Stereoselective stille coupling of enantiopure haloallenes and alkenylstannanes for the synthesis of allenyl carotenoids. Experimental and computational studies

Article abstract of DOI:10.1021/jo800756b

(Chemical Equation Presented) The stereoselectivity of the Stille cross-coupling of chiral enantiopure haloallenes and alkenylstannanes en route to allenic carotenoids is shown to depend on the nature of the halogen and palladium catalyst as well as on th

Full text of DOI:10.1021/jo800756b

Stereoselective Stille Coupling of Enantiopure Haloallenes and
Alkenylstannanes for the Synthesis of Allenyl Carotenoids.
Experimental and Computational Studies
´
Bele´n Vaz, Raquel Pereira, Mart´ın Pe´rez, Rosana Alvarez,* and Angel R. de Lera*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidade de Vigo, 36310 Vigo, Spain
qolera@uVigo.es; rar@uVigo.es
ReceiVed April 8, 2008
The stereoselectivity of the Stille cross-coupling of chiral enantiopure haloallenes and alkenylstannanes
en route to allenic carotenoids is shown to depend on the nature of the halogen and palladium catalyst
as well as on the presence of DMF as coordinating ligand and solvent. The results are consistent with
DFT studies (B3LYP/6-31G*) on haloallene model systems, which compare the energetics of the competing
oxidative addition to the allene-halogen bond (with retention of configuration) and the SN2′ displacement
of the haloallene (with inversion of configuration) by the palladium complex.
Introduction
Carotenoids, an important family of chemically sensitive
natural pigments isolated from plant and animal kingdoms, have
been traditionally synthesized by CdC double bond forming
strategies.1 Classical condensations, prominently the Wittig and
the Julia olefinations performed in consecutive fashion, have
proven efficient for the preparation of carotenoids even at the
industrial scale.2 The generally more stereoselective transition-
metal-catalyzed reactions3 for C-C single bond formation have
recently been applied to the preparation of both symmetrical
and nonsymmetrical highly functionalized carotenoids.4 The
synthesis of peridinin 15 (Figure 1),6 a C37-norcarotenoid7 with
an abnormal arrangement of methyl groups on the side chain
and endowed also with a γ-alkylidenebutenolide ring, five chiral
FIGURE 1. Synthetic approaches to peridinin 1 featuring Stille
coupling reactions.
centers, and the chiral allene axis, has been a tour de force in
this regard. Two alternative synthetic approaches to peridinin
featured the application of either convergent or sequential Stille
cross-coupling reactions to construct the final polyene or the
functionalized fragments from which the carotenoid was ac-
quired with the application of a (Sylvestre) Julia olefination.6a,b
´
(1) For recent monographs, see: (a) Britton, G., Liaaen-Jensen, S., Pfander,
H., Eds. Carotenoids. Part 1A. Isolation and Analysis; Birkha¨user: Basel,
Switzerland, 1995. (b) Britton, G., Liaaen-Jensen, S., Pfander, H., Eds.
Carotenoids. Part 1B. Spectroscopy; Birkha¨user: Basel, Switzerland, 1995.
(2) Britton, G., Liaaen-Jensen, S., Pfander, H. ,Eds. Carotenoids. Part 2.
Synthesis; Birkha¨user: Basel, Switzerland, 1996.
(6) (a) Vaz, B.; Alvarez, R.; Bru¨ckner, R.; de Lera, A. R. Org. Lett. 2005,
´
7, 545. (b) Vaz, B.; Dom´ınguez, M.; Alvarez, R.; de Lera, A. R. Chem.sEur.
J. 2007, 13, 1273. For other synthetic approaches to peridinin, see: (c) Furuichi,
N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S. Angew. Chem., Int. Ed. 2002,
41, 1023. (d) Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.; Katsumura,
S. J. Org. Chem. 2004, 69, 7949. (e) Olpp, T.; Bru¨ckner, R. Angew. Chem., Int.
Ed. 2005, 44, 1553. (f) Olpp, T.; Bru¨ckner, R. Angew. Chem., Int. Ed. 2006, 45,
4023.
(7) For standard nomenclature and numbering of carotenoids, see: (a) IUPAC
Commission on Nomenclature of Organic Chemistry and the IUPAC-IUB
Commission on Biochemical Nomenclature. Pure Appl. Chem. 1975, 41, 407.
(b) Weedon, B. C. L.; Moss, G. P. Structure and Nomenclature; in ref 1a, Chapter
3, p 27.
(3) (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b) Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
´
(4) (a) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719. (b) Vaz, B.; Alvarez,
R.; de Lera, A. R. J. Org. Chem. 2002, 67, 5040.
(5) For the isolation of peridinin 1, see: Song, P. S.; Koka, P.; Prezelin, B. B.;
Haxo, F. T. Biochemistry 1976, 15, 4422.
6534 J. Org. Chem. 2008, 73, 6534–6541
10.1021/jo800756b CCC: $40.75 2008 American Chemical Society
Published on Web 08/06/2008

Stille Coupling of Haloallenes and Alkenylstannanes
on the organometallic component, we decided to carry out a
comprehensive study of the stereoselectivity of the Stille
coupling of enantiopure haloallenes 2 (X ) I, Br) and related
substrates with two different alkenylstannanes 3 and 7. The main
finding of this study is that the bias of substrate 2 to react with
the palladium catalyst at the Csp2 position vicinal to the axial
tertiary hydroxyl group can be shifted to the direct oxidative
addition reaction using a palladium catalyst that includes a
coordinating solvent as ligand (DMF). Alternatively, protection
of the hydroxyl group also hinders the SN2′ displacement of
the allenyl halide. Computational studies of the competing metal-
mediated processes are in agreement with the experimental
findings and confirm the intriguing role played by the axial
tertiary hydroxyl group of reactant 2.
Results and Discussion
In the absence of precedents, except our previous results on
the Stille cross-coupling reaction of chiral enantiopure haloal-
lenes with alkenylstannanes,6a,b a survey of reaction conditions
for the coupling between haloallenes 2, 8, 11, and alkenylstan-
nanes 3 and 7 was carried out. The most significant results from
the series of reaction conditions and palladium sources surveyed
are listed in Table 1.
The reaction of 3 with bromoallene (aR)-2a was highly
diastereoselective (entries 1 and 2) and afforded sulfone (aS)-
4, the product of inversion of configuration, as confirmed by
X-ray diffraction analysis.11 Inversion of configuration was also
predominantly obtained using iodoallene (aR)-2b (entries 3-5),
although allene (aR)-4 was also produced in appreciable amounts
(entries 4 and 5) when Pd2dba3 was used as catalyst at 25 °C.
Bulky phosphines (entry 5) slowed down the reaction rates, and
starting material was partially recovered. Thus, we did not
observe the results reported by Vermeer for organozinc reagents
showing a clear dependence of the diastereoselectivity on the
nature of the halogen (Br: inversion; I: retention).
The inversion of configuration of the allene axis in both Stille
and Negishi couplings could be the consequence of an initial
anti-SN2′ displacement of halide by palladium.12 In the case of
(aR)-2, this transformation would generate 6-anti, and this
intermediate would undergo a suprafacial-[1,3]-sigmatropic shift
of propargyl to allenyl palladium,12c leading to (aS)-5 before
transmetalation and progression through the catalytic cycle
(Figure 3).13 A more favored anti-SN2′ displacement, as opposed
to the oxidative addition and the alternative syn-SN2′ reaction,
would explain the configuration of the product (aS)-4 (inversion)
upon reaction of (aR)-2a. These pathways appear to be competi-
FIGURE 2. Reactants and vinyallene products resulting from the Stille
coupling reactions (see Table 1).
In order to fully exploit the potential of the metal-catalyzed
single bond forming processes in the synthesis of polyenes, the
retention of configuration of the alkenyl coupling partners
(halides or triflates as electrophiles, several metals as nucleo-
philes) must be obeyed.3 Although this is often the case,8 allene-
containing polyenes add a further complication to the stereo-
selectivity analysis since both retention and inversion of
configuration at the allene chiral axis9 are possible when
enantiopure allene partners are used in the coupling. During
the peridinin synthetic endeavor,6a we observed that the Stille
reaction of bromoallene (aR)-2a and stannane 3 (Figure 2) took
place with inversion of configuration of the chiral axis to give
(aR)-4 (Table 1, entry 1) leading finally to the 6′-epimer of the
natural product.6a,b
Vermeer et al. previously reported that enantiopure 1-bro-
moallenes reacted with the organozinc reagent Ph2Zn using
Pd(PPh3)4 as catalyst to afford the phenyl-substituted allenes
with complete inversion of configuration, but 1-iodoallenes
coupled with retention of configuration at the allene moiety
under the same Negishi reaction conditions.10 To our disap-
pointment, our first Stille coupling trials using iodoallene (aR)-
2b and stannane 3 provided a stereorandom mixture of the
vinylallenes (aS)-4 and (aR)-4, the products of inversion and
retention of configuration, respectively.
(11) (aS)-4 (CCDC-267166): Empirical formula (C24H29NO5S2). Formula
weight (475.60). Temperature [173(2) K]. Wavelength (0.71073 Å). Crystal
system (Monoclinic). Space group [P2(1)]. Unit cell dimensions (a ) 10.2154(8)
Å, R ) 90°, b ) 21.8191(17) Å, ꢀ ) 106.447(2)°, c ) 11.5734(9) Å, γ ) 90°).
Volume (2474.1(3) Å3), Z (4). Density (calculated) (1.277 Mg/m3). Absorption
coefficient (0.249 mm-1). F(000) [1008]. Crystal size (0.49 × 0.33 × 0.24 mm3).
Theta range for data collection (1.83 to 28.03°). Index ranges (-13 ) h ) 11,-
24 ) k ) 28,-14 ) l ) 15). Reflections collected (15659). Independent
reflections 9768 [R(int) ) 0.0259]. Completeness to theta ) 28.03° (96.6%).
Absorption correction (SADABS). Max and min transmission (1.000000 and
0.874679). Refinement method (full-matrix least-squares on F2), Data/restraints/
parameters (9768/1/594). Goodness-of-fit on F2 (0.862). Final R indices [I >
2σ(I)] (R1 ) 0.0400, wR2 ) 0.0652). R indices (all data) (R1 ) 0.0600, wR2 )
0.0695). Absolute structure parameter [0.00(4)]. Largest diff. peak and hole (0.274
Concerned with the inconsistencies on the stereochemical
outcomes of Pd-catalyzed cross-coupling processes that differ
(8) (a) For examples of partial isomerization in Pd-catalyzed alkynylation
with alkenyl halides, see: Shi, J.; Zeng, X.; Negishi, E. Org. Lett. 2003, 5, 1825.
(b) For examples of clean inversion of configuration with organozinc reagents,
see: Zeng, X.; Hu, Q.; Qian, M.; Negishi, E. J. Am. Chem. Soc. 2003, 125,
13636.
(9) (a) For recent review and monographs on allenes, see: KrauseN.;
HashmiA. S. K. Modern Allene Chemistry; Wiley-VCH: Weinheim, Germany,
2004. (b) Ma, S. Chem. ReV. 2005, 105, 2829.
and-0.281 e · Å-3
)
(10) (a) Ruitenberg, K.; Kleijn, H.; Elsevier, C. J.; Meijer, J.; Vermeer, P.
Tetrahedron Lett. 1981, 22, 1451. (b) Elsevier, C. J.; Mooiweer, H. H.; Kleijn,
H.; Vermeer, P. Tetrahedron Lett. 1984, 25, 5571. (c) Elsevier, C. J.; Vermeer,
P. J. Org. Chem. 1985, 50, 3042. (d) Elsevier, C. J.; Kleijn, H.; Boersma, J.;
Vermeer, P. Organometallics 1986, 5, 716.
(12) For these mechanistic proposals, see: (a) Senn, H. M.; Ziegler, T.
Organometallics 2004, 23, 2980. (b) Stille, J. K.; Lau, K. S.Y. Acc. Chem. Res.
1977, 10, 434. For palladium rearrangement, see: (c) Takahashi, Y.; Tsutsumi,
K.; Nakagai, Y.; Morimoto, T.; Kakiuchi, K.; Ogoshi, S.; Kurosawa, H.
Organometallics 2008, 27, 276.
J. Org. Chem. Vol. 73, No. 17, 2008 6535

Vaz et al.
TABLE 1. Diastereoselectivity on the Stille Coupling of Haloallenes 2, 8, and 11 and Stannanes 3 and 7 under Different Reaction Conditions
e
conditionsa
solvent
t (h)
yield (%)f
(aR):(aS)g
-
No.
haloallene
stannane
product
1
2
3
4
5
6
7
8
(aR)-2a
(aR)-2a
(aR)-2b
(aR)-2b
(aR)-2b
(aR)-8a
(aR)-8a
(aR)-8a
(aR)-8a
(aR)-2b
(aR)-2b
(aR)-2b
(aR)-2b
(aS)-2b
(aS)-2b
(aS)-2b
(aR)-11a
(aR)-11a
(aR)-11b
(aR)-11b
3
3
3
3
3
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
4
4
4
4
4
9
9
9
9
10
10
10
10
10
10
10
12
12
12
12
a
b
a
b
c
b
a
d
e
b
a
d
e
b
a
d
e
b
e
b
DMF/THF
DMF
DMF
DMF
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
3
2
3.5
1
6
1
3
20
8
1
3
73
80
40
62
40h
63
84
52
88
89
89
51
63
89
95
51
92
98
39
60
0:100
0:100
29:71
42:58
40:60i
0:100
0:100
40:60
32:68
28:72
42:58
100:0
100:0
14:86
40:60
0:100
100:0
79:21
100:0
90:10
9
10
11
12
13
14
15
16
17
18
19
20
20
2.5
1
3
20
15
1.5
3
1.5
a PdCl2(PhCN)2 (20%), i-Pr2NEt. b Pd2dba3 ·CHCl3 (10%). c Pd2dba3 (10%), DPPB (di-tert-butylbiphenylphosphine), Ph2PO2NBu4. d Pd2dba3 (10%),
AsPh3. e Pd(PPh3)4 (10%). All reactions were performed at 25 °C. f Yields refer to the mixture of reaction products. g The ratio was determined by
integration of 1H NMR signals on the reaction mixtures (entries 1-5) or after isolation of the vinylallenes by chromatography (entries 6-20). h 75%
conversion. i Taken from ref 6a.
SCHEME 1a
a Reagents and reaction conditions: (a) I2, CH2Cl2, 25 °C (85%); (b)
Pd(PPh3)4, CuI, (i-Pr)2NH, 25 °C (84%); (c) DIBAL-H, CH2Cl2, 0 °C (50%).
reactions.14 The possibility that palladium complexes containing
PdL2 or PdL(DMF) (L ) AsPh3 or PPh3) also promote a faster
oxidative addition to (aR)-8a was tested. In fact, the use of these
conditions with (aR)-8a led to mixtures of retention and
inversion vinylallene products (aR)-9/(aS)-9 [Pd(AsPh3)4, entry
8, 40:60; Pd(PPh3)4, entry 9, 32:68], although longer reaction
times were needed. Interestingly, these modifications altered the
stereochemical course of the coupling of iodoallenes, affording
the retention product (aR)-10 as the only edduct from the
coupling of iodide (aR)-2b and stannane 7 (entries 12 and 13).
Evidence for the stereochemical outcome was obtained for (aS)-4
by X-ray analysis as described6 and for (aR)-9 by comparison
of the 1H NMR spectra15a with those of the vinylallene obtained
alternatively with retention of configuration using the well-
defined stereospecific syn-SN2′ reduction of alkynyloxiranes with
excess DIBAL-H (Scheme 1).15b
In order to examine a potential coordination effect of the
hydroxyl group, which would contribute to favor the SN2′
displacement at the proximal Csp2-allene atom, we carried out
the coupling of 7 with epimer iodoallene (aS)-2b and also with
allenes (aR)-11a and (aR)-11b having a TMS-protected hydroxyl
group (Table 1). In all cases, the main (entries 14, 15, 18, and
20) or exclusive product (entries 16, 17, and 19) showed
retention of configuration with the different sources of palladium
FIGURE 3. Oxidative addition or SN2′ displacement (syn and anti)
by palladium on haloallenes determines the configuration of the product,
as shown for substrate 2.
tive for iodides (aR)-2b in accordance with the appearance of
the retention product (aR)-4, which is presumably formed
through allenyl palladium (aR)-5 (Figure 3).
Stannane 7 also produced a single diastereomer (aS)-9 from
(aR)-8a upon treatment with Pd2dba3 ·CHCl3 or PdCl2(PhCN)2
in the presence of i-Pr2NEt as catalysts (entries 6 and 7), and
thus these conditions favor the SN2′ reaction of allenylbromides.
It has been reported that a coordinating solvent (such as DMF,
NMP, or THF) generates a more reactive PdL(S) species in
equilibrium with PdL2 in palladium-catalyzed cross-coupling
(13) Other isomerization mechanism cannot be discarded. Allenyl palladium
intermediates have been proposed to isomerize in the presence of monodentate
palladium ligands: Yoshida, M.; Hayashi, M.; Shishido, K. Org. Lett. 2007, 9,
1643. In addition, optically active allenylpalladium species are racemized through
the formation of dinuclear complexes: Ogoshi, S.; Nishida, T.; Shinagawa, T.;
Kurosawa, H. J. Am. Chem. Soc. 2001, 123, 7164. Moreover, allenes are
configurationally unstable in the presence of Pd(II)/LiBr through anti-bromopal-
ladation processes: Horva´th, A.; Ba¨ckvall, J. E. Chem. Commun 2004, 964.
(14) (a) Amatore, C.; Bacaille, A.; Fuxa, A.; Jutand, A.; Meyer, G.; Ndedi
Ntepe, A. Chem.sEur. J. 2001, 7, 2134. (b) Amatore, C.; Bahsoun, A. A.; Jutand,
A.; Meyer, G.; Ndedi Ntepe, A.; Ricard, L. J. Am. Chem. Soc. 2003, 125, 4212.
(c) Ahlquist, M.; Norrby, P.-O. Organometallics 2007, 26, 550.
6536 J. Org. Chem. Vol. 73, No. 17, 2008

Stille Coupling of Haloallenes and Alkenylstannanes
TABLE 2. Thermodynamic Data (Relative Free Energies of
Activation ∆G#, kcal/mol) of the Transition Strucures for the Model
Reactions Depicted on Figure 4
gas phase (∆G#)a COSMO (DMF, ∆G#)b
entry allene
catalyst
(aR)-16a Pd(PMe3)2
Pd(PMe3)(DMF) 20.4 8.9 8.1d 26.3
(aR)-16b Pd(PMe3)2 27.3 16.9 20.1 32.6
Pd(PMe3)(DMF) 22.9 10.6 7.4d 27.9
syn anti O.A.b syn
24.9 15.1 20.1 30.7
anti
O.A.c
1
2
3
4
5
6
7
22.6
16.4
24.5
17.9
24.5
25.7
26.9
17.3
9.2d
18.7
8.7d
15.1
13.3
14.1
FIGURE 4. Haloallene model systems used in the computational study
of the competing syn-SN2′ and anti-SN2′ displacements and the oxidative
addition reaction with Pd(PMe3)2 and Pd(PMe3)(DMF) as palladium
catalysts.
(aS)-17a Pd(PMe3)2
(aS)-16a Pd(PMe3)2
(aS)-16b Pd(PMe3)2
25.9 20.4 18.7
21.3 19.7 14.9
22.3 21.1 13.8
31.2
28.6
29.8
d
a Gas phase. b DMF (COSMO). c Oxidative addition. ∆G# for the
oxidative addition to the monophosphine complex Pd(PMe3) obtained
formally from the dissociation of DMF from the starting Pd(PMe3)(DMF).
regardless of the halogen used. The protected bromoallene (aR)-
11a produced efficiently (92% yield) the corresponding viny-
lallene (aR)-12 with retention of configuration. Thus, it appears
that the proximal tertiary hydroxyl diverts the Stille reaction
toward the formation of the undesired SN2′ product, and this
effect could be counteracted with its protection as silyl ether.
Aimed to shed some light into the dependence of the
diastereoselectivity with both the halogen and the palladium
catalyst composition, we carried out a computational study of
the competing processes, the oxidative addition into the
Csp2-Hal bond, and the SN2′ displacement of halogen by
palladium with anti and syn trajectories. The model systems
selected (Figure 4) were both axial diastereomers of the
(deacetylated) haloallene 16 as well as the analogous bromoal-
lene 17a lacking the tertiary hydroxyl group (note the change
of stereochemical descriptor of 17a relative to 16 for the same
relative arrangement of groups on the allene axis). Model
palladium catalysts [Pd(PMe3)2] and [Pd(PMe3)(DMF)] were
reasonably chosen with a PMe3 ligand that is smaller than PPh3
and the same coordinating solvent used in the experiments.
The B3LYP/6-31G*-SDD computational level was used due
to the satisfactory results obtained in previous computational
studies for the Stille reaction to afford dienes.16 All the
calculations were performed with the Gaussian03 suite of
programs.17 The solvent effect (DMF) was taken into account
with sequential single-point calculations at the gas-phase
optimized geometries using a continuum model.18 Figure 4
depicts the model systems and reactions used in the calculations,
and Table 2 summarizes the energy values for the located
transition structures of the selected transformations.
The two main findings of the computations are the effect of
the catalyst composition, in particular, the presence of a
coordinating solvent as palladium ligand, and the role of the
tertiary hydroxyl group of the substrates.
First, when computing the oxidative addition reaction of (aR)-
16a and (aR)-16b with Pd(PMe3)2 and Pd(PMe3)(DMF) com-
plexes, it was noted that the concerted transition structure for
the latter model catalyst could not be located. Instead, we could
characterize a stepwise process involving the loss of DMF
followed by the oxidative addition via the monophosphine
palladium complex.19 This step shows energies of activation of
8.1 and 7.4 kcal/mol for (aR)-16a and (aR)-16b, respectively,
which is consistent with previous reports of rate acceleration
on the oxidative addition to aryl halides of monophosphine
palladium complexes and also with the observation that highly
bulky phosphines accelerate cross-coupling processes most likely
entering the catalytic cycles as Pd(PR3) complexes.20
Regardless of the halogen, the lowest barrier computed for
the reaction of (aR)-16a and (aR)-16b with Pd(PMe3)2 corre-
sponds to the anti-SN2′ displacement (15.1 and 16.9 kcal/mol,
respectively), in full agreement with our earlier findings. In
contrast, the global barrier for the two-step oxidative addition
of Pd(PMe3)(DMF) to bromoallene (aR)-16a is similar to that
of the anti-SN2′ competing reaction, which explains the stereo-
random outcome experimentally obtained with (aR)-8a (Table
1, entries 8 and 9). Interestingly, the oxidative addition to
iodoallene (aR)-16b is the most favored path when the mixed
complex Pd(PMe3)(DMF) is used (7.4 vs 10.6 kcal/mol for the
oxidative addition and anti-SN2′, and 22.9 kcal/mol for the syn-
SN2′), in full agreement with the complete stereoselectivity of
(aR)-2b and (aS)-2b obtained experimentally (Table 1, entries
12 and 16). Our computations confirm that the combined effect
of the greater reactivity of the C-I bond and the more reactive
palladium source [PdL(S)] contribute to the retention of
configuration of the allenyl iodides through a “classical” Stille
catalytic cycle starting from the concerted oxidative addition
step.
(15) (a) The resonance of the allene proton on the aS diastereomers is shifted
downfield relative to those of the aR counterparts. (b) The preparation of
carotenoid allenols from alkynyloxiranes was first described by Widmer, E. Pure
Appl. Chem. 1985, 57, 741.
´
(16) (a) Alvarez, R.; Nieto Faza, O.; Silva Lo´pez, C.; de Lera, A. R. Org.
´
Lett. 2006, 8, 35. (b) Alvarez, R.; Nieto Faza, O.; de Lera, A. R.; Ca´rdenas, D.
´
AdV. Synth. Catal. 2007, 349, 887. (c) Alvarez, R.; Pe´rez, M.; Nieto-Faza, O.;
de Lera, A. R. Organometallics 2008, in press. (d) For computational details
see Supporting Information.
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M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y. ; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian,
H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
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Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.;
Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian03; Gaussian, Inc.: Wallingford CT, 2004.
The second observation from these studies is the effect on
the SN2′ substitution reaction of the tertiary hydroxyl group
located vicinal to the allene. Comparison of the energy values
between pairs of epimers of 16a and 16b indicates that the axial
hydroxyl group lowers the activation energy for the anti-SN2′
displacement in (aR)-16 by about 5 kcal/mol. In fact, bromoal-
(19) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
(20) (a) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. Organometallics
2006, 25, 54. (b) Ahlquist, M.; Fristrup, P.; Tanner, D.; Norrby, P. O.
Organometallics 2006, 25, 2066. (c) Lam, K. C.; Marder, T. B.; Lin, Z.
Organometallics 2007, 26, 758.
(18) (a) Onsager, L. J. Am. Chem. Soc. 1936, 58, 1486. (b) Tomasi, J.; Persico,
M. Chem. ReV. 1994, 94, 2027. (c) Tomasi, J.; Mennucci, B.; Cammi, R. Chem.
ReV. 2005, 105, 2999.
J. Org. Chem. Vol. 73, No. 17, 2008 6537

Vaz et al.
FIGURE 5. Transition structures (aR)-TS.16a.OA, (aR)-TS.16a.anti, and (aS)-TS.16a.OA for the oxidative addition (OA) and anti-SN2′ displacement
of substrate 16a with Pd(PMe3)2. Relevant bond distances (in angstroms) and bond angle (R, in degrees) are highlighted.
lene (aS)-17a, which lacks the hydroxyl, is predicted to couple
with retention of configuration given the lowest energy com-
puted for the oxidative addition reaction relative to the SN2′
alternative (18.7 vs 20.4 kcal/mol, Table 2, entry 5). Moreover,
the axially oriented hydroxyl group appears to conversely
increase the energy of activation of the competing oxidative
addition process in these isomers (aR)-16 by the same amount
when compared to diastereomers (aS)-16 (cf. Table 2, entries 1
and 6).
the role of the hydroxyl group on further modulating the
reactivity by providing assistance and/or stabilization of the
reactive intermediates. Together these results are of value since
they overcome the synthetic limitation previously reported
during the Stille approach to allenic carotenoids.6
Experimental Section
(1S,3R,4aR)-3-Hydroxy-3,5,5-trimethyl-4-(2-iodovinylidene)cy-
clohexyl Acetate (aR)-2b. CuI (0.478 g, 2.51 mmol), NH4I (0.182
g, 1.25 mmol), and HI (57% aq, 0.60 mL, 4.01 mmol) were added
sequentially to a cooled (-10 °C) solution of (1R,3S,6R)-6-ethynyl-
1,5,5-trimethyl-7-oxabicyclo[4.1.0]heptan-3-ol6b (0.457 g, 2.51
mmol) in Et2O (11.0 mL). After stirring for 1.5 h, an aqueous
solution of NH4Cl/NH3 1:1 (10 mL) was added, and the layers were
separated. The organic layer was washed with brine (3×) and dried
(Na2SO4), and the solvent was evaporated. The residue was purified
by column chromatography (silica gel, 60:40 hexane/EtOAc) to
afford 0.630 g (81%) of a white solid, which was used in the next
step without further purification. Ac2O (0.863 mL, 9.22 mmol) was
added to a solution of the diol obtained before (0.568 g, 1.84 mmol)
in pyridine (5.7 mL). After stirring for 3 h, the mixture was extracted
with Et2O (3×). The combined organic layers were washed with a
saturated aqueous CuSO4 solution (2×) and dried (Na2SO4), and
the solvent was evaporated. The residue was purified by column
chromatography (silica gel, gradient from 90:10 to 80:20 hexane/
EtOAc) to afford 0.59 g (91%) of a white solid identified as
(1S,3R,4aR)-3-hydroxy-3,5,5-trimethyl-4-(2-iodovinylidene)cyclo-
hexyl acetate (aR)-2b and 0.05 g (8%) of a white solid identified
as (1S,3R,4aS)-3-hydroxy-3,5,5-trimethyl-4-(2-iodovinylidene)cy-
clohexyl acetate (aS)-2b.
A potential role of the hydroxyl group in assisting the reaction
is suggested by its distance to the palladium center in the
transition state for the anti-SN2′ displacement [H-Pd bond
distance of 2.56 Å for (aR)-16a and 2.57 Å for (aR)-16b, Figure
5]. Interactions between hydrogen bound to oxygen or nitrogen
and transition metals in low oxidation states have been ob-
served21 and exhibit features of the classical hydrogen bond. A
similar interaction between the hydroxyl and the halogen atoms
as gathered from the elongated C-Br bond (2.74 vs 2.49 Å for
(aS)-16a and (aR)-16a, respectively, Figure 5) might also explain
the lower barriers obtained for the oxidative addition of (aS)-
16b and (aS)-16b (14.9 and 13.8 kcal/mol, respectively).
Solvent effects were calculated using COSMO. In general,
there is a lowering of the energies of activation for the oxidative
addition processes most likely due to the concerted nature of
the transition state. However, the reverse trend is computed for
the halogen displacement processes (syn or anti, most pro-
nounced for the latter). This is consistent with the polar nature
of the SN2′ reaction, a process of associative/dissociative nature,
which is not properly described by the current methods.
In summary, the Stille reaction of highly functionalized allenyl
halides and alkenyl stannanes takes place with either retention
(via oxidative addition) or inversion of configuration (via SN2′
displacement and 1,3-palladotropy) at the allene axis.22 Both
the nature of the halogen and the reaction conditions, particularly
the free axial hydroxyl substituent and the presence of coordi-
nating solvents as part of the composition of the palladium
catalyst, play a crucial role on the stereochemical outcome. DFT
computations of the competing reactivities of model systems,
including an explicit solvent molecule on Pd, are consistent with
the experimental results. Furthermore, the computations confirm
1
Data for (1S,3R,4aR)-2b: H NMR (400 MHz, CDCl3) δ 5.72
(s, 1H), 5.25 (m, 1H), 2.17 (ddd, J ) 12.9, 4.1, 2.1 Hz, 1H), 1.97
(22) Unfortunately, we could not generalize this finding, due to the instability
of the samples obtained when simple enantiopure iodoallenes 18 and 19 were
coupled with alkenylstannane 7 under the optimized conditions.These enantiopure
allenes were prepared using the SN2′ displacement of a propargylic mesylate
with a cuprate, as described by Vermeer (Elsevier, C. J.; Meijer, J.; Tadema,
G.; Stehouwer, P. M.; Bos, H. J. T.; Vermeer, P.; Runge, W. J. Org. Chem.
1982, 47, 2194-2196) and Marshall (Marshall, J. A.; Grant, C. M. J. Org. Chem.
1999, 64, 8214, respectively.
The copper-catalyzed N-allenylation of amides (Trost, B. M.; Stiles, D. T. Org.
Lett. 2005, 7, 2117) using simple enantiopure iodoallenes takes place with
retention of configuration (Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.;
Zhang, X. Org. Lett. 2005, 7, 3081).
(21) Hallman, K.; Fro¨lander, A.; Wondimagegn, T.; Svensson, M.; Moberg,
C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5400, and references cited therein.
6538 J. Org. Chem. Vol. 73, No. 17, 2008

Stille Coupling of Haloallenes and Alkenylstannanes
(s, 3H), 1.87 (dd, J ) 12.4, 4.0, 2.1 Hz, 1H), 1.44 (t, J ) 11.5 Hz,
2H), 1.4-1.3 (m, 1H), 1.36 (s, 3H), 1.30 (s, 3H), 1.10 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 201.6 (s), 170.4 (s), 119.0 (s), 71.5
(s), 67.5 (d), 44.5 (t, 2×), 38.3 (d), 35.0 (s), 30.8 (q), 30.4 (q),
29.4 (q), 21.2 (q); MS (ESI+) m/z (%) 374 (14), 373 (M+ + 23,
100), 273 (11); HMRS (ESI+) calcd for C13H19INaO3, 373.0271;
found, 373.0264. Anal. Calcd for C13H19IO3: C, 44.59; H, 5.47.
Found: C, 44.62; H, 5.44.
DMF (12 mL). At this point, the reaction mixture was thoroughly
degassed using freeze-thaw cycles (3×) [where required, (iPr)2NEt
(1.5 mmol) was added at this point]. After stirring at 25 °C for the
time period listed in Table 1, an aqueous saturated KF solution
was added, the layers were separated, and the aqueous layer was
extracted with EtOAc (3×). The combined organic layers were
washed with brine (3×) and dried (Na2SO4), and the solvent was
removed. The residue was purified by chromatography on silica
gel to afford the corresponding vinylallene.
1
Data for (1S,3R,4aS)-2b: H NMR (400 MHz, CDCl3) δ 5.84
(s, 1H), 5.28 (m, 1H), 2.19 (ddd, J ) 12.9, 4.2, 2.2 Hz, 1H), 1.98
(s, 3H), 1.89 (ddd, J ) 12.3, 4.1, 2.2 Hz, 1H), 1.4-1.3 (m, 2H),
1.37 (s, 3H), 1.32 (s, 3H), 1.08 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 200.7 (s), 170.2 (s), 118.9 (s), 71.2 (s), 67.5 (d), 44.7 (t),
44.5 (t), 38.7 (d), 34.7 (s), 31.9 (q), 30.6 (q), 28.1 (q), 21.2 (q);
MS (ESI+) m/z (%) 374 (13), 373 (M+ + 23, 100), 273 (6); HMRS
(ESI+) calcd for C13H19INaO3, 373.0271; found, 373.0263.
(-)-(1R,3S,6aR)-6-(2-Bromovinylidene)-3-(tert-butyldimethylsi-
lyloxy)-1,5,5-trimethylcyclohexan-1-ol (aR)-8a. CuBr (0.23 g, 1.58
mmol), NH4Br (0.08 g, 0.79 mmol), and HBr (48% aq, 0.29 mL,
2.53 mmol) were added sequentially to a cooled (-10 °C) solution
of tert-butyldimethylsilyl (1R,3S,6R)-6-ethynyl-1,5,5-trimethyl-7-
oxabicyclo[4.1.0]heptan-3-yl ether6b (0.47 g, 1.58 mmol) in Et2O
(7.7 mL). After stirring for 30 min, an aqueous solution of NH4Cl/
NH3 1:1 (10 mL) was added, and the layers were separated. The
organic layer was washed with brine (3×) and dried (Na2SO4), and
the solvent was evaporated. The residue was purified by column
chromatography (silica gel, gradient from 95:5 to 90:10 hexane/
EtOAc) to afford 0.172 g (29%) of a white solid identified as
(1R,3S,6aR)-6-(2-bromovinylidene)-3-(tert-butyldimethylsilyloxy)-
1,5,5-trimethylcyclohexan-1-ol (aR)-8a. A fraction containing
a mixture of products was further purified by HPLC (Nova-Pak
HR, 6 mm, 30 × 1.9 cm, 97:3 hexane/AcOEt, 3 mL/min) to
afford 8.1 mg of the corresponding (1R,3S,6aS)-6-(2-bromovi-
nylidene)-3-(tert-butyldimethylsilyloxy)-1,5,5-trimethylcyclohexan-
1-ol (aS)-8a.
(+)-(1R,5S,2aR)- and (+)-(1R,5S,2aS)-5-(tert-Butyldimethylsi-
lyloxy)-2-[(3E)-5-hydroxypenta-1,3-dienylidene]-1,3,3-trimethylcy-
clohexanol 9. Following the general procedure for the cross-coupling
reaction, the reaction between bromoallene (aR)-8a (0.03 g, 0.08
mmol), stannane 7 (0.04 g, 0.16 mmol), and Pd(PPh3)4 (0.009 g,
0.008 mmol) afforded, after purification by chromatography on
silica gel (70:30 hexane/EtOAc), 0.017 g (60%) of (1R,5S,2aS)-9
1
and 0.008 g (28%) of (1R,5S,2aR)-9. Data for (1R,5S,2aR)-9: H
NMR (400 MHz, CDCl3) δ 6.01 (ddt, J ) 15.1, 10.2, 1.0 Hz, 1H),
5.88 (d, J ) 10.2 Hz, 1H), 5.79 (dt, J ) 15.2, 5.9 Hz, 1H), 4.25
(tt, J ) 11.0, 4.2 Hz, 1H), 4.17 (dd, J ) 5.9, 1.0 Hz, 2H), 2.10
(ddd, J ) 13.1, 4.1, 2.2 Hz, 1H), 1.78 (ddd, J ) 12.6, 4.1, 2.1 Hz,
1H), 1.59 (br s, 2H), 1.42 (dd, J ) 13.1, 10.9 Hz, 1H), 1.33 (s,
3H), 1.31 (dd, J ) 13.6, 10.4 Hz, 1H), 1.29 (s, 3H), 1.03 (s, 3H),
0.89 (s, 9H), 0.90 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ
203.5 (s), 129.6 (d), 127.6 (d), 116.4 (s), 96.3 (d), 72.8 (s), 64.8
(d), 63.4 (t), 49.7 (t), 49.1 (t), 35.5 (s), 32.1 (q), 31.2 (q), 29.2 (q),
25.9 (q, 3×), 18.2 (s), -4.6 (q, 2×) ppm; MS (ESI+) 375 ([M +
Na]+, 100); HRMS (ESI+) calcd for C20H36NaO3Si, 375.2326;
found, 375.2323; IR (NaCl) ν 3600-3100 (br, OH), 2956 (s, C-H),
2927 (s, C-H), 1939 (w, CdCdC); [R]22D +86.0 (c 0.02, MeOH).
1
Data for (1R,5S,2aS)-9: H NMR (400 MHz, CDCl3) δ 6.07 (ddt,
J ) 14.8, 10.4, 1.0 Hz, 1H), 6.00 (d, J ) 10.4 Hz, 1H), 5.80 (dt,
J ) 14.8, 5.8 Hz, 1H), 4.25 (tt, J ) 11.1, 4.2 Hz, 1H), 4.18 (dd, J
) 5.8, 1.0 Hz, 2H), 2.08 (ddd, J ) 13.1, 4.2, 1.8 Hz, 1H), 1.75
(ddd, J ) 12.6, 4.1, 2.1 Hz, 1H), 1.71-1.54 (br s, 1H), 1.38 (dd,
J ) 13.1, 10.9 Hz, 1H), 1.32 (s, 3H), 1.31 (s, 3H), 1.32-1.30 (m,
1H), 1.03 (s, 3H), 0.89 (s, 9H), 0.08 (s, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ 203.2 (s), 129.9 (d), 127.8 (d), 116.4 (s), 96.6 (d),
72.9 (s), 64.8 (d), 63.3 (t), 49.5 (t), 48.9 (t), 35.3 (s), 32.0 (q), 31.2
(q), 29.9 (q), 25.9 (q, 3×), 18.1 (s), -4.6 (q, 2×) ppm; MS (ESI+)
375 ([M + Na]+, 100); HRMS (ESI+) calcd for C20H36NaO3Si,
375.2326; found, 375.2324; IR (NaCl) ν 3600-3100 (br, OH), 2956
1
Data for (aR)-8a: H NMR (400 MHz, CDCl3) δ 5.92 (s, 1H),
4.21 (m, 1H), 2.06 (ddd, J ) 13.3, 4.2, 2.3 Hz, 1H), 1.74 (ddd, J
) 12.8, 4.1, 2.3 Hz, 1H), 1.42 (dd, J ) 13.3, 10.9 Hz, 1H), 1.37
(s, 3H), 1.4-1.3 (m, 1H), 1.27 (s, 3H), 1.09 (s, 3H), 0.88 (s, 9H),
0.06 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 198.2 (s), 124.4
(s), 73.9 (d), 72.2 (s), 64.3 (d), 49.0 (t), 48.6 (t), 35.7 (s), 31.2 (q),
30.5 (q), 29.2 (q), 25.7 (q), 18.0 (s), -4.7 (q, 2×) ppm; MS (EI+)
m/z (%) 319 (M+ - tBu, 2), 317 (M+ - tBu, 2), 261 (19), 181
(100), 165 (91), 163 (21), 145 (38), 143 (17), 129 (20), 121 (33),
120 (16), 119 (21), 115 (28), 107 (28), 105 (70), 93 (44), 91 (24),
77 (16), 75 (97), 73 (58); HMRS (EI+) calcd for C13H2279BrO2Si
[M+ - tBu], 317.0572; found, 317.0577; IR (NaCl) ν 3600-3100
(br, OH), 2958 (s, C-H), 2929 (s, C-H), 2857 (m, C-H), 1950
(s, C-H), 2927 (s, C-H), 1939 (w, CdCdC); [R]22 +165.4 (c
D
0.02, MeOH).
(+)-(1S,3R,4aR)- and (+)-(1S,3R,4aS)-3-Hydroxy-4-[(E)-5-hy-
droxypenta-1,3-dienylidene]-3,5,5-trimethylcyclohexyl Acetate 10.
Following the general procedure for the cross-coupling reaction,
the reaction between iodoallene (aR)-2b (0.02 g, 0.06 mmol),
stannane 7 (0.03 g, 0.08 mmol), and PdCl2(PhCN)2 (0.002 g, 0.006
mmol) afforded, after purification by chromatography on silica gel
(60:40 hexane/EtOAc), 0.006 g (12%) of (1S,3R,4aR)-10 and 0.008
(28%) of (1S,3R,4aS)-10. Data for (1S,3R,4aR)-10: 1H NMR (400
MHz, CDCl3) δ 6.03 (ddt, J ) 15.1, 10.3, 1.3 Hz, 1H), 5.92 (d, J
) 10.3 Hz, 1H), 5.80 (dt, J ) 15.1, 5.8 Hz, 1H), 5.34 (tt, J ) 11.5,
4.2 Hz, 1H), 4.18 (dd, J ) 5.8, 1.0 Hz, 2H), 2.24 (ddd, J ) 12.8,
4.2, 2.2 Hz, 1H), 2.03 (s, 3H), 1.94 (ddd, J ) 12.5, 4.1, 2.2 Hz,
1H), 1.74 (s, 1H), 1.53 (s, 1H), 1.47 (dd, J ) 12.7, 11.6 Hz, 1H),
1.38 (t, J ) 12.0 Hz, 1H), 1.34 (s, 6H), 1.06 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 203.5 (s), 170.5 (s), 129.9 (d), 127.2
(d), 115.8 (s), 96.6 (d), 72.4 (s), 68.0 (d), 63.3 (t), 45.2 (t), 45.0
(t), 35.5 (s), 32.0 (q), 31.0 (q), 29.1 (q), 21.4 (q) ppm; MS (ESI+)
303 ([M + Na]+, 100); HRMS (ESI+) calcd for C16H24NaO4,
303.1567; found, 303.1564; IR (NaCl) ν 3600-3100 (br, OH), 2963
(w, CdCdC), 1470 (m), 1380 (m), 1256 (m, C-O), 1082 (s) cm-1
.
Anal. Calcd for C17H31BrO2Si: C, 54.39; H, 8.32. Found: C, 54.34;
H, 8.37. [R]22 -30.9 (c 0.04, CHCl3).
D
1
Data for (aS)-8a: H NMR (400 MHz, CDCl3) δ 6.10 (s, 1H),
4.23 (m, 1H), 2.07 (ddd, J ) 13.1, 3.9, 2.2 Hz, 1H), 1.74 (ddd, J
) 12.7, 4.1, 2.2 Hz, 1H), 1.36 (s, 2H), 1.3-1.2 (m, 3H), 1.31 (s,
3H), 1.07 (s, 3H), 0.86 (s, 9H), 0.06 (s, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ 197.4 (s), 124.5 (s), 75.0 (d), 72.1 (s), 64.5 (d),
49.2 (t), 48.6 (t), 35.5 (s), 31.8 (q), 30.9 (q), 29.1 (q), 25.9 (q),
18.2 (s), -4.6 (q, 2×) ppm; MS (EI+) m/z (%) 376 (M+, 2), 374
(M+, 2), 295 (12), 263 (29), 261 (32), 260 (19), 181 (11), 145 (12),
105 (12), 75 (100), 73 (50); HMRS (EI+) calcd for C17H3179BrO2Si
[M+], 374.1277; found, 374.1279; IR (NaCl) ν 3600-3100 (br,
OH), 2958 (s, C-H), 2929 (s, C-H), 2856 (m, C-H), 1945 (w,
CdCdC), 1472 (m), 1384 (m), 1256 (m, C-O), 1081 (s) cm-1
;
[R]22 -45.4 (c 0.02, CHCl3).
(s, C-H), 2926 (s, C-H), 1939 (w, CdCdC); [R]22 +285.2 (c
D
D
General Procedure for the Cross-Coupling Reaction. The
palladium source [for PdCl2(PhCN)2, 0.1 or 0.2 mmol; for
Pd2(dba)3 ·CHCl3 and Pd(PPh3)4, 0.1 mmol; for Pd2(dba)3 and
AsPh3, 0.1 and 0.7 mmol, respectively] was added to a solution of
corresponding haloallene (1 mmol) and stannane (1.5 mmol) in
0.02, MeOH). Data for (1S,3R,4aS)-10: 1H NMR (400 MHz, CDCl3)
δ 6.09 (dd, J ) 15.0, 10.4 Hz, 1H), 6.01 (d, J ) 10.4 Hz, 1H),
5.80 (dt, J ) 15.0, 5.6 Hz, 1H), 5.33 (tt, J ) 11.5, 4.1 Hz, 1H),
4.18 (s, 2H), 2.21 (ddd, J ) 12.8, 4.1, 2.1 Hz, 1H), 2.02 (s, 3H),
1.91 (ddd, J ) 12.3, 4.0, 2.1 Hz, 1H), 1.44 (t, J ) 12.0 Hz, 1H),
J. Org. Chem. Vol. 73, No. 17, 2008 6539

Vaz et al.
1.37 (s, 3H), 1.33 (s, 3H), 1.33 (t, J ) 11.5 Hz, 1H), 1.05 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 203.2 (s), 170.6 (s), 130.2
(d), 127.2 (d), 115.6 (s), 96.9 (d), 72.4 (s), 68.1 (d), 63.1 (t), 45.0
(t), 44.9 (t), 35.2 (s), 31.9 (q), 31.0 (q), 29.7 (q), 21.4 (q) ppm; MS
(ESI+) 303 ([M + Na]+, 100); HRMS (ESI+) calcd for C16H24NaO4,
303.1567; found, 303.1567; IR (NaCl) ν 3600-3100 (br, OH), 2965
(d), 127.0 (d), 116.6 (s), 98.2 (d), 76.6 (s), 69.3 (d), 63.8 (t), 49.3
(t), 47.2 (t), 37.0 (s), 33.6 (q), 31.6 (q), 30.4 (q), 30.3 (q), 22.2 (s),
3.3 (q, 3×) ppm; MS (ESI+) 375 ([M + Na]+, 100); HRMS (ESI+)
calcd for C19H32NaO4Si, 375.1962; found, 375.1958; IR (NaCl) ν
3600-3100 (br, OH), 2961 (s, C-H), 2866 (s, C-H), 1941 (w,
CdCdC); [R]22 +42.4 (c 0.04, MeOH). Data for (1S,3R,4aS)-
D
1
(s, C-H), 2926 (s, C-H), 1940 (w, CdCdC); [R]22 +256.8 (c
12: H NMR (400 MHz, acetone-d6) δ 6.2-6.1 (m, 1H), 6.08 (d,
D
0.03, MeOH).
J ) 10.5 Hz, 1H), 5.83 (dt, J ) 14.6, 5.4 Hz, 1H), 5.30 (tt, J )
11.6, 4.2 Hz, 1H), 4.11 (td, J ) 5.5, 1.4 Hz, 2H), 3.74 (t, J ) 5.6
Hz, 1H), 2.17 (ddd, J ) 12.4, 4.1, 2.3 Hz, 1H), 1.97 (s, 3H), 1.90
(ddd, J ) 12.2, 4.2, 2.3 Hz, 1H), 1.42 (s, 3H), 1.4-1.3 (m, 1H),
1.37 (s, 3H), 1.29 (t, J ) 11.9 Hz, 1H), 1.06 (s, 3H), 0.15 (s, 9H)
ppm; 13C NMR (100 MHz, acetone-d6) δ 204.1 (s), 171.3 (s), 134.2
(d), 126.7 (d), 116.9 (s), 98.7 (d), 76.7 (s), 69.4 (d), 63.9 (t), 49.3
(t), 47.2 (t), 36.9 (s), 33.6 (q), 31.5 (q), 31.3 (q), 31.1 (q), 22.2 (s),
3.5 (q, 3×) ppm; MS (ESI+) 375 ([M + Na]+, 100); HRMS (ESI+)
calcd for C19H32NaO4Si, 375.1962; found, 375.1958; IR (NaCl) ν
3600-3100 (br, OH), 2961 (s, C-H), 2866 (s, C-H), 1940 (w,
General Procedure for the Protection of Alcohols with TM-
SOTF. To a stirred solution of alcohol 2 (0.17 mmol) in CH2Cl2
(0.8 mL) at 0 °C were added 2,6-lutidine (2.05 mmol) and TMSOTf
(1.37 mmol). The mixture was allowed to warm up to 25 °C (2 h),
and the reaction was quenched with water and extracted with AcOEt
(3×). The combined organic layers were washed with brine (3×)
and dried (Na2SO4), and the solvent was removed. The residue was
purified by chromatography on silica gel (97:1:2 hexane/AcOEt/
Et3N) to afford the corresponding protected alcohol.
(-)-(1S,3R,4aR)-4-(2-Iodovinylidene)-3,5,5-trimethyl-3-(trimeth-
ylsilyloxy)cyclohexyl Acetate 11b. Following the general procedure
for the protection of alcohols as TMS ethers, the reaction between
alcohol (aR)-2b (0.06 g, 0.17 mmol) and TMSOTf in the presence
of 2,6-lutidine afforded, after purification by chromatography on
silica gel (97:1:2 hexane/AcOEt/Et3N), 0.054 g of a yellow oil
(75%) identified as (1S,3R,4aR)-11b: 1H NMR (400 MHz, acetone-
d6) δ 6.01 (s, 1H), 5.27 (tt, J ) 11.6, 4.1 Hz, 1H), 2.21 (ddd, J )
12.6, 4.0, 2.4 Hz, 1H), 1.97 (s, 3H), 1.91 (ddd, J ) 12.3, 4.2, 2.0
Hz, 1H), 1.47 (s, 3H), 1.39 (dd, J ) 12.0, 11.6 Hz, 1H), 1.33 (t, J
) 12.1 Hz, 1H), 1.33 (s, 3H), 1.14 (s, 3H), 0.13 (s, 9H) ppm; 13C
NMR (100 MHz, acetone-d6) δ 203.6 (s), 171.3 (s), 120.1 (s), 75.8
(s), 68.8 (d), 48.6 (t), 46.6 (t), 39.9 (d), 36.7 (s), 32.6 (q), 31.1 (q),
30.8 (q), 22.2 (q), 3.3 (q, 3×) ppm; MS (FAB+) 423 ([M + 1]+,
25), 422 ([M]+, 4); HRMS (FAB+) calcd for C16H27IO3Si, 422.0774;
found, 422.0764; IR (NaCl) ν 2961 (s, C-H), 1950 (w, CdCdC),
CdCdC); [R]22 -43.0 (c 0.11, MeOH).
D
(+)-(5E,1R,4S,6R)-(4-(tert-Butyldimethylsilyloxy)-2,2,6-trimethyl-
7-oxabicyclo[4.1.0]heptan-1-yl)pent-2-en-4-yn-1-ol 15. Pd(PPh3)4
(0.002 g, 0.002 mmol) and CuI (0.0003 g, 0.002 mmol) were added
to a solution of alkyne 136b (0.049 g, 0.17 mmol) and iodide 146b
(0.037 g, 0.20 mmol) in iPr2NH (0.9 mL). After stirring for 1.5 h,
a saturated aqueous solution of NH4Cl was added and the mixture
was extracted with Et2O (3×). The combined organic layers were
washed with brine (3×) and dried (Na2SO4), and the solvent was
evaporated. The residue was purified by column chromatography
(silica gel, 80:20 hexane/EtOAc) to afford 0.049 g (84%) of a
1
yellow oil identified as 15: H NMR (400 MHz, CDCl3) δ 6.24
(dt, J ) 15.9, 5.1, 1H), 5.75 (d, J ) 15.9, 1H), 4.17 (s, 2H), 3.8-3.7
(m, 1H), 2.20 (dd, J ) 14.5, 4.9, 1H), 1.9-1.8 (m, 1H), 1.63 (dd,
J ) 14.5, 8.0, 1H), 1.5-1.4 (m, 1H), 1.44 (s, 3H), 1.20 (s, 3H),
1741 (s, CdO); [R]22 -49.1 (c 0.14, MeOH).
1.2-1.1 (m, 1H), 1.07 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H) ppm; 13
C
D
NMR (100 MHz, CDCl3) δ 142.5 (d), 109.7 (d), 87.1 (s), 83.7 (s),
67.1 (s), 64.3 (d), 63.9 (s), 62.7 (t), 45.7 (t), 40.3 (t), 34.4 (s), 29.7
(q), 25.84 (q), 25.7 (q), 21.8 (q), 18.1 (s), -4.7 (q), -4.8 (q) ppm;
MS (ESI+) m/z (%) 389 (M+ + 39, 13), 373 (M+ + 23, 33), 351
(M+ + 1, 100), 333 (7), 173 (7); HMRS (ESI+) calcd for
C20H35O3Si, 351.2350; found, 351.2346; IR (NaCl) ν 3600-3100
(br, OH), 2954 (s, C-H), 2930 (s, C-H), 2858 (s, C-H), 2150
(+)-(1S,3R,4aR)-4-(2-Bromovinylidene)-3,5,5-trimethyl-3-(tri-
methylsilyloxy)cyclohexyl Acetate 11a. Following the general
procedure for the protection with TMSOTF, the reaction between
alcohol (aR)-2a (0.055 g, 0.16 mmol) and TMSOTf in the presence
of 2,6-lutidine afforded, after purification by chromatography on
silica gel (97:1:2 hexane/AcOEt/Et3N), 0.057 g of a yellow oil
(89%) identified as (1S,3R,4aR)-11a: 1H NMR (400 MHz, acetone-
d6) δ 6.23 (s, 1H), 5.29 (tt, J ) 11.5, 4.0 Hz, 1H), 2.24 (ddd, J )
12.7, 3.9, 2.4 Hz, 1H), 1.98 (s, 3H), 1.94 (ddd, J ) 12.5, 4.2, 2.5
Hz, 1H), 1.48 (s, 3H), 1.43 (t, J ) 12.0 Hz, 1H), 1.36 (t, J ) 12.0
Hz, 1H), 1.35 (s, 3H), 1.14 (s, 3H), 0.14 (s, 9H) ppm; 13C NMR
(100 MHz, acetone-d6) δ 200.1 (s), 171.2 (s), 125.1 (s), 76.0 (s),
75.8 (d), 68.7 (d), 48.7 (t), 46.7 (t), 37.4 (s), 32.8 (q), 31.0 (q),
30.4 (q), 22.2 (q), 3.3 (q, 3×) ppm; MS (FAB) m/z (%) 376 ([M]+
[81Br], 5), 374 ([M]+ [79Br], 5), 317 ([M - CO2CH3]+ [81Br], 30),
316 (21), 315 ([M - CO2CH3]+ 33), 314 (16), 236 (19), 235 (82),
227 (52), 226 (16), 225 (52), 157 (18), 156 (100); HRMS calcd
for C16H2781BrO3Si, 376.0892 and C16H2779BrO3Si, 374.0913; found,
376.0906 and 374.0922; IR (NaCl) ν 3057 (s, C-H), 1949 (w,
(w, CtC); [R]19 + 39.4 (c 0.17, MeOH).
D
(1R,5S,2aR)-5-(tert-Butyldimethylsilyloxy)-2-[(3E)-5-hydroxypenta-
1,3-dienylidene]-1,3,3-trimethylcyclohexanol 9. DIBAL-H (1.41 mL,
1 M in THF, 1.41 mmol) was added to a solution of 15 (0.049 g,
0.141 mmol) in CH2Cl2 (1.4 mL) at 0 °C, and the mixture was
stirred for 2.5 h at 0 °C and for 1 h at 25 °C. After careful addition
of H2O (5 mL) at 0 °C and a 10% aqueous solution of HCl, the
mixture was extracted with EtOAc (3×). The combined organic
layers were washed with brine (3×), dried (Na2SO4), and concen-
trated. The residue was purified by column chromatography (silica
gel, 70:30 hexane/EtOAc) to afford 0.025 g (50%) of a yellow oil
identified as (1R,5S,2aR)-9.
Computational Details. All computations in this study have been
performed using the Gaussian03 suite of programs.17 To include
electron correlation at a reasonable computational cost, density
functional theory (DFT)23 was used. The Becke three-parameter
exchange functional and the nonlocal correlation functional of Lee,
Yang, and Parr (B3LYP) was selected.24 Given the complexity of
the structures and transition states, the 6-31G* basis set for C, H,
and P, in conjunction with the Stuttgart/Dresden -relativistic-
effective core potentials for Pd and Br, was chosen to compute the
geometries, energies, and normal mode vibration frequencies of
the starting material, the corresponding transition structures, and
the products. No symmetry constraints were imposed during
CdCdC), 1742 (s, CdO); [R]22 +94.5 (c 0.03, MeOH).
D
(+)-(1S,3R,4aR)- and (-)-(1S,3R,4aS)-4-[(E)-5-Hydroxypenta-
1,3-dienylidene]-3,5,5-trimethyl-3-(trimethylsilyloxy)cyclohexyl Ac-
etate 12. Following the general procedure for Stille cross-coupling,
the reaction between iodoallene (aR)-11a (0.015 g, 0.04 mmol),
stannane 7 (0.020 g, 0.06 mmol), and Pd2dba3 ·CHCl3 (0.004 g,
0.004 mmol) afforded, after purification by chromatography on
silica gel (80:20 hexane/EtOAc), 0.011 g (77%) of (1S,3R,4aR)-12
1
and 0.003 (21%) of (1S,3R,4aS)-12. Data for (1S,3R,4aR)-12: H
NMR (400 MHz, acetone-d6) δ 6.05 (ddt, J ) 15.1, 10.3, 1.6 Hz,
1H), 5.94 (d, J ) 10.3 Hz, 1H), 5.82 (dt, J ) 15.1, 5.3 Hz 1H),
5.30 (tt, J ) 11.6, 4.1 Hz, 1H), 4.10 (td, J ) 5.5, 1.5 Hz, 2H), 3.74
(t, J ) 5.6 Hz, 1H), 2.19 (ddd, J ) 12.4, 4.1, 2.3 Hz, 1H), 1.96 (s,
3H), 1.91 (ddd, J ) 12.3, 4.1, 2.3 Hz, 1H), 1.5-1.4 (m, 1H), 1.41
(s, 3H), 1.4-1.3 (m, 1H), 1.32 (s, 3H), 1.05 (s, 3H), 0.12 (m, 9H)
ppm; 13C NMR (100 MHz, acetone-d6) δ 204.7 (s), 171.3 (s), 133.6
(23) (a) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and
Molecules; Oxford: New York, 1989. (b) Ziegler, T. Chem. ReV. 1991, 91, 651.
(24) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
6540 J. Org. Chem. Vol. 73, No. 17, 2008

Stille Coupling of Haloallenes and Alkenylstannanes
structural optimizations. The stationary points were characterized
by means of harmonic analysis, and for all the transition structures,
the vibration related to the imaginary frequency was confirmed to
correspond to the nuclear motion along the reaction coordinate under
study. All energy results presented correspond to Gibbs energies
at 298.15 K. The effect of the solvent at 298.15 K was taken into
account through single-point calculations at each optimized geom-
etry using the COSMO model18 as implemented in Gaussian03.
cia (Parga Pondal Contract to M.P.; PGIDIT07PXIBIB3174174
PR to R.A.), and the Spanish Ministerio de Educacio´n y Ciencia
(SAF07-63880-FEDER).
Supporting Information Available: General experimental
methods, physical and spectroscopic data for all compounds,
and final SCF energies, geometries, and number of imaginary
frequencies. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. The authors are grateful to the European
Union (EPITRON, LSHC-CT-2005-518417), the Xunta de Gali-
JO800756B
J. Org. Chem. Vol. 73, No. 17, 2008 6541