Synthesis of the monomeric unit of the lomaiviticin aglycon

Article abstract of DOI:10.1002/anie.200902509

The right building blocks: The monomeric unit of the lomaiviticin aglycon (see structures) was synthesized through an enantioselective route featuring an Ullmann coupling, a benzoin-type cyclization, and a novel SmI₂- mediated allylic alcohol f

Full text of DOI:10.1002/anie.200902509

Communications
DOI: 10.1002/anie.200902509
Natural Products
Synthesis of the Monomeric Unit of the Lomaiviticin Aglycon**
K. C. Nicolaou,* Andrea L. Nold, and Hongming Li
Reported in 2001, lomaiviticins A (1) and B (2; Scheme 1)
were isolated from Micromonospora lomaivitiensis and
demonstrated striking molecular architectures and impressive
antitumor and antibiotic activities against a variety of cancer
cell lines and bacteria.[1] These natural products apparently
exert their action through a novel mechanism involving the
cleavage of DNA.[2] Their chemical synthesis presents a
formidable challenge, and reports describing partial success
have already appeared.[3] Herein, we describe the synthesis of
the monomeric aglycon unit of the lomaiviticins (3;
Scheme 1), which is reminiscent of the kinamycins (i.e.
kinamycin C (4); Scheme 1).
The dimeric structure of the lomaiviticins renders itself to
a symmetrical retrosynthetic dissection through the center of
the molecule. This dissection reveals monomeric unit 3
(Scheme 2) as a possible precursor to both 1 and 2—a
scenario that might not be so dissimilar to their biosynthetic
pathway. Our approach to enantiopure pre-lomaiviticin
Scheme 1. Structures of lomaiviticins A (1) and B (2), their monomeric
structure 3 followed our general strategy towards the
kinamycins[4] (defining bromoaldehyde 5 and iodoenone 7
as the possible building blocks as shown in Scheme 2), and
involved an Ullmann coupling reaction and a benzoin-type
cyclization as the main processes to construct its molecular
framework. However, the approach required special design
features (e.g. substrate 6, see below, to achieve high regio-
control) and the development of a novel samarium-mediated
1,3-allylic hydroxy group transposition (see below) that
allowed significant shortening of the synthetic route.
unit (3), and kinamycin C (4).
The required building blocks 6 and 7 were synthesized
from starting materials 5 and 8, respectively, as summarized in
Scheme 3. Thus, readily available bromoaldehyde 5[4] was
debenzylated (AlCl3, 80% yield)[5] and selectively oxidized
with PhI(CF3CO2)2[6] to the expected p-quinone (97% yield),
[*] Prof. Dr. K. C. Nicolaou, A. L. Nold, Dr. H. Li
Department of Chemistry
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
Scheme 2. Retrosynthetic analysis of lomaiviticin aglycon monomer 3.
Bn=benzyl, SEM=2-(trimethylsilyl)ethoxymethyl.
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
which was reduced with Na2S2O4 to the corresponding
dihydroquinone and protected with SEM groups (SEMCl,
iPr2NEt, 92% yield for two steps) to afford bromoaldehyde 6.
Meanwhile, enantioselective asymmetric dihydroxylation of
enone 8[7] (AD-mix-b, single recrystallization, 69% yield,
> 95% ee)[8] afforded the corresponding 1,2-diol, whose
protection (2-methoxypropene, PPTS) furnished acetonide 9
in 94% yield. Conversion of the latter into its TMS enol ether
(TMSOTf, Et3N), and subsequent exposure to O2 in the
presence of catalytic amounts of Pd(OAc)2,[9] led to enone 10
(83% yield), whose iodination (I2, py) afforded iodoenone 7
in 91% yield.
[**] We thank Dr. D. H. Huang and Dr. L. Pasterneck for assistance with
NMR spectroscopy and Dr. G. Siuzdak for assistance with mass
spectrometry. Financial support for this work was provided by
grants from the National Institutes of Health (U.S.A.) and the
Skaggs Institute for Chemical Biology, and predoctoral fellowships
from the American Chemical Society (A.L.N.) and Bristol–Myers
Squibb (A.L.N.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902509.
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to afford desired tetracyclic structure 13a (as was previously
observed in the kinamycin case).[4] However, despite its
efficiency (76% combined yield), the latter reaction [11 plus
12 (cat.), Et3N] gave a disappointing ratio of the benzoin
product 13a and its isomer 13b (Stetter product resulting
from 1,4-addition; 13a/13b ca. 1:1.5).[12] We attributed the
formation of the latter compound to the preference of
cyclization precursor ketoaldehyde 11 and its latent reaction
species to reside in the conformation shown (see also
ꢀ
Figure 1, the calculated C4a C5 distance for 11 is 3.1 ꢀ),
Scheme 3. Construction of key building blocks bromoaldehyde 6 and
iodoenone 7. Reagents and conditions: a) AlCl3 (1.2 equiv), CH2Cl2,
258C, 3 h, 80%; b) PhI(CF3CO2)2 (3.0 equiv), MeCN, H2O, 258C,
30 min, 97%; c) Na2S2O4 (5.0 equiv), EtOAc, H2O, 258C, 10 min; then
SEMCl (4.0 equiv), iPr2NEt (6.0 equiv), DMF, 258C, 18 h, 92%; d) AD-
mix-b (1.4 equiv), H2NSO2Me (1.0 equiv), NaHCO3 (3.0 equiv), tolu-
ene, tBuOH, H2O, 08C, 36 h, 69%, >95% ee; e) 2-methoxypropene
(5.0 equiv), PPTS (0.1 equiv), CH2Cl2, 258C, 18 h, 94%; f) TMSOTf
(1.35 equiv), Et3N (1.5 equiv), THF, 08C, 30 min; then Pd(OAc)2
(0.1 equiv), O2 (balloon), DMSO, 258C, 18 h, 83%; g) I2 (3.0 equiv),
CH2Cl2, py, 258C, 30 min, 91%. DMF=N,N-dimethylformamide,
DMSO=dimethyl sulfoxide, PPTS=pyridinium 4-toluenesulfonate,
py=pyridine, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
Figure 1. Calculated preferred conformations of 11 and 14 (Chem3D
MM2).
With ample quantities of 5, 6, and 7 available, we
proceeded to explore ways to advance them to the target
molecule 3. Our initial foray, as shown in Scheme 4, involved
Ullmann coupling of benzyloxy bromoaldehyde 5 with
iodoenone 7 ([(Pd2(dba)3] (cat.), CuI (cat.), Cu)[10] to afford
coupling product 11 in 83% yield, whose intramolecular
benzoin-type reaction with Rovis catalyst 12[11] was expected
thereby favoring the Stetter product 13b. To avoid this
predicament, we designed coupled product 14a (from 6 and 7,
utilizing the same Ullmann coupling conditions; Scheme 5),
whose preferred conformation was expected to be that shown
ꢀ
in Scheme 5 (14b, see also Figure 1, the calculated C4a C5
distance for 14 is 2.9 ꢀ) owing to the bulky OSEM group
exerting its influence six carbon atoms away.
Thus, it was reasoned that by its mere presence at C10, the
OSEM group would force the OMe group at C11 towards the
carbonyl moiety at C4a, thus causing the OSEM group to
rotate (with its carrier bicyclic ring system) away and into a
position to interact with the aldehyde group in the desired
fashion to give the benzoin product (14b). Indeed, when
ketoaldehyde 14a was heated in CH2Cl2 at reflux in the
presence of catalyst 12 and Et3N, the OSEM group served its
function well, and the desired benzoin product 15 was formed
with greater than 20:1 selectivity (70% yield, ca. 3:1 d.r. at
C4a) over its Stetter counterpart. We believe that the
beneficial effect of the OSEM group in this cyclization
stems primarily from its steric bulk rather than its electron-
donating nature, as the corresponding C10, C7 bis(methoxy)
substrate (not shown) exhibits only about 3:1 selectivity in
favor of the desired benzoin product. Furthermore, it should
be noted that Ullmann coupling substrates equipped at C10
Scheme 4. Failure of the original synthetic plan. Reagents and con-
ditions: a) 5 (1.0 equiv), 7 (1.5 equiv), CuI (0.4 equiv), [Pd2(dba)3]
(0.1 equiv), Cu (10.0 equiv), DMSO, 658C, 2.5 h, 83%; b) 12
(0.2 equiv), Et3N (2.0 equiv), CH2Cl2, 428C, 18 h, 76%, ca. 1:1.5 ben-
zoin product/Stetter product. dba=trans,trans-dibenzylideneacetone.
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provided an important hint (in the form of trace amounts of
the desired product (16) in the samarium-mediated step),
namely that the sequence could be replaced with a one-step
procedure. Indeed, exposure of hydroxy ketone 15 to the SmI2
conditions[13] resulted in 10% yield of the desired rearranged
alcohol 16. Our initial suspicions of this process occurring
through an intramolecular delivery of oxygen were dispelled
when a single diastereomer of 15 led to a mixture of epimeric
alcohols (16). We soon realized that the reaction of 15 with
SmI2, and subsequent bubbling of O2 through the reaction
mixture directly generated the desired fluorenone 16 in 76%
yield (ca. 1.5:1 d.r. at C1).
The mechanism of this remarkably regioselective oxygen-
ation at C1 was probed through the use of 18O2, and the results
are shown in Scheme 6. Thus, exposure of hydroxy ketone 15
(ca. 3:1 d.r.) to SmI2/MeOH likely forms extended enolate 20
(through two sequential single-electron transfers). This spe-
cies reacts with 18O2 regioselectively (but not stereoselec-
tively) at C1 (which is the most reactive position of the
Scheme 5. Completion of the synthesis of the monolomaiviticin agly-
con (3). Reagents and conditions: a) 6 (1.0 equiv), 7 (1.5 equiv), CuI
(0.4 equiv), [Pd2(dba)3] (0.1 equiv), Cu (10.0 equiv), DMSO, 658C, 3 h,
69%; b) 12 (0.2 equiv), Et3N (2.0 equiv), CH2Cl2, 428C, 18 h, 70%, 3:1
mixture of diastereomers, >20:1 benzoin product/Stetter product;
c) SmI2 (4.0 equiv), MeOH (10.0 equiv), THF, ꢀ788C, 5 min; then
ꢀ78!258C; then O2 (balloon), 258C, 18 h, 76%, 1.5:1 mixture of
diastereomers; d) TsNHNH2 (5.0 equiv), aq HCl (1m)/iPrOH (1:100),
258C, 18 h, 91%, 1:1 mixture of E/Z isomers of a 1.5:1 mixture of
diastereomers; e) DMP (5.0 equiv), CH2Cl2, 258C, 1.5 h, 62%;
f) Na2S2O4 (5.0 equiv), EtOAc, H2O, 258C, 5 min; then Ac2O
(10.0 equiv), Et3N (10.0 equiv), DMAP (1.0 equiv), CH2Cl2, 258C,
20 min, 91%; g) TMSOTf (5.0 equiv), CH2Cl2, 258C, 20 min, 96%;
h) CAN (3.0 equiv), MeCN, pH 7 phosphate buffer, 258C, 20 min,
96%; i) aq KOH (1m), THF, H2O, 258C, 30 min, 95%. CAN=cerium
ammonium nitrate, DMAP=4-dimethylaminopyridine, DMP=Dess–
Martin periodinane, THF=tetrahydrofuran, Ts=4-toluenesulfonyl.
and C7 with groups that are bulkier than OSEM, such as
OTES, OTIPS, and OBn, failed to couple with iodoenone 7
under the same reaction conditions employed for 5 and 6, thus
precluding them from serving as viable precursors. These
observations underscore the importance of the OSEM group
as a unique design feature to ensure the sequential success of
both the Ullmann coupling and the benzoin-like cyclization
reactions.
With the first hurdle in the synthesis behind us, we were
now faced with a second challenge, that of improving our
previously devised allylic alcohol transposition to convert 15
into hydroxyfluorenone 16 (Scheme 5). Although our origi-
nally employed four-step protocol[4] for this transformation
formed the desired product (16) in only 42% overall yield, it
Scheme 6. 18O2 labeling studies to elucidate the samarium-mediated
1,3-allylic alcohol transposition reaction (15!16). Reagents and
conditions: a) 1. SmI2 (4.0 equiv), MeOH (10.0 equiv), THF, ꢀ788C,
5 min; then ꢀ78!258C; 2. 18O2 (balloon), 258C, 18 h; 3. aq Na2S2O3,
258C, 30 min, 76%, 1.5:1 mixture of diastereomers; 4. CSA,
(5.0 equiv), ꢀ78!258C, 10 min, 72% 1.5:1 mixture of diastereomers;
5. Davis oxaziridine (2.0 equiv), THF, 08C, 2 h, 85%, 1.5:1 mixture of
diastereomers. CSA=10-camphorsulfonic acid.
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enolate for radical chemistry) to afford, through the inter-
mediacy of peroxide species 21[14] and upon work-up with
aqueous Na2S2O3, hydroxyfluorenone 16-O18 in 76% yield,
along with ketone 23-O18 (10% yield). Although labile, the
hydroperoxide species derived from the aqueous work-up of
power of remote group interactions and cascade reactions[18]
in achieving control and efficiency in chemical synthesis.
Received: May 12, 2009
Published online: July 2, 2009
1
21 was detected by H NMR spectroscopy and mass spec-
Keywords: antibiotics · antitumor agents · natural products ·
trometry. Interestingly, by quenching the samarium enolate 20
with CSA, or Davisꢁ oxaziridine, under anaerobic condi-
tions[15] resulted in functionalization at C4a (as is typically the
case with extended enolates), rather than C1, to furnish
products 22 (72% yield, ca. 1.5:1 d.r.)[16] and 15 (85% yield,
ca. 1.5:1 d.r.), respectively.
.
samarium diiodide · Ullmann reaction
[1] Isolation: H. He, W.-D. Ding, V. S. Bernan, A. D. Richardson,
C. M. Ireland, M. Greenstein, G. A. Ellestad, G. T. Carter, J.
Am. Chem. Soc. 2001, 123, 5362.
The final steps of the synthesis of 3 (Scheme 5) involved
initial formation of a hydrazone within fluorenenone 16
(TsNHNH2, aq HCl)[17] and subsequent treatment with DMP,
which concurrently oxidized the hydrazone moiety, the
secondary alcohol, and the bis(SEM) aromatic system to
afford diazo quinone 17 in 56% overall yield. The quinone
structural motif within the latter needed to be transposed to
its proper position; to this end, 17 was sequentially exposed to
Na2S2O4 and Ac2O/Et3N [91% yield of acetonide bis-
(acetate)] and afforded, upon treatment with TMSOTf,
dihydroxy bis(acetate) 18 in 96% yield. Finally, oxidation of
18 with CAN and subsequent deacetylation (aq KOH) led to
the coveted lomaiviticin aglycon monomer (ꢀ)-3 in 91%
overall yield.
The application of the developed samarium-mediated 1,3-
allylic alcohol transposition procedure to our kinamycin
synthesis[4] reduced the previously employed sequence
(involving Ac2O, Et3N, DMAP; SmI2, MeOH; Et3N; SeO2)
to a single operation, and significantly increased the overall
yield (from 55% over four steps to 83% over one step;
Scheme 7).[4]
[2] D. P. Arya, Top. Heterocycl. Chem. 2006, 2, 129.
[3] a) K. C. Nicolaou, R. M. Denton, A. Lenzen, D. J. Edmonds, A.
Li, R. R. Milburn, S. T. Harrison, Angew. Chem. 2006, 118, 2130;
Angew. Chem. Int. Ed. 2006, 45, 2076; b) E. S. Krygowski, K.
Murphy-Benenato, M. D. Shair, Angew. Chem. 2008, 120, 1704;
Angew. Chem. Int. Ed. 2008, 47, 1680.
[4] K. C. Nicolaou, H. Li, A. L. Nold, D. Pappo, A. Lenzen, J. Am.
Chem. Soc. 2007, 129, 10356.
[5] H. Laatsch, Liebigs Ann. Chem. 1985, 102, 1847.
[6] R. M. Moriarty, O. Prakash, Org. React. 2001, 57, 327.
[7] J.-P. Barnier, V. Morisson, I. Volle, L. Blanco, Tetrahedron:
Asymmetry 1999, 10, 1107.
[8] P. J. Walsh, K. B. Sharpless, Synlett 1993, 605.
[9] H. Suzuki, N. Yamazaki, C. Kibayashi, J. Org. Chem. 2001, 66,
1494.
[10] M. G. Banwell, B. D. Kelly, O. J. Kokas, D. W. Lupton, Org. Lett.
2003, 5, 2497. The addition of catalytic amounts of CuI, in our
case, markedly improved the yield of the Ullmann coupling
product.
[11] M. S. Kerr, J. R. deAlaniz, T. Rovis, J. Org. Chem. 2005, 70, 5725.
[12] For a review, see: H. Stetter, Angew. Chem. 1976, 88, 695;
Angew. Chem. Int. Ed. Engl. 1976, 15, 639.
[13] For reviews, see: a) G. A. Molander, C. R. Harris, Tetrahedron
1998, 54, 3321; b) H. B. Kagan, Tetrahedron 2003, 59, 10351;
c) D. J. Edmonds, D. Johnston, D. J. Procter, Chem. Rev. 2004,
104, 3371; d) K. Gopalaiah, H. B. Kagan, New J. Chem. 2008, 32,
607.
[14] For previously postulated peroxo-samarium species, see: a) E. J.
Corey, Z. Wang, Tetrahedron Lett. 1994, 35, 539; b) S. Fielder,
D. D. Rowan, M. S. Sherburn, Synlett 1996, 349.
[15] F. A. Davis, B. C. Chen, Chem. Rev. 1992, 92, 919.
[16] b,g-Unsaturated ketone 22 proved rather labile and, therefore,
was immediately converted (by exposure to Et3N) into its
conjugated counterpart (22a, not shown) and was characterized
as such (see the Supporting Information).
Scheme 7. Streamlining the kinamycin samarium-mediated 1,3-allylic
alcohol transposition. Reagents and conditions: a) SmI2 (4.0 equiv),
MeOH (10.0 equiv), THF, ꢀ788C, 5 min; then ꢀ78!258C; then O2
(balloon), 258C, 18 h, 83%, single diastereomer. TBS=tert-butyldime-
thylsilyl.
[17] T. Kumamoto, Y. Kitani, H. Tsuchiya, K. Yamaguchi, H. Seki, T.
Ishikawa, Tetrahedron 2007, 63, 5189.
[18] For reviews, see: a) K. C. Nicolaou, T. Montagnon, S. A. Snyder,
Chem. Commun. 2003, 551; b) L. F. Tietze, G. Brasche, K.
Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH,
Weinheim, 2006, p. 672; c) K. C. Nicolaou, D. J. Edmonds, P. G.
Bulger, Angew. Chem. 2006, 118, 7292; Angew. Chem. Int. Ed.
2006, 45, 7134.
The chemistry described here provides a rapid entry into
the monomeric unit of the lomaiviticins that should facilitate
further synthetic, biosynthetic, and biological studies within
this important area of investigation. It also demonstrates the
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