Synthesis of the AB subunit of angelmicin B through a tandem alkoxy radical fragmentation-etherification sequence

Article abstract of DOI:10.1021/ol703036y

(Chemical Equation Presented) The synthesis of the tricyclic enone 2, corresponding to the AB subunit of the novel tyrosine kinase inhibitor angelmicin B, is described. The strategy centers on an intramolecular Diels-Alder (IMDA) reaction on triene 4 to p

Full text of DOI:10.1021/ol703036y

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1337-1340
Synthesis of the AB Subunit of
Angelmicin B through a Tandem Alkoxy
Radical Fragmentation-Etherification
Sequence
Jialiang Li, Louis J. Todaro, and David R. Mootoo*
Department of Chemistry, Hunter College, 695 Park AVenue, New York, New York
10065 and The Graduate Center, CUNY, 365 5th AVenue, New York, New York 10016
dmootoo@hunter.cuny.edu
Received December 14, 2007
ABSTRACT
The synthesis of the tricyclic enone 2, corresponding to the AB subunit of the novel tyrosine kinase inhibitor angelmicin B, is described. The
strategy centers on an intramolecular Diels Alder (IMDA) reaction on triene 4 to provide the complex decalin 3, which is elaborated to 2. Other
−
key steps are the formation of the THF ring in 2 through a tandem alkoxy radical fragmentation-etherification on the lactol derived from 3, and
the synthesis of 4 via a ring-closing ene-yne metathesis (RCEYM).
Angelmicin B, was first isolated from Microbispora rosea
by Uehara and co-workers in 1993, and later independently
found with other congeners in a different subspecies, and
named hibarimicin B (Figure 1).1-3 Angelmicin B has
attracted interest as a potential agent in differentiation therapy
because it inhibits proliferation and induces differentiation
in HL-60 human myeloid leukemia tumor cells (IC50: 0.10
( 0.02 µg/mL). It has been suggested that these effects might
be linked to the specific inhibition of src tyrosine kinase.
However, a more complex mechanism appears to be involved
(1) Uehara, Y.; Li, P. M.; Fukazawa, H.; Mizuno, S.; Nihei, U.; Nishio,
M.; Hanada, M.; Yamamoto, C.; Furumai, T.; Oki, T. J. Antibiot. 1993,
46, 1306.
(2) (a) Hori, H.; Higashi, K.; Ishiyama, T.; Uramoto, M.; Uehara, Y.;
Figure 1. Angelmicin B (1).
Oki, T. Tetrahedron Lett. 1996, 37, 2785. (b) Kajiura, T.; Furumai, T.;
Igarashi, Y.; Hori, H.; Higashi, K.; Ishiyama, T.; Uramoto, M.; Uehara,
Y.; Oki, T. J. Antibiot. 1998, 51, 394.
because both the antiproliferative activity and the induction
of differentiation occur at about 100-fold lower concentration
than src tyrosine kinase inhibiton.4
Angelmicin B is pseudo-dimer comprised of similar
anthraquinoid derived cyclitol segments ABCD and A′B′C′D′
segments, which are connected through the D-D′ biaryl
(3) (a) Cho, S. I.; Fukazawa, H.; Honma, Y.; Kajiura, T.; Hori, H.;
Igarashi, Y.; Furumai, T.; Oki, Y.; Uehara, Y. J. Antibiot. 2002, 55, 270.
(b) Igarashi, Y.; Kajiura, T.; Furumai, T.; Hori, H.; Higashi, K.; Ishiyama,
T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 61. (c) Kajiura,
T.; Furumai, T.; Igarashi, Y.; Hori, H.; Higashi, K.; Ishiyama, T.; Uramoto,
M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 53. (d) Hori, H.; Kajiura, T.;
Igarashi, Y.; Furumai, T.; Higashi, K.; Ishiyama, T.; Uramoto, M.; Uehara,
Y.; Oki, T. J. Antibiot. 2002, 55, 46.
10.1021/ol703036y CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/07/2008

bond. The A and A′ cyclitol residues are glycosylated and
the BCD and B′C′D′ segments vary in the oxidation states
of the individual rings. The absolute configurations of the
sugar units E, F, and G, the configuration at C13′, and the
relative stereochemistry between distal rings A and A′ are
unknown. In addition, it is unclear whether the natural
structure represents a preferred atropisomer with respect to
the D-D′ linkage. Contradicting results pertaining to this
issue have been reported by Roush and Sulikowski.5a,6b The
structural complexity and ambiguities combined with the
intriguing biological properties make angelmicin B an
important synthetic target.5,6
Sulikowski and co-workers have described an intermo-
lecular Diels-Alder approach to a relatively simple model
for the AB and A′B′ rings.6 More recently, the Roush group
has disclosed the synthesis of a derivative of the tricyclic
enone 2, which contained different alcohol protecting groups.
This synthesis entails a key intramolecular aldol reaction on
a stereochemically complex tetrahydrofuran substrate. Over-
all, the final product was obtained in 16 steps and less than
2% starting from a L-glyceraldehyde derivative and a chiral
(Z)-γ-silyl-allylborane.5
Scheme 2
crude product provided a 90% yield of 5 and its epimer 7
(respective ratio, ca 5:1). Similar selectivity has been
observed for the addition of acetylide anions to related
substrates.12 The stereochemistry of 5 was confirmed by
NOESY of later products (3, 9, 15) and single-crystal X-ray
crystallography on 15 (vide infra).
RCEYM on enyne diol 5 was effected under Mori’s
conditions, using 10% Grubb’s second generation catalyst
under an ethylene atmosphere at room temperature in CH2-
Cl2 (Scheme 3).13 Diene 9 was obtained in 50% isolated yield
Scheme 3
We envisaged an approach to 2 that centered on the
elaboration of a complex decalin 3, which could be obtained
from the IMDA7 reaction on triene 4 (Scheme 1). Triene 4
Scheme 1. Retrosynthetic Analysis of the AB Subunit
or 85% based on recovered 5. Attempts to optimize this
reaction by increasing the reaction temperature, varying the
alcohol protecting groups or using the TMS protected
acetylene were not successful. The ethylene atmosphere was
also found to be essential. Selective esterification of diol 9
with acroyl chloride provided 4, the triene substrate for the
was expected from enyne 5 through a RCEYM strategy.8,9
The known lactone 610 appeared to be an appropriate
precursor to 5.
(7) For recent reviews on IMDA see: (a) Bear, B. R.; Sparks, S. M.;
Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820-849. (b) Nicolaou, K.
C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668-1698. (c) Takao, K.-I.; Munakata, R.; Tadano,
K.-I. Chem. ReV. 2005, 105, 4779-4807.
(8) For recent reviews on RCEYM see: (a) Diver, S. T.; Giessert, A. J.
Chem. ReV. 2004, 104, 1317-1382. (b) Bruneau, C.; Dixneuf, P. H. Angew.
Chem., Int. Ed. 2006, 45, 2716-2203.
(9) For RCEYM on carbohydrate derivatives see: (a) Poulsen, C. S.;
Madsen, R. J. Org. Chem. 2002, 67, 4441-4449. (b) Dolhem, F.; Lie`vre,
C.; Demailly, G. Eur. J. Org. Chem. 2003, 2336-2342. (c) Dolhem, F.;
Lie`vre, C.; Demailly, G. J. Org. Chem. 2004, 69, 3400-3407.
(10) Jia, C.; Zhang, Y.; Zhang, L. Tetrahedron: Asymmetry 2003, 14,
2195.
(11) The synthesis of 6 in ref 10 is achieved in eight steps from 1,2,5,6-
di-O-isopropylidene-R-D-glucofuranose. In the present study, using a
variation of this approach, 6 was obtained in six steps and ca 80% overall
yield from methyl-R-D-glucopyranoside (supporting information).
Treatment of lactone 611 with nPrMgCl at -78 °C
provided the hemiketal product, which was exposed in a
separate step to TMSCCLi (Scheme 2). Desilylation of the
(4) (a) Yokoyama, A.; Okabekado, J.; uehara, Y.; Oki, T.; Tomoyasu,
S.; Tsuruoka, N.; Honma, Y. Leuk. Res. 1996, 20, 491. (b) Showalter, H.
D. H.; Kraker, A. J. Pharmacol. Ther. 1997, 76, 55.
(5) (a) Narayan, S.; Roush, W. R. Org. Let. 2004, 6, 3789. (b) Lambert,
W. T; Roush, W. R. Org. Let. 2005, 7, 5501.
(6) (a) Lee, C. S.; Audelo, M. Q.; Reibenpies, J.; Sulikowski, G. A.
Tetrahedron 2002, 58, 4403. (b) Maharoof, U. S.; Sulikowski, G. A.
Tetrahedron Lett. 2003, 44, 9021. (c) Kim, K.; Maharoof, U. S.; Raushel,
J.; Sulikowski, G. A. Org. Lett. 2003, 5, 2777-2780. (d) Lee, W.; Kim,
K.; Sulikowski, G. A. Org. Lett. 2005, 7, 1687.
1338
Org. Lett., Vol. 10, No. 7, 2008

key IMDA reaction. The reaction of 4 in xylene at reflux
afforded the exo adduct 3 with the desired configuration at
the ring junction (C9), as the sole DA product. The structure
of 3 was confirmed by 2D COSY, NOESY, and HSQC
experiments (Supporting Information). High exo selectivity
in IMDA reactions of related substrates has been previously
noted.14
In preparation for the introduction of the THF ring in the
final product, lactol 11 was treated with diiodosobenzene
diacetate/I2 following the conditions developed by Sua´rez
(Scheme 4).15 Although we had anticipated a mixture of
epimeric iodides 13a and 13b, we isolated the cyclic ether
12 directly as the major product in 63% yield. Iodide 13a
(21%) and a small amount of lactone 10 (11%) were also
obtained but there was no evidence for 13b. Lactone 10 was
inseparable from 12 and product separation was facilitated
by treatment of the mixture with K2CO3 in MeOH/CH2Cl2.
This reaction gave the tricylcic diol 14 and recovered lactone
10, which were easily separated. The overall yield of 14 from
11 was 62%. The structure of 14 was confirmed through
X-ray crystallography of the later derivative, 15 (vide infra,
Scheme 5). Iodide 13a was assigned from 2D COSY,
NOESY, and HSQC experiments (Supporting Information).
Scheme 4
The mechanism for the formation of THF 12 is at this
point unclear. It is possible that the reaction proceeds
through fragmentation of an initial alkoxy radical, thence a
mixture of 13a and 13b. The absence of 13b in the reaction
mixture could be an indication that this compound is
rapidly converted to 12 via an intramolecular displacement
pathway, whereas 13a is not. Although related radical
pathways to cyclic acetals have been reported, the analogous
transformation to cyclic ethers is unusual.15 Notwithstanding
the mechanistic underpinings, this reaction provides simul-
taenous entry to potential precursors to both the AB and A′B′
subunits of Angelmicin B, that is, THF 12 and iodide 13a,
respectively. In this vein, elaboration of 12 to a more
advanced precursor for the AB subunit was next investigated.
The IMDA product 3 appeared exquisitely suited for
elaboration to the desired target 2. Thus the convex topog-
raphy of 3 suggested that stereoselective dihydroxylation of
the alkene would facilitate the introduction of the C14,15
acyloin moiety, and oxidative fragmentation of the lactol
derived from 3 should pave the way for tetrahydrofuran
formation. Accordingly, treatment of 3 under standard
dihydroxylation conditions afforded a single triol diastere-
omer (Scheme 3), in which the stereoselectivity of the
dihydroxylation was deduced in a later derivative (cf 15,
Scheme 5). After selective protection of the secondary
Accordingly, 14, the aforementioned diol derivative of 12
was subjected to standard alcohol protecting group changes,
to give diol 15. Treatment of 15 with o-iodoxybenzoic acid
(IBX) in DMSO/PhF at 75 °C for 20 h according to the
Nicolaou procedure gave cyclohexanone 16 in 90% yield.16
In contrast to the reported reactivity of this reagent, a
prolonged reaction time, higher temperatures, or treatment
of 16 with IBX in a separate step, did not effect further
oxidation to the cyclohexenone 2. Eventually, using the
Sharpless-Reich protocol17 that was applied to a similar
intermediate in the Roush synthesis,5b 16 was converted to
Scheme 5
1
2 in 66% isolated yield (80% brsm). The H and 13C NMR
data for 2 was very similar to the data for the Roush
derivative, which was different with respect to the alcohol
protecting groups.
(13) Mori, M.; Sakaibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082-6083.
(14) Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1992,
114, 8333-8334.
(15) (a) Freire, R.; Marrero, J. J.; Rodriguez, M. S.; Sua´rez, E.
Tetrahedron Lett. 1986, 27, 383-385. (b) Bentancor, C.; Freire, R.; Pe´rez-
Martin, I.; Prange´, T.; Sua´rez, E. Org. Lett. 2002, 4, 1295-1297. (c)
Bentancor, C.; Freire, R.; Pe´rez-Martin, I.; Prange´, T.; Sua´rez, E. Tetra-
hedron 2005, 61, 2803-2814.
(16) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596-7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.;
Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245-2258. (c) Kaliappan, K.
P.; Ravikumar, V. Org. Lett. 2007, 9, 2417-2419.
(17) (a) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem.
Soc. 1973, 95, 6137. (b) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am.
Chem. Soc. 1975, 97, 5434. (c) Danishefsky, S.; Vaughan, K.; Gadwood,
R.; Tsuzuki, K. J. Am. Chem. Soc. 1981, 103, 4136.
alcohol as the triethylsilyl ether, the resulting lactone 10 was
treated with DIBAL-H to give lactol 11 in 90% yield from
3. The overall yield of the highly substituted decalin 11 from
enyne diol 5 was 53% based on recovered 5 (31% isolated).
(12) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-569.
(b) Boyer, F.-D.; Hanna, I.; Richard. L. Org. Lett. 2001, 3, 3095-3098.
Org. Lett., Vol. 10, No. 7, 2008
1339

In summary, the AB ring subunit of angelmicin B
(hibarimicin B) was prepared in 15 steps and 9% yield (17%
brsm) from the known carbohydrate lactone 6. The synthetic
strategy, which sequences a RCEYM/IMDA protocol and
an unusual tandem alkoxy radical fragmetation-etherification,
is conceptually very different from an earlier synthesis of a
closely related target. Application of this approach to the
A′B′ subunit of angelimicin B and congeners is being
pursued and will be reported in due course.
Medical Sciences of the National Institutes of Health (NIH).
“Research Centers in Minority Institutions” award RR-03037
from the National Center for Research Resources of the NIH,
which supports the infrastructure and instrumentation of the
Chemistry Department at Hunter College, is also acknowl-
edged.
Supporting Information Available: Procedures and
characterization of all new compounds, NMR charts for
selected intermediates, and X-ray data for 15. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This investigation was supported by
grant R01 GM57865 from the National Institute of General
OL703036Y
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Org. Lett., Vol. 10, No. 7, 2008