Nitroso-dienophile additions to dendralenes: A short synthesis of branched aminosugars

Article abstract of DOI:10.1021/ol302619r

The first heteroatom-based dienophile cycloadditions to cross-conjugated alkenes ([n]dendralenes) are reported. Nitroso-dienophiles undergo smooth single and double Diels-Alder additions to the parent dendralenes with orientational regio- and stereoselectivity and, notably, with reactivity that depends upon the parity of the [n]dendralene. The first crystal structure of a cross-conjugated hexaene is reported. Vasellas nitroso-sugar reagent gives a highly enantiomerically enriched double cycloadduct with [3]dendralene. This bicyclic oxazine is successively dihydroxylated and then ring-opened to form a branched chain diamino tetrol.

Full text of DOI:10.1021/ol302619r

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5652–5655
Nitroso-Dienophile Additions to
Dendralenes: A Short Synthesis
of Branched Aminosugars
Ruomeng Wang,† Gomotsang Bojase,† Anthony C. Willis,†,§ Michael N. Paddon-Row,*,‡
and Michael S. Sherburn*,†
Australian Research Council Centre of Excellence for Free Radical Chemistry and
Biotechnology, Research School of Chemistry, Australian National University,
Canberra, ACT 0200, Australia, and School of Chemistry,
The University of New South Wales, Sydney, NSW 2052, Australia
m.paddonrow@unsw.edu.au; sherburn@rsc.anu.edu.au
Received September 23, 2012
ABSTRACT
The first heteroatom-based dienophile cycloadditions to cross-conjugated alkenes ([n]dendralenes) are reported. Nitroso-dienophiles undergo
smooth single and double DielsꢀAlder additions to the parent dendralenes with orientational regio- and stereoselectivity and, notably, with
reactivity that depends upon the parity of the [n]dendralene. The first crystal structure of a cross-conjugated hexaene is reported. Vasella’s
nitroso-sugar reagent gives a highly enantiomerically enriched double cycloadduct with [3]dendralene. This bicyclic oxazine is successively
dihydroxylated and then ring-opened to form a branched chain diamino tetrol.
Cross-conjugated trienes ([3]dendralenes)1 have the un-
ique ability to participate in diene-transmissive2 Dielsꢀ
Alder (DA) sequences.3 Thus, in one synthetic operation,
the triene 1 (Scheme 1) serves as a double diene, uniting
Scheme 1. Prototypical Diene-Transmissive Double
DielsꢀAlder Sequence Involving [3]Dendralene
with two dienophiles to form four new CꢀC bonds and a
decalin framework 2 in a sequence of two concerted
reactions, which can often be conducted in a “one pot”
manner.4 It is hard to conceive of a more step-efficient and
atom-economical route to the decalin framework.
† Australian National University.
The higher dendralenes can also undergo sequences of
DA reactions.5,6 Despite their enormous potential in this
regard, relatively little is known, since members of the
[n]dendralene family higher than the tetraene (i.e., n =
5ꢀ8) were made available in useful amounts only in 2009.7
In fact, the only reactions of the higher dendralenes reported
so far involve the dienophile N-methyl maleimide (NMM).
Herein we report the first examples of DA reactions
of dendralenes with heteroatom-containing dienophiles,
‡ The University of New South Wales.
§ To whom correspondence should be addressed regarding X-ray crystal
structures. E-mail: willis@rsc.anu.edu.au.
(1) For a recent review of dendralenes, see: Hopf, H.; Sherburn, M. S.
Angew. Chem., Int. Ed. 2012, 51, 2298–2338.
(2) This term was coined by Tsuge: Tsuge, O.; Wada, E.; Kanemasa,
S. Chem. Lett. 1983, 12, 239–242.
(3) For a review of DielsꢀAlder sequences, see: Winkler, J. D. Chem.
Rev. 1996, 96, 167–176.
(4) Bradford, T. A.; Payne, A. D.; Willis, A. C.; Paddon-Row, M. N.;
Sherburn, M. S. J. Org. Chem. 2010, 75, 491–494.
(5) For [4]dendralene, see: Payne, A. D.; Willis, A. C.; Sherburn,
M. S. J. Am. Chem. Soc. 2005, 127, 12188–12189.
(6) For [5]dendralene, see: Bojase, G.; Payne, A. D.; Willis, A. C.;
Sherburn, M. S. Angew. Chem., Int. Ed. 2008, 47, 910–912.
(7) Payne, A. D.; Bojase, G.; Paddon-Row, M. N.; Sherburn, M. S.
Angew. Chem., Int. Ed. 2009, 48, 4836–4839.
r
10.1021/ol302619r
Published on Web 10/30/2012
2012 American Chemical Society

namely nitroso-compounds.8 We show that, in agreement
with the aforementioned study involving the carbo-
dienophile NMM,7 the parent [n]dendralenes exhibit chemi-
cal reactivity that is dependent upon parity n, with odd and
even [n]dendralenes displaying markedly differing behavior.
As part of this study, we also report the first X-ray crystal
structure analysis of a [6]dendralene,9 the molecular struc-
ture from which displays a conformation that is consistent
with our earlier theoretical predictions.7 We also show that
this chemistry allows the rapid synthesis of new variations on
natural structures, specifically branched chain amino-sugars.
The results of nitrosobenzene dienophile cycloaddi-
tions to the [n]dendralene family are depicted in Schemes 2
and 3. The odd [n]dendralenes, namely [3]dendralene 1,
[5]dendralene 5, and [7]dendralene 7, undergo selective
single cycloadditions at the terminal diene site to form
the corresponding mono-oxazines 3, 6, and 8, respectively,
in good yields. The mass balance from these reactions is
unreacted starting dendralene and multiple adducts. It is
noteworthy that the orientational regioisomer (i.e., 4) is
not observed in these reactions.
Scheme 3. Selective Double/Triple Cycloadditions of Even
[n]Dendralenes with Nitrosobenzene as Dienophile
In contrast, the even [n]dendralenes gave monocyclo-
adducts as minor products on exposure to 1 mol equiv of
nitrosobenzene. With 2 mol equiv of dienophile, however,
[6]dendralene 11 and [8]dendralene 13 underwent smooth
transformations into terminal-terminal double adducts
12 and 14, respectively (Scheme 3). [4]Dendralene 9 be-
haves in the same way but also participates in a third
cycloaddition at the “transmitted” diene, resulting in
mixtures of double and triple products. The use of 3 mol
equiv of nitrosobenzene, however, gives a reasonable
isolated yield of triple adduct 10. Minor products resulting
from additions to internal dienes and orientational regio-
isomers were also observed in these reactions.
Scheme 2. Selective Single Cycloadditions of Odd
[n]Dendralenes with Nitrosobenzene as Dienophile
Leach and Houk reviewed the available experimen-
tal data and performed DFT calculations on nitroso-
dienophile additions to substituted 1,3-butadienes.10 In both
experiment and calculations, reactions of 2-substituted
1,3-butadienes give moderate to poor orientational regio-
selectivity. Our reactions of dendralenes (Schemes 2 and 3)
contrast with these previous studies since they exhibit high
orientational regioselectivities, and our calculations agree
with these findings, with a predicted kinetic product ratio
of 99.8%:0.2% for 3:4 (only 3 is detected experimentally).
The calculated transition structures leading to these two
products (3-TS and 4-TS) are depicted in Figure 1.
As can be seen from inspection of 3-TS and 4-TS
(Figure 1), the cycloaddition of nitrosobenzene and
[3]dendralene proceeds through highly asynchronous TSs.
These TSs have biradicaloid character and can be approxi-
mated to biradicals 3-birad and 4-birad, in which the
shorter developing bond in the TS is fully formed.11 The
TS leading to the major orientational regioisomer, namely
(8) Reviews: (a) Weinreb, S. M.; Staib, R. R. Tetrahedron 1982, 38,
3087–3128. (b) Waldmann, H. Synthesis 1994, 535–551. (c) Streith, J.;
Defoin, A. Synthesis 1994, 1107–1117. (d) Streith, J.; Defoin, A. Synlett
1996, 189–200. (e) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317–
1348. (f) Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem. 2006, 2031–
2043. (g) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80,
595–607.
(9) Structures of substituted [3]- and [4]dendralenes have been pre-
viously reported. For X-ray crystal structures of [4]dendralenes, see: (a)
Katoh, T.; Ogawa, K.; Inagaki, Y.; Okazaki, R. Bull. Chem. Soc. Jpn.
1997, 70, 1109–1114. (b) Reference 6. (c) Kanibolotsky, A. L.; Forgie,
J. C.; McEntee, G. J.; Talpur, M. M. A.; Skabara, P. J.; Westgate,
T. D. J.; McDouall, J. J. W.; Auinger, M.; Coles, S. J.; Hursthouse, M. B.
Chem.;Eur. J 2009, 15, 11581–11593.
(10) Leach, A. G.; Houk, K. N. J. Org. Chem. 2001, 66, 5192–5200.
(11) (a) Paddon-Row, M. N.; Sherburn, M. S. Chem. Commun. 2012,
48, 832–834. (b) Toombs-Ruane, H.; Pearson, E. L.; Paddon-Row,
M. N.; Sherburn, M. S. Chem. Commun. 2012, 48, 6639–6641.
Org. Lett., Vol. 14, No. 22, 2012
5653

3-TS, enjoys stabilization through pentadienyl radical-like
delocalization. The TS leading to the minor regioisomer
has only allyl radical-like character. A pentadienyl radical
is calculated to be 22.6 kJ/mol more stable than an allyl
radical,12 hence explaining the strong preference for regio-
isomer 3 over 4.13
Figure 2. Molecular structures of dendralenes 12 and 14 from
single crystal X-ray analyses. Polyene groups are highlighted in
green, and phenyl groups are omitted for clarity.
Scheme 4. Diene-Transmissive Two- and Threefold
Cycloadditions of Nitrosobenzene to [3]- and [5]Dendralenesa
Figure 1. B3LYP/6-31G(d) transition structures for reaction of
[3]dendralene and PhNdO leading to regioisomers 3 and 4.
Single crystal X-ray analyses were conducted on samples
ofthe threeproducts depicted inScheme 3,14 which secured
the assignment of orientational regioselectivity of the
cycloadditions and also gave insights into the preferred
conformations of cross-conjugated polyenes more gener-
ally. The molecular structures obtained from analyses of
tetraene 12 and hexaene 14 are shown in Figure 2. These
substituted [4]- and [6]dendralene structures comprise two
and three s-trans-1,3-butadienes, respectively, in which
adjacent butadiene units are arranged in an approximately
orthogonal manner. To our knowledge, no X-ray crystal
structure of a cross-conjugated polyene higher than a
[4]dendralene has been previously reported.15 These ex-
perimental structures closely match the calculated lowest
energy conformations for the parent even [n]dendralenes.7
Odd dendralenes are by no means limited to single
additions (Scheme 4). Thus, [3]dendralene 1 undergoes a
diene-transmissive double cycloaddition with nitrosoben-
zene to give fused bicyclic oxazine 16 as the major prod-
uct. As is the case with many such nitroso-DielsꢀAlder
reactions,10 the orientational regioselectivity of the second
cycloaddition is poor and isomer 15 is also formed in
sizable amounts. [5]Dendralene 5 undergoes a related
a Phenyl groups are omitted from the X-ray structures for clarity.
diene-transmissive triple DA sequence to form tricyclic
adduct 17 as the major product.
These reactions appear to be quite general for nitroso
dienophiles and, moreover, display significant synthetic
potential. As shown in Scheme 5, [3]dendralene 1 under-
goes selective single and double cycloadditions with the
nitrosocarbonyl dienophile16 prepared in situ from per-
iodate oxidation of CbzNHꢀOH [N-(benzyloxycarbonyl)-
hydroxylamine, 18]. Interestingly, the orientational regio-
selectivity of the second cycloaddition is much higher in this
(12) See the Supporting Information for details.
(13) Experiments on PhNHOH have shown that the OꢀH bond
dissociation energy (BDE) is 42 kJ molꢀ1 weaker than the NꢀH BDE:
Bordwell, F. G.; Liu, W.-Z. J. Am. Chem. Soc. 1996, 118, 8777–8781.
Our preliminary B3LYP/6-31G(d) calculations are consistent with theꢀse1
findings and predict that the PhNHꢀO• nitroxide radical is 25 kJ mol
more stable than the PhN•(OH) oxyaminyl radical.
(14) CCDC 892226ꢀ892232 contain the crystallographic data for
compounds 10, 12, 14, 16, 17, 21, and 24, respectively. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(15) Search conductedon the Cambridge Crystallographic Database,
June 2012.
(16) For a recent review, see: Bodnar, B. S.; Miller, M. J. Angew.
Chem., Int. Ed. 2011, 50, 5630–5647.
5654
Org. Lett., Vol. 14, No. 22, 2012

Scheme 5. Three-Step Synthesis of Branched Chain
Diamino-Tetrol 22 in Racemic Form
Scheme 6. Enantioselective Synthesis of Branched Chain
Diamino-Tetrol (þ)-22
series than with nitrosobenzene (cf. 3 f 15 þ 16, Scheme 4).
Presumably, this outcome is brought about by the signifi-
cant steric requirements of the Cbz group. The trisubstituted
alkene of bicyclic oxazine 20 was dihydroxylated to give a
single diastereomer of diol 21. Simultaneous Cbz-deprotec-
tion, ring-opening, and N-methylation17 afforded racemic
diamino-tetrol (()-22. In this short sequence, a heteroatom
has been added to each of the six carbons of [3]dendralene to
generate a highly functionalized chiral product with (within
the limits of detection) complete control of diastereoselectivity.
Evidently, an enantioselective version of this transforma-
tion would be more attractive. The successful realization of
this goal is depicted in Scheme 6. Thus, Vasella’s nitroso-sugar
2318 brings about a highly (er = 97:3) enantioselective second
cycloaddition reaction to give bicyclic oxazine 24. Protection,
diastereoselective dihydroxylation, and deprotection/ring-
opening/N-methylation furnish the enantioenriched branched
diamino-tetrol (þ)-22. The easy access to this new compound,
combined with its structural similarity to natural aminosugars,
will stimulate further synthetic and biological investigations
into dendralene-derived branched chain sugars.
In conclusion, this project has shed new light on the
physical and chemical behavior of the fundamental class of
hydrocarbon structures known as dendralenes. Moreover,
the first hetero-DielsꢀAlder reactions on the dendralene
family have underscored the immense synthetic potential
of this fascinating and neglected group of compounds.
Acknowledgment. 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 Computa-
tional Merit Allocation Scheme supported by the Austra-
lian Government. We thank Mr. Tony Herlt (ANU) for
assistance with HPLC separations.
Supporting Information Available. Experimental pro-
cedures and characterization data; cifs and atomic dis-
placement ellipsoid plots for compounds 10, 12, 14, 16,
17, 21, and 24; computational details; 1H and 13C NMR
spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Xu, C.-P.; Xiao, Z.-H.; Zhuo, B.-Q.; Wang, Y.-H.; Huang, P.-Q.
Chem. Commun. 2010, 46, 7834–7836.
(18) (a) Vasella, A. Helv. Chim. Acta 1977, 60, 1273–1295. (b)
Aebischer, B. M.; Hanssen, H. W.; Vasella, A. T.; Schweizer, W. B.
J. Chem. Soc., Perkin Trans. 1 1982, 2139–2147. (c) Felber, H.; Kresze, G.;
Prewo, R.; Vasella, A. Helv. Chim. Acta 1986, 69, 1137–1146. (d) Basha, A.;
Henry, R.; McLaughlin, M. A.; Ratajczyk, J. D.; Wittenberger, S. J. J. Org.
Chem. 1994, 59, 6103–6106.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
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