The first asymmetric synthesis of all four isomers of cis- and trans-3,4-dihydroxy-3,4-dihydromollugin

Article abstract of DOI:10.1016/j.tetlet.2008.09.138

Asymmetric synthesis of all the four stereoisomers of cis-3,4-dihydroxy-3,4-dihydromollugins 4 and 6 and trans-3,4-dihydroxy-3,4-dihydromollugins 5 and 7 was achieved. The O-methoxymethyl mollugin derivatives were dihydroxylated to (-)- and (+)-cis-3,4-di

Full text of DOI:10.1016/j.tetlet.2008.09.138

Tetrahedron Letters 49 (2008) 6980–6983
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Tetrahedron Letters
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The first asymmetric synthesis of all four isomers of cis- and
trans-3,4-dihydroxy-3,4-dihydromollugin
*
Naga Venkata Sastry Mudiganti, Sven Claessens, Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric synthesis of all the four stereoisomers of cis-3,4-dihydroxy-3,4-dihydromollugins 4 and 6
and trans-3,4-dihydroxy-3,4-dihydromollugins 5 and 7 was achieved. The O-methoxymethyl mollugin
derivatives were dihydroxylated to (ꢀ)- and (+)-cis-3,4-dihydroxy-3,4-dihydromollugin derivatives using
Received 6 August 2008
Accepted 17 September 2008
Available online 27 September 2008
both AD-mix-a and AD-mix-b. Deprotection of the MOM-ethers of cis-dihydroxy compounds resulted in
the targeted stereoisomers (ꢀ)-(3R,4R)-cis-3,4-dihydroxy-3,4-dihydromollugin 4, (ꢀ)-(3R,4S)-trans-3,4-
dihydroxy-3,4-dihydromollugin 5, (+)-(3S,4S)-cis-3,4-dihydroxy-3,4-dihydromollugin 6 and (+)-(3S,4R)-
trans-3,4-dihydroxy-3,4-dihydromollugin 7. These routes were paved with difficulties, for example,
incompatibility of the substrates with AD-mixes, the unexpected formation of trans-dihydroxy com-
pounds and failures in deprotection protocols.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
mers 4–7 has not been reported yet. In continuation of our work
herein, we wish to report the first enantioselective synthesis of
Mollugin 1 and its analogues cis-3,4-dihydroxy-3,4-dihydro-
mollugin 2 and trans-3,4-dihydroxy-3,4-dihydromollugin 3 have
been isolated from Pentas longiflora and Rubia cordifolia, and consti-
tute a class of benzisochromene natural products with potent bio-
logical activities.1 The Sharpless asymmetric dihydroxylation using
preformed AD mixes is an excellent and practical method to
prepare dihydroxy compounds with high enantioselectivity.2
However, poor enantioselectivities were obtained in the case of
cis-olefins with an exception of cis-allylic and homoallylic alco-
hols.3,4 Only limited reports are found in the literature for the
asymmetric dihydroxylation of cyclic cis-disubstituted olefins,
such as chromenes, using AD-mixes. To the best of our knowledge,
the highest obtained ee’s for chromenes were only up to 70% using
commercially available AD-mixes.5
Very recently, we reported the racemic syntheses of dihydr-
oxymollugins 2 and 3.6 The cis-dihydroxy compound 2 was
synthesized by a dihydroxylation reaction using OsO4, and the
trans-dihydroxy compound 3 was prepared using oxone on O-pro-
tected mollugin derivatives. The synthesis of racemic trans-3,4-
dihydroxy-3,4-dihydromollugin 3 has been reported by Wang
et al, by reacting dimethyldioxirane (DMD) with mollugin 1 in
62% yield.7 In our hands, by employing the same reaction condi-
tions the trans-3,4-dihydroxy-3,4-dihydromollugin 3 was only
formed in 30% yield along with the formation of several side prod-
ucts. The selective asymmetric synthesis of all the four stereoiso-
all four stereoisomers of 3,4-dihydroxy-3,4-dihydromollugin 4–7.
2. Results and discussion
At the beginning, the synthesis of both stereoisomers of
(ꢀ)-(3R,4R)-cis-3,4-dihydroxy-3,4-dihydromollugin 4 and (+)-(3S,
4S)-cis-3,4-dihydroxy-3,4-dihydromollugin 6 was attempted. The
strategy for the synthesis of target compounds was based on
Sharpless asymmetric dihydroxylation reaction using AD mixes.
As encountered in the previous case, due to complex formation
of the osmium species with the acidic phenolic hydroxyl moiety
of mollugin 1, only complex reaction mixtures were obtained by
attempted dihydroxylation of mollugin 1 using AD-mix-
a and
AD-mix-b.6 Therefore, reactions were attempted on the protected
mollugins such as the O-methyl ether protected mollugin 8 using
AD-mix-b in a solvent mixture of t-BuOH:H2O (1:1). After stirring
for 24 h at 0–10 °C, the corresponding dihydroxy compound 9
was formed in 10% yield along with several unidentified side prod-
ucts (Scheme 1). Repeated endeavours by changing the solvent
mixture (t-BuOH:H2O, 1:1.5 or 1.5:1) failed. On the other hand,
the addition of a small amount of tetrahydrofuran (THF) resulted
in the improvement of the yield of dihydroxy compound
(+)-(3S,4S)-9. Thus, the reaction of methyl ether protected mollu-
gin 8 with AD-mix-b in a solvent mixture of t-BuOH:H2O:THF
(8:8:1) at 0–10 °C for 24 h afforded the methyl ether of (+)-cis-
3,4-dihydroxy-3,4-dihydromollugin 9 in 33% yield, along with the
corresponding
a-hydroxyketone 10 in 20% yield (Scheme 1), and
* Corresponding author. Tel.: +32 92645962.
E-mail address: norbert.dekimpe@UGent.be (N. D. Kimpe).
together with unidentified products. Having this result in hand,
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.138

N. V. S. Mudiganti et al. / Tetrahedron Letters 49 (2008) 6980–6983
6981
OH
O
OH
O
OH
O
OMe
OMe
OH
OMe
OH
O
O
O
OH
OH
2
1
3
rac-trans-3,4-dihydroxy-
rac-cis-3,4-dihydroxy-
Mollugin
3,4-dihydromollugin
3,4-dihydromollugin
source: Galium mollugo
Rubia cordifolia
OH
O
O
OH
O
O
Pentas longiflora
OMe
OH
OMe
OH
OH
OH
4
5
(3R,4R)-cis-3,4-dihydroxy-
(3R,4S)-trans-3,4-dihydroxy-
3,4-dihydromollugin
3,4-dihydromollugin
Pentas longiflora
Rubia cordifolia
Pentas longiflora
OH
O
OH
O
O
OMe
OH
OMe
OH
O
OH
OH
6
7
(3S,4S)-cis-3,4-dihydroxy-
3,4-dihydromollugin
(3S,4R)-cis-3,4-dihydroxy-
3,4-dihydromollugin
the effect of methanesulfonamide as an additive and the amount of
AD-mixes were explored in order to improve the yield.
O-benzyl compound 11 provided the corresponding cis-diol 13 in
30% yield (hydroxyketone 14, 22%), whereas the methoxymethyl
ether of mollugin 12 gave the corresponding cis-dihydroxy com-
pound 15 in 32% yield, along with only a small amount of the
hydroxyketone 16 (5%). The yields were not changed much by
switching AD-mix-b to AD-mix-a. The yields of dihydroxy com-
pounds as well as hydroxy ketones were a little higher (30–33%
for diols, 5–22% for hydroxyketones) with AD-mix-b, when com-
pared to AD-mix-a 25–30% for diols, 5–19% for hydroxy ketones).
Nhe absolute configuration of dihydroxy compounds 9, 13 and 15
that are formed with AD-mix-b were assigned as 3S,4S using the
enantioselective mnemonic of the AD reactions and by comparing
analogous dihydroxylations in the literature.8 Similarly, the
dihydroxy compounds 17, 19 and 21 which were formed with
In general, the standard AD procedure calls for 1.4 g of AD-mix
per millimole of olefin and 1 equiv of MeSO2NH2 for all substrates
other than terminal alkenes.2b Surprisingly, the addition of Me-
SO2NH2 diminished the yield. Thus, a reaction was carried on O-
methyl mollugin 8 using AD-mix-b in the presence of 1 equivalent
of MeSO2NH2 in a solvent mixture of t-BuOH:H2O:THF (8:8:1) at
0–10 °C for 48 h affording only 18% of the (+)-(3S,4S)-cis-3,
4-dihydroxy-3,4-dihydro mollugin 9, along with several unidenti-
fied side products. It was also observed that, either increasing or
decreasing the amount of AD-mix leads to complex reaction
mixtures with diminished yields of the dihydroxy compound 9.
In order to investigate the effect of the protecting group to further
improve the yield of the dihydroxy compound, the phenolic hydro-
xy moiety of mollugin was protected with different protecting
groups.
AD-mix-a, were assigned as 3R,4R. The enantiomeric excess of
the compound (+)-(3S,4S)-15 was determined by 1H NMR experi-
ments of the corresponding compound with Pirkle alcohol as a
chiral co-solvent.9 Thus, the highest enantioselectivity was
obtained in the case of O-methoxymethyl-(3S,4S)-cis-3,4-di-
hydroxy-3,4-dihydromollugin 15 using AD-mix-b10 and was found
Thus, mollugin 1 was protected as the O-benzyl and O-
methoxymethyl ether6 and subsequently asymmetric dihydroxyla-
tion reactions were attempted on these O-protected mollugins
(Scheme 2). No significant improvement in the yield of the
required dihydroxy compound was observed both with the O-
benzylmollugin 11 and mollugin methoxymethyl ether 12. The
to be 84% (½a 2D5
ꢁ
+10.9, c 1.3, CHCl3) (see Table 1). Using AD-mix-a,
78% ee was found in the case of O-methoxymethyl-(3R,4R)-cis-3,4-
dihydroxy-3,4-dihydromollugin 21 (½a D25
ꢁ
ꢀ11.0, c 1.75, CHCl3).
MeO
O
O
MeO
O
MeO
O
O
β
AD-mix-
OMe
OH
OMe
OMe
O
+
t-BuOH:H2O:THF (8:8:1)
0-10 °C, 24 h
(+)
O
OH
OH
9
(33%)
10 (20%)
8
Scheme 1.

6982
N. V. S. Mudiganti et al. / Tetrahedron Letters 49 (2008) 6980–6983
AD-mix
K2CO3
K3Fe(CN)6
K2OsO2(OH)4
(DHQD)2-PHAL
β
OR
O
OR
O
O
OR
O
O
OMe
OMe
OH
OMe
O
+
O
OH
OH
t-BuOH:H2O:THF
(8:8:1)
0 °C - rt, 24 h
3S,4S
3S
8
R = Me
(+)-9 R = Me, 33%
(-)-13 R = Bn, 30%
(+)-10 R = Me, 20%
(-)-14 R = Bn, 22%
(+)-16 R = MOM, 5%
11 R = Bn
12 R = MOM
(+)-15 R = MOM, 32%
AD-mix
K2CO3
K3Fe(CN)6
K2OsO2(OH)4
(DHQD)2-PHAL
α
OR
O
OR
O
OR
O
O
OMe
OMe
O
OMe
OH
+
O
O
OH
t-BuOH:H2O:THF
(8:8:1)
OH
0 °C - rt, 24 h
3R,4R
3R
(-)-17 R = Me, 30%
(+)-19 R = Bn, 25%
(-)-21 R = MOM, 28%
(-)-18 R = Me, 18%
(+)-20 R = Bn, 19%
(-)-22 R = MOM,5%
8
R = Me
11 R = Bn
12 R = MOM
Scheme 2.
Subsequently, having O-protected cis-3,4-dihydroxy-3,4-
dihydromollugins in hand, research was focused on the deprotec-
tion of these compounds to obtain the targeted optically active
3,4-dihydroxy-3,4-dihydromollugins 4 and 6. However, the depro-
tection reactions attempted on O-methyl dihydroxy compounds 9
or 17 either using boron(III) bromide in CH2Cl2 or using ceric(IV)
ammonium nitrate in CH3CN led to the formation of complex reac-
tion mixtures. Similarly, the O-benzyl deprotection of dihydroxy
compounds 13 or 19 using 10 mol % of Pd(0) in different solvents
under H2 atmosphere or using 2.5 equiv of CAN in CH3CN failed.
As explained in a previous article, racemic O-methoxymethyl 3,4-
dihydroxy-3,4-dihydromollugin was successfully deprotected
using 6 N HCl in THF.6 Similarly, the deprotection reaction of
O-methoxymethyl-(3S,4S)-cis-3,4-dihydroxy-3,4-dihydromollugin
12 carried out using 18 equiv of 6 N HCl in THF at 0 °C for 3 h, re-
sulted in the formation of the required (3S,4S)-cis-3,4-dihydroxy-
3,4-dihydromollugin 6 in 60% yield along with the corresponding
trans isomer (3S,4R)-trans-3,4-dihydroxy-3,4-dihydromollugin 7
in 20% yield. The ee of compound 4 was found to be 83% by com-
Table 1
Optical rotations of 3,4-dihydroxy-3,4-dihydromollugin derivatives (9,13,15,17,19,21)
and the corresponding hydroxy ketone compounds (10,14,16,18,20,22)
Entry
Compound
Optical rotation (in CHCl3)
1
2
9
½
½
½
½
½
½
½
½
½
½
½
½
½
½
½
½
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
a 2D5
ꢁ
+4.2, c 1.00
+4.4, c 2.10
ꢀ10.8, c 1.00
ꢀ1.1, c 2.10
+10.9, c 1.30
+1.5, c 2.50
ꢀ3.4, c 0.55
ꢀ3.1, c 0.75
+9.6, c 0.25
+3.0, c 0.50
ꢀ11.0, c 1.75
ꢀ1.8, c 3.00
ꢀ9.6, c 0.75
ꢀ11.2, c 0.75
+10.7, c 1.25
+12.5, c 0.75
10
13
14
15
16
17
18
19
20
21
22
4
ꢁ
3
ꢁ
4
ꢁ
5
ꢁ
6
ꢁ
7
ꢁ
8
ꢁ
9
ꢁ
10
11
12
13
14
15
16
ꢁ
ꢁ
ꢁ
ꢁ
5
ꢁ
6
ꢁ
7
ꢁ
paring the optical rotation of the natural product {½a D25
ꢁ
+10.7, c 1.2,
MOMO
O
OH
O
O
OH
O
O
7
6
6a
5
8
OMe
OH
OMe
OH
6N HCl
OMe
OH
4a
+
9
THF, (1:1)
10a
10b
O
4
10
0 °C-rt, 3 h
1
3
OH
OH
OH
2
(+)-15
(+)-7
(+)-6
20%
60%
-H+
OH
O
O
OH
O
OMe
OH2
OMe
H2O
OH
-H2O
+
+O
OH
23
24
Scheme 3.

N. V. S. Mudiganti et al. / Tetrahedron Letters 49 (2008) 6980–6983
6983
CHCl3; lit ½a 2D5
ꢁ
ꢀ12.9, c 0.35, CHCl3)}1h,11. This unusual formation of
1869; (f) Itokawa, H.; Qiao, Y.; Takeya, K. Phytochemistry 1991, 30, 637; (g) Kuo,
S.-C.; Chen, P.-R.; Lee, S.-W.; Chen, Z.-T. J. Chin. Chem. Soc. 1995, 42, 869; (h) El-
Hady, S.; Bukuru, J.; Kesteleyn, B.; Van Puyvelde, L.; Nguyen Van, T.; De Kimpe,
N. J. Nat. Prod. 2002, 65, 1377.
a trans-diol 7 from cis-diol 6 can be explained as follows (Scheme
3). Deprotection of the MOM-ether (+)-15 obviously results in
(+)-cis-diol 6. However, under excess acidic conditions the hydro-
xyl moiety at position 4 is protonated and easily eliminated by
an electron push mechanism starting from the electron lone pair
of the pyranyl-oxygen. In this way, a reactive charged ortho-quino-
methide intermediate 24 is formed to which water attacks and
results in the formation of the more stable trans isomer (+)-7.
2. (a) Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric Dihydroxylation. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993;
pp 227–272; (b) Kolb, H. C.; VanNieuwenhze, S. M.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
3. (a) VanNieuwenhze, S. M.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 843; (b)
Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568.
4. Wang, Z-. M.; Kakiuchi, K.; Sharpless, K. B. J. Org. Chem. 1994, 59, 6895.
5. Wang, Q.; She, X. K.; Ren, X.; Ma, J.; Pan, X. Tetrahedron: Asymmetry. 2004, 15,
29.
6. Mudiganti, N. V. S.; Claessens, S.; Habonimana, P.; De Kimpe, N. J. Org. Chem.
2008, 73, 3867.
3. Conclusion
7. Wang, X.; Lee, Y. R. Tetrahedron Lett. 2007, 48, 6275.
8. (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A. J. Org. Chem. 1992,
57, 2768; (b) Becker, H.; King, B.; Taniguchi, M.; Vanhessche, K. M.; Sharpless,
K. B. J. Org. Chem. 1995, 60, 3940.
The asymmetric syntheses of (ꢀ)-(3R,4R)-cis-3,4-dihydroxy-
3,4-dihydromollugin 4, (ꢀ)-(3R,4S)-trans-3,4-dihydroxy-3,4-dihy-
dromollugin 5, (+)-(3S,4S)-cis-3,4-dihydroxy-3,4-dihydromollugin
6 and (+)-(3S,4R)-trans-3,4-dihydroxy-3,4-dihydromollugin 7 was
achieved for the first time. Although the lower yields and side
products are the drawbacks of this protocol, the enantioselecti-
vities are good to excellent. These reactions showed that much
experimentation was necessary to achieve the dihydroxylation of
such pyranes due to side reaction at all stages of the synthetic
protocol.
9. (a) Pirkle, W. H.; Sikkenga, D. L.; Pavlin, M. S. J. Org. Chem. 1977, 42, 384; (b)
Parker, D. Chem. Rev. 1991, 91, 1441.
10. The general experimental procedure for AD of O-protected mollugin
derivatives 8–12 using AD-mixes by taking compound 12 with AD-mix-b as
a
representative example. To a stirred solution of AD-mix-b (1.4 g) in
t-BuOH:H2O (1:1 v/v, 8 ml) was added a THF solution (0.5 ml) of compound
12 (328 mg, 1 mmol) at 0 °C. After stirring the resulting solution at 0–10 °C for
24 h, a saturated solution of aqueous sodium bisulfite (10 ml) was added,
stirred for 1 h and then extracted with dichloromethane (3 ꢂ 20 ml). The
combined organic layers were washed with brine (20 ml), dried over
magnesium sulfate, and evaporated under reduced pressure. The crude
product was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate 60/40 Rf 0.8) affording (+)-(3S,4S)-methyl
cis-3,4-dihydroxy-6-methoxymethoxy-2,2-dimethyl-3,4-dihydro-2H-benzo-
[h]-chromene-5-carboxylate 15 in 32% yield and (+)-(3S)-methyl 3-hydroxy-
6-methoxymethoxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[h]-chromene-
5-carboxylate 16 in 5% yield (petroleum ether/ethyl acetate 80/20 Rf 0.6).
11. The experiments carried out with Pirkle alcohol as a chiral resolving agent
were not much useful in determing the enantiomeric excess of the compounds
at this stage.
References and notes
1. (a) Inoue, K.; Shiobara, Y.; Nayenshiro, H.; Inouye, H.; Wilson, G.; Zenk, M. H.
Phytochemistry 1984, 73, 307; (b) Gonzalez, A. G.; Barroso, J. T.; Cardona, R. J.;
Medina, J. M.; Rodriguez Luis, F. An. Quim. 1977, 73, 538; (c) Itokawa, H.; Qiao,
Y.; Takeya, K. Phytochemistry 1989, 28, 3465; (d) Koyama, J.; Ogura, T.;
Tagahara, K.; Konoshima, T.; Kozuka, M. Phytochemistry 1992, 31, 2907; (e)
Itokawa, H.; Ibraheim, Z. Z.; Qiao, Y.; Takeya, K. Chem. Pharm. Bull. 1993, 41,