Halo-enediynes: Probing the electronic and stereoelectronic contributions to the Bergman cycloaromatization

Article abstract of DOI:10.1021/jo025763e

A series of halogen-substituted cyclic enediynes were prepared with use of carbenoid coupling strategy. DFT analysis, initially used to identify synthesis candidates, was also employed to rationalize the propensity for cycloaromatization of the compounds. In all cases studied the halogen atom had a strongly retardative effect on the thermal Bergman cycloaromatization reaction. The isolation of the first C-9 monochloroenediyne is noteworthy, and may find application in prodrug design.

Full text of DOI:10.1021/jo025763e

Ha lo-En ed iyn es: P r obin g th e Electr on ic a n d Ster eoelectr on ic
Con tr ibu tion s to th e Ber gm a n Cycloa r om a tiza tion
Gary W. Plourde II, Philip M. Warner, Dennis A. Parrish, and Graham B. J ones*
Department of Chemistry, Northeastern University, Boston, Massachusetts 02115
gr.jones@neu.edu
Received March 26, 2002
A series of halogen-substituted cyclic enediynes were prepared with use of carbenoid coupling
strategy. DFT analysis, initially used to identify synthesis candidates, was also employed to
rationalize the propensity for cycloaromatization of the compounds. In all cases studied the halogen
atom had a strongly retardative effect on the thermal Bergman cycloaromatization reaction. The
isolation of the first C-9 monochloroenediyne is noteworthy, and may find application in prodrug
design.
Interest in the enediyne antibiotics stems from their
observed antitumoral activity, as exemplified by cali-
cheamicin and esperamicin, both of which have entered
clinical trials.1 The enediynes are not biologically active
per se, but undergo cycloaromatization of the enediyne
core to yield cytotoxic diyl radicals which subsequently
interact with macromolecule targets.2 In the case of cyclic
C-10 enediynes, this process is generally referred to as
the Bergman cycloaromatization, following the pioneering
discoveries made on related hex-3-en-1,5-diynes.3 The
naturally occurring enediynes all possess triggering
functions, which become activated in vitro to promote the
Bergman cycloaromatization.2,4 This typically involves a
conformational change in the architecture of the enediyne
such that on relief of strain, the alkyne termini adopt a
more favorable orientation for the cycloaromatization
event. In this manner, a strained enediyne that is
indefinitely stable at ambient temperature can be con-
verted to a species with a half-life of seconds. Accordingly,
much research has been conducted to exploit this method
of activation together with investigation of alternate
modes of triggering.4
Though strain relief plays a commanding role in the
cycloaromatization profiles of many natural and synthetic
enediynes,5 a variety of other factors can influence the
process, including subtle electronic effects. In the case
of synthetic C-10 enediyne cores, the electronic contribu-
tion to Bergman cyclization was first examined with
quinone enediyne 1.6 Bioreduction of the quinone to the
hydroquinone form serves to stabilize the enediyne
(1) Schor, N. F. In Cancer Therapeutics: Experimental and Clinical
Agents; Teicher, B., Ed.; Humana Press: Totowa, NJ , 1996; pp 229-
240. Schmitt, D. A.; Kisanuki, K.; Kimura, S.; Oka, K.; Pollard, R. B.;
Maeda, H.; Suzuki, F. Anticancer Res. 1992, 12, 2219. Takahashi, T.;
Yamaguchi, T.; Kitamura, K.; Noguchi, A.; Mitsuyo, H.; Otsuji, E. J pn.
J . Cancer Res. 1993, 84, 976. Lee, M. D.; Durr, F. E.; Hinman, L. H.;
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1993; Vol. 2.
(2) Xi, Z.; Goldberg, I. DNA damaging enediyne compounds. In
Comprehensive Natural Products Chemistry; Barton, D. H. R., Nakan-
ishi, K., Eds.; Pergamon: Oxford, UK, 1999; Vol. 7, p 553. Smith, A.
L.; Nicolaou, K. C. J . Med. Chem. 1996, 39, 2103. Grissom, J . W.;
Gunawardena, G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52,
6453.
(5) Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J . P. J . Am. Chem.
Soc. 1990, 112, 4986.
(3) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
(4) Reviews of enediyne prodrugs: Maier, M. E. Synlett 1995, 13.
J ones, G. B.; Fouad, F. S. Curr. Pharm. Des. 2002, 8, in press.
(6) Nicolaou, K. C.; Smith, A. L.; Wendeborn, S. V.; Hwang, C. K.
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10.1021/jo025763e CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/20/2002
J . Org. Chem. 2002, 67, 5369-5374
5369

Plourde et al.
TABLE 1. Th eor etica lly Ca lcu la ted Ber gm a n Cycliza tion Ba r r ier s for Su bstitu ted En ed iyn es 4, a n d 7a
d
c
comnpd
enediyneb
transition stateb
∆HI
∆∆HIThinSpace d
refs
4, X ) Y ) H
4.546
4.544
4.477
4.494
4.523
4.325
4.344
2.924
2.923
2.925
2.926
2.934
2.934
2.935
3.405
3.403
3.401
3.402
3.425
3.400
3.400
3.400
3.389
4.020
3.580
4.010
4.000
3.573
4.011
3.960
2.078
2.039
2.046
2.050
2.036
2.006
2.013
1.947
1.908
1.914
1.918
1.924
1.879
1.884
1.973
1.938
1.945
1.949
1.961
1.908
1.915
1.937
1.954
1.988
1.966
1.945
1.953
1.939
1.967
1.917
27.4
29.1
28.9
28.9
32.7
31.5
30.9
15.4
17.2
17.1
16.9
20.2
20.5
19.9
23.7
26.2
26.0
25.9
30.2
30.0
29.3
26.0
24.5
28.8
30.6
31.2
30.9
33.4
34.8
34.3
(0.0)
1.7
1.5
1.5
5.3
4.1
3.5
(0.0)
1.8
1.7
1.5
4.8
5.1
4.5
(0.0)
2.5
2.3
2.2
6.5
6.3
5.6
2.3
0.8
(0.0)
1.8
2.4
2.1
4.6
6.0
5.5
10-13
4, X ) F, Y ) H
10
4, X ) Cl, Y ) H
4, X ) Br, Y ) H
4, X ) Y ) F
10
this work
10
10
4, X ) Y ) Cl
4, X ) Y ) Br
this work
11, this work
this work
this work
this work
this work
this work
this work
10, 11
7a , X ) Y ) H
7a , X ) F, Y ) H
7a , X ) Cl, Y ) H
7a , X ) Br, Y ) H
7a , X ) Y ) F
7a , X ) Y ) Cl
7a , X ) Y ) Br
7b, X ) Y ) H
7b, X ) F, Y ) H
7b, X ) Cl, Y ) H
7b, X ) Br, Y ) H
7b, X ) Y ) F
this work
10
this work
this work
this work
this work
this work
this work
this work
11, this work
this work
this work
this work
this work
this work
7b, X ) Y ) Cl
7b, X ) Y ) Br
7b, X ) syn-OH, Y ) H
7b, X ) anti-OH, Y ) H
7c, X ) Y ) H (Cs)
7c, X ) Y ) H (C2)
7c, X ) F, Y ) H (Cs)
7c, X ) Cl, Y ) H (Cs)
7c, X ) Cl, Y ) H (C2)
7c, X ) Y ) F (Cs)
7c, X ) Y ) Cl (Cs)
a
Calculations are at the BLYP/6-311+G**//BLYP/6-31G* level, with rovibrational corrections from the BLYP/6-31G* frequency results.
d is the distance, in Å, between the terminal acetylenic carbons of the enediyne unit (“c-d” distance2) and the same distance in the
b
cyclization transition state. c ∆HI is the enthalpy difference between the enediyne and its associated cyclization transition state. ∆∆HI
d
is the difference between ∆HI for a substituted case and its cognizant unsubstituted parent.
toward cycloaromatization, constituting a form of redox-
activation. Another interesting example is the bicyclo-
[7.3.1] system 2. Though this enediyne is essentially
stable, the parent structure (devoid of the alkoxyaryl
group on the vinyl position) cyclizes readily, pointing to
a potent electronic contribution.7 Electronic contributions
also play a role in the photo-Bergman cycloaromatization
of heterocycle 3,8 and it is conceivable that various aryl
substituents would have a marked impact on the pro-
cess.9 Intrigued by these observations, we undertook a
series of DFT studies to try to identify specific vinyl
substituents that would have a marked impact on the
Bergman process, and that might be amenable to chemi-
cal synthesis with methods developed in this and other
laboratories.
1. It is seen that the apparent enediyne-stabilizing effect
of halogen is greater for the cyclodecenediyne than for
the other cases. As discussed in detail in our earlier
paper,10 the stabilizing effect of halogen can be attributed
to a destabilizing interaction between an in-plane halogen
lone pair and an in-plane acetylenic filled orbital. This
interaction grows as the acetylenes bend inward toward
the cyclization transition state. Since the nine-membered
ring is already considerably bent, the increase in the
destabilizing interaction as the transition state is ap-
proached may be muted relative to that of the 10-
Th eor etica l Stu d ies
We have previously conducted a theoretical analysis
of the effects of halogens and chalcogens on the cycliza-
tion barriers of linear enediynes (e.g. 4 f 5 f 6, X ) F,
Cl, OH; Y ) H, F, Cl).10 Since cyclic enediynes represent
realistic drug candidates, we undertook a study of several
cyclic analogues 7, including examples with 9, 10-, and
11-membered rings. The data are summarized in Table
membered ring interactions. It is also seen that the
various halogens have quite similar effects, which prob-
ably represents a balance between orbital size matching
(between F and C) and atomic size. For synthetic
purposes, Br and/or Cl would appear the best choices.
The fact that a second halogen has a more than additive
inhibitory effect on cyclization may be due to halogen-
(7) Maier, M. E.; Greiner, B. Liebigs Ann. Chem. 1992, 855.
(8) Choy, N.; Blanco, B.; Wen, J .; Krishan, A.; Russell, K. C. Org.
Lett. 2000, 2, 3761.
(9) Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett. 2002,
4, 1119.
(10) J ones, G. B.; Warner, P. M. J . Am. Chem. Soc. 2001, 123, 2134.
5370 J . Org. Chem., Vol. 67, No. 15, 2002

Halo-Enediynes
SCHEME 1. P r ojected Keto-Diyn e Rou te to Ha lo a n d Oxo En ed iyn es
SCHEME 2. Syn th esis a n d Attem p ted Closu r e on Br om oa ld eh yd e 15
prisingly, this isomer is associated with a Cs cyclization
transition state that lies 4.4 kcal/mol below the C2
transition state; both transition states have a similar d
value (see Table 1). A similar situation applies to the
3-chlorocycloundec-3-ene-1,5-diyne case, where the Cs-
like conformer is 2.3 kcal/mol more stable than the C2-
like one, and the Cs-like transition state is 4.8 kcal/mol
below the C2-like one. Figure 1 depicts the structures
viewed from the side. The Cs-type transition state has a
conformation in which C-9 is flipped down relative to the
Cs-type enediyne conformation. This is made possible by
the smaller d in the transition state; attempts to find the
transition state Cs conformation for the enediyne struc-
ture and the enediyne Cs conformation for the transition
state structure returned only the conformations shown.
It is intriguing that the higher energy C2-type conformer
might also cyclize via the Cs-type transition state by
flipping C-8 downward, but this would not be kinetically
distinguishable from Cs-type cyclization in these simple
systems. A recent X-ray analysis of a tribenzo 11-
membered-ring enediyne revealed a Cs structure (al-
though a C2 structure is probably prohibited by the benzo
fusions).14
F IGURE 1. 3-Chlorocycloundec-3-ene-1,5-diyne and related
cyclization transition state conformations.
SCHEME 3. In tr a m olecu la r Ca r ben oid Rou te to
Un su bstitu ted En ed iyn es
Taken in entirety, the DFT results (Table 1) confirmed
that both halo and oxo substituents would be attractive
targets for synthesis, with marked changes in properties
(relative to parent structure) expected.15 Moreover, in
addition to allowing inductive effects to be gauged, these
functional groups might also serve as sites for subsequent
introduction of other functional groups to produce librar-
ies of analogues.
In itia l Syn th etic Rou te. Our original route to the
desired oxo and haloenediynes was to involve cyclic
ketodiyne 9, which might be accessed via Ni/Cr coupling
of bromoaldehyde 8 and subsequent oxidation.16 Keto-
enol tautomerization in combination with R-halogenation
would then give access to a range of substituted ene-
diynes,17 including 10-13 (Scheme 1). Accordingly, a
halogen repulsion, which moves them relatively closer
to the in-plane acetylenic position.
Hydroxyl substitution leads to two rotational isomers:
the ca. 1 kcal/mol more stable anti isomer ( C4C3OH )
180°) has similar reactivity to the parent case, while the
syn isomer ( C4C3OH ) 0°) has the same inhibitory effect
as a halogen. It thus appears that cyclic 3,4-dioxy
substitution has the potential to mimic 3,4-dihalo sub-
stitution, an interesting possibility for theoretical and
experimental pursuit.
An unexpected observation when analyzing the 11-
membered-ring cases was the emergence of unusual
conformational effects. Prior work elucidated the cycliza-
tion of the parent C2 conformer.11 We also located a 2.6
kcal/mol more stable Cs conformer that has a ca. 0.5 Å
longer distance (d) between the acetylene termini. Sur-
(12) Cramer, C. J . J . Am. Chem. Soc. 1998, 120, 6261.
(13) Grafenstein, J .; Hjerpe, A. M.; Kraka, E.; Cremer, D. J . Phys.
Chem. 2000, 104, 1748.
(14) Wandel, H.; Wiest, O. J . Org. Chem. 2002, 67, 388.
(15) J ones, G. B.; Plourde, G. W. Org. Lett. 2000, 2, 1757.
(16) Place, P.; Verniere, C.; Gore, J . Tetrahedron 1981, 37, 1359.
(17) Majetich, G.; Zhang, Y.; Dreyer, G. Tetrahedron Lett. 1993, 34,
449.
(11) Schreiner, P. R. J . Am. Chem. Soc. 1998, 120, 4184.
J . Org. Chem, Vol. 67, No. 15, 2002 5371

Plourde et al.
SCHEME 4. Syn th esis of Mon och lor oen ed iyn es
SCHEME 5. Mod ified Rou tes to Br om o- a n d Iod oen ed iyn es
SCHEME 6. Syn th esis of Dih a locyclod ecen ed iyn es
SCHEME 7. Con tr olled Cycloa r om a tiza tion of
Ch lor oen ed iyn es
model substrate 15 was prepared from commercially
available diyne 14 via hydroxymethylation, monobromi-
nation, and oxidation (Scheme 2). Unfortunately, even
under a wide range of prescribed conditions, efficient
closure to alcohol 16 could not be effected; rather, product
decomposition or polymerization occurred. In light of this
problem we focused our efforts on modification of a
related closure developed in this laboratory for the
synthesis of unsubstituted cyclic enediynes.18 Specifically,
intramolecular coupling of propargylic bromides 17 pro-
ceeds via intermediate bromodiyne 18 to give enediynes
19 directly.
The process is amenable to synthesis of (9-11)-
membered systems,18 and also oxygenated heterocycles
(Scheme 3).19 Accordingly, we entertained the possibility
of modifying this route to incorporate halogen functional-
ity. Since no obvious method for conversion of 17 to 20
is available,20 we opted to modify the synthesis. Thus,
dialkynes 23 (X ) -, CH2, or CH2CH2) were converted
to hydroxyaldehydes 24 and then subjected to trichlori-
nation to give 25 (Scheme 4). Intramolecular carbenoid
coupling gave enediynes 27 in moderate to good yield,
via the presumed intermediates 26. Though the chlo-
roenediynes proved more thermally stable than their
unsubstituted analogues, they were routinely stored as
the corresponding cobalt carbonyl complexes 28, and
readily converted back to the desired enediyne on de-
mand with TBAF.21 Particularly encouraging was isola-
tion of the C-9 chloroenediyne 27, X ) -, the unsubsti-
tuted parent of which has never been isolated. Spurred
by these findings, we also investigated bromo and io-
doenediyne preparation. Tribromination of 24, X ) CH2
was followed by direct conversion to the bromoenediyne.
However, this product proved extremely difficult to
handle, and instead was isolated as the cobalt complex
29 (Scheme 5). Similar efforts for the iodo enediyne were
unsuccessful, since required triiodide 30 decomposed
rapidly on forming, precluding purification.
(18) J ones, G. B.; Wright, J . M.; Plourde, G. W., II; Hynd, G.; Huber,
R. S.; Mathews, J . E. J . Am. Chem. Soc. 2000, 122, 1937.
(19) J ones, G. B.; Kilgore, M. W.; Pollenz, R. S.; Li, A.; Mathews, J .
E.; Wright, J . M.; Huber, R. S.; Tate, P. L.; Price, T. L.; Sticca, R. P.
Bioorg. Med. Chem. Lett. 1996, 6, 1971.
(20) J ones, G. B.; Mathews, J . E. Synthesis of Carbon Atoms Bearing
Halogens and Heteroatoms. In Organic Functional Group Transforma-
tions; Pergamon: Oxford, UK, 1995; p 35.
(21) J ones, G. B.; Wright, J . M.; Rush, T. M.; Plourde, G. W., II;
Kelton, T. F.; Mathews, J . E.; Huber, R. S.; Davidson, J . P. J . Org.
Chem. 1997, 62, 9379.
5372 J . Org. Chem., Vol. 67, No. 15, 2002

Halo-Enediynes
SCHEME 8. Syn th etic Ma n ip u la tion of Mon och lor oen ed iyn es
TABLE 2. Kin etic Da ta for Ber gm a n Cycliza tion of
In the case of dihaloenediyne synthesis, conditions
were again modified: dialdehyde 31, which was available
via hydroxymethylation of 14 followed by oxidation, was
initially tetrachlorinated to give 32 (Scheme 6). Car-
benoid coupling gave dichloroenediyne 33 directly, its
remarkable thermal stability removing the need for
cobalt protection. Similarly, tetrabromination of 31 gave
35, which could be converted, in moderate yield, to
dibromoenediyne 36. Interestingly, all attempts to com-
plex this enediyne resulted in formation of the red
monocomplex 34.
Ha lo-Su bstitu ted Cyclic En ed iyn es 37 a n d Com p a r ison to
Th eor etica l P r ed iction sa
t1/2
(h)
temp
(K)
∆H#
(kcal/mol)
∆S#
(eu)
X
R
H
∆H#(calcd)
-
8.0
0.1
60
28
18
5.0
273
313
313
318
323
333
373
443
373
443
17.7
24.0
-15
-7
17.1
CH2
H
26.0
CH2CH2
CH2
H
45
2
b
c
b
c
30.9
30.0
Deter m in a tion of h a lf-lives. With a variety of sub-
strates in hand, and intrigued by the predicted effect of
the halogen on cycloaromatization based on calculations,
controlled Bergman rearrangements were conducted.
Conversion of mono- and dihaloenediynes 37 to the
corresponding cycloaromatized arenes 38 (Scheme 7) at
various temperatures was assessed by using neat 1,4-
cyclohexadiene as hydrogen donor, since it has been
reported that the availability of trapping agent has a
profound impact on the cycloaromatization profile at low
concentration (Table 2).22 Though labile, the controlled
cycloaromatization of the nine-membered enediyne 27,
X ) -, is noteworthy, as its parent is unisolable. A clear
correlation of half-life with temperature emerged for C-10
monochloroenediyne, whereas in the case of the C-11
monochloroenediyne and C-10 dichloroenediyne, the en-
hanced stability of the substrates was marked, and high-
temperature decomposition prevented us from obtaining
even approximate activation parameters. The observed
activation enthalpies are in good agreement with calcula-
tions (Table 2), and in the case of the C-11 monochlo-
roenediyne, the conformational effects may relate to the
finding on half-life (Figure 1). Unfortunately, repeated
attempts to subject bromoenediyne 36 and that derived
from 29 to controlled cycloaromatization resulted in
decomposition, preventing accurate determination of half-
lives. Clearly, the impact of the halogen atom on cy-
cloaromatization is pronounced, and the results also serve
to underscore the predictive role of DFT analysis. Indeed,
based on these findings, it is likely that halogen-
stabilized analogues of various naturally occurring ene-
Cl 60
24
a
b
See Table 1. Activation parameters were not calculated
because the reaction at 443 K is dominated by decomposition, in
addition to cyclization. The ∆G# ) 31.4 kcal/mol value at 373 K
compares with ∆G#(calcd) ) 30.9 kcal/mol at 298 K. c Activation
parameters were not calculated because the reaction at 443 K is
dominated by decomposition, in addition to cyclization. The ∆G#
) 31.6 kcal/mol value at 373 K compares with ∆G#(calcd) ) 32.5
kcal/mol at 298 K.
diynes could be designed. In the case of the enediyne
chromoproteins C-1027 and kedarcidin, stabilizing in-
teractions between the chromophore (enediyne) and
apoprotein have been suggested, yet in-depth spectro-
scopic analysis is hindered due to the lability of the
chromophore.2 It is thus conceivable that halo-substituted
analogues might find application as tools for structure-
activity correlation.
Der ivitiza tion of Cor e Tem p la te. Due to the sta-
bility of the halo enediynes, it became feasible to conduct
chemistry on the free enediynes, and in the case of 39, X
) CH2, in addition to trapping the thermally generated
diradical with hydrogen donors, we were also able to
isolate the products from chlorine capture (40) and
oxidation (41) (Scheme 8).23 Alternatively, ambient alky-
nylation gave an enediyne product that decomposed
rapidly. However, the C-11 chloroenediyne 39, X ) CH2-
CH2, was coupled under identical conditions to give 42,
which was stable at room temperature. The ability to use
the carbon-halogen bond to vary the vinyl substituent
(22) Semmelhack, M. F.; Neu, T.; Foubelo, F. J . Org. Chem. 1994,
59, 5038.
(23) Grissom, J . W.; Gunawardena, G. U. Tetrahedron Lett. 1995,
36, 4951.
J . Org. Chem, Vol. 67, No. 15, 2002 5373

Plourde et al.
of C-9/C-10 enediynes has potential ramifications in the
design of bioactivated enediyne prodrugs. From the ab
initio studies, we were able to identify specific prodrug
candidates for synthesis from 39 which are predicted to
be more stable than either the chloro enediyne or
parent.10 Accordingly, metal halogen exchange routes
were briefly investigated in the case of 39, X ) CH2.
Though trace quantities of 43 could be detected following
quench of the alkynyl zinc intermediate, metalation and
quench en route to formation of 44-45 failed to give any
of the desired products, resulting in rapid decomposition.
Clearly, to capitalize on these enediynes as synthetic
building blocks, milder coupling and derivitization meth-
ods will need to be identified. Nonetheless, the ready
availability of enediynes 39 via the expeditious route
outlined will help facilitate this quest, which will be aided
in turn by the inherent thermal stability of this class.
In summary, new classes of vinyl-substituted ene-
diynes, calculated to have vastly different chemical
stability than the parent system have been prepared and
the electronic contribution to Bergman cyclization quan-
titiated.24 Additionally, these unprecedented species are
amenable to substitution and manipulation and can now
be regarded as building blocks for materials chemistry25
and antitumor agent design.
26
Ack n ow led gm en t. We wish to acknowledge finan-
cial support from the NIH (5RO1GM57123), NSF
(MCB98661), PRF (33920AC1), American Cancer Soci-
ety, Elsa U. Pardee Foundation, Massachusetts Depart-
ment of Health, and the GHS-CU Biomedical Coopera-
tive research program.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and spectroscopic data for the preparation of all com-
pounds and calculation coordinates for compounds 4 and 7.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O025763E
(24) Clark, A. E.; Davidson, E. R.; Zaleski, J . M. J . Am. Chem. Soc.
2001, 123, 2650.
(25) Diederich, F.; Gobbi, L. Top. Curr. Chem. 1999, 201, 43.
(26) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene Chemistry;
Stang, P. J ., Diederich, F., Eds.; VCH: Weinheim, Germany, 1995; pp
203-284.
5374 J . Org. Chem., Vol. 67, No. 15, 2002