Enantioselective synthesis of (+)-patulolide C via proline-catalyzed sequential α-aminooxylation and Horner-Wadsworth-Emmons olefination

Article abstract of DOI:10.1016/j.tetlet.2010.05.063

The enantioselective total synthesis of (+)-patulolide C isolated from Penicillium urticae has been achieved from commercially available 9-decen-1-ol. Jacobsen's kinetic resolution and sequential a-aminooxylation and Horner-Wadsworth-Emmons (HWE) olefinat

Full text of DOI:10.1016/j.tetlet.2010.05.063

Tetrahedron Letters 51 (2010) 3824–3826
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Enantioselective synthesis of (+)-patulolide C via proline-catalyzed sequential
a-aminooxylation and Horner–Wadsworth–Emmons olefination
*
Gowravaram Sabitha , G. Chandrashekhar, K. Yadagiri, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, 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:
The enantioselective total synthesis of (+)-patulolide C isolated from Penicillium urticae has been achieved
Received 6 April 2010
Revised 13 May 2010
Accepted 17 May 2010
Available online 21 May 2010
from commercially available 9-decen-1-ol. Jacobsen’s kinetic resolution and sequential a-aminooxylation
and Horner–Wadsworth–Emmons (HWE) olefination followed by Yamaguchi lactonization are used as
the key reaction steps.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Macrolide
MacMillan
Nitrosobenzene
-proline
a-hydroxylation
D
Yamaguchi lactonization
HWE
1. Introduction
2. Results and discussion
Patulolides A 1, B 2, and C 3 (Fig. 1) were isolated from the cul-
ture broth of the Penicillium urticae S11R59 and characterized by
Yamada and co-workers.1 These macrolides were found to show
antifungal, antimicrobial, and anti-inflammatory activities. The re-
ported pharmacological properties and structural features of patu-
lolides make them highly attractive target molecules for the
synthesis. Although several racemic2 and enantioselective3 ap-
proaches have been reported for the synthesis, most of them are
rather lengthy, suffer from poor enantiocontrol, and use of inacces-
sible materials.
The synthesis commences with 9-decen-1-ol 6, protected as its
benzyl ether 7 (Scheme 2). Epoxidation of alkene 7 with m-chloro-
benzoic acid (MCPBA) gave the racemic epoxide, which was
subjected to Jacobsen’s hydrolytic kinetic resolution5 using (S,S)-
(+)-N,N0-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-
cobalt(II) to give chiral epoxide 8, 46%, (98% ee). Epoxide 8 on
treatment with LAH in THF at 0 °C to rt for 2 h afforded secondary
alcohol 9 in 87% yield, which was protected as its TBS ether 10 with
TBSCl and imidazole in dry CH2Cl2. The subsequent removal of
benzyl group using Li in liquid NH3 in dry THF gave the primary
alcohol, which was oxidized using IBX in dry CH2Cl2/DMSO to give
the key aldehyde 5 in 82% yield.
Within our recently initiated program on the synthesis of mac-
rolides,4 herein, we report an efficient synthesis of (+)-patulolide C
3 from the readily available 9-decen-1-ol utilizing Jacobsen’s
The sequential
a
-aminooxylation-olefination6 on aldehyde 5
-proline using nitrosobenzene in DMSO at
hydrolytic kinetic resolution and the MacMillan
a
-hydroxylation
catalyzed by 40 mol % D
for the creation of two stereogenic centers. Finally, Yamaguchi’s
protocol was used for the construction of macrolide.
room temperature followed by in situ Horner–Wadsworth–Em-
mons (HWE) olefination with triethyl phosphonoacetate and
The retrosynthetic approach is outlined in Scheme 1. Patulolide
C 3 could be envisioned to be obtained by Yamaguchi lactonization
of enone 4, which in turn could be made by a
D-proline-catalyzed
Macmillan -hydroxylation and tandem olefination of aldehyde
5, which could be obtained from commercially available 9-decen-
a
O
O
1-ol 6.
O
O
OH
O
O
O
O
(+)-patulolide C
patulolide B 2
patulolide A 1
* Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
Figure 1. Twelve-membered natural macrolides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.063

G. Sabitha et al. / Tetrahedron Letters 51 (2010) 3824–3826
3825
OTBS
OTBS
CHO
OH
CO2Et
O
OH
OMOM
5
O
4
(+)-patulolide C 3
6
Scheme 1. Retrosynthesis.
a
b
O
OH
OBn
OBn
6
7
8
OTBS
c
OR
e
d
CHO
OBn
5
9 R = H
10 R = TBS
OTBS
OTBS
f
CO2Et
CO2Et
OH
ONHPh
11
11a
OTBS
OR
g
h
CO2Et
CO2H
OMOM
OMOM
4
12 R = TBS
13 R = H
i
ref 3b
O
O
O
patulolide A 1
O
O
OH
OMOM
O
O
14
patulolide C
3
Scheme 2. Reagents and conditions. (a) BnBr, NaH, dry THF, 0 °C to rt, 4 h, 95%; (b) (i) m-CPBA, NaHCO3, dry DCM, 0 °C to rt, 4 h, 87%; (ii) (S,S)-Salen-Co(III-)-(OAc),
(0.5 mol %), dist. H2O (0.55 equiv), 0 °C to rt, 19 h, 46% (98% ee); (c) (i) LAH, dry THF, 0 °C to rt, 2 h, 87%; (ii) TBSCI, imidazole, dry DCM, 0 °C 1 h, 92%; (d) (i) Li, liq NH3, dry THF,
10 min, rt, 95%; (ii) IBX, dry DCM/DMSO, 0 °C, 4 h, 82%; (e) (i) PhNO, D-proline (40 mol %), triethyl phosphonoacetate, cesium carbonate, dry DMSO, rt, 1 h, 57%; (ii) Cu(OAc)2,
EtOH, rt, 12 h, 85%, (98% de); (f) MOMCl, N,N-diisopropylethyl amine, dry DCM, 0 °C, 5 h, 83%; (g) (i) LiOH, MeOH/H2O, (4:1), 0 °C to rt, 14 h, 92%; (ii) PPTS, THF/H2O, (1:1), rt,
18 h, 68%; (h) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, toluene, reflux, 16 h, 70%; (i) CeCl3ꢀ7H2O, CH3CN/MeOH (2:1), 48 h, reflux, 60%.
Cs2CO3 as a base resulted in the formation of aminooxy olefinic es-
ter 11a in 57% yield, which followed by cleavage of the O–N bond
using Cu(OAc)2 in EtOH at rt gave the c-hydroxy a,b-unsaturated
under neutral conditions using CeCl3ꢀ7H2O in CH3CN/MeOH
(2:1)8 furnished the target patulolide C 3. The spectroscopic prop-
erties and optical rotation of synthetic 3 were identical with those
reported for the natural product.1a
In conclusion, a short synthesis of (+)-patulolide C has been
achieved featuring Jacobsen’s kinetic resolution, MacMillan amino-
oxylation, and HWE followed by Yamaguchi lactonization as the
key reaction steps. Since patulolide C can be converted to patulo-
lide A3b by simple oxidation reaction it becomes the formal synthe-
sis of 1.
ester 11 (98% de), a key intermediate in 85% yield. The hydroxy
group was protected as its MOM ether 4 which followed by hydro-
lysis of ethyl ester using LiOH in aq MeOH gave the corresponding
carboxylic acid 12 in 92% yield. Removal of the TBS group became
problematic and could not be cleaved using TBAF and p-TsOH in
MeOH (unidentified material with disappearance of double bond
protons in 1H NMR spectroscopy), but finally in the presence of
PPTS in THF/H2O (1:1) we were successful in removal affording
the corresponding hydroxyacid 13 in 68% yield. The hydroxyacid
13 was subjected to macrolactonization by using the Yamaguchi
procedure7 (2,4,6-trichlorobenzoyl chloride and triethyl amine in
THF followed by treatment with DMAP) to provide patulolide C
MOM ether 14 in 70% yield. Removal of MOM group failed under
the conditions using PTSA/MeOH, where the decomposition of
material was observed. Finally, removal of the MOM group in 14
3. Selected spectral data
3.1. (2S)-2-[8-(Benzyloxy)octyl]oxirane (8)
½
a 2D5
ꢁ
: ꢂ5.7 (c 1, CHCl3); 1H NMR: (CDCl3, 300 MHz): d 7.31–7.27
(m, 5H), 4.46 (s, 2H), 3.42 (t, J = 6.6 Hz, 2H), 2.86–2.81 (m, 1H), 2.68
(t, J = 4.15 Hz, 1H), 2.4 (dd, J = 2.64, 5.1 Hz, 1H), 1.64–1.23 (m,

3826
G. Sabitha et al. / Tetrahedron Letters 51 (2010) 3824–3826
14H); 13C NMR; 132.7, 129.4, 128.2, 127.5, 127.3, 72.7, 70.4, 65.1,
52.3, 47.1, 32.4, 29.6, 29.3, 29.2, 29.1, 29, 28.6, 26.1, 26, 25.9,
25.8; IR (Neat): 1718, 1455. 1274, 1104 cmꢂ1; LC–MS m/z: 285,
[M+Na]+.
17.6 Hz, 2H), 4.23–4.16 (m, 1H), 3.81–3.71 (m, 1H) 3.36 (s, 3H)
1.65–1.25 (m, 13H), 1.18 (d, J = 6.1 Hz, 3H), 13CNMR (CDCl3,
75 MHz): 170.3, 150.9, 120.9, 94.7 75.1, 68.1, 55.6, 39.2, 34.7,
29.6, 29.6, 29.4, 25.6, 24.9, 23.4. IR (Neat): 3446, 2927, 2855,
1703, 1657, 1270, 1100, 1034 cmꢂ1; mass: 297 [M+Na]+. HRMS:
m/z calcd for C14H26O5 + Na [M+Na]+: 297.1276; found: 297.1284.
3.2. (2R)-10-(Benzyloxy)decan-2-ol (9)
½
a 2D5
ꢁ
: ꢂ4.8 (c 1, CHCl3); 1H NMR: (CDCl3, 300 MHz): d 7.33–7.27
3.7. (5S,12S)-5-(Methoxymethoxy)-12-methyl-1-oxa-3-
cyclododecen-2-one (14)
(m, 5H), 4.46 (s, 2H), 3.79–3.69 (m, 1H), 3.42 (t, J = 6.1 Hz, 2H),
1.63–1.53 (m, 2H), 1.42–1.26 (m, 13H), 1.16 (d, J = 6.1 Hz, 3H);
13C NMR: 138.5, 128.2, 127.5, 127.3, 126.7, 72.7, 70.3, 69.9, 39.2,
29.6, 29.4, 29.2, (2C), 26, 25.6, 23.3; IR (Neat): 3387, 2928, 2854,
1455, 1103 cmꢂ1; LC–MS m/z: 287 [M+Na]+.
½
a 2D5
ꢁ
: ꢂ24.4 (c 1, CHCl3); 1H NMR: (CDCl3, 300 MHz): d 6.77 (dd,
J = 7.5, 15.8 Hz, 1H), 6.01 (d, J = 16.6 Hz, 1H), 5.08–4.98 (m, 1H),
4.57 (dd, J = 6.7, 15.1 Hz, 2H), 4.34–4.27 (m, 1H), 3.33 (s, 3H),
1.86–1.14 (m, 12H), 1.29 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3,
75 MHz): 167.4, 148.4, 122.8, 75, 73.2, 55.3, 33.8, 33, 29.6, 28.1,
3.3. Ethyl (E,4S,11R)-11-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-4-
hydroxy-2-dodecenoate (11)
27.6, 22.5, 21.2, 19.5. IR (Neat): 2923, 1722, 1649, 1461 cmꢂ1
;
mass: 279 [M+Na]+. HRMS: m/z calcd for C14H24O4 + Na [M+Na]+:
½
a 2D5
ꢁ
: +1.4 (c 1, CHCl3); 1H NMR (CDCl3, 300 MHz): d 6.89 (dd,
279.1572; found: 279.1581.
J = 4.8, 15.6 Hz, 1H), 5.98 (d, J = 15.6 Hz, 1H), 4.29–4.24 (m, 1H),
4.18 (q, J = 7.8, 14.6 Hz, 2H), 3.77–3.71 (m, 1H), 1.60–1.53 (m,
2H), 1.49–1.28 (m, 11H), 1.30 (t, 3H, J = 6.8 Hz), 1.1 (d, 3H,
J = 5.8 Hz), 0.87 (s, 9H), 0.02 (d, J = 2.9 Hz, 6H); 13C NMR (CDCl3,
75 MHz): 166.7, 150.1, 120.2, 71.1, 68.5, 60.4, 39.6, 36.5, 29.5,
29.4, 25.8, 25.6, 25.1, 23.8, 14.2, 14.1; IR (Neat): 3447, 2930,
1719, 1655, 1463, 1254, 1042 cmꢂ1; mass: 395 [M+Na]+.
3.8. (5S,12S)-5-Hydroxy-12-methyl-1-oxa-3-cyclododecen-2-
one (3)
½
a 2D5: +5.7 (c 1, MeOH); 1H NMR: (CDCl3, 300 MHz): d 6.84 (dd,
J = 6.4, 15.8 Hz, 1H), 6.08 (dd, J = 1.5, 15.8 Hz, 1H,), 5.06 (m, 1H),
4.49 (m, 1H), 1.81–1.13 (m, 12H), 1.29 (d, J = 6.79 Hz, 3H); 13CNMR
(CDCl3, 75 MHz): 19.8, 23.7, 24.1, 27.9, 28.5, 34.2, 36.3, 69.1, 71.5,
ꢁ
3.4. Ethyl (E,4S,11R)-11-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-4-
(methoxymethoxy)-2-dodecenoate (4)
120.1, 150.1, 166.3. IR (Neat): 3448, 2924, 2854, 1731, 1642 cmꢂ1
mass: 234 [M+Na]+.
;
½
a 2D5
ꢁ
: ꢂ4.4 (c 1, CHCl3), 1H NMR: (CDCl3, 300 MHz): d 6.75 (dd,
Acknowledgment
J = 6.4, 15.6 Hz, 1H), 5.92 (d, J = 15.6 Hz, 1H), 4.56 (dd, J = 6.7,
20.1 Hz, 2H), 4.18 (q, J = 7.1, 14.3 Hz, 2H), 4.16–4.12 (m, 1H),
3.78–3.70 (m, 1H), 3.35 (s, 3H), 1.63–1.17 (m, 15H), 1.09 (d,
J = 6.1 Hz, 3H), 0.87 (s, 9H), 0.02 (d, J = 1.5 Hz, 6H). 13CNMR (CDCl3,
75 MHz): 167.6, 149.8, 121.3, 94.5 72.2, 69.5, 61.4, 52.3 39.5, 35.5,
29.6, 29.5, 25.7, 25.6, 24.9, 23.8, 14.2, 14.1.IR (Neat): 2934, 1722,
1635, 1452, 1254, 1120, 1050 cmꢂ1; mass: 439 [M+Na]+. HRMS:
G. C. and K. Y. thanks UGC, New Delhi, for the award of
fellowships.
References and notes
1. (a) Sekiguchi, J.; Kuruda, H.; Yamada, Y.; Okada, H. Tetrahedron Lett. 1985, 26,
2341; (b) Rodpha, D.; Sekiguchi, J.; Yamada, Y. J. Antibiot. 1986, 629.
2. (a) Dorling, E. K.; Thomas, E. J. Tetrahedron Lett. 1999, 40, 471; (b) Kaisalo, L.;
Koskimies, J.; Hase, T. Synth. Commun. 1999, 29, 399; (c) Solladie, G.; Gerber, Ch.
Synlett 1992, 449.
m/z calcd for
439.1216.
C
22H44O5Si + Na [M+Na]+: 439.1212; found:
3. (a) Thijs, L.; Egenberger, D. M.; Zwanenburg, B. Tetrahedron Lett. 1989, 30, 2153;
(b) Yang, H.; Kuroda, H.; Miyashita, M.; Irie, H. Chem. Pharm. Bull. 1992, 40, 1616;
(c) Leemhuis, F. M. C.; Thijs, L.; Zwanenburg, B. J. Org. Chem. 1993, 58, 7170; (d)
Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org. Chem. 1998, 63,
7505; (e) Tian, J.; Yamagiva, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2003, 5,
3021; (f) Babu, K. V.; Sharma, G. V. M. Tetrahedron: Asymmetry 2008, 19, 577; (g)
Mori, K.; Sakai, T. Liebigs Ann. Chim. 1988, 13.
4. (a) Sabitha, G.; Padmaja, P.; Sudhakar, K.; Yadav, J. S. Tetrahedron: Asymmetry
2009, 20, 1330; (b) Sabitha, G.; Yadagiri, K.; Swapna, R.; Yadav, J. S. Tetrahedron
Lett. 2009, 50, 5417; (c) Herbarumin III: Sabitha, G.; Srinivas, Ch.; Maruthi, Ch.;
Yadav, J. S. Helv. Chim. Acta, in press.
5. (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; (b) Louis, J.
T.; Nelson, W. L. J. Org. Chem. 1987, 52, 1309.
6. (a) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696; (b)
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, C. W. C. J. Am. Chem. Soc. 2003,
125, 10808; (c) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (d) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293; (e) Zhong, G.
Chem. Commun. 2004, 606.
3.5. (E,4S,11R)-11-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4-
(methoxymethoxy)-2-dodecenoic acid (12)
½
a 2D5
ꢁ
: ꢂ24 (c 1, CHCl3), 1H NMR: (CDCl3, 300 MHz): d 6.89 (dd,
J = 6.1, 15.1 Hz, 1H), 5.96 (d, J = 15.8 Hz, 1H), 4.58 (dd, J = 6.7,
14.3 Hz, 2H), 4.23–4.15 (m, 1H), 3.78–3.69 (m, 1H) 3.36 (s, 3H)
1.64–1.24 (m, 13H), 1.09 (d, J = 6.1 Hz, 3H), 0.87 (s, 9H), 0.03 (d,
J = 2.2 Hz, 6H). 13CNMR (CDCl3, 75 MHz): 170.8, 150.8, 121, 94.7
75.2, 68.6, 55.6, 39.6, 34.7, 29.6, 29.6, 29.5, 29.4, 25.9, 25.6, 25,
23.8, ꢂ4.4, ꢂ4.7. IR (Neat): 3432, 2930, 1698, 1653, 1459,
1034 cmꢂ1; MASS: 411 [M+Na]+. HRMS: m/z calcd for C20H40O5S-
i + Na [M+Na]+: 411.1315; found: 411.1324.
3.6. (E,4S,11R)-11-Hydroxy-4-(methoxymethoxy)-2-dodecenoic
acid (13)
7. (a) Inanaga, J.; Hirata, K.; Sacki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.
Jpn. 1979, 52, 1989; (b) ulzer, J.; Kirstein, H. M.; Buschmann, J.; Lehmann, C.;
Luger, P. J. Am. Chem. Soc. 1991, 113, 910.
8. Sabitha, G.; Fatima, N.; Gopal, P.; Reddy, C. N.; Yadav, J. S. Tetrahedron:
Asymmetry 2009, 20, 184.
½
a 2D5
ꢁ
: ꢂ70.2 (c 1, CHCl3), 1H NMR: (CDCl3, 300 MHz): d 6.89 (dd,
J = 5.3, 15.1 Hz, 1H), 5.96 (d, J = 15.9 Hz, 1H), 4.58 (dd, J = 7.1,