A bifunctional β-isocupreidine derivative as catalyst for the enantioselective morita-baylis-hillman reaction and a mechanistic rationale for enantioselectivity

Article abstract of DOI:10.1002/ejoc.201200405

Starting from β-isocupreidine (β-ICD), a series of difunctional catalysts were synthesized to ascertain their usefulness in the asymmetric Morita-Baylis-Hillman (MBH) reaction. The trichloroacetylcarbamate derivative was found to give the (R)-MBH adducts in excellent optical purities (90-99% ee) and moderate to good yields (43-83%), in some cases, better than β-ICD. A number of acrylates were also tested and 2,6-dimethyl-4-nitrophenyl acrylate was identified as a suitable alternative to the popular hexafluoroisopropyl acrylate, with both the β-ICD and trichloroacetylcarbamate derivatives. The mechanism of the rate- and selectivity-determining step was ascertained by means of experimental observations and a computational investigation aimed at clarifying the transition state structures is reported. These studies have clarified the reasons for the effectiveness of these structurally related catalysts in the asymmetric MBH reaction between acrylates and aldehydes. β-Isocupreidine derivatives were used tocatalyze the asymmetric Morita-Baylis-Hillman (MBH) reaction, giving the (R)-MBH adducts in excellent optical purities and moderate to good yields. Both 2,6-dimethyl-4-nitrophenyl and hexafluoroisopropyl acrylate could be used. The rate- and selectivity-determining step was identified and the structures of the preferred transition states were computed.

Full text of DOI:10.1002/ejoc.201200405

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
FULL PAPER
DOI: 10.1002/ejoc.201200405
A Bifunctional β-Isocupreidine Derivative as Catalyst for the Enantioselective
Morita–Baylis–Hillman Reaction and a Mechanistic Rationale for
Enantioselectivity
Gianluca Martelli,[a] Mario Orena,[a] and Samuele Rinaldi*[a]
Dedicated to Professor Gianni Porzi on the occasion of his retirement
Keywords: Asymmetric catalysis / Computational chemistry / Donor-acceptor systems / Enantioselectivity / Transition
states
Starting from β-isocupreidine (β-ICD), a series of difunctional
catalysts were synthesized to ascertain their usefulness in the
asymmetric Morita–Baylis–Hillman (MBH) reaction. The tri-
chloroacetylcarbamate derivative was found to give the (R)-
MBH adducts in excellent optical purities (90–99% ee) and
moderate to good yields (43–83%), in some cases, better than
β-ICD. A number of acrylates were also tested and 2,6-di-
methyl-4-nitrophenyl acrylate was identified as a suitable al-
ternative to the popular hexafluoroisopropyl acrylate, with
both the β-ICD and trichloroacetylcarbamate derivatives.
The mechanism of the rate- and selectivity-determining step
was ascertained by means of experimental observations and
a computational investigation aimed at clarifying the transi-
tion state structures is reported. These studies have clarified
the reasons for the effectiveness of these structurally related
catalysts in the asymmetric MBH reaction between acrylates
and aldehydes.
ee value of the products is partially due to a kinetic resolu-
tion that removes most of the minor enantiomer by forma-
tion of substantial amounts of undesired dioxanones.[6]
Introduction
The Morita–Baylis–Hillman (MBH) reaction is a very
appealing transformation for synthetic purposes because
the α-methylene-β-hydroxycarbonyl products are highly
valuable intermediates in organic synthesis.[1,2] However, de-
spite great efforts directed towards the optimization of
asymmetric methodologies,[1,3] until now only partial suc-
cess has been obtained; the reaction between acrylates and
common aldehydes has been particularly challenging.[4]
In fact, the most efficient approach to highly enantioen-
riched 2-methylene-3-hydroxycarbonyl alkanoates is still
represented by the β-isocupreidine (β-ICD)/hexafluoroiso-
propyl acrylate (HFIPA) method,[5] the yields and applica-
bility of which has recently been slightly improved through
the use of azeotropically dried β-ICD,[5d] and extended in
scope with the introduction of an enantiocomplementary
catalyst derived from quinine.[5c] However, reactions using
these methodologies must be performed at low temperature
(–55 °C), sometimes for prolonged periods, and the yields
are somewhat erratic. Moreover, when the reactive p-ni-
trobenzaldehyde or aliphatic aldehydes are used, the high
Results and Discussion
Methodology Development and Optimization
Taking advantage of our previous experience within the
extension of hydroxy functionalities by means of electro-
philic reagents,[7] we devised a method to convert the free
phenolic hydroxy group of β-ICD (1) into a carbamate or
an acyl carbamate (Scheme 1).
[a] Di.S.V.A. - CHEMISTRY, Polytechnic University of Marche,
Via Brecce Bianche, 60131 Ancona, Italy
Scheme 1. Synthesis of catalysts 2a–h.
Fax: +39-071-2204714
E-mail: s.rinaldi@univpm.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200405.
According to this strategy, derivatives 2a–h were ob-
tained in moderate to good yield by reaction of the phenolic
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
functionality of 1 with a series of isocyanates and acyl iso-
cyanates, which were prepared according to literature meth-
ods.[8] It was readily apparent that for catalysts 2a–h the
acidity of the NH proton of the resulting carbamates, or
acyl carbamates, can be easily modulated by appropriately
choosing the R1 group. Thus, both the positioning of this
acidic functionality, which is clearly different from that of
the parent hydroxyl group, and the variety of R1 groups,
lead to very different steric requirements in all the reaction
steps in which they participate. In particular, it has recently
been determined both experimentally and computationally
that the rate-determining (and product-determining) step in
the MBH reaction is not the formation of the C–C bond
during the aldol reaction between the zwitterionic enolate
and the aldehyde, which is essentially a rapid equilibrium,
but rather the proton transfer in the adduct that causes the
successive regeneration of the catalyst.[9]
However, it has also been stated that for reactive alde-
hydes, in which the addition step is more exothermic, there
could be a reduced reversibility and consequently a concur-
rence, at least partial, of the stereoselectivity of the addition
step to the overall result.[9f] A similar behaviour could be
the basis of the higher selectivities generally obtained in the
aza counterpart of the MBH reaction (aza-MBH), in which
the addition to N-activated imines is more exothermic than
Scheme 2. Transition states A–D and the possible roles of catalysts
1 and 2a–h on the rate-determining and selectivity-determining step
(proton transfer).
In the presence of protic sources (i.e., the acidic function-
addition to aldehydes. Thus, in these cases, an enhanced ality of the catalyst) or by intervention of the MBH adduct
selectivity due to the clearer discrimination between the itself in the late stage of the reaction, another six-membered
four possible diastereomers of the aldol addition step, with transition state could be formed; Aggarwal pathways, B for
respect to that between the four or eight diastereomers (vide β-ICD (1), and D for catalysts 2a–h. Hypothesizing again a
infra) present in the proton transfer step, cannot definitely thermodynamic equilibrium of all the steps preceding the
be excluded.
proton transfer, the selectivity of the reaction will rely on
The large amount of data available from kinetic experi- the ability of the acidic moiety to act predominantly as a
ments, ESI-MS identification of elusive key intermediates, proton shuttle, by means of six-membered transition states,
and computational studies indicate that, depending on the on only one of the four possible diastereomers or, alterna-
specific reaction conditions, there will be a prevalence of tively, to the two diastereomers displaying the same config-
one of the two competing mechanisms for the proton trans- uration at the carbon indicated by the asterisk printed in
fer, namely pathways proposed by McQuade[9b,9c] and grey in Scheme 2.
Aggarwal.[9e,9f] Referring to our particular system and fo-
Within this scenario, the possible effects of changing the
cusing on the aspect of stereoselection, based on both the acidic functions in the series 2a–h with respect to β-isocup-
proposed mechanistic possibilities in the rate-determining reidine (1), can be examined. The ability of the various NH
proton transfer step, the following observations can be groups to favour the reaction from a particular dia-
made about the effects that could be brought about by stereomer will be different to that of the OH group in 1,
structural and electronic changes passing from 1 to 2a–h due to the clear geometrical distortions that come about
(Scheme 2).
because of the change in the distance from the phenolic
In particular, the proton transfer step should occur pre- oxygen, leading to a different positioning of the negatively
dominantly through a six-membered transition state Ϫ charged oxygen.
McQuade pathways, A for β-ICD (1), and C for catalysts
In addition, the R1 substituent will also have a strong
2a–h Ϫ at the early stage of the reaction and in absence of effect on the acidity of the NH group, changing the charge
protic species, after the formation of a hemiacetal species transfer interaction with the negatively charged oxygen.
by addition of a second molecule of aldehyde.
Consequently, the actual basicity of the hemiacetalic oxy-
Thus, supposing a rapid and complete equilibration of gen should be inversely dependent on the amount of nega-
all the eight possible diastereomers with their respective tive charge transferred to the NH hydrogen. Because a less
conformers, the success in obtaining high ee values closely reactive system should allow better discrimination between
relies on the ability of the hydrogen-bond donor function- the various diastereomers, a better selectivity would be ex-
ality to selectively promote the proton transfer from one (or pected for catalysts with a more acidic NH function.
more) of the diastereomers possessing the desired absolute
configuration of the carbon indicated in Scheme 2 with the greatly both in steric bulk and in the hybridization at the
asterisk printed in grey. carbon atom attached to the nitrogen. The proton transfer
The alkyl or acyl substituents R1 in catalysts 2a–h differ
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
Enantioselective Morita–Baylis–Hillman Reaction
should be favoured for cases in which there is less destabiliz- only 7% yield was obtained after 10 days reaction at
ing interaction with the rest of the molecule, in particular –18 °C, strongly suggesting that, in this case, the activity of
with the R2 groups.
the catalyst was greatly reduced by the high acidity of the
Having compounds 2a–h in hand, all displaying the ex- NH hydrogen. However, we were pleased to observe that
tended functionality, we undertook a screening to ascertain by using catalyst 2a (R1 = trichloroacetyl, Table 1, entry 1),
their usefulness as catalysts for the enantioselective MBH product 5a was obtained in good yield and with an encour-
reaction. With the aim of evaluating whether these catalysts aging 85% ee. Moreover, the product could be easily recrys-
may be good candidates with respect to realistic reaction tallized to give 98% ee with a final yield of 55%.
times, we chose to use a relatively poorly reacting aldehyde,
benzaldehyde, during the optimization.
Catalyst 2a was then used in conjunction with acrylates
4b–d (Table 1, entries 3–5), leading to a very rapid and se-
For the acrylate partner in the reaction, we decided to lective reaction with 2,6-dimethyl-4-nitrophenyl acrylate
use relatively activated species that possess differing steric (DMNPA) 4d (Table 1, entry 5), albeit in low yield. How-
bulk and preferred conformations, such as α-naphthyl acryl- ever, we observed that most conversion occurred very
ate (4b), which has already been used in enantioselective rapidly in the initial phase of the reaction, and was then
MBH reactions,[3a,3b,10] 4-nitrobenzyl acrylate (4c), and two significantly slowed by the formation of substantial
2,6-dimethylphenyl derivatives having a methyl (4a) or a ni- amounts of the dioxanone derivative with concomitant pro-
tro (4d) group at position 4 of the aromatic ring (Table 1), duction of 2,6-dimethyl-4-nitrophenol. This latter product
respectively. The acrylates were freshly prepared and used is sufficiently acidic to greatly suppress the catalytic activity
free of impurities (including stabilizer), to avoid possible by acid-base reaction with the basic nitrogen of 2a (pKa of
mechanistic interference.
the parent 4-nitrophenol is 7.14 in H2O, whereas quinidine,
which is probably less basic than 1 and 2a, has a pKa of
conjugate acid of 7.95 and quinuclidine has a pKa of conju-
gate acid of 11.0[11]).
Table 1. Synthesis of adducts 5a–d catalyzed by 2a–h.
Taking DMNPA 4d as the best candidate due to its high
reactivity and selectivity, we performed the reactions with
catalysts 2c–h (Table 1, entries 6–10). Catalyst 2c, which dif-
fers from 2b in that it lacks the p-nitro substitution in the
aromatic ring, unexpectedly showed no catalytic ability in
the production of 5d, with the dimerization of 4d being the
only reaction observed (Table 1, entry 6). On the other
hand, catalyst 2d, differing from 2a by the change of the
highly electron-withdrawing CCl3 group to the mildly elec-
tron-donating and slightly less sterically demanding CH3,
furnished a reaction with formation of inseparable byprod-
ucts (Table 1, entry 7 vs. entry 5) and a worse stereoselec-
tion that that observed with 2a. This last observation is
probably attributable to the reduced acidity of NH in 2d
with respect to 2a, leading to lower stereocontrol in the pro-
ton transfer step (see the above discussion).
Thus, catalysts 2f–h furnished product 5d with appreci-
able ee values but in low yields (Table 1, entries 8–10), and
it was far from clear which catalytic species was involved.
In fact, NMR analysis of samples taken directly from the
reaction provided evidence that compounds 2f–h, in con-
trast to the other catalysts, are unstable even in the absence
of water or other deleterious impurities, and can easily de-
Entry[a]
4
Cat
T [°C]
t
Yield, %[b] (ee, %)[c]
1
2
3
4
5
6
7
8
9
4a
4a
4b
4c
4d
4d
4d
4d
4d
4d
2a
–18
–18
–18
–18
0
–18
–18
0
20 d
10 d
18 d
23 d
18 h
2 d
71 (85)
7 (75)
2b
2a
43 (70)
78 (45)
38 (89)
2a
2a
[d]
2c
–
2d
3 d
21[e] (79)
16 (78)
15 (76)
55 (58)
2f[f]
2g[f]
2h[f]
24 h
24 h
5 d
0
r.t.
10
[a] Reagents and conditions (1 mmol scale): aldehyde, acrylate
(1 equiv.), catalyst (10 mol-%), anhydrous DMF (0.3 mL). [b] Yield
of pure isolated product. [c] Determined by HPLC analysis. [d]
Only dimerization of acrylate was observed. [e] Product not sepa-
rated from byproducts. [f] Partial decomposition of catalyst was
observed.
Initially, a brief survey of various solvents and amounts compose to β-isocupreidine (1) by reaction with the MBH
of catalyst demonstrated that, as for β-ICD, anhydrous adduct itself. Thus, the good enantioselection is very proba-
N,N-dimethylformamide (DMF) was needed together with bly due to the intervention of both the original catalysts 2f–
at least 10 mol-% catalyst to achieve the best results in h and β-ICD (1).
terms of both enantioselection and reaction rate. Thus, cat-
Encouraged by these results, our attention focused on
alysts 2a–h and acrylates 4a–d were tested with benzalde- catalyst 2a and we carried out a comparison with β-isocup-
hyde under these conditions at various temperatures reidine (1; Table 2).
(Table 1). Compound 2e decomposed to a great extent dur-
ing chromatographic purification.
We used both DMNPA (4d) and the well-known and ef-
fective hexafluoroisopropyl acrylate (HFIPA; 4e). In reac-
Acrylate 4a underwent very clean reactions, however, it tions with acrylate 4d, the differences in stereocontrol be-
was very slow to react (Table 1, entries 1 and 2). In particu- tween 1 and 2a at all the temperatures were very low,
lar, with catalyst 2b (R1 = 4-nitrobenzoyl, Table 1, entry 2) whereas the yields were improved in the case of 2a by about
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
G. Martelli, M. Orena, S. Rinaldi
Table 3. Synthesis of MBH adducts 5d–j catalyzed by 2a.
FULL PAPER
Table 2. Synthesis of adducts 5d and 5e; comparison between cata-
lysts 1 and 2a.
Entry[a]
4
Cat
T [°C]
t
Yield, %[b] (ee, %)[c]
Entry[a]
1
3
4
T [°C]
t
Product Yield, %[b] (ee, %)[c]
1
2
3
4
5
6
7
4d
4d
4d 2a
4d
4d 2a
4e
4e 2a
1
1
0
18 h
3 d
3 d
2 d
3 d
4 h
1 h
33 (88)
50 (96)
55 (97)
45 (98)
58 (99)
52 (81)
65 (88)
–18
–18
–35
–35
0
3a 4d –35
3 d
5d
58 (99)
[52, 100][d]
83 (98)[e]
48 (94)[f,g]
[39, 99][d]
63 (91)[h,i]
53 (90)[j]
[43, 98][d]
46 (99)
1
2
3
3a 4e –55
3b 4d –35
3 h
18 h
5e
5f
1
0
4
5
3b 4e –55
3c 4d
2 h
4 d
5g
5h
0
[a] Reagents and conditions (1 mmol scale): aldehyde, acrylate
(1 equiv.), catalyst (10 mol-%), anhydrous DMF (0.3 mL). [b] Yield
of pure isolated product. [c] Determined by HPLC analysis.
6
7
3d 4d –35
3e 4d –18
18 h
4 d
5i
5j
43 (95)[k]
[a] Reagents and conditions (1 mmol scale): aldehyde, acrylate
(1 equiv.), catalyst (10 mol-%), anhydrous DMF (0.3 mL). [b] Yield
of pure isolated product. [c] Determined by HPLC analysis.
[d] Yields and ee values, respectively, after fractional crystallization.
[e] The corresponding (R,R)-cis-dioxanone was obtained in 5%
yield and 45% ee. [f] DMF (1 mL) was used. [g] The corresponding
(R,R)-cis-dioxanone was obtained in 11% yield and 49% ee.
[h] DMF (2 mL) was used. [i] The corresponding (R,R)-cis-diox-
anone was obtained in 14% yield and 16% ee. [j] DMF (0.5 mL)
was used. [k] The corresponding dioxanone was obtained in 5%
yield and 29% ee (cis/trans ratio 45:55).
5–8% (Table 2, entry 1 vs. Table 1, entry 5, and Table 2, en-
tries 2 vs. 3, and entries 4 vs. 5). The very similar behaviour
of 1 and 2a was also evident in the lower conversions and
yields obtained at the higher temperature (0 °C), caused in
both cases by the rapid production of the undesired diox-
anone and then of the acidic 2,6-dimethyl-4-nitrophenol. In
addition, when acrylate 4e (HFIPA) was used together with
catalyst 2a at 0 °C, increased yield in a shorter reaction time
and higher ee values were observed that those obtained with
catalyst 1 (Table 2, entries 6 and 7).
The usefulness of the enantioselective Morita–Baylis–
The reactions of aldehydes 3a and 3b with HFIPA, car-
Hillman reaction catalyzed by 2a was next examined at the ried out at the same temperature (–55 °C, Table 3, entries 2
lowest temperatures compatible with sustainable reaction and 4) as Hatakeyama’s original and improved methods,
times (Table 3). In fact, starting from aromatic aldehydes furnished the MBH adduct 5e with better results with re-
and exploiting DMNPA (4d), the corresponding adducts spect to both β-ICD and HFIPA methodologies,[5a,5d] with
5d, 5f and 5h were obtained with an outstanding enantiose- 98% ee and 83% yield being achieved in only three hours,
lection (Ն 90% ee), whereas the yields were moderate but whereas adduct 5g was obtained in 91% ee and 63% yield
were not sensitive to the electronic properties of the aro- after two hours; a result that was intermediate between
matic ring, the presence of strong (NO2) or moderately elec- those of the original and the improved β-ICD/HFIPA
tron-withdrawing (Cl) groups being well-tolerated.
methods.
When DMNPA was used in conjunction with linear and
Contrary to our expectations, the reaction with the
highly reactive 4-nitrobenzaldehyde was relatively sluggish α-branched aldehydes, 3d and 3e (Table 3, entries 6 and 7),
in comparison with the reaction with benzaldehyde at the the corresponding adducts 5i and 5j where obtained with a
same temperature (–35 °C), whereas 4-chlorobenzaldehyde greater (99 vs. 97% ee) or a lesser selectivity (95 vs. 99%
required a temperature of 0 °C to proceed within a reason- ee), respectively, compared to the use of the β-ICD/HFIPA
able time (Table 3, entries 3 and 5). This was caused by their couple, but with a substantial decrease in the amount of
low solubility, concomitant with a reduced solubility of ac- dioxanone byproducts formed.[5a]
rylate 4d at the lowest temperatures, and by the significant
From the data reported, it is then evident that catalyst
negative impact in the rate law (second order in aldehyde 2a, when used in conjunction with either acrylate DMNPA
and first order in acrylate[9c]) of the actual concentrations. (4d) or HFIPA (4e), shows an efficacy comparable, and
In fact, with these aldehydes, the dilution of the reaction sometimes slightly superior to that of the parent β-isocupre-
caused a beneficial effect on the rate (see notes in Table 3). idine (1). In addition, the new and easily synthesised acry-
It is noteworthy that adducts 5d, 5f and 5h are all solids late DMNPA allows selectivities to be obtained that are
and were easily purified by fractional crystallization (data equal to or better than HFIPA, albeit with slightly lower
in square brackets, Table 3), and ee values in excess of 98% yields, using both catalysts 1 and 2a.
were always obtained, albeit with a further decrease in the
The absolute configuration of the previously unknown
final yields (39–52%).
adducts 5a, 5c, 5d, 5f and 5h–j generated by using 2a as
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
Enantioselective Morita–Baylis–Hillman Reaction
catalyst was determined as R after conversion into the cor- bulkiness of the R1 substituent in catalysts 2a–h, it seems
responding methyl esters and comparison of their optical clear that, in the case of acylic groups, a large steric encum-
rotation with literature data.
brance such as that of a phenyl group is sufficient to prevent
the reaction, however, it is not clear at which step this oc-
curs.
Having demonstrated, with a high degree of confidence,
the mechanism operating in the rate-determining step, we
Mechanistic Considerations
In addition to ascertaining the effectiveness of the pres- started a computational investigation to obtain information
ent methodology, many other important experimental ob- on the real geometry of the transition states and then to
servations can be made: (i) Chiral HPLC analysis of all the shed light, at least qualitatively, on the interaction between
reactions reported here revealed no detectable change in the the catalyst moiety and the remaining part of the reactant
enantiomeric excess of the products during the entire reac- complex.
tion time. Thus, under these experimental conditions and
for the time of interest, the reactions proceed under kinetic
Computational Investigation
control; (ii) The preceding observation of a time-indepen-
dent enantioselection also ruled out, in this case, both a
mechanistic shift of the rate-determining proton-transfer
step (from McQuade to Aggarwal models or vice versa) and
an intervention of the MBH adduct itself in the transition
states when the conversion proceeds. Considering that the
two mechanisms have a different order in the rate law with
respect to the aldehyde,[9b,9c,9e,9f] it is also clear from the
observed constant proportion of reactants over the entire
course of the reaction that, in this case, a change in the
stereoselection from that of the McQuade pathway in the
initial phase, to that of the Aggarwal pathway in the late
stage is unlikely.[12] Thus, it can be safely assumed that only
one mechanism is operating; (iii) The formation of diox-
anones from reactive aldehydes and acrylates with a good
leaving group suggests that, for these cases, the only op-
erating mechanism is the McQuade non-alcohol-catalyzed
process, with two molecules of aldehyde in the rate-de-
termining step (Scheme 2, TSs A and C). In fact, the forma-
tion of dioxanone could theoretically occur even on the
MBH adduct itself, but, in this case, a change in the ratio
[MBH]/[dioxanone] and also in the ee of the MBH adduct
Recent computational investigations have aimed to eluci-
date the nature of the rate-determining step under different
experimental conditions; all used high levels of theory and
considered the solvent, at least as bulk, to obtain a quanti-
tative energetic description of the entire mechan-
ism.[9d,9f,9g,9j,9k] Simplified model systems were used to re-
duce the computational effort; thus model catalysts, alde-
hydes and acrylate were used (Scheme 3).
Scheme 3. Model compounds.
We used the AM1[14–15] semiempirical method to under-
would be expected as the reaction proceeded, as a result of take a preliminary search of McQuade’s proton transfer
two consecutive reactions. However, as stated before, the transition states obtained from the model compounds and
ee values were constant and, in addition, NMR analysis confirmed that Aggarwal’s TSs could not be identified un-
performed on same samples taken during the reaction der these conditions. The model structures were then re-
clearly showed that no change in the ratio between the con- fined with DFT computations using the hybrid functional
centration of the MBH adducts and the dioxanones oc- M06–2X.[16] To take into account bulk solvent effects, full
curred. These experimental findings are only consistent geometry optimizations within a continuum solvent model
with two parallel irreversible reactions; a McQuade mecha- (with N,N-dimethylformamide as solvent) were carried out
nism seems very likely, in which the two observed products by applying the self-consistent reaction field (SCRF) ap-
originate from the same common hemiacetalic intermedi- proach, using the polarizable continuum model (IEF-PCM)
ate; (iv) A very fine tuning of the electronic and steric prop- method.[17] Given the system’s dimension and the number
erties of the acidic arm in the catalyst, starting from the of TSs to calculate, the 6-31G(d) basis set was used for
common β-ICD skeleton, is essential for effective discrimi- atoms that have a prominent influence in determining the
nation between the eight possible, rapidly equilibrating, dia- stereoselection, whereas the 3-21G* basis set was used to
stereomers of the hemiacetal species. In particular, it ap- calculate the remaining atoms (see the Supporting Infor-
pears that an excessively acidic moiety strongly decreases, mation for a detailed description). Finally, single point cal-
or even suppresses, the catalytic activity. In the opposite culations with the 6-311++G(d,p) basis set were executed
case, a weak interaction with the negatively charged hemi- on all the computed TS structures; the resulting values are
acetalic oxygen can cause a loss in the directing effect on used in the following discussion on the the energetics of the
the preferred conformation of the six-membered proton systems (see below).
transfer TSs (Scheme 2, TS C), that is responsible for the
Initially, we searched the expected four hydrogen
effectiveness of the kinetic resolution. Concerning the bonded[18] chair TSs obtained from catalyst m-1, methyl
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
acrylate (m-Ac) and two molecules of formaldehyde
(m-Al1), starting from structures in which the methyleneiso-
cupreidinium group lies in either an axial or an equatorial
conformation and the carbon losing the transferred proton
as either R or S configuration (Scheme 4).
Scheme 4. Model transition states computed for the McQuade pro-
ton transfer obtained from m-Al1, m-Ac and m-1.
In spite of many attempts, starting from a chair with an
equatorial methyleneisocupreidinium group conformation
and the R configuration at the carbon losing the proton,
the minimization process invariably distorted the initial
structures to the boat conformation TS-R2, whereas in all
the other cases the expected chair structures were obtained.
Modifying the four previous structures by addition of the
two methyl groups in any of the possible combinations, we
evaluated the stability and the steric features of all sixteen
model TSs arising from substitution of acetaldehyde, m-
Al2, in place of formaldehyde, m-Al1 (Scheme 5).
The descriptors R and S again refer to the configuration
of the carbon losing the transferred proton – the α-carbon
with respect to the ester – whereas the other conformations
(with the ax or eq inscription) indicate the orientation in
the chair of the two methyl groups, starting from the one
closest to the ester functionality.
The relative energies reported in Table 4 are in very good 10
agreement with the experimentally observed enantio-
selectivity. In fact, TS-R1-eq-eq is by far the more stable
transition state (Table 4, entry 1); this conformation has an
axial methyleneisocupreidinium group, R configuration at
the α-carbon, and both the methyl groups adopt equatorial
orientations.
It is readily apparent from Figure 1 that the preferred
proton transfer occurs through a chair conformation that
lacks destabilizing steric interactions both between the chair
Scheme 5. Model transition states computed for the McQuade pro-
ton transfer obtained from m-Al2, m-Ac and m-1.
Table 4. Relative energies of the model transition states with model
catalyst m-1.
Entry
Model TS
Configuration of
Model MBH[a]
Relative E
[kcal/mol][b]
1
2
3
4
5
6
7
8
9
TS-R1-eq-eq
TS-R1-eq-ax
TS-S1-eq-eq
TS-S1-eq-ax
TS-R1-ax-eq
TS-R1-ax-ax
TS-S1-ax-eq
TS-S1-ax-ax
TS-R2-eq-eq
TS-R2-eq-ax
TS-S2-eq-eq
TS-S2-eq-ax
TS-R2-ax-eq
TS-R2-ax-ax
TS-S2-ax-eq
TS-S2-ax-ax
R
R
S
S
S
S
R
R
S
S
R
R
R
R
S
S
0.0
+1.5
+8.5
+6.5
+5.2
+8.3
+5.9
+7.7
+2.0
+4.4
+1.9
+4.6
+5.3
+9.0
+5.5
+9.6
11
12
13
14
15
16
[a] Configuration of the model MBH adduct after the hemiacetal
decomposition. [b] Energies relative to the more stable transition
state.
substituents, and between the chair substituents and the Table 4, entry 1). The contribution of all the other TSs to
catalyst moiety. the formation of both the enantiomers of the m-MBH ad-
Two others TSs (Table 4, entries 2 and 11) also contrib- duct was found to be negligible.
ute to the overall predominance of the R enantiomer,
The very high energy of TS-S1-eq-eq (Table 4, entry 3)
whereas the only significant structure giving the S enantio- may seem surprising, considering the stability of the parent
mer (Table 4, TS-R2-eq-eq, entry 9 and Figure 2) lies TS-S1 with formaldehyde (Scheme 4) and the diequatorial
2.0 kcal/mol above the global minimum (TS-R1-eq-eq; arrangement of the methyl groups, but an inspection of its
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
Enantioselective Morita–Baylis–Hillman Reaction
Table 5. Relative energies of the model transition states with model
catalyst m-2.
Entry
Model TS
Configuration of
Model MBH[a]
Relative E
[kcal/mol][b]
1
2
3
4
5
6
7
8
TS-R1-eq-eq
TS-R1-eq-ax
TS-S1-eq-eq
TS-S1-eq-ax
TS-R1-ax-eq
TS-R1-ax-ax
TS-S1-ax-eq
TS-S1-ax-ax
TS-R2-eq-eq
TS-R2-eq-ax
TS-S2-eq-eq
TS-S2-eq-ax
TS-R2-ax-eq
TS-R2-ax-ax
TS-S2-ax-eq
TS-S2-ax-ax
R
R
S
S
S
S
R
R
S
S
R
R
R
R
S
S
0.0
+1.4
+6.2
+4.0
+4.6
+7.7
+6.4
+8.1
+10.5
+11.5
+2.7
+3.8
+12.0
+15.1
+6.7
+9.9
Figure 1. Different views of TS-R1-eq-eq with catalyst m-1 (dis-
tances in angstroms [Å]; unnecessary hydrogen atoms omitted for
clarity).
9
10
11
12
13
14
15
16
[a] Configuration of the model MBH adduct after the hemiacetal
decomposition. [b] Energies relative to the more stable transition
state.
In spite of the distortions imposed by the change in the
acidic moiety, the relative energies were found to be globally
similar between catalysts m-1 and m-2, with some excep-
tions. The preferred transition states leading to the R en-
antiomer still resulted from TS-R1-eq-eq, TS-R1-eq-ax and
TS-S2-eq-eq, with relative energies that are very close to
those obtained with catalyst m-1 (compare entries 1, 2 and
11 in Tables 4 and 5); the most striking difference was found
to be the very high energy of the four structures derived
Figure 2. TS-S1-eq-eq (left) and TS-R2-eq-eq (right) with catalyst
m-1 (distances in angstroms [Å], unnecessary hydrogen atoms omit-
ted for clarity).
structure clearly reveals that both the methyl groups suffer from TS-R2.
destabilizing steric interactions with the aromatic portion
In particular, for catalyst m-1, the TS-R2-eq-eq structure
of the catalyst and, even more, with the hydrogen atoms of represents by far the major contribution to the formation
the quinuclidine cage (Figure 2).
of the S enantiomer of the product, being 2.0 kcal/mol
In fact, these interactions are so strong that any change above the global minimum TS-R1-eq-eq, whereas for cata-
in the disposition of the methyl groups in the other TS- lyst m-2 this value becomes 10.5 kcal/mol (compare entry 9
S1-derived transition states causes a stabilization (Table 4, in Table 4 and Table 5), thus completely ruling out TS-R2-
entries 4, 7 and 8 vs. entry 3).
eq-eq for the production of the small amount of the experi-
It can reasonably be assumed that the formation of the mentally observed minor enantiomer. In effect, the only
small amount of the S enantiomer experimentally observed lowest energy TSs furnishing the S enantiomer in the reac-
may be due only to TS-R2-eq-eq (Figure 2), in which the tion with m-2 catalyst are TS-S1-eq-ax (+4.0 kcal/mol;
equatorial methyl groups do not suffer any steric interac- Table 5, entry 4) and TS-R1-ax-eq (+4.6 kcal/mol; Table 5,
tions but the arrangement of the six-membered cycle is al- entry 5), which are more stable with respect to their coun-
most identical to that of the intrinsically less stable boat terparts with catalyst m-1. These energy differences are in
structure of the parent TS-R2 with formaldehyde reasonably good agreement with the excellent 99% ee ob-
(Scheme 4).
We recomputed all the model TSs using m-2 as catalyst pionaldehyde; Table 3, entry 6) and catalyst 2a.
to evaluate if the different acidity and the longest spanning It was also interesting to note that, as expected, the
tained in the reaction with a linear aliphatic aldehyde (pro-
of its NH, with respect to the OH of m-1, could impose a acidic arm of catalyst m-2 imposes a significant distortion
reasonable distortion (or even a complete change) in the on the transition states with respect to the OH of m-1, as
structures and lead to a variation in the energetics of the exemplified by the superimposition of the respective TS-
proton transfer TSs (Table 5). To ensure that the most R1-eq-eq structures shown in Figure 3.
stable structures were computed, many different initial dis-
Whereas the tricyclic cages of the catalysts and the two
positions of the acidic arm were tried for TS-R1-eq-eq, TS- carbon atoms directly attached to them are practically coin-
S1-eq-eq, TS-R2-eq-eq and TS-S2-eq-eq, then all the other cident in both the TS-R1-eq-eq structures, the bond con-
TSs were obtained by including appropriate changes to the necting the cage nitrogen and the adjacent exocyclic methyl-
methyl substituents in the six-membered cycle.
ene is rotated by –120° upon changing from m-1 to m-2.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
desired concentration. The absolute configuration of the Morita–
Baylis–Hillman adducts 5, or of their methyl derivatives, were de-
termined by comparison of their optical rotation with literature
values, except in the case of product 5h, the R-configuration of
which was assumed by chemical analogy.
Materials: Analytical and HPLC-grade solvents for workup and
purification procedures and HPLC analysis were purchased from
commercial suppliers and used as received. Anhydrous methanol
was purchased from Aldrich. Anhydrous CH2Cl2 and DMF were
obtained, respectively, by distillation over CaH2 and P4O10, then
stored over 4 Å molecular sieves under an inert atmosphere for a
maximum of one month. Benzaldehyde, propionaldehyde and iso-
butyraldehyde were purified by distillation at atmospheric pressure,
p-chlorobenzaldehyde was sublimated twice (50 °C/2 Torr) and p-
nitrobenzaldehyde was dissolved in CH2Cl2 and passed through a
short column of basic aluminium oxide, then concentrated. All al-
dehydes were stored, tightly capped, under an inert atmosphere for
a maximum of one (benzaldehyde, propionaldehyde and isobutyral-
dehyde) or five months (p-nitro- and p-chlorobenzaldehyde). Hexa-
fluoroisopropyl acrylate (HFIPA) was purchased from Aldrich and
used as received. Racemic samples of MBH adducts were prepared
by using DABCO as the catalyst at room temperature. β-ICD was
synthesized following a literature procedure.[5a] Trichloroacetyl iso-
cyanate was purchased from Aldrich and used as received; other
isocyanates and acyl isocyanates were prepared according to the
literature.[8] Column chromatography was performed with Kiesel-
gel 60 (Merck, 230–400 mesh ASTM). TLC analysis was performed
with Fluka silica gel TLC-PET foil. TLC plates were analyzed by
exposure to UV light and by submersion in an aqueous KMnO4
solution, followed by heating.
Figure 3. Different views of the superimposition of TS-R1-eq-eq
with catalyst m-1 (ball and stick with radii scaled by 20%) and
catalyst m-2 (tube). Distances are in angstroms [Å], and all hydro-
gen atoms, except the transferred protons and the OH or NH pro-
tons, are omitted for clarity.
This variation in the final positioning of the chair structure
is partially counterbalanced by the rotation of the bond
connecting the same methylene group and the subsequent
α-carbon (+86°). Moreover, the aromatic moiety in TS-R1-
eq-eq with catalyst m-2 is rotated by +33°, with respect to
that with catalyst m-1, and a detailed visual inspection also
revealed that, in this case, the TS structure is not a perfect
chair but is slightly twisted.
Conclusions
We report here an improved asymmetric Morita–Baylis–
Hillman reaction that exploits the new difunctional catalyst
2a and the new 2,6-dimethyl-4-nitrophenyl acrylate
(DMNPA; 4d). Moreover, identification of the reaction
mechanism, supported by experimental data and computa-
tional investigations, has shed light on the reasons behind
the enantioselectivity observed with catalysts 1 (β-ICD) and
General Procedure for the Preparation of Catalysts 2a–h: To a solu-
tion of β-isocupreidine (2 mmol) in anhydrous CH2Cl2 (4 mL) un-
der an inert atmosphere, the appropriate isocyanate (3 mmol) or
acyl isocyanate (2.2 mmol) was added at room temperature. The
reaction was stirred for the appropriate time (see below) and then
2a. Novel β-isocupreidine derivatives are under study as cat- directly submitted to chromatographic purification (CH2Cl2/
MeOH), to give the pure product, except in the case of 2b and 2e,
which were inseparable from by-products.
alysts, both theoretically and experimentally, and results
will be reported in due course.
Caution: All the products, in particular 2b and 2e–h, can undergo
slow methanolysis, especially at the end of the evaporation, and
must be concentrated at room temperature. The yields and purities
were slightly improved when the evaporation was stopped when the
products started to become viscous, then a small amount of
CH2Cl2 was added and the product was finally concentrated. The
pure products are sensitive to moisture and carbon dioxide and
must be stored tightly capped and under an inert atmosphere if
extended preservation is desired.
Experimental Section
General Methods: Melting points were measured with an Electro-
thermal IA 9000 apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded at 200 and 50 MHz, respectively, with a Var-
ian Gemini 200 spectrometer in CDCl3 at 25 °C. Chemical shifts
are reported in ppm relative to residual solvent signals (δ =7.26
and 77.0 ppm for 1H and 13C NMR, respectively), and coupling
constants (J) are given in Hz. LC electrospray ionization mass spec-
tra were obtained with an Agilent Technologies MSD1100 single-
quadrupole mass spectrometer. Specific rotation measurements {[α]
2D5} were recorded at room temperature with a Perkin–Elmer
Model 241 polarimeter at the sodium D line (concentration given
in g/100 mL). Elemental analyses were performed with a Carlo
Erba CHN Elemental Analyzer. The ee values of Morita–Baylis–
Hillman adducts were verified by HPLC analysis, eluting solutions
with a concentration between 0.02 and 0.2 mg/mL in a Hewlett–
Packard 1100 chromatograph equipped with a Daicel Chiralcel
OD-H column and a diode-array UV detector (210, 230 and
250 nm). To obtain reliable results, even in the case of solid com-
pounds, before HPLC analysis all the product was completely dis-
solved in 2-propanol until a clear homogeneous solution was ob-
tained, then a suitable aliquot was diluted with n-hexane to the
4-[(5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl]quinolin-6-
yl (2,2,2-Trichloroacetyl)carbamate (2a): Following the general pro-
cedure (1 h reaction time) the title compound was obtained in 85%
yield as a brownish amorphous solid; m.p. 185–190 °C (dec.).
1
[α]2D5 = –21.1 (c = 0.71, CH2Cl2). H NMR (200 MHz, CDCl3): δ
= 1.08 (t, J = 7.3 Hz, 3 H), 1.60 (dd, J = 6.4, 13.4 Hz, 1 H), 1.81
(q, J = 7.3 Hz, 2 H), 1.93–2.14 (m, 3 H), 2.48–2.51 (m, 1 H), 3.16
(d, J = 14.1 Hz, 1 H), 3.43–3.53 (m, 2 H), 4.18 (d, J = 14.1 Hz, 1
H), 4.32 (d, J = 6.4 Hz, 1 H), 6.05 (s, 1 H), 7.30 (dd, J = 2.4,
9.1 Hz, 1 H), 7.56 (d, J = 4.4 Hz, 1 H), 7.92 (d, J = 2.4 Hz, 1 H),
7.96 (d, J = 9.1 Hz, 1 H), 8.73 (d, J = 4.4 Hz, 1 H), 9.40 (br. s, 1
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 7.0, 21.1, 21.3, 27.0,
32.1, 46.1, 53.5, 58.9, 71.1, 75.8, 103.7, 118.5, 122.2, 125.9, 131.6,
138.0, 143.2, 146.5, 156.8, 165.2 ppm. ESI-MS: m/z = 498 [M(3 ϫ
35Cl) + H]+, 500 [M(2 ϫ 35Cl, 1 ϫ 37Cl) + H]+. C22H22Cl3N3O4
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
Enantioselective Morita–Baylis–Hillman Reaction
(498.79): calcd. C 52.98, H 4.45, N 8.42; found C 53.00, H 4.50, N
8.36.
yield as a pale-yellow waxy solid. [α]2D5 = +81.1 (c = 0.88, CH2Cl2).
1H NMR (200 MHz, CDCl3): δ = 1.00 (t, J = 7.3 Hz, 3 H), 1.15
(dd, J = 6.4, 12.2 Hz, 1 H), 1.38–1.72 (m, 5 H), 1.60 (d, J = 6.7 Hz,
3 H), 2.07–2.12 (m, 1 H), 2.58 (d, J = 13.6 Hz, 1 H), 2.67–2.82 (m,
2 H), 3.46 (d, J = 6.4 Hz, 1 H), 3.52 (d, J = 13.6 Hz, 1 H), 4.92
(dq, J = 6.7, 6.7 Hz, 1 H), 5.92 (s, 1 H), 7.15–7.50 (m, 6 H), 7.70–
7.83 (m, 3 H), 8.06 (d, J = 9.1 Hz, 1 H), 8.83 (d, J = 4.4 Hz, 1
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 7.2, 21.7, 23.4, 24.0,
27.3, 32.8, 46.2, 50.6, 54.4, 56.3, 72.9, 77.1, 114.0, 119.3, 124.4,
125.7, 126.3, 127.2, 128.5, 131.5, 142.9, 144.3, 145.7, 148.8, 149.6,
153.9 ppm. ESI-MS: m/z = 458 [M + H]+. C28H31N3O3 (457.57):
calcd. C 73.50, H 6.83, N 9.18; found C 73.55, H 6.86, N 9.14.
4-[(5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl]quinolin-6-
yl (4-Nitrobenzoyl)carbamate (2b): Following the general procedure
(2 h reaction time) the title compound was obtained in 55% yield
as a brownish amorphous solid (a preliminary elution with ethyl
acetate was necessary before eluting with CH2Cl2/MeOH); m.p.
152–158 °C (dec.). [α]2D5 = –48.7 (c = 0.55, CH2Cl2). 1H NMR
(200 MHz, CDCl3): δ = 1.02 (t, J = 7.3 Hz, 3 H), 1.29 (dd, J = 6.2,
13.4 Hz, 1 H), 1.48–1.82 (m, 5 H), 2.15–2.19 (m, 1 H), 2.69 (d, J
= 13.8 Hz, 1 H), 2.98–3.04 (m, 2 H), 3.54 (d, J = 4.9 Hz, 1 H), 3.58
(d, J = 13.8 Hz, 1 H), 5.98 (s, 1 H), 7.58 (dd, J = 2.4, 9.1 Hz, 1 H),
7.81 (d, J = 4.4 Hz, 1 H), 7.87 (d, J = 2.4 Hz, 1 H), 8.21 (d, J =
9.1 Hz, 1 H), 8.35–8.39 (m, 4 H), 8.95 (d, J = 4.4 Hz, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 7.2, 23.3, 23.9, 27.3, 32.8, 46.6,
54.6, 56.8, 72.9, 77.3, 114.0, 119.7, 123.7, 124.0, 125.9, 131.4, 132.2,
134.6, 144.3, 146.2, 148.4, 150.3, 151.0, 163.4 ppm. ESI-MS: m/z =
503 [M + H]+. C27H26N4O6 (502.53): calcd. C 64.53, H 5.22, N
11.15; found C 64.60, H 5.31, N 11.08.
4-[(5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl]quinolin-6-
yl [(S)-1-Phenylethyl]carbamate (2g): Following the general pro-
cedure (5 h reaction time) the title compound was obtained in 81%
yield as a pale-yellow waxy solid. [α]2D5 = –86.2 (c = 1.02, CH2Cl2).
1H NMR (200 MHz, CDCl3): δ = 1.00 (t, J = 7.3 Hz, 3 H), 1.23
(dd, J = 6.2, 12.8 Hz, 1 H), 1.60 (d, J = 6.7 Hz, 3 H), 1.55–1.83
(m, 5 H), 2.12–2.17 (m, 1 H), 2.65 (d, J = 13.7 Hz, 1 H), 2.85–3.01
(m, 2 H), 3.55–3.65 (m, 2 H), 4.99 (dq, J = 6.7, 6.7 Hz, 1 H), 5.90
(s, 1 H), 7.13–7.49 (m, 6 H), 7.55–7.62 (m, 1 H), 7.68 (d, J = 4.4 Hz,
1 H), 7.83 (d, J = 2.4 Hz, 1 H), 8.04 (d, J = 9.1 Hz, 1 H), 8.83 (d,
J = 4.4 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 7.3, 22.1,
23.2, 23.6, 27.4, 46.2, 50.9, 54.2, 56.5, 72.6,77.1, 113.9, 119.3, 124.8,
125.7, 126.1, 127.4, 128.7, 131.6, 143.2, 143.8, 145.9, 149.0, 149.7,
153.8 ppm. ESI-MS: m/z = 458 [M + H]+. C28H31N3O3 (457.57):
calcd. C 73.50, H 6.83, N 9.18; found C 73.53, H 6.87, N 9.12.
4-[(5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl]quinolin-6-
yl Benzoylcarbamate (2c): Following the general procedure (8 h re-
action time) the title compound was obtained in a crude yield of
68% (not separated from byproducts), as a brownish waxy solid.
1
[α]2D5 = –15.8 (c = 1.32, CH2Cl2). H NMR (200 MHz, CDCl3): δ
= 1.04 (t, J = 7.3 Hz, 3 H), 1.36 (dd, J = 6.2, 13.4 Hz, 1 H), 1.62–
1.77 (m, 4 H), 1.85 (dd, J = 6.2, 13.4 Hz, 1 H), 2.22–2.27 (m, 1 H),
2.76 (d, J = 13.8 Hz, 1 H), 3.10–3.16 (m, 2 H), 3.71–3.80 (m, 2 H),
6.12 (s, 1 H), 7.40–7.68 (m, 5 H), 7.78 (d, J = 4.4 Hz, 1 H), 7.96
(d, J = 2.4 Hz, 1 H), 8.18–8.27 (m, 3 H), 8.94 (d, J = 4.4 Hz, 1
H) ppm. ESI-MS: m/z = 458 [M + H]+. C27H27N3O4 (457.53):
calcd. C 70.88, H 5.95, N 9.18; found C 70.91, H 6.01, N 9.11.
4-[(5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl]quinolin-6-
yl (2-Benzamidoethyl)carbamate (2h): Following the general pro-
cedure (5 h reaction time) the title compound was obtained in 63%
yield as a yellow waxy solid. [α]2D5 = –3.8 (c = 1.13, CH2Cl2). 1H
NMR (200 MHz, CDCl3): δ = 0.92 (t, J = 7.4 Hz, 3 H), 1.39–1.66
(m, 5 H), 2.04 (br. s, 1 H), 2.68 (d, J = 13.6 Hz, 1 H), 2.97–3.01
(m, 2 H), 3.22 (d, J = 5.5 Hz, 1 H), 3.45–3.80 (m, 5 H), 5.75 (s, 1
H), 6.75–6.83 (m, 2 H), 7.00–7.07 (m, 1 H), 7.40 (dd, J = 2.2,
9.1 Hz, 1 H), 7.49–7.57 (m, 3 H), 7.94 (d, J = 2.2 Hz, 1 H), 8.06–
8.11 (m, 2 H), 8.76 (d, J = 4.5 Hz, 1 H), 9.61 (br. s, 1 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 7.1, 22.6, 22.8, 27.1, 32.5, 39.7, 40.3,
46.0, 53.8, 56.4, 71.9, 76.8, 114.7, 119.3, 124.5, 125.7, 126.7, 127.7,
130.8, 131.9, 133.1, 143.2, 145.7, 149.0, 149.5, 155.9, 167.2 ppm.
ESI-MS: m/z = 501 [M + H]+. C29H32N4O4 (500.60): calcd. C
69.58, H 6.44, N 11.19; found C 69.64, H 6.51, N 11.15.
4-[(5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl]quinolin-6-
yl Acetylcarbamate (2d): Following the general procedure (5 h reac-
tion time) the title compound was obtained in 57% yield as a pale-
yellow solid; m.p. 166–169 °C (dec.). [α]2D5 = –6.5 (c = 1.47,
1
CH2Cl2). H NMR (200 MHz, CDCl3): δ = 0.97 (t, J = 7.3 Hz, 3
H), 1.19 (dd, J = 6.4, 12.2 Hz, 1 H), 1.41–1.72 (m, 5 H), 2.04–2.10
(m, 1 H), 2.30 (s, 3 H), 2.62 (d, J = 13.6 Hz, 1 H), 2.91–2.97 (m, 2
H), 3.40 (d, J = 6.2 Hz, 1 H), 3.47 (d, J = 13.6 Hz, 1 H), 5.88 (s, 1
H), 7.40 (dd, J = 2.4, 9.1 Hz, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 7.73
(d, J = 4.5 Hz, 1 H), 8.10 (d, J = 9.1 Hz, 1 H), 8.87 (d, J = 4.5 Hz,
1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 7.2, 21.0, 23.5, 24.6,
27.3, 32.8, 46.7, 54.8, 56.6, 73.0, 77.2, 113.7, 119.4, 124.3, 125.7,
131.8, 144.5, 146.0, 148.5, 149.9, 169.3 ppm. ESI-MS: m/z = 396
[M + H]+. C22H25N3O4 (395.46): calcd. C 66.82, H 6.37, N 10.63;
found C 66.85, H 6.42, N 10.62.
General Procedure for the Preparation of Acrylates 4a–d: To a solu-
tion of the appropriate phenol or alcohol (20 mmol) dissolved in
anhydrous CH2Cl2 (20 mL) under an inert atmosphere, TEA
(3 mL, 21 mmol) and DMAP (250 mg, 2 mmol) were sequentially
added. The reaction was brought to 0 °C with an ice bath, then
acryloyl chloride (1.68 mL, 20 mmol) dissolved in CH2Cl2 (3 mL)
was slowly added. After removal of the bath, the reaction was
stirred for 24 h (8 h in the case of 4b and 4d) at room temperature,
then the solvent was partially evaporated under vacuum and the
residue was diluted with ethyl acetate (100 mL) and 0.2 m HCl
(20 mL). After separation, the organic layer was washed with water
(10 mL). The unified aqueous phases were further extracted with
ethyl acetate (20 mL) and the second organic phase was washed
with water (10 mL). The unified organic phases were dried with
anhydrous Na2SO4 and concentrated under vacuum, and the resi-
dues were purified by silica gel chromatography (c-hexane/ethyl
acetate) to give acrylates 4a–d.
4-[(5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl]quinolin-6-
yl Benzylcarbamate (2e): Following the general procedure (24 h re-
action time) the title compound was obtained in a crude yield of
70 % (not separated from byproducts), as a yellow waxy solid.
1
[α]2D5 = –1.5 (c = 1.78, CH2Cl2). H NMR (200 MHz, CDCl3): δ =
1.04 (t, J = 7.3 Hz, 3 H), 1.33 (dd, J = 6.4, 12.2 Hz, 1 H), 1.55–
1.86 (m, 5 H), 2.20–2.25 (m, 1 H), 2.75 (d, J = 13.6 Hz, 1 H), 3.03–
3.11 (m, 2 H), 3.67–3.76 (m, 2 H), 4.50 (d, J = 6.8 Hz, 2 H), 5.95
(t, J = 6.8 Hz, 1 H), 6.03 (s, 1 H), 7.29–7.41 (m, 5 H), 7.56 (dd, J
= 2.1, 9.1 Hz, 1 H), 7.74 (d, J = 4.4 Hz, 1 H), 7.87 (d, J = 2.1 Hz,
1 H), 8.13 (d, J = 9.1 Hz, 1 H), 8.90 (d, J = 4.4 Hz, 1 H) ppm. ESI-
MS: m/z = 444 [M + H]+. C27H29N3O3 (443.54): calcd. C 73.11, H
6.59, N 9.47; found C 73.23, H 6.68, N 9.37.
4-[(5S)-3-Ethyl-4-oxa-1-azatricyclo[4.4.0.03,8]decan-5-yl]quinolin-6- Mesityl Acrylate (4a): Starting from 2,4,6-trimethylphenol, the title
yl [(R)-1-Phenylethyl]carbamate (2f): Following the general pro-
compound was obtained in 78% yield as a colourless oil. 1H NMR
cedure (5 h reaction time) the title compound was obtained in 85%
(200 MHz, CDCl3): δ = 2.17 (s, 6 H), 2.28 (s, 3 H), 6.04 (dd, J =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
1.5, 10.3 Hz, 1 H), 6.40 (dd, J = 10.3, 17.3 Hz, 1 H), 6.68 (dd, J =
1.5, 17.3 Hz, 1 H), 6.93 (s, 2 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 16.1, 20.7, 127.6, 129.1, 129.6, 132.1, 135.2, 145.7, 163.9 ppm.
ESI-MS: m/z = 190 [M]+. C12H14O2 (190.24): calcd. C 75.76, H
7.42; found C 75.80, H 7.49.
standing. Recrystallization from c-hexane/ethyl acetate (2 crops)
furnished colourless crystals in 55% final yield; m.p. 75–79 °C. The
ee of the product was determined by HPLC using a Chiralcel OD-
H column (n-hexane/2-propanol 9:1, flow rate 1.0 mL/min, λ =
210 nm): tR = 6.9 (R), 7.6 (S) min; 85 and 98% ee before and after
recrystallization, respectively. [α]2D5 = –26.3 (c = 0.95, CH2Cl2), 98%
ee. The absolute configuration of compound 5a was determined
as (R) after conversion into the corresponding methyl ester and
comparison of its optical rotation {[α]2D5 = –109.0 (c = 0.62,
MeOH), 98% ee} with literature values {[α]1D8 = –109.3 (c = 0.45,
MeOH), 95% ee.[5a] [α]1D8 = –111.1 (c = 1.11, MeOH)[13]}. 1H NMR
(200 MHz, CDCl3): δ = 1.90 (s, 6 H), 2.25 (s, 3 H), 2.91 (br. s, 1
H), 5.67 (s, 1 H), 6.10 (s, 1 H), 6.62 (s, 1 H), 6.83 (s, 2 H), 7.22–
7.45 (m, 5 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 15.8, 20.6,
73.1, 126.3, 126.7, 127.8, 128.3, 129.0, 129.5, 135.3, 141.2, 141.6,
145.4, 164.2. ESI-MS: m/z = 296 [M]+. C19H20O3 (296.37): calcd.
C 77.00, H 6.80; found C 77.08, H 6.90.
Naphthalen-1-yl Acrylate (4b): Starting from 1-naphthol, the title
compound was obtained in 86% yield as a colourless oil and iden-
1
tified by comparison of its H NMR spectrum with the literature
data.[19]
4-Nitrobenzyl Acrylate (4c): Starting from 4-nitrobenzyl alcohol,
the title compound was obtained in 89% yield as a colourless oil
that rapidly solidify to white crystals; m.p. 50–52 °C. 1H NMR
(200 MHz, CDCl3): δ = 5.30 (s, 2 H), 5.92 (dd, J = 1.5, 10.3 Hz, 1
H), 6.20 (dd, J = 10.3, 17.2 Hz, 1 H), 6.50 (dd, J = 1.5, 17.2 Hz, 1
H), 7.50–7.57 (m, 2 H), 8.20–8.26 (m, 2 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 64.8, 123.8, 127.7, 128.4, 131.9, 143.1,
165.6 ppm. ESI-MS: m/z = 208 [M + H]+. C10H9NO4 (207.19):
calcd. C 57.97, H 4.38, N 6.76; found C 58.00, H 4.40, N 6.71.
(R)-Naphthalen-1-yl 2-[Hydroxy(phenyl)methyl]acrylate (5b): Fol-
lowing the general procedure (catalyst 2a, –18 °C, 18 d) the title
compound was obtained in 43% yield as a pale-yellow oil and iden-
tified by comparison of its NMR spectra with literature data.[10b]
The ee of the product was determined by HPLC using a Chiralcel
OD-H column (n-hexane/2-propanol 9:1, flow rate 1.0 mL/min, λ
= 210 nm): tR = 16.7 (R), 19.7 (S) min; 70% ee. [α]2D5 = –8.2 (c =
0.97, CHCl3), 70% ee. The absolute configuration of compound 5b
was determined as (R) by comparison of its optical rotation with
the literature value[10b] {[α]1D8 = +10.9 (c = 0.80, CHCl3), 92% ee}.
2,6-Dimethyl-4-nitrophenyl Acrylate (4d): Starting from 2,6-di-
methyl-4-nitrophenol, the title compound was obtained in 97%
yield as a white amorphous solid. Recrystallization from ethyl acet-
ate furnished white crystals; m.p. 103–104 °C. 1H NMR (200 MHz,
CDCl3): δ = 2.25 (s, 6 H), 6.12 (dd, J = 1.4, 10.3 Hz, 1 H), 6.38
(dd, J = 10.3, 17.2 Hz, 1 H), 6.70 (dd, J = 1.4, 17.2 Hz, 1 H), 7.98
(s, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 16.4, 123.7, 126.6,
132.2, 133.7, 145.3, 152.9, 162.8 ppm. ESI-MS: m/z = 222
[M + H]+. C11H11NO4 (221.21): calcd. C 59.73, H 5.01, N 6.33;
found C 59.77, H 5.06, N 6.30.
(R)-4-Nitrobenzyl 2-[Hydroxy(phenyl)methyl]acrylate (5c): Follow-
ing the general procedure (catalyst 2a, –18 °C, 23 d) the title com-
pound was obtained in 78 % yield as a white amorphous solid.
Recrystallization from CH2Cl2 furnished colourless crystals; m.p.
90–94 °C. The ee of the product was determined by HPLC using a
Chiralcel OD-H column (n-hexane/iPrOH, 9:1, flow rate 1.0 mL/
General Procedure for the Enantioselective Morita–Baylis–Hillman
Reactions and for Conversion of Adducts 5a–h into Methyl Deriva-
tives 6a–c: Catalyst 1 or 2 (0.1 mmol) was brought into a dried two-
necked 5 mL flask by diluting a known amount with anhydrous
CH2Cl2, then keeping a suitable aliquot and evaporating CH2Cl2.
After drying of the catalyst by dissolution in anhydrous THF
(0.5 mL) followed by evaporation and redissolution in anhydrous
DMF (0.3 mL, unless otherwise noted), aldehyde 3 (1 mmol) and
freshly activated powdered 4 Å molecular sieves (about 50 mg) were
sequentially added. The mixture was stirred for 10 min at room
temperature and cooled (thermostat control) in a cryogenic bath
(or ice bath for reactions at 0 °C) for 20 min, then acrylate 4
(1 mmol) was slowly added. When the conversion [monitored by 1H
NMR analysis of samples taken directly from the reaction mixture
(about 20 μL) and diluted in CDCl3] stopped increasing, the reac-
tion was quenched by addition of 0.1 m HCl (3 mL) and extracted
with ethyl acetate (20 mL). The organic phase was successively
washed with 0.1 m HCl (2ϫ 1 mL) and brine (2 mL). The unified
aqueous phases were extracted with additional ethyl acetate
(10 mL), which was washed with fresh 0.1 m HCl (2ϫ 1 mL) and
brine (2 mL). The unified organic phases were dried with anhy-
drous Na2SO4 and concentrated under vacuum. Purification of the
crude residue by silica gel chromatography (c-hexane/ethyl acetate)
furnished the pure Morita–Baylis–Hillman adducts 5a–h. Conver-
sion into the corresponding methyl esters was accomplished by dis-
solving adducts 5a–h in anhydrous MeOH (1 mL), adding triethyl-
amine (0.5 mL), and stirring at room temperature for 1 h (5 h for
5a and 5c). After evaporation of the volatiles under vacuum, the
residue was purified by silica gel chromatography (c-hexane/ethyl
acetate), to give the methyl esters in 80–95% yield.
min, λ = 210 nm): tR = 26.3 (S), = 28.7 (R) min; 45% ee. [α]2D5
=
–9.6 (c = 1.77, CHCl3); 45% ee. The absolute configuration of com-
pound 5c was determined as (R) after conversion into the corre-
sponding methyl ester and comparison of its optical rotation
{[α]2D5 = –50.7 (c = 1.03, MeOH), 45% ee} with the literature values
{[α]1D8 = –109.3 (c = 0.45, MeOH), 95% ee[5a]; [α]1D8 = –111.1 (c =
1
1.11, MeOH)[13]}. H NMR (200 MHz, CDCl3): δ = 3.14 (br. s, 1
H), 5.13 (d, J = 13.6 Hz, 1 H), 5.22 (d, J = 13.6 Hz, 1 H), 5.56 (s,
1 H), 6.00 (s, 1 H), 6.43 (s, 1 H), 7.25–7.34 (m, 7 H), 8.09 (d, J =
8.7 Hz, 2 H). 13C NMR (50 MHz, CDCl3): δ = 64.8, 72.7, 123.5,
126.4, 126.6, 127.8, 127.9, 128.3, 141.1, 141.6, 142.7, 147.4, 165.4.
ESI-MS: m/z = 313 [M]+. C17H15NO5 (313.31): calcd. C 65.17, H
4.83, N 4.47; found C 65.20, H 4.88, N 4.41.
(R)-2,6-Dimethyl-4-nitrophenyl 2-[Hydroxy(phenyl)methyl]acrylate
(5d): Following the general procedure (catalyst 2a, –35 °C, 3 d), the
title compound was obtained in 58% yield as a white amorphous
solid. Recrystallization from diethyl ether (3 crops) furnished the
enantiopure product as white crystals in 52% final yield; m.p. 78–
80 °C. The ee of the product was determined by HPLC using a
Chiralcel OD-H column (n-hexane/iPrOH, 8:2; flow rate 0.25 mL/
min; λ = 210 nm): tR = 32.6 (R), 34.6 (S) min; 99 and 100% ee
before and after recrystallization, respectively. [α]2D5 = –19.5 (c =
1.74, CH2Cl2); 99% ee. The absolute configuration of compound
5d was determined as (R) after conversion into the corresponding
methyl ester and comparison of its optical rotation {[α]2D5 = –110.9
(c = 1.23, MeOH); 100% ee} with the literature values {[α]1D8
=
(R)-Mesityl 2-[Hydroxy(phenyl)methyl]acrylate (5a): Following the
general procedure (catalyst 2a, –18 °C, 20 d) the title compound
was obtained in 71% yield as a colourless oil that solidified upon
–109.3 (c = 0.45, MeOH); 95% ee[5a]; [α]1D8 = –111.1 (c = 1.11,
1
MeOH)[13]}. H NMR (200 MHz, CDCl3): δ = 2.01 (s, 6 H), 2.60
(br. s, 1 H), 5.70 (s, 1 H), 6.24–6.25 (m, 1 H), 6.66–6.67 (m, 1 H),
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
Enantioselective Morita–Baylis–Hillman Reaction
1
7.27–7.47 (m, 5 H), 7.91 (s, 2 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 16.2, 73.0, 123.7, 126.8, 127.5, 128.3, 128.7, 132.2, 140.9, 141.1,
145.4, 152.7, 163.1 ppm. ESI-MS: m/z = 327 [M]+. C18H17NO5
(327.34): calcd. C 66.05, H 5.23, N 4.28; found C 66.09, H 5.29, N
4.20.
other cases. H NMR (200 MHz, CDCl3): δ = 2.05 (s, 6 H), 2.68
(br. s, 1 H), 5.66 (s, 1 H), 6.22–6.23 (m, 1 H), 6.68 (s, 1 H), 7.31–
7.40 (m, 4 H), 7.92 (s, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 16.3, 72.4, 127.9, 128.2, 128.8, 132.2, 134.2, 139.5, 140.8, 145.4,
152.6, 163.0 ppm. ESI-MS: m/z = 361 [M (35Cl)]+. C18H16ClNO5
(361.78): calcd. C 59.76, H 4.46, N 3.87; found C 59.83, H 4.52, N
3.79.
(R)-1,1,1,3,3,3-Hexafluoroprop-2-yl 2-[Hydroxy(phenyl)methyl]-
acrylate (5e): Following the general procedure (catalyst 2a, –55 °C,
3 h) the title compound was obtained in 83% yield as a colourless
(R)-2,6-Dimethyl-4-nitrophenyl 3-Hydroxy-2-methylenepentanoate
(5i): Following the general procedure (catalyst 2a, –35 °C, 18 h) the
title compound was obtained in 46% yield as a colourless oil. The
ee of the product was determined by HPLC using a Chiralcel OD-
H column (n-hexane/iPrOH, 95:5; flow rate 1 mL/min; λ =
210 nm): tR = 12.1 (R), 13.8 (S) min; 99% ee. [α]2D5 = +0.5 (c =
1.05, CHCl3); 99% ee. The absolute configuration of compound 5i
was determined as (R) after conversion into the corresponding
methyl ester and comparison of its optical rotation {[α]2D5 = +7.8 (c
= 0.61, CHCl3); 99% ee} with the literature value {[α]D = +7.7 (c
= 0.50, CHCl3), 100% ee[20]}. 1H NMR (200 MHz, CDCl3): δ =
1.02 (t, J = 7.4 Hz, 3 H), 1.69–1.86 (m, 2 H), 2.25 (s, 6 H), 2.29
(br. s, 1 H), 4.49 (q, J = 6.2 Hz, 1 H), 6.12 (s, 1 H), 6.61 (s, 1 H),
8.00 (s, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 10.1, 16.8,
29.4, 72.8, 124.0, 127.7, 132.4, 141.4, 152.8, 163.6 ppm. ESI-MS:
m/z = 279 [M]+. C14H17NO5 (279.29): calcd. C 60.21, H 6.14, N
5.02; found C 60.32, H 6.21, N 4.90.
1
oil. The identity was verified by comparison of its H NMR with
literature data.[5a] The ee of the product was determined, on both
5e and its methyl derivative, by HPLC using a Chiralcel OD-H
column {5e: n-hexane/iPrOH, 99:1; flow rate 0.5 mL/min; λ =
210 nm: tR = 23.0 (S), 25.2 (R) min; 98% ee; methyl derivative: n-
hexane/iPrOH, 98:2; flow rate 0.7 mL/min; λ = 210 nm: tR = 27.1
(S), 29.0 (R) min; 98% ee}. [α]2D5 = –54.8 (c = 1.15, CHCl3); 98%
ee. The absolute configuration of compound 5e was determined as
(R) by comparison of its optical rotation with the literature value
{[α]2D2 = –53.2 (c = 1.045, CHCl3); 95% ee[5a]}.
(R)-2,6-Dimethyl-4-nitrophenyl 2-[Hydroxy(4-nitrophenyl)methyl]-
acrylate (5f): Following the general procedure (1 mL of DMF, cata-
lyst 2a, –35 °C, 18 h) the title compound was obtained in 48% yield
as a yellow amorphous solid. Recrystallization from diethyl ether
(3 crops) furnished almost enantiopure product as pale-yellow crys-
tals in 39% final yield; m.p. 106–110 °C. The ee of the product was
determined after derivatization to the corresponding methyl ester,
by HPLC using a Chiralcel OD-H column [n-hexane/iPrOH, 95:5,
flow rate 0.7 mL/min, λ = 210 nm]: tR = 32.2 (R), 35.3 (S) min; 94
(R)-2,6-Dimethyl-4-nitrophenyl 3-Hydroxy-4-methyl-2-methylene-
pentanoate (5j): Following the general procedure (catalyst 2a,
–18 °C, 4 d) the title compound was obtained in 43% yield as a
colourless oil. The ee of the product was determined by HPLC
using a Chiralcel OD-H column (n-hexane/iPrOH, 90:10; flow rate
0.5 mL/min; λ = 210 nm): tR = 13.5 (R), 16.1 (S) min; 95% ee.
[α]2D5 = –5.2 (c = 2.24, CHCl3); 95% ee. The absolute configuration
of compound 5j was determined as (R) after conversion into the
corresponding methyl ester and comparison of its optical rotation
{[α]2D5 = +12.7 (c = 0.78, CHCl3); 95% ee} with the literature value
{[α]2D4 = +13.1 (c = 0.38, CHCl3); 99% ee[5a]}. 1H NMR (200 MHz,
CDCl3): δ = 0.97 (d, J = 6.6 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H),
1.91–2.10 (m, 1 H), 2.15 (br. s, 1 H), 2.24 (s, 6 H), 4.26 (d, J =
6.2 Hz, 1 H), 6.09 (s, 1 H), 6.63 (s, 1 H), 7.99 (s, 2 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 16.5, 17.2, 19.5, 32.8, 77.0, 123.8,
128.3, 132.3, 140.6, 145.4, 152.8, 163.4 ppm. ESI-MS: m/z = 293
[M]+. C15H19NO5 (293.32): calcd. C 61.42, H 6.53, N 4.78; found
C 61.49, H 6.60, N 4.67.
and 99% ee before and after recrystallization, respectively. [α]2D5
=
+8.1 (c = 1.30, CH2Cl2), 99% ee. The absolute configuration of
compound 5f was determined as (R) after conversion into the cor-
responding methyl ester and comparison of its optical rotation
{[α]2D5 = –83.5 (c = 0.72, MeOH), 99% ee} with the literature value
{[α]2D5 = –76.9 (c = 1.03, MeOH); 91% ee[5a]}. 1H NMR (200 MHz,
CDCl3): δ = 2.08 (s, 6 H), 2.97 (br. d, J = 4.8 Hz, 1 H), 5.78 (br.
d, J = 4.8 Hz, 1 H), 6.25 (s, 1 H), 6.75 (s, 1 H), 7.61–7.66 (m, 2 H),
7.94 (s, 2 H), 8.21–8.26 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 16.4, 72.3, 123.8, 123.9, 127.5, 128.9, 132.1, 140.2, 145.5, 148.0,
152.4, 162.9 ppm. ESI-MS: m/z = 372 [M]+. C18H16N2O7 (372.33):
calcd. C 58.06, H 4.33, N 7.52; found C 58.17, H 4.41, N 7.40.
(R)-1,1,1,3,3,3-Hexafluoroprop-2-yl 2-[Hydroxy(4-nitrophenyl)-
methyl]acrylate (5g): Following the general procedure (2 mL of
DMF, catalyst 2a, –55 °C, 2 h) the title compound was obtained in
63% yield as a colourless oil. The identity was verified by compari-
son of its 1H NMR spectra with the literature data.[5a] The ee of the
product was determined after derivatization to the corresponding
methyl ester, by HPLC using a Chiralcel OD-H column (n-hexane/
iPrOH, 95:5; flow rate 0.7 mL/min; λ = 210 nm): tR = 32.2 (R),
35.3 (S) min; 91% ee. [α]2D5 = –39.4 (c = 1.33, CHCl3); 91% ee. The
absolute configuration of compound 5g was determined as (R) by
Supporting Information (see footnote on the first page of this arti-
cle): Computational details, cartesian coordinates, energies and
number of imaginary frequencies of all the computed structures;
1H and 13C NMR spectra of new compounds.
Acknowledgments
comparison of its optical rotation with the literature value {[α]2D5
–39.7 (c = 1.01, CHCl3); 91% ee[5a]}.
=
This work was supported by the Polytechnic University of Marche,
Ancona, Italy.
(R)-2,6-Dimethyl-4-nitrophenyl 2-[(4-Chlorophenyl)(hydroxy)meth-
yl]acrylate (5h): Following the general procedure (0.5 mL of DMF,
catalyst 2a, 0 °C, 4 d) the title compound was obtained in 53%
yield as a white amorphous solid. Recrystallization from diethyl
ether (3 crops) furnished the product as colourless crystals in 43%
final yield; m.p. 99–103 °C. The ee of the product was determined
by HPLC using a Chiralcel OD-H column (n-hexane/iPrOH, 97:3;
flow rate 1.0 mL/min; λ = 210 nm): tR = 44.1 (R), 49.3 (S) min; 90
[1] For reviews, see: a) S. E. Drewes, G. H. P. Roos, Tetrahedron
1988, 44, 4653–4670; b) D. Basavaiah, P. D. Rao, R. S. Hyma,
Tetrahedron 1996, 52, 8001–8062; c) E. Ciganek, in: Organic
Reactions (Ed.: L. A. Paquette), Wiley, New York, 1997, vol.
51, pp. 201–350; d) P. Langer, Angew. Chem. 2000, 112, 3177–
3180; Angew. Chem. Int. Ed. 2000, 39, 3049–3052; e) D. Basa-
vaiah, A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811–
892; f) G. Masson, C. Housseman, J.-P. Zhu, Angew. Chem.
2007, 119, 4698–4712; Angew. Chem. Int. Ed. 2007, 46, 4614–
and 98% ee before and after recrystallization, respectively]. [α]2D5
=
–14.7 (c = 2.60, CH2Cl2); 98% ee. The absolute configuration of
compound 5h was assumed as (R) by chemical analogy with all the
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
4628; g) D. Basavaiah, K. V. Rao, R. J. Reddy, Chem. Soc. Rev.
2007, 36, 1581–1588; h) Y.-L. Shi, M. Shi, Eur. J. Org. Chem.
2007, 2905–2916; i) C. Menozzi, P. I. Dalko, Organocatalytic
Enantioselective Morita–Baylis–Hillman Reactions in Enantio-
selective Organocatalysis, in: Reactions and Experimental Pro-
cedures (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, Germany,
2007; j) V. Singh, S. Batra, Tetrahedron 2008, 64, 4511–4574;
k) V. Declerck, J. Martinez, F. Lamaty, Chem. Rev. 2009, 109,
1–48; l) G.-N. Ma, J.-J. Jiang, M. Shi, Y. Wei, Chem. Commun.
2009, 45, 5496–5514; m) D. Basavaiah, B. S. Reddy, S. S. Bad-
sara, Chem. Rev. 2010, 110, 5447–5674; n) Y. Wei, M. Shi, Acc.
Chem. Res. 2010, 43, 1005–1018; o) D. Basavaiah, G. Veerar-
aghavaiah, Chem. Soc. Rev. 2012, 41, 68–78; p) R. Rios, Catal.
Sci. Technol. 2012, 2, 267–278.
For selected recent examples on the use of MBH adducts in
the synthesis of important natural products, of their derivatives
and analogues, or of useful building blocks, not covered by
the preceding reviews, see: a) V. Sharma, M. L. McLaughlin,
J. Comb. Chem. 2010, 12, 327–331; b) D. Basavaiah, D. V. Le-
nin, Eur. J. Org. Chem. 2010, 5650–5658, and references cited
therein c) G. W. Amarante, M. Cavallaro, F. Coelho, Tetrahe-
dron Lett. 2010, 51, 2597–2599, and references cited therein d)
X.-Y. Guan, Y. Wei, M. Shi, Chem. Eur. J. 2010, 16, 13617–
13621, and references cited therein e) W. Zhong, W. Ma, Y. Liu,
Tetrahedron 2011, 67, 3509–3518, and references cited therein f)
C. Liu, B.-X. Tan, J.-L. Jin, Y.-Y. Zhang, N. Dong, X. Li, J.-P.
Cheng, J. Org. Chem. 2011, 76, 5838–5845, and references cited
therein g) C.-C. Wang, X.-Y. Wu, Tetrahedron 2011, 67, 2974–
2978; h) F. Zhong, X. Han, Y. Wang, Y. Lu, Angew. Chem.
Int. Ed. 2011, 50, 7837–7841; i) F. P. L. Silva, P. A. C. de Assis,
C. G. L. Junior, N. G. de Andrade, S. M. D. da Cunha, M. R.
Oliveira, M. L. A. A. Vasconcellos, Eur. J. Med. Chem. 2011,
46, 4295–4301, and references cited therein j) Z. Zhuang, F.
Pan, J.-G. Fu, J.-M. Chen, W.-W. Liao, Org. Lett. 2011, 13,
6164–6167; k) W. Sun, X. Ma, L. Hong, R. Wang, J. Org.
Chem. 2011, 76, 7826–7833; l) P. Radha Krishna, M. Alivelu,
T. Prabhakar Rao, Eur. J. Org. Chem. 2012, 616–622; m) P.
Radha Krishna, R. R. Kadiyala, Tetrahedron Lett. 2012, 53,
744–747.
For recent examples on the enantioselective MBH reaction, not
covered by the preceding reviews, see: a) K. Yuan, H.-L. Song,
Y. Hu, X.-Y. Wu, Tetrahedron 2009, 65, 8185–8190; b) J.-J.
Gong, K. Yuan, X.-Y. Wu, Tetrahedron: Asymmetry 2009, 20,
2117–2120; c) Y.-L. Liu, B.-L. Wang, J.-J. Cao, L. Chen, Y.-X.
Zhang, C. Wang, J. Zhou, J. Am. Chem. Soc. 2010, 132, 15176–
15178; d) C. Anstiss, F. Liu, Tetrahedron 2010, 66, 5486–5491;
e) A. Bugarin, B. T. Connell, Chem. Commun. 2010, 46, 2644–
2646; f) X.-Y. Guan, Y. Wei, M. Shi, Chem. Eur. J. 2010, 16,
13617–13621; g) J. Shah, Z. Yacob, A. Bunge, J. Liebscher, Syn-
lett 2010, 2079–2082; h) F. Zhong, G.-Y. Chen, Y. Lu, Org.
Lett. 2011, 13, 82–85; i) F. Zhong, Y. Wang, X. Han, K.-W.
Huang, Y. Lu, Org. Lett. 2011, 13, 1310–1313; j) C.-C. Wang,
X.-Y. Wu, Tetrahedron 2011, 67, 2974–2978; k) H.-L. Song, K.
Yuan, X.-Y. Wu, Chem. Commun. 2011, 47, 1012–1014; l) S.
Takizawa, K. Kiriyama, K. Ieki, H. Sasai, Chem. Commun.
2011, 47, 9227–9229; m) F. Wang, S. Li, M. Qu, M.-X. Zhao,
L.-J. Liu, M. Shi, Chem. Commun. 2011, 47, 12813–12815.
J. Ishihara, S. Hatakeyama, Org. Lett. 2006, 8, 5357–5360; f)
S. M. Sarkar, E. N. Wanzala, S. Shibahara, K. Takahashi, J.
Ishihara, S. Hatakeyama, Chem. Commun. 2009, 5907–5909.
The formation of dioxanones is a typical reaction when the
alcohol moiety of acrylate is a good leaving group, see: a) S. E.
Drewes, N. D. Emslie, N. Karodia, A. A. Khan, Chem. Ber.
1990, 123, 1447–1448; b) A. A. Khan, N. D. Emslie, S. E.
Drewes, J. S. Field, N. Ramesar, Chem. Ber. 1993, 126, 1477–
1480; c) P. Perlmutter, E. Puniani, G. Westman, Tetrahedron
Lett. 1996, 37, 1715–1718.
a) R. Galeazzi, G. Martelli, M. Orena, S. Rinaldi, Synthesis
2004, 2560–2566; b) R. Galeazzi, G. Martelli, G. Mobbili, M.
Orena, S. Rinaldi, Org. Lett. 2004, 6, 2571–2574; c) R. Ga-
leazzi, G. Martelli, M. Orena, S. Rinaldi, P. Sabatino, Tetrahe-
dron 2005, 61, 5465–5473; d) R. Galeazzi, G. Martelli, M. Or-
ena, S. Rinaldi, Monatsh. Chem. 2006, 137, 357–363; e) E.
Marcucci, G. Martelli, M. Orena, S. Rinaldi, Monatsh. Chem.
2007, 138, 27–33; f) G. Martelli, E. Marcucci, M. Orena, S.
Rinaldi, Molecules 2009, 14, 2824–2835; g) G. Martelli, M. Or-
ena, S. Rinaldi, P. Sabatino, Amino Acids 2010, 39, 489–497.
For the synthesis of isocyanates from amines, see: a) J. S. Now-
ick, D. L. Holmes, G. Noronha, E. M. Smith, T. M. Nguyen,
S.-L. Huang, J. Org. Chem. 1996, 61, 3929–3934; For the syn-
thesis of acylisocyanates from amides, see: b) A. J. Speziale,
L. R. Smith, J. Org. Chem. 1962, 27, 3742–3743; c) A. J. Spezi-
ale, L. R. Smith, J. Org. Chem. 1963, 28, 1805–1811.
For recent mechanistic studies on MBH and aza-MBH reac-
tions, see: a) L. S. Santos, C. H. Pavam, W. P. Almeida, F. Co-
elho, M. N. Eberlin, Angew. Chem. 2004, 116, 4430–4433; An-
gew. Chem. Int. Ed. 2004, 43, 4330–4333; b) K. E. Price, S. J.
Broadwater, H. M. Jung, D. T. McQuade, Org. Lett. 2005, 7,
147–150; c) K. E. Price, S. J. Broadwater, B. J. Walker, D. T.
McQuade, J. Org. Chem. 2005, 70, 3980–3987; d) J. Xu, THEO-
CHEM 2006, 767, 61–66; e) V. K. Aggarwal, S. Y. Fulford,
G. C. Lloyd-Jones, Angew. Chem. 2005, 117, 1734–1736; An-
gew. Chem. Int. Ed. 2005, 44, 1706–1708; f) R. Robiette, V. K.
Aggarwal, J. N. Harvey, J. Am. Chem. Soc. 2007, 129, 15513–
15525; g) D. Roy, R. B. Sunoj, Org. Lett. 2007, 9, 4873–4876;
h) G. W. Amarante, H. M. S. Milagre, B. G. Vaz, B. R. Vil-
achã Ferreira, M. N. Eberlin, F. Coelho, J. Org. Chem. 2009,
74, 3031–3037; i) D. Roy, C. Patel, R. B. Sunoj, J. Org. Chem.
2009, 74, 6936–6943; j) G. W. Amarante, M. Benassi, H. M. S.
Milagre, A. A. C. Braga, F. Maseras, M. N. Eberlin, F. Coelho,
Chem. Eur. J. 2009, 15, 12460–12469; k) D. Cantillo, C. O.
Kappe, J. Org. Chem. 2010, 75, 8615–8626; l) T. Regiani, V. G.
Santos, M. N. Godoi, B. G. Vaz, M. N. Eberlin, F. Coelho,
Chem. Commun. 2011, 47, 6593–6595.
a) W.-D. Lee, K.-S. Yang, K. Chen, Chem. Commun. 2001,
1612–1613; b) M. Shi, J.-K. Jiang, Tetrahedron: Asymmetry
2002, 13, 1941–1947; c) K.-S. Yang, W.-D. Lee, J.-F. Pan, K.
Chen, J. Org. Chem. 2003, 68, 915–919.
Bordwell pKa Table http://www.chem.wisc.edu/areas/reich/
pkatable/index.htm.
A constant enantioselection in the case of two mechanisms op-
erating in different proportions during the entire course of the
reaction will be possible, in theory, only if both mechanisms
possess intrinsically the same selectivity, a highly improbable
occurrence.
S. E. Drewes, N. D. Emsile, J. S. Field, A. A. Kahn, N. Rame-
sar, Tetrahedron: Asymmetry 1992, 3, 255–260.
All the computations were carried out with the Gaussian 09
software package: M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Car-
icato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G.
Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R.
Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr., J. E. Per-
alta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K.
[6]
[7]
[2]
[8]
[9]
[3]
[10]
[11]
[12]
[4]
[5]
For a recent alternative synthesis of α-methylene-β-hydroxy es-
ters, based on the asymmetric allylic hydroxylation of racemic
MBH carbonates, see: B. Zhu, L. Yan, Y. Pan, R. Lee, H. Liu,
Z. Han, K.-W. Huang, C.-H. Tan, Z. Jiang, J. Org. Chem. 2011,
76, 6894–6900.
a) Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama,
J. Am. Chem. Soc. 1999, 121, 10219–10220; b) Y. Iwabuchi, M.
Furukawa, T. Esumi, S. Hatakeyama, Chem. Commun. 2001,
2030–2031; c) A. Nakano, M. Ushiyama, Y. Iwabuchi, S.
Hatakeyama, Adv. Synth. Catal. 2005, 347, 1790–1796; d) A.
Nakano, S. Kawahara, S. Akamatsu, K. Morokuma, M. Naka-
tani, Y. Iwabuchi, K. Takahashi, J. Ishihara, S. Hatakeyama,
Tetrahedron 2006, 62, 381–389; e) A. Nakano, K. Takahashi,
[13]
[14]
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
Enantioselective Morita–Baylis–Hillman Reaction
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tom-
asi, M. Cossi, N. Rega, N. J. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pom-
elli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dap-
prich, A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J.
Cioslowski, D. J. Fox, Gaussian 09, rev. A.1, Gaussian, Inc.,
Wallingford CT, 2009.
Chem. 1990, 29, 3881–3890; i) M. J. S. Dewar, A. J. Holder, Or-
ganometallics 1990, 9, 508–511; j) E. Anders, R. Koch, P.
Freunscht, J. Comput. Chem. 1993, 14, 1301–1312.
[16] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215–241.
[17] a) M. Cossi, V. Barone, B. Mennucci, J. Tomasi, Chem. Phys.
Lett. 1998, 286, 253–260; b) B. Mennucci, J. Tomasi, J. Chem.
Phys. 1997, 106, 5151–5158; c) U. C. Singh, P. A. Kollman, J.
Comput. Chem. 1983, 4, 129–145.
[18] We also computed some non-hydrogen-bonded TSs, starting
from TS-S1 and TS-R1 with catalyst m-1, to be sure of not
discarding plausible alternative pathways, but they were many
kcal/mol less stable than the corresponding H-bonded struc-
tures (see the Supporting Information).
[19] C. L. Rigby, D. J. Dixon, Chem. Commun. 2008, 3798–3800.
[20] L. J. Brzezinski, S. Rafel, J. W. Leahy, Tetrahedron 1997, 53,
16423–16434.
[15] a) M. J. S. Dewar, W. Thiel, J. Am. Chem. Soc. 1977, 99, 4899–
4907; b) M. J. S. Dewar, M. L. McKee, H. S. Rzepa, J. Am.
Chem. Soc. 1978, 100, 3607; c) M. J. S. Dewar, E. G. Zoebisch,
E. F. Healy, J. Am. Chem. Soc. 1985, 107, 3902–3909; d)
M. J. S. Dewar, C. H. Reynolds, J. Comput. Chem. 1986, 2,
140–143; e) M. J. S. Dewar, C. Jie, E. G. Zoebisch, Organome-
tallics 1988, 7, 513–521; f) M. J. S. Dewar, K. M. Merz, Orga-
nometallics 1988, 7, 522–524; g) M. J. S. Dewar, C. Jie, THEO-
CHEM 1989, 187, 1; h) M. J. S. Dewar, Y.-C. Yuan, Inorg.
Received: March 29, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13

Job/Unit: O20405
/KAP1
Date: 14-06-12 16:45:00
Pages: 14
G. Martelli, M. Orena, S. Rinaldi
FULL PAPER
Asymmetric Catalysis
β-Isocupreidine derivatives were used to
catalyze the asymmetric Morita–Baylis–
Hillman (MBH) reaction, giving the (R)-
MBH adducts in excellent optical purities
and moderate to good yields. Both 2,6-di-
methyl-4-nitrophenyl and hexafluoroiso-
propyl acrylate could be used. The rate-
and selectivity-determining step was ident-
ified and the structures of the preferred
transition states were computed.
G. Martelli, M. Orena,
S. Rinaldi* ...................................... 1–14
A Bifunctional β-Isocupreidine Derivative
as Catalyst for the Enantioselective
Morita–Baylis–Hillman Reaction and
Mechanistic Rationale for Enantioselectiv-
ity
a
Keywords: Asymmetric catalysis / Compu-
tational chemistry / Donor-acceptor sy-
stems
states
/ Enantioselectivity / Transition
14
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0