Long-range diastereoseIectivity in Ugi reactions of 2-substituted dihydrobenzoxazepines

Article abstract of DOI:10.3762/bjoc.7.109

The Ugi reaction of 2-substituted dihydrobenzoxazepines was found to proceed with unexpectedly good diastereoselectivitiy (diastereoisomeric ratios up to 9:1), despite the large distance between the pre-existing stereogenic centre and the newly generated

Full text of DOI:10.3762/bjoc.7.109

Long-range diastereoselectivity in Ugi reactions of
2-substituted dihydrobenzoxazepines
Luca Banfi*, Andrea Basso, Valentina Cerulli, Valeria Rocca
and Renata Riva
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 976–979.
Department of Chemistry and Industrial Chemistry, University of
Genova, I-16146 Genova, Italy
doi:10.3762/bjoc.7.109
Received: 10 May 2011
Accepted: 22 June 2011
Published: 13 July 2011
Email:
Luca Banfi* - banfi@chimica.unige.it; Andrea Basso -
basso@chimica.unige.it; Valentina Cerulli - cerullivale@libero.it;
Valeria Rocca - valeria@chimica.unige.it; Renata Riva -
riva@chimica.unige.it
This article is part of the Thematic Series "Multicomponent reactions".
Guest Editor: T. J. J. Müller
* Corresponding author
© 2011 Banfi et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
benzoxazepines; cyclic imines; long range stereoinduction;
multicomponent reactions; Ugi reaction
Abstract
The Ugi reaction of 2-substituted dihydrobenzoxazepines was found to proceed with unexpectedly good diastereoselectivitiy
(diastereoisomeric ratios up to 9:1), despite the large distance between the pre-existing stereogenic centre and the newly generated
one. This result represents the first good 1,4 asymmetric induction in an Ugi reaction as well as the first example of diastereoselec-
tive Ugi reaction of seven membered cyclic imines. It allows the diversity-oriented synthesis of various tetrahydro[f][1,4]benzox-
azepines.
Introduction
The Ugi reaction is probably the most renowned and widely bring about no or very little diastereoselectivity, whereas some
used multicomponent reaction. Its great utility in the highly relative asymmetric induction has been reported only with
convergent and diversity-oriented synthesis of libraries of chiral amines as auxiliaries [6], or with chiral cyclic imines.
heterocyclic compounds, stemming from the possibility to intro-
duce up to four diversity inputs in a single step, has been fully The use of cyclic imines (three-component Ugi–Joullié reac-
demonstrated [1-5]. However, a main drawback of this vener- tion) [7,8] is particularly useful, because the resulting Ugi prod-
able reaction is the poor diastereoselectivity typically experi- ucts are necessarily nitrogen heterocycles. However, good dia-
enced when using chiral inputs. It is well known that chiral stereoselectivity has been obtained so far only with a few types
isocyanides, aldehydes/ketones and carboxylic acids always of chiral substrates [9-15]. In most cases these are represented
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Beilstein J. Org. Chem. 2011, 7, 976–979.
by five-membered imines (pyrrolines) with a stereogenic centre is worth noting that the Mitsunobu reaction is not effective on
α to the imine carbon (1,2-induction), although this relative unprotected salicylaldehyde. 2,3-Dihydrobenzo[f][1,4]ox-
arrangement is not a guarantee of good stereoselectivity azepines similar to 5a,b have been previously prepared, but
[8,14,16]. Examples of 1,3-induction on chiral imines with the through less general routes [22-24].
stereocentre β to the carbon [14,16], or α to the nitrogen, of the
C=N moiety [13,15,17] are rarer. More often, when the stereo-
centre is not in α, poor diastereoselectivity is observed [18,19].
This fact limits the diversity of heterocycles that can be
accessed stereoselectively from the three-component Ugi–
Joullié reaction of cyclic imines.
Results and Discussion
We report here some preliminary results disclosing a new
family of chiral 7-membered cyclic imines that afford good
levels of diastereoselectivity when submitted to an Ugi–Joullié
reaction, despite the fact that the stereogenic centre is only γ to
the imine carbon (1,4 relative induction). This is, to our know-
ledge, the first example of 1,4 asymmetric induction in an
isocyanide based multicomponent reaction of chiral carbonyl
compounds or imines, and the first example of diastereoselec-
tive Ugi reaction on chiral seven-membered imines [20,21].
Scheme 1: a) TBAD [(t-BuO2C−N=)2], PPh3, THF, −15 °C → rt, 49%
(3a), 62% (3b); b) LiAlH4, Et2O–THF, 0 °C, 90% (4a), 88% (4b); c)
HCl, CH2Cl2–H2O, rt; d) R2NC, R3CO2H, MeOH, rt.
The two imines 5a,b (Scheme 1) have been convergently
synthesized in three steps from Weinreb hydroxamate 1, in turn
prepared in one step from salicylic acid (Supporting Informa-
tion File 1). The key step of the synthesis is the intramolecular Compounds 5a,b were reacted with a series of isocyanides and
condensation of 1 with racemic alcohols 2a,b through a carboxylic acids to give, in good yields, nine different
Mitsunobu reaction. The moderate yields are due to the tetrahydro[f][1.4]benzoxazepines 6, equipped with three diver-
consumption of alcohols 2, which undergo side-reactions, sity points.
resulting in incomplete transformation of 1, even when using
1.3–1.5 equiv of 2. The use of a larger excess of 2 would prob- As shown in Table 1, all the tested Ugi reactions proceeded
ably increase the yields, but this is not particularly convenient with remarkably high diastereoselectivity, if one considers that
(especially if one plans to use enantiomerically pure 2). In any the R1 substituent is quite far away from the imine carbon. This
case, unreacted 1 may be recovered. Alcohol 2b behaves some- long range diastereoselectivity (from 5.25:1 up to 9:1) is
what better than 2a in this reaction. The other two steps completely unprecedented for an isocyanide based multicompo-
proceeded with no problems to give imines 5a,b in high yield. It nent reaction.
Table 1: Results of Ugi reactions of imines 5a,b.
Product
R1
R2
R3
Yielda
drb
6a
6b
6c
6d
6e
6f
Me
Me
Me
iBu
iBu
iBu
iBu
iBu
iBu
Cy
Et
MeOCH2
BocNHCH2
MeOCH2
Et
70%
77%
71%
56%
59%
64%
57%
78%
70%
85:15
87:13
84:16
90:10
86:14
88:12
88:12
89:11
88:12
t-Bu
Bn
4-BnOC6H4CH2CH2
Cy
t-Bu
n-Bu
t-Bu
n-Bu
Bn
6g
6h
6i
3-BrC6H4
5-Cl-2-thienyl
Z-NH-CH2CH2
aIsolated yields (after chromatography) from aldehydes 4a,b. bDetermined by HPLC or by 1H NMR (for 6f, 6h, 6i only by NMR).
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Beilstein J. Org. Chem. 2011, 7, 976–979.
A slight increase in the dr was observed on passing from R1 = strain with the peri H-7. Therefore, if the preferred con-
Me to bulkier R1 = iBu. On the other hand the structure and the formation of the imine is the one depicted in Figure 1, with R1
nature of both isocyanides and carboxylic acids seem to have equatorial, axial attack would give the cis adducts. The impor-
little influence on the diastereoselectivity. NMR characteriza- tance of the unfavorable peri interaction is confirmed by the
tion of the products is reported in Supporting Information fact that the isocyanide derived substituent prefers an axial pos-
File 2. Minimization of the cyclic imine 5a using CSC Chem3D ition in both stereoisomers, as demonstrated by NOE experi-
(v10) indicates that there are only two significant conforma- ments carried out on 6e (Supporting Information File 2). Thus,
tions, and that the one with the substituent at C-2 in the equato- after attack, the trans initial adduct 10 undergoes a con-
rial position is strongly favored. In this situation (Figure 1), the formational change to 11. The two vicinal J2-3 (i.e., 2.1 and
substituent at C-2 should be quite far away from the site of 9.3 Hz for 6h) in the major diastereomers are in agreement with
isocyanide attack, being unable to discriminate the two dia- the chair-like conformation 8 of the cis adduct, whereas the
stereotopic faces.
same coupling constants in the minor diastereoisomer (i.e., 3.6
and 8.7 Hz. for 6h) fit the boat-like conformation 11 of the
trans adduct. However, the difference between these coupling
constants for the two stereoisomers is not large enough to guar-
antee the undisputable assignment of the cis relative configur-
ation to the major adduct. In the presented hypothesis, the func-
tion of the substituent at C-2 would therefore not be to shield
one of the two diastereotopic faces, but only to fix the con-
formation by favoring an equatorial disposition of R1. We are
planning to prove the relative configuration of the major
adducts and to prepare analogues with further substituents in
order to get more clues on this unusual diastereoselectivity and,
hopefully, to further improve stereoselectivity.
Figure 1: Model of the expected preferred conformation of imine 5a,
as minimized using CSC Chem3D (MOPAC-PM3).
Thus, rationalization of the observed stereoselectivity is not In conclusion, the methodology presented herein appears par-
trivial, also because we have not yet proved unambiguously the ticularly well suited for the stereoselective preparation of
relative configuration of the major adducts. Some authors have libraries of peptidomimetics based on the tetrahydrobenzox-
suggested, for six membered rings, a preferential axial attack of azepine ring. Although structures of general formula 6 are
the isocyanide [14,16], since it relieves unfavorable steric strain unprecedented, other tetrahydrobenzoxazepines have shown
in the forming tetrahedric adduct (Scheme 2). In our case, equa- interesting pharmacological properties [25,26]. The possibility
torial attack, leading to intermediate 9, would experience steric to introduce up to 4 points of diversity (including also
Scheme 2: Possible explanation of diastereoselectivity in Ugi reactions of imines 5.
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Beilstein J. Org. Chem. 2011, 7, 976–979.
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Supporting Information File 1
Complete experimental procedures.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-109-S1.pdf]
18.Banfi, L.; Basso, A.; Guanti, G.; Merlo, S.; Repetto, C.; Riva, R.
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Supporting Information File 2
NMR characterization of products 6 and NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
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Acknowledgements
We wish to thank Benedetta Pollarolo for her collaboration to
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