Diastereoselective cascade synthesis of azabicyclo[3.1.0]hexanes from acyclic precursors

Article abstract of DOI:10.1039/b110890e

The diastereoselective synthesis of azabicyclo[3.1.0]hexanes bearing different substituents on all positions of the cyclopropane ring has been achieved in moderate to good yields.

Full text of DOI:10.1039/b110890e

Diastereoselective cascade synthesis of azabicyclo[3.1.0]hexanes from
acyclic precursors
Jutta Böhmer, Ronald Grigg* and John D. Marchbank
Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds
University, Leeds, UK LS2 9JT. E-mail: r.grigg@chem.leeds.ac.uk
Received (in Cambridge, UK) 28th November 2001, Accepted 5th March 2002
First published as an Advance Article on the web 12th March 2002
The diastereoselective synthesis of azabicyclo[3.1.0]hexanes
bearing different substituents on all positions of the cyclo-
propane ring has been achieved in moderate to good
yields.
Propargylic carbonates are valuable substrates in Pd(0)-
catalysed processes. Their reactivity towards the catalyst differs
mechanistically from that of simple alkynes in that they form
allenylpalladium(II) complexes.1
We2 along with others3 have shown that these versatile
intermediates can serve a double function as both starter and
terminating species in a biscylisation–anion capture cascade
process4 generating azabicyclo[3.1.0]hexanes (Scheme 1).
Scheme 3 Reagents and conditions: a) TsCl, pyridine, DMAP 2 mol%, 0 °C
to rt, 15 h, 96%; b) allyl alcohol (see Table 1), DEAD, PPh3, THF, 0 °C to
rt, 15 h, (1a, 89%; 1b, 96%; 1c. 78%; 1d, 57%; 1e, 62%); c) n-BuLi, 278
°C, THF, 30 min then (CH2O)n, 278 °C to rt, 15 h, then ClCO2Me, 278 °C
to rt, 6 h, (2a, 68%; 2b, 75%; 2c, 72%; 2d, 58%; 2e, 68%); d)
bromoacetaldehyde dimethyl acetal, CH3CN, reflux, 36 h, 74%; e) 80%
AcOH(aq), 100 °C, 2 h, 84%; f) Ph3PNCO2Me, MeOH, 0 °C, 30 min, 85%
(1+2 mixture of 2f+2g).
Hz) and trans ( ~ 4 Hz) coupling constants between the C(5) and
Scheme 1
C(6) protons.
No products resulting from elimination–readdition processes
are observed, showing that 3-exo-trig cyclisation is faster than
The reported examples of this process have not addressed
substitution at the C(6) position. Due to the fact that a number
b-hydride elimination, even in the presence of two further b-
of substituted azabicyclo[3.1.0]hexanes occur as core structures
hydrogen atoms (entries 1–3 and 7). Possible coordination by an
in biologically active compounds, e.g. Trovan,5 it was important
NTs substituent has been suggested as a mechanism for
to establish the diastereoselectivity of the process at C(6).
suppressing b-hydride elimination.6 However, the oxygen
Substrates 2a–g with R1 or R2 ≠ H were therefore prepared.
Provided that no isomerisation occurs during the cyclisation
process, e.g. via b-hydride elimination–readdition processes
Table 1 Diastereoselective synthesis of azabicyclo[3.1.0]hexanes
(Scheme 2), the stereochemistry of 2a–g should control the
diastereoselectivity of C(6) in the azabicyclo[3.1.0]hexanes.
Carbonates 2a–g were synthesised from propargylamine
(Scheme 3) and the stereochemistry of the double bond of each
compound was confirmed by 1H NMR.
For this study, organotin(IV) reagents were chosen as the
anion capture agents due to their ease of preparation and
Yield (%)a
tolerance to air and moisture. The experimental conditions for
the palladium-catalysed cascade were as follows: carbonate 2a–
g (1.0 mol eq.), Pd(OAc)2 (0.1 mol eq.), PPh3 (0.2 mol eq.) and
Bu3SnY (Y = organic group) were dissolved in THF (4 ml
mmol21) and heated at reflux under nitrogen for 2–4 h. The
results of this study (Table 1) show that E-substituted olefins
(entries 1–6) and Z-substituted olefins (entries 7–13) afford
azabicyclo[3.1.0]hexanes 3 and 4 diastereoselectively in mod-
erate to good yield. The relative stereochemistry of 3 and 4 was
assigned on the basis of NOE data and the characteristic cis ( ~ 8
Entry
R1
R2
Y
3
4
1(2a)
2(2a)
3(2a)
4(2b)
Et
Et
Et
Ph
H
H
H
H
H
H
Et
Ph
CH2OBn
CH2OBn
CH2OBn
CO2Me
CO2Me
2-Furyl
81
85
40
68
38
74c
2-Thienyl
(Phenyl)ethynyl
2-Furyl
(Phenyl)ethynyl
2-Furyl
2-Thienyl
2-Thienyl
2-Furyl
2-Thienyl
(Phenyl)ethynyl
2-Furyl
5 (2b) Ph
6 (2f)b CO2Me
7 (2c)
8 (2d)
9 (2e)
10 (2e)
11 (2e)
12 (2g)
13 (2g)
H
H
H
H
H
H
H
53
51
60
73
53
56d
68d
2-Thienyl
a Isolated yield. b 8+1 mixture of E/Z isomers. c 8+1 mixture of diastereoi-
somers. d Trace ( < 5%) of other diastereoisomer observed (NMR).
Scheme 2
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CHEM. COMMUN., 2002, 768–769
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atoms of a sulfonamide are expected to be poor donors and there
are other examples in which no proximal NTs substituent is
present.7 The trace amounts of alternate diastereoisomer
observed in a few instances (entries 12 and 13) are thought to be
caused by conjugate addition–elimination of methoxide which
is generated in-situ from the carbonate group, rather than
elimination–readdition processes. The observed diastereose-
lectivity demonstrates the configurational stability of the
intermediate alkylpalladium(II) species (B) (Scheme 4).
The origin of the diastereoselectivity can be accounted for by
examining the transition state of the reaction prior to anion
capture (Scheme 4).
A pseudo 1-3 diaxial interaction which exists between the
protons and the Z-olefin substituent in the allenylpalladium(II
)
species (A) increases in (B) and in the vinylpalladium(II
)
species (C) and in the transition state leading to (C). This steric
interaction decreases the rate of 5-exo-trig cyclisation, resulting
in competitive premature cross coupling (direct capture)8 in
some cases.
In conclusion, this powerful methodology allows access to
azabicyclo[3.1.0]hexanes bearing a wide variety of substituents
diastereoselectively.
We thank Leeds University, the EU and EPSRC for
support.
Notes and references
1 J. Tsuji and T. Mandai, Angew. Chem., Int. Ed. Engl., 1995, 34, 2598.
2 R. Grigg, R. Rasul, J. Redpath and D. Wilson, Tetrahedron Lett., 1996,
37, 4609.
3 W. Oppolzer, A. Pimm, B. Stammen and W. E. Hume, Helv. Chim. Acta.,
1997, 80, 623; A. G. Steinig and A. de Meijere, Eur. J. Org. Chem., 1999,
1333.
4 For a definition of anion capture and other examples of biscyclistion–
anion capture see: R. Grigg and V. Sridharan, J. Organomet. Chem.,
1999, 576, 65.
5 K. W. Garey and G. W. Amsden, Pharmacotherapy, 1999, 19, 21.
6 C.-W. Lee, K. S. Oh, K. S. Kim and K. H. Ahn, Org. Lett., 2000, 2,
1213.
7 R. Grigg and V. Sridharan, J. Organomet. Chem., 1999, 576, 65.
8 For a study of the occurrence of direct capture in Pd catalysed cyclisations
see: E. Negishi, Y. Noda, F. Lamaty and E. J. Vawter, Tetrahedron Lett.,
1990, 31, 4393.
Scheme 4
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