Stereoselective total synthesis of xyolide

Article abstract of DOI:10.1016/j.tetlet.2013.08.038

A stereoselective total synthesis of xyolide is described employing MacMillan α-hydroxylation, Steglich esterification, and ring closing metathesis as key steps. The use of organocatalytic MacMillan α-hydroxylation to construct two of the chiral centers o

Full text of DOI:10.1016/j.tetlet.2013.08.038

Tetrahedron Letters 54 (2013) 5758–5760
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Tetrahedron Letters
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Stereoselective total synthesis of xyolide
a
a
a
B. V. Subba Reddy a, , P. Sivaramakrishna Reddy , B. Phaneendra Reddy , J. S. Yadav ,
⇑
Ahamad Al Khazim Al Ghamdi b
a Natural Products Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective total synthesis of xyolide is described employing MacMillan a-hydroxylation, Steglich
Received 19 July 2013
Revised 8 August 2013
Accepted 11 August 2013
Available online 16 August 2013
esterification, and ring closing metathesis as key steps. The use of organocatalytic MacMillan
a-hydrox-
ylation to construct two of the chiral centers of the xyolide makes this approach attractive.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Xyolide
MacMillan aminooxylation
Steglich esterification
Ring closing metathesis
Nonenolides have emerged as attractive synthetic targets due to
their potent biological activities.1 Many of these lactones are being
produced by fungi, bacteria, and marine organisms. A few of them
are isolated from plants or insects (pheromones).
L
-proline at ꢀ20 °C followed by olefination to furnish the
lide 4 in 60% yield.8 Sharpless asymmetric dihydroxylation9 of
-butenolide 4 with AD-mix- in tert-butanol and water system
c-buteno-
c
a
gave the diol 5 in 94% yield. Protection of the diol with 2,2-dime-
thoxypropane in the presence of PPTS gave the lactone 6 which
was then reduced with DIBAL-H to give the lactol 7 in 92% yield.
Lactol 7 was subjected to one carbon Wittig homologation with
methyltriphenylphosphonium iodide in the presence of KOtBu to
give the alkenol 8 in 82% yield (Scheme 2).10
Next, we focused on the synthesis of another key intermediate
13 which was commenced from pentane-1,5-diol 3. Mono-protec-
tion of the diol 3 with BnBr in the presence of NaH in THF afforded
The 10-membered macrolides such as stagonolides A–I,2 deca-
restrictines A, D, and J,3 herbarumins I–III,4 and microcarpalide5
(Fig. 1) are known to exhibit potent biological activities such as
antibacterial, antifungal, cytotoxic, and phytotoxic behavior which
make them attractive synthetic targets. In particular, xyolide (1), a
10-membered macrolide isolated from the Amazonian endophytic
fungus, Xylaria feejeensis is important. The structure of 1 was estab-
lished by 1D and 2D NMR and the absolute configuration was deter-
mined by exciton-coupled circular dichroism. The minimum
inhibitory concentration (MIC) of xyolide against P. ultimum was
425 l
M.6
O
O
In continuation of our interest on the total synthesis of biolog-
ically active molecules,7 herein we report the stereoselective total
synthesis of xyolide employing n-nonanal as a cost-effective and
readily available precursor. Our retrosynthetic analysis of xyolide
1 reveals that it could be synthesized by means of RCM of 14,
which in turn could be prepared through the esterification of
alkenoic acid 13 with alkenol 8. The intermediates 13 and 8 could
easily be accessed from the commercially available pentane-1,5-
diol 3 and n-nonanal 2, respectively (Scheme 1).
HO
O
OH
OH
OH
OH
O
O
O
O
OH
O
O
O
5
Xyolide (1)
Herbarumin I
Stagonolide A
OH
O
O
OH
OH
OH
Accordingly, the synthesis of xyolide 1 began from n-nonanal 2,
which was subjected to a sequential aminoxylation catalyzed by
O
HO
O
5
OH
HO
O
O
O
Herbarumin Il
decarestrictine J
microcarpalide
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
Figure 1. Examples of 10-membered macrolides.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.038

B.V.S. Reddy et al. / Tetrahedron Letters 54 (2013) 5758–5760
5759
O
a
b
HO
OH
BnO
O
3
3
OTBS
O
9
3
O
O
HO
OH
OH
O
O
O
OTBS
OH
c
O
14
OH
O
1
BnO
BnO
5
2
2
5
11
10
OTBS
O
OTBS
OTBS
OH
d
e
O
HO
HO
2
2
OH
+
5
8
O
13
12
13
O
Scheme 3. Reagents and conditions: (a) (i) BnBr, NaH, THF, 0 °C to rt., 6 h, 88%. (ii)
IBX, DMSO, CH2Cl2, 0 °C to rt, 4h, 87%; (b) PhNO, -proline (40 mol %), DMSO, rt,
D
30 min then NaBH4, EtOH, then CuSO4, MeOH, 12 h, 60%; (c) (i) NaH, N-tosylim-
idazole, 80%. (ii) Me3SI, n-BuLi, THF, ꢀ20 °C, 88%; (iii) TBSCl, imidazole, CH2Cl2, 2 h,
95%; (d) Li, naphthalene, ꢀ20 °C, 90%; (e) TEMPO–BAIB, CH3CN, H2O (1:1) rt, 85%.
HO
OH
O
6
2
3
Scheme 1. Retrosynthetic analysis of xyolide.
OTBS
OH
O
O
O
O
a
the benzyl ether in 88% yield, which was further subjected to
oxidation with IBX to give the aldehyde 9 in 87% yield. -Amino-
oxylation of compound 9 with nitrasobenzene using -proline fol-
b
8
+
13
O
O
a
O
D
O
5
5
lowed by reduction with NaBH4 and subsequent cleavage of the
aminooxy alcohol with CuSO4ꢁ5H2O furnished the required diol
10 (98% ee, by HPLC analysis) in 60% yield.11 Treatment of the diol
10 with NaH and N-tosylimidazole gave the epoxide in 80% yield.
The epoxide formed was treated with trimethylsulfonium iodide
in the presence of n-BuLi in THF at ꢀ20 °C to give the desired allylic
alcohol in 88% yield,12 which was then protected as its TBS ether 11
using TBSCl and imidazole. Compound 11 was treated with
Li/naphthalene to afford the alcohol 12 in 90% yield. One-pot oxi-
dation of compound 12 with TEMPO–BAIB afforded the acid 13
in 85% yield (Scheme 3).
Finally, we attempted the coupling of alcohol 8 with carboxylic
acid 13 so as to construct a 10-membered ring via RCM reaction.
Under Steglich conditions (DCC/DMAP), the coupling of alcohol
8 with acid 13 gave the corresponding ester 14 in 85% yield.13
Removal of TBS ether using HF-pyridine followed by ring-closing
metathesis of 14 using Grubbs’ second generation catalyst14 in
CH2Cl2 under reflux conditions for 6 h gave the 10-membered
macrolide 15 (exclusively as its E-isomer) in 80% yield. Esterifica-
14
15
O
O
O
O
O
O
O
O
O
c
d
O
OH
OH
OH
O
OH
O
5
5
16
1
Scheme 4. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, rt, 85%; (b) (i) HF-
pyridine, THF, 0 °C to rt, 10 h, 89%; (ii) Grubbs’ catalyst-II, CH2Cl2, reflux, 3 h, 80%;
(c) C4H4O3, DMAP, CH2Cl2, 89%; (d) 2 N HCl, THF, 4 h, 73%.
tion of the macrolide 15 with succinic anhydride15 followed by re-
moval of the acetonide using 2 N HCl furnished the target molecule
xyolide 1 in 73% yield (Scheme 4). The spectral data (1H and 13C
NMR, IR, ½a 2D0
ꢂ
) of xyolide 1 were identical in all respects with the
data reported in the literature.6
In summary, we have developed a concise and convergent ap-
proach for the total synthesis of xyolide in a highly stereoselective
O
O
manner. MacMillan organocatalytic
a-hydroxylation and asym-
a
O
6
b
O
6
metric dihydroxylation are successfully employed to establish
the chiral centers of xyolide.
OH
O
6
OH
2
4
5
Acknowledgments
OH
O
P.S.R.K.R. and B.P.R. thank CSIR, New Delhi for the award of
fellowships. J.S.Y. thanks CSIR, New Delhi for Bhatnagar Fellowship.
O
6
O
6
O
c
O
d
O
O
Supplementary data
6
7
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.
038.
OH
6
e
O
O
8
References and notes
Scheme 2. Reagents and conditions: (a) (i) PhNO,
20 °C; (ii) (CF3CH2O)2P(O)CH2CO2CH3, DBU, LiCl, THF, ꢀ20 °C then MeOH, NH4Cl,
Cu(OAc)2, rt, 24 h; (b) AD-mix- , t-BuOH, H2O (1:1). (c) 2,2-DMP, PPTS, CH2Cl2, 89%;
(d) DIBAL-H, THF, 0 °C to rt, 92%. (e) CH3PPh3I, KOtBu, THF, 0 °C to rt, 82%.
L-proline (40 mol %), DMSO,
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