A versatile approach to protected (4S,5R)-4-hydroxy-5-(α- hydroxyalkyl)-2-pyrrolidinones

Article abstract of DOI:10.1055/s-2006-939695

Starting from (S)-N,O-dibenzylmalimide (7), a versatile four-step approach to (4S,5R)-N-benzyl-4-benzyloxy-5-(α-hydroxyalkyl)-2-pyrrolidinones 9 is reported. The method consists of Grignard reagent addition, p-toluenesulfonic acid monohydrate-mediated deh

Full text of DOI:10.1055/s-2006-939695

LETTER
1235
A Versatile Approach to Protected (4S,5R)-4-Hydroxy-5-(a-hydroxyalkyl)-2-
pyrrolidinones
(
4
S
,5R
)-4-Hydroxy
i
-5-(
a
-
a
n
yl)-2-pyrroli
g
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of China
Fax +86(592)2186400; E-mail: pqhuang@xmu.edu.cn
Received 11 November 2005
Dedicated to Professor Ben-Li Huang on the occasion of his 80th birthday
In recent years, we have been engaged8 in the develop-
Abstract: Starting from (S)-N,O-dibenzylmalimide (7), a versatile
ment of carbanion-based asymmetric approaches to 5-
four-step approach to (4S,5R)-N-benzyl-4-benzyloxy-5-(a-hy-
alkyl 4-hydroxy-2-pyrrolidinones (via tetramates),9 2-
droxyalkyl)-2-pyrrolidinones 9 is reported. The method consists of
alkyl-3-pyrrolidinols,3a,10 2,5-dialkyl-3-pyrrolidinols,9a
Grignard reagent addition, p-toluenesulfonic acid monohydrate-
mediated dehydration, one-pot epoxidation–methanol ring-opening and 2-(a-hydroxyalkyl) 3-amino-pyrrolidines.11 As a con-
reaction and reductive demethoxylation. 2-Pyrrolidinones 9 were
obtained with excellent trans-diastereoselectivity in the pyrrolidi-
none ring and low diastereoselectivity at the carbinol center.
tinuation of these studies and in connection with a related
project, we now report a flexible approach to 5-(a-hy-
droxyalkyl) 4-hydroxy-2-pyrrolidinones 2.
Key words: dehydration, enamide, 2-pyrrolidinones, epoxidation,
asymmetric synthesis
Our approach to 2 arose from some unexpected results in
a related project.12 When we attempted the a-amidoallyla-
tion (AllTMS, BF3·OEt2, CH2Cl2, –78 °C to r.t., 15 h) of
N,O-acetals 5a,d,e,g (a. R = H; d. R = n-Pr; e. R = i-Pr; g.
Carbanion-based C–C bond formation is a fundamental
R = n-C6H13),12 only 5a led to the desired a-amidoallyla-
transformation in organic chemistry. While a huge num-
tion product, the reaction of 5d,e,g gave the dehydrated
ber of methods have been developed for the carbanion
products 6d,e,g, respectively, in 75–82% yields
generation and subsequent C–C bond formation,1 there
(Scheme 2). In view of the recent advances in the enamide
still exist many challenges in the classical carbanion
chemistries,13,14 it was realized that these findings would
chemistry.2 The generation and C–C bond formation of
found a basis of a versatile approach to 5-(a-hydroxy-
chiral non-racemic N-a-carbanion of protected 4-hy-
alkyl)-4-hydroxy-2-pyrrolidinones 2, and thus provided
droxy-2-pyrrolidinone A is one such challenge.3 4-Hy-
an alternative solution to the challenging problem.
droxy-2-pyrrolidinone N-a-carbanion A represents a
highly desirable synthon according to a conceptually
BnO
BnO
HO
attractive retrosynthetic analysis of 2-(a-hydroxyalkyl) 5-
substituted 3-pyrrolidinols 1 (Scheme 1), the common
structural motifs shared by a number of bioactive polyhy-
droxylated alkaloids4 and azasugars5 such as swainsonine6
(3) and bulgecinine7 (4).
conditions
R
N
O
R
N
O
H
Bn
Bn
5
6
Scheme 2
reductive
alkylation
HO
HO
HO
*
*
To this end, a further investigation on the acid-catalyzed
dehydration13 of N,O-acetals 512 was undertaken
(Scheme 2) and the results were summarized in Table 1.
As can be seen from Table 1 (entries 1–5, 10), the dehy-
dration of N,O-acetals 5 can be promoted by either Lewis
acid or Brønsted acid. Comparable yields were obtained
when using BF3·OEt2 or TsOH·H2O as an acid catalyst un-
der optimized conditions (Table 1, entries 1, 2 vs. entry 3).
The reaction can also be promoted by trifluoroacetic an-
hydride (TFAA)–pyridine system (Table 1, entry 6).13e,g
However, this system was not adapted considering the
complication in the work-up procedure, the cost and the
safety of the chemicals used. Although the use of Lewis
acid BF3·OEt2 also led to satisfying results, the simplicity
in using TsOH·H2O as a catalyst led us to select it for fur-
ther investigation.
?
R1
*
R1
*
*
*
*
N
R2
N
O
N
O
RCHO +
this work
OH
R
1
Bn
A
OH
R
2
RMgX
BnO
HO
HO
OH
H
HO
O
N
O
OH
N
H
COOH
N
Bn
7
swainsonine (3)
bulgecinine (4)
Scheme 1
SYNLETT 2006, No. 8, pp 1235–1239
Advanced online publication: 05.05.2006
1
5.
0
5.
2
0
0
6
DOI: 10.1055/s-2006-939695; Art ID: W31105ST
© Georg Thieme Verlag Stuttgart · New York

1236
X. Zhou, P.-Q. Huang
LETTER
Table 1 Effects of the Reaction Condition on the Dehydration Reaction of 5c,d,e,h
Entry
Starting material
Dehydration agent
BF3·OEt2, CH2Cl2
BF3·OEt2, CH2Cl2
p-TsOH, CH2Cl2
p-TsOH, CH2Cl2
p-TsOH, CH2Cl2
TFAA/pyridine, THF
Ac2O, CH2Cl2
Temperature
–78 °C, r.t.
–78 °C, r.t.
r.t.
Time
12 h
12 h
50 min
1.5 h
2 h
Yield (%)
1
2
5da
5ea
5cb
5cb
5cb
5cb
5cb
5cb
5ha
5hb
75–77
74–83
79
3
4
0 °C
68
5
–12 °C
0 °C
58
6
1 h
78
7
r.t.
48 h
48 h
3 d
ca. n.r.
ca. n.r.
54
8
Ac2O/pyridine, CH2Cl2
Ac2O/pyridine, CH2Cl2
p-TsOH, CH2Cl2
r.t.
9
reflux
r.t.
10
3 h
77
a Two diastereomers were used for the dehydration.
b Only trans-diastereomers were used for the dehydration.
The reaction was then extended to other N,O-acetals 5,
which were obtained by Grignard reaction with (S)-N,O-
dibenzylmalimide (7) as described previously12
(Scheme 3). Most of the N,O-acetals (5a–g and 5i) were
obtained with excellent C-2 regioselectivities (only one
regioisomer was obtained in each case) and with diastere-
oselectivities ranged from 6:1 to 8:1 in favor of trans-di-
astereomer (trans-5). Only the reaction with benzyl
magnesium bromide led to a 1:1 diastereomeric ratio. The
results of the TsOH-promoted (5% molar equiv) dehydra-
tion reaction of the major diastereomers of 5 were dis-
played in Table 2. It is worth noting that the dehydration
of 5a was unsuccessful under several acidic conditions
(TsOH, TFA, CSA, HCl, H2SO4).
Table 2 Grignard Reagents Addition with 7 and the Subsequent
TsOH-Mediated Dehydration Reaction15
Entry
RCH2MgX
Product 5
Product 6
(yield %)
(yield %)
1
2
3
4
5
6
7
8
9
CH3MgI
5a (95)a
5b (83)a
5c (99)a
5d (95)a
5e (86)a
5f (81)a
5g (90)a
5h (92)b
5i (95)a
NR
MeCH2MgBr
EtCH2MgBr
n-PrCH2MgBr
i-PrCH2MgBr
n-BuCH2MgBr
n-C6H13CH2MgBr
PhCH2MgBr
BnCH2MgBr
6b (67,c 95d)
6c (79,c 93d)
6d (74,c 97d)
6e (83,c 95d)
6f (69,c 91d)
6g (63,c 92d)
6h (77,c 93d)
6i (55,c 89d)
BnO
HO
BnO
BnO
O
RCH2MgX
+
R
CH2Cl2, –15 °C
O
N
O
N
O
N
HO
Bn
cis-5
Bn
trans-5
Bn
R
a Diastereomeric ratios: 6:1 to 8: 1, only the major diastereomers were
used for the dehydration.
7
b Diastereomeric ratio: ca. 1:1, only the trans-diastereomer was used
for the dehydration.
BnO
TsOH·H2O
(5% equiv)
a R = H; b R = Me;
c R = Et ; d R = n-Pr;
e R = i-Pr; f R = n-Bu;
g R = n-C6H13; h R = Ph;
i R = CH2Ph
c Isolated yield.
R
N
O
CH2Cl2, r.t.
d Yield based on the recovered starting material (cis-diastereomer).
H
Bn
6
Scheme 3
Another feature of the dehydration reaction is that the
reaction is highly stereoselective, and only E-enamides
It is also important to note that all the dehydration reac- (6) were obtained. The stereochemistry of 6d was deter-
tions were incomplete, and partial epimerization of trans- mined by NOESY experiences (1H NMR).
diastereomers (trans-5) to cis-diastereomers (cis-5) was
Next, one-pot epoxidation–ring-opening of compounds 6
observed according TLC monitoring. The cis-diastereo-
mers were poorly reactive towards the dehydration reac-
tion and couldn’t react completely. These results suggest
that cis-5 are thermodynamically more stable diastereo-
was investigated by using the method of Nagasaka and co-
workers.14 Thus, when 6d was treated with MCPBA in ab-
solute MeOH and CH2Cl2, the desired products 8d were
obtained as a mixture of four diastereomers with a com-
bined yield of 83% (Scheme 4). To confirm the structure
of the products, flash column chromatography separation
mers. The low reactivity of the cis-N,O-acetals (cis-5) can
be attributed to stereoelectronic effect.16,17
Synlett 2006, No. 8, 1235–1239 © Thieme Stuttgart · New York

LETTER
(4S,5R)-4-Hydroxy-5-(a-hydroxyalkyl)-2-pyrrolidinones
1237
BnO
BnO
MeO
Table 3 Results of MCPBA Epoxidation–Ring-Opening of 6 and
the Subsequent Reductive Demethoxylation Reaction Leading to 9
Et3SiH, BF3·OEt2
MCPBA
R
R
CH2Cl2,
−78 °C to r.t.
CH2Cl2–
MeOH
N
O
N
O
Entry
Starting Epoxidation–
material ring-opening
product
Reductive
deoxygenation selectivity
Diastereo-
H
Bn
OH Bn
8
6
product
at C-1¢
(8d characterized)
(yield, %)a
(yield, %)b
b R = Me
c R = Et
BnO
BnO
d R = n-Pr
e R = i-Pr
f R = n-Bu
g R = n-C6H13
h R = Ph
1
2
3
4
5
6
7
8
6b
6c
6d
6e
6f
8b (85)
8c (90)
8d (83)
8e (80)
8f (86)
8g (86)
8h (90)
8i (93)
9b (85)
9c (74)
9d (78)
9e (85)
9f (78)
9g (81)
9h (98)
9i (98)
1:1.6d
1:2c
R
R
N
O
N
O
H
OH Bn
OH Bn
1:2c
i R = CH2Ph
BF3OH
9
B
1:4d
Scheme 4
1:1c
6g
6h
6i
1:4c
of a sample of diastereomeric mixture of 8d was under-
taken, two pure diastereomers, and a mixture of the other
two diastereomers were isolated and characterized.
1:2.6e
1:1.5c
The diastereomeric mixture of 8d was then subjected to
Lewis acid mediated ionic hydrogenation (BF3·OEt2,
Et3SiH, CH2Cl2, –78 °C to r.t.),18,12 which gave two
separable diastereomers trans-9d15 in 1:2 ratio with a
combined yield of 78%. The fact that the reductive deoxy-
genation of a mixture of four diastereomers (8d) led to
only two diastereomers (9d) might implicate that the
transformation of 8d to 9d proceeded via the intermediacy
of N-acyliminium ion19 B (R = n-Pr), and the stereoselec-
tivity in the 2-pyrrolidinone ring was higher than 95%.
Both diastereomers 9d were assigned to trans according
to the observed vicinal coupling constant20,12 (both
a Combined yield of four diastereomers.
b Combined yield of two diastereomers.
c Ratio determined by chromatography separation.
d Ratio determined by 1H NMR.
e Ratio determined by HPLC.
Acknowledgment
The authors are grateful to the NSF of China (20390050,
20572088), the Ministry of Education (Key Project 104201) and the
NSF of Fujian Province (China) (C0510001) for financial support.
J
4,5 = ca. 0 Hz). That oxidation of the diastereomeric mix-
ture of 9d (1:2; PCC, CH2Cl2, r.t., 4 h, yield 70%) afforded
the corresponding ketone as the sole diastereomer
(J4,5 = ca. 0 Hz), confirmed the trans-stereochemistry in
the 2-pyrrolidinone ring. The stereochemistries of the two
diastereomers of 9d at the C-1¢ position were not deter-
mined.
References and Notes
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(l) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929.
With the MCPBA epoxidation–ring-opening of 6d and
the subsequent reductive deoxygenation reactions se-
cured, the syntheses of other homologues or analogues of
9d were investigated and the results were outlined in
Table 3. The results displayed in Table 3 showed that the
one-pot epoxidation–ring-opening of other enamides 6
worked similarly as 6d did in terms of chemical yields and
diastereoselectivities, which demonstrated the flexibility
of the method.
In summary, stemmed from some unexpected findings in
a related research project, a flexible four-step trans-dia-
stereoselective approach to (4S,5R)-N-benzyl-4-benzyl-
oxy-5-hydroxyalkyl-2-pyrrolidinones 9 was established
starting from the known (S)-N,O-dibenzyl malimide (7).
To the best of our knowledge, this represents the first
flexible asymmetric approach to 9, the protected form of
2, and provides an alternative solution to the challenging
problem showed retrosynthetically in Scheme 1. Applica-
tion of the present method to the asymmetric synthesis of
hydroxylated pyrrolidine-ring-containing alkaloids is un-
der investigation and will be reported in due course.
(2) For a series of papers on functionalized organolithium
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(3) For a short discussion on challenges associated with the
generation and C–C bond formation of chiral non-racemic
N-a-carbanion of protected 4-hydroxy-2-pyrrolidinone A,
see: (a) Zheng, X.; Feng, C.-G.; Ye, J.-L.; Huang, P.-Q. Org.
Lett. 2005, 7, 553. (b) For a synthesis of a specific 2-
pirrolidinone derivative of type 9, see: Poisson, J. F.;
Normant, J. F. Org. Lett. 2001, 3, 1889. (c) For a related
work, see: Iula, D. M.; Gawley, R. E. J. Org. Chem. 2000,
65, 6196.
Synlett 2006, No. 8, 1235–1239 © Thieme Stuttgart · New York

1238
X. Zhou, P.-Q. Huang
LETTER
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column chromatography on silica gel eluting with EtOAc–
PE to give 6. To a solution of 6 (1.0 mmol) in a mixture of
abs. MeOH (20 mL) and dry CH2Cl2 (10 mL) was added
dropwise a solution of MCPBA (3.0 mmol) in CH2Cl2 (10
mL) at –78 °C under nitrogen atmosphere. After the mixture
stirred for 1 h, it was allowed to reach r.t. and stirred
overnight. Then, the reaction was quenched with a solution
of aq Na2S2O3 (10%) and sat. NaHCO3. The mixture was
extracted with CH2Cl2 (3 × 40 mL). The combined extracts
were washed with brine, dried over anhyd Na2SO4, filtered
and concentrated in vacuum. Filtration through a short pad
of SiO2 eluting with EtOAc–PE gave 8 as a mixture of
diastereomers. The diastereomeric ratios were determined
either by flash chromatographic separation or by analysis of
1H NMR spectra of the crude mixture. To a cooled (–78 °C)
solution of diastereomeric mixture of 8 (1.0 mmol) in dry
CH2Cl2 (10 mL) were added dropwise triethylsilane (10
mmol) and BF3·OEt2 (10.0 mmol) under nitrogen
Tetrahedron: Asymmetry 2000, 11, 1645.
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reaction was allowed to warm up and stirred at r.t. overnight.
The reaction was quenched with sat. aq NaHCO3 and
extracted with CH2Cl2 (3 × 20 mL). The combined extracts
were washed with brine, dried over anhyd Na2SO4, filtered
and concentrated in vacuum. The residue was purified by
flash column chromatography on silica gel eluting with
EtOAc–PE to give 9.
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Selected physical and spectral data for 6d: [a]D20 +62.0 (c
0.4, CHCl3). IR (film): 3060, 3023, 1719, 1674 cm–1. 1H
NMR (500 MHz, CDCl3): d = 0.80 (t, J = 7.3 Hz, 3 H, CH3),
1.22–1.38 (m, 2 H, MeCH2), 1.94–2.12 (m, 2 H, EtCH2),
2.68 (dd, J = 1.7, 17.8 Hz, 1 H, COCH2), 2.78 (dd, J = 7.0,
17.8 Hz, 1 H, COCH2), 4.42 (d, J = 11.2 Hz, 1 H, PhCH2O),
4.53 (d, J = 11.2 Hz, 1 H, PhCH2O), 4.70 (s, 2 H, PhCH2N),
4.74 (dd, J = 1.7, 7.0 Hz, 1 H, BnOCH), 4.84 (t, J = 7.5 Hz,
1 H, =CH), 7.20–7.40 (m, 10 H, Ar) ppm. 13C NMR (125
MHz, CDCl3): d = 13.6, 23.3, 28.7, 36.6, 43.4, 69.9, 70.2,
108.0, 127.0, 127.2, 128.0, 128.1, 128.3, 128.4, 128.5,
135.8, 137.3, 138.9, 173.1 ppm. MS (ESI): m/z (%) = 336
(100) [M + H+]. Anal. Calcd for C22H25NO2: C, 78.77; H,
7.51; N, 4.18. Found: C, 78.81; H, 7.47; N, 4.00.
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Selected physical and spectral data for 9d: major
diastereomer: colorless oil; [a]D20 +44.2 (c 1.0, CHCl3). IR
(film): 3378, 3063, 3031, 1671 cm–1. 1H NMR (500 MHz,
CDCl3): d = 0.84 (t, J = 7.1 Hz, 3 H, CH3), 1.22–1.48 [m, 4
H, Me(CH2)2], 2.50 (dd, J = 1.3, 17.4 Hz, 1 H, COCH2), 2.80
(dd, J = 6.9, 17.4 Hz, 1 H, COCH2), 3.00 (br s, 1 H, OH),
3.40 (d, J = 4.9 Hz, 1 H, BnNCH), 3.78–3.84 (m, 1 H,
CHOH), 4.18 (d, J = 15.0 Hz, 1 H, PhCH2N), 4.19 (dd,
J = 1.3, 6.9 Hz, 1 H, BnOCH), 4.40 (d, J = 11.7 Hz, 1 H,
PhCH2O), 4.48 (d, J = 11.7 Hz, 1 H, PhCH2O), 5.00 (d,
J = 15.0 Hz, 1 H, PhCH2N), 7.20–7.40 (m, 10 H, Ar) ppm.
13C NMR (125 MHz, CDCl3): d = 13.9, 19.3, 34.8, 38.6,
44.2, 68.0, 68.8, 70.4, 71.9, 127.7, 127.8, 128.4, 128.8,
136.2, 137.5, 174.2 ppm. MS (ESI): m/z (%) = 376 (100) [M
+ Na+]; minor diastereomer: white crystals, mp 77–79 °C;
[a]D20 +13.9 (c 0.4, CHCl3). IR (KBr, pellet): 3394, 3062,
3031, 1669 cm–1. 1H NMR (500 MHz, CDCl3): d = 0.88 (t,
J = 7.3 Hz, 3 H, CH3), 1.10–1.32 [m, 3 H, Me(CH2)2], 1.42–
1.52 [m, 1 H, Me(CH2)2], 2.33 (br s, 1 H, OH), 2.51 (d,
J = 17.7 Hz, 1 H, COCH2), 2.75 (dd, J = 6.4, 17.7 Hz, 1 H,
COCH2), 3.58 (d, J = 4.6 Hz, 1 H, BnNCH), 3.61–3.65 (m,
1 H, CHOH), 4.02 (d, J = 6.4 Hz, 1 H, BnOCH), 4.18 (d,
J = 15.2 Hz, 1 H, PhCH2N), 4.42 (s, 2 H, PhCH2O), 5.02 (d,
J = 15.2 Hz, 1 H, PhCH2N), 7.20–7.40 (m, 10 H, Ar) ppm.
13C NMR (125 MHz, CDCl3): d = 13.8, 19.2, 34.8, 38.2,
45.9, 67.8, 70.2, 71.3, 73.8, 127.5, 127.6, 127.7, 127.9,
128.4, 128.6, 136.3, 137.6, 174.3 ppm. MS (ESI): m/z (%) =
(15) All new compounds (6 and 9) gave satisfactory analytical
and spectral data.
General Procedure for the Synthesis of 9.
To a solution of the more polar diastereomer of 512 (1.0
mmol) in CH2Cl2 (10 mL) was added 0.05 mmol of p-TSA.
The mixture was stirred at r.t. for 1 h. Then the reaction was
quenched with sat. aq NaHCO3 and extracted with CH2Cl2
(3 × 10 mL). The combined extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The resulting residue was purified by
Synlett 2006, No. 8, 1235–1239 © Thieme Stuttgart · New York

LETTER
354 (67) [M + H+], 376 (100) [M + Na+]. Anal. Calcd for
(4S,5R)-4-Hydroxy-5-(a-hydroxyalkyl)-2-pyrrolidinones
1239
(17) (a) For a related stereoelectronic effect observed in another
class of N,O-acetals, see: Chen, M.-D.; He, M.-Z.; Zhou, X.;
Huang, L.-Q.; Ruan, Y.-P.; Huang, P.-Q. Tetrahedron 2005,
61, 1335. (b) For an example of stereoelectronic control of
oxazolidine ring-opening, see: Sélambarom, J.; Monge, S.;
Carré, F.; Roque, J. P.; Pavia, A. A. Tetrahedron 2002, 58,
9559.
(18) For reviews on the Et3SiH-mediated ionic hydrogenation,
see: (a) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M.
Synthesis 1974, 633. (b) Nagai, Y. Org. Prep. Proced. Int.
1980, 12, 13.
(19) For recent reviews on the chemistry of N-acyliminiums, see:
(a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000,
56, 3817. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431.
(c) Royer, J. Chem. Rev. 2004, 104, 2311.
C22H27NO3: C, 74.76; H, 7.70; N, 3.96. Found: C, 74.77; H,
7.94; N, 4.02.
(16) (a) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983. See also:
(b) Kirby, A. J. The Anomeric Effect and Related
Stereoelectronic Effects at Oxygen; Springer: New York,
1983. (c) Thatcher, G. R. J. The Anomeric Effect and
Associated Stereoelectronic Effects; ACS Symposium
Series 593, American Chemical Society: Washington DC,
1993. (d) Juaristi, E.; Cuevas, G. The Anomeric Effect; CRC:
Boca Raton, FL, 1995.
(20) Bernardi, A.; Micheli, F.; Potenza, D.; Scolastico, C.; Villa,
R. Tetrahedron Lett. 1990, 31, 4949.
Synlett 2006, No. 8, 1235–1239 © Thieme Stuttgart · New York