A new family of conformationally constrained bicyclic diarylprolinol silyl ethers as organocatalysts

Article abstract of DOI:10.1002/adsc.201200922

Simple chemical manipulations of trans-4-L-hydroxy proline allow the access to a new family of bicyclic silyl ether organocatalysts that display some remarkable features. Apart from being extremely stable to hydrolytic conditions and possessing excellent catalytic performances, the rigidity of the bicyclic structure imposes a synclinal endo disposition of the bulky substituents with respect to the pyrrolidine ring, opposed to the more stable synclinal exo conformations of Jorgensen-Hayashi catalysts.

Full text of DOI:10.1002/adsc.201200922

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DOI: 10.1002/adsc.201200922
A New Family of Conformationally Constrained Bicyclic
Diarylprolinol Silyl Ethers as Organocatalysts
Marco Lombardo,a,* Elisa Montroni,a,b Arianna Quintavalla,a
and Claudio Trombinia
a
Dipartimento di Chimica “G. Ciamician”, Universitꢀ degli Studi di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax : (+39)-051-2099456; e-mail: marco.lombardo@unibo.it
Consorzio Interuniversitario “C.I.N.M.P.I.S.”, via Orabona 4, 70125 Bari, Italy
b
Received: October 16, 2012; Published online: November 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200922.
Abstract: Simple chemical manipulations of trans-4-
l-hydroxy proline allow the access to a new family
of bicyclic silyl ether organocatalysts that display
some remarkable features. Apart from being ex-
tremely stable to hydrolytic conditions and possess-
ing excellent catalytic performances, the rigidity of
the bicyclic structure imposes a synclinal endo dis-
position of the bulky substituents with respect to
the pyrrolidine ring, opposed to the more stable
synclinal exo conformations of Jørgensen–Hayashi
catalysts.
tivation modes.[5] Among them, a central role is cer-
tainly played by MacMillanꢁs imidazolidinones[6] (2)
and by Jørgensen-Hayashiꢁs diarylprolinol silyl
ethers[7] (3) (Figure 1).
Due to the ease of their preparation, the wide ver-
satility of their applications and the almost invariable
high stereochemical efficiency, Jørgensen–Hayashiꢁs
diarylprolinol silyl ethers 3 [3a: R=CH3, Ar=Ph; 3b:
R=CH3, Ar=3,5-(CF3)2C6H3] have become a de
facto standard when iminium/enamine-based reactivi-
ty is considered. They have been successfully em-
ployed in many useful asymmetric transformations,
such as carbonyl a-functionalisations, Michael addi-
tions, epoxidation, aziridination or cyclopropanation
reactions, as well as in amino-catalysed cascade reac-
tions.[8] More recently, the concept of trienamine acti-
vation mode was introduced[9] and diarylprolinol silyl
ethers have been used for the asymmetric functionali-
zation of g,d-double bonds.[10]
Keywords: bicyclic scaffolds; conformational con-
straints; diarylprolinol silyl ethers; hydrolytic stabil-
ity; organocatalysis
Thanks to the outstanding results obtained over the
A drawback of this family of compounds is their
last few years, asymmetric organocatalysis is now be- relative instability towards protodesilylation reactions,
coming one of the methods of choice for many syn- as recently reported by Zeitler and Gschwind.[11] Such
thetic transformations,[1] alongside the metal-catalysed parasitic reactions can significantly affect the catalytic
reactions[2] and organic bio-transformations.[3]
performances of diarylprolinol silyl ethers, both in
Starting with simple proline (1), initially proposed terms of activity and stereoselectivity,[12] and also
by List and Barbas III for the asymmetric intermolec- make catalyst storage and handling somewhat trou-
ular aldol addition reaction,[4] a number of classes of blesome.
“privileged” organocatalysts have further emerged,
A second issue recently addressed regards the rela-
able to promote many different reaction types, based tive orientation of the bulky O-protected diarylme-
either on covalent (iminium/enamine pathway) or thanol group with respect to the pyrrolidine ring, de-
ionic (hydrogen-bonding or ion-pairs interactions) ac- termining which one of the two substituents, namely
the aryl or the O-protecting group, effectively shields
one face of the reactive iminium/enamine intermedi-
ate, thus determining the stereoselectivity outcome of
a reaction. Despite the huge number of publications
using the Jørgensen–Hayashi catalysts 3, only very
few studies on active intermediate conformations
have been reported so far, giving somewhat contradic-
Figure 1. “Privileged” secondary amine organocatalysts.
tory results. A series of papers by Jørgensen and co-
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A New Family of Conformationally Constrained Bicyclic Diarylprolinol Silyl Ethers
Figure 2. Diarylprolinol ethers (3) possible conformations
À
around the exocyclic C-2 C1’ bond.
workers reported the results of B3LYP/6-31G(d) DFT
calculations on various iminium/enamine intermedi-
ates, invariably possessing the sc-endo conformation
À
B (Figure 2) around the exocylic C-2 C-1’ bond of
3.[13]
Scheme 1. Synthesis of catalysts 8. Reaction conditions: i)
Some years later, Seebach and Uchimaru reported
the X-ray structures of several iminum salt derivatives
of 3 with cinnamaldehyde, in which the sc-exo confor-
mations A were exclusively adopted. These results
Ph3P, DEAD, THF, room temperature, 5 h; 67%. ii) Ar-
MgBr, THF, room temperature, 2–8 h; 51–85%. iii) R2SiCl2,
imidazole, DMF, room temperature, 18 h; 63–70%. iv) Pd/C,
H2, THF:MeOH (1:1), room tempearture, 18–36 h; 55-85%.
were supported by MP2/6-311G
ACHTUNGTREN(NUNG d,p) single point en-
ergies calculations (both in gas-phase and using
CPCM solvatation model) on B3LYP/6-31G(d) opti- purchased catalysts 3 may contain up to 10–15% of
mised geometries for all the possible conformers A–C their deprotected analogues.[11]
of the former iminium ions and of the dienamine de-
To quantitatively assess the relative stability of 8 to
riving from (E)-pent-2-enal. In all examined cases, sc- protonolysis, we followed the desilylation reaction of
exo conformations A were more stable than B by 8a by 1H NMR in DMSO-d6 in the presence of
more than about 3.2 kcalmolÀ1.[14] More recently, PhCOOH as additive (100 mol%, 50 mM), as de-
Gschwind and co-workers studied the conformational scribed by Zeitler and Gschwind.[11] When Jørgensen–
preferences of several diarylprolinol enamines in solu- Hayashi catalyst 3a (R=CH3, Ar=Ph) was subjected
tion by NMR spectroscopy.[15] While sc-endo confor- to the same experimental conditions, 50% of the desi-
mations B become relevant in unprotected diarylpro- lylated compound was observed after only about
linol derivatives (R=H in Figure 2), due to a stabiliz- 45 min and an almost complete desilylation reaction
ing hydrogen bond between the exocyclic hydroxy occurred within 5 h (~90%). On the contrary, we did
group and the pyrrolidine nitrogen, O-protected proli- not observe any trace of the desilylated product deriv-
nol ethers 3 largely prefer the sc-exo conformation A. ing from 8a, even after more than 48 h (see Support-
Finally, the same authors also studied the conforma- ing Information).
tional preferences of the pyrrolidine ring itself. Ring
These new catalysts not only possess a much higher
puckering can indeed have a potential influence on stability towards protonolysis, but thanks to the con-
the overall preferred conformations of the reacting in- formational rigidity conferred them by the bridgehead
termediates, determining both the distance and the bicyclic structure, they steer the bulky substituent on
relative orientation of the bulky substituent with re- C-2 in the opposite sc-endo conformation with respect
spect to the pyrrolidine ring plane, thus contributing to the parent diarylprolinol silyl ethers 3, therefore di-
both to determine the reactivity and the efficiency of recting an aromatic ring, and not the O-protected
a catalyst.
group, towards one face of the reacting intermediate.
To address conformational and stability issues of 3, Thus, it is possible in principle to fine tune the effi-
we rationally designed a new family of bicyclic silyl ciency and the selectivity of these catalysts by chang-
ethers 8a–d characterised by a 2,4-dioxa-3-sila-7- ing the nature and the substitution pattern of the aro-
azabicyclo
ACHTUNGTRENNUNG[4.2.1]nonane scaffold, in which the free ro- matic rings.
À
tation around the exocylic C-2 C1’ bond is prevented.
Finally, the bridge between the C-2 and C-4 carbon
They are easily obtained in good yields from commer- atoms effectively blocks the pyrrolidine ring from
cially available N-Cbz-trans-4-l-hydroxyproline 4 in puckering, forcing the ring in the “down”[15] envelope
a few standard synthetic steps (Scheme 1, see Sup- conformation and thus exposing the less hindered
porting Information).
convex bottom face to the attack of the reaction part-
Catalysts 8a–d are bench-stable solids that can be ner. The B3LYP/6-31G(d) optimised geometry for the
stored for several months at room temperature with- cinnamoylidene imminium adduct of catalyst 8d is re-
out noticeable decomposition, whereas commercially ported in Figure 3.
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Marco Lombardo et al.
COMMUNICATIONS
ence of stoichiometric amounts of 2,6-lutidine as the
base and in CH2Cl2 as the solvent.[16] Results obtained
using 3a and 8a–d in exactly the same reaction proto-
col are reported in Table 1.
While catalyst 8c (R=Ph, Ar=Ph) afforded more
or less the same result as 3a, both in terms of activity
and selectivity (Table 1, entries 8 and 9), catalysts 8a
(R=CH3, Ar=Ph) and 8d (R=CH3, Ar=2-naph-
thyl) proved to be slightly better, affording higher
conversions and higher ees in the same reaction time
(Table 1, entries 3, 4, 10, and 11). Surprisingly, catalyst
8b [R=CH3, Ar=3,5-(CF3)2C6H3], possessing two
CF3 groups in the meta positions of the phenyl ring,
not only afforded lower ees, but also showed a noticea-
ble activity decrease (Table 1, entries 5–7). It should
be noted that the same authors also reported the use
of catalyst 3b [R=CH3, Ar=3,5-(CF3)2C6H3] in the
cyclopropanation reaction, using Et3N as the base. In
this case they obtained a very low yield (<20%) and
thus the ee was not determined.
Figure 3. DFT-B3LYP/6-31G(d) optimised geometry for the
s-trans iminium adduct of catalyst 8d with cinnamaldehyde.
A similar trend of reactivity was also observed in
the conjugate Michael addition of nitromethane to
With catalysts 8a–d in our hands, we started testing (E)-cinnamaldehyde, a reaction reported by many
their activity in a number of bench-mark transforma- groups to give excellent results using Jørgensen–
tions where Jørgensen–Hayashi catalysts 3 were re- Hayashi catalysts 3 in rather different reaction condi-
ported to afford excellent results.
tions.[17] We decided to attempt the reaction in almost
We first examined the cyclopropanation reaction of the same conditions as reported by Ye and co-work-
a,b-unsaturated aldehydes with a-bromomalonates, ers, using 5 mol% of catalyst and catalytic amounts of
À
a reaction affording two new C C bonds, two new NaOAc as the base (30 mol%) in mixture of CH2Cl2
stereogenic centers and one quaternary carbon atom. and methanol (9:1) as the solvent.[17d] Results ob-
We decided to test the reaction in the conditions re- tained using 3a and 8a–d are collected in Table 2.
cently reported by Wang and co-workers, in which
Once again catalyst 8b proved to be the least reac-
catalyst 3a (10 mol%) was efficiently used in the pres- tive one, even if in this reaction it afforded a very
Table 1. Organocatalytic cyclopropanation reaction of trans-4-nitrocinnamaldehyde (Ar=4-NO2C6H4) with dimethyl a-bro-
momalonate.
Entry
Cat.
Time [h]
Conversion [%][a]
Yield [%][b]
73
dr (anti:syn)[a]
>30:1
ee [%][c]
1
2
3
4
3a
4
6
4
6
74
82
84
86
0
91
8a
8b
76
18
>30:1
>30:1
94
80
5
3
6
7
8
9
10
11
24
51
5
6
4
10
24
73
80
84
89
8c
74
83
>30:1
>30:1
92
95
8d
6
[a]
1
Determined by H NMR.
[b]
[c]
Isolated yield after purification by flash-chromatography on silica.
Determined by chiral HPLC on purified product.
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A New Family of Conformationally Constrained Bicyclic Diarylprolinol Silyl Ethers
Table 2. Organocatalytic enantioselective Michael addition
of nitromethane to (E)-cinnamaldehyde.
Table 3. Organocatalytic Diels–Alder reaction of (2E,4E)-
hexadienal with 3-olefinic oxindole 9.
Entry
Cat.
Yield [%][a]
ee [%][b]
Entry Cat. Additive Time Conversion Yield
ee
[h]
[%][a]
[%][b]
[%][c]
1
2
3
4
5
3a
8a
8b
8c
8d
76
40
16
44
70
97
96
94
96
98
1[d]
2
3
4
5
6
7
8
3c
8a
OFBA[e]
OFBA
4
99
32
45
76
99
85
99
99
92
28
38
64
84
73
86
87
98
93
96
94
94
94
95
96
24
48
4
24
9
8d OFBA
8a
8a
8a
8a
CA[f]
[a]
Isolated yield after purification by flash-chromatography
on silica.
Determined by chiral HPLC on purified product.
CA
MNBA[g]
[b]
DFPA[h]
9
9
8d DFPA
good stereochemical result (Table 2, entry 3). The
other three catalyst (8a, c, d) all afforded ees compa-
rable with catalyst 3a (Table 2, entries 2, 4 and 5), but
only 8d gave similar results in terms of reactivity.
Since catalyst 8b consistently afforded poor results
and considering that 8a and 8c afforded so far almost
the same stereochemical outcomes and displayed sim-
ilar reactivity, we decided to continue the screening of
catalysts performances using only 8a and 8d, employ-
ing them in some recent Diels–Alder reactions based
[a]
[b]
1
Determined by H NMR.
Isolated yield after purification by flash-chromatography
on silica.
[c]
[d]
[e]
[f]
Determined by chiral HPLC on purified product.
Data taken from ref.[10]
OFBA=ortho-fluorobenzoic acid.
CA=chloroacetic acid.
MNBA=4-methyl-2-nitrobenzoic acid.
DFPA=a,a-difluorophenylacetic acid.
[g]
[h]
on a novel trienamine activation mode.[10] The first at- and acid additive pKa, with higher conversions and
tempted reaction was the organocatalysed Diels– shorter reaction times required when stronger acids
Alder reaction of (2E,4E)-hexadienal with the 3-ole- are used (Table 3, entries 2, 4–7). In particular a,a-di-
finic oxindole 9, affording spirocyclic oxidole 10 as fluorophenylacetic acid appeared to be the best addi-
a single diastereoisomer. As reported by the authors, tive, allowing us to obtain for both 8a and 8d quanti-
catalyst 3c (R=Et, Ar=Ph) gave the best results in tative conversions and very high stereoselectivity
this reaction when used in 20 mol%, in the presence values, albeit slightly lower than those with 3c
of 20 mol% ortho-fluorobenzoic acid (OFBA) as the (Table 3, entries 1, 7 and 8).
additive and using CHCl3 as the solvent (Table 3).
To further demonstrate the general applicability of
In these reaction conditions 8a and 8d displayed our catalysts, we used 8d in a second Diels–Alder ad-
only a slightly diminished stereoselectivity compared dition between (2E,4E)-hexadienal and the ethyl cya-
to 3c, but a remarkable reduced activity, with very nophenylacrylate 11 (Table 4), a reaction reported by
low conversions even after prolonged reaction times Jørgensen to require a much more encumbered orga-
(Table 3, entries 1–3).
nocatalyst [3d, R=Et, Ar=4-OMe-3,5ACTHNGUTERNNU(G di-t-Bu)Ph]
Acid additives are known for their central role in and higher temperatures to achieve good conversions
determining secondary amine organocatalysts activity. with acceptable ees.[10]
Seebach and Hayashi recently reported a very inter-
Surprisingly, the use of OFBA was in this case suffi-
esting mechanistic study on the effect of the addition cient to afford a comparable conversion and better
of a number of different acid additives in the Michael stereochemical outcomes with respect to the use of 3d
addition of aldehydes to nitroalkenes catalysed by (Table 4, entries 1 and 2), while CA afforded this time
3a.[18] They demonstrated that the acid additive may a much lower yield, although with a very good ee
play many different roles in the organocatalytic cycle, value (Table 4, entry 3), suggesting that no general
but also that a strong relationship exists between acid rule can be simply derived for determining the effica-
strength and catalyst activity. So we tested the former cy of an acid additive on the activity of a determined
Diels–Alder reaction in the presence of different acid catalyst.
additives, and in particular chloroacetic acid (CA), 4-
methyl-2-nitrobenzoic acid (MNBA) and a,a-difluor-
In conclusion, stability and conformational issues of
a family of known “privileged” organocatalysts
ophenylacetic acid (DFPA). Using 8a we found an ap- guided us in the design and preparation of some
parent direct relationship between catalyst activity cyclic analogues 8 which display some remarkable
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Table 4. Organocatalytic Diels–Alder reaction of (2E,4E)-
hexadienal with ethyl cyanophenylacrylate 11.
(0.14 mmol, 0.025 mg). The reaction was stirred at room
temperature for the specified time. The product was purified
by flash-cromatography on silica gel (cyclohexane/ethyl ace-
tate 8:2). 1H NMR (400 MHz, CDCl3): d=9.59 (d, J=
3.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.2 Hz,
2H), 3.88–3.83 (m, 4H), 3.54 (s, 3H), 3.47 (dd, J=7.6,
3.8 Hz, 1H).
1
Conversions were determined by H NMR using the dou-
blet at 8.19 ppm of the product and the singlet at 4.87 ppm
of the bromomethylmalonate. The racemic product was syn-
thesised under the same conditions with racemic proline
(10%). The enantiomeric excess was determined after deri-
vatisation of the product with Ph3P=CHCOOEt. Separation
conditions in chiral HPLC: AD 90:10 n-Hex/IPA for 15 min
then 80:20 in 10 min, 0.7 mLminÀ1, 408C, l=230 nm.
Entry
Cat.
Additive
Yield [%][a]
ee [%][c]
dr[c]
1[d]
2
3
3d
8d
8d
OFBA[e]
OFBA
CA[f]
87
83
58
86
89
92
80:20
80:20
80:20
[a]
Isolated yield after purification by flash-chromatography
on silica.
Determined by chiral HPLC on purified product.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR.
Organocatalytic Enantioselective Michael Addition of
Nitromethane to (E)-Cinnamaldehyde (Table 2)
Data taken from ref.[10]
OFBA=ortho-fluorobenzoic acid.
CA=chloroacetic acid.
To a solution of catalyst (5%) in a DCM/MeOH mixture
(9:1, 0.6 mL) was added cinnamaldehyde (0.3 mmol,
0.038 mL), nitromethane (0.9 mmol, 0.048 mL) and finally
sodium acetate (30%, 7.4 mg). The reaction was stirred at
room temperature for 22 h. The mixture was diluted with
DCM and extracted with water. The water was washed two
times with DCM and the organic phases were collected,
dried over anhydrous Na2SO4, filtered and the solvent was
evaporated under reduced pressure. The residue was puri-
fied by flash-cromatography on silica gel (cyclohexane/ethyl
features. First of all, they are easily accessible in good
yields using simple synthetic procedures, they are
much more stable to hydrolytic conditions and so
more easily stored and handled. Furthermore, their
activity and selectivity are comparable to the ones dis-
played by Jørgensen–Hayashi catalysts, but the ste-
reochemical outcomes of their reactions mainly
depend on the nature of the aromatic substituents of
the bulky O-protected diarylmethanol group; this
opens up the possibility to further modulate their effi-
cacy and activity by varying the nature and the substi-
tution pattern of the aromatic rings.
We firmly believe that this family of compounds
may be employed successfully not to replace Jørgen-
sen–Hayashi catalysts, so far among the best organo-
catalysts proposed for iminium/enamine activation
mode, but to complement their use, for example,
when strong acids and prolonged reaction times are
necessary, and more in general to widen the choice of
tools available for asymmetric organocatalytic trans-
formations. Investigations to expand the scope of
these new organocatalysts to other reactions and acti-
vation modes, as well as the synthesis of new mem-
bers of this family of compounds are currently under-
way and will be reported in due course.
1
acetate 9:1). H NMR (CDCl3, 400 MHz): d=9.69 (s, 1H),
7.22–7.35 (m, 5H), 4.60–4.69 (m, 2H), 4.06–4.08 (m, 1H),
2.94 (d, J=3.5 Hz, 2H).
Conversions were determined by H NMR using the dou-
1
blet at 2.94 ppm of the product and the dd at 6.69 ppm of
cinnamaldehyde. The racemic product was synthesised
under the same conditions with racemic Jørgensen–Hayashi
catalyst (20%). The enantiomeric excess was determined
after reduction of the product with NaBH4 in ethanol. Sepa-
ration conditions in chiral HPLC: IB 90:10 n-Hex/IPA,
0.5 mLminÀ1, 408C, l=230 nm.
Organocatalytic Diels–Alder Reaction of (2E,4E)-
Hexadienal with 3-Olefinic Oxindole 9 (Table 3)
To a solution of catalyst (20%) and acid (20%) in CHCl3
(1 mL) were added the dienophile (0.1 mmol, 0.032 g) and
the aldehyde (0.15 mmol, 0.017 mL). The reaction was
stirred at room temperature for the specified time. The
product was purified by flash-cromatography on silica gel
(cyclohexane/ethyl acetate from 9:1 to 8:2). 1H NMR
(400 MHz, CDCl3): d=9.69 (s, 1H), 7.89 (d, J=8.2 Hz, 1H),
7.33–7.28 (m, 1H), 7.26–7.21 (m, 1H), 7.10–7.03 (m, 1H),
6.02–5.95 (m, 1H), 5.80–5.71 (m, 1H), 3.93 (q, J=7.2 Hz,
2H), 3.32–3.19 (m, 2H), 3.02–2.93 (m, 1H), 2.86–2.73 (m,
1H), 2.63–2.51 (m, 1H), 2.41 (dd, J=18.5, 5.0 Hz, 1H), 1.64
(s, 9H), 1.05 (t, J=7.1 Hz, 3H). The conversions were deter-
Experimental Section
Organocatalytic Cyclopropanation Reaction of trans-
4-Nitrocinnamaldehyde with Dimethyl a-Bromo-
malonate (Table 1)
1
mined by H NMR using the multiplet at 5.83–5.70 ppm of
the product and the doublet at 8.69 ppm of the isatin deriva-
tive. The racemic product was synthesised under the same
conditions with pyrrolidine (20%). The enantiomeric excess
was determined after derivatisation of the product with
To a solution of catalyst (10%) in DCM (0.5 mL) was added
methyl bromomalonate (0.12 mmol, 0.018 mL), 2,6-lutidine
(0.13 mmol, 0.015 mL) and finally 4-nitrocinnamaldehyde
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A New Family of Conformationally Constrained Bicyclic Diarylprolinol Silyl Ethers
Ph3P=CHCOOEt. Separation conditions in chiral HPLC:
AD 95:5 n-Hex/IPA, 1 mLminÀ1, 408C, l=230 nm.
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Organocatalytic Diels–Alder Reaction of (2E,4E)-
Hexadienal with (E)-Ethyl 2-Cyano-3-phenylacrylate
11 (Table 4)
To a solution of catalyst (20%) and acid (20%) in CHCl3
(0.5 mL) were added the dienophile (0.1 mmol, 0.020 g) and
the aldehyde (0.2 mmol, 0.022 mL). The reaction was stirred
at 508C for the specified time. The product was purified by
flash-cromatography on silica gel (cyclohexane/ethyl acetate
from 9:1 to 8:2). 1H NMR (400 MHz, CDCl3): d=9.68 (s,
1H), 7.51–7.22 (m, 5H), 6.01–5.92 (m, 1H), 5.77–5.70 (m,
1H), 3.97–3.85 (m, 2H), 3.65–3.57 (m, 1H), 3.26 (dd, J=
11.3, 5.5 Hz, 1H), 3.15 (dd, J=19.0, 8.5 Hz, 1H), 2.72–2.63
(m, 1H), 2.59 (dd, J=18.8, 4.7 Hz, 1H), 2.51–2.40 (m, 1H),
1.00 (t, J=7.1 Hz, 3H).
1
Conversions were determined by H NMR using the mul-
tiplets at 5.77–5.70 ppm and 5.58–5.53 ppm of the two dia-
stereoisomers of the product and the singolet at 8.27 ppm of
the ethyl cyanophenylacrylate. The dr was determined by
1H NMR using the multiplets at 5.77–5.70 ppm and 5.58–
5.53 ppm of the two diastereoisomers of the product. The
racemic product was synthesised under the same conditions
with pyrrolidine (20%). The enantiomeric excess was deter-
mined after derivatisation of the product with Ph3P=
CHCOCH3. Separation conditions in chiral HPLC: OD
80:20 n-Hex/IPA for 11 min at 0.7 mLminÀ1 then to
1 mLminÀ1 in 1 min, 408C.
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Acknowledgements
This
work
was
supported
by
MIUR
(PRIN
20099PKPHH 004-2009, FIRB RBFR08TTWW 001-2008),
University of Bologna and in part by COST Action CM0905
ORCA.
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