Asymmetric total synthesis of (+)-crassalactone D

Article abstract of DOI:10.1021/jo902055b

(Chemical Equation Presented) The asymmetric total synthesis of (+)-crassalactone D (4), a naturally occurring antitumor agent, has been achieved by employing an oxidative spirocyclization of furan 11 as the key step. Two close analogues, 7-epi-crassalact

Full text of DOI:10.1021/jo902055b

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Asymmetric Total Synthesis of (þ)-Crassalactone D
Zhicai Yang,* Phung Tang, Jolicia F. Gauuan, and
Bruce F. Molino
Medicinal Chemistry Department, AMRI, 26 Corporate
Circle, P.O. Box 15098, Albany, New York 12212-5098
zhicai.yang@amriglobal.com
Received September 23, 2009
FIGURE 1. The structures of crassalactones A-D (1-4).
The asymmetric total synthesis of (þ)-crassalactone D
(4), a naturally occurring antitumor agent, has been
achieved by employing an oxidative spirocyclization of
furan 11 as the key step. Two close analogues, 7-epi-
crassalactone D (14) and 5-epi-7-epi-crassalactone D (15),
also have been prepared in the course of the synthesis of
(þ)-crassalactone D.
unsaturated keto-aldehyde 6. The oxidation of furan 7 would
provide keto-aldehyde 6, as described by Robertson in the
synthesis of pyrenolide D analogues utilizing m-CPBA oxida-
tion of a very similar substrate.4 The antihydroxyl groups in
compound 7 could be generated from either cis-olefin 8 or
trans-olefin 9 (Scheme 1).
Our asymmetrictotal synthesis of (þ)-crassalactone D (4) is
illustrated in Scheme 2. It has been reported that the asym-
metric dihydroxylation of trans olefins5 provides greater
enantioselectivity than cis olefins.6 Therefore, the known
trans-olefin 97 was prepared by reaction of the commercially
available bromide 10 and 2-furyllithium and subjected to
Sharpless asymmetric dihydroxylation to provide the desired
diol 11 in 89% yield and greater than 99% ee.8 Attempts at
oxidation of furan 11 with N-bromosuccinimide9 or Rose
Bengal-sensitized photooxidation10 of 11 failed in our hands
to provide the desired products. However, oxidative spiro-
cyclization of furan 11 with m-CPBA4,11 worked well and
Four new styryl-lactones, (þ)-crassalactones A-D (1-4,
Figure 1), have been recently isolated from the leaves and twigs
of Polyalthia crassa.1 The structure of (þ)-crassalactone D (4),
which possesses a spiroketal chiral center, was elucidated on the
basis of spectroscopic methods. The relative configuration of
compound 4 was established by single-crystal X-ray diffraction
analysis and its absolute stereochemistry was determined as
(5S,7S,8R) by NMR studies on (R)-and(S)-MTPAestersof4.1
Similar to other styryl-lactones, (þ)-crassalactone D has shown
broad cytotoxic activity against human and rat cancer cell lines.1
Popsavin and co-workers have accomplished the first total
synthesis of crassalactone C (3) from D-xylose.2 More recently,
Pavlakos and co-workers reported the first synthesis of crassa-
lactone D and its 4-epimer by a very similar route, but with
modest enantiomeric excess.3 We report herein the asymmetric
total synthesis of (þ)-crassalactone D (4) where high enantio-
selectivity has been achieved.
(4) (a) Robertson, J.; Meo, P.; Dallimore, J. W. P.; Doyle, B. M.; Hoarau,
C. Org. Lett. 2004, 6, 3861–3863. (b) Robertson, J.; Stevens, K.; Naud, S.
Synlett 2008, 14, 2083–2086.
(5) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768–2771.
(6) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568–7570.
(7) Zhang, S.; Marshell, D.; Liebeskind, L. S. J. Org. Chem. 1999, 64,
2796–2804.
(8) The ee value was determined by chiral HPLC on a Chiralcel OJ-H
column (250 ꢀ 4.6 mm) by comparison to the corresponding (()-11. See the
Supporting Information for the preparation of (()-11.
(9) (a) McDermott, P. J.; Stockman, R. A. Org. Lett. 2005, 7, 27–29. (b)
Krishna, U. M.; Srikanth, G. S. C.; Trivedi, G. K. Tetrahedron Lett. 2003, 44,
8227–8228. (c) Harris, J. M.; O’Doherty, G. A. Org. Lett. 2000, 2, 2983–2986.
(d) Grapsas, I.; Couladouros, E. A.; Georgiadis, M. P. Pol. J. Chem. 1990, 64,
823. (e) Georgiadis, M. P.; Couladouros, E. A. J. Org. Chem. 1986, 51, 2725–
2727.
(10) (a) Fukuda, H.; Takeda, M.; Sato, Y.; Mitsunobu, O. Synthesis 1979,
5, 368–370. (b) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem.
Res. 2008, 41, 1001–1011.
In our retrosynthetic analysis, we envisaged that the spiro-
ketal center in lactol 5, which could serve as the precursor of
compound 4, could be established by spirocyclization of
(1) Tuchinda, P.; Munyoo, B.; Pohmakotr, M.; Thinapong, P.;
Sophasan, S.; Santisuk, T.; Reutrakul, V. J. Nat. Prod. 2006, 69, 1728–1733.
(2) (a) Popsavin, V.; Benedekovic, G.; Sreco, B.; Popsavin, M.; Francuz,
J.; Kojic, V.; Bogdanoviv, G. Org. Lett. 2007, 9, 4235–4238. (b) Popsavin, V.;
Benedekovic, G.; Sreco, B.; Popsavin, M.; Francuz, J.; Kojic, V.;
Bogdanoviv, G. Bioorg. Med. Chem. Lett. 2008, 18, 5178–5181.
(3) Pavlakos, E.; Georgiou, T.; Tofi, M.; Montagnon, T.; Vassilikogiannakis,
G. Org. Lett. 2009, 11, 4556–4559.
(11) (a) Wu, H.-J.; Lin, C.-C. J. Org. Chem. 1996, 61, 3820–3828. (b)
Laliberte, R.; Medawar, G.; Lefebvre, Y. J. Med. Chem. 1973, 16, 1084–1089.
(c) Lefebvre, Y. Tetrahedron Lett. 1972, 133–136.
9546 J. Org. Chem. 2009, 74, 9546–9549
Published on Web 11/19/2009
DOI: 10.1021/jo902055b
r
2009 American Chemical Society

Yang et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis of Crassalactone D (4)
SCHEME 2. Total Synthesis of Crassalactone D (4)
afforded an inseparable mixture of two lactols 12 and 13 in a
ratio of 2:1 in the crude reaction mixture by 1H NMR analysis.
Interestingly, it was observed that the less stable isomer 13
could be converted to the more stable 12 in a solution of
dichloromethane or deuterated chloroform in 24 h to give a 3:1
mixture of 12 and 13 by 1H NMR analysis. Recrystallization of
the mixture from dichloromethane by allowing the solvent to
evaporate slowly over a period of 3 days significantly improved
the ratio to 10:1 by 1H NMR in favor of the desired isomer 12.
The structure of compound 12 was established on the basis of
1H, 13C, 2D-COSY, 2D-HSQC, and 1D-NOE NMR studies.
The key NOE correlations of compound 12 are shown in
Figure 2.
To further explore the conversion of 12 to 13, the
corresponding acetates 16 and 17 (Figure 2) were prepared
from alcohols. The acetates were separable by column
chromatography, and their structures were elucidated
through interpretation of various one-dimensional (1H,
13C, NOE) and two-dimensional (COSY, HSQC) NMR
experiments. Key NOE correlations in 16 and 17 are
shown in Figure 2. It was observed that compound 17
was slowly transformed into the more stable 16 in deute-
rated chloroform to give a mixture of 16 and 17 in a ratio of
3:1 after several days. Therefore, a similar equilibrium
between 16 and 17 seems to exist as those observed with 12
and 13.
Subsequent selective oxidation of the mixture of lactols 12
and 13 with pyridinium dichromate provided 7-epi-crassa-
lactone D (14) and 5-epi-7-epi-crassalactone D (15), which
were separable by chromatography, in 74% and 7% yield,
respectively. Results of NMR (1H, 13C, 2D-COSY, and 2D-
HSQC) experiments and the diagnostic NOE difference
between compounds 14 and 15 (shown in Figure 2) sup-
ported the assignment of the structures and stereochemistry
of these two lactones and their precursors.
presence of sodium benzoate12 was investigated. The reac-
tion was very slow at room temperature on this hindered
hydroxyl group, but fortunately occurred at 50 °C to
provide (þ)-crassalactone D (4) in 35% yield, in addition
1
to recovery of lactone 14 in 40% yield. Both H and 13C
NMR data of compound 4 are consistent with the naturally
occurring (þ)-crassalactone D1 and its physical properties are
in agreement with those reported in the literature.13 Finally,
the structure of 4 was confirmed by single-crystal X-ray
analysis.14
In conclusion, starting from inexpensive and readily avail-
able starting material and employing Sharpless asymmetric
dihydroxylation and furan oxidative spirocyclization, we
accomplished a highly enantioselective total synthesis of
(þ)-crassalctone D, a naturally occurring styryl lactone
possessing remarkable in vitro antitumor activity against
mammalian cancer cell lines.
To invert the 7-OH in 7-epi-crassalactone D (14), a
Mitsunobu reaction of 14 with trifluoroacetic acid in the
(13) Our optical rotation value [R]20D is slightly greater than the data for
D
(12) (a) Varasi, M.; Walker, K. A. M.; Maddox, M. L. J. Org. Chem.
1987, 52, 4235–4238. (b) Stork, G.; West, F.; Lee, H. Y.; Isaacs, R. C. A.;
Manabe, S. J. Am. Chem. Soc. 1996, 118, 10660–10661.
[R]30 reported in ref 1. A similar result was obtained for synthetic (þ)-
crassalactone C reported in ref 2a.
(14) See the Supporting Information for more details.
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Yang et al.
JOCNote
chromatography (silica, 0-50% ethyl acetate/hexanes) to
afford diol 11 (270 mg, 89%) as a white solid: mp 60-61 °C;
D
[R]20 þ7.5 (c 1.0, CH3OH); IR (KBr) νmax 3431, 3262, 3146,
3116, 3060, 3026, 2996, 2904, 1603, 1510, 1448, 1323, 1098, 1070,
1003, 932 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.30-7.41 (m,
6H), 6.30 (dd, J=5.0, 2.0 Hz, 1H), 6.11 (dd, J=3.0, 1.0 Hz, 1H),
4.55 (dd, J=6.0, 3.0 Hz, 1H), 4.01-4.05 (m, 1H), 2.72-2.81 (m,
3H), 2.43 (d, J=4.0 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ
154.4, 143.4, 142.2, 129.2 (2C), 128.6, 128.1 (2C), 111.2, 107.6,
77.6, 75.4, 33.0; APCI MS m/z 219 [M þ H]þ; HRMS calcd
for C13H15O3 [M þ H]þ: 219.1021, found: 219.1021; chiral
HPLC >99% ee.
(5S,7R,8R)-7-Phenyl-1,6-dioxaspiro[4.4]non-3-ene-2,8-diol (12).
To a solution of furan 11 (250 mg, 1.15 mmol) in dichloromethane
(5 mL) at 0 °C under nitrogen was added m-CPBA (77%, 336 mg,
1.50 mmol) in portions. The mixture was stirred under nitrogen for
3 h. After this time, the reaction mixture was diluted with ethyl
acetate (50 mL), washed with a saturated solution of sodium
carbonate (2 ꢀ 10 mL) and brine (20 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (silica,
0-100% ethyl acetate/hexanes) to give a mixture of lactols 12
and 13 as a white solid. The material was dissolved in dichloro-
methane (10 mL), and the solvent was slowly evaporated over a
period of 3 days to provide a mixture of 12 and 13 (180 mg, 67%) in
a ratio of 10:1. Analytical data for 12: IR (KBr) νmax 3410, 3060,
2943, 1498, 1440, 1409, 1277, 1140, 1092, 988, 961, 805 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.30-7.43 (m, 5H), 6.26 (d, J=5.5 Hz,
1H), 6.10 (d, J=5.5 Hz, 1H), 5.83 (d, J=9.0 Hz, 1H), 5.33 (d, J=
3.0 Hz, 1H), 4.50 (m, 1H), 2.92 (d, J=10.0 Hz, 1H), 2.60 (dd, J=
14.5, 5.5 Hz, 1H), 2.39 (dd, J=14.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 135.5, 134.2, 131.2, 128.7 (2C), 128.3, 126.8 (2C), 116.7,
101.2, 84.9, 74.2, 44.1; ESI MS m/z 257 [M þ Na]þ; ESI MS m/z
233 [M - H]-; HRMS calcd for C13H14O4Na [M þ Na]þ
257.0790, found 257.0785.
FIGURE 2. Key NOE correlations in 12, 14, 15, 16, and 17.
Experimental Section
(þ)-7-epi-Crassalactone D (14) and 5-epi-7-epi-crassalac-
tone D (15). To a mixture of lactols 12 and 13 (120 mg, 0.51
2-Cinnamylfuran (9). To a solution of furan (1.40 g, 20.6
mmol) in anhydrous THF (20 mL) at -50 °C under nitrogen was
added dropwise tert-butyllithium (1.7 M in pentane, 9.67 mL,
16.4 mmol). The mixture was allowed to warm to 0 °C and
stirred under nitrogen for 3 h. After this time, the mixture was
again cooled to -50 °C. Bromide 10 (2.70 g, 13.7 mmol) in THF
(10 mL) was added dropwise. The reaction mixture was slowly
warmed to -5 °C and then quenched with a saturated solution
of ammonium chloride. The organic layer was separated and the
aqueous layer was extracted with diethyl ether (2 ꢀ 50 mL). The
combined organic extracts were washed with brine (20 mL),
dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica, 0-5% ethyl acetate/hexanes) to give
˚
mmol), 3 A molecular sieves (100 mg), and DMF (2 mL) at 0 °C
under nitrogen was added PDC (290 mg, 0.77 mmol). The
mixture was stirred under nitrogen at 0 °C for 4 h. After this
time, the reaction mixture was diluted with ethyl acetate
(40 mL), washed with water (2 ꢀ 20 mL) and brine (20 mL),
dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica, 0-80% ethyl acetate/hexanes) to give
lactone 14 (88 mg, 74%) as a white solid and lactone 15 (8 mg,
7%) as a white solid. Analytical data for 14: mp 130-132 °C;
[R]20 -64.5 (c 0.3, EtOH); IR (KBr) νmax 3489, 3388, 3140,
D
2910, 1764, 1612, 1499, 1457, 1408, 1338, 1286, 1178, 1077, 1016,
1
914 cm-1; H NMR (500 MHz, CDCl3) δ 7.35-7.44 (m, 6H),
6.15 (d, J=5.5 Hz, 1H), 5.43 (d, J=2.5 Hz, 1H), 4.62-4.64 (m,
1H), 2.82 (dd, J=15.0, 5.0 Hz, 1H), 2.54 (d, J=15.0 Hz, 1H),
1.34 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 170.0, 152.9,
134.2, 128.8 (2C), 128.7, 126.7 (2C), 122.8, 113.7, 86.5, 73.8,
43.2; ESI MS m/z 233 [M þ H]þ; HRMS calcd for C13H13O4 [M
þ H]þ 233.0814, found 233.0812. Analytical data for 15: mp
1
furan 9 (1.83 g, 73%) as a colorless oil: H NMR (300 MHz,
CDCl3) δ 7.00-7.38 (m, 6H), 6.49 (d, J = 15.9 Hz, 1H),
6.25-6.35 (m, 2H), 6.07 (dd, J = 3.0, 1.0 Hz, 1H), 3.55 (d,
J=6.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 153.9, 141.4,
137.3, 132.1, 128.6 (2C), 127.4, 126.3 (2C), 125.6, 110.4, 105.7,
31.8; ESI MS m/z 185 [M þ H]þ.
151-154 °C; [R]20 -48.2 (c 0.2, EtOH); IR (KBr) νmax 3417,
D
(1R,2R)-3-(Furan-2-yl)-1-phenylpropane-1,2-diol (11). To a
mixture of AD-mix-β (1.96 g), methanesulfonamide (0.134 g,
1.40 mmol), tert-butanol (7 mL), and water (7 mL) at 0 °C was
added 2-cinnamylfuran (9, 0.259 g, 1.40 mmol), then the reac-
tion mixture was stirred vigorously at 0 °C for 24 h. After this
time, the reaction mixture was quenched with 1 N sodium sulfite
(1 mL) and stirred for 1 h at room temperature. The mixture was
then extracted with methylene chloride (3 ꢀ 10 mL). The
combined organic extracts were washed with 2 N potassium
hydroxide solution, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by column
3106, 3080, 2918, 1732, 1605, 1495, 1448, 1420, 1325, 1197, 1107,
1026, 930 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.33-7.41 (m,
5H), 7.20 (d, J=6.0 Hz, 1H), 6.24 (d, J=6.0 Hz, 1H), 5.39 (d, J=
4.0 Hz, 1H), 4.57-4.60 (m, 1H), 2.64 (dd, J=14.0, 5.0 Hz, 1H),
2.54 (d, J=14.0 Hz, 1H), 1.99 (d, J=8.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 169.2, 151.7, 135.2, 128.6 (2C), 128.4,
126.7 (2C), 124.5, 114.1, 88.9, 72.9, 44.3; ESI MS m/z 233
[M þ H]þ; HRMS calcd for C13H13O4 [M þ H]þ 233.0814,
found 233.0813.
(þ)-Crassalactone D (4). To a solution of lactone 14 (60 mg,
0.26 mmol) in THF (1 mL) at room temperature under nitrogen
9548 J. Org. Chem. Vol. 74, No. 24, 2009

Yang et al.
JOCNote
was added diethyl azodicarboxylate (54 mg, 0.31 mmol), fol-
lowed by trifluoroacetic acid (36 mg, 0.31 mmol) and triphenyl-
phosphine (81 mg, 0.31 mmol). The mixture was stirred under
nitrogen for 5 min and sodium benzoate (45 mg, 0.31 mmol) was
added. The reaction mixture was stirred at room temperature
for 2 h and then at 50 °C for 20 h. After this time, the reaction
mixture was cooled to room temperature, diluted with ethyl
acetate (40 mL), washed with a saturated solution of sodium
bicarbonate (20 mL) and brine (20 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pres-
sure. The residue was purified by column chromatography
(silica 0-50% ethyl acetate/hexanes) to give lactone 14 (24
mg) and (þ)-crassalactone D (4, 21 mg, 35%) as a white solid:
mp 138-140 °C; [R]20D þ13.6 (c 0.2, EtOH) {lit.1 mp 138-139
°C; [R]30D þ7.0 (c 0.2, EtOH)}; 1H NMR (500 MHz, CDCl3) δ
7.37-7.41 (m, 2H), 7.31-7.34 (m, 3H), 7.29 (d, J = 5.5 Hz,
1H), 6.28 (d, J=5.5 Hz, 1H), 5.40 (d, J=2.0 Hz, 1H), 4.42 (dt,
J=6.0, 1.5, 1.5 Hz, 1H), 2.74 (br s, 1H), 2.56 (dd, J=14.0, 6.5 Hz,
1H), 2.30 (dd, J = 14.0, 1.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 168.9, 150.9, 138.4, 128.7 (2C), 128.2,
125.0 (2C), 124.9, 114.3, 91.5, 78.2, 42.4; ESI MS m/z 233
[M þ H]þ; HRMS calcd for C13H13O4 [M þ H]þ 233.0814,
found 233.0817.
Acknowledgment. The authors thank Dr. Keith Barnes
for helpful discussion. The Analytical Department at AMRI
has performed IR, HRMS, and ee value determination.
Supporting Information Available: Crystallographic data of
compound 4, experimental procedures for (()-11, 1H NMR
1
spectra for compound 12, and H and 13C NMR spectra for
compounds 11, 14, 15, and 4. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 24, 2009 9549