Stereoselectivity of the benzannulation reaction: Efficient central-to-axial chirality transfer

Article abstract of DOI:10.1021/ja0201505

High diastereoselectivity is observed in the preparation of configurationally stable allocolchicinoids 5 from Fischer carbene complexes 4 and 1-pentyne. The analogous reaction of complexes 8 gives 9 with moderate diastereoselectivity for the opposite atro

Full text of DOI:10.1021/ja0201505

Published on Web 05/16/2002
Stereoselectivity of the Benzannulation Reaction: Efficient Central-to-Axial
Chirality Transfer
Andrei V. Vorogushin,†,‡ William D. Wulff,*,† and Hans-Ju¨rgen Hansen‡
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824, and Institute of Organic
Chemistry, UniVersity of Zu¨rich, Winterthurerstrasse 190, CH-8057, Zu¨rich, Switzerland
Received January 29, 2002
Scheme 1 a
Axially chiral biaryls are not only common structural subunits
in numerous pharmacologically important natural products,1 but also
the backbone of the growing number of highly effective chiral
ligands2 for the asymmetric synthesis. Despite the availability of
various procedures for the resolution of racemic mixtures of chiral
biaryls,3 the development of atropisomer-selective methods is a topic
of considerable current interest. This problem has been previously
approached in a number of different ways,4 including kinetic
resolution of racemic substrates,4c desymmetrization of prochiral
biaryls,4d chirality transfer from central,4e-g axial,4h and planar4i,j
asymmetry present in the substrate, and, most recently, asymmetric
catalytic coupling.4k Although the latter is certainly the most
convenient approach, the coupling efficiency and stereochemical
outcome of such processes is greatly influenced by the steric and
electronic nature of substituents on the aromatic rings being
coupled.4k Coupling reactions of planar chiral arene chromium
tricarbonyl complexes developed by the groups of Nelson4i and
Uemura4j can serve as examples of nearly complete atroposelec-
tivity.
The benzannulation reaction of R,â-unsaturated chromium car-
bene complexes5 allows for the construction of an arene ring in
the coordination sphere of the metal from three different ligands:
carbene, carbon monoxide, and alkyne. Since the arene ring is
assembled at the metal center, asymmetric induction can be expected
from existing chirality on one of the ligands, leading to a facial
selectivity in chromium coordination,6 which can have further
stereochemical consequences. Up to this point, this has been
reported for central-to-central,6a,b central-to-planar,6c-g and planar-
to-axial6h chirality transfer. Here we report the first examples of
central-to-axial chirality transfer in the benzannulation reaction of
carbene complexes and these are set in the context of the design of
a convergent synthesis7 of configurationally stable ring C func-
tionalized derivatives of allocolchicinoids.8
Synthesis of the carbene complexes 4 was performed starting
from the known9 benzosuberone 1. Vinyl bromide 2 was prepared
by the reaction of 1 with 2,2,2-tribromo-1,3,2-benzodioxaphos-
phole10 (Scheme 1). Allylic bromination of 2 followed by solvolysis
in the appropriate alcohol gave substrates 3a-d.11 Preparation of
carbene complexes 4 was achieved from the bromides 3 by using
a modified7 Fischer procedure followed by alkylation of the
intermediate lithium (R ) Me, Et) or tetramethylammonium (R )
i-Pr) salts of the corresponding metal acylates with ROTf.
We have examined the reaction of carbene complexes 4,
substituted with R, R1 groups of different size, with 1-pentyne
followed by oxidative demetalation and were pleased to observe
high to complete diastereoselectivity in every case (Table 1).
a Key: (a) 2,2,2-tribromo-1,3,2-benzodioxaphosphole, CH2Cl2, 0 °C, 30
min., rt, 15 min, 74%; (b) NBS, (PhCO)2O2, CCl4, reflux, 20 min; (c) R1OH,
NaHCO3, rt, 12-36 h, 3a (R1 ) Me) 54%, 3b (R1 ) Et) 50%, 3c (R1 )
i-Pr) 47%, 3d (R1 ) t-Bu, not isolated11).
Table 1. Atropisomer-Selective Benzannulation of Carbene
Complexes 4 with 1-Pentynea
yield
3 f 4 (%)
yieldb 5
I + II (%)
1
entry
4
R
R
drc (I:II)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Et
Me
Et
i-Pr
t-Bu
Me
Me
67
64
57
75
69
36e
40
43
47
50
73
72
II onlyd
II onlyd
II onlyd
II onlyd
1:13.2
i-Pr
1:12.5
a All reactions were run in benzene at 55-58 °C for 36 h with 0.33
equiv of 4 in 1 M 1-pentyne. b Isolated yield. c Determined by 1H NMR
integration from the crude product mixture and then confirmed after
chromatographic separation of diastereomers. d Diastereomer I could not
be detected by NMR, HPLC, and TLC even in the mixture of side products.
e Yield over two steps from 3.
Variations in the steric size of the R1 substituents had no effect
on the stereoselectivity of the reaction (entries 1-4): the only
phenolic products isolated from the reactions of 4a-d were
identified as the (aR,7R; aS,7S) diastereomers of 5a-d. However,
an increase in the size of the R group on 4 leads to a slight decrease
in the stereoselectivity: from complete with 4a (R ) Me) to
12.5 :1 with 4f (R ) i-Pr), all still favoring the (aR,7R; aS,7S)
diastereomer (entries 1, 5, and 6).
In an attempt to gain selective access to the allocolchicinoids
with an opposite biaryl twist, a series of complexes 8 with different
substituents R, R1 have been prepared from the corresponding
precursors 7, analogously to the above-described conversion of 3
to 4. Bromides 7 can be readily synthesized by using a silver-
assisted ring-opening reaction of dibromocyclopropane 67 in the
presence of the appropriate alcohol (Scheme 2).
The benzannulation reaction of carbene complexes 8 with
1-pentyne followed by oxidative demetalation afforded a mixture
of atropisomers 9 with the (aR,7S; aS,7R) diastereomer as the major
component (Table 2). In this case, the diastereoselectivity observed
* Corresponding author. E-mail: wulff@cem.msu.edu.
† Michigan State University.
‡ University of Zu¨rich.
9
6512
J. AM. CHEM. SOC. 2002, 124, 6512-6513
10.1021/ja0201505 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
In conclusion, we have developed a highly atropisomer-selective
preparation of configurationally stable (aR,7R; aS,7S) allocolchi-
cinoids 5 using a central-to-axial chirality transfer benzannulation
strategy. We have demonstrated that (aR,7S; aS,7R) allocolchici-
noids 9 can also be accessible in a stereoselective manner by using
a benzannulation reaction-thermal epimerizaton protocol. Ad-
ditional synthetic and mechanistic studies of these reactions are
underway.
a Key: (a) AgBF4, CaCO3, R1OH, 65-80 °C, 24-36 h.
Table 2. Atropisomer-Selective Benzannulation of Carbene
Complexes 8 with 1-Pentynea
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (NIH GM 33589). A.V. is grateful
to the Swiss National Science Foundation for the financial support
of the collaborative project. We thank Dr. A. Linden and the
University of Zu¨rich Crystallographic Center for determining the
structure of 9a,I. This work was carried out at both Michigan State
University and the University of Zu¨rich.
c
yieldb
7 f 8 (%)
yield 9
1
entry
8
R
R
I + II (%)
drd (I:II)
1
2
3
4
5
6
7
8a
8b
8c
8d7
8e
8f
Me
Me
Me
Me
Et
Me
Et
66
55
42
54
52
47e
29e
53
45
51
48
45
45
48
3.0:1
2.4:1
2.4:1
2.0:1
2.1:1
2.1:1
3.4:1
Supporting Information Available: Full experimental details and
characterization data for compounds 2-5 and 7-9 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
i-Pr
t-Bu
Me
Me
t-Bu
i-Pr
i-Pr
References
8g
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Table 3. Thermal Epimerization of Phenols 9, I, and IIa
1
entry
9
R
R
t, h
I:IIb
I + II,c %
1
2
3
4
5
9a
9b
9c
9e
9g
Me
Me
Me
Et
Me
Et
i-Pr
Me
t-Bu
22
28
48
22
22
94:6
95:5
96:4
96:4
97:3
90
96
95
100
82
i-Pr
a All epimerizations were run in toluene solution (10 mg/mL) at 120 °C
in a sealed tube under Ar. b Determined by 1H NMR integration. c Recovery
after column chromatography.
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To obtain information about the thermodynamics of the diast-
ereomer distribution, selected allocolchicinoids 9 were subjected
to thermal epimerization conditions. Equilibrium between the
diastereomers was achieved starting from both pure I and II in
each case in 22-48 h at 120 °C. We were glad to discover that in
all cases the equilibrium mixture strongly favored the desired
atropisomers 9,I (Table 3). High levels of material recovery make
these allocolchicinoids selectively available from the benzannulation
reaction of 8 followed by a first-order asymmetric transformation.4e
Assignment of (aR,7S; aS,7R) configuration to 9a,I has been
secured by X-ray diffraction studies. Consequently, the (aR,7R; aS,
7S) configuration has been assigned to 9a,II. The structure of other
phenols 5 and 9 has been determined by analysis of their 1H NMR
spectra12 relative to those of 9a, based on the difference in chemical
shifts of C7-H and coupling constants8b between C7-H and C6-
HaHb for both atropisomers I and II.
(9) Koo, J. J. Am. Chem. Soc. 1953, 75, 720. For modified synthesis, see the
Supporting Information.
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(11) Substrate 3d (R1 ) t-Bu) thus prepared could not be purified from the
side products. For an alternative route, see the Supporting Information.
(12) For a more detailed description of the stereochemical assignment, see the
Supporting Information.
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J. AM. CHEM. SOC. VOL. 124, NO. 23, 2002 6513