A diversity-oriented synthesis of bicyclic cis -dihydroarenediols, cis -4-hydroxyscytalones, and bicyclic conduritol analogues

Article abstract of DOI:10.1021/ol100557f

A common-intermediate-based enantioselective strategy has been developed aiming at bicyclic arene cis-dihydrodiols, cis-4-hydroxyscytalones, and bicyclic mimics of conduritol. Key features of this protocol include Barrett's asymmetric hydroxyallylation, ring-closing metathesis (RCM), and completely regioselective Wacker oxidation of internal cyclic olefins.

Full text of DOI:10.1021/ol100557f

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2472-2475
A Diversity-Oriented Synthesis of
Bicyclic cis-Dihydroarenediols,
cis-4-Hydroxyscytalones, and Bicyclic
Conduritol Analogues
Parag Mukherjee, Soumya J. Singha Roy, and Tarun K. Sarkar*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
tksr@chem.iitkgp.ernet.in
Received March 7, 2010
ABSTRACT
A common-intermediate-based enantioselective strategy has been developed aiming at bicyclic arene cis-dihydrodiols, cis-4-hydroxyscytalones,
and bicyclic mimics of conduritol. Key features of this protocol include Barrett’s asymmetric hydroxyallylation, ring-closing metathesis (RCM),
and completely regioselective Wacker oxidation of internal cyclic olefins.
The chemically sensitive cis-keto-diol 1 and corresponding
monomethyl ether 2 motifs are present in a host of natural
products, some of which show promising biological profiles
(Figure 1). Examples of such natural products include the
phytotoxic cis-6-deoxy-4-hydroxyscytalone (3a) and 4-hy-
droxyscytalone (3b),1 cladosporol (4),2 which shows hyper
parasitic activity, and the antiangiogenic chrysanthone A (5),3
to name a few. In view of the absence of any general
(1) (a) Krohn, K.; Biele, C.; Drogies, K.; Steingrover, K.; Aust, H.;
Figure 1. Some bioactive natural products containing cis-keto-diol
Draeger, S.; Schulz, B. Eur. J. Org. Chem. 2002, 2331, and references cited
therein. (b) Inacio, M. L.; Silva, G. H.; Teles, H. L.; Trevisan, H. C.;
Cavalheiro, A. J.; Bolzani, V. S.; Young, M. M.; Pfenning, L. H.; Araujo,
A. R. Biochem. Syst. Ecol. 2006, 34, 822. (c) Yamaguchi, Y.; Masuma, R.;
Kim, Y. P.; Uchida, R.; Tomodo, H.; Omura, S. Mycoscience 2004, 45, 9.
(d) Gremaud, G.; Tabacchi, R. Phytochemistry 1996, 42, 1547.
(2) Nasini, G.; Arnone, A.; Assante, G.; Bava, A.; Moricca, S.; Ragazzi,
A. Phytochemistry 2004, 65, 2107.
motifs.
methodology for the construction of the common motifs 1
and 2, it was deemed important to develop one. For this we
first targeted the scytalone derivative 3a,1 a widely reported
secondary metabolite in the literature, as a synthetic exercise
toward the array of natural products containing the keto-
(3) (a) Giannini, G.; Penco, S.; Pisano, C.; Riccioni, T.; Nasini, G.;
Candiani, G. Fitoterapia 2003, 74, 323, and references cited therein. (b)
Penco, S. WO 0168071, 2001.
10.1021/ol100557f  2010 American Chemical Society
Published on Web 05/05/2010

diol motif 1. In addition, the questionable absolute
stereochemistry4a and conflicting biological profile4b of 3a
provided additional impetus to target it in the first place.
Retrosynthetically, a late-stage metal-mediated oxidation
of cis-dihydroarenediols such as 7 could install the keto
functionality in 6 (Figure 2). However, there are only a
importance in medicinal chemistry. Apart from this and
Jerina’s early chemical synthesis of the racemic cis-dihy-
drodiol derivative of naphthalene12 and resolutions thereof,13
the armamentum of synthetic organic chemists lacks a
general and enantiocontrolled method for easy access to cis-
dihydroarenediols with varied substituents on the aryl ring.
In view of this, development of an alternative and flexible
route to cis-dihydroarenediols, such as 7, was desirable. To
accomplish this task, we envisaged that the systematic use
of Barrett’s asymmetric hydroxyallylation methodology14
9 f 8 followed by RCM 8 f 7 could lead to the desired
motifs rapidly. The Barrett methodology was attractive since
using either antipode of a chiral auxiliary, such as B-
methoxydiisopinocampheylborane (Ipc2BOMe), could give
access to different stereoisomers with complete control of
regio-, stereo-, and enantioselectivity.
To test this hypothesis, we first attempted the synthesis
of the simplest of the bicyclic cis-dihydroarenediols, e.g., 7.
Accordingly, the starting o-vinylbenzaldehyde 915 was
subjected to the aforementioned allylborane methodology.
Thus, metalation of allyl(diisopropylamino)dimethylsilane16
using n-butyllithium and TMEDA at 0 °C and sequential
reaction of the resultant E-lithio derivative with (-)-B-
methoxydiisopinocampheylborane and BF3-etherate gave the
E-reagent 12 (Scheme 1). Addition of o-vinylbenzaldehyde
9 at -78 °C gave an intermediate anti-ꢀ-hydroxysilane
Figure 2. Retrosynthetic analysis.
handful of methods known in the literature for the preparation
of bicyclic cis-dihydroarenediols, among which the method
of choice is undoubtedly the one via chemoenzymatic
oxidation pioneered by Gibson5 in the early 1970s and later
developed extensively by the research groups of Boyd,6
Hudlicky,7 and others.8 The applications of cis-dihydroare-
nediols obtained by the enzymatic methodology is prominent
in their use as chiral intermediates for natural product
synthesis,9 for designing chiral ligands,10 and as precursors
to conduritol analogues such as 10,11 which have some
Scheme 1. Synthesis of cis-1,2-Dihydro-1,2-naphthalenediol
(4) During the course of our work, the controversy regarding the absolute
stereochemistry of 3a was, however, settled by Hernandez-Galan et al.;
see: (a) Jimenej-Teja, D.; Daoubi, M.; Collado, I. G.; Hernandez-Galan, R.
Tetrahedron 2009, 65, 3392. (b) For the discussion of the conflicting
biological profile of 3a in a larger context of its racemic synthesis, see:
Couche, E.; Fkyerat, A.; Tabacchi, R. HelV. Chim. Acta 2009, 92, 903.
(5) Jerina, D. M.; Daly, J. W.; Jeffrey, A. M.; Gibson, D. T. Arch.
Biochem. Biophys. 1971, 142, 394.
(6) (a) Boyd, D. R.; Bugg, T. D. H. Org. Biomol. Chem. 2006, 4, 181.
(b) Kwit, M.; Gawronski, J.; Boyd, D. R.; Sharma, N. D.; Kaik, M.; More
O’Ferrall, R. A.; Kundavalli, J. S. Chem.sEur. J. 2008, 14, 11500. (c)
Boyd, D. R.; Sheldrake, G. N. Nat. Prod. Rep. 1998, 15, 309. (d) Boyd,
D. R.; Sharma, N. D.; Dorrity, M. R. J.; Hand, M. V.; MacMordie, R. A. S.;
Malone, J. F.; Porter, H. P.; Dalton, H.; Chima, J.; Sheldrake, G. N. J. Chem.
Soc., Perkin Trans. 1 1993, 1065. (e) Boyd, D. R.; Sharma, N. D.;
Modyanova, L. V.; Carroll, J. G.; Malone, J. F.; Allen, C. C. R.; Hamilton,
J. T. G.; Gibson, D. T.; Parales, R. E.; Dalton, H. Can. J. Chem. 2002, 80,
589.
(10) Boyd, D. R.; Sharma, N. D.; Sbircea, L.; Murphy, D.; Belhocine,
T.; Malone, J. F.; James, S. L.; Allen, C. C. R.; Hamilton, J. T. G. Chem.
Commun. 2008, 5535.
(7) (a) Hudlicky, T.; Reed, J. W. Chem. Soc. ReV. 2009, 38, 3117. (b)
Hudlicky, T.; Reed, J. W. Synlett 2009, 685. (c) Endoma, M. A.; Bui, V. P.;
Hansen, J.; Hudlicky, T. Org. Process Res. DeV. 2002, 6, 525. (d) Hudlicky,
T.; Gonzalez, D.; Gibson, D. T. Aldrichim. Acta 1999, 32, 35. (e) Hudlicky,
T.; Endoma, M. A. Tetrahedron: Asymmetry 1996, 7, 61. (f) Whited, G. M.;
Downie, J. C.; Hudlicky, T.; Fearnley, S. P.; Duddimg, T. C.; Olivo, H. F.;
Parker, D. Bioorg. Med. Chem. 1994, 2, 727.
(11) (a) Desjardins, M.; Lallemand, M. C.; Freeman, S.; Hudlicky, T.;
Abboud, K. A. J. Chem. Soc., Perkin Trans. 1 1999, 621. (b) Lallemand,
M. C.; Desjardins, M.; Freeman, S.; Hudlicky, T. Tetrahedron Lett. 1997,
38, 7693. (c) Orsini, F.; Sello, G.; Bernasconi, S.; Fallacara, G. Tetrahedron
Lett. 2004, 45, 9253. (d) Mehta, G.; Ramesh, S. S. Chem. Commun. 2000,
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(8) (a) Johnson, R. A. Org. React. 2004, 63, 117. (b) Bestetti, G.;
Bianchi, D.; Bosetti, A.; Leoni, B.; Pelizzoni, F.; Sello, G. Appl. Microbiol.
Biotechnol. 1995, 44, 306. (c) Carless, H. A. J. Tetrahedron: Asymmetry
1992, 3, 795. (d) Widdowson, D. A.; Ribbons, D. W.; Thomas, S. D. Janssen
Chim. Acta 1990, 8, 3. (e) Shindo, K.; Osawa, A.; Kasai, Y.; Iba, N.;
Saotome, A.; Misawa, N. J. Mol. Catal. B: Enzym. 2007, 48, 77. (f) Orsini,
F.; Sello, G.; Travaini, E.; Di Gennaro, P. Tetrahedron: Asymmetry 2002,
13, 253. (g) Feng, Y.; Ke, C.; Xue, G.; Que, L. Chem. Commun. 2009, 50.
(9) (a) Banwell, M. G.; Coster, M. J.; Karunaratne, O. P.; Smith, J. A.
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(13) Allen, C. C. R.; Boyd, D. R.; Dalton, H.; Sharma, N. D.; Brannigan,
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(16) Commercially available from Aldrich.
Org. Lett., Vol. 12, No. 11, 2010
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Scheme 2. Differently Substituted Bicyclic cis-Dihydroarenediols
boronate ester which, on oxidative workup with hydrogen
peroxide under basic conditions, afforded diol 8 in 52% yield
as a single diastereomer (ee ) 90%).17,18
appropriate o-vinyl benzaldehydes 14a,22 14b,23 and 14c25
in moderate to good overall yields (Scheme 2).
Application of this methodology to heterocyclic analogues
would help prove its generality at this stage.
Unfortunately, our initial attempts to carry out RCM on
the free diol 8 failed. This led us to use protecting groups
for the anti-diol which would be likely to liberate the free
diol under nonacidic conditions, which would be essential
to prevent possible aromatization. Heating the acetonide-
protected diol in benzene at reflux with Grubbs II catalyst
1319 gave us the protected cis-dihydroxytetrahydronaphtha-
lene 11.20 Expectedly, the deprotection step proved most
challenging. Attempts were initially made to transform to
the cis-1,2-dihydrodiol by exposure to Amberlyst 15 in
methanol. TLC analysis showed formation of the product
alongside naphthols. This failure to isolate the product
directed us toward the need for neutral deprotection con-
ditions. Thus, we used Lipshutz’s methodology with
PdCl2(MeCN)2 as a catalyst,21 which ultimately gave our
desired product 75 in good yield.
With this end in view, we attempted to prepare cis-5,6-
dihydroisoquinoline-5,6-diol. However, as the pyridine ni-
trogen was likely to deactivate the catalyst during RCM,26
it was both sterically and electronically shielded by putting
chlorine atoms27 adjacent to it. As shown in Scheme 3, this
modification allowed successful synthesis of the cis-dihy-
droarenediol 22 in good overall yield from 19.28
After developing a successful new methodology for
preparing cis-dihydroarenediols, our remaining important
goal was to convert them to the corresponding keto-diols.
To this end, Wacker oxidation appeared to be a judicious
choice. Previous reports31 suggested that, for cyclic and
(22) Prepared from commercially available 2-bromo-5-fluorobenzalde-
hyde by Stille reaction using tributylvinyltin reagent in 94% yield.
(23) Prepared from the corresponding alcohol24 by oxidation with Collins
reagent.
To evaluate the generality of our strategy, we next
attempted to access cis-dihydroarenediol derivatives that are
available in poor yield via the bioconversion pathway. In
this regard, we have prepared fluoro-substituted cis-dihy-
droarenediol 17a6b and methoxy-substituted cis-dihydroare-
nediols 17b8a,b,e and 17c8a,b,e along the same route from
(24) Kumar, V.; Shaw, A. K. J. Org. Chem. 2008, 73, 7526.
(25) Nemoto, H.; Miyata, J.; Joshida, M.; Raku, N.; Fukumoto, K. J.
Org. Chem. 1997, 62, 7850.
(26) Felpin, F. X.; Girard, S.; Thanh, G. V.; Robins, R. J.; Villieras, J.;
Lebreton, J. J. Org. Chem. 2001, 66, 6305, and references therein.
(27) van den Hoogenband, A.; den Hartog, J. A. J.; Faber-Hilhorst, N.;
Lange, J. H. M.; Terpstra, J. W. Tetrahedron Lett. 2009, 50, 5040.
(28) Compound 19 was prepared from the reported lactone 1829 in three
steps as follows:
(17) Enantiomeric excess (ee) was determined by Mosher ester analysis;
see: Davisson, V. J.; Poulter, C. D. J. Am. Chem. Soc. 1993, 115, 1245
.
(18) The relative and absolute configuration of this product is based on
Barrett’s work14 and further confirmed by comparison of the sign of optical
rotation of its derived cis-dihydroarenediol with those in the literature (see
the Supporting Information).
(19) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(20) Orsini, F.; Pelizzoni, F. Tetrahedron: Asymmetry 1996, 7, 1033.
(21) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron
Lett. 1985, 26, 705.
(29) Panda, B.; Basak, S.; Hazra, A.; Sarkar, T. K. J. Chem. Res. 2010,
2010, 109.
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Org. Lett., Vol. 12, No. 11, 2010

antipodal Ipc2BOMe and replacing the OMe group in 14c
by a suitable silyloxy group coupled with its fluoride-
induced cleavage at a later stage could provide the
naturally occurring 3a.
Scheme 3. Heterobicyclic cis-Dihydroarenediol
We next examined the preparation of conduritol analogues,
and we report here the first chemical synthesis of a
heterobicyclic conduritol 27 following the route described
in Scheme 5. Thus, Sharpless asymmetric dihydroxylation
Scheme 5. Synthesis of a Heterobicyclic Conduritol Analogue
acyclic systems, chelation controls the regioselectivity of
Markovnikov-type hydroxypalladation. However, for sub-
stituted styrenes anti-Markovnikov addition is also reported32
due to participation of allylic hydrogens. When 11 was
exposed to the regular Wacker conditions at 50 °C only 23
was formed, unaccompanied by even traces (TLC) of the
other regioisomer (Scheme 4).
of 21 followed by deprotection of 26 gave 27 in good overall
yield. We expect that this protocol will prove useful for
generating libraries of heterobicyclic conduritols for lead
discovery in the realm of chemical biology.
In conclusion, we have reported an enantioselective
approach for obtaining bicyclic arene cis-dihydrodiols, one
of which led to the first chemical synthesis of the phenolic
methyl ether of ent-3a. Furthermore, we have shown that
this methodology is also applicable to the synthesis of
bicyclic conduritol analogues. The generality of this approach
serves as a foundation for further efforts toward other keto-
diol-containing natural products. Work directed toward this
and all other stereoisomers of bicyclic and heterobicyclic
conduritols and conduramines is in progress.
Scheme 4
.
Regioselective Wacker Oxidation of Internal Cyclic
Olefin
Acknowledgment. This work was supported by DST &
CSIR, Government of India. P.M. is grateful to CSIR,
Government of India, for a Senior Research Fellowship. We
are thankful to the reviewers for helpful suggestions. We
are also thankful to Prof. R. V. Venkateswaran, Prof. S.
Ghosh, and Mr. S. Mondal (IACS, Kolkata) for continued
help and support.
A similar reaction was next performed with 16c. Gratify-
ingly, only one product 24 was obtained having a keto group
at the benzylic position. Removal of the acetonide under the
previously mentioned conditions21 then afforded 25, which
is the phenolic methyl ether of ent-3a. Clearly, using the
(30) The relative and absolute configuration of this diol is based on
Barrett’s work.14
(31) (a) Kang, S. K.; Jung, K. Y.; Chung, J. U.; Namkoong, E. Y.; Kim,
T. H. J. Org. Chem. 1995, 60, 4678. (b) Skaanderup, P. R.; Madsen, R. J.
Org. Chem. 2003, 68, 2115.
(32) Gaunt, M. J.; Yu, J.; Spencer, J. B. Chem. Commun. 2001, 1844.
Supporting Information Available: Experimental details
and full spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL100557F
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