Desymmetrization of metallated cyclohexadienes with chiral N-tert-butanesulfinyl imines

Article abstract of DOI:10.1021/ol800478q

This communication describes the desymmetrization of various achiral metallated cyclohexadienes with a series of chiral N-tert-butanesulfinyl imines. Depending on the metal used, either the symmetrical diene (dicyclohexadienyl- zinc) or the desymmetrized

Full text of DOI:10.1021/ol800478q

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1847-1850
Desymmetrization of Metallated
Cyclohexadienes with Chiral
N-tert-Butanesulfinyl Imines
Modhu Sudan Maji, Roland Fro¨hlich, and Armido Studer*
NRW Graduate School of Chemistry and Fachbereich Chemie, Organisch-Chemisches
Institut, Westfa¨lische Wilhelms-UniVersita¨t, Corrensstrasse 40,
48149 Mu¨nster, Germany
studer@uni-muenster.de
Received March 3, 2008
ABSTRACT
This communication describes the desymmetrization of various achiral metallated cyclohexadienes with a series of chiral N-tert-butanesulfinyl
imines. Depending on the metal used, either the symmetrical diene (dicyclohexadienyl-zinc) or the desymmetrized diene (cyclohexadienyl-
MgCl) is obtained in a good regioselectivity with excellent diastereoselectivity. The products formed should be useful building blocks for
natural product synthesis. The symmetrical 1,4-dienes are readily oxidized to the corresponding diarylmethylamine derivatives.
The desymmetrization of 1,4-cyclohexadienes is a highly
useful route to interesting chiral building blocks for natural
product synthesis. Ionic and radical C-C bond forming
reactions, cycloadditions, and transition-metal mediated
processes have been successfully used to achieve that goal.1
We have recently shown that the chiral cyclohexadienyl-
Ti complex 1reacts highly stereoselectively with various
aldehydes to the desymmetrized cyclohexadienes 2.2 More
recently, a catalytic variant was developed using silylated
cyclohexadiene 33 in combination with a chiral Cu-catalyst.4
So far, our research in this area focused on the study of chiral
cyclohexadienyl nucleophiles. In the present communication,
we describe the desymmetrization of achiral metallated
cyclohexadienes with the aid of a chiral electrophile. As
promising electrophiles, we decided to study chiral N-tert-
butanesulfinyl imines 4, which have often been used in
stereoselective synthesis5,6 to give dienes of type 5 (Scheme 1).
The influence of the metal M on the desymmetrization
reaction was studied first. To this end, various cyclohexa-
dienyl metal compounds, which were readily prepared from
the corresponding Li-derivative via transmetalation, were
reacted with chiral sulfonyl imine 4a (R ) Ph). Along with
the desired desymmetrization product 5a, the symmetrical
(3) For the use of silylated cyclohexadienes in radical chemistry, see:
(a) Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080. (b) Studer,
A.; Amrein, S.; Schleth, F.; Schulte, T.; Walton, J. C. J. Am. Chem. Soc.
2003, 125, 5726. (c) Walton, J. C.; Studer, A. Acc. Chem. Res. 2005, 38,
794.
(4) Umeda, R.; Studer, A. Org. Lett. 2007, 9, 2175.
(5) Reviews: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984. (b) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39. (c)
Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (d) Morton,
(1) Reviews: (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999,
1765. (b) Rahman, A. N.; Landais, Y. Curr. Org. Chem. 2002, 6, 1369. (c)
Hoffmann, R. W. Synthesis 2004, 2075. (d) Schleth, F.; Studer, A. Synlett
2005, 3033.
D.; Stockman, R. A. Tetrahedron 2006, 62, 8869
.
(6) Some recent examples on allyl metal additions:(a) Li, S.-W.; Batey,
R. A. Chem. Commun. 2004, 1382. (b) Foubelo, F.; Yus, M. Tetrahedron:
Asymmetry 2004, 15, 3823. (c) Kolodney, G.; Sklute, G.; Perrone, S.;
(2) (a) Schleth, F.; Studer, A. Angew. Chem., Int. Ed. 2004, 43, 313.
(b) Schleth, F.; Vogler, T.; Harms, K.; Studer, A. Chem.-Eur. J. 2004, 10,
4171.
Knochel, P.; Marek, I. Angew. Chem., Int. Ed. 2007, 46, 9291
.
10.1021/ol800478q CCC: $40.75
Published on Web 04/09/2008
2008 American Chemical Society

Scheme 1
.
Desymmetrization of Cyclohexadienes
Table 1. Reaction of Various Metallated Cyclohexadienes
with 4a
entry
M
temp [°C]
5a [%]
6a [%]
1
2
3
4
5
6
7
8
Li
-50
-50
-30b
-78c
-50d
-50
-78
-78
50
11a
62
50
29a
9
55
6
8
ZnC6H7
ZnC6H7
ZnC6H7
ZnC6H7
ZnCl
14a
24a
18a
58
13a
69
77
MgCle
diene 6a was formed in larger amounts depending on the
metal used. The relative configuration of the major isomer
5a was unambiguously assigned by X-ray analysis (see
Figure 1). For the symmetrical diene 6a the relative config-
uration was assigned in analogy to the X-ray structure of its
derivative 6b.
MgClf
a Isolated as an inseparable mixture with other isomers. b Reaction was
run for 18 h. c Reaction was run for 64 h. d Reaction was conducted in
Et2O. e Transmetalation with 0.55 equiv MgCl2. f Transmetalation with 1.0
equiv MgCl2.
zinc derivative.7 The symmetrical isomer 6a was isolated
as major compound in 62% yield with a high diastereose-
lectivity (entry 2).8 The diene 5a was isolated as an
inseparable mixture containing the diastereoisomer of 6a and
another unidentified isomer in 14% combined yield. The
same reaction at -30 °C afforded a similar result (entry 3).
At -78 °C, reaction with 4a was far slower and a lower
selectivity resulted (entry 4). Interestingly, the selectivity was
reversed upon switching to Et2O as a solvent (entry 5). We
assume that transmetalation to zinc did not occur under these
conditions since the selectivity was similar to the selectivity
obtained for the Li-experiment. Reaction of the more Lewis-
acidic cyclohexadienyl-ZnCl-derivative with 4a gave a
slightly lower selectivity as compared with the result obtained
using the dicyclohexadienyl zinc derivative (entry 6). The
addition of cyclohexadienyl-triisopropoxy titanate (M )
Ti(Oi-Pr)3) to 4a at -78 °C occurred with low selectivity (6
isomers were identified by GC analysis) and with a low
combined yield (32%, not shown in Table 1). At higher
temperature, the Ti-cyclohexadienyl derivative was not
stable.9 Pleasingly, with the cyclohexadienyl-MgCl com-
pound the desired desymmetrized product 5a was obtained
with excellent diastereoselectivity (69% yield, ds > 99%,
entry 7). The diene 6a was isolated in 6% yield as the only
detectable side product. The other possible three isomers of
the product 1,3-diene were not identified. A slightly lower
regioselectivity but higher yield was obtained upon using
1.0 equiv of MgCl2 in the transmetalation step (entry 8). To
Figure 1. X-ray structures of compounds 5a and 6b.
(7) Allyl-zinc compounds have successfully been used in stereoselective
allylations: (a) Ren, H.; Dunet, G.; Mayer, P.; Knochel, P J. Am. Chem.
Soc. 2007, 129, 5376. (b) Dunet, G.; Mayer, P.; Knochel, P Org. Lett. 2008,
10, 117. See also ref. 6c.
The reactive cyclohexadienyl-Li compound provided the
desired desymmetrization product 5a (50%) along with an
inseparable mixture of an unidentified isomer and the
symmetrical diene 6a (Table 1, entry 1). A reversal of the
regioselectivity was achieved with the dicyclohexadienyl
(8) An authentic sample of the diastereoisomer of symmetrical diene
6a was prepared for comparison. In the fraction of the inseparable isomers
(14% combined yield), the diastereoisomer of 6a was identified and the
diastereoselectivity was calculated to be 50:1.
(9) Knoop, C. A.; Studer, A. AdV. Synth. Catal. 2005, 347, 1542.
1848
Org. Lett., Vol. 10, No. 9, 2008

summarize the screening studies we can state that depending
on the metal used, either the symmetrical diene 6a (cyclo-
hexadienyl-ZnC6H7) or the diene 5a (cyclohexadienyl-MgCl)
could be obtained in a good yield with good regioselectivity
and excellent diastereoselectivity.
Excellent diastereoselectivities were obtained for the
reaction with the p-substituted sulfinyl aryl amines 4b and
4d to give 5b and 5d as major compounds with good yields
and high regioselectivities (entries 1,3). The ortho-substituted
congeners delivered similar results (entries 2,4). A high
regioselectivity was also achieved with the furyl derivative
4f (entry 5). Nonaromatic sulfinyl imines 4g-k reacted with
cyclohexadienyl-MgCl with excellent diastereoselectivities
and good to excellent regioselectivities (entries 6-10).
Compared to the Mg-dienyl complex, the dicyclohexadi-
enyl zinc derivative provided slightly lower selectivities
favoring the symmetrical dienes 6 (Table 3). Aromatic N-tert-
butanesulfinyl imines 4b-e provided the dienes 6b-e in
moderate to good yields with high diastereoselectivities
(49-64%, entries 1-4).10 The 1,3-dienes were formed as a
mixture of isomers in 10-24% combined yield. A lower
regioselectivity was obtained with the furyl derivative 4f
(entry 5). High regioselectivities, excellent diastereoselec-
tivities and good yields were achieved with the alkylsulfinyl
imines 4h and 4i (entries 6,7).
Table 2. Reaction of Cyclohexadienyl-MgCl with Various
Iminesa
entry
R
compd 5 [%] ds (5) [%]b 6 [%]
1
2
3
4
5
6
7
8
9
4-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
2-furyl
trans-PhCH)CH
i-Pr
C6H11
b
c
d
e
f
g
h
i
74
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
4
13
5
8
5
5
4
9
1
69c
86
72
77
75
As a mechanism to explain the regiodivergent outcome
and the stereoselectivities of the reactions, we suggest the
following two models. The Grignard reagent probably reacts
from its symmetrical cyclohexadienyl-MgCl isomer via a six-
membered chair transition state according to model A
(Scheme 2). The Mg-metal acts as Lewis acid to complex
79d
74d
58d, e
48c,d
t-Bu
PhCH2
j
k
10
3
a Conditions: 1,4-cyclohexadiene (1.0 mmol), s-BuLi (1.1 mmol),
TMEDA (1.1 mmol) in THF at -78 °C for 1.5 h, then MgCl2 (0.55 mmol)
at -78 °C for 3 h, imines 4 for 30 min at -78 °C. b Diastereoselectivity
with respect to the other three possible 1,3-diene isomers. c Containing 2%
of the diastereoisomer of 6. d The symmetrical diene 6 could not be separated
from 5. Yield was calculated based on the ratio 5 to 6 measured by
GC-analysis. e The diastereoisomer of 6j was detected by GC analysis
(<1%).
Scheme 2. Models to Explain the Selectivity
To study the scope and limitations of our new method,
various imines were reacted under the optimized conditions with
cyclohexadienyl-MgCl (Table 2) and with the dicyclohexadienyl
zinc derivative (Table 3). The relative configuration of the
products 5b-k was assigned in analogy to compound 5a, and
the assignment of the relative configuration of products 6a and
6c-i is based on the X-ray structure of 6b.
the nitrogen lone pair and the oxygen atom of the sulfinyl
group.11 The sulfinyl imine reacts via its cis isomer12 to 5.
Reaction of the dicyclohexadienyl-zinc compound probably
occurs via the non symmetrical dienyl metal structure as
depicted in B to provide 6. A similar transition state model
was recently suggested by Marek for diastereoselective
allylations of allyl zinc derivatives to chiral N-tert-butane-
sulfinyl imines.6c
Table 3. Reaction of Cyclohexadienyl-ZnC6H7 with Various
Iminesa
entry
R
compd 6 [%] dr (6) other isomers [%]b
1
2
3
4
5
6
7
4-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
2-furyl
b
c
d
e
f
64
30:1
9:1
11:1
n.d.
n.d.
>99:1
>99:1
16
24
10
18
22
9
49
59c
49c
32
(10) An authentic sample of the diastereoisomer of symmetrical diene
6a was prepared for comparison. The 1H NMR showed characteristic signals
which were used to identify the presence of the diastereoisomers of 6b-d.
Due to signal overlap, the diastereosiomer ratio could not be determined
for 6e and f. By GC analysis, the diastereoisomer of 6i was not identified.
Selectivity of 6h was assigned in analogy.
i-Pr
C6H11
h
i
57c
58c
4
a Conditions: 1,4-cyclohexadiene (2.0 mmol), s-BuLi (2.2 mmol),
TMEDA (2.2 mmol) in THF at -78 °C for 1.5 h, then ZnCl2 (1.1 mmol)
at -78 °C for 3 h, then imines 4, at -50 °C for 18 h to 2d. b Combined
yield of other isomers formed. c The other isomer(s) could not be separted.
Yield calculated based on the ratio determined by GC- or 1H NMR analysis.
(11) Tang, T. P; Ellman, J. A J. Org. Chem. 1999, 64, 12.
(12) Stereoselective additions onto cis-imines: (a) Corey, E. J.; Decicco,
C. P.; Newbold, R. C Tetrahedron Lett. 1991, 32, 5287. (b) Roy, U. K.;
Roy, S. Tetrahedron Lett. 2007, 48, 7177.
Org. Lett., Vol. 10, No. 9, 2008
1849

Hence, treatment of 6b or 6c with DDQ in benzene at room
temperature afforded the corresponding protected diarylm-
ethylamines 7b and 7c in good yields as diastereoisomerically
pure compounds (Scheme 3).
Scheme 3. DDQ Mediated Oxidation
In summary, we present a novel approach for the desym-
metrization of achiral metallated cyclohexadienes with chiral
N-tert-butanesulfinyl imines. The reaction of readily gener-
ated cyclohexadienyl-MgCl with various N-tert-butanesulfi-
nyl imines provided the corresponding desymmetrized 1,3-
dienes with excellent diastereoselectivities and high
regioselectivities. The regioselectivity could be reversed by
using dicyclohexadienyl-Zn. The 1,4-dienes obtained with
the Zn-chemistry were readily oxidized to the corresponding
diarylmethylamine derivatives.
Finally, we decided to oxidize the product dienes to the
corresponding chiral diarylmethylamine derivatives. This
important structural unit can be found in biologically active
compounds.13 In agreement with our previous studies,14 the
1,3-dienes 5 could not be cleanly oxidized. However, smooth
oxidation of the symmetrical 1,4-dienes could be achieved.
Acknowledgment. We thank the NRW Graduate School
of Chemistry (stipend to M.S.M.), Novartis Pharma AG
(Young Investigator Award to A.S.), and the Fonds der
Chemischen Industrie for supporting our work.
(13) Stereoselective syntheses: (a) Hayashi, T.; Ishigedani; M, J. Am.
Chem. Soc. 2000, 122, 976. (b) Plobeck, N.; Powell, D. Tetrahedron:
Assymetry 2002, 13, 303. (c) Tokunaga, N.; Otomaru, Y.; Okamoto, K.;
Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
(d) Castagnolo, D.; Giorgi, G.; Spinosa, R.; Corelli, F.; Botta, M. Eur. J.
Org. Chem. 2007, 3676.
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Umeda, R.; Studer, A. Org. Lett. 2008, 10, 993.
OL800478Q
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Org. Lett., Vol. 10, No. 9, 2008