Synthetic studies of lepranthin, a lichen-produced dimeric macrolide. stereoselective synthesis of a seco-acid based on stereospecific epoxide-opening reactions

Article abstract of DOI:10.3987/COM-10-12106

The stereoselective synthesis of a seco-acid derivative of lepranthin (1), a lichen-produced unique 16-membered dimeric macrolide, is described wherein all asymmetric carbon centers were constructed in a highly stereoselective manner, respectively, by usi

Full text of DOI:10.3987/COM-10-12106

HETEROCYCLES, Vol. 83, No. 2, 2011
293
HETEROCYCLES, Vol. 83, No. 2, 2011, pp. 293 - 298. © The Japan Institute of Heterocyclic Chemistry
Received, 19th November, 2010, Accepted, 20th December, 2010, Published online, 28th December, 2010
DOI: 10.3987/COM-10-12106
SYNTHETIC STUDIES OF LEPRANTHIN, A LICHEN-PRODUCED
DIMERIC MACROLIDE. STEREOSELECTIVE SYNTHESIS OF A
SECO-ACID BASED ON STEREOSPECIFIC EPOXIDE-OPENING
REACTIONS
Hisashi Takada,a Shinji Nagumo,a* Eiko Yasui,a Megumi Mizukami,b and
Masaaki Miyashitaa*
a) Department of Applied Chemistry, Kogakuin University, Nakano 2665-1,
Hachioji, Tokyo, 192-0015, Japan
b) Hokkaido Pharmaceutical University, School of Pharmacy, Katsuraoka 7-1,
Otaru 047-0264, Japan
Abstract – The stereoselective synthesis of a seco-acid derivative of lepranthin
(1), a lichen-produced unique 16-membered dimeric macrolide, is described
wherein all asymmetric carbon centers were constructed in a highly
stereoselective manner, respectively, by using different epoxide-opening reactions
of the -unsaturated -epoxy ester system and an epoxy alcohol derivative as
the key steps.
O
AcO
OAc OH
OH OAc
O
O
AcO
O
lepranthin (1)
Figure 1
Bacteria, fungi and algae produce a large number of macrolides which are classified as polyketide-derived
macrolides in their biosynthetic pathways. These compounds often provided us with good opportunities
discovering new drugs. Interestingly, a few macrolides have been isolated from lichens too, which may
imply a symbiotic relationship between fungi and algae.1 Lepranthin (1) was isolated from the
crustaceous lichen Arthonia impolita (Ehrh.) Borrer by Zopf in 1904.2 Nearly century later, a NMR

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HETEROCYCLES, Vol. 83, No. 2, 2011
investigation and X-ray analysis by Huneck et al. revealed 1 to be a 16-membered homo-macrodiolide
which contains two secondary hydroxyl groups and four secondary acetates.3 Although biological
properties and synthetic studies of 1 have not been reported so far, its unique diolide structure would
attract attention of synthetic chemists. We report herein the stereoselective synthesis of a seco-acid
derivative 28, the key monomer segment of 1, based on stereospecific epoxide-ring opening strategies.
a
b
OH
OH
CO2Me
O
O
OTBDPS
OTBDPS
87%
91%
OTBDPS
2
3 (d.r. >20 : 1)
4
e
f
c
OH
CO2Me
85% TBDPSO
OR
TBDPSO
OTES
96%
86%
5 (R = H)
6 (R = TES)
7
d 96%
OH
O
g
h
CO2Me
O
TBDPSO
OTES
TBDPSO
OTES
75%
96%
8 (d.r. >15 : 1)
9
i
j
CO2Me
CO2Me
OH
O
70%
TBDPSO
TBDPSO
OH
TBDPSO
TBDPSO
OH OH
95%
10
11
7
5
k
l
CO2Me
O
O
O
O
97%
90%
Ph
Ph
12
13
OH
OH
m
O
TBDPSO
O
O
TBDPSO
O
O
OH
89%
Ph
Ph
14
15
Scheme 1. (a) L-(+)-DET, Ti(OiPr)4, TBHP, CH2Cl2, -30 oC; (b) Dess-Martin periodinane,
CH2Cl2, then Ph3P=CHCO2Me; (c) Pd2(dba)3・CHCl3, HCO2H, Et3N, Ph3P; (d) TESCl,
imidazole, CH2Cl2; (e) DIBAH, THF, 0 oC; (f) L-(+)-DET, Ti(OiPr)4, TBHP, CH2Cl2, -30 oC;
(g) Dess-Martin periodinane, CH2Cl2, then Ph3P=CHCO2Me; (h) DDQ, THF, H2O; (i) Me3Al,
H2O, CH2Cl2, -50 oC; (j) PhCHO, TsOH・H2O, benzene, reflux; (k) DIBAH, THF, 0 oC; (l)
L-(+)-DET, Ti(OiPr)4, TBHP, CH2Cl2, -30 oC; (m) CuCN, MeLi, Et2O, -50 to -30 oC.
Our synthesis started with allyl alcohol 2 which was prepared from commercially available methyl
(R)-3-hydroxybutylate in five steps.4 First, 2 was converted to -unsaturated ,-epoxy ester 4 by a
two-step reaction sequence: (1) Katsuki-Sharpless epoxidation5 with L-(+)-DET, Ti(OiPr)4, and TBHP in

HETEROCYCLES, Vol. 83, No. 2, 2011
295
CH2Cl2 at -30 oC, leading to epoxy alcohol 36 (87%); (2) Dess-Martin oxidation7 followed by Wittig
8
olefination (91% yield). Reductive cleavage of the epoxide 4 with HCO2H and Pd2(dba)3･CHCl3
smoothly occurred to give alcohol 5 in 85% yield, which was then transformed into allyl alcohol 7
through the sequence of protection of the secondary alcohol with a silyl group and subsequent DIBAH
reduction. The allyl alcohol 7 thus obtained was again transformed into -unsaturated ,-epoxy ester 9
by the same reaction sequence as that for 2: (1) Katsuki-Sharpless epoxidation leading to 86 (86%); (2)
Dess-Martin oxidation; (3) a Wittig olefination (75%, two steps). After removal of the TES group in 9
with DDQ,9 treatment of the resulting epoxy alcohol 10 with Me3Al-H2O in CH2Cl2 at -50 oC afforded the
desired product 11 in 70% yield.10 Protection of syn-1,3-diol 11 with a benzylidene acetal group furnished
1211 in high yield, which was further converted to epoxy alcohol 1412 in two steps: (1) reduction with
DIBAH in THF (97%); (2) Katsuki-Sharpless epoxidation with L-(+)-DET, Ti(OiPr)4, and TBHP in
o
13
o
CH2Cl2 at -30 C (90%). Upon treatment of 14 with Me2CuCNLi2 in Et2O at -50 to -30 C, the
regioselective methyl substitution reaction smoothly occurred to give 15 as a single product in 89% yield.
Thus, the requisite five stereogenic centers in the targeted molecule were stereoselectively constructed by
using different epoxide-opening reactions of the two -epoxy unsaturated esters, 4 and 10, and the
epoxy alcohol 14.
The remaining task for the synthesis of a seco-acid was discrimination of the five hydroxyl groups in 15.
To this end, sequential oxidations of 15 with TEMPO14 and then with NaClO215 followed by esterification
with CH2N2 produced ester 17 in 67% overall yield. Next, the hydroxyl group in 17 was protected with a
MOM group by treatment with MOMCl, DIPEA, and NaI in 1,2-DME, giving rise to 18 in 85% yield.
Among discrimination of the five hydroxyl groups, the most difficult task was that between C5 and C7
hydroxyl groups protected by benzylidene acetal. All attempts aiming at a regioselective reductive
cleavage of the benzylidene acetal moiety in 18 failed unfortunately. Eventually, distinction between
these hydroxyl groups was performed as follows. Removal of the silyl group in 18 with TBAF/AcOH in
DMF (90%) followed by treatment of the resulting alcohol with BzCl and pyridine in CH2Cl2 furnished
20 (96%), which was converted to diol 21 by catalytic hydrogenolysis with PtO2 in EtOH. Unexpectedly,
the benzene ring in 20 was smoothly hydrogenated concomitantly to produce 21. Further treatment of 21
with PPTS16 in refluxing 1,2-dichloroethane in the presence of pyridine resulted in facile lactonization to
give lactone 22, whose hydroxyl group was then protected with ethyl vinyl ether and PPTS16 in CH2Cl2 to
afford ethoxyethyl ether 23 quantitatively. Unfortunately, however, subsequent hydrolysis of 23 under
alkaline conditions underwent elimination of the MOM group to give unsaturated lactone exclusively. To
overcome this difficulty, the lactone 23 was reduced with LiAlH4 in THF and subsequent regioselective

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HETEROCYCLES, Vol. 83, No. 2, 2011
protection of the primary alcohol with a TBDPS group produced diol 25 (87%). After protection of the
diol with acetyl groups (84%), removal of the TBDPS group with TBAF in THF gave the primary alcohol
(90%), which was successfully converted to seco-acid 2817 for the total synthesis of lepranthin (1), in two
steps: (1) TEMPO oxidation; (2) sodium chlorite oxidation (82%).
a
c
7
5
7
5
15
R
CO2Me
OMOM
75%
85%
TBDPSO
O
O
OH
TBDPSO
O
O
Ph
Ph
18
16 (R = CHO)
b
89%
17 (R = CO2Me)
CO2Me
OMOM
7
5
d
f
CO2Me
OH
O
OH
RO
O
O
OMOM
90%
O
Ph
21
19 (R = H)
20 (R = Bz)
96%
e
OMOM
OR
g
i
O
OH OMOM
OEE
O
OR
HO
quant.
66%
2 steps
O
O
24 (R = H)
j
87%
22 (R = H)
23 (R = EE)
99%
h
25 (R = TBDPS)
OR
k
m
CO2H
OAc OMOM
OAc OMOM
OEE
OAc OEE
AcO
84%
82%
28
26 (R = TBDPS)
27 (R = H)
90%
l
Scheme 2. (a) TEMPO, PhI(OAc)2, CH2Cl2; (b) (1) NaClO2, NaH2PO4 ・ 2H2O,
t
o
2-methyl-2-butene, THF, BuOH, H2O, (2) CH2N2, Et2O, 0 C; (c) MOMCl, DIPEA, NaI,
1,2-DME, reflux; (d) TBAF, AcOH, DMF; (e) BzCl, pyridine, CH2Cl2; (f) PtO2, H2, EtOH; (g)
PPTS, pyridine, (CH2Cl)2, reflux; (h) Ethyl vinyl ether, PPTS, CH2Cl2; (i) LiAlH4, THF; (j)
TBDPSCl, imidazole, CH2Cl2, -25 oC; (k) AcCl, pyridine, CH2Cl2; (l) TBAF, THF; (m) (1)
TEMPO, TBAB, NaOCl, CH2Cl2, NaHCO3 aq., 0 oC, (2) NaClO2, 2-methyl-2-butene,
NaH2PO4･2H2O, THF, H2O.
In summary, we completed the asymmetric synthesis of the seco-acid 28, the key monomer of lepranthin
(1), based on stereospecific epoxide-opening reactions including the stereospecific methylation reaction
of the ,-epoxy unsaturated ester 10 with Me3Al-H2O system. Further studies of the crucial
macrolactonization of the seco-acid 28 toward total synthesis of lepranthin (1) are now in progress in our
laboratory.

HETEROCYCLES, Vol. 83, No. 2, 2011
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ACKNOWLEDGEMENTS
Financial support from the Ministry of Education, Culture, Sports, Science and Technology, Japan (a
Grant-in-Aid for Scientific Research (B) (No. 19350027) and Advanced Promotion Research Program for
Education of Graduate School) is gratefully acknowledged.
REFERENCES (AND NOTES)
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11. Benzyl proton peak in 1H NMR spectrum of compound 12 showed the NOE correlations with peaks
at the C5 and C7 positions (each ca. 10%).
12. The peaks for a diastereomer were not observed in the 1H NMR spectrum of compound 14.
13. B. H. Lipshutz, J. Kozlowski, and R. S. Wilhelm, J. Am. Chem. Soc., 1982, 104, 2305.
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17. Seco-acid 28 was obtained as a diastereomeric mixture (ca. 0.55 : 0.45) concerning the ethoxyethyl
27
group. []D -19.21 (c 1.38, CHCl3); FAB-MS (POSI) m/z 465 (MH+), 433, 386; HR-FABMS m/z
465.2722 (calcd for C22H41O10: 465.2700); IR (ATR) 2978, 1732, 1456 cm-1; 1H NMR (400 MHz,
CDCl3)  5.16-5.11 (1H, m), 5.09-5.00 (1H, m), 4.72 (1H×0.55, q, J = 5.6 Hz), 4.69-4.65 (2H, m),
4.60 (1H×0.45, q, J = 5.2 Hz), 3.70-3.43 (5H, m), 3.39 (3H, s), 2.98-2.90 (1H, m), 2.15-1.98 (2H,
m), 2.06 (3H×0.55, s), 2.05 (3H×0.45, s), 2.02 (3H×0.45, s), 2.01 (3H×0.55, s), 1.95-1.73 (3H,

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HETEROCYCLES, Vol. 83, No. 2, 2011
m), 1.60-1.49 (1H, m), 1.284 (3H×0.45, d, J = 5.2 Hz), 1.283 (3H×0.55, d, J = 5.6 Hz), 1.26-1.22
(6 H, m), 1.21 (3H×0.45, t, J = 6.8 Hz), 1.16 (3H×0.55, t, J = 7.2 Hz), 0.97 (3H×0.55, d, J = 7.6
Hz), 0.96 (3H×0.45, d, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3)  179.39 (C), 179.14 (C), 170.69
(C), 170.67 (C), 170.22 (C), 170.19 (C), 101.23 (CH), 98.26 (CH2), 98.23 (CH2), 97.55 (CH), 83.25
(CH), 83.10 (CH), 72.25 (CH), 71.27 (CH), 71.07 (CH), 68.84 (CH), 68.32 (CH), 67.84 (CH), 60.49
(CH2), 60.07 (CH2), 56.28 (CH3), 56.26 (CH3), 43.05 (CH), 43.01 (CH), 41.33 (CH2), 41.05 (CH2),
38.51 (CH for both isomers), 35.83 (CH2), 34.42 (CH2), 21.27 (CH3), 21.25 (CH3), 21.13 (CH3),
21.10 (CH3), 20.75 (CH3), 20.63 (CH3), 20.36 (CH3), 20.34 (CH3), 15.27 (CH3), 15.25 (CH3), 12.83
(CH3), 12.77 (CH3), 11.36 (CH3), 11.22 (CH3).