Practical synthesis of 1,5-dimethyl substituted conjugated polyenes from geranyl acetate

Article abstract of DOI:10.1016/j.tet.2008.03.094

A protocol to synthesize 1,5-dimethyl substituted conjugated polyenes via dehydrogenation of geranyl acetate was established. C₅ unit elongation to multi-1,5-dimethyl substituted conjugated polyenes was also achieved via Horner-Wadsworth-Emmons

Full text of DOI:10.1016/j.tet.2008.03.094

Tetrahedron 64 (2008) 4972–4978
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Practical synthesis of 1,5-dimethyl substituted conjugated
polyenes from geranyl acetate
*
Yu-Jun Zhao, Teck-Peng Loh
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A protocol to synthesize 1,5-dimethyl substituted conjugated polyenes via dehydrogenation of geranyl
acetate was established. C5 unit elongation to multi-1,5-dimethyl substituted conjugated polyenes was
also achieved via Horner–Wadsworth–Emmons olefination in good yields and good selectivities.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 December 2007
Received in revised form 10 March 2008
Accepted 27 March 2008
Available online 3 April 2008
Keywords:
Elimination
Olefination
Conjugated
Terpenoids
Natural Products
1. Introduction
lycopenes,3 calbistrins,4 retinoids and carotenoids5 that possess
interesting biological activities (Fig. 1). In the course of making
There is a large and diverse group of natural products containing
the 1,5-dimethyl substituted conjugated polyene unit. Some of
these natural products include malabaricanes,1 isomalabaricanes,2
some of these natural products, we are interested to develop
a practical synthesis for the preparation of multi-1,5-dimethyl
substituted type conjugated polyenes.
O
O
H
HO
OH
MeOCO
H
Paracentrone
Stellettin H
OH
O
O
HO
O
H
O
CO2H
O
CO2H
H
O
H
Calbistrin A
Rhabdastrellic Acid A
CO2H
Figure 1.
* Corresponding author. Tel.: þ65 6316 8899; fax: þ65 6791 1961.
E-mail address: teckpeng@ntu.edu.sg (T.-P. Loh).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.094

Y.-J. Zhao, T.-P. Loh / Tetrahedron 64 (2008) 4972–4978
4973
Table 1
AcO
AcO
AcO
Coupling reactions of 8-methoxy-8-oxo-dehydrogeranal
NaClO2 3.0 equiv
NaH2PO4 3.0 equiv
SeO2 1.5 equiv
EtOH 95%
Ylid 2.0 equiv
2-Isopentene 4.0 equiv
Base 1.5 equiv
-78 °C 12 hr
MeO2C
X
R
MeO2C
O
tBuOH
reflux 1 h
44% yield
20% Alcohol
rt 24 h
or Phosphate 2.0 equiv
Base 1.5 equiv, -78 °C
then 0 °C to rt 12 hr
or Amine 1.0 equiv
94% yield
3
2
1
CO2H
O
AcO
AcO
Na2SO4 THF rt, 12 hr
SeO2 1.0 equiv
EtOH 95%
DCC 1.5 equiv
MeOH rt 1 day
85% yield
reflux 16 h
54% yield
recover SM
41% yield
Entry
1c
Reagent
Yielda (%)
Ratiob
85:15
76:24e
OH
5
4
80
95
Ph3P
ClPh3P
CO2Me
Ph
CO2Me
CO2Me
AcO
2c
1.MsCl 3.0 equiv
Py 5.0 equiv
rt 6 h
HO
K2CO3
MeOH
rt 16 h
88% yield
PhO2S
3c
4c
Et
PPh3Br
52
91
55:45
83:17
1. PBr3 Et2O
0 °C to rt, 6 h
2.DBU 2.0 equiv
Toluene
BrPh3P
Ph
CO2Me
2. PhSO2Na 1.5 equiv
DMF rt, 24 h
90% yield, 2 steps
E:Z = 83:17
reflux 1.5 h
51% yield
5d
6e
90
88:12
79:21
6
(EtO)2OP
7
9
CO2Me
over 2 steps
CO2Me
Ph NH2
OH
88f
E:Z = 84:16
CO2Me
IBX 2.0 equiv
Py 2.0 equiv
DMSO rt 1 h
Yield: 95%
7e
95f
86:14
(S)
H2N
Ph
(R)
E:Z = 85:15
a
Isolated yield unless otherwise stated.
b
c
d
e
f
Ratio was determined by 1H NMR and/or 13C NMR.
Wittig reaction with corresponding ylide.
HWE olefination with corresponding phosphate.
Schiff base formation.
MeO2C
O
8
Over all 8 steps, 14% yield, 2.05g
Crude yield.
Scheme 1.
conjugated polyene compounds (Table 1) or elongated to multi-
1,5-dimethyl substituted conjugated polyenes (Scheme 3). Before
we proceeded to C5 chain elongation, a model study was carried
out. To our delight, olefination reaction proceeded smoothly with
good yields and good selectivities using acceptor synthon 8.
These results are shown in Table 1. From the single crystal X-ray
structure of A10 (Table 1, entry 1), we were able to further trace
back and confirm the stereochemistry of the major isomer of 8. It
was found that all double bonds adopted the E conformation
(Fig. 2).
With this information in hand, we further proceeded to
investigate C5 unit elongation of 8 to construct multi-1,5-dimethyl
substituted conjugated polyenes. Prenyl acetate is a naturally
abundant hemiterpene and has been used as C5 elongation unit
synthon by Rein and Akermark.11 However, phosphate 14 they
obtained was a mixture of isomers (E/Z¼55:45), which resulted in
moderate selectivity of the corresponding HWE olefination.11 We
solved the problem by using SeO2 promoted selective allylic
oxidation of prenyl acetate, under which conditions E-alcohol 11
Nature uses isopentenyl pyrophosphate (IPP) or dimethylallyl
pyrophosphate (DMAP) as building blocks for the synthesis of
conjugated polyene chain. Enzymes assemble these basic C5 units
providing a diverse range of isoprenoids.6 The most common
strategies employed by chemists to access 1,5-dimethyl substituted
conjugated polyenes involve the use of the Wittig reaction, Horner–
Wadsworth–Emmons (HWE) reaction, Julia olefination and tran-
sition metal catalyzed cross-coupling reactions.7 Recently, Koo et al.
reported an efficient synthesis of a carotenoidal conjugated polyene
chain structure using 4-bromo-3-methyl-2-butenyl phenyl sulfide
as a chain-extension C5 unit.8 However, protocols using natural
occurring unsaturated polyene backbone for the construction of
conjugated polyene skeletons are still rare. Herein, we present the
synthesis of multi-1,5-dimethyl substituted conjugated polyenes
using dehydrogenated geranyl acetate 6 (Scheme 1).
2. Results and discussion
Dehydrogenated geranyl acetate 6 was synthesized in five steps
from naturally occurring geranyl acetate 1 as shown in Scheme 1. In
our synthetic route, allylic oxidations using SeO2 were employed
twice.9 Aldehyde 2 was obtained as major product in 44 % yield
together with the corresponding alcohol in 20% yield. This alcohol
can be easily recycled to the desired aldehyde 2. On the other hand,
alcohol9b 5 was obtained as major product in 54% yield (starting
material recovered in 41% yield). Efforts to increase the yield by
prolonging reaction time and loading excess of SeO2 resulted in the
increase in over-oxidized ketone side product. Acetate 6 was then
converted to aldehyde 8 in another two steps. Overall, aldehyde 8
was obtained in 14% yield over eight steps (2.05 g, isomer
ratio¼85:15).
MeO2C
CO2Me
A
The aldehyde 8 (8-methoxy-8-oxo-dehydrogeranal) is a versa-
tile intermediate, which can be readily converted to different
Figure 2.

4974
Y.-J. Zhao, T.-P. Loh / Tetrahedron 64 (2008) 4972–4978
1. MsCl 1.1 equiv
performed using Merck 60 F254 precoated silica gel plate (0.2 mm
thickness). Subsequent to elution, plates were visualized using UV
radiation (254 nm) on Spectroline Model ENF-24061/F 254 nm.
Further visualization was possible by staining with basic solution of
potassium permanganate or acidic solution of ceric molybdate,
followed by heating on a hot plate. Flash chromatography was
performed using Merck silica gel 60 with distilled solvents.
Columns were typically packed as slurry and equilibrated with
hexane prior to use. Infrared spectra were recorded on a Shimadzu
IR Prestige-21 FT-IR Spectrometer. Liquid samples were examined
as film between NaCl or KBr salt plates. Proton nuclear magnetic
1. SeO2 1.0 equiv
EtOH
Et3N 1.2 equiv
Py 1.5 equiv
DMF rt, 12 h
OAc
OAc
OAc
reflux 12 h
2. NaBH4 1.0 equiv
0 °C to rt 12 h
42% yield, 2 steps
2. (EtO)3P
reflux 12 h
60% yield
O
P OEt
OEt
OH
10
11
12
over two steps
IBX 2.0 equiv
DMSO rt
OH
DIBAL-H
2.0 equiv
30 min
O
-78 °C 5 h
52% yield
80% yield
O
P OEt
OEt
O
P OEt
OEt
resonance (1H NMR) and carbon nuclear magnetic resonance (13
C
13
14
NMR) spectroscopy were performed on a Bruker Advance 300, 400
and 500 NMR spectrometers. Low resolution mass spectrum anal-
ysis was performed on Finnigan polaris Q, GC–MS XP mass spec-
trometer (Thermo Electron Corporation). High resolution mass
spectral analysis (HRMS) was performed on Finnigan MAT 95 XP
mass spectrometer (Thermo Electron Corporation). X-ray crystal-
lography analysis was performed on Bruker X8 APEX X-ray
diffractometer.
Scheme 2.
was obtained almost exclusively. Over another three steps of
reaction (Scheme 2), we were able to synthesize phosphonate 14 in
an excellent isomer ratio (E/Z¼96:4).
With the C5 unit 14 synthon in hand, we successfully elongated
aldehyde 8 using Horner–Wadsworth–Emmons olefination to form
12-methoxy-12-oxo-dehydrofarnesal (15) (Scheme 3). After that,
we further elongated aldehyde 15 to form 16-methoxy-16-oxo-
dehydrogeranylgeranal (16). Both elongations proceeded with good
yields and good selectivities. It is worth noting that the corre-
sponding imines were obtained after the reaction. The imines were
converted to the desired aldehyde during silica gel flash chroma-
tography purification.
4.2. Synthesis of 8-methoxy-8-oxo-dehydrogeranal (8)
4.2.1. (2E,6E)-8-Acetoxy-2,6-dimethylocta-2,6-dienoic aldehyde (2)
To a round-bottom flask equipped with a magnetic stirring bar
were added geranyl acetate 1 (9.75 g, 50 mmol, 1.0 equiv), SeO2
(11.91 g, 100 mmol, 2.0 equiv) and EtOH (95%, 250 mL). The mixture
was heated at reflux for 2 h. The mixture was diluted with ethyl
acetate (200 mL). The aqueous layer was extracted with ethyl
acetate (3ꢀ50 mL) and the combined organic layers were washed
with brine (3ꢀ100 mL). The organic layer was dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The residual crude
product was purified by flash column chromatography to afford
desired aldehyde 3 in 44% yield as a colourless oil. The corre-
sponding alcohol was also isolated in 20% yield. All spectra data of
aldehyde 2 match the previous reported results.12
1. Phosphonate 14 2.0 equiv
BnNH2 2.0 equiv
THF 30 min
MeO2C
O
8
2. 2.0 equiv LiHMDS
MS 4Å 0.1 g
-78 °C to rt 12 h
75% yield
Isomer ratio: 96:4
15
4.2.2. (2E,6E)-8-Acetoxy-2,6-dimethylocta-2,6-dienoic acid (3)
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar were added aldehyde 2 (5.45 g, 26 mmol, 1.0 equiv),
2-methyl-2-butene (200 mL) and tBuOH (200 mL). The mixture was
cooled to 0 ꢁC and a mixture of NaH2PO4 (42 g, 350 mmol, 13 equiv)
and NaClO2 (70% technical grade, 42 g, 33 mmol, 13 equiv) aqueous
solution was added via pressure-equilibrating dropping funnel at
0 ꢁC. The reaction mixture was gradually warmed up to room tem-
perature and was stirred for another 12 h. The mixture was diluted
with ethyl acetate (200 mL). The aqueous layer was extracted with
ethyl acetate (3ꢀ50 mL) and the combined organic layers were
washed with water (50 mL) and brine (50 mL). The organic layer was
dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
The residual crude product was purified by flash column chroma-
tography to afford acid 3 in 94% yield as a colourless oil. Rf: 0.25
(hexane/ethyl acetate¼4:1).1H NMR (400 MHz, CDCl3): 10.0–9.0 (br,
1H, CO2H), 6.83 (t, J¼7.2 Hz,1H, C]CH), 5.34 (t, J¼6.9 Hz,1H, C]CH),
4.58 (d, J¼7.2 Hz, 2H, CH2OAc), 2.31 (q, J¼7.4 Hz, 2H, ]CH–CH2), 2.15
(t, J¼7.4 Hz, 2H, CH2–C(Me)]CH), 2.02 (s, 3H, C(O)–Me), 1.80 (s, 3H,
Me), 1.69 (s, 3H, Me). 13C NMR (100 MHz, CDCl3): 173.3, 171.2, 143.9,
140.9, 127.5, 119.2, 61.2, 37.8, 27.0, 21.0, 16.4, 12.0. HRMS (CI): m/z
calculated for C12H17O4 [MꢂH]þ: 225.1127, found [MꢂH]þ: 225.1123.
1. Phosphonate 14 2.0 equiv
BnNH2 2.0 equiv
THF 30 min
MeO2C
O
2. 2.0 equiv LiHMDS
MS 4Å 0.1 g
16
-78 °C to rt 12 h
83% yield
Isomer ratio: 72:28
Scheme 3.
3. Conclusion
In conclusion, we have developed a new protocol to carry out
large-scale preparation of 1,5-dimethyl substituted conjugated
polyene via dehydrogenation of geranyl acetate. In addition, elon-
gation of 8-methoxy-8-oxo-dehydrogeranal to multi-1,5-dimethyl
substituted conjugated polyenes using Horner–Wadsworth–
Emmons olefination was also achieved in good yields and good
selectivities. Efforts to utilize them for the synthesis of natural
products are in progress.
4. Experimental section
4.1. General
FTIR (KBr): n 3439 (br), 2980, 1720 (br), 1640 cmꢂ1
.
4.2.3. (2E,6E)-Methyl 8-acetoxy-2,6-dimethylocta-2,6-dienoate (4)
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar were added acid 3 (10.69 g, 47.2 mmol, 1.0 equiv) and
DMAP (610 mg, 5.0 mmol, 0.1 equiv). The mixture was azeotropi-
cally dried with dry THF (2ꢀ20 mL). Anhydrous methanol (40 mL)
All reagents were of the highest purity available, obtained from
commercial suppliers and used as received. Solvents were of
analytical grade. Analytical thin layer chromatography (TLC) was

Y.-J. Zhao, T.-P. Loh / Tetrahedron 64 (2008) 4972–4978
4975
and THF (100 mL) wereadded via syringe. The mixturewas cooled to
0 ꢁC and DCC (1.0 M solution in CH2Cl2, 70 mL, 70 mmol, 1.50 equiv)
was added via pressure-equilibrating dropping funnel over 30 min.
The reaction mixture was gradually warmed to room temperature
and was stirred for another 24 h. The reaction mixture was con-
centrated in vacuo. The mixture was diluted with hexane (200 mL)
and filtered through a pad of CeliteÒ. The CeliteÒ was washed with
hexane (2ꢀ200 mL). The combined organic layers were concen-
trated in vacuo. The residual crude product was purified by flash
column chromatography to afford ester 4 in 85% yield as a colourless
oil. Rf: 0.75 (hexane/ethyl acetate¼4:1). 1H NMR (400 MHz, CDCl3):
6.69 (td, J¼7.4, 1.5 Hz, 1H, ]CH), 5.34 (tq, J¼7.0, 1.2 Hz, 1H, ]CH),
4.56 (d, J¼6.9 Hz, 2H, CH2–OAc), 3.71 (s, 3H, OMe), 2.29 (q, J¼7.4 Hz,
2H, ]CH–CH2), 2.14 (t, J¼7.5 Hz, 2H, CH2–C(Me)]CH), 2.03 (s, 3H,
C(O)Me),1.81 (s, 3H, Me),1.70 (s, 3H, Me).13C NMR (100 MHz, CDCl3):
171.1, 168.5, 141.4, 141.0, 127.9, 119.1, 61.2, 51.7, 38.0, 26.8, 21.0, 16.4,
12.4. HRMS (CI): m/z calculated for C13H21O4 [MþH]þ: 241.1440,
138.3, 138.0, 128.5, 127.1, 124.0, 61.06, 51.8, 20.9, 12.8, 12.6. HRMS
(CI): m/z calculated for C13H18O4 [M]þ: 238.1205, found: 238.1210.
FTIR (KBr): n 1760 (br), 1699, 1616, 1543 cmꢂ1
.
4.2.6. (2E,4E,6E)-Methyl 8-hydroxy-2,6-dimethylocta-
2,4,6-trienoate (7)
To a round-bottom flask equipped with a magnetic stirring bar
were added ester 6 (3.02 g, 12.7 mmol, 1.0 equiv) and MeOH
(100 mL). The mixturewas cooled to 0 ꢁC and K2CO3 (7.18 g, 52 mmol,
4.0 equiv)wasadded. The reactionmixturewasgradually warmedup
to room temperature and was stirred for another 24 h. The mixture
was poured into ice water (100 mL). The aqueous layer was extracted
with ethyl acetate (3ꢀ50 mL) and the combined organic layers were
washed with water (50 mL) and brine (50 mL). The organic layer was
dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The
residual crude product was purified by flashcolumn chromatography
to afford alcohol 7 in 88% yield as a colourless oil. Rf: 0.13 (hexane/
ethyl acetate¼4:1). Major isomer: 1H NMR (400 MHz, CDCl3): 7.29–
7.22 (m, 1H, ]CH), 6.59–6.43 (m, 2H, CH]CH), 5.83 (t, J¼6.7 Hz, 1H,
]CH–CH2), 4.34 (d, J¼6.7 Hz, 2H, CH2–OH), 3.76 (s, 3H, OMe),1.98 (s,
3H, Me), 1.86 (s, 3H, Me). 13C NMR (100 MHz, CDCl3): 168.9, 143.3,
138.7,135.8,134.3,126.7,123.4, 59.5, 51.8,12.80,12.56. HRMS (CI): m/z
calculated for C11H16O3 [M]þ: 196.1089, found: 196.1088. FTIR (KBr): n
found [MþH]þ: 241.1339. FTIR (KBr): n 1760, 1705 (br), 1651 cmꢂ1
.
4.2.4. (2E,6E)-Methyl 8-acetoxy-5-hydroxy-2,6-
dimethylocta-2,6-dienoate (5)
To a round-bottom flask equipped with a magnetic stirring bar
were added ester
4 (9.6 g, 40 mmol, 1.0 equiv), SeO2 (4.4 g,
40 mmol, 1.0 equiv) and ethanol (200 mL, 95%). The mixture was
heated at reflux for 24 h. The mixture was diluted with ethyl acetate
(100 mL). The organic layer was washed with brine (3ꢀ50 mL). The
organic layer was dried over anhydrous Na2SO4, filtered and con-
centrated in vacuo. The residual crude product was purified by flash
column chromatography to afford alcohol 5 in 54% yield as a col-
ourless oil. Rf: 0.55 (hexane/ethyl acetate¼4:1). 1H NMR (400 MHz,
CDCl3): 6.74 (t, J¼7.1 Hz, 1H, ]CH), 5.62 (t, J¼6.6 Hz, 1H, ]CH), 4.62
(d, J¼6.7 Hz, 2H, CH2OAc), 4.17 (t, J¼6.3 Hz, 1H, OCH), 3.73 (s, 3H,
OMe), 2.44 (t, J¼7.1 Hz, 2H, ]CH–CH2), 2.06 (s, 3H, C(O)Me), 1.85 (s,
3H, Me), 1.72 (s, 3H, Me). 13C NMR (100 MHz, CDCl3): 171.0, 168.3,
142.3, 137.7, 129.7, 120.2, 75.6, 60.8, 51.8, 34.5, 21.0, 12.7, 12.3. HRMS
(CI): m/z calculated for C13H21O5 [MþH]þ: 257.1389, found [MþH]þ:
3427 (br), 1629 (br), 1508 cmꢂ1
.
4.2.7. (2E,4E,6E)-Methyl 2,6-dimethyl-8-oxoocta-2,4,6-trienoate
(8-methoxy-8-oxo-dehydrogeranal) (8)
To a round-bottom flask equipped with a magnetic stirring bar
were added alcohol 7 (2.19 g, 11.1 mmol, 1.0 equiv) and DMSO
(50 mL). The mixture was cooled to 0 ꢁC and IBX (6.22 g, 22.2 mmol,
2.0 equiv) was added. The reaction mixture was gradually warmed
up to room temperature and was allowed to stir for another 3 h. The
mixture was poured into ice water (100 mL). The aqueous layer was
extracted with ethyl acetate (3ꢀ50 mL) and the combined organic
layers were washed with water (50 mL) and brine (50 mL). The
organic layer was dried over anhydrous Na2SO4, filtered and con-
centrated in vacuo. The residual crude product was purified by flash
column chromatography to afford aldehyde 8 in 95% yield (2.05 g) as
a yellow solid, mp 82–83 ꢁC. Isomer ratio¼85:15. Rf: 0.25 (hexane/
ethyl acetate¼4:1). Major isomer: 1H NMR (400 MHz, CDCl3): 10.16
(d, J¼7.9 Hz, 1H, CHO), 7.29 (d, J¼11.1 Hz, 1H, ]CH), 7.20 (dd, J¼15.2,
11.1 Hz,1H, ]CH), 6.63 (d, J¼15.2 Hz,1H, ]CH), 6.06 (d, J¼7.9 Hz,1H,
]CH), 3.80 (s, 3H, OMe), 2.35 (s, 3H, Me), 2.06 (s, 3H, Me). 13C NMR
(100 MHz, CDCl3): 191.2, 168.3, 153.0, 141.2, 136.8, 131.3, 131.2, 130.2,
52.1, 13.2, 13.0. HRMS (CI): m/z calculated for C11H14O3 [M]þ:
257.1390. FTIR (KBr): n 1760, 1695 (br), 1655 cmꢂ1
.
4.2.5. (2E,4E,6E)-Methyl 8-acetoxy-2,6-
dimethylocta-2,4,6-trienoate (6)
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar were added alcohol 5 (6.41 g, 25.0 mmol, 1.0 equiv),
pyridine (8.1 mL, 100 mmol, 4.0 equiv) and CH2Cl2 (100 mL). The
mixture was cooled to 0 ꢁC and MeSO2Cl (5.8 mL, 75 mmol,
3.0 equiv) was added via syringe. The reaction mixture was grad-
ually warmed to room temperature and was stirred for another 6 h.
The mixture was poured into ice water (100 mL). The aqueous layer
was extracted with ethyl acetate (3ꢀ50 mL) and the combined or-
ganic layers were washed with saturated NaHCO3 aqueous solution
(100 mL), water (50 mL) and brine (50 mL). The organic layer was
dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
The residual crude product was purified by flash column chroma-
tography to afford a mixture of corresponding allylic chloride and
the desired alkene 5 as a colourless oil. The mixture was dissolved
in toluene (100 mL) and DBU (5.6 mL, 50 mmol, 2.0 equiv) was
added via syringe. The reaction mixture was heated at reflux for
1.5 h. The mixture was diluted with CH2Cl2 (3ꢀ100 mL). The or-
ganic layer was washed with brine (50 mL). The organic layer was
dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
The residual crude product was purified by flash column chroma-
tography to afford ester 6 in 51% yield as a colourless oil. Isomer
ratio¼84:16. Rf: 0.76 (hexane/ethyl acetate¼4:1). Major isomer: 1H
NMR (400 MHz, CDCl3): 7.24 (d, J¼7.9 Hz, 1H, ]CH), 6.55–6.50 (m,
2H, CH]CH), 5.75 (t, J¼6.9 Hz,1H, ]CH–CH2), 4.74 (d, J¼6.9 Hz, 2H,
CH2OAc), 3.76 (s, 3H, OMe), 2.07 (s, 3H, C(O)Me), 1.99 (s, 3H, Me),
1.89 (s, 3H, Me). 13C NMR (100 MHz, CDCl3): 170.8, 168.7, 142.6,
194.0943, found: 194.0937. FTIR (KBr): n 1707, 1654 (br) cmꢂ1
(2E,4Z,6E)-Methyl 2,6-dimethyl-8-oxoocta-2,4,6-trienoate.
.
A
colourless oil, minor isomer. Rf: 0.27 (hexane/ethyl acetate¼4:1). 1H
NMR (400 MHz, CDCl3): 10.21 (d, J¼7.6 Hz, 1H, CHO), 7.53 (d,
J¼15.1 Hz, 1H, ]CH), 7.32 (dq, J¼11.5, 1.2 Hz, 1H, ]CH), 6.89 (dd,
J¼15.1, 11.5 Hz, 1H, ]CH), 5.97 (d, J¼7.6 Hz, 1H, ]CH), 3.80 (s, 3H,
OMe), 2.16 (d, J¼1.2 Hz, 3H, Me), 2.05 (d, J¼1.2 Hz, 3H, Me). 13C NMR
(100 MHz, CDCl3): 189.02, 167.7, 152.4, 136.7, 132.6, 131.4, 130.9,
129.9, 52.4, 21.5, 13.8. HRMS (CI): m/z calculated for C11H14O3 [M]þ:
194.0943, found: 194.0947. FTIR (KBr): n 1764, 1644 (br) cmꢂ1
.
4.2.8. (2E,4E,6E)-Methyl 2,6-dimethyl-8-(phenylsulfonyl)octa-
2,4,6-trienoate (9)
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar were added alcohol 7 (500 mg, 2.5 mmol,1.0 equiv) and
Et2O (20 mL). The mixture was cooled to 0 ꢁC and PBr3 (0.25 mL,
1.1 equiv, 2.7 mmol) was added. The reaction mixture was gradually
warmed to room temperature and was allowed to stir for another
4 h. The mixture was poured into saturated NaHCO3 aqueous
solution (50 mL). The aqueous layer was extracted with Et2O
(3ꢀ50 mL) and the combined organic layers were washed with

4976
Y.-J. Zhao, T.-P. Loh / Tetrahedron 64 (2008) 4972–4978
water (50 mL) and brine (50 mL). The organic layer was dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The residual
crude product was used without further purification. To an oven-
dried round-bottom flask equipped with a magnetic stirring bar
was added the crude bromide. The bromide was azeotropically
dried with dry THF (2ꢀ10 mL). To the round-bottom flask were
added PhSO2Na (0.57 g, 1.3 equiv, 3.2 mmol) and dry DMF (15 mL).
The reaction mixture was allowed to stir for another 24 h. The
mixture was poured into ice water (30 mL). The aqueous layer was
extracted with ethyl acetate (3ꢀ40 mL) and the combined organic
layers were washed with water (40 mL) and brine (40 mL). The
organic layer was dried over anhydrous Na2SO4, filtered and con-
centrated in vacuo. The residual crude product was purified by flash
column chromatography to afford sulfone 9 in 90% yield as a col-
ourless oil. Isomer ratio¼83:17. Rf: 0.13 (hexane/ethyl acetate¼4:1).
Major isomer: 1H NMR (400 MHz, CDCl3): 7.85–7.82 (m, 2H,
]CH(Ph)), 7.70–7.60 (m, 1H, ]CH(Ph)), 7.59–7.46 (m, 2H,
]CH(Ph)), 7.19 (d, J¼10.4 Hz,1H, ]CH), 6.53–6.32 (m, 2H, CH]CH),
5.57 (t, J¼8.4 Hz, 1H, ]CH–CH2), 3.97 (d, J¼8.4 Hz, 2H, CH2), 3.74 (s,
3H, OMe), 1.95 (s, 3H, Me), 1.52 (s, 3H, Me). 13C NMR (100 MHz,
CDCl3): 168.7, 142.2, 141.8, 138.6, 138.0, 133.8, 129.2, 128.4, 128.0,
124.9, 119.7, 56.6, 51.9, 12.9, 12.3. HRMS (CI): m/z calculated for
CDCl3): 169.1,144.5,139.2,135.1,132.9,129.5,128.2,125.6,122.4, 51.7,
13.6, 12.8, 12.5. HRMS (CI): m/z calculated for C13H18O2 [M]þ:
206.1307, found: 206.1306. FTIR (KBr): n 1707, 1637 (br) cmꢂ1
.
4.3.4. (2E,4E,6E,8E,10E)-Methyl 2,6-dimethyl-11-phenylundeca-
2,4,6,8,10-pentaenoate
Yield: 91%, yellow solid, mp 113–114 ꢁC. Isomer ratio¼83:17. Rf:
0.63 (hexane/ethyl acetate¼4:1). 1H NMR (400 MHz, CDCl3): 7.50–
7.40 (m, 2H, ]CH(Ph)), 7.39–7.28 (m, 4H, ]CH and ]CH (Ph)), 7.19
(dd, J¼15.1, 11.3 Hz, 1H, ]CH), 6.71 (d, J¼14.5 Hz, 1H, ]CH), 6.68 (d,
J¼14.5 Hz, 1H, ]CH), 6.58 (dd, J¼15.1, 11.1 Hz, 1H, ]CH), 6.38 (d,
J¼11.1 Hz, 1H, ]CH), 3.80 (s, 3H, OMe), 2.02 (d, J¼1.0 Hz, 3H, Me),
2.02 (s, 3H, Me). 13C NMR (100 MHz, CDCl3): 168.9, 143.9, 139.0,
137.3,135.8,135.5,135.1,133.6,129.5,129.3,128.7,127.8,126.5,126.1,
123.3, 51.8, 12.9, 12.7. HRMS (CI): m/z calculated for C20H22O2 [M]þ:
294.1620, found: 294.1615. FTIR (KBr): n 1697, 1639 (br), 1568 cmꢂ1
.
4.3.5. (2E,4E,6E,8E)-Dimethyl 2,6-dimethyldeca-2,4,6,8-
tetraenedioate
Yield: 90%, yellow solid, mp 127–128 ꢁC. Isomer ratio¼88:12. Rf:
0.50 (hexane/ethyl acetate¼4:1). Major isomer: 1H NMR (400 MHz,
CDCl3): 7.69 (dd, J¼15.1, 12.0 Hz, 1H, ]CH), 7.28 (dd, J¼10.8, 1.4 Hz,
1H, ]CH), 6.70 (dd, J¼15.1, 10.8 Hz, 1H, ]CH), 6.60 (d, J¼15.1 Hz,
1H, ]CH), 6.33 (d, J¼12.0 Hz, 1H, ]CH), 5.98 (d, J¼15.2 Hz, 1H,
]CH), 3.78 (s, 3H, OMe), 3.78 (s, 3H, OMe), 2.08 (s, 3H, Me), 2.03 (s,
3H, Me). 13C NMR (100 MHz, CDCl3): 168.6, 167.5, 143.2, 142.5, 140.0,
138.0, 131.5, 128.5, 126.4, 122.0, 52.0, 51.6, 13.0, 12.9. HRMS (CI): m/z
calculated for C14H18O4 [M]þ: 250.1205, found: 250.1225. FTIR
C
17H20O4S [M]þ: 320.1082, found: 320.1094. FTIR (KBr): n 1703 (br),
1631 (br), 1616, 1554, 1305, 1234, 1149, 1109 cmꢂ1
.
4.3. Olefination and imine formation reaction of aldehyde (8)
General procedure. To a round-bottom flask equipped with
a magnetic stirring bar were added aldehyde 8 (20 mg, 0.1 mmol,
1.0 equiv), ylide (140 mg, 0.4 mmol, 4.0 equiv) and THF (10 mL). The
mixture was refluxed for another 4 h. The mixture was concen-
trated in vacuo. The residual crude product was purified by flash
column chromatography to afford desired product.
(KBr): n 1701 (br), 1624 (br) cmꢂ1
.
4.3.6. (2E,4E,6E,8E)-Methyl (2,6-dimethyl-8-phenylimino)octa-
2,4,6-trienoate
Yield: 88%, red solid, mp 96–97 ꢁC. Isomer ratio¼79:21. Rf: 0.25
(hexane/ethyl acetate¼4:1). Major isomer: 1H NMR (500 MHz,
CDCl3): 8.58 (d, J¼9.6 Hz, 1H, N]CH), 7.41–7.36 (m, 2H, ]CH), 7.32
(dd, J¼11.2, 1.2 Hz, 1H, ]CH), 7.25–7.21 (m, 1H, ]CH), 7.19–7.16 (m,
2H, ]CH), 6.80 (dd, J¼15.2, 11.2 Hz, 1H, ]CH), 6.71 (d, J¼15.2 Hz,
1H, ]CH), 6.53 (d, J¼9.9 Hz, 1H, ]CH), 3.81 (s, 3H, OMe), 2.22 (s,
3H, Me), 2.06 (s, 3H, Me). 13C NMR (100 MHz, CDCl3): 168.6, 157.9,
152.2, 145.7, 142.4, 137.8, 133.0, 129.2, 129.1, 127.0, 126.3, 121.0, 52.0,
13.2, 13.1. HRMS (CI): m/z calculated for C17H19NO2 [M]þ: 269.1416,
4.3.1. (2E,4E,6E,8E)-Dimethyl 2,5,9-trimethyldeca-2,4,6,8-
tetraenedioate (A)
Yield: 80%, yellow solid, mp 125–126 ꢁC. Recrystallization yield:
36%. Isomer ratio¼85:15. Rf: 0.50 (hexane/ethyl acetate¼4:1). Major
isomer: 1H NMR (400 MHz, CDCl3):7.58 (dd, J¼12.2,1.3 Hz,1H, ]CH),
7.32–7.22 (m, 1H, ]CH), 6.70–6.63 (m, 2H, ]CH), 6.48 (d, J¼12.2 Hz,
1H, ]CH), 3.79(s, 3H, OMe), 3.78 (s, 3H, OMe), 2.07 (s, 3H, Me), 2.02 (s,
6H, Me). 13C NMR (100 MHz, CDCl3): 168.9, 168.7, 143.3, 141.7, 138.3,
133.5, 129.2, 128.5, 127.9, 125.6, 52.0, 51.9, 13.0, 12.9, 12.8. HRMS (CI):
m/z calculated for C15H20O4 [M]þ: 264.1362, found: 264.1360. FTIR
found: 269.1410. FTIR (KBr): n 1633 (br), 1516 cmꢂ1
.
4.3.7. (2E,4E,6E,8E)-Methyl 8-((1R,2S)-1-hydroxy-1-phenylpropan-
2-ylimino)-2,6-dimethylocta-2,4,6-trienoate
(KBr): n 1685 (br), 1662 (br), 1618 (br), 1560, 1500 cmꢂ1
.
Yield: 95%, yellow solid, mp 85–86 ꢁC. Recrystallization yield:
45%. Isomer ratio¼86:14. Major isomer: 1H NMR (400 MHz, CDCl3):
8.29 (d, J¼9.6 Hz, 1H, N]CH), 7.41–7.33 (m, 6H, ]CH and
]CH(Ph)), 6.74 (dd, J¼15.2,11.2 Hz,1H, CH]CH), 6.61 (d, J¼15.2 Hz,
1H, CH]CH), 6.29 (d, J¼9.3 Hz, 1H, CH–C]N), 4.78 (d, J¼4.4 Hz, 1H,
OCH), 3.80 (s, 3H, OMe), 3.53–3.45 (m, 1H, CH–Me), 2.60 (br, 1H,
OH), 2.07 (s, 3H, Me), 2.04 (s, 3H, Me), 1.14 (d, J¼6.2 Hz, 3H, Me–CH).
13C NMR (100 MHz, CDCl3): 168.7, 158.8, 143.7, 141.3, 137.9, 132.2,
128.6, 128.2, 128.1, 127.4, 126.6, 126.5, 126.3, 77.0, 71.8, 52.0, 16.3,
13.0, 12.9. HRMS (CI): m/z calculated for C20H25NO3 [M]þ: 327.1834,
4.3.2. (2E,4E,6E,8E)-Methyl 2,6-dimethyl-9-phenylnona-2,4,6,8-
tetraenoate
Yield: 95%, yellow solid, mp 73–74 ꢁC. Isomer ratio¼76:24. Rf:
0.75 (hexane/ethyl acetate¼4:1). Major isomer: 1H NMR (400 MHz,
CDCl3): 7.50–7.45 (m, 2H, ]CH(Ph)), 7.41–7.25 (m, 3H, ]CH(Ph)),
7.34 (d, J¼15.0 Hz, 1H, ]CH), 7.19 (dd, J¼15.2, 11.2 Hz, 1H, ]CH),
6.71 (d, J¼15.2 Hz, 1H, ]CH), 6.68 (d, J¼15.0 Hz, 1H, ]CH), 6.57 (dd,
J¼15.0, 11.2 Hz, 1H, ]CH), 6.44 (d, J¼11.4 Hz, 1H, ]CH), 3.80 (s, 3H,
OMe), 2.07 (s, 3H, Me), 2.04 (s, 3H, Me). 13C NMR (100 MHz, CDCl3):
168.9, 144.0, 139.1, 137.4, 135.7, 135.2, 134.8, 129.2, 128.7, 127.9,
126.6, 125.1, 123.4, 51.8, 12.9, 12.8. HRMS (CI): m/z calculated for
found: 327.1835. FTIR (KBr): n 3435 (br), 1720, 1625 (br), 1556 cmꢂ1
.
C
18H20O2 [M]þ: 268.1463, found: 268.1460. FTIR (KBr): n 1760, 1643
(br), 1635 (br), 1560 cmꢂ1
4.4. Elongation of 8-methoxy-8-oxo-dehydrogeranal (8)
.
4.4.1. (E)-4-Hydroxyprenyl acetate (11)
4.3.3. (2E,4E,6E,8E)-Methyl 2,6-dimethyldeca-2,4,6,8-tetraenoate
Yield: 95%, yellow solid. Isomer ratio¼55:45. Rf: 0.35 (hexane/
ethyl acetate¼4:1). Major isomer: 1H NMR (400 MHz, CDCl3): 7.20–
7.00 (m,1H, ]CH), 6.60–6.23 (m, 3H, ]CH), 5.80 (dq, J¼13.9, 7.0 Hz,
1H, ]CH), 6.12 (d, J¼11.3 Hz,1H, ]CH), 3.37 (s, 3H, OMe),1.92 (s, 3H,
Me), 1.91 (s, 3H, Me), 1.78 (d, J¼7.0 Hz, 3H, Me). 13C NMR (100 MHz,
To a round-bottom flask equipped with a magnetic stirring bar
were added prenyl acetate (25.6 g, 200 mmol, 1.0 equiv), SeO2
(22.2 g, 200 mmol, 1.0 equiv) and ethanol (250 mL, 95%). The mix-
ture was heated at reflux for 24 h. The mixture was diluted with
ethyl acetate (100 mL). The organic layer was washed with brine
(3ꢀ50 mL). The organic layer was dried over anhydrous Na2SO4,

Y.-J. Zhao, T.-P. Loh / Tetrahedron 64 (2008) 4972–4978
4977
filtered and concentrated in vacuo until 40 mL liquid was left. The
mixture was cooled to 0 ꢁC and NaBH4 (1.9 g, 50 mmol, 0.25 equiv)
was added slowly. The reaction was stirred for another 12 h. The
mixture was diluted with ethyl acetate (100 mL). The organic layer
was washed with water (50 mL) and brine (50 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and concentrated
in vacuo. The residual crude product was purified by flash column
chromatography to afford desired product 11 in 42% yield as a col-
ourless oil. Rf: 0.13 (hexane/ethyl acetate¼4:1). 1H NMR (300 MHz,
CDCl3): 5.63 (t, J¼5.1 Hz, 1H, ]CH), 4.65 (d, J¼5.1 Hz, 2H, CH2–OAc),
4.06 (s, 2H, CH2–OH), 2.06 (s, 3H, C(O)–Me), 1.73 (s, 3H, Me). 13C
NMR (75 MHz, CDCl3): 170.1, 140.8, 118.6, 67.7, 60.9, 21.0, 13.8.
HRMS (CI): m/z calculated for C7H12O3 [M]þ: 144.0860, found:
(5 mL). The mixture was cooled to 0 ꢁC and IBX (560 mg, 2.0 mmol,
2.0 equiv) was added. The reaction mixture was gradually warmed
to room temperature and was allowed to stir for another 30 min.
Then the mixture was poured into ice water (30 mL). The aqueous
layer was extracted with ethyl acetate (3ꢀ50 mL) and the combined
organic layers were washed with brine (10 mL). The organic layer
was dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The residual crude product was purified by flash column
chromatography to afford desired product 14 in 80% yield as a col-
ourless oil. Isomer ratio¼96:4. Rf: 0.30 (ethyl acetate). 1H NMR
(400 MHz, CDCl3): 9.99 (d, J¼7.8 Hz, 1H, CHO), 5.96 (t, J¼7.8 Hz, 1H,
]CH), 4.13 (quintet, J¼7.2 Hz, 4H, O–CH2), 2.75 (d, J¼23.9 Hz, 2H,
P–CH2), 2.33 (dd, J¼3.6, 1.2 Hz, 3H, ]C–Me), 1.33 (t, J¼7.2 Hz, 6H,
O–CH2–Me). 13C NMR (75 MHz, CDCl3): 190.4 (d, J¼3.7 Hz), 153.7 (d,
J¼11.1 Hz), 130.7 (d, J¼11.0 Hz), 62.4 (d, J¼6.6 Hz), 40.8, 38.4 (d,
J¼133.5 Hz), 18.7 (d, J¼2.7 Hz), 16.3 (d, J¼6.1 Hz). HRMS (CI): m/z
calculated for C9H17O4P [M]þ: 220.0865, found: 220.0862. FTIR
144.0856. FTIR (KBr): n 1739, 1645 (br) cmꢂ1
.
4.4.2. (E)-4-Diethoxyphosphorylprenyl acetate (12)
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar were added alcohol 11 (12.1 g, 84 mmol, 1.0 equiv),
pyridine (8.9 mL, 109 mmol, 1.3 equiv) and DMF (200 mL). The
mixture was cooled to 0 ꢁC and MeSO2Cl (7.80 mL, 101 mmol,
1.2 equiv)was addedvia syringe. Thereaction mixturewasgradually
warmed to room temperature and was stirred for another 6 h. The
mixture was poured into ice water (100 mL). The aqueous layer was
extracted with ethyl acetate (3ꢀ50 mL) and the combined organic
layers were washed with aqueous HCl (50 mL, 0.3 M), water (50 mL)
and brine (50 mL). The organic layer was dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The residual crude
product was used for the next step without purification. The mixture
was transferred into a round-bottom flask and P(OEt)3 (14.6 mL,
84 mmol,1.0 equiv)was added via syringe. The reaction mixturewas
heated at 150 ꢁC for 24 h. The residual crude product was purified by
flash column chromatography to afford desired product 12 in 60%
yield as a colourless oil. Rf: 0.13 (ethyl acetate). 1H NMR (400 MHz,
CDCl3): 5.51 (q, J¼6.8 Hz, 1H, ]CH), 4.61 (dd, J¼7.1, 4.3 Hz, 2H, CH2–
OAc), 4.16–4.05 (m, 4H, O–CH2–Me), 2.59 (d, J¼22.2 Hz, 2H, CH2–P),
2.04 (s, 3H, C(O)–Me),1.87 (d, J¼2.9 Hz, 3H, ]C–Me),1.31 (t, J¼7.1 Hz,
6H, OCH2–Me).13C NMR (75 MHz, CDCl3): 170.8,132.6 (d, J¼10.9 Hz),
123.5 (d, J¼13.0 Hz), 61.9 (d, J¼5.3 Hz), 60.8, 36.8 (d, J¼136.3 Hz),
20.8 (d, J¼5.7 Hz), 17.6 (d, J¼3.0 Hz), 16.3 (d, J¼4.9 Hz). HRMS (CI):
m/z calculated for C11H22O5P [MþH]þ: 265.1205, found [MþH]þ:
(KBr): n 2984, 2931, 2908, 1682, 1635, 1029, 967 cmꢂ1
.
4.4.5. (2E,4E,6E,8E,10E)-Methyl 2,6,10-trimethyl-12-oxododeca-
2,4,6,8,10-pentaenoate ((2E,4E,6E,8E,10E)-12-methoxy-12-oxo-
dehydrofarnesal) (15)
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar were added alcohol 14 (110 mg, 0.5 mmol, 2.5 equiv),
BnNH2 (54 mg, 0.5 mmol, 2.5 equiv) and THF (5 mL). The mixture
was stirred for 30 min before THF was azeotropically removed. The
reaction mixture was azeotropically dried with dry THF (2ꢀ5 mL).
To the reaction mixture MS 4 Å (0.1 g) and THF (3 mL) were added.
The reaction mixture was cooled to ꢂ78 ꢁC before LiHMDS (1.0 M in
THF, 0.5 mL, 0.5 mmol, 2.5 equiv) was added. The reaction mixture
was stirred for 10 min at ꢂ78 ꢁC before a THF (1.0 mL) solution of
aldehyde 8 (39 mg, 0.2 mmol, 1.0 equiv) was added via syringe. The
reaction mixture was gradually warmed to room temperature and
was allowed to stir for another 12 h. The mixture was poured into
ice water (20 mL). The aqueous layer was extracted with ethyl
acetate (3ꢀ250 mL) and the combined organic layers were washed
with water (20 mL) and brine (20 mL). The organic layer was dried
over anhydrous Na2SO4, filtered and concentrated in vacuo. The
residual crude product was purified by flash column chromatog-
raphy to afford desired product 15 in 75% yield as a yellow solid, mp
123–124 ꢁC. Isomer ratio¼96:4. Rf: 0.20 (hexane/ethyl
acetate¼4:1). Major isomer: 1H NMR (400 MHz, CDCl3): 10.12 (d,
J¼8.1 Hz, 1H, CHO), 7.32–7.25 (m, 1H, ]CH), 7.11 (dd, J¼15.1, 11.4 Hz,
1H, ]CH), 6.70–6.57 (m, 2H, ]CH), 6.47 (d, J¼15.1 Hz, 1H, ]CH),
6.37 (d, J¼11.4 Hz, 1H, ]CH), 6.01 (d, J¼8.1 Hz, 1H, ]CH), 3.78 (s,
3H, OMe), 2.34 (d, J¼0.9 Hz, 3H, Me), 2.06 (s, 3H, Me), 2.02 (d,
J¼1.2 Hz, 3H, Me). 13C NMR (100 MHz, CDCl3): 191.1, 168.7, 154.0,
143.0, 139.9, 138.3, 136.9, 133.8, 131.6, 129.9, 127.7, 125.4, 51.8, 13.0,
13.0, 12.9. HRMS (CI): m/z calculated for C16H20O3 [M]þ: 260.1412,
265.1200. FTIR (KBr): n 1739, 1647 (br), 1236, 1068 cmꢂ1
.
4.4.3. (E)-4-Diethoxyphosphorylprenol (13)
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar were added ester 12 (530 mg, 2.0 mmol, 1.0 equiv) and
toluene (6 mL). The mixture was cooled ꢂ78 ꢁC and DIBAL-H (1.0 M
in heptane, 4 mL, 2.0 mmol, 2.0 equiv) was added via syringe. The
reaction mixture was stirred for another 12 h at ꢂ78 ꢁC. The
mixture was poured into ice water (20 mL) and potassium and
sodium tartrate saturated solution (20 mL). The aqueous layer was
extracted with ethyl acetate (3ꢀ50 mL). The organic layers were
combined and dried over anhydrous Na2SO4, filtered and concen-
trated in vacuo. The residual crude product was purified by flash
column chromatography to afford desired product 13 in 52% yield
as a colourless oil. Rf: 0.07 (ethyl acetate). 1H NMR (400 MHz,
CDCl3): 5.58 (q, J¼6.8 Hz, 1H, ]CH), 4.18 (t, J¼5.7 Hz, 2H, CH2–OH),
4.15–4.05 (m, 4H, O–CH2–Me), 2.57 (d, J¼22.1 Hz, 2H, P–CH2), 1.83
(d, J¼3.2 Hz, 3H, ]C–Me), 1.32 (t, J¼6.8 Hz, 6H, CH2–Me). 13C NMR
(100 MHz, CDCl3): 129.3 (d, J¼13.0 Hz), 129.0, 62.0 (d, J¼7.3 Hz),
58.8, 36.6 (d, J¼136.4 Hz), 17.5 (d, J¼2.9 Hz), 16.4 (d, J¼5.9 Hz).
HRMS (CI): m/z calculated for C9H19O4P [M]þ: 222.1021, found:
found: 260.1419. FTIR (KBr): n 1701, 1660, 1647, 1616, 1595 cmꢂ1
.
4.4.6. (2E,4E,6E,8E,10E,12E,14E)-Methyl 2,6,10,14-tetramethyl-16-
oxohexadeca-2,4,6,8,10,12,14-heptaenoate
((2E,4E,6E,8E,10E,12E,14E)-16-methoxy-16-oxo-
dehydrogeranylgeranal) (16)
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar were added alcohol 14 (88 mg, 0.4 mmol, 7.0 equiv),
BnNH2 (43 mg, 0.4 mmol, 7.0 equiv) and THF (5 mL). The mixture
was stirred for 30 min before THF was azeotropically removed. The
reaction mixture was azeotropically dried with dry THF (2ꢀ5 mL).
To the reaction mixture MS 4 Å (0.1 g) and THF (3 mL) were added.
The reaction mixture was cooled to ꢂ78 ꢁC before LiHMDS (1.0 M in
THF, 0.4 mL, 0.4 mmol, 7.0 equiv) was added. The reaction mixture
was stirred for 10 min at ꢂ78 ꢁC before a THF (1.0 mL) solution of
aldehyde 15 (16 mg, 0.06 mmol, 1.0 equiv) was added via syringe.
The reaction mixture was gradually warmed to room temperature
222.1020. FTIR (KBr): n 3427 (br), 1647, 1211, 1053, 970 cmꢂ1
.
4.4.4. (E)-4-Diethoxyphosphorylprenal (14)
To a round-bottom flask equipped with a magnetic stirring bar
were added alcohol 13 (222 mg, 1.0 mmol, 1.0 equiv) and DMSO

4978
Y.-J. Zhao, T.-P. Loh / Tetrahedron 64 (2008) 4972–4978
Hooper, J. N. A.; Harper, M. K.; Ireland, C. M. J. Nat. Prod. 2002, 65, 210–214; (e)
Meragelman, K. M.; McKee, T. C.; Boyd, M. R. J. Nat. Prod. 2001, 64, 389–392; (f)
Che, C. T.; Zhang, W. H. J. Nat. Prod. 2001, 64, 1489–1492; (g) McKee, T. C.;
Bokesch, H. R.; McCormick, J. L.; Rashid, M. A.; Spielvogel, D.; Gustafson, K. R.;
Alavanja, M. M.; Cardellina, J. H., II; Boyd, M. R. J. Nat. Prod. 1997, 60, 431–438;
(h) Rao, Z. G.; Deng, S. Z.; Wu, H. M.; Jiang, S. K. J. Nat. Prod. 1997, 60, 1163–1164;
(i) Su, J. Y.; Meng, Y. H.; Zeng, L. M. J. Nat. Prod. 1994, 57, 1450–1451.
3. Jackson, H. L.; Nadolski, G. T.; Braun, C.; Lockwood, S. F. Org. Process Res. Dev.
2005, 9, 830–836 and references therein.
and was stirred for another 12 h. The mixture was poured into ice
water (20 mL). The aqueous layer was extracted with ethyl acetate
(3ꢀ250 mL) and the combined organic layers were washed with
water (20 mL) and brine (20 mL). The organic layer was dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The residual
crude product was purified by flash column chromatography to af-
ford desired product in 85% yield as a dark red solid, mp 81–82 ꢁC.
Isomer ratio¼72:28. Rf: 0.28 (hexane/ethyl acetate¼4:1). Major
isomer: 1H NMR (500 MHz, CDCl3): 10.11 (d, J¼8.1 Hz,1H, CHO), 7.29
(dd, J¼10.5,1.0 Hz,1H, ]CH), 7.11 (dd, J¼14.8,11.5 Hz,1H, ]CH), 6.76
(dd, J¼14.8,11.5 Hz,1H, ]CH), 6.63 (d, J¼14.8 Hz,1H, ]CH), 6.56 (dd,
J¼15.1, 11.1 Hz, 1H, ]CH), 6.46 (d, J¼11.2 Hz, 1H, ]CH), 4.41 (d,
J¼11.2 Hz,1H, ]CH), 6.34 (d, J¼10.5 Hz,1H, ]CH), 6.30 (d, J¼11.1 Hz,
1H, ]CH), 6.98 (d, J¼8.1 Hz,1H, ]CH), 3.77 (s, 3H, OMe), 2.33 (s, 3H,
Me), 2.05 (s, 3H, Me), 2.01 (s, 3H, Me), 2.00 (s, 3H, Me). 13C NMR
(125 MHz, CDCl3): 191.1,168.9,154.3,143.8,140.8,139.0,138.8,136.8,
135.9,135.3,132.2,132.1,129.5,126.8,126.4,123.7, 51.8,13.1,13.1,12.9,
12.9. HRMS (CI): m/z calculated for C21H26O3 [M]þ: 326.1882, found:
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We thank Dr. Yong-Xin Li for X-ray analyses. We gratefully
acknowledge the Nanyang Technological University and the Sin-
gapore Ministry of Education Academic Research Fund Tier 2 (No.
T206B1221) for the funding of this research.
Supplementary data
Copies of 1H NMR and 13C spectrums for compounds 3–9, 11–16,
products of Table 1 and X-ray data for compound A are available.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.03.094.
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References and notes
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