Asymmetric synthesis of a new simplified dynemicin analogue equipped with a handle

Article abstract of DOI:10.1016/j.tetlet.2004.04.029

The new simplified dynemicin analogue 16 was prepared enantio- and diastereoselectively in 17 steps starting from monoacetate (S) 7. It is equipped with a side arm containing a protected primary alcoholic function ('handle'), which can be used for conjugation with DNA-complexing agents or for devising new types of trigger.

Full text of DOI:10.1016/j.tetlet.2004.04.029

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4221–4223
Asymmetric synthesis of a new simplified dynemicin
analogue equipped with a handle
Luca Banfi,* Andrea Basso, Valentina Gandolfo, Giuseppe Guanti and Renata Riva*
Dipartimento di Chimica e Chimica Industriale, via Dodecaneso 31, I-16146 Genova, Italy
Received 11 March 2004; revised 7April 2004; accepted 7April 2004
Abstract—The new simplified dynemicin analogue 16 was prepared enantio- and diastereoselectively in 17steps starting from
monoacetate (S) 7. It is equipped with a side arm containing a protected primary alcoholic function (‘handle’), which can be used for
conjugation with DNA-complexing agents or for devising new types of trigger.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Enediyne antibiotics,1 such as the calicheamicins2 and
dynemicin A 13–5 are among the most powerful antitumor
compounds known. In these substances, the reactive
enediyne moiety is stabilized by a structural feature
that prevents Bergman cycloaromatization. In the
Dynemicins this bias is represented by the trans epoxide.
A chemical triggering event removes this constraint,
unleashing the powerful DNA-cleaving properties of the
cyclic enediyne, enhanced by the presence of DNA-
complexing substructures (a sort of delivery device). This
mechanism of action has attracted the attention of many
research groups who devoted their efforts to the rational
design of simplified analogues of natural enediynes.6 We7
and others3;8–10 have reported in the past the synthesis of
symplified dynemicin analogues of general formula 2,
lacking the quinone moiety, the phenolic hydroxyl group
and the cyclohexene ring (Scheme 1). Such compounds
showed interesting biological activities, especially when a
triggering device was installed onto the nitrogen
atom.7;8;11 However, some drawbacks were found in the
simplified molecules, since in natural Dynemicins the
quinone moiety not only acts as a trigger, but it also fa-
vors complexation with DNA. Its absence may therefore
be deleterious for the overall biological activity.
Scheme 1.
In this communication we wish to report our efforts to
prepare dynemicin analogues provided with additional
functional groups (‘handles’) that could act as linkers
for DNA-complexing substructures. So far, analogues 2
have been prepared without easily derivatizable addi-
tional functionalities. Therefore we have designed
compounds 3 and 4, equipped with a protected primary
alcohol on a side arm. The varying lenght of the ali-
phatic chain was planned also to explore triggering
devices alternative to the carbamate moiety.
Keywords: Enediynes; Dynemicin; Quinoline; Corey–Fuchs reaction.
* Corresponding authors. Tel.: +39-0103536119; fax: +39-0103536118;
e-mail addresses: banfi@chimica.unige.it; riva@chimica.unige.it
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.029

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L. Banfi et al. / Tetrahedron Letters 45 (2004) 4221–4223
Our efforts have been devoted also to the enantioselec-
tive synthesis of 3 and 4, since the efficient complexation
with DNA may depend also on the absolute configura-
tion. To the best of our knowledge, there is only one
example in the literature10 of optically active analogues
2, obtained via resolution of an intermediate of the
synthesis. Our approach starts from monoacetate 7,
easily accessible on large scale by an efficient chemo-
enzymatic methodology.12
zation in these two routes was demonstrated by
Mosher’s ester analysis on the alcohol 9.
The ensuing synthetic steps have been carried out only
on the (S) enantiomer of 8. Addition of the magnesium
acetylide onto the quinoline in the presence of phenyl
chloroformate13 proceeded in excellent yield. Moreover
the diastereoselectivity was surprisingly high, taking
into account the distance between the two stereogenic
centers and the moderate steric difference between the
two conformationally flexible CH2OSiMe2tBu and
CH2CH2OAc side chains.16
The key step for the synthesis of 3 is the protecting
group controlled addition of trimethylsilylacetylide to
asymmetrically diprotected 2-(4-quinolyl)-1,3-propane-
diols. The stereochemical course of this reaction was
already reported by us.13 However, all the attempts to
convert a series of dihydroquinolines 5 into 3 have failed
so far.14
The synthesis was continued on the major diastereo-
isomer (Scheme 3), following a synthetic strategy
already employed by us for the synthesis of analogues 2
(R1 ¼ Ph, R1, R2 ¼ Me, H).7 Removal of the tBuMe2Si
group was followed by modified Swern oxidation. In
order to avoid epimerization, it is essential to use
Thus we turned our attention to the synthesis of dyne-
micin analogues 4, provided with a longer side arm. The
choice of protecting groups for the two alcoholic moie-
ties was crucial in order to achieve a good long-range
stereocontrol during acetylide addition onto the quino-
line ring. After a thorough investigation14 we selected
compound 10, having an acetyl group on the longer arm
and a Me2tBuSi group on the shorter one, as optimal
substrate (Scheme 2). This compound was straightfor-
wardly obtained from (S) 7 in seven steps (49% overall
yield) through the nitrile (S) 8.15 Thanks to the latent
symmetry in 7, also the enantiomer (R) 8 could be pre-
pared in the same number of steps, opening an easy
entry to the enantiomers of 4. The absence of racemi-
€
Hunig’s base, to carry out the reaction at )78 ꢁC and,
during work-up, to carefully remove the amine, through
an acidic washing, before concentration. The subsequent
Corey–Fuchs reaction17 to give 13 turned out to be more
problematic than in our previous synthesis.7 When,
following the standard procedure, the aldehyde 12 was
added at )78 ꢁC to a preformed (at 0 ꢁC) mixture of
CBr4 and PPh3, the reaction did not proceed at tem-
peratures <)20 ꢁC. However on warming up to this
temperature, decomposition of the starting material
Scheme 3. (a) HF, CH3CN–H2O, 0 ꢁC; (b) (COCl)2, EtN(iPr)2,
DMSO, CH2Cl2, )78 ꢁC, 14 h; (c) CBr4, PPh3, CH2Cl2,
)78 ꢁC fi )40 ꢁC; (d) n-BuLi, )78 ꢁC; (e) K2CO3, MeOH, 0 ꢁC; (f)
tBuMe2SiCl, imidazole, DMF; (g) MCPBA, CH2Cl2, T amb.; (h)
I2ꢀmorpholine, benzene, rt, 46 h; (i) (Z) Me3SnCH@CHSnMe3,
Pd(PPh3)4, LiCl, DMF.
Scheme 2. (a) tBuMe2SiCl, imidazole, DMF; (b) KOH, MeOH, 0 ꢁC;
(c) TsCl, pyridine; (d) KCN, nBu4NI, DMSO; (e) 0.17M MeONa,
MeOH–THF, 0 ꢁC, 80 min; (f) DIBALH, )70 ꢁC; (g) NaBH4, MeOH
)40 fi )10 ꢁC; (h) Ac2O, pyridine; (i) Me3SiCBCMgBr, ClCO2Ph,
THF, )78 ꢁC.

L. Banfi et al. / Tetrahedron Letters 45 (2004) 4221–4223
4223
6. Kraka, E.; Cremer, D. J. Am. Chem. Soc. 2000, 122, 8245–
8264; Maier, M. E. Synlett 1995, 13–26.
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3976.
8. Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl.
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took place affording 13 in very low yields. On the other
hand we found that, by slowly adding a PPh3 solution to
the mixture of the aldehyde and CBr4 in CH2Cl2 at
)78 ꢁC,18 the reaction was fast, reaching completion
below )40 ꢁC and affording the desired adduct in good
yield.19
Treatment of the vicinal dibromide 13 with n-BuLi at
)78 ꢁC formed the corresponding alkyne, contaminated
by 10–20% of a deacetylated by-product. This mixture
was directly treated with K2CO3 in methanol, which
removed both the acetyl and the trimethylsilyl groups,
10. Nishikawa, T.; Yoshikai, M.; Obi, K.; Kawai, T.; Unno,
R.; Jomori, T.; Isobe, M. Tetrahedron 1995, 51, 9339–
9352.
11. Nicolaou, K. C.; Dai, W.-M.; Tsay, S.-C.; Estevez, V. A.;
Wrasidlo, W. Science 1992, 256, 1172–1178.
12. Banfi, L.; Guanti, G.; Mugnoli, A.; Riva, R. Tetrahedron:
Asymmetry 1998, 9, 2481–2492.
13. Guanti, G.; Perrozzi, S.; Riva, R. Tetrahedron: Asymmetry
2002, 13, 2703–2706.
14. Details on this chemistry will be reported in a forthcoming
full paper.
15. All new compounds (except for those that were submitted
to the next step without a complete purification) were fully
characterized by 1H NMR, 13C NMR, GC–MS (when
feasible), and elemental analysis.
16. The relative configuration was established by a series of 1H
NMR analogies with compounds 17 (R1 ¼ H, R2 ¼
OSiMe2tBuSi, and R1, R2 ¼ OR) whose relative configu-
ration was unambigously established.13 For a general
rationalization of the stereochemical course of these
additions see our previous paper.13 Although that model,
based only on steric arguments, may well explain the
predominance of (2R,20S) 11, the high degree of induction
is someway surprising. As a comparison, compound 17
(R1 ¼ H, R2 ¼ OSiMe2tBuSi) gave a 68:32 ratio, whereas
compound 17 (R1 ¼ CH@CH2, R2 ¼ OSiMe2tBuSi) gave
only a 60:40 ratio.14 Since it is hard to consider CH2OAc
smaller than H or CH@CH2, a stereoelectronic effect or an
assistance of the OAc group to the nucleophile entrance
should be considered.
to give diyne 14 (½aŠ +282.6, c 1.2, CHCl3). Reprotec-
D
tion as tBuMe2Si ether was followed by completely
diastereoselective epoxidation and diiodination of the
terminal alkynes. Now the set was ready for the final
cyclization, which was successfully accomplished by a
modification7 of the method developed by Danishefsky
during his total synthesis of dynemicin A.5 The new
dynemicin analogue 16 (½aŠ +394.2, c 1.5, CHCl3) was
D
obtained as a white foam in 5.5% overall yield from (S) 7
(17steps). It is worth noting that the enantiomer of 16 is
accessible as well, starting again from (S) 7, but going
through (R) 8 (Scheme 2). On the other hand the C-20
epimers may be synthesized from the minor adduct of
acetylide addition. However for that synthesis we plan
to use a different combination of protecting group that
produces a lower diastereoselectivity. Studies toward
this goal are in progress and will be reported in a
forthcoming full paper.
Acknowledgements
We wish to thank the University of Genoa, and
M.U.R.S.T. (COFIN 00) for financial assistance, and
Laura Bondanza for her precious collaboration to this
work.
References and notes
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19. We believe that different mechanisms are operating in the
two cases: when the phosphorane Ph3P@CBr2 is pre-
formed, normal Wittig reaction takes place only at
temperatures higher than )20 ꢁC. On the other hand, by
adding PPh3 to CBr4 in the presence of the aldehyde, a
different faster mechanism is operating, probably involv-
ing an intermediate of phosphorane formation.
5. Danishefsky, S. J.; Shair, M. D. J. Org. Chem. 1996, 61,
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