Alkyne-assisted approach to the formal synthesis of antibiotic macrolide (-)-A26771B

Article abstract of DOI:10.1055/s-0031-1290130

A stereoselective formal synthesis of a 16-membered antibiotic macrolide (-)-A26771B is described starting from (R)-propylene oxide and (+)-diethyl tartrate. Key steps involved in this alkyne-assisted convergent approach are alkyne zipper reaction, Cadiot

Full text of DOI:10.1055/s-0031-1290130

272
LETTER
Alkyne-Assisted Approach to the Formal Synthesis of Antibiotic Macrolide
(–)-A26771B
F
ormal Synthesis
h
of
A
ntibioti
a
c
Macrolide
d
(–)-A26771
a
B
Raji Reddy,* Devatha Suman, Nagavaram Narsimha Rao
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: rajireddy@iict.res.in
Received 24 October 2011
tionality in 6 was shifted to the terminal position by the
Abstract: A stereoselective formal synthesis of a 16-membered an-
tibiotic macrolide (–)-A26771B is described starting from (R)-pro-
pylene oxide and (+)-diethyl tartrate. Key steps involved in this
alkyne-assisted convergent approach are alkyne zipper reaction,
Cadiot–Chodkiewicz coupling, and Yamaguchi macrolactoniza-
tion.
treatment of 6 under alkyne zipper reaction conditions
(KH, 1,3-diamino propane) to obtain compound 4 in 81%
yield.4
O
Key words: alkyne, macrolide, zipper reaction, Cadiot–Chod-
kiewicz reaction, Yamaguchi macrolactonization
O
O
1
O
(–)-A26771B (1, Figure 1) is a 16-membered macrocyclic
lactone, which was isolated from Pencillium turbatum in
1977.1 This macrolide was found to be moderately active
against Gram-positive bacteria, mycoplasma, and fungi.
Structurally it possesses a g-oxo-d-acyloxy-a,b-unsaturat-
ed carboxyl functionality and two asymmetric centers.
The interesting structural features as well as biological ac-
tivity of (–)- A26771B have made it as an attractive target
to the synthetic community, and various strategies have
been developed either in enantiomeric or in racemic ap-
proach.2 Our interest in alkyne-based chemistry towards
synthesis of macrolides3 prompted us to attempt the syn-
thesis of (–)-A26771B. Described herein is a different ap-
proach to the formal synthesis of (–)-A26771B, featuring
a zipper reaction, and Cadiot–Chodkiewicz coupling fol-
lowed by Yamaguchi macrocyclization as the key steps.
This alkyne-based convergent route is envisaged to link
the two fragments 4 and 5 at C7–C8 bond towards 3,
which can be transformed into 2 via Yamaguchi macro-
lactonization (Scheme 1).
2
OH
O
OH
3
O
O
OH
+
OBn
Br
O
4
5
Scheme 1 Retrosynthetic analysis of 1
OH
a
b
O
4
6
Scheme 2 Reagents and conditions: (a) 1-hexyne, n-BuLi, THF,
HMPA, –40 °C to 0 °C to –20 °C, 8 h, 84%; (b) KH, 1,3-diaminopro-
pane, r.t., 6 h, 81%.
O
O
O
O
1
Next, the synthesis of the chiral C5 hydroxy subunit began
from (+)-diethyl tartrate (Scheme 3) which was trans-
formed into alcohol 7 in three steps using a literature pro-
cedure.5 Conversion of alcohol 7 into alkyne 9 took place
smoothly via Parikh–Doering oxidation conditions
(SO3·py, DMSO, Et3N)6 to aldehyde and subsequent treat-
ment with Ohira–Bestmann reagent 8 under K2CO3/
MeOH.7 The terminal alkyne functionality in 9 was then
transformed into alkynyl bromide 5 by the reaction with
NBS/AgNO3 in acetone.8
O
7
15
CO2H
8
1
Figure 1 Structure of (–)-A26771B (1)
As shown in Scheme 2, alkynol 4 was obtained from (R)-
propylene oxide, which was subjected to epoxide-opening
reaction with 1-hexyne and n-BuLi–HMPA in THF to
provide alcohol 6 in 84% yield. The internal alkyne func-
With the required fragments 4 and 5 in hand, our antici-
pated plan was to use Cadiot–Chodkiewicz coupling reac-
tion to couple these two units.9 Thus, the reaction of
alkyne 4 with alkynyl bromide 5 in the presence of CuCl
(2 mol%), NH2OH×HCl, 30% n-BuNH2 in H2O provided
SYNLETT 2012, 23, 272–274
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290130; Art ID: B59011ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

LETTER
Formal Synthesis of Antibiotic Macrolide (–)-A26771B
273
O
O
O
a
b
c
HO
5
OBn
O
OBn
OBn
O
OH
O
O
O
7
9
10
OH
O
OH
O
d
e
f
3
OEt
OH
O
O
11
12
O
O
O
P
O
O
OMe
OMe
g
ref. 2a,2g
1
O
N2
8
2
Scheme 3 Reagents and conditions: (a) (i) SO3·py, DMSO, Et3N, CH2Cl2, 0 °C, 1 h; (ii) 8, K2CO3, MeOH, r.t., 12 h, 89%; (b) NBS, AgNO3,
acetone, 0 °C to r.t., 30 min, 93%; (c) 4, n-BuNH2, NH2OH·HCl, CuCl, 0 °C to r.t., 1 h, 78%; (d) H2, 10% Pd/C, EtOH, r.t., 36 h, 84%; (e)
TEMPO, BAIB, PPh3=CHCO2Et, CH2Cl2, r.t. to 0 °C to r.t., 3 h, 78%; (f) LiOH, THF–H2O (1:1), r.t., 12 h, 99%; (g) 2,4,6-trichlorobenzoyl
chloride, Et3N, 0 °C, 2 h, DMAP, toluene, 100 °C, 12 h, 87%.
612. (d) Nagarajan, M. Tetrahedron Lett. 1999, 40, 1207.
(e) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J. Org. Chem.
1993, 58, 7789. (f) Quinkert, G.; Kueber, F.; Knauf, W.;
Wacker, M.; Koch, U.; Becker, H.; Nestler, H. P.; Durner,
G.; Zimmermann, G.; Bats, J. W.; Egert, E. Helv. Chim. Acta
1991, 74, 1853. (g) Tatsuta, K.; Amemiya, Y.; Kanemura,
Y.; Kinoshita, M. Bull. Chem. Soc. Jpn. 1982, 55, 3248.
For racemic synthesis, see: (h) Trost, B. M.; Brickner, S. J.
J. Am. Chem. Soc. 1983, 105, 568. (i) Fujisawa, T.; Okada,
N.; Takeuchi, M.; Sato, T. Chem. Lett. 1983, 1271.
(j) Asaoka, M.; Abe, M.; Mukuta, T.; Takei, H. Chem. Lett.
1982, 215. (k) Asaoka, M.; Yanagida, N.; Takei, H.
Tetrahedron Lett. 1980, 21, 4611.
the coupled product 10 in 78% yield. Diyne 10 underwent
clean saturation under standard hydrogenation conditions
(H2, 10% Pd/C in EtOH) to afford diol 3 in 84% yield.
Selective oxidation of primary hydroxyl group of 3 to
aldehyde (BAIB/TEMPO) and subsequent one-pot Wittig
olefination with
a
stable two-carbon ylide
(Ph3P=CHCO2Et) provided the a,b-unsaturated ester 11
in 78% yield.10 The ester was then hydrolyzed under
LiOH conditions, and the resulting hydroxy acid 12 was
subjected to Yamaguchi macrolactonization11 to get the
desired macrolactone 2 in 87% yield (Scheme 3).12 This
macrolactone has previously been used to accomplish the
synthesis of (–)-A26771B.2a,g
(3) (a) Reddy, Ch. R.; Rao, N. N. Tetrahedron Lett. 2009, 50,
2478. (b) Reddy, Ch. R.; Srikanth, B. Synlett 2010, 1536.
(4) (a) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97,
891. (b) Kimmel, T.; Becker, D. J. Org. Chem. 1984, 49,
2494.
(5) Horvath, A.; Benner, J.; Backvall, J.-E. Eur. J. Org. Chem.
2004, 3240.
(6) Parikh, J. R.; Doering, W. v. E. v. E. J. Am. Chem. Soc. 1967,
89, 5505.
(7) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Roth, G. J.;
Liepold, B.; Müller, S. G.; Bestmann, H. J. Synlett 1996,
521. (c) Roth, G. J.; Bernd, L.; Müller, S. G.; Bestmann,
H. J. Synthesis 2004, 59.
In conclusion, this convergent formal synthesis of (–)-
A26771B is achieved in seven steps in the longest linear
sequence from the (R)-propylene oxide with 29.9% over-
all yield. This approach relies on the use of two alkyne
fragments, which were easily obtained from (R)-propy-
lene oxide and (+)-diethyl tartrate. The present route pro-
vides a useful showcase of alkyne-assisted strategy
through zipper reaction, Cadiot–Chodkiewicz coupling,
and Yamaguchi macrolactonization in the synthesis of
macrolides.
(8) Hofmeister, H.; Annen, K.; Laurent, H.; Weichert, R.
Angew. Chem., Int. Ed. Engl. 1984, 23, 727.
(9) (a) Chodkiewicz, W. Ann. Chim. Paris 1957, 2, 819.
(b) Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes;
Viehe, H. G., Ed.; Marcel Dekker: New York, 1969, 597.
(10) Vatele, J.-M. Tetrahedron Lett. 2006, 47, 715.
(11) Inanaga, J.; Hirata, K.; Sacki, H.; Hatsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
Acknowledgment
D.S. and N.N.R. thank Council of Scientific and Industrial
Research, New Delhi for the award of research fellowship.
(12) Spectral Data of Representative New Compounds
References and Notes
Compound 9: [a]D20 –24.8 (c 1.0, CHCl3). IR (KBr): nmax
2989, 2933, 2864, 2121, 1726, 1635, 1454, 1376, 1241,
1214, 1086, 852, 740, 398 cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.30–7.27 (m, 5 H), 4.59 (s, 2 H), 4.49 (dd,
=
(1) Michel, K. H.; Demoarco, P. V.; Nagarajan, R. J. Antibiot.
1977, 30, 571.
(2) For enantioselective synthesis, see: (a) Gebauer, J.;
Blechert, S. J. Org. Chem. 2006, 71, 2021. (b) Lee, W.;
Shin, H. J.; Chang, S. Tetrahedron: Asymmetry 2001, 12,
29. (c) Kobayashi, Y.; Okui, H. J. Org. Chem. 2000, 65,
J = 2.2, 6.8 Hz, 1 H), 4.25–4.18 (m, 1 H), 3.60 (d, J = 4.5 Hz,
2 H), 2.44 (d, J = 2.2 Hz, 1 H), 1.48 (s, 3 H), 1.41 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 137.5, 128.3, 127.7, 127.6,
110.8, 80.8, 80.6, 74.6, 73.5, 68.9, 67.1, 26.8, 26.0. ESI-
© Thieme Stuttgart · New York
Synlett 2012, 23, 272–274

274
C. Raji Reddy et al.
LETTER
HRMS: m/z calcd for C15H18O3Na [M + Na]+: 269.1153;
found: 269.1146.
MHz, CDCl3): d = 108.4, 81.5, 76.9, 68.0, 62.0, 39.2, 33.0,
29.55, 29.51, 29.4, 29.3, 27.2, 26.9, 25.8, 25.6, 23.3. ESI-
HRMS: m/z calcd for C17H34O4Na [M + Na]+: 325.2354;
found: 325.2363.
Compound 5: [a]D20 –43.0 (c 1.0, CHCl3). IR (KBr): nmax
=
2988, 2926, 2214, 1722, 1626, 1376, 1217, 1081, 1022, 851,
742, 700 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.34–7.27
(m, 5 H), 4.59 (s, 2 H), 4.53 (d, J = 7.5 Hz, 1 H), 4.35–4.18
(m, 1 H), 3.59 (d, J = 4.5 Hz, 2 H), 1.48 (s, 3 H), 1.41 (s, 3
H). 13C NMR (75 MHz, CDCl3): d = 137.6, 128.3, 127.6,
127.5, 110.8, 80.4, 76.9, 73.4, 68.9, 68.0, 47.1, 26.8, 26.0.
ESI-MS: m/z = 347 [M + Na]+.
Compound 11: [a]D20 –10.3 (c 1.6, CHCl3). IR (KBr): nmax
=
3452, 2938, 2855, 1722, 1655, 1373, 1300, 1260, 1169,
1042, 771, 555 cm–1. 1H NMR (300 MHz, CDCl3): d = 6.83
(dd, J = 5.0, 15.0 Hz, 1 H), 6.08 (d, J = 15.0 Hz, 1 H), 4.21
(q, J = 7.0 Hz, 2 H), 4.11 (t, J = 7.0 Hz, 1 H), 3.80–3.73 (m,
1 H), 3.69 (q, J = 7.0 Hz, 1 H), 1.61–1.54 (m, 2 H), 1.51–
1.22 (m, 16 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.31 (t, J = 7.0
Hz, 3 H), 1.18 (d, J = 6.0 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 166.0, 144.1, 122.5, 109.2, 80.5, 80.1, 68.0,
60.5, 39.2, 32.0, 29.5, 29.4, 29.3, 27.2, 26.5, 25.8, 25.6, 23.4,
14.1. ESI-HRMS: m/z calcd for C21H38O5Na [M + Na]+:
393.2616; found: 393.2627.
Compound 10: [a]D20 –59.9 (c 1.0, CHCl3). IR (KBr): nmax
3426, 2932, 2861, 2254, 1718, 1633, 1454, 1375, 1219,
1087, 1035, 851, 741, 699 cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.35–7.26 (m, 5 H), 4.57 (s, 2 H), 4.55 (d,
J = 6.8 Hz, 1 H), 4.25–4.18 (m, 1 H), 3.80–3.71 (m, 1 H),
=
3.58 (d, J = 4.5 Hz, 2 H), 2.29 (t, J = 6.8 Hz, 2 H), 1.60–1.36
(m, 8 H), 1.47 (s, 3 H), 1.40 (s, 3 H), 1.17 (d, J = 6.0 Hz, 3
H). 13C NMR (75 MHz, CDCl3): d = 137.6, 128.2, 127.5,
127.4, 110.7, 81.9, 80.5, 73.3, 72.0, 71.3, 68.9, 67.6, 67.6,
64.3, 38.8, 28.5, 27.8, 26.7, 25.9, 24.9, 23.2, 18.9. ESI-MS:
m/z = 407 [M + Na]+.
Compound 2: [a]D20 +5.6 (c 0.78, CHCl3). IR (KBr): nmax
=
2928, 2856, 1715, 1458, 1374, 1257, 1177, 1055, 987, 862
cm–1. 1H NMR (300 MHz, CDCl3): d = 6.88 (dd, J = 7.0,
16.0 Hz, 1 H), 6.12 (d, J = 16.0 Hz, 1 H), 5.07–4.99 (m, 1 H),
4.13 (t, J = 7.0 Hz, 1 H), 3.78–3.72 (m, 1 H), 1.86–1.77 (m,
1 H), 1.69–1.58 (m, 2 H), 1.53–1.41 (m, 2 H), 1.43 (s, 3 H),
1.42 (s, 3 H), 1.35–1.18 (m, 13 H), 1.26 (d, J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.5, 144.3, 123.6, 109.2,
80.7, 80.0, 71.1, 35.2, 31.0, 27.8, 27.2, 27.1, 26.9, 26.5, 26.4,
24.7, 23.3, 20.5. ESI-HRMS: m/z calcd for C19H32O4Na
[M + Na]+: 347.2198; found: 347.2206.
Compound 3: [a]D20 –20.7 (c 1.0, CHCl3). IR (KBr): nmax
=
3413, 2926, 2856, 1631, 1455, 1374, 1220, 1049, 851, 763
cm–1. 1H NMR (300 MHz, CDCl3): d = 3.85–3.80 (m, 1 H),
3.74 (dd, J = 3.0, 12.0 Hz, 2 H), 3.68–3.63 (m, 1 H), 3.54
(dd, J = 4.0, 12.0 Hz, 1 H),1.56–1.25 (m, 18 H), 1.38 (s, 3
H), 1.37 (s, 3 H), 1.17 (d, J = 6.0 Hz, 3 H). 13C NMR (75
Synlett 2012, 23, 272–274
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