Unprecedented catalytic enantioselective trapping of arene oxides with dialkylzinc reagents

Article abstract of DOI:10.1039/b108541g

The first catalytic enantioselective trapping of symmetrical and racemic arene oxides with organometallic reagents is reported.

Full text of DOI:10.1039/b108541g

Unprecedented catalytic enantioselective trapping of arene oxides with
dialkylzinc reagents†
Fabio Bertozzi,a Paolo Crotti,a Federica Del Moro,a Ben L. Feringa,*b Franco Macchiaa and
Mauro Pineschi*a
a Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa,
Italy. E-mail: pineschi@farm.unipi.it; Fax: +3905043321
b Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of
Groningen, Nijenborgh 4, NL9747, AG Groningen, The Netherlands
Received (in Cambridge, UK) 24th September 2001, Accepted 30th October 2001
First published as an Advance Article on the web 15th November 2001
The first catalytic enantioselective trapping of symmetrical
and racemic arene oxides with organometallic reagents is
reported.
component 1a determines the reactions of the system with most
agents.3
Table 1 Enantioselective trapping-ring-opening of benzene oxide 1a with
R2Zna
Arene oxide has been subjected to several studies since the
demonstration that this class of compounds is formed from
aromatic hydrocarbons by the microsomial enzyme fraction
from mammalian liver.1 Much interest, therefore, has been
generated concerning the solution chemistry of arene oxide. The
nucleophiles utilized in these studies were in most cases
heteronucleophiles such as water, alcohols, thiols and amines.2
There are only few reports dealing with ring-opening reactions
of arene oxide carried out with organometallic reagents.2a,3
Moreover, none of these procedures employing organometallic
reagents are catalytic or enantioselective.
We have recently reported a new kinetic resolution of cyclic
vinyl oxiranes,4 a desymmetrization of symmetrical methyli-
dene cycloalkene oxides5 and a new catalytic regiodivergent
kinetic resolution (RKR)6 based on dialkylzinc reagents and
chiral copper complexes of phosporamidite ligands.7 In the
RKR, a single chiral catalyst induces the formation of a distinct
regioisomer from each substrate enantiomer with a high ee. The
procedure was useful to gain insight into the reaction mecha-
nism of this particular kind of copper-catalyzed allylic alkyla-
tion, pointing to reductive elimination as the regio- and stereo-
determining step of the addition reaction.
We herein report an unprecedented catalytic and enantiose-
lective desymmetrization of symmetrical arene oxides 1a,b
with hard alkylmetal, and a new, highly enantioselective RKR
starting from the racemic arene oxide 8 (Schemes 1, 2 and 3).
Benzene oxide (1a) and indan-8,9-oxide (1b) were examined
as symmetrical arene-oxide substrates (Schemes 1 and 2).
Benzene oxide is known to exist in equilibrium with its
tautomeric valence structure, the oxepin 1aA. This compound
exists mainly as oxepin at room temperature, even if the oxide
Entry
Substrate
R
Ratio a:g Yield (%)b ee (%)c
1
2
1a
1a
Me
Et
69+31
38+62
85
88
93
64
a Conditions: all reactions were run in accordance with the typical
procedure (see ref. 8).b Yields are determined on the basis of weight, 1H
NMR and GC analysis of the crude reaction mixture.c Determined by GC on
CSP.
Epoxide 1a was allowed to react at 278 °C (1 h, 95%
conversion) with Me2Zn (1.5 equiv.) in the presence of a
catalytic amount of Cu(OTf)2 (0.015 equiv.) and the chiral
ligand (R,R,R)-2 (0.030 equiv.) to give a crude reaction mixture
consisting of the not previously synthesized regioisomeric
dienols (1S,6S)-3a (a-adduct) and 5a (g-adduct) (entry 1, Table
1).8 The reaction with Et2Zn gave a slightly different result, with
a predominance of the achiral g-adduct 6a (entry 2, Table 1).9
The substituted enantioenriched dihydroaromatic a-adducts
(1S,6S)-3a (93% ee) and (1S,6S)-4a (64% ee) were obtained
with a complete anti stereoselectivity.10
Indan 8,9-oxide (1b), containing a tetrasubstituted epoxide is
known to exist only in the oxide form. The copper-phosphor-
amidite catalyzed addition of R2Zn at 278 °C to 1b (3 h, 95%
conversion) gave a ca. 80:20 mixture of the corresponding a-
and g-adducts 3b+5b (R = Me) and 4b+6b (R = Et) (Scheme
2).11
It is remarkable that the a-adducts 3b (495% ee) and 4b
exclusively derive from an anti-stereoselective 1,6-addition
pathway (and therefore more appropriately called e-adducts,
Scheme 2). This unexpected regiochemical behavior could be of
interest to gain further insight into the interconversion between
the regioisomeric (s-allyl)copper(III) complexes of type 7A–C
that are formed during the oxidative step.12 Considering the
conjugate nature of the starting epoxide, this interconversion
between the regioisomeric (s-allyl)copper(III) complexes of
type 7A–C probably occurs by means of an intermediate
delocalized (p-allyl)copper(III) species of type 7D.13 In this
biased framework the attack at the tertiary carbon terminus
atom of 7D to give 7B is not favourable for steric reasons, while
the attack at the secondary terminus of 7D to give the (s-
allyl)copper(III) complex 7C could be highly favoured. The
subsequent rate limiting reductive elimination step on 7C
affords the e-adducts 3b,4b (1,6-addition products), as ob-
served.
Naphthalene 1,2-oxide (8) seems to exist only in the oxide
form and it is very prone to spontaneous epoxide ring-opening
and aromatization. Despite its extreme chemical reactivity, the
addition of Et2Zn (1.5 equiv.) to racemic 8 in the presence of
Cu(OTf)2 (0.015 equiv.) and chiral ligand (R,R,R)-2 (0.030
Scheme 1
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b1/b108541g/
2606
Chem. Commun., 2001, 2606–2607
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b108541g

be operative in a biased system such as indan 8,9-oxide for this
particular kind of allylic alkylation.
We gratefully acknowledge funding by the MURST (Rome),
the University of Pisa, and Merck (2000 ADP Chemistry Award
to P. C.).
Notes and references
1 (a) D. M Jerina, J. W. Daly, B. Witkop, P. Zaltzman-Niremberg and S.
Udenfriend, J. Am. Chem. Soc., 1968, 90, 6525; (b) D. M. Jerina and J.
W. Daly, Science, 1974, 185, 573; (c) T. C. Bruice and P. Y. Bruice,
Acc. Chem. Res., 1976, 9, 378; (d) D. R. Boyd and D. M. Jerina, in Small
Ring Heterocycles, Part 3, Chemistry of Heterocyclic Compounds, vol.
42, ed. A. Hassner, Wiley, New York, 1985, p. 197.
2 (a) A. M. Jeffrey, H. J. C. Yeh, D. M. Jerina, R. M. DeMarinis, C. H.
Foster, D. E. Piccolo and G. A. Berchtold, J. Am. Chem. Soc., 1974, 96,
6929; (b) G. H. Posner and D. Z. Rogers, J. Am. Chem. Soc., 1977, 99,
8214; (c) M. J. McManus and G. A. Berchtold, J. Am. Chem. Soc., 1985,
107, 2977; (d) For recent enzymatic transformations, see: D. R. Boyd, J.
T. G. Hamilton, N. D. Sharma, J. S. Harrison, W. C. McRoberts and D.
B. Harper, Chem. Commun., 2000, 1481; (e) S. K. Balani, I. N.
Brannigan, D. R. Boyd, N. D. Sharma, F. Hempenstall and A. Smith, J.
Chem. Soc., Perkin Trans. 1, 2001, 1091; (f) T. Hudlicky, D. Gonzales
and D. T. Gibson, Aldrichimica Acta, 1999, 32, 34, and references
therein.
3 E. Vogel and H. Günther, Angew. Chem., Int. Ed., 1967, 6, 385.
4 (a) F. Bertozzi, P. Crotti, B. L. Feringa, F. Macchia and M. Pineschi,
Synthesis, 2001, 483; (b) F. Badalassi, P. Crotti, F. Macchia, M.
Pineschi, A. Arnold and B. L. Feringa, Tetrahedron Lett., 1998, 39,
7795.
5 F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, A. Arnold and B. L.
Feringa, Org.Lett., 2000, 2, 933.
6 F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi and B. L. Feringa,
Angew. Chem., Int. Ed. Engl., 2001, 40, 930 and references therein..
7 For an overview of phosphoramidite in catalytic asymmetric conjugate
addition, see: B. L. Feringa, Acc. Chem. Res., 2000, 33, 346.
8 Typical procedure: a solution of Cu(OTf)2 (5.8 mg, 0.015 mmol) and 2
(16.2 mg, 0.03 mmol) in anhydrous toluene (2 ml) was stirred at room
temperature for 40 min. The colorless solution was cooled to 278 °C
and subsequently additioned with a solution of arene oxide (1.0 mmol)
in toluene (0.5 ml) and 1.5 mmol of R2Zn (solution in toluene). The
reaction was followed by GC analysis and quenched with saturated
aqueous NH4Cl (see the Supporting Information for further details).
9 The conjugate g-adducts 5a and 6a were obtained only in a mixture with
regioisomeric a-adducts 3a and 4a. In our hands, it was not possible to
isolate in a pure state the achiral g-adducts 5a and 6a, or some simple
derivatives of theirs, probably due to a rapid aromatization process.
10 The anti-stereochemistry of 3a was demonstrated by comparison with
the product obtained by the addition of MeLi to benzene oxide 1a, a
Scheme 2
equiv.) proceeded very cleanly to afford a 66+34 mixture of
regioisomeric dihydronaphthols 9 (g-adduct) and 10 (a-adduct),
the latter with a remarkable enantioselectivity ( > 98% ee)
(Scheme 3).11,14 On the other hand, the addition of Et2Zn to
racemic 8 catalyzed by a copper complex with the racemic
ligand (S,S,S)(R,R,R)-2 afforded with almost complete ( > 96%)
regioselectivity the racemic g-adduct 9. A complete examina-
tion of these results clearly indicates that also arene oxide rac-8
exhibits a complementary enantiomer-dependent regioselectiv-
ity typical of a RKR process, in which the a-adduct 10 is
obtained from the less reactive enantiomer (1S,2R)-8 of the
racemic substrate, while the g-adduct derives from the more
reactive (1R,2S)-8.6,14
reaction that is known to proceed with syn-stereoselectivity2a
.
11 It is worthy of mention that all the corresponding “blank reactions”,
performed on epoxides 1a,b and 8 in the same reaction conditions but in
the absence of the chiral ligand (R,R,R)-2, afforded the corresponding
rearranged phenols as the main product (phenol from 1a, 4-indanol from
1b, and 1-naphthol from 8).
12 For very recent experimental evidence supporting the intervention of
Cu(III) intermediates, see: A. S. E. Karlström and J.-E. Bäckwall, Chem.
Eur. J., 2001, 7, 1981 and references therein. Even if not indicated in
Scheme 2 for the sake of simplicity, the copper(III) complexes 7A–D are
probably cationic species with OTf2 as a possible counterion.
13 The interconversion between the regioisomeric (s-allyl)copper(III
)
Scheme 3
complexes of type 7A–C could be reasonably explained also by the
intervention of suprafacial 1,3-shifts.
14 All the attempted analyses of the enantiopurity of alcohol 9 both by
HPLC- and GC-CSPs gave extensive decomposition of the compound.
The absolute configuration of compound (1R,2S)-10 was demonstrated
by a single crystal X-ray analysis after derivatization of the enantiomer
(1S,2R)-10 with a chiral auxiliary derived from 4,5-dichlorophthalic
acid and (1S,2R,4R)-(2)-2,10-camphorsultam. Details of the procedure
will be reported separately in a forthcoming paper.
In summary, the present work describes an unprecedented
catalytic and enantioselective trapping of symmetrical and
racemic arene oxides. This method offers a new route to
enantioenriched dihydroaromatic alcohols, not easily accessible
by means of other synthetic methods. An examination of the
regiochemical outcome indicated that a 1,6-addition mode may
Chem. Commun., 2001, 2606–2607
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