Total Synthesis of Lactonamycinone

Article abstract of DOI:10.1002/anie.200352592

A revised strategy was required for the installation of the remaining polyoxygenated E and F rings of lactonamycinone (2). Key features in the successful route include dihydroxylation of a ketoquinone, the use of a furanone as a lactone surrogate (see 1),

Full text of DOI:10.1002/anie.200352592

Angewandte
Chemie
Natural Product Synthesis
Total Synthesis of Lactonamycinone**
Tony Siu, Christopher D. Cox, and
Samuel J. Danishefsky*
In the previous Communication in this issue, we described an
approach to the total synthesis of lactonamycinone (2), the
aglycone of the antibiotic of lactonamycin (1). This effort
culminated in a highly concise assembly of the tetracyclic
intermediate 3 (see Scheme 1),[1] containing the core func-
tionality, which, in principle, could be exploited in a total
synthesis of 2. As described herein, the first total synthesis of
lactonamycinone (2) has now been completed. To reach our
[*] Prof. S. J. Danishefsky, T. Siu, Dr. C. D. Cox
Department of Chemistry, Columbia University
Havemeyer Hall, New York, NY 10021 (USA)
E-mail: s-danishefsky@ski.mskcc.org
Prof. S. J. Danishefsky
Laboratory for Bioorganic Chemistry
Sloan-Kettering Institute for Cancer Research
1275 York Ave., New York, NY 10021 (USA)
Fax: (+1)212-772-8691
[**] This work was supported by the National Institutes of Health (Grant
number: HL25848). A Postdoctoral Fellowship is gratefully
acknowledged by C.C. (NIH, Grant Number F32-CA84758). The
authors thank Dr. Tekeuchi of The Institute of Microbial Chemistry
for kindly providing the 1HNMR spectra of 33 and lactonamycin,
Yashuiro Itagaki for high-resolution mass spectral analyses, and
Professor Ged Parkin and Dr. David Churchill for crystallographic
analysis of compound 8.
Angew. Chem. Int. Ed. 2003, 42, 5629 –5634
DOI: 10.1002/anie.200352592
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5629

Communications
groups in the ABC domain are not specified, the concept
suggests progression of 3 to hemiacetal 4. The introduction of
the methyl ether at C3’ (in 2) might involve methanolysis of a
system such as 4 through oxonium formation at C3’.
The effort began with a novel and highly diastereoselec-
tive dihydroxylation of the quinone moiety of 5 with osmium
tetroxide and pyridine. This reaction led to the clean
formation (90% yield) of compound 6, which incorporates
the required cis relationship of the hydroxy groups at C1’ and
C5’ (Scheme 2). The stereochemical sense of this dihydrox-
ylation reaction follows well from Kishi's model, in which
OsO4 approaches the olefin in its lowest-energy conformer
(based on minimization of the 1,3-allylic strain) from the face
opposite to the hydroxy group.[3] Notably, had the C3’ alcohol
been homochiral and of the required absolute configuration,
the diol at C1’ and C5’ would have been installed with
enantiotopic control. Treatment of 6 with TFA brought about
concurrent cleavage of the octyloxymethyl acetal and of the
tert-butyl ester linkages as well as cyclization to afford lactone
7 in 97% yield. A variety of conditions were screened to
goal, it became necessary to devise a new end-game sequence
to overcome a virtually complete breakdown of the chemistry
that was workable in several model settings.[2] The new route
highlights some important principles, which are likely to
prove valuable in any future synthesis of lactonamycinone.
Our original strategy for constructing the E and F rings is
summarized in Scheme 1 (3!4!2). Although the protecting
Scheme 1. Proposed construction of the E and F rings.
Scheme 2. Reagents and conditions. a) 1) OsO4, pyridine, THF; 2) NaHSO3, 90%; b) TFA, CH2Cl2, H2O, 97%; c) TBSOTf, 2,6-lutidine, 73%.
d) LDA, TMSCl, NIS, THF, ꢀ788C, 61%; e) Cs2CO3, THF, 83%; f) BBr3, CH2Cl2, ꢀ788C; g) Al2O3, CHCl3, 65% (two steps). TFA=trifluoroacetic
acid; TBS=tert-butyldimethylsilyl; Tf=trifluoromethanesulfonyl; LDA=lithium diisopropylamide; TMS=trimethylsilyl; NIS=N-iodosuccinimide.
5630
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5629 –5634

Angewandte
Chemie
oxidize the alcohol at C3’ to the ketolactone. As was
the case in our earlier model studies,[2] all attempts
were unsuccessful, The inability to execute this
seemingly simple operation forced recourse to new
methods to install the angular methoxy function.
The “C3’” alcohol was converted into its tert-
butyldimethylsilyl ether derivative with concomitant
silylation of one of the phenolic hydroxy groups to
give 8. X-ray crystallographic analysis confirmed
this structure and, accordingly, the structures of the
precursors throughout the project.[4]
a-Iodination of lactone 8 was achieved through
initial formation of an intermediate silyl ketene
acetal (not isolated), which was treated with NIS
(Scheme 2). Elimination of the b-siloxy group with
Cs2CO3 furnished vinyl iodide 9 in 51% yield (over
two steps). Deprotection of the benzyl ether fol-
lowed by stirring with weakly acidic alumina yielded
Scheme 3. Failure to adapt model studies 11!12!13 to 10!14!15.
tetrahydrofuran 10 in 65% yield (over two steps). The
complete hexacyclic ring system of lactonamycin was now in
place as a mixture of iodo diastereomers. Interestingly, no
intramolecular Michael addition occurs without the activation
of the double bond by the iodide substituent.
reflecting electronic depletion of the quinone by the proximal
acyl group. However, the transformation was accomplished
by using osmium tetroxide coordinated to TMEDA.[6] Reduc-
tive cleavage of the osmate ester afforded 17 in 77% yield.
Treatment of 17 with TFA did indeed give rise to
ketolactone 18 (along with variable amounts of the decar-
boxylated product of 18). Unfortunately, we were unable to
cleave the benzyl ether of the labile ketolactone 18, which was
required to trigger the proposed hemiacetal formation. It was
found that 18 could be converted into its methyl enol ether 19
(22% over two steps).[7,8] With the added robustness of the
vinylogous carbonate ensemble, came the ability to cleave the
benzyl ether (see 19). Unfortunately, all attempts at intra-
molecular conjugate addition, which would have delivered 2,
failed. Essentially, the vinylogous carbonate double bond in
19 had resisted Michael addition by the now liberated
hydroxy group at C5. In fact, methyl tetronate is apparently
rather inert to 1,4-additions under acidic conditions.[9]
The total synthesis project now appeared to be almost
complete. In our model studies, compound 11 had been
converted into 13 through methanolysis of the strained double
bond of vinyl triflate 12 (Scheme 3).[2] However, various
attempts to adapt this chemistry to the case of 10 were
unsuccessful. Without presently describing all these initiatives
in detail, the overriding difficulty was our inability, in the
hexacyclic series, to generate a junction olefin (as in 14).
Given that the oxidation of the alcohol at C3’ was
apparently not feasible at the stage of lactone 7, it became
difficult to install the angular methoxy functional group. It
was decided to try to oxidize quinone 5 to the unstable
ketoquinone 16 (Scheme 4). Accordingly, the oxidation was
conducted with Dess–Martin periodinane[5] at the stage of 5 to
afford 16 in 96% yield. Dihydroxylation was now difficult,
Given the nonreactivity of methyl enol ether 19, we
revisited the ketolactone concept (see 4). The main stumbling
Scheme 4. Reagents and conditions. a) Dess–Martin periodinane, CH2Cl2, 96%; b) 1) OsO4, TMEDA, CH2Cl2, 2) HCl (1n), NaHSO3, THF, 77%;
c) TFA/CH2Cl2, 20–55%; d) TBSOTf, 2,6-lutidine, ꢀ788C, CH2Cl2; e) TMSCHN2, DIPEA, MeCN/CH2Cl2, 22% (two steps); f) BBr3, CH2Cl2, ꢀ788C,
95%. TMEDA=N,N,N’,N’-tetramethylethylenediamine; DIPEA=N,N-diisopropylethylamine.
Angew. Chem. Int. Ed. 2003, 42, 5629 –5634
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5631

Communications
block in obtaining the ketolactone with a free
hydroxy group at C5 had been our inability to
remove the benzyl ether with the ketolactone
moiety in place. As we were unable to deprotect
the alcohol from its benzyl ether, it would be
necessary to have the latent hydroxy group at
C5 protected in an acid-labile form (20).
Accordingly, in this connection, following pro-
tocols very similar to those described above and
previously,[1] compound 20, which contains the
acid-labile MOM group on the C5 alcohol, was
synthesized. Treatment of this compound with
acid did indeed result in liberation of the
primary alcohol by cleavage of its protecting
group. However, instead of prompting cycliza-
tion to lactonamycinone (2), the principal prod-
uct of treatment of 20 with acid in methanol was
21 (Scheme 5). Thus, the hemiacetal cyclization
step that we sought had occurred, but was
accompanied by opening of the lactone ring. We
Scheme 6. Proposed new strategy to form the E and F rings.
Our campaign commenced with the addition of
(1,3-dioxolan-2-ylmethyl)magnesium bromide[10]
to aldehyde 26[1] followed by oxidation to produce
quinone 27 in 55% yield over two steps
(Scheme 7). As described earlier, the strategic
alcohol function at the future C3’ in 27 directed the
Tamura reaction with the previously described
homophthalic anhydride 28,[1] thereby affording 29
in 42% yield. Subsequent oxidation followed by
Scheme 5. Failed attempt at lactonamycinone.
dihydroxylation afforded 30 (89%, two steps).
With diol 30 in hand, treatment with aqueous HCl
cannot speak rigorously as to the timing of these events, but
preliminary experiments suggest that lactone degradation
precedes hemiacetal formation.
(3n) led to deprotection of the octyloxymethyl ether with
concomitant intramolecular attack of the tertiary alcohol at
the proximal acetal to afford butenolide 24 in 82% yield.
Deprotection of the benzyloxy ether produced the pivotal
intermediate 31 (Scheme 8). Gratifyingly, when this com-
pound was heated at reflux with HCl/dioxane/methanol,
acetal 32 was obtained in 51% yield (over two steps, based on
recovered starting material). Hydrolysis of 32 gave rise to an
anomeric mixture of lactols in quantitative yield, with the C3’
methoxy group intact.
At this point, a new approach was needed to overcome the
limitations encountered in the previous routes. In compound
10, the hexacyclic ring system had been reached; however, all
efforts to introduce the angular methoxy were unsuccessful.
Methyl enol ether 19 contains the required methoxy func-
tional group and the correct oxidation state at C3’, but the
cyclization of the E ring did not occur, apparently due to the
stable nature of the vinylogous system. Ketolactone 20
contains the functionality to cyclize the E ring with the
addition of the angular methoxy group, but the lactone moiety
is vulnerable to the harshly acidic conditions of the cyclization
reaction.
The key departure in our new approach was the presen-
tation of the F ring as a vinylogous butenolide 24 (Scheme 6).
Given the instability of ketolactone 20, it was hoped that the
stable, structurally simpler vinylogous butenolide could
function as a more durable surrogate. Moreover, since
decarboxylation was a serious problem in reaching the
lactone, the vinylogous butenolide would prove to be more
amenable to a straightforward construction of the F ring. The
hope was that methanol-induced cyclization would lead to 25.
Conversion of 25 into 2 should be straightforward, even
though the oxidation state would require adjustment.
During the planning stages of the new strategy, the task of
oxidizing a lactol to a lactone seemed straightforward.
Unfortunately, what had initially been anticipated to be an
uneventful oxidation turned out to be anything but routine.
After a systematic survey of many oxidants, it was discovered
that only TEMPO[11]-mediated oxidation was able to com-
plete the transformation to lactonamycinone (2) (58% yield).
1
The H and 13C NMR spectra of the synthetic aglycone of
lactonamycin were similar to those of the natural product,
lactonamycin, which bears the carbohydrate attachment.[12]
Conclusive comparison data came from the identical NMR
spectra of synthetic peracetylated lactonamycinone 33 and
naturally derived peracetylated lactonamycinone, kindly
provided by Tekeuchi and co-workers.
In the total synthesis of lactonamycinone, it was found
that there was considerable kinetic resistance to fashioning a
5632
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5629 –5634

Angewandte
Chemie
Scheme 7. Reagents and conditions. a) (1,3-dioxolan-2-ylmethyl)-magnesium bromide, LiBr, THF, reflux, 69%; b) CAN, 08C, CH3CN/H2O (1:1),
80%; c) NaH, 28,[1] THF, 42%; d) Dess–Martin periodinane, CH2Cl2, quantitative; e) 1) OsO4, TMEDA, CH2Cl2, 2) HCl (1n), NaHSO3, THF, 89%;
f) HCl (3n), acetone/THF, reflux, 82% (based on recovered starting material).
32). Clearly, there is much still to be learnt about the
origins of the resistance to formation of this
hexacyclic array at the ring F lactone level of
oxidation.
It is tempting to conjecture that, with such
understanding, could come valuable insight into the
role of this novel ring system in the biological
function of the antibiotic itself. Although some yield
issues must be overcome,[1] and a scheme for an
enantiocontrolled synthesis implemented, the con-
ciseness of the present synthesis will be of great
advantage in dealing with these problems.
As we address these challenges, we also plan to
generalize the concept of using proximal intramo-
lecular catalytic devices to differentiate closely
balanced functional groups.[1] The ability to distin-
Scheme 8. Reagents and conditions. a) BBr3, CH2Cl2, ꢀ788C, b) HCl (4.0n), diox-
ane/MeOH, 658C, 51% (two steps, based on recovered starting material); c) HCl
(1n)/THF, quantitative yield; d) TEMPO, PhI(OAc)2, CH2Cl2, 58%.
TEMPO=2,2,6,6 tetramethyl-1-piperidinyloxy free radical.
guish between cognate functions in a multifunc-
tional setting is surely one of the continuing
challenges of organic synthesis.
Received: August 7, 2003 [Z52592]
Keywords: antibiotics · Diels–Alder reaction · natural products ·
.
quinones · total synthesis
[1]C. D. Cox, T. Siu, S. J. Danishefsky, Angew. Chem. 2003, 115,
5783 – 5787; Angew. Chem. Int. Ed. 2003, 42, 5625 – 5629.
[2]a) C. Cox, S. J. Danishefsky, Org. Lett. 2000, 2, 3493 – 3496; b) C.
Cox, S. J. Danishefsky, Org. Lett. 2001, 3, 2899 – 2902.
[3]a) J. K. Cha, W. J. Christ, Y. Kishi, Tetrahedron Lett. 1983, 24,
3943; b) W. J. Christ, J. K. Cha, Y. Kishi, Tetrahedron Lett. 1983,
24, 3947c) J. K. Cha, W. J. Christ, Y. Kishi, Tetrahedron 1984, 40,
2247.
full hexacyclic system by closure of the tetrahydrofuran E ring
at C3’ in a reversible reaction. A dihydrofuranone was used to
overcome this problem. This allowed us to craft a setting for
closure, by which concurrent methanolysis at C3’ caps the
reaction in the “forward” sense (see formation of compound
[4]CCDC-216742 ( 8) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
Angew. Chem. Int. Ed. 2003, 42, 5629 –5634
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5633

Communications
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
literature: W. R. Roush, B. B. Brown, J. Org. Chem. 1993, 58,
2162, and references therein.
[9]A. Bertucco, J. Brennan, M. Fachini, S. Kliage, P. J. Murphy, F.
Pasutto, R. Signorini, H. L. Williams, Tetrahedron 1994, 50, 8237.
[10]M. Schmeichel, H. Redlich, Synthesis 1996, 8, 1002 – 1006.
[11]A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli,
J. Org. Chem. 1997, 62, 6974.
[5]D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277 –
7287.
[6]E. J. Corey, S. Sarshar, M. D. Azimioara, R. C. Newbold, M. C.
Noe, J. Am. Chem. Soc. 1996, 118, 7851.
[7]T. Aoyama, S. Terasawa, K. Sudo, T. Shioiri, Chem. Pharm. Bull.
1984, 32, 3759.
[8]Intermediate 19 was assigned as the methyl tetronate as opposed
to the ketene acetal by comparison with related systems in the
[12]The spectra of lactonamycin and its aglycone are quite similar,
except for the protons from the glycoside and one of the protons
at C5, whose signal differs by 0.2 ppm presumably due to the
perturbation of the glycoside.
5634
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5629 –5634