The first stereo selective total synthesis of (3R),(5R)-5-hydroxy-de-O-methyllasiodiplodin and its epimer via an RCM protocol

Article abstract of DOI:10.1016/j.tetlet.2010.05.115

The first total synthesis of (3R),(5R)-5-hydroxy-de-O-methyllasiodiplodin and its epimer is reported from malic acid. The adopted approach is highly convergent and stereoselective. The strategy utilizes syn selective reduction and ring-closing metathesis

Full text of DOI:10.1016/j.tetlet.2010.05.115

Tetrahedron Letters 51 (2010) 4050–4052
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The first stereo selective total synthesis of (3R),(5R)-5-hydroxy-de-O-
methyllasiodiplodin and its epimer via a RCM protocol
*
J. S. Yadav , Saibal Das, J. Satyanarayana Reddy, N. Thrimurtulu, A. R. Prasad
Organic Division-1, Indian Institute of Chemical Technology (CSIR), Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of (3R),(5R)-5-hydroxy-de-O-methyllasiodiplodin and its epimer is reported from
malic acid. The adopted approach is highly convergent and stereoselective. The strategy utilizes syn selec-
tive reduction and ring-closing metathesis as key steps.
Received 7 April 2010
Revised 24 May 2010
Accepted 25 May 2010
Available online 1 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Lasiodiplodin and its family are identified to be very efficient
inhibitors of prostaglandin biosynthesis, and exhibit significant
anti-leukemic and potato micro-tuber inducing activities.1 The
hydroxyl-lasiodiplodins were isolated from the mycelium extracts
of a fungus where Lasiodiplodia theobromae IFO 31059, and their
structures were acknowledged as (3R),(5R)-5-hydroxy-de-O-
methyllasiodiplodin (1), (3R),(4S)-4-hydroxylasiodiplodin (3) and
(3R),(6R)-6-hydroxy-de-O-methyllasiodiplodin (4)2 which was
found to implement strong potato micro-tuber inducing activity
in the growth of higher plants and produces various organic
metabolites3 where earlier reports also revealed the presence of
some biologically active compounds from IFO 31059 namely jas-
monic acid, mellein, theobroxide, and 5-hydroxy lasiodiplodins3
(2a/2b) (Fig. 1). And lately it has also been reported to show anti-
microbial activities.4
Considering the growing importance of this family of com-
pounds and our ongoing interest in the total synthesis of biologi-
cally active natural products, herein we report the first total
synthesis of (3R),(5R)-5-hydroxy-de-O-methyllasiodiplodin (1)
and (3R),(5S)-5-hydroxy-de-O-methyllasiodiplodin (2), its epimer.
The strategy involves syn-stereoselective 1,3-asymmetric
reduction and ring-closing metathesis as the key steps, utilizing a
LiAlH4–LiI8 in ether, anti:syn diols were obtained in the ratio of
30(8):70(9) with 92% yield. Both the isomers were easily separated
and taken forward towards the desired target (Scheme 2).
Secondary alcohols 8 and 9, thus obtained were protected to its
benzyl ethers 10 and 11, respectively to undergo acid-catalyzed
hydrolysis in aqueous methanol, to furnish the corresponding diols
12 and 13 in excellent yields. Then chemoselective tosylation of
terminal alcohols provided the mono-tosylated compounds, which
upon treatment with LAH9 furnished the required secondary alco-
hols 14 and 15 in 70–73% yield to be utilized for esterification
(Scheme 3).
Having both the intermediate alcohols 1410 and 1511 in hand for
synthesizing 1 and 2, respectively, we then focused our interest
towards the synthesis of required intermediate 20 (Scheme 4)
starting from readily available 2,4,6-trihydroxy benzoic acid,
which furnished compound 16 in good yields (75%) under classical
R1
OH
O
O
O
O
O
=
very common and inexpensive starting material,
(Scheme 1).
L-malic acid
HO
OH
OH
HO
R2
Accordingly, (3R),(5R)-5-hydroxy-de-O-methyllasiodiplodin (1)
and (3R),(5S)-5-hydroxy-de-O-methyllasiodiplodin (2) were pre-
pared from 5, which was obtained using classical chemistry from
1
2 R1 = H, R2
OH
2a R1 = CH3, R2
2b R1 = CH3, R2
=
=
OH
OH
L
-malic acid.5 Compound 5 was then transformed into its Weinreb
amide 6 in 90% excellent yield, under the conditions defined by
Williams et al.,6 after which it was treated with homoallylmagne-
sium bromide to afford the corresponding homoallylic ketone 77 in
78% yield. Compound 7 was then subjected to syn selective 1,3-
asymmetric reduction following the method of Mori et al. using
OH
O
OH
O
O
O
HO
HO
OH
4
3
* Corresponding author. Tel.: +91 40 2716 3030; fax: +91 40 2716 0387.
E-mail addresses: yadavpub@iict.res.in, saibal.sky007@gmail.com (J.S. Yadav).
Figure 1. Molecules from Lasiodiplodin family.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.115

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 4050–4052
4051
OH
O
OH
O
O
O
O
O
O
O
Tf2O, Pyridine,
BnBr, NaH,
O
O
HO
R
O
BnO
R
THF, rt,
DCM, 0ºC-rt,
BnO
OH
HO
OH
6 h, 98%
81%
16
17
1 R =
2 R =
OH
20
22
R = OBn
R =
OH
OBn
O
O
O
O
Pd (PPh3)4,
AllylBu3Sn,
O
OH
R
NaH, THF/DMF,
O
O
O
+
BnO
BnO
OTf LiCl, DMF, BnO
60 C, 8 h,
71%
14, 12 h, 0ºC-rt.
BnO
14
15 R =
R = OBn
º
81%
18
19
OBn
19
OH
O
OH
O
O
Grubbs II
catalyst,
O
Tri-hydroxy benzoic acid
L-Malic acid
DCM, reflux,
12 h, 64%
OBn
OH
BnO
OBn
Scheme 1. Retro synthesis of 5-hydroxy-de-O-methyllasioplodins.
20
21
O
2
Pd/C, MeOH,
6 h, 85%.
iPrMgCl,
(MeO)MeNH.HCl,
O
4
O
O
ref 5
OMe
O
HO
OH
L-Malic acid
O
O
THF, -15°C, 0.5 h,
90%
1
5
Scheme 4.
O
O
O
Homoallylbromide,
O
O
O
O
81% yield. Then diene 20 was engaged for the key RCM reaction
with 5 mol % Grubb’s II catalyst under high dilution conditions15
(0.001 M in DCM) to afford the cyclic ester 21 in 64% yield, which
was further reacted with Pd/C in methanol to deliver the desired
compound 1 in 85% yield, wherein, benzyl deprotection along with
the reduction of the olefin was accomplished in single step. The
spectral data of thus synthesized compound 116 was in agreement
with the natural product2 and was further confirmed by NOE
experiment by irradiation of proton present at position 2, also val-
idating the 14 as anti-diol and 15 as syn-diol at 2 and 4 positions.
It is noteworthy that the crucial esterification12 of alcohols 14
and 15 to furnish the desired dienes 20 and 22, respectively, which
were obtained using diluted solution of compound 19 in dry THF/
DMF (1:1) with moderate yield.
Mg, THF,
-78ºC-40°C
78%,
N
7
6
LiAlH4-LiI
(3 equiv, 1:1),
OH
OH
O
O
+
THF,
-78ºC-0ºC,
Et2O, 92%
9
8
Scheme 2.
reaction conditions.12 Selective O-benzylation of 16 produced 17
under mild conditions with an excellent yield of 98%. The aromatic
alcohol 17 was then treated with Tf2O to obtain 1813 in 81% yield,
which upon Pd-catalyzed Stille coupling14 with allylstannane in
the presence of LiCl yielded the desired product 19 in 71% yield.
Compound 19 was then treated with formerly prepared alcohol
14, which was deprotonated in situ with NaH to obtain the alkox-
ide anion for the esterification to afford the required diene12 20 in
Once esterification furnished compound 22, was then treated
with 5 mol % Grubb’s II catalyst under high diluted conditions
(0.001 M in DCM)15 to afford the lactone 23 in 68% yield, which
upon treatment with palladium on carbon provided the desired
compound 217 in 87% yield (Scheme 5).
OH
O
R
O
PTSA, MeOH,
BnBr, NaH,
NaH, THF/DMF,
O
Grubbs II catalyst,
8/9
O
19
rt, 30 min,
90%
THF, rt, 6 h,
95%
BnO
OBn
OBn
15
,
13h, 0ºC-rt.
85%
DCM, reflux, 12h
68%
10
11
R = OBn
R =
OBn
22
OH
O
OH
O
i) TsCl, Et3N,
cat. DMAP,
CH2Cl2, rt,
3 h, 75%.
Pd/C, MeOH,
6h, 87%.
O
O
OH
R
OH
2
R
HO
HO
OH
BnO
4
ii) LAH, THF,
0ºC, 73%
12
13 R =
14
15 R =
R = OBn
R = OBn
OBn
OBn
23
2
Scheme 3.
Scheme 5.

4052
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 4050–4052
5.84–5.69 (m, 1H), 5.03–4.91 (m, 2H), 4.52 (s, 2H), 4.12–4.0 (m, 1H), 3.72–3.63
In summary, we have demonstrated for the first time a simple
and concise total synthesis of (3R),(5R)-5-hydroxy-de-O-methylla-
siodiplodin 1 and its epimer 2 employing ring-closing metathesis
strategy, wherein L-malic acid was engaged as the common and
inexpensive starting material towards the access of both the
desired compound.
(m, 1H), 2.1 (q, 2H, J = 6.8, 14.3 Hz), 1.85–1.50 (m, 4H), 1.15 (d, 3H, J = 6.3 Hz).
13C NMR (CDCl3, 75 MHz): d 138.2, 128.4, 127.9, 127.7, 114.7, 76.5, 71.1, 64.6,
41.3, 32.6, 29.6, 23.6. IR (neat):
m 3440, 3072, 2929, 2858, 1738, 1641, 1461,
1253, 1084 cmꢁ1. MS (LCMS): m/z 257 [M+23]+.
11. (a) Gerlach, H.; Wetter, H. Helv. Chim. Acta 1974, 57, 2306–2321; (b) Narasaka,
K.; Pai, H. C. Chem. Lett. 1980, 1415–1418; (c) Bartlett, P. A.; Jernstedt, K. K.
Tetrahedron Lett. 1980, 21, 1607–1610; (d) Sato, T.; Itoh, T.; Hattori, C.;
Fujisawa, T. Chem. Lett. 1983, 1391–1392; (e) Spectral data (15): (2R,4S)-4-
(benzyloxy) oct-7-en-2-ol, light yellow syrup. ½a D25
ꢀ
¼ þ45 (c 0.2, CHCl3); 1H
NMR (CDCl3, 200 MHz): d 7.26–7.23 (m, 5H), 5.86–5.72 (m, 1H), 5.06–4.93 (m,
2H), 4.53 (dd, 2H, J = 11.3, 48.3 Hz), 3.98–3.86 (m, 1H), 3.74–3.64 (m, 1H),
2.20–2.0 (m, 2H), 1.78–1.50 (m, 4H), 1.14 (d, 3H, J = 6.3 Hz). 13C NMR (CDCl3,
75 MHz): d 138.1, 128.5, 127.8, 127.8, 114.7, 79.2, 70.5, 67.6, 42.5, 32.4, 28.7,
Acknowledgment
J.S.R. and N.T. thanks CSIR, New Delhi for the award of fellow-
ships to perform the research.
23.5. IR (neat):
m .
3440, 3072, 2929, 2858, 1738, 1641, 1461, 1253, 1084 cmꢁ1
MS (LCMS): m/z 257 [M+23]+.
12. (a) Bhattacharjee, A.; De Brabander, J. K. Tetrahedron Lett. 2000, 41, 8069–8073;
(b) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew. Chem., Int. Ed. 2002, 41, 3701–
3704; (c) Hilli, F.; White, J. M.; Rizzacasa, M. A. Tetrahedron Lett. 2002, 43,
8507–8710.
13. Chakraborty, T. K.; Chattopadhyay, A. K. J. Org. Chem. 2008, 73, 3578–3581.
14. (a) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813–817; (b) Farina, V.;
Krishna, B. J. Am. Chem. Soc. 1991, 113, 9585–9595; (c) Mitchell, T. N. Synthesis
1992, 803–815; (d) Furstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org.
Chem. 2000, 65, 7990–7995; (e) Furstner, A.; Seidel, G.; Kindler, N. Tetrahedron
1999, 55, 8215–8230.
References and notes
1. (a) Yao, X. S.; Ebizuka, Y.; Noguchi, H.; Kiuchi, F.; Shibuya, M.; Iitaka, Y.; Seto,
H.; Sankawa, U. Chem. Pharm. Bull. 1991, 39, 2956–2961; (b) Lee, K.-H.; Hayashi,
N.; Okhano, M.; Hall, I. H.; Wu, R.-Y.; McPhail, A. T. Phytochemistry 1982, 21,
1119–1121; (c) Cambie, R. C.; Lal, A. R.; Rutledge, P. S.; Woodgate, P. D.
Phytochemistry 1991, 30, 287–292.
2. Yang, Q.; Asai, M.; Matsuura, H.; Yoshihara, T. Phytochemistry 2000, 54, 489–
494.
3. Matsuura, H.; Nakamori, K.; Omer, E. A.; Hatakeyama, C.; Yoshihara, T.;
Ichihara, A. Phytochemistry 1998, 49, 579–584.
4. Yang, R.-Y.; Li, C.-Y.; Lin, Y.-C.; Peng, G.-T.; She, Z.-G.; Zhou, S.-N. Bioorg. Med.
Chem. Lett. 2006, 16, 4205–4208.
5. (a) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu, S.;
Moriwake, T. Chem. Lett. 1984, 1389–1392; (b) Saito, S.; Ishikawa, T.; Kuroda,
A.; Koga, K.; Moriwake, T. Tetrahedron 1992, 48, 4067–4086; (c) Boukouvalas, J.;
Fortier, G.; Radu, I. I. J. Org. Chem. 1998, 63, 916–917.
15. (a) Yadav, J. S.; Thrimurtulu, N.; Venkatesh, M.; Raghavendra Rao, K. V.; Prasad,
A. R.; Subba Reddy, B. V. Synthesis 2010, 73–78; (b) Bajwa, N.; Jennings, M. P.
Tetrahedron Lett. 2008, 49, 390–393; For previous efforts see (c) Furstner, A.;
Kindler, N. Tetrahedron Lett. 1996, 37, 7005–7008.
16. Spectral data (1): (3R),(5R)-5-hydroxy-de-O-methyllasiodiplodin, white
powder (mp: 150–155 °C). ½a D25
ꢀ
¼ þ19:1 (c 1.1, MeOH); 1H NMR (CD3OD,
300 MHz): d 6.18 (d, 1H, J = 2.45 Hz), 6.12 (d, 1H, J = 2.6 Hz) 5.24–5.04 (m, 1H),
4.05–3.94 (m, 1H), 3.78–3.60 (m, 1H), 2.31–2.18 (m, 1H), 2.12–1.95 (m, 1H),
1.85–1.44 (m, 7H) 1.35 (d, 3H, J = 6.04). 13C NMR (CDCl3, 75 MHz): d 173.1,
166.6, 163.8, 150.1, 112.2, 105.0, 101.9, 73.3, 70.7, 62.2, 41.9, 35.7, 35.1, 33.0,
6. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.;
Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–5464.
29.1, 21.7, 19.5. IR (neat):
m 3432, 2926, 2856, 1640, 1459, 1259, 1169,
7. Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 850–853.
8. (a) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett. 1988, 29,
5419–5422; (b) Mori, Y.; Takeuchi, A.; Kageyama, H.; Suzuki, M. Tetrahedron
Lett. 1988, 29, 5423–5426; (c) Mori, Y.; Suzuki, M. Tetrahedron Lett. 1989, 30,
4387–4388; (d) Mori, Y.; Kuhara, M.; Ota, T.; Suzuki, M. Tetrahedron Lett. 1990,
31, 2915–2916; (e) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67, 8783–8788; (f)
Sabitha, G.; Sudhakar, K.; Mallikarjun Reddy, N.; Rajkumar, M.; Yadav, J. S.
Tetrahedron Lett. 2005, 46, 6567–6570.
1024 cmꢁ1. MS (LCMS): m/z 295 [M+1]+.
17. Spectral data (2): (3R),(5S)-5-hydroxy-de-O-methyllasiodiplodin, white powder
(mp: 130–135 °C). ½a D25
ꢀ
¼ þ15 (c 0.3, MeOH); 1H NMR (CDCl3, 200 MHz): d
11.79 (s, 1H), 6.27 (d, 1H, J = 2.6 Hz), 6.22 (d, 1H, J = 2.64 Hz) 5.56–5.45 (m, 1H),
4.04–3.95 (m, 1H), 3.43–3.32 (m, 1H), 2.42–2.19 (m, 3H), 1.98–1.88 (dd, 1H,
J = 5.2, 15.8 Hz), 1.82–1.45 (m, 7H) 1.36 (d, 3H, J = 6.2 Hz). 13C NMR (CDCl3,
75 MHz): d 171.6, 165.3, 160.0, 148.9, 110.5, 105.4, 101.3, 69.6, 68.9, 38.4, 33.0,
31.8, 25.9, 20.9, 20.0. IR (neat):
m 3432, 2926, 2856, 1640, 1459, 1259, 1169,
9. Radha Krishna, P.; Srinivas, R. Tetrahedron: Asymmetry 2008, 19, 1153–1160.
10. Spectral data (14): (2R,4R)-4-(benzyloxy)oct-7-en-2-ol, a light yellow syrup.
1024 cmꢁ1. MS (LCMS): m/z 295 [M+1]+.
½
a 2D5
ꢀ
¼ ꢁ18:2 (c 0.9, CHCl3); 1H NMR (CDCl3, 200 MHz): d 7.32–7.22 (m, 5H),