The first stereoselective total synthesis of the Z-isomer of cytospolide e

Article abstract of DOI:10.1016/j.tetlet.2012.08.108

A convergent and highly stereoselective total synthesis of the Z-isomer of cytospolide E has been achieved via Evan's aldol reaction, Sharpless kinetic resolution and RCM cyclisation.

Full text of DOI:10.1016/j.tetlet.2012.08.108

Tetrahedron Letters 53 (2012) 6048–6050
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Tetrahedron Letters
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The first stereoselective total synthesis of the Z-isomer of cytospolide E
J. S. Yadav a, , T. Pandurangam a, A. Suman Kumar a, P. Adi Narayana Reddy a, A. R. Prasad a,
⇑
B. V. Subba Reddy a, K. Rajendraprasad b, A. C. Kunwar b
a Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Center for Nuclear Magnetic Resonance, 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:
Received 6 July 2012
Revised 23 August 2012
Accepted 24 August 2012
Available online 1 September 2012
A convergent and highly stereoselective total synthesis of the Z-isomer of cytospolide E has been
achieved via Evan’s aldol reaction, Sharpless kinetic resolution and RCM cyclisation.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cytotoxic
Macrolide
Evan’s aldol
Ring closing metathesis
6
4
OH
3
5
OR
7
The genus Cytospora sp. is a rich source of biologically active
secondary metabolites such as antibiotic grahamimycins,1 antibac-
terial cytoskyrins2 and cytotoxic cytosporinols.3 Of these, cytospo-
lides A–E (Fig. 1) are of immense interest because of their potent
anticancer activity. These cytotoxic nonanolides were isolated
from the endophytic fungus Cytospora sp.4 The structure was
established by spectroscopic, chemical and single-crystal X-ray
analyses. The C-2 methyl group plays an important role in growth
inhibition of tumour cell lines. Due to their fascinating biological
profiles and structural features, cytospolides have become highly
attractive synthetic targets. Of these, cytospolide E shows high
cytotoxic activity, which encouraged us to take up its total synthe-
sis. In continuation of our interest on the total synthesis of biolog-
ically active molecules,5 herein, we report the synthesis of
cytospolide E.
2
8
O
O
1
HO
9
RO
O
O
A R1 = Ac, R2 = H
B R1 = H, R2 = Ac
C R1 = R2 = Ac
D R1 = R2 = H
1
E ( )
Figure 1. Structure of cytospolide A–E.
OH
OMOM
O
O
HO
MOMO
Our retrosynthetic analysis of cytospolide E, 1 reveals that it
could be synthesised by means of RCM cyclisation of precursor
14, which in turn could be prepared through the esterification of
acid 6 with alcohol 13. The intermediates 6 and 13 could easily
be prepared from a commercially available acrolein 2 and n-hex-
anal 7 ‘respectively’ (Scheme 1).
Accordingly, we began the synthesis of cytospolide E by means
of asymmetric aldol reaction between acrolein 2 and imide 3 to af-
ford the Evans’ syn-aldol product 4 in 88% yield (de >95:5).6 Protec-
tion of the resulting alcohol 4 with MOMCl in the presence of
Hunig’s base afforded the MOM ether 5 in 92% yield. Hydrolysis
O
O
14
1
OH
MOMO
O
+
OH
3
OMOM
13
6
( )
O
O
3
2
7
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Scheme 1. Retrosynthetic analysis of cytospolide E.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.108

J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 6048–6050
6049
OH
O
O
O
O
a
N
O
N
O
O
+
O
O
5
4
3
Bn
Bn
7
2
3
4
6
8
9
MOMO
5
O
MOMO
b
c
2
N
1
O
OH
10
Bn
6
Scheme 2. Synthesis of fragment
6
via Evan’s aldol reaction. Reagents and
conditions: (a) n-Bu2BOTf, i-Pr2NEt, CH2Cl2, ꢀ78–0 °C, 1 h, 88%; (b) DIPEA, MOMCl,
CH2Cl2, 0 °C, 2 h, 92%; (c) LiOH, 35% aq H2O2, THF/H2O (4:1) 0 °C, 5 h, 90%.
of the 5 with LiOH/H2O27 afforded the corresponding acid 6 in 90%
yield (Scheme 2).
Figure 2. Characteristic nOe’s of the Z-isomer of cytospolide E.
Next we attempted the synthesis of compound 13 from a com-
mercially available n-hexanal. Initially, n-hexanal was converted
into allylic alcohol 8 in 92% yield using vinyl magnesium bromide.
The Sharpless kinetic resolution8 of allylic alcohol 8 using Ti(OiPr)4,
(ꢀ)-DIPT and TBHP in dichloromethane gave the enantiomerically
pure epoxy alcohol 9 in 42% yield (ee 97%). Protection of secondary
hydroxyl group with TBSCl in the presence of imidazole afforded
the TBS ether 10 in 91% yield. The regioselective opening of epox-
ide 10 with allyl magnesium bromide in the presence of CuCN gave
the secondary alcohol 11 in 95% yield. Protection of secondary
alcohol with MOMCl in the presence of diisopropylethylamine
gave the MOM ether 12 in 90% yield. Desilylation of compound
12 with TBAF gave the alcohol 13 in 92% yield (Scheme 3).
OH
3
OH
OH
a
b
( )
+
( )
( )
( )
3
(S)- 8
O
3
3
8
O
7
9
OH
OTBS
OTBS
c
d
( )
( )
( )
3
3
3
O
O
OH
9a
10
11
OTBS
OH
e
f
( )
( )
3
3
OMOM
OMOM
13
12
Scheme 3. Synthesis of fragment 13. Reagents and conditions: (a) vinyl magnesium bromide, THF, 0 °C, 92%; (b) Ti(OiPr)4, (ꢀ)-DIPT, TBHP, CH2Cl2, 4 A MS, ꢀ20 °C 8 h, 42%; (c)
TBSCl, imidazole, DCM, 1 h, 91%; (d) Mg, allyl chloride, CuCN, THF, 0 °C, 95%; (e) DIPEA, MOMCl, CH2Cl2, 0 °C, 2 h, 90%; (f) TBAF, THF, 0 °C, 92%.
OMOM
O
OH
3
MOMO
a
O
MOMO
+
OH
( )
O
OMOM
13
14
6
HO
MOMO
b
c
O
OH
O
OMOM
O
O
16
15
Scheme 4. Synthesis of the Z-isomer of cytospolide E. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 °C to rt, 6 h, 85%; (b) Grubb’s catalyst-II, CH2Cl2, reflux, 3 h, 70%; (c)
CeCl3ꢁ7H2O, CH3CN, reflux, 3 h, 88%.

6050
J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 6048–6050
7.37–7.31 (m, 2H), 7.31–7.25 (m, 1H), 7.21 (d, J = 6.9 Hz, 2H), 5.86 (ddd,
Finally, we attempted the coupling of 6 with 13 so as to con-
J = 17.3, 10.4, 5.7 Hz, 1H), 5.36 (d, J = 17.3 Hz, 1H), 5.23 (d, J = 10.4 Hz, 1H),
4.75–4.68 (m, 1H), 4.53–4.49 (m, 1H), 4.26–4.17 (m, 2H), 3.92–3.85 (m, 1H),
3.26 (dd, J = 13.8, 3.4 Hz, 1H), 2.80 (dd, J = 12.7, 9.2 Hz, 1H), 1.26 (d, J = 6.9 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 176.4, 153.0, 137.2, 134.9, 129.3, 128.9,
struct a 10-membered ring via the RCM reaction. Accordingly,
the coupling of acid 6 with alcohol 13 under Steglich conditions
gave the ester 14 in 85% yield.9 Upon treatment of 14 with the
Grubbs’ second generation catalyst10 in CH2Cl2 at reflux tempera-
ture for 3 h gave the Z-isomer of cytospolide E 15 in 70% yield.
The structure of 15 was ascertained by its NMR spectrum. The
geometry of the olefin in 15 was determined as ‘Z’ from its coupling
constants, while one of the olefinic proton signals appears at d
5.71 ppm as a dt (J = 3.0, 12.0 Hz) and another signal for the olefinic
proton appears at d 5.14 ppm as a triplet (J = 9.8 Hz) which clearly
reveals the Z geometry of the olefin. Deprotection of MOM ethers of
15 using CeCl3ꢁ7H2O11 in refluxing CH3CN gave the Z-isomer of
cytospolide E 16 in 88% yield (Scheme 4).
127.3, 116.2, 72.5, 66.1, 55.0, 42.4, 37.7, 10.9; IR (neat): vmax 3489, 2926, 2851,
1778, 1697, 1605, 1454, 1386, 1213, 1108, 977, 702 cmꢀ1. MS (ESI): m/z 312
[M+Na]+. (S)-4-Benzyl-3-((2S,3R)-3-(methoxymethoxy)-2-methylpent-4-enoyl)
oxazolidin-2-one (5): ½a D20
ꢂ
23.7 (c = 2.6, CHCl3); 1H NMR (300 MHz, CDCl3): d
7.37–7.19 (m, 5H), 5.87–5.74 (ddd, J = 17.3, 10.5, 7.5 Hz, 1H), 5.29 (d, J = 7.5 Hz,
1H), 5.25 (s, 1H), 4.68–4.58 (m, 2H), 4.55–4.50 (m, 1H), 4.26 (t, J = 6.7 Hz, 1H),
4.19–4.16 (m, 2H), 4.12 (t, J = 6.7 Hz, 1H), 3.35 (s, 3H), 3.29 (dd, J = 13.5, 3.7 Hz,
1H), 2.77 (dd, J = 13.5, 9.8 Hz, 1H), 1.28 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 173.8, 152.7, 135.1, 134.8, 128.9, 128.4, 126.8, 118.4, 93.5, 76.5,
65.5, 55.2, 55.1, 41.6, 37.3, 12.3; IR (neat): vmax 3065, 2981, 2934, 2849, 1781,
1700, 1604, 1454, 1385, 1216, 1097, 1029, 703 cmꢀ1
. MS (ESI): m/z 356
[M+Na]+. (2S,3R)-3-(Methoxymethoxy)-2-methylpent-4-enoic acid (6):
½ ꢂ
a 2D0
ꢀ67.5 (c = 2.8, CHCl3). 1H NMR (300 MHz, CDCl3): d 5.82–5.68 (ddd, J = 17.5,
10.0, 8.1 Hz, 1H), 5.33 (d, J = 2.2 Hz, 1H), 5.29 (d, J = 1.7 Hz, 1H), 4.64 (q,
J = 6.8 Hz, 2H), 4.31 (t, J = 6.2 Hz, 1H), 3.37(s, 3H), 2.71 (t, J = 6.0 Hz, 1H), 1.23
(d, J = 6.9 Hz, 3H); 13C NMR CDCl3, 75 MHz): d 179.2, 135.0, 119.4, 93.8, 77.9,
55.6, 44.5, 11.8; IR (neat)): vmax 3084, 2984, 2940, 1736, 1713, 1458, 1383,
The relative stereochemistry of 16 was deduced from the 1H–1H
coupling constants and NOESY data. The geometry of the
bond was assigned as Z based on the proton coupling constant
(3JH4 H5
= 11.1 Hz) and nOe studies. The presence of nOe between
H-2 and H-4, H-5 and H-7b, indicates the b-orientation of these
protons. The nOe between H-3 and H-10, H-3 and H-6 indicates
the -orientation of H-3, H6 and H10 (Fig. 2). The above observa-
D
4 double
1219, 1153, 1032, 772 cmꢀ1 MS (ESI): m/z 197 [M+Na]+. (5S,6R)-6-(tert-
;
,
Butyldimethylsilyloxy)undec-1-en-5-ol (11): ½a D20
ꢂ
ꢀ12.6 (c = 2.3, CHCl3); 1H NMR
(300 MHz, CDCl3): d 5.88–5.78 (m, 1H), 5.04 (d, J = 16.8 Hz, 1H), 4.97 (d,
J = 9.8 Hz, 1H), 3.64–3.56 (m, 2H), 2.30–2.20 (m, 1H), 2.15–2.04 (m, 1H), 1.65
(brs, 1H), 1.56–1.17 (m, 10H), 0.91–0.85 (m, 12H), 0.06 (s, 6H); 13C NMR (CDCl3,
75 MHz): d 138.5, 114.7, 75.3, 73.9, 32.0, 30.9, 30.7, 30.3, 25.8, 25.3, 22.5, 18.0,
14.0, ꢀ4.4; IR (neat): vmax 3480, 3078, 2931, 2858, 1641, 1465, 1362, 1255,
1081, 836, 775 cmꢀ1. MS (ESI): m/z 323 [M+Na]+. (5S,6R)-5-(But-3-enyl)-8,8,9,9-
a
a
a
tion reveals the Z stereochemistry of the cytospolide E.12
In summary, we have developed an efficient synthetic route for
the stereoselective total synthesis of the Z-isomer of cytospolide E
starting from a readily available acrolein and n-hexanal. The syn-
thetic strategy involves asymmetric Aldol reaction, Sharpless ki-
netic resolution and RCM cyclisation as key steps. The total
synthesis of 16 was accomplished in 12 steps, with 15% overall
yield.
tetramethyl-6-pentyl-2,4,7-trioxa-8-siladecane (12): ½ ꢂ ½ ꢂ ꢀ33.6 (c = 2.2,
a 2D0 a 2D0
CHCl3); 1H NMR (500 MHz, CDCl3): d 5.87–5.76 (m, 1H), 5.02 (d, J = 15.0 Hz,
1H), 4.96 (d, J = 10.3 Hz, 1H), 4.69 (q, J = 6.9 Hz, 2H), 3.69–3.63 (m, 1H), 3.54–
3.48 (m, 1H), 3.38 (s, 3H), 2.28–2.13 (m, 1H), 2.12–2.02 (m, 1H), 1.67–1.17 (m,
10H), 0.91–0.84 (m, 12H), 0.06 (s, 6H); 13C NMR (CDCl3,75 MHz): d 138.6,
114.5, 96.0, 79.9, 74.5, 55.7, 32.9, 32.0, 30.2, 29.8, 25.9, 25.5, 22.5, 18.1, 14.0,
ꢀ4.2, ꢀ4.6; IR (neat): vmax 3078, 2951, 2859, 1641, 1465, 1382, 1253, 1147,
1096, 1038, 915, 835, 775 cmꢀ1 MS (ESI): m/z 367 [M+Na]+. (5S,6R)-5-
;
(Methoxymethoxy)undec-1-en-6-ol (13): ½ ꢂ
a 2D0 8.3 (c = 2.7, CHCl3). 1H NMR
(500 MHz, CDCl3): d 5.89–5.74 (m, 1H), 5.09–4.95 (m, 2H), 4.70 (q, J = 6.8 Hz,
2H), 3.65–3.50 (m, 2H), 3.43 (s, 3H), 2.30–2.16 (m, 1H), 2.15–2.00 (m, 1H),
1.74–1.17 (m, 10H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3,75 MHz): d 138.2,
114.9, 97.2, 83.4, 73.0, 55.8, 31.9, 31.5, 29.3, 25.8, 25.6, 22.6, 14.0; IR (neat):
vmax 3456, 3077, 2931, 2858, 1736, 1642, 1455, 1378, 1150, 1098, 1036,
914 cm-1; MS (ESI): m/z 253 [M+Na]+. (2S,3R)-((5S,6R)-5-(Methoxymethoxy)
Acknowledgements
T.P., A.S., P.A.R., and A.R. are thankful to the UGC, CSIR, New Del-
hi, for the award of fellowships.
undec-1-en-6-yl) 3-(methoxymethoxy)-2-methylpent-4-enoate (14): ½a D20
ꢀ54.2
ꢂ
(c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d 5.88–5.67 (m, 2H), 5.31–5.20 (m,
2H), 5.08–4.94 (m, 3H), 4.70 (dd, J = 9.0, 6.8 Hz, 2H), 4.55 (dd, J = 12.8, 6.8 Hz,
2H), 4.18 (t, J = 7.5 Hz, 1H), 3.66–3.59 (m, 1H), 3.38 (s, 3H), 3.36 (s, 3H), 2.64 (t,
J = 6.8 Hz, 1H), 2.31–2.00 (m, 2H), 1.70–1.46 (m,3H), 1.38–1.16 (m, 10H), 0.88
(t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 173.7, 138.1, 135.7, 119.1, 115.0,
95.9, 93.9, 78.4, 77.2, 74.9, 55.7, 55.6, 45.2, 31.6, 29.8, 29.6, 29.2, 25.3, 22.5,
13.9, 13.1; IR (neat): vmax 3079, 2930, 2857, 1733, 1641, 1458, 1377, 1153,
References and notes
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1705; (c) Yadav, J. S.; Pattanayak, M. R.; Das, P. P.; Mohapatra, D. K. Org. Lett.
2011, 13, 1710; (d) Yadav, J. S.; Rajender, V. Eur. J. Org. Chem. 2010, 2148; (e)
Yadav, J. S.; Pandurangam, T.; Reddy, V. V.; Reddy, B. V. S. Synthesis 2010, 4300.
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M.; Viti, M. S.; Walker, J. F.; Woodard, S. S. Pure Appl. Chem. 1983, 55, 589.
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B. V. S. Tetrahedron 2010, 66, 334.
10. (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446; (b) Deiters,
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1149.
;
1034, 920, 768 cmꢀ1 MS (ESI): m/z 409 [M+Na]+. (3S,4R,9S,10R,Z)-4,9-
Bis(methoxymethoxy)-3-methyl-10-pentyl-3,4,7,8,9,10-hexahydrooxecin-2-one
(15): ½a 2D0
ꢂ
ꢀ37.5 (c = 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.73 (dt, J = 12.0,
3.0 Hz, 1H), 5.17 (t, J = 9.8 Hz, 1H), 5.08–5.00 (m, 1H), 4.73 (d, J = 6.8 Hz, 1H),
4.62 (q, J = 6.8 Hz, 2H), 4.51 (t, J = 6.8 Hz, 2H), 3.62 (t, J = 5.2 Hz, 1H), 3.42 (s,
3H), 3.38 (s, 3H), 2.67–2.51 (m, 2H), 2.19-2.00 (m, 2H), 1.70-1.46 (m, 3H), 1.43-
1.22 (m, 10H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 172.7, 135.8,
127.0, 94.5, 93.9, 77.2, 74.9, 72.5, 55.7, 47.5, 31.5, 31.3, 30.3, 29.7, 24.9, 24.7,
22.5, 15.4, 13.9; IR (neat): vmax 2931, 2857, 1740, 1456, 1370, 1252, 1152,
1099, 1035, 920, 745 cmꢀ1; MS (ESI): m/z 381 [M+Na]+. (3S,4R,9S,10R,Z)-4,9-
Dihydroxy-3-methyl-10-pentyl-3,4,7,8,9,10-hexahydrooxecin-2-one (16): White
solid, mp 136–140ꢀC; ½a D20
ꢂ
26.6 (c = 0.8, CHCl3); 1H NMR (500 MHz, CDCl3): d
5.75 (ddd, J = 11.1, 4.5, 1.1 Hz, 1H), 5.37 (dt, J = 9.9, 2.2 Hz, 1H), 5.12 (dt, J = 9.5,
3.7 Hz,1H), 4.64 (t, J = 9.9 Hz, 1H), 3.81 (dt, J = 4.6, 3.7 Hz, 1H), 2.73 (dq, J = 12.9,
3.9 Hz, 1H), 2.51 (qd, J = 9.9, 6.9 Hz, 1H), 2.13–1.90 (m, 2H), 1.67–1.49 (m, 2H),
1.44–1.20 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 174.6,
133.8, 129.9, 77.6, 74.3, 69.5, 49.1, 31.3, 30.8, 29.6, 25.2, 25.1, 22.4, 14.8, 13.8;
IR (KBr): vmax 3236, 2923, 2855, 1729, 1449, 1253, 1039, 766 cmꢀ1; MS (ESI):
m/z 293 [M+Na]+.
12. Spectral data for (S)-4-Benzyl-3-((2S,3R)-3-hydroxy-2-methylpent-4-enoyl)
oxazolidin-2-one (4): ½a D20
ꢂ
53.7 (c = 0.7, CHCl3); 1H NMR (500 MHz, CDCl3): d