Total synthesis of virgatolide B

Article abstract of DOI:10.1021/ol402191t

The first total synthesis of the benzannulated spiroketal virgatolide A is presented. Key features include sp³-sp² Suzuki coupling of an enantiomerically enriched β-trifluoroboratoamide and an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction followed by global deprotection/cyclization with regioselectivity governed by internal hydrogen bonding.

Full text of DOI:10.1021/ol402191t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Total Synthesis of Virgatolide B
Paul A. Hume, Daniel P. Furkert, and Margaret A. Brimble*
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland,
New Zealand
m.brimble@auckland.ac.nz
Received August 1, 2013
ABSTRACT
The first total synthesis of the benzannulated spiroketal virgatolide A is presented. Key features include sp3ꢀsp2 Suzuki coupling of an
enantiomerically enriched β-trifluoroboratoamide and an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective
Mukaiyama aldol reaction followed by global deprotection/cyclization with regioselectivity governed by internal hydrogen bonding.
In 2011, Che et al. reported the isolation and character-
ization of three novel structurally related spiroketals1 from
the endophytic fungus Pestalotiopsis virgatula (L147).
Virgatolides AꢀC (1ꢀ3) (Figure 1) contain a common
tetracyclic core and differ only in their stereochemistry and
substitution at C-4 and C-13. The absolute stereochemical
configurations of these natural products were inferred by
comparison of their CD spectra tothose of pestaphthalides
A and B.2 Preliminary biological data revealed that the
compounds exhibit moderate cytotoxicity against HeLa
(cervical epithelium) cells with IC50 values of 19.0, 22.5,
and 20.6 μM, respectively.1 To date, no total synthesis of the
virgatolide family has been reported. Herein, we present the
first enantioselective total synthesis of virgatolide B (2).
Disconnection of the spiroketal moiety in 2 affords the
Figure 1. Virgatolides AꢀC, 1ꢀ3.
corresponding dihydroxyketone 4 (Scheme 1). In order to
avoid acid-catalyzed elimination of the sensitive β-hydroxy
moiety of 4,3 a synthetic route was developed that facilitated
global deprotection/cyclization under mild conditions.
We hypothesized that intramolecular hydrogen bonding
between the phthalide carbonyl and the neighboring phe-
nol would allow differentiation of the two possible spir-
oketal regiosiomers, facilitating selective formation of 2. In
turn, ketone 4 would be accessed by a 1,3-anti-selective
Mukaiyama aldol reaction4 between methyl ketone 6 and
(1) Li, J.; Li, L.; Si, Y.; Jiang, X.; Guo, L.; Che, Y. Org. Lett. 2011, 13,
2670.
(2) Ding, G.; Liu, S.; Guo, L.; Zhou, Y.; Che, Y. J. Nat. Prod. 2008,
71, 615.
(3) (a) Yuen, T.-Y.; Yang, S.-H.; Brimble, M. A. Angew. Chem., Int.
Ed. 2011, 50, 8350. (b) Initial studies toward 2 used ethoxymethyl (EOM)
instead of benzyloxymethyl (BOM) as a protecting group for the
phenolic OH groups. It was found that acid-catalyzed removal of the
EOM groups caused degradation of the starting material.
(4) (a) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett. 1984,
25, 729. (b) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett.
1994, 35, 8537. (c) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.
J. Am. Chem. Soc. 1996, 118, 4322.
r
10.1021/ol402191t
XXXX American Chemical Society

PMB protected (S)-3-hydroxybutanal 5. The phthalide
subunit present in 6 was to be constructed from iodide 7
by intramolecular carboalkoxylation.5 Iodide 7 would be
assembled via Sharpless asymmetric dihydroxylation6 of
alkene 8 followed by iodination.
accessed by benzylation of enolates,8 conjugate addition of
aryl organometallics,9 Negishi cross-coupling,10 or catalytic
asymmetric hydrogenation of R,β-unsaturated carbonyls.11
Each of these methods suffers from various drawbacks.7 Our
synthetic strategy sought to utilize methodology recently
developed by Molander et al. for the Suzuki cross-coupling
of enantiomerically enriched potassium β-trifluoroboratoa-
mide 97 with aryl bromide 10.
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of Bromide 10
Construction of aryl bromide 10 began from commer-
cially available 3,5-dihydroxybenzoic acid 11 (Scheme 2).
Bromination,12 BOM protection, and adjustment of the
oxidation state gave aldehyde 12 in 61% yield over four
steps. Wittig reaction of 12 with ethyltriphenylphospho-
nium iodide afforded 10 in 85% yield as an inseparable
mixture of E/Z isomers. Isomerization of E/Z-10 using
catalytic Ru(CO)ClH(PPh3)3 in refluxing toluene13 pro-
vided isomerically pure 10 in 96% yield.
Trifluoroboratoamide 9 has been preparedby Molander
et al. by alkylation of amide 16 with iodide 15 and conversion
of the pinacol boronate species 17 to the trifluoroborate salt
9.7 Preparation of iodide 15 by alkylation of isopropyl-
pinacolboronate14 proved inefficient and required two dis-
tillations. We were pleased to find that the use of Brown’s
method15 provided 15 in sufficient purity simply by treatment
of boronate 14 with pinacol, washing the organic layer with
water, and subsequent concentration in vacuo (Scheme 3).
Alkylation of amide 1616 with 15 followed by conversion to
the trifluoroborate with KHF2 according to Molander’s
procedure afforded 9 in high yield and excellent diaster-
eoselectivity.7 The diastereoselectivity was >95:5 by 1H
NMR analysis of 17, and the values of the spectroscopic
data and optical rotation value for 9 compared well to the
literature values.7
Alkene 8 contains a synthetically challenging R-chiral
β-arylated ketone. There is a scarcity of direct methods for
the construction of such motifs,7 which are most commonly
(5) (a) Stille, J. K.; Wong, P. K. J. Org. Chem. 1975, 40, 532. (b)
Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193. (c) Izumi, T.;
Itou, O.; Kodera, K. J. Chem. Technol. Biotechnol. 1996, 67, 89. (d)
Dang, Q.; Brown, B. S.; van Poelje, P. D.; Colby, T. J.; Erion, M. D.
Biorg. Med. Chem. Lett. 1999, 9, 1505. (e) Lindsell, W. E.; Palmer, D. D.;
Preston, P. N.; Rosair, G. M. Organometallics 2005, 24, 1119. (f) Hu, Y.;
€
Liu, J.; Lu, Z.; Luo, X.; Zhang, H.; Lan, Y.; Lei, A. J. Am. Chem. Soc.
2010, 132, 3153.
(6) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968.
ꢀ
(7) (a) Molander, G. A.; Shin, I.; Jean-Gerard, L. Org. Lett. 2010, 12,
4384. (b) Hung Lee, J. C.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3,
894. (c) Smith, S. M.; Hoang, G. L.; Pal, R.; Bani Khaled, M. O.; Pelter,
L. S. W.; Cheng Zeng, X.; Takacs, J. M. Chem. Commun. 2012, 48, 12180.
(8) (a) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1994; Vol. 3, pp 1ꢀ100. (b) Lutomski, K. A.;
Meyers, A. I. In Asymmetric Synthesis, Morrison, J. D., Ed.; Academic
Press: New York, 1994; Vol. 3, pp 213ꢀ274.
(12) Durola, F.; Hanss, D.; Roesel, P.; Sauvage, J.-P.; Wenger, O. S.
Eur. J. Org. Chem. 2007, 125.
ꢀ
ꢀ
ꢀ
(13) Fustero, S.; Sanchez-Rosello, M.; Jimenez, D.; Sans-Cervera,
J. F.; Del-Pozo, C.; Acena, J. L. J. Org. Chem. 2006, 71, 2706.
(14) (a) Molander, G. A.; Febo-Ayala, W.; Ortega-Guerra, M. Org.
Lett. 2008, 73, 6000. (b) Smoum, R.; Rubinstein, A.; Srebnik, M. Bioorg.
Chem. 2003, 31, 464.
(9) Posner, G. H. In Organic Reactions; Wiley: New York, 1972; Vol.
19, pp 1ꢀ113.
(10) (a) Rilatt, I.; Caggiano, L.; Jackson, R. F. W. Synlett 2005, 2701.
(b) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am.
Chem. Soc. 1987, 109, 8056.
(15) (a) Soundararajan, R.; Li, G.; Brown, H. C. J. Org. Chem. 1996,
61, 100. (b) Roy, C. D.; Soundararajan, R.; Brown, H. C. Monatsh.
Chem. 2008, 139, 241.
(16) (a) Myers,A.G.;Yang,B.H.;Chen,H.;Gleason,J.L.J. Am. Chem.
Soc. 1994,116,9361.(b)Myers,A.G.;Yang,B.H.;Chen,H.;McKinstry,L.;
Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(11) (a) Sugimura, T.; Uchida, T.; Watanabe, J.; Kubota, T.; Okamoto,
Y.; Misaki, T.; Okuyama, T. J. Catal. 2009, 262, 57. (b) Lu, W.-J.; Chen,
Y.-W.; Hou, X.-L. Angew. Chem., Int. Ed. 2008, 47, 10133. (c) Lu, S.-M.;
Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 8920. (d) Li, S.; Zhu, S.-F.;
Zhang, C.-M.; Song, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2008, 130, 8584.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Synthesis of Trifluoroboratoamide 9
Scheme 5. Formation of Phthalide 6
Scheme 6. Synthesis of Virgatolide B, 2
Scheme 4. Synthesis of Iodide 7
knowledge this is the first reported palladium-catalyzed
carboalkoxylation where both 5- and 6-membered cycliza-
tion products are possible.
Attention next turned to the key aldol reaction to unite
methyl ketone 6 with aldehyde 5 using a Mukaiyama
protocol.18 Simultaneous conversion of 6 to the TMS enol
ether and protection of the secondary alcohol as a TMS
ether was effected with TMSOTf (Scheme 6). The crude
enol ether was then added to a preformed complex of
Gratifyingly, despite the use of a sterically demanding,
electron-rich aryl bromide, Suzuki coupling of 9 and 10
proceeded cleanly using Pd(OAc)2 and RuPhos,17 furnish-
ing amide 18 (Scheme 4). We believe this provides the first
demonstrated use of Molander’s trifluoroboratoamide
Suzuki cross-coupling methodology in a total synthesis.
Conversion of 18 to methyl ketone 8 with methyllithium16
proceeded in high yield without significant loss of material
due to double alkylation. Sharpless asymmetric dihydroxyl-
ation6 of 8 using AD-mix R afforded diol 19 in high yield as a
single diastereoisomer by 1H NMR. Selective monoiodina-
tion of the aromatic ring afforded iodide 7 with a trace
amount of the easily separable di-iodinated product.
Carbonylation of iodide 7 with concomitant intramole-
cular alkoxylation5 afforded phthalide 6 in 75% yield
(Scheme 5). Pleasingly, the intramolecular cyclization
completely favored formation of phthalide 6 over isochro-
manone 20, even at the elevated temperature at which the
reaction was conducted, indicating a strong kinetic pre-
ference for 5-membered ring formation. To the best of our
aldehyde 5 and BF3 OEt2 in dichloromethane at ꢀ78 °C.
3
On completion of the reaction, the crude aldol adduct was
dissolved in methanol and treated with saturated aqueous
potassium carbonate to liberate the latent alcohol func-
tionality. Ketone 4 was isolated in 65% yield over three
steps with excellent diastereoselectivity (single diastereo-
mer by 1H and 13C NMR). Finally, global deprotection of
the two BOM groups and the PMB group under hydro-
genolysis followed by equilibration with a catalytic
amount of CSA yielded virgatolide B, 2, in 55% over
two steps. Pleasingly, the spiroketal isomer 21 produced by
cyclization of the other phenolic oxygen peri to the phtha-
lide carbonyl was not observed.
Spectroscopic data (1H NMR, 13C NMR, and HRMS
analyses) for synthetic virgatolide B, 2, were in full agree-
ment with those reported for the natural product.1
Furthermore, the absolute stereochemistry of naturally
occurring virgatolide B was confirmed by comparison of
(17) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
Org. Lett., Vol. XX, No. XX, XXXX
(18) Peuchmaur, M.; Wong, Y.-S. J. Org. Chem. 2007, 72, 5374.
C

the optical rotation values ([R]25D þ19.1 (c 0.25 in MeOH)),
{lit. þ25.0, (c 0.07 in MeOH)}.
the construction of analogues and the remaining members of
this novel family of natural products.
In summary, the first total synthesis of virgatolide B, 2,
has been achieved via a highly convergent synthesis. Key
features include the first example of Suzuki coupling of a
chiral trifluoroboratoamide in a total synthesis,7 the first
example of an intramolecular carboalkoxylation to form
a phthalide where formation of an isochromanone is also
possible,5 and a 1,3-anti-selective Mukaiyama aldol reaction.4,18
Preservation of the rotational symmetry about the aroma-
tic ring enabled the requirement for regioselectivity to be
delayed until control could be governed by intramolecular
hydrogen-bonding interactions. The overall approach
is enantioselective, scalable, and highly amenable to
Acknowledgment. We thank the University of Auckland
for the award of an Auckland Doctoral Scholarship to
P.A.H. We also thank Prof. Molander and Inji Shin
(University of Pennsylvania) for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX