Asymmetric synthesis of (1S,2R)-2-aminocyclooctanecarboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2008.12.018

A highly efficient asymmetric synthesis of (1S,2R)-2-aminocyclooctanecarboxylic acid has been completed. This asymmetric synthesis using cycloocta-1,5-diene as the starting material is achieved in 77% yield via a four-step sequence from tert-butyl cycloocta-1,7-dienecarboxylate 10 where the extra double bond adjacent to the unsaturated ester is essential to improve the yield. Furthermore, the Michael adduct intermediate (1S,2R,αR)-14 could be used towards the synthesis of the natural product tashiromine.

Full text of DOI:10.1016/j.tetasy.2008.12.018

Tetrahedron: Asymmetry 19 (2008) 2895–2900
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of (1S,2R)-2-aminocyclooctanecarboxylic acid
a
a
a
a
Narciso M. Garrido a, , Magda Blanco , Imanol F. Cascón , David Díez , Victor M. Vicente ,
*
Francisca Sanz b, Julio G. Urones a
a Dpto. de Química Orgánica, Facultad de Ciencias Quimicas, Universidad de Salamanca, 37008 Salamanca, Spain
b Servicio de Rayos X, Facultad de Ciencias Químicas, Universidad de Salamanca, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient asymmetric synthesis of (1S,2R)-2-aminocyclooctanecarboxylic acid has been com-
pleted. This asymmetric synthesis using cycloocta-1,5-diene as the starting material is achieved in 77%
yield via a four-step sequence from tert-butyl cycloocta-1,7-dienecarboxylate 10 where the extra double
bond adjacent to the unsaturated ester is essential to improve the yield. Furthermore, the Michael adduct
Received 21 October 2008
Accepted 10 December 2008
Available online 20 January 2009
intermediate (1S,2R,
a
R)-14 could be used towards the synthesis of the natural product tashiromine.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
(IC50 = 3.87 and 3.64 l
g/mL, respectively). Fülöp et al.8 have
reported the asymmetric synthesis of cyclic (size from 5 to 8 carbon
atoms) b-amino acids by enzyme-catalyzed (lipase B from Candida
antarctica) ring-opening resolution of unactivated alicyclic b-lac-
tams. The b-amino acids obtained have been incorporated into dif-
ferent oligomers, as a way to offer a widely applicable alternative
route for b-peptides and for combinatorial peptide libraries.9
In the retrosynthetic synthesis (Scheme 1), we proposed to
accomplish the asymmetric synthesis of 2-aminocyclooctanecarb-
A range of methodologies for the asymmetric synthesis of cyclic
derived b-amino acids have been devised, with much recent inter-
est focusing around strategies for the asymmetric synthesis of the
cis- and trans-diastereoisomers of 2-aminocyclopentanecarboxylic
acid (cispentacin 1 and transpentacin 2, respectively, Fig. 1). The
cis-diastereoisomer shows potent antifungal activity,1 while
Fülöp et al. have recently demonstrated that oligomers of cispent-
acin adopt a sheet-type structure in DMSO.2 Furthermore, Gellman
et al. have demonstrated that short chain b-peptides derived from
transpentacin and trans-2-aminocyclohexanecarboxylic acid adopt
12-membered helical structures both in the solid state and in solu-
tion,3 while 3-substituted transpentacin and differently substi-
tuted cyclohexanic derivatives fold in water, which should
facilitate the design of b-peptides for biological applications
(Fig. 1).4
oxylic acid from cyclooctadiene using lithium N-benzyl-N-
a-meth-
ylbenzylamide (R)-5 as the chiral reagent.
In addition, we report herein the asymmetric synthesis of three
intermediates, which are synthetic building blocks, with the cor-
rect grouping to be applied to the synthesis of important natural
bioactive products including (+)-tashiromine. Recently, Marsden
et al.10 have reported its racemic total synthesis and therein the
13 previous successful total synthesis of tashiromine are cited.
We have demonstrated the asymmetric synthesis of the stereo-
isomers of 2-amino-5-carboxymethylcyclopentane-1-carboxylate
in enantiomerically pure form, via a domino reaction involving
2. Results and discussion
an asymmetric Michael addition of chiral lithium N-benzyl-N-a-
Three intermediates 9, 10 and 13 were synthesized (Scheme 2).
The syntheses of 9 and 10 were achieved by starting with cyclooc-
ta-1,5-diene following route A. Intermediate 13 was synthesized
following route B that began with cyclooctene.
methylbenzylamide (R)-5 to (E,E)-octa-2,6-diendioate and a subse-
quent 5-exotrig intramolecular cyclization.5 Later, the versatility of
this methodology was extended, and
e and f-functionalized a,b-
unsaturated esters were shown to participate in conjugate-addi-
tion–cyclization reactions providing the synthesis of b-amino acid
derivatives of cyclohexane and piperidine rings.6
A general asymmetric synthesis of higher cyclic compounds such
as cyclooctane is desired, for instance Kaushik et al.7 recently pub-
lished the synthesis of b-amino acids containing peptides such as 3
and 4 (Fig. 1), which are shown to have antimalarial properties
Treatment of cycloocta-1,5-diene with MCPBA for 90 min pro-
vided the monoepoxide that under treatment with cyanotrimeth-
ylsilane11 using Et2AlCl as catalyst yielded regio and
stereoselectively 2-trimethylsiloxy-cycloct-5-enocarbonitrile 6 in
100% yield (Scheme 2).
By treatment of the nitrile 6 with KOH followed by HCl addi-
tion12 we obtained a 1:1 mixture of the acids 7 and 8 that could
be resolved by column chromatography, but are best isolated by
the CC at the ester stage, and are easily esterified by a normal pro-
cedure under treatment with TFAA and tert-butanol to obtain the
* Corresponding author. Tel.: +34 923 294474; fax: +34 923 294574.
E-mail address: nmg@usal.es (N.M. Garrido).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.018

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N. M. Garrido et al. / Tetrahedron: Asymmetry 19 (2008) 2895–2900
H2N
CO2H
O
O
O
R
O
N
H
N
H
Ph
NHCOOtBu
O
MeOOC
NH
O
n
cispentacin 1
trans-oligomer = 12 helix
O
H
N
N
H
O
3
R= CH2CH(CH3)2
R= CH2C6H5
H2N
CO2H
H2N
CONH2
4
n
transpentacin 2
cis-oligomer = strand
Figure 1.
stereoselectively the corresponding b-amino ester derivatives:
(1S,2R,aR)-14, (1S,2R,aR)-15 and (1S,2R,aR)-16, respectively, in
42%, 100% and 15% yields (de >95%) (Scheme 3). Davies et al.13 have
recently published a comprehensive review in this area of chemis-
try covering the scope, limitations and synthetic applications of the
use of enantiomerically pure lithium amides as homochiral ammo-
nia equivalents in conjugate addition reactions.
Ph
NBn
Li
(R)-5
COOR
COOR
Contrary to (1S,2R,
silica gel, when crude (1S,2R,
silica gel, we obtained the required (1S,2R,
22% yield together with cycloocta-1,7-diencarboxylate and (R)-N-
benzyl-N- -methylbenzylamine. To assess this reaction, a solution
of (1S,2R, R)-15 with SiO2 in DCM was stirred for 1 h, and the ret-
ro-Michael compounds 10 and N-benzyl-N- -methylbenzylamine
were obtained quantitatively. The higher acidity of H–C-1 within
(1S,2R, R)-15 related to the other Michael adduct accounts for this
behaviour and could be used in the synthetic targets.14 Neverthe-
less, crude (1S,2R, R)-15 could be used for further reaction or puri-
a
R)-14 and (1S,2R,
R)-15 was chromatographed over
R)-15 compound in
aR)-16, that were stable in
a
a
CH2OH
H
H2N
H2N
COOH
COOH
X
a
a
N
a
(-)-Tashiromine
a
Scheme 1. Proposed strategy for the synthesis of cyclooctane b-amino acid
derivatives and applications.
a
fied by crystallization in a mixture of hexane and ether. The results
obtained suggest a way to differentiate the Michael acceptors 9
and 10 (Table 1). Interestingly, when a 1:1 mixture of 9 and 10
was subjected to reaction with (R)-5 (1.6 equiv) (Table 1, entry 4)
tert-butyl ester 9 and 10, respectively, as a 1:1 mixture. Alterna-
tively, starting with cyclooctene, route B and following the same
path of reactions: epoxidation, opening of epoxide (20%) and
hydrolysis gave the compound 12 that by esterification led to the
parent ester 13. This route gave poor yield, especially in the open-
ing of the epoxide even when we tried with different Lewis acid
catalysts.11 Nevertheless, hydrogenation of 9 and 10 separately,
or as a mixture, gave compound 13 with excellent yield.
over 30 min (1S,2R,
minute amount of (1S,2R,
The 1H NMR of (1S,2R,
aR)-15 was obtained together with 9 and a
aR)-14 that can be easily separated.
aR)-14 shows an NOE effect between H–
C-1 and H–C-2 confirming a cis relationship, which was anticipated
by the established way of addition of lithium amide (R)-5,15 and
when the acceptor has an
a
-alkyl substituent,16 as applied by
With the tert-butyl cyclooct-1-encarboxylates 9, 10 and 13 in
hand, we tried the protocol of asymmetric Michael addition of chi-
ral lithium N-benzyl-N-a-methylbenzylamide (R)-5, obtaining
Davies et al. to the synthesis of cispentacin.17 The configuration
of the newly formed stereogenic centre was confirmed to be
(1S,2R) through single-crystal X-ray structure analysis (Fig. 2), in
the case of (1S,2R,a
R)-15 product,18 and corroborated the stereo-
chemistry of related compounds.
COOR
COOR
+
Me3SiO
a
CN
The cyclooctene ring is not conformationally stable so the major
planarity provided by the extra double bond adjacent to the conju-
gate ester must account for the excellent yield.19
b
1:1
Hydrogenolysis of (1S,2R,
compound (1S,2R, R)-17 in poor yield (23%), probably due to
retro-Michael reaction, but the strategy of hydrogenation to give
(1S,2R, R)-16 (77%), followed by hydrogenolysis (100%), provided
aR)-15 gave the monodebenzylated
A
a
8
6
7
9
R= H
c
10
R= tBu
a
(1S,2R)-18 with an excellent overall 77% yield in four steps. Treat-
d
ment of (1S,2R)-18 with trifluoroacetic acid gave rise to the b-ami-
COOR
Me3SiO
a
CN
no acid (1S,2R)-19 quantitatively, ½a D26
ꢀ
¼ ꢁ16:5 (c 0.7, H2O); {lit.8a
for (1R,2S)-19 ½a D25
¼ þ17:8 (c 0.4, H2O)}.
ꢀ
b
12
R= H
c
Interestingly, compound (1S,2R,aR)-14 has the right functional
13 R= tBu
groups to be used in the asymmetric synthesis of tashiromine, fur-
ther work is being undertaken to improve the yield and to oxidize
the remaining double bond. In due course a range of different
substituted b-amino cyclooctanecarboxylic acid derivatives will
be available.
B
11
Scheme 2. Reagents and conditions: (a) (i) MCPBA; (ii) Me3SiCN/Et2AlCl, 100% for 6,
20% for 11; (b) (i) KOH/ethylenglycol; (ii) HCl aq, quant; (c) TFAA/tBuOH, 80% (15%
of the acid was recovered); (d) PtO2/H2, EtOAc, 97%.

N. M. Garrido et al. / Tetrahedron: Asymmetry 19 (2008) 2895–2900
2897
COOtBu
COOtBu
Ph
NBn
a
+
10
Ph
NHBn
9
42%
26%
b
)-14
(1S,2R,αR
9
+
100%
Ph
a
(1S
,2R,
αR
)-14
COOtBu
COOtBu
Ph
NBn
NH
COOtBu
2%
+
c
a
(1S
,2R,
αR
)-15
23%
100%
49%
(1S,2R,αR)-15
)-17
(1S,2R,αR
57%
H2N
10
d
77%
c
H2N
COOtBu
COOH
COOtBu
Ph
NBn
COOtBu
e
c
100%
a
100%
15%
(1S,2R)-19
(1S,2R)-18
(1S,2R,αR)-16
13
Scheme 3. Reagents and conditions: (a) lithium N-benzyl-N-
(d) PtO2, H2, EtOAc, 3 h, 77%; (e) TFA, quant.
a-methylbenzylamide ((R)-5, 3.2 equiv), THF, ꢁ78 °C, 2 h; (b) SiO2, DCM, quant; (c) Pd/C, H2, AcOH, 4 atm, 24 h;
Table 1
Resolution of the mixture of 9:10 by (R)-5
Entry
9:10 ratio
t (min)
(R)-5 (equiv)
9 (%)
(1S,2R,
a
R)-14 (%)
(1S,2R,aR)-15 (%)
1
2
3
4
1:0
0:1
1:3
1:1
120
120
120
30
2.4
2.4
2.4
1.6
42
100
60
49
10
2
26
essential to improve the yield of the addition. Importantly, the
analogous series of reactions deploying the enantiomers of lithium
amide (S)-5 in the conjugate addition step will allow simple access
to (1R,2S)-19. Further investigation is undertaken in our group in
order to obtain different substituted 2-aminocyclooctanecarboxy-
lic acids and towards the asymmetric synthesis of tashiromine
and will be published in due course.
4. Experimental
4.1. General
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available, and were used without fur-
ther purification. IR spectra were recorded on a AVATAR 370 FT-IR
Thermo Nicolet spectrophotometer. 1H and 13C NMR spectra were
performed in CDCl3 and referenced to the residual peak of CHCl3 at
d 7.26 ppm and d 77.0 ppm, for 1H and 13C, respectively, using Var-
ian 200 VX and Bruker DRX 400 instruments. Chemical shifts are
reported in d ppm and coupling constants (J) are given in Hertz.
The electron impact (EI) mass spectra were run on a VG-TS 250
spectrometer at 70 eV ionising voltage. HRMS were recorded using
a VG Platform (Fisons) spectrometer using Chemical Ionization
(ammonia as gas) or Fast Atom Bombardment (FAB) technique or
a QSTAR XL spectrometer using electrospray technique. Optical
rotations were determined in a Perkin–Elmer 241 polarimeter in
1 dm cells and are given in units of 10ꢁ1 deg cm2 gꢁ1. Thin layer
chromatography (TLC) was performed on aluminium sheets coated
with 60 F254 silica. Sheets were visualized using iodine, UV light or
1% aqueous KMnO4 solution. Column chromatography was per-
formed with Merck Silica Gel 60 (70–230 mesh). Diethyl ether
Figure 2. Representation of the X-ray crystal structure of (1S,2R,
omitted for clarity).
a
R)-15 (some H
3. Conclusions
In conclusion we have demonstrated a novel efficient diastereo-
selective synthesis of (1S,2R)-2-aminocycloocatanecarboxylic acid
using as the key step the Michael addition of lithium amide (R)-
5. This asymmetric synthesis is achieved in 77% yield via a four-
step sequence from tert-butyl cycloocta-1,7-dienecarboxylate
where cycloocta-1,5-diene is used as the starting material. The
extra double bond adjacent to the conjugate ester has proved

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N. M. Garrido et al. / Tetrahedron: Asymmetry 19 (2008) 2895–2900
and THF were distilled from sodium, and dichloromethane was dis-
tilled under argon from CaH2. Melting points were recorded on a
Leica VMTG Galen III apparatus and are uncorrected. Elemental
analysis was performed by the microanalysis service of the ‘Labor-
atorio de Analisis Químicos, Universidad de Salamanca’.
4.1.5.1. 2-Trimethylsiloxi-cyclooct-5-enecarbonitrile, 6. IR (film)
(cmꢁ1) 3017, 2951, 2241, 1653, 1251, 1096, 1071, 843; dH
m
(400 MHz; CDCl3) 0.17 (9H, s, Me3SiO), 1.66 (2H, m), 1.87–2.23
(6H, m), 3.03 (1H, ddd, J = 11.7, 7.9 and 3.9 Hz, H-1), 3.90 (1H, td,
J = 7.9 and 3.4 Hz, H-2), 5.56 (1H, dt, J = 7.0 and 2.7 Hz, H-6), 5.73
(1H, dt, J = 10.8 and 7.0 Hz, H-5); dC (50 MHz; CDCl3) 0.8
(3 ꢂ CH3, Me3SiO), 2.27 (CH2, C-8), 23.8 (CH2 , C-3), 28.8 (CH2 , C-
7), 35.9 (CH2 , C-4), 37.6 (CH, C-1), 71.6 (CH, C-2), 121.5 (C,
C„N), 127.2 (CH, C-6), 131.2 (CH, C-5); m/z (CI+) 223 (M+,1), 208
(50), 195 (3), 180 (6), 167 (3), 152 (10), 126 (16), 116 (21), 101
(47), 80 (23), 73 (100), 59 (48).
4.1.1. General procedure 1 for lithium amide reaction
n-BuLi was added dropwise to a stirred solution of secondary
amine in THF at ꢁ78 °C under argon atmosphere and was stirred
for 30 min prior to the addition of a solution of acceptor in THF
at ꢁ78 °C. After 2 h, saturated aqueous NH4Cl solution was added
and the resultant solution was warmed to room temperature, par-
titioned between DCM (3 ꢂ 50 mL) and brine, dried and concen-
trated in vacuo. Purification by chromatography on silica gel gave
the desired product. This residue was partitioned between DCM
and 10% citric acid solution, organic layer washed in succession
with aqueous NaHCO3 solution and brine, dried and concentrated
in vacuo before purification via column chromatography.
4.1.6. Hydrolysis of the nitrile, 7 and 8
The previous product (9 g, 38.6 mmol, 1 equiv) was dissolved in
a solution of KOH (2.9 g) and ethane-1,2-diol (47 mL), and the mix-
ture was refluxed at 200 °C for 20 h. The mixture was cooled with
an ice bath and H2O (50 mL) was added, the crude was extracted
with ether and the organic layer was separated. The aqueous solu-
tion was made acidic by addition of HCl. The organic layer was
washed with H2O (2 times) and saturated NaCl (2 times), dried
over Na2SO4, filtered and concentrated in vacuo to give the reaction
product (5.9 g) in 100% yield. 1H NMR of the crude shows a product
7:8 ratio of 1:1. A part was purified on column chromatography by
elution with hexane–EtOAc 4:1 to afford the acids 7 and 8.
4.1.2. General procedure 2
Pd/C (10% Pd by mass) was added to b-amino ester substrate in
glacial acetic acid and the resultant suspension stirred under
hydrogen (5 atm) for 24 h. After filtration through Celite (eluent
DCM), the organic layer was washed with saturated NaHCO3, dried
with Na2SO4, filtered and concentrated in vacuo before purification
via column chromatography.
4.1.6.1. Cycloocta-1,5-dienecarboxylic acid, 7. IR (film)
m )
(cmꢁ1
3600–2500, 2958, 2934, 1684, 1622; dH (400 MHz; CDCl3) 1.56
(4H, m), 2.21 (2H, m), 2.50 (2H, m), 5.85 (2H, m, H-5 and H-6),
7.28 (1H, m, H-2); dC (50 MHz; CDCl3) 21.5 (CH2, C-4), 25.6 (CH2,
C-7), 25.8 (CH2, C-3), 29.8 (CH2, C-8), 124.0 (CH, C-5), 131.0 (C, C-
1), 136.8 (CH, C-6), 139.3 (CH, C-2), 173.0 (C, COOH); m/z (CI+)
153 (M+, 32), 136 (26), 124 (10), 107 (74), 89 (72), 77 (100), 69
4.1.3. General procedure 3
PtO2 was added to a solution of unsaturated derivatives in
EtOAc. The system was purge and stirred under hydrogen atmo-
sphere for 3 h. Purification by chromatography on silica gel gave
the desired product.
(32), 63 (25),
1
(57). HRMS (CI+) C9H12O2 [M]+, requires
4.1.4. Preparation of 1,2-epoxycyclooct-5-ene
152.0837; found: 152. 0817.
To a stirred solution of 1,5-cyclooctadiene (10.0 g, 96 mmol,
1.0 equiv) in dry DCM (150 mL) at 0 °C was added slowly MCPBA
(18.5 g, 113 mmol, 1.2 equiv). The mixture was stirred for 1 h
4.1.6.2. Cycloocta-1,7-dienecarboxylic acid, 8. IR (film)
m )
(cmꢁ1
3600–2450, 3021, 2930, 2857, 1690, 1622; dH (400 MHz; CDCl3)
1.25 (2H, m), 1.48 (2H, m), 2.13 (2H, m), 2.31 (2H, m), 5.88 (1H,
dt, J = 11.3 and 7.2 Hz, H-7), 6.13 (1H, d, J = 11.3, H-8), 7.08 (1H,
t, J = 8.0 Hz, H-2); dC (50 MHz; CDCl3) 22.6 (CH2), 25.5 (CH2), 28.2
(CH2), 28.4 (CH2), 122.5 (CH), 129.3 (C, C-1), 133.9 (CH), 144.9
(CH, C-2), 171.2 (C, COOH); m/z (CI+) 152 (M+, 10), 135 (9), 107
(41), 89 (36), 77 (100), 63 (23), 1 (56). HRMS (CI+) C9H12O2 [M]+, re-
quires 152.0837; found: 152. 0833.
30 min at room temperature. Then
a saturated solution of
Na2S2O3 (15 mL) was added and extracted with DCM. The organ-
ic layer was washed with H2O (2 times), saturated NaHCO3 (2
times) and saturated Na2S2O3 (2 times). The organic layer was
then dried with Na2SO4, filtered and concentrated in vacuo. Puri-
fication of crude product by fractional distillation vacuum
(15 mmHg, 65 °C) afforded the product as a liquid (8.6 g, 72%).
IR (film)
m
(cmꢁ1
)
3050, 2955, 1655, 1229, 936, 862; dH
(400 MHz; CDCl3) 1.90–2.25 (6H, m, H-3, H-8, H-4
a
and H-7 ),
a
4.1.7. Esterification of the acids mixture, 9 and 10
2.30–2.55 (2H, m, H-4b and H-7b), 3.02 (2H, m, H-1 and H-2),
5.52 (2H, m, H-5 and H-6); dC (50 MHz; CDCl3) 23.5 (CH2),
28.0 (CH2), 56.4 (CH), 128.7 (CH); m/z (CI+) 124 (M+, 2), 95
(14), 80 (100), 67 (100), 54 (37).
To a mixture (1:1) of acids 7 and 8 (5.11 g, 34 mmol, 1 equiv)
was added TFAA (9 mL, 64 mmol, 1.8 equiv) at 0 °C and was stirred
for 15 min. After that, the reaction mixture was cooled to 0 °C and
tert-butanol (11 mL, 110 mmol, 3.2 equiv) was added and stirred
for 4 h at room temperature. The reaction was quenched with
NaOH 10% (50 mL). Ether was added and the organic layer was
washed with NaOH 1 M (2 times) and saturated NaCl (2 times),
dried with Na2SO4, filtered and concentrated in vacuo. Purification
by flash column chromatography afforded tert-butyl cyclooct-1,5-
dienecarboxylate 9 (3.41 g, 48%) and tert-butyl cyclooct-1,7-diene-
carboxylate 10 (2.18 g, 31%). The aqueous basic solution was
acidified, and ether extraction followed by usual procedure yielded
767 mg (15%) of starting acids 7 and 8.
4.1.5. Reaction of 1,2-epoxycyclooct-5-ene with trimethylsilyl-
cyanide, 6
A dry and argon-flushed flask equipped with a magnetic stir-
rer and a septum was charged under argon with Et2AlCl (1.0 M
in heptane) (2.30 mL, 2 mmol, 0.04 equiv) and Me3SiCN
(7.50 mL, 56 mmol, 1.2 equiv) and stirred for 30 min at room
temperature. Then 1,2-epoxycyclooct-5-ene (5.72 g, 46 mmol,
1 equiv) was added dropwise to the previous solution by canula
over 15 min. An exothermic reaction was observed, the mixture
was stirred for 30 min. The reaction was poured onto a 200 mL
mixture of ice and NaOH 3 M and extracted with ether. The
organic solution was washed with saturated NaCl (2 times)
and dried over Na2SO4, concentration of the filtrate and column
4.1.7.1. tert-Butyl cycloocta-1,5-dienecarboxylate, 9. IR (film)
m
(cmꢁ1) 2932, 1709, 1368, 1155; dH (400 MHz; CDCl3) 1.43 (9H, s,
COOC(CH3)3), 2.06 (4H, m, H-4 and H-7), 2.33 (4H, m, H-3 and H-
8), 5.69 (2H, m, H-5 and H-6), 6.92 (1H, s, H-2); dC (50 MHz; CDCl3)
21.9 (CH2), 24.1 (CH2), 26.3 (CH2), 28.2 (3 ꢂ CH3, COOC(CH3)3), 29.8
(CH2), 79.9 (C, COOC(CH3)3), 124.5 (CH), 133.6 (C, C-1), 135.4 (CH),
chromatography (hexane–EtOAc 4:1) afforded the product
(10.3 g) in 100 % yield.
6

N. M. Garrido et al. / Tetrahedron: Asymmetry 19 (2008) 2895–2900
2899
135.7 (CH, C-2), 166.0 (C, COOC(CH3)3); m/z (CI+) 208 (M+, 1), 152
(M+-56, 36), 135 (13), 123 (6), 107 (35), 93 (5), 79 (32), 77 (13),
57 (100). HRMS (CI+) C13H20O2 [M]+, requires 208.1463; found:
208.1444.
1651, 1541, 1493, 1456, 1368, 1248, 1155, 1030, 783, 750, 700; dH
(400 MHz; CDCl3) 1.17 (3H, d, J = 7.0 Hz, C( )Me); 1.56 (9H, m,
COOC(CH3)3); 1.65–1.75 (4H, m, H-4 and H-5); 1.90–2.10 (5H, m,
H-1, H-3 and H-6); 3.61 (1H, AB, JAB = 15.2 Hz, NCHACHB); 3.65
(1H, m, H-2); 3.77 (1H, AB, JAB = 15.2 Hz, NCHACHB); 4.08 (1H, q,
a
4.1.7.2. tert-Butyl cycloocta-1,7-dienecarboxylate, 10. IR (film)
m
J = 7.0 Hz, C(
8); 7.26 (10H, m, H-Ar); dC (100 MHz; CDCl3) 20.7 (CH3, C(
26.3 (CH2); 27.3 (CH2); 27.5 (CH2); 28.4 (CH3 ꢂ 3, COOC(CH3)3);
30.2 (CH2); 48.1 (CH, C-1); 50.8 (CH2, CH2Ph); 63.2 (CH, CH( ));
65.8 (CH, C-2); 80.5 (C, COOC(CH3)3); 126.4 (CH); 128.6 (CH)
126.5–128.3 (10 ꢂ CH, o,m,p-Ph); 143.2 (C, Cipso); 144.0 (C, Cipso);
173.1 (C, COOC(CH3)3). m/z (CI+) 420 (M+, 70), 258 (22), 154 (52),
105 (100). HRMS (CI+) C28H37NO2 [M]+, requires 419.2824; found:
419.2819.
a
)H); 5.74 (1H, m, H-7); 5.85 (1H, t, J = 10.1 Hz, H-
(cmꢁ1) 2930, 1717, 1456, 1368, 1159; dH (400 MHz; CDCl3) 1.49
(9H, s, COOC(CH3)3), 2.11 (4H, m, H-4 and H-5), 2.24 (4H, m, H-3
and H-6), 5.80 (1H, dt, J = 11.2 and 7.2 Hz, H-7), 6.09 (1H, d,
J = 11.2 Hz, H-8), 6.85 (1H, t, J = 8.0 Hz, H-2); dC (50 MHz; CDCl3)
22.4 (CH2), 22.9 (CH2), 28.2 (3 ꢂ CH3, COOC(CH3)3), 28.3 (CH2),
28.4 (CH2), 80.1 (C, COOC(CH3)3), 123.7 (CH, C-7), 131.8 (C, C-1),
132.8 (CH, C-8), 141.3 (CH, C-2), 166.6 (C, COOC(CH3)3); m/z (CI+)
208 (M+, 1), 152 (31), 135 (12), 123 (6), 107 (32), 92 (12), 79
(41), 67 (13), 57 (100). HRMS (CI+) C13H20O2 [M]+, requires
208.1463; found: 208. 1458.
a)Me);
a
4.1.12. Treatment of a mixture of 9:10 with lithium (R)-N-
benzyl-N-
Following general procedure 1, a mixture (1:1) of 9 and 10
(362 mg, 1.75 mmol) in THF (3 mL), (R)-N-benzyl-N- -methylben-
zylamine (591 mg, 2.8 mmol) in THF (10 mL) and n-BuLi (1.6 M,
1.7 mL, 2.9 mmol) stirred for 30 min gave a reaction crude that
by 1H NMR analysis shows the following composition:
a-methylbenzylamide
4.1.8. Preparation of tert-butyl cyclooct-1-enecarboxylate, 13
Upon subjecting 500 mg of cyclooctene to the series of reaction
described above the following compounds were obtained: epoxy-
cyclooctene (100%), 2-trimethylsiloxy-cyclooctanecarbonitrile 11
(20%), cyclooctenecarboxylic acid 12 (85%) and tert-butyl cycloct-
1-enecarboxylate 13 (80%) together with 12 (15%).
a
(1S,2R,aR)-15 (49%), (1S,2R,aR)-14 (2%) and 9 (26%). Compounds
were purified by crystallization of (1S,2R,aR)-15 or by Kugelrohr
4.1.9. Hydrogenation reactions of 9 and 10, 13
distillation of 9.
Following general procedure 3 and as starting material (270 mg,
1.3 mmol) 9, 10 or a mixture (1:1) of both for a one-hour period,
compound 13 was obtained (263 mg, 97%).
Accordingly the mixture (1:3) of 9 and 10 described in Table 1,
entry 3 gave the results shown.
4.1.13. Preparation of tert-butyl (1S,2R,
methylbenzylamino-cyclooctanecarboxylate, (1S,2R,
Following general procedure 1, 13 (500 mg, 2.4 mmol) in THF
(3 mL), (R)-N-benzyl-N- -methylbenzylamine (1.2 g, 5.8 mmol) in
THF (10 mL) and n-BuLi (1.6 M, 3.6 mL, 5.7 mmol) gave after chro-
a
R)-2-N-benzyl-N-
a-
4.1.10. Preparation of tert-butyl (1S,2R,
methylbenzylamino-cyclooct-5-enecarboxylate, (1S,2R,
Following general procedure 1, 9 (233 mg, 1.1 mmol) in THF
(3 mL), (R)-N-benzyl-N- -methylbenzylamine (541 mg, 2.6 mmol)
a
R)-2-N-benzyl-N-
a
-
aR)-16
a
R)-14
a
a
in THF (10 mL) and n-BuLi (1.6 M, 1.6 mL, 2.5 mmol) gave after
chromatographic purification on silica (hexane–Et2O 9:1)
matographic purification on silica (hexane–Et2O 9:1) (1S,2R,
a
R)-16
R)-15
(152 mg, 15%). Following general procedure 3, (1S,2R,
a
(1S,2R,
a
R)-14 (194 mg, 42%).
¼ þ98:0 (c 1.2, CHCl3); C28H37NO2 requires C, 80.2; H, 8.9;
N, 3.3; found C, 80.0; H, 8.5; N, 3.2; IR (film)
(cmꢁ1) 3854, 3752,
3677, 2932, 1653, 1700, 1559; dH (400 MHz; CDCl3) 1.37 (9H, s,
COOC(CH3)3), 1.45 (3H, d, J = 6.8 Hz, C( )Me), 1.5–2.4 (8H, m, H-
(338 mg, 0.8 mmol) in EtOAc (20 mL), PtO2 (93 mg, 0.4 mmol) gave
crude (1S,2R, R)-16 (261 mg, 77%) and 23% of staring material was
recovered. This compound was purified by crystallization from a
½
a 2D6
ꢀ
a
m
mixture of hexane–ether. Mp = 110 °C.
a
½
a 2D6
ꢀ
¼ þ109 (c 1.0, CHCl3); C28H39NO2 requires C, 79.8; H, 9.3;
N, 3.3; found C, 80.1; H, 9.5; N, 3.0; IR (film)
(cmꢁ1) 2970,
2927, 2852, 1719, 1455, 1370, 1148; dH (400 MHz; CDCl3) 1.26
(3H, d, J = 7 Hz, C( )Me); 1.41 (9H, s, COOC(CH3)3); 1.57–1.62
3, H-4, H-7, H-8), 2.50 (1H, m, H-1), 3.85 (1H, m, H-2), 3.85 (1H,
AB, JAB = 17.1 Hz, NCHAHBPh), 4.10 (1H, AB, JAB = 17.1 Hz,
m
NCHAHBPh), 4.25 (1H, q, J = 6.8 Hz, C(
(1H, m, H-6), 7.30 (10H, m, H-Ar); dC (100 MHz; CDCl3) 13.2
(CH3, C( )Me), 25.8 (CH2), 27.5 (CH2, C-8), 27.9 (C, COOC(CH3)3),
30.1(CH2), 30.6 (CH2), 51.7 (CH2, NCH2), 53.5 (CH, C-1), 54.7 (CH,
CH(
a)H), 5.80 (1H, m, H-5), 6.05
a
(8H, m); 2.24 (2H, m); 2.50 (2H, m); 3.12 (1H, m, H-1); 3.15 (1H,
m, H-2); 3.85 (1H, AB, JAB = 14.0 Hz, NCHACHB); 3.90 (1H, AB,
a
JAB = 14.0 Hz, NCHACHB); 3.96 (1H, q, J = 6.5 Hz, C(
a)H).; dC
a
)), 56.5 (CH, C-2), 80.0 (COOC(CH3)3), 126.5–129.9 (10 ꢂ CH,
(50 MHz; CDCl3) 17.0 (CH3, C(
a
)Me); 24.3 (CH2); 26.1 (CH2 ꢂ 2);
Ar), 128.0 (CH, C-5), 129.6 (CH, C-6), 141.9 (C, Cipso), 144.1 (C, Cipso),
174.9 (C, COOC(CH3)3); m/z (CI+) 419 (M+, 19), 258 (21),205 (8), 172
(11), 136 (6), 105 (100), 77 (33). HRMS (CI+) C28H37NO2 [M]+,
requires 419.2824; found: 419.2843.
28.2 (CH3 ꢂ 3, COOC(CH3)3); 28.3 (CH2); 29.5 (CH2); 29.6 (CH2);
49.7 (CH, C-1); 51.6 (CH2, CH2Ph); 54.8 (CH, C-2); 58.7 (CH,
CH(a)); 80.2 (C, COOC(CH3)3); 126.5 (CH, o-Ph); 126.8 (CH, o-Ph);
128.0 (CH, m-Ph) 128.2 (CH, m-Ph); 128.2 (CH, p-Ph); 128.2 (CH,
p-Ph); 143.2 (C, Cipso); 145.3 (C, Cipso); 176.3 (C, COOC(CH3)3). HRMS
(CI+) C28H40NO2 [M+H]+, requires 422.3054; found: 422.3039.
4.1.11. Preparation of tert-butyl (1S,2R,
methylbenzylamino-cyclooct-7-enecarboxylate (1S,2R,
Following general procedure 1, 10 (242 mg, 1.2 mmol) in THF
(3 mL), (R)-N-benzyl-N- -methylbenzylamine (633 mg, 3 mmol)
in THF (10 mL) and n-BuLi (1.6 M, 1.8 mL, 2.9 mmol) gave crude
(1 S,2R, R)-15 (503 mg, 100%). We used it without further purifica-
a
R)-2-N-benzyl-N-
a-
a
R)-15
4.1.14. Preparation of tert-butyl (1S,2R,
zylamino-cyclooctanecarboxylate, (1S,2R,
Following general procedure 2. (1S,2R,
a
R)-2-N-
a-methylben
a
aR)-17
R)-15 (67 mg, 0.2 mmol)
a
a
in glacial acetic acid (3 mL), Pd/C (10% Pd by mass, 35 mg) and H2
(4 atm) for 24 h, gave after purification by column chromatography
tion or by crystallization from
a mixture of hexane–ether.
Mp = 119 °C.
(hexane–EtOAc 1:1) (1S,2R,
IR (film)
(cmꢁ1) 2973, 2924, 2856, 1723, 1452, 1367, 1151; dH
(400 MHz; CDCl3) 1.34 (3H, d, J = 6.2 Hz, C( )Me); 1.49 (9H, s,
COOC(CH3)3); 1.20–1.70 (10H, m); 1.80–1.95 (2H, m); 2.75 (1H,
m, H-1); 2.95 (1H, m, H-2); 3.90 (1H, m, N-C( )H); 7.26 (5H, m,
H-Ar); dC (50 MHz; CDCl3) 24.6 (CH3, C( )Me) 24.8 (CH2); 25.5
(CH2); 26.0 (CH2); 27.1 (CH2); 27.5 (CH2); 28.4 (CH3 ꢂ 3,
aR)-17 (12 mg, 23%).
After chromatographic purification of crude (1S,2R,
(100 mg) on silica gel (hexane–Et2O 9:1), 10 (30 mg, 60%),
(1S,2R, R)-15 (22 mg, 22%) together with (R)-N-benzyl-N- -meth-
ylbenzylamine were obtained.
¼ ꢁ4:7 (c 0.96, CHCl3); C28H37NO2 requires C, 80.2; H, 8.9;
N, 3.3; found C, 79.9; H, 8.5; N, 3.1%; IR (film)
(cmꢁ1) 2939, 1717,
aR)-15
m
a
a
a
a
½
a 2D6
ꢀ
a
m

2900
N. M. Garrido et al. / Tetrahedron: Asymmetry 19 (2008) 2895–2900
COOC(CH3)3); 32.3 (CH2); 46.7 (CH, C-1); 54.3 (CH, C(a)); 55.4 (CH,
References
C-2); 80.5 (C, COOC(CH3)3); 126.9 (CH ꢂ 2, o-Ph); 127.1 (CH ꢂ 2, m-
Ph); 128.5 (CH, p-Ph); 146.5 (C, Cipso); 174.9 (C, COOC(CH3)3). HRMS
(ESI) C21H34NO2 [M+H]+, requires 332.2584; found: 332.2572.
1. (a) Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki, T.; Kawaguchi, H. J.
Antibiot. 1989, 42, 1749; (b) Oki, T.; Hirano, M.; Tomatsu, K.; Numata, K.; Kamei,
H. J. Antibiot. 1989, 42, 1756.
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2002, 41, 1718.
4.1.15. Hydrogenolysis of (1S,2R,aR)-16 and (1S,2R,aR)-17.
Preparation of tert-butyl (1S,2R)-2-amino-
cyclooctanecarboxylate, (1S,2R)-18
Following general procedure 2. (1S,2R,aR)-16 (67 mg, 0.2 mmol)
in glacial acetic acid (4 mL), Pd/C (10% Pd by mass, 35 mg) and H2
(4 atm) for 24 h after, gave after purification by column chroma-
3. (a) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang, X.;
Barchi, J. J.; Gellman, S. H. Nature 1997, 387, 381; (b) Appella, D. H.;
Christianson, L. A.; Klein, D. A.; Richards, M. R.; Powell, D. R.; Gellman, S. H. J.
Am. Chem. Soc. 1999, 121, 7574; (c) Barchi, J. J.; Huang, X.; Appella, D. H.;
Christianson, L. A.; Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122, 2711;
(d) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219. and
references cited therein.
4. Woll, M. G.; Fisk, J. D.; LePlae, P. R.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124,
12447.
5. (a) Urones, J. G.; Garrido, N. M.; Díez, D.; El Hammoumi, M. M.; Domínguez, S.
H.; Casaseca, J. A.; Davies, S. G.; Smith, D. Org. Biomol. Chem. 2004, 2, 364–372;
(b) Urones, J. G.; Garrido, N. M.; Díez, D.; Domínguez, S. H.; Davies, S. G.
Tetrahedron: Asymmetry 1997, 8, 2683–2685.
6. Davies, S. G.; Díez, D.; Domínguez, S. H.; Garrido, N. M.; Kruchinin, D.; Price, P.
D.; Smith, D. Org. Biomol. Chem. 2005, 3, 1284–1301.
7. Sathe, M.; Thavaselvam, D.; Srivastava, A. K.; Kaushik, M. P. Molecules 2008, 13,
432–443.
8. (a) Forró, E.; Fülöp, F. Org. Lett. 2003, 5, 1209–1212; (b) Forró, E.; Árva, J.; Fülöp,
F. Tetrahedron: Asymmetry 2001, 12, 643–649.
9. Fülöp, F.; Forró, E.; Tóth, G. K. Org. Lett. 2004, 6, 4239–4241.
10. Marsden, S. P.; McElhinney, A. D. Beilstein J. of Org. Chem. 2008, 4. doi:10.1186/
1860-5397-4-8.
11. Imi, K.; Yanagihara, N.; Utimoto, K. J. Org. Chem. 1987, 52, 1013–1016.
12. Prout, F. S.; Hartman, R. J.; Huang, E. P.-Y.; Korpics, C. J.; Tichelaar, G. R. Org.
Synth. Coll. 1963, 4, 93–98.
13. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833–
2891.
tography (1S,2R)-18 (45 mg, 100%). (1S,2R,
0.03 mmol) gave (1S,2R)-18 (4.3 mg, 57%).
aR)-17 (11 mg,
4.1.15.1. tert-Butyl
(1S,2R)-2-amino-cyclooctanecarboxylate,
(1S,2R)-18. ½a 2D6
ꢀ
¼ ꢁ11:2 (c 1.2, CHCl3); IR (film)
m
(cmꢁ1) 3375,
2922, 2847, 1724, 1464, 1370, 1153; dH (400 MHz; CDCl3) 1.43
(9H, s, COOC(CH3)3; 1.53–1.65 (6H, m); 1.75–1.90 (6H, m, H-4, H-
8, H-3); 2.62 (1H, m, H-1); 3.27 (1H, m, H-2); dC (50 MHz; CDCl3)
23.6 (CH2); 23.8 (CH2); 25.9 (CH2); 26.7 (CH2); 28.2 (CH2); 28.3
(CH3 ꢂ 3, COOC(CH3)3); 33.8 (CH2); 47.6 (CH, C-1); 51.7 (CH, C-
2); 80.4 (C, COOC(CH3)3); 175.6 (C, COOC(CH3)3). HRMS (ESI)
C13H26NO2 [M+H]+, requires 228.1958; found: 228.1941.
4.1.16. Preparation of (1S,2R)-2-amino-cyclooctanecarboxylic
acid by hydrolysis of the b-amino ester, (1S,2R)-19
The b-amino ester (1S,2R)-18 (34 mg, 0.2 mmol) was dissolved
in CF3COOH (0.5 mL, 7 mmol) and was stirred for 1 h 30 min at
room temperature. The solution was concentrated in vacuo, and
organic impurities were washed with EtOAc, and dried to give
14. Garrido, N. M.; Díez, D.; Domínguez, S. H.; García, M.; Sánchez, M. R.; Davies, S.
G. Tetrahedron: Asymmetry 2006, 17, 2183–2186.
15. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 5, 1999–
2008.
16. Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Chem.
Commun 1993, 1153–1154.
17. (a) Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461; (b) Davies, S. G.;
Ichihara, O.; Lenoir, I.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1411.
(1S,2R)-19 (29 mg, 100%).
½
a 2D6
ꢀ
¼ ꢁ16:5 (c 0.7, H2O); dH
(400 MHz; D2O) 1.49–1.52 (4H, m, H-5, H-6); 1.60–1.74 (4H, m,
H-4, H-7); 1.86–1.88 (4H, m, H-3, H-8); 3.04 (1H, ddd, J = 8.5, 5.0
and 3 Hz, H-1); 3.73 (1H, ddd, J = 9, 6.3 and 3 Hz, H-2); dC
(50 MHz; D2O) 23.0 (CH2, C-5); 24.4 (CH2, C-6); 25.0 (CH2, C-4);
25.7 (CH2, C-7); 26.5 (CH2, C-8); 28.7 (CH2, C-3); 42.7 (CH, C-1);
50.9 (CH, C-2); 177.6 (C, C-9). HRMS (ESI) C9H18NO2 [M+H]+, re-
quires 172.1332; found: 172.1336.
18. A single crystal of (1S,2R,
aR)-15 compound was subjected to X-ray diffraction
studies on a Seifert 3003 SC four-circle diffractometer (Cu K
a
radiation, graphite
monochromator) at 293(2) K. Crystal data for 1: C28H37N1O2, M = 419.59,
monoclinic, space group P21 (no. 4), a = 10.202(2) Å, b = 10.819(2) Å,
c = 11.253(2) Å, b = 90.87(3)°, V = 1241.9(4) Å3, Z = 2, Dc = 1.122 Mg/m3,
m = (Cu K
3.80 6 2h 6 60.00 and merged to give 1947 unique reflections, of which 1885
with I > 2 I were considered to be observed. The structure was solved by direct
a
) = 0.535 mmꢁ1, F(000) = 456. 5148 reflections were collected at
r
method and the non-hydrogen atoms were refined anisotropically by full-matrix
least squares. H atoms attached to methyl groups were positioned geometrically
and the rest of the hydrogen atoms were located in a difference Fourier map. The
Acknowledgements
final R factors were R1 = 0.0293 and
xR2 = 0.0721 for a total of 407 parameters.
We are indebted to Junta de Castilla y León and F.S.E. for finan-
cial support (SA045A05) and Spanish MEC (CTQ2006-08296/BQU).
We also thank the support from Servicios de la Universidad de
Salamanca: Dr. A.M. Lithgow for the NMR spectra and Dr. César
Raposo for the mass spectra. M.B. is grateful for a doctoral fellow-
ship to the Grupo de Santander.
Crystallographic data (excluding structure factors) for this structure have been
deposited at the Cambridge Crystallographic Data Centre as supplementary
material no. CCDC 705369.
19. The addition of (R)-5 to methyl (R)-6-methyl-cyclohex-1,3-dienecarboxylate
with 86% yield in the formal synthesis of (ꢁ)-pumiliotoxin
C has been
reported: Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996, 7, 1595–1596.