Stereoselective total synthesis of paecilomycin e

Article abstract of DOI:10.1016/j.tetlet.2011.10.137

First total synthesis of recently isolated resorcylic acid lactone paecilomycin E has been accomplished. The key reactions include olefin metathesis, Mitsunobu reaction, Stille coupling and regioselective allylation.

Full text of DOI:10.1016/j.tetlet.2011.10.137

Tetrahedron Letters 53 (2012) 56–58
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Tetrahedron Letters
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Stereoselective total synthesis of paecilomycin E
⇑
P. Srihari , B. Mahankali, K. Rajendraprasad
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
First total synthesis of recently isolated resorcylic acid lactone paecilomycin E has been accomplished. The
key reactions include olefin metathesis, Mitsunobu reaction, Stille coupling and regioselective allylation.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 September 2011
Revised 20 October 2011
Accepted 23 October 2011
Available online 31 October 2011
Keywords:
Resorcylic acid lactone
Macrolactone
Mitsunobu
Stille coupling
Metathesis
Ever since the isolation and biological evaluation of radicicol, a
b-resorcylic acid lactone, there has been an increased interest in
other naturally occurring resorcylic acid lactones (RAL).1 This has
been mainly attributed to the potent biological properties such
as antifungal,2 antimalarial, antiviral, antiparasitic,3 cytotoxic,4
oestrogenic,5 nematicidal,6 protein tyrosine kinase and ATPase
inhibition activities7 being displayed by them. Recently, Chen et
al.8 have disclosed isolation of new resorcylic acid lactones from
paecilomyces fungus SC0924 and named them paecilomycins A–F
along with other known RALs (Fig. 1).
in turn was obtained from alkyne 15 via an epoxide opening reac-
tion. The compound 15 can be accessed from commercially avail-
able L-(+)-diethyl tartarate.
The aromatic acid was synthesized as depicted in Scheme 2 start-
ing from 2,4,6-trihydroxybenzoic acid. Accordingly, the 2,4,6-trihy-
droxybenzoic acid was subjected to Danishefsky’s modified
protocol10 for the conversion to the corresponding acetonide pro-
tected compound 12 using trifluoroacetic acid and trifluoroacetic
Of the new compounds, paecilomycin E was found to display
antiplasmodial activity against Plasmodium falciparum line 3D7
with IC50 value of 20.0 nM and moderate activity against P. falcipa-
rum line Dd2. The structure and preliminary biological property of
paecilomycin E has prompted us to take up its total synthesis along
with its analogues for further biological property evaluation. In
continuation to our programme on the total synthesis of newly iso-
lated potent natural products,9 we here-in describe a convergent
approach for the total synthesis of paecilomycin E.
Our retrosynthetic analysis revealed two key fragments: an ali-
phatic side chain with free secondary hydroxyl moiety 9, and an
aromatic acid 10 which can be coupled via Mitsunobu esterifica-
tion to give the intermediate 8 (Scheme 1). The intermediate 8
upon olefin metathesis reaction followed by MOM and acetonide
deprotection provides the target molecule 5. While the aromatic
acid 10 can be synthesized from 2,4,6-trihydroxybenzoic acid 11
in six steps, the chiral aliphatic fragment 9 was obtained from 12
in four steps. The compound 12 could be obtained from 13 which
OH
O
OH
O
O
O
OH
R2 R1
H3CO
OH
H3CO
O
OH OH
OH
OH
Paecilomycin C : R =H. R2 =OH
Paecilomycin D : R =OH. R2 =H
1
3
OH
1
1
Paecilomycin A
4
OH
O
1
13
OH
O
12
11
O
O
O
4
10
9
H3CO
OH
7
H3CO
OH
OH
8
5
R1
R2
HO
Paecilomycin B
OH
Paecilomycin E 5 :
2
R1=H. R2 =OH, C10-C11 = CH2-CH2
Paecilomycin F6 :
R1=OH. R2 =H, C10-C11 = CH2-CH2
LL-Z1640-2 7 :
R1, R2 = O, C10-C11 = CH=CH
⇑
Corresponding author. Tel.: +91 4027191815; fax: +91 4027160512.
E-mail addresses: sriharipabbaraja@yahoo.com, srihari@iict.res.in (P. Srihari).
Figure 1. Structures of paecilomycins A–F 1–6.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.137

P. Srihari et al. / Tetrahedron Letters 53 (2012) 56–58
57
OH
O
1
OH
O
O
O
O
OH
2,2-DMP,
pTsOH
C6H6, 90 oC,
15 h, 90%
10
OEt
OEt
O
O
EtO
EtO
O
16
O
4
OH
L(+)-DET
O
H3CO
OH
H3CO
OMOM
9
OH
O
8
O
O
7
OH
NaH, BnBr,
LiAlH4,
THF, 40 oC,
5 h, 95%
O
OH
OH
18
8
Paecilomycin E
HO
BnO
THF, rt,
O
OH
OH
O
O
OH
O
3 h, 80%
17
OMOM O
OH
O
HO
OH
O
+
3
i) Swern oxidation
n-BuLi, BF3.Et2O, THF
-78 oC, 6 h, 82%
O
H3CO
BnO
11
10
9
ii) X, K2CO3, MeOH
rt, 8 h, 65% over 2 steps
O
OH
15
X = Dimethyl(1-diazo-2-oxopropyl)phosphonate
O
O
OTBS
OTBS
O
HO
BnO
O
TBSOTf,
OH
OTBS
O
O
2,6-lutidine
BnO
12
13
BnO
CH2Cl2, 0 oC,
30 min, 94%
O
O
O
O
19
13
BnO
+
L(+)-DET
i) Swern Oxidation
OTBS ii) Zn, allylbromide
THF/NH4Cl, rt, 5 h
O
O
14
15
H2, Pd/C, THF
rt, 24 h, 90%
HO
3
iii)MOM-Cl, DIPEA
Scheme 1. Retrosynthesis for paecilomycin E.
O
CH2Cl2, rt, 6 h
12
63% overall for 3 steps
OMOM O
O
OTBS
anhydride. Regioselective methylation on 4-hydroxy group was
achieved under Mitsunobu conditions11 to get 13. The free 2-hydro-
xy group (phenol) was converted to the corresponding triflate 14
with trifluoromethanesulfonic anhydride and was then subjected
to Stille coupling12 with vinyl tributyl tin to afford styrene 15.
Deprotection of isoproylidene moiety with LiOHꢀH2O afforded the
aromatic key fragment 10.
OMOM O
O
OH
TBAF, THF, rt
5 h, 97%
3
3
9
20
Scheme 3. Synthesis of aliphatic side chain 9.
The synthesis of other key fragment 9 commenced with the
conversion of L-(+)-DET to its corresponding acetonide 16 with
followed by zinc mediated allylation,18 and in situ protection with
MOMCl afforded corresponding MOM ether 2019 along with its dia-
stereomer 20a in 9:1 ratio. Deprotection of silyl ether in 20 with
TBAF yielded the aliphatic key fragment 9 in quantitative yield
(Scheme 3).
Withthetwointermediatesinhand, thestage wasset forcomple-
tion of total synthesis. Accordingly, the two fragments 9 and 10 were
subjected to esterification reaction employing Mitsunobu condi-
tions to get an ester 8. Exposure of ester 8 with two free terminal ole-
fins to Grubbs II generation catalyst at room temperature provided
the trans olefin 21 exclusively.20 The compound 21 upon treatment
2,2-dimethoxy propane in the presence of pTSA.13 The compound
16 was treated with LiAlH4 to get the diol 1714 which was mono
protected as its corresponding benzyl ether 18 upon treatment
with benzyl bromide in the presence of NaH. The free primary hy-
droxyl moiety was oxidised under Swern condition15 to get the
aldehyde and then subjected to Bestmann Ohira reaction16 to yield
the terminal acetylene 15. The alkyne 15 was metallated with
nBuLi and then treated with (R)-propylene oxide to afford the chiral
homo-propargyl alcohol 19.17 The alkynol 19 was protected as the
corresponding silyl ether 13 with TBDMSOTf in the presence of 2,
6-lutidine and was then subjected to one pot alkyne reduction
and benzyl deprotection with Pd/C under hydrogen atmosphere
to yield alcohol 12. Oxidation of alcohol under Swern conditions
OH
O
OMOMO
O
OH
PPh3, DIAD
HO
+
COOH
toluene, rt,
O
O
3
9
OCH3
30 min., 71%
HO
OH
TFA, TFAA,
PPh3, DIAD,
10
O
acetone, rt,
MeOH, THF
rt, 3 h, 85%
48 h, 55% HO
OH
O
OH
12
OH
O
11
O
Grubbs-II catalyst
H3CO
OMOM
O
CH2Cl2, 48 h, rt, 85%
SnBu3,
O
O
Tf2O, Py
Pd(PPh3)4
O
O
O
0 oC, 3 h, 95%
O
LiCl, PPh3,
DMF, rt,
4 h, 90%
8
H3CO
OH
O
H3CO
OTf
13
14
OH
O
OH
O
O
O
O
2N HCl,
OH
O
LiOH.H2O,
THF:H2O (2:1)
rt, 10 h, 86%
H3CO
OMOM
THF,15 h,
rt, 87%
O
OH
H3CO
OH
O
H3CO
H3CO
OH
O
21
Paecilomycin E 5
OH
10
15
Scheme 4. Synthesis of paecilomycin E.
Scheme 2. Synthesis of key fragment 10.

58
P. Srihari et al. / Tetrahedron Letters 53 (2012) 56–58
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with 2 N HCl underwent one pot MOM and acetonide deprotection
to yield the target molecule paecilomycin E (Scheme 4).
When the spectral and analytical data of our synthetic com-
pound were compared with that of isolated product,8a it was found
that the structure was identical to the reported paecilomycine E,
and surprisingly, the analytical data21 was matching with the data
given to paecilomycin F. As the configuration at C8 and C9 stereo-
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Paecilomycin F was also isolated from culture broth of Cochlioolus lunatus (b)
Shao, C.-L.; Wu, H.-X.; Wang, Ch.-Y.; Liu, Q.-A.; Xu, Y.; Wei, M.-Y.; Qian, P.-Y.;
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Janakiram, R. V.; Shashi, V. K. J. Org. Chem. 2011, 76, 2568–2576; (c) Srihari, P.;
Kumaraswamy, B.; Shankar, P.; Ravishashidhar, V.; Yadav, J. S. Tetrahedron Lett.
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10. Dushin, R. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1992, 114, 655–659.
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The transformation was also achieved in two steps using Corey Fuchs protocol
yielding the desired product in 67% yield.
centres were derived from L-(+)-diethyl tartarate, the configuration
at these centres are unequivocally established by our synthesis.
In conclusion, the first total synthesis of paecilomycin E has
been achieved. The strategy can be also utilised for generation of
other analogues by either varying the chiral epoxide or esterifica-
tion reaction. Also by varying the allylation conditions, the other
diastereomers can be made accessible. Further studies toward
the total synthesis of other paecilomycins and their analogues
are being currently investigated.
Acknowledgements
B.M. thanks UGC, New Delhi for the financial assistance. P.S.
acknowledges research Grant (P 81-113) from the Human Re-
sources Research Group-New Delhi through the Council of Scien-
tific & Industrial Research (CSIR) Young Scientist Award Scheme.
The authors also thank Dr. J. S. Yadav, Director, IICT for his constant
support and encouragement.
17. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
18. Chattopadhyay, A.; Dhotare, B. Tetrahedron Asymm. 1998, 9, 2715–2723.
19. The product obtained after allylation was a mixture of diastereomers which
were inseparable and were directly treated with MOMCl to get the
corresponding MOM ether. The products (diastereomers) at this stage were
easily separated by flash chromatography. The percentage of diastereomers
(9:1) was calculated based on the weight of the MOM protected products.
20. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956; (b)
Fuse, S.; Sugiyama, S.; Takahashi, T. Chem. Asian J. 2010, 5, 2459–2462.
Supplementary data
21. Spectroscopic data for selected products 9. ½a D20
= ꢂ20.25 (c 0.8, CHCl3); IR (neat):
ꢁ
Supplementary data (experimental procedures and analytical
data for all the new compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.10.137.
3433, 3077, 2931, 1641, 1458, 1374, 1248, 1214, 1152, 1101, 1038, 917,
879 cmꢂ1 1H NMR (300 MHz, CDCl3): d 5.91–5.77 (m, 1H), 5.14–5.06 (m, 2H),
;
4.65(q, J = 6.7 Hz, 2H), 3.94–3.88 (m, 1H), 3.84–3.76 (m, 1H), 3.71–3.62 (m, 2H),
3.36 (s, 3H), 2.39–2.34 (m, 2H), 1.62–1.42 (m, 6H), 1.36 (s, 3H), 1.35 (s, 3H),
1.12 (d, J = 6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 134.2, 117.5, 108.4, 96.1,
81.4, 78.4, 77.1, 67.7, 55.7, 39.0, 35.5, 34.1, 27.3, 27.0, 23.3, 22.4; MS (ESI): m/
z = 325 [M+Na]; HRMS (ESI): calcd for C16H30O5Na, 325.1990, found 325.1999.
References and notes
8. ½a 2D0
ꢁ
= +8.5 (c 0.6, CHCl3); IR (neat): 3448, 3168, 2921, 2851, 1647, 1609,
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1573, 1385, 1257, 1209, 1159, 1036, 916, 770 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d 11.73 (s, 1H), 7.25 (dd, J = 17.3, 11.3 Hz, 1H), 6.42 (d, J = 2.2 Hz, 1H), 6.36 (d,
J = 2.2 Hz, 1H), 5.90–5.76 (m, 1H), 5.37 (dd, J = 17.3, 2.2 Hz,1H), 5.22–5.13 (m,
2H), 5.08–5.05 (m, 1H), 4.63 (q, J = 6.7 Hz, 2H), 3.91–3.84 (m, 1H), 3.82 (s, 3H),
3.70–3.58 (m, 2H), 3.34–3.33 (m, 1H), 3.31 (s, 3H), 2,44–2.28 (m, 2H), 1.85–
1.43 (m, 6H), 1.37 (d, J = 6.7 Hz, 3H), 1.35 (s, 3H), 1.34 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 170.7, 164.9, 163.8, 143.6, 138.5, 134.1 (2C), 117.5, 115.2,
108.4, 108.1, 100.0, 96.0, 81.4, 78.4, 77.1, 72.5, 55.7, 55.3, 35.7, 35.6, 34.1, 27.3,
26.5, 21.9, 19.9; MS (ESI): m/z = 501 [M+Na]; HRMS (ESI): calcd for C26H38O8Na
501.2464, found 501.2452. 21. mp 119 °C; ½a D20
= ꢂ131.49 (c 1.16, CHCl3); IR
ꢁ
(KBr): 2982, 2933, 1647, 1608, 1574, 1445, 1376, 1357, 1319, 1257, 1211,
1159, 1103, 1034, 967, 864, 757 cmꢂ1 1H NMR (300 MHz, CDCl3): d 11.92 (s,
;
1H), 7.15 (dd, J = 15.8, 2.2 Hz, 1H), 6.40 (s, 2H), 5.80–5.70 (m, 1H), 5.17–5.06
(m,1H), 4.79 (q, J = 6.7 Hz, 2H), 4.30–4.26 (m, 1H), 4.16–4.08 (m, 1H), 3.87 (dd,
J = 8.3, 1.5 Hz, 1H), 3.82 (s, 3H), 3.42 (s, 3H), 2.78–2.69 (m, 1H), 2.39–2.26 (m,
1H), 1.84–1.53 (m, 6H), 1.42 (d, J = 6.0 Hz, 3H), 1.38 (s, 3H), 1.32 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 171.1, 165.2, 163.8, 142.6, 133.9, 128.4, 123.5, 108.6,
100.2, 96.9, 78.9, 74.9, 74.1, 73.2, 55.5, 55.3, 36.5, 35.5, 32.5, 27.2, 26.8, 20.1,
18.9; MS (ESI): m/z = 473 [M+Na]; HRMS (ESI): calcd for C24H34O8Na 473.2151,
found 473.2151. Paecilomycine E 5. mp 168 °C; ½a D20
= ꢂ93.83 (c 0.12, MeOH);
ꢁ
6. Dong, J.; Zhu, Y.; Song, H.; Li, R.; He, H.; Liu, H.; Huang, R.; Zhou, Y.; Wang, L.;
Cao, Y.; Zhang, K. J. Chem. Ecol. 2007, 33, 1115–1126.
IR (KBr): 3448, 2926, 1616, 1595, 1508, 1367, 1264, 1153, 1087, 1012, 964, 778,
7. (a) Abid, E. S.; Ouanes, Z.; Hassen, W.; Baudrimont, I.; Creppy, E.; Bacha, H.
Toxicol. In Vitro 2004, 18, 467–474; (b) Furstner, A.; Langemann, K. J. Am. Chem.
Soc. 1997, 119, 9130–9136; (c) Kwon, H. J.; Yoshida, M.; Abe, K.; Horinouchi, S.;
Beppu, T. Biosci. Biotechnol. Biochem. 1992, 56, 538–539; (d) Chanmugam, P.;
Feng, L.; Liou, S.; Jang, B. C.; Boudreau, M.; Yu, G.; Lee, J. H.; Kwon, H. J.; Beppu,
T.; Yoshida, M.; Xia, Y.; Wilson, C. B.; Hwang, D. J. Biol. Chem. 1995, 270, 5418–
5426; (e) Takehara, K.; Sato, S.; Kobayashi, T.; Maeda, T. Biochem. Biophys. Res.
Commun. 1999, 257, 19–23; (f) Giese, N. A.; Lokker, N. Int. Pat. WO9613259;
691 cmꢂ1 1H NMR (500 MHz, CDCl3): d 12.22 (s, 1H), 7.12 (d, J = 14.8 Hz, 1H),
;
6.38 (s, 2H), 5.70–5.64 (m, 1H), 5.00–4.90 (m, 1H), 4.19–4.13 (m, 2H), 3.79 (s,
3H), 3.52 (s, 1H), 2.69–2.66 (m, 1H), 2.52–2.44 (m, 1H), 1.96–1.78 (m, 2H),
1.64–1.41 (m, 2H), 1.38 (d, J = 5.9 Hz, 3H), 1.34–1.28 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 171.4, 165.9, 164.0, 142.9, 134.1, 127.3, 109.0, 103.3, 100.2,
76.1, 73.7, 68.8, 66.9, 55.4, 38.7, 35.2, 30.9, 21.2, 20.9; MS (ESI): m/z = 389
[M+Na]; HRMS (ESI): calcd for C19H26O7Na 389.1576, found 389.1591.