Synthesis of an advanced precursor of demethoxyviridin

Article abstract of DOI:10.1080/00397911.2012.737078

The synthesis of a potential precursor 3 to demethoxyviridin (1b) is described. The centerpiece of this strategy was the conversion of the previously described dibromoolefin 6 to the masked alkyne β-hydroxyaldehyde 5 in a single step. Further elaboration then produced the alkyne oxazole 4, which on thermolysis, followed by in situ tautomerization and silylation, led directly to 3. Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for full experimental and spectral details.

Full text of DOI:10.1080/00397911.2012.737078

This article was downloaded by: [East Carolina University]
On: 11 July 2013, At: 01:00
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of an Advanced Precursor of
Demethoxyviridin
Evans O. Onyango a & Peter A. Jacobi a
a Department of Chemistry , Dartmouth College , Hanover , New
Hampshire , USA
Published online: 08 Jul 2013.
To cite this article: Evans O. Onyango & Peter A. Jacobi (2013) Synthesis of an Advanced Precursor of
Demethoxyviridin, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:20, 2748-2755, DOI: 10.1080/00397911.2012.737078
To link to this article: http://dx.doi.org/10.1080/00397911.2012.737078
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 43: 2748–2755, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.737078
SYNTHESIS OF AN ADVANCED PRECURSOR OF
DEMETHOXYVIRIDIN
Evans O. Onyango and Peter A. Jacobi
Department of Chemistry, Dartmouth College, Hanover,
New Hampshire, USA
GRAPHICAL ABSTRACT
Abstract The synthesis of a potential precursor 3 to demethoxyviridin (1b) is described.
The centerpiece of this strategy was the conversion of the previously described dibromoole-
fin 6 to the masked alkyne b-hydroxyaldehyde 5 in a single step. Further elaboration then
produced the alkyne oxazole 4, which on thermolysis, followed by in situ tautomerization
and silylation, led directly to 3.
Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for full experimental and spectral details.
Keywords Demethoxyviridin; Diels–Alder=retro-Diels–Alder reaction; furanosteroids;
Stille coupling
INTRODUCTION
The furanosteroids are a class of highly substituted steroid derivatives, sharing
in common a furan ring bridging the C4- and C6-positions, which introduces con-
siderable strain into the pentacyclic skeleton (Fig. 1). Members of this class were first
identified in 1945,[1] and in the intervening years they have attracted much attention
from both synthetic and medicinal chemists. Initially this was due to their significant
antifungal and anti-inflammatory activity,[1,2] but more recently attention has
focused on their activity as potent inhibitors of phosphoinositide-3-kinases.[3] Viridin
(1a) and wortmannin (2a) have been particularly well studied in this regard, along
with simpler analogs providing both greater activity and selectivity.[4–8] Not surpris-
ingly, 1a and 2a have also been popular synthetic targets, noteworthy in this area are
the elegant total synthesis of 1a by the Sorensen group[9] and two syntheses of 2a by
Shibasaki et al.[10–12] (one de novo).
Received September 11, 2012.
Address correspondence to Peter A. Jacobi, Department of Chemistry, Dartmouth College,
Hanover, NH 03755, USA. E-mail: peter.a.jacobi@dartmouth.edu
2748

ADVANCED PRECURSOR OF DEMETHOXYVIRIDIN
2749
Figure 1. Viridin and wortmannin classes of furanosteroids.
Scheme 1. Previous synthesis of viridin’s pentacyclic core.
Recently we described the synthesis of the pentacyclic core skeleton 7 of the
viridin class of furanosteroids, involving a tandem alkyne oxazole intramolecular
Diels–Alder=retro-Diels–Alder reaction of 9, followed by vinylogous Mukaiyama
aldol condensation of 8 to close ring A (Scheme 1).[13] In this article we report the
synthesis of a potential precursor to demethoxyviridin (1b), a naturally occurring
furanosteroid that has P13-kinase inhibition activity comparable to that of
wortmannin.[14]
RESULTS AND DISCUSSION
We envisioned that the masked furanoaldehyde 3 would be an attractive pre-
cursor to demethoxyviridin (1b), via hydrolysis and vinylogous Mukaiyama aldol
condensation as outlined previously for the synthesis of 7 (Scheme 2).[13] In our ret-
rosynthetic analysis, the immediate precursor to 3 would be the alkyne oxazole
derivative 4, which on thermolysis and in situ silylation would produce 3 in a single
step. We further planned that 4 might be synthesized by palladium-catalyzed C-C
bond formation between an appropriate oxazole derivative and the alkyne triflate
5, itself derived via lithiation of the previously described dibromoolefin 6,[13]
followed by trapping with a protected malonic dialdehyde derivative.
In accord with this plan, our synthesis of 3 commenced with the lithiation of
dibromoolefin 6, itself prepared in six steps, and good overall yield, beginning with
hydroxyindanone 10 (Scheme 3).[13] In situ trapping of the resulting lithium acetylide
with 3,3-dimethoxypropanal (11)[15] then afforded the propargylic alcohol 5 in a

2750
E. O. ONYANGO AND P. A. JACOBI
Scheme 2. Retrosynthetic analysis.
yield of 43%. We next devoted considerable effort to studying the coupling chemistry
of 5. Unfortunately, we were unable to effect the direct insertion of an oxazole ketone
into 5 by employing cross-coupling methodology. Also, our initial attempts at Stille
coupling of 5 with tributyl(vinyl)tin were sluggish and gave only trace amounts of the
corresponding vinyl arene. Reasoning that the free alcohol in 5 was interfering with
the desired coupling reaction, we studied the effect of various protecting groups.
Along these lines, both silyl and acetate protecting groups were introduced without
incident, but the resulting derivatives were still unreactive toward Stille
cross-coupling with tributyl (vinyl)tin. Exploring other options, all attempts at intro-
ducing a Bn or para-methoxybenzyl protecting group under either basic (NaH=BnBr;
NaH=para-methoxybenzyl chloride) or acidic conditions [TfOH=BnOC(¼ NH)CCl3]
led only to decomposition of the starting material. Eventually, though, we found that
the PMB ether 12 could be synthesized in 90% yield by employing the reagent com-
bination of catalytic Cu(OTf)2 and para-methoxybenzyl trichloroacetimdate.[16] With
Scheme 3. Synthesis of vinyl arene 13.

ADVANCED PRECURSOR OF DEMETHOXYVIRIDIN
2751
Scheme 4. Synthesis of Diels–Alder precursor 18.
a ready supply of 12 in hand, we were pleased to find that this derivative underwent
smooth Stille cross-coupling with tributyl(vinyl)tin, affording an 85% yield of vinyl
arene 13 by employing the catalyst system PdCl2(MeCN)2=DPEPhos in dimethylfor-
mamide (DMF) at 110 ꢀC.
The successful synthesis of vinyl arene 13 was followed by oxidative cleavage of
the olefin moiety to the aldehyde 14, a transformation that was accomplished in 75%
yield using OsO4=NaIO4=2,6-lutidine[17] (Scheme 4). Addition of the lithiated
triisopropylsilyl oxazole 15 to the aldehyde 14 then gave the secondary alcohol 16
in a yield of 77% as an inconsequential mixture of diastereomers. Next, Dess–Martin
periodinane oxidation of 16 to the corresponding ketone 17 was accomplished in
86% yield, followed by 1 N HCl mediated hydrolysis of both the TIPS and ketal pro-
tecting groups to give 18 (78%). Interestingly, the dimethyl acetal functionality in 18
was remarkably stable under these acidic conditions.
At this point we were disappointed to find that alkyne oxazole 18 was unreac-
tive toward Diels–Alder cyclization, returning only starting material at temperatures
up to 140 ꢀC and suffering extensive decomposition under more forcing conditions.
This necessitated further activation of the dienophile component, which was
accomplished by oxidative removal of the p-methoxybenzyl protecting group
(2,3-dichloro-5,6-dicyanobenzoquinone=CH2Cl2=H2O, rt), followed by Dess–Martin
oxidation of the resulting alcohol to the corresponding ketone 19 (59% yield)
(Scheme 5). Gratifyingly, heating the propargylic ketone 19 in 1,2-dichlorobenzene
at 150 ꢀC for 5 h then provided the unstable cyclohexadienone derivative 20, which
underwent clean aromatization and silylation on treatment with excess TBSOTf=
Et3N. The target phenol TBS ether derivative 3 was obtained in an overall yield
of 80% from 19.
The TBS phenol derivative 3 was in principle only one step removed
from demethoxyviridin (1b), via a vinylogous Mukaiyama aldol-type reaction
(Scheme 6). A notable intramolecular example of this reaction employing a dimethyl
acetal was reported by Armstrong et al. during their synthesis of the core structure

2752
E. O. ONYANGO AND P. A. JACOBI
Scheme 5. Synthesis of the advanced precursor 3.
Scheme 6. Attempted cyclization of 3.
of CP-225,917.[18] Thus far, however, we have been unsuccessful in effecting the
conversion of 3 to 1b. The most promising conditions involved treatment of 3 with
TiCl4=CH2Cl2, which gave a good yield of the stable Z-enol derivative 21, previously
synthesized by an independent, less-efficient route.[13] It seemed plausible that
compound 21 might still undergo cyclization via an aldehyde tautomer. However,
1
this material exhibited little aldehyde character by H NMR analysis, and in the
Z-enolic form is geometrically constrained from cyclization.
CONCLUSION
In conclusion, we have synthesized the masked furanoaldehyde 3, a potential
precursor to demethoxyviridin in 10 steps and in an overall yield of 6% from the pre-
viously described dibromoolefin 6. Further modifications to the skeleton of 3 to
facilitate cyclization to 1b are currently under investigation.
EXPERIMENTAL
All reactions were performed in the appropriate oven-dried glass apparatus
under a balloon of nitrogen gas (N2). Solvents were reagent grade and in most cases

ADVANCED PRECURSOR OF DEMETHOXYVIRIDIN
2753
rigorously dried before use. Tetrahydrofuran (THF), dioxane, and Et2O were
distilled from sodium. Toluene, dimethylformamide (DMF), methylene chloride,
and Et3N were distilled from calcium hydride. All reagents were obtained commer-
cially as reagent grade and, unless otherwise noted, used without further purification.
Reaction temperatures were measured externally. Reactions were monitored by
thin-layer chromatography (TLC) silica-gel plates (0.25 mm) and visualized by ultra-
voilet light, I2, or spraying with KMnO4 or p-anisaldehyde. Column chromato-
graphy was performed using silica gel (60, particle size 40–60 mm). Preparative
TLC was carried out on 1000-mm silica-gel plates. The organic extracts were dried
over anhydrous MgSO4. Melting points are uncorrected. Infrared (IR) spectra were
recorded on a Fourier transform (FT)=IR spectrometer and absorptions are reported
in reciprocal centimeters (cmꢁ1). Proton (1H) and carbon (13C) nuclear magnetic res-
onance spectra were recorded at 300 or 500 MHz and 75 or 125 MHz, respectively.
Chemical shifts are reported in parts per million (ppm, d) with the residual nondeut-
erated solvent as an internal standard (7.26 ppm for chloroform). Splitting patterns
are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
High-resolution mass spectra (HRMS) were obtained employing either electronspray
ionization (ESI) or electron ionization (EI) employing TOF as the mass analyzer.
5’-(5-Hydroxy-7,7-dimethoxyhept-3-yn-2-yl)-2’,3’-dihydrospiro[1,3-
dioxolane-2,1’-indene]-4’-yl Trifluoromethanesulfonate (5)
n-BuLi (1.6 M solution in hexanes, 11.7 mL, 18.66 mmol) was added dropwise
over 1 h to a solution of compound 6 (5 g, 9.33 mmol) in THF (120 mL) at ꢁ78 ꢀC.
After an additional 30 min, aldehyde 11 (1.65 g, 14.0 mmol) was added and the reac-
tion mixture was warmed to ꢁ55 ꢀC, stirred overnight (14 h), and then quenched
with KH2PO4. The resulting white suspension was warmed to room temperature,
extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated
in vacuo. Purification by column chromatography (SiO2, 2:1 hexanes=EtOAc) gave
1.98 g (43%) of the propargyl alcohol 5 as a yellow oil. Rf ¼0.25 (1:1 hexanes=
EtOAc).1H NMR (300 MHz, CDCl3) d 7.60 (1H, d, J ¼ 7.8 Hz), 7.35 (1H, d,
J ¼ 7.8 Hz), 4.68 (1H, t, J ¼ 5.7 Hz), 4.55 (1H, bd, J ¼ 6 Hz), 4.21–4.05 (5H, m),
3.37 (3H, s), 3.35 (3H, s), 3.32–3.02 (2H, m), 2.35–2.31 (2H, m), 2.04–2.00 (2H,
m), 1.46 (3H, d, J ¼ 7.2 Hz). 13C NMR (125 MHz, CDCl3) d 183.6, 145.7, 141.8,
137.5, 135.7, 130.0, 124.2, 120.0, 117.5, 116.5, 100.8, 94.7, 82.0, 65.7, 65.6, 53.8,
49.2, 37.3, 37.2, 26.5, 22.9. FT–IR (CDCl3, cmꢁ1) 3442, 2948, 1732, 1615, 1514,
1408, 1318, 916. HRMS (EI) calcd. for C21H25F3O8S 494.1298; found 494.1292.
12-(3,3-Dimethoxypropanoyl)-10-methyl-14-oxatertacyclo
[7.7.0.0.2,6.011,15] hexadeca-1,6,8,11(15),12-pentaene-5,16-dione (20)
A solution of alkyne oxazole 19 (250 mg, 0.63 mmol) in 10 mL of dry
1,2-dichlorobenzene was stirred in a 30-mL, round-bottom flask at 150 ꢀC under a
nitrogen atmosphere for 5 h. After cooling to rt, the solution was passed through
a plug of silica gel using hexanes to elute 1,2-dichlorobenzene. The product was then
eluted from the silica gel with 2:1 hexanes=EtOAc to give 200 mg of 20 as a yellow
1
oil, Rf ¼ 0.44 (1:1 hexanes=EtOAc). H NMR (300 MHz, CDCl3) d 8.31 (1H, s),

2754
E. O. ONYANGO AND P. A. JACOBI
7.95 (1H, d, J ¼ 8.1 Hz), 7.58 (1H, d, J ¼ 8.1 Hz), 7.56 (1H, d, J ¼ 7.8 Hz), 4.92 (1H, t,
J ¼ 5.4 Hz), 4.73 (1H, q, J ¼ 6.9 Hz), 3.78–3.70 (2H, m), 3.42 (6H, s), 3.24 (2H, d,
J ¼ 5.7 Hz), 3.00 (3H, s), 2.78–2.74 (2H, m), 1.60 (3H, d, J ¼ 7.2 Hz).
1-f5,16-Bis[tert-butyldimethylsilyl)oxy]-10-methyl-14-oxatetracyclo
[7.7.0.02,6.0.11,15]hexadecA-1,4,6,8,12,15-heptaen-12-ylg-3,3-
dimethoxypropan-1-one (3)
Et3N (301 mL, 2.16 mmol) was added to a solution of keto-enone 20 (200 mg,
0.54 mmol) in CH2Cl2 (30 mL) at ice bath temperature, followed by TBSOTf
(372 mL, 1.62 mmol). The resulting mixture was then gradually warmed to rt and stir-
red for an additional 30 min before quenching with saturated aqueous NaHCO3. The
two layers were separated and the aqueous layer was extracted twice with CH2Cl2.
The combined organic extracts were washed with brine, dried over MgSO4, and
concentrated in vacuo. Purification by column chromatography (SiO2, 10:1 hexanes=
EtOAc) gave 470 mg (80%) of 3 as a pale yellow oil. Rf ¼ 0.85 (4:1 hexanes=EtOAc).
1H NMR (300 MHz, CDCl3) d 8.31 (1H, s), 8.18 (1H, d, J ¼ 8.7 Hz), 7.61 (1H, d,
J ¼ 8.7 Hz), 5.58 (1H, d, J ¼ 2.4 Hz), 5.00 (1H, t, J ¼ 5.4 Hz), 3.93 (2H, d, J ¼ 1.8 Hz),
3.44 (6H, s), 3.24 (2H, d, J ¼ 5.7 Hz), 3.00 (3H, s), 2.79–2.75 (2H, m), 0.98 (9H, s), 0.91
(9H, s), 0.42 (6H, s), 0.29 (6H, s).13C NMR (125 MHz, CD2Cl2) d 192.1, 180.2, 153.9,
153.4, 133.9, 137.7, 130.9, 125.4, 123.9, 123.0, 122.0, 116.7, 106.2, 90.1, 46.6, 38.2,
32.1, 31.5, 29.9, 29.6, 26.3, 25.5, 22.9, 17.2, 14.1, 8.4, ꢁ2.5, ꢁ4.8. FT–IR (CDCl3,
cmꢁ1) 2928, 1615, 1353, 1253, 834. HRMS (ESI) calcd. for C33H49O6Si2 [M þH]þ
597.3068; found 597.3055.
SUPPORTING INFORMATION
Full experimental details and 1H and 13C NMR spectra of all new compounds
can be found via the ‘‘Supplementary Content’’ section of this article’s webpage.
REFERENCES
1. Brian, P. W.; Curtis, P. J.; Hemming, H. G.; McGowan, J. C. Ann. Appl. Biol. 1946, 33,
190–200.
2. Brian, P. W.; Curtis, P. J.; Hemming, H. G.; Norris, G. L. F. Trans. Br. Mycol. Soc. 1957,
40, 365–368.
3. Liu, Y.; Shreder, K. R.; Gai, W.; Corral, S.; Ferris, D. K.; Rosenblum, J. S. Chem. Biol.
2005, 12, 99–107.
4. Norman, B. H.; Shih, C.; Toth, J. E.; Ray, J. E.; Dodge, J. A.; Johnson, D. W.;
Rutherford, P. G.; Schultz, R. M.; Worzalla, J. F.; Vlahos, C. J. J. Med. Chem. 1996,
39, 1106–1111.
5. Norman, B. H.; Paschal, J.; Vlahos, C. J. Bioorg. Med. Chem. Lett. 1995, 5, 1183–1186.
6. Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053–2061.
7. Ihle, N. T.; Williams, R.; Chow, S.; Chew, W.; Berggren, M. I.; Paine-Murrieta, G.;
Minion, D. J.; Halter, R. J.; Wipf, P.; Abraham, R.; Kirkpatrick, L.; Powis, G. Mol.
Cancer Ther. 2004, 3, 763–772.
8. Creemer, L. C.; Kirst, H. A.; Vlahos, C. J.; Schultz, R. M. J. Med. Chem. 1996, 39,
5021–5024.

ADVANCED PRECURSOR OF DEMETHOXYVIRIDIN
2755
9. Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem., Int. Ed. 2004, 43,
1998–2001.
10. Sato, S.; Nakada, M.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 6141–6144.
11. Mizutani, T.; Honzawa, S.; Tosaki, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2002, 41,
4874–4876.
12. Shigehisa, H.; Mizutani, T.; Tosaki, S.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61,
5057–5065.
13. Onyango, E. O.; Jacobi, P. A. J. Org. Chem. 2012, 77, 7411–7427.
14. Woscholski, R.; Kodaki, T.; McKinnon, M.; Waterfield, M. D.; Parker, P. J. FEBS Lett.
1994, 342, 109–114.
15. Bi, L.; Zhang, Y.; Zhao, M.; Wang, C.; Chan, P.; Tok, J. B.; Peng, S. Bioorg. Med. Chem.
2005, 13, 5640–5646.
16. Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267–2269.
17. Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–3219.
18. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.; Kelsey, R. D.; Mortlock, A. A.
J. Chem. Soc., Perkin Trans. 1 2002, 1344–1350.