Efficient entry to the [2.2.2]-diazabicyclic ring system via diastereoselective domino reaction sequence

Article abstract of DOI:10.1021/ol3007056

A domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular hetero-Diels-Alder cycloaddition for the synthesis of [2.2.2]-diazabicyclic structures is reported. Excellent diastereofacial control during the cycloaddition is enforced with a removable chiral phenyl aminal diketopiperazine substituent. The reaction sequence rapidly generates molecular complexity and is competent with both enolizable and nonenolizable aldehyde substrates (nine examples total). Progress toward the synthesis of malbrancheamide B, a protypical member of the [2.2.2]-diazabicyclic natural product family, is also disclosed.

Full text of DOI:10.1021/ol3007056

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2458–2461
Efficient Entry to the [2.2.2]-Diazabicyclic
Ring System via Diastereoselective
Domino Reaction Sequence
Kaila A. Margrey, Alex J. Chinn, Stephen W. Laws, 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 March 20, 2012
ABSTRACT
A domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular hetero-DielsꢀAlder cycloaddition for the
synthesis of [2.2.2]-diazabicyclic structures is reported. Excellent diastereofacial control during the cycloaddition is enforced with a removable
chiral phenyl aminal diketopiperazine substituent. The reaction sequence rapidly generates molecular complexity and is competent with both
enolizable and nonenolizable aldehyde substrates (nine examples total). Progress toward the synthesis of malbrancheamide B, a protypical
member of the [2.2.2]-diazabicyclic natural product family, is also disclosed.
The [2.2.2]-diazabicyclic ring skeleton is shared among a
number of prenylated indole alkaloids including the brevia-
namides, paraherquamides, stephacidins, notamides, and
malbrancheamides (Figure 1).1 These fungal-derived natural
products possess a wide spectrum of biological activities
including antitumor, antihelminthic, antibacterial, calmodu-
lin inhibition, and insecticidal properties.2 Impressive struc-
tural diversity is observed across the alkaloid family,
although all members share a [2.2.2]-diazabicyclic core. In
addition to potent bioactivity and remarkable chemical
structure, there are engaging biosynthetic questions regarding
the origin of the [2.2.2]-diazabicyclic structural motif. The
functionality is putatively derived from a biogenic intramo-
lecular hetero-DielsꢀAlder cycloaddition (IMDA).3
total synthesis, five general synthetic strategies have
been successfully employed to prepare the [2.2.2]-diaza-
bicylic core:4 (1) biomimetic DielsꢀAlder cycloaddition5
(Williams, Liebscher), (2) radical cyclization6 (Myers,
Simpkins), (3) oxidative enolate coupling7 (Baran),
(4) SN20 enolate alkylation8 (Williams), and (5) cationꢀ
olefin cyclization9 (Simpkins).
Because the DielsꢀAlder reaction establishes two bonds
in concerted fashion, the biomimetic IMDA approach
pioneered by Williams provides one of the most efficient
(4) Synthetic approaches to [2.2.2]-diazabicycles have been re-
viewed: Miller, K. A.; Williams, R. M. Chem. Soc. Rev. 2009, 38,
3160–3174.
(5) (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. (c) Jin, S.;
Wessig, P.; Liebscher., J. J. Org. Chem. 2001, 66, 3984–3997.
(6) (a) Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127,
5342–5344. (b) Crick, P. J.; Simpkins, N. S.; Highton, A. Org. Lett. 2011,
13, 6472–6475. (c) Simpkins, N.; Pavlakos, I.; Male, L. Chem. Commun.
2012, 48, 1958–1960.
(7) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero,
C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678–8693.
(8) (a) Williams, R. M.; Glinka, T.; Kwast, E. J. Am. Chem. Soc.
1988, 110, 5927–5929. (b) Cushing, T. D.; Sanz-Cervera, J. F.; Williams,
R. M. J. Am. Chem. Soc. 1993, 115, 9323–9324. (c) Artman, G. D.;
Grubbs, A. W.; Williams, R. M. J. Am. Chem. Soc. 2007, 129, 6336–
6342.
(9) (a) Frebault, F. C.; Simpkins, N. S. Tetrahedron 2010, 66, 6585–
6596. (b) Frebault, F.; Simpkins, N. S.; Fenwick, A. J. Am. Chem. Soc.
2009, 131, 4214–4215.
Alkaloids within this family have attracted significant
attention from the synthetic community. In the context of
(1) (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.
(2) (a) Qian-Cutrone, J. F.; Huang, S.; Shu, Y. Z.; Vyas, D.; Fairchild,
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.
(3) Williams, R. M.; Stocking, E. M.; Sanz-Cervera, J. F. Biosynthe-
sis of Prenylated Alkaloids Derived from Tryptophan. In Biosynthesis:
Aromatic Polyketides, Isoprenoids, Alkaloids; Springer-Verlag: Berlin,
2000; Vol. 209, pp 97ꢀ173.
r
10.1021/ol3007056
Published on Web 05/09/2012
2012 American Chemical Society

Figure 2. Synthesis of (()-Stephacidin via Biomimetic Dielsꢀ
Alder cycloaddition by Williams and co-workers.
Figure 1. Representative [2.2.2]-diazabicyclic indole alkaloids.
B13 (4) and VM5559914 (5), the two known asymmetric
biomimeticIMDAcycloadditions. The IMDAleading to4
intercepts a chiral sprirooxindole intermediate that does
not discriminate the azadiene stereofaces during cycload-
dition (dr 1.4:1). The azadiene intermediate leading to 5
contains a vicinal stereocenter that enforces reasonable
face selection (dr 7:3:2:0). Based on our experience with a
chiral DKP azadiene bearing a tert-butyl aminal,15 we
anticipated that a phenyl aminal auxiliary could impart
strong facial bias during DKP cycloaddition and offer
reductive strategies for aminal cleavage and auxiliary
removal (in addition to acidic aminal hydrolysis). Prepara-
tion of the desired DKP derivative was accomplished in
three steps (two chromatographic separations) starting
from N-chloroacyl L-serine methyl ester (Scheme 1).16
Following the final step of this synthesis, Staudinger
reduction with resin-bound phosphine, the diastereomeric
DKP lactim ether products 8 and 9 were obtained in 36%
and 19% yield over the three steps. The absolute structure
of major isomer 8 was validated through X-ray crystal-
lographic analysis (see the Supporting Information).
We explored initial reactions of DKP 8 with 10, an easily
prepared substrate that contained both an aldehyde to
engage in enolate-based reactions and an alkene that we
anticipated would participate in the DKP azadiene cy-
cloaddition (Scheme 1). We quickly determined that a
domino17 reaction sequence with DKP 8 could be initiated
by enolization and subsequent aldol condensation to give
intermediate 11. Under the basic conditions (NaOMe
in MeOH at reflux), isomerization of the exocyclic
alkene in 11 to the endocyclic DKP azadiene in 12 precedes
intramolecular DielsꢀAlder cycloaddition with the
terminal alkene to give the observed cycloadduct 13.18
entries to the [2.2.2]-diazabicyclic core. In the laboratory,
the biomimetic DielsꢀAlder reaction often suffers from
limited stereoselectivity. The elegant synthesis of stephaci-
din A (3) by Williams and co-workers is depicted as an
illustrative example (Figure 2).10 In the key step, preste-
phacidin 6 (illustrated as the reactive diketopiperazine
(DKP) azadiene tautomer) reacts via IMDA to afford
diastereomeric [2.2.2]-bicyclic products (()-3 and (()-
C6-epi-7 (dr 2.1:1). This modest diastereomeric ratio has
been consistent with other related biomimetic DA cycload-
ditions. Because prestephacidin 6 is achiral, the diastereo-
meric cycloadducts are necessarily produced as racemic
mixtures.
The biosynthesis of 3 likely intercepts an achiral
intermediate that closely resembles 6, although the
products isolated from the fungal hosts appear to con-
tain only one stereochemical relationship at C6 and are
observed in a single enantiomeric series.11 This observa-
tion adds intrigue to the biosynthesis of this family of
alkaloids and possibly indicates the intervention of a
desymmetrizing biomolecule, although identification
and characterization of a DielsꢀAlderase enzyme
remain elusive.12
In the absence of an enzyme or other known catalysts to
control the hetero-DielsꢀAlder cycloaddition, we pursued
a general approach based on a chiral DKP azadiene in
order to control the facial selectivity of the reaction. We
were encouraged by, but hoped to improve upon, the
selectivity observed during the synthesis of versicolamide
(10) Greshock, T. J.; Williams, R. M. Org. Lett. 2007, 9, 4255–4258.
(11) The antipodes of some alkaloids have been isolated from
different fungal producers: Greshock, T. J.; Grubbs, A. W.; Jiao, P.;
Wicklow, D. T.; Gloer, J. B.; Williams, R. M. Angew. Chem., Int. Ed.
2008, 47, 3573–3577.
(15) Morris, E. N.; Nenninger, E. K.; Pike, R. D.; Scheerer, J. R. Org.
Lett. 2011, 13, 4430–4433.
(12) (a) Li, S.; Finefield, J. M.; Sunderhaus, J. D.; McAfoos, T. J.;
Williams, R. M.; Sherman, D. H. J. Am. Chem. Soc. 2012, 134, 788–791.
(b) Sunderhaus, J. D.; Sherman, D. H.; Williams, R. M. Israel J. Chem.
2011, 51, 442–452.
(13) Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009,
1, 63–68.
(16) Bedurftig, S.; Wunsch, B. Bioorg. Med. Chem. 2004, 12, 3299–
3311.
(17) Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
(18) Alkene isomerization in related systems to the endocyclic DKP
azadiene is precendented in neat AcCl for 20 days (see ref 5c) and under
basic conditions (KOH in MeOH): Williams, R. M.; Sanz-Cervera, J. F.;
Sancenon, F.; Marco, J. A.; Halligan, K. M. Bioorg. Med. Chem. 1998, 6,
1233–1241.
(14) Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 2002,
124, 2556–2559.
Org. Lett., Vol. 14, No. 10, 2012
2459

The one-pot synthetic operation occurs in good yield
(76%) and delivers the product in favorable diastereos-
electivity (95:5). The structure of pentacyclic adduct 13was
verified by single-crystal X-ray analysis (see the Support-
ing Information) and confirmed that the cycloaddition
occurred on the azadiene face opposite the phenyl aminal
substituent from the endo transition state to produce the
anti configuration19 at C8.
Scheme 1. Synthesis of Chiral Nonracemic Diketopiperazines
and Initial Discovery of Domino Reaction Sequence
Figure 3. Reaction sequence with nonenolizable aldehydes.
Reaction conditions A: 8 (1 equiv), RCHO (1.2 equiv) at
0.1ꢀ0.2 M in MeOH), NaOMe (3 equiv), 65 °C, 16ꢀ24 h.
aIsolated yield of an inseparable 90:10 mixture of diastereomers.
bDetermined by 1H NMR spectroscopy on the unpurified
c
d
product mixture. Isolated yield of single isomer. 2 equiv of
16 was used.
cycloadduct 21 was prepared from hexenal 20 in one
reaction vessel and 52% yield over the reaction se-
quence. The structure of 21 was confirmed by X-ray
analysis and the stereochemistry is consistent with
cycloadducts derived from nonenolizable aldehydes
(e.g., 15, Figure 3).
Reaction conditions B proved general for nonenolizable
aldehydes; 22, 24, and 26 delivered products 23, 25, and
27. Hexynal 24 demonstrates that the reaction is compe-
tent with alkyne substrates. Overall, reaction conditions B
afforded lower product yields (31ꢀ51%) than the condi-
tions used for nonenolizable aldehydes (50ꢀ86%). All
reactions were stereoselective, though an erosion of selec-
tivity was observed with 3,3-dimethylhexenal (26). The
observed product 27 was produced as an 85:15 mixture of
diastereomers.
The chemistry detailed above establishes a clear path-
way for the enantioselective synthesis of many members of
the [2.2.2]-diazabicyclic natural product family. In this
regard, we initiated a synthesis of (þ)-malbrancheamide
B (2), a new calmodulin (CaM) inhibitor, to validate our
methodology and demonstrate efficient production of
this exceptional alkaloid (Scheme 2).20,21 Key to the
synthesis was the reverse prenylated indole carboxal-
dehyde 28, which was prepared largely according to pre-
cendent.21a Reaction of 28 with DKP 9 under methanolic
Encouraged by the reactivity and selectivity of this initial
result, we explored other substrates (Figures 3 and 4).
Aromatic aldehydes such as allyl benzaldehyde 14 and
vinyl benzaldehyde 16 proceeded in comparable fashion to
give the six- and five-membered carbocyclic ring fused
cycloadducts 15 and 17. Other nonenolizable aldehydes
were competent in the domino reaction sequence with
methanolic sodium methoxide (reaction conditions A).
Aldehyde 18 bearing an R-quaternary substitution pro-
vided product 19 in excellent diastereoselectivity.
Alternate reaction conditions were required to effect
the aldol condensation, isomerization, and cycloaddition
with enolizable aldehyde dieneophile substrates (Figure 4).
For example, the reaction sequence with 5-hexenal (20)
was realized by first preparing the enolate of DKP 8
(LiHMDS, ꢀ78 °C, toluene). Addition of 20 followed by
acetic anhydride and warming to ambient temperatures
afforded the intermediate β-acetoxy aldol addition product.
Acetate elimination to the exocyclic alkene and isomeriza-
tion to the reactive endocyclic DKP azadiene IMDA pre-
cursor was accomplished under mild conditions with DBU.
Although elimination and isomerization was rapid at room
temperature, the ensuing intramolecular cycloaddition was
slow. In practice, the cycloaddition was driven to comple-
tion at elevated temperatures (90 °C). In summary,
(20) (a) Figueroa, M.; Gonzalez, M. D. C.; Mata, R. Nat. Prod. Res.
2008, 22, 709–714. (b) Martinez-Luis, S.; Rodriguez, R.; Acevedo, L.;
Gonzalez, M. C.; Lira-Rocha, A.; Mata, R. Tetrahedron 2006, 62, 1817–
1822.
(19) Williams has adopted syn/anti nomeclature for [2.2.2]-diazabi-
cyclic scaffolds that correspond to the diastereomeric relationship
found in, for example, stephacidin A (syn) and brevianamide B (anti)
(Figure 1).
(21) For a previous synthesis of (()-2, see: (a) Miller, K. A.; Welch,
T. R.; Greshock, T. J.; Ding, Y. S.; Sherman, D. H.; Williams, R. M.
J. Org. Chem. 2008, 73, 3116–3119. (b) For a synthesis of ent-(ꢀ)-2,
see ref 9.
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Org. Lett., Vol. 14, No. 10, 2012

in malbrancheamide B (2) and converts the chiral aminal to
a benzylamine for subsequent elaboration to the natural
product. To complete the synthesis, one final annulation is
required to append the pyrrolidine ring. Completion of the
synthesis will soon be reported.
Scheme 2. Toward Malbracheamide B (2): Reaction with
Indolecarboxaldehyde, Reductive Cleavage of Aminal Auxiliary
Figure 4. Domino reaction sequence with enolizable alde-
hydes. Reaction conditions B: 8 (1 equiv), LiHMDS (1.1 equiv),
ꢀ78 °C; RCHO (1.2 equiv); Ac2O (1.3 equiv), ꢀ78 to rt; DBU
(2 equiv) rt to 90 °C, 12ꢀ16 h. aIsolated yield of a single isomer.
bDetermined by 1H NMR spectroscopy on the unpurified product
mixture. cIsolated yield of a mixture of 85:15 mixture of isomers.
a Combined yield of 30a, 30b (epi-C12a).
b Isolated yield 30a (35%); 30b (24%); mix fractions (17%).
sodium methoxide (conditions A) afforded a mixture of
diastereomeric cycloadducts 29a and 29b (dr 2:1) in
86% combined yield. This reaction outcome demon-
strates that the chiral aminal effectively controls the
diastereoface of the intramolecular DKP cycloaddition,
however, the auxilary imparts little influence on the diaster-
eoselectivity at C12a relative to related achiral variants.21a It
is noteworthy that the major product (29a) resulting from
cycloaddition with the reverse prenyl substituent in 28 is
diastereomeric (at C12a) to the observed reaction products
illustrated in Figures 3 and 4, a result consistent with previous
experimental evidence22 and theoretical studies.23
Although 29a and 29b were partially separable by chro-
matography, it was more convenient to carry the mixture
through one additional synthetic operation prior to separa-
tion. Correspondingly, the lactim methyl ether in 29 was
cleaved with TMSI. After chromatographic separation, the
derived major bislactam 30a was reduced to aminolactam
31 with excess DIBAL at 0 °C.24 This reduction establishes
both the requisite oxidation state of the [2.2.2]-diazabicycle
To summarize, we developed a domino reaction sequence
involving aldol condensation, alkene isomerization, and
intramolecular DKP DielsꢀAlder cycloaddition. In one
synthetic operation, the reaction sequence rapidly generates
molecular complexity (three bonds, two rings) and is com-
patible with enolizable and nonenolizable aldehyde sub-
strates. Excellent stereoselection is observed and consistent
with cycloaddition on the azadiene face opposite the chiral
phenyl aminal. Because the aminal auxiliary is somewhat
removed from the olefinic components of the cycloaddition,
the origin of selectivity may be partly stereoelectronic in
nature. The aminal does not appear to notably effect
cycloaddition diastereoselectivity with regard to the
2π component (dieneophile alkene face) relative to known
DKP IMDA examples. Overall, the methods described
provide an efficient and diastereoselective method to pre-
pare the [2.2.2]-diazabicyclic skeleton common to many
biologically relevant prenylated indole alkaloids.
Acknowledgment. This work was supported by the
donors of the ACS Petroleum Research Fund and the
Research Corporation for Scientific Advancement. A.J.C.
was supported in part by funding from a Howard Hughes
Medical Institute Undergraduate Science Education
Grant to The College of William & Mary.
(22) In addition to numerous total syntheses (see refs 1 and 4),
several model systems also fortify these trends: (a) 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.
(b) Adams, L. A.; Gray, C. R.; Williams, R. M. Tetrahedron Lett.
2004, 45, 4489–4493. (c) Adams, L. A.; Valente, M. W. N.; Williams,
R. M. Tetrahedron 2006, 62, 5195–5200.
(23) (a) Domingo, L. R.; Sanz-Cervera, J. F.; Williams, R. M.;
Picher, M. T.; Marco, J. A. J. Org. Chem. 1997, 62, 1662–1667.
(b) Domingo, L. R.; Zaragoza, R. J.; Williams, R. M. J. Org. Chem.
2003, 68, 2895–2902.
(24) (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.
Supporting Information Available. Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
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