Asymmetric Solid-Phase Synthesis of (3′R,4′R)-Di-O-cis-acyl 3-Carboxyl Khellactones

Article abstract of DOI:10.1021/ol991168w

Matrix Presented We describe a practical parallel synthesis of (3′R,4′R)-di-O-cis-acyl 3-carboxyl khellactones on a solid phase in high yield. The highlights of this synthesis include a Knoevenagel condensation, asymmetric dihydroxylation, catalyzed acylation, and product cleavage from the solid support.

Full text of DOI:10.1021/ol991168w

ORGANIC
LETTERS
1999
Vol. 1, No. 13
2113-2115
Asymmetric Solid-Phase Synthesis of
(3′R,4′R)-Di-O-cis-acyl 3-Carboxyl
Khellactones†
Yi Xia, Zheng-Yu Yang, Arnold Brossi, and Kuo-Hsiung Lee*
Natural Products Laboratory, School of Pharmacy, UniVersity of North Carolina,
Chapel Hill, North Carolina 27599-7360
khlee@unc.edu
Received October 19, 1999
ABSTRACT
We describe a practical parallel synthesis of (3′R,4′R)-di-O-cis-acyl 3-carboxyl khellactones on a solid phase in high yield. The highlights of
this synthesis include a Knoevenagel condensation, asymmetric dihydroxylation, catalyzed acylation, and product cleavage from the solid
support.
Substituted khellactones exhibit a broad range of biological
activities, including antifungal, antitumor, and antiviral
effects.1 In addition, our laboratory has discovered that
(3′R,4′R)-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK)
displayed extremely potent inhibitory activity against HIV-1
replication.2 DCK was more potent than AZT as an anti-
HIV agent in the same assay. Therefore, (3′R,4′R)-di-O-cis-
substituted khellactones have proven to be crucial drug leads
and have elicited considerable pharmaceutical interest. Thus,
a general method of rapidly preparing analogues of khel-
lactones would be advantageous and merits investigation for
drug discovery. Meanwhile, solid-phase synthesis of small
organic molecules has emerged as an important technology,
enabling chemists to synthesize numerous pharmaceutically
interesting compounds.3 The relative ease of automation,
along with a multiple parallel synthesis strategy, has greatly
supported the growing needs for identifying novel biologi-
cally active lead compounds and accelerated structure-
activity relationship studies in drug discovery. We report here
the first asymmetric solid-phase synthetic route to (3′R,4′R)-
di-O-cis-acyl 3-carboxyl khellactones.
The synthetic route is described in Scheme 1. The strategy
we used is to attach a polystyrene resin to the khellactone
ring skeleton through a C-3 carboxylate group. The linker
group of the Wang resin could serve as a carboxyl protecting
group, because a free carboxyl is not compatible with the
asymmetric dihydroxylation (AD) or acylation reaction
conditions. In addition, this linkage is cleaved under mild
acidic conditions that are compatible with the desired
compounds. We chose different supports, including low
divinylbenzene-cross-linked polystyrene beads (ArgoPore),
which are relatively hydrophobic matrices, and ArgoGel
† Anti-AIDS Agents. 40.
(1) (a) Lee, T. T. Y.; Kashiwada, Y.; Huang, L.; Snider, J.; Cosentino,
M.; Lee, K. H. Bioorg. Med. Chem. 1994, 2, 1051-1056. (b) Bandara, B.
M. R.; Gunatilaka, A. A. L.; Wijeratne, E. M. K.; Macleod, J. K.
Phytochemistry 1990, 29, 297. (c) Gunatilaka, A. A. L.; Kingston, D. G.
I.; Wijeratne, E. M. K.; Bandara, B. M. R.; Hofmann, G. A.; Johnson, R.
K. J. Nat. Prod. 1994, 57, 518.
(2) (a) Xie, L.; Crimmins, M. T.; Lee, K. H. Tetrahedron Lett. 1995,
36, 4529. (b) Huang, L.; Kashiwada, Y.; Consentino, L. M.; Fan, S.; Chen,
C.; McPhail, A. T.; Fujioka, T.; Mihashi, K.; Lee, K. H. J. Med. Chem.
1994, 37, 3947.
(3) (a) Balkenhohl, F.; Bussche-Hunnefeld, C.; Lansky, A.; Zechel, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2289. (b) Baldwin, J.; Henderson,
I. Med. Res. ReV. 1996, 16, 391. (c) Ellman, J. A.; Thiompson, L. A. Chem.
ReV. 1996, 96, 555. (d) Creswell, M. W.; Bolton, G. L.; Hodges, J. C.;
Meppen, M. Tetrahedron 1998, 54, 3983.
10.1021/ol991168w CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/09/1999

Scheme 1
Scheme 2
The next key step was asymmetric dihydroxylation of the
khellactone. Sharpless asymmetric dihydroxylation (AD)
reactions have been successfully and widely used in the
solution phase, but AD reactions on solid phase have been
reported only infrequently.8 However, a high percent enan-
tiomeric excess (% ee) value has not been accomplished for
the AD reaction of a styrene-like olefin contained in a six-
membered ring fused with benzene on a solid phase. Our
asymmetric synthesis of (3′R,4′R)-cis-dihydroxykhellactone
(4) was successful on a solid phase using (DHQ)2-PHAL as
ligand and catalytic OsO4. The 3′,4′-dihydroxy 3-carboxyl
khellactone 6 (R ) H) was obtained by cleaving the resin 4
using 50% trifluoroacetic acid in DCM. The % ee of the
AD reaction was 91%.9 The acyl khellactones 5 were
synthesized by acylation of the resin 4. Symmetrical anhy-
drides were prepared from the desired carboxylic acid using
1 equiv of DIC in dichloromethane. Then, in an automated
parallel synthesis using the Quest 210 Organic Synthesizer,
excess anhydride was added to the resin 4 and the reaction
proceeded for 8 h in the presence of DIEA and DMAP. After
a second acylation, the resin was washed with DMF and
DCM. The resins 5 then were treated with 50% trifluoroacetic
acid in DCM for 2 h to cleave the target 3-carboxyl
khellactones (6a-f).10 The crude products cleaved from the
resin showed excellent purity (>90%). Silica gel column
chromatography then gave the pure compounds. Representa-
tive compounds are listed in Figure 1. Yields correspond to
purified products and were calculated on the basis of the
hydroxyl group of the Wang resin. The structure and identity
of the products were compared to those produced via solution
synthesis, and 1H NMR and electrospray mass spectrometric
data were satisfactory.
resin, which is considered a relatively hydrophilic tentacle
polymer with more “solution like” characteristics.4 Because
the solvents in the Sharpless AD reaction proposed in the
following reaction are t-BuOH and water, ArgoGel resin was
found more suitable for the reaction, as well as for better
swelling.
The scaffold of the khellactone 3-carboxyl ring skeleton
was prepared by a Knoevenagel condensation5 between ethyl
malonate bound to the Wang resin (1) and o-hydroxyaryl-
aldehyde (2). In the previous solution-phase synthesis, we
reacted 7-hydroxycoumarin with 3-chloro-3-methybut-1-yne
followed by a Claisen rearrangement to generate the khel-
lactone ring skeleton.6 Although we obtained the highly
regiospecific product in high yield, the reaction was carried
out at high temperature. Therefore, we have adapted a
Knoevenagel condensation, treating resin 1 with 2 at room
temperature with a catalytic amount of piperidine to create
the khellactone scaffold. The reaction condition is very mild,
which is more amenable for solid-phase synthesis.
The synthesis of o-hydroxyarylaldehyde (2) is illustrated
in Scheme 2. Grignard addition of acetyl acetaldehyde
dimethyl acetal (7) with methylmagnesium bromide in diethyl
ether afforded 8. Nucleophilic substitution of 2,4-dihydroxy-
benzoylaldehyde, followed by regiospecific aromatic cy-
clization, gave 2.7
In conclusion, we have developed a novel, straightforward,
easily automated solid-phase procedure for the synthesis of
(3′R,4′R)-di-O-cis-acyl 3-carboxyl khellactones. The proce-
dure is particularly useful because of its efficiency and ease
(4) Jung, G. Combinatorial Peptide and Nonpeptide Libraries; VCH:
New York, 1996; Chapter 2.
(5) (a) Zaragoza, F.; Tetrahedron Lett. 1995, 36, 8677. (b) Gordeev, M.
F.; Patel, D. V.; Wu, J.; Gordon, E. M. Tetrahedron Lett. 1996, 37, 4643.
(c) Watson, B. T.; Christiansen, G. E. Tetrahedron Lett. 1998, 39, 6087.
(d) Hamper, B. C.; Kolodziej, S. A.; Scates, A. M. Tetrahedron Lett. 1998,
39, 2047.
(7) 1H NMR (300 MHz, CDCl3) data for 5-Hydroxy-2,2-dimethyl-2H-
chromene-6-carbaldehyde (2): δ 1.38 (s, 6H, 2 × CH3), 5.54 (d, J )
10.1 Hz, 1H, H-3), 6.36 (d, J ) 8.4 Hz, 1H, H-8), 6.62 (d, J ) 10.1 Hz,
1H, H-4), 7.21 (d, J ) 8.4 Hz, 1H, H-7), 9.59 (s, 1H, aldehyde). Yield:
29.4%. Mp: 69-70 °C.
(8) Han, H.; Janda, K. P. Angew. Chem., Int. Ed. Engl. 1997, 36, 1731.
(9) The percent enantiomeric excess was determined by 1H NMR analysis
of the bis-(-)-camphanic esters.
(6) Hlubucek, J.; Rittchie, E.; Taylor, W. C. Aust. J. Chem. 1971, 24,
2347.
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Org. Lett., Vol. 1, No. 13, 1999

National Institute of Allergies and Infectious Diseases at the
NIH, Grant No. AI 33066, awarded to K.-H.L.
Supporting Information Available: Procedures for the
formation of 3′,4′-di-O-cis-acyl 3-carboxyl khellactones and
characterization data for 6 and 6a. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL991168W
(10) General procedure for the synthesis of 3′,4′-di-O-cis-acyl 3-carboxyl
khellactones: ArgoGel Wang resin (1 equiv), purchased from Argonaut
with a loading of 0.39 mmol/g, was washed with DMF (3×) and methylene
chloride (3×) and dried in vacuo. Ethyl potassium malonate (10 equiv)
was added followed by N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide
hydrochloride (10 equiv), and the reaction mixture was shaken at room
temperature for 16 h. The resin was filtered and washed: 9/1 DMF/H2O
(3×), DMF (3×), methylene chloride (3×). Then, resin 1 was suspended
in pyridine; compound 2 (10 equiv) and piperidine (40 µL) were added.
The reaction mixture was shaken for 16 h at room temperature, and then
the resin was filtered and washed with 9/1 DMF/H2O (3×), DMF (3×),
and methylene chloride (3×), retreated with the reagents, and washed again
as described to obtain resin 3. For synthesis of resin 4, a small aliquot of
OsO4 (0.1 equiv) in t-BuOH (2.5% solution (wt %)) was added to a mixture
of (DHQ)2-PHAL (2.5 equiv), K3[Fe(CN)6] (6 equiv), K2CO3 (3 equiv),
and methanesulfonamide (1 equiv) in t-BuOH/water (4 mL, v/v 1/1) at room
temperature. After the reaction mixture was stirred for 10 min, resin 3 (1
equiv) was added in one portion, and the mixture was further stirred for 36
h. Solid Na2S2O5 was added; the mixture was stirred for an additional 20
min, filtered, and successively washed with acetone and dichloromethane.
The resin was dried and then acylated. First, to a dry flask under nitrogen
was added the desired carboxylic acid (10 equiv), anhydrous CH2Cl2, and
DIC (10 equiv) and the solution was stirred for 30 min. The resulting
symmetrical anhydride was added to resin 5, DIEA (20 equiv), and DMAP
(10 equiv), and then the mixture was shaken for 2 h. The acylation procedure
was repeated, and then the suspension was drained and washed and the
products 6a-f were cleaved from the resin by treatment with 50% TFA/
CH2Cl2 for 2 h. All new compounds gave satisfactory analytical and
spectroscopic data.
Figure 1. 3-Carboxyl khellactones 6a-f. Yields in parentheses
correspond to purified products and were calculated on the basis
of the hydroxyl group of Wang resin.
of operation. It is well-suited to the preparation of analogues
for SAR studies.
Acknowledgment. We thank Dr. Susan Morris-Natschke
for her critical reading. This research was supported by the
Org. Lett., Vol. 1, No. 13, 1999
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