Nucleophilic addition of potassium organotrifluoroborates to chiral cyclic N-acyliminium ions: stereoselective synthesis of functionalized N-heterocycles

Article abstract of DOI:10.1016/j.tet.2008.02.006

The stereoselective nucleophilic addition of potassium aryl- and alkynyltrifluoroborates to cyclic N-acyliminium ion derivatives from N-benzyl-3,4,5-triacetoxy-2-pyrrolidinone, affording the respective 5-substituted 2-pyrrolidinone is described. The products were obtained in moderate to good yields and with preference for the syn diastereomer.

Full text of DOI:10.1016/j.tet.2008.02.006

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3306e3314
www.elsevier.com/locate/tet
Nucleophilic addition of potassium organotrifluoroborates to chiral
cyclic N-acyliminium ions: stereoselective synthesis
of functionalized N-heterocycles
b
a
Adriano S. Vieira a, , Fernando P. Ferreira , Pedro F. Fiorante ,
*
Rafael C. Guadagnin , Helio A. Stefani
a
a,b,c,
*
´
a Faculdade de Cieˆncias Farmaceˆuticas, Universidade de S~ao Paulo, SP, Brazil
b Departamento de Biofisica, Universidade Federal de S~ao Paulo, SP, Brazil
c Instituto de Qu´ımica, Universidade de S~ao Paulo, S~ao Paulo, SP, Brazil
Received 13 December 2007; received in revised form 28 January 2008; accepted 4 February 2008
Available online 7 February 2008
Abstract
The stereoselective nucleophilic addition of potassium aryl- and alkynyltrifluoroborates to cyclic N-acyliminium ion derivatives from
N-benzyl-3,4,5-triacetoxy-2-pyrrolidinone, affording the respective 5-substituted 2-pyrrolidinone is described. The products were obtained in
moderate to good yields and with preference for the syn diastereomer.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
investigated3a and the intermediates thereof have been
employed in polar cycloadditions.3b,c
N-Acyliminium ions1 are very important in organic synthe-
sis since they are reactive intermediates involved in the synthe-
sis of many compounds with interesting biological properties.
Nucleophilic additions to N-acyliminium ions constitute an
important method to provide a-functionalized amino com-
pounds and for the preparation of alkaloids and many other
biologically active nitrogen heterocycles.2 Of particular inter-
est are the intermolecular nucleophilic substitution reactions
of cyclic N-acyliminium ions precursors (N,O-acetal deriva-
tives) with carbon-based nucleophiles through activation by
a Lewis acid (a-amidoalkylation reaction) (Scheme 1).
Different classes of carbon nucleophiles can react with
N-acyliminium ions, including allylsilanes,4 allyl-,5 alkyl-
and aryl-4e,6 and alkynylmetal,7 TMSCN,4d,8 isonitriles,8c enol
derivatives,2b,4d,i,j,8c,9 and aromatics.2e,10
While a wide variety of nucleophiles are known to attack
N-acyliminium ions, there are few reactions with alkenyl-,
alkynyl- or arylmetal derivatives.4e,11 Batey et al.12a and
Pyne et al.12b reported the stereoselective addition reaction
of alkenyl- and arylboronates to activated N-acyliminium ion
precursor under Lewis acidic catalysis.12
In the recent years, organoboron compounds have become
one of the most popular organometallic reagents into the car-
The activation of the N,O-acetal derivatives in order to
perform a-amidoalkylations3 can be carried out under mild
conditions with catalytic amounts of acid to access sensitive
target molecules. a-Amidoalkylation has been extensively
R2
R2
Nu
R1
R1
R2
OR4
R1
Lewis acid
CH2Cl2, -78 °C
NuH
O
O
O
H
N
N
R3
N
R3
R3
* Corresponding authors. Tel.: þ55 11 30913654; fax: þ55 11 3815 4418.
E-mail addresses: as.vieira@hotmail.com (A.S. Vieira), hstefani@usp.br
(H.A. Stefani).
Scheme 1. Nucleophilic additions to the N-acyliminium ions.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.006

A.S. Vieira et al. / Tetrahedron 64 (2008) 3306e3314
3307
bonecarbon bond formation chemistry.13 The organoboron
compounds most used are boronic acids and boronate esters,
but these compounds have some drawbacks, among them we
can mention the low stability, very high price of some reagents
and high sensitivity to air and moisture. To solve the problems
those organoboron have been replaced by potassium organotri-
fluoroborate salts. These latter reagents are very stable to air
and moisture, crystalline solids, easily prepared from inexpen-
sive materials and show a greater nucleophilicity compared
with their boronic acids or boronate esters analogues.14a Peta-
sis et al. developed a three-component coupling reaction of
alkenyl- and arylboronic acids with aldehydes and amines,
for the synthesis of allylamines and a-amino acids.15 Similar
reactions were performed with potassium organotrifluoro-
borates in the synthesis of allylic-,16 homoallylic-,17 propargyl-,18
tertiary-19 and a-(fluoroalkyl)amines.20 These reactions were
demonstrated not to occur via direct addition to free iminium
ions. However, we considered that the greater reactivity of
N-acyliminium ions could enable reaction with potassium
organotrifluoroborates.
diastereoisomers.9c After acylation of the alcohol with acetic
anhydride, the desired N-acyliminium ion precursor 4 was
obtained in good yield. The stereochemistry of the major
syn-isomer was determined on the basis of the J(H4eH5) cou-
pling constant of 2.0 Hz.
Our initial studies were focused on the development of an
optimum set of reaction conditions. For initial screening
experiments N-benzyl-3,4,5-triacetoxy-2-pyrrolidinone 4 and
potassium phenyltrifluoroborate 5a were selected as starting
materials and dichloromethane as solvent. Reaction of 4
with potassium phenyltrifluoroborate in the absence of a Lewis
acid did not lead to the desired adducts and the starting mate-
rial 4 was recovered unchanged. The requirement for Lewis
acidic activation strongly implies the intermediacy of N-acyl-
iminium ions in this kind of reaction. In view of this result, we
initially evaluated the influence of the Lewis acid on the ste-
reoselective addition of potassium phenyltrifluoroborate. For
this purpose, the N-benzyl-3,4,5-triacetoxy-2-pyrrolidinone 4
was treated with BF3$Et2O (1.0 equiv) at ꢀ78 ꢁC to ensure
in situ formation of the corresponding N-acyliminium ion
4a, which was formed in 30 min (Scheme 3), as evidenced
by the consumption of 4 by TLC analysis.
2. Results and discussion
AcO
AcO
OAc
Ph
OAc
OAc
AcO
OAc
H
In connection with our research interest on the preparation
and reactivity of potassium organotrifluoroborates, and their
use as intermediates in organic synthesis,14 we wish to report
here the stereoselective addition reactions of aryl- and alkynyl-
trifluoroborates to the endocyclic N-acyliminium ion deriva-
tive from L-tartaric acid 3,4,5-triacetoxy-2-pyrrolidinone 4.
L-Tartaric and L-malic acids have proven to be useful pre-
cursors for N-acyliminium ion reactions leading to enantiopure
pyrrolidine derivatives.1 The N-benzyl imide 2 was prepared
from inexpensive L-tartaric acid 1, according to literature
procedure9c (Scheme 2).
PhBF3M
6h, r.t.
Lewis acid
O
O
O
N
solvent,
-78 °C, 1h
N
N
Ph
Ph
Ph
4a
4
6a
Scheme 3. Lewis acid-mediated nucleophilic addition of phenyltrifluoroborate
to the substrate 4.
Next, potassium phenyltrifluoroborate 5a (1.2 equiv) was
added and the reaction was allowed to warm to room temper-
ature and stirred for 6 h. The desired product 6a was obtained
in only 21% isolated yield as a mixture in 75:25 ratio of the
syn and anti diastereoisomers, respectively (Table 1, entry 2).
HO
OH
OAc
O
AcO
O
Table 1
Conditions and results for the synthesis of compound 6a according to
Scheme 3
(a)
HO2C
CO2H
N
Ph
Entry Lewis acid
(equiv)
Solvent
M
syn/anti Yieldb (%)
Ratioa
1
2
OAc
OAc
AcO
O
1
d
CH2Cl2
K
K
K
K
K
K
d
d
21
23
46
85
84
81
67
54
51
82
13
d
d
OAc
AcO
(b)
(c)
2
BF3$Et2O (1.0) CH2Cl2
BF3$Et2O (2.0) CH2Cl2
BF3$Et2O (3.0) CH2Cl2
BF3$Et2O (4.0) CH2Cl2
BF3$Et2O (5.0) CH2Cl2
BF3$Et2O (4.0) CH2Cl2
BF3$Et2O (4.0) CH3CN
BF3$Et2O (4.0) Toluene
BF3$Et2O (4.0) Toluene
BF3$Et2O (4.0) Cl(CH2)2Cl
75:25
75:25
80:20
90:10
90:10
3
O
OH
N
N
4
Ph
Ph
5
4
3
6c
7
Scheme 2. Reagents and conditions: (a) (i) CH3COCl, reflux, 24 h; (ii) benzyl
amine, THF, rt, 4 h; (iii) CH3COCl, reflux, 5 h (2, 78%); (b) NaBH4, EtOH,
THF, ꢀ30 ꢁC, 30 min (3, 83%); (c) Ac2O, Et3N, 4-DMAP, CH2Cl2, rt, 3 h
(4, 88%).
n-Bu4Nþ 90:10
8
K
K
65:35
60:40
9
10
11
12
13
14
a
n-Bu4Nþ 60:40
K
K
K
K
90:10
50:50
d
TiCl4 (4.0)
SnCl4 (4.0)
ZnBr2 (4.0)
CH2Cl2
CH2Cl2
CH2Cl2
Acid 1 was successively treated with acetyl chloride, benz-
yl amine and acetyl chloride to afford the respective imide 2.
Regio- and stereoselective reduction of the imide 2 was
accomplished by the reaction with excess sodium borohydride
in ethanol/THF at ꢀ30 ꢁC for 30 min to give the 5-hydroxy-
2-pyrrolidinone derivative 3 as a 95:5 mixture of syn/anti
d
Ratios determined by 1H NMR (300 MHz) integration of the hydrogen
attached to the a-nitrogen carbon on the crude reaction mixture.
b
Isolated yields of the pure product after flash chromatography.
The reaction was performed at room temperature for 24 h.
c

3308
A.S. Vieira et al. / Tetrahedron 64 (2008) 3306e3314
Table 2 (continued)
Table 2
5-Substituted 2-pyrrolidinones 6aej
Entry Nucleophile (5)
syn/anti Yieldb
Ratioa (%)
Product (6)
syn/anti Yieldb
Ratioa (%)
Entry Nucleophile (5)
Product (6)
AcO
O
OAc
AcO
6-CH3Oe
C10H6C^C
(5j)
OAc
10
70:30 71
N
C6H5BF3K
(5a)
Bn
O
1
90:10 84
N
Bn
OCH3
6j
a
Ratios determined by 1H NMR (300 MHz) integration of the hydrogen
attached to the a-nitrogen carbon on the crude reaction mixture.
6a
b
Isolated yields of the pure product after flash chromatography.
AcO
O
OAc
Surprisingly, potassium phenyltrifluoroborate did not react
when SnCl4 and ZnBr2 were used as Lewis acids and the
use of TiCl4 led to very low yields and diastereoselectivity
(Table 1, entries 12e14). However, with 4.0 equiv of
BF3$Et2O the reaction proceeded to completion in 6 h, afford-
ing the product 6a in very good yield and diastereomeric ratio
(Table 1, entry 5). When higher amounts of BF3$Et2O were
employed, no improvement on the yield and selectivity was
observed, even when the reaction was performed at room
temperature for 24 h (Table 1, entry 6).
The use of smaller amounts of BF3$Et2O resulted in very
low yields (Table 1, entries 2e4). Next, we evaluated the in-
fluence of the organotrifluoroborate counter ion and found
no significant influence on the reaction behaviour in respect
to yield and diastereoisomeric ratio by using the tetra-n-butyl-
ammonium derivative (Table 1, entries 7 and 10). The use of
other solvents such as acetonitrile and toluene afforded low
isolated yields, and 1,2-dichloroethane produces similar
results to CH2Cl2 (Table 1, entry 8e11).
Among the several reaction conditions tested the use of
4.0 equiv of BF3$Et2O as Lewis acid and 1.2 equiv of the potas-
sium organotrifluoroborate in CH2Cl2 at ꢀ78 ꢁC, under anhy-
drous and inert atmosphere for 1 h and room temperature for
6 h afforded the 5-substituted-2-pyrrolidinone 6a in 84% yield
in a 90:10 diastereomeric ratio in favour to the syn-isomer
(determined by 1H NMR analysis).
These optimised conditions were subsequently applied to
the different potassium aryl- and alkynyltrifluoroborates 5bej
as outlined in Table 2. The reaction proceeded with satisfac-
tory to good yields and in good levels of diastereoselection in
most cases. The scope of the reaction has been demonstrated
by the evaluation of an array of donoreacceptor nucleophiles
alkynyl-, aryl- and heteroaryltrifluoroborate combinations
(Scheme 4).
4-CH3OC6H4-
BF3K (5b)
2
3
4
90:10 87
90:10 68
70:30 65
N
Bn
OCH3
6b
AcO
OAc
4-FC6H4BF3K
(5c)
O
N
Bn
F
6c
OAc
AcO
O
CF3
3,5(CF3)2C6H3-
BF3K (5d)
N
Bn
6d
CF3
OAc
AcO
CH3
2-CH3C6H4-
BF3K (5e)
O
5
6
7
90:10 76
85:15 71
90:10 73
N
Bn
6e
AcO
O
OAc
3-C4H3SBF3K
(5f)
N
Bn
S
6f
AcO
OAc
C6H5C^CBF3K
(5g)
O
N
Bn
Ph
6g
AcO
O
OAc
Reaction of N-acyliminium ion precursor 4 with electron-
rich potassium aryltrifluoroborate 5b led to 5-aryl-2-pyrrolidi-
none in a very good yield and diastereoselectivity (Table 2,
n-C4H9C^C-
BF3K (5h)
8
9
70:30 83
N
Bn
n-C4H9
6h
AcO
O
OAc
OAc
AcO
O
OAc
R1
Bn
6 syn
AcO
O
OAc
R1
Bn
6 anti
1) BF3.OEt2 (4.0 eq.)
CH2Cl2, -78 °C, 1h
2) R1BF3K (5) (1.2 eq.)
AcO
O
OAc
+
CH3OCH2C^C-
BF3K (5i)
N
N
N
80:20 78
OCH3
N
Bn
Bn
-78 °C- r.t., 6h
4
6i
Scheme 4. Stereoselective addition of potassium organotrifluoroborates to
N-acyliminium ion.
(continued)

A.S. Vieira et al. / Tetrahedron 64 (2008) 3306e3314
3309
entry 2). Even with electron-poor potassium aryltrifluorobo-
rates as nucleophiles the reaction proceeded in satisfactory
yield (Table 2, entries 3 and 4). Similar level of diastereoselec-
tivity and yields were also obtained by employing potassium
alkynyltrifluoroborates 5gej.
the adjacent s bonds becomes critical factors for the syn
additions.
3. Conclusion
Concerning the mechanism of this reaction, BF3$Et2O re-
acts with potassium organotrifluoroborate to provide, as de-
scribed by Kaufmann et al.,21 organoboron difluoride, which
was detected by 11B NMR20,21 (Scheme 5). The organoboron
difluoride is also a Lewis acid able to activate the hemiaminal
and generate iminium and nucleophilic species. Thus, the ac-
tive nucleophile may be the R1BF2 species in this kind of
reaction.20
In summary, functionalized N-heterocycles are efficiently
formed by the reaction of potassium aryl- and alkynyltrifluoro-
borates with activated N-acyliminium ion precursor under
Lewis acidic conditions, affording preferentially the syn-5-
substituted-2-pyrrolidinones in good diastereoselectivity. This
methodology is advantageous relative to many N-acyliminium
ion based strategies, because of the ready availability, high
stability, low toxicity and mild nucleophilic character of the
potassium organotrifluoroborate salts. Studies towards the
employing of this methodology in the synthesis of indolizidine
ring system are under investigation and will be reported in due
course.
R1-BF3K + BF3
R1-BF2
KBF4
Scheme 5. Generation of R1BF2 species.
4. Experimental
The stereochemistry of the newly created stereogenic cen-
1
tre of 6b was determined by H NMR analysis of the crude
4.1. General
mixture. The cis relative stereochemistry of the major product
was established after analysis of the multiplicity and vicinal
coupling constant of the hydrogen attached to the a-nitrogen
(H-5) and then was extended to the other related compounds.
In this way, the relative stereochemistry of compounds 6aej
was assigned by the correlation of the chemical shifts and coup-
ling constant data with similar compounds already described in
the literature.2e,22
All air-sensitive and/or water-sensitive reactions were car-
ried out under nitrogen atmosphere with dry solvents under an-
hydrous conditions. Standard syringe techniques were applied
for transfer of dry solvents and some air-sensitive reagents.
The reactions were monitored by TLC carried out on Merck sil-
ica gel (60 F254) by using UV light as visualising agent and 5%
vanillin in 10% H2SO4 and heat as developing agents. Merck
silica gel (particle size 0.040e0.063 mm) was used for flash
chromatography. CH2Cl2 and CH3CN were distilled from
For the analogous 2-pyrrolidinones the vicinal coupling
3
constant J(H5eH4) for the syn-isomer shows smaller value
˚
than the anti-isomer. These chemical correlations are in agree-
ment with the major isomer obtained by us and the relative ste-
reochemistry of the major isomer was assigned as being syn.23
This result is unexpected, since neighbouring group participa-
tion of the 4-O-acetyl group in the stereocontrol does not seem
to be affective; but it is rather the 3-O-acetyl group that pro-
vides anchimeric assistance, which leads to preferential forma-
tion of the syn-isomer (Scheme 6).
Several studies in the literature report on the preferential cis
addition of nucleophiles to N-acyliminium ions, revealing that
the stereochemical outcome is not ruled by steric effects. The
syn preference indicate favourable orbital interaction24 over
steric interaction experienced during syn approach of the bo-
ron nucleophile to the resident OAc group of N-acyliminium
intermediate 4a in the presence of BF3$Et2O. Danishefsky
et al.25 hypothesised that in the Lewis acid catalysed processes
the stabilisation of the emerging s* orbital interaction with
P2O5 and stored over MS 4 A under atmosphere of dry nitrogen.
Toluene was distilled from CaH2 and stored over sodium-wire.
Dry THF was distilled from sodium benzophenone ketyl prior to
use. EtOH was dried, distilled from CaH2 and stored over MS
˚
4 A. Et3N was distilled from KOH pellets. Acetic anhydride
was distilled from P2O5 and stored under atmosphere of dry
nitrogen. NMR spectra were recorded with Bruker DPX 300
(300 MHz) instrument using CDCl3 as solvent and calibrated
using tetramethylsilane as internal standard. Chemical shifts
are reported in d parts per million relative to (CH3)4Si for H
and CDCl3 for 13C NMR. Coupling constants (J) are reported
in hertz. Diastereomeric ratios were determined by peak inte-
1
gration in the H NMR spectra of the crude product. Infrared
(IR) spectra were obtained from CHCl3 solutions, using a Varian
3100 FT-IR spectrophotometer and wavelengths are reported in
cmꢀ1. Mass spectra (MS) were measured on a Shimadzu
GCMS-QP5050A mass spectrometer. The HRMS spectra
1
AcO
AcO
OAc
R1
AcO
OAc
H
R1BF2
O
O
O
O
Nu
N
N
CH3
O
N
Ph
Ph
4a
6 syn
Ph
Scheme 6. Stereoselective addition of the R1BF2 to N-acyliminium ions.

3310
A.S. Vieira et al. / Tetrahedron 64 (2008) 3306e3314
were measured on a Bruker Daltonics Micro TOF (direct inlet
probe).
anhydride (8.8 mL, 70 mmol) and 4-(N,N-dimethylamino)pyri-
dine (430 mg, 5 mmol). The reaction was allowed to warm up to
room temperature, and stirred for 3 h. The mixture was diluted
with CH2Cl2 (100 mL) and washed with 10% HCl (40 mL), sat-
urated NaHCO3 (40 mL) and water (2ꢂ60 mL). The organic
phase was dried over MgSO4 and filtered, and the solvent was
removed under reduced pressure. The residue was chromato-
graphed on silica gel (230e400 mesh, 30% ethyl acetate in hex-
anes) to afford 4 (14.3 g, 44 mmol) in 88% yield in a 96:4
mixture of syn/anti diastereoisomers and as a pale yellow oil.
Syn-Isomer: 1H NMR (CDCl3, 300 MHz): d 1.89 (s, 3H), 2.07
(s, 3H), 2.18 (s, 3H), 4.35 (d, J¼15.0 Hz, 1H), 4.65 (d,
J¼15.0 Hz, 1H), 5.21 (dd, J¼4.0, 2.0 Hz, 1H), 5.36 (d,
J¼4.0 Hz, 1H), 6.05 (d, J¼2.0 Hz, 1H), 7.23e7.36 (m, 5H).
13C NMR (CDCl3, 75 MHz): d 20.4, 20.5 (2C), 44.9, 73.1,
75.9, 83.4, 127.9, 128.5, 128.8, 135.2, 167.8, 169.5, 169.6,
170.0. IR cmꢀ1 (CHCl3 solution): 2970, 1743, 1695. GC/MS:
m/z (relative intensity) 289 (9%), 188 (10%), 124 (9%), 91
(45%), 43 (100%).
4.2. Synthesis of N-acyliminium ion precursor 4
The N-acyliminium ion precursor was prepared starting
from L-tartaric acid using standard procedures.9c
4.2.1. (3R,4R)-3,4-Bis-(acetoxy)-1-benzyl-2,5-
dioxopyrrolidin-3-yl acetate (2)
A mixture of L-tartaric acid (15.0 g, 100 mmol) and acetyl
chloride (70 mL, 1.0 mol) was stirred under reflux for 24 h un-
der nitrogen atmosphere, during which the solution became ho-
mogeneous. Excess acetyl chloride was removed by distillation
at 1 atm and trace amounts were removed under vacuum. The
crude anhydride resulting was dissolved in dry THF (120 mL)
and benzyl amine (10.7 g, 100 mmol) was slowly added. After
the solution was stirred for 4 h, it was concentrated in vacuum
and the residue was refluxed with acetyl chloride (70 mL,
1.0 mol) for another 5 h. After concentration of the reaction
mixture in vacuum, the residue was purified by using column
chromatography (n-hexane/ethyl acetate, 2:1) to give 2
4.3. Synthesis of potassium aryl- and alkynyltrifluoroborates
(5aej)
1
(23.8 g, 78%) as a white solid, mp¼120e121 ꢁC. H NMR
(CDCl3, 300 MHz) d 2.18 (s, 6H), 4.72 (s, 2H), 5.53 (s, 2H),
7.29e7.35 (m, 5H). 13C NMR (CDCl3, 75 MHz) d 20.3, 43.0,
72.7, 128.2, 128.3, 129.1, 136.2. IR cmꢀ1 (CHCl3 solution):
3007, 2970, 1739, 1689.
The organotrifluoroborates were prepared according litera-
ture procedures.26
4.3.1. General procedure for the synthesis of the potassium
aryltrifluoroborates (5aef)26a
4.2.2. (3R,4R,5R)-3,4-Bis-(acetoxy)-5-hydroxy-1-benzyl-2-
pyrrolidinone (3)
A solution of the arylmagnesium bromide (10 mmol,
1.0 equiv) in 20 mL of dry THF was cooled to ꢀ78 ꢁC under
nitrogen atmosphere, trimethylborate (1.56 g, 15 mmol,
1.5 equiv) was then added dropwise at ꢀ78 ꢁC. The solution
was stirred at this temperature for 1 h after which it was allowed
to warm to ꢀ20 ꢁC for 1 h. A saturated aqueous solution of po-
tassium hydrogen difluoride (4.7 g, 60 mmol, 6.0 equiv) was
added to the vigorously stirred solution. The resulting mixture
was allowed to stir for 1 h at ꢀ20 ꢁC after which it was allowed
to warm to room temperature for 1 h. The solvent was removed
under reduced pressure, and the resulting white solid was dried
under high vacuum for 2 h to remove all water. The solid was
then washed with acetone and hot acetone. The resulting
organic solution was filtered, and the solvent was removed to
afford a fluffy white solid. This solid was then dissolved in
hot acetone and precipitated with diethyl ether, after which
the solution was cooled to ꢀ20 ꢁC to complete precipitation
of the solid. The product 5a was collected as a white crystalline
solid (1.52 g, 83%).
To a solution of the imide 2 (21.3 g, 70 mmol) in a mixture
of 300 mL of EtOH and 100 mL of THF was added at ꢀ30 ꢁC
NaBH4 (13.3 g, 350 mmol) portion wise under nitrogen atmo-
sphere. After the addition was completed (5 min), the reaction
was stirred at ꢀ30 ꢁC for 1 h, and was acidified with 10% HCl
until pH 2e3, followed by neutralisation with saturated
NaHCO3. The reaction mixture was partitioned between
300 mL of CH2Cl2 and 100 mL of water. The layers were sep-
arated and the aqueous phase was extracted with three 150 mL
portions of CH2Cl2. The combined organic phases were dried
over MgSO4, filtered, and concentrated in vacuum to give the
crude 5-hydroxy-2-pyrrolidinone 3 in a 95:5 mixture of syn/
anti diastereoisomers (17.8 g, 83%) as a white solid. Recrys-
tallisation (EtOAc) gave white crystals, mp¼91e92 ꢁC. syn-
1
Isomer: H NMR (CDCl3, 300 MHz) d 2.10 (s, 3H), 2.15 (s,
3H), 4.23 (d, J¼15.0 Hz, 1H), 4.50 (d, J¼15.0 Hz, 1H), 5.13
(dd, J¼4.2, 2.1 Hz, 1H), 5.37 (d, J¼4.2 Hz, 1H), 6.11 (d,
J¼2.1 Hz, 1H), 7.23e7.35 (m, 5H). 13C NMR (CDCl3,
75 MHz) d 20.6, 20.7, 43.2, 74.3, 79.2, 83.1, 127.9, 128.5,
128.8, 135.2, 166.8, 170.5, 170.6. IR cmꢀ1 (CHCl3 solution):
3259, 2987, 1751, 1671.
4.3.2. General procedure for the synthesis of the potassium
alkynyltrifluoroborates (5gej)26b
A solution of 1-hexyne (0.82 g, 10 mmol, 1.0 equiv) in
20 mL of dry THF was cooled to ꢀ78 ꢁC under nitrogen atmo-
sphere, n-BuLi (6.25 mL, 1.6 M in hexane, 10 mmol, 1.0 equiv)
was added dropwise, and the solution was stirred for 1 h at this
temperature. Trimethylborate (1.56 g, 15 mmol, 1.5 equiv) was
then added dropwise at ꢀ78 ꢁC. The solution was stirred at this
temperature for 1 h after which it was allowed to warm to
4.2.3. (3R,4R,5R)-3,4,5-Tris-(acetoxy)-1-benzyl-2-
oxopyrrolidin-3-yl acetate (4)
To a solution of the 5-hydroxy-2-pyrrolidinone 3 (15.3 g,
50 mmol) in CH2Cl2 (150 mL) under nitrogen atmosphere,
cooled to 0 ꢁC were added Et3N (7.0 mL, 50 mmol), acetic

A.S. Vieira et al. / Tetrahedron 64 (2008) 3306e3314
3311
ꢀ20 ꢁC for 1 h. A saturated aqueous solution of potassium hy-
4.4.2. (3R,4R)-3,4-Diacetoxy-5-(4-methoxyphenyl)-1-benzyl-
2-pyrrolidinone (6b)
drogen difluoride (4.7 g, 60 mmol, 6.0 equiv) was added to the
vigorously stirred solution. The resulting mixture was allowed
to stir for 1 h at ꢀ20 ꢁC after which it was allowed to warm to
room temperature for 1 h. The solvent was removed under
reduced pressure, and the resulting white solid was dried under
high vacuum for 2 h to remove all water. The solid was washed
first with acetone and then with hot acetone. The resulting
organic solution was filtered, and the solvent was removed to
afford a fluffy white solid. This solid was then dissolved in
hot acetone and precipitated with diethyl ether, after which
the solution was cooled to ꢀ20 ꢁC to complete precipitation
of the solid. The product 5h was collected as a white crystalline
solid (1.66 g, 78%). Mp¼256 ꢁC (decomp.).26b
The product 6b was prepared as described in the general pro-
cedure and was obtained in a 90:10 syn/anti mixture as a colour-
less oil in 87% yield (345 mg). Major isomer: syn-6b. 1H NMR
(300 MHz, CDCl3) d 2.08 (s, 3H), 2.12 (s, 3H), 3.72 (s, 3H), 3.97
(d, J¼15.0 Hz, 1H), 4.08 (dd, J¼5.0, 5.2 Hz, 1H), 4.52 (d,
J¼5.0 Hz, 1H), 5.01 (d, J¼15.0 Hz, 1H), 5.27 (d, J¼5.2 Hz,
1H), 6.82 (d, J¼8.3 Hz, 2H), 6.88 (d, J¼8.3 Hz, 2H), 7.18e
7.24 (m, 5H). 13C NMR (75 MHz, CDCl3) d 20.6, 20.7, 45.0,
55.3, 60.2, 74.7, 76.6, 111.1, 114.5, 120.7, 123.2, 128.5,
128.8, 129.3, 130.5, 135.4, 167.8, 169.8, 170.0. GC/MS: m/z
(%)¼397 (3) [Mþ], 337 (39), 295 (33), 278 (17), 204 (56), 91
(100), 43 (63). HRMS (ESI, positive) m/z calcd for
C22H23NO6 398.1579 ([MþH]þ); found 398.1563 ([MþH]þ).
IR cmꢀ1 (CHCl3 solution): 3027, 2936, 1752, 1719, 1229. Mi-
1
4.4. General procedure for the synthesis of 5-aryl and
nor isomer: anti-6b. H NMR (300 MHz, CDCl3) d 2.09 (s,
5-alkynyl-2-pyrrolidinones (6aej)
3H), 2.14 (s, 3H), 3.75 (s, 3H), 3.98 (d, J¼15.0 Hz, 1H), 4.33
(dd, J¼8.0, 8.0 Hz, 1H), 4.45 (d, J¼8.0 Hz, 1H), 4.90 (d,
J¼15.0 Hz, 1H), 5.37 (d, J¼8.0 Hz, 1H), 6.85 (d, J¼8.3 Hz,
2H), 6.88 (d, J¼8.3 Hz, 2H), 7.18e7.24 (m, 5H). 13C NMR
(75 MHz, CDCl3) d 20.4, 20.5, 45.2, 55.4, 60.3, 74.6, 76.9,
111.2, 114.7, 120.8, 123.3, 128.6, 128.8, 129.3, 130.6, 135.6,
167.7, 169.9, 170.2.
4.4.1. (3R,4R)-3,4-Diacetoxy-5-phenyl-1-benzyl-2-
pyrrolidinone (6a)
To a solution of the 5-acetoxy-2-pyrrolidinone 4 (349 mg,
1.0 mmol) in CH2Cl2 (4.0 mL) at ꢀ78 ꢁC under nitrogen atmo-
sphere was added dropwise the BF3$Et2O (0.50 mL, 4.0 mmol,
4.0 equiv). The reaction was kept for 1 h at ꢀ78 ꢁC when potas-
sium phenyltrifluoroborate (220 mg, 1.2 mmol, 1.2 equiv) was
added in one portion. After 1 h at ꢀ78 ꢁC the reaction mixture
was stirred for 6 h at room temperature when it was quenched
with saturated NaHCO3 (10 mL). The mixture was diluted
with CH2Cl2 (20 mL), and the organic phase was washed with
10% HCl (10 mL), saturated NaHCO3 (10 mL) and dried over
MgSO4. Evaporation under reduced pressure, followed by col-
umn chromatography on silica gel (20% ethyl acetate in hex-
anes) afforded 6a in a 90:10 syn/anti mixture as a colourless
oil, in 84% yield (312 mg). Both isomers have nearly the same
Rf values and they could not be separated by column chromatog-
raphy. The syn/anti ratio was determined to be 90:10 by the 1H
NMR (300 MHz) analysis of the crude product. Major isomer:
4.4.3. (3R,4R)-3,4-Diacetoxy-5-(4-fluorophenyl)-1-benzyl-
2-pyrrolidinone (6c)
The product 6c was prepared as described in the general pro-
cedure and was obtained in a 90:10 syn/anti mixture as a colour-
less oil in 68% yield (261 mg). Major isomer: syn-6c. 1H NMR
(300 MHz, CDCl3) d 2.19 (s, 3H), 2.25 (s, 3H), 4.28 (d, J¼
14.6 Hz, 1H), 4.94 (dd, J¼6.2, 2.0 Hz, 1H), 5.08 (d, J¼
14.6 Hz, 1H), 5.15 (d, J¼2.0 Hz, 1H), 5.76 (d, J¼6.2 Hz, 1H),
7.12 (t, J¼8.8 Hz, 2H), 7.31e7.42 (m, 5H), 7.83 (dd, J¼8.3,
2.1 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 20.4, 20.7, 45.0,
63.2, 75.0, 77.5, 115.1, 127.7, 128.1, 128.4, 128.7, 134.6,
137.4, 167.6, 169.9, 170.2. GC/MS: m/z (%)¼385 (3) [Mþ],
309 (64), 187 (29), 177 (12), 117 (100), 105 (53), 91 (80), 43
(98). HRMS (ESI, positive) m/z calcd for C21H20FNO5
385.1325 ([MþH]þ); found 385.1332 ([MþH]þ). IR cmꢀ1
(CHCl3, solution): 3021, 2937, 1750, 1724. Minor isomer:
1
syn-6a. H NMR (300 MHz, CDCl3) d 2.06 (s, 3H), 2.21 (s,
3H), 4.22 (d, J¼15.0 Hz, 1H), 4.89 (dd, J¼6.2, 2.0 Hz, 1H),
5.05 (d, J¼15.0 Hz, 1H), 5.10 (d, J¼2.0 Hz, 1H), 5.71 (d,
J¼6.2 Hz, 1H), 7.28e7.40 (m, 7H), 7.50 (t, J¼7.4 Hz, 1H),
7.78 (d, J¼7.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 20.4,
20.6, 43.1, 61.5, 73.9, 78.7, 127.1, 128.0, 128.5, 128.8, 129.0,
132.3, 134.5, 135.5, 166.8, 167.6, 170.2. GC/MS: m/z
(%)¼367 (5) [Mþ], 291 (70), 262 (3), 187 (28), 117 (100),
105 (57), 91 (84), 77 (8), 43 (94). HRMS (ESI, positive) m/z
calcd for C21H21NO5 368.1419 ([MþH]þ); found 368.1408
([MþH]þ). IR cmꢀ1 (CHCl3 solution): 3023, 2938, 1755,
1721, 1451. Minor isomer: anti-6a. 1H NMR (300 MHz,
CDCl3) d 2.08 (s, 3H), 2.22 (s, 3H), 4.05 (d, J¼15.0 Hz, 1H),
4.58 (dd, J¼8.2, 5.4 Hz, 1H), 5.01 (d, J¼15.0 Hz, 1H), 5.08
(d, J¼5.4 Hz, 1H), 5.36 (d, J¼8.2 Hz, 1H), 7.28e7.40 (m,
7H), 7.50 (t, J¼7.4 Hz, 1H), 7.78 (d, J¼7.4 Hz, 2H). 13C
NMR (75 MHz, CDCl3) d 20.3, 20.5, 43.0, 61.3, 73.7, 78.6,
127.0, 128.0, 128.5, 128.8, 129.0, 132.3, 134.5, 135.5, 166.7,
167.5, 170.2.
1
anti-6c. H NMR (300 MHz, CDCl3) d 2.07 (s, 3H), 2.21 (s,
3H), 4.25 (d, J¼14.5 Hz, 1H), 4.62 (dd, J¼7.8, 7.8 Hz, 1H),
5.01 (d, J¼14.5 Hz, 1H), 5.13 (d, J¼7.8 Hz, 1H), 5.71 (d,
J¼7.8 Hz, 1H), 7.12 (t, J¼8.8 Hz, 2H), 7.31e7.42 (m, 5H),
7.83 (dd, J¼8.3, 2.1 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 20.3, 20.5, 44.6, 63.1, 74.8, 76.8, 115.0, 127.6, 128.1, 128.4,
128.6, 134.5, 137.3, 167.5, 169.8, 170.0.
4.4.4. (3R,4R)-3,4-Diacetoxy-5-[3,5-bis-(trifluoromethyl)-
phenyl]-1-benzyl-2-pyrrolidinone (6d)
The product 6d was prepared as described in the general pro-
cedure and was obtained in a 70:30 syn/anti mixture as a colour-
less oil in 65% yield (326 mg). Major isomer: syn-6d. 1H NMR
(300 MHz, CDCl3) d 2.13 (s, 3H), 2.27 (s, 3H), 4.21 (dd, J¼6.1,
6.1 Hz, 1H), 4.37 (d, J¼14.6 Hz, 1H), 4.67 (d, J¼6.1 Hz, 1H),
5.05 (d, J¼14.6 Hz, 1H), 5.87 (d, J¼6.1 Hz, 1H), 7.30e7.42

3312
A.S. Vieira et al. / Tetrahedron 64 (2008) 3306e3314
(m, 5H), 8.05 (s, 1H), 8.32 (s, 2H). 13C NMR (75 MHz, CDCl3)
d 20.2, 20.4, 45.3, 69.5, 72.0, 75.0, 125.0, 128.2, 128.4, 128.8,
128.9, 129.0, 131.0, 134.2, 134.9, 168.2, 170.2, 170.4. GC/
MS: m/z (%)¼503 (1) [Mþ], 427 (34), 310 (5), 295 (8), 117
(100), 106 (15), 91 (66), 43 (65). HRMS (ESI, positive) m/z
calcd for C23H19F6NO5 504.1246 ([MþH]þ); found 504.1230
([MþH]þ). IR cmꢀ1 (CHCl3 solution): 3036, 2939, 1750,
(300 MHz, CDCl3) d 2.07 (s, 3H), 2.21 (s, 3H), 3.69 (d, J¼
14.5 Hz, 1H), 4.76 (dd, J¼8.1, 8.1 Hz, 1H), 5.09 (d,
J¼14.5 Hz, 1H), 5.34 (d, J¼8.1 Hz, 1H), 5.84 (d, J¼8.1 Hz,
1H), 6.86 (dd, J¼6.3, 3.5 Hz, 1H), 6.98 (d, J¼4.0 Hz, 1H),
7.03 (d, J¼4.0 Hz, 1H), 7.20e7.34 (m, 5H). 13C NMR
(75 MHz, CDCl3) d 20.1, 20.4, 44.9, 56.2, 71.3, 74.8, 127.0,
128.2, 128.4, 128.6, 128.7, 128.9, 134.4, 136.8, 166.4, 167.8,
170.3.
1
1707. Minor isomer: anti-6d. H NMR (300 MHz, CDCl3)
d 2.12 (s, 3H), 2.24 (s, 3H), 4.11 (d, J¼14.6 Hz, 1H), 4.49 (dd,
J¼7.3, 7.3 Hz, 1H), 4.96 (d, J¼7.3 Hz, 1H), 5.03 (d,
J¼14.6 Hz, 1H), 5.43 (d, J¼7.4 Hz, 1H), 7.30e7.42 (m, 5H),
7.97 (s, 1H), 8.24 (s, 2H). 13C NMR (75 MHz, CDCl3) d 20.1,
20.3, 45.1, 69.4, 71.8, 74.9, 125.1, 128.1, 128.4, 128.7, 128.9,
129.0, 130.8, 134.1, 134.8, 168.1, 170.2, 170.3.
4.4.7. (3R,4R)-3,4-Diacetoxy-5-(2-phenyl-1-ethynyl)-1-
benzyl-2-pyrrolidinone (6g)
The product 6g was prepared as described in the general pro-
cedure and was obtained in a 90:10 syn/anti mixture as a colour-
less oil in 73% yield (285 mg). Major isomer: syn-6g. 1H NMR
(300 MHz, CDCl3) d 2.09 (s, 3H), 2.19 (s, 3H), 4.23 (d,
J¼15.0 Hz, 1H), 4.28 (d, J¼5.7 Hz, 1H), 5.18 (d, J¼15.0 Hz,
1H), 5.50 (d, J¼5.7 Hz, 1H), 5.56 (dd, J¼5.7, 5.7 Hz, 1H),
7.30e7.46 (m, 5H). 13C NMR (75 MHz, CDCl3) d 20.7, 20.9,
45.0, 51.5, 73.7, 76.2, 82.3, 88.0, 128.3, 128.6, 128.8, 129.0,
129.3, 129.4, 132.1, 135.2, 166.4, 169.9, 170.5. GC/MS: m/z
(%)¼391 (4) [Mþ], 331 (15), 289 (54), 220 (9), 198 (17), 157
(13), 115 (11), 91 (84), 43 (100). HRMS (ESI, positive) m/z
calcd for C23H21NO5 392.1498 ([MþH]þ); found 392.1485
([MþH]þ). IR cmꢀ1 (CHCl3 solution): 3066, 2932, 2231,
1754, 1724. Minor isomer: anti-6g. 1H NMR (300 MHz,
CDCl3) d 2.14 (s, 3H), 2.22 (s, 3H), 4.14 (d, J¼15.0 Hz, 1H),
4.79 (d, J¼7.8 Hz, 1H), 5.11 (d, J¼15.0 Hz, 1H), 5.23 (dd,
J¼7.8 Hz, 1H), 5.75 (d, J¼7.8 Hz, 1H), 7.30e7.46 (m, 5H).
13C NMR (75 MHz, CDCl3) d 20.8, 21.0, 45.6, 51.8, 73.9,
76.5, 82.4, 88.2, 128.3, 128.7, 128.9, 129.1, 129.3, 129.5,
132.0, 134.7, 166.4, 169.8, 170.1.
4.4.5. (3R,4R)-3,4-Diacetoxy-5-(2-methylphenyl)-1-benzyl-
2-pyrrolidinone (6e)
The product 6e was prepared as described in the general pro-
cedure and was obtained in a 90:10 syn/anti mixture as a colour-
less oil in 76% yield (289 mg). Major isomer: syn-6e. 1H NMR
(300 MHz, CDCl3) d 2.18 (s, 3H), 2.21 (s, 3H), 2.52 (s, 3H), 4.08
(d, J¼14.6 Hz, 1H), 4.19 (dd, J¼5.1, 5.1 Hz, 1H), 4.64 (d,
J¼5.1 Hz, 1H), 5.08 (d, J¼14.6 Hz, 1H), 5.39 (d, J¼5.1 Hz,
1H), 7.23 (d, J¼8.2 Hz, 1H), 7.30e7.51 (m, 7H), 7.81 (d,
J¼8.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 20.4, 20.6,
22.1, 44.5, 60.3, 72.0, 74.9, 124.9, 127.8, 128.3, 128.6, 128.7,
128.8, 130.1, 132.0, 134.5, 136.5, 167.6, 169.8, 170.1. GC/
MS: m/z (%)¼381 (5) [Mþ], 305 (48), 261 (20), 233 (19), 187
(12), 159 (10), 128 (21), 117 (80), 91 (100), 43 (80). HRMS
(ESI, positive) m/z calcd for C22H23NO5 382.1655 ([MþH]þ);
found 382.1671([MþH]þ). IR cmꢀ1 (CHCl3 solution): 3029,
2933, 1753, 1723, 1451, 1225. Minor isomer: anti-6e. 1H
NMR (300 MHz, CDCl3) d 2.16 (s, 3H), 2.20 (s, 3H), 2.49 (s,
3H), 4.13 (dd, J¼6.3, 6.3 Hz, 1H), 4.30 (d, J¼14.6 Hz, 1H),
4.94 (d, J¼6.3 Hz, 1H), 5.02 (d, J¼14.6 Hz, 1H), 5.76 (d,
J¼6.3 Hz, 1H), 7.21 (d, J¼8.2 Hz, 1H), 7.30e7.51 (m, 7H),
7.81 (d, J¼8.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 20.3,
20.5, 22.0, 45.0, 60.4, 71.9, 74.8, 124.8, 127.7, 128.3, 128.5,
128.7, 128.8, 130.0, 131.8, 134.4, 136.4, 167.5, 169.7, 170.0.
4.4.8. (3R,4R)-3,4-Diacetoxy-5-(1-hexynyl)-1-benzyl-2-
pyrrolidinone (6h)
The product 6h was prepared as described in the general pro-
cedure and was obtained in a 70:30 syn/anti mixture as a colour-
less oil in 83% yield (308 mg). Major isomer: syn-6h. 1H NMR
(300 MHz, CDCl3) d 0.92 (t, J¼7.0 Hz, 3H), 1.21e1.45 (m,
4H), 2.08 (s, 3H), 2.16 (s, 3H), 2.23 (t, J¼7.0 Hz, 2H), 4.15
(d, J¼14.8 Hz, 1H), 4.71 (dd, J¼6.2, 2.0 Hz, 1H), 4.93 (d,
J¼2.0 Hz, 1H), 5.08 (d, J¼14.8 Hz, 1H), 5.53 (d, J¼6.2 Hz,
1H), 7.28e7.34 (m, 5H). 13C NMR (75 MHz, CDCl3) d 13.3,
18.6, 20.4, 20.5, 25.3, 30.2, 44.6, 48.9, 71.1, 73.2, 87.3, 89.1,
127.8, 128.3, 128.5, 134.5, 166.1, 169.6, 170.1. GC/MS: m/z
(%)¼371 (3) [Mþ], 311 (16), 269 (72), 252 (20), 200 (17),
178 (18), 137 (14), 91 (100), 43 (90). HRMS (ESI, positive)
m/z calcd for C21H25NO5 372.1811 ([MþH]þ); found
372.1853 ([MþH]þ). IR cmꢀ1 (CHCl3 solution): 3032, 2957,
2239, 1754, 1723. Minor isomer: anti-6h. 1H NMR
(300 MHz, CDCl3) d 0.91 (t, J¼7.0 Hz, 3H), 1.21e1.45 (m,
4H), 2.07 (s, 3H), 2.15 (s, 3H), 2.23 (t, J¼7.0 Hz, 2H), 4.01
(d, J¼14.8 Hz, 1H), 4.60 (d, J¼7.6 Hz, 1H), 5.01 (dd, J¼7.6,
7.6 Hz, 1H), 5.11 (d, J¼14.8 Hz, 1H), 5.68 (d, J¼7.6 Hz,
1H), 7.28e7.34 (m, 5H). 13C NMR (75 MHz, CDCl3) d 13.2,
18.7, 20.3, 20.4, 25.3, 30.0, 44.9, 50.6, 71.0, 73.1, 87.2, 89.0,
127.7, 128.2, 128.3, 134.5, 166.0, 169.5, 170.1.
4.4.6. (3R,4R)-3,4-Diacetoxy-5-(thiophen-3-yl)-1-benzyl-2-
pyrrolidinone (6f)
The product 6f was prepared as described in the general pro-
cedure and was obtained in a 85:15 syn/anti mixture as a colour-
less oil in 71% yield (264 mg). Major isomer: syn-6f. 1H NMR
(300 MHz, CDCl3) d 2.10 (s, 3H), 2.24 (s, 3H), 3.72 (d, J¼
14.0 Hz, 1H), 4.85 (dd, J¼5.7, 5.7 Hz, 1H), 5.12 (d, J¼
14.0 Hz, 1H), 5.19 (d, J¼5.7 Hz, 1H), 5.51 (d, J¼5.7 Hz, 1H),
6.85 (dd, J¼6.3, 3.5 Hz, 1H), 6.99 (d, J¼4.0 Hz, 1H), 7.02 (d,
J¼4.0 Hz, 1H), 7.20e7.34 (m, 5H). 13C NMR (75 MHz,
CDCl3) d 20.3, 20.5, 45.2, 56.4, 72.1, 75.7, 127.1, 128.3,
128.5, 128.7, 128.8, 128.9, 134.5, 137.0, 166.5, 169.8, 170.6.
GC/MS: m/z (%)¼373 (3) [Mþ], 313 (9), 282 (5), 271 (39),
254 (17), 200 (19), 180 (22), 139 (40), 91 (100), 43 (83).
HRMS (ESI, positive) m/z calcd for C19H19NO5S 374.1062
([MþH]þ); found 374.1083 ([MþH]þ). IR cmꢀ1 (CHCl3 solu-
tion): 3032, 2934, 1749, 1706. Minor isomer: anti-6f. 1H NMR

A.S. Vieira et al. / Tetrahedron 64 (2008) 3306e3314
3313
`
Fundac¸ao de Amparo a Pesquisa do Estado de Sao Paulo
(FAPESP 06/50190-7) for financial support.
~
~
4.4.9. (3R,4R)-3,4-Diacetoxy-5-(3-methoxy-1-propynyl)-1-
benzyl-2-pyrrolidinone (6i)
The product 6i was prepared as described in the general pro-
cedure and was obtained in a 80:20 syn/anti mixture as a colour-
less oil in 78% yield (280 mg). Major isomer: syn-6i. 1H NMR
(300 MHz, CDCl3) d 2.10 (s, 3H), 2.16 (s, 3H), 3.32 (s, 3H),
4.00 (d, J¼14.8 Hz, 1H), 4.08 (s, 2H), 4.56 (d, J¼6.1 Hz,
1H), 5.04 (d, J¼14.8 Hz, 1H), 5.12 (dd, J¼6.1, 6.1 Hz, 1H),
5.64 (d, J¼6.1 Hz, 1H), 7.24e7.30 (m, 5H). 13C NMR
(75 MHz, CDCl3) d 20.6, 20.7, 45.4, 49.1, 57.6, 59.6, 71.4,
72.5, 77.9, 84.5, 128.2, 128.5, 128.9, 134.3, 166.2, 169.8,
170.3. GC/MS: m/z (%)¼359 (3) [Mþ], 299 (11), 267 (13),
257 (19), 240 (18), 225 (14), 197 (13), 187 (13), 106 (16), 91
(100), 43 (91). HRMS (ESI, positive) m/z calcd for
C19H21NO6 360.1447 ([MþH]þ); found 360.1459 ([MþH]þ).
IR cmꢀ1 (CHCl3 solution) 3032, 2937, 2238, 1750, 1715,
1452, 1230. Minor isomer: anti-6i. 1H NMR (300 MHz,
CDCl3) d 2.14 (s, 3H), 2.19 (s, 3H), 3.35 (s, 3H), 3.76 (d,
J¼14.8 Hz, 1H), 4.12 (s, 2H), 4.30 (d, J¼8.7 Hz, 1H), 5.38
(dd, J¼8.7, 8.7 Hz, 1H), 5.49 (d, J¼8.7 Hz, 1H), 7.24e7.30
(m, 5H). 13C NMR (75 MHz, CDCl3) d 20.5, 20.6, 45.3, 49.1,
57.4, 59.5, 71.4, 72.3, 77.8, 84.6, 128.1, 128.5, 128.9, 134.2,
166.1, 169.7, 170.3.
References and notes
1. For reviews of N-acyliminium ion chemistry, see: (a) de Koning, H.;
Speckamp, W. N. In Houben-Weyl, Stereoselective Synthesis; Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; 1995; Vol. E21,
p 1953; (b) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817; (c) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431.
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4.4.10. (3R,4R)-3,4-Diacetoxy-5-[(6-methoxynaphthalen-2-yl)-
ethynyl]-1-benzyl-2-pyrrolidinone (6j)
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The product 6j was prepared as described in the general pro-
cedure and was obtained in a 70:30 syn/anti mixture as a colour-
less oil in 71% yield (334 mg). Major isomer: syn-6j. 1H NMR
(300 MHz, CDCl3) d 2.08 (s, 3H), 2.18 (s, 3H), 3.91 (s, 3H), 4.16
(d, J¼14.7 Hz, 1H), 4.31 (d, J¼5.8 Hz, 1H), 5.10 (d, J¼14.7 Hz,
1H), 5.50 (d, J¼5.8 Hz, 1H), 5.58 (dd, J¼5.6, 5.6 Hz, 1H), 7.11
(s, 1H), 7.17 (dd, J¼8.5, 2.2 Hz, 1H), 7.34e7.42 (m, 6H), 7.62
(d, J¼8.5 Hz, 1H), 7.70 (d, J¼8.3 Hz, 1H), 7.85 (d, J¼8.3 Hz,
1H). 13C NMR (75 MHz, CDCl3) d 20.7, 44.9, 51.5, 55.3,
71.8, 73.6, 81.7, 89.0, 105.8, 116.2, 119.7, 127.0, 128.1,
128.2, 128.7, 128.9, 129.4, 131.9, 132.0, 134.6, 135.1, 158.7,
166.3, 170.0, 170.4. GC/MS: m/z (%)¼471 (7) [Mþ], 411
(15), 369 (36), 352 (20), 300 (11), 278 (17), 185 (8), 91 (98),
43 (100). HRMS (ESI, positive) m/z calcd for C28H25NO6
472.1695 ([MþH]þ); found 472.1682 ([MþH]þ). IR cmꢀ1
(CHCl3 solution): 3059, 2932, 2228, 1753, 1719, 1231. Minor
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1
isomer: anti-6j. H NMR (300 MHz, CDCl3) d 2.11 (s, 3H),
2.20 (s, 3H), 3.89 (s, 3H), 4.11 (d, J¼14.7 Hz, 1H), 4.81 (d,
J¼7.5 Hz, 1H), 5.08 (d, J¼14.7 Hz, 1H), 5.23 (dd, J¼7.5,
7.5 Hz, 1H), 5.78 (d, J¼7.5 Hz, 1H), 7.11 (s, 1H), 7.17 (dd,
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1H), 7.70 (d, J¼8.3 Hz, 1H), 7.85 (d, J¼8.3 Hz, 1H). 13C
NMR (75 MHz, CDCl3) d 20.8, 45.1, 51.4, 55.2, 71.6,
73.5, 81.5, 88.9, 105.8, 116.1, 119.7, 127.1, 128.1, 128.2,
128.7, 128.9, 129.4, 131.9, 132.0, 134.6, 135.1, 158.7, 166.2,
170.1, 170.3.
ˆ
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3314
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3
H5 d¼4.68 ppm; J(H5eH4)¼7.3 Hz; anti-isomer: H5 d¼4.53 ppm;
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