Total synthesis of jadomycin A and a carbasugar analogue of jadomycin B

Article abstract of DOI:10.1002/anie.201005329

One's trash is another one's treasure: The first syntheses of jadomycin A and the carbasugar analogue of jadomycin B have been achieved in 6 and 20 longest linear steps, respectively. The key ring system of the aglycone was prepared by a 6π-electron elect

Full text of DOI:10.1002/anie.201005329

Communications
DOI: 10.1002/anie.201005329
Synthetic Methods
Total Synthesis of Jadomycin A and a Carbasugar Analogue of
Jadomycin B**
Mingde Shan, Ehesan U. Sharif, and George A. OꢀDoherty*
Jadomycins A and B are unique members of the angucycline
family of natural products with the unusual 8H-
benz[b]oxazolo[3,3-f]-phenanthridine
ring
system
(Scheme 1). Both jadomycins A and B are produced by the
Gram-positive soil bacteria Streptomyces venezuelae ISP5230
Scheme 2. Retrosynthetic comparison for phenanthridine B-ring forma-
tion.
could skirt the stereoelectronic disadvantages of the 6-endo-
dig ring closures (10 to 9).[9] To the best of our knowledge this
is the first time that switching to an electrocyclic ring closure
was used to change the regioselectivity for ring closure. This
may also be the biosynthetic mode of ring closure and thus
implying that the B-ring cyclization step does not need
enzyme mediation to control the regioselectivity of cycliza-
tion.
Retrosynthetically, we envisioned 1 and 2 arising from the
condensation of a protected amino acid 11 and aldehyde 4 to
form imine 10. A 6p-electron electrocyclic ring closure would
form the desired benzo[b]-phenanthridine 9 after hydration
and oxidation. Finally an acid-catalyzed deprotection/dehy-
dration would install the final oxazolone ring in jadomycin
(Scheme 3). Following precedent, a Stille coupling could be
employed to prepare 4.[6] In accordance with the proposed
biosynthetic pathway,[5] the l-digitoxose could be incorpo-
rated earlier (e.g., 4) or on jadomycin A—this would depend
on the stability of the glycosidic bond to the required acid-
catalyzed transformations.
Scheme 1. Jadomycin A, B and its analogue.
under specific nutrient and environmental stress.[1] They
display important bioactivities, including antitumor, antimi-
crobial, anti-viral, as well as, aurora-B kinase inhibition and
DNA-cleaving capacity.[2–4]
There has been no total synthesis of jadomycin A or B,
although libraries of jadomycin analogues have been pro-
duced through fermentation approaches.[5] Several
approaches to the benzo[b]-phenanthridine ring system
have been developed (Scheme 2).[6,7] From these studies one
can conclude that for stereoelectronic reasons the B-ring is
best constructed by a cyclization of a 2-amino-3-phenyl-
naphthoquinone (e.g., 6 to 5), rather than an amine cycliza-
tion onto the 2-position of an anthroquinone (e.g., 8 to 5).
However, these results stand in contrast to the proposed
biosynthetic route (e.g., 1/2 through 4, Scheme 1).
Our ongoing interest in the synthesis and study of
biologically active carbohydrate containing natural prod-
ucts,[8] along with these biosynthetic questions, made us
interested in this class of natural products. Specifically, we
were interested in testing our hypothesis that by employing a
6p-electrocylic ring closure for the B-ring construction, one
[*] M. Shan, E. U. Sharif, Prof. G. A. O’Doherty
Department of Chemistry and Chemical Biology
Northeastern University, Boston, MA 02115 (USA)
E-mail: G.O’Doherty@neu.edu
Homepage: http://www.as.wvu.edu/~odoherty/site/
[**] We are grateful to the NIH (GM088839) and NSF (CHE-0749451)
for their generous support of our research program. A dissertation
fellowship to M.S. from WVU’s Office of Graduate Study and Life is
greatly appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005329.
Scheme 3. Our biomimetic approach toward the jadomycins.
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Our synthesis began with commercially available phenol
12,[6] which was then protected as MOM and BOM ethers 13a
(68%) and 13b (70%). ortho-Metalation of 13a/b gave
stannanes 14a (68%) and 14b (49%) in modest yields along
with some recovered starting material (ca. 30%). The other
coupling partner 16 was prepared by benzylation of commer-
cially available bromojuglone 15 (Scheme 4).[10]
aldehydes 19. Unfortunately, when 19 was subjected to
condensation conditions with protected isoleucine 11 no
products of cyclizations were detected (e.g., 20). We surmised
that replacing the MOM-ether with a phenol would turn the
negative ortho–ortho steric interaction into a positive hydro-
gen bonding interaction.
Turning to an unselective acetal cleavage conditions (2.4m
HCl in CH3CN, 4–8 min, 59–90%)[11] acetals 17a–c were
converted into aldehydes 18a/b. To our delight, when
aldehyde 18a was condensed with 11 a smooth imine
formation and cyclization occurred to give hemiaminal 21a
(91%), which when treated with neat TFA underwent a tert-
butyl ester hydrolysis, oxazolone ring formation, and benzyl
ether cleavage to give the natural product jadomycin A (74%,
d.r. = 6:1).
The discovery of the surprising acid sensitivity of the
benzyl ether in 21a led us to our optimal synthesis of
jadomycin A. Thus exposure of 18b to the previous imine
formation/electrocyclic ring closure conditions cleanly gave
21b mixture of diastereomers (55%) and subsequent expo-
sure of 21b to neat TFA gave jadomycin A (1) in 50% yield.
This optimized route allowed for the formation of jadomy-
cin A in six steps from both commercially available 12 and 15
in 17% overall yield. A plausible mechanism for this key ring
closure is outlined in Scheme 6.
Scheme 4. Synthesis of the desired coupling partners: MOM=methox-
ymethyl, BOM=benzyloxymethyl, DIPEA=N,N-diisopropylethylamine.
Coupling between stannane 14a and juglone 16 gave 17a
in 73% yield (5 mol% [Pd2(dba)3]·CHCl3, 20 mol% PPh3 and
20 mol% CuI co-catalyst in THF, 758C for 12 h) (Scheme 5).
Under identical conditions, unprotected juglone 15 was
coupled with 14a and 14b to similar yields of 17b (76%)
and 17c (54%). Selective acetal cleavage on 17a (TFA(aq)
/
THF, 10 min, 86%) gave the desired cyclization precursor
Scheme 6. A plausible mechanism for ring closure.
We next decided to undertake a chemical glycosylation
using our carbohydrate approach as a part of our effort to
study structure–activity relationships (SARs) of jadomycin B
(2). The synthesis of glycosyl donors 27, 31, 32, and 33 was
achieved by a asymmetric conversion with achiral acylfuran as
the starting material (Scheme 7).[12] Following a procedure we
previously disclosed for its enantiomer, acylfuran 26 was
enantioselectively converted into tert-butyl carbonate 28 in
six steps through a-pyranone 27.[13] An NIS-promoted iodo-
carbonate cyclization installed the desired digitoxose config-
uration in 29 and a radical TTMSS ((Me3Si)3SiH) deiodina-
tion gave 30, which could be debenzylated to give 31.[14] The
anomeric alcohol in 31 could be activated for a Schmidt
glycosylation[15] as an unstable trichloroacetimidate 32, which
Scheme 5. Synthesis of jadomycin A (1): dba=dibenzylideneacetone,
TFA=trifluoroacetic acid.
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Scheme 8. Asymmetric synthesis of a cyclitol donor: Boc=tert-butyl
carboxylate, DIAD=diisopropyl azodicarboxylate, NBSH=o-nitroben-
zenesulfonylhydrazide, NMO=N-methylmorpholine N-oxide,
DMP=2,2-dimethoxypropane, TsOH=p-toluenesulfonic acid.
With the cyclitol donor 40 in hand, we employed the
proposed Mitsunobu cyclitolization with jadomycin A (1), but
unfortunately no cyclitol product 41 was observed
(Scheme 9). Success occurred when we performed the Mitsu-
Scheme 7. Synthesis of glycosyl donors: NIS=N-iodosuccinimide,
AIBN=azobisisobutyronitrile, DBU=1,8-diazabicyclo[5.4.0]undec-7-
ene.
was used in situ. Simply switching the cyclic carbonate
protecting group of 30 to an acetonide and debenzylation
gave another potential glycosyl donor 33 (Scheme 7).[16]
We primarily focused on the installation of the l-
digitoxose onto the aglycon employing mild Mitsunobu
conditions to construct jadomycin B (e.g., 31 or 33 and 17b/
c or 1 with DIAD/PPh3, À788C to RT).[17] While these
reaction conditions had TLC (thin-layer chromatography)
evidence consistent with the formation of the desired
glycosidic bond (a distinctive wine-red spot),[18] unfortunately,
none of the desired products could be isolated from these
reaction mixtures. Changing of solvent and/or order of
addition did not seem to have any significant effect, whereas,
raising the temperature above À208C caused the in situ
formed wine-red product to disappear. Schmidt glycosylation
using 32 failed to produce the desired in situ product as
determined by TLC.[15] The acid sensitivity of the glycosylated
hydroxyquinones was evident by the fact that even our non-
Lewis acidic Pd-catalyzed glycosylation of 1 and 17b/c with
pyranone 27 also failed. This instability of jadomycin B
precluded a practical SAR type study and thus, we decided
to investigate the synthesis of a less acid sensitive cyclitol
analogue 3.
Scheme 9. Synthesis of jadomycin B carbasugar analogue 3.
The synthesis of carbasugar glycosyl donor equivalent of
l-digitoxose starts from quinic acid (Scheme 8). Following a
known procedure, d-(À)-quinic acid was converted into
dihydroxyketone 35 in nine steps.[19] Boc protection followed
by base mediated elimination resulted in enone 36 (88%, two
steps). A diastereoselective substrate-controlled reduction of
ketone 36 afforded 37 (94%). A Myers reductive rearrange-
ment (NBSH/DIAD/PPh3) cleanly gave alkene 38 (87%).[20]
Stereoselective dihydroxylation using OsO4 and subsequent
diol protection gave acetonide 39 (80%, two steps). Finally,
our proposed Mitsunobu-type cyclitolization precursor 40 was
prepared by a low-temperature LiAlH4 removal of the Boc
group (97%).
nobu reaction on oxazolone precursors (e.g., 17b and 17c).
As before these reactionsꢀ TLCs showed the characteristic
wine-red spots, which this time did not disappear upon
warming to room temperature. More convincingly, stable
products 42a and 42b were isolated in excellent yields (84%
and 91% respectively) when the reactions were run at room
temperature. These acid-stable products 42a and 42b could
be globally deprotected upon exposure to aqueous acid (2.4m,
HCl/MeCN) giving moderate yield of 43 (59% from 42a,
56% from 42b).
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Chemie
[6] O. de Frutos, C. Atienza, A. M. Echavarren, Eur. J. Org. Chem.
As before with the aglycone, the cyclitol analogues 43
could be annulated with isoleucine tert-butyl ester 11. Thus,
condensation of aldehyde 43 with aminoester 11 followed by
a 6p-electrocyclic ring closure resulted in the formation of the
desired ring system 44. Finally acid-catalyzed transesterifica-
tion leads to the formation of carbasugar analogue of
jadomycin B as an inseparable mixture of 2.5:1 diastereomers
(Scheme 9).
In conclusion, the first total synthesis of jadomycin A (1)
was accomplished in six longest linear steps in 17% overall
yield. A cyclitol analogue of jadomycin B (2) has been
successfully achieved in 20 longest linear steps in a 5% overall
yield.[21] A 6p-electrocyclic ring closure was used to obtain the
jadomycin ring system, which should be compatible with the
incorporation of various other amino acids for rapid synthesis
of analogues. This synthesis supports the conclusions by Rix
et al. that the isoleucine incorporation and consequent
formation of the oxazolophenanthridine ring system occur
non-enzymatically.[5b] The application of this methodology for
further analogue synthesis and biological testing is ongoing.
2001, 163.
[7] Y. Akagi, S. Yamada, N. Etomi, T. Kumamoto, W. Nakanishi, T.
Ishikawa, Tetrahedron Lett. 2010, 51, 1338.
[8] a) H. Guo, G. A. OꢀDoherty, Angew. Chem. 2007, 119, 5298;
Angew. Chem. Int. Ed. 2007, 46, 5206; b) M. Zhou, G. A.
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OꢀDoherty, Org. Lett. 2006, 8, 4339; d) D. Balachari, G. A.
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[9] For examples of diastereoselective aza–triene electrocyclic ring
closures in synthesis, see: G. Li, R. P. Hsung, B. W. Slafer, I. K.
Sagamanova, Org. Lett. 2008, 10, 4991.
[10] M. E. Jung, J. A. Hagenah, J. Org. Chem. 1987, 52, 1889.
[11] We found that most Brønsted/Lewis acid conditions for MOM/
BOM groups removal lead to decomposition of starting mate-
rial. We experienced similar problems with the hydrogenolysis of
the BOM group. After some careful study we found a small
window of opportunity with the short-term exposure (4–8 min)
of both the MOM- and BOM-ether to concentrated HCl/
acetonitrile (v/v 1:5).
[12] R. S. Babu, G. A. OꢀDoherty, J. Am. Chem. Soc. 2003, 125,
12406.
[13] H. Guo, G. A. OꢀDoherty, J. Org. Chem. 2008, 73, 5211.
[14] M. Shan, Y. Xing, G. A. OꢀDoherty, J. Org. Chem. 2009, 74, 5961.
[15] T. Mꢁller, R. Schneider, R. R. Schmidt, Tetrahedron Lett. 1994,
35, 4763.
[16] R. S. Babu, M. Zhou, G. A. OꢀDoherty, J. Am. Chem. Soc. 2004,
126, 3428.
[17] a) O. Mitsunobu, Y. Yamada, Bull. Chem. Soc. Jpn. 1967, 40,
2380; b) O. Mitsunobu, Synthesis 1981, 1.
[18] Jakeman et al. reported similar color changes, see: D. L. Jake-
man, S. N. Dupuis, C. L. Graham, Pure Appl. Chem. 2009, 81,
1041.
[19] M. Shan, G. A. OꢀDoherty, Org. Lett. 2008, 10, 3381.
[20] a) A. G. Myers, B. Zheng, J. Am. Chem. Soc. 1996, 118, 4492;
b) A. G. Myers, B. Zheng, Tetrahedron Lett. 1996, 37, 4841;
c) A. G. Myers, B. Zheng, M. Movassaghi, J. Org. Chem. 1997,
62, 7507; d) M. H. Haukaas, G. A. OꢀDoherty, Org. Lett. 2002, 4,
1771; Ref. [8c].
Received: August 26, 2010
Published online: October 26, 2010
Keywords: carbasugars · electrocyclic ring-closure · jadomycin ·
.
total synthesis
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[21] The route is 20 longest linear steps from quinic acid but only nine
steps from known starting material 36.
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