Asymmetric total synthesis and revision of the absolute configuration of 4-keto-clonostachydiol

Article abstract of DOI:10.1021/jo900370a

(Chemical Equation Presented) The first total synthesis of the 14-membered natural macrocyclic bislactone 4-keto-clonostachydiol, along with its enantiomer, has been accomplished in 13 steps with overall yields of 8.4% and 8.0%, respectively. The absolute

Full text of DOI:10.1021/jo900370a

Asymmetric Total Synthesis and Revision of the
Absolute Configuration of 4-Keto-Clonostachydiol
Junjie Han,† Yingpeng Su,† Tuo Jiang,† Yanfen Xu,†
Xing Huo,† Xuegong She,*,†,‡ and Xinfu Pan†
Department of Chemistry, State Key Laboratory of Applied
Organic Chemistry, Lanzhou UniVersity, Lanzhou 730000,
People’s Republic of China, and State Key Laboratory for
Oxo Synthesis and SelectiVe Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou
730000, People’s Republic of China
FIGURE 1. Structure of 4-Keto-Clonostachydiol (1) and Clonostachy-
diol (2).
SCHEME 1. Retrosythetic Analysis of 4-Keto-Clonostachy-
diol 1
shexg@lzu.edu.cn
ReceiVed February 18, 2009
SCHEME 2. Synthesis of Enoate Alcohol 5
The first total synthesis of the 14-membered natural macrocyclic
bislactone 4-keto-clonostachydiol, along with its enantiomer,
has been accomplished in 13 steps with overall yields of 8.4%
and 8.0%, respectively. The absolute configuration of 4-keto-
clonostachydiol 1 has been revised as (5S,10S,13S).
4-Keto-clonostachydiol 1, a 14-membered nonsymmetric
macrocyclic bislactone, was first isolated from New Zealand
marine alga-derived fungus Gliocladium sp.1 4-Keto-clonostachy-
diol 1 exhibits various biological properties, such as strong
cytotoxicity against P388 cells (IC50 0.55 µM) and significant
activities against Bacillus subtilis, the fungi trichophyton
mentagrophytes, and cladosporium resinae. The originally
proposed stereochemistry of 1 was assigned as (5R,10R,13R)
based on the comparison of NMR spectra and optical rotation
of a known compound clonostachydiol 2, which was the Luche
reduction product of 1 (Figure 1).3,4 The structure of 1 has
recently been patented for its excellent cytotoxic and antibacte-
rial activities.2 Syntheses toward clonostachydiol 2 have been
reported by two individual groups.5,6 Herein we describe the
first asymmetric total synthesis of 4-keto-clonostachydiol from
commercially available chiral methyloxirane along with the
revision of the absolute configuration of 1 as (5S,10S,13S).
As outlined in Scheme 1, we envisioned that the lactone ring
of 4-keto-clonostachydiol 1 could be closed by an intramolecular
Yamaguchi lactonization reaction of dihydroxy acid 3, which
was assembled of carboxylic acid 4 and enoate alcohol 5 via
Mitsunobu reaction. The two stereocenters in acid 4 could easily
be established by Sharpless asymmetric dihydroxylation of the
corresponding diene while fragment 5 was prepared from (S)-
(+)-methyloxirane 6 and allyl magnesium bromide.
Synthesis of alcohol 5 began with commercially available
(S)-methyloxirane 6 (Scheme 2). Regioselective ring-opening
of epoxide 6 by allyl magnesium bromide in the presence of
† Lanzhou University.
‡ Chinese Academy of Sciences.
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Cummings, N. J.; Cole, A. L. J.; Munro, M. H. J. Nat. Prod. 2006, 69, 621–
624.
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3930 J. Org. Chem. 2009, 74, 3930–3932
10.1021/jo900370a CCC: $40.75 2009 American Chemical Society
Published on Web 04/21/2009

SCHEME 3. Synthesis of Acid 4
FIGURE 2. ∆δ values for the MTPA esters of 17 and 1a (∆δ ) δS - δR).
SCHEME 4. Synthesis of 4-Keto-Colonstachydiol 1
SCHEME 5. Synthesis of Fragments 5a and 4a
hydrolysis of the methyl ester group with LiOH in THF/H2O gave
dihydroxy acid 3, which underwent intramolecular ring closure by
using Yamaguchi’s protocol17 to afford 14-membered macrolide
16. Then PDC oxidation of 16, followed by deprotection of MOM
ether with TFA,18 gave the 4-keto-clonostachydiol 1, whose spectral
data (1H and 13C NMR) were in good agreement with the literature
(see the Supporting Information). The specific optical rotation of
synthetic 4-keto-clonostachydiol ([R]20 -76 (c 0.1, CH3OH)) is
D
quite different from that of the natural one ([R]20 +49 (c 0.33,
D
CH3OH)). To confirm our result and further determine the absolute
configuration, the modified Mosher’s method19 was adopted.
Removal of the MOM group in 16 with TFA afforded 4-epi-
clonostachydiol 17. Upon treatment of 17 with (R)- and (S)-
MTPACl [R-methoxy-R-(trifluoromethyl)phenylacetyl chloride],
CuI yielded the alcohol, which was protected as benzyl ether 7
(85% yield for two steps). Asymmetric dihydroxylation of the
terminal olefin with AD-mix-ꢀ afforded diol 8 (dr 5:1).8
protection of the primary and secondary hydroxyl group as TBS
ether and MOM ether, respectively, resulted in compound 9.
Desilylation of 9 with treatment with TBAF generated primary
alcohol 10. After sequential Swern oxidation9 and Horner-
Wadsworth-Emmons olefination,10 enoate 11 was obtained.
Subsequently, enoate 11 was subjected to oxidative debenzylation
with DDQ11 in aqueous CH2Cl2 to yield enoate alcohol 5.
Synthesis of acid 4 started from (2E,4E)-tert-butyl hexa-2,4-
dienoate 12. Regioselective Sharpless asymmetric dihydroxylation
of ester 12 with AD-mix-ꢀ (89% ee)12,13 afforded the corresponding
syn diol 13, which was converted to key fragment 4 through acidic
hydrolysis and acetonide protection (Scheme 3).14
1
(S)- and (R)-MTPA esters were obtained, respectively. H-1H
COSY data enabled assignment of the proton signals for MTPA
ester. Analysis of the ∆δS-R values (Figure 2) for the two
diastereomeric esters confirmed the absolute configuration of 17
at C-4 as R and that at C-10 as R, but the optical rotation symbols
of synthetic product and natural product were opposite, indicating
that our synthetic 4-keto-clonostachydiol 1 was actually the
enantiomer of the natural product, which prompted our further
synthesis toward its antipode.
The antipode of 1 was then prepared from precursors 7 and 12
through similar routes. Treatment of benzyl ether 7 with AD-mix-R
produced diol 8a, which was converted into 5a according to the
above procedures (see the Supporting Information). Fragment 4a
was prepared from dienoate 12 following the same pathway of 4
except the AD-mix-ꢀ reagent was replaced by AD-mix-R (Scheme
5).
With fragments 4 and 5in hand (Scheme 4), the Mitsunobu
reaction15 was employed to construct dienoate 14 with the inversion
of the C-13 configuration. Deprotection of 14,16 followed by
(8) Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483–2547.
Condensation of fragments 4a and 5a under Yamaguchi
condition provided enoate 14a in a yield of 76%, while Keck
protocol only yielded 35%.20 Consecutive manipulation, includ-
ing deprotection, hydrolysis, esterification, oxidation, and depro-
tection, finally led to (+)-4-keto-clonostachydiol 1a (Scheme
6) (see the Supporting Information). The spectral data (1H and
13C NMR) and optical rotation of synthetic (+)-4-keto-
clonostachydiol 1a were both in accord with the reported ones
(9) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1978, 43, 4537–
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1738.
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7570–7571.
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Soc. 1997, 119, 10247–10248. (b) Sunazuka, T.; Hirose, T.; Chikaraishi, N.;
Harigaya, Y.; Hayashi, M.; Komiyama, K.; Sprengeler, P. A.; Smith, A. B., III;
Omura, S. Tetrahedron 2005, 61, 3789–3803.
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J. Org. Chem. Vol. 74, No. 10, 2009 3931

SCHEME 6. Synthesis of (+)-4-Keto-Colonstachydiol 1a
121.7, 109.2, 94.6, 81.6, 76.4, 74.8, 70.9, 55.6, 51.6, 31.4, 30.7,
27.2, 26.6, 19.9, 16.6; IR (film) Vmax 3365, 2983, 1721, 1272, 1095,
1036, 984, 919 cm-1; HRMS (ESIMS) calcd for C20H36NO8 [M +
NH4]+ 418.2435, found 418.2426.
Macrolide 16. To a solution of seco-acid 3 (40 mg, 0.12 mmol)
in anhydrous THF (1 mL) under argon was added Et3N (63 µL, 0.46
mmol), after 30 min, followed by trichlorobenzoyl chloride (20 µL,
0.47 mmol). The resulting heterogeneous mixture was stirred at room
temperature for 18 h. The reaction mixture was diluted with dry toluene
(100 mL) and the supernatant solution was transferred to a flask. The
resulting solution was slowly added (5 mL/h) to a refluxing solution
of DMAP (107 mg, 0.88 mmol) in toluene (50 mL) over 20 h. The
mixture was refluxed for a further 11 h, and then diluted with diethyl
ether. The organic layer was washed with brine and dried by MgSO4,
then the solvents were evaporated. The crude product was purified by
column chromatography on silica gel (hexanes/EtOAc 2:1) to give 28
1
mg of 17 (75%) as a colorless oil: [R]20 +22 (c 2.7, CH Cl3); H
D
NMR (400 MHz, CDCl3) δ 6.78 (m, 2 H), 6.15 (d, J ) 15.6 Hz, 1
H), 5.89 (d, J ) 15.6 Hz, 1 H), 5.32 (m, 1 H), 5.19 (m, 1 H), 4.60 (m,
2 H), 4.50 (m, 1 H), 4.45 (m, 1 H), 3.36 (m, 1 H), 2.03-2.09 (m,
1H), 1.53-1.76 (m, 3 H), 1.44 (d, J ) 6.3 Hz, 3 H), 1.20 (d, J ) 6
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 165.8, 165.7, 150.0, 146.8,
122.2, 121.5, 94.6, 74.0, 73.2, 71.1, 69.4, 55.5, 27.1, 26.1, 17.4, 15.9;
IR (film) Vmax 3502, 2984, 1713, 1361, 1223, 1043, 513 cm-1; HRMS
(ESIMS) calcd for C16H28NO7 [M + NH4]+ 346.1860, found 346.1870.
4-Keto-Clonostachydiol 1. Under Ar atmosphere, pyridinium
dichromate (PDC) (515 mg, 2.88 mmol) was added in portions to a
stirred solution of the alcohol 17 (75 mg, 0.23 mmol) and molecular
sieves 4Å (450 mg) in CH2Cl2 (10 mL) at 0 °C. After continuous
stirring for 1 h at rt, the reaction mixture was diluted with ether (50
mL) and filtered through Celite. The solvents were evaporated. The
crude product was purified by column chromatography on silica gel
of the natural product. Upon treatment of 1a with (R)- and (S)-
MTPACl, (S)- and (R)-MTPA esters were obtained, respectively.
Analysis of the ∆δS-R values for the two diastereomeric esters
demonstrated that the absolute configuration of 1a at C-10 was
S (Figure 2). Therefore, we corrected the absolute configuration
of the natural product 4-keto-clonostachydiol 1 as (5S,10S,13S).
In summary, we have finished the total synthesis of both (+)-
and (-)-4-keto-clonostachydiol through a highly stereoselective
route, and the result was further confirmed by Mosher’s method.
The absolute configuration of 4-keto-clonostachydiol was
revised as (5S,10S,13S) on the basis of our current synthesis.
Experimental Section
(hexanes/EtOAc 5:1) to give 59 mg of the corresponding ketone (80%)
1
as a colorless oil: [R]20 -44 (c 1.3, CHCl3); H NMR (400 MHz,
D
(2R,5S)-5-(Benzyloxy)hexane-1,2-diol (8). A mixture of AD-
mix-ꢀ (7.0 g, 5 mmol) in 50 mL of t-BuOH/H2O (1:1 v:v) was stirred at
rt for 15 min, and then cooled to 0 °C. To this solution was added benzyl
ether 7 (0.95 g, 5 mmol). The reaction mixture was stirred at 0 °C for
48 h and then quenched with Na2SO3 (7.5 g) at 0 °C within 0.5 h. EtOAc
was added to the reaction mixture, and the aqueous layer was further
extracted with EtOAc twice. The combined organic layers were dried over
Na2SO4 and the solvents were evaporated. The crude product was purified
by column chromatography on silica gel (hexanes/EtOAc 1:1) to give
1.03 g of the corresponding diol 8 (92%) as a colorless oil: [R]20D +29 (c
1.18, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.26-7.34 (m, 5 H), 4.59
(d, J ) 11.4 Hz, 1 H), 4.20 (d, J ) 11.4 Hz, 1 H), 3.52-3.62 (m, 3 H),
3.52-3.62 (m, 2 H), 2.79 (s, 1 H), 1.59-1.70 (m, 2 H), 1.47-1.58 (m,
2 H), 1.21 (d, J ) 6.3 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 138.3,
128.4, 127.8, 127.6, 74.8, 72.1, 70.3, 66.7, 32.7, 29.0, 19.3; IR (film) Vmax
3384, 2930, 1066, 738, 698 cm-1; HRMS (ESIMS) calcd for C13H21O3
[M + H]+ 225.1485, found 225.1492.
Dienoate 14. To a solution of 4 (400 mg, 1.6 mmol) and
triphenylphosphine (852 mg, 3.2 mmol) in benzene (20 mL) was
added a solution of DIAD (657 mg, 3.2 mmol) and acid 5 (358
mg, 1.9 mmol) in benzene (20 mL) over 30 min at rt. The reaction
mixture was stirred overnight, and then quenched with H2O (40
mL). This mixture was extracted with CHCl3, washed with brine,
and dried by Na2SO4, then the solvents were evaporated. The crude
product was purified by column chromatography on silica gel
(hexanes/EtOAc 10:1) to give 572 mg of 15 (85%) as a colorless
oil: [R]20D +19 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.81
(m, 2 H), 6.09 (d, J ) 15.3 Hz, 1 H), 5.98 (d, J ) 15.9 Hz, 1 H),
4.97 (m, 1 H), 4.58 (dd, J ) 14.7, 6.3 Hz, 2 H), 4.18 (m, 1 H),
4.05 (m, 1 H), 3.83 (m, 1 H), 3.73 (s, 3 H), 3.35 (s, 3 H), 1.64 (br,
4 H), 1.46 (s, 4 H), 1.30 (d, J ) 6 Hz, 3 H), 1,23 (d, J ) 6 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 166.5, 165.4, 147.5, 143.3, 123.1,
CDCl3) δ 7.31 (d, J ) 16 Hz, 1 H), 7.02 (dd, J ) 15.6, 4 Hz, 1 H),
6.48 (d, J ) 16 Hz, 1 H), 6.14 (dd, J ) 15.6, 1.2 Hz, 1 H), 5.31 (q,
J ) 7.2 Hz, 1 H), 5.05 (m, 1 H), 4.64 (m, 2 H), 4.44 (m, 1 H), 3.38
(s, 3 H), 1.81-1.92 (m, 3 H), 1.60 (m, 1 H), 1.56 (d, J ) 6.4 Hz, 3
H), 1.28 (d, J ) 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.5,
165.7, 164.1, 150.1, 135.3, 131.1, 120.6, 94.7, 75.6, 74.0, 72.0, 55.7,
28.3, 28.1, 18.5, 16.4; IR (film) Vmax 3420, 2935, 1722, 1263, 1042,
981 cm-1; HRMS (ESIMS) calcd for C16H26NO7 [M + NH4]+
344.1704, found 344.1710.
Trifluoroacetic acid (1.5 mL) was added to a solution of the ketone
(13 mg, 0.04 mmol) in CH2Cl2 (0.5 mL) at 0 °C under Ar atmosphere.
After continuous stirring for 2 h at rt the solvents were evaporated.
The crude product was purified by column chromatography on silica
gel (hexanes/EtOAc 2:1) to give 8 mg of 4-keto-clonostachydiol 1
(85%) as a colorless oil: [R]20D -76 (c 0.1, CH3OH); 1H NMR (400
MHz, DMSO-d6) δ 7.37 (d, J ) 16 Hz, 1 H), 7.20 (dd, J ) 15.6, 3.2
Hz, 1 H), 6.39 (d, J ) 16 Hz, 1 H), 5.93 (dd, J ) 15.6, 2 Hz, 1 H),
5.21 (d, J ) 4.4 Hz, 1 H), 5.16 (q, J ) 7.2 Hz, 1 H), 4.92 (m, 1 H),
4.36 (br, 1 H), 1.89 (m, 1 H), 1.68 (m, 1 H), 1.56 (m, 1 H), 1.49 (d,
J ) 7.2 Hz, 4 H), 1.20 (d, J ) 6.4 Hz, 3 H); 13C NMR (100 MHz,
DMSO-d6) δ 200.3, 165.8, 164.0, 154.5, 136.8, 129.9, 118.1, 75.4,
72.0, 68.6, 30.4, 27.6, 18.6, 15.9; IR (film) Vmax 3375, 2990, 1764,
1243, 1058 cm-1; HRMS (ESIMS) calcd for C14H22NO6 [M + NH4]+
300.1442, found 300.1444.
Acknowledgment. We are grateful for the generous financial
support by the NSFC (QT program, 20872054, 20732002),
NCET-05-0879.
Supporting Information Available: General experimental
details and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394–2395.
JO900370A
3932 J. Org. Chem. Vol. 74, No. 10, 2009