New synthetic routes toward polyketide-like macrolides

Article abstract of DOI:10.1055/s-2006-932495

New pathways toward the synthesis of polyketide-like macrolides have been developed through the functionalization of long chain polyolic fragments readily obtained from 3,3′-methylenebis{[6-(benzyloxy)methoxy]cyclohept-3-en-1- ol} derivatives 6. This synt

Full text of DOI:10.1055/s-2006-932495

LETTER
685
New Synthetic Routes toward Polyketide-like Macrolides
S
ynthesis of Polyk
é
etide-like
M
r
a
crolid
a
e
s
ld Coste, Sandrine Gerber-Lemaire*
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), Batochime, 1015 Lausanne,
Switzerland
Fax +41(21)6939355; E-mail: Sandrine.Gerber@epfl.ch.
Received 12 December 2005
Abstract: New pathways toward the synthesis of polyketide-like
O
macrolides have been developed through the functionalization of
long chain polyolic fragments readily obtained from 3,3¢-methyl-
enebis{[6-(benzyloxy)methoxy]cyclohept-3-en-1-ol} derivatives 6.
This synthetic route generates a large variety of stereoisomers and
thus can be applied to the preparation of a library of polyhydroxyl-
ated macrocycles, analogues of natural bioactive macrolides.
O
1
ref. 8
+
O
O
O
O
O
O
O
O
Key words: long chain polyols, macrolactonization, olefination,
polyketide macrolides, ring-closing metathesis
(±)-threo-3
meso-2
A great variety of natural products of biological interest
includes polyketides (1,3-polyoxo, 1,3-polyols, aldols)
such as the large family of polyene macrolides,1 erythro-
mycins,2 spongistatins3 and leucascandrolides.4 Many
synthetic efforts have been directed toward the design of
efficient routes toward these complex molecules.5
Vogel’s group has developed a non-iterative asymmetric
synthesis of fifteen-carbon 1,3-polyols based on the ste-
reoselective functionalization of dialkenes of type meso-
46 and ( )-threo-5,7 readily obtained from the bicycload-
ducts resulting from the double [4+3] cycloaddition of
2,2¢-methylenedifuran to 1,1,3-trichloro-2-oxyallyl cation
(Scheme 1).8
PO
OP PO
OP
OH
OH
OH
OH
meso-4
(±)-threo-5
ref. 6, 7
P = PMBz, BOM
*
*
*
*
*
*
OH OP OH OH OH OH OP OH
Scheme 1 Non-iterative synthesis of long-chain polyols
macrolactonization reaction required the differentiation of
the terminal alcohols of the polyolic chain. Treatment of
8 with Candida cylindracea lipase in vinyl acetate led to
the monoacetylation of the diol derivative to provide two
diastereoisomers 9 and 10 (1:1 ratio) in 52% yield. None
of our attempts to separate these two compounds were met
with success. Nevertheless, we continued our explora-
tions and submitted this mixture of isomers to a two-step
oxidation under Swern conditions, followed by treatment
with NaClO2 of the intermediate aldehydes. Hydrolysis of
the acetates led to the seco-acid 1111 in 33% yield (from 9,
10). Macrolactonization under Yamagushi’s conditions12
provided a 1:1 mixture of the stereoisomeric macrolac-
tones 12 and 1313 in quantitative yield.
In particular, this methodology was applied to the total
asymmetric synthesis of the polyol subunit of the oxo-
polyene macrolide antibiotic RK-397.9 We report here a
further application of this non-iterative method to the
preparation of polyketide macrolides, analogues of com-
plex natural macrolides.10
Our first studies focused on the conversion of fifteen-car-
bon polyolic chains into polyhydroxylated macrolactones
(Scheme 2).
Diolefin (–)-6 was submitted to a sequence of ozonolysis
followed by in situ reduction of the intermediate diozon-
ide by Me2S and subsequent diastereoselective reduction
of the resulting diketo-dialdehyde derivative. Selective
silylation of the primary alcohols provided the semi-pro-
tected polyol (–)-7 in 53% overall yield. The remaining
secondary alcohols were transformed into methyl ethers
and the tert-butyldimethylsilyl groups were cleaved in the
presence of aqueous HF in acetonitrile (50%, 2 steps). At
that stage (8), conversion into a seco-acid precursor for a
In order to differentiate the two terminal functions of the
polyolic chain, we turned our attention to the functional-
ization of hemiketal 14 that can be obtained from (–)-6 by
performing diastereoselective reduction of the diketo-di-
aldehyde intermediate at low temperature, as previously
reported7b (Scheme 3). The 5,7-anti and 9,11-syn config-
urations of this derivative result from the initial reduction
of one of the hemiketals obtained after ozonolysis,
allowing the diastereoselective reduction of the C-9 oxo
moiety, controlled by the C-11 hydroxyl group. The sub-
sequent reduction of the carbonyl group at C-7 is then
SYNLETT 2006, No. 5, pp 0685–0688
1
7.
0
3.
2
0
0
6
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-932495; Art ID: G37905ST
© Georg Thieme Verlag Stuttgart · New York

686
G. Coste, S. Gerber-Lemaire
LETTER
7
5
9
11
13
PO
PO
OP
ref. 7b
3
1–4
(–)-6
O
OH OH OH OP OH
3 steps
53%
1
OH
14
P = BOM
OH
P = BOM
OH
(–)-6
1
Bu3P
CO2Me
15
5, 6
OTBS OP
OH OH OH OH OP OTBS
(-)-7
50%
MeO2C
2, 3
OP OH OH OH OH OP OH
65%
16 (74%, E/Z = 10:1)
7
OH OP
OMe OMe OMe OMe OP OH
52%
8
13
5
7
9
11
2
HO2C
OP
OH OH OH OH OP OH
4, 5
17
49%
OAc OP OMe OMe OMe OMe OP OH
O
9
+
8–10
33%
O
OAc OP
OMe OMe OMe OMe OP OH
10
PO
HO
HO
PO
CO2H
OH
OH OP
OMe OMe OMe OMe OP
11, 12
quant.
OH
syn
18
11 (2 diastereoisomers)
O
O
Scheme 3 Synthesis of an 18-membered macrolactone. Reagents
and conditions: 1. PhMe, 80 °C; 2. H2, Pd/C, EtOAc; 3. LiOH, MeOH
4. 2,4,6-trichloroBzCl, (i-Pr)2NEt; 5. DMAP, PhH, reflux.
O
O
+
PO
MeO
MeO
PO
PO
MeO
MeO
PO
OMe
OMe
OMe
OMe
into a favorable conformation for macrocyclization.
Furthermore, we found out that in the case of selective
protection of only the 1,3-syn diol at C-11, C-13, the mac-
rolactonization process occurred but led to low yield and
purity of the resulting macrolide. These observations
prompted us to focus on unprotected macrocyclization
precursors, thus avoiding protection steps.
13
12
Scheme 2 Synthesis of 16-membered macrolactones. Reagents and
conditions: 1. O3, CH2Cl2, –78 °C; 2. DMS, –78 °C; 3. Et2BOMe,
NaBH4, THF–MeOH; 4. TBSCl, imidazole, DMF, 0 °C; 5. NaH, MeI,
THF, 0–25 °C; 6. aq HF (40%), MeCN; 7. H2C=CH(OAc), Candida
cylindracea lipase; 8. (COCl)2, DMSO, CH2Cl2, then Et3N, –78 °C to
–30 °C; 9. NaClO2, NaH2PO4, t-BuOH–H2O; 10. K2CO3, MeOH; 11.
2,4,6-trichloroBzCl, (i-Pr)2NEt, PhH; 12. DMAP, PhH, reflux.
A ring-closing metathesis reaction was also envisaged for
the preparation of polyketide-like macrolides (Scheme 4).
The previously reported polyol 19,7b was oxidized under
Ley’s conditions to provide the corresponding dialdehyde
that was directly treated with triphenylphosphonium
methyl ylide to afford diolefin 2016 in 31% yield (2 steps).
Treatment of this intermediate with Grubbs II catalyst
under diluted conditions17 only led to open-chain cross-
metathesis products. The acetonide protective groups
were thus removed under acidic conditions. The resulting
tetrol 2118 was reacted with Grubbs II catalyst, leading to
a first reaction of cross-metathesis followed by cycliza-
tion of the ‘dimeric’ intermediate through ring-closing
metathesis to provide the polyhydroxylated tridecane 2219
after hydrogenation of the olefin moieties.
controlled by the newly generated alcohol at C-9. Treat-
ment of 14 with the olefination reagent 1514 led to the
corresponding a,b-unsaturated ester 16 as a mixture of
isomers (E:Z = 10:1), in 74% yield. The olefin was re-
duced through catalytic hydrogenation (H2, Pd/C, EtOAc)
and the methyl ester was saponified to produce the seco-
acid 17 (65%). This intermediate was submitted to a mac-
rolactonization process under Yamagushi’s conditions to
provide the 18-membered macrolactone 1815 as the major
compound (49%). Other derivatives, probably resulting
from macrolactonizations involving secondary alcohols
were also isolated in trace amounts. We observed that
protection of the secondary alcohols as acetonides
completely blocked the macrolactonization process. The
conformational constraints resulting from acetonide pro-
tection of both 1,3-anti and 1,3-syn diols at C-7, C-9 and
C-11, C-13 seem to prevent the seco-acid precursor to fold
Different synthetic routes were developed for the prepara-
tion of polyketide-like macrolides and analogues through
the efficient functionalization of long-chain polyol inter-
mediates readily obtained from diolefin 6. The method-
ology disclosed here can provide an access to a large
number of stereoisomers by variation of the configuration
Synlett 2006, No. 5, 685–688 © Thieme Stuttgart · New York

LETTER
Synthesis of Polyketide-like Macrolides
687
Schaer, K.; Gamboni, R.; Chen, W.; Loeser, E.; Kinder, F.
R. Jr.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Repic,
O.; Wang, R. M.; Florence, G.; Lyothier, I.; Paterson, I. Org.
Process Res. Dev. 2004, 8, 122. (b) Yeung, K. S.; Paterson,
I. Chem. Rev. 2006, in press. (c) Turks, M.; Huang, X.;
Vogel, P. Chem. Eur. J. 2005, 11, 465. (d) Turks, M.;
Fonquerne, F.; Vogel, P. Org. Lett. 2004, 6, 1053.
(e) Gerber-Lemaire, S.; Ainge, S. W.; Glanzmann, C.;
Vogel, P. Helv. Chim. Acta 2002, 85, 417. (f) Narkevitch,
V.; Schenk, K.; Vogel, P. Angew. Chem. Int. Ed. 2000, 39,
1806. (g) Marchionni, C.; Vogel, P. Helv. Chim. Acta 2001,
84, 431. (h) Sevin, A.-F.; Vogel, P. J. Org. Chem. 1994, 59,
5920.
1, 2
31%
OH OP
P = BOM
O
O
O
O
OP OH
19
OP
O
O
O
O
OP
3
42%
20
(6) (a) Schwenter, M. E.; Vogel, P. Chem. Eur. J. 2000, 6, 4091.
(b) Schwenter, M. E.; Vogel, P. J. Org. Chem. 2001, 66,
7869. (c) Meilert, K.; Pettit, G. R.; Vogel, P. Helv. Chim.
Acta 2004, 87, 1493. (d) Coste, G.; Gerber-Lemaire, S.
Tetrahedron: Asymmetry 2005, 16, 2277. (e) Vogel, P.;
Gerber-Lemaire, S.; Carmona Asenjo, A. T.; Meilert, K.;
Schwenter, M. E. Pure Appl. Chem. 2005, 131.
OP
OH OH OH OH OP
4, 5
32%
21
OP OH OH OH OH OP
(7) (a) Csákÿ, A. G.; Vogel, P. Tetrahedron: Asymmetry 2000,
11, 4935. (b) Gerber-Lemaire, S.; Vogel, P. Eur. J. Org.
Chem. 2003, 2959.
(8) Meilert, K. T.; Schwenter, M. E.; Shatz, Y.; Dubbaka, S. R.;
Vogel, P. J. Org. Chem. 2003, 68, 2964.
(9) Gerber-Lemaire, S.; Carmona, A. T.; Meilert, K. T.; Vogel,
P. Eur. J. Org. Chem. 2006, in press.
(10) For other recent approaches toward polyketide macrolides,
see: (a) Kohli, R. M.; Burke, M. D.; Tao, J.; Walsh, C. T. J.
Am. Chem. Soc. 2003, 125, 7160. (b) Schmidt, D. R.;
Kwon, O.; Schreiber, S. L. J. Comb. Chem. 2004, 6, 286.
(c) Beeler, A. B.; Acquilano, D. E.; Su, Q.; Yan, F.; Roth, B.
L.; Panek, J. S.; Porco, J. A. Jr. J. Comb. Chem. 2005, 7,
673. (d) Zacuto, M. J.; Leighton, J. L. Org. Lett. 2005, 7,
5525.
OP OH OH OH OH OP
22
Scheme 4 Reagents and conditions: 1. Pr4NRuO4 cat., NMO, 4 Å
MS, CH2Cl2; 2. Ph3PCH3Br, n-BuLi, –78 °C to 25 °C; 3. p-TsOH cat.,
MeOH; 4. Grubbs II cat., CH2Cl2, 70 °C; 5. H2, Pd/C, EtOAc.
of the starting diolefin and of the reducing agent used after
the ozonolysis step. Moreover, further derivatization of
these core macrolides and analogues should afford a li-
brary of more complex molecules of biological interest.
(11) Analytical Data for 11.
A 1:1 mixture of diastereoisomers. IR (film): 3420, 2940,
2600, 2500, 1580, 1555, 1455, 1385, 1080, 1035, 740, 700
cm–1. 1H NMR (400 MHz, MeOD): d = 6.71–6.10 (m, 10 H),
4.52, 4.48 (2 d, 4 H, 2J = 5.6 Hz), 4.35, 4.33 (2 d, 4 H,
2J = 8.0 Hz), 3.98 (m, 1 H), 3.76 (m, 1 H), 3.51 (t, 2 H,
3J = 5.2 Hz), 3.46–3.22 (m, 4 H), 3.22, 3.21, 3.19, 3.18 (4 s,
Acknowledgment
This work was supported by the Swiss National Foundation (grant
n° 200020-100028 / 1). We thank Mr. Martial Rey and Mr.
Francesco Sepulveda for technical help.
12 H), 3.64–2.31 (2 m, 2 H), 1.96–1.56 (m, 12 H) ppm. 13
C
NMR (100 MHz, MeOD): d = 179.3, 139.3, 129.4, 128.9,
128.7, 95.4, 76.5, 76.2, 74.5, 74.4, 70.8, 59.4, 56.3, 43.9,
43.8, 42.0, 41.6, 40.7, 39.3, 39.2, 43.8 ppm. MALDI-MS:
673.7 [M + Na], 689.7 [M + K]. HRMS: m/z calcd for
C35H54O11 + Na: 673.3564; found 673.3561.
References and Notes
(1) For leading reviews, see for example: (a) Aparicio, J. F.;
Mendes, M. V.; Anton, N.; Recio, E.; Martin, J. F. Curr.
Med. Chem. 2004, 11, 1645. (b) Zotchev, S. B. Curr. Med.
Chem. 2003, 10, 211. (c) Rychnovsky, S. D. Chem. Rev.
1995, 95, 2021. (d) Kerridge, D. Drugs Today 1988, 24,
705. (e) Crandall, L. W.; Hamill, R. L. Bacteria 1986, 9,
355. (f) Omura, S.; Tanaka, H. Macrolide Antibiotics:
Chemistry, Biology and Practice; Academic Press: New-
York, 1984.
(2) Zhanel, G. G.; Dueck, M.; Hoban, D. J.; Vercaigne, L. M.;
Embil, J. M.; Gin, A. S.; Karlowsky, J. A. Drugs 2001, 61,
443.
(3) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd,
M. R.; Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993,
58, 1302. (b) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald,
C. L.; Boyd, M. R. J. Chem. Soc., Chem. Commun. 1993,
1166.
(12) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamagushi,
M. Bull. Chem. Soc. Jpn. 1979, 52.
(13) Preparation and Analytical Data for Compounds 12 and
13.
seco-Acid 11 (10 mg, 0.015 mmol) was dissolved in 1 mL of
MeCN. A solution of (i-Pr)2NEt in benzene (0.4 M, 1.1 mL,
0.460 mmol, 30 equiv) and a solution of 2,4,6-trichloro-
benzoyl chloride in benzene (0.4 M, 770 mL, 0.307 mmol, 20
equiv) were added. The resulting mixture was stirred at
25 °C for 3 h before being diluted with 9 mL of benzene.
This mixture was added via a syringe pump to a refluxing
solution of DMAP (315 mg, 2.55 mmol, 50 equiv) in 18 mL
of benzene over 7 h. The reaction mixture was poured into a
sat. aq solution of NaHCO3 (15 mL) and extracted with
EtOAc (15 mL, 3 times). The combined organic extracts
were washed with brine (10 mL), dried over MgSO4 and
concentrated in vacuo. Purification of the residue by flash
chromatography (MeOH–CH2Cl2, 3:97) afforded 12 and 13
as a pale yellow oil (9.5 mg, 100%).
(4) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv.
Chim. Acta 1996, 79, 51.
(5) For illustrative examples, see: (a) Mickel, S. J.; Niederer,
D.; Daeffler, R.; Osmani, A.; Kuesters, E.; Schmid, E.;
Synlett 2006, No. 5, 685–688 © Thieme Stuttgart · New York

688
G. Coste, S. Gerber-Lemaire
LETTER
IR (film): 2930, 1730, 1650, 1580, 1455, 1385, 1280, 1165,
1100, 860 cm–1. 1H NMR (400 MHz, C6D6): d = 7.35–7.27
(m, 6 H), 7.12–7.08 (m, 4 H), 4.79, 4.76 (2 d, 4 H, 2J = 6.8
Hz), 4.63, 4.57 (2 s, 4 H), 4.42–4.38 (m, 1 H), 4.32–4.23 (2
m, 1 H), 4.06–4.04 (m, 1 H), 3.63–3.39 (m, 4 H), 3.15–3.12
was poured into H2O (15 mL) and extracted with EtOAc (20
mL, 3 times). The combined organic extracts were washed
with brine (50 mL), dried over MgSO4 and concentrated in
vacuo. Purification of the residue by flash chromatography
(EtOAc–PE, 1:7) afforded 20 as a colorless oil (75 mg, 31%
over two steps). IR (film): 2940, 1640, 1440, 1390, 1100,
1040, 915, 740, 700 cm–1. 1H NMR (400 MHz, MeOD):
d = 7.35–7.27 (m, 10 H), 5.85 (ddd, 2 H, 3J = 17.2, 10.0, 6.0
Hz), 5.08 (d, 2 H, 3J = 17.2 Hz), 5.03 (d, 2 H, 3J = 10.0 Hz),
4.82, 4.78 (2 d, 4 H, 2J = 6.0, 7.0 Hz), 4.63, 4.61 (2 d, 4 H,
2J = 5.2, 4.9 Hz), 4.12–3.92 (m, 4 H), 3.91–3.88, 3.87–3.78
(2 m, 4 H), 2.34, 2.32 (2 dd, 4 H, 3J = 6.4, 5.6 Hz), 1.62–1.37
(m, 10 H), 1.33, 1.29, 1.27 (3 s, 12 H) ppm. 13C NMR (100
MHz, MeOD): d = 138.4, 138.3, 134.8, 128.4, 127.8, 127.7,
116.7, 100.5, 98.8, 94.5, 94.2, 75.2, 74.1, 69.7, 69.6, 66.0,
65.8, 63.7, 63.3, 43.3, 42.3, 42.1, 40.0, 39.9, 38.6, 37.5, 29.5,
19.2, 24.4, 24.3 ppm. MALDI-MS: m/z = 675.441 [M + Na].
Anal Calcd for C39H56O8: C, 71.75; H, 8.65. Found: C,
71.78; H, 8.67.
(m, 12 H), 2.69–2.40 (m, 2 H), 2.09–1.47 (m, 12 H) ppm. 13
C
NMR (100 MHz, C6D6): d = 170.3, 138.7, 138., 128.4,
128.0, 127.7, 94.1, 93.7, 93.5, 75.8, 75.7, 75.6, 75.5, 74.7,
74.4, 72.7, 72.3, 71.8, 71.4, 69.6, 69.5, 60.7, 60.6, 56.4, 56.3,
56.2, 56.1, 55.9, 55.8, 55.7, 41.2, 39.8, 40.6, 39.4, 38.8, 38.4,
37.9, 36.8 ppm. MALDI-MS: m/z = 655.75 [M + Na],
671.72 [M + K]. Anal. Calcd for C35H52O10: C, 66.40; H,
8.33. Found: C, 66.63; H, 8.39.
(14) (a) Aspinall, I. H.; Cowley, P. M.; Mitchell, G.; Raynor, C.
M.; Stoodley, R. J. J. Chem. Soc., Perkin Trans. 1 1999,
2591. (b) Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591.
(15) Preparation and Analytical Data for Compound 18.
seco-Acid 17 (32 mg, 0.052 mmol) was dissolved in 1 mL of
MeCN. A solution of (i-Pr)2NEt in benzene (0.4 M, 3.9 mL,
1.55 mmol, 30 equiv) and a solution of 2,4,6-trichloro-
benzoyl chloride in benzene (0.4 M, 2.6 mL, 1.05 mmol, 20
equiv) were added. The resulting mixture was stirred at
25 °C for 3 h before being diluted with 12.5 mL of benzene.
This mixture was added via a syringe pump to a refluxing
solution of DMAP (315 mg, 2.55 mmol, 50 equiv) in 25 mL
of benzene over 6 h. The reaction mixture was poured into
H2O (30 mL) and extracted with EtOAc (30 mL, 3 times).
The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. Purification of the residue by flash
chromatography (2% of MeOH in CH2Cl2) afforded 18 as a
pale yellow oil (15 mg, 49%). IR (film): 3420, 2930, 1735,
1580, 1450, 1375, 1275, 1160, 1120, 1040, 740, 700 cm–1.
1H NMR (400 MHz, MeOD): d = 7.35–7.27 (m, 10 H), 4.77–
4.74, 4.68–4.66 (2 m, 4 H), 4.66–4.59 (m, 4 H), 4.56–4.52
(m, 2 H), 4.05–3.87 (m, 6 H), 2.40–2.30 (m, 2 H), 2.10–1.90
(2 m, 16 H) ppm. 13C NMR (100 MHz, MeOD): d = 164.3,
138.3, 138.2, 128.4, 128.0, 127.7, 94.5, 94.3, 75.2, 73.4,
69.8, 69.2, 67.1, 66.9, 64.9, 58.5, 45.3, 45.0, 44.9, 43.6, 42.8,
38.4, 38.3, 34.7, 20.6 ppm. MALDI-MS: m/z = 627.10 [M +
Na], 643.06 [M + K]. HRMS: m/z calcd for C33H48O10 + Na:
627.3145; found: 627.3142.
(16) Preparation and Analytical Data for Compound 20.
To a solution of 19 (245 mg, 0.371 mmol) in 2 mL of dry
CH2Cl2, were added 4 Å MS (185 mg), 4-methylmorpholine
N-oxide (105 mg, 0.778 mmol, 2.1 equiv) and tetrapropyl-
ammonium perruthenate (13 mg, 0.037 mmol, 0.1 equiv).
The mixture was stirred at 25 °C for 1 h and then filtered
over a pad of Celite®. The solvent was removed under
reduced pressure and filtration of the residue over a short pad
of silica (6% MeOH in CH2Cl2) afforded the corresponding
dialdehyde as a brown oil. Triphenylphosphonium methyl
bromide (450 mg, 1.256 mmol, 5 equiv) was dissolved in 2
mL of anhyd THF. The mixture was cooled at –78 °C and
n-BuLi (1.5 M in THF, 800 mL, 1.256 mmol, 5 equiv) was
added dropwise. The solution was warmed to 25 °C for 45
min. A solution of the crude dialdehyde in THF (1 mL) was
added to the resulting yellow mixture at –78 °C. At the end
of the addition the cooling bath was removed and the
reaction mixture was stirred for 3 h at 25 °C. The mixture
(17) (a) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6,
525. (b) Lee, C. W.; Grubbs, R. H. Org. Lett. 2000, 2, 2145.
(18) Analytical Data for 21.
IR (film): 3415, 2935, 1640, 1435, 1375, 1100, 1035, 915,
740, 695 cm–1. 1H NMR (400 MHz, MeOD): d = 7.35–7.27
(m, 10 H), 5.88–5.82 (m, 2 H), 5.11–5.03 (m, 4 H), 4.83 (s,
4 H), 4.64, 4.62 (2 s, 4 H,), 4.10–3.95 (m, 6 H), 2.39–2.33
(m, 4 H), 1.62–1.50 (m, 10 H) ppm. 13C NMR (100 MHz,
MeOD): d = 138.3, 134.9, 134.8, 128.4, 128.0, 127.7, 116.7,
94.2, 75.0, 74.8, 69.8, 69.7, 69.2, 67.1, 66.8, 64.7, 45.3, 45.0,
44.9, 43.0, 42.6, 39.9, 39.8 ppm. MALDI-MS: m/z = 573.84
[M + Na].
(19) Preparation and Analytical Data for 22.
To a solution of 21 (25 mg, 0.044 mmol) in dry CH2Cl2 (25
mL, 0.002 mM), tricyclohexylphosphine [1,3-bis(2,4,6-
trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzyl-
idine] ruthenium(IV) dichloride (7.5 mg, 8.731 mmol, 0.2
equiv) was added. The resulting pink solution was heated at
50 °C for 7 h. The solvent was removed under reduced
pressure and the residue was filtered on a pad of silica (3–
10% MeOH in CH2Cl2) affording a brown oil that was
dissolved in EtOAc (2 mL) and treated with a catalytic
amount of palladium (10% on activated charcoal) under 1
atm of H2. After 1 h at 25 °C, the resulting mixture was
filtered over a pad of Celite®. Removal of the solvent under
reduced pressure and purification of the residue was by flash
chromatography (3–10% MeOH in CH2Cl2) afforded 22 as a
pale yellow oil (7.5 mg, 32%). IR (film): 3410, 2940, 2515,
1425, 1380, 1165, 1100, 1040, 740, 700 cm–1. 1H NMR (400
MHz, MeOD): d = 7.34–7.25 (m, 20 Harom), 4.79 (s, 8 H),
4.58 (s, 8 H), 4.10–3.90 (m, 8 H), 3.90–3.80 (m, 4 H), 1.80–
1.50 (m, 28 H), 1.50–1.35 (m, 8 H) ppm. 13C NMR (100
MHz, MeOD): d = 138.4, 128.4, 127.9, 127.7, 94.2, 94.1,
93.9, 75.4, 75.2, 75.1, 75.0, 69.7, 69.6, 68.3, 68.2, 66.8, 66.7,
66.6, 66.5, 65.1, 64.9, 45.4, 45.3, 45.1, 45.0, 44.9, 42.8, 42.7,
42.1, 42.0, 37.8, 34.9, 25.1, 25.0, 24.9, 24.8 ppm. MALDI-
MS: m/z = 1116.35 [M + Na], 1131.36 [M + K]. HRMS:
m/z calcd for C62H92O16 + Na: 1115.6283; found: 1115.6287.
Anal. Calcd for C62H92O16: C, 68.11; H, 8.51. Found: C,
68.00; H, 8.48.
Synlett 2006, No. 5, 685–688 © Thieme Stuttgart · New York