New synthetic methodology toward macrolides/macrolactams via palladium-catalyzed carbon-heteroatom bond-forming reactions

Article abstract of DOI:10.1055/s-0030-1260812

A concise and versatile syntheses of 11-16-membered macrolides and 13-15-membered macrolactams have been achieved using a Tsuji-Trost type reaction. This approach is composed of intramolecular cyclization employing ethyl carbonate with carboxylic acids and catalytic amount of Pd(PPh ₃)₄ to form carbon-heteroatom covalent bonds with no use of stoichiometric reagents. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260812

1766
LETTER
New Synthetic Methodology toward Macrolides/Macrolactams via Palladium-
Catalyzed Carbon–Heteroatom Bond-Forming Reactions
P
alladium-Cata
e
lyze
d
Macr
t
olacton
s
ization/M
u
acrolactamiz
y
ation a Sengoku,a Tomoya Hamamatsu,a Toshiyasu Inuzuka,b Masaki Takahashi,a Hidemi Yoda*a
a
Department of Materials Science, Faculty of Engineering, Shizuoka University,
3-5-1 Johoku, Naka-ku, Hamamatsu, Shizuoka 432-8561, Japan
Fax +81(53)4781150; E-mail: tchyoda@ipc.shizuoka.ac.jp
b
Division of Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Received 31 March 2011
efficient and general method for constructing 11–16-
membered macrolides with Pd(0) catalyst and further ex-
tension of this method to the synthesis of 13–15-mem-
bered macrolactams. For the purpose of the construction
Abstract: A concise and versatile syntheses of 11–16-membered
macrolides and 13–15-membered macrolactams have been
achieved using a Tsuji–Trost type reaction. This approach is com-
posed of intramolecular cyclization employing ethyl carbonate with
carboxylic acids and catalytic amount of Pd(PPh3)4 to form carbon– of macrocycles, we use ethyl carbonate as the leaving
heteroatom covalent bonds with no use of stoichiometric reagents.
group, because cleavage of the allylic carbon–oxygen
bond in allylic carbonate would provide p-allylpalladium
intermediate, readily giving rise to cyclization under base-
free conditions (Scheme 1).
Key words: macrolactones, macrolactams, palladium-catalyzed
reaction, carbon–heteroatom bond formation
O
O
O
Macrocyclic lactones, so-called macrolides, are important
molecules in biological and medicinal chemistries, be-
cause they often show notable bioactivities as represented
by erythromycins1 and epothilones.2 In addition, their in-
triguing structures have also attracted considerable atten-
tion from the synthetic community, and numerous efforts
have been devoted to synthesize macrolides and their
derivatives.3 The conventional synthetic approaches
constructing macrolides involve carbon–oxygen bond for-
mation by the use of condensing agents such as bis(4-
pyridyl)disulphide (PySSPy),4 2,4,6-trichlorobenzoyl
chloride,5 and 2-methyl-6-nitrobenzoic anhydride (NMBA).6
Although they have been also used for the synthesis of
macrocyclic natural products, it is indispensable to use
stoichiometric reagents for achievement of macrolacton-
ization.
NuH
OCO2Et
Nu
Nu
Pd(0)
Pd
EtOH, CO2
Nu = O, NH
Scheme 1
OTBS
OR1
a
n
n
CHO
OR2
1a–f
R1 = TBS, R2 = H: 2a (49%), 2b (73%)
2c (81%), 2d (71%)
b
2e (96%), 2f (88%)
R1 = H, R2 = CO2Et: 3a (98%), 3b (92%)
3c (94%), 3d (95%)
3e (87%), 3f (83%)
Thus, along these lines the development of a variety of the
stoichiometric macrolactonization has been accompanied
up to date,3a however, catalytic reactions for the construc-
tion of macrolides have not so far been established. Re-
cently, White and co-workers have reported an example
of macrolactonization employing catalytic Pd(OAc)2/BQ
a-olefin allylic oxidation system, expanding the utility of
transition-metal-catalyzed reaction for macrocyclic car-
bon–oxygen bond formation.7 Considering that the reac-
tion proceeds via a Pd-templated p-allyl carboxylate
intermediate, intramolecular Tsuji–Trost-type reaction
with carboxylic acids bearing allylic leaving groups
would be expected to afford macrolides. To the best of our
knowledge, only one example of this type of reaction has
been reported by Trost in his review, and the catalytic syn-
thesis remained undeveloped.8 In this paper, we report an
c
n
CO2H
OCO2Et
4a (45%), 4b (47%), 4c (59%)
4d (57%), 4e (57%), 4f (45%)
CO2H
d
b, c
OTBS
1c
OH
5 (74%)
OCO2Et
6 (22%)
Scheme 2 Reagents and conditions: a n = 1, b n = 2, c n = 3, d
n = 4, e n = 5, f n = 6: (a) (i) (EtO)2P(O)CH2CO2Et, KOt-Bu, THF,
–78 °C; (ii) DIBAL-H, CH2Cl2, –78 °C; (b) (i) ethyl chlorocarbonate,
pyridine; (ii) PPTS, EtOH; (c) (i) PDC, MS 4 Å, CH2Cl2; (ii) NaClO2,
NaH2PO4·2H2O, 2-methyl-2-butene, t-BuOH; (d) vinylmagnesium
chloride, THF, 0 °C.
SYNLETT 2011, No. 12, pp 1766–1768
Advanced online publication: 29.06.2011
DOI: 10.1055/s-0030-1260812; Art ID: U03111ST
x
x
.x
x
.2
0
1
1
The preparation of cyclization precursors 4a–f (n = 1–6)
are shown in Scheme 2. Linear aldehydes9 1a–f under-
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed Macrolactonization/Macrolactamization
1767
went Horner–Emmons reaction and DIBAL-H reduction with nearly complete control of regioselectivity (a/g >
to give E-allyl alcohols 2a–f, respectively. Allylic alcohol 97:3, Table 1, entries 2–4), whereas relatively mild regio-
moieties were then converted into corresponding allyl eth- selectivities were obtained for substrates 4e,f with a long-
yl carbonates followed by deprotection of TBS protecting er chain (Table 1, entries 5 and 6). The E/Z ratios of a-7b–
groups to afford 3a–f, respectively. The resulting primary d seem to be significantly influenced by the ring sizes, fa-
hydroxy groups were subsequently oxidized in a stepwise voring E-isomer. It is worth noting that 6, a regioisomeric
manner to give 4a–f.
substrate of 4c, gave macrolides 7c with the almost same
regio- and geometric isomer ratios as the use of 4c
(Table 1, entry 7; 55% yield, a/g = 99:1, E/Z = 86:14).
These results indicate that the reactions occurred accord-
ing to the same mechanism involving formation of the p-
allylpalladium intermediate, extrusion of CO2, and in-
tramolecular nucleophilic attack of the carboxylate.
Meanwhile, we also prepared regioisomeric ethyl carbon-
ate 6. Thus, addition of vinylmagnesium chloride to 1c
gave allyl alcohol 5 in 74% yield. This intermediate was
readily converted to 6c through the same sequence as used
for the synthesis of 4.
In an initial series of experiments, we examined the for-
mation of 13-membered macrolide a-7c upon treatment of
4c in the presence of palladium catalyst. After screening
the detailed reaction conditions using a variety of phos-
phine ligands and solvents, we found that the reaction us-
ing 20 mol% of Pd(PPh3)4 in a highly diluted CH2Cl2
solution (c 2.0 mM) at room temperature afforded the op-
timal result. Under these conditions, lactone a-7c was
formed in 51% yield as an E/Z mixture (83:17), while its
regioisomer g-7c was not at all formed from observation
Encouraged by this successful implementation of the Pd-
catalyzed macrocyclization of carboxylic acids 4, we
turned our attention to the synthesis of corresponding
nitrogen-containing heterocycles (Scheme 3, Table 2).
Although carboxylic acid 4c could be smoothly converted
to the corresponding amide 8c, subsequent attempts to
perform the Pd(PPh3)4-catalyzed macrocyclization unfor-
tunately resulted in decomposition of the starting material
(Table 2, entry 1). Alternatively, Boc- and Cbz-protected
amides 9c and 10c prepared from 8c12 were found to un-
dergo efficient macrocyclization in the presence of
Pd(PPh3)4 and KOt-Bu13 to give 13-membered lactams
12c and 13c with complete regioselectivities in favor of
the E-isomers (Table 2, entries 2 and 3). Furthermore,
9d,e also cyclized to yield 14- and 15-membered lactams
12d,e with high regioselectivities, respectively (Table 2,
entries 4 and 5).
1
of its H NMR spectroscopy (Table 1, entry 3).10 Com-
pounds 4b,d–f also efficiently underwent the macrolac-
tonization to generate 7b,d–f in moderate to good yields,
respectively (Table 1, entries 2, 4–6) with the exception
that the use of 4a (n = 1) resulted in a low-yield formation
of desired a-7a with a substantial amount of byproducts
(Table 1, entry 1).11 As a consequence, 7b–d were given
Table 1 Pd(0)-Catalyzed Macrolactonization
O
n
CO2H
OCO2Et
n CONHR
OCO2Et
a
O
n
4c–e
R = H: 8c (58%)
8d (69%)
8e (65%)
b
Pd(PPh3)4
(20 mol%)
α-7
c
R = Boc: 9c (75%)
9d (57%)
n
CO2H
+
CH2Cl2 (2 mM)
9e (75%)
OCO2Et
O
r.t., 20 h
R = Cbz: 10c (71%)
4a–f
O
n
O
O
Pd(PPh3)4 (20 mol%)
t-BuOK (1.0 equiv)
γ-7
THF (2 mM), reflux, 7 h
NR
NR
Entry
Substrate
4a n = 1
4b n = 2
4c n = 3
4d n = 4
4e n = 5
4f n = 6
6
Yield (%)a
7a 6
a/gb
E/Zb
n
n
+
see Table 2
c
1
2
3
4
5
6
7
100:0
97:3
–
γ-11 R = H
γ-12 R = Boc
γ-13 R = Cbz
α-11 R = H
7b 31
7c 51
7d 70
7e 64
7f 73
64:36
α-12 R = Boc
α-13 R = Cbz
100:0
99:1
83:17
100:0
Scheme 3 Reagents and conditions: c; n = 3, d; n = 4, e; n = 5: (a)
(i) DCC, HOSu, Et3N, CH2Cl2; (ii) HCO2NH4, Et3N, 1,4-dioxane; (b)
(COCl)2, ClCH2CH2Cl, reflux, then t-BuOH, 0 °C; (b) (COCl)2,
ClCH2CH2Cl, reflux, then BnOH, 0 °C.
c
86:14
67:33
99:1
–
c
–
In summary, we demonstrated the new synthetic method-
ology for catalytic macrocyclizations associated with car-
bon–oxygen and carbon–nitrogen bond formations.
Compared to the conventional macrolactonizations, this
7c 55
86:14
a Isolated and combined yields.
b Ratios were determined by 1H NMR analysis (300 MHz, CDCl3).
c E/Z ratios could not be determined.
Synlett 2011, No. 12, 1766–1768 © Thieme Stuttgart · New York

1768
T. Sengoku et al.
LETTER
(4) (a) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96,
5614. (b) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S. J. Am.
Chem. Soc. 1975, 97, 653.
Table 2 Pd(0)-Catalyzed Macrolactamization
Entry
Substrate
Yield (%)a
11c 0
a/gb
–
E/Zb
–
(5) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
1
2
3
4
5
8c
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(6) (a) Shiina, I.; Ibuka, R.; Kubota, M. Chem. Lett. 2002, 31,
286. (b) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett.
2002, 43, 7535.
(7) (a) Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White,
M. C. J. Am. Chem. Soc. 2006, 128, 9032. (b) Stang, E. M.;
White, M. C. Nat. Chem. 2009, 1, 547.
(8) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173.
(9) (a) Liu, L.; Floreancig, P. E. Org. Lett. 2009, 11, 3152.
(b) Kim, S.; Adiyaman, Y.; Saha, G.; Powell, W. S.; Rokach,
J. Tetrahedron Lett. 2001, 42, 4445. (c) Nagano, H.; Tada,
A.; Isobe, Y.; Yajima, T. Synlett 2000, 1193. (d) Makado,
G.; Morimoto, T.; Sugimoto, Y.; Tsutsumi, K.; Kagawa, N.;
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Soll, C. E.; Chavadi, S. S.; Quadri, L. E. N. J. Am. Chem.
Soc. 2009, 131, 16744.
(10) We observed that the reaction with the isolated single (E)-a-
7c under the same reaction conditions afforded a 90:10
mixture of E/Z-isomers without production of g-7c
(Scheme 4).
9c
12c 68
13c 68
12d 67
12e 34
100:0
100:0
99:1
95:5
84:16
87:13
83:17
73:27
10c
9d
9e
a Isolated and combined yields.
b Ratios were determined by 1H NMR analysis (300 MHz, CDCl3).
approach is advantageous in that only easily removable al-
cohols and CO2 were formed as side products during the
course of the reactions. The success of this diverse and ef-
ficient macrocyclization could show broader applicability
of this methodology to the synthesis of macrocyclic natu-
ral products, and, in addition, represents the first example
of Pd-catalyzed macrolactamization to generate 13–15-
membered lactams.
O
O
O
O
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Pd(PPh3)4 (20 mol%)
CH2Cl2 (2 mM)
r.t., 20 h
Acknowledgment
(E)-α-7c
(E,Z)-α-7c
(E/Z = 90:10)
(E/Z = 100:0)
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Scheme 4
(11) This would be attributed to the strain based on the ring size.
(12) Leonard, N. J.; Cruickshank, K. A. J. Org. Chem. 1985, 50,
2480.
(13) The macrolactamization of 9c in the absence of KOt-Bu
resulted in a-12c in 44% yield (Scheme 5).
References and Notes
(1) (a) Vester, B.; Douthwaite, S. Antimicrob. Agents
Chemother. 2001, 45, 1. (b) Schlunzen, F.; Zarivach, R.;
Harms, J.; Bashan, A.; Tocilj, A.; Albrecht, R.; Yonath, A.;
Franceschi, F. Nature (London) 2001, 413, 814. (c)Hansen,
J. L.; Ippolito, J. A.; Ban, N.; Nissen, P.; Moore, P. B.; Steitz,
T. A. Mol. Cells 2002, 10, 117.
O
NBoc
(2) (a) Gerth, K.; Bedorf, N.; Hofle, G.; Irschik, H.;
Reichenbach, H. J. Antibiot. 1996, 49, 560. (b) Hofle, G.;
Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35,
1567; Angew. Chem. 1996, 108, 1671.
(3) For recent reviews, see: (a) Parenty, A.; Moreau, X.;
Campagne, J.-M. Chem. Rev. 2006, 106, 911. (b) Yeung,
K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237.
Pd(PPh3)4 (20 mol%)
CONHBoc
THF (2 mM)
reflux, 7 h
OCO2Et
9c
α-12c
(44%, E/Z = 85:15)
Scheme 5
Synlett 2011, No. 12, 1766–1768 © Thieme Stuttgart · New York

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