Total synthesis of (-)-5,6-dihydrocineromycin B

Article abstract of DOI:10.1021/jo802503x

An asymmetric total synthesis of (-)-5,6-dihydrocineromycin B has been accomplished in 13 steps from (-)-linalool O-triethylsilyl ether or 12 steps from geraniol. The present synthesis features (i) an intermolecular Wittig reaction involving an aldehyde possessing a ketophosphonate functionality and (ii) an intramolecular Horner-Wadsworth-Emmons olefination.

Full text of DOI:10.1021/jo802503x

SCHEME 1. Synthetic Strategy for 5,6-Dihydrocineromycin B
Total Synthesis of (-)-5,6-Dihydrocineromycin B
Guozhi Li,† Xiaoxia Yang,†,§ and Hongbin Zhai*,†,‡
Laboratory of Modern Synthetic Organic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China, and The State Key
Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking UniVersity,
38 College Road, Beijing 100083, China
zhaih@mail.sioc.ac.cn
ReceiVed NoVember 13, 2008
SCHEME 2. Synthesis of Alcohol 9
An asymmetric total synthesis of (-)-5,6-dihydrocineromycin
B has been accomplished in 13 steps from (-)-linalool
O-triethylsilyl ether or 12 steps from geraniol. The present
synthesis features (i) an intermolecular Wittig reaction
involving an aldehyde possessing a ketophosphonate func-
tionality and (ii) an intramolecular Horner-Wadsworth-
Emmons olefination.
synthetic strategy for assembling 1 would rely on the combina-
tion of four components: geraniol (2), (-)-linalool (3), phos-
phonate 4, and ylide 5. The addition of R-deprotonated
phosphonate to aldehyde, Wittig reaction, esterification, and
intramolecular Horner-Wadsworth-Emmons (HWE) olefina-
tion can serve as key reactions to connect the above four
substances.
Our synthesis commenced from elaboration of geraniol (2),
which was transformed into the known chiral vicinal diol 6 via
Sharpless asymmetric epoxidation3 (TBHP, L-(+)-DIPT, Ti(O-
iPr)4, molecular sieves, CH2Cl2) followed by regio- and stereo-
selective reductive ring opening4 (NaBH3CN, BF3 ·Et2O, THF)
according to the documented procedures (Scheme 2). Selective
tosylation of the primary hydroxyl (TsCl, Et3N, DMAP, CH2Cl2,
86%) followed by reductive cleavage5 (LiAlH4, THF, 90%) of
the sulfonate led to the formation of alcohol 8 in high overall
yield. Configuration inversion of the hydroxyl-bearing stereo-
center in 8 was realized via sequential Mitsunobu esterification6
(p-O2N-C6H4CO2H, PPh3, DIAD, THF) and methanolysis in
the presence of KOH; the key intermediate, 9, was thus obtained
in 78% yield over two steps from 8.
5,6-Dihydrocineromycin B (1),1a together with cineromycin
B and some other secondary metabolites, was isolated by Zeeck
et al. in 1999 from Streptomyces sp. (strain Go¨ 40/10).1b The
structural features of the macrolide antibiotic include four
stereogenic centers, two carbon-carbon double bonds, two
hydroxyls, and an ester functionality embedded on a 14-
membered macrocycle. Owing to their antibiotic activity against
staphylococci, cineromycins and albocyclins have become
alluring targets for total synthesis.2 However, only one total
synthesis of 5,6-dihydrocineromycin B has been published so
far.2a Herein we report a novel asymmetric synthesis of 5,6-
dihydrocineromycin B (1). As outlined in Scheme 1, our
† Shanaghai Institute of Organic Chemistry.
‡ Peking University.
§ Current address: Unilever Research China, 3/F, Xinmao Building, 99
Tianzhou Road, Shanghai 200233, China.
(1) (a) Schiewe, H. J.; Zeeck, A. J. Antibiot. 1999, 52, 635. (b) As reported
by Zeeck et al.,1a the isolated sample of dihydrocineromycin B had an optical
rotation ([R]20D) of +10 (c 0.1, MeOH) corresponding to the proposed
structure of 1 (Scheme 1). In contrast, we found that the optical rotation
data for the structure 1 had a negative sign after its total synthesis was
completed (see text).
(2) (a) For synthesis of 5,6-dihydrocineromycin B, see: Tietze, L. F.; Vo¨lkel,
L. Angew. Chem., Int. Ed. 2001, 40, 901. (b) For synthesis of ingramycin, see:
Tanner, D.; Somfai, P. Tetrahedron 1987, 43, 4395. (c) For synthesis of
cineromycin B, see: Takahashi, T.; Watanabe, H.; Kitahara, T. Tetrahedron Lett.
2003, 44, 9219.
In the meantime, (-)-linalool (3) was converted to triethylsilyl
(TES) ether 107 (Scheme 3). A two-step sequence, comprising
(3) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
(4) Taber, D. F.; Home1, J. B. J. Org. Chem. 1994, 59, 4004.
1356 J. Org. Chem. 2009, 74, 1356–1359
10.1021/jo802503x CCC: $40.75 2009 American Chemical Society
Published on Web 12/30/2008

SCHEME 3. Synthesis of (-)-Dihydrocineromycin B (1) and Its Epimer 7-epi-1
(i) chemoselective dihydroxylation8 of the more electron-rich
carbon-carbon double bond (OsO4, K3Fe(CN)6, K2CO3,
MeSO2NH2, tBuOH, H2O) and (ii) vicinal diol cleavage (NaIO4,
H2O, Me2CO), furnished aldehyde 11 in good yield (78%).
Ketophosphonates 12 (dr ) 1:1) were prepared in 78% yield
over two steps through addition9 of R-deprotonated phosphonate
4 to aldehyde 11 followed by oxidation10 of the resultant alcohol
with IBX in refluxing EtOAc. Ozonolysis of 12 provided
aldehyde 13 (69%), which, after being subjected to Wittig
reaction with ylide 5 in toluene at 80 °C overnight, was
transformed into 14, an unsaturated methyl ester (73%).
Apparently, the potential tandem intermolecular proton transfer/
intramolecular HWE olefination process was not favored since
only a little cyclohexenone derivative was formed.11 Further-
more, oligomerization or polymerization did not seem to take
place to an appreciable extent under the reaction conditions.
Next, saponification of 14 with LiOH in THF-H2O (1:1)
afforded, after an acidic workup, carboxylic acid 15 in 90%
yield; the latter was subsequently coupled with alcohol 9 (DCC,
DMAP, CH2Cl2)12 to furnish ester 16 in 65% yield. The trialkyl-
substituted olefin moiety was then chemoselectively cleaved to
give 17 in good yield (85%) over two steps {(i) OsO4, NMO,
MeSO2NH2, Me2CO, H2O;8 (ii) NaIO4, Me2CO, H2O}. The next
step was to perform an intramolecular HWE olefination. Indeed,
exposure of 17 to DIPEA and LiCl13 in acetonitrile effected
the desired HWE reaction, which formed macrocycle 18 in
moderate yield (65%).
With 18 in hand, the remaining tasks were to stereoselectively
reduce14 the carbonyl functionality of the enone moiety and
remove the silyl protecting group. Several reduction methods
were examined without success. For instance, Luche reduction15
gave exclusively 19 (in 80% yield), in which the stereochemical
configuration at C-7 was opposite to that of the target molecule.
The stereocontrol observed in this reaction might arise from
the macrocyclic conformation of 18. Mitsunobu reaction
(p-O2N-C6H4CO2H, PPh3, DIAD, THF, 0 °C then rt) of allylic
alcohol 19 followed by methanolysis (K2CO3, MeOH, rt) failed
to give 20 because the first step involved an SN2′ rather than
SN2 reaction. In addition, the Corey-Bakshi-Shibata (CBS)
reduction protocol16 proved to be unfruitful on this particular
substrate. However, treatment17 of 18 with (S)-BINAL-H18
(prepared from LiAIH4, (S)-BINOL and EtOH, in a 1:1:1 ratio)
in THF at -100 to -78 °C provided the anticipated alcohol 20
(63%) together with 19 (25%), which could either be oxidized10
to regenerate enone 18 (IBX, EtOAc, reflux, 95%) for the
recycling purpose or be converted to 7-epi-1 (87%) after
desilylation2c with TBAF in THF. Finally, desilylation2c of 20
(10) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(11) To the best of our knowledge, this represents the first example of a
successful intermolecular Wittig reaction involving an aldehyde possessing a
ketophosphonate functionality. For an example of intermolecular HWE reaction
involving an aldehyde possessing a ketophosphonate functionality, see: Hosoka-
wa, S.; Seki, M.; Fukuda, H.; Tatsuta, K. Tetrahedron Lett. 2006, 47, 2439.
(12) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
(13) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(14) For reduction of macrocyclic ketones, see: (a) Keller, T. H.; Neeland,
E. G.; Rettig, S.; Trotter, J.; Weiler, L. J. Am. Chem. Soc. 1988, 110, 7858. (b)
Keller, T. H.; Weiler, L. J. Am. Chem. Soc. 1990, 112, 450.
(5) Li, W.-G.; Zhang, Z.-G.; Xiao, D.-M.; Zhang, X.-M. J. Org. Chem. 2000,
65, 3489.
(6) Mitsunobu, O. Synthesis 1981, 1–28.
(15) Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1981, 103, 5454.
(16) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am.
Chem. Soc. 1987, 109, 7925.
(7) Ikawa, T.; Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2004, 60, 6901.
(8) 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.-Q.; Zhang,
X.-L. J. Org. Chem. 1992, 57, 2768.
(17) The reaction was performed by following Tietze’s protocol.2a
(18) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6717.
(9) Richardson, T. I.; Rychnovsky, S. D. Tetrahedron 1999, 55, 8977.
J. Org. Chem. Vol. 74, No. 3, 2009 1357

7.5 Hz, 3H), 0.61 (q, J ) 7.5 Hz, 3H), 0.93 (t, J ) 7.5 Hz, 4.5H),
0.94 (t, J ) 7.5 Hz, 4.5H), 0.96 (d, J ) 8.1 Hz, 1.5H), 0.97 (d, J
) 7.8 Hz, 1.5H) 1.21 (d, J ) 6.3 Hz, 3H), 1.32-1.37 (m, 3H),
1.31 (t, J ) 6.9 Hz, 6H), 1.38 (d, J ) 0.9 Hz, 3H), 1.60-1.64 (m,
2H), 1.78-1.87 (m, 3H), 2.41-2.94 (m, 4H), 3.12-3.27 (m, 1H),
4.06-4.16 (m, 4H), 4.83-4.91 (m, 1H), 5.93 (d, J ) 15.6 Hz,
1H), 6.80 (d, J ) 15.6 Hz, 0.5H), 6.82 (d, J ) 15.6 Hz, 0.5H) 9.78
(t, J ) 1.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 6.4 (3C), 6.9
(3C), 10.8 (0.5C), 10.9 (0.5C), 14.5 (1C), 16.1 (1C), 16.2 (1C),
16.2 (1C), 24.3 (1C), 27.7 (0.5C), 27.8 (0.5C), 36.1 (1C), 36.2 (1C),
36.8 (1C), 37.7 (0.5C), 37.8 (0.5C), 41.4 (1C), 46.5 (d, J ) 126.5
Hz, 1C), 62.3-62.5 (m, 2C), 73.7 (1C), 74.3 (1C), 119.2 (0.5C),
119.3 (0.5C), 153.9 (0.5C), 154.0 (0.5C), 166.0 (1C), 202.1 (1C),
205.5 (1C); ESI-MS m/z 617 (M + MeOH + Na), 585 (M + Na);
ESI-HRMS calcd for C27H51O8SiPNa 585.2989, found 585.2983.
Compound 18. (a) Prepared by HWE of 17. To a solution of
17 (60 mg, 0.11 mmol) in CH3CN (117 mL) were added LiCl (75
mg, 1.8 mmol) and DIPEA (0.30 mL, 1.7 mmol). The mixture was
stirred overnight and diluted with water. After CH3CN was removed
under reduced pressure, the residue was extracted with EtOAc. The
combined organic layers were dried (MgSO4), filtered, and con-
centrated. The residue was purified by flash chromatography to give
under the same conditions used for 19 produced in 77% yield
5,6-dihydrocineromycin B (1) as a colorless solid {mp 143-146
°C; lit.1a 145-155 °C}. The structure of 1 was unambiguously
confirmed by X-ray crystallographic analysis, while the 1H and
13C NMR spectroscopic data essentially match those disclosed
in the literature1a (see the Supporting Information). However,
the optical rotation data of 1 determined in two different solvents
{[R]23 -72.5 (c 0.1, MeOH); [R]25 -95.5 (c 0.15, CHCl3)}
D
D
were opposite in sign to and prominently different in magnitude
from that reported by Zeeck1a {[R]20 +10 (c 0.1, MeOH)}.
D
In summary, a concise asymmetric total synthesis of (-)-
dihydrocineromycin B (1) has been accomplished in 13 steps
(in 3.6% overall yield, without considering recycling of 19) from
(-)-linalool O-TES ether. The present synthesis features (i) an
intermolecular Wittig reaction involving an aldehyde possessing
a ketophosphonate functionality and (ii) an intramolecular HWE
olefination. The strategy opens a practically viable way to
construct a series of medicinally attractive cineromycin analogues.
Experimental Section
18 (28.5 mg, 65%) as a colorless oil: [R]24.3 -53.48 (c 0.746,
D
CHCl3); IR (film) ν 2956, 2876, 1716, 1664, 1456, 1283, 1256,
The synthesis, purification, and analytical data of the intermedi-
ates 7-9 and 11-15 are described in the Supporting Information.
Compound 16. To a solution of alcohol 9 (688 mg, 4.40 mmol)
and acid 15 (2.38 g, 5.28 mmol) in CH2Cl2 (20 mL) at 0 °C were
added DCC (1.80 g, 8.72 mmol) and DMAP (54 mg, 0.44 mmol).
The mixture was stirred for 5 h. After filtration and evaporation of
the solvent, the residue was purified by flash chromatography to
give 16 (1.68 g, 65%) as a colorless oil: IR (film) ν 2960, 2936,
2877, 1717, 1456, 1378, 1256, 1162, 1108, 1050, 1023, 964, 744;
1H NMR (CDCl3, 300 MHz) δ 0.60 (q, J ) 7.5 Hz, 3H), 0.61 (q,
J ) 7.5 Hz, 3H), 0.92 (t, J ) 7.5 Hz, 9H), 0.96 (d, J ) 10.8 Hz,
1.5H), 0.97 (d, J ) 10.5 Hz, 1.5H), 1.10-1.20 (m, 1H), 1.18 (d, J
) 6.3 Hz, 3H), 1.31 (t, J ) 6.6 Hz, 6H), 1.38 (s, 3H), 1.35-1.39
(m, 3H), 1.63-1.66 (m, 2H), 1.60 (s, 3H), 1.68 (s, 3H), 1.82-2.07
(m, 4H), 2.44-2.94 (m, 2H), 3.11-3.27 (m, 1H), 4.06-4.16 (m,
4H), 4.84-4.93 (m, 1H), 5.09 (t, J ) 6.9 Hz, 1H), 5.92 (d, J )
15.3 Hz, 1H), 6.80 (d, J ) 15.6 Hz, 0.5H), 6.81 (d, J ) 15.6 Hz,
0.5H); 13C NMR (CDCl3, 100 MHz) δ 6.6 (3C), 7.0 (3C), 10.9
(0.5C), 11.0 (0.5C), 14.4 (1C), 15.8 (0.5C), 15.8 (0.5C), 16.3 (1C),
16.3 (1C), 17.6 (1C), 25.4 (1C), 25.6 (1C), 27.7 (0.5C), 27.8 (0.5C),
32.6 (1C), 36.3 (0.5C), 36.4 (0.5C), 36.9 (1C), 37.8 (0.5C), 37.9
(0.5C), 46.7 (d, J ) 126.4 Hz, 1C), 62.4-62.5 (m, 2C), 74.2 (1C),
74.3 (0.5C), 74.3 (0.5C), 119.7 (0.5C), 119.8 (0.5C), 124.3 (1C),
131.5 (1C), 153.5 (0.5C), 153.6 (0.5C), 166.1 (0.5C), 166.2 (0.5C),
205.6 (0.5C), 205.6 (0.5C); ESI-MS m/z 611 (M + Na); ESI-HRMS
calcd for C30H57O7SiPNa 611.3509, found 611.3503.
Compound 17. To a mixture of 16 (943 mg, 1.60 mmol), acetone
(16 mL), and water (2 mL) were added OsO4 (4% in water, 1 mL,
0.16 mmol), NMO (50% in water, 0.50 mL, 2.4 mmol), and
MeSO2NH2 (152 mg, 1.60 mmol). The mixture was stirred until
the color turned light yellow. Then saturated aqueous Na2SO3
solution was added, and the stirring was continued for 30 min. After
the acetone was removed, the mixture was extracted with EtOAc.
The combined organic layers were dried (Na2SO4), filtered, and
concentrated to give a crude diol, which was used directly in the
next step without further purification.
The above crude diol was dissolved in acetone (10 mL), and
NaIO4 (680 mg, 3.18 mmol) was added. Then water was added
dropwise until NaIO4 was dissolved completely. The resultant
mixture was stirred for 1 h and quenched with saturated aqueous
Na2S2O3 solution. After removing acetone under reduced pressure,
the aqueous layer was extracted with EtOAc. The combined organic
layers were dried (MgSO4), filtered, and concentrated. The residue
was purified by flash chromatography to give 17 (770 mg, 85%)
as a colorless oil: IR (film) ν 2958, 2877, 1718, 1458, 1378, 1255,
1162, 1021, 965, 744; 1H NMR (CDCl3, 300 MHz) δ 0.60 (q, J )
1
1159, 1107, 1005, 744; H NMR (CDCl3, 300 MHz) δ 0.63 (q, J
) 7.5 Hz, 6H), 0.95 (d, J ) 6.9 Hz, 3H), 0.97 (t, J ) 7.5 Hz, 9H),
1.22 (d, J ) 6.0 Hz, 3H), 1.36 (s, 3H), 1.41-1.52 (m, 3H), 1.75
(s, 3H), 1.97-2.30 (m, 5H), 2.85-2.95 (m, 1H), 4.65-4.75 (m,
1H), 6.05 (d, J ) 15.3 Hz, 1H), 6.62 (t, J ) 7.2 Hz, 1H), 6.66 (d,
J ) 15.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 6.6, 7.0, 11.9,
17.5, 18.7, 26.7, 27.9, 31.6, 33.5, 38.8, 39.0, 75.2, 75.6, 120.5,
136.4, 143.7, 153.6, 165.8, 203.5; ESI-MS m/z 431 (M + Na); ESI-
HRMS calcd for C23H40O4SiNa 431.2594, found 431.2588.
(b) Prepared by Oxidation of 19. To a solution of 19 (35 mg,
0.085 mmol) in EtOAc (5 mL) was added IBX (104 mg, 0.371
mmol), and the reaction was refluxed for 4 h. After filtration through
Celite, the filtrate was concentrated under reduced pressure and
the residue was purified by flash chromatography to give 18 (33
mg, 95%) as a colorless oil.
Compounds 19 and 20 (Prepared by Reduction with (S)-
BINAL-H). A solution of compound 18 (26.0 mg, 0.0636 mmol)
in THF (1 mL) was treated at -100 °C for 1 h and at -78 °C for
2 h with (S)-BINAL-H, which was prepared from LiAIH4 (95%,
15.2 mg, 0.380 mmol), ethanol (22.2 µL, 0.380 mmol), and (S)-
BINOL (108 mg, 0.377 mmol) in THF (1 mL) at rt. The mixture
was quenched with methanol, warmed to rt, and diluted with EtOAc.
After evaporation of the solvents, the residue was purified by
column chromatography to give 19 (6.6 mg, 25%) and 20 (16.4
mg, 63%) as colorless oils.
Compound 19: [R]22.4 -49.91 (c 0.985, CHCl3); IR (film) ν
D
3456, 2955, 2876, 1714, 1459, 1376, 1259, 1156, 1107, 1047, 1008,
725; 1H NMR (CDCl3, 300 MHz) δ 0.61 (q, J ) 8.1 Hz, 6H), 0.93
(d, J ) 6.6 Hz, 3H), 0.96 (t, J ) 8.1 Hz, 9H), 1.29 (d, J ) 6.0 Hz,
3H), 1.33 (s, 3H), 1.41-1.52 (m, 2H), 1.56 (s, 3H), 1.64-2.11
(m, 7H), 3.96 (m, 1H), 4.53-4.62 (m, 1H), 5.43 (t, J ) 6.9 Hz,
1H), 5.87 (d, J ) 15.0 Hz, 1H), 6.92 (d, J ) 15.3 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 6.7, 7.0, 14.9, 16.6, 19.1, 22.9, 27.2,
29.7, 33.1, 37.9, 39.0, 74.7, 75.0, 75.1, 118.2, 126.7, 136.1, 155.5,
166.5; ESI-MS m/z 433 (M + Na), 393 (M - OH); ESI-HRMS
calcd for C23H42O4SiNa 433.2750, found 433.2753.
Compound 20: [R]22.2 -71.57 (c 0.810, CHCl3), IR (film) ν
D
3456, 2956, 2876, 1713, 1648, 1458, 1376, 1296, 1258, 1163,
1
1107,1043, 1010, 743, 725; H NMR (CDCl3, 300 MHz) δ 0.59
(q, J ) 7.8 Hz, 6H), 0.92 (d, J ) 6.9 Hz, 3H), 0.94 (t, J ) 7.8 Hz,
9H), 1.28 (d, J ) 6.3 Hz, 3H), 1.33 (s, 3H), 1.36-1.44 (m, 2H),
1.49 (s, 3H), 1.54-1.60 (m, 1H), 1.66-2.06 (m, 6H), 3.86 (dd, J
) 5.7, 4.2 Hz, 1H), 4.53-4.63 (m, 1H), 5.41 (dd, J ) 9.6, 1.2 Hz,
1H), 5.90 (d, J ) 15.0 Hz, 1H), 6.66 (d, J ) 15.3 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 6.6, 7.0, 11.1, 17.0, 19.1, 23.0, 28.5,
1358 J. Org. Chem. Vol. 74, No. 3, 2009

29.0, 32.9, 38.1, 39.8, 74.8, 75.3, 80.3, 119.0, 128.4, 135.4, 154.6,
166.4; ESI-MS m/z 433 (M + Na), 393 (M - OH); ESI-HRMS
calcd for C23H42O4SiNa 433.2750, found 433.2746.
319 (M + Na), 279 (M - OH); ESI-HRMS calcd for C17H28O4Na
319.1885, found 319.1879.
Compound 7-epi-1. To a solution of 19 (27 mg, 0.066 mmol)
in THF (1 mL) was added TBAF (1 M in THF, 80 µL, 0.080 mmol)
at 25 °C. The mixture was stirred for 30 min and diluted with water.
The two layers were separated, and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed with brine,
dried (Na2SO4), filtered, and concentrated. The residue was purified
by flash chromatography to give 7-epi-1 (17 mg, 87%) as a colorless
oil: [R]24.6D -47.2 (c 0.186, CHCl3) {lit: [R]20D -46 ( 1 (c 0.195,
CHCl3)}; IR (film) ν 3411, 2933, 2876, 1699, 1651, 1644, 1456,
Compound 19 (Prepared by Luche Reduction). To a solution
of 18 (50 mg, 0.12 mmol) in MeOH (2 mL) and CH2Cl2 (1 mL) at
0 °C were added CeCl3 ·7H2O (68 mg, 0.18 mmol) and NaBH4
(6.4 mg, 0.17 mmol). The mixture was stirred at this temperature
for 15 min and diluted with EtOAc and water. The two layers were
separated, and the organic layer was washed successfully with water
and brine, dried (Na2SO4), filtered, and concentrated. The residue
was purified by flash chromatography to give 19 (40 mg, 80%) as
a colorless oil.
1
1379, 1269, 1150, 1105, 1044, 983, 732; H NMR (CDCl3, 300
MHz) δ 0.94 (d, J ) 6.9 Hz, 3H), 1.29 (d, J ) 6.0 Hz, 3H), 1.33
(s, 3H), 1.38-1.52 (m, 2H), 1.60 (s, 3H), 1.68-1.78 (m, 3H),
1.82-1.96 (m, 3H), 2.01-2.18 (m, 1H), 3.92-3.99 (m, 1H),
4.53-4.64 (m, 1H), 5.43-5.52 (m, 1H), 5.91 (d, J ) 15.6 Hz,
1H), 7.07 (d, J ) 15.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
15.2, 16.6, 19.1, 23.4, 27.0, 30.1, 33.3, 37.6, 39.1, 72.9, 75.2, 75.3,
118.2, 127.1, 136.2, 154.4, 166.3; ESI-MS m/z 319 (M + Na); ESI-
HRMS calcd for C17H28O4Na 319.1885, found 319.1882.
Compound 1. To a solution of 20 (34 mg, 0.083 mmol) in THF
(1 mL) was added TBAF (1 M in THF, 110 µL, 0.110 mmol) at
25 °C. The mixture was stirred for 30 min and diluted with water.
The two layers were separated, and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed with brine,
dried (Na2SO4), filtered, and concentrated. The residue was purified
by flash chromatography to give 1 (19 mg, 77%) as a colorless
solid: mp 143-146 °C (hexanes-CH2Cl2) (lit: 145-155 °C); [R]23
D
-72.5 (c 0.1, MeOH), [R]25 -95.5 (c 0.15, CHCl3) {lit: [R]20
D
D
+10 (c 0.1, MeOH), [R]20D +53 ( 1 (c 0.178, CHCl3)}; IR (film)
ν 3421, 2929, 1698, 1645, 1456, 1377, 1268, 1153, 1104, 1042,
Acknowledgment. Financial support was provided by the
grants from NSFC (90713007; 20772141; 20625204; 20632030)
and MOST_863 (2006AA09Z405; 2006AA09Z446).
1
984; H NMR (CDCl3, 300 MHz) δ 0.94 (d, J ) 6.9 Hz, 3H),
1.25-1.32 (m, 1H), 1.30 (d, J ) 6.3 Hz, 3H), 1.35 (s, 3H),
1.37-1.45 (m, 1H), 1.54 (s, 3H), 1.57-1.61 (m, 1H), 1.67-1.73
(m, 2H), 1.75-1.89 (m, 3H), 2.02-2.16 (m, 1H), 3.98 (t, J ) 6.0
Hz, 1H), 4.51-4.60 (m, 1H), 5.51 (dd, J ) 9.9, 2.7 Hz, 1H), 5.95
(d, J ) 15.9 Hz, 1H), 6.84 (d, J ) 15.6 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 11.1, 17.2, 19.0, 23.8, 28.2, 29.3, 33.2, 38.1, 39.0,
73.1, 75.5, 79.6, 118.9, 128.8, 135.2, 153.8, 166.1; ESI-MS m/z
Supporting Information Available: Experimental proce-
1
dures, analytical data, and copies of H and 13C NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO802503X
J. Org. Chem. Vol. 74, No. 3, 2009 1359