Efficient synthesis of quaternary α-hydroxy acids by alkylation of α-ketoamide-derived dienediolates

Article abstract of DOI:10.1055/s-2005-918481

Double deprotonation of α-ketoamides generates dienediolates, which undergo regioselective α-alkylation to yield α-substituted-α- hydroxy-β,γ-unsaturated amides. 1,2-Disubstituted alkenes are generated exclusively as the E-isomer. 1,1-Disubstituted and 1,

Full text of DOI:10.1055/s-2005-918481

PAPER
3263
Efficient Synthesis of Quaternary a-Hydroxy Acids by Alkylation of
a-Ketoamide-Derived Dienediolates
Efficient
S
ynthes
e
is of
Q
uate
b
rnary
a
-Hyd
e
A
cids cca Newton, Stephen P. Marsden*
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
Fax +44(113)3436565; E-mail: s.p.marsden@leeds.ac.uk
Received 6 September 2005
Dedicated to Professor Steven Ley, FRS, on the occasion of his 60th birthday
duction of further functionality; and thirdly, the presence
of a terminal substituent R1 other than hydrogen allows
for the simultaneous generation of a second stereochemi-
cal element in the form of olefin geometry. All of these
Abstract: Double deprotonation of a-ketoamides generates diene-
diolates, which undergo regioselective a-alkylation to yield a-sub-
stituted-a-hydroxy-b,g-unsaturated amides. 1,2-Disubstituted
alkenes are generated exclusively as the E-isomer. 1,1-Disubstituted
and 1,1,2-trisubstituted olefins can also be prepared. The amides factors combine to add significant molecular complexity
can be readily converted to the corresponding acids.
to a simple educt in a single operation.
Key words: ketoamides, alkylations, dianions, hydroxy acids,
stereoselective olefin synthesis
HO R2
O
NR2
NR2
R1
R1
O
O
1
4
The a-hydroxy-a,a-disubstituted carboxyl function is a
commonly found motif in both natural and synthetic tar-
gets of biological interest. Examples of the former range
from relatively simple structures such as the nitrogenase
co-factor component (R)-homocitrate1 and the anti-col-
lagenolytic fukinolic and cimifugic acids2 to complex nat-
ural products such as the squalene synthase inhibiting
zaragozic acids (squalestatins).3 The motif can also be
found in pharmaceuticals such as the anti-androgen
bicalutamide4 (marketed as Casodex® for the treatment of
prostate cancer) and agrochemicals such as the insecticid-
al sodium channel blocker indoxacarb5 (Avaunt®). There
has therefore been much interest in the development of
methods for the construction of these motifs. One of the
most popular approaches involves the a-alkylation of sub-
stituted glycolate equivalents, particularly where the con-
trol of absolute stereochemistry can be enforced. The
work of Seebach6 and Ley7 on chiral relay-based ap-
proaches and Seebach6 and Evans8 on alkylation/aldol re-
actions of tartaric acid-derived enolates has been
particularly widely adopted.
R2X
base
OLi
OLi
base
NR2
OLi
NR2
R1
R1
2
3
O
Scheme 1 Proposed synthesis of a-alkyl a-hydroxy amides by
alkylation of dienediolates derived from a-ketoamides.
In fact, a preliminary investigation of such an approach
appeared in the literature some years ago. In 1986 Koft re-
ported the alkylation of dianions generated by treatment
of diethyl 2-ketobutyramide (1, NR2 = NEt2, R1 = H) with
LDA–HMPA.9 The reaction was only successful with pri-
mary alkyl halides (29–67% yield), did not work with
benzylic halides, and usually returned some unreacted
starting material. To our knowledge, this work has not
been followed up since. We felt that these preliminary re-
sults were encouraging and that the method would have
great synthetic potential if the deprotonation protocol
could be improved (complete deprotonation; avoid carci-
nogenic HMPA) and the range of ketoamide substrates
and reactive electrophiles expanded significantly. We re-
port here the results of our studies in this area.
We became interested in the possibility of an alternative
approach to the generation of a-hydroxy-a,a-disubstituted
carboxylic acids, centred on the chemistry of diene-
diolates. Specifically, we envisaged that double deproto-
nation of a-ketoamides 1 would lead to the formation of
dienediolates 2 by way of the intermediate monoenolate 3.
Regioselective a-alkylation would then lead to the b,g-un-
saturated a-alkyl,a-hydroxy amides 4 (Scheme 1). This
chemistry was attractive to us for several reasons. Firstly,
the starting ketoamides are trivial to prepare; secondly,
the olefin generated serves as a useful handle for the intro-
Initially, we focused upon optimisation of the deprotona-
tion conditions. Treatment of diethyl 2-ketobutyramide
with 2.2 equivalents of LDA and 6 equivalents of LiCl in
THF at 0 °C, followed by alkylation with iodomethane
gave a ca. 1:1 mixture of product to starting material. The
use of LTMP as base was more effective, giving a ca.
2.5:1 mixture of product and starting material when used
alone and a ca. 4:1 mixture when used with added LiCl.10
Finally, we found that the use of 3 equivalents of LTMP
and 6 equivalents of LiCl at 0 °C gave a clean alkylation
reaction with < 8% returned starting material. We also in-
vestigated the influence of the nature of the carboxyl sub-
SYNTHESIS 2005, No. 19, pp 3263–3270
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918481; Art ID: C06305SS
© Georg Thieme Verlag Stuttgart · New York

3264
R. Newton, S. P. Marsden
PAPER
stituent on the reaction. Attempted formation of expected to be prone to elimination (entries 6 and 7 re-
dienediolates of a-ketoesters was unsuccessful even at spectively).
–78 °C, with the liberation of the alcohol substituent indi-
cating that an a-elimination pathway was operating. The
use of anilides was similarly unsuccessful, but other ali-
phatic amides could be used. Our further studies have fo-
cused upon piperidinyl amides, owing to the ease of
preparation of higher substituted substrates in this series
(see below).
We next wished to investigate the generality of the pro-
cess with respect to the substitution pattern of the diene-
diolate. This required the preparation of diverse a-
ketoamides, which we accomplished by selective mono-
substitution of dipiperidinyl oxalamide 13 with Grignard
reagents or organolithiums (Scheme 3, Table 2).11 This
process ought to be applicable to the preparation of other
Having identified our optimal reaction conditions, we a-ketoamides, but we found that the reactions of tetraethyl
then examined the scope of the reaction in terms of elec- oxalamide with hindered organometallics were much less
trophile. Thus, the dienediolate from piperidinyl 2-oxobu- efficient.
tyramide 5 (prepared in 92% yield by DCC coupling of
piperidine and 2-oxobutyric acid) was treated with a range
of alkylating agents and the results are shown in
Scheme 2, Table 1.
O
O
RM
N
N
N
R
O
O
5, 14–19
13
i. LTMP (3 equiv),
LiCl (6 equiv), THF, –78 °C
O
HO
R
Scheme 3
N
N
ii. R–X
O
O
5
Table 2 Synthesis of Diverse a-Ketoamides from Oxalamide 13
6–12
Scheme 2
Entry
RM
Product
5
Yield (%)
1
2
3
4
5
6
7
CH3CH2MgBr
CH3CH2CH2MgBr
PhCH2CH2MgBr
(CH3)2CHMgCl
c-C6H11MgCl
88
90
88
50
53
67
79
Table 1 Reaction of Piperidinyl 2-Ketobutyrate-Derived Dianionic
Dienediolates with a Range of Electrophiles
14
Entry
RX
Product
Yield (%)
15
1
2
3
4
5
6
7
CH3I
6
7
63
55
51
71
74
62
54
16
CH2=CHCH2Br
PhCH2Br
17
8
CH3CH2(CH3)CHLi
(CH3)2CHCH2MgBr
18
(4-MeOPh)CH2Br
CH3CH2CH2I
(CH3)2CHCH2Br
(CH3)2CHI
9
19
10
11
12
With these materials in hand, we first investigated the
generation of 1,2-disubstituted alkenes in the alkylation
reactions (Scheme 4, Table 3). Koft reported one example
of methylation of N,N-diethyl 2-oxopentamide to yield se-
lectively the E-isomer in 38% yield.9 Under our reaction
conditions, methylation of the piperidinyl analogue 14
gave a 66% yield of the alkylated product 20 as a single
E-isomer, although an extended period at room tempera-
ture was required for full deprotonation. Alkylations of 14
with iodopropane and allyl bromide were similarly suc-
cessful and stereoselective. The presence of an aryl group
as the R1 substituent was also probed in substrate 15; al-
though the reactions were slightly lower yielding the re-
gio- and stereoselectivities of the alkylations mirrored
those of the alkyl series.
Some aspects of these results are worthy of discussion. In
all cases, the crude reaction mixtures consist almost ex-
clusively of the alkylation products and so the moderate
isolated yields in some cases may reflect loss of the highly
polar materials on chromatography. Whilst simple prima-
ry alkyl electrophiles worked well, as expected from the
precedent of Koft (entries 1, 2 and 5), we were pleased to
find that under our reaction conditions the use of benzylic
electrophiles was well tolerated (entries 3 and 4). This
may be a consequence of the reaction conditions: Koft
does not state conditions for his alkylations, but indicates
that products of benzyl carbenoid formation were ob-
served. Under our conditions, alkylation proceeds on
warming from –78 °C to 0 °C and only minor formation
of carbenoid products was seen. It is also noteworthy that,
despite the strongly basic nature of the dienediolates, effi-
cient alkylation is also observed with b-branched primary
alkyl and secondary alkyl electrophiles, which might be
HO R2
i. LTMP (3 equiv),
LiCl (6 equiv)
O
N
N
R1
R1
THF, –78 °C
ii. R2–X
14 R1 = Me
O
O
20–25
15 R1 = Ph
Scheme 4
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PAPER
Efficient Synthesis of Quaternary a-Hydroxy Acids
3265
Table 3 Synthesis of E-Disubstituted Olefins by Alkylation of
Ketoamide-Derived Dienediolates
of 4:1. These arise from the availability of two non-iden-
tical sets of protons for removal in the intermediate eno-
late, with deprotonation at the methyl substituent
dominating over the ethyl group.
Entry
R1
R2X
Product
20
Yield (%)
1
2
3
4
5
6
Me
Me
Me
Ph
CH3I
66
82
62
61
65
46
O
i. LTMP (3 equiv),
LiCl (6 equiv)
CH3CH2CH2I
CH2=CHCH2Br
CH3I
21
HO Me
N
N
22
THF, –78 °C
ii. MeI
O
O
17
29
23
30%
Ph
CH3CH2CH2I
CH2=CHCH2Br
24
HO Me
N
N
Ph
25
i. LTMP (3 equiv),
LiCl (6 equiv)
O
30
31
O
N
The selective formation of the E-isomer can be rationa-
lised by minimisation of A1,3-strain in the deprotonation
of the intermediate monoenolate by placement of the hy-
drogen substituent proximal to the oxyanion in preference
to the C4-substituent (Me, Ph; Figure 1).
THF, –78 °C
ii. MeI
HO Me
O
18
O
37%; 4:1
Scheme 6 Alkylation of dienediolates derived from ketoamides 17
and 18.
NR2
NR2
H
H
B
B
O
O
vs
O
O
Me
H
Li
Li
H
Me
All attempts to generate dienediolates from the ketoamide
19 were, however, unsuccessful (Scheme 7). It appears
that the strain associated with accommodating an ‘inside’
substituent in the reactive conformation for deprotonation
is prohibitively high.
Figure 1 Rationalisation of the stereochemical outcome of diene-
diolate formation.
Attention then turned to the generation of 1,1-disubstitut-
ed olefins by alkylation of dienediolates derived from ke-
toamide 16. As shown in Scheme 5, clean alkylation was
observed with iodomethane, iodopropane and allyl bro-
mide, indicating that the presence of the additional C3-
substituent is not an impediment to the second deprotona-
tion, despite the unavoidable development of A1,3-strain in
the resulting dienediolate.
O
i. LTMP (3 equiv),
LiCl (6 equiv)
HO Me
N
N
THF, –78 °C
ii. MeI
O
O
19
32
0%
NR2
H
B
O
Li
O
Me
Me
O
i. LTMP (3 equiv),
LiCl (6 equiv)
HO R
Scheme 7 Failure of attempted alkylations of ketoamide 19.
N
N
THF, –78 °C
ii. R–X
O
O
16
Finally, we wished to demonstrate that substitution chem-
istry was feasible at the hindered a-quaternary tertiary
amides. Basic hydrolyses of the crude reaction mixtures
leading to a-hydroxyamides 8 and 23 were carried out.
Following extractive workup, the clean a-hydroxyacids
33 and 34 were isolated in 49% and 86% yields, respec-
tively, over the two steps (Scheme 8).
26 R = Me 69%
27 R = n-Pr
28 R = allyl
OLi
NR2
Me
60%
68%
LiO
via
Scheme 5 Alkylation of dienediolates derived from ketoamide 16.
HO R2
i. LTMP (3 equiv), LiCl (6 equiv),
Finally, we wished to examine the possibility of generat-
ing trisubstituted olefins in the alkylation reaction, utilis-
ing substrates 17–19. The alkylation of the cyclohexyl-
substituted ketoamide 17 required an extended period for
dienediolate formation (23 h, cf 1 h for 15 and 16) and
generated the endocyclic olefin 29 in a moderate 30%
yield (Scheme 6). Although deprotonation of the sec-bu-
tyl-substituted ketoamide 18 proceeded under normal
conditions, a similarly modest 37% yield was obtained in
the alkylation. As expected, an inseparable mixture of two
regioisomeric products 30 and 31 was obtained in a ratio
OH
THF, –78 °C; BnBr or MeI
R1
5, 15
ii. 5 M KOH, EtOH, reflux
O
33 R1 = H, R2 = Bn 49%
34 R1 = Ph, R2 = Me 86%
Scheme 8 Preparation of free a-hydroxy acids.
In summary, we have conducted a detailed examination of
the scope and limitations of the alkylation reactions of di-
enediolates derived from readily prepared a-ketoamides.
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3266
R. Newton, S. P. Marsden
PAPER
IR (neat): 1709 (C=O), 1643 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.56 (t, J = 5.4 Hz, 2 H, NCH2),
We have identified optimised conditions for the formation
of reactive dienediolates, which widens the scope of ac-
ceptable electrophiles, gives improved yields and avoids 3.33 (t, J = 5.4 Hz, 2 H, NCH2), 2.72 (t, J = 7.4 Hz, 2 H,
the undesirable use of HMPA. We have also demonstrated
that products containing monosubstituted, E-1,2- and 1,1-
disubstituted and 1,1,2-trisubstituted olefins can be ac-
cessed, but that the formation of 1,2,2-trisubstituted ole-
fins is unsuccessful. Further studies on synthetic
applications of these useful building blocks will be report-
ed in due course.
CH2CH2CH3), 1.57–1.71 [m, 8 H, CH2CH2CH3, NCH2(CH2)3], 0.97
(t, J = 7.4 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 202.2 (C=O), 166.3 (NC=O), 47.1
(NCH2), 42.8, 42.5 (NCH2, C=OCH2), 26.8, 25.7, 24.8
[NCH2(CH2)3], 16.8 (CH3CH2), 14.1 (CH3).
MS (ESI+): m/z = 184 [M+ + H].
Anal. Calcd for C10H17NO2: C, 65.54; H, 9.35; N, 7.64. Found: C,
65.60; H, 9.45; N, 7.70.
All reactions were carried out under an atmosphere of dry N2 and
carried out using oven-dried glassware unless otherwise stated.
THF and Et2O were distilled from sodium benzophenone ketyl;
CH2Cl2 and toluene from CaH2; TMP from NaOH. All other re-
agents and solvents were purified by standard procedures or were
used as obtained from commercial sources as appropriate. Light pe-
troleum ether (PE) used had a bp range of 40–60 °C, unless other-
wise stated and was distilled prior to use. Flash chromatography
was carried out using silica gel (35–70 mm particles). TLC was car-
ried out on commercially available pre-coated plates (Merck silica
Kieselgel 60F254) and visualised by UV fluorescence or KMnO4
dip. Melting points were measured using a Reichert hot stage appa-
ratus and are uncorrected. IR spectra were recorded on a Perkin
Elmer FT-IR infrared spectrophotometer. 1H NMR spectra were re-
corded on a Bruker AM 300 FT spectrometer using an internal deu-
terium lock. 13C NMR spectra were recorded at 75 MHz on a Bruker
AM 300 FT spectrometer. Chemical shifts are quoted in ppm down-
field of TMS and values of coupling constants (J) are given in Hz.
Mass spectra were recorded using electrospray techniques on a Mi-
cromass LCT KA111 spectrometer (nominal) and a Waters LCT
time-of-flight spectrometer (accurate). Microanalyses were deter-
mined in microanalytical laboratories at the Department of Chemis-
try, University of Leeds.
4-Phenyl-1-piperidin-1-ylbutane-1,2-dione (15)
Prepared according to the typical procedure on a 22.3 mmol scale,
using PhCH2CH2MgBr (1.1 M in Et2O, 33.5 mmol); mp 42–46 °C;
Rf 0.21 (PE–Et2O, 1:1).
IR (CHCl3): 1713 (C=O), 1635 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.17–7.30 (m, 5 H, Ph), 3.53 (t,
J = 5.4 Hz, 2 H, NCH2), 3.16 (t, J = 5.4 Hz, 2 H, NCH2), 3.10 (app
dt, J = 2.1, 7.2 Hz, 2 H, CH2), 2.99 (t, J = 7.2 Hz, 2 H, CH2), 1.45–
1.68 [m, NCH2(CH2)3, 6 H].
13C NMR (75 MHz, CDCl3): d = 201.2 (C=O), 165.9 (NC=O),
140.6 (Cq), 129.0 (CH), 128.8 (CH), 126.7 (CH), 47.0 (NCH2), 42.8
(NCH2), 41.9 (CH2), 29.2 (CH2), 26.7, 25.7, 24.7 [NCH2(CH2)3].
MS (ESI+): m/z = 245 [M+ + H].
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.40; H, 7.70; N, 5.70.
3-Methyl-1-piperidin-1-ylbutane-1,2-dione (16)
Prepared according to the typical procedure on an 8.9 mmol scale,
using i-PrMgCl (2.0 M in Et2O, 17.9 mmol); Rf 0.24 (PE–EtOAc,
3:1).
IR (neat): 1710 (C=O), 1634 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.58 (t, J = 5.4 Hz, 2 H, NCH2),
3.29 (t, J = 5.4 Hz, 2 H, NCH2), 3.18 [sept, J = 7.1 Hz, 1 H,
CH(CH3)2], 1.58–1.72 [m, NCH2(CH2)3, 6 H], 1.16 [d, J = 7.1 Hz,
6 H, CH(CH3)2].
13C NMR (75 MHz, CDCl3): d = 205.2 (C=O), 166.5 (NC=O), 47.2
(NCH2), 42.7 (NCH2), 37.9 [CH(CH3)2], 26.7, 25.7, 24.7
[NCH2(CH2)3], 17.1 [CH(CH3)2].
Synthesis of a-Ketoamides: 1-Piperidin-1-ylbutane-1,2-dione
(5); Typical Procedure
A solution of oxalamide 13 (10.0 g, 44.6 mmol) in THF (100 mL)
was cooled to 0 °C under N2. EtMgBr (3 M in Et2O, 17.9 mL, 53.6
mmol) was added dropwise and the reaction was allowed to warm
to r.t. over 18 h. The orange solution was cooled to 0 °C and 3 M
HCl (50 mL) was added cautiously. The solution was extracted with
EtOAc (3 × 50 mL) and the combined organic extracts were dried
over MgSO4, filtered and concentrated under reduced pressure to
return a yellow oil. Flash chromatography eluting with PE–EtOAc
(2:1) gave the a-ketoamide 5 (6.66 g, 88%) as a pale yellow oil; Rf
0.30 (PE–EtOAc, 1:1).
MS (ESI+): m/z = 184 [M+ + H].
Anal. Calcd for C10H17NO2: C, 65.54; H, 9.35; N, 7.64. Found: C,
65.35; H, 9.20; N, 7.90.
1-Cyclohexyl-2-piperidin-1-ylethane-1,2-dione (17)
Prepared according to the typical procedure on an 8.9 mmol scale,
using CyMgCl (2.0 M in Et2O, 17.9 mmol); mp 32–35 °C; Rf 0.30
(PE–EtOAc, 3:1).
IR (neat): 1710 (C=O), 1634 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.56 (t, J = 5.4 Hz, 2 H, NCH2),
3.32 (t, J = 5.4 Hz, 2 H, NCH2), 2.78 (q, J = 7.3 Hz, 2 H, CH2CH3),
1.56–1.72 [m, 6 H, NCH2(CH2)3], 1.14 (t, J = 7.3 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): d = 202.8 (C=O), 166.4 (NC=O), 47.2
(NCH2), 42.8 (NCH2), 33.9 (CH3CH2), 26.8, 25.7, 24.8
[NCH2(CH2)3], 7.3 (CH3CH2).
IR (CHCl3): 1704 (C=O), 1639 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.57 (t, J = 5.4 Hz, 2 H, NCH2),
3.29 (t, J = 5.4 Hz, 2 H, NCH2), 2.87–2.97 (m, 1 H, CHC=O), 1.12–
1.96 [m, 16 H, NCH2(CH2)3, 5 × CH2].
13C NMR (75 MHz, CDCl3): d = 204.6 (C=O), 166.6 (NC=O), 47.3
(HCC=O), 47.2 (NCH2), 42.6 (NCH2), 27.5, 26.8, 26.2, 25.8, 24.8
[NCH2(CH2)3, 5 × CH2].
MS (ESI+): m/z = 184 [M+ + H].
Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28. Found: C,
63.60; H, 9.15; N, 8.55.
MS (ESI+): m/z = 224 [M+ + H].
Anal. Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27. Found: C,
69.80; H, 9.55; N, 6.20.
1-Piperidin-1-ylpentane-1,2-dione (14)
Prepared according to the typical procedure on a 22.3 mmol scale,
using n-PrMgBr (2 M in Et2O, 26.8 mmol); Rf 0.28 (PE–EtOAc,
2:1).
Synthesis 2005, No. 19, 3263–3270 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Quaternary a-Hydroxy Acids
3267
3-Methyl-1-piperidin-1-ylpentane-1,2-dione (18)
13C NMR (75 MHz, CDCl3): d = 173.2 (C=O), 140.5 (CH2=CH),
115.7 (CH2=CH), 73.2 (Cq), 48.0, 45.4 (br, 2 × NCH2), 26.2, 24.7,
24.6 [NCH2(CH2)3, CH3].
MS (ESI+): m/z = 184 [M+ + H].
HRMS: m/z [M + H]+ calcd for C10H18NO2: 184.1338; found:
A solution of oxalamide 13 (2.0 g, 8.9 mmol) in THF (20 mL) was
cooled to –78 °C under N2. s-BuLi (1.3 M in cyclopentane, 6.9 mL,
8.9 mmol) was added dropwise and the reaction was stirred at –78
°C for 1 h before allowing to warm to r.t. over 18 h. The yellow so-
lution was cooled to 0 °C and 2 M HCl (20 mL) was added cautious-
ly. The solution was extracted with EtOAc (3 × 25 mL) and the
combined organic extracts were dried over MgSO4, filtered and
concentrated under reduced pressure to return a yellow oil. Flash
chromatography eluting with PE–EtOAc (6:1) gave the a-ketoam-
ide 18 (1.17 g, 67%) as a colourless oil; Rf 0.32 (PE–EtOAc, 3:1).
184.1345.
2-Hydroxy-1-piperidin-1-yl-2-vinylpent-4-en-1-one (7)
Rf 0.20 (PE–EtOAc, 4:1).
IR (neat): 3368 (OH), 1622 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.04 (dd, J = 10.7, 17.3 Hz, 1 H,
CH2=CHC), 5.80–5.87 (m, 1 H, CH2=CHCH2), 5.39 (d, J = 17.3 Hz,
1 H, CHH=CHC), 5.27 (d, J = 10.7 Hz, 1 H, CHH=CHC), 5.14 (d,
J = 11.5 Hz, 1 H, CHH=CHCH2) 5.13 (d, J = 15.8 Hz, 1 H,
CHH=CHCH2), 4.94 (s, 1 H, OH), 3.55 (m, 4 H, 2 × NCH2), 2.62
(d, J = 7.0 Hz, 2 H, CH2=CHCH2), 1.53–1.67 [m, 6 H,
NCH2(CH2)3].
IR (neat): 1706 (C=O), 1634 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.58 (t, J = 5.4 Hz, 2 H, NCH2),
3.31 (t, J = 5.4 Hz, 2 H, NCH2), 3.02 (sext, J = 6.9 Hz, 1 H,
CHC=O), 1.81 (dp, J = 7.4, 14.9 Hz, 1 H, CH3CHHCH), 1.50–1.73
[m, 6 H, NCH2(CH2)3], 1.38 (dp, J = 7.4, 14.9 Hz, 1 H,
CH3CHHCH), 1.13 (d, J = 7.0 Hz, 3 H, CHCH3), 0.96 (t, J = 7.4 Hz,
3 H, CH3CH2).
13C NMR (75 MHz, CDCl3): d = 171.7 (C=O), 139.7 (CqCH=CH2),
133.2 (H2C=CHCH2), 119.1 (H2C=CHCH2), 116.3 (CqCH=CH2),
75.6 (Cq), 47.2, 45.5 (br, 2 × NCH2), 42.7 (H2C=CHCH2), 26.2, 24.7
[NCH2(CH2)3].
13C NMR (75 MHz, CDCl3): d = 204.5 (C=O), 166.1 (NC=O), 46.7
(NCH2), 44.3 (CH), 42.4 (NCH2), 26.3, 25.4, 24.4, 24.3
[NCH2(CH2)3, CH2], 14.0 (CH3CH), 11.5 (CH3CH2).
MS (ESI+): m/z = 198 [M+ + H].
MS (ESI+): m/z = 210 [M+ + H].
Anal. Calcd for C11H19NO2: C, 66.97; H, 9.71; N, 7.10. Found: C,
67.00; H, 9.60; N, 7.25.
Anal. Calcd for C12H19NO2: C, 68.87; H, 9.15; N, 6.69. Found: C,
68.60; H, 9.30; N, 6.40.
4-Methyl-1-piperidin-1-ylpentane-1,2-dione (19)
Prepared according to the typical procedure on an 8.9 mmol scale,
using i-BuMgBr (2.0 M in Et2O, 10.7 mmol); Rf 0.25 (PE–EtOAc,
5:1).
2-Benzyl-2-hydroxy-1-piperidin-1-ylbut-3-en-1-one (8)
Mp 83–88 °C; Rf 0.20 (PE–EtOAc, 4:1).
IR (CHCl3): 3368 (OH), 1624 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.19–7.26 (m, 5 H, Ph), 6.13 (dd,
J = 10.7, 17.4 Hz, 1 H, CH2=CH), 5.42 (d, J = 17.4 Hz, 1 H,
CHH=CH), 5.30 (d, J = 10.7 Hz, 1 H, CHH=CH), 4.81 (s, 1 H, OH),
3.29–3.66 (m, 4 H, 2 × NCH2), 3.16 (s, 2 H, PhCH2), 1.57–1.66 [m,
6 H, NCH2(CH2)3].
IR (neat): 1708 (C=O), 1639 (NC=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.56 (t, J = 5.4 Hz, 2 H, NCH2),
3.34 (t, J = 5.4 Hz, 2 H, NCH2), 2.63 (d, J = 6.8 Hz, 2 H,
CHCH2C=O), 2.21 [sept, J = 6.7 Hz, 1 H, CH(CH3)2], 1.58–1.71
[m, 6 H, NCH2(CH2)3], 0.98 [d, J = 6.7, 6 H, CH(CH3)2].
13C NMR (75 MHz, CDCl3): d = 171.7 (C=O), 140.0 (CH=CH2),
136.1 (Cq), 130.7 (CH), 128.4 (CH), 127.3 (CH), 116.6 (CH2=CH),
76.6 (Cq), 46 (br, NCH2), 44.1 (PhCH2), 26.0, 24.8 [NCH2(CH2)3].
13C NMR (75 MHz, CDCl3): d = 201.8 (C=O), 166.2 (NC=O), 49.4
(CH2C=O), 47.1 (NCH2), 42.8 (NCH2), 26.8, 25.8, 24.8
[NCH2(CH2)3], 24.2 (CH), 23.0 (2 × CH3).
MS (ESI+): m/z = 260 [M+ + H].
MS (ESI+): m/z 198 [M+ + H].
Anal. Calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C,
73.80; H, 8.30; N, 5.30.
Anal. Calcd for C11H19NO2: C, 66.97; H, 9.71; N, 7.10. Found: C,
66.80; H, 9.50; N, 7.30.
2-Hydroxy-2-(4-methoxybenzyl)-1-piperidin-1-ylbut-3-en-1-
one (9)
Mp 79–82 °C; Rf 0.27 (PE–EtOAc, 3:1).
IR (CHCl3): 3368 (OH), 1623 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.14 (d, J = 8.6 Hz, 2 H, ArH),
6.80 (d, J = 8.6 Hz, 2 H, ArH), 6.12 (dd, J = 10.6, 17.4 Hz, 1 H,
CH2=CH), 5.41 (d, J = 17.4 Hz, 1 H, CHH=CH), 5.30 (d, J = 10.6
Hz, 1 H, CHH=CH), 4.83 (s, 1 H, OH), 3.77 (s, 3 H, OMe), 3.64 (m,
4 H, 2 × NCH2), 3.13 (d, J = 15.0 Hz, 1 H, PhCHH), 3.08 (d, J =
15.0 Hz, 1 H, PhCHH), 1.57–1.67 [m, 6 H, NCH2(CH2)3].
13C NMR (75 MHz, CDCl3): d = 171.8 (C=O), 158.9 (Cq), 140.0
(CH=CH2), 131.7 (CH), 128.1 (Cq), 116.6 (CH=CH2), 113.9 (CH),
76.7 (Cq), 55.5 (OMe), 47 (br, NCH2), 43.1 (PhCH2), 26.1, 24.8
[NCH2(CH2)3].
Alkylation of a-Ketoamides: 2-Hydroxy-2-methyl-1-piperidin-
1-ylbut-3-en-1-one (6); Typical Procedure
A flask charged with LiCl (150 mg, 3.55 mmol) was flame-dried
under vacuum then purged with N2. THF (2 mL) and 2,2,6,6-tetra-
methylpiperidine (300 mL, 1.78 mmol) were added and the mixture
cooled to –78 °C before a solution of n-BuLi (1.6 M in hexanes,
1.11 mL, 1.78 mmol) was added. The reaction mixture was stirred
at 0 °C for 30 min, then a solution of a-ketoamide 5 (100 mg, 0.59
mmol) in THF (2 mL) was added. The mixture was stirred at 0 °C
for 30 min then recooled to –78 °C before adding MeI (184 mL, 2.96
mmol). The reaction mixture was allowed to slowly warm to r.t.
over 20 h, then quenched with sat. aq NH4Cl solution (5 mL), dilut-
ed with water (10 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic extracts were dried over MgSO4, filtered and
evaporated under reduced pressure. Flash chromatography eluting
with PE–EtOAc (2:1) gave the product 6 (69 mg, 63%) as a pale yel-
low oil; Rf 0.34 (PE–EtOAc, 1:1).
MS (ESI+): m/z = 290 [M+ + H].
Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.30; H, 8.25; N, 4.70.
IR (neat): 3378 (OH), 1615 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.03 (dd, J = 10.3, 17.4 Hz, 1 H,
CH2=CH), 5.34 (d, J = 17.4 Hz, 1 H, CHH=CH), 5.27 (d, J = 10.3
Hz, 1 H, CHH=CH), 5.19 (s, 1 H, OH), 3.54 (m, 4 H, 2 × NCH2),
1.55–1.68 [m, 9 H, NCH2(CH2)3, CH3].
2-Hydroxy-1-piperidin-1-yl-2-propylbut-3-en-1-one (10)
Rf 0.33 (PE–EtOAc, 3:1).
Synthesis 2005, No. 19, 3263–3270 © Thieme Stuttgart · New York

3268
R. Newton, S. P. Marsden
PAPER
IR (neat): 3367 (OH), 1622 (C=O) cm–1.
HRMS: m/z [M + Na]+ calcd for C11H19NO2Na: 220.1313; found:
220.1315.
1H NMR (300 MHz, CDCl3): d = 5.96 (dd, J = 10.5, 17.4 Hz, 1 H,
CH=CH2), 5.31 (d, J = 17.4 Hz, 1 H, CH=CHH), 5.18 (s, 1 H, OH),
5.17 (d, J = 10.5 Hz, 1 H, CH=CHH), 3.48 (br m, 4 H, 2 × NCH2),
(E)-2-Hydroxy-1-piperidin-1-yl-2-propylpent-3-en-1-one (21)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 14, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; Rf 0.29 (PE–EtOAc, 4:1).
1.71–1.79 (m,
2 H, CHHCH2CH3), 1.42–1.69 [m, 7 H,
CHHCHHCH3, NCH2(CH2)3], 1.01–1.19 (m, 1 H, CHHCHHCH3),
0.86 (t, J = 7.3 Hz, 3 H, CHHCH3).
13C NMR (75 MHz, CDCl3): d = 171.0 (C=O), 138.9 (CH=CH2),
114.7 (CH=CH2), 74.6 (Cq), 46.1, 44.5 (br, 2 × NCH2), 38.5
(CH2CH2CH3), 24.8, 23.3 [NCH2(CH2)3], 15.8 (CH2CH3), 13.3
(CH2CH3).
MS (ESI+): m/z = 212 [M+ + H].
HRMS: m/z [M + H]+ calcd for C12H22NO2: 212.1651; found:
IR (neat): 3366 (OH), 1619 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 5.80 (dq, J = 6.4, 15.6 Hz, 1 H,
CH3CH=CH), 5.67 (dd, J = 1.3, 15.6 Hz, 1 H, CH3CH=CH), 5.26
(s, 1 H, OH), 3.55 (br m, 4 H, 2 × NCH2), 1.46–1.82 [m, 12 H,
NCH2(CH2)3, CHHCHHCH3; including 1.73 (dd, J = 1.3, 6.4 Hz, 3
H, CH3CH=CH)], 1.03–1.20 (m, 1 H, CHHCHHCH3), 0.92 (t, J =
7.2 Hz, 3 H, CH3CH2).
13C NMR (75 MHz, CDCl3): d = 172.6 (C=O), 133.3 (CH3CH=CH),
127.0 (CH3CH=CH), 75.2 (Cq), 47.6, 45.1 (br, 2 × NCH2), 40.1
(CH2CH2CH3), 25.9, 24.4 [NCH2(CH2)3], 18.0 (CH3CH=CH), 16.9
(CH2CH2CH3), 14.3 (CH2CH2CH3).
212.1654.
2-Hydroxy-4-methyl-1-piperidin-1-yl-2-vinylpentan-1-one (11)
Rf 0.17 (PE–EtOAc, 3:1).
IR (neat): 3354 (OH), 1622 (C=O) cm–1.
MS (ESI+): m/z = 226 [M+ + H].
1H NMR (300 MHz, CDCl3): d = 6.02 (dd, J = 10.6, 17.3 Hz, 1 H,
CH2=CH), 5.37 (dd, J = 0.8, 17.3 Hz, 1 H, CHH=CH), 5.28 (s, 1 H,
OH), 5.22 (dd, J = 0.8, 10.6 Hz, 1 H, CHH=CH), 3.50 (br m, 4 H,
2 × NCH2), 1.80–1.88 (m, 3 H, CHCH2), 1.56–1.78 [m, 6 H,
NCH2(CH2)3], 0.98 (d, J = 6.1 Hz, 3 H, CH3CH), 0.87 (d, J = 6.2
Hz, 3 H, CH3CH).
13C NMR (75 MHz, CDCl3): d = 173.0 (C=O), 140.9 (CH2=CH),
115.8 (CH2=CH), 75.8 (Cq), 47 (br, NCH2), 46.3 (CH2CH), 45 (br,
NCH2), 26.0, 24.7 [NCH2(CH2)3], 24.9, 24.6, 24.1 (CH3CHCH3).
Anal. Calcd for C13H23NO2: C, 69.29; H, 10.29; N, 6.22. Found: C,
69.00; H, 10.50; N, 6.25.
(E)-2-Allyl-2-hydroxy-1-piperidin-1-ylpent-3-en-1-one (22)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 14, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; Rf 0.20 (PE–EtOAc, 4:1).
IR (neat): 3362 (OH), 1621 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 5.78–5.86 (m, 2 H, CH3CH=CH,
CH2CH=CH2), 5.69 (dd, J = 1.3, 15.4 Hz, 1 H, CH3CH=CH), 5.12
(d, J = 11.8 Hz, 1 H, CH2CH=CHH), 5.11 (d, J = 15.4 Hz, 1 H,
CH2CH=CHH), 5.08 (s, 1 H, OH), 3.34–3.81 (br m, 4 H, 2 × NCH2),
2.61 (dd, J = 6.4, 14.1 Hz, 1 H, CH2CH=CHH), 2.57 (dd, J = 7.7,
14.1 Hz, 1 H, CH2CH=CHH), 1.74 (dd, J = 1.3, 6.4 Hz, 3 H,
CH3CH=CH), 1.54–1.72 [m, 6 H, NCH2(CH2)3].
13C NMR (75 MHz, CDCl3): d = 171.9 (C=O), 133.0, 132.6, 127.3
(3 × =CH), 118.4 (CH=CH2), 75.1 (Cq), 47.6, 45.1 (br, 2 × NCH2),
42.7 (CH2CH=CH2), 25.8, 24.5 [NCH2(CH2)3], 18.0 (CH3).
MS (ESI+): m/z = 225 [M+ + H].
Anal. Calcd for C13H23NO2: C, 69.29; H, 10.29; N, 6.22. Found: C,
69.00; H, 10.05; N, 6.05.
(E)-2-Hydroxy-2-isopropyl-1-piperidin-1-ylbut-3-en-1-one (12)
Rf 0.20 (PE–EtOAc, 3:1).
IR (neat): 3341 (OH), 1622 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.11 (dd, J = 10.6, 17.0 Hz, 1 H,
CH2=CH), 5.47 (dd, J = 1.2, 17.0 Hz, 1 H, CHH=CH), 5.27 (dd, J =
1.2, 10.6 Hz, 1 H, CHH=CH), 5.19 (s, 1 H, OH), 3.56 (br m, 4 H, 2
× NCH2), 2.10 (sept, J = 6.6 Hz, 1 H, CH), 1.56–1.71 [m, 6 H,
NCH2(CH2)3], 0.99 (d, J = 6.6 Hz, 3 H, CH3), 0.84 (d, J = 6.6 Hz, 3
H, CH3).
MS (ESI+): m/z = 224 [M+ + H].
HRMS: m/z [M + H]+ calcd for C13H22NO2: 224.1651; found:
224.1556.
13C NMR (75 MHz, CDCl3): d = 173.0 (C=O), 139.0 (CH=CH2),
117.8 (CH=CH2), 79.0 (Cq), 47.0 (br, 2 × NCH2), 34.2 (CH), 26.2,
24.8 [NCH2(CH2)3], 17.2 (CH3), 16.9 (CH3).
(E)-2-Hydroxy-2-methyl-4-phenyl-1-piperidin-1-ylbut-3-en-1-
one (23)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 15, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; mp 110–113 °C; Rf 0.14 (PE–EtOAc, 3:1).
MS (ESI+): m/z = 212 [M+ + H].
Anal. Calcd for C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C,
68.00; H, 9.90; N, 6.65.
IR (CHCl3): 3364 (OH), 1622 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.22–7.40 (m, 5 H, Ph), 6.68 (d,
J = 16.2 Hz, 1 H, CH), 6.37 (d, J = 16.2 Hz, 1 H, CH), 5.31 (s, 1 H,
OH), 3.58 (br m, 4 H, 2 × NCH2), 1.54–1.65 [m, 9 H, NCH2(CH2)3;
including 1.65 (s, 3 H, CH3)].
13C NMR (75 MHz, CDCl3): d = 173.0 (C=O), 136.3 (Cq), 131.3,
130.5 (HC=CH), 128.6 (CH), 128.0 (CH), 126.6 (CH), 72.7 (Cq),
47.6, 45.5 (br, 2 × NCH2), 25.9, 24.3 [NCH2(CH2)3], 25.2 (CH3).
2-Hydroxy-2-methyl-1-piperidin-1-ylpent-3-en-1-one (20)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 14, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; Rf 0.38 (PE–EtOAc, 1:1).
IR (neat): 3381 (OH), 1621 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 5.80 (dq, J = 6.4, 15.6 Hz, 1 H,
CH3CH=CH), 5.66 (dd, J = 1.4, 15.6 Hz, 1 H, CH3CH=CH), 5.19
(s, 1 H, OH), 3.52 (br m, 4 H, 2 × NCH2), 1.74 (dd, J = 1.4, 6.4 Hz,
3 H, CH3CH=CH), 1.51–1.66 [m, 9 H, NCH2(CH2)3, CH3].
13C NMR (75 MHz, CDCl3): d = 173.4 (C=O), 133.4 (HC=CHCH3),
126.7 (HC=CHCH3), 72.3 (Cq), 47.7, 45.0 (br, 2 × NCH2), 25.9,
24.4 [NCH2(CH2)3], 24.8 (CH3Cq), 17.9 (CH3CH=CH).
MS (ESI+): m/z = 260 [M+ + H].
Anal. Calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C,
73.80; H, 8.35; N, 5.35.
2-Hydroxy-1-piperidin-1-yl-2-[(E)-styryl]pentan-1-one (24)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 15, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; Rf 0.36 (PE–EtOAc, 3:1).
MS (ESI+): m/z = 198 [M+ + H].
Synthesis 2005, No. 19, 3263–3270 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of Quaternary a-Hydroxy Acids
3269
IR (neat): 3363 (OH), 1615 (C=O) cm–1.
26.3, 24.8 [NCH2(CH2)3], 19.4 (CH3C=CH2), 17.5 (CH2CH2CH3),
14.9 (CH2CH2CH3).
MS (ESI+): m/z = 226 [M+ + H].
1H NMR (300 MHz, CDCl3): d = 7.20–7.40 (m, 5 H, Ph), 6.70 (d,
J = 16.1 Hz, 1 H, CH), 6.38 (dd, J = 2.2, 16.1 Hz, 1 H, CH), 5.37 (d,
J = 2.2 Hz, 1 H, OH), 3.59 (br m, 4 H, 2 × NCH2), 1.82–1.99 (m, 2
H, CH2CH2CH3), 1.55–1.66 [m, 7 H, NCH2(CH2)3, CH2CHHCH3],
1.13–1.28 (m, 1 H, CH2CHHCH3), 0.97 (t, J = 7.3 Hz, 3 H, CH3).
Anal. Calcd for C13H23NO2: C, 69.29; H, 10.29; N, 6.22. Found: C,
69.00; H, 10.55; N, 6.25.
13C NMR (75 MHz, CDCl3): d = 172.3 (C=O), 136.6 (Cq), 131.1,
130.9 (HC=CH), 128.6 (CH), 127.9 (CH), 126.5 (CH), 75.5 (Cq),
46.2 (br, 2 × NCH2), 40.4 (CH2CH2CH3), 26.0, 24.4 [NCH2(CH2)3],
17.0 (CH2CH2CH3), 14.3 (CH2CH2CH3).
2-Hydroxy-2-isopropenyl-1-piperidin-1-ylpent-4-en-1-one (28)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 16, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; Rf 0.23 (PE–EtOAc, 4:1).
MS (ESI+): m/z = 288 [M+ + H].
IR (neat): 3366 (OH), 1634 (C=O) cm–1.
HRMS: m/z [M + Na]+ calcd for C18H25NO2Na: 310.1783; found:
310.1796.
1H NMR (300 MHz, CDCl3): d = 5.75–5.89 (m, 1 H, CH), 5.06–
5.14 (m, 5 H, 2 × alkene CH2, OH), 3.29–3.57 (br, 4 H, 2 × NCH2),
2.77 (dd, J = 5.6, 13.8 Hz, 1 H, CHHCH=CH2), 2.63 (dd, J = 8.2,
13.8 Hz, 1 H, CHHCH=CH2), 1.74 (3 H, CH3), 1.43–1.67 [m, 6 H,
NCH2(CH2)3].
13C NMR (75 MHz, CDCl3): d = 171.4 (C=O), 146.8 (Cq), 133.7
(CH), 118.8 (CH2=CH), 112.2 (CH2=C), 77.7 (Cq), 47.2, 45.0 (br,
2 × NCH2), 41.1 (CH2CH=CH2), 26.2, 24.8 [NCH2(CH2)3], 19.4
(CH3).
2-Hydroxy-1-piperidin-1-yl-2-[(E)-styryl]pent-4-en-1-one (25)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 15, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; Rf 0.30 (PE–EtOAc, 3:1).
IR (neat): 3365 (OH), 1622 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.17–7.40 (m, 5 H, Ph), 6.70 (d,
J = 16.2 Hz, 1 H, HC=CH), 6.38 (d, J = 16.2 Hz, 1 H HC=CH),
5.82–5.95 (m, 1 H, H2C=CH), 51.4–5.19 (m, 2 H, H2C=CH), 5.07
(s, 1 H, OH), 3.58 (br m, 4 H, 2 × NCH2), 2.72 (d, J = 7.2 Hz, 2 H,
CH2CH=CH2), 1.42–1.63 [m, 6 H, NCH2(CH2)3].
MS (ESI+): m/z = 224 [M+ + H].
Anal. Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27. Found: C,
69.70; H, 9.75; N, 6.20.
13C NMR (75 MHz, CDCl3): d = 171.5 (C=O), 136.4 (Cq), 132.8
(CH), 131.0 (CH), 130.5 (CH), 128.6 (CH), 128.0 (CH), 126.5
(CH), 118.9 (CH=CH2), 75.5 (Cq), 47.2 (br, 2 × NCH2), 43.2
(CH2CH=CH2), 25.9, 24.4 [NCH2(CH2)3].
MS (ESI+): m/z = 286 [M+ + H].
HRMS: m/z [M + Na]+ calcd for C18H23NO2Na: 308.1626; found:
2-Cyclohex-1-enyl-2-hydroxy-1-piperidin-1-ylpropan-1-one
(29)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 17, the reaction was stirred at 25 °C for 23 h
before cooling to –78 °C; Rf 0.26 (PE–EtOAc, 4:1).
IR (neat): 3367 (OH), 1618 (C=O) cm–1.
308.1639.
1H NMR (300 MHz, CDCl3): d = 5.81–5.88 (m, 1 H, CH), 5.29 (s,
1 H, OH), 3.33–3.78 (br m, 4 H, 2 × NCH2), 2.01–2.28 (m, 4 H,
CH2CH=CCH2), 1.35–1.85 [m, 13 H, CH3, 2 × CH2, NCH2(CH2)3].
2-Hydroxy-2,3-dimethyl-1-piperidin-1-ylbut-3-en-1-one (26)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 16, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; mp 89–91 °C; Rf 0.16 (PE–EtOAc, 4:1).
13C NMR (75 MHz, CDCl3): d = 173.8 (C=O), 139.8 (Cq), 123.3
(CH), 75.3 (Cq), 46.9, 44.7 (br, 2 × NCH2), 26.4, 25.6, 24.8, 24.6,
23.1, 22.6 [NCH2(CH2)3, 4 × CH2], 23.7 (CH3).
IR (CHCl3): 3368 (OH), 1621 (C=O) cm–1.
MS (ESI+): m/z = 238 [M+ + H].
1H NMR (300 MHz, CDCl3): d = 5.30 (s, 1 H, OH), 5.14 (s, 1 H,
CH), 5.04 (s, 1 H, CH), 3.53 (br m, 4 H, 2 × NCH2), 1.74 (s, 3 H,
CH3C=CH2), 1.42–1.70 [m, 9 H, NCH2(CH2)3; including 1.56 (s, 3
H, CH3)].
13C NMR (75 MHz, CDCl3): d = 172.8 (C=O), 146.8 (Cq), 111.9
(CH2), 74.8 (Cq), 47.0, 44.8 (br, 2 × NCH2), 25.8, 24.3
[NCH2(CH2)3], 23.7 (CH3COH), 18.7 (CH3C=CH2).
Anal. Calcd for C14H23NO2: C, 70.85; H, 9.77; N, 5.90. Found: C,
70.80; H, 10.05; N, 5.60.
3-Ethyl-2-hydroxy-2-methyl-1-piperidin-1-ylbut-3-en-1-one
(30) and (E)-2-Hydroxy-2,3-dimethyl-1-piperidin-1-ylpent-3-
en-1-one (31)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 18, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; Rf 0.20 (PE–EtOAc, 3:1).
MS (ESI+): m/z = 198 [M+ + H].
Anal. Calcd for C11H19NO2: C, 66.97; H, 9.71; N, 7.10. Found: C,
67.10; H, 10.00; N, 6.80.
IR (neat; mixture of 30 and 31): 3367 (OH), 1633 (C=O) cm–1.
Major Isomer 30
2-Hydroxy-3-methyl-1-piperidin-1-yl-2-propylbut-3-en-1-one
(27)
Prepared according to the typical procedure except that after the ad-
dition of a-ketoamide 16, the reaction was stirred at 25 °C for 1 h
before cooling to –78 °C; Rf 0.25 (PE–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d = 5.24 (s, 1 H, OH), 5.17 (s, 1 H,
C=CHH), 4.99 (s, 1 H, C=CHH), 3.40–3.55 (br m, 4 H, 2 × NCH2),
2.10–2.20 (m, 1 H, CH3CHH), 1.72–1.80 (m, 1 H, CH3CHH), 1.49–
1.62 [m, 9 H, NCH2(CH2)3, CH3], 1.01 (t, J = 7.3 Hz, 3 H, CH3CH2).
IR (neat): 3355 (OH), 1622 (C=O) cm–1.
Minor Isomer 31
1H NMR (300 MHz, CDCl3): d = 5.63 (q, J = 6.7 Hz, 1 H,
CH3CH=C), 5.24 (s, 1 H, OH), 3.40–3.55 (br m, 4 H, 2 × NCH2),
1.60 (d, J = 6.7 Hz, 3 H, CH3CH=C), 1.49–1.62 [m, 12 H,
NCH2(CH2)3, 2 × CH3].
1H NMR (300 MHz, CDCl3): d = 5.28 (s, 1 H, OH), 5.12 (s, 1 H,
CH), 5.03 (s, 1 H, CH), 3.32–3.91 (br m, 4 H, 2 × NCH2), 1.78–1.98
(m, 2 H, CH2CH2CH3), 1.73 (s, 3 H, CH3), 1.24–1.70 [m, 7 H,
NCH2(CH2)3, CH2CHHCH3], 1.00–1.09 (m, 1 H, CH2CHHCH3),
0.95 (t, J = 6.9 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): d = 172.1 (C=O), 147.3 (Cq), 112.1
(CH2), 77.7 (Cq), 47.3, 45.3 (br, 2 × NCH2), 38.3 (CH2CH2CH3),
13C NMR (75 MHz, CDCl3; mixture of 30 and 31): d = 173.8, 173.5
(2 × C=O), 152.9 (Cq), 137.8 (Cq), 120.7 (CH), 109.5 (CH2), 76.1,
Synthesis 2005, No. 19, 3263–3270 © Thieme Stuttgart · New York

3270
R. Newton, S. P. Marsden
PAPER
75.6 (2 × Cq), 47.4, 45.2 (4 × NCH2), 26.2, 24.8, 24.0 [2 ×
NCH2(CH2)3, CH3CH2], 24.3, 23.9, 13.9, 13.0, 12.3 (5 × CH3).
1H NMR (300 MHz, MeOD): d = 7.09–7.31 (m, 5 H, Ph), 6.66 (d,
J = 16.1 Hz, 1 H, HC=CH), 6.34 (d, J = 16.1 Hz, 1 H, HC=CH), 1.47
(s, 3 H, CH3).
13C NMR (75 MHz, MeOD): d = 178.3 (C=O), 138.3 (Cq), 133.3
(CH), 130.4 (CH), 129.9 (CH), 129.0 (CH), 127.9 (CH), 75.9 (Cq),
27.2 (CH3).
MS (ESI+): m/z = 212 [M+ + H].
HRMS: m/z [M + H]+ calcd for C12H22NO2: 212.1651; found:
212.1642.
2-Benzyl-2-hydroxybut-3-enoic Acid (33)
HRMS: m/z [M – H]+ calcd for C11H11O3: 191.0708; found:
191.0692.
A flask charged with LiCl (1.50 g, 35.5 mmol) was flame-dried un-
der vacuum then purged with N2. THF (10 mL) and 2,2,6,6-tetra-
methylpiperidine (3.01 mL, 17.8 mmol) were added and the mixture
was cooled to –78 °C before a solution of n-BuLi (1.6 M in hexanes,
1.11 mL, 17.8 mmol) was added. The reaction mixture was stirred
at 0 °C for 30 min, then a solution of a-ketoamide 5 (1.00 g, 5.9
mmol) in THF (10 mL) was added. The mixture was stirred at 0 °C
for 30 min then recooled to –78 °C before adding BnBr (3.5 mL,
29.6 mmol). The reaction mixture was allowed to slowly warm to
r.t. over 20 h, then quenched with sat. aq NH4Cl solution (20 mL),
diluted with water (25 mL) and extracted with EtOAc (3 × 50 mL).
The combined organic extracts were dried over MgSO4, filtered and
evaporated under reduced pressure. The crude product was dis-
solved in absolute EtOH (10 mL) and 5 M KOH (15 mL) and heated
to reflux for 24 h. The reaction mixture was cooled to 25 °C before
adding Et2O (25 mL). The organic phase was separated and further
extracted with 2 M KOH (2 × 25 mL). The combined basic aqueous
phases were ice-cooled then acidified with concd HCl (15 mL) and
extracted with Et2O (5 × 25 mL). The combined organics were dried
over MgSO4, filtered and concentrated under reduced pressure to
return the acid 33 (554 mg, 49%) as a pale yellow solid. An analyt-
ical sample was recrystallised from toluene to return a white solid;
mp 120–123 °C.
Acknowledgment
We thank GlaxoSmithKline for generous unrestricted financial sup-
port and Dr Ben McKeever and Dr Richard Gallagher (AstraZene-
ca) for measurement of the accurate mass spectra.
References
(1) Einsle, O.; Tezcan, F. A.; Andrade, S. L. A.; Schmid, B.;
Yoshida, M.; Howard, J. B.; Rees, D. C. Science 2002, 297,
1696.
(2) Kusano, A.; Seyama, Y.; Nagai, M.; Shibano, M.; Kusano,
G. Biol. Pharm. Bull. 2001, 24, 1198.
(3) Dawson, M. J.; Farthing, J. E.; Marshall, P. S.; Middleton, R.
F.; O’Neill, M. J.; Shuttleworth, A.; Stylli, C.; Tait, R. M.;
Taylor, P. M.; Wildman, H. G.; Buss, A. D.; Langley, D.;
Hayes, M. V. J. Antibiot. 1992, 45, 639.
(4) Tucker, H.; Crook, J. W.; Chesterson, G. J. J. Med. Chem.
1988, 31, 954.
(5) Wing, K. D.; Sacher, M.; Kagaya, Y.; Tsurubuchi, Y.;
Mulderig, L.; Connair, M.; Schnee, M. Crop Protection
2000, 19, 537.
(6) (a) Naef, R.; Seebach, D. Angew. Chem. 1981, 93, 1113.
(b) Seebach, D.; Naef, R. Helv. Chim. Acta 1981, 64, 2704.
(c) Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R.
Helv. Chim. Acta 1987, 70, 1194.
(7) (a) Boons, G.-J.; Downham, R.; Kim, K.-S.; Ley, S. V.;
Woods, M. Tetrahedron 1994, 50, 7157. (b) Diez, E.;
Dixon, D. J.; Ley, S. V. Angew. Chem. Int. Ed. 2001, 40,
2906.
(8) Evans, D. A.; Barrow, J. C.; Leighton, J. L.; Robichaud, A.
J.; Sefkow, M. J. Am. Chem. Soc. 1994, 116, 12111.
(9) Koft, E. R.; Williams, M. D. Tetrahedron Lett. 1986, 27,
2227.
IR (diamond transmission cell): 3450 (OH), 2961 (COOH), 1732
(C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.04–7.17 (m, 5 H, Ph), 6.14 (dd,
J = 10.5, 17.1 Hz, 1 H, CH2=CH), 5.53 (dd, J = 1.0, 17.1 Hz, 1 H,
CHH=CH), 5.27 (dd, J = 1.0, 10.5 Hz, 1 H, CHH=CH), 3.22 (d, J =
13.6 Hz, 1 H, PhCHH), 2.96 (d, J = 13.6 Hz, 1 H, PhCHH).
13C NMR (75 MHz, CDCl3): d = 178.3 (C=O), 138.2 (CH=CH2),
135.4 (Cq), 130.7 (CH), 128.7 (CH), 127.6 (CH), 116.4 (CH=CH2),
78.4 (Cq), 45.5 (PhCH2).
HRMS: m/z [M – H]+ calcd for C11H11O3: 191.0708; found:
191.0699.
(E)-2-Hydroxy-2-methyl-4-phenylbut-3-enoic Acid (34)
Method as above except that after the addition of a-ketoamide 15,
the reaction was stirred at 25 °C for 1 h before cooling to –78 °C and
addition of MeI (1.84 mL, 29.6 mmol). Hydrolysis was performed
as previously described to return the acid 34 (979 mg, 86%) as a
brown solid. An analytical sample was recrystallised from toluene
to return a white solid; mp 133–137 °C.
(10) Lithium halides are known to influence reactivity of lithium
amide bases by deaggregation: (a) De Pue, J. S.; Collum, D.
B. J. Am. Chem. Soc. 1988, 110, 5518. (b) De Pue, J. S.;
Collum, D. B. J. Am. Chem. Soc. 1988, 110, 5524.
(11) For previous examples of this approach to a-ketoamides,
see: (a) Sibi, M. P.; Sharma, R.; Paulson, K. L. Tetrahedron
Lett. 1992, 33, 1941. (b) Burton, A. J.; Caldwell, K. S.;
Fuchter, M. J.; Lindvall, M. K.; Patel, R.; Packham, T. W.;
Prodger, J. C.; Schilling, M. B.; Walker, M. D. Tetrahedron
Lett. 2003, 44, 5653.
IR (diamond transmission cell): 3428 (OH), 2933 (COOH), 1719
(C=O) cm–1.
Synthesis 2005, No. 19, 3263–3270 © Thieme Stuttgart · New York