Studies toward the total synthesis of angelmicin B (hibarimicin B): Synthesis of a model CD-D′ arylnaphthoquinone

Article abstract of DOI:10.1021/ol048436x

(Chemical Equation Presented) A synthesis of arylnaphthoquinone 22 corresponding to the CD-D′ unit of angelmicin B via the Suzuki coupling of the D′ arylboronic acid 15 with the CD bromonaphthoquinone 21 is described. The mild conditions for the Suzuki cross-coupling leading to 22 may prove to be useful for the eventual late-stage coupling of the two highly functionalized halves of angelmicin B.

Full text of DOI:10.1021/ol048436x

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3789-3792
Studies Toward the Total Synthesis of
Angelmicin B (Hibarimicin B): Synthesis
of a Model CD−D′ Arylnaphthoquinone
Sridhar Narayan and William R. Roush*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48109
roush@umich.edu
Received August 8, 2004
ABSTRACT
A synthesis of arylnaphthoquinone 22 corresponding to the CD−D′ unit of angelmicin B via the Suzuki coupling of the D′ arylboronic acid 15
with the CD bromonaphthoquinone 21 is described. The mild conditions for the Suzuki cross-coupling leading to 22 may prove to be useful
for the eventual late-stage coupling of the two highly functionalized halves of angelmicin B.
Angelmicins A and B were isolated from Microbispora rosea
by Uehara and co-workers in 1993.1,2 Initially, these com-
pounds were reported to be highly specific inhibitors of
protein tyrosine kinase involved in oncogenic src signal
transduction, while no effect was observed on protein kinases
A and C.2 Later, angelmicin B was also shown to inhibit
the growth of tumor cells and induce differentiation in human
myeloid leukemia (HL-60) cell lines.3 However, these
activities do not appear to be directly related since the
effective concentration of angelmicin B (the most active
member of the family) in src tyrosine kinase inhibition is
about 100-fold higher than that required for cell growth
suppression. This suggests that the angelmicins may be
involved in the modulation of more than one physiological
pathway.4 Several members of the same class of natural
products (subsequently named hibarimicins) were later
isolated from a different subspecies of Microbispora rosea.4
It has been speculated that the hibarimicins’ activity as
cancer cell growth inhibitors may arise from topoisomerase
II inhibition.3a Biosynthetic studies on the hibarimicins
indicate that cyclization of a polyacetate precursor to generate
an aglycone monomer, followed by oxidative dimerization,
gives rise to the aglycone (hibarimicinone).5
It is interesting to note that while hibarimicinone is a strong
tyrosine kinase inhibitor, it has no effect on HL-60 cells.5b
The novel structure of angelmicin B (1, Figure 1), together
with its significant biological properties, defines this com-
pound as an important synthetic target.6 Angelmicin B is
(4) (a) Kajiura, T.; Furumai, T.; Igarashi, Y.; Hori, H.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 1998, 51, 394.
(b) Cho, S. I.; Fukazawa, H.; Honma, Y.; Kajiura, T.; Hori, H.; Igarashi,
Y.; Furumai, T.; Oki, T.; Uehara, Y. J. Antibiot. 2002, 55, 270.
(5) (a) Hori, H.; Kajiura, T.; Igarashi, Y.; Furumai, T.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 46.
(b) Kajiura, T.; Furumai, T.; Igarashi, Y.; Hori, H.; Higashi, K.; Ishiyama,
T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 53. (c) Igarashi,
Y.; Kajiura, T.; Furumai, T.; Hori, H.; Higashi, K.; Ishiyama, T.; Uramoto,
M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 61.
(6) For synthetic studies on the angelmicins/hibarimicins: (a) Lee, C.
S.; Audelo, M. Q.; Reibenpies, J.; Sulikowski, G. A. Tetrahedron 2002,
58, 4403. (b) Maharoof, U. S. M.; Sulikowski, G. A. Tetrahedron Lett.
2003, 44, 9021.
(1) Uehara, Y.; Li, P. M.; Fukazawa, H.; Mizuno, S.; Nihei, Y.; Nishio,
M.; Hanada, M.; Yamamoto, C.; Furumai, T.; Oki, T. J. Antibiot. 1993,
46, 1306.
(2) For structure elucidation, see: (a) Hori, H.; Higashi, K.; Ishiyama,
T.; Uramoto, M.; Uehara, Y.; 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.
(3) (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.
10.1021/ol048436x CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/11/2004

Scheme 1. Representative Unsuccessful Cross-Coupling
Strategies
Figure 1. Angelmicin B (1, also known as hibarimicin B) and
proposed functionalized A′B′C′D′ (2) and ABCD (3) monomers
(R ) H or protecting group).
7, and 10) as well as the relative instability of CD arylmetal
derivatives (cf., 5 and 8). In most cases, demetalated products
such as 6 were recovered along with unreacted aryl halide/
triflate, while only traces of coupled biaryl product (see 9)
were observed. Attempted couplings of fragments such as
10 and 11 under Ullmann conditions were also unsuccessful,
giving rise instead to dehalogenated products (12).
We speculated that the highly electron-rich nature of the
aryltriflate/arylbromide fragments such as 4, 7, 10, and 11,
along with a significant steric congestion around C(2),
contributes to the poor reactivity of these (potentially)
electrophilic coupling partners. In view of these difficulties,
we considered the possibility that a bromoquinone could be
used as the electrophilic coupling partner in the cross-
coupling sequence.9 This led to the development of a concise
synthesis of a model CD-D′ fragment of angelmicin B,
which is reported herein.
pseudodimeric with respect to the D-D′ biaryl bond; the
two halves differ only in the oxidation states of the B/B′,
C/C′, and D/D′ rings. The absolute configurations of the
sugar units (E, F, and G), the configuration of the C13′
stereocenter, and the relative stereochemistry between distal
rings A and A′ are unknown at present. In addition, it is
unclear if the barrier to rotation about the D-D′ bond is
high enough to allow the existence of atropisomers and, if
so, what the stereochemistry is about this linkage.7
We have focused on a synthetic strategy that involves the
late-stage coupling of functionalized ABCD and A′B′C′D′
monomers (see 2 and 3, Figure 1), to exploit the near
symmetry of 1 in earlier stages of the synthesis. While the
convergence of this approach is attractive, late-stage con-
struction of the D-D′ biaryl bond is expected to be
challenging due to the tetra-ortho substitution about the biaryl
linkage; a considerable steric barrier would have to be
overcome in the bond-forming step. In addition, the problem
of axial chirality remains to be addressed.6b,7
The synthesis of D′ arylboronic acid 15 is summarized in
Scheme 2. Veratraldehyde (13) was converted to trialkoxy-
In a series of extensive preliminary studies, we evaluated
cross-couplings of CD metal derivatives (aryl boronates,
stannanes, and zinc derivatives) such as 5 and 8 with C′D′
electrophiles (bromides, iodides, and triflates) such as 4, 7,
and 10 (Scheme 1).8 However, all experiments along these
lines were ultimately unproductive due to the lack of
reactivity of the electron-rich aromatic electrophiles (cf. 4,
Scheme 2. Synthesis of the D′ Arylboronic Acid 15
(7) Using MM2 calculations, we estimated the barrier to rotation about
the biaryl axis to be about 20 kcal/mol. While this barrier is generally
sufficient for atropisomers to be resolvable at 23 °C, the atropisomer
situation in angelmicin is uncertain in view of the studies by Sulikowski
(ref 6b). However, the model D-D′ biaryl system studied by Sulikowski
has fewer substituents in the positions flanking the 2-2′ biaryl bond than
in angelmicin B itself, and it is unclear if the rapid atropisomerism (via
tautomerization pathways) noted by Sulikowski will be relevant to the
natural product itself.
benzene derivative 14 in 84% yield by Bayer-Villiger
oxidation of the aldehyde followed by hydrolysis of the
intermediate formate and benzylation of the resultant phenol.
Subsequently, selective ortho-lithiation of the 2 position of
14 by using s-BuLi/TMEDA10 followed by addition of
(8) Full details of these studies will be reported elsewhere.
3790
Org. Lett., Vol. 6, No. 21, 2004

trimethylborate afforded arylboronic acid 15 in 55% yield.
Arylboronic acid 15 proved to be somewhat unstable, under-
going protodeboronation to 14 in the presence of aqueous
acid (e.g., under standard acidic workup conditions).11
The CD bromonaphthoquinone 21 was synthesized from
methoxyhydroquinone (16) as shown in Scheme 3. Thus,
intermediate generated from 19 under these conditions readily
combined with the furan derivative.14 Upon mild acidic
workup, naphthols 20a,b were directly obtained as a nearly
1:1 mixture. This mixture was quickly taken on to the
subsequent step, since naphthols 20a,b were found to be
extremely susceptible to air oxidation. For instance, a sample
of 20a,b left on the benchtop readily decomposed to
unidentified quinone products within several hours. Thus,
treatment of the 20a,b mixture with NaH and benzyl
bromide, followed by addition of TBAF, effected its direct
conversion to bis-benzyl ether 11 (75% yield). Due to the
instability of the intermediate naphthols, this three-step
sequence comprising of benzyl protection, TIPS ether
cleavage, and reprotection as the benzyl ether was best
accomplished in a one-pot protocol. If the same set of
transformations was carried out stepwise, less than 25% yield
of 11 was obtained.
Scheme 3. Synthesis of CD Naphthoquinone Bromide 12
As previously noted, attempts to effect cross-coupling
reactions with highly electron-rich, highly substituted aryl
halides and triflates (see Scheme 1) were consistently
unsuccessful. Indeed, all attempts to effect the cross-coupling
of 15 and 11 met with failure. We envisaged that quinone
21 would be a much more electrophilic coupling partner and
therefore be able to undergo oxidative addition of Pd(0) at
a much faster rate than 11. Accordingly, deprotection of the
MOM ethers of 11 with TFA‚water afforded a stable 1,4-
hydroquinone derivative, which was oxidized to naphtho-
quinone 21 with either silver(I) oxide or ceric ammonium
nitrate.15 After exploring a number of reaction conditions,
we were pleased to find that the cross-coupling of arylboronic
acid 15 with bromonaphthoquinone 21 could be accom-
plished using Cl2Pd(dppf) in dimethoxyethane-water, with
K3PO4 as the base (Scheme 4). This provided the model
CD-D′ biaryl unit 22 in 59% yield.
bromination of 16 was performed according to a literature
method.12 While this procedure has been reported to provide
tribromoquinone 17 in 90% yield, we always obtained a
mixture of 17 and hydroquinone 18. This mixture was
directly subjected to dithionite reduction13 to afford hydro-
quinone 18. Treatment of 18 with MOM-Cl in the presence
of Hu¨nig’s base afforded bis-methoxymethyl ether 19 in 74%
yield over three steps. We found it necessary to add the
Hu¨nig’s base to a cooled mixture of 18 and MOM-Cl. If,
however, the base was added first, up to 45% of a
monodebrominated hydroquinone was isolated as its bis-
methoxymethyl ether (19 lacking one of the bromine
substituents). Furthermore, 17, 18, and 19 were found to be
fairly unstable, giving rise to debrominated materials upon
storage (neat, -20 °C) for several weeks.
Scheme 4. Synthesis of Aryl-quinone 22 via Cross-Coupling
of Arylboronic Acid 15 with Bromonaphthoquinone 21
A mixture of tribromide 19 and 2-triisopropylsilyloxyfuran
was treated with n-BuLi in THF at -78 °C. The benzyne
(9) For examples of uses of haloquinones in Pd(0)-mediated cross-
coupling reactions: (a) Fukuyama, Y.; Kiriyama, Y.; Kodama, M.
Tetrahedron Lett. 1993, 34, 7637. (b) Echavarren, A. M.; Tamayo, N.;
Cardenas, D. J. J. Org. Chem. 1994, 59, 6075. (c) Stagliano, K. W.;
Malinakova, H. C. J. Org. Chem. 1999, 64, 8034. (d) De Frutos, O.; Atienza,
C.; Echavarren, A. M. Eur. J. Org. Chem. 2001, 163.
The coupling reaction depicted in Scheme 4 is noteworthy,
because the highly substituted, polyoxygenated D′ and CD
rings could be coupled in an efficient manner. This is in
(10) Snieckus, V. Chem. ReV. 1990, 90, 879.
(11) For studies on the acid-promoted deboronation of arylboronic acids,
see: Kuivila, H. G.; Nahabedian, K. V. J. Am. Chem. Soc. 1961, 83, 2159.
(12) Davis, T. L.; Harrington, V. F. J. Am. Chem. Soc. 1934, 56, 129.
(13) Roush, W. R.; Coffey, D. S.; Madar, D. J. J. Am. Chem. Soc. 1997,
119, 11331.
(14) (a) Dekoning, C. B.; Giles, R. G. F.; Engelhardt, L. M.; White, A.
H. J. Chem. Soc., Perkin Trans. 1 1988, 3209. (b) Matsumoto, T.;
Yamaguchi, H.; Suzuki, K. Tetrahedron 1997, 53, 16533.
(15) (a) Syper, L.; Kloc, K.; Mlochowski, J.; Szulc, Z. Synthesis 1979,
521. (b) Ho, T.-L.; Hall, T. W.; Wong, C. M. Chem. Ind. 1972, 729.
Org. Lett., Vol. 6, No. 21, 2004
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contrast to previous reports, where cross-couplings to form
aryl-quinone derivatives containing four ortho substituents
flanking the biaryl bond were found to be inefficient or
unsuccessful.10 Moreover, the use of a suitable chiral ligand
in the Suzuki reaction would potentially allow asymmetric
induction in the biaryl coupling step.16 Finally, the conditions
developed for the hindered biaryl coupling in angelmicin B
may prove to be useful in the synthesis of other biaryl-
containing natural products.17
With a model D′-CD ring system in hand, we sought to
gain some experimental insight regarding the atropisomer
situation in angelmicin B. The methylene protons of the D′
ring benzyl ether in 22 appear as an AB quartet (∆υ ) 21.4
Hz; JAB ) 12.6 Hz), indicating that an element of asymmetry
is present in the molecule. Accordingly, we performed
variable-temperature 1H NMR studies in order to determine
the barrier to rotation about the D′-D bond. Even at 150
°C (the upper limit of our measurement), the AB pattern
was discernible, indicating that free rotation about the biaryl
axis was not possible at this temperature. Using this
information, the energy barrier for atropisomerization in 22
must be greater than 22 kcal/mol.18 Using MM2 calculations,
we estimated the energy barrier in 23 (a simplified version
of 22) to be 25.6 kcal/mol (Figure 2). Although 22 with three
benzyl ethers represents a derivatized version of the D′-
CD ring system of angelmicin B, the high barrier to rotation
Figure 2. Comparison of measured and calculated energy barriers
for atropisomerization in compounds related to angelmicin B.
Experimental energy barrier for 22: >22 kcal/mol. Calculated
energy barrier for 23: 25.6 kcal/mol.
suggests that the natural product could exist as a single
atropisomer.7
In conclusion, we have synthesized a model D′-CD ring
system of angelmicin B via the Suzuki reaction of D′
arylboronic acid 15 with CD bromonaphthoquinone 21. This
cross-coupling proceeds under mild conditions, which should
allow for this reaction to be used in a planned late-stage
coupling of two highly functionalized halves of angelmicin
B. Further progress toward the total synthesis of angelmicin
B will be reported in due course.
Acknowledgment. We thank the National Institutes of
Health (BM 38907) for support of this work. S.N. thanks
the Department of Chemistry, University of Michigan, for a
Margaret and Herman Sokol Graduate Fellowship.
(16) (a) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes, R.;
Solomon, M. E.; Ramanjulu, J. M.; Boddy, C. N. C.; Takayanagi, M. Angew.
Chem., Int. Ed. 1998, 37, 2708. (b) Cammidge, A. N.; Crepy, K. V. L.
Chem. Commun. 2000, 1723. (c) Yin, J. J.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 12051. (d) Bringmann, G.; Hamm, A.; Schraut, M. Org.
Lett. 2003, 5, 2805.
Supporting Information Available: Experimental details
and spectroscopic data for compounds 11, 14, 15, 17-19,
21, and 22. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.; Tasler, S. In
Progress in the Chemistry of Organic Natural Products; Herz, W., Falk,
H., Kirby, G. W., Moore, R. E., Eds.; Springer-Verlag Wien: New York,
2001; Vol. 81, pp 1-293.
(18) Oki, M. Top. Stereochem. 1983, 14, 1.
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