Stereoselective total synthesis of achaetolide and reconfirmation of its absolute configuration

Article abstract of DOI:10.1016/j.tetlet.2010.09.070

The stereoselective total synthesis of achaetolide 1 has been achieved and its absolute stereochemistry has been reconfirmed to be 3S,6R,7S,9R configuration. Keck allylation, Sharpless asymmetric dihydroxylation, and ring closing metathesis are the key steps involved in the target synthesis.

Full text of DOI:10.1016/j.tetlet.2010.09.070

Tetrahedron Letters 51 (2010) 6174–6176
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Tetrahedron Letters
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Stereoselective total synthesis of achaetolide and reconfirmation
of its absolute configuration
⇑
P. Srihari , B. Kumaraswamy, P. Shankar, V. Ravishashidhar, J. S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, CSIR, 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:
Received 28 July 2010
Revised 16 September 2010
Accepted 19 September 2010
Available online 9 October 2010
The stereoselective total synthesis of achaetolide 1 has been achieved and its absolute stereochemistry
has been reconfirmed to be 3S,6R,7S,9R configuration. Keck allylation, Sharpless asymmetric dihydroxy-
lation, and ring closing metathesis are the key steps involved in the target synthesis.
Ó 2010 Elsevier Ltd. All rights reserved.
Lactone containing molecules have attracted significant atten-
tion due to their potent biological activities.1 Fungi have been a
great source for several lactone containing macrolides which are
being continuously isolated. A few recently isolated 10-membered
macrolides include achaetolide 1,2 decarestrictines A, D and J 3–6,3
herbarumins I–III 7–9,4 microcarpalide 25 (Fig. 1), modiolides A
and B6 and stagonolides A-I.7 Many of these molecules exhibit
potent biological activities, such as antibacterial, antifungal, cyto-
toxic, and phytotoxic properties. The potent biological properties
coupled with the scarce availability of these natural materials have
made them good target molecules for total synthesis. Achaetolide,
isolated from the culture broth of Achaetomium cristalliferum in
1983, was found to increase transpiration of cut barley leaves. Very
recently, Takada and co-workers have established the structure of
achaetolide8 by relative stereochemical assignment involving 1H
NMR analysis and Mosher’s method. In continuation of our interest
in targeting lactone containing molecules9 for total synthesis, here-
in we describe the stereoselective total synthesis of achaetolide
and re-confirm its absolute configuration.
Retrosynthetically, the target molecule was envisioned to be
obtained from the intermediate 10 by deprotection of isopropyli-
dene moiety. The compound 10 could be obtained by coupling
two key fragments, acid 11 and alcohol 12, involving esterification
followed by a ring closing metathesis to realize the 10-membered
macrolide skeleton (Scheme 1). While the acid 11 could be ob-
tained from commercially available D-aspartic acid or 3-butene-
1-ol, the alcohol 8 was obtained from commercially available
n-octanal.
O
OH
OH
O
O
HO
OH
O
O
OH
OH
Microcarpalide 2
Achaetolide 1
O
Me
Me
O
Me
O
O
O
R
R'
HO
O
HO
OH
O
Decarestrictine A1 3:
OH
R = H; R' = OH
Decarestrictine J 6
Decarestrictine D 5
Decarestrictine A2 4:
R = OH; R' = H
HO
HO
HO
Herbarumin II 8
HO
O
O
O
HO
OH
O
O
O
Herbarumin I 7
Herbarumin III 9
Figure 1. Few 10-membered macrolides.
15 (in 9:1 ratio Z:E).11 Sharpless asymmetric dihydroxylation of the
olefin 15 with ADmix-b in tert-butanol and water yielded diol 16.
Protection of diol with 2,2-dimethoxy propane in the presence of
PPTS yielded the ester 17 which was reduced with DIBAL-H to yield
alcohol 18. Swern oxidation followed by one carbon Wittig homol-
ogation with methyltriphenylphosphonium iodide in the presence
of KOtBu, yielded the olefin 19 (Scheme 2). Exposure of 19 to TBAF
yielded a key intermediate alcohol 12. The other key fragment 11
Accordingly, our synthesis started with the Keck allylation of
n-octanal employing S-BINOL, Ti(OiPr)4, and allyltributyltin to pro-
vide the homoallyl alcohol 13 in 91% yield with 93% ee.10 The chiral
secondary alcohol was protected as the corresponding tert-butyldi-
methylsilyl ether 14. Ozonolysis followed by Horner–Emmons
was synthesized starting from
procedures.12 Thus, the amino acid was subjected to diazotization
followed by bromination to yield -bromo succinic acid 20. Reduc-
D-aspartic acid following the known
olefination of 14 using Ando’s protocol gave
a,b-unsaturated ester
a
tion of the two carboxylic groups was achieved with BH3–THF to
provide 2-bromo-1,4-diol 21 which was converted to benzyl pro-
tected oxirane 22 in a one-pot reaction utilizing NaH and benzyl
⇑
Corresponding author. Tel.: +91 4027191490; fax: +91 4027160512.
E-mail addresses: srihari@iict.res.in, sriharipabbaraja@yahoo.com (P. Srihari).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.070

P. Srihari et al. / Tetrahedron Letters 51 (2010) 6174–6176
6175
10
acid 11 with sodium chlorite (NaClO2), sodium dihydrogen phos-
phate (NaH2PO4) in tert-butanol-water in an overall 96% yield
(Scheme 3).15
O
1
O
9
6
O
O
7
3
With the two key intermediates acid 11 and alcohol 12 in hand,
the stage was set for their coupling to realize the macrolide skele-
ton. The coupling of acid 11 and alcohol 12 was achieved using
DCC, DMAP to give an ester 27 in 61% yield (90% based on recov-
ered starting material). When attempts were made for ring closing
metathesis, both Grubbs’ 1st and Grubbs’ 2nd generation catalysts
did not give the product as expected and ended up with recovery of
the starting material. Incidentally, similar results were also ob-
served during the total synthesis of stagonolide B,9b wherein iden-
tical substitution was present in the precursor for ring closing
metathesis. Based on our earlier experience, we proceeded further
for desilylation to get the free hydroxyl group. Thus, treatment of
27 with triethylamine tris(hydrogen fluoride) (Et3Nꢀ3HF) in tetra-
hydrofuran provided free allyl alcohol 28. Ring closing metathesis
was attempted directly by exposing the substrate 28 to Grubbs 2nd
generation catalyst under reflux condition in 1,2-dichloroethane to
yield the product 1016 with isopropylidene protection along with a
byproduct 29. The product 10 was treated with TFA at 0 °C for 2 h
to yield the target molecule, achaetolide 1 in 86% yield (Scheme 4).
The spectroscopic data17 of the synthetic compound were found to
be similar to that of the natural product.2,8
HO
O
OH
HO
O
10
O
OH
Achaetolide 1
OH
O
NH2
OH
HO
+
H15C7
HO
O
OTBDPS
9 steps
O
12
O
11
8 steps
8 steps
D-Aspartic acid
n-Octanal
OH
3-Butene,1-ol
Scheme 1. Retrosynthesis.
bromide and TBAI. The compound 22 can also be obtained from
homoallylic alcohol 13 in three steps involving, benzylation, epox-
idation, and Jacobsen’s kinetic resolution as reported earlier by our
group.13
Treatment of the chiral epoxide 22 with trimethylsulfonium io-
dide and n-butyllithium provided the chiral secondary allyl alcohol
23.14 The secondary hydroxyl group was protected as the tert-
butyldiphenylsilyl ether 24 and was further treated with DDQ to
get the free primary alcohol 25. The resulting alcohol was sequen-
tially oxidized to aldehyde 26 under Swern conditions and then to
In conclusion, we have accomplished the total synthesis of
achaetolide 1 following a convergent approach. The overall yield
was found to be 12.4% and 11.6% starting from n-octanal and
i) (S)-BINOL-Ti(OiPr)4, 5 mol%
4 Ao MS, -15 ºC
OH
OTBS
SnBu3
ii)
Imidazole, TBSCl
CH2Cl2, 0 oC- rt, 4 h, 98%
n-Octanal
H15C7
H15C7
toluene, 48 h, 91%
13
14
OTBS
OTBS
i) O3, CH2Cl2, -78 ºC, TPP
OH
ADmix-β
tBuOH:H2O, 4 days,
CO2Et
H15C7
ii) NaH, (o-cresol)2P(O)CH2CO2Et
-78 ºC, THF, 6 h, 84%, 9:1 (Z:E),
CO2Et
H
15C7
15
OH
16
OTBS
O
OTBS
O
DIBAL-H, -78 - 0 ºC
CH2Cl2, 2 h, 93%
2,2-DMP
CO2Et
OH
H15C7
OH
H15C7
CH2Cl2, PPTS, rt, 3 h,
overall yield 78% for two steps
O
O
O
18
17
OTBS
O
Swern oxidation
CH3PPh3I, KOtBu,
THF, 0 ºC-rt, 89%
TBAF, THF
H15C7
H15C7
reflux, 4 h, 97%
O
19
O
12
Scheme 2.
O
Br
Br
i) NaH, THF
-10 ºC, 1 h
NH2
O
O
NaNO2, KBr
H2SO4, -5 ºC,
3 h, 85%
BH3, THF
OH
OH
OH
HO
HO
HO
0 ºC - rt,
5 h, 93%
ii) BnBr, TBAI
-10 ºC- rt, 78%
20
O
21
OH
OTBDPS
TBDPSCl,
Imidazole
O
(CH3)3SI, n-BuLi
DDQ
BnO
BnO
BnO
THF, -20 oC,
4 h, 78%
CH2Cl2:H2O (19:1)
4 h, reflux, 92%
CH2Cl2, 12 h, 95%
22
23
24
OTBDPS
NaClO2, NaH2PO4
H
Swern oxidation
rt, 3.5 h, 98%
HO
tBuOH/H2O (9:1)
2-methyl-2-butene
4 h, 96%
HO
O
OTBDPS
26
O
OTBDPS
11
25
Scheme 3.

6176
P. Srihari et al. / Tetrahedron Letters 51 (2010) 6174–6176
G-1 (20 mol%)
O
O
CH2Cl2, reflux
DCC, DMAP
O
O
O
11 + 12
CH2Cl2, 12 h,
0 ºC-rt, 90%
TBDPSO
O
O
TBDPSO
G-2 (20 mol%)
CH2Cl2, reflux
O
O
27
G-1: Grubbs First generation catalyst
G-2: Grubbs Second generation catalyst
O
O
O
O
G-2 (25 mol%)
DCE, reflux, 9 h
O
O
O
Et3N.3HF, THF
+
27
refiux, 4 h 95%
O
HO
O
O
HO
O
O
28
24%
29
40%
10
O
O
TFA, 0ºc
2h, 86%
HO
OH
OH
1
Scheme 4.
D
-aspartic acid, respectively. Also the absolute configuration of
12. Jeffrey, A. F.; John, B. K.; Andreas, B.; Jill, M. A.; Henry, R. Synthesis 1992, 621–
623.
13. Yadav, J. S.; Premalatha, K.; Harshavardhan, S. J.; Subbareddy, B. V. Tetrahedron
Lett. 2008, 49, 6765–6767.
14. Alcaraz, J.; Harneet, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449–5452.
achaetolide has been reconfirmed to be 3S,6R,7S,9R.
Acknowledgment
15. Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.
16. The 1H NMR of this compound revealed the presence of a single conformer as
reported earlier by Tayone, W. C.; et al. See Ref. 8.
B. Kumaraswamy and P. Shankar thank CSIR, New Delhi for
financial assistance in the form of fellowships.
17. Spectroscopic data for representative examples: Compound 11: Yellow liquid;
½ ꢁ
a 3D2 +9 (c 1.0, CHCl3); 1H NMR (300 MHz; CDCl3): d 7.67–7.60 (m, 4H); 7.39–
References and notes
7.29 (m, 6H), 5.82 (ddd, J = 6.8, 10.6, 16.6 Hz, 1H), 5.03–4.94 (m, 2H), 4.53 (q,
J = 6.8 Hz, 1H), 2.54 (dd, J = 6.8, 15.1 Hz, 1H), 2.41 (dd, J = 6.0, 15.1 Hz, 1H), 1.04
(s, 9H); 13C NMR (75 MHz; CDCl3): d 175.8, 138.7, 135.9, 135.8, 133.4, 129.8,
1. (a) Ken, I. Biosci. Biotechnol. Biochem. 2009, 73, 971–979; (b) Nicolaou, K. C.;
Chen, J. S.; Dalby, S. M. Bioorg. Med. Chem. 2009, 17, 2290–2303; (c) Piel, J. Nat.
Prod. Rep. 2009, 26, 338–362; (d) Riatto, V. B.; Pilli, R. A.; Victor, M. M.
Tetrahedron 2008, 64, 2279–2300; (e) Hendrik, G.; Peter, J. S.; Ekaterina, E.;
Stefan, K.; Gabriele, M. K. J. Nat. Prod. 2008, 71, 1651–1653; (f) Ferraz, H. M. C.;
Bombonato, F. I.; Longo, L. S., Jr. Synthesis 2007, 21, 3261–3285; (g) Surat, B.;
Prasat, K.; Masahiko, I.; Daraporn, P.; Morakot, T.; Yodhathai, T. J. Nat. Prod.
2001, 64, 965–967; (h) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48. and
references therein.
129.8, 127.6, 127.4, 115.8, 115.8, 71.3, 43.0, 26.9, 19.2; IR (neat)
vmax = 3449,
2926, 2885, 1713, 1464, 1110, 772 cmꢂ1
;
HRMS m/z calculated for
C
21H26O3SiNa 377.1543 for (M+Na)+, found 377.1534. Compound 16:
Colorless liquid; ½a D30
ꢁ
ꢂ5.8 (c 1.3, CHCl3); 1H NMR (300 MHz; CDCl3): d 4.26
(qd, J = 7.0, 1.9 Hz, 2H), 4.21–4.12 (m, 2H), 4.02 = 3.91 (m, 1H), 1.4–1.72 (m,
1H), 1.59–1.46 (m, 1H), 1.40 (ddd, J = 1.51, 6.2, 14.73 Hz, 1H); 1.31 (s, 3H);
1.30–1.19 (m, 11H); 0.89 (s, 12H), 0.08 (d, 6H); 13C NMR (75 MHz; CDCl3): d
172.5, 74.3, 70.6, 70.1, 61.7, 36.6, 36.1, 29.7, 29.3, 25.9, 25.5, 22.7, 18.0, 14.3,
2. Bodo, B.; Molho, L.; Davoust, D.; Molho, D. Phytochemistry 1983, 22, 447–451.
3. (a) Grabley, S.; Granzer, E.; Hütter, K.; Ludwig, D.; Mayer, M.; Thiericke, R.; Till,
G.; Wink, J.; Philipps, S.; Zeeck, A. J. Antibiot. 1992, 45, 56; (b) Göhrt, A.; Zeeck,
A.; Hütter, K.; Kirsch, R.; Kluge, H.; Thiericke, R. J. Antibiot. 1992, 45, 66.
4. (a) Rivero-Cruz, J. F.; Garcia-Aguieee, G.; Cerda-Garcia-Rojas, C. M.; Mata, R.
Tetrahedron 2000, 56, 5337–5344; (b) Rivero-Cruz, J. F.; Martha, M.; Cerda-
Garcia-Rojas, C. M.; Mata, R. J. Nat. Prod. 2003, 66, 511–514.
5. Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. Org. Lett. 2001,
3, 3479–3481.
6. Tsuda, M.; Mugishima, T.; Komatsu, K.; Sone, T.; Tanaka, M.; Mikami, Y.;
Kobayashi, J. J. Nat. Prod. 2003, 66, 412–415.
14.2, ꢂ4.4, ꢂ4.8; IR (neat):
vmax = 3461, 2925, 2856, 1738, 1634, 1218,
772 cmꢂ1; HRMS m/z calculated for C20H42O5SiNa 413.2694 (M+Na)+ found
413.2692. Compound 10: light brown color; ½a D27
ꢁ
ꢂ30 (c 0.4, CHCl3); lit ½a D24
ꢁ
ꢂ33 (c 0.34, CHCl3);8 1H NMR (300 MHz; CDCl3): d 5.56 (dd, J = 8.9, 16.0 Hz,
1H), 5.42 (dd, J = 7.7, 16.0 Hz, 1H), 4.63 (ddd, J = 5.6, 8.9, 14.2 Hz, 1H), 4.38 (dd,
J = 6.0, 8.9 Hz, 1H), 4.26 (q, J = 7.7 Hz, 1H), 3.91 (dd, J = 6.0, 10.2 Hz, 1H), 2.66
(dd, J = 7.8, 13.0 Hz, 1H), 2.16 (dd, J = 7.9, 13.0 Hz, 1H), 2.09 (dd, J = 5.5, 10.2 Hz,
1H), 1.52–1.46 m, 1H), (1.44 (d, J = 15.8 Hz, 1H), 1.33 (s, 4H), 1.19 (s, 3H), 1.16–
1.08 (m, 10H), 0.79 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz; CDCl3): d 170.0, 133.5,
129.6, 108.6, 80.8, 77.3, 74.9, 70.0, 43.8, 38.0, 35.7, 31.7, 29.3, 29.1, 28.0, 25.5,
25.3, 22.6, 14.0; IR (neat)
v ;
max = 3459, 2928, 1728, 1636, 1221, 771 cmꢂ1
HRMS m/z calculated for
C
19H32O5Na 363.2142 (M+Na)+ found 363.2139.
7. (a) Evidente, A.; Cimmino, A.; Berestetskiy, A.; Mitina, G.; Andolfi, A.; Motta, A.
J. Nat. Prod. 2008, 71, 31–34; (b) Evidente, A.; Cimmino, A.; Be restetskiy, A.;
Andolfi, A.; Motta, A. J. Nat. Prod. 2008, 71, 1897–1901; (c) Yuzikhin, O.; Mitina,
G.; Berestetskiy, A. J. Agric. Food Chem. 2007, 55, 7707–7711.
Achaetolide 1 ½a D30
ꢁ
ꢂ25 (c 0.15, MeOH); lit ½a D21
ꢁ
ꢂ27 (c 0.52, MeOH);8 1H NMR
(200 MHz; CDCl3): d 5.98 (dd, J = 3.2, 16.4 Hz, 1H), 5.66 (dd, J = 2.4, 16.4 Hz,
1H), 4.89–4.67 (m, 2H), 4.58–4.48 (m, 1H), 3.72 (d, J = 9.8 Hz, 1H), 2.56 (d,
J = 3.3 Hz, 2H), 2.32–2.12 (m, 2H), 1.70–1.43 (m, 3H), 1.19–1.35 (m, 10H), 0.89
(t, J = 6.6 Hz, 3H); 1H NMR (300 MHz; CD3OD): major conformer d 5.97 (dd,
J = 3.2, 15.8 Hz, 1H), 5.70 (dd, J = 1.32, 15.8 Hz, 1H), 4.78–4.65 (m, 2H), 4.48–
4.40 (m, 1H), 3.64 (d, J = 9.8 Hz, 1H), 2.51 (dd, J = 3.8, 11.8 Hz, 1H), 2.49 (dd,
J = 3.4, 11.7 Hz, 1H), 2.40–2.32 (m, 1H), 1.88–147 (m, 2H), 1.42 (s, 1H), 1.34–
1.25 (m, 10H), 0.89 (t, J = 6.4 Hz, 3H), minor conformer d 5.58 (dd, J = 7.1,
16.4 Hz, 1H), 5.41 (dd, J = 8.8, 16.4 Hz, 1H), 4.48–4.40 (m, 1H), 4.28 (dd, J = 2.8,
6.6 Hz, 1H), 3.47–3.41 (m, 1H), 2.93 (dd, J = 7.55, 13.4 Hz, 1H), 2.42–2.31 (m,
1H), 2.26 (dd, J = 8.68, 13.4 Hz, 1H), 1.75–1.65 (m, 1H), 1.57–1.53 (m, 1H), 1.38
(s, 1H); 13C NMR (75 MHz; CD3OD): d 172.2, 172.3, 136.6, 131.7, 131.1, 127.8,
78.3, 77.6, 76.7, 74.7, 74.6, 74.5, 71.6, 68.1, 38.3, 38.0, 37.6, 36.1, 33.0, 30.8,
8. (a) Tayone, W. C.; Shindo, S.; Murakami, T.; Hashimoto, M.; Tanaka, K.; Takada, N.
Tetrahedron 2009, 65, 7464–7467; (b)
A publication on total synthesis of
achaetolide appeared after we communicated the manuscript. See
Chandrasekhar, S.; et al. Tetrahedron Lett. 2010. doi:10.1016/j.tetlet.2010.07.127.
9. (a) Srihari, P.; Kumaraswamy, B.; Maheswara Rao, G.; Yadav, J. S. Tetrahedron:
Asymmetry 2010, 21, 106–111; (b) Srihari, P.; Kumaraswamy, B.; Somaiah, R.;
Yadav, J. S. Synthesis 2010, 1039–1045; (c) Srihari, P.; Vijaya Bhasker, E.; Bal
Reddy, A.; Yadav, J. S. Tetrahedron Lett. 2009, 50, 2420–2424; (d) Srihari, P.;
Rajendar, G.; Srinivasa Rao, R.; Yadav, J. S. Tetrahedron Lett. 2008, 49, 5590–
5592; (e) Yadav, J. S.; Kumar, V. N.; Rao, R. S.; Srihari, P. Synthesis 2008, 1938–
1942; (f) Srihari, P.; Kumar, B. P.; Subbarayudu, K.; Yadav, J. S. Tetrahedron Lett.
2007, 48, 6977–6981.
30.6, 30.5, 30.4, 26.9, 26.3, 23.7, 14.4; IR(neat) vmax = 3457, 2926, 2856, 1725,
1162 cmꢂ1 HRMS m/z calculated for C16H28O5Na 323.1829 (M+Na)+ found
10. Kurosu, M.; Miguel, L. Synlett 2005, 1109–1112.
11. Ando, K. J. Org. Chem. 1998, 63, 8411–8416. The diastereomers were easily
separable with column chromatography.
323.1832.