The stereoselective total synthesis of isocladosorpin

Article abstract of DOI:10.1016/j.tetlet.2013.07.055

A highly stereoselective total synthesis of isocladosorpin is described. The key steps involved in this synthesis are oxa-Michael reaction, asymmetric propargylation, and Alder-Rickerts reaction.

Full text of DOI:10.1016/j.tetlet.2013.07.055

Tetrahedron Letters 54 (2013) 5185–5187
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The stereoselective total synthesis of isocladosorpin
a
b
B. V. Subba Reddy a, , P. Janardhan Reddy , C. Suresh Reddy
⇑
a Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective total synthesis of isocladosorpin is described. The key steps involved in this syn-
thesis are oxa-Michael reaction, asymmetric propargylation, and Alder–Rickerts reaction.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 4 May 2013
Revised 8 July 2013
Accepted 9 July 2013
Available online 16 July 2013
Keywords:
Isocladosorpin
Oxa-Michael reaction
Asymmetric propargylation
Alder–Rickerts reaction
The isocladosorpin (1),1 a dihydroisocoumarin natural product,
was isolated from the fungus Cladosporium cladosporioides in 1993.
Another dihydroisocoumarin natural product that is cladosorpin
(2), an antifungal antibiotic and plant growth inhibitor was iso-
lated from various fungal species2,3 such as Aspergillus flavus. The
relative configuration of isocladosorpin was confirmed in 2012
by Xuegong et al. through its asymmetric total synthesis.4 Both
isocladosorpin (1) and cladosorpin (2) constitute a 2,6-disubsti-
tuted tetrahydropyran (THP) ring and a d-valerolactone with a
fused 1,3-dihydroxybenzene ring (Fig. 1). Owing to their challeng-
ing structural features and promising biological activities, isoclado-
sorpin and cladosorpin have attracted many synthetic organic
chemists. As a part of our interest on the total synthesis of dihydro-
isocoumarin natural products5a (involving Alder–Rickerts reaction
to construct aromatic core and oxa-Michael reaction for the con-
struction of cis-2,6-disubstituted tetrahydropyran ring),5b we here-
ester 7. The Michael acceptor 7 could inturn be prepared from 5-
hexene-1-ol using known literature procedures.
The synthesis of a key fragment 4 is illustrated in Scheme 2.
Accordingly, compound 9 was prepared using known procedures.6
Deprotection of benzyl ether of 9 with Li in liq. ammonia afforded
OH
O
OH
O
O
O
O
O
HO
HO
1
2
Figure 1. Structures of isocladosorpin (1) and cladosorpin (2).
OH
O
OMe
CO2Me
OTBS
in describe
a
highly stereoselective total synthesis of
O
O
O
isocladosorpin (1) based on oxa-Michael reaction, asymmetric
propargylation, and Diels–Alder reaction.
HO
MeO
3
1
Retrosynthetic analysis of isocladosorpin (1) has been outlined
in Scheme 1. The synthesis of isocladosorpin (1) was proposed to
accomplish from the construction of aromatic moiety 3 which in-
turn could be prepared via the Alder–Rickert reaction between die-
nophile 4 and 1,4-cyclohexadiene 5. The chiral acetylenic ester 4
can be prepared through enantioselective propargylation of alde-
hyde, which could be obtained from the ester functionality 6. The
formation of pyran ring 6 could be achieved via an intramolecular
OMe
MeO2C
O
TBSO
+
MeO
4
5
OH
O
EtO2C
oxa-Michael addition of secondary alcohol onto
a,b-unsaturated
EtO2C
7
6
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B. V. S. Reddy).
Scheme 1. Retrosynthetic analysis of isocladosorpin (1).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.055

5186
B. V. S. Reddy et al. / Tetrahedron Letters 54 (2013) 5185–5187
OTBS
OMe
a
ref 6
a
BnO
HO
MeO2C
TBSO
O
+
8
9
MeO
MeO
5
4
OTBS
OTBS
b
c
OMe O
OMe
EtO2C
HO
CO2Me
OTBS
O
b
10
O
O
11
MeO
3
14
OH
O
d
e
EtO2C
EtO2C
OH
O
7
6
c
O
O
HO
OH
O
1
f
O
TBSO
13
Scheme 3. Reagents and conditions: (a) N,N-dimethylaniline, 180 °C, sealed tube,
48 h,60%; (b) TBAF, THF, 0 °C to rt, 3 h, 80%; (c) AlI3, TBAI, phloroglucinol, benzene,
0 °C, 80%.
12
g
MeO2C
TBSO
O
The required 1,4-diene 5 was prepared from a commercially
available 3-methoxyanisole under Birch conditions10 in the pres-
ence of Li metal in liq. ammonia in ethanol.11
4
R
Next, we attempted the Diels–Alder reaction between an
acetylenic ester 4 and 1,4-diene 5 to construct the aromatic moi-
ety of the target molecule. Accordingly, the Diels–Alder reaction
was performed in a sealed tube at 180 °C with a catalytic amount
of N,N-dimethylaniline to produce the aromatic core 3 in 60%
yield.12 Deprotection of the TBS ether followed by lactonization
was accomplished by treatment of 3 with TBAF in THF to afford
dihydroisocoumarin 14 in 80% yield. Demethylation of methoxy
groups from 14 was successfully achieved under Maier’s condi-
tions (AlI3, TBAI, phloroglucinol)13 in benzene at 0 °C to furnish
the target molecule (1) in quantitative yield. The spectral data
and optical rotation of the synthetic compound (1)14 are indistin-
guishable with the data reported for the natural product
(Scheme 3).1,4
O
O
O
P
OH
R
R = 2,4,6-(i-Pr)3C6H3
Catalyst (R)-(4)
Scheme 2. Synthesis of acetylenic ester 4. Reagents and conditions: (a) Li in liquid
NH3, THF, ꢀ33 °C, 20 min, 85%; (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 1 h, 80%;
(ii) Ph3P = CHCO2Et, benzene, reflux, 8 h, 75% (over two steps); (c) CSA, MeOH, 0 °C,
3 h, 80%; (d) NaH, THF, rt, 80%; (e) (i) DIBAL-H, CH2Cl2, ꢀ78 °C, 20 min; (ii) catalyst
(R)-4, allenylboronic acid pinacol ester, toluene, ꢀ30 °C, 70% over two steps; (f)
TBSCl, DMAP, imidazole, CH2Cl2, 0 °C to rt, 3 h, 92%; (g) ClCO2Me, n-BuLi, THF,
ꢀ78 °C, 1 h, 80%.
In summary, we have successfully demonstrated the stereose-
lective total synthesis of isocladosorpin via an intramolecular het-
ero-Michael reaction, asymmetric propargylation, and Alder–
Rickert reaction as the key steps. This approach has successfully
demonstrated the synthetic application of asymmetric propargyla-
tion with allenylboronic acid pinacol ester using a chiral binol
phosphoric acid to construct the chiral center of the lactone ring.
the primary alcohol 10 in 85% yield. Oxidation of 10 under Swern
conditions gave the aldehyde which was subsequently homolo-
gated with a two carbon stable ylide to afford the a,b-unsaturated
ester 11 in 75% yield over two steps. Deprotection of silyl ether
from compound 11 under mild acidic conditions7 gave the desired
Michael-acceptor 7 in quantitative yield. We next attempted an
intramolecular hetero-Michael reaction to construct the pyran ring
system. This process could easily be accomplished by exposure of
compound 7 to sodium hydride in THF at room temperature
affording a thermodynamically stable cis-2,6-disubstitued tetrahy-
dropyran ring 6 in 80% yield.8 Partial reduction of ester 6 using
1.1 equiv of DIBAL-H, in CH2Cl2, at ꢀ78 °C in 20 min gave the low
boiling aldehyde, which was then immediately subjected to asym-
metric propargylation with allenylboronic acid pinacol ester using
the (R)-2,20-bis(triisoporopyl)binol phosphoric acid as a chiral cat-
alyst to afford the chiral homopropargyl alcohol 12 (dr ꢁ 9.4:0.6,
determined by HPLC) in 70% yield (over two steps).9 The configura-
tion of the chiral alcohol 12 was confirmed by comparison of the
optical rotation and spectral data of the isocladosorpin4 synthe-
sized by She and co-workers. Protection of the alcohol 12 with
TBSCl, in the presence of imidazole and cat. DMAP in CH2Cl2 gave
the TBS ether 13 in 92% yield. Treatment of alkyne 13 with n-BuLi
followed by the addition of methyl chloroformate gave the acety-
lenic ester 4 in 80% yield (Scheme 2).
Acknowledgement
P.J.R. thanks CSIR, New Delhi, India for the award of
fellowship.
a
References and notes
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293.13757.
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pyran-2-yl)propyl)-4,6-dimethoxybenzoate (3): Rf 0.50 (20% EtOAc in hexane);
½
a 2D0
ꢂ
ꢀ12.0 (c 1.2, CHCl3); 1H NMR (CDCl3, 600 MHz): d 6.41 (1H, d, J = 1.5 Hz),
6.32 (1H, d, J = 1.5 Hz), 4.17–4.09 (1H, m), 3.89–3.87 (1H, m), 3.86 (3H, s), 3.79
(3H, s), 3.78 (3H, s), 3.44–3.32 (2H, m), 2.76 (1H, dd, J = 5.6, 13.9 Hz), 2.69 (1H,
dd, J = 6.7, 13.9 Hz), 1.81–1.74 (1H, m), 1.59–1.36 (6H, m), 1.13 (3H, d,
J = 6.0 Hz), 0.86 (9H, s), ꢀ0.01 (3H, s), ꢀ0.18 (3H, s); 13C NMR (CDCl3, 75 MHz);
d 160.9, 139.2, 107.6, 96.6, 73.6, 73.5, 68.9, 55.9, 55.3, 52.0, 44.3, 42.4, 33.2,
31.8, 25.9, 23.8, 22.0, 18.0, ꢀ4.8, ꢀ5.2; IR (KBr): vmax 2932, 2853, 1728, 1604,
1462, 1271, 1137,1080 cmꢀ1; ESI-MS: m/z 489 [M+Na]+; HRMS (ESI) calcd for
10. (a) Birch, A. J. J. Chem. Soc. 1944, 430; (b) Birch, A. J.; Subba Rao, G. S. R. Adv. Org.
Chem. 1972, 8, 1.
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1423; (b) Kanakum, C. C.; Mani, N. S.; Ramanathan, H.; Subba Rao, G. S. R J.
Chem. Soc., Perkin Trans. 1 1989, 1907.
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Parton, B.; Price, A. W.; Somvichien, N. Tetrahedron Lett. 1966, 35, 4153; (b)
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14. Spectral data for selected compounds:
C25H42NaO6Si: 489.26429, found: 489.26382.
(R)-1-((2R,6R)-6-Methyl-tetrahydro-2H-pyran-2-yl)pent-4-yn-2-ol (12): Rf 0.50
(10% EtOAc in hexane); ½a D20
ꢂ
ꢀ9.0 (c 0.7, CHCl3); 1H NMR (CDCl3, 300 MHz): d
4.13–4.02 (1H, m), 3.75–3.63 (1H, m), 3.53–3.40 (2H, m), 2.46–2.32 (2H, m),
2.02 (1H, t, J = 2.6 Hz), 1.88–1.70 (2H, m), 1.68–1.19 (6H, m), 1.15 (3H, d,
J = 6.2 Hz); 13C NMR (CDCl3, 75 MHz): d 81.3, 75.4, 74.1, 70.1, 67.5, 40.5, 33.0,
30.7, 26.9, 23.4, 22.1; IR (KBr): vmax 3448, 3039, 2927, 2855, 1730, 1374,
1079 cmꢀ1; ESI-MS: m/z 183 [M+H]+; HRMS (ESI) calcd for C11H20O2: [M+H]+
183.13795, found: 183.13796.
Ethyl 2-((2R,6R)-6-methyl-tetrahydro-2H-pyran-2-yl)acetate (6): Rf 0.60
Isocladosorpin (1): Rf 0.30 (50% EtOAc in hexane); ½a D20
ꢂ
ꢀ6.2 (c 0.75, CHCl3); mp
(10% EtOAc in hexane); ½a D31
ꢂ
ꢀ3.0 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz):
155–156 °C; 1H NMR (CDCl3, 300 MHz): d 11.12 (1H, s), 7.03–6.99 (1H, br s),
6.34 (1H, d, J = 2.0 Hz), 6.17 (1H, s), 4.88–4.76 (1H, m), 3.75–3.66 (1H, m), 3.55–
3.40 (1H, m), 2.88–2.67 (2H, m), 1.96–1.69 (3H, m), 1.65–1.45 (3H, m), 1.29–
1.20 (2H, m), 1.16 (3H, d, J = 6.2 Hz); 13C NMR (CDCl3, 75 MHz): d 170.3, 164.3,
163.3, 141.9, 106.8, 102.0, 101.5, 76.0, 74.2, 73.3, 41.6, 33.6, 33.1, 31.6, 23.4,
d 4.13 (2H, q, J = 6.7 Hz), 3.82–3.70 (1H, m), 3.52–3.39 (1H, m), 2.53 (1H, dd,
J = 7.5, 15.2 Hz), 2.36 (1H, dd, J = 6.0, 15.1 Hz), 1.86–1.74 (1H, m), 1.69–1.43
(5H, m), 1.24 (3H, t, J = 6.7 Hz), 1.13 (3H, d, J = 6.8 Hz); 13C NMR (CDCl3,
75 MHz):
d 171.4, 74.3, 74.0, 60.2, 41.7, 32.8, 30.9, 23.4, 22.0, 14.1; IR
(KBr): vmax 2923, 2856, 1737, 1449, 1373, 1190, 1073 cmꢀ1; ESI-MS: m/z 187
21.9; IR (KBr):
v
max 3382, 3148, 2932, 1667, 1640, 1437, 1328, 1157 cmꢀ1; ESI-
[M+H]+.