Directing effects of tethered alkenes in nickel-catalyzed coupling reactions of 1,6-enynes and aldehydes

Article abstract of DOI:10.1016/j.tet.2006.03.122

Nickel-catalyzed reductive coupling reactions of aldehydes and 1,6-enynes proceed in excellent regioselectivity in the absence of a phosphine, and the use of a monodentate phosphine additive leads to the formation of the opposite regioisomer with equally high selectivity. Both products are the result of the same fundamental mechanism, with the inversion of regioselectivity being the result of stereospecific ligand substitution at the metal center.

Full text of DOI:10.1016/j.tet.2006.03.122

Tetrahedron 62 (2006) 7598–7610
Directing effects of tethered alkenes in nickel-catalyzed
coupling reactions of 1,6-enynes and aldehydes
Ryan M. Moslin,a Karen M. Millerb and Timothy F. Jamisona,
*
aMassachusetts Institute of Technology, Department of Chemistry, Cambridge, MA 02139, USA
bNovartis Institute for Biomedical Research, Inc., 250 Massachusetts Ave., Cambridge, MA 02139, USA
Received 7 December 2005; revised 1 March 2006; accepted 1 March 2006
Available online 15 June 2006
Dedicated to Professor G€unther Wilke in honor of his groundbreaking contributions to organonickel chemistry
Abstract—Nickel-catalyzed reductive coupling reactions of aldehydes and 1,6-enynes proceed in excellent regioselectivity in the absence of
a phosphine, and the use of a monodentate phosphine additive leads to the formation of the opposite regioisomer with equally high selectivity.
Both products are the result of the same fundamental mechanism, with the inversion of regioselectivity being the result of stereospecific ligand
substitution at the metal center.
Ó 2006 Elsevier Ltd. All rights reserved.
Ni(cod)2
PR3
OH
R1
1. Introduction
+
R
R1CHO
R1CHO
Ar
Ar
(1)
(2)
Et3B
Substrate-directable reactions are an important class of
selective organic transformations, and understanding their
mechanism of direction is paramount to their utility.1 Re-
cently, we reported a substrate-directed, nickel-catalyzed
reductive coupling of 1,6-enynes and aldehydes in which the
regioselectivity of the reaction was controlled by a tethered
olefin.2 Herein we report a full account of this class of
coupling reactions, as well as a description of the likely
mechanism by which regioselectivity is controlled.
R
>95 : 5 regioselectivity
R3
OH
R3
R5
Ni(cod)2
PR3
R2
R1
+
R2
Et3B
R4 R5
>90 : 10 regioselectivity
R4
Scheme 1.
The high degree of regioselectivity observed with certain
classes of 1,3-enynes led us to hypothesize that an interaction
between the alkene and the metal center has an influence on
selectivity (Fig. 1).4f Assuming that the reaction proceeds
through an oxametallacyclopentene intermediate, interaction
of the conjugated alkene with the metal center could result in
a stabilizing interaction, thus favoring formation of the re-
gioisomer shown.5 These results led us to conduct a thorough
investigation of the directing effects of tethered alkenes in
reductive coupling reactions of alkynes and aldehydes.6
The nickel-catalyzed coupling of alkynes and aldehydes has
emerged as a powerful method for the efficient and selective
preparation of allylic alcohols.3,4 In most cases, the regio-
selectivity of these coupling reactions is determined by a
steric or electronic difference in the alkyne substituents. For
example, previous investigations in our laboratory have
shown that alkynes conjugated to either an aryl or alkenyl
substituent undergo nickel-catalyzed reductive coupling
with aldehydes in high regioselectivity (Scheme 1, Eqs. 1
and 2).4b,d,f
Cyp3P
R3
R3
OH
R4
R3
R
aldehyde
O
Ni
Et3B
R4
R2
R2
R2
Ni(cod)2/PCyp3
R1
R
R1
R = aryl,
alkyl (1°, 2°, 3°)
(cat.)
R1
R
oxametallacyclopentene
>90 : 10 regioselectivity
Figure 1.
* Corresponding author. Tel.: +1 617 253 2135; fax: +1 617 324 0253; e-mail: tfj@mit.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.122

R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
7599
2. Results and discussion
observed when 1,2-dihydro-4 was coupled to isobutyralde-
hyde in the presence of tricyclopentylphosphine (PCyp3)
(77%, 50:50 regioselectivity) it is likely that the tethered ole-
fin is responsible for the regioselectivity both in the presence
and absence of a phosphine additive.
2.1. Discovery of ligand-switchable nickel-catalyzed
couplings of aldehydes and 1,6-enynes
A study of nickel-catalyzed reductive coupling reactions of
isobutraldehyde with enynes of different tether lengths re-
vealed a marked difference in reactivity and selectivity
when the alkyne and alkene were separated by three methyl-
ene units (Table 1, entry 4). As it is very unlikely that 4
is significantly different sterically or electronically than
alkynes 2, 3, or 5, it seems that involvement of the olefin
in the reaction occurs uniquely in the case of the 1,6-enyne.
Also interesting is that conjugated enynes do not couple ef-
fectively in the absence of a phosphine additive (entry 1),
suggesting that the origin of the high regioselectivity
observed with 1,3-enynes is different than that observed
with 1,6-enynes.
Although directing effects of tethered alkenes have been
demonstrated in other metal-mediated reactions,11 the only
other examples in which the sense of the effect was reversed
by an additive are Pd-catalyzed enyne isomerizations re-
ported by Trost.12 However, in this case high regioselectivity
was observed in only one direction (ꢁ15:1 vs 1:2.5), while
we observe equal and opposite regioselectivity in the pres-
ence or absence of an additive.
2.2. Origin of regioselectivity in the nickel-catalyzed
reductive coupling of aldehydes and 1,6-enynes
Reductive coupling reactions of 1,6-enynes and aldehydes in
the absence of phosphine additive proved remarkably gen-
eral, considering that previous systems had all required the
addition of a phosphine (Table 2).2,4,7 Also noteworthy is
that the presence of an olefin tether is sufficient to overcome
an inherent steric preference for the B regioisomer (entry
4).4c Heteroatoms, which could conceivably compete with
the olefin for binding, are well tolerated and augment the
versatility of the directed transformation (entries 6–8).
Our investigation of additive effects (Table 3) led us to pro-
pose that three different pathways could be operating in
these reactions depending upon which phosphine is used:
one that exclusively forms A (Scheme 2, type I), one that ex-
clusively forms B (type II), and one that gives a mixture of
regioisomers A and B (type III). We propose a mechanistic
rationale for each of the observed regiochemical outcomes,
each of which is based on the assumption that the active
catalyst involves a trisubstituted, planar, d8 metal center
undergoing stereospecific ligand substitution.13
The effect of different phosphine additives on the regio-
selectivity of reductive coupling reactions of enyne 4 and
isobutyraldehyde was also investigated and provided valu-
able insight into the mechanism of these transformations
(Table 3).8 Electron-rich phosphines afforded superior
yields and, remarkably, with very large phosphines (cone
angle >160ꢀ), the sense of regioselectivity was completely
reversed, giving >95:5 of regioisomer B (Table 3, entries
1–3).9 The use of smaller phosphines, even those marginally
so ferrocenyldiphenylphosphine (PFcPh2) (cone angle
w155ꢀ),10 resulted in a significant loss of regioselectivity
(entries 4–6, Table 3). Since no regioselectivity was
type I
B
B
RCHO
A
A
Ni
20
Ni
O
L
Me
Me
H
21
R
B
C-C bond
formation
A
Ni
Me
regioisomer A
O
H
R
type II
R
B
B
RCHO
PCyp
PCyp
3
H
20
O
Table 1. Directing effects of tethered alkenesa
A
A
Ni
Ni
PCyp
Me
Me
3
3
Me
HO
22
23
Ni(cod)2
iPrCHO
+
OH
Me
(10 mol%)
R
n-hex
Me
C-C bond
formation
B
+
n
n
Et3B
(3)
regioisomer B
A
n
n-hex Me
n-hex
O
H
EtOAc
Me
Ni
1-5
A
B
PCyp
3
Alkyne
n
Yield
Regioselectivityb
type III
1
2
3
4
5
6
1
2
3
4
5
0
1
2
3
4
n.a.
<5
<5
<5
53c
<5
28c
n.d.
n.d.
n.d.
>95:5
n.d.
50:50
B
RCHO
RCHO
PBu
PBu
3
A
Ni
Me
3
R
24
B
B
n-Pentyl–C^C–n-hexyl
H
PBu
O
3
O
A
A
Ni
Ni
a
Standard procedure: The alkyne (0.50 mmol) was added to a 0 ꢀC solution
of Ni(cod)2 (0.05 mmol), i-PrCHO (1.00 mmol), and Et3B (1.00 mmol)
in EtOAc (0.5 mL), and the solution was allowed to stir 15 h at room
temperature.
PBu
Me
Me
3
H
25
26
R
regioisomer A
regioisomer B
+
Determined by 1H NMR and/or GC.
b
c
Some alkylative coupling (transfer of Et from Et3B) also observed.
Scheme 2.

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R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
Table 2. Highly regioselective, catalytic reductive coupling reactions directed by a remote alkenea
Entry
1
Enyne
Aldehyde
Product
Yield, regioselectivity (A:B)
69% (>95:5)
OH
nhex
O
R
Me
3
nhex
H
O
Me
4
6A
OH
OTBS
Bn
R
2
3
4
58% (>95:5)
60% (>95:5)
OTBS
Bn
H
nhex
7A
OH
O
R
4
nhex
8A
H
OH
Me
Me
Me
O
R
4
64% (>95:5)
iPr
10A
H
Me
3
9
OH
OTBS
O
O
R
Me
5
6
7
62% (>95:5)
60% (>95:5)
3
H
H
Me
Me
OTBS
11
12A
npentyl
OH
Me
O
O
npentyl
13
14A
npentyl
npentyl
OH
iPr
Bn
N
Bn
N
O
O
62% (>95:5)
68% (>95:5)
H
H
iPr
npentyl
16A
15
OH
Ts
N
Ts
N
8
Me
Me
npentyl
17
18A
See Eq. 3, Table 1. R¼(CH2)3CH]CH2. Regioselectivity determined by 1H NMR and/or GC.
a
In all cases, C–C bond formation is believed to occur
through an oxanickellacyclopentene.2,4 Also, in all cases
the third ligand (L) is assumed to be an olefin14 and, as it
is not part of a bidentate chelate, is considered to be the
most weakly bound ligand. Therefore, in substitution reac-
tions of 20, L is the ligand that is preferentially displaced
from the metal center.
Table 4. Coupling reactions of chiral 1,6-enynes
OH
OH
Me
+
R'
Me
conditions
Table 3. Effect of phosphine ligand on regioselectivity in reductive cou-
plings of 4 and isobutyraldehyde
O
Me
a b
,
R'
+
iPrCHO
Me
R
Me
Me
29A, 30A
Me
Entry
PR3
PR3 cone angle
19A
19B
Yieldc
27 R = Et
29B, 30B
28 R = tBu
1
2
3
4
5
6
7
PCyp3
PCy3
PiPr3
PFcPh2
PCyPh2
PBu3
NDd
170
161
155e
152
132
—
5
5
5
>95
>95
>95
60
58
58
50
30
25
20
30
75
50
Entry Enyne
Reaction
Products A:Bb
dr Ac
dr Bc
conditionsa
40
42
42
>95
1
2
3
27 (R¼Et)
I
II
III
29A, B >95:5
<5:95
55:45
95:5 —
— 45:55
50:50 45:55
None
5
a
Conditions (see Eq. 3): 0.5 mmol scale, 10 mol % Ni(cod)2, 20 mol %
ligand, 100 mol % alkyne, 200 mol % i-PrCHO, 200 mol % Et3B, EtOAc,
0 ꢀC to rt, 15 h. Regioselectivity determined by GC analysis.
Ref. 8.
4
5
6
28 (R¼tBu)
I
II
III
30A, B >95:5 >95:5
—
—
42:58
45:55 42:58
<5:95
51:49
b
c
a
10–15% reductive cyclization product observed in all cases (cf. 2.4);
yields are approximated based on 1H NMR integration of the mixture.
A value for the cone angle of PCyp3 has not been reported.
Ref. 9.
I: Ni(cod)2 (10 mol %), Et3B (200 mol %). II: Reaction conditions
I+PCyp3 (20 mol %). III: Reaction conditions I+PBu3 (20 mol %).
Based on isolated yields.
d
e
b
c
Determined by 1H NMR.

R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
7601
Table 5. Couplingreactionsof chiral, enantiomerically enriched 1,6-enynesa
with ferrocenyl-containing phosphines
In the absence of a phosphine ligand (Scheme 2, type I),
ligand substitution places the aldehyde cis to the alkyne car-
bon that is distal to the alkene (C(A)) and cis to the bound
olefin, giving 21. C–C bond formation occurs at C(A) while
the olefin tether is coordinated to the nickel, resulting in
exclusive formation of regioisomer A. In the presence of
a large, electron-rich phosphine (e.g., PCyp3), L is again dis-
placed, but in this case by the phosphine, giving complex 22
(Scheme 2, type II). As the phosphine is coordinated more
strongly to the metal center than the tethered alkene, the
latter is preferentially displaced by the aldehyde in a stereo-
specific fashion, ultimately leading to regioisomer B by way
of 23. Thus, despite not being bound during the C–C bond
formation, the olefin nevertheless determines regioselectiv-
ity. When the smaller tri-n-butylphosphine (PBu3) is em-
ployed (type III), two equivalents of phosphine are bound
to the metal center, displacing both the olefin tether and L
to give 24. In this case, regioselectivity is not determined
by the olefin, and a non-selective displacement of either
phosphine by the aldehyde leads to a mixture of 25 and
26, which in turn affords a mixture of regioisomers A and B.
iPrCHO
Ni(cod) (10 mol%),
2
ligand (20 mol%)
+
29A
+
29B
Me
Et B
3
O
Et
iPr
27
P
Fc
Ph
(R)-31
Ligand
A:Bb
dr 29A (R:S)c
dr 29Bd
(R)-31
(S)-31
FcPPh2
48:52
55:45
54:46
30:70
66:34
56:44
28:72
68:32
48:52
a
Enantiomerically enriched (>90% ee) 27 was used (Scheme 3).
Based on isolated yields.
Configuration of allylic alcohol stereogenic center.
Relative stereochemistry not determined.
b
c
d
To this end, we subjected enyne 27 and isobutyraldehyde to
reductive coupling conditions in the presence of an achiral
or chiral ferrocenyl-containing phosphine (Table 5).4c,15
Nearly equimolar amounts of regioisomers A and B were
obtained in all cases, suggesting that the reaction occurs via
a type III mechanistic pathway (cf. Scheme 2). Both the R
and S phosphine ligands afforded modest diastereoinduc-
tion. These results demonstrate that the enyne stereocenter
exerts little to no influence on the diastereoselectivity and
clearly indicate that phosphine is bound to nickel during
the C–C bond-forming step.
In order to test these mechanistic hypotheses and the overrid-
ing assumption of a planar, three-coordinate nickel complex,
we evaluated the effect of a stereogenic center in the olefin
tether. We hypothesized that in the absence of a phosphine
(type I), coordination of the olefin to the metal center should
enhance diastereoselection, while conditions employing
achiral phosphines (types II and III) should lead to lower dia-
stereoselectivity since the olefin would be dissociated during
the C–C bond-forming step.
2.3. Origin of diastereoselectivity in the coupling of
chiral 1,6-enynes
Thus, chiral 1,6-enynes 27 and 28 were synthesized and cou-
pled with isobutyraldehyde under three distinct sets of cata-
lytic conditions (Table 4): (I) Ni(cod)2 with no additive; (II)
Ni(cod)2+PCyp3; and (III) Ni(cod)2+PBu3.
The high levels of diastereoselectivity afforded by enynes 27
and 28 in the absence of phosphine (Table 4, entries 1 and 4),
prompted us to investigate coupling reactions of these chiral
enynes further. In order to determine the sense of induction
in the formation of regioisomer A, enantiomerically en-
riched enyne 27 was prepared (Scheme 3). 1-Penten-3-ol
was resolved using a Sharpless asymmetric epoxidation,16,17
and Williamson ether synthesis using the (S) enantiomer
afforded enyne 27.
As predicted, under type I reaction conditions (no phos-
phine) both enynes gave exclusively regioisomer A (Table
4, entries 1 and 4). In addition, both allylic alcohols were
formed in excellent diastereoselectivity, indicating a strong
influence of the stereogenic center in the tether, despite
being separated from the site of C–C bond formation by five
atoms (1,6-induction).
NaH,
Ti(OiPr) ,
Me
OH
OH
Conversely, under type II reaction conditions, regioisomer B
is formed exclusively, but diastereoselection is negligible
(entries 2 and 5). Type III reaction conditions are neither
regioselective nor diastereoselective (entries 3 and 6).
4
1-bromo-
2-butyne
D-(-)-DIPT,
O
TBHP
DCM
THF
Et
27
[ ] = +21.3
α
D
[α] = –75.7
D
>90% ee
Taken together, these experiments strongly support the
notion that, in the absence of phosphine (type I), the alkene
is coordinated to Ni during the C–C bond-forming step and
that, in the presence of phosphine (type II or III), the alkene
is not coordinated to Ni during the C–C bond-forming step.
In other words, the critical aspect of the type II and type III
mechanisms is that the phosphine is bound to the Ni during
the C–C bond-forming step. We reasoned that since the
influence of the chiral center in the tether in these cases
is minimal, any diastereoselectivity induced by a chiral
phosphine could be attributed to the phosphine alone, a result
that would be consistent with phosphine being bound to Ni
as the C–C bond is formed.
O
Me
Me
(S)-26
+
1. Ac O, NEt ,
Ni(cod)
2
3
2
Me
DMAP
(10 mol%)
OAc
(+)-32
[α] = +6.7
29A
Et B
3
2. O , PPh
3 3
iPrCHO
D
Scheme 3.
Nickel-catalyzed reductive coupling of (S)-27 and i-PrCHO
in the absence of a phosphine (type I reaction conditions)
afforded 29A in >95:5 regioselectivity and 95:5 diastereo-
selectivity. Conversion to the corresponding acetate followed

7602
R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
by ozonolysis afforded ketone (+)-32. The sign of the spe-
cific rotation of this compound was opposite that of (ꢂ)-32
prepared from commercially available (S)-2-hydroxy-3-
methylbutyric acid,18 thus establishing the allylic alcohol
configuration in 29A as R.
sense of induction, determined to be R using the same
sequence of operations shown in Scheme 3, was also the
same as that observed with enynes 27 and 28. Thus, an
oxygen atom and a CH2 group at this position in the tether
have similar (albeit measurably different) effects in type I
coupling reactions.
One possible explanation for the high diastereoselectivity
was that the oxygen in the ethereal tether was binding to the
aldehyde via the boron (Fig. 2), thus directing the aldehyde
to the top face due to the conformation of the ring chelate.
The exact mode of diastereoinduction is unknown. However,
since the size of the alkyl substituent of the chiral center has
very little effect on the diastereoinduction (Table 4, entries 1
and 4), and since the oxygen of the ethereal tether does not
appear to be involved, therefore, it is likely that the alkyl sub-
stituent controls the conformation of the ring chelate and it is
the conformation of the ring chelate rather than the chiral
center itself that interacts with the aldehyde and determines
the stereochemical outcome of the reaction.
X
n
B
O
O
H
R
R
Ni
L
Me
2.4. Carbocyclization
Figure 2.
In the presence of a phosphine additive, 38 is observed as
a minor product of nickel-catalyzed couplings of 1,6-enynes
and aldehydes (Scheme 6).2 This compound is thought
to arise from complex 22 in a manner analogous to the
nickel(0)-promoted enyne cyclizations previously reported
by Tamao et al.20 We propose that this side reaction is seen
only in the presence of a phosphine additive because the for-
mation of 23 (from 22) will be slow relative to the formation
of 21 (from 20), since L is presumed to be more weakly
bound than the tethered olefin.
To evaluatewhether the oxygen atom of the tether plays a sig-
nificant role in the reaction, we synthesized a 1,6-enyne (33)
in which the oxygen was replaced with a methylene group, by
wayofahighlydiastereoselectiveMyersalkylation, followed
by Swern oxidation and Wittig olefination (Scheme 4)19.
1. LDA, LiCl, THF
O
Me
Me
Et
OH
2.
Ph
Et
N
I
Me
Me
OH
3. LDA, H B•NH , THF
3
3
Me
X
OH
iPrCHO
X
34
35, >90% ee
Ni PR3
R'
X
Me
Me
Ni
22
k1
Et3B
PR3
R'
R'
38
(COCl) , Et N
3
2
THF
DMSO
iPrCHO
O
Me
iPr
X
X
X
Et
BrCH PPh , KOtBu
3
3
H
iPrCHO
k2
H
O
PR3
Ni
Ni
Ni
O
Et O
2
L
R'
R'
R'
H
Et
33, [ ] = –21.1
Me
23
20
21
iPr
α
36
D
k2 > k1
Scheme 4.
Scheme 6.
Under type I coupling conditions, enyne 33 gave results sim-
ilar to those obtained with the enynes possessing an ethereal
tether between the alkene and the alkyne. Nickel-catalyzed
reductive coupling of 33 and i-PrCHO afforded allylic alco-
hol 37 in very high regioselectivity and in slightly reduced
but nevertheless high diastereoselectivity (Scheme 5). The
3. Conclusion
In summary, alkene-directed, nickel-catalyzed reductive
coupling of 1,6-enynes and aldehydes is a versatile tool for
organic synthesis. The chelation-controlled, highly dia-
stereoselective transformations possible in the absence of
a phosphine additive have clear synthetic utility, while in
the presence of a well-suited chiral phosphine, an enantio-
selective method for the production of regioisomer B might
also be achieved.
Me
OH
iPrCHO
Me
Ni(cod)
2
Et B
3
Et
Et
Me
Me
37
(91:9 dr)
33
Three distinct mechanistic pathways and their associated re-
action conditions have been described, and our observations
support the hypothesis that nickel-catalyzed reductive cou-
pling reactions of alkynes and aldehydes proceed through an
approximately planar, three-coordinate d8 nickel complex.
The mechanistic insight gained through this investigation
should facilitate the development of other selective, nickel-
catalyzed transformations.
O
Me
1. Ac O, NEt ,
2
3
DMAP
(+)-32, [ ] = +7.7
D
Me
Me
2. O , PPh
3
3
OAc
Scheme 5.

R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
7603
4. Experimental
4.1. General methods
100 mL round-bottomed flask filled with DCM (25 mL). To
this suspension was added diisopropyl D-tartrate (352 mL,
2.1 mmol) and racemic penten-3-ol (3 g, 34 mmol). The sus-
pension was cooled to ꢂ5 ꢀC and Ti(OiPr)4 (414 mL,
1.4 mmol) was added. The reaction was stirred for 30 min,
and then t-BuOOH (5.5 M in decanes, 6 mL, 33 mmol) was
added. The reaction was warmed to 0 ꢀC and stirred for
7 h. The slurry was added to a solution of iron(II) sulfate
(11 g) and citric acid (3.5 g) in water (30 mL) and diluted
with ether (80 mL). The layers were separated and the aque-
ous layer extracted once with diethyl ether. The combined
organics were washed with brine, dried over magnesium
sulfate, and filtered. Solvent was removed under atmospheric
pressure via distillation through a Vigereux column (10 cm).
Fractional distillation (20 Torr, 50 ꢀC) of the residue then
provided (+)-penten-3-ol as a clear oil (1 g, 33% yield).
[a]2D2 +21.6 (c 0.37, CHCl3). The optical rotation was com-
pared to literature values,17 and the stereocenter was deter-
mined to be (S).
Unless otherwise noted, all reactions were performed under
an oxygen-free atmosphere of argon using standard Schlenk-
line techniques. Bis(cyclooctadienyl)nickel(0) (Ni(cod)2)
and tricyclopentylphosphine (PCyp3) were purchased from
Strem Chemicals, Inc. and used without further purification.
Triethylborane (Et3B), triethylamine, methylsulfoxide, tri-
butylphosphine (PBu3), and penten-3-ol were purchased
from Aldrich Chemical Co. and, unless otherwise stated,
used as received. Isobutyraldehyde (Alfa Aeser) was dis-
tilled from anhydrous magnesium sulfate (MgSO4) prior to
use. (ꢃ)-4,4-Dimethyl-penten-3-ol was synthesized accord-
ing to the literature procedure, and distilled prior to use.21
Tetrahydrofuran (THF) and diethyl ether were freshly
distilled over sodium/benzophenone ketyl, and dichloro-
methane (DCM) was freshly distilled from calcium hydride.
Toluene was distilled from sodium metal, ethyl acetate was
distilled from anhydrous magnesium sulfate, both toluene
and ethyl acetate were sparged for 10 min with argon prior
to use in coupling experiments.
4.2.3. (L)-3-But-2-ynyloxy-pent-1-ene (27).
Me
O
Et
4.2. Preparation of starting materials
27
Sodium hydride (7.5 g,w58%,w180 mmol) was loaded into
a round-bottom flask and rinsed with anhydrous pentanes
(3ꢄ50 mL) and dried in vacuo. THF (200 mL) was added
followed by addition of (+)-penten-3-ol (3.08 mL, 30 mmol),
and the mixture was stirred for 3 h at room temperature prior
to addition of 1-bromo-2-butyne (5.25 mL, 60 mmol). After
stirring overnight, the reaction was quenched by careful
addition of saturated aqueous ammonium chloride. The
organics were extracted with diethyl ether (3ꢄ150 mL),
washed with brine, dried over magnesium sulfate, filtered,
and concentrated (0 ꢀC, 50 Torr). The product (as a solution
in THF) was loaded directly onto silica (7 cmꢄ5 cm) and
chromatographed (10:1 pentanes/diethyl ether). Removal of
the solvent (0 ꢀC, 50 Torr) followed by distillation through
a short-path apparatus (35 ꢀC, 1 Torr) yielded (ꢂ)-27 as
a clear oil (3.83 g, 92%, >90% ee). Compound (ꢂ)-27:
[a]2D2 ꢂ75.7 (c 3.09, CHCl3); chiral GC analysis (Varian
CP-3800, G-TA column, 50 ꢀC, 0.7 mL/min H2 carrier) tR
(S) 14.4 min, tR (R) 14.9 min; IR 2964 (m), 2924 (s), 2856
The synthesis of 6-tridecyne, 2–5, 9, 11, 13, 15, and 17 have
been reported previously.2
4.2.1. 1-Decen-3-yne22 (1).
Me
1
1-Octyne (2.21 mL, 15 mmol) was dissolved in THF
(15 mL) and cooled to 0 ꢀC. Then n-BuLi (15 mmol, 6 mL
of 2.5 M solution in hexanes) was added dropwise, and the
mixture was stirred at 0 ꢀC for 30 min. A solution of dry
ZnCl2 (2.04 g, 15 mmol) in THF (10 mL) was added via can-
nula and the mixture was allowed to warm to room temper-
ature. In a 250 mL round-bottom flask, vinyl bromide
(25 mmol, 25 mL of a 1 M solution in THF) and Pd(PPh3)4
(0.69 g, 0.6 mmol) were combined. The alkynyl zinc solu-
tion was transferred to the palladium solution via cannula.
The bright yellow solution was stirred for 2 h, and then
quenched with 1 M HCl (75 mL). The organics were ex-
tracted with pentanes (2ꢄ75 mL), washed with saturated
NaCl, dried over MgSO4, and filtered. Pentanes were re-
moved via distillation, and the residue was then distilled
under reduced pressure to provide 1 (0.95 g, 7.0 mmol,
47% yield). 1H NMR (300 MHz, CDCl3) d 5.78 (ddt,
J¼17.4, 10.8, 2.1 Hz, 1H); 5.54 (dd, J¼17.4, 2.3 Hz, 1H);
5.37 (dd, J¼10.8, 2.3 Hz, 1H); 2.29 (dt, J¼10.2, 2.1 Hz,
2H); 1.48–1.57 (m, 2H); 1.25–1.44 (m, 6H); 0.89 (t,
J¼7 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 125.6,
117.9, 91.5, 76.5, 31.6, 28.9, 28.8, 22.8, 19.6, 14.3.
1
(m), 2248 (w), 1457 (b, w), 1057 (s), 910 (s) cmꢂ1; H
NMR (500 MHz, CDCl3) d 5.63 (ddd, J¼17.0, 11.0,
8.5 Hz, 1H), 5.23 (dd, J¼8.5, 2.0 Hz, 1H), 5.22 (dd,
J¼17.0, 2.0 Hz, 1H), 4.15 (dq, Jd¼15.0 Hz, Jq¼2.0 Hz,
1H), 3.97 (dq, Jd¼15.0 Hz, Jq¼2.0 Hz, 1H), 3.73 (q,
J¼7.0 Hz, 1H), 1.86 (t, J¼2.0 Hz, 3H), 1.66 (apparent sep-
tet, J¼7.0 Hz, 1H), 1.52 (apparent septet, J¼7.0 Hz, 1H),
0.91 (t, J¼7.5 Hz, 3H). 13C NMR (125.8 MHz, CDCl3)
d 138.3, 118.1, 81.9, 81.8, 75.8, 56.1, 28.3, 9.9, 3.9.
4.2.4. ( )-3-But-2-ynyloxy-4,4-pent-1-ene (28).
Me
4.2.2. (+)-Penten-3-ol.
O
OH
tBu
28
Me
According to the procedure for 27, (ꢃ)-4,4-dimethyl-
penten-3-ol (1.71 g, 15 mmol) was reacted with 600 mol %
NaH and 300 mol % 1-bromo-2-butyne to give 2 g (80%)
Synthesized according to a literature procedure.23 Flame-
˚
dried molecular sieves 4 A (ca. 5 g) were loaded into a

7604
R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
of a clear oil after chromatography (25:1 pentanes/diethyl
ether) and distillation (65 ꢀC, 1 Torr). Compound 28: IR
2956 (s), 2870 (m), 2361 (w), 1464 (b, w), 1363 (m), 1136
The solution was warmed to 0 ꢀC and stirred for 10 min,
then H3B$NH3 (407 mg, 13.2 mmol) was added in a single
portion. The reaction was stirred at 0 ꢀC for an additional
15 min and then warmed to room temperature for 15 min.
The reaction was re-cooled (0 ꢀC) for the dropwise addition
of 40 (1.0 g, 3.3 mmol) in THF (8.3 mL), and then warmed
back up to room temperature until the reaction was deter-
mined to be complete by TLC (2 h). The system was cooled
to 0 ꢀC and 33 mL of 3 N HCl was added carefully. The slurry
was stirred for 30 min at 0 ꢀC, the product was extracted with
ether, and the combined organics washed with 1 N HCl, 1 N
NaOH, and brine. The crude product was dried over magne-
sium sulfate, filtered, concentrated, and chromatographed
(5:2 hexanes/diethyl ether) to give 35 as a clear oil
(267 mg, 81%). The enantiomeric excess was approximated
by formation of the Mosher ester of this sample and of race-
mic material26 and then comparing their respective 1H NMR
spectra. [a]2D2 ꢂ4.6, (c 3.37, CHCl3); IR 3348 (b, m), 2961 (s),
2921 (s), 2876 (s), 2361 (m), 2341 (m), 1461 (m), 1380 (w),
1043 (m) cmꢂ1; 1H NMR (500 MHz, CDCl3) d 3.60 (m, 2H),
2.19 (m, 2H), 1.79 (t, J¼2.5 Hz, 3H), 1.55 (m, 2H), 1.39 (m,
3H), 0.92 (t, J¼7.5 Hz, 3H); 13C NMR (125.8 MHz, CDCl3)
d 79.5, 75.9, 64.9, 41.3, 30.1, 23.4, 16.6, 11.3, 3.7.
(m) cmꢂ1 1H NMR (500 MHz, CDCl3) d 5.68 (ddd,
;
J¼17.0, 10.5, 8.5 Hz, 1H), 5.27 (dd, J¼10.5, 1.5 Hz, 1H),
5.19 (dd, J¼17.0, 1.5 Hz, 1H), 4.14 (dq, Jd¼15.0 Hz,
Jq¼2.0 Hz, 1H), 3.92 (dq, Jd¼15.0 Hz, Jq¼2.0 Hz, 1H),
3.42 (d, J¼8.5 Hz, 1H), 1.86 (t, J¼2.0 Hz, 3H), 0.91 (s,
9H). 13C NMR (125.8 MHz, CDCl3) d 135.4, 119.2, 88.0,
81.5, 76.1, 56.4, 34.4, 26.3, 3.9; HRMS m/z (ESI, M+Na+)
calcd 189.1250 found 189.1256.
I
Me
O
Cl
O
Me
NEt3,
THF
LDA, LiCl,
THF
+
Me
Et
Ph
Me OH
39
N
Me
Ph
N
H
(4)
OH
O
LDA,
Et
.
H3B NH3,
Et
OH
Xψ+
THF
Me
Me
40
35
4.2.5. 2-Ethyl-hept-5-yn-1-ol (35). The synthesis of 35 was
accomplished following the work of Myers and co-
workers.19 Butyryl chloride (3.1 mL, 30 mmol) was added
dropwise to a chilled (0 ꢀC) solution of (+)-(S, S)-pseudo-
ephedrine (4.95 g, 30 mmol) and NEt3 (5.4 mL, 39 mmol)
in THF (10 mL). The reaction was stirred for 30 min and
then quenched by the addition of water. The product mixture
was partitioned between ethyl acetate and brine, the organic
layer was separated, washed two times with brine, and then
dried over sodium sulfate. The solvent was removed in vacuo
and the crude solid recrystallized from toluene (20 mL) to
give 39 as white crystals (5.15 g, 74%). NMR matched
known values.24
4.2.6. 2-Ethyl-hept-5-ynal (36).
O
Me
H
Et
36
DMSO (298 mL, 4.2 mmol) was added to oxalyl chloride
(262 mL, 3 mmol) in cold (ꢂ78 ꢀC) dichloromethane
(20 mL), and the mixture was stirred for 10 min before 35
(280 mg, 2 mmol) was added. After stirring for an additional
20 min, NEt3 (836 mL, 6 mmol) was added in a single por-
tion, and the cold bath subsequently removed. The reaction
was allowed to warm for 30 min before being quenched via
the addition of water. The product was extracted with ether
and the combined organics dried over magnesium sulfate.
The solvent was removed under reduced pressure (80 Torr,
0 ꢀC, rotary evaporator), and the crude mixture was flushed
through a silica plug eluting with 10:1 pentanes/diethyl ether
and then concentrated to give a clear oil (274 mg, 99%). IR
2964 (m), 2923 (m), 2361 (s), 2341 (s), 1726 (m), 1380 (b,
n-Butyllithium (2.5 M in hexanes, 9.8 mL, 24.5 mmol) was
added dropwise to a cold (ꢂ78 ꢀC) slurry of i-Pr2NH
(3.7 mL, 26 mmol) and LiCl (flame dried under vacuum
prior to use) (3.23 g, 77 mmol) in THF (17 mL). The suspen-
sion was warmed to 0 ꢀC for 5 min then cooled to ꢂ78 ꢀC.
Compound 39 (2.96 g, 12.6 mmol) was added dropwise as
a solution in cold (0 ꢀC) THF (37 mL) and the reaction
stirred at ꢂ78 ꢀC for 1 h, 0 ꢀC for 15 min and then room tem-
perature for 5 min before being re-cooled to 0 ꢀC. 5-Iodo-2-
pentyne (1.16 g, 6.0 mmol), available in two steps from the
corresponding alcohol,25 was added in a single portion and
the reaction was stirred at 0 ꢀC for 2 h before being allowed
to gradually warm to room temperature overnight. The re-
action was quenched via the addition of saturated aqueous
ammonium chloride and the product extracted with ethyl
acetate. The combined organics were dried over sodium sul-
fate, filtered, concentrated, and then chromatographed (3:2
hexanes/ethyl acetate) to give 40 as a viscous pale yellow
oil (1.34 g, 73%). The relative stereochemistry of 40 was
assigned by analogy to Myers’ work.19
1
m), 1261 (w) cmꢂ1; H NMR (500 MHz, CDCl3) d 9.64
(d, J¼2.5 Hz, 1H), 2.39 (dtt, Jd¼2.5, Jt¼7.5, 5.5 Hz, 1H),
2.18 (m, 2H), 1.87 (m, 1H), 1.77 (t, J¼2.5 Hz, 3H), 1.70
(m, 1H), 1.66–1.52 (m, 4H), 0.94 (t, J¼7.5 Hz, 3H); 13C
NMR (125.8 MHz, CDCl3) d 205.2, 78.3, 76.9, 52.4, 27.7,
21.7, 16.8, 11.5, 3.6; HRMS m/z (ESI, M+Na+) calcd
161.0937 found 161.0944.
4.2.7. 3-Ethyl-oct-1-en-6-yne (33).
Me
Et
33
Freshly dried methyltriphenylphosphonium bromide
(1.02 g, 2.86 mmol) was added in one portion to a cooled
(0 ꢀC) suspension of KOtBu (355 mg, 2.86 mmol) in ether
(4 mL), resulting in the suspension turning bright yellow.
The suspension was warmed to room temperature and stirred
Compound 40 was reduced using LDA and H3B$NH3 (LAB)
prepared as follows: n-Butyllithium (2.5 M in hexanes,
5.3 mL, 13.2 mmol) was added dropwise to a cold (ꢂ78 ꢀC)
solution of i-Pr2NH (2.0 mL, 13.9 mmol) in THF (14 mL).

R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
7605
for 40 min, 36 (274 mg, 2 mmol) was added from a 10 mL
pear-shaped flask, rinsing with ether (total volume 2 mL).
Stirring was continued for 45 min at room temperature and
then the reaction was quenched with water (200 mL). The
suspension was stirred until all of the precipitate collected
at the bottom of the flask (5 min) leaving a clear liquid phase.
The flask was equipped with a short-path distillation appara-
tus and heated to 50 ꢀC to remove most of the diethyl ether.
The receiving flask was then cooled to ꢂ78 ꢀC and the sys-
tem was placed under vacuum resulting in the instantaneous
transfer of all remaining liquid materials (a mixture of di-
ethyl ether, t-BuOH, water, and 33) to the cooled receiving
flask. Sodium sulfate was added to the biphasic mixture
and then the material was passed through a plug of silica
eluting with pentanes. The solvent was removed (0 ꢀC,
140 Torr) to give 33 as a clear oil (175 mg, 64%). [a]D22
ꢂ21.1 (c 0.41, DCM); IR 3077 (w), 2964 (s), 2921 (s),
2875 (m), 2361 (w), 1640 (w), 1455 (m), 997 (m), 914
30 min to promote quenching of the catalyst. Reactions,
which were run neat, were first diluted with 2 mL of reagent
grade ethyl acetate prior to being opened to the air. The crude
mixture was concentrated and purified by flash chromato-
graphy.
4.3.2.1. 4-Hexyl-2-methyl-deca-4,9-dien-3-ol (19A).
OH
iPr
nhex
19A
Procedure A (no additive) (half-scale): Reaction of iso-
butyraldehyde (45 mL, 0.5 mmol) and 4 (45 mg, 0.25 mmol)
in the presence of Ni(cod)2 (7 mg, 0.025 mmol) and Et3B
(75 mL, 0.5 mmol) in EtOAc (0.25 mL) afforded an 85:15
mixture of the title compound and the corresponding alkyl-
ative coupling product (transfer of an ethyl group instead
of a hydrogen from Et3B) (34 mg, 53% yield (46% reduc-
tive), >95:5 regioselectivity). An analytically pure sample
of 19A was obtained via flash chromatography on silica gel
impregnated with 5% silver nitrate. Rf¼0.40 (10:1 hex-
(s) cmꢂ1
;
1H NMR (500 MHz, CDCl3) d 5.48 (ddd,
J¼17.0, 10.0, 9.5 Hz, 1H), 5.00 (m, 2H), 2.16 (m, 1H),
2.06 (m, 1H), 1.98 (m, 1H), 1.79 (t, J¼2.5 Hz, 3H), 1.60
(m, 1H), 1.40 (m, 2H), 1.26 (m, 1H), 0.86 (t, J¼7.5 Hz,
3H); 13C NMR (125.8 MHz, CDCl3) d 142.3, 115.3, 79.5,
75.5, 45.2, 34.1, 27.7, 16.8, 11.8, 3.7; HRMS m/z (EI, M+)
calcd 136.1248 found 136.1247.
1
anes/ethyl acetate). H NMR (500 MHz, CDCl3) d 5.78–
5.87 (m, 1H); 5.35 (t, J¼7.5 Hz, 1H); 4.99–5.04 (m, 1H);
4.95–4.98 (m, 1H); 3.66 (d, J¼7.5 Hz, 1H); 1.92–2.10 (m,
6H); 1.78 (oct., J¼7 Hz, 1H); 1.44–1.51 (m, 2H); 1.24–
1.43 (m, 8H); 0.96 (d, J¼7 Hz, 3H); 0.89 (t, J¼7 Hz, 3H);
0.84 (d, J¼7 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 141.8, 139.0, 127.4, 114.7, 82.9, 33.7, 31.9, 31.9, 31.8,
30.3, 30.2, 29.3, 28.2, 27.2, 22.9, 20.1, 18.3, 14.3. IR (thin
film NaCl): 3623, 3428, 3078, 2956, 2929, 2871, 2859,
1823, 1641, 1468, 1379, 1365, 1295, 1246, 1169, 1130,
1116, 1007. HRMS (ESI) m/z 275.235 [(M+Na)+; calcd
for C17H32O: 275.235]. Regioselectivity confirmed by
GC analysis (chiral B-PH, 125 ꢀC, 2.5 mL/min): 21.30,
22.06 min.
4.3. Alkene-directed reductive coupling of alkynes and
aldehydes
4.3.1. General procedure A. In a glove box, Ni(cod)2
(14 mg, 0.05 mmol) was placed into an oven-dried, single-
necked round-bottom flask, and the flask was then sealed
with a rubber septum. The flask was removed from the glove
box, placed under argon, and degassed ethyl acetate (0.5 mL)
was added via syringe, followed immediately by Et3B
(0.15 mL, 1.0 mmol). The reaction could also be run in the
absence of any additional solvent with no detrimental effect.
The resulting solution was then cooled to 0 ꢀC, and isobutyr-
aldehyde (90 mL, 1.0 mmol) was added dropwise via micro-
syringe. After stirring for 5 min, the enyne (0.5 mmol) was
added. The reaction was allowed to gradually warm to
room temperature and stirred for 15 h. The septa was then re-
moved and the reaction opened to air for 30 min to promote
quenching of the catalyst. Reactions, which were run neat,
were first diluted with 2 mL of reagent grade ethyl acetate
prior to being opened to the air. The crude mixture was con-
centrated and purified by flash chromatography.
4.3.2.2. 4-Hexyl-2-methyl-dec-4-en-3-ol (41A) and
2-methyl-4-pentyl-undec-4-en-3-ol (41B).
OH
OH
i-Pr
n-pent
41B
+
n-pent
i-Pr
n-hex
n-hex
41A
Procedure A (no additive): Reaction of isobutyraldehyde
and 6-tridecyne (90 mg, 0.5 mmol) afforded an 85:15 mix-
ture of the title compounds and the corresponding alkylative
coupling products (transfer of an ethyl group instead of a
hydrogen from Et3B) as a clear oil (36 mg, 28% yield (24%
reductive), 51:49 mixture of regioisomers 41A and 41B).
4.3.2. General procedure B (with phosphine additive). In
a glove box, Ni(cod)2 (14 mg, 0.05 mmol) and PR3
(0.1 mmol) were placed into an oven-dried, single-necked
round-bottom flask, and the flask was then sealed with a rub-
ber septum. The flask was removed from the glove box,
placed under argon, and degassed ethyl acetate (0.5 mL)
was added via syringe, followed immediately by Et3B
(0.15 mL, 1.0 mmol). The reaction could also be run in the
absence of any additional solvent with no detrimental
effect. The resulting solution was then cooled to 0 ꢀC, and
isobutyraldehyde (90 mL, 1.0 mmol) was added dropwise
via microsyringe. After stirring for 5 min, the enyne
(0.5 mmol) was added. The reaction was allowed to gradu-
ally warm to room temperature and stirred for 15 h. The
septa was then removed and the reaction opened to air for
Procedure B (PCyp3): Reaction of isobutyraldehyde and
6-tridecyne (90 mg, 0.5 mmol) afforded a 51:49 mixture
of regioisomers 41A and 41B as a clear oil (98 mg, 77%
yield). Rf¼0.39 (10:1 hexanes/ethyl acetate). 1H NMR
(500 MHz, CDCl3) d 5.35 (t, J¼7 Hz, 1H); 3.65 (d, J¼
7.5 Hz, 1H); 1.92–2.07 (m, 4H); 1.78 (oct., J¼7 Hz, 1H);
1.24–1.44 (m, 14H); 0.96 (d, J¼6 Hz, 3H); 0.87–0.92
(m, 6H); 0.84 (d, J¼6.5 Hz, 3H). 13C NMR (125 MHz,
CDCl3) d 141.3, 128.0, 83.0, 83.0, 32.7, 32.0, 31.9, 31.8,
31.8, 30.3, 30.2, 30.0, 30.0, 29.7, 29.3, 28.2, 28.1, 27.8,
27.7, 22.9, 22.9, 22.8, 22.7, 20.1, 18.3, 14.3, 14.3, 14.3,

7606
R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
14.3. IR (thin film NaCl): 3624, 3423, 2957, 2927, 2872,
2859, 1713, 1661, 1467, 1379, 1366, 1297, 1244, 1169,
1105, 1008. HRMS (ESI) m/z 277.251 [(M+Na)+; calcd
for C17H34O: 277.250]. Regioselectivity determined by
GC analysis (chiral B-PH, 110 ꢀC, 2.0 mL/min): 51.08,
52.04 min.
of 3-phenylpropionaldehyde (132 mL, 1 mmol) and 4
(89 mg, 0.5 mmol) afforded the title compound as a clear
oil (95 mg, 60% yield, >95:5 regioselectivity). Rf¼0.23
1
(10:1 hexanes/ethyl acetate). H NMR (500 MHz, CDCl3)
d 7.27–7.31 (m, 2H); 7.17–7.22 (m, 3H); 5.78–5.87 (m,
1H); 5.41 (t, J¼7 Hz, 1H); 5.00–5.04 (m, 1H); 4.95–4.98
(m, 1H); 4.05 (t, J¼6.5 Hz, 1H); 2.70–2.76 (m, 1H); 2.60–
2.66 (m, 1H); 1.96–2.11 (m, 6H); 1.84–1.89 (m, 2H); 1.47
(quin., J¼7.5 Hz, 2H); 1.24–1.42 (m, 8H); 0.89 (t,
J¼7 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 142.4,
142.4, 138.9, 128.6, 128.6, 126.8, 126.0, 114.8, 76.3, 37.6,
33.6, 32.5, 31.9, 30.2, 30.1, 29.9, 27.8, 27.2, 22.9, 14.3. IR
(thin film NaCl): 3360, 3077, 3064, 3027, 2954, 2928,
2858, 1940, 1821, 1727, 1641, 1604, 1496, 1455, 1415,
1378, 1301, 1154, 1048, 1031, 992. HRMS (ESI) m/z
337.250 [(M+Na)+; calcd for C22H34O: 337.250].
4.3.2.3. 3-Hexyl-nona-3,8-dien-2-ol (6A).
OH
Me
3
nhex
6A
Procedure A (no additive) (modification: toluene used in
place of EtOAc as the reaction solvent): reductive coupling
of acetaldehyde (100 mL, 2 mmol) and 4 (89 mg, 0.5 mmol)
afforded the title compound as a clear oil (77 mg, 69%
yield, >95:5 regioselectivity). Rf¼0.19 (10:1 hexanes/ethyl
acetate). 1H NMR (500 MHz, CDCl3) d 5.78–5.86 (m, 1H);
5.41 (t, J¼7 Hz, 1H); 4.99–5.05 (m, 1H); 4.94–4.98 (m,
1H); 4.23 (q, J¼6.5 Hz, 1H); 1.95–2.12 (m, 6H); 1.46
(quin., J¼7.5 Hz, 2H); 1.28–1.42 (m, 8H); 1.27 (d,
J¼6.5 Hz, 3H); 0.90 (t, J¼6.5 Hz, 3H). 13C NMR
(125 MHz, CDCl3) d 143.8, 139.0, 125.2, 114.7, 72.3,
33.6, 31.9, 30.1, 30.0, 29.2, 27.8, 27.1, 22.9, 22.6, 14.3.
IR (thin film NaCl): 3349, 3078, 2957, 2928, 2858, 1641,
1458, 1415, 1378, 1366, 1283, 1116, 1062. HRMS (ESI)
m/z 247.203 [(M+Na)+; calcd for C15H28O: 247.203].
4.3.2.6. 3-Isopropyl-nona-3,8-dien-2-ol (10A).
OH
Me
3
iPr
10A
Procedure A (no additive) (modification: toluene used in
place of EtOAc as the reaction solvent): reductive coupl-
ing of acetaldehyde (100 mL, 1.8 mmol) and 9 (68 mg,
0.5 mmol) afforded the title compound as a clear oil
(58 mg, 64% yield, >95:5 regioselectivity). Rf¼0.20 (10:1
hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3)
d 5.78–5.86 (m, 1H); 5.47 (t, J¼7 Hz, 1H); 4.99–5.04 (m,
1H); 4.95–4.98 (m, 1H); 4.30 (q, J¼6.5 Hz, 1H); 2.76 (sep-
tet, J¼7 Hz, 1H); 2.05–2.13 (m, 4H); 1.47 (quin., J¼7 Hz,
2H); 1.29 (d, J¼6.5 Hz, 3H); 1.11 (d, J¼7 Hz, 3H); 1.05
(d, J¼7 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 149.4,
139.0, 124.2, 114.7, 68.4, 33.6, 29.4, 28.2, 27.0, 24.2,
22.0, 21.7. IR (thin film NaCl): 3361, 3078, 2962, 2929,
2872, 1824, 1641, 1460, 1415, 1365, 1304, 1282, 1217,
1150, 1111, 1060. HRMS (ESI) m/z 205.156 [(M+Na)+;
calcd for C12H22O: 205.156].
4.3.2.4. 1-(tert-Butyl-dimethyl-silanyloxy)-3-hexyl-nona-
3,8-dien-2-ol (7A).
OH
OTBS
3
nhex
7A
Procedure A (no additive) (modification: toluene used
in place of EtOAc as the reaction solvent): reductive cou-
pling of (tert-butyldimethylsilyloxy)acetaldehyde (190 mL,
1 mmol) and 4 (89 mg, 0.5 mmol) afforded the title com-
pound as a clear oil (102 mg, 58% yield, >95:5 regioselec-
tivity). Rf¼0.42 (10:1 hexanes/ethyl acetate). 1H NMR
(500 MHz, CDCl3) d 5.77–5.86 (m, 1H); 5.48 (t, J¼7 Hz,
1H); 5.10 (dd, J¼17, 1 Hz, 1H); 4.96 (dt, J¼10,
1 Hz, 1H); 4.08 (dd, J¼8.5, 3 Hz, 1H); 3.64 (dd, J¼10,
3 Hz, 1H); 3.42 (dd, J¼10, 8.5 Hz, 1H); 2.03–2.12 (m,
5H); 1.87–1.94 (m, 1H); 1.47 (quin., J¼7.5 Hz, 2H); 1.24–
1.40 (m, 8H); 0.91 (s, 9H); 0.89 (t, J¼7 Hz, 3H); 0.09 (s,
6H). 13C NMR (125 MHz, CDCl3) d 139.0, 138.4, 127.2,
114.7, 75.7, 67.3, 33.7, 31.9, 29.9, 29.8, 29.2, 28.6, 27.2,
26.1, 22.9, 18.5, 14.3, ꢂ5.1, ꢂ5.1. IR (thin film NaCl):
3572, 3472, 3078, 2956, 2929, 2858, 1824, 1730, 1641,
1471, 1464, 1390, 1362, 1316, 1255, 1223, 1099, 1057,
1006, 992. HRMS (ESI) m/z 377.284 [(M+Na)+; calcd for
C21H42O2Si: 377.285].
4.3.2.7. 3-(tert-Butyl-dimethyl-silanyloxymethyl)-nona-
3,8-dien-2-ol (12A).
OH
Me
3
OTBS
12A
Procedure A (no additive) (modification: toluene used in
place of EtOAc as the reaction solvent): reductive coupl-
ing of acetaldehyde (100 mL, 1.8 mmol) and 11 (119 mg,
0.5 mmol) afforded the title compound as a clear oil
(88 mg, 62% yield, >95:5 regioselectivity). Rf¼0.40 (10:1
hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) d 5.76–
5.85 (m, 1H); 5.49 (t, J¼7.5 Hz, 1H); 4.99–5.04 (m, 1H);
4.95–4.98 (m, 1H); 4.31–4.40 (m, 3H); 2.00–2.10 (m, 4H);
1.48 (quin., J¼7.5 Hz, 2H); 1.34 (d, J¼6 Hz, 3H); 0.92 (s,
9H); 0.12 (s, 3H); 0.11 (s, 3H). 13C NMR (125 MHz,
CDCl3) d 140.0, 138.7, 127.7, 114.9, 72.4, 60.2, 33.4, 28.9,
26.9, 26.1, 22.2, 18.4, ꢂ5.3. IR (thin film NaCl): 3421,
3078, 2956, 2929, 2886, 2858, 1668, 1641, 1472, 1463,
1442, 1406, 1390, 1362, 1255, 1072. HRMS (ESI) m/z
307.206 [(M+Na)+; calcd for C16H32O2Si: 307.206].
4.3.2.5. 4-Hexyl-1-phenyl-deca-4,9-dien-3-ol (8A).
OH
Bn
3
nhex
8A
Procedure A (no additive) (modification: toluene used in
place of EtOAc as the reaction solvent): reductive coupling

R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
7607
4.3.2.8. 5-Allyloxy-3-pentyl-pent-3-en-2-ol (14A).
1H); 5.26 (t, J¼7 Hz, 1H); 5.14–5.18 (m, 2H); 4.16 (q,
J¼6.5 Hz, 1H); 3.86 (d, J¼6.5 Hz, 2H); 3.79–3.81 (m,
2H); 2.44 (s, 3H); 2.02–2.08 (m, 1H); 1.89–1.96 (m, 1H);
1.22–1.36 (m, 6H); 1.20 (d, J¼6.5 Hz, 3H); 0.89 (t,
J¼7 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 148.0,
143.4, 137.7, 133.4, 129.8, 127.4, 119.0, 118.9, 71.3, 49.9,
44.2, 32.4, 29.7, 28.0, 22.6, 22.4, 21.7, 14.2. IR (thin film
NaCl): 3521, 2957, 2931, 2870, 1644, 1598, 1495, 1446,
1418, 1402, 1343, 1305, 1289, 1264, 1213, 1159, 1119,
1092, 1059. HRMS (ESI) m/z 388.192 [(M+Na)+; calcd
for C20H31NO3S: 388.192].
OH
O
Me
npentyl
14A
Procedure A (no additive) (modifications: toluene used in
place of EtOAc as the reaction solvent, and slow addition
of the enyne over 3 h via syringe pump): reductive coupl-
ing of acetaldehyde (100 mL, 1.8 mmol) and 13 (83 mg,
0.5 mmol) afforded the title compound as a clear oil
(64 mg, 60% yield, >95:5 regioselectivity). Rf¼0.17 (5:1
hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3)
d 5.90–5.97 (m, 1H); 5.64 (t, J¼6.5 Hz, 1H); 5.27–5.32
(m, 1H); 5.19–5.22 (m, 1H); 4.27 (q, J¼6.5 Hz, 1H); 4.05
(d, J¼6.5 Hz, 2H); 3.99 (dt, J¼6, 1.5 Hz, 2H); 2.09–2.16
(m, 1H); 1.98–2.04 (m, 1H); 1.20–1.42 (m, 11H); 0.90 (t,
J¼7 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 147.8,
135.0, 121.2, 117.4, 71.6, 71.6, 66.5, 32.4, 30.0, 28.2,
22.7, 22.4, 14.2. IR (thin film NaCl): 3392, 2957, 2932,
2861, 1647, 1459, 1367, 1212, 1065. HRMS (ESI) m/z
235.166 [(M+Na)+; calcd for C13H24O2: 235.167].
4.3.2.11. 2-Methyl-4-pent-4-enyl-undec-4-en-3-ol (19B).
nhex
iPr
OH
19B
Procedure B (general for all phosphines listed in Table 3)
(modification: aldehyde added over 3 h via syringe pump):
Reaction of isobutyraldehyde and 4 (89 mg, 0.5 mmol)
provided 19B as a clear oil (57 mg, 45% yield). Following
initial purification, flash chromatography on silica gel
impregnated with 5% silver nitrate was required to remove
minor impurities. Rf¼0.40 (10:1 hexanes/ethyl acetate). 1H
NMR (500 MHz, CDCl3) d 5.79–5.87 (m, 1H); 5.36 (t,
J¼7 Hz, 1H); 5.01–5.05 (m, 1H); 4.96–4.99 (m, 1H); 3.65
(d, J¼7 Hz, 1H); 1.95–2.13 (m, 6H); 1.78 (oct., J¼7 Hz,
1H); 1.46–1.56 (m, 2H); 1.24–1.40 (m, 8H); 0.96 (d, J¼
7 Hz, 3H); 0.89 (t, J¼7 Hz, 3H); 0.83 (d, J¼7 Hz, 3H).
13C NMR (125 MHz, CDCl3) d 141.0, 138.9, 128.4, 114.9,
83.0, 34.6, 32.0, 31.8, 30.0, 29.5, 29.3, 27.8, 27.5, 22.8,
20.08, 18.4, 14.3. IR (thin film NaCl): 3415, 3077, 2956,
2928, 2858, 1823, 1722, 1641, 1467, 1379, 1366, 1297,
1249, 1168, 1113, 1010. HRMS (ESI) m/z 275.235
[(M+Na)+; calcd for C17H32O: 275.235]. Regioselectivity
confirmed by GC analysis (chiral B-PH, 125 ꢀC, 2.5 mL/
min): 21.30, 22.06 min.
4.3.2.9. 6-(Allyl-benzyl-amino)-2-methyl-4-pentyl-hex-
4-en-3-ol (16A).
OH
Bn
N
iPr
npentyl
16A
Procedure A (no additive) (modification: toluene used in
place of EtOAc as the reaction solvent): reductive coupling
of isobutyraldehyde (90 mL, 1.0 mmol) and 15 (128 mg,
0.5 mmol) afforded the title compound as a clear oil
(102 mg, 62% yield, >95:5 regioselectivity). Rf¼0.22 (5:1
hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3)
d 7.23–7.36 (m, 4H); 5.86–5.95 (m, 1H); 5.52 (t, J¼
6.5 Hz, 1H); 5.20 (dd, J¼17.5, 2 Hz, 1H); 5.16 (d, J¼
10 Hz, 1H); 3.69 (d, J¼7 Hz, 1H); 3.57 (s, 2H); 3.12 (d,
J¼7 Hz, 2H); 3.09 (d, J¼6.5 Hz, 2H); 1.97–2.04 (m, 1H);
1.89–1.95 (m, 1H); 1.79 (octet, J¼7 Hz, 1H); 1.22–1.38
(m, 6H); 0.95 (d, J¼6.5 Hz, 3H); 0.88 (t, J¼7 Hz, 3H);
0.86 (d, J¼7 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 144.5, 139.7, 136.2, 129.2, 128.4, 127.0, 124.7, 117.7,
82.4, 58.3, 57.1, 50.9, 32.6, 31.7, 29.9, 28.4, 22.7, 20.1,
18.1, 14.3. IR (thin film NaCl): 3423, 3065, 3028, 2956,
2930, 2870, 1643, 1495, 1455, 1366, 1255, 1118, 1073,
1012. HRMS (ESI) m/z 330.279 [(M+Na)+; calcd for
C22H35NO: 330.279].
4.3.2.12. 6-(1-Ethyl-allyloxy)-2,4-dimethyl-hex-4-en-
3-ol (29A).
OH
O
iPr
Et
Me
29A
Procedure A (no additive) (no EtOAc): 27 (69 mg, 0.5 mmol)
was reacted with i-PrCHO (90 mL, 1.0 mmol) in the presence
of Ni(cod)2 (14 mg, 0.05 mmol) and Et3B (0.15 mL,
1.0 mmol). Crude material was chromatographed with 15:1
hexanes/diethyl ether/7:1 hexanes/ethyl acetate to give
59 mg (56%) of 29A as a clear oil. Rf¼0.30 (6:1 hexanes/
EtOAc, KMnO4) (single regioisomer, 95:5 mixture of S, R
and S, S).
4.3.2.10. N-allyl-N-[3-(1-hydroxyethyl)-oct-2-enyl]-
benzenesulfonamide (18A).
OH
Ts
N
Me
npentyl
4.3.2.13. 4-(1-Ethyl-allyloxymethyl)-2-methyl-hex-4-
en-3-ol (29B).
18A
Procedure A (no additive) (modification: toluene used in
place of EtOAc as the reaction solvent): reductive coupl-
ing of acetaldehyde (200 mL, 3.6 mmol) and 17 (160 mg,
0.5 mmol) afforded the title compound as a clear oil
(125 mg, 68% yield, >95:5 regioselectivity). Rf¼0.29 (3:1
hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) d 7.71
(d, J¼8.5 Hz, 2H); 7.30 (d, J¼8.5 Hz, 2H); 5.64–5.73 (m,
Et
OH
iPr
O
Me
29B
Procedure B (PCyp3) (no EtOAc): 27 (69 mg, 0.5 mmol) was
reacted with i-PrCHO (90 mL, 1.0 mmol) in the presence of

7608
R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
Ni(cod)2 (14 mg, 0.05 mmol), PCyp3 (28 mL, 0.1 mmol),
and Et3B (0.15 mL, 1.0 mmol). Crude material was chroma-
tographed with 15:1 hexanes/diethyl ether/9:1 hexanes/
ethyl acetate to give 25 mg (24%) of 29B as a clear oil
Rf¼0.46 (6:1 hexanes/EtOAc, KMnO4) (single regioisomer,
55:45 mixture of diastereomers).
diastereomer were 1H NMR (500 MHz, CDCl3) d 4.06 (dd,
J¼12.0, 5.5 Hz, 1H), 3.94 (dd, J¼12.0, 7.0 Hz, 1H).
Compound 29B: IR 3454 (b, m), 2962 (s), 2934 (s), 2872 (s),
1669 (w), 1466 (m), 1319 (m), 1056 (s) cmꢂ1; the dia-
stereomers were not separated, peaks belonging to a specific
diastereomer are indicated by subscript A or B, those peaks
labeled A were favored with achiral phosphines and (R)-31.
1H NMR (500 MHz, CDCl3) d 5.70 (m, 1H), 5.64 (m, 1H),
5.24 (m, 2H), 4.30A (d, J¼11.0 Hz, 1H), 4.09B (d,
J¼11.0 Hz, 1H), 4.04B (d, J¼11.0 Hz, 1H), 3.80A (d, J¼
11.0 Hz, 1H), 3.58 (m, 2H), 2.86 (OH) (d, J¼7.0 Hz, 1H),
1.80 (m, 1H), 1.69 (apparent t, J¼7.0 Hz, 3H), 1.63 (M,
1H), 1.52 (m, 1H), 1.03A (d, J¼6.0 Hz, 3H), 1.03B
(d, J¼6.0 Hz, 3H), 0.91A (t, J¼7.5 Hz, 3H), 0.89B (t, J¼
7.5 Hz, 3H), 0.77A (d, J¼6.0 Hz, 3H), 0.75B (d, J¼6.0 Hz,
3H); no attempt was made to specify which carbon signals
belonged to each diastereomer, there are exactly double
the number of expected signals for a single compound.
13C NMR (125.8 MHz, CDCl3) d 138.7, 138.7, 127.2,
127.0, 118.0, 117.8, 84.3, 84.0, 83.6, 83.3, 64.5, 64.2,
32.6, 32.5, 28.6, 28.5, 19.8, 19.8, 19.3, 19.2, 13.4, 13.4,
10.1, 9.9; HRMS m/z (ESI, M+Na+) calcd 235.1669 found
235.1672.
Compounds 29A+29B. Procedure B (PBu3) (no EtOAc): 27
(69 mg, 0.5 mmol) was reacted with i-PrCHO (90 mL,
1.0 mmol) in the presence of Ni(cod)2 (14 mg, 0.05 mmol),
PBu3 (25 mL, 0.1 mmol), and Et3B (0.15 mL, 1.0 mmol).
Crude material was chromatographed with 15:1 hexanes/
diethyl ether/9:1 hexanes/ethyl acetate to give 19.3 mg
(18%) of 29A and 16 mg (15%) of 29B as clear oils (29A:
50:50 mixture of diastereomers; 29B: 55:45 mixture of
diastereomers).
Compounds 29A+29B. Procedure B ((R)-31)27 (no EtOAc):
27 (69 mg, 0.5 mmol) was reacted with i-PrCHO (90 mL,
1.0 mmol) in the presence of Ni(cod)2 (14 mg, 0.05 mmol)
(R)-31 (41 mg, 0.1 mmol), and Et3B (0.15 mL, 1.0 mmol).
Crude material was chromatographed with 15:1 hexanes/
diethyl ether/9:1 hexanes/ethyl acetate to give 9 mg (8%)
of 29A and 10 mg (9%) of 29B as clear oils (29A: 30:70 mix-
ture of S, R:S, S; 29B: 72:28 mixture of diastereomers).
The relative stereochemistry of 30A was assigned based on
analogy to 29A.
Compounds 29A+29B. Procedure B ((S)-31)27 (no EtOAc):
27 (69 mg, 0.5 mmol) was reacted with i-PrCHO (90 mL,
1.0 mmol) in the presence of Ni(cod)2 (14 mg, 0.05 mmol)
(S)-31 (41 mg, 0.1 mmol), and Et3B (0.15 mL, 1.0 mmol).
Crude material was chromatographed with 15:1 hexanes/
diethyl ether/9:1 hexanes/ethyl acetate to give 10.6 mg
(10%) of 29A and 8.9 mg (9%) of 29B as clear oils (29A:
66:34 mixture of S, R:S, S; 29B: 32:68 mixture of dia-
stereomers).
4.3.2.14. 6-(1-tert-Butyl-allyloxy)-2,4-dimethyl-hex-4-
en-3-ol (30A).
OH
O
iPr
tBu
Me
30A
Compounds 29A+29B. Procedure B (FcPPh2) (no EtOAc):
27 (69 mg, 0.5 mmol) was reacted with i-PrCHO (90 mL,
1.0 mmol) in the presence of Ni(cod)2 (14 mg, 0.05 mmol),
FcPPh2 (37 mg, 0.1 mmol), and Et3B (0.15 mL, 1.0 mmol).
Crude material was chromatographed with 15:1 hexanes/
diethyl ether/9:1 hexanes/ethyl acetate to give 8.2 mg
(7%) of 29A and 7.2 mg (6%) of 29B as clear oils (29A: 56:
44 mixture of S, R:S, S; 29B: 52:48mixture of diastereomers).
Procedure A (no additive) (no EtOAc): 28 (83 mg,
0.5 mmol) was reacted with i-PrCHO (90 mL, 1.0 mmol) in
the presence of Ni(cod)2 (14 mg, 0.05 mmol) and Et3B
(0.15 mL, 1.0 mmol). Crude material was chromatographed
with 15:1 hexanes/diethyl ether/8:1 hexanes/ethyl acetate
to give 33 mg (28%) of 30A as a clear oil Rf¼0.43 (6:1
hexanes/EtOAc, KMnO4) (single regioisomer, >95:5 (ꢃ)
S,S:S,R).
Compound 29A: [a]2D2 ꢂ23.4 (c 0.86, CHCl3); IR 3429 (b,
4.3.2.15. 4-(1-tert-Butyl-allyloxymethyl)-2-methyl-hex-
4-en-3-ol (30B).
m), 2962 (s), 2934 (s), 2872 (s), 1465 (m), 1094 (s), 1017
1
(s) cmꢂ1; H NMR (500 MHz, CDCl3)—data are for (S,R)
tBu
OH
iPr
diastereomer—d 5.68 (ddd, J¼17.0, 10.5, 8.0 Hz, 1H),
5.55 (t, J¼6.0 Hz, 1H), 5.20 (dd, J¼10.5, 1.0 Hz, 1H),
5.18 (dd, J¼17.0, 1.0 Hz, 1H), 4.10 (dd, J¼12.0, 6.5 Hz,
1H), 3.90 (dd, J¼12.0 Hz, 6.5 Hz, 1H), 3.64 (dd, J¼8.0,
3.0 Hz, 1H), 3.56 (q, J¼6.5 Hz, 1H), 1.78 (apparent hex,
J¼6.5 Hz, 1H), 1.62 (m, 1H), 1.60 (s, 3H), 1.55 (OH)
(br s, 1H), 1.49 (apparent sept, J¼7.0 Hz, 1H), 0.98 (d,
J¼6.5 Hz, 3H), 0.90 (t, J¼7.5 Hz, 3H), 0.81 (d, J¼6.5 Hz,
3H); 13C NMR (125.8 MHz, CDCl3) d 140.3, 139.3,
124.5, 117.2, 83.6, 82.4, 64.5, 31.0, 28.5, 19.6, 18.5, 11.9,
10.0; HRMS m/z (ESI, M+Na+) calcd 235.1669 found
235.1670.
O
Me
30B
Procedure B (PCyp3) (no EtOAc): 28 (83 mg, 0.5 mmol) was
reacted with i-PrCHO (90 mL, 1.0 mmol) in the presence of
Ni(cod)2 (14 mg, 0.05 mmol), PCyp3 (28 mL, 0.1 mmol),
and Et3B (0.15 mL, 1.0 mmol). Crude material was chroma-
tographed with 15:1 hexanes/diethyl ether/9:1 hexanes/
ethyl acetate to give 22 mg (18%) of 30B as a clear oil
Rf¼0.55 (6:1 hexanes/EtOAc, KMnO4) (single regioisomer,
42:58 mixture of diastereomers).
The (S,S) diastereomer was not independently synthesized;
however, those peaks, which were resolvable from the (S,R)
Compounds 30A+30B. Procedure B (PBu3) (no EtOAc): 28
(83 mg, 0.5 mmol) was reacted with i-PrCHO (90 mL,

R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
7609
1.0 mmol) in the presence of Ni(cod)2 (14 mg, 0.05 mmol),
PBu3 (25 mL, 0.1 mmol), and Et3B (0.15 mL, 1.0 mmol).
Crude material was chromatographed with 15:1 hexanes/
diethyl ether/9:1 hexanes/ethyl acetate to give 15.6 mg
(13%) of 30A and 14.8 mg (12%) of 30B as clear oils
(30A: 45:55 mixture of diastereomers; 30B: 42:58 mixture
of diastereomers).
to give 82 mg (78%) of 37 as a single regioisomer and as
a mixture of diastereomers (91:1 R, R, to R, S). Rf¼0.48
(6:1 hexanes/EtOAc, KMnO4) [a]2D2 ꢂ0.45 (c 0.84, DCM);
IR 3391 (b, m), 2959 (s), 2922 (s), 2872 (s), 1640 (w),
1460 (m), 1121 (w), 1010 (s), 911 (s) cmꢂ1 1H NMR
;
(500 MHz, CDCl3)—data are for (R,R) diastereomer—
d 5.52 (ddd, J¼17.0, 10.0, 9.0 Hz, 1H), 5.34 (t, J¼7.0 Hz,
1H), 5.00 (dd, J¼10.0, 2.0 Hz, 1H), 4.95 (dd, J¼17.0,
2.0 Hz, 1H), 3.57 (dd, J¼9.0, 3.0 Hz, 1H), 2.01 (m, 2H),
1.86 (m, 1H), 1.76 (m, 1H), 1.58 (s, 3H), 1.43 (m, 2H),
1.39 (OH) (d, J¼3.0 Hz, 1H), 1.28 (m, 2H), 0.99 (d,
J¼7.0 Hz, 3H), 0.85 (t, J¼7.0 Hz, 3H), 0.78 (d, J¼7.0 Hz,
3H); 13C NMR (125.8 MHz, CDCl3) d 143.1, 136.5, 128.2,
114.8, 84.5, 45.7, 34.6, 31.3, 28.0, 25.4, 19.7, 18.9, 11.9,
11.4.
Compound 30A: IR 3411 (b, m), 2962 (s), 2956 (s), 2872 (s),
2870 (s), 2361 (w), 1465 (m), 1363 (s), 1016 (b, s), 925
1
(s) cmꢂ1; H NMR (500 MHz, CDCl3)—data are for (ꢃ)-
(R,R) diastereomer—d 5.72 (ddd, J¼17.5, 10.0, 8.5 Hz,
1H), 5.52 (t, J¼6.0 Hz, 1H), 5.25 (dd, J¼10.0, 1.5 Hz,
1H), 5.14 (dd, J¼17.5, 1.5 Hz, 1H), 4.08 (dd, J¼12.5,
6.0 Hz, 1H), 3.86 (dd, J¼12.5 Hz, 7.0 Hz, 1H), 3.64 (dd,
J¼8.5, 3.0 Hz, 1H), 3.21 (d, J¼8.5 Hz, 1H), 1.78 (apparent
hex, J¼7.0 Hz, 1H), 1.60 (s, 3H), 1.54 (OH) (d, J¼3.0 Hz,
1H), 0.99 (d, J¼7.0 Hz, 3H), 0.88 (s, 9H), 0.82 (d,
J¼7.0 Hz, 3H); 13C NMR (125.8 MHz, CDCl3) d 140.3,
139.3, 124.5, 117.2, 83.6, 82.4, 64.5, 31.0, 28.5, 19.6,
18.5, 11.9, 10.0; HRMS m/z (ESI, M+Na+) calcd 263.1982
found 263.1982.
The (R,S) diastereomer was not independently synthesized;
however, those peaks which were resolvable from the
(R,R) diastereomer were 1H NMR (500 MHz, CDCl3)
d 5.56 (ddd, J¼17.0, 10.0, 9.0 Hz, 1H), 4.10 (dd, J¼9.0,
3.0 Hz, 1H), 1.07 (d, J¼6.0 Hz, 3H), 0.72 (d, J¼6.0 Hz, 3H).
4.3.2.17. (+)-Aceticacid 1-isopropyl-2-oxo-propyl ester
((+)-32).
The (ꢃ)-(R,S) diastereomer was not independently synthe-
sized; however, those peaks that were resolvable from the
(ꢃ)-(R,R) diastereomer were H NMR (500 MHz, CDCl3)
O
1
iPr
Me
d 4.05 (dd, J¼12.5, 5.5 Hz, 1H), 3.23 (d, J¼8.5 Hz, 1H),
0.97 (d, J¼6.5 Hz, 3H), 0.89 (s, 9H).
OAc
32
Compound 30B: IR 3462 (b, m), 2956 (s), 2870 (s), 2361
(w), 1670 (b, w), 1465 (m), 1364 (m), 1068 (s) cmꢂ1; the
diastereomers were not separated, peaks belonging to a spe-
cific diastereomer are indicated by subscript A or B, with
achiral phosphines A was the major product. 1H NMR
(500 MHz, CDCl3) d 5.72 (m, 1H), 5.61 (apparent q,
J¼6.5 Hz, 1H), 5.32A (dd, J¼10.5, 2.0 Hz, 1H), 5.31B (dd,
J¼10.5, 2.0 Hz, 1H), 5.21 (d, J¼17.5 Hz, 1H), 4.29B
(d, J¼11.0 Hz, 1H), 4.08A (d, J¼11.0 Hz, 1H), 3.94A (d,
J¼11.0 Hz, 1H), 3.74B (d, J¼11.0 Hz, 1H), 3.56 (q, J¼
7.0 Hz, 1H), 3.27B (d, J¼8.0 Hz, 1H), 3.23A (d, J¼8.0 Hz,
1H), 2.85B (OH) (d, J¼7.0 Hz, 1H), 2.82A (OH) (d,
J¼7.0 Hz, 1H), 1.80 (m, 1H), 1.66 (m, 3H), 1.63 (M, 1H),
1.03 (apparent t, J¼6.5 Hz, 3H), 0.90B (s, 9H), 0.89A
(s, 9H), 0.76 (apparent t, J¼6.0 Hz, 3H); no attempt was
made to specify which carbon signals belonged to each dia-
stereomer, there are exactly double the number of expected
signals for a single compound. 13C NMR (125.8 MHz,
CDCl3) d 137.3, 137.1, 135.9, 135.8, 126.8, 126.7, 119.5,
119.3, 90.6, 90.6, 84.4, 84.3, 65.0, 64.8, 34.6, 34.6, 32.5,
32.4, 26.4, 26.3, 19.9, 19.8, 19.3, 19.3, 13.4, 13.4; HRMS
m/z (ESI, M+Na+) calcd 263.1982 found 263.1986.
To a cold (0 ꢀC) solution of (ꢂ)-29A (35 mg, 0.165 mmol) in
DCM (1.5 ml) was added NEt3 (71 mL, 0.51 mmol), Ac2O
(24 mL, 0.25 mmol), and DMAP (2 mg, 0.016 mmol). The
mixture was warmed to room temperature and stirred for
1.5 h. At this point it was concentrated in vacuo and filtered
through silica eluting with 10:1 hexanes/ethyl acetate. This
afforded the crude acetate-protected product, which was
carried on to the ozonolysis without purification. The inter-
mediate was dissolved in DCM (3 mL) cooled to ꢂ78 ꢀC
and exposed to O3 until the reaction was dark blue. The
solution was then degassed with argon and PPh3 (600 mg)
was added. The reaction was allowed to warm to 0 ꢀC over
4 h, and then concentrated in vacuo. The crude material was
loaded onto a column (15:1 pentanes/DCM) with a minimal
amount of DCM and then eluted with 15:1 pentanes/DCM
until separation of PPh3 and byproducts was complete,
then column was flushed with 1:1 pentanes/diethyl ether to
give (+)-32 as a clear oil (15.1 mg, 58% over two steps).
1
[a]2D2 +6.7 (c 1.01, DCM); H NMR (500 MHz, CDCl3)
d 4.87 (d, J¼4.0 Hz, 1H), 2.24 (m, 1H), 2.17 (s, 3H), 2.16
(s, 3H), 1.01 (d, J¼7.0 Hz, 3H), 0.93 (d, J¼7.0 Hz, 3H);
13C NMR (125.8 MHz, CDCl3) d 205.6, 171.0, 83.0, 29.6,
27.2, 20.8, 19.4, 17.0.
4.3.2.16. 8-Ethyl-2,4-dimethyl-deca-4,9-dien-3-ol (37).
Compound (+)-32: Following the above procedure, 37
(42 mg, 0.2 mmol) was converted to (+)-32 (20.5 mg,
66%) over two steps. [a]2D2 +7.7 (c 1.4, DCM).
OH
iPr
Et
Me
37
Procedure A (no additive) (no EtOAc): 33 (68 mg,
0.5 mmol) was reacted with i-PrCHO (90 mL, 1.0 mmol) in
the presence of Ni(cod)2 (14 mg, 0.05 mmol) and Et3B
(0.15 mL, 1.0 mmol). Crude material was chromatographed
with 15:1 hexanes/diethyl ether/8:1 hexanes/ethyl acetate
Acknowledgements
This work was supported by the National Institute of General
Medical Science (GM-063755). We thank Dr. Li Li (MIT
Department of Chemistry Instrumentation Facility) for

7610
R. M. Moslin et al. / Tetrahedron 62 (2006) 7598–7610
J. Am. Chem. Soc. 2001, 123, 9174; (c) Nomura, N.; Tsurugi,
K.; RaganBabu, T. V.; Kondo, T. J. Am. Chem. Soc. 2004,
124, 5354.
obtaining mass spectrometry data. The MIT DCIF is sup-
ported in part by the NSF (CHE-9809061 and DBI-
9729592) and the NIH (1S10RR13886-01).
12. Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.;
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16. Hill, M. L.; Raphael, R. A. Tetrahedron 1990, 46, 4487.
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