Preorganization in highly enantioselective diaza-Cope rearrangement reaction

Article abstract of DOI:10.1021/ja055776k

Crystal structure and activation entropy data indicate that H-bond directed diaza-Cope rearrangement of chiral diimines takes place with a high degree of preorganization. CD spectroscopy and HPLC data show that there is inversion of stereochemistry for th

Full text of DOI:10.1021/ja055776k

Published on Web 11/08/2005
Preorganization in Highly Enantioselective Diaza-Cope Rearrangement
Reaction
†
†
†
‡
†
Hae-Jo Kim, Hyunwoo Kim, Gamil Alhakimi, Eui June Jeong, Nirusha Thavarajah,
†
†
†
,‡
,†
Lisa Studnicki, Alicja Koprianiuk, Alan J. Lough, Junghun Suh,* and Jik Chin*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto M5S 3H6, Canada, and
Department of Chemistry, College of Natural Sciences, Seoul National UniVersity, Seoul 151-742, Korea
Received August 23, 2005; E-mail: jchin@chem.utoronto.ca
There is much current interest in developing new methods for
making chiral 1,2-diamines since they are building blocks not only
Scheme 1
1
for stereoselective catalysts but also for a variety of therapeutic
2
agents. Many interesting meso-1,2-diamines have been synthesized
3
4
by the diaza-Cope rearrangement reaction (Scheme 1a). We
recently showed that the success of this strategy is due in large
5
part to resonance assisted hydrogen bonds (RAHB) that dramati-
cally shift the reaction equilibrium to one side (Scheme 1a). In
5
RAHBs, the H-bonds are strengthened by π delocalization (2, 4).
Here we investigate the mechanism of the rearrangement reaction
for making chiral diamines (Scheme 1b).
While the two reactions in Scheme 1 are obviously related, there
are also striking differences. The two H-bonds in 1 are positioned
to stabilize the boat-like transition state (5), while the two H-bonds
in 3 are positioned to stabilize the chair-like transition state (6). If
1
were to rearrange by a chair-like transition state or 3 were to
rearrange by a boat-like transition state, there could only be one
Scheme 2
6
internal H-bond at the transition state due to structural constraints.
4
Crystal structures of 1 and 2 reveal that the two compounds are in
staggered conformation (Scheme 2). Compound 1 is expected to
go from a staggered conformation in the ground state to an eclipsed
conformation in the transition state (5). In contrast, the crystal
7
structure (Figure 1) of 4 is remarkably close to the expected chair
form of the six-membered ring transition state of the rearrangement
reaction with all of the aryl substituents in the equatorial position
(6). Here, both the ground state and the transition state are in
staggered conformation. The two imine carbons in 4 are in close
proximity to each other (<3.74 Å). It appears that the chiral diimine
is highly preorganized for the rearrangement reaction while the meso
diimine is not.
diimine. This is a substantial difference in reactivity given that
the two reactions are so closely related. The enthalpic barrier is
q
slightly greater for the chiral diimine rearrangement (∆H ) 21.7
q
kcal/mol) than for the meso diimine rearrangement (∆H ) 18.1
kcal/mol). Overall, the rate constant for the chiral diimine rear-
-
4
-1
rangement reaction (k ) 6.4 × 10
than that for the meso diimine rearrangement reaction (k ) 2.0 ×
) at 50 °C.
The crystal structure of 4 shows that the chiral diimine rear-
s ) is about 30 times greater
-
5
-1
10
s
rangement reaction takes place with inversion of stereochemistry.
Thus the final diimine has the opposite configuration as the starting
diimine. The inversion of stereochemistry can also be confirmed
by circular dichroism (CD) spectroscopy (Figure 2). The CD
spectrum of 4 formed from the rearrangement of (R,R)-3 is identical
in magnitude but opposite in sign to that of (R,R)-4 directly
synthesized from the corresponding (R,R)-diamine with 2 equiv of
salicylaldehyde. CD spectroscopy can also be used for the purpose
of assigning the absolute configuration of the diimine. Bisignate
sign due to exciton coupling of the two hydroxyphenyl rings in 4
is observed around its UV maximum at 320 nm. According to the
To further probe the extent of preorganization in the rearrange-
ment reactions, we measured the activation entropy for the
q
rearrangement of the meso diimine (∆S ) -24 cal/mol/K) and
q
8
the chiral diimine (∆S ) -6 cal/mol/K). Consistent with the above
q
interpretation of the crystal data, the entropic barrier (-T∆S ) is
much greater for the meso diimine rearrangement (7.0 kcal/mol at
2
2
5 °C) than for the chiral diimine rearrangement (1.8 kcal/mol at
5 °C). Based on the entropic barrier alone, the chiral diimine is
expected to be about 6000 times more reactive than the meso
†
University of Toronto.
Seoul National University.
‡
9
exciton coupling analysis, the negative Cotton effect at 332 nm
16370
9
J. AM. CHEM. SOC. 2005, 127, 16370-16371
10.1021/ja055776k CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
However, even the meso diimine was below the detection limit of
the HPLC. Thus the enantioselectivity of the chiral diimine
rearrangement reaction is exceptionally high.
In summary, crystallographic and activation entropy data indicate
a high degree of preorganization for the diazo-Cope rearrangement
of the chiral diimine but not for that of the meso diimine. The
rearrangement of the chiral diimine takes place with inversion of
stereochemistry as supported by crystallography and CD spectros-
copy. 1H NMR and chromatographic analyses show that the
rearrangement reaction takes place with quantitative yield and with
exceptional enantioselectivity.
Figure 1. ORTEP diagrams of 4 with 30% probability thermal ellipsoids.
All the nonpolar hydrogens except the ones at C1 and C16 are omitted for
clarity. Selected interatomic distances (Å): O1‚‚‚N1, 2.600; N1‚‚‚C2, 1.279;
C2‚‚‚C17, 3.739.
Acknowledgment. We thank the Natural Sciences and Engi-
neering Research Council of Canada for financial support. H.-J.K.
thanks the Korea Science and Engineering Foundation of Korea
for a postdoctoral fellowship.
Supporting Information Available: Experimental procedure and
characterization details, including HPLC chromatogram for 4 (PDF),
X-ray structural data for 4 (CIF), and kinetic studies. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
Figure 2. Circular dichroism spectra of (R,R)-4 (open square) and (S,S)-4
(
1) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
(
open circle) and their UV-vis spectrum (filled square), where CD
1
997, 277, 936-938. (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew.
intensities of 4 are measured in tetrahydrofuran at 25 °C (80 µM, 1 cm cell
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Chem., Int. Ed. 1998, 37, 2580-2627. (c) Bobb, R.; Alhakimi, G.;
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(
2) (a) Bernhardt, G.; Gust, R.; Reile, H.; Vom Orde, H.-D.; M u¨ ller, R.; Keller,
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followed by the positive Cotton effect at 308 nm is consistent with
R,R)-4.10 Similarly, the positive Cotton effect at 332 nm followed
(
208. (b) Lee, Y.-A.; Lee, S. S.; Kim, K. M.; Lee, C. O.; Sohn, Y. S. J.
by the negative Cotton effect at 308 nm is consistent with (S,S)-4.
To gain some insight into the origin of stereoselectivity of the
rearrangement reaction (Scheme 1), three possible transition states
Med. Chem. 2000, 43, 1409-1412. (c) Vassilev, L. T.; Vu, B. T.; Graves,
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(7, 8, 9) for the reaction were considered. Transition state 7 is
(3) V o¨ gtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40.
(
4) Chin, J.; Mancin, F.; Thavarajah, N.; Lee, D.; Lough, A.; Chung, D. S. J.
expected to be the most stable since all four substituents are in the
equatorial position. In the case of the chair form of phenyl
cyclohexane, the phenyl group is more stable in the equatorial
position than in the axial position by about 3.0 kcal/mol.11 Thus
Am. Chem. Soc. 2003, 125, 15276-15277.
(5) See IIa and IIb in: Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am.
Chem. Soc. 2000, 122, 10405-10417.
(
6) Even without any H-bonds, meso diimines are expected to rearrange by
boat-like transition states and chiral diimines are expected to rearrange
by chair-like transition states. (a) V o¨ gtle, F.; Goldschmitt, E. Angew.
Chem., Int. Ed. Engl. 1973, 12, 767-768. (b) V o¨ gtle, F.; Goldschmitt, E.
Angew. Chem., Int. Ed. Engl. 1974, 13, 480-482.
(S,S)-3 should give mainly (R,R)-4 through transition state 7 with
negligible amounts of the meso diimine (by 8) and even less of the
S,S-enantiomer (by 9). The two internal hydrogen bonds in 7 are
expected to gain in strength as they progress from regular hydrogen
bonds to RAHBs during the course of the rearrangement reaction.
The hydrogen bonds should be stronger at the transition state than
in the starting material and strongest in the product. Thus the
hydrogen bonds should speed up the rearrangement reaction and
also drive the stereoselective reaction to completion.
(
7) Crystal structure of 4: C30
H
28
N O
2 4
, M
0.10 × 0.06 mm , triclinic P 1h , a ) 9.2775(7) Å, b )10.3554(8) Å, c
) 13.6763(8) Å; R ) 85.718(4)°, â ) 73.325(4)°, γ ) 83.745(4)°; V )
w
) 480.54, yellowish crystal 0.20
3
×
3
3
1
249.87(15) Å , Z ) 2, Fcalcd ) 1.277 Mg/m , µ(MoΚR, 0.71073) ) 0.085
-1
mm , 2θmax ) 55.08; 11 660 measured reflections, of which 5065 were
unique. The structure was solved by direct methods and refined by full-
matrix least squares calculations with SHELX-97. The final R1 ) 0.0645,
wR2 ) 0.1580 (I > 2σ(I)); R1 ) 0.1462, wR2 ) 0.2010 (all data);
measurements, Nonius SMART CCD equipped with a graphite crystal
incident-beam monochromator Lp.
(
8) To slow the rearrangement reactions of chiral diimines, the o-methoxy
substituents were replaced with p-dimethylamino substituents.
The enantioselectivity of the rearrangement reaction was deter-
mined by chiral HPLC. (S,S)-3 gave (R,R)-4 in quantitative yield
with no observable loss in enantiopurity (>99.8% ee). Similarly,
(9) Nakanishi, K.; Berova, N. In Circular Dichroism; Nakanishi, K., Berova,
N., Woody, R. W., Eds.; Wiley-VCH: New York, 1994; pp 361-398.
10) Spodine, E.; Zolezzi, S.; Calvo, V.; Decinti, A. Tetrahedron: Asymmetry
2000, 11, 2277-2288.
(
(
R,R)-3 gave (S,S)-4 in quantitative yield with no loss in enan-
12
(11) Garbish, E. W., Jr.; Patterson, D. B. J. Am. Chem. Soc. 1963, 85, 3228-
tiopurity. On the basis of this result, we expect 7 to be more stable
than 9 by at least 4.0 kcal/mol. Since 8 is expected to be more
stable than 9, there is a greater chance of forming the meso diimine
than the wrong enantiomer from the rearrangement reaction.
3
231.
(12) CHIRALCEL OD-H, 10% i-PrOH in hexane, 0.8 mL/min, 7.5 min for
R,R)-4 and 10.2 min for (S,S)-4.
(
JA055776K
J. AM. CHEM. SOC.
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VOL. 127, NO. 47, 2005 16371