Acid promoted CIDT for the deracemization of dihydrocinnamic aldehydes with Betti's base

Article abstract of DOI:10.1039/c0gc00013b

Racemic α-epimerizable and unfunctionalized aldehydes have been converted into enantiomerically enriched mixtures through a sequence of (i) a conversion into the diastereoisomeric 3-substituted 1-phenyl-2,3-dihydro-1H- naphtho[1,2-e][1,3]oxazines by reaction with the (R)- or (S)-1-(α- aminobenzyl)-2-naphthol (Betti's base), (ii) an acid promoted crystallization-induced diastereoisomer transformation (CIDT), and (iii) a clean cleavage of the dihydro-1,3-naphthoxazinic ring of the enriched diastereoisomer, easily collected by filtration, allowing the recovery of the enantiomerically enriched aldehydes and the chiral auxiliary.

Full text of DOI:10.1039/c0gc00013b

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Acid promoted CIDT for the deracemization of dihydrocinnamic aldehydes
with Betti’s base†
Goffredo Rosini,* Claudio Paolucci, Francesca Boschi, Emanuela Marotta, Paolo Righi and Francesco Tozzi
Received 19th April 2010, Accepted 10th August 2010
DOI: 10.1039/c0gc00013b
Racemic a-epimerizable and unfunctionalized aldehydes have been converted into
enantiomerically enriched mixtures through a sequence of (i) a conversion into the
diastereoisomeric 3-substituted 1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines by reaction
with the (R)- or (S)-1-(a-aminobenzyl)-2-naphthol (Betti’s base), (ii) an acid promoted
crystallization-induced diastereoisomer transformation (CIDT), and (iii) a clean cleavage of the
dihydro-1,3-naphthoxazinic ring of the enriched diastereoisomer, easily collected by filtration,
allowing the recovery of the enantiomerically enriched aldehydes and the chiral auxiliary.
diastereoisomeric imines obtained with trans-(1R,2R)-6-nitro-
Introduction
1-aminoindan-2-ol, the only amine of the eight examined that
The progress in the field of asymmetric synthesis during the
provided crystalline imines.
last two decades is indubitable and impressive.1 In spite of
As part of our program on the development of efficient and
this progress due to the creativity and ingenuity of the many
practical processes for the preparation of commercially impor-
practitioners of the field, several hurdles hamper the use of
tant molecules,8 we needed new methodologies to prepare enan-
enantioselective catalysis in industry.2 The optical resolution
of racemates3 via formation of diastereoisomeric p and n
derivatives with an enantiopure auxiliary and their separation
tiomerically enriched a-epimerizable a-alkyl aldehydes without
the major limits of the classical resolution and those associated
to the asymmetric synthesis. Therefore, our efforts were oriented
by crystallization is still the preferred route in the preparation
towards the deracemization by CIDT methodology adopting the
of a vast majority of enantiomeric pure or highly enriched
compounds required for the manufacture of pharmaceuticals,
agrochemicals and fragrances. More practical and efficient
is the crystallization-induced diastereoisomer transformation
(CIDT)4 by which the racemic mixture of an epimerizable
same critical success factors indicated by Kosˇmrlj and Weigel to
evaluate the “industrial feasibility” of their process: (a) >90%
yield; (b) >90% ee; (c) protocol as simple as a resolution; (d)
>95% recovery of the chiral auxiliary.
Attracted by the potentialities of the enantiomers of 1-(a-
chiral compound can be, in principle, entirely converted into the
aminobenzyl)-2-naphthol (Betti’s base),9,10 easily made available
desired highly enriched enantiomer by using an apt chiral non
by the very efficient and straightforward kinetic resolution
racemic auxiliary. In CIDT processes a 100% yield of a single
recently developed by Hu11 with (R,R)-tartaric acid (Scheme 1),
diastereoisomer can be reached whenever the epimerization of
we focused the attention on the deracemization of some
the more soluble stereoisomer occurs with the precipitation
of the less soluble diastereoisomer. Therefore, this kind of
processes is very attractive for the pharmaceutical and fine
chemical industries allowing the production of enantiomerically
“real world targets”12 such as 3-(benzo[d][1,3]dioxol-5-yl)-2-
R
methylpropanal13 (Helional,ꢀ d,l-2a), 3-(4-tert-butylphenyl)-
R
2-methylpropanal14 (Lilial,ꢀ d,l-2b), 3-(4-isopropylphenyl)-2-
methylpropanal15 (Cyclamal, d,l-2c), and 3-(4-methoxyphenyl)-
pure drugs and intermediates in higher yields (up to 100%)
R
2-methylpropanal (Canthoxalꢀ, d,l-2d), important perfumery
minimizing the problems associated with waste or recycling of
ingredients,16 readily available in racemic form.
the unwanted enantiomer, according to the principles of green
chemistry.5
While a variety of very efficient examples4,6 of this approach
are reported in the literature, and applied at industrial scale
too, little interest has been devoted to a-epimerizable, unfunc-
tionalized aldehydes until Kosˇmrlj and Weigel7 demonstrated
that ( )-2-ethylhexanal can be converted into (R)-2-ethylhexanal
(94% yield, er = 99 : 1) by CIDT with methanol of the
Dipartimento di Chimica Organica “A. Mangini”, Alma Mater
Studiorum – Universita` di Bologna, Viale del Risorgimento 4, I-40136,
Bologna, Italy. E-mail: goffredo.rosini@unibo.it; Fax: +39 051 2093654
† Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of racemic aldehydes 2d–f. CCDC
reference number 773610. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c0gc00013b
Scheme 1 Hu’s kinetic resolution of Betti’s base.
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Racemic Betti’s base, 1-(a-aminobenzyl)-2-naphthol (1), is
easily available by a three-component condensation of b-
naphthol with benzaldehyde and ammonia in a ratio 1 : 2 : 1
performed in alcoholic solution at room temperature for sev-
eral hours, which is followed by acidic hydrolysis to furnish
the base as hydrochloride together with one equivalent of
benzaldehyde.17 This reaction was discovered by M. Betti
in Florence18 at the beginning of the 20th century and in
1906 Betti himself successfully resolved19 1-(a-aminobenzyl)-2-
naphthol with L-(+)-tartaric acid obtaining the corresponding
enantiomers that successively he used to resolve some racemic
aldehydes.20 In 1970 Smith and Cooper have summarized the
vicissitudes of the structure assignment to the condensation
product, and reported the former spectroscopic evidences
that showed this as a ring-chain tautomeric equilibrium of
three forms: two isomeric naphthoxazines (ring) and a Schiff
base (chain).21 More recently, Fu¨lo¨p and co-workers22 through
the NOESY spectra in CDCl3 at 300 K on the 2,6-diaryl-
perhydro-1,3-oxazines unequivocally showed that the major
ring component in all tautomeric equilibria contains the 1,3-
diaryl substituents in the trans position (Scheme 2). Therefore
a naphthoxazinic system with two chiral centres could be
represented by four stereoisomers but two of them, the trans-
disposed ones, are decidedly predominant.
Scheme 3 Imine/enamine equilibrium of naphthoxazines derived from
Betti’s base and racemic a-alkyldihydrocinnamic aldehydes.
Scheme 2 Tautomeric equilibria of imines derived from Betti’s base.
Results and discussion
We were spurred by the peculiar role that the open chain
component, the Schiff base, could play in favouring the major
ring component, the trans 2,4-disubstituted 1,3-naphthoxazine
in such equilibrium game.
R
Scheme 4 Reaction of (S)-1 with racemic Helionalꢀ in methanol.
the 1,3-oxazine ring, the preferred disposition already observed
and reported by Fu¨lo¨p and coworkers.21,22 The independent
preparation of (1S,3R,S)-3a and of (1S,3R,R)-3a by reaction
of (S)-1 with, respectively, (S)-2a (er = 95 : 5)24 and (R)-2a
(er = 93 : 7) allowed the assignment of the signals of the NMR
spectra registered on the 1 : 1 mixture as well as the assignment
of the corresponding absolute configurations. Moreover, the
solubility in methanol of both diastereisomers was very low, but
(1S,3R,R)-3a (76 mg/100 mL) was revealed to be three times
less soluble when compared to (1S,3R,S)-3a (227 mg/100 ml).
The 1 : 1 mixture of (1S,3R,R)-3a and (1S,3R,S)-3a when sus-
pended in refluxing methanol (10 mL mmol-1 of substrate) and
monitored by HPLC, remained unchanged in composition dur-
ing many hours. However, a clean and progressive diastereoiso-
meric enrichment was observed when the same mixture was
suspended in 2.5% acetic acid in methanol (10 mL mmol-1 of
substrate) and heated at 65 ◦C under stirring.25 The progress of
the CIDT reactions was efficiently monitored by TLC, 1H NMR
and HPLC analysis of aliquots of precipitate. The equilibrium
was driven by the precipitation of the less soluble (1S,3R,R)-3a
to reach a dr = 92 : 8 after 24 h and a dr = 96.8 : 3.2 after 90 h.
The 1,3-naphthoxazine obtained from
a racemic a-
alkylaldehyde and (S)-1-(a-aminobenzyl)-2-naphthol [(S)-1] has
three stereogenic centres, one of which is defined, therefore
should be represented by four stereoisomers. Only two of them
are predominant due to the preferred trans disposition of the
substituents and, more importantly, the possible equilibration
through the Schiff base in a classical equilibrium. Of course,
we figured on a concomitant imine-enamine equilibrium that
can modify the configuration of the chiral centre of the starting
aldehyde (Scheme 3). The reaction of (S)-1-(a-aminobenzyl)-2-
naphthol [(S)-1] with a slight excess of racemic aldehydes (2a–e)
in methanol (5 mL mmol-1) for 2 h at rt, gave the precipitation
in almost quantitative yield of a 1 : 1 mixture of the two
epimeric 1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines
1S,3R,R)- and (1S,3R,S)-3a–e (Scheme 4) as white solids.
They were clearly detected and quantified by HPLC analysis23
while structure assignment was based on 1H and 13C NMR
spectra. NOE experiments confirmed each epimer has the trans
disposition of the two hydrogen atoms of the chiral centres of
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The isolation of the enriched isomer was performed in almost
quantitative yield simply by filtration and washing of the solid
(Scheme 5).
mixture (1 : 1 : 0.05; 4 mL mmol-1). During the reaction the
aldehyde (+)-2a passed in solution as hydrolysis occurred while
(S)-(+)-1-(a-aminobenzyl)-2-naphthol [(S)-1] was catched by
the Dowex resin. After 13 h at room temperature under magnetic
stirring, the polymer-supported Betti’s base was collected simply
by filtration. The neutralized solution (Na2CO3) was added with
water and the aldehyde was extracted with ether. The crude
aldehyde was purified by bulb-to-bulb distillation (>90% yield).
To determine the enantiomeric excess, a sample of this enriched
(R)-(+)-Helional [(R)-(+)-2a] was reduced (NaBH4 in methanol)
to the corresponding alcohol (4a) and the enantiomeric purity
determined by HPLC on a chiral stationary phase. The er
of the aldehyde, when compared with the dr of the starting
dihydro-naphthoxazine, showed a low erosion (1–5%) of the
enantiomeric enrichment during the hydrolysis step. The (S)-
1-(a-aminobenzyl)-2-naphthol free base [(S)-1] was released
enantiomerically pure in quantitative yield, simply by treatment
of the resin with aq. NH4OHconc/methanol/THF (2 : 1 : 8) under
magnetic stirring at room temperature for 24 h.
Scheme 5 The acid-promoted CIDT enrichment through naphthox-
azinic derivatives.
The following example clearly shows the amazingly simplicity
and efficiency of our CIDT protocol based on the utilization
(S)-1 or (R)-1 as chiral auxiliaries. In fact, the more soluble
oxazine (1S,3R,S)-3a (dr = 97.8 : 2.2), independently prepared
from an enantiomerically enriched sample of the aldehyde (S)-2
and Betti base (S)-1, underwent the acid promoted CIDT (2.5%
acetic acid in methanol, 10 mL mmol-1, 65 ◦C, 32 h) to give the
less soluble (1S,3R,R)-3a that was isolated by a simple filtration
in 95% yield and dr = 93 : 7 (Fig. 1).
Similar experiments performed on four additional racemic
a-epimerizable, a-alkylhydrocinnamic aldehydes 2b–e showed
that the process is general for this kind of substrate (Table 1).
Without optimization, dihydronaphthoxazines 3b–d underwent
significant diastereisomeric enrichment and their hydrolysis
R
afforded enantiomerically enriched Lilialꢀ (2b), Ciclamal (2c)
R
and Canthoxalꢀ (2d), important perfumery ingredients.16
The aldehydes 2d and 2e differ only in the substituent
adjacent to the carbonyl group, methyl group against isopropyl
group, but the corresponding 1 : 1 mixtures of their naphthox-
azines [respectively (1S,3R,R)-3d/(1S,3R,S)-3d and (1S,3R,R)-
3e/(1S,3R,S)-3e] when treated according to the same protocol,
gave a different diastereoisomeric enrichment. The 1 : 1 mixture
of (1S,3R,R)-3e/(1S,3R,S)-3e underwent a more significant acid
promoted enrichment giving the less soluble diastereoisomer
in 85% yield (dr = 97 : 3). This encouraging result spurred
us to undertake the preparation of a more ambitious “real
world target”. In facing this challenge we were well aware of
the necessity that chiral intermediates involved as precursors
in the multistep synthesis of pharmaceuticals must have, at
least, an er > 99 : 1 and, more importantly, the performances
of our approach will be compared with those of the existing
methodologies already developed to prepare important chiral
building blocks. One of such targets is alcohol 4f, the chiral
building block A of Aliskiren.
Fig. 1 The conversion of (1S,3R,S)-3a into (1S,3R,R)-3a by CIDT.
R
Aliskiren (CGP60536B, SPP-100, trade-names Tekturaꢀ,
R
Higher dr, up to 99 : 1, can be obtained by prolonging
reaction times. Therefore, an almost complete epimerization of
(1S,3R,S)-3a was accomplished indicating that the conversion
of the enriched aldehyde (S)-2 into the other enatiomer (R)-2
could be carried out with the Betti’s base (S)-1 and vice versa
by using the Betti’s base (R)-1. The same experiment performed
in parallel on a sample of the less soluble (1S,3R,R)-3a with a
dr = 98.3 : 1.7 gave a product with an increased diastereisomeric
purity (dr > 99 : 1).
Then we faced the crucial step of the hydrolysis of dihydro-
naphthoxazinic derivatives to obtain the enantiomerically en-
riched aldehydes and the recovery the Betti’s base. We success-
fully accomplished this task by suspending (1S,3R,R)-3a and
Dowex 50W ¥ 8-100 (2 g mmol-1) in a THF : EtAc : 2% aq. TsOH
Rasilezꢀ) is a highly efficient, nonpeptidic, orally administered
drug that represents a novel class of renin inhibitors26,27 with
a huge potential for treatment of hypertension and related
cardiovascular diseases. Currently, the development of more
efficient and alternative methods for the synthesis of this
compound is the focus of several pharmaceutical companies
and academic groups.28 Three main approaches have been
followed for the preparation of the alcohol (R)-4f: (a) the
amidation of the corresponding dihydrocynnamic acid (6)
with (+)-pseudoephedrine followed by the diastereoselective
alkylation with 2-iodopropane (Scheme 6)28b according to the
Myers methodology that gave a single diastereoisomer (dr >
97.5 : 2.5), then reduced, without epimerization, to the desired
alcohol 4f (er > 97.5 : 2.5); (b) by diastereoselective alkylation of
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Table 1 The enantiomeric enrichment of the aldehydes by acid promoted CIDT of the corresponding naphthoxazines with (S)-Betti’s base [(S)-1]
Scheme 7 i. 1M LiHMBS, THF, 10, -70 ◦C to r.t.; 86%. ii. LiOH, 30%
Scheme 6 i. H2, Pd/C, EtOAc, rt; ii. (COCl)2, DMF, rt; iii. (+)-
pseudoephedrine, NaOH, PhMe–H2O, rt; iv. LDA, LiCl, THF, 0 ◦C;
v. 2-iodopropane, rt-reflux; vi. BH3.NH3, n-BuLi, THF.
H2O2 soln., THF–H2O 3 : 1, 0 ◦C to r.t.; 95%. iii. NaBH4, I2, THF, 4d at
r.t.; 90%.
the lithium enolate of (4R)-3-isovaleroyl-4-benzyl-oxazolidin-2-
one [(R)-9] with 4-methoxy-3-(3-methoxypropoxy)benzyl bro-
mide (10) following the method of Evans and co-workers
(Scheme 7).28d Working at -75 ◦C in THF (at 460 g scale) a
unique alkylation product (dr = 99 : 1) was obtained, successively
hydrolyzed and then reduced to the R alcohol; (c) by synthesis
and asymmetric catalytic hydrogenation of (E)-2-(4-methoxy-3-
(3-methoxypropoxy)-benzylidene)-3-methylbutanoic acid (13)
to obtain (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-
methylbutanoic acid (14) that was reduced to the corresponding
alcohol (Scheme 8). This enantioselective hydrogenation was
carried out by using a variety of chiral ligands together with
Rh- or Ru- precursors in situ to prepare the chiral non racemic
Rh-complex.
Scheme 8
benzylidene)-3-methylbutanoic acid (13) can be seen as an
emblematic case: with the best catalysts very appreciable perfor-
mances were reported: er > 97.5 : 2.5, S C-1 ratios greater than
5000, and turnover frequencies greater than 1000 mol mol-1h-1.
These achievements resulted from the many studies devoted to
the fine tuning of the chiral ligand as well as to the careful choice
of reaction conditions.29 However, a typical target value for the
enantiomeric purity required for pharmaceutical applications is
99.5% and, therefore, the optical purity of the hydrogenation
product, the acid (R)-14 was recently enhanced to >99% ee
by crystallization (from diethyl ether) of its salt with (S)-(-)-a-
methyl benzylamine.30
Even for a well developed methodology, such as catalytic
asymmetric hydrogenation, its application to a moderately com-
plex substrate rarely yields the necessary enantiomeric purity
and further manipulations are necessary. The catalytic asymmet-
ric hydrogenation of (E)-2-(4-methoxy-3-(3-methoxypropoxy)-
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To verify the effectiveness of our approach to the enan-
tiomerically enriched aldehyde 2f through the utilization
of (S)-1-(a-aminobenzyl)-2-naphthol [(S)-1], we prepared
racemic ethyl 2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-
methylbutanoate (15)29g which was reduced to the corresponding
racemic aldehyde 2f (Scheme 9).
above for the preparation of building block A of aliskiren (see
Schemes 6, 7 and 8).
Conclusions
The CIDT process we have developed for the enantiomeric
enrichment of racemic a-alkylated, a-epimerizable aldehydes
exploits the enantiomers of 1-(a-aminobenzyl)-2-naphthol (1).
The method, when applied to a variety of “real world tar-
gets” having in common the a-alkyldihydrocinnamic structure,
appears almost general and potentially scalable. Moreover, it
fulfils the following requirements: (a) high availability of the
enantiomers of Betti base used as chiral auxiliaries, easily
prepared and resolved by using relatively inexpensive raw
materials and reagents, (b) “fast-and-cheap-arrival” to stable
1 : 1 mixtures of epimeric naphthoxazines 3a–f, (c) an efficient
acid promoted crystallization-induced epimerization to the less
soluble naphthoxazine conducted in an heterogeneous system
with a minimum amount of methanol, (d) an effective and
clean hydrolysis step to obtain the enantiomerically enriched
aldehyde, avoiding significant racemisation during the chemical
manipulations, (e) a straightforward recovery of (S)- and (R)-1-
(a-aminobenzyl)-2-naphthol, and Dowex 50WX8-100, (f) the
enantiomeric enrichment of the less soluble naphthoxazine
obtained by the CIDT process can be further improved by
crystallization and the diastereoisomers contained in the mother
liquors can be treated again to undergo another CIDT enrich-
ment without any loss of material.
The modest results obtained with racemic aldehydes 2b–c
may be improved by effecting the tuning of the chiral auxil-
iary, choosing the more appropriate Betti base. In fact, 1-(a-
aminobenzyl)-2-naphthol is only the prototype (lead) of wide
family of compounds. A large library of these compounds can
be prepared by a domino, three-component reaction between b-
naphthols, arylaldehydes and ammonia or primary amines that
give rise the desired compounds in high yield and with high
atom economy. Each racemic Betti base obtained by a parallel
synthesis methodology, may be used directly with the racemic
chiral aldehyde targeted to be enriched by the CIDT process
we have described. The HPLC analyses of the diastereisomeric
mixtures can drive the choice of the right Betti base for each
chiral aldehyde we want to enrich and then try to effect its
Scheme 9
The reaction of a slight excess of racemic aldehyde 2f with
(S)-1-(a-aminobenzyl)-2-naphthol [(S)-1] in hot methanol for
30 min gives a 1 : 1 mixture of the two diastereoisomers 3f
(Scheme 10). Acetic acid is then added to the stirred mixture.
After a few minutes a white solid starts to precipitate. After 24 h
the solids are filtrated (73% yield; dr 96.4 : 3.6). Recrystallization
from diisopropyl ether affords (1S,3R,R)-3f in a 64% overall
yield and with dr 99.5 : 0.5. Moreover, the residue recovered
by evaporation of the recrystallization mother liquors can be
combined with the solvent obtained after the filtration at the
end of the CIDT reaction. After stirring at r.t. for 64 h a
second crop of (1S,3R,R)-3f (22% overall yield; dr 98.4 : 1.6) was
obtained by filtration. The combined crops of naphthoxazine 3f
(dr = 99.2 : 0.8) were suspended in THF : EtOAc : 2% aq. TsOH =
1 : 1 : 0.05 (4 mL mmol-1) and Dowex 50WX8-100 (2g mmol-1)
was added. The resulting mixture was stirred for 13–14 h during
which time the organic solids progressively dissolved. The resin
was then filtered and washed with Et2O to recover the released
aldehyde. Finally, a sample of the enriched aldehyde (R)-2f
was reduced by sodium borohydride in methanol, giving the
corresponding alcohol (R)-4f (er = 98.8 : 1.2) in 93% yield. These
results clearly indicate that the CIDT methodology constitutes
a viable and convenient alternative to the procedures described
Scheme 10
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resolution only after having verified the best performances. Only
two main signals, corresponding to four stereoisomers of the
eight theoretically possible, are shown by HPLC analysis, each
representative of a single racemic diastereoisomer, and the entity
of their presence in the mixture can be monitored during an
acid promoted CIDT process carried out as we have depicted.
This approach allows the choice of the acid and the correct
concentration of the acid in methanol, or other solvents, too.
9 : 1, 1 mL min-1, l = 245 nm, 20 ◦C: tR = 6.9) of a sample of the
solid revealed the complete conversion of the aldehyde into the
naphthoxazine (1S,3R,R)-3a. The white solid was collected by
◦
filtration in 97% yield: mp = 182–185 C; [a]2D1 -134.3 (c 1.29,
1
CH2ClCH2Cl). H NMR (400 MHz, CDCl3) d: 7.76–7.69 (m,
2H), 7.36–7.30 (m, 1H), 7.30–7.21 (m, 7H), 7.08 (d, J = 9.0 Hz,
1H), 6.45 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 1.6 Hz, 1H), 6.18 (dd,
J = 7.8 and 1.7 Hz, 1H), 5.84–5.81 (m, 2H), 5.51 (s, 1H), 4.51
(d, J = 3.4 Hz, 1H), 2.64 (dd, J = 13.4 and 8.1 Hz, 1H), 2.42
(bs, 1H), 2.38 (dd, J = 13.4 and 6.8 Hz, 1H), 2.18–2.06 (m, 1H),
0.99 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 153.0,
147.3, 145.4, 142.9, 134.0, 131.7, 129.4, 129.0, 128.6, 128.4,
128.1, 127.2, 126.4, 123.0, 122.9, 121.9, 119.2, 114.5, 109.3,
107.8, 100.5, 83.6, 53.8, 39.4, 38.4, 13.5. IR (KBr): 3357.9,
3070.1, 2893.0, 1616.6, 1590.8, 1487.6, 1435.9, 1391.7, 1240.5,
1185.2, 1041.5, 930.9, 816.6, 748.8, 719.6 cm-1.
Experimental
General experimental
(S)-1-(a-aminobenzyl)-2-naphthol [(S)-1] has been obtained
enantiomerically pure by the efficient and practical kinetic
resolution of racemic 1-(a-aminobenzyl)-2-naphtol (Betti
base, rac-1)31 with L-(+)-tartaric acid in acetone, developed
by Hu and co-workers,32 based on an enantioselective
N,O-deketalization. Racemic 3-(benzo[d][1,3]dioxol-5-yl)-2-
Synthesis of (1S,3R)-3-((S)-1-(benzo[d][1,3]dioxol-5-yl)-
propan-2-yl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxa-
zine [(1S,3R,S)-3a]. (S)-1-(a-Aminobenzyl)-2-naphthol [(S)-
1], (2.5 g, 10 mmol) was suspended in methanol (5 mL mmol-1)
in a 100 mL round-bottomed flask with a stirring bar and
R
methylpropanal (Helionalꢀ, rac-2a), (4-tert-butylphenyl)-2-
R
methylpropanal (Lilial,ꢀ rac-2b), 3-(4-isopropylphenyl)-2-
methylpropanal (Cyclamal, rac-2c), 3-(4-methoxyphenyl)-
R
2-methylpropanal (Cantoxalꢀ, rac-2d) are commercial
(S)-3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal
[(S)-2a,
compounds and were used as obtained. Samples of (S)-(-)-
er = 97.8 : 2.2] (2.5 g, 10 mmol) was added. The mixture was
maintained at ambient temperature under stirring for 2 h. Chiral
R
R
Helionalꢀ (er = 97.8 : 2.2) and (R)-(+)-Helionalꢀ (er = 98.4 : 1.6)
were kindly furnished by ENDURA S.p.A
–
Ravenna
2-(4-methoxybenzyl)-3-methylbutanal
2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-
R
HPLC analysis (CHIRALPAKꢀ AD-H, hexane/i-PrOH =
90 : 10, 1 mL min-1, l = 245 nm, 20 ◦C: tR = 8.2 min) of a
sample of the solid revealed the complete conversion of the
aldehyde into the naphthoxazine (1S,3R,S)-3a. The white solid
was collected by filtration in 96% yield: mp = 147–150 ◦C; [a]D22
+40.1 (c 1.12, CH2ClCH2Cl). 1H NMR (400 MHz, CDCl3)
d: 7.77–7.65 (m, 2H), 7.35–7.28 (m, 1H), 7.28–7.18 (m, 7H),
7.13 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 6.58 (d,
J = 1.6 Hz, 1H), 6.48 (dd, J = 8.0 and 1.7 Hz, 1H), 5.85 (s,
2H), 5.48 (s, 1H), 4.49 (d, J = 5.1 Hz, 1H), 2.87 (dd, J = 13.4
and 4.4 Hz, 1H), 2.41 (bs, 1H), 2.38 (dd, J = 13.4 and 9.5 Hz,
1H), 2.03–1.92 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d: 152.8, 147.3, 145.5, 142.9, 134.0, 131.9,
129.3, 129.0, 128.6, 128.4, 128.1, 127.1, 126.5, 123.1, 122.8,
122.1, 119.3, 114.5, 109.6, 107.9, 100.6, 84.5, 53.9, 39.6, 37.9,
13.4. IR (KBr): 3357.8, 3062.2, 2938.6, 2882.2, 1619.3, 1596.6,
1508.0, 1468.4, 1444.5, 1405.7, 1328.1, 1233.3, 1136.1, 1012.3,
945.0, 901.3, 808.7, 753.8, 736.7, 705.2 cm-1.
(Italy).
Racemic
and
(rac-2e)
3-methylbutanal (rac-2f) were prepared by reduction (DiBAH)
of, respectively, ethyl 2-(4-methoxybenzyl)-3-methylbutanoate
and
ethyl
2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-
methylbutanoate prepared according to a well established
procedure consisting into the synthesis of, respectively, ethyl
(E)-ethyl 2-(4-methoxybenzylidene)-3-methylbutanoate and
(E)-ethyl
2-[4-methoxy-3-(3-methoxypropoxy)benzylidene]-
3-methylbutanoate33 followed by palladium catalyzed
hydrogenation (Electronic Supplementary Information,
ESI†). Dowex 50WX8-100 has been purchased from Aldrich
and used as received. During the crystallization-induced
diastereoisomer transformations (CIDT), the diastereisomer
ratios (dr) of naphthoxazines 3a–f were monitored by HPLC
R
analysis using a chiral Daicel CHIRALPAKꢀ AD-H column
and by 1H NMR. The enantiomeric excess (ee) of the aldehydes
2a, 2d–f were indirectly determined, by analysis of the
R
corresponding alcohols using a chiral Daicel CHIRALCELꢀ
Synthesis of (1S,3R,SR)-3-(1-arylalk-3-yl)-1-phenyl-2,3-
R
OD-H column (4a, 4e–f) or a chiral Daicel CHIRALCELꢀ
dihydro-1H-naphtho[1,2-e][1,3]oxazine
[(1S,3R,SR)-3a–e]:
General procedure. (S)-1-(a-Aminobenzyl)-2-naphthol [(S)-
1], (2.5 g, 10 mmol) was suspended in methanol (5 mL mmol-1)
in a 100 mL round-bottom flask with a stirring bar and racemic
aldehyde (rac-2a–c) was added in a slight excess. The mixture
was maintained at ambient temperature under stirring for 2 h.
Chiral HPLC analysis of a sample of the solid revealed the
complete conversion of the aldehyde into a 1 : 1 mixture of two
epimeric 1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines
(1S,3R,R)-3a–e and (1S,3R,S)-3a–e. The solid was collected by
filtration in a almost quantitative yield.
OJ-H column (4d). The enantiomeric excess of aldehydes 2b–c
has been indirectly determined by analysis of the corresponding
R
p-methoxybenzoates 5b–c using a chiral Daicel CHIRALCELꢀ
OD-H column.
Synthesis of (1S,3R)-3-((R)-1-(benzo[d][1,3]dioxol-5-yl)-
propan-2-yl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxa-
zine [(1S,3R,R)-3a]. (S)-1-(a-Aminobenzyl)-2-naphthol [(S)-
1], (2.5 g, 10 mmol) was suspended in methanol (5 mL mmol-1)
in a 100 mL round-bottomed flask with a stirring bar and
(R)-3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal
[(R)-2a,
dr = 98.4 : 1.6] (2.5 g, 10 mmol) was added. The mixture was
maintained for 2 h at ambient temperature under stirring. Chiral
(1S,3R,SR)-3-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-1-
phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine [(1S,3R,SR)-
3a]. 95% yield of a white solid consisting into a 1 : 1 mixture
R
HPLC analysis (CHIRALPAKꢀ AD-H, hexane/i-PrOH =
1752 | Green Chem., 2010, 12, 1747–1757
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©

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of (1S,3R,S) and (1S,3R,R) isomers (HPLC analysis with
the suspension was filtered to afford naphthoxazine (1S,3R,R)-
3a (dr = 93 : 7) as a solid (95% yield).
-1
R
CHIRALPAKꢀ AD-H, hexane/i-PrOH = 90 : 10, 1 mL min ,
◦
l = 245 nm, 20 C: tR = 6.9 and 8.2 min), [a]2D1 -114.5 (c 1.05,
Further enrichment of (1S,3R,R)-3a by CIDT procedure.
CIDT conditions: 2.5% AcOH, MeOH, 10 mL mmol-1,
65 ◦C. The reaction was performed by using naphthoxazine
(1S,3R,R)-3a (dr = 98.3 : 1.7). After 22 h the suspension was
filtered to afford (1S,3R,R)-3a in 95% yield with dr = 99 : 1.
CH2ClCH2Cl).
(1S,3R,SR)-3-(1-(4-tert-butylphenyl)propan-2-yl)-1-phenyl-
2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine
[(1S,3R,SR)-3b].
97% yield of a white solid consisting into 1 : 1 mixture of
R
(1S,3R,S) and (1S,3R,R) (HPLC analysis with CHIRALPAKꢀ
CIDT of (1S,3R,SR)-3-(1-(4-tert-butylphenyl)propan-2-yl)-1-
phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine [(1S,3R,SR)-
3b]. CIDT conditions: 10% AcOH, MeOH, 3 mL mmol-1,
60 ◦C. After 60 h the suspension was filtered to afford (1S,3R,S)-
3b as a solid (96% yield, dr = 90 : 10). [a]2D0 +20.5 (c 1.09,
AD-H, hexane/i-PrOH = 95 : 5, 1 mL min-1, l = 230 nm, 25 ◦C:
tR = 4.1 and 4.9 min); [a]2D0 -38.9 (c 1.08, CH2ClCH2Cl).
(1S,3R,SR)-3-(1-(4-isoproylphenyl)propan-2-yl)-1-phenyl-2,3-
dihydro-1H-naphtho[1,2-e][1,3]oxazine [(1S,3R,SR)-3c]. 96%
yield of a white solid consisting into 1 : 1 mixture of (1S,3R,S)
1
CH2ClCH2Cl2); (1S,3R,S)-3b (HPLC tR = 4.9 min). H NMR
(400 MHz, CDCl3) d: 7.78–7.70 (m, 2H), 7.37–7.31 (m, 1H),
7.31–6.98 (m, 12H), 5.54 (s, 1H), 4.52 (d, J = 5.0 Hz, 1H), 2.93
(dd, J = 13.3 and 4.6 Hz, 1H), 2.49 (bs, 1H), 2.47 (dd, J = 13.3
and 9.3 Hz, 1H), 2.05 (m, 1H), 1.28(s, 9H), 0.95 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) d: 152.9, 148.5, 142.9, 137.0,
131.7, 129.3, 129.0, 128.9, 128.6, 128.4, 128.2, 127.1, 126.5,
124.9, 123.0, 122.8, 119.3, 114.5, 84.6, 53.9, 39.3, 37.6, 34.3, 31.4,
13.6. Minor isomer (1S,3R,S)-3b diagnostic signals; (HPLC tR =
R
and (1S,3R,R) isomers (HPLC analysis with CHIRALPAKꢀ
AD-H, hexane/i-PrOH = 90 : 10, 1 mL min-1, l = 245 nm,
20 ◦C: tR = 4.0 and 4.6 min) [a]D21 -46.3 (c 1.00, CH2ClCH2Cl).
(1S,3R,SR)-3-(1-(4-methoxyphenyl)propan-2-yl)-1-phenyl-
2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine
[(1S,3R,SR)-3d].
96% yield of a white solid consisting into 1 : 1 mixture
of (1S,3R,S) and (1S,3R,R) isomers (HPLC analysis with
1
-1
4.1 min) H NMR (400 MHz, CDCl3) d: 6.74(d, J = 8.2 Hz,
R
CHIRALPAKꢀ AD-H, hexane/i-PrOH = 95 : 5, 1 mL min ,
l = 230 nm, 20 ◦C: tR = 7.6 and 8.5 min); [a]2D0 -42.5 (c 0.99,
2H), 2.68(dd, J = 13.4 and 8.2 Hz, 1H), 2.18(m, 1H), 1.24(s,
9H), 1.01(d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 153.1, 148.2, 142.9, 137.0, 131.6, 129.5, 129.0, 128.9, 128.6,
128.3, 128.1, 127.0, 126.4, 124.9, 123.0, 122.9, 119.2, 114.4, 83.6,
53.8, 39.2, 38.2, 34.2, 31.3, 13.6.
CH2ClCH2Cl).
(1S,3R,SR)-3-(1-(4-methoxyphenyl)-3-methylbutan-2-yl)-1-
phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine [(1S,3R,SR)-
3e]. 91% yield of a white solid consisting of 1 : 1 mixture
CIDT of (1S,3R,SR)-3-(1-(4-isoproylphenyl)propan-2-yl)-1-
phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine [(1S,3R,SR)-
3c]. CIDT conditions: 10% AcOH, MeOH, 10 mL mmol-1,
60 ◦C. After 60 h the suspension was filtered to afford (-)-3c as a
solid (83% yield, dr = 75 : 25). [a]2D0 -105.0 (c 1.00, CH2ClCH2Cl).
Major isomer (HPLC tR = 4.0 min) 1H NMR (400 MHz,CDCl3)
d: 7.75–7.65 (m, 2H), 7.36–7.17(m, 8H), 7.12–7.04 (m, 1H), 6.90
(d, J = 7.8 Hz, 2H), 6.74 (d, J = 7.8 Hz, 2H), 5.51 (s, 1H), 4.51
(d, J = 3.5 Hz, 1H), 2.87–2.68 (m, 1H), 2.69 (dd, J = 13.3 and
8.1 Hz, 1H), 2.43 (dd, J = 13.3 and 6.7 Hz, 1H), 2.38 (bs, 1H),
2.16 (m, 1H), 1.17 (d, J = 6.9 Hz, 6H), 1.00 (d, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) d: 153.1, 146.0, 142.9, 137.4,
131.7, 129.5, 129.0, 128.9, 128.6, 128.4, 128.1, 127.1, 126.4,
126.1, 123.0, 122.9, 119.3, 114.5, 83.7, 53.8, 39.2, 38.3, 33.6,
24.1, 23.9, 13.5; Minor isomer (+)-3c diagnostic signals; (HPLC
tR = 4.6 min) 1H NMR (400 MHz, CDCl3) d: 5.48(s, 1H), 2.92
(dd, J = 13.4 and 4.4 Hz, 1H), 2.03 (m, 1H), 1.20 (d, J = 6.9 Hz,
6H), 0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 152.9, 146.2, 142.9, 137.4, 131.7, 129.3, 129.2, 129.0, 128.6,
128.4, 128.2, 127.1, 126.5, 126.1, 123.0, 122.9, 119.2, 114.4, 84.6,
53.9, 39.4, 37.7, 33.6, 24.04, 23.96, 13.6
1
of (1S,3R,S) and (1S,3R,R) isomers determined by H NMR
analysis: (400 MHz, C6D6) diagnostic signals; (1S,3R,R)-3e d:
5.16(s, 1H), 4.80(bs, 1H) 3.36 (s, 3H), 2.86 (dd, J = 13.8 and
4.7 Hz, 1H), 2.45 (dd, J = 13.8 and 7.5 Hz, 1H), 0.85 (d, J =
6.8 Hz, 3H) 0.80 (d, J = 6.8 Hz, 3H); (1S,3R,3S)-3e34 d: 5.13 (s,
1H), 4.73 (bs, 1H), 3.31 (s, 3H), 2.79 (dd, J = 13.8 and 8.7 Hz,
1H), 2.56 (dd, J = 13.8 and 5.0 Hz, 1H), 0.96 (d, J = 6.9 Hz 3H),
0.90 (d, J = 6.9 Hz, 3H; [a]2D0 +19.9 (c 1.12, CH2ClCH2Cl); [a]2D0
+19.9 (c 1.12, CH2ClCH2Cl).
CIDT of (1S,3R,SR)-3-(1-arylalk-3-yl)-1-phenyl-2,3-dihydro-
1H-naphtho[1,2-e][1,3]oxazines (1S,3R,SR)-3a–e: General pro-
cedure. The 1 : 1 diastereoisomeric mixture of (1S,3R,S)- and
(1S,3R,R)-oxazine 3a–e was suspended in methanol and acetic
acid was added as specified in each case. The solid was collected
by filtration after stirring at 60–68 ◦C for the time indicated.
Diastereoisomeric ratios (dr) were determined by HPLC analysis
as already described for the 1 : 1 mixtures of isomers.
CIDT of (1S,3R,SR)-3-(1-(benzo[d][1,3]dioxol-5-yl)propan-
2-yl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine [(1S,
3R,SR)-3a]. CIDT ◦ conditions: 2.5% AcOH, MeOH,
10 mL mmol-1, 65–68 C. After 24 h the suspension was filtered
to afford (1S,3R,R)-3a as a solid (84% yield, dr = 93 : 7), [a]D22
-128.3 (c 1.205, CH2ClCH2Cl). After 90 h: 83% yield, dr =
96 : 4.
CIDT of (1S,3R,SR)-3-(1-(4-methoxyphenyl)propan-2-yl)-1-
phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine [(1S,3R,SR)-
3d]. CIDT conditions: 5% AcOH, MeOH, 10 mL mmol-1,
60 ◦C. After 48 h the suspension was filtered to afford
(1S,3R,R)-3c as a solid (86% yield, dr = 73 : 23). [a]2D1 -81.5
(c 0.71, CH2ClCH2Cl). Major isomer (1S,3R,R)-3d (HPLC tR =
Epimerization of naphthoxazine (1S,3R,S)-3a by CIDT
into (1S,3R,R)-3a. CIDT conditions: 2.5% AcOH, MeOH,
10 mL mmol-1, 65 ◦C. The epimerization reaction was performed
by using naphthoxazine (1S,3R,S)-3a (dr = 97.8 : 2.2). After 32 h
1
7.6 min), H NMR (400 MHz,CDCl3) d: 7.76–7.66 (m, 2H),
7.36–7.30 (m, 1H), 7.30–7.21 (m, 7H), 7.07 (d, J = 8.9 Hz, 1H),
6.72 (m, 2H), 6.58 (m, 2H), 5.53 (s, 1H), 4.51 (d, J = 3.8 Hz, 1H),
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3.70 (s, 3H), 2.65 (dd, J = 13.5 and 8.3 Hz, 1H), 2.45 (bs, 1H),
2.41 (dd, J = 13.5 and 6.6 Hz, 1H), 2.13 (m, 1H), 1.00 (d, J =
87.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d: 157.5, 153.1,
143.0, 132.4, 131.7, 129.9, 129.5, 129.0, 128.6, 128.4, 128.2,
127.1, 126.4, 123.0, 122.9, 119.2, 114.4, 113.5, 83.6, 55.1, 53.8,
39.4, 37.8, 13.5. Minor isomer 1S,3R,S-3d diagnostic signals
133.1, 130.4, 129.9, 129.7, 129.5, 128.9, 127.9, 127.4, 123.95,
123.92, 122.2, 120.4, 115.9, 115.7, 113.3, 84.2, 70.0, 66.7, 58.9,
56.3, 54.7, 50.8, 32.7, 30.9, 28.4, 20.9, 20.2; IR (KBr): 3366.4,
3049.2, 2054.9, 2894.9, 2889.2, 2834.9, 2792.0, 1622.1, 1597.8,
1519.6, 1469.9, 1445.9, 1264.3, 1247.2, 1234.3, 1139.5, 1117.4,
886.6, 812.7 cm-1. Minor isomer (1S,3R,S)-3f diagnostic signals
(HPLC tR = 8.4 min), NMR (400 MHz,CDCl3) d: 5.13(s, 1H),
3.42(s, 3H), 3.05(s, 3H), 2.61(dd. J = 13.8 and 5.3 Hz, 1H),
0.94(d, J = 6.8 Hz, 3H), 0.90(d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d: 154.0, 150.1, 149.2, 144.0, 135.3, 133.1,
130.5, 129.9, 129.7, 129.4, 129.1, 127.8, 127.3, 124.0, 123.9,
122.4, 120.3, 115.7, 115.6, 113.2, 84.9, 70.0, 66.7, 58.9, 56.2,
54.6, 51.4, 33.4, 30.9, 29.2, 21.4, 20.8.
1
(HPLC tR = 8.5 min), H NMR (400 MHz,CDCl3) d: 3.72(s,
3H), 2.88(dd. J = 13.5 and 4.4 Hz, 1H), 1.99(m, 1H), 0.92(d, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d: 157.7, 152.8, 142.9,
132.1, 131.7, 130.2, 129.3, 128.9, 128.5, 128.4, 128.2, 127.6,
126.4, 123.0, 122.8, 119.3, 114.4, 113.5, 84.6, 55.2, 53.9, 39.5,
37.2, 13.5.
CIDT of (1S,3R,SR)-3-(1-(4-methoxyphenyl)-3-methylbutan-
2-yl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine [(1S,
3R,SR)-3e]. CIDT conditions: 5% AcOH, MeOH,
10 mL mmol-1, 60 ◦C. After 48 h the suspension was
filtered to afford (1S,3R,R)-3e as a solid (85% yield, dr =
The naphthoxazines 3f, recovered from the mother liquor
of crystallization, were added to the original methanol–AcOH
filtrate of the CIDT reaction. After stirring for 64 h at ambient
temperature a second crop of (1S,3R,R)-3f (0.655 g, 21.9%, dr =
98.4 : 1.6) was obtained simply by filtration.
◦
97 : 3). [a]1D9 +130.2 (c 0.84, CH2ClCH2Cl2), mp = 154–156 C.
(1S,3R,R)-isomer: 1H NMR (400 MHz,C6D6) d: 7.78–7.68 (m,
2H), 7.36–7.31 (m, 1H), 7.30–7.08 (m, 10H), 6.79 (d, J = 8.7 Hz,
2H), 5.52 (s, 1H), 4.70 (d, J = 4.0 Hz, 1H), 3.78 (s, 3H), 2.79
(dd, J = 13.8 and 5.4 Hz, 1H), 2.56 (dd, J = 13.8 and 6.9 Hz,
1H), 2.40 (bs, 1H), 2.03–1.86 (m, 2H), 0.84 (d, J = 6.7 Hz, 3H),
0.81 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, C6D6) d: 159.1,
154.2, 144.0, 134.8, 133.2, 131.1, 130.5, 130.0, 129.9, 129.6,
129.0, 128.0, 127.5, 124.04, 124.02, 120.5, 115.8, 114.8, 84.3,
55.5, 54.8, 51.0, 32.3, 28.4, 21.0, 20.3; IR (KBr): 3328.7, 3055.5,
3023.6, 2958.0, 2932.0, 1621.7, 1597.0, 1513.5, 1462.8, 1244.0,
1233.8, 1029.4, 896.5, 822.3, 803.3, 749.7, 736.9, 699.8 cm-1.
Hydrolysis of diastereoisomerical enriched naphtoxazines
3a–f to non racemic aldehydes 2a–f: General procedure. To a
suspension36 of diastereoisomerical enriched naphthooxazines
3a–f in THF : EtOAc 1 : 1 (4 mL mmol-1) a 2% aqueous solution
of TsOH (0.2 mL mmol-1) and Dowex 50WX8-100 (2g mmol-1)
were added. The resulting mixture was stirred for 13–14 h during
which time the organic solids progressively dissolved. The resin
was filtered and washed with Et2O (three times with 4 mL g-1
of resin). The organic solution was transferred into a separator
funnel and the red aqueous phase was removed. The organic
solution was then cooled with a water-ice bath and neutralized
by addition of saturated aqueous solution of Na2CO3. The
organic layer was then washed with water, brine and dried over
Na2SO4. After solvent distillation the non racemic aldehydes
2a–f were purified by bulb to bulb distillation:
Synthesis of (1S,3R,R)-3-(1-(4-methoxy-3-(3-methoxypro-
poxy)phenyl)-3-methylbutan-2-yl)-1-phenyl-2,3-dihydro-1H-na-
phtho[1,2-e][1,3]oxazine [(1S,3R,R)-3f] through
a one-pot
condensation-CIDT process. Racemic aldehyde 2f (1.72 g,
5.83 mmol) was added dropwise to a stirred suspension of
(S)-1-(a-aminobenzyl)-2-naphthol [(S)-1], (1.4 g, 5.77 mmol)
in methanol (28.8 mL) and the mixture was warmed to 55–
60 ◦C. After 15 min HPLC and NMR analysis of an aliquot
of the solution showed two diastereoisomeric compounds in
(R)-3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanal
[(R)-2a].
1
Colorless oil (90% yield), [a]2D0 +4.1 (c 1.30, CHCl3), H and
13C NMR spectra are in agreement with those previously
reported.13b
(S)-3-(4-tert-butylphenyl)-2-methylpropanal [(S)-2b]. Color-
less oil (99% yield), [a]D26 +3.4 (c 1.03, CHCl3); for (R)-2b, lit14b
R
1 : 1 ratio (CHIRALPAKꢀ AD-H, hexane/i-PrOH = 90 : 10,
1 mL min-1, l = 230 nm, 20 ◦C: tR = 8.4 and 10.0 min).
After 30 min a solution of acetic acid in methanol (9 : 1 ratio,
28.8 mL) was added and the reaction was left to cool at ambient
temperature under an efficient stirring. Within few minutes a
solid product began to form and the resulting suspension was
stirred for an additional 24 h. The naphthoxazine (1S,3R,R)-3f
(white solid,35 2.208 g, 72.8% yield, dr = 96.4 : 3.6) was collected
by filtration. The diastereoisomeric purity of (1S,3R,R)-3f was
further increased to dr = 99.5 : 0.5 (1.94 g, 64% overall yield)
by crystallization from diisopropyl ether (66 mL): mp = 108–
110 ◦C; (HPLC tR = 10.0 min), [a]D20 +83.3 (c 1.03, PhCH3);
1H NMR (400 MHz, C6D6) d: 7.76–7.70 (m, 1H), 7.57 (d, J =
9.0 Hz, 1H), 7.41–7.35 (m, 1H), 7.32–7.24 (m, 3H), 7.15–6.93
(m, 6H), 6.82 (dd, J = 8.2 and 2.0 Hz, 1H), 6.65 (d, J = 8.2 Hz,
1H), 5.18 (s, 1H), 4.88–4.78 (m, 1H), 4.06–3.93 (m, 2H), 3.47
(s, 3H), 3.42–3.35 (m, 2H), 3.06 (s, 3H), 2.90 (dd, J = 13.8 and
5.0 Hz, 1H), 2.51 (dd, J = 13.8 and 7.6 Hz, 1H), 2.11–1.93 (m,
5H), 0.87 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H); 13C
NMR (100 MHz, C6D6) d: 154.1, 150.1, 149.3, 143.9, 135.4,
1
[a]2D5 -5.1 (c 1.00, CHCl3), H and 13C NMR spectra are in
agreement with those previously reported.9
(-)-3-(4-isopropylphenyl)-2-methylpropanal [(-)-2c]. Color-
less oil (93% yield), [a]2D3 -3.1 (c 1.88, CHCl3); 1H NMR
spectrum is in agreement with that previously reported.37 13C
NMR (100 MHz, CDCl3) d: 204.9, 147.3, 136.5, 129.3, 126.9,
48.4, 36.7, 34.1, 24.4, 13.6.
(R)-3-(4-methoxyphenyl)-2-methylpropanal [(R)-2d]. Color-
less oil (88% yield), [a]2D4 -1.6 (c 1.50, CHCl3); 1H and 13C NMR
spectra are in agreement with those previously reported.38
(-)-2-(4-methoxybenzyl)-3-methylbutanal [(-)-2e]. Colorless
oil (95% yield), [a]2D1 -36.4 (c 1.89, CHCl3); 1H NMR (400 MHz,
CDCl3) d: 9.68 (d, J = 2.7 Hz, 1H), 7.07 (m, 2H), 6.81 (m, 2H),
6.79 (m, 1H), 3.77 (s, 3H), 2.93 (dd, J = 14.3 and 9.2 Hz, 1H),
2.71 (dd, J = 14.3 and 5.1 Hz, 1), 2.46 (m, 1H), 2.05 (m, 1H),
0.96 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d: 205.2, 158.0, 131.5, 129.8, 113.9, 59.9,
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55.2, 31.2, 28.2, 19.9, 19.8; IR (film): 2960.8, 2873.6, 2835.7,
2717.6, 1724.0, 1612.1, 1513.2, 1465.2, 1247.9, 1178.4, 1036.2,
911.0, 733.2 cm-1.
(+)-3-(4-methoxyphenyl)-3-methylbutan-1-ol,
[(+)-4e]. Rf
0.37, colorless oil obtained in 93% yield with 92% ee, determined
R
by HPLC analysis using a CHIRALCELꢀ OD-H column,
hexane/i-PrOH = 95 : 5, 1 mL min-1, l = 230 nm, 25 ◦C: (S)-4c
tR = 8.9 and (R)-4c tR = 12.1 min. [a]2D1 +11.5 (c 1.74, CHCl3).
1H NMR (400 MHz, CDCl3) d: 7.10 (m, 2H), 6.83 (m, 2H),
3.78 (s, 3H), 3.54 (d, J = 5.6 Hz, 2H), 2.65 (dd, J = 13.8 and
5.5 Hz, 1H), 2.46 (dd, J = 13.8 and 9.1 Hz, 1H), 1.90–1.78 (m,
1H), 1.66–1.57 (m, 1H), 1.22 (bs, 1H), 0.97 (d, J = 6.9 Hz, 3H),
0.95 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 157.7,
133.3, 129.8, 113.7, 62.9, 55.2, 48.8, 33.4, 27.7, 19.6, 19.4. IR
(film): 3368.0, 2955.8, 2834.5, 1611.4, 1512.0, 1465.5, 1246.8,
1177.3, 1037,3, 818.2 cm-1.
(R)-2-(4-methoxy-3-(3methoxypropoxy)benzyl)-3-methylbu-
tanal [(R)-2f]. Colorless oil (95% yield), [a]1D8 -28.2 (c 1.02,
1
CHCl3); H NMR (400 MHz, CDCl3) d: 9.68 (d, J = 2.8 Hz,
1H), 6.77 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.69
(dd, J = 8.1 and 2.0 Hz, 1H), 4.09 (t, J = 6.5 Hz, 2H), 3.82 (s,
3H), 3.57 (t, J = 6.2 Hz, 2H), 3.36 (s, 3H), 2.92 (dd, J = 14.2 and
9.2 Hz, 1H), 2.70 (dd, J = 14.2 and 5.0 Hz, 1H), 2.50–2.44 (m,
1H), 2.14–1.99 (m, 3H), 1.04 (d, J = 8.0 Hz, 3H), 1.03 (d, J =
8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d: 205.2, 148.4, 147.9,
132.1, 121.0, 114.1, 111.9, 69.3, 66.0, 59.7, 58.6, 56.0, 31.7, 29.6,
28.3, 19.9, 19.8; IR(film): 2959.3, 2931.9, 2874.3, 2834.0, 2723.3,
1722.3, 1607.0, 1590.0, 1515.9, 1464.9, 1442.9, 1261.2, 1236.8,
1140.1, 1120.5, 1027.5 cm-1.
(R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl-
butan-1-ol, [(R)-4f]. Purified by bulb to bulb distillation and
obtained as colorless oil in 98% yield with 97.5% ee, determined
R
by HPLC using a CHIRALCELꢀ OD-H column, hexane/i-
Reduction of non racemic aldehydes 2a–f to non racemic
alcohols 4a–f: General procedure. NaBH4 (2 eq.) was added to
a water-ice cooled solution of enriched aldehyde 2a–f in MeOH
(2 mL mmol-1). The resulting solution was stirred for 1 h at
0 ◦C and 1 h at ambient temperature. After solvent evaporation
the residue was partitioned between 2N HCl (2 mL mmol-1
of aldehyde) and CH2Cl2. The organic layer was washed with
water, brine and dried over MgSO4. After solvent evaporation,
the residue was directly purified by flash-chromatography on
silica gel (Pet. Ether/Et2O = 3 : 2).
PrOH = 97 : 3, 1 mL min-1, l = 230 nm, 20 ◦C: (S)-4c tR
=
22.2 and (R)-4c tR = 24.7 min. [a]1D8 +8.5 (c 1.49, CHCl3). H
and IR spectra coincided with those previously reported.28d 13C
NMR (100 MHz, CDCl3) d: 148.2, 147.5, 134.0, 121.1, 114.2,
111.7, 69.3, 65.9, 62.7, 58.5, 55.9, 48.6, 33.9, 29.5, 27.6, 19.5,
19.4.
1
Synthesis of 4-methoxybenzotes 5b–c from non racemic alco-
hols 4b–c: General procedure. To a solution of alcohol 4b–c in
CHCl3 (filtered on neutral alumina), 1 mL mmol-1, and Et3N
◦
(2 eq) at 0 C was added 4-methoxybenzoyl chloride (1.5 eq).
(R)-3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropan-1-ol,
[(R)-
After 2 h the cold bath was removed and the reaction was
stirred at ambient temperature for 13 h. Et2O (10 mL mmol-1 of
substrate) was added and washed, in succession, with HCl 1 N,
water (three times) and brine. The organic solution was dried on
MgSO4 and after solvent evaporation ester 5b–c were isolated
by flash chromatography on silica gel (Pet. Ether/Et2O = 4 : 1)
4a]. Rf 0.33, colorless oil obtained in 88% yield with 86% ee,
R
determined by HPLC using a CHIRALCELꢀ OD-H column,
hexane/i-PrOH = 95 : 5, 1 mL min-1, l = 254 nm, 25 ◦C: (R)-4a
tR = 11.4 and (S)-4a tR = 12.5 min. [a]2D0 +9.9 (c 1.34, CHCl3);
1
lit:13b ee = 90% [a]D22 +11.1 (c 0.98, CHCl3); H and 13C NMR
spectra coincided with those previously reported.13b
(S)-3-(4-tert-butylphenyl)-2-methylpropyl 4-methoxybenzoate
[(S)-5b]. Colorless oil obtained in 98% yield with 70% ee,
determined by HPLC analysis using a CHIRALCELꢀR OD-
H column, hexane/i-PrOH = 95 : 5, 1 mL min-1, l = 254 nm,
25 ◦C: (S)-5b tR = 5.4 and (R)-5b tR = 9.1 min. [a]2D6 +18.0 (c
S)-3-(4-tert-butylphenyl)-2-methylpropan-1-ol, [(S)-4b]. Rf
0.39, colorless oil obtained in 84% yield. [a]2D6 -2.4 (c 1.25,
1
CHCl3), lit:39 ee = 99%, [a]D -4.9 (c 2.5, CHCl3). H and 13C
NMR spectra coincided with those previously reported.39
1
(+)-3-(4-isopropylphenyl)-2-methylpropan-1-ol, [(+)-4c]. Rf
0.38,◦colorless oil obtained in 90% yield after distillation, bp =
128 C at 1 mmHg. [a]D24 +5.0 (c 1.87, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 7.16–7.12 (m, 2H), 7.11–7.07 (m, 2H),
3.53 (dd, J = 10.6 and 5.8 Hz, 1H), 3.46 (dd, J = 10.6 and 6.0 Hz,
1H), 2.88 (hept, J = 6.9 Hz, 1H), 2.70 (dd, J = 13.5 and 6.4 Hz,
1H), 2.40 (dd, J = 13.5 and 8.6 Hz, 1H), 1.93 (m, 1H), 1.43 (bs,
1H), 1.24 (d, J = 6.9 Hz, 6H), 0.92 (d, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d: 146.4, 137.8, 129.0, 126.3, 67.7, 39.3, 37.8,
33.6, 24.0, 16.5; IR (film) 3340.0, 2958.8, 2925.5, 2871.1, 1512.2,
1461.1, 1419.9, 1382.1, 1034.8, 986.2, 846.8, 799.8 cm-1.
1.39, CHCl3). H NMR (400 MHz, CDCl3) d: 8.02–7.98 (m,
2H), 7.32–7.28 (m, 2H), 7.13–7.09 (m, 2H), 6.94–6.90 (m, 2H),
4.18 (dd, J = 10.8 and 5.8 Hz, 1H), 4.12 (dd, J = 10.8 and 6.2 Hz,
1H), 3.85 (s, 3H), 2.78 (dd, J = 13.7 and 6.5 Hz, 1H), 2.53 (dd,
J = 13.7 and 7.7 Hz, 1H), 2.24 (m, 1H), 1.30 (s, 9H) 1.02 (d,
J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 166.3, 163.3,
148.8, 136.5, 131.5, 128.8, 125.2, 122.9, 113.6, 66.8, 55.4, 39.4,
34.7, 34.3, 31.4, 17.0; IR (film): 2960.4, 1713.5, 1606.7, 1511.0,
1274.6, 1256.9, 1167.2, 1101.6 cm-1.
(-)-3-(4-isopropylphenyl)-2-methylpropyl 4-methoxybenzoate
[(-)-5c]. Colorless oil obtained in 95% yield with 50% ee,
R
(R)-3-(4-methoxyphenyl)-2-methylpropan-1-ol, [(R)-4d]. Rf
determined by HPLC analysis using a CHIRALCELꢀ OD-H
0.28, colorless oil obtained in 92% yield with 42% ee, determined
column, hexane/i-PrOH = 95 : 5, 1 mL min-1, l = 254 nm, 25 ◦C:
minor isomer-5b tR = 7.6 and major-5b tR = 10.5 min. [a]2D4 -13.5
(c 2.34, CHCl3). 1H NMR (400 MHz, CDCl3) d: 8.02–7.97 (m,
2H), 7.16–7.08 (m, 4H), 6.94–6.89 (m, 2H), 4.18 (dd, J = 10.8 and
5.9 Hz, 1H), 4.12 (dd, J = 10.8 and 6.2 Hz, 1H), 3.84 (s, 3H), 2.87
(m, 1H), 2.78 (dd, J = 13.6 and 6.6 Hz, 1H), 2.52 (dd, J = 13.6
and 7.7 Hz, 1H), 2.23 (m, 1H), 1.23 (d, J = 7.0 Hz, 6H) 1.02 (d,
R
by HPLC analysis using a CHIRALCELꢀ OJ-H column,
hexane/i-PrOH = 90 : 10, 1 mL min-1, l = 230 nm, 25 ◦C: (R)-4d
tR = 9.4 and (S)-4d tR = 10.5 min. [a]2D5 +4.7 (c 1.43, CHCl3);
lit40 99% ee, [a]D25 +12.9 (c 0.96, CHCl3). 1H NMR spectrum is in
agreement with that previously reported.40 13C NMR (100 MHz,
CDCl3) d: 157.8, 132.6, 130.0, 113.7, 67.6, 55.2, 38.8, 37.9, 16.4.
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J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 166.2, 163.1,
146.3, 137.1, 131.4, 128.9, 126.2, 122.8, 113.5, 68.8, 55.3, 39.6,
34.8, 33.8, 24.13, 24.06, 17.0; IR (film) 3008.2, 2959.9, 2932.8,
2840.8, 1713.6, 1606.5, 1511.8, 1462.6, 1316.1, 1257.4, 1167.1,
1101.9, 1031.3, 847.0, 770.5, 696.3 cm-1.
Acknowledgements
This research was supported in part by Alma Mater Studio-
rum – Universita` di Bologna, and MiUR, Italy (PRIN 2007:
“Metodologie stechiometriche e catalitiche innovative per la
sintesi enantio- e diastereoselettiva di molecole organiche target
polifunzionalizzate”; 2007FJC4SF_004).
(R)-2-(4-methoxybenzyl)-3-methylbutyl 4-methylbenzenesul-
fonate, [(R)-5e]. To a solution of (R)-4e (208 mg, 1 mmol)
in CHCl3 (2 mL, filtered on neutral alumina) and Et3N (202 mg,
2 mmol) at 0 ◦C p-toluenesulfonyl chloride (286 mg, 1.5 mmol)
was added. After 30 min the cold bath was removed. The reaction
was allowed to stand at ambient temperature for 9 h, then
Et2O (10 mL) was added and the organic phase was washed,
in succession, with HCl 1N, water (three times) and brine. The
organic solution was dried (MgSO4), the solvent distilled and
the crude product was purified by flash chromatography (Pet.
ether/Et2O = 4 : 1, Rf 0.27) to obtain 334 mg (92% yield) of
(R)-5e: crystallized from n-hexane, mp = 71–73 ◦C; 99.9% ee,
Notes and references
1 (a) For authoritative monographs, see: Comprehensive Asymmetric
Catalysis, ed., E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer,
Heidelberg, 1996; (b) I. Ojima, Asymmetric Synthesis, VCH,
Weinheim, 2nd ed., 2000; (c) M. Breuer, K. Ditrich, T. Habicher, B.
Hauer, M. Kesseler, R. Sturmer and T. Zelinsky, Angew. Chem., Int.
Ed., 2004, 43, 788–824; (d) V. Farina, J. T. Reeves, C. H. Senanayake
and J. J. Song, Chem. Rev., 2006, 106, 2734–2793; (e) S. Jaroch, H.
Weinmann and K. Zeitler, ChemMedChem, 2007, 2, 1261–1264; (f) A.
Dondoni and A. Massi, Angew. Chem., Int. Ed., 2008, 47, 2–25.
2 (a) H. U. Blaser, Chem. Commun., 2003, 293 and literature cited
therein; (b) H.-J. Federsel, Nat. Rev. Drug Discovery, 2005, 4, 685;
(c) Asymmetric Catalysis on Industrial Scale, ed., H. U. Blaser,
E. Schmidt, Wiley-VCH, Weinheim, 2004; (d) J. M. Hawkins and
T. J. N. Watson, Angew. Chem., Int. Ed., 2004, 43, 3224–3228.
3 (a) J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Race-
mates, and Resolutions, Wiley & Sons, New York, 1981; (b) For
a comprehensive survey of studies on this method for obtaining
enantiopure compounds, see: CRC Handbook of Optical Resolutions
via Diastereoisomeric Salt Formation, ed. David Kozma, CRC Press,
London, 2001; (c) E. Fogassy, M. Nogradi, D. Kozma, G. Egri, E.
Pa´lovics and V. Kiss, Org. Biomol. Chem., 2006, 4, 3011; (d) F. Faigl,
E. Fogassy, M. No´gra´di, E. Pa´lovics and J. Schindler, Tetrahedron:
Asymmetry, 2008, 19, 519–536.
4 (a) K. M. Brands and A. J. Davies, Chem. Rev., 2006, 106, 2711–2733;
(b) N. G. Anderson, Org. Process Res. Dev., 2005, 9, 800–813.
5 A common definition of “green chemistry” is “the design, develop-
ment, and implementation of chemical processes and products to
reduce or eliminate substances hazardous to human health and the
environment” (P. T. Anastas and J. Warner, Green Chemistry Theory
and Practice, Oxford Universirty Press, Oxford, 1998). A more recent
article expands this definition to twelve principles (; M. Poliakoff,
J. M. Fittzpatrick, T. R. Farren and P. T. Anastas, Science, 2002,
297, 807) reported also in; National Research Council- Committee
on Challenges for the Chemical Sciences in 21st Century, Beyond
the Molecular Frontier- Challenges for Chemistry and Engineering
Chemistry, The National Academy Press, Washington, D.C., 2003,
pp 150–153, www.nap.edu.
6 In general, the CIDT methods concerning a-substituted carbonyl
compounds rely upon well defined functional groups that intimately
participate to the process. See the examples quoted in the Supporting
Information Section of the reference 7.
7 J. Kosˇmrlj, L. O. Weigel, D. A. Evans, C. W. Downey and J. Wu,
J. Am. Chem. Soc., 2003, 125, 3208–3209.
8 (a) G. Rosini, C. Ayoub, V. Borzatta, E. Marotta, A. Mazzanti and
P. Righi, Green Chem., 2007, 9, 441–448; (b) G. Rosini, C. Ayoub, V.
Borzatta, A. Mazzanti, E. Marotta and P. Righi, Chem. Commun.,
2006, 4294–4296; (c) G. Rosini, V. Borzatta, F. Boschi, G. Candido,
E. Marotta and P. Righi, Chem. Commun., 2007, 2717–2719; (d) G.
Rosini, V. Borzatta, C. Paolucci and P. Righi, Green Chem., 2008, 10,
1146–1151.
9 (a) For a historical reports on the Betti reaction see: H. Wynberg,
J. Macromol. Sci., Part A: Pure Appl. Chem., 1989, A26, 1033; (b) G.
Rosini, La Chim. e l’Ind. (Milan), 1999, 81, 231–238; (c) G. Rosini,
Atti Acc. Scienze detta dei XV, 121, 2003, 27-I, 7–22; (d) For a review,
see: I. Szatma´ri and F. Fu¨lo¨p, Curr. Org. Synth., 2004, 1, 155–165;
(e) In the past decade interest in the Betti base has intensified. This
sort of “new life” for the Betti base derivatives is mainly due to
the great interest they aroused as chiral non racemic ligands and
auxiliaries in asymmetric synthesis (For selected references, see: C.
Cardellicchio, G. Ciccarella, F. Naso, E. Schingaro and F. Scordari,
Tetrahedron: Asymmetry, 1998, 9, 3667–3675; (f) C. Cardellicchio,
G. Ciccarella, F. Naso, F. Perna and P. Tortorella, Tetrahedron, 1999,
55, 14685–14692; (g) G. Palmieri, Tetrahedron: Asymmetry, 2000, 11,
R
determined by HPLC analysis using a CHIRALPAKꢀ AD-H
column, hexane/i-PrOH = 95 : 5, 1 mL min-1, l = 254 nm, 20 ◦C:
(R)-5e tR = 11.8 min [(S)-5e tR = 10.9 undetected]. [a]2D2 +28.4 (c
1.05, CHCl3). 1H NMR (400 MHz, CDCl3) d: 7.73 (m, 2H), 7.31
(m, 2H), 6.92 (m, 2H), 6.74 (m, 2H), 3.92 (dd, J = 9.7 and 4.8 Hz,
1H), 3.87 (dd, J = 9.7 and 5.3 Hz, 1H), 3.77 (s, 3H), 2.62 (dd,
J = 13.9 and 5.5 Hz, 1H), 2.42 (s, 3H), 2.39 (dd, J = 13.9 and
9.4 Hz, 1H), 1.79 (m, 1H), 1.66 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H),
0.88 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 157.9,
144.6, 133.0, 131.8, 129.8, 129.7, 127.9, 113.7, 70.1, 55.2, 46.0,
32.9, 27.6, 21.6, 19.6, 19.3; IR (KBr): 2973.7, 2933.6, 2872.2,
1610.8, 1597.6, 1511.7, 1354.6, 1244.8, 1190.0, 1175.3, 1038.6,
939.1, 912.1, 836.3, 819.5 cm-1.
´
´
(R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl-
butanoic acid, [(R)-5f]. To a solution of (R)-4f (195 mg,
0.5 mmol) in acetone (6.5 mL) at 0 ◦C, Jones reagent was
added dropwise until the orange colour persists (0.6 mL). After
60 min the reaction was quenched by isopropyl alcohol (0.5 mL)
addition and stirred for further 30 min. The solid salt was
eliminated by filtration on celite and washing with Et2O. The
organic layer was neutralized with aqueous NaHCO3 and the
organic solvents evaporated. The residue was taken up with
CH2Cl2 and washed with water, brine and dried on MgSO4.
After solvent evaporation the residue was purified by flash
chromatography (pet. ether/EtOAc 1 : 4) to give 123 mg (66%
yield) of (R)-5f as light yellow oil; [a]2D1 +36.8 (c 1.00, CH2Cl2),
lit28d [a]2D1 +42.1 (c 1.00, CH2Cl2); 13C NMR (100 MHz, CDCl3)
d: 180.0, 148.1, 147.9, 132.2, 120.9, 114.1, 111.8, 69.4, 65.9, 58.6,
55.9, 54.4, 35.0, 30.3, 29.4, 20.4, 19.9; 1H and IR spectra are in
agreement with those previously reported.28d
Recovery of (S)-Betti, [(S)-1]. The polymer-supported Betti
base, as recovered by filtration from hydrolysis of di-
astereoisomerical enriched naphtoxazines 3a-f, was treated
for three times and under slow stirring with a solution of
THF/NH4OHconc/MeOH in 8 : 2 : 1 ratio (3 mL g-1 polymer-
supported). After solvent evaporation under reduced pressure
the Betti base (S)-1 was recovery with 99% yield and er >
99.75 : 0.25.
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3361–3373; (h) D. Liu, L. Zhang, Q. Wang, C. Da, Z. Xin, R. Wang,
M. C. K. Choi and A. S. C. Chan, Org. Lett., 2001, 3, 2733–2735; (i) C.
Cimarelli, A. Mazzanti, G. Palmieri and E. Volpini, J. Org. Chem.,
2001, 66, 4759–4765; (j) Y. Wang, X. Li and K. Ding, Tetrahedron:
Asymmetry, 2002, 13, 1291–1297; (k) J. Ji, L. Qiu, C. W. Yip and
A. S. C. Chan, J. Org. Chem., 2003, 68, 1589–1590; (l) J. Lu, X.
Xu, C. Wang, J. He, Y. Hu and H. Hu, Tetrahedron Lett., 2002, 43,
8367–8369; (m) J. Lu, X. Xu, S. Wang, C. Wang, Y. Hu and H. Hu,
J. Chem. Soc., Perkin Trans. 1, 2002, 2900–2903; (n) X. Xu, J. Lu, Y.
Dong and Y. Hu, Synlett., 2004, 122–124; (o) X. Xu, J. Lu, Y. Dong,
R. Li, Z. Ge and Y. Hu, Tetrahedron: Asymmetry, 2004, 15, 475–479;
(p) Y. Dong, J. Sun, X. Wang, X. Xu, L. Cao and Y. Hu, Tetrahedron:
Asymmetry, 2004, 15, 1667–1672; (q) X. Wang, Y. Dong, J. Sun, X.
Xu, R. Li and Y. Hu, J. Org. Chem., 2005, 70, 1897–1900.
structure was then assigned to the diastereoisomeric derivatives
obtained by reaction of the enantiomers of 1-(a-aminobenzyl)-2-
naphthol (1) with racemic aldehydes resolved by Betti.
19 (a) M. Betti, Gazz. Chim. Ital., 1903, 33-I, 17; M. Betti, J. Chem. Soc.,
1903, 84-I, 510; (b) M. Betti and V. Foa, Gazz. Chim. Ital., 1903, 33-I,
27; M. Betti and V. Foa, J. Chem. Soc., 1903, 84-I, 511.
20 (a) M. Betti, Atti Acc. Lincei, 1930, 11, 587–593 (Chem. Abstr. 1930,
24, 4473); (b) M. Betti and P. Pratesi, Atti Acc. Lincei, 1930, 11, 646–
649 (Chem. Abstr. 1930, 24, 3771); (c) M. Betti and P. Pratesi, Ber.,
1930, 63B, 874–5; (d) M. Betti and P. Pratesi, Biochem. Z., 1934, 274,
1–3 (Chem. Abstr. 1935, 29, 733h).
21 H. E. Smith and N. E. Cooper, J. Org. Chem., 1970, 35, 2212–
2215.
22 I. Szatmari, T. A. Martinek, L. Lazar and F. Fu¨lo¨p, Tetrahedron,
2003, 59, 2877.
10 For a very recent, excellent and authoritative review on Betti’s base
and its history, see: C. Cardellicchio, M. A. M. Capozzi and F. Naso,
Tetrahedron: Asymmetry, 2010, 21, 507–517.
23 CHIRALPAKꢀR AD-H, n-hexane/i-PrOH
=
95/5 or 90/10,
1 ml min-1, 230 nm, 20 ◦C.
11 Y. Dong, R. Li, J. Lu, X. Xu, X. Wang and Y. Hu, J. Org. Chem.,
2005, 70, 8617.
24 For a discussion on the use of “% ee” and “% de” as expressions of
stereoisomer composition, see: R. E. Gawley, J. Org. Chem., 2006,
71, 2411.
25 A variety of carboxylic acids with different pKa have been used in
different concentrations in methanol. Among them we chose acetic
acid in the reported concentrations in methanol to have a satisfying
reaction rate avoiding a concomitant decomposition.
26 Renin is an important enzyme at the beginning of the renin
angiotensin system (RAS), one of the key regulators of blood
pressure. Efficient renin inhibitors decrease the plasma renin activity
and reduce the production of angiotensin I from agiotensinogen.
27 The team of scientists (Novartis Institutes of Biomedical Research,
NIBR) who invented aliskiren have been named Heroes of Chemistry
2009; Chem. Eng. News September 21, 2009, 46.
28 (a) H. Ru¨eger, S. Stutz, R. Go¨schke, F. Spindler and J. Maibaum,
Tetrahedron Lett., 2000, 41, 10085–10089; (b) D. A. Sandham, R. J.
Taylor, J. S. Carey and A. Fa¨ssler, Tetrahedron Lett., 2000, 41,
10091–10094; (c) A. Dondoni, G. De Lathauwer and D. Perrone,
Tetrahedron Lett., 2001, 42, 4819–4823; (d) R. R. Go¨schke, S. Stutz,
W. Heinzelmann and J. Maibaum, Helv. Chim. Acta, 2003, 86, 2848–
2870; (e) H. Dong, Z.-L. Zhang, J.-H. Huang, R. Ma, S.-H. Chen
and G. Li, Tetrahedron Lett., 2005, 46, 6337–6340; (f) K. B. Lindsay
and T. Skrydstrup, J. Org. Chem., 2006, 71, 4766–4777.
12 The expressions “real world targets” and “real-life substrates” are
referred to those products and intermediates that play a key role in the
synthesis of chemicals currently exploited to solve some important
problem of present days, by which there is a great interest, and
therefore, an actual challenge to devise a more practical, efficient and
economically convenient methodology to prepare them according to
the green chemistry rules too.
13 (a) Racemic HelionalꢀR (IFF), also named TropionalꢀR , is a fragrance
produced industrially via a cross-aldol condensation of piperonal and
propanal followed by catalytic hydrogenation (K. Bauer, D. Garbe,
H. Surburg, Common Fragrance and Flavor Materials, Wiley-VCH,
1997) with an annual production of about 300–350 tons; (b) Enders
and Backes have published the first EPC synthesis of both enan-
tiomers (ee = 90%) through the SAMP/RAMP hydrazone-alkylation
strategy (D. Enders and M. Backes, Tetrahedron: Asymmetry, 2004,
15, 1813–1817) and described the olfactory evaluations and odour
threshold values of each enantiomer.
14 (a) Racemic LilialꢀR (Givaudan) is a lily-of-the-valley odorant and
a precursor of the fungicide Fenpropimorph (W. Himmele, F.-
Kohlmann, W. Herberle, German Patent, DE 2822326). Similarly to
HelionalꢀR it is produced industrially via a cross-aldol condensation of
4-tert-butyl-benzaldehyde and propanal followed by hydrogenation
(M. S. Carpenter, W. M. Jr Easter, U.S. Patent, 2,875,131, 1959,
Givaudan); (b) The EPC synthesis of both enantiomers of Lilial
has been performed exploiting the SAMP/RAMP methodology
for enantioselective alkylation reactions (D. Enders and H. Dyker,
Liebigs Ann. Chem., 1990, 11, 1107); (c) Through the enantios-
elective hydrogenation of the corresponding unsaturated alcohol
catalyzed by an iridium complex followed by oxidation (A. Lightfoot,
P. Schinder and A. Pfaltz, Angew. Chem., Int. Ed., 1998, 37,
2897); (d) The hydrogenation of the corresponding unsaturated
acid with a ruthenium complex incorporating (R)-BINAP followed
by reduction (T. Yamamoto, in Current Topics in Flavours and
FragrancesK. A. D. Swift, ed., Kluver Academic, Dordrech, The
Nederlands1999, pp 33–38).
29 (a) H.-U. Blaser, B. Pugin, F. Spindler and M. Thommen, Acc. Chem.
Res., 2007, 40, 1240–1250; (b) J. A. F. Boogers, U. Felfer, M. Koohaus,
L. Lefort, G. Steinbauer, A. H. M. de Vries and J. G. de Vries, Org.
Process Res. Dev., 2007, 11, 585–591; (c) J. G. de Vries and L. Lefort,
Chem.–Eur. J., 2006, 12, 4722–4734; (d) P. M. Jackson, I. C. Lennon
and M. E. Fox, US Patent 2009/0099358 A1, applicant Dow Global
Technologies Inc., 2009; WO 2007/123957 A2, 2007; (e) W. Chen,
F. Spindler and B. Pugin, WO 2007116081 A1, applicant Solvias
AG, 2007; (f) T. Strurm, W. Weissensteiner and F. Spindler, Adv.
Synth. Catal., 2003, 345, 160–164; (g) P. Herold and S. Stutz, WO
2002002500 A1, assigned to Speedel Pharma AG, 2002.
30 N. Andrusko, V. Andrusko, T. Thyrann, G. Ko¨nig and A. Bo¨rner,
Tetrahedron Lett., 2008, 49, 5980–5982.
31 M. Betti, Organic Syntheses, Wiley & Sons: New York, Coll. Vol. 1,
15 The fragrance Cyclamal was progressively substituted by the more
(1941), pp 381–383.
R
stable Lilialꢀ. Its preparation is very similar to those reported for
32 Y. Dong, R. Li, J. Lu, X. Xu, X. Wang and Y. Hu, J. Org. Chem.,
2005, 70, 8617–8620.
the other a-methyl hydrocinnamic aldehydes and, to the best of our
knowledge, no asymmetric synthesis of Cyclamal has been published.
16 (a) L. A. Saudan, Acc. Chem. Res., 2007, 40, 1309; (b) A. P. S. Narula,
Helv. Chim. Acta, 2004, 87, 1992; (c) S. Lamboley, C. Morel, J. Y. De
Saint Laumere, A. F. Boshung, N. G. J. Richards and B. M. Winter,
Helv. Chim. Acta, 2004, 87, 1767; (d) E. Brenna, C. Fuganti and S.
Serra, Tetrahedron: Asymmetry report N. 54, 2003, 14, 1; (e) G. Frater,
J. A. Bajgrowikz and P. Kraft, Tetrahedron, 1998, 54, 7633.
33 P. Herold and S. Stutz, PCT WO 02/02500 A1 for Speedel Pharma
AG.
34 13C NMR (100 MHz, C6D6) of (1S,3R,3S)-3e isomer d: 159.0, 154.2,
144.2, 134.6, 133.2, 131.1, 130.7, 130.0, 129.9, 129.5, 129.0, 127.9,
127.4, 124.1, 124.0, 120.5, 115.7, 114.8, 84.8, 55.4, 54.9, 51.5, 32.9,
28.5, 22.0, 20.8.
35 HPLC analysis (1S,3R,R)/(1S,3R,R)
= 96.4 (tR = 10.03) :
17 M. Betti, Organic Syntheses, Wiley & Sons: New York, 1941; Collect.
3.6 (tR = 8.42) ratio. The methanol–AcOH filtrate showed a
(1S,3R,R)/(1S,3R,R) = 64.8 : 29.8 ratio.
Vol. 1, pp 381–383.
18 M. Betti, Gazz. Chim. Ital., 1900, 30-II, 301–309; M. Betti, Gazz.
Chim. Ital., 1900, 30-II, 310–309At that time the structure as-
signments were based on a variety of tests specific for functional
groups. In particular, the positive response to the FeCl3 test for
phenol convinced the Author, perhaps a pupil of Ugo Schiff, to
prefer the structure of a Schiff base for the condensation product
that underwent hydrochloric acid hydrolysis, thus changing the
first assignment consisting into the 1,3-diphenyl-2,3-dihydro-1H-
naphtho[1,2-e][1,3]oxazine structure (see Scheme 2). The same iminic
36 Only the naphthoxazine 3f was completely soluble.
37 K. Kogami, O. Takahashi and J. Kumanotani, Bull. Chem. Soc. Jpn.,
1972, 45, 604–607.
38 A. Scrivanti, M. Bertoldini, V. Beghetto and U. Matteoli, Tetrahe-
dron, 2008, 64, 543–548.
ˇ
39 A. Avdagic´, M. Gelo-Pujic´ and V. Sunjic´, Synthesis, 1995, 1427–
1431.
40 M. Kinoshita, T. Miyake, Y. Arima, M. Oguma and H. Akita, Chem.
Pharm. Bull., 2008, 56, 118–123.
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