Diels-Alder cycloaddition of chiral nonracemic 2,5-diketopiperazine dienes

Article abstract of DOI:10.1021/ol201768f

Preparation of a chiral, nonracemic 2,5-diketopiperazine diene has enabled the investigation of intermolecular hetero-Diels-Alder cycloadditions. The diketopiperazine diene is reactive with both electron-rich and -deficient alkene substrates. Diastereofacial control in the cycloaddition is enforced with a removable aminal substituent. This study partly illuminates the regiochemical, stereoelectronic, and reactivity preferences of the diketopiperazine cycloaddition as well as provides a direct diastereoselective synthetic route to bicyclo[2.2.2]diazaoctane structures.

Full text of DOI:10.1021/ol201768f

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4430–4433
DielsꢀAlder Cycloaddition of Chiral
Nonracemic 2,5-Diketopiperazine Dienes
Erin N. Morris, E. Katherine Nenninger, Robert D. Pike, and Jonathan R. Scheerer*
Department of Chemistry, The College of William & Mary, P.O. Box 8795,
Williamsburg, Virginia 23187, United States
jrscheerer@wm.edu
Received July 1, 2011
ABSTRACT
Preparation of a chiral, nonracemic 2,5-diketopiperazine diene has enabled the investigation of intermolecular hetero-DielsꢀAlder cycloadditions.
The diketopiperazine diene is reactive with both electron-rich and -deficient alkene substrates. Diastereofacial control in the cycloaddition is
enforced with a removable aminal substituent. This study partly illuminates the regiochemical, stereoelectronic, and reactivity preferences of the
diketopiperazine cycloaddition as well as provides a direct diastereoselective synthetic route to bicyclo[2.2.2]diazaoctane structures.
Brevianamide A was the first isolated fungal meta-
bolite that displayed a [2.2.2]-diazabicyclic core.1 In the
decades since this initial discovery, a large family of
prenylated indole alkaloids has been revealed, including
the paraherquamides, stephacidins, and notamides.2
Many of these natural products possess potent and
varied biological activities including antitumor, antihel-
mintic, antibacterial, and insecticidal properties.3 The
[2.2.2]-diazabicyclic structural motif shared among
these alkaloids is postulated to arise through a biogenic
intramolecular hetero-DielsꢀAlder cycloaddition be-
tween an unactivated terminal alkene and a 2,5-diketo-
piperazine (DKP) tautomeric azadiene intermediate
(Figure 1).4
Figure 1. Structure of brevianamide A, a representative [2.2.2]-
diazabicyclic indole alkaloid, and the proposed biosynthesis.
Support for this biosynthetic hypothesis was first rea-
lized by Porter and Sammes when they demonstrated the
DielsꢀAlder cycloaddition of a symmetric pyrazine with
both a strained alkene and dimethyl acetylenedicarboxy-
late (Figure 2).5 More recently, Williams and co-workers
have explored intramolecular variants of the DKP Dielsꢀ
Alder in the context of several elegant biomimetic total
syntheses.6,2 To date, three distinct dieneophiles have been
employed in the DKP cycloaddition: unactivated alkenes
(including intramolecular variants), acetylene dicarboxylate,
(1) Birch, A. J.; Wright, J. J. J. Chem. Soc., Chem. Commun. 1969,
644–645.
(2) (a) Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711–740. (b)
Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127–139.
(3) (a) Qian-Cutrone, J. F.; Huang, S.; Shu, Y. Z.; Vyas, D.; Fair-
child, C.; Menendez, A.; Krampitz, K.; Dalterio, R.; Klohr, S. E.; Gao,
Q. J. Am. Chem. Soc. 2002, 124, 14556–14557. (b) Martinez-Luis, S.;
Rodriguez, R.; Acevedo, L.; Gonzalez, M. C.; Lira-Rocha, A.; Mata, R.
Tetrahedron 2006, 62, 1817–1822. (c) Williams, R. M.; Stocking, E. M.;
Sanz-Cervera, J. F. Top. Curr. Chem. 2000, 209, 97–173.
(4) (a) For reviews of biogenic DielsꢀAlder reactions, see:
(a) Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42,
3078–3115. (b) Williams, R. M.; Stocking, E. M.; Sanz-Cervera, J. F.
Biosynthesis of Prenylated Alkaloids Derived from Tryptophan. Bio-
synthesis: Aromatic Polyketides, Isoprenoids, Alkaloids; Springer-Verlag
Berlin: Berlin, 2000; Vol. 209, pp 97ꢀ173.
(5) Porter, A. E. A.; Sammes, P. G. J. Chem. Soc., Chem. Commun.
1970, 1103.
(6) For reviews, see: (a) Miller, K. A.; Williams, R. M. Chem. Soc.
Rev. 2009, 38, 3160–3174. (b) Williams, R. M.; Cox, R. J. Acc. Chem.
Res. 2003, 36, 127–139.
r
10.1021/ol201768f
Published on Web 07/19/2011
2011 American Chemical Society

and diazodicarboxylate.7 These mostly symmetric or teth-
ered substrates validate the reaction with dieneophiles of
disparate electronic character but offer only a limited view
of other reaction attributes including the regiochemical
and stereochemical preferences of the DKP DielsꢀAlder
cycloaddition.
envisioned that a removable chiral tert-butyl aminal aux-
iliary could impart a strong facial bias during the cycload-
dition and inform selective bond formation. Exploiting the
concept of self-regeneration of stereocenters as pioneered
by Seebach,11 we initiated our synthesis of the chiral DKP
diene from L-serine methyl ester. Preparation of the desired
DKP was facile and required only modifications to pre-
cedented procedures.12 First, the R-amino and β-hydroxy
functions were engaged to form the derived cyclic tert-
butyl aminal 1 (Scheme 1).13 Acylation of the unstable
Scheme 1. Synthesis of Chiral Diketopiperazine Diene
Figure 2. Initial discovery of the DKP DielsꢀAlder cycloaddition.
Additionally, the prior work by Williams and co-work-
ers in the biomimetic total synthesis of VM555998 was of
particular interest as the only example of an intermediate
bearing a stereogenic center adjacent to the DKP azadiene
(Figure 3).9 In the key cycloaddition step, the exocyclic
alkene in the DKP starting material isomerized to the
reactive endocyclic azadiene over two weeks in acetyl chlor-
ide. Subsequent intramolecular DielsꢀAlder cycloaddition
afforded a mixture of three of the four possible diaster-
eomers (35:15:10:0), the major product resulting from
apparent contrasteric cycloaddition on the face syn to the
C-17 methyl group.10
aminal mixture (dr 1:1) with chloroacetyl chloride at 0 °C
gave predominantly the kinetic product, cis-configured
oxazolidine 2 (dr >10:1). In addition to providing one
major diastereomer, acylation also rendered the aminal
function configurationally stable to the required subse-
quent chemical transformations. Staudinger reduction of
the derived azide with triphenylphosphine under anhy-
drous conditions (toluene, 90 °C) permitted cyclization of
the resulting aza-Wittig intermediate at the pendant
methyl ester, thereby establishing both the DKP ring and
the lactim ether moiety.14 In summary, the DKP diene
precursor 3 could be prepared in four steps (two chroma-
tographic separations) and 60% overall yield.
(7) (a) Jin, S.; Wessig, P.; Liebscher, J. J. Org. Chem. 2001, 66, 3984–
3997. (b) Alen, J.; Smets, W. J.; Dobrzanska, L.; De Borggraeve, W. M.;
Compernolle, F.; Hoornaert, G. J. Eur. J. Org. Chem. 2007, 965–971. (c)
Sanz-Cervera, J. F.; Williams, R. M.; Marco, J. A.; Lopez-Sanchez,
J. M.; Gonzalez, F.; Martinez, M. E.; Sancenon, F. Tetrahedron 2000,
56, 6345–6358.
(8) (a) Stocking, E. M.; Sanz-Cervera, J. F.; Williams, R. M. J. Am.
Chem. Soc. 2000, 122, 1675–1683. (b) Sanz-Cervera, J. F.; Williams,
R. M. J. Am. Chem. Soc. 2002, 124, 2556–2559.
(9) The synthesis of versicolamide B intercepts a chiral spriooxindole;
however in this case, the stereogenic center is removed from the DKP
diene functionality and imparts only modest facial selectivity: Miller,
K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009, 1, 63–68.
(10) The DKP DielsꢀAlder cycloaddition pertinent to VM99955 has
been modeled: Domingo, L. R.; Zaragoza, R. J.; Williams, R. M. J. Org.
Chem. 2003, 68, 2895–2902.
(11) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708–2748.
(12) (a) Brunner, M.; Saarenketo, P.; Straub, T.; Rissanen, K.;
Koskinen, A. M. P. Eur. J. Org. Chem. 2004, 3879–3883. (b) Cagnon,
J. R.; LeBideau, F.; MarchandBrynaert, J.; Ghosez, L. Tetrahedron
Lett. 1997, 38, 2291–2294.
Figure 3. Synthesis of VM55599 via DKP [4 þ 2] by Williams.
(13) Seebach, D.; Stucky, G.; Renaud, P. Chimia 1988, 42, 176–178.
(14) Nicolaou, K. C.; Lizos, D. E.; Kim, D. W.; Schlawe, D.; de
Noronha, R. G.; Longbottom, D. A.; Rodriquez, M.; Bucci, M.; Cirino,
G. J. Am. Chem. Soc. 2006, 128, 4460–4470.
In the context of this background, we wanted a readily
prepared, chiral, nonracemic DKP diene model to explore
diastereoselective cycloadditions in greater detail. We
Org. Lett., Vol. 13, No. 16, 2011
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Oxidation of bicycle 3 with DDQ gave a mixture of the
desired DKP diene 4 and the regioisomeric exocyclic diene
5 (64% combined yield, 85:15 ratio). The diene isomers
were inseparable by chromatography, and the desired
diene 4 decomposed on exposure to air.15 Consequently,
the acidic hydroquinone byproduct was removed by filtra-
tion and base wash, and the resulting diene mixture was
submitted directly to the DielsꢀAlder without purification.
With the aim of obtaining a crystalline cycloadduct, N-
phenylmaleimide was first examined in the DielsꢀAlder
reaction with DKP diene 4. We observed efficient reaction
on heating in toluene (110 °C, 0.1 M) to afford cycloadduct
6 as a single diastereomer (dr >95:5) in 62% yield. The
structure of product 6, verified by single crystal X-ray
analysis, reveals that cycloaddition occurred on the DKP
face opposite the tert-butyl aminal substituent and from
the endo transition state (Scheme 2).
Table 1. Diketopiperazine Diene DielsꢀAlder Cycloadditiona
Scheme 2. DKP DielsꢀAlder with N-Phenylmaleimide
Because both the endo and exo transition states for the
DKP diene cycloaddition have possible secondary orbital
interactions with π-electrons, the exclusive preference for
the endo transition state in this case was surprising and is
not easily rationalized from related azadiene substrates.
Although the preference for the endo-approach in the
DielsꢀAlder reaction with carbocyclic dienes is well docu-
mented;particularly with maleic acid derivatives;nitro-
gen-containing dienes often prefer the exo approach.16 In
particular, 2-azadiene derivatives generally favor the exo
approach.17 DKP 4 behaves distinctly from other known
azadienes.
We were encouraged by the reactivity and selectivity of
the maleimide example and set out to explore the scope of
the thermal cycloaddition with DKP diene 4. A variety of
dieneophilic substrates, both electron-rich and -deficient,
a Standard conditions: 4 (and 5), tol 110 °C (0.1 M), dieneophile
(1.1 equiv), 16 h. b Isolated yield of a single (major) isomer. c Isolated
yield of combined isomers. d Determined by 1H NMR spectroscopy of
the unpurified product mixture.
(15) DKP dienes rapidly undergo cycloaddition with molecular
oxygen: Machin, P. J.; Porter, A. E. A.; Sammes, P. G. J. Chem. Soc.,
Perkin Trans. 1 1973, 404–409.
(16) Exo adducts with maleimide involve heterocyclic dienes. See:
Eckroth, D. R. J. Org. Chem. 1976, 41, 394–395 and references therein.
(17) (a) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617–2618
and references therein. (b) For general reviews of azadienes in the
DielsꢀAlder reaction, see: (b) Boger, D. L. Tetrahedron 1983, 39,
2869–2939. (c) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetra-
hedron 2002, 58, 379–471. (d) Boger, D. L.; Weinreb, S. M. Hetero
DielsꢀAlder Methodology in Organic Synthesis; Academic Press: San
Diego, 1987.
were equally competent in the cycloaddition. Representative
results are summarized in Table 1. Diene face selectivity was
excellent; in no case were products detected from cycloaddition
on the DKP diene face syn to the tert-butyl aminal substituent.
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Org. Lett., Vol. 13, No. 16, 2011

Due to the dissonant18 relationship of heteroatoms in
DKP diene 4, prediction of the major cycloadduct regioio-
somer was not obvious a priori. However, as we explored
unsymmetric substrates, two different regiochemical pre-
ferences emerged, one for reverse electron demand cy-
cloaddition (electron-rich dieneophiles), another under
normal electron demand conditions (electron-deficient
dieneophiles). For electron-rich dieneophiles such as phe-
nylacetylene, styrene, and R-methyl styrene (entries 2ꢀ4),
the more nucleophilic terminus of the dieneophile aligns
with the C-3 imino functionality of DKP diene 4. In
contrast, electron-deficient unsaturated esters (entries
5ꢀ8) reverse this trend, aligning the less nucleophilic
terminus with C-3 of DKP 4. Unsaturated ester dieneo-
philes (entries 5ꢀ8) also show a preference for the endo
transition state. Selectivity varies from 84:16 for acrylate
(entry 5, combined endo/exo) to approximately 2:1 for
cinnamate, sorbate, and crotonate (entries 6ꢀ8). These
selectivities, and that of the previously mentioned malei-
mide derivate (>95:5 endo, Scheme 2), loosely correlate
with endo/exo ratios for thermal DielsꢀAlder cycloaddi-
tion between the illustrated dieneophiles and carbocyclic
dienes like cyclopentadiene19 or cyclohexadiene.20
In an attempt to probe the ambiphilic nature of the DKP
diene DielsꢀAlder reaction, benzyl sorbate (entry 8) was
selected as a unique dieneophile possessing two alkene
functions. Cycloaddition of DKP diene 4 with sorbate
indicated a small preference (3:2 ratio) for reaction at the
more electron-rich ψ,δ-unsaturation relative to the more
electron-deficient R,β-unsaturation (see adducts 14aꢀd).
Cycloadduct 8a was chosen as a model substrate to
demonstrate cleavage of the tert-butyl aminal residue
(Scheme 3). In order to facilitate aminal removal, it proved
necessary to first convert the basic lactim ether function-
ality into a lactam. Toward this end, the lactim ether in 8a
was efficiently deprotected by alkylative de-etherification
with in situ prepared TMSI.21 The resulting lactam was
benzylated on nitrogen to afford intermediate product 15.
The tert-butyl aminal was then removed with HCl in the
presence of 1,3-propanedithiol as an aldehyde trapping
agent.22 The resulting product 16 was cleanly obtained
after removal of the dithiane byproduct. The N-benzyl
amide protection was not necessary for aminal cleavage
but differentiated the two lactams in product 16 and
greatly aided solubility; the derived product lacking the
benzyl amide was virtually insoluble in common organic
solvents (e.g., MeOH, acetone, DMF).
Scheme 3. Cleavage of tert-Butyl Aminal Auxiliary
To summarize, we have successfully expanded the scope
ofthe DKP diene DielsꢀAlder cycloaddition. The reaction
is compatible with a variety of alkene (or alkyne) dieneo-
philes. The dominant product regioisomer is predictable,
and stereochemistry favors reaction from the endo transi-
tion state with electron-deficient R,β-unsaturated esters
and imides. The methods explored in this initial report
offer a synthetic tool for chemists in the construction of
asymmetric molecules that contain a [2.2.2]-diazabicyclic
skeleton.
Acknowledgment. This work was funded by the Petro-
leum Research Fund, Research Corporation for Scientific
Advancement, and the College of William & Mary. E.N.
M. and E.K.N. were supported in part by funding from a
Howard Hughes Medical Institute Undergraduate Science
Education Grant to the College of William & Mary.
Supporting Information Available. Experimental pro-
cedures and spectral data (PDF). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(18) For explanation of dissonant bond paths, a phraseintroduced by
David A. Evans, see: Hudlicky, T.; Reed, J. W. The Way of Synthesis:
Evolution of Design and Methods for Natural Products; Wiley-VCH:
Weinheim, 2007; Chapter 2.4.5, p 186.
(20) Mellor, J. M.; Webb, C. F. J. Chem. Soc., Perkin Trans. 2 1974,
22–25.
(21) Morita, T.; Okamoto, Y.; Sakurai, H. J. Chem. Soc., Chem.
Commun. 1978, 874–875.
(22) Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992, 114,
10677–10678.
(19) (a) Methyl acrylate (75:25 endo/exo): Mellor, J. M.; Webb, C. F.
J. Chem. Soc., Perkin Trans. 2 1974, 17–22. (b) Methyl crotonate (1:1
endo/exo): Kobuke, Y.; Fueno, T.; Furukawa, J. J. Am. Chem. Soc.
1970, 92, 6548–6553. (c) Methyl cinnamate (53:47 endo/exo): Mama-
ghani, M. Tetrahedron 2002, 58, 147–151.
Org. Lett., Vol. 13, No. 16, 2011
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