Stereoselective formal total synthesis of (+)-methynolide

Article abstract of DOI:10.1021/jo0704762

(Chemical Equation Presented) A highly stereoselective and convergent formal total synthesis of (+)-methynolide is described. The salient features of this synthesis have been the construction of the C1-C7 and C8-C11fragments via a desymmetrization approach, Sharpless asymmetric epoxidation of an allyl alcohol, respectively, and linkage of both the fragments by Nozaki-Hiyama-Kishi reaction.

Full text of DOI:10.1021/jo0704762

Masamune, several reports on the total synthesis6 or the
corresponding seco acid derivative of methynolide7 (Figure 1)
have been published. In continuation of our ongoing research
on the synthesis of polyketide natural products using the
desymmetrization strategy, we report herein the formal and
convergent total synthesis of (+)-methynolide 1.
The retrosynthetic analysis of 1 is depicted in Figure 2. The
key intermediate 3 led us to a convergent approach (Figure 2).
Methynolide can be derived from the intermediate 3, which in
turn can be obtained by coupling of 4 (C1-C7) and 5 (C8-
C11) fragments. Compound 4 can be derived from lactone 7
via triol 6, and vinyl iodide 5 can be obtained from the R,â-
unsaturated ester 9.
Stereoselective Formal Total Synthesis of
(+)-Methynolide
J. S. Yadav,* T. V. Pratap, and V. Rajender
Organic Chemistry DiVision-I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India
yadaVpub@iict.res.in
ReceiVed March 20, 2007
Synthesis of the fragment 4 (Scheme 1) began with the
reductive cleavage of the bicyclic lactone 7, the synthesis of
which was discussed earlier by the desymmetrization of a
bicyclic olefin.8 Thus treatment of 7 with lithium aluminum
hydride (LAH) in THF at rt furnished triol 10 in 90% yield.
The transformation of 10 into 4 warranted the configuration of
the hydroxyl group at the C3 position to be inverted and the
C5 oxygen to be deoxygenated. Accordingly, the triol 10 was
chemoselectively protected as disilyl ether9 11 using TBSCl and
imidazole in dichloromethane. Attempted inversion of the
secondaryhydroxylgroupin11usingtheMitsunobuprotocol10met
with failure. Alternatively, it was achieved by oxidation followed
by reduction of 11. Thus oxidation of 11 with Dess-Martin
periodinane11 yielded ketone 12 in 92% overall yield from 10.
Subsequently, reduction of 12 with DIBAL-H afforded exclu-
sively alcohol 13, a result of 1,3-syn reduction12 with an overall
inversion of the C3 hydroxyl group. Protection of the hydroxyl
group as its MOM ether13 14 using MOM-Cl and diisopropy-
lethyl amine and treatment of 14 with DDQ14 in a biphasic
mixture of dichloromethane and water (10:1) yielded a second-
ary alcohol 15. Xanthate ester 16 was obtained on treatment of
A highly stereoselective and convergent formal total syn-
thesis of (+)-methynolide is described. The salient features
of this synthesis have been the construction of the C1-C7
and C8-C11fragments via a desymmetrization approach,
Sharpless asymmetric epoxidation of an allyl alcohol,
respectively, and linkage of both the fragments by Nozaki-
Hiyama-Kishi reaction.
Stereocontrolled synthesis of macrolide antibiotics is one of
the most attractive areas in current synthetic organic chemistry,
and various new synthetic methodologies have been developed
en route to the synthesis of such complex molecules.1 The
methymycin family of antibiotics comprises three 12-membered
macrolides isolated from Streptomyces species methymycin,2
neomethymycin, and 10-deoxymethymycin3 that display anti-
biotic activity against Gram-positive bacteria. The structures of
all of these three macrolides were confirmed by the chemical
degradation studies, spectroscopic analysis, and finally by their
total synthesis.4
Efforts toward the total synthesis of methynolide mainly
centered on the construction of Prelog Djerassi lactone unit5 7,
a key degradation product retaining the original four chiral
centers present in the C1 to C7 segment of the methynolide
skeleton. Since the first total synthesis of methynolide by
(6) (a) Nakano, A.; Takimoto, S.; Inanaga, J.; Katsuki, T.; Ouchida, S.;
Inoue, K; Aiga, M.; Okukado, N.; Yamaguchi, M. Chem. Lett. 1979, 1019-
1020. (b) Inanaga, J.; Katsuki, T.; Takimoto, S.; Ouchida, S.; Inoue, K.;
Nakano, A.; Okukado, N.; Yamaguchi, M. Chem. Lett. 1979, 1021-1024.
(c) White, J. D.; Fukuyama, Y. J. Am. Chem. Soc. 1979, 101, 226-228.
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3647-3650. (e) Oikawa, Y.; Tanaka, T.; Horita, K.; Noda, I.; Nakajima,
N.; Kakusawa, N.; Hamada, T.; Yonemitsu, O. Chem. Pharm. Bull. 1987,
35, 2184-2195. (f) Oikawa, Y.; Tanaka, T.; Hamada, T.; Yonemitsu, O.
Chem. Pharm. Bull. 1987, 35, 2196-2202. (g) Tanaka, T.; Oikawa, Y.;
Nakajima, N.; Hamada, T.; Yonemitsu, O. Chem. Pharm. Bull. 1987, 35,
2203-2208. (h) Ditrich, K. Liebigs Ann. Chem. 1990, 789-793.
(7) (a) Grieco, P. A.; Ohfune, Y.; Yokoyama, Y.; Owens, W. J. Am.
Chem. Soc. 1979, 101, 4749-4752. (b) Ireland, R. E.; Daub, J. P.; Mandel,
G. S.; Mandel, N. S. J. Org. Chem. 1983, 48, 1312-1325. (c) Vedejs, E.;
Buchanan, R. A.; Watanabe, Y. J. Am. Chem. Soc. 1989, 111, 8430-8438.
(d) Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron 2002, 58, 5909-5922.
(8) (a) Yadav, J. S.; Srinivas Rao, C.; Chandrasekhar, S.; Rama Rao, A.
V. Tetrahedron Lett. 1995, 36, 7717-7720. (b) Yadav, J. S.; Abraham, S.;
Muralidhar Reddy, M.; Sabitha, G.; Ravi Sankar, A.; Kunwar, A. C.
Tetrahedron Lett. 2001, 42, 4713-4716. (c) Yadav, J. S.; Ahmed, M. M.
Tetrahedron Lett. 2002, 43, 7147-7150. (d) Yadav, J. S.; Srinivas, R.;
Sathaiah, K. Tetrahedron Lett. 2006, 47, 1603-1606.
(1) (a) Masamune, S.; Bates, G. S.; Corcoran, J. W. Angew. Chem., Int.
Ed. Engl. 1977, 16, 585-607. (b) Paterson, I.; Mansuri, M. M. Tetrahedron
1985, 41, 3569-3624. (c) Boeckman, R. H.; Goldstein, M. In The Total
Synthesis of Natural Products; Apsimon, J., Ed.; Wiley: New York, 1988;
Vol. 7, p 1. (d) Tatsuda, K. In Recent Progress in the Chemical Synthesis
of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer: Berlin, 1990; p 1.
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Georghiou, P. E.; Bates, G. S. J. Am. Chem. Soc. 1975, 97, 3512-3513.
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Soc. 1975, 97, 3513-3515.
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6395. (b) For a review on the synthesis of Prelog Djerassi lactone, see:
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10.1021/jo0704762 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/29/2007
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J. Org. Chem. 2007, 72, 5882-5885

under Birch conditions24 with liquid ammonia and lithium metal
afforded the primary alcohol 27, which was oxidized using Dess-
Martin periodinane to yield the aldehyde 28.
The aldehyde was treated with carbon tetrabromide and
triphenylphosphine (Corey-Fuch’s protocol)25 to obtain the
corresponding dibromoolefin 29 in an overall yield of 65% over
three steps. The dibromoolefin 29 upon treatment with 6.0 equiv
of ethyl magnesium bromide yielded alkyne 30 in 90% yield.
Hydrostannation of 30 with tri-n-butyl tin hydride in the
presence of a catalytic amount of radical initiator AIBN in
benzene under reflux conditions afforded exclusively trans-
vinylstannane 31, treatment of which with 2.0 equiv of iodine
in dichloromethane furnished trans-vinyl iodide 5 in 93% overall
yield for two steps. Alternatively, the trans-iodoolefin 5 can
also be obtained from aldehyde 28 by Takai’s olefination as
mentioned in previous reports.7d The trans-configuration was
confirmed by the coupling constant of the olefinic protons (14.3
Hz). The optical rotation of compound 5, [R]25D ) +2.4 (c 1.85,
CHCl3), was in agreement with a literature report.7d
Fragments 4 and 5 were then coupled following Nozaki-
Hiyama-Kishi protocol26 (Scheme 3). The aldehyde 4 was
added to a suspension of CrCl2 and NiCl2 in anhydrous DMF
at rt, followed by the addition of the iodo compound 5
predissolved in DMF, to afford the coupled product 32 in the
form of a diastereomeric mixture in 65% yield. Hydrolysis of
32 with a catalytic amount of K2CO3 in methanol afforded diol
33 in quantitative yield, which on oxidation with Dess-Martin
periodinane afforded the ketoaldehyde which was further
oxidized to acid 3 using NaClO227 in the presence of 2-methyl-
2-butene in a mixture of tert-butanol and water at 0 °C in 90%
yield.
The optical rotation and the spectral data of the acid 3 were
in accordance with literature.7b The synthesis of (+)-methynolide
in two steps from the acid intermediate 3 has been reported by
Masamune.4b Thus, a formal total synthesis of (+)-methynolide
has been accomplished.
In conclusion, we have completed the formal total synthesis
of (+)-methynolide in a convergent manner employing the
Nozaki-Hiyama-Kishi coupling for the union of two fragments
4 and 5, a desymmetrization approach for highly stereoselective
synthesis of the C1-C7 fragment 4, and Sharpless asymmetric
epoxidation of an allyl alcohol as a key transformation for the
synthesis of C8-C11 fragment 5.
FIGURE 1. Structures of methynolide (1), seco acid (2), and an
advanced intermediate (3).
15 with NaH, carbon disulfide, and methyl iodide. Deoxygen-
ation of xanthate ester15 using tri-n-butyl tin hydride in the
presence of a catalytic amount of AIBN as a radical initiator
yielded 17 in 85% overall yield over three steps.
The deoxygenated product 17 on treatment with 6 N HCl in
wet THF afforded the triol 6. 1,3-Diol system of triol 6 was
protected as its corresponding benzylidene acetal 18 with
dimethyl acetal of p-methoxy benzaldehyde16 in the presence
of a catalytic amount of CSA in dichloromethane. The primary
hydroxyl group was subsequently protected as silyl ether 19
using TBS-Cl and imidazole in an overall yield of 83% over
three steps. The benzylidene acetal was regioselectively re-
duced17 using DIBAL-H in dichloromethane at -15 °C to yield
a free primary alcohol 20, which was protected as its acetate
21 in 90% overall yield. Deprotection of p-methoxybenzyl ether
using DDQ in a biphasic mixture of dichloromethane and water
yielded alcohol, which was protected as corresponding silyl ether
22 using TBDMSOTf18 and 2,6-lutidine in 83% overall yield
for two steps. The primary silyl group in 22 was chemoselec-
tively deprotected using PPTS19 to afford the alcohol 23 in 95%
yield. The primary hydroxyl group of 23 was subjected to
oxidation with Dess-Martin periodinane to yield the fragment
4 in 90% yield.
Synthesis of fragment 5 (Scheme 2) began with the Wittig
reaction of ethyl-2-(triphenylphosphoranylidene)propanoate20
with propanal to yield an R,â-unsaturated ester 9 with exclu-
sively trans-configuration in 93% yield. The ester 9 was
subjected to alane reduction21 to yield a trans allylic alcohol
24 in 90% yield. The allylic alcohol 24 upon Sharpless
asymmetric epoxidation22,23-using D-(-)-DIPT afforded the
corresponding epoxide 8 in 90% yield in 94% ee. The hydroxyl
group of 8 was converted into its corresponding benzyl ether
25 using NaH, BnBr, and a catalytic amount of TBAI in THF.
The latter subsequently on treatment with anhydrous acetone
in the presence of BF3-Et2O23 at 0 °C furnished the acetonide
26 in 90% overall yield for the last two steps. Debenzylation
Experimental Section
(E,2S,3S,4S,6R)-9-((4S)-5-Ethyl-2,2,4-trimethyl-1,3-dioxolan-
4-yl)-3-hydroxy-7-O-(tert-butyldimethylsilyl)-2,4,6-trimethylnon-
8-enyl acetate, 32. In a 25 mL clean and dry two-neck round-
bottomed flask equipped with a magnetic bar and septum was
weighed anhydrous CrCl2 (146 mg, 1.18 mmol) and a trace of
anhydrous NiCl2. To it was added 2.0 mL of anhydrous DMF, and
the suspension was stirred at rt for 10 min. Aldehyde 4 (104 mg,
0.297 mmol) predissolved in 1.0 mL of dry DMF was added to the
reaction mixture and stirred at rt for 10 min. To the reaction mixture
then was added the iodoolefin 5 (176 mg, 0.594 mmol) in anhydrous
DMF (1 mL). The reaction was stirred at rt for 20 h. After the
completion of the reaction, the reaction mixture was diluted with
(15) Barton, D. H. R.; Mc Combie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
(16) Kloosterman, M.; Slaghek, T.; Hermans, J. P. G.; VanBoom, J. H.;
Recl, J. R. Neth. Chem. Soc. 1984, 103, 335-341.
(17) Schreiber, S. L.; Wang, Z.; Schulte, G. Tetrahedron Lett. 1988, 29,
4085-4088.
(18) Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1985, 26, 5239-5242.
(19) Prakash, C.; Saleh, S.; Blair, A. Tetrahedron Lett. 1989, 30, 19-
22.
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(21) (a) Jorgenson, M. J. Tetrahedron Lett. 1962, 3, 559-562. (b) Dilling,
W. L.; Plepys, R. A. J. Org. Chem. 1970, 35, 2971-2976.
(22) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974-5976. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(23) Colvin, E. W.; Robertson, A. D.; Wakharkar, S. J. Chem. Soc.,
Chem. Commun. 1983, 312-314.
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30, 281-286.
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(26) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc.
1977, 99, 3179-3181.
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J. Org. Chem, Vol. 72, No. 15, 2007 5883

FIGURE 2. Retrosynthetic analysis of an advanced intermediate 3.
SCHEME 1. Synthesis of C1-C7 Fragment, 4a
a Reagents and conditions: (a) LiAlH4, ether, 0 °C to rt, 90%; (b) TBDMSCl, imidazole, CH2Cl2, 0 °C; (c) Dess-Martin, CH2Cl2, 95% from 10; (d)
DIBAL-H, CH2Cl2, -78 °C; (e) MOM-Cl, DIPEA, CH2Cl2, 0 °C, 90% from 12; (f) DDQ, CH2Cl2/H2O; (g) NaH, CS2, MeI, THF, 0 °C; (h) (nBu)3SnH,
cat. AIBN, benzene, reflux, 85% from 14; (i) 6 N HCl/THF; (j) (MeO)2CH(C6H4)OMe, cat. CSA; (k) TBDMSCl, imidazole, CH2Cl2, 83% from 17; (l)
DIBAL-H, CH2Cl2, 0 °C; (m) Ac2O, py, DMAP, CH2Cl2, 90% from 19; (n) (i) DDQ, CH2Cl2/H2O, (ii) TBDMSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 83%
over two steps; (o) PPTS, MeOH, rt, 95%; (p) Dess-Martin, CH2Cl2, 90%.
ether and quenched with an aqueous solution of NH4Cl. The product
was extracted with ether twice. The combined organic layers were
dried over anhydrous Na2SO4 and concentrated to afford a crude
product. The product was then purified on silica gel column using
15% AcOEt/petroleum ether (v/v) as eluent to furnish the pure
product 32 as a mixture of epimers (152 mg, 65% yield): 1H NMR
(300 MHz, CDCl3) δ 5.62 (m, 2H), 4.05 (m, 1H), 3.83 (m, 2H),
3.65 (m, 2H), 2.03 (s, 3H), 1.98 (m, 1H), 1.79 (m, 2H), 1.57 (m,
3H), 1.44 (s, 3H), 1.40 (s, 3H), 1.29 (m, 7H), 1.00 (d, J ) 7.6 Hz,
3H), 0.95 (d, J ) 6.8 Hz, 3H), 0.943 (d, J ) 6.8 Hz, 3H), 0.89 (m,
9H), 0.04 (d, 6H); HRMS (ES) m/z ([M + Na]+ 537.3609; calcd
for C28H54O6NaSi 537.3587).
(E,2R,3S,4S,6R)-9-((4S)-5-Ethyl-2,2,4-trimethyl-1,3-dioxolan-
4-yl)-3-O-(tert-butyldimethylsilyl)-2,4,6-trimethyl-7-oxonon-8-
enoic acid, 3. To a solution of the diol 33 (115 mg, 0.24 mmol) in
dichloromethane in a 25 mL round-bottomed flask equipped with
a magnetic bar and nitrogen inlet was added Dess-Martin periodi-
nane reagent (248 mg, 0.58 mmol) at 0 °C, and the reaction mixture
was stirred at rt. After the completion of the reaction, petroleum
ether (10 mL) was added. The precipitate formed was filtered and
the filtrate comprising the ketoaldehyde was concentrated, and the
same was used in the next step with out purification. To a solution
of ketoaldehyde in a mixture of solvents, tert-butanol and water in
3:1 (volume) ratio, at 0 °C was added NaH2PO4 (110 mg, 0.705
5884 J. Org. Chem., Vol. 72, No. 15, 2007

SCHEME 2. Synthesis of C8-C11 Fragment, 5a
a Reagents and conditions: (a) propanaldehyde, CH2Cl2, rt, 93%; (b) LiAlH4, AlCl3, ether, -10 °C to rt, 90%; (c) D-(-)-DIPT, Ti(OiPr)4, TBHP, 4 Å MS,
CH2Cl2, -30 °C, 92%; (d) NaH, BnBr, THF, 0 °C to rt; (e) BF3-Et2O, acetone, 0 °C, 90% from 8; (f) Li/liquid NH3, THF; (g) Dess-Martin, CH2Cl2; (h)
CBr4, PPh3, CH2Cl2, -15 °C, 65% from 26; (i) EtMgBr, THF, 0 °C to rt, 90%; (j) (nBu)3SnH, cat. AIBN, C6H6, reflux; (k) I2, CH2Cl2, rt, 93% from 29.
SCHEME 3. Coupling of Fragments 4 and 5 and Completion of Formal Synthesisa
a Reagents and conditions: (a) CrCl2/NiCl2, DMF, rt, 65%; (b) cat. K2CO3, MeOH, rt, quantitative; (c) (i) Dess-Martin periodinane, CH2Cl2, (ii) NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (3:1), 0 °C, 90% over two steps.
mmol) followed by 2-methyl-2-butene (230 µL, 0.23 mmol) and
stirred for 5 min. NaClO2 (63 mg, 0.705 mmol) was added, and
the reaction mixture was stirred at 0 °C. After the completion of
the reaction, the solvent mixture was evaporated under reduced
pressure and the residue was diluted with AcOEt. The organic layer
was washed once with brine and dried over Na2SO4 and concen-
trated to yield a residue which on chromatography (petroleum ether/
AcOEt 3:1) afforded the stereochemically pure compound 3 in good
Hz, 3H), 0.91 (m, 12H), 0.07 (2s, 6H); 13C NMR (100 MHz, CDCl3)
δ 147, 126, 108, 86.1, 86.07, 82.2, 76.7, 43, 36, 35, 30, 28, 27.9,
26.4, 26, 24.6, 23.2, 18.3, 17.9, 16.4, 11.3, -4.0, -4.2; HRMS
(ES) m/z ([M+ Na]+ 507.3114; calcd for C26H48O6NaSi 507.3117).
Acknowledgment. T.V.P. and V.R. thank CSIR-New Delhi
for the award of research fellowship. Dr. A. C. Kunwar, Head
of NMR division, IICT, is gratefully acknowledged for providing
the valuable high-resolution NMR data for the final compound.
yield (78 mg, 70% yield): [R]25 ) +9.2 (c 0.35, CHCl3), (lit.
D
[R]25D ) +8.6 (c 0.39, CHCl3)); IR (KBr) 3450, 1720, 1675, 1600
Supporting Information Available: Detailed experimental
procedures and copies of 1H NMR and 13C NMR spectra are
available. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
cm-1; H NMR (400 MHz, CDCl3) δ 6.77 (d, J ) 15.5 Hz, 1H),
6.46 (d, J ) 15.5 Hz, 1H), 3.84-3.80 (m, 2H), 2.79 (ddq, J ) 4.8,
10, 7 Hz, 1H), 2.63 (dq, J ) J′ ) 7 Hz, 1H), 1.88 (ddd, J ) 3.8,
10, 14 Hz, 1H), 1.59 (br m, 2H), 1.53-1.43 (m, 8H), 1.42 (s, 3H),
1.18 (d, J ) 6.6 Hz, 3H), 1.12 (d, J ) 6.6 Hz, 3H), 1.02 (t, J ) 7.3
JO0704762
J. Org. Chem, Vol. 72, No. 15, 2007 5885