Synthesis of γ,δ-unsaturated-β-keto lactones via sequential cross metathesis-lactonization: A facile entry to macrolide antibiotic (-)-A26771B

Article abstract of DOI:10.1021/jo052421a

A simple access to γ,δ-unsaturated-β-keto lactones is presented, allowing a rapid total synthesis of the naturally occurring 16-membered macrolide antibiotic (-)-A26771B via cross metathesis, asymmetric dihydroxylation, and lactonization as the key steps.

Full text of DOI:10.1021/jo052421a

Synthesis of γ,δ-Unsaturated-â-keto Lactones via Sequential Cross
Metathesis-Lactonization: A Facile Entry to Macrolide Antibiotic
(-)-A26771B
Julian Gebauer and Siegfried Blechert*
Institut fu¨r Chemie, Technische UniVersita¨t Berlin, Strasse des 17, Juni 135, D-10623 Berlin, Germany
blechert@chem.tu-berlin.de
ReceiVed NoVember 23, 2005
A simple access to γ,δ-unsaturated-â-keto lactones is presented, allowing a rapid total synthesis of the
naturally occurring 16-membered macrolide antibiotic (-)-A26771B via cross metathesis, asymmetric
dihydroxylation, and lactonization as the key steps.
SCHEME 1. Concept for Synthesis of
γ,δ-Unsaturated-â-keto Lactones
Introduction
Because of their unique biological properties and synthetically
challenging structures, the development of methodology for the
preparation of macrolides has received much synthetic attention
during the past decades.1 Although a mild and quite high
yielding macrocyclization strategy, the thermal cycloreversion
of dioxolenones followed by intramolecular ketene trapping2
has remained rather unexploited in natural product synthesis.3
Intrigued by its potential we set out to combine this general
lactonization method with the high efficiency of olefin metath-
esis.4 Thus, selective cross metathesis (CM) of hydroxyalkenes
such as 1 with the conjugated dienone 2, followed by ther-
molysis under suitable high dilution conditions, was considered
to conveniently deliver monomeric γ,δ-unsaturated-â-keto lac-
tones of type 4 (Scheme 1).
Furthermore, functionalization of the CM-generated double
bond as well as transformation of the â-keto lactone moiety
would enable access to substituted derivatives, as demonstrated
by the total synthesis of the macrolide antibiotic (-)-A26771B
(Figure 1).
(1) Tadashi, N. In Macrolide Antibiotics: Chemistry, Biology and
Practice, 2nd ed.; Omura, S., Ed.; Academic Press: San Diego, 2002; pp
181-284.
(2) See, for example: (a) Eisenberg, S. W. E.; Chen, C.; Wu, J.; Lebrilla,
C.; Kurth, M. J. Tetrahedron Lett. 1996, 37, 7683-7686. (b) Petasis, N.
A.; Patane, M. A. J. Chem. Soc., Chem. Commun. 1990, 11, 836-837. (c)
Boeckman, R. K.; Perni, R. B. J. Org. Chem. 1986, 51, 5486-5489.
(3) For two recent examples, see: (a) Cramer, N.; Laschat, S.; Baro,
A.; Schwalbe, H.; Richter, C. Angew. Chem. 2005, 117, 831-833. (b) Trost,
B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124,
10396-10415.
FIGURE 1. Antibiotic (-)-A26771B.
(4) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim,
2003.
10.1021/jo052421a CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/01/2006
J. Org. Chem. 2006, 71, 2021-2025
2021

Gebauer and Blechert
TABLE 1. Results and Conditions of CM Reactions and
Subsequent Lactonizations
SCHEME 2. Synthesis of CM Precursors
equiv
mol %
yield 3
yield 4
yield 12
alcohol
n
R
2
11
(%)
(%)
(%)
1a
1b
1c
1d
5
7
8
9
H
H
Me
H
1
1
1
1
5
5
5
5
71
75
78
77
71a
c
44a/78b
82a
85a
a Method A. b Method B. c Not isolated.
Results and Discussion
SCHEME 3. Retrosynthetic Analysis of (-)-A26771B
The intramolecular trapping of hydroxyalkylketenes derived
from substrates such as 3 is quite sensitive to transition-state
conformational effects manifested by ring size.5 Whereas the
preparation of saturated eight-membered â-keto lactones worked
well,2b the cyclization to corresponding 10- and 11-membered
analogues failed even under high dilution conditions (<10-4
M).2a For this reason and with respect to the additional
unsaturation in the starting material lowering the conformational
flexibility, we focused our investigations on the synthesis of
simple 14- to 18-membered macrolactones.
In addition to purchasable 9-decen-1-ol (1a), the long-chain
alcohols 1b-d were favored as adequate substrates because they
can be easily derived from commercially available compounds
(Scheme 2). While dodecenol 1b6 and tetradecenol 1c7 could
be prepared according to literature procedures, the direct
conversion of 11-bromo-1-undecanol (8) with allylmagnesium
bromide in the presence of CuI produced significant amounts
of byproduct. However, refluxing the corresponding THP ether
with excess allylmagnesium chloride8 in THF gave the known
tetradecenol 1d9 in 67% overall yield after deprotection.
5 mol % of the commercial ruthenium catalyst 1111 under
standardized conditions (CH2Cl2, 40 °C, 24 h). In this manner,
the desired hydroxyalkenyldioxolenones 3a-d were obtained
with high E-selectivity (E/Z > 20:1) in good yields after column
chromatographic separation from some amount of partially
homodimerized alcohol.
The subsequent lactonizations were initially performed on a
0.1 mmol scale by refluxing a dilute solution (∼10-4 M) of the
cyclization precursors in n-heptane for 9 h (method A). Although
the use of toluene resulted in shorter reaction times (3 h), the
crude products contained significant amounts of solvent-derived
byproducts, complicating their column chromatographical pu-
rification.
Concerning the synthesis of dienone 2, acetonization of the
known â-keto ester 910 and subsequent chloride elimination were
found to be an efficient strategy, which at the same time should
allow access to various substituted congeners.
The results and conditions of the CM reactions and subse-
quent lactonizations are presented in Table 1. As indicated, the
CM reactions between alcohols 1a-d and dienone 2 were
preferentially carried out stoichiometrically in the presence of
Whereas the formation of 14-membered lactones by ring-
closing metathesis is usually easy,12 FAB mass spectrometry
revealed that the main product obtained upon thermal cyclization
of 3a was the 28-membered diolide 12a and no monomeric
(5) Sato, M.; Sakaki, J.; Sugita, Y.; Yasuda, S.; Sakoda, H.; Kaneko, C.
Tetrahedron 1991, 47, 5689-5708.
(6) Crouch, D. R.; Mehlmann, J. F.; Herb, B. R.; Mitten, J. V.; Dai, G.
H. Synthesis 1999, 4, 559-561.
(7) Kobayashi, Y.; Nakano, M.; Kumar, B. G.; Kishihara, K. J. Org.
Chem. 1998, 63, 7505-7515.
(11) For a short review on its unique activity, see: (a) Hoveyda, A. H.;
Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.;
Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 8-23. (b)
Connon, S. J.; Blechert, S. Angew. Chem. 2003, 115, 1944-1968.
(12) See, for example: (a) Lee, C. W.; Grubbs, R. H. Org. Lett. 2000,
2, 2145-2147. (b) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 7, 792-
803.
(8) Taber, D. F.; Green, J. H.; Geremia, J. M. J. Org. Chem. 1997, 62,
9342-9344.
(9) Yamanaka, T.; Imai, T. Bull. Chem. Soc. Jpn. 1981, 54, 1585-2586.
(10) Hoffman, R. V.; Kim, H.; Wilson, A. L. J. Org. Chem. 1990, 55,
2820-2822.
2022 J. Org. Chem., Vol. 71, No. 5, 2006

Facile Entry to Macrolide Antibiotic (-)-A26771B
SCHEME 4. Synthesis of (-)-A26771B
lactone could be isolated. Somewhat surprised at this outcome,
via chemoselective asymmetric dihydroxylation, diol protection,
and lactonization.
we continued with the 16-membered ring precursor 3b. In this
1
case two lactones in a ratio of about 1:1 (determined by H
Accordingly, our intended total synthesis began with the
preparation of the homochiral tridecenol 16 by ring opening of
commercially available (R)-methyloxirane (Scheme 4). To avoid
homodimerization, the following CM of 16 was carried out with
1.5 equiv of 2, affording the desired cyclization precursor 15
in excellent yield (E/Z > 20:1). Asymmetric dihydroxylation
of 15 using a modified AD-mix-R17 and tBuOH/H2O as solvent
occurred smoothly and with high chemoselectivity over 16 h at
room temperature. Protection of the crude diol and direct
thermolysis (method A) of the reaction mixture furnished the
â-keto lactone 14 in 65% yield as a single diastereoisomer that
appeared to be partially enolized. As expected, mesylation of
the diastereoisomeric alcohols obtained upon NaBH4 re-
duction of 14, followed by treatment with DBU, finally
furnished in high overall yield the lactone 13, whose spectral
NMR) were obtained of which the less polar one (SiO2; 1%
acetone in CH2Cl2) appeared to be the known â-keto lactone
4b.13 In an attempt to favor its formation, the macrocyclization
was conducted by slow addition of a dilute toluene solution of
3b to refluxing toluene over 4 h and additional stirring for 3 h
(method B). Under these conditions, the concentration of
dioxolenone was always <10-4 M and only trace amounts of
dimeric lactone were observed, affording 4b in a considerably
improved yield of 78%. Pleased by these results, we turned to
the last two substrates 3c and 3d. Interestingly, in both cases
application of method A led to the exclusive formation of the
corresponding monomeric lactones 4c and 4d.
Regarding a first application of our methodology to natural
product synthesis, the 16-membered macrolide antibiotic (-)-
A26771B (5) was considered a suitable target (Figure 1).
Isolated from the fungus Penicillium turbatum,14 its unique
antimicrobial profile has generated tremendous interest among
organic chemists. Of numerous enantioselective approaches,15
two more recent ones aimed at the asymmetric synthesis of
lactone 13,15c,d whose successful transformation into 5 has
already been reported (Scheme 3).15e,f Since the conversion of
â-keto esters into R,â-unsaturated derivatives is easy,16 the
â-keto lactone 14 represents a useful intermediate that should
in turn be readily available from enantiopure CM product 15
and physical data {[R]20 +5.4 (c 1.0, CHCl3)} agreed with
D
that reported.15e,f
As previously reported attempts to selectively oxidize the
allylic hydroxy group of the diol derived from 13 were
unsuccessful, a regioselective monosuccinylation followed by
Swern oxidation of the remaining allylic alcohol afforded the
natural product in 48% overall yield from 13.15f In our search
for an appropriate reagent allowing the selective oxidation, we
were encouraged to find that a similar TEMPO-mediated
oxidation has recently been employed in the synthesis of
grahamimycin A.18
(13) Booth, P. M.; Broughton, H. B.; Ford, M. J.; Fox, C. M. J.; Ley, S.
V.; Slawin, A. M. Z.; Williams, D. J.; Woodward, P. R. Tetrahedron 1989,
45, 7565-7580.
(14) Michel, K. H.; Demarco, P. V.; Nagarajan, R. J. Antibiot. 1977,
30, 571-575.
(15) See, for example: (a) Lee, W.; Shin, H. J.; Chang, S. Tetrahedron:
Asymmetry 2001, 12, 29-31. (b) Kobayashi, Y.; Okui, H. J. Org. Chem.
2000, 65, 612-615. (c) Nagarajan, M. Tetrahedron Lett. 1999, 40, 1207-
1210. (d) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J. Org. Chem. 1993,
58, 7789-7796. (e) Quinkert, G.; Kueber, F.; Knauf, W.; Wacker, M.; Koch,
U.; Becker, H.; Nestler, H. P.; Du¨rner, G.; Zimmermann, G.; Bats, J. W.;
Egert, E. HelV. Chim. Acta 1991, 74, 1853-1923. (f) Tatsuta, K.; Amemiya,
Y.; Kanemura, Y.; Kinoshita, M. Bull. Chem. Soc. Jpn. 1982, 55, 3248-
3253.
In this case, deprotection of 13 and treatment of the crude
diol with 2 equiv of TEMPO and pTsOH in CH2Cl2 produced
the hydroxyketone 17 in moderate yield. As its corresponding
MOM ether has already been converted into 5 without epimer-
ization in 63% yield via deprotection and succinylation in the
prescence of DMAP,15b esterification of 17 under analogous
conditions gave in 74% yield (-)-A26771B (5), which showed
spectral and physical data consistent with the literature {[R]20
D
-13.2 (c 0.19, MeOH)}.15e,f
(16) See, for example: (a) Taber, D. F.; Neubert, T. D. J. Org. Chem.
2001, 66, 143-147. (b) Kimura, Y.; Atarashi, S.; Takahashi, M.; Hayakawa,
I. Chem. Pharm. Bull. 1994, 42, 1442-1454.
(17) Sharpless, B. K.; Walsh, P. J. Synlett 1993, 8, 605-606.
(18) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002, 4, 4447-4450.
J. Org. Chem, Vol. 71, No. 5, 2006 2023

Gebauer and Blechert
2.19 (m, 2H), 1.70 (s, 6H), 1.35-1.45 (m, 5H), 1.25-1.35 (m,
12H), 1.18 (d, J ) 6.2 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz)
δ 163.5, 162.2, 142.8, 122.5, 106.3, 93.3, 68.2, 39.4, 32.8, 29.7,
29.6, 29.5, 29.4, 29.3, 28.4, 25.8, 25.1, 23.6 ppm; IR (ATR) ν 3429
(br), 2926, 2854, 1725, 1653, 1592, 1390, 1274, 1205, 1019, 903
cm-1; HRMS (EI) m/z calcd for C19H32O4 (M+) 324.2301, found
324.2306; Anal. Calcd for C19H32O4: C, 70.34; H, 9.94. Found:
C, 69.97; H, 9.86.
Conclusion
In summary, we have described an efficient synthesis of γ,δ-
unsaturated-â-keto lactones via sequential CM-lactonization
resulting in a concise total synthesis of the macrolide antibiotic
(-)-A26771B {17% overall yield from commercial (R)-methyl-
oxirane}. Furthermore, the simple choice of starting material
and AD-mix enables access to all nonnatural isomers, of which
the (5R,15R)-diastereomer proved to be twice as active as the
natural product.15f
(5S,6S,16R)-5,6-(Isopropylidendioxy)-16-methyl-oxacyclo-
hexadeca-2,4-dione (14). A solution of 15 (65 mg, 0.2 mmol) in
tBuOH/H2O (1:1, 1.0 mL) was added to a vigorously stirred
suspension of AD-mix-R (280 mg), K2OsO2 (0.44 mg), NaHCO3
(50 mg, 0.6 mmol), and MeSO2NH2 (19 mg, 0.2 mmol) in tBuOH/
H2O (1:1, 1.0 mL) at 0 °C. After 16 h at room temperature the
mixture was quenched with a dilute Na2SO3 solution (5 mL) and
extracted with MTB (4 × 5 mL). Drying of the combined organic
phases (Na2SO4) and evaporation of the solvent gave a residue that
was dissolved in acetone (4 mL) and treated with pTsOH (3.8 mg,
0.02 mmol). After being stirred for 60 h at room temperature, the
mixture was diluted with n-heptane (1600 mL) and refluxed for 7
h under nitrogen. Evaporation of the solvent and purification by
flash chromatography (SiO2; MTB/hexane ) 1:10) afforded 44 mg
Experimental Section
6-(2-Chloro-ethyl)-2,2-dimethyl-[1,3]dioxin-4-one (10). To a
solution of 9 (1.03 g, 5 mmol) and Ac2O (1.5 g, 15 mmol) in
acetone (10 mmol, 0.75 mL) was added concentrated H2SO4 (5
mmol, 0.28 mL) dropwise at 0 °C. The mixture was stirred at room
temperature for 16 h, diluted with H2O (50 mL), and extracted with
CH2Cl2 (3 × 50 mL). Drying of the combined organic phases
(Na2SO4), evaporation of the solvent, and purification by flash
chromatography (SiO2; MTB/hexane ) 1:2) afforded 730 mg (76%)
of 10 as a yellow liquid: Rf ) 0.14 (MTB/hexane ) 1:2); 1H NMR
(CDCl3, 500 MHz) δ 5.36 (s, 1H), 3.69 (t, J ) 6.4 Hz, 2H), 2.70
(t, J ) 6.4 Hz, 2H), 1.71 (s, 6H) ppm; 13C NMR (CDCl3, 125 MHz)
δ 167.1, 160.8, 107.0, 95.8, 39.4, 36.6, 25.1 ppm; IR (ATR) ν 2999,
1728, 1638, 1392, 1273, 1203, 1016, 901 cm-1; HRMS (EI) m/z
calcd for C8H11ClO3 (M+) 190.0397, found 190.0388.
2,2-Dimethyl-6-vinyl-[1,3]dioxin-4-one (2). To a solution of 10
(720 mg, 3.8 mmol) in CH2Cl2 (10 mL) was added NEt3 (764 mg,
7.55 mmol) dropwise at room temperature. The mixture was stirred
at room temperature for 3 h, diluted with CH2Cl2 (70 mL) and
washed with 1 N HCl (20 mL). Drying of the organic phase
(Na2SO4), evaporation of the solvent and purification by flash
chromatography (SiO2; MTB/hexane ) 1:2) afforded 500 mg (85%)
of 2 as a yellow liquid: Rf ) 0.26 (MTB/hexane ) 1:2); 1H NMR
(CDCl3, 500 MHz) δ 6.20 (dd, J ) 17.2, 10.7 Hz, 1H), 6.01 (d, J
) 17.2 Hz, 1H), 5.59 (d, J ) 10.7 Hz, 1H), 5.34 (s, 1H), 1.71 (s,
6H) ppm; 13C NMR (CDCl3, 125 MHz) δ 162.9, 161.8, 129.4,
123.9, 106.6, 95.3, 25.1 ppm; IR (ATR) ν 2999, 1728, 1645, 1581,
1391, 1273, 1205, 1045, 999, 903 cm-1; HRMS (EI) m/z calcd for
C8H10O3 (M+) 154.0630, found 154.0631.
(65%) of 14 as a colorless viscous oil: Rf ) 0.18 (MTB/hexane )
1
1:10); [R]20 ) +14.5 (c ) 1.0, CHCl3); H NMR (CDCl3, 500
D
MHz, keto-/enol-form ) 2:1) δ 11.9 (s, 1H, enol-form), 5.23 (s,
1H, enol-form), 5.20 (m, 1H, enol-form), 4.94 (m, 1H, keto-form),
4.24 (m, 1H, keto- and enol-form), 4.09 (d, J ) 7.0 Hz, 1H, keto-
form), 3.85 (d, J ) 8.5 Hz, 1H, enol-form), 3.70 (d, J ) 15 Hz,
1H, keto-form) 3.60 (d, J ) 15 Hz, 1H, keto-form), 1.20-1.80
(m, 27H) ppm; 13C NMR (CDCl3, 125 MHz, keto- and enol-form)
δ 202.0, 172.1, 171.8, 166.4, 110.3, 110.0, 93.4, 85.4, 82.5, 77.7,
77.3, 77.1, 76.8, 76.7, 73.0, 70.2, 45.9, 35.6, 32.1, 32.09, 28.1, 27.4,
27.3, 27.0, 26.9, 26.85, 26.8, 26.4, 26.0, 25.9, 25.8, 24.5, 23.5, 23.3,
23.0, 20.1 ppm; IR (ATR) ν 2985, 2932, 2859, 1747, 1721, 1651,
1460, 1381, 1235, 1063, 868, 804 cm-1; HRMS (EI) m/z calcd for
C19H32O5 (M+) 340.2250, found 340.2252. Anal. Calcd for
C19H32O5: C, 67.03; H, 9.47. Found: C, 66.71; H, 9.11.
(E,5S,6S,16R)-5,6-(Isopropylidendioxy)-16-methyl-oxacyclo-
hexadec-3-en-2-one (13). To a stirred solution of 14 (34 mg, 0.1
mmol) in MeOH (1.0 mL) was added NaBH4 (3.8 mg, 0.1 mmol)
at room temperature. After 5 min the mixture was quenched with
a saturated NaCl solution (5 mL) and extracted with Et2O (3 × 5
mL). Drying of the combined organic phases (Na2SO4) and
evaporation of the solvent gave a 2:1 mixture of two diastereomeric
alcohols that was dissolved in pyridine (1 mL) and treated with
MsCl (23 mg, 0.2 mmol). After being stirred for 2 h at room
temperature the mixture was diluted with H2O (5 mL) and extracted
with CH2Cl2 (3 × 5 mL). Drying of the combined organic phases
(Na2SO4) and evaporation of the solvent gave a residue that was
dissolved in CH2Cl2 (1 mL), treated with DBU (30 mg, 0.2 mmol)
and stirred for 1 h at room temperature. Evaporation of the solvent
and purification by flash chromatography (SiO2; MTB/hexane )
1:10) afforded 26 mg (80%) of 13 as a white solid: Rf ) 0.21
(R)-Tridec-12-en-2-ol (16). A solution of 9-decenylmagnesium
bromide [freshly prepared from 10-bromo-1-decene (510 mg, 2.3
mmol) and Mg (62 mg, 2.55 mmol) in THF (3 mL)] was added
over 30 min to a stirred suspension of (R)-methyloxirane (90 mg,
1.55 mmol) and CuCN (7 mg, 78 µmol) in THF (2 mL) at -78
°C. The mixture was allowed to warm to room temperature over 2
h, quenched with 1 N HCl (10 mL), and extracted with MTB (3 ×
10 mL). Drying of the combined organic phases (Na2SO4),
evaporation of the solvent, and purification by flash chromatography
(SiO2; MTB/hexane ) 1:4) afforded 260 mg (85%) of 16 as a
colorless liquid: Rf ) 0.15 (MTB/hexane ) 1:4); [R]20 ) -6.2
(c ) 1.0, CHCl3); H NMR (CDCl3, 500 MHz) δ 5.80 (m, 1H),
D
1
(MTB/hexane ) 1:10); mp 71-72 °C; [R]20 ) +5.4 (c ) 1.0,
D
1
4.90-5.00 (m, 2H), 3.79 (m, 1H), 2.04 (m, 2H), 1.25-1.45 (m,
17H), 1.18 (d, J ) 6.2 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz)
δ 139.3, 114.2, 68.3, 39.4, 33.9, 29.7, 29.65, 29.6, 29.5, 29.2, 29.0,
25.8, 23.6 ppm; IR (ATR) ν 3349 (br), 2925, 2854, 1641, 1465,
1373, 909 cm-1; HRMS (EI) m/z calcd for C13H26O (M+) 198.1984,
found 198.1980.
CHCl3); H NMR (CDCl3, 500 MHz) δ 6.88 (dd, J ) 15.7, 6.8
Hz, 1H), 6.12 (d, J ) 15.7 Hz, 1H), 5.03 (m, 1H), 4.13 (t, J ) 7.5
Hz, 1H), 3.75 (m, 1H), 1.80 (m, 1H), 1.63 (m, 2H), 1.35-1.50 (m,
2H) 1.43 (s, 3H), 1.42 (s, 3H), 1.15-1.35 (m, 13H), 1.25 (d, J )
6.3 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz) δ 165.6, 144.4,
123.7, 109.3, 80.9, 80.2, 71.2, 35.4, 31.1, 27.9, 27.4, 27.37, 27.3,
27.1, 26.7, 26.6, 24.9, 23.4, 20.6 ppm; IR (ATR) ν 2986, 2929,
6-[(E,R)-12-Hydroxy-tridec-1-enyl]-2,2-dimethyl-[1,3]dioxin-
4-one (15). A solution of 16 (100 mg, 0.5 mmol), 2 (116 mg, 0.75
mmol), and catalyst 11 (16 mg, 0.025 mmol) in dry CH2Cl2 (5
mL) under nitrogen was stirred at 40 °C for 24 h. Evaporation of
the solvent and purification by flash chromatography (SiO2; 5%
AcMe/CH2Cl2) afforded 142 mg (88%) of 15 as a light brown
2858, 1709, 1661, 1458, 1369, 1257, 1182, 1055, 990, 862 cm-1
;
HRMS (EI) m/z calcd for C19H32O4 (M+) 324.2301, found 324.2297.
(E,6S,16R)-6-Hydroxy-16-methyl-oxacyclohexadec-3-en-2,5-
dione (17). To a stirred solution of 13 (25 mg, 0.077 mmol) in
MeCN/H2O (2:1, 0.9 mL) was added TFA (0.6 mL) dropwise at 0
°C. The mixture was allowed to warm to room temperature over 1
h, diluted with CH2Cl2 (60 mL), and washed with a saturated
NaHCO3 solution (30 mL). Drying of the organic phase (Na2SO4)
viscous oil: Rf ) 0.16 (5% AcMe/CH2Cl2); [R]20 ) -4.2 (c )
D
1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 6.55 (dt, J ) 15.5, 7.0
Hz, 1H), 5.88 (d, J ) 15.5 Hz, 1H), 5.23 (s, 1H), 3.78 (m, 1H),
2024 J. Org. Chem., Vol. 71, No. 5, 2006

Facile Entry to Macrolide Antibiotic (-)-A26771B
and evaporation of the solvent gave a yellow solid that was
dissolved in dry CH2Cl2 (3 mL) and treated with pTsOH (29 mg,
0.15 mmol) and TEMPO (24 mg, 0.15 mmol) at 0 °C. After being
stirred for 5 h at room temperature the solvent was evaporated,
and the resulting residue was purified by flash chromatography
(SiO2; MTB/hexane ) 1:4). Recrystallization from hexane afforded
Evaporation of the solvent and purification by flash chromatography
(SiO2; 5% MeOH/CH2Cl2) afforded 5 mg (74%) of 5 as a white
solid: Rf ) 0.21 (5% MeOH/CH2Cl2); mp 121-122 °C; [R]20
)
D
-13.2 (c ) 0.19, MeOH); 1H NMR (CDCl3, 500 MHz) δ 7.22 (d,
J ) 15.8, 1H), 6.75 (d, J ) 15.8 Hz, 1H), 5.32 (t, J ) 5.4 Hz, 1H),
5.14 (m, 1H), 2.73 (m, 4H), 1.90 (m, 2H), 1.68 (m, 1H), 1.55 (m,
1H) 1.10-1.50 (m, 15H), 1.30 (d, J ) 6.3 Hz, 3H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 195.5, 176.2, 171.5, 164.9, 135.3, 132.6, 78.0,
72.6, 34.6, 28.9, 28.7, 28.6, 28.0, 27.9, 27.3, 27.1, 27.0, 23.6, 22.3,
19.9 ppm; IR (ATR) ν 2928, 2857, 1742, 1703, 1381, 1300, 1196,
1165 cm-1; MS (FAB) m/z calcd for C20H31O7 (MH+) 383, found
383.
13 mg (60%) of 17 as a white solid: Rf ) 0.11 (MTB/hexane )
1
1:4); mp 84-85 °C; [R]20 ) +22.4 (c ) 1.0, CHCl3); H NMR
D
(CDCl3, 500 MHz) δ 7.25 (d, J ) 15.7, 1H), 6.79 (d, J ) 15.7 Hz,
1H), 5.18 (m, 1H), 4.54 (m, 1H), 3.45 (br. s, 1H), 1.85 (m, 2H),
1.73 (m, 1H), 1.52 (m, 3H) 1.05-1.45 (m, 14H), 1.30 (d, J ) 6.2
Hz, 3H), 0.98 (m, 1H) ppm; 13C NMR (CDCl3, 125 MHz) δ 201.5,
165.1, 135.0, 132.6, 76.5, 72.7, 34.3, 31.2, 28.2, 28.1, 27.4, 27.1,
26.9, 23.5, 20.7, 19.7 ppm; IR (ATR) ν 3490 (br), 2928, 2856,
1714, 1697, 1642, 1460, 1354, 1287, 1191, 1059, 983 cm-1; HRMS
(EI) m/z calcd for C16H27O4 (MH+) 283.1909, found 283.1914.
Mono[(E,6S,16R)-16-methyl-2,5-dioxooxacyclohexadec-3-en-
6-yl]succinate (A26771B) (5). A solution of 17 (5 mg, 17.7 µmol),
succinic anhydride (3.5 mg, 35 µmol), and DMAP (2.4 mg, 20
µmol) in CH2Cl2 (0.3 mL) was stirred for 24 h at room temperature.
Supporting Information Available: General experimental
details and characterization data for the products from Table 1
1
and H NMR spectra for the compounds 2, 5, 10, and 13-17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052421A
J. Org. Chem, Vol. 71, No. 5, 2006 2025