Straightforward stereoselective synthesis of polyfunctionalised cyclohexenols using a multicomponent approach

Article abstract of DOI:10.1016/j.tet.2010.01.097

An intramolecular Ugi 5-centre-4-component reaction (U-5C-4CR) followed by a palladium-catalysed ring-opening has been employed to transform oxabicycloheptene-based β-amino acids into two families of regioisomeric polyfunctionalised cyclohexenols. The whole process is completely stereoselective and enantiomerically pure products are obtained in high overall yields.

Full text of DOI:10.1016/j.tet.2010.01.097

Tetrahedron 66 (2010) 2390–2397
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Straightforward stereoselective synthesis of polyfunctionalised cyclohexenols
using a multicomponent approach
*
Andrea Basso , Luca Banfi, Giuseppe Guanti, Renata Riva
`
Universita degli Studi di Genova, Dipartimento di Chimica e Chimica Industriale. Via Dodecaneso 31, 16146 Genova, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An intramolecular Ugi 5-centre-4-component reaction (U-5C-4CR) followed by a palladium-catalysed
Received 5 October 2009
Received in revised form
14 December 2009
Accepted 27 January 2010
Available online 2 February 2010
ring-opening has been employed to transform oxabicycloheptene-based b-amino acids into two fami-
lies of regioisomeric polyfunctionalised cyclohexenols. The whole process is completely stereoselective
and enantiomerically pure products are obtained in high overall yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyclohexenols
Multicomponent reactions
Norbornenyl amino acids
Ring-opening reactions
Enantioselective synthesis
Diversity oriented synthesis
1. Introduction
reaction has been widely explored by Lautens et al.,9 three features
make our approach interesting and original: (1) the presence of
Isocyanide-based multicomponent reactions (I-MCRs)1 fol-
lowed by post-condensation transformations2 are currently widely
used by both academia and industry3 to modify the classic Passerini
and Ugi adducts into more valuable, pharmacologically relevant
compounds. Within this strategy we have recently reported4 the
various additional functional groups that could interfere with the
reaction, (2) the non-symmetrical bicyclic system that could lead to
two distinct regioisomers, (3) the chiral information, that is,
R1
O
H
N
O
O
R2 CHO, R3 NC
MeOH
behaviour of oxabicycloheptene b-amino acids of general formula 1
R3
N
R1
that, reacted with various aldehydes and isocyanides in alcoholic
medium, give a stereoselective Ugi 5-centre-4-component reaction
leading to final compounds 2 (Scheme 1). Depending on the dif-
ferent functionalities displayed by 2, various transformations can
follow the multicomponent step, such as retroDiels–Alder re-
action,5 ring-opening/ring-closing metathesis or enyne metathesis
followed by cycloadditions6 leading to structurally different com-
plex molecules in a highly convergent manner. In view of all the
possible transformations that Ugi adducts 2 can undergo, these
compounds can be defined pluripotent substrates7 and can find
applications in Diversity Oriented Synthesis.8 In this paper we re-
port the transformation of pluripotent substrate 2 into two classes
of regioisomeric cyclohexenols exploiting a transition-metal cata-
lysed ring-opening of the oxanorbornene system. Although this
N
H
2
R2
CO2Me
1
CO2H
retroDiels-Alder
ROM/RCM
O
enyne
R1
N
O
ROM/RCM,
Diels-Alder
R3
N
H
R3
N
R2
N
MeO2C
O
R2
CO2Me
H
R4
R4
O
R3
N
N
H
O
R2
CO2Me
* Corresponding author. Tel.: þ39 010 3536117; fax: þ39 010 3536118.
E-mail address: andreab@chimica.unige.it (A. Basso).
Scheme 1. Oxabicycloheptene derivatives as pluripotent substrates.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.097

A. Basso et al. / Tetrahedron 66 (2010) 2390–2397
2391
intrinsic in the substrate and therefore renders the search for
enantioselective catalysts unnecessary.
catalyst was performed instead. Further optimisation, in particular
the use of bis(triphenylphosphine)propane as ligand for the metal
catalyst, allowed us to obtain the final products in 80% yield and as
a 7:3 mixture of regioisomers in favour of the one with the two
hydroxy groups far apart.
2. Discussion
In order to find the optimal procedure to perform the ring-
opening reaction, we prepared racemic compound 3 (Scheme 2)
according to our reported procedure4 and submitted it to different
experimental conditions. Our first attempts regarded simple acid-
or base-mediated fragmentation reactions to break the bicyclic C–O
bond: in a first experiment we investigated a KHMDS-mediated
fragmentation reaction, reported by Steel et al.10 on a similar sub-
strate, however treatment of 3 with base did not afford any product,
neither did the reaction with BuLi and catalytic TiCl4 according to
Arjona et al.,11 or the reaction with stoichiometric TiCl4 according to
Harwood et al.12 The presence of a basic nitrogen and/or an acidic
NH on the substrate probably prevented these reactions occurring.
We therefore investigated alternative ring-opening reactions me-
diated by nucleophiles in the presence of metal catalysts, pro-
ceeding this time in a nearly neutral environment; the final
products, with this alternative strategy, would also incorporate the
nucleophile as an additional diversity input, increasing the number
of different molecules obtainable. In particular we investigated two
distinct processes, one with Ni, Zn and iodoarenes,13 and another
with Pd and boronic acids.14 At this stage we had to face another
problem, due to the lability of substrate 3 to the moderately high
temperatures required by these reactions: indeed, under these
conditions the main product isolated was the retroDiels–Alder ad-
duct 4, with only trace amounts of the desired ring-opening ad-
ducts. Thoroughly optimised conditions for the reaction with
iodoarenes furnished a 60% yield of a nearly 1:1 mixture of the
regioisomeric compounds 5 and 6; however the large excess of
metal species employed and the persistent presence of adduct 4
(10%), stimulated us to look for an alternative strategy that could
suppress the undesired retroDiels–Alder reaction.
3
O
N
Bn
i
N
H
Ph
Ph
8
O
O
OH OH
ii
N
Bn
N
H
OH
N
O
7
Bn
OH
N
H
9
OH
Scheme 3. Ring-opening reaction of racemic alcohol derivative 7. Reagents and con-
ditions: (i) LAH, Et2O, 0 ꢀC, 96%; (ii) Phenylboronic acid, [Pd(C6H5CN)2]Cl2, 1,3-bis(di-
phenyl-phosphino)propane, Cs2CO3, H2O, MeOH, 60 ꢀC, 80%.
The correct assignment of the two regioisomers was made
thanks to 2D NMR experiments and was confirmed by the fact that
when compound 10, obtained similarly to 3, was reacted under the
same conditions with excess thiopheneboronic acid, the
regioisomer with the two vicinal hydroxy groups was isolated as
the corresponding cyclic boronate 11, while regioisomer 12 would
be sterically prevented to form such a species (Scheme 4). As
expected for the mechanism of this reaction16 and as demonstrated
by NMR experiments, the ring-opening occurred with syn stereo-
selectivity, as a result of exo attack of the nucleophile to the oxa-
bicyclic unit.
O
O
N
Bn
N
N
H
N
H
MeO2C
4
11
O
O
S
S
B
O
O
O
O
i
O
N
Bn
N
Bn
N
H
i
N
N
H
N
H
S
MeO
3
5
10
CO2Me
OH
O
CO2Me
OH
OH
N
N
H
OH
O
N
Bn
12
MeO
N
H
OH
Scheme 4. Ring-opening reaction with 3-thiopheneboronic acid. Reagents and con-
ditions: (i) 3-Thiopheneboronic acid, [Pd(C6H5CN)2]Cl2, 1,3-bis(diphenyl-phosphino)-
propane, Cs2CO3, H2O, MeOH, 60 ꢀC, 100%.
6
CO2Me
Scheme 2. Ring-opening reaction of racemic ester derivative 3. Reagents and con-
ditions:(i) 3-Iodoanisole, Zn dust, Ni(PPh3)2Cl2, acetonitrile, 50 ꢀC.
This synthetic approach was employed to prepare a small library
of optically pure cyclohexenol derivatives starting either from de-
rivative 13 or from its enantiomer, both obtained according to
a previously reported procedure.5 Amino acid 16, to be employed in
the U-5C-4CR, was synthesised by a modification of the above
mentioned methodology: cleavage of the MeOZ protecting group
and reductive amination with benzaldehyde furnished 14 nearly
quantitatively. This was subjected to epimerisation with NaOMe in
MeOH to give the desired trans-configured derivative 15, which was
finally hydrolysed to 16 (Scheme 5); ent-16 was obtained similarly
from ent-13.
We postulated that removal of the ester moiety, endowed with
strong electron withdrawing properties, would kinetically dis-
favour retro cycloaddition processes, while being of little or no in-
fluence in the ring-opening reaction. Gratifyingly, treatment of 3
with LAH15 gave the corresponding alcohol 7 in high yields
(Scheme 3), without affecting the other functionalities in the
molecule; curiously compound 7 was unreactive under the condi-
tions previously optimised, while the expected mixture of
regioisomers 8 and 9 was obtained in moderate yield (64%) when
the alternative reaction with phenylboronic acid and a Pd(II)

2392
A. Basso et al. / Tetrahedron 66 (2010) 2390–2397
O
O
OMe
OMe
Bn
N
OH
O
O
i, ii
NHMeOZ
CO2Bn
NHBn
Ph
CO2Bn
N
H
13
14
Bn
23
iii
i
OH
Bn
N
20
21
22
O
O
NHBn
NHBn
CO2Me
N
H
iv
Bn
OH OH
Ph
Ph
24
16
15
CO2H
Scheme 5. Synthesis of optically pure oxabicycloheptene amino acid 16. Reagents and
conditions: (i) TFA, DCM, 95%; (ii) Benzaldehyde, AcOH, MeOH then NaBH3CN, 0 ꢀC,
97%; (iii) NaOMe, MeOH, 77%; (iv) 1 M NaOH, dioxane then neutralisation with 1 M
HCl, 100%.
Bn
N
OH
O
Bn
i
N
H
Ph
N-Benzylamino acid 16 was separately reacted with various alde-
hydes and isocyanides to afford compounds 17, 18 and 19, that were
then treated with LAH to give, respectively, 20, 21 and 22in highyields
(Scheme 6); ent-20–22 were prepared analogously from ent-16.
25
OH
Bn
N
OH
O
Bn
Ph
Bn
O
O
O
O
N
H
R2
N
i
Bn
N
H
16
26
R1
CO2Me
17-19
R1 CHO, R2 NC
i
OH
Bn
N
O
Bn
1
2
N
H
17 20
,
18 21
,
R =Bn R =4-MeO-Ph
ii
1
2
Bn
R =Ph R =Bn
Ph
27
19, 22 R1=Bn R2=Bn
O
O
Bn
N
B
ii
R2
N
H
Bn
N
O
R1
OH
Bn
20-22
N
H
Bn
OH OH
Ph
28
Scheme 6. Synthesis of optically pure substrates for ring-opening reactions. Reagents
and conditions: (i) MeOH, 57–93%; (ii) LAH, Et2O, 0 ꢀC, 85–86%.
Bn
N
OH
O
Finally, Ugi adducts 20, 21 and 22 and their enantiomers were
reacted, under the conditions described for racemic 7 and 10, with
phenylboronic acid. Compound 22 was also reacted with 3-pyr-
idineboronic acid. Interestingly, the reaction outcome was highly
dependent on the nature of the substrates. In fact, while compound
20 gave the expected regioisomers 23 and 24 in a 65:35 ratio,
compound 21 furnished only regioisomer 25. Moreover, compound
22 gave, together with regioisomer 26, cyclic boronate 27 when
reacted with phenylboronic acid, but not when reacted with 3-pyr-
idineboronic acid: in this case the two regioisomers 29 and 30 were
obtained regularly in a 6:4 ratio (Scheme 7). Compound 28 was then
quantitatively recovered from boronate 27 via basic hydrolysis.
These reaction outcomes revealed that the nature of the sub-
stituents of the bicyclic moiety could not direct the ring-opening
process to the selective formation of one regioisomer, while con-
formational issues seemed more important. Indeed, in the case of
compound 21 it is likely that one of the aromatic rings of the amino
acidic side chain is in close proximity of the bicyclic double bond, as
confirmed by the shielded signals of H-1, H-5 and H-6 in the 1H NMR
spectrum (respectively, 3.41, 6.12 and 6.07 ppm instead of 4.82–4.90,
6.31–6.34 and 6.41–6.44 ppm); according to the reaction mecha-
nism16 the attack of the Pd species would therefore be favoured on
H-5, generating solely compound 25. More difficult is to explain why
cyclic boronates are formed only in some cases, and probably this is
influenced not only by specific conformations assumed by the
cyclohexenol derivatives but also by the different reactivity of the
boronic acids employed. It is worth noting that in the case of
N
Bn
N
H
Bn
29
iii
OH
Bn
N
22
O
Bn
N
H
Bn
OH OH
N
30
Scheme 7. Ring-opening reaction of optically pure substrates. Reagents and condi-
tions: (i) Phenylboronic acid, [Pd(C6H5CN)2]Cl2, 1,3-bis(diphenyl-phosphino)propane,
Cs2CO3, H2O, MeOH, 60 ꢀC, 68–82%; (ii) 4 M NaOH, dioxane, 77%; (iii) 3-Pyridinebor-
onic acid, [Pd(C6H5CN)2]Cl2, 1,3-bis(diphenyl-phosphino)propane, Cs2CO3, H2O, MeOH,
60 ꢀC, 74%.
compounds 10 and 22 the formation of cyclic boronates was faster
than the ring-opening reaction: indeed when stoichiometric amount
of boronic acid was employed the reaction did not reach completion,
and the cyclic boronate was stable enough not to be hydrolysed
under the reaction conditions. The hypothesis that specific confor-
mational dispositions are influencing the reaction outcomes is
somehow confirmed by the fact that compounds of general formula
31 (Fig. 1), prepared by us with an alternative synthetic approach,17
having a similar but more flexible side chain, underwent the ring-
opening reactions with reproducible outcomes, independent of the
nature of the R group and the boronic acid.

A. Basso et al. / Tetrahedron 66 (2010) 2390–2397
2393
65.8 (CH), 86.4 (CH), 127.6 (CH), 127.8 (CH), 128.7 (CH), 137.8 (C),
152.1 (CH), 169.7 (C), 170.2 (C). nmax(liquid film) 3430, 2932, 2870,
1675, 1599, 1506, 1440, 1352, 1255, 1140 cmꢂ1. GC–MS (9.8 min) 318
(3, M) 185 (12), 184 (MꢂBnNHCO, 100), 110 (9), 91 (21), 84 (12), 82
(7), 69 (8), 59 (7), 43 (6), 42 (16), 41 (6). HRMS expected for
C18H26N2O3: 318.1943, found: 318.1934, ꢂ2.8 ppm.
O
H
N
O
R
N
H
OH
Figure 1. General structure of substrates that underwent the ring-opening reaction
with reproducible outcomes.
4.2.2. (1SR,2RS,5RS,6SR)-Methyl 2-(N-((RS)-1-(benzylcarbamoyl)-3-
methylbutyl)-N-methylamino)-6-hydroxy-5-(3-methox-
yphenyl)cyclohex-3-enecarboxylate (5). Colourless oil. Rf 0.17 (EtOAc/
In order to prove the complete stereoselectivity of the whole
synthetic process and that no racemisation occurred throughout
the various reactions, compound 28 and its enantiomer were
analysed by HPLC using a chiral column (Diacel Chiralpak) and the
absence of cross contaminant peaks confirmed our hypothesis.
PE 3:7).1H NMR (CDCl3, 300 MHz)
d
0.93 (d, J¼6.6, 3H), 0.98 (d, J¼6.3,
3H),1.40–1.80 (m, 4H), 2.38(s, 3H), 2.67 (t, J¼10.8,1H), 3.23 (dd, J¼8.2,
6.7, 1H), 3.44 (s, 3H), 3.73 (dd, J¼5.4, 4.2, 1H), 3.79 (s, 3H), 3.96 (dd,
J¼10.5,1.8,1H), 4.18 (dd, J¼11.1, 6.1, 1H), 4.37 (dd, J¼14.7, 5.5,1H), 4.46
(dd, J¼14.7, 5.8,1H), 5.84 (ddd, J¼10.2, 4.5, 2.1,1H), 5.91 (d, J¼10.2, 1H),
6.66 (t, J¼5.4, 1H), 6.76–6.90 (m, 3H), 7.20–7.40 (m, 5H). 13C NMR
3. Conclusions
In conclusion in this paper we have reported an additional
transformation of pluripotent substrates 2 to yield two novel
classes of regioisomeric cyclohexenol derivatives and have dem-
onstrated that ring-opening reactions can be performed also on
complex polyfunctionalised norbornene derivatives, although
probably the conformation of the substrate has an influence on the
reaction outcome. It is worth noting that this synthetic approach is
completely stereoselective, both at the stage of the multicompo-
nent condensation and of the ring-opening reaction, and that both
enantiomers of the final compounds can be independently
prepared.
This diversity-oriented approach has been recently exploited to
discover novel inhibitors of protein–protein interactions involved in
apoptotic processes17 and will be further developed to produce an
even larger collection of diversified structures, starting from com-
mon substrates, such as 2, to be tested for their biological activity.
(CDCl3, 75 MHz)
d 22.5 (CH3), 23.3 (CH3), 25.2 (CH), 33.8 (CH3), 39.9
(CH2), 43.2 (CH2), 46.7 (CH), 48.5 (CH), 51.6 (CH3), 55.2 (CH3), 60.4
(CH),65.5(CH),69.8(CH),113.2(CH),116.1(CH),126.0(CH),127.5(CH),
127.8 (CH), 128.3 (CH), 128.7 (CH), 129.4 (CH), 129.7 (CH), 138.1 (C),
138.3 (C), 159.8 (C), 174.0 (C), 174.2 (C). nmax(liquid film) 3567, 3355,
2947, 1725, 1656, 1598, 1451, 1208, 1155, 1046 cmꢂ1. HRMS expected
for C29H38N2O5: 494.2781, found: 494.2800, 3.8 ppm.
4.2.3. (1RS,4SR,5RS,6SR)-Methyl 6-(N-((RS)-1-(benzylcarbamoyl)-3-
methylbutyl)-N-methylamino)-5-hydroxy-4-(3-methox-
yphenyl)cyclohex-2-enecarboxylate (6). Colourless oil. Rf 0.30
(EtOAc/PE 3:7). 1H NMR (CDCl3, 300 MHz)
d
0.93 (d, J¼6.6, 3H), 0.94
(d, J¼6.6, 3H), 1.17 (br s, 1H), 1.42–1.80 (m, 3H), 2.44 (s, 3H), 3.42
(dd, J¼8.1, 6.6,1H), 3.51 (d, J¼11.1,1H), 3.54 (s, 3H), 3.65 (br s,1H), 3.76
(ddt, J¼10.8, 3.6, 2.1, 1H), 3.82 (s, 3H), 4.10 (br s, 1H), 4.33 (dd, J¼14.7,
5.1, 1H), 4.46 (dd, J¼14.7, 6.0, 1H), 5.69 (br d, J¼10.2, 1H), 5.78 (dt,
J¼10.2, 2.1, 1H), 6.70 (m, 1H), 6.75 (d, J¼7.5, 1H), 6.86 (dd, J¼8.1, 2.5,
1H), 7.08 (t, J¼5.1, 1H), 7.20–7.27 (m, 5H), 7.30 (t, J¼7.8, 1H). 13C NMR
4. Experimental part
4.1. General
(CDCl3, 75 MHz)
d 22.5 (CH3), 23.3 (CH3), 25.2 (CH), 34.5 (CH3), 38.8
(CH2), 42.9 (CH), 43.3 (CH3), 49.0 (CH), 52.0 (CH3), 55.3 (CH3), 62.5
(CH), 63.6 (CH), 69.7 (CH), 112.7 (CH), 114.2 (CH), 120.7 (CH), 126.2
(CH), 127.3 (CH), 127.6 (CH), 127.7 (CH), 128.6 (CH), 130.1 (CH), 138.6
(C),141.4 (C),160.1 (C),174.6 (C),174.8 (C). nmax(liquid film) 3553, 3361,
2948, 1724, 1660, 1596, 1454, 1363, 1227, 1025 cmꢂ1. HRMS expected
for C29H38N2O5: 494.2781, found: 494.2789, 1.6 ppm.
All solvents and reagents were obtained from commercial sup-
pliers and used without further purification. NMR spectra were
recorded with a VARIAN ‘MERCURYplus 3000 spectrometer. IR
spectra were recorded on a Perkin–Elmer 881 spectrophotometer
in CHCl3 solution. GC–MS analyses were carried out on a Hewlett
Packard 5890 Series II, using a HP-1 column, coupled with a HP-
5971A spectrometer (electron impact). HRMSs were recorded
with a MicroMass Autospec Instrument. Optical rotations were
determined with a Jasco DP-181 polarimeter, using a Jasco cyclin-
drical cell 10ꢁ100 mm.
4.3. Ring-opening of racemic bicyclic alcohol 7
Substrate 7 (69 mg, 0.19 mmol), phenylboronic acid (28 mg,
0.23 mmol), Pd(C6H5CN)2Cl2 (7 mg, 0.019 mmol) and 1,3-bis(di-
phenylphosphine)propane (8 mg, 0;021 mmol) were placed under
Ar and MeOH (2.4 mL) and 5 M Cs2CO3 (0.19 mmol, 38 mL) were
4.2. Ring-opening of racemic bicyclic ester 3
added. The reaction was heated at 60 ꢀC overnight, then diluted
with brine and extracted with EtOAc. The crude was purified by
flash chromatography (PE/EtOAc 4:6 to 3:7), yielding 67 mg (80%)
of a 62:38 mixture of compounds 8 and 9.
A mixture of zinc dust (420 mg, 6.5 mmol) and Ni(PPh3)2Cl2
(42 mg, 65 mmol) in dry acetonitrile (2 mL) was vigorously stirred
for 20 min under Ar at 50 ꢀC, then substrate 3 (50 mg, 0.13 mmol)
dissolved in acetonitrile (1 mL) was added and after 15 min also 3-
iodoanisole (31 mL, 0.26 mmol) was added. The reaction mixture
was stirred for 48 h, then filtered over a Celite pad and purified by
flash chromatography (PE/AcOEt 7:3 to 1:1) yielding 4 mg of adduct
4 (10%), 19 mg of adduct 5 (30%) and 19 mg of adduct 6 (30%).
4.3.1. (RS)-2-(N-((1RS,4RS,5SR,6RS)-5-Hydroxy-6-(hydroxymethyl)-
4-phenylcyclohex-2-enyl)-N-methylamino)-N-benzyl-4-methyl-
pentanamide (8). Colourless oil. Rf 0.38 (EtOAc/PE 6:4). 1H NMR
(CDCl3, 300 MHz)
d
0.96 (t, J¼6.4, 6H), 1.55–1.70 (m, 3H), 1.85–1.95
(m, 1H), 2.44 (s, 3H), 3.27 (t, J¼7.2, 1H), 3.53 (d, J¼9.6, 1H), 3.66 (dd,
J¼5.8, 3.6, 1H), 3.74 (dd, J¼10.9, 6.3, 1H), 3.85 (dd, J¼10.9, 4.5, 1H),
3.91 (dd, J¼10.8, 6.1, 1H), 4.41 (dd, J¼14.6, 5.6, 1H), 4.50 (dd, J¼14.6,
6.0, 1H), 5.85 (m, 2H), 6.40 (t, J¼5.7, 1H), 7.20–7.40 (m, 10H). 13C
4.2.1. (E)-Methyl
methylamino)acrylate (4). Colourless oil. Rf 0.30 (EtOAc/PE 3:7). 1H
NMR (CDCl3, 300 MHz)
3-(N-(1-(benzylcarbamoyl)-3-methylbutyl)-N-
d
0.90 (d, J¼6.6, 3H), 0.94 (d, J¼6.6, 3H),
NMR (CDCl3, 75 MHz) d 22.6 (CH3), 23.5 (CH3), 25.4 (CH), 33.3 (CH3),
1.40–1.80 (m, 3H), 2.72 (s, 3H), 3.62 (s, 3H), 3.89 (dd, J¼9.9, 5.4, 1H),
4.42 (d, J¼5.7, 1H), 4.68 (d, J¼13.2, 1H), 6.38 (t, J¼5.4, 1H), 7.20–7.40
39.8 (CH and CH2), 43.7 (CH2), 47.1 (CH), 61.7 (CH), 64.3 (CH2), 66.5
(CH), 70.7 (CH), 127.79 (CH), 127.85 (CH), 128.1 (CH), 128.3 (CH),
128.8 (CH), 128.9 (CH), 130.2 (CH), 130.5 (CH), 137.5 (C), 138.3 (C),
173.4 (C). nmax(liquid film) 3600–3200 (br), 3427, 2953, 1661, 1452,
(m, 5H) 7.52 (d, J¼12.9, 1H). 13C NMR (CDCl3, 75 MHz)
d 21.5 (CH3),
23.2 (CH3), 24.6 (CH), 33.3 (CH3), 37.5 (CH2), 43.6 (CH2), 50.7 (CH3),

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A. Basso et al. / Tetrahedron 66 (2010) 2390–2397
1251, 1168, 1028 cmꢂ1. HRMS expected for C27H36N2O3: 436.2726,
found: 436.2712, ꢂ3.2 ppm.
(qd, J¼10.6, 4.4, 1H), 2.32 (s, 3H), 3.00 (dd, J¼8.7, 6.2, 1H), 3.40 (d,
J¼10.6, 1H), 3.83 (t, J¼10.6, 1H), 3.96 (t, J¼4.0,1H), 4.24–4.33 (m, 2H),
5.85 (d, J¼10.4, 1H), 6.01–6.09 (m, 1H), 6.07 (s, 1H), 7.04 (br s, 1H),
7.16 (dd, J¼4.9, 1.1, 1H), 7.21 (dd, J¼7.3, 2.8, 1H), 7.29 (dd, J¼7.3, 2.8,
1H), 7.32 (dd, J¼4.8, 1.1, 1H), 7.76 (dd, J¼4.9, 1.1). 13C NMR (CDCl3,
4.3.2. (RS)-2-(N-((1SR,2RS,5SR,6RS)-6-Hydroxy-2-(hydroxymethyl)-
5-phenylcyclohex-3-enyl)-N-methylamino)-N-benzyl-4-methyl-
pentanamide (9). Colourless oil. Rf 0.44 (EtOAc/PE 6:4). 1H NMR
75 MHz)
d 22.4 (CH3), 23.6 (CH3), 25.2 (CH), 28.7 (CH3), 33.9 (CH3),
(CDCl3, 300 MHz)
d
0.94 (d, J¼5.9, 6H), 1.25 (br s, 1H), 1.50–1.80 (m,
35.1 (CH), 40.3 (CH2), 41.2 (CH), 50.6 (C), 59.1 (CH), 64.7 (CH2), 67.1
(CH), 72.6 (CH), 123.5 (CH), 124.6 (CH), 125.0 (CH), 127.5 (CH), 129.9
(CH), 130.3 (CH), 131.4 (CH), 134.8 (CH), 139.1 (C), 173.3 (C).
3H), 2.57 (s, 3H), 2.92(m,1H) 3.21 (dd, J¼10.6, 0.8,1H), 3.35 (dd, J¼8.4,
6.1, 1H), 3.62 (m, 1H), 3.66 (dd, J¼10.6, 7.4, 1H), 3.79 (dd, J¼10.6, 3.9,
1H), 4.11 (m, 1H), 4.32 (dd, J¼14.5, 5.1, 1H), 4.54 (dd, J¼14.5, 6.2, 1H),
5.64 (dm, J¼10.2,1H), 5.70 (ddd, J¼10.2, 2.1,1.8,1H), 6.50(t, J¼5.3,1H),
nmax(liquid film) 3426, 2957, 1665, 1500,1394,1284,1190, 1028 cmꢂ1
.
GC–MS (14.8 min) 400 (31, Mꢂt-BuNHCO) 200 (9),175 (23),153 (13),
128 (13), 100 (100), 97 (89), 79 (14), 57 (32), 42 (25). HRMS expected
for C26H37BN2O3S2: 500.2339, found: 500.2321, ꢂ3.5 ppm.
7.10–7.40 (m, 10H). 13C NMR (CDCl3, 75 MHz)
d 22.7 (CH3), 23.3 (CH3),
25.5 (CH), 34.3 (CH3), 35.6 (CH), 39.5 (CH2), 43.8 (CH2), 49.5 (CH), 65.2
(CH), 66.5 (CH), 66.9 (CH2), 70.7 (CH), 127.4 (CH), 127.6 (CH), 127.8
(CH), 128.1 (CH), 128.7 (CH), 128.9 (CH), 129.1 (CH), 130.1 (CH), 138.3
(C),140.5 (C),173.9 (C). nmax(liquid film) 3600–3200 (br), 3429, 2949,
1664, 1601, 1490, 1184, 1023 cmꢂ1. HRMS expected for C27H36N2O3:
436.2726, found: 436.2718, ꢂ1.8 ppm.
4.3.6. (RS)-2-(N-((1SR,2RS,5SR,6RS)-6-Hydroxy-2-(hydroxymethyl)-
5-(thiophen-3-yl)cyclohex-3-enyl)-N-methylamino)-N-tert-butyl-4-
methylpentanamide (12). It was obtained according to the
procedure described in Section 4.3, purification by flash chroma-
tography (eluent: PE/EtOAc 4:6, yield 62%). Colourless oil. Rf 0.48
4.3.3. (RS)-2-(N-((1RS,2SR,3RS,4SR)-3-(Hydroxymethyl)-7-oxa-bicy-
clo[2.2.1]hept-5-en-2-yl)-N-methylamino)-N-benzyl-4-methyl-
pentanamide (7). Compound 3 (256 mg, 0.66 mmol) dissolved in
dry diethylether (2 mL) was added at 0 ꢀC to a suspension of LAH
(50 mg, 1.32 mmol) in dry diethylether (2 mL) under a nitrogen at-
mosphere. After 1 h the reaction was complete by TLC analysis and
was quenched by addition of EtOAc and 0.2 M HCl; the mixture was
then filtered over a Celite pad and the organic phase washed with
saturated sodium bicarbonate and brine. The crude (228 mg, 96%)
did not need further purification. Colourless oil. Rf 0.10 (EtOAc/PE
(EtOAc/PE 7:3). 1H NMR (CDCl3, 300 MHz)
d
0.95 (d, J¼6.0, 6H), 1.37
(s, 9H), 1.37–1.68 (m, 5H), 2.59 (s, 3H), 2.95 (m, 1H), 3.14–3.21
(m, 2H), 3.67 (dd, J¼10.0, 8.9, 1H), 3.77 (t, J¼3.1, 1H), 3.84 (dd,
J¼10.7, 3.6,1H), 4.20 (br s,1H), 5.68 (m, 2H), 5.73 (br s,1H), 6.94 (dd,
J¼5.0, 1.3, 1H), 7.10 (br s, 1H), 7.36 (dd, J¼5.0, 2.9, 1H). 13C NMR
(CDCl3, 75 MHz) d 22.6 (CH3), 23.6 (CH3), 25.5 (CH), 28.9 (CH3), 34.4
(CH3), 35.4 (CH), 39.7 (CH2), 45.4 (CH), 51.4 (C), 65.1 (CH), 67.3
(CH2), 67.5 (CH), 69.7 (CH), 122.3 (CH), 126.8 (CH), 127.4 (CH), 127.7
(CH), 129.8 (CH), 141.3 (C), 173.1 (C). nmax(liquid film) 3600–3200
(br), 3430, 2998, 2955, 1667, 1451, 1364, 1191, 1046 cmꢂ1. GC–MS
(11.2 min) 308 (100, Mꢂt-BuNHCO), 161 (5), 142 (6), 123 (6), 100
(60), 84 (10), 72 (5), 58 (21), 57 (15), 42 (14). HRMS expected for
C22H36N2O3S: 408.2447, found: 408.2454, 1.7 ppm.
7:3). 1H NMR (CDCl3, 300 MHz)
d
0.92 (d, J¼6.9, 3H), 0.94 (d, J¼6.9,
3H), 1.40–1.95 (m, 3H), 2.29 (m, 1H), 2.52 (s, 3H), 2.58 (d, J¼3.6, 1H),
3.20 (dd, J¼11.4, 7.8,1H), 3.36 (dd, J¼11.1, 6.3, 1H), 3.57 (dd, J¼9.9, 4.5,
1H), 4.40 (d, J¼6.0, 2H), 4.84 (d, J¼4.2, 1H), 4.96 (s, 1H), 6.20
(dd, J¼6.0, 1.8, 1H), 6.32 (dd, J¼6.0, 1.5, 1H), 7.20–7.40 (m, 5H) 8.37
4.4. Synthesis of optically pure bicyclic amino acids
(br s, 1H). 13C NMR (CDCl3, 75 MHz)
d 22.0 (CH3), 23.7 (CH3), 25.6
(CH), 34.4 (CH3), 37.4 (CH2), 43.6 (CH2), 44.1 (CH), 64.1 (CH2), 65.7
(CH), 66.8 (CH), 79.3 (CH), 81.3 (CH), 127.6 (CH), 128.3 (CH), 128.8
(CH), 135.3 (CH), 136.0 (CH), 138.4 (C), 171.5 (C). nmax(liquid film)
4.4.1. (1S,2R,3S,4R)-Benzyl 3-(benzylamino)-7-oxa-bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (14). Compound 13 (865 mg, 2.11 mmol)
was dissolved in dry DCM (9 mL) and treated with trifluoroacetic
acid (1 mL) under a N2 atmosphere. After 1 h (TLC monitoring) the
solvents were removed under reduced pressure and the crude was
partitioned between Et2O and 1 M HCl; the aqueous phase was
then neutralised with solid sodium carbonate (pH 9) and extracted
with DCM/MeOH 9:1. The organic phase was dried and the solvents
removed under vacuum, the crude material (95%) was used without
further purification in the following reaction. Deprotected bicyclic
amino ester (491 mg, 2.00 mmol) was dissolved in MeOH (12.8 mL)
3600–3200 (br), 3430, 2986, 1655, 1448, 1224, 1134, 1045 cmꢂ1
.
GC–MS (9.8 min) 318 (3, M),185 (12),184 (MꢂBnNHCO,100), 110 (9),
91 (21), 84 (12), 82 (7), 69 (8), 59 (7), 43 (6), 42 (16), 41 (6). HRMS
expected for C21H30N2O3: 358.2256, found: 358.2271, 4.1 ppm.
4.3.4. (RS)-2-(N-((1RS,2SR,3RS,4SR)-3-(Hydroxymethyl)-7-oxa-bicy-
clo[2.2.1]hept-5-en-2-yl)-N-methylamino)-N-tert-butyl-4-methyl-
pentanamide (10). It was obtained similarly to
corresponding ester (yield 91%). Colourless oil. Rf 0.85 (EtOAc/PE
7:3). 1H NMR (CDCl3, 300 MHz)
7 from the
and AcOH (3.2 mL) and benzaldehyde (304 mL, 3.00 mmol) was
d
0.92 (d, J¼6.6, 3H), 0.94 (d, J¼6.6,
added under a N2 atmosphere. After 1.5 h the reaction mixture was
cooled to 0 ꢀC and NaBH3CN (220 mg, 3.51 mmol) was added por-
tionwise over a 10 min period. After 0.5 h the reaction mixture was
poured into saturated NaHCO3 (30 mL) and the aqueous phase
extracted with DCM (3ꢁ25 mL). The combined organics were dried
and concentrated under vacuum, yielding 651 mg (97%) of a col-
3H), 1.34 (s, 9H), 1.38–1.74 (m, 3H), 2.26 (tdd, J¼11.1, 4.2, 3.5, 1H),
2.33 (s, 3H), 2.48 (d, J¼3.6, 1H), 2.96 (br s, 1H), 3.19 (dd, J¼9.0,5.5,
1H), 3.38 (dd, J¼11.1, 7.4, 1H), 3.44 (dd, J¼11.1, 6.7, 1H), 4.86 (s, 1H),
4.92 (d, J¼4.5, 1H), 6.37 (dd, J¼5.8, 1.4, 1H), 6.41 (dd, J¼5.8, 1.8, 1H),
6.49 (br s, 1H). 13C NMR (CDCl3, 75 MHz)
d 22.2 (CH3), 23.6 (CH3),
25.6 (CH), 28.6 (CH3), 34.4 (CH3), 38.7 (CH2), 43.2 (CH), 50.9 (C),
64.7 (CH2), 65.2 (CH), 66.7 (CH), 79.3 (CH), 82.2 (CH), 135.4 (CH),
135.7 (CH), 173.5 (C). nmax(liquid film) 3600–3200 (br), 3425, 2994,
1660, 1443, 1332, 1181, 1041 cmꢂ1. HRMS expected for C18H32N2O3:
324.2413, found: 324.2413, 0 ppm.
ourless oil. Rf 0.40 (EtOAc/PE 1:1). 1H NMR (CDCl3, 300 MHz)
d 1.79
(s, 1H), 2.77 (d, J¼8.1, 1H), 3.18 (d, J¼8.1, 1H), 3.71 (d, J¼13.8, 1H),
3.87 (d, J¼13.8, 1H), 4.83 (s, 1H), 5.08 (s, 1H), 5.16 (d, J¼12.6, 1H),
5.21 (d, J¼12.6, 1H), 6.30 (dd, J¼6.0, 1.5, 1H), 6.35 (dd, J¼6.0, 1.5, 1H),
7.20–7.41 (m, 10H). 13C NMR (CDCl3, 75 MHz)
d 47.8 (CH), 51.8 (CH2),
59.8 (CH), 66.6 (CH2), 79.5 (CH), 80.9 (CH), 126.8 (CH), 127.8 (CH),
128.2 (CH), 128.3 (CH), 128.5 (CH), 135.5 (CH), 135.8 (C), 137.1 (CH),
139.8 (C), 172.3 (C). nmax(liquid film) 3036, 2942, 1722, 1601, 1442,
4.3.5. (RS)-2-(N-((4aRS,5RS,8RS,8aSR)-4a,5,8,8a-Tetrahydro-2,8-
di(thiophen-3-yl)-4H-benzo[d][1,3,2]dioxaborinin-5-yl)-N-methyl-
amino)-N-tert-butyl-4-methylpentanamide (11). It was obtained
according to the procedure described in Section 4.3, purification by
flash chromatography (eluent: PE/EtOAc 8:2, yield 38%). Colourless
1367, 1163, 1107, 1010 cmꢂ1
335.1521, found: 335.1518, ꢂ0.8 ppm.
. HRMS expected for C21H21NO3:
oil. Rf 0.85 (EtOAc/PE 7:3). 1H NMR (CDCl3, 300 MHz)
3H), 0.97 (d, J¼7.5, 3H), 1.35 (s, 9H), 1.50–1.73 (m, 3H), 2.17
d
0.95 (d, J¼7.5,
4.4.2. (1S,2S,3S,4R)-Methyl
3-(benzylamino)-7-oxa-bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (15). Derivative 14 (710 mg, 2.12 mmol)

A. Basso et al. / Tetrahedron 66 (2010) 2390–2397
2395
was dissolved in dry MeOH (7.5 mL) and sodium hydride (60% in
mineral oil,127 mg, 3.18 mmol) was added portionwise. The reaction
mixture was left stirring at room temperature under a nitrogen at-
mosphere for 4 h, then diluted with EtOAc and washed with satu-
rated NaHCO3. The organic phase was dried, concentrated in vacuo
and purified by flash chromatography (eluent from PE/EtOAc 7:3 to
4:6), yielding 450 mg (1.74 mmol, 82%) of product as a colourless oil.
(dd, J¼5.8, 1.8, 1H), 6.29 (dd, J¼5.8, 1.5, 1H), 7.24–7.44 (m, 15H), 8.22
(dd, J¼7.5, 3.8, 1H). 13C NMR (CDCl3, 75 MHz)
d 43.1 (CH2), 47.3 (CH),
50.3 (CH2), 52.2 (CH3), 65.1 (CH), 67.2 (CH), 77.8 (CH), 80.2 (CH),
127.1 (CH), 127.47 (CH), 127.52 (CH), 128.2 (CH), 128.48 (CH), 128.58
(CH), 128.64 (CH), 128.8 (CH), 130.3 (CH), 135.4 (CH), 136.0 (C), 136.8
(CH), 138.6 (C), 138.8 (C), 171.0 (C), 172.7 (C). nmax(liquid film) 3425,
20
3025, 1720, 1663, 1490, 1449, 1269, 1164, 1007 cmꢂ1. [
a
]
ꢂ26.3
D
Rf 0.32 (PE/EtOAc 1:1). 1H NMR (CDCl3, 300 MHz)
d
1.63 (s, 1H), 2.77
(c 1.0, CHCl3). HRMS expected for C30H30N2O4: 482.2206, found:
482.2198, ꢂ1.7 ppm.
(dd, J¼4.9, 2.7, 1H), 3.18 (d, J¼2.7, 1H), 3.66 (s, 3H), 3.88 (s, 2H), 4.83
(s, 1H), 5.12 (d, J¼2.7, 1H), 6.37 (dd, J¼6.0, 1.4, 1H), 6.41 (dd, J¼6.0, 1.7,
1H), 7.24–7.37 (m, 5H). 13C NMR (CDCl3, 75 MHz)
d
51.8 (CH), 52.1
4.5.4. (1R,2R,3R,4S)-Methyl
3-(N-((S)-1-(benzylcarbamoyl)(phe-
(CH2), 52.4 (CH3), 62.2 (CH), 78.5 (CH), 83.5 (CH), 127.0 (CH), 128.1
(CH), 128.8 (CH), 135.4 (CH), 135.5 (CH), 139.8 (C), 171.8 (C). nmax(li-
quid film) 2947, 1728, 1490, 1434, 1342, 1269, 1053 cmꢂ1. HRMS
expected for C15H17NO3: 259.1208, found: 259.1209, 0.4 ppm.
nyl)methyl)-N-benzylamino)-7-oxa-bicyclo[2.2.1]hept-5-ene-2-car-
20
boxylate ent-(18). [
a
]
þ27.0 (c 1.0, CHCl3).
D
4.5.5. (1S,2S,3S,4R)-Methyl 3-(N-((R)-1-(benzylcarbamoyl)-2-phenyl-
ethyl)-N-benzylamino)-7-oxa-bicyclo[2.2.1]hept-5-ene-2-carboxylate
(19). Yield 93%. Colourless oil. Rf 0.40 (PE/EtOAc 7:3). 1H NMR (CDCl3,
4.4.3. (1S,2S,3S,4R)-3-(Benzylamino)-7-oxa-bicyclo[2.2.1]hept-5-
ene-2-carboxylic acid (16)5. Compound 15 (450 mg,1.74 mmol) was
dissolved in dioxane (3 mL) and a 1 M volumetric standard NaOH
solution (1.91 mmol, 2.021 g) was added. After consumption of the
300 MHz)
d
2.90 (t, J¼4.2,1H), 2.99 (dd, J¼12.0, 6.3,1H), 3.33 (d, J¼3.9,
1H), 3.38 (dd, J¼12.0, 7.5, 1H), 3.55 (s, 3H), 3.78 (t, J¼6.0, 1H), 3.97 (d,
J¼15.3, 1H), 4.06 (d, J¼15.3, 1H), 4.31 (dd, J¼15.0, 6.6, 1H), 4.43 (dd,
J¼15.0,6.6,1H), 4.79(s,1H), 4.86(d, J¼4.2,1H), 6.32(dd,J¼6.0,1.3,1H),
6.35 (dd, J¼6.0,1.7,1H), 6.88 (t, J¼6.0,1H), 7.13–7.33 (m,15H).13C NMR
starting material
a 1 M volumetric standard HCl solution
(1.91 mmol, 1.980 g) was added and the solvents were removed in
vacuo. The resulting white solid containing 1.74 mmol of product
and 1.91 mmol of NaCl was used without further purification.
(CDCl3, 75 MHz)
d 35.6 (CH2), 43.2 (CH2), 47.3 (CH), 51.4 (CH2), 51.9
(CH3), 63.5 (CH), 64.1 (CH), 78.2 (CH), 82.7 (CH),126.3 (CH),127.0(CH),
127.3 (CH), 127.7 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.6 (CH),
129.3 (CH),135.7 (CH),136.0 (CH),138.2 (C),139.2 (C),139.4 (C),172.26
4.4.4. (1R,2R,3R,4S)-3-(Benzylamino)-7-oxa-bicyclo[2.2.1]hept-5-
ene-2-carboxylic acid ent-(16). The compound was prepared simi-
larly to 16 starting from ent-13, prepared according to a previously
reported procedure.5
(C), 172.28 (C). nmax(liquid film) 3388, 3029, 1727, 1665, 1492, 1218,
20
1026 cmꢂ1. [
a]
D
ꢂ28.9 (c 1.0, CHCl3). HRMS expected for C31H32N2O4:
496.2362, found: 496.2344, ꢂ3.6 ppm.
4.5. Synthesis of optically pure bicyclic alcohols 20–22
4.5.6. (1R,2R,3R,4S)-Methyl 3-(N-((S)-1-(benzylcarbamoyl)-2-phe-
nylethyl)-N-benzylamino)-7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbox-
20
Derivative 16 (1.00 mmol) or ent-16 was suspended in dry MeOH
(1 mL) and the aldehyde (1.10 mmol) and isocyanide (1.10 mmol)
were added at room temperature. The reaction mixture was left
stirring at room temperature for 24–48 h, then the solvent evapo-
rated and the crude purified by flash chromatography (PE/EtOAc
eluent). Ugi adducts 17–19 were reduced to the corresponding al-
cohols according to the procedure described in Section 4.3.3.
ylate ent-(19). [
a]
þ24.7 (c 1.0, CHCl3).
D
4.5.7. (R)-2-(N-Benzyl-N-((1R,2S,3R,4S)-3-(hydroxymethyl)-7-oxa-
bicyclo[2.2.1]hept-5-en-2-yl)amino)-N-(4-methoxyphenyl)-3-phe-
nylpropanamide (20). Yield 85%. Colourless oil. Rf 0.28 (EtOAc/PE
1:1). 1H NMR (CDCl3, 300 MHz)
d 1.85 (s, 1H), 2.38 (m, 1H), 2.80 (d,
J¼4.0, 1H), 3.04 (dd, J¼13.6, 5.1, 1H), 3.37 (dd, J¼13.6, 8.4, 1H), 3.43–
3.53 (m, 2H), 3.76 (s, 3H), 3.77 (dd, J¼8.4, 5.1, 1H), 3.88 (d, J¼14.7,
1H), 4.28 (d, J¼14.7, 1H), 4.90 (s, 1H), 4.96 (d, J¼4.4, 1H), 6.34 (dd,
J¼5.9, 1.4, 1H), 6.44 (dd, J¼5.9, 1.8, 1H), 6.80 (d, J¼9.0, 2H), 7.17–7.41
4.5.1. (1S,2S,3S,4R)-Methyl 3-(N-((R)-1-(4-methoxyphenylcarbamoyl)-
2-phenylethyl)-N-benzylamino)-7-oxa-bicyclo[2.2.1]hept-5-ene-2-car-
boxylate (17). Yield 72%. Colourless oil. Rf 0.4 (PE/EtOAc 7:3). 1H NMR
(m, 12H), 8.17 (s, 1H). 13C NMR (CDCl3, 75 MHz)
d 33.9 (CH2), 45.9
(CDCl3, 300 MHz)
d
3.04 (dd, J¼13.8, 6.0, 1H), 3.05 (t, J¼4.2, 1H), 3.38
(CH), 51.1 (CH2), 55.4 (CH3), 63.1 (CH), 64.5 (CH), 65.0 (CH2), 79.0
(CH), 81.8 (CH), 114.1 (CH), 121.0 (CH), 126.3 (CH), 127.3 (CH), 128.4
(CH), 128.5 (CH), 128.7 (CH), 129.3 (CH), 130.9 (C), 135.3 (CH), 135.9
(d, J¼4.0, 1H), 3.43 (s, 3H), 3.48 (dd, J¼13.8, 7.1, 1H), 3.80 (s, 3H), 3.85
(dd, J¼7.2, 6.0, 1H), 3.96 (d, J¼14.9, 1H), 4.17 (d, J¼14.9, 1H), 4.92 (s,
1H), 5.32 (d, J¼4.5, 1H), 6.39 (dd, J¼5.8, 1.2, 1H), 6.43 (dd, J¼5.8, 1.3,
1H), 6.82 (d, J¼9.0, 2H), 7.18–7.39 (m, 12H), 8.46 (s, 1H). 13C NMR
(CH), 139.3 (C), 139.7 (C), 156.1 (C), 171.0 (C). nmax(liquid film) 3600–
20
3200 (br), 3425, 3021,1660,1502,1195,1023 cmꢂ1. [
a
]
þ11.1 (c 1.0,
D
(CDCl3, 75 MHz)
d
34.4 (CH2), 48.3 (CH), 52.1 (CH3), 55.5 (CH3), 64.5
CHCl3). HRMS expected for C30H32N2O4: 484.2362, found:
(CH), 64.6 (CH), 78.4 (CH), 82.4 (CH),114.1 (CH),121.0 (CH),126.3 (CH),
127.4 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH), 129.3 (CH), 131.2 (C),
135.6 (CH), 136.2 (CH), 139.36 (C), 139.42 (C),156.1 (C), 170.4 (C), 172.4
484.2349, ꢂ2.7 ppm.
4.5.8. (S)-2-(N-Benzyl-N-((1S,2R,3S,4R)-3-(hydroxymethyl)-7-oxa-
(C). nmax(liquid film) 3004, 1725, 1676, 1601, 1504, 1428, 1297, 1181,
bicyclo[2.2.1]hept-5-en-2-yl)amino)-N-(4-methoxyphenyl)-3-phe-
1026 cmꢂ1. [
a
]
ꢂ24.8 (c 1.0, CHCl3). HRMS expected for C31H32N2O5:
nylpropanamide ent-(20). [
a
]
ꢂ10.8 (c 1.0, CHCl3).
20
20
D
D
512.2311, found: 512.2319, 1.6 ppm.
4.5.9. (R)-2-(N-Benzyl-N-((1R,2S,3R,4S)-3-(hydroxymethyl)-7-oxa-
bicyclo[2.2.1]hept-5-en-2-yl)amino)-N-benzyl-2-phenylacetamide
(21). Yield 86%. Colourless oil. Rf 0.42 (EtOAc/PE 7:3). 1H NMR (CDCl3,
4.5.2. (1R,2R,3R,4S)-Methyl 3-(N-((S)-1-(4-methoxyphenylcarbamoyl)-
2-phenylethyl)-N-benzylamino)-7-oxa-bicyclo[2.2.1]hept-5-ene-2-car-
20
boxylate ent-(17). [
a
]
þ25.5 (c 1.0, CHCl3).
300 MHz)
d
2.30 (m, 1H), 2.46 (dd, J¼5.5, 3.4, 1H), 3.00 (d, J¼4.3, 1H),
D
3.17 (td, J¼9.9, 3.1, 1H), 3.41 (s, 1H), 3.56 (d, J¼15.1, 1H), 3.67 (dt,
J¼9.9, 5.2, 1H), 4.31 (d, J¼15.1, 1H), 4.38 (dd, J¼14.7, 5.4, 1H), 4.49 (s,
1H), 4.50 (dd, J¼14.7, 6.4, 1H), 4.68 (d, J¼4.4, 1H), 6.07 (dd, J¼5.8, 1.8,
1H), 6.12 (dd,1H, J¼5.8,1.6,1H), 7.19–7.42 (m,15H), 7.72 (t, J¼5.7,1H).
4.5.3. (1S,2S,3S,4R)-Methyl
3-(N-((R)-1-(benzylcarbamoyl)(phe-
nyl)methyl)-N-benzylamino)-7-oxa-bicyclo[2.2.1]hept-5-ene-2-car-
boxylate (18). Yield 57%. Colourless oil. Rf 0.28 (PE/EtOAc 7:3). 1H
NMR (CDCl3, 300 MHz)
d
2.99 (t, J¼4.5, 1H), 3.44–3.45 (m, 2H), 3.59
13C NMR (CDCl3, 75 MHz)
d 43.1 (CH2), 44.6 (CH), 50.1 (CH2), 65.0
(s, 3H), 3.61 (d, J¼15.0,1H), 4.25 (dd, J¼15.0, 3.8,1H), 4.26 (d, J¼15.0,
1H), 4.57 (s, 1H), 4.88 (dd, J¼15.0, 7.5, 1H), 4.95 (d, J¼4.5, 1H), 6.07
(CH), 65.1 (CH2), 67.0 (CH), 78.3 (CH), 80.1 (CH), 127.18 (CH), 127.23
(CH), 127.6 (CH), 128.1 (CH), 128.47 (CH), 128.53 (CH), 128.6 (CH),

2396
A. Basso et al. / Tetrahedron 66 (2010) 2390–2397
130.1 (CH), 133.9 (CH), 136.0 (C), 136.9 (CH), 138.7 (C), 139.3 (C), 171.7
(CH2), 55.4 (CH3), 56.2 (CH), 61.1 (CH2), 65.4 (CH), 69.7 (CH), 114.1
(CH), 121.6 (CH), 126.4 (CH), 127.3 (CH), 127.7 (CH), 128.4 (CH), 128.6
(CH),128.8 (CH), 129.1 (CH), 129.4 (CH), 129.6 (CH), 130.1 (CH), 130.3
(CH), 130.5 (C), 137.9 (C), 138.8 (C), 140.0 (C), 156.4 (C), 171.1 (C).
(C). nmax(liquid film) 3600–3200 (br), 3349, 2997, 1655, 1493, 1205,
20
1015 cmꢂ1
.
[a]
ꢂ33.2 (c 1.0, CHCl3). HRMS expected for
D
C29H30N2O3: 454.2256, found: 454.2251, ꢂ1.1 ppm.
nmax(liquid film) 3600–3200 (br), 3002, 1667, 1597, 1505, 1189,
20
4.5.10. (S)-2-(N-Benzyl-N-((1S,2R,3S,4R)-3-(hydroxymethyl)-7-oxa-
1026 cmꢂ1
.
[
a
]
D
þ47.9 (c 1.2, CHCl3). HRMS expected for
bicyclo[2.2.1]hept-5-en-2-yl)amino)-N-benzyl-2-phenylacetamide
C36H39N2O4: 563.2910, found: 563.2899, ꢂ1.9 ppm.
20
ent-(21). [
a
]
þ31.1 (c 1.0, CHCl3).
D
4.6.4. (S)-2-(N-Benzyl-N-((1S,4S,5R,6S)-5-hydroxy-6-(hydroxy-
4.5.11. (R)-2-(N-Benzyl-N-((1R,2S,3R,4S)-3-(hydroxymethyl)-7-oxa-
bicyclo[2.2.1]hept-5-en-2-yl)amino)-N-benzyl-3-phenylpropanamide
(22). Yield 85%. Colourless oil. Rf 0.28 (PE/EtOAc 1:1). 1H NMR
methyl)-4-phenylcyclohex-2-enyl)amino)-N-(4-methoxyphenyl)-3-
20
phenylpropanamide ent-(24). [
a
]
D
ꢂ54.8 (c 0.9, CHCl3).
(CDCl3, 300 MHz)
d
1.95 (t, J¼4.8, 1H), 2.21 (m, 1H), 2.88 (d, J¼3.9,
4.6.5. (R)-2-(N-Benzyl-N-((1S,2R,5S,6R)-6-hydroxy-2-(hydroxy-
methyl)-5-phenylcyclohex-3-enyl)amino)-N-benzyl-2-phenyl-
acetamide (25). Yield 82%. Yellowish foam. Rf 0.38 (PE/EtOAc 6:4).
1H), 3.02 (dd, J¼18.9, 5.4, 1H), 3.27 (dd, J¼18.9, 8.7, 1H), 3.33–3.34
(m, 2H), 3.62 (dd, J¼8.7, 5.4, 1H), 3.92 (d, J¼15.0, 1H), 4.17 (d, J¼15.0,
1H), 4.25 (dd, J¼14.7, 5.7, 1H), 4.33 (dd, J¼14.7, 5.7, 1H), 4.79 (d,
J¼4.5, 1H), 4.82 (s, 1H), 6.31 (dd, J¼5.9, 1.5, 1H), 6.41 (dd, J¼5.9, 1.8,
1H), 6.45 (t, J¼6.0, 1H), 7.09–7.32 (m, 15H). 13C NMR (CDCl3,
1H NMR (CDCl3, 300 MHz)
d 2.81 (br s, 2H), 3.33 (br s, 1H), 3.70–
3.90 (m, 3H), 4.29–4.48 (m, 5H), 4.83 (t, J¼6.3, 1H), 5.63 (d, J¼9.9,
1H), 5.81 (t, J¼5.4, 1H), 5.94 (dt, J¼9.9, 2.1, 1H), 6.84–7.47 (m, 20H).
75 MHz)
d
34.7 (CH2), 43.2 (CH2), 45.5 (CH), 50.9 (CH2), 62.8 (CH),
13C NMR (CDCl3, 75 MHz)
d 37.3 (CH), 43.4 (CH2), 49.0 (CH), 52.8
64.1 (CH), 65.1 (CH2), 78.9 (CH), 82.3 (CH), 126.3 (CH), 127.1 (CH),
127.4 (CH),127.9 (CH),128.2 (CH), 128.5 (CH),128.6 (CH),129.2 (CH),
135.2 (CH), 135.9 (CH), 138.1 (C), 139.0 (C), 139.9 (C), 172.8 (C).
(CH2), 58.5 (CH), 63.0 (CH2), 66.0 (CH), 71.7 (CH), 126.7 (CH), 126.8
(CH), 127.1 (CH), 127.4 (CH), 127.7 (CH), 128.09 (CH), 128.14 (CH),
128.4 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 129.0 (CH), 129.7
(CH), 133.0 (CH), 137.4 (C), 137.9 (C), 140.4 (C), 140.7 (C), 172.9 (C).
nmax(liquid film) 3600–3200 (br), 3419, 3005, 1653, 1496, 1214,
20
1017 cmꢂ1
.
[a
]
þ7.2 (c 1.0, CHCl3). HRMS expected for
nmax(liquid film) 3600–3200 (br), 3419, 2991, 1664,1598,1491, 1447,
D
1206, 1042 cmꢂ1. [
a]
ꢂ153.0 (c 1.1, CHCl3). HRMS expected for
20
C30H32N2O3: 468.2413, found: 468.2401, ꢂ2.6 ppm.
D
C35H37N2O3: 533.2804, found: 533.2800, ꢂ0.8 ppm.
4.5.12. (S)-2-(N-Benzyl-N-((1S,2R,3S,4R)-3-(hydroxymethyl)-7-oxa-
bicyclo[2.2.1]hept-5-en-2-yl)amino)-N-benzyl-3-phenylpropanamide
4.6.6. (S)-2-(N-Benzyl-N-((1R,2S,5R,6S)-6-hydroxy-2-(hydroxy-
20
ent-(22). [
a
]
D
ꢂ6.9 (c 1.0, CHCl3).
methyl)-5-phenylcyclohex-3-enyl)amino)-N-benzyl-2-phenyl-
20
acetamide ent-(25). [
a
]
þ151.2 (c 0.9, CHCl3).
D
4.6. Ring-opening of optically pure bicyclic alcohols 20–22
4.6.7. (R)-2-(N-Benzyl-N-((1S,2R,5S,6R)-6-hydroxy-2-(hydroxy-
methyl)-5-phenylcyclohex-3-enyl)amino)-N-benzyl-3-phenyl-
propanamide (26). Yield 40%. Yellowish foam. Rf 0.25 (PE/EtOAc
Compounds 20–22 and ent-20-ent-22 underwent the ring-
opening process according to the procedure described in Section
4.3.
7:3). 1H NMR (CDCl3, 300 MHz)
d 1.56 (br s, 1H), 2.77 (br s, 1H), 3.18
and 3.24 (part AB of an ABX system, Jax¼3.4, Jbx¼11.8, Jab¼11.8, 2H),
3.24–3.51 (m, 3H), 3.66–3.75 (m, 3H), 3.90 (d, J¼13.5, 1H), 4.18 (dd,
J¼14.8, 5.4, 1H), 4.31 (dd, J¼14.8, 4.3, 1H), 4.38 (s, 1H), 4.57 (d,
J¼13.5, 1H), 5.41 (t, J¼4.8, 1H), 5.67 (d, J¼10.5, 1H), 5.80 (dt, J¼10.5,
4.6.1. (R)-2-(N-Benzyl-N-((1S,2R,5S,6R)-6-hydroxy-2-(hydroxy-
methyl)-5-phenylcyclohex-3-enyl)amino)-N-(4-methoxyphenyl)-3-
phenylpropanamide (23). Yield 44%. Yellowish foam. Rf 0.48 (PE/
EtOAc 6:4). 1H NMR (CDCl3, 300 MHz)
d
1.51 (d, J¼2.3, 1H), 2.87 (br
1.9, 1H), 6.90–7.42 (m, 20H). 13C NMR (CDCl3, 75 MHz)
d 34.8 (CH2),
s, 1H), 3.21–3.50 (m, 5H), 3.70 (br s, 1H), 3.74 (s, 3H) 3.77–3.80 (m,
1H) 3.94 (d, J¼13.7, 1H), 3.92–3.98 (m, 1H), 4.42 (br s, 1H), 4.50 (d,
J¼13.7, 1H), 5.66 (d, J¼10.2, 1H), 5.78 (dt, J¼10.2, 1.9, 1H), 6.77 (d,
37.4 (CH), 43.2 (CH2), 49.7 (CH), 52.2 (CH2), 59.1 (CH), 63.8 (CH),
64.6 (CH2), 71.3 (CH), 126.3 (CH), 126.9 (CH), 127.28 (CH), 127.31
(CH), 127.7 (CH), 128.45 (CH), 128.47 (CH), 128.51 (CH), 128.6 (CH),
128.95 (CH), 129.03 (CH), 129.3 (CH), 131.4 (CH), 137.7 (C), 138.5 (C),
J¼9.0, 1H), 7.12–7.43 (m, 17H). 13C NMR (CDCl3, 75 MHz)
d 34.8
(CH2), 37.4 (CH), 49.7 (CH), 52.3 (CH2), 55.4 (CH3), 60.0 (CH), 64.0
(CH), 65.3 (CH2), 70.5 (CH), 114.0 (CH), 121.8 (CH), 126.4 (CH), 126.9
(CH), 127.4 (CH), 127.5 (CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 129.0
(CH), 129.26 (CH), 129.29 (CH), 130.5 (CH), 131.1 (C), 139.0 (C), 140.0
140.2 (C), 140.5 (C), 172.9 (C). nmax(liquid film) 3600–3200(br),
20
3425, 3021, 1658, 1600, 1490, 1449, 1210, 1135, 1062 cmꢂ1. [
a]
D
ꢂ91.0 (c 1.5, CHCl3). HRMS expected for C36H39N2O3: 547.2961,
found: 547.3001, 7.3 ppm.
(C), 140.4 (C), 156.4 (C), 171.3 (C). nmax(liquid film) 3600–3200 (br),
20
2998, 1675, 1598, 1494, 1188, 1053, 1022 cmꢂ1. [
a
]
ꢂ92.7 (c 1.0,
4.6.8. (S)-2-(N-Benzyl-N-((1R,2S,5R,6S)-6-hydroxy-2-(hydroxy-
D
CHCl3). HRMS expected for C36H39N2O4: 563.2910, found:
methyl)-5-phenylcyclohex-3-enyl)amino)-N-benzyl-3-phenyl-
20
563.2892, ꢂ3.2 ppm.
propanamide ent-(26). [
a]
þ94.8 (C 0.7, CHCl3).
D
4.6.2. (S)-2-(N-Benzyl-N-((1R,2S,5R,6S)-6-hydroxy-2-(hydroxy-
4.6.9. (R)-2-(N-Benzyl-N-((1R,4R,5S,6R)-5-hydroxy-6-(hydroxy-
methyl)-4-phenylcyclohex-2-enyl)amino)-N-benzyl-3-phenyl-
propanamide (28). Yield 71% from 27. Yellowish foam. Rf 0.10 (PE/
methyl)-5-phenylcyclohex-3-enyl)amino)-N-(4-methoxyphenyl)-3-
20
phenylpropanamide ent-(23). [
a
]
þ99.8 (c 1.2, CHCl3).
D
EtOAc 7:3). 1H NMR (CDCl3, 300 MHz)
d
1.62 (tt, J¼10.6, 3.2, 1H) 1.97
4.6.3. (R)-2-(N-Benzyl-N-((1R,4R,5S,6R)-5-hydroxy-6-(hydroxy-
methyl)-4-phenylcyclohex-2-enyl)amino)-N-(4-methoxyphenyl)-3-
phenylpropanamide (24). Yield 24%. Yellowish foam. Rf 0.25 (PE/
(d, J¼7.4, 1H), 3.12 (d, J¼3.1, 1H), 3.19–3.38 (m, 3H), 3.65–3.74 (m,
3H), 3.94 (d, J¼14.0, 1H), 4.07–4.15 (m, 2H), 4.12 (d, J¼14.0, 1H), 4.17
(dd, J¼14.8, 5.6, 1H), 4.27 (dd, J¼14.8, 6.0, 1H), 5.42 (br s, 1H), 5.88
(ddd, J¼10.1, 5.0, 2.4, 1H), 6.18 (d, J¼10.2, 1H), 6.88–7.27 (m, 20H).
EtOAc 6:4). 1H NMR (CDCl3, 300 MHz)
d
1.74 (m, 1H), 1.90 (d, J¼5.9,
1H), 2.88 (br s, 1H), 3.13 (dd, J¼11.9, 1.8, 1H), 3.43–3.56 (m, 2H),
3.66–3.85 (m, 3H), 3.74 (s, 3H), 3.90 (d, J¼8.5, 1H), 3.98 (d, J¼13.8,
1H), 4.02–4.12 (m, 1H), 4.14 (d, J¼13.8, 1H), 5.89 (ddd, J¼10.3, 4.9,
2.4, 1H), 6.22 (d, J¼10.3, 1H), 6.77 (d, J¼9.0, 1H), 7.18–7.38 (m, 19H).
13C NMR (CDCl3, 75 MHz)
d 33.3 (CH2), 42.2 (CH), 43.2 (CH2), 46.7
(CH), 52.2 (CH2), 55.4 (CH), 60.0 (CH2), 65.3 (CH), 69.1 (CH), 126.4
(CH), 127.2 (CH), 127.4 (CH), 127.5 (CH), 127.7 (CH), 128.2 (CH), 128.5
(CH), 128.6 (CH), 128.7 (CH), 128.8 (CH), 129.3 (CH), 129.6 (CH),
130.4 (CH), 130.9 (CH), 137.5 (C), 138.4 (2ꢁC), 140.4 (C), 172.8 (C).
13C NMR (CDCl3, 75 MHz)
d 33.4 (CH2), 42.3 (CH), 46.6 (CH), 52.4

A. Basso et al. / Tetrahedron 66 (2010) 2390–2397
2397
nmax(liquid film) 3600–3200 (br), 3425, 3042, 2917, 1659, 1599,
(CDCl3, 75 MHz)
d
33.1 (CH2), 42.1 (CH), 43.1 (CH2), 44.4 (CH), 52.4
20
1490, 1448, 1356, 1223, 1040 cmꢂ1. [
a
]
þ23.4 (c 1.1, CHCl3). HPLC
(CH2), 54.7 (CH), 59.0 (CH2), 65.4 (CH), 68.6 (CH), 122.9 (CH), 126.4
(CH), 127.4 (CH), 127.5 (CH), 127.6 (CH), 128.4 (CH), 128.5 (CH), 128.6
(CH), 128.7 (CH), 129.3 (CH), 132.3 (CH), 134.6 (C), 137.5 (C), 137.9
(CH), 138.1 (C), 140.0 (C), 147.9 (CH), 151.3 (CH), 173.0 (C). nmax(liquid
D
(Diacel Chiralpack): 5.34 min (100%). HRMS expected for
C36H39N2O3: 547.2961, found: 547.2958, ꢂ0.5 ppm.
4.6.10. (S)-2-(N-Benzyl-N-((1S,4R,5R,6S)-5-hydroxy-6-(hydroxy-
film) 3600–3200 (br), 3427, 2962, 1651, 1491, 1229, 1116, 1046 cmꢂ1
.
20
methyl)-4-phenylcyclohex-2-enyl)amino)-N-benzyl-3-phenyl-
[a
]
þ4.5 (c 1.5, CHCl3). HRMS expected for C35H38N3O3: 548.2913,
D
20
propanamide ent-(28). [
a]
ꢂ22.7 (c 1.1, CHCl3). HPLC (Diacel
found: 548.2928, 2.7 ppm.
D
Chiralpack): 12.99 min (100%).
4.6.14. (S)-2-(N-Benzyl-N-((1S,4S,5R,6S)-5-hydroxy-6-(hydroxy-
4.6.11. (R)-2-(N-Benzyl-N-((1S,2R,5S,6R)-6-hydroxy-2-(hydroxy-
methyl)-5-(pyridin-3-yl)cyclohex-3-enyl)amino)-N-benzyl-3-phenyl-
propanamide (29). Yield 40%. Yellowish foam. Rf 0.70 (DCM/
methyl)-4-(pyridin-3-yl)cyclohex-2-enyl)amino)-N-benzyl-3-phenyl-
20
propanamide ent-(30). [
a]
ꢂ11.0 (c 0.93, CHCl3).
D
Acetone 1:1). 1H NMR (CDCl3, 300 MHz)
d 1.78 (br s, 1H), 2.77 (d,
Acknowledgements
J¼8.7, 1H), 3.15 and 3.25 (part AB of an ABX system, Jab¼11.9,
Jax¼3.4, Jbx¼11.7, 2H), 3.29–3.45 (m, 1H), 3.50 (d, J¼10.6, 1H), 3.63
(m, 2H), 3.79 (m, 2H), 3.95 (d, J¼13.9, 1H), 4.20 (dd, J¼14.7, 5.4, 1H),
4.31 (dd, J¼14.7, 6.0, 1H), 4.37 (s, 1H), 4.57 (d, J¼13.9, 1H), 5.39 (t,
J¼5.4, 1H), 5.62 (d, J¼10.0, 1H), 5.89 (dt, J¼10.1, 2.3, 1H), 6.92 (m,
1H), 7.16–7.34 (m, 15H), 7.56 (d, J¼7.9, 1H), 8.40 (d, J¼4.7, 1H), 8.44
The authors thank Dott.ssa Romina Vitale for her important
contribution to this work. Financial assistance by the University of
Genova, the Ministry of University and Research (PRIN 2006 project
"Diversity-oriented synthetic methodologies and strategies for the
preparation of biologically active compounds") and Fondazione S.
Paolo is gratefully acknowledged.
(d, J¼1.8, 1H). 13C NMR (CDCl3, 75 MHz)
d 35.0 (CH2), 37.7 (CH), 43.3
(CH2), 47.5 (CH), 52.4 (CH2), 58.3 (CH), 64.1 (CH2 and CH), 72.0 (CH),
123.6 (CH),126.0 (CH),126.5 (CH),127.4 (CH),127.8 (CH), 128.5 (CH),
128.6 (CH), 128.7 (CH), 128.9 (CH), 129.2 (CH), 132.6 (CH), 136.3
(CH), 136.5 (C), 137.6 (C), 138.2 (C), 140.2 (C), 148.4 (CH), 150.0 (CH).
References and notes
nmax(liquid film) 3600–3200 (br), 3428, 2987,1660, 1493, 1177,1123,
1. Do¨mling, A. Chem. Rev. 2006, 106, 17–89.
1067 cmꢂ1
.
[
a
]
ꢂ86.0 (c 1.26, CHCl3). HRMS expected for
20
2. Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125–147.
3. Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324–331.
4. Basso, A.; Banfi, L.; Riva, R.; Guanti, G. Tetrahedron Lett. 2004, 45, 587–590.
5. Basso, A.; Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005, 70, 575–579.
6. Basso, A.; Banfi, L.; Riva, R.; Guanti, G. Tetrahedron 2006, 62, 8830–8837.
7. Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58.
8. Schreiber, S. L. Science 2000, 287, 1964–1969.
9. Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48–58.
10. Bunnage, M. E.; Ganesh, T.; Masesane, I. B.; Orton, D.; Steel, P. G. Org. Lett. 2003,
5, 239–242.
11. Arjona, O.; Delapradilla, R. F.; Garcia, E.; Martindomenech, A.; Plumet, J. Tetra-
hedron Lett. 1989, 30, 6437–6440.
12. Harwood, L. M.; Jackson, B.; Prout, K.; Witt, F. J. Tetrahedron Lett. 1990, 31,
1885–1888.
13. Feng, C.-C.; Nandi, M.; Sambaiah, T.; Cheng, C.-H. J. Org. Chem. 1999, 64,
3538–3543.
D
C35H38N3O3: 548.2913, found: 548.2902, ꢂ2.0 ppm.
4.6.12. (S)-2-(N-Benzyl-N-((1R,2S,5R,6S)-6-hydroxy-2-(hydroxy-
methyl)-5-(pyridin-3-yl)cyclohex-3-enyl)amino)-N-benzyl-3-phenyl-
20
propanamide ent-(29). [
a
]
þ89.0 (c 0.35, CHCl3).
D
4.6.13. (R)-2-(N-Benzyl-N-((1R,4R,5S,6R)-5-hydroxy-6-(hydroxy-
methyl)-4-(pyridin-3-yl)cyclohex-2-enyl)amino)-N-benzyl-3-phenyl-
propanamide (30). Yield 26%. Yellowish foam. Rf 0.58 (DCM/
Acetone 1:1). 1H NMR (CDCl3, 300 MHz)
d
1.53 (t, J¼10.5, 1H), 2.67
(br s,1H), 3.13 and 3.28 (part AB of an ABX system, Jab¼15.9, Jax¼2.0,
Jbx¼10.1, 2H), 3.21 (d, J¼10.1, 1H), 3.64–3.84 (m, 3H), 3.91 (d, J¼14.1,
1H), 4.02 (d, J¼14.1, 1H), 4.24–4.36 (m, 4H), 5.26 (br s, 1H), 5.88
(ddd, J¼10.1, 5.1, 2.4,1H), 6.22 (d, J¼10.4,1H), 6.88 (m,1H), 7.16–7.34
(m, 15H), 7.58 (d, J¼7.8, 1H), 8.42 (d, J¼4.6,1H), 8.47 (s, 1H). 13C NMR
14. Lautens, M.; Dockendorff, C. Org. Lett. 2003, 5, 3695–3698.
15. Winkler, J. D.; Asselin, S. M.; Shepard, S.; Yuan, J. Org. Lett. 2004, 6, 3821–3824.
16. Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2001, 123, 6834–6839.
17. Di Micco, S.; Vitale, R.; Pellecchia, M.; Rega, M. F.; Riva, R.; Basso, A.; Bifulco, G.
J. Med. Chem. 2009, 52, 7856–7867.