Diastereoselective synthesis of 3,6-disubstituted 3,6-dihydropyridin-2-ones

Article abstract of DOI:10.1016/S0040-4039(02)02677-1

In a short sequence, 5-vinyloxazolidin-2-ones were converted into the 3,6-disubstituted 3,6-dihydropyridin-2-ones via Pd-catalysed carbonylation and enolate alkylation with high diastereoselectivity. Alkylation of 6-substituted N-methylpyridin-2-ones give

Full text of DOI:10.1016/S0040-4039(02)02677-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 757–760
Diastereoselective synthesis of 3,6-disubstituted
,6-dihydropyridin-2-ones
3
Thomas F. Anderson, Julian G. Knight* and Kirill Tchabanenko
School of Natural Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
Received 14 October 2002; accepted 22 November 2002
Abstract—In a short sequence, 5-vinyloxazolidin-2-ones were converted into the 3,6-disubstituted 3,6-dihydropyridin-2-ones via
Pd-catalysed carbonylation and enolate alkylation with high diastereoselectivity. Alkylation of 6-substituted N-methylpyridin-2-
ones gives stereoselectively the 3,6-anti diastereoisomer with MeI, BuI and i-PrI. Alkylation of the corresponding N-BOC
pyridinones gives the 3,6-syn diastereoisomer with high selectivity. © 2003 Elsevier Science Ltd. All rights reserved.
The piperidine ring is common to several classes of
naturally occurring alkaloids. One of the most notable
is the ergot alkaloids due to their pharmacological
We have recently reported the synthesis of 3,6-disubsti-
tuted pyridinones via diastereospecific palladium-
catalysed carbonylation of 5-alkenyloxazolidinones.
5
,6
1
2–4
properties. The total synthesis of Agroclavine I 1
In order to use this approach to the synthesis of 2
requires a Z-syn oxazolidinone such as 3. In order to
currently being undertaken in our group required a
stereoselective synthesis of the 3,6-disubstituted pyridi-
none 2.
1
investigate this route, 3a (R =TBS) was prepared from
serine. Addition of lithiated propyne to the protected
7
serinal 4 proceeded with in situ formation of a 3:2
mixture of epimeric oxazolidinones 5 which was
reduced by Lindlar hydrogenation to give the Z-
propenyloxazolidinones 3a,b which were separated by
8
column chromatography (Scheme 1). As expected from
6
our earlier work on related systems, carbonylation of
each of the diastereoisomeric oxazolidinones 3a and 3b
gave a single pyridinone 2a and 2b, respectively. Since
Scheme 1. Reagents and conditions: (a) Propyne (excess), BuLi (2.5 equiv.), THF, −78°C, then 4, −78°C to rt, 75%; (b) Lindlar
catalyst, H , quinoline, EtOH, 98%; column chromatography 3a/3b 3:2; (c) PdCl (PPh ) (10 mol%), EtOH, CO (65 atm), 60°C,
2
2
3 2
4
8 h, (2a, 27%; 2b, 31%); (d) NaH (1 equiv.), MeI (2 equiv.), THF, 0°C to rt, (6a, 75%; 6b, 78%).
*
Corresponding author. Tel.: +44-(0)191-2227068; fax: +44-(0)191-2227068; e-mail: j.g.knight@ncl.ac.uk
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02677-1

7
58
T. F. Anderson et al. / Tetrahedron Letters 44 (2003) 757–760
Agroclavine I is N-methylated, pyridinones 2a,b were
also methylated (NaH, MeI) to give 6a,b in good yield.
We have previously demonstrated the stereospecificity
6
1
of the carbonylation by comparison of the H NMR
spectra of a 3,6-disubstituted pyridinone product with
that of the same compound prepared by a stereochemi-
9
cally unambiguous synthesis. Thus, Z-syn oxazolidi-
nones (such as 3a) give 3,6-anti pyridinones (such as 6a)
and Z-anti oxazolidinones give 3,6-syn pyridinones.
Unfortunately, in the case of the oxazolidinones 3a,b,
the carbonylations required a long time to reach com-
pletion and the yields of pyridinones were rather low.
This, coupled with the low diastereoselectivity of
alkynyl-lithium addition and the need for an elaborate
diastereoisomer separation, has prompted us to look
for an alternative stereoselective synthesis of pyridinone
Scheme 2. Reagents and conditions: (a) Vinylmagnesium bro-
mide (2.5 equiv.), THF, −78°C to rt, 85%; (b) KO Bu, THF,
2.
t
7
3
1
0%; (c) PdCl (PPh ) (10 mol%), EtOH, CO (65 atm), 60°C,
2 h, 85%; (d) NaH, THF, 0°C, then MeI, 0°C to rt, (8, 80%;
2 3 2
One such approach is to introduce the 3-substituent by
alkylation of the corresponding pyridinone enolate. The
stereoselectivity of alkylation should then be controlled
by the substituents on the 6-position and on nitrogen.
While there have been several reports of the
diastereoselective enolate alkylation of 6-substituted
0, 68%); (e) BOC O, DMAP (10 mol%), MeCN, 90%.
2
1
0–15
piperidin-2-ones,
we were surprised that the corre-
sponding alkylation of pyridinones had not been
reported.
The 3-unsubstituted pyridinone 7 was prepared in three
steps from the protected serinal 4 in good yield via our
carbonylation methodology (Scheme 2). In order to
investigate the influence of the group on nitrogen, the
Scheme 3. Reagents and conditions: (a) LDA (1 equiv.), THF,
3
−
78°C; (b) R X (2 equiv.), −78 to 0°C.
16
N-methyl 8 and N-Boc derivatives 9 were prepared.
Pyridinone 10, which contains a non-coordinating sub-
stituent in the 6-position, was also prepared by N-
methylation of the corresponding lactam (Scheme 2).
pyridinones in an 82:18 ratio (Table 1, entry 1). The
major isomer was identical to the 3,6-anti isomer 6a,
previously prepared via carbonylation of oxazolidinone
5
3
a (Scheme 1). The minor isomer was the 3,6-syn
The 6-substituted pyridin-2-ones 8, 9, and 10 were
deprotonated (LDA, THF, −78°C) and alkylated with a
pyridinone 6b. For the N-methylpyridinones 8 and 10
reacting with alkyl iodides, the anti selectivity increases
with increasing size of the electrophile (entries 1–3,
1
7
range of alkyl halides (Scheme 3).
18
9
–10).
Exchange of the potentially coordinating
The results of these alkylations are presented in Table
CH OTBS substituent for benzyl has very little effect
on the level of diastereoselectivity (compare entries 1
and 2 with 9 and 10). The nature of the group on
2
1. Alkylation of the N-methylpyridinone 8 with MeI
gave the corresponding diastereoisomeric 3-methyl
Table 1.
R1
R2
R X
3
Yielda (%)
anti:synb
Entry
Lactam
1
2
3
4
5
6
7
8
9
8
8
8
8
8
9
9
9
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
Ph
Me
Me
Me
Me
MeI
BuI
PrI
BnBr
AllylBr
MeI
BuI
BnBr
MeI
BuI
BnBr
80
71
72
65
67
89
90
79
75
79
69
82:18
86:14
100:0
50:50
50:50
0:100
0:100
50:50
78:22
85:15
50:50
i
Me
BOC
BOC
BOC
Me
Me
Me
10
10
10
10
1
Ph
Ph
1
a
Isolated yield.
b
Measured by 1H NMR.

T. F. Anderson et al. / Tetrahedron Letters 44 (2003) 757–760
759
In the related piperidinone system, isomerisation of a
,6-anti diastereoisomer into the corresponding 3,6-syn
3
compound has been accomplished by deprotonation
followed by quench of the enolate with a proton
13
source. In order to investigate this sequence in the
pyridinone system, the deep red enolate solution
derived from the 3,6-syn benzyl bromide alkylation
product 11 was quenched with ammonium chloride at
both −78°C and at 0°C (Scheme 4). The quench at
−78°C gave a 1/1 mixture of the syn and anti products
in 87% yield. On the contrary, the quench of the
enolate derived from 11 at 0°C gave the single syn
pyridinone in a 70% yield, thus the substituent at the
Scheme 4. Reagents and conditions: (a) LDA, THF, −78°C,
0 min; (b) NH Cl (aq.), −78°C, 87% (syn:anti 1:1); (c) NH Cl
3
4
4
6
-position seems to exert a more pronounced effect on
the stereoselectivity at higher temperature.
(
aq.), 0°C, 70% (syn only).
Our attempts to widen the range of electrophiles
included reactions with benzaldehyde and ethyl isocya-
nate. The aldol reaction between the enolate derived
from 8 and benzaldehyde produced an inseparable mix-
ture of all four possible diastereomeric adducts in a
1
:1:1.5:3 ratio. Reaction of the enolate with ethyl isocy-
anate gave the synthetically versatile enone 12 in excel-
lent yield (Scheme 5). Presumably, migration of the
double bond in this case is facilitated by reduction in
the pKa of the 3-hydrogen by the carboxamido
substituent.
Scheme 5. Reagents and conditions: (a) LDA (1 equiv.), THF,
78°C; EtNCO (2 equiv.), −78 to 0°C, 86%.
−
nitrogen, however, has a profound influence on the
sense of diastereoselection. Alkylation of N-BOC pro-
tected 6-substituted piperidin-2-ones is reported to be
In conclusion: we have established a synthetic route
towards 3,6-disubstituted 3,6-dihydropyridin-2-ones via
a sequence of a palladium catalysed carbonylation of
vinyl oxazolidinones, enolisation of the resulting 6-sub-
stituted pyridin-2-ones and stereoselective quench with
a range of electrophiles. The alkylation of N-
methylpyridinones is anti selective with MeI, BuI, and
1
0–13
highly anti selective.
This has been attributed to
pseudoallylic A(1,3) strain between the BOC group and
the 6-substituent leading to a chair-like conformation in
which the 6-substituent is axial and consequently
favours alkylation to form the 3,6-anti product. In the
present case, alkylation of the N-methyl pyridinones 8
and 10 was found to be anti selective. Remarkably, the
N-BOC pyridinone 9 gives exclusively the syn isomer
with MeI and BuI (entries 6 and 7) in complete contrast
to the reported alkylations of the corresponding pipe-
ridinone systems. The reversal in stereoselectivity was
i
PrI but is stereorandom with allyl and benzyl bromide.
Alkylation of N-BOC pyridinones shows a remarkable
reversal in selectivity to favour the syn product. Further
investigations into the scope of the reaction will be
presented in future publications.
19
confirmed by BOC deprotection (TFA/CH Cl , 0°C,
2
2
2
0 min, 95%) of the major product from alkylation of 9
with MeI (Table 1, entry 6). This led to a compound
identical to 2b, the product of carbonylation of 3b.
Although we do not have an explanation for the unex-
pected syn selectivity of alkylation of 9, it is presumably
a reflection of the influence of the extra double bond on
the transition state geometry. One would expect the
enolate to be rather flatter than in the case of the
corresponding piperidinone systems.
Acknowledgements
We thank the EPSRC for funding.
References
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dried (MgSO ) and concentrated. Flash column chro-
4
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afforded the syn 6b and anti 6a products as colourless
20
oils. 6b: (29.5 mg, 14%); [h]D +104 (c 0.85, CHCl3);
−1
wmax/cm (film) 2954, 1712; lH (500 MHz, CDCl ) 5.73–
3
5.64 (2H, m, vinylic H), 3.84 (1H, m, H-6), 3.69 (1H, dd,
J 10.3, 4.6, one of CH OTBS), 3.58 (1H, dd, J 10.3, 3.9,
2
one of CH OTBS), 2.98 (3H, s, NMe), 2.91–2.86 (1H, m,
2
H-3), 1.28 (3H, d, J 7.4, MeC-3), 0.84 (9H, s, t-Bu), 0.00
(
6H, s, Me Si); l (125 MHz, CDCl ) 172.0, 130.9, 122.7,
2 C 3
9
6
4.0, 62.5, 35.6, 33.4, 25.8, 18.3, 18.1, −5.4; m/z (CI+) 270
+
+
(
MH , 45%), 254 (57), 212 (60), 124 (100). Found (MH )
2
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1
1
70.2249, C H NO Si requires 270.2253. 6a: (144 mg,
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−1
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712; lH (500 MHz, CDCl ) 5.77 (1H, ddd, J 10.1, 4.3,
3
.2; H-4), 5.63 (1H, ddd, J 10.1, 3.9, 0.9; H-5), 3.85–3.80
(
1H, m, H-6), 3.62 (1H, dd, J 10.1, 4.9, one of
CH OTBS), 3.59 (1H, dd, J 10.1, 4.6, one of CH OTBS),
2
2
1
3321–13332.
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7
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(
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(
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1
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14
27
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1
8. In both this and our previous work, the appearance of
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6, 1035–1038.
1
the H NMR resonances due to the vinyl protons of the
1
1
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the stereochemistry of the piperidinones for which an
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means (i.e. Table 1, entries 2, 3, 7, 9 and 10).
4
2, 3407–3410.
7. Typical procedure: To a stirred solution of diisopropyl-
amine (101 mg, 1 mmol) in THF (5 ml) was added BuLi
(0.32 ml, 2.5 M solution in hexanes, 0.8 mmol) at −78°C
and the resulting solution was stirred for 20 min. A
solution of pyridinone 8 (200 mg, 0.78 mmol) in THF (3
ml) was added dropwise. The dark red solution was
stirred for 30 min and MeI (100 ml, 1.56 mmol) was
added in one portion. Stirring was continued at −78°C
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