Synthesis of macrocyclic dilactones through lipases

Article abstract of DOI:10.1055/s-2005-917099

We report herein a selective and efficient method to prepare macrocyclic dilactones in good yields from diols and succinic anhydride through a biocatalytic condensation reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917099

LETTER
2611
Synthesis of Macrocyclic Dilactones through Lipases
S
ynthesis of Macrocyc
ª
lic
D
ilactone
P
throughLipa
i
se
s
lar Bosch,* Angel Guerrero*
Department of Biological Organic Chemistry, IIQAB (CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
Fax +34(93)2045904; E-mail: pbvqob@iiqab.csic.es; E-mail: agpqob@iiqab.csic.es
Received 7 July 2005
with lipase P (Pseudomonas sp.) to provide pheromone
components of grain beetles12 or a key intermediate for the
synthesis of the anti-obesity agent tetrahydrolipstatin with
PPL has been described.13
Abstract: We report herein a selective and efficient method to pre-
pare macrocyclic dilactones in good yields from diols and succinic
anhydride through a biocatalytic condensation reaction.
Key words: Candida antarctica B, macrocyclic dilactones, lipases,
synthesis, biocatalysis
Initially, we tested the reaction of 1,6-hexanediol and suc-
cinic anhydride in the presence of several lipases (PS, AP-
6, Mucor miehei, Candida rugosa, CALB and Pseudomo-
nas fluorescens) in a number of solvents and under differ-
ent experimental conditions.
The synthetically challenging structures of macrolides
have attracted the attention of organic chemists for a long
time but only recently have efforts in this direction begun
to gain momentum.1 Particularly attractive are macrocy-
clic dilactones, not only because of their remarkable bio-
logical activities but also because of their ability to
complex and transport alkali metal cations and their utili-
zation in the perfume industry.2 However, only a limited
number of methods for preparation of macrocyclic dilac-
tones are currently available. They comprise the reaction
of the dicesium salts of pyridindicarboxylic acids with di-
bromides,3 reaction of dioxodioic acid chlorides with oli-
goethylene glycols,4 condensation of the dipotassium salt
of maleic, citraconic and o-phthalic acids with alkyl or
alkynyl dibromides,5 condensation of benzyl bromides
with homologous series of dicarboxylic acids,6 reaction of
substituted dicarboxylic acid chlorides with w-bromoal-
cohols followed by reaction with lithium or potassium
salts of dicarboxyxlic acids,7 condensation of diacid chlo-
rides with diols using metal carbonates and KF as bases
under phase-transfer catalysis,8 or via cyclization of (w-
carboxyalkyl)diphenylsulfonium salts in the presence of
cesium carbonate under high dilution conditions.9 How-
ever, many of these methods provide mixtures of dilac-
tones and tetralactones, in some cases in low yields and
under harsh reaction conditions. Only one case has been
found in the literature in which macrocyclic lactones are
prepared enzymatically by reaction of acyclic diacids with
diols in the presence of C. cylindracea, Pseudomonas sp.
and porcine pancreatic lipase.10 However, even in this
case mixtures of mono- and dilactones were obtained in
moderate yields, the dilactones being produced in the
range of 5–19% yield.
Scheme 1 Enzymatic reaction of diol 1d with succinic anhydride 2
The reaction resulted in a mixture of variable amounts of
starting diol 1d, hydroxyacid 3d, dilactone 4d and diacid
5d14 (Scheme 1) by GC analysis after esterification with
MeI/K2CO3.15 Under these conditions, compounds 3d and
5d are converted into 6d and 7d, respectively (Table 1).
In this paper we present a simple and high yielding meth-
od to selectively prepare macrocyclic dilactones by reac-
tion of 1,n-diols with succinic anhydride11 in the presence
of Candida Antarctica B lipase (CALB, Novozyme 435).
Intramolecular lactonization of long chain hydroxyesters
Among the lipases tested, AP-6, C. rugosa and P. fluore-
scens were completely unable to produce dilactones 4d,
but lipase PS (entry 2), M. miehei (entry 11) and especial-
ly CALB (entries 13–18) afforded variable amounts of the
dilactones, the latter with every solvent used (toluene,
methyl tert-butyl ether, diethyl ether and acetone). The
SYNLETT 2005, No. 17, pp 2611–2614
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917099; Art ID: D18805ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.1
0
.2
0
0
5

2612
M. P. Bosch, A. Guerrero
LETTER
Table 1 Lipase-Catalyzed Reaction of 1,6-Hexanediol (1d) with Succinic Anhydride (2)
Entry
1
Lipase
PS
Solvent
C6H5CH3
MTBE
C6H5CH3
C6H5CH3
MTBE
MTBE
Et2O
Time (h)
70
70
70
24
120
24
24
24
48
24
7
Temp (°C)
30
1da
23
14
10
39
100
100
34
9
6da
45
39
30
46
–
7da
31
35
60
15
–
4da
–
2
PS
30
12
–
3
AP-6
AP-6
AP-6
AP-6
AP-6
AP-6
AP-6
AP-6
30
4
30
–
5
30
–
6
30
–
–
–
7
30
58
59
39
45
35
44
44
5
8
–
8
Et2O
40
32
54
17
40
55
8
–
9
Et2O
30
7
–
10
11
12
13
14
15
16
17
18
19
Me2CO
30
38
17
5
–
Mucor miehei C6H5CH3
30
8
C. rugosa
CALB
CALB
CALB
CALB
CALB
CALB
C6H5CH3
C6H5CH3
C6H5CH3
C6H5CH3
MTBE
79
1
30
–
20
38
21
4
10
53
92
8
2
20
21
1
24
2
30
3
30
40
60
35
3
30
12
25
37
22
18
25
60
Et2O
2
30
10
15
–
Me2CO
2
30
P. fluorescens C6H5CH3
72
30
a By GC analysis.
effect of the solvent was variable; whereas toluene with miehei, the poorest result of all obtained with this enzyme.
CALB provided the best yield of 4d (92%, entry 15), with The reaction did not proceed in the absence of enzyme.
lipase PS the reaction completely failed. In contrast,
MTBE with lipase PS gave 12% of the dilactone (entry 2),
no dilactone with AP-6 and only 8% (entry 11) with M.
The best conditions found were then applied to other 1,n-
diols (n = 2, 3, 4, 8, 10) to explore the scope of the reac-
tion (Scheme 2). The reactions were run at 30 °C for 24
hours. In all cases they led to formation of the correspond-
ing dilactones 4a, 4b, 4c, 4e and 4f in good isolated yields
(Table 2).16 The open chain acids 3a–f and 5a–f were ob-
tained in very low, almost negligible, amounts. It should
be noted that the efficiency of the lactonization is inde-
pendent of the size of the macrocycle to be formed, and
thus analogous good yields were obtained when the ring
contained 16 (n = 2) or 32 atoms (n = 10).
When the reaction was extended to substituted diols, such
as 2,2-dimethyl-1,3-propanediol, or unsaturated diols,
such as (Z)-1,4-butenediol, no traces of dilactone were ob-
tained. As shown by X-ray crystallography, CALB, com-
pared to other lipases, has very limited space available at
the active site pocket, which is composed of two channels,
one hosting the acyl part and the other hosting the alcohol
moiety of the substrate.17 The acyl channel is more spa-
Scheme 2 C. antarctica-catalyzed reaction of diols 1a–f with
cious than the alcohol channel, and therefore the enzyme
is expected to exert a broad specificity towards acyl
succinic anhydride (2)
Synlett 2005, No. 17, 2611–2614 © Thieme Stuttgart · New York

LETTER
Synthesis of Macrocyclic Dilactones through Lipases
2613
Table 2 Reaction of Diols 1a–f with Succinic Anhydride in the Presence of CALB in Toluenea
Diol
1a
1b
1c
n
Recovered diolb
1a (–)
Hydroxy acidb
3a (7)
Diacidb
5a (5)
5b (5)
5c (2)
5d (1)
5e (3)
5f (2)
Dilactoneb
4a (88)
4b (85)
4c (94)
4d (92)
4e (90)
4f (89)
Dilactonec
4a (79)
4b (77)
4c (86)
4d (84)
4e (81)
4f (80)
2
3
4
6
8
1b (5)
3b (5)
1c (–)
3c (4)
1d
1e
1d (4)
3d (3)
1e (3)
3e (4)
1f
10
1f (4)
3f (5)
a All reactions were run at 30 °C for 24 h.
b GC yield of the corresponding methyl ester.
c Isolated yield.
G.; Brieva, R.; Sánchez, V. M.; Bayod, M.; Gotor, V. J. Org.
Chem. 2003, 68, 3333.
(12) Mori, K. Synlett 1995, 1097.
donors and a much higher degree of selectivity towards al-
cohol substrates.18 These considerations are in line with
our observations.
(13) Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 2001, 1475.
(14) As a typical example, in a 25 mL Erlenmeyer flask was
placed a mixture of 0.118 g (1 mmol) of hexanediol, 0.100 g
(1 mmol) of succinic anhydride, 15 mL of toluene and 0.100
g of Candida antarctica B lipase. The Erlenmeyer flask was
capped, placed in a tempered bath at 30 °C, and shaken at 80
U. The reaction was monitored by GC and when the
transformation was complete (24 h reaction), the mixture
was filtered and the enzyme washed with Et2O and MeOH.
The solvent was stripped off and the resulting crude purified
by column chromatography on silica gel eluting with
hexane–Et2O mixtures to furnish 0.337 g (84%) of lactone
4d. Mp 96–98 °C. IR (KBr): 2984, 2945, 2864, 1728, 1268,
1172 cm–1. 1H NMR (300 MHz): d = 4.06 (t, J = 6.6 Hz, 8 H,
4 CH2O), 2.58 (s, 8 H, 4 CH2CO), 1.54 (m, 8 H, 4 CH2), 1.34
(m, 8 H, 4 CH2). 13C NMR (75 MHz): d = 172.01 (CO),
64.51 (OCH2), 29.42, 29.28, 28.44, 28.37, 25.47. Anal.
Calcd for C20H32O8: C, 59.98; H, 8.05. Found: C, 60.12; H,
8.08. MS (CI): m/z (%) = 401 (100) [M+ + 1], 429 (8) [M+ +
29], 441 (5) [M+ + 41].
In summary, we have developed a selective and high
yielding biocatalytic method for the synthesis of macrocy-
clic dilactones (16–32 atoms) under very mild conditions
and using readily available starting materials.
Acknowledgment
We gratefully acknowledge CICYT (AGL 2003-06599-C02-01),
PTR (1995-0656-OP) and Generalitat de Catalunya (2001 SGR-
00342) for financial support. We are also indebted to Novo Nordisk
for a free gift of CALB.
References
(1) (a) Griesbeck, A. G.; Henz, A.; Hirt, J. Synthesis 1996,
1261. (b) Masamune, S.; Bates, S. G.; Corcoran, J. W.
Angew. Chem., Int. Ed. Engl. 1977, 16, 585. (c) Nicolaou,
K. C. Tetrahedron 1977, 33, 683. (d) Paterson, I.; Mansuri,
M. M. Tetrahedron 1985, 41, 3569.
(2) Bradshaw, J. S.; Maas, G. E.; Izatt, R. M.; Christensen, J. J.
Chem. Rev. 1979, 79, 37.
(3) Piepers, O.; Kellogg, R. M. J. Chem. Soc., Chem. Commun.
1978, 383.
(4) Asay, R. E.; Bradshaw, J. S.; Nielsen, S. F.; Thompson, M.
D.; Snow, J. W.; Masihdas, D. R. K.; Izatt, R. M.;
Christensen, J. J. J. Heterocycl. Chem. 1977, 14, 85.
(5) (a) Drewes, S. E.; Coleman, P. C. J. Chem. Soc., Perkin
Trans. 1 1972, 2148. (b) Drewes, S. E.; Riphagen, B. G. J.
Chem. Soc., Perkin Trans. 1 1974, 1908.
(6) Drewes, S. E.; Riphagen, B. G. J. Chem. Soc., Perkin Trans.
1 1974, 323.
(7) Samat, A.; Bibout, M. E. M.; Elguero, J. J. Chem. Soc.,
Perkin Trans. 1 1985, 1717.
(15) Esterification was achieved by addition of anhyd DMF (0.90
mL) and K2CO3 (93 mg, 0.65 mmol) to the crude lipase-
catalyzed reaction (52 mg). The suspension was
magnetically stirred for 20 min, then MeI (0.300 mL, 4.81
mmol) was added and the mixture stirred for 16 h. After
conventional work up, a mixture of the methyl esters 6d and
7d, starting material 1d, and dilactone 4d were obtained in
almost quantitatively yield.
(16) Spectroscopic and analytical data of compounds 4a–f.
Compound 4a: mp 84 –87 °C. IR (KBr): 2963, 1727, 1265,
1182 cm–1. 1H NMR (300 MHz): d = 4.28 (s, 8 H, 4 CH2O),
2.66 (s, 8 H, 4 CH2CO). 13C NMR (75 MHz): d = 171.53
(CO), 62.46 (CH2O), 29.31. Anal. Calcd for C12H16O8: C,
50.00; H, 5.59. Found: C, 49.89; H, 5.47. MS (CI):
m/z (%) = 289 (100) [M+ + 1].
Compound 4b: mp 86–88 °C. IR (KBr): 2967, 1722, 1275,
1193 cm–1. 1H NMR (300 MHz): d = 4.14 (t, J = 5.7 Hz, 8 H,
4 CH2O), 2.62 (s, 8 H, 4 CH2CO), 1.94 (q, J = 6.0 Hz, 4 H,
2 CH2). 13C NMR (75 MHz): d = 171.77 (CO), 60.83
(CH2O), 29.59, 27.67. Anal. Calcd for C14H20O8: C, 53.16;
H, 6.37. Found: C, 53.05; H, 6.22. MS (CI): m/z (%) = 317
(100) [M+ + 1].
Compound 4c: mp 88–92 °C. IR (KBr): 2964, 1716, 1265,
1176 cm–1. 1H NMR (300 MHz): d = 4.09 (m, 8 H, 4 CH2O),
2.62 (s, 8 H, 4 CH2CO), 1.68 (m, 8 H, 4CH2). 13C NMR (75
(8) (a) Singh, P.; Kumar, M.; Singh, H. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1987, 26, 64. (b) Singh, H.;
Kumar, M.; Singh, P. J. Chem. Res., Miniprint 1989, 4, 675.
(9) Nakamura, T.; Matsuyama, H.; Kamigata, N.; Iyoda, M. J.
Org. Chem. 1992, 57, 3783.
(10) Zhi-Wei, G.; Sih, C. J. J. Am. Chem. Soc. 1988, 110, 1999.
(11) Cyclic anhydrides have been used as acylating agents in
enzyme-catalyzed reactions. See for instance: de Gonzalo,
Synlett 2005, No. 17, 2611–2614 © Thieme Stuttgart · New York

2614
M. P. Bosch, A. Guerrero
LETTER
MHz): d = 171.94 (CO), 64.36 (CH2O), 29.53, 25.24. Anal.
Calcd for C16H24O8: C, 55.81; H, 7.02. Found: C, 55.82; H,
7.11. MS (CI): m/z (%) = 345 (100) [M+ + 1].
Compound 4e: mp 87–91 °C. IR (KBr): 2948, 1726, 1265,
1173 cm–1. 1H NMR (300 MHz): d = 4.06 (t, J = 6.0 Hz, 8 H,
4 CH2O), 2.60 (s, 8 H, 4 CH2CO), 1.52 (m, 8 H, 4 CH2), 1.30
(s, 16 H, 8 CH2). 13C NMR (75 MHz): d = 177.11 (CO),
64.71 (CH2O), 29.54, 29.10, 28.54, 25.75. Anal. Calcd for
C24H40O8: C, 63.14; H, 8.83. Found: C, 63.24; H, 8.94. MS
(CI): m/z (%) = 457 (100) [M+ + 1].
1172 cm–1. 1H NMR (300 MHz): d = 4.08 (t, J = 6.6 Hz, 8 H,
4 CH2O), 2.62 (s, 8 H, 4 CH2CO), 1.60 (m, 8 H, 4 CH2), 1.29
(s, 24 H, 12 CH2). 13C NMR (75 MHz): d = 172.15 (CO),
64.79 (CH2O), 29.51, 29.38, 29.30, 29.18, 28.56, 25.83.
Anal. Calcd for C28H48O8: C, 65.60; H, 9.44. Found: C,
65.66; H, 9.41. MS (CI): m/z (%) = 513 (100) [M+ + 1].
(17) Uppenberg, J.; Öhrner, N.; Norin, M.; Hult, K.; Kleywegt,
G. J.; Patkar, S.; Waagen, V.; Anthonsen, T.; Jones, A.
Biochemistry 1995, 34, 16838.
(18) Arroyo, M.; Sinisterra, J. V. J. Org. Chem. 1994, 59, 4410.
Compound 4f: mp 69–72 °C. IR (KBr): 2923, 1729, 1266,
Synlett 2005, No. 17, 2611–2614 © Thieme Stuttgart · New York