A highly enantio- and diastereoselective 1,3-dimethylallylation of aldehydes

Article abstract of DOI:10.1016/j.tet.2006.07.070

A highly enantio- and diastereoselective pentenylation of aldehydes is described. The homoallylic alcohol derived from 1,3-dimethylallylation of (-)-menthone undergoes an efficient allyl-transfer reaction with a wide range of aliphatic aldehydes in the pr

Full text of DOI:10.1016/j.tet.2006.07.070

Tetrahedron 62 (2006) 11391–11396
A highly enantio- and diastereoselective 1,3-dimethylallylation
of aldehydes
y
*
Yu Yuan, Amy J. Lai, Christina M. Kraml and Chulbom Lee
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
Received 12 July 2006; revised 23 July 2006; accepted 24 July 2006
Available online 17 August 2006
Abstract—A highly enantio- and diastereoselective pentenylation of aldehydes is described. The homoallylic alcohol derived from 1,3-
dimethylallylation of (–)-menthone undergoes an efficient allyl-transfer reaction with a wide range of aliphatic aldehydes in the presence
of an acid catalyst to give rise to the corresponding 4-methyl-2(E)-penten-4-yl-5-ol products in good yields with high enantio- and 4,5-
syn-selectivities.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
as Hoffmann’s boronic ester 5.4 While this plan could indeed
be practiced, the high cost for the large-scale preparation and
reaction of 5 led us to explore an alternative approach.8 Not-
ing the allyl-transfer reactions developed by Nokami9 and
Loh,10 we sought to examine the prospect of extending these
methods to the synthesis of 6. Herein, we report the design,
synthesis, and application of a (–)-menthone-derived homo-
allylic alcohol that accomplishes an allyl-transfer reaction
with a range of aldehydes to provide 4-methyl-2-penten-4-
yl-5-ol systems with high stereoselectivities.
The stereocontrolled synthesis of homoallylic alcohols re-
mains an important subject in organic synthesis due to the
wide occurrence of these structural motifs in a number of
polyketide natural products. Moreover, homoallylic alcohols
can serve as aldol surrogates upon elaboration on the alkene
moiety,1 and as substrates for the Prins reaction that provides
tetrahydropyrans (Eq. 1).2 Accordingly, many methods have
been developed for the synthesis of homoallylic alcohols,
largely making use of the asymmetric allylation of alde-
hydes.3 However, rarely do these protocols allow for access
to a disubstituted homoallylic alcohol system (1, R1 and
R2sH),4,5 the precursor for a decorated bispropionate 2 or
tetrahydropyran 3. Thus, the development of an efficient
method for the preparation of substituted homoallylic alco-
hols with reliable control of stereochemistry would be of
significant synthetic value.
2. Results and discussion
The design of an allyl-transfer reagent was based on a
2-oxonia-[3,3]-sigmatropic rearrangement mechanism as
depicted in Scheme 2. In order to procure 12 (cf. 1, R1¼
R2¼CH3) with E- and syn-selectivities, the condensation
of the Z-configured 9 with an aldehyde would seem required
to achieve transfer of the pentenyl unit through a chair-like
transition state adopting the sterically demanding RL group
at an equatorial position. An additional consideration was
the utilization of a tertiary alcohol as the pentenyl donor,
which should establish a favorable equilibrium for the
product formation due to the stability of oxocarbenium ion
OH
R
O
R3
R2
OH OH
R2
R3
or
R
R1
ð1Þ
R
R1
R1 R2
2
OH
3
1
In our investigations aimed at the chemical synthesis of ken-
domycin,6 we envisioned that the C-aryl glycoside core
could be assembled by a Prins reaction with homoallylic
alcohol 6 and aromatic aldehyde 7 (Scheme 1).7 It was antic-
ipated that the requisite intermediate 6 would arise from the
asymmetric pentenylation of aldehyde 46 with a reagent such
ꢀ
intermediate 11 vis-a-vis that of 10. While the feasibility
of an allyl-transfer process had never been demonstrated
for the preparation of a disubstituted homoallylic alcohol
such as 12,11 the high levels of enantioselectivities,
observed in monosubstituted systems,9c,9d,10 held promise
for an analogous approach to stereospecific pentenyl-
transfer processes.
* Corresponding author. Tel.: +1 609 258 6253; fax: +1 609 258 6746;
e-mail: cblee@princeton.edu
AccelaPure Corporation.
The preparation of an appropriate pentenyl donor of general
type 9 was initiated by evaluating 1,3-dimethylallylation of
y
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.070

11392
Y. Yuan et al. / Tetrahedron 62 (2006) 11391–11396
O
X
Cy
OR
H
O
B
Cy
OH
O
RO
O
O
O
X
5
OR
7
OH
HO
OR
H
O
HO
Hoffmann Pentenylation
Prins Cyclization
O
H
O
R
4
O
6
OR
Kendomycin
8
Scheme 1. The Prins approach to the total synthesis of kendomycin.
O
O
H2O
H2O
RS RL
R
H
OH
OH
RL
RL
[3,3]
O
O
RL
RS
R
R
R
RS
10
RS
11
9
12
Scheme 2. Strategy for stereospecific pentenylation of aldehydes.
several chiral ketones, among which we focused on men-
thone due to its ready availability and the well established
stereochemical outcome in carbonyl addition processes.12
In practice, the addition of 1,3-dimethylallyl Grignard re-
agent 13a to (–)-menthone gave the desired alcohol 15a as
the major product along with minor diastereomers 15b–d
in a 10:2:1:2 ratio (Scheme 3). With titanium reagent
13b,9c,13 the diastereoselectivity was significantly increased
to a ratio of 30:4:1:2. Using these two protocols, 15a could
be obtained as a single isomer (>99%) in 30–40% yield after
simple chromatographic purification.14 The major isomer
15a appears to be derived from transition state 14a, in which
the 1,3-dimethylallyl unit adds to the carbonyl group via the
syn,anti conformation to minimize the gauche interactions
of the methyl group with the ligands that are more unfavor-
able than its A1,3 interaction with the hydrogen,13 thus form-
ing the Z geometry in 15a. It should also be noted that the
configuration of the carbinol center of 15a–d results from
the exclusive b-face attack of 13, as predicted on the basis
of the strong facial preference of (–)-menthone.12
stereoselectivities. The major diastereomers were uniformly
found to be of E-geometry and 4,5-syn-stereochemistry, and
enantiomerically pure as determined by chiral HPLC or chi-
ral SFC analysis (>99% ee). Typically, the reactions were
performed with 2.0 equiv of 15a and 10 mol % p-toluenesul-
fonic acid monohydrate in CH2Cl2 at ambient temperature
for 12 h. Lowering the amount of the pentenyl donor 15a
to 1.0 equiv resulted in diminished yields mainly due to
the competing Prins process of the product with the starting
aldehyde. Both linear and a-branched aldehydes worked
well, with the latter requiring longer reaction times (24–
48 h, entries 3 and 4). Notably, in addition to aldehyde
16e, its dimethyl acetal 16f also proved to be a viable sub-
strate for the reaction without deprotection, thus highlight-
ing an advantage unavailable from the pentenylboronate
addition method (entries 5 vs 6).4 Finally, aldehyde 4, the
intermediate used in our Prins approach to kendomycin,
participated well in the reaction providing the desired homo-
allylic alcohol 6 in 80% yield with 10:1 diastereoselectivity
(entry 8).
With homoallylic alcohol 15a in hand, we then tested its
capability to stereospecifically transfer the pentenyl group
to aldehydes. As illustrated in Table 1, a range of aldehydes
underwent the desired pentenylation process to give rise to
the corresponding adducts in good yields with high
Although the present reaction could be applied to a range of
substrates, it did not fare well with sterically hindered (16h),
a,b-unsaturated (16i), and aromatic (16j) aldehydes (Fig. 1).
In these cases, no or very low conversion (<15%) occurred
over a prolonged reaction time (>48 h).
L
L
M
M
O
O
OH
OH
L
L
L
THF
–78 °C
M
14a
14b
15a
15b
+
O
L
M
L
M
13a M = MgCl
13b M = Ti(O Pr)3
(–)-menthone
O
O
OH
OH
i
L
14c
14d
15c
15d
Scheme 3. Double stereodifferentiating 1,3-dimethylallyl addition to (–)-menthone.

Y. Yuan et al. / Tetrahedron 62 (2006) 11391–11396
Table 1. Stereospecific pentenyl-transfer reactions of 15a with aldehydes 16
11393
Entry
Aldehyde
Product
Yield (%)a
drb
erc
OH
O
Ph
1
71
17:1
>99:1
Ph
H
16a
17a
OH
O
TBDPSO
2
3
4
5
6
7
57
9:1
5:1
>99:1
>99:1f
—
TBDPSO
16b
H
17b
O
OH
H
64
16c
17c
O
OH
67 (81)d
>20:1g
H
H
TBDPSO
16d
TBDPSO
17d
O
79e
10:1
>99:1
>99:1
>99:1f
OH
16e
16f
16g
4
OMe
OMe
17e
66e
10:1
OH
O
69
11:1
H
O
17g
OH
H
8
80
10:1g
—
6
a
Isolated yield.
Diastereomeric ratio determined by 1H NMR.
Enantiomeric ratio determined by chiral HPLC or chiral SFC.
Yield based on the recovered aldehyde.
Combined yield of the mixture of two inseparable diastereomers.
b
c
d
e
f
Enantiomeric ratio determined as the corresponding benzoate ester.
Only two diastereomers were detected.
g
The proposed mechanism of the reaction is shown in Scheme
4, in which the stereospecific 1,3-dimethylallyl-transfer
from homoallylic alcohol 15a to an aldehyde is achieved
through a 2-oxonia-[3,3]-sigmatropic rearrangement.9,10
Under acid catalysis, alcohol 15a is condensed with the alde-
hyde to form oxocarbenium ion 18, which exists in fast equi-
librium with 19 via an oxonia-Cope process that involves
a chair-like transition state employing the R group at an
equatorial position. The more populated cation 19 is then
hydrolyzed to afford the homoallylic alcohol 12 and
(–)-menthone.15 This mechanism explains the E-olefin
geometry and syn-stereochemistry observed in the major
RCHO H2O
H
H
H
[3,3]
OH
O
O
R
R
15a
18
19
H2O
(–)-menthone
O
O
O
H
H
OH
H
HO
R
R
16h
16i
16j
12
Figure 1. Unreactive aldehydes.
Scheme 4. Proposed mechanism of pentenylation.

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Y. Yuan et al. / Tetrahedron 62 (2006) 11391–11396
diastereomer, and the attenuated reactivity of 15a toward the
aldehydes (cf. Fig. 1) that would have to generate a sterically
congested (R¼t-Bu) or too stable (R¼alkenyl, aromatic)
oxocarbenium ion 18.
15a (790 mg, 35% after a single separation; the mixed frac-
tions could be collected and further purified) as a colorless
liquid: [a]2D3 +6.2 (c 2.3, CHCl3); IR (film) 3010, 2953,
2869, 1456, 1378, 1178 cmꢀ1
;
1H NMR (500 MHz,
CDCl3) d 5.69 (dq, J¼10.9, 6.9 Hz, 1H), 5.38 (ddq,
J¼10.9, 10.2, 1.8 Hz, 1H), 3.07 (dq, J¼10.2, 6.9 Hz, 1H),
2.18 (m, 1H), 1.76 (m, 2H), 1.71 (dd, J¼6.8, 1.8 Hz, 3H),
1.53 (m, 2H), 1.40 (m, 1H), 1.31 (s, 1H), 1.29 (m, 1H),
1.01 (m, 1H), 0.96 (d, J¼6.9 Hz, 3H), 0.93 (d, J¼6.9 Hz,
3H), 0.91 (d, J¼7.0 Hz, 3H), 0.86 (d, J¼6.5 Hz, 3H), 0.83
(m, 1H); 13C NMR (75 MHz, CDCl3) d 132.6, 127.1,
77.25, 46.2, 41.7, 37.6, 35.6, 27.7, 25.5, 23.6, 22.9, 20.7,
18.1, 15.8, 13.6; HRMS-EI (m/z): [M]+ calcd for C15H28O
224.2140, found 224.2141.
3. Conclusion
In summary, an efficient and highly stereospecific penteny-
lation reagent for aldehydes has been developed. The
Z-homoallylic alcohol 15a readily prepared from (–)-men-
thone reacts smoothly with a range of aliphatic aldehydes
under operationally simple and mild acid-catalyzed condi-
tions to provide the corresponding 4-methyl-2-penten-4-yl-
5-ol product with high 2E- and 4,5-syn-selectivities.
4.2.2. Method B: synthesis of 15a by addition of titanium
reagent 13b to (–)-menthone. To a THF suspension of
magnesium powder (480 mg, 19.8 mmol) were added a
few drops of dibromoethane followed by slow addition of
dimethylallyl chloride12 (1.04 g, 10.0 mmol) at room tem-
perature. Upon completion of the addition, the suspension
was stirred for 1 h and filtered through a sintered glass funnel
under argon. The filtrate was slowly cannulated to a THF so-
lution of ClTi(OiPr)3 (1.0 M in THF, 10.0 mL, 10.0 mmol) at
ꢀ78 ꢁC. The resulting solution was stirred at ꢀ78 ꢁC for
additional 1 h, and a THF solution of (–)-menthone
(1.54 g, 10.0 mmol) was added dropwise. The reaction mix-
ture was stirred for an additional 4 h at ꢀ78 ꢁC and quenched
by aqueous NH4Cl. The aqueous layer was extracted with
EtOAc (3ꢂ25 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and
4. Experimental
4.1. General method
Unless otherwise noted, commercially available reagents
were used without further purification. Thin layer chromato-
graphy (TLC) was performed using Silicycle silica gel 60
F254 plates and visualized using UV light, anisaldehyde,
ceric sulfate or potassium permanganate. Flash chromato-
graphy was performed on Silicycle silica gel 60 (40–
63 mm). H and 13C NMR spectra were recorded in CDCl3
on a Varian Inova 400 MHz, 500 MHz or 600 MHz spec-
trometer. Chemical shifts in 1H NMR spectra were reported
in parts per million (ppm) on the d scale from an internal
1
1
1
standard of residual chloroform (7.27 ppm). Data for H
concentrated. The H NMR analysis of the crude product
NMR are reported as follows: chemical shift, multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet),
coupling constant in hertz (Hz), and integration. Data for
13C NMR spectra are reported in terms of chemical shift
in parts per million from the central peak of CDCl3
(77.23 ppm). Infrared (IR) spectra were recorded on a Nico-
let 730 FT-IR spectrometer and reported in frequency of the
absorption (cmꢀ1). High resolution mass spectra (HRMS)
were obtained from the Princeton University Mass Spec-
trometry Facility. Optical rotations were measured on a
Perkin–Elmer 341 polarimeter at 589 nm.
indicated 55% conversion and the diastereomeric ratio to
be 30:4:1:2. Purification of the major isomer by flash column
chromatography (silica gel, hexanes/toluene¼15/1 to 10/1 to
4/1) afforded analytically pure 15a (838 mg, 37% after a
single separation; the mixed fractions could be collected
and further purified) as a colorless liquid.
4.3. General procedure for homoallylic alcohol 17
synthesis (Table 1)
To a 1.0 mL CH2Cl2 solution of 15a (112 mg, 0.50 mmol)
and aldehyde 16 (0.25 mmol) was added TsOH$H2O
(4.8 mg, 0.025 mmol) at 25 ꢁC. This solution was stirred
for 12–24 h while the progress of the reaction was being
monitored by TLC. After complete consumption of alde-
hyde 16, the reaction mixture was concentrated, and the
crude product was analyzed by 1H NMR for the determina-
tion of the diasteromeric ratio (dr). Purification of the crude
product by flash column chromatography afforded alcohol
17 in a diastereomerically pure form. The enatiomeric ratio
(er) of the major diastereomer was determined by chiral
HPLC or chiral SFC.
4.2. Synthesis of 15a
4.2.1. Method A: synthesis of 15a by addition of Grignard
reagent 13a to (–)-menthone. To a THF suspension of
magnesium powder (480 mg, 19.8 mmol) were added a
few drops of dibromoethane followed by slow addition of
dimethylallyl chloride16 (1.04 g, 10.0 mmol) at room tem-
perature. Upon completion of the addition, the suspension
was cooled to 0 ꢁC, and a THF solution of (–)-menthone
(1.54 g, 10 mmol) was added dropwise. After 3 h at 0 ꢁC,
the reaction was quenched by the addition of saturated aque-
ous NH4Cl, and the layers were separated. The aqueous layer
was extracted with EtOAc (3ꢂ25 mL). The combined
organic layers were washed with brine, dried over anhydrous
4.3.1. (E)-(3R,4R)-4-Methyl-1-phenyl-hept-5-en-3-ol
(17a). Following the general procedure, the reaction of alde-
hyde 16a (34 mg, 0.25 mmol) with 15a gave alcohol 17a
(36 mg, 71%) as a colorless oil: dr¼17:1 by 1H NMR
(600 MHz); er>99:1 by chiral HPLC (Chiralpak AD, 10%
water in methanol, 1.0 mL/min, 4.40 min (+) isomer,
4.85 min for (ꢀ) isomer); [a]2D3 +35 (c 0.95, CHCl3); IR
1
Na2SO4, and concentrated. The H NMR analysis of the
crude product indicated 70% conversion of (–)-menthone
and the diastereomeric ratio to be 10:2:1:2. Separation of
the major isomer by flash column chromatography (silica
gel, hexanes/toluene¼15/1 to 10/1 to 4/1) afforded pure

Y. Yuan et al. / Tetrahedron 62 (2006) 11391–11396
11395
(film) 3396, 3026, 2933, 2879, 1496, 1453 cmꢀ1; 1H NMR
(500 MHz, CDCl3) d 7.31 (m, 2H), 7.23 (m, 3H), 5.53
(dqd, J¼15.2, 6.6, 0.9 Hz, 1H), 5.37 (ddq, J¼15.2, 7.6,
1.5 Hz, 1H), 3.49 (m, 1H), 2.88 (ddd, J¼13.8, 10.5,
5.2 Hz, 1H), 2.65 (ddd, J¼13.5, 9.8, 5.2 Hz, 1H), 2.27 (m,
1H), 1.83 (m, 1H), 1.70 (dd, J¼6.4, 0.6 Hz, 3H), 1.65 (m,
1H), 1.49 (s, 1H), 1.02 (d, J¼6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 142.6, 133.4, 128.7, 128.6, 126.5,
126.0, 74.6, 42.9, 35.9, 32.7, 18.3, 15.3; HRMS-EI (m/z):
[MꢀH2O]+ calcd for C14H18 186.1409, found 186.1410.
4.3.5. (E)-(2R,3R)-3-Methyl-1-phenyl-hex-4-en-2-ol
(17e). Following the general procedure, the reaction of alde-
hyde 16e (31 mg, 0.25 mmol) with 15a afforded a mixture of
alcohols 17e and its diastereomer of undetermined stereo-
chemistry (38 mg, 79%) as a colorless oil. The same alcohol
17e (48 mg, 66%) was obtained from the reaction of
dimethyl acetal 16f (42 mg, 0.25 mmol) with 15a according
to the general procedure: dr¼10:1 by 1H NMR (500 MHz);
er of the major alcohol 17e>99:1 by chiral HPLC (Chiralpak
AD, 10% water in methanol, 1.0 mL/min, 4.75 min (+) iso-
mer, 6.13 min for (ꢀ) isomer); [a]2D3 +6.6 (c 0.70, CHCl3);
[a]2D3 +43 (c 0.83, CHCl3); IR (film) 3441, 3027, 2963,
4.3.2. (E)-(3R,4R)-1-(tert-Butyldiphenylsilanyloxy)-4-
methyl-hept-5-en-3-ol (17b). Following the general proce-
dure, the reaction of aldehyde 16b17 (78 mg, 0.25 mmol)
with 15a afforded alcohol 17b (54 mg, 57%) as a colorless
oil: dr¼9:1 by 1H NMR (500 MHz); er>99:1 by chiral
SFC ((R,R) Whelk-01 (25ꢂ0.46 cm), 10% isopropanol
(0.1% DEA) in CO2 (100 bar), 3.0 mL/min, 3.26 min (ꢀ)
isomer, 3.57 min for (+) isomer); [a]2D3 +6.6 (c 0.70,
CHCl3); IR (film) 3510, 2860, 1470, 1430, 1110,
2917, 2880, 1495, 1453 cmꢀ1
;
1H NMR (500 MHz,
CDCl3) d 7.31 (m, 2H), 7.23 (m, 3H), 5.55 (dq, J¼15.2,
6.1 Hz, 1H), 5.45 (ddq, J¼15.2, 7.3, 1.2 Hz, 1H), 3.67 (m,
1H), 2.89 (dd, J¼13.8, 3.7 Hz, 1H), 2.58 (dd, J¼13.8,
9.5 Hz, 1H), 2.29 (m, 1H), 1.71 (d, J¼6.1 Hz, 3H), 1.52
(d, J¼4.0 Hz, 1H), 1.09 (d, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 139.4, 133.7, 129.5, 128.7, 126.5,
126.3, 76.3, 42.4, 41.0, 18.4, 15.6; HRMS-EI (m/z): [M]+
calcd for C13H18O 190.1358, found 190.1365.
1
1080 cmꢀ1; H NMR (500 MHz, CDCl3): d 7.67 (m, 4H),
7.42 (m, 6H), 5.46 (dqd, J¼15.3, 6.4, 0.7 Hz, 1H), 5.35
(ddq, J¼15.3, 7.9, 1.6 Hz, 1H), 3.85 (m, 2H), 3.68 (m,
1H), 3.10 (d, J¼3.1 Hz, 1H), 2.21 (m, 1H), 1.71 (m, 1H),
1.66 (d, J¼6.2 Hz, 3H), 1.62 (m, 1H), 1.05 (s, 9H), 1.03
(d, J¼6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 135.7,
133.8, 133.2, 129.9, 127.9, 125.6, 75.4, 63.8, 43.2, 35.8,
4.3.6. (E)-(2R,3R)-1-Cyclohexyl-3-methyl-hex-4-en-2-ol
(17g). Following the general procedure, the reaction of alde-
hyde 16g19 (26 mg, 0.21 mmol) with 15a afforded alcohol
17g (28 mg, 69%) as a colorless oil: dr¼11:1 by H NMR
1
(500 MHz); er>99:1 (determined as a benzoate ester) by
chiral HPLC (Chiralpak AD, 5% water in methanol,
1.0 mL/min, 5.34 min (+) isomer, 6.02 min for (ꢀ) isomer);
[a]2D3 +44 (c 0.42, CHCl3); IR (film) 3370, 2920, 2850, 1450,
990, 970; 1H NMR (500 MHz, CDCl3): d 5.50 (ddq, J¼15.3,
6.4, 0.9 Hz, 1H), 5.37 (ddq, J¼15.3, 7.6, 1.5 Hz, 1H), 3.57
(m, 1H), 2.19 (m, 1H), 1.81 (app. d, J¼12.8 Hz, 1H), 1.69
(d, J¼6.1 Hz, 3H), 1.69–1.63 (m, 4H), 1.45 (m, 1H), 1.33–
1.10 (m, 6H), 0.91 (m, 1H), 0.97 (d, J¼7.0 Hz, 3H), 0.82
(m, 1H); 13C NMR (125 MHz, CDCl3); d 133.5, 126.1,
72.3, 42.9, 41.6, 34.6, 34.2, 32.7, 26.7, 26.5, 26.2, 18.2,
14.8; HRMS-EI (m/z): [MꢀH2O]+ calcd for C13H22
178.1721, found 178.1712.
t
26.9, 19.2, 18.2, 16.0; HRMS-EI (m/z): [Mꢀ Bu]+ calcd
for C20H25O2Si 325.1624, found 325.1606.
4.3.3. (E)-(1R,2R)-1-Cyclohexyl-2-methyl-pent-3-en-1-ol
(17c). Following the general procedure, the reaction of alde-
hyde 16c (28 mg, 0.25 mmol) with 15a afforded alcohol 17c
(29 mg, 64%) as a colorless oil: dr¼5:1 by 1H NMR
(500 MHz); er>99:1 by chiral HPLC (Chiralpak AD, 5%
water in methanol, 1.0 mL/min, 5.12 min (ꢀ) isomer,
5.71 min for (+) isomer); [a]2D3 +26 (c 0.35, CHCl3); IR
1
(film) 3390, 2930, 2850, 1450, 980, 970 cmꢀ1; H NMR
(500 MHz, CDCl3); d 5.48 (dqd, J¼15.3, 6.1, 1.0 Hz, 1H),
5.40 (ddq, J¼15.4, 6.7, 1.5 Hz, 1H), 3.14 (t, J¼5.8 Hz,
1H), 2.34 (m, 1H), 1.90 (m, 1H), 1.74 (m, 2H), 1.68 (dd,
J¼6.1, 1.3 Hz, 3H), 1.64 (m, 1H), 1.58 (m, 1H), 1.46 (s,
1H), 1.40 (m, 1H), 1.29–0.94 (m, 5H), 0.97 (d, J¼6.7 Hz,
3H); 13C NMR (125 MHz, CDCl3): d 134.8, 125.3, 79.2,
40.4, 38.9, 29.9, 28.2, 26.7, 26.5, 26.2, 18.3, 13.8; HRMS-
EI (m/z): [M]+ calcd for C12H22O 182.1671, found 182.1674.
4.3.7. (E)-(4R,5R,8S)-4,8-Dimethyl-undec-2-en-9-yn-5-ol
(6). Followingthegeneralprocedure, thereactionofaldehyde
46 (99 mg, 0.80 mmol) with 15a afforded alcohol 6 (125 mg,
1
80%) as a colorless oil: dr¼10:1 by H NMR (500 MHz);
[a]2D3 +51 (c 0.45, CHCl3); IR (film) 3392, 2964, 2931,
2858, 1451, 1429, 1376 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 5.52 (dqd, J¼15.3, 6.1, 0.9 Hz, 1H), 5.39 (ddq, J¼15.3,
6.6, 1.5 Hz, 1H), 3.46 (m, 1H), 2.42 (m, 1H), 2.25 (m, 1H),
1.79 (d, J¼2.4 Hz, 3H), 1.70 (dd, J¼6.1, 1.5 Hz, 3H), 1.38–
1.64 (m, 5H), 1.15 (d, J¼7.0 Hz, 3H), 1.01 (d, J¼7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 133.7, 126.3, 83.8,
76.1, 75.0, 42.8, 33.7, 31.7, 26.0, 21.7, 18.3, 15.1, 3.7;
HRMS-EI (m/z): (the corresponding TBS ether) [MꢀMe]+
calcd for C18H33OSi 293.2301, found 293.2290.
4.3.4. (E)-(2S,3S,4R)-2-(tert-Butyldiphenylsilanyloxy)-4-
methyl-hept-5-en-3-ol (17d). Following the general proce-
dure, the reaction of aldehyde 16d18 (78 mg, 0.25 mmol)
with 15a afforded alcohol 17d (64 mg, 67%) as a colorless
1
oil: dr>20:1 by H NMR (600 MHz); [a]2D3 +5.42 (c 1.53,
CHCl3); IR (film) 3561, 2961, 2931, 2858, 1427,
1
1112 cmꢀ1; H NMR (500 MHz, CDCl3) d 7.70 (m, 4H),
7.42 (m, 6H), 5.27 (dq, J¼15.3, 6.1 Hz, 1H), 5.19 (ddq,
J¼15.3, 7.6, 1.5 Hz, 1H), 3.93 (qd, J¼6.4, 3.3 Hz, 1H),
3.05 (td, J¼7.6, 3.3 Hz, 1H), 2.44 (d, J¼7.6 Hz, 1H), 2.28
(m, 1H), 1.56 (d, J¼6.1 Hz, 3H), 1.08 (s, 9H), 1.05 (d,
J¼6.4 Hz, 3H), 1.02 (d, J¼6.7 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 136.2, 136.1, 134.5, 134.3, 133.4,
130.0, 129.8, 127.9, 127.6, 125.4, 79.7, 70.4, 40.3, 27.3,
Acknowledgements
We thank the NIH-NIGMS (GM 073065) for financial
support of this work. A.J.L. thanks Princeton University
for support through the Princeton Undergraduate Research
Program. AccelaPure Corporation is gratefully acknowl-
edged for chiral HPLC and chiral SFC services.
t
21.2, 19.6, 18.2, 16.5; HRMS-EI (m/z): [Mꢀ Bu]+ calcd
for C20H25O2Si 325.1624, found 325.1626.

11396
Y. Yuan et al. / Tetrahedron 62 (2006) 11391–11396
Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118,
12475–12476.
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