluent) to give the title compound as an oil
(0.781 g, 83%, dr¼91:9). Rf: 0.26 (1:1, EtOAc/petrol); MS
ꢃ
HRMS (EI) calcd for C19H19NO2 (Mþ ): 293.1415, found:
293.1409.
ꢃ
(EI) m/z 385 (100%); HRMS (EI) calcd for C26H27NO2 (Mþ ):
385.2041, found: 385.2039; dH 7.32e7.02 (15H, m, ArH),
4.9 (1H, d, J¼15.5 Hz, H30), 4.45 (1H, d, J¼11.5 Hz, H40),
4.36 (1H, d, J¼11.5 Hz, H40), 3.97 (1H, d, J¼15.5 Hz, H30),
3.93 (1H, d, J¼6.5 Hz, H4), 3.52 (1H, br d, J¼8.5 Hz,
H5), 2.74 (1H, dd, J¼6.5, 17.5 Hz, H3), 2.55e2.52 (2H, m,
H3, H10), 2.48e2.45 (1H, m, H10), 1.94e1.93 (1H, m, H20),
1.67e1.69 (1H, m, H20); dC 172.5 (C2), 140.5 (ArC), 137.3
(ArC), 136.0 (ArC), 128.6 (ArC), 128.4 (ArC), 128.3 (ArC),
128.0 (ArC), 127.9 (ArC), 127.8 (ArC), 127.6 (ArC), 127.4
(ArC), 126.1 (ArC), 76.7 (C4), 70.5 (C40), 62.8 (C5), 44.1
(C30), 37.2 (C3), 32.2 (C3), 31.0 (C10).
3.1.22. (4S )-1-Benzyl-4-(benzyloxy)-5-hydroxy-
5-styrylpyrrolidin-2-one (21)
Magnesium turnings (0.302 g, 12.6 mmol) were stirred
overnight under N2, and anhydrous THF (5 mL) was added
to the flask. Neat trans-b-bromostyrene (0.461 g, 2.52 mmol)
was added dropwise at rt. The reaction mixture was stirred
at 40 ꢀC for 1 h. The pyrrolidine-2,5-dione 20 (0.50 g,
1.68 mmol) was dissolved in dry THF (10 mL) and the solu-
tion was cooled to ꢁ78 ꢀC. 2-Phenylvinylmagnesium bromide
was then transferred to the solution via syringe. The reaction
mixture was stirred at ꢁ78 ꢀC for 4 h, and then warmed slowly
to ꢁ10 ꢀC. Saturated aqueous NH4Cl solution (20 mL) was
added and the aqueous layer was extracted with CH2Cl2
(3ꢂ15 mL). The combined organic extracts were dried (anhy-
drous Na2SO4), filtered and concentrated in vacuo. The crude
product was purified by column chromatography (1:1, EtOAc/
petrol as eluent) to give the title compound as an oil (0.306 g,
45%, dr¼58:42). Rf: 0.54 (1:1, EtOAc/petrol); MS (EI) m/z
3.1.24. (4S, 5R)-1-Benzyl-4-hydroxy-5-phenethylpyrrolidin-
2-one (23)
To a solution of 22 (0.050 g, 0.130 mmol) in MeOH (3 mL)
was added PdCl2 (0.018 g, 0.10 mmol). The mixture was
stirred at rt under an atmosphere of H2 for 1 h, then the flask
was flushed with N2 before the mixture was filtered through
CeliteÒ and the solids were washed with MeOH (2ꢂ10 mL).
The filtrate was evaporated in vacuo and the crude product
was purified by column chromatography (1:1, EtOAc/petrol
as eluent) to give the title product as an oil (0.030 g, 76%).
Rf: 0.19 (1:1, EtOAc/petrol); MS (EI) m/z 295 (80%);
ꢃ
399 (100%); HRMS (EI) calcd for C26H25NO3 (Mþ ):
399.1834, found: 399.1819.
Major diastereomer: dH 7.31e7.17 (15H, m, ArH), 6.79
(1H, d, J¼16.0 Hz, H20), 5.86 (1H, d, J¼16.0 Hz, H10), 4.60
(2H, s, H40), 4.85 (1H, d, J¼15.0 Hz, H30), 4.42 (1H, d,
J¼15.0 Hz, H30), 4.03 (1H, br s, OH), 4.00e3.98 (1H, m,
H4), 2.70 (1H, dd, J¼7.0, 17.0 Hz, H3), 2.58 (1H, dd, J¼
4.5, 17.0 Hz, H3); dC 171.6 (C2), 138.3 (ArC), 135.3 (ArC),
132.4 (C20), 128.5 (ArC), 128.4 (ArC), 128.3 (ArC), 128.2
(ArC), 128.2 (ArC), 128.2 (ArC), 128.1 (ArC), 128.0 (ArC),
127.7 (ArC), 127.6 (ArC), 127.3 (ArC), 126.8 (ArC), 126.7
(C10), 90.5 (C5), 77.2 (C4), 72.3 (C40), 43.0 (C30), 35.5
(C3). Minor diastereomer: dH 7.30e7.19 (15H, m, ArH),
6.85 (1H, d, J¼16.5 Hz, H20), 6.25 (1H, d, J¼16.5 Hz, H10),
ꢃ
HRMS (EI) calcd for C19H21NO2 (Mþ ): 295.1572, found:
295.1556; nmax/cmꢁ1 3359, 1663, 1474, 1451, 1244, 1081;
dH 7.26e7.04 (10H, m, ArH), 4.94 (1H, d, J¼15.0 Hz, H30),
4.21 (1H, d, J¼6.0 Hz, H4), 3.99 (1H, d, J¼15.0 Hz, H30),
3.35 (1H, br d, J¼7.0 Hz, H5), 2.80 (1H, dd, J¼6.0,
17.5 Hz, H3), 2.64e2.62 (1H, m, H10), 2.53e2.50 (1H, m,
H10), 2.39 (1H, d, J¼17.5 Hz, H3), 1.95e1.52 (1H, m, H20),
1.63e1.60 (1H, m, H20); dC 171.9 (C2), 141.0, 136.4 (ArC),
128.9 (ArC), 128.8 (ArC), 128.4 (ArC), 128.2 (ArC), 127.8

I.R. Morgan et al. / Tetrahedron 64 (2008) 1409e1419
1419
(ArC), 126.4 (ArC), 69.3 (C4), 66.4 (C5), 44.6 (C30), 40.4
(C3), 32.4 (C20), 31.4 (C10).
2g (cis/trans 83:17), 2h (cis/trans¼66:34), 2i (cis/trans¼80:20) and 2l
(cis/trans¼57:43). For six-membered ring examples see Refs. 2l (cis/
trans¼76:24) and 2o (cis/trans¼63:27). For the cis-selective allylation
(cis/trans¼77:23) of the O-TBS, methylcarbamate analogue of 1 (n¼1,
Scheme 2) see Ref. 2a.
Acknowledgements
4. For the synthesis of cis-adducts from aryl or alkynyl migration from a C-3
silyl ether to C-2 iminium ion see: (a) Tomooka, K.; Nakazaki, A.; Nakai,
T. J. Am. Chem. Soc. 2000, 122, 408e409; (b) Huang, J.-M.; Hong, S.-C.;
Wu, K.-L.; Tsai, Y.-M. Tetrahedron Lett. 2004, 45, 3047e3050.
5. (a) Batey, R. A.; MacKay, D. B.; Santhakumar, V. J. Am. Chem. Soc. 1999,
121, 5075e5076; (b) Batey, R. A.; MacKay, D. B. Tetrahedron Lett. 2000,
41, 9935e9938.
We thank the Australian Research Council and the Univer-
sity of Wollongong for financial support.
References and notes
6. Ruan, Y.-P.; Wei, B.-G.; Xu, X.-Q.; Liu, G.; Yu, D.-S.; Liu, L.-X.; Huang,
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T.; Tang, M. Synlett 2004, 2670e2680; (g) Au, C. W. G.; Pyne, S. G.
J. Org. Chem. 2006, 71, 7097e7099.
7. (a) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
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hedron Lett. 1993, 34, 583e586; (c) Petasis, N. A.; Zavialov, I. A. J. Am.
Chem. Soc. 1997, 119, 445e446.
9. The 5-O-methyl, N-benzyl analogue of 12 was also poorly diastereoselec-
tive with silicon based nucleophiles, except propargyl trimethylsilane
(100% trans selective).2o
2. (a) Thaning, M.; Wistrand, L.-G. J. Org. Chem. 1990, 55, 1406e1408; (b)
Bernardi, A.; Micheli, F.; Potenza, D.; Scolastico, C.; Villa, R. Tetra-
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S.; Ostendorf, M.; Boom, A.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
1996, 52, 2603e2628; (f) Lennartz, M. L.; Sadakane, M.; Steckhan, E.
Tetrahedron 1999, 55, 14407e14420; (g) Lennartz, M.; Steckham. Synlett
2000, 319e322; (h) Russowsky, D.; Petersen, R. Z.; Godoi, M. N.; Pilli,
R. A. Tetrahedron Lett. 2000, 41, 9939e9942; (i) Klitzke, C. F.; Pilli,
R. A. Tetrahedron Lett. 2001, 42, 5605e5608; (j) Okitsu, O.; Suzuki, R.;
Kobayashi, S. J. Org. Chem. 2001, 66, 809e823; (k) Washburn, D. G.;
Heidebrecht, R. W.; Martin, S. F. Org. Lett. 2003, 5, 3523e3525; (l) Huang,
P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663e1667; (m) Huang, P.-Q.;
Lu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003, 5, 1927e1929; (n) Meng,
W.-H.; Wu, T.-J.; Zhang, H.-K.; Huang, P.-Q. Tetrahedron: Asymmetry 2004,
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2825e2828; (q) Othman, R. B.; Bousquet, T.; Othman, M.; Dalla, V. Org.
Lett. 2005, 7, 5335e5337; (r) Huang, P.-Q. Synlett 2006, 1133e1149; (s)
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ꢀ
10. Prepared from the known (3S)-hydroxysuccinimide (Kocalka, P.; Pohl, R.;
Rejmam, D.; Rosenberg, I. Tetrahedron 2006, 62, 5763e5774) by NaBH4
reduction.
1
11. (a) Compound 11 was formed as a single isomer. The H NMR spectrum
of 11 showed a very small J4,5 coupling constant, J4,5¼1.0 Hz, consistent
with the 4,5-trans-stereochemistry. However, obtaining J4,5 for its C-5
epimer (see (b) below) from NMR analysis of a mixture of 11 and its
C-5 epimer was difficult and therefore we are not 100% confident of
the stereochemistry at C-5 in 11. (b) A referee has suggested that com-
pound 13 may be 5-epi-11 rather than the epoxide. We have made a mix-
ture (80:20, respectively) of 11 and 5-epi-11 by treating 11 with 10%
HCl/THF at rt for 16 h. This mixture could not be separated by TLC,
however, the 1H NMR resonances for 5-epi-11 (dH (d4-MeOH) (in
part) 4.24 (1H, app q, J ca. 6 Hz, H4), 2.62 (1H, dd, J¼7.0, 16.5 Hz,
H3), 2.42 (1H, dd, J¼5.5, 16.5 Hz, H3)) were different to that of 13.
Furthermore, 13 was much less polar (much higher Rf value) than the
mixture of 11 and 5-epi-11, again consistent with the epoxide structure
for 13.
12. Prepared according to Ref. 2r and references cited therein.
13. For a review on trifluoroborate salt chemistry see: Stefani, H. A.; Cella,
A. S.; Vieira, A. S. Tetrahedron 2007, 63, 3623e3658.
14. Williams, A. L.; Grillo, T. A.; Comins, D. L. J. Org. Chem. 2002, 67,
1972e1973.
3. The addition of allyltrimethylsilane or tributylstannane to five- and six-
membered ring N-acyliminium ions derived from precursors C or D
(Scheme 1), gives product mixtures that favour the cis isomer, however,
this selectivity is only modest. For five-membered ring examples see
Refs. 2a (cis/trans¼77:23), 2b (cis/trans¼80:20), 2f (cis/trans¼83:17),
15. Yoda, H.; Kitayama, H.; Yamada, W.; Katagiri, T.; Takabe, K. Tetra-
hedron: Asymmetry 1993, 4, 1451e1454.