Total syntheses of all stereoisomers of phenatic acid B

Article abstract of DOI:10.1021/jo901927w

(Chemical Equation Presented) The total syntheses of all stereoisomers of phenatic acid B and determination of their absolute configuration are described. The synthetic strategy is based on an efficient combination of the Sharpless asymmetric dihydroxylat

Full text of DOI:10.1021/jo901927w

pubs.acs.org/joc
Acholeplasma laidlawii.2 The absolute and relative stereo-
Total Syntheses of All Stereoisomers of Phenatic
Acid B
chemistry and syntheses of 1-5 are not yet known. Phenatic
acid B 2 has four possible stereoisomers. Two of them have
the 2,3-anti- and the others 2,3-syn-relative configurations
(2a, 2b, ent-2a, and ent-2b, Scheme 1).
Rodney A. Fernandes* and Asim K. Chowdhury
Department of Chemistry, Indian Institute of Technology
Bombay, Powai 400076 Mumbai, Maharashtra India
rfernand@chem.iitb.ac.in
Received September 9, 2009
FIGURE 1. Phenatic acid A 1, phenatic acid B 2, actiphenol 4,
Nong-kang 101-G 5, and 101-F 3.
SCHEME 1. Retrosynthetic Analysis of Phenatic Acid B
Stereoisomers
The total syntheses of all stereoisomers of phenatic acid B
and determination of their absolute configuration are
described. The synthetic strategy is based on an efficient
combination of the Sharpless asymmetric dihydroxyla-
tion, the Johnson-Claisen rearrangement, and hydro-
boration-oxidation. It involves 11-12 steps and overall
yield of 5-8%.
In continuation of our research efforts in the asymmetric
synthesis of natural products,4,5 we have recently demon-
strated that chiral vicinal diols are good platforms for separ-
able diastereomers in the Johnson-Claisen rearrangement.5
We envisioned a similar strategy to synthesize the stereoi-
somers of phenatic acid B 2 (Figure 1) and elucidate their
absolute configurations. Our retrosynthetic plan is shown in
Scheme 1. From compound 6a, we planned to have 2a
through a three-step sequence, viz. hydroboration-oxidation
of terminal olefin, hydroxyl oxidation, and demethylation.
Compound 6a would be produced as a C-4 diastereomer
mixture with 6b after the Johnson-Claisen rearrangement
of 7 followed by lactonization. We have demonstrated earlier
that such C-4 diastereomers based on vicinal diols are separ-
able.5 The allyl alcohol 7 could be derived from 8, and the
latter can be prepared from the olefin 9 through the Sharpless
asymmetric dihydroxylation. The diastereomer 6b would give
2b. Similarly, ent-2a and ent-2b can be synthesized using ent-8
through ent-6a and ent-6b, respectively.
Fungal infections have aroused a major public concern in
recent years.1 Immune-deficient patients are prone to such
infections, in particular of the fungi Candida albicans.1 Given
the urgency for new antifungal combination therapies for
increased effectiveness in treatment, the search for new
antifungal compounds with better and different mode of
action is a research priority. Tomoda and co-workers2
recently isolated two new 2,4-dimethyl phenols named phe-
natic acid A 1 and B 2 (Figure 1) from the culture of
Streptomyces sp. K03-0132. Their structures were elucidated
by NMR spectroscopy.2 Related compounds such as
actiphenol 4, Nong-kang 101-G 5, and 101 F 3 (Figure 1)
were isolated long ago.3 Compounds 1 and 2 showed
miconazole activity against Candida albicans. Phenatic
acid B also showed moderate activity against Bacillus
subtilis, Staphylococcus aureus, Bacteroides fragilis, and
(4) (a) Fernandes, R. A.; Chavan, V. P.; Ingle, A. B. Tetrahedron Lett.
2008, 49, 6341–6343. (b) Fernandes, R. A.; Chavan, V. P. Tetrahedron Lett.
2008, 49, 3899–3901. (c) Fernandes, R. A. Tetrahedron: Asymmetry 2008, 19,
15–18. (d) Fernandes, R. A. Eur. J. Org. Chem. 2007, 5064–5070.
(1) Nishiyama, Y.; Yamaguchi, H. Antibiot. Chemother. 2000, 16, 19–26.
(2) Fukuda, T.; Matsumoto, A.; Takahashi, Y.; Tomoda, H.; Omura, S.
J. Antibiot. 2005, 58, 252–259.
(3) Hua, J. C.; Xie, Y. Y. Hua Hsueh Hsueh Pao 1980, 38, 275–282.
(5) Fernandes, R. A.; Ingle, A. B. Tetrahedron Lett. 2009, 50, 1122–1124.
8826 J. Org. Chem. 2009, 74, 8826–8829
Published on Web 10/28/2009
DOI: 10.1021/jo901927w
r
2009 American Chemical Society

Fernandes and Chowdhury
JOCNote
The synthesis of 7 and ent-7 is shown in Scheme 2. The
phenol 106 was methylated to 11 (98%), and subsequent
Wittig-Horner reaction afforded the olefin 9 in excellent
yield (96%). The Sharpless asymmetric dihydroxylation7
precursors for the anticipated Johnson-Claisen rearrange-
ment.9
The Johnson-Claisen rearrangement of 7 with trimethyl-
orthoacetate and catalytic propionic acid gave the diastereo-
meric mixture 14 in 88% yield (ent-7 provided 15, Scheme 3).
1H NMR of the crude product 14 indicated a 55:45 C-3
diastereomeric mixture. Acetonide deprotection of 14 with
3 N HCl resulted in concomitant lactonization to give
6a and 6b (15 led to ent-6a and ent-6b). As expected,
SCHEME 2. Enantioselective Synthesis of Allyl Alcohols 7 and
ent-7
SCHEME 3. Johnson-Claisen Rearrangement of 7 and ent-7
these diastereomers could easily be separated by silica gel
flash column chromatography as crystalline solids. The
syn-product 6b (44%) was eluted first followed by 6a
(53%). Similarly ent-6a (53%) and ent-6b (44%) were
separated. The relative configuration of 6a and 6b is based
on the comparison of the 1H NMR chemical shifts of
Hb protons in the lactones (Figure 2). In 6a, the Hb proton
is syn to the vinyl group and is shielded to δ 4.38 as compared
to Hb (δ 4.70) in 6b. This was further ascertained by a single-
crystal X-ray diffraction analysis of 6a and 6b.10 Asymmetric
reaction on olefin 9 was performed following standard
procedure: with (DHQD)2-PHAL as the stereoinducing
ligand, we obtained the diol (2S,3R)-8 (88%) and with
(DHQ)2-PHAL ligand the diol (2R,3S)-ent-8 (87%). Enan-
tioselectivities were excellent (99 and 98% ee, respectively) as
revealed by chiral HPLC.8 Sequential acetonide protection
of diol 8 to 12 (99%), DIBAL-H reduction to the aldehyde,
and Wittig-Horner reaction afforded the R,β-unsaturated
ester 13 (97%). Similarly, ent-8 led to ent-13. Further, the
DIBAL-H reduction of the ester groups in 13 and ent-13
furnished the allyl alcohols 7 and ent-7, respectively, the
FIGURE 2. Comparison of chemical shifts of Hb proton in 6a and
6b.
(6) Knight, P. D.; O’Shaughnessy, P. N.; Munslow, I. J.; Kimberley, B. S.;
Scott, P. J. Organomet. Chem. 2003, 683, 103–113.
dihydroxylation ascertains the C-2 and C-3 configurations
in 8 to be (2S,3R). These centers will have the configura-
tion carried in 6a and 6b. Since 6a has the C-4/C-5 anti-
relative configuration in the lactone (as revealed by X-ray
(7) Reviews: (a) Zaitsev, A. B.; Adolfsson, H. Synthesis 2006, 1725–1756.
(b) Bolm, C.; Hildebrand, J. P.; Muniz, K. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 399-428. (c) Kolb, H.
C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
(8) Enantiomeric excess was determined by chiral HPLC. Column:
Chiralpak IA. Eluent: n-hexane/i-PrOH (95:5); flow rate = 0.5 mL/min;
UV detector = 240 nm; tR = 20.53 min for 8, 24.21 min for ent-8.
(9) For the Johnson-Claisen rearrangement see: (a) Ziegler, F. Chem.
Rev. 1988, 88, 1423–1452. (b) Chan, K.-K.; Cohen, N.; De Noble, J. P.;
Specian, A. C. Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497–3505. (c) Johnson,
W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-T.; Faulkner,
D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741–743.
(10) See Supporting Information for the ORTEP diagrams. CCDC
725576 (6a) and CCDC 725575 (6b) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
J. Org. Chem. Vol. 74, No. 22, 2009 8827

Fernandes and Chowdhury
JOCNote
crystallography analysis), the absolute configuration will
be (4S,5R); 6b has the C-4/C-5 syn-relative configuration
and hence will have (4R,5R) absolute configuration. Simi-
larly, ent-6a should have (4R,5S) and ent-6b the (4S,5S)
configurations. With these separated stereoisomers in hand,
the stage was now set to finally target all the stereoisomers of
phenatic acid B (Schemes 4 and 5).
diminished yields. To check this hypothesis, the hydroxyl
group in 6a was oxidized with IBX12 to give the keto-
compound 19 in quantitative yield (Scheme 4). Further
hydroboration-oxidation of 19 led to the diastereomeric
mixture 20 (74%), which on subsequent oxidation afforded
the acid 17 in 72% yield. Overwhelmingly, this three-step
sequence gave improved yield of 17 from 6a (overall 48%)
as compared to the two-step conversion of 6a to 17 (23%)
via 16. Finally, demethylation of 17 with AlCl3 cleanly
provided (2R,3R)-phenatic acid B 2a in 80% yield. Simi-
larly, the ketone 21 obtained from 6b was converted to the
diol 22 (64%) and further oxidized to the acid 23 (64%) and
demethylated to provide (2R,3S)-phenatic acid B 2b (80%).
Thus a stereodivergent synthesis of both diastereomers 2a
and 2b was achieved from a single stereoisomer 7 (although
there was lack of stereoselectivity in the Johnson-Claisen
rearrangement). In a similar sequence of reactions, ent-6a
(f ent-19 f 24 f ent-17 f ent-2a) and ent-6b (f ent-21
f 25 f ent-23 f ent-2b) led to (2S,3S)-phenatic acid B ent-2a
and (2S,3R)-phenatic acid B ent-2b, respectively (Scheme 5).
The absolute and relative stereochemistry of the naturally
isolated phenatic acid B is not known.2 The C-2 proton for
SCHEME 4. Synthesis of Phenatic Acid B Stereoisomers 2a and
2b
SCHEME 5. Synthesis of Phenatic Acid B Stereoisomers ent-2a
and ent-2b
The hydroboration reaction on 6a (Scheme 4) with
BH3 Me2S followed by oxidative workup afforded the diol
3
16 in 36% optimized yield.11 The oxidation of both hydro-
xyl groups in 16 led to the keto-acid 17 in 72% yield. The
hydroboration-oxidation of 6b (Scheme 4) with BH3
3
Me2S failed to deliver the diol 18.11 We believed that the
free hydroxyl group in 6a or 6b might be complexing with
the borane reagent during hydroboration and provided
(12) IBX applications: (a) Nicolaou, K. C.; Mathison, C. J. N.;
Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192–5201. (b) Nicolaou,
K. C.; Baran, P. S.; Kranich, R.; Zhong, Y.-L. Angew. Chem., Int. Ed. 2001,
40, 202-206. Reviews: (c) Stang, P. J. J. Org. Chem. 2003, 68, 2997–3008. (d)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584.
(11) Other variations of hydroboration-oxidation using Cy2 BH or
3
9-BBN or changes in reagent to substrate ratio, solvents, and temperature
did not improve the reaction either.
8828 J. Org. Chem. Vol. 74, No. 22, 2009

Fernandes and Chowdhury
JOCNote
2997, 2926, 2831, 1752, 1479, 1355, 1273, 1214, 1167, 1139, 1100,
the natural product appears at δ 5.70 ppm in the 1H NMR.2
The synthetic syn-stereoisomers (2b and ent-2b) had the C-2
proton appearing at δ 6.05 ppm, while the anti-stereoisomers
(2a and ent-2a) had the same proton at δ 5.69 ppm.13 From
this observation, we believe the natural isolate to be the anti-
stereoisomer (relative configuration) and should have either
(2R,3R) or (2S,3S) absolute configurations. Due to a large
difference in optical rotation value of synthetic (-115.7 for
2a and þ109.8 for ent-2a) in comparison to natural isolate
(-2.2), we could not make the assignment of absolute
configuration unambiguously to the natural phenatic acid
B at this stage. Also, the natural isolate was not available for
further studies.
In summary, we have achieved the first total syntheses of
all stereoisomers of phenatic acid B. The synthetic strategy is
based on an efficient combination of the Sharpless asym-
metric dihydroxylation, Johnson-Claisen rearrangement,
and hydroboration-oxidation as the key steps. The syn-
thesis of phenatic acid B stereoisomers is completed in
high enantio- and diastereoselectivity in 11-12 steps and
overall yield of 5-8%. We have also established the absolute
configurations of all stereoisomers of phenatic acid B.
The naturally isolated product is an anti-stereoisomer,
while the absolute stereochemistry could be (2R,3R) or
(2S,3S). The synthetic strategy is flexible and will poten-
tially allow us to synthesize the other members of the
phenatic acid family (Figure 1). Work in this direction is in
progress.
1
1041, 1009, 876, 794, 667 cm-1; H NMR (400 MHz, CDCl3/
TMS) δ = 7.04 (s, 1H), 6.95 (s, 1H), 5.5-5.6 (m, 1H), 4.98-5.04
(m, 3H), 4.38 (dd, J = 7.6, 4.2 Hz, 1H), 3.75 (s, 3H), 3.18-3.23
(m, 1H), 2.97 (br s, 1H, OH), 2.79 (dd, J = 17.2, 9.5 Hz, 1H),
2.45 (dd, J = 17.2, 9.5 Hz, 1H), 2.27 (s, 3H), 2.26 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ = 175.7, 153.8, 135.8, 133.7, 132.1,
131.3, 130.7, 125.7, 117.3, 87.5, 69.5, 61.0, 41.2, 35.0, 20.8, 16.1;
HRMS (ESIþ) calcd for [C16H20O4 þ Na]þ 299.1259, found
299.1252.
[(2R,3R)-2-(2-Hydroxy-3,5-dimethylbenzoyl)-5-oxotetrahy-
drofuran-3-yl]acetic acid (Phenatic Acid B, 2a): To a solution of
17 (0.13 g, 0.42 mmol) in dry CH2Cl2 (5 mL) at 0 °C was added
AlCl3 (0.198 g, 1.48 mmol, 3.5 equiv) in portions, and the
reaction mixture was stirred for 15 min. The ice bath was
removed and stirring continued at room temperature for
1.5 h. It was then quenched with water (5 mL), and the solution
was extracted with CH2Cl2 (5 ꢀ 25 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and
concentrated. The residue was purified by silica gel flash
column chromatography using petroleum ether/EtOAc (1:1)
as eluent to provide 2a (0.099 g, 80%) as a white solid: mp
185-187 °C; [R]25 = -115.7 (c = 0.2, MeOH); IR (KBr
D
pallet) ν = 3445, 3231, 2925, 2853, 1783, 1756, 1705, 1645,
1474, 1414, 1376, 1321, 1290, 1193, 1177, 1091, 1056, 1019,
1
919, 860, 787, 767, 702 cm-1; H NMR (400 MHz, CDCl3/
TMS) δ = 11.8 (s, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 5.69 (d, J =
3.0 Hz, 1H), 3.1-3.15 (m, 1H), 2.85 (dd, J = 17.7, 8.5 Hz, 1H),
2.75 (dd, J = 17.1, 7.9 Hz, 1H), 2.64 (dd, J = 17.1, 6.7 Hz, 1H),
2.32 (dd, J = 17.7, 3.7 Hz, 1H), 2.27 (s, 3H), 2.23 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ = 198.5, 175.9, 175.2, 159.9,
140.0, 128.0, 127.7, 126.8, 115.8, 80.5, 37.0, 34.5, 33.0, 20.4,
15.4; HRMS (ESIþ) calcd for [C15H16O6 þ H]þ 293.1025,
found 293.1035.
Experimental Section
(4S,5R)-5-[(R)-Hydroxy-(2-methoxy-3,5-dimethylphenyl)methyl]-
4-vinyldihydrofuran-2(3H)-one (6a) and (4R,5R)-5-[(R)-Hydroxy-(2-
methoxy-3,5-dimethylphenyl)methyl]-4-vinyldihydrofuran-2(3H)-one
(6b): To a solution of allyl alcohol 7 (1.3 g, 4.45 mmol) in toluene (15
mL) were added trimethylorthoacetate (5.34 g, 5.6 mL, 44.46 mmol,
10 equiv) and EtCO2H (cat, 5 drops), and the solution was refluxed
for 12 h. After cooling to room temperature, the volatile material was
removed under reduced pressure and the residue was purified by
silica gel flash column chromatography using petroleum ether/
EtOAc (95:5) as eluent to provide 14 (1.36 g, 88%) as a colorless
[(2R,3S)-2-(2-Hydroxy-3,5-dimethylbenzoyl)-5-oxotetrahy-
drofuran-3-yl]acetic acid (Phenatic Acid B, 2b): The title com-
pound was prepared from 23 (0.028 g, 0.091 mmol) by a similar
procedure as described for the conversion of 17 to 2a with
AlCl3 to give 2b (0.0214 g, 80%) as white solid: mp 188-190 °C;
[R]25 = -103.3 (c = 0.3, MeOH); IR (thin film) ν = 3395,
D
3134, 2923, 2854, 1790, 1750, 1725, 1634, 1474, 1422, 1282, 1262,
1227, 1173, 1143, 1100, 1053, 1041, 978, 845, 796,
696 cm-1 1H NMR (400 MHz, CDCl3/TMS) δ = 11.9 (s,
;
1H), 7.28 (s, 1H), 7.27 (s, 1H), 6.05 (d, J = 7.9 Hz, 1H),
3.32-3.38 (m, 1H), 2.79 (dd, J = 17.4, 8.5 Hz, 1H), 2.56 (dd,
J = 17.4, 10.4 Hz, 1H), 2.38-2.41 (m, 2H), 2.26 (s, 3H), 2.24 (s,
3H); 13C NMR (100 MHz, CDCl3) δ = 199.7, 175.4, 175.2,
159.9, 140.4, 128.2, 128.1, 126.2, 116.9, 77.0, 35.4, 33.9, 32.7,
20.5, 15.4; HRMS (ESIþ) calcd for [C15H16O6 þ H]þ 293.1025,
found 293.1031.
1
oil. Analysis of crude 14 by H NMR indicated calcd 55:45 C-3
diastereomeric mixture.
To a solution of 14 (1.36 g, 3.9 mmol) in MeOH (25 mL) was
added 3 N HCl (3 mL) and stirred for 12 h at room temperature.
It was then quenched with powdered NaHCO3 (1.0 g) and
filtered. The filtrate was concentrated and the residue purified
by silica gel flash column chromatography using petroleum
ether/EtOAc (85:15) as eluent to provide 6b (0.475 g, 44%) as
white crystalline solid. Further elution gave 6a (0.57 g, 53%)
as colorless crystalline solid. Data for 6b: mp 144-146 °C;
Acknowledgment. This work was financially sponsored by
IRCC, IIT-Bombay. A.K.C. is grateful to CSIR New Delhi
for a research fellowship. We are thankful to SAIF IIT-
Bombay for X-ray facility, and Prof. H. Tomoda and co-
[R]25 = -135.7 (c = 0.14, CHCl3); IR (KBr film) ν = 3458,
D
2991, 2954, 2826, 1753, 1475, 1409, 1350, 1313, 1249, 1213, 1188,
1136, 1069, 1012, 930, 803, 672 cm-1 1H NMR (400 MHz,
;
1
workers for providing copies of H and 13C NMR of the
CDCl3/TMS) δ = 7.0 (s, 1H), 6.95 (s, 1H), 6.02-6.12 (m, 1H),
5.21-5.33 (m, 2H), 5.11-5.16 (m, 1H), 4.70 (dd, J = 8.2, 2.1 Hz,
1H), 3.75 (s, 3H), 3.28-3.37 (m, 1H), 3.01 (br s, 1H, OH), 2.84
(dd, J = 17.2, 10.2 Hz, 1H), 2.58 (dd, J = 17.4, 9.1 Hz, 1H), 2.27
(s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 177.0,
153.7, 134.8, 133.7, 132.0 (2C), 130.7, 126.0, 118.9, 84.8, 69.4,
61.0, 43.0, 34.4, 20.8, 16.1; HRMS (ESIþ) calcd for [C16H20O4
þ Na]þ 299.1259, found 299.1247. Data for 6a: mp 84-86 °C;
natural phenatic acid B.
Supporting Information Available: General information
and experimental procedures for preparation and compound
characterization data of 11, 9, 8, ent-8, 12, ent-12, 13, ent-13, 7,
ent-7, ent-6a, ent-6b, 16, 17, 19, 20, 21, 22, 23, ent-19, ent-21, 24,
25, ent-17, ent-23, ent-2a, and ent-2b, copies of NMR spectra for
all new compounds. Crystallographic data for compounds 6a
and 6b. This material is available free of charge via the Internet
at http://pubs.acs.org.
[R]25 = -50.0 (c = 0.16, CHCl3); IR (KBr film) ν = 3429,
D
(13) See Supporting Information for a comparison.
J. Org. Chem. Vol. 74, No. 22, 2009 8829