Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin

Article abstract of DOI:10.1016/j.tet.2006.05.019

The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.

Full text of DOI:10.1016/j.tet.2006.05.019

Tetrahedron 62 (2006) 11437–11449
Domino intramolecular enyne metathesis/cross metathesis
approach to the xanthanolides. Enantioselective synthesis
of (D)-8-epi-xanthatin
*
David A. Kummer, Jehrod B. Brenneman and Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300,
Austin, TX 78712-0165, USA
Received 14 April 2006; accepted 9 May 2006
Available online 2 June 2006
Abstract—The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24,
which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in
four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a
deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process
to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed
metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.
Ó 2006 Published by Elsevier Ltd.
O
O
O
O
OAc
1. Introduction
10
8
O
O
The xanthanolide sesquiterpene lactones are isolated pri-
marily from the genus Xanthium (family Compositae). The
phytochemical composition of this genus is quite homo-
geneous, and xanthanolides are isolated from every species.1
The xanthanolides can be divided into two structural classes
depending upon the stereochemistry at C(8), although both
are characterized by a five-membered g-butyrolactone that is
fused to a seven-membered carbocycle. The xanthumin class
is exemplified by (+)-8-epi-xanthatin (1) and xanthumin
(2), which comprise a cis-fused g-butyrolactone, whereas
(ꢀ)-dihydroxanthatin (3) and 8-epi-tomentosin (4) are rep-
resentative of the xanthinin class and incorporate a trans-
fused lactone. 8-epi-Xanthatin has not only been isolated
from various species in the genus Xanthium,1c,2 but it has
also been obtained by elimination of acetic acid from 2.3
7
O
O
O
O
1
2
H
O
H
O
H
H
4
3
falciparum strain K1 with IC50 values of 125 and 31 mg/mL,
respectively.4 More recently, 1 has been shown to inhibit the
in vitro proliferation of several cultured human tumor cell
lines, including A-549 (lung adenocarcinoma), SK-OV-3
(ovarian adenocarcinoma), SK-MEL-2 (malignant mela-
noma), XF-498 (central nervous system carcinoma), and
HCT-15 (colon adenocarcinoma) with ED50 values ranging
between 0.2 and 1.5 mg/mL (IC50 values ranging between
0.8 and 6.1 mM).5 Because 4 was found to be inactive toward
these tumor cell lines, it is apparent that the a-methylene-
g-butyrolactone and the conjugated enone functionalities
contribute to cytotoxicity.5a,6 In conjunction with these
tumor inhibition studies, 1 was found to inhibit the in vitro
farnesylation of human lamin-B by farnesyltransferase in
a dose-dependent manner (IC50¼64 mM).5b
The structures of numerous xanthanolides are well docu-
mented, and many, including 1, exhibit interesting biological
profiles. For example, xanthanolides 1 and 2 have been
shown to halt the larval growth of Drosophila melanogaster
(fruit fly) at doses as small as 1.3 mg of 1 or 2 in 2 g of
growth medium.2b Compounds 1 and 2 also display antima-
larial activity against the chloroquine resistant Plasmodium
Keywords: Cross metathesis; Ring-closing metathesis; Enantioselective;
Domino reactions.
* Corresponding author. Tel.: +1 512 471 3915; fax: +1 512 471 4180;
e-mail: sfmartin@mail.utexas.edu
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.05.019

11438
D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
O
Despite their promising biological activities and interesting
structures, there have been few accounts of synthetic efforts
directed toward the xanthanolide core.7 In the first reported
total synthesis of a xanthanolide, Morken utilized a stereo-
selective Oshima–Utimoto reaction8 and sequential ruthe-
nium-catalyzed metathesis reactions to synthesize 3.9 Our
contemporaneous interest in 8-epi-xanthatin arose as a result
of our ongoing efforts to expand the scope of ruthenium-
catalyzed ring-closing metathesis (RCM) reactions in the
context of natural product total synthesis. We have recently
applied RCM cyclizations to the syntheses of a number of
complex targets including dihydrocorynantheol10 as well
as the anticancer alkaloids manzamine A,11 FR900482,12
and (ꢀ)-peduncularine13 together with the potent nicotinic
acetylcholine receptor (+)-anatoxin-a.14 In the context of
these studies, we envisioned that an attractive strategy for
constructing the xanthanolide core and the (E)-conjugated
dienone present in many of the members of this class of
natural products might feature a domino enyne RCM/cross
metathesis (CM) process. Despite the extensive use of enyne
RCM reactions in organic synthesis,15 there are few applica-
tions of this reaction coupled with a subsequent CM in
a domino sequence.16 Coupled with the biological activity
profiles of the xanthanolides and a lack of synthetic ap-
proaches for their construction, we undertook the total
synthesis of (+)-8-epi-xanthatin (1), the details of which
we report in this account.17
10
Lactonization
8
O
Domino
7
O
enyne RCM/CM
1
Pd-catalyzed
carbonylation
10
8
OTBS
O
Aldol reaction
7
Xc
5
Xc = chiral auxiliary
Asymmetric
O
O
conjugate addition
O
N
O
+
10
H
Bn
TMS
7
6
O
O
N
O
R
8
Scheme 1.
2. Results and discussion
diastereoselectivity of the pivotal conjugate addition. The
known acyl oxazolidinone 8b25 and the new acyl oxazolidi-
none 8c were therefore prepared (Scheme 3). The synthesis
of 8c commenced with the treatment of L-serine methyl ester
hydrochloride (10) with phosgene to afford a known inter-
mediate oxazolidinone,26 which was allowed to react with
excess 2-naphthyllithium to provide tertiary alcohol 11.
Alcohol 11 was deoxygenated according to the method of
Gribble to afford 12,27 which was acylated with (E)-crotonyl
chloride to provide 8c. The conjugate addition reactions
employing 8b and 8c provided the adducts 9b and 9c with
roughly a twofold enhancement in the diastereomeric ratio
obtained with 8a (Scheme 2). Although the yield of 9b
was comparable to that of 9a, the yield of 9c was somewhat
lower.
2.1. First generation approach
In our first approach to 1, we targeted enyne 5 as a versatile
gateway because it contains the requisite absolute stereo-
chemistry at C(7)–C(8) and C(10) as well as the appropriate
functional handles for completing the synthesis (Scheme 1).
This advanced intermediate would allow for the construction
of the seven-membered cycloheptene ring and (E)-conju-
gated dienone moieties via a domino enyne RCM/CM
sequence prior to installing the reactive a-methylene-g-
butyrolactone functionality. We envisaged the assembly of
enyne 5 via an asymmetric aldol reaction18 between the
known oxazolidinone 619 and the functionalized aldehyde
7, which in turn would be assembled using an asymmetric
conjugate addition of an appropriate metal acetylide to the
chiral N-enoyloxazolidinone 8. For example, Kunz has
shown that dialkylaluminum chlorides as well as mixed
organoaluminum reagents participate in diastereoselective
conjugate additions to N-enoyloxazolidinones derived
from amino acids and carbohydrates.20,21
O
O
O
O
10
Me2AlC CTMS
PhMe, 0 °C
N
O
N
O
TMS
R
R
a
8a: R = Ph
b: R = CH(Ph)2
c: R = CH(2-naphthyl)2
9a: 93% (dr = 1.9:1)
b: 92% (3.4:1)
c: 78% (3.2:1)
In accordance with the above retrosynthetic analysis, we be-
gan to explore reaction conditions for constructing aldehyde
7 via a diastereoselective conjugate addition of an aluminum
acetylide species to the chiral N-enoyloxazolidinones 8a–c
(Scheme 2). In a preliminary experiment, we found that re-
action of 8a22 and the organoaluminum species derived from
the transmetalation of lithium (trimethylsilyl)acetylene with
Me2AlCl at 0 ꢁC delivered the desired 1,4-addition product
9a in 93% yield (dr¼1.9:1)23 (Scheme 2).24 Inspired by
these results, we reasoned that increasing the steric bulk at
the 4-position of the oxazolidinone might improve the
a
The dr reflects the ratio of C(10S:10R) (see ref 24).
Scheme 2.
Although the stereoinduction provided by the chiral oxazo-
lidinones in 8a–c was modest, these auxiliaries did indeed
afford the addition products with the appropriate stereo-
chemistry at C(10).24 In an effort to improve upon the dia-
stereoselectivity obtained during these addition reactions,
we turned our attention to the method of Schwartz, who

D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
11439
1) Cl2CO, K2CO3, KHCO3
PhMe/H2O
With 14 in hand, we explored conditions to effect the key
enyne RCM/CM transformation. The phosphine-free ruthe-
nium catalyst 1732 was employed owing to its reported supe-
riority in tandem RCM/CM reactions.16b We first conducted
the domino enyne RCM/CM sequence using dioxolane 18,33
which has been found to participate in CM reactions,34
because its use would introduce the requisite enone moiety
in a suitably protected form. In this way, subsequent
transformation of the oxazolidinone moiety in 15 to the
a-methylene-g-butyrolactone could be performed without
additional protection/deprotection steps (Scheme 5). How-
ever, the enyne RCM/CM reaction of 14 and 18 gave only
the cyclic diene 15 (50%) with the remainder of the mass
balance corresponding to the homodimer of 15;35 none of
the desired 16 was isolated. When the metathesis reaction
was conducted under an atmosphere of ethylene, 15 was
produced in 59% yield, but 16 was still not detected in the
reaction mixture. Interestingly, formation of the homodimer
of 15 was completely suppressed under these conditions.
Failing in these attempts to perform a domino RCM/CM,
we examined the simple CM reaction of 15 with 18 as a route
to 16, but all such experiments were unavailing, even when
large excesses of 18 were used; only 15 was recovered.
These results led us to the inescapable conclusion that the
protected enone 18 was not a suitable coupling partner for
this particular CM reaction.
HCl•H2N
MeO2C
OH
O
2) 2-naphthyllithium, THF
63%
10
HN
O
n-BuLi, THF
then
8c
COCl
R
84%
11: R = OH
12: R = H
NaBH4, TFA
CH2Cl2
98%
Scheme 3.
developed a procedure for the nickel(I)-catalyzed conjugate
addition of aluminum acetylides to achiral enones.28 We
queried whether use of a nickel acetylide species might
lead to improved diastereoselection. However, when we ap-
plied the Schwartz protocol without added chiral ligands to
additions to 8a–c, 9a–c were formed in lower yields (<70%)
with no diastereoselectivity.29
Although we had not been able to secure 9a with high dia-
stereoselectivity, it was possible to separate it from the minor
C(10) epimer so we could examine the viability of the key
domino enyne RCM/CM reaction.24 Toward this end, imide
9a was reduced, and the resulting alcohol was oxidized un-
der Swern conditions to provide aldehyde 7 (Scheme 4).30
The boron-mediated asymmetric aldol reaction between 7
and oxazolidinone 6 proceeded in 82% yield and excellent
diastereoselectivity (dr>95:5)23 to afford 13. This aldol re-
action proceeded in highest yield when toluene was used
as the solvent and EtN(i-Pr)2 as the base; employing
CH2Cl2 as the solvent and Et3N as the base consistently
gave 13 in 10–20% lower yield. Protection of the secondary
alcohol as a tert-butyldimethylsilyl ether followed by depro-
tection of the alkyne provided 14.31
TBS
O
17 (20 mol %)
18, CH2Cl2
O
O
OTBS
O
N
O
rt
45 °C
50%
Bn
N
O
Bn
O
14
15
17 (20 mol %)
19 (5 equiv)
CH2Cl2, 45 °C
62%
O
O
OTBS
O
O
OTBS
O
Bn
N
O
O
O
O
O
1) LiBH4, MeOH, THF
2) Swern oxidation
77%
Bn
N
O
H
N
O
16
O
TMS
TMS
7
Ph
20
9a
MesN
NMes
O
OH
O
6, Bu2BOTf
O
Cl
Cl
O
O
N
O
Ru
O
EtN(i-Pr)2, PhMe
82% (dr > 95:5)
TMS
Bn
18
19
13
17
Scheme 5.
TBS
O
O
O
1) TBSOTf, 2,6-lutidine
In the wake of these disappointments, we were pleased to
discover that the domino RCM/CM reaction of enyne 14
and methyl vinyl ketone (19) proceeded cleanly to provide
20 in 62% yield.36 This result was indeed promising as it
nicely supported our original hypothesis that we could
induce a domino enyne RCM/CM reaction to assemble the
N
O
2) AgNO3, 2,6-lutidine
THF/EtOH/H2O
Bn
75%
14
Scheme 4.

11440
D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
seven-membered ring and pendant enone found in the xan-
thanolides.
1) DIBAL-H
2) CBr4, PPh3
62%
Br2C
OTs
MeO
OR
26
O
2.2. Second-generation approach
24: R = H
25: R = Ts
TsCl, Et3N
DMAP
96%
Inasmuch as the conjugate additions of aluminum acetylides
to N-enoyloxazolidinones proceeded with modest diastereo-
selectivity, we queried whether an alternative route to the
synthesis of 1 would prove viable. Moreover, it occurred
to us that incorporating the a-methylene-g-butyrolactone
prior to the key domino RCM/CM sequence would enable
us to minimize unproductive functional group manipula-
tions. Indeed, Paquette had shown that the a-methylene-g-
butyrolactone functionality is stable to the conditions of
ruthenium-catalyzed RCM reactions.37 A second-generation
strategy was thus designed in which the lactone moiety in 21
would be elaborated via a palladium-catalyzed carbonyla-
tion of the enol triflate 22 followed by a lactonization
(Scheme 6). The stereocenters at C(7)–C(8) in 22 would
be assembled by an asymmetric aldol reaction of oxazolidi-
none 6 and aldehyde 23, whereas the remaining stereocenter
at C(10) would be obtained from enantiomerically pure 24,
which is commercially available.
O
n-BuLi, THF
then TIPSOTf
70%
DIBAL-H
83%
R
H
TIPS
TIPS
23
KCN, DMSO 27: R = OTs
60 °C
64%
28: R = CN
TIPS
29
Scheme 7.
The aldol coupling reaction between 23 and 6 proceeded in
good yield to afford 30 with excellent diastereoselectivity
(dr>95:5)23 (Scheme 8). The secondary alcohol group of
the N,O-dimethyl amide 31, which was prepared from 30
using the method of Weinreb,40 was protected as its tert-
butyldimethylsilyl ether to deliver 32. Subsequent treatment
of amide 32 with MeMgBr provided the corresponding
ketone, which was readily transformed into the requisite
enol triflate 22 in 85% overall yield by kinetic deprotonation
using KHMDS and trapping of the resultant enolate with
N-(5-chloro-2-pyridyl)triflimide (33).41
O
10
8
O
Domino
7
O
enyne RCM/CM
1
10
Lactonization
8
TIPS
OTBS
OTf
O
O
OH
O
Aldol
reaction
O
7
O
6, Bu BOTf
N
O
2
H
TIPS
EtN(i-Pr) , PhMe
21
22
2
Pd-catalyzed
carbonylation
Bn
TIPS
23
88% (dr > 95:5)
30
O
O
N
O
H
R
O
O
O
+
OMe
HCl•HN(OMe)Me
Me AlCl, CH Cl
N
TIPS
Bn
23
TIPS
TBSOTf
Me
2
2
2
6
60%
31: R = H
2,6-lutidine
99%
10
32: R = TBS
MeO
OH
O
TBS
O
24
1) MeMgBr
Scheme 6.
OTf
2) KHMDS, 33
TIPS
Cl
The first step in reducing the strategy in Scheme 6 to practice
involved converting the ester 24 into the tosylate 25 (Scheme
7). Reduction of the ester moiety and application of the
Corey–Fuchs homologation38 protocol to the resulting
aldehyde delivered vinyl dibromide 26, which upon treat-
ment with n-BuLi and trapping the lithium acetylide gener-
ated in situ with TIPSOTf afforded alkyne 27. Displacement
of the primary tosylate in 27 with potassium cyanide
afforded the corresponding nitrile 28 in modest yield
(64%) owing to competitive b-elimination to form enyne 29
(20%). Reduction of nitrile 28 with DIBAL-H afforded alde-
hyde 23.39
85%
22
Tf
N
N
Tf
33
Scheme 8.
The final phase of the synthesis was initiated with the palla-
dium-catalyzed carbonylation of 22 in the presence of

D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
11441
MeOH to deliver acrylate 34 in 85% yield (Scheme 9).42
4. Experimental
Simultaneous removal of the two silyl protecting groups
and intramolecular lactonization was effected with TBAF
to afford 21 in 78% yield,43 thereby setting the stage for
the pivotal domino enyne RCM/CM sequence. In the event,
reaction of enyne 21 and enone 19 in the presence of catalyst
17 provided 1 in 83% yield. The 1H and 13C NMR spectral
data of the synthetic 1 thus obtained were consistent with
those previously reported.2b,5a,b,44,45 Moreover, it exhibited
an optical rotation {[a]D24 +23.4 (c 0.333, CHCl3)} in close
accord with the previously reported value {[a]2D0 +25
(c 0.5, CHCl3)}.5b
4.1. General
Unless otherwise indicated, all starting materials and sol-
vents were obtained from commercial suppliers and used
without further purification. All solvents contained less
than 50 ppm H2O by Karl Fisher coulometric moisture anal-
ysis. Tetrahydrofuran (THF) was dried by passage through
two columns of activated neutral alumina and stored under
argon. Methanol (MeOH) and dimethylformamide (DMF)
were dried by passage through two columns of activated
molecular sieves and stored under argon. Toluene (PhMe)
was first passed through a column of neutral alumina,
then through a column of Q5 reactant and stored under
argon. Methylene chloride (CH2Cl2), triethylamine (Et3N),
TBS
O
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
OTf
2,6-lutidine, Hunig’s base (EtN(i-Pr) ), trimethylsilyl chlo-
2
¨
CO, Et3N, MeOH, DMF
85%
TIPS
ride (TMSCl), triisopropyl silyltrifluoromethanesulfonate
(TIPSOTf), and dimethylsulfoxide (DMSO) were distilled
from calcium hydride and used immediately. Reactions in-
volving air or moisture-sensitive reagents or intermediates
were performed in flame-dried glassware under an atmo-
sphere of dry nitrogen or argon. All reaction temperatures
are reported as the temperature of the surrounding bath.
Flash chromatography was performed following the Still46
protocol with ICN Silitech 32-63 D 60A silica gel with the
indicated solvents. Analytical thin layer chromatography
was performed using Merck 250 micron 60F-254 silica
plates. The plates were visualized with ultraviolet light,
potassium permanganate, or ceric ammonium molybdate.
Proton (1H) and carbon (13C) NMR spectra were obtained
using a Varian Unity Plus (400 MHz) or Varian Unity Plus
(500 MHz) spectrometer as solutions in CDCl3, unless other-
wise indicated. Chemical shifts are reported as parts per
million (ppm, d) and referenced to the residual protic solvent.
Coupling constants are reported in Hertz (Hz). Splitting pat-
terns are designated as s, singlet; d, doublet; t, triplet; q,
quartet; br, broad; m, multiplet; comp, complex multiplet;
app, apparent. Low-resolution chemical ionization mass
spectra (CI) were obtained on a Finnigan TSQ-70 instrument
in positive ionization mode. High-resolution mass spectra
(HRMS) were obtained on a VG Analytical ZAB-2E instru-
ment in positive ionization mode. IR spectra were recorded
on a Perkin–Elmer 1600 series FTIR either neat or as solu-
tions in CDCl3 on sodium chloride plates or as a KBr pellet
and are reported in wavenumbers (cmꢀ1). Melting points are
uncorrected. Percent yields are given for compounds that
were ꢂ95% pure as judged by 1H NMR spectroscopy.
22
TBS
O
TBAF, THF
0 °C rt
78%
OMe
TIPS
O
34
O
(19, 10 equiv)
17 (20 mol%)
O
CH2Cl2, 45 °C, 13 h
O
83%
21
O
O
O
1
Scheme 9.
3. Conclusions
The first total synthesis of the sesquiterpene lactone (+)-8-
epi-xanthatin has been completed by a route that required
only 14 steps in the longest linear sequence and proceeded
in an overall yield of 5.5%. The essential elements of the
approach comprise a sequence for palladium-catalyzed car-
bonylation and lactonization to construct the a-methylene-
g-butyrolactone functionality and a domino enyne RCM/
CM process to elaborate the seven-membered carbocycle
with its pendant enone array. Indeed, the synthesis under-
scores the significant utility of domino ruthenium-catalyzed
metathesis reactions for the rapid construction of functional-
ized, polycyclic ring systems that are found in natural prod-
ucts. During the course of these studies, we also investigated
aluminum-mediated conjugate addition reactions to chiral
a,b-unsaturated imides. Other applications of olefin meta-
thesis to solve challenging problems in total synthesis are
under active investigation in our laboratories, and the results
of these studies will be disclosed in due course.
4.1.1. (3S)-(3-Methyl-5-trimethylsilanylpent-4-ynoyl)-
(4R)-phenyloxazolidin-2-one (9a). A solution of n-BuLi
(2.46 M in hexane, 4.4 mL, 11.0 mmol) was added drop-
wise to a solution of (trimethylsilyl)acetylene (1.5 mL,
11.0 mmol) in PhMe (80 mL) at 0 ꢁC. The mixture was
stirred at this temperature for 0.5 h, whereupon the cooling
bath was removed and stirring continued at room tempera-
ture for an additional 0.5 h. The solution was then cooled
to 0 ꢁC, whereupon Me2AlCl (1.0 M in hexane, 11.0 mL,
11.0 mmol) was added dropwise and stirring continued for
0.5 h. To this mixture was added a solution of 8a (998 mg,
4.32 mmol) in PhMe (30 mL), and stirring was continued
at 0 ꢁC for 0.5 h. The reaction was then slowly quenched
by the sequential addition of saturated aqueous Rochelle’s

11442
D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
salt (40 mL), H2O (40 mL), and EtOAc (50 mL). The result-
ing mixture was stirred at room temperature overnight and
then extracted with EtOAc (3ꢃ20 mL). The combined or-
ganic layers were dried (MgSO4), filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography eluting with Et2O/pentane (2:1) to afford
873 mg (61%) of the desired major diastereomer 9a as a
colorless solid and 458 mg (32%) of the undesired adduct
(10R)-9a as a colorless solid.
4.1.3. (4R)-[(Dinaphthalen-2-yl)methyl]-3-[(3S)-methyl-
5-trimethylsilanylpent-4-ynoyl]oxazoldin-2-one [(10S)-
9c] and [(10R)-9c]. Prepared as a white foam in 78% yield
according to the procedure described above for 9a (dr¼
3.2:1); mp (mixture)¼24–25 ꢁC; 1H NMR (500 MHz,
DMSO-d6) (mixture of diastereomers) d 7.95–7.82 (comp,
6.5H), 7.76 (br s, 1H), 7.70 (br s, 1H), 7.56–7.48 (comp, 4H),
7.32 (dd, J¼8.6, 1.8 Hz, 0.28H), 7.27 (dd, J¼8.5, 1.7 Hz,
0.78H), 7.21 (overlapping pair of dd, J¼8.3, 1.8 Hz for the
minor set, and J¼8.6, 1.8 Hz for the major set, total integral
is 1H), 5.45–5.50 (m, 1H), 4.91 (d, J¼4.1 Hz, 0.76H), 4.86
(d, J¼5.1 Hz, 0.26H), 4.78–4.71 (m, 1H), 4.55 (dd, J¼9.2,
2.3 Hz, 0.72H), 4.51 (dd, J¼9.2, 2.3 Hz, 0.25H), 3.11 (dd,
J¼16.7, 6.6 Hz, 0.73H), 2.98–2.82 (comp, 2.23H), 1.11 (d,
J¼6.8 Hz, 2.33H), 0.98 (d, J¼6.2 Hz, 0.75H), 0.13 (s, 6.3H),
0.11 (s, 2.1H); 13C NMR (125 MHz, DMSO-d6) (mixture of
diastereomers) d 170.4, 169.9, 153.6, 153.5, 137.6, 137.5,
136.4, 136.3, 133.2, 133.1, 133.0, 132.5, 132.1, 128.7,
128.6, 128.5, 128.3, 128.2, 127.9, 127.9, 127.7, 127.6,
126.8, 126.6, 126.5, 126.4, 126.2, 111.6, 110.8, 85.5, 84.2,
65.2, 64.8, 55.8, 50.7, 50.1, 42.3, 23.0, 22.5, 20.7, 20.5,
0.4, 0.3 d; IR (neat) 2962, 2164, 1782, 1704, 1385, 1249,
1212, 842, 759 cmꢀ1; mass spectrum (CI) m/z 520.2306
[C33H34NO3Si (M+1) requires 520.2308], 520, 267 (base).
Major diastereomer (9a): mp¼24–25 ꢁC; 1H NMR
(500 MHz) d 7.38–7.26 (comp, 5H), 5.44–5.38 (m, 1H),
4.69–4.65 (m, 1H), 4.27–4.24 (m, 1H), 3.22 (app d,
J¼6.1 Hz, 1H), 3.06–2.94 (comp, 2H), 1.17 (d, J¼6.8 Hz,
3H), 0.07 (s, 9H); 13C NMR (125 MHz) d 170.3, 153.6,
138.9, 129.2, 128.7, 125.9, 109.8, 84.5, 70.0, 57.7, 42.4,
22.7, 20.8, 0.1; IR (CDCl3) 2958, 2173, 1784, 1713, 1384,
1197, 843 cmꢀ1; mass spectrum (CI) m/z 330.1542
[C18H24NO3Si (M+1) requires 330.1526], 330 (base), 314.
Minor diastereomer (10R)-9a: mp¼25–26 ꢁC; 1H NMR
(500 MHz) d 7.38–7.26 (comp, 5H), 5.42 (dd, J¼8.8,
3.8 Hz, 1H), 4.67 (t, J¼8.8 Hz, 1H), 4.26 (dd, J¼8.8,
3.8 Hz, 1H), 3.21–3.14 (m, 1H), 3.04–2.95 (comp, 2H),
1.14 (d, J¼6.8 Hz, 3H), 0.08 (s, 9H); 13C NMR (125 MHz)
d 170.3, 153.7, 139.0, 129.2, 128.7, 125.9, 109.7, 84.7,
70.0, 57.6, 42.2, 23.0, 20.8, 0.1; IR (neat) 2959, 2171,
1786, 1708, 1386, 1198, 843 cmꢀ1; mass spectrum (CI) m/z
330.1537 [C18H24NO3Si (M+1) requires 330.1526], 330
(base), 314.
4.1.4. (4R)-[Hydroxy(dinaphthalen-2-yl)methyl]oxazoli-
din-2-one (11). A solution of tert-BuLi (1.7 M in pentane,
2.8 mL, 4.7 mmol) was added dropwise via syringe to a solu-
tion of 2-bromonaphthalene (0.49 g, 2.4 mmol) in THF
(5 mL) at ꢀ78 ꢁC. The resulting yellowish-green slurry
was stirred at ꢀ78 ꢁC for 10 min, whereupon the mixture
was transferred to a 0 ꢁC bath and stirring continued for
10 min. The mixture was cooled to ꢀ78 ꢁC, whereupon a
solution of the oxazolidinone derived from 1025 (0.11 g,
0.76 mmol) in THF (2 mL) was added via cannula. The mix-
ture was stirred at ꢀ78 ꢁC for 1 h, whereupon a saturated
aqueous solution of NH4Cl (10 mL) was added and the cool-
ing bath removed. The mixture was poured into brine
(30 mL), and the biphasic mixture was extracted with EtOAc
(3ꢃ15 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure.
The crude residue was dissolved in a minimal volume of
DMSO and purified by flash chromatography eluting with
EtOAc/hexanes (4:1) to afford 188 mg (67%) of 11 as a white
solid (63% from 10); mp¼197–199 ꢁC; 1H NMR (500 MHz,
DMSO-d6) d 8.15–8.14 (m, 1H), 8.10–8.09 (m, 1H), 7.92 (br
t, J¼7.8 Hz, 2H), 7.83–7.81 (comp, 2H), 7.77 (dd, J¼9.0,
3.8 Hz, 2H), 7.70 (br s, 1H), 7.52–7.45 (comp, 6H), 6.30
(s, 1H), 5.29–5.26 (m, 1H), 4.32 (t, J¼8.8 Hz, 1H), 4.21
(dd, J¼8.6, 5.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d 159.1, 142.0, 141.9, 132.6, 132.5, 131.9, 131.8, 128.3,
128.2, 127.7, 127.4, 127.3, 127.2, 126.1, 126.0, 125.9,
125.8, 125.4, 125.1, 124.7, 124.3, 77.9, 65.0, 57.5; IR
(KBr) 3402, 1732, 1416, 1236, 1033, 754 cmꢀ1; mass spec-
trum (CI) m/z 370. 1453 [C24H20NO3 (M+1) requires
370.1443], 370 (base), 352, 283, 169.
4.1.2. (4R)-Benzhydryl-3-[(3S)-methyl-5-trimethylsila-
nylpent-4-ynoyl]oxazolidin-2-one (9b). Prepared as awhite
foam in 71% yield along with 21% yield of the undesired
adduct (10R)-9b as a white foam according to the procedure
described above for 9a.
Major diastereomer (9b): mp¼24–25 ꢁC; 1H NMR
(500 MHz) d 7.34–7.27 (comp, 5H), 7.26–7.24 (m, 1H),
7.12–7.10 (comp, 2H), 7.08–7.06 (comp, 2H), 5.32–5.29
(m, 1H), 4.75 (d, J¼5.0 Hz, 1H), 4.46–4.39 (comp, 2H),
3.11–2.94 (comp, 3H), 1.19 (app dd, J¼6.9, 1.7 Hz, 3H),
0.14 (s, 9H); 13C NMR (125 MHz) d 170.6, 153.3, 139.5,
137.9, 129.4, 128.9, 128.7, 128.3, 127.9, 127.1, 110.2,
84.5, 64.7, 56.2, 50.2, 42.5, 22.6, 20.8, 0.2; IR (neat)
2962, 2165, 1784, 1704, 1389, 1280, 1249, 1212, 838,
756, 697 cmꢀ1
; mass spectrum (CI) m/z 420.1986
[C25H30NO3Si (M+1) requires 420.1995], 420 (base), 404,
326, 254, 167.
Minor diastereomer (10R)-9b: mp¼25–26 ꢁC; 1H NMR
(500 MHz) d 7.34–7.26 (comp, 5H), 7.24–7.20 (m, 1H),
7.17–7.14 (comp, 2H), 7.10–7.07 (comp, 2H), 5.34–5.30
(m, 1H), 4.67 (d, J¼5.8 Hz, 1H), 4.43–4.36 (comp, 2H),
3.04 (dd, J¼15.9, 6.8 Hz, 3H), 2.96 (app sext, J¼6.7 Hz,
1H), 2.87 (dd, J¼15.9, 6.4 Hz, 1H), 1.13 (app d,
J¼6.6 Hz, 3H), 0.12 (s, 9H); 13C NMR (125 MHz)
d 170.4, 153.3, 139.5, 138.0, 129.3, 128.9, 128.7, 128.4,
127.9, 127.1, 109.8, 84.9, 65.2, 56.3, 51.0, 42.3, 22.9,
20.9, 0.1; IR (neat) 2966, 2167, 1784, 1702, 1496, 1455,
1390, 1367, 1249, 1208, 1114, 844, 756, 703 cmꢀ1; mass
spectrum (CI) m/z 420.1985 [C25H30NO3Si (M+1) requires
420.1995], 420 (base), 404, 326, 167.
4.1.5. (4R)-[(Dinaphthalen-2-yl)methyl]oxazolidin-2-one
(12). TFA (3 mL) was added dropwise via syringe to a slurry
of 11 (185 mg, 0.501 mmol) and NaBH4 (95 mg, 2.5 mmol)
in CH2Cl2 (7 mL) at room temperature, during which time
a vigorous evolution of H2 was observed. The reaction mix-
ture was stirred at room temperature for 21 h, diluted with

D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
11443
H2O (10 mL), and neutralized (pH¼7) by the addition of
solid KOH pellets. The resulting biphasic mixture was
extracted with EtOAc (3ꢃ10 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude yellow solid thus obtained was
purified by recrystallization from MeOH–hexanes. The crys-
tals were collected by vacuum filtration, rinsed with cold
hexanes (2ꢃ5 mL), and dried under reduced pressure to af-
ford 173 mg (98%) of 12 as an off-white crystalline solid;
841, 760 cmꢀ1
[C9H19OSi (M+1) requires 171.1205], 171 (base), 155, 139.
;
mass spectrum (CI) m/z 171.1207
4.1.8. (3S)-Methyl-5-trimethylsilanylpent-4-ynal (7). To
a solution of oxalyl chloride (410 mL, 4.66 mmol) in
CH2Cl2 (58 mL) at ꢀ78 ꢁC DMSO (0.67 mL, 9.4 mmol)
was added via syringe. The mixture was stirred at ꢀ78 ꢁC
for 15 min, whereupon a solution of the above alcohol
(264 mg, 1.55 mmol) in CH2Cl2 (4 mL) was added via can-
nula and stirring continued for 1 h. Et3N (2.6 mL, 19 mmol)
was added via syringe, and the reaction mixture was trans-
ferred to a 0 ꢁC bath and stirring continued for 0.5 h. The
reaction was quenched by adding H2O (15 mL) and poured
into 1 N HCl (70 mL). The biphasic mixture was extracted
with CH2Cl2 (2ꢃ20 mL). The combined organic phases were
dried (MgSO4), filtered through a 0.5-in. plug of neutral
Al2O3 rinsing with CH2Cl2 (300 mL) and Et2O (200 mL),
and concentrated at atmospheric pressure. The resulting
crude residue was triturated with pentane (5 mL) and fil-
tered. Concentration of the filtrate at atmospheric pressure
afforded 246 mg (94%) of 7 as a yellow oil; 1H NMR
(400 MHz) d 9.76 (t, J¼2.1 Hz, 1H), 2.97 (app sext,
J¼6.8 Hz, 1H), 2.63–2.41 (comp, 2H), 1.21 (d, J¼6.8 Hz,
3H), 0.11 (s, 9H); 13C NMR (100 MHz) d 201.1, 109.1,
85.7, 49.8, 21.5, 20.9, 0.1; IR (neat) 2962, 2169, 1714,
1410, 1250, 842, 760 cmꢀ1; mass spectrum (CI) m/z
169.1050 [C9H17OSi (M+1) requires 169.1049], 169 (base).
1
mp¼120–122 ꢁC; H NMR (500 MHz, DMSO-d6) d 7.98
(br d, J¼3.6 Hz, 2H), 7.91–7.86 (comp, 3H), 7.84–7.80
(comp, 4H), 7.53–7.42 (comp, 6H), 5.06–5.01 (m, 1H),
4.40–4.36 (comp, 2H), 4.04–3.98 (m, 1H); 13C NMR
(125 MHz, DMSO-d6) d 158.7, 139.0, 138.6, 133.1, 133.0,
132.0, 131.9, 128.2, 128.1, 127.8, 127.7, 127.5, 127.4,
126.8, 126.7, 126.6, 126.4, 126.3, 126.1, 125.9, 125.7,
67.9, 56.3, 54.2; IR (neat) 3274, 3053, 1756, 1404, 1239,
1026, 756 cmꢀ1; mass spectrum (CI) m/z 354.1492
[C24H20NO2 (M+1) requires 354.1494], 355 (base), 267, 129.
4.1.6. 3-But-2-enoyl-(4R)-(dinaphthalen-2-ylmethyl)oxa-
zolidin-2-one (8c). A solution of n-BuLi (2.36 M in hex-
anes, 63 mL, 0.15 mmol) was added to a solution of 12
(44 mg, 0.13 mmol) in THF (0.5 mL) at ꢀ78 ꢁC, whereupon
the mixture was stirred for an additional 0.5 h. To this mix-
ture was added freshly distilled trans-crotonyl chloride
(18 mL, 0.19 mmol). The solution was allowed to warm to
room temperature over a 2 h period and then quenched by
adding a solution of saturated aqueous NH4Cl (2 mL). The
resulting layers were separated, and the aqueous phase was
extracted with EtOAc (3ꢃ2 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with hexanes/
EtOAc (2:3) to afford 44 mg (84%) of 8c as a white solid;
4.1.9. 3-[(2S)-Allyl-(3R)-hydroxy-(5S)-methyl-7-tri-
methylsilanylhept-6-ynoyl]-(4S)-benzyloxazolidin-2-one
(13). To a solution of oxazolidinone 6 (594 mg, 2.29 mmol)
and EtN(i-Pr)2 (400 mL, 2.29 mmol) in anhydrous PhMe
(12 mL) at ꢀ78 ꢁC was added Bu2BOTf (570 mL,
2.30 mmol).47 The mixture was stirred at ꢀ78 ꢁC for 1 h,
whereupon aldehyde 7 (285 mg, 1.69 mmol) in anhydrous
PhMe (2 mL) was added dropwise via cannula. The mixture
was stirred at ꢀ78 ꢁC for 30 min and then at room tempera-
ture for 6 h. The mixture was cooled to 0 ꢁC, whereupon pH
7.0 phosphate buffer (2 mL), MeOH (1 mL), and 30% H2O2
(500 mL) were added successively, and stirring was contin-
ued for 1 h. The mixture was poured into H2O (30 mL),
and the resulting biphasic mixture extracted with CH2Cl2
(3ꢃ10 mL). The combined organics were dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash
chromatography eluting with hexane/EtOAc (3:2) to give
1
mp¼48–51 ꢁC; H NMR (400 MHz) d 7.88–7.74 (comp,
6H), 7.66–7.57 (comp, 2H), 7.54–7.45 (comp, 4H), 7.35–
7.24 (comp, 3H), 7.20–7.08 (m, 1H), 5.62–5.58 (m, 1H),
5.14 (d, J¼5.1 Hz, 1H), 4.57–4.48 (comp, 2H), 1.93 (d,
J¼6.8 Hz, 3H); 13C NMR (100 MHz) d 164.7, 153.2,
146.9, 137.1, 135.4, 133.2, 133.0, 132.6, 132.2, 128.5,
128.3, 127.7, 127.6, 127.5, 127.4, 127.1, 126.3, 126.2,
126.1, 126.0, 121.5, 64.7, 56.1, 50.8, 18.4; IR (neat) 3054,
2957, 2932, 2870, 1779, 1682, 1634, 1340, 1208, 749,
668 cmꢀ1; mass spectrum (CI) m/z 422.1752 [C28H24NO3
(M+1) requires 422.1756], 422 (base), 354, 267.
1
615 mg (82%) of 13 as a colorless oil (dr>95:5 by H
4.1.7. (3S)-Methyl-5-trimethylsilanylpent-4-yn-1-ol.
Solid LiBH4 (49 mg, 2.1 mmol) and dry MeOH (78 mL,
1.9 mmol) were sequentially added to a solution of 9a
(637 mg, 1.93 mmol) in THF (19 mL) at 0 ꢁC. The mixture
was stirred at 0 ꢁC for 0.5 h, whereupon the cooling bath was
removed and stirring continued at room temperature for 8 h.
The reaction was poured into a mixture of 25% aqueous
NaOH (40 mL) and Et2O (10 mL), and the resulting biphasic
mixture was extracted with Et2O (3ꢃ15 mL). The combined
organic phases were dried (MgSO4), filtered, and concen-
trated at atmospheric pressure. The residue was purified by
flash chromatography eluting with Et2O/pentane (4:1) to af-
ford 270 mg (82%) of the product as a yellow oil; 1H NMR
(400 MHz) d 3.83–3.70 (comp, 2H), 2.66–2.55 (m, 1H), 1.93
(br s, 1H), 1.73–1.58 (comp, 2H), 1.17 (d, J¼6.8 Hz, 3H),
0.11 (s, 9H); 13C NMR (100 MHz) d 111.2, 85.2, 61.2,
39.3, 23.9, 21.1, 0.1; IR (neat) 3350, 2961, 2167, 1250,
NMR); 1H NMR (500 MHz) d 7.33–7.29 (comp, 2H),
7.27–7.23 (m, 1H), 7.21–7.18 (comp, 2H), 5.89–5.80 (m,
1H), 5.13–5.09 (m, 1H), 5.05–5.02 (m, 1H), 4.72–4.67 (m,
1H), 4.25–4.19 (comp, 2H), 4.17–4.09 (comp, 2H), 3.28
(dd, J¼13.5, 3.4 Hz, 1H), 2.75–2.69 (m, 1H), 2.68–2.55
(comp, 3H), 2.44–2.38 (m, 1H), 1.63–1.50 (comp, 2H),
1.18 (d, J¼7.0 Hz, 3H), 0.12 (s, 9H); 13C NMR
(125 MHz) d 174.8, 153.7, 135.3, 135.2, 129.4, 129.0,
127.4, 117.3, 110.9, 85.2, 70.4, 66.0, 55.6, 47.3, 40.5,
38.0, 32.1, 23.8, 21.4, 0.1; IR (neat) 3524, 2963, 2165,
1782, 1698, 1386, 1249, 1208, 1102, 842, 760, 701 cmꢀ1
;
mass spectrum (CI) m/z 428.2254 [C24H34NO4Si (M+1)
requires 428.2257], 428 (base), 412, 356, 250.
4.1.10. 3-[(2S)-Allyl-(3R)-(tert-butyldimethylsilanyloxy)-
(5S)-methyl-7-trimethylsilanylhept-6-ynoyl]-(4S)-benzyl-
oxazolidin-2-one. To a solution of alcohol 13 (463 mg,

11444
D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
1.08 mmol) in anhydrous CH2Cl2 (20 mL) at 0 ꢁC was added
2,6-lutidine (1.2 mL, 10.0 mmol) and TBDMSOTf (720 mL,
3.1 mmol). The resulting solution was stirred at 0 ꢁC for 2 h,
whereupon MeOH (3 mL) was added and the cooling bath
removed. After warming to room temperature, the mixture
was poured into H2O (20 mL), and the resulting biphasic
mixture was extracted with CH2Cl2 (3ꢃ5 mL). The com-
bined organics were dried (Na2SO4), filtered, and concen-
trated. The residue was purified by flash chromatography
eluting with hexane/EtOAc (3:2) to give 536 mg (92%) of
and then cooled to room temperature, whereupon DMSO
(50 mL) was added and stirring continued for 12 h. The mix-
ture was concentrated under reduced pressure and purified
by flash chromatography eluting with pentane/Et2O (2:1)
to give 10 mg (50%) of 15 as a yellow oil; 1H NMR
(500 MHz) d 7.33–7.29 (comp, 2H), 7.27–7.25 (m, 1H),
7.21–7.19 (comp, 2H), 6.21 (dd, J¼17.4, 10.9 Hz, 1H),
5.74–5.71 (m, 1H), 5.09 (d, J¼17.4 Hz, 1H), 4.91 (d,
J¼10.9 Hz, 1H), 4.61–4.56 (m, 1H), 4.24–4.21 (m, 1H),
4.19–4.16 (m, 1H), 4.14–4.07 (comp, 2H), 3.27 (dd,
J¼13.3, 3.2 Hz, 1H), 3.03–2.96 (m, 1H), 2.83–2.76 (m,
1H), 2.72 (dd, J¼13.3, 9.8 Hz, 1H), 2.25–2.14 (comp, 2H),
1.78 (ddd, J¼14.7, 6.1, 2.0 Hz, 1H), 1.21 (d, J¼7.4 Hz,
3H), 0.84 (s, 9H), 0.05 (s, 3H), ꢀ0.07 (s, 3H); 13C NMR
(125 MHz) d 173.9, 153.3, 145.5, 140.2, 135.5, 129.5,
128.9, 128.4, 127.3, 110.4, 71.9, 65.8, 55.8, 45.8, 38.3,
37.9, 31.2, 25.8, 24.0, 20.5, 17.9, ꢀ4.4, ꢀ5.5; IR (neat)
2929, 1784, 1698, 1388, 1350, 1242, 1210, 1099, 1072,
1
the product as a yellow oil; H NMR (500 MHz) d 7.32–
7.28 (comp, 2H), 7.26–7.22 (m, 1H), 7.22–7.19 (comp,
2H), 5.90–5.81 (m, 1H), 5.14–5.09 (m, 1H), 5.04–5.01
(m, 1H), 4.64–4.59 (m, 1H), 4.25–4.21 (m, 1H), 4.17–4.14
(m, 1H), 4.12–4.03 (m, 1H), 3.28 (dd, J¼13.3, 3.1 Hz,
1H), 2.67 (dd, J¼13.3, 10.0 Hz, 1H), 2.58–2.48 (comp,
2H), 2.34–2.26 (m, 1H), 1.81–1.75 (m, 1H), 1.68–1.63 (m,
1H), 1.18 (d, J¼6.9 Hz, 3H), 0.84 (s, 9H), 0. 13 (s, 9H),
0.09 (s, 3H), 0.05 (s, 3H); 13C NMR (125 MHz) d 174.0,
153.1, 135.5, 135.3, 129.5, 128.9, 127.3, 117.1, 111.4,
85.5, 71.9, 65.7, 56.0, 48.1, 41.5, 37.7, 33.1, 25.7, 24.0,
21.6, 18.0, 0.2, ꢀ4.4, ꢀ4.7; IR (neat) 2955, 2167, 1784,
1696, 1384, 1248, 1207, 1095, 837, 778 cmꢀ1; mass spec-
trum (CI) m/z 542.3120 [C30H48NO4Si2 (M+1) requires
542.3122], 542 (base), 526, 484, 410.
835, 776 cmꢀ1
; mass spectrum (CI) m/z 470.2728
[C27H40NO4Si (M+1) requires 470.2727], 470 (base), 338.
4.1.13. (4S)-Benzyl-(3S)-[7(R)-(tert-butyldimethylsilanyl-
oxy)-5(S)-methyl-4-(3-oxobut-1-enyl)cyclohept-3-ene-
carbonyl]oxazolidin-2-one (20). A solution of 14 (364 mg,
0.775 mmol) in anhydrous CH2Cl2 (155 mL) was degassed
with argon for 10 min, whereupon freshly distilled methyl
vinyl ketone (320 mL, 3.88 mmol) and catalyst 17 (97 mg,
0.160 mmol) were added. The mixture was stirred at 45 ꢁC
for 20 h and cooled to room temperature, whereupon
DMSO (600 mL) was added and stirring continued for 6 h.
The mixture was concentrated under reduced pressure and
purified by flash chromatography eluting with pentane/
Et2O (1:1) to give 245 mg (62%) of 20 as a white solid;
4.1.11. 3-[(2S)-Allyl-(3R)-(tert-butyldimethylsilanoxyl)-
(5S)-methylhept-6-ynoyl]-(4S)-benzyloxazolidin-2-one
(14). Solid AgNO3 (3.30 g, 19.0 mmol) was added in one
portion to a solution of the preceding alkyne (695 mg,
1.28 mmol) in THF/EtOH/H2O/2,6-lutidine (1:1:1:0.1)
(65 mL) at room temperature. The resulting solution was
stirred for 30 min and filtered through a pad of Celite
(3 cm) rinsing with Et2O (300 mL). The combined filtrate
and washings were washed with brine (200 mL) and H2O
(100 mL). The layers were separated, and the aqueous phase
was extracted with Et2O (3ꢃ75 mL). The combined or-
ganics were dried (MgSO4), filtered, and concentrated under
reduced pressure The residue was purified by flash chroma-
tography eluting with pentane/Et2O (2:1) to afford 493 mg
1
mp¼24–26 ꢁC; H NMR (500 MHz) d 7.34–7.30 (comp,
2H), 7.28–7.24 (m, 1H), 7.20–7.18 (comp, 2H), 7.02 (d,
J¼16.1 Hz, 1H), 6.20 (m, 1H), 6.08 (d, J¼16.1 Hz, 1H),
4.61–4.56 (m, 1H), 4.27–4.25 (m, 1H), 4.16–4.07 (comp,
3H), 3.27 (dd, J¼13.4, 3.3 Hz, 1H), 3.13–3.06 (m, 1H),
2.82–2.75 (m, 1H), 2.73 (d, J¼13.3, 9.7 Hz, 1H), 2.32–
2.27 (comp, 4H), 2.23–2.17 (m, 1H), 1.80 (ddd, J¼14.7,
5.6, 1.8 Hz, 1H), 1.23 (d, J¼7.2 Hz, 3H), 0.85 (s, 9H),
0.05 (s, 3H), ꢀ0.08 (s, 3H); 13C NMR (125 MHz) d 198.9,
173.3, 153.3, 147.6, 144.7, 138.8, 135.3, 129.4, 129.0,
127.4, 124.8, 71.7, 65.9, 55.8, 45.7, 38.0, 37.8, 31.8, 27.3,
25.8, 24.4, 20.4, 17.8, ꢀ4.3, ꢀ5.6; IR (neat) 2928, 2856,
1778, 1702, 1667, 1590, 1386, 1354, 1256, 1195, 985,
1
(82%) of 14 as a yellow oil; H NMR (500 MHz) d 7.32–
7.28 (comp, 2H), 7.26–7.23 (m, 1H), 7.22–7.19 (comp,
2H), 5.89–5.80 (m, 1H), 5.12–5.08 (m, 1H), 5.04–5.00 (m,
1H), 4.65–4.60 (m, 1H), 4.28–4.24 (m, 1H), 4.15–4.04
(comp, 3H), 3.28 (dd, J¼13.4, 3.2 Hz, 1H), 2.64 (dd,
J¼13.5, 10.2 Hz, 1H), 2.55–2.47 (comp, 2H), 2.39–2.33
(m, 1H), 2.05 (d, J¼2.2 Hz, 1H), 1.78–1.67 (comp, 2H),
1.21 (d, J¼7.0 Hz, 3H), 0.83 (s, 9H), 0.10 (s, 3H), 0.06 (s,
3H); 13C NMR (125 MHz) d 174.0, 153.1, 135.5, 135.2,
129.5, 128.9, 127.3, 117.1, 88.6, 71.9, 69.3, 65.7, 56.0,
48.0, 41.7, 37.8, 33.4, 25.8, 22.8, 21.8, 18.0, ꢀ4.4, ꢀ4.6;
IR (neat) 3307, 2931, 1784, 1696, 1384, 1249, 1208, 1096,
837, 774 cmꢀ1
; mass spectrum (CI) m/z 512.2833
[C29H42NO5Si (M+1) requires 512.2832], 512 (base), 494,
454, 380, 362, 205, 163.
4.1.14. (2S)-Methyl-3-(toluene-4-sulfonyloxy)propionic
acid methyl ester (25). To a solution of alcohol 24
(5.36 g, 45.4 mmol) in anhydrous CH2Cl2 (65 mL) at 0 ꢁC
was added Et3N (7.60 mL, 54.4 mmol), DMAP (1.10 g,
9.07 mmol), and TsCl (10.4 g, 54.4 mmol) successively.
The cooling bath was removed after 1 h, and the mixture
was stirred at room temperature for 20 h. The mixture was
poured into water (50 mL), and the resulting biphasic solu-
tion was extracted with CH2Cl2 (3ꢃ25 mL). The combined
organic layers were washed with saturated aqueous NaHCO3
(50 mL), brine (50 mL), dried (Na2SO4), filtered, and con-
centrated under reduced pressure to a volume of approxi-
mately 15 mL. This solution was filtered through a pad of
837, 779 cmꢀ1
; mass spectrum (CI) m/z 470.2720
[C27H40NO4Si (M+1) requires 470.2727], 470 (base), 454,
412, 338.
4.1.12. (4S)-Benzyl-(3S)-[(7R)-(tert-butyldimethylsilanyl-
oxy)-(5S)-methyl-4-vinylcyclohept-3-enecarbonyl]oxa-
zolidin-2-one (15). A solution of 14 (20 mg, 0.0426 mmol)
in anhydrous CH2Cl2 (1.5 mL) was degassed by bubbling
with a stream of argon for 10 min, whereupon dioxolane 18
(15 mg, 0.128 mmol) and catalyst 17 (5 mg, 0.009 mmol)
were added. The mixture was stirred at 45 ꢁC for 22 h

D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
11445
silica (2 cm) rinsing with CH2Cl2 (100 mL). The filtrate was
concentrated under reduced pressure to afford 11.8 g (96%)
of 25 as a light yellow oil with spectral characteristics iden-
tical to those previously reported.48
(400 MHz) d 7.79–7.77 (comp, 2H), 7.35–7.33 (comp, 2H),
4.06 (dd, J¼9.2, 5.8 Hz, 1H), 3.87 (dd, J¼9.2, 7.8 Hz, 1H),
2.87–2.78 (m, 1H), 2.45 (s, 3H), 1.19 (d, J¼6.8 Hz, 3H),
1.04–0.96 (comp, 21H); 13C NMR (125 MHz) d 144.8,
133.1, 129.8, 127.9, 107.4, 82.9, 72.6, 27.2, 21.6, 18.5,
17.7, 11.1; IR (neat) 2942, 2865, 2170, 1599, 1463, 1365,
1190, 1178, 1098, 980, 667, 554 cmꢀ1; mass spectrum (CI)
m/z 395.2075 [C21H35O3SiS (M+1) requires 395.2076],
395, 351, 329, 285 (base).
4.1.15. 4,4-Dibromo-(2R)-methyl-1-(toluene-4-sulfonyl-
oxy)but-3-ene (26). To a solution of ester 25 (2.0 g,
7.34 mmol) in anhydrous PhMe (36.5 mL) at ꢀ78 ꢁC was
added DIBAL-H (1 M in PhMe, 8.1 mL, 8.08 mmol) drop-
wise via syringe. The mixture was stirred for 1.5 h at
ꢀ78 ꢁC, whereupon EtOAc (30 mL) was added and the cool-
ing bath removed. Once the mixture had warmed to room
temperature, saturated aqueous Rochelle’s salt (100 mL)
was added, and the biphasic mixture was stirred vigorously
for 3 h. The layers were separated, and the aqueous phase
was extracted with EtOAc (3ꢃ20 mL). The combined
organics were washed with water (2ꢃ30 mL) and brine
(2ꢃ30 mL), dried (Na2SO4), filtered, and concentrated under
reduced pressure (20 mmHg) to afford the crude aldehyde
(ca. 2.0 g) as a yellow oil that was used in the next step with-
out further purification.
4.1.17. (3S)-Methyl-5-triisopropylsilanylpent-4-yne-
nitrile (28). To a solution of tosylate 27 (1.11 g, 2.81 mmol)
in anhydrous DMSO (11.2 mL) was added anhydrous KCN
(385 mg, 5.91 mmol). The mixture was stirred at 60 ꢁC for
3 h and then allowed to cool to room temperature, whereupon
it was slowly poured into a 15% brine (40 mL). The resulting
mixture was extracted with Et2O (3ꢃ10 mL), and the com-
bined organics were dried (Na2SO4), filtered, and concen-
trated at atmospheric pressure. The residue was purified by
flash chromatography eluting with pentane/Et2O (4:1) to
give 451 mg (64%) of the nitrile 28 and 125 mg (20%) of
enyne 29 as colorless oils; 1H NMR (400 MHz) d 2.91–2.83
(m, 1H), 2.58–2.47 (comp, 2H), 1.35 (d, J¼6.8 Hz, 3H),
1.08–1.02 (comp, 21H); 13C NMR (125 MHz) d 117.4,
108.5, 83.2, 25.4, 24.4, 20.6, 18.5, 11.1; IR (neat) 2943,
Solid CBr4 (4.88 g, 14.7 mmol) was added in one portion to
a solution of PPh3 (7.70 g, 29.4 mmol) in anhydrous CH2Cl2
(37 mL) at 0 ꢁC. After stirring for 10 min, a solution of the
preceding aldehyde (ca. 2.0 g) and 2,6-lutidine (1.7 mL,
14.7 mmol) in CH2Cl2 (5 mL) was added dropwise via
syringe. Stirring was continued at 0 ꢁC for 1 h, whereupon
saturated aqueous NH4Cl (6 mL) was added and the cooling
bath removed. The reaction mixture was poured into satu-
rated aqueous NH4Cl (40 mL), and the resulting biphasic
mixture was extracted with CH2Cl2 (3ꢃ15 mL). The com-
bined organics were dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was purified by
flash chromatography eluting with Et2O/pentane (2:1) to
give 1.82 g (62% from 25) of 26 as a white solid; mp 74–
2866, 2173, 1463, 1382, 1331, 1120, 996, 883, 667 cmꢀ1
;
mass spectrum (CI) m/z 250.1991 [C15H28NSi (M+1) requires
250.1991], 250 (base), 206, 157.
Enyne 29: 1H NMR (500 MHz) d 5.34–5.33 (m, 1H), 5.24–
5.22 (m, 1H), 1.91–1.90 (comp, 3H), 1.08–1.07 (comp,
21H); 13C NMR (125 MHz) d 127.2, 122.2, 108.5, 89.3,
23.5, 18.6, 11.3; IR (neat) 2944, 2865, 2253, 1465, 1383,
1096 cmꢀ1; mass spectrum (CI) m/z 223.1875 [C14H27Si
(M+1) requires 223.1882], 223 (base), 181, 157.
1
76 ꢁC; H NMR (400 MHz) d 7.79–7.77 (m, 2H), 7.37–
4.1.18. (3S)-Methyl-5-triisopropylsilanylpent-4-ynal
(23). DIBAL-H (1 M in CH2Cl2, 5.4 mL, 5.35 mmol) was
added dropwise via syringe to a solution of nitrile 28
(445 mg, 1.78 mmol) in anhydrous CH2Cl2 (18 mL) at
ꢀ78 ꢁC. The reaction mixture was stirred at ꢀ78 ꢁC for
3 h, whereupon 1 N HCl (5 mL) was added and the cooling
bath was removed. The mixture was poured into 1 N HCl
(25 mL), and the resulting biphasic mixture was extracted
with CH2Cl2 (3ꢃ10 mL). The combined organics were
washed with brine (25 mL), dried (Na2SO4), filtered, and
concentrated at atmospheric pressure. The residue was puri-
fied by flash chromatography eluting with pentane/Et2O
(3:1) to give 371 mg (83%) of 23 as a yellow oil; 1H NMR
(500 MHz) d 9.81 (t, J¼2.1 Hz, 1H), 2.99 (app sext.,
J¼6.9 Hz, 1H), 2.54 (ddd, J¼16.5, 7.4, 2.1 Hz, 1H), 2.48
(ddd, J¼16.5, 6.9, 2.1 Hz, 1H), 1.24 (d, J¼6.9 Hz, 3H),
1.05–0.98 (comp, 21H); 13C NMR (125 MHz) d 201.2,
111.0, 81.7, 50.0, 21.8, 21.2, 18.6, 11.2; IR (neat) 2943,
2866, 2167, 1730, 1463, 996, 883, 676 cmꢀ1; mass spectrum
(CI) m/z 253.1990 [C15H29OSi (M+1) requires 253.1988],
253 (base), 209, 157.
7.35 (m, 2H), 6.13 (d, J¼9.2 Hz, 1H), 3.92–3.90 (comp,
2H), 2.83–2.73 (m, 1H), 2.45 (s, 3H), 1.02 (d, J¼6.8 Hz,
3H); 13C NMR (100 MHz) d 145.3, 138.5, 132.9, 130.2,
128.2, 91.3, 72.2, 38.1, 21.9, 15.7; IR (CDCl3) 2973, 1598,
1458, 1360, 1176, 1097, 973, 813, 784, 666 cmꢀ1; mass
spectrum (CI) m/z 396.9119 [C12H15O3SBr2 (M+1) requires
396.9109], 401, 399 (base), 397.
4.1.16. Toluene-4-sulfonic acid-(2R)-methyl-4-triisopro-
pylsilanylbut-3-ynyl ester (27). n-BuLi (2.47 M in hexane,
4.10 mL, 10.1 mmol) was added dropwise via syringe to a
solution of the preceding dibromide (1.61 g, 4.04 mmol) in
anhydrous THF (13.3 mL) at ꢀ78 ꢁC. After 1 h at ꢀ78 ꢁC,
the reaction mixture was allowed to warm to ꢀ20 ꢁC, and
stirring was continued at this temperature for 1 h. The reac-
tion mixture was cooled to ꢀ78 ꢁC, whereupon TIPSOTf
(3.30 mL, 12.1 mmol) was added. The cooling bath was
removed, and the reaction mixture was stirred at room tem-
perature for 4 h, whereupon MeOH (4 mL) was added and
stirring continued for 10 min. The reaction mixture was
pouredintosaturated aqueousNH4Cl(30 mL), andtheresult-
ing biphasic mixture was extracted with Et2O (3ꢃ10 mL).
The combined organics were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was puri-
fied by flash chromatography eluting with pentane/Et2O
4.1.19. 3-[(2S)-Allyl-(3R)-hydroxy-(5S)-methyl-7-tri-
isopropylsilanylhept-6-ynoyl]-(4S)-benzyloxazolidin-2-
one (30). Bu2BOTf (470 mL, 1.88 mmol)47 was added via
syringe to a solution of oxazolidinone 6 (407 mg, 1.57 mmol)
and EtN(i-Pr)2 (330 mL, 1.88 mmol) in anhydrous PhMe
1
(3:1) to give 1.11 g (70%) of 27 as a yellow oil; H NMR

11446
D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
(11 mL) at ꢀ78 ꢁC. The mixture was stirred at ꢀ78 ꢁC for
1 h, whereupon aldehyde 23 (475 mg, 1.88 mmol) in anhy-
drous PhMe (2 mL) was added dropwise via syringe. The
mixture was stirred at ꢀ78 ꢁC for 30 min and then at room
temperature for 6 h. The mixture was cooled to 0 ꢁC, where-
upon pH 7.0 phosphate buffer (2 mL), MeOH (1 mL), and
30% H2O2 (500 mL) were added successively; stirring was
continued for 1 h. The mixture was poured into H2O
(30 mL), and the resulting biphasic mixture was extracted
with CH2Cl2 (3ꢃ10 mL). The combined organics were dried
(Na2SO4), filtered, and concentrated. The residue was puri-
fied by flash chromatography eluting with hexane/EtOAc
(2:1) to give 705 mg (88%) of 30 as a colorless oil
(dr>95:5 by H NMR); H NMR (500 MHz) d 7.33–7.30
(comp, 2H), 7.27–7.24 (m, 1H), 7.21–7.19 (comp, 2H),
5.88–5.80 (m, 1H), 5.12–5.08 (m, 1H), 5.03–5.01 (m, 1H),
4.68 (ddt, J¼10.2, 7.0, 3.6 Hz, 1H), 4.28–4.25 (comp, 2H),
4.15–4.09 (comp, 2H), 3.27 (dd, J¼13.3, 3.2 Hz, 1H), 2.80–
2.72 (m, 1H), 2.65–2.56 (comp, 2H), 2.42–2.37 (m, 1H),
1.65–1.60 (m, 1H), 1.54–1.50 (m, 1H), 1.20 (d, J¼6.8 Hz,
3H), 1.06–0.97 (comp, 21H); 13C NMR (125 MHz)
d 174.8, 153.6, 135.3, 135.2, 129.4, 128.9, 127.3, 117.2,
112.8, 80.8, 70.6, 65.9, 55.6, 47.4, 40.8, 38.0, 32.1, 23.9,
21.7, 18.6, 11.2; IR (neat) 3523, 2942, 2162, 1782, 1698,
1462, 1386, 1350, 1237, 1208, 1102, 997, 918, 883,
702 cmꢀ1; mass spectrum (CI) m/z 512.3195 [C30H45NO4Si
(M+1) requires 512.3196], 512 (base), 468, 318.
0 ꢁC was added 2,6-lutidine (460 mL, 3.97 mmol) and
TBDMSOTf (300 mL, 1.32 mmol). The resulting solution
was stirred at 0 ꢁC for 1 h, whereupon MeOH (3 mL) was
added and the cooling bath removed. After warming to
room temperature, the mixture was poured into H2O
(20 mL), and the resulting biphasic mixture was extracted
with CH2Cl2 (3ꢃ5 mL). The combined organics were dried
(Na2SO4), filtered, and concentrated. The residue was puri-
fied by flash chromatography eluting with hexane/EtOAc
(3:1) to give 334 mg (99%) of 32 as a yellow oil; 1H NMR
(500 MHz) d 5.74 (ddt, J¼17.1, 10.0, 7.1 Hz, 1H), 5.07–
5.02 (m, 1H), 4.97–4.94 (m, 1H), 4.11–4.07 (m, 1H), 3.62
(s, 3H), 3.15 (s, 3H), 3.08–3.00 (br s, 1H), 2.55–2.49 (m,
1H), 2.45–2.40 (m, 1H), 2.26–2.21 (m, 1H), 1.67–1.62
(comp, 2H), 1.18 (d, J¼7.0 Hz, 3H), 1.06–0.96 (comp,
21H), 0.86 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H); 13C NMR
(125 MHz) d 174.4, 136.5, 116.4, 113.5, 80.6, 72.2, 61.1,
47.5, 42.7, 33.3, 32.0, 26.0, 24.1, 22.2, 18.6, 18.1, 11.3,
ꢀ4.2; IR (neat) 2941, 2864, 2163, 1668, 1463, 1382, 1253,
1096, 996, 883, 838, 776, 676 cmꢀ1; mass spectrum (CI)
m/z 510.3798 [C28H56NO3Si2 (M+1) requires 510.3799],
510 (base), 466, 452.
1
1
4.1.22. (3S)-Allyl-(4R)-(tert-butyldimethylsilanyloxy)-
(6S)-methyl-8-triisopropylsilanyloct-7-yn-2-one.
MeMgBr (3 M in Et2O, 1.10 mL, 3.27 mmol) was added
dropwise via syringe to a solution of the preceding amide
(333 mg, 0.653 mmol) in anhydrous THF (6.6 mL) at
ꢀ78 ꢁC. The reaction mixture was stirred at ꢀ78 ꢁC for
30 min and then at 0 ꢁC for 1.5 h, whereupon saturated aque-
ous NH4Cl (5 mL) was added. The mixture was poured into
a 15% brine solution (20 mL), and the resulting biphasic
mixture was extracted with EtOAc (3ꢃ5 mL). The com-
bined organics were dried (Na2SO4), filtered, and concen-
trated. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (5:1) to give 292 mg (96%) of
4.1.20. (2S)-Allyl-(3R)-hydroxy-(5S)-methyl-7-triisopro-
pylsilanylhept-6-ynoic acid methoxymethylamide (31).
Me2AlCl (1 M in hexane, 5.25 mL, 5.25 mmol) was added
dropwise via syringe to a solution of HCl$HN(OMe)Me
(512 mg, 5.25 mmol) in anhydrous CH2Cl2 (8.0 mL) at
0 ꢁC. The mixture was stirred at 0 ꢁC for 45 min, the cooling
bath was removed, and stirring was continued at room tem-
perature for 30 min. The mixture was cooled to 0 ꢁC, where-
upon alcohol 30 (671 mg, 1.31 mmol) in anhydrous CH2Cl2
(2 mL) was added dropwise via syringe. The mixture was
stirred at 0 ꢁC for 30 min and then at room temperature for
6 h. The reaction was quenched at 0 ꢁC with 1 N HCl
(5 mL). The mixture was poured into 1 N HCl (20 mL),
and the resulting biphasic mixture was extracted with
CH2Cl2 (3ꢃ10 mL). The organic layers were combined,
dried (Na2SO4), filtered, and concentrated. The residue
was purified by flash chromatography eluting with hexane/
EtOAc (3:2) to give 311 mg (60%) of 31 as a colorless oil;
1H NMR (500 MHz) d 5.75 (ddt, J¼17.1, 10.0, 7.0 Hz,
1H), 5.06 (dd, J¼17.1, 1.6 Hz, 1H), 4.97 (dd, J¼10.0,
0.8 Hz, 1H), 4.16–4.13 (m, 1H), 3.65 (s, 3H), 3.17 (s, 3H),
3.08–3.00 (br s, 1H), 2.76 (dtd, J¼10.9, 7.0, 4.1, 1H),
2.55–2.48 (m, 1H), 2.38–2.33 (m, 1H), 1.69 (ddd, J¼13.4,
10.0, 4.1 Hz, 1H), 1.42 (ddd, J¼13.4, 10.9, 2.4 Hz, 1H),
1.20 (d, J¼7.0 Hz, 3H), 1.05–0.96 (comp, 21H); 13C NMR
(125 MHz) d 176.2, 136.1, 116.7, 113.2, 80.5, 70.3, 61.5,
45.3, 42.0, 31.9, 30.9, 24.0, 21.8, 18.6, 11.2; IR (neat)
3449, 2941, 2865, 2161, 1640, 1463, 1384, 994, 817, 883,
676 cmꢀ1; mass spectrum (CI) m/z 396.2934 [C22H42NO3Si
(M+1) requires 396.2934], 397 (base), 352.
1
the ketone as a yellow oil; H NMR (500 MHz) d 5.72
(ddt, J¼17.1, 10.3, 7.2 Hz, 1H), 5.05–4.96 (comp, 2H),
4.12–4.08 (m, 1H), 2.83–2.79 (m, 1H), 2.59–2.50 (m, 1H),
2.45–2.38 (m, 1H), 2.22 (s, 3H), 2.04–1.97 (m, 1H), 1.51–
1.44 (m, 1H), 1.29–1.22 (m, 1H), 1.18 (d, J¼6.8 Hz, 3H),
1.08–1.01 (comp, 21H), 0.92 (s, 9H), 0.17 (s, 3H), 0.15 (s,
3H); 13C NMR (125 MHz) d 210.1, 136.2, 116.5, 113.0,
81.0, 72.1, 58.9, 41.2, 32.8, 32.3, 25.9, 24.2, 22.2, 18.6,
18.1, 11.5, ꢀ4.0, ꢀ4.6; IR (neat) 2942, 2865, 2162, 1714,
1642, 1463, 1253, 1171, 1085, 837, 776, 677 cmꢀ1; mass
spectrum (CI) m/z 465.3582 [C27H53O2Si2 (M+1) requires
465.3584], 465, 449, 421 (base), 407, 367, 199.
4.1.23. Trifluoromethanesulfonic acid (2S)-allyl-(3R)-
(tert-butyldimethylsilanyloxy)-(5S)-methyl-1-methylene-
7-triisopropylsilanylhept-6-ynyl ester (22). A solution of
the preceding ketone (48 mg, 0.103 mmol) in anhydrous
THF (200 mL) was added dropwise via cannula to a solution
of KHMDS (0.5 M in PhMe, 410 mL, 0.207 mmol) in THF
(200 mL) at ꢀ78 ꢁC. The solution was stirred at ꢀ78 ꢁC
for 20 min, whereupon triflimide 33 (100 mg, 0.258 mmol)
in anhydrous THF (300 mL) was added via cannula. The re-
sulting mixture was stirred at ꢀ78 ꢁC for 1 h, 0 ꢁC for 1 h,
then at room temperature for 1 h. The reaction was quenched
at 0 ꢁC with saturated aqueous NH4Cl (2 mL). The mixture
was poured into a 15% brine solution (10 mL), and the result-
ing biphasic mixture was extracted with Et2O (3ꢃ5 mL).
4.1.21. (2S)-Allyl-(3R)-(tert-butyldimethylsilanyloxy)-
(5S)-methyl-7-triisopropylsilanylhept-6-ynoic acid meth-
oxymethylamide (32). To a solution of the preceding amide
(262 mg, 0.662 mmol) in anhydrous CH2Cl2 (9.5 mL) at

D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
11447
The combined organics were dried (Na2SO4), filtered, and
concentrated. The residue was purified by flash chromato-
graphy eluting with pentane/Et2O (20:1) to give 55 mg
1H), 1.23 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz)
d 170.4, 138.6, 134.4, 122.3, 118.3, 87.3, 79.1, 69.9, 42.3,
38.1, 32.6, 23.0, 21.7; IR (neat) cmꢀ1; mass spectrum (CI)
m/z 205.1229 [C13H17O2 (M+1) requires 205.1229], 409
(dimer), 205 (base).
1
(89%) of 22 as a yellow oil; H NMR (500 MHz) d 5.75
(ddt, J¼17.1, 10.2, 6.8 Hz, 1H), 5.24 (d, J¼4.0 Hz, 1H),
5.11–5.04 (comp, 2H), 4.91 (d, J¼4.0 Hz, 1H), 4.08–4.05
(m, 1H), 2.60–2.52 (m, 1H), 2.51–2.48 (m, 1H), 2.29–2.19
(comp, 2H), 1.54–1.45 (comp, 2H), 1.19 (d, J¼7.0 Hz,
3H), 1.06–0.99 (comp, 21H), 0.87 (s, 9H), 0.13 (s, 3H),
0.06 (s, 3H); 19F NMR (470 MHz) d ꢀ74.59 (s, 3F); 13C
NMR (125 MHz) d 155.9, 134.9, 118.4 (JCF¼320.3 Hz),
117.4, 112.8, 105.7, 81.1, 71.7, 51.1, 41.5, 32.5, 25.9,
24.1, 22.2, 18.6, 18.1, 11.2, ꢀ4.1, ꢀ4.4; IR (neat) 2942,
2865, 2162, 1660, 1422, 1251, 1213, 1143, 936, 838,
4.1.26. 8-epi-Xanthatin (1). A solution of lactone 21 (7 mg,
0.034 mmol) in anhydrous CH2Cl2 (6.9 mL) was degassed
by bubbling through a stream of argon for 10 min, where-
upon freshly distilled methyl vinyl ketone (29 mL,
0.34 mmol) and catalyst 17 (4.3 mg, 0.007 mmol) was
added. The mixture was stirred at 45 ꢁC for 12 h and then
cooled to room temperature, whereupon DMSO (50 mL)
was added and stirring continued for 6 h. The mixture was
concentrated and then purified by flash chromatography
eluting with Et2O to give 7 mg (83%) of 1 as a colorless
776, 677 cmꢀ1
; mass spectrum (CI) m/z 597.3078
[C28H52O4Si2F3 requires 597.3077], 597, 441, 367 (base).
1
oil; [a]2D4 +23.4 (c 0.333, CHCl3); H NMR (400 MHz)
4.1.24. (3R)-Allyl-(4R)-(tert-butyl-dimethyl-silanyloxy)-
(6S)-methyl-2-methylene-8-triisopropylsilanyl-oct-7-
ynoic acid methyl ester (34). A solution of 22 (54 mg,
0.091 mmol) in anhydrous DMF (400 mL) was degassed
by bubbling with a stream of CO for 5 min and then added
to a solution of similarly degassed anhydrous MeOH
(150 mL, 3.62 mmol), Et3N (25 mL, 0.181 mmol), Pd(OAc)2
(2 mg, 0.009 mmol), and PPh3 (4 mg, 0.0181 mmol). The
mixture was stirred under an atmosphere of CO (balloon)
at room temperature for 3.5 h. The reaction mixture was
poured into H2O (10 mL), and the resulting biphasic mixture
was extracted with Et2O (3ꢃ5 mL). The combined organics
were dried (Na2SO4), filtered, and concentrated. The residue
was purified by flash chromatography eluting with pentane/
d 6.97 (d, J¼16.1 Hz, 1H), 6.32 (d, J¼3.4 Hz, 1H), 6.20
(dd, J¼9.0, 6.3 Hz, 1H), 6.13 (d, J¼16.1 Hz, 1H), 5.57 (d,
J¼2.9 Hz, 1H), 4.68–4.62 (m, 1H), 3.45–3.37 (m, 1H),
2.87–2.78 (m, 1H), 2.65–2.56 (m, 1H), 2.53–2.46 (m, 1H),
2.29 (s, 3H), 2.17 (ddd, J¼14.2, 7.1, 2.2 Hz, 1H), 1.95–1.86
(m, 1H), 1.17 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz)
d 198.7, 170.0, 146.7, 143.1, 138.3, 135.9, 126.1, 122.8,
78.4, 41.4, 36.5, 31.9, 27.9, 27.2, 21.7; IR (neat) 2957,
2360, 1761, 1664, 1619, 1592, 1274, 1256, 980 cmꢀ1
;
mass spectrum (CI) m/z 247.1333 [C15H19O3 (M+1) requires
247.1334], 247 (base), 249.
Acknowledgements
1
Et2O (20:1) to give 39 mg (85%) of 34 as a yellow oil; H
NMR (500 MHz) d 6.27–6.26 (m, 1H), 5.47–5.46 (m, 1H),
5.72–5.64 (m, 1H), 4.99–4.92 (comp, 2H), 3.95 (ddd,
J¼9.2, 5.0, 2.7 Hz, 1H), 3.71 (s, 3H), 2.95–2.91 (m, 1H),
2.58–2.50 (m, 1H), 2.42–2.37 (m, 1H), 2.22–2.16 (m, 1H),
1.56–1.51 (m, 1H), 1.40–1.35 (m, 1H), 1.16 (d, J¼6.8 Hz,
3H), 1.06–1.00 (comp, 21H), 0.85 (s, 9H), 0.11 (s, 3H),
0.04 (s, 3H); 13C NMR (125 MHz) d 168.1, 140.5, 136.7,
126.0, 116.1, 113.5, 80.5, 72.7, 51.8, 46.0, 42.3, 34.2,
26.0, 23.9, 22.1, 18.6, 18.2, 11.3, ꢀ4.0, ꢀ4.1; IR (neat)
2943, 2864, 2163, 1724, 1463, 1253, 1155, 1090, 1058,
996, 883, 837, 775, 660 cmꢀ1; mass spectrum (CI) m/z
507.3688 [C29H55O3Si2 (M+1) requires 507.3690], 507
(base), 449, 375.
We thank the National Institutes of Health (GM31077),
Pfizer, Inc., Merck Research Laboratories, and the Robert
A. Welch Foundation for their generous support of this
research. We are also grateful to Dr. Richard Fisher (Materia,
Inc.) for catalyst support and helpful discussions. We addi-
tionally thank Dr. Shi Yong Ryu of the Korea Research
C
NMR spectra of natural 1. D.A.K. thanks Pfizer, Inc. for
an undergraduate research fellowship.
Institute of Chemical Technology for providing 1H and 13
References and notes
4.1.25. (4R)-Allyl-(5R)-[(2S)-methylbut-3-ynyl]-3-meth-
ylenedihydrofuran-2-one (21). A solution of TBAF$3H2O
(74 mg, 0.233 mmol) in THF (500 mL) was added via
syringe to a solution of acrylate 34 (38 mg, 0.075 mmol)
in anhydrous THF (1 mL) at 0 ꢁC. The mixture was stirred
at 0 ꢁC for 30 min and then at room temperature for 6 h.
The mixture was poured into saturated aqueous NH4Cl
(10 mL), and the resulting biphasic mixture was extracted
with Et2O (3ꢃ5 mL). The combined organics were dried
(Na2SO4), filtered, and concentrated. The residue was puri-
fied by flash chromatography eluting with pentane/Et2O
1. (a) Bohlmann, F.; Zdero, C. Phytochemistry 1981, 20, 2429–
2430; (b) Seaman, F. C. Bot. Rev. 1982, 48, 121–595; (c)
Ghazy, N. M.; Omar, A. A.; Elrashidy, E. M.; Metwally,
A. M. Egypt. J. Pharm. Sci. 1988, 29, 39–42; (d) Cumanda,
J.; Marinoni, G. J. Nat. Prod. 1991, 54, 460–465.
2. (a) McMillan, C.; Chavez, P. I.; Mabry, T. J. Biochem. Syst.
Ecol. 1975, 3, 137–141; (b) Kawazu, K.; Nakajima, S.;
Ariwa, M. Experientia 1979, 35, 1294–1295; (c) Bohlmann,
F.; Singh, P.; Joshi, K. C.; Singh, C. L. Phytochemistry 1982,
21, 1441–1443; (d) Ahmed, A. A.; Jakupovic, J.; Bohlmann,
F.; Regaila, H. A.; Ahmed, A. M. Phytochemistry 1990, 29,
2211–2215.
1
(3:1) to give 12 mg (78%) of 21 as a yellow oil; H NMR
(400 MHz) d 6.23 (d, J¼2.2 Hz, 1H), 5.77 (ddt, J¼17.1,
10.3, 6.8 Hz, 1H), 5.57 (d, J¼2.2 Hz, 1H), 5.17–5.09
(comp, 2H), 4.89 (ddd, J¼10.9, 7.2, 2.4 Hz, 1H), 3.20–
3.13 (m, 1H), 2.82–2.73 (m, 1H), 2.37–2.22 (comp, 2H),
2.09 (d, J¼2.4 Hz, 1H), 1.69–1.62 (m, 1H), 1.59–1.52 (m,
3. Minato, H.; Horibe, I. J. Chem. Soc. 1965, 7009–7017.
4. Joshi, S. P.; Rojatkar, S. R.; Nagasampagi, B. A. J. Med.
Aromatic Plant Sci. 1997, 19, 366–368.
5. (a) Ahn, J.-W.; No, Z.; Ryu, S.-Y.; Zee, O.-P.; Kim, S.-K. Nat.
Prod. Sci. 1995, 1, 1–4; (b) Kim, Y. S.; Kim, J. S.; Park, S.-H.;

11448
D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
Choi, S.-U.; Lee, C. O.; Kim, S.-K.; Kim, Y.-K.; Kim, S. H.;
Ryu, S. Y. Planta Med. 2003, 69, 375–377.
6. Kupchan, M. S.; Eakin, M. A.; Thomas, A. M. J. Med. Chem.
1971, 14, 1147–1152.
7. For synthetic studies directed toward the preparation of the
xanthanolide core, see: (a) Bhanot, O. S.; Dutta, P. C.
J. Chem. Soc. C 1968, 2583–2588; (b) Nosse, B.; Chhor,
23. The diastereoselectivities in all reactions were determined by
1H NMR and integrating diagnostic signals for the two stereo-
isomers.
24. Assignment of the stereochemistry at C(10) in 9a was unequi-
1
vocally established by comparing the H NMR spectrum of
the intermediate 13 derived from 9a with that of a sample of
13 independently synthesized from ester 24 as outlined in
Schemes 7 and 8.
R. B.; Jeong, W. B.; Bohm, C.; Reiser, O. Org. Lett. 2003, 5,
¨
941–944; (c) Rudler, H.; Alvarez, C.; Parlier, A.; Perez, E.;
Denise, B.; Xu, Y.; Vaissermann, J. Tetrahedron Lett. 2004,
45, 2409–2411.
25. Sibi, M. P.; Deshpande, P. K.; Ji, J. Tetrahedron Lett. 1995, 36,
8965–8968.
26. Sibi, M. P.; Rutherford, D.; Sharma, R. J. Chem. Soc., Perkin
Trans. 1 1994, 1675–1678.
27. Gribble, G. W.; Leese, R. M.; Evans, B. E. Synthesis 1977,
172–176.
8. (a) Fugami, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett.
1987, 28, 809–812; (b) Fugami, K.; Oshima, K.; Utimoto, K.
Bull. Chem. Soc. Jpn. 1989, 62, 2050–2054.
9. Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371–3373.
10. Deiters, A.; Martin, S. F. Org. Lett. 2002, 4, 3243–3245.
11. (a) Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett.
1994, 35, 691–694; (b) Martin, S. F.; Humphrey, J. M.; Ali, A.;
Hillier, M. C. J. Am. Chem. Soc. 1999, 121, 866–867; (c)
Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.;
Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc.
2002, 124, 8584–8592.
12. (a) Martin, S. F.; Wagman, A. S. Tetrahedron Lett. 1995, 36,
1169–1170; (b) Fellows, I. M.; Kaelin, D. E., Jr.; Martin,
S. F. J. Am. Chem. Soc. 2000, 122, 10781–19787.
13. Washburn, D. G.; Heidebrecht, R. W., Jr.; Martin, S. F. Org.
Lett. 2003, 5, 3523–3525.
28. (a) Hansen, R. T.; Carr, D. B.; Schwartz, J. J. Am. Chem. Soc.
1978, 100, 2244–2245; (b) Schwartz, J.; Carr, D. B.; Hansen,
R. T.; Dayrit, F. M. J. Org. Chem. 1980, 45, 3053–3061.
29. Use of chiral ligands has been reported to induce diastereo-
selectivity in nickel-catalyzed conjugate additions of alkynyl
organoaluminum species, see: Kwak, Y.-S.; Corey, E. J. Org.
Lett. 2004, 6, 3385–3388.
30. Mancuco, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
43, 2480–2482.
31. For a AgNO3 deprotection of a silyl alkyne, see: Carreira,
E. M.; Bois, J. D. J. Am. Chem. Soc. 1995, 117, 8106–8125.
32. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179.
14. (a) Brenneman, J. B.; Martin, S. F. Org. Lett. 2004, 6, 1329–
1331; (b) Brenneman, J. B.; Machauer, R.; Martin, S. F.
Tetrahedron 2004, 60, 7301–7314.
33. (a) Hahn, E. F. J. Org. Chem. 1973, 38, 2092–2093; (b)
Gassman, P. G.; Burns, S. J.; Pfister, K. B. J. Org. Chem.
1993, 58, 1449–1457.
15. For reviews of enyne metathesis, see: (a) Mori, M. Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vol. 2, pp 176–204; (b) Mori, M. Topics in Organometallic
Chemistry; Springer: New York, NY, 1998; Vol. 1, pp 133–
154; (c) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1–18; (d)
Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317–
1382; (e) For a general review of RCM, see: Deiters, A.;
Martin, S. F. Chem. Rev. 2004, 104, 2199–2238.
16. For leading references on domino enyne RCM/CM reactions,
see: (a) Randl, S.; Lucas, N.; Connon, S. J.; Blechert, S. Adv.
Synth. Catal. 2002, 344, 631–633; (b) Royer, F.; Vilain, C.;
Elkaim, L.; Grimaud, L. Org. Lett. 2003, 5, 2007–2009; (c)
Lee, H.-Y.; Kim, H. Y.; Tae, H.; Kim, B. G.; Lee, J. Org.
Lett. 2003, 5, 3439–3442; (d) Clark, J. S.; Elustondo, F.;
Kimber, M. C. Chem. Commun. 2004, 2470–2471; (e)
Kitamura, T.; Sato, Y.; Mori, M. Tetrahedron 2004, 60,
9649–9657; (f) Salim, S. S.; Bellingham, R. K.; Brown,
R. C. D. Eur. J. Org. Chem. 2004, 800–806.
34. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2002, 125, 11360–11370.
35. The homodimer of 15 was isolated following chromatography
and characterized by 1H NMR and mass spectrometry.
36. For other examples of CM with methyl vinyl ketone, see: Dewi,
P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005, 46, 577–580
and references cited therein.
´
37. (a) Paquette, L. A.; Mendez-Andino, J. Tetrahedron Lett. 1999,
40, 4301–4304; (b) Mendez-Andino, J.; Paquette, L. A. Adv.
´
Synth. Catal. 2002, 344, 303–311.
38. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769–
3772.
39. The TMS-protected alkyne corresponding to 27 was also
prepared, but the derived nitrile was volatile and difficult to
obtain in reasonable yield. However, sufficient material with
the TMS-protected alkyne was carried forward to confirm
the stereochemistry of the conjugate addition reactions, see
Ref. 24.
17. For a preliminary account of some of this work, see: Kummer,
D. A.; Brenneman, J. B.; Martin, S. F. Org. Lett. 2005, 7, 4621–
4623.
18. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127–2129.
19. Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy, A. L.
J. Org. Chem. 2000, 65, 8499–8509.
20. (a) Kunz, H.; Pees, K. J. J. Chem. Soc., Perkin Trans. 1 1989,
40. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
48, 4171–4174.
41. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–
6302.
42. Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26,
1109–1112.
43. Crisp, G. T.; Meyer, A. G. Tetrahedron 1995, 51, 5831–5846.
44. Yokotani-Tomita, K.; Kato, J.; Kosemura, S.; Yamamura, S.;
Kushima, M.; Kakuta, H.; Hasegawa, K. Phytochemistry
1997, 46, 503–506.
1168–1169; (b) Ruck, K.; Kunz, H. Angew. Chem., Int. Ed.
¨
Engl. 1991, 30, 694–696; (c) Ruck, K.; Kunz, H. Synthesis
¨
1993, 1018–1028.
21. (a) Ruck, K.; Kunz, H. Synlett 1992, 343–344; (b) Elzner, S.;
Maas, S.; Engel, S.; Kunz, H. Synthesis 2004, 2153–2164.
22. Qian, X.; Russell, K. C.; Boteju, L. W.; Hruby, V. J.
Tetrahedron 1995, 51, 1033–1054.
45. NMR data for natural 1: 1H NMR (400 MHz, CDCl3) d 6.98 (d,
J¼16.0 Hz), 6.32 (d, J¼3.0 Hz), 6.20 (dd, J¼9.0, 6.5 Hz), 6.14
(d, J¼16.0 Hz), 5.57 (d, J¼3.0 Hz), 4.65 (ddd, 12, 8.5, 2.5 Hz),
3.40 (m), 2.83 (ddq, J¼12, 7, 6 Hz), 2.60 (ddd, J¼14, 11.5,
9 Hz), 2.50 (ddd, J¼14, 6.5, 5 Hz), 2.26 (s), 2.19 (ddd, J¼14,
¨

D. A. Kummer et al. / Tetrahedron 62 (2006) 11437–11449
11449
6, 2.5 Hz), 1.91 (ddd, J¼14, 12, 12 Hz), 1.18 (d, J¼7 Hz).44
13C NMR (CDCl3) d 198.3, 169.6, 146.4, 142.7, 138.0, 135.6,
125.8, 122.4, 78.1, 41.1, 36.2, 31.6, 27.6, 26.9, 21.4.2b
46. Still, W. C.; Khan, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–
2925.
47. Bu2BOTf was prepared according to: Evans, D. A.; Nelson,
J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103,
3099–3111.
48. Aissa, C.; Riveiros, R.; Ragot, J.; Furstner, A. J. Am. Chem.
Soc. 2003, 125, 15512–15520.
¨