Organocatalytic asymmetric synthesis of β-aryl-β-isocyano esters

Article abstract of DOI:10.1002/adsc.201200140

The asymmetric addition of malonates to in situ generated N-formylimines of aromatic aldehydes was achieved under phase-transfer catalysis using Cinchona alkaloids-derived quaternary ammonium salts. The resulting β- formamidomalonates have been efficientl

Full text of DOI:10.1002/adsc.201200140

FULL PAPERS
DOI: 10.1002/adsc.201200140
Organocatalytic Asymmetric Synthesis of b-Aryl-b-isocyano
Esters
Fabio Morana,a Andrea Basso,a Marco Bella,b Renata Riva,a and Luca Banfia,*
a
Department of Chemistry and Industrial Chemistry, University of Genova, via Dodecaneso 31, 16146 Genova, Italy
Fax : (+39)-010-353-6118; phone: (+39)-010-353-6111; e-mail: banfi@chimica.unige.it
Department of Chemistry, “Sapienza” University, piazzale A. Moro 5, 00185 Roma, Italy
b
Received: February 18, 2012; Revised: April 24, 2012; Published online: && &&, 0000
Dedicated to Professor Alfredo Ricci on the occasion of his retirement.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200140.
Abstract: The asymmetric addition of malonates to action with chiral cyclic imines has been demonstrat-
in situ generated N-formylimines of aromatic alde- ed.
hydes was achieved under phase-transfer catalysis
using Cinchona alkaloids-derived quaternary ammo-
nium salts. The resulting b-formamidomalonates Keywords: b-aryl-b-isocyano esters; imines; Mannich
have been efficiently converted into b-aryl-b-isocya- reaction; multicomponent reactions; organic cataly-
no esters. Their utility in the multicomponent Ugi re- sis; phase-transfer catalysis
Introduction
plored so far is represented by a-isocyano esters, that
can be prepared in a stereoconservative way from
Isocyanide-based
multicomponent
reactions commercially available a-amino acids.[7] They have
(IMCR)[1] are an invaluable tool for diversity-oriented been efficiently employed in the Passerini reaction,[8]
synthesis,[2] granting a significant increase of structural but are more troublesome in the Ugi condensation,
complexity in a single step. Moreover, they allow the due to their possible racemisation or epimerisation
simultaneous introduction of several diversity inputs, under the reaction conditions.[9] However, recently
whereas intramolecular modifications[3] or post-con- a thorough study has demonstrated that these un-
densation transformations[4] give access to a variety of wanted processes may be suppressed in most cases.[10]
heterocyclic scaffolds.
a-Isocyano esters may also be used in a variety of
The non-isocyanide components of classical IMCRs useful multicomponent reactions involving the rela-
(aldehydes/ketones and carboxylic acids in the Passer- tively acidic a-position, but obviously in these ap-
ini reaction[5] and aldehydes/ketones, carboxylic acids proaches the stereochemical information is lost.[7b]
and amines in the Ugi reaction[1a,b]) are easily avail-
On the contrary, chiral b-isocyano esters of general
able in thousands of diverse structures, also in chiral formula 1 may be very useful in the convergent as-
enantiomerically pure forms. On the other hand, rela- sembly of peptidomimetics through the Ugi reaction.
tively fewer isocyanides are commercially available or They are expected to be more resistant to racemisa-
easily synthesised. Most of them are achiral and un- tion. Moreover, they will introduce in the final ad-
functionalised. A look at the recent literature on ducts two potential pharmacophores: an aryl group,
IMCRs shows that, in nearly all cases, the decorations capable of p-p interactions, and a carboxylate group.
introduced by the isocyanide component are simple The latter will be able to form, after deprotection to
achiral alkyl or cycloalkyl groups, which have a scarce the free carboxylate, an anion species. For example,
exploratory value and are unlikely to act as real phar- these two moieties may be useful in the design of pep-
macophores. Therefore, a broader access to function- tidomimetic integrin ligands.[11]
alised and/or chiral, enantiomerically pure isocyanides
However, we could find only one report dealing
would be particularly welcomed. Notable efforts in with the synthesis of enantioenriched b-isocyano
this direction have appeared just recently.[6] The only esters,[12] and it was of very limited scope. Thus we de-
general family of enantiomerically pure isonitriles ex- cided to design a general asymmetric method to
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access both enantiomers of compounds 1 in high opti- by using modified catalyst 10b, where the benzyl was
cal purity.
replaced by an o-methoxybenzyl group.[16a,18]
A possible mechanism is depicted in Scheme 3. In
the first stage a stoichiometric quantity of the base is
necessary to promote the sulphinate elimination af-
fording the N-formylimine 5. This reaction probably
Results and Discussion
Scheme 1 shows our retrosynthetic design. b-Isocyano
esters 1 are planned to be obtained through dehydra-
tion of formamides 2, which can in turn be synthes-
ised through an asymmetric Mannich-type addition of
malonates to N-formylimines 4.
However, we could not find any report on the isola-
tion of N-formylimines 4 in pure form. Actually, when
we attempted the preparation of 4a from formamido
sulphone 5a (Ar=Ph),[13] under the conditions that
are typically used for preparing pure N-Boc-imines
(K2CO3 in THF at reflux, followed by filtration of po-
tassium sulphinate),[14] only benzaldehyde was detect-
ed after filtration, probably because of the high hy-
drolytic lability of this imine. Therefore we decided to
explore a one-pot strategy based on in situ generation
of this labile imine.[15] We were particularly attracted
by the excellent work by Ricci and Bernardi,[16] where
they succeeded to obtain high enantiomeric excesses
in the addition of malonates to N-Boc- or N-Cbz-
imines, generated in situ from a-ureido sulphones,
under asymmetric phase-transfer catalysis.[17]
Scheme 2. Organocatalytic synthesis of 8a and 9a.
In a preliminary test, amido sulphone 5a was dis-
solved in toluene and treated, at 08C, for 48 h, with
diethyl malonate and with 6 equivalents of 50% aque-
ous K2CO3 in the presence of quinine-derived catalyst
10a (Scheme 2). To our delight, the desired adduct 8a
was obtained in fair (65%) yield, albeit with low se-
lectivity (23% ee) (ee=enantiomeric excess). Despite
the presence of water in the reaction mixture, and the
possible high hydrolytic lability, the intermediate N-
formylimine was evidently stable enough to react with
the malonate. No product derived from the addition
of the malonate to benzaldehyde was detected.
A significant improvement was achieved by using
malonate 7, that was already reported by Ricci and
Bernardi[16a] to enhance enantioselectivity in some
critical cases. With this reagent, the ee rose to 50%
(yield: 71%), and also the rate of reaction had signifi-
cantly increased (the reaction being complete in
10 h). A further improvement (60% ee) was achieved
Scheme 3. Proposed mechanism for the phase-transfer reac-
tion.
Scheme 1. Retrosynthetic design.
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Organocatalytic Asymmetric Synthesis of b-Aryl-b-isocyano Esters
Table 2. Effect of base on the enantioselective synthesis of
9a.[a]
takes place in the organic phase by the action of tet-
raalkylammonium hydroxide. Then, in the second
stage, the tetraalkylammonium hydroxide deproto-
Entry
Base[b]
Conversion[c]
ee [%][d]
nates the malonate which, as a ion pair with the chiral
cation, attacks the N-formylimine. The resulting nitro-
gen anion takes a proton from the malonate and thus
the base, for this second stage, is only catalytic. It is
important to note that this reaction also takes place,
although much slower, in the absence of the catalyst.
This background reaction probably involves acid-base
reactions at the interface.
1
2
3
4
5
6
7
8
9
50% K2CO3
10% K2CO3
dry K2CO3
20% Na2CO3
37% Cs2CO3
1% Li2CO3
5% NaHBO3
33% NH3
69%
36%
64%
28%
23%
31%
<10%
30%
46%
66
66
50
66
37
66
66
66
3
At this point we decided to optimise the reaction
conditions with malonate 7 and catalyst 10b.
10% LiOH
[a]
Substrate concentration: 0.05M in toluene; catalyst:
10%, base: 6 equiv., time: 2 h, temperature: 08C.
w/w.
Determined by NMR of the crude product.
Determined by HPLC on a chiral stationary phase.
We first studied the effect of catalyst loading, also
in order to evaluate the importance of the back-
ground reaction. Surprisingly, on passing from 10 to
20 mol% loading no difference in ee was observed,
whereas higher loadings decreased the enantioselec-
tivity to 40%, maybe because of aggregation phenom-
ena due to the limited solubility of the catalyst.
[b]
[c]
[d]
was observed, while the yield remained unaffected
Thus 10 mol% catalyst loading was used for further (Table 1, entry 9).
refinements. Table 1 reports selected data for solvent
Another important parameter is represented by the
screening (more data can be found in the Supporting nature, quantity and concentration of the base
Information). In practice, only toluene was able to (Table 2). The screening reported in Table 2 has been
afford a good enantioselectivity. The use of non-aro- carried out with a short reaction time (only 2 h) in
matic solvents (entries 3–5) resulted in a slower and order to also get information on the differences in
poorly enantioselective reaction, but also aromatic rate.
solvents different from toluene caused a dramatic
In most cases the use of different aqueous bases
drop of enantioselectivity (entry 2). In the attempt to was influential in terms of rate, but not for the ee.
increase the solubility of both substrate and catalyst Both the countercation (compare entries 1, 4, 6) and
we also tried to add small amounts of a co-solvent, the counteranion (compare entries 1, 7, 8) seem to be
but even in the presence of only 5% of CHCl3 insignificant for the enantioselectivity, probably be-
(entry 7) the product was obtained in nearly racemic cause the actual reacting species in the organic phase
form.
is the tetraalkylammonium hydroxide. Even aqueous
By lowering the substrate concentration from 0.1 to ammonia, rarely used in this type of reactions, afford-
0.05M a significant improvement of enantioselectivity ed the same enantiomeric excess (entry 8). However,
a decrease of enantioselectivity was observed with
cesium carbonate (entry 5) or with stronger bases
(entry 9). In the absence of water (compare entries 1
and 3) a decrease of enantioselectivity was observed.
In this case the reaction cannot be promoted by the
Table 1. Effect of the the solvent on the enantioselective
synthesis of 9a.[a]
Entry
Solvent
Yield[b]
ee [%][c]
tetraalkylammonium hydroxide, which might explain
the difference. Taking into account the yields, aque-
ous K2CO3 turned out to be the most convenient
base. Although a higher dilution (that is more water
in the reaction mixture) does not seem to influence
the enantioselectivity, a higher concentration (50%)
granted a higher rate (entries 1 and 2).
When we studied the effect of temperature, we
were rather disappointed to find that the enantiose-
lectivity decreased upon lowering the temperature
(Table 3, entries 1–4), whilst the ideal temperature re-
mained 08C.
1
2
3
4
5
6
7
8
9
toluene
benzene
n-hexane
MeO-t-Bu (MTBE)
CH2Cl2
toluene/CHCl3 9:1
toluene/CHCl3 19:1
toluene/CH2Cl2 9:1
toluene[d]
98%
89%
26%
29%
40%
91%
98%
85%
97%
60
7
5
10
21
8
7
21
66
[a]
Substrate concentration: 0.1M in the organic solvent
except for entry 9; base: 6 equiv. of 50% aqueous K2CO3
(w/w), catalyst: 10 mol%, temperature: 08C, time: 20 h.
Isolated yield after chromatography (not optimised).
Determined by HPLC on a chiral stationary phase.
Substrate concentration: 0.05M.
However, when we reduced the number of equiva-
lents of base, from 6 to 1.5, a slight increase of enan-
tioselectivity was detected at 08C (entries 1 and 5)
but, most importantly, the expected temperature de-
[b]
[c]
[d]
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Table 3. Effect of temperature and equivalents of base on
the enantioselective synthesis of 9a.[a]
lectivity (83% ee), although with a lower conversion
(44% after 48 h). A 5–10 mol% loading of the catalyst
turned out to be ideal. With 5% catalyst, the ee de-
creased only slightly (80% ee, 84% yield), whereas
with 1%, the enantioselectivity dropped markedly
(54% ee).
Having found the best experimental conditions, we
went back to try other malonates, to check if the use
of 7 was really needed. Using diethyl malonate, under
the conditions of entry 7 of Table 3 (48 h), the conver-
sion was lower than 20%, showing that the aryl
groups in 7 are essential for an efficient catalysis. The
enantioselectivity was quite low too (26% ee) proba-
bly because of competition by the background reac-
tion. With dibenzyl malonate, 30% conversion and
64% ee were obtained. Finally, with diphenyl malo-
nate the conversion was good (90%), but again the
enantioselectivity was inferior to 7 (67% ee). These
Entry Temp. Time Equiv. base Conversion[b] ee[c] [%]
1
2
3
4
5
6
7
8
9
08C
10 h
6
6
6
6
93%
63%
54%
<50%
quant.
quant.
93%
73%
41%
67
60
54
54
70
80
82
78
55
À108C 10 h
À208C 10 h
À308C 10 h
08C
20 h 1.5
À158C 48 h 1.5
À158C 48 h 1.3
À248C 60 h 1.5
À408C 72 h 1.5
[a]
Substrate concentration: 0.05M in toluene; catalyst:
10 mol%, base: 50% aqueous K2CO3 (w/w).
Determined by NMR of the crude product.
[b]
[c]
Determined by HPLC on a chiral stationary phase.
pendence was restored. The enantiomeric excess in- data clearly demonstrate the importance for the rate
creased significantly on going down to À158C. of using a diaryl malonate and the higher enantiose-
Under the best conditions (those of entry 7) the ee lectivity achieved with 7.
rose to 82%. A possible explanation is that the back-
At this point we turned our attention to catalyst en-
ground uncatalysed reaction proceeds through reac- gineering, preparing 23 different quaternary ammoni-
tion of the malonate with K2CO3 at the interface and um salts based on quinine, quinidine, dihydroquinine,
thus its rate depends on the overall amount of base. cinchonine and cinchonidine (Figure 1). Selected re-
On the contrary, in the catalysed, enantioselective re- sults are reported in Table 4, whereas the full screen-
action, the active species is continuously formed in ing is described in the Supporting Information. Some
the organic phase, and its concentration is limited by of these quaternary salts were already known, where-
the amount of catalyst employed. Thus the effect of as other ones are new.
base concentration is stronger on the background re-
action than on the catalysed one.
From the results of Table 4 it appears that the pres-
ence of an ortho substituent on the benzyl ring is im-
Interestingly, under these optimised conditions, also portant. The effect seems more steric than electronic:
33% NH3 as the base gave a very similar enantiose- catalyst 10d with three fluorine atoms is among the
Figure 1. Catalysts tested in the asymmetric addition of malonate 7 to formylimine 4a.
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Organocatalytic Asymmetric Synthesis of b-Aryl-b-isocyano Esters
Table 4. Screening of various catalysts and conditions for the
enantioselective synthesis of 9a.[a]
the imine may be activated by a hydrogen bond be-
tween the nitrogen and the catalyst OH, whereas p-p
interactions between the malonate aryl groups and
the quinoline and the benzyl on nitrogen place the
enolate selectively of one side of the imine C=N
bond.
Entry
Catalyst
Yield[b]
ee [%][c]
Configuration
1[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
10a
10b
10c
10d
10e
10f
10g
10h
10i
10l
10n
11
65%
88%
90%
72%
66%
95%
86%
62%
99%
65%
95%
84%
76%
70%
66%
64
82
79
78
75
70
66
66
64
60
53
74
78
4
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(R)
The absolute configuration of (+) 9a, obtained with
catalyst 10b, was unambiguously demonstrated by its
independent
synthesis
from
known
(S)-15
(Scheme 4).[16,20]
We then proceeded to determine the scope of the
reaction, using a series of formamido sulphones, syn-
thesised from the corresponding benzaldehydes by
the method developed by Sisko (Scheme 5).[13b]
Table 5 reports the isolated yields after crystallisation
of formamido sulphones 5 (most of them are new)
and the yields and the ees of the organocatalytic reac-
tion to give 9. It should be noted that in these reac-
tions only 5 mol% loading of catalyst was employed.
Formamido sulphone 5f, derived from o-methoxyben-
zaldehyde, gave the highest ee. Also the b-naphthyl
derivative 5h gave a better ee than the parent unsub-
stituted compound 5a.
12
13a
14a
28
[a]
Substrate concentration: 0.05M in toluene; catalyst:
10 mol%, time: 48 h, base: 1.3 equiv. of 50% aqueous
K2CO3 (w/w).
Isolated yields after chromatography (unoptimised).
Determined by HPLC on a chiral stationary phase.
[b]
[c]
best ones (compare entry 4 with entry 2). Thus we
prepared a series of derivatives ortho-substituted with
an alkoxy group (10e, 10f, 10k), but none of them sur-
passed the methoxy derivative 10b; 10c, having two
additional methoxy groups behaved very similar to
10b (compare entries 2 and 3).
The quinoline methoxy group seems important:
with catalysts derived from cinchonidine (e.g., 13a) or
cinchonine (e.g., 14a) the enantiomeric excesses were
always <28% (entries 14 and 15). Hydrogenation of
the C=C double bond to give 11 gave a catalyst that
was slightly less selective (entry 12). Finally, it should
be noted that a nearly racemic product was observed
when employing quaternary salts protected at the qui-
nine alcoholic moiety, indicating that it is essential for
selectivity.
Scheme 4. Assignment of the absolute configuration.
In conclusion, after this long screening, the best cat-
alysts turned out to be 10b, 10c and 10d, with the first
one being slightly superior.
The analogue of 10b derived from quinidine (12)
was nearly as efficient that its diastereomer, allowing
the formation in good ee of the (R) enantiomer. Vari-
ous results suggest that the enantioselectivity should
derive from an interaction of imine 4 and malonate 7
with the OH group, the benzyl substituent on nitro-
gen, and the quinoline system, with a scarce influence
of the quinuclidine part and its stereogenic centres.
These evidences are (i) the nearly opposite enantiose-
lectivity of 10b and 12; (ii) the strong importance of
the quinoline methoxy group; (iii) the essential role
of the free OH group in the catalyst; and (iv) the
need for aryl groups in the malonate. We think that Scheme 5. Synthesis of various malonates 9a–h.
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Table 5. Enantioselective synthesis of various malonates 9.[a]
Starting aldehyde
Ar
Yield of sulphone 5
Yield of 9[b]
ee of 9 [%][c]
16a
16b
16c
16d
16e
16f
16g
16h
16i
Ph
98%
91%
51%
65%
65%
51%
78%
95%
24%
83%
84%
85%
80%
87%
87%
62%
78%
78%
80
72
60
67
69
90
67
84
70
4-MeOC6H4
4-ClC6H4
3-MeOC6H4
3-BrC6H4
2-MeOC6H4
3-thienyl
b-naphthyl
a-naphthyl
[a]
Conditions: catalyst: 10b (5 mol%), 0.5 mmol of substrate in 10 mL of toluene, temp.: À158C, time: 48 h, base: 1.3 equiv.
of 50% aqueous K2CO3.
Isolated yields after chromatography (unoptimised).
[b]
[c]
Determined by HPLC on chiral stationary phase.
The enantiomeric excess can be further improved pure enantiomer. The overall yield of this pure enan-
through crystallisation. This was demonstrated in the tiomer 9a was 68% from the formamido sulphone 5a.
case of compound 9a (Scheme 6). When a sample This procedure was carried out on a multigram scale.
with 80% ee (obtained using 5% catalyst loading, see
Adduct 9a was then converted into (S) isocyano
Table 5) was dissolved in the minimum amount of ester 1a by a three-step straightforward procedure.
CH2Cl2 and then diluted with i-PrOH, a white precipi- Treatment with EtONa in EtOH gave a fast transes-
tate was slowly formed. The yield of this solid was terification, which was followed by monohydrolysis of
16%, and HPLC on a chiral stationary phase showed the resulting diethyl malonate 8a. Upon acidification
that it was nearly racemic (only 24% ee). On the and decarboxylation, formamido ester 2a was ob-
other hand, the mother liquors afforded, after evapo- tained in excellent overall yield. Finally, dehydration
ration, in 84% yield, a solid with a lower melting gave the target isocyanide 1a in 85% yield (55% over-
point, which was found to have 98% ee. Thus in this all yield from formamido sulphone 5a). It is worth
case the racemate crystallises preferentially over the noting that dehydration on the malonate 9a did not
afford the desired product, because of formamido
group elimination, giving an alkylidenemalonate.
Moreover, synthesis of the corresponding p-methoxy-
phenyl b-isocyanophenylpropionate was less efficient,
because of lower yields both in the monohydrolysis
and in the dehydration steps.
The above reported synthesis of 1a is therefore well
suited for the large-scale preparation of this isonitrile
in nearly pure enantiomeric form. HPLC on chiral
stationary phase showed an ee of 93%, thus slightly
lower than that of starting malonate. Using the quini-
dine-derived catalyst 12 for the organocatalytic reac-
tion, the (R) enantiomer of 9a should be equally
available.
As a first application of this chiral isocyanide, we
performed (Scheme 6) a highly diastereoselective Ugi
reaction with both enantiomers of imine 16, prepared
by us through a recently reported biocatalytic proce-
dure.[11a] These imines are useful intermediates for the
synthesis of conformationally biased peptidomimetics
because: (i) they give complete diastereoselection (fa-
vouring the trans adduct) in Ugi reactions; (ii) they,
and their Ugi adducts, are fairly rigid; (iii) removal of
the acetal group allows modulation of the polarity
and conformational behaviour of the final products.
As expected, also in this case only trans products
were obtained. Reaction of (S)-1a with the two enan-
Scheme 6. Synthesis of chiral isocyanide 1a and its use in
a diastereoselective Ugi reaction.
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Organocatalytic Asymmetric Synthesis of b-Aryl-b-isocyano Esters
BuOH and 9 mL AcOH, followed by warming). Rf values
were measured after an elution of 7–9 cm. Column chroma-
tographies were done with the “flash” methodology using
220–400 mesh silica. Petroleum ether (40–608C) is abbrevi-
ated as PE. In extractive work-up, aqueous solutions were
always reextracted three times with the appropriate organic
solvent. Organic extracts were always dried over Na2SO4
and filtered, before evaporation of the solvent under re-
duced pressure. All reactions employing dry solvents were
carried out under a nitrogen atmosphere.
tiomers of imine 17 gave two distinct diastereoisomers
18 and 19, which were clearly distinguished in HPLC,
TLC, and NMR. HPLC analysis indicated a diastereo-
meric ratio of 94:6 (18) and 95:5 (19), which reflected
the ees of the starting isocyanide and imines [96%
and 98% for (3aR,6aS)-17 and (3aS,6aR)-17, respec-
tively]. Pure 18 and 19 could be obtained by chroma-
tography, since they are separable through this meth-
odology.
General Procedure for the Preparation of Formamido
Sulphones 5a–i[13b]
Conclusions
A solution of the starting aryl or heteroaryl aldehyde
(15 mmol) in dry CH3CN (10 mL) and dry toluene (10 mL)
was treated with formamide (2.5 equiv.) and trimethylsilyl
chloride (1.1 equiv.). The mixture was stirred at 508C for 5 h
and then freshly prepared p-toluenesulphinic acid[13b]
(1.1 equiv.) was added. The mixture was stirred for further
4 h at 508C. After cooling, methyl tert-butyl ether (10 mL)
and distilled water (50 mL) were added. The mixture was
cooled to 08C until precipitation was complete. The result-
ing solid was recovered by suction, washed with a little
water and methyl tert-butyl ether, and finally thoroughly
dried in a dessiccator under vacuum in the presence of P2O5.
In conclusion, we have developed a new, efficient,
and short asymmetric synthesis of b-aryl-b-isocyano
esters, based on an organocatalytic phase-transfer
Mannich-type reaction. The readily available catalyst
(derived in one step from quinine or quinidine) and
the need for a relatively low loading (5 mol%) ren-
ders this methodology amenable for large-scale syn-
thesis. The enantioselectivity obtained is significantly
good, but not yet excellent. However, we have dem-
onstrated the possibility to increase to 98% the ees of
the key intermediate by a simple crystallisation with
only a slight loss in overall yield. These isocyano
esters may find application in the stereocontrolled as-
sembly of conformationally biased peptidomimetics
through their Ugi reactions with cyclic imines. A first
example of this general strategy has already been re-
ported here.
1
The purity was assessed by H NMR. Some of these form-
amido sulphones were already known: 5a,[13a,b] 5b,[13a,b] 5d,[21]
5f,[21] 5g,[13a,b] although only 5a was fully characterised.
N-[(4-Methoxyphenyl)ACTHUNRGTNE(NUG tosyl)methyl]formamide (5b): mp
1
145.2–1478C. H NMR [300 MHz, DMSO-d6; 2 conformers
(A and B) are present in an 81:19 ratio]: d=9.73 (A) (d, J=
10.8 Hz, 0.81H, NH), 9.37 (B) (t, J=10.5 Hz, 0.19H, NH),
7.94 (A) (d, J=0.9 Hz, 0.81H, CHO), 7.87 (B) (d, J=
10.5 Hz, 0.19H, CHO), 7.71 (A) (d, J=8.4 Hz, 1.62H, H
ortho to SO2), 7.57 (B) (d, J=8.4 Hz, 0.38H, H ortho to
SO2), 7.48 (A) (d, J=8.7 Hz, 1.62H, H meta to OMe), 7.43
[d, J=8.4 Hz, 2H, H meta to SO2 (A+B)+H meta to OMe
(B)], 7.40 (B) (d, J=8.4 Hz, 0.38H, H meta to SO2), 6.98
(A) (d, J=8.7 Hz, 1.62H, H ortho to OMe), 6.93 (B) (d, J=
8.7 Hz, 0.38H, H ortho to OMe), 6.33 (A) (d, J=10.5 Hz,
0.81H, ArCH), 6.20 (B) (d, J=10.5 Hz, 0.19H, ArCH), 3.78
(A) (s, 2.43H, OCH3), 3.76 (B) (s, 0.57H, OCH3), 2.41 (A+
B) (s, 3H, ArCH3); 13C NMR (75 MHz, DMSO-d6; only the
peaks of the main conformer are reported): d=160.0 (C=
Experimental Section
NMR spectra were taken at room temperature in CDCl3 or
DMSO-d6 at 300 MHz (1H), and 75 MHz (13C), using as in-
1
1
ternal standards: for H NMR in CDCl3: TMS; for H NMR
in DMSO: the central peak of DMSO (2.506); for 13C in
CDCl3 the central peak of CDCl3 (at 77.02 ppm); for
13C NMR in DMSO: the central peak of DMSO (39.43).
Chemical shifts are reported in ppm (d scale), coupling con-
stants are reported in Hertz. Peak assignments were also
made with the aid of gCOSY and gHSQC experiments. In
an ABX system, the proton A is considered upfield and B
downfield. GC-MS were carried out using an HP-1 column
(12 m long, 0.2 mm diameter), electron impact at 70 eV, and
a mass temperature of about 1708C. Only m/z>33 were de-
tected. All analyses were performed (unless otherwise
stated) with a constant He flow of 1.0 mLminÀ1 with initial
temperature 608C, initial time 2 min, rate 208CminÀ1, final
temperature 2808C, injection temperature 2508C, detection
temperature 2808C. HR-MS were recorded by employing
either the ESI+ or the ESIÀ ionisation method. IR spectra
were recorded as CHCl3 solutions. TLC analyses were car-
ried out on silica gel plates and viewed under UV (254 nm)
and developed with Hanessian stain [dipping into a solution
À
O+C OMe), 144.6, 133.5, 121.9 (quat.), 130.7 (C meta to
OMe), 129.5 (C meta to SO2), 129.0 (C ortho to SO2), 113.7
(C ortho to OMe), 69.7 (ArCH), 55.2 (OCH3), 21.1
(ArCH3); IR (CHCl3): n=3002, 1693, 1609, 1484, 1304,
1178, 1142, 1081, 1026, 918 cmÀ1; HR-MS (ESI+): m/z=
342.0769; calcd. for C16H17NO4SNa [M+Na]+: 342.0776.
(S)-Bis(4-methoxyphenyl) 2-[FormamidoACHTNUTRGNE(UNG phenyl)-
methyl]malonate (9a)
A solution of 5a (1.00 g, 3.45 mmol)[13a,b] and malonate 7[16a]
(1.31 g, 4.14 mmol) in toluene (35 mL) was treated with cat-
alyst 10b (336 mg, 350 mmol, 10%) and cooled to À158C.
50% (w/w) aqueous K2CO3 (d=1.36) (915 mL, 4.50 mmol)
was added and the mixture stirred for 48 h at À158C. The
mixture was evaporated to dryness and immediately chro-
matographed through 80 g of silica (CH2Cl2/AcOEt from
of (NH4)4MoO4·4 H2O (21 g) and CeACHTUNGRTNE(UNG SO4)2·4 H2O (1 g) in
H2SO4 (31 mL) and H2O (469 mL) and warming] or, when
specified, with ninhydrin (900 mg of ninhydrin in 300 mL n-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

Fabio Morana et al.
FULL PAPERS
95:5 to 85:15) to give pure 9a as a solid; yield: 1.30 g (83%).
Using 5% of catalyst, the yield was 84% and the ee was
80%. The ee was determined by chiral HPLC (Daicel Chiral
20.30; Rf =0.48 (CH2Cl2/AcOEt 90:10); [a]D: À6.4 (c 1,
1
CHCl3); H NMR [300 MHz., CDCl3; 2 conformers (A and
B) are present, in a 88:12 ratio; only selected signals of con-
former B are reported]: d=8.34 (A) (s, 0.88H, CH=O), 8.23
(B) (d, J=11.7 Hz, 0.12H, CH=O), 7.70 (B) (d, J=8.4 Hz,
0.12H, NH), 7.43–7.35 [m, 5.86H, NH (A)+CH of Ph], 7.04
(A) (d, J=9.3 Hz, 1.76H), 6.90 (A) (d, J=9.0 Hz, 1.76H),
6.86 (A) (s, 3.72H), 6.19 (A) (dd, J=4.5, 10.0 Hz, 0.88H,
CHNH), 5.45 (B) (dd, J=5.7 Hz, 10.6 Hz, 0.12H, CHNH),
4.41 (A) (d, J=4.5 Hz, 0.88H, NHCHCH), 3.39 (B) (d, J=
5.7 Hz, 0.12H, NHCHCH), 3.80 (A+B) (s, 3H, OCH3),
3.78 (A+B) (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3;
only the peaks of main conformer are reported): d=167.0,
pak AD 250ꢁ4.6 mm,
Vinj =20 mL, T=408C, eluent:
hexane/i-PrOH 25:75; flow: 0.5 mLminÀ1). Rt (S): 20.14; Rt
(R): 16.49. Crystallisation of the chromatographed product
(1.36 g) from CH2Cl2/i-PrOH (1:9; about 65 mL) gave
a white solid (mp 143.5–145.38C) (yield: 210 mg), having
ee=24%. The mother liquors, after evaporation, afforded
a pale yellow solid (mp 113.8–115.78C) (yield: 1.06 g) which,
by HPLC analysis, had an ee=98%. [a]D; +3.6 (c 2,
CHCl3). The yield of this pure enantiomer is therefore 68%.
1
Rf 0.50 (CH2Cl2/AcOEt 90:10); H NMR [300 MHz., CDCl3;
À
2 conformers (A and B) are present in an 86:14 ratio]: d=
8.34 (A) (s, 0.86H, CH=O), 8.25 (B) (d, J=11.4 Hz, 0.14H,
CH=O), 7.47–7.30 [m, 5.86H, NH (A)+CH of Ph], 7.05
(A) (d, J=9.0 Hz, 1.72H), 6.90 (A) (d, J=9.0 Hz, 1.72H),
6.83 (A) (s, 3.64H), 6.25 (A) (dd, J=4.4, 9.7 Hz, 0.86H,
CHNH), 5.48 (B) (dd, J=5.8 Hz, 10.6 Hz, 0.14H, CHNH),
4.46 (A) (d, J=4.5 Hz, 0.86H, NHCHCH), 4.43 (B) (d, J=
5.8 Hz, 0.14H, NHCHCH), 3.80 (A+B) (s, 3H, OCH3),
3.77 (A+B) (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3;
only the peaks of main conformer are reported): d=167.1,
165.6, 160.6 (C=O), 157.8 (C OMe), 143.5, 143.3 (COCO),
136.4, 134.2 (quat.), 129.1 (ꢁ2), 127.9 (ꢁ2), 122.0 (ꢁ2), 121.9
(ꢁ2), 114.63 (ꢁ2), 114.58 (ꢁ2) (aromatic CH), 56.2
(NHCHCH), 55.6 (ꢁ2) (OCH3), 49.7 (CHNH); IR (CHCl3):
n=3673, 3605, 3412, 2994, 1747, 1687, 1598, 1486, 1193,
1134, 1019, 920 cmÀ1; HR-MS (ESI+): m/z=484.1164, calcd.
for C25H23ClNO7 [M+H]+: 484.1163.
(S)-Bis(4-methoxyphenyl) 2-[formamido(3-methoxyphen-
yl)methyl]malonate (9d): It was prepared following the pro-
cedure above described for 9a; yield: 80%; ee=67% (deter-
mined by chiral HPLC on a Daicel Chiral pak AD 250ꢁ
4.6 mm column, Vinj =20 mL, T=408C, eluent: hexane/i-
PrOH 25:75; flow: 0.5 mLminÀ1); Rt (S): 19.73; Rt (R):
16.92; Rf =0.38 (CH2Cl2/AcOEt 90:10); [a]D: À1.6 (c 1,
À
165.8, 160.6 (C=O), 157.7 (C OMe), 143.6, 143.3 (COCO),
137.8 (quat. Ph), 128.9 (ꢁ2), 128.2, 126.4 (ꢁ2), 122.1 (ꢁ2),
121.9 (ꢁ2), 114.6 (ꢁ2), 114.5 (ꢁ2) (aromatic CH), 56.4
(NHCHCH), 55.58, 55.56 (OCH3), 50.2 (CHNH); IR
(CHCl3): n=3676, 3601, 3414, 3000, 1746, 1688, 1596, 1489,
1352, 1174, 1132, 918 cmÀ1; HR-MS (ESI+): m/z=450.1556,
calcd. for C25H24NO7 [M+H]+: 450.1553.
1
CHCl3); H NMR [300 MHz., CDCl3; 2 conformers (A and
B) are present, in a 85:15 ratio; only selected signals of con-
former B are reported]: d=8.34 (A) (s, 0.85H, CH=O), 8.24
(B) (d, J=11.7 Hz, 0.15H, CH=O), 7.36 (A) (d, J=10.2 Hz,
0.85H, NH), 7.31 (A+B) (t, J=8.1 Hz, 1H, H meta to OMe
in Ar), 7.05 (A) (d, J=9.3 Hz, 1.70H), 6.90 (A) (d, J=
9.0 Hz, 1.70H), 7.08–6.80 (m, 7.60H), 6.21 (A) (dd, J=4.5,
9.7 Hz, 0.85H, CHNH), 5.44 (B) (dd, J=5.8 Hz, 10.6 Hz,
0.15H, CHNH), 4.45 (A) (d, J=4.5 Hz, 0.85H, NHCHCH),
4.43 (B) (d, J=5.8 Hz, 0.15H, NHCHCH), 3.81 (A+B) (s,
3H, OCH3), 3.80 (A+B) (s, 3H, OCH3), 3.77 (A+B) (s,
3H, OCH3); 13C NMR (75 MHz, CDCl3; only the peaks of
main conformer are reported): d=167.1, 165.8, 160.6 (C=
O), 160.0, 157.7 (ꢁ2) (C-OMe), 143.6, 143.4 (COCO), 139.4
(quat.), 130.0, 122.1 (ꢁ2), 122.0 (ꢁ2), 118.5, 114.6 (ꢁ2),
114.5 (ꢁ2), 113.6, 112.4 (aromatic CH), 56.3 (NHCHCH),
55.60, 55.57, 55.3 (OCH3), 50.1 (CHNH); IR (CHCl3): n=
3675, 3597, 3411, 3040, 2956, 1747, 1688, 1597, 1488, 1417,
1177, 1133, 1028, 921 cmÀ1; HR-MS (ESI+): m/z=480.1658,
calcd. for C26H26NO8 [M+H]+: 480.1658.
(S)-Bis(4-methoxyphenyl) 2-[formamido(4-methoxyphen-
yl)methyl]malonate (9b): It was prepared following the pro-
cedure above described for 9a; yield: 84%; ee=72% (deter-
mined by chiral HPLC on a CHIRALPAK IB column,
eluant hexane/i-PrOH 80:20, flow 0.9 mLminÀ1; Rt (S)=
51.7 min; Rt (R)=39.3 min; Rf =0.31 (CH2Cl2/AcOEt
90:10); [a]D: À9.7 (c 1, CHCl3); 1H NMR [300 MHz.,
CDCl3; 2 conformers (A and B) are present, in an 85:15
ratio]: d=8.33 (A) (s, 0.85H, CH=O), 8.24 (B) (d, J=
11.7 Hz, 0.15H, CH=O), 7.37–7.27 (A+B) (m, 3H, NH+
CH meta to OMe in Ar), 7.04 (A) (d, J=9.0 Hz, 1.70H),
6.97–6.85 (m, 8.30H, other aromatic CH), 6.18 (A) (dd, J=
4.6, 9.8 Hz, 0.85H, CHNH), 5.43 (B) (dd, J=5.8 Hz,
10.3 Hz, 0.15H, CHNH), 4.41 (A) (d, J=4.5 Hz, 0.86H,
NHCHCH), 4.39 (B) (d, J=6.0 Hz, 0.14H, NHCHCH), 3.83
(B) (s, 0.45H, OCH3), 3.82 (A) (s, 2.55H, OCH3), 3.80 (A+
B) (s, 3H, OCH3), 3.78 (A+B) (s, 3H, OCH3); 13C NMR
(75 MHz, CDCl3; only the peaks of main conformer are re-
(S)-Bis(4-methoxyphenyl) 2-[formamido(3-bromophenyl)-
methyl]malonate (9e): It was prepared following the proce-
dure above described for 9a; yield: 87%; ee=69% (deter-
mined by chiral HPLC on a Daicel Chiral pak AD 250ꢁ
4.6 mm column, Vinj =20 mL, T=408C, eluent: hexane/i-
PrOH 25:75; flow: 0.5 mLminÀ1); Rt (S): 21.55; Rt (R):
14.08; Rf =0.49 (CH2Cl2/AcOEt 90:10); [a]D: À1.9 (c 1,
À
ported): d=167.1, 165.9, 160.5 (C=O), 159.4, 157.7 (C
OMe), 143.6, 143.4 (COCO), 129.9 (quat.), 127.7 (ꢁ2), 122.1
(ꢁ2), 122.0 (ꢁ2), 114.7 (ꢁ2), 114.6 (ꢁ2) 114.3 (ꢁ2) (aromat-
ic CH), 56.6 (NHCHCH), 55.6 (ꢁ2), 55.3 (OCH3), 49.8
(CHNH); IR (CHCl3): n=3670, 3597, 3410, 2997, 1747,
1688, 1599, 1493, 1171, 1132, 1023, 920 cmÀ1; HR-MS
(ESI+): m/z=480.1672, calcd. for C26H26NO8 [M+H]+:
480.1658.
1
CHCl3); H NMR [300 MHz., CDCl3, 2 conformers (A and
B) are present in an 89:11 ratio; only selected signals of con-
former B are reported]: d=8.35 (A) (s, 0.89H, CH=O), 8.24
(B) (d, J=11.4 Hz, 0.11H, CH=O), 7.60 (A) (s, 0.89H, H
ortho to Br and CH), 7.49 (A) (dt, J=7.8 Hz), 1.3 (t, 0.89H,
H meta to Br and CH), 7.40 (A) (d, J=9.9 Hz, 0.89H, NH),
7.37 (A) (d, J=2.6 Hz, 1.78H, H para to CH), 7.29 (A) (d,
J=7.8 Hz, 0.89H, H para to Br), 7.05 (A) (d, J=9.0 Hz,
(S)-Bis(4-methoxyphenyl) 2-[formamido(4-chlorophenyl)-
methyl]malonate (9c): It was prepared following the proce-
dure above described for 9a; yield: 85%; ee=60% (deter-
mined by chiral HPLC on a Daicel Chiral pak AD 250ꢁ
4.6 mm column, Vinj =20 mL, T=408C, eluent: hexane/i-
PrOH 40:60; flow: 0.5 mLminÀ1). Rt (S): 23.90; Rt (R):
8
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Organocatalytic Asymmetric Synthesis of b-Aryl-b-isocyano Esters
1.78H), 6.91 (A) (d, J=9.0 Hz, 1.78H), 6.93–6.83 (m, 4H),
6.20 (A) (dd, J=4.2, 9.9 Hz, 0.89H, CHNH), 5.45 (B) (dd,
J=5.4 Hz, 10.8 Hz, 0.11H, CHNH), 4.42 (A) (d, J=4.2 Hz,
0.89H, NHCHCH), 4.40 (B) (d, J=5.4 Hz, 0.11H,
NHCHCH), 3.80 (A+B) (s, 3H, OCH3), 3.78 (A+B) (s,
3H, OCH3); 13C NMR (75 MHz, CDCl3; only the peaks of
4.43 (B) (d, J=5.2 Hz, 0.14H, NHCHCH), 3.80 (A+B) (s,
3H, OCH3), 3.78 (A+B) (s, 3H, OCH3); 13C NMR
(75 MHz, CDCl3; only the peaks of main conformer are re-
À
ported): d=167.1, 165.7, 160.4 (ꢁ2) (C=O), 157.8, 157.7 (C
OMe), 143.6, 143.4 (COCO), 139.0 (quat. thienyl), 127.0,
126.1, 122.4, 122.1 (ꢁ2), 122.0 (ꢁ2), 114.60 (ꢁ2), 114.57 (ꢁ2)
main conformer are reported): d=167.0, 165.6, 160.6 (C= (aromatic CH), 55.9 (NHCHCH), 55.6 (ꢁ2) (OCH3), 46.7
À
O), 157.8 (ꢁ2) (C OMe), 143.5, 143.3 (COCO), 131.4,
130.5, 129.6, 125.2, 122.0 (ꢁ2), 121.8 (ꢁ2), 114.7 (ꢁ2), 114.6
(ꢁ2) (aromatic CH), 123.0 (quat.), 56.1 (NHCHCH), 55.6 (ꢁ
2) (OCH3), 49.7 (CHNH); IR (CHCl3): n=3671, 3600, 3405,
2995, 1745, 1706, 1597, 1490, 1412, 1359, 1190, 1134, 1023,
(CHNH); IR (CHCl3): n=3676, 3594, 3412, 3002, 1748,
1687, 1596, 1490, 1357, 1171, 1132, 1041, 922 cmÀ1; HR-MS
(ESI+): m/z=456.1129, calcd. for C23H22NO7 [M+H]+:
456.1117.
(S)-Bis(4-Methoxyphenyl) 2-[formamido(b-naphthyl)meth-
yl]malonate (9h): It was prepared following the procedure
above described for 9a; yield: 78%; ee=84% (determined
by chiral HPLC on a Daicel Chiral pak AD 250ꢁ4.6 mm
column, Vinj =20 mL, T=408C, eluent: hexane/i-PrOH
25:75; flow: 0.5 mLminÀ1); Rt (S): 24.59; Rt (R): 19.08; Rf =
0.43 (CH2Cl2/AcOEt 90:10); [a]D: À38.0 (c 1, CHCl3);
1H NMR [300 MHz, CDCl3; 2 conformers (A and B) are
present in an 86:14 ratio; only selected signals of conformer
B are reported]: d=8.40 (A) (s, 0.86H, CH=O), 8.31 (B) (d,
J=11.7 Hz, 0.14H, CH=O), 7.95–7.78 (m, 4H), 7.57–7.47
[3.86H, m. NH (A)+3CH of naphthyl], 7.06 (A) (d, J=
9.0 Hz, 1.72H), 6.90 (A) (d, J=9.0 Hz, 1.72H), 6.79 (A) (s,
3.64H), 6.41 (A) (dd, J=4.6, 9.9 Hz, 0.86H, CHNH), 5.65
(B) (dd, J=5.7 Hz, 10.5 Hz, 0.14H, CHNH), 4.57 (A) (d,
J=4.6 Hz, 0.86H, NHCHCH), 4.55 (B) (d, J=5.7 Hz,
0.14H, NHCHCH), 3.80 (A) (s, 2.58H, OCH3), 3.79 (B) (s,
0.42H, OCH3), 3.77 (A+B) (s, 3H, OCH3); 13C NMR
(75 MHz, CDCl3; only the peaks of main conformer are re-
920 cmÀ1
;
HR-MS (ESI+): m/z=528.0665, calcd. for
C25H23BrNO7 [M+H]+: 528.0658.
(S)-Bis(4-methoxyphenyl) 2-[formamido(2-methoxyphen-
yl)methyl]malonate (9f): It was prepared following the pro-
cedure above described for 9a; yield: 87%; ee=90% (deter-
mined by chiral HPLC on a Daicel Chiral pak AD 250ꢁ
4.6 mm column, Vinj =20 mL, T=408C, eluent: hexane/i-
PrOH 25:75; flow: 0.5 mLminÀ1); Rt (S): 22.51; Rt (R):
12.14; Rf =0.38 (CH2Cl2/AcOEt 90:10); [a]D: À8.0 (c 1,
1
CHCl3); H NMR [300 MHz., CDCl3; 2 conformers (A and
B) are present in an 71:29 ratio]: d=8.30 (A) (s, 0.71H,
CH=O), 8.29 (B) (d, J=11.7 Hz, 0.29H, CH=O), 7.42–7.27
[m, 2.71H, NH (A)+2 aromatic CH (A+B)], 7.10–6.67 [m,
10.29H, NH (B)+other aromatics], 6.37 (A) (dd, J=6.0,
10.2 Hz, 0.71H, CHNH), 5.48 (B) (dd, J=8.1 Hz, 10.8 Hz,
0.29H, CHNH), 4.67 (B) (d, J=8.1 Hz, 0.29H, NHCHCH),
4.66 (A) (d, J=6.0 Hz, 0.71H, NHCHCH), 3.96 (A+B) (s,
3H, OCH3), 3.79 (B) (s, 0.87H, OCH3), 3.78 (A) (s, 2.13H,
OCH3), 3.770 (A) (s, 2.13H, OCH3); 3.767 (B) (s, 0.87H,
OCH3); 13C NMR (75 MHz, CDCl3): d=167.0 (A), 166.4
(B), 166.0 (A), 165.4 (B), 164.4 (B), 160.63 (A) (C=O),
157.7 (B), 157.62 (B), 157.59 (A), 157.56 (A), 156.6 (B),
À
ported): d=167.2, 165.9, 160.6 (C=O), 157.7 (C OMe),
143.6, 143.3 (COCO), 135.2, 133.2, 132.9 (quat. naphthyl),
128.9, 128.1, 127.7, 126.6, 126.5, 125.5, 124.2, 122.1 (ꢁ2),
121.9 (ꢁ2), 114.6 (ꢁ2), 114.5 (ꢁ2) (aromatic CH), 56.3
(NHCHCH), 55.61, 55.56 (OCH3), 50.3 (CHNH); IR
(CHCl3): n=3675, 3605, 3404, 2997, 1747, 1685, 1595, 1489,
1353, 1246, 1171, 1132, 1025, 919 cmÀ1; HR-MS (ESI+):
m/z=500.1714, calcd. for C29H26NO7 [M+H]+: 500.1709.
(S)-Bis(4-methoxyphenyl) 2-[formamido(a-naphthyl)me-
thyl]malonate (9i): It was prepared following the procedure
above described for 9a; yield: 78%; ee=70% (determined
by chiral HPLC on a Daicel Chiral pak AD 250ꢁ4.6 mm
column, Vinj =20 mL, T=408C, eluent: hexane/i-PrOH
25:75; flow: 0.5 mLminÀ1); Rt (S): 19.39; Rt (R): 13.89; Rf =
0.51 (CH2Cl2/AcOEt 90:10); [a]D: À7.7 (c 1, CHCl3);
1H NMR [300 MHz., CDCl3; 2 conformers (A and B) are
present in an 84:16 ratio; only selected signals of conformer
B are reported]: d=8.37 (A) (s, 0.84H, CH=O), 8.31 (B) (d,
J=11.9 Hz, 0.16H, CH=O), 8.26 (A) (d, J=8.4 Hz, 0.84H),
7.94 (A) (d, J=8.4 Hz, 0.84H), 7.87 (A) (d, J=8.1 Hz,
0.84H), 7.65–7.73 [m, 1.84H, NH (A) and 1CH (A+B)],
7.57 (A+B) (t, J=7.0 Hz, 0.84H), 7.47 (A) (t, J=7.6 Hz,
0.84H), 7.11 (A) (d, J=9.0 Hz, 1.68H), 7.04 (A) (dd, J=3.7,
9.5 Hz, 0.84H, CHNH), 6.92 (A) (d, J=9.0 Hz, 1.68H),
6.84–6.72 (A+B) (m, 4H), 6.26 (B) (dd, J=5.0 Hz, 10.4 Hz,
0.16H, CHNH), 4.60 (A+B) (d, J=3.7 Hz, 1H,
NHCHCH), 3.81 (A) (s, 2.52H, OCH3), 3.80 (B) (s, 0.48H,
OCH3), 3.75 (A+B) (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3; only the peaks of main conformer are reported): d=
À
156.5 (A) (C OMe), 143.7 (A), 143.5 (A+B), 143.4 (B)
(COCO), 130.3 (B), 129.6 (A), 129.2 (B), 128.5 (A), 122.1
(A) (ꢁ2), 122.04 (A) (ꢁ2), 121.98 (B) (ꢁ2), 121.8 (B) (ꢁ2),
121.1 (B), 120.8 (A), 114.6 (B) (ꢁ2), 114.5 (A) (ꢁ2), 114.4
(A+B) (ꢁ2), 111.0 (B), 110.7 (A) (aromatic CH), 125.3
(A), 124.9 (B) (quat.), 55.7 (B) 54.7 (A) (NHCHCH), 55.6
(A+B) (ꢁ3) (OCH3), 53.9 (B), 47.4 (A) (CHNH); IR
(CHCl3): n=3676, 3615, 3419, 2970, 1747, 1690, 1597, 1491,
1358, 1182, 1134, 1026, 906 cmÀ1; HR-MS (ESI+): m/z=
480.1655, calcd. for C26H26NO8 [M+H]+: 480.1658.
(S)-Bis(4-methoxyphenyl) 2-[formamido(3-thienyl)meth-
yl]malonate (9g): It was prepared following the procedure
above described for 9a; yield: 62%; ee=67% (determined
by chiral HPLC on a Daicel Chiral pak AD 250ꢁ4.6 mm
column, Vinj =20 mL, T=408C, eluent: hexane/i-PrOH
25:75; flow: 0.5 mLminÀ1); Rt (S): 22.93; Rt (R): 17.85; Rf =
0.37 (CH2Cl2/AcOEt 90:10); [a]D: À2.1 (c 1, CHCl3);
1H NMR [300 MHz., CDCl3; 2 conformers (A and B) are
present in an 86:14 ratio; only selected signals of conformer
B are reported]: d=8.32 (A) (s, 0.86H, CH=O), 8.26 (B) (d,
J=11.7 Hz, 0.14H, CH=O), 7.43 (B) (dd, J=3.0 and 4.8 Hz,
0.14H, CH of thienyl), 7.37 (A) (dd, J=3.0 and 5.0 Hz,
0.86H, CH of thienyl), 7.32–7.24 [m, 1.86H, NH (A)+1CH
of thienyl], 7.14 (A+B) (dd, J=1.2 and 5.0 Hz, CH of
thienyl), 7.05 (A) (d, J=9.0 Hz, 1.72H), 6.90 (A) (d, J=
9.0 Hz, 1.72H), 6.87 (A) (s, 3.64H), 6.29 (A) (dd, J=4.0,
9.9 Hz, 0.86H, CHNH), 5.52 (B) (dd, J=5.2 Hz, 10.4 Hz,
0.14H, CHNH), 4.47 (A) (d, J=4.0 Hz, 0.86H, NHCHCH),
À
167.3, 166.0, 160.4 (C=O), 157.8, 157.7 (C OMe), 143.7,
143.2 (COCO), 133.9, 133.2, 130.0 (quat. naphthyl), 129.4,
129.2, 127.4, 126.2, 125.1, 124.0, 122.2 (ꢁ2), 122.1, 121.9
Adv. Synth. Catal. 0000, 000, 0 – 0
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FULL PAPERS
(ꢁ2), 114.6 (ꢁ2), 114.5 (ꢁ2) (aromatic CH), 55.62, 55.56
(OCH3), 55.3 (NHCHCH), 46.9 (CHNH); IR (CHCl3): n=
3675, 3602, 3411, 3001, 1745, 1688, 1597, 1488, 1420, 1355,
1183, 1132, 1024, 919 cmÀ1; HR-MS (ESI+): m/z=500.1724,
calcd. for C29H26NO7 [M+H]+: 500.1709.
The reaction mixture was stirred at this temperature for 4 h
and 30 min, and then poured into saturated aqueous
NaHCO3, extracted with Et2O, and chromatographed (PE/
Et2O 75:25) to give pure 1a as a yellowish oil; yield: 283 mg
(85%). This compound tends to slowly decompose upon
standing in the freezer for some months. Therefore it is ad-
visable to use it within few days after preparation. Rf 0.44
(PE/Et2O 7:3); [a]D: À35.2 (c 1.2 CHCl3); 1H NMR
(300 MHz., CDCl3): d=7.45–7.32 (m, 5H, CH of Ph), 5.18
(dd, J=5.7 and 8.7 Hz, 1H, CHNC), 4.27–4.10 (m, 2H,
CH2CH3), 3.01 (dd, J=8.9 and 16.0 Hz, 1H, CHHCO2Et),
2.87–2.75 (m, 1H, CHHCO2Et), 1.26 (t, J=7.2 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3): d=168.8 (C=O), 136.0
(quat), 129.1 (ꢁ2), 128.8, 125.9 (ꢁ2) (aromatic CH), 61.4
(CH2CH3), 54.7 (t, J=6.2 Hz), 43.5 (CHNC), 14.1 (CH3); IR
(CHCl3): n=2984, 2143, 1727, 1598, 1371, 1350, 1183, 1005,
(S)-Ethyl 3-Formamido-3-phenylpropanoate (2a)
A solution of malonate (S)-9a (ee 98%; 809 mg, 1.80 mmol)
in dry EtOH (32 mL) and THF (8 mL) was cooled to 08C,
and treated with a commercial 21% (w/w) (2.68M) solution
of EtONa in absolute EtOH (800 mL, 2.14 mmol). After
30 min the cooling bath was removed and the solution fur-
ther stirred for 90 min at room temperature. After addition
of saturated aqueous NH4Cl (40 mL), most of the EtOH
was evaporated. The resulting mixture was extracted with
AcOEt, washed with saturated NaCl, and evaporated to dry-
ness. The crude product was chromatographed (CH2Cl2/
AcOEt from 100:0 to 95:5) in order to separate diethyl mal-
onate 8a from p-methoxyphenol. Diethyl malonate 8a was
obtained as an oil (yield: 528 mg). It was taken up in EtOH
(17.3 mL) and treated, at 08C, with 0.5M aqueous NaOH
(4.34 mL, 2.17 mmol). After 30 min the cooling bath was re-
moved, and the solution stirred for further 90 min at room
temperature. After addition of saturated NaCl (15 mL), and
1M NaH2PO4 (15 mL), most of the EtOH was evaporated.
The resulting mixture was adjusted to pH 2 by addition of
2M HCl, and extracted with AcOEt, washed with saturated
NaCl, and evaporated to dryness. It was taken up in toluene
(10 mL), and refluxed for 6 h. After evaporation and chro-
matography, pure 2a was obtained as a slightly yellow oil;
yield: 376 mg (95%); Rf 0.30 (CH2Cl2/AcOEt 80:20); [a]D:
À73.2 (c 1.6 CHCl3); 1H NMR [300 MHz., CDCl3; 2 con-
formers (A and B) are present in an 80:20 ratio; only select-
ed signals of conformer B are reported]: d=8.21 (A) (s,
0.80H, CH=O), 8.15 (B) (d, J=11.7 Hz, 0.20H, CH=O),
7.40–7.20 (m, 5 H CH of Ph), 6.89 (A) (d, J=8.5 Hz, 0.80H,
NH), 6.69 (B) (t, J=10.6 Hz, 0.20H, NH), 5.51 (A) (dt, J=
5.8 (t), 8.5 (d), 0.80H, CHNH), 5.51 (B) [dt, J=6.5 (t),
9.5 Hz (d), 0.20H, CHNH], 4.12 (B) (q, J=7.0 Hz, 0.40H,
CH2CH3), 4.07 (A) (q, J=7.1 Hz, 1.60H, CH2CH3), 2.93 and
2.84 [AB part of ABX syst., J=15.7 (ab), 5.9 (ax), 6.0 (bx)
Hz, 2H, CH2CO2Et], 1.21 (B) (t, J=6.9 Hz, 0.60H,
CH3CH2), 1.17 (A) (t, J=7.2 Hz, 2.40H, CH3CH2);
13C NMR (75 MHz, CDCl3; both conformers A and B are
reported): d=171.0 (A), 170.3 (B), 164.3 (B), 160.4 (A) (C=
O), 140.0 (B), 139.9 (A) (quat), 129.0 (ꢁ2) (B), 128.7 (ꢁ2)
(A), 128.1 (B), 127.7 (A), 126.2 (ꢁ2) (A), 126.0 (ꢁ2) (B) (ar-
omatic CH), 61.1 (B), 60.9 (A) (CH2CH3), 52.7 (B), 48.2
(A) (CHNH), 41.6 (B), 39.9 (A) (CH2CO2Et), 14.0 (A+B)
(CH3); IR (CHCl3): n=3419, 2969, 1722, 1685, 1485, 1375,
1164, 1019, 917 cmÀ1; GC-MS: Rt 8.86 min; m/z=221 (M+,
17.2%); 192 (64.8); 176 (18.7); 175 (34.2); 147 (77.5); 146
(14.3); 134 (94.0); 131 (45.4); 119 (53.9); 106 (85.0); 104
(100.0); 103 (32.5); 79 (55.8); 77 (53.6); 51 (19.8); HR-MS
(ESI+): m/z=244.0954, calcd. for C12H15NO3Na [M+H]+:
244.0950.
822 cmÀ1
C11H13O2 [M-NC]+: 177.0910. The ee (93%) was determined
by chiral HPLC (Daicel Chiral pak AD 250ꢁ4.6 mm, Vinj
;
HR-MS (ESI+): m/z=177.0915, calcd. for
=
20 mL, T=408C, eluent: hexane/i-PrOH 99:1; flow:
0.5 mLminÀ1); Rt (S): 41.09; Rt (R): 37.27.
(S)-Ethyl 3-[(3aS,4R,6aR)-5-(2-Methoxyacetyl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxoloACHTUNGTREN[NUGN 4,5-c]pyrrole-4-
carboxamido]-3-phenylpropanoate (18)
(+)ACHTNUTRGNEUNG(4S,5R)-5-[(Azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]methyl butanoate was converted, as previously describ-
ed,[11a] into crude imine (3aS,6aR)-17 (containing also
PPh3O). An amount of this imine corresponding to
480 mmol (calculated on the basis of the starting azidobuta-
noate) was dissolved in dry MeOH (1.5 mL) and treated
with powdered 4 ꢂ mol. sieves (50 mg), methoxyacetic acid
(31 mL, 400 mmol), and finally with a solution of isocyanide
1a (58 mg, 285 mmol) in MeOH (2 mL). The solution was
stirred at room temperature for 48 h, and then evaporated
to dryness. The crude product was taken up in AcOEt,
washed with saturated aqueous NaHCO3, evaporated again,
and chromatographed (PE/AcOEt/acetone 46:36:18) to give
pure 18 as a colourless oil; yield: 79.1 mg (64%); Rf =0.39
(PE/AcOEt 2:8); [a]D: +40.1 (c 1, CHCl3); 1H NMR
(300 MHz., CDCl3; 2 conformers A and B in 83:17 were
visible): d=7.53 (A+B) (d, J=8.4 Hz, 1H, NH), 7.37–7.18
(A+B) (m, 5H), 5.34 (A+B) (q, J=7.2 Hz, 1H,
PhCHNH), 5.10 (A) (d, J=6.0 Hz, 0.83H, H-3a), 5.00 (B)
(d, J=5.7 Hz, 0.17H, H-3a), 4.87 (A) (s, 0.83H, H-4), 4.83
(A) (t, J=5.3 Hz, 0.83H, H-6a), 4.76 (B) (t, J=5.3 Hz,
0.17H, H-6a), 4.69 (B) (s, 0.17H, H-4), 4.36 (B) (d, J=
13.4 Hz, 0.17H, H-6), 4.15–3.96 (A+B) (m, 4H, CH2OMe+
CH2CH3), 3.82 (A) (d, J=12.4 Hz, 0.83H, H-6), 3.46 (A)
(dd, J=4.6 and 12.4 Hz, 0.83H, H-6), 3.32 (A) (s, 2.49H,
OCH3), 3.30 (B) (s, 0.51H, OCH3), 3.27 (B) (dd, J=5.1 and
13.4 Hz, 0.17H, H-6), 2.92–2.75 (B) (m, 0.34H, CH2CO2Et),
2.85 and 2.79 (A) [AB part of an ABX syst., J=14.6 (ab),
5.6 (ax), 6.0 (bx) Hz., 1.66H, CH2CO2Et], 1.42 (A) (s,
2.49H, CH3), 1.40 (B) (s, 0.51H, CH3), 1.32 (A) (s, 2.49H,
CH3), 1.30 (B) (s, 0.51H, CH3), 1.19 (A) (t, J=7.0 Hz,
2.49H, CH3CH2), 1.18 (B) (t, J=7.0 Hz, 0.51H, CH3CH2);
13C NMR (75 MHz, CDCl3): d=170.7 (B), 170.4 (A), 169.2
(A), 168.6 (B), 167.8 (A), 167.7 (B) (C=O), 140.4 (A), 140.1
(B) (quat.), 128.8 (B) (ꢁ2), 128.7 (A) (ꢁ2), 127.9 (B), 127.6
(A), 126.2 (A) (ꢁ2), 126.1 (B) (ꢁ2) (aromatic CH), 111.9
(S)-Ethyl 3-Isocyano-3-phenylpropanoate (1a)
A solution of formamide 2a (360 mg, 1.63 mmol) in dry
CH2Cl2 (12 mL) was cooled to À308C, and treated with
Et3N (775 mL, 5.55 mmol) and POCl3 (166 mL, 1.80 mmol).
10
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Organocatalytic Asymmetric Synthesis of b-Aryl-b-isocyano Esters
(A), 111.7 (B) (OCO), 82.8 (B), 79.9 (A), 79.7 (A), 78.0 (B)
(C-3a and C-6a), 73.1 (B), 71.6 (A) (CH2OCH3), 66.9 (B),
65.6 (A) (C-4), 60.9 (B), 60.8 (A) (CH2CH3), 59.0 (B), 58.9
(A) (CH3O), 51.8 (A), 51.5 (B) (C-6), 50.1 (A), 49.8 (B)
(CHNH), 40.7 (A), 40.1 (B) (CH2CO2Et), 26.72 (A), 26.68
(B), 24.7 (A), 24.6 (B) (H3C-C-CH3), 14.1 (A+B)
(CH3CH2); IR (CHCl3): n=3675, 3613, 3008, 2969, 1726,
1668, 1512, 1476, 1424, 1384, 1331, 1228, 1203, 1128, 1042,
and the University of Genova (Ateneo 2010) are acknowl-
edged for financial assistance.
References
928 cmÀ1
;
HR-MS (ESI+): m/z=435.2159, calcd. for
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C22H31N2O7 [M+H]+: 435.2131.
(S)-Ethyl 3-[(3aR,4S,6aS)-5-(2-methoxyacetyl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxoloACTHNUTRGNE[NUG 4,5-c]pyrrole-4-
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It was prepared by the same procedure as described for 18,
but using this time crude imine (3aR,6aS)-17 synthesized
from (À)
ACHTUNGTRENNUNG(4R,5S)-5-(azidomethyl)-2,2-dimethyl-1,3-dioxolan-
4-yl)methyl acetate;[11a] yield: 66% (colourless oil); Rf =0.33
(PE/AcOEt 2:8); [a]D: À83.3 (c 1, CHCl3); 1H NMR
(300 MHz., CDCl3; 2 conformers A and B in 82:18 were
visible): d=7.50 (A+B) (d, J=8.4 Hz, 1H, NH), 7.40–7.20
(A+B) (m, 5H), 5.37 (B) [dq, J=6.6 Hz (q), 8.4 (d) Hz,
0.18H, PhCHNH], 5.33 (A) (q, J=6.6 Hz, 0.82H,
PhCHNH), 5.06 (A) (d, J=5.7 Hz, 0.82H, H-3a), 5.00 (B)
(d, J=6.0 Hz, 0.18H, H-3a), 4.86 (A) (t, J=5.4 Hz, 0.82H,
H-6a), 4.83 (A) (s, 0.82H, H-4), 4.77 (B) (t, J=5.3 Hz,
0.18H, H-6a), 4.66 (B) (s, 0.18H, H-4), 4.40 (B) (d, J=
13.5 Hz, 0.18H, H-6), 4.18 and 4.09 (A) (AB syst., 1.64H,
CH2OMe), 4.04 (A) (q, J=7.0, 1.64H, CH2CH3), 4.13–4.02
(B) (m, 0.72H, CH2OMe and CH2CH3), 3.88 (A) (d, J=
12.6 Hz, 0.82H, H-6), 3.60 (A) (dd, J=4.6 and 12.4 Hz,
0.82H, H-6), 3.46 (A) (s, 2.46H, OCH3), 3.28 (B) (s, 0.54H,
OCH3), 3.34 (B) (dd, J=5.1 and 13.5 Hz, 0.18H, H-6), 2.92–
2.75 (B) (m, 0.36H, CH2CO2Et), 2.77 (A) (d, J=6.9 Hz,
1.64H, CH2CO2Et), 1.42 (A) (s, 2.46H, CH3), 1.40 (B) (s,
0.54H, CH3), 1.31 (A) (s, 2.46H, CH3), 1.30 (B) (s, 0.54H,
CH3), 1.17 (A+B) (t, J=7.2 Hz, 3H, CH3CH2); 13C NMR
(75 MHz, CDCl3): d=170.7 (B), 170.5 (A), 169.5 (A), 168.7
(B), 167.9 (A), 167.6 (B) (C=O), 140.1 (A), 140.0 (B)
(quat.), 128.8 (A+B)(x2), 127.9 (B), 127.7 (A), 126.3 (A) (ꢁ
2), 126.2 (B) (ꢁ2) (aromatic CH), 111.8 (A), 111.7 (B)
(OCO), 82.9 (B), 79.8 (A), 79.7 (A), 78.0 (B) (C-3a and C-
6a), 73.0 (B), 71.6 (A) (CH2OCH3), 67.0 (B), 65.5 (A) (C-4),
60.9 (B), 60.7 (A) (CH2CH3), 59.0 (B), 58.9 (A) (CH3O),
51.7 (A), 51.3 (B) (C-6), 50.0 (A), 49.8 (B) (CHNH), 40.7
(A), 40.1 (B) (CH2CO2Et), 26.7 (A+B), 24.6 (A+B) (H3C-
C-CH3), 14.0 (A+B) (CH3CH2); IR (CHCl3): n=3673,
2999, 2933, 1726, 1667, 1497, 1429, 1373, 1345, 1239, 1155,
1128, 1112, 1047, 918 cmÀ1; HR-MS (ESI+): m/z=435.2144,
calcd. for C22H31N2O7 [M+H]+: 435.2131.
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Acknowledgements
We thank Dr. Luca Bernardi for helpful advices, Dr. Valeria
Rocca for collaboration in chiral HPLC analyses, and Dr.
Sine Mandrup Bertozzi (I.I.T.) for high-resolution mass spec-
tra. Fondazione San Paolo, MIUR (PRIN 2009 “Synthetic
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