Efficient and highly selective cyclization induced by Lewis acid to generate 2-hydroxyl-α-cyclogeraniol

Article abstract of DOI:10.1080/00397911.2016.1239739

A cyclization reaction of the hydroxyl-protected geraniol epoxide induced by the different Lewis acids to generate 2-hydroxyl-α-cyclogeraniol has been explored. Compared with the previous methods, this method enhances the production and selectivity of this reaction without the consumption of a large amount of solvent. Also, the coordination of the metal with two oxygen atoms of hydroxyl groups might be crucial for the reaction is first addressed.

Full text of DOI:10.1080/00397911.2016.1239739

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient and highly selective cyclization
induced by Lewis acid to generate 2-hydroxyl-α-
cyclogeraniol
Zi Wang, Weiyi Qi, Yixuan Yan, Youhong Hu & Linhua Song
To cite this article: Zi Wang, Weiyi Qi, Yixuan Yan, Youhong Hu & Linhua Song (2016) Efficient
and highly selective cyclization induced by Lewis acid to generate 2-hydroxyl-α-cyclogeraniol,
Synthetic Communications, 46:23, 1932-1939, DOI: 10.1080/00397911.2016.1239739
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1239739
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Date: 17 November 2016, At: 02:43

SYNTHETIC COMMUNICATIONS®
2016, VOL. 46, NO. 23, 1932–1939
http://dx.doi.org/10.1080/00397911.2016.1239739
Efficient and highly selective cyclization induced by Lewis acid
to generate 2-hydroxyl-α-cyclogeraniol
Zi Wanga, Weiyi Qib, Yixuan Yanc, Youhong Hub, and Linhua Songa
b
aCollege of Science, China University of Petroleum (East China), Qingdao, China; State Key Laboratory of Drug
c
Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; School of
Pharmacy Lanzhou University, Lanzhou, Gansu, China
ABSTRACT
ARTICLE HISTORY
Received 5 July 2016
A cyclization reaction of the hydroxyl-protected geraniol epoxide
induced by the different Lewis acids to generate 2-hydroxyl-α-
cyclogeraniol has been explored. Compared with the previous
methods, this method enhances the production and selectivity of
this reaction without the consumption of a large amount of solvent.
Also, the coordination of the metal with two oxygen atoms of
hydroxyl groups might be crucial for the reaction is first addressed.
KEYWORDS
concentration; cyclization;
2-Hydroxyl-α-cyclogeraniol;
Lewis acids; protecting
groups
GRAPHICAL ABSTRACT
Introduction
2-Hydroxyl-α-cyclogeraniol, which derives from inexpensive geranyl acetate, is an important
intermediate in the total synthesis of many natural products, e.g., R-damascone,[1]
(þ)-apotrisporin E,[2] and (–)-karahana ether[3] (Fig. 1). Also, the structure of this unit
was found in a large variety of substances, such as taxol,[4] achilleol A,[5] and cordiaquinones
C,[6g] which exhibit potent biological activities (Fig. 1).
Although electrophilic cyclization induced by Lewis acid was chosen as an efficient
synthetic method to construct terpenoids and other cyclic compounds,[6] few methods
devised to synthesize 2-hydroxyl-α-cyclogeraniol involved the cyclization of geraniol
epoxide with unsatisfied results (Scheme 1). For example, zirconium tetrachloride
mediated the cyclization of geraniol epoxide to produce 2-hydroxyl-α-cyclogeraniol by
carrying out at low concentration (approximately ca. 0.007 M of substrate)[7] (Scheme 1,
A). It means to scale up the reaction by consuming large amounts of solvent and operate
CONTACT Linhua Song
Qingdao, 266580, China.
281170984@qq.com
College of Science, China University of Petroleum (East China),
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data (full experimental details, 1H and13CNMR spectra, HRMS, and x-ray crystal data) can be accessed on
the publisher’s website.
© 2016 Taylor & Francis

SYNTHETIC COMMUNICATIONS®
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Figure 1. Natural products and bioactive related compounds with the cyclogeraniol core.
Scheme 1. Previous methods to prepare 2-hydroxyl-α-cyclogeraniol.
the synthetic procedure with difficultly. The cyclization of tetramethylsilane (TMS)–
protected geraniol epoxide by the treatment of tin tetrachloride affords 2-hydroxyl-α-
cyclogeraniol as an endo-olefin with the by-product of exo-olefin, which was hardly
separated by chromatography[4] (Scheme 1, B). Moreover, the yields (52–66%) of these
reactions still need to be improved. To solve these problems, we herein describe an efficient
method to produce 2-hydroxyl-α-cyclogeraniol and its derivatives selectively from
hydroxyl-protected geraniol epoxide at high concentration by ZrCl4 or FeCl3. In addition,
we disclose the coordination of the metal with two oxygen atoms might be crucial for the
selectivity of endo formation, avoiding the ether generation.
Results and discussion
Considering that free hydroxyl group might have an effect on the reaction at high
concentration of ZrCl4,[7] we used TMS-protected geraniol epoxide 1a as the substrate to
investigate this reaction. Compound 1a was synthesized from commercially available

1934
Z. WANG ET AL.
geranyl acetate by Sharpless asymmetric dihydroxylation (85% ee by high-performance
liquid chromatography, HPLC), methylsulfonyl chloride–assisted epoxidation and hydroxyl
protection with TMS.[4] When treated with 0.5 eq. of ZrCl4 for 1a, the desired endo-olefin 2a
was obtained in 50% yield with minor cycle inner ether 2c (Table 1, entry 1).
Encouraged by the result described, we examined the effect of equivalents and classes of
Lewis acids. An exploration of different equivalents of ZrCl4 uncovered that the reaction
induced by insufficient ZrCl4 could produce minor cycle ether 2c (Table 1, entries 1 and
2). However, more than 1.0 equiv. of ZrCl4 would decrease the yield of 2a and cause the
reaction complicated (Table 1, entries 4 and 5). One equiv. of ZrCl4 provided the efficient
reaction to give endo-olefin 2a in high yield without 2c (Table 1, entry 3). Surprisingly, the
metallic atom of the Lewis acid containing multiple empty electronic orbitals, such as
ZrCl4, FeCl3, TiCl4 (Table 1, entries 3, 6, and 7), generates endo-olefin 2a as the sole
product. In contrast, the other Lewis acid (Table 1, entries 9–12) possessing fewer empty
orbitals could produce a certain amount of cycle ether 2c. Moreover, the reaction induced
by ZrCl4 or FeCl3 did not form exo-olefin comparing with SnCl4. Noteworthy, FeCl3 as the
cheap and environmentally friendly Lewis acid can also promote cyclization of epoxide
to endo-olefin efficiently. When 2 mol% of TfOH was tested in the cyclization, only the
deprotection of substrate occurred (Table 1, entry 13).
Subsequent studies for among different concentrations of substrate 1a showed that the
yield of the reaction would be decreased by the increasing the concentration of the substrate
using ZrCl4 or FeCl3 as Lewis acid (Table 2, entries 1–3). Also, reducing reaction tem-
perature (Table 2, entries 4 and 5) or using some other solvent, such as hexane, toluene,
Table 1. Optimization of acid for the cyclization of 1a.a
2a and 2b
Entry
Acid
Eq.
Yieldb (%)
Ratioc
Yield of 2cb (%)
1
ZrCl4
ZrCl4
0.5
0.75
1
50
100:0
100:0
100:0
100:0
—
100:0
100:0
81:19
100:0
78:22
77:23
66:33
19
7
2
68
3
ZrCl4
80
66
—
—
—
—
—
—
19
35
28
16
—
4
ZrCl4
ZrCl4
FeCl3
TiCl4
SnCl4
InBr3
AlCl3
BF3•Et2O
ZnCl2
TfOH
1.5
2
5
Complicated
6
1
76
38
62
24
32
31
33
7
1
8
1
9
1
10
11
12
13
1
1
1
0.02
Deprotection
aUnless otherwise noted, reactions were carried out under the standard conditions.
bYield of isolated product based on 1a of 0.5-mmol scale.
cDetermined by 1H NMR.

SYNTHETIC COMMUNICATIONS®
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Table 2. Optimizing for the concentration of epoxide 1a, reaction temperature, and solvent.a
Entry
Lewis acid
Temp.
Solvent
Concentration of 1a (M)
Yieldb (%)
1
ZrCl4
ZrCl4
FeCl3
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrCl4
rt
rt
DCM
DCM
0.2
0.5
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
69
2
44
3
rt
DCM
66
63
41
39
75
38
4
0 °C
–20 °C
rt
DCM
DCM
Hexane
Toluene
CH3CN
THF
5
6
7
rt
8
rt
9
rt
Deprotection
Complicated
Complicated
10
11
rt
DMF
DMSO
rt
aUnless otherwise noted, reactions were carried out under the standard conditions.
bYield of isolated product based on 1a of 0.5-mmol scale.
and acetonitrile (Table 2, entries 6–8) would decrease the yield. Probably owing to the effect
of oxygen in tetrahydrofuran (THF) on Lewis acid, when using THF as solvent, only the
deprotection of 1a occured (Table 2, entries 9). In addition, solvent DMF or DMSO, which
contain acyl or sulfinyl, would totally complicate the cyclization (Table 2, entries 10 and 11).
Next, we applied the optimized condition to various hydroxyl protected epoxides 1 to
find the correlation of the reaction with another oxygen. As expected, 1b without a protect-
ing group gives 2a in low yield, accompanied by complicated products as reported before.[7]
The different silyl protecting group for hydroxyl could afford 2a in the moderate yields
(Table 3, entries 2 and 3). Obviously, the steric hindering effect impacts the reaction
dramatically. With the alkoxy group, the substrate 1e or 1f could also be transformed to
the corresponding product in good yield efficiently and selectively (Table 3, entries 4 and
5). However, the reaction that acyl group was selected as a protecting group (Table 3, entries
6 and 7) generated the endo-olefin along with exo-olefin in low yield. In addition, when
replacing hydroxy of substrate with methyl, only minor tetra-substituted olefin 2i was
generated (Table 3, entry 8). From these results, the factors of Lewis acid possessing multiple
empty orbitals together with the protected hydroxy play important roles in the cyclization to
produce the desired endo-olefin 2.
To explain this results and the configuration of the product, we proposed the mechanism
shown in Scheme 2. At first, epoxide 1a is cleaved under the inducement of zirconium
tetrachloride to produce cationic species M1, which undergoes π-electron pair transfer to
cyclic intermediate M2. Because of the multiple empty orbitals of zirconium, the metal could
strongly coordinate with two oxygen atoms to constitute part of the potential favorable
six-membered ring, which can stabilize carbocation M2 and prevent the formation of cyclic
ether. It may be the reason that employing the Lewis acid insufficiently (Table 1, entries 1
and 2) or the other Lewis acid without enough empty orbitals (Table 1, entries 9–12) formed
the internal ether. Moreover, the electron-withdrawing and steric hindering group would
decrease the effect of coordination between zirconium and oxygen atoms of hydroxyl
groups, and then restrained the formation of six-membered ring to afford the endo-olefin
2 in lower yield (Table 3, entries 6 and 7). Analogously, the yield of reaction that involved

1936
Z. WANG ET AL.
Table 3. Effect on the different R groups for the cyclization.a
Entry
1
1
Yield of 2b (%)
2
25
2
3
4
59
63
67
5
6
66
13
7
8
17
15
aUnless otherwise noted, reactions were carried out under the standard conditions.
bYield of isolated product based on 1 of 0.5-mmol scale.
cDetermined by 1H NMR.
1i without hydroxyl oxygen selected as substrate was lower (Table 3, entry 8), probably
because the formation of six-membered ring could be totally prevented. After favorable
β-elimination of proton of M2, corresponding olefin 2a can be generated.
Under the optimized reaction conditions, we also investigated the ability of ZrCl4 to
promote the cyclization reaction of chiral epoxyneryl ether 1j, which was synthesized from

SYNTHETIC COMMUNICATIONS®
1937
Scheme 2. Proposed mechanism.
neryl acetate by the similar procedure. The compound 2j is the transformation by
the analysis of nuclear Overhauser effect (NOE) spectra and further confirmed by x-ray
crystallographic analysis[8] (Scheme 3). According to the proposed mechanism, the desired
product 2j was obtained in a reasonable, low yield due to axial TMS-carbinol group of 1j,
which prevented the formation of Zr-O six-membered ring.
Scheme 3. Cyclization of epoxyneryl ether 1j to trans-diol 2j.

1938
Z. WANG ET AL.
Conclusion
In conclusion, we have developed an efficient and solvent-saving electrophilic cyclization of
the hydroxyl-protected geraniol epoxide, which promoted by zirconium tetrachloride or
ferric trichloride. Notably, the factors of Lewis acid possessing multiple empty orbitals
together with the protecting group for hydroxyl play important roles in the cyclization
to produce the desired endo-olefin 2. We first proposed that the coordination of the metal
with two oxygen atoms of hydroxyl groups might be crucial for the reaction. Under the
optimized reaction condition, (2R,6R)-2-hydroxyl-α-cyclogeraniol 2j was synthesized and
confirmed by x-ray crystallographic analysis. This efficient and easily operational method
could be applicable to the preparation of intermediate of numerous natural products and
bioactive molecule.
Experimental
All reactions were performed in oven-dried flask containing a septum and Teflon-coated
stirrer bar under a nitrogen atmosphere. All 1H NMR and 13C NMR spectra were measured
in CDCl3 or d-DMSO with TMS as the internal standard. Chemical shifts are expressed in
parts per million (ppm) and J values are given in hertz (Hz). Infrared (IR) spectra were
obtained on a Lumex Infralum FT-02 spectrometer with absorption in cmÀ 1. Column
chromatography was performed with 200- to 300-mesh silica gel.
Standard condition for preparing 2a
ZrCl4 (117 mg, 0.5 mmol) was added to a solution of 1a (121 mg, 0.5 mmol) in dry DCM
(5 mL) at room temperature under nitrogen atmosphere. After stirring for 1 h, 1.0 M HCl
(5 mL) was added and the two layers were separated. The aqueous layer was extracted
with DCM (3 � 10 mL) and the combined organic layers were washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica-gel chromatography (PE/EA ¼ 3) to afford
2a (68 mg, 80%).
(2R,6S)-2-Hydroxyl-α-cyclogeraniol (2a)
Rf ¼ 0.42 (stained by PMA, PE/EA ¼ 2:1). IR (KBr, cmÀ 1): 3226, 2975, 2919, 2884, 1713,
1674, 1472, 1036, 906. 1H NMR (500 MHz, chloroform-d) δ 5.49 (ddq, J ¼ 5.3, 2.7,
1.4 Hz, 1H), 3.81 (d, J ¼ 2.5 Hz, 2H), 3.66 (d, J ¼ 43.4 Hz, 2H), 3.44 (d, J ¼ 4.8 Hz, 1H),
2.42 (ddq, J ¼ 18.7, 5.0, 2.5 Hz, 1H), 2.15 (dddd, J ¼ 18.6, 4.3, 2.6, 1.3 Hz, 1H), 1.79 (h,
J ¼ 1.2 Hz, 3H), 1.77 (s, 1H), 1.14 (s, 3H), 0.98 (s, 3H). 13C NMR (126 MHz, chloroform-
d) δ 131.62, 120.42, 71.41, 58.81, 51.10, 37.16, 32.28, 28.62, 24.36, 22.61. HRMS (EI) calcd.
for [M]þ: 170.1307; found: 170.1306.
Funding
The authors thank the National Natural Science Foundation of China (81225022) for financial
support.

SYNTHETIC COMMUNICATIONS®
1939
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