Asymmetric synthesis of pent-3-yl (R)-6-methyl-cyclohex-1-ene carboxylate

Article abstract of DOI:10.1016/j.tetasy.2006.06.048

An expeditious asymmetric synthesis of pent-3-yl (R)-6-methyl-cyclohex-1-enecarboxylate has been achieved in four steps in 42% overall yield employing as the key step a domino reaction initiated by a highly diastereoselective lithium amide 1,4-conjugate a

Full text of DOI:10.1016/j.tetasy.2006.06.048

Tetrahedron: Asymmetry 17 (2006) 2183–2186
Asymmetric synthesis of pent-3-yl
(R)-6-methyl-cyclohex-1-ene carboxylate
a
a
a
Narciso M. Garrido,a, David Dıez, Sara H. Domınguez, Mercedes Garcıa,
*
´
´
´
a
b
´
M. Rosa Sanchez and Stephen G. Davies
aDepartamento de Quı´mica Orga´nica, Universidad de Salamanca, Plaza de los Caı´dos 1-5, 37008 Salamanca, Spain
bChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Received 20 May 2006; accepted 26 June 2006
Dedicated with respect and affection to Professor J. G. Urones on the occasion of his 65th birthday
Abstract—An expeditious asymmetric synthesis of pent-3-yl (R)-6-methyl-cyclohex-1-enecarboxylate has been achieved in four steps in
42% overall yield employing as the key step a domino reaction initiated by a highly diastereoselective lithium amide 1,4-conjugate addi-
tion to a nona-2,7-diendioic diester followed by a 6-exo-trig cyclisation of the thus formed enolate. Cope elimination protocol of the
cyclic adduct affords, depending on the lithium amide used, the corresponding nitro-compound or the expected cyclohexene derivative.
The methyl group attached to the cyclohexane ring is achieved by selective ester hydrolysis and subsequent Barton decarboxylation.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
skeleton, first isolated from Dendrobates pumilio, is one of
the most prominent members among the alkaloids isolated
from Dendrobates spp. (poison dart frog).3 An impressive
effort has been devoted to the asymmetric synthesis
because of its structure, a cis-fused perhydroquinoline
skeleton featuring four stereogenic centres.4 In Scheme 1
are shown some of the cyclohexanic derivatives used
recently in the asymmetric synthesis of pumiliotoxin C,
and the related compound pent-3-yl (R)-6-methyl-cyclo-
The methodologies and strategies for the stereoselective
construction of substituted cyclohexane rings are very pow-
erful synthetic tools since such rings are incorporated in
many naturally occurring products. Representative exam-
ples are: morphine1 with a cyclohexane ring trans,trans-
trisubstituted and luciduline2 where the ring is cis,cis-tri-
substituted. Pumiliotoxin C with a cis-decahydroquinoline
BnO
O
O
O
H
OH
Fukumoto et al.4a
H
H
COOR
Back et al.4b
N
H
H
R= CH(CH2CH3)2
COOMe
1
(R)-
(-)-pumiliotoxin C
O
Feringa et al.4c
Davies et al.4d
Scheme 1.
*
Corresponding author. Tel.: +34 923 294 474; fax: +34 923 294 574; e-mail addresses: nmg@usal.es; nmg@gugu.usal.es
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.048

2184
N. M. Garrido et al. / Tetrahedron: Asymmetry 17 (2006) 2183–2186
Ph
Ph
Ph
NO2
Ph
N
Ph
N
Ph
N
Li
)-5
COOMe
COOMe
COOMe
COOMe
COOR
COOR
COOR
COOR
i
(
R
53%
i
(1R,2R,6R)-6
4a-d
2a-d
(1R,2R,6R,αR)-2a
a, R= Me,
72-84%
b, R=Et,
ii
c, R=tBu,
Ph
Ph
d, R= CH(CH2CH3)2
(1 ,2 ,6 ,α )-2a
70% (2:3)
N
Ph
H
Ph
MeOOC
N
H
H
Ph
Ph
COOMe
R
R R R
O-
N+
+
HO
N
Ph
(3
R,7R)-3
COOMe
COOMe
COOMe
COOMe
Scheme 2. Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-
methylbenzylamide [(R)-5, 1.6 equiv, THF, ꢀ78 °C]; (ii) lithium (R)-N-
benzyl-N-a-methylbenzylamide [(R)-5, 12 equiv, THF, ꢀ78 °C].
7
8
Scheme 3. Reagents and conditions: (i) m-CPBA (4 equiv), 3 days.
hex-1-enecarboxylate ester (R)-1, whose synthesis is re-
ported here.
(1R,2R,6R)-6, in 53% isolated yield8 as a single diastereoiso-
mer. Presumably with all groups especially the large amino
group equatorial in the trisubstituted chair conformation of
the cyclohexane, in the N-oxide initially formed 7. It is dif-
ficult to adopt the syn-periplanar conformation required to
generate a cyclohexene derivative, favouring Cope elimina-
tion with a hydrogen from the a-methyl group yielding styr-
ene and the hydroxy-amine 8. Subsequent dehydration and
further oxidation would produce an N-oxide oxaziridine
derivative, rearrangement of which would give benzalde-
hyde and a nitroso compound, which after additional
oxidation would account for the production of
(1R,2R,6R)-6.9 Due to this unexpected result10 and the
versatility of the nitro group that can, for example, be trans-
formed to carbonyl functionality through a Nef reaction,11
further investigations on the scope of this reaction are
currently being performed in our laboratory.
We have previously demonstrated the asymmetric synthesis
of the cyclic monoaddition and open chain diaddition
products 2 and 3 from (E,E)-nona-2,7-diendioate 4a–d
(Scheme 2).5 The cyclic adduct 2 is obtained by addition
of homochiral lithium N-benzyl-N-a-methylbenzylamide
(R)-5 (1.6 equiv) via a domino6 reaction initiated in an
asymmetric conjugate addition followed by an intramolec-
ular 6-exo-trig cyclisation of the enolate formed with the
remaining a,b-unsaturated ester. On the other hand, addi-
tion of (E,E)-deca-2,8-diendioate to an excess of lithium
amide gave the diaddition adduct as the only isolated prod-
uct.5 However addition of methyl (E,E)-nona-2,7-diendio-
ate 4a to an excess of amide (R)-5 (12 equiv) gave the
diaddition adduct (3R,7R)-3 and cyclic 2a in a 3:2 ratio.
Nevertheless, compound (3R,7R)-3, has been obtained
completely selectively in a strategy based on (Z,E)-nona-
2,7-diendioate by reaction with (R)-5 producing the
b,c-unsaturated monoaddition product, which by base
catalysed isomerisation to the a,b-unsaturated ester and
new addition, yields (3R,7R)-3. In this way, meso-3 could
be obtained as well when (S)-5 is added to the monoaddi-
tion derivative.5a This sequential strategy allows the stereo-
chemical control of the two new stereogenic centres.
The less bulky chiral lithium (S)-N-methyl-N-a-methyl-
benzylamide (S)-9, has been demonstrated previously to
favour Cope eliminations.12 Addition of dipent-3-yl
(E,E)-nona-2,7-diendioate 4d to (S)-9 (1.8 equiv) at
ꢀ78 °C followed by quenching with saturated aqueous
ammonium chloride gave the readily separable, by flash
chromatography (silica; 5% EtOAc in hexane), cyclohexane
20
adduct (1S,2S,6S,aS)-10,8 ½aꢁD ¼ ꢀ2:5 (c 1.4, CHCl3), to-
In order to demonstrate further the versatility of this
lithium methodology by generating chiral methyl cyclohex-
ane derivatives, a study with sequential amine elimination,
selective ester hydrolysis and Barton’s decarboxylation on
4d was undertaken.
gether with the diaddition adduct (3S,7S)-11 in 65% and
10% isolated yields, respectively (Scheme 4). This result
suggests that the ratio of adducts obtained, depends not
only on the amount but also on the size of the lithium
amide used. Thus slow addition of (S)-9 to 4d at ꢀ78 °C
provided (1S,2S,6S,aS)-10 as the only isolated compound
in 80% yield.
2. Results and discussion
We envisaged that Cope elimination between H-1 and the
Oxidation of (1S,2S,6S,aS)-10 with m-chloroperbenzoic
amino
group
in
the
cyclohexane
compound
acid (Scheme 4) generated the expected cyclohexene
20
(1R,2R,6R,aR)-2a (Scheme 3) would provide the alkene
derivative in accordance with previous observations in the
cyclopentane series.7 However, treatment of compound
(1R,2R,6R,aR)-2a with m-chloroperbenzoic acid over a
long period of time generated, the nitro derivative
derivative (S)-12, ½aꢁD ¼ þ11:5 (c 0.6, CHCl3), together
with the hydroxylamines (1S,2S,6S)-13 and (S)-14, in
65%, 17% and 75% yields, respectively. The hydroxylamine
14 derives from the expected Cope elimination of the
trans-b amino ester moiety within (1S,2S,6S,aS)-10 whereas

N. M. Garrido et al. / Tetrahedron: Asymmetry 17 (2006) 2183–2186
2185
obtained in 46% isolated yield after column chromatogra-
phy, together with the related cyclohexanyl hydroxyl-
amine in 33% yield. The highest yielding (42% overall)
route to the final product is 4d ! (1S,2S,6S,aS)-
10 ! (S)-12 ! (R)-1, gglobal = 42%.
COOR
COOR
Conditions
Product yield (%)
i
ii
10 (65)
11 (10)
10 (80)
---
4d
R=CH(CH2CH3)2
Me
(S)-9
Neither Cope elimination, ester hydrolysis or Barton decar-
boxylation involve the C-6 configuration that therefore
remains as generated in the first addition–cyclisation
Ph
N
Li
Me
1
Ph
N
reaction. In confirmation H NMR in the presence of the
Me
Me
(3
N
Ph
COOR
Ph
N
COOR
chiral shift reagent (9-anthryl-trifluoroethanol) does not
show the splitting of the methyl group signal, which is
clearly observed when the racemic compound ethyl ( )-6-
methyl-cyclohex-3-enecarboxylate ( )-1b,15 was analysed
similarly (2:1 chiral shift reagent:substrate), and an ee
>95% can therefore be assigned for (R)-1. Importantly,
the analogous series of reactions deploying the enantio-
meric lithium amide (R)-9, in the initial conjugate addition
step will obviously allow simple access to (S)-1.
+
ROOC
Me
COOR
)-10
iii
(1S,2S,6S,αS
S,
7S)-11
OH
N
COOR
COOR
Me
COOR
COOR
)-13
Ph
N
+
+
OH
(
S
)-12
65%
(1
S,2
S
,6
S
(
S
)-14
75%
17%
3. Conclusion
Scheme 4. Reagents and conditions: (i) (S)-(N-methyl-N-a-methylbenzyl-
amide [(S)-9, 1.8 equiv, THF, ꢀ78 °C]; (ii) (S)-(N-methyl-N-a-meth-
ylbenzylamide [(S)-9, 1.2 equiv, THF, ꢀ78 °C]; (iii) m-CPBA (2.2 equiv),
18 h.
In conclusion, an expeditious synthesis of pent-3-yl (R)-6-
methyl-cyclohex-1-ene carboxylate (R)-1 in only four steps
from dipent-3-yl (E,E)-nona-2,7-diendioate 4 as the prochi-
ral precursor and in 42% overall yield was achieved. The
highly stereoselective domino reaction initiated by the Mi-
chael addition of chiral (S)-9 provide the required (R)-con-
figuration in the final product. With the cyclohexane
adduct (1S,2S,6S,aS)-10 in hand, the sequence: Cope elim-
ination, selective hydrolysis of the less steric demanding es-
ter and efficient Barton decarboxylation generates the C-6
methyl group without loss of the stereochemical integrity.
hydroxylamine (1S,2S,6S)-13 derives from elimination in
the a-methylbenzyl moiety.
Selective ester hydrolysis of (S)-12 and (1S,2S,6S,aS)-10
with LiOHÆH2O in MeOH/THF/H2O afforded, respec-
tively (S)-16 and (1S,2S,6S,aS)-158 in quantitative and
79% yields, respectively (Scheme 5). To generate a methyl
group attached to the cyclohexane ring, both compounds
were subjected to Barton’s thiohydroxamic ester radical
decarboxylation protocol,13,14 providing efficiently in the
The described product can be considered a precursor of
pumiliotoxin-(C), and further investigation to this end is
underway.
first case, (R)-1 with 82% isolated yield after flash chroma-
20
tography, ½aꢁD ¼ þ46:0 (c 0.5, CHCl3), and (1S,2S,6R)-17,
20
in the second ½aꢁD ¼ ꢀ6:2 (c 0.7, CHCl3), in 51% isolated
Acknowledgements
yield. Similarly, when (1S,2S,6R)-17 was subjected to the
Cope elimination protocol described before, (R)-1 was
´
We are indebted to Junta de Castilla y Leon and F.S.E.
for financial support (SA045A05) and Spanish MEC
(CTQ2005-06813/BQU). The authors also thank Dr. A. M.
Me
Me
Me
´
Ph
ii
79%
N
Lithgow for the NMR spectra and Dr. Cesar Raposo for
Ph
N
Ph
iii
N
COOR
COOH
COOR
COOR
COOR
the mass spectra.
51%
(1
(1
S,2
S
,6
S
,αS
)-15
S
,2
S
,6
S,αS
)-17
(1
S,2
S,6
S
,αS
)-10
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56%
i
65%
46%
i
i
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iii
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ii
98%
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(
S
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(S)-16
(R)-1
R=CH(CH2CH3)2
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´
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´
´
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98%
iii
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8. All new compounds were fully characterised including
1
71%
elemental analysis or high resolution mass spectrometry. H
63% ii
NMR (400 MHz) spectroscopy including two-dimensional
homonuclear COSY, heteronuclear HMQC and HMBC,
NOE and ROESY experiments for (1R,2R,6R)-6 and
(1S,2S,6S,aS)-15 are in accordance with the structure and
stereochemistry assigned.
COOEt
OH
COOEt
OMs
COOEt
v
iv
89%
69%
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( )-1b
10. To the best of our knowledge, this is the first example in
which this chiral auxiliary is debenzylated to produce the
nitro oxidation state.
Reagents and conditions: (i) NaBH4/CeCl3/MeOH; (ii) H2/
Pd–C/EtOAc; (iii) NaBH4/Pyr; (iv) MsCl/Et3N/DCM; (v)
DBU/THF/D.