Enantioselective total synthesis of the (-)-(6R,11R,14S)-isomer of colletallol

Article abstract of DOI:10.1021/jo970020s

The total synthesis of the (-)-(6R,11R,14S)-isomer of colletallol was achieved in 15 steps. The key steps of the sequence were the building of the macrocycle via two consecutive Wittig reactions, the first intermolecular and the second intramolecular, instead of the classical macrolactonization methods.

Full text of DOI:10.1021/jo970020s

6374
J . Org. Chem. 1997, 62, 6374-6378
En a n tioselective Tota l Syn th esis of th e (-)-(6R,11R,14S)-Isom er of
Colleta llol
Sonia J . Amigoni,† Lo¨ıc J . Toupet,‡ and Yves J . Le Floc’h*,†
Synthe`ses et Activations de Biomole´cules, CNRS ESA 6052, Ecole Nat. Sup. de Chimie de Rennes, av. du
Ge´ne´ral Leclerc, 35700 Rennes, France, and Groupe Matie`re Condense´e et Mate´riaux, CNRS URA 804,
Universite´ de Rennes, av. du Ge´ne´ral Leclerc, 35042 Rennes Cedex, France
Received J anuary 2, 1997X
The total synthesis of the (-)-(6R,11R,14S)-isomer of colletallol was achieved in 15 steps. The key
steps of the sequence were the building of the macrocycle via two consecutive Wittig reactions, the
first intermolecular and the second intramolecular, instead of the classical macrolactonization
methods.
Sch em e 1
The family of macrodiolide antibiotics consists of two
classes of natural compounds displaying interesting
biological properties.1 The first class consists of 16-
membered macrocycles with C2 symmetry, such as pyreno-
phorol, pyrenophorin, and vermiculin. The second class
comprises those compounds possessing an unsymmetrical
14-membered macrocycle such as colletallol (1), colletol,
colletoketol, and colletodiol.2 Quite recently, two novel
metabolites possessing a 13-membered macrocyclic ring,
bartanol and bartallol, have been also isolated.3
Many syntheses of macrodiolides have been reported
already.2 However, in order to obtain detailed structure-
activity relashionships in these series, it appears impor-
tant to design a versatile synthetic scheme giving a
unified access to the natural macrodiolides, their stere-
oisomers, and selected structural analogues. Towards
this goal we proposed a strategy involving two key
points: (a) the use of two consecutive Wittig reactions to
build efficiently the macrodiolide with a complete control
of the ring size4 and (b) the use of a versatile key
intermediate (enone 2) for the control of the stereogenic
centers.5 To fully demonstrate the potential of this
approach, we selected the colletallol derivative 1 as a
target molecule. Since the natural product (6R,11R,14R)
has been already prepared and was found biologically
inactive, its (6R,11R,14S) isomer was chosen in order to
start some structure-activity data in this family.
upper segment is easily accessible in two steps from
commercial (R)-ethyl 3-hydroxybutanoate (3).
Resu lts a n d Discu ssion
The purpose of this paper is to report the total
synthesis of the colletallol isomer 1. One of the key
points during the synthesis was the protection of the
alcohol function at C11: the p-anisyl group proved to be
the best choice since it is easily introduced by a Mit-
sunobu-type procedure and is efficiently removed under
mild conditions during the last step.
The synthesis started with the preparation of the
protected enone 25 followed by a diastereoselective reduc-
tion with the oxazaborolidine derived from (S)-2-(hy-
droxydiphenylmethyl)pyrrolidine and bis(trifluoroethyl)
n-butylboronate according to Corey and Link.7 This
procedure was simpler and easier to reproduce than the
initially described CBS method8 (Scheme 2).
Our strategy was clearly formulated in previous
papers.2,4-6 The retrosynthetic Scheme 1 shows the two
fragments that join by the means of two successive Wittig
reactions. The lower segment can be prepared from the
polyfunctional enone 2, for which the synthesis and
asymmetric reduction were described recently.5 The
This reduction by BH3-Me2S as the reductant and
with 1 equiv of oxazaborolidine at rt in THF afforded
allylic alcohol 4 (86%) in 95% de. The (S)-configuration
of the newly created asymmetric carbon was inferred
later by an X-ray structural analysis of the target
compound 1. On the basis of the mechanistic studies of
Corey et al.,9 we have to consider the acetal group as the
smaller one although this statement seems to be coun-
terintuitive. This could be explained by the possible
steric hindrance during the reaction between the phenyl
groups of the catalyst and those of the protecting group
† CNRS ESA 6052.
‡ CNRS URA 804.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) Omura, S. Macrolide Antibiotics: Chemistry, Biology and Prac-
tice; Academic; New York: 1984; pp 538-541.
(2) For full documentation about macrodiolides up to 1995, see:
Amigoni, S. J . Ph.D. Thesis, Rennes I University, 1996, and Le Floc’h,
Y.; Dumartin, H.; Gre´e R. Bull. Soc. Chim. Fr. 1995, 132, 114-118.
(3) Hanson, K.; O’Neill, J . A.; Simpson, T. J .; Willis, C. L. J . Chem.
Soc., Perkin Trans. 1 1994, 2493-2497.
(4) Yvergnaux, F.; Le Floc’h, Y.; Gre´e, R. Tetrahedron Lett. 1989,
30, 7397-7398. Le Floc’h, Y.; Yvergnaux, F.; Gre´e, R. Bull. Soc. Chim.
Fr. 1992, 129, 62-70.
(5) Dumartin, H.; Le Floc’h, Y.; Gre´e, R. Tetrahedron Lett. 1994,
35, 6681-6684. Contrary to an earlier report from one of us, the
reduction of enone 2 with the (S)-CBS reagent gave an allylic alcohol
with (S)-configuration; the right columns of Tables 1 and 2 in the cited
article thus concern the ratio 7/6 and not 6/7.
(6) Dommerholt, L. J .; Thijs, L.; Zwanenburg, B. Tetrahedron Lett.
1991, 32, 1495-1498.
(7) Corey, E. J .; Link, J . O. Tetrahedron Lett. 1992, 33, 4141-4144.
(8) Corey, E. J .; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611-614.
(9) Corey, E. J .; Azimioara, M.; Sarshar, S. Tetrahedron Lett. 1992,
33, 3429-3430.
S0022-3263(97)00020-0 CCC: $14.00 © 1997 American Chemical Society

Enantioselective Synthesis of (-)-(6R,11R,14S)-Colletallol
J . Org. Chem., Vol. 62, No. 18, 1997 6375
Sch em e 2a
Sch em e 3a
a
(i) (S)-CBS-nBu, BH3‚Me2S, THF, rt (86%); (ii) H2, Pd/C 10%,
AcOEt, rt (68%); (iii) p-MeOC6H4OH, PPh3, DEAD, THF, 80 °C
(85%); (iv) nBu4N+F-, THF, rt (81%).
on the γ-hydroxyl function of enone 2. This hypothesis
did not find any confirmation in the literature. Allylic
alcohol 4 was then hydrogenated under standard condi-
tions (10% Pd/C) in good yield to give the saturated
alcohol 5. It was necessary to protect the free secondary
hydroxyl group. After many studies, the protection of
this alcohol 5 as a p-anisyl ether was found to be the best
solution. We also verified that the deprotection of this
secondary alcohol could be achieved in acceptable yield
while sparing the various functionalities present in the
molecule. According to the literature,10 p-methoxyphenyl
ethers can resist various drastic acidic, basic, and oxida-
tive conditions. The formation of p-anisyl ethers from
secondary alcohols has already been used by Corey and
Link11 to invert an asymmetric carbon. We found that
this protection was conveniently achieved via a Mit-
sunobu reaction (PPh3, DEAD) with p-methoxyphenol in
THF at 80 °C for 3 h. Compound 6 was obtained in good
yield (85%). In agreement with preceding results, this
reaction proceeded with inversion of configuration as
unambiguously established by 1H (400 MHz) and 13C (100
MHz) NMR analysis. The comparison of chemical shifts
for the H1, C3, and C4 signals of 5 (2S,5S) and deprotected
6 (2R,5S) showed that they were diastereomers.
The protected diol acetal 6 was submitted to the action
of the tetrabutylammonium fluoride to afford 7 (81%).
This monoprotected diol possesses two asymmetric cen-
ters, each of which can be independently set, and so this
basic strategy could be used for the construction of
several isomers of macrodiolides such as pyrenophorol
and colletallol.
The alcohol 7 (Scheme 3) was esterified using bro-
moacetyl bromide and pyridine in CH2Cl2 at -20 °C to
give the bromo ester 8a (86%) which was converted
almost quantitatively into the phosphonium salt 8b by
addition of triphenylphosphine. Concurrently, the com-
mercial (R)-ethyl 3-hydroxybutanoate (3) was trans-
formed into the corresponding aldehyde 9b by almost
quantitative silylation of the free hydroxyl function under
classical conditions (ClSi+BuPh2, imidazole, DMF, rt)12
followed by reduction of the ester by DIBALH at -78 °C
according to Baker’s method13 to give aldehyde 9b in 87%
a
(i) BrCOCH2Br, pyridine, CH2Cl2, -20 °C (86%), (ii) PPh3,
CH3CN, rt (94%); (iii) ClSitBuPh2, imidazole, THF, rt (96%), (iv)
DIBALH, Et2O, -78 °C (87%); (v) TEA, CH3CN, 40 °C (74%); (vi)
nBu4N+F-, THF, rt (73%); (vii) BrCOCH2Br, pyridine, CH2Cl2, -20
°C (90%); (viii) HCOOH, rt (93%); (ix) PPh3, CH3CN, rt (quant);
(x) TEA, CH3CN, high dilution, 70 °C (65%); (xi) CAN, CH3CN/
H2O, 0 °C (70%).
yield. The phosphonium salt 8b was treated with 0.8
equiv of TEA to generate in situ the corresponding
phosphorane which was condensed with 1.5 equiv of the
aldehyde 9b in CH3CN to give enoate 10 in good yield
(74%). The exclusively (E)-configuration of the double
bond was established by the large (15.8 Hz) vicinal
coupling observed between the olefinic protons. At this
stage of the synthesis, the upper segment of the target
molecule has been introduced with a new asymmetric
center. The cleavage of the silyl ether 10 was next
achieved with tetrabutylammonium fluoride in THF
(Scheme 3).
These conditions afforded alcohol 11a in good yield.
Esterification with bromoacetyl bromide proceeded
smoothly to afford 11b. Deprotection of the aldehyde
function in neat formic acid for 12 h at rt then yielded
12 (93%) (Scheme 3).
The addition of triphenylphosphine generated the
phosphonium salt which was directly dissolved in a large
volume of acetonitrile. This dilute solution (4 × 10-2 mol/
L) was added over 35 h to a solution of 6 equiv of TEA in
CH3CN heated at 70 °C. These high-dilution conditions
allowed the cyclic monomer 13 to be formed exclusively
in relatively good yields (65%). This intramolecular
(10) The p-methoxyphenyl group has been used in order to protect
some primary alcohols: Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M.
Tetrahedron Lett. 1985, 26, 6291-6292. Petitou, M.; Duchaussoy, P.;
Choay, J . Tetrahedron Lett. 1988, 29, 1389-1390. To our knowledge,
this is the first time that this group has been used for the protection
of a secondary alcohol.
(11) Corey, E. J .; Link, J . O. Tetrahedron Lett. 1992, 33, 3431-3434.
(12) Hopkins, M. H.; Overman, L. E.; Rishton, G. M. J . Am. Chem.
Soc. 1991, 113, 5354-5365.
(13) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J . Org. Chem. 1983,
48, 5180-5182.

6376 J . Org. Chem., Vol. 62, No. 18, 1997
Amigoni et al.
matography on silica gel (E/PE (10/90)) yielded 4 (0.86 g, 86%).
1H NMR: δ 7.70-7.40 (m, 10H), 5.88 (dd, J ) 15.6 Hz and
5.4 Hz, 1H), 5.65 (dd, J ) 15.6 Hz and 5.4 Hz, 1H), 4.38 (m,
1H), 4.22 (d, J ) 6.0 Hz, 1H), 4.10 (m, 1H), 3.90-3.50 (m, 4H),
2.25 (d, J ) 3.4 Hz, 1H), 1.25 (t, J ) 7.1 Hz, 3H), 1.19 (t, J )
7.1 Hz, 3H), 1.15 (d, J ) 6.3 Hz, 3H), 1.08 (s, 9H). 13C NMR:
δ 15.3, 15.4, 19.3, 24.2, 27.0, 63.4, 63.5, 69.6, 72.0, 104.7, 126.2,
127.4, 127.5, 129.5, 134.2, 134.6, 135.9, 136.0, 136.6. IR:
Wittig reaction afforded the (E)-alkene as established by
the large (15.7 Hz) vicinal coupling between the olefinic
protons. The (E)-configuration of the double bonds and
the configurations of the three asymmetric carbons of the
molecule were verified by X-ray crystallographic analysis.
Cleavage of the p-anisyl ether with CAN in aqueous
acetonitrile at 0 °C afforded the (-)-(6R,11R,14S)-isomer
of colletallol 1 in 70% yield; the structure was again
unambiguously established by X-ray crystallography.15
This total synthesis gave the desired colletallol stere-
oisomer 1 in 15 steps and 4% overall yield. It is
important to note that the enantiomers of the starting
building blocks are commercially available and that the
two esterifications with bromoacetyl bromide could be
achieved using bromoacetic acid under Mitsunobu condi-
tions14 with inversion of configuration at the asymmetric
centers. Similarly, the asymmetric reduction of enone 2
by Corey’s (R)-oxazaborolidine gives allylic alcohol 4′
(2R,5S) with the same de as previously reported for the
(S)-enantiomer and in good yields. Thus this strategy is
extremely flexible and should be useful for the prepara-
tion of any stereoisomer of colletallol. It could be
similarly developed for the synthesis of the symmetrical
16-membered macrodiolides such as pyrenophorol2 for
instance.
3475.0 cm-1. [R]25 ) -38.1 (c 4.06; CH2Cl2). Rf ) 0.45 E/PE
D
(50/50). Anal. Calcd for C26H38O4Si: H, 8.66; C, 70.55.
Found: H, 8.64; C, 70.27.
(2R,3E,5S)-1,1-Dieth oxy-5-((ter t-bu tyldiph en ylsilyl)oxy)-
3-h exen -2-ol (4′). 1H NMR: δ 7.67-7.36 (m, 10H), 5.85 (dd,
J ) 15.6 Hz and 5.4 Hz, 1H), 5.70 (dd, J ) 15.6 Hz and 5.4
Hz, 1H), 4.35 (m, 1H), 4.16 (d, J ) 6.0 Hz, 1H), 4.02 (m, 1H),
3.85-3.45 (m, 4H), 2.16 (d, J ) 3.6 Hz, 1H), 1.25 (t, J ) 7.0
Hz, 3H), 1.19 (t, J ) 7.0 Hz, 3H), 1.15 (d, J ) 6.3 Hz, 3H),
1.08 (s, 9H). 13C NMR: δ 15.3, 15.4, 19.2, 24.2, 26.9, 63.4,
63.7, 69.6, 72.1, 104.8, 126.0, 127.4, 127.5, 129.5, 134.2, 134.5,
135.9, 136.9. IR: 3475.0 cm-1. [R]25D ) -15.4 (c 4.02; CH2Cl2).
Rf ) 0.45 E/PE (50/50).
(2S,5S)-1,1-Dieth oxy-5-((ter t-bu tyld ip h en ylsilyl)oxy)-
2-h exa n ol (5). A solution of allylic alcohol 4 (1.17 g, 2.6 mmol)
in ethyl acetate (50 mL) containing 10% Pd/C (0.11 g, 10% by
weight) was stirred overnight at rt under a hydrogen atmo-
sphere (1 atm). The mixture was filtered on silica gel and
chromatographed (E/PE (10/90)) to afford 5 (0.8 g, 68%). 1H
NMR: δ 7.70-7.40 (m, 10H), 4.19 (d, J ) 5.6 Hz, 1H), 3.87
(m, 1H), 3.80-3.52 (m, 4H), 3.45 (m, 1H), 2.19 (d, J ) 3.6 Hz,
1H), 1.30-1.80 (m, 4H), 1.22 (t, J ) 7.1 Hz, 3H), 1.19 (t, J )
7.1 Hz, 3H), 1.05 (d, J ) 5.9 Hz, 3H), 1.04 (s, 9H). 13C NMR:
δ 15.4, 19.3, 23.2, 27.0, 35.5, 63.4, 69.8, 72.0, 105.1, 127.4,
Exp er im en ta l Section
127.5, 129.4, 129.5, 134.4, 134.9, 135.9. IR: 3435.0 cm-1
.
Gen er a l P r oced u r es. Melting points are uncorrected.
Optical rotations were measured at 25 °C. IR spectra were
recorded on a FT-IR spectrometer. 1H NMR spectra were
recorded at 400 MHz and 13C NMR at 100 MHz in CDCl3. Mass
spectra were obtained at 70 eV either in EI mode (HRMS) or
using CI/NH3 (MS). Elemental analyses were performed by
the Service de microanalyses (ICSN Gif sur Yvette). All
separations were carried out under flash chromatographic
conditions on Merck silica gel Geduran Si60 (230-240 mesh)
using as eluent mixtures of ether (E) and low-boiling (<60 °C)
petroleum ether (PE). CH2Cl2 was distilled from P2O5, toluene
from CaCl2, and THF from sodium/benzophenone.
[R]25D ) -16.8 (c 1.04; CH2Cl2). Rf ) 0.60 E/PE (50/50). HRMS
(EI) for C26H40O4Si calcd: 341.1573. Found: 341.1574.
(2R,5S)-1,1-Dieth oxy-5-((ter t-bu tyld ip h en ylsilyl)oxy)-
2-h exa n ol (5′). 1H NMR: δ 7.67-7.37 (m, 10H), 4.21 (d, J )
6.1 Hz, 1H), 3.93 (m, 1H), 3.80-3.42 (m, 5H), 2.11 (d, J ) 3.7
Hz, 1H), 1.30-1.80 (m, 4H), 1.23 (t, J ) 7.2 Hz, 3H), 1.21 (m,
3H), 1.20 (t, J ) 7.2 Hz, 3H), 1.1 (s, 9H). 13C NMR: δ 15.4,
19.3, 23.1, 27.0, 35.0, 63.5, 69.4, 71.9, 105.1, 127.4, 127.5, 129.4,
129.5, 134.5, 134.9. IR: 3435.0 cm-1. [R]25 ) -2.6 (c 3.09;
D
CH2Cl2). Rf ) 0.60 E/PE (50/50).
(2R,5S)-1,1-Dieth oxy-5-((ter t-bu tyld ip h en ylsilyl)oxy)-
2-(4′-m eth oxyp h en oxy)h exa n e (6). DEAD (0.42 mL, 2.7
mmol, 1.6 equiv) was added dropwise to a solution of alcohol
5 (0.76 g, 1.7 mmol), p-methoxyphenol (0.72 g, 5.8 mmol, 3.4
equiv), and triphenylphosphine (0.65 g, 2.4 mmol, 1.5 equiv)
in THF (45 mL). The mixture was heated at 90 °C for 3 h
and the solvent evaporated. The crude product was extracted
with ether (25 mL) and filtered. The solution was dried and
concentrated under vacuo. Chromatography on silica gel (E/
PE (5/95)) yielded 6 (0.8 g, 85%). 1H NMR: δ 7.80-7.30 (m,
10H), 6.80 (m, 4H), 4.43 (d, J ) 5.6 Hz, 1H), 4.04 (m, 1H),
3.84 (m, 1H), 3.76 (s, 3H), 3.85-3.40 (m, 4H), 1.45-1.90 (m,
4H), 1.21 (t, J ) 7.1 Hz, 3H), 1.12 (t, J ) 7.1 Hz, 3H), 1.04
(d, J ) 6.6 Hz, 3H), 1.03 (s, 9H). 13C NMR: δ 15.4, 15.3,
19.2, 23.1, 25.5, 27.0, 34.8, 55.7, 63.9, 69.4, 80.5, 103.7,
114.4, 117.5, 127.4, 127.5, 129.4, 134.5, 134.9, 135.9, 153.2,
(2S,3E,5S)-1,1-Dieth oxy-5-((ter t-bu tyldiph en ylsilyl)oxy)-
3-h exen -2-ol (4). To a solution of borane in THF (1 M, 0.018
mL, 17.5 mmol) was slowly added at 0 °C 2,2,2-trifluoroethanol
(3.5 mL, 47.8 mmol, 2.7 equiv). The mixture was stirred for
20 min at rt, and THF was removed by distillation (70-80
°C). After the residual oil was cooled to rt, tributylborane in
THF (1 M, 9.5 mL, 9.5 mmol, 0.5 equiv) and borane in THF (1
M, 0.48 mL, 0.48 mmol, 0.03 equiv) were successively added.
The solution was heated at 90 °C for 3 h and the solvent
removed by distillation (70-80 °C). Distillation of the crude
product in vacuo (bp 60-70 °C at 0.1 mmHg) afforded the
n-butylboronate (3 g, 56%).
To a solution of (S)-2-(hydroxydiphenylmethyl)pyrrolidine
(0.55 g, 2.2 mmol) in anhydrous toluene (2 mL) was added the
boronate (0.65 mL, 4.4 mmol, 2 equiv). The reaction mixture
was stirred at rt for 20 min and evaporated. The residue was
heated for 1 h 30 min at 130 °C under reduced pressure (0.1
mmHg). Borane-dimethyl sulfide complex (0.45 mL, 4.5
mmol, 2 equiv) and a solution of 2 (1 g, 2.3 mmol, 1 equiv) in
THF (2 mL) were successively added at 0 °C. After being
stirred for 30 min, the reaction was hydrolyzed with MeOH
(2 mL) and 1 N HCl (25 mL) was added. The product was
extracted with ether, and the organic layer was washed with
water (2 × 25 mL), dried (MgSO4), and concentrated. Chro-
153.9. IR: 2924.2, 1222.0, and 1103.0 cm-1. [R]25 ) -10.2
D
(c 0.98; CH2Cl2). Rf ) 0.95 E/PE (50/50). Anal. Calcd for
C33H46O5Si: H, 8.42; C, 71.96. Found: H, 8.51; C, 72.08.
(2R ,5S )-1,1-Die t h oxy-2-(4′-m e t h oxyp h e n oxy)-5-h e x-
a n ol (7). To a solution of compound 6 (0.8 g, 1.5 mmol) in
THF (65 mL) was added a solution of tetrabutylammonium
fluoride in THF (1 M, 5.7 mL, 5.7 mmol, 3.8 equiv) at -20 °C.
The mixture was warmed up to rt and stirred for 3 days. The
reaction was hydrolyzed with brine (50 mL), and the product
was extracted with ether (50 mL). The organic layer was dried
(MgSO4) and concentrated. Chromatography of the residual
oil on silica gel (E/PE (50/50)) afforded 7 (0.37 g, 81%). 1H
NMR: δ 6.86 (m, 4H), 4.50 (d, J ) 5.1 Hz, 1H), 4.16 (m, 1H),
3.80 (m, 1H), 3.76 (s, 3H), 3.75-3.50 (m, 4H), 1.60-2.00 (m,
4H), 1.23 (t, J ) 7.1 Hz, 3H), 1.18 (d, J ) 6.1 Hz, 3H), 1.13 (t,
J ) 7.1 Hz, 3H). 13C NMR: δ 15.3, 15.4, 19.2, 23.4, 26.2, 35.0,
55.7, 64.1, 68.0, 80.3, 103.7, 114.6, 117.4, 153.0, 154.1. IR:
(14) Mitsunobu, O. Synthesis 1981, 1-28. Hughes, D. L.; Reamer,
R. A.; Bergan, J . J .; Grabowski, E. J . J . J . Am. Chem. Soc. 1988, 110,
6487-6491.
(15) The author has deposited atomic coordinates for structures 1
and 13 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.

Enantioselective Synthesis of (-)-(6R,11R,14S)-Colletallol
J . Org. Chem., Vol. 62, No. 18, 1997 6377
3450.5 cm-1. [R]25 ) +24.8 (c 1.01; CH2Cl2). Rf ) 0.15 E/PE
gave 10 (0.28 g, 74%). 1H NMR: δ 6.91 (m, 2H), 6.87 (m, 1H),
6.80 (m, 2H), 5.73 (d, J ) 15.8 Hz, 1H), 4.96 (m, 1H), 4.48 (d,
J ) 5.1 Hz, 1H), 4.12 (m, 1H), 3.95 (m, 1H), 3.75 (s, 3H), 3.80-
3.40 (m, 4H), 2.30 (m, 2H), 1.78 (m, 4H), 1.21 (m, 6H), 1.12 (t,
J ) 7.1 Hz, 3H), 1.08 (d, J ) 6.1 Hz, 3H), 1.04 (s, 9H). 13C
NMR: δ 15.3, 19.2, 19.9, 23.2, 25.7, 26.9, 31.6, 42.1, 55.6, 63.9,
64.0, 68.5, 70.4, 79.9, 103.5, 114.5, 117.4, 123.8, 127.5, 127.6,
129.5, 129.6, 133.9, 134.3, 135.8, 145.2, 153.0, 165.9. IR:
D
(50/50). Anal. Calcd for C17H28O5: H, 9.04; C, 65.34. Found:
H, 9.03; C, 65.08.
Br om oa cetic Acid , (2R,5S)-1,1-Dieth oxy-2-(4′-m eth oxy-
p h en oxy)-5-h exyl Ester (8a ). To a solution of alcohol 7 (0.37
g, 1.2 mmol) and pyridine (0.19 mL, 2.3 mmol, 1.9 equiv) in
CH2Cl2 (15 mL) was added bromoacetyl bromide (0.12 mL, 1.4
mmol, 1.2 equiv). After being stirred for 20 min, at rt the
reaction mixture was filtered on silica gel and the solvent
evaporated. The residual oil was chromatographed on silica
gel (E/PE (10/90)) to yield 8a (0.44 g, 86%). 1H NMR: δ 6.85
(m, 4H), 4.97 (m, 1H), 4.49 (d, J ) 4.5 Hz, 1H), 4.13 (m, 1H),
3.77 (s, 5H), 3.75-3.45 (m, 4H) 1.95-1.55 (m, 4H), 1.25 (d, J
) 6.1 Hz, 3H), 1.23 (t, J ) 7.1 Hz, 3H), 1.13 (t, J ) 7.1 Hz,
3H). 13C NMR: δ 15.3, 15.4, 19.7, 25.4, 26.4, 31.3, 55.7, 64.1,
64.2, 73.2, 79.8, 103.4, 114.6, 117.4, 152.9, 154.1, 166.9. IR:
1721.9 and 1651.6 cm-1. [R]25 ) +30.7 (c 0.65; CH2Cl2). Rf
D
) 0.75 E/PE (50/50). Anal. Calcd for C39H54O7Si: H, 8.22; C,
70.66. Found: H, 7.98; C, 70.80.
(5R)-5-Hyd r oxyh ex-2-en oa te 11a . To a solution of com-
pound 10 (0.28 g, 0.42 mmol) in anhydrous THF (4 mL) were
added tetrabutylammonium fluoride in THF (1 M, 1.2 mL, 1.2
mmol, 2.8 equiv) and acetic acid (0.07 mL, 1.22 mmol, 2.9
equiv) at -20 °C. The mixture was stirred at rt for 4 days,
and the reaction was hydrolyzed with brine (25 mL). The
aqueous layer was extracted with ether (50 mL), the organic
layer was dried (MgSO4) and concentrated, and the residue
was purified by chromatography on silica gel (E/PE (50/50))
to yield 11a (0.13 g, 73%). 1H NMR: δ 6.92 (m, 3H), 6.80 (m,
2H), 5.83 (d, J ) 15.8 Hz, 1H), 4.97 (m, 1H), 4.48 (d, J ) 5.1
Hz, 1H), 4.12 (m, 1H), 3.95 (m, 1H), 3.77 (s, 3H), 3.50-3.75
(m, 4H), 2.34 (t, J ) 7.4 Hz, 2H), 1.79 (m, 4H), 1.22 (m, 9H),
1.13 (t, J ) 7.1 Hz, 3H). 13C NMR: δ 15.3, 20.0, 23.2, 25.6,
31.6, 41.9, 55.7, 64.1, 66.7, 70.7, 79.9, 103.5, 114.5, 117.4, 124.3,
1743.0 cm-1. [R]25 ) +12.6 (c 0.87; CH2Cl2). Rf ) 0.70 E/PE
D
(50/50). HRMS (EI) for C19H29BrO6 calcd: 432.1147. Found:
432.1151. Anal. Calcd for C19H29BrO6: H, 6.75; C, 52.66.
Found: H, 6.73; C, 52.36.
P h osp h on iu m sa lt 8b. A solution of 8a (0.4 g, 0.9 mmol)
and triphenylphosphine (0.3 g, 1.1 mmol, 1.2 equiv) in aceto-
nitrile (68 mL) was stirred at rt for 24 h. The solvent was
evaporated, and the residue washed with ether (3 × 50 mL)
to yield 8b (0.7 g, 94%). 1H NMR: δ 7.80 (m, 15 H), 6.84 (m,
4H), 5.63 (dd, J ) 15.5 Hz and 14.3 Hz, 1H), 5.24 (dd, J )
16.3 Hz and 14.2 Hz, 1H), 4.75 (m, 1H), 4.45 (d, J ) 5.1 Hz,
1H), 4.03 (m, 1H), 3.75 (s, 3H), 3.75-3.45 (m, 4H), 1.80-1.35
(m, 4H), 1.20 (t, J ) 7.1 Hz, 3H), 1.12 (t, J ) 7.1 Hz, 3H), 1.03
(d, J ) 6.1 Hz, 3H). 13C NMR: δ 15.3, 15.4, 19.2, 25.5, 31.2,
33.5 (d, J CP ) 55.7 Hz), 55.7, 64.3, 64.4, 74.7, 79.7, 103.4, 114.6,
117.2, 118.1 (d, J CP ) 89.3 Hz), 130.3 (d, J CP ) 13.0 Hz), 134.0
(d, J CP ) 10.7 Hz), 135.1 (d, J CP ) 3.0 Hz), 152.9, 154.0, 164.1
144.7, 153.0, 154.0, 166.0. IR 3458.6, 1722.0 and 1658.0 cm-1
.
[R]25D ) +13.0 (c 0.30; CH2Cl2). Rf ) 0.10 E/PE (50/50). Anal.
Calcd for C23H36O7: H, 8.55; C, 65.06. Found: H, 8.25; C, 64.93.
(5R)-5-(Br om oa cetoxy)h ex-2-en oa te 11b. To a solution
of alcohol 11a (0.3 g, 0.7 mmol) and pyridine (0.3 mL, 2.5
mmol, 3.5 equiv) in CH2Cl2 (20 mL) was added bromoacetyl
bromide (0.2 mL, 2.3 mmol, 3 equiv) at -20 °C. The reaction
mixture was stirred for 30 min at -20 °C and filtered on silica
gel. The residue was concentrated when chromatography on
silica gel (E/PE (20/80)) afforded 11b (0.35 g, 90%). 1H NMR:
δ 6.93 (m, 2H), 6.87 (m, 1H), 6.82 (m, 2H), 5.87 (d, J ) 15.6
Hz, 1H), 5.07 (m, 1H), 4.99 (m, 1H), 4.49 (d, J ) 5.2 Hz, 1H),
4.15 (m, 1H), 3.81 (s, 2H), 3.78 (s, 3H), 3.50-3.78 (m, 4H), 2.50
(m, 2H), 1.80 (m, 4H), 1.31 (d, J ) 6.4 Hz, 3H), 1.26 (d, J )
6.4 Hz, 3H), 1.24 (t, J ) 7.0 Hz, 3H), 1.14 (t, J ) 7.1 Hz, 3H).
13C NMR: δ 15.2, 15.3, 19.3, 19.9, 25.6, 25.9, 31.5, 38.0, 55.6,
64.0, 70.8, 71.4, 79.9, 103.4, 114.5, 117.3, 124.9, 142.3, 152.9,
(d, J CP ) 3.8 Hz). IR: 1722.8 and 1635.3 cm-1. [R]25 ) +6.1
D
(c 1.14; CH2Cl2). Rf ) 0.00 E/PE (50/50). HRMS (FAB) for
C37H44BrO6P calcd: 615.2876. Found: 615.2882.
Eth yl (3R)-3-((ter t-Bu tyld ip h en ylsilyl)oxy)bu ta n oa te
(9a ). A solution of ethyl (R)-(-)-3-hydroxybutyrate (3) (1 g,
7.6 mmol), tert-butyldiphenylsilyl chloride (2.5 g, 9.0 mmol,
1.2 equiv), and imidazole (1.3 g, 19.0 mmol, 2.5 equiv) in DMF
(70 mL) was stirred for 3 days at rt. Water was added, and
the aqueous layer was extracted with ether (100 mL). The
organic layer was dried (MgSO4), concentrated, and chromato-
153.9, 165.6, 166.6. IR: 1714.8 and 1665.6 cm-1
+19.4 (c 0.30; CH2Cl2). Rf ) 0.60 E/PE (50/50). HRMS (EI)
for C25H37BrO8 calcd: 544.1671. Found: 544.1664.
. )
[R]25
1
graphed on silica gel (E/PE (5/95)) to yield 9a (2.7 g, 96%). H
D
NMR: δ 7.72-7.41 (m, 10H), 4.33 (m, 1H), 4.08 (m, 2H), 2.57
(dd, J ) 14.5 Hz and 6.9 Hz, 1H), 2.41 (dd, J ) 14.5 Hz and
5.8 Hz, 1H), 1.23 (t, J ) 7.2 Hz, 3H), 1.14 (d, J ) 6.3 Hz, 3H),
1.05 (s, 9H). 13C NMR: δ 14.1, 19.2, 23.6, 26.9, 44.7, 60.3,
66.9, 127.5, 129.6, 133.9, 134.3, 135.8, 135.9, 171.5. IR: 1739.0
Ald eh yd e 12. To a solution of compound 11b (0.35 g, 0.64
mmol) in CH2Cl2 (1 mL) was added formic acid (0.5 mL, 13.0
mmol, 20 equiv). The mixture was stirred for 12 h, and the
solvent and formic acid were removed under vacuo to afford
12 (0.28 g, 93%). 1H NMR: δ 9.71 (d, J ) 2.1 Hz, 1H), 6.89
(m, 1H), 6.84 (s, 4H), 5.87 (d, J ) 15.6 Hz, 1H), 5.10 (m, 1H),
5.00 (m, 1H), 4.44 (m, 1H), 3.82 (s, 2H), 3.78 (s, 3H), 2.50 (m,
2H), 1.87 (m, 4H), 1.32 (d, J ) 6.3 Hz, 3H), 1.28 (d, J ) 6.4
Hz, 3H). 13C NMR: δ 19.5 and 20.0, 26.0, 26.1, 31.0, 38.1,
55.7, 70.1, 71.4, 82.1, 114.9, 116.5, 124.7, 143.0, 151.6, 154.7,
165.6, 166.7, 202.9. IR: 1739.7, 1718.2, 1662.3, and 1597.7
cm-1
.
[R]25 ) -15.0 (c 2.07; CH2Cl2). Rf ) 0.90 E/PE (50/
D
50). Anal. Calcd for C22H30O3Si: H, 8.17; C, 71.31. Found:
H, 8.13; C, 71.47.
(3R)-3-((ter t-Bu tyld ip h en ylsilyl)oxy)bu ta n a l (9b). To
a solution of ester 9a (1 g, 3.4 mmol) in anhydrous ether (2
mL) was added dropwise a solution of DIBALH in toluene (1M,
4 mL, 4.0 mmol, 1.2 equiv) at -78 °C over 1 h. The reaction
mixture was stirred for 1 h at -78 °C and hydrolyzed with an
aqueous solution of 2 N NaOH (25 mL). The organic layer
was washed with water (2 × 25 mL), dried (MgSO4), and
concentrated. The crude product was chromatographed on
silica gel (E/PE (5/95)) to afford 9b (0.75 g, 87%). 1H NMR: δ
9.75 (t, J ) 2.0 Hz, 1H), 7.90-7.50 (m, 10H), 4.34 (m, 1H),
2.53 (ddd, J ) 15.8 Hz, 6.1 Hz and J ) 3.0 Hz, 1H), 2.47 (ddd,
J ) 15.8 Hz, 5.6 Hz and 2.0 Hz, 1H), 1.17 (d, J ) 6.1 Hz, 3H),
1.00 (s, 9H). 13C NMR: δ 19.2, 23.8, 26.9, 52.7, 65.7, 127.6,
cm-1
.
[R]25 ) +50.7 (c 0.67; CH2Cl2). Rf ) 0.40 E/PE (50/
D
50). HRMS (EI) for C21H27BrO7 calcd: 470.0940. Found:
470.0973.
(6R,11R,14S)-O-p-An isylcolleta llol (13). A solution of
aldehyde 12 (0.25 g, 0.56 mmol) and triphenylphosphine (0.2
g, 0.76 mmol, 1.3 equiv) in acetonitrile (50 mL) was stirred
overnight at rt. The solvent was removed, and the residue
was washed with ether (3 × 50 mL). The crude product (0.4
g, 0.55 mmol) was dissolved in acetonitrile (70 mL) and was
added over 40 h to a solution of TEA (0.5 mL, 3.3 mmol, 6
equiv) in acetonitrile (15 mL) heated at 70 °C. The reaction
mixture was stirred for 24 h at 70 °C and the solvent removed.
The crude product was extracted with ether (50 mL) and
concentrated. Chromatography on silica gel (E/PE (10/90))
afforded 13 (0.14 g, 65%). 1H NMR: δ 6.86 (dd, J ) 15.8 Hz
and 3.9 Hz, 1H), 6.80 (s, 4H), 6.76 (ddd, J ) 15.7 Hz, 8.7 Hz
and 6.7 Hz, 1H), 6.02 (dd, J ) 15.8 Hz and 1.7 Hz, 1H), 5.80
(d, J ) 15.7 Hz, 1H), 5.27 (m, 1H), 5.10 (m, 1H), 4.75 (m, 1H),
3.80 (s, 3H), 2.77 (m, 1H), 2.18 (m, 1H), 1.75-1.65 (m, 2H),
127.7, 129.7, 129.9, 133.5, 134.0, 135.8, 202.1. IR 1732.8 cm-1
.
[R]25D ) +10.3 (c 0.98; CH2Cl2). Rf ) 0.90 E/PE (50/50). Anal.
Calcd for C20H26O2Si: H, 8.03; C, 73.57. Found: H, 8.20; C,
73.31.
(5R)-5-((ter t-Bu tyld ip h en ylsilyl)oxy)h ex-2-en oa te 10.
To a solution of phosphonium salt 8b (0.4 g, 0.50 mmol) and
TEA (0.07 mL, 0.46 mmol, 0.8 equiv) in acetonitrile (20 mL)
was added the aldehyde 9b (0.25 g, 0.84 mmol, 1.5 equiv). The
mixture was heated at 40 °C for 24 h and the solvent removed.
The residual oil was dissolved in ether (25 mL), filtered, and
concentrated. Chromatography on silica gel (E/PE (10/90))

6378 J . Org. Chem., Vol. 62, No. 18, 1997
Amigoni et al.
1.41 (d, J ) 6.5 Hz, 3H), 1.25 (d, J ) 6.4 Hz, 3H). 13C
NMR: δ 19.6, 20.2, 28.3, 29.0, 37.8, 55.7, 69.2, 70.5, 76.2, 114.7,
116.9, 121.7, 125.0, 143.9, 147.8, 151.2, 154.2, 165.9. IR:
1H), 4.39 (m, 1H), 2.76 (m, 1H), 2.35 (m, 1H), 1.96 (m, 1H),
1.79 (d, J ) 4.1 Hz, 1H), 1.65-1.45 (m, 3H), 1.39 (d, J ) 6.6
Hz, 3H), 1.22 (d, J ) 6.6 Hz, 3H). 13C NMR: δ 19.4, 20.2,
28.0, 31.0, 37.5, 69.2, 70.2, 70.3, 120.2, 125.0, 143.9, 150.3,
1707.8, 1651.6, and 1595.3 cm-1
.
[R]25 ) -30.5 (c 0.59;
D
CH2Cl2). Rf ) 0.35 E/PE (50/50). Mp: 122 °C. HRMS (EI)
for C21H26O6 calcd: 374.1729. Found: 374.1773. Anal. Calcd
for C21H26O6: H, 7.00; C, 67.35. Found: H, 6.96; C, 67.28.
(6R,11R,14S)-Isom er of Colleta llol (1). To a solution of
compound 13 (0.09 g, 0.24 mmol) in acetonitrile/water (12/3)
(15 mL) was added CAN (0.3 g, 0.55 mmol, 2 equiv) at -20
°C. The reaction mixture was stirred for 20 min at -20 °C
and was extracted with ether. The organic layer was washed
with water (2 × 25 mL), dried (MgSO4), and concentrated.
Chromatography on silica gel (E/PE (50/50)) gave 1 (0.045 g,
70%). 1H NMR: δ 6.80 (dd, J ) 15.8 Hz and 3.6 Hz, 1H), 6.74
(dd, J ) 15.3 Hz and 7.4 Hz, 1H), 6.00 (dd J ) 15.8 Hz and
2.0 Hz, 1H), 5.77 (d, J ) 15.3 Hz, 1H), 5.23 (m, 1H), 5.10 (m,
165.9, 166.1. IR: 1715.0 and 1653.6 cm-1. [R]25 ) -99.0 (c
D
0.02; CH2Cl2). Rf ) 0.10 E/PE (50/50). Mp: 72 °C. MS (CI,
NH3): m/z 286.3, 268.3. HRMS (EI) for C14H20O5 (M -
C2H4O•)+ calcd: 224.1048. Found: 224.1034. Anal. Calcd for
C14H20O5: H, 7.52; C, 62.66. Found: H, 7.51; C, 62.73.
Ack n ow led gm en t. We thank R. Gre´e and J . Doyon
(CNRS ESA 6052) for several helpful discussions of this
work. This research was supported by a grant from the
French Ministry of Science and Research.
J O970020S