(E)-β-borylstyrene in the diels-alder reaction with 3,5-dibromo-2-pyrone for the syntheses of (±)-1-epi-pancratistatin and (±)-pancratistatin

Article abstract of DOI:10.1021/ol4028623

New synthetic routes to (±)-1-epi-pancratistatin and (±)-pancratistatin were devised using (E)-β-borylstyrene as a dienophile for the key Diels-Alder reaction with 3,5-dibromo-2-pyrone. The boronate in the cycloadduct was oxidized to provide the pivotal C1-hydroxyl group of the titled compounds.

Full text of DOI:10.1021/ol4028623

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5806–5809
(E)‑β-Borylstyrene in the DielsꢀAlder
Reaction with 3,5-Dibromo-2-pyrone for
the Syntheses of (()-1-epi-Pancratistatin
and (()- Pancratistatin
Hyun-Kyu Cho, Hwa-Yeon Lim, and Cheon-Gyu Cho*
Department of Chemistry, Hanyang University, Seoul, Korea 133-791
ccho@hanyang.ac.kr
Received October 4, 2013
ABSTRACT
New synthetic routesto(()-1-epi-pancratistatin and (()-pancratistatin were devisedusing (E)-β-borylstyrene as a dienophile for the keyDielsꢀAlder
reaction with 3,5-dibromo-2-pyrone. The boronate in the cycloadduct was oxidized to provide the pivotal C1-hydroxyl group of the titled compounds.
Pancratistatin 1, along with its related Amaryllidaceae
natural products (Figure 1), is one of the most actively
pursued synthetic targets primiarily due to its potent anti-
cancer activities.1 The mode of action on the anticarcino-
genisis is not clear but believed to be associated with the
disruption of peptide biosynthesis.2 While the immediate
clinical development is hampered by its low bioavailability
as well as poor water solubility, it is still a highly attractive
and promising anticancer drug candidate. Structurally,
pancratistatin is built on a heavily fused tricyclic frame-
work entailing six contiguous stereogenic centers on ring
Figure 1. Selected natural isocarbostyryls.
C, five substituents on the aromatic A ring, and a highly
strained B-ring lactam.
As a part of our ongoing study exploring the synthetic
utility of 3,5-dibromo-2-pyrone toward target-oriented
synthesis,3 we have reportedthe synthesesof pancratistatin
133b as well as its close relative trans-dihydronarciclasine 2.3g
(1) For reviews on the synthesis, see: (a) Jin, Z. Nat. Prod. Rep. 2011,
28, 1126. (b) Manpadi, M.; Kornienko, A. Org. Prep. Proced. Int. 2008,
40, 107. (c) Chapleur, Y.; Chretien, F.; Ahmed, S. I.; Khaldi, M. Current
Org. Synth. 2006, 3, 341. (d) Rinner, U.; Hudlicky, T. Synlett 2005, 365.
(e) Prabhakar, S.; Tavares, M. R. Alkaloids Chem. Biol. 2001, 15, 433. (f)
Polt, R. Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.;
JAI: Greenwich, CT, 1997; Vol. 3, p 109. (g) Martin, S. F. In The Alkaloid;
Bross, A. R., Ed.; Academic: New York, 1987; Vol. 40, p 251.
(2) For reviews or leading articles on the biological activities, see: (a)
Griffin, C.; Karnik, A.; McNulty, J.; Pandey, S. Mol. Cancer Ther. 2011,
10, 57. (b) Pettit, G. R.; Orr, B.; Ducki, S. Anti-Cancer Drug Des. 2000,
15, 389. (c) Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Kirsi, J. J.;
Hollingshead, M.; Shannon, W. M.; Pettit, G. R. In Natural Products as
Antiviral Agents; Chu, C. K.; Cutler, H. G., Eds.; Plenum: New York, 1992,
pp 121ꢀ135. (d) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M.; Herald,
D. L.; Singh, S. B.; Cragg, G. M.; Schmidt, J. M.; Boettner, F. E.;
Williams, M.; Sagawa, Y. J. Nat. Prod. 1986, 49, 995.
(3) (a) Jung, Y.-G.; Lee, S.-C.; Cho, H.-K.; Darvatkar, N. B.; Song,
J.-Y.; Cho, C.-G. Org. Lett. 2013, 15, 132. (b) Jung, Y.-G.; Kang, H.-U.;
Cho, H.-K.; Cho, C.-G. Org. Lett. 2011, 13, 5890. (c) Chang, J. H.;
Kang, H.-U.; Jung, I.-H.; Cho, C.-G. Org. Lett. 2010, 12, 2016. (d) Tam,
N. T.; Jung, E.-J.; Cho, C.-G. Org. Lett. 2010, 12, 2012. (e) Tam, N. T.;
Cho, C.-G. Org. Lett. 2008, 10, 601. (f) Tam, N. T.; Chang, J.; Jung,
E.-J.; Cho, C.-G. J. Org. Chem. 2008, 73, 6258. (g) Shin, I.-J.; Choi,
E.-S.; Cho, C.-G. Angew. Chem., Int. Ed. 2007, 46, 2303. (h) Tam, N. T.;
Cho, C.-G. Org. Lett. 2007, 9, 3391. (i) Kim, H.-Y.; Cho, C.-G. Progress
in Heterocyclic Chem. 2007, 18, 1. (j) Ryu, K.; Cho, Y.-S.; Cho, C.-G.
Org. Lett. 2006, 8, 3343.
r
10.1021/ol4028623
Published on Web 10/28/2013
2013 American Chemical Society

In the synthesis of trans-dihydronarciclasine, styrene 6 was
employed as a dienophile in the inverse electron-demand
DielsꢀAlder reaction with 3,5-dibromo-2-pyrone 5, which
afforded bicyclolactone 7 in high yield and endo-selectivity
(Scheme 1).
circle. For further practice of our 2-pyrone strategy to the
synthesis of pancratistatin,4 we needed a synthetic equiva-
lent of the hydroxyl group at the β-position of the styrene
dienophile for the installation of the C1ꢀOH group
of pancratistatin. Toward this end, β-silyl styrene 9 was
prepared and heated for the DielsꢀAlder reaction with
3,5-dibromo-2-pyrone 5. The resultant endo-cycloadduct
10 was converted into ester 12 before the subjection into
the FlemingꢀTamao oxidation conditions. However, all
the attempts to oxidize the silyl group into the hydroxyl
group were fruitless.5 These failures forced us to conceive
another route involving elimination and epoxidation of the
resultant double bond, which eventually allowed the com-
pletion of the synthesis.3b During the investigation, we had
looked into the possible use of a more readily oxidizable
boronyl ester as a synthetic equivalent of the hydroxyl
group (Scheme 2).
Scheme 1. Previous Syntheses of trans-Dihydronarciclasine and
Pancratistatin
Scheme 2. Retrosynthesis of (()-Pancratistatin
As shown, pancratistatin 1 can be retrosynthetically trans-
lated into the pivotal intermediate ester 16. Further analysis
would call for bicyclolactone 17a, the endo-cycloadduct
between 3,5-dibromo-2-pyrone 5 and (Z)-β-borylstyrene
dienophile 18a. A literature search revealed two isolated
reports on (E)-β-borylstyrene used as a dienophile in a
DielsꢀAlder reaction, but none on (Z)-β-borylstyrene. In
those two examples, a (E)-β-borylstyrene dienophile required
either high reaction temperature (190 °C) or highly activated
o-quinodimethanes as a diene partner.6 Due to the lack
of proper literature precendents on the β-borylstyrene die-
nophile, we have prepared (Z)-β-styrylboronate 19a7 for the
Subsequent transformations including debrominations,
methanolysis, and OsO4-mediated dihydroxylation pro-
vided the key intermediate 8 equipped with all functional
groups required to complete the synthesis of trans-
dihydronarciclasine. In this synthesis, the styrene dienophile
6 takes up the left side of the molecule marked with the red
(4) (a) Akai, S.; Kojima, M.; Yamauchi, S.; Kohji, T.; Nakamura, Y.;
Sato, K.-i. Asian J. Org. Chem. 2013, 2, 299. (b) Cagide-Fagın, F.;
ꢀ
Nieto-Garcıa, O.; Lago-Santome, H.; Alonso, R. J. Org. Chem. 2012,
77, 11377. (c) Dam, J. H.; Madsen, R. Eur. J. Org. Chem. 2009, 4666. (d)
Li, M.; Wu, A. M.; Zhou, P. J. Tetrahedron Lett. 2006, 47, 3707. (e) Kim,
S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343. (f) Rigby, J. H.;
Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc. 2000, 122, 6624.
(g) Magnus, P.; Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341. (h)
Doyle, T. J.; Hendrix, M.; VanDerveer, D.; Javanmard, S.; Haseltine, J.
(5) (a) Mader, M. M.; Norrby, P.-O. J. Am. Chem. Soc. 2001, 123,
1970. (b) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc. Perkin Trans. 1 1995, 317.
(6) (a) Yoshida, H.; Mukae, M.; Ohshita, J. Chem. Commun. 2010,
46, 5253. (b) Batey, R. A.; Thadani, A. N.; Lough, A. J. J. Am. Chem.
Soc. 1999, 121, 450.
€
Tetrahedron 1997, 53, 11153. (i) Hudlicky, T.; Tian, X.; Konigsberger,
K.; Maurya, R.; Rouden, J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752.
(j) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143. (k)
€
Tian, X. R.; Hudlicky, T.; Konigsberger, K. J. Am. Chem. Soc. 1995,
117, 3643. (l) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111,
4829.
(7) Deloux, L.; Srebnik, M. J. Org. Chem. 1994, 59, 6871.
Org. Lett., Vol. 15, No. 22, 2013
5807

model cycloaddition reaction with 3,5-dibromo-2-pyrone 5
(Scheme 3).
Scheme 4. Synthesis of (()-1-epi-Pancratistatin
Scheme 3. DielsꢀAlder Reaction with β-Borylstyrene and
Oxidation Reaction
Despite our concern, (Z)-β-borylstyrene 19a produced
the cycloadducts 20a and 20b in the isolation yields of 46%
and 23%, respectively, when heated in toluene at 80 °C.
However, subsequent oxidation of the boronate group
turned out to be problematic. While exo-adduct 20b was
readily oxidized to give alcohol 21b in 85% yield (eq 2),
endo-isomer 20a did not afford the expected alcohol
product 21a (eq 1), when treated with sodium perborate
under the standard reaction conditions.8 Attempted oxi-
dation under various other literature conditions gave no
improvement. Rather than digging into these interesting
results in further detail, we came to believe that the
orientation of the boronate group would bring about such
an unexpected reactivity difference. Thus, we opted to
prepare (E)-β-borylstyrene 19b9for the cycloaddition reac-
tion with 3,5-dibromo-2-pyrone 5 (eq 3). When heated in
toluene, the reaction provided mostly endo-adduct 20c
where the boronate group is oriented away from the olefin
bridge. To our delight, oxidation with sodium perborate
afforded the corresponding alcohol 21c in 93% yield.
Encouraged by the model study, we started the synthesis
of (()-pancratistatin by preparing the fully substituted
(E)-β-borylstyrene 18b from alkyne 22 (Scheme 4).
5 to afford endo-bicyclolactone 17b in 86% yield after 20 h.
Treatment with sodium perborate provided the desired
alcohol 23 in 81% yield. Debromination and methanolysis
gave diol 25. Subsequent Upjohn dihydroxylation with
OsO4/NMO provided the corresponding tetraol 26 in
quantitative yield. The methyl ester was hydrolyzed into
acid 27 for the ensuing Curtius rearrangement. Treat-
ment with DPPA/DMAP afforded imidazolidinone 28
in 77% yield. Evidently, the initailly formed isocyanate
intermediate underwent an addition reaction with the near-
by hydroxyl group. Successive treatments with NaOMe
and Ac2O provided methyl carbamate 29 in 67% total
yield over two steps. The BischlerꢀNapieralski lactam
formation under the Banwell’s modified conditions gave
lactam 30a and its regioisomer 30b as an inseparable
mixture (3:2).10 Demethylation reaction of the mixture
provided 31 free from its regioisomer in 40% overall
When heated in toluene, (E)-β-borylstyrene 18b was
smoothly cycloadded to the diene 3,5-dibromo-2-pyrone
~
(8) Hussain, M. M.; Li, H.; Hussain, N.; Urena, M.; Carroll, P. J.;
Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 6516.
(9) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.
5808
Org. Lett., Vol. 15, No. 22, 2013

The same route can also be applied to the synthesis of
pancratistatinwiththe configurationalinversion of the C1-
hydroxyl group at an appropriate stage during the synthesis.
Toward this, diol 25 was chosen for selective protection
of the C2-hydroxyl group. To our convenience, a simple
silylation with TBDPSCl under the usual reaction condi-
tions provided the desired C2-OTBDPS 33a in 88% yield
(Scheme 5). The dihydroxylation and subsequent protection
of the resulting syn-1,2-diol gave acetonide 35. Unfortu-
nately, attempted Mitsunobu inversion of the C1-OH group
resulted in no success, presumably due to the steric hin-
drance. As a quick alternative, a pathway involving oxidi-
tion/reduction was followed, instead. Thus, alcohol 35 was
oxidized into ketone 36 which was then reduced with NaBH4
to provide the desired alcohol 37 in 95% overall yield. In the
reduction, the hydride was delivered exclusively from the
face opposite to the bulky aryl group. Successive removal of
the acetonide and TBDPS protecting groups afforded tetraol
39. The rest of the synthesis en route to (()-pancratistatin 1
is identical to our previously reported process.3b
Scheme 5. Synthesis of (()-Pancratistatin
In summary, new synthetic routes to (()-1-epi-
pancratistatin and (()-pancratistatin were devised, utilizing
(E)-β-borylstyrene as a dienophile for the inverse electron-
demand DielsꢀAlder cycloaddition with 3,5-dibromo-
2-pyrone. The boronate in the cycloadduct was readily
oxidized to ultimately provide the C1-OH of (()-1-epi-
pancratistatin 32 and (()-pancratistatin 1.
Acknowledgment. We thank National Research
Foundation of Korea (2012R1A2A4A01005064 and
2012M3A7B4049661) for the financial support.
Supporting Information Available. Details of experi-
mental procedures and characterization data. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
yield from tetraacetate 29 (two steps). Finally, removal of
ester protecting groups furnished hitherto unknown
(()-1-epi-pancratistatin 32.11
(11) 3,4-Acetonide of 1-epi-pancratistatin has been prepared during
the semisynthesis of (þ)-pancratistatin from (þ)-narciclasine. (a) Pettit,
G. R.; Melody, N.; Herald, D. L. J. Org. Chem. 2001, 66, 2583. (b)
Marion, F.; Anereau, J.-P.; Fahy, J. Nitrogenated derivatives of pan-
cratistatin. PCT Int. Appl. WO2010012714, July 29, 2009.
(10) (a) In, J.; Hwang, S.; Kim, C.; Seo, J. H.; Kim, S. Eur. J. Org.
Chem. 2013, 965. (b) Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden,
C. J.; Hockless, D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W.
J. Chem. Soc., Chem. Commun. 1995, 2551.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
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