Enantioselective synthesis of daurichromenic acid and confluentin

Article abstract of DOI:10.1002/ejoc.200901403

The first asymmetric synthesis of daurichromenic acid and confluentin is described. The key step of the sequence leading to both natural products is a highly enantioselective domino aldol/oxa Michael, reaction (97 % ee) of farnesal and 2-methoxy-4-methylsalicylaldehyde.

Full text of DOI:10.1002/ejoc.200901403

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901403
Enantioselective Synthesis of Daurichromenic Acid and Confluentin
Kegang Liu[a] and Wolf-D. Woggon*[a]
Keywords: Organocatalysis / Aldol reactions / Domino reactions / Michael reaction / Chromenes
The first asymmetric synthesis of daurichromenic acid and
confluentin is described. The key step of the sequence lead-
ing to both natural products is a highly enantioselective
domino aldol/oxa Michael reaction (97% ee) of farnesal and
2-methoxy-4-methylsalicylaldehyde.
farnesal 4 and salicylaldehyde 5 to yield the chiral lactol 6
in acceptable yield and excellent enantioselectivity
(Scheme 2).
Introduction
The MeOH extract of leaves and twigs of the asian plant
Rhododendron dauricum contains several anti-HIV-active
chromenes[1] which derive from the parent daurichromenic
acid (1). This compound is the main component of the ex-
tract and its absolute configuration S at C2 was deduced
by X-ray crystal structure determination of a derivative of
the related chromane 2 (Scheme 1). 1 is the most potent
anti-HIV component as demonstrated in experiments with
acutely infected H9 cells (EC50 = 5.6 ng/mL).[1] Several
short syntheses of racemic daurichromenic acid have al-
ready been published.[2–4] Here we wish to report the first
enantioselective synthesis of natural 1.
This method was developed for the synthesis of all-R-
configured α-tocopherol[5] and was subsequently also used
for the preparation of chiral xanthones.[6] During the work
on vitamin E[5] we had observed that the proline derivative
3, derived from natural (S)-proline catalyzed the formation
of a 2S-configured lactol, whereas the enantiomer of 3 gave
the 2R configuration with high diastereoselectivity (de =
97%). Hence we anticipated that for the synthesis of 1 the
organocatalyst 3 would be the ideal choice to generate 6 in
high enantioselectivity. This was indeed the case, the ee
value of lactol 6 (97%) was determined on the correspond-
ing lactone 7.
Though the lactol 6 is a versatile intermediate several
problems en route to 1 were decisive for selecting the opti-
mal reaction sequence and protecting groups. From lactol
6 one carbon has to be removed preferably by decarbon-
ylation[7] at the aldehyde level (Scheme 3). This reaction,
however, requires elevated temperatures and hence was un-
successful using 8 for example. Further, it would have been
of advantage to introduce the double bond in the chromane
system at the final stage of the synthesis as it is known that
chromenes can be rather unstable.[8,9] Conditions of chro-
mane dehydrogenation using DDQ have been reported.[10]
We have examined suitable intermediates of the synthesis
such as 9 and 10 in the oxidation with DDQ in refluxing
benzene,[11–12] however, the chromanes/chromenes did not
survive these reaction conditions (Scheme 3).
Scheme 1. Absolute configuration of daurichromenic acid (1) de-
duced by crystal structure determination of the p-bromophenacyl
derivative of 2.
Accordingly, we used a more elaborate sequence shown
in Scheme 4. The lactol 6 was reduced quantitatively to the
diol 11, the primary alcohol was then selectively protected
as the silyl ether and the resulting 12 reacted further with
allyl bromide to yield 13. Three different protecting groups
are present in 13 for the following reasons i) the phenyl
methyl ether was necessary to obtain high enantioselectivity
in the domino aldol/oxa-Michael reaction (Scheme 2); ii) in
contrast to a silyl protecting group (see 8 in Scheme 3) the
allyl ether at C4 of the chromane system is stable under
Results and Discussion
The synthetic strategy employs the proline derivative 3
which catalyzes the domino aldol/oxa-Michael reaction of
[a] Department of Chemistry, University of Basel,
St. Johanns Ring 19, 4056 Basel, Switzerland
Fax: +41-61-2671103
E-mail: wolf-d.woggon@unibas.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901403.
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K. Liu, W.-D. Woggon
SHORT COMMUNICATION
conditions of decarbonylation, vide infra; iii) the TBS group
at the primary alcohol can be selectively removed in the
presence of the other protecting groups.
Scheme 4. Synthesis of confluentin (17). Experimental conditions:
a) LAH, THF, 0 °C to room temp., 100%; b) TBSCl, imidzole,
DMF, 85%; c) allylic bromide, 60% NaH, THF, 97%; d) TBAF,
THF, 97%; e) Dess–Martin periodinane, DCM, 87%; f) i.
Rh(dppp)2Cl, p-cymene, 140 °C, N2, 75%; ii. Ni(dppp)Cl2, DI-
BAL-H, toluene, 80%; g) i. PPh2Li, THF, 40 °C, 12 h, 80%; ii.
MsCl, Et3N, THF, KHMDS, 50%.
Hence, deprotection of the primary alcohol of 13 gave 14
which underwent a Dess–Martin oxidation to furnish the
desired aldehyde 15 in overall excellent yield. In the pres-
ence of the allyl protecting group decarbonylation pro-
ceeded readily in 75% yield. Subsequent deallylation, how-
Scheme 2. Organocatalyzed domino aldol/oxa-Michael reaction to
produce chiral lactol 6. Experimental conditions: 30 mol-% 3, ben-
zoic acid, toluene, 76 h, room temp., 63%.
Scheme 3. Various unsuccessful attempts to generate the chromene system of 1.
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Enantioselective Synthesis of Daurichromenic Acid and Confluentin
ever, was rather difficult; out of six different reaction condi-
tions only Ni-catalyzed reduction was satisfactory and gave
the benzylic alcohol 16 in 80% yield.[13] Demethylation of
the phenol ether was accomplished under mild reductive
conditions and the product immediately converted into the
chromene 17 via mesylation/elimination in one pot. At this
stage of the synthesis we were able to separate the enantio-
mers of the product and it was shown that 17 displayed an
excellent enantiomeric excess of 97%, in agreement with 7.
The chromene 17 is known as the natural product conflu-
entin exhibiting weak antagonist activity at the human van-
illoid receptor VR1. 17 was first isolated as a racemate from
the fruitbodies of the fungi genus Albatrellus spp.[14] and
more recently from the leaves Rhododendron dauricum.[15] In
view of the facile ring opening of chromenes[8,9] (Scheme 5)
racemization of natural 17 most likely occurred during iso-
lation from the fungi.
Conclusions
In conclusion, the synthesis of two physiologically sig-
nificant natural chromenes confluentin (17) and daurichro-
menic acid (1) has been accomplished using an organocata-
lytic, highly enantioselective aldol/oxa-Michael reaction as
a key step.
Experimental Section
Aldol/Oxa-Michael Reaction: To a solution of aldehyde 5 (294 mg,
1.8 mmol) and proline-catalyst 3 (345 mg, 0.54 mmol) in toluene
(1.8 mL) was added solid benzoic acid (66 mg, 0.54 mmol) at room
temp. under argon, then followed by addition of a solution of far-
nesal (4) (595 mg, 2.7 mmol) in toluene (3.6 mL) during 3 h by
means of a syringe pump. The reaction mixture was stirred at room
temp. for 3 d and directly purified by flash chromatography on sil-
ica gel, hexane/ethyl acetate (4:1, v/v) as an eluent to afford com-
pound 6 (430 mg, yield 63%) as a yellowish oil. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 6.27 (s, 1 H), 6.14 (s, 1 H), 5.26 (m,
1 H), 5.07–5.15 (m, 2 H), 4.92 (m, 1 H), 3.71 (s, 3 H), 3.65 (d, J =
5.20 Hz, 1 H), 2.29 (s, 3 H), 1.96–2.20 (m, 8 H), 1.55–1.75 (m, 4
H), 1.68 (s, 3 H), 1.59 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 157.32, 156.57, 140.53, 135.82, 131.57, 124.46, 123.82,
108.81, 106.39, 103.04, 90.23, 76.02, 62.07, 55.61, 44.47, 41.64,
39.84, 32.91, 26.86, 25.88, 22.14, 21.45, 17.87, 16.18 ppm. ESI-MS:
m/z = 409.2 [M + Na]+, 795.1 [2M + 1]+. [α]2D0 = +0.4 (c = 1.36,
CHCl3); elemental analysis calcd. (%) for C24H34O4·H2O (404.26):
C 71.26, H 8.97; found C 71.08, H 8.75.
Confluentin (17) from Alcohol 16: To a solution of diphenylphos-
phane (42 mg, 0.223 mmol) in THF (0.5 mL) was added a solution
of nBuLi (0.21 mL, 0.335 mmol, 1.6  in hexane) dropwise at 0 °C.
The reaction mixture was stirred at room temp. for 20 min. Then
a solution of alcohol 16 (20 mg, 0.056 mmol) in THF (1 mL) was
added dropwise and heated to 40 °C overnight. The reaction was
quenched with satd. aq. NH4Cl and extracted three times with ethyl
acetate. The combined organic phases were washed with water,
brine and dried with Na2SO4. After concentration under vacuum,
the residue was purified by flash chromatograph on silica gel using
hexane/ethyl acetate (8:1, v/v) as an eluent to give the phenol
(15.2 mg, yield 80%) as a yellowish very unstable oil. To a solution
of the diol (19.26 mg, 0.056 mmol) in THF (1.5 mL) was added
Et3N (34 mg, 0.336 mmol) at –30 °C. Then a solution of MsCl
(19.21 mg, 0.168 mmol) in THF (0.5 mL) was added dropwise at
the same temperature. The reaction mixture was warmed to room
temp. and stirred for 1 h. Then the solution was cooled down to
0 °C, and a solution of KHMDS in toluene (0.5 , 0.5 mL,
0.25 mmol) was added dropwise. The resulting mixture was stirred
for 20 min at the same temperature, quenched with satd. aq. NH4Cl
and extracted with diethyl ether. The combined organic phases
were washed with brine, dried with Na2SO4. After concentration
under vacuum, the residue was purified by flash chromatograph on
silica gel using hexane/ethyl acetate (10:1, v/v) as an eluent and
Scheme 5. Racemization of 17.
Assisted by the free phenol bromination of 17 occurred
regioselectively in ortho position and subsequent carboxyla-
tion furnished the final target compound 1 with [α]D20
=
+30.0 (CHCl3), in agreement with natural 1 within the ex-
perimental error: [α]2D0 = +30.4 (CHCl3).[1] The enantio-
meric excess of 1 was further confirmed at the derivative 18
(97% ee) being identical with 17 (Scheme 6).
1
17 (9.13 mg, yield 50%) was isolated as a yellowish oil. H NMR
(400 MHz, CDCl3, 25 °C): δ = 6.60 (d, J = 10.0 Hz, 1 H), 6.24 (s,
1 H), 6.11 (s, 1 H), 5.49 (d, J = 10.0 Hz, 1 H), 5.06–5.11 (m, 2 H),
4.62 (br., 1 H), 2.20 (s, 3 H), 2.01–2.13 (m, 4 H), 1.95 (m, 2 H),
1.65–1.78 (m, 2 H), 1.67 (s, 3 H), 1.59 (s, 3 H), 1.57 (s, 3 H), 1.37
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 154.32,
151.18, 139.73, 135.44, 131.51, 127.41, 124.54, 124.23, 116.86,
110.06, 108.45, 106.93, 78.39, 41.27, 39.86, 26.87, 26.46, 25.88,
22.81, 21.68, 17.86, 16.15 ppm. ESI-MS: m/z = 349.2 [M + Na]+.
Scheme 6. Synthesis of daurichromenic acid (1). Experimental con-
ditions: a) NBS, DCM, 81%; b) nBuLi, CO2, 60%; c) TMS-
CH2N2, methanol, diethyl ether, 100%.
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K. Liu, W.-D. Woggon
SHORT COMMUNICATION
[α]2D0 = +71.0 (c = 0.5, CHCl3); enantiomeric excess: 97%, deter-
mined by HPLC on Chrialpak AD-H column (n-hexane/2-propa-
nol, 90:10), 20 °C, UV 220 nm, 0.5 mL/min; major enantiomer tR
= 10.50 min, minor enantiomer tR = 9.37 min.
126.46, 124.50, 123.96, 117.01, 111.84, 107.23, 105.09, 79.90, 51.98,
41.78, 39.85, 27.21, 26.85, 25.88, 24.62, 22.75, 17.86, 16.15 ppm.
ESI-MS: 407.2 [M + Na]+. [α]2D0 = +31.5 (c = 0.38, CHCl3); enan-
tiomeric excess: 97%, determined by HPLC on Chrialpak AD-H
column (n-hexane/2-propanol, 98:2), 20 °C, UV 250 nm, 0.5 mL/
Daurichromenic Acid (1): To a solution of 17 (10 mg, 0.031 mmol)
in DCM (1 mL) was added a solution of NBS (6 mg, 0.034 mmol)
in DCM (1 mL) very slowly at 30 °C. After addition, the reaction
was stirred at 20 °C for 30 min when TLC showed that 17 was
consumed. The reaction was quenched with silica gel and directly
purified by flash chromatograph on silica gel using hexane/ethyl
acetate (20:1v/v) as an eluent to give crude bromide (10 mg, yield
81%) as yellowish oil. To a solution of the bromide (10 mg,
0.025 mmol) in THF (1 mL) was added a solution of nBuLi (1.6 ,
62.5 µL) in hexane dropwise at –30 °C. The reaction was stirred for
1.5 h between –30 and –15 °C. When all bromide was consumed,
the reaction was cooled down to –70 °C, and bubbled with CO2 for
3 h at –70 °C to –50 °C. The reaction was quenched with water,
adjusted to pH 7 using 1  HCl, then extracted three times with
ethyl acetate. The combined organic phases were washed with brine
and dried with Na2SO4. After concentration under vacuum the res-
idue was purified by flash chromatograph on silica gel using hex-
ane/ethyl acetate (1:1 to 0:100, v/v) as an eluent to give 1 (5.56 mg,
min, major enantiomer tR = 8.45 min, minor enantiomer tR
9.57 min.
=
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and analytical data for com-
pounds 1, 6, 7, 11–18, are provided with copies of the respective
1H NMR and 13C NMR spectra and HPLC chromatograms of 17
and 18.
[1] Y. Kashiwada, K. Yamazaki, Y. Ikeshiro, T. Yamagishi, T. Fu-
jioka, K. Mihashi, K. Mizuki, L. M. Cosentino, K. Fowke,
S. L. Morris-Natschke, K.-H. Lee, Tetrahedron 2001, 57, 1559–
1563.
[2] Y. Kang, Y. Mei, Y. Du, Z. Jin, Org. Lett. 2003, 5, 4481–4484.
[3] A. V. Kurdyumov, R. P. Hsung, K. Ihlen, J. Wang, Org. Lett.
2003, 5, 3935–3938.
[4] a) H. Hu, T. J. Harrison, P. D. Wilson, J. Org. Chem. 2004, 69,
3782–3786; b) Y. R. Lee, X. Wang, S. K. Noh, W. S. Lyoo,
Synth. Commun. 2006, 36, 3329–3334.
1
60%) as a yellowish oil. H NMR (400 MHz, CDCl3, 25 °C): δ =
[5] K. Liu, A. Chougnet, W.-D. Woggon, Angew. Chem. Int. Ed.
2008, 47, 5827–5829.
6.73 (d, J = 10.0 Hz, 1 H), 6.23 (s, 1 H), 5.48 (d, J = 10.0 Hz, 1
H), 5.07–5.11 (m, 2 H), 2.52 (s, 3 H), 1.95–2.09 (m, 6 H), 1.65–1.77
(m, 2 H), 1.67 (s, 3 H), 1.59 (s, 3 H), 1.57 (s, 3 H), 1.40 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 175.17,
160.82, 159.00, 144.38, 135.69, 131.55, 126.47, 124.50, 123.90,
116.87, 112.22, 107.21, 103.76, 80.21, 41.86, 39.85, 27.34, 26.85,
25.88, 24.64, 22.76, 17.87, 16.16 ppm. ESI-MS: 369.2 [M – H]–.
[α]2D0 = +30.0 (c = 0.25, CHCl3).
[6] N. Volz, M. C. Bröhmer, M. Nieger, S. Bräse, Synlett 2009, 4,
550–553.
[7] a) M. Kreis, A. Palmelund, L. Bunch, R. Madsen, Adv. Synth.
Catal. 2006, 348, 2148–2154; b) T. C. Fessard, S. P. Andrews,
H. Motoyoshi, E. M. Carreira, Angew. Chem. Int. Ed. 2007, 46,
9331–9334.
[8] P. Wipf, W. S. Weiner, J. Org. Chem. 1999, 64, 5321–5324.
[9] L.-F. Tietze, G. Von Kiedrowski, B. Berger, Synthesis 1982,
683–684.
Methyl Ester of Daurichromenic Acid 18: To a solution of 1 (5.0 mg,
0.135 mmol) in methanol (0.5 mL) and diethyl ether (0.5 mL) was
added a solution of TMS-CH2N2 in hexane until the color of the
solution became yellow at 0 °C. The reaction mixture was stirred
at same temperature for 0.5 h. The reaction was quenched with
acetic acid and concentrated under vacuum to afford a residue that
was purified by flash chromatography on silica gel using hexane/
ethyl acetate (40:1, v/v) as an eluent to give the ester 18 (5.2 mg,
100%) as colorless oil. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
11.97 (s, 1 H), 6.72 (d, J = 10.0 Hz, 1 H), 6.19 (s, 1 H), 5.47 (d, J
= 10.0 Hz, 1 H), 5.05–5.11 (m, 2 H), 3.91 (s, 3 H), 2.45 (s, 3 H),
1.92–2.13 (m, 6 H), 1.62–1.78 (m, 2 H), 1.67 (s, 3 H), 1.59 (s, 3 H),
1.56 (s, 3 H), 1.39 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ = 172.56, 159.94, 158.04, 142.92, 135.63, 131.53,
[10] A. Stocker, T. Netscher, A. Rüttimann, R. K. Müller, H.
Schneider, L. J. Todaro, G. Derungs, W.-D. Woggon, Helv.
Chim. Acta 1994, 77, 1721–1737.
[11] B. M. Trost, H. C. Shen, J.-P. Surivet, J. Am. Chem. Soc. 2004,
126, 12565–12579.
[12] V. K. Ahluwalia, R. S. Jolly, Synthesis 1982, 74–75.
[13] T. Taniguchi, K. Ogasawara, Angew. Chem. Int. Ed. 1998, 37,
1136–1137.
[14] V. Hellwig, R. Nopper, F. Mauler, J.-K. Liu, Z.-H. Ding, M.
Stadler, Arch. Pharm. (Weinheim, Ger.) 2003, 336, 119–126.
[15] N. Iwata, N. Wang, X. Yao, S. J. Kitanaka, J. Nat. Prod. 2004,
67, 1106–1109.
Received: December 3, 2009
Published Online: January 7, 2010
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