Studies on the reduction and reductive alkylation of amino acid-derived spirocyclic 2,6-dioxopiperazines

Article abstract of DOI:10.1016/j.tet.2007.01.022

The regio- and diastereoselective reduction and reductive alkylation of 3-spiro-2,6-dioxopiperazines are described via a two-step process, which involves addition of NaBH₄ or Grignard reagents, followed by TFA-mediated dehydration with a second

Full text of DOI:10.1016/j.tet.2007.01.022

Tetrahedron 63 (2007) 2675–2683
Studies on the reduction and reductive alkylation of amino
acid-derived spirocyclic 2,6-dioxopiperazines
ꢀ
ꢀ
Juan A. Gonzalez-Vera, Pilar Ventosa-Andres, Joanne Casey,
*
ꢀ
M. Teresa Garcıa-Lopez and Rosario Herranz
ꢀ
´
Instituto de Quꢀımica Medica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
Received 1 December 2006; revised 8 January 2007; accepted 14 January 2007
Available online 17 January 2007
Abstract—The regio- and diastereoselective reduction and reductive alkylation of 3-spiro-2,6-dioxopiperazines are described via a two-step
process, which involves addition of NaBH4 or Grignard reagents, followed by TFA-mediated dehydration with a second NaBH4 addition. The
results show that the reactivity of 2,6-dioxopiperazines is limited by their steric hindrance and by the volume of the nucleophile, which
preferably add to the C6 carbonylic carbon with complete diastereoselectivity. The diastereoselectivity of the first step is mainly governed
by electronic factors, which direct the addition of the nucleophile from the most hindered face, while in the second step, the NaBH4 attacks
from the less crowded face. This second step proceeds with partial or complete racemization.
Ó 2007 Elsevier Ltd. All rights reserved.
R1
N
R1
N
1. Introduction
OH
Nu1
O
O
O
Nu1
a
Piperazines and their spiro derivatives are included among
the most frequently occurring privileged substructures found
in compounds of therapeutic interest.1 Amongst them, 1,4-
disubstituted piperazine derivatives1b,d and 2,5-dioxopiper-
azines (cyclic dipeptides)1c,2 have been the main focus of
interest. However, 2,6-dioxopiperazine derivatives have
received scarce attention, apart from certain antitumoral
bis(2,6-dioxopiperazine) derivatives (topoisomerase II in-
hibitors),2a,3 and some inhibitors of the influenza virus endo-
nuclease, such as flutimide.4 From the synthetic point of
view, the 2,6-dioxopiperazine system could be considered
as a versatile template for the synthesis of diversity of scaf-
folds, due to the presence of the reactive endocyclic imide
group. This group is highly reactive toward nucleophiles,5
and is a potential precursor of N-acyliminium ions,6 which
are very useful and versatile reactive species in organic syn-
thesis. Perhaps, one of the most successful and versatile
methods for obtaining N-acyliminium ion precursors has
been the selective addition of hydride or organometallic re-
agent to one carbonyl group of a cyclic imide.5,6 As shown in
Scheme 1, most of the described methods for the reduction
of cyclic imides (A) to lactam derivatives (D) involve
a two-step process: a first step of addition of a nucleophile
(a metal hydride7 or an organometallic compound8) to
give a hydroxylactam (B). In the second step, this hydroxy-
lactam in acid media generates an unstable N-acyliminium
ion intermediate (C), which adds a second nucleophile
(Et3SH8b–d,9 or an organometallic compound7a,c,8a,b).
A
B
H
R1
N
R1
N
Nu1
Nu2
Nu2
b
O
Nu1
O
D
C
Nu1 and Nu2 = hydrides or organometallics
Scheme 1. General process of cyclic imide reduction to lactams.
In the course of a project focused on diversity-oriented
synthesis, we have recently reported a general method for
the synthesis of a-amino acid-derived spirocyclic 2,6-dioxo-
piperazines from a-quaternary-a-amino nitriles.10 Now,
having in mind the synthetic potential of cyclic imides, we
have explored and reported herein our studies on reduction
and reductive alkylation of 2,6-dioxopiperazine-3-spiro-
cyclohexane derivatives as a source of diverse and highly
substituted spirocyclic piperazines.
2. Results and discussion
Spirocyclic 2,6-dioxopiperazines 1a and 1b, derived from
L-phenylalanine, and 1c, derived from L-aspartic acid
(Scheme 2),10 were selected for the studies reported herein.
First, we studied the reduction of these dioxopiperazines
with NaBH4. As shown in Scheme 2, treatment of 1a–c
with 3 equiv of NaBH4 in MeOH at room temperature
quantitatively led to a (6:1) mixture of the corresponding
* Corresponding author. Tel.: +34 91 5622900; fax: +34 91 5644853;
e-mail: rosario@iqm.csic.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.022

2676
J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 2675–2683
6-hydroxy- and 2-hydroxypiperazine derivatives 2a–c and
3a–c, respectively.
In most of the reported precedents of reduction of cyclic im-
ides to lactams,8b–d,9 the reduction of the hydroxylactam B in
the second step of Scheme 1 is carried out with Et3SiH, using
BF3$OEt2 as acid to generate the intermediate N-acyl-
iminium ion C. However, taking into account our experience
in the reduction of 5-hydroxypyrrolidin-2-ones with NaBH4
in neat TFA,12 we applied these reagents to the reduction of
the major 6-hydroxypiperazines 2a–c and the minor
2-regioisomer derived from phenylalanine 3a. This reduc-
tion quantitatively yielded the oxopiperazines 7a–c and 8a.
We also tried to transform directly 2,6-dioxopiperazines
1a–c into the oxopiperazines 7a–c and 8a–c by using
NaBH4 in neat TFA. However, in contrast to the reactivity
of 1a–c toward NaBH4 in MeOH, these dioxopiperazines
were recovered unaltered. This different behavior depending
on the solvent showed up the suggested participation of
MeOH in the reduction of carbonyl groups by NaBH4.13
R2
O
N
2'
2
4
1
6
1'
3
O
6' HN
5
R1
(S)
R1
a Ph
b Ph
R2
1a
1b
1c
Me
CH2Ph
c CO2Me Me
NaBH4/MeOH
HO
R2
O
R2
N
(S)
N
∗
OH
O
+
H
R1
NOE
HN
HN
R1
(S)
(S)
2a (85%)
2b (87%)
2c (82%)
3a (15%)
3b (13%)
3c (18%)
Taking into account the potential tautomerization of the
N-acyliminium intermediate 4 to the enamine 5, and thereby
the possible racemization,14 the enantiomeric purity of the
reaction products was investigated. Firstly, we attempted
this objective by means of chiral HPLC, using a CHIRALPAK
IA column (150ꢀ4.6 mm, 5 mm) for the analysis of the
reduction products. For this purpose, the reactions shown
in Scheme 2 were repeated starting from the enantiomeric
(R)-form of the 2,6-dioxopiperazines 1a–c, derived from
the corresponding D-amino acid derivative. Then, all the
reaction products were analyzed on chiral HPLC, and the
results for each enantiomeric pair were compared. Unfortu-
nately, only the phenylalanine-derived pair 7a showed
enough enantiomeric resolution to be able to quantify
racemization (ee¼76). As an alternative methodology, the
racemization was indirectly determined by the measure of
D-incorporation at position 5, replacing NaBH4 with
NaBD4 and using deuterated solvents (CD3OD and deuter-
ated TFA) in the two steps of Scheme 2. Then, the D-incor-
poration was determined by the integral decrease for 5-H
in the 1H NMR spectra. As the racemization should be due
to the hydride addition to the enamine intermediate 5, the
percentage of D-incorporation at C5 should be twice the per-
centage of racemization. This study showed the absence of
racemization in the first step of addition of hydride to the
2,6-dioxopiperazines 1a–c, while avariable rate of racemiza-
tion was determined for the reduction of the 6-hydroxy-2-
oxopiperazines 2a–c (ee¼80 for 7a, 60 for 7b, and 0 for 7c).
TFA/NaBH4
O
TFA/NaBH4
R2
R2
O
R2
N
N
N
O
HN
HN
HN
R1
R1
R1
(S)
(S)
4
5
6
R2
R2
R2
O
O
N
N
N
O
+
5
5
HN
HN
HN
R1
R1
R1
(S)
(S)
(R)
8a (100%)
7a (100%)
7b (100%)
7c (100%)
Scheme 2. NaBH4 mediatedreductionofspirocyclic2,6-dioxopiperazines 1.
1
The H NMR spectra of 6-hydroxy-2-oxopiperazines 2a–c
showed the presence of the 6-H proton as a doublet (2a,b),
coupled to 5-H, or as a triplet (2c), coupled to 5-H and 6-OH,
at d 4.46–4.49 ppm, while the spectra of the 2-hydroxy iso-
mers 3a–c showed the presence of 2-H as a singlet at d 4.40–
4.44 ppm. The 13C NMR spectra of these hydroxylactams
showed the disappearance of one of the carbonylic carbons
and the appearance of a new carbon in the aliphatic carbon
region (83–87 ppm). The reduction position was confirmed
by the 1H–13C correlations observed in the HMBC spectra.
As indicated in Scheme 2, the stereochemistry at C6 in the
6-hydroxy-2-oxopiperazines 2a–c was assigned as 6S based
on the NOE effect observed between 6-H and 5-CH2 protons
in their 1D NOESY spectra. These results showed that the
nucleophilic attack of NaBH4 at C6 was completely dia-
stereoselective, syn to the amino acid side chain. As it has
been previously proposed for the addition of nucleophiles
to cyclic ketones,11 this high preference for the axial addi-
tion of the nucleophile on the most hindered face of the
dioxopiperazine ring could be due to the higher electronic
stabilizing syn interaction of the emerging s* orbital with
the C5–H bond than with the C5–C bond. The addition of
NaBH4 to C2 was also completely stereoselective, obtaining
only one of the possible diastereoisomers 3a–c, but, due to
the absence of NOE effects on 2-H, we could not assign
the configuration at C2.
As an alternative for the regioselective synthesis of the
6-oxopiperazine 8a, we studied its preparation by reduction
of the L-phenylalanine-derived a-amino nitrile 910 (Scheme
3). Initially, the reduction of the cyano group was unsuccess-
fully attempted by catalytic hydrogenation. Thus, using 10%
Pd(C) or Raney Ni as catalyst at room temperature and
1–3 atm of H2 pressure, conditions previously used for the
reduction of other a-amino-nitriles,15 the starting material
was recovered unaltered after 2 days. Similarly, the attempts
of cyano-reduction by hydrogen transfer from hydrazine
monohydrate16 or formate17 were also unsuccessful. Finally,
the cyano-reduction was achieved using NaBH4 in the pres-
ence of CoCl2.18 As shown in Scheme 3, the treatment of 9
with 10 equiv of NaBH4 and 2 equiv of CoCl2 in MeOH led
to a 42% of the N-unsubstituted-6-oxopiperazine 10, along
with a 21% of the N-cyclohexyl-L-phenylalanine derivative

J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 2675–2683
2677
11, resulting from the removal of HCN, followed by reduc-
tion of the intermediate imine. Alkylation of 10 by treatment
with MeI in the presence of Cs2CO3 gave a 90% of 8a.
intermediates 15 and 16, to the 2-oxopiperazines 17a and
17b. The assignment of relative configuration at C6 was
based on the NOE effects indicated in Scheme 5. According
to this assignment, and contrary to the commented addition
of NaBH4 and MeMgBr to 2,6-dioxopiperazines, the addi-
tion of hydride to the N-acyliminium ions was mainly gov-
erned by steric factors, thus, the nucleophile attacked the
intermediate 15 from the less hindered face, anti to the
amino acid side chain.
CN
CO2Me
HN
Ph
9
NaBH4/CoCl2/MeOH
R2
O
NH
H
N
2
2'
CO2Me
Ph
1
O
+
3
6
O
6'1H' N4
HN
5
(S)
HN
10 (42%)
Ph
R1
a Ph
b Ph
R2
R1
1a
1b
1c
11 (21%)
Me
CH2Ph
MeI, Cs2CO3/CH3CN
c CO2Me Me
MeMgBr/THF
O
Me
N
R2
O
CH3
O
O
N
(S)
N
OH
HN
8a (90%)
+
Ph
CH3
OH
HN
HN
(S)
(S)
NOE
R1
Scheme 3. Regioselective synthesis of 6-oxopiperazine derivatives.
13a (85%)
13c (46%)
14c (24%)
Having in mind the recently reported regioselective reduction
of glutarimide derivatives to d-lactams by treatment with
Et3N, followed by reaction with LiAlH4 in refluxing THF,19
we also studied the application of these reaction conditions
to the L-phenylalanine-derived dioxopiperazines 1a,b. In
this case, LiAlH4 reduced both carbonyl groups at C2 and
C6 to give the respective piperazines 12a and 12b (Scheme 4).
TFA/NaBH4
R2
R2
R1
O
O
N
N
CH3
CH3
HN
HN
(S)
R1
H
15
16
R1
R1
O
N
N
R2
R2
O
O
TEA, LiAlH4
O
N
(R)
N
(S)
Δ/THF
H
CH3
HN
HN
+
CH3
H
Ph
Ph
HN
HN
H
(R)
(S)
1a: R1 = Me
1b: R1 = CH2Ph
12a: R1= Me (87%)
12b: R1 = CH2Ph (98%)
NOE
NOE
R1
R1
Scheme 4. LiAlH4 mediated reduction of 2,6-dioxopiperazines.
17a (65%)
17c (86%)
In parallel to the reduction studies, the reductive alkylation
of 2,6-dioxopiperazines 1a–c was studied via reaction
with Grignard reagents, such as MeMgBr, EtMgBr, and
PhCH2MgCl. As shown in Scheme 5, the reactivity of
1-methyl-2,6-dioxopiperazines 1a and 1c toward MeMgBr
was, in part, similar to that commented above for their reduc-
tion with NaBH4 in MeOH, however, the 1-benzyl analog 1b
was unreactive. The addition of MeMgBr to 1a and 1c was
completely regioselective at C6, and, as in the case of the
reduction, also completely diastereoselective for the syn
addition with respect to the amino acid side chain, to give
the 6-hydroxy-2-oxopiperazine derivatives 13a and 13c, re-
spectively. In the case of the aspartic acid derivative 1c, the
alcohol 14c, resulting from a double addition of MeMgBr to
the methyl ester of the side chain, was obtained as side prod-
uct. The assignment of the nucleophilic addition position
was based on the 1H–13C correlations observed in the
HMBC spectra of 13a and 13c. Particularly, those of C2
with 20-H or 60-H, and 5-H with C6 and 6-CH3. In a second
reaction step, the treatment of the 6-hydroxy-2-oxopiper-
azines 13a and 13c with NaBH4 in neat TFA led, via the
Scheme 5. Reaction of 2,6-dioxopiperazines 1a–c with MeMgBr.
Steric factors were also responsible for the different reactiv-
ity of these spirocyclic 2,6-dioxopiperazines with Grignard
reagents more voluminous than MeMgBr. Thus, as shown
in Scheme 6, the reaction of 1a with EtMgBr gave a complex
mixture, which was chromatographically resolved into the
(z7:1) diastereoisomeric mixture of 6-hydroxy-2-oxopiper-
azines 18a and 19a (35%), their ketone tautomer 21a (30%),
and the tertiary alcohol 20a (20%), resulting from the attack
of EtMgBr to 21a. Interestingly, the diastereoisomeric mix-
ture of 18a and 19a was unstable due to their transformation
into the ketone 21a. In view of this transformation,8c the sec-
ond step of NaBH4 mediated reduction was carried out with
the 18a+19a+21a mixture, which gave the 6-ethylidene-2-
oxopiperazine derivative 23a (76%) as the only reaction
1
product. The NOE effects observed in the H 1D NOESY
spectrum of 23a, between the N–Me and the olefinic proton,
and between 5-H and the allylic protons, allowed the assign-
ment of E configuration to the double bond. The preference

2678
J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 2675–2683
for the deprotonation to the reduction reaction due to the
slight increase in volume from the Me to the Et group
showed that the entrance of hydride was strongly limited
by the high steric crowding in the N-acyliminium ion. Sim-
ilarly, the steric hindrance to the entrance of the nucleophile
could be the reason for the unreactivity of the 2,6-dioxopi-
perazines 1a–c toward PhCH2MgCl.
ring is mainly governed by electronic factors, which deter-
mine the preferential entrance of the nucleophile to C6
from the most hindered face, syn to the amino acid side
chain. However, in the resulting 6-hydroxypiperazines, the
diastereoselectivity of the acid-mediated dehydration/
NaBH4 addition is determined by steric factors, to give the
product of nucleophilic attack from the less hindered face,
anti to the amino acid side chain. This second reduction
step produces partial or total racemization. The steric crowd-
ing of the 3-spiro-2,6-dioxopiperazine skeleton limits its
reactivity to hydride and low volume Grignard reagents.
O
Me
N
O
HN
Ph
1a
4. Experimental
4.1. General
EtMgBr/THF
O
O
O
Me
OH
Me
Et
Me
OH
N
N
N
H
All reagents were of commercial quality. Solvents were dried
and purified by standard methods. Analytical TLC was per-
formed on aluminum sheets coated with a 0.2 mm layer of
silica gel 60 F254. Silica gel 60 (230–400 mesh) was used
for flash chromatography. Preparative circular chromato-
graphy was performed on 20 cm diameter glass plates coated
with a 1-mm layer of silica gel PF254. Analytical RP-HPLC
was performed on a Novapak C18 (3.9ꢀ150 mm, 4 mm) col-
umn, with a flow rate of 1 mL/min, and using a tunable UV
detector set at 214 nm. Mixtures of CH3CN (solvent A) and
0.05% TFA in H2O (solvent B) were used as mobile phases.
Analytical chiral HPLC was carried out on a CHIRALPAK
IA (150ꢀ4.6 mm, 5 mm) column of Daicel Chemical Indus-
tries Ltd., with a flow rate of 1 mL/min. EtOH of 10–1% in
hexane was tried as mobile phase, although the best enantio-
Et
+
+
Et
Ph
OH
HN
HN
HN
Et
Ph
Ph
20a (20%)
18a
19a
18a + 19a (7:1, 35%)
Me
NH
O
O
HN
Et
Ph
21a (30%)
NaBH4/TFA
O
1
mer resolution was obtained with 1% of EtOH. H NMR
O
Me
N
Me
N
spectra were recorded at 300 or 400 MHz, using TMS as
reference, and 13C NMR spectra were recorded at 75 or
100 MHz. The NMR spectral assignment was based on
COSY, HSQC, and HMBC spectra. ES-MS spectra were per-
formed, in positive mode, using MeOH as solvent.
H
H
HN
Me
HN
Me
Ph
Ph
22a
4.2. General procedure for the NaBH4 mediated reduc-
tion of 2,6-dioxopiperazine-3-spirocyclohexanes 1a–c.
Synthesis of the hydroxypiperazines 2a–c and 3a–c
NOE
O
Me
N
H
NaBH4 (28.4 mg, 0.75 mmol) was slowly added to a 0 ꢁC
cooled solution of the corresponding 2,6-dioxopiperazines
1a–c10 (0.25 mmol) in MeOH (4 mL). After reaching
room temperature, the reaction mixture was stirred for 2 h.
Then, the solvent was removed under reduced pressure and
the residue was dissolved in CH2Cl2 (20 mL). This solution
was successively washed with H2O (5 mL) and brine (5 mL),
dried over Na2SO4, and evaporated to dryness. The residue
was purified by flash chromatography, using 6–35% gradient
of MeOH in CH2Cl2 as eluant. In this purification the 6-hy-
droxy-2-oxopiperazines 2a–c, of higher Rf, were separated
from their regioisomers 3a–c. Significant analytical and
spectroscopic data of these hydroxypiperazines are summa-
rized in Tables 1 and 2.
HN
Me
H
NOE
Ph
23a (76%)
Scheme 6. Reaction of the 2,6-dioxopiperazine 1a with EtMgBr.
The racemization rate in the two steps of the reductive alkyl-
ations of Schemes 5 and 6 was also determined by chiral
HPLC and by the measure of D-incorporation at C5. Both
methodologies showed a complete racemization (ee¼0) for
the second reaction step in the synthesis of 17a, 17c, and
23a.
3. Conclusion
4.3. General procedure for the NaBH4 mediated reduc-
tion of hydroxypiperazines. Synthesis of the oxopiper-
azines 7a–c, 8a, and 17a,c
In conclusion, the overall results herein disclosed show the
potential of spirocyclic 2,6-dioxopiperazine as a source of
diverse piperazine derivatives, via regio- and diastereoselec-
tive reduction and reductive alkylation. The addition of
NaBH4 or Grignard reagents to the 2,6-dioxopiperazine
NaBH4 (23.8 mg, 0.63 mmol) was slowly added to a 0 ꢁC
cooled solution of the corresponding hydroxypiperazines

J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 2675–2683
Table 1. Significant analytical and spectroscopic data of 6-hydroxy-2-oxopiperazines
2679
R2
O
N
2
4
2'
1'
OH
R3
R1
1
3
6
5
6' HN
2a
2b
2c
13a
13c
18a+19a
R1
Ph
Me
H
C17H24N2O2
85
289.2
169–171
(Benzene)
2.31 (30:70)
Ph
CH2Ph
H
C23H28N2O2
87
365.1
156–157
(Benzene)
3.84 (40:60)
CO2Me
Me
H
C13H22N2O4
82
271.2
Ph
Me
Me
C18H26N2O2
85
CO2Me
Me
Me
C14H24N2O4
46
Ph
Me
Et
C19H28N2O2
35
317.1
Syrup
R2
R3
Formulaa
Yield (%)
ES-MS [M+1]+
Mp (ꢁC)
303.2
Syrup
285.1
Syrup
Syrup
tR (min) (A:B)b
1.59 (25:75)
2.11 (50:50)
1.89 (25:75)
7.79 (14%) and 8.39
(86%) (25:75)
1H NMRc
5-H
2.94
2.51, 3.25
1.94
1.01–1.71
7.23
2.85
3.00
2.49, 3.15
2.09
1.11–1.80
7.14–7.33
4.38, 5.11, 7.14–7.33
4.49
7.5
3.21
2.52, 2.87
2.09
1.25–1.93
3.72
2.92
2.92
2.45, 3.20
1.95
1.06–1.58
7.30
2.91
3.23
2.34, 2.80
2.04
1.24–1.90
3.72
2.89
1.32
—
2.49
3.09, 3.23
2.50, 2.56, 2.62
1.10–1.98
1.10–1.98
7.13–7.77
5-CH2
20-Hax
Cyclohexyl
R1
R2
2.89, 2.92
0.90, 1.04, 1.87, 1.91
—-
R3
4.46
7.5
4.46
7.5
1.46
—
J5,6 (Hz)
OH
NDd
2.74
NDd
NDd
NDd
13C NMRe
C2
C3
C5
175.0
58.1
55.7
84.4
174.5
58.1
56.1
81.9
174.9
58.3
51.9
83.8
36.7
174.2
58.6
60.0
86.6
174.5
58.9
56.0
85.9
35.2
NDd
NDd
NDd
NDd
NDd
NDd
C6
5-CH2
38.3
38.2
35.9
R1
126.9, 128.7,
129.0, 137.8
30.1
126.6, 128.4,
128.7, 137.2
44.84, 127.0, 128.6,
129.1 137.5
—
52.0, 172.4
127.0, 128.7,
128.9, 138.5
26.8
52.0, 173.1
R2
30.1
26.7
NDd
R3
Cyclohexyl
—
19.8, 20.6, 24.8,
29.4, 35.6
—
20.3, 20.7, 25.1,
30.1, 35.6
19.1
19.7, 20.7, 24.7,
29.1, 36.2
18.9
20.5, 20.9,
25.1, 30.3, 36.3
NDd
NDd
19.7, 20.5, 24.6,
30.1, 35.7
a
Satisfactory analysis for C, H, and N.
Novapak C18 (3.9ꢀ150 mm, 4 mm). A¼CH3CN, B¼0.05% TFA in H2O.
b
c
d
e
Spectra registered at 300 or 400 MHz, in CDCl3, assigned with the help of COSY spectra.
ND¼not determined.
Spectra registered at 75 or 100 MHz, in CDCl3, assigned with the help of HSQC and HMBC spectra.
2a–c, 3a, and 13a,c (0.21 mmol) in TFA (3 mL). After
reaching room temperature, the reaction mixture was stirred
for 3 h. Then, the solvent was removed under reduced
pressure and the residue was dissolved in CH2Cl2
(20 mL). This solution was successively washed with H2O
(5 mL) and brine (5 mL), dried over Na2SO4, and evapo-
rated to dryness. The residue was purified by flash chroma-
tography, using 10–40% gradient of MeOH in CH2Cl2 as
eluant. The significant analytical and spectroscopic data
of the 6-oxopiperazine 8a are summarized in Table 2, while
those of the 2-oxopiperazines 7a–c and 17a,c are summa-
rized in Table 3.
room temperature, the reaction mixture was stirred for 1 h.
Then, the solvent was removed under reduced pressure and
the residue was dissolved in EtOAc (20 mL). This solution
was successively washed with H2O (5 mL) and brine
(5 mL), dried over Na2SO4, and evaporated to dryness.
The residue was purified by flash chromatography, using
10–50% gradient of EtOAc in hexane as eluant. In this puri-
fication the 6-oxopiperazine 10 (49.2 mg, 42%), whose sig-
nificant analytical and spectroscopic data are summarized in
Table 2, was separated from N-cyclohexyl-L-phenylalanine
methyl ester (11).
4.4.1. N-Cyclohexyl-L-phenylalanine methyl ester (11).
Syrup (25.7 mg, 21%); HPLC [Novapak C18 (3.9ꢀ
150 mm, 4 mm) (A:B, 25:75)] tR 5.46 min; 1H NMR
(300 MHz, CDCl3) 1.00–1.76 (m, 10H, cyclohexyl), 2.27
(m, 1H, 10-H), 2.79 (dd, 1H, J¼7 and 13.5 Hz, 3-H), 2.89
(dd, 1H, J¼7 and 13.5 Hz, 3-H), 3.54 (s, 3H, OCH3), 3.58
(t, 1H, J¼7 Hz, 2-H), 7.17 (m, 5H, Ph); ES-MS m/z 262.0
[M+1]+. Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N,
5.36. Found: C, 73.74; H, 8.92; N, 5.16.
4.4. Synthesis of (5S)-5-phenylmethyl-6-oxopiperazine-
3-spirocyclohexane (10) and N-cyclohexyl-L-phenyl-
alanine methyl ester (11)
NaBH4 (171.7 mg, 4.5 mmol) and CoCl2 (118 mg,
0.9 mmol) were slowly added to a 0 ꢁC cooled solution of
N-(1-cyanocyclohexyl)-L-phenylalanine methyl ester (9)10
(128.7 mg, 0.45 mmol) in MeOH (7 mL). After reaching

2680
J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 2675–2683
Table 2. Significant analytical and spectroscopic data of 6-oxopiperazines
R3
R2
N
∗
O
HN
R1
3a
3b
3c
8a
10
R1
Ph
Me
OH
C17H24N2O2
15
289.2
Ph
CH2Ph
OH
C23H28N2O2
13
365.2
CO2Me
Me
OH
C13H22N2O4
18
271.2
Ph
Me
H
C17H24N2O
100
273.2
Ph
H
H
R2
R3
Formulaa
Yield (%)
ES-MS [M+1]+
tR (min) (A:B)b
C16H22N2O
42
259.3
2.32 (30:70)
3.50 (40:60)
2.77 (25:75)
2.83 (25:75)
2.06 (25:75)
1H NMRc
2-H
5-H
4.42
3.66
4.40
3.80
4.44
3.88
3.02, 3.07
3.52
2.94, 3.04
3.63
5-CH2
Cyclohexyl
R1
2.67, 3.52
1.11–1.67
7.27
2.75, 3.59
1.02–1.62
7.12–7.38
4.22, 5.22,
7.12–7.38
2.57, 3.11
1.15–1.62
3.70
2.77, 3.28
1.29–1.70
7.27
2.88, 3.29
1.19–1.64
7.21
R2
3.01
3.00
2.91
6.12
13C NMRd
C2
C3
C5
86.3
54.0
56.0
170.5
39.9
126.6, 128.7,
129.2, 138.6
32.1
83.1
58.4
56.5
170.3
40.3
126.7, 128.5,
129.4, 137.4
47.3, 127.5, 128.7,
129.4, 137.6
21.2, 21.3,
25.5, 31.8, 34.6
87.0
55.6
51.0
173.0
38.7
51.6, 172.6
60.7
50.7
56.2
170.3
39.9
127.3, 129.3,
130.2, 140.6
36.7
51.9
49.6
54.6
171.8
38.0
126.6, 128.5,
129.2, 138.1
—
C6
5-CH2
R1
R2
33.8
Cyclohexyl
20.9, 21.6, 25.6,
29.8, 34.4
20.8, 21.2, 25.7,
29.9, 33.8
22.5, 27.1,
32.1, 38.1
21.5, 21.6, 25.9,
30.6, 37.1
a
Syrups, satisfactory analysis for C, H, and N.
Novapak C18 (3.9ꢀ150 mm, 4 mm). A¼CH3CN, B¼0.05% TFA in H2O.
b
c
d
Spectra registered at 300 or 400 MHz, in CDCl3, assigned with the help of COSY spectra.
Spectra registered at 75 or 100 MHz, in CDCl3, assigned with the help of HSQC and HMBC spectra.
4.5. Regioselective synthesis of (5S)-1-methyl-5-phenyl-
methyl-6-oxopiperazine-3-spirocyclohexane (8a)
The combined filtrates were evaporated to dryness and the
residue was dissolved in EtOAc (20 mL). This solution
was successively washed with H2O (5 mL) and brine
(5 mL), dried over Na2SO4, and evaporated to dryness.
The residue was purified by flash chromatography, using
20–45% gradient of EtOAc in hexane as eluant.
MeI (16.3 mL, 0.26 mmol) and Cs2CO3 (85.2 mg,
0.26 mmol) were successively added under argon to a solu-
tion of the 6-oxopiperazine 10 in dry CH3CN (2.5 mL). This
reaction mixture was stirred at 50 ꢁC for 2 h. Then, the
solvent was evaporated and the residue was dissolved in
CH2Cl2 (20 mL). The solution was successively washed
with H2O (5 mL) and brine (5 mL), dried over Na2SO4,
and evaporated to dryness. The residue was purified by
circular chromatography, using 15–25% gradient of EtOAc
in hexane as eluant, to obtain the 1-methyl-6-oxopiperazine
8a (43 mg, 90%).
4.6.1. (5S)-1-Methyl-5-phenylmethylpiperazine-3-spiro-
cyclohexane (12a). Syrup (33.7 mg, 87%); HPLC [Novapak
1
C18 (3.9ꢀ150 mm, 4 mm) (A:B, 25:75)] tR 1.79 min; H
NMR (300 MHz, CDCl3) d 1.08–1.57 (m, 10H, cyclohexyl),
1.62 (t, 1H, J¼10.5 Hz, 6-H), 1.64 (d, 1H, J¼11 Hz, 2-H),
2.18 (s, 3H, 1-CH3), 2.55 (dd, 1H, J¼8 and 13 Hz,
5-CH2), 2.64 (dd, 1H, J¼6 and 13 Hz, 5-CH2), 2.67 (d,
1H, J¼11 Hz, 2-H), 2.73 (dd, 1H, J¼2.5 and 10.5 Hz,
6-H), 3.26 (m, 1H, J¼2.5, 6, and 8 Hz, 5-H), 7.23 (m, 5H,
4.6. General procedure for the synthesis of piperazines
12a and 12b
Ph); 13C NMR (75 MHz, CDCl3) d 21.6 and 21.8 (C3 and
0
0
0
0
0
C5 ), 26.2 (C4 ), 31.8 and 38.5 (C2 and C6 ), 41.0 (5-CH2),
46.6 (CH3), 50.2 (C5), 51.4 (C3), 62.1 (C6), 64.7 (C2),
126.3, 128.4, 129.0, and 138.5 (Ph); ES-MS m/z 259.3
[M+1]+. Anal. Calcd for C17H26N2: C, 79.02; H, 10.14; N,
10.84. Found: C, 79.22; H, 10.24; N, 10.72.
TEA (25.1 mL, 0.18 mmol) was added under argon to a solu-
tion of the corresponding 2,6-dioxopiperazines 1a and 1b
(0.15 mmol) in dry THF (4 mL). After 30 min of stirring
at room temperature, LiAlH4 (17.1 mg, 0.45 mmol) was
added to the reaction mixture, and it was heated at reflux
temperature for 3 h. Then, the reaction mixture was cooled
at room temperature and saturated solution of NH4Cl
(1 mL) was added to destroy the excess of LiAlH4. The pre-
cipitated Al(OH)3 was filtered off and washed with THF.
4.6.2. (5S)-1,5-Di(phenylmethyl)piperazine-3-spirocyclo-
hexane (12b). Syrup (50.1 mg, 98%); HPLC [Novapak C18
1
(3.9ꢀ150 mm, 4 mm) (A:B, 40:60)] tR 8.42 min; H NMR
(300 MHz, CDCl3) d 1.04–1.53 (m, 10H, cyclohexyl), 1.59

J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 2675–2683
Table 3. Significant analytical and spectroscopic data of 2-oxopiperazines
2681
R2
O
N
2
2'
1
R3
R1
3
6
1'
6'HN4
5
7a
7b
7c
17a
17c
R1
Ph
Me
H
C17H24N2O
100
273.2
Ph
CH2Ph
H
C23H28N2O
100
349.2
CO2Me
Me
H
C13H22N2O3
100
255.1
Ph
Me
Me
C18H26N2O
70
287.3
CO2Me
Me
Me
C14H24N2O3
90
269.2
R2
R3
Formulaa
Yield (%)
ES-MS [M+1]+
tR (min) (A:B)b
3.47 (25:75)
17.20 (25:75)
1.64 (25:75)
1.78 (50:50)
1.82 (25:75)
1H NMRc
5-H
6-H
4.38
3.80
4.35
3.34
3.15
2.58, 2.69
1.97
1.10–1.65
7.22–7.33
2.91
1.23
3.5
3.63
3.22
2.37, 2.46
2.05
1.15–1.87
3.71
2.89
1.16
3.5
3.28, 3.79
3.06, 3.56
2.28
1.49–2.24
7.32
2.85
3.18, 3.50
2.94, 3.18
2.23
1.34–2.09
7.22–7.33
4.38, 5.11, 7.14–7.33
—
3.58, 3.89
2.98, 3.24
2.19–2.30
1.35–2.30
3.73
2.92
—
4.5 and 11.5
5-CH2
20-Hax
Cyclohexyl
R1
R2
R3
J5,6 (Hz)
—
4.5 and 11.5
4 and 11.5
13C NMRd
C2
C3
C5
167.1
62.2
49.7
49.9
172.3
61.6
50.6
51.4
172.6
63.7
47.6
50.7
34.5
174.0
58.8
52.4
58.2
172.4
59.9
48.7
57.7
36.2
C6
5-CH2
36.4
239.2
38.3
R1
127.7, 129.1,
129.5, 135.1
32.9
128.7, 130.0,
130.6, 138.7
51.4, 128.7, 130.0,
130.6, 138.7
—
53.4, 168.4
126.7, 128.7,
128.8, 138.2
34.2
52.6, 172.4
R2
35.7
31.3
R3
Cyclohexyl
—
20.4, 20.8, 24.3,
31.1, 34.4
—
21.3, 21.5, 25.6,
31.9, 33.7
12.6
20.2, 20.9, 24.9,
30.3, 36.2
13.1
20.9, 21.2, 25.4,
30.1, 34.7
21.6, 22.2, 26.3
32.4, 35.7
a
Satisfactory analysis for C, H, and N.
Novapak C18 (3.9ꢀ150 mm, 4 mm). A¼CH3CN, B¼0.05% TFA in H2O.
b
c
d
Spectra registered at 300 or 400 MHz, in CDCl3, assigned with the help of COSY spectra.
Spectra registered at 75 or 100 MHz, in CDCl3, assigned with the help of HSQC and HMBC spectra.
(d, 1H, J¼11 Hz, 2-H), 1.74 (t, 1H, J¼10.5 Hz, 6-H), 2.47
(dd, 1H, J¼8.5 and 13.5 Hz, 5-CH2), 2.58 (d, 1H,
J¼11 Hz, 2-H), 2.60 (dd, 1H, J¼5.5 and 13.5 Hz, 5-CH2),
2.75 (dd, 1H, J¼2.5 and 10.5 Hz, 6-H), 3.21 (m, 1H,
J¼2.5, 5.5, and 8.5 Hz, 5-H), 3.25 (d, 1H, J¼13.5 Hz,
1-CH2), 3.50 (d, 1H, J¼13.5 Hz, 1-CH2), 7.11–7.29 (m,
10H, Ph); 13C NMR (75 MHz, CDCl3) d 21.6 and 21.7
temperature for 3 h. Afterward, the reaction mixture was
evaporated to dryness and the residue was dissolved in
CH2Cl2 (20 mL). The solution was successively washed
with H2O (5 mL) and brine (5 mL), dried over Na2SO4,
and evaporated to dryness. The residue was purified by
circular chromatography, using 15–40% gradient of EtOAc
in hexane as eluant, to give the compounds shown in
Schemes 5 and 6. Significant analytical and spectroscopic
data of the 6-hydroxy-2-oxopiperazines 13a, 13c, and
18a+19a are summarized in Table 1.
0
0
0
0
0
(C3 and C5 ), 26.2 (C4 ), 31.8 and 38.4 (C2 and C6 ), 41.0
(5-CH2), 50.5 (C5), 51.6 (C3), 60.6 (C6), 61.9 (C2), 62.9
(1-CH2), 126.3, 126.8, 128.1, 128.4, 128.6, 129.0, 138.8,
and 138.9 (Ph); ES-MS m/z 335.2 [M+1]+. Anal. Calcd for
C23H30N2: C, 82.59; H, 9.04; N, 8.37. Found C, 82.43; H,
9.24; N, 8.57.
4.7.1. (5S)-5-(2-Hydroxy-2-methyl)propyl-1-methyl-
2,6-dioxopiperazine-3-spirocyclohexane (14c). Syrup
(12.9 mg, 24%); HPLC [Novapak C18 (3.9ꢀ150 mm,
4 mm) (A:B, 25:75)] tR 4.03 min; 1H NMR (300 MHz,
CDCl3) d 1.31 and 1.33 [2s, 6H, Me (isopropyl)], 1.25–
1.62 (m, 8H, cyclohexyl), 1.69 (dd, 1H, J¼10.5 and
14.5 Hz, 5-CH2), 2.03 (m, 1H, 20-Hec), 2.21 (m, 1H,
60-Hax), 2.44 (dd, 1H, J¼2.5 and 14.5 Hz, 5-CH2), 3.12 (s,
3H, 1-Me), 3.86 (dd, 1H, J¼2.5 and 10.5 Hz, 5-H); 13C
4.7. General procedure for the reaction of 2,6-dioxo-
piperazines 1a–c with Grignard reagents. Synthesis
of hydroxypiperazines 13a,c, 18a, and 19a
The corresponding Grignard reagent, MeMgBr, EtMgBr
(3 M solution in diethyl ether, 200 mL, 0.6 mmol), or
PhCH2MgCl (1 M solution in diethyl ether, 600 mL,
0.6 mmol), was added under argon to a ꢂ40 ꢁC cooled solu-
tion of the 2,6-dioxopiperazines 1a–c (0.2 mmol) in dry
THF (3 mL), and the reaction mixture was stirred at this
0
0
0
NMR (75 MHz, CDCl3) d 20.5 (C3 and C5 ), 24.3 (C4 ),
26.7 (1-Me), 28.2 and 31.1 [Me (isopropyl)], 29.2 and 34.6
0
0
(C2 and C6 ), 42.2 (5-CH2), 51.3 (C5), 58.9 (C3), 70.5 (iso-
propyl), 173.1 (C6), 176.1 (C2); ES-MS m/z 269.2 [M+1]+.

2682
J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 2675–2683
Anal. Calcd for C14H24N2O3: C, 62.66; H, 9.01; N, 10.44.
Found: C, 62.46; H, 8.79; N, 10.62.
ES-MS m/z 299.3 [M+1]+. Anal. Calcd for C19H26N2O:
C, 76.47; H, 8.78; N, 9.39. Found: C, 76.59; H, 8.48;
N, 9.17.
4.7.2. N-Methyl-1-[(2S)-3-ethyl-3-hydroxy-1-phenyl-
pentan-2-yl]aminocyclohexylcarboxamide (20a). Syrup
(24.2 mg, 20%); HPLC [Novapak C18 (3.9ꢀ150 mm,
4 mm) (A:B, 25:75)] tR 9.95 min; 1H NMR (300 MHz,
CDCl3) d 0.70 and 0.90 [2t, 6H, J¼7.5 Hz, CH3 (Et)],
0.95–1.82 (m, 10H, cyclohexyl), 1.45 and 1.49 [2q, 4H,
CH2 (Et)], 2.61 (dd, 1H, J¼7.5 and 14.5 Hz, CH2–Ph),
2.68 (dd, 1H, J¼6.5 and 14.5 Hz, CH2–Ph), 2.74 (d, 3H,
J¼5 Hz, NH–CH3), 3.17 (dd, 1H, J¼6.5 and 7.5 Hz, NH–
CH), 6.37 (br s, 1H, NH–CH3), 7.23 (m, 5H, Ph); 13C
NMR (75 MHz, CDCl3) d 7.2 and 7.3 [CH3 (Et)], 22.0,
22.1, 25.4, 33.2, 35.2, and 60.5 (cyclohexyl), 26.3 (NH–
CH3), 28.3 and 28.6 [CH2 (Et)], 38.6 (CH2–Ph), 57.6
(NH–CH), 74.7 (C–OH), 126.1, 128.3, 129.1, and 140.1
(Ph), 177.3 (CONH); ES-MS m/z 347.1 [M+1]+. Anal. Calcd
for C21H34N2O2: C, 72.79; H, 9.89; N, 8.08. Found: C,
73.12; H, 10.04; N, 7.96.
4.9. Determination of the racemization ratio by the
measure of deuterium incorporation
The procedures described above for the synthesis of oxo-
piperazines 7a–c, 8a, 17a, 17c, and 23a were carried out
replacing NaBH4 by NaBD4 and the corresponding solvents
MeOH and TFA by CD3OD and deuterated TFA. The result-
ing products were chromatographically (TLC and HPLC)
identical to the respective nondeuterated compounds, as
1
well as their H NMR data, except for the commented de-
crease in the signals corresponding to the protons, which
have been partial or completely replaced by deuterium.
The 50% decrease in the integral of 5-H was used as a mea-
sure for the percentage of configuration inversion at C5 for
the calculation of the enantiomer excesses.
4.7.3. N-Methyl-1-[(2S)-3-oxo-1-phenylpentan-2-yl]-
aminocyclohexylcarboxamide (21a). Syrup (33.2 mg,
30%); HPLC [Novapak C18 (3.9ꢀ150 mm, 4 mm) (A:B,
Acknowledgements
This work was supported by CICYT (SAF2003-07207-C02-
01). J.A.G.-V holds a postgraduate I3P fellowship from the
CSIC.
1
25:75)] tR 17.27 min; H NMR (300 MHz, CDCl3) d 0.97
[(t, 3H, J¼7.5 Hz, CH3 (Et)], 1.02–1.92 (m, 10H, cyclo-
hexyl), 2.18 (d, 3H, J¼5 Hz, NH–CH3), 2.36 (dd, 1H,
J¼9.5 and 13.5 Hz, CH2–Ph), 2.39 [q, 2H, J¼7.5 Hz, CH2
(Et)], 2.71 (dd, 1H, J¼4.5 and 13.5 Hz, CH2–Ph), 3.29
(dd, 1H, J¼4.5 and 9.5 Hz, NH–CH), 6.05 (br s, 1H, NH–
CH3), 7.22 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3)
d (ppm): 7.5 [CH3 (Et)], 21.6, 22.0, 25.2, 31.8, 36.8, and
61.5 (cyclohexyl), 25.8 (NH–CH3), 35.3 [CH2 (Et)], 41.9
(CH2–Ph), 63.6 (NH–CH), 126.9, 128.6, 129.6, and 138.0
(Ph), 176.7 (CONH), 214.9 (COEt); ES-MS m/z 317.1
[M+1]+. Anal. Calcd for C19H28N2O2: C, 72.12; H, 8.92;
N, 8.85. Found: C, 72.22; H, 8.75; N, 9.11.
References and notes
1. For some recent reviews on privileged structures, see: (a)
Patchett, A. A.; Nargund, R. P. Annual Reports in Medicinal
Chemistry; Doherty, A. M., Ed.; Academic: San Diego, CA,
2000; Vol. 35, pp 289–298; (b) Klabunde, T.; Hessler, G.
ChemBioChem 2002, 3, 928–944; (c) Horton, D. A.; Bourne,
G. T.; Smythe, M. L. J. Comput. Aided Mol. Des. 2002, 16,
415–430; (d) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893–930; (e) Bondensgaard, K.;
Ankersen, M.; Thøgersen, H.; Hansen, B. S.; Wulff, B. S.;
Bywater, R. P. J. Med. Chem. 2004, 47, 888–899.
4.8. Synthesis of 6-[(E)-ethylidene-1-methyl-5-phenyl-
methyl-2-oxopiperazine-3-spirocyclohexane (23a)
2. For some reviews on 2,5-dioxopiperazines, see: (a) Witiak,
D. T.; Wei, Y. Progress in Drug Research; Jucker, E., Ed.;
NaBH4 (18.7 mg, 0.49 mmol) was slowly added to a 0 ꢁC
cooled solution of a mixture of the 6-hydroxypiperazines
18a+19a and their ketone epimer 21a (52.0 mg,
0.16 mmol) in TFA (3 mL). After reaching room tempera-
ture, the reaction mixture was stirred for 3 h. Then, the sol-
vent was removed under reduced pressure and the residue
was dissolved in CH2Cl2 (20 mL). This solution was succes-
sively washed with H2O (5 mL) and brine (5 mL), dried
over Na2SO4, and evaporated to dryness. The residue was
purified by flash chromatography, using 10–40% gradient
of MeOH in CH2Cl2 as eluant, to give 23a (37.2 mg,
76%); HPLC [Novapak C18 (3.9ꢀ150 mm, 4 mm) (A:B,
ꢀ
Birkhauser: Basel, 1990; Vol. 35, pp 249–363; (b) Prasad, C.
Peptides 1995, 16, 151–164; (c) Dinsmore, C. J.; Beshore,
D. C. Tetrahedron 2002, 58, 3297–3312; (d) Fischer, P. M.
J. Pept. Sci. 2003, 9, 9–35.
3. (a) Andoh, T.; Ishida, R. Biochim. Biophys. Acta 1998, 1400,
155–171; (b) Andoh, T. Biochimie 1998, 80, 235–246; (c)
Nair, V. N.; Witiak, D. T. J. Chem. Educ. 1998, 65, 534–
538.
4. (a) Tomassini, J. E.; Davies, M. E.; Hastings, J. C.; Lingham,
R.; Mojena, M.; Raghoobar, S. L.; Singh, S. B.; Tkacz, J. S.;
Goetz, M. A. Antimicrob. Agents Chemother. 1996, 40, 1189–
1193; (b) Singh, S. B.; Tomassini, J. E. J. Org. Chem. 2001,
66, 5504–5516.
5. (a) Challis, B. C.; Challis, J. A. Comprehensive Organic
Chemistry. Synthesis and Reactions of Organic Compounds;
Barton, D., Ollis, W. D., Eds.; Pergamon: Oxford, 1979;
Vol. 2, pp 957–1065; (b) Hiemstra, H.; Speckamp, W. N.
Comprehensive Organic Synthesis. Selectivity, Strategy and
Efficiency in Modern Organic Chemistry; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 1047–
1082.
1
25:75)] tR 9.01 min; H NMR (500 MHz, CDCl3) d 1.24–
1.65 (m, 9H, cyclohexyl), 1.51 [d, 3H, J¼7 Hz, CH3 (ethyl-
idene)], 2.03 (m, 1H, 20-Hax), 2.87 (dd, 1H, J¼6 and
13.5 Hz, 5-CH2), 2.91 (dd, 1H, J¼6 and 13.5 Hz, 5-CH2),
2.98 (s, 3H, 1-CH3), 4.19 (t, 1H, J¼6 Hz, 5-H), 4.96 [q,
1H, J¼7 Hz, CH (ethylidene)], 7.23 (m, 5H, Ph); 13C
NMR (125 MHz, CDCl3) d 12.0 [CH3 (ethylidene)], 21.1,
21.3, 25.6 (C9), 31.6 and 33.7 (cyclohexyl), 32.0 (1-CH3),
40.6 (5-CH2), 51.4 (C5), 57.0 (C3), 104.6 [CH (ethylidene)],
126.7, 128.3, 129.4, and 137.5 (Ph), 139.7 (C6), 175.0 (C2);

J. A. Gonzaꢀlez-Vera et al. / Tetrahedron 63 (2007) 2675–2683
2683
ꢀ
12. (a) Gutierrez-Rodrıguez, M.; Garcıa-Lopez, M. T.; Herranz, R.
Tetrahedron 2004, 60, 5177–5183; (b) Alonso De Diego, S. A.;
ꢀ
ꢀ
ꢀ
6. (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367–4416; (b) Speckamp, W. N.; Moolenaar, M. J. Tetra-
hedron 2000, 56, 3817–3856; (c) Maryanoff, B. E.; Zhang,
H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431–1628.
7. (a) Ryu, Y.; Kim, G. J. Org. Chem. 1995, 60, 103–108; (b) Pilli,
R. A.; Russowsky, D. J. Org. Chem. 1996, 61, 3187–3190; (c)
Ostendorf, M.; Romagnoli, R.; Pereiro, I. C.; Roos, E. C.;
Moolenaar, M. J.; Speckamp, W. N.; Hiemstra, H. Tetrahedron:
Asymmetry 1997, 8, 1773–1789; (d) Hsu, R.-T.; Cheng, L.-M.;
Chang, N.-C.; Tai, H.-M. J. Org. Chem. 2002, 67, 5044–5047;
(e) Gill, C. D.; Greenhalgh, D. A.; Simpkins, N. S. Tetrahedron
2003, 59, 9213–9230; (f) Simpkins, N. S.; Gill, C. D. Org. Lett.
2003, 5, 535–537.
ꢀ
Gutierrez-Rodrıguez, M.; Perez de Vega, M. J.; Gonzalez-
Mun˜iz, R.; Herranz, R.; Martın-Martınez, M.; Cenarruzabeitia,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
E.; Frechilla, D.; Del Rıo, J.; Jimeno, M. L.; Garcıa-Lopez,
M. T. Bioorg. Med. Chem. Lett. 2006, 16, 3396–3400.
ꢀ
ꢀ
13. Smith, M. B.; March, J. March’s Advanced Organic Chemistry.
Reactions, Mechanisms, and Structure, 5th ed.; Wiley-
Interscience: New York, NY, 2001; pp 1197–1203.
14. (a) Beausoleil, E.; L’Archeveque, B.; Belec, L.; Atfani, M.;
ꢀ
Lubell, W. D. J. Org. Chem. 1996, 61, 9447–9454; (b) Martın-
Martınez, M.; Bartolome-Nebreda, J. M.; Gomez-Monterrey,
ꢀ
ꢀ
ꢀ
˜
ꢀ
ꢀ
I.; Gonzalez-Muniz, R.; Garcıa-Lopez, M. T.; Ballaz, S.;
Barber, A.; Fortun˜o, A.; Del Rıo, J.; Herranz, R. J. Med.
ꢀ
8. (a) Schuch, C. M.; Pilli, R. A. Tetrahedron: Asymmetry 2000,
11, 753–764; (b) Schuch, C. M.; Pilli, R. A. Tetrahedron:
Asymmetry 2002, 13, 1973–1980; (c) Liu, L.-X.; Ruan, Y.-P.;
Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69, 6001–
6009; (d) Chen, M.-C.; He, M.-Z.; Zhou, X.; Huang, L.-Q.;
Ruan, Y.-P.; Huang, P.-Q. Tetrahedron 2005, 61, 1335–1344.
9. Dixon, R. A.; Jones, S. Tetrahedron: Asymmetry 2002, 13,
1115–1119.
Chem. 1997, 40, 3402–3407.
ꢀ
ꢀ
ꢀ
ꢀ
˜
15. Suarez-Gea, M. L.; Garcıa-Lopez, M. T.; Gonzalez-Muniz, R.;
Herrero, S.; Herranz, R. Tetrahedron Lett. 1996, 37, 2083–
2084.
ꢀ
ꢀ
16. (a) Herrero, S.; Garcıa-Lopez, M. T.; Herranz, R. J. Org. Chem.
2003, 68, 4582–4585; (b) Herrero, S.; Garcıa-Lopez, M. T.;
ꢀ
ꢀ
ꢀ
Cenarruzabeitia, E.; Del Rıo, J.; Herranz, R. Tetrahedron
2003, 59, 4491–4499.
ꢀ
ꢀ
ꢀ
10. Gonzalez-Vera, J. A.; Garcıa-Lopez, M. T.; Herranz, R. J. Org.
17. Gowda, S.; Gowda, C. Tetrahedron 2002, 58, 2211–2213.
18. (a) Osby, J. O.; Heinzman, S. W.; Ganem, B. J. Am. Chem. Soc.
1986, 108, 67–72; (b) Gaucher, A.; Bintein, F.; Wakselman,
M.; Mazaleyrat, J. P. Tetrahedron Lett. 1998, 39, 575–578.
19. Chen, C.-Y.; Chang, B.-R.; Tsai, M.-R.; Chang, M.-Y.; Chang,
N.-C. Tetrahedron 2003, 59, 9383–9387.
Chem. 2005, 70, 3660–3666.
11. (a) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540–4552; (b)
Danishefsky, S. J.; Cabal, M. P.; Chow, K. J. Am. Chem. Soc.
1989, 111, 3456–3457; (c) Jeroncic, L. O.; Cabal, M.-P.;
Danishefsky, S. J. J. Org. Chem. 1991, 56, 387–395.