endo-1-Phenylborneol as a novel, alternative chiral auxiliary for the aza-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2020.152165

We report the synthesis and preliminary evaluation of (1S,2S,4R)-7,7-dimethyl-1-phenylbicyclo[2.2.1]heptan-2-ol 1a, which was obtained in 3 steps from inexpensive starting materials, as a chiral auxiliary. The potential for asymmetric induction was investigated by carrying out aza-Diels-Alder reactions with cyclopentadiene and imine derivatives of 1a from (R)-(+)-1-phenylethylamine, (S)-(?)-1-phenylethylamine and benzylamine. The results showed marked exo selectivity and good diastereoisomeric excess when 1a was combined with (R)-(+)-1-phenylethylamine. These results are comparable with those reported using (?)-8-phenylmenthol, suggesting that 1a can represent an economically viable alternative to current chiral auxiliaries.

Full text of DOI:10.1016/j.tetlet.2020.152165

Journal Pre-proofs
endo-1-Phenylborneol as a Novel, Alternative Chiral Auxiliary for the Aza-
Diels-Alder Reaction
Marco Bassani, Alessandro Scarso, Maria Drago, Alfonso Zambon, Fabrizio
Fabris
PII:
S0040-4039(20)30625-0
DOI:
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https://doi.org/10.1016/j.tetlet.2020.152165
TETL 152165
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Tetrahedron Letters
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18 June 2020
Please cite this article as: Bassani, M., Scarso, A., Drago, M., Zambon, A., Fabris, F., endo-1-Phenylborneol as a
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endo-1-Phenylborneol as a Novel, Alternative Chiral Auxiliary for the Aza-Diels-
Alder Reaction
Marco Bassani,a Alessandro Scarso,a Maria Drago,b Alfonso Zambon*,b and Fabrizio Fabrisa
R
N
OH
O
O
O
OH
O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
endo-1-Phenylborneol as a Novel, Alternative Chiral Auxiliary for the Aza-Diels-
Alder Reaction
Marco Bassani,a Alessandro Scarso,a Maria Drago,b Alfonso Zambon*,b and Fabrizio Fabrisa
a Dipartimento di Scienze Molecolari e Nanosistemi, Università Ca’ Foscari Venezia, via Torino 155, 30172, Mestre Venezia (ITALY)
b Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Modena e Reggio Emilia, via Campi 103, 41125, Modena (ITALY)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report the synthesis and preliminary evaluation of (1S,2S,4R)-7,7-dimethyl-1-
phenylbicyclo[2.2.1]heptan-2-ol 1a, which was obtained in 3 steps from inexpensive starting
materials, as a chiral auxiliary. The potential for asymmetric induction was investigated by
carrying out aza-Diels-Alder reactions with cyclopentadiene and imine derivatives of 1a from
(R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine and benzylamine. The results showed
marked exo selectivity and good diastereoisomeric excess when 1a was combined with (R)-(+)-
1-phenylethylamine. These results are comparable with those reported using (-)-8-
phenylmenthol, suggesting that 1a can represent an economically viable alternative to current
chiral auxiliaries.
Available online
Keywords:
Chiral Auxiliaries
Hetero Diels Alder reaction
Asymmetric induction
Cycloadditions
Asymmetric synthesis
1. Introduction
Hetero Diels-Alder (DA) reactions are an important synthetic tool for the synthesis of heterocycles and natural products.1 Crucially,
imino DA reactions can provide rapid access to functionalized heterocyclic rings with controlled stereochemistry; imines can be easily
obtained from the corresponding aldehydes and ketones, and are typically the dienophile in DA reactions.2 The use of chiral auxiliaries
is one of the main strategies to exert asymmetric induction in a reaction. Among the most common chiral auxiliaries, Corey’s (−)-8-
phenylmenthol3 has been applied to imino cycloadditions such as the synthesis of 3-functionalized 2-azabicyclo[2.2.1]hept-5-enes as
intermediates for a range of compounds including amidomycin and carbovir,4 generally with moderate yields and diastereoisomeric
ratios.2
Although (−)-8-phenylmenthol has proven to be a very versatile chiral auxiliary, having been applied in various organic
transformations with good results,5–7 it is expensive and requires a 4-step synthesis and a crystallization step in order to be obtained in a
distereoisomeric pure form starting from enantioenriched (R)-(+)-pulegone.8 Furthermore, it is worth noting that there is an over 100-
fold difference in price between the two enantiomers of pulegone as precursors for chiral auxiliaries, which makes (+)-8-phenylmenthol
much more expensive compared to its enantiomer and almost inaccessible in practice. Some efficient alternatives to (−)-8-
phenylmenthol, such as (+)- and (-)-trans-2-(α-cumyl)cyclohexanol share the same scaffold and require an enzymatic resolution to be
obtained.9,10
There is thus scope for the identification of novel chiral auxiliaries, which are readily accessible from the chiral pool, possibly
available as both enantiomers. Herein we introduce chiral alcohol 1a, derived from the under explored benzo-camphor scaffold 1, as an
easy to obtain, versatile chiral scaffold for applications as a chiral auxiliary. To the best of our knowledge, 1 has been reported only
once as tool compound for chiroptical studies and the present contribution describes its first application in synthesis.11
O
OH
1a
1
Figure 1. Structures of benzocamphor 1 and the proposed chiral auxiliary alcohol 1a.
According to our rationale, 1a should be able to exert strong asymmetric induction on a substrate bound to the hydroxyl moiety
through the steric hindrance of the rigid camphor backbone, while the presence of a neighboring phenyl group should provide
stabilizing  interactions between the aromatic ring and the dienophile in hetero DA reactions.12 Notably, these features are similar to
those of (−)-8-phenylmenthol, whose asymmetric induction properties have been explained based on both steric and electronic effects.13

2
Tetrahedron
2. Synthesis of benzocamphonic alcohol 1a
The synthetic route to 1a started from chetopinic acid 2, a derivative of (R)-camphor. Unlike the starting material for (−)-8-
phenylmenthol, (S)-camphor, while more expensive than (R)-camphor, is still readily available and affordable; therefore the enantiomer
of (R)-1a should be comparatively easier and less expensive to obtain with respect to (+)-8-phenylmenthol.
Benzocamphor 1 was previously obtained via the decarboxylation of chetopinic acid in benzene promoted by Pb(OAc)4.11,14 In our
hands this methodology was poorly reproducible and plagued by the low solubility and ease of degradation of Pb(OAc)4 in the reaction
medium. Furthermore, the use of Pb(OAc)4 should be discouraged due to its toxicity and environmental impact. We thus sought an
O
(i)
+
O
Cl
O
OH
1a
4
(ii)
4
O
O
O
5
alternative methodology to access the benzocamphor scaffold 1.
Most tertiary radicals have a tendency to disproportionate rather than react as nucleophiles.15 In contrast, bridgehead radicals have
nucleophilic character due to the rigidity of the fused polycyclic system which disfavours disproportionation.16 Phenyl derivatives on
the bridgehead position of adamantane and 1-apocamphane have been obtained from decomposition to radicals of the corresponding
tert-butyl peresters in benzene.16 We applied the same methodology to the camphor scaffold starting from ketopinyl chloride 2, which
can be obtained in quantitative yield from inexpensive ketopinic acid.17 Acyl chloride 2 afforded perester 3 in 90% yield upon treatment
with tert-butyl hydroperoxide under standard conditions. Perester 3 then underwent thermal decomposition in benzene giving the
benzo-camphor 1 in 37% yield (Scheme1).
Due to the steric hindrance exerted by the apical methyl groups, the approach of hydride agents such as LiAlH4 to the camphor
carbonyl group occurs specifically on the (Si) face, leading to the exo alcohol.18 We thus obtained 1a by reduction with sodium in the
presence of tert-butyl alcohol as a proton source, which favoured the formation of the more stable endo anion intermediate and thus of
Scheme 1. Synthesis of glyoxylate 5. (i) DMAP, Et3N, CH2Cl2, 25
°C, 92%; (ii) OsO4, NaIO4, dioxane/water, RT, 2 h, 77%.
1a upon quenching with water.19 The stereochemistry of the reduction product was confirmed by the NOE interaction between the
apical methyl group and the hydrogen atom on the alcoholic carbon.
3. Evaluation of 1a as a chiral auxiliary
(i)
t BuOOH
O
O
O
O
O
Cl
2
t-Bu O
3
(iii)
(ii)
3
O
OH
1
1a
In order to evaluate the potential for asymmetric induction using 1a, we carried out aza-Diels-Alders reactions with cyclopentadiene
on its imine derivatives; the resulting 2-azabicyclo[2.2.1]heptenes are used as precursors of a range of compounds of chemical,

3
biological and pharmaceutical interest.20 We compared the outcomes of these cycloadditions with those reported using (-)-8-
phenylmenthol as a chiral auxiliary. (-)-8-Phenylmenthol was developed by Corey in 1975 and is one of the most commonly used and
effective chiral auxiliaries for various chemical trasformations,5–7 such as asymmetric Diels-Alder reactions,5,21,22 nucleophilic
alkylation23 and dihydroxylation.24
To this aim, we first synthesized glyoxylate derivative 5 in good yield starting from 1a. Compound 1a was reacted with acryloyl
chloride under standard conditions, and the resulting acrylate 4 underwent oxidative cleavage by Lemieux–Johnson oxidation (Scheme
2).
We then formed 3 different iminium salts derivatives of glyoxylate 5 by reaction with (R)-(+)-1-phenylethylamine, (S)-(-)-1-
.
phenylethylamine and benzylamine, which then underwent cycloadditions with cyclopentadiene in CH2Cl2 using BF3 Et3O as a Lewis
acid according to an established procedure (Scheme 3).21 The diastereomeric ratio was assessed by integration of the crude reaction
mixture and isolation of the diastereomeric products by column chromatography. The assignment of the absolute configuration of the
latters was achieved by conversion of the isolated products into known compounds, according to well established methodologies, and
comparing the spectra and optical rotations of the derivatives as detailed in the Supplementary Information.25,26 The diastereoisomeric
distribution of the reaction outcomes was compared with those obtained using (-)-8-phenylmenthol as a benchmark chiral auxiliary,21,4
as reported in Table 1.
Gratifyingly, the use of (R)-(+)-1-phenylethylamine (Table 1, Entry 1) as a secondary chiral auxiliary afforded compound 9a (exo-
(1S,4R) in 60% isolated yield; we were also able to isolate compounds exo-(1R,4S) 7a and endo-(1R,4S) 8a in 4% and 8% yield,
respectively. These results are comparable with those reported for (-)-8-phenylmenthol and is most likely due to a cooperative effect
between the (R)-(+)-1-phenylethylamine and the chiral auxiliary (+)-4 (matching effect), as previously observed for (-)-8-
phenylmenthol.21
Interestingly, the same reaction carried out using (S)-(-)-1-phenylethylamine (Table 1, Entry 2) did not reach completion and led to
Scheme 2. Synthesis of 1a. Reagents and conditions: (i) DMAP
(cat), Py, 0 °C, 18 h, 89%; (ii) Benzene, 150 °C, 2 h, 37%; (iii) Na,
THF, 0 °C, 2 h, 32%.
much lower overall yields, affording exo-(1R,4S) compound 9b in 11% isolated yield along with endo-(1R,4S) 10b and exo-(1S,4R) 7b
in 9% and 5% yield, respectively. Again, the diastereomeric ratio of this reaction closely resembles the one obtained with (-)-8-
phenylmenthol, albeit with lower isolated yields.
Finally, when benzyl phenylethylamine was employed to form the imino derivative, literature data reports uniquely the isolation of
4
the exo-(1S,4R) isomer and no endo isomer formed. We were able to isolate both exo-(1R,4S) 7c and exo-(1S,4R) 9c in 6% and 23%
yield, respectively (Table 1, Entry 3).
(i)
H2N
(ii)
+
+
+
O
O
O
O
5
O
O
+
O
Ra-c
O
O
O
H
N
N
Ra-c
N
Ra-c
N
Ra-c
N
Ra-c
CF3CO2
Ra-c
6a-c
7a-c
8a-c
Rc=
9a-c
10a-c
(R)
Ra=
(S)
Rb=
Scheme 3. Synthesis of imino derivatives of 5 and their aza-Diels Alder reactions with cyclopentadiene. (i) CH2Cl2, 4Å MS, CF3COOH, 0 to -
78 °C, 1 h; (ii) BF3Et2O, cyclopentadiene, -78 °C, 5 h.
exo-(1R,4S)
endo-(1R,4S)
exo-(1S,4R)
endo-(1S,4R)
AUX
=
R
N
COAux
COAux
R
N
O
N
N
COAux
COAux
R
R
R=
(R)

4
Tetrahedron
Entry 1
Entry 2
Entry 3
7a
8a
9a
10a
4%
8%
60% (79%21)
ND
7b
8b
9b
10b
R=
R=
(S)
5% (35%21)
(15%21)
11% (25%21)
9%
7c
8c
9c
10c
6%
ND
23% (57%4)
ND
Table 1. Diasteromeric distribution of the aza-Diels Alder reaction between cyclopentadiene and imino derivatives of chiral auxiliary 1a. In
parenthesis are the values observed in the case of (-)-8-phenylmenthol as a chiral auxiliary.
As previously observed, in all cases the cycloaddition reactions were characterized by marked exo selectivity;22,27 this result has been
explained by assuming that the dienophile iminium ion adopts an E configuration, and that the 1-phenylethyl group exerts a larger
steric hindrance with respect to the ester group in proximity of the C=N bond.4,21 On the basis of what is known in the literature for (-)-
8-phenylmenthol, the mechanism of action of 1a in these aza-Diels-Alder reactions can be rationalised assuming that the dienophile is
held in place by π-π interactions with the phenyl ring of the chiral auxiliary. In the case of the (R)-(+)-1-phenylethylamine derivative,
the phenyl group points away from the benzene ring of 1a and the approach of the diene from the Si face leading to compound 9a is
favoured (Fig. 2A). Conversely, the phenyl group of the (S)-(-)-1-phenylethylamine derivative needs to move close to the benzene ring
of 4, causing a steric clash that destabilizes this approach and thus leads to a reduced diastereoselectivity (Fig. 2B).
In conclusion, we demonstrated that enantiopure alcohol 1a can be synthesised in three steps from inexpensive starting materials
avoiding the use of toxic Pb(OAc)4. The evaluation of 1a as a chiral auxiliary in aza-Diels Alder reactions showed that it induces
diastereomeric excesses comparable to (-)-8-phenylmenthol, thus representing a viable alternative to current chiral auxiliaries.
A
Si-face
R
N
1S
H
H
O
R
N
H
O
O
H
O
exo- Si approach
6a
Favored
B
S
1S
H
O
N
Si-face
N
H
S
H
O
O
H
exo- Si approach
O
6b
Hindered
Figure 2. Model for the approach of cyclopentadiene to
iminoacetals bearing a secondary chiral auxiliary: the configuration
allowing the exo-Si approach of the diene is favored for adduct 6a
with (R)-(+)-1-phenylethylamine (A) and destabilized for adduct 6b
with (S)-(+)-1-phenylethylamine (B).
Acknowledgements
The authors acknowledge Università degli Studi di Modena e Reggio Emilia, Università Ca’ Foscari Venezia and MIUR for support.

5
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Supplementary Material
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



endo-1-Phenylborneol 1a bears the under-explored benzocamphor scaffold
1a was obtained from economic starting materials avoiding the use of toxic reagents
1a was evaluated as a chiral auxiliary in asymmetric aza-Diels Alder reactions
1a induces diastereomeric excesses comparable to (-)-8-phenylmenthol