An efficient total synthesis and absolute configuration determination of varitriol

Article abstract of DOI:10.1039/b603931f

The first total synthesis and the absolute configuration determination of varitriol are described. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b603931f

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An efficient total synthesis and absolute configuration determination of
varitriol{{
Ryan T. Clemens and Michael P. Jennings*
Received (in Bloomington, IN, USA) 17th March 2006, Accepted 9th May 2006
First published as an Advance Article on the web 25th May 2006
DOI: 10.1039/b603931f
nitrile functional group. Selective manipulation of either moiety
residentin6shouldallowforthe synthesisofbothenantiomersof 4.
Thus, the b-C-furanoside subunit 4 could readily be derived
from the aminal 5, which in turn would originate from the
‘‘pseudo’’ C2 symmetric compound 6. We envisaged the final key
convergence of the top styrene derivative 2 with the substituted
furan 4 via an olefin cross-metathesis reaction.3
The first total synthesis and the absolute configuration
determination of varitriol are described.
First isolated from the marine-derived strain of the fungus
Emericella variecolor and disclosed in 2002 by Barrero and co-
workers, varitriol (1) represented a novel, low-molecular weight,
natural product that exhibited significant activity against a variety
of tumor cell lines.1 In particular, 1 showed a more than 100-fold
increased potency over the mean toxicity toward the RXF 393,
T-47D, and SNB-75 cell lines with GI50 values ranging from 1.63
to 2.44 6 1027 M. In spite of the impressive levels of biological
activity, the mechanism of action has not yet been established.2 To
date no synthetic approaches to 1 have been reported. Due to the
relatively simple structure and coupled with its high level of
cytotoxicity, we were interested in pursuing the total synthesis and
determining the absolute configuration of 1.
The completion of 1 commenced with the synthesis of the
substituted styrene 2 as highlighted in Scheme 2. Hence, Suzuki–
Miyaura4 coupling of the previously reported aryl triflate 35 with
potassium vinyl trifluoroborate, utilizing Molander’s procedure,
readily provided substituted styrene 7 in 93% yield.6 Subsequent
manipulation of the 2,2-dimethyl-1,3-benzodioxan-4-one func-
tional group to the methoxy benzyl ester 8 was accomplished by
the treatment of 7 with the sodium anion of benzyl alcohol
followed by an ensuing etherification of the free phenol with MeI
and K2CO3 with a combined yield of 85% over two steps from 7.
Final reduction of the ester moiety resident in 8 with DIBAL-H
and protection of the corresponding benzylic alcohol as a TBS
ether provided the substituted styrene 2 in 82% yield over two
steps.
The retrosynthetic analysis of 1 is delineated in Scheme 1. We
initially surmised that the natural antipode might be derived from
D-ribose due to the similarities between the bottom portion of 1and
the natural carbohydrate. Given thatcompound 1was tested by the
National Cancer Institute (NCI) against the 60-cell line in vitro
panel, we were interested in synthesizing both the natural and
unnatural product for further physiological and biological testing.
Consequently, our synthetic blueprint required swift access to
either enantiomer of 4, based on the limited availability of L-ribose.
Furanoside 6 serves this purpose quite well with two orthogonal
aldehyde surrogates present as a protected primary alcohol and a
With the completion of 2, our attention was then focused on the
synthesis of the b-C-furanoside subunit 4 as shown in Scheme 3.
Following the general procedure of Utimoto, we utilized an
Scheme 2 Synthesis of intermediate 2. Reagents and conditions: (a)
potassium vinyl trifluoroborate (1.1 equiv.), Et3N (1.3 equiv.), Pd(dppf)Cl2
(5 mol%), 80 uC, 4.5 h, 93%; (b) benzyl alcohol (10 equiv.), NaH
(2.1 equiv.), DMF, 0 uC to rt, 30 min, then 7, 3 h, rt, 97%; (c) K2CO3
(2.5 equiv.) MeI (1.2 equiv.), THF, 0 uC to rt, 2 h, 88%; (d) DIBAL-H
(2.5 equiv.), toluene, 278 uC to rt, 2 h, 85%; (e) TBSCl (1.2 equiv.),
imidazole (3 equiv.), DMF, rt, 4 h, 97%. dppf = bis(diphenylpho-
sphino)ferrocene; Bn = benzyl; DIBAL = diisobutylaluminum hydride;
TBSCl = tert-butyldimethylsilyl chloride; imid = imidazole.
Scheme 1 Retrosynthetic analysis of 1.
Department of Chemistry, The University of Alabama, Tuscaloosa, AL,
USA. E-mail: jenningm@bama.ua.edu; Fax: +1 (205) 348-9104;
Tel: +1 (205) 348-0351
{ Electronic supplementary information (ESI) available: Full data for
compounds 1, 2, 4, 8, and 12. See DOI: 10.1039/b603931f
{ We thank the University of Alabama for support.
2720 | Chem. Commun., 2006, 2720–2721
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Scheme 4 Synthesis of (2)-varitriol 1. Reagents and conditions: (a) 14
(5 mol%), CH2Cl2, reflux, 18 h, 59%; (b) 1 M HCl, THF, rt, 2 h, 72%.
resultant leaving group with LiAlH4 provided the protected aminal
12 in an 87% yield over two steps. Removal of the aminal in 12 by
means of PTSA furnished 13 and resulting olefination of the
aldehyde moiety via the methylene Wittig reagent allowed for the
formation of the desired b-C-furanoside 4 with a collective modest
yield of 27% from aminal 12.
Scheme 3 Synthesis of intermediate 4. Reagents and conditions: (a)
TMSCN (4.5 equiv.), BF3?OEt2 (1.1 equiv.), CH2Cl2, rt, 2 h, 85%; (b)
NH3, MeOH, 0 uC, 4.5 h, 82%; (c) DMP (2.5 equiv.), HClO4 (0.5 equiv.),
acetone, rt, 2 h, 95%; (d) Raney nickel (20 equiv.), sodium hypophosphite
(5.5 equiv.), N,N9-diphenylethylenediamine (1.4 equiv.), HOAc–pyridine–
H2O (1:2:1), rt, 1 h, 82%; (e) LiAlH4 (3 equiv.), THF, 278 uC, 3 h, 92%; (f)
TsCl (2.1 equiv.), pyridine, 0 uC to rt, 24 h, 95%; (g) LiAlH4 (3 equiv.),
THF, 278 uC, 3 h, 92%; (h) PTSA (2.5 equiv.), acetone, CH2Cl2, 5 min at
0 uC then rt, 1 h, 48%; (i) tBuOK (2.1 equiv.), methyltriphenylpho-
sphonium bromide (2 equiv.), ether, 12 h, 56%. TMSCN = trimethylsilyl
With the two key intermediates in hand, the stage was set for
final convergence of 2 and 4 and ultimate completion of the target,
product 1 (Scheme 4). Thus, treatment of 2 and 4 with Grubbs’
second-generation carbene catalyst readily promoted the envi-
sioned cross-metathesis to provide the protected natural product
15 in 59% yield.9 Final global deprotection of 15 with aqueous
HCl in THF furnished varitriol (1) in 72% yield. The spectral data
(1H NMR, 500 MHz;13C NMR, 125 MHz) and HRMS data of
synthetic varitriol were in agreement with the natural sample.1
However, the optical rotation ([a]rDt 218.2u, c = 0.0033 g ml21
MeOH) confirmed that 1 is the enantiomer of the natural product.
In conclusion, we have completed a highly convergent total
synthesis of (2)-varitriol. The late stage convergence allows for the
synthesis of a variety of analogues to examine the bioactivity of
structurally diverse ‘‘varitriol-like’’ compounds against a collection
of tumor cell lines.
cyanide; DMP
= 2,2-dimethoxypropane; TsCl = p-toluenesulfonyl
chloride; PTSA = p-toluenesulfonic acid.
anchimeric assisted nucleophilic addition of a cyanide anion via
TMSCN to the in situ generated oxocarbenium cation derived
from 9.7 This procedure readily allowed for the stereoselective
synthesis of the ‘‘pseudo’’ C2 symmetric intermediate 6 in an
isolated 85% yield which can serve as a divergent point toward
both enantiomers of 4. With 6 in hand, all of the required
stereochemistry was in place for the completion of 4. Selective
removal of the secondary benzoate esters by means of
dissolved NH3 in MeOH at 0 uC provided the syn diol 10 in
82% yield.8 Reprotection of the free hydroxyl groups as the
acetonide was then readily accomplished upon the treatment of
10 with 2,2-dimethoxypropane and HClO4 to afford the
b-C-furanoside 11.
Notes and references
1 J. Malmstrøm, C. Christophersen, A. F. Barrero, J. E. Oltra, J. Justicia
and A. Rosales, J. Nat. Prod., 2002, 65, 364.
2 A. M. S. Mayer and K. R. Gustafson, Eur. J. Cancer, 2004, 40, 2676.
3 M. Lera and C. J. Hays, Org. Lett., 2001, 3, 2765.
Ensuing reduction of the nitrile functional group present in 11
with Raney nickel coupled with N,N9-diphenylethylenediamine
furnished the corresponding aminal.8 This was followed by
removal of the benzoate ester via LiAlH4 to afford intermediate
5 in a combined yield of 75% from 11. Subsequent tosylation of
the free primary hydroxyl moiety resident in 5 and reduction of the
4 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
5 A. Furstner, O. R. Thiel and G. Blanda, Org. Lett., 2000, 2, 3731.
6 G. A. Molander and M. R. Rivero, Org. Lett., 2002, 4, 107.
7 K. Utimoto and T. Moriie, Tetrahedron Lett., 1982, 23, 237.
8 H. P. Albrecht, D. B. Repke and J. G. Moffatt, J. Org. Chem., 1973, 38,
1836.
9 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1, 953.
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