Synthesis and reactivity of a 9-membered azaenediyne: Importance of proximity effect in N-alkylation

Article abstract of DOI:10.1039/b601348a

Synthesis of a 9-membered azaenediyne has been achieved for the first time via intramolecular N-alkylation; the importance of proximity of the reacting centres via cobalt carbonyl complexation of the acetylenic moiety and not the activation of propargylic

Full text of DOI:10.1039/b601348a

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Synthesis and reactivity of a 9-membered azaenediyne: importance of
proximity effect in N-alkylation{
Sandip Kumar Roy and Amit Basak*
Received (in Cambridge, UK) 27th January 2006, Accepted 3rd March 2006
First published as an Advance Article on the web 16th March 2006
DOI: 10.1039/b601348a
isolate a dimeric macrocyclic enediyne 2 via initial intermolecular
N-alkylation (Fig. 1).14 This change of reactivity was attributed to
the stereoelectronic constraint imposed by the severely strained
9-membered enediynyl system. Recently we reported15 the
synthesis of two macrocyclic enediynes 4 and 5 (Fig. 2).
Compound 5, which has the ability to form a 10-membered ring
via an intramolecular nucleophilic attack, was found to be unstable
and thus underwent BC after the initial transannular reaction
which the compound 4 cannot undergo because that would
involve the formation of a 9-membered ring.
Synthesis of a 9-membered azaenediyne has been achieved for
the first time via intramolecular N-alkylation; the importance of
proximity of the reacting centres via cobalt carbonyl complexa-
tion of the acetylenic moiety and not the activation of
propargylic carbon has been demonstrated.
Natural product chemistry that includes isolation, structure
elucidation, synthesis and property evaluation has regained its
momentum in recent years after a temporary slump in the mid
eighties.1 This revival has been primarily possible because of the
discovery in the late eighties of molecules with intricate structural
features and fascinating modes of biological action. The enediyne
class of natural products2 certainly belongs to that group. In 1987
researchers at Lederle3 and Bristol Myers4 reported the exciting
and unprecedented structures of calicheamicins and esperamicins.
This was soon followed by the discovery of related molecules like
dynemicin,5 kedercidin6 and C-1027.7 All these molecules show
their biological activity (cytotoxicity) via Bergman cyclization
(BC)8 after an initial triggering. It is interesting to note that
molecules like kedercidin and C-1027 have a more reactive
9-membered enediyne9 as compared to the comparatively more
stable 10-ring system present in calicheamicin, esperamicin and
dynemicin. Thus, not only are these products of Nature complex
but they are also unstable. It is this instability factor that has
translated into a constant tussle against the inherent decomposi-
tion processes and as such has stretched the bounds of
contemporary organic synthesis and the skills of the researcher
at the bench. Right after the unraveling of structures of natural
enediynes with a 9-membered ring system, the development of
methodology for the synthesis of this key ring system has become
an active area of research. Seminal contributions have appeared
from the laboratories of Magnus10 and Hirama.11 Over the past
few years, we have also been interested in the synthesis of a
9-membered enediyne system containing a nitrogen atom as a
replacement for the nonenediynyl carbons. It may be mentioned
that nitrogen containing cyclic enediynes have assumed significant
importance in recent years.9,12 The key step in the synthesis of such
Encouraged by the reported success of the Magnus group in
synthesizing a 9-membered carbocyclic enediyne10 via intramole-
cular Nicholas reaction,16 we envisioned that a similar complexa-
tion of the alkynyl functionality with cobalt carbonyl might
facilitate the intramolecular attack by the nitrogen on to the
activated propargylic centre. Proximity of the reacting centres due
to bending of the otherwise linear C(sp)–C(sp)–C(sp3) axis and the
extra flexibility offered by the slight elongation of the triple bond
after complexation1,16 might also aid the cyclization. With the
above logic, we went ahead with efforts to synthesize for the first
time a 9-membered N-containing enediyne 14 in complexed form.
Our success in doing so is reported herein.
In order to reach our target, the acyclic enediynyl alcohol 7 was
first synthesized following our published procedures.13,17 The
synthesis includes sequential Sonogashira coupling18 and func-
tional group manipulation. Realizing that conversion of hydroxyl
into a good leaving group might be difficult after cobalt
complexation, compound 7 was first converted into a stable
mesylate 8, which was then treated with dicobalt octacarbonyl
(2.2 eq).19 The isolated bis-alkyne complex 920 was subjected to
ring closure conditions (K2CO3/DMF,
3 h) followed by
a
system (10-membered or more) is the intramolecular
Fig. 1 Attempted synthesis of 9-membered azaenediyne by direct
N-alkylation.
N-alkylation of an acyclic substrate, which worked nicely to give
the cyclic product in high yield.13
However, our attempt to extend the same methodology to
prepare the 9-membered analogue 1 failed and we could only
Bioorganic Laboratory, Department of Chemistry, Indian Institute of
Technology, Kharagpur, India. E-mail: absk@chem.iitkgp.ernet.in;
Fax: 91 3222 282252; Tel: 91 3222 283300
{ Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra; mass spectra. See DOI: 10.1039/b601348a
Fig. 2 Fate of macrocyclic enediynyl amino ketones.
1646 | Chem. Commun., 2006, 1646–1648
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deprotection with iodine/THF.1,21 A new product 10 was isolated
by Si-gel chromatography (hexane–ethyl acetate 7 : 1 as eluent). Its
1H-NMR spectrum22 showed complete consumption of the
mesylate as revealed by the absence of the three-proton singlet at
d 3.17; instead, a new 3-proton singlet appeared at d 2.04,
characteristic of an acetylenic methyl. The spectrum also contained
a 2-proton doublet at d 3.98, which was coupled to a triplet at d
8.14; the latter signal got exchanged with D2O. The characteristic
peaks for the tosylate (aromatic protons as well as the aromatic
methyl) were also present in the NMR spectrum. The compound
was finally assigned the structure 10, which was based on 13C (four
acetylenic carbons) as well as mass spectral data (Scheme 1). A
similar observation was also reported by Magnus et al.1 in their
attempt to induce intramolecular Nicholas reaction.16
Having failed to induce the intramolecular alkylation, we
realized that the propargylic carbon in the acetylenic arm
containing the mesylate 8 becomes too strongly electrophilic after
complexation and possibly abstracts hydride from the solvent. This
prompted us to focus our attention on preparing compound 12 in
which the acetylenic arm containing the sulfonamide moiety is
complexed to cobalt (Scheme 1). Thus the mesylate 8 was treated
with 1.1 equivalent of cobalt octacarbonyl for 5 min at 0 uC. This
produced a mixture of complexes 9, 11 and 12 in the ratio of y 1 :
1 : 2. Complexes 9 and 11, which were inseparable in tlc, were
subjected to an alkylation–decomplexation protocol which led to
the reduced product 10 like the previous reaction. The other
isomeric cobalt complex 12,22 to our delight, underwent smooth
intramolecular alkylation to afford the target 9-membered
enediyne 1422 in the complexed form. The reaction was actually
much faster (40 min) as compared to the formation of the
Fig. 3 1H NMR spectra.
Fig. 4 HPLC trace of cyclized products using a C18 reverse phase
column and MeOH as mobile phase.
1
10-membered ring system (3 h).23 The H NMR (Fig. 3) showed
two separate two-proton broad singlets corresponding to the two
NCH2 protons. The methylene adjacent to the acetylene
complexed to cobalt appeared downfield at d 4.61 compared to
the methylene adjacent to the uncomplexed acetylene, which
resonated at d 4.20. The mass spectrum showed a molecular ion
peak at m/z 607. The peak at m/z 523 indicated the loss of three
CO molecules. The formation of the 9-membered system was
further confirmed by a decomplexation–BC protocol. Upon
deprotection (I2/THF, 0 uC, 1 h), the compound immediately
underwent BC to produce three distinct products resulting from
abstraction of either H (compound 17) or iodine (compound 19) or
both (compound 18) (ratio 3 : 5 : 25) (Scheme 1). All three
cyclization products were separated by HPLC (Fig. 4) and their
structures confirmed by NMR and mass spectral analysis.22 From
our observations, it can be concluded that for the formation of a
9-membered ring by intramolecular alkylation, proximity of the
reacting centres is more important than the activation of the
propargylic carbon with a good nucleofugal group like mesyl by
complexation.
In conclusion, we have developed a synthetic route to an
N-based 9-membered cyclic enediyne via a cobalt complexation
route. The importance of the proximity of reacting centers rather
than the activation of the propargyl centre has been shown. The
facile BC of the 9-membered ring system which is similar to that of
the carbocyclic counterpart under ambient conditions has also
been successfully demonstrated.
AB thanks DST, Government of India for a research grant.
SKR is grateful to CSIR, Government of India for a senior
research fellowship.
Scheme 1 Synthesis and reactivity of 9-membered azaenediyne.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 1646–1648 | 1647

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20 The bis alkyne complex 9, after close inspection, was found to be
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22 Selected spectral data: For 10: (200 MHz, [D6]DMSO): d = 8.14 (d, 3J
(H,H) = 6.0 Hz, 1H; NH), 7.72 (d, 3J (H,H) = 8.2 Hz, 2H; aryl-H),
7.35–7.20 (m, 5H; aryl-H), 6.97 (m, 1H; aryl-H), 3.98 (d, 3J (H,H) =
6.0 Hz, 2H; CH2N), 2.29 (s, 3H; Ts-CH3), 2.04 ppm (s, 3H; aliphatic-
CH3). For 12: (200 MHz, CDCl3): d = 7.82 (bd, 3J (H,H) = 8.0 Hz, 2H;
aryl-H), 7.26–7.49 (6H, bm, aryl-H), 5.06 (bm, 1H; NH), 4.93 (bs, 2H;
CH2OMs), 4.61 (bm, 2H; CH2NH), 3.08 (bs, 3H; Ms-CH3), 2.43 ppm
(bs, 3H; Ts-CH3). For 14: (200 MHz, CDCl3): d = 7.73–7.26 (bm, 8H;
aryl-H), 4.61 (bs, 2H; CoCCH2N), 4.20 (bs, 2H; CCCH2N), 2.44 ppm
(bs, 3H; Ts-CH3); HRMS calcd for C25H15O8NSCo2 (MH+) 607.9256,
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3
found 607.9559. For 17: (500 MHz, CDCl3): d = 7.79 (d, J (H,H) =
3.2 Hz, 2H; aryl-H), 7.76 (q, 3J (H,H) = 1.2 Hz, 2H; aryl-H), 7.62 (s, 1H;
3
3
aryl-H), 7.43 (q, J (H,H) = 1.2 Hz, 2H; aryl-H), 7.31 (d, J (H,H) =
3.2 Hz, 2H; aryl-H), 7.26 (s, 1H; aryl-H), 4.74 (s, 4H; CH2NCH2),
2.38 ppm (s, 3H; Ts-CH3); HRMS calcd for C19H17O2NS (MH+)
3
324.1054, found 324.1072. For 18: (500 MHz, CDCl3): d = 8.02 (d, J
3
(H,H) = 3.1 Hz, 1H; aryl-H), 7.82 (d, J (H,H) = 3.2 Hz, 2H; aryl-H),
7.70 (d, 3J (H,H) = 3.1 Hz, 1H; aryl-H), 7.56–7.48 (m, 3H; aryl-H), 7.33
(d, 3J (H,H) = 3.2 Hz, 2H; aryl-H), 4.88 (s, 2H; CICCH2N), 4.07 (s, 2H;
CHCCH2N), 2.39 ppm (s, 3H; Ts-CH3); HRMS calcd for
C19H16O2NSI (MH+) 450.0021, found 450.0034. For 19: (500 MHz,
CDCl3): d = 8.02 (q, 3J (H,H) = 1.2 Hz, 2H; aryl-H), 7.83 (d, 3J (H,H) =
3.2 Hz, 2H; aryl-H), 7.58 (q, 3J (H,H) = 1.2 Hz, 2H; aryl-H), 7.34 (d, 3J
(H,H) = 3.2 Hz, 2H; aryl-H), 4.84 (s, 4H; CH2NCH2), 2.39 ppm (s, 3H;
Ts-CH3); HRMS calcd for C19H15O2NSI2 (MH+) 575.8988, found
575.8964.
23 J. C. Shain, Ph.D. thesis, IIT, Kharagpur, 2000.
1648 | Chem. Commun., 2006, 1646–1648
This journal is ß The Royal Society of Chemistry 2006