First total synthesis of achaetolide

Article abstract of DOI:10.1016/j.tetlet.2010.07.127

The first total synthesis of achaetolide, a 10-membered macrolactone was achieved using Mitsunobu reaction and Grubbs ring-closing metathesis reaction as the key steps for ring construction. The desired stereo centres were generated by Jacobsen hydrolytic kinetic resolution, dihydroxylation and Sharpless asymmetric epoxidation reactions.

Full text of DOI:10.1016/j.tetlet.2010.07.127

Tetrahedron Letters 51 (2010) 5164–5166
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First total synthesis of achaetolide
*
S. Chandrasekhar , S. V. Balaji, G. Rajesh
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, 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 achaetolide, a 10-membered macrolactone was achieved using Mitsunobu
reaction and Grubbs ring-closing metathesis reaction as the key steps for ring construction. The desired
stereo centres were generated by Jacobsen hydrolytic kinetic resolution, dihydroxylation and Sharpless
asymmetric epoxidation reactions.
Received 24 June 2010
Revised 15 July 2010
Accepted 22 July 2010
Available online 29 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
In 1983, Bodo et al. reported the isolation of achaetolide
(1, Fig. 1) from the culture broth of Achaetomium crisalliferum.1
However, the stereochemistry of 1 was unknown until recently.
In 2009, Takada and co-workers established the stereochemistry
of 1 after isolating it from a different species, Ophiobolus sp.2 achae-
tolide is a 10-membered macrolide having four stereo centres,
three hydroxyl groups and a trans-olefin functionality. The biolog-
ical activity of 1 was also unknown. The structural features of
achaetolide combined with our interest on synthesis of macro-
lides3 prompted us for the synthesis of achaetolide. Further, its
chemical synthesis would allow to evaluate the biological activity.
Our retrosynthetic plan was to construct the complete skeleton
through the assembly of the fragments: secondary alcohol 2 and
acid 3 through a Mitsunobu esterification followed by ring closing
metathesis (RCM) reaction. The fragment 2 was envisioned from
epichlorohydrin (6) using Jacobsen hydrolytic kinetic resolution
and dihydroxylation for the generation of stereo centres and the
acid fragment 3 can be obtained from the known epoxy alcohol
which in turn is prepared from 1,3-propane diol (Scheme 1).
The synthesis of alcohol 2 began from the commercially avail-
able epichlorohydrin (6), regioselective ring opening of the epoxide
ring by n-hexylmagnesium bromide in the presence of CuCN fol-
lowed by intramolecular substitution using NaOH to give nonene
oxide 8 in 70% (for two steps). The epoxide was enantioselectively
resolved using (S,S)-Jacobsen’s catalyst (I) by hydrolytic kinetic res-
olution to give 9 in 43% yield.4 Next, ring opening of the epoxide
with lithium salt of ethyl propiolate gave the homopropargylic
alcohol 10 (80%).5 To make a six-membered unsaturated lactone,
a two-step sequence was followed; partial hydrogenation of the
alkyne using Lindlar’s catalyst (palladium on CaCO3, poisoned with
Pb, quinoline) followed by lactonisation using catalytic p-TSA affor-
ded the lactone 12 in 82% yield (for two steps). Dihydroxylation of
12 using catalytic OsO4 and NMO was highly diasteroselective. The
diol 13 was obtained as a sole product in 58% yield, which was
protected as its acetonide using 2,2-DMP and cat. PPTS to afford
the lactone 14 in 72% yield.6 The lactone was then reduced to lactol
þ
15 (78%) using DIBAL-H which on homologation using PPh3
CH3Brꢀ gave the alcohol 2 in 77% yield (Scheme 2).
The synthesis of acid 3 (Scheme 3) began with 1,3-propane diol
7 which was transformed to epoxy alcohol 5 using a known
sequence.7 The epoxy alcohol 5 was then iodinated using TPP,
iodine and imidazole, which on refluxing in ethanol in the presence
of zinc transforms to secondary allylic alcohol followed by the
O
4
C7H15
9
1
O
5
HO
OH
OH
1
Figure 1. Structure of achaetolide.
C7H15
OH
O
O
OH
1
+
O
HO
3
2
HO
C7H15
O
COOEt
TBDPSO
HO
OH
4
5
O
OH
Cl
6
7
* Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.127

S. Chandrasekhar et al. / Tetrahedron Letters 51 (2010) 5164–5166
5165
HO
OH
O
a
O
c
d
O
b
COOEt
C7H15
Cl
C7H15
C7H15
C7H15
COOEt
5
8
9
10
11
C7H15
O
O
O
C7H15
O
OH
O
O
O
C7H15
C7H15
O
e
i
O
f
g
h
OH
13
O
O
OH
15
12
14
OH
O
C7H15
2
O
N
O
N
Co
O
t-Bu
t-Bu
t-Bu
t-Bu
(S,S)-I catalyst
Scheme 2. Reagents and conditions: (a) (i) n-C6H13MgBr, CuCN, THF, ꢀ78 °C, 3 h; (ii) NaOH, THF, 0 °C to rt, 70% (for two steps), (b) (S,S)-I, H2O AcOH, toluene. 0 °C to rt, 10 h,
43%; (c) ethyl propiolate, n-BuLi, BF3ꢁOEt2, THF, ꢀ78 °C, 80%; (d) Lindlar’s catalyst, quinoline (cat), H2, benzene, 1 h; (e) p-TSA (cat), benzene 82% (for two steps); (f) OsO4,
NMO, acetone/H2O (7:3), rt, 58%, 12 h; (g) 2,2-DMP, PPTS (cat), CH2Cl2, 72%, 2 h; (h) DIBAL-H, CH2Cl2, ꢀ78 °C, 30 min, 78%; (i) PPh þCH3Brꢀ, n-BuLi, THF, 0 °C to rt, 4 h, 77%.
3
etc.9 The diene 18 on RCM reaction condition did not afford the ex-
a, b, c
ref-7
O
7
TBDPSO
OTBS
OH
pected product, therefore the TBS group was deprotected using
1 M solution of TBAF to afford the allylic alcohol 19 in 87% yield.
This allylic alcohol underwent RCM reaction neatly under refluxing
CH2Cl2 in 2 h. Though the reaction was successful, a mixture of Z
(20a, 23%) and E alkenes (20b, 47%) was formed in 4:6 ratio, which
was easily separated by column chromatography. Acetonide
deprotection of 20b using TFA gave achaetolide 1 (Scheme 4).
The spectroscopic data of 1 were compared with that of the natural
product data and were found to exist as a mixture of conformers as
reported by Takada.2,10
5
OTBS
17
d
e, f
TBDPSO
HOOC
HO
16
OTBS
3
Scheme 3. Reagents and conditions: (a) TPP, I2, imidiazole, Et2O/CH3CN (3:1), 0 °C
to rt 30 min, 88%; (b) Zn, ethanol, reflux, 2 h, 85%; (c) TBSCl, imidiazole, CH2Cl2, 0 °C
to rt, 95%; (d) NH4þFꢀ, CH3OH, 10 h, 80%; (e) IBX, DMSO, THF, rt, 1 h; (f) NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (7:3), 6 h, 76%.
In conclusion, for the first time, we have accomplished the total
synthesis of achaetolide. The synthetic sequence demonstrates the
application of Mitsunobu reaction and ring-closing metathesis for
the construction of a macrolide as key steps.
O
C7H15
O
C7H15
c
Acknowledgement
a
HO
O
TBSO
O
b
2
3
O
O
S.V.B and G.R. thank the CSIR and UGC, New Delhi, for financial
support.
18
19
O
O
O
O
C7H15
C7H15
O
O
C7H15
References and notes
O
O
d
HO
1. Bodo, B.; Molho, L.; Davoust, D.; Molho, D. Phytochemistry 1983, 22, 447–451.
2. Tayone, W. C.; Shindo, S.; Murakami, T.; Hashimoto, M.; Tanaka, K.; Takada, N.
Tetrahedron 2009, 65, 7464–7467.
3. (a) Chandrasekhar, S.; Reddy, Ch. R. Tetrahedron:Asymmetry 2002, 13, 261–268;
(b) Chandrasekhar, S.; Vijeender, K.; Chandrasekhar, G.; Reddy, Ch. R.
Tetrahedron: Asymmetry 2007, 18, 2473–2478; (c) Chandrasekhar, S.;
Yaragorla, S. R.; Sreelakshmi, L.; Reddy, Ch. R. Tetrahedron 2008, 64, 5174–
5183; (d) Chandrasekhar, S.; Rambabu, C.; Reddy, A. S. Org. Lett. 2008, 10, 4355–
4357.
HO
O
O
O
HO
OH
O
OH
20b
1
20a
Scheme 4. Reagents and conditions: (a) DIAD, PPh3, benzene, 6 h, 0 °C to rt, 62%; (b)
TBAF, 1 M solution, THF, 0 °C to rt, 1 h, 87%; (c) Grubbs’ catalyst II, 3 h, 40 °C, 70%
(mixture of cis and trans); (d) TFA, CH2Cl2, 0 °C to rt, 1 h, 65%.
4. (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould,
A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315; (b)
Haase, B.; Schneider, M. P. Tetrahedron: Asymmetry 1993, 4, 1017–1026.
5. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
6. (a) Ramachandran, P. V.; Prabhudas, B.; Chandra, S. J.; Reddy, M. V. R. J. Org.
Chem. 2004, 69, 6294–6304; (b) Khalaf, K.; Datta, A. J. Org. Chem. 2005, 70,
6937–6940.
7. Narco, K.; Baltas, M.; Gorrichon, L. Tetrahedron 1999, 55, 14013–14030.
8. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Stephen, F.; Martin, S. F.; Dodge, J. A.
Tetrahedron Lett. 1991, 32, 3017–3020.
9. (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452; (b)
Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826–2830; (c) Mohapatra, D. K.;
Ramesh, K. D.; Giardello, M. A.; Chorghade, M. S.; Gurjara, M. K.; Grubbs, R. H.
Tetrahedron Lett. 2007, 48, 2621–2625; (d) Liu, J.; Zhang, L.; He, J.; He, L.; Ma, B.;
Pan, X.; She, X. Tetrahedron: Asymmetry 2008, 19, 906–911; (e) Giri, A. G.;
Mondal, M. A.; Puranik, V. G.; Ramana, C. V. Org. Biomol. Chem. 2010, 8, 398–
406.
protection as TBS ether 16 in 88% (for three steps). Selective depro-
tection of the TBDPS ether using NH4+Fꢀ gave the alcohol 17 in 80%
yield. The alcohol on oxidation with IBX afforded the aldehyde,
which on further oxidation using NaClO2 and NaH2PO4 in the pres-
ence of 2-methyl-2-butene gave the acid 3 in 76% yield (two steps).
The alcohol 2 and the acid 3 were coupled under Mitsunobu
conditions to afford the diene 18 in 62% yield, with the inversion
of configuration at the hydroxyl carbon.8 Having the diene in hand,
the stage is set for the RCM reaction. Though RCM reaction is an
efficient method for the construction of macrolide core, it is well
documented that the outcome of an RCM reaction depends upon
the stereochemistry near the alkene, protecting group, catalyst

5166
S. Chandrasekhar et al. / Tetrahedron Letters 51 (2010) 5164–5166
10. Spectral data of representative compounds: Compound 11: colourless liquid:
4.7 (c 0.69, MeOH); 1H NMR (300 MHz, CDCl3): d 6.3–6.4 (1H, m), 5.89 (1H,
29.5, 29.2, 28.0, 25.5, 25.4, 22.6, 14.0; IR mmax (KBr): 3468, 2926, 2857,
1045 cmꢀ1; (ESI-MS): m/z 293 (M+Na); HRMS: calcd for C16H30NaO3: 293.2089
½ ꢂ
a 3D2
td, J = 11.3, 1.5 Hz), 4.16 (2H, q, J = 6.7 Hz), 3.66–3.79 (1H, m), 2.76 (2H, ddd,
J = 8.3, 6.0, 1.5 Hz), 1.98 (1H, d, J = 4.5 Hz), 1.20–1.52 (15H, m), 0.85 (3H, t,
J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): 166.8, 146.2, 121.5, 71.1, 60.0, 37.4, 36.4,
31.7, 29.5, 29.1, 25.5, 22.5, 14.1, 13.9. IR mmax (KBr): 3426, 2927, 2858, 1715,
(M+Na), found: 293.2087. Compound 19: colourless liquid; ½a D32
ꢀ19.8 (c 0.53,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3): d 5.67–5.91 (2H, m), 5.31–5.35 (1H, m),
5.25–5.29 (1H, m), 5.19–5.25 (1H, m), 5.09–5.16 (1H, m), 5.01–5.09 (1H, m),
4.43–4.54 (2H, m), 4.15 (1H, dd, J = 6.2, 2.8 Hz), 3.0 (1H, br s), 2.54 (1H, dd,
J = 15.8, 3.7 Hz), 2.44 (1H, dd, J = 15.8, 8.3 Hz), 1.46–1.70 (2H, m), 1.45 (3H, s),
1.24–1.34 (15H, m), 0.89 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3): d 171.8,
138.7, 134.0, 118.5, 115.3, 108.4, 79.4, 74.4, 72.5, 68.9, 41.4, 34.9, 34.6, 31.7,
29.6, 29.3, 29.1, 28.1, 25.6, 22.6, 14.0; IR mmax (KBr): 3449, 2926, 2856, 1731,
1375, 1217, 1044 cmꢀ1; (ESI-MS): m/z 391 (M+Na). Compound 20a: colourless
1177 cmꢀ1; (ESI-MS): m/z 243 (M+H). Compound 12: colourless liquid: ½a 3D3
ꢂ
88.5 (c 0.51, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.79–6.86 (1H, m), 5.99 (1H,
td, J = 9.8, 1.5 Hz), 4.33–4.43 (1H, m), 2.28–2.34 (2H, m), 1.73–1.86 (1H, m),
1.22–1.68 (11 H, m), 0.89 (3H, t, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d 164.6,
145, 121.4, 78.0, 34.8, 31.7, 29.4, 29.3, 29.1, 24.8, 22.6, 14.0.; IR mmax (KBr):
2926, 2857, 1718, 1638 cmꢀ1; (ESI-MS): m/z 197 (M+H) HRMS: calcd for
liquid; ½a 3D2
ꢂ
13.5 (c 0.25, CHCl3); 1H NMR (500 MHz, CDCl3/C6D6, 1:1): d 5.59–
C
12H20NaO2: 219.1356 (M+Na), found: 219.1354. Compound 13: white solid;
5.65 (1H, dd, J = 11.8, 10.5 Hz), 5.50–5.56 (2H, m), 5.05–5.12 (1H, m), 4.54–4.59
(1H, m), 4.20–4.25 (1H, m) 2.53 (1H, dd, J = 11.8, 5.2 Hz), 2.31–2.35 (1H, m),
2.29 (1H, br s), 1.88–1.96 (2H, m), 1.51–1.60 (1H, m), 1.46–1.49 (4H, m), 1.20–
1.33 (13H, m), 0.88 (3H, t, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3: C6D6, 1:1): d
169.0, 131.5, 130.3, 106.8, 76.1, 73.6, 67.9, 71.4, 40.7, 35.1, 35.0, 31.0, 28.8,
28.6, 28.0, 25.2, 22.1, 24.8, 13.3; IR mmax (KBr): 3458, 2926, 2858, 1728, 1253,
1166, 1044 cmꢀ1; (ESI-MS): m/z 363 (M+Na). Compound 1: solid; mp: 122–
mp: 90–92 °C; ½a 3D3
ꢂ
ꢀ32.0 (c 0.18, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.67–
4.78 (1H, m), 4.27–4.31 (1H, m), 4.0 (1H, m), 3.43 (1H, br s), 2.7 (1H, br s) 2.2
(1H, td, J = 14.3, 3.7 Hz), 1.2–1.85 (13H, m), 0.89 (3H, t, J = 6.7 Hz); 13C NMR
(75 MHz, CDCl3): d 174.2, 78.3, 70.4, 65.9, 35.5, 33.8, 31.6, 29.2, 29.0, 24.7, 22.5,
14.0; IR mmax (KBr): 3390, 2920, 2851, 1728, 1229, 1109 cmꢀ1; (ESI-MS): m/z
231 (M+H). Compound 15: colourless liquid; ½a D33
ꢀ45.3 (c 0.91, CHCl3); 4.6
ꢂ
(1H, d, J = 5.8 Hz), 4.29–4.33 (1H, m), 3.67 (1H, t, J = 5.8 Hz), 3.57–3.64 (1H, m),
2.9 (1H, br s), 1.88–1.93 (1H, m), 1.64 (1H, ddd, J = 14.6, 10.9, 3.9 Hz), 1.1–1.5
(18H, m), 0.82 (3H, t, J = 6.8 Hz) 109.1, 96.4, 76.5, 70.5, 72.8, 35.4, 32.6, 31.7,
29.5, 29.1, 27.9 25.8, 25.4, 22.6, 14.0.; IR mmax (KBr): 3422, 2926, 2856,
1051 cmꢀ1; (ESI-MS): m/z 295 (M+Na) HRMS: calcd for C15H28NaO4: 295.1880
124 °C; ½a 3D0
ꢂ
ꢀ24 (c 0.23, MeOH); [lit.1 mp 122 °C; ½a D23
ꢀ27 (c 0.52, MeOH)];
ꢂ
1H NMR (500 MHz, CDCl3):
d 6.02 (1H, dd, J = 15.6, 2.9 Hz), 5.68 (1H, d,
J = 15.6 Hz), 4.82 (1H, dt, J = 7.8, 6.8 Hz), 4.76 (1H, m), 4.57 (1H, m), 3.6 (1H, d,
J = 9.7 Hz), 2.62 (1H, dd, J = 11.7, 3.9 Hz), 2.58 (1H, dd, J = 11.7, 3.9 Hz), 2.34
(1H, m), 2.25 (1H, br s), 1.63 (2H, br s), 1.55 (2H, m), 1.48 (1H, d, J = 15.6 Hz),
1.26 (10H, m), 0.88 (3H, t, J = 7.8 Hz) (peaks corresponding to minor conformer
are omitted); 13C NMR (75 MHz, CDCl3): d 171.0, 130.8, 125.1, 75.3, 73.3, 67.2,
43.8, 36.9, 36.8, 31.7, 29.7, 29.4, 29.1, 25.03, 22.6, 14.1; IR mmax (KBr): 3455,
2927, 2857, 1713, 1171 cmꢀ1; (ESI-MS): m/z 323 (M+Na); HRMS: calcd for
(M+Na) found: 295.1877. Compound 2: colourless liquid; ½a D32
ꢀ14.0 (c 0.2,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3): d 5.76 (1H, ddd J = 17.3, 9.8, 7.5 Hz), 5.20–
5.34 (2H, m), 4.52 (1H, td, J = 7.5, 0.8 Hz), 4.31 (1H, ddd, J = 9.8, 6.0, 3.7 Hz),
3.69–3.79 (1H, m), 3.0 (1H, br s), 1.23–1.53 (20H, m), 0.89 (3H, t, J = 6.7 Hz); 13
C
NMR (75 MHz, CDCl3): d 133.8, 118.6, 108.2, 79.8, 78.4, 71.3, 37.5, 37.2, 31.7,
C16H28O5Na: 323.1834 (M+Na), found: 323.1830.