The exocyclic olefin geometry control via Ireland-Claisen rearrangement: Stereoselective total syntheses of Barmumycin and Limazepine e

Article abstract of DOI:10.1021/ol4019453

Stereoselective total syntheses of Limazepine E and Barmumycin, potent, naturally occurring antitumor agents, are described. The total syntheses control the olefin geometry via a highly selective chelation-controlled Ireland-Claisen rearrangement of a seven-membered lactone-derived boron enolate for the synthesis of (E)-4-ethylidene proline, a crucial building block for a number of natural products.

Full text of DOI:10.1021/ol4019453

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
The Exocyclic Olefin Geometry Control
via IrelandÀClaisen Rearrangement:
Stereoselective Total Syntheses of
Barmumycin and Limazepine E
Gints Smits and Ronalds Zemribo*
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia
ronalds@osi.lv
Received July 10, 2013
ABSTRACT
Stereoselective total syntheses of Limazepine E and Barmumycin, potent, naturally occurring antitumor agents, are described. The total syntheses
control the olefin geometry via a highly selective chelation-controlled IrelandÀClaisen rearrangement of a seven-membered lactone-derived boron
enolate for the synthesis of (E)-4-ethylidene proline, a crucial building block for a number of natural products.
Barmumycin 1was isolated from the marine actinomycete
Streptomyces sp. BOSC-022A by Lorente et al (Figure 1).1
Its structure was confirmed by total synthesis. Barmumycin
was found to be cytotoxic against various human tumor
cell lines. Limazepine E 4 was isolated from a culture broth
of Micrococcus sp. strain ICBB 81772 and belongs to the
pyrrolo[1,4]benzodiazepine (PBD) class of natural products
whose antitumor antibiotic properties are due to their ability
to covalently bind to the minor groove of DNA.3 Both
natural products possess an (E)-ethylidene substituent at C-4
of the pyrrolidine ring.
Figure 1. Representatives of the 4-ethylidene proline fragment
containing natural products.
Although total syntheses of barmumycin 11 and several
members of (E)-2-ethylidene PBDs, including prothracar-
cin 2 and tomaymycin 3,4 have been reported, efficient
control of the olefin geometry has not been achieved.
Moreover, the classical olefination methods (Wittig and
JuliaÀKocienski) resulted in predominant formation of
the undesired (Z)-isomer.1,4
Herein we report a stereoselective synthesis of (S)-E-4-
ethylidene proline and its application in the total syntheses
of 1 and 4.
Our retrosynthetic analysis of barmumycin 1 and lima-
zepine E 4 is outlined in Scheme 1. Since the classical
olefination methods showed poor (E)-selectivity,1,4 we
proposed an IrelandÀClaisen5 rearrangement of enolate
6, as a crucial stereochemistry forming step.6 The enolate 6
(1) Lorente, A.; Pla, D.; Canedo, L. M.; Albericio, F.; Alvarez, M.
J. Org. Chem. 2010, 75, 8508–8515.
(2) Fotso, S.; Zabriskie, T. M.; Proteau, P. J.; Flatt, P. M.; Santosa,
D. A.; Mahmud, S.; Mahmud, T. J. Nat. Prod. 2009, 72, 690–695.
ꢀ
(3) For a recent review, see: Cipolla, L.; Araujo, A. C.; Airoldi, C.;
Bini, D. Anticancer Agents Med. Chem. 2009, 9, 1–31.
(4) (a) Mori, M.; Uozumi, Y.; Kimura, M.; Ban, Y. Tetrahedron
1986, 42, 3793–3806. (b) Langley, D. R.; Thurson, D. E. J. Org. Chem.
1987, 52, 91–97.
r
10.1021/ol4019453
XXXX American Chemical Society

Table 1. Optimization of IrelandÀClaisen Rearrangement
Scheme 1. Retrosynthetic Analysis of 1 and 4
isolated yield
entry
avbX
TMS
method
E/Za
1:2
of 14 (%)
1
2
3
4
5
A
A
A
A
B
18
15
À
TBS
1:1
À
TIPS
(n-Bu)2B
Zn
>95:5b
À
85
À
a The E/Z ratio was determined by signal integration in 1H NMR
spectrum, and the olefin geometry of individual isomers was assigned
based on NOE experiments. b The minor isomer was not observed by
NMR.
Scheme 2. Synthesis of Seven-Membered Lactone
at using the Kazmaier protocol10 also failed (entry 5). On
the other hand, dibutylboron triflate11 showed excellent
selectivity and high yield (entry 4). Remarkably, additional
experiments showed that the IrelandÀClaisen rearrange-
ment proceeded to full conversion at temperatures as
low as 10 °C. To facilitate product isolation, the formed
carboxylic acid boron or silicon esters were converted to a
methyl ester in situ.
would be derived from a seven-membered lactone 7, which
could be easily constructed from allylic alcohol 9 and
glycine derivative 8.
Scheme 3. Stereochemical Model
Toward this goal, alkylation of PMB-protected glycine
tert-butyl ester7 with allyl bromide 9, easily obtainable
form (S)-ethyl lactate,8 gave the corresponding amine 10
(Scheme 2). Cleavage of the ester protecting group, fol-
lowed by macrolactonization, afforded the desired seven-
membered lactone 11 in good yield.
Our screening of reagents for the proposed IrelandÀ
Claisen rearrangement is shown in Table 1. The use of silyl
triflates gave poor selectivity and low yields9 or no reaction
at all in the case of TIPS triflate (entries 1À3). Our attempt
The rationale for this outome could involve coordina-
tionofthe boron with the lone pair of the nitrogen atom,11a
which would stabilize the desirable, boat-like, late transi-
tion state in the rearrangement step (Scheme 3). Without
the possibility of such coordination, as in the case of silyl
(5) (a) For reviews on the IrelandÀClaisen rearrangement, see:
Castro, A. M. M. Chem. Rev. 2004, 104, 2939. (b) Chai, Y.; Hong, S.;
Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58,
2905. (c) Hiersemann, M.; Nubbemeyer, U. The Claisen Rearrangement;
WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2007.
(d) Ilardi, E., A.; Stivala, C., E.; Zakarian, A. Chem. Soc. Rev. 2009, 38,
3133.
(6) For recent examples of IrelandÀClaisen rearrangement, see:
(a) Majumdar, K. C.; Nandi, R. K. Tetrahedron 2013, 69, 6921. (b)
Fairhurst, N. W. G.; Mahon, M. F.; Munday, R. H.; Carbery, D. R.
Org. Lett. 2012, 14, 756. (c) Tellam, J. P.; Carbery, D. R. Tetrahedron
Lett. 2011, 52, 6027.
(7) Arnott, G.; Clayden, J.; Hamilton, S. D. Org. Lett. 2006, 8, 5325.
(8) Kulinkovich, O. G.; Kozyrkov, Y. Y.; Bekish, A. V.; Matiushenkov,
E. A.; Lysenko, I. L. Synthesis 2004, 10, 1713.
(10) (a) Kazmaier, U. Angew. Chem. 1994, 106, 1046. Kazmaier, U.
Angew. Chem., Int. Ed. Engl. 1994, 33, 998. (b) Kazmeier, U. Liebigs
Ann./Recl. 1997, 285. (c) Kazmeier, U. Org. Lett. 1999, 1, 1763. (d)
Kazmeier, U.; Mues, H.; Krebs, A. Chem. - Eur. J. 2002, 8, 1850. (e)
Kazmeier, U.; Schneider, C. Synlett 1996, 975. (f) Kazmeier, U.;
Schneider, C. Synthesis 1998, 1321.
(11) For precedents of boron enolate IrelandÀClaisen rearrange-
ment, see: (a) Oh, T.; Wrobel, Z.; Devin, P. N. Synlett 1992, 81. (b)
Corey, E. J.; Lee, D. H. J. Am. Chem. Soc. 1991, 113, 4026. (c) Corey,
E. J.; Roberts, B. E.; Dixon, B. R. J. Am. Chem. Soc. 1995, 117, 193.
(9) A number of byproducts were observed by HPLC/MS analysis of
the crude reaction mixture, mainly an acyclic diene, formed by elimina-
tion of the starting lactone 7.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 4. Synthesis of Barmumycin
Scheme 5. Synthesis of Limazepine E
ketene acetal, a slight preference for the chairlike transition
state is observed.
With this method in hand, we proceeded to the synthesis
of barmumycin 1 (Scheme 4). The PMB protecting group
was easily cleaved by 1-chloroethyl chloroformate (ACE-
Cl),12 and the intermediate amine was directly coupled to
vanillic acid. Selective reduction of the ester moiety with
lithium borohydride gavebarmumycin1 ingoodyield. The
spectral data of the synthetic sample were identical to those
reported for the natural product.1
Next we turned to the total synthesis of limazepine E 4
(Scheme 5). Although a number of methods for the con-
struction of the PBD skeleton are reported, typically
N-protected anthranilic acids or amino group precursors
(nitro or azido) are used.13 We found that, by using the BOP
reagent, it was possible to couple the proline ester inter-
mediate to the unprotected anthranilic acid derivative 1514
directly to form PBD dilactam 17 in 64% yield, as the
intermediate amide 16 cyclizes under the reaction conditions.
Finally, application of the Stille15 protocol for selective
reduction of one of the amide functions provided the target
limazepine E 4, which appeared labile.16 The spectral data of
our synthetic sample were identical to those reported for the
natural product,2 except the optical rotation.17 Interestingly,
the impurity profile in 1H NMR spectra of both natural and
synthetic samples appeared to be the same.18
Figure 2. X-ray crystal structure of PBD dilactam 17.
Scheme 6. Confirmation of Absolute Configuration of 14
Moreover, a crystal structure of dilactam 17 was ob-
tained by X-ray crystallography (Figure 2).
Additional experiments were performed to confirm
the absolute configuration of the obtained proline 14
(Scheme 6). Employing the above-described procedure
with unsubstituted anthranilic acid, a PBD dilactam 19 was
obtained, which upon ozonolysis gave a known ketone 20.19
(12) Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 3, 195.
(13) For a recent review, see: Antonow, D.; Thurston, D. E. Chem.
Rev. 2011, 111, 2815.
(14) For synthesis of 15, see Supporting Information.
(15) Pena, M., R.; Stille, J. K. J. Am. Chem. Soc. 1989, 111, 5417.
(16) Although HPLC/MS analysis of the crude reaction mixture of
the reduction step showed a clean reaction, a significant loss of 4 in the
purification process was observed due to its instability. A sample of pure
4 in CDCl3 dramatically changes color, and precipitation occurs upon
standing at rt for a few days.
(17) No satisfactory results were obtained from measuring [R]D in
MeOH solution, as the values fluctuated. A possible explanation could
be a well-known property of PBDs to form aminals in protic media.
(18) See Supporting Information page SI-36
(19) Antonow, D.; Jenkins, T. C.; Howard, P. W.; Thurston, D. E.
Bioorg. Med. Chem. 2007, 15, 3041.
The spectral data of this compound, as well as the optical
rotation, were identical to those reported in the literature.
Org. Lett., Vol. XX, No. XX, XXXX
C

In conclusion, stereoselective total syntheses of barmu-
mycin and limazepine E have been achieved. The key
steps involve a novel stereoselective strategy for efficient
synthesis of (E)-4-ethylidene proline via IrelandÀClaisen
rearrangement and further transformation of this building
block into the target natural products via a protecting-
group-free strategy.
Pharmaceuticals and European Social Fund within the
project “Support for the implementation of master studies
at Riga Technical University”.
Supporting Information Available. Detailed compari-
son of the NMR data between natural Barmymycine,
Limazepine E and synthetic samples, experimental pro-
cedures, spectroscopic data, and copies of NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to Dr. A. Misnev’s
group (Latvian Institute of Organic Synthesis) for X-ray
crystallograpic analysis. This work was supported by Merz
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX