Two approaches for efficient synthesis of (-)-colletol

Article abstract of DOI:10.1016/j.tetlet.2005.11.161

The synthesis of (-)-colletol was achieved from (R)-pent-4-en-2-ol by using enantioselective allyltitanations to control the stereogenic centers at C5 and cross-metathesis, ring-closing metathesis reactions to control the configuration of the double bonds.

Full text of DOI:10.1016/j.tetlet.2005.11.161

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 901–904
Two approaches for efficient synthesis of (ꢀ)-colletol
*
Samir BouzBouz and Janine Cossy
Laboratoire de Chimie Organique UMR 7084, CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 30 October 2005; revised 29 November 2005; accepted 30 November 2005
Available online 20 December 2005
Abstract—The synthesis of (ꢀ)-colletol was achieved from (R)-pent-4-en-2-ol by using enantioselective allyltitanations to control the
stereogenic centers at C5 and cross-metathesis, ring-closing metathesis reactions to control the configuration of the double bonds.
Ó 2005 Elsevier Ltd. All rights reserved.
(
ꢀ)-Colletol (1) is a 14-membered bis-macrolactone iso-
The two possible pathways, implying a common inter-
mediate B (Scheme 1), have been envisaged for obtain-
ing the 14-membered ring present in (ꢀ)-colletol (1)
lated from the fermentation broth of Collectotrichum
capsici in 1973 along with related bis-lactones colletodiol
(
1
2), colletoketol (3), and colletallol (4) (Fig. 1). Although
no biological activity was reported for these macrolac-
tones, interest in these compounds was stimulated when
O
O
the isolation of grahamimycin A (5), which displayed
1
potent activity against bacteria, algae, and fungi was
2
,3
reported. These macrolactones can result from a bio-
4
synthesis via the macrodiolide colletotriene (6) (Fig. 1).
HO
Path a
Path b
RO
O
The promising biological activity and the unique struc-
ture of this family of macrolactones make them attrac-
tive synthetic targets and there have been several
O
O
O
O
O
O
(-)-Colletol
5
synthesis of colletol.
RO
O
O
OH O OH
O
O
O
OR OH
O
O
A
F
O
HO
HO
O
O
B
HO
HO
HO
O
O
O
O
O
O
O
OR OR'
Colletol (1)
Colletodiol (2)
Colletoketol (3)
HO
C
O
O
O
O
O
OR OR'
O
HO
D
HO
OR'
O
O
O
O
O
O
O
E
Colletallol (4)
Grahamimycin A (5)
Colletotriene (6)
1
Figure 1. Natural 14-membered macrolactones.
OH
7
*
0
Corresponding author. Fax: +33 0140794660; e-mail: samir.
bouzbouz@wanadoo.fr
Scheme 1. Retrosythetic analysis of (ꢀ)-colletol.
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.161

902
S. BouzBouz, J. Cossy / Tetrahedron Letters 47 (2006) 901–904
(
Scheme 1). One involves a macrolactonization and the
The synthetic scheme to prepare compound A began
with the preparation of the pure syn 1,3-diol 9 from
the commercially available (R)-pent-4-en-2-ol. After
protection of the hydroxy group of (R)-pent-4-en-2-ol
7 (TBSOTf, 2,6-lutidine, ꢀ78 °C, 95% yield), the silyl
second one involves a ring-closing metathesis (RCM)
as we wanted to examine the potential of metathesis
reactions in the synthesis of (ꢀ)-colletol. The synthesis
of (ꢀ)-colletol should be achieved in a limited number
6
of steps using enantioselective allyltitanations to pro-
ether 8 was oxidatively cleaved (OsO , NMO then
4
7
duce the syn 1,3-diol units.
NaIO , acetone/H O = 3/1) to produce an aldehyde of
4
2
type E, which was directly treated with the optically
active allyltitanium complex (R,R)-I and transformed
to the syn 1,3-diol 9 with a good diastereoselectivity
(dr >95/5) in 78% overall yield from 7. After protection
of the hydroxy group (MOMCl, i-Pr NEt, CH Cl ,
A first retrosynthetic analysis envisioned the formation
of the macrolactone by using a ring-closing metathesis
(
RCM), applied to compound A and involved an acti-
vated olefin and a non-activated olefin. Compound A
should be synthesized from B by esterification with
acryloyl chloride. The unsatured carboxylic acid C,
precursor of B, should be obtained by using a cross-
metathesis (CM) between the homoallylic alcohol D
and acrylic acid. The optically active syn 1,3-diols pres-
ent in D should be obtained from the optically active
2
2
2
25 °C, yield = 90%), the resulting compound 10 was in-
volved in a CM reaction with acrylic acid (3 equiv) in the
presence of the Hoveyda-Grubbs catalyst (HG 5 mol %,
CH Cl , 25 °C, 16 h) and transformed to the E-unsatu-
2
2
rated carboxylic acid in 82% yield and with a E/Z ratio
of 20/1. In order to introduce the non-activated olefin,
which will be involved in the RCM, carboxylic acid 11
was treated with (R)-pent-4-en-2-ol under the Yamagu-
chiÕs conditions (2,4,6-Cl C H COCl, Et N, DMAP,
8
commercially available homoallylic alcohol 7 via the
protected b-hydroxy-aldehyde E by utilizing an enantio-
selective allyltitanation (Scheme 1, path a).
3
6
3
3
9
2
5 °C). Ester 12 was isolated in 72% yield and then con-
verted to alcohol 13 using NH F in refluxing methanol
for 12 h (yield 83%) (Scheme 2).
10
A second retrosynthetic analysis involving a penultimate
macrolactonization of the seco-acid F was envisaged. In
this scheme, the two E-double bonds will be introduced
by using two cross-metatheses, one between D and
acrylic acid (C2–C3) and one chemoselective CM
between B and acrylic acid (C8–C9) (Scheme 1, path b).
4
1
1
A ring-closing metathesis reaction has been achieved on
14 in order to obtain the macrolactone ring of (ꢀ)-colle-
tol. At first, compound 13 was esterified using acryloyl
TBSOTf, 2.6-lutidine
OH
OTBS
CH Cl , -78˚C, 95 %
2
2
8
7
i. OsO , NMO, NaIO4
4
Acetone/H O, 25 ˚C
2
ii. (R,R)-I, ether
-
78˚C, 3h, 78%
MOMCl, iPr NEt
2
CH Cl , 25 C,
OH OTBS
OR OTBS
2
2
˚
9
0%
9
1
0 R = MOM
Acrylic acid (3eq.)
HGcat ( 5mol%)
CH Cl , 25 ˚C, 82%
2
2
O
OR OTBS
O
OR OTBS 2,4,6-Cl3C6H3COCl
Et N, Toluene, 25˚C
3
O
HO
7
, DMAP, Toluene, 72%
1
1R = MOM
1
2 R = MOM
NH F, MeOH
4
6
5˚C, 83%
Ph
Ph
O
O
OR OH
Ti
O
*
*
O
O
(R,R)-I
O
Ph
Ph
13 R = MOM
N
N
Cl
Cl
Ru
O
HG
Scheme 2. Synthesis of the common fragment 13.

S. BouzBouz, J. Cossy / Tetrahedron Letters 47 (2006) 901–904
903
chloride (i-Pr NEt, CH Cl , ꢀ78 °C, yield = 92%)
Acrylic acid (3eq.)
HGcat ( 5mol%)
2
2
2
O
OR OH
O
OR OH
and the obtained unsaturated ester 14 was treated
with the Hoveyda-Grubbs catalyst HG (5 mol %) in
O
CH Cl , 25˚C, 78%
2
2
O
ꢀ
3
CH Cl (c = 10 M, 25 °C). After 72 h, macrolactone
CO2H
2
2
1
5 was obtained in 32% as a mixture of two insepara-
13
R = MOM
1
6 R = MOM
ble isomers, E,E/E,Z in a ratio of 2.8/1 in favor of the
2
,4,6-Cl C H COCl
3 6 3
1
2
E,E-isomer. To our knowledge, no precedent of a for-
mation of 14-membered macrolactone of the type 15 by
a RCM with 25 °C in the presence of Hoveyda-Grubbs
catalyst HG was deferred.
Et N, Toluene, 25 ˚C
3
DMAP, Toluene
1
10˚C, 60%
O
O
2
O
O
HCl (2N), THF
5˚C, 79%
3
After deprotection (HCl, THF, 24 h, 25 °C), the insepar-
2
1
3,14
ables (ꢀ)-colletol 1 and its (E,Z)-isomer
were iso-
1
0
MOMO
9
lated in 77% yield in a ratio of 2.8/1 (Scheme 3).
HO
O
O
O
O
To our knowledge, it is the first time that a 14-mem-
bered macrolactone can be synthesized from an a,b-
unsaturated acrylate using a RCM, however the yield
is modest as well as the E,E/Z,E ratio of the formed ole-
fins. It is worth noting that the ring-closing metathesis of
a,b-unsaturated acrylate by using second generation
(
-)-Colletol
17
Scheme 4. Synthesis of (ꢀ)-colletol by macrolactonization.
Acknowledgments
1
5,16
Grubbs catalyst affords cyclic dimers or trimers.
We thank Dr. Fisher and Dr. Trimmer from Materia
(
US) for a generous gift of Hoveyda-Grubbs catalyst.
Due to this non-stereoselective RCM, compound 13 has
been transformed to acrylic acid 16 in order to achieve a
macrolactonization. Compound 13 was submitted to a
CM using acrylic acid (HG 5 mol %, CH Cl , 25 °C,
References and notes
2
2
1
6 h) to form the conjugated unsaturated acid 16 as a
0/1 mixture of E/Z isomers in 78% yield. The obtained
1
. (a) MacMillan, J.; Pryce, R. J. Tetrahedron Lett. 1968,
497; (b) MacMillan, J.; Simpson, T. J. J. Chem. Soc.,
Perkin Trans. 1 1973, 1487.
2
5
seco-acid 16 was macrolactonized under the Yama-
1
7
guchiÕs conditions (2,4,6-Cl C H COCl, Et N, DMAP,
2. Gurusiddaiah, S.; Ronald, R. C. Antimicrob. Agents
Chemother. 1981, 19, 153.
3
6
3
3
toluene) to afford the macrolactone 17 in 60% yield,
which after treatment with HCl was converted to (ꢀ)-
3. (a) OÕNeill, J. A.; Simpson, T. J.; Willis, C. L. J. Chem.
Soc., Chem. Commun. 1993, 738; (b) Keck, G. E.; Boden,
E. P.; Wiley, M. R. J. Org. Chem. 1989, 54, 896.
1
8
colletol (Scheme 4).
4
. Munoz, D. C.; Passey, S. C.; Simpson, T. J.; Willis, C. L.;
Campbell, J. B.; Rosser, R. Aust. J. Chem. 2004, 57, 645.
The spectra and physical data for the isolated material
were in accordance with the data reported in the litera-
ture ( H NMR, C NMR, IR).
1
13
5. (a) Keck, G. E.; Murry, J. A. J. Org. Chem. 1991, 56, 6606;
b) Shimizu, I.; Omura, T. Chem. Lett. 1993, 1759; (c)
(
Sharma, G. V. M.; Raja Rao, A. V. S.; Murthy, V. S.
Tetrahedron Lett. 1995, 36, 4117; (d) Solladi e´ , G.; Gressot,
L.; Colobert, F. Eur. J. Org. Chem. 2000, 357; (e) Hunter,
T. J.; OÕDoherty, G. A. Org. Lett. 2002, 4, 4447.
By using a macrolactonization and two CM, (ꢀ)-colletol
was obtained in nine steps with an overall yield of 12%.
This synthesis is the shortest synthesis described up to
now.
6. Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rothe-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114,
2
321.
O
7
. BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 501.
Acryloyl chloride,
O
OR OH
O
OR O
8. Commercially available (R)-pent-4-en-2-ol 7 is sold at
iPr NEt, CH Cl ,
2
2
2
Aldrich ꢁ $80/g.
O
-78 C, 92%
˚
O
25
D
9
. Spectral data for common intermediate 12: ½aꢂ +5.3 (c
1
1
3 3
.23, CHCl ). H NMR (CDCl , 300 MHz) d: 6.90 (td,
1
3 R = MOM
J = 7.5 and 15.8 Hz, 1H), 5.81 (dt, J = 1.5 and 15.8 Hz,
1
4 R = MOM
HGcat ( 5mol%)
1H), 5.71 (m, 1H), 5.09–4.92 (m, 3H), 4.58 (m, 2H), 3.87
-
3
(
ddd, J = 6.0, 12.0, and 18.4 Hz, 1H), 3.76 (ddd, J = 6.4,
CH Cl2 (10 M),
2
1
1
1.7, and 12.8 Hz, 1H), 3.32 (s, 3H), 2.50–2.19 (m, 4H),
.74 (td, J = 6.4 and 13.9 Hz, 1H), 1.47 (ddd, J = 6.0,
25˚C, 72h, 32%
O
12.4, and 13.9 Hz, 1H), 1.19 (d, J = 6.4 Hz, 3H), 1.11 (d,
O
13
2
J = 6.0 Hz, 3H), 0.83 (s, 9H), 0.02 and 0.01 (2s, 6H).
C
O
O
HCl (2N), THF
5˚C, 77%
NMR (CDCl , 75 MHz) d: 165.7 (s), 144.9 (d), 133.7 (d),
3
3
2
124.0 (d), 117.6 (t), 95.4 (t), 73.5 (d), 69.8 (d), 65.6 (d), 55.6
1
0
(q), 44.4 (t), 40.3 (t), 37.4 (t), 25.8 (3q), 23.7 (q), 19.5 (q),
MOMO
9
HO
ꢀ1
1
8.0 (s), ꢀ4.3 (q), ꢀ4.7 (q). IR (neat) m (cm ): 2934, 2856,
O
O
+
O
O
1718, 1655, 1256, 1034. MS m/z: 400 (M , absent), 343
Mꢀt-Bu, 6), 299 (3), 253 (19), 213 (49), 198 (16), 169 (21),
59 (100), 145 (80), 133 (30), 101 (29), 89 (25), 73 (26), 59
(11).
(
1
(
-)-Colletol
15
Scheme 3. Synthesis of (ꢀ)-colletol by RCM.

904
S. BouzBouz, J. Cossy / Tetrahedron Letters 47 (2006) 901–904
2
D
5
1
0. Spectral data for common intermediate 13: ½aꢂ +49.3 (c
4.80 (m, 1H), 4.73 (m, 2H), 3.94 (m, 1H), 3.40 (s, 3H),
1
1
.8, CHCl
3
). H NMR (CDCl
3
, 300 MHz) d: 6.92 (td,
J = 7.5 and 15.4 Hz, 1H), 5.86 (dt, J = 1.5 and 15.4 Hz,
2.41–2.0 (m, 5H), 1.81 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H),
1
3
1.24 (d, J = 6.0 Hz, 3H); C NMR (CDCl , 75 MHz) d:
3
1
2
2
1
3
1
6
H), 5.75 (m, 1H), 5.06 (m, 2H), 5.02 (m, 1H), 4.70 (m,
H), 3.95 (m, 2H), 3.39 (s, 3H), 2.95 (sl, 1H, OH), 2.50–
.25 (m, 4H), 1.74 (m, 1H), 1.58 (ddd, J = 3.2, 4.8, and
6 Hz, 1H), 1.25 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz,
165.2 (s), 164.4 (s), 144.5 (d), 141.8 (d), 124.5 (d), 123.5 (d),
95.2 (t), 73.0 (d), 67.7 (d), 67.3 (d), 55.5 (q), 41.9 (t), 38.6
+
(t), 31.1 (t), 20.6 (q), 17.8 (q). MS m/z 312 (M , absent),
281 (0.19), 251 (2), 206 (5), 183 (61), 157 (7), 121 (55), 113
1
3
ꢀ1
H). C NMR (CDCl
3
, 75 MHz) d: 165.6 (s), 144.0 (d),
(100), 95 (48), 68 (43). For two isomers: IR (neat) m (cm ):
33.5 (d), 124.3 (d), 117.6 (t), 95.3 (t), 75.8 (d), 70.0 (d),
2933, 1717, 1655, 1260, 1032.
1
6.6 (d), 55.8 (q), 43.2 (t), 40.2 (t), 37.3 (t), 23.6 (q), 19.4
13. Spectral data for (ꢀ)-colletol E/Z isomer: H NMR
ꢀ1
(
q). IR (neat) m (cm ): 3457, 2934, 1714, 1654, 1266, 1032.
3 3
(CDCl , 300 MHz) d: 6.65 (m, 1H, H ), 6.34 (td, J = 6.4
+
MS m/z: 286 (M , absent), 287 (M+1, 0.05), 227 (1), 211
1), 198 (30), 169 (56), 154 (4),139 (41), 113 (22), 101 (100),
1 (12), 69 (54).
and 11.3 Hz, 1H, H10), 5.97 (dapparent, J = 11.3 Hz, 1H,
(
8
H
9
), 5.79 (td, J = 2.6 and 15.8 Hz, 1H, H ), 5.32 (m, 1H),
2
4.81 (m, 1H), 4.10 (m, 1H), 2.68–2.23 (m, 4H), 2.05 (m,
1H), 1.79 (ddd, J = 3.4, 8.3, and 14.3 Hz, 1H), 1.70 (br s,
1H, OH), 1.29 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.0 Hz,
1
1
1. The treatment of 12 by TBAF does not lead to compound
0
13 but to diene 12 .
1
3
3
1
6
3
H). C NMR (CDCl , 75 MHz) d: 165.2 (s), 164.4 (s),
O
OR OTBS
TBAF 1M in THF
5 ˚C, 77%
O
OH
44.2 (d), 142.0 (d), 124.4 (d), 123.6 (d), 68.0 (d), 67.7 (d),
7.4 (d), 43.7 (t), 41.3 (t), 31.2 (t), 20.5 (q), 17.8 (q). MS
m/z 312 (M , absent), 281 (0.19), 251 (2), 206 (5), 183 (61),
O
O
+
2
1
57 (7), 121 (55), 113 (100), 95 (48), 68 (43). IR (neat) m
1
2 R = MOM
12'
ꢀ1
(
cm ): 3350, 2984, 2922, 1709, 1653, 1258, 1177.
1
2. The E/Z ratio has been determined by H NMR. Spectral
14. In Ref. 5e OÕDoherty and all was obtained the (ꢀ)-colletol
1 and its (Z,E)-isomer in a 1:1 mixture from colletodiol.
15. Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66,
7155.
1
data for compound 15: Major isomer EE: H NMR
(
CDCl
3
, 300 MHz) d: 6.75–6.60 (2ddd, J2–3 = J9–10
=
1
1
4
5.8 Hz, 2H, H , H10), 5.81 (dt, J = 1.5 and 15.8 Hz,
H), 5.77 (dt, J = 1.5 and 15.4 Hz, 1H), 5.30–5.12 (m, 2H),
.73 (m, 2H), 3.85 (m, 1H), 3.40 (s, 3H), 2.71 (m, 1H), 2.52
3
16. Deiters, A.; Martin, S. Chem. Rev. 2004, 104, 2199.
17. Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
2
5
(
td, J = 3.7 and 12.8 Hz, 1H), 2.25 (m, 2H), 1.90 (td,
18. Spectroscopic data of (ꢀ)-colletol: ½aꢂ ꢀ13.5 (c 0.32,
D
1
J = 3.4 and 15.4 Hz, 1H), 1.36 (d, J = 6.4 Hz, 3H), 1.31 (d,
J = 6.8 Hz, 3H). C NMR (CDCl , 75 MHz) d: 166.1 (s),
3
CHCl ). H NMR d: 6.72 (ddd, J = 4.9, 9.0, and 15.8 Hz,
1
3
1H), 6.72 (ddd, J = 6.8, 8.3, and 15.4 Hz, 1H), 5.80 (dt,
J = 1.13 and 15.8 Hz, 1H), 5.77 (d, J = 0.75 and 15.4 Hz,
1H), 5.30–5.12 (m, 2H), 4.05 (m, 1H), 2.57–2.47 (m, 2H),
2.36–2.20 (m, 2H), 1.99 (dt, J = 3.0 and 15.8 Hz, 1H), 1.51
(ddd, J = 3.0, 6.0, and 15.8 Hz, 1H), 1.36 (d, J = 6.4 Hz,
3
165.3 (s), 144.3 (d), 143.6 (d), 126.2 (d), 124.9 (d), 95.8 (t),
74.3 (d), 68.4 (d), 68.0 (d), 55.8 (q), 40.9 (t), 38.8 (t), 37.0
+
(
(
(
(
t), 20.5 (q), 18.3 (q). MS m/z: 312 (M , absent), 281
0.07), 251 (3), 206 (8), 180 (26), 157 (33), 127 (23), 115
78), 95 (63), 68 (100). For minor isomer EZ: H NMR
CDCl
1
13
3H), 1.35 (d, J = 6.8 Hz, 3H); C NMR d: 166.0 (s), 165.3
3
, 300 MHz) d: 6.64 (m, 1H, H
3
), 6.32 (td, J = 6.4
(s), 144.0 (d), 143.8 (d), 126.2 (d), 125.1 (d), 68.4 (d), 68.2
and 11.7 Hz, 1H, H ), 5.97 (dapparent, J = 11.7 Hz, 1H,
(2d), 40.9 (t), 40.3 (t), 40.1 (t), 20.6 (q), 18.2 (q). IR (neat) m
(cm ): 3350, 2984, 2922, 1709, 1653, 1258, 1177.
1
0
ꢀ
1
H ), 5.79 (td, J = 2.6 and 15.8 Hz, 1H, H ), 5.33 (m, 1H),
9
2