Two-step, stereoselective synthesis of linalyl oxides by asymmetric allylic O-alkylation

Article abstract of DOI:10.1016/j.tetasy.2010.08.011

Each of the four tetrahydrofuran linalyl oxides was prepared by a Sharpless asymmetric dihydroxylation of geranyl acetate with AD-mix-α or AD-mix-β, followed by a stereoselective palladium-mediated cyclization using the chiral ligand C₃-TunePhos.

Full text of DOI:10.1016/j.tetasy.2010.08.011

Tetrahedron: Asymmetry 21 (2010) 2425–2428
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Two-step, stereoselective synthesis of linalyl oxides by asymmetric allylic
O-alkylation
⇑
Kanny K. Wan, Jonathan P. Litz, David A. Vosburg
Department of Chemistry, Harvey Mudd College, Claremont, CA 91711, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Each of the four tetrahydrofuran linalyl oxides was prepared by a Sharpless asymmetric dihydroxylation
Received 11 August 2010
Accepted 12 August 2010
Available online 20 October 2010
of geranyl acetate with AD-mix-
a or AD-mix-b, followed by a stereoselective palladium-mediated cycli-
zation using the chiral ligand C3-TunePhos.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
mediated cyclization reaction with (S)- or (R)-C3-TunePhos. This
strategy is conceptually related to a study by Sinou et al. that
used achiral ligands, racemic diols, and allylic carbonate leaving
groups.3a
Asymmetric transition-metal-catalyzed allylic alkylation has
emerged as a powerful reaction for the formation of stereocenters
in both inter- and intramolecular contexts.1 Typical reaction part-
ners are soft, polarizable nucleophiles (such as malonates, carbox-
ylates, and phenols) and unhindered allylic electrophiles
(normally with a disubstituted alkene). Examples with weak
nucleophiles or more hindered electrophiles are known,2 but
the combination of these factors for an asymmetric reaction is
quite rare.3 During the course of our synthesis of the antifungal
natural product davanone, we found that the chiral ligand (S)-
C3-TunePhos enabled a stereoselective cyclization of hydroxyester
1 to davana acid ethyl ester 2a as shown in Scheme 1.3b The use
of the enantiomeric ligand (R)-C3-TunePhos resulted in the trans
diastereomer 2b. Notably, these diastereoselective intramolecular
allylic alkylation reactions combine a weak nucleophile and a
The stereoselectivities of the cyclization reactions were similar
to those observed in the davanone synthesis. The most selective
cyclizations occurred with TunePhos ligands, and the reaction
was complete in 72 h at 88 °C or 5 min at 200 °C in a microwave.7
While we had refrained from adding a base in the cyclization of 1
due to the possibility of promoting an undesired retro-aldol reac-
tion under these forcing conditions, we found that triethylamine
moderately enhanced the stereoselectivity of cyclizations with
3a and 3b. Our most significant results are summarized in Table 1.
The greatest selectivity for the cis product was 2.2:1, while the
greatest selectivity for the trans product was 19:1. The difficulty
of selectively producing the cis product may be attributed to diax-
ial strain in the transition state.3a Other solvents (hexanes, tolu-
ene, dichloroethane, NMP, and DMSO) resulted in less selective
reactions and the geometry of the double bond (i.e., geranyl ver-
sus neryl) had no effect on the reaction diastereoselectivity, as
observed previously.3a Altering the nature of the leaving group of-
fered no advantages (Scheme 3 and Table 2).8 Methyl carbonate
59 gave very similar results to acetate 3a, while tertiary acetate
6, derived from (À)-linalool,10 yielded low selectivity in the
cyclizations.
hindered allylic electrophile to generate
stereocenter.
a fully substituted
2. Results and discussion
Encouraged by these results in the davanone synthesis, we
examined the stereoselectivity of a closely related cyclization
in the synthesis of the furanoid linalyl oxides (see Scheme 2).
These natural products are found in essential oils and are used
in commercial perfumes;4 they can be prepared by a number
of different synthetic routes.3a,5 Most of these syntheses are
lengthy and also produce isomeric pyranoid compounds. We
envisaged a two-step synthesis of each of the four possible fura-
noid linalyl oxides using a Sharpless asymmetric dihydroxylation
of geranyl acetate to give 3a or 3b6 followed by a palladium-
3. Conclusion
In conclusion, we have described a two-step, diastereoselective
synthesis of furanoid linalyl oxides using a Sharpless asymmetric
dihydroxylation and a diastereoselective cyclization using palla-
dium and C3-TunePhos. No protecting groups are required, both
steps are catalytic, and no competing elimination or cyclization
to the isomeric pyranoid linalyl oxides is observed.
⇑
Corresponding author. Tel.: +1 909 607 9701; fax: +1 909 607 7577.
E-mail address: vosburg@hmc.edu (D.A. Vosburg).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.011

2426
K. K. Wan et al. / Tetrahedron: Asymmetry 21 (2010) 2425–2428
O
H
O
OEt
OH
O
2a
AcO
a or b
+
OEt
O
H
O
1
OEt
2b
Scheme 1. Asymmetric allylic alkylation in the synthesis of davanone.3b Reagents and conditions: (a) Pd2(dba)3, (S)-C3-TunePhos, THF, 88 °C, 72 h, 2a/2b 2.5:1; (b) Pd2(dba)3,
(R)-C3-TunePhos, THF, 88 °C, 72 h, 2a/2b 1:12.
H
O
OH
OH
OH
OH
OH
MeO2CO
a or b
OH
(R)
(S)
(S)
4a + 4b
(S)
AcO
a or b
4a
(S)
H
O
5
6
3a
OH
(S)
4b
OH
(R)
AcO
a or b
4a + 4b
(S)
H
O
OH
OH
OH
OH
(S)
(R)
(R)
c or d
AcO
4c
Scheme 3. Variation of allylic electrophiles for the cyclization reaction. Reagents
and conditions: (a) Pd2(dba)3, (S)-C3-TunePhos, THF, 88 °C, 72 h; (b) Pd2(dba)3, (R)-
C3-TunePhos, THF, 88 °C, 72 h. See Table 2 for results.
(R)
H
O
3b
(R)
4d
Scheme 2. Synthesis of linalyl oxides by diastereoselective, palladium-catalyzed
cyclizations. Reagents and conditions: (a) Pd2(dba)3, (S)-C3-TunePhos, Et3N, THF,
88 °C, 72 h, 4a/4b 2.2:1; (b) Pd2(dba)3, (R)-C3-TunePhos, Et3N, THF, 88 °C, 72 h, 4a/
4b 1:19; (c) Pd2(dba)3, (R)-C3-TunePhos, Et3N, THF, 88 °C, 72 h, 4c/4d 2.2:1; (d)
Pd2(dba)3, (S)-C3-TunePhos, Et3N, THF, 88 °C, 72 h, 4c/4d 1:19.
stirring. Anhydrous tetrahydrofuran was obtained from a SolvPure
anhydrous solvent system using activated alumina. Napthyl and
phenyl Trost ligands and Pd(PPh3)4, were purchased from Strem.
Pd2(dba)3 was purchased from Frontier, tert-butanol was pur-
chased from Fisher, and ethanol was purchased from AAPER. All
other chemicals were purchased from Sigma–Aldrich, Alfa Aesar,
or Spectrum. Triethylamine was distilled from CaH2 and stored
over KOH before use. Reactions were monitored with thin-layer
chromatography (TLC) on glass plates coated with mesh 400 silica
gel and visualized under UV light or with anisaldehyde stain. Con-
centration refers to evaporation on a rotary evaporator, followed
by evaporation on a vacuum line as necessary. Column chromatog-
4. Experimental
4.1. General
All reactions, unless otherwise noted, were carried out under an
atmosphere of argon using oven-dried glassware and magnetic
Table 1
Ligand screen for the diastereoselective cyclization of 3a to cis-4a and trans-4b linalyl oxidesa
Entry
Ligand
Additional conditions
Et3N (2 equiv)
4a (cis)/4b (trans) ratio
% Conversion
1a
2b
(R)-C3-TunePhos
(R)-C3-TunePhos
(R)-C3-TunePhos
(R)-C3-TunePhos
(S,S)-DuPhos
(R,R)-DACH-naphthyl Trost
(R)-Binap
(R,R)-Diop
1:19
1:11
1:9
100
100
100
100
25
65
100
92
100
100
49
96
93
3c
DBU
Toluene
4d
1:7
5b
1:4.2
1:3.7
1:3.4
1:3.3
1:2.4
1:2.3
1:2.0
1:1.5
1.5:1
2:1
6b
7b
8b
9b
(S,S)-DACH-phenyl Trost
(R,R)-DACH-phenyl Trost
(S,R)-JosiPhos
10b
11b
12b
13b
14b
15a
(S)-Binap
(S)-DifluorPhos
(S)-C3-TunePhos
(S)-C3-TunePhos
100
100
Et3N (2 equiv)
2.2:1
a
b
c
The reaction was conducted for 72 h at 88 °C with 3a, ligand, Pd2(dba)3, Et3N and THF.
The reaction was conducted for 72 h at 88 °C with 3a, ligand, Pd2(dba)3 and THF.
The reaction was conducted for 72 h at 88 °C with 3a, ligand, Pd2(dba)3, DBU and THF.
The reaction was conducted for 72 h at 88 °C with 3a, ligand, Pd2(dba)3 and toluene.
d

K. K. Wan et al. / Tetrahedron: Asymmetry 21 (2010) 2425–2428
2427
Table 2
Substrate comparison for asymmetric allylic alkylation reactionsa
Entry
Starting material
Ligand
4a (cis)/4b (trans) ratio
% Conversion
1
2
3
4
Geranyl methyl carbonate diol 5
Geranyl methyl carbonate diol 5
Linalyl acetate diol 6
(R)-C3-TunePhos
(S)-C3-TunePhos
(R)-C3-TunePhos
(S)-C3-TunePhos
1:5.8
1.5:1
1:2
100
100
100
100
Linalyl acetate diol 6
1:1.4
a
The reactions were conducted for 72 h at 88 °C with starting material, ligand, Pd2(dba)3, and THF.
raphy was performed using silica gel. 1H NMR spectra were re-
corded on a Bruker Avance 400 MHz spectrometer at ambient tem-
perature. Data are reported as follows: chemical shift in parts per
million (d, ppm) with chloroform (CHCl3) taken as 7.26 ppm,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, and
m = multiplet), coupling constants (Hz), and integration. GC–MS
was performed with an Agilent 5975C using electron impact ioni-
zation. Electrospray ionization MS (ESI-MS) was performed using a
Varian 500-MS with an ion trap.
the TunePhos and thereby improve chromatographic separation.
The reaction was stirred at room temperature for an additional
30 min. The organic layer was then extracted with ether, washed
with brine, dried with MgSO4, filtered through Celite, and concen-
trated. The cyclization diastereoselectivity was determined by 1H
NMR analysis of the crude product. Purification using flash chro-
matography (10:1 hexanes/ether) resulted in a mixture of two dia-
stereomeric linalyl oxides.
4.5. (2R,5S)-Linalyl oxide 4a or (2S,5R)-linalyl oxide 4c
4.2. (6S)-Geranyl acetate diol 3a
Rf = 0.7 (1:1 hexane/ether); 1H NMR (400 MHz, CDCl3): d = 5.96–
6.03 (dd, J = 17.7, 10.8, 1H, @CH–), 5.21 (dd, J = 17.0, 1.4, 1H,
@CHH), 5.01 (dd, J = 10.5, 1.5, 1H, @CHH), 3.87 (t, J = 7.0, 1H,
CHO), 2.19 (s, 1 H, OH), 1.71–1.94 (m, 4H, CH2CH2), 1.33 (s, 3H,
CH3), 1.25 (s, 3H, CH3), 1.16 (s, 3H, CH3). These data are in agree-
ment with the literature;3a,5f,l GC–MS (EI): m/z (%) 155(8)
(M+ÀCH3), 137(9) (M+ÀCH3–H2O), 111(42) (M+ÀC3H7O), 94(62),
82(26), 59(100) (C3H7O).
Following the general procedure of Vidari,5k AD-mix-
a (17.53 g)
and MeSO2NH2 (1.22 g, 12.8 mmol) were dissolved in 1:1 t-BuOH/
H2O (128 mL). The stirred solution was cooled to 0ꢀC and geranyl
acetate (2.73 mL, 12.8 mmol) was added to the reaction mixture.
The resulting solution was kept at 0 °C for 24 h. The reaction was
then quenched by the addition of Na2SO3 (17.25 g, 128 mmol),
and the organic phase was extracted with methylene chloride,
washed with 2 M NaOH and brine, dried with MgSO4 and concen-
trated. The crude product was purified via flash chromatography
(4:1 hexanes/EtOAc) to obtain clean geranyl acetate diol (2.15 g,
9.34 mmol, 73% yield). The enantiomeric excess was determined
as 77% by 1H NMR analysis of its corresponding (R)-Mosher ester.
Rf = 0.1 (4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): 5.40 (tq,
J = 7.2, 1.3, 1H, @CH), 4.60 (td, J = 13.3, 7.2, 2H, OCH2), 3.36 (ddd,
J = 10.5, 2.0, 2.3, 1H, CHOH) 2.34 (m, 2H, CH2), 2.09–2.18 (m, 2H,
CH2), 2.07 (s, 3H, CH3), 1.73 (s, 3H, CH3), 1.58–1.67 (m, 1H, OH),
1.41–1.51 (m, 1H, OH), 1.22 (s, 3H, CH3), 1.18 (s, 3H, CH3); These
data are consistent with literature values;11 ESI-MS: 253.1
[M++Na+].
4.6. (2S,5S)-Linalyl oxide 4b or (2R,5R)-Linalyl oxide 4d
Rf = 0.7 (1:1 hexanes/ether); 1H NMR (400 MHz, CDCl3): d =
5.87–5.94 (dd, J = 17.7, 10.8, 1H, =CH-), 5.21 (dd, J = 17.0, 1.4, 1H,
@CHH), 5.01 (dd, J = 10.5, 1.5, 1H, @CHH), 3.82 (t, J = 7.0, 1H,
CHO), 2.19 (s, 1 H, OH), 1.71–1.94 (m, 4H, CH2CH2), 1.33 (s, 3H,
CH3), 1.25 (s, 3H, CH3), 1.16 (s, 3H, CH3). These data are in agree-
ment with the literature;3a,5f,l GC-MS (EI): m/z (%) 155(8)
(M+ÀCH3), 137(9) (M+ÀCH3–H2O), 111(42) (M+ÀC3H7O), 94 (62),
82(26), 59(100) (C3H7O).
Acknowledgments
4.3. (6R)-Geranyl acetate diol 3b
This work was supported by an Arnold and Mabel Beckman
Scholars Award (to K.K.W.), a Pfizer Summer Undergraduate
Research Fellowship (to J.P.L.), a Camille and Henry Dreyfus Foun-
dation Faculty Startup Award, National Science Foundation REU
Grant CHE-0353662, the Merck/AAAS Undergraduate Science
Research Program, the Beckman Foundation, the Harvey Mudd
College (HMC) Chemistry Department, and the Christian Scholars
Foundation. We thank Karen C. Morrison from HMC for her contri-
butions to this project.
Using the above procedure with AD-mix-b, the enantiomeric
geranyl acetate diol was obtained (2.47 g, 10.7 mmol, 84% yield).
The enantiomeric excess was determined to be 80% by 1H NMR
analysis of its corresponding (S)-Mosher ester. Rf = 0.1 (4:1 hex-
anes/EtOAc); 1H NMR (400 MHz, CDCl3): 5.40 (tq, J = 7.2, 1.3, 1H,
@CH), 4.60 (td, J = 13.3, 7.2, 2H, OCH2), 3.36 (ddd, J = 10.5, 2.0,
2.3, 1H, CHOH) 2.34 (m, 2H, CH2), 2.09–2.18 (m, 2H, CH2), 2.07
(s, 3H, CH3), 1.73 (s, 3H, CH3), 1.58–1.67 (m, 1H, OH), 1.41–1.51
(m, 1H, OH), 1.22 (s, 3H, CH3), 1.18 (s, 3H, CH3). These data are con-
sistent with literature values;11 ESI-MS: 253.1 [M++Na+].
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