A concise asymmetric route to the antibiotic macrolides patulolide A and pyrenophorin

Article abstract of DOI:10.1016/j.tetlet.2006.07.026

In this letter, we describe an enantiospecific route to patulolide A and pyrenophorin through the synthesis of known protected seco acid precursors starting from commercially available (S)-ethyl lactate.

Full text of DOI:10.1016/j.tetlet.2006.07.026

Tetrahedron Letters 47 (2006) 6623–6626
A concise asymmetric route to the antibiotic macrolides
patulolide A and pyrenophorin
K. Srinivasa Rao,a,b D. Srinivasa Reddy,a,* K. Mukkanti,b Manojit Pala and Javed Iqbala,*
aDiscovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 049, AP, India
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
Received 17 April 2006; revised 23 June 2006; accepted 6 July 2006
Available online 1 August 2006
Abstract—In this letter, we describe an enantiospecific route to patulolide A and pyrenophorin through the synthesis of known
protected seco acid precursors starting from commercially available (S)-ethyl lactate.
Ó 2006 Elsevier Ltd. All rights reserved.
Molecules belonging to the medium and large size ring
lactones have attracted considerable attention from syn-
thetic chemists due to their interesting biological proper-
ties. Though many macrolides have complex structures
with high substitution, simple macrolides also possess
important properties which make them worth explor-
ing.1 Most of the physiologically active macrolactones
often have a double bond at the a,b-position and a keto
or hydroxy functional group at the c-position (see,
Fig. 1).2
Recently, we disclosed an efficient and highly
trans-selective conjugate hydride addition on c-hydroxy-
a,b-alkynoic esters using LiAlH4 to produce c-hydroxy-
a,b-(E)-alkenoic esters (Scheme 1).3 As
a direct
application of this method, we were interested in the
synthesis of bioactive macrocycles possessing c-hydroxy
or c-keto-a,b-(E)-alkenoic ester functionalities. In this
letter, we report asymmetric routes to (S)-patulolide A
and (S,S)-pyrenophorin via their seco acid precursors.
O
O
Me
Me
O
Me
O
Patulolide A is a twelve-membered lactone isolated from
the culture broth of Penicillium urticae mutant S11R59.4
The interesting biological activity5 (antifungal, antibac-
terial, and antiinflammatory) of this twelve-membered
lactone and related molecules has attracted the attention
of synthetic chemists and resulted in several syntheses.6
In our synthesis, commercially available (S)-ethyl lactate
1 was converted into aldehyde 2 following the literature
protocol.7 Wittig olefination followed by reduction of
the double bond gave saturated ester 3. The aldehyde
4 obtained from 3 through DIBAL–H reduction, was
coupled with ethyl propiolate in the presence of LDA
O
O
O
O
O
(
S,S)-pyrenophorin
(S)-patulolide A
O
Me
Me
OH
O
X
O
Me
O
O
O
X = α-OH (+)-macrosphelide A
X = O (+)-macrosphelide B
Figure 1. Selected antibiotic macrolides with c-keto-a,b-unsaturated
(E)-alkenoic acid moieties.
OEt
OEt
LiAlH4
O
R
R
Keywords: Patulolide A; Pyrenophorin; Macrolide.
O
0 oC to RT
THF
q DRL Publication No. 456-B.
OH
(>95%
OH
*
Corresponding authors. Tel.: +91 40 2304 5439; fax: +91 40 2304
5438; e-mail addresses: javediqbaldrf@hotmail.com; javediqbalpr@
yahoo.co.in
E
-selectivity)
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.026

6624
K. S. Rao et al. / Tetrahedron Letters 47 (2006) 6623–6626
COOEt
i)
COOEt
5
COOEt
i. TBSCl, imid.
CHO
Ph3P
iii. DIBAL-H,
-78 oC
4
ii) H2, 10% Pd/C
50%
OTBS
ii. DIBAL-H,
-78 oC
OH
OTBS
78%
1
2
3
73%
OH
OH
LiAlH4
LDA, HMPA
CHO
OEt
5
5
OEt
0 oC to RT
65%
5
COOEt
74%
OTBS
OTBS
OTBS
O
O
4
5
6
OMEM
ref. 6d
DIPEA
MEMCl
92%
OEt
5
O
O
OTBS
O
O
7
(S)-patulolide A
Scheme 2.
to give compound 5 as diastereomeric mixture.8 The ste-
reochemistry of the newly formed center is not impor-
tant as this center represents a carbonyl group in the
natural product. As expected, conjugate reduction of 5
using LiAlH4 resulted in the desired (E)-alkenoic ester
6 in 65% isolated yield (Scheme 2). The hydroxy func-
tional group was protected as its 2-methoxyethoxy-
methyl ether to furnish known seco acid precursor 7,
which has previously been used to prepare the natural
product (S)-patulolide A.6d The spectral data of com-
pound 7 were compared with literature data and found
to be identical.9
followed by hydrogenation. The homologated ester 9
was transformed into the c-hydroxy-a,b-(E)-alkenoic es-
ter 12 via intermediates 10 and 11 using a similar proce-
dure to that described for patulolide A. Finally, the
known protected seco acid precursor 1311f of (S,S)-pyre-
nophorin was synthesized from compound 12 through
oxidation of the hydroxyl group and protection of the
resulting ketone with ethylene glycol, followed by
hydrolysis (Scheme 3). The spectral data for compound
13 were compared with the reported data of the same
compound and found to be identical.9
In summary, we have prepared known seco acid precur-
sors 7 and 13 starting from commercially available
(S)-ethyl lactate. We have demonstrated the utility of
the recently developed trans-selective conjugate reduction
of c-hydroxy-a,b-alkynoic esters to c-hydroxy-a,b-(E)-
alkenoic esters in macrocyclic natural product synthesis.
Application of this methodology for the synthesis of
other bioactive natural products will be the subject of
future publications.
Pyrenophorin, a sixteen-membered diolide isolated from
Pyrenophora avenae, is a powerful antifungal agent. This
C2-symmetric dilactone is derived by head-to-tail dimer-
ization of two identical C8 units.10 This compound has
been a target for many groups due to its interesting
structural features combined with its biological activ-
ity.11 In our route to pyrenophorin, aldehyde 812 was
converted to the ester 9 via two-carbon homologation
Ph3P
i)
COOEt
COOEt
CHO
DIBAL-H,
-78 oC
80%
COOEt
i) TBDPSCl, imid.
ii) H2, 10% Pd/C
82%
OTBDPS
OH
ii) DIBAL-H, -78
oC
OTBDPS
1
8
9
78%
OH
OH
LiAlH4
LDA, HMPA
COOEt
72%
CHO
OTBDPS
10
OEt
OEt
0 oC to RT
64%
OTBDPS
11
OTBDPS
12
O
O
O
O
ref.11f
O
O
i) Swern oxidation
OH
O
O
ii) (CH2OH)2, HC(OEt)3,
OTBDPS
O
O
BF3.Et2O
iii) NaOH
13
O
(S,S)-pyrenophorin
33%
Scheme 3.

K. S. Rao et al. / Tetrahedron Letters 47 (2006) 6623–6626
6625
(s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 50 MHz): À4.7,
À4.4, 14.2, 18.1, 23.8, 25.1, 25.7, 25.9, 29.4, 29.5, 36.7,
39.7, 60.4, 68.6, 71.2, 120.2, 150.0; MS (CI) 373 (M+1,
30%); HRMS calcd. for C20H41O4Si (M+1): 373.2774,
found. 373.2780. Compound 7: A mixture of compound 6
(51 mg, 0.137 mmol), DIPEA (0.07 ml, 0.41 mmol) in 3 ml
of dichloroethane was stirred for 30 min at room temper-
ature. The mixture was cooled to 0 °C and MEMCl
(37 mg, 0.3 mmol) was added dropwise and the mixture
heated to reflux for 60 h. The reaction mixture was cooled
to room temperature, diluted with DCM, washed with
NaHCO3 solution, and brine, the organic phase dried over
Na2SO4, and concentrated. The crude product was puri-
fied over silica gel (eluent: 0–3% ethyl acetate: petroleum
ether) to give the required compound 7 (58 mg) as a
colorless liquid. Yield = 92%; IR (neat): 2931, 2858,
Acknowledgements
We thank Dr. Reddy’s Laboratories Ltd. for the sup-
port and encouragement. Help from the analytical
department in recording spectral data is appreciated.
References and notes
1. (a) Clemer, C. F. W. D. Pure Appl. Chem. 1971, 28, 413;
(b) Boeckman, R. K., Jr.; Fayos, J.; Clardy, J. J. Am.
Chem. Soc. 1974, 96, 5954; (c) Omura, O.; Nakagawa, A.
J. Antibiot. 1975, 28, 401; (d) Omura, S. Macrolide
Antibiotics Chemistry, Biology and Practice; Academic
Press: New York, 1984.
2. (a) Nicolaou, K. C. Tetrahedron 1977, 33, 683; (b)
Mansuri, M. M.; Paterson, I. Tetrahedron 1985, 41,
3569; (c) Asaoka, M.; Takei, H. J. Synth. Org. Chem.
Jpn. 1986, 44, 819; (d) Boeckman, R. H., Jr.; Goldstein, S.
W. In The Total Synthesis of Natural Products; ApSimon,
J., Ed.; John Wiley and Sons: New York, 1988; Vol. 7,
Chapter 1; (e) Back, T. G. Tetrahedron 1995, 51, 3041–
3059; (f) Frensch, V. K.; Vogtle, F. Tetrahedron Lett.
1997, 38, 2573; (g) Roxburgh, C. J. Tetrahedron 1995, 51,
9767; (h) Kuroda, T.; Imashiro, R.; Seki, M. J. Org. Chem.
2000, 65, 4213.
1724 cmÀ1 1H NMR (CDCl3, 400 MHz): d 6.82 (dd,
;
J1 = 6.4 Hz, J2 = 15.86 Hz, 1H), 5.97 (dd, J1 = 1.35 Hz,
J2 = 15.85 Hz, 1H), 4.69 (s, 2H), 4.21–4.16 (m, 3H), 3.78–
3.73 (m, 2H), 3.66–3.61 (m, 1H), 3.54 (t, J = 4.84 Hz, 2H),
3.37 (s, 3H), 1.34–1.31 (m, 12H), 1.30 (t, J = 6.98 Hz, 3H),
1.10 (d, J = 6.2 Hz, 3H), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s,
3H); 13C NMR (CDCl3, 50 MHz): À4.72, À4.42, 14.2,
23.7, 25.0, 25.8 (3C), 29.5, 34.7, 39.6, 58.9, 60.4, 67.1, 68.5,
71.6, 75.3, 76.3, 77.0, 77.6, 93.6, 121.8, 147.8, 166.2; MS
(CI) 461 (M+1, 50%). Compound 13: A solution of oxalyl
chloride (0.79 g, 6.27 mmol) in 30 ml of DCM was cooled
to À78 °C and DMSO (0.98 g, 12.5 mmol) in 10 ml of
DCM was added dropwise. After stirring for 30 min,
alcohol 12 (2.3 g, 5.2 mmol) in 10 ml of DCM was added
dropwise. After 1 h, triethylamine (3.6 ml) was added, the
mixture again stirred for 1 h at À78 °C and at room
temperature for 30 min. Ammonium chloride solution was
added to the reaction mixture which was extracted with
DCM. The organic layer was washed with water, brine
and dried over Na2SO4. The residue obtained after
removal of the solvent was purified using flash column
chromotography to give the corresponding keto ester
(1.37 g) as a colorless liquid. Yield = 60%; IR (neat): 2932,
3. Rao, K. S.; Mukkanti, K.; Reddy, D. S.; Pal, M.; Iqbal, J.
Tetrahedron Lett. 2005, 46, 2287.
4. Sekiguchi, J.; Kuroda, H.; Yamada, Y.; Okada, H.
Tetrahedron Lett. 1985, 26, 2341.
5. (a) Rodphaya, D.; Sekiguchi, J.; Yamada, Y. J. Antibiot.
1986, 39, 629; (b) Matika, A.; Yamada, Y.; Okada, H. J.
Antibiot. 1986, 39, 1259; (c) Sarma, A.; Sankaranarayan,
S.; Chattopadhyaya, S. J. Org. Chem. 1996, 61, 1814.
6. (a) Ayyanger, N. R.; Chanda, B.; Waharkar, R. D.;
Kasar, R. A. Synth. Commun. 1988, 18, 2103; (b) Mori,
K.; Sakai, T. Liebigs. Ann. Chem. 1988, 13–17; (c) Yadav,
J. S.; Radha Krishna, P.; Gurjar, M. K. Tetrahedron 1989,
45, 6263; (d) Solladie, G.; Gerber, C. Synlett 1992, 449; (e)
Bestmann, H. J.; Kellermann, W.; Pecher, B. Synthesis
1993, 149.
7. (a) Nokami, J.; Mandai, T.; Nishimura, A.; Takeda, T.;
Wakabayashi, S. Tetrahedron Lett. 1986, 27, 5109; (b)
Dolle, R. E.; Li, C.-S.; Novelli, R.; Kruse, L. I.; Eggleston,
D. J. Org. Chem. 1992, 57, 128; (c) Kang, S. H.; Kim, M.;
Ryu, D. H. Synlett 2003, 1149.
2858, 1727, 1702, 1472, 1427 cmÀ1 1H NMR (CDCl3,
;
400 MHz) d 7.67–7.64 (m, 4H), 7.44–7.34 (m, 6H), 6.98 (d,
J = 15.85 Hz, 1H), 6.58 (d, J = 16.1 Hz, 1H), 4.29 (q,
J = 7.25 Hz, 2H), 3.95 (pent, J = 6.18 Hz, 1H), 2.68–2.60
(m, 2H), 1.80–1.71 (m, 2H), 1.35 (t, J = 6.98 Hz, 3H), 1.08
(d, J = 6.17 Hz, 3H), 1.05 (s, 9H); 13C NMR (CDCl3,
50 MHz): 10.5, 15.4, 19.5, 23.2, 28.9, 33.3, 57.6, 64.6,
123.7, 123.8, 125.8, 125.9, 126.7, 130.2, 130.5, 131.9, 132.0,
135.5, 161.6, 195.6; MS (CI) 439 (M+1, 10%), 381 (10%),
361 (20%), 183 (100%); HRMS calcd. for C26H35O4Si
(M+1): 439.2304, found. 439.2298. To a solution of the
above keto ester (1.3 g, 2.9 mmol) in 20 ml of benzene
were added ethanediol (0.39 g, 6.2 mmol), ethyl orthofor-
mate (0.82 g, 5.5 mmol), 4–5 drops of BF3Æ(OEt)2 and the
resulting mixture was refluxed for 24 h. The reaction
mixture was cooled to room temperature, diluted with
dichloromethane, washed with NaHCO3 solution, and
brine and the organic phase dried over Na2SO4, and
concentrated. The crude product was purified over silica
gel (eluent: 0–3% ethyl acetate: petroleum ether) to give
the required compound (1.14 g) as a viscous liquid.
Yield = 80%; IR (neat): 2962, 2858, 1723, 1472,
8. (a) Hirama, M.; Nishizaki, I.; Shigemoto, T.; Ito, S.
J. Chem. Soc., Chem. Commun. 1986, 393; (b) Hirama,
M.; Shigemoto, T.; Ito, S. J. Org. Chem. 1987, 52,
3342.
9. All products were characterized on the basis of spectral
data (IR, H NMR, 13C NMR, and MS). Compound 6:
1
To a suspension of lithium aluminium hydride (20 mg,
0.54 mmol) in 10 ml of dry THF was added compound 5
(0.2 g, 0.54 mmol) in 5 ml of THF dropwise at 0 °C and
the reaction allowed to stir at room temperature. After the
starting material had disappeared (tlc), the reaction was
quenched with saturated ammonium chloride solution,
diluted with ether, filtered over celite, and the organic
layer dried over Na2SO4. The residue obtained after
removal of the solvent was purified by column chroma-
tography (eluent: 0–3% ethyl acetate: petroleum ether) to
furnish the desired compound (130 mg) as a colorless
1428 cmÀ1 1HNMR (CDCl3, 400 MHz) d 7.69–7.65 (m,
;
4H), 7.42–7.33 (m, 6H), 6.70 (d, J = 15.58 Hz, 1H), 6.04
(d, J = 15.58 Hz, 1H), 4.23 (q, J = 6.99 Hz, 2H), 3.91–3.80
(m, 5H), 1.81–1.68 (m, 2H), 1.56–1.50 (m, 2H), 1.32 (t,
J = 7.26 Hz, 3H), 1.04 (d, J = 2.96 Hz, 3H), 1.03 (s, 9H);
13C NMR (CDCl3, 50 MHz): 14.2, 19.2, 23.1, 27.0 (3C),
29.4, 32.5, 33.1,60.5, 64.83, 64.85, 69.1, 108.3, 119.4, 121.6,
127.4 (2C), 127.5 (2C), 129.3, 129.4, 134.3, 134.7, 135.8,
1
liquid. Yield = 65%; H NMR (CDCl3, 400 MHz): d 6.96
(dd, J1 = 5.1 Hz, J2 = 15.85 Hz, 1H), 6.04 (dd,
J1 = 1.6 Hz, J2 = 15.85 Hz, 1H), 4.31 (t, J = 4.8 Hz, 1H),
4.23 (q, J = 7.0 Hz, 2H), 3.78 (q, J = 5.9 Hz, 1H), 1.64–
1.25 (m, 16H), 1.11 (d, J = 6.2 Hz, 3H), 0.88 (s, 9H), 0.04

6626
K. S. Rao et al. / Tetrahedron Letters 47 (2006) 6623–6626
149.0, 170.9; MS (CI) 472 (M+NH4, 80%), 455 (M+H+1
135.87, 146.3, 166.2; MS (CI) 483 (M+1, 40%). The ester
,
(200 mg, 0.41 mmol) and NaOH (33 mg, 0.82 mmol) in a
mixture of MeOH:THF:water (3:1:1) were stirred at room
temperature for 4 days after which the mixture was
acidified with 2 N HCl (ꢀ5 ml) and extracted with CHCl3.
The combined organic layer was washed with brine, and
dried over Na2SO4. The residue obtained after the removal
of the solvent was purified by flash column chromoto-
graphy (eluent. 0–2% MeOH:CHCl3) to give the seco acid
13 (130 mg) as a colorless liquid. Yield = 69%; IR (neat):
3382, 1703 cmÀ1; 1HNMR (CDCl3, 400 MHz) d 7.67–7.65
(m, 4H), 7.42–7.33 (m, 6H), 6.80 (d, J = 15.58 Hz, 1H),
6.05 (d, J = 15.58 Hz, 1H), 3.92–3.82 (m, 5H), 1.82–1.68
(m, 2H), 1.55–1.48 (m, 2H), 1.05 (d, J = 2.90 Hz, 3H), 1.04
(s, 9H); 13C NMR (CDCl3, 50 MHz): 14.1, 19.2, 23.1, 27.0
(3C), 32.5, 60.4, 64.9, 69.1, 108.1, 120.7, 127.4 (2C), 127.49
(2C), 127.5 (2C), 129.4, 129.5, 134.3, 134.7, 135.8, 135.87,
90%), 199 (100%).
10. (a) Nozoe, S.; Hirai, K.; Tsuda; Ishibashi, K.; Shirasaka,
M. Tetrahedron Lett. 1965, 49, 4675; (b) Kis, Z.; Furger,
P.; Sigg, H. P. Experientia 1969, 25, 123; (c) Grove, J. F. J.
Chem. Soc., C 1971, 2261.
11. (a) Asaoka, M. T.; Takei, H. Tetrahedron Lett. 1981, 22,
735; (b) Hase, T. A.; Ourila, A.; Holmberg, C. J. Org.
Chem. 1981, 46, 3137; (c) Fujisawa, T.; Takeuchi, M.;
Sato, T. Chem. Lett. 1982, 1795; (d) Stelion, K.; Poupart,
M. A. J. Am. Chem. Soc. 1983, 105, 7130; (e) Yamada, S.;
Ozaki, Y.; Ban, Y. Tetrahedron Lett. 1985, 26, 1989; (f)
Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K.
J. Org. Chem. 1998, 63, 7505–7515.
12. Protection of the hydroxy group with TBDPS resulted in
clean reactions and better yields compared to the TBDMS
group.