Total synthesis of 10-deoxymethynolide, the aglycon of the macrolide antibiotic 10-deoxymethymycin

Article abstract of DOI:10.1021/jo9809433

A short efficient total synthesis of 10-deoxymethynolide (2c), the aglycon of 10-deoxymethymycin (1c), has been accomplished in 16 steps and 12% overall yield from (S)-3-O-p-toluenesulfonyl-3-hydroxy-2-methylpropanal (15c). The synthesis features an expeditious preparation of (+)-5a, a synthetic equivalent of the Prelog-Djerassi lactonic acid, and the construction of a 12-membered lactone through an intramolecular Nozaki- Hiyama-Kishi coupling reaction.

Full text of DOI:10.1021/jo9809433

J . Org. Chem. 1998, 63, 7811-7819
7811
Tota l Syn th esis of 10-Deoxym eth yn olid e, th e Aglycon of th e
Ma cr olid e An tibiotic 10-Deoxym eth ym ycin
Ronaldo A. Pilli,†,* Carlos Kleber Z. de Andrade,† Carlos Roberto O. Souto,† and
Armin de Meijere‡
Instituto de Quı´mica, Unicamp, Cx. Postal 6154, 13083-970 Campinas, SP Brasil and Institut fu¨r
Organische Chemie, Georg-August Universita¨t, Tammannstraâe 2, Go¨ttingen, Germany
Received May 19, 1998
A short and efficient total synthesis of 10-deoxymethynolide (2c), the aglycon of 10-deoxymethymycin
(1c), has been accomplished in 16 steps and 12% overall yield from (S)-3-O-p-toluenesulfonyl-3-
hydroxy-2-methylpropanal (15c). The synthesis features an expeditious preparation of (+)-5a , a
synthetic equivalent of the Prelog-Djerassi lactonic acid, and the construction of a 12-membered
lactone through an intramolecular Nozaki-Hiyama-Kishi coupling reaction.
In tr od u ction
structural elucidation of the Prelog-Djerassi lactonic acid
(3) which was first isolated as an oxidative degradation
product of several macrolide antibiotics and emerged as
a key building block in several total syntheses of this
macrolide family.9
The therapeutic properties and the complex architec-
ture displayed by the polyoxomacrolide antibiotics have
made them a highly valued family of synthetic targets.1
Biogenetically oriented approaches toward their total
syntheses based on the construction of a suitable seco-
acid derivative, followed by its macrolactonization, have
been explored.2 The development of new methodologies
for macrolactonizations3 and asymmetric synthesis2 and
the discovery of new semisynthetic erythromycin A
derivatives with better bioavailability and efficiency4
have recently renewed the interest in the development
of more efficient routes to this family of biologically active
compounds.
The methymycin family of antibiotics comprises three
12-membered macrolides which have been isolated from
Streptomyces species (methymycin 1a ,5 neomethymycin
1b,5 and 10-deoxymethymycin 1c6) which were shown to
display antibiotic activity against Gram positive bacteria.
Their structures have been established through chemical
degradation,6 spectroscopic studies,7 and total synthesis.8
Central to the earlier efforts in this area was the
Methymycin (1a ) was the first macrolide antibiotic to
yield to total synthesis, and the Prelog-Djerassi lactonic
acid (3) was used as the synthetic equivalent of the C1-
C7 fragment of the natural product.8 After that, several
successful approaches to its aglycon 2a and to the
corresponding seco-acid followed10,11 as well as reports
by Yamaguchi et al. on the total synthesis of neo-
methynolide (2b), the aglycon of neomethymycin (1b).12
As to the synthetic efforts toward 10-deoxymethymycin
(1c) or its aglycon 2c, Ireland and co-workers described
* To whom correspondence should be addressed: Fax number: 55-
19-7883023, e. mail: pilli@iqm.unicamp.br.
† Unicamp.
‡ Georg-August Universita¨t.
(1) (a) Masamune, S.; Bates, G. S.; Corcoran, J . W. Angew. Chem.,
Int. Ed. Engl. 1977, 16, 585. (b) Omura, S., Ed. Macrolide Antibiotics:
Chemistry, Biology, and Practice; Academic Press: Orlando, Fl, 1984.
(2) (a) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569. (b)
Boeckman, R. H.; Goldstein, M. in The Total Synthesis of Natural
Products; ApSimon, J ., Ed.; J ohn Wiley & Sons: New York, 1988; Vol.
7, p 1.
(3) Meng, Q.; Hesse, M. Top. Curr. Chem. 1991, 161, 107.
(4) (a) Lartley, P. A.; Nellans, H. N.; Tanaka, S. K. Adv. Pharmacol.
1994, 28, 307. (b) Kirst, H. A. in Progress in Medicinal Chemistry; Ellis,
G. P.; Luscombe, D. K., Eds., Elsevier: New York, 1993; Vol. 30, p 57.
(c) J aynes, B. H.; Dirlam, J . P.; Hecker, S. J . in Annual Reports in
Medicinal Chemistry; Bristol, J . A., Ed., Academic Press: New York,
1996; Vol. 31, p 31.
(9) Martin, S. F.; Guinn, D. E. Synthesis 1991, 245.
(10) For the total syntheses of methynolide (2a ), see: (a) Nakano,
A.; Takimoto, S.; Inanaga, J .; Katsuki, T.; Ouchida, S.; Inoue, K.; Aiga,
M.; Okukado, N.; Yamaguchi, M. Chem. Lett. 1979, 1019. (b) Inanaga,
J .; Katsuki, T.; Takimoto, S.; Ouchida, S.; Inoue, K.; Nakano, A.;
Okukado, N.; Yamaguchi, M. Chem. Lett. 1979, 1021. (c) Tanaka, T.;
Oikawa, Y.; Nakajima, N.; Hamda, T.; Yonemitsu, O. Chem. Pharm.
Bull. 1987, 35, 2203. (d) Oikawa, Y.; Tanaka, T.; Hamada, T.;
Yonemitsu, O. Chem. Pharm. Bull. 1987, 35, 2202. (e) Oikawa, Y.;
Tanaka, T.; Yonemitsu, O. Tetrahedron Lett. 1986, 27, 3647. (f) Vedejs,
E.; Buchanan, R. A.; Conrad, P.; Meier, G. P.; Mullins, M. J .; Watanabe,
Y. J . Am. Chem. Soc. 1987, 109, 5878. (g) Vedejs, E.; Buchanan, R.
A.; Watanabe, Y. J . Am. Chem. Soc. 1989, 111, 8430. (h) Ditrich, K.
Liebigs Ann. Chem. 1990, 789.
(5) (a) Djerassi, C.; Halpern, O. J . Am. Chem. Soc. 1957, 79, 2022.
(b) Djerassi, C.; Halpern, O. Tetrahedron 1958, 3, 255.
(6) Kinumaki, A.; Suzuki, M. J . Chem. Soc., Chem. Commun. 1972,
744.
(7) (a) Rickards, R. W.; Smith, R. M. Tetrahedron Lett. 1970, 1025.
(b) Manwaring, D. G.; Rickards, R. W.; Smith, R. M. Tetrahedron Lett.
1970, 1029.
(8) For the total synthesis of methymycin, see: (a) Masamune, S.;
Kim, C. U.; Wilson, K. E.; Spessard, G. O.; Georghiou, P. E.; Bates, G.
S. J . Am. Chem. Soc. 1975, 97, 3512. (b) Masamune, S.; Yamamoto,
H.; Kamata, S.; Fukuzawa, A. J . Am. Chem. Soc. 1975, 97, 3513.
(11) For the total synthesis of protected forms of the methynolide
seco-acid, see: (a) Grieco, P. A.; Ohfune, Y.; Yokoyama, Y.; Owens, W.
J . Am. Chem. Soc. 1979, 101, 4749. (b) Ireland, R. E.; Daub, J . P.;
Mandel, G. S.; Mandel, N. S. J . Org. Chem. 1983, 48, 1312.
(12) For the total synthesis of neomethynolide (2b), see: (a) Inanaga,
J .; Kawamani, Y.; Yamaguchi, M. Bull. Chem. Soc. J pn. 1986, 59, 1521.
(b) Inanaga, J .; Kawamani, Y.; Yamaguchi, M. Chem. Lett. 1981, 1415.
10.1021/jo9809433 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/09/1998

7812 J . Org. Chem., Vol. 63, No. 22, 1998
Pilli et al.
Sch em e 1
Sch em e 2a
a
(a) nBu3SnH, AIBN (cat.), 80 °C (80%); (b) I2, CCl4, rt (85%);
(c) pimelic acid, DCC, DMAP(cat.), CH2Cl2, rt (62% for 10; 79%
for 12); (d) (i) (COCl)2, DMF(cat.), CH2Cl2; 0 °C; (ii) 12, THF,
CH3CN, C5H5N, -30 °C; (e) LiAlH(OtBu)3, CuI (10 mol %), THF,
-78 °C (51%, two steps); (f) CrCl2 (9 equiv), NiCl2 (0.09 equiv),
DMF(7.5 × 10-3 M), rt (63%); (g) PDC, CH2Cl2 (75%).
the total synthesis of the 3-OTBS derivative of 10-
deoxymethynolide from D-glucose11b (23 steps and less
than 1% overall yield), and Yamaguchi et al. reported
on the total synthesis of 10-deoxymethynolide (2c),13 in
12 steps and less than 0.1% overall yield from methyl
(2S, 3R)-2,3-epoxybutanoate and the methyl ester of the
Prelog-Djerassi lactonic acid (3), prepared via a nonste-
reoselective route from cis-2,4-dimethylglutaric anhy-
dride.
chloride functionality was employed14 or when the potas-
sium salt from 10 was used. Protodestannation prevailed
and forced us to explore the Nozaki-Hiyama-Kishi
coupling.
Vinylic iodide 9 was readily prepared from vinylic
stannane 8 and esterified with pimelic acid. After
conversion of the carboxylic acid to the corresponding acyl
chloride and reduction with LiAlH(OtBu)3, aldehyde 13
smoothly underwent intramolecular Nozaki-Hiyama-
Kishi coupling reaction when treated with an excess of
CrCl2 (9 equiv) containing 1 mol % of NiCl2 in degassed
DMF (7.5 × 10-3 M). The corresponding allylic alcohol
was isolated in 63% yield and oxidized with PDC in CH2-
Cl2 to provide 14, in 75% yield.
Having selected an attractive methodology to construct
a 12-membered lactone ring, a convergent and efficient
route to 4b still had to be accomplished. This naturally
led us to consider the preparation of δ-lactone 5a , a
synthetic equivalent of the Prelog-Djerassi lactonic acid,
and vinylic iodide 6b in their enantiomerically pure forms
through enantioselective aldol condensation.16
At the outset we were attracted by the possibility of
construction of the δ-lactone ring required in 5a through
an intramolecular alkylation process which builds upon
the stereochemical and the structural platform provided
by the preceding enantioselective aldol condensation step.
We and others17 have previously turned this synthetic
plan into practice. Although in the present case we were
Taking into account that the previous approaches to
this family of macrolides have generally relied on a low
yield esterification/lactonization strategy to construct the
macrolide core, we considered a novel strategy to 10-
deoxymethynolide (2c) based on the formation of the
C(7)-C(8) bond as the final maneuver in the formation
of the macrocycle. The ultimate precursor 4a or 4b,
containing all the carbon atoms and stereochemical
elements required for 10-deoxymethynolide (2c), was
planned to undergo an intramolecular Stille coupling
reaction or an intramolecular Nozaki-Hiyama-Kishi
reaction, respectively, to provide a protected form of 10-
deoxymethynolide (2c). Access to these advanced syn-
thetic intermediates would be provided by δ-lactone 5a ,
a synthetic equivalent of the Prelog-Djerassi lactonic
acid (3), which we planned to prepare in a reduced
number of steps via a combination of an enantioselective
aldol condensation to set the proper configuration at C-2
and C-3 and an intramolecular alkylation step. Accord-
ingly, vinylic stannane 6a or vinylic iodide 6b would also
be provided by a short sequence involving an enantiose-
lective aldol reaction to establish the stereogenic centers
at C-10 and C-11 (Scheme 1).
Resu lts a n d Discu ssion
(14) Baldwin, J . E.; Adlington, R. M.; Ramcharitar, S. H. Tetrahe-
dron 1992, 48, 2957.
(15) (a) Cintas, P. Synthesis 1992, 248. (b) Kishi, Y. Pure Appl.
Chem. 1992, 64, 343. For examples of the use of the intramolecular
version, see: (c) Schreiber, S. L.; Meyers, H. V. J . Am. Chem. Soc. 1988,
110, 5198. (d) Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J . Am. Chem.
Soc. 1993, 115, 11393. (e) MacMillan, D. W. C.; Overman, L. E. J . Am.
Chem. Soc. 1995, 117, 10391. (f) Harwig, C. W.; Py, S.; Fallis, A. G. J .
Org. Chem. 1997, 62, 7902.
(16) Kim, B. M.; Williams, S. F.; Masamune, S. in Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds. Pergamon Press:
New York, 1991; Vol. 2, p 239.
(17) For the preparation of δ-lactones through the intramolecular
alkylation of ester enolates, see: (a) Pilli, R. A.; Murta, M. M. J . Org.
Chem. 1993, 58, 338. (b) White, J . D.; Amedio, J . C., J r.; Gut, S.; Ohira,
S.; J ayasinghe, L. R. J . Org. Chem. 1992, 57, 2270. (c) Matsuda, F.;
Tomiyoshi, N.; Yanagiya, M.; Matsumoto, T. Tetrahedron 1990, 46,
3469. (d) Nakai, E.; Kitahara, E.; Sayo, N.; Ueno, Y.; Nakai, T. Chem.
Lett. 1985, 1725.
To validate the construction of the dodecanolide ring
system through a carbon-carbon bond-forming approach,
we first examined the preparation of the model com-
pounds 11 and 13 (Scheme 2). The corresponding car-
boxylic acids 10 and 12 were readily assembled as
depicted in Scheme 2. However, all attempts to convert
carboxylic acid 10 to the corresponding acyl chloride 11
failed, even when the protocol described by Baldwin et
al. to prepare â-stannylalkenoates containing an acyl
(13) Inanaga, J .; Kawamani, Y.; Sakata, I.; Okukado, M.; Yamagu-
chi, M. 24th Symposium on the Chemistry of Natural Products, Osaka,
J apan, 1981; Hashiwa Publ. Co. Nagoya, J apan, 1961; pp 654-661.

Total Synthesis of 10-Deoxymethynolide
J . Org. Chem., Vol. 63, No. 22, 1998 7813
Sch em e 3a
described for the intramolecular alkylation of ester
enolates failed17b-d when applied to (-)-18f. However,
treatment of (-)-18f with freshly sublimed tert-BuOK (4
equiv) in THF (0 °C to room temperature) afforded a 2:1
mixture of epimeric lactones 5a /5b (68% yield). Under
equilibrating conditions (tert-BuOK/tert-BuOH, rt) this
ratio could be improved to 10:1 in favor of (+)-5a .18
The success of the lactonization and equilibration steps
led us to consider a more direct route to (-)-18e which
required the preparation of O-tosyl aldehyde 15c. At-
tempts to carry out the reduction of methyl (S)-3-O-
(p-toluenesulfonyl)-3-hydroxy-2-methylpropionate with
DIBAL in CH2Cl2 at -78 °C led to the formation of 15c
in low yield together with the corresponding alcohol.22
When the reaction was carried out in toluene and the
temperature of the cooling bath (liquid N2/hexanes)
carefully controlled below -90 °C, overreduction was
suppressed. Isolated crude aldehyde 15c was shown to
1
be pure enough by H NMR spectroscopy to be used in
the next step without further purification.
The di-n-butyl boron triflate/diisopropylethylamine
reaction conditions were sufficiently mild to allow us to
carry out the desired aldol condensation of the base
sensitive aldehyde 15c with the boron enolate of imide
(+)-16. Stereochemically homogeneous aldol (-)-17c was
1
a
(a) (i) Bu2BOTf, CH2Cl2, DIPEA, 0 °C; (ii) 15a or 15b or 15c,
isolated in 73% overall yield, as judged by its H NMR
-78 °C; (iii) H2O2, MeOH, 0 °C (17a , 89%, 17b, 79%, 17c, 73%);
(b) HF, CH3CN, H2O, rt; (c) TsCl, Et3N, DMAP(cat.), CH2Cl2, 0
°C (c1: 81%, two steps, for 17c; c2: 100% for 18e); (d) LiBH4,
MeOH, THF, 0 °C; (e) TBDMSCl, Et3N, DMAP(cat.), CH2Cl2, rt
(80% from 17a ; 91% from 17c); (f) H2, Pd/C, EtOH (78%); (g)
(CH3CH2CO)2O, Et3N, DMAP(cat.), CH2Cl2 (95%); (h) (i) tert-
BuOK, THF, rt; (ii) tert-BuOK, tert-BuOH, rt (62%).
spectrum (300 MHz).
The syn,anti-Felkin stereochemistry of (-)-17c was
assigned after comparison with an authentic sample
prepared from (-)-17b:23 desilylation of (-)-17b (HF/CH3-
CN/H2O) followed by tosylation of the primary alcohol
(TsCl, Et3N, CH2Cl2, DMAP) afforded (-)-17c in 81%
yield. Reduction of (-)-17c with LiBH4 and protection
of the primary alcohol with TBDMSCl afforded (-)-18e
(91% overall yield) and recovered (R)-4-benzyl-2-oxazo-
lidinone (83% yield), after purification by column chro-
matography. Propionylation of (-)-18e afforded (-)-18f
(95% yield), and intramolecular alkylation, as described
above, was followed by equilibration in tert-BuOK/tert-
BuOH to afford (+)-5a in 62% yield.
After developing a short and efficient preparation of
the C-1/C-7 fragment (+)-5a (five steps, 39% overall yield
from 15c), we moved to the preparation of the required
vinylic iodide (+)-6b: the enantioselective aldol conden-
sation of the boron enolate derived from (-)-16 and
propionaldehyde afforded diastereomerically pure (+)-
1924 (77% yield) which was uneventfully converted to
aldehyde (+)-22. Vinylic iodide (+)-6b was prepared as
a 18:1 mixture of E:Z isomers from (+)-22 following the
olefination procedure developed by Takai and co-workers
(Scheme 4).25
not sure about the stereochemical outcome at C-6, we
were confident that the thermodynamically favored cis
configuration of the methyl groups at C-4 and C-6 in 5a
would be properly established after equilibration under
basic conditions of an epimeric mixture at C-6 eventually
obtained after the intramolecular alkylation step.18
Initially, the preparation of the required tosyl deriva-
tive 18e was envisaged from 17a , based on the known
preference for the syn,anti-Felkin stereochemistry in the
aldol adduct obtained from (+)-15a and the boron enolate
of (R)-4-benzyl-3-propionyl-2-oxazolidinone (16) (Scheme
3). Indeed, the reaction of the boron enolate of imide (+)-
1620 and aldehyde 15a 19 afforded aldol (-)-17a in 89%
yield after purification by flash chromatography. The
syn,anti-stereochemistry of (-)-17a was established after
its LiBH4 reduction to afford known diol 18a 17a,21 which
required careful purification by flash chromatography on
silica gel to be separated from (R)-4-benzyl-2-oxazolidi-
none. Preparatively, the crude mixture of 18a and
oxazolidinone was silylated (TBDMSCl, Et3N, cat. DMAP,
CH2Cl2), and alcohol (+)-18b (80% overall yield) was
readily separated from the recovered chiral auxiliary
(80% yield) by column chromatography.
The coupling of the C(1)-C(7) and C(8)-C(13) frag-
ments required some previous functional group manipu-
lations in order to adjust the requisite oxidation states
at C-1 and C-7 carbon atoms of (+)-5a (Scheme 5).
Although several scenarios could be envisioned for the
Alcohol (+)-18b was transformed into the tosyl deriva-
tive (-)-18e after hydrogenolysis and tosylation (78%
overall yield). Most of the reaction conditions previously
(22) The DIBAL-H reduction of methyl (R)-O-p-toluenesulfonyl-3-
hydroxy-2-methylpropionate in CH2Cl2 has been previously described:
van Maarseveen, J . H.; Scheeren, H. W. Tetrahedron 1993, 49, 2325.
(23) The preparation of (+)-17b has been previously described:
Clark, D. L.; Heathcock, C. H. J . Org. Chem. 1993, 58, 5878. We thank
the authors for a copy of its 1H NMR spectrum.
(24) For the preparation of (-)-19, see: Chan, P. C-M.; Chong, J .
M.; Kousha, K. Tetrahedron 1994, 50, 2703.
(25) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408.
(18) Suzuki, K.; Tomooka, K.; Katayama, E.; Matsumoto, T.; Tsuchi-
hashi, G. J . Am. Chem. Soc. 1986, 108, 5221.
(19) J ackson, R. F. W.; Sutter, M. A.; Seebach, D. Liebigs Ann. Chem.
1985, 2313.
(20) Gage, J . R.; Evans, D. A. Organic Synthesis; Wiley: New York,
1993; Collect. Vol. VIII, p 339.
(21) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.

7814 J . Org. Chem., Vol. 63, No. 22, 1998
Pilli et al.
Sch em e 4a
Sch em e 6a
a
(a) (i) nBu2BOTf, DIPEA, CH2Cl2, 0 °C; (ii) C2H5CHO, -78 °C
(77%); (b) AlMe3, MeONHMe‚HCl (93%); (c) TBDMSCl, DMF,
imidazole (76%); (d) DIBAL-H, toluene, -78 °C (78%); (e) CrCl2
(6 equiv), CHI3 (2 equiv), THF, rt (59%); (f) HF, CH3CN, H2O, rt
(94%).
Sch em e 5a
a
(a) 2,4,6-Trichlorobenzoyl chloride, Et3N, THF; then (+)-6b
(97%); (b) HF, CH3CN, H2O, rt (94%); (c) Dess-Martin periodinane
(c1: 100% and c2: 77%); (d) CrCl2 (20 equiv), NiCl2 (0.2 equiv),
DMF, rt (74%); (e) DDQ, CH2Cl2, H2O (96%).
Deprotection of (+)-28 followed by oxidation with
Dess-Martin periodinane set the stage for the key step
in the synthetic scheme: when crude aldehyde 29 was
treated with excess of CrCl2 (10 equiv)28 containing 1%
of NiCl2, a smooth reaction ensued to afford a 1:1 mixture
of diastereoisomeric allylic alcohols 30a /30b, in 74% yield
(Scheme 6).29 As the stereochemistry at C-7 was of no
consequence for the total synthesis of 10-deoxymethyno-
lide (2c), the epimeric mixture of 30a /30b was oxidized
with Dess-Martin periodinane to afford (+)-31 followed
by deprotection of the secondary alcohol upon treatment
with DDQ. Synthetic (+)-10-deoxymethynolide (2c),
obtained in 74% yield after two steps, displayed spectro-
scopic data (1H and 13C NMR) identical to those reported
by Lambalot and Cane for 10-deoxymethynolide produced
by S. venezuelae.30
In conclusion, a short preparation of (+)-5a , a synthetic
equivalent of the Prelog-Djerassi lactonic acid in five
steps and 39% overall yield has been developed employ-
ing an enantioselective aldol reaction of a chiral â-tosy-
loxy aldehyde. This intermediate was converted in 11
steps and 32% yield to (+)-10-deoxymethynolide (2c), the
aglycon of 10-deoxymethymycin, featuring an efficient
construction of the 12-membered macrolactone ring
through an intramolecular Nozaki-Hiyama-Kishi cou-
pling reaction. Studies are underway aimed at control-
a
(a) LiAlH4, THF, rt (94%); (b) p-MeOC6H4CH(OMe)2, CH2Cl2,
CSA(cat.), rt (98%); (c) TIPSCl, DMF, imidazole (100%); (d) DIBAL-
H, toluene, 0 °C (99%); (e) CrO3, H2SO4, acetone, rt (71%).
conversion of (+)-5a to (-)-27, this was efficiently carried
out through the intervention of p-methoxybenzylidene-
acetal (-)-25, readily prepared by LiAlH4 reduction of
(+)-5a , reaction with p-methoxybenzylidene dimethyl-
acetal and protection of the primary hydroxyl group (92%
overall yield). When (-)-25 was treated with DIBAL-H
in toluene at 0 °C, a regioselective reductive ring opening
of the 1,3-dioxane ring took place from the sterically less
congested carbinolic position,26 thus allowing differentia-
tion of the two primary alcohols at C(1) and C(7) and the
secondary one at C(3) which remained protected as the
corresponding p-methoxybenzyl ether. J ones oxidation
of (+)-26 afforded carboxylic acid (-)-27 (71% yield) which
was esterified with alcohol (+)-6b under the conditions
developed by Yamaguchi and co-workers (97% yield).27
(28) The Nozaki-Hiyama-Kishi coupling experiments were carried
out with CrCl2 purchased from Merck Schuchardt and dried at 1 mmHg
and 250 °C for 8 h immediately prior to use.
(29) The stereochemical assignment at C(7) of epimeric alcohols 30a
(more polar) and 30b (less polar) rests solely on the analysis of their
1H NMR spectra assuming a Celmer type conformation of the 12-
membered lactone: H-7 in less polar isomer 30b appeared as a double
doublet at δ 4.15 ppm and coupling constants of 10.0 and 5.0 Hz
consistent with a trans-diaxial relationship for H-7 and H-6 while in
the more polar isomer 30a the corresponding signal is a broad singlet.
(30) Lambalot, R. H.; Cane, D. E. J . Antibiot. 1992, 45, 1981.
(26) (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem.
Lett. 1983, 1593. (b) Evans, D. A.; Ng, H. P.; Rieger, D. L. J . Am. Chem.
Soc. 1993, 115, 11446.
(27) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.

Total Synthesis of 10-Deoxymethynolide
J . Org. Chem., Vol. 63, No. 22, 1998 7815
at 0 °C was added oxalyl chloride (0.10 mL, 0.14 g, 1.1 mmol)
dropwise. After 1 h, the volatiles were removed under vacuum
(0.1 mmHg), and CH3CN (0.6 mL) and THF (0.1 mL) were
added to the white solid residue. The suspension was cooled
to -30 °C, and a solution of 12 (0.14 g, 0.43 mmol) and pyridine
(0.030 mL, 0.37 mmol) in THF (0.6 mL) was added dropwise.
After 1 h at -30 °C, CuI (0.0071 g, 0.037 mmol) was added,
the mixture was cooled to -78 °C, and a solution of LiAlH-
(OtBu)3 (0.21 g, 0.82 mmol) in THF (1.0 mL) was added. The
reaction mixture was stirred 30 min at -78 °C, quenched with
2 N HCl (1.0 mL), and extracted with ether (3 × 5 mL). The
combined organic layers were washed with satd NaHCO3 (10
mL) and processed. Purification of the residue by flash
chromatography (5% ethyl acetate-pentane) afforded 0.070 g
of aldehyde 13 (0.22 mmol, 51% yield). IR: 2975, 1720, 1735;
1H NMR (250 MHz): δ 1.3-1.4 (m, 2H), 1.6-1.8 (m, 4H), 2.31
(t, 2H, J ) 7.0), 2.35-1.50 (m, 4H), 4.12 (t, 2H, J ) 7.0), 6.23
(d, 1H, J ) 14.4), 6.50 (dt, 1H, J ) 14.4 and 7.2), 9.81 (t, 1H,
J ) 1.6); 13C NMR (62.5 MHz): δ 21.6, 24.5, 28.4, 33.8, 35.1,
43.5, 62.1, 77.3, 141.6, 173.2, 202.3.
ling the stereochemical outcome of this reaction as
applied to the formation of medium- and large-ring
lactones.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted materials were obtained
from commercial suppliers and were used without further
purification. THF and ether were distilled from sodium-
benzophenone ketyl prior to use. Diisopropylamine, diisopro-
pylethylamine, triethylamine, dichloromethane, and N,N-
dimethylformamide were distilled from calcium hydride.
nBu2BOTf was prepared according to ref 20 and distilled
immediately prior to use. Potassium tert-butoxide was sub-
limed prior to use, and CrCl2 containing 1 mol % of NiCl2 was
activated 8 h at 250 °C in a vacuum (1 mmHg) and weighed
under argon atmosphere in a glovebox. All the reactions
involving organometallic reagents, metallic hydrides and nBu2-
BOTf were carried out under an argon atmosphere with heat-
dried glassware. The normal processing of organic extracts
consisted of drying over MgSO4, filtration, and concentration
with a rotary evaporator at 40 mmHg. Melting points are
uncorrected and 1H NMR spectra were recorded in CDCl3
solution at 300 MHz and 13C NMR spectra at 75.2 MHz, unless
otherwise noted. J values are given in hertz.
(E)-7-Oxo-8-d od ecen olid e (14). To a suspension of an-
hydrous CrCl2 containing 1 mol % of NiCl2 (0.35 g, 2.8 mmol)
in degassed DMF (34 mL) was added a solution of aldehyde
13 (0.10 g, 0.31 mmol) in degassed DMF (6.0 mL), and the
reaction mixture was stirred 2 h at room temperature and
under an argon atmosphere. The reaction mixture was poured
into water (10 mL) and extracted with ether (3 × 15 mL). The
organic layers were combined and normally processed, and the
residue was dissolved in CH2Cl2 (2.0 mL) and treated with
PDC (0.25 g, 0.66 mmol), anhydrous MgSO4 (0.050 g, 0.42
mmol) and Celite (0.050 g). The reaction mixture was stirred
14 h at room temperature and, filtered through a Celite pad,
and the solvent was removed under reduced pressure. Puri-
fication of the crude product by flash chromatography (10%
ethyl acetate-pentane) afforded lactone 14 (0.029 g, 0.15
mmol), in 47% yield (mp 76-77 °C). IR (KBr): 2960, 2870,
(E)-1-(Tr i-n -bu tylsta n n yl)-1-bu ten -4-ol (8). A mixture
of 3-butyn-1-ol (1.17 g 16.7 mmol), tributyltin hydride (7.30 g,
25.0 mmol), and AIBN (0.085 g, 0.52 mmol) was heated 16 h
in an oil bath at 90-100 °C. The crude mixture of the (E:Z)-
8 was purified by flash chromatography (5% ethyl acetate-
pentane) to afford 4.82 g (13.4 mmol) of (E)-8 (80% yield). IR
1
(film, NaCl): 3400 (br), 2960, 2984, 980 cm-1; H NMR (250
MHz): δ 0.8-1.0 (m, 15H), 1.2-1.4 (m, 6H), 1.4-1.6 (m, 6H),
2.42 (q, 2H, J ) 6.9), 3.6-3.7 (m, 2H), 5.95 (dt, 1H, J ) 6.8
and 18.9), 6.05 (d, 1H, J ) 18.9); 13C NMR (62.5 MHz): 9.4,
13.7, 27.3, 29.1, 41.2, 61.4, 132.1, 144.8.
1721, 1691,1630, 1150 cm-1 1H NMR (C6D6, 500 MHz): δ
;
(E)-4-Iod o-3-bu ten -1-ol (9). To a solution of alcohol 8 (0.97
g, 2.7 mmol) in CCl4 (10 mL) was added resublimed iodine
(1.70 g, 6.70 mmol), and the mixture was stirred 1 h at room
temperature when it was treated with 10% aq NaHSO3 (10
mL) and extracted with ether (3 × 15 mL). The combined
organic layers were washed with brine (15 mL) and processed.
The crude product was purified by flash chromatography (5%
ethyl acetate-pentane) to yield 0.46 g of vinylic iodide 9 (2.3
mmol, 85% yield). IR (film, NaCl): 3410 (br), 3060, 2975, 1632,
1.02-1.06 (m, 2H), 1.20-1.26 (m, 2H), 1.29-1.36 (m, 2H),
1.69-1.74 (m, 2H), 2.00-2.04 (m, 2H), 2.07-2.10 (m, 2H),
3.83-3.86 (m, 2H), 5.91 (dt, 1H, J ) 15.5 and 0.8), 6.28 (dt,
1H, J ) 15.5 and 7.8); 13C NMR: δ 23.5, 23.7, 24.7, 32.5, 32.7,
40.9, 60.3, 134.4, 139.5, 172.6, 202.2. MS (m/z): 41, 55, 81
(100%), 99, 196 (M+.), 197 (M + 1+.).
(4R)-N-[(2′R,3′S,4′S)-5′-O-Ben zyl-2′,4′-d im eth yl-3′,5′-d i-
h yd r oxy-1′-oxop en tyl]-4-ben zyl-2-oxa zolid in on e (17a ). To
a 0.5 M soln of imide (+)-16 (1.6 g, 6.9 mmol) in CH2Cl2, under
an argon atmosphere at 0 °C, was added di-n-butylboron
triflate (2.1 mL, 8.3 mmol) followed by diisopropylethylamine
(1.6 mL, 9.0 mmol). After allowing 30 min for complete
enolization, the reaction mixture was cooled to -78 °C, and
aldehyde 15a 19 (0.98 g, 5.5 mmol of 0.5 M soln in CH2Cl2) was
added dropwise. Stirring was continued for 30 min at -78
°C, followed by 2.0 h at 0 °C. The reaction mixture was
quenched with pH 7.0 phosphate buffer (6.0 mL) and methanol
(18 mL). A solution of hydrogen peroxide (30% v/v, 6.0 mL)
in methanol (12 mL) was added and the mixture allowed to
stir for 1.0 h at 0 °C. The reaction mixture was diluted with
Et2O (50 mL) and successively washed with 5% aq NaHCO3
(40 mL), 10% HCl (40 mL), and brine (40 mL). The organic
layer was normally processed, and purification by column flash
chromatography on silica gel (20% EtOAc in hexanes, v/v)
afforded 17a (2.0 g, 4.9 mmol), in 89% yield. [R]25D ) -37.8 (c
0.9, CHCl3); IR (NaCl, film): 3490, 2970, 1779, 1697, 1210
1100 cm-1 1H NMR (250 MHz): δ 2.10 (s, br, 1H), 2.32 (q,
;
2H, J ) 6.4), 3.63 (t, 2H, J ) 6.4), 6.20 (d, 1H, J ) 14.7), 6.54
(dt, 1H, J ) 14.7 and 7.3); 13C NMR (62.5 MHz): δ 39.0, 60.8,
77.0, 142.6.
(E)-4-(Tr i-n -bu tylsta n n yl)-3-bu ten yl P im ela te (10). A
solution of pimelic acid (0.57 g, 3.6 mmol) in CH2Cl2 (16.5 mL)
was treated with a solution of DMAP (0.13 g, 1.1 mmol) and
DCC (0.73 g, 3.5 mmol) in CH2Cl2 (7.0 mL). The mixture was
stirred 30 min at room temperature when a white precipitate
was formed. To this mixture was added dropwise a solution
of 8 (0.86 g, 2.4 mmol) in CH2Cl2 (4.8 mL), and the mixture
was stirred 2 h at room temperature. The solids were filtered
off and washed with CH2Cl2 (40 mL), and the organic layers
were combined and processed. The crude mixture was purified
by column chromatography (20% ethyl acetate-pentane) to
afford 0.78 g (1.5 mmol, 62% yield) of ester 10. IR (film,
NaCl): 3350-2500 (br), 2926 (br), 1739, 1710, 1174 cm -1; 1H
NMR (250 MHz): δ 0.8-1.0 (m, 15H), 1.2-1.8 (m, 18H), 2.3-
2.5 (m, 6H), 4.10 (t, 2H, J ) 7.3), 5.92 (dt, 1H, J ) 19.6 and
4.9), 6.00 (d, 1H, J ) 19.6), 10.51 (s, br, 1H); 13C NMR (62.5
MHz): δ 9.3, 13.5, 24.2, 24.4, 27.1, 28.9, 29.0, 33.7, 33.9, 36.8,
63.4, 131.2, 143.7, 173.5, 179.3.
cm-1 1H NMR: δ 0.96 (d, 3H, J ) 7.0), 1.26 (d, 3H, J ) 6.7),
.
1.92-2.06 (m, 1H), 2.76 (dd, 1H, J ) 13.3 and 9.9), 3.31 (dd,
1H, J ) 13.3 and 3.0), 3.50-3.65 (m, 2H), 3.85-4.00 (m, 2H),
4.16 (d, 2H, J ) 5.4 Hz), 4.51 (s, 2H), 4.61-4.70 (m, 1H), 7.2-
7.4 (m, 10H); 13C NMR (75.5 MHz): δ 9.5, 13.4, 35.9, 37.6,
40.5,55.5, 66.1, 73.4, 74.8, 75.2, 127.4, 127.7, 127.8, 128.5,
129.0, 129.5, 135.4, 137.8, 153.2, 176.3. Anal. Calcd for
(E)-4-Iod obu ten -3-yl P im ela te (12). The same procedure
as described above afforded ester 12, in 79% yield. IR (film,
NaCl): 3400-2600 (br), 1735, 1710, 1125 cm-1; 1H NMR (250
MHz): δ 1.3-1.5 (m, 2H), 1.5-1.8 (m, 4H), 2.2-2.4 (m, 6H),
4.12 (t, 2H, J ) 7.0), 6.14 (d, 1H, J ) 15.0), 6.51 (dt, 1H, J )
7.3 and 14.7).
C
24H29NO5: C, 70.05; H, 7.10; N, 3.40. Found: C, 70.37; H,
7,01; N, 3.26.
(S)-O-p -Tolu e n e su lfon yl-3-h yd r oxy-2-m e t h ylp r op a -
n a l (15c). To a soln of methyl (S)-O-p-toluenesulfonyl-3-
hydroxy-2-methylpropionate11 (0.65 g, 2.4 mmol) in toluene at
(E)-4-Iod obu ten -3-yl 6-F or m ylh exa n oa te (13). To a
mixture of DMF (0.030 mL, 0.39 mmol) and CH2Cl2 (0.6 mL)

7816 J . Org. Chem., Vol. 63, No. 22, 1998
Pilli et al.
-95 °C (liquid N2/hexanes bath) was added dropwise (ca. 0.8
mL min-1) a 1.0 M soln of DIBAL in toluene (3.1 mL, 3.1
mmol). The reaction mixture was stirred 1.5 h at -95 °C,
quenched with ethyl acetate (3.0 mL), followed by addition of
Et2O (20 mL) and satd soln of sodium and potassium tartrate
(1.5 mL). The reaction mixture was allowed to warm to room
temperature, and stirring was continued until phase separa-
tion. The organic layer was separated, the aqueous one was
further extracted with Et2O (2 × 20 mL), the combined organic
layers were concentrated under reduced pressure, and the
residue was filtered through Celite. Evaporation under re-
duced pressure afforded crude 15c (0.50 g) which was used in
the next step without further purification. IR (film, NaCl):
2979, 1735, 1359, 1177 cm-1; 1H NMR: δ 1.16 (d, 3H, J ) 7.3),
2.46 (s, 3H), 2.70-2.80 (m, 1H), 4.15 (dd, 1H, J ) 9.9 and 5.5),
4.25 (dd, 1H, J ) 9.9 and 6.1), 7.36 (d, 2H, J ) 8.1), 7.78 (d,
2H, J ) 8.1), 9.60 (s, 1H); 13C NMR: δ 10.5, 21.6, 45.5, 68.9,
127.9, 129.8, 129.9, 145.1, 200.7.
(4R)-N-[(2′R,3′S,4′S)-2′,4′-Dim et h yl-3′-h yd r oxy-5′-O-p -
t o lu e n e s u lfo n y l-1′-o x o p e n t y l]-4-b e n zy l-2-o x a zo lid i-
n on e (17c). (a ) F r om 15c: The same procedure described
above for 17a afforded 17c (0.88 g, 1.9 mmol, 73% yield) as a
colorless oil from imide (+)-16 (0.72 g, 3.1 mmol) and aldehyde
15c (0.62 g, 2.6 mmol) after purification by flash chromatog-
raphy on silica gel (35% ethyl acetate/hexanes). [R]25D ) -27.7
(c 2.5, CHCl3); IR (film, NaCl): 3500 (br), 2982, 1782, 1700,
1400, 1355, 1181 cm-1; 1H NMR: δ 0.94 (d, 3H, J ) 6.9), 1.21
(d, 3H, J ) 6.9), 1.9-2.0 (m, 1H), 2.44 (s, 3H), 2.79 (dd, br,
2H, J ) 13.3 and 9.3), 3.22 (dd, 1H, J ) 13.3 and 3.3), 3.78
(dd, 1H, J ) 8.6 and 2.9), 3.85 (dq, 1H, J ) 6.9 and 2.9), 4.10-
4.31 (m, 4H), 4.67-4.73 (m, 1H), 7.20-7.35 (m, 7H), 7.78 (d,
2H, J ) 8.3); 13C NMR: δ 10.2, 13.3, 21.6, 35.6, 37.7, 39.2,
54.9, 66.2, 71.4, 72.4, 127.4, 127.9, 128.9, 129.4, 129.8, 132.8,
134.9, 144.6, 152.8, 177.4. Anal. Calcd for C24H29NO7S: C,
60.61, H, 6.15, N, 2.94. Found: C, 60.25, H, 5.94, N, 2.75. (b)
F r om 17b: To 17b (0.52 g, 1.2 mmol), prepared according to
ref 23, was added a soln (4.0 mL) of 15% HF (0.5 mL) in CH3-
CN (8.6 mL) and water (0.9 mL). The reaction mixture was
stirred 30 min at room temperature, diluted with Et2O (30
mL), washed with brine (10 mL), and dried over MgSO4. After
removal of the solvent under reduced pressure, the residue
was dissolved in CH2Cl2 (5.0 mL), and Et3N (0.18 mL, 0.128
g, 1.27 mmol), DMAP (0.015 g, 0.12 mmol), and tosyl chloride
(0.241 g, 1.27 mmol) were added successively. The mixture
was stirred 3 h at room temperature, diluted with Et2O (20
mL), and washed with 5% NaHCO3 (10 mL), water (10 mL),
and brine (10 mL). The organic phase was processed, and the
residue was purified by column chromatography on silica gel
(35% ethyl acetate/hexanes) to afford 17c (0.46 g, 0.97 mmol),
in 81% yield.
36.9, 67.1, 73.0, 74.9, 75.2, 127.2, 127.3, 128.1, 138.0. Anal.
Calcd for C20H36O3Si: C, 68.13, H, 10.29. Found: C, 68.37,
H, 10.60.
(2S,3S,4S)-1-O-(ter t-bu tyld im eth ylsilyl)-2,4-d im eth yl-
1,3,5-p en ta n etr iol (18c). To a soln of 18b (0.70 g, 2.0 mmol)
in ethanol (10 mL) was added 10% Pd on charcoal (0.02 g),
and the mixture was allowed to stir under hydrogen pressure
(3 atm) for 7.5 h in a Parr apparatus. The reaction mixture
was filtered over Celite, diluted with ether (30 mL), and
washed with satd NaHCO3 (3 × 15 mL) and brine (10 mL).
The organic layer was processed, and purification by silica gel
chromatography (20% ethyl acetate/hexanes) afforded 18c
(0.410 g, 1.56 mmol, 78% yield), as a colorless oil. [R]25
)
D
+9.4 (c 2.4, CH2Cl2); IR (film, NaCl): 3376, 2955, 2857, 1471,
1
1255, 1094 cm-1; H NMR: δ -0.11 (s, 6H), 0.56 (d, 3H, J )
6.9), 0.70 (s, 9H), 0.79 (d, 3H, J ) 7.0), 1.50-1.60 (m, 1H),
1.60-1.70 (m, 1H), 3.40-3.50 (m, 2H), 3.53 (dd, 1H, J ) 9.6
and 3.7), 3.59 (dd, 1H, J ) 9.6 and 1.7), 3.67 (dd, 1H, J ) 9.6
and 3.2). 13C NMR (CCl4): δ -5.8,-5.7, 8.9, 13.3, 17.9, 25.7,
36.3, 37.1, 68.0, 68.4, 79.3. Anal. Calcd for C13H30SiO3: C,
59.49; H, 11.52. Found: C, 59.35; H, 11.78.
(2S,3R,4S)-5-O-(ter t-Bu tyld im eth ylsilyl)-2,4-d im eth yl-
1-O-p-tolu en esu lfon yl-1,3,5-p en ta n etr iol (18e). (a ) F r om
18c: To a soln of 18c (0.27 g, 1.0 mmol) in CH2Cl2 (20 mL) at
0 °C were added Et3N (0.15 mL, 1.1 mmol), DMAP (0.012 g,
0.10 mmol), and p-toluenesulfonyl chloride (0.21 g, 1.1 mmol).
After stirring 3 h at 0 °C, the reaction mixture was diluted
with CH2Cl2 (10 mL), and washed with water (5 mL), 1% aq
HCl (5 mL), satd NaHCO3 (5 mL), and brine (5 mL). The
organic layer was normally processed, and the residue was
purified by column chromatography on silica gel (10% ethyl
acetate/hexanes) to afford 18e (0.42 g, 1.0 mmol), in quantita-
tive yield, as a colorless oil. [R]25 ) -4.0 (c 2.2, CHCl3); IR
D
(film, NaCl): 2928, 1359, 1177, 839 cm-1; H NMR (CCl4): δ
1
0.08 (s, 6H), 0.88 (d, 3H, J ) 7.0), 0.91 (d, 3H, J ) 7.0), 0.92
(s, 9H), 1.65-1.75 (m, 1H), 1.75-1.85 (m, 1H), 2.48 (s, 3H),
2.75 (s, br, 1H), 3.57 (d, 1H, J ) 9.6), 3.66 (dd, 1H, J ) 8.3
and 4.7), 3.74 (dd, 1H, J ) 8.3 and 3.7), 4.0-4.1 (m, 2H), 7.32
(d, 2H, J ) 8.1), 7.77 (d, 2H, J ) 8.1); 13C NMR (CCl4): δ -5.7,
-5.6, 8.7, 13.3, 18.0, 21.4, 25.8, 35.5, 36.3, 68.3, 72.2, 73.5,
127.8, 129.2, 134.3, 143.1.
(b) F r om 17c: To a soln of 17c (0.628 g, 1.32 mmol) in THF
(10 mL) was added methanol (0.08 mL) followed by LiBH4
(0.043 g, 2.0 mmol). The reaction mixture was stirred 1 h at
0 °C and quenched with 1.0 M sodium and potassium tartrate
soln. After stirring 1 h at 0 °C, it was extracted with Et2O (2
× 20 mL), and the organic extract was washed with brine (10
mL) and dried over MgSO4. The solvent was removed under
reduced pressure, and the residue was dissolved in CH2Cl2 (10
mL) followed by addition of Et3N (0.21 mL, 0.15 g, 1.5 mmol),
DMAP (0.018 g, 0.15 mmol), and TBDMSCl (0.23 g, 1.5 mmol).
The reaction mixture was stirred 2 h at room temperature,
diluted with Et2O (40 mL), and washed with water (15 mL),
10% HCl (10 mL), and brine (10 mL). The organic phase was
processed, and the residue was purified by column chroma-
tography on silica gel, as described above, to afford 18e (0.49
g, 1.2 mmol, 91% yield) and (R)-4-benzyl-2-oxazolidinone (0.20
g, 1.1 mmol, 83% yield).
(2S,3S, 4S)-5-O-Ben zyl-1-O-(ter t-b u t yld im et h ylsilyl)-
2,4-d im eth yl-1,3,5-p en ta n etr iol (18b). To a soln of 17a
(0.97 g, 2.4 mmol) in THF (5.0 mL) at 0 °C was added MeOH
(0.1 mL), and a 0.5 M soln of LiBH4 (2.4 mmol) in THF (4.7
mL) was added dropwise. After stirring 40 min at 0 °C a satd
soln of sodium and potassium tartrate (15 mL) was added. The
reaction mixture was allowed to warm to room temperature
and extracted with CH2Cl2 (2 × 20 mL). The combined organic
layer was washed with brine (20 mL) and processed.
(2S,3R,4S)-5-O-(ter t-Bu tyld im eth ylsilyl)-2,4-d im eth yl-
3-O-p r op ion yl-1-O-p -t olu en esu lfon yl-1,3,5-p en t a n et r iol
(18f). To a soln of 18e (0.40 g, 0.96 mmol) in CH2Cl2 (2.0 mL)
were added Et3N (0.15 mL, 0.11 g, 1.1 mmol), DMAP (0.012
g, 0.10 mmol), and propionic anhydride (0.20 mL, 0.20 g, 1.5
mmol). The reaction mixture was allowed to stir 30 min at
room temperature, and it was diluted with CH2Cl2 (10 mL)
and washed with 1% aq HCl (5 mL), satd NaHCO3 (5 mL) and
brine (5 mL), successively. The organic layer was dried over
MgSO4 and, filtered and the solvent removed under reduced
pressure. Purification by column chromatography on silica gel
(10% ethyl acetate/hexanes) afforded 18f (0.43 g, 0.91 mmol),
The crude mixture was dissolved in CH2Cl2 (14 mL), and
Et3N (0.4 mL, 2.8 mmol), DMAP (0.030 g, 0.28 mmol), and
TBDMSCl (0.42 g, 2.8 mmol) were added. After stirring 1 h
at room temperature, the reaction mixture was diluted with
Et2O (20 mL), washed with satd NH4Cl (20 mL) and brine (20
mL), and dried over MgSO4. After filtration the solvent was
removed under reduced pressure, and the crude product was
chromatographed on flash silica gel to afford 18b (0.675 g, 1.92
mmol, 80% yield, eluted with 5% ethyl acetate/hexanes) and
(R)-4-benzyl-2-oxazolidinone (0.335 g, 1.89 mmol, 80% yield,
eluted with 50% ethyl acetate/hexanes). 18b: [R]25 ) +18.6
D
(c 1.6, CHCl3); IR (film, NaCl): 3506, 2958, 2860, 1472, 1093
in 95% yield. [R]25 ) -4.4 (c 4.6 CH2Cl2); IR (film, NaCl):
D
cm-1
;
1H NMR (CCl4): δ 0.07 (s, 6H), 0.82 (d, 3H, J ) 6.9),
2940, 1739, 1365, 1178 cm -1; 1H NMR (CCl4): δ 0.00 (s, 6H),
0.82 (d, 3H, J ) 6.9), 0.86 (s, 9H), 0.95 (d, 3H, J ) 6.9), 1.09
(t, 3H, J ) 7.6), 1.81-1.85 (m, 1H), 2.0-2.1 (m, 1H), 2.22 (q,
2H, J ) 7.6), 2.45 (s, 3H), 3.31 (dd, 1H, J ) 8.2 and 6.2), 3.38
0.86 (d, 3H, J ) 7.0), 0.90 (s, 9H), 1.6-1.7 (m, 1H), 1.8-1.9
(m, 1H), 3.0 (s, br, 1H), 3.4-3.6 (m, 5H), 4.53 (s, 2H), 7.20-
7.30 (m, 5H); 13C NMR: δ -5.7, -5.6, 8.8, 13.5, 18.0, 25.8, 35.6,

Total Synthesis of 10-Deoxymethynolide
J . Org. Chem., Vol. 63, No. 22, 1998 7817
(dd, 1H, J ) 8.6 and 6.9), 3.74 (dd, 1H, J ) 9.6 and 6.9), 3.92
(dd, 1H, J ) 9.6 and 4.4), 4.87 (dd, 1H, J ) 8.2 and 3.9), 7.30
(d, 2H, J ) 8.3), 7.72 (d, 2H, J ) 8.3); 13C NMR (CCl4): δ -5.8,
-5.7, 9.0, 10.5, 14.0, 18.0, 21.3, 25.7, 26.9, 34.8, 36.9, 64.9,
70.7, 73.3, 127.9, 129.26, 134.1, 143.4, 172.2. Anal. Calcd for
layer was processed, and the residue was purified by flash
chromatography (30% ethyl acetate-hexanes) to afford amide
(+)-20 (0.96 g, 5.5 mmol), in 93% yield and (S)-4-benzyl-2-
oxazolidinone (0.89 g, 5.0 mmol, 84% yield). Amide (+)-20:
[R]D ) +17.0 (c 2.0, CH Cl3); IR (film, NaCl): 3407(br), 2972,
1637, 1460, 1390, 979 cm-1; 1H-NMR: δ 0.94 (t, 3H, J ) 7.4),
1.14 (d, 3H, J ) 7.1), 1.35-1.50 (m, 1H), 1.50-1.65 (m, 1H),
2.00 (s, br, 1H), 2.90 (s, br, 1H), 3.18 (s, 3H), 3.69 (s, 3H), 3.70-
3.80 (m, 1H). 13C NMR: δ 10.0, 10.3, 26.7, 31.8, 38.1, 61.5,
73.0, 173.1.
C
23H40SiO6S: C, 58.42; H, 8.53. Found: C, 58.55; H, 8.23.
(3R,5S,6S,1′S)-Tetr a h yd r o-6-(1′-m eth yl-2′-(ter t-bu tyld i-
m eth yl- silyloxy)eth yl)-3,5-dim eth yl-2H-pyr an -2-on e (5a).
To a soln of freshly sublimed tert-BuOK (0.095 g, 0.85 mmol)
in THF (4.0 mL) at 0 °C was added dropwise a soln of 18f
(0.10 g, 0.21 mmol) in THF (1.0 mL). The reaction mixture
was allowed to stir 30 min at room temperature and quenched
with satd NH4Cl (1.0 mL). The aqueous layer was extracted
with Et2O (3 × 5.0 mL), the combined organic layers were
washed with brine (10 mL) and dried over MgSO4, and the
solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel (20% ethyl
acetate/hexanes) to afford a 2:1 molar ratio of 5a /5b (0.043 g,
0.14 mmol, 67% yield), as determined by 1H NMR (300 MHz).
This mixture was dissolved in tert-BuOH (2.0 mL), tert-BuOK
(0.017 g, 0.15 mmol) was added, and the reaction mixture was
stirred 70 h at room temperature. The reaction was quenched
with satd NH4Cl (1.0 mL) and extracted with Et2O (3 × 5 mL),
and the combined organic phase was washed with brine (2 ×
5 mL) and dried over MgSO4. The solvent was removed under
reduced pressure, and the residue was purified by flash
chromatography (10% ethyl acetate/hexanes) to afford 5a
(2S,3R)-N-Meth yl-N-m eth oxy-2-m eth yl-3-(ter t-bu tyld i-
m eth ylsilyloxy) p en ta n a m id e (21). To a solution of amide
20 (0.200 g, 1.14 mmol) in DMF (0.4 mL) were added imidazole
(0.194 g, 2.85 mmol) and TBSCl (0.206 g, 1.37 mmol). The
reaction mixture was stirred 24 h at room temperature, diluted
with hexanes (10 mL), and washed with water (5 mL) and
brine (5 mL). The organic phase was processed, and the crude
product was purified by flash chromatography (15% ethyl
acetate-hexanes) to afford amide 21 (0.250 g, 0.865 mmol),
in 76% yield. [R]D ) + 3.9 (c 2.2, CH2Cl2); IR (film, NaCl):
2959, 2935, 2884, 2857, 1665, 1463, 1383, 1254, 1048, 1000
1
cm-1; H NMR: δ 0.06 (s, 6H), 0.87 (t, 3H, J ) 7.5), 0.90 (s,
9H), 1.15 (d, 3H, J ) 6.9), 1.40-1.60 (m, 2H), 3.00 (s, br, 1H),
3.17 (s, 3H), 3.69 (s, 3H), 3.89 (dt, 1H, J ) 8.0 and 4.7); 13C
NMR: δ -4.4, -4.2, 8.5, 14.7, 18.2, 26.0, 28.2, 32.2., 40.1, 61.4,
74.2, 176.7.
(2S,3R)-3-(ter t-Bu tyld im eth ylsilyloxy)-2-m eth ylp en ta -
n a l (22). To a solution of amide 21 (0.24 g, 0.83 mmol) in
toluene (2.0 mL) at -78 °C was added DIBAL-H in toluene
(1.66 mL of a 1.0 M soln in toluene, 1.66 mmol), and the
reaction mixture was stirred 1.5 h at -78 °C. The reaction
was quenched with ethyl acetate (1.0 mL), poured into a
mixture containing CH2Cl2 (4.0 mL) and 1 M HCl (10.0 mL)
and stirred 30 min at room temperature. The organic layer
was separated, and the aqueous one was extracted with CH2-
Cl2 (3 × 15 mL). The combined organic layers were washed
with satd aq NH4Cl (20 mL) and a satd aq soln of sodium and
potassium tartrate (20 mL) and dried over MgSO4. The
solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography (5% ethyl
acetate-hexanes) to yield aldehyde 22 (0.15 g, 0.65 mmol), in
78% yield. [R]D ) + 67.2 (c 3.1, CH2Cl2); IR (film, NaCl): 2958,
(0.039 g, 0.13 mmol, 62% yield) as a colorless oil. [R]25
)
D
+55.5 (c 2.7, CHCl3); lit.8: [R]25 ) +47.3 (c 2.7, CHCl3); IR
D
(film, NaCl): 1734, 1096, 837 cm-1 1H NMR: δ 0.02 (s, 6H),
.
0.81 (d, 3H, J ) 6.9), 0.85 (s, 9H), 0.92 (d, 3H, J ) 6.4), 1.25
(d, 3H, J ) 6.9), 1.34 (q, 1H, J ) 13.1), 1.85-1.95 (m, 3H),
2.40-2.50 (m, 1H), 3.46 (dd, 1H, J ) 9.8 and 6.1), 3.64 (dd,
1H, J ) 9.7 and 8.7), 4.15 (d, 1H, J ) 10.3). 13C NMR: δ -5.4,
8.9, 17.1, 17.3, 18.2, 25.9, 30.6, 36.2, 37.4, 37.7, 64.6, 85.5,
174.6. Anal. Calcd for
C16H32O3Si: C, 63.95; H, 10.73.
Found: C, 64.21; H, 10.95.
(4S)-N-[(2′S,3′R)-3′-Hyd r oxyl-2′-m eth yl-1′-oxop en tyl]-4-
ben zyl-2-oxa zolid in on e (19). To a solution of oxazolidinone
(-)-16 (1.03 g, 4.42 mmol) in CH2Cl2 (9.0 mL) at 0 °C were
added dropwise di-n-butylboron triflate (1.51 g, 5.52 mmol) and
N,N-diisopropylethylamine (1.04 mL, 0.77 g, 5.98 mmol). After
stirring 30 min at 0 °C, the reaction mixture was cooled to
-78 °C, and propionaldehyde (0.64 mL, 0.51 g, 8.9 mmol) was
added dropwise. The reaction mixture was stirred 45 min at
-78 °C and 2 h at 0 °C, quenched with phosphate buffer (pH
7.0, 6 mL), and extracted with CH2Cl2 (3 × 20 mL). The
solvent was removed under reduced pressure, the residue was
dissolved in methanol (10 mL), and a 3:1 (v/v) solution of
methanol-20% H2O2 (15 mL) was added dropwise at 0 °C.
After stirring 1 h at 0 °C, the reaction mixture was diluted
with ether (40 mL), washed with 5% NaHCO3 (30 mL), 10%
HCl (30 mL), and brine (30 mL), and the organic phase was
normally processed. The residue was purified by flash chro-
matography (15% ethyl acetate-hexanes) to afford (+)-19 (0.98
g, 3.4 mmol), in 77% yield as a white solid (mp: 77-79 °C).
1
2932, 2882, 1727, 1463, 1254, 1048, 837, 775 cm-1; H NMR
(CCl4): δ 0.04 (s, 3H), 0.07 (s, 3H), 0.87 (s, 9H), 0.89 (t, 3H, J
) 7.2), 1.06 (d, 3H, J ) 6.9), 1.44-1.62 (m, 2H), 2.42-2.52
(m, 1H), 4.02 (dt, 1H, J ) 7.2 and 3.6), 9.77 (d, 1H, J ) 1.0);
13C NMR (CCl4): δ -4.7, -4.2, 7.5, 10.1, 18.0, 25.7, 27.4, 50.8,
73.4, 205.5.
(E)-(3R,4R)-1-Iod o-3-m eth yl-4-(ter t-bu tyld im eth ylsilyl-
oxy)-1-h exen e (23). To a suspension of CrCl2 (0.218 g, 1.77
mmol) in degassed THF (8.5 mL) at 0 °C were added iodoform
(0.167 g, 0.424 mmol) and a solution of aldehyde 22 (0.050 g,
0.22 mmol) in THF (2.0 mL). The reaction mixture was stirred
1.5 h at 0 °C, and the reaction was quenched with water (5
mL). The organic layer was separated, and the aqueous one
was saturated with NaCl and extracted with ether (3 × 15
mL). The combined organic layers were washed with brine
(20 mL) and dried over MgSO4 and the solvent was removed
under reduced pressure. The crude product was purified by
flash chromatography (hexanes) to yield vinylic iodide 23
(0.045 g, 0.13 mmol), in 59% yield. [R]D ) +32.2 (c 3.9, CH2-
Cl2); IR (film, NaCl): 2958, 2928, 2855, 1602, 1462, 1016, 834
[R]25 ) +38.5 (c 1.07, CHCl3); IR (KBr): 3524, 2975, 1761,
D
1700, 1388, 1221 cm-1; 1H NMR: δ 0.98 (t, 3H, J ) 7.4), 1.25
(d, 3H, J ) 7.1), 1.4-1.7 (m, 2H), 2.80 (dd, 1H, J ) 13.3 and
9.3), 2.95 (s, br, 1H), 3,25 (dd, 1H, J ) 13.3 and 3.4), 3.80 (dq,
1H, J ) 7.1 and 2.7), 3.8-3.9 (m, 1H), 4.1-4.3 (m, 2H), 4.7-
4.8 (m, 1H), 7.2-7.4 (m, 5H); 13C NMR: δ 10.3, 10.5, 26.8, 37.9,
41.8, 55.2, 63.3, 73.1, 127.7, 129.2, 129.7, 135.3, 153.3, 177.8.
(2S,3R)-N-Meth yl-N-m eth oxy-3-h yd r oxy-2-m eth ylp en -
ta n a m id e (20). To a suspension of N,O-dimethylhydroxyl-
amine hydrochloride (1.18 g, 12.1 mmol) in CH2Cl2 was added
dropwise a 2.0 M solution of trimethylaluminum in toluene
(6.13 mL, 12.3 mmol). After stirring 1 h at room temperature,
the mixture was cooled to -20 °C, and a solution of (-)-19
(1.73 g, 5.94 mmol) in CH2Cl2 (10 mL) was added dropwise.
The reaction mixture was let to warm to room temperature
and stirred 1.5 h. The reaction was quenched with 1.0 M
tartaric acid (30 mL), and after stirring 15 h at room temper-
ature, the organic layer was separated and the aqueous one
was extracted with CH2Cl2 (3 × 50 mL). The combined organic
cm-1 1H NMR (CCl4): δ 0.00 (s, 6H), 0.81 (t, 3H, J ) 7.5),
;
0.85 (s, 9H), 0.93 (d, 3H, J ) 6.9), 1.35-1.45 (m, 2H), 2.22-
2.32 (m, 1H), 3.42 (q, 1H, J ) 4.3), 5.93 (dd, 1H, J ) 14.5 and
1.0), 6.42 (dd, 1H, J ) 14.5 and 7.8); 13C NMR (CCl4, 75.5
MHz): δ -4.5, -4.3, 9.5, 13.7, 18.0, 25.8, 26.6, 44.7, 74.4, 76.1,
149.0.
(E)-(3R,4R)-6-Iod o-4-m eth yl-5-h exen -3-ol (6b). A 0.85
mL volume of a soln of HF prepared from 48% aq HF (0.5 mL),
CH3CN (8.5 mL), and water (0.5 mL) was added to vinylic
iodide 23 (0.150 g, 0.424 mmol), and the mixture was stirred
4 h at room temperature. After dilution of the reaction
mixture with ether (15 mL) and neutralization with satd
NaHCO3, the organic phase was washed with water (2 × 3.0

7818 J . Org. Chem., Vol. 63, No. 22, 1998
Pilli et al.
mL) and brine (3.0 mL). The organic layer was normally
processed, and the crude product was purified by column
chromatography (50% ethyl acetate in hexanes) to yield 6b
(0.096 g, 0.400 mmol), in 94% yield). [R]D ) +28.0 (c 2.9, CH2-
Cl2); IR (film, NaCl): 3400 (br), 3080, 2982, 2955, 2880, 1600,
1464, 946 cm-1; 1H NMR: δ 0.94 (t, 3H, J ) 7.4), 1.03 (d, 3H,
J ) 6.8), 1.29-1.44 (m, 1H), 1.47-1.64 (m, 2H), 2.26-2.37 (m,
1H), 3.40 (dt, 1H, J ) 5.1 and 8.8), 6.09 (dd, 1H, J ) 14.4 and
1.0), 6.52 (dd, 1H, J ) 14.4 and 8.1); 13C NMR: δ 10.2, 13,9,
26.9, 46.1, 75.4, 75.7, 148.7.
(2S,3S,4S,6R)-2,4,6-Tr im eth yl-1,3,7-h ep ta n etr iol. To a
suspension of LiAlH4 (0.050 g, 1.3 mmol) in THF (2.0 mL) at
0 °C was added dropwise a solution of 5a (0.204 g, 0.68 mmol)
in THF (1.0 mL). The reaction mixture was let to warm to
room temperature and to stir for 22 h. The reaction was
quenched at 0 °C by the addition of water (0.050 mL), 15% aq
KOH (0.050 mL), and water (0.150 mL), successively, and kept
24 h under vigorous stirring at room temperature. The
inorganic solids were filtered off and washed with ether (3 ×
10 mL), and the solvent was removed under reduced pressure.
The crude product was eluted through a pad of silica gel with
ethyl acetate to yield (2S,3S,4S,6R)-2,4,6-trimethyl-1,3,7-
heptanetriol (0.122 g, 0.642 mmol), in 94% yield. [R]D ) -8.9
(c 1.9, CHCl3); IR (film, NaCl): 3350 (br), 2982, 2950, 2900,
1473, 1400, 1054, 1000 cm-1; 1H NMR: δ 0.83 (d, 3H, J ) 6.6),
0.88 (d, 3H, J ) 6.9), 0.80-0.90 (m, 1H), 0.95 (d, 3H, J ) 6.6),
1.6-1.9 (m, 4H), 3.37-3.46 (m, 2H), 3.57-3.65 (m, 3H), 3.9-
4.3 (m, br, 3H); 13C NMR: δ 8.9, 16.7, 18.8, 33.2, 34.1, 36.1,
37.3, 66.1, 67.1, 78.2; HRMS calcd for C10H22O3: 190.1569.
Found: 190.1571.
(2R,4S)-4-[(2′R,4′S,5′S)-2′-(4-Meth oxyp h en yl)-5′-m eth yl-
1′,3′-d ioxa n -4-yl]-2-m eth ylp en ta n -1-ol (24). A solution of
the aforementioned triol (0.112 g, 0.589 mmol), p-anisaldehyde
dimethylacetal (0.128 g, 0.703 mmol), and camphorsulfonic
acid (0.0068 g, 0.030 mmol) in CH2Cl2 (3.0 mL) was stirred 12
h at room temperature and quenched with satd NaHCO3 (1.0
mL). The mixture was diluted with ether (10 mL), and the
organic layer was washed with water (2.0 mL) and brine (2.0
mL) and dried with MgSO4. The solvent was removed under
reduced pressure, and the crude product was purified by
column chromatography (30% ethyl acetate-hexanes) to afford
alcohol 24 (0.178 g, 0.578 mmol), in 98% yield. [R]D ) -39.7
(c 1.5, CHCl3). IR (film, NaCl): 3445 (br), 2982, 2945, 2890,
2864, 1605, 1400, 1264 cm-1; 1H NMR: δ 0.86 (d, 3H, J ) 6.8),
0.85-0.95 (m, 1H), 0.93 (d, 3H, J ) 6.4), 1.15 (d, 3H, J ) 6.9),
1.6-1.8 (m, 5H), 3.40-3.50 (m, 3H), 3.79 (s, 3H), 4.02 (d, 2H,
J ) 1.8), 5.42 (s, 1H), 6.87-6.90 (m, 2H), 7.38-7.41 (m, 2H);
13C NMR: δ 10.8, 15.6, 18.6, 31.1., 32.4, 33.6, 37.4, 55.2, 67.1,
73.9, 85.0, 101.9, 113.6, 127.2, 131.3, 159.8; HRMS calcd for
of satd soln of sodium and potassium tartrate (1.0 mL). The
mixture was vigorously stirred for 6 h and extracted with ether
(4 × 10 mL). The organic layer was washed with brine (3.0
mL) and processed. The crude product was purified by column
chromatography (25% ethyl acetate-hexanes) to afford 26
(0.148 g, 0.317 mmol), in 99% yield. [R]D ) +7.8 (c 2.1, CHCl3);
IR (film, NaCl): 3400 (br), 2965, 2880, 1620, 1520, 1472, 1260
cm-1 1H NMR: δ 0.85-1.10 (m, 1H), 0.94 (d, 6H, J ) 6.8),
;
0.95 (d, 3H, J ) 6.7), 1.04-1.06 (m, 21H), 1.60-2.00 (m, 5H),
3.33 (dd, 1H, J ) 3.0 and 6.4), 3.44-3.48 (m, 1H), 3.54-3.59
(m, 3H), 3.80 (s, 3H), 4.50 (AB system, 2H, J ) 11.0, ∆νAB )
40.6), 6.86 (d, 2H, J ) 8.6), 7.26 (d, 2H, J ) 8.6); 13C NMR: δ
11.5, 11.9, 16.8, 18.0, 18.5, 32.9, 33.5, 37.0, 37.2, 55.2, 67.0,
68.1, 73.2, 84.1, 113.7, 129.1, 131.1, 159.0; HRMS calcd for
C
27H50O4Si: 466.3478. Found: 466.3435.
(2R,3S,4S,6R)-3-(4-Meth oxyben zyloxy)-7-(tr iisop r op yl-
silyloxy)-2,4,6-tr im eth ylh ep ta n oic Acid (27). To a solution
of alcohol 26 (0.019 g, 0.041 mmol) in acetone (1.0 mL) at 0 °C
was added J ones reagent (0.060 mL, 0.085 mmol). After 20
min stirring at 0 °C, an additional amount of J ones reagent
was added (0.030 mL, 0.042 mmol). After 40 min stirring at
0 °C, the reaction was quenched with 2-propanol (0.15 mL,
let to warm to room temperature, and diluted with ether (10
mL). The organic layer was normally processed, and the crude
product was purified by filtration through a pad of silica gel
(50% ethyl acetate-hexanes) to afford 27 (0.014 g, 0.029
mmol), in 71% yield. [R]D ) -5.3 (c 1.6, CHCl3); IR (film, NaCl)
3600-2400, 2962, 2873, 1710, 1512, 1480, 1250 cm-1 1H
;
NMR: δ 0.90-1.10 (m, 1H), 0.93 (d, 3H, J ) 6.7), 0.95 (d, 3H,
J ) 7.1), 1.03-1.05 (m, 21H), 1.21 (d, 3H, J ) 7.0), 1.55-1.90
(m, 3H), 2.74 (dq, 1H, J ) 6.9 and 5.4), 3.37 (dd, 1H, J ) 9.5
and 4.7), 3.57 (dd, 1H, J ) 9.6 and 4.7), 3.61 (t, 1H, J ) 5.7),
3.78 (s, 3H), 4.48 (s, 2H), 6.85 (d, 2H, J ) 8.7), 7.23 (d, 2H, J
) 8.7); 13C NMR: δ 11.3, 11.8, 16.9, 17.9, 18.5, 33.5, 34.2, 36.6,
41.5, 55.1, 68.0, 73.8, 84.2, 113.7, 129.3, 130.8, 159.2, 182.2;
HRMS calcd for C27H48O5Si: 480.3271. Found: 480.3297.
(E)-(2R,3S,4S,6R,3′R,4′R)-6′-Iod o-3′-m eth yl-1′-h exen -4′-
yl 3-(4-Meth oxyben zyloxy)-7-(tr iisop r op ylsilyloxy)-2,4,6-
tr im eth ylh ep ta n oa te (28). To a solution of carboxylic acid
27 (0.050 g, 0.10 mmol) in THF (1.0 mL) at room temperature
were added triethylamine (0.019 mL, 0.014 g, 0.135 mmol) and
2,4,6-trichlorobenzoyl chloride (0.0305 g, 0.125 mmol). The
reaction mixture was stirred 2 h at room temperature, and
the solids were filtered off and washed with hexanes. The
solvent was evaporated under reduced pressure, the residue
was dissolved in benzene (1.5 mL), and a solution of alcohol
6b (37.5 mg, 0.156 mmol) and DMAP (0.0165 g, 0.135 mmol)
in benzene (0.5 mL) was added. After stirring 24 h at room
temperature, the reaction was diluted with ether (20 mL),
washed with satd NaHCO3 (2.0 mL) and brine (2.0 mL), and
dried over MgSO4. The organic phase was processed, and the
crude product was purified by column chromatography (20%
ethyl acetate-hexanes) to yield 28 (0.068 g, 0.097 mmol), in
97% yield. [R]D ) +56.7 (c 1.2, CHCl3); IR (film, NaCl): 2980,
C
18H28O4: 308.1988. Found: 308.1987.
(2R,4S)-4-[(2′R,4′S,5′S)-2′-(4-Meth oxyp h en yl)-5′-m eth yl-
1′,3′-d ioxa n -4-yl]-2-m et h yl-1-(t r iisop r op ylsilyloxy)p en -
ta n e (25). A solution of alcohol 24 (0.120 g, 0.390 mmol),
imidazole (0.120 g, 1.76 mmol), and triisopropylsilyl chloride
(0.150, 0.779 mmol) in DMF (0.5 mL) was stirred 24 h at room
temperature, diluted with ether (20 mL), and washed with
water (2 × 1 mL) and brine (1 mL). The organic layer was
processed, and the crude product was purified by column
chromatography (20% ethyl acetate-hexanes) to yield 25
(0.181 g, 0.390 mmol), in quantitative yield. [R]D ) -27.7 (c
1.8, CHCl3); IR (film, NaCl): 2964, 2950, 2864, 1618, 1520,
1464, 1263, 1120 cm-1; 1H NMR: δ 0.84 (d, 3H, J ) 6.7), 0.82-
0.88 (m, 1H), 0.93 (d, 3H, J ) 6.4), 1.02 (s, 3H), 1.03 (s, 18H),
1.14 (d, 3H, J ) 6.8), 1.60-1.90 (m, 4H), 3.36-3.43 (m, 2H),
3.56 (dd, 1H, J ) 4.6 and 4.5), 3.8 (s, 3H), 3.97-4.07 (m, 2H),
5.41 (s, 1H), 6.85-6.88 (m, 2H), 7.39-7.43 (m, 2H); 13C NMR:
δ 10.9, 11.9, 14.9, 18.0, 18.7, 30.1, 32.3, 33.5, 37.7, 55.2, 68.2,
74.0, 84.9, 101.5, 113.3, 127.2, 131.7, 159.6; HRMS calcd for
1
2955, 2872, 1735, 1510, 1475, 1250 cm-1; H NMR: δ 0.86 (t,
3H, J ) 7.3), 0.94 (d, 3H, J ) 6.9), 0.94-1.15 (m, 1H), 0.97 (d,
3H, J ) 7.5), 1.02 (d, 3H, J ) 6.8), 1.04-1.06 (m, 21H), 1.23
(d, 3H, J ) 7.1), 1.48-1.86 (m, 5H), 2.42-2.54 (m, 1H), 2.70
(dq, 1H, J ) 7.0 and 1.5), 3.35 (dd, 1H, J ) 9.5 and 7.0), 3.54-
3.62 (m, 2H), 3.80 (s, 3H), 4.48 (s, 2H), 4.74 (dt, 1H, J ) 8.0
and 5.1), 6.07 (dd, 1H, J ) 14.5 and 1.0), 6.47 (dd, 1H, J )
14.5 and 7.8), 6.85 (m, 2H), 7.25 (m, 2H); 13C NMR: δ 9.4,
11.6, 12.4, 14.4, 16.9, 18.8, 18.3, 23.6, 33.5, 34.3, 36.1, 42.1,
43.1, 55.1, 68.0, 73.6, 75.9, 77.1, 84.0, 113.7, 129.2, 131.1, 147.6,
158.2, 175.8; HRMS calcd for C34H59O5SiI: 702.3176. Found:
702.3174.
(E)-(2R,3S,4S,6R,3′R,4′R)-6′-iod o-3′-m eth yl-1′-h exen -4′-
yl 3-(4-Met h oxyb en zyloxy)-7-h yd r oxy-2,4,6-t r im et h yl-
h ep ta n oa te. Ester 28 (0.036 g, 0.051 mmol) was treated at
room temperature with 0.030 mL of a solution containing 48%
HF (0.5 mL), acetonitrile (8.6 mL), and water (0.9 mL), added
every 3 h. After addition of five aliquots every 3 h, the reaction
mixture was stirred 5 h at room temperature, diluted with
ether (5 mL), and neutralized with satd NaHCO3 (1 mL). The
organic layer was separated, the aqueous layer was extracted
C
27H48O4Si: 464.3322. Found: 464.3237.
(2S,3S,4S,6R)-3-(4-Meth oxyben zyloxy)-7-(tr iisop r op yl-
silyloxy)-2,4,6-tr im eth ylh ep ta n -1-ol (26). To a solution of
25 (0.149 g, 0.321 mmol) in toluene (2.0 mL) at 0 °C was added
dropwise a 1 M solution of DIBAL-H in toluene (0.96 mL, 0.96
mmol). The reaction mixture was stirred 1 h at 0 °C and
quenched with ethyl acetate (1.0 mL), followed by the addition

Total Synthesis of 10-Deoxymethynolide
J . Org. Chem., Vol. 63, No. 22, 1998 7819
with ether (2 × 3.0 mL), and the combined organic extract was
washed with water (1.0 mL) and brine (1.0 mL) and dried over
MgSO4. The solvent was removed under reduced pressure,
and the crude product was purified by column chromatography
(30% ethyl acetate-hexanes) to afford the desired alcohol
(0.026 g, 0.048 mmol), in 94% yield. [R]D ) +46.0 (c 1.0,
CHCl3); IR (film, NaCl): 3327, 2935, 2865, 1715, 1640, 1530,
1464, 1390 cm-1; 1H NMR (CDCl3, 300 MHz): δ 0.87 (t, 3H, J
) 7.3), 0.95 (d, 3H, J ) 6.5), 0.98 (d, 3H, J ) 6.7), 0.90-1.03
(m, 1H), 1.03 (d, 3H, J ) 6.9), 1.25 (d, 3H, J ) 7.0), 1.50-1.90
(m, 6H), 2.50 (dt, 1H, J ) 1.0 and 6.0), 2.75 (qt, 1H, J ) 6.7),
3.42 (d, 2H, J ) 4.8), 3.55 (dd, 1H, J ) 6.5 and 4.7), 3.80 (s,
3H), 4.49 and 4.54 (AB system, 2H, J ) 10.7, ∆ν ) 14.5 Hz),
4.75 (dt, 1H, J ) 8.6 and 5.1), 6.08 (dd, 1H, J ) 14.5 and 1.0),
6.47 (dd, 1H, J ) 14.5 and 7.8), 6.86-6.89 (m, 2H), 7.25-7.28
(m, 2H). 13C NMR (CDCl3, 75.5 MHz): δ 10.2, 13.5, 15.0, 18.2,
18.8, 24.2, 33.5, 34.7, 35.6, 43.2, 43.6, 55.6, 67.2, 74.8, 76.5,
77.8, 84.9, 114.1, 129.7, 131.0, 147.6, 159.5, 175.9. HRMS
calcd for C25H39O5: 546.1842. Found: 546.1844.
(2R,3S,4S,6R,3′R,4′R)-(E)-6′-iod o-3′-m eth yl-1′-h exen -4′-
yl 3-(4-Met h oxyb en zyloxy)-6-for m yl-2,4-d im et h ylh ep -
ta n oa te (29). To a suspension of Dess-Martin periodinane
(0.022 g, 0.051 mmol) in CH2Cl2 (0.1 mL) was added a solution
of the alcohol prepared above (0.011 g, 0.020 mmol) and
pyridine (0.017 g, 0.21 mmol) in CH2Cl2. The reaction mixture
was stirred 8 h at room temperature, and it was diluted with
ethyl acetate (3.0 mL). After the addition of satd NaHCO3
(0.5 mL), the organic layer was separated and the aqueous
layer was extracted with ethyl acetate (2 × 2.0 mL). The
combined organic layers were washed with 1.0 M Na2S2O3 (1.0
mL) and dried under MgSO4, and the solvent was removed
under reduced pressure. The crude product was filtered
through a pad of silicagel (70% ethyl acetate-benzene) to yield
aldehyde 29 (0.011 g, 0.020 mmol), in quantitative yield. 1H
NMR: δ 0.87 (t, 3H, J ) 7.3), 0.98 (d, 3H, J ) 6.9), 1.03 (d,
3H, J ) 6.6), 1.09 (d, 3H, J ) 6.9), 1.0-1.2 (m, 1H), 1.25 (d,
3H, J ) 6.9), 1.45-1.75 (m, 3H), 1.97 (ddd, 1H, J ) 14.0, 9.6,
4.3), 2.40-2.60 (m, 2H), 2.73 (qt, 1H, J ) 6.9), 3.59 (dd, 1H, J
) 5.7 and 5.1), 3.80 (s, 3H), 4.51 (AB system, 2H, J ) 10.8, ∆ν
) 20.5 Hz), 4.75 (dt, 1H, J ) 8.0 and 5.1), 6.09 (dd, 1H, J )
14.6 and 1.1), 6.48 (dd, 1H, J ) 14.6 and 7.7), 6.85-6.92 (m,
2H), 7.24-7.28 (m, 2H), 9.5 (d, 1H, J ) 2.9). 13C NMR: δ 9.5,
12.7, 14.3, 14.5, 17.0, 23.6, 33.0, 34.4, 42.6, 43.0, 44.0, 55.1,
74.3, 76.0, 77.4, 84.1, 113.8, 129.4, 130.8, 147.6, 150.4, 175.5,
205.8.
NMR: δ 0.90-1.14 (m, 1H), 0.90 (t, 3H, J ) 7.4), 0.96 (d, 3H,
J ) 6.7), 1.05 (d, 3H, J ) 6.6), 1.07 (d, 3H, J ) 6.7), 1.27 (d,
3H, J ) 6.8), 1.5-1.7 (m, 4H), 1.95-2.05 (m, 2H), 2.44-2.54
(s, br, 1H), 2.64 (dq, 1H, J ) 6.8 and 3.5), 3.46 (dd, 1H, J )
10.3 and 1.5), 3.80 (s, 3H), 4.15 (dd, 1H, J ) 10.0 and 5.0),
4.57 (AB system, 2H, J ) 10.6, ∆ν ) 13.0), 5.04 (ddd, 1H, J )
8.6, 5.5 and 2.9), 5.52 (ddd, 1H, J ) 15.5, 9.7 and 1.9), 5.70
(dd, 1H, J ) 15.5 and 3.1), 6.86 (m, 2H), 7.26 (m, 2H); 13C
NMR: δ 9.5, 10.3, 14.5, 16.3, 17.5, 24.8, 31.6, 33.0, 33.2, 37.9,
43.5, 55.2, 74.0, 75.5, 76.4, 86.8, 113.7, 126.6, 129.2, 130.8,
137.8, 159.2, 175.8; HRMS calcd for C25H38O5: 418.2719.
Found: 418.2715.
(2R,3S,4S,6R,10R,11R)-(E)-11-Eth yl-7-oxo-3-(4-m eth oxy-
ben zyloxy)-2,4,6,10-tetr a m eth yl-8-d od ecen olid e (31). To
a suspension of Dess-Martin periodinane (0.101 g, 0.248
mmol) in CH2Cl2 (0.5 mL) at 0 °C was added a soln in CH2Cl2
(0.5 mL) of pyridine (0.0078 g, 0.99 mmol) and allylic alcohols
30a /30b (0.013 g, 0.031 mmol). The reaction mixture was
stirred 12 h at room temperature and quenched with ethyl
acetate (2.0 mL) and filtered. The organic layer was washed
with satd NaHCO3 (1.0 mL) and processed. The crude product
was purified by flash chromatography (20% ethyl acetate-
hexanes) to afford the 31 (0.010 g, 0.024 mmol) in 77% yield.
[R]D ) +97.2 (c 1.0, CHCl3); IR (film, NaCl): 2964, 2935, 1735,
1700, 1630, 1180 cm-1; 1H NMR: δ 0.91 (t, 3H, J ) 7.4), 1.05-
1.80 (m, 5H), 1.06 (d, 3H, J ) 6.6), 1.10 (d, 3H, J ) 6.8), 1.19
(d, 3H, J ) 7.0), 1.30 (d, 3H, J ) 6.9), 2.48-2.79 (m, 3H), 3.45
(d, 1H, J ) 10.2), 3.80 (s, 3H), 4.57 (AB system, 2H, J ) 10.4,
∆ν ) 13.0), 4.97 (ddd, 1H, J ) 8.4, 5.7, 2.5), 6.41 (dd, 1H, J )
15.7 and 1.2), 6.74 (dd, 1H, J ) 15.7 and 5.4), 6.80 (d, 2H, J )
8.7), 7.26 (d, 2H, J ) 8.7); 13C NMR: δ 9.5, 10.3, 16.3, 17.6,
18.2, 25.1, 34.0, 34.1, 37.9, 43.5, 45.1, 55.2, 73.6, 76.4, 86.3,
113.8, 125.8, 129.2, 130.6, 146.8, 159.2, 175.0, 205.1; HRMS
calcd for C25H36O5: 416.2563. Found: 416.2550.
(2R,3S,4S,6R,10R,11R)-(E)-11-E t h yl-7-oxo-3-h yd r oxy-
2,4,6,10-tetr a m eth yl-8-d od ecen olid e (2c). To a solution of
the macrolide above (0.010 g, 0.025 mmol) in CH2Cl2 (1.2 mL)
were added water (0.063 mL, 0.063 g, 3.5 mmol) and DDQ
(0.011 g, 0.050 mmol). The reaction mixture was stirred 1.5
h at room temperature and diluted with CH2Cl2 (2.0 mL) and
satd NaHCO3 (0.1 mL). The organic layer was separated and
the aqueous phase extracted with CH2Cl2 (2 × 1.0 mL). The
combined organic phase was processed, and the crude product
was purified by flash chromatography (30% ethyl acetate-
hexanes) to yield 2c (0.007 g, 0.024 mmol), in 96% yield. [R]D
) +89.0 (c 0.86, CHCl3); IR (film, NaCl): 3464 (br), 2974, 2927,
2860, 1727, 1702, 1620 cm-1; 1H NMR: δ 0.91 (t, 3H, J ) 7.3),
1.0 (d, 3H, J ) 6.2), 1.12 (d, 3H, J ) 6.6), 1.22 (d, 3H, J )
6.9), 1.30 (d, 3H, J ) 6.6), 1.20-1.37 (m, 2H), 1.47-1.78 (m,
4H), 2.46-2.66 (m, 3H), 3.56 (d, 1H, J ) 10.4), 5.00 (ddd, 1H,
J ) 8.5, 5.7 and 2.2), 6.42 (dd, 1H, J ) 15.7 and 1.2), 6.78 (dd,
1H, J ) 15.7 and 5.4); 13C NMR: δ 9.3, 10.0, 16.1, 17.2, 17.4,
24.9, 33.0, 33.2, 37.8, 43.2,, 45.0, 73.7, 78.2, 125.8, 147.3, 175.1,
205.4; HRMS calcd for C17H28O4: 296.1988. Found: 296.1987.
(2R,3S,4S,6R,7R/S,10R,11R)-(E)-11-Eth yl-7-h yd r oxy-3-
(4-m eth oxyben zyloxy)- 2,4,6,10-tetr a m eth yl-8-d od ecen o-
lid e (30a a n d 30b). To a suspension of CrCl2 (0.035 g, 0.29
mmol) containing 1% mol of NiCl2 (0.0075 g, 0.0058 mmol) in
degassed DMF (3.5 mL) was added, under ice bath, a solution
of 29 (0.015 g, 0.027 mmol) in DMF (1.5 mL). The reaction
mixture was stirred 12 h at room temperature, and the solvent
was removed under vacuum (0.1 mmHg). The residue was
dissolved in water (1.0 mL) and extracted with ether (4 × 5
mL). The organic layer was washed with water (2 × 2.0 mL)
and brine (2.0 mL) and processed. The crude product was
purified by flash chromatography (20% ethyl acetate-hexanes)
to yield a 1:1 mixture of 30a and 30b (0.0085 g, 0.020 mmol)
in 74% yield. More polar isomer (30a ): IR (film, NaCl): 3500
Ack n ow led gm en t. This research was supported by
research grants from FINEP (Brazil), Volkswagen Stif-
tung (Germany), and IFS (Sweden). Fellowships to
C.K.Z.A. and C.R.O.S. (FAPESP, CAPES, CNPq, and
FAEP-UNICAMP) and to R.A.P. (DAAD and CAPES)
are gratefully acknowledged.
(br), 2990, 1735, 1610 cm-1 1H NMR: δ 0.89-1.05 (m,1H),
;
0.91 (t, 3H, J ) 7.4), 0.96 (d, 3H, J ) 7.0), 1.05 (d, 3H, J )
6.9), 1.11 (d, 3H, J ) 6.8), 1.27 (d, 3H, J ) 6.9), 1.5-1.7 (m,
4H), 1.86-2.0 (m, 2H), 2.54-2.62 (s,br, 1H), 2.68 (dq, 1H, J )
6.7 and 3.5), 3.45 (dd, 1H, J ) 10.0 and 1.5), 3.8 (s, 3H), 4.11
(s, br, 1H), 4.57 (AB system, 2H, J ) 10.6, ∆ν ) 15.8 Hz), 5.0
(ddd, 1H, J ) 8.8, 5.4 and 3.2), 5.55 (ddd, 1H, J ) 15.8, 3.5
and 1.6), 5.69 (ddd, 1H, J ) 15.8, 4.4, 1.6), 6.87 (d, 2H, J )
7.5), 7.2 (d, 2H, J ) 7.5); 13C NMR: δ 10.4, 10.7, 16.4, 17.7,
20.4, 24.4, 32.9, 33.5, 35.4, 37.7, 43.4, 55.2, 75.8, 76.2, 77.2,
86.6, 113.7, 128.5, 129.2, 130.7, 130.9, 159.1, 175.7. Less polar
isomer (30b): IR (film, NaCl): 3500 (br), 1732, 1615 cm-1; 1H
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds 5a , 6, 17c, 25, 27, 28, 30a , 30b,
10-deoxymethynolide (2c) and its 3-O-p-methoxybenzyl deriva-
tive (20 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9809433