A macrocyclic approach to tetracycline natural products. Investigation of transannular alkylations and Michael additions

Article abstract of DOI:10.1021/ol302691j

A new approach to the tetracycline core structure is presented. The pivotal intermediate is identified as macrocycle III. The two interior bonds (C4a-C12a and C5a-C11a) are to be constructed through sequential transannular Michael additions (III-II) and compression-promoted transannular isoxazole alkylations from intermediate II.

Full text of DOI:10.1021/ol302691j

ORGANIC
LETTERS
2012
Vol. 14, No. 23
5840–5843
A Macrocyclic Approach to Tetracycline
Natural Products. Investigation
of Transannular Alkylations and
Michael Additions
€
Joseph S. Wzorek, Thomas F. Knopfel, Ioannis Sapountzis, and David A. Evans*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
evans@chemistry.harvard.edu
Received September 28, 2012
ABSTRACT
A new approach to the tetracycline core structure is presented. The pivotal intermediate is identified as macrocycle III. The two interior bonds
(C4aÀC12a and C5aÀC11a) are to be constructed through sequential transannular Michael additions (IIIÀII) and compression-promoted
transannular isoxazole alkylations from intermediate II.
The tetracycline antibiotics, such as (À)-tetracycline
(1)1 and (À)-oxytetracycline (2),2 have been the subject
of sustained research since their discovery in 19483
(Figure 1). More recent isolates with intriguing anti-
cancer properties, SF2575 (3)4 and TAN-1518A/B (4, 5),5
have expanded both the structural complexity and known
biological activity of this natural product family.
Herein, we report a new approach to the construction
of the tetracycline nucleus involving advanced macro-
cyclic intermediate III (vide supra).6 From this intermediate,
(1) (a) Booth, J. H.; Morton, J., II; Petisi, J. P.; Wilkinson, R. G.;
Williams, J. H. J. Am. Chem. Soc. 1953, 75, 4621. (b) Conover, L. H.;
Moreland, W. T.; English, A. R.; Stephens, C. R.; Pilgrim, F. J. J. Am.
Chem. Soc. 1953, 75, 4622–4623.
(2) Finlay, A. C.; Hobby, G. L.; P’an, S. Y.; Regna, P. P.; Routien,
J. B.; Seeley, D. B.; Shull, G. M.; Sobin, B. A.; Solomons, I. A.; Vinson,
J. W.; Kane, J. H. Science 1950, 111, 85.
Figure 1. Representative tetracycline natural products.
(3) Duggar, B. M. Ann. N.Y. Acad. Sci. 1948, 51, 177–181.
(4) Hatsu, M.; Sasaki, T.; Watabe, H.; Miyadoh, S.; Nagasawa, M.;
Shomura, T.; Sezaki, M.; Inouye, S.; Kondo, S. J. Antibiot. 1992, 45,
320–324. (b) Hatsu, M.; Sasaki, T.; Gomi, S.; Kodama, Y.; Sezaki, M.;
Inouye, S.; Kondo, S. J. Antibiot. 1992, 45, 325–330.
a subsequent stereoselective transannular Michael addi-
tion (C4aÀC12a) followed by an internal alkylation
(C5aÀC11a) is planned for the formation of the two
internal CÀC bonds.7
(5) Horiguchi, T.; Hayashi, K.; Tsubotani, S.; Iineuma, S.; Harada,
S.; Tanida, S. J. Antibiot. 1994, 47, 545–556.
r
10.1021/ol302691j
Published on Web 11/12/2012
2012 American Chemical Society

It is anticipated that the transannular ring strain inherent
in intermediate II should enhance the facility of the alkyl-
ation step. This communication focuses on the stereo-
chemical outcome of this transannular Michael addition
(cf. IIIÀII) and provides some preliminary results on the
strain-enhanced transannular alkylation event.
This synthesis plan exploits the resident carbonyl group
polarities derived from the biosynthetic origin of the
tetracyclines while also incorporating flexibility depen-
dent upon the identities of the substituents at the C4-
and C6-positions. We have incorporated the popular
StorkÀHagedorn benzyloxyisoxazole synthon for the
vinylogous carbamic acid moiety.8 The 1,3-diketone
proximal to the D-ring is masked as a second isoxazole
synthon. This heterocycle maintains the CdO derived
functional group polarity while also enabling reagent-
selective activation of either the C11a or C12a position.
two C4a alcohol diastereomers did not efficiently dehy-
drate under the identical conditions. Conversion of 8
to oxime 9 via a three-step procedure was uneventful.
Macrocyclization was effected in good yield via the
implementation of dipolar cycloaddition conditions re-
ported by Mulzer,12 producing macrocycle 10 after selec-
tive dehydration13 and oxidation.
Scheme 2. Synthesis of the R-NHBoc Macrocycle 10
Scheme 1. Complementary Approaches to Macrocycle Synthesis
a Yield reported corresponds to the major aldol diastereomer.
Scheme 3. Synthesis of the β-OTBS Macrocycle 16
Macrocycle Synthesis. To maximize convergency, two
complementary disconnections for the deconstruction
of III have been explored: a nitrile-oxide cycloaddition
and a Reformatsky aldol addition (Scheme 1).9 Due to the
orthogonality of these two reactions, minor variations
in the coupling partners provide access to either option.
In practice, both assemblage variants have been utilized
to synthesize the macrocycles discussed herein.
NHBoc macrocycle 10 was constructed via an initial
Reformatsky aldol to couple fragments 6 and 7,10 afford-
ing 8 in reasonable yield after deprotection (Scheme 2).11
The two aldol diastereomers were separated at this point
and carried on individually to 10. It is noteworthy that the
The alternate macrocycle synthesis strategy was arbi-
trarily employed for the synthesis of C4-β-OTBS macro-
cycle 16 (Scheme 3). An initial nitrile-oxide cycloaddition
was performed to couple subunits 6 and 13, producing 14
after primary alcohol oxidation. A Reformatsky aldol
macrocyclization was then implemented to afford macro-
cycle 15 after dehydration. Two remaining functional
group manipulations were performed to convert the
TES-silyl ether to elaborated macrocycle 16. The C4-R-
OTBS macrocycle 17 was synthesized in direct analogy to
16 (cf. Scheme 4).
(6) For related strategies, see: (a) Evans, D. A.; Ripin, D. H. B.;
Halstead, D. P.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 6816–6826.
(b) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531–13540.
(c) Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans, D. A. J. Am.
Chem. Soc. 2007, 129, 8968–8969.
(7) The numbering of the tetracycline structure is maintained in the
illustrated macrocyclic intermediates.
(8) Stork, G.; Hagedorn, A. A., III. J. Am. Chem. Soc. 1978, 100,
3609–3611.
(9) Please see the Supporting Information for information regarding
fragment syntheses.
(10) Please see the Supporting Information for fragment syntheses.
(11) (a) Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128,
15106–15107. (b) Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org.
Lett. 2008, 10, 1291–1294.
(12) Enev, V. S.; Drescher, M.; Mulzer, J. Tetrahedron 2007, 63,
5930–5939.
(13) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003–
5010.
Org. Lett., Vol. 14, No. 23, 2012
5841

Scheme 4. Transannular C4aÀC12a Michael Bond Constructions
Scheme 5. Rationalization of Michael Selectivities for 17 and 10
Enolate conformational analysis provides a rationaliza-
tion for the observed stereochemical outcomes (Scheme 5).
Upon enolization, it is likely that macrocycles 10 and 17
proceed to two major enolate conformers 21 and 22.16
When the C4-substituent is an NHBoc group, chelation
between theboc group and theproximal isoxazolenitrogen
could reinforce conformer 21that proceeds tothe observed
product.17 However, experimental results suggest that the
C4-silyloxy systems are reacting through enolate confor-
mers 22.18 While ground state conformational preferences
undoubtedly affect transition state barrier heights, the
transition state stabilization imparted by the orientation
of the C4-OR substituent in the axial conformation was
unexpected. Studies on the effects of related intermolecular
cuprate additions have been reported;19 however, they are
not relevant to the present cases where conformational
rigidity is strongly reinforced. While the origin of this
substituent effect is currently not understood, it is possible
thattransitionstate dipoleminimizationbetween the resident
C4-OR substituent and the developing enolate might be a
significant factor within the conformational constraints of
this system.
Transannular Michael Additions. With reliable methods
for macrocycle construction in hand, attention was direc-
ted to the Michael addition study to form the A-ring and
to establish the C4a-stereocenter. Following optimiza-
tion, we were able to establish conditions to promote this
reaction employing Cu(OAc)2•H2O to mediate the trans-
formation (Scheme 4). We hypothesize that enolization
occurs through bidentate Cu(II) complexation, followed
by acetate-mediated deprotonation. Previously, we had
used ligandÀCu(OAc)2 complexes for a catalytic enantio-
selective Henry reaction.14
Each of the Michael additions depicted in Scheme 4 was
highly diastereoselective; only one isomer was observed in
each instance. These cases highlight the importance of the
C4-substituent and its influence on the stereochemical
outcome. For example, the Michael addition employing
macrocycle 16 afforded 18 (eq 1), containing the correct
C4a configuration when compared to the antibiotic
tetracyclines.15 Michael addition of the diastereomeric
macrocycle 17 produced the alternate C4a diastereomer
19 (eq 2). Since the relative orientation of oxygen sub-
stituents at the C4- and C6-positions is now inverted with
respect to 18, Michael adduct 19 is appropriately config-
ured for ent-anticancer tetracyclines. Lastly, the transan-
nular Michael addition employing the C4ÀNHBoc
substituent 10 afforded an appropriate C4ÀC4a product
diastereomer for the antibiotic tetracyclines (eq 3). The
diastereochemical outcome of the Michael additions
of the substrates 17 and 10 is surprising (eq 2 vs 3). This
result was unanticipated considering that both macro-
cycles 10 and 17 contain the same configuration at C4 and
both the NHBoc group and OTBS substituents are com-
parable in size.
Scheme 6. Synthesis Plan for Tetracycline Core
(16) Macrocycle 16 would proceed to analogous enantiomeric
enolates.
(17) At this point we have no definitive evidence that chelation is
involved in this transformation.
(18) (a) Seeman, J. I. Chem. Rev. 1983, 83, 83–134. (b) Seeman, J. I.
J. Chem. Educ. 1986, 1, 42–48.
(14) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–12693.
(15) Stereospecific displacement of a suitably functionalized C4-
substituent with a nucleophilic nitrogen (such as dimethylamine or
azide) would produce the correct C4/C4a stereoarray for the antibiotic
tetracyclines.
5842
Org. Lett., Vol. 14, No. 23, 2012

Scheme 7. Ce(III)- and Cu(II)/Ce(III)-Mediated Multistep Transformations
Preliminary Transannular Alkylations. With the suc-
cessful development of transannular Michael additions
appropriate for either the antibiotic or (ent)-anticancer
tetracyclines, we are now integrating these results into a
synthesis plan. Future work will entail the execution of
several transformations including the obligatory transan-
nular alkylation step (Scheme 6).
In accordance with the proposed endgame, we report
preliminary studies on the transannular isoxazole alkyla-
tion. We anticipated that a mild Lewis acid would facil-
itate coupling of the isoxazole and proximal ketone to
produce VII from VIII. In a subsequent transformation,
we would then tackle C12a-hydroxylation in the conver-
sion of VII to II.
macrocycle 16 with 5 mol % Cu(OAc)2 H2O and 4 equiv
of Ce(OAc)3 H2On under an atmosphere of molecular
oxygen yields 27 as a single diastereomer in 60% yield
(eq 6). Several features of this reaction deserve comment.
Due to the ability of Cu(II) to facilitate enolate chlorina-
tion in the presence of chloride ions, we found it necessary
3
3
to utilize Ce(OAc)3 H2On in the cascade rather than
CeCl3 7H2O. Additionally, since the Michael addition
3
3
requires methanol as solvent, we found that the inter-
mediate oxocarbenium ion produced following isoxazole
substitution was trapped by solvent to form methanol
adduct E. Lastly, under these conditions, there is no
longer a requirement for reduction of the intermediate
peroxide with dimethyl sulfide since this is now accom-
plished in situ.
In practice we have discovered that CeCl3 7H2O is
3
capable of facilitating both transformations in an atmo-
sphere of molecular oxygen (Scheme 7).20 Exposure of
either 19 or 20 to these conditions smoothly furnished
products 25 and 26, respectively, after peroxide reduction
with dimethyl sulfide. Both reactions are exceedingly
selective, producing a single detectable diastereomer.
Importantly, while Michael product 19 proceeds to 25,
which contains a cis C4a/C12a ring fusion (eq 4), Michael
product 20 proceeds to a trans ring fusion (eq 5). Con-
sidering that the cis C4a/C12a ring fusion is nearly
ubiquitous within the tetracycline family, these results
suggest that a viable total synthesis endeavor will employ
the C4-silyloxy macrocycle 16 rather than 10.
These preliminary transannular alkylation studies
coupled with our newfound understanding of the stereo-
chemical consequence of the C4-substitutent within the
Michael addition provide exciting new avenues of re-
search. Incorporation of the results from this work into
a larger synthesis effort will be reported in due course.
Acknowledgment. Financial support has been provided
by the National Institutes of Health (GM-33328-21 and
GM-081546-04). A postdoctoral fellowship from the Swiss
National Science Foundation and from the Novartis
Foundation for T.F.K. and a DAAD Fellowship for I.S.
are greatly appreciated.
Following further optimization, we have also discov-
ered that all three processes (Michael addition, transan-
nular alkylation, and C12a-oxidation) can be merged
into a single multistep transformation. Treatment of
Supporting Information Available. Complete experi-
mental details, proton and carbon NMR spectra for all
new compounds, and stereochemical determination. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H.
J. Am. Chem. Soc. 1992, 114, 7652–7660.
(20) Oxidation of 1,3-dicarbonyl compounds with Ce(III) is known;
please see: Christoffers, J.; Werner, T. Synlett. 2002, 1, 119–121.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
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