Enantiospecific photochemical Norrish/Yang type II reaction of nonbiaryl atropchiral α-oxoamides in solution-axial to point chirality transfer

Article abstract of DOI:10.1021/ja9050586

(Chemical Equation Presented) α-Oxoamides 1 with o-tert-butyl substitution on the N-phenyl moiety were found to be stable axially chiral atropisomers. These axially chiral α-oxoamides undergo enantiospecific photochemical γ-Hydrogen abstraction in CHCl

Full text of DOI:10.1021/ja9050586

Published on Web 07/24/2009
Enantiospecific Photochemical Norrish/Yang Type II Reaction of Nonbiaryl
Atropchiral r-Oxoamides in Solution—Axial to Point Chirality Transfer
Anoklase Jean-Luc Ayitou, Josepha L. Jesuraj, Nilotpal Barooah, Angel Ugrinov, and J. Sivaguru*
Department of Chemistry and Molecular Biology, North Dakota State UniVersity, Fargo, North Dakota 58105
Received June 19, 2009; E-mail: sivaguru.jayaraman@ndsu.edu
Scheme 1. γ-Hydrogen Abstraction Involving Axially Chiral 1a-b
Axial chirality has attracted great interest among synthetic chemists
in recent years, due to its increasingly significant role in catalytic
enantioselective thermal reactions.1 On the other hand, the use of axial
chirality to induce enantioselectivity in photochemical transformations
has not been explored in detail. Achieving high enanitoselectivity in
photoreactions in solution2 by utilizing conventional chiral perturbers
employed in thermal/catalytic reactions has inherent limitations as it
alters the diastereomeric activation energies of the prochiral substrates
in the ground state.2 To achieve high enantioselectivity in photochemi-
cal reactions in solution,2 chiral discrimination between the prochiral
faces has to occur within the short lifetime of the excited molecules,
intermediates, and/or transition states. Over the decades, elegant
methodologies involving supramolecular assemblies3 have provided
opportunities to carry out stereoselective phototransformations with
varying degrees of success. Yet, highly enantioselective photoreactions
in solution2 have not met the same level of success as conventional
thermal/catalytic reactions. Our approach was to employ molecularly
chiral chromophores to achieve high stereoselection during phototrans-
formations in solution.4 Recently we reported4 that molecularly chiral
acrylanilides could be effectively employed in asymmetric phototrans-
formations leading to >90% enantiomeric excess in solution. Here we
report a highly enantiospecific photochemical Norrish/Yang type II
reaction (γ-hydrogen abstraction) of axially chiral R-oxoamides 1 [axial
chirality arising from restricted N-C(Aryl) bond rotation].5
It is well established in literature that N-methyl substituted acryla-
nilide6 and N,N′-disubstituted benzamides7 with bulky ortho substit-
uents (o-tBu) in the phenyl ring are axially chiral due to the hindered
N-C(Aryl) bond rotation. Based on the above literature precedence,
we synthesized R-oxoamides 1 with the o-tert-butyl substituent on the
N-phenyl ring and tested if they would be axially chiral. R-Oxoamides
1 with o-tert-butyl substitution on the N-phenyl ring were found to be
axially chiral (P and M isomers). The individual P and M isomers
were easily isolable on a chiral stationary phase and were characterized
by NMR and CD spectroscopy, optical rotation, HRMS, and single
crystal XRD.8 These axially chiral optically pure R-oxoamides 1a-b
were stable at room temperature and could be stored at 0 °C for months
without enantiomerization.8 Due to the slow enantiomerization rate
of optically pure 1 at room temperature, the kinetics of enantiomer-
ization was performed at +50 °C, revealing ∆G‡ of enantiomerization
to be ∼27 kcal/mol.8 The optically pure axially chiral 1 were
investigated for axial to point chirality transfer during γ-hydrogen
abstraction5 leading to photoproducts 2-4. Photoproducts 2 and 4 are
expected to be a mixture of enantiomers as the N-C(Aryl) bond was
shown to rotate freely due to the reduced C-N-C bond angle.9
Table 1. Enantiomeric Ratios and Activation Parameters (∆∆H‡
a
c
-
and ∆∆S‡) for γ-Hydrogen Abstraction of 1 in CHCl3
T
(°C)
time
(min)
entry
(-)-1a
(+)-1a
(-)-1b
(+)-1b
1
2
3
4
5
6
7
8
9
40
30
20
10
0
-20
-40
30
30
30
30
60
74:26 (A) 26:74 (B) 70:30 (A) 30:70 (B)
76:24 (A) 23:77 (B) 72:28 (A) 27:73 (B)
79:21 (A) 21:79 (B) 74:26 (A) 25:75 (B)
82:18 (A) 18:82 (B) 78:22 (A) 22:78 (B)
85:15 (A) 15:85 (B) 81:19 (A) 20:80 (B)
89:11 (A) 11:89 (B) 84:16 (A) 15:85 (B)
90:10 (A) 11:89 (B) 86:14 (A) 14:86 (B)
120
360
∆∆H‡ (kcal/mol)
∆∆S‡ (cal/mol/K)
-2.11
2.14
4.65
-1.80
-3.93
1.60
3.26
-4.50
a Values are an average of 3 runs ((2% error). b A and B refer to the
first and second peaks that elute in the HPLC on a chiral stationary
c
phase. ∆∆H‡, ∆∆S‡ were computed from Eyring plots (eqs 1 and 2,
refs 2a and 8).
Pyrex cutoff and a cooling jacket under a constant flow of nitrogen
at various temperatures (+40 to -40 °C). The reaction was found
to be clean and efficient with >95% conversion after 3 h at 30 °C.8
At low temperatures, the reaction was slow and longer irradiation
times were necessary to achieve higher conversions. The photo-
products were purified by chromatography and characterized by
NMR and CD spectroscopy, optical rotation, and single crystal
XRD.8 HPLC analysis of the photolysate on a chiral stationary
phase gave the enantiomeric ratio (e.r.) in the ꢀ-lactam 2 (Table
1). The optical antipodes of 1 gave opposite enantiomers in the
ꢀ-lactam 2 as expected. Additionally, the e.r. values in 2 were found
to be dependent on the reaction temperature (Figure 1). For example,
in the case of 1a, e.r. values increased (with the same enantiomer)
from ∼74:26 to ∼90:10 upon changing the temperature from +40
°C to -40 °C.
ln(kR/kS) ) ln[(100 + %ee)/(100 - %ee)]
(1)
ln(kR/kS) ) ∆∆G‡ ) ∆∆S‡R-S/R - ∆∆H‡R-S/RT (2)
Photoirradiation of optically pure atropisomers of 1 (Scheme 1)
was preformed using a 450 W medium pressure Hg lamp with a
9
11314 J. AM. CHEM. SOC. 2009, 131, 11314–11315
10.1021/ja9050586 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
The differential activation parameters (∆∆H‡ and ∆∆S‡) were
computed using Eyring plots (eqs 1 and 2).2a,8 The enantioselectivity
(∆∆G‡) depends on both ∆∆H‡ and ∆∆S‡. The magnitude and more
importantly the signs of ∆∆H‡ and ∆∆S‡ help explain the effect
of temperature on e.r. values. Since the ∆∆H‡/RT term is
proportional to the reciprocal temperature (eq 2), the ln(kR/kS), i.e.,
the ∆∆G‡ value, is determined mostly by the enthalpic contribution
at low temperatures; however, as the temperature increases, the
relative contribution from the ∆∆S‡/R term increases and contributes
substantially to ln(kR/kS) at higher temperatures. As both ∆∆H‡ and
∆∆S‡ have the same sign, the decrease in temperature enhances
the same isomer as the magnitude of ∆∆G‡ increases (eq 2). Hence
the enantioselectivity (e.r. values) should increase upon lowering
the temperature as observed. The opposite signs with similar
magnitude of ∆∆H‡ and ∆∆S‡ for a given pair of axially chiral (P
and M) R-oxoamides 1 are reflected in the optical antipodes of the
enhanced ꢀ-lactam 2. The activation parameters and its influence
on e.r. values in 2 are indicative of conformational factors playing
a pivotal role in the reaction pathway.2a
by the differential activation parameters (∆∆H‡ and ∆∆S‡). We
believe that, upon lowering the temperature, the rate of intercon-
version between the two 1,4-diradicals (rad-1 and ent-rad-1) is
lowered with respect to the rate of ring closure, as bond rotations
are slower at lower temperatures resulting in efficient axial chirality
transfer leading to high enantioselectivity (e.r. values) in ꢀ-lactam
2 as observed. This speculation can be ascertained based on indirect
evidence from ∆G‡ for enantiomerization. Molecular constraints
based on restricted bond rotation are enhanced in 1a (k ) 2.6 ×
10-6 s-1)8 compared to 1b (k ) 4.0 × 10-6 s-1)8 with respect to
the rate of enantiomerization. This is reflected in the slower rate of
enantiomerization8 resulting in the more efficient chiral transfer in
1a than in 1b. A closer look at the e.r. values reveals that the
selectivity in the di-tert-butyl derivative 1a is slightly higher than
the corresponding mono-tert-butyl derivative 1b adding credibility
to the above rationale. Thus this simple mechanistic model enables
us to rationalize the observed temperature dependence of e.r. values
in 2.
Our investigation has paved the way to employ a new class of
nonbiaryl atropisomers, Viz. axially chiral R-oxoamides 1, for
asymmetric photochemical transformations in solution. Irradiation
of axially chiral chromophores that equilibrate very slowly in the
ground state leads to very high enantioselectivity in the photoprod-
ucts. We are currently exploring this strategy for various asymmetric
phototransformations in solution.
Figure 1. Enantiomeric ratios in 2a at various temperatures in CHCl3.
Acknowledgment. J.S. thanks the financial support of the NSF
(CAREER: CHE-0748525). This paper is dedicated to Prof. K. K.
Balasubramanian, Indian Institute of TechnologysMadras (IIT
Madras), an inspiring teacher on the occasion of his 70th birthday.
NMR analysis of 1 (pure P or M) showed that both E and Z
NsCO rotamers exist in solution.8 The dynamic nature of NsCO
rotation in axially chiral amides is well established.6,7 Analysis of
the crystal structures of 1 reveals that the two carbonyl groups are
at 90° to each other.8 The free NsCO rotation in solution likely
enables 1 to adopt a conformation ideal for photochemical
γ-hydrogen abstraction defined by Scheffer and co-workers.10 The
established mechanism5c of photoreaction in R-oxoamides involves
a net hydrogen transfer to the photoexcited carbonyl group either
by direct hydrogen abstraction or in a sequential two-step process,
Viz. single electron transfer (SET) followed by proton transfer
(Scheme 1). Unlike aromatic ketones that undergo γ-hydrogen
abstraction from the nπ* triplet state,5b photochemical γ-hydrogen
abstraction in R-oxoamides is mediated by the electron transfer
pathway even if the lowest triplet excited state of the ketone is the
otherwise unreactive ππ* state.5c Depending on the axial chirality
(P or M) in 1, the torsion angle OdCsCRsNꢀ could be positive
or negative leading to the possibility of γ-hydrogen abstraction from
one face of the carbonyl resulting in the 1,4-diradical (rad-1 or
ent-rad-1).
In general, the chirality of the ꢀ-lactam photoproduct 2 is decided
at the stage of ring closure of the 1,4-diradical intermediate, i.e.,
which face of the benzylic radical center adds to the γ-carbon
radical. The 1,4-diradical is free to rotate in solution, and the
competition between bond rotations vs bond formation in the 1,4-
diradical likely determines the extent of chiral induction in the
photoproducts. In other words, the rate of interconversion between
the two diradicals (rad-1 and ent-rad-1) and the rate of ring closure
leading to 2 impart a dynamic nature in the system as ascertained
Supporting Information Available: Experimental procedures for
synthesis and photoreactions, characterization of R-oxoamides 1 and
ꢀ-lactam 2. This material is available free of charge via the Internet at
http://pubs.acs.org.
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