Synthetic efforts toward the macrolactone core of leucascandrolide A

Article abstract of DOI:10.1021/jo701315h

(Chemical Equation Presented) A chemoselective synthesis of 1, the macrocyclic core of leucascandrolide A, has been achieved by utilizing highly enantioselective allylmetalations, an enantioselective Noyori reduction of a propargylic ketone, and olefin metatheses as the key steps.

Full text of DOI:10.1021/jo701315h

Synthetic Efforts toward the Macrolactone Core of
Leucascandrolide A
Laurent Ferrie´, Lucie Boulard, Fabienne Pradaux, Samir Bouzbouz, Se´bastien Reymond,
Patrice Capdevielle, and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France
janine.cossy@espci.fr
ReceiVed June 26, 2007
A chemoselective synthesis of 1, the macrocyclic core of leucascandrolide A, has been achieved by
utilizing highly enantioselective allylmetalations, an enantioselective Noyori reduction of a propargylic
ketone, and olefin metatheses as the key steps.
Leucascandrolide A was isolated in 1996 from the calcareous
sponge Leucascandra caVeolata,1 which was collected along
the east coast of New Caledonia. Although leucascandrolide A
was isolated in a significant amount (70 mg from 240 g of
sponge, 0.03%), further attempts to isolate leucascandrolide A
from the sponge have proven unsuccessful since. In fact, this
compound is not a metabolite of Leucascandra itself but rather
that of an opportunistic bacteria that colonized the sponge.2 The
gross structure and relative configuration of leucascandrolide
1
A were assigned on the basis of HRMS, MS-MS, H NMR,
13C NMR, and DEPT experiments, as well as elaborate 2D NMR
studies. The absolute configurations were determined from
degradation and Mosher ester analysis.1 As shown in Figure 1,
leucascandrolide A displays several distinctive architectural
features. This compound is constituted by a 2,4-disubstituted
oxazole on the lateral chain and an 18-membered macrolactone
that encompasses two trisubstituted tetrahydropyrans (THP), one
of which is a trans-2,6-disubstituted THP, and the second is a
2,6-cis-disubstituted THP. In all, eight stereogenic centers are
present in the macrocyclic core of leucascandrolide A (Figure
1).
Leucascandrolide A displays a significant in vitro cytotoxicity
(IC50 ) 0.05 and 0.25 µg/mL with KB and P388 cells,
respectively), as well as significant antifungal properties. Due
FIGURE 1. Structures of leucascandrolide A and its macrolactone
core.
to its structural complexity, its interesting biological properties
and the lack of availability from natural sources, leucascan-
drolide A has sollicited considerable interest among organic
chemists.3-5 Recently, we reported the formal synthesis of
leucascandrolide A,6 and we would like to report here a full
account of our synthetic studies toward the macrocyclic core
of leucascandrolide A 1 by utilizing enantioselective reactions
and olefin metatheses with chiral titanium complexes and
ruthenium catalysts (Figure 2).
(1) D’Ambrosio, M.; Guerriero, M.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51.
(2) D’Ambrosio, M.; Tato, M.; Debitus, C.; Pietra, F. HelV. Chim. Acta
1999, 82, 347.
10.1021/jo701315h CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/30/2008
1864
J. Org. Chem. 2008, 73, 1864-1880

Macrolactone Core of Leucascandrolide A
SCHEME 1
FIGURE 2. Chiral titanium complexes and ruthenium catalysts used
in this study.
First Strategy
with allyltitanium complex (R,R)Ti-I (1.1 equiv, Et2O, -78 °C)9
led to the corresponding homoallylic alcohol which was directly
transformed to the methyl ether 410 (MeI, NaH, THF) with an
overall yield of 76% for the two steps. In order to control the
C7 stereogenic center, the required aldehyde for the enantiose-
lective allylmetalation was easily obtained after ozonolysis of
the terminal double bond present in 4. Due to the instability of
this aldehyde, the latter compound was directly treated with the
highly face-selective allyltitanium complex (R,R)Ti-I. The
resulting homoallylic alcohol was not fully purified but treated
with TBSOTf (2.2 equiv) [2,6-lutidine (4.4 equiv), CH2Cl2, -78
°C] to produce the desired protected triol 5 in 68% yield for
the three-step sequence (from 4) and with a diastereomeric ratio
superior to 95:5.11
In order to obtain the C5-C11 fragment and to control the
C5 stereogenic center, olefin 5 was subjected to ozonolysis (O3,
PPh3, CH2Cl2), leading to the corresponding aldehyde, which
was engaged in a third enantioselective allyltitanation using the
(R,R)Ti-I complex.9 The obtained homoallylic alcohol was
directly protected as a MOM ether (MOMCl, i-Pr2NEt) to afford
olefin 6 (67% overall yield from 5) with an excellent diaster-
eomeric ratio of 95/5.10 In order to build up the cis-THP, by
using an intramolecular 1,4-addition of an alcoholate on an
unsaturated ester, a CM reaction between 6 and ethyl acrylate
was achieved with Ru-III (2.5 mol %) to afford the R,â-
unsaturated ester 7 in 85% yield. After selective deprotection
of the primary alcohol (NH4F, MeOH, reflux, 65% yield),12
Our first retrosynthetic analysis for the synthesis of the
macrocyclic core of leucascandrolide A, compound 1, is
illustrated in Scheme 1. Compound 1 would be obtained from
aldehyde A, the C15 stereogenic center of which would be
controlled by the addition of trimethylallylsilane on an oxonium
species generated from lactol B. Lactol B would be prepared
from C by using a one-pot sequence cross-metathesis (CM)/
hydrogenation/cyclization utilizing acrolein as the CM partner.7
The cis-THP present in C could be easily obtained from D
through an intramolecular 1,4-addition of the hydroxyl group
present at C7 on the unsaturated ester. This R,â-unsaturated ester
would be built by using a cross-metathesis applied to compound
E followed by a stereoselective crotylmetalation to control the
stereogenic centers at C11 and C12. In order to control the C5,
C7, and C9 stereogenic centers in E, iterative enantioselective
allylmetalations applied to aldehyde F could be utilized. The
starting aldehyde F would be easily prepared from 1,3-
propanediol 2 (Scheme 1).
The synthesis of the C1-C12 fragment of leucascandrolide
A started with the preparation of aldehyde 3, easily accessible
in two steps from 1,3-propanediol 2.8 Treatment of aldehyde 3
(3) a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem.
Soc. 2000, 122, 12894. (b) Wang, Y.; Janjic, J.; Kozmin, S. A. J. Am. Chem.
Soc. 2002, 124, 13670. (c) Fettes, A.; Carreira, E. M. Angew. Chem., Int.
Ed. 2002, 41, 4098. (d) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68,
9274. (e) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343. (f)
Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833. (g) Wang, Y.; Jelena,
J.; Kozmin, S. A. Pure Appl. Chem. 2005, 77, 1161. (h) Su, Q.; Paneck, J.
S. Angew. Chem., Int. Ed. 2005, 44, 1223. (g) Su, Q.; Dakin, L. A.; Paneck,
J. S. J. Org. Chem. 2005, 72, 2.
(4) For syntheses of the macrolide core of leucascandrolide A, see: (a)
Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123, 8420. (b)
Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066. (c) Williams, D. R.;
Plummer, S. V.; Patnaik, S. Angew. Chem., Int. Ed. 2003, 42, 3934. (d)
Williams, D. R.; Patnaik, S.; Plummer, S. V. Org. Lett. 2003, 5, 4641. (e)
Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, 5, 4641.
(5) For syntheses of other fragments of leucascandrolide A, see: (a)
Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2, 579. (b)
Kozmin, S. A. Org. Lett. 2001, 3, 755. (c) Wipf, P.; Graham, T. H. J. Org.
Chem. 2001, 66, 3242. (h) Dakin, L. A.; Langille, N. F.; Paneck, J. S. J.
Org. Chem. 2002, 67, 6812. (g) Dakin, L. A.; Paneck, J. S. Org. Lett. 2003,
5, 3995.
(6) Ferrie´, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2007,
9, 2461.
(7) Bargiggia, F. C.; Bouzbouz, S.; Cossy, J. Tetrahedron Lett. 2002,
43, 6715.
(8) (a) Nacro, K.; Balats, M.; Gorrichon, L. Tetrahedron 1999, 55,
14013-14030. (b) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A.
D.; Halterman J. Am. Chem. Soc. 1990, 112, 6339.
(9) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rhote-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(10) Paterson, I.; Ashton, K.; Britton, R.; Knust, H. Org. Lett. 2003, 5,
1963.
1
(11) dr based on the H NMR spectra of the crude reaction mixture.
(12) Crich, D.; Herman, F. Tetrahedron Lett. 1993, 34, 3385.
J. Org. Chem, Vol. 73, No. 5, 2008 1865

Ferrie´ et al.
SCHEME 2
SCHEME 3
alcohol 8 was oxidized to the corresponding aldehyde (DMP,
CH2Cl2, rt), which was directly treated with the highly face-
selective crotyltitanium complex (R,R)Ti-II.9 The homoallylic
alcohol 9 was isolated in 65% yield with good diastereoselec-
tivity (dr > 95:5).10 Unfortunately, when compound 9 was
treated with TBAF (5 equiv, THF, rt), a poor yield in the
expected intramolecular 1,4-addition product 10 (6% yield) was
obtained, accompanied by the (E,E)-dienoate 11 as the major
product (65% yield), which is the result of the elimination of
the methoxymethyl ether at C5 (Scheme 2).
At this point, a second strategy was considered, based again
on a ring-closing metathesis to construct the trans-tetrahydro-
pyran.
Second Strategy
In this strategy, we envisioned to install at first the trans-
THP instead of the cis-THP as in the previous strategy. The
synthesis of the C1-C22 fragment of leucascandrolide A was
envisaged from aldehyde ester A, and a vinylzincation of the
aldehyde moiety would be used to control the C17 stereogenic
center. As in our first strategy, an intramolecular 1,4-addition
of the alkoxide at C7 on the unsaturated ester present in G would
establish the cis-THP, and the unsaturated ester present in G
would be assembled by using a cross-metathesis between H
and ethyl acrylate. In compound H, the control of the stereogenic
centers at C9, C7, and C5 would be achieved by using
enantioselective allyltitanations applied to aldehydes. Tetrahy-
dropyran I, precursor of H, would be obtained by allylation of
an oxonium species obtained from lactol acetate J. This latter
compound will be generated from a lactone, which will be the
result of a ring-closing metathesis applied to dienic ester K
(Scheme 3).
This new synthesis of the macrocyclic lactone of leucascan-
drolide A started with protected hydroxyaldehyde 3.8 To control
the stereogenic centers at C11 and C12, aldehyde 3 was treated
with the highly face-selective crotyltitanium complex (R,R)Ti-
II.9 The homoallylic alcohol 12 was isolated in 89% yield with
1866 J. Org. Chem., Vol. 73, No. 5, 2008

Macrolactone Core of Leucascandrolide A
SCHEME 4
SCHEME 5
SCHEME 6
obtained in 72% yield.4b After hydrogenation (H2, PtO2),
reduction (DIBAL-H), and acetylation,15 the acetoxylactol 14
was isolated (73% yield) and treated with trimethylallylsilane
in the presence of BF3‚OEt2 to afford the trans-THP 15 in 96%
a 9:1 diastereomeric ratio.13 The precursor of the trans-THP
was achieved in six steps. After treatment of 12 with acryloyl
chloride, the obtained dienic ester was submitted to a ring-
closing metathesis (Ru-II),14 and the unsaturated lactone 13 was
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(15) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(13) Cuzzupe, A. N.; Hutton, C. A.; Lilly, M. J.; Mann, R. K.; McRae,
K. J.; Zammit, S. C.; Rizzacasa, M. A. J. Org. Chem. 2001; 66; 2382.
J. Org. Chem, Vol. 73, No. 5, 2008 1867

Ferrie´ et al.
SCHEME 7
yield (dr ) 9:1).16 After an oxidative cleavage of the double
bond in 15 (OsO4/NaIO4), reduction of the aldehyde (NaBH4),
protection of the alcohol (MOMCl, i-Pr2NEt), selective depro-
tection (TBAF), and Swern oxidation (84% yield over five steps
from 15), the obtained aldehyde 16 was submitted to the
(R,R)Ti-I allyltitanium complex9 to afford the homoallylic
alcohol 17 (84%, dr ) 95/5).10 After transformation of the newly
created hydroxyl group at C8 into a methyl ether (MeOTf, 2,6-
tert-butylpyridine),17 the obtained compound was transformed
to 18 by using two successive oxidative cleavage/allyltitanation
sequences using the (R,R)Ti-I complex to control the stereogenic
centers at C5 and C7. We have to point out that no protection
of the hydroxyl group at C7 is required to run the second
allyltitanation.18 Compound 18 was transformed to the unsatur-
ated ester 19 by using a CM reaction in the presence of ethyl
acrylate in the aim of building up cis-THP by an intramolecular
1,4-addition. Unfortunately, treatment of 19 under basic condi-
tions (NaHMDS, THF, -78 f 0 °C f rt) did not lead to the
desired product 20 (Scheme 4). Due to this failure, a third
strategy was then envisaged, utilizing chemoselective reactions
in order to minimize the number of protecting groups.
(16) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 4976. (b) Danishefsky, S. J.; Kerwin, J. F. J. Org. Chem. 1982, 47,
3803. (c) Kozikowski, A. P.; Sorgi, K. L. Tetrahedron Lett. 1983, 24, 1563.
(d) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25, 2383.
(e) Giannis, A.; Sandhoff, K. Tetrahedron Lett. 1985, 26, 1479.
(17) Walba, D. M.; Thurmes, W. H.; Haltiwanger, R. C. J. Org. Chem.
1988, 53, 1046.
Third Strategy6
In the third strategy, the formation of the cis-THP would be
synthesized as previously by using an intramolecular 1,4-
(18) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 501.
1868 J. Org. Chem., Vol. 73, No. 5, 2008

Macrolactone Core of Leucascandrolide A
SCHEME 8
addition of the alkoxide at C7 on the unsaturated ester L which
would be obtained from the homoallylic alcohol M by using a
cross-metathesis reaction with methyl acrylate. As in our
previous strategies, all the stereogenic centers at C5, C7, and
C9 would be controlled by applying stereoselective allylmeta-
lations to aldehydes, and the C11 and C12 stereogenic centers
would be introduced by using an enantioselective crotylmeta-
lation. However, contrary to the two previous approaches, the
stereogenic center at C17 would be controlled at the beginning
of the synthesis by applying a ruthenium-catalyzed Noyori
reduction of a propargylic ketone. The addition of enol ether
27 to an oxonium species derived from J would allow us to
control the stereogenic center at C15. In order to access the
trans-THP, a RCM applied to diene N, which would be
synthesized from the protected aldehyde F, was envisaged
(Scheme 5).
By using this strategy, the synthesis of leucascandrolide A
started with the preparation of the homoallylic alcohol 228b by
adding (R,R)Ti-II9 to aldehyde 21, in order to control the
stereogenic centers at C11 and C12. The desired homoallylic
alcohol 22 was produced in 86% yield and with a dr superior
to 95:5.10
After transformation of 22 to the unsaturated ester 23
(acryloyl chloride, Et3N, CH2Cl2), two one-pot sequences were
successfully applied to produce the desired acetoxy acetal 25.
The first one-pot reaction involved a tandem RCM/hydrogena-
tion7 [Ru-II11 (3 mol %), 40 °C, then H2, Pd/C] forming
compound 24 in 70% yield.4b The second one-pot reaction was
the transformation of 24 to 25 in 98% yield by reduction of
lactone 24 with DIBAL-H followed by acylation of the alkoxy
aluminum intermediate (Ac2O, Py, DMAP).13
intermediate was generated from 25 by treatment with ZnBr2
at -78 °C and quenched with the enol ether 27 to afford
compound 28 (trans/cis ) 13/1, 89% yield).19 In order to install
the stereogenic center at C17, a Noyori reduction of propargylic
ketone 28 was planned. However, when classical reaction
conditions were used [(R,R)Ru-IV (1-5 mol %), HCOOH,
Et3N], the reduction also resulted in the removal of the TBS
protecting group. When the reduction of 28 was achieved under
non-classical phase-transfer conditions, using (R,R)Ru-IV (HCO2-
Na, n-Bu4NCl, H2O/CH2Cl2),20 the desired propargylic alcohol
29 was isolated in 76% yield accompanied by ketone 30 (18%
yield).21 It is worth noting that the use of the 16-electron Noyori
catalyst in i-PrOH was also tested, but in this case, alcohol 29
was also accompanied by the saturated ketone 30 and the amount
of catalyst needed was higher (10 mol %). Propargyl alcohol
29 was reduced to the (E)-allylic alcohol utilizing Red-Al (8
equiv), but a partial deprotection of the primary TBS ether at
C9 was observed. Due to the formation of this byproduct, the
crude material was directly subjected to TBSOTf (2,6-lutidine,
92% yield over the two steps) to give compound 31. The primary
alcohol was chemoselectively deprotected (NH4F, MeOH, 60
°C, 4 h)12 to afford alcohol 32 (80% yield) along with diol 33
(13%). Despite the formation of byproduct 33, this latter
compound could be easily recycled to 31. Once primary alcohol
32 was obtained, it was oxidized (Dess-Martin periodinane)
to an unstable aldehyde which was directly treated with the
highly face selective titanium complex (R,R)Ti-I9 to produce
homoallylic alcohol 34 (80% yield from 32, dr > 95:5).10 The
hydroxyl group at C9 in compound 34 was then transformed to
a methyl ether (Ag2O, MeI, 96% yield), leading to compound
35. In order to introduce the stereogenic center at C7 by
allylation, compound 35 had to be converted to an aldehyde by
oxidative cleavage of the terminal double bond. However, it
was necessary to perform a selective cleavage of the terminal
double bond over the internal C18-C19 double bond. To realize
this chemoselective transformation, the internal double bond was
On the other hand, the known silyl enol ether 273b was
prepared in two steps from the commercially available 4-methyl
pent-1-yne 26. The starting alkyne was acylated via an orga-
nozinc intermediate (n-BuLi, then ZnCl2 and AcCl) providing
the propargylic ketone (76% yield). This ketone was then treated
with LiHMDS, and the lithium enolate was trapped with TMSCl
to give the silyl enol ether 27 (86% yield) (Scheme 6).
Fragment C16-C22 was then coupled with the C9-C15
fragment by using a Mukaiyama-type reaction.3b,4d An oxonium
(19) Trans/cis ratio determined by GC/MS and GC analysis.
(20) Matsumura, K.; Hashigushi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
(21) A single diastereoisomer was observed by GC and NMR.
J. Org. Chem, Vol. 73, No. 5, 2008 1869

Ferrie´ et al.
SCHEME 9
protected by the use of the sterically hindered TBS group at
C17.22 A dihydroxylation of 35 (OsO4, NMO) led chemose-
lectively to diol 36 (61% yield, 32% unreacted starting material,
dr ) 1:1), which was then treated with NaIO4 to furnish the
desired aldehyde. This aldehyde was directly subjected to an
enantioselective allylation using (R,R)Ti-II9 to produce homoal-
lylic alcohol 37 (78% from diol 36). In order to control the
stereogenic center at C5, alcohol 37 was transformed to an
aldehyde using again the same chemoselective two-step oxida-
tive cleavage. At first, triol 38 was obtained by dihydroxylation
(OsO4, 66% yield, 17% starting material recovered, dr ) 1:1),
and subsequent oxidative cleavage by NaIO4 led to the corre-
sponding aldehyde. At this stage, the stereodirected introduction
of the C5 stereocenter was envisaged by using a stereoselective
allylstannylation.23 The unstable â-hydroxy aldehyde was
directly treated with a solution of allylSnCl3 in CH2Cl2 at -78
°C (prepared from allyltrimethylsilane and SnCl4 at rt)24 and
was transformed to the syn-1,3-diol 39 (74% yield, two steps
from 38) (Scheme 7). The origin of the chiral induction giving
the syn-diol in this reaction is not clear. Some stereodirected
allylmetalations involving a chelation between the allylmetal
and â-hydroxyaldehyde have been reported in the literature, but
these reactions give the anti-diol.25 This syn diastereoselectivity
could be obtained via an internal delivery of the allyl moiety
as it is obtained when â-allylsilyloxyaldehydes are treated with
The formation of 43 can be rationalized by the fact that during
the reaction with t-BuOK, unsaturated ester 40 was transformed
to a mixture of cis-41 and trans-41.31 When cis-41 was treated
with t-BuOK, no epimerization to trans-41 was observed. On
the other hand, when trans-41 was treated with an excess of
t-BuOK (5 equiv), (Z,E)-dienoic acid 43 was obtained, and no
trace of cis-41 was observed. It means that under these basic
conditions, lactonization of trans-41 to a bicyclic compound
proceeds, followed by the formation of enolate 44. This latter
leads to the opening of the strained bicyclic system to give an
intermediate R,â-unsaturated lactone 45 which, under basic
conditions, produces (Z,E)-dienoic acid 46.32 After treatment
of 46 with TBAF, it is transformed to (Z,E)-dienoic acid 43. It
is worth noting that cis-41 cannot lactonize under these
conditions due to the disfavored stereochemistry and does not
lead to the formation of (Z,E)-dienoic acid 46 (Scheme 9).
In order to proceed to the macrocyclization, the seco-acid
47 was obtained from cis-42 under mild saponification condi-
tions utilizing TMSOK in Et2O.33 With the seco-acid 47 in hand,
two attempts were achieved for the cyclization to the macro-
cyclic lactone 1. The first protocol involved the addition of
trichlorobenzoyl chloride to a solution of DMAP, Et3N, and 47
(22) (a) Reymond, S.; Cossy, J. Tetrahedron 2007, 63, 5918. (b)
Reymond, S.; Cossy, J. Eur. J. Org. Chem. 2006, 4800.
(23) (a) Allais, F.; Cossy, J. Org. Lett. 2006, 8, 3655. (b) Allais, F.;
Louvel, M.-C.; Cossy, J. Synlett, 2007, 451. (c) Allais, F.; Roche, C.;
Bouzbouz, S.; Cossy, J. unpublished results.
(24) (a) Dias, L. C.; Giacomini, R. J. Braz. Chem. Soc., 1998, 9, 357.
(b) Dias, L. C.; Meira, P. R. R. Org. Lett. 1999, 1, 1335. (c) Dias, L. C.;
Giacomini, R.; Meira, P. R. R.; Ferreira, E.; Ferreira, A. A.; Diaz, G.; Dos
Santos, D. B.; Steil, L. J. ArkiVoc 2003, 10, 240.
(25) (a) Kabalka, G. W.; Narayana, C.; R. Kesavulu Tetrahedron Lett.
1996, 37, 2181. (b) Reetz, M. T. Angew. Chem., Int. Ed. 1984, 23, 556.
(26) (a) Reetz, M. T.; Jung, A.; Bolm, C. Tetrahedron 1988, 44, 3889.
(b) Reetz, M. T. Pure Appl. Chem. 1985, 57, 1981.
(27) Kingbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda,
A. H. J. Am. Chem. Soc. 2000, 122, 8168.
(28) Bouzbouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465.
(29) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446.
(30) The major isomer cis-20 shown the same spectral data as the one
described in the literature; see ref 4e.
(31) (a) Palazo´n, J. M.; Soler, M. A.; Ramirez, M. A.; Mart´ın, V. S.
Tetrahedron Lett. 1993, 34, 5467. (b) Banwell, M. G.; Bui, C. T.; Pham,
H. T. T.; Simpson, G. W. J. Chem. Soc., Perkin Trans. 1 1996, 967.
(32) (a) Roush, W. R.; Spada, A. P. Tetrahedron Lett. 1982, 23, 3773.
(b) Nakata, T.; Hata, N.; Oishi, T. Heterocycle 1990, 330.
26
TiCl4 (Scheme 7).
At this point of the synthesis, seven of the eight stereogenic
centers of leucascandrolide A were installed. To complete the
synthesis of macrolactone 1 and to introduce the last stereogenic
center at C3, an intramolecular 1,4-addition of the hydroxyl
group at C7 to an R,â-unsaturated ester was still envisaged.
Compound 39 was treated with methyl acrylate in the presence
of Hoveyda-Grubbs catalyst Ru-III27 (15 mol %) to provide
chemoselectively the unsaturated ester 40 (84% yield).28 The
elaboration of the cis-THP was realized under basic conditions
using a catalytic amount of t-BuOK29 (20 mol %), which
afforded two diastereoisomers, cis-41 and trans-41, in a modest
ratio of 3:1. The two epimers cis-41 and trans-41 were difficult
to separate at this stage, but fortunately, they were separable
by column chromatography on silica gel in the next step. After
treatment with TBAF in THF, diol 42 was isolated as a single
cis diastereoisomer (38% over the two steps)30 accompanied
by the (Z,E)-dienoic acid 43 in 31% yield (Scheme 8).
(33) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
1870 J. Org. Chem., Vol. 73, No. 5, 2008

Macrolactone Core of Leucascandrolide A
SCHEME 10
(30 mL) at 0 °C was added dropwise 1,3-propanediol 2 (1.5 g,
19.71 mmol, 1 equiv). After 5 min of stirring, tert-butyldiphenylsilyl
chloride (5.55 mL, 21.68 mmol, 1.1 equiv) was added, and the
reaction mixture was stirred for 3 h at rt. Water (50 mL) was added,
and the aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated. The crude material is directly engaged in the next
step without further purification.
To a solution of oxalyl chloride (4.82 mL, 55.23 mmol, 2.1 equiv)
in CH2Cl2 (120 mL) at -78 °C was added dropwise a solution of
DMSO (8.21 mL, 115.72 mmol, 4.4 equiv) in CH2Cl2 (3 mL). The
reaction mixture was stirred for 20 min at -78 °C, and a solution
of the above 3-[(tert-butyldiphenylsilyl)oxy]propan-1-ol (8.7 g, 26.3
mmol, 1 equiv) in CH2Cl2 (10 mL) was added. The reaction mixture
was stirred for 90 min at -78 °C, and then Et3N (30.6 mL, 8.2
equiv) was added dropwise. After 30 min at 0 °C, the temperature
was raised to rt, and the reaction mixture was quenched with water
(10 mL). The aqueous layer was extracted with CH2Cl2, and the
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. A purification of the residue
by silica gel chromatography (petroleum ether/EtOAc 90/10)
afforded aldehyde 3 (5.58 g, 68% over two steps) as a colorless
oil: IR (neat) 3010, 2940, 1715, 1470, 1425, 1390, 1360, 1280,
1130, 1010, 940, 820, 745, 700 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 9.85 (t, J ) 2, 2 Hz, 1H), 7.70-7.62 (m, 4H), 7.50-7.34 (m,
6H), 4.05 (t, J ) 5.9 Hz, 2H), 2.63 (td, J ) 5.9, 2.2 Hz, 2H), 1.07
(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 201.7 (d), 135.4 (4d), 134.7
(s), 133.1 (s), 129.7 (2d), 127.6 (4d), 58.2 (t), 46.2 (t), 26.6 (3q),
19.0 (s); MS (EI) 256 (2), 199 (100), 181 (4), 152 (2), 137 (2),
121 (2), 105 (1), 77 (6), 51 (1).
tert-Butyl-(3-methoxyhex-5-enyloxy)diphenylsilane (4). To a
suspension of (R,R)-TaddolCpTiCl complex (4.55 g, 7.44 mmol,
1.3 equiv) in Et2O (120 mL) at 0 °C was added allylmagnesium
chloride (3.15 mL, 2.0 M in THF, 6.29 mmol, 1.1 equiv), and the
reaction mixture was stirred at 0 °C for 90 min and then cooled to
-78 °C. A solution of aldehyde 3 (2.02 g, 5.72 mmol, 1 equiv) in
Et2O was added at -78 °C. After 16 h at -78 °C, deionized water
(50 mL) was added, and the reaction mixture was stirred at rt for
3 days. Celite was added, and the mixture was filtered on Celite
(washing with Et2O). The resulting solution was dried over MgSO4,
filtered, and concentrated. Purification of the residue by silica gel
chromatography (petroleum ether/EtOAc 90/10) afforded impure
alcohol (2.61 g) as a light yellow oil along with (R,R)-TADDOL
which could not be separated from the product.
in toluene at 60 °C over 24 h.34 Under these conditions, the
macrocyclic lactone was formed but the hydroxyl group at C5
was esterified affording 48 in 72% yield. On the contrary, when
the reaction was performed under milder conditions,35 in toluene
at rt for 48 h, the desired macrocyclic lactone 1 was isolated in
75% yield (Scheme 10).
Macrolide 1 was identical in all respect with the spectral data
and the specific rotation reported previously.3,4
Three approaches of the macrolactone core of the leucascan-
drolide A were examined. Two of them failed in the formation
of the cis-THP moiety, utilizing an intramolecular 1,4-addition
of an alkoxide on an R,â-unsaturated ester. On the contrary,
the third approach allowed us to minimize the number of steps
by using chemoselective sequences, which avoids the protection/
deprotection steps. Although side reactions occurred during the
construction of the cis-THP, we were able to circumvent these
difficulties in synthesizing macrolide 1 in 25 steps and 1.2%
yield from but-1-en-ol. Synthetic highlights include highly
stereoselective allylations to control the stereogenic centers at
C5, C7, C9, C11, and C12, and an enantioselective Noyori
reduction of an acetylenic ketone to control the stereogenic
center at C5, a cross-metathesis reaction followed by an
intramolecular 1,4-addition to build up the cis-tetrahydropyran
and a ring-closing metathesis-Mukaiyama reaction to establish
the trans-tetrahydropyran. Furthermore, by using chemoselective
reactions such as selective deprotection of TBS, dihydroxylation,
and cross-metatheses, this synthesis of the macrolide core of
leucascandrolide A appears to be one of the shortest, considering
the total number of steps.
To a solution of the above impure alcohol in CH2Cl2 (50 mL)
was added methyl iodide (12.48 g, 5.47 mmol, 15 equiv) and then
sodium hydride (2.36 g, 48 mmol, 10 equiv, 60% in mineral oil)
by portion. After 5 h of stirring, the reaction mixture was quenched
by dropwise addition of a solution of NH4Cl and was then extracted
with EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated to give a residue which
was purified by silica gel chromatography (petroleum ether/EtOAc
90:10) to afford methyl ether 4 (1.78 g, 76% over two steps) as a
light yellow oil: [R]2D0 +2.1 (c 1.04, CHCl3); IR (neat) 2930,
1
1427, 1086, 912 cm-1; H NMR (CDCl3, 400 MHz) δ 7.75-7.65
(m, 4H), 7.50-7.43 (m, 6H), 5.82 (m, 1H), 5.15-5.02 (m, 2H),
3.89-3.71 (m, 2H), 3.52 (m, 1H), 3.35 (s, 3H), 2.30 (tapp, J ) 7.5
Hz, 2H) 1.80-1.70 (m, 2H) 1.08 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 135.6 (4d), 134.8 (d), 134.0 (2s), 129.6 (2d), 127.6 (4d),
117.0 (t), 77.2 (d), 60.5 (t), 56.7 (q), 37.8 (t), 36.6 (t), 27.0 (3q),
t
19.2 (s); MS (EI) 311 (M - Bu+, 9), 279 (M, 10), 243 (27), 225
(15), 213 (M - H - 2Ph+, 100), 183 (46), 153 (17), 135 (22), 81
(38).
Experimental Section
8-[(tert-Butyldiphenylsilyl)oxy]-4-[(tert-butyldimethylsilyl)-
oxy]-6-methoxyoct-1-ene (5). To a solution of olefin 4 in CH2Cl2
(40 mL) at -78 °C was bubbled ozone until the solution turned
3-(tert-Butyldiphenylsilanyloxy)propionaldehyde (3).8 To a
solution of sodium hydride (788 mg, 19.71 mmol, 1 equiv) in THF
(34) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(35) Hikota, M.; Sakura¨ı, Y.; Horita, K.; Yonemitsu, O. Tetrahedron
Lett. 1990, 31, 6367.
J. Org. Chem, Vol. 73, No. 5, 2008 1871

Ferrie´ et al.
blue, and then argon was bubbled through until the blue color
vanished and triphenylphosphine (3.17 g, 12.07 mmol, 2.5 equiv)
was added. After being stirred for 2 h at rt, the reaction mixture
was concentrated and the residue was purified by silica gel
chromatography (petroleum ether/EtOAc 90:10 to 95:5) to afford
the corresponding aldehyde (1.77 g, 98%): [R]2D0 +3.4 (c 1.04,
CHCl3); IR (neat) 2930, 1709, 1427, 1105 cm-1; 1H NMR (CDCl3,
400 MHz) δ 9.81 (t, J ) 2.3 Hz, 1H), 7.78-7.62 (m, 4H), 7.50-
7.33 (m, 6H), 3.98 (quintapp, J ) 6.0 Hz, 1H), 3.89-3.70 (m, 2H),
3.35 (s, 3H), 2.64-2.55 (m, 2H), 1.95-1.70 (m, 2H), 1.09 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ 201.5 (d), 135.6 (4d), 133.6 (2s),
129.8 (2d), 127.7 (4d), 73.6 (d), 60.1 (t), 57.0 (q), 48.2 (t), 36.7
To a suspension of (R,R)-TaddolCpTiCl complex (3.02 g, 4.93
mmol, 1.4 equiv) in Et2O (80 mL) at 0 °C was added allylmag-
nesium chloride (2.63 mL, 5.25 mmol, 1.1 equiv). The reaction
mixture was stirred at 0 °C for 90 min and then cooled to -78 °C,
and a solution of the above aldehyde (1.85 g, 3.50 mmol, 1 equiv)
in a small amount of Et2O was added at -78 °C. After 4 h at
-78 °C, deionized water (40 mL) was added, and the reaction
mixture was stirred at rt for 3 days. Celite was added, and the
mixture was filtered on Celite (washing with Et2O). The resulting
solution was dried over MgSO4, filtered, and concentrated, and the
residue was purified by silica gel chromatography (petroleum ether/
EtOAc 98:2 to 90:10) to afford corresponding allylic alcohol (1.47
g, 74%) as a light yellow oil: [R]2D0 -25.3 (c 1.01, CHCl3); IR
t
(t), 27.0 (3q), 19.2 (s); MS (EI) 313 (M - Bu+, 2), 281 (M, 14),
(neat) 3448, 2929, 1640, 1472, 1428, 1361, 1253, 1106, 1080 cm-1
;
251 (17), 225 (20), 213 (36), 199 (100), 183 (28), 78 (43), 53
(29).
1H NMR (CDCl3, 400 MHz) δ 7.60-7.50 (m, 4H), 7.35-7.18 (m,
6H), 5.71 (m, 1H), 5.04-4.93 (m, 2H), 3.96 (m, 1H), 3.71 (m,
1H), 3.68-3.52 (m, 2H), 3.36 (m, 1H), 3.15 (s, 3H), 3.10 (br s,
1H), 2.11 (tapp, J ) 6.6 Hz, 2H), 1.71-1.35 (m, 6H), 0.94 (s, 9H),
0.78 (s, 9H), 0.00 (s, 3H), -0.02 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 135.4 (4d), 134.8 (d), 133.6 (2s), 129.5 (2d), 127.5 (4d),
117.3 (t), 74.8 (d), 70.3 (d), 69.9 (d), 60.2 (t), 56.3 (q), 42.9 (t),
42.3 (t), 42.0 (t), 36.8 (t), 26.7 (3q), 25.7 (3q), 19.1 (s), 17.7 (s),
-4.1 (q), -4.8 (q); MS (EI) 481 (2), 453 (3), 381 (13), 269 (15),
255 (33), 213 (100), 199 (53), 183 (48), 159 (35), 135 (64), 75
(72); HRMS (CI+, CH4) calcd for C33H54O4Si2 + H+ 571.3639,
found 571.3646.
To a suspension of (R,R)-TaddolCpTiCl complex (3.8 g, 6.21
mmol, 1.3 equiv) in Et2O (100 mL) at 0 °C was added allylmag-
nesium chloride (2.63 mL, 2.0 M in THF, 5.25 mmol, 1.1 equiv),
and the reaction mixture was stirred at 0 °C for 90 min and then
cooled to -78 °C. A solution of the above aldehyde (1.77 g, 4.78
mmol, 1 equiv) in Et2O was added at -78 °C. After 4 h at 78 °C,
deionized water (40 mL) was added, and the reaction mixture was
stirred at rt for 3 days. Celite was added, and the mixture was
filtered on Celite (washing with Et2O). The resulting solution was
dried over MgSO4, filtered, and concentrated to afford crude allylic
alcohol which could not be purified from (R,R)-TADDOL by flash
chromatography on silica gel. The crude material was used without
further purification in the next step.
To a solution of the above alcohol (1.42 g, 2.48 mmol, 1 equiv)
in CH2Cl2 (30 mL) at 0 °C were added i-Pr2NEt (3.46 mL, 19.84
mmol, 8 equiv) and MOMCl (756 µL, 9.95 mmol, 4 equiv). After
24 h of stirring at rt, the reaction mixture was quenched by adding
a saturated solution of NH4Cl and extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated, and the residue was purified
by silica gel column chromatography (petroleum ether/EtOAc 90:
10) to afford compound 6 (1.45 g, 95%) as a colorless oil: [R]D20
+4.2 (c 1.02, CHCl3); IR (neat) 2929, 2856, 1640, 1472, 1428,
1361, 1253, 1084, 1037 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.63-
7.55 (m, 4H), 7.40-7.25 (m, 6H), 5.78 (m, 1H), 5.09-4.97 (m,
2H), 4.58 (s, 2H), 3.82 (quintapp, J ) 6.0 Hz, 1H), 3.77-3.60 (m,
3H), 3.41 (m, 1H), 3.30 (s, 3H), 3.20 (s, 3H), 2.37-2.13 (m, 2H),
1.76-1.42 (m, 6H), 1.00 (s, 9H), 0.82 (s, 9H), 0.01 (s, 3H), 0.00
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 135.4 (4d), 134.5 (d), 133.8
(2s), 129.4 (2d), 127.5 (4d), 117.1 (t), 95.3 (t), 74.9 (d), 74.1 (d),
66.8 (d), 60.4 (t), 56.2 (q), 55.4 (q), 41.9 (t), 41.6 (t), 38.9 (t), 37.1
(t), 26.8 (3q), 25.8 (3q), 19.0 (s), 17.8 (s), -4.3 (q), -4.5 (q); MS
To a solution of above crude allylic alcohol in CH2Cl2 at
-78 °C were added 2,6-lutidine (2.44 mL, 21.04 mmol, 4.4 equiv)
and TBSOTf (2.42 mL, 10.52 mmol, 2.2 equiv). After 3.5 h at
-78 °C, the reaction mixture was quenched with a saturated solution
of NaHCO3 and then extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated. The residue was purified by silica gel chromatography
(petroleum ether/EtOAc: 98/2) to afford silyl ether 5 (2.03 g, 81%
over two steps) as a light yellow oil: [R]2D0 +12.3 (c 1.06, CHCl3);
IR (neat) 2929, 1640, 1471, 1427, 1360, 1253, 1106, 1082 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.68-7.60 (m, 4H), 7.42-7.28 (m,
6H), 5.78 (m, 1H), 5.05-4.95 (m, 2H), 3.83-3.63 (m, 3H), 3.45
(m, 1H), 3.22 (s, 3H), 2.32-2.10 (m, 2H), 1.80-1.60 (m, 2H),
1.56-1.42 (m, 2H), 1.03 (s, 9H), 086 (s, 9H), 0.02 (s, 3H), 0.01
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 135.4 (4d), 135.0 (d), 133.8
(2s), 129.4 (2d), 127.5 (4d), 116.8 (t), 74.9 (d), 69.0 (d), 60.4 (t),
56.1 (q), 41.7 (t), 41.2 (t), 37.0 (t), 26.7 (3q), 25.8 (3q), 19.1 (s),
t
(EI) 481 (M - Bu - Ph+, 0.4), 255 (4), 213 (15), 199 (63), 183
t
18.0 (s), -3.1(q), -4.4 (q); MS (EI) 469 (M - Bu+, 0.4), 453
(7), 135 (8), 75 (100).
(11), 213 (90), 185 (100), 159 (50), 135 (52), 107 (52), 89 (32), 75
(52), 73 (55).
11-[(tert-Butyldiphenylsilyl)oxy]-7-[(tert-butyldimethylsilyl)-
oxy]-9-methoxy-5-methoxyethylundec- 2-enoic Acid Ethyl Ester
(7). To a solution of olefin 6 (1.37 g, 2.22 mmol, 1 equiv) in CH2-
Cl2 (10 mL) at rt was added ethyl acrylate (720 µL, 6.66 mmol, 3
equiv) followed by Grubbs-Hoveyda catalyst Ru-III (35 mg, 2.5
mol %). After 24 h at rt, the brown reaction mixture was
concentrated, and the residue was purified by silica gel chroma-
tography (petroleum ether/EtOAc 95:5) to afford unsaturated ester
7 (1.30 g, 85%): [R]2D0 -2.2 (c 1.05, CHCl3); IR (neat) 2930,
1720, 1472, 1428, 1257, 1087, 1034 cm-1; 1H NMR (CDCl3, 400
MHz) δ 7.67-7.55 (m, 4H), 7.40-7.23 (m, 6H), 6.94 (dt, J )
15.8, 7.4 Hz, 1H), 5.81 (d, J ) 15.8 Hz, 1H), 4.58 (d, J ) 6.6 Hz,
1H), 4.54 (d, J ) 6.6 Hz, 1H), 4.11 (q, J ) 7.4 Hz, 2H), 3.90-
3.75 (m, 2H), 3.75-3.60 (m, 2H), 3.41 (m, 1H), 3.30 (s, 3H), 3.20
(s, 3H), 2.52-2.26 (m, 2H), 1.77-1.43 (m, 6H), 1.22 (t, J ) 7.4
10-[(tert-Butyldiphenylsilyl)oxy]-6-[(tert-butyldimethylsilyl)-
oxy]-8-methoxy-4-methoxymethyldec-1-ene (6). To a solution of
olefin 5 (1.31 g, 2.48 mmol, 1 equiv) in CH2Cl2 (30 mL) at
-78 °C was bubbled ozone until the solution turned blue, and then
argon was bubbled until the blue color vanished and triphenylphos-
phine (2.6 g, 9.94 mmol, 4 equiv) was added. After being stirred
for 80 min at rt, the reaction mixture was concentrated, and the
residue was purified by silica gel chromatography (petroleum ether/
EtOAc 95:5 to 90:10) to afford the corresponding aldehyde (1.29
g, 98%) as a colorless oil: [R]2D0 -6.5 (c 1.3, CHCl3); IR (neat)
2929, 1725, 1472, 1428, 1361, 1253, 1085 cm-1; 1H NMR (CDCl3,
400 MHz) δ 9.74 (t, J ) 2.2 Hz, 1H), 7.65-7.55 (m, 4H), 7.40-
7.26 (m, 6H), 4.30 (m, 1H), 3.78-3.60 (m, 2H), 3.42 (m, 1H),
3.20 (s, 3H), 2.60-2.40 (m, 2H), 1.80-1.52 (m, 4H), 1.00 (s, 9H),
0.81 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 202.1
(d), 135.4 (4d), 133.6 (2s), 129.5 (2d), 127.5 (4d), 74.5 (d), 65.5
(d), 60.2 (t), 56.1 (q), 50.5 (t), 42.0 (t), 36.5 (t), 26.7 (3q), 25.6
(3q), 19.0 (s), 17.8 (s), -4.5 (q), -4.9 (q); MS (EI) 433 (M - Ph
- H2O+, 2), 339 (3), 307 (8), 229 (16), 213 (35), 199 (100), 183
(19), 135 (11), 108 (9), 77 (20).
Hz, 3H), 1.00 (s, 9H), 0.82 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); 13
C
NMR (CDCl3, 100 MHz) δ 166.0 (s), 145.0 (d), 135.4 (4d), 133.87
(2s), 129.5 (2d), 127.5 (4d), 123.6 (d), 95.4 (t), 74.8 (d), 73.4 (d),
66.7 (d), 60.4 (t), 60.0 (t), 56.1 (q), 55.5 (q), 41.8 (t), 41.6 (t), 37.4
(t), 36.9 (t), 26.8 (3q), 25.8 (3q), 19.0 (s), 17.8 (s), 14.1 (q), -4.3
(q), -4.5 (q); MS (EI) 507 (0.5), 491 (2), 433 (6), 309 (7), 283
1872 J. Org. Chem., Vol. 73, No. 5, 2008

Macrolactone Core of Leucascandrolide A
(12), 213 (27), 199 (77), 183 (14), 135 (14), 75 (100), 56 (10);
HRMS (CI+, NH3) calcd for C38H62O7Si2 + NH4+ 704.4378, found
704.4371.
with brine, dried over MgSO4, filtered, and then concentrated. The
residue was purified by silica gel chromatography (petroleum ether/
EtOAc 60:40) to afford the expected THP 10 (15 mg, 6%) and
(E,E)-dienoate 11 (140 mg, 65%): [R]2D0 +12.6 (c 1.0, CHCl3); IR
(neat) 3478, 2927, 1737, 1151, 1083, 1039 cm-1; 1H NMR (CDCl3,
400 MHz) δ 5.78 (m, 1H), 5.06-4.94 (m, 2H), 4.61 (s, 2H), 4.08
(q, J ) 7.0 Hz, 2H), 4.00-3.52 (m, 5H), 3.30 (s, 3H), 3.28 (s,
3H), 2.40 (dd, J ) 15.2, 8.6 Hz, 1H), 2.28 (dd, J ) 15.2, 4.9 Hz,
1H), 2.15 (m, 1H), 1.90-1.30 (m, 8H), 1.19 (t, J ) 7.1 Hz, 3H),
0.98 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 171.2
(s), 140.7 (d), 115.31 (t), 95.0 (t), 76.0 (d), 71.6 (d), 69.7 (d), 69.4
(d), 69.2 (d), 60.4 (t), 56.7 (q), 55.4 (q), 44.2 (d), 41.3 (t), 38.9 (t),
36.8 (t), 36.7(t), 35.8 (t), 15.8 (q), 14.2 (q); MS (EI) 389 (M +
H+, 0.04), 355 (M - H - MeOH+, 0.1), 315 (M - COOEt+, 1),
301 (25), 269 (M, 3), 239 (29), 221 (30), 209 (10), 169 (100), 141
(20), 123 (22), 95 (18), 81 (44), 59 (16); HRMS (CI+, CH4) calcd
for C20H36O7 + H+ 389.2539, found 389.2544.
7-[(tert-Butyldimethylsilyl)oxy]-11-hydroxy-9-methoxy-5-meth-
oxymethylundec-2-enoic Acid Ethyl Ester (8). To a solution of
compound 7 (1.12 g, 1.63 mmol) in refluxing methanol (25 mL)
was added NH4F (80 mg, 2.16 mmol, 13 equiv). After 12 h of
stirring at methanol reflux, the reaction mixture was quenched by
addition of brine and extracted with AcOEt. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated, and the residue was purified by silica gel chroma-
tography (petroleum ether/EtOAc 90/10 to 50/50 to afford 8 (500
mg, 65%) as an oil: [R]2D0 +25.4 (c 1.0, CHCl3); IR (neat) 3463,
2929, 1719, 1256, 1094, 1033 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 6.90 (dt, J ) 15.4, 7.4 Hz, 1H), 5.82 (dt, J ) 15.8, 1.5 Hz, 1H),
4.58 (s, 2H), 4.12 (q, J ) 7.0 Hz, 2H), 3.89-3.65 (m, 4H), 3.49
(m, 1H), 3.32 (s, 3H), 3.29 (s, 3H), 2.52-2.30 (m, 2H), 1.86-
1.49 (m, 6H), 1.22 (t, J ) 7.0 Hz, 3H), 0.83 (s, 9H), 0.01 (s, 3H),
0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.2 (s), 144.8 (d),
123.9 (d), 95.6 (t), 77.8 (d), 73.6 (d), 66.7 (d), 60.7 (t), 60.3 (t),
56.3 (q), 55.8 (q), 41.1 (t), 40.5 (t), 37.4 (t), 35.5 (t), 25.8 (3q),
18.0 (s), 14.3 (q), -4.3 (q), -4.5 (q); MS (EI) 359 (0.2), 309 (3),
257 (2), 243 (11), 189 (10), 171 (8), 157 (7), 141 (8), 131 (8), 115
(23), 89 (43), 75 (100), 59 (22).
7-[(tert-Butyldimethylsilyl)oxy]-11-hydroxy-9-methoxy-5-meth-
oxymethyl-12-methyltetradeca-2,13-dienoic Acid Ethyl Ester (9).
To a solution of alcohol 8 (500 mg, 1.11 mmol, 1 equiv) in CH2-
Cl2 (15 mL) at rt was added Dess-Martin periodinane (865 mg,
2.11 mmol, 1.9 equiv). After 1.5 h of stirring, the reaction mixture
was quenched by addition of a solution of Na2S2O3 (15 mL),
followed by the addition of a saturated solution of NaHCO3 (15
mL) and then diluted with Et2O (15 mL). The reaction mixture
was stirred for 15 min and was extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was engaged in the next step without
further purification (due to its presumably unstability).
To a suspension of (R,R)-TaddolCpTiCl complex (883 mg, 1.44
mmol, 1.3 equiv) in Et2O (20 mL) at 0 °C was added 2-butenyl-
magnesium chloride (3.49 mL, 0.5 M in THF, 1.22 mmol, 1.1
equiv), and the reaction mixture was stirred at 0 °C for 90 min and
then cooled to -78 °C. A solution of the above aldehyde (1.85 g,
3.50 mmol, 1 equiv) in Et2O was added at -78 °C. After 2 h at
-78 °C, deionized water (30 mL) was added, and the reaction
mixture was stirred at rt for 1 day. Celite was added, and the mixture
was filtered on Celite (washing with EtOAc). The resulting solution
was dried over MgSO4, filtered, and concentrated, and the residue
was purified by silica gel chromatography (petroleum ether/EtOAc
80:20) to afford alcohol 9 (374 mg, 67% over two steps) as a light
yellow oil: [R]2D0 +5.0 (c 1.0, CHCl3); IR (neat) 3498, 2929,
1720, 1257, 1150, 1093, 1033 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 6.90 (dt, J ) 14.7, 7.4 Hz, 1H), 5.83 (dt, J ) 15.8, 1.5 Hz, 1H),
5.72 (m, 1H), 5.07-4.95 (m, 2H), 4.58 (s, 2H), 4.12 (q, J ) 7.0
Hz, 2H), 3.89-3.72 (m, 2H), 3.68 (m, 1H), 3.56 (m, 1H), 3.31 (s,
3H), 3.29 (s, 3H), 2.71 (br s, 1H), 2.51-2.29 (m, 2H), 2.15 (m,
1H), 1.89-1.36 (m, 6H), 1.21 (t, J ) 7.0 Hz, 3H), 1.00 (d, J ) 6.6
Hz, 3H), 0.82 (s, 9H), 0.00 (2s, 6H); 13C NMR (CDCl3, 100 MHz)
δ 166.0 (s), 144.7 (d), 140.3 (d), 123.6 (d), 115.3 (t), 95.5 (t), 76.1
(d), 73.5 (d), 71.4 (d), 66.6 (d), 60.0 (t), 56.5 (q), 55.6 (q), 44.1
(d), 41.8 (t), 40.6 (t), 37.5 (t), 36.8 (t), 25.7 (3q), 17.8 (s), 15.7 (q),
14.1 (q), -4.5 (2q); MS (EI) 381 (0.6), 329 (6), 283 (8), 243 (14),
213 (10), 99 (11), 89 (13), 75 (100), 59 (19); HRMS: (CI+, CH4)
calcd for C26H50O7Si + H+ 503.3404, found 503.3397.
1-[(tert-Butyldiphenyl)silyloxy]-4-methylhex-5-ene-1,3-diol (12).
To a suspension of (R,R)-TaddolCpTiCl complex (3.18 g, 5.2 mmol,
1.3 equiv) in Et2O (30 mL) at 0 °C was added 2-butenylmagnesium
chloride (14.7 mL, 0.5 M in THF, 4.4 mmol, 1.1 equiv), and the
reaction mixture was stirred at 0 °C for 90 min and then cooled to
-78 °C. A solution of aldehyde 3 (1.25 g, 5.72 mmol, 1 equiv) in
Et2O was added at -78 °C. After 16 h at -78 °C, deionized water
(30 mL) was added, and the reaction mixture was stirred at rt for
3 days. Celite was added, and the mixture was filtered on Celite
(washing with Et2O). The resulting solution was dried over MgSO4,
filtered, and concentrated. Purification of the residue by silica gel
chromatography (petroleum ether/EtOAc 90:10) afforded alcohol
12 (1.32 g, 89%): [R]2D0 -4.6 (c 1.09, CHCl3); IR (neat) 3460,
2900, 1960, 1820, 1640, 1590, 1470, 1425, 1390, 110, 910, 820,
1
740 cm-1; H NMR (CDCl3, 400 MHz) δ 7.70 (m, 4H), 7.44 (m,
6H), 5.86 (m, 1H), 5.10 (m, 2H), 3.92 (m, 2H), 3.78 (m, 1H), 3.06
(d, J ) 2.6 Hz, 1H, OH), 2.28 (m, 1H), 1.70 (m, 2H), 1.07 (d, J )
6.6 Hz, 3H), 1.09 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 140.5
(d), 135.5 (4d), 133.1 (2s), 129.6 (2d), 127.6 (4d), 115.1 (t), 74.4
(d), 63.2 (t), 43.8 (d), 35.5 (t), 26.7 (3q), 18.9 (s), 15.7 (q); MS
(EI) 311 (M-tBu+, 3), 293 (3), 255 (18), 230 (4), 211 (8), 199 (100),
183 (15), 167 (3), 151 (3), 135 (16), 117 (6), 95 (7), 67 (10), 55
(7); HRMS (CI+, CH4) calcd for C23H32O2Si + H+ 369.2250, found
369.2249.
6-[2-(tert-Butyldiphenylsilanyloxy)ethyl]-5-methyl-5,6-dihy-
dropyran-2-one (13). To a solution of i-Pr2NEt (4.2 mL, 24.3
mmol, 8 equiv) and alcohol 12 (1.12 g, 3.0 mmol, 1 equiv) in CH2-
Cl2 (20 mL) at - 78 °C was added dropwise acryloyl chloride (1.0
mL, 12.2 mmol, 4 equiv). After 20 min, the reaction mixture was
quenched by addition of a saturated solution of NH4Cl (20 mL),
and the aqueous phase was extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated, and the residue was purified by silica gel column
chromatography (petroleum ether/EtOAc 95/5) to afford the cor-
responding ester (1.16 g, 90%) as a light yellow oil: [R]2D0 +14.5
(c 0.96, CHCl3); IR (neat) 3060, 2960, 1725, 1640, 1470, 1425,
1
1400, 1270, 1190, 1110, 965, 820, 740 cm-1; H NMR (CDCl3,
400 MHz) δ 7.70 (m, 4H), 7.43 (m, 6H), 6.40 (dd, J ) 1.5, 17.3
Hz, 1H), 6.11 (dd, J ) 17.3, 10.3 Hz, 1H), 5.85-5.73 (m, 1H),
5.81 (dd, J ) 10.3, 1.5 Hz), 55.20 (m, 1H), 5.05 (m, 2H), 3.73 (t,
J ) 6.6 Hz, 2H), 2.53 (m, 1H,), 1.86 (m, 2H), 1.09 (s, 9H), 1.04
(d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.6 (s),
139.2 (4d), 135.5 (2s), 133.5 (2d), 130.1 (t), 129.5 (d), 128.7 (d),
127.5 (4d), 155.5 (t), 73.9 (d), 60.2 (t), 41.3 (d), 33.9 (t), 26.8 (3q),
19.0 (s), 15.5 (q); MS (EI) 423 (M + 1, 80), 391 (5), 365 (14),
351 (68), 311 (3), 287 (8), 269 (26), 233 (30), 193 (11), 167 (9),
95 (100), 79 (17); HRMS (CI+, CH4) calcd for C26H35O3Si + H+
423.2355, found 423.2346.
[6-(4-Hydroxy-2-methoxy-5-methylhept-6-enyl)-4-methoxym-
ethyltetrahydropyran-2-yl]ethanoic Ethyl Ester (10). To a solu-
tion of unsaturated ester 9 (331 mg, 0.66 mmol) in THF (1 mL) at
rt was added TBAF (3.3 mL, 1.0 M in THF, 5 equiv). After 18 h
of stirring, the reaction mixture was quenched with brine and
extracted with EtOAc. The combined organic layers were washed
To a solution of the above ester (1.00 g, 2.37mmol, 1 equiv) in
CH2Cl2 (40 mL) at reflux was added Grubbs catalyst second-
generation Ru-II (0.100 g, 0.12 mmol, 0.05 equiv). After 3 h of
J. Org. Chem, Vol. 73, No. 5, 2008 1873

Ferrie´ et al.
stirring at reflux, the reaction mixture was concentrated, and the
residue was purified by silica gel column chromatography (petro-
leum ether/EtOAc 9/1) to afford unsaturated lactone 13 (0.747 g,
80%): [R]2D0 +27.0 (c 1.00, CHCl3); IR (neat) 1730, 1430, 1470,
purified by silica gel chromatography (petroleum ether/AcOEt 95:
5) to afford olefin 15 (0.550 g, 96%) as a light yellow oil: [R]D20
+27.1 (c 1.00, CHCl3); IR (neat) 2960, 1425, 1110, 820, 700 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.69 (m, 4H), 7.41 (m, 6H), 5.76
(m, 1H), 5.00 (m, 2H), 3.77 (m, 3H), 3.50 (ddd, J ) 3.3, 6.6, 9.2
Hz, 1H), 2.43 (m, 1H), 2.16 (m, 1H), 1.82-1.38 (m, 7H), 1.06 (s,
9H), 0.94 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
135.5 (d, 5C), 134.0 (s, 2C), 129.3 (d, 2C), 127.4 (d, 4C), 116.1
(t), 73.0 (d), 70.9 (d), 60.8 (t), 36.8 (t), 35.5 (t), 33.5 (d), 27.1 (t),
26.5 (t), 26.7 (q, 3C), 19.1 (s), 18.2 (q); MS (EI) 381 (5), 365 (48),
255 (9), 225 (13), 199 (100), 183 (31), 149 (35), 135 (20), 121
(13), 107 (32), 93 (27), 81 (24), 77 (7), 67 (18), 55 (6); HRMS
(CI+, CH4) calcd for C27H38O2Si + H+ 423.2719, found 423.2721.
1
1250, 1100, 825 cm-1; H NMR (CDCl3, 400 MHz) δ 7.66 (m,
4H), 7.42 (m, 6H), 6.65 (dd, J ) 2.4, 9.6 Hz, 1H), 5.97 (dd, J )
2.4, 9.6 Hz, 1H), 4.32 (m, 1H), 3.90 (m, 2H), 2.55 (m, 1H), 1.92
(m, 2H), 1.14 (d, J ) 7.4 Hz, 3H), 1.06 (s, 9H); 13C NMR (CDCl3,
100 MHz) δ 163.8 (s), 151.3 (d), 135.4 (4d), 133.14 (2s), 129.6
(2d), 127.6 (4d), 120.0 (d), 80.3 (d), 59.2 (t), 35.6 (t), 33.1 (d),
26.7 (3q) 19.0 (s), 16.4 (q); MS (EI) 323 (M - tBu - OAc+, 52),
267 (100), 245 (16), 199 (83), 183 (28), 159 (10), 135 (11), 123
(8), 105 (10), 77 (6). Anal. Calcd for C24H30O3Si (394.60): C,
73.05; H, 7.66. Found: C, 73.15; H, 7.76.
[6-(2-Methoxymethoxyethyl)-3-methyltetrahydropyran-2-yl]-
acetaldehyde (16). To a solution of olefin 15 (0.550 g, 1.30 mmol,
1 equiv) in a mixture of acetone/water (3:1, 7 mL/2.3 mL) were
added NMO (0.259 g, 2.21 mmol, 1.7 equiv) and OsO4 (0.25 mL,
2.5 wt % in t-BuOH, 2.24 µmol, 0.018 equiv). The solution was
stirred at rt until total disappearance of the starting material by TLC,
and then NaIO4 (0.554 g, 2.60 mmol, 2 equiv) and H2O (5 mL)
were added. After 1 h of stirring, the white suspension was filtered
and washed with acetone, and the solution was concentrated under
reduced pressure. The resulting mixture was extracted with EtOAc,
and the combined organic layers were washed with a solution of
Na2S2O3 and brine, dried over MgSO4, filtered, and concentrated.
The residue was purified by silica gel chromatography column
(petroleum ether/AcOEt 9/1) to furnish the corresponding aldehyde
(0.446 g, 84%) as a pale yellow oil: [R]2D0 +30.8 (c 0.85, CHCl3);
Acetic Acid 6-[2-(tert-Butyldiphenylsilanyloxy)ethyl]-5-me-
thyltetrahydropyran-2-yl Ester (14). To a solution of unsaturated
lactone 13 (1.09 g, 2.76 mmol, 1 equiv) in AcOEt (85 mL) was
added PtO2 (0.013 g, 55.2 µmol, 0.02 equiv), and the black
suspension was stirred at rt under an atmosphere of H2. After
filtration of the suspension on Celite, the colorless solution was
concentrated to afford the corresponding lactone (1.01 g, 93%)
without further purification: [R]2D0 +45.1 (c 1.05, CHCl3); IR
1
(neat) 2900, 1730, 1110, 745, 700 cm-1; H NMR (CDCl3, 400
MHz) δ 7.68 (m, 4H), 7.42 (m, 6H), 4.17 (td, J ) 9.2, 2.2 Hz,
1H), 3.90 (m, 2H), 2.60 (ddd, J ) 17.7, 7.0, 4.8 Hz, 1H), 2.46
(ddd, J ) 17.7, 9.7, 7.0 Hz, 1H), 1.93 (m, 2H), 1.75 (m, 2H), 1.53
(m, 1H), 1.07 (s, 9H), 1.01 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 171.4 (s), 135.4 (4d), 133.6 (2s), 129.6 (2d), 127.6
(4d), 82.4 (d), 59.3 (t), 36.4 (t), 32.3 (d), 29.3 (t), 27.7 (t), 26.7
IR (neat) 3060, 2920, 1725, 1585, 1430, 1390, 1110, 820 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 9.70 (dd, J ) 2.2, 2.6 Hz), 7.72
(m, 4H), 7.43 (m, 6H), 4.28 (m, 1H), 3.77 (m, 2H), 3.57 (m, 1H),
2.75 (ddd, J ) 2.6, 8.5, 15.8 Hz, 1H), 2.42 (ddd, J ) 2.2, 5.5, 15.8
Hz, 1H), 1.83-1.37 (m, 7H), 1.10 (s, 9H), 0.99 (d, J ) 6.6 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 201.3 (d), 135.4 (d, 4C), 133.8
(s, 2C), 129.4 (d, 2C), 127.5 (d, 4C), 73.6 (d), 69.4 (d), 60.5 (t),
46.6 (t), 35.1 (t), 32.9 (d), 27.5 (t), 26.1 (t), 26.8 (q, 3C), 19.0 (s),
18.1 (q); MS (EI) 367 (M-57, 31), 323 (8), 289 (5), 267 (25), 255
(10), 245 (13), 225 (44), 211 (11), 199 (100), 183 (67), 151 (21),
139 (15), 117 (16), 107 (22), 95 (15), 81 (15), 67 (6), 55 (14).
t
(3q) 19.1 (s), 17.4 (q); MS (EI) 351 (M-45, 0.2), 339 (M - Bu+,
45), 309 (51), 261 (44), 199 (100), 183 (25), 139 (16), 77 (7). Anal.
Calcd for C24H32O3Si (396.62): C, 72.68; H, 8.13. Found: C, 72.55;
H, 8.31.
To a solution of the above lactone (1.75 mmol, 0.695 g, 1 equiv)
in dry CH2Cl2 (11 mL) at -78 °C was added dropwise DIBAL-H
(3.5 mL, 1.0 M in hexanes, 3.5 mmol, 2 equiv), and the solution
was stirred for 1.5 h at -78 °C. Pyridine (0.425 g, 5.25 mmol, 3
equiv), DMAP (0.428 g, 3.5 mmol, 2 equiv), and finally Ac2O (0.99
mL, 10.5 mmol, 6 equiv) were then added to the solution. The
reaction mixture was stirred for 15 h at -78 °C and then warmed
to 0 °C. The reaction was quenched by addition of a saturated
aqueous solution of potassium sodium tartrate. After 10 min, a
saturated aqueous NaHCO3 solution was added. After being stirred
for 20 min, the aqueous layer was extracted with Et2O, and the
combined organic layers were washed with a saturated aqueous
NaHCO3 solution, with 1 M KHSO4 solution, and finally with brine.
The organic layer was dried over MgSO4, filtered, and concentrated,
and the residue was purified by silica gel column chromatography
(petroleum ether/AcOEt 9:1) to afford the acetate 14 (606 mg,
79%): [R]2D0 +10.0 (c 1.00, CHCl3); IR (neat) 2900, 1430, 1370,
To a solution of the above aldehyde (0.460 g, 1.08 mmol, 1
equiv) in MeOH (5 mL) at 0 °C was added NaBH4 (0.061 g, 1.62
mmol, 1.5 equiv) in two portions. After 1 h of stirring, the reaction
mixture was quenched with H2O (10 mL) and extracted with AcOEt.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated to afford the corresponding
alcohol (0.460 g, quantitative): [R]2D0 +26.8 (c 1.00, CHCl3); IR
(neat) 3400, 2920, 1460, 1425, 1390, 1110, 820, 740 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 7.70 (m, 4H), 7.42 (m, 6H), 3.88-3.57 (m,
6H), 2.27 (br s, 1H, OH), 1.99-1.54 (m, 9H), 1.06 (s, 9H), 0.98
(d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 135.5 (d,
4C), 133.8 (s, 2C), 129.5 (d, 2C), 127.5 (d, 4C), 73.3 (d), 69.9 (d),
60.7 (t), 60.2 (t), 35.1 (t), 35.0 (t), 32.8 (d), 26.7 (q), 27.6, 26.1
(2t), 19.1 (s), 18.2 (q); MS (EI) 427 (M + 1+, 18), 425 (M - 1+,
7), 349 (10), 291 (35), 271 (100), 241 (7), 199 (4), 171 (6), 153
(13), 135 (42), 109 (5); HRMS (CI+, CH4) calcd for C26H38O3Si
+ H+ 427.2668, found 427.2673.
To a solution of the above alcohol (72 mg, 0.17 mmol, 1 equiv)
and i-Pr2NEt (0.059 mL, 0.34 mmol, 2 equiv) in CH2Cl2 (2.3 mL)
at 0 °C was added MOMCl (0.026 mL, 0.34 mmol, 2 equiv). After
15 h of stirring at rt, the reaction mixture was quenched by addition
of a saturated solution of NH4Cl (3 mL) and was extracted with
CH2Cl2. The combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated, and the residue was purified
by silica gel column chromatography (petroleum ether/AcOEt 7:3)
to afford the corresponding MOM ether (75 mg, 94%): [R]D20
+31.7 (c 1.00, CHCl3); IR (neat) 2940, 1460, 1425, 1390, 1100,
920, 820, 745, 700 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.70 (m,
4H), 7.41 (m, 6H), 4.55 (s, 2H), 3.90 (m, 1H), 3.78 (m, 2H), 3.58-
1
1230, 1110, 820, 740, 710 cm-1; H NMR (CDCl3, 400 MHz) δ
7.68 (m, 4H), 7.42 (m, 6H), 5.62 (dd, J ) 9.6, 2.2, 1H), 3.90-
3.74 (m, 2H), 3.37 (td, J ) 9.2, 2.2, 1H), 2.10(s, 3H), 1.96 (m,
1H), 1.85 (m, 2H), 1.66-1.31 (m, 4H), 1.05 (s, 9H), 0.84 (d, J )
6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.9 (s), 135.5 (4d),
134.0 (s), 133.8 (s), 129.4 (2d), 127.5 (4d), 94.9 (d), 79.1 (d), 59.9
(t), 35.8 (t), 34.0 (d), 31.0 (t), 30.4 (t), 26.7 (3q), 21.1 (q), 19.0 (s),
17.0 (q); MS (EI) 323 (M - tBu - OAc+, 52), 267 (100), 245
(16), 199 (83), 183 (28), 159 (10), 135 (11), 123 (8), 105 (10), 77 (6).
[2-(6-Allyl-3-methyltetrahydropyran-2-yl)ethoxy]-tert-butyl-
diphenylsilane (15). To a solution of acetate 14 (0.600 g, 1.36
mmol, 1 equiv) in CH2Cl2 (9 mL) at -78 °C were added
allyltrimethylsilane (0.43 mL, 2.72 mmol, 2 equiv) and BF3‚Et2O
(0.26 mL, 2.04 mmol, 1.5 equiv) dropwise. After 1 h of stirring, a
saturated solution of NaHCO3 (10 mL) was added, and the solution
was warmed to rt for 1 h. The reaction mixture was extracted with
CH2Cl2, and the combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. The residue was
1874 J. Org. Chem., Vol. 73, No. 5, 2008

Macrolactone Core of Leucascandrolide A
3.47 (m, 3H), 3.32 (s, 3H), 2.03-1.28 (m, 9H), 1.06 (s, 9H), 0.94
(d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 135.4 (d,
4C), 133.9 (s, 2C), 129.4 (d, 2C), 127.5 (d, 4C), 96.3 (t), 72.6 (d),
67.9 (d), 64.5 (t), 60.7 (t), 54.9 (q), 35.5 (t), 33.6 (d), 32.1 (t), 26.7
(q, 3C), 27.9 (t), 26.6 (t), 19.0 (s), 18.2 (q); MS (EI) 439 (M -
CH3O+, 0.3), 413 (5), 381 (9), 351 (10), 291 (19), 255 (28), 225
(27), 213 (36), 199 (100), 183 (59), 165 (23), 153 (17), 135 (46),
121 (19), 107 (22), 91 (33), 71 (23), 55 (12).
To a solution of the above MOM ether (0.460 g, 0.98 mmol, 1
equiv) in THF (5 mL) at rt was added dropwise TBAF (3.9 mL, 1
M in THF, 3.90 mmol, 4 equiv). After disappearance of the starting
material by TLC, the reaction mixture was quenched with H2O
(5 mL) and extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, filtered, and concen-
trated, and the residue was purified by silica gel column chroma-
tography (petroleum ether/AcOEt 5:5 to 3:7) to furnish the
corresponding primary alcohol (0.220 g, 96%) as an oil: [R]D20
+53.7 (c 1.15, CHCl3); IR (neat) 3420, 2920, 1460, 1380, 1210,
1150, 1100, 1040, 920 cm-1; 1H NMR (CDCl3, 400 MHz) δ 4.63
(s, 2H), 4.07 (m, 1H), 3.75 (m, 2H), 3.63 (m, 2H), 3.45 (td, J )
2.6, 8.8 Hz, 1H), 3.37 (s, 3H), 3.07 (m, 1H, OH), 2.17-1.32 (m,
9H), 0.87 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
96.3 (t), 75.4 (d), 69.2 (d), 64.6 (t), 60.9 (t), 55.1 (q), 34.7 (d),
34.6 (t), 30.5 (t), 28.4 (t), 26.8 (t), 17.9 (q); MS (EI) 200 (M-32,
30), 187 (25), 169 (26), 155 (34), 143 (100), 125 (63), 115 (43),
107 (79), 95 (71), 87 (91), 73 (29), 67 (45), 55 (87).
1.30 (m, 7H), 0.89 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 139.1 (d), 117.0 (t), 96.2 (t), 72.6 (d), 69.2 (d), 67.1 (d),
64.9 (t), 55.0 (q), 41.9 (t), 38.5 (t), 34.4 (d), 30.5 (t), 28.6 (t), 27.1
(t), 17.9 (q); MS (EI) 241 (M-CH3O+, 2), 209 (2), 199 (100), 183
(10), 169 (11), 155 (17), 143 (19), 125 (17), 107 (22), 95 (50), 87
(25), 81 (33), 71 (29), 55 (38); HRMS (CI+, CH4) calcd for
C15H28O4 + H+ 273.2066, found 273.2062.
8-Methoxy-9-[6-(2-methoxymethoxyethyl)-3-methyltetrahy-
dropyran-2-yl]non-1-ene-4,6-diol (18). To a solution of 2,6-di-
tert-butylpyridine (0.62 mL, 2.78 mmol, 2 equiv) and alcohol 17
(0.380 g, 1.39 mmol, 1 equiv) in CH2Cl2 (4 mL) at 0 °C was added
MeOTf (0.21 mL, 1.81 mmol, 1.3 equiv) dropwise. After 2 h of
stirring at 0 °C and 15 h of stirring at rt, the reaction mixture was
quenched with a saturated solution of NaHCO3 and extracted with
CH2Cl2, and the combined organic layers were washed with brine,
dried over MgSO4, and concentrated. The residue was purified by
silica gel chromatography to afford the corresponding methyl ether
(0.360 g, 90%) as an oil: [R]2D0 +74.9 (c 1.04, CHCl3); IR (neat)
1
2920, 1640, 1460, 1380, 1150, 1100, 1040, 920 cm-1; H NMR
(CDCl3, 400 MHz) δ 5.79 (m, 1H), 5.07 (m, 2H), 4.62 (s, 2H),
3.94 (m, 1H), 3.60 (m, 2H), 3.48 (m, 2H), 3.39, 3.35 (2s, 6H),
2.30 (m, 2H), 2.06 (dddd, J ) 5.5, 9.6, 11.0, 14.7 Hz,), 1.80-1.35
(m, 8H), 0.79 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 134.3 (d), 116.9 (t), 96.3 (t), 76.0, 71.7 (2d), 68.0 (d), 64.4 (t),
56.5 (q), 54.9 (q), 37.8 (t), 37.7 (t), 34.3 (d), 31.8 (t), 28.1 (t), 26.7
(t), 18.1 (q); MS (EI) 245 (M - allyl+, 13), 213 (19), 187 (38),
157 (61), 141 (11), 125 (27), 107 (24), 99 (100), 85 (85), 75 (6),
67 (22), 55 (31); HRMS (CI+, CH4) calcd for C16H30O4 + H+
287.2222, found 287.2229.
To a solution of oxalyl chloride (0.32 mL, 3.63 mmol, 2.5 equiv)
in CH2Cl2 (8.5 mL) at -78 °C was added dropwise a solution of
DMSO (0.41 mL, 7.25 mmol, 4 equiv) in CH2Cl2 (3 mL). The
reaction mixture was stirred for 20 min at -78 °C, and a solution
of the above alcohol (0.336 g, 1.45 mmol, 1 equiv) in CH2Cl2 (3
mL) was added. The reaction mixture was stirred for 90 min at
-78 °C, and then Et3N (1.0 mL, 7.25 mmol, 5 equiv) was added
dropwise. After 30 min of stirring at 0 °C, the temperature was
raised to rt, and the reaction mixture was quenched with water (20
mL). The aqueous layer was extracted with CH2Cl2, and the
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. A purification of the residue
by silica gel chromatography (petroleum ether/EtOAc 8:2 to 7/3)
afforded aldehyde 16 (0.330 g, 99%) as a colorless oil: [R]D20
+43.8 (c 1.03, CHCl3); IR (neat) 2920, 1720, 1450, 1150, 1110,
To a solution of the above olefin (0.270 g, 0.96 mmol, 1 equiv)
in a mixture of acetone/water (3:1, 6 mL/2 mL) were added NMO
(0.190 g, 1.62 mmol, 1.7 equiv) and OsO4 (0.19 mL, 2.5% in
t-BuOH, 1.73 µmol, 0.018 equiv). The solution was stirred at rt
until total disappearance of the starting material by TLC, and then
NaIO4 (0.41 g, 1.91 mmol, 2 equiv) and H2O (5 mL) were added.
After 1 h of stirring, the white suspension was filtered and washed
with acetone, and the solution was concentrated under reduced
pressure. The resulting mixture was extracted with EtOAc, and the
combined organic layers were washed with a solution of Na2S2O3
and brine, dried over MgSO4, filtered, and concentrated. The residue
was purified by silica gel chromatography column (petroleum ether/
AcOEt 7:3) to furnish the corresponding aldehyde (0.240 g, 85%)
as a pale yellow oil: [R]2D0 +56.8 (c 1.00, CHCl3); IR (neat) 2920,
1
1040 cm-1; H NMR (CDCl3, 400 MHz) δ 9.70 (t, J ) 2.6 Hz,
1H), 4.53 (s, 2H), 3.92 (m, 1H), 3.78 (m, 1H), 3.50 (dd, J ) 5.5,
7.4 Hz, 2H), 3.27 (s, 3H), 2.50 (dd, J ) 2.6, 6.3 Hz, 2H), 2.03 (m,
1H), 1.73-1.30 (m, 6H), 0.85 (d, J ) 6.3 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 201.5 (d), 96.2 (t), 71.3 (d), 68.8 (d), 64.2
(t), 54.7 (q), 46.7 (t), 34.3 (d), 30.9 (t), 27.9 (t), 26.5 (t), 17.7 (q);
MS (EI) 201 (M - CHO+, 69), 183 (75), 165 (75), 141 (100), 123
(41), 109 (50), 100 (27), 95 (75), 87 (56), 81 (50), 71 (69), 55
(92).
1
1720, 1460, 1380, 1210, 1150, 1100, 1030, 920 cm-1; H NMR
(CDCl3, 400 MHz) δ 9.78 (t, J ) 2.2 Hz, 1H), 4.60 (s, 2H), 3.91
(m, 2H), 3.56 (m, 2H), 3.44 (m, 1H), 3.32 (s, 3H), 3.30 (s, 3H),
2.57 (dd, J ) 2.2, 5.5 Hz, 2H), 2.00 (m, 1H), 1.79-1.33 (m, 8H),
0.88 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 201.2
(d), 96.3 (t), 72.9 (d), 71.9 (d), 68.2 (d), 64.3 (t), 56.8 (q), 54.9 (q),
48.2 (t), 38.5 (t), 34.2 (d), 31.7 (t), 28.0 (t), 26.6 (t), 18.1 (q); MS
(EI) 256 (2), 243 (37), 224 (6), 211 (26), 199 (8), 187 (18), 167
(53), 149 (26), 141 (25), 123 (35), 107 (38), 99 (100), 91 (12), 81
(62), 71 (46), 55 (64).
To a suspension of (R,R)-TaddolCpTiCl complex (0.643 g, 1.06
mmol, 1.3 equiv) in Et2O (17 mL) at 0 °C was added allylmag-
nesium chloride (0.45 mL, 2 M in THF, 0.90 mmol, 1.1 equiv),
and the reaction mixture was then stirred at 0 °C for 90 min and
then cooled to -78 °C. A solution of the above aldehyde (0.240 g,
0.83 mmol, 1 equiv) in a small amount of Et2O was added at
-78 °C. After 4 h at -78 °C, deionized water (15 mL) was added,
and the reaction mixture was stirred at rt for 1 day. Celite was
added, and the mixture was then filtered on Celite (washing with
AcOEt). The resulting solution was dried over MgSO4, filtered,
and concentrated, and the residue was purified by silica gel
chromatography (petroleum ether/EtOAc 7:3) to afford the corre-
sponding allylic alcohol (210 mg, 78%) as an oil: [R]2D0 +46.0 (c
1.00, CHCl3); IR (neat) 3440, 1640, 1460, 1380, 1150, 1105, 920
cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.84 (m, 1H), 5.10 (m, 2H),
1-[6-(2-Methoxymethoxyethyl)-3-methyltetrahydropyran-2-
yl]pent-4-en-2-ol (17). To a suspension of (R,R)-TaddolCpTiCl
complex (1.33 g, 2.17 mmol, 1.3 equiv) in Et2O (14 mL) at 0 °C
was added allylmagnesium chloride (0.92 mL, 2 M in THF, 1.84
mmol, 1.1 equiv), and the reaction mixture was stirred at 0 °C for
90 min and then cooled to -78 °C. A solution of aldehyde 16 (0.380
g, 1.650 mmol, 1 equiv) in a small amount of Et2O was added at
-78 °C. After 2 h at -78 °C, deionized water (15 mL) was added,
and the reaction mixture was stirred at rt for 1 day. Celite was
added, and the mixture was filtered on Celite (washing with AcOEt).
The resulting solution was dried over MgSO4, filtered, and
concentrated, and the residue was purified by silica gel chroma-
tography (petroleum ether/EtOAc 8:2 to 7:3) to afford alcohol 17
(380 mg, 84%) as an oil: [R]2D0 +53.5 (c 1, CHCl3); IR (neat)
1
3440, 2900, 1640, 1450, 1210, 1150, 1105, 1030, 920 cm-1; H
NMR (CDCl3, 400 MHz) δ 5.85 (m, 1H), 5.06 (m, 2H), 4.61 (s,
2H), 4.05 (m, 1H), 3.94 (m, 1H), 3.62 (m, 2H), 3.55 (m, 1H), 3.38
(s, 3H), 3.30 (br s, 1H, OH), 2.21 (m, 3H), 1.80 (m, 1H), 1.62-
J. Org. Chem, Vol. 73, No. 5, 2008 1875

Ferrie´ et al.
4.62 (s, 2H), 3.92 (m, 1H), 3.80 (m, 1H), 3.62 (m, 3H), 3.47 (m,
1H), 3.38 (s, 3H), 3.36 (s, 3H), 3.29 (br s, 1H, OH), 2.22 (dd, J )
1.1, 7.0 Hz, 2H), 2.00 (dddd, J ) 5.9, 9.2, 11.0, 14.3 Hz, 1H),
1.72-1.37 (m, 10H), 0.96 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 134.9 (d), 117.2 (t), 96.3 (t), 77.5 (d), 73.1 (d), 69.2
(d), 68.0 (d), 64.5 (t), 56.4 (q), 55.0 (2q), 42.2 (t), 40.8 (t), 37.9
(t), 34.0 (d), 32.2 (t), 27.9 (t), 26.4 (t), 18.2 (q); MS (EI) 298 (M-
32, 2), 257 (9), 239 (8), 225 (54), 209 (33), 195 (29), 187 (17),
177 (15), 165 (12), 155 (63), 143 (31), 123 (48), 107 (46), 99 (100),
85 (89), 71 (65), 59 (80); HRMS (CI+, CH4) calcd for C18H34O5 +
H+ 331.2484, found 331.2487.
To a solution of the above olefin (0.140 g, 0.4 mmol, 1 equiv)
in a mixture of acetone/water (3:1, 2.5 mL/0.85 mL) were added
NMO (0.081 g, 0.70 mmol, 1.7 equiv) and OsO4 (2.5 wt % in
t-BuOH, 0.080 mL, 0.018 equiv). After 4 h, NaIO4 (0.170 g, 0.82
mmol, 2 equiv) and H2O (2 mL) were added. After 1 h, the resulting
mixture was extracted with EtOAc, and the combined organic layers
were washed with a solution of Na2S2O3 and brine, dried over
MgSO4, filtered, and concentrated. The obtained crude aldehyde
(0.140 g, 0.42 mmol) was used in the next step without further
purification.
1-(tert-Butyldimethylsilanyloxy)-4-methylhex-5-en-3-ol (22).
To a suspension of (R,R)-TaddolCpTiCl complex (17.00 g, 27.8
mmol, 1.4 equiv) in Et2O (200 mL) at 0 °C was added a solution
of 2-butenylmagnesium chloride (45.7 mL, 0.5 M in THF, 22.8
mmol, 1.15 equiv). After 2.5 h at 0 °C, the solution was cooled to
-78 °C, and a solution of aldehyde 21 (3.74 g, 19.9 mmol, 1.0
equiv) in dry Et2O (30 mL) at -78 °C was added via canula. After
16 h at -78 °C, deionized water (50 mL) was added, and the
reaction mixture was stirred at rt for 3 days. Celite was added, and
the mixture was filtered on a pad of Celite (washing with Et2O).
The resulting solution was dried over MgSO4, filtered, and
concentrated. The residue was diluted with pentane, and the white
precipitate [(R,R)-TADDOL] was sonicated, filtered, and dried in
vacuo (12.59 g, 97%). Pentane was evaporated and the residue was
purified by silica gel chromatography (petroleum ether/Et2O 9:1)
to afford the homoallylic alcohol 22 (4.20 g, 86%): [R]2D0 -9.7 (c
1.10, CHCl3); IR (neat) 3383, 3000-2800, 1639, 1463, 1255, 1086,
1003 cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.83 (m, 1H), 5.06 (m,
2H), 3.88 (dt, J ) 10.1, 5.0 Hz, 1H), 3.80 (m, 1H), 3.68 (dt, J )
7.2, 5.0 Hz, 1H), 3.20 (br s, 1H, OH), 2.23 (sextapp, J ) 6.8 Hz,
1H), 1.70-1.56 (m, 2H), 1.03 (d, J ) 6.9 Hz, 3H), 0.89 (s, 9H),
0.07 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 140.7 (d), 115.1 (t),
75.1 (d), 62.8 (t), 43.9 (d), 35.5 (t), 25.9 (q, 3C), 18.2 (s), 15.7 (q),
-5.5 (q, 2C); MS (EI), 189 (M - CH2dCHCHMe+, 37), 145 (11),
131 (46), 105 (52), 101 (35), 95 (100), 89 (38), 75 (93), 73 (41),
67 (23); HRMS (ESI) calcd for C13H28O2Si + Na+ 267.1751, found
267.1750.
Acrylic Acid 1-[2-(tert-Butyldimethylsilanyloxy)ethyl]-2-me-
thylbut-3-enyl Ester (23). To a solution of alcohol 22 (4.99 g,
20.4 mmol, 1 equiv) and Et3N (5.67 mL, 40.8 mmol, 2 equiv) in
Et2O (70 mL) at -18 °C was added dropwise acryloyl chloride
(2.25 mL, 26.5 mmol, 1.3 equiv). The mixture was allowed to stir
for 2 h, quenched by addition of a saturated solution of NaHCO3,
and then stirred at rt for 15 min. The aqueous layer was extracted
with Et2O, and the organic extracts were washed with aqueous 8%
H3PO4 and brine, dried over MgSO4, and filtered on a pad of silica
gel. After concentration, the acrylic ester 23 (5.62 g, 92%) was
obtained: [R]2D0 +21.0 (c 0.98 CHCl3); IR (neat) 3000-2800,
1724, 1638, 1462, 1404, 1255, 1190, 1094 cm-1; 1H NMR (CDCl3,
400 MHz) δ 6.38 (dd, J ) 17.3, 1.5 Hz, 1H), 6.10 (dd, J ) 17.3,
10.4 Hz, 1H), 5.81 (dd, J ) 10.4, 1.5 Hz, 1H), 5.76 (m, 1H), 5.09-
5.02 (m, 3H), 3.63 (ddd, J ) 10.3, 6.7, 5.7 Hz, 1H), 3.60 (dt J )
10.2, 7.5 Hz, 1H), 2.23 (sextapp, J ) 7.0 Hz, 1H), 1.78 (m, 2H),
1.03 (d, J ) 6.9 Hz, 3H), 0.88 (s, 9H), 0.02 (2s, 6H); 13C NMR
(CDCl3, 100 MHz) δ 165.8 (s), 139.3 (d), 130.3 (t), 128.8 (t), 115.6
(t), 74.2 (d), 59.7 (t), 41.6 (d), 34.3 (t), 25.9 (q), 18.2 (s), 15.6 (q),
-5.5 (q); MS (EI) 243 (M - CH2dCH2CO+, 12), 171 (10), 169
(15), 129 (96), 101 (18), 95 (100), 89 (13), 75 (31), 73 (17), 67
(15), 55 (34); HRMS (ESI) calcd for C16H30O3Si + Na+ 321.1856,
found 321.1856.
To a suspension of (R,R)-TaddolCpTiCl complex (0.310 g, 0.51
mmol, 1.3 equiv) in Et2O (5 mL) at 0 °C was added allylmagnesium
chloride (0.21 mL, 2 M in THF, 0.43 mmol, 1.1 equiv), and the
reaction mixture was stirred at 0 °C for 90 min and then cooled to
-78 °C. A solution of the above aldehyde (0.130 g, 0.39 mmol, 1
equiv) in a small amount of Et2O was added at -78 °C. After 4 h
at -78 °C, deionized water (10 mL) was added, and the reaction
mixture was stirred at rt for 1 day. Celite was added, and the mixture
was then filtered on Celite (washing with AcOEt). The resulting
solution was dried over MgSO4, filtered, and concentrated, and the
residue was purified by silica gel chromatography (petroleum ether/
EtOAc 5:5 to 0:10) to afford diol 18 (105 mg, 69%) as an oil:
[R]2D0 +40.0 (c 1.00, CHCl3); IR (neat) 3400, 2920, 1640, 1440,
1
1380, 1210, 1150, 1100, 1030, 920 cm-1; H NMR (CDCl3, 400
MHz) δ 5.83 (m, 1H), 5.10 (m, 2H), 4.62 (s, 2H), 4.20 (br s, 1H,
OH), 3.93 (m, 4H), 3.60 (m, 3H), 3.45 (m, 1H), 3.37 (s, 3H), 3.35
(s, 3H), 2.23 (m, 2H), 2.02-1.37 (m, 13H), 0.95 (d, J ) 6.3 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 134.7 (d), 117.2 (t), 96.2 (t),
77.4 (d), 73.3 (d), 71.4 (d), 70.9 (d), 68.0 (d), 64.4 (t), 56.3 (q),
55.1 (q), 42.7 (t), 42.1 (t), 42.0 (t), 37.6 (t), 34.2 (d), 31.9 (t), 27.9
(t), 26.4 (t), 18.2 (q); MS (EI) 375 (M + 1+, 52), 343 (100), 311
(19), 301 (16), 293 (15), 271 (9), 239 (9), 225 (4), 187 (7), 173
(1), 143 (11), 135 (20), 113 (3); HRMS (CI+, CH4) calcd for
C20H38O6 + H+ 375.2747, found 375.2746.
5,7-Dihydroxy-9-methoxy-10-[6-(2-methoxymethoxyethyl)-3-
methyltetrahydropyran-2-yl]dec-2-enoic Acid Ethyl Ester (19).
To a solution of diol 18 (42 mg, 0.11 mmol, 1 equiv) in CH2Cl2 (1
mL) was added ethyl acrylate (72 µL, 0.68 mmol, 6 equiv) followed
by Hoveyda-Grubbs catalyst Ru-III (3.5 mg, 5.6 µmol, 5 mol
%). After 1.5 h at rt, the reaction mixture was concentrated and
the residue was purified by silica gel chromatography (petroleum
ether/EtOAc 2:8 to 0:10) to afford diol 19 (44 mg, 89%) as a brown
oil: [R]2D0 +31.4 (c 1.00, CHCl3); IR (neat) 3420, 2920, 1720,
1650, 1440, 1370, 1270, 1150, 1100, 980, 920, 850 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 6.99 (td, J ) 7.4, 15.4 Hz, 1H), 5.88 (dt, J
) 1.5, 15.8 Hz, 1H), 4.61 (s, 2H), 4.25 (br s, 1H, OH), 4.22 (br s,
1H, OH), 4.18 (q, J ) 7.0 Hz, 2H), 4.06-3.89 (m, 3H), 3.60 (m,
3H), 3.42 (m, 1H), 3.36 (s, 3H), 3.35 (s, 3H), 2.37 (m, 2H), 2.00-
1.38 (m, 13H), 1.28 (t, J ) 7.0 Hz, 3H), 0.95 (d, J ) 6.3 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 166.2 (s), 145.1 (d), 123.4 (d),
96.2 (t), 77.9 (d), 73.6 (d), 71.3 (d), 70.8 (d), 68.1(d), 64.3 (t),
60.1 (t), 56.3 (q), 55.1 (q), 42.8 (t), 42.1 (t), 40.3 (t), 37.5 (t), 34.2
(d), 31.9 (t), 27.9 (t), 26.4 (t), 18.2 (q), 14.1 (q); MS (EI) 447 (M
+ 1+, 15), 415 (100), 383 (16), 365 (7), 353 (5), 301 (5), 271 (3),
239 (4), 225 (1), 187 (3), 143 (5), 135 (1); HRMS (CI+, CH4) calcd
for C23H42O8 + H+ 447.2958, found 447.2947.
6-[2-(tert-Butyldimethylsilanyloxy)ethyl]-5-methyltetrahydro-
pyran-2-one (24). To a solution of ester 23 (5.49 g, 18.4 mmol, 1
equiv) in CH2Cl2 at 40 °C was added Grubbs catalyst second-
generation Ru-II (475 mg, 0.55 mmol, 0.03 equiv). After being
refluxed for 48 h, the solution was allowed to cool to rt, and Pd/C
5% (790 mg, 0.37 mmol, 0.02 equiv) was added. The solution was
stirred under a gentle bubbling of H2 for 8 h and was left overnight
under a H2 atmosphere. The black suspension was filtered on Celite
and then the solution was concentrated in vacuo. The residue was
purified by silica gel chromatography (petroleum ether/ Et2O 7:3)
to afford tetrahydropyran 24 (3.50 g, 70%): [R]2D0 +60.0 (c 0.58,
CHCl3); IR (neat) 3000-2800, 1733, 1462, 1250, 1208, 1087, 1035,
1001, 833 cm-1; 1H NMR (CDCl3, 400 MHz) δ 4.10 (td, J ) 9.5,
2.4 Hz, 1H), 3.81 (ddd, J ) 10.2, 8.4, 5.0 Hz, 1H), 3.78 (ddd, J )
10.2, 6.6, 4.5 Hz, 1H), 2.61 (ddd, J ) 17.7, 6.8, 4.8 Hz, 1H), 2.46
(ddd, J ) 17.7, 9.7, 7.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.81-1.66
(m, 2H), 1.55 (m, 1H), 1.02 (d, J ) 6.6 Hz, 3H), 0.88 (s, 9H), 0.05
(s, 6H); 13C NMR (CDCl3, 100 MHz) δ 171.7 (s), 82.7 (d), 58.6
1876 J. Org. Chem., Vol. 73, No. 5, 2008

Macrolactone Core of Leucascandrolide A
(t), 36.7 (t), 32.5 (d), 29.5 (t), 27.8 (t), 25.9 (q, 3C), 18.2 (s), 17.5
(q), -5.4 (q, 2C); MS (EI) 215 (M- t-Bu+, 37), 197 (59), 185
(100), 171 (9), 129 (26), 123 (38), 95 (28), 75 (71); HRMS (ESI)
calcd for C14H28O3Si + Na+ 295.1700, found 295.1700.
1-{6-[2-(tert-Butyldimethylsilanyloxy)ethyl]-5-methyltetrahy-
dropyran-2-yl}-6-methylhept-3-yn-2-one (28). To a solution of
the freshly prepared silyl enol ether 27 (4.66 g, 23.8 mmol, 2 equiv)
and freshly prepared acetate 25 (3.76 g, 11.9 mmol, 1.0 equiv) in
CH2Cl2 (160 mL) at -78 °C was added a solution of ZnCl2 (26.2
mL, 1.0 M in Et2O, 26.18 mmol, 2.2 equiv). The reaction mixture
was allowed to warm to rt, quenched by addition of a saturated
solution of NaHCO3, and diluted with Et2O. The aqueous layer
was extracted with Et2O, and the combined organic extracts were
washed with brine, dried over MgSO4, filtered, and concentrated.
The residue was purified by silica gel chromatography (petroleum
ether/Et2O 95:5 to 90:10) to afford the trans-tetrahydropyran 28
(4.03 g, 89%)-(trans/cis THP 13:1 by GC): [R]2D0 +44.9 (c 0.92,
CHCl3); IR (neat) 3000-2800, 2210, 1673, 1462, 1251, 1165, 1083
Acetic acid 6-[2-(tert-Butyldimethylsilanyloxy)ethyl]-5-meth-
yltetrahydropyran-2-yl Ester (25). To a solution of lactone 24
(11.96 mmol, 3.24 g, 1 equiv) in dry CH2Cl2 (75 mL) at -78 °C
was added dropwise DIBAL-H (16.74 mL, 1.0 M in hexanes, 16.74
mmol, 1.4 equiv), and the solution was stirred for 1.5 h at -78 °C.
Pyridine (4.74 g, 60 mmol, 5 equiv), DMAP (4.36 g, 36 mmol, 3
equiv), and finally Ac2O (6.12 g, 60 mmol, 5 equiv) were then
added. The reaction mixture was stirred for 30 min at -78 °C and
then warmed to 0 °C. The reaction was quenched by addition of a
saturated aqueous solution of potassium sodium tartrate. After 10
min, a saturated aqueous NaHCO3 solution was added. After being
stirred for 20 min, the aqueous layer was extracted with Et2O, and
the combined organic layers were washed with a saturated aqueous
NaHCO3 solution, with a saturated aqueous CuSO4 solution, and
finally with brine. The organic layer was dried over MgSO4, filtered
on a plug of silica gel (4 cm, Et2O/petroleum ether 50:50), and
concentrated to afford the unstable acetate 25 (3.76 g, 98%) in a
12:1 ratio. This compound was directly engaged in the next step:
1H NMR (C6D6, 400 MHz) δ 5.70 (dd, J ) 9.3, 3.0 Hz, 1H), 3.90
(ddd, J ) 9.8, 8.4, 5.7 Hz, 1H), 3.80 (ddd, J ) 9.8, 6.7, 4.3 Hz,
1H), 3.21 (td, J ) 9.5, 2.3 Hz, 1H), 1.90 (dddd, J ) 13.9, 8.4, 6.8,
2.3 Hz, 1H), 1.65 (s, 3H), 1.60 (m, 1H), 1.54 (m, 1H), 1.48 (tdd,
J ) 12.5, 9.5, 4.2 Hz, 1H), 1.40 (m, 1H), 1.15 (m, 1H), 0.88 (dddd,
J ) 13.4, 12.5, 11.9, 5.2 Hz, 1H), 1.00 (s, 9H), 0.58 (d, J ) 6.6
Hz, 3H), 0.13 (s, 3H) 0.09 (s, 3H); 13C NMR (C6D6, 100 MHz) δ
168.6 (s), 94.8 (d), 79.2 (t), 59.6 (d), 36.7 (t), 34.4 (t), 31.4 (t),
30.8 (t), 26.2 (q, 3C), 20.73 (q), 18.5 (s), 17.1 (q), -5.2 (q, 2C).
Trimethyl(5-methyl-1-methylenehex-2-ynyloxy)silane (27). To
a solution of 4-methylpentyne 26 (5.88 mL, 50 mmol, 1 equiv) in
Et2O (150 mL) at -78 °C was added dropwise n-BuLi (24.4 mL,
2.15 M in hexanes, 52.5 mmol, 1.05 equiv), and the solution was
stirred at -78 °C for 1.5 h. A freshly prepared solution of ZnBr2
(60 mL, 1.2 M in Et2O, 1.45 equiv, 72 mmol) was then added, and
the reaction mixture was raised to 0 °C for 30 min. The solution
was transferred by cannula to a solution of AcCl (7.85 g, 2 equiv,
100 mmol) in Et2O (60 mL) at -78 °C, and the solution was
allowed to stir at rt for 1 h. The ethereal solution was carefully
concentrated under vacuum and diluted with a mixture of pentane/
Et2O (8:2, 30 mL). This solution was filtered on a short silica gel
column containing a Celite layer upside (pentane/Et2O 8:2). After
careful evaporation of the solvent, the methyl propargylic ketone
(4.71 g, 76%) was obtained: IR (neat) 3000-2800, 2207, 1675,
1
cm-1; H NMR (CDCl3, 400 MHz) δ 4.60 (dddd, J ) 7.7, 6.4,
5.0, 4.6 Hz, 1H), 3.70 (ddd, J ) 10.0, 7.5, 5.1 Hz, 1H), 3.61 (m,
1H), 3.36 (ddd, J ) 8.7, 7.3, 3.7 Hz, 1H), 2.90 (dd, J ) 15.1, 7.7
Hz, 1H), 2.66 (dd, J ) 15.1, 6.4 Hz, 1H), 2.26 (d, J ) 6.6 Hz,
2H), 1.90 (m, J ) 6.7 Hz, 1H), 1.82-1.64 (m, 4H), 1.54-1.28
(m, 3H), 1.01 (d, J ) 6.7 Hz, 6H), 0.93 (d, J ) 6.7, 3H), 0.88 (s,
9H), 0.04 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 185.8 (s), 93.6
(s), 81.8 (s), 73.8 (d), 67.7 (d), 60.1 (t), 48.6 (t), 35.8 (t), 33.6 (d),
28.0 (t), 27.6 (d), 27.5 (t), 26.6 (t), 26.0 (q, 3C), 22.0 (q, 2C), 18.3
(s), 18.2 (q), -5.3 (2q); MS (EI), 323 (M - t-Bu+, 27), 293 (58),
199 (100), 175 (10), 143 (37), 139 (14), 131 (19), 109 (41), 107
(34), 99 (25), 81 (M - C7H9O, 15), 75 (48); HRMS (ESI) calcd
for C22H40O3Si + Na+ 403.2639, found 403.2640.
1-{6-[2-(tert-Butyldimethylsilanyloxy)ethyl]-5-methyltetrahy-
dropyran-2-yl}-6-methylhept-3-yn-2-ol (29). To a solution of the
propargylic ketone 28 (732 mg, 1.93 mmol, 1 equiv) in a mixture
of CH2Cl2 (4 mL) and H2O (4 mL) were added HCOONa (1.31 g,
19.3 mmol, 10 equiv), n-Bu4Cl (96 mg, 0.579 mmol, 0.3 equiv),
and Noyori catalyst (R,R)Ru-IV (12.3 mg, 0.0193 mmol, 0.01
equiv). The solution was stirred for 24 h at rt, and two new portions
of catalyst (2 × 0.01 equiv) were added after 24 h and after 48 h
of stirring. After 72 h, the aqueous layer was extracted with Et2O,
and the combined organic extracts were washed with brine, dried
over MgSO4, filtered, and concentrated. The residue was purified
by silica gel chromatography (AcOEt/petroleum ether 8:92) to
afford the propargylic alcohol 29 (558 mg, 76%): [R]2D0 +134.7 (c
1.15, CHCl3); IR (neat) 3431, 3000-2800, 1462, 1253, 1141, 1089,
1054, 835, 775 cm-1; 1H NMR (CDCl3, 400 MHz) δ 4.56 (m, 1H),
4.23 (m, 1H), 3.78-3.66 (m, 2H), 3.55 (m, 1H), 3.27 (d, J ) 7.0,
1H, OH), 2.12 (m, 1H), 2.09 (dd, J ) 6.6, 2.0 Hz, 2H), 1.92-1.66
(m, 4H), 1.64-1.43 (m, 4H), 1.37 (m, 1H), 0.99 (d, J ) 6.5 Hz,
3H), 0.98 (d, J ) 7.0, 6H), 0.89 (s, 9H), 0.05 (2s, 6H); 13C NMR
(CDCl3, 100 MHz) δ 84.2 (s), 82.0 (s), 73.9 (d), 68.3 (d), 60.7 (d),
59.8 (t), 40.1 (t), 35.3 (t), 32.8 (d), 28.0 (d), 27.9 (t), 27.6 (t), 26.0
(t), 25.9 (q, 3C), 22.0 (q, 2C), 18.3 (s), 18.2 (q), -5.3 (q), -5.4
(q); MS (EI), 364 (M - 18+, 0.1), 325 (M-tBu+, 1), 217 (26),
199 (38), 143 (31), 125 (32), 107 (49), 105 (36), 101 (30), 99 (100),
95 (39), 81 (33), 75(75), 55 (23); HRMS (ESI) calcd for C22H42O3-
Si + Na+ 405.2795, found 405.2795.
1
1358, 1226, 1196 cm-1; H NMR (CDCl3, 400 MHz) δ 2.30 (s,
3H), 2.23 (d, J ) 6.7 Hz, 2H), 1.88 (m, J ) 6.7 Hz, 1H), 0.98 (d,J
) 6.7 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 184.8 (s), 93.1 (s),
82.2 (s), 32.7 (q), 27.9 (t), 27.5 (d), 21.9 (q, 2C); MS (EI) 124
(M•+, 3), 109 (M - Me+, 100), 82 (81), 79 (9), 67 (22).
To a solution of the above methyl propargylic ketone (3.54 g,
28.5 mmol, 1 equiv) in THF (100 mL) at -78 °C was added
LiHMDS (7.55 g, 45.2 mmol, 1.6 equiv) in THF (20 mL). After
20 min, TMSCl (4.13 mL, 34.2 mmol, 1.2 equiv) was added
dropwise, and the solution was stirred for 30 min at 0 °C. The
solution was concentrated under vacuum until the precipitation of
the salts and was diluted with pentane (150 mL). The resulting
suspension was filtered on Celite (washing with pentane) and was
concentrated under vacuum. Distillation of the residue (43-50 °C,
0.5 mbar) afforded the TMS enol ether 27 (4.81 g, 86%): IR (neat)
3000-2800, 1605, 1286, 1251, 911, 839, 760, 674 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 4.76 (d, J ) 0.4 Hz, 1H), 4.75 (d, J ) 0.4
Hz, 1H), 1.93 (d, J ) 6.5 Hz, 2H), 1.61 (m, J ) 6.7 Hz, 1H), 0.82
(d, J ) 6.7 Hz, 6H), 0.24 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
140.3 (s), 101.4 (t), 87.9 (s), 80.0 (s), 28.3 (t), 28.1 (d), 22.0 (q,
2C), 0.3 (q, 3C); MS (EI) 196 (M•+, 29), 181 (M - Me+, 27), 153
(M - i-Pr+, 58), 154 (79), 139 (M - CH2-i-Pr+, 100), 75 (63), 73
(36).
2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-6-[2-(tert-butyldim-
ethylsilanyloxy)-6-methylhept-3-enyl]-3-methyltetrahydropyr-
an (31). To a solution of propargyl alcohol 29 (522 mg, 1.367
mmol, 1 equiv) in THF (15 mL) was added dropwise a Red-Al
solution (3.3 mL, 70% in toluene, 10.9 mmol, 8 equiv). After 18 h
at 30 °C, the reaction mixture was quenched at 0 °C by a dropwise
addition of a saturated solution of potassium sodium tartrate, and
the reaction mixture was stirred 30 min at rt. The aqueous layer
was extracted with AcOEt (4 × 40 mL), and the combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated under vacuum.
To a solution of the above residue in CH2Cl2 (25 mL) was added
2,6-lutidine (650 µL, 5.47 mmol, 4 equiv). The solution was cooled
to -18 °C, and TBSOTf (941 µL, 4.10 mmol, 3 equiv) was added
dropwise. The solution was stirred for 2 h at 0 °C, and the reaction
J. Org. Chem, Vol. 73, No. 5, 2008 1877

Ferrie´ et al.
was quenched with a saturated aqueous solution of NaHCO3. The
organic layer was extracted with Et2O, and the combined organic
extracts were washed with H3PO4 8% and brine, dried over MgSO4,
filtered, and concentrated under vaccum. The residue was purified
by silica gel chromatography to afford the allylic TBS ether 31
(624 mg, 92%): [R]2D0 +36.6 (c 1.02, CHCl3); IR (neat) 3000-
2800, 1463, 1254, 1089, 1053, 971, 938, 833, 774 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 5.52 (dt, J ) 15.1, 7.0 Hz, 1H), 5.41 (dd, J
) 15.1, 6.5 Hz, 1H), 4.16 (ddd, J ) 9.5, 6.5, 3.0 Hz, 1H), 4.01 (m,
1H), 3.78 (ddd, J ) 9.8, 7.8, 4.8 Hz, 1H), 3.69 (dt, J ) 9.8, 7.3
Hz, 1H), 3.29 (td, J ) 9.0, 3.0 Hz, 1H), 1.98-1.86 (m, 3H), 1.86-
1.72 (m, 2H), 1.68-1.56 (m, 3H), 1.46-1.24 (m, 4H), 0.86-0.91
(m, 9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 6H), 0.03
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 135.4 (d), 128.5 (d), 72.3
(d), 70.4 (d), 68.1 (d), 60.5 (t), 41.6 (t), 40.1 (t), 36.6 (t), 34.8 (d),
29.0 (t), 28.4 (d), 27.4 (t), 26.0 (q, 3C), 25.9 (q, 3C), 22.4 (q), 22.3
(q), 18.3 (q), 18.3 (s), 18.2 (s), -4.0 (q), -4.7 (q), -5.2 (q, 2C);
MS (EI), 441 (M - t-Bu+, 11), 331 (12), 309 (15), 239 (24), 227
(95), 217 (24), 199 (21), 187 (27), 171 (45), 131 (29), 107 (35), 99
(39), 89 (31), 75 (100), 73 (65); HRMS (ESI) calcd for C28H58O3-
Si2 + Na+ 521.3817, found 521.3812.
2-{6-[2-(tert-Butyldimethylsilanyloxy)-6-methylhept-3-enyl]-
3-methyltetrahydropyran-2-yl}ethanol (32). To a solution of
compound 31 (3.04 g, 6.09 mmol, 1 equiv) in MeOH (183 mL)
was added NH4F (4.50 g, 122 mmol, 20 equiv), and the reaction
was stirred for 4 h at 60 °C. The reaction was quenched by addition
of an aqueous solution saturated NaHCO3 (50 mL) and brine (50
mL) and diluted with Et2O (150 mL). The aqueous layer was
extracted with Et2O (4 × 50 mL), dried over MgSO4, and
concentrated. The residue was purified by silica gel chromatography
(Petroleum Ether/AcOEt : 92/8 to 50/50) to afford the unreacted
starting material 32 (103 mg, 4%), the monoprotected alcohol 32
(1.88 g, 80%), and the diol 33 (211 mg, 13%): [R]2D0 +34.3 (c
0.81, CHCl3); IR (neat) 3442, 3000-2800, 1461, 1250, 1070, 1006,
970, 938, 833, 774 cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.53 (dt,
J ) 15.3, 7.0 Hz, 1H), 5.41 (ddt, J ) 15.1, 6.5, 1.3 Hz, 1H), 4.19-
4.08 (m, 2H), 3.79 (ddd, J ) 10.8, 6.5, 3.7 Hz, 1H), 3.75 (ddd, J
) 10.8, 7.5, 3.5 Hz, 1H), 3.40 (td, J ) 9.0, 3.0 Hz, 1H), 1.99 (ddd,
J ) 14.3, 9.5, 3.3 Hz, 1H), 1.94-1.80 (m, 4H), 1.54-1.72 (m,
3H), 1.51-1.37 (m, 3H), 1.36-1.20 (m, 2H), 0.89 (d, J ) 6.7 Hz,
3H), 0.88 (d, J ) 6.5 Hz, 3H), 0.87 (s, 9H), 0.84 (d, J ) 6.8 Hz,
3H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
135.1 (d), 129.1 (d), 76.2 (d), 70.8 (d), 69.0 (d), 61.6 (t), 41.5 (t),
39.4 (t), 35.2 (d), 34.8 (t), 29.1 (t), 28.4 (d), 27.3 (t), 25.9 (q, 3C),
22.4 (q), 22.3 (q), 18.2 (s), 18.1 (q), -3.9 (q), -4.9 (q); MS (EI),
327 (M - t-Bu+, 0.4), 227 (4), 217 (3), 199 (3), 187 (2), 171 (2),
143 (2), 131 (6), 125 (5), 99 (10), 75 (100); HRMS (ESI) calcd for
C22H44O3Si + Na+ 407.2952, found 405.2952.
a solution of the above crude aldehyde in dry Et2O (10 mL) was
added via syringe. After 16 h at -78 °C, deionized water (20 mL)
was added, and the reaction mixture was stirred at rt for 3 days.
Celite was added, and the mixture was filtered on Celite (washing
with Et2O). The resulting solution was dried over MgSO4, filtered,
and concentrated. The residue was diluted with pentane, and the
white precipitate [(R,R)-TADDOL] was sonicated, filtered, and dried
in vacuo (2.5 g). Pentane was evaporated and the residue was
purified by silica gel chromatography (petroleum ether/Et2O 95:5
to 7:3) to afford the homoallylic alcohol 34 (1.87 g 80%) and (R,R)-
TADDOL (0.95 g, 95% in total): [R]2D0 +31.4 (c 0.51, CHCl3); IR
(neat) 3446, 3000-2800, 1641, 1462, 1383, 1251, 1141, 1070,
1
1053, 972, 912, 835, 776 cm-1; H NMR (CDCl3, 400 MHz) δ
5.83 (ddt, J ) 17.1, 10.3, 7.1 Hz, 1H), 5.53 (dt, J ) 15.3, 7.0 Hz,
1H), 5.41 (ddt, J ) 15.1, 7.0, 1.2 Hz, 1H), 5.13-5.06 (m, 2H),
4.19 (ddd, J ) 9.5, 7.0, 3.1 Hz, 1H), 4.12 (m, 1H), 3.97 (m, 1H),
3.49 (dt, J ) 9.4, 5.3 Hz, 1H), 3.16 (d, J ) 3.5 Hz, 1H, OH), 2.29
(dtt, J ) 13.9, 7.0, 1.3 Hz, 1H), 2.22 (m, 1H), 2.00 (ddd, J ) 14.2,
9.8, 3.3 Hz, 1H), 1.92-1.81 (m, 3H), 1.67 (dd, J ) 5.8, 5.1, 2H),
1.66-1.56 (m, 2H), 1.55-1.42 (m, 2H), 1.38 (ddd, J ) 14.2, 9.5,
4.0 Hz, 1H), 1.35-1.20 (m, 1H), 0.89 (d, J ) 6.6 Hz, 3H), 0.88
(d, J ) 6.6 Hz, 3H), 0.87 (s, 9H), 0.82 (d, J ) 6.5 Hz, 3H), 0.06
(s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 135.2 (d),
135.1 (d), 128.9 (d), 117.3 (t), 73.2 (d), 70.7 (d), 69.0 (d), 67.8 (t),
42.1 (t), 41.5 (t), 39.1 (t), 38.1 (t), 34.5 (d), 29.2 (t), 28.3 (d), 27.5
(t), 25.9 (q, 3C), 22.4 (q), 22.3 (q), 18.2 (s), 18.1 (q), -4.0 (q),
-4.8 (q); MS (EI), 367 (M - t-Bu+, 3), 257 (36), 239 (12), 227
(33), 187 (18), 165 (20), 145 (42), 131 (35), 99 (39), 95 (58), 75
(100); HRMS (ESI) calcd for C25H48O3Si + Na+ 447.3263, found
447.3265.
tert-Butyl-{1-[6-(2-methoxypent-4-enyl)-5-methyltetrahydro-
pyran-2-ylmethyl]-5-methylhex-2-enyloxy}dimethylsilane (35).
To a solution of the homoallylic alcohol 34 (1.80 g, 4.37 mmol, 1
equiv) in Et2O (8 mL) were added MeI (12.4 g, 87.40 mmol, 20
equiv), Drierite (2 g), and freshly prepared Ag2O (3.04 g, 13.11
mmol, 3 equiv). After 20 h of vigorous stirring at 20 °C, the brown
reaction mixture was filtered on a pad of Celite and concentrated,
and the residue was purified by silica gel chromatography (petro-
leum ether/Et2O 96/4) to afford the methyl ether 35 (1.79 g, 96%):
[R]2D0 +48.0 (c 0.55, CHCl3); IR (neat) 3000-2800, 1642, 1462,
1252, 1096, 1074, 971, 911, 835, 776 cm-1; 1H NMR (CDCl3, 400
MHz) δ 5.80 (ddt, J ) 17.2, 10.1, 7.1 Hz, 1H), 5.54 (dt, J ) 15.3,
7.1 Hz, 1H), 5.42 (ddt, J ) 15.3, 6.7, 1.2 Hz, 1H), 5.03-5.12 (m,
2H), 4.20 (ddd, J ) 9.2, 6.9, 3.0 Hz, 1H), 4.05 (m, 1H), 3.57 (m,
1H), 3.38 (m, 1H), 3.38 (s, 3H), 2.29 (m, 2H), 1.99 (ddd, J ) 14.1,
9.5, 3.3 Hz, 1H), 1.91 (m, 2H), 1.80 (m, 1H), 1.70 (ddd, J ) 14.4,
10.1, 2.1 Hz, 1H), 1.66-1.53 (m, 2H), 1.48-1.25 (m, 5H), 0.89
(s, 9H), 0.88 (d, J ) 6.6 Hz, 3H), 0.87 (d, J ) 6.6 Hz, 3H), 0.86
(d, J ) 6.1 Hz, 3H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 135.3 (d), 134.5 (d), 128.5 (d), 117.2 (t), 76.4 (d),
71.4 (d), 70.4 (d), 68.4 (d), 56.5 (q), 41.5 (t), 40.0 (t), 38.5 (t),
37.8 (t), 35.4 (d), 29.2 (t), 28.3 (d), 27.5 (t), 25.9 (q, 3C), 22.4 (q),
22.2 (q), 18.3 (q), 18.2 (s), -3.9 (q), -4.6 (q); MS (EI), 438 (M•+,
0.1), 381 (M - t-Bu+, 7), 349 (9), 257 (9), 239 (10), 230 (11), 229
(60), 227 (75), 187 (50), 171 (31), 147 (37), 131 (40), 95 (40), 85
(100), 75 (73), 73 (44); HRMS (ESI) calcd for C26H50O3Si + Na+
461.3421, found 461.3419.
1-{6-[2-(tert-Butyldimethylsilanyloxy)-6-methylhept-3-enyl]-
3-methyltetrahydropyran-2-yl}pent-4-en-2-ol (34). To a solution
of the primary alcohol 32 (2.12 g, 5.52 mmol, 1 equiv) in CH2Cl2
(110 mL) was added dropwise the Dess-Martin periodinane reagent
(24.0 mL, 15 wt % in CH2Cl2, 11.04 mmol, 2 equiv) at 0 °C. The
solution was stirred for 2 h at rt, and the reaction was quenched by
the addition of a saturated aqueous solution of K2CO3 (20 mL), an
aqueous solution of 10% Na2S2O3 (20 mL), and water (20 mL).
The reaction mixture was stirred for 30 min and then diluted with
pentane (100 mL). The aqueous layer was extracted with Et2O (2
× 50 mL), and the combined organic extracts were washed with a
saturated solution of NaHCO3 (20 mL) and brine (30 mL). The
organic solution was dried over MgSO4, filtered over a small pad
of silica gel (3 cm, washing with Et2O), and concentrated under
vacuum to obtain the crude aldehyde, which was used in the next
step without further purification.
5-{6-[2-(tert-Butyldimethylsilanyloxy)-6-methylhept-3-enyl]-
3-methyltetrahydropyran-2-yl}-4-methoxypentane-1,2-diol (36).
To a solution of olefin 35 (1.78 g, 4.06 mmol, 1 equiv) and
N-methylmorpholine N-oxide (4.26 mmol, 435 mg, 1.05 equiv) in
a mixture of t-BuOH (40 mL) and H2O (20 mL) at 0 °C was added
a solution of OsO4 (2.57 mL, 2.5 wt % in t-BuOH, 0.203 mmol,
0.05 equiv), and the solution was stirred at 0 °C for 18 h. After 30
min at rt, the reaction mixture was quenched by addition of
Na2S2O3, and the solution was stirred for 30 min. The solution was
diluted with EtOAc and the aqueous layer was extracted with
EtOAc. The organic layer was finally washed with brine, dried over
To a suspension of (R,R)-TaddolCpTiCl complex (4.73 g, 7.73
mmol, 1.4 equiv) in Et2O (60 mL) at 0 °C was added a solution of
allylmagnesium chloride (3.3 mL, 0.5 M in THF, 6.62 mmol, 1.2
equiv). After 2.5 h at 0 °C, the solution was cooled to -78 °C and
1878 J. Org. Chem., Vol. 73, No. 5, 2008

Macrolactone Core of Leucascandrolide A
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography (petroleum ether/ EtOAc 50:
50) to afford diol 36 (1.169 g, 61%) in a 1:1 ratio of diastereoi-
somers and the unreacted starting material 35 (561 mg, 32%): IR
(neat) 3398, 3000-2800, 1461, 1380, 1251, 1075, 971, 938, 835,
diluted with EtOAc, and the aqueous layer was extracted with
AcOEt. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography (petroleum ether/ EtOAc 20:
80 to 0:100) to afford the diol 38 (603 mg, 66%) in a 1:1 ratio of
diastereoisomers and the unreacted starting material 37 (149 mg,
17%): IR (neat) 3368, 3000-2800, 1461, 1381, 1251, 1075, 971,
836, 776 cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.51 (dt, J ) 15.2,
6.8 Hz, 1H), 5.40 (dd, J ) 15.2, 7.0 Hz, 1H), 4.24-3.94 (m, 4H),
3.73-3.60 (m, 2.5H), 3.60-3.46 (m, 1.5H), 3.38 (s, 1.5H), 3.37
(s, 1.5H), 3.31 (m, 1H), 1.96-1.28 (m, 18H), 0.91-0.85 (m, 9H),
0.88 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 135.0 (d), 129.1 (d), 129.1 (d), 78.9 (d), 78.6 (d), 77.2
(d), 77.4 (d), 73.0 (d), 72.9 (d), 70.9 (d), 70.8 (d), 69.0 (d), 68.9
(d), 68.9 (3d), 66.7 (t), 56.2 (q), 56.1 (q), 41.5 (t), 40.0 (3t), 38.5
(t), 38.3 (t), 35.5 (2d), 29.0 (2t), 28.3 (d), 27.2 (2t), 25.9 (q), 22.4
(q), 22.3 (q), 18.3 (2s), 18.2 (q), -3.9 (2q), -4.6 (2q); HRMS (ESI)
C28H56O6Si + Na+ 539.3739, found 539.3733.
1
776 cm-1; H NMR (CDCl3, 400 MHz) δ 5.52 (dt, J ) 15.3, 6.9
Hz, 1H), 5.42 (dd, J ) 15.3, 6.8, Hz 1H), 4.18 (m, 1H), 4.03 (m,
1.5H), 3.89 (m, 0.5H), 3.78 (m, 0.5H), 3.71 (m, 0.5H), 3.61 (m,
1H), 3.46 (m, 1H), 3.41 (s, 1.5H), 3.38 (s, 1.5H), 3.42-3.30 (m,
1H), 2.32 (m, 0.5H), 2.08-1.16 (m, 15.5H), 0.92-0.84 (m, 18H),
0.06 (s, 1.5H), 0.07 (s, 1.5H), 0.03 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 135.1 (2d), 129.0 (d), 128.9 (d), 77.5 (d), 76.6 (d), 72.6
(d), 72.2 (d), 70.8 (d), 70.7 (d), 70.6 (d), 69.5 (d), 68.8 (d), 68.7
(d), 67.0 (2t), 57.1 (q), 56.2 (q), 41.5 (2t), 40.1 (t), 40.0 (t), 38.6
(t), 38.3 (t), 37.4 (d), 35.5 (d), 35.4 (d), 35.0 (d), 29.1 (t), 29.0 (t),
28.4 (2d), 27.3 (2t), 25.9 (2q, 3C), 22.4 (2q), 22.3 (2q), 18.3 (2s),
18.2 (2q), -3.9 (2q), -4.6 (2q); HRMS (ESI) calcd for C26H52O5-
Si + Na+ 495.34762, found 495.34727.
7-{6-[2-(tert-Butyldimethylsilanyloxy)-6-methylhept-3-enyl]-
3-methyltetrahydropyran-2-yl}-6-methoxyhept-1-en-4-ol (37).
To a solution of diol 36 (1.15 g, 2.44 mmol, 1 equiv) and n-Bu4NCl
(121 mg, 0.732 mmol, 0.3 equiv) in THF (20 mL) was added a
saturated aqueous solution of NaIO4 (20 mL, 0.6 M in H2O, 12.2
mmol, 5 equiv), and the reaction mixture was stirred for 30 min at
rt. Celite was added, and the reaction mixture was filtered on a
pad of Celite and washed with Et2O. The ethereal solution was
dried over MgSO4, filtered on a pad of silica gel eluting with Et2O,
and concentrated. The crude aldehyde was used in the next step
without further purification.
9-{6-[2-(tert-Butyldimethylsilanyloxy)-6-methylhept-3-enyl]-
3-methyltetrahydropyran-2-yl}-8-methoxynon-1-ene-4,6-diol (39).
To a solution of 38 (595 mg, 1.153 mmol, 1 equiv) and n-Bu4NCl
(57 mg, 0.346 mmol, 0.3 equiv) in a mixture of THF (20 mL) and
H2O (10 mL) was added a solution of NaIO4 (10 mL, 0.6 M in
H2O, 5.77 mmol, 5 equiv), and the reaction mixture was stirred
for 30 min at rt. Celite was added, and the reaction mixture was
filtered on a pad of Celite and eluted with Et2O. The ethereal
solution was dried over Na2SO4, filtered on a pad of silica gel
eluting with Et2O, and concentrated. The crude aldehyde was used
in the next step without further purification. To a solution of
allylTMS (4 mmol, 634 µL) in CH2Cl2 (10 mL) was added SnCl4
(4 mmol, 460 µL), and the solution was stirred for 18 h at rt to
prepare a solution of allylSnCl3 (0.36 M).
To a suspension of (R,R)-TaddolCpTiCl complex (3.9 mmol, 2.39
g, 1.6 equiv) in Et2O (28 mL) at 0 °C was added a solution of
allylmagnesium chloride (1.71 mL, 2.0 M in THF, 3.42 mmol, 1.4
equiv). After 2.5 h at 0 °C, the solution was cooled to -78 °C,
and a solution of the above crude aldehyde in dry Et2O (10 mL)
was added by syringe. After 16 h at -78 °C, deionized water (15
mL) was added, and the reaction mixture was stirred at rt for 3
days. Celite was added and the mixture was filtered on Celite
(washing with Et2O). The resulting solution was dried over MgSO4,
filtered, and concentrated. The residue was diluted with pentane,
and the white precipitate [(R,R)-TADDOL] was sonicated and
filtered. Pentane was evaporated, and the residue was purified by
silica gel chromatography (toluene/Et2O 95:5 to 90:10) to afford
the homoallylic alcohol 37 (918 mg, 78%): [R]2D0 +26.4 (c 0.69,
CHCl3); IR (neat) 3436, 3000-2800, 1641, 1462, 1382, 1252, 1073,
To a solution of the above crude aldehyde in CH2Cl2 (3 mL) at
-78 °C was added allylSnCl3 (4.75 mL, 0.36 M in CH2Cl2, 1.73
mmol, 1 equiv), and the solution was stirred for 1 h at -78 °C.
The reaction mixture was quenched by the addition of MeOH (0.5
mL) and stirred for 30 min at -78 °C. A saturated aqueous solution
of NH4Cl was then added (3 mL) with apparition of a white
precipitate. After warming at rt, the white mixture was filtered on
Celite, and the aqueous layer was extracted with Et2O, dried over
Na2SO4, and concentrated. The residue was purified by silica gel
chromatography (petroleum ether/AcOEt 75:25) to afford the diol
39 (448 mg, 74%): [R]2D0 +25.8 (c 0.87, CHCl3); IR (neat) 3400,
3000-2800, 1642, 1461, 1407, 1382, 1251, 1075, 971, 913, 835,
1
1073, 970, 911, 834, 775 cm-1, H NMR (CDCl3, 400 MHz) δ
1
776 cm-1; H NMR (CDCl3, 400 MHz) δ 5.83 (ddt, J ) 17.1,
5.83 (ddt, J ) 17.3, 10.2, 7.1 Hz, 1H), 5.52 (dt, J ) 15.3, 7.1 Hz,
1H), 5.40 (ddt, J ) 15.3, 6.9, 1.2 Hz, 1H), 5.14-5.06 (m, 2H),
4.19 (ddd, J ) 9.0, 7.0, 3.5 Hz, 1H), 4.03 (m, 1H), 3.83 (dtd, J )
9.3, 6.1, 2.5 Hz, 1H), 3.70 (m, 1H), 3.34 (m, 1H), 3.37 (s, 3H),
3.20 (br s, 1H, OH), 2.23 (m, 2H), 1.97-1.74 (m, 5H), 1.69 (ddd,
J ) 14.4, 9.4, 7.7 Hz, 1H), 1.66-1.54 (m, 3H), 1.53-1.40 (m,
3H), 1.38-1.25 (m, 2H), 0.99-0.86 (m, 9H), 0.88 (s, 9H), 0.06
(s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 135.1 (d),
134.9 (d), 128.9 (d), 117.4 (t), 77.8 (d), 72.4 (d), 70.7 (d), 69.8
(d), 68.7 (d), 56.1 (q), 42.3 (t), 41.5 (t), 40.8 (t), 40.0 (t), 38.8 (t),
35.4 (d), 29.0 (t), 28.4 (d), 27.3 (t), 25.9 (q, 3C), 22.4 (q), 22.2 (q),
18.3 (s), 18.2 (q), -3.9 (q), -4.6 (q); MS (EI), 283 (5), 227 (7),
209 (4), 199 (3), 187 (4), 171 (4), 145 (7), 131 (7), 95 (9), 75
(100); HRMS (ESI) calcd for C28H54O4Si + Na+ 505.3684, found
505.3679.
7-{6-[2-(tert-Butyldimethylsilanyloxy)-6-methylhept-3-enyl]-
3-methyltetrahydropyran-2-yl}-6-methoxyheptane-1,2,4-triol (38).
To a solution of olefin 37 (857 mg, 1.77 mmol, 1 equiv) and
N-methylmorpholine N-oxide (198.6 mg, 1.95 mmol, 1.1 equiv) in
a mixture of t-BuOH (20 mL) and H2O (10 mL) at 0 °C was added
a solution of OsO4 (900 µL, 2.5 wt % in t-BuOH, 0.071 mmol,
0.04 equiv), and the solution was stirred at 0 °C for 18 h. After 30
min at rt, the reaction mixture was quenched by addition of
Na2S2O3, and the solution was stirred for 30 min. The solution was
10.3, 7.1 Hz, 1H), 5.51 (dt, J ) 15.3, 7.1 Hz, 1H), 5.40 (dd, J )
15.3, 6.9 Hz, 1H), 5.13-5.05 (m, 2H), 4.19 (ddd, J ) 9.0, 7.4, 3.5
Hz, 1H), 4.07-3.99 (m, 2H), 3.92 (m, 1H), 3.66 (m, 1H), 3.35 (s,
3H), 3.28-3.37 (m, 1H), 2.30-2.15 (m, 2H), 1.96-1.70 (m, 6H),
1.40-1.67 (m, 8H), 1.39-1.25 (m, 2H), 0.87 (s, 9H), 0.90-0.85
(m, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 135.1 (d), 134.9 (d), 129.0 (d), 117.4 (t), 78.1 (d), 72.8 (d), 71.8
(d), 71.6 (d), 70.8 (d), 68.9 (d), 56.1 (q), 42.8 (t), 42.2 (t), 42.1 (d),
41.5 (t), 39.9 (t), 38.4 (t), 35.5 (d), 29.0 (t), 28.3 (d), 27.2 (t), 25.9
(q), 22.4 (q), 22.2 (q), 18.3 (q), 18.1 (s), -3.9 (q), -4.6 (q); HRMS
(ESI) calcd for C30H58O5Si + Na+ 549.3946, found 549.3938.
10-{6-[2-(tert-Butyldimethylsilanyloxy)-6-methylhept-3-enyl]-
3-methyltetrahydropyran-2-yl}-5,7-dihydroxy-9-methox-dec-2-
enoic Acid Methyl Ester (40). To a solution of olefin 39 (0.195
mmol, 102.5 mg, 1 equiv) and methyl acrylate (1.95 mmol, 168
mg, 10 equiv) in CH2Cl2 (1 mL) was added Grubbs-Hoveyda
catalyst Ru-III (18.3 mg, 29.5 µmol, 0.15 equiv). After being
stirred for 18 h, the reaction mixture was concentrated in vacuo,
and the residue was purified by silica gel chromatography (petro-
leum ether/AcOEt 70:30) to afford the unsaturated ester 40 (96.0
mg, 84%): [R]2D0 +16.2 (c 1.04, CHCl3); IR (neat) 3433, 3000-
2800, 1726, 1658, 1461, 1436, 1365, 1251, 1075, 972, 938, 835,
1
776 cm-1; H NMR (CDCl3, 400 MHz) δ 7.00 (dt, J ) 15.7, 7.4
J. Org. Chem, Vol. 73, No. 5, 2008 1879

Ferrie´ et al.
Hz, 1H), 5.89 (d, J ) 15.7 Hz, 1H), 5.50 (dt, J ) 15.2, 7.0 Hz,
1H), 5.40 (dd, J ) 15.2, 7.0 Hz, 1H), 4.30-4.13 (m, 2H), 4.08-
3.98 (m, 3H), 3.72 (s, 3H), 3.67 (m, 1H), 3.35 (s, 3H), 3.27 (m,
1H), 2.45-2.28 (m, 2H), 1.96-1.68 (m, 6H), 1.66-1.40 (m, 8H),
1.35-1.20 (m, 2H), 0.90-0.83 (m, 9H), 0.87 (s, 9H), 0.05 (s, 3H),
0.02 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.8 (s), 145.6 (t),
135.0 (d), 129.0 (d), 123.1 (d) 78.3 (d), 72.9 (d), 71.9 (d), 71.0 (d),
70.8 (d), 68.9 (d), 56.0 (q), 51.4 (q), 42.9 (t), 42.1 (d), 41.5 (t),
40.4 (t), 39.9 (t), 38.2 (t), 35.5 (d), 29.0 (t), 28.3 (d), 27.2 (t), 25.9
(q, 3C), 22.4 (q), 22.2 (q), 18.3 (q), 18.1 (s), -3.9 (q), -4.7 (q);
HRMS (ESI) calcd for C32H60O7Si + Na+ 607.4001, found
607.3993.
(4-Hydroxy-6-{3-[6-(2-hydroxy-6-methylhept-3-enyl)-3-meth-
yltetrahydropyran-2-yl]-2-methoxypropyl}tetrahydropyran-2-
yl)acetic Acid Methyl Ester (42). To a solution of the unsaturated
ester 40 (46.9 mg, 80 µmol, 1 equiv) in THF (10 mL) at 0 °C was
added t-BuOK (80 µmol, 1 mg, 0.1 equiv), and the solution was
stirred for 1 h. A second portion of t-BuOK (0.1 equiv) was then
added, and the reaction was stirred for 1 h. The reaction was
quenched by addition of a saturated aqueous solution of NH4Cl,
the aqueous layer was extracted with AcOEt, and the organic layer
was washed with brine, dried over MgSO4, and concentrated to
afford the THP ring 41 in a 3/1 (41-cis/ 41-trans) ratio.
To a solution of the above crude residue in THF (10 mL) was
added TBAF (1.6 mL, 1.6 mmol, 1.0 M in THF, 20 equiv), and
the reaction mixture was stirred for 24 h. The reaction was quenched
by addition saturated NaHCO3 solution, extracted with AcOEt, dried
over Na2SO4, filtered, and concentrated. The residue was first
purified by silica gel chromatography (AcOEt) to afford a mixture
of the two diastereoisomers cis-42 and trans-42 THP (19.8 mg,
52%, cis/trans: 3/1) and (Z,E)-dienoic acid 43 (31%). This mixture
of diastereoisomers was purified by silica gel chromatography
(petroleum ether/AcOEt 20:80) to afford cis-42 THP isomer (14.8
mg, 38%)28 and trans-42 THP isomer (5.0 mg, 13%): [R]2D0 +21.3
(c 0.075, CHCl3); IR (neat) 3338, 3000-2800, 1737, 1460, 1379,
1256, 1164, 1087, 1047 cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.65
(dtd, J ) 15.3, 7.2, 1.0 Hz, 1H), 5.49 (ddt, J ) 15.3, 6.2, 1.1 Hz,
1H), 4.35 (m, 1H), 4.26-4.18 (m, 2H), 4.00 (m, 1H), 3.85 (m,
1H), 3.66 (s, 3H), 3.60 (m, 1H), 3.53 (m, 1H), 3.30 (s, 3H), 3.20
(br s, 1H, OH), 2.50 (dd, J ) 15.1, 8.5 Hz, 1H), 2.37 (dd, J )
15.1, 4.9 Hz, 1H), 1.95-1.16 (m, 18H), 1.00 (d, J ) 6.6 Hz, 3H),
0.87 (d, J ) 6.6 Hz, 3H), 0.86 (s, J ) 6.6 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 171.9 (s), 134.5 (d), 129.2 (d), 74.8 (d), 73.2
(d), 68.9 (d), 68.6 (d), 68.4 (d), 66.9 (d), 64.5 (d), 56.4 (q), 51.7
(q), 41.6 (t), 41.1 (t), 40.6 (t), 40.2 (t), 38.7 (t), 38.1 (t), 37.9 (t),
33.3 (d, C12), 28.3 (d), 27.7 (t), 26.2 (t), 22.3 (q), 22.2 (q), 18.5
(q); HRMS (ESI) calcd for C26H46O3Si + Na+ 493.3141, found
493.3130.
2,4,6-Trichlorobenzoic Acid ester of “Macrocyclic Core of
Leucascandrolide A” (48). To a solution of the ester cis-42 (11.0
mg, 23.4 µmol, 1 equiv) in Et2O (5 mL) was added TMSOK (10.0
mg, 70 µmol, 3 equiv). After being stirred for 16 h, the reaction
mixture was diluted with CH2Cl2 and quenched by addition of an
aqueous solution of KHSO4 0.1 N until pH 2. The aqueous layer
was extracted with CH2Cl2 (6 × 30 mL), and then the combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated. The crude carboxylic acid 47 was dried by
azeotropic removal of water with toluene (2 × 20 mL) and used in
the next step without further purification.
with brine (30 mL), dried over MgSO4, filtered, and concentrated.
The residue was purified by silica gel chromatography (AcOEt/
petroleum ether 40:60) to afford the unexpected 2,4,6-trichloro-
benzoic acid ester of leucascandrolide A macrolactone 48 (11.0
mg, 72%) as an oil: [R]D20 +35.8 (c 0.45, CHCl3); IR (neat)
3000-2800, 1738, 1579, 1547, 1460, 1369, 1270, 1193, 1160, 1117,
1
1080, 1058, 965 cm-1; H NMR (CDCl3, 400 MHz) δ 7.39 (s,
1.5H), 7.34 (s, 0.5H), 5.69 (dt, J ) 14.3, 7.3 Hz, 1H), 5.47 (t, J )
3.0 Hz, 1H), 5.40-5.30 (m, 2H), 4.09 (tapp, J ) 11.1 Hz, 1H),
3.88 (dapp, J ) 12.1, 1H), 3.66 (tapp, J ) 11.8 Hz 1H), 3.52 (m,
2H), 3.35 (s, 3H), 2.53 (dd, J ) 13.1, 3.7 Hz, 1H), 2.33 (m, 1H),
2.35 (dd, J ) 13.1, 11.5 Hz, 1H), 2.05-1.20 (m, 15H), 1.16 (d, J
) 7.1 Hz, 3H), 0.99 (m, 1H), 0.87 (m, 1H), 0.84 (d, J ) 6.6 Hz,
3H), 0.84 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
169.3 (s), 163.2 (s), 136.3 (s), 132.5 (d), 132.4 (s, 2C), 132.1 (s),
130.0 (d), 128.2 (d, 2C), 73.6 (d), 73.2 (d), 71.2 (d), 70.9 (d), 69.9
(d), 69.6 (d), 63.0 (d), 57.3 (q), 43.1 (t), 42.8 (t), 41.6 (t), 39.1 (t),
35.5 (t), 35.2 (t), 35.1 (t), 30.9 (d), 28.1 (d), 27.1 (t), 24.2 (t), 22.2
(q, 2C), 18.2 (q); HRMS (ESI) calcd for C32H43O7Cl3 + Na+
667.1967, found 667.1962.
Macrocyclic Core of Leucascandrolide A (1). To a solution
of the ester cis-42 (10.0 mg, 21.3 µmol, 1 equiv) in Et2O (5 mL)
was added TMSOK (8.2 mg, 64 µmol, 3 equiv). After being stirred
for 16 h, the reaction mixture was diluted with CH2Cl2 and
quenched by addition of an aqueous solution of KHSO4 0.1 N until
pH 2. The aqueous layer was extracted with CH2Cl2 (6 × 30 mL),
and then the combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated. The crude carboxylic acid
47 was dried by azeotropic removal of water with toluene (2 × 20
mL) and used in the next step without further purification.
To a solution of the above carboxylic acid in toluene (100 mL)
was added Et3N (130 µL, 937 µmol, 44 equiv), followed by 2,4,6-
trichlorobenzoyl chloride (133 µL, 852 µmol, 40 equiv) and DMAP
(25.8 mg, 213 µmol, 10 equiv). After stirring for 1 h at rt, a second
portion of DMAP (10 equiv) was added, and the reaction was stirred
for 48 h. The reaction mixture was quenched by addition of a
saturated aqueous solution of NaHCO3 (30 mL) and water (20 mL).
After stirring for 20 min, the aqueous layer was extracted with
AcOEt (20 mL), and the combined organic layers were washed
with aqueous KHSO4 0.1 N (30 mL). The last acidic aqueous phase
was extracted with AcOEt (20 mL), and the combined organic
phases were washed with brine (30 mL), dried over MgSO4, filtered,
and concentrated. The residue was purified by silica gel chroma-
tography (AcOEt/petroleum ether 50:50) to afford the leucascan-
drolide A macrolactone 1 (7.0 mg, 75%) as an oil: [R]2D0 +58.5 (c
0.205, EtOH); IR (neat) 3429, 3000-2800, 1738, 1461, 1385, 1272,
1
1238, 1195, 1167, 1142, 1111, 1076, 1034, 1004, 964 cm-1; H
NMR (C5D5N, 400 MHz) δ 6.38 (br s, 1H, OH), 5.81-5.70 (m,
2H), 5.53 (dd, J ) 15.4, 6.9 Hz, 1H), 4.62 (tapp, J ) 11.6 Hz, 1H),
4.41 (m, 1H), 4.17 (tapp, J ) 11.3 Hz, 1H), 4.05 (dapp, J ) 10.9,
1H), 3.91 (tapp, J ) 10.5 Hz, 1H), 3.74 (tapp, J ) 10.7 Hz, 1H),
3.36 (s, 3H), 2.67 (dd, J ) 12.9, 3.8 Hz, 1H), 2.57-2.42 (m, 2H),
2.10 (app t, J ) 12.5 Hz, 1H), 1.95-1.13 (m, 14H), 1.06 (d, J )
7.0 Hz, 3H), 1.12-0.99 (m, 2H), 0.77 (d, J ) 6.6 Hz, 3H), 0.76
(d, J ) 6.6 Hz, 3H); 13C NMR (C5D5N, 100 MHz) δ 170.3 (s),
131.9 (d), 131.5 (d), 73.9 (d), 73.8 (d), 70.9 (d), 69.9 (d), 69.7 (d),
63.8 (d), 63.1 (d), 56.7 (q), 43.9 (t), 43.4 (t), 41.7 (t), 39.9 (t), 39.6
(t), 39.5 (t), 35.9 (t), 31.4 (d), 28.3 (d), 27.4 (t), 24.2 (t), 22.3 (q),
22.2 (q), 18.4 (q); HRMS (ESI) calcd for C25H42O6 + Na+
461.2874, found 461.2870.
Acknowledgment. We are grateful to Rhodia for financial
support. L.B. thanks the CNRS and Rhodia for a grant, and
two of us (L.F. and F.P.) thank the MRES for a grant.
Supporting Information Available: 1H and 13C NMR spectra
for compounds 3-10, 12-19, 22-25, 27-29, 30-32, 34-40, 42,
1, and 48. This material is available free of charge via the Internet
at http://pubs.acs.org.
To a solution of the above carboxylic acid in toluene (25 mL)
was added Et3N (73 µL, 526 µmol, 15 equiv), followed by 2,4,6-
trichlorobenzoyl chloride (83 µL, 526 µmol, 15 equiv) and DMAP
(113 mg, 936 µmol, 40 equiv). After 24 h of stirring at 60 °C, the
reaction mixture was quenched by addition of a saturated aqueous
solution of NaHCO3 (30 mL) and water (20 mL). After stirring for
20 min, the aqueous layer was extracted with AcOEt (20 mL), and
the combined organic layers were washed with aqueous KHSO4
0.1 N (30 mL). The last acidic aqueous phase was extracted with
AcOEt (20 mL), and the combined organic phases were washed
JO701315H
1880 J. Org. Chem., Vol. 73, No. 5, 2008