Towards a new type of aromatic diynes activation : Synthesis of a novel bicyclic enediyne

Article abstract of DOI:10.1055/s-1998-1693

The aromatic acyclic diynes 2 and 3 have been synthesised in order to test the feasibility of a new activation towards their cyclisation. In addition, a difference of stability between 13 and 20 during the Nozaki-Kishi cyclisation reaction occurs when the aromatic ring possesses or not an intramolecular trigger device. Thus, the aromatic bicyclic enediyne 14 is stable while 21 has not been isolated.

Full text of DOI:10.1055/s-1998-1693

May 1998
SYNLETT
537
Towards a New Type of Aromatic Diynes Activation : Synthesis of a Novel Bicyclic Enediyne
Stéphane Raeppel, Dominique Toussaint and Jean Suffert*
Laboratoire de Pharmacochimie de la Communication Cellulaire, Université Louis Pasteur,
Faculté de Pharmacie, ERS 655 du CNRS - 74, route du Rhin - BP 24 - F-67401 Illkirch Cedex - France
Fax (33) 3 88 67 47 94 ; e-mail jeansu@pharma.u-strasbg.fr
Received 4 February 1998
Abstract : The aromatic acyclic diynes 2 and 3 have been synthesised
in order to test the feasibility of a new activation towards their
cyclisation. In addition, a difference of stability between 13 and 20
during the Nozaki-Kishi cyclisation reaction occurs when the aromatic
ring possesses or not an intramolecular trigger device. Thus, the
aromatic bicyclic enediyne 14 is stable while 21 has not been isolated.
in 26% yield. In view of this result, acylation of 2 (intermolecular
activation) may lead to 5, which can liberate an acetate molecule owing
to the release of the intramolecular trigger device (dimethylamino), and
generate two possible intermediates [(E)-conformer 6 + (Z)-conformer
7]. Unfortunately, we were not able to isolate any products which would
result from a Saito/Myers cycloaromatisation (Scheme 2), even in the
presence of a radical scavenger.
1
In our endeavour for the synthesis of cyclic enediynes and
2
3
dienediynes, analogs of the potent antitumor natural products , we
4
considered applying the prodrug concept to our target molecules in
order to stabilize these strongly labile compounds. Thus, we proposed a
new type of activation of acyclic diynes bearing an aromatic moiety.
The first step would be an intermolecular activation of the prodrug
5
followed by the intramolecular trigger device release (e.g., electron-
donating group as illustrated in molecule 5) with the aim of generating
an activated species. The second step would be the addition of a
nucleophile to the activated species to give rise to a diradical through a
6
Saito/Myers cycloaromatisation. This cascade reaction would allow us
to reach our objective. In a preliminary study, we planned to illustrate
this mode of activation on simple model compounds (Scheme 1).
Thereafter, we have intended to apply this new type of activation to the
cyclic enediynes 21 in order to favor the cycloaromatisation process by
blocking the two acetylenic arms in a rigid cyclic system which would
eventually lead to a strong interaction between the two triple bonds. In a
first step, 13 was synthesised in order to study the sensitive cyclisation
9
10
key step. Compound 13 was obtained from 8 and 10 by convergent
synthesis (Scheme 3). First, ester reduction of 8 to the aldehyde (“tear
11
oil” unstable) with Dibal-H and addition of TMSC≡CCeCl followed
2
by silylation of the alcohol with TBDPSCl gave enyne 9 in 68% yield
(three steps). Reduction of 10 with NaBH in ethanol and desilylation
4
Thus, the compounds 2 and 3 were synthesised from 1 in order to
8
by phase transfer catalysis with ammonium fluoride gave 11 in 80%
investigate the feasibility of the process. Palladium catalysed cross-
7
yield (two steps). Palladium catalysed cross-coupling between 9 and 11
7
coupling between 1 and (trimethylsilyl)acetylene is followed by the
produced aromatic acyclic enediyne 12 in very good yield. Selective
lithium (trimethylsilyl)acetylide addition to the aldehyde. The acyclic
12
8
monodesilylation of 12 with K CO in methanol and iodination with
2
3
diyne 2 yielded 3 after full desilylation. These compounds (2,3)
the presence of morpholine, followed by benzyl alcohol oxidation, using
proved to be fairly stable. When 3 was subjected to acylation, it was
completely consumed and only decomposition was observed after a few
minutes (TLC control). In contrast to compound 3, 2 reacted slowly,
(probably because of steric hindrance between both trimethylsilyl
groups on the two terminal alkynes) and 4 was isolated after reduction
13
the Dess-Martin periodinane afforded 13 in 80% yield (3 steps).
14
Finally, the ring closure of 13 according to the Nozaki-Kishi reaction
12b
by employing the conditions described by Eckhardt-Brückner
allowed us to isolate 14 in 37% yield as a 1/1 inseparable diastereomeric

538
LETTERS
SYNLETT
16
mixture. This cyclic enediyne, which does not possess a trigger device
on the aromatic ring, remains fairly sensitive.
47% yield (three steps). Furthermore, dimethylation of 17, followed
17
by a regioselective formylation step, yielded iodo arene 1 in 76%
7
yield (two steps). Palladium catalysed cross-coupling between 16 and 1
afforded 18 in very good yield.
Desilylation of the alkyne with K CO in methanol/dichloromethane (2/
2
3
1) and reduction of the aldehyde with NaBH in ethanol/THF (2/1)
4
furnished the intermediate 19 in 90% yield (two steps). Finally,
12
iodination with the presence of morpholine and benzylic alcohol
18
19
oxidation with TPAP and NMO gave the acyclic enediyne 20 in
62% yield (two steps), precursor of bicycle 21. Unfortunately, the ring
closure carried out following the conditions used for 13 led after several
attemps to a complex mixture of unidentified compounds. Probably the
cyclisation step occurs, however the trigger device must be activated
and releases a reaction cascade.
In conclusion, a new type of aromatic acyclic diynes activation was
conceived and tested on model substrates. Studies towards the synthesis
and the activation in presence of a nucleophile (e. g., thiol) of these
simple aromatic acyclic diynes are in progress and will be reported in
due course.
References and Notes
(1) a) Suffert, J. Tetrahedron Lett. 1990, 31, 7437-7440. b) Suffert, J.;
Toussaint, D. Tetrahedron Lett. 1997, 38, 5507- 5510. c)
Toussaint, D. PhD thesis, University Louis Pasteur of Strasbourg
(France), 1996.
(2) a) Eckhardt, M.; Brückner, R.; Suffert, J. Tetrahedron Lett. 1995,
36, 5167-5170. b) Suffert, J.; Abraham, E.; Raeppel, S.; Brückner,
R. Liebigs Ann. 1996, 447-456. c) Brickmann, K.; Hambloch, F.;
Suffert, J.; Brückner, R. Liebigs Ann. 1996, 457-471.
(3) Reviews : a) Nicolaou, K. C.; Dai, W. M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1387-1416; Angew. Chem. 1991, 103, 1453-1481.
b) Lhermitte, H.; Grierson, D. S. Cont. Org. Synth. 1996, 3, 41-63;
ibid. 1996, 3, 93-124.
(4) Maier, M. E. Synlett 1995, 13.
(5) Mastalerz, H.; Doyle, T. W.; Kadow, J. F.; Vyas, D. M.
Tetrahedron Lett. 1996, 37, 8683-8686.
(6) a) Myers, A. G.; Proteau, P. J. J. Am. Chem. Soc. 1989, 111, 1146-
1147. b) Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito, I.
Tetrahedron Lett. 1980, 21, 217-220.
(7) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4410.
(8) Herold, P. Helv. Chem. Acta 1988, 71, 354-362.
(9) Marek, I.; Alexakis, A.; Normant, J.-F. Tetrahedron Lett. 1991,
32, 5329-5332.
(10) Austin,W. B.; Bilow, N.; Kelleghan, W. J.; Lau, K. S. Y. J. Org.
Chem. 1981, 46, 2280-2286.
(11) Imamoto, T.; Sugiura, Y.; Takaiyama, N. Tetrahedron Lett. 1984,
25, 4233-4236.
(12) a) Southwick, P. L.; Kirchner, J. R. J. Org. Chem. 1962, 27, 3305-
3308. b) Eckhardt, M.; Brückner, R. Liebigs Ann. 1996, 473-488.
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(14) a) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.;
Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048-6050. b) Jin, H.;
Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108,
5644-5646. c) Crevisy, C.; Beau, J.-M. Tetrahedron Lett. 1991,
32, 3171-3174.
In the same way, 20 was obtained from 15 and 17 by convergent
synthesis (Scheme 4). Commercially available allylic alcohol 15 was
15
oxidized with activated MnO
to the aldehyde (very volatile and
2
unstable) which immediately reacted subsequently with lithium
trimethylsilylacetylide, and protected as a silylated ether to give 16 in
(15) Goldman, I. M. J. Org. Chem. 1969, 34, 1979-1981.

May 1998
SYNLETT
539
3
3
(16) Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673-1674.
J = 11.7 Hz, J = 2.7 Hz, H-7, dia II), 7.13-7.49 [m, 10H,
13
Si(Ph) ], 7.66-7.90 (m, 4H, aromatic H). – C NMR (CDCl - 50
(17) Ask, A.-L.; Ögren, S.-O.; Ross, S. B. J. Med. Chem. 1978, 21, 56-
2
3
MHz) : δ = 19.22 [SiC(CH ) ], 26.82 [SiC(CH ) ], 62.44-62.85
63.
3 3
3 3
(C-8), 64.21-65.53 (C-1), 85.10-86.28-91.45-95.78 (C-4, 5, 9, 10),
109.78-110.55 (CH), 120.74-121.07 (C quat), 127.53-127.73-
(18) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J.
Chem. Soc., Chem. Commun. 1987, 1625-1627.
128.02-128.31-128.82-128.93-129.91-130.14-131.82
(CH),
1
13
(19) All new compounds are characterized by H and C NMR, and
133.09-133.17 (C quat), 134.77-135.80-136.02 (CH), 139.11 (C
microanalysis.
+
quat), 139.59-141.62 (CH). – MS, m/z (%) : 448 (26) [M ], 391
1
13 : H NMR (CDCl - 200 MHz) : δ = 1.08 [s, 9H, SiC (CH ) ],
3
3 3
(84), 314 (47), 252 (48), 199 (100).
3
3
5.50 (d, 1H, J = 8.8 Hz, H-5"), 5.77 (d, 1H, J = 10.5 Hz, H-3"),
6.09 (dd, 1H, J = 10.5 Hz, J = 8.8 Hz, H-4"), 7.12-7.69 [m, 10H,
Si(Ph) ], 7.72-7.90 (m, 4H, aromatic H), 10.13 (s, 1H, H-1). –
– microanalysis : % C (th. = 76.10, exp. = 75.97), % H (th. =
3
3
13
6.97, exp. = 7.22).
C
2
1
20 : H NMR (CDCl - 200 MHz) : δ = 0.15-0.17 [2 s, 6H,
3
NMR (CDCl - 50 MHz) : δ = 3.65 (C-7"), 19.26 [SiC(CH ) ],
3
3 3
4
Si(CH ) ], 0.92 [s, 9H, SiC(CH ) ], 2.01 (d, 3H, J = 1.3 Hz,
3 2
3 3
26.49 [SiC(CH ) ], 63.40 (C-5"), 90.93-91.11-93.14 (C-1", 2",
3 3
3
CH ), 3.10 [s, 6H, N(CH ) ]; 5.54 (d, 1H, J = 8.8 Hz, H-5"), 5.85
3
3 2
6"), 109.53 (C quat), 126.18-126.95-127.57-128.71-129.77 (CH),
132.75 (C quat), 133.38-133.45 (CH), 135.69 (C quat), 135.88-
142.01 (CH), 191.08 (C-1). – microanalysis : % C (th. = 62.72,
exp. = 62.81), % H (th. = 4.74, exp. = 4.87).
3
4
(dq, 1H, J = 8.8 Hz, J = 1.3 Hz, H-4") ; 6.64-6.77 ABX signal
(BX part, m, 2H, H-3' and H-5'); ABX signal (A part, 1H, δ
=
A
13
7.85, J = 9.7 Hz, H-6'), 10.25 (s, 1H, H-1). – C NMR (CDCl
AB
3
1
- 50MHz) :
δ = – 4.52 [Si(CH ) ], 2.14 (C-7"), 18.33
3 2
14 : H NMR (CDCl - 200 MHz) : δ = 1.09 [s, 9H, SiC (CH ) ,
3
3 3
3
[SiC(CH ) ], 22.91 (CH ), 25.86 [SiC(CH ) ], 40.10 [N(CH ) ],
dia I], 1.11 [s, 9H, SiC(CH ) , dia II], 2.13 (d, 1H, J = 7.1 Hz,
OH, dia I), 2.20 (d, 1H, J = 7.6 Hz, OH, dia II), 5.09 (m, 1H, H-8,
dia I), 5.17 (m, 1H, H-8, dia II), 5.23 (d, 1H, J = 7.6 Hz, H-1, dia
II), 5.40 (dd, 1H, J = 7.1 Hz, J = 1.7 Hz, H-1, dia I), 5.75 (d, 1H,
J = 11.7 Hz, H-6, dia I), 5.76 (d, 1H, J = 11.7 Hz, H-6, dia II),
5.88 (dd, 1H, J = 11.7 Hz, J = 3.8 Hz, H-7, dia I), 5.98 (dd, 1H,
3 3
3
3 3
3 2
3 3
3
63.57 (C-5"); 91.55-92.12-94.35 (C-1", 2", 6"), 111.90 (C-5'),
114.43 (C-3'), 119.82 (C-3"), 124.81-128.08 (C-1', 2'), 129.38 (C-
6'), 137.00 (C-4"), 153.46 (C-4'), 189.42 (C-1).
3
3
5
3
3
– microanalysis : % C (th. = 54.43, exp. = 54.56), % H (th. =
5.96, exp. = 6.02), % N (th. = 2.76, exp. = 2.73).
3
3