The allenic Alder-ene reaction: constitutional group selectivity and its application to the synthesis of ovalicin

Article abstract of DOI:10.1016/j.tet.2006.06.115

The scope of the novel allenic Alder-ene reaction using Rh(I) and Ir(I) catalysts has been extended to differentially substituted 1,1,3-trisubstituted allenes. This allenyl substitution pattern can give three possible cross-conjugated triene products. The

Full text of DOI:10.1016/j.tet.2006.06.115

Tetrahedron 62 (2006) 10541–10554
The allenic Alder-ene reaction: constitutional group selectivity
and its application to the synthesis of ovalicin
*
Kay M. Brummond and Jamie M. McCabe
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 17 April 2006; revised 24 April 2006; accepted 9 June 2006
Available online 14 August 2006
Abstract—The scope of the novel allenic Alder-ene reaction using Rh(I) and Ir(I) catalysts has been extended to differentially substituted
1,1,3-trisubstituted allenes. This allenyl substitution pattern can give three possible cross-conjugated triene products. The selectivity of
this transformation can be controlled by varying reaction temperature, solvent, and catalyst. Progress toward the synthesis of ovalicin using
this triene forming protocol is described.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, rhodium has stepped into the limelight and proven
itself as a useful and powerful transition metal catalyst for
the Alder-ene reaction.11 In 2000, Zhang demonstrated the
first Rh(I)-catalyzed Alder-ene reaction with 1,6-enynes,
yielding 1,4-dienes.12 Rhodium was beneficial over ruthe-
nium, cobalt, or iron because reactions could be performed
at room temperature and the ligands on the catalyst could
be easily tuned to accommodate steric or electronic factors
in the substrates.13
Transition metal-catalyzed carbon–carbon bond formation
is an efficient method to rapidly increase molecular
complexity via skeletal reorganization and/or cycloaddition
processes.1 The mild conditions, functional group compati-
bility, and high regio- and stereoselectivities of these transi-
tion metal-catalyzed reactions are just a few reasons for their
prominence in natural product synthesis. Transition metal-
catalyzed cycloisomerizations such as the formal Alder-
ene reaction utilize functionalized enynes or allenynes to
access a unique array of cyclic structures.2 For example,
Trost3 has worked extensively on the intramolecular Alder-
ene reaction of 1,6-enynes using palladium or ruthenium to
obtain 1,3- or 1,4-dienes, respectively. Ruthenium gives
exclusively the 1,4-diene regioisomer while palladium gives
regioisomeric ratios dependent on the substrate structure.
Trost has also used ruthenium to effect an intermolecular
Alder-ene allene–ene coupling to give diene substrates.4
Buchwald5 and Takacs6 formed 1,4-dienes from enynes se-
lectivity using either titanium or iron catalysts, respectively.
We have previously reported the reaction of Rh(I) with alle-
nynes to produce cross-conjugated trienes. One example is
shown in Scheme 1, where allenyne 1 affords an 85% yield
of triene 2.14 This formal allenic Alder-ene reaction is
unique from others because the reaction conditions are used
to direct which double bond of the allene reacts. For ex-
ample, Malacria7 and Sato10 reported the same reactivity
pattern using cobalt and titanium, respectively; however,
p-bond selectivity was obtained using substrate control
(sterics and ring strain).15 Rhodium, unlike other transition
metals, was found to give selective cyclization with the distal
double bond of the allene regardless of the substitution
pattern on the allene or tether length.16
Intramolecular Alder-ene reactions of allene–ynes are not as
widely studied and only a few examples are known. Both
Malacria7 and Livinghouse8 used cobalt to effect an intra-
molecular allenic Alder-ene reaction. Malacria used this
cycloisomerization reaction in a synthesis of steroidal ana-
logs,9 while the triene was obtained as a by-product in 33%
yield by Livinghouse. Sato10 demonstrated an allenic Alder-
ene reaction using stoichiometric amounts of titanium.
TMS
TMS
[Rh(CO)2Cl]2
TsN
TsN
toluene, rt, 85%
•
C5H11
C4H9
[E : Z] = 5 : 1
1
2
Scheme 1. Rh(I)-catalyzed allenic Alder-ene reaction.
Keywords: Allenes; Alder-ene; Catalysis; Iridium; Rhodium; Trienes.
* Corresponding author. Fax: +1 412 624 8611; e-mail: kbrummon@pitt.
edu
Cross-conjugated trienes are seldom found in the literature,
which may be attributed to a lack of general procedures for
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.115

10542
K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
the formation of these highly unsaturated systems.17 Brum-
mond et al. have shown that the formal Alder-ene reaction
gives high yields of trienes with moderate E/Z selectivity
for a variety of substrates and that rhodium biscarbonyl chlo-
ride dimer is a general catalyst. The E/Z selectivity was in-
creased by changing the neutral Rh(I) catalyst to a cationic
Rh(I) or Ir(I) catalyst; altering selectivity from 5:1 to 13:1
or 99:1, respectively.14
found to inhibit endothelial cell proliferation. However,
the mechanism of action for this inhibition is still unclear.
Clardy21 illustrated that fumagillin, ovalicin, and TNP-470
covalently bind to a cobalt-containing enzyme called meth-
ionine amino peptidase (MetAP-2), but do not bind to the
closely related MetAP-1. It is significant that this binding
is selective since inhibition of both MetAP-1 and MetAP-2
is lethal.22 Methionine amino peptidase-2 removes methio-
nine residues from the N-termini of proteins in a critical
co-translational processing event and there is a strong corre-
lation between inhibition of endothelial cell proliferation
and inhibition of MetAP-2.23 However, the significance of
the binding is still under great debate since recently it was
reported that MetAP-2 function is independent of endothe-
lial cell production.24 Despite the enigmatic mechanisms
of action for these natural products, they are still under
investigation in the biological and clinical sector and are
synthetically popular targets.25
The high yields and mild conditions of the Rh(I)-catalyzed
allenic Alder-ene reaction motivated us to examine its value
in natural product synthesis. The application of this carbo-
cyclization process to the ovalicin/fumagillol class of ses-
quiterpenoids was the most exciting, due in part to the
potentially rapid access to the entire carbocyclic skeleton
and the interesting biological activity associated with these
compounds (Fig. 1).
Fumagillin (5), ovalicin (4), and analogs of these compounds
have been shown to inhibit angiogenesis in vivo.18 Angio-
genesis is essential for tumor growth and by suppressing
this process the tumor does not grow beyond a few cubic
millimeters, nor does it metastasize.19 Fumagillol (3) and
the analog TNP-470 (6) have been found to have an inhibi-
tory effect on the growth and metastasis of various cancers
including breast, colon, gastric, renal, ovarian, and pro-
state.20 It is known that endothelial cells play a necessary
role in angiogenesis, and both ovalicin and TNP-470 were
Corey was the first to synthesize (ꢀ)-ovalicin in 1985 in
12 steps. After the novel formation of an epoxy ketone, he
stereoselectively added the lithiated diene to give the desired
carbocyclic skeleton (Fig. 2).26 Subsequently, Corey pub-
lished an asymmetric synthesis of ovalicin by preparing
the epoxy ketone via an asymmetric dihydroxylation reac-
tion.27 Bath28 and Barco29 gain access to (ꢁ)-ovalicin by
manipulating naturally occurring optically pure building
blocks L-quebrachitol and (ꢁ)-quinic acid, respectively.
The most recent syntheses of (ꢁ)-ovalicin were reported
by Takahashi who starts with a simple sugar, D-mannose,
while also featuring ring closing metathesis and Hayashi
whose approach is similar to that of Corey.30
O
O
O
O
H
OH
OCH3
OCH3
OR
O
Our retrosynthetic analysis of ovalicin (4) is outlined in
Scheme 2. Conversion of 7 to ovalicin will be accomplished
by a stereoselective hydroxyl directed epoxidation of the
double bond, and conversion of the primary hydroxyl group
into the terminally trisubstituted double bond via an oxida-
tion and homologation sequence similar to the strategy
used by Taber in his synthesis of fumagillin.31 The highly
functionalized cyclohexanone 7, in turn, can be prepared
via a series of selective oxidations carried out on triene 8.
Fumagillol (3) R = H
Fumagillin (5) R =
Ovalicin (4)
O
OH
Cl
4
O
O
H
N
TNP-470 (6) R =
O
Figure 1. Structure of fumagillol, fumagillin, TNP-470, and ovalicin.
O
OH
OH
O
HO
HO
O
Ovalicin (4)
+
Li
OH
OCH3
D-Mannose
Corey 1985, 1994
Takahashi 2005
OH
OH
COOH
OH
OH
OH
HO
HO
OH
OCH3
OH
L-Quebrachitol
(-)-Quinic acid
Barco 1998
Bath 1994,1995
Figure 2. Previous synthetic strategies.
CH3
CH3
O
OP
OP
(4)
OH
OCH3
•
OP
Ovalicin
HO
H3C
O
OH
7
8
9
Scheme 2. Retrosynthetic analysis of ovalicin (7).

K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
10543
We plan to use the secondary hydroxyl group to direct the re-
gio- and stereoselectivities of the oxidation reactions. The
successful conversion of allene 9 to the desired triene 8
will require a regio- and stereoselective b-hydride elimina-
tion step. For example, when 1,1,3-trisubstituted allene 9 is
used, b-hydride elimination can occur to give E-10, Z-11,
and the constitutional isomer 12 (Scheme 3). Selective trans-
formations of this type have not been previously addressed in
our group32 and to the best of our knowledge, little is known
about the selectivity of these elimination reactions.
Treatment of the resulting iodide with benzenesulfinic acid
sodium salt formed sulfone 14 in 2 h in 76% yield.35 Addi-
tion of a-sulfonyl anion to 2-octynal followed by quenching
with acetic anhydride gave the crude acetate as a 1:1 mixture
of diastereomers. This diastereomeric mixture was reacted
with DBU to give enyne E-15 selectively in 60% yield in
three steps. Then a conjugate 1,6-addition of lithium di-
methylcuprate to enyne 15 gave a mixture of allene 16 and
diene 17 in 67% yield.36 Unfortunately, compounds 16 and
17 were only separable via HPLC; therefore, they were taken
on as a mixture to the next step. Treatment of sulfonyl allene
16 and diene 17 with 5 mol% of [Rh(CO)2Cl]2 gave trienes
E-18, Z-18, 19, and unreacted 17 in a 90% yield as a 3:5:1
ratio of trienes, respectively. This is a rare example of the
Z-isomer 18 predominating in any transition metal-catalyzed
Alder-ene reaction (entry 1, Table 1).37
R1
Rh(I)
+
+
CH2R1
•
R1
R1
CH3
CH3
Z-11
H3C
9, R1 = H
E-10
12
This seemingly anomalous result can be understood by con-
sideringthemetallocycleintermediatesIandII(Fig. 3). Inor-
der for b-hydride elimination to occur the dihedral angle of
the Rh–C–C–Ha arrangement must be almost syn periplanar.
Two competing conformations are depicted in I and II, lead-
ing to the E-18 and Z-18 isomers, respectively. Conformation
I reveals an eclipsing interaction between the methyl and bu-
tyl groups as well as possible steric interference between the
butyl group and the ligands on the rhodium. Conformation II
alleviates these steric and eclipsing interactions but possesses
Scheme 3. Rh(I)-catalyzed Alder-ene reaction.
Trost observed competing b-hydride eliminations in a Pd-
catalyzed cycloisomerization of 1,6-enynes; however, these
cases were different because the elimination reactions gave
either 1,3-diene or 1,4-diene products. Trost was able to alter
the product distribution by changing the functional groups
on the substrates.33 Backvall’s34 Pd-catalyzed carbocycliza-
€
tion of ene–allenes gave constitutional isomers resulting
from b-hydride elimination of differentially substituted
allenes, which produced 1,4-dienes in a 1:1 ratio. Altering
the functional groups on the starting material gave complete
constitutional group selectivity. Because so little is known
about the selectivity of this reaction, we initiated our synthe-
sis of ovalicin by first examining the selectivity of the key
Alder-ene reaction on a readily available precursor. More-
over, since we have previously demonstrated that E/Z iso-
meric ratios can be significantly increased by altering the
catalyst,13 we planned on first taking advantage of reagent
control and then if necessary substrate control.
A
1,3 strain. Thus, it is postulated that the Z-isomer is formed
preferentially via the selective reaction of conformation II.
Interestingly, removal of the TMS moiety from the terminus
of the alkyne caused a reversal in the E/Z selectivity (compare
entries 2 and 12, Table 1).
Triene E-18 is the desired isomer for the synthesis of ovalicin;
therefore, a systematic study to obtain E-18 selectively was
initiated and the results are summarized in Table 1. Reaction
of allenyne 16 with [Rh(CO)2Cl]2 gave Z-18 as the major
product at 50 ꢂC and room temperature (entries 1 and 2, Table
1). Because cationic Rh(I) or Ir(I) catalysts give E-isomers
preferentially,13 allene 16 was subjected to [Rh(COD)Cl]2/
AgBF4. This afforded E-18 in preference to Z-18, but signif-
icant quantities of the constitutional isomer 19 were also
formed (E-18:19¼1:1) (entry 3, Table 1). Exposure of 16 to
the cationic iridium conditions ([Ir(COD)Cl]2/AgBF4) gave
a 9:1:5 ratio of trienes E-18:Z-18:19, respectively (entry 4,
Table 1). The use of cationic Rh(I) and Ir(I) catalysts reversed
the E/Z selectivity (1:2 to 9:1), as expected, yet decreased the
constitutionalgroupselectivity(8:1to2:1)(entries1–4, Table
1). We donothavean explanationfortheseresults atthistime.
2. Results and discussion
With an eye toward the synthesis of ovalicin, model sulfonyl
allenyne 16 was prepared to explore the constitutional group
selectivity of the b-hydride elimination in the Alder-ene
reaction. Reaction of commercially available 5-chloro-1-(tri-
methylsilyl)-1-pentyne (13) with NaI/acetone gave 5-iodo-1-
(trimethylsilyl)-1-pentyne in a 99% yield (Scheme 4).
a, b
c
Cl
PhO2S
Next, a series of reactions were performed on allene 16 using
[Ir(COD)Cl]2/AgBF4 as the catalyst (entries 4–7, Table 1)
and varying only the temperature. These experiments
revealed an increase in selectivity at lower reaction temper-
ature. At ꢁ30 ꢂC a 6:1 E/Z isomeric ratio and a 7:1 constitu-
tional isomeric ratio were obtained (entry 7, Table 1). This
produced a 3:1 ratio (E-18 to Z-18+19) and confirms that
the regio- and stereoselectivity can be governed by the reac-
tion conditions.
TMS
TMS
13
14
TMS
TMS
PhO2S
TMS
d
+
C5H11
CH3
•
C5H11
PhO2S
C5H11
PhO2S
H3C
15
16
17
Scheme 4. Preparation of allenyne 16. Reagents and conditions: (a) NaI,
acetone, reflux, 99%; (b) benzenesulfinic acid sodium salt, DMF, 50 ꢂC,
76%; (c) 2-octynal, n-BuLi, THF, ꢁ78 ꢂC, quench Ac2O; DBU, THF,
0 ꢂC, 60% (three steps); (d) CuI, MeLi, TMSOTf, ether, ꢁ30 ꢂC, 67%
[16:17¼7:1].
The Alder-ene reactions summarized in Table 1 illustrate
that one constitutional isomer (E/Z-18) is preferred over
the other (19). The selectivity between the constitutional

10544
K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
Table 1. Results of rhodium-catalyzed Alder-ene reaction with sulfonyl allenynes 16 and 16aa
R
R
R
TMS
CH3
CH3
CH2
C4H9
+
+
C5H11
•
C4H9
C5H11
PhO2S
SO2Ph
SO2Ph
SO2Ph
19
H3C
TBAF
buffer
R = TMS 16
R = H 16a
E-18
Z-18
E-18a
Z-18a
19a
Entry
Substrate
Catalystb
Solvent
t (ꢂC)
E-18:Z-18:19
18:19
E-18:Z-18
Yield (%)
1
2
16
16
16
16
16
16
16
16
16
16
16
16a
A
A
B
C
C
C
C
D
D
D
D
A
Toluene
Toluene
DCE
DCE
DCE
50
rt
rt
rt
0
ꢁ10
ꢁ30
rt
ꢁ30
ꢁ40
ꢁ60
rt
3:5:1
2:4:1
1:0:1
9:1:5
4:1:1
5:1:2
6:1:1
4:1:2
4:1:1
NR
8:1
6:1
1:1
2:1
5:1
3:1
7:1
3:1
5:1
3:5
1:2
1:0
9:1
4:1
5:1
6:1
4:1
4:1
73d
93
3
97
4c
5
44d
80
6
DCE
DCE
7
80
85
80
8c
9
Acetone/DCE
Acetone/DCE
Toluene
Toluene
Toluene
10
11
12
NR
2:1:1
3:1
2:1
87
For reaction conditions see Section 4. Product ratios were determined by integration of olefin peaks in the 1H NMR.
A: 3–5 mol % [Rh(CO)2Cl]2; B: 5 mol % [Rh(COD)Cl]2, 10 mol % AgBF4; C: 10 mol % [Ir(COD)Cl]2, 20 mol % AgBF4; D: 5 mol % [Ir(COD)Cl]2,
a
b
10 mol % In(OTf)3.
Desilylated trienes E/Z-18a and 19a were obtained.
Nonpolar impurity was seen during reaction.
c
d
TMS
TMS
TMS
TMS
Ln
Ln
CH3
CH3
Ha
Rh
C4H9
C4H9
Rh
Ln
Ln
H
PhO2S
H
+
PhO2S
CH3
C2H5
H
CH3
H
C2H5
SO2Ph
SO2Ph
E-18
I
III
E/Z-18
Eclipsing CH3-CH2
TMS
TMS
Ln
Ha
TMS
TMS
CH3
H5C2
CH2
C5H11
Ln
H
Ln
Rh
Ln
Rh
PhO2S
PhO2S
+
C4H9
H
CH3
H
H
SO2Ph
C2H5
SO2Ph
II
Z-18
A1,3 Strain
IV
19
Figure 4. Explanation of constitutional group selectivity.
Figure 3. Explanation of E/Z selectivity.
yield with MeNHOMe$HCl and i-PrMgCl. Addition of the
lithium anion of silyl protected 4-pentyn-1-ol39 to the
Weinreb amide gave alkynyl ketone 21.40 Exposure of
ketone 21 to the Luche reduction conditions gave the desired
propargylic alcohol in a 58% yield (over two steps) as a
isomers is rationalized by the ability of either group (meth-
ylene (18) or methyl (19)) to stabilize the partial positive
charge developing in the b-hydride elimination step of the
reaction. Consequently, the b-hydride elimination is more
favorable from the methylene group in III rather than the
methyl group in IV; ultimately favoring elimination from
intermediate III to give E/Z-18, predominately (Fig. 4).
1
single diastereomer by H NMR. The propargylic alcohol
was converted to a mesylate with Et3N and MsCl. After
workup the crude mesylate was subjected to lithium di-
methylcuprate at ꢁ78 ꢂC forming allenyne 22a and enyne
23 in 80% yield in a 23:1 ratio, respectively.41 Treatment of
allenyne 22a with [Rh(CO)2Cl]2 gave an 83% yield of trienes
E-24a, Z-24a, and 25a in a 13:5:2 ratio, respectively (entry 1,
Table 2).42 These E/Z ratios were similar to those observed
previously, but are interesting considering that the E/Z ratios
were reversed for the sulfone system (E/Z-18) (entries 1 and
2, Table 1). It is possible that this reversal is due to the dif-
fering electronic natures of the sulfone group of 16 and the
disilyl ether groups of 22. This is evidenced by the difference
in thereactionrates for 16 and 22 (30 minvs24 h atrt, respec-
tively). Hence, the slower reaction revealed an increase in
the amount of the thermodynamic product, E-24a.
These studies suggested that we could not obtain the desired
selectivity by only altering the reaction conditions, and
needed some assistance from the substrate. With this in
mind we turned our focus on the preparation of allenyne
22, which is particularly advantageous due to the changes
that can be made to R1 and R2, in addition to being a well-
suited substrate for the synthesis of ovalicin/fumagillol.
Allene 22 is obtained by the addition of 4-magnesium-
bromo-1-(trimethylsilyl)-1-butyne to ethyl glyoxylate fol-
lowed by protection of the newly formed a-hydroxy group
to give silyl ether 20 in a 65% combined yield (Scheme 5).38
Ester 20 was transformed into the Weinreb amide in an 80%

K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
10545
TBDPSO
Ln
Ha
Rh
Ln
Ha
Rh
TBDPSO
EtO
TMS
TMS
Ha
a, b
TMS
OTBS
TMS
H
CH3
O
O
O
O
RO
RO
O
H
a CH3
H
H
20
21
CH3
VI
V
TMS
Figure 5. Explanation of changes in constitutional group selectivity.
TMS
OTBS
c, d
+
•
13 vs 14). More polar solvents are known to increase the re-
action rates in Pd-catalyzed Alder-ene reactions43 and Rh-
catalyzed cycloadditions44 due to their ability to stabilize
charge separation. Also, changing the solvent from toluene
to DCE gave isomeric ratios closer to that seen for the
sulfone system (3:5:1 vs 4:5:1; compare entry 1, Table 1 to
entry 11, Table 2). Altering the temperature had no effect
on the E/Z selectivity or constitutional selectivity when
toluene was used as the solvent (compare entries 1 vs 2, 5
vs 6, and 9 vs 10, Table 2); however, decreasing the reaction
temperature when using DCE as the solvent further increased
the amount of kinetic product shifting the E/Z ratio from 1:1
to 1:4 (entry 15 vs 16, Table 2).
OR1
R2O
H3C
22a R1 = TBS, R2 = TBDPS
23
Scheme 5. Preparation of allenyne 22. Reagents and conditions: (a)
MeNHOMe$HCl, i-PrMgCl, THF, 0 ꢂC, 80%; (b) n-BuLi, tert-butyldi-
methyl(pent-4-ynyloxy)silane, ꢁ78 to 0 ꢂC; (c) CeCl3$7H2O, NaBH4,
ꢁ20 to 0 ꢂC, 58% (two steps); (d) MsCl, TEA, CH2Cl2, 0 ꢂC; CuI, MeLi,
THF, ꢁ78 ꢂC, 80% [22a:23¼23:1].
Allenyne 22a was subjected to the optimized reaction condi-
tions worked out for sulfone 16 [Ir(COD)Cl]2/AgBF4, which
led to complete decomposition of the starting material (entry
4). Switching the additive from AgBF4 to In(OTf)3 in DCE
gave good selectivity but only a trace amount of product for-
1
Further attempts were made to increase the formation of the
desired E-24 by modifying R1 of 22. Changing R1 from silyl
ether to ester functionality revealed a slight decrease in con-
stitutional group selectivity (9:1 to 4:1) and E/Z selectivity
(7:3 to 6:4; compare entries 1 and 5). The free hydroxyl
group had a similar, yet more enhanced effect decreasing
the constitutional group selectivity from approximately 9:1
to 3:1 ratio, and it did not effect on the E/Z selectivity (com-
pare entries 3 vs 8 and 11 vs 15). This increase in the amount
of isomer 25 is believed to result from coordination of the
free hydroxyl V and ester group VI to the rhodium metallo-
cycle (Fig. 5). Syn periplanar alignment of the Rh–C–C–Ha
mation and mostly starting material were observed by H
NMR. The insolubility of indium triflate in DCE is a likely
reason for the reaction inhibition; however, changing from
DCE to acetone, a solvent that indium triflate is soluble in,
resulted in complete decomposition of the starting material.
Since the cationic iridium conditions were not applicable to
this system, only moderate variations in rhodium-catalyzed
reaction conditions could be made. Changing the solvent
in the reaction conditions from toluene to DCE showed
a rate enhancement, (12 h at 55 ꢂC to 30 min at rt) and a re-
versal in E/Z selectivity (7:3 to 4:6; see entries 10 vs 11 and
Table 2. Results of rhodium-catalyzed Alder-ene reaction with sulfonyl allenynes 22a–fa
TMS
TMS
TMS
TMS
CH3
CH3
CH2
OR1
OR1
+
+
•
OR1
R2O
OR2
OR2
Z-24a-f
OR1
OR2
H3C
22a-f
E-24a-f
25a-f
Entry
Substrate
R1
R2
Catalystb
Solvent
t (ꢂC)
E-24:Z-24:25
24:25
E-24:Z-24
Yield (%)
83
1
2
22a
22a
22a
22a
22b
22b
22b
22c
22d
22d
22d
22d
22e
22e
22f
TBS
TBDPS
A
Ac
A
B
A
A
C
A
A
A
A
B
A
A
A
A
Toluene
Toluene-d8
DCE
55
rt
rt
rt
55
rt
13:5:2
11:6:3
9:8:3
13:0:7
10:6:4
11:6:3
12:3:5
5:7:8
18:2
17:3
17:3
13:7
16:4
17:3
15:5
12:8
18:2
17:3
18:2
7:3
6:4
5:5
10:0
6:4
6:4
8:2
4:6
7:3
7:3
4:6
3
55
NA
87
85
67e
50
85
95
4d
5
DCE
Ac
TBDPS
Toluene
Toluene
DCE
6
7
8
9
10
11f
12d
13f
14
15
16
rt
rt
H
TBS
TBDPS
TBS
DCE
Toluene
Toluene
DCE
80
55
55
55
rt
rt
rt
0
12:6:2
12:5:3
8:10:2
DCE
NA
Ac
H
TBS
TBS
Toluene
DCE
DCE
11:6:3
8:9:3
7:8:5
17:3
17:3
15:5
13:7
6:4
5:5
5:5
2:8
60
66
60
22f
DCE
3:10:7
For reaction conditions see Section 4. Product ratios were determined by integration of olefin peaks in the 1H NMR.
A: 5–10 mol % [Rh(CO)2Cl]2; B: 10 mol % [Ir(COD)Cl]2, 20 mol % In(OTf)3; C: 10 mol % [Ir(COD)Cl]2, 20 mol % AgBF4.
Catalyst (1 equiv) was used; no yield was calculated.
Starting materials were recovered and experiments were irreproducible.
Yield includes a mixture of inseparable by-products.
Large amount of product was obtained; exact yield was not calculated.
a
b
c
d
e
f

10546
K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
during the b-hydride elimination step is conformationally
hindered by this coordination, leading to an increase in the
formation of triene 25.45
and i-PrMgCl generates amide 27 in a 91% yield. Subjection
of amide 27 to 1.5 equiv of sodium hexamethyldisilazide and
1.5 equiv of 2-(phenylsulfonyl)-3-phenyloxaziridine gave
a 86% yield of the a-hydroxy amide. The a-hydroxyl group
was protected as a tert-butyldimethylsilyl ether using Et3N
and TBSOTf to give amide 28, which in turn was subjected
to the lithium anion of tert-butyldimethyl(pent-4-ynyloxy)-
silane to give a 77% yield of alkynone 29.
Allenynes 22b and 22c were subjected to the iridium condi-
tions ([Ir(COD)Cl]2/AgBF4) in hopes that they would toler-
ate these conditions better than the bis-silylated allenyne
22a. Trienes E/Z-24b and 25b were obtained in a 67% yield;
however, the yield included a mixture of inseparable by-
products and the reaction was irreproducible (entry 7,
Table 2). Subjection of allenyne 22c to [Ir(COD)Cl]2/AgBF4
led to complete decomposition of the starting material.
Ketone 29 was reduced using Luche conditions to yield
a propargylic alcohol in a 7:1 diastereomeric ratio. The dia-
stereomers were not separated but taken on to the next step.
The propargylic alcohol was converted to its mesylate using
Et3N and MsCl, then after workup the crude mesylate was
subjected to lithium dimethylcuprate. Allenyne 22d was
obtained in an 86% yield as a 7:1 diastereomeric ratio as
seen by 1H NMR. Treatment of allenyne 22d with
[Rh(CO)2Cl]2 and heating to 80 ꢂC gave trienes E-24d/Z-
24d/25d in a 6:3:1 ratio, respectively, and in 95% yield.46
After finding the best isomeric ratios with the bis-silylated
allenyne systems (22a and 22d) we decided to separate our
desired E-24 isomer and turned our attention to the function-
alization of the triene systems toward the synthesis of ovali-
cin. Diverging from the initial route, esterification of
carboxylic acid 19 with MeI and KHCO3 gave a 76% yield
of ester 26 (Scheme 6). Reaction of 26 with MeNHOMe$HCl
Separation of these trienes required removal of both of the
silyl ether protecting groups (Scheme 7).47 Buffering this de-
protection reaction was essential, since decomposition of the
trienes occurred in the absence of NH4Cl. After 12 h at
50 ꢂC, complete bis-desilylation was observed, giving tri-
enes E/Z-30 and 31 in 92% yield. The trienes were separated
using silica gel chromatography; eluting with isopropanol/
pentanes. The primary hydroxyl group on E-30 was selec-
tively protected using Et3N and TBDMSCl giving a 75%
yield of triene 32. Next, a selective dihydroxylation of the
endocyclic double bond of 32 was tested via a hydroxyl
directed dihydroxylation protocol developed by Donohoe.48
When triene 32 was subjected to TMEDA and 1 equiv of
OsO4 in CH2Cl2 at ꢁ78 ꢂC, osmylation to occured forming
the stable osmate esters 33 and a by-product 34 in a 6:1 ratio.
Unfortunately, a small discrepancy in the 1H NMR prevents
us from knowing conclusively whether we formed our de-
sired product 33. Futurework entails complete determination
of the dihydroxylation product followed by further steps to
complete the synthesis of ovalicin (7).
TBSO
c, d
TMS
TMS
O
O
(MeO)(Me)N
R
26, R = OH
27, R = NMeOMe
28
a,b
TMS
TBSO
f, g
TMS
OTBS
e
•
O
OTBS
TBSO
H3C
22d
29
TMS
TMS
CH3
CH2
OTBS
OTBS
h
+
OTBS
E-24d : Z-24d
OTBS
25d
Scheme 6. Alternative preparation of trienes E/Z-24 and 25. Reagents and
conditions: (a) KHCO3, MeI, DMF, 76%; (b) MeNHOMe$HCl, i-PrMgCl,
THF, 0 ꢂC, 91%; (c) NaHMDS, PhNOCHPh, THF, 86%; (d)TEA, TBSOTf,
CH2Cl2, 94%; (e) n-BuLi, tert-butyldimethyl(pent-4-ynyloxy)silane, ꢁ78
to 0 ꢂC, 77%; (f) CeCl3$7H2O, NaBH4, ꢁ20 to 0 ꢂC, 88%; (g) MsCl,
TEA, CH2Cl2, 0 ꢂC; CuI, MeLi, THF, ꢁ30 ꢂC, 86% [22d:23¼7:1]; (h)
[Rh(CO)2Cl]2, toluene, 80 ꢂC, 95% [E-24d:Z-24d:25d¼6:3:1].
3. Conclusion
In summary, Rh(I)-catalyzed allenic Alder-ene reaction
of 16 and 22a–f leads to the formation of trienes E/Z-18,
TMS
CH3
TMS
CH2
a
OH
OH
b
E-24d : Z-24d : 25d
+
OH
OH
E/Z-30
31
N
O
TMS
TMS
H3C
N
CH3
OTBS
CH3
Os
O
O
O
OTBS
c
O
O
TMS
N
+
Os
OTBS
O
N
O
OH
OH
OH
34
32
33
Scheme 7. Attempted dihydroxylation of triene E-30. Reagents and conditions: (a) TBAF, NH4Cl, THF, 50 ꢂC, 92%; (b) TBDMSCl, TEA, CH2Cl2, 75%;
(c) TMEDA, OsO4, CH2Cl2, ꢁ78 ꢂC, 90%, (33:34¼6:1).

K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
10547
E/Z-24a–f, 19, and 25 in good yields and moderate regio-
selectivities (Tables 1 and 2). The regioselectivities of the
Alder-ene reaction are found to be dependent on a number
of factors: temperature, solvent, catalyst (cationic vs neu-
tral), and the ability of the substrate to coordinate with the
catalyst. Furthermore, the products from the allenic Alder-
ene reaction are useful substrates for further functionaliza-
tion; and in turn will be a synthetically useful intermediate
for the synthesis of ovalicin (4).
by addition of water and the aqueous layer was extracted
with Et2O (3ꢃ). The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by silica gel chromatography
eluting with hexanes to afford the iodide (6.06 g, 99%) as
a colorless liquid. To a solution of 5-iodo-1-(trimethyl-
silyl)-1-pentyne (11.3 g, 42.3 mmol) in 50 mL of DMF
was added anhydrous benzenesulfinic acid sodium salt
(8.34 g, 50.7 mmol). The mixture was warmed to 50 ꢂC
and after 1.5 h complete consumption of starting material
was observed by TLC. The mixture was poured into an
Et2O/water mixture. The aqueous layer was separated and
extracted with Et2O (3ꢃ). The combined organic layers
were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was puri-
fied by silica gel chromatography eluting with 10% EtOAc/
hexanes to afford sulfone 14 (9.08 g, 76%) as a white solid.
Rf 0.2 (20% EtOAc/hexanes); mp¼33 ꢂC; 1H NMR
(300 MHz, CDCl3): d 0.12 (s, 9H), 1.78–1.87 (m, 2H),
2.26 (t, J¼6.8 Hz, 2H), 3.15–3.20 (m, 2H), 7.48–7.64 (m,
3H), 7.82–7.86 (m, 2H); 13C NMR (75 MHz, CDCl3):
d ꢁ0.18 (3C), 18.4, 21.7, 54.8, 86.3, 104.2, 127.7 (2C),
129.1 (2C), 133.5, 138.9; IR (neat) 2958, 2175, 1447,
1307 cmꢁ1; MS (GC/MS) m/e (relative intensity) 280
([MꢁCH3]+, 0.4), 265 (50), 135 (100), 77 (51), 73 (63);
HRMS calcd for C13H17O2SiS: 265.0719 [MꢁCH3]+;
found: 265.0721 [MꢁCH3]+.
4. Experimental
4.1. General
All reactions were performed using syringe–septum cap
techniques under a nitrogen atmosphere and glassware was
flame dried prior to use. All commercially available com-
pounds were purchased from Aldrich Chemical Co., GFS
Chemicals, Strem Chemicals, and Acros Organics and
used as received, unless otherwise specified. Tetrahydro-
furan (THF), diethyl ether (Et2O), and dichloromethane
(DCM) were purified with alumina using the Sol-Tek
ST-002 solvent purification system. Toluene, N,N,N0,N0-
tetramethylethylenediamine (TMEDA), and triethylamine
(Et3N) were freshly distilled from CaH2 prior to use. Tri-
methylsilyl trifluoromethanesulfonate (TMSOTf) was dis-
tilled from phosphorus pentoxide (P2O5) and stored in a
septum sealed flask in the freezer. Copper iodide (CuI) was
purified by following the procedure in Ref. 49.
4.2.2. (5-Benzenesulfonyltridec-5-ene-1,7-diynyl)tri-
methylsilane (15). To a solution of sulfone 14 (1.00 g,
3.57 mmol) in 15 mL of THF at ꢁ78 ꢂC was added n-butyl-
lithium (2.70 mL of a 1.6 M hexanes solution, 4.28 mmol)
dropwise over 10 min. After 1 h at ꢁ78 ꢂC, a solution of
2-octynal (0.53 g, 4.28 mmol) in 3 mL of THF was added
via cannula and the mixture was kept at ꢁ78 ꢂC for 1 h
and then allowed to warm to 10 ꢂC at which time complete
consumption of starting material was observed by TLC.
The mixture was then cooled to ꢁ78 ꢂC and acetic anhydride
(1.47 g, 14.4 mmol) was added. The mixture was quenched
at ambient temperature with NH4Cl(aq), and the aqueous
layer was separated and washed with Et2O (3ꢃ). The com-
bined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure.
The crude mixture was purified by silica gel chromatography
eluting with 10% EtOAc/hexanes. The mixture of diastereo-
mers was collected (1.40 g, 3.14 mmol) and azeotroped in
vacuo with benzene (3ꢃ), diluted with 8 mL of THF, and
cooled to 0 ꢂC. DBU (0.52 g, 3.45 mmol) was added to the
solution and after 30 min a 10% HCl/ether solution was
added to the reaction. The aqueous layer was separated
and extracted with Et2O (3ꢃ). The combined organic layers
were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was puri-
fied by silica gel chromatography eluting with 10% EtOAc/
hexanes to afford enyne 15 (738 mg, 60% over two steps) as
a colorless oil. 1H NMR (300 MHz, CDCl3): d 0.13 (s, 9H),
0.92 (t, J¼7.0 Hz, 3H), 1.28–1.45 (m, 4H), 1.59 (qn,
J¼7.1 Hz, 2H), 2.35–2.47 (m, 4H), 2.59–2.65 (m, 2H),
6.84 (t, J¼2.2 Hz, 1H), 7.52–7.67 (m, 3H), 7.87–7.90 (m,
2H); 13C NMR (75 MHz, CDCl3): d 0.0 (3C), 13.8, 19.0,
19.8, 22.0, 27.8, 28.0, 30.9, 75.0, 85.2, 105.0, 106.7,
122.3, 128.0 (2C), 129.2 (2C), 133.5, 139.1, 148.5; IR
(neat) 2958, 2932, 2860, 2213, 2177, 1446 cmꢁ1; MS
Purification of the products by flash chromatography was
˚
performed using silica gel (32–63 mm particle size, 60 A
pore size) purchased from SAI. TLC analyses were per-
formed on EM Science Silica Gel 60 F254 plates (250 mm
thickness). HPLC purification was performed on a Varian-
Prostar 210 instrument using a Varian Microsorb Dynamax
100-5 Si column (5 mm packing, 250 mmꢃ10 mm) or
Varian Pursuit C8 column (5 mm packing, 250 mmꢃ10 mm).
Melting points were determined using a Laboratory Devices
1
Mel-Temp II apparatus. All H and 13C spectra were ob-
tained on either Bruker Avance 300 MHz or Bruker Avance
DRX 500 MHz instrument, and chemical shifts (d) were re-
ported relative to residual peak CHCl3 or toluene. All NMR
spectra were obtained at room temperature unless otherwise
specified and are tabulated as follows: chemical shift,
multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
qn ¼ quintet, m ¼ multiplet), coupling constant(s), number
of protons. IR spectra were obtained using a Nicolet Avatar
E.S.P. 360 FT-IR. EI mass spectrometry was performed on
a Micromass Autospec high-resolution mass spectrometer.
ES low-resolution mass spectrometry was performed on an
HPMSD 1100 LC/MS and high-resolution was performed
on ESI Biosystem time of flight mass spectrometer.
4.2. Preparation of compounds 14–32
4.2.1. 1-Phenylsulfonyl-5-(trimethylsilyl)-4-pentyne (14).
To a solution of 5-chloro-1-(trimethylsilyl)-1-pentyne
(4.47 mL, 22.9 mmol) in 8 mL of acetone was added NaI
(5.15 g, 34.4 mmol). The mixture was brought to reflux
and the progress of the reaction was monitored by 1H
NMR spectroscopy. After 24 h the mixture was quenched

10548
K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
(GC/MS) m/e (relative intensity) 386 ([M]+, 2), 371 (3), 135
(45), 73 (100); HRMS calcd for C22H30O2SiS: 386.1736;
found: 386. 1739.
d 0.93 (t, J¼6.7 Hz, 3H), 1.27–1.51 (m, 6H), 1.94 (m, 3H),
2.28–2.37 (m, 4H), 2.52–2.57 (m, 2H), 6.07 (d, J¼11.8 Hz,
1H), 7.52–7.66 (m, 4H), 7.86–7.90 (m, 2H).
4.2.3. (5-Benzenesulfonyl-8-methyltrideca-6,7-dien-1-
yne)-trimethylsilane (16). To a suspension of CuI (1.51 g,
7.94 mmol) in 40 mL of ether at ꢁ30 ꢂC was added MeLi
(12.4 mL of a 1.3 M diethyl ether solution, 15.8 mmol)
dropwise. The mixture was allowed to warm to 0 ꢂC over
a 30 min period and it changed from cloudy yellow to a clear
solution. The flask was cooled to ꢁ50 ꢂC and a solution of
enyne 15 (1.53 g, 3.97 mmol) and TMSOTf (0.77 mL,
3.97 mmol) in 20 mL of ether was added dropwise with
a cannula. The mixture was kept at ꢁ50 to ꢁ30 ꢂC for 3 h
and then was warmed to ꢁ15 ꢂC and kept at that temperature
for 7 h before NH4Cl(aq) and ether were added. The biphasic
solution was stirred vigorously until the aqueous layer
turned deep blue. The solution was then filtered through
a sintered glass funnel of medium porosity packed with Cel-
ite to remove the copper salts and aqueous layer. The Celite
was rinsed with ether to assure complete filtration of prod-
ucts. The organic layer was concentrated under reduced
pressure and the residue was purified by silica gel chromato-
graphy eluting with 3% EtOAc/hexanes to afford 1.08 g of
4.3. General procedure for allenic Alder-ene
reaction (Table 1)
4.3.1. [4-Benzenesulfonyl-2-(1-methylhept-1E-enyl)-
cyclohex-2-enylidenemethyl]trimethylsilane (E-18), [4-
methylene-3-(1-methylhept-1Z-enyl)-cyclohex-2-enesul-
fonylbenzene]trimethylsilane (Z-18), and [4-methylene-
3-(1-methyleneheptyl)-cyclohex-2-enesulfonylbenzene]-
trimethylsilane (19). Method A: (entries 1, 2, and 12) to
a flame dried test tube was added a mixture of allene 16
and diene 17, which was then azeotroped under vacuum
with benzene and charged with N2 (3ꢃ). Toluene (0.2 M)
was added and the test tube was evacuated under vacuum
and charged with N2 three times. Then, 5 mol %
[Rh(CO)2Cl]2 was added at ambient temperature and the
system was evacuated and charged with N2 once more.
The reaction was monitored by GC and quenched by addi-
tion to a silica gel plug eluting with 5% EtOAc/hexanes
to afford trienes E-18, Z-18, and 19 and recovered 17 or
E-18a, Z-18a, and 19a. The crude mixture was analyzed
1
1
a mixture of allene 16 and diene 17 in a 7:1 ratio (by H
by H NMR and the ratios were determined by integration
of distinct olefinic peaks from each isomer. Attempted sepa-
ration of the isomers by chromatography was unsuccessful.
NMR) for a 67% yield. The mixture was taken on to the
next step. However, pure allene 16 was obtained by HPLC
for spectroscopic purposes (Varian Microsorb Dynamax
100-5 Si column, 23 ꢂC, EtOAc/hexanes¼5%, flow
Method B: (entries 3–11) to a flame dried test tube was added
a mixture of allene 16 and diene 17, which was azeotroped
under vacuum with benzene (3ꢃ). Dichloroethane (0.2 M)
was added and the test tube was evacuated under vacuum
and charged with N2 (3ꢃ). Then, 10 mol % [Ir(COD)Cl]2
or [Rh(COD)Cl]2 was added followed by 20 mol % AgBF4
(0.05 M dichloroethane solution) or In(OTf)3 (0.05 M ace-
tone solution) and the system was evacuated and charged
with N2 once more. The mixture was monitored by GC
and quenched by addition to a silica gel plug eluting with
5% EtOAc/hexanes to afford a mixture of trienes E-18,
Z-18, and 19, and recovered 17 or E-18a, Z-18a, and 19a
depending on conditions (see Table 1). The crude mixture
1
rate¼3 mL/min). H NMR (300 MHz, CDCl3): d 0.14 (s,
9H), 0.88 (t, J¼6.3 Hz, 3H), 1.19–1.35 (m, 4H), 1.30 (d,
J¼2.3 Hz, 3H), 1.75–1.90 (m, 4H), 2.18–2.52 (m, 4H),
3.68 (ddd, J¼2.8, 8.5, 11.1 Hz, 1H), 4.88–4.97 (m, 1H),
7.53–7.70 (m, 3H), 7.87–7.92 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 0.5 (3C), 14.4, 17.8, 18.2, 22.8, 26.5,
27.3, 31.9, 33.9, 66.1, 84.0, 86.7, 103.2, 105.3, 129.2 (2C),
129.7 (2C), 133.8, 138.4, 206.0; IR (neat) 2957, 2858,
2175, 1950, 1447, 1307 cmꢁ1; MS (GC/MS) m/e (relative
intensity) 402 ([M]+, 0.6), 387 (0.6), 277 (12), 125 (12), 73
(100); HRMS calcd for C23H34O2Si1S1: 402.2049; found:
402.2047. Only crude 1H NMR spectra were obtained for di-
ene 17 after desilylation. 1H NMR (300 MHz, CDCl3): d 0.93
(t, J¼6.7 Hz, 3H), 1.27–1.51 (m, 6H), 1.94 (m, 4H), 2.28–
2.37 (m, 4H), 2.52–2.57 (m, 2H), 6.07 (d, J¼11.8 Hz, 1H),
7.52–7.66 (m, 4H), 7.86–7.90 (m, 2H).
1
was analyzed by H NMR and the ratios were determined
by integration of distinct olefinic peaks from each isomer;
however, pure trienes E-18a, Z-18a, and 19a were obtained
by HPLC for spectroscopic purposes (Varian Microsorb
Dynamax 100-5 Si column, 23 ꢂC, EtOAc/hexanes¼5%,
flow rate¼3 mL/min [E-18a and 19a], Varian Pursuit C8,
5 mm, 23 ꢂC, H2O/MeCN¼25%, flow rate¼5 mL/min
4.2.4. (5-Benzenesulfonyl-8-methyltrideca-6,7-dien-1-
yne) (16a). To a solution of allenyne 16 (0.11 g,
0.26 mmol) in 1.3 mL of THF at 0 ꢂC was added a mixture
of TBAF (0.26 mL of a 1 M THF solution, 0.26 mmol) and
0.02 mL of pH 7.38 phosphate buffer solution dropwise via
syringe. After 1 h the reaction was quenched at room temper-
ature with NH4Cl(aq), and the aqueous layer was separated
and washed with EtOAc (3ꢃ). The combined organic layers
were washed with brine, dried over NaSO4, filtered, and con-
centrated under reduced pressure. The residue was purified
by silica gel chromatography eluting with 5% EtOAc/
hexanes to afford 81 mg of allenyne 16a in 94% yield as a col-
1
[Z-18a]). H NMR (300 MHz, CDCl3) E-18a: d 0.93 (t,
J¼7.0 Hz, 3H), 1.30–1.44 (m, 4H), 1.70 (s, 3H), 1.85–1.98
(m, 1H), 2.00–2.31 (m, 4H), 2.32–2.45 (m, 1H), 3.86–3.98
(m, 1H), 4.89 (s, 1H), 4.92 (s, 1H), 5.27 (t, J¼7.2 Hz, 1H),
5.67 (d, J¼2.7 Hz, 1H), 7.50–7.70 (m, 3H), 7.85–7.92 (m,
2H); 13C NMR (75 MHz, CDCl3): 14.2, 16.9, 22.6, 23.8,
27.9, 29.5, 31.8, 63.2, 114.3, 116.2, 129.1 (2C), 129.5
1
(2C), 130.6, 134.0, 134.5, 137.3, 140.0, 150.2; H NMR
(300 MHz, CDCl3) Z-18a: d 0.80–0.90 (m, 3H), 1.18–1.28
(m, 6H), 1.74 (s, 3H), 1.90–2.05 (m, 1H), 2.05–2.20 (m,
1H), 2.21–2.35 (m, 1H), 2.40–2.53 (m, 1H), 3.90–3.98 (m,
1H), 4.88 (s, 1H), 4.94 (s, 1H), 5.30–5.38 (m, 1H), 5.56–
5.60 (m, 1H), 7.52–7.69 (m, 3H), 7.86–7.91 (m, 2H); 13C
NMR (75 MHz, CDCl3): 14.0, 22.3, 23.3, 24.3, 28.9, 29.7,
32.0, 63.0, 113.4, 117.1, 128.9, 129.0 (2C), 129.2 (2C),
1
orless oil (3:1, allene 16a/diene 17a). H NMR (300 MHz,
CDCl3) allene 16a: d 0.87 (t, J¼7.2 Hz, 3H), 1.12–1.29 (m,
7H), 1.76–1.90 (m, 4H), 1.07 (t, J¼2.4 Hz, 1H), 2.18–2.48
(m, 4H), 3.69 (ddd, J¼2.9, 8.6, 11.0 Hz, 1H), 4.90–4.96
(m, 1H), 7.53–7.67 (m, 3H), 7.88–7.91 (m, 2H); diene 17a:

K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
10549
133.7, 133.9, 137.5, 138.8, 146.5; IR (neat) 2956, 2927,
(neat) 2956, 2857, 2211, 2176, 1675 cmꢁ1; MS (GC/MS)
m/e (relative intensity) 603 ([MꢁCH3]+, 1.6), 516 (60), 197
(60), 135 (100); HRMS calcd for C35H51O3Si3: 603.3146
[MꢁCH3]+; found: 603.3120 [MꢁCH3]+.
1
1447, 1306 cmꢁ1; H NMR (300 MHz, CDCl3) constitu-
tional isomer 19a: d 0.89 (t, J¼6.6 Hz, 3H), 1.00–1.42 (m,
6H), 1.88–2.30 (m, 5H), 2.38–2.49 (m, 1H), 3.88–3.96
(m, 1H), 4.80 (d, J¼2.2 Hz, 1H), 4.90–4.99 (m, 3H), 5.67
(d, J¼2.8 Hz, 1H), 7.52–7.69 (m, 3H), 7.86–7.92 (m, 2H);
13C NMR (75 MHz, CDCl3): 14.2, 22.6, 23.6, 27.9, 29.3,
31.5, 36.1, 63.0, 114.3, 114.5, 117.0, 129.1 (2C), 129.4
(2C), 133.9, 137.2, 139.8, 147.6, 148.9.
4.3.3. 11-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphe-
nylsilyloxy)-8-methyl-1-trimethylsilylundeca-6,7-dien-1-
yne (22a). Ketone 21 and tert-butyldimethyl(pent-4-ynyl-
oxy)silane (z2.1 mmol) were diluted with CeCl3$7H2O
(6.83 mL of a 0.4 M methanol solution, 2.73 mmol), cooled
to ꢁ20 ꢂC, and NaBH4 (0.10 g, 2.73 mmol) was added in
one portion. The mixture was allowed to warm to 0 ꢂC and
after 30 min complete consumption of starting material
was observed by TLC. The reaction was quenched with
slow addition of H2O, and the aqueous layer was separated
and washed with Et2O (3ꢃ). The combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel chro-
matography eluting with 3–10% EtOAc/hexanes to afford
the alcohol (772 mg, 58%) over two steps. Rf 0.6 (20%
4.3.2. 11-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphe-
nylsilyloxy)-1-trimethylsilylundeca-1,7-diyn-6-one (21).
To a solution of ester 20 (1.20 g, 2.57 mmol) in 5 mL of
THF was added MeNHOMe$HCl (0.38 g, 3.86 mmol) and
the flask was cooled to 0 ꢂC. Then i-PrMgCl (2.60 mL of
a 2.0 M THF solution, 5.15 mmol) was added dropwise
and after addition was finished complete consumption of
starting material was observed by TLC. The mixture was
quenched with NH4Cl(aq), and the aqueous layer was sepa-
rated and washed with CH2Cl2 (3ꢃ). The combined organic
layers were dried over MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was purified by silica gel
chromatography eluting with 10–15% EtOAc/hexanes to
afford amide (1.01 g, 80%) as a colorless oil. Rf 0.4 (20%
1
EtOAc/hexanes); H NMR (300 MHz, CDCl3): d 0.06 (s,
6H), 0.12 (s, 9H), 0.90 (s, 9H), 1.10 (s, 9H), 1.65–1.91 (m,
3H), 2.12–2.32 (m, 5H), 3.66 (t, J¼6.1 Hz, 2H), 3.88 (q,
J¼5.3 Hz, 1H), 4.30 (m, 1H), 7.37–7.49 (m, 6H), 7.72
(t, J¼6.8 Hz, 4H); 13C NMR (75 MHz, CDCl3): d ꢁ5.3
(2C), 0.1 (3C), 15.2, 15.8, 18.3, 19.5, 25.9 (3C), 27.1 (3C),
31.6, 31.9, 61.6, 65.3, 75.5, 79.0, 84.7, 86.2, 106.5, 127.6
(2C), 127.7 (2C), 129.8 (2C), 133.4 (2C), 133.6 (2C),
135.87 (2C); IR (neat) 3451, 2956, 2858, 2175 cmꢁ1; MS
(GC/MS) m/e (relative intensity) 620 ([M]+, 0.3), 563 (10),
199 (97), 135 (100); HRMS calcd for C32H47O3Si3:
563.2833 [MꢁC(CH3)3]+; found: 563.2830 [MꢁC(CH3)3]+.
To a solution of 11-(tert-butyldimethylsilyloxy)-5-(tert-
butyldiphenylsilyloxy)-1-trimethylsilyl-1-undeca-1,7-diyn-
6-ol (0.33 g, 0.51 mmol) in 1.7 mL of CH2Cl2 was added
Et3N (96.0 mL, 0.69 mmol) and the solution was cooled to
0 ꢂC. Then MsCl (48.0 mL, 0.62 mmol) was added and after
30 min at 0 ꢂC the reaction mixture was diluted with pen-
tanes. The solution was then filtered through a sintered glass
funnel of medium porosity packed with Celite and the
resulting solution was washed with NaHCO3(aq) and brine.
The organic layer was dried over MgSO4, filtered, and con-
centrated under reduced pressure. To a suspension of CuI
(0.12 g, 0.62 mmol) in 2 mL of THF at ꢁ30 ꢂC was added
MeLi (0.64 mL of a 1.6 M diethyl ether solution,
1.03 mmol) dropwise. The reaction mixture was allowed
to warm to 0 ꢂC over a 30 min period while it changed
from a cloudy yellow to clear solution. It was cooled to
ꢁ78 ꢂC and a solution of the mesylate in 1.7 mL of THF
was added dropwise with a cannula. The reaction mixture
was kept at that temperature for 1 h before NH4Cl(aq) and
Et2O were added. The biphasic solution was stirred vigor-
ously until the aqueous layer turned deep blue. The solution
was then filtered through a sintered glass funnel of medium
porosity packed with Celite to remove the copper salts and
aqueous layer. The organic layer was concentrated under
reduced pressure and the residue was purified by silica gel
chromatography eluting with 3% EtOAc/hexanes to afford
allene 22a (256 mg, 80%) as a colorless oil (23:1, allene
22a/enyne 23, ratio based upon integration of peaks in
the 1H NMR). Rf 0.8 (20% EtOAc/hexanes); 1H NMR
(300 MHz, CDCl3): d 0.04 (s, 6H), 0.12 (s, 9H), 0.98
(s, 9H), 1.06 (s, 9H), 1.42–1.52 (m, 2H), 1.60 (d,
1
EtOAc/hexanes); H NMR (300 MHz, CDCl3): d 0.12 (s,
9H), 1.10 (s, 9H), 1.91–1.98 (m, 2H), 2.36 (dt, J¼6.6,
17.1 Hz, 1H), 2.49 (dt, J¼7.8, 17.1 Hz, 1H), 2.90 (s, 3H),
3.11 (s, 3H), 4.66 (t, J¼5.8 Hz, 1H), 7.33–7.45 (m, 6H),
7.68–7.75 (m, 4H); 13C NMR (75 MHz, CDCl3): d 0.1
(3C), 15.9, 19.5, 27.0 (3C), 32.2, 33.7, 60.7, 68.9, 84.8,
106.7, 127.3 (2C), 127.5 (2C), 129.5, 129.6, 133.5 (2C),
133.6 (2C), 136.0, 136.2, 173.1; IR (neat) 2959, 2933,
2857, 2174, 1681 cmꢁ1; MS (GC/MS) m/e (relative inten-
sity) 466 ([MꢁCH3]+, 7), 424 (100): HRMS calcd for
C26H36N1O3Si2: 466.2234 [MꢁCH3]+; found: 466.2244
[MꢁCH3]+. To a solution of tert-butyldimethyl(pent-4-yny-
loxy)silane (0.82 g, 4.15 mmol) in 14 mL of THF at
ꢁ78 ꢂC was added n-butyllithium (1.74 mL of a 2.5 M hex-
ane solution, 4.36 mmol) dropwise. The flask was kept at
ꢁ78 ꢂC for 10 min and then placed in a bath at ꢁ20 ꢂC
for 20 min. It was then cooled to ꢁ78 ꢂC and added to a solu-
tion of 2-(tert-butyldiphenylsilyloxy)-6-trimethylsilylhex-5-
ynoic acid methoxy methyl amide (1.00 g, 2.08 mmol) in
5 mL of THF at ꢁ78 ꢂC via cannula. The mixture was then
allowed to slowly warm over 2 h to 0 ꢂC at which time com-
plete consumption of starting material was observed by TLC.
The reaction mixture was quenched with NH4Cl(aq), and the
aqueous layer was separated and extracted with Et2O (3ꢃ).
The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. The resi-
due was purified by silica gel chromatography eluting with
5% EtOAc/hexanes to afford ketone 21 and tert-butyl-
dimethyl(pent-4-ynyloxy)silane. The mixture was not sepa-
rated at this point but pure ketone 21 was obtained for
spectroscopic purposes. Rf 0.7 (20% EtOAc/hexanes);
1H NMR (300 MHz, CDCl3): d 0.05 (s, 6H), 0.13 (s, 9H),
0.90 (s, 9H), 1.12 (s, 9H), 1.66–1.75 (m, 2H), 1.85–2.06
(m, 2H), 2.21–2.41 (m, 4H), 3.65 (t, J¼6.5 Hz, 2H), 4.30
(t, J¼5.6 Hz, 1H), 7.33–7.47 (m, 6H), 7.64–7.68 (m, 4H);
13C NMR (75 MHz, CDCl3): d ꢁ5.4 (2C), 0.1 (3C), 15.3,
15.7, 18.3, 19.5, 25.9 (3C), 27.0 (3C), 30.7, 33.7, 61.3,
78.2, 79.4, 85.2, 97.7, 106.1, 127.6 (2C), 127.7 (2C), 129.8,
129.9, 133.1 (2C), 133.3 (2C), 135.8, 136.0, 188.3; IR

10550
K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
1
J¼2.8 Hz, 3H), 1.65–1.90 (m, 4H), 2.25–2.34 (m, 2H), 3.51
(t, J¼6.4 Hz, 2H), 4.27–4.38 (m, 1H), 4.95–5.02 (m, 1H),
7.33–7.45 (m, 6H), 7.67–7.71 (m, 4H); IR (neat) 2956,
2858, 2175, 1966 cmꢁ1; MS (GC/MS) m/e (relative inten-
sity) 618 ([M]+, 5), 561 (100), 199 (94); HRMS calcd for
C37H58O2Si3: 618.3745; found: 618.3751.
resolved. H NMR (300 MHz, toluene-d8): d 0.12* (s, 9H),
1.04* (s, 18H), 1.16* (s, 9H), 1.77* (s, 3H), 1.82–1.90 (m,
4H), 2.00–2.12 (m, 2H), 2.16–2.30 (m, 2H), 2.65–2.75* (m,
1H), 3.32–3.40* (m, 2H), 4.50* (dt, J¼3.3, 9.5 Hz, 1H),
5.23–5.32* (m, 1H), 5.61* (s, 1H), 5.65* (d, J¼3.4 Hz,
1H), 7.16–7.21 (m, 20H), 7.60–7.68* (m, 6H), 7.72–7.79*
(m, 4H); IR (neat) 3383, 2957, 2857, 1427 cmꢁ1; MS (GC/
MS) m/e (relative intensity) 504 ([M]+, 55), 199 (85), 73
(100); HRMS calcd for C31H44O2Si2: 504.2880; found:
504.2899; 1H NMR (300 MHz, CDCl3) constitutional isomer
25c: d 0.10 (s, 9H), 1.07 (s, 9H), 1.56–1.64 (m, 3H), 1.75–
1.85 (m, 2H), 2.16–2.26 (m, 3H), 2.55–2.64 (m, 1H), 3.60
(dd, J¼11.6, 6.3 Hz, 2H), 4.34 (m, 1H), 4.82 (d, J¼2.3 Hz,
1H), 4.96 (m, 1H), 5.41 (s, 1H), 5.51 (d, J¼3.3 Hz, 1H),
7.34–7.47 (m, 6H), 7.68–7.71 (m, 4H); IR (neat) 3373,
2926, 2855, 1463, 1428 cmꢁ1; MS (GC/MS) m/e (relative
intensity) 504 ([M]+, 18), 199 (100), 73 (89); HRMS calcd
for C31H44O2Si2: 504.2880; found: 504.2882.
4.4. Procedures for data in Table 2
For entries 1–3, 5–11, and 13–16 general procedure for
allenic Alder-ene reaction using method A was followed.
The crude mixture of products was analyzed by H NMR
1
and the ratios were determined by integration of distinct
olefinic peaks from each isomer.
For entries 4 and 12 general procedure for allenic Alder-ene
reaction using method B was followed. The crude mixture
of products was analyzed by H NMR and the ratios were
1
determined by integration of distinct olefinic peaks from
each isomer.
4.4.2. 6-Trimethylsilylhex-5-ynoic acid methoxy methyl
amide (27). To a solution of acid 26 (0.60 g, 3.26 mmol)
in 2 mL of DMF were added KHCO3 (0.82 g, 8.15 mmol)
and MeI (1.16 g, 8.15 mmol). The mixture changed from
clear to yellow to orange/brown color and was left at ambient
temperature. After 24 h complete consumption of the start-
ing material was seen by TLC and the mixture was poured
into EtOAc/water solution. The aqueous layer was separated
and extracted with EtOAc (3ꢃ). The combined organic
layers were washed with H2O, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue
was purified by silica gel chromatography eluting with
5% EtOAc/hexanes to afford the ester (499 mg, 76%) as
a yellow oil. Rf 0.4 (20% EtOAc/hexanes); 1H NMR
(300 MHz, CDCl3): d 0.15 (s, 9H), 1.85 (qn, J¼7.2 Hz,
2H), 2.30 (t, J¼6.9 Hz, 2H), 2.45 (t, J¼7.4 Hz, 2H), 3.69
(s, 3H). To a solution of 6-trimethylsilylhex-5-ynoic acid
methyl ester (0.50 g, 2.52 mmol) in 5 mL of THF was added
MeNHOMe$HCl (0.37 g, 3.78 mmol) and the flask was
cooled to ꢁ25 ꢂC. Then i-PrMgCl (3.78 mL of a 2.0 M
THF solution, 7.56 mmol) was added dropwise and after
addition was finished complete consumption of starting ma-
terial was observed by TLC. The mixture was quenched with
NH4Cl(aq), and the aqueous layer was separated and washed
with Et2O (3ꢃ). The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by silica gel chromatography
eluting with 20% EtOAc/hexanes to afford amide 27
(520 mg, 91%) as a colorless oil. Rf 0.2 (20% EtOAc/hex-
4.4.1. 4-[3-(tert-Butyldiphenylsilyloxy)-6-trimethylsilyl-
methylenecyclohex-1-enyl]-pent-3E-en-1-ol (E-24c),
4-[3-(tert-butyldiphenylsilyloxy)-6-trimethylsilylmethyl-
enecyclohex-1-enyl]-pent-3Z-en-1-ol (Z-24c), and 4-[3-
(tert-butyldiphenylsilyloxy)-6-trimethylsilylmethylene-
cyclohex-1-enyl]-pent-4-en-1-ol (25c). To a flame dried test
tube was added allene 22c (0.01 g, 0.02 mmol), which was
azeotroped under vacuum with benzene (3ꢃ). Dichloro-
ethane (0.3 mL) was added and the test tube was evacuated
under vacuum and charged with N2 (3ꢃ). Then, [Ir(COD)Cl]2
(2.00 mg, 2.00 mmol) was added followed by AgBF4
(85.0 mL of a 0.05 M dichloroethane solution, 4.00 mmol)
and the system was evacuated and charged with N2 once
more. The solution was quenched after 1.75 h by addition
to a silica gel plug eluting with 5% EtOAc/hexanes to afford
9 mg of a mixture of products. This mixture of products was
diluted with 1.6 mL of wet MeOH and one drop of water.
Then the solution was cooled to 0 ꢂC and K2CO3 (0.02 g,
0.11 mmol) was added. It was then allowed to warm to ambi-
ent temperature and after 2 h a complete consumption of the
starting material was seen by TLC. The mixture was filtered
and concentrated under reduced pressure. The residue was
purified by silica gel chromatography eluting with 10%
EtOAc/hexanes to afford 5 mg of trienes E-24c, Z-24c, and
25cin60%yield. Puretrienescouldbeobtainedwhenalarger
scale reaction was performed. The minor isomer was sepa-
rated with silica gel chromatography and the other two iso-
mers were separated on HPLC for spectroscopic purposes
(Varian Microsorb Dynamax 100-5 Si column, 23 ꢂC,
EtOAc/hexanes¼5%, flow rate¼4 mL/min). Rf 0.3 (10%
EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) major isomer
E-24c: d 0.10 (s, 9H), 1.07 (s, 9H), 1.71 (s, 3H), 1.74–1.83 (m,
2H), 2.15–2.24 (m, 1H), 2.35 (q, J¼6.8 Hz, 2H), 2.54–2.62
(m, 1H), 3.67 (dd, J¼6.3, 11.9 Hz, 2H), 4.32–4.37 (m, 1H),
5.23 (dt, J¼1.3, 7.3 Hz, 1H), 5.31 (s, 1H), 5.50 (d,
J¼3.2 Hz, 1H), 7.35–7.47 (m, 6H), 7.68–7.73 (m, 4H). 13C
NMR (75 MHz, CDCl3) (one extra peak); IR (neat) 3374,
2957, 2929, 2856, 1472, 1428 cmꢁ1; MS (GC/MS) m/e
(relative intensity) 504 ([M]+, 4), 199 (94), 73 (100): HRMS
calcd for C31H44O2Si2: 504.2880; found: 504.2903; minor
isomer at 343 K with unknown TBDPS impurity from prior
reaction. * Designates product Z-24c where peaks were
1
anes); H NMR (300 MHz, CDCl3): d 0.12 (s, 9H), 1.77–
1.86 (m, 2H), 2.29 (t, J¼6.8 Hz, 2H), 2.54 (t, J¼7.4 Hz,
2H), 3.16 (s, 3H), 3.67 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 0.0 (3C), 19.3, 23.2, 30.4, 32.1, 61.1, 85.1,
106.5, 173.8; IR (neat) 3483, 2959, 2901, 2174,
1667 cmꢁ1; MS (GC/MS) m/e (relative intensity) 227
([M]+, 10), 212 (18), 167 (65), 73 (100); HRMS calcd for
C11H21N1O2Si1: 227.1342; found: 227.1341.
4.4.3. 2-(tert-Butyldimethylsilyloxy)-6-trimethylsilylhex-
5-ynoic acid methoxy methyl amide (28). To a flame dried
round bottom flask was added 20 mL of THF and the flask
was cooled to ꢁ78 ꢂC. NaHMDS (8.58 mL of a 1 M THF
solution, 8.58 mmol) was first added and then a solution
of amide 27 (1.30 g, 5.72 mmol) in 40 mL of THF was

K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
10551
added. The solution was left at ꢁ78 ꢂC for 30 min and then
a solution of PhSO2NOCHPh (2.24 g, 8.58 mmol) in 30 mL
of THF was added via cannula. After 30 min complete con-
sumption of the starting material was seen by TLC. The mix-
ture was quenched with NH4Cl(aq) and allowed to warm to
ambient temperature. The stir bar was removed and the
organic layer was removed under reduced pressure. The
mixture was diluted with Et2O and the aqueous layer was
separated and washed with Et2O (3ꢃ). The combined
organic layers were dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The resulting solids were
diluted with 3:1 hexane/chloroform solution and filtered
via gravity filtration. After removal of solvent, the residue
was purified by silica gel chromatography eluting with
20% EtOAc/hexanes to afford a-hydroxy amide (1.20 g,
concentrated under reduced pressure. The residue was puri-
fied by silica gel chromatography eluting with 1–5% EtOAc/
hexanes to afford ketone 29 (1.66 mg, 77%). Rf 0.8 (20%
1
EtOAc/hexanes); H NMR (300 MHz, CDCl3): d 0.03 (s,
6H), 0.06 (s, 3H), 0.08 (s, 3H), 0.12 (s, 9H), 0.87 (s, 9H),
0.91 (s, 9H), 1.70–1.86 (m, 3H), 1.87–2.01 (m, 1H), 2.34
(t, J¼6.6 Hz, 2H), 2.47 (t, J¼7.1 Hz, 2H), 3.67 (t,
J¼5.8 Hz, 2H), 4.24 (dd, J¼3.8, 8.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d ꢁ5.4 (2C), ꢁ5.2, ꢁ4.6, 0.1 (3C),
15.7, 15.8, 18.2 (2C), 25.8 (3C), 25.9 (3C), 30.8, 33.3,
61.2, 77.5, 79.3, 85.7, 97.5, 105.9, 189.3; IR (neat) 2956,
2930, 2858, 2211, 2176, 1676 cmꢁ1; MS (GC/MS) m/e (rel-
ative intensity) 479 ([MꢁCH3]+, 2), 269 (58), 73 (100);
HRMS calcd for C25H47O3Si3: 479.2833 [MꢁCH3]+; found:
479.2844 [MꢁCH3]+.
1
86%). Rf 0.2 (30% EtOAc/hexanes); H NMR (300 MHz,
CDCl3): d 0.13 (s, 9H), 1.57–1.70 (m, 1H), 1.89–2.06 (m,
1H), 2.37–2.54 (m, 2H), 3.25 (s, 3H), 3.24 (br d, J¼4.9 Hz,
1H), 3.72 (s, 3H), 4.49 (t, J¼6.9 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d 0.1 (3C), 16.0, 32.4, 33.7, 61.4, 67.3,
4.4.5. 5,11-Bis-(tert-butyldimethylsilyloxy)-8-methyl-1-
trimethylsilylundeca-6,7-dien-1-yne (22d). The ketone
29 (0.44, 0.89 mmol) was diluted with a solution of
CeCl3$7H2O (2.89 mL of a 0.4 M solution in methanol,
1.16 mmol), cooled to ꢁ20 ꢂC, and NaBH4 (0.04 g,
1.16 mmol) was added in one portion. The mixture was al-
lowed to warm to 0 ꢂC and after 30 min complete consump-
tion of the starting material was observed by TLC. The
solution was quenched with slow addition of H2O, and the
aqueous layer was separated and washed with Et2O (3ꢃ).
The combined organic layers were dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The residue
was purified by silica gel chromatography eluting with 5%
EtOAc/hexanes to afford alcohol (388 mg, 88%) as a 7:1 dia-
stereomeric ratio (based upon integration of peaks in the 1H
NMR). * Designates major diastereomer where peaks were
resolved. Rf 0.6 (20% EtOAc/hexanes); 1H NMR
(300 MHz, CDCl3): d 0.03 (s, 6H), 0.12 (s, 15H), 0.87 (s,
9H), 0.90 (s, 9H), 1.63–1.91 (m, 4H), 2.23–2.32 (m, 4H),
2.38 (d, J¼6.7 Hz, 1H), 3.65 (t, J¼6.0 Hz, 2H), 3.81–3.91
(m, 1H), 4.15–4.22* (m, 1H), 4.32–4.36 (m, 1H); 13C
NMR (75 MHz, CDCl3) (major diastereomer): d ꢁ5.4
(2C), ꢁ4.50, ꢁ4.47, 0.0 (3C), 15.2, 15.9, 18.1, 18.2, 25.9
(6C), 31.6, 32.2, 61.6, 65.3, 74.2, 79.5, 85.1, 85.7, 106.6;
IR (neat) 3456, 2956, 2857, 2175 cmꢁ1; MS (GC/MS) m/e
(relative intensity) 496 ([M]+, 0.2), 307 (4), 73 (100);
HRMS calcd for C22H43O3Si3: 439.2520 [MꢁC(CH3)3]+;
found: 439.2526 [MꢁC(CH3)3]+. To a solution of 5,11-
bis-(tert-butyldimethylsilyloxy)-1-trimethylsilylundeca-
1,7-diyn-6-ol (0.39 g, 0.78 mmol) in 2.6 mL of CH2Cl2 was
added Et3N (140 mL, 1.0 mmol) and the solution was cooled
to 0 ꢂC. Then MsCl (73 mL, 0.94 mmol) was added and after
30 min at 0 ꢂC the mixture was diluted with pentanes. The
mixture was then filtered through a sintered glass funnel of
medium porosity packed with Celite and the resulting solu-
tion was washed with NaHCO3(aq) and brine. The organic
layer was dried over MgSO4, filtered, and concentrated
under reduced pressure. To a suspension of CuI (0.18 g,
0.94 mmol) in 3.1 mL of THF at ꢁ30 ꢂC was added MeLi
(977 mL of a 1.6 M diethyl ether solution, 1.56 mmol) drop-
wise. The mixture was allowed to warm to 0 ꢂC over a
30 min period while it changed from a cloudy yellow to clear
solution. It was then cooled to ꢁ78 ꢂC and a solution of me-
sylate in 2.6 mL of THF was added dropwise with a cannula.
The mixture was kept at that temperature for 45 min before
NH4Cl(aq) and Et2O were added. The biphasic solution was
stirred vigorously until the aqueous layer turned deep blue.
84.8, 106.2, 174.5; IR (neat) 3445, 2960, 2174, 1660 cmꢁ1
;
MS (GC/MS) m/e (relative intensity) 228 ([MꢁCH3]+, 40),
155 (30), 73 (100), 61 (91); HRMS calcd for C10H18N1O3Si1:
228.1056 [MꢁCH3]+; found: 228.1052 [MꢁCH3]+. To a
solution of 2-hydroxy-6-trimethylsilylhex-5-ynoic acid
methoxy methyl amide (1.20 g, 4.93 mmol) in 15 mL of
CH2Cl2 at 0 ꢂC was added Et3N (1.37 mL, 9.86 mmol) and
then TBSOTf (1.70 mL, 7.40 mmol). After 20 min at 0 ꢂC
a complete loss of the starting material was seen by TLC.
The solution was quenched with NH4Cl(aq) and Et2O, and
the aqueous layer was separated and washed with Et2O
(3ꢃ). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography elut-
ing with 10% EtOAc/hexanes to afford 28 (1.65 g, 94%) as
a colorless oil. Rf 0.5 (20% EtOAc/hexanes); 1H NMR
(300 MHz, CDCl3): d 0.09 (s, 3H), 0.10 (s, 3H), 0.14 (s,
9H), 0.91 (s, 9H), 1.72–1.91 (m, 2H), 2.28–2.51 (m, 2H),
3.19 (s, 3H), 3.72 (s, 3H), 4.72–4.83 (m, 1H). 13C NMR
(75 MHz, CDCl3): d ꢁ5.3, ꢁ4.7, 0.1 (3C), 16.0, 18.3, 25.8
(3C), 32.7, 33.1, 61.4, 68.0, 85.2, 106.3, 174.5; IR (neat)
3445, 2960, 2174, 1660 cmꢁ1; MS (GC/MS) m/e (relative
intensity) 342 ([MꢁCH3]+, 0.1), 300 (80), 73 (100); HRMS
calcd for C13H26NO3Si2: 300.1451 [MꢁC(CH3)3]+; found:
300.1445 [MꢁC(CH3)3]+.
4.4.4. 5,11-Bis-(tert-butyldimethylsilyloxy)-1-trimethyl-
silylundeca-1,7-diyn-6-one (29). To a solution of tert-butyl-
dimethyl(pent-4-ynyloxy)silane (1.30 g, 6.51 mmol) in 18 mL
of THF at ꢁ78 ꢂC was added n-butyllithium (4.07 mL of
a 1.6 M hexane solution, 6.51 mmol) dropwise. The flask
was left at ꢁ78 ꢂC for 10 min and then placed in a ꢁ20 ꢂC
bath for 20 min and then cooled to ꢁ78 ꢂC and added to a
solution of amide 28 (1.55 g, 4.34 mmol) in 9 mL of THF
at ꢁ78 ꢂC via cannula. The mixture was then allowed to
slowly warm over 2 h to ꢁ10 ꢂC and the temperature was
kept at ꢁ10 ꢂC for 30 min at which time complete consump-
tion of starting material was observed by TLC. The solution
was quenched with NH4Cl(aq), the stir bar was removed, and
the organic layer was removed under reduced pressure. The
mixture was diluted with Et2O and the aqueous layer
was separated and washed with Et2O (3ꢃ). The combined
organic layers were dried over MgSO4, filtered, and

10552
K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
The solution was then filtered through a sintered glass funnel
of medium porosity packed with Celite to remove the copper
salts and aqueous layer. The organic layer was concentrated
under reduced pressure and the residue was purified by silica
gel chromatography eluting with 1% EtOAc/hexanes to
afford allene 22d (330 mg, 86%) as a 7:1 allene 22d/
Ene-yne 23 ratio (based upon integration of peaks in the
1H NMR). Pure allene 22d was obtained by HPLC for spec-
troscopic purposes (Varian Microsorb Dynamax 100-5 Si
column, 23 ꢂC, EtOAc/hexanes¼1%, flow rate¼3 mL/
analysis. The mixture was quenched after 1 h by running
through a silica gel plug eluting with 5% EtOAc/hexanes
to afford 1.57 g of trienes E-24d, Z-24d, and 25d in 6:2:1 ra-
tio, respectively, and a 95% crude yield.
4.4.9. 3-(4-Hydroxy-1-methylbut-1E-enyl)-4-trimethyl-
silylmethylenecyclohex-2-enol (E-30), 3-(4-hydroxy-1-
methylbut-1Z-enyl)-4-trimethylsilylmethylenecyclohex-
2-enol (Z-30), and 3-(4-hydroxy-1-methylenebutyl)-4-tri-
methylsilylmethylenecyclohex-2-enol (31). To a solution
of trienes E-24d, Z-24d, and 25d (0.16 g, 0.32 mmol) in
8 mL of THF was added NH4Cl(s) (0.1 g, 1.86 mmol) and
then TBAF (1.3 mL of a 1 M THF solution, 1.3 mmol).
The mixture was heated to 50 ꢂC and after 12 h was
quenched by addition of water. The stir bar was removed
and the organic layer was evaporated under reduced pres-
sure. The mixture was diluted with Et2O and the aqueous
layer was separated and washed with Et2O (3ꢃ). The com-
bined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was puri-
fied by silica gel chromatography eluting with 30% EtOAc/
hexanes to afford trienes E-30, Z-30, and 31 (78 mg, 92%).
Rf 0.1 (30% EtOAc/hexanes); Rf 0.42, 0.6, 0.45 (E-30, Z-
1
min). Rf 0.8 (10% EtOAc/hexanes); H NMR (300 MHz,
CDCl3): d 0.05 (s, 6H), 0.07 (s, 3H), 0.08 (s, 3H), 0.15 (s,
9H), 1.59–1.82 (m, 7H), 1.90–2.10 (m, 2H), 2.29 (t,
J¼7.3 Hz, 2H), 3.63 (t, J¼6.4 Hz, 2H), 4.16–4.26 (m, 1H),
4.95–5.03 (m, 1H); 13C NMR (75 MHz, CDCl3): d ꢁ5.3
(2C), ꢁ4.9, ꢁ4.3, 0.1 (3C), 16.1, 18.2, 18.3, 19.3, 25.9
(3C), 26.0 (3C), 30.2, 31.0, 37.4, 62.8, 70.5, 84.5, 94.7,
100.9, 107.3, 199.7; IR (neat) 2956, 2857, 2176,
1965 cmꢁ1; MS (GC/MS) m/e (relative intensity) 494
([M]+, 1.2), 479 (1.5), 269 (45), 73 (100); HRMS calcd for
C27H54O2Si3: 494.432; found: 494.3442.
4.4.6. 7-(tert-Butyldimethylsilyloxy)-4-methyl-11-tri-
methylsilyl-1-undeca-4,5-dien-10-ynyl acetate (22e). H
1
1
30, 31) (10% isopropanol/pentanes); H NMR (300 MHz,
NMR (500 MHz, CDCl3): d 0.06 (s, 3H), 0.07 (s, 3H),
0.14 (s, 9H), 0.89 (s, 9H), 1.60–1.81 (m, 7H), 1.95–2.05
(m, 5H), 2.25–2.31 (m, 2H), 4.08 (t, J¼6.6 Hz, 2H), 4.22
(q, J¼6.2 Hz, 1H), 4.98–5.05 (m, 1H); 13C NMR
(125 MHz, CDCl3): d ꢁ4.9, ꢁ4.4, 0.1 (3C), 16.1, 18.1,
18.2, 20.9, 25.8 (3C), 26.7, 30.1, 37.4, 64.0, 70.2, 84.6,
95.2, 100.2, 107.2, 171.1, 199.7; IR (neat) 2956, 2929,
2174, 1744 cmꢁ1; MS (GC/MS) m/e (relative intensity)
422 ([M]+, 38), 365 (45), 269 (60), 73 (100); HRMS calcd
for C23H42O3Si2: 422.2673; found: 422.2664.
CDCl3) E-30: d 0.11 (s, 9H), 1.58–1.70 (m, 1H), 1.72 (d,
J¼0.5 Hz, 3H), 2.00 (ddd, J¼4.2, 8.1, 16.5 Hz, 1H), 2.10
(br s, 1H), 2.25–2.40 (m, 3H), 2.55 (ddd, J¼3.7, 7.8,
14.6 Hz, 1H), 3.66 (t, J¼6.6 Hz, 2H), 4.27–4.35 (m, 1H),
5.31 (dt, J¼1.3, 7.2 Hz, 1H), 5.37 (s, 1H), 5.63 (d, J¼
3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 0.0 (3C), 17.2,
28.1, 31.6, 32.8, 62.1, 66.2, 124.7, 127.0, 128.4, 138.5,
147.5, 149.3; IR (neat) 3319, 2952, 1578, 1437 cmꢁ1; MS
(GC/MS) m/e (relative intensity) 266 ([M]+, 1), 192 (34),
145 (100); HRMS calcd for C15H26O2Si: 266.1702; found:
1
266.1693; H NMR (300 MHz, CDCl3) Z-30: d 0.12 (s,
4.4.7. 7-(tert-Butyldimethylsilyloxy)-4-methyl-11-tri-
methylsilyl-1-undeca-4,5-dien-10-ynyl-1-ol (22f). 1H NMR
(500 MHz, CDCl3): d 0.05 (s, 3H), 0.06 (s, 3H), 0.12 (s,
9H), 0.87 (s, 9H), 1.62–1.78 (m, 7H), 1.95–2.08 (m, 2H),
2.20–2.31 (m, 2H), 3.64 (t, J¼6.4 Hz, 2H), 4.22 (q, J¼
6.3 Hz, 1H), 4.95–5.02 (m, 1H); 13C NMR (125 MHz,
CDCl3): d ꢁ5.0, ꢁ4.4, 0.1 (3C), 16.0, 18.1, 19.1, 25.8 (3C),
30.2, 30.4, 37.3, 62.3, 70.2, 84.6, 94.8, 100.7, 107.2, 199.7;
IR (neat) 3347, 2955, 2929, 2175, 1250 cmꢁ1; MS (GC/MS)
m/e (relative intensity) 380 ([M]+, 30), 323 (20), 269 (60),
75 (100); HRMS calcd for C21H40O2Si2: 380.2567; found:
380.2558.
9H), 1.60–1.75 (m, 1H), 1.81 (s, 3H), 2.00–2.19 (m, 3H),
2.29–2.41 (m, 1H), 2.62 (ddd, J¼3.7, 6.8, 14.6 Hz, 1H),
3.51–3.63 (m, 2H), 4.31–4.38 (m, 1H), 5.36 (dt, J¼1.0,
6.4 Hz, 1H), 5.44 (s, 1H), 5.60 (d, J¼3.1 Hz, 1H); 13C
NMR (75 MHz, CDCl3): d 0.0 (3C), 24.9, 27.9, 29.7, 32.7,
62.5, 66.3, 123.6, 126.0, 129.7, 138.5, 143.3, 148.5; IR
(neat) 3318, 2953, 1577, 1434 cmꢁ1; MS (GC/MS) m/e
(relative intensity) 266 ([M]+, 1.4), 248 (8.4), 73 (100);
HRMS calcd for C15H26O2Si: 266.1702; found: 266.1698;
1H NMR (300 MHz, CDCl3) constitutional isomer 31:
d 0.13 (s, 9H), 1.59–1.76 (m, 3H), 2.03 (ddd, J¼4.3, 8.1,
16.8 Hz, 1H), 2.23 (t, J¼7.6 Hz, 2H), 2.36 (dddd, J¼1.3,
3.7, 9.8, 14.7 Hz, 1H), 2.57 (ddd, J¼3.8, 7.9, 14.6 Hz, 1H),
3.63 (t, J¼6.6 Hz, 2H), 4.32–4.37 (m, 1H), 4.89 (d,
J¼2.2 Hz, 1H), 5.02 (dt, J¼1.3, 2.2 Hz, 1H), 5.49 (s, 1H),
5.67 (d, J¼3.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 0.0
(3C), 27.9, 31.2, 32.3, 32.8, 62.4, 66.2, 114.3, 127.5, 129.2,
144.9, 148.8, 149.1; IR (neat) 3332, 2949, 1577,
1435 cmꢁ1; MS (GC/MS) m/e (relative intensity) 248
([MꢁH2O]+, 8), 73 (100); HRMS calcd for C15H24OSi:
248.1596 [MꢁH2O]+; found: 248.1588 [MꢁH2O]+.
4.4.8. 3-(tert-Butyldimethylsilyloxy)-1-[4-(tert-butyl-
dimethylsilyloxy)-1-methylbut-1E-enyl]-6-trimethyl-
silylmethylenecyclohexene (E-24d), 3-(tert-butyl-
dimethylsilyloxy)-1-[4-(tert-butyldimethylsilyloxy)-1-
methyl-but-1Z-enyl]-6-trimethylsilylmethylenecyclo-
hexene (Z-24d), and 3-(tert-butyldimethylsilyloxy)-1-[4-
(tert-butyldimethylsilyloxy)-1-methylenebutyl]-6-tri-
methylsilylmethylenecyclohexene (25d). To a flame dried
test tube was added allene 22d (1.66 g, 3.36 mmol), which
was azeotroped under vacuum with benzene (3ꢃ). Toluene
(17 mL) was added and the test tube was evacuated under
vacuum and charged with N2 (3ꢃ). Then, [Rh(CO)2Cl]2
(0.04 g, 0.09 mmol) was added at ambient temperature and
the system was evacuated and charged with N2 once more.
The mixture was heated to 80 ꢂC and followed by GC
4.4.10. 3-[4-(tert-Butyldimethylsilyloxy)-1-methylbut-1-
enyl]-4-trimethylsilyl methylenecyclohex-2-enol (32). To
a solution of triene E-30 (0.07 g, 0.26 mmol) in 1.3 mL of
CH2Cl2 were added Et3N (150 mL, 1.10 mmol) and
TBDMSCl (0.08 g, 0.29 mmol) at 0 ꢂC. The solution was
then warmed to ambient temperature and left overnight.

K. M. Brummond, J. M. McCabe / Tetrahedron 62 (2006) 10541–10554
10553
distal double bond. Likewise, Sato’s substrate required a short
two carbon tether on the allenyne in order for the reaction to
occur at the distal double bond of the allene.
The mixture was quenched by addition of water, and the
aqueous layer was separated and washed with CH2Cl2
(3ꢃ). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography elut-
ing with 5% EtOAc/hexanes to afford 32 (74 mg, 75%). Rf
16. Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.;
Rickards, B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4, 1931
Computational insight concerning catalytic decision points of
the transition metal-catalyzed [2+2+1] cycloisomerization re-
action of allenes. Bayden, A. S.; Brummond, K. M.; Jordan,
K. D., submitted for publication.
17. Tsuge, O.; Wada, E.; Kanemasa, S. Chem. Lett. 1983, 239.
18. Sin, N.; Meng, L.; Wang, M. Q. W.; Wen, J. J.; Bornmann,
W. G.; Crews, C. M. Proc. Natl. Acad. Sci. U.S.A. 1997, 94,
6099; Zhou, G.; Tsai, C. W.; Liu, J. O. J. Med. Chem. 2003,
46, 3452 and references therein.
19. Griffith, E. C.; Su, Z.; Turk, B. E.; Chen, S.; Chang, Y.; Wu, Z.;
Biemann, K.; Liu, J. O. Chem. Biol. 1997, 4, 461; Mazitschek,
R.; Huwe, A.; Giannis, A. Org. Biomol. Chem. 2005, 3, 2150.
20. Inoue, K.; Chikazawa, M.; Fukata, S.; Yoshikawa, C.; Shuin, T.
Clin. Cancer Res. 2003, 9, 886 and references therein.
21. Liu, S.; Widom, J.; Kemp, C. W.; Crews, C. M.; Clardy, J.
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1
0.6 (30% EtOAc/hexanes); H NMR (300 MHz, CDCl3):
d 0.07 (s, 6H), 0.12 (s, 9H), 0.90 (s, 9H), 1.62–1.70 (m,
1H), 1.73 (s, 3H), 1.93–2.05 (m, 1H), 2.28–2.38 (m, 3H),
2.55 (ddd, J¼3.6, 7.9, 14.5 Hz, 1H), 3.65 (t, J¼7.0 Hz,
2H), 4.24–4.28 (m, 1H), 5.31 (t, J¼7.2 Hz, 1H) 5.41 (s,
1H), 5.62 (d, J¼3.0 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d ꢁ5.2 (2C), 0.1 (3C), 17.2, 18.3, 26.0 (3C), 28.0, 32.0,
32.9, 62.8, 66.3, 125.4, 127.1, 128.0, 137.2, 147.9, 149.3;
IR (neat) 3334, 2954, 2858, 1578 cmꢁ1; MS (GC/MS) m/e
(relative intensity) 380 ([M]+, 3), 145 (40), 73 (100);
HRMS calcd for C21H40O2Si2: 380.2567; found: 380.2567.
Acknowledgements
We thank the University of Pittsburgh, the National Science
Foundation, and the Johnson and Johnson Focused Giving
Award for financial support of this research. J.M.M. thanks
Pfizer for the 2004 Pfizer Research Fellowship Supporting
Diversity in Organic Chemistry.
22. Addlagatta, A.; Hu, X.; Liu, J. O.; Matthews, B. W.
Biochemistry 2005, 44, 14741; Brdlik, C. M.; Crews, C. M.
J. Biol. Chem. 2004, 279, 9475.
23. Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Chirality 2003, 15,
156; Zhang, Y.; Griffith, E. C.; Sage, J.; Jacks, T.; Lin, J. O.
Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 6427.
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