Domino cycloaddition organocascades of dendralenes

Article abstract of DOI:10.1002/anie.201302185

Hooray Horeau! Highly enantioselective organocatalyzed Diels-Alder reaction cascades are disclosed for the first time. The reaction enables the efficient and rapid construction of enantiopure polycycles from simple achiral, acyclic polyenes. Copyright

Full text of DOI:10.1002/anie.201302185

Angewandte
Chemie
Communications
Synthetic Methods
N. J. Green, A. L. Lawrence, G. Bojase,
A. C. Willis, M. N. Paddon-Row,*
M. S. Sherburn*
&&&& — &&&&
Domino Cycloaddition Organocascades
of Dendralenes
Hooray Horeau! Highly enantioselective
organocatalyzed Diels–Alder reaction
cascades are disclosed for the first time.
The reaction enables the efficient and
rapid construction of enantiopure poly-
cycles from simple achiral, acyclic poly-
enes.
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Communications
DOI: 10.1002/anie.201302185
Synthetic Methods
Domino Cycloaddition Organocascades of Dendralenes**
Nicholas J. Green, Andrew L. Lawrence, Gomotsang Bojase, Anthony C. Willis,
Michael N. Paddon-Row,* and Michael S. Sherburn*
In the past decade, organocascade reactions[1–3] have been the
subject of intense interest, primarily because of their capacity
to combine two or more bond-forming events into a single
synthetic operation. Considering the topical nature of organo-
cascades and the complexity-generating power of the Diels–
Alder (DA) reaction, it is surprising that there have been no
reports of organocascades featuring more than one DA event.
Branched acyclic polyenes ([n]dendralenes 1–6;
Scheme 1), have only recently become synthetically accessi-
ble[4] and are excellent starting materials for domino reac-
tions.[5] The potential of these structures in enantioselective
catalysis has, until now, remained untapped.[6] Herein we
disclose the first organocatalyzed cascades involving two DA
reactions (Scheme 1).[7,8] This unique combination of organo-
cascade catalysis and p-bond-rich hydrocarbons provides
exquisite examples of the amplification of enantiopurity
which is predicted by the Horeau principle,[9,10] thus trans-
Scheme 1. Summary of the present work. Tf=trifluoromethanesulfonyl.
forming simple starting materials into complex products with
superb enantioselectivity (e.r. > 99.5:0.5).
We initially set about performing enantioselective single
cycloadditions with [3]dendralene[11] and b-substituted acro-
lein dienophiles, catalyzed by MacMillanꢀs imidazolidi-
nones[12,13] (Scheme 2). Optimized reaction conditions[14,15]
resulted in high yields and good enantioselectivities (e.r.
92:8–96:4) for the conversion of [3]dendralene (1) into
a range of monocycloadducts.[16]
We next turned our attention to the organocatalyzed
reaction between [4]dendralene and acrolein. Although
initially apprehensive ([4]dendralene has shown variable
levels of regio- and chemoselectivity as a diene in DA
reactions),[17] we were delighted to find that terminal double
Scheme 2. Single cycloadditions with [3]dendralene. See the Support-
ing Information for full details. [a] The e.r. values were determined by
HPLC analysis using a chiral stationary phase.
cycloaddition was favored under organocatalytic conditions,
À
thus furnishing a bicycle with four new C C bonds (Scheme 1,
R = H). The second cycloaddition was so fast that the
intermediate of this domino sequence[18] was not detected.
Indeed, in a separate experiment employing one molar
equivalent of both acrolein and [4]dendralene, a 1:1 mixture
of [4]dendralene and the bis(adduct) was formed, thus
indicating a very short-lived monoadduct intermediate.
Similar reactivity was exhibited by [6]- and [8]dendralene
(Table 1, entries 2 and 3) and, in accordance with the Horeau
principle, very high enantioselectivity was observed for each
double cycloaddition (e.r. > 99.5:0.5). The double cycloaddi-
tion organocascade also tolerated substitution at the b posi-
tion of the dienophile, thus leading to a range of highly
enantioenriched products (Table 1, entries 1–6).
[*] N. J. Green, Dr. A. L. Lawrence, Dr. G. Bojase, Dr. A. C. Willis,[+]
Prof. M. S. Sherburn
Research School of Chemistry, Australian National University
Canberra, ACT 0200 (Australia)
E-mail: sherburn@rsc.anu.edu.au
Prof. M. N. Paddon-Row
School of Chemistry, The University of New South Wales
Sydney, NSW 2052 (Australia)
E-mail: m.paddonrow@unsw.edu.au
[+] Crystallography (willis@rsc.anu.edu.au)
[**] This work was supported by the Australian Research Council.
M.N.P.-R. acknowledges that the computational component of this
research was undertaken with the assistance of resources provided
at the NCI National Facility through the National Computational
Merit Allocation Scheme supported by the Australian Government.
The authors thank Tony Herlt (ANU) for assistance with HPLC
separations.
Are the very high enantiomeric ratios observed in this
organocascade truly the result of two catalyst-controlled
cycloadditions? We reflected that the first-formed stereogen-
ic center(s) (i.e., from the first cycloaddition step) might be
influencing the stereochemical outcome of the second cyclo-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302185.
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Table 1: Double cycloadditions with even dendralenes.
These examples can be combined with the data from HPLC
traces to provide the basis for a clear and straightforward
demonstration of the Horeau principle in the context of
double enantioselective catalysis (Scheme 3). Using the final
e.r. (R,R/S,S) and d.r. (C2/meso) values, catalyst stereoselec-
Entry
n
R
Product
e.r.[a]
d.r.[b]
Yield
[%][c]
1
2
3
4
6
8
4
4
4
H
H
H
CO2Me
Ph
8
9
10
11
12
13
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
99:1
89:11
95:5
90:10
91:9
82:18
74:26
70
72
62[d]
71
4[e]
5[f]
6[g]
50
45
iPr
99:1
[a] Determined by HPLC analysis using a chiral stationary phase. See the
Supporting Information for full details. [b] Determined by either HPLC
1
analysis using a chiral stationary phase, or H NMR spectroscopic
analysis. See the Supporting Information. [c] Yield of the isolated
product after reduction with sodium borohydride. See the Supporting
Information. [d] Yield estimated by 1H NMR spectroscopic analysis with
an internal standard. [e] Isolated and characterized as the bis(lactone).
See the Supporting Information. [f] Performed at 558C. [g] Performed at
708C.
Scheme 3. Stereochemical pathways for cycloaddition leading to
observed amplification of enantiopurity.
tivity for each step of about 95:5 is determined, which
matches the stereoselectivity observed for single cycloaddi-
tions.
addition.[19] To test for the presence of this potential double
stereodifferentiative effect, the racemic imidazolidinone
organocatalyst (Æ)-7 was synthesized. A double cycloaddition
sequence between acrolein and [4]dendralene (4) catalyzed
by the racemate furnished a statistical mixture of products
composed of two diastereomers: an achiral meso compound
and a racemic mixture of C2-symmetric enantiomers (e.r. =
50:50, d.r. = 1:1).[20] This result indicates that the high
enantiopurity of the bis(adduct)s produced by the homochiral
catalytic system stems purely from catalyst control and hence,
the Horeau principle. Identical results were obtained for the
range of dienophiles employed in double cycloaddition
reactions (Table 1).[21] Remarkably, even when increasingly
vigorous reaction conditions were used, resulting in lower
observed diastereoselectivity (Table 1, entries 5 and 6), sat-
isfactorily high product e.r. values of 99:1 were still observed.
The symmetrical, bifunctional[22] nature of the even parity
dendralenes determines that two different reaction pathways,
each featuring a single catalytic system error (formation of an
S-configured stereocenter), lead to the meso bis(adduct).
Products of this enantioselective double cycloaddition
(Table 1, entries 1 and 4) react readily and in high yield with
dienophiles such as N-methylmaleimide (NMM; 14), di-
methylacetylenedicarboxylate (15), and benzoquinone (16) to
generate enantioenriched triple cycloadducts: multicyclic
systems containing aliphatic and aromatic rings (Scheme 4).
These highly enantiomerically enriched, functionalized poly-
cyclic frameworks are generated in only two steps from
achiral and acyclic [4]dendralene, a hydrocarbon which is
prepared in only one step from the commodity chemical
chloroprene.
Mechanistic insight into the enantioselectivity of the
organocatalyzed DA reactions was provided by B3LYP/6-
31G(d) calculations on the reaction between [3]dendralene
(1) and acrolein, catalyzed by the imidazolidinone 7. Twenty-
one gas-phase transition structures (TSs) were located,
comprising different conformations associated with the four
basic modes of addition, namely, endo(N)/exo(X) modes
leading to R- and S-configured adducts. The lowest energy
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Figure 1. B3LYP/6-31G(d) transition structures (and schematic dia-
gram) for the reaction between [3]dendralene and acrolein catalyzed by
imidazolidinone 7. Calculated M06-2X/6-311+G(2df,p)//B3LYP/6-
31G(d) gas phase relative enthalpies (free energies, kJmolÀ1) [CH3CN
solvent values in square brackets] are listed in blue. Developing bond
lengths are shown in black and the phenyl centroid to closest H
distances are shown in green.
Scheme 4. Third cycloaddition yielding tricycles, tetracycles, and hexa-
cycles. Reaction conditions: a) 14 (1.3 mol equiv), CDCl3, RT, 24 h,
70%. b) 15 (2.0 mol equiv), [D6]DMSO, 708C, 15 h, 94%. c) 16 (2.5
mol equiv), [D6]DMSO, 358C, 2 h, 95%. d) 16 (0.5 mol equiv),
[D6]DMSO, 708C, 15 h, 89%. e) 14 (1.1 mol equiv), [D6]DMSO/
[D3]MeCN (1:1), 908C, 24 h, 79%. DMSO=dimethylsulfoxide.
0.33–0.44 electrons are transferred from diene to dienophile
in these TSs.
TSs for each mode of addition are shown in Figure 1, together
with their M06-2X/6-311 + G(2df,p)//B3LYP/6-31G(d) rela-
tive enthalpies and free energies (258C), for both gas phase
and acetonitrile as a solvent. The R adduct is predicted to be
the major one, in agreement with previous experimental
findings with 7.[12] Furthermore, the calculated e.r. values of
96:4 (gas) and 97:3 (CH3CN) are in agreement with the
experimental value of 92:8. The origin of the enantioselec-
tivity is largely the consequence of the benzyl group lying
directly over the iminium cation—a result of both stabilizing
phenyl–p/iminium–p and phenyl–p/CH3 interactions[23]
(Figure 1)—thereby blocking approach to that face by the
dendralene.
All four TSs, although concerted, display an extremely
high degree of bond-forming asynchronicity, with the bond
between the central methylene carbon atom of [3]dendralene
and the b-carbon atom of the dienophile being well advanced
(2.1–2.2 ꢁ) and that between the terminal methylene carbon
atom of the dendralene and the a-carbon atom of the
dienophile barely progressed at all (3.3–3.9 ꢁ). This high
degree of asynchronicity, which is significantly higher than
that found in earlier studies,[23,24] also occurs in the TSs for DA
dimerizations of dendralenes and was attributed in the latter
case to the presence of strong pentadienyl radical character in
the TSs.[25] In the present case, however, the asynchronicity is
attributed to the TSs acquiring quasipentadienyl cation
character, thereby facilitating delocalization of the positive
charge. Indeed, Mulliken population analysis reveals that
In summary, dendralenes have been used to execute the
first organocatalyzed double enantioselective cycloaddition
cascades. Since the stereoselectivity of each cycloaddition is
controlled solely by the catalyst—and in accordance with the
Horeau principle—the enantiopurity of the organocascade
products is extremely high. The C2-symmetric, chiral double
cycloadducts undergo a third DA cycloaddition to generate
highly functionalized hydrophenanthrenes. In terms of prod-
À
uct enantiopurity and number of C C bonds formed, these
double cycloaddition organocascades transcend all previous
efforts in organocascade catalysis.[1–3] Furthermore, the ease
of downstream manipulation of the products, coupled with
simple preparation of the p-bond-rich hydrocarbon precur-
sors, makes this new approach a convenient and powerful
method for polycycle construction.
Received: March 15, 2013
Published online: && &&, &&&&
Keywords: cycloaddition · hydrocarbons · polycycles · polyenes ·
.
synthetic methods
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[6] So far, substituted [3]dendralenes have only been utilized in the
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[15] For details of precursor substitutions tolerated (and not toler-
ated) and reaction optimization, see the Supporting Information.
[16] To obtain material more suited to purification and e.r. determin-
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borohydride to their corresponding alcohols.
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[20] The structure of the meso and C2-symmetric bis(adduct)s were
confirmed by single-crystal X-ray analysis, and optical rotation
(see the Supporting Information). CCDC 906640 and 906641
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[21] For the case of R = iPr, a very slight double stereodifferentiative
effect was observed (meso/rac = 54:46).
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