Synthesis of the spiroketal core of integramycin

Article abstract of DOI:10.3762/bjoc.9.282

A concise synthetic strategy towards the spiroketal core of the HIV-integrase inhibitor integramycin (1) was developed. The required ketone precursor was efficiently constructed from two simple and easily accessible subunits by means of a hydrozirconation/copper catalyzed acylation reaction. The effects of different protecting groups on the spiroketalization step were also investigated.

Full text of DOI:10.3762/bjoc.9.282

Synthesis of the spiroketal core of integramycin
Evgeny. V. Prusov
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2446–2450.
Department of Medicinal Chemistry, Helmholtz Centre for Infection
Research, Inhoffenstr. 7, 38124 Braunschweig, Germany
doi:10.3762/bjoc.9.282
Received: 14 August 2013
Accepted: 23 October 2013
Published: 12 November 2013
Email:
Evgeny. V. Prusov - evgeny.prusov@helmholtz-hzi.de
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
Keywords:
anti-infectives; hydrozirconation; natural products; spiroketals; total
synthesis
Guest Editor: J. S. Dickschat
© 2013 Prusov; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A concise synthetic strategy towards the spiroketal core of the HIV-integrase inhibitor integramycin (1) was developed. The
required ketone precursor was efficiently constructed from two simple and easily accessible subunits by means of a hydrozircona-
tion/copper catalyzed acylation reaction. The effects of different protecting groups on the spiroketalization step were also investi-
gated.
Findings
Integramycin is a polyketide natural product isolated from concise and modular approach towards integramycin and
Actinoplanes sp. by the Singh group at Merck [1] (Figure 1). related natural products.
The compound was found to inhibit HIV-1 integrase coupled
strand transfer reactions with IC50 values of 3 and 4 μM, res- According to the retrosynthetic analysis, which is outlined in
pectively. Structurally, the molecule architecture of inte- Figure 2, the target molecule may be assembled from an appro-
gramycin features four distinct elements: a 3,5-dihydroxy- priate spiroketal advanced intermediate 4. This spiroketal com-
substituted aromatic ring, a spiroketal core, a highly functional- pound is logically traced back to ketone 5, which can be further
ized octalin moiety and a 5-hydroxylated 3-acyltetramic acid. divided in the vicinity of the C22 carbonyl group into two
Studies on the syntheses of the spiroketal core [2,3] and the readily accessible building blocks 6 and 7. For the construction
octalin fragment [4] of integramycin were recently reported by of the octalin fragment we planned to use two sequential olefi-
Roush and Floreancig, however, a total synthesis of this rather nation reactions followed by an intramolecular Diels–Alder
complex natural product has yet to be accomplished. Intrigued cycloaddition. The installation of the tetramic acid moiety
by its biological properties and capitalizing on our previous would proceed via Lassey–Dickmann condensation with subse-
experience [5] in the total synthesis of natural products with quent introduction of the 5-hydroxy group by oxidation of the
tetramic acid fragments we embarked on the development of a corresponding vinylogous enolate. Herein a straightforward
2446

Beilstein J. Org. Chem. 2013, 9, 2446–2450.
Figure 1: Structure of integramycin (1) and its producing organism, Actinoplanes sp. (Photo: J. Wink, HZI, Microbial drugs).
Figure 2: Retrosynthetic analysis of integramycin.
synthesis of the C16–C35 spiroketal core of integramycin based tion with (R)-α-methoxyphenylacetic acid with subsequent
on a hydrozirconation/acylation reaction sequence is reported.
NMR analysis and found to be close to 90%. The resulting
alcohol was protected as TBS and TES ethers to investigate the
The synthesis of the aryl-substituted part of the spiroketal frag- cleavage regime of different protecting groups during the acid
ment was started from 3,5-dihydroxybenzoate 8 which was catalyzed ketalization step.
converted into aldehyde 9 via protection and partial reduction
[6] (Scheme 1). Subsequent Leighton crotylation [7] using The second part of the spiroketal core was constructed from the
commercially available (R,R)-E-Crotyl-Mix was employed to PMB-protected 3-hydroxypropanal via Horner–Wadsworth-
introduce the two stereocenters at C25/C26 with anti-relation- Emmons olefination, reduction to the allylic alcohol and
ship in excellent yield and enatioselectivity. The enantiomeric Sharples epoxidation [8] (Scheme 2). Subsequent Cu-catalyzed
excess of the crotylation product was estimated by esterifica- epoxide-opening using methylmagnesium bromide [9] produced
2447

Beilstein J. Org. Chem. 2013, 9, 2446–2450.
Scheme 1: Synthesis of the aromatic subunit.
Scheme 2: Sharpless epoxidation/Myers alkylation approach to the C16–C22 carboxylic acid fragment.
an inseparable mixture of 1,2- and 1,3-diol products, which Finally, several conditions were studied for the spiroacetaliza-
upon treatment with sodium periodate furnished pure 13. The tion step. Exposure of the all-TBS protected ketone 17 to
primary hydroxy group was selectively converted to alkyl moderately strong acids, e.g. the HF–pyridine complex in THF
iodide by using Ph3P/I2/imidazole conditions [10]. Then the or CSA in THF/H2O mixture, resulted in the predominant
protected iodide 14 was subjected to Myers alkylation [11] cleavage of the TBS group at C18, whereas the benzylic TBS
reaction with an excess of enolate to install the last required ether remained mostly untouched. Application of more acidic
stereocenter. Hydrolytic cleavage of the pseudoephedrine auxil- conditions (3 N HCl in THF) led to a messy reaction. However,
iary by prolonged exposure to sodium hydroxide at elevated treatment of the same ketone with an excess of TBAF buffered
temperature afforded the carboxylic acid 16.
with acetic acid caused removal of all protecting groups with
concomitant spiroketalization and upon reinstallation of the
With both fragments in hand, the key coupling was attempted. phenolic protecting groups the desired compound 4 was
Initially, the conditions recently reported by Vasse [12] were obtained in 35% yield. The stereochemistry of the spiroketal
investigated (Scheme 3). In the event, treatment of the was confirmed by observation of the strong NOE-correlation for
carboxylic acid 16 with Ghosez reagent [13] provided the H-18 and H-22 protons in the NOESY spectrum of 4 (see
corresponding acid chloride 7, which was allowed to react with Supporting Information File 2). In the case of the ketone with
the hydrozirconation products of alkenes 6 and 10 in the TES-protected benzylic alcohol, exposure to 2 N HCl in
dichloromethane in the presence of a stoichiometric amount of THF resulted in formation of numerous products, including the
CuBr·Me2S. The reaction was rather capricious and produced spiroketal 4, thus demanding further optimization of this reac-
only modest amounts of the target compound. However, appli- tion.
cation of the original Wipf protocol [14] resulted in a much
more favourable outcome and, upon some further optimization In summary, an efficient route to the C16–C35 spiroketal frag-
of the catalyst load, provided the desired ketone in 65% yield ment of integramycin was developed. The key step of the syn-
for the TBS protected alkene. The yield for the TES-protected thesis is a Cu-catalysed coupling of an acid chloride with an
alkene was somewhat lower, probably due to a partial cleavage alkyl zirconium species. The stereocenters were introduced
of the protecting group during the acylation or hydrozircona- using Leighton crotylation, Sharpless epoxidation and Myers
tion step.
alkylation. Although the presented route achieves approxi-
2448

Beilstein J. Org. Chem. 2013, 9, 2446–2450.
Scheme 3: Coupling of the fragments and spiroketalization.
5. Höfle, G.; Gerth, K.; Reichenbach, H.; Kunze, B.; Sasse, F.; Forche, E.;
Prusov, E. V. Chem.–Eur. J. 2012, 18, 11362–11370.
doi:10.1002/chem.201201879
mately the same overall yield of target compound as that of
Floreancig [2] (11.2 vs 11.5%, respectively), it features utiliza-
tion of easily scalable transformation and upon further optimiz-
ation of the spiroketalization step would be advantageous for
the preparation of intermediate 4. Efforts towards the comple-
tion of the total synthesis of integramycin are currently
underway in our laboratory and will be reported in due course.
6. Abe, T.; Haga, T.; Negi, S.; Morita, Y.; Takayanagi, K.; Hamamura, K.
Tetrahedron 2001, 57, 2701–2710.
doi:10.1016/S0040-4020(01)00143-0
7. Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133,
6517–6520. doi:10.1021/ja200712f
8. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974–5976. doi:10.1021/ja00538a077
9. Hodgson, D. M.; Arif, T. Org. Lett. 2010, 12, 4204–4207.
doi:10.1021/ol101843q
Supporting Information
10.Paterson, I.; Britton, R.; Delgado, O.; Gardner, N. M.; Meyer, A.;
Naylor, G. J.; Poullennec, K. G. Tetrahedron 2010, 66, 6534–6545.
doi:10.1016/j.tet.2010.01.083
Supporting Information File 1
Experimental procedures.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-282-S1.pdf]
11.Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
doi:10.1021/ja970402f
Supporting Information File 2
Copies of NMR spectra.
12.Coia, N.; Mokhtari, N.; Vasse, J.-L.; Szymoniak, J. Org. Lett. 2011, 13,
6292–6295. doi:10.1021/ol202796w
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-282-S2.pdf]
13.Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez, L.
J. Chem. Soc., Chem. Commun. 1979, 1180–1181.
doi:10.1039/C39790001180
14.Wipf, P.; Xu, W. Synlett 1992, 718–720. doi:10.1055/s-1992-21466
References
1. Singh, S. B.; Zink, D. L.; Heimbach, B.; Genilloud, O.; Teran, A.;
Silverman, K. C.; Lingham, R. B.; Felock, P.; Hazuda, D. J. Org. Lett.
2002, 4, 1123–1126. doi:10.1021/ol025539b
2. Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6, 569–572.
doi:10.1021/ol036339i
3. Sun, H.; Abbott, J. R.; Roush, W. R. Org. Lett. 2011, 13, 2734–2737.
doi:10.1021/ol200834p
4. Dineen, T. A.; Roush, W. R. Org. Lett. 2005, 7, 1355–1358.
doi:10.1021/ol050191g
2449

Beilstein J. Org. Chem. 2013, 9, 2446–2450.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.9.282
2450