Solid-phase organic synthesis of polyisoprenoid alcohols with traceless sulfone linker

Article abstract of DOI:10.1021/jo8010182

(Chemical Equation Presented) Solid-phase organic synthesis of polyprenols with a traceless sulfone linker is described. The polymerbound benezenesulfinate is first linked with the "tail" building blocks of isoprenyl chlorides via S-alkylation. With use of dimsyl anion as an appropriate base, the polymer-bound α-sulfonyl carbanion is generated and coupled with other "body" building blocks in an efficient manner. After repeated processes and a global palladium-catalyzed desulfonation with LiEt₃BH as the reducing agent, the desired polyprenols with various chain lengths and geometrical configurations are obtained in 32-59% overall yields. The solid-phase synthesis offers the advantage in facile isolation of polyprenols without tedious operation or time-consuming purification.

Full text of DOI:10.1021/jo8010182

Solid-Phase Organic Synthesis of Polyisoprenoid Alcohols with
Traceless Sulfone Linker
Yi-Fan Chang,† Chen-Yu Liu,‡ Chih-Wei Guo,† Yen-Chih Wang,† Jim-Min Fang,*,‡ and
Wei-Chieh Cheng*,†
The Genomics Research Center, Academia Sinica, Nankang, Taipei, 115, Taiwan, and Department of
Chemistry, National Taiwan UniVersity, Taipei 106, Taiwan
wcheng@gate.sinica.edu.tw; jmfang@ntu.edu.tw
ReceiVed May 13, 2008
Solid-phase organic synthesis of polyprenols with a traceless sulfone linker is described. The polymer-
bound benezenesulfinate is first linked with the “tail” building blocks of isoprenyl chlorides via S-alkylation.
With use of dimsyl anion as an appropriate base, the polymer-bound R-sulfonyl carbanion is generated
and coupled with other “body” building blocks in an efficient manner. After repeated processes and a
global palladium-catalyzed desulfonation with LiEt3BH as the reducing agent, the desired polyprenols
with various chain lengths and geometrical configurations are obtained in 32-59% overall yields. The
solid-phase synthesis offers the advantage in facile isolation of polyprenols without tedious operation or
time-consuming purification.
Introduction
Many biologically important molecules contain polyiso-
prenoid alcohols as the essential moieties to fulfill their
functions.1,2 Naturally occurring polyisoprenoid alcohols can
be classified into four categories according to their structures:
(i) all-trans prenols, (ii) dolichol type prenols with ditrans-poly
cis configuration and a saturated isoamyl moiety, (iii) bacteria-
† The Genomics Research Center, Academia Sinica.
FIGURE 1. General structures of natural polyprenols.
‡ Department of Chemistry, National Taiwan University.
(1) (a) Fahy, E.; Subramaniam, S.; Brown, H. A.; Glass, C. K.; Merrill, A. H.,
Jr.; Murphy, R. C.; Raetz, C. R. H.; Russell, D. W.; Seyama, Y.; Shaw, W.;
Shimizu, T.; Spener, F.; van Meer, G.; VanNieuwenhze, M. S.; White, S. H.;
Witztum, J. L.; Dennis, E. A. J. Lipid Res. 2005, 5, 839. (b) Fujihashi, M.;
Zhang, Y.; Higuchi, Y.; Li, X.; Koyama, T.; Miki, K. Proc. Natl. Acad. Sci.
U.S.A. 2001, 8, 4337. (c) Kharel, Y.; Takahashi, S.; Yamashita, S.; Koyama, T.
FEBS J. 2006, 3, 647. (d) Kleinig, H. Annu. ReV. Plant Physiol. Plant Mol.
Biol. 1989, 40, 39.
(2) (a) Benetka, W.; Koranda, M.; Eisenhaber, F. Monatsh. Chem. 2006, 10,
1241. (b) Bifulco, M. Life Sci. 2005, 14, 1740. (c) Kasradze, V. G.; Salimova,
E. V.; Kukovinets, O. S.; Galin, F. Z.; Makara, N. S.; Karachurina, L. T.; Kuchin,
A. V.; Koroleva, A. A. Chem. Nat. Compd. 2003, 3, 307. (d) Prendergast, G. C.;
Oliff, A. Semin. Cancer Biol. 2000, 6, 443. (e) Tachibana, A.; Yano, Y.; Otani,
S.; Nomura, N.; Sako, Y.; Taniguchi, M. Eur. J. Biochem. 2000, 2, 321.
and betulaprenols with ditrans-poly cis configuration, and (iv)
ficaprenol with tritrans-poly cis configuration (Figure 1).3
The phosphate or pyrophosphate derivatives of polyprenols
are intermediates in the biosynthesis of various glycoproteins,
peptidoglycans, and polysaccharides. For example, undecaprenol
phosphate (C55-OP) is an important substrate for biosynthesis
(3) (a) Bamba, T.; Fukusaki, E.; Minakuchi, H.; Nakazawa, Y.; Kobayashi,
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10.1021/jo8010182 CCC: $40.75
Published on Web 08/16/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7197–7203 7197

Chang et al.
derivatives as well as the polyprenol-based chemical probes for
biological studies. Indeed, several solution-phase synthetic
methods have been reported.8-10 However, all these methods
have common drawbacks of tedious operation and limited
diversity. We thus explore a more efficient approach using solid-
phase organic synthesis (SPOS) to prepare a library of poly-
prenols with various lengths and geometrical configurations. As
a general strategy for the preparation of peptides, nucleosides,
and oligosaccharides,11 SPOS has several advantages over the
solution-phase organic synthesis.12 In particular, isolation of the
polymer-bound intermediates is typically accomplished by a
simple filtration. To the best of our knowledge, however, this
technology has not been applied to the synthesis of polyprenols.
In any SPOS-based strategy, selection of an appropriate linker
(the moiety that covalently connects the polymeric support to
the building block) is essential. The ideal linker allows easy
attachment of the substrate to the solid support, is stable to the
reaction conditions used to produce the desired product, and
can be cleaved under specific and orthogonal conditions.13 The
previous studies by us14 and other groups15 have shown that a
sulfone linker, such as that derived from the polymer-bound
sulfinate 1 (Figure 3), fulfills these requirements.
Results and Discussion
Strategy and Design of Solid-Phase Organic Synthesis. On
the basis of our previous experience with sulfone linkers14 and
the availability of suitable building blocks, we proposed a
strategy entailing attachment of the polymer-bound sulfinate 1
to the tail building block, followed by extension of the carbon
chain toward a headgroup (Figure 3). In this study, four tail
building blocks (2, 12, 13, and 14), three body building blocks
(4, 15, and 26), and four head building blocks (4, 15, 16, and
26)9,16,17 were selected to show the generality of this method
(Figure 4). These building blocks were easily prepared from
inexpensive nerol, geraniol, farnesol, and citronellol.16,17 Note-
worthily, the RO functional groups present in building blocks
12-14 can be further transformed into chromophores and
photoaffinity labels for bioassay and mechanistic studies.
FIGURE 2. Examples of polyprenol-containing biologically interesting
molecules.
of undecaprenyl GlcNAc-MurNAc(pentapeptide)-pyrophosphate
(lipid II, Figure 2), which is the precursor of bacterial cell wall
peptidoglycan.4 The truncated lipid II without the polyprenol
moiety cannot be recognized by the cell wall biosynthetic
enzymes. However, the lipid II analogy bearing a shorter
polyprenol chain, e.g. betulaheptaprenol (C35-OH), can serve
as an alternative substrate of bacterial transglycosylase.5 In the
post-translational modification of nascent polypeptide chains,
the oligosaccharide Glc3-Man9-GlcNAc2 bearing a dolichol
pyrophosphate moiety renders an N-glycosylation to certain
asparagines residues.6 Mannosyl-ꢀ-1-phosphodolichol (C35-
MPD) is a synthetic polyprenol glycolipid, which is presented
by CD1c for T cell recognition.7 Thus, polyprenols with different
chain lengths and configurations may play important roles in
diverse biological applications.
(8) Sato, K.; Miyamoto, O.; Inoue, S.; Matsuhashi, Y.; Koyama, S.; Kaneko,
T. J. Chem. Soc., Chem. Commun. 1986, 1761.
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Salvino, J. M.; Zhang, W. J. Comb. Chem. 2007, 9, 855. (b) Dolle, R. E.; Le
Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.; Salvino, J. M. J. Comb. Chem.
2006, 8, 597. (c) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555. (d)
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Sammelson, R. E.; Kurth, M. J. Chem. ReV. 2001, 101, 137. (c) Thompson,
L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555.
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2005, 61, 11527. (b) Scott, P. J. H.; Steel, P. G. Eur. J. Org. Chem. 2006, 2251.
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Zhang, X.-L.; Liu, X.-L.; Wei, M.-H. J. Comb. Chem. 2006, 8, 805. (d) Cheng,
W.-C.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 2001, 66, 5528. (e) Cheng,
W.-C.; Wong, M.; Olmstead, M. M.; Kurth, M. J. Org. Lett. 2002, 4, 741. (f)
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Y.; Lai, Y.-H. Org. Lett. 2003, 5, 1067. (h) Chen, Y.; Lam, Y.; Lai, Y.-H. Org.
Lett. 2002, 4, 3935.
Due to the difficulties in isolation of pure polyprenols from
natural sources and the limitations of chemical transformations
of natural polyprenols, the organic synthesis obviously provides
an alternative approach to produce various desired polyprenols,
which can be converted to their phosphate and pyrophosphate
(4) (a) Schwartz, B.; Markwalder, J. A.; Wang, Y. J. Am. Chem. Soc. 2001,
123, 11638. (b) VanNieuwenhze, M. S.; Mauldin, S. C.; Zia-Ebrahimi, M.;
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3997.
7198 J. Org. Chem. Vol. 73, No. 18, 2008

Organic Synthesis of Polyisoprenoid Alcohols
On the basis of the above consideration, the synthesis of a
25-carbon pentaprenol 7a16 was first conducted in the solution
phase (Scheme 1). Treatment of (E,E)-farnesyl chloride 223 with
sodium benzenesulfinate gave (E,E)-farnesyl phenyl sulfone 3,
which underwent monolithiation with dimsyl anion (3 equiv)
at room temperature and reacted subsequently with a C10
isoprenoid building block 416 to afford the coupling product 5
in 78% yield over two steps. After removal of the TBDPS group
in 5, the alcohol 6 was subject to reductive desulfonation in
varied conditions (Table 1).16,24-27 Compound 6 was rather inert
to magnesium, whereas the reaction with lithium was compli-
cated to give a low yield (10%) of the desulfonation product
7a. Treatment of 6 with sodium in ethanol gave a mixture of
1
7a and its isomer 7b in a ratio of 7:3 as shown by H NMR
analysis. Compound 7b was characterized by showing the C11-
methyl group as a doublet at δ 0.94 ppm and the C8-methylene
group as a multiplet at δ 2.66 ppm. These two isomers were
inseparable by silica gel column chromatography.16 Fortunately,
we found that the reductive desulfonation of 6 was effectively
carried out by using LiBHEt3 (Super-Hydride) in the presence
of PdCl2(dppp) catalyst in THF solution to furnish a single
product of 7a in 83% yield.
Solid-Phase Organic Synthesis of Polyprenols. Using the
reaction protocols developed in the above-mentioned solution-
phase synthesis, we constructed a small library of polyprenols
7a, 11, and17-2428-30 by SPOS in 32-59% isolated yields
(Table 2 and Figure 6). These products were diverse polyprenol
structures including the all-trans, all-cis, bacteria, betula, and
dolichol types. A typical procedure for the SPOS of polyprenol
11 was delineated in Scheme 2.
The synthetic work began with the S-alkylation of the sulfinate
resin 1 (sulfinate loading ) 0.8 mmol/g) with the tail building
block 2. The reaction was easily monitored by FTIR spectra,
which showed disappearance of sulfinate absorption at 1028
cm-1 along with occurrence of the sulfone absorptions at ∼1300
and ∼1140 cm-1. Resin 8 was treated with dimsyl anion (3
equiv) at room temperature to give the corresponding R-sulfonyl
carbanion, which reacted with the building block 4 to furnish a
chain elongation product, resin 9a. This transformation was
confirmed by a diagnostic absorption of the Si-O bond at
∼1110 cm-1 in the single-bead FTIR spectrum of 9a.
The TBAF-mediated O-deprotection of 9a, followed by
mesylation, chlorination, and sulfonation, afforded resin 9d. The
process of carbanion generation and coupling reaction with
building block 4 was repeated to give resin 10, which contained
one sulfone moiety on the resin linker and the other sulfone
FIGURE 3. General synthetic route to polyprenols from the polymer-
bound benzenesulfinate resin 1.
Inspired by the stepwise principle of solid-phase peptide
synthesis,18 our synthesis of polyprenols relies on seven key
steps (Figure 5): (i) S-alkylation of the sulfinate resin 1, (ii)
generation of R-sulfonyl carbanion followed by the coupling
reaction with the respective building block, (iii) O-deprotection,
(iv) activation of the hydroxyl group by mesylation, halogena-
tion, and sulfonation, (v) iterative coupling reaction to link other
building blocks, (vi) O-deprotection, and (vii) global desulfona-
tion with concomitant release of the target molecule of poly-
prenols from the solid support. The repeated cycle of steps iv
f vi by activation, coupling, and deprotection would allow for
diversity of the desired products.
Model Synthetic Studies in the Solution Phase. Preliminary
solution-phase experiments were undertaken to explore the
feasible reaction conditions, and to establish the required
modifications for a practical SPOS. For example, the choice of
base and solvent is an important issue for the coupling reaction
between allylic sulfones and alkyl halides. The conventional
use of aqueous sodium hydroxide as a base19 is not suitable for
the solid-phase synthesis because of the low-swelling behavior
of polystyrene-based resins in aqueous solution.14,15,20 Use of
n-butyllithium as a base may cause undesired dialkylation,14,15,20
even the reaction is conducted at low temperature (-78 °C).21
To circumvent these problems, we chose to perform the coupling
reactions in THF solution by using dimsyl anion as the
appropriate base. The dimsyl anion can be formed in situ from
DMSO with n-BuLi, and utilized to generate the carbanion of
the sulfone resin for monoalkylation.22
(23) (a) Davisson, V. J.; Woodside, A. B.; Neal, T. R.; Stremler, K. E.;
Muehlbacher, M.; Poulter, C. D. J. Org. Chem. 1986, 51, 4768. (b) Jin, Q.;
Williams, D. C.; Hezari, M.; Croteau, R.; Coates, R. M. J. Org. Chem. 2005,
70, 4667.
Several O-protecting groups, such as Bn and THP, can be
used in the tail building blocks 12-14, whereas the TBDPS
group was the choice for incorporation into the body and head
building blocks 4, 15, and 16 because it is stable in the basic
conditions involving dimsyl anion and can be removal by TBAF
selectively.
(24) (a) Costa, A.; Na´jera, C.; Sansano, J. M. J. Org. Chem. 2002, 67, 5216.
(b) Crowley, P. J.; Fawcett, J.; Griffith, G. A.; Moralee, A. C. Org. Biomol.
Chem. 2005, 3, 3294.
(25) Liu, H. J.; Yip, J. Tetrahedron Lett. 1997, 38, 2253.
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51, 5100.
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R. B. J. Am. Chem. Soc. 1963, 85, 2149.
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Soc., Chem. Commun. 1987, 1036.
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7709. (b) Cheng, W.-C.; Halm, C.; Evarts, J. B.; Olmstead, M. M.; Kurth, M. J.
J. Org. Chem. 1999, 64, 8557.
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Med. Chem. 2002, 10, 1249. (b) Mohri, M.; Kinoshita, H.; Inomata, K.; Kotake,
H.; Takagaki, H.; Yamazaki, K. Chem. Lett. 1986, 1177. (c) Orita, A.; Watanabe,
A.; Otera, J. Chem. Lett. 1997, 1025. (d) Orita, A.; Watanabe, A.; Tsuchiya, H.;
Otera, J. Tetrahedron 1999, 55, 2889. (e) Robustell, B.; Abe, I.; Prestwich, G. D.
Tetrahedron Lett. 1998, 39, 957. (f) Bouzbouz, S.; Kirschleger, B. Synthesis
1994, 714. (g) Eis, K.; Schmalz, H. G. Synthesis 1997, 202.
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M. R.; Brennan., P. J.; Crick, D. C. J. Bacteriol. 2005, 187, 2747.
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Chem. Lett. 1984, 1105. (b) Noma, H.; Tanaka, H.; Noguchi, H.; Shibuya, M.;
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J. Org. Chem. Vol. 73, No. 18, 2008 7199

Chang et al.
FIGURE 4. Chemical structures of building blocks for tail, body, and head groups.
TABLE 1. Reductive Desulfonation of Compound 6
isolated
solvent/ temp/ time yield (%)aof 7a
entry
reagents
Mg/ethanol
Mg/methanol
Li/naphthalene
Na/ethanol
1
2
3
4
5
EtOH/rt/48 h
MeOH/rt/48 h
THF/0 °C/1 h
EtOH/rt/2 h
0b
23c
10d
45e
83
LiBHEt3/PdCl2(dppp) THF/0 °C/2 h
a Isolated by silica-gel column chromatography. b Only the starting
material of 6 was recovered. c The starting material was recovered in
77% yield. d The reaction was complicated by other intractable products.
e The crude product mixture consisted of 7a and its isomer 7b in a ratio
FIGURE 5. Key steps of solid-phase polyprenol synthesis.
SCHEME 1. Solution-Phase Synthesis of Polyprenol 7a
(Model Study)
1
of 7:3 as shown by the H NMR analysis.
TABLE 2. Solid-Phase Synthesis of Polyprenols
overall yields (%)
producta
building blocks
total steps
based on resin 1b
7a
11
17
18
19
20
21
22
23
24
24
2 + 4
4
8
4
8
8
8
8
4
8
56
37
57
38
36
39
32
59
40
11
34
2 + 4 + 4
2 + 15
2 + 15 + 15
12 + 4 + 4
13 + 4 + 4
14 + 4 + 4
2 + 16
2 + 4 + 16
2 + 4 + 4 + 4 + 4
2 + 26 + 26
16
8
a Purification by silica-gel column chromatography. b The sulfinate
loading on resin 1 is 0.8 mmol/g.
from the starting resin 1, i.e., an average yield of 88% for each
of the eight solid-phase reactions.
In connection with our research on the transglycosylation of
bacterial cell wall, the undecaprenol 24 is needed for the
synthesis of lipid II (see in Figure 2) as the substrate of
transglycosylase.30 Because isolation of the undecaprenol 24
from bacteria is difficult, a practical synthesis of 24 is desirable
(Figure 7). In our original approach, resin 8 was subject to four
cycles of reaction sequence with the C10 building block 4 to
generate the corresponding resin 25 possessing 11 isoprene units.
All the sulfonyl groups on resin 25 were then removed by a
Pd-catalyzed reduction to afford the target molecule 24 in 11%
overall yield, from the starting resin 1, after purification by
silica-gel column chromatography. Alternatively, the C20 build-
ing block 26 was used in two elongation cycles on resin 8 to
afford 25, and ended up with formation of undecaprenol 24 in
34% overall yield. The dramatic improved yield was attributable
to the fewer reaction steps in the latter approach. This is the
first report on the efficient solid-phase synthesis of undecaprenol
24 (C55-OH).
group attached to the polyprenol backbone. After deprotection
of the TBDPS group from resin 10, a global desulfonation
afforded the desired product 11 (C35-OH)8 in 37% overall yield
7200 J. Org. Chem. Vol. 73, No. 18, 2008

Organic Synthesis of Polyisoprenoid Alcohols
FIGURE 7. Solid-phase synthesis of polyprenol 24 (a component of
lipid II).
FIGURE 6. Chemical structures of the polyprenols prepared in this
prenol 24 of lipid II component, is thus successfully constructed
in reasonable yields. Our approach has several merits: (i)
iterative elongation cycle (a sequence of coupling, deprotection,
and activation) on solid support is remarkably efficient; (ii) no
tedious operation or time-consuming purification are required;
(iii) the S-alkylation, deprotection, and activation (steps i, iii,
iv, and vi) are easily monitored by FTIR analysis; and (iv) all
sulfonyl groups on the resin and the molecular backbone are
simultaneously removed by a Pd-catalyzed reduction. Trans-
formation of polyprenols 7a and 11 to their corresponding
phosphate derivatives has been performed in our laboratory.
Modification of the polyprenols by incorporation of chro-
mophores and photoaffinity labels will be conducted in due
course for further biological studies.
study.
SCHEME 2. Solid-Phase Synthesis of Polyprenol 11
(Representative Example)
Experimental Section
(2Z,6Z,10E,14E)-3,7,11,15,19-Pentamethyl-9-(phenylsulfonyl)i-
cosa-2,6,10,14,18-pentaen-1-ol (6). Dimsyl anion was prepared by
the dropwise addition of n-BuLi (0.18 mL, 0.44 mmol) to a solution
of DMSO (0.04 g, 0.03 mL, 0.44 mmol) in THF (0.5 mL) at
ambient temperature, followed by stirring for 20 min. The freshly
prepared dimsyl anion was added dropwise to a solution of 3 (0.10
g, 0.29 mmol) in THF (0.5 mL), and the color of the reaction
mixture changed from white to orange. After 2 h, the building block
4 (0.12 g, 0.27 mmol) in THF (0.7 mL) was added to this mixture.
The mixture was stirred at ambient temperature for 4 h, and the
reaction was quenched with satd. NH4Cl solution (20 mL). The
mixture was extracted with ethyl acetate (3 × 20 mL), washed with
satd. NaCl (3 × 20 mL), dried (MgSO4), and concentrated to give
5 (0.16 g, 0.22 mmol). The solution of compound 5 in THF (2
mL) was stirred with TBAF (1.0 M in THF, 0.87 mL, 0.87 mmol)
at ambient temperature for 4 h. The mixture was concentrated and
purified by CC (33% EtOAc in hexanes) to give 6 (0.11 g, 0.22
mmol, 76% for two steps from 3) as a colorless oil: 1H NMR (600
MHz, CDCl3) δ 1.11 (s, 3H), 1.55 (s, 3H), 1.57 (s, 3H), 1.58 (s,
3H), 1.65 (s, 3H), 1.71 (s, 3H), 1.90-2.01 (m, 12H), 2.47 (dd, 1H,
J ) 13.3, 11.0 Hz), 2.80 (dd, 1H, J ) 13.3, 3.0 Hz), 2.84 (td, 1H,
J ) 11.0, 3.0 Hz), 4.06 (d, 2H, J ) 7.1 Hz), 4.93 (d, 1H, J ) 10.3
Hz), 4.99 (t, 1H, J ) 4.4 Hz), 5.05 (t, 1H, J ) 6.8 Hz), 5.17 (t,
1H, J ) 6.8 Hz), 5.41 (t, 1H, J ) 7.1 Hz), 7.47-7.60 (m, 3H),
7.82 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 145.6, 139.6, 138.0,
136.0, 133.6, 131.6, 131.2, 129.4, 129.4, 128.9, 128.8, 128.2, 124.9,
124.4, 123.5, 117.2, 63.8, 59.1, 39.9, 39.8, 32.1, 29.6, 26.9, 26.8,
26.3, 25.9, 23.8, 23.7, 17.9, 16.4, 16.1; HRMS calcd for [C31H46O3S
+ NH4]+ 516.3506, found 516.3505.
(2Z,6Z,10E,14E)-3,7,11,15,19-Pentamethylicosa-2,6,10,14,18-pen-
taen-1-ol (7a).16 a. Solution-Phase Synthesis. Lithium triethylboro-
hydride (Super-Hydride) (0.5 mL, 0.5 mmol) was added dropwise
over 2 h to a solution of 6 (50 mg, 0.1 mmol) and bis(diphe-
nylphosphino)propanepalladium(II) dichloride [(dppp)PdCl2] (3 mg,
Conclusion
In this study, we have devised a practical solid-phase synthetic
route to varied polyprenols by using sulfone resin as a traceless
and robust linker. A library of polyprenols, including undeca-
J. Org. Chem. Vol. 73, No. 18, 2008 7201

Chang et al.
0.005 mmol) in THF (1 mL) at 0 °C. After the mixture was stirred
for 12 h, satd. NH4Cl solution (10 mL) was added and the mixture
was extracted with ether (3 × 20 mL). The combined organic
extracts were washed with satd. NaCl solution (3 × 20 mL), dried
(MgSO4), concentrated, and purified by CC (17% EtOAc in
hexanes) to give 7a (31 mg, 0.087 mmol, 87%) as a colorless oil.
b. Solid-Phase Synthesis. Starting from resin 1 with building
blocks 2 and 4, the reaction sequence (1 f 8 f 9a f 9b f 7a)
was carried out, as that described for 11, to give 7a (16 mg, 0.045
mmol, 56% overall yield from 1) as a colorless oil.
H2O (2 × 10 mL), DCM (2 × 10 mL), MeOH (2 × 10 mL), and
ether (10 mL). The resin was then dried overnight in a vacuum
oven (40 °C, 5 mmHg) to afford resin 9d as yellow beads: IR (single
bead reflectance) 1596.4, 1493.1, 1446.3, 1304.8, 1143.2 cm-1
.
(2Z,6Z,10Z,14Z,18E,22E)-1-(tert-Butyldiphenyl)siloxy-
3,7,11,15,19,23,27-heptamethyl-9-phenylsulfonyl-17-(PS/DVB-sul-
fonyl)triaconta-2,6,10,14,18,22,26-heptaene (10a). Polymer 9d (100
mg) was swollen in THF (0.5 mL) for 15 min, and the freshly
prepared dimsyl anion (5 equiv., 0.4 mmol) in THF (0.5 mL) was
added dropwise. The mixture was gently stirred for 2 h, the excess
dimsyl anion was removed, and the resin was washed with dry
THF (2 × 0.5 mL). The building block 4 (68 mg, 0.16 mmol) in
THF (1 mL) was added to the reaction and the mixture was gently
stirred at ambient temperature for 12 h. The resin was collected by
filtration, then washed with MeOH/H2O (2 × 10 mL), DCM (2 ×
10 mL), MeOH (2 × 10 mL), and ether (10 mL). The resin was
then dried overnight in a vacuum oven (40 °C, 5 mmHg) to afford
10a as yellow beads: IR (single bead reflectance) 1595.9, 1492.5,
1
7a: H NMR (600 MHz, CDCl3) δ 1.58 (s, 9H), 1.66 (s, 6H),
1.72 (s, 3H), 1.93-2.07 (m, 16H), 4.05 (d, 2H, J ) 7.0 Hz),
5.06-5.10 (m, 4H), 5.41 (t, 1H, J ) 7.0 Hz); 13C NMR (150 MHz,
CDCl3) δ 139.9, 136.3, 135.4, 135.1, 131.4, 124.7, 124.6, 124.5,
124.4, 124.2, 59.1, 39.9, 39.8, 32.4, 32.1, 27.0-26.5 (several, m),
25.8, 23.6, 23.5, 17.8, 16.1; HRMS calcd for [C25H42O + Na]+
381.3128, found 381.3126.
(2E,6E)-1-(PS/DVB-sulfonyl)-3,7,11-trimethyldodeca-2,6,10-
triene (8). The polymer-bound benzenesulfinate 1 (1 g, 0.8 mmol;
sulfinate loading ) 0.8 mmol/g) was swollen in DMF/THF (1:1, 5
mL) at room temperature for 15 min, and the building block 2 (5
equiv., 0.96 g, 4.0 mmol) was added. The mixture was gently stirred
at 60 °C for 48 h. The resin was collected by filtration, then washed
with MeOH/H2O (2 × 10 mL), DCM (2 × 10 mL), MeOH (2 ×
10 mL), and ether (10 mL). The resin was then dried overnight in
a vacuum oven (40 °C, 5 mmHg) to afford resin 8 as yellow beads:
IR (single bead reflectance) 1596.6, 1492.9, 1450.4, 1303.2, 1146.0
1449.3, 1302.5, 1143.9, 1111.2 cm-1
.
(2Z,6Z,10Z,14Z,18E,22E)-3,7,11,15,19,23,27-Heptamethyl-9-phe-
nylsulfonyl-17-(PS/DVB-sulfonyl)triaconta-2,6,10,14,18,22,26-hep-
taen-1-ol (10b). Polymer 10a (100 mg) was swollen in THF (0.5
mL) for 15 min, and TBAF (1.0 M in THF, 0.4 mmol, 0.4 mL)
was added. The reaction was stirred at ambient temperature for
8 h, and the resin was collected by filtration, then washed with
MeOH/H2O (2 × 10 mL), DCM (2 × 10 mL), MeOH (2 × 10
mL), and ether (10 mL). The resin was then dried overnight in a
vacuum oven (40 °C, 5 mmHg) to afford 10b as yellow beads: IR
(single bead reflectance) 1596.4, 1491.5, 1451.7, 1300.6, 1143.3
cm-1
.
(2Z,6Z,10E,14E)-1-(tert-Butyldiphenyl)silyloxy-3,7,11,15,19-pen-
tamethyl-9-(PS/DVB-sulfonyl)icosa-2,6,10,14,18-pentaene (9a). Poly-
mer 8 (500 mg) was swollen in THF (3 mL) for 15 min, and the
freshly prepared dimsyl anion THF solution (3 equiv, 1.2 mmol)
was added dropwise. The mixture was gently stirred for 2 h, the
excess dimsyl anion was removed, and the resin was washed with
dry THF (2 × 1 mL). The building block 4 (340 mg, 0.8 mmol) in
THF (5 mL) was added, and the mixture was gently stirred at
ambient temperature for 12 h. The resin was collected by filtration,
then washed with MeOH/H2O (2 × 10 mL), DCM (2 × 10 mL),
MeOH (2 × 10 mL), and ether (10 mL). The resin was then dried
overnight in a vacuum oven (40 °C, 5 mmHg) to afford 9a as yellow
beads: IR (single bead reflectance) 1596.6, 1492.9, 1451.0, 1301.9,
cm-1
.
(2Z,6Z,10Z,14Z,18E,22E)-3,7,11,15,19,23,27-Heptamethyltriaconta-
2,6,10,14,18,22,26-heptaen-1-ol (11).8 Lithium triethylborohydride
(Super Hydride) (1.0 M in THF, 0.4 mmol, 0.4 mL) was added
dropwise over 2 h to a solution of 10b (100 mg) and bis(diphe-
nylphosphino)propanepalladium(II) dichloride [(dppp)PdCl2] (2.3
mg, 0.004 mmol) in THF (1.0 mL) at 0 °C. After the mixture was
stirred for 12 h, the reaction was quenched with satd. NH4Cl (1
mL) and the resin was removed by filtration. The filtrate was
extracted with ether (3 × 2 mL). The combined organic extracts
were washed with satd. NH4Cl (1 × 2 mL) and brine (2 × 2 mL),
concentrated, and then purified by CC (17% EtOAc in hexanes) to
give 11 (14.6 mg, 0.029 mmol, 37% for 8 steps from 1) as a
colorless oil: Analytical RP-HPLC (Method A) tR ) 12.5 min; 1H
NMR (600 MHz, CDCl3) δ 1.58 (s, 9H), 1.66 (s, 12H), 1.72 (s,
3H), 1.94-2.07 (m, 24H), 4.07 (d, 2H, J ) 7.0 Hz), 5.07-5.11
(m, 6H), 5.41 (t, 1H, J ) 7.0 Hz); 13C NMR (150 MHz, CDCl3) δ
139.8, 136.0, 135.4, 135.3, 135.2, 134.9, 131.2, 125.0, 124.9, 124.6,
124.5, 124.4, 124.2, 124.1, 59.0, 39.8, 39.7, 32.3, 32.2, 32.0, 31.9,
26.8-26.3 (several, m), 25.6, 23.4, 23.3, 17.6, 16.0; HRMS calcd
for [C35H58O + Na]+ 517.4380, found 517.4379.
1142.8, 1110.4 cm-1
.
(2Z,6Z,10E,14E)-3,7,11,15,19-pentamethyl-9-(PS/DVB-sulfonyl)i-
cosa-2,6,10,14,18-pentaen-1-ol (9b). Polymer 9a (500 mg) was
swollen in THF (3 mL) for 15 min, and TBAF (1.0 M in THF, 5
equiv, 2 mmol, 2 mL) was added. The reaction was stirred at
ambient temperature for 8 h, and the resin was collected by filtration,
then washed with MeOH/H2O (2 × 10 mL), DCM (2 × 10 mL),
MeOH (2 × 10 mL), and ether (10 mL). The resin was then dried
overnight in a vacuum oven (40 °C, 5 mmHg) to afford 9b as yellow
beads: IR (single bead reflectance) 1596.6, 1492.9, 1451.0, 1301.9,
(2Z,6Z,10Z,14Z,18Z)-22-Benzyloxy-3,7,11,15,19-pentamethyl-
docosa-2,6,10,14,18-pentaen-1-ol (19). Starting from resin 1 with
building blocks 12 and 4 (two cycles), the reaction was carried
out, as that described for 11, to give 19 (14.2 mg, 0.029 mmol,
36% overall yield from 1) as a colorless oil after purification with
CC (17% EtOAc in hexanes): Analytical RP-HPLC (Method A) tR
1142.8 cm-1
.
(2Z,6Z,10E,14E)-1-Chloro-3,7,11,15,19-pentamethyl-9-(PS/DVB-
sulfonyl)icosa-2,6,10,14,18-pentaene (9c). Polymer 9b (500 mg) was
swollen in DMF (5 mL) for 15 min. After addition of LiCl (0.17
g, 4.0 mmol) and collidine (0.78 g, 6.4 mmol), MsCl (0.28 g, 2.4
mmol) was added dropwise into the mixture at 0 °C. The mixture
was gently stirred for 2 h and quenched with H2O, then the resin
was collected by filtration, washed with MeOH/H2O (2 × 10 mL),
DCM (2 × 10 mL), MeOH (2 × 10 mL), and ether (10 mL), and
allowed to dry in air at ambient temperature for 2 h to afford 9c as
yellow beads: IR (single bead reflectance) 1596.5, 1492.6, 1451.4,
1
) 5.1 min; H NMR (600 MHz, CDCl3) δ 1.58-1.69 (m, 14H),
1.72 (s, 3H), 1.91-2.07 (m, 18H), 3.43 (t, 2H, J ) 6.6 Hz), 4.07
(t, 2H, J ) 5.0 Hz), 4.48 (s, 2H), 5.09-5.13 (m, 4H), 5.42 (d, 1H,
J ) 6.8 Hz), 7.25-7.32 (m, 5H); HRMS calcd for [C34H52O2 +
Na]+ 515.3860, found 515.3864.
(2Z,6Z,10Z,14Z,18Z)-22-(4-Methoxybenzyloxy)-3,7,11,15,19-pen-
tamethyldocosa-2,6,10,14,18-pentaen-1-ol (20). Starting from resin
1 with building blocks 13 and 4 (two cycles), the reaction was
carried out, as that described for 11, to give 20 (16.3 mg, 0.031
mmol, 39% overall yield from 1) as a colorless oil after purification
with CC (17% EtOAc in hexanes): Analytical RP-HPLC (Method
1301.8, 1141.5 cm-1
.
(2Z,6Z,10E,14E)-3,7,11,15,19-Pentamethyl-1-phenylsulfonyl-9-
(PS/DVB-sulfonyl)icosa-2,6,10,14,18-pentaene (9d). Polymer 9c
(500 mg) was swollen in DMF/THF (1:1, 3 mL) at room
temperature for 15 min, and benzenesulfinic acid sodium salt (3.3
g, 2 mol) was added. The mixture was gently stirred at 60 °C for
48 h. The resin was collected by filtration, then washed with MeOH/
1
A) tR ) 5.3 min; H NMR (600 MHz, CDCl3) δ 1.58-1.67 (m,
14H), 1.72 (S, 3H), 1.95-2.07 (m, 18H), 3.40 (t, 2H, J ) 6.6 Hz),
7202 J. Org. Chem. Vol. 73, No. 18, 2008

Organic Synthesis of Polyisoprenoid Alcohols
3.78 (S, 3H), 4.07 (d, 2H, J ) 6.8 Hz), 4.40 (s, 2H), 5.08-5.12
(m, 4H), 5.42 (t, 1H, J ) 7.1 Hz), 6.85 (d, 2H, J ) 8.6 Hz), 7.24
(d, 2H J ) 8.4 Hz); HRMS calcd for [C35H54O3 + Na]+ 545.3965,
found 545.3961.
yield from starting resin 1) as a colorless oil after purification with
CC (17% EtOAc in hexanes). Alternatively, undecaprenol 24 was
prepared from resin 1 with building blocks 2 and 26 (two cycles
via 25) in 34% yield after purification with CC (17% EtOAc in
hexanes): Analytical RP-HPLC (Method C) tR ) 6.0 min; 1H NMR
(600 MHz, CDCl3) δ 1.62 (s, 9H), 1.70 (s, 24H), 1.77 (s, 3H),
1.98-2.12 (m, 40H), 4.11 (d, 2H, J ) 5.0 Hz), 5.11-5.16 (m,
10H), 5.47 (t, 1H, J ) 7.0 Hz); HRMS calcd for [C55H90O + NH4]+
784.7330, found 784.7338.
(2Z,6Z,10Z,14Z,18Z)-3,7,11,15,19-Pentamethyl-22-(tetrahydro-
2H-pyran-2-yloxy)docosa-2,6,10,14,18-pentaen-1-ol (21). Starting
from resin 1 with building blocks 14 and 4 (two cycles), the reaction
was carried out, as that described for 11, to give 21 (12.4 mg, 0.026
mmol, 32% overall yield from 1) as a colorless oil after purification
with CC (17% EtOAc in hexanes): Analytical RP-HPLC (Method
1
Acknowledgment. This work was supported by the National
Science Council and Academic Sinica.
A) tR ) 5.5 min; H NMR (600 MHz, CDCl3) δ 1.47-1.70 (m,
20H), 1.72 (s, 3H), 1.98-2.07 (m, 18H), 3.35 (m, 1H), 3.47 (m,
1H), 3.69 (m, 1H), 3.84 (m, 1H), 4.06 (d, 2H, J ) 6.0 Hz), 4.55 (t,
1H, J ) 3.9 Hz), 5.08-5.11 (m, 4H), 5.41 (t, 1H, J ) 7.1 Hz);
HRMS calcd for [C32H53O3 + Na]+ 508.3892, found 508.3892.
(2Z,6Z,10Z,14Z,18Z,22Z,26Z,30Z,34E,38E)-3,7,11,15,19,23,27,
31,35,39,43-Undecamethylpentaconta-2,6,10,14,18,22,26,30,34,38,
42-undecaen-1-ol (24).8 Starting from resin 1 with building blocks
2 and 4, four cycles of reaction sequence were carried out, as that
described for 11, to give 24 (6.7 mg, 0.0088 mmol, 11% overall
Supporting Information Available: General procedures and
preparation procedures for compounds 3, 17, 18, 22, and 23
1
and copies of H and 13C NMR spectra for the compounds
prepared. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO8010182
J. Org. Chem. Vol. 73, No. 18, 2008 7203