Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A through a quinine-catalyzed asymmetric intramolecular oxo-Michael addition

Article abstract of DOI:10.1016/S0040-4039(00)01820-7

Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A was achieved by a quinine-catalyzed asymmetric intramolecular oxo-Michael addition as a key step. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01820-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10229–10232
Enantioselective total synthesis of anti HIV-1 active
(+)-calanolide A through a quinine-catalyzed asymmetric
intramolecular oxo-Michael addition
Tomohiro Tanaka, Takuya Kumamoto and Tsutomu Ishikawa*
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
Received 4 September 2000; revised 10 October 2000; accepted 12 October 2000
Abstract
Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A was achieved by a quinine-cata-
lyzed asymmetric intramolecular oxo-Michael addition as a key step. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: asymmetric synthesis; Michael reactions; isomerizations; coumarins.
(+)-Calanolide A (1), isolated as a strong anti HIV-1 active coumarin from Calophyllum
lanigerum var. austrocoriaceum (Guttiferae),1 is presently being examined as a possible candidate
for an AIDS drug at the clinical level in USA.2 The (10R,11S,12S) stereochemistry of the
2,3-dimethyl-4-chromanol skeleton (the ring D) in 1 is suggested to be the most responsible
function for anti HIV-1 activity.1,3 We have approached the enantioselective construction of the
chromanone ring, easily leading to the corresponding chromanol skeleton by hydride reduction,
by intramolecular oxo-Michael addition (IMA) of an o-tigloylphenol in the presence of
chincona alkaloids such as (−)-quinine, and effective asymmetric induction (up to 87% ee) was
achieved in cis-chromanone cyclization in model studies using coumarin 2 lacking a 4-propyl
group.4 However, not only was there no diastereoselectivity between cis- and trans-products 3
but also the enantioselectivity in the trans-chromanone cyclization was poor.
Me
MeO
R
Me
Me
O
MeO
R
(-)-quinine
C
O
O
O
HO
Me
O
O
A
B
O
O
O
Me
O
O
D
Me
Me
Me
OH
cis-3: R=H (87% ee; 0% de in THF)
cis-5: R=Pr (98% ee; 60% de in PhCl)
2: R=H
4: R=Pr
Me
(+)-calanolide A (1)
* Corresponding author. Tel/fax: +81-43-290-2910; e-mail: benti@p.chiba-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01820-7

10230
Further examination of the quinine-catalyzed IMA using coumarin 4 in various solvents
toward (+)-calanolide A (1) synthesis led to predominant formation (60% de) of (+)-enantiomer-
rich cis-chromanone cis-5 (98% ee) when chlorobenzene was used as a solvent.5 In this
communication we present the enantioselective total synthesis of 1 by application of the
quinine-catalyzed IMA in chlorobenzene followed by cis–trans epimerization of the formed
chromanones as the key steps.
For the total synthesis of calanolide A (1) composed of a four-ring system (rings A–D) from
coumarin substrates, two basic routes of either IMA followed by C ring construction (route A)
or the reverse order of the reactions (routes B or C) are available (Scheme 1). We have found
that cis-chromanone–coumarin cis-5 [cis-form in 8 (R1=Me)] was enantioselectively given by
the quinine-catalyzed IMA of 4;5 however, trials for demethylation of the 5-methoxy group in
5 according to route A was not successful. Furthermore, introduction of a tigloyl group into a
pyranocoumarin like 10 according to route B resulted in formation of a complex mixture.5 Thus,
a new access to a 10-tigloylpyranocoumarin like 11 by route C, in which 5,7-oxygenated
coumarin 7 with different substituents at the 5- and 7-positions such as alkoxy and silyloxy
groups is needed for selective cleavage of the 5-oxygen function, should be examined. Methoxy
and triisopropylsilyl (TIPS) groups were chosen as the protecting groups for this purpose.
Me
Me
R1O
R1O
Me
route A
Me
IMA
R2O
Me
O
O
O
O
O
Me
Me
O
Me
O
Me
O
O
Me
7
8
R1O
route C
1
O
O
R2O
O
O
Me
Me
O
Me
Me
O
6
Me
Me
Me
O
Me
9
R2O
Me
O
O
route B
IMA
R2O
O
O
O
10
Me
11
Scheme 1.
Treatment of 125 with triisopropylchlorosilane (TIPCS) in the presence of benzyltriethyl-
ammonium chloride6 as a phase transfer catalyst afforded the silylated derivative 13. Selective
demethylation of the ortho methoxy group in 13 was achieved by treatment with boron
trichloride to give the desired product 14 in 71% yield,7 which was converted into coumarin 15
in 58% yield8 by Wittig-type reaction.9 Friedel–Crafts reaction of TIPS-protected coumarin 15
with tigloyl chloride followed by deprotection of the TIPS group with tetrabutylammonium
fluoride afforded 5-hydroxy-8-tigloylcoumarin 17.10 2,2-Dimethylpyran ring formation on 17 by
propargylation11 and then Claisen rearrangement12 gave the desired 10-tigloylpyranocoumarin13
18, demethylation of which yielded 19, the starting substrate for IMA. Application of the
quinine15-catalyzed asymmetric IMA in chlorobenzene5 to o-tigloylphenol 19 at 4–5°C16 for 23
h afforded a cyclization product quantitatively, in which cis-chromanone cis-9 was, as expected,

10231
yielded in 60% de and 94% ee.17 The stereochemistry of cis-9 could be deduced to be (10R,11S)
from the results in the model studies.4
(+)-Calanolide A (1) has a trans-2,3-dimethyl-4-chromanol system in its molecule, for the
reductive construction of which a trans-chromanone ring should be needed. Treatment of cis-9
(94% ee) with MgI2·6H2O18 in refluxing benzene successfully afforded trans-9 with satisfactory
ee (90%).19 Although in this isomerization the starting cis-9 was recovered in 50% yield, this
method should be practically valuable because of the recovery of cis-9 as a re-useable form
without loss of optical activity.
Reduction of the enantiomerically rich trans-9 with lithium tri(tert-butoxy)aluminum
hydride20 afforded (+)-calanolide A (1) in 41% yield after purification (see Scheme 2), which
24
showed [h] +72 (c=1.1×10−3, CHCl3)21 in good accordance with the reported data.
589
Me
Me
Me
O
Me
Me
O
Me
RO
TIPSO
R1O
(f)
(d)
(c)
RO
Me
O
O
MeO
Me
O
O
(g)
MeO
O
O
MeO
OR2
15
O
O
12: R1=H; R2=Me
(a)
(b)
Me
Me
13: R1=TIPS; R2=Me
14: R1=TIPS; R2=H
18: R=Me
19: R=H
16: R=TIPS
17: R=H
(h)
(e)
(i)
Me
Me
O
Me
Me
O
Me
O
Me
O
(j)
(k)
O
(50%)
(+)-calanolide A
Me
O
O
O
O
O
(1)
Me
(50%)
Me
Me
trans-9
O
O
Me
trans-9
(90% ee)
Me
cis-9
(80%; 94% ee)
(20%; -)
Scheme 2. Reagents and conditions: (a) TIPCS, BnEt3NCl in PhH-20% NaOH, rt , 20 min (100%); (b) BCl3 in CH2Cl2,
−78°C, 1 h (71%); (c) Ph3PꢀCHCO2Et in PhNEt2, 215°C, 30 min (72%); (d) tigloyl chloride, SnCl4 in CH2Cl2, 7ꢀ8°C,
7 days (72%); (e) TBAF in CH2Cl2–THF, 0°C, 5 min (58%); (f) 3-chloro-3-methyl-1-butyne, DBU, CuCl in MeCN,
7ꢀ8°C, 16 h (71%); (g) PhNEt2, 150°C, 80 min (93%); (h) MgI2 in PhH, reflux, 2.5 h (77%); (i) (−)-quinine in PhCl,
3ꢀ4°C, 23 h (100%); (j) MgI2·6H2O in PhH, reflux, 2.5 h (100%); (k) LiAl(OBut)3H in THF, −15ꢀ−10°C, 2 h (41%)
In conclusion, we have succeeded in enantioselective total synthesis of (+)-calanolide A (1)
through the quinine-catalyzed asymmetric IMA of o-tigloylphenol followed by MgI2-mediated
isomerization of the formed cis-chromanone into trans-one. Although (+)-calanolide A (1) has
been prepared by two groups,22,25 it is noteworthy that our method described here would be
applicable to operationally simple, large-scale production.

10232
Acknowledgements
We thank the Futaba Electron Memorial Foundation for partial financial support to this work.
References
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6. No reaction was observed by treatment either with TIPCS and imidazole or with triisopropylsilyl triflate and
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7. The hydroxybutyrophenone 12 was also obtained in 29% yield as a simply desilylated product.
8. Deprotection of the TIPS group was observed during the coumarin construction to give 5-hydroxycoumarin in
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dehydration using toluene and then drying.
16. The cyclization was smoothly proceeded at rt (10 h) and cis-9 was obtained with high ee (93%). However, de was
lowered to 50%.
17. Each enantiomer of cis-9 was observed at retention times of 22.2 and 28.4 min, respectively when Chiralcel AS
(Daicel Co. Ltd.,) was used as a column under the following conditions; eluent: n-hexane: EtOH=9:1, flow rate:
1.0 ml/min, detection: 254 nm.
18. Treatment of cis-9 (88% ee) with LDA afforded a complex mixture composed of cis-9 (37%; 77% ee), trans-9 (11%),
and retro-Michael product 19 (39%), in which trans-9 was obtained in a racemic form.
19. Each enantiomer of trans-9 was observed at retention times of 12.2 and 13.4 min, respectively when Chiralpak
AD-RH (Daicel Co. Ltd.,) was used as a column under the following conditions; eluent: MeOH, flow rate: 1.0
ml/min, detection: 254 nm.
20. Ishikawa, T.; Oku, Y.; Kotake, K.-I. Tetrahedron 1997, 53, 14915–14928.
21. Optical rotation was measured with a JASCO ORDM-306W. Slightly different values of [h]D have been reported
on optically active calanolide A; for (+)-enantiomer [h]2D5 +60 (c=0.5, CHCl3),1 [h]2D5 +66 (c=0.5, CHCl3),22 [h]2D0
+72 (c=0.51, CHCl3),22 and [h]D25 +68.8 (c=0.7, CHCl3),23 whereas for (−)-enantiomer [h]D20 −66 (c=0.5, CHCl3),22
[h]2D5 −75.6 (c=0.7, CHCl3),23 and [h]D25 −64.2 (c=0.5, CHCl3).24
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W.; Mata, E.; Pengsuparp, T.; Pezzuto, J. M.; Hughes, S. H.; Flavin, T. M.; Cibulski, M.; Boulanger, W. A.; Shone,
R. L.; Xu, Z.-Q. J. Med. Chem. 1996, 39, 1303–1313.
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25. Khilevich, A.; Mar, A.; Flavin, M. T.; Rizzo, J. D.; Lin, L.; Dzekhtser, S.; Brankovic, D.; Zhang, H.; Chen, W.;
Liao, S.; Zembower, D. E.; Xu, Z.-Q. Tetrahedron: Asymmetry 1996, 7, 3315–3326. Enantiomeric (−)-calanolide
A has been also synthesized by two groups.22,24