[4 + 2]-Annulations of chiral organosilanes: Application to the total synthesis of leucascandrolide A

Article abstract of DOI:10.1021/jo0610412

Complete details of an asymmetric synthesis of leucascandrolide A (1) are described. The synthesis highlights the use of two diastereoselective [4 + 2]-annulations for the assembly of the functionalized bispyranyl macrolide 3. An efficient assembly and un

Full text of DOI:10.1021/jo0610412

[4 + 2]-Annulations of Chiral Organosilanes: Application to the
Total Synthesis of Leucascandrolide A
Qibin Su, Les A. Dakin, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment, Metcalf Center
for Science and Engineering, 590 Commonwealth AVenue, Boston UniVersity, Boston, Massachusetts 02215
panek@bu.edu
ReceiVed May 22, 2006
Complete details of an asymmetric synthesis of leucascandrolide A (1) are described. The synthesis
highlights the use of two diastereoselective [4 + 2]-annulations for the assembly of the functionalized
bispyranyl macrolide 3. An efficient assembly and union of the oxazole-containing side chain 4 with
macrolide 3 was carried out using a Mitsunobu reaction. A convergent route to the oxazole side chain
was developed using a Sonogashira cross-coupling between 2-trifloyloxazole 16 and alkyne 17, which
allowed for the installation of the C9′-C10′ (Z)-olefin.
Introduction
Leucascandrolide A (1) is a doubly O-bridged, 18-membered
macrolide isolated from the calcareous sponge, Leucascandra
caVeolata, obtained from the northeastern coast of New Cale-
donia in the Coral Sea.1 Further evaluation of the same sponge
resulted in the isolation of the second member of leucascan-
drolide family, leucascandrolide B (2) (Figure 1), an extensive
methyl-branched and polyoxygenated 16-membered macrolide.2
The relative stereochemistry of 1 was determined by extensive
1
two-dimensional H NMR analysis, while the absolute stereo-
chemistry was assigned through correlation of the C5 stereo-
center by employing Mosher’s method at the C5 hydroxyl. It
has been reported that leucascandrolide A exhibits high in vitro
cytotoxicity against human KB and p388 tumor cell lines
displaying low IC50’s of 0.05 and 0.26 µg/mL, respectively. This
agent also exhibits potent antifungal activity against Candida
albicans, a pathogenic yeast that attacks AIDS patients and other
immunocompromised individuals (Figure 1).
FIGURE 1. The leucascandrolides.
Recent reports indicate that leucascandrolide A is no longer
available from its original natural source, supporting the notion
that 1 is not a metabolite of Leucascandra caVeolata, but rather
that of an opportunistic bacteria that colonized the sponge, as
evidenced by the large amounts of dead tissue in the initial har-
vest of the marine sponge.2 This fact, in addition to its structural
complexity, has spurred many synthetic efforts including a report
of the first total synthesis from the Leighton group.3
(1) D’Ambrosio, M.; Guerriero, M.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51.
(2) D’Ambrosio, M.; Tato, M.; Pocsfalvi, G.; Debitus, C.; Pietra, F. HelV.
Chim. Acta 1999, 82, 347.
Herein, we detail our efforts that have culminated in an
enantioselective total synthesis of (+)-leucascandrolide A (1).4
10.1021/jo0610412 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/01/2006
2
J. Org. Chem. 2007, 72, 2-24

[4 + 2]-Annulations of Chiral Organosilanes
SCHEME 1. Retrosynthesis of Leucascandrolide A
SCHEME 3. Retrosynthesis of the Leucascandrolide A
Macrolide (Route 2)
SCHEME 2. Retrosynthesis of the Leucascandrolide A
Macrolide (Route 1)
SCHEME 4. Retrosynthesis of the C1′-C11′ Fragment of
Leucascandrolide A
In our initial approach (Route 1), we envisioned that
macrolide 3 could be derived from the C1-C22 fragment 5
(Scheme 2). Further analysis of 5 showed that it could be divided
at the C8-C9 bond to give the Mukaiyama aldol-coupling
partners: left tetrahydropyran 6 and silyl enol ether 7. The latter
material 7 could be derived from enantiopure terminal epoxide
(S)-10. The C9-C22 left tetrahydropyran 6 can be synthesized
either from diol (R)-8 (first generation approach) or aldehyde 9
(second generation approach).
Concurrent with our study toward the total synthesis of 1, an
efficient formal [4 + 2]-annulation of chiral allylsilanes and
aldehydes leading to the enantioselective formation of dihy-
dropyrans was emerging from our laboratory.5 Upon analysis
of 3, we envisioned that a spontaneous macrolactol formation
from acyclic hydroxyaldehyde 11, followed by a mild oxidation
of the resulting macrolactol to its corresponding macrolactone,
could be a feasible macrocyclization strategy (Route 2, Scheme
3). Retrosynthetically, the C17 allylic alcohol could be obtained
from the addition of an alkenyl zinc species to aldehyde 12. It
was our thought that this segment 12 could be obtained in a
stereocontrolled and efficient fashion employing two consecu-
tive, formal [4 + 2]-annulations. The synthesis of this bis-
tetrahydropyran intermediate could be an excellent testing
ground of our formal [4 + 2]-annulation reactions. Accordingly,
we could evaluate the feasibility and applicability of an
annulation strategy using aldehyde 15, chiral allylsilane 13, and
chiral crotylsilane 14 to generate the bispyran 12.
Retrosynthesis of Leucascandrolide A. Our retrosynthesis
of 1 is depicted in Scheme 1 and begins with a disconnection
of the C5 ester linkage, revealing macrolide 3 and oxazole-
containing side chain 4.
Retrosynthetic Analysis of the Leucascandrolide A Mac-
rolide (3). The structurally challenging macrolide 3 attracted
our interest in synthetic efforts toward 1. In this fragment, two
tetrahydropyrans are embedded in an 18-membered lactone,
bearing eight stereogenic centers. Of the total number of routes
designed to access the macrolide, two independent approaches
were chosen to investigate the assembly of fragment 3, both of
which extensively integrated our pyran annulation methodology.
(3) For total syntheses of leucascandrolide A, see: (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)
Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343. (e) Fettes,
A.; Carreira, E. M. J. Org. Chem. 2003, 68, 9274. (f) Paterson, I.; Tudge,
M. Tetrahedron 2003, 59, 6833. (g) Wang, Y.; Jelena, J.; Kozmin, S. A.
Pure Appl. Chem. 2005, 77, 1161. For syntheses of the leucascandrolide A
macrolide, see: (h) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc.
2001, 123, 8420. (i) Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066.
(j) Williams, D. R.; Plummer, S. V.; Patnaik, S. Angew. Chem., Int. Ed.
2003, 42, 3934. (k) Williams, D. R.; Patnaik, S.; Plummer, S. Org. Lett.
2003, 5, 5035. (l) Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, 5,
4641. Other reports of leucascandrolide A fragments include: (m) Crimmins,
M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2, 579. (n) Kozmin, S.
A. Org. Lett. 2001, 3, 755. (o) Dakin, L. A.; Langille, N. F.; Panek, J. S.
J. Org. Chem. 2002, 67, 6812. (p) Wipf, P.; Graham, T. H. J. Org. Chem.
2001, 66, 3242.
Retrosynthetic Analysis of the Leucascandrolide A Ox-
azole Side Chain (4). Aligned with our efforts toward the
leucascandrolide A macrolide (3) was the synthesis of the
(4) Portions of these results have been published in the following
communications: (a) Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org.
Chem. 2002, 67, 6812. (b) Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5,
3995. (c) Su, Q.; Panek, J. S. Angew. Chem., Int. Ed. 2005, 44, 1223.
(5) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836.
J. Org. Chem, Vol. 72, No. 1, 2007 3

Su et al.
SCHEME 5. Synthesis of the Leucascandrolide A Fragment 7
leucascandrolide A C1′-C11′ oxazole-containing side chain (4).
From a retrosynthetic perspective, we anticipated that discon-
nection at the C8′-C9′ bond could reveal the two potential
coupling partners: the 2-trifloyloxazole 16 and terminal alkyne
17 (Scheme 4). We planned to explore the viability of a Pd-
(0)-mediated cross-coupling strategy, specifically, a Sonogashira
coupling, and partial hydrogenation of the alkyne-oxazole using
Lindlar’s catalyst to introduce the C9′-C10′ (Z)-olefin and finish
the assembly of side chain 4 in a convergent manner.6
-78 °C afforded a 1,3-syn reduction to the 1,3-diol 20 (80%,
dr > 15:1). Protection of the diol as its acetonide (2,2-
dimethoxypropane, p-TsOH, 99%) and cleavage of the terminal
olefin (O3, Me2S, MeOH) gave the C1-C8 methyl ketone 22
in 95% yield. Finally, treatment of methyl ketone 22 with the
bulky lithium anion of 2,2,6,6-tetramethylpiperidine gave the
desired kinetic enolate, which was then trapped with TMSCl,
completing the synthesis of the C1-C8 silyl enol ether coupling
partner 7 (77%).
Two independent approaches have been developed to syn-
thesize the left-hand tetrahydropyran subunit. The first route
was initiated by differentiation of the two hydroxyls of HKR-
derived diol (R)-8 through a selective protection of the primary
hydroxyl group as its tert-butyldiphenylsilyl ether (TBDPSCl,
imidazole, 99%), followed by protection of the secondary
hydroxyl group as its benzyl ether (NaH, BnBr, 95%) yielding
ester 23 (Scheme 6). Ester 23 was then converted to its
corresponding aldehyde 24, which could be accomplished by
treatment with DIBAL-H at -78 °C in CH2Cl2 for 15 min
(80%). Aldehyde 24 served as the requisite electrophile for an
anti 1,3-allylation by treatment with TiCl4 and allyltrimethyl-
silane (90%, dr > 20:1), which cleanly installed leu-
cascandrolide A’s C15 stereochemistry. The stereochemical
course of this reaction is documented and, in the present case,
is consistent with a well precedented chelation-controlled anti
1,3-induction model.9 The resulting allylic alcohol was protected
as its tert-butyldimethylsilyl ether (TBSOTf, 2,6-lutidine, 95%)
affording terminal olefin 25. This material was converted to its
corresponding primary iodide in a three-step process: ozonolysis
of the olefin to the corresponding aldehyde (O3, Me2S, 99%),
reduction of the generated aldehyde (NaBH4) to the primary
Results and Discussion
Initial Approach to the Leucascandrolide A Macrolide (3)
(Route 1). Synthesis of silyl enol ether 7 began with the
enantiomerically enriched epoxide (S)-10 (99% ee), available
from a hydrolytic kinetic resolution (HKR) of racemic terminal
epoxide (()-10 (Scheme 5).7 Treatment of (S)-10 with the
lithium enolate of tert-butyl acetate in THF at -50 °C gave the
unstable â-ketoester 18 in 70% yield. Subsequent treatment of
18 with isopropenylmagnesium bromide in the presence of 20
mol % of CuI provided the â-hydroxy ketone 19 (75%).
Treatment of 19 with freshly prepared Zn(BH4)28 in CH2Cl2 at
(6) (a) Campbell, I. B. In Organocopper Reagents. A Pratical Approach;
Taylor, R. J. K., Ed.; Oxford University Press: Oxford, 1994; Chapter 10,
pp 217-236. (b) Sonogashira, K. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 521-
548.
(7) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307.
(8) For reviews on the preparation and synthetic applications of zinc
borohydride, see: (a) Narasimhan, S.; Balakumar, R. Aldrichimica Acta
1998, 31, 19. (b) Hoyveda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV.
1993, 93, 1307. (c) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V.
J. J. Am. Chem. Soc. 1998, 120, 5921. (d) Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 8,
pp 5536-5539.
(9) (a) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994,
537. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang M. J. J. Am. Chem.
Soc. 1996, 118, 4322.
4 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
SCHEME 6. Synthesis of the Alkyl Iodide Fragment 27
SCHEME 7. Synthesis of the Leucascandrolide A Fragment 31
SCHEME 8. Synthesis of the Anomeric Acetate 34
alcohol 26, and then conversion of this material to alkyl iodide
27 by treatment with (PhO)3P+CH3I- (85%). The alkyl iodide
27 would serve as the requisite electrophile for a diastereo-
selective alkylation to install the C12 stereocenter of the target
molecule.
Treatment of alkyl iodide 27 with Myers’ (R,R)-pseudoephe-
drine-derived amide enolate 28 cleanly installed the correct
configuration at C12 giving amide 29 in excellent yield and
diastereoselectivity (95%, dr > 20:1) (Scheme 7).10 Cleavage
of the chiral auxiliary and cyclization of the resulting carboxylic
acid were best accomplished in a three-step process. This was
initiated by treatment of amide 29 with a mixture of tetrabu-
tylammonium fluoride and tetrabutylammonium hydroxide,
which simultaneously deprotects the two silyl ethers while
cleaving the (R,R)-pseudoephedrine auxiliary, yielding carboxy-
lic acid 30 (99%). Subsequent cyclization of the crude carboxylic
acid 30 was accomplished by treatment with a stoichiometric
quantity of pyridinium p-toluenesulfonic acid at room temper-
ature for 12 h, giving the required lactone (90%). The primary
hydroxyl group at C18 was then oxidized to an aldehyde by
treatment with Dess-Martin periodinane (82%), which yielded
the key C11-C18 leucascandrolide A fragment 31.
A modified Takai olefination between the C11-C18 aldehyde
31 and isovaleraldehyde-derived geminal diiodide 32 was
utilized to generate the (E)-double bond isomer of lactone 33
(Scheme 8). This olefination was best performed using freshly
flame-dried chromium(II) chloride in a mixed solvent system
of tetrahydrofuran and N,N-dimethylformamide (v/v ) 5:1),
which gave the desired (E)-olefin 33 as a single isomer and in
good yield (75%).11 With the C19-C22 (E)-olefin alkyl chain
installed, completion of tetrahydropyran 6 was the next objec-
tive. This was initiated by conversion of the lactone to the
(10) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
J. Org. Chem, Vol. 72, No. 1, 2007 5

Su et al.
SCHEME 9. Synthesis of the C9-C22 Tetrahydropyran Fragment 6
anomeric acetate 34 through lactol formation using a DIBAL-H
reduction followed by acetylation (Ac2O, Et3N) to afford the
acylated hemiacetal 34 in 90% yield for the two steps.
SCHEME 10. Stereoselective Synthesis of Dihydropyrans
The completion of tetrahydropyran 6 was accomplished by
a ZnCl2-mediated C-glycosidation of anomeric acetate 34 with
the acetaldehyde-derived enol silane 35 (Scheme 9).12 Treatment
of acetate 34 with freshly fused ZnCl2 generated oxonium ion
36 in situ, which was then trapped by the nucleophilic enol silane
35. This reaction served to replace the anomeric acetate,
completing the C9-C22 tetrahydropyran fragment 6 while
efficiently installing leucascandrolide’s C11 stereocenter (74%,
dr > 20:1). The stereochemical outcome for this reaction is
illustrated in Scheme 9, with carbon-carbon bond formation
occurring preferentially in the pseudoaxial orientation. The
pseudoaxial delivery yields the desired anti stereochemistry
based on the stereoelectronic effect, specifically, that the
approach of the nucleophile 35 toward the electrophile 36 occurs
anti-periplanar to one of the lone pairs of electrons on the
tetrahydropyran 6 via a low energy chair-like transition state.
TABLE 1. Aldehyde Screen in the [4 + 2]-Annulation Toward the
C9-C16 Dihydropyran
This reaction sequence completed the synthesis of the C9-C22
tetrahydropyran fragment 6 in 16 steps and 26% overall yield.
During the course of the synthesis of tetrahydropyran 6, a
viable and interesting alternative using a chiral crotylsilane
approach to synthesize substituted dihydropyrans was discovered
in our laboratories. It was found that treatment of anti-silane
(S,S)-37 with a substoichiometric amount of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) in the presence of an
aldehyde led to a stereoselective synthesis of dihydropyrans
through a formal [4 + 2]-annulation mechanism.5 This annu-
lation is elegant in that it yields stereochemically well-defined
dihydropyrans and creates two new stereocenters on the dihy-
dropyran in a single step (Scheme 10). The resulting stereo-
chemistry was reminiscent of the leucascandrolide A C9-C22
fragment 6, and accordingly, it was postulated that chiral
crotylsilane (S,S)-37 could potentially serve as the starting
material to constitute an alternative approach to fragment A.
To initiate the organosilane approach to the leucascandrolide
C9-C22 tetrahydropyran fragment 6, the [4 + 2]-annulation
of silane (S,S)-37 with appropriately functionalized aldehydes
was evaluated. A crucial structural requirement of the aldehyde
was that it needed to be able to serve as precursor for the C9
2°-hydroxyl-bearing stereocenter. In the initial screen, five
protected 3-hydroxypropionaldehyde derivatives (38a-e) were
evaluated in annulations with (S,S)-37; however, all gave the
dihydropyrans (39a-e) in poor to modest yields (<71%) and
diastereoselectivities (dr e 5:1) (Table 1).
entry
aldehyde (R)
38a (benzyl)
38b (p-methoxybenzyl)
38c (pivaloyl)
38d (benzoyl)
38e (trityl)
% yielda
diastereoselectivityb
1
2
3
4
5
50
40
71
66
0
2:1
2.5:1
5:1
3:1
na
a Yields are based on pure materials isolated by chromatography on SiO2.
b The ratio of products was determined by 1H NMR (400 MHz), operating
at a S/N ratio of >200:1.
ylsilyl)propenal (40), catalyzed by TMSOTf at -50 °C gave
the requisite intermediate C9-C16 dihydropyran 41 in excellent
yield (95%) and diastereoselectivity (dr > 20:1) (Scheme 11).
The increased yield and enhanced level of diastereoselectivity
obtained in this reaction may be attributed to a stabilization of
the oxonium ion via a resonance delocalization of the positive
charge. The utility of this annulation approach is illustrated by
the efficient manner in which it installed the C11 and C12
stereocenters of leucascandrolide A in a single step, while the
C15 stereocenter was already present in (S,S)-37.
After careful examination, it was determined that the reaction
of (S,S)-37 with the R,â-unsaturated aldehyde, 3-(dimethylphen-
With efficient access to dihydropyran 41, construction of the
aldehyde 6 was initiated (Scheme 12). Elaboration of 41 began
with saturation of the olefins using standard hydrogenation
conditions (H2, Pd/C) to afford tetrahydropyran 42. Next, it was
necessary to oxidize the dimethylphenylsilyl substituent to give
the necessary aldehyde synthon at C9. This conversion was best
(11) (a) Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987,
109, 951. For the preparation of geminal alkyl diiodies, see: (b) Pross, A.;
Sternhill, S. Aust. J. Chem. 1970, 23, 989.
(12) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 4976. (b) Tino, J. A.; Lewis, M. D.; Kishi, Y. Heterocycles 1987, 25,
97.
6 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
SCHEME 11. Construction of the Leucascandrolide A C9-C16 Subunit 41
SCHEME 12. Synthesis of the C9-C22 Fragment 48
accomplished by a Fleming-Tamao oxidation13 using Hg(OAc)2
in peracetic acid to give primary alcohol 43 in 75% yield.
Protection of the emerged C9 primary alcohol as its tert-
butyldiphenylsilyl ether (TBDPSCl, imidazole) gave the primary
silyl ether 44. Reduction of the methyl ester (DIBAL-H) at C16
proceeded smoothly to give the primary alcohol 45, which was
then converted to the alkyl iodide 46 through treatment with
(PhO)3P+CH3I- in DMF (77% yield over two steps). At this
stage, it was then necessary to install the C17-C22 side chain.
Although several options were considered, it was ultimately
accomplished via an alkylation of iodide 46 with the lithium
anion of dithiane 4714 using a THF/HMPA (10:1) solvent
system15 to provide the fully elaborated C9-C22 carbon
fragment 48 (97%).
At this stage, it was then necessary to unveil the R,â-
unsaturated ketone through removal of the dithiane at C17. This
proved more challenging than originally anticipated, and an
extensive review of conditions that promote the removal of
dithiane protecting groups was undertaken. Among the standard
conditions surveyed was the use of N-halosuccinimide re-
agents,16 mercury perchlorate,17 and ceric ammonium nitrate.18
All of these proved ineffective, giving low yields (below 40%)
and significant amounts of decomposition. A notable exception
was the application of Stork and Zhao’s method in which bis-
(trifluoroacetoxy)iodobenzene (BTI) in a MeOH/H2O solvent
mixture was reported to remove a series of 1,3-dithianes.19
Indeed, treatment of dithiane 48 with BTI in MeOH/THF/H2O
(8:1:1) for 5 min afforded the desired R,â-unsaturated ketone
49 in a 70% yield. Varying amounts (∼15-20%) of multiple
olefin isomers were obtained as side products. Increased reaction
time (>10 min) resulted in larger amounts of decomposition to
undesired materials.
Concerned by the prospect of significant material loss during
scale-up procedures, we sought a milder and more predictable
method for our dithiane removal. We postulated that Dess-
Martin periodinane (DMP) would affect the desired transforma-
tion in a similar manner since it is well established that DMP
tolerates a myriad of functional groups. Despite the widespread
use of DMP in oxidative applications, there were no known
reports of DMP-mediated thioacetal or thioketal removal.
Gratifyingly, treatment of dithiane 48 with DMP in a MeOH/
THF/H2O (8:1:1) solvent system for 12 h gave the desired R,â-
unsaturated ketone 49 excellent yield (91%) (Scheme 13).20
The next task toward the assembly of the leucascandrolide
A C9-C22 tetrahydropyran 6 was the installation of the C17
(13) (a) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317. (b) Tamao, K.; Ishida,
N. J. Organomet. Chem. 1984, C37.
(14) Dithiane was prepared from the known R,â-unsaturated aldehyde:
Vig, O. P.; Bari, S. S.; Puri, S. K.; Dua, D. M. Ind. J. Chem. 1981, 20B,
342.
(15) For leading references on dithiane alkylation, see: (a) Smith, A.
B.; Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925 and references therein.
(b) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365-377.
(c) Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147-6212.
(16) Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553.
(17) Aso, M.; Hayakawa, K.; Kanematsu, K. J. Org. Chem. 1989, 54,
5597.
(18) Ho, T. L.; Ho, H. C.; Wong, C. M. J. Chem. Soc., Chem. Commun.
1972, 791.
(19) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
J. Org. Chem, Vol. 72, No. 1, 2007 7

Su et al.
SCHEME 13. Dithiane Removal Mediated by Dess-Martin Periodinane
SCHEME 14. Synthesis of the Allylic Alcohol Fragment 51
SCHEME 15. Synthesis of the C9-C22 Aldehyde 6
stereocenter. After a careful examination of the system, it was
To complete the C9-C22 tetrahydropyran fragment 6, the
found that the C17 stereocenter could be installed through a
catalytic asymmetric reduction with Corey’s chiral borane, (S)-
CBS 50, in the presence of BH3‚SMe2 to cleanly give the desired
(R)-alcohol 51 (80%, dr > 15:1).21 The rationale for asymmetric
reduction is provided by the model originally proposed by
Corey, which differentiates the size of the substituents at the R
and R′ positions of prochiral ketones. Analysis of Corey’s model
to the present case suggested that the C18-C22 R,â-unsaturated
portion of ketone 49 is considered to be the large substituent,
which adopts the least sterically demanding position, while the
C9-C16 tetrahydropyran portion is considered to be the smaller
substituent (Scheme 14). Indeed, this model holds true in our
case, as the absolute stereochemistry of the reduction was
assigned through the method of Mosher.22
emerged allylic alcohol at C17 was protected as its benzyl ether
(BnBr, n-Bu4NI, DMF, 90%). Installation of the C9 aldehyde
was accomplished through deprotection of the primary silyl ether
(TBAF, 99%) followed by a Dess-Martin oxidation of the
resulting primary alcohol (80%). Thus, the synthesis of the C9-
C22 tetrahydropyran 6 was completed in 12 steps with an overall
yield of 32% (Scheme 15).
To undertake the assembly of the C1-C22 segment 5, a
fragment coupling using a Mukaiyama aldol between the C9-
C22 aldehyde 6 and the C1-C8 silyl enol ether 7 was
investigated. After a brief survey of the reaction, it was
determined that the coupling was best accomplished by treatment
of a mixture of 6 and 7 in CH2Cl2 with BF3‚OEt2 at -78 °C
for 4 h (Scheme 16). Gratifyingly, the coupling proceeded in
good yield (81%) and diastereoselectivity (dr > 15:1) to provide
(20) For the initial communication of this reaction and a discussion of
its scope, see: Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003,
5, 575.
(21) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611.
(c) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(22) (a) Dale, J. A.; Mosher, H. S. L. J. Am. Chem. Soc. 1973, 95, 512.
(b) Trost, B. M.; Belletire, J. L.; Godleski, J.; McDougal, D. G.; Balkovec,
J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer,
J. P. J. Org. Chem. 1986, 51, 2370.
8 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
SCHEME 16. Synthesis of C1-C22 Leucascandrolide Fragment 5
SCHEME 17. Proposed Model for 1,3-anti Induction
the desired 1,3-anti induction product alcohol 52. Despite the
monodentate nature of BF3‚OEt2, there is ample precedent for
1,3-anti induction in similar systems.23 The absolute stereo-
chemistry at C9 was assigned using the method of Mosher.22
Methylation of the emerged hydroxyl group at C9 was achieved
by treatment of 52 with Meerwein’s reagent in the presence of
Proton Sponge (99%), thereby completing the C1-C22 fragment
5.
It has been well documented that BF3‚OEt2-catalyzed addi-
tions of enol silanes to â-alkoxy-substituted aldehydes proceed
with a high level of diastereoselectivity favoring the anti isomer.
A model proposed by Evans for 1,3-anti induction for BF3‚
OEt2-catalyzed enol silane additions to â-alkoxy-substituted
aldehydes is shown in Scheme 17. In the illustrated transition
state, the â-alkoxy tetrahydropyran orients itself anti to the
carbonyl of the aldehyde, minimizing dipole interactions.
Additionally, the system orients itself perpendicular to the
carbonyl, giving the most stable staggered conformation based
on sterics. The enol silane approach to the carbonyl is favored
to proceed past the smaller hydrogens, giving the desired 1,3-
anti induction. The conformer that would yield undesired 1,3-
syn induction is destabilized via a steric interaction between
the tetrahydropyran’s bulky isobutyl side chain and the aldehyde
carbonyl.
This synthesis of the leucascandrolide A C1-C22 fragment
5 completed the carbon framework of the macrocycle 3 and
installed seven of the eight stereocenters of the natural product.
The C1-C22 fragment 5 was now ready for the bis-tetrahy-
dropyran to be assembled (Scheme 18). This sequence of
transformations was initiated by the deprotection of the acetonide
of 5 using a substoichiometric amount of 10-camphorsulfonic
acid in anhydrous methanol. These conditions served to depro-
tect the acetonide, which spontaneously closed to form hemi-
acetal 53 as a 2:1 mixture of diastereomers (85%). Installation
(23) (a) Paterson, I.; Smith, J. D. J. Org. Chem. 1992, 57, 3261. (b)
Evans, D. A.; Duffy, J. L. Tetrahedron Lett. 1994, 35, 8537. (c) Evans, D.
A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston, A. B. J. Am. Chem.
Soc. 1995, 117, 6619. (c) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984,
23, 556. (d) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322.
J. Org. Chem, Vol. 72, No. 1, 2007 9

Su et al.
SCHEME 18. Synthesis of the Protected seco-Acid Fragment 54
SCHEME 19. Removal of the C17 Benzyl Ether Giving
Undesired Triol
gave mixtures of products. Unfortunately, the following common
debenzylating reagents that were evaluated proved incompatible
with the benzyl ether of 54 and resulted in extensive decom-
position of the starting material along with loss of the protecting
group: BCl3,26 FeCl3,27 DDQ,28 and SnCl4.29
Synthesis of the Leucascandrolide A Macrolide 3 (Route
2). During the course of our study of the synthesis of
leucascandrolide A (1), we planned a revised route to synthesize
the intriguing bis-tetrahydropyranyl ring system moiety using
two consecutive pyran annulations (Scheme 3). We also believed
the further development of this revised synthetic approach could
lead to the synthesis of diastereomeric analogues of 1 for
biological evaluation. This would be accomplished by employing
a set of stereochemically diversified chiral silane reagents
available in our laboratory. Syntheses of diastereomeric ana-
logues of 1 are currently under investigation in our laboratory
and will be reported at a later time.
The synthesis started with hydrosilylation of commercially
available propargylic alcohol 56 catalyzed by Pt(0) catalyst 57
in 90% yield (Scheme 20). Sharpless asymmetric epoxidation
of the resulting allylic alcohol 58 provided the epoxy alcohol
59 in 95% yield and in excellent enantiomeric excess (ee )
97%).30 Protection of the primary alcohol 59 as a TMS ether
was necessary to achieve a high-yielding epoxide-opening
reaction with vinylmagnesium bromide in the presence of CuI.
This choice of protecting group shut down the potential Peterson
olefination pathway, which is thought to proceed through a
hypervalent silicate intermediate.31 After exchanging the primary
protecting group from a trimethylsilane to a mesitylenesulfonate
(citric acid, MeOH, then MesSO2Cl, DMAP, and pyridine),
chiral allylsilane 13 was obtained in 65% overall yield. The
sequence can be carried out on a 40 mmol scale, readily
producing 20 g of the chiral allylsilane 13. The success of this
of the C7 stereochemistry was accomplished through a hydride
reduction of hemiacetal 53 with BF3‚OEt2 and Et3SiH through
an intermediate oxonium ion.12 The stereochemical outcome of
the reduction is argued to be due to stereoelectronic control
causing the hydride delivery to occur axially. This reaction
cleanly gives the protected ester 54 of the leucascandrolide A
macrolide (85%, dr > 20:1).
Completion of the assembly of the macrolide 3 was to be
initiated by deprotection of the C17 benzyl ether, removal of
the tert-butyl ester at C1, followed by macrolactonization. Due
to the C18-C19 (E)-olefin in 54, hydrogenolysis of the C17
benzyl ether was precluded. Initially, we examined dissolving
metal reductions to remove the C17 benzyl ether. Unfortunately,
24
treatment of benzyl ether 54 with either Na/NH3 or lithium
di-tert-butylbiphenyl (LiDBB)25 in THF at -78 °C for 30 s
resulted in clean benzyl ether deprotection and reduction of the
tert-butyl ester at C1 to the primary alcohol, giving triol 55
exclusively (Scheme 19). Differentiation of the C1 primary
alcohol and the C17 allylic alcohol proved unsuccessful, as
attempts at monoprotection of different esters or silyl ethers
(26) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc.
1989, 111, 1923.
(27) Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. Tetrahedron Lett.
1996, 37, 5477.
(28) Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 4560.
(29) Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989,
54, 1346.
(24) Philips, K. D.; Zemlicka, J.; Horowitz, J. P. Carbohydr. Res. 1973,
30, 281.
(30) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(31) Peterson, D. J. J. Org. Chem. 1968, 33, 78.
(25) Shimshock, S. J.; Waltermire, R. E.; DeShong, P. J. Am. Chem.
Soc. 1991, 113, 8791.
10 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
SCHEME 20. Synthesis of the Chiral syn Allylsilane 13
SCHEME 21. Synthesis of Aldehyde 15
SCHEME 22. Synthesis of the Right-Hand Tetrahydropyran Fragment 66
sequence for preparing chiral allylsilane reagents ensured our
material supply for the synthesis of complex natural products.
The necessary [4 + 2]-annulation partner, aldehyde 15, was
readily prepared from the known chiral epoxide (R)-62, which
was obtained from Jacobsen’s HKR in excellent yield and
enantiomeric excess (ee > 99%, Scheme 21).7 A CuI-catalyzed
opening of epoxide (R)-62 was followed by methylation of the
resulting secondary alcohol using Meerwein’s reagent to produce
methyl ether 63. Ozonolytic cleavage of 63 provided the desired
aldehyde 15 in good overall yield.
With both the chiral allylsilane and aldehyde available, we
began our approach toward the synthesis of the leucascandrolide
A macrolide (3). In that regard, we were pleased to find that
annulation of aldehyde 15 with chiral allylsilane 13 proceeded
smoothly in the presence of TfOH32 to afford the desired 2,6-
cis-dihydropyran 64 in 80% yield (dr ) 12.5:1, Scheme 22).
The presence of a sulfonate group in this product allowed for
a necessary one-carbon homologation. An SN2 displacement
using NaCN installed a nitrile that was used as a masked
carboxylate functionality and gave the one-carbon-homologated
dihydropyran 65. We next focused our attention on the instal-
lation of the C5 stereocenter. Stereocontrolled nucleophilic
addition to a conformationally well-defined olefin (e.g., alkene
on substituted cyclohexenes) with activation by an electrophile
is documented in the elegant work of Brown. This work
demonstrated that a highly diastereoselective functionalization
of unsaturated six-membered rings could be achieved by an
oxymercuration reaction.33 Gratifyingly, the oxymercuration of
the double bond of dihydropyran 65 using mercury(II) trifluo-
roacetate, followed by a subsequent reductive demercuration
using NaBH4, installed the required C5 axial hydroxyl group
as a single regio- and diastereoisomer.
While many mechanistic scenarios can be envisioned, one
possible explanation suggests the regio- and stereochemical
course of the oxymercuration may be determined from steric
and electronic considerations; trans diaxial trapping of the
mercuronium ion leads to a chair-like TS, where an equatorial
opening would lead to a trans-diequatorial product thought a
higher energy boat-like TS (Scheme 23).34 The mercuronium
(33) Brown, H. C.; Geoghegan, P., Jr. J. Am. Chem. Soc. 1967, 89, 1522.
(34) (a) Pasto, D. J.; Gontarz, J. A. J. Am. Chem. Soc. 1971, 93, 6902.
(b) Pasto, D. J.; Gontarz, J. A. J. Am. Chem. Soc. 1971, 93, 6909. (c) Pasto,
D. J.; Gontarz, J. A. J. Am. Chem. Soc. 1970, 92, 7480. (d) Pasto, D. J.;
Gontarz, J. A. J. Am. Chem. Soc. 1969, 91, 719.
(32) Huang, H.; Panek, J. S. Org. Lett. 2004, 6, 4383.
J. Org. Chem, Vol. 72, No. 1, 2007 11

Su et al.
SCHEME 23. Proposed Pathway for Oxymercuration of Dihydropyran 65
SCHEME 24. Synthesis of the Aldehyde Fragment 69
species underwent a regioselective attack by a nucleophile (H2O)
to produce a trans-diaxial intermediate (Fu¨rst-Plattner rule).35
Subsequent reductive demercuration afforded the hydroxyl pyran
66 in 75% yield.
The requisite aldehyde 69 to be used in the second [4 +
2]-annulation was obtained in a straightforward three-step
reaction sequence. Protection of the C5 secondary alcohol 66
as a TBDPS ether was followed by subsequent debenzylation
with BCl3 that furnished the primary alcohol 68 (Scheme 24).
A pyridinium chlorochromate (PCC) oxidation of the resulting
alcohol provided aldehyde 69.
After obtaining the â-methoxy aldehyde, our efforts were then
directed to the second crucial [4 + 2]-annulation between
aldehyde 69 and chiral crotylsilane 14. Under the previously
described annulation conditions (TMSOTf, DCM, -50 °C),5,36
the reaction between aldehyde 69 and chiral crotylsilane 14a
proceeded smoothly, however, with a low selectivity (dr (2,6-
cis/2,6-trans) ) 1:2) of the newly formed left-hand dihydropyran
(entry 1, Table 2). Considerable experimentation was needed
to optimize the selectivity of this annulation, and the important
results are summarized in Table 2.
optimize the selectivity of this annulation, a fact came to our
attention that, for a monosubstituted cyclohexane ring, the A
value of an ethyl ester is around 0.2 kcal/mol lower than that
of a methyl ester (Amethylester ) 1.3 kcal/mol, Aethylester ) 1.1
kcal/mol; A value is the free energy required for substituted
groups to go from the equatorial position to the axial position
and is used to demonstrate the extent of preference for the
substituent to adopt the equatorial orientation).37 In one of the
possible transition states for this annulation, an axial orientation
of the methyl ester would produce a trans-dihydropyran (inset,
Table 2). Therefore, using this loose analogy, silane 14c was
synthesized and tested in the annulation reaction. Interestingly,
a slight increase of selectivity was observed in this annulation
(entry 3 vs entry 1, Table 2). Encouraged by this result, we
synthesized the isopropyl derivative crotylsilane 14, obtained
by transesterification of corresponding methyl ester 14a with
isopropyl alcohol. To our delight, enhanced selectivity for the
2,6-trans isomer was observed (dr (2,6-cis/2,6-trans) ) 1:5).
Considering the instability of the tert-butyl group to the acidic
reaction conditions, no further attempt to increase the steric
bulkiness of the ester moiety of the silane reagent 14 was made.
Another trial based on the consideration of A value was carried
out, employing a cyanosilane (ACN ) 0.2 kcal/mmol) in this
annulation. However, to our disappointment, the resulting
cyanohydrin crotylsilane 14d (X ) CN, not shown) failed to
participate in the annulation and was recovered intact after the
Annulation of silane 14b, bearing an acetoxy group, with
aldehyde 69 afforded the left-hand dihydropyran yet with lower
selectivity (entry 2, Table 2). During experiments designed to
(35) (a) Fu¨rst, A.; Plattner, A. HelV. Chim. Acta 1949, 32, 275. (b)
Henbest, H. B.; Smith, M.; Thomas, A. J. Am. Chem. Soc. 1958, 80, 3253.
(36) (a) Huang, H.; Panek, J. S. Org. Lett. 2003, 5, 1991. (b) Roush, W.
R.; Dilley, G. J. Synlett 2001, SI, 955.
(37) Smith, M. B.; March, J. AdVanced Organic Chemistry, 5th ed.; John
Wiley & Sons: New York, 2001; p 174.
12 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
TABLE 2. Optimization of the Second [4 + 2]-Annulationa
entry
silane (X)
reaction temperature
Lewis acid
conversion (dr) 2,6-trans/2,6-cis)a
1
2
3
4
14a (CO2Me)
14b (CH2OAc)
14c (CO2Et)
14 (CO2iPr)
-50 °C
-50 °C
-50 °C
-50 °C
TMSOTf
TMSOTf
TMSOTf
TMSOTf
100% (2:1)
100% (1:1)
100% (3:1)
100% (5:1)
1
a The % conversion and % dr were measured by H NMR (400 MHz) analysis of the crude reaction mixture.
SCHEME 25. Synthesis of the C1-C22 Bis-tetrahydropyran Fragment 73
reaction. One possible explanation for the loss of the reactivity
can be attributed to the strong electron-withdrawing ability of
CN, therefore resulting in the attenuation of nucleophilicity of
the neighboring silyl ether.
reagent. Addition of the alkenyl zinc to aldehyde 12 afforded
allylic alcohol in a good combined yield (80%), albeit with
disappointingly low selectivity ((R)-17:(S)-17 ) 2:1). To our
satisfaction, the desired (R)-17 alcohol 73 could be obtained in
53% yield as a single diastereomer after careful chromatographic
separation of the two isomers.
Having discovered the optimal conditions for the second
annulation to produce 70 with useful selectivity (5:1) and yield
(73%), we were ready to install the C17-C22 side chain while
establishing the C17 stereocenter of the macrolactone (3).
Reduction of dihydropyran 70 under a hydrogen atmosphere
catalyzed by Pd/C produced the bis-tetrahydropyran 71 in 86%
yield (Scheme 25). A fully chemoselective reduction of the
tetrahydropyran isopropyl ester was carried out using DIBAL-H
(2.1 equiv) in diethyl ether at -78 °C, thus providing aldehyde
72 in 93% yield. Homologation of aldehyde 72 via a phosphorus-
based olefination with methoxymethylenetriphenylphosphine
and subsequent mercury acetate-mediated hydrolysis of the
resulting enol ether furnished aldehyde 12 in 87% yield over
two steps.
At this stage, our approach called for the selective introduction
of the C17 allylic alcohol, which we anticipated would take
place with the use of a vinylmetal species. A one-pot preparation
of the vinyl zinc reagent from an alkyne reported by Wipf was
an attractive option.38 Accordingly, hydrozirconation of 4-meth-
yl-1-pentyne followed by transmetalation to the vinyl zinc
species using dimethyl zinc afforded the desired vinyl zinc
With the advanced hydroxyl nitrile 73 in hand, we were ready
to examine the cyclization of this intermediate to form the
macrolide. Inspired by the spontaneous lactol formation reported
by Kozmin, we employed a similar set of conditions for our
macrolactonization strategy.3b Accordingly, reduction of the
nitrile group using a cold solution of DIBAL-H (-78 °C) in
CH2Cl2 was followed by an acidic hydrolysis of the resulting
imine to afford a transient hydroxyaldehyde 11 (Scheme 26).
Gratifyingly, we found that this hydroxyaldehyde cyclized to
form macrolactol 7439 at room temperature in 64% yield.
During the study of this macrolactol formation, an unexpected
minor product 77 was observed. The primary amine 77
presumably results from over reduction of intermediate 76 and
was isolated in variable quantities depending on the amount of
DIBAL-H employed in the reaction. This observation implicates
(38) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Wipf,
P.; Ribe, S. J. Org. Chem. 1998, 63, 6454.
(39) Spontaneous lactolization produced 77 as a single diastereomer.
However, the absolute stereochemistry was not determined.
J. Org. Chem, Vol. 72, No. 1, 2007 13

Su et al.
SCHEME 26. Synthesis of the Leucascandrolide A TBDPS-Protected Lactone 75
SCHEME 27. Retrosynthetic Analysis of the C1′-C11′
TMANO) to afford racemic diol (()-79 (Scheme 28). Selective
oxidation of the secondary alcohol using the conditions de-
scribed by Ishii, 1.6 mol % of pyridinium peroxotungstophos-
phate (80) and H2O2, gave the hydroxy ketone 81 in 95% yield.40
Cyclization of 81 to oxazolone 82 was accomplished using a
three-step, one-pot protocol. Treatment of 81 with a solution
of phosgene in toluene, followed by exposure to aqueous NH4-
OH, and then brief acidification with concentrated H2SO4 (pH
< 3.5) afforded oxazolone 82 in 85% yield. Treatment of 82
with 2,6-lutidine and trifluoromethanesulfonic anhydride (Tf2O)
completed the synthesis of the C3′-C8′ 2-trifloyloxazole 16.
Alkyne 17 was synthesized through the addition of propar-
gylamine (83) to methyl chloroformate (84), giving carbamate
17 in 75% yield (Scheme 29).
In an effort to expand the use of our earlier work concerning
the development of Pd(0)-mediated cross-coupling of trifloyl-
substituted heterocycles,41 we sought an alternative coupling
strategy that would allow for the construction of the key
leucascandrolide A oxazole side chain intermediate 86. Hoping
that the 2-trifloyloxazole fragment 16 would not be limited to
cross-couplings with organotin species, we explored the viability
of a Sonogashira cross-coupling strategy. In this case, the
alkynylmetal species 85 is copper-based and is generated in situ
from a catalytic amount of Cu(I) (Scheme 30).
Oxazole
a possible involvement of activated intermediate 76 in the
reduction process, which serves as circumstantial evidence for
the preorganized conformation of the acyclic precursor 11, which
would properly align the π* orbital of the aldehyde or imine
for cyclization. Oxidation of 74 to the macrolactone 75 using
PCC was followed by TBAF-promoted desilylation to furnish
the completed leucascandrolide A macrolactone (3).
Synthesis of the Leucascandrolide A C1′-C11′ Oxazole
Fragment (4) via a Sonogashira Coupling. Concurrent with
our efforts toward the leucascandrolide A macrolide (3) was
an efficient and high-yielding synthesis of the leucascandrolide
A oxazole side chain (4). From a retrosynthetic perspective,
disconnection at the C8′-C9′ bond revealed the two potential
coupling partners: 2-trifloyloxazole 16 and terminal alkyne 17
(Scheme 27).
To determine the feasibility of the approach, we tested
reaction conditions using the 2-trifloyloxazole 16 and alkyne
17. With our initial Sonogashira coupling conditions (5% Pd-
(PPh3)4, 10% CuI, DMF, Et3N, 65 °C, Table 3, entry 1), only
The synthesis began with the TBDPS protection of com-
mercially available 4-penten-1-ol, giving silyl ether 78, which
was followed by dihydroxylation of the terminal olefin (OsO4,
(40) Sakata, Y.; Ishii, Y. J. Org. Chem. 1991, 56, 6233.
(41) Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469.
14 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
SCHEME 28. Synthesis of the 2-Trifloyloxazole Fragment 16
SCHEME 29. Synthesis of the Alkyne Fragment 17
DMF did not promote any unwanted decomposition even after
6 h. Indeed, substitution of Et3N with 2,6-lutidine in DMF at
65 °C afforded the desired C3′-C11′ coupling fragment 86,
albeit in a modest 55% yield along with triflate decomposition
products (Table 3, entry 2). In efforts to preserve the chemical
integrity of 16 throughout the reaction, we attempted to lower
the reaction temperature. Unfortunately, this approach did not
yield significant amounts of the coupled fragment (<10%
isolated yield). Empirically, it was determined that a solvent
substitution of 1,4-dioxane for DMF greatly increased the
efficiency of the Sonogashira coupling. Although the precise
reasons for this remain unclear, the coupling now proceeded
smoothly at ambient temperature with 2,6-lutidine in dioxane
to provide the key C3′-C11′ coupling fragment 86 in 84% yield
in only 4 h (Table 3, entry 4).
SCHEME 30. Retrosynthesis of the C3′-C11′ Oxazole
Fragment 86
With the alkynyl oxazole 86 in hand, a straightforward
sequence was used to complete the C1′-C11′ oxazole side chain
of leucascandrolide A (4) (Scheme 31). Installation of the C9′-
C10′ (Z)-olefin using a Lindlar reduction, followed by removal
of the silyl protecting group with TBAF buffered with acetic
acid gave the alcohol 87 in 80% yield for the two steps.
Oxidation of this intermediate using Dess-Martin periodinane
in the presence of pyridine cleanly afforded aldehyde 88 in 99%
yield. A Still-Gennari olefination42 installed the C2′-C3′ (Z)-
olefin as a single isomer in 72% yield and completed the C1′-
C11′ carbon chain, giving fragment 89. Finally, hydrolysis of
the C1′ methyl ester with aqueous 1 M LiOH completed the
synthesis of the C1′-C11′ leucascandrolide A oxazole side chain
(4).
Completion of the Total Synthesis of Leucascandrolide
A (1). After completing the assembly of the side chain and with
the macrolide in hand, we were positioned to complete the total
synthesis of 1. In this regard, it has been documented that the
direct acylation of the axially oriented C5 hydroxyl group with
the fully elaborated side chain 4 is difficult to achieve, due to
the hindered nature of the alcohol and the (Z)-R,â-unsaturated
carboxylic acid. Therefore, a Mitsunobu esterification method
was employed to install the fully functionalized side chain onto
the macrolide (Scheme 32). Accordingly, the C5 axial alcohol
3 was inverted to its equatorial isomer 91 using a two-step
oxidation and reduction sequence. Dess-Martin periodinane
oxidation of 3 furnished ketone 90 in a 95% yield. Reduction
of ketone 90 with NaBH4 produced the equatorial alcohol 91
(95%, dr ) 14:1), consistent with an axially favored addition
of the small hydride source to a conformationally biased
cyclohexanone. Finally, union of the macrolactone 91 and the
TABLE 3. Optimization of the Sonogashira Coupling of
Fragments 16 and 17
entry
base
Et3N
2,6-lutidine
2,6-lutidine
2,6-lutidine
solvent
temp
time (h)
yield (%)e
1
2
3
4
DMF
DMF
DMF
dioxane
65 °C
65 °C
rt
12
12
12
4
trace
55
trace
84
rt
a A brief Pd(0) source screen determined Pd(PPh3)4 was optimal. b A
copper(I) source screen determined the following reactivity trend: CuI >
CuBr > (CH3CN)4CuPF6 > CuCl; 10 mol % of CuI was used. c Five
equivalents of amine base were used. d Reactions run 0.3 M in solvent.
e Isolated yield after SiO2 chromatography.
a trace amount of desired oxazole product 86 was obtained
(<10% isolated yield), along with decomposition products of
the 2-trifloyloxazole 16. Due to the relative chemical instability
of 16, we sought milder conditions for the cross-coupling. In
control experiments to examine the stability of 2-trifloyloxazole
16 in the reaction, it was observed that Et3N caused extensive
decomposition of 16 in approximately 25 min. Seeking a
compatible amine, we examined a number of alternatives that
could promote coupling without destroying the sensitive 2-tri-
floyloxazole 16. Notably, treatment of 16 with 2,6-lutidine in
(42) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
J. Org. Chem, Vol. 72, No. 1, 2007 15

Su et al.
SCHEME 31. Synthesis of the Leucascandrolide A Side Chain 4
SCHEME 32. Completion of Leucascandrolide A (1)
oxazole-containing side chain 4 under Mitsunobu conditions
(DIAD, TPP) proceeded in 70% yield and completed our total
synthesis of leucascandrolide A, 1.43
Conclusions
In summary, a convergent total synthesis of the marine natural
product, leucascandrolide A (1), was completed. The synthesis
was accomplished in 17 steps over the longest linear sequence
and in a 3.7% overall yield starting from readily available chiral
(43) Mitsunobu, O. Synthesis 1981, 1.
16 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
extracted 3 times with CH2Cl2. The combined organic extracts were
washed with ∼100 mL of 5% HCl, water, dried with MgSO4,
filtered, and concentrated giving the crude reaction product which
was purified by flash chromatography (SiO2, 10% EtOAc/hexanes)
giving 7.30 g (82%) of aldehyde 24 as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 1.04 (9H, s), 2.69 (2H, d, J ) 6.0 Hz), 3.67
(1H, dd, J ) 5.6, 10.4 Hz), 3.77 (1H, dd, J ) 4.4, 10.4 Hz), 4.00-
4.04 (1H, m), 4.53 (2H, qAB, J ) 12.0 Hz), 7.23-7.42 (11H, m),
7.60-7.63 (4H, m), 9.77 (1H, s); 13C NMR (75 MHz, CDCl3) δ
19.2, 26.6, 26.8, 46.3, 65.2, 72.1, 74.9, 127.8, 128.0, 128.4, 129.6,
129.8, 133.1, 133.2, 134.8, 135.6, 138.1, 200.9; IR (neat) νmax 3071,
2931, 2858, 1728, 1472, 1428, 1391, 1361, 1113, 1028, 740; HRMS
(CI, NH3) m/z calcd for C27H33O3Si1 [M + H]+ 433.2199, found
silane reagent 13. This synthesis was highlighted by the chiral
silane-based methodology for the asymmetric synthesis of
dihydropyrans and a Pd(0)-mediated Sonogashira cross-coupling
to efficiently assemble the oxazole-containing side chain. This
leucascandrolide A synthesis underscores the salient utility of
chiral organosilane reagents in the stereocontrolled construction
of oxygen heterocycles and their subsequent use in the enan-
tioselective synthesis of complex natural products.
Experimental Section
General experimental details and spectra of key intermediates
64, 74, and 75 as well as leucascandrolide A (1) can be found in
the Supporting Information.
433.2188; [R]23 ) +20.27° (c ) 1.12, CHCl3).
D
(6R)-Benzyloxy-7-(tert-butyldiphenylsilanyloxy)hept-1-en-
(4S)-tert-butyldimethylsilanol (25). To a 250 mL round-bottom
flask charged with a magnetic stir bar and 5.63 g (13.01 mmol) of
aldehyde 24 was added 44 mL of anhydrous CH2Cl2. The reaction
was cooled to -78 °C, and 2.96 mL (15.62 mmol) of freshly
distilled TiCl4 was added dropwise via syringe. The reaction was
allowed to stir for 5 min before 3.31 mL (20.82 mmol) of
allyltrimethylsilane was added via syringe. The reaction was stirred
for 20 min at -78 °C before the addition of ∼10 mL of EtOAc.
The reaction was allowed to stir for 5 min followed by the addition
of ∼50 mL of saturated aqueous NaHCO3. The reaction mixture
was extracted 3 times with CH2Cl2, the combined organic extracts
were washed with brine, dried with MgSO4, and concentrated. The
crude reaction mixture was purified by flash chromatography (SiO2,
5% f 15% EtOAc/hexanes) giving 4.94 g (80%, de > 20:1) of
desired homoallylic alcohol as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 1.04 (9H, s), 1.59-1.63 (1H, m), 1.64-1.78 (1H, m),
2.18 (2H, t, J ) 7.2 Hz), 2.49 (1H, d, J ) 3.6 Hz), 3.66-3.69 (1H,
m), 3.70-3.79 (2H, m), 3.81-3.89 (1H, m), 4.58 (2H, qAB, J )
11.6 Hz), 5.05 (1H, s), 5.08 (1H, d, J ) 5.2 Hz), 5.73-5.84 (1H,
m), 7.24-7.42 (11H, m), 7.64-7.67 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 19.2, 26.9, 38.0, 42.3, 66.0, 67.7, 72.4, 117.5, 127.7,
127.9, 128.4, 129.8, 133.3, 133.4, 133.5, 134.9, 135.6, 138.5; IR
(neat) νmax 3457, 3071, 2930, 3858, 1653, 1641, 1589, 1472, 1391,
1028, 998, 824; HRMS (CI, NH3) m/z calcd for C30H39O3Si1 [M +
(3R)-Benzyloxy-4-(tert-butyldiphenylsilanyloxy)butyric Acid
Benzyl Ester (23). To a 250 mL round-bottom flask charged with
a magnetic stir bar and 4.24 g (20.17 mmol) of (3R)-4-dihydroxy-
butyric acid benzyl ester was added 41 mL of anhydrous DMF.
Imidazole (2.20 g/32.272 mmol) was added, the reaction was cooled
to 0 °C, and tert-butyldiphenylsilyl chloride (5.74 mL/21.78 mmol)
was added via syringe, and the reaction was allowed to stir for 2
h at 0 °C. The reaction was then diluted with ∼100 mL of H2O
and extracted 3 times with Et2O. The combined organic extracts
were then washed with H2O, brine, dried with MgSO4, filtered,
and concentrated to give the crude reaction product which was
purified by flash chromatography (SiO2, 5% f 10% EtOAc/
hexanes) giving 9.45 g (99%) of desired secondary alcohol as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 2.58
(2H, dd, J ) 2.0, 4.8 Hz), 2.84 (1H, d, J ) 4.8 Hz), 3.64 (2H, ddd,
J ) 4.4, 10.0, 15.2 Hz), 4.17 (1H, dddd, J ) 3.6, 4.8, 10.0, 15.2
Hz), 5.11 (2H, s), 7.33-7.41 (11H, m), 7.62 (4H, d, J ) 8.0 Hz);
13C NMR (75 MHz, CDCl3) δ 19.3, 26.9, 38.2, 66.5, 66.7, 68.7,
127.8, 128.2, 128.6, 129.8, 133.1, 135.5, 135.7, 171.8; IR (neat)
ν
max 3506, 3071, 2931, 2858, 1734, 1589, 1472, 1361, 1217, 1111,
998, 740; HRMS (CI, NH3) m/z calcd for C27H32O4Si1 [M + H]+
449.2148, found 449.2131; [R]23 ) +12.16° (c ) 0.49, CHCl3).
D
To a 250 mL round-bottom flask charged with a magnetic stir bar
and 9.45 g (21.06 mmol) of secondary alcohol was added 84 mL
of anhydrous Et2O. 2,2,2-Trichloroacetimidic acid benzyl ester (5.28
mL/28.44 mL) was added, and the reaction was cooled to 0 °C.
Trifluoromethanesulfonic acid (60 µL/0.632 mmol) was added via
syringe, and the reaction was allowed to warm slowly to room
temperature with stirring over 12 h. The reaction was quenched by
the addition of ∼100 mL of saturated aqueous solution of NaHCO3.
The layers were separated, and the aqueous layer was extracted 3
times with Et2O. The combined organic extracts were then washed
with H2O, brine, dried with MgSO4, filtered, and concentrated to
give the crude reaction product which was purified by flash
chromatography (SiO2, 5% EtOAc/hexanes) giving 11.92 g (99%)
of benzyl ether 23 as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 1.03 (9H, s), 2.62 (1H, dd, J ) 8.0, 15.8 Hz), 2.74 (1H, dd, J )
4.8, 15.8 Hz), 3.64 (1H, dd, J ) 5.4, 10.4 Hz), 3.74 (1H, dd, J )
5.4, 10.4 Hz), 4.03 (1H, dddd, J ) 5.4, 10.4, 14.0, 15.8 Hz), 4.51
(2H, qAB, J ) 11.6 Hz), 5.09 (2H, qAB, J ) 12.8 Hz), 7.18-7.41
(16H, m), 7.59-7.63 (4H, m); 13C NMR (75 MHz, CDCl3) δ 19.3,
26.9, 37.7, 65.4, 66.4, 72.5, 76.6, 127.5, 127.8, 128.2, 128.3, 128.5,
129.8, 133.3, 133.4, 135.6, 136.0, 138.5, 171.5; IR (neat) νmax 3069,
2931, 2858, 1737, 1497, 1472, 1455, 1428, 1361, 1260, 1168, 1028,
739; HRMS (CI, NH3) m/z calcd for C34H39O4Si1 [M + H]+
H]+ 475.2668, found 475.2666; [R]23 ) +23.41° (c ) 0.68,
D
CHCl3). To a 250 mL round-bottom flask charged with a magnetic
stir bar and 4.30 g (9.06 mmol) of the resulting homoallylic alcohol
was added 45 mL of anhydrous CH2Cl2. To the mixture was added
2,6-lutidine (4.22 mL/36.2 mmol), and the reaction was cooled to
0 °C. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.12 mL/
13.59 mmol) was added via syringe, and the reaction was stirred
for 2 h before being diluted with ∼100 mL of H2O. The layers
were separated, and the aqueous layer was extracted 3 times with
CH2Cl2. The combined organic extracts were washed with H2O,
dried with MgSO4, and concentrated. The crude reaction mixture
was purified by flash chromatography (SiO2, 5% EtOAc/hexanes)
giving 5.15 g (97%) of bis-silyl ether 25 as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ -0.03 (3H, s), -0.01 (3H, s), 0.88
(9H, s), 1.05 (9H, s), 1.52-1.69 (2H, m), 2.17-2.28 (2H, m), 3.61-
3.78 (3H, m), 3.95-4.01 (1H, m), 4.58 (2H, qAB, J ) 11.6 Hz),
4.99 (1H, d, J ) 6.8 Hz), 5.02 (1H, s), 5.74-5.84 (1H, m), 7.22-
7.43 (11H, m), 7.66 (4H, t, J ) 8.8 Hz); 13C NMR (75 MHz, CDCl3)
δ -4.4, -3.9, 18.1, 19.2, 25.8, 26.9, 39.8, 42.8, 66.8, 68.8, 71.8,
116.9, 127.3, 127.4, 127.5, 127.7, 128.2, 129.6, 133.7, 134.8, 135.6,
139.2; IR (neat) νmax 3072, 2956, 1472, 1361, 1256, 998, 913, 739;
HRMS (CI, NH3) m/z calcd for C36H52O3Si2 [M + H]+ 589.3533,
539.2617, found 539.2629; [R]23 ) +11.92° (c ) 0.97, CHCl3).
D
found 589.3566; [R]23 ) +26.62° (c ) 0.71, CHCl3).
D
(3R)-Benzyloxy-4-(tert-butyldiphenylsilanyloxy)butryalde-
hyde (24). To a 500 mL round-bottom flask charged with a
magnetic stir bar and 11.09 g (20.58 mmol) of benzylester 23 was
added 206 mL of anhydrous CH2Cl2. The reaction was cooled to
-78 °C, and 51.46 mL of a 1 M solution of DIBAL-H in hexanes
was added dropwise via syringe. The reaction was stirred for 15
min at -78 °C before being quenched with ∼20 mL of MeOH.
The reaction was stirred to room temperature and diluted with ∼100
mL of H2O. The layers were separated, and the aqueous layer was
(5R)-Benzyloxy-(3S)-(tert-butyldimethylsilanyloxy)-6-(tert-bu-
tyldiphenylsilanyloxy)hexan-1-ol (26). To a 500 mL round-bottom
flask charged with a magnetic stir bar and 5.15 g (8.74 mmol) of
terminal olefin 25 were added 175 mL of MeOH and 20 mL of
CH2Cl2. Pyridine (2.83 mL/34.96 mmol) was added, and the
reaction was cooled to -78 °C. Ozone was bubbled through the
reaction for 45 min before dimethyl sulfide (6.42 mL/87.44 mmol)
was added, and the reaction was allowed to warm slowly to room
J. Org. Chem, Vol. 72, No. 1, 2007 17

Su et al.
temperature with stirring for 12 h. The solvent was removed under
vacuum, giving the crude aldehyde which was immediately
dissolved in 50 mL of MeOH. The reaction was cooled to 0 °C,
and NaBH4 (0.826 g/21.85 mmol) was added in one portion. The
reaction was stirred for 20 min at 0 °C before being quenched by
the addition of ∼50 mL of a saturated aqueous solution of NH4Cl.
The layers were separated, and the aqueous layer was re-extracted
3 times with EtOAc. The combined organic extracts were washed
with H2O, dried with MgSO4, and concentrated. The crude reaction
product was purified by flash chromatography (SiO2, 20% EtOAc/
hexanes) giving 3.80 g (75%) of primary alcohol 26 as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 0.03 (3H, s), 0.06 (3H, s), 0.87
(9H, s), 1.05 (9H, s), 1.59-1.64 (1H, m), 1.72-1.86 (3H, m), 2.03
(1H, br s), 3.58-3.72 (3H, m), 3.74-3.82 (2H, m), 4.06-4.10 (1H,
m), 4.53 (2H, qAB, J ) 11.6 Hz), 7.24-7.42 (11H, m), 7.61-7.69
(4H, m); 13C NMR (75 MHz, CDCl3) δ -4.5, -4.3, 17.9, 19.2,
25.9, 26.9, 39.2, 39.8, 59.8, 66.3, 69.1, 71.7, 127.5, 127.6, 127.7,
128.3, 129.7, 133.4, 133.5, 135.6, 138.8; IR (neat) νmax 3428, 3071,
2930, 2857, 1472, 1428, 1389, 1257, 1113, 836; HRMS (CI, NH3)
m/z calcd for C35H53O4Si2 [M + H]+ 593.3482, found 593.3471;
(400 MHz, CDCl3) δ 0.0 (6H, s), 0.86 (9H, s), 1.01-1.08 (15H,
m), 1.25-1.41 (4H, m), 1.58-1.61 (3H, m), 2.49-2.51 (1H, m),
2.76 (2.4H, s), 2.83* (0.6H, s), 3.59-3.71 (3H, m), 3.82-3.90 (1H,
m), 4.38-4.42 (1H, br s), 4.56 (1H, t, J ) 7.2 Hz), 4.57 (2H, qAB
,
J ) 11.6 Hz), 7.19-7.42 (16H, m), 7.65 (4H, t, J ) 6.4 Hz); 13C
NMR (75 MHz, CDCl3) δ -4.5, -3.9, 14.4, 17.1, 18.0, 19.2, 25.9,
26.8, 28.9, 32.8, 35.7, 36.7, 39.9, 66.7, 71.8, 77.1, 126.3, 126.9,
127.2, 127.3, 127.4, 127.6, 128.1, 128.3, 128.6, 129.6, 133.5, 135.6,
139.1, 142.5, 178.9; IR (neat) νmax 3854, 3744, 3397, 2931, 2858,
1700, 1653, 1559, 1061, 836, 667; HRMS (CI, NH3) m/z calcd for
C48H70N1O5Si2 [M + H]+ 796.4792, found 796.4727; [R]23
-6.86° (c ) 0.69, CHCl3).
)
D
(2R)-2-(Benzyloxy)-3-[(2S,5S)-5-methyl-6-oxotetrahydro-2H-
pyran-2-yl]propanal (31). To a 250 mL round-bottom flask
charged with a magnetic stir bar was added 4.68 g (5.88 mmol) of
amide 29. Anhydrous THF (30 mL) was added, and the reaction
was cooled to 0 °C. Tetrabutylammonium fluoride (14.70 mL of a
1 M solution of in THF) was added via syringe, and the reaction
was allowed to stir for 6 h before being concentrated in vacuo.
The resulting oil was dissolved in 80 mL of a 3:1 t-BuOH/H2O
solvent system; 7.70 mL (29.4 mmol) of tetra-n-butylammonium
hydroxide was added, and the resulting mixture was refluxed for
24 h. The reaction was then cooled to room temperature and
acidified to pH ∼4 by the addition of an aqueous 10% HCl solution.
The reaction was then poured into a separatory funnel and extracted
4 times with EtOAc. The combined organic extracts were washed
with H2O, brine, dried with MgSO4, filtered, and concentrated. The
resulting residue was then dissolved in 75 mL of anhydrous CH2-
Cl2. Pyridinium p-toluenesulfonate (1.47 g/5.88 mmol) was added
in one portion, and the reaction was allowed to stir for 24 h at
ambient temperature. The reaction was quenched by the addition
of ∼50 mL of H2O. The layers were separated, and the aqueous
layer was extracted 3 times with EtOAc. The combined organic
extracts were then washed with H2O, brine, dried with MgSO4,
filtered, and concentrated to give the crude reaction product which
was purified by flash chromatography (SiO2, 20% f 75% EtOAc/
hexanes) giving 1.47 g (90%) acie 30 as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 1.17 (3H, d, J ) 6.4 Hz), 1.21-1.26 (1H,
m), 1.28-1.71 (2H, m), 1.81-1.90 (2H, m), 1.99-2.04 (1H, m),
2.41 (1H, tq, J ) 7.6, 10.8 Hz), 3.46-3.51 (1H, m), 3.81-3.89
(2H, m), 4.36 (1H, dd, J ) 2.4, 10.4 Hz), 4.58 (2H, qAB, J ) 11.6
Hz), 7.24-7.39 (5H, m); 13C NMR (75 MHz, CDCl3) δ 15.9, 25.6,
27.2, 32.9, 37.9, 64.0, 72.5, 74.4, 75.6, 127.9, 128.0, 128.5, 138.2,
175.9; IR (neat) νmax 3466, 2935, 2876, 1734, 1617, 1496, 1455,
1380, 1191, 1028, 667; HRMS (CI, NH3) m/z calcd for C16H23O4
[M + H]+ 796.4792, found 796.4727; [R]23D ) +96.61° (c ) 0.59,
CHCl3). To a 100 mL round-bottom flask charged with a magnetic
stir bar and (6S)-((2R)-benzyloxy-3-hydroxypropyl)-(3S)-methyltet-
rahydropyran-2-one (0.64 g, 2.31 mmol) was added 23 mL of
anhydrous CH2Cl2. Dess-Martin periodinane (1.96 g/4.62 mmol)
was added followed by distilled pyridine (1.12 mL/13.86 mmol).
The reaction was allowed to stir for 45 min at ambient temperature
before being diluted with ∼25 mL of a saturated aqueous solution
of NaHCO3. The layers were separated, and the aqueous phase was
extracted 3 times with EtOAc. The combined organic extracts were
washed with H2O, brine, dried with MgSO4, filtered, and concen-
trated to give the crude reaction product which was purified by
flash chromatography (SiO2, 30% EtOAc/hexanes) giving 0.520 g
(82%) of aldehyde 31 as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 1.19 (3H, d, J ) 6.8 Hz), 1.44-1.73 (3H, m), 1.83-
1.89 (1H, m), 1.91-2.09 (2H, m), 2.42-2.49 (1H, m), 4.20 (1H,
dddd, J ) 0.8, 2.8, 4, 10.8 Hz), 4.43 (1H, dddd, J ) 2.8, 5.6, 10.8,
10.8 Hz), 4.52 (1H, d, J ) 11.2 Hz), 4.74 (1H, d, J ) 11.2 Hz),
7.27-7.36 (5H, m), 9.65 (1H, d, J ) 0.8 Hz); 13C NMR (75 MHz,
CDCl3) δ 16.0, 25.5, 27.0, 33.1, 35.7, 73.2, 73.5, 77.2, 79.8, 128.3,
128.6, 137.1, 175.5, 202.0; IR (neat) νmax 3020, 2937, 2877, 1497,
1455, 1382, 1190, 934; HRMS (CI, NH3) m/z calcd for C16H21O4
[R]23 ) +15.52° (c ) 0.71, CHCl3).
D
(5R)-Benzyloxy-1-iodo-(3S)-(tert-butyldimethylsilanyloxy)-6-
(tert-butyldiphenylsilanyloxy)hexane (27). To a 100 mL round-
bottom flask charged with a magnetic stir bar and 4.16 g (7.02
mmol) of primary alcohol 26 was added 15 mL of anhydrous DMF.
The reaction was cooled to 0 °C, (PhO)3P+CH3I- (4.76 g/10.53
mmol) was added in one portion, and the reaction was stirred for
1 h at 0 °C before being diluted with ∼50 mL of Et2O. The reaction
was poured onto water (∼150 mL) and extracted 3 times with Et2O.
The combined organic extracts were then washed 4 times with H2O,
brine, dried with MgSO4, filtered, and concentrated to give the crude
reaction product which was purified by flash chromatography (SiO2,
2.5% EtOAc/hexanes) giving 4.53 g (92%) of iodide 27 as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.03 (3H, s), 0.05
(3H, s), 0.86 (9H, s), 1.05 (9H, s), 1.57-1.63 (1H, m), 1.68-1.74
(1H, m), 1.94-2.06 (2H, m), 3.12-3.17 (2H, m), 3.59-3.63 (2H,
m), 3.71-3.76 (1H, m), 3.87-3.91 (1H, m), 4.53 (2H, qAB, J )
11.6 Hz); 13C NMR (75 MHz, CDCl3) δ -4.3, -4.1, 1.9, 18.0,
19.2, 25.9, 26.9, 39.7, 42.3, 66.2, 70.1, 127.4, 127.6, 127.7, 128.3,
129.7, 133.4, 133.5, 135.6, 138.8; IR (neat) νmax 2955, 2929, 2857,
1472, 1428, 1361, 1257, 1217, 1006, 938; HRMS (CI, NH3) m/z
calcd for C35H51I1O3Si2 [M + H]+ 703.2459, found 703.2464; [R]23
) +12.38° (c ) 0.42, CHCl3).
D
(7R)-Benzyloxy-(5S)-(tert-butyldimethylsilanyloxy)-8-(tert-bu-
tyldiphenylsilanyloxy)-2-methyloctanoic acid ((2R)-hydroxy-
(1R)-methyl-2-phenylethyl)methyl amide (29). To a 250 mL
round-bottom flask charged with a magnetic stir bar was added
3.4 g (24.64 mmol) of anhydrous LiCl. The flask was placed under
vacuum, and the LiCl was flame-dried. The flask was allowed to
cool under vacuum, removed, and immediately purged with argon.
Diisopropylamine (3.71 mL/26.49 mmol) was added followed by
18 mL of anhydrous THF. The suspension was cooled to -78 °C,
and 9.86 mL of a 2.5 M solution of n-BuLi in hexanes was added
dropwise via syringe. The suspension was allowed to warm to room
temperature for 5 min before being recooled to -78 °C. A 0 °C
solution of 2.86 g (12.93 mmol) of (-)-pseudoephedrine amide 28
in 40 mL of anhydrous THF was then added dropwise via syringe.
The reaction was stirred for 1 h at -78 °C, 15 min at 0 °C, and 5
min at room temperature before being recooled to 0 °C. A solution
of 4.33 g (6.16 mmol) of alkyl iodide 27 in 10 mL of anhydrous
THF was then added dropwise to the reaction. The reaction was
then allowed to stir at 0 °C for 8 h before being quenched by the
addition of ∼100 mL of a saturated aqueous solution of NH4Cl.
The layers were separated, and the aqueous layer was extracted 3
times with EtOAc. The combined organic extracts were then washed
with H2O, brine, dried with MgSO4, filtered, and concentrated to
give the crude reaction product which was purified by flash
chromatography (SiO2, 30% EtOAc/hexanes) giving 4.68 g (95%,
de > 20:1) of amide 29 as a 5:1 mixture of amide rotamers (minor
rotamer peaks denoted by an asterisk) as a colorless oil: 1H NMR
[M + H]+ 277.1439, found 277.1442; [R]23 ) +103.83° (c )
D
0.47, CHCl3).
18 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
1,1-Diiodo-3-methyl butane (32). To a 100 mL round-bottom
flask charged with a magnetic stir bar and 6.00 mL (56.0 mmol)
isovaleraldehyde was added 10 mL of hydrazine hydrate. The
reaction was warmed to 50 °C in an oil bath with stirring for 3 h
before being diluted with ∼50 mL of H2O. The layers were
separated, and the aqueous layer was extracted 3 times with CHCl3.
The combined organic extracts were washed with H2O, dried with
MgSO4, filtered, and concentrated giving the intermediate hydrazone
which was used immediately without further purification. The
hydrazone was dissolved in 50 mL of Et2O and 38 mL of
triethylamine in a 250 mL round-bottom flask equipped with a
magnetic stir bar. A solution of 20 g of I2 in 50 mL of Et2O was
added dropwise via a Pasteur pipet to the reaction until the cessation
of N2 was observed and the iodine color persisted. The reaction
was then diluted with ∼50 mL of a 5% aqueous Na2S2O3 solution
and allowed to stir for 10 min. The layers were separated, and the
organic extracts were washed with 100 mL of 10% aqueous HCl,
100 mL of a saturated solution of NaHCO3, brine, dried with
MgSO4, filtered, and concentrated. The crude oil was purified by
flash chromatography (SiO2, hexanes) giving 9.50 g (54%) of
diiodide 32 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.88
(6H, d, J ) 6.8 Hz), 1.69 (1H, tq, J ) 6.8, 7.6 Hz), 2.24 (2H, dd,
J ) 6.4, 7.6 Hz), 5.04 (1H, t, J ) 7.6 Hz); 13C NMR (75 MHz,
CDCl3) δ -27.2, 20.8, 30.8, 57.3; IR (neat) νmax 3448, 3072, 2932,
2858, 1731, 1464, 1282, 1113, 821, 702; HRMS (CI, NH3) m/z
calcd for C5H10I2 [M + H]+ 324.8950, found 324.8961.
temperature. The reaction was then quenched by the addition of
∼25 mL of H2O. The layers were separated, and the aqueous layer
was extracted 3 times with EtOAc. The combined organic extracts
were washed with H2O, brine, dried with MgSO4, filtered, and
concentrated to give the crude reaction product which was purified
by flash chromatography (SiO2, 10% EtOAc/hexanes) giving 0.864
g (77%) of acetate 34 as a colorless oil. The product was isolated
as a 3:1 mixture of anomers that were used immediately. Charac-
terization for the major anomer is as follows: 1H NMR (400 MHz,
CDCl3) δ 0.80-0.90 (6H, m), 1.02 (3H, d, J ) 7.2 Hz), 1.35-
1.42 (3H, m), 1.52-1.81 (5H, m), 1.84-1.93 (2H, m), 1.94 (3H,
s), 3.96 (1H, dt, J ) 4.0, 8.8 Hz), 4.10 (1H, dddd, J ) 3.2, 6.4,
12.0, 14.4 Hz), 4.40 (2H, qAB, J ) 11.6 Hz), 5.30 (1H, dd, J )
8.8. 14.8 Hz), 5.62 (1H, dt, J ) 7.0, 14.8 Hz), 5.78 (1H, br s),
7.22-7.35 (5H, m); IR (neat) νmax 2954, 2868, 1751, 1653, 1497,
1454, 1437, 1385, 1371, 967, 698; HRMS (CI, NH3) m/z calcd for
C23H34O4 [M + H]+ 375.2535, found 375.2531; [R]23D ) +38.87°
(c ) 0.62, CHCl3).
[(6S)-((2R)-Benzyloxy-6-methylhept-3-enyl)-(3S)-methyltet-
rahydropyran-(2S)-yl]acetaldehyde (6). To a 50 mL round-bottom
flask charged with a magnetic stir bar and acetate 34 (0.870 g/2.35
mmol) were added 5 mL of anhydrous CH2Cl2 and 5 mL of
anhydrous Et2O. Freshly prepared trimethylvinyloxysilane 35 (1.35
g/11.61 mmol) was added via syringe, and the reaction was cooled
to 0 °C. A solution of freshly flame-dried ZnCl2 (1.58 g/11.63
mmol) in 5 mL of CH2Cl2 was added dropwise via syringe. The
reaction was stirred at 0 °C for 1 h before being diluted with a
saturated solution of NaHCO3 (∼15 mL). The phases were
separated, and the aqueous phase was extracted 3 times with CH2-
Cl2. The combined organic phases were dried with MgSO4, filtered,
and concentrated. The crude oil was purified by flash chromatog-
raphy (SiO2, 5% f 15% EtOAc/hexanes) giving 715 mg (86%) of
aldehyde 6 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.88-
0.91 (9H, m), 1.26-1.44 (3H, m), 1.45-1.63 (2H, m), 1.65-1.81
(1H, m), 1.91-1.97 (4H, m), 2.50 (2H, dd, J ) 2.80, 6.4 Hz), 3.72-
3.83 (2H, m), 4.12 (1H, m, J ) 2.6, 4.4, 9.2, 10.8 Hz), 4.41 (2H,
(6S)-((2R)-Benzyloxy-6-methylhept-3-enyl)-(3S)-methyltet-
rahydropyran-2-one (33). To a 100 mL round-bottom flask
charged with a magnetic stir bar was added 1.84 g (15.04 mmol)
of anhydrous CrCl2. The flask was placed under vacuum, and the
CrCl2 was flame-dried. The flask was allowed to cool under
vacuum, removed, and immediately purged with argon. The CrCl2
was suspended in 38 mL of anhydrous THF and 1.16 mL of
anhydrous DMF. A premixed solution of 1.20 g (3.77 mmol) of
1,1-diiodo-3-methyl butane 32 and aldehyde 31 in 6 mL of
anhydrous THF was then added to the suspension with stirring.
The reaction was allowed to stir for 1 h at ambient temperature
before being diluted with ∼25 mL of H2O. The layers were
separated, and the aqueous layer was extracted 3 times with EtOAc.
The combined organic extracts were washed with H2O, brine, dried
with MgSO4, filtered, and concentrated to give the crude reaction
product which was purified by flash chromatography (SiO2, 10%
EtOAc/hexanes) giving 0.466 g (75%) of the desired trans olefin
33 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.84-0.90
(6H, m), 1.18 (3H, d, J ) 6.8 Hz), 1.41-1.63 (3H, m), 1.74 (2H,
t, J ) 7.2 Hz), 1.81-1.90 (1H, m), 1.94 (2H, t, J ) 5.6 Hz), 2.00-
2.04 (1H, m), 2.52 (1H, ddt, J ) 7.6, 10.8, 14.4 Hz), 4.07 (1H, q,
J ) 7.6 Hz), 4.42 (2H, qAB, J ) 11.6 Hz), 4.51-4.60 (1H, m),
5.31 (1H, dd, J ) 8.8, 14.8 Hz), 5.67 (1H, dt, J ) 7.2, 14.8 Hz),
7.23 ) 7.38 (5H, m); 13C NMR (75 MHz, CDCl3) δ 16.0, 22.2,
25.7, 27.1, 28.2, 33.1, 41.6, 42.2, 70.2, 74.4, 75.9, 76.6, 127.5,
127.9, 128.3, 131.1, 133.4, 138.7, 176.2; IR (neat) νmax 2956, 2870,
1740, 1496, 1456, 1381, 1183, 1142, 1074, 1028, 754; HRMS (CI,
NH3) m/z calcd for C21H30O3 [M + H]+ 331.2273, found 331.2295;
qAB, J ) 11.6 Hz), 5.34 (1H, dd, J ) 8.4, 15.2 Hz), 5.63 (1H, dt,
J ) 7.6, 15.2 Hz), 7.23-7.31 (5H, m), 9.67 (1H, t, J ) 2.8 Hz);
13C NMR (75 MHz, CDCl3) δ 17.9, 22.3, 22.4, 26.8, 28.2, 28.4,
34.5, 38.0, 41.6, 47.0, 68.5, 70.1, 71.8, 76.9, 127.3, 127.9, 128.2,
131.9, 132.7, 138.9, 201.9; IR (neat) νmax 2955, 1727, 1457, 1383,
1070, 973, 735, 697; HRMS (CI, NH3) m/z calcd for C23H35O3 [M
+ H]+ 359.2586, found 359.2577; [R]23 ) +33.03° (c ) 0.66,
D
CHCl3).
2(E)-3-(Dimethylphenylsilyl)propenal (40). To a 500 mL three
neck bottom flask charged with a magnetic stir bar and fitted with
a reflux condenser were added propargyl alcohol (3.00 g/53.5 mmol)
and 100 mL of anhydrous THF. Dimethylphenylsilane (8.61 mL/
56.19 mmol) was added followed by the addition of 15 mg of
platinum hydrosilylation catalyst and 5 mg of sodium metal. The
reaction was heated to reflux for 24 h before being cooled to room
temperature. The THF was removed in vacuo, and the resulting
crude reaction product was purified by flash chromatography (SiO2,
10% f 25% EtOAc/hexanes) giving 9.37 g (90%) of the desired
allylic alcohol as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
0.34 (6H, s), 1.39 (1H, dd, J ) 6.0, 7.2 Hz), 4.19 (2H, ddd, J )
1.6, 6.0, 7.2 Hz), 6.04 (1H, ddd, J ) 1.6, 3.6, 18.8 Hz), 6.23 (1H,
ddd, J ) 4.4, 8.4, 18.8 Hz), 7.33-7.39 (3H, m), 7.49-7.52 (2H,
m); 13C NMR (75 MHz, CDCl3) δ -2.8, 65.4, 127.2, 127.3, 127.9,
129.1, 133.9, 146.7; IR (neat) νmax 3450, 3199, 1662, 1504, 1103,
891; HRMS (CI, NH3) m/z calcd for C11H17O1Si1 [M + H]+
193.1048, found 193.1048. A 500 mL round-bottom flask charged
with a magnetic stir bar were added 22 g of Celite and CH2Cl2
(170 mL). Pyridinium chlorochromate (22.0 g/98.8 mmol) was
added to the slurry slowly over 10 min. To this mixture was added
dropwise a solution of allylic alcohol (9.30 g/49.4 mmol) in 25
mL of CH2Cl2, and the reaction was allowed to stir at ambient
temperature for 45 min before being filtered through a pad of SiO2
and concentrated. The resulting residue was purified by flash
chromatography (SiO2, 10% f 25% EtOAc/hexanes) giving 7.00
[R]23 ) +116.32° (c ) 0.44, CHCl3).
D
Acetic acid (6S)-((2R)-Benzyloxy-6-methylhept-3-enyl)-(3S)-
methyltetrahydropyran-2-yl Ester (34). To a 100 mL round-
bottom flask charged with a magnetic stir bar and lactone 33 (0.987
g/3.00 mmol) was added 15 mL of anhydrous CH2Cl2. The reaction
was cooled to -78 °C, and DIBAL-H (6.00 mL of a 1 M solution
of in hexanes) was added dropwise via syringe. The reaction was
stirred for 30 min at this temperature before being quenched with
∼10 mL of MeOH. The reaction was poured onto water, and the
layers were separated. The aqueous layer was extracted 3 times
with CH2Cl2, and the combined organic extracts were dried with
MgSO4, filtered, and concentrated to yield the intermediate lactol
which was immediately dissolved in 15 mL of anhydrous CH2Cl2.
Triethylamine (1.04 mL/7.50 mmol), (dimethylamino)pyridine (∼10
mg), and acetic anhydride (0.567 mL/6.00 mmol) were then added
sequentially, and the reaction was allowed to stir for 2 h at ambient
J. Org. Chem, Vol. 72, No. 1, 2007 19

Su et al.
g (75%) of aldehyde 40 as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 0.45 (6H, s), 6.52 (1H, dd, J ) 7.2, 18.4 Hz), 7.32 (1H,
d, J ) 18.4 Hz), 7.37-7.39 (m, 3H), 7.49-7.53 (m, 2H), 9.51
(1H, d, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ -3.6, 128.2,
129.8, 133.8, 135.8, 145.1, 156.5, 194.7; IR (neat) νmax 3157, 3051,
1755, 1609, 1511, 1199, 855, 711; HRMS (CI, NH3) m/z calcd for
C11H14O1Si1 [M + H]+ 191.0892, found 191.0881.
EtOAc was washed once with H2O, 2 × 80 mL with 1 M aqueous
CuSO4, dried with MgSO4, filtered, and concentrated. The crude
oil was purified by flash chromatography (SiO2, 10% EtOAc/
hexanes) to give 273 mg (99%) of methyl ether 5 as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 0.85-0.92 (9H, m), 1.09 (1H,
q, J ) 11.6 Hz), 1.30 (3H, s), 1.42 (9H, s), 1.43 (3H, s), 1.46-
1.56 (4H, m), 1.57-1.74 (6H, m), 1.86-1.90 (1H, m), 1.94 (2H,
t, J ) 7.2 Hz), 2.24 (1H, dd, J ) 5.6, 15.2 Hz), 2.32-2.38 (2H,
m), 2.46-2.65 (3H, m), 3.25 (3H, s), 3.39 (1H, dt, J ) 4.0, 7.6
Hz), 3.79-3.82 (1H, m), 3.89 (1H, dt, J ) 3.2, 9.6 Hz), 4.04-
4.11 (1H, m), 4.20-4.33 (2H, m), 4.46 (2H, qAB, J ) 11.6 Hz),
5.34 (1H, dd, J ) 8.4, 15.2 Hz), 5.62 (1H, dt, J ) 7.2, 15.2 Hz),
7.21-7.31 (5H, m); 13C NMR (75 MHz, CDCl3) δ 18.3, 19.6, 22.2,
22.3, 26.9, 28.0, 28.2, 28.4, 29.9, 34.6, 36.2, 38.6, 41.6, 42.7, 48.7,
50.1, 57.1, 65.4, 66.0, 67.9, 70.0, 72.1, 73.7, 77.2, 80.5, 98.8, 127.2,
127.6, 128.3, 132.1, 132.5, 139.0, 170.0, 206.9; IR (neat) νmax 3112,
2997, 1729, 1466, 1307, 1201, 1175, 942, 882, 751; HRMS (CI,
NH3) m/z calcd for C39H63O8 [M + H]+ 659.4523, found 659.4521;
(6S)-[2-(Dimethylphenylsilyl)vinyl]-(5S)-methyl-5,6-dihydro-
2H-pyran-(2S)-carboxylic Acid Methyl Ester (41). To a 1 L
round-bottom flask charged with a magnetic stir bar were added
organosilane (S,S)-37 (9.30 g/26.52 mmol) and aldehyde 40 (6.06
g/31.82 mmol). CH2Cl2 (530 mL) was added, and the reaction
mixture was cooled to -50 °C. Freshly distilled TMSOTf (2.94
g/13.26 mmol) was added dropwise to the reaction. The reaction
was allowed to stir at -50 °C for 4 h before being quenched by
the addition of saturated aqueous NaHCO3 (∼200 mL) and allowed
to stir while warming to room temperature. The reaction mixture
was poured into a separatory funnel and extracted 3 times with
CH2Cl2. The combined organic extracts were dried with MgSO4,
filtered, and concentrated. The crude oil was purified by flash
chromatography (SiO2, 3% EtOAc/hexanes) giving 7.97 g (95%)
of 41 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.34 (3H,
s), 0.36 (3H, s), 0.91(3H, d, J ) 7.2 Hz), 2.09-2.19 (1H, m), 3.73
(3H, s), 3.89 (1H, dd, J ) 5.6, 8.8 Hz), 4.78 (1H, br d, J ) 2.8
Hz), 5.76-5.86 (2H, m), 6.10-6.18 (2H, m), 7.30-7.33 (3H, m),
7.49-7.52 (2H, m); 13C NMR (75 MHz, CDCl3) δ -2.8, -2.9,
16.6, 32.9, 51.9, 72.2, 79.8, 122.3, 127.8, 129.0, 131.6, 133.2, 133.9,
138.4, 145.4, 171.6; IR (neat) νmax 3069, 3040, 2957, 1755, 1622,
[R]23 ) +19.07° (c ) 0.60, CHCl3).
D
((6S)-{3-[6-((2R)-Benzyloxy-6-methylhept-3-enyl)-(3S)-meth-
yltetrahydropyran-(2S)-yl]-(2R)-methoxypropyl}-(4S)-hydroxy-
6-methoxytetrahydropyran-(2R)-yl)acetic acid tert-Butyl Ester
(53). A 50 mL round-bottom flask was charged with a magnetic
stir bar and 86 mg (0.132 mmol) of acetonide 5. Methanol (22
mL) was added followed by 10-camphorsulfonic acid (30.8 mg/
0.132 mmol). The reaction was allowed to stir for 24 h at ambient
temperature. The reaction was quenched by the addition of ∼10
mL of a saturated aqueous solution of NaHCO3. The reaction was
poured into a separatory funnel and extracted 3 times with EtOAc.
The combined organic phase was washed with H2O, brine, dried
with MgSO4, filtered, and concentrated. The crude oil was purified
by flash chromatography (SiO2, 20% EtOAc/hexanes) giving 57
mg (68%, dr ∼ 2:1) of acetal 53 as colorless oil: 1H NMR (400
MHz, CDCl3) δ 0.76-0.93 (9H, m), 1.03-1.09 (2H, m), 1.28-
1.41 (5H, m), 1.42 (9H, s), 1.58-1.75 (6H, m), 1.86 (1H, dd, J )
5.6, 14.4 Hz), 1.94 (2H, t, J ) 6.8 Hz), 1.98-2.16 (2H, m), 2.18
(1H, dd, J ) 3.2, 12.8 Hz), 2.30 (1H, dd, J ) 4.8, 15.0 Hz), 2.41
(1H, dd, J ) 8.4, 15.0 Hz), 3.16 (3H, s), 3.28 (1H, s), 3.29 (2H, s),
3.29-3.39 (1H, m), 3.48-3.53 (1H, m), 3.61-3.66 (1H, m), 3.83-
3.97 (2H, m), 4.05-4.08 (1H, m), 4.45 (2H, qAB, J ) 11.6 Hz),
5.34 (1H, dd, J ) 8.0, 15.4 Hz), 5.60 (1H, dt, J ) 6.8, 15.4 Hz),
7.23-7.31 (5H, m); 13C NMR (75 MHz, CDCl3) δ 18.4, 22.3, 27.0,
28.1, 28.2, 28.5, 29.7, 34.8, 36.6, 38.3, 39.1, 39.9, 40.4, 41.6, 42.4,
47.5, 55.4, 56.8, 66.0, 68.3, 70.1, 72.1, 73.2, 77.2, 80.5, 100.6,
127.3, 127.7, 128.3, 132.1, 132.4, 138.9, 170.5; IR (CHCl3 thin
film) νmax 3459, 3020, 3055, 3020, 2956, 2928, 2400, 1735, 1717,
1534, 1366, 1216, 1148, 928, 754; HRMS (EI) m/z calcd for
C37H60O8 [M+]+ 632.4288, found 632.4331; [R]23D ) +11.55° (c
) 0.09, CHCl3).
((6S)-{3-[(6S)-((2R)-Benzyloxy-6-methylhept-3-enyl)-(3S)-
methyltetrahydropyran-(2S)-yl]-(2S)-methoxypropyl}-(4R)-hy-
droxytetrahydropyran-(2R)-yl)acetic acid tert-Butyl Ester (54).
To a 25 mL conical flask charged with a magnetic stir bar was
added acetal 53 (58.5 mg/0.092 mmol). Anhydrous CH2Cl2 (2 mL)
and freshly distilled triethylsilane (0.293 mL/1.84 mmol) were
added. The reaction was then cooled to -78 °C, and freshly distilled
BF3‚OEt2 (0.12 mL/0.93 mmol) was then added dropwise via
syringe. The reaction was warmed to -50 °C and allowed to stir
for an additional 4 h before being quenched by the addition of ∼5
mL of a saturated aqueous solution of NaHCO3. The reaction was
poured into a separatory funnel and extracted 4 times with CH2-
Cl2. The combined organic phase was washed with H2O, dried with
MgSO4, filtered, and concentrated. The crude oil was purified by
flash chromatography (SiO2, 10% EtOAc/hexanes) giving 41 mg
(73%, dr > 9:1) of bis-tetrahydropyran 54 as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 0.86-0.90 (9H, m), 1.10-1.21 (2H,
m), 1.24-1.37 (1H, m), 1.41 (9H, s), 1.42-1.53 (4H, m), 1.56-
1.79 (9H, m), 1.89-1.91 (1H, m), 1.94 (2H, t, J ) 7.6 Hz), 2.24
(1H, dd, J ) 6.4, 14.8 Hz), 2.41 (1H, dd, J ) 6.8, 14.8 Hz), 3.20
(3H, s), 3.36-3.42 (3H, m), 3.62-3.71 (1H, m), 3.89 (1H, dt, J )
1427, 1148, 733; HRMS (CI, NH3) m/z calcd for C18H24O3Si1 [M
23
+ H]+ 316.4669, found 316.1520; [R]
CHCl3).
) -41.21° (c ) 0.82,
D
(6-{5-[6-(2-Benzyloxy-6-methylhept-3-enyl)-3-methyltetrahy-
dropyran-2-yl]-4-hydroxy-2-oxopentyl}-2,2-dimethyl-[1,3]dioxan-
4-yl)acetic acid tert-Butyl Ester (52). To a 25 mL round-bottom
flask charged with a magnetic stir bar were added aldehyde 6 (220
mg/0.614 mmol) and silyl enol ether 7 (220 mg/0.614 mmol). CH2-
Cl2 (5 mL) of was added, and the reaction was cooled to -78 °C.
Freshly distilled BF3‚OEt2 (117 µL/0.921 mmol) was then added
dropwise to the cooled reaction mixture. The reaction was allowed
to stir at this temperature for 90 min before being quenched by the
addition of saturated aqueous NaHCO3 (∼10 mL). The reaction
mixture was poured into a separatory funnel and extracted 3 times
with CH2Cl2. The combined organic extracts were dried with
MgSO4, filtered, and concentrated. The crude oil was purified by
flash chromatography (SiO2, 15% EtOAc/hexanes) to give 321 mg
(81%) of secondary alcohol 52 as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 0.86-0.91 (9H, m), 1.24 (1H, q, J ) 6.8 Hz),
1.30 (3H, s), 1.41 (9H, s), 1.42 (3H, s) 1.46-1.47 (2H, m), 1.55-
1.67 (7H, m), 1.71-1.79 (1H, m), 1.94 (2H, t, J ) 6.4 Hz), 1.95-
1.99 (1H, m), 2.15-2.39 (3H, m), 2.47 (1H, dd, J ) 4.0, 16.8 Hz),
2.54-2.64 (2H, m), 3.46 (1H, d, J ) 3.2 Hz), 3.49 (1H, dt, J )
5.6, 8.4 Hz), 3.91 (1H, dt, J ) 3.2, 9.6 Hz), 4.11-4.18 (1H, m),
4.21-4.29 (3H, m), 4.45 (2H, qAB, J ) 7.6 Hz), 5.35 (1H, dd, J )
8.4, 15.2 Hz), 5.63 (1H, dt, J ) 7.2, 15.2 Hz), 7.21-7.29 (5H, m);
13C NMR (75 MHz, CDCl3) δ 18.1, 19.6, 22.3, 22.4, 27.2, 28.1,
28.2, 28.7, 29.9, 34.4, 36.2, 37.8, 38.9, 41.6, 42.7, 49.7, 51.0, 64.5,
65.5, 66.1, 68.5, 70.1, 72.6, 80.6, 98.9, 127.2, 127.6, 128.3, 131.9,
132.8, 139.0, 170.0, 209.0; IR (neat) νmax 3472, 2953, 1730, 1456,
1381, 1368, 1201, 1154, 1070, 977, 846, 697; HRMS (CI, NH3)
m/z calcd for C38H61O8 [M + H]+ 645.4366, found 645.4397; [R]23
) +21.86° (c ) 0.22, CHCl3).
D
(6-{5-[6-(2-Benzyloxy-6-methylhept-3-enyl)-3-methyltetrahy-
dropyran-2-yl]-4-methoxy-2-oxopentyl}-2,2-dimethyl-[1,3]dioxan-
4-yl)acetic acid tert-Butyl Ester (5). To a 50 mL round-bottom
flask charged with a magnetic stir bar was added alcohol 53 (270
mg/0.42 mmol). The alcohol was dissolved in 17 mL of CH2Cl2
followed by the addition of Proton Sponge (538 mg/2.51 mmol),
800 mg of dry 4 Å molecular sieves, and Me3O‚BF4 (311 mg/2.1
mmol). The reaction was stirred for 1 h before being diluted with
EtOAc (∼20 mL) and passed through a glass-fritted funnel. The
20 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
3.2, 8.6 Hz), 4.08-4.13 (1H, m), 4.45 (2H, qAB, J ) 11.2 Hz),
5.35 (1H, dd, J ) 8.6, 15.0 Hz), 5.60 (1H, dt, J ) 7.6, 15.0 Hz),
7.24-7.31 (5H, m); 13C NMR (75 MHz, CDCl3) δ 18.4, 22.3, 23.5,
27.1, 28.2, 28.3, 29.7, 31.1, 31.9, 34.9, 38.4, 38.8, 40.5, 41.7, 43.0,
56.1, 68.1, 70.2, 71.9, 74.2, 74.5, 74.8, 76.0, 80.2, 127.3, 127.7,
128.3, 132.2, 132.3, 139.0, 170.6; IR (CHCl3 thin film) νmax 3601,
3391, 3105, 1706, 1655, 1580, 1200, 989, 791; HRMS (EI) m/z
(2R,6R)-2,4,6-Trimethylbenzenesulfonic acid 6-[(4R)-(4-ben-
zyloxy-2-methoxybutyl)]-5,6-dihydro-2H-pyran-2-ylmethyl Es-
ter (64). A solution of aldehyde 15 (930 mg, 4.2 mmol) and silane
13 (3.56 g, 7.3 mmol) in DCM at -78 °C (65 mL) was treated
with TfOH (833 mg, 5.55 mmol). The mixture was stirred for 12
h at this temperature before a saturated aqueous solution of NaHCO3
(60 mL) was added. The mixture was extracted with CH2Cl2 (3 ×
60 mL), and combined organic layers were dried over MgSO4.
Removal of the solvents under reduced pressure and purification
of the residue by flash column chromatography (silica gel, 20%
EtOAc in hexane) afforded the pyran 64 as a pale yellow oil (1.67
g, 82%, dr ) 12:1 (cis:trans)). 1H NMR (400 MHz, CDCl3) δ 7.34-
7.26 (5H, m), 6.92 (2H, s), 5.87 (1H, m), 5.53 (1H, dd, br, J ) 2,
10 Hz), 4.47 (2H, s), 4.29 (1H, m), 3.96 (1H, dd, J ) 4, 10 Hz),
3.87 (1H, dd, J ) 6, 10 Hz), 3.62 (1H, m), 3.52 (2H, m), 3.45 (1H,
m), 3.25 (3H, s), 2.61 (6H, s), 2.27 (3H, s), 1.90 (2H, m), 1.77
(3H, m), 1.49 (1H, m); 13C NMR (75 MHz, CDCl3) δ 143.2, 140.0,
138.5, 131.7, 131.6, 128.4, 127.8, 127.7, 127.6, 124.9, 74.9, 72.9,
72.3, 70.7, 70.5, 66.7, 56.3, 39.3, 33.7, 30.8, 22.4, 20.8; IR (neat)
calcd for C37H60O8 [M+]+ 632.4288, found 632.4331; [R]23
+22.22° (c ) 0.22, CHCl3).
)
D
(2S,3S)-2,4,6-Trimethylbenzenesulfonic acid 3-(dimethylphen-
ylsilanyl)-2-trimethylsilanyloxypent-4-enyl Ester (13). Mesityl-
enesulfonyl chloride (14.52 g, 66 mmol) was added to a solution
of diol 61 (13.1 g, 55.5 mmol), pyridine (8.8 g, 111 mmol), and
DMAP (677 mg, 0.55 mmol) in DCM (150 mL). The mixture was
stirred for 72 h at room temperature. Removal of the solvents under
reduced pressure and purification by flash column chromatography
(silica gel, 8% EtOAc in hexane) afforded the corresponding
sulfonate as a pale yellow oil (20.6 g, 89%). A solution of the
resulting sulfonate (1.67 g, 4 mmol) in THF (20 mL) was treated
with pyridine (1.26 g, 16 mmol) and TMSCl (1.29 g, 12 mmol).
The reaction mixture was stirred for 12 h before water (20 mL)
was added. The mixture was extracted with Et2O (3 × 20 mL),
and the combined organic layers were dried over MgSO4. Removal
of the solvents under reduced pressure and purification by flash
column chromatography (silica gel, 2% EtOAc in hexane) afforded
the silyl ether 13 as a pale yellow oil (1.8 g, 92%): 1H NMR (400
MHz, CDCl3) δ 7.41 (2H, m), 7.32-7.25 (3H, m), 6.93 (2H, s),
5.58 (1H, m), 4.88 (1H, dd, J ) 10, 1.6 Hz), 4.74 (1H, d, J ) 16.8
Hz), 3.97 (1H, m), 3.70 (1H, dd, J ) 4, 10 Hz), 3.62 (1H, dd, J )
6.4, 10 Hz), 2.54 (6H, s), 2.30 (3H, s), 1.97 (1H, dd, J ) 14.4, 5.2
Hz), 0.25 (6H, s), 0.00 (9H, s); 13C NMR (75 MHz, CDCl3) δ 143.1,
139.7, 137.7, 135.9, 134.0, 131.6, 130.4, 128.9, 127.5, 114.8, 72.6,
71.8, 40.0, 22.3, 20.7, 0.03, -3.1, -3.5; IR (neat) νmax 2956, 1604,
ν
max 2939, 1604, 1355 1097; [R]23D ) +20.5° (c ) 0.55, CH2Cl2);
CIHRMS [M + 1]+ calcd for C27H36O6S 488.2266, found 489.2333.
(2S,6S)-{6-[(2R)-(4-Benzyloxy-2-methoxybutyl)]-5,6-dihydro-
2H-pyran-2-yl}acetonitrile (65). A solution of sulfonate 64 (1.62
g, 3.3 mmol) in DMF (11 mL) was treated with NaCN (650 mg,
13.3 mmol). The mixture was stirred for 60 h at 60 °C before water
(50 mL) was added. The mixture was extracted with EtOAc (2 ×
50 mL). The combined organic layers were washed with brine (4
× 20 mL) and dried over MgSO4. Removal of the solvents under
reduced pressure and purification of the residue by flash column
chromatography (silica gel, 15-20% EtOAc in hexane) afforded
the pyran 65 as a pale yellow oil (0.9 g, 87%): 1H NMR (400
MHz, CDCl3) δ 7.34-7.26 (5H, m), 5.97 (1H, m), 5.62 (1H, m),
4.48 (2H, s), 4.35 (1H, m), 3.72 (1H, m), 3.59-3.48 (3H, m), 3.29
(3H, s), 2.51 (2H, m), 2.00 (2H, m), 1.85 (3H, m), 1.60 (1H, m);
13C NMR (75 MHz, CDCl3) δ 138.4, 128.2, 127.8, 127.5, 127.4,
126.4, 117.0, 74.7, 72.7, 70.8, 69.9, 66.6, 56.2, 39.1, 33.7, 30.5,
24.1; IR (neat) νmax 2926, 2862, 2250, 1454, 1093; [R]23D ) +23.4°
(c ) 0.44, CH2Cl2); CIHRMS [M + 1]+ calcd for C19H25NO3
316.1868, found 316.1924.
1358, 1251, 977; [R]23 ) -4.6° (c ) 0.65, CH2Cl2); CIHRMS
D
[M]+ calcd for C25H38O4SSi2 490.2029, found 490.2007.
(5S)-(3-Methoxyhex-5-enyloxymethyl)benzene (63). In a 1000
mL round-bottom flask, trimethyloxonium tetrafluoroborate (7.8
g) was added to a solution of alcohol44 (4 g, 19.4 mmol), molecular
sieves (13.6 g), and Proton Sponge (13.6 g) in DCM (400 mL).
The resulting mixture was stirred for 2 h before additional portions
of Proton Sponge (9 g) and trimethyloxonium tetrafluoroborate (5
g) were added. The suspension was stirred overnight before being
filtered through a pad of Celite. The yellow filtrate was washed
with an HCl solution (1 N), and the organic layer was dried over
MgSO4. Removal of the solvents under reduced pressure and
purification of the residue by flash chromatography (silica gel, 5%
EtOAc in hexane) afforded the methyl ether 63 (3.8 g, 89%): 1H
NMR (400 MHz, CDCl3) δ 7.35-7.24 (5H, m), 5.79 (1H, m), 5.06
(1H, m), 5.03 (1H, m), 4.48 (2H, abq, J ) 11.6 Hz), 3.54 (2H, m),
3.38 (1H, m), 3.32 (3H, s), 2.26 (2H, dd, J ) 6, 7.2 Hz), 1.77 (2H,
m); 13C NMR (67.5 MHz, CDCl3) δ 138.5, 134.6, 128.3, 127.6,
127.5, 117.1, 77.5, 73.0, 66.9, 56.8, 37.9, 33.9; IR (neat) νmax 2925,
(2S,4S,6S)-{6-[(2R)-(4-Benzyloxy-2-methoxybutyl)]-4-hydroxy-
tetrahydropyran-2-yl}acetonitrile (66). A solution of olefin 65
(650 mg, 2.06 mmol) in THF (16 mL) and water (12 mL) was
treated with mercury trifluoroacetate (4.38 g, 10.3 mmol). The
mixture was stirred for 18 h before NaOH solution (3 N, 13.6 mL)
and NaBH4 (392 mg in NaOH solution (3.7 mL, 3 N)) were added.
The mixture was stirred for 10 min and extracted with EtOAc (2
× 40 mL), and the combined organic layers were dried over MgSO4.
Removal of the solvents under reduced pressure and purification
of the residue by flash column chromatography (silica gel, 50-
60% EtOAc in hexane) afforded the pyran 66 as a pale yellow oil
(522 mg, 76%): 1H NMR (400 MHz, CDCl3) δ 7.33-7.25 (5H,
m), 4.48 (2H, abq, J ) 12.8 Hz), 4.27 (1H, m), 4.03 (1H, m), 3.95
(1H, m), 3.58-3.46 (3H, m), 3.29 (3H, s), 2.45 (2H, m), 1.87-
1.72 (3H, m), 1.64-1.55 (2H, m), 1.53-1.38 (3H, m); 13C NMR
(75 MHz, CDCl3) δ 138.4, 128.3, 127.7, 127.5, 117.3, 75.0, 72.8,
68.8, 67.0, 66.8, 63.6, 56.2, 39.3, 37.9, 37.1, 33.6, 24.3; IR (neat)
1604, 1094; [R]23 ) +28.1° (c ) 3.3, CH2Cl2); CIHRMS M+
D
calcd for C14H20O2 220.1463, found 220.1425.
(3R)-5-Benzyloxy-3-methoxypentanal (15). Ozone gas was
bubbled through a solution of 63 (3.5 g, 15.9 mmol) in DCM (317
mL) at -78 °C until the solution turned blue. PPh3 (12.5 g) was
then added. The mixture was slowly warmed to room temperature
and stirred overnight. Removal of the solvents under reduced
pressure and purification of the residue by flash column chroma-
tography (silica gel, 25% EtOAc in hexane) afforded the aldehyde
15 (3.88 g, ca. 100%): 1H NMR (400 MHz, CDCl3) δ 9.77 (1H,
t, J ) 3 Hz), 7.35-7.25 (5H, m), 4.47 (2H, s), 3.89 (1H, m), 3.55
(2H, m), 3.33 (3H, s), 2.59 (2H, m), 1.90 (1H, m), 1.79 (1H, m);
13C NMR (75 MHz, CDCl3) δ 201.4, 138.3, 128.4, 127.7, 73.7,
νmax 3438, 2922, 2251, 1074; [R]23 ) +16.7° (c ) 0.55, CH2-
D
Cl2); CIHRMS [M + 1]+ calcd for C19H27NO4 334.1974, found
334.1990.
(2S,4S,6S)-{6-[(2R)-(4-Benzyloxy-2-methoxybutyl)]-4-(tert-bu-
tyldiphenylsilanyloxy)tetrahydropyran-2-yl}acetonitrile (67). A
solution of alcohol 66 (630 mg, 1.89 mmol) in DMF (3.8 mL) was
treated with imidazole (386 mg, 5.67 mmol) and TBDPSCl (780
mg, 2.85 mmol). The resulting mixture was stirred for 72 h before
water (50 mL) was added. The mixture was then extracted with
EtOAc (2 × 40 mL), and the combined organic layers were washed
with brine (3 × 20 mL) and dried over MgSO4. Removal of the
solvents under reduced pressure and purification of the residue by
flash column chromatography (silica gel, DCM then 20% EtOAc
73.0, 66.2, 56.9, 48.1, 34.0; IR (neat) νmax 2930, 1723, 1095; [R]23
D
) +13.5° (c ) 0.93, CH2Cl2); CIHRMS M+ calcd for C13H18O3
223.1289, found 223.1314.
(44) For the physical data of the alcohol, see: Short, R. P.; Masamune,
S. J. Am. Chem. Soc. 1989, 111, 1892.
J. Org. Chem, Vol. 72, No. 1, 2007 21

Su et al.
in hexane) afforded the pyran 67 as a pale yellow oil (1.03 g,
95%): 1H NMR (400 MHz, CDCl3) δ 7.60 (4H, m), 7.44-7.25
(11H, m), 4.49 (2H, m), 4.22 (1H, m), 4.14 (2H, m), 3.55 (2H, m),
3.45 (1H, m), 3.27 (3H, s), 2.42 (2H, m), 1.82 (2H, m), 1.76 (1H,
m), 1.60 (2H, m), 1.44 (1H, m), 1.35 (1H, m), 1.23 (1H, m), 1.06
(9H, s); 13C NMR (75 MHz, CDCl3) δ 138.6, 135.7, 135.7, 133.8,
133.77, 129.9, 128.4, 127.8, 127.7, 127.69, 127.5, 117.3, 74.9, 72.9,
69.3, 67.5, 66.8, 65.5, 56.5, 39.7, 38.2, 37.8, 34.0, 26.8, 24.5, 19.1;
IR (neat) νmax 2929, 2251, 1107; [R]23D ) +0.65° (c ) 0.77, CH2-
Cl2); CIHRMS [M + 1]+ calcd for C35H45NO4Si 572.3151, found
572.3189.
(2S,5S,6R,3Z)-6-{3-(2R,4S,6S)[4-(tert-Butyldiphenylsilanyloxy)-
6-cyanomethyltetrahydropyran-2-yl]-(2S)-2-methoxypropyl}-5-
methyl-5,6-dihydro-2H-pyran-2-carboxylic Acid Isopropyl Ester
(70). A solution of aldehyde 69 (400 mg, 0.83 mmol) and
crotylsilane 14 (463 mg, 1.51 mmol) in DCM (16.7 mL) at -50
°C was treated with TMSOTf (240 mg, 1.08 mmol). The resulting
mixture was stirred for 12 h at this temperature before a saturated
aqueous solution of NaHCO3 (50 mL) was added. The mixture was
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were dried over MgSO4. Removal of the solvents under reduced
pressure yielded a crude mixture (dr ) 5:1 (trans:cis), determined
1
by H NMR analysis of the crude reaction mixture). Purification
(2S,4S,6R)-{4-(tert-Butyldiphenylsilanyloxy)-6-[(2R)-(4-hydroxy-
2-methoxybutyl)]tetrahydropyran-2-yl}acetonitrile (68). A solu-
tion of benzyl ether 67 (1130 mg, 1.97 mmol) in DCM (44 mL) at
-78 °C was treated with BCl3 (13.3 mL, 1.0 M in hexane). The
mixture was stirred for 20 h at this temperature before MeOH (10
mL) and a saturated aqueous NaHCO3 solution (100 mL) were
added. The mixture was stirred for 20 min and then extracted with
EtOAc (2 × 40 mL). The combined organic layers were washed
with brine (3 × 20 mL) and dried over MgSO4. Removal of the
solvents under reduced pressure and purification of the residue by
flash column chromatography (silica gel, 45% EtOAc in hexane)
afforded the pyran 68 as a pale yellow oil (957 mg, 90%): 1H
NMR (400 MHz, CDCl3) δ 7.60 (4H, m), 7.44-7.34 (6H, m), 4.23
(1H, m), 4.16 (1H, m), 4.07 (1H, m), 3.77 (2H, m), 3.59 (1H, m),
3.32 (3H, s), 2.59 (1H, br), 2.43 (2H, m), 1.86 (2H, m), 1.74 (1H,
m), 1.61 (1H, m), 1.50 (1H, m), 1.44 (1H, m), 1.35 (1H, m), 1.27
(1H, m), 1.06 (9H, s); 13C NMR (75 MHz, CDCl3) δ 135.7, 135.7,
133.8, 133.7, 130.0, 127.8, 127.8, 117.5, 77.8, 69.2, 67.7, 65.5,
60.9, 56.4, 38.8, 38.4, 37.8, 35.5, 26.9, 24.6, 19.1; IR (neat) νmax
of the residue by flash column chromatography (silica gel, 15-
20% EtOAc in hexane) afforded the trans-pyran 70 as a pale yellow
oil (385 mg, 73%, a single trans-diastereoisomer): 1H NMR (400
MHz, CDCl3) δ 7.62 (4H, m), 7.44-7.34 (6H, m), 5.82 (1H, m),
5.72 (1H, m), 5.06 (1H, hept, J ) 6.4 Hz), 4.63 (1H, m), 4.22 (1H,
m), 4.21-4.14 (2H, m), 3.75 (1H, m), 3.65 (1H, m, J ) 9.2 Hz),
3.4 (3H, s), 2.43 (2H, m), 2.03 (1H, m), 1.90-1.75 (3H, m), 1.66-
1.49 (3H, m), 1.36-1.29 (1H, m), 1.25 (3H, d, J ) 6 Hz), 1.22
(3H, d, J ) 6 Hz), 1.21 (1H, m), 1.06 (9H, s), 0.94 (3H, d, J ) 7.2
Hz); 13C NMR (67.5 MHz, CDCl3) δ 170.3, 135.6, 135.6, 133.8,
133.7, 133.4, 129.7, 129.7, 127.7, 127.6, 122.5, 117.3, 74.5, 74.1,
72.1, 69.4, 68.1, 67.5, 65.7, 56.7, 40.0, 39.5, 38.5, 37.9, 33.8, 26.9,
24.6, 21.8, 19.2, 17.2; IR (neat) νmax 2930, 2251, 1746, 1106; [R]23
D
) -24° (c ) 0.67, CH2Cl2); CIHRMS [M + 1]+ calcd for C37H51-
NO6Si 633.3486, found 633.3457.
(2S,6R)-6-{3-(2R,4S,6S)-[4-(tert-Butyldiphenylsilanyloxy)-6-
cyanomethyltetrahydropyran-2-yl]-2-(2S)-methoxypropyl}-5-
(5S)-methyltetrahydropyran-2-carboxylic Acid Isopropyl Ester
(71). A solution of olefin 70 (385 mg, 0.61 mmol) in EtOAc (23
mL) was treated with Pd/C (77 mg) and then placed under a H2
atmosphere and stirred for 18 h. The heterogeneous solution was
filtered through a pad of Celite. Removal of the solvents under
reduced pressure and purification of the residue by flash column
chromatography (silica gel, 20% EtOAc in hexane) afforded the
trans-pyran 71 as a pale yellow oil (342 mg, 89%): 1H NMR (400
MHz, CDCl3) δ 7.62 (4H, m), 7.44-7.34 (6H, m), 5.09 (1H, hept,
J ) 6.4 Hz), 4.36 (1H, m), 4.22 (1H, m), 4.21-4.12 (2H, m), 3.66-
3.59 (2H, m), 3.39 (3H, s), 2.43 (2H, m), 2.06 (1H, m), 1.87-1.72
(3H, m), 1.65-1.50 (5H, m), 1.44-1.15 (4H, m), 1.25 (3H, d, J )
6.8 Hz), 1.24 (3H, d, J ) 6 Hz), 1.06 (9H, s), 0.84 (3H, d, J ) 6.8
Hz); 13C NMR (67.5 MHz, CDCl3) δ 171.8, 135.6, 135.6, 133.8,
133.7, 129.7, 129.7, 127.7, 127.6, 117.2, 75.7, 74.5, 72.5, 69.4,
67.9, 67.5, 65.7, 56.9, 40.4, 39.6, 38.5, 37.8, 35.1, 28.7, 27.0, 26.9,
24.6, 21.9, 21.8, 19.2, 18.2; IR (neat) νmax 2929, 2251, 1738, 1106;
3439, 2930, 2252, 1105; [R]23 ) +6.91° (c ) 0.55, CH2Cl2);
D
CIHRMS [M + 1]+ calcd for C28H39NO4Si 482.2682, found
482.2696.
[4-(tert-Butyldiphenylsilanyloxy)-6-(2-methoxy-4-oxobutyl)-
tetrahydropyran-2-yl]acetonitrile (69). A solution of alcohol 68
(475 mg, 0.99 mmol) and molecular sieves (2.4 g) in DCM (37
mL) was treated with PCC (804 mg, 2.9 mmol). The mixture was
stirred for 2 h and then filtered through a short pad of silica to
afford the pyran 69 as a pale yellow oil (402 mg, 85%): 1H NMR
(400 MHz, CDCl3) δ 9.80 (1H, dd, J ) 2.0, 2.4 Hz), 7.60 (4H, m),
7.44-7.34 (6H, m), 4.23 (1H, m), 4.16 (1H, m), 4.11 (1H, m),
3.88 (1H, m), 3.31 (3H, s), 2.67 (1H, d, J ) 2 Hz), 2.66 (1H, d, J
) 2.4 Hz), 2.43 (2H, m), 1.83 (1H, m), 1.60 (1H, m), 1.53 (1H,
m), 1.49 (1H, m), 1.38-1.22 (2H, m), 1.07 (9H, s); 13C NMR (67.5
MHz, CDCl3) δ 201.4, 135.5, 133.6, 135.5, 129.7, 129.6, 117.2,
73.0, 68.6, 67.5, 65.4, 56.4, 47.8, 39.0, 38.2, 37.7, 26.9, 24.5, 19.1;
IR (neat) νmax 2930, 2251, 1724, 1427, 1105; [R]23 ) -1.05° (c
[R]23 ) +14.4° (c ) 0.52, CH2Cl2); CIHRMS [M + 1]+ calcd
D
D
) 0.47, CH2Cl2); CIHRMS [M + 1]+ calcd for C28H37NO4Si
for C37H53NO6Si 636.3676, found 636.3668.
480.2525, found 480.2587.
(2S,4S,6R)-{4-(tert-Butyldiphenylsilanyloxy)-(2S)-6-[(2R,3S,
6S)-3-(6-formyl-3-methyltetrahydropyran-2-yl)-2-methoxypro-
pyl]tetrahydropyran-2-yl}acetonitrile (72). A solution of ester
70 (110 mg, 0.17 mmol) in Et2O (4.3 mL) at -78 °C was treated
with DIBAL-H (0.363 mL, 1.0 M in hexane). The mixture was
stirred for 1 h before MeOH (1 mL) was added at -78 °C followed
by the addition of a saturated aqueous solution of Rochelle’s salts
(10 mL). The mixture was stirred for 1.5 h and slowly warmed to
room temperature. The reaction mixture was acidified (5% aqueous
HCl, 3 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine (20 mL) and dried over
MgSO4. Removal of the solvents under reduced pressure and
purification of the residue by flash column chromatography (silica
gel, 40% EtOAc in hexane) afforded the aldehyde 72 as a pale
yellow oil (92 mg, 93%): 1H NMR (400 MHz, CDCl3) δ 9.85
(1H, d, J ) 2 Hz), 7.62 (4H, m), 7.44-7.33 (6H, m), 4.23 (1H,
m), 4.21-4.08 (3H, m), 3.71 (1H, m), 3.41 (1H, m), 3.35 (3H, s),
2.44 (2H, m), 2.09 (1H, m), 1.87-1.69 (3H, m), 1.66-1.45 (5H,
m), 1.42-1.22 (4H, m), 1.07 (9H, s), 0.82 (3H, d, J ) 6.8 Hz);
13C NMR (67.5 MHz, CDCl3) δ 205.8, 135.6, 133.7, 133.7, 129.8,
129.7, 127.7, 127.6, 117.2, 78.8, 77.1, 73.9, 69.2, 67.5, 65.7, 56.7,
39.8, 38.7, 38.6, 37.8, 34.7, 28.9, 26.9, 24.6, 23.9, 19.2, 17.9; IR
(2R,3S,4E)-3-(Dimethylphenylsilanyl)-2-hydroxyhex-4-enoic
Acid Isopropyl Ester (14). A solution of the methyl ester45 (582
mg, 2.09 mmol) in iPrOH (15 mL) was treated with Otera’s catalyst
(119 mg).46 The mixture was refluxed for 120 h in a sealed tube
(ca. 110 °C). The resulting mixture was concentrated and purified
by silica column chromatography (2% EtOAc in hexane) to afford
the crotylsilane as a pale yellow oil (530 mg, 83%): 1H NMR (400
MHz, CDCl3) δ 7.56 (2H, m), 7.34 (3H, m), 5.38 (1H, m), 5.25
(1H, m), 4.99 (1H, hept, J ) 6.4 Hz), 4.14 (1H, m), 2.84 (1H, br
d, J ) 4.8 Hz), 2.06 (1H, dd, J ) 2.8, 10.4 Hz), 1.59 (3H, dd, J )
2, 6.8 Hz), 1.19 (3H, d, J ) 6.4 Hz), 1.15 (3H, d, J ) 6.4 Hz),
0.37 (3H, s), 0.31 (3H, s); 13C NMR (67.5 MHz, CDCl3) δ 174.8,
137.7, 134.2, 128.9, 127.6, 126.8, 124.9, 71.3, 69.2, 38.2, 21.9,
21.8, 18.1, -3.8, -4.0; IR (neat) νmax 3513, 2980, 1723, 1247,
1106; [R]23 ) +35.1° (c ) 0.49, CH2Cl2); CIHRMS [M + 1]+
D
calcd for C17H26O3Si 307.1685, found 307.1719.
(45) Panek, J. S.; Yang, M.; Solomon, J. S. J. Org. Chem. 1993, 58,
1003.
(46) For preparation of Otera’s catalyst, see: Otera, J.; Dan-oh, N.;
Nozaki, H. J. Org. Chem. 1991, 56, 5307.
22 J. Org. Chem., Vol. 72, No. 1, 2007

[4 + 2]-Annulations of Chiral Organosilanes
(neat) νmax 2929, 2251 1732, 1105; [R]23 ) +35.3° (c ) 0.30,
3456, 2928, 1427, 1105; [R]23 ) +16.5° (c ) 0.32, CH2Cl2);
D
D
CIHRMS [M]+ calcd for C41H61NO5Si 675.4319, found 675.4334.
CH2Cl2); CIHRMS [M + 1]+ calcd for C34H47NO5Si 578.3257,
found 578.3353.
(1R,3S,5R,7R,9R,12R,14S,17S,18S)-7-(tert-Butyldiphenylsila-
nyloxy)-3-methoxy-18-methyl-13-(1E)-(4-methylpent-1-enyl)-
12,19,20-trioxatricyclo[13.3.1.15,9]icosan-11-one (75). A solution
of nitrile 73 (55 mg, 0.0815 mmol) in DCM (2.0 mL) at -78 °C
was slowly treated with DIBAL-H (0.212 mL, 1.0 M in hexane).
The mixture was stirred for 2 h at this temperature before HCl
(1.0 N, 3 mL) was added at -78 °C, and the resulting mixture was
stirred for 20 min and slowly warmed to room temperature. The
reaction mixture was extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine (20 mL) and dried
over MgSO4. Removal of the solvents under reduced pressure and
purification of the residue by flash column chromatography (silica
gel, EtOAc) afforded the crude aldehyde. The mixture was kept at
room temperature for 18 h. Purification by flash column chroma-
tography (silica gel, 20% EtOAc in hexane) afforded the lactol as
a thick oil (29 mg, 55%), and the polar residue was kept at room
temperature for another 5 days before another portion of lactol 74
(5 mg, 9%) was isolated. A solution of lactol 74 (25 mg) and
molecular sieves (300 mg) in DCM (3 mL) was treated with PCC
(50 mg), and the mixture was stirred at room temperature for 22 h.
Purification by flash column chromatography (silica gel, 20%
EtOAc in hexane) afforded the lactone 75 as a thick oil (22 mg,
87%): 1H NMR (400 MHz, CDCl3) δ 7.62 (4H, m), 7.44-7.33
(6H, m), 5.70 (1H, m), 5.41-5.28 (2H, m), 4.28-4.25 (2H, m),
3.93-3.87 (2H, m), 3.64 (1H, m, J ) 10.8 Hz), 3.51 (1H, m, J )
10.8 Hz), 3.32 (3H, s), 2.50-2.42 (2H, m), 2.23 (1H, m, J ) 12.4
Hz), 1.94-1.00 (17H, m), 1.16 (3H, d, J ) 7.2 Hz), 1.09 (9H, s),
0.83 (6H, d, J ) 6.4 Hz); 13C NMR (75 MHz, CDCl3) δ 170.0,
135.7, 135.7, 134.1, 134.1, 132.2, 130.2, 129.9, 129.9, 127.8, 73.6,
73.5, 70.7, 69.5, 69.4, 66.2, 63.2, 57.2, 43.2, 43.0, 41.6, 38.9, 38.6,
38.5, 35.5, 30.8, 29.6, 28.0, 27.1, 26.9, 24.0, 22.2, 19.3, 18.2; IR
(2S,4S,6R)-(4-(tert-Butyldiphenylsilanyloxy)-(2S)-6-{2-meth-
oxy-(2R,3S,6S)-3-[3-methyl-6-(2-oxoethyl)tetrahydropyran-2-yl]-
propyl}tetrahydropyran-2-yl)acetonitrile (12). Preparation of
Wittig reagent (0.25 M in THF): A suspension of (methoxymethyl)-
triphenylphosphonium chloride (800 mg) in THF (6.32 mL) at -78
°C was treated with LiHMDS (2.12 mL, 1.0 M in THF). The
reaction mixture was then warmed to room temperature. A deep
red solution formed. A solution of aldehyde 72 (92 mg, 0.16 mmol)
in THF (2 mL) at -78 °C was treated with the solution (1.5 mL)
prepared above. The mixture was stirred for 4.5 h and slowly
warmed to room temperature before water (10 mL) was added. The
reaction mixture was extracted with EtOAc (3 × 10 mL), and the
combined organic layers were washed with brine (20 mL) and dried
over MgSO4. Removal of the solvents afforded the enol ether as a
dark brown oil. A solution of the crude enol ether in THF (4.8
mL) and water (2.4 mL) was treated with mercury acetate (432
mg). The reaction mixture was stirred for 15 min before KI solution
(8% in water, 25 mL) was added. The resulting mixture was stirred
for another 20 min and was extracted with DCM (3 × 10 mL).
The combined organic layers were dried over MgSO4. Removal of
the solvents under reduced pressure and purification of the residue
by flash column chromatography (silica gel, 30-50% EtOAc in
hexane) afforded the aldehyde 12 as a pale yellow oil (82 mg,
87%): 1H NMR (400 MHz, CDCl3) δ 9.79 (1H, m), 7.62 (4H, m),
7.44-7.33 (6H, m), 4.38 (1H, m), 4.22 (1H, m), 4.18 (1H, m),
4.09 (1H, m), 3.55 (1H, m), 3.45 (1H, m), 3.26 (3H, s), 2.85 (1H,
ddd, J ) 2.4, 8.4, 16 Hz), 2.44 (2H, m), 2.42 (1H, ddd, ovrlp, J )
1.2, 4.8 Hz), 1.75-1.23 (13H, m), 1.06 (9H, s), 0.97 (3H, d, J )
6.8 Hz); 13C NMR (67.5 MHz, CDCl3) δ 201.6, 135.6, 133.7, 129.8,
127.7, 127.6, 117.3, 74.1, 73.2, 69.2, 67.5, 66.5, 65.7, 56.6, 46.7,
39.7, 38.6, 38.0, 37.9, 33.5, 27.6, 26.9, 26.2, 24.6, 19.2, 18.2; IR
(neat) νmax 2928, 1741, 1111; [R]23 ) +41.3° (c ) 0.375, CH2-
D
Cl2); CIHRMS [M + 1]+ calcd for C41H60O6Si 677.4193, found
(neat) νmax 2929, 2251 1725, 1105; [R]23 ) +20.4° (c ) 0.30,
D
677.4428.
CH2Cl2); CIHRMS [M + 1]+ calcd for C34H47NO5Si 591.3380,
((R,E)-1-((2S,5S,6R)-6-((S)-3-(2R,4S,6S)-6-(2-aminoethyl)-4-
(tert-butyldiphenylsilyloxy)tetrahydro-2H-pyran-2-yl)-2-meth-
oxypropyl)-5-methyltetrahydro-2H-pyran-2-yl)-6-methylhept-
3-en-2-ol (77): 1H NMR (400 MHz, CDCl3) δ 7.92 (2H, br), 7.61-
7.58 (4H, m), 7.43-7.33 (6H, m), 5.61 (1H, m), 5.48 (1H, dd, J )
6, 11.2 Hz), 4.24 (1H, m), 4.12 (2H, m), 4.00 (2H, m), 3.52 (1H,
m), 3.37 (1H, m), 3.32 (3H, s), 3.28 (1H, m, ovlp), 3.1 (1H, m),
2.11 (1H, m), 1.87 (5H, m), 1.73-1.23 (8H, m), 1.12 (1H, m),
1.06 (14H, s), 0.88 (3H, d, J ) 6 Hz), 0.84 (3H, d, J ) 6.8 Hz),
0.83 (3H, d, J ) 6.4 Hz); 13C NMR (75 MHz, CDCl3) δ 135.6,
134.1, 134.0, 133.8, 129.8, 129.7, 127.7, 127.7, 74.3, 73.2, 71.4,
69.7, 68.3, 68.1, 65.5, 56.2, 41.6, 39.3, 39.0, 38.7, 38.3, 37.5, 35.4,
32.2, 28.8, 28.2, 27.4, 27.0, 22.4, 22.3, 19.3, 18.2; IR (neat) νmax
found 591.3379.
(2S,4S,6R)-(4-(tert-Butyldiphenylsilanyloxy)-(2S)-6-{(2R,3S,
6S)-3-[6-(2S,3E)-(2-hydroxy-6-methylhept-3-enyl)-3-methyltet-
rahydropyran-2-yl]-2-methoxypropyl}tetrahydropyran-2-yl)-
acetonitrile (73). A suspension of bis(cyclopentadienyl)zirconium
chloride hydride (250 mg, 0.97 mmol) in DCM (4.4 mL) at room
temperature was treated with 4-methyl-1-pentyne (114.3 µL, 0.97
mmol). The mixture was stirred for 15 min until a clear yellow
solution was formed. The resulting solution was cooled to -60 °C
and was treated with ZnMe2 (0.486 mL, 2.0 M in toluene). The
reaction mixture was stirred for 20 min at this temperature and
was warmed to 0 °C and stirred for another 5 min. A solution of
aldehyde 12 (115 mg, 0.19 mmol) in DCM (5 mL) was cooled to
0 °C before being transferred to the vinyl zinc solution prepared
as described above. The mixture was stirred at 0 °C for 3.5 h before
a saturated aqueous solution of NH4Cl (10 mL) was added. The
reaction mixture was extracted with DCM (3 × 10 mL). The
combined organic layers were washed by brine (20 mL) and dried
over MgSO4. Removal of solvent and filtration through a short pad
of silica (80% EtOAc in hexane) afforded the alcohol as a mixture
of diastereomers (105 mg, 80%, dr ) 2:1). The resulting mixture
was subjected to a careful purification by flash column chroma-
tography (10/12.5/15% EtOAc in DCM) to afford desired alcohol
73 (72 mg, 55% as a single diastereomer) as a clear thick oil: 1H
NMR (400 MHz, CDCl3) δ 7.62-7.59 (4H, m), 7.44-7.33 (6H,
m), 5.64 (1H, m), 5.48 (1H, dd, J ) 6, 11.2 Hz), 4.33 (1H, m),
4.22 (1H, m), 4.18 (1H, m), 4.06 (2H, m), 3.60 (2H, m), 3.31 (3H,
s), 2.42 (2H, m), 2.09 (1H, m), 1.97-1.22 (18H, m), 1.06 (9H, s),
0.97 (3H, d, J ) 6.4 Hz), 0.86 (3H, d, J ) 6.8 Hz), 0.85 (3H, d,
J ) 6.4 Hz); 13C NMR (75 MHz, CDCl3) δ 135.7, 135.7, 134.3,
133.9, 133.8, 129.9, 129.4, 127.8, 127.8, 117.4, 74.4, 72.9, 69.2,
68.7, 67.6, 67.4, 65.7, 56.5, 41.6, 40.0, 39.4, 38.6, 37.9, 37.6, 33.5,
28.2, 27.8, 26.9, 26.3, 24.6, 22.2, 22.2, 19.1, 18.4; IR (neat) νmax
3396, 2929, 1462, 1111; [R]23 ) +22.8° (c ) 1.0, CH2Cl2);
D
CIHRMS [M + 1]+ calcd for C41H65NO5Si 680.4666, found
680.4660.
Trifluoromethanesulfonic Acid 4-[3-(tert-butyldiphenylsila-
nyloxy)propyl]oxazol-2-yl Ester (16). A 100 mL round-bottom
flask was charged with oxazolone 82 (0.250 g/0.655 mmol) and a
stir bar. CH2Cl2 (3.5 mL) was added, and the reaction was cooled
to -78 °C. 2,6-Lutidine (0.140 g/1.31 mmol) was then added via
syringe followed by the addition of Tf2O (0.277 g/0.983 mmol).
The reaction was then allowed to warm to room temperature with
stirring for 30 min before being diluted with water (50 mL) and
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were washed with brine, dried with MgSO4, filtered, and concen-
trated in vacuo. The residue was purified on SiO2 (10% Et2O/
pentane) to give 0.280 g of 16 (80%) as a colorless oil. Triflate 16
is chemically unstable and used immediately after preparation: 1H
NMR (400 MHz, CDCl3) δ 7.64-7.60 (m, 4H), 7.41-7.34 (m,
6H), 7.12 (s, 1H), 3.67 (t, 2H, J ) 6.0 Hz), 2.61 (t, 2H, J ) 7.6
Hz), 1.85 (tt, 2H, J ) 6.0, 7.6 Hz), 1.03 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 149.5, 142.1, 135.5, 133.9, 133.7, 129.8, 129.6,
127.7, 127.6, 118.5 (q, CF3, J ) 319.7 Hz), 62.54; IR (neat) νmax
J. Org. Chem, Vol. 72, No. 1, 2007 23

Su et al.
2932, 2361, 1735, 1426, 1248, 1030, 702; HRMS (CI, CH4) m/z
calcd for C23H26NO5SSi [M]+ 513.1253, found 513.1282.
1.13 (3H, d, J ) 7.2 Hz), 1.03 (1H, m), 0.84 (3H, s), 0.82 (3H, s);
13C NMR (75 MHz, CDCl3) δ 205.8, 168.7, 132.9, 129.9, 74.4,
73.5, 73.4, 71.2, 63.1, 57.3, 47.8, 47.3, 43.3, 42.7, 41.5, 39.5, 35.5,
30.8, 28.0, 27.0, 24.0, 22.1, 18.1; [R]23D ) +54° (c ) 0.05, EtOH);
IR (neat) νmax 2927, 1740, 1464, 1385, 1270, 1155; CIHRMS [M
+ 1]+ calcd for C25H40O6 437.2858, found 437.2863.
(3-{4-[3-(tert-Butyldiphenylsilanyloxy)propyl]oxazol-2-yl}-
prop-2-ynyl)carbamic Acid Methyl Ester (86). A 50 mL round-
bottom flask was charged with freshly prepared triflate 16 (0.130
g/0.253 mmol) and a stir bar. 1,4-Dioxane (1.2 mL) and 2,6-lutidine
(0.136 g/1.23 mmol) were added with stirring. Alkyne 17 (0.045
g/0.405 mmol), Pd(PPh3)4 (30 mg/0.025 mmol), and CuI (3 mg/
0.013 mmol) were added, and the reaction was stirred at room
temperature for 4-5 h. The reaction was then diluted with EtOAc
(∼10 mL) and filtered through a thin pad of SiO2 and concentrated
in vacuo. The residue was purified on SiO2 (30% EtOAc/hexanes)
to give 0.101 g of 86 (84%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 7.64-7.62 (m, 4H), 7.41-7.32 (m, 6H), 7.21 (s, 1H),
4.90 (br s, 1H), 4.22-4.19 (m, 2H), 3.69 (br s, 3H), 3.66 (t, 2H, J
) 6.4 Hz), 2.61 (t, 2H, J ) 7.6 Hz), 1.87 (tt, 2H, J ) 6.4, 7.6 Hz),
1.03 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 156.5, 145.5, 141.7,
135.5, 135.1, 133.7, 129.5, 127.6, 87.9, 71.3, 62.7, 52.5, 31.2, 30.8,
26.8, 22.4, 19.1; IR (neat) νmax 3542, 3072, 2956, 2931, 2859, 2252,
1724, 1515, 1253, 1110, 734; HRMS (CI, CH4) m/z calcd for
C28H33N2O4Si [M + H]+ 477.2209, found 477.2208.
(1R,3S,5R,7S,9R,12R,14S,17S,18S)-7-Hydroxy-3-methoxy-18-
methyl-13-(1E)-(4-methylpent-1-enyl)-12,19,20-trioxatricyclo-
[13.3.1.15,9]icosan-11-one (91). A solution of ketone 90 prepared
as described above (15 mg, 0.034 mmol) in MeOH (0.7 mL) at 0
°C was treated with NaBH4 (2.6 mg, 0.068 mmol). The mixture
was stirred for 0.5 h before adding AcOH (19 µL). The resulting
mixture was concentrated, and the residue was purified by flash
column chromatography (silica gel, 80% EtOAc in hexanes) to
afford the alcohol 91 as a thick oil (14 mg, 93% as a 15:1 mixture
of diastereomers): 1H NMR (400 MHz, CDCl3) δ 5.68 (1H, m),
5.33 (2H, m), 3.86 (2H, m), 3.68 (1H, m), 3.49 (2H, m), 3.33 (3H,
s), 3.19 (1H, t, J ) 11.2 Hz), 2.54 (1H, dd, J ) 3.6, 13.2 Hz), 2.35
(2H, m), 2.00 (2H, m), 1.86 (4H, m), 1.69-1.39 (6H, m), 1.31-
1.18 (4H, m), 1.14 (3H, d, J ) 5.4 Hz), 0.98 (1H, m), 0.82 (3H, d,
J ) 6.4 Hz), 0.82 (3H, d, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3)
δ 169.5, 132.4, 130.1, 73.6, 73.5, 73.0, 72.2, 70.8, 67.9, 63.0, 57.2,
43.0, 42.8, 41.5, 41.0, 40.7, 39.1, 35.4, 30.9, 28.0, 27.0, 24.0, 22.1,
18.1; [R]23D ) +55° (c ) 0.05, EtOH); IR (neat) νmax 3435, 2927,
1739, 1652, 1464, 1385, 1274, 1110; CIHRMS [M + 1]+ calcd
for C25H42O6 439.3015, found 439.3013.
Leucascandrolide A (1). A solution of alcohol 91 (15 mg, 0.034
mmol), acid 4 (34.4 mg, 0.122 mmol), and triphenyl phosphine
(35.53 mg, 0.135 mmol) in benzene (1.87 mL) and THF (0.5 mL)
at 0 °C was treated with DIAD (26.67 µL). The mixture was stirred
for 14 h and warmed to room temperature. The reaction mixture
was concentrated, and the residue was purified by flash column
chromatography (silica gel, 20-40% EtOAc in DCM) to afford
the leucascandrolide A (1) as thick glass (18.5 mg, 77%). The
chromatographic and spectroscopic data of synthetic 1 are fully
consistent with those of an authentic sample:47 1H NMR (400 MHz,
CDCl3) δ 7.37 (1H, s), 6.31 (1H, m), 6.26 (1H, m), 6.07 (1H, m),
5.87 (1H, d, J ) 11.6 Hz), 5.68 (1H, m), 5.52 (1H, br), 5.32 (2H,
m), 5.23 (1H, t, J ) 2.8 Hz), 4.29 (2H, t, J ) 5.6 Hz), 3.99 (1H,
m), 3.87 (1H, m), 3.66 (3H, s), 3.53 (3H, m), 3.32 (3H, s), 3.02
(2H, m), 2.70 (2H, t, J ) 7.2 Hz), 2.51 (1H, dd, J ) 4, 13.2 Hz),
2.32 (2H, m), 1.95-1.80 (5H, m), 1.72-1.17 (11H, m), 1.14 (3H,
d, J ) 7.2 Hz), 0.97 (1H, m), 0.82 (6H, d, J ) 6.4 Hz); 13C NMR
(75 MHz, CDCl3) δ 169.5, 165.4, 160.1, 157.2, 149.4, 141.1, 136.4,
134.0, 132.5, 131.1, 120.7, 116.6, 73.6, 73.3, 70.8, 70.0, 69.6, 67.3,
63.0, 57.2, 52.1, 43.2, 42.7, 41.5, 39.3, 99.1, 35.5, 35.4, 30.9, 28.0,
27.5, 27.0, 25.6, 24.2, 22.1, 18.1; [R]23D ) +41° (c ) 0.065, EtOH);
IR (neat) νmax 2953, 1717, 1276; CIHRMS [M + 1]+ calcd for
C38H56N2O10 700.3935, found 700.3912.
(1R,3S,5R,7R,9R,12R,14S,17S,18S)-7-Hydroxy-3-methoxy-18-
methyl-13-(1E)-(4-methylpent-1-enyl)-12,19,20-trioxatricyclo-
[13.3.1.15,9]icosan-11-one (3). A solution of silyl ether 75 (35 mg,
0.052 mmol) in THF (3.5 mL) at -20 °C was treated with TBAF
(0.26 mL, 1.0 M in THF). The mixture was warmed to room
temperature and stirred for 2 h. The same operation was repeated
3 times. The reaction mixture was diluted with a saturated aqueous
solution of NH4Cl (10 mL) and was extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (20
mL) and dried over MgSO4. Removal of the solvents under reduced
pressure and purification of the residue by flash column chroma-
tography (silica gel, 80% EtOAc in hexane) afforded the alcohol 3
as a thick oil (22.5 mg, ca. 100%): 1H NMR (400 MHz, C5D5N)
δ 5.85-5.76 (2H, m), 5.58 (2H, dd, J ) 6.4, 15.2 Hz), 4.68 (2H,
m), 4.46 (1H, m), 4.22 (1H, m, J ) 11.2 Hz), 4.09 (1H, m, J )
11.2 Hz), 3.96 (1H, m), 3.78 (1H, m), 3.41 (3H, s), 2.73 (1H, dd,
J ) 13.2, 4 Hz), 2.57-2.49 (2H, m), 2.15 (1H, dd, J ) 12.8, 10.4
Hz), 1.97-1.85 (5H, m), 1.77 (1H, m), 1.69 (2H, m), 1.55 (2H,
m), 1.43-1.20 (2H, m), 1.14-1.04 (2H, m), 1.10 (3H, d, J ) 6.4
Hz), 0.82 (3H, d, J ) 6.8 Hz), 0.81 (3H, d, J ) 6.4 Hz); 13C NMR
(75 MHz, C5D5N) δ 170.8, 132.4, 131.9, 74.3, 74.2, 71.3, 70.2,
70.0, 64.1, 63.5, 57.0, 44.2, 43.7, 42.0, 40.2, 39.9, 39.8, 36.1, 31.7,
28.6, 27.6, 24.5, 22.6, 22.5, 18.7; IR (neat) νmax 3435, 2927, 1739,
1652, 1464, 1385, 1274, 1110; [R]23 ) +27° (c ) 0.1, EtOH);
D
CIHRMS [M + 1]+ calcd for C25H42O6 439.3015, found 439.3087.
(1R,3S,5R,9R,12R,14S,17S,18S)-3-Methoxy-18-methyl-13-(1E)-
(4-methylpent-1-enyl)-12,19,20-trioxatricyclo[13.3.1.15,9]icosan-
7,11-dione (90). A solution of alcohol 3 (19 mg, 0.043 mmol) in
DCM (1.2 mL) was treated with DMP (55.2 mg, 0.13 mmol) and
pyridine (10.5 µL). The mixture was stirred for 2 h before diluting
with saturated aqueous solutions of NaHCO3 and NaS2O3 (10 mL).
The resulting mixture was extracted with EtOAc (3 × 10 mL).
The combined organic layers were washed with brine (20 mL) and
dried over MgSO4. Removal of the solvents under reduced pressure
and purification of the residue by flash column chromatography
(silica gel, 20% EtOAc in DCM) afforded the ketone 90 as a thick
oil (18 mg, 95%): 1H NMR (400 MHz, CDCl3) δ 5.70 (1H, m),
5.33 (2H, m), 4.00 (1H, m), 3.87 (1H, m), 3.48 (3H, m), 3.35 (3H,
s), 2.62 (1H, dd, J ) 3.6, 13.2 Hz), 2.44 (2H, m), 2.36-2.22 (4H,
m), 2.08 (1H, m), 1.86 (3H, m), 1.73-1.22 (6H, m), 1.28 (2H, m),
Acknowledgment. Financial support was obtained from the
NIH GM55740. J.S.P. is grateful to Amgen, Johnson & Johnson,
Merck Co., Novartis, Pfizer, and GSK for financial support.
Supporting Information Available: General experimental pro-
cedures, including spectroscopic and analytical data. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO0610412
(47) (a) D’Ambrosio, M.; Guerriero, M.; Debitus, C.; Pietra, F. HelV.
Chim. Acta 1996, 79, 51.
24 J. Org. Chem., Vol. 72, No. 1, 2007