Total synthesis of leucascandrolide A: A new application of the Mukaiyama aldol-Prins reaction

Article abstract of DOI:10.1021/jo070901r

(Chemical Equation Presented) A total synthesis of the marine natural product leucascandrolide A has been completed. The titanium tetrabromide- mediated Mukaiyama aldol-Prins (MAP) reaction with aldehydes developed in our group provided a highly convergent and stereoselective method for assembling the core of the molecule. A new class of MAP reactions with acetals is introduced, and mechanistic considerations for both MAP methods are described. The total synthesis was completed by coupling of the side chain through two avenues: a known Still-Gennari olefination and a new Z-selective aldol/dehydroselenation reaction. Both procedures were highly selective and provided the natural product.

Full text of DOI:10.1021/jo070901r

Total Synthesis of Leucascandrolide A: A New Application of the
Mukaiyama Aldol-Prins Reaction
Lori J. Van Orden, Brian D. Patterson, and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of CaliforniasIrVine,
IrVine, California 92697
srychnoV@uci.edu
ReceiVed April 30, 2007
A total synthesis of the marine natural product leucascandrolide A has been completed. The titanium
tetrabromide-mediated Mukaiyama aldol-Prins (MAP) reaction with aldehydes developed in our group
provided a highly convergent and stereoselective method for assembling the core of the molecule. A
new class of MAP reactions with acetals is introduced, and mechanistic considerations for both MAP
methods are described. The total synthesis was completed by coupling of the side chain through two
avenues: a known Still-Gennari olefination and a new Z-selective aldol/dehydroselenation reaction.
Both procedures were highly selective and provided the natural product.
Introduction
In 1989, Pietra and co-workers first isolated leucascandrolide
A off the coast of New Caledonia from a new genus of
calcareous sponges called L. caVeolata (Figure 1).1 Leucascan-
drolide A has an unusual 18-membered macrolide ring with an
alternating oxygenation pattern and a disubstituted oxazole-
containing side chain. These structural features are not charac-
teristic of the other metabolites isolated from this class of
sponges.2 This structurally interesting macrolide is also the most
active metabolite isolated from calcareous sponges, with high
cytotoxicity in vitro against human KB tumor cell lines (IC50
) 50 ng/mL) and P388 leukemia cell lines (IC50 ) 250 ng/
mL) as well as potent antifungal inhibition against Candida
albicans. The biological and medicinal interest in leucascan-
drolide A prompted unsuccessful attempts to reisolate it, and
its actual origin is now believed to be from an opportunistic
microbial colony.1
FIGURE 1. Leucascandrolide A.
by Pietra’s group.3 Since then, there have been elegant total
syntheses reported by Paterson,4 Kozmin,5 and most recently
by Panek.6 In addition to these projects, many formal syntheses
have been reported including ones by Carreira,7 Crimmins,8
Wipf,9 and Williams.10 Our group also has reported a formal
Currently, the only reliable source of leucascandrolide A is
through chemical synthesis. In 2000, Leighton reported the first
total synthesis, confirming the stereochemical assignments made
(3) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem.
Soc. 2000, 122, 12894-12895.
(4) (a) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343-
347. (b) Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833-6849.
(5) (a) Wang, Y.; Janjic, J.; Kozmin, S. A. Pure Appl. Chem. 2005, 77,
1161-1169. (b) Wang, Y.; Janjic, J.; Kozmin, S. A. J. Am. Chem. Soc.
2002, 124, 13670-13671.
(1) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51-60.
(2) This particular class of sponges typically produces compounds
consisting of 2-amino imidazoles. See ref 1.
(6) (a) Su, Q.; Dakin, L. A.; Panek, J. S. J. Org. Chem. 2006, 72, 2-24.
(b) Su, Q.; Panek, J. S. Angew. Chem., Int. Ed. 2005, 44, 1223-1224.
10.1021/jo070901r CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/27/2007
5784
J. Org. Chem. 2007, 72, 5784-5793

Synthesis of Leucascandrolide A
SCHEME 1. Two Variants of the Mukaiyama Aldol-Prins
Reactions
through transvinylations of the corresponding alcohols, which
have been previously synthesized by many methods.14 The
approach envisioned for aldehyde 11 involved silyl enol ether
(14)4 addition to R-acetoxy ether 13, which would be obtained
from a sequence of steps involving a ring closing metathesis of
a homoallylic ether 15 derivative. This alcohol (15) would be
accessed from an asymmetric crotylation of the TIPS-mono-
protected aldehyde from 1,3-propanediol.15
Results
Synthesis of the MAP Coupling Partners. The enol ether
coupling partners 16a and 16b were accessed in a single step
by mercuric trifluoroacetate-catalyzed transvinylation of their
corresponding homoallylic alcohols (eq 1).16 A lower yield is
reported for ester-substituted enol ether 16a due to a shorter
reaction time, which was necessary to prevent decomposition
of the product under the reaction conditions.
synthesis, which introduced the Mukaiyama aldol-Prins (MAP)
cyclization as an effective method for generating 2,6-cis-
tetrahydropyran (THP) rings in complex systems (Scheme 1,
top).11 The lengthy sequence required to synthesize the requisite
enol ether allylsilane precursor, as well as subsequent elaboration
of the core (4) for the completion of the macrocycle, made the
overall synthetic strategy inefficient.
Methodology recently developed in our group has shown
potential for streamlining the synthesis of the 2,6-cis-THP of
leucascandrolide A. A titanium tetrabromide-promoted MAP
cyclization of simple homoallylic enol ethers and R-oxygenated
aldehydes was reported to provide 2,4,6-cis-THP rings with good
stereoselectivity (Scheme 1, bottom).12 This modified approach
allowed accessible cyclization precursors to be used and also
afforded more highly functionalized products with three new
stereocenters set in a single transformation.
Our new retrosynthetic plan for leucascandrolide A was
designed around the new methodology and is detailed below
(Figure 2). A cesium carboxylate side chain13 displacement of
the macrocyclic secondary bromide 8 would afford the natural
product. A late-stage titanium tetrabromide-promoted MAP
cyclization of aldehyde 11 and one of the homoallylic enol ethers
12 was anticipated to provide the desired 2,4,6-cis-THP. The
precedent in Scheme 1 suggested that an aldehyde with a
chelatable R-alkoxy functional group would provide good
selectivity at the alcohol center and moderate selectivity for the
equatorial bromide in the MAP reaction. Because our proposed
aldehyde coupling partner has a â-alkoxy group from the 2,6-
trans-THP, we would expect to see results similar to that of
the R-benzyloxy model system. Enol ethers 12 could be accessed
Synthesis of the 2,6-trans-THP of leucascandrolide A was
initiated from homoallylic alcohol 15.15 Acylation with acryloyl
chloride provided acrylate 17, which was subjected to ring
closing metathesis (RCM) conditions (Scheme 2). Although
there are several protocols for such metatheses,17 we were most
interested in a recent report by Grubbs of a one-pot tandem
RCM/hydrogenation procedure.18 In the first few attempts, the
acrylate was subjected to the ruthenium catalyst in one portion
(5 mol %) and the solution was heated at reflux for 5 h.
Following the olefin reduction at 23 °C, lactone 18 was isolated
in only 65% yield along with the reduced acrylate as a major
byproduct. Presumably, the ruthenium catalyst was undergoing
slow decomposition at elevated temperatures,19 leaving unre-
acted starting material to be reduced in the hydrogenation step.
A modification was made to the procedure in which the catalyst
was added in two portions. This improved the RCM efficiency
to afford 18 in 91% yield. Subsequent reductive acetylation,
using conditions developed in our group, provided R-acetoxy
ether 13.20 Silyl enol ether 14, which was synthesized from the
corresponding enone,21 was then coupled with 18 in the presence
of catalytic zinc bromide to generate 19 in 92% yield.22 Axial
(14) (a) Preparation of 12a: Bennett, F.; Knight, D. W.; Fenton, G. J.
Chem. Soc., Perkin Trans. 1 1991, 133-140. (b) Preparation of 12b: Keck,
G. E.; Truong, A. P. Org. Lett. 2005, 7, 2153-2156.
(15) La Cruz, T. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1873-1875.
(16) Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79, 2828-
2833.
(17) For a recent comprehensive review, see: Grubbs, R. H. Tetrahedron
2004, 60, 7117-7140.
(18) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312-11313.
(19) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202-7207.
(20) (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,
8317-8320. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000,
65, 191-198. (c) Kopecky, D. J.; Rychnovsky, S. D. Org. Synth. 2003, 80,
177.
(21) Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem.
2002, 67, 4615-4618.
(22) A similar approach was used by Paterson to assemble the C11-
C15 THP ring (ref 4).
(7) (a) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68, 9274-9283.
(b) Fettes, A.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 4098-
4101.
(8) Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, 5, 4641-4644.
(9) Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066-2067.
(10) (a) Williams, D. R.; Plummer, S. V.; Patnaik, S. Angew. Chem.,
Int. Ed. 2003, 42, 3934-3938. (b) Williams, D. R.; Patnaik, S.; Plummer,
S. V. Org. Lett. 2003, 5, 5035-5038.
(11) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123,
8420-8421.
(12) Patterson, B.; Marumoto, S.; Rychnovsky, S. D. Org. Lett. 2003,
5, 3163-3166.
(13) At this stage, we planned to use the combined procedures of
Leighton and Kozmin (cf. refs 3 and 5) to access the side chain.
J. Org. Chem, Vol. 72, No. 15, 2007 5785

Van Orden et al.
FIGURE 2. Second generation retrosynthesis of leucascandrolide A.
SCHEME 2. Synthesis of the 2,6-trans-THP
TABLE 1. 1,2-Reduction of the Unsaturated Ketone 19
approach of the nucleophile to the oxocarbenium ion intermedi-
ate shown afforded the trans-THP in high diastereoselectivity
(20:1).23
Based on precedence from Paterson’s synthesis of leuca-
scandrolide A, we intended to set the C17 stereocenter through
a regioselective and highly diastereoselective reduction of enone
19.4 Formation of either the (R)- or the (S)-configuration at C17
would be tolerated as the macrocyclization could proceed with
either a Yamaguchi macrolactonization7,8,10,11 or a Mitsunobu
reaction,4,9 both of which have precedent. Paterson found that
LiHAl(OBut)3 reduction of an enone, which is different from
19 only at remote stereocenters, led to the R-allylic alcohol with
32:1 stereoselectivity. Applying these reduction conditions to
our enone, however, provided primarily ketone 22 as a result
of 1,4-reduction (Table 1, entry 1). The selectivity in Paterson’s
system was attributed to either a highly lithium-coordinated
intermediate, which would have directed the reduction through
a lowest energy conformation, or an Evans-type polar addition.4
Although no modeling studies have been done to investigate
the differences between 19 and Paterson’s substrate, it is likely
that enhanced lithium chelation was responsible for the reported
regioselective and stereoselective hydride addition. Luche
reduction conditions and DIBAL-H provided the correct 1,2-
regiochemistry for the reduction but offered no stereoselectivity
yields (%)
entry
reducing agent
temp (°C)
20:21
22
1
2
3
4
5
6
7
LiHAl(OBut)3
DIBAL-H
NaBH4/CeCl3‚7H2O
(R)-CBSa/BH3‚DMS
(R)-CBS/BH3‚DMS
(R)-CBS/BH3‚DMS
(S)-CBS/BH3‚DMS
-78 to -10
3:4
70
-78
0 or -78
-78
-40
0
43:43
35:35
traceb
60:6
83:0
26:62
0c
a All CBS catalysts were freshly prepared according to the reported
procedure (ref 25). b Starting ketone recovered. c Lower temperatures
provided lower conversions and less selectivity.
(entries 2 and 3). Corey’s oxoborilidine (CBS) catalyst, which
is typically used for enantioselective reductions of ketones and
enones,24,25 showed promise for the diastereoselective reduction
of enone 19. Although only starting material was recovered from
(23) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon: New York, 1983; pp 209-221. (b) Stevens, R. V.; Lee,
A. W. M. J. Am. Chem. Soc. 1979, 101, 7032-7035. (c) Stevens, R. V.
Acc. Chem. Res. 1984, 17, 289-296. (d) Lewis, M. D.; Cha, J. K.; Kishi,
Y. J. Am. Chem. Soc. 1982, 104, 4976-4978.
(24) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V.
K. J. Am. Chem. Soc. 1987, 109, 7925-7926. (b) Corey, E. J.; Helal, C. J.
Angew. Chem., Int. Ed. 1998, 37, 1986-2012.
5786 J. Org. Chem., Vol. 72, No. 15, 2007

Synthesis of Leucascandrolide A
SCHEME 3. Completion of the Aldehyde MAP Coupling
Partner
As shown in the retrosynthetic analysis (Figure 2), enol ether
12a would have been the ideal coupling partner for our key
MAP cyclization because the ethyl ester would be at the correct
oxidation state for leucascandrolide A. The undesired axial
diastereomer, however, was shown to be favored in a 2:1 ratio
for this MAP reaction, and only modest yields were observed.
These results supported those obtained in the segment-coupling
Prins reaction: electron-withdrawing groups were shown to
diminish the yield and to favor axial selectivity for nucleophilic
trapping at the C4 position of the THP.27
MAP reactions with the corresponding TBDPS ether (12b)
were consistently high yielding (97%) and slightly favored the
desired equatorial bromide 10b. The axial and equatorial
bromide adducts (10b and 24b), which were separable by
chromatography, were individually methylated with methyl
trifluoromethanesulfonate. The diastereomeric ratios of the
methoxy epimers were determined to be approximately 7.8:1
for the axial bromide diastereomer and 4.5:1 for the equatorial
bromide diastereomer. Although no studies were done to
determine the absolute configuration of the C9 center, we
presumed that the major diastereomers formed (as shown in
Table 2) were those that would arise from a preferred 1,3-anti
aldol addition (see Discussion).28 Subsequent spectroscopic
correlation with authentic leucascandrolide A substantiated this
assumption.
CBS reductions at -78 °C (entry 4), the reaction proceeded
smoothly to approximately 75% conversion at -45 °C (entry
5). Increasing the temperature to 0 °C gave optimal results for
the reduction, with the (R)-CBS catalyst generating 20 in an
83% yield as a single diastereomer (entry 6). The reduction
selectivity manifested from the (S)-CBS catalyst was inferior,
providing a diastereomeric mixture of alcohols favoring 21 in
a ratio of 2.5:1 (entry 7).
With all four stereocenters in the C9-C24 fragment of
leucascandrolide A established, three additional transformations
provided the aldehyde coupling partner for the anticipated MAP
cyclization (Scheme 3). Protection of secondary alcohol 20 with
triisopropylsilyl trifluoromethanesulfonate (TIPS-OTf) afforded
bis-protected diol 23 in quantitative yield. Various conditions
were surveyed to achieve selective deprotection of the primary
TIPS-ether. Initial attempts utilizing tetrabutylammonium fluo-
ride readily removed both TIPS groups, but a milder p-
toluenesulfonic acid (p-TsOH)-mediated deprotection was se-
lective. Although subjecting 23 to stoichiometric p-TsOH
afforded primarily the bis-deprotected diol, catalytic acid (20
mol %) provided the desired alcohol in reasonable yields (55-
60%). The recovered bis-protected starting material was recycled
to supply an overall yield of 73%. Aldehyde 11 was then
prepared in 91% yield by Dess-Martin oxidation.
As an interesting observation, tin tetrabromide, which is a
popular Lewis acid for initiating Mukaiyama aldol reactions,
failed to provide good conversion to the desired products in
any of the MAP reactions investigated (eq 2). These conditions
afforded acetals 26 as the major products. MAP reactions require
a Lewis acid that can serve as a source of bromide ion to trap
the cyclized THP carbenium ion after the initial aldol reaction.
If the Lewis acid is not reactive enough or cannot provide a
sufficiently nucleophilic bromide source, the intermediate oxo-
carbenium ion will be trapped with an extra equivalent of
aldehyde. Model studies demonstrated that titanium tetrabromide
was active enough to convert acetals similar to 26 to the
corresponding Prins products, but that tin tetrabromide was not.29
The Mukaiyama Aldol-Prins Reaction with Acetals.
Before continuing on with the proposed synthesis, we decided
to investigate the possibility of directly installing the C9 methyl
ether through an acetal MAP reaction. Dimethyl acetal 27 was
prepared by camphorsulfonic acid-catalyzed acetalization of
aldehyde 11 (Table 3). The titanium tetrabromide/titanium
tetraisopropoxide mixed Lewis acid system that was successful
for the aldehyde MAP reaction was not optimal in the acetal
MAP reaction, providing mainly starting materials (entries 1
The Mukaiyama Aldol-Prins Reaction with Aldehydes.
The key MAP reaction between aldehyde 11 and enol ether 12a
or 12b was anticipated to provide the 2,4,6-cis-THP of leuca-
scandrolide A. Subjection of aldehyde 11 and enol ether 12a
or 12b to cyclization conditions (titanium tetrabromide and 2,6-
di-tert-butyl-4-methylpyridine (2,6-DBMP)), however, provided
undesired adduct 25 as the major product (Table 2, entries 1
and 5). It was presumed that titanium tetrabromide, in addition
to mediating the desired MAP reaction, also complexed to and
activated the siloxy group, facilitating an allylic displacement
by bromide. An aluminum tribromide/trimethyl aluminum mixed
Lewis acid system provided similar results (entries 2 and 6).26
Attenuation of the titanium tetrabromide with 50% titanium
tetraisopropoxide resulted in only starting materials (entries 3
and 7), but a 9:1 mixture of the two Lewis acids circumvented
the side reaction and provided desired products 10 and 24, each
as a mixture of diastereomers at the alcohol center (entries 4
and 8).
(25) Synthesis of the pyrrolidinol ligands: (a) Nikolic, N. A.; Beak, P.
Organic Syntheses; Wiley & Sons: New York, 1998; Collect. Vol. 9, pp
391-397. (b) Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.;
Carroll, J. D.; Corley, E. G.; Desmond, R. Organic Syntheses; Wiley &
Sons: New York, 1998; Collect. Vol. 9, pp 676-689. Synthesis of the
catalyst: (c) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.;
Reamer, R. A.; Mohan, J. J.; Turner Jones, E. T.; Hoogsteen, K.; Baum,
M. W.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751-762. (d) Mathre,
D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.;
Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880-2888.
(26) Jung, M. E.; Ho, D.; Chu, H. V. Org. Lett. 2005, 7, 1649-1651.
(27) Jasti, R.; Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc.
2005, 127, 9939-9945.
(28) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322-4343.
(29) Patterson, B. D. Ph.D. Thesis, University of CaliforniasIrvine,
Irvine, CA, 2004.
J. Org. Chem, Vol. 72, No. 15, 2007 5787

Van Orden et al.
TABLE 2. MAP Reactions with Aldehydes
enol
ether
Lewis acid
(equiva)
base/additive
(equiv)
yield 10+24
ratio
ratio of 10
alcohol
formation
of 25
entry
(%)
10:24b
1
2
3
4
5
6
7
8
12a
TiBr4 (2.0)
AlBr3 (1.5)
2,6-DBMPc (1.5)
Me3Al (0.3)
2,6-DBMP (1.5)
2,6-DBMP (1.5)
2,6-DBMP (1.5)
Me3Al (0.3)
minor
minor
<10e
57
minor
minor
0e
majord
major
0
0
major
major
0
TiBr4/Ti(OiPr)4 (1.0:1.0)
TiBr4/Ti(OiPr)4 (3.5:0.5)
TiBr4 (2.0)
1:2.0f
1.3:1
NDg
12b
AlBr3 (1.5)
TiBr4/Ti(OiPr)4 (1.0:1.0)
TiBr4/Ti(OiPr)4 (1.8:0.2)
2,6-DBMP (1.5)
2,6-DBMP (1.5)
97
4.5:1
0
1
a All equivalents are relative to starting aldehyde. b As determined by crude H NMR analysis. c 2,6-DBMP ) 2,6-di-tert-butyl-4-methylpyridine. d The
major product is the combined diastereomers and regioisomers of 25. e Starting materials were recovered for these reactions. f Average of three runs; for
these reactions, the bromide selectivity was inconsistent. g The alcohol ratio was not determined.
TABLE 3. MAP Reactions with Acetal Electrophiles
ratiosb 28a or 28b
enol
ether
Lewis acid
(equiva)
yield 28a
or 28b (%)
(OMe epimers/
eq-Br:ax-Br)
recovered
acetal (%)
entry
1
2
3
4
5
12a
12b
TiBr4/Ti(OiPr)4 (3.5:0.5)
TiBr4 (2.0)
0
69
61
100
100
65
15
39
2.5:1/3.9:1
TiBr4/Ti(OiPr)4 (1.8:0.2)
TiBr4/Ti(OiPr)4 (3.5:0.5)
TiBr4 (4.0)
1.0:1/8.0:1
1.0:1/8.0:1
1
a Equivalents are relative to the starting aldehyde. b As determined by crude H NMR analysis.
and 3). Increasing the equivalents of this mixed Lewis acid
(entry 4) or employing titanium tetrabromide alone (entries 2
and 5) afforded quantitative yields of bis-THP 28b for the case
of the TBDPS-substituted enol ether 12b and a useful 69% yield
for the ester-substituted enol ether 12a. We presumed that lower
yields with 12a could be attributed to an electron-withdrawing
effect as described earlier. It was surprising that titanium
tetrabromide alone led to no observed siloxy displacement,
which was prevalent in the aldehyde system with this Lewis
acid. The diastereoselectivities from the acetal MAP reaction
were also different. In the cases where enol ether 12b was
employed (entries 4 and 5), the initial aldol reaction into the
acetal was completely unselective, but selectivity for the
equatorial bromide improved significantly from ca. 1.3:1 to 8.0:
1. A rationale for this interesting change in selectivity will be
described in the Discussion section.
to the aldehyde system. Because of these limitations, we chose
to complete the leucascandrolide A macrocycle synthesis from
intermediate 10b, the major diastereomer obtained from the
aldehyde MAP reaction (Scheme 4). Following methylation of
the C9 alcohol, the TBDPS ether was deprotected under basic
conditions to provide primary alcohol 29. This alcohol could
be transformed to the carboxylic acid in two steps by a Dess-
Martin oxidation and subsequent Kraus oxidation,30,31 or more
directly by Jones oxidation to provide the acid in one step. The
TIPS protecting group was removed with TBAF to provide seco
acid 30 in 80% yield over two steps. A Mitsunobu reaction with
tributylphosphine and diisopropyl azodicarboxylate (DIAD)
afforded macrolactone 8 in 75% yield. The use of tributylphos-
phine was critical to avoid a macrocyclization with retention
of configuration or DIAD-trapped products, which were com-
Completion of the Leucascandrolide A Macrocycle. Al-
though the acetal MAP reaction provided excellent diastereo-
selectivity at the bromide center with enol ether 12b, the 1:1
mixture at the methoxy center was inseparable and contributed
to a lower overall yield of the desired diastereomer, as compared
(30) (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175-
1176. (b) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888-
890. (c) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
(31) In many syntheses of leucascandrolide A, a similar two-step
oxidation is performed: see refs 4, 9, 10, and 11.
5788 J. Org. Chem., Vol. 72, No. 15, 2007

Synthesis of Leucascandrolide A
TABLE 4. Summary of Nucleophiles Investigated for Bromide
Displacements
SCHEME 4. Completion of a Formal Synthesis
yield 38/39
a
entry 8 or 37 R1
R2
pKa
(%)
1
2
3
8
Cs CH3 (40)
Hc 34
Cs CH2SePh (41)
4.74
4.70d
3.75
85b
45e
78
4
5
6
7
8
37
Cs CH2SePh (41)
3.75
45f
Hc CH2P(O)(OCH2CF3)2
3.30g
Cs CH2P(O)(OCH2CF3)2 (42) 3.30g
Hc CtCCH3
2.66
2.66
Cs CtCCH3 (43)
mon side reactions with triphenylphosphine. Displacement of
the equatorial bromide generated in the MAP reaction with
cesium acetate, followed by acetate methanolysis, provided
macrocyclic alcohol 31 in 60% yield over the two steps. It is
important to note that no elimination was observed during the
bromide displacement, and the macrocyclic lactone was stable
to the acetate cleavage conditions.
a For the cesium carboxylates, the numbers are for the corresponding
acid. b See Scheme 4. c Cs2CO3 was used as an additive. d Data are for a
similar Z-olefinic acid. e See eq 4. f Remaining material was starting
materials. g Data are for the corresponding ethyl phosphonate.
isomer of leucascandrolide A (35) were formed in a 1:1 mixture
(eq 4). While 36 may have arisen from an excess of basic cesium
carbonate in solution, it was presumed that the Z to E
isomerization of 35 occurred by an addition/elimination of a
cesium carboxylate nucleophile or a transient radical.
Synthesis and Coupling of the Oxazole-Containing Side
Chain. Although the sequence described above constituted a
formal synthesis of the natural product, we wanted to further
highlight the utility of the equatorial bromide formed in the MAP
reaction. A direct displacement of this bromide by the cesium
carboxylate derivative of the side chain would complete the total
synthesis in one step fewer than completion of the formal
synthesis. The 12-step synthesis of side chain aldehyde 33
followed Leighton’s reported procedure (eq 3).3 The final two-
step sequence, including a Still-Gennari olefination32 and
hydrolysis to form carboxylic acid 34, was achieved through
the procedure of Kozmin.5
Model bromide 37 and macrocycle 8 were used to identify
alternative nucleophiles that could be used in the displacement
reaction and further derivatized in the real system to give the
natural product (Table 4). Isolated â-phosphono-cesium car-
boxylate 42 or the corresponding carboxylic acid underwent
decomposition in the harsh reaction conditions34 (entries 5 and
6), and cesium 2-butynoate (43) or its corresponding acid
The in situ formation of nucleophilic cesium carboxylates
from cesium carbonate and their subsequent displacement
reactions are well-precedented.33 We anticipated that the addition
of cesium carbonate to side chain acid 34, 18-crown-6, and
macrocyclic bromide 8 would generate leucascandrolide A in
a single step. Unfortunately, elimination product 36 and an olefin
(34) Cesium carbonate is often used as a base in Horner-Emmons-
Wadsworth reactions, and presumably decomposition occurs via deproto-
nation of an R-proton: (a) Yamanoi, T.; Akiyama, T.; Ishida, E.; Abe, H.;
Amemiya, M.; Inazu, T. Chem. Lett. 1989, 335-337. (b) Bloch, R.; Seck,
M. Tetrahedron Lett. 1987, 28, 5819-5820.
(32) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(33) (a) Kruizinga, W. H.; Kellogg, R. M. J. Am. Chem. Soc. 1981, 103,
5183-5189. (b) Burch, J. D. Ph.D. Thesis, Harvard University, Cambridge,
MA, 2005.
J. Org. Chem, Vol. 72, No. 15, 2007 5789

Van Orden et al.
SCHEME 5. Completion of the Total Synthesis by Aldol
Reaction and Dehydroselenation
SCHEME 6. Mechanistic Rationale: Aldehyde MAP
Reactionsa
(entries 7 and 8) failed to displace the bromide. An examination
of the approximate pKa values of each of these acids provided
insight into the displacement reaction. Cesium acetate (40) and
an alkenyl cesium carboxylate with pKa values of ca. 4.70 served
as effective coupling partners (entries 1 and 2), but compounds
with lower pKa values were not effective.
Cesium 2-(phenylselanyl)acetate (41) was shown to be an
effective coupling partner on both the model system and the
macrocyclic bromide 8 (Table 4, entries 3 and 4). Utilizing
methodology discovered by Toru,35 the oxazole-containing side
chain could then be attached through a syn-selective aldol
reaction and stereospecific dehydroselenation to afford the
Z-olefin and leucascandrolide A in an unoptimized 40% yield
over the two steps (Scheme 5).36 To confirm the structure of
synthetic leucascandrolide A prepared by this method, the total
synthesis was also completed by Leighton’s two-step procedure,
which included acylation of macrocyclic alcohol 31 and a
subsequent Still-Gennari olefination reaction.3
a Note: TiBr4 and not the mixed Lewis acid system which was actually
used for the synthesis was illustrated for simplicity.
Discussion
Recent studies with the segment coupling Prins reaction have
provided insight into the stereoselectivity of the MAP process.
Because of the disparity in diastereoselectivities derived from
the aldehyde and acetal MAP reactions, they will be discussed
separately. For â-alkoxy aldehydes, an initial coordination of
titanium tetrabromide would provide intermediate 45, which has
been activated toward the nucleophilic attack of 12b (Scheme
6). This coordination would be expected to favor 1,3-anti attack
through six-membered transition state C (see Figure 3, left),
and this model is consistent with the reaction outcome.
Additionally, â-alkoxy aldehydes have been described by Evans
to favor a lowest-energy polarized transition state A, which also
results in 1,3-anti aldol products upon the addition of a
nucleophile.28 Because of the use of a titanium Lewis acid in
our system, it is most likely that the addition is controlled by
the classic chelation model.
FIGURE 3. Rationale for the OH/OMe selectivity of MAP reactions.
The expected intermediate bromoether 46 would engage in
the Prins cyclization upon activation by a Lewis acid.37
Interaction of 46 and titanium tetrabromide would generate the
contact ion pair 48. Cyclization to the THP cation, as modeled
by Alder,38 and direct collapse of this ion pair would favor the
axial 4-bromo-THP 24b through a least-motion pathway. This
(35) Nakamura, S.; Hayakawa, T.; Nishi, T.; Watanabe, Y.; Toru, T.
Tetrahedron 2001, 6703-6711.
(36) This reaction was not optimized due to the lack of the aldehyde
coupling partner at the end of the total synthesis. The unreacted starting
material was recovered from the reaction, which shows that optimization
should be possible.
(37) Bromoether intermediates have been identified in low-temperature
NMR studies on simple Prins cyclization systems and were found to be
major components in solution (ref 27).
(38) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002,
124, 4960-4961.
5790 J. Org. Chem., Vol. 72, No. 15, 2007

Synthesis of Leucascandrolide A
SCHEME 7. Mechanistic Rationale: Acetal MAP Reactions
52. In this case, the active Lewis acid in the system is either
titanium tetrabromide or titanium tribromomethoxide. Activation
with these Lewis acids would lead to contact ion pair 53 (or
-
the TiBr5 analogue). As discussed above, direct collapse of
this contact ion pair would favor the axial product 55, and
formation of a solvent-separated ion pair 54 would favor the
equatorial product 28b. In this case, the oxocarbenium ion 53
shows the expected Prins reactivity, and most of the material
passes through the solvent-separated ion pair 54 en route to the
equatorial 4-bromo-THP 28b. We attribute the difference in
selectivity between the aldehyde and acetal substrates to the
higher reactivity of the aldehyde-derived contact ion pair 48
compared with 53.
Recall that the unusual preference for an axial 4-bromo-Prins
adduct does not correlate with the Mukaiyama aldol-Prins
reaction or even the use of R- or â-alkoxy aldehydes. The axial
selectivity is found with R- or â-alkoxy aldehydes that are
expected to chelate effectively, such as benzyl ethers, and it is
not observed with nonchelating alkoxy groups such as TBS
ethers.12 The model that we propose here is based on the unusual
reactivity of the titanium-chelated oxocarbenium ion 48 and is
consistent with the observed higher axial selectivity for fast-
collapsing ion pairs.39,41
Scheme 7 also provides an explanation for the absence of
solvolysis of the allyl siloxy group without titanium tetraiso-
propoxide attenuation of titanium tetrabromide. During the
formation of oxocarbenium ion 46, 1 equiv of methoxide ion
was dissociated from 46, thus forming the attenuated Lewis acid
MeOTiBr3 in situ.
Conclusion
A total synthesis of the structurally complex marine natural
product leucascandrolide A has been completed. The synthesis
required 17 steps for the longest linear sequence from known
alcohol 15 with an overall yield of 4.3%. The MAP reaction
with aldehyde 11 was demonstrated to be a highly efficient and
diastereoselective process in forming the core of the molecule.
The MAP reaction with acetals was also introduced in this
synthesis as a method for installing methyl ethers and obtaining
high diastereoselectivity for a tetrahydropyranyl equatorial
bromide. Studies of this key step led us to formulate mechanistic
rationales for both classes of MAP reactions, which led to a
better understanding of the origins of diastereoselectivity.
Furthermore, this synthesis is the first application of Toru’s two-
step Z-selective olefination on a complex molecule and high-
lights it as a new method for the installation of the leucascan-
drolide A side chain unit.
outcome is similar to what we have observed for the bromo-
trimethylsilane-induced Prins cyclization.39 Alternatively, if the
reaction of the ion pair were slow, the contact ion pair would
form a solvent-separated ion pair 49, and this intermediate would
cyclize to form the equatorial 4-bromo-THP 10b preferentially,
based on the preferred orbital alignment present in the tetrahy-
dropyran cation.38 The key partitioning event takes place at the
contact ion pair 48. We postulate that the chelated titanium
oxocarbenium ion 48 is more reactive than a typical oxocar-
benium ion. High reactivity of the electrophile would favor a
fast collapse and lead to axial product. Lower reactivity would
allow the ions to separate and ultimately lead to the equatorial
product. Neither pathway is expected to be completely selective.
The underlying reasons for greater reactivity of the titanium-
chelated oxocarbenium ion 48 are not obvious.
For the acetal case, a slightly modified mechanistic scheme
was proposed (Scheme 7). Initial coordination of titanium
tetrabromide would provide intermediate 50, which decomposes
to oxocarbenium ion 51 and the methoxy titanium tetrabromide
“ate” complex shown. A chelation-controlled nucleophilic
addition to 51 is no longer possible, and because a 1:1 mixture
of methoxy diastereomers was observed for this addition, it can
be assumed that neither of the polar transition states D or E
(Figure 3) was preferred. Ward also reported lower stereo-
selectivity for the aldol addition of an allylsilane to a â-alkoxy
acetal (ca. 1:1) as compared to the corresponding aldehyde (>9:
1), but offered no explanation of these results.40 The Mukaiyama
aldol reaction with 12b would generate bromoether intermediate
Experimental Section
General experimental details, experimental data for all intermedi-
ates, and spectra for key intermediates and leucascandrolide A can
be found in the Supporting Information.
Lactone 18. To a solution of acrylate 17 (0.76 g, 2.2 mmol, 1.0
equiv) in anhydrous, degassed 1,2-dichloroethane (45 mL) was
added Grubbs’ second generation ruthenium catalyst42 (47.0 mg,
0.056 mmol, 0.03 equiv). The solution was heated at reflux for 2
(40) Ward, D. E.; Gai, Y.; Kaller, B. F. J. Org. Chem. 1995, 60, 7830-
7836.
(41) Jasti, R.; Rychnovsky, S. D. J. Am. Chem. Soc. 2006, 128, 13640-
13648.
(39) Jasti, R.; Vitale, J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004,
126, 9904-9905.
(42) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
J. Org. Chem, Vol. 72, No. 15, 2007 5791

Van Orden et al.
h, then another equal portion of the catalyst (47.0 mg, 0.056 mmol,
0.03 equiv) was added. After heating at reflux for an additional 90
min, the dark brown solution was allowed to cool to 23 °C. The
open reaction vessel was quickly transferred to a Parr bomb, which
was then pressurized with hydrogen gas (100 psi), and stirred
vigorously for 16 h. The reaction mixture was then concentrated
in vacuo and purified by flash chromatography (10-40% diethyl
ether/hexanes) to afford 0.64 g (91%) of 18 as a clear, colorless
equiv) in ethyl vinyl ether (30.0 mL) was added mercuric
trifluoroacetate (241 mg, 0.564 mmol, 0.10 equiv). This mixture
was allowed to stir in a capped vessel for 48 h. The mixture was
then diluted with diethyl ether (75 mL), and the layers were
separated. The organic layer was washed with saturated aqueous
sodium bicarbonate (50 mL) and brine (50 mL), dried over
anhydrous sodium sulfate, and concentrated in vacuo. The crude
oil was immediately purified by flash chromatography on deacti-
vated silica gel (1% triethylamine in the desired eluant) (0-10%
diethyl ether/hexanes) to provide 1.93 g (90%) of 12b as a clear,
colorless oil: [R]23D -9.26 (c ) 2.00, dichloromethane); IR (neat)
3072, 2931, 2858, 1636, 1112 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.76-7.68 (m, 4H), 7.50-7.41 (m, 6H), 6.37 (dd, J ) 14.1, 6.6
Hz, 1H), 5.84 (ddt, J ) 16.9, 14.1, 7.0 Hz, 1H), 5.14 (d, J ) 4.1
Hz, 1H), 5.11 (s, 1H), 4.36 (dd, J ) 14.1, 1.4 Hz, 1H), 4.22-4.13
(m, 1H), 4.03 (dd, J ) 6.6, 1.4 Hz, 1H), 3.83 (dt, J ) 13.2, 6.7
Hz, 1H), 3.75 (dt, J ) 10.7, 5.4 Hz, 1H), 2.42-2.35 (m, 2H), 1.88-
1.79 (m, 2H), 1.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 151.6,
135.8, 134.2, 133.9, 129.8, 127.9, 117.7, 88.3, 76.2, 60.2, 38.8,
36.9, 27.1, 19.4; HRMS (ESI) calcd for C24H36O2SiN [M + NH4]+
398.2515, found 398.2498. Anal. Calcd for C24H32O2Si: C, 75.74;
H, 8.47. Found: C, 75.90; H, 8.51.
oil: [R]22 +63.7 (c ) 1.00, chloroform); IR (neat) 2943, 2868,
D
1742, 1094 cm-1; H NMR (500 MHz, CDCl3) δ 4.16 (td, J )
1
10.4, 2.4 Hz, 1H), 3.94-3.84 (m, 2H), 2.61 (ddd, J ) 17.7, 6.8,
4.8 Hz, 1H), 2.47 (ddd, J ) 17.7, 9.6, 6.0 Hz, 1H), 1.95 (dddd, J
) 14.5, 8.6, 6.3, 2.4 Hz, 1H), 1.92 (ddt, J ) 13.4, 6.9, 4.8 Hz,
1H), 1.82-1.70 (m, 2H), 1.61-1.52 (m, 1H), 1.07-1.03 (m, 24H);
13C NMR (125 MHz, CDCl3) δ 171.9, 82.9, 59.1, 37.1, 32.7, 29.7,
28.0, 18.2, 17.7, 12.1; HRMS (EI) calcd for C14H27O3Si [M - iPr]+
271.1729, found 271.1733.
Tetrahydropyran 19. To a solution of acetoxy ether 13 (0.62
g, 1.79 mmol, 1.0 equiv) and silyl enol ether 14 (0.71 g, 3.58 mmol,
2.0 equiv) in anhydrous dichloromethane (18 mL) was added zinc
bromide (40.0 mg, 0.179 mmol, 0.1 equiv). The slurry was stirred
for 4 h then was concentrated in vacuo and immediately purified
by flash chromatography (0-7% diethyl ether/hexanes) to give 0.70
g (92%) of 19 as a clear, colorless oil with a 2,6-trans/cis
diastereomeric ratio of >95:5 (as determined by crude proton NMR
spectroscopy): [R]23D +35.5 (c ) 100, chloroform); IR (neat) 2956,
MAP Products 10b and 24b. Aldehyde 11 (62.2 mg, 0.146
mmol, 1.0 equiv), enol ether 12b (55.7 mg, 0.146 mmol, 1.0 equiv),
and 2,6-di-tert-butyl-4-methylpyridine (45.0 mg, 0.219 mmol, 1.5
equiv) were dissolved in anhydrous dichloromethane (6.0 mL). This
solution was cooled to -78 °C, and a 9:1 titanium tetrabromide/
titanium tetraisopropoxide Lewis acid blend43 as a solution in
dichloromethane (0.78 mL, 0.298 mmol, 0.34 M, 2.0 equiv) was
added dropwise. After 2 h, a 1:1 mixture of methanol and
triethylamine (6 mL) was added dropwise, followed by the addition
of saturated aqueous sodium bicarbonate (2 mL). The biphasic
mixture was allowed to warm to 23 °C and was diluted with diethyl
ether (10 mL). The layers were separated, and the aqueous layer
was extracted with diethyl ether (3 × 10 mL). The combined
organic layers were washed with saturated aqueous sodium
bicarbonate (1 × 10 mL), water (1 × 10 mL), and brine (1 × 10
mL), dried over anhydrous sodium sulfate, and concentrated in
vacuo. The crude oil was purified by flash chromatography (0-
100% diethyl ether/hexanes) to yield 68.0 mg (53%) of 10b as a
4.5:1 mixture of diastereomers at the alcohol center and 57 mg
(44%) of 24b as a 7.8:1 mixture of diastereomers at the alcohol
1
1673, 1629, 1463, 1092, 883 cm-1; H NMR (500 MHz, C6D6) δ
6.72 (dt, J ) 15.8, 7.4 Hz, 1H), 6.04 (td, J ) 15.8, 1.4 Hz, 1H),
4.39 (app q, J ) 6.1 Hz, 1H), 3.90 (ddd, J ) 7.7, 6.4, 2.6 Hz, 2H),
3.54 (ddd, J ) 9.6, 6.4, 3.3 Hz, 1H), 2.83 (dd, J ) 15.0, 7.1 Hz,
1H), 2.43 (dd, J ) 15.0, 6.4 Hz, 1H), 1.95-1.87 (m, 1H), 1.80 (td,
J ) 7.5, 3.3 Hz, 1H), 1.77 (td, J ) 6.8, 1.4 Hz, 2H), 1.56-1.36
(m, 4H), 1.34-1.26 (m, 1H), 1.14-1.18 (m, 24H), 0.88 (d, J )
6.8 Hz, 3H), 0.75 (d, J ) 6.7 Hz, 6H); 13C NMR (125 MHz, C6D6)
δ 195.9, 145.3, 132.1, 74.1, 67.9, 60.8, 44.3, 41.7, 36.3, 33.6, 28.1,
28.0, 26.8, 22.4, 18.5, 18.4, 12.4; HRMS (EI) calcd for C22H41O3-
Si [M - iPr]+ 381.2825, found 381.2834. Anal. Calcd for C25H48O3-
Si: C, 70.70; H, 11.39. Found: C, 70.90; H, 11.33.
Aldehyde 11. To a solution of the primary alcohol from 23 (50.0
mg, 0.117 mmol, 1.0 equiv) in anhydrous dichloromethane (3 mL)
was added pyridine (40.0 µL, 0.492 mmol, 4.2 equiv), followed
by Dess-Martin periodinane (99.0 mg, 0.234 mmol, 2.0 equiv). This
mixture was stirred for 2 h then diluted with diethyl ether (10 mL).
A 1:1 mixture of saturated aqueous sodium bicarbonate and
saturated aqueous sodium bisulfite (5 mL) was added, and the
resultant biphasic mixture was stirred for 5 min. The layers were
separated, and the aqueous layer was extracted with diethyl ether
(3 × 20 mL). The combined organic layers were washed with
saturated aqueous sodium bicarbonate (1 × 20 mL) and brine (1
× 20 mL), dried over anhydrous sodium sulfate, and concentrated
in vacuo. The crude oil was purified by flash chromatography on
deactivated silica gel (1% triethylamine in the desired eluant) (5-
60% diethyl ether/hexanes) to provide 45 mg (91%) of 11 as a
clear, colorless oil: [R]23D +35.3 (c ) 0.90, chloroform); IR (neat)
2931, 2718, 1731, 1094 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.79
(dd, J ) 3.4, 2.0 Hz, 1H), 5.53 (dt, J ) 14.9, 7.1 Hz, 1H), 5.38
(dd, J ) 15.4, 7.6 Hz, 1H), 4.25 (td, J ) 8.1, 4.6 Hz, 1H), 3.93
(dq, J ) 9.3, 4.9 Hz, 1H), 3.80 (ddd, J ) 12.5, 8.6, 3.9 Hz, 1H),
2.58 (ddd, J ) 15.7, 3.8, 2.0 Hz, 1H), 2.49 (ddd, J ) 15.4, 8.8, 3.2
Hz, 1H), 2.20 (ddd, J ) 13.9, 9.5, 4.6 Hz, 1H), 1.96-1.86 (m,
2H), 1.82-1.73 (m, 1H), 1.67-1.58 (m, 2H), 1.54-1.35 (m, 4H),
1.09-1.03 (m, 21H), 0.93-0.86 (m, 9H); 13C NMR (125 MHz,
CDCl3) δ 202.2, 134.2, 130.5, 72.0, 71.7, 69.3, 47.6, 41.8, 40.2,
35.1, 28.9, 28.6, 27.2, 22.7, 22.5, 18.3, 12.6; HRMS (ESI) calcd
for C25H48O3SiNa [M + Na]+ 447.3271, found 447.3279. Anal.
Calcd for C25H48O3Si: C, 70.70; H, 11.39. Found: C, 70.56; H,
11.45.
23
center. 10b: [R]D +21.9 (c ) 1.15, dichloromethane); IR (thin
1
film) 3515, 2952, 2930, 2865, 1111 cm-1; H NMR (500 MHz,
CDCl3) δ 7.65 (d, J ) 6.4 Hz, 4H), 7.46-7.36 (m, 6H), 5.56 (dt,
J ) 14.5, 7.0 Hz, 1H), 5.41 (dd, J ) 15.5, 7.3 Hz, 1H), 4.29 (app
q, J ) 8.4 Hz, 1H), 4.10 (tt, J ) 10.1, 5.0 Hz, 1H), 4.06-3.95 (m,
2H), 3.77 (dtd, J ) 11.5, 5.4, 1.2 Hz, 1H), 3.71 (dt, J ) 10.6, 5.8
Hz, 1H), 3.67 (d, J ) 1.6 Hz, 1H), 3.60-3.42 (m, 2H), 2.29-2.13
(m, 3H), 1.97-1.86 (m, 2H), 1.86-1.25 (m, 16H), 1.13-1.00 (m,
30H), 0.92-0.87 (m, 6H), 0.85 (d, J ) 6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 136.0, 135.8, 135.7, 135.5, 134.5, 133.9,
133.8, 130.1, 129.9, 127.9, 75.1, 75.0, 73.6, 71.7, 71.6, 69.3, 67.1,
60.2, 45.5, 43.5, 43.3, 41.8, 40.0, 39.9, 38.9, 34.5, 29.1, 28.6, 27.5,
27.1, 22.7, 22.5, 19.4, 18.5, 18.4, 12.6; HRMS (ESI) calcd for
C49H81BrO5Si2Na [M + Na]+ 907.4703, found 907.4703. Anal.
Calcd for C49H89O5Si2Br: C, 66.41; H, 9.21. Found: C, 66.60; H,
9.44.
23
24b: [R]D +20.9 (c ) 2.15, dichloromethane); IR (thin film)
3518, 2952, 2930, 2865, 1095 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.79-7.63 (m, 4H), 7.48-7.37 (m, 6H), 5.57 (dt, J ) 15.0, 7.1
Hz, 1H), 5.42 (dd, J ) 15.4, 7.4 Hz, 1H), 4.71 (t, J ) 2.8 Hz, 1H),
4.32 (dd, J ) 12.9, 7.7 Hz, 1H), 4.22-4.06 (m, 3H), 4.02-3.93
(m, 1H), 3.82-3.71 (m, 2H), 3.54-3.48 (m, 1H), 2.18 (ddd, J )
13.8, 8.8, 5.1 Hz, 1H), 2.05 (dd, J ) 12.6, 1.7 Hz, 1H), 2.00-1.83
(m, 5H), 1.81-1.27 (m, 14H), 1.19-1.00 (m, 30H), 0.95-0.87 (m,
(R)-3-(Vinyloxy)hex-5-enyloxy-tert-butyldiphenylsilane (12b).
To a solution of secondary alcohol 16b (2.00 g, 5.64 mmol, 1.0
(43) See the Supporting Information for more details on the preparation
of this Lewis acid.
5792 J. Org. Chem., Vol. 72, No. 15, 2007

Synthesis of Leucascandrolide A
6H), 0.87 (d, J ) 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
136.0, 135.8, 135.7, 135.5, 134.5, 134.0, 133.9, 130.1, 129.8, 127.9,
73.4, 72.6, 71.6, 70.0, 69.9, 69.2, 67.8, 60.4, 50.2, 50.1, 43.2, 41.8,
40.3, 39.3, 38.5, 34.7, 29.0, 28.6, 27.5, 27.1, 22.7, 22.5, 19.4, 18.5,
18.4, 12.6; HRMS (ESI) calcd for C49H81BrO5Si2Na [M + Na]+
907.4703, found 907.4714.
131.5, 73.9, 73.8, 70.9, 69.9, 69.7, 63.8, 63.1, 56.7, 44.0, 43.4, 41.8,
39.9, 39.7, 39.5, 35.9, 31.4, 28.3, 27.4, 24.3, 22.3, 22.3, 18.4; HRMS
(ESI) calcd for C25H42O6Na [M + Na]+ 461.2879, found 461.2859.
Leucascandrolide A (1). To a solution of R-selenyl ester 38
(16.0 mg, 0.025 mmol, 1.0 equiv) in anhydrous dichloromethane
(0.5 mL) at -78 °C was added titanium tetrachloride (55.0 µL,
0.055 mmol, 1.0 M, 2.2 equiv) as a solution in anhydrous
dichloromethane, dropwise. The addition of diisopropylethyl amine
(9.6 µL, 0.055 mmol, 2.2 equiv) followed, and the dark red solution
was allowed to stir for 1 h. Triphenylphosphine oxide (15.3 mg,
0.055 mmol, 2.2 equiv), as a solution in 0.05 mL anhydrous
dichloromethane, was then added. The resultant solution was stirred
for 1 h, then a solution of aldehyde 33 (9.1 mg, 0.038 mmol, 1.5
equiv) in 0.05 mL of anhydrous dichloromethane was added. After
stirring for an additional 1 h, saturated aqueous ammonium chloride
(1 mL) was added and the mixture was stirred vigorously and
allowed to warm to 23 °C. The mixture was then diluted with
dichloromethane (5 mL) and water (5 mL), and the layers were
separated. The aqueous layer was extracted with dichloromethane
(3 × 5 mL). The combined organic layers were washed with brine
(1 × 5 mL), dried over anhydrous sodium sulfate, and concentrated
in vacuo. The crude oil was subjected to flash chromatography (10-
100% ethyl acetate/hexanes), which provided 7.0 mg of the starting
R-selenyl ester 38 and 15.0 mg of a mixture of the desired aldol
product, aldehyde 33, and triphenylphosphine oxide. The latter
mixture was redissolved in anhydrous dichloromethane (0.1 mL),
and the resultant solution was cooled to 0 °C. A solution of
methanesulfonyl chloride (12.2 µL, 0.106 mmol, 6.2 equiv) and
pyridine (13.7 µL, 0.170 mmol, 10 equiv) in anhydrous dichlo-
romethane (0.1 mL) was added, and the mixture was stirred for 3
h. Water (1 mL) was then added, and the biphasic mixture was
allowed to warm to 23 °C. The mixture was then diluted with
dichloromethane (5 mL) and water (5 mL), and the layers were
separated. The aqueous layer was extracted with dichloromethane
(3 × 5 mL). The combined organic layers were washed with brine
(1 × 5 mL), dried over anhydrous sodium sulfate, and concentrated
in vacuo. The crude oil was subjected to flash chromatography (5-
60% ethyl acetate/hexanes), which provided 4.0 mg (40%, over
Macrocyclic Bromide 8. To a solution of tributylphosphine (0.40
mL, 1.59 mmol, 5.0 equiv) in degassed, anhydrous toluene (55 mL)
was added neat diisopropyl azodicarboxylate (0.26 mL, 1.33 mmol,
4.2 equiv). Seco acid 30 (170 mg, 0.318 mmol, 1.0 equiv) was
then added as a solution in degassed, anhydrous toluene (11 mL).
After 50 min, the mixture was concentrated in vacuo and the crude
oil was purified by flash chromatography (0-50% diethyl ether/
hexanes) to provide 119 mg (75%) of macrocyclic bromide 8 as a
white solid: [R]23D +49.45 (c ) 0.62, chloroform); IR (thin film)
2955, 2925, 2854, 1732, 1088 cm-1; 1H NMR (600 MHz, CDCl3)
δ 5.71 (td, J ) 14.3, 7.1 Hz, 1H), 5.50-5.30 (m, 2H), 4.18 (tt, J
) 11.9, 4.2 Hz, 1H), 3.88 (d, J ) 11.8 Hz, 1H), 3.74 (t, J ) 11.0
Hz, 1H), 3.50 (q, J ) 10.0 Hz, 2H), 3.35 (s, 3H), 3.23 (t, J ) 10.7
Hz, 1H), 2.57 (dd, J ) 13.2, 3.7 Hz, 1Η), 2.38 (t, J ) 14.5 Hz,
1H), 2.31 (t, J ) 13.6 Hz, 1H), 2.19 (d, J ) 9.6 Hz, 1H), 2.01 (t,
J ) 12.2 Hz, 1H), 1.96-1.20 (m, 14H), 1.17 (d, J ) 7.0 Hz, 3H),
1.08-0.97 (m, 1H), 0.86 (d, J ) 6.6 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 169.1, 132.8, 130.2, 75.3, 74.2, 73.8, 73.5, 71.2, 63.2,
57.5, 45.4, 43.1, 43.0, 43.0, 42.9, 42.9, 41.8, 39.1, 35.7, 31.2, 29.9,
28.3, 27.3, 24.3, 22.5, 18.4; HRMS (ESI) calcd for C25H41BrO5Na
[M + Na]+ 523.2035, found 523.2026.
Macrocyclic Alcohol 31. To a solution of the macrocyclic
bromide 8 (5.0 mg, 0.010 mmol, 1.0 equiv) in anhydrous toluene
(0.35 mL) were added cesium acetate (13.4 mg, 0.070 mmol, 7.0
equiv) and 18-crown-6 (18.4 mg, 0.010 mmol, 1.0 equiv). This
mixture was heated at 110 °C in a sealed tube for 20 h. After cooling
to 23 °C, the mixture was diluted with dichloromethane (5 mL)
and water (5 mL). The layers were separated, and the aqueous layer
was extracted with dichloromethane (3 × 5 mL). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated in vacuo. The crude oil was filtered through a silica
gel plug (0-60% ethyl acetate/hexanes) to provide an oil, upon
concentration of the fractions. This oil was dissolved in methanol
(0.5 mL), and potassium carbonate (1.3 mg, 0.010 mmol, 1 equiv)
was added. After 45 min, the mixture was filtered through Celite,
and the resulting filtrate was concentrated in vacuo. The crude
mixture was purified by flash chromatography (20-100% ethyl
acetate/hexanes) to provide 2.6 mg (60% over the two steps) of
the two steps) of leucascandrolide A as a clear, colorless oil: [R]23
D
+ 39.5 (c ) 0.32, ethanol); IR (thin film) 3336, 2954, 2927, 2870,
1716, 1646, 1274, 1168, 1081 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.40 (s, 1H), 6.34 (dt, J ) 14.7, 7.7 Hz, 1H), 6.31 (d, J ) 12.7
Hz, 1H), 6.10 (dt, J ) 12.7, 6.6 Hz, 1H), 5.91 (d, J ) 11.5 Hz,
1H), 5.75-5.67 (m, 1H), 5.57-5.47 (m, 1H), 5.40-5.33 (m, 2H),
5.27 (t, J ) 2.6 Hz, 1H), 4.36-4.26 (m, 2H), 4.02 (t, J ) 11.3 Hz,
1H), 3.90 (d, J ) 11.9 Hz, 1H), 3.69 (s, 3H), 3.62-3.51 (m, 3H),
3.36 (s, 3H), 3.11-3.00 (m, 2H), 2.74 (t, J ) 7.2 Hz, 2H), 2.60-
2.50 (m, 1H), 2.47-2.27 (m, 2H), 2.00-1.82 (m, 4H), 1.80-1.48
(m, 7H), 1.36-1.20 (m, 4H), 1.17 (d, J ) 7.1 Hz, 3H), 1.07-0.99
(m, 1H), 0.86 (d, J ) 6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3)
δ 169.6, 165.5, 160.3, 157.4, 149.5, 141.3, 136.6, 134.1, 132.6,
130.3, 120.9, 116.9, 73.9, 73.5, 71.1, 70.2, 69.8, 67.5, 63.3, 57.5,
52.4, 43.5, 42.5, 41.8, 39.6, 39.4, 35.8, 35.7, 31.2, 29.9, 27.9, 27.4,
25.9, 24.5, 22.5, 18.5; HRMS (ESI) calcd for C38H56O10N2Na [M
+ Na]+ 723.3832, found 723.3845.
macrocyclic alcohol 31 as a white solid: [R]23 +32.9 (c ) 0.13,
D
ethanol); IR (thin film) 3444, 2957, 2925, 2855, 1738, 1262, 1061,
1032 cm-1; 1H NMR (600 MHz, CDCl3) δ 5.71 (td, J ) 14.4, 7.3
Hz, 1H), 5.44-5.34 (m, 2H), 4.31 (br s, 1H), 4.17 (t, J ) 11.4 Hz,
1H), 3.90 (d, J ) 11.5 Hz, 1H), 3.73 (dt, J ) 9.3, 3.4 Hz, 1H),
3.60 (t, J ) 10.6 Hz, 1H), 3.55 (t, J ) 10.8 Hz, 1H), 3.36 (s, 3H),
2.54 (dd, J ) 13.0, 3.9 Hz, 1Η), 2.45 (t, J ) 13.0 Hz, 1H), 2.32
(t, J ) 12.9 Hz, 1H), 2.14-1.20 (m, 16H), 1.17 (d, J ) 7.1 Hz,
3H), 1.05-0.97 (m, 1H), 0.86 (dd, J ) 6.6, 1.7 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 169.9, 132.5, 130.5, 73.9, 73.7, 70.9, 69.2,
69.1, 65.0, 63.2, 57.5, 43.6, 43.1, 41.8, 39.6, 38.8, 38.7, 35.9, 31.2,
1
29.9, 28.4, 27.3, 24.3, 22.5, 18.5; H NMR (500 MHz, C5D5N) δ
6.39 (br s, 1H), 5.84-5.71 (m, 2H), 5.55 (dd, J ) 15.2, 6.6 Hz,
1H), 4.64 (t, J ) 11.6 Hz, 1H), 4.42 (br s, 1H), 4.18 (t, J ) 11.6
Hz, 1H), 4.06 (d, J ) 11.8 Hz, 1H), 3.93 (t, J ) 10.5 Hz, 1H),
3.75 (t, J ) 10.8 Hz, 1H), 3.37 (s, 3H), 2.68 (dd, J ) 12.9, 3.5 Hz,
1Η), 2.54-2.45 (m, 2H), 2.11 (t, J ) 12.9 Hz, 1H), 1.99-1.80
(m, 4H), 1.80-1.40 (m, 3H), 1.40-1.15 (m, 7H), 1.15-0.97 (m,
2H), 1.09 (d, J ) 7.0 Hz, 3H), 0.79 (dd, J ) 6.5 Hz, 3H), 0.78
(dd, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, C5D5N) δ 170.3, 132.0,
Acknowledgment. This work was supported by the National
Cancer Institute (CA-081635).
Supporting Information Available: Experimental procedures
and NMR spectra of the new compounds are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO070901R
J. Org. Chem, Vol. 72, No. 15, 2007 5793