A chiral pool and cross metathesis based synthesis of gingerdiols

Article abstract of DOI:10.1002/ejoc.201301727

Both (3R,5S)- and (3R,5R)-gingerdiols were synthesized. Their 1,3-diol motifs were derived from enantiopure epoxy chiral building blocks that were readily accessible from D-gluconolactone. The effect of deuterating the OH groups of the natural isomer on its optical rotation was also examined. In the course of the syntheses of the targets, an unexplored cross-metathesis (CM) reaction of unprotected 5-substituted pent-1-ene-3,5-diols was investigated, in which the CM product readily underwent an allylic epimerization and oxidation, as the starting diols rearranged into ketones with unprecedented ease. These problems were eventually resolved by performing the CM reaction in toluene in the presence of phenol. The cause of these unexpected, yet very interesting phenomena, was determined to be the presence of the unprotected OH group at C-5 of the 5-substituted pent-1-ene-3,5-diol. A mechanistic rationale is also presented. Copyright

Full text of DOI:10.1002/ejoc.201301727

FULL PAPER
DOI: 10.1002/ejoc.201301727
A Chiral Pool and Cross Metathesis Based Synthesis of Gingerdiols
Zhi-Li Wan,[a,b] Guo-Liang Zhang,[b] Hui-Jun Chen,[b] Yikang Wu,*[b] and Yan Li*[a]
Keywords: Natural products / Chiral pool / Total synthesis / Metathesis / Ruthenium / Alcohols
Both (3R,5S)- and (3R,5R)-gingerdiols were synthesized.
Their 1,3-diol motifs were derived from enantiopure epoxy
product readily underwent an allylic epimerization and oxi-
dation, as the starting diols rearranged into ketones with un-
precedented ease. These problems were eventually resolved
by performing the CM reaction in toluene in the presence of
phenol. The cause of these unexpected, yet very interesting
phenomena, was determined to be the presence of the un-
protected OH group at C-5 of the 5-substituted pent-1-ene-
3,5-diol. A mechanistic rationale is also presented.
chiral building blocks that were readily accessible from
D-
gluconolactone. The effect of deuterating the OH groups of
the natural isomer on its optical rotation was also examined.
In the course of the syntheses of the targets, an unexplored
cross-metathesis (CM) reaction of unprotected 5-substituted
pent-1-ene-3,5-diols was investigated, in which the CM
Introduction
Antioxidants are involved in various important bio-
logical and industrial processes and, therefore, have received
much attention from the scientific community. They have
anticancer, anticardiovascular, and anti-inflammatory prop-
erties as well as many other activities.[1] Substituted phenols
such as vitamin E as well as gingerols[2] and its derivatives
are among the most studied antioxidants.
Dihydrogingerol (i.e., gingerdiol, 1) was first isolated
from ginger by Murata[3] and co-workers in 1972, and its
planar structure was established by 1H NMR and IR analy-
ses of its triacetate (see Figure 1). Later, in 1992, Nakatani[4]
1
and co-workers disclosed the H NMR spectroscopic data
of (3R,5S)- and (3S,5S)-1 along with the 13C NMR, optical
rotation, and HRMS data. In 2007, both (3R,5S)- and
(3S,5S)-1 were also isolated by Liang and co-workers from
Ramulus cinnamomi (Cinnamomum cassin Presl., known for
centuries in China as the traditional Chinese medicine “Gui
Zhi”).[5]
Figure 1. The structures of 1 and 2 as well as those for the [6]-,
[8]-, and [10]-gingerols (square brackets indicate the position of the
hydroxy group with respect to the terminal methyl group).
A distinct feature of 1 is the presence of the 1,3-diol sub-
unit, which is a structural motif that is also found in hun-
dreds of other natural products.[6] To gain access to such
functionalities, we previously developed a practical route to
enantiopure epoxy chiral building blocks[7] by using inex-
pensive and readily available d-gluconolactone as the start-
ing material. With such epoxy chiral building blocks as the
source of the 1,3-diol subunit, a range of natural products
that contained this functionality were synthesized.[8] In this
endeavor, we targeted (3R,5S)-1[9] with the cis-1,3-diol con-
figuration, which is interestingly opposite to that of 2 (also
a natural product[8g,10]). For comparison,[11] unknown[11]
[a] Hubei Collaborative Innovation Center for Advanced Organic isomer (3R,5R)-1 was also synthesized.
Chemical Materials and Ministry-of-Education Key
During the synthesis of 1, several unexpected side prod-
Laboratory for Synthesis and Application of Organic
Functional Molecules, Hubei University,
ucts were produced in significant yields as a result of the
CM (cross-metathesis) reaction. Subsequent investigations
into this interesting phenomena led to the identification of
a key structural factor as the source of the unusual results.
These details add a useful piece of knowledge to this pres-
ently considered well-understood reaction and are pre-
sented herein.
Wuhan 430062, China
[b] State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
E-mail: yikangwu@sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301727.
2128
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2128–2139

A Chiral Pool and Cross Metathesis Based Synthesis of Gingerdiols
to give 8 in essentially 100% yield. Finally, the hydrolysis
of the acetyl protecting groups under alkaline conditions
afforded diol 9.
Results and Discussion
The synthesis of (3R,5S)-1 emerged from the ring-open-
ing reaction of the above-mentioned epoxy chiral building
block 3[7] by using nBuLi in the presence of CuI (see
Scheme 1). The reaction worked equally well if CuCN was
used in place of CuI. The resulting diol 4 was treated with
Ac2O in CH2Cl2 with the assistance of Et3N and 4-(dimeth-
ylamino)pyridine (DMAP) to give diacetate 5 in quantita-
tive yield.
The connection of the known[17a] substituted styrene 10
(also a natural product[17b]) to 9 was then attempted
through a CM reaction by using the Hoveyda–Grubbs II
catalyst (11, see Scheme 2 and Table 1).[17c] Initial trials
with CH2Cl2 as the solvent were not straightforward. The
self-coupling product of 10, substituted stilbene 12 (also a
natural product[17b]), was formed in significant quantities.
Unexpectedly, ketone 13[18] was also formed as a major
product, which accounted for 71% of added starting mate-
rial 9. A mixture of the desired CM products 14 and 14Ј
1
(inseparable, 14/14Ј, ~4:1 as shown by H NMR) was iso-
lated in 21% yield. Ketone 14ЈЈ[19] was also isolated in 7%
yield. Increasing the amounts of 10 and catalyst 11 (added
in portions several hours apart) in the reaction system did
not improve the yield of 14.
Scheme 1. Reagents and conditions: (a) nBuLi, tetrahydrofuran
(THF), CuI, –78 °C, 3 h, 91%; (b) Ac2O, Et3N, CH2Cl2, DMAP,
room temp., 4 h, 98%; (c) 2,3-dichloro-5,6-dicyano-1,4-benzoquin-
one (DDQ), MeCN/H2O (9:1 v/v), 50 °C, 1.5 h, 82% or AcOH/
H2O (4:1, v/v), 30 min, 84%; (d) methanesulfonyl chloride (MsCl),
Et3N, CH2Cl2, 0 °C, 3 h; (e) Zn dust, NaI, N,N-dimethylformamide
(DMF), 150 °C, 5 h, 70% from 6; (f) imidazole, I2, Ph3P, THF,
50 °C, 45 min, 100%; (g) NaOH, MeOH, room temp., 20 h, 95%.
The acetonide protecting group was then removed. As a
result of the acetyl (Ac) adjacent to the hydroxy group, the
normally simple hydrolysis was complicated by the acyl
[12]
group migration(s). Under aqueous F3CCO2H/CH2Cl2
conditions, the acyl migration product was produced well
before starting material 5 was fully consumed. The DDQ/
MeCN/H2O/50 °C[13] conditions gave better results. Careful
monitoring of the reaction revealed that the maximal yield
(75–82%) of 6 occurred after approximately 1.5 h, but start-
ing material 5 was still present. Extending the time led to
increased amounts of the acyl migration product(s). Em-
ploying AcOH/H2O (4:1) at 50 °C, which proved to be the
best conditions for the similar hydrolysis of acetonides in
optically active monoglycerides (very sensitive sub-
strates),[14] was then attempted. By carefully controlling the
time (50 °C/30 min), diol 6 was readily obtained in 84%
yield.
Scheme 2. Reagents and conditions: (a) see Table 1 and Results and
Discussion; (b) 11 (7 mol-%), CH2Cl2, room temp., 16 h, 41% for
16; (c) 11 (10 mol-%), CH2Cl2, room temp., 16 h, 63% for 18. Mes
= 2,4,6-trimethylphenyl, TBS = tert-butyldimethylsilyl.
The conversion of the 1,2-diol into a double bond was
first attempted through a dimesylate. Thus, the treatment
Using toluene instead of CH2Cl2 as the solvent for the
of 6 with MsCl/Et3N/DMAP[15] led to 7, which upon expo- CM reaction led to a remarkable simplification of the prod-
sure to Zn/I2 in refluxing DMF resulted in alkene 8 in 70% uct composition. The desired 14 was formed as a single iso-
yield (from 6). The same conversion could be more conve- mer (essentially free from 14Ј) in 24% yield along with 69%
niently realized under Ph3P/imidazole/I2/THF conditions[16] of 13 and a trace amount of 14ЈЈ.
Eur. J. Org. Chem. 2014, 2128–2139
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2129

Z.-L. Wan, G.-L. Zhang, H.-J. Chen, Y. Wu, Y. Li
FULL PAPER
Table 1. The CM reaction between 9 and 10 under different condi- (3R,5S)-1, which was obtained as a result of the CM reac-
tions.[a]
tion in CH2Cl2, was assigned as anti-1,3-diol 14Ј [the anti-
pode of (3R,5R)-1], as all the extra signals in the 1H and 13
C
Entry Conditions
Products [% yield]
NMR spectra precisely matched those in the corresponding
spectra for (3R,5R)-1.
1
2
3
4
11 (10 mol-%)/CH2Cl2/16 h
11 (11 mol-%)/toluene/16 h
11 (11 mol-%)/PhOH/CH2Cl2/16 h
11 (12 mol-%)/PhOH/toluene/16 h
13 (73), 14/14Ј (21),[b] 14ЈЈ (7)
13 (69), 14 (24),[c] 14ЈЈ (trace)
13 (31), 14/14Ј (55),[a] 14ЈЈ (9)
13 (12), 14 (63),[d] 14ЈЈ (9)
[a] All experiments were performed at ambient temperature (see
Exp. Section for further details; for detailed structures, see
Scheme 2). [b] Approximate molar ratio of 14/14Ј was 4:1. [c] Es-
sentially free from 14Ј. [d] Contained only a trace amount of 14Ј.
In conjunction with the CM reaction between 9 and 10,
we also performed the CM reaction with 15[20] and 17,[20]
respectively, in place of 9 under otherwise the same condi-
tions (see lower half of Scheme 2). Much better yields of
the expected CM products 16 and 18 (41 and 63%, respec-
tively) were obtained, which strongly suggests that the low
yield for the reactions with 9 must be a consequence of the
particular diol structure employed (vide infra).
In continuation of the synthesis, the C–C double bond
of 14 was then saturated through a catalytic hydrogenation
with 10% Pd-C to deliver diol 19 in an essentially quantita-
tive yield (see Scheme 3). Finally, the acetyl protecting
group of 19 was removed under basic conditions to afford
1
the end product (3R,5S)-1, which had consistent H and
13C NMR spectroscopic data with those reported for its
natural counterpart (see Supporting Information).
Scheme 4. Reagents and conditions: (a) nBuLi, THF, CuI, –78 °C,
3 h, 92%; (b) Ac2O, Et3N, CH2Cl2, DMAP, room temp., 4 h, 100%;
(c) AcOH/H2O (4:1, v/v), 30 min, 79%; (d) imidazole, I2, Ph3P,
THF, 50 °C, 45 min, 100%; (e) NaOH, MeOH, room temp., 20 h,
95%; (f) styrene 10, 11, C6H5CH3, room temp., 16 h, 23% for 26
along with ent-13 (69%) and 12 (discarded without calculating the
yield); (g) 10% Pd-C, H2 (1 atm), EtOAc, room temp., 3 h, 100%;
(h) K2CO3, MeOH, room temp., 40 min, 86%.
We then turned our attention to the above-mentioned
CM reaction with the unexpectedly facile formation of
ketone 13. Rearrangements of 4-substituted but-1-en-3-ols
into the corresponding ethyl ketones appear to be a well-
studied subject. However, most documented precedents[21]
Scheme 3. Reagents and conditions: (a) 10% Pd-C, H2 (1 atm),
EtOAc, room temp., 3 h, 100%; (b) K2CO3, MeOH, room temp.,
40 min, 100%.
In a previous[8g] study, we observed that the optical rota- do not involve ruthenium catalysts, which are often em-
tion of 2 changed from [α]2D4 = –4.7 (c = 1.0, MeOH) to ployed in the synthesis of natural products (e.g., 11 or 28
[α]2D4 = –5.8 (c = 1.0, MeOH) after exposure to CD3OD. and 29, the Grubbs I and II catalysts, respectively). In many
Because the effects of deuteration on the optical rotation cases, the addition of a base was essential to achieve the C–
are not yet fully understood, we remeasured the optical ro- C bond arrangement in synthetically useful yields.
1
tation for (3R,5S)-1 after recording its H NMR spectro-
The rearrangements of 4-substituted but-1-en-3-ols into
scopic data using CD3OD. The optical rotation data the corresponding ketones by employing Grubbs I catalyst
recorded on the sample before and after its exposure to (28, see Scheme 5) were separately reported by Fürstner,[22a]
CD3OD were [α]D28 = +11.8 (c = 1.7, CHCl3) and [α]2D7
=
Gurjar and Yakambram,[22b] and Quayle,[22c] and these
+9.3 (c = 0.93, CHCl3), respectively. Accumulation of such studies are closely related to ours. Their results, however,
data may help to understand similar data variations in were acquired in the absence of another competing alkene
other cases.
(not under CM conditions), and the rearrangements oc-
By using epoxy chiral building 20 instead of 3, (3R,5R)- curred at much higher temperatures. These distinct differ-
1 was also prepared in a similar fashion (see Scheme 4). ences suggest that the facile formation of 13 under mild
With the help of this sample and the mechanistic rational- reaction conditions must be induced by some thus far un-
ization (vide infra), the aforementioned impurity in recognized factor(s).
2130
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2128–2139

A Chiral Pool and Cross Metathesis Based Synthesis of Gingerdiols
unprotected OH group indeed plays a critical role in facili-
tating the isomerization into the ketone under mild condi-
tions.
Three model reactions with substrates 40, 17, and 43,
respectively, were then performed in the absence of any
added styrene 10 (see Scheme 7). Diol 40,[26] a close ana-
logue of 9, furnished ketone 41[27] in 37 and 62% yield after
16 h by using 10 mol-% of 11 and 29, respectively, as the
catalyst. Under otherwise the same conditions, no reactions
were observed for 17, which revealed that an unprotected
OH group at the carbon β to the allylic position was essen-
tial for the rearrangement to occur under mild conditions.
As 17 underwent a reaction with 10 under the given condi-
tions, the failure to undergo a self-coupling reaction re-
flected that the allylic OH group probably bonded more
easily to the Ru atom than the terminal vinyl group. In
monoalcohol 43,[28] the OH group was sterically more
crowded than that in 17, and, thus, it was more difficult
for the OH group to bond to the Ru catalyst. As a result,
compound 43 underwent reaction more easily at the vinyl
site to lead to 44 as the predominant product (along with
more than seven unidentified minor side products).
Scheme 5. Reagents and conditions: (a) 28 (20 mol-%), CH2Cl2, re-
flux, 20 h, 29% (ref.[22a]); (b) 28 (5 mol-%), Cl(CH2)2Cl or toluene,
reflux, 1–4 h, 52–80% (ref.[22b]); (c) 28 (5 mol-%), toluene, 120 °C,
30% (ref.[22c]).
Schimdt and Hauke[23] recently reported (see Scheme 6)
that the cross-coupling reaction between 3-substituted
prop-1-en-3-ols 36 and 37 with Grubbs II catalyst (29) was
followed by the unexpected formation of 39, which was be-
lieved to occur through a shift of the C–C double bond
followed by an enol–ketone rearrangement of CM product
38. They postulated that the bonding of the carbonyl oxy-
gen atom of the enolized ester to the ruthenium catalyst
facilitated the normally unobserved allylic alcohol to
ketone rearrangement. Their hypothesis encouraged us to
consider that the facile conversion of 9 into 13 might be
triggered by the extra hydroxy group in the substrate.
Scheme 7. Reagents and conditions: (a) 11 (10 mol-%), CH2Cl2,
room temp., 16 h, 37%; (b) 29 (10 mol-%), CH2Cl2, room temp.,
16 h, 62%; (c) 11 (10 mol-%), CH2Cl2, room temp., 12 h, no reac-
tion occurred; (d) 29 (10 mol-%), CH2Cl2, room temp., 12 h, no
reaction occurred; (e) 11 (10 mol-%), CH2Cl2, room temp., 12 h,
72%; (f) 11 (10 mol-%), CH2Cl2, room temp., 12 h, 65%.
Scheme 6. Reagents and conditions: (a) 29 (2.5–5 mol-%), toluene,
110 °C, 41–80% for 39 (ref.[23]).
These results, together with those in Scheme 2, argue fa-
vorably for the notion that the presence of the second OH
group two carbon atoms away from the allylic one could be
A literature search revealed that to date there have been an essential factor for the ease of the rearrangement into
no reports of cross-metathesis reactions that employed un- ketone 13 (and its counterparts). In addition, a substituent
protected 5-substituted pent-1-ene-3,5-diols, although cor- at C-5 of the pent-1-ene-3,5-diols, which makes it easier for
responding protected diols smoothly underwent reactions the second OH group to adopt a suitable conformation and
in many cases.[8f,8g,24] Unprotected 3-substituted prop-1-en- form a cyclic structure with the Ru catalyst (similar to those
3-ols, which have only one OH group (at the allylic posi- of Schmidt and Hauke[23]), appears to lend further strong
tion) often underwent CM reactions very well.[25] Thus, it support for the role of the second OH group (see Figure 2).
appears that unprotected 5-substituted pent-1-ene-3,5-diols
On the basis of the above reasoning, the observations of
such as 9 are indeed somewhat unique, and the additional the CM reactions can be rationalized (see Scheme 8). The
Eur. J. Org. Chem. 2014, 2128–2139
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2131

Z.-L. Wan, G.-L. Zhang, H.-J. Chen, Y. Wu, Y. Li
FULL PAPER
mation by the presence of second OH group is unmistak-
able. Further exploration of this previously unknown role
of the remote OH moiety may lead to new synthetically
useful applications.
The expected CM product 14 may further bond to the
Ru catalyst at the 1,3-diol moiety. Such interactions make
the deprotonation at C-3 more readily to occur than other-
wise. If the proton shifts to C-1 (the benzylic position)
either inter- or intramolecularly as shown in pathway a of
Scheme 8, then C-3 becomes an olefinic carbon and, there-
fore, loses its chirality (i.e., forming either 14 and 14Ј). If
the deprotonation at C-3 was followed by the breaking of
the O–Ru bond as shown in pathway b of Scheme 8 (or a
reductive elimination of a [Ru-H] species), oxidation prod-
uct 14ЈЈ is generated.
Figure 2. Formation of a cyclic intermediate with the Ru catalyst
is impossible for 17, possible yet disfavored for 15, and favorable
for 9 and 40.
When the CM reaction was performed in toluene instead
of CH2Cl2, the lower dipole of the solvent and the π-π inter-
actions between the phenyl rings of 14 and toluene might
make it more difficult for 14 to bond to the Ru catalyst,
and this could suppress the formation of 14Ј and 14ЈЈ. Note
that the reaction that leads to 13 (and a priori, the interac-
tions of the two OH groups of 9 with the Ru catalyst) was
almost unaffected. The ratio of the two major reaction
branches for 9 (i.e., the isomerization to give 13 and the
CM reaction with 10) was also approximately the same, as
shown by the almost unchanged total yield of 13, 14, 14Ј,
and 14ЈЈ in these two solvents under the same conditions.
Up to this point, it was clear why the yields of the ex-
pected cross-coupling products 14 and 26 were so low and
why no precedents[29] of CM reactions that involved unpro-
tected 5-substituted pent-1-en-3,5-diols could be found in
the literature. On the basis of these understandings, we
speculated that the introduction of an acid to the CM sys-
tem might suppress the deprotonation at C-3 in 9 and,
therefore, might suppress the formation of 13 and improve
the yield of 14 (or 26). Indeed, under the same conditions,
the addition of phenol,[30] which is expected to be more
acidic than the proton at C-3 of 9, to the CM mixture in
CH2Cl2 dramatically reduced the yield of 13 from 73% (in
the absence of phenol) to 31%, and the yields of 14 and 14Ј
(an inseparable mixture; 14/14Ј, ca. 4:1) increased from 21
to 55% along with a 9% yield for 14ЈЈ. When toluene was
used as the solvent for the CM reaction instead of CH2Cl2,
the desired product 14 (with trace amounts of 14Ј) was iso-
lated in 63% yield along with approximately 12 and 9%
yields of 13 and 14ЈЈ, respectively.
reversible bonding of diol 9 to the Ru catalyst through the
two OH groups followed by a formal 1,3-proton transfer
(not necessarily intramolecular) affords an enolate interme-
diate. The dissociation of the Ru species from the enolate
leads to ketone 13, which is thermodynamically more stable
than diol 9 and, thus, favored.
Scheme 8. A schematic rationalization for the unexpected forma-
tion of 13, 14Ј, and 14ЈЈ in the CM reaction between the diol 9 and
substituted styrene 10. For clarity, the self-coupling of 10 to afford
12 is not shown.
Conclusions
By employing the readily accessible chiral building
blocks 3 and 20 as the source for the 1,3-diol stereogenic
Compared with their allylic alcohol/monoalcohol[21] (i.e., centers, natural (3R,5S)-1 and its (3R,5R) isomer were syn-
without the second unprotected OH group on the carbon β thesized. The effect of deuterating the OH groups of
to the allylic OH) counterparts, the rearrangements of the (3R,5S)-1 on its optical rotation was also examined. During
diols occurred under much milder conditions, and the yields the synthesis of the chosen target products, a CM-based
remained good. Therefore, the facilitation of the transfor- chain-extension approach was exploited at the acetonide
2132
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2128–2139

A Chiral Pool and Cross Metathesis Based Synthesis of Gingerdiols
3 h. The cooling bath was warmed to ambient temperature. When
TLC showed that the reaction had reached completion, a saturated
aqueous solution of NH4Cl (20 mL) was added. The dark grey sol-
ids were removed by filtration. The combined filtrate and EtOAc
washings were extracted with EtOAc (3ϫ 50 mL). The combined
organic layers were washed with water and brine and then dried
with anhydrous Na2SO4. The solvent was removed by rotary evapo-
ration. Column chromatography on silica gel (PE/EtOAc, 2:1) gave
diol 4 (1.782 g, 7.23 mmol, 91% from 3) as a white solid.; m.p. 31–
33 °C. [α]2D7 = +10.8 (c = 2.55, CHCl3). 1H NMR (400 MHz,
end rather than the epoxy end of the building blocks, as in
our previous studies, and, thus, created some new utilities.
If the reactions were performed in CH2Cl2, the expected
CM products were obtained in moderate yields along with
their allylic epimerization and oxidation products. The oc-
currence of the allylic side reactions was avoidable by using
toluene as the reaction solvent.
A major portion of the starting unprotected 5-substi-
tuted pent-1-ene-3,5-diols was transformed into the corre-
sponding ethyl ketones under the CM conditions with or CDCl3): δ = 4.06–4.00 (m, 2 H), 4.00–4.91 (m, 2 H), 3.91–3.84 (m,
2 H), 3.57 (br. s, 2 H, OH), 1.77 (br. d, J = 14.6 Hz, 1 H), 1.57–
1.20 (m, 9 H), 1.42 (s, 3 H), 1.36 (s, 3 H), 0.89 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 109.2, 78.7, 72.9, 72.8,
65.8, 39.0, 38.1, 31.9, 26.6, 25.3, 25.0, 22.6, 14.1 ppm. FTIR (film
without the added alkene coupling partner. Similar allylic
alcohols (monoalcohols) were known to undergo such re-
arrangements but only at much higher temperatures with
the addition of a base in most cases. Therefore, the unprece-
dented ease with which the unprotected 5-substituted pent-
1-ene-3,5-diols rearranged to give the corresponding
ketones illustrates a thus far unrecognized facilitating effect
of an additional unprotected OH group on a carbon β to
the allylic position in the substrate. Given the good yields
and the mild reaction conditions, further exploration of the
effect of the additional secondary OH group may lead to
useful synthetic applications. Finally, the effective suppres-
sion of the facile diol to ketone rearrangement at ambient
temperature by the addition of phenol and the concurrent
increase in the yield of the desired cross-coupling product
may facilitate future uses of unprotected 5-substituted pent-
1-ene-3,5-diols and related diols in CM reactions. The pro-
tection of the diol unit prior to a CM reaction, at least in
some cases, may no longer be necessary.
of a concentrated solution in CHCl ): ν = 3407, 2986, 2955, 2929,
˜
3
2870, 2858, 1456, 1371, 1259, 1214, 1158, 1067, 853 cm–1. ESI-MS:
m/z = 269.1 [M + Na]+. ESI-HRMS: calcd. for C13H26NaO4 [M +
Na]+ 269.17233; found 269.17233.
Acetylation of Diol 4 To Afford Diacetate 5: Ac2O (0.7 mL,
7.41 mmol) was added to a solution of diol 4 (581 mg, 2.36 mmol)
and DMAP (870 mg, 7.09 mmol) in dry CH2Cl2 (10 mL) that was
stirred at 0 °C. The mixture was stirred at ambient temperature for
4 h and then washed with HCl (1 n, 2ϫ 10 mL). The aqueous
phases were combined and back extracted with EtOAc. The com-
bined organic layers were washed with aqueous saturated NaHCO3
solution, water, and brine and then dried with anhydrous Na2SO4.
The solvent was removed by rotary evaporation. Column
chromatography on silica gel (PE/EtOAc, 5:1) furnished diacetate
5 (767 mg, 2.32 mmol, 98%) as a colorless oil; [α]2D5 = –9.0 (c =
2.13, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 5.04 (q, J =
5.9 Hz, 1 H), 4.93 (quint, J = 6.2 Hz, 1 H), 4.12 (q, J = 6.1 Hz, 1
H), 4.02 (dd, J = 6.8, 8.5 Hz, 1 H), 3.76 (dd, J = 5.8, 8.3 Hz, 1 H),
2.08 (s, 3 H), 2.04 (s, 3 H), 1.88 (t, J = 6.2 Hz, 2 H), 1.66–1.55 (m,
2 H), 1.41 (s, 3 H), 1.37 (s, 3 H), 1.34–1.18 (m, 6 H), 0.88 (t, J =
6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.6, 170.4,
109.8, 76.9, 71.4, 70.8, 66.0, 35.0, 33.8, 31.7, 26.4, 25.2, 24.8, 22.6,
Experimental Section
General Methods: The NMR spectroscopic data were recorded with
a Bruker Avance NMR spectrometer that operated at 400 MHz for
1H NMR, unless otherwise stated. IR spectra were recorded with
a Nicolet 380 Infrared spectrophotometer. ESI-MS data were ac-
quired with a Shimadzu LCMS-2010EV mass spectrometer. ESI-
HRMS data were obtained with a Bruker APEXIII 7.0 Tesla FT-
MS spectrometer. EI-MS were recorded with an Agilent Technol-
ogies 5973N spectrometer. EI-HRMS were acquired with a Waters
Micromass GCT Premier instrument. Optical rotations were mea-
sured with a Jasco P-1030 polarimeter. Melting points were mea-
sured with a hot-stage melting point apparatus that was equipped
with a microscope. Dry THF was obtained by distillation over Na/
Ph2CO under argon. Toluene and CH2Cl2 were dried over activated
MS (molecular sieves, 4 Å). Degassed MeOH, CH2Cl2, and toluene
were obtained by bubbling argon into the given dry solvent for
15 min prior to use. All reagents were reagent grade and used as
purchased. Column chromatography was performed on silica gel
(300–400 mesh) under a slightly positive pressure. Petroleum ether
(PE, b.p. 60–90 °C) was used as a solvent for chromatography.
21.3, 21.2, 14.1 ppm. FTIR (film): ν = 2988, 2931, 2859, 1741,
˜
1457, 1372, 1233, 1157, 1066, 1024, 961, 852 cm–1. ESI-MS: m/z =
353.2 [M + Na]+. ESI-HRMS: calcd. for C17H30NaO6 [M + Na]+
353.19346; found 353.19500.
Hydrolysis of Acetonide Moiety of Diacetate 5 To Afford Diol 6
Method A: To a round-bottomed flask (25 mL) that was equipped
with a reflux condenser was added a solution of 5 (734 mg,
2.22 mmol) in MeCN/H2O (9:1 v/v, 20 mL). DDQ (53 mg,
0.23 mmol) was added, and the red mixture was stirred in a 50 °C
bath for 1.5 h. The mixture was chromatographed on silica gel (PE/
EtOAc, 1:2) to give diol 6 (527 mg, 1.82 mmol, 82% from 5) as a
colorless oil.
Method B: AcOH/H2O (from a stock solution prewarmed at 50 °C,
4:1 v/v, 4.0 mL) was added to 5 (123 mg, 0.37 mmol). The mixture
was stirred in a 50 °C bath for 30 min, and then the heating bath
was removed. To the mixture were added water (5 mL) and satu-
rated aqueous NaHCO3 (3ϫ 10 mL). The resulting mixture was
extracted with EtOAc (3ϫ 30 mL). The combined organic layers
Chain Elongation of Epoxide 3 To Afford Diol 4: nBuLi (2.5 m in were washed with water and brine and then dried with anhydrous
hexanes, 10 mL, 25 mmol) was added dropwise through a syringe Na2SO4. The solvent was removed by rotary evaporation. Column
to a mixture of CuI (4.42 g, 23.22 mmol) in dry THF (20 mL) that chromatography on silica gel (PE/EtOAc, 1:2) furnished 6 (89 mg,
was stirred at –78 °C under argon (balloon technique). The grad-
ually darkened mixture was stirred at –78 °C for 1 h, and then a
solution of 3 (1.496 g, 7.95 mmol) in dry THF (10 mL) was intro-
duced through a syringe. The stirring was continued at –78 °C for
0.31 mmol, 84% from 5) as a colorless oil; [α]2D6 = –2.31 (c = 1.30,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.95 (br. quint, J =
6.3 Hz, 1 H), 4.90 (br. dt, J = 3.8, 7.5 Hz, 1 H), 3.67–3.63 (m, 2
H), 3.53 (dd, J = 6.5 Hz, 1 H), 2.86–2.70 (a lump, 2 H, OH), 2.17–
Eur. J. Org. Chem. 2014, 2128–2139
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2133

Z.-L. Wan, G.-L. Zhang, H.-J. Chen, Y. Wu, Y. Li
FULL PAPER
2.03 (m, 1 H), 2.09 (s, 3 H), 2.05 (s, 3 H), 1.95 (dd, J = 7.0, 14 Hz, due was diluted with water, and the solution was extracted with
1 H), 1.65 (dt, J = 15, 3.0 Hz, 1 H), 1.55 (dd, J = 9.8, 15 Hz, 1 H), EtOAc (3ϫ 10 mL). The combined organic layers were washed
1.51–1.38 (m, 2 H), 1.49–1.17 (m, 6 H), 0.88 (t, J = 6.8 Hz, 3 with brine and dried with anhydrous Na2SO4. The solvent was re-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.4, 171.2, 72.9, 72.0,
71.6, 62.6, 35.2, 34.2, 31.6, 24.9, 22.6, 21.4, 21.2, 14.1 ppm. FTIR
moved by rotary evaporation to give a rather pure diol 9 (12 mg,
0.070 mmol, 95%) as a colorless oil; [α]2D8 = +2.6 (c = 2.22, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 5.86 (ddd, J = 6.1, 11, 17 Hz, 1
H), 5.24 (br. d, J = 17 Hz, 1 H), 5.08 (br. d, J = 11 Hz, 1 H), 4.38–
4.32 (m, 1 H), 3.90–3.80 (m, 1 H), 3.82 (s, 2 H, OH), 1.65 (dt, J =
15, 3.0 Hz, 1 H), 1.55 (dd, J = 9.8, 15 Hz, 1 H), 1.55–1.23 (m, 8
H), 0.89 (t, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 140.8, 114.4, 73.8, 72.5, 42.8, 38.1, 31.9, 25.1, 22.7, 14.1 ppm.
(film): ν = 3432, 2956, 2932, 2861, 1736, 1466, 1437, 1374, 1240,
˜
1119, 1027 cm–1. ESI-MS: m/z = 313.2 [M + Na]+. ESI-HRMS:
calcd. for C14H26NaO6 [M + Na]+ 313.16216; found 313.16193.
Conversion of Diol 6 into Alkene 8
Method A (Direct Conversion): Imidazole (67 mg, 0.99 mmol) and
Ph3P (242 mg, 0.92 mmol) were added in succession to a solution
of diol 6 (69 mg, 0.24 mmol) in dry THF (3 mL). The mixture was
stirred in a 50 °C bath. I2 (241.7 mg, 0.95 mmol) was then added
in small portions over 10 min. The mixture was stirred at 50 °C for
an additional 45 min. The heating bath was removed, and an aque-
ous saturated solution of Na2S2O3 was added to decompose the
excess amount of I2. The phases were separated, and the aqueous
layer was back extracted with Et2O. The combined organic layers
were washed with brine and dried with anhydrous Na2SO4. The
solvent was removed by rotary evaporation, and column
chromatography on silica gel (PE/EtOAc, 10:1) afforded alkene 8
(61 mg, 0.24 mmol, 100%) as a colorless oil.
FTIR (film): ν = 3369, 3078, 2929, 2858, 1725 (w), 1699 (w), 1610,
˜
1458, 1354, 1318, 1235, 1113, 1074, 1052, 990, 922, 850 cm–1. ESI-
MS: m/z = 195.2 [M + Na]+. ESI-HRMS: calcd. for C10H20NaO2
[M + Na]+ 195.1356; found 195.1358.
Cross-Metathesis Reaction of Diol 9 with Styrene 10 To Afford 14
with 13, 14Ј, and 14ЈЈ
Method A (in CH2Cl2 without Phenol): A mixture of diol 9 (45 mg,
0.26 mmol), styrene 10 (488 mg, 2.54 mmol), and catalyst 11
(17 mg, 27 μmol) in dry degassed CH2Cl2 (3 mL) was stirred at
ambient temperature for 16 h under argon (balloon technique). The
flask was then opened. The mixture was diluted with Et2O (5 mL)
followed by the slow addition of 15% H2O2 (15 mL). The mixture
was stirred at ambient temperature for 20 min and then extracted
with Et2O. The organic extract was washed in succession with
brine, aqueous saturated Na2SO3 solution, and brine. The organic
layer was dried with anhydrous Na2SO4. The solvent was removed
by rotary evaporation to give a crude oil, which was chromato-
graphed on silica gel (eluting first with CH2Cl2/Et2O, 2:1) to afford
(in eluting sequence) 12 (89 mg, 0.25 mmol, 20% from 10) and
ketone 14ЈЈ (6 mg, 0.018 mmol, 7% from 9), ketone 13 (33 mg,
0.19 mmol, 73% from diol 9) and a mixture of diol 14 and 14Ј (5:1,
18 mg, 0.054 mmol, 21% from diol 9).
Method B (through Dimesylate 7): MsCl (40 μL, 0.52 mmol) was
added slowly to a solution of 6 (30 mg, 0.10 mmol) and Et3N
(150 μL, 1.08 mmol) in dry CH2Cl2 (1.0 mL) that was stirred at
0 °C. After completion of the addition, the mixture was stirred at
the same temperature for 3 h, which was when TLC indicated that
the reaction had reached completion. An aqueous solution of HCl
(1 n, 5 mL) was added slowly followed by the addition of CH2Cl2.
The phases were separated. The organic layer was washed with
water and brine and then dried with anhydrous Na2SO4. The sol-
vent was removed by rotary evaporation to give a crude oil (dimes-
ylate 7), which was dissolved in dry DMF (1 mL). To this solution
were then added activated Zn dust (9.2 mg, 0.14 mmol) and NaI
(10 mg, 0.07 mmol). The mixture was stirred and heated at reflux
in a 150 °C bath for 5 h under argon (balloon technique) with the
exclusion of direct light. The bath was removed. The mixture was
diluted with EtOAc (10 mL) followed by the addition of water
(5 mL). The phases were separated. The aqueous layer was back
extracted with EtOAc. The combined organic layers were washed
with water and brine and then dried with anhydrous Na2SO4. The
solvent was removed by rotary evaporation, and column
chromatography on silica gel (PE/EtOAc, 10:1) gave alkene 8
(18 mg,0.070 mmol,70%overtwostepsfromdiol6) asacolorlessoil;
Method B (in Toluene without Phenol): A mixture of diol 9 (12 mg,
0.070 mmol), styrene 10 (56 mg, 0.29 mmol), and catalyst 11
(4.8 mg, 7.6 μmol) in dry degassed toluene (1 mL) was stirred at
ambient temperature for 16 h under argon (balloon technique).
Et2O (5 mL) was added followed by the slow addition of 15% H2O2
(15 mL). The mixture was stirred at ambient temperature for
20 min and then extracted with Et2O. The organic extract was
washed in succession with brine, aqueous saturated Na2SO3 solu-
tion, and brine. The organic layer was dried with anhydrous
Na2SO4. The solvent was removed by rotary evaporation to give a
crude oil, which was chromatographed on silica gel (eluting first
with PE/EtOAc, 2:1) to afford 12 (21 mg, 0.06 mmol, 41% from
10) and ethyl ketone 13 (8.3 mg, 0.048 mmol, 69% from diol 9)
followed by (eluting with CH2Cl2/Et2O, 5:1) diol 14 (5.6 mg,
0.017 mmol, 24% from diol 9).
1
[α]2D4 = –18.3 (c = 0.077, CHCl3). H NMR (400 MHz, CDCl3): δ
= 5.77 (ddd, J = 6.8, 11, 17 Hz, 1 H), 5.28 (br. q, J = 6.8 Hz, 1 H),
5.24 (br. d, J = 17 Hz, 1 H), 5.19 (br. d, J = 11 Hz, 1 H), 4.91 (br.
quint, J = 6.3 Hz, 1 H), 2.06 (s, 3 H), 2.04 (s, 3 H), 1.99 (ddd, J =
6.3, 8.1, 14 Hz, 1 H), 1.79 (ddd, J = 4.5, 7.0, 14 Hz, 1 H), 1.65–
1.49 (m, 2 H), 1.38–1.16 (m, 6 H), 0.88 (t, J = 6.5 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.7, 170.2, 135.9, 117.5, 72.2,
71.0, 38.6, 34.4, 31.7, 29.8, 24.8, 22.6, 21.4, 14.1 ppm. FTIR (film):
Method C (in CH2Cl2 with Phenol): By following the same pro-
cedure as Method A with the addition of PhOH, compound 9
(66 mg, 0.38 mmol), 10 (378 mg, 1.97 mmol), 11 (24 mg,
0.04 mmol), and PhOH (22 mg, 0.23 mmol, 0.61 mol equiv. with
respect to 9) afforded 13 (20 mg, 0.116 mmol, 31% from 9), a mix-
ture of 14 and 14Ј (~4:1, 70 mg, 0.208 mmol, 55% from 9), and
14ЈЈ (12 mg, 0.0359 mmol, 9% from 9).
ν = 3583, 2959, 2927, 2852, 1741, 1457, 1365, 1236, 1093, 1018,
˜
934, 859, 798 cm–1. ESI-MS: m/z = 279.2 [M + Na]+. ESI-HRMS:
calcd. for C14H24NaO4 [M + Na]+ 279.15668; found 279.15608.
Saponification of Diacetate 8 To Afford Diol 9: Solid NaOH (12 mg,
0.29 mmol) was added to a solution of 8 (19 mg, 0.074 mmol) in
MeOH (1.0 mL) that was stirred at ambient temperature. The stir-
ring was continued for 20 h, which was when TLC indicated that
the reaction had reached completion. The mixture was neutralized
by the addition of aqueous HCl (1 n) to give pH ≈ 7, and the
resulting mixture was concentrated by rotary evaporation. The resi-
Method D (in Toluene with Phenol): By following the same pro-
cedure as Method B with the addition of PhOH, compound 9
(59 mg, 0.34 mmol), 10 (364 mg, 1.89 mmol), 11 (23 mg,
0.04 mmol), and PhOH (22 mg, 0.23 mmol, 0.70 mol equiv. with
respect to 9) afforded 13 (7.2 mg, 0.0418 mmol, 12% from 9), 14
(72 mg, 0.214 mmol, 63% from 9), and 14ЈЈ (10 mg, 0.0299 mmol,
9% from 9).
2134
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2128–2139

A Chiral Pool and Cross Metathesis Based Synthesis of Gingerdiols
Compound 12: White solid, m.p. 235–236 °C; ref.[17b] m.p. 227–
1510, 1465, 1417, 1370, 1286, 1268, 1286, 1218, 1199, 1155, 1120,
289.4
[M + Na]+. ESI-HRMS: calcd. for C14H18NaO5 [M + Na]+
229 °C; ref.[17c] m.p. 228–229 °C. 1H NMR (400 MHz, CDCl3): δ = 1033, 967, 905, 865, 823, 754 cm–1. ESI-MS: m/z
=
7.10 (s, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 7.02 (d, J = 8.0 Hz, 2 H),
7.01 (s, 2 H), 3.89 (s, 6 H), 2.33 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.2, 151.4, 139.6, 136.4, 128.5, 123.1, 119.4, 110.3,
289.1054; found 289.10465.
Cross-Metathesis Reaction Between 10 and Diol 17 To Afford 18:
The same procedure for the CM between 9 and 10 to give 14
(Method A, in CH2Cl2) was employed. Column chromatography
on silica gel (PE/EtOAc, 3:1) afforded 18 (74 mg, 0.19 mmol, 63%
from 17) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 6.93–
6.89 (m, 3 H), 6.60 (d, J = 16 Hz, 1 H), 6.18 (dd, J = 5.6, 16 Hz,
1 H), 4.54 (br. q, J = 5.6 Hz, 1 H), 3.95–3.90 (m, 1 H), 3.83 (s, 1
H), 3.88–3.83 (m, 1 H), 3.56 (br. s, 1 H, OH), 2.30 (s, 3 H), 1.89–
1.78 (m, 2 H), 0.92 (s, 9 H), 0.09 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.2, 151.2, 139.2, 136.3, 132.6, 129.0,
122.9, 119.2, 110.2, 72.3, 62.2, 55.9, 38.7, 26.0, 20.8, 18.2, –5.4,
56.0, 20.8 ppm. FTIR (film): ν = 1754, 1598, 1514, 1472, 1451,
˜
1422, 1371, 1330, 1301, 1254, 1201, 1168, 1122, 1030, 986, 935,
906, 868, 827 cm–1. ESI-MS: m/z = 357.5 [M + H]+.
Ketone 13: Colorless oil; [α]2D8 = +35.4 (c = 1.12, CHCl3). For the
1
antipode, ref.[18] [α]2D8 = –34.8 (c = 0.34, CHCl3), 93%ee. H NMR
(400 MHz, CDCl3): δ = 4.07–4.00 (m, 1 H), 3.21 (s, 1 H, OH), 2.60
(dd, J = 2.8, 17 Hz, 1 H), 2.51 (dd, J = 9.0, 18 Hz, 1 H), 2.47 (br.
q, J = 7.2 Hz, 1 H), 1.57–1.20 (m, 8 H), 1.06 (t, J = 7.2 Hz, 3 H),
0.89 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
212.9, 67.7, 48.7, 36.8, 36.5, 31.8, 25.2, 22.6, 14.1, 7.6 ppm. FTIR
(film): ν = 3452, 2956, 2931, 2859, 1709, 1510, 1460, 1408, 1377,
˜
–5.4 ppm. FTIR (film): ν = 3484, 3005, 2953, 2929, 2856, 1766,
˜
1275, 1197, 1211, 1027, 922, 862, 827, 769, 725 cm–1. ESI-MS: m/z
1601, 1509, 1464, 1417, 1369, 1285, 1257, 1198, 1155, 1120, 1095,
=
195.2 [M +
Na]+. ESI-HRMS: calcd. for C10H20NaO2
1034, 1008, 967, 939, 903, 836, 777, 721, 662 cm–1. ESI-MS: m/z =
[M + Na]+ 195.13555; found 195.13565.
403.4 [M
+
Na]+. ESI-HRMS: calcd. for C20H32NaO5Si
[M + Na]+ 403.1911; found 403.1916.
Compound 14: Colorless oil; [α]2D8 = +1.60 (c = 1.31, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 6.97 (s, 1 H), 6.96 (d, J = 8.3 Hz, 1
H), 6.93 (d, J = 8.3 Hz, 1 H), 6.55 (d, J = 16 Hz, 1 H), 6.16 (dd, J
= 6.4, 16.0 Hz, 1 H), 4.56–4.51 (m, 1 H), 3.96–3.84 (m, 1 H), 3.83
(s, 3 H), 3.25–2.75 (an almost unrecognizable lump, 2 H, OH), 2.31
(s, 3 H), 1.73 (dt, J = 15, 3.3 Hz, 1 H), 1.65 (dd, J = 9.6, 15 Hz, 1
H), 1.56–1.19 (m, 8 H), 0.89 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.2, 151.2, 139.4, 135.9, 132.5, 129.3,
122.9, 119.3, 110.2, 73.6, 72.7, 55.9, 43.3, 38.3, 31.9, 25.1, 22.7,
Hydrogenation of 14 To Afford 19: A mixture of 14 (82 mg,
0.24 mmol) and 10% Pd-C (8.5 mg) in EtOAc (2.5 mL) was stirred
for 3 h under H2 (1 atm). When TLC indicated that the reaction
had reached completion, the solids were removed by filtration. The
filtrate was concentrated with a rotary evaporator. The residue was
chromatographed on silica gel (PE/EtOAc, 2:1) to furnish 19
(81 mg, 0.24 mmol, 100%) as a colorless oil; [α]2D8 = +11.5 (c =
1.34, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 6.92 (d, J =
7.8 Hz, 1 H), 6.80 (br. s, 1 H), 6.76 (d, J = 8.0 Hz, 1 H), 3.88–3.80
(m, 2 H), 3.80 (s, 3 H), 3.62 (s, 2 H, 2 OH), 2.78–2.71 (m, 1 H),
2.68–2.60 (m, 1 H), 2.29 (s, 3 H), 1.83–1.65 (m, 2 H), 1.60 (br. d,
J = 15 Hz, 1 H), 1.55–1.25 (m, 9 H), 0.89 (t, J = 6.4 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.5, 150.8, 141.2, 137.8, 122.5,
120.5, 112.7, 73.2, 72.2, 55.9, 42.8, 39.7, 38.3, 31.9, 31.6, 25.1, 22.7,
20.8, 14.1 ppm. FTIR (film): ν = 3397, 2931, 2857, 1765, 1600,
˜
1509, 1464, 1416, 1369, 1267, 1197, 1155, 1120, 1033, 967,
903 cm–1. ESI-MS: m/z = 359.4 [M + Na]+. ESI-HRMS: calcd. for
C19H28O5Na [M + Na]+ 359.18290; found 359.1844.
Compound 14Ј: Characterization data were not possible to acquire.
1
The identity was established by comparing the H and 13C NMR
spectroscopic data of (3R,5R)-1 (the antipode of 14Ј) with the extra
20.7, 14.1 ppm. FTIR (film): ν = 3388, 2930, 2857, 1765, 1604,
˜
1
signals in the corresponding H and 13C NMR spectra of the mix-
1510, 1464, 1419, 1369, 1315, 1280, 1217, 1199, 1151, 1122, 1089,
1034, 1010, 936, 901, 846, 827, 726 cm–1. ESI-MS: m/z = 361.4 [M
+ Na]+. ESI-HRMS: calcd. for C19H30NaO5 [M + Na]+ 361.1985;
found 361.1982.
ture of 14 and 14Ј.
Compound 14ЈЈ: Colorless oil; [α]2D9 = +20.4 (c = 0.40, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 16 Hz, 1 H), 7.15 (br.
d, J = 8.3 Hz, 1 H), 7.13 (s, 1 H), 7.07 (br. d, J = 8.0 Hz, 1 H),
6.67 (d, J = 16 Hz, 1 H), 4.19–4.09 (m, 1 H), 3.87 (s, 3 H), 3.16
(br. s, 1 H, OH), 2.88 (dd, J = 2.7, 17 Hz, 1 H), 2.76 (dd, J = 9.0,
17 Hz, 1 H), 2.33 (s, 3 H), 1.65–1.52 (m, 2 H), 1.52–1.40 (m, 2
H), 1.40–1.29 (m, 2 H), 0.90 (t, J = 6.3 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 200.9, 168.9, 151.7, 142.9, 142.0, 133.3,
126.7, 123.5, 121.8, 111.6, 68.0, 56.1, 47.1, 36.7, 31.9, 25.4, 22.8,
Saponification of 19 To Afford (3R,5S)-1: K2CO3 (15 mg,
0.11 mmol) was added to a solution of 19 (62 mg, 0.18 mmol) in
degassed MeOH (2 mL). The mixture was stirred at ambient tem-
perature for 40 min, which was when TLC indicated that the hy-
drolysis had reached completion. A solution of aqueous HCl (1 n)
was added to acidify the mixture, and the solvent was removed with
a rotary evaporator. The residue was chromatographed on silica gel
(PE/EtOAc, 1:1) to give (3R,5S)-1 (53 mg, 0.18 mmol, 100%) as a
colorless oil. [α]2D8 = +11.8 (c = 1.67, CHCl3); ref.[4] [α]1D4 = +10.4
(c = 1.8, CHCl3); ref.[4] [α]2D5 = +7.5 (c = 1.5, CHCl3); ref.[9a] [α]D
= +11 (c = 1, CHCl3); ref.[2b] [α]2D5 = +8.1 (c = 2, CHCl3). After
exposure to CD3OD, [α]2D7 = +9.3 (c = 0.93, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 6.82 (d, J = 8.0 Hz, 1 H), 6.70 (br. s, 1 H),
6.68 (d, J = 7.7 Hz, 1 H), 3.90 (a lump, 3 H, OH), 3.85 (s, 3 H),
3.89–3.81 (m, 2 H), 2.69 (ddd, J = 5.7, 9.5, 15 Hz, 1 H), 2.60 (ddd,
J = 7.0, 9.3, 15 Hz, 1 H), 2.62–2.56 (m, 1 H), 1.81–1.62 (m, 2 H),
1.61 (br. d, J = 15 Hz, 1 H), 1.58–1.20 (m, 9 H), 0.88 (t, J = 6.8 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 146.6, 143.8, 134.0,
121.0, 114.5, 111.2, 73.3, 72.5, 55.9, 42.9, 40.1, 38.3, 31.9, 31.5,
20.8, 14.2 ppm. FTIR (film): ν = 3504, 3009, 2953, 2927, 2855,
˜
1766, 1685, 1650, 1609, 1509, 1466, 1418, 1370, 1297, 1268, 1197,
1159, 1123, 1033, 1011, 980, 903, 822, 724 cm–1. ESI-MS: m/z =
335.3 [M + Na]+. ESI-HRMS: calcd. for C16H26O5Na [M + Na]+
357.16725; found 357.16688.
Cross-Metathesis Reaction Between 10 and Diol 15 To Afford 16:
The same procedure for the CM between 9 and 10 to give 14
(Method A, in CH2Cl2) was employed. Column chromatography
on silica gel (Et2O/CH2Cl2, 4:1) afforded 16 (65 mg, 0.24 mmol,
1
41% from 15) as a colorless oil. H NMR (400 MHz, CDCl3): δ =
6.98–6.92 (m, 3 H), 6.56 (d, J = 16 Hz, 1 H), 6.19 (dd, J = 6.4,
16 Hz, 1 H), 4.53 (br. q, J = 6.0 Hz, 1 H), 3.98–3.76 (m, 2 H), 3.83
(s, 3 H), 2.67 (a lump, 2 H, 2OH), 2.31 (s, 3 H), 1.90–1.80 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.3, 151.2, 139.4,
135.9, 132.3, 129.5, 122.9, 119.3, 110.3, 72.4, 61.1, 56.0, 38.6,
1
25.1, 22.7, 14.1 ppm. H NMR (400 MHz, CD3OD): δ = 6.80 (d,
J = 1.2 Hz, 1 H), 6.72 (d, J = 7.9 Hz, 1 H), 6.66 (dd, J = 1.2,
7.8 Hz, 1 H), 3.86 (s, 3 H), 3.82–3.74 (m, 2 H), 2.58 (ddd, J = 5.8,
10, 14 Hz, 1 H), 2.46 (ddd, J = 6.5, 9.6, 14 Hz, 1 H), 1.70–1.55 (m,
20.8 ppm. FTIR (film): ν = 3390, 3006, 2924, 2852, 1763, 1601,
˜
Eur. J. Org. Chem. 2014, 2128–2139
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2135

Z.-L. Wan, G.-L. Zhang, H.-J. Chen, Y. Wu, Y. Li
FULL PAPER
2 H), 1.54–1.40 (m, 2 H), 1.40–1.12 (m, 8 H), 0.94 (t, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CD3OD): δ = 149.7, 146.3, 136.1,
122.6, 116.9, 114.0, 72.5, 71.9, 57.2, 45.8, 41.7, 39.5, 34.0, 33.2,
[M + NH4]+. ESI-HRMS: calcd. for C14H24NaO4 [M + Na]+
279.1567; found 279.1558.
Conversion of Diacetate 24 into Diol 25: The same procedure for
the conversion of 8 into 9 was employed to give 25 (277 mg,
1.61 mmol, 95% from 24) as a colorless oil; [α]2D6 = +5.6 (c = 0.94,
27.0, 24.6, 15.3 ppm. FTIR (film): ν = 3367, 2931, 2857, 1602,
˜
1515, 1455, 1430, 1373, 1270, 1234, 1152, 1124, 1088, 1034, 934,
848, 815, 797, 727 cm–1. ESI-MS: m/z = 319.4 [M + Na]+. ESI-
HRMS: calcd. for C17H28NaO4 [M + Na]+ 319.18798; found
319.1882.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 5.92 (ddd, J = 5.6, 11,
17 Hz, 1 H), 5.28 (br. d, J = 17 Hz, 1 H), 5.13 (br. d, J = 11 Hz, 1
H), 4.45 (br. q, J = 5.3 Hz, 1 H), 3.91 (d quint, J = 7.5, 3.5 Hz, 1
H), 3.13 (s, 2 H, OH), 1.73–1.62 (m, 2 H), 1.58–1.23 (m, 8 H), 0.89
(t, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.9,
114.4, 70.6, 69.2, 42.3, 37.6, 31.9, 25.4, 22.7, 14.1 ppm. FTIR
Conversion of Epoxide 20 into 21: The same procedure for the con-
version of 3 into 4 was employed to give 21 (903 mg, 4.8 mmol,
92% from 20) as a white solid; m.p. 37–40 °C. [α]2D7 = +2.28 (c =
1.09, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.09–3.90 (m, 5
H), 2.30–2.00 (a lump, 2 H, OH), 1.63 (t, J = 5.6 Hz, 2 H), 1.58–
1.44 (m, 3 H), 1.42 (s, 3 H), 1.37 (s, 3 H), 1.35–1.26 (m, 5 H), 0.89
(t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 109.2,
78.4, 69.5, 69.1, 65.6, 38.5, 37.5, 31.8, 26.6, 25.4, 25.3, 22.6,
(film): ν = 3356, 3078, 3036, 3009, 2956, 2931, 2859, 1641, 1459,
˜
1421, 1376, 1310, 1126, 1052, 989, 921, 825, 724 cm–1. EI-MS: m/z
(%) = 146 (9) [M – acetylene]+, 128 (17), 127 (88), 126 (80), 125
(24), 120 (38), 114 (14), 115 (100), 107 (13), 101 (24), 91 (26), 77
(35). EI-HRMS: calcd. for C10H19O2 [M – H]– 171.1385, found
171.1390.
14.0 ppm. FTIR (film of a concentrated solution in CHCl ): ν =
˜
3
3404, 2982, 2959, 2931, 2872, 2857, 1456, 1372, 1258, 1214, 1157,
1064, 852 cm–1. ESI-MS: m/z = 269.3 [M + Na]+. ESI-HRMS:
calcd. for C13H26NaO4 [M + Na]+ 269.1723; found 269.1733.
Cross-Metathesis Reaction of Diol 25 and Styrene 10 To Afford Diol
26 and Ethyl Ketone (ent)-13: The same procedure for the cross-
metathesis reaction of 9 and 10 to afford 13 and 14 was employed
to give 26 and (ent)-13. Compound 12 was formed, but it was dis-
carded. Data for (ent)-13: Colorless oil (123 mg, 0.72 mmol, 69%
from diol 25); [α]2D5 = –41.96 (c = 0.96, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 4.07–4.00 (m, 1 H), 3.09 (s, 1 H, OH), 2.61
(dd, J = 2.8, 17 Hz, 1 H), 2.52 (dd, J = 9.2, 18 Hz, 1 H), 2.46 (br.
q, J = 7.6 Hz, 1 H), 1.53–1.22 (m, 8 H), 1.06 (t, J = 7.2 Hz, 3 H),
0.89 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
212.9, 67.8, 48.7, 36.9, 36.6, 31.9, 25.3, 22.7, 14.1, 7.6 ppm. EI-MS:
m/z (%) = 171 (0.1) [M – H]–, 154 (20) [M – H2O], 143 (45), 125
(90), 101 (98), 83 (80), 57 (100). EI-HRMS: calcd. for C10H19O2
[M – H]– 171.1385; found 171.1381. Data for 26: Colorless oil
(81 mg, 0.24 mmol, 23% from diol 25); m.p. 71–72 °C. [α]2D7 = –9.80
(c = 0.97, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.03–6.90 (m,
3 H), 6.56 (d, J = 15.6 Hz, 1 H), 6.22 (dd, J = 5.6, 15.6 Hz, 1 H),
4.62 (br. q, J = 4.7 Hz, 1 H), 4.01–3.90 (m, 1 H), 3.83 (s, 3 H),
3.40–2.60 (a lump, 2 H, OH), 2.03 (s, 3 H), 1.76 (br. t, J = 5.6 Hz,
2 H), 1.61–1.16 (m, 8 H), 0.88 (t, J = 6.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.3, 151.2, 139.3, 136.0, 132.6, 129.2,
122.9, 119.2, 110.3, 70.4, 69.5, 55.9, 42.6, 37.6, 31.9, 25.4, 22.7,
Conversion of Diol 21 into Diacetate 22: The same procedure for
the conversion of 4 into 5 was employed to give 22 (735 mg,
2.3 mmol, 100% from 21) as a colorless oil; [α]2D9 = –17.7 (c = 1.09,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 5.04 (dt, J = 9.6, 4.8 Hz,
1 H), 4.94 (br. d, J = 6.0 Hz, 1 H), 4.16 (br. q, J = 6.0 Hz, 1 H),
4.03 (dd, J = 6.8, 8.4 Hz, 1 H), 3.77 (dd, J = 6.4, 8.8 Hz, 1 H), 2.06
(s, 3 H), 2.02 (s, 3 H), 1.86–1.76 (m, 2 H), 1.58 (dt, J = 7.2, 14 Hz,
1 H), 1.51 (dt, J = 7.2, 14 Hz, 1 H), 1.42 (s, 3 H), 1.34 (s, 3 H),
1.28–1.18 (m, 6 H), 0.88 (t, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.8, 170.5, 109.9, 77.0, 69.80, 69.78, 66.0,
34.5, 34.2, 31.8, 26.4, 25.2, 24.9, 22.6, 21.2, 21.1, 14.1 ppm. FTIR
(film): ν = 2984, 2956, 2933, 2869, 1741, 1454, 1431, 1372, 1241,
˜
1154, 1122, 1062, 1023, 961, 935, 850 cm–1. ESI-MS: m/z = 353.4
[M + Na]+. ESI-HRMS: calcd. for C17H30NaO6 [M + Na]+
353.1935; found 353.1936.
Conversion of Acetonide 22 into Diol 23: The same procedure for
the conversion of 5 into 6 was employed to give 23 (527 mg,
1.82 mmol, 79% from 22) as a colorless oil; [α]2D8 = –10.6 (c = 2.13,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 5.06–4.91 (m, 1 H), 4.86
(tt, J = 2.7, 6.0 Hz, 1 H), 3.66–3.60 (m, 2 H), 3.51 (dd, J = 6.4,
12.3 Hz, 1 H), 3.31 (a lump, 2 H, OH), 2.08 (s, 3 H), 2.03 (s, 3 H),
1.99 (ddd, J = 2.8, 11, 14 Hz, 1 H), 1.87 (ddd, J = 3.0, 11, 14 Hz,
1 H), 1.60–1.47 (m, 2 H), 1.41–1.16 (m, 6 H), 0.88 (t, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.8, 171.0, 73.2,
70.3, 70.0, 62.6, 34.9, 34.8, 31.7, 24.9, 22.5, 21.1, 21.0, 14.0 ppm.
20.7, 14.1 ppm. FTIR (film): ν = 3327, 3009, 2953, 2931, 2857,
˜
1765, 1601, 1509, 1465, 1417, 1369, 1292, 1267, 1215, 1198, 1155,
1120, 1033, 1009, 967, 903, 864, 822, 792, 717, 669 cm–1. ESI-MS:
m/z = 359.4 [M + Na]+. ESI-HRMS: calcd. for C19H28NaO5 [M +
Na]+ 359.18290; found 359.1830.
Hydrogenation of 26 To Afford 27: The same procedure for the con-
version of 14 into 19 was employed to give 27 (5 mg, 0.01 mmol,
100% from 26) as a white solid; m.p. 87–88 °C. [α]2D7 = +2.00 (c =
0.60, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 6.91 (d, J =
8.0 Hz, 1 H), 6.80 (br. s, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 3.98–3.89
(m, 2 H), 3.80 (s, 3 H), 3.16 (s, 2 H, OH), 2.80–2.70 (m, 1 H), 2.66–
2.59 (m, 1 H), 2.29 (s, 3 H), 1.88–1.69 (m, 2 H), 1.66–1.55 (m, 2
H), 1.55–1.26 (m, 8 H), 0.89 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.5, 150.9, 141.2, 137.8, 122.5, 120.5,
112.7, 69.4, 68.6, 55.9, 42.5, 39.1, 37.5, 32.2, 31.9, 25.5, 22.7, 20.7,
FTIR (film): ν = 3459, 2956, 2932, 2861, 1736, 1463, 1434, 1374,
˜
1246, 1119, 1025, 960, 937, 876, 801 cm–1. ESI-MS: m/z = 313.3 [M
+ Na]+. ESI-HRMS: calcd. for C14H26O6Na [M + Na]+ 313.16216;
found 313.1629.
Conversion of Diol 23 into Alkene 24: The same procedure for the
conversion of 6 into 8 (Method A) was employed to give 24
(470 mg, 1.83 mmol, 100% from 23) as a colorless oil; [α]2D7 = –14.5
1
(c = 1.04, CHCl3). H NMR (400 MHz, CDCl3): δ = 5.79 (ddd, J
14.1 ppm. FTIR (film): ν = 3393, 2927, 2852, 1764, 1599, 1507,
˜
= 6.3, 11, 17 Hz, 1 H), 5.29 (br. q, J = 5.3 Hz, 1 H), 5.25 (br. d, J
= 17 Hz, 1 H), 5.16 (br. d, J = 11 Hz, 1 H), 4.99 (br. quint, J =
6.4 Hz, 1 H), 2.06 (s, 3 H), 2.03 (s, 3 H), 1.90–1.76 (m, 2 H), 1.61–
1.46 (m, 2 H), 1.42–1.17 (m, 6 H), 0.88 (t, J = 6.0 Hz, 3 H) ppm.
1463, 1414, 1365, 1278, 1217, 1197, 1151, 1119, 1032, 1006, 937,
902, 818 cm–1. ESI-MS: m/z = 361.3 [M + Na]+. ESI-HRMS: calcd.
for C19H30NaO5 [M + Na]+ 361.19855; found 361.1990.
13C NMR (100 MHz, CDCl3): δ = 170.7, 170.3, 136.4, 116.7, 70.9, Saponification of 27 To Afford (3R,5R)-1: The same procedure for
70.1, 38.7, 34.8, 31.8, 24.9, 22.6, 21.20, 21.17, 14.1 ppm. FTIR
conversion of 19 into (3R,5S)-1 was employed to give (3R,5R)-1
(37 mg, 0.12 mmol, 86% from 27) as a white solid, m.p. 105–
106 °C; ref.[4] m.p. 76 °C. [α]2D7 = –0.20 (c = 0.93, CHCl3), data
(film): ν = 3086, 2958, 2931, 2859, 1742, 1645, 1462, 1426, 1372,
˜
1243, 1151, 1129, 1022, 989, 935, 780 cm–1. ESI-MS: m/z = 273.9
2136
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2128–2139

A Chiral Pool and Cross Metathesis Based Synthesis of Gingerdiols
fluctuated significantly with a standard deviation of 0.2; ref.[4]
[α]2D5 = –1.2 (c = 0.8, CHCl3); ref.[9a] [α]D = –3.8 (c = 0.13, CHCl3);
ref.[2b] [α]2D5 = –1.0 (c = 3, CHCl3). 1H NMR (400 MHz, CDCl3): δ
= 6.82 (d, J = 8.0 Hz, 1 H), 6.70 (br. s, 1 H), 6.68 (d, J = 8.0 Hz,
1 H), 6.00–5.50 (a lump, 1 H, OH), 4.03–3.88 (m, 2 H), 3.85 (s, 3
H), 3.00–2.50 (a lump, 2 H, OH), 2.75–2.66 (m, 1 H), 2.66–2.50
(m, 1 H), 1.93–1.68 (m, 2 H), 1.68–1.57 (m, 2 H), 1.57–1.13 (m, 8
H), 0.88 (t, J = 6.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 146.6, 143.8, 134.0, 121.0, 114.5, 111.2, 69.6, 68.9, 56.0, 42.5,
39.5, 37.6, 32.0, 31.9, 25.5, 22.7, 14.1 ppm. FTIR (film of a concen-
solution in CH Cl ): ν = 3415, 2956, 2921, 2869, 2846, 1449, 1435,
˜
2 2
1150, 987, 917, 797 cm–1. EI-MS: m/z = 248 [M + H]+. EI-HRMS:
calcd. for C17H28O [M]+ 248.2140; found 248.2143.
Conversion of 43 into 44: The same procedure for the rearrangement
of 40 under CM conditions was employed for the conversion of 43
into 44. Using catalysts 11 (10 mol-%) and 29 (10 mol-%) and col-
umn chromatography on silica gel (CH2Cl2/Et2O, 5:1) gave 44 in
72% (20 mg, 0.043 mmol) and 65% (17 mg, 0.036 mmol) yield,
respectively, as a white solid; m.p. 185–187 °C. [α]2D8 = +29.1 (c =
0.76, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.77 (d, J =
1.0 Hz, 2ϫ 1 H), 5.20 (br. s, 2ϫ 1 H), 4.50 (br. s, 2ϫ 1 H), 2.48
(br. s, 2ϫ 1 H), 1.98–1.86 (m, 2ϫ 2 H), 1.84–1.75 (m, 2ϫ 2 H),
1.68–1.50 (m, 2ϫ 3 H), 1.63 (s, 2ϫ 3 H, 2 Me), 1.50–1.40 (m, 2ϫ
2 H), 1.25–1.20 (m, 2ϫ 1 H), 1.04–0.90 (m, 2ϫ 2 H), 0.88 (d, J =
5.9 Hz, 2ϫ 3 H, 2 CH3), 0.87 (d, J = 7.3 Hz, 2ϫ 3 H, 2 CH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 135.4, 132.9, 120.8, 71.9, 42.5,
42.3, 39.5, 37.7, 35.8, 27.9, 26.9, 26.3, 26.0, 24.0, 19.9, 10.2 ppm.
trated solution in CHCl ): ν = 3348, 2931, 2852, 1602, 1516, 1462,
˜
3
1426, 1373, 1271, 1230, 1150, 1120, 1035, 852, 817, 793 cm–1. ESI-
MS: m/z = 319.3 [M + Na]+. ESI-HRMS: calcd. for C17H28NaO4
[M + Na]+ 319.18798; found 319.1886.
Rearrangement of Diol 40 under CM Conditions To Afford Ketone
41
Method A (with Catalyst 11): A solution of 40 (102 mg, 0.71 mmol)
and catalyst 11 (44 mg, 0.070 mmol) in degassed, dry CH2Cl2
(7 mL) was stirred at ambient temperature for 16 h under argon
(balloon technique). Et2O (10 mL) was added followed by the ad-
dition of 15% H2O2 (20 mL). The mixture was stirred for 15 min,
and the phases were separated. The organic layer was washed with
aqueous saturated Na2SO3 solution and brine and then dried with
anhydrous Na2SO4. The solvent was removed by rotary evapora-
tion, and column chromatography on silica gel (PE/EtOAc, 4:1)
furnished known[27] 41 (37 mg, 0.26 mmol, 37%) as a colorless oil
along with recovered 40 (49 mg, 48%).
FTIR (film of a concentrated solution in CHCl ): ν = 3338, 2960,
˜
3
2921, 2867, 2850, 1728, 1670, 1663, 1568, 1435, 1380, 1281, 1212,
1185, 1144, 1121, 1091, 1074, 1027, 987, 962, 912, 859, 821, 796,
757, 718 cm–1. ESI-MS: m/z = 491.8 [M + Na]+. ESI-HRMS: calcd.
for C32H52NaO2 [M + Na]+ 491.3858; found 491.3860.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra as well as FTIR spec-
tra for all new compounds.
Method B (with Catalyst 29): Employing the same procedure as
given above, but with catalyst 29 (10 mol-%) instead of catalyst 11,
gave 41 (36 mg, 0.25 mmol, 62%) and recovered 40 (14 mg,
Acknowledgments
1
This work was supported by the National Basic Research Program
of China (973 Program, grant number 2010CB833200), the
National Natural Science Foundation of China (NSFC) (grant
numbers 21372248, 21172247, and 21032002), and the Chinese
Academy of Sciences.
0.097 mmol, 24%). Data for 41: H NMR (400 MHz, CDCl3): δ =
4.06 (d quint, J = 7.5, 3.5 Hz, 1 H), 3.21–3.00 (a lump, 1 H, OH),
2.60 (dd, J = 2.8, 17.3 Hz, 1 H), 2.50 (dd, J = 8.7, 19 Hz, 1 H),
2.46 (q, J = 7.3 Hz, 2 H), 1.57–1.46 (m, 2 H), 1.44–1.33 (m, 2 H),
1.07 (t, J = 7.2 Hz, 3 H), 0.93 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 212.9, 67.5, 48.7, 38.7, 36.9, 18.7, 14.0,
7.6 ppm. FTIR (film): ν = 3470, 2960, 2932, 2872, 1708, 1459,
˜
[1] E. J. Lien, S. Ren, H.-H. Bui, R. Wang, Free Radical Biol. Med.
1999, 26, 285–294.
[2] a) F. Kiuchi, S. Iwakami, M. Shibuya, F. Hanaoka, U. Sank-
awa, Chem. Pharm. Bull. 1992, 40, 387–391; b) G. Sabitha, C.
Srinivas, T. R. Reddy, K. Yadagiri, J. S. Yadav, Tetrahedron:
Asymmetry 2011, 22, 2124–2133.
1409, 1377, 1284, 1215, 1120, 1090, 1013, 950, 843, 742 cm–1. ESI-
MS: m/z = 167.2 [M + Na]+.
Synthesis of Alcohol 43: In an ice-water bath under argon (balloon
technique), a solution of dihydroartemisinyl aldehyde (440 mg,
2.0 mmol) in dry THF (20 mL) was stirred. CH2=CHMgBr (1.0 m
in THF, 2.4 mL, 2.4 mmol) was added, and the resulting mixture
was stirred at the same temperature for 30 min, which was when
TLC indicated that the reaction had reached completion. Water
(2 mL) was added carefully, and the resulting mixture was extracted
with EtOAc (3ϫ 20 mL). The combined organic layers were
washed with water and brine and then dried with anhydrous
Na2SO4. The solvent was removed by rotary evaporation, and col-
umn chromatography on silica gel (PE/EtOAc, 30:1) gave 43 (the
less polar isomer, 120 mg, 0.48 mmol, 24%) as a white solid along
with a mixture of 43 and its more polar epimer (1.4:1 mixture,
[3] T. Murata, M. Shinohara, M. Miyamoto, Chem. Pharm. Bull.
1972, 20, 2291–2292.
[4] H. Kikuzaki, S.-M. Tsai, N. Nakatani, Phytochemistry 1992,
31, 1783–1786.
[5] S. Zhou, H. Liang, S.-Q. Cai, Y.-Y. Zhao, J. Chin. Pharm. Sci.
2007, 16, 24–25, no optical rotation data were provided.
[6] S. D. Rychnovsky, Chem. Rev. 1995, 95, 2021–2040.
[7] a) J. Mulzer, C. Pietschman, B. Schollhorn, J. Buschmann, P.
Luger, Liebigs Ann. 1995, 1433–1439 (the first report for the
epoxy chiral building blocks); b) J.-Z. Wu, J. Gao, G.-B. Ren,
Z.-B. Zhen, Y.-H. Zhang, Y. Wu, Tetrahedron 2009, 65, 289–
299 (a practical route to the epoxy chiral building blocks using
d-gluconolactone as the starting material).
214 mg, 0.86 mmol, 43%). Data for 43: M.p. 41–42 °C; [α]2D5
=
+41.0 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 5.90
(ddd, J = 17, 10, 4.3 Hz, 1 H), 5.24 (dt, J = 17, 1.7 Hz, 1 H), 5.17
(br. s, 1 H), 5.13 (dt, J = 10, 1.8 Hz, 1 H), 4.44–4.40 (m, 1 H),
2.50–2.43 (m, 1 H), 1.97–1.84 (m, 2 H), 1.84–1.70 (m, 2 H), 1.61
(s, 3 H), 1.67–1.58 (m, 2 H), 1.58–1.50 (m, 2 H), 1.50–1.37 (m, 2
H), 1.26–1.18 (m, 1 H), 1.03–0.90 (m, 2 H), 0.86 (d, J = 6.5 Hz, 3
H), 0.83 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 141.5, 135.1, 120.6, 113.6, 72.1, 42.2, 42.0, 39.0, 37.5, 35.6, 27.7,
26.7, 26.1, 25.8, 23.8, 19.8, 9.8 ppm. FTIR (film of a concentrated
[8] a) L. He, S. Zhang, Y. Wu, Y. Li, Chin. J. Chem. 2011, 29,
2664–2668; b) S. Zhang, Y. Wu, Chin. J. Chem. 2011, 29, 2798–
2802; c) G.-B. Ren, Y.-X. Huang, Y.-P. Sun, Z.-H. Li, Y.-K.
Wu, J. Org. Chem. 2009, 75, 5048–5064; d) X. Yan, S.-M.
Zhang, Y.-K. Wu, P. Gao, Org. Biomol. Chem. 2011, 9, 6797–
6806; e) P. Jiang, S.-M. Zhang, L. He, Y.-K. Wu, Y. Li, Tetrahe-
dron 2011, 67, 2651–2660; f) S.-M. Zhang, X.-W. Lu, Y.-K. Wu,
Asian J. Org. Chem. 2012, 1, 245–250; g) C.-Y. Chen, W.-B.
Han, H.-J. Chen, Y.-K. Wu, P. Gao, Eur. J. Org. Chem. 2013,
348–1355.
Eur. J. Org. Chem. 2014, 2128–2139
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2137

Z.-L. Wan, G.-L. Zhang, H.-J. Chen, Y. Wu, Y. Li
FULL PAPER
[9]
Rec. 2007, 7, 238–253; g) B. Alcaide, P. Almendros, A. Luna,
Chem. Rev. 2009, 109, 3817–3858; h) B. Schmidt, J. Mol. Catal.
A 2006, 254, 53–57; B. Schmidt, Eur. J. Org. Chem. 2004, 1865–
1880; for a previous occurrence of the isomerization of an all-
ylic alcohol with an additional OH, see: i) B. Schmidt, L.
Staude, A. Kelling, U. Schilde, Eur. J. Org. Chem. 2011, 1721–
1727.
For previous syntheses of (3R,5S)- and (3S,5S)-1, see: a) M.
Franck-Neumann, P. Geoffroy, P. Bissinger, S. Adelaide, Tetra-
hedron Lett. 2001, 42, 6401–6404; b) G. Sabitha, C. Srinivas,
T. R. Reddy, K. Yadagiri, J. S. Yadav, Tetrahedron: Asymmetry
2011, 22, 2124–2133.
[10]
[11]
B. Modak, R. Torres, E. Lissi, F. D. Monache, Nat. Prod. Res.
2003, 17, 403–407.
In ref.[9a], the (3R,5R) isomer was briefly mentioned to have
been synthesized, but neither experimental details nor spectro-
scopic and physical data were given.
[23]
[24]
B. Schmidt, S. Hauke, Org. Biomol. Chem. 2013, 11, 4194–
4206.
a) C. O. Kangani, A. M. Brueckner, D. P. Curran, Org. Lett.
2005, 7, 379–382; b) G. W. O’Neil, A. J. Phillips, J. Am. Chem.
Soc. 2006, 128, 5340–5341; c) A. Fujino, T. Sugai, Adv. Synth.
Catal. 2008, 350, 1712–1716; d) F. Fu, T.-P. Loh, Tetrahedron
2009, 50, 3530–3533; e) S. B. Han, A. Hassan, I. S. Kim, M. J.
Krische, J. Am. Chem. Soc. 2010, 132, 15559–15561; f) G. Sabi-
tha, B. Vangala, S. S. S. Reddy, J. S. Yadav, Helv. Chim. Acta
2010, 93, 329–338; g) G. Sabitha, M. N. Prasad, K. Shanka-
raiah, N. M. Reddy, J. S. Yadav, Synthesis 2010, 3891–3898; h)
P. K. Jana, S. B. Mandal, A. Bhattacharjya, Tetrahedron Lett.
2011, 52, 6767–6771; i) P. A. Evans, M.-H. Huang, M. J.
Lawler, S. Maroto, Nature Chem. 2012, 4, 680–684; j) Y. Zou,
Y.-K. Wu, Angew. Chem. 2012, 124, 5052; Angew. Chem. Int.
Ed. 2012, 51, 4968–4971; k) W. Zhang, Q. Liang, H. Li, X.
Meng, Z. Li, Tetrahedron 2013, 69, 664–672.
a) S. M. Hande, J. Uenishi, Tetrahedron Lett. 2009, 50, 189–
192; b) P. Sawant, M. E. Maier, Synlett 2001, 3002–3004; c) B.
Samir, R. Simmons, J. Cossy, Org. Lett. 2004, 6, 3465–3467; d)
J. D. Waetzig, P. R. Hanson, Org. Lett. 2006, 8, 1673–1676; e)
M. J. Comin, D. A. Parrish, J. R. Deschamps, V. E. Marquez,
Org. Lett. 2006, 8, 705–708; f) A. K. Ghosh, S. Kulkarni, Org.
Lett. 2008, 10, 3907–3909; g) L. Soulère, Y. Queneau, A. Dou-
theau, Chem. Phys. Lipids 2007, 150, 239–243; h) S. Mix, S.
Blechert, Adv. Synth. Catal. 2007, 349, 157–160; i) D. Stead, P.
O’Brien, A. Sanderson, Org. Lett. 2008, 10, 1409–1412; j) A.
Miura, S. Kuwahara, Tetrahedron 2009, 65, 3364–3368; k) A.
Sharma, S. Mahato, S. Chattopadhyay, Tetrahedron Lett. 2009,
50, 4986–4988; l) G. Sabitha, N. Fatima, P. Gopal, C. N. Reddy,
J. S. Yadav, Tetrahedron: Asymmetry 2009, 24, 184–191; m) H.
Fuwa, H. Yamaguchi, M. Sasaki, Org. Lett. 2010, 12, 1848–
1851; n) H. Fuwa, H. Yamaguchi, M. Sasaki, Tetrahedron
2010, 66, 7492–7503; o) G. Sabitha, S. S. S. Reddy, V. Bhaskar,
J. S. Yadav, Synthesis 2010, 1217–1222; p) G. Sabitha, B. Van-
gala, S. S. S. Reddy, J. S. Yadav, Helv. Chim. Acta 2010, 93,
329–338; q) D. K. Reddy, V. Shekhar, P. Prabhakar, B. C. Babu,
B. Siddhardha, U. S. N. Murthy, Y. Venkateswarlu, Eur. J. Med.
Chem. 2010, 45, 4657–4663; r) J. Guan, Z.-B. Zhen, Y. Zou,
Z.-Y. Yue, P. Jiang, Y. Li, Y.-K. Wu, Tetrahedron 2011, 67, 860–
865; s) S. P. Reddy, B. Chinnabab, V. Shekhar, D. K. Reddy,
G. V. S. Bhanuprakash, L. R. Velatoor, J. V. Rao, Y. Venkates-
warlu, Bioorg. Med. Chem. Lett. 2012, 22, 4182–4184; t) J. K.
Park, D. T. McQuade, Angew. Chem. 2012, 124, 2771; Angew.
Chem. Int. Ed. 2012, 51, 2717–2721.
[12]
a) A. B. Smith III, V. A. Doughty, C. Sfonggatakis, C. S. Be-
nett, J. Koyangagi, M. Takeuchi, Org. Lett. 2002, 4, 783–786;
b) A. B. Smith III, T. M. Razler, G. R. Pettit, J.-C. Chapuis,
Org. Lett. 2005, 7, 4403–4406.
J. M. G. Fernández, C. O. Mellet, A. M. Marín, J. Fuentes,
Carbohydr. Res. 1995, 274, 263–268.
a) K. Mori, Tetrahedron 2012, 68, 8441–8449; b) C.-Y. Chen,
W.-B. Han, H.-J. Chen, Y.-K. Wu, P. Gao, Eur. J. Org. Chem.
2013, 4311–4318; c) H.-J. Chen, C.-Y. Chen, P. Gao, Y.-K. Wu,
Tetrahedron 2013, 69, 9848–9851.
B. Dhotare, S. A. Hassarajani, A. Chattopadhyay, Molecules
2000, 5, 1051–1054.
For original reports, see: a) P. J. Garegg, B. Samuelsson, Syn-
thesis 1979, 469–470; b) P. J. Garegg, B. Samuelsson, Synthesis
1979, 813–814; for recent applications, see: c) H. B. Mereyala,
P. M. Goud, R. R. Gadikota, K. R. Reddy, J. Carbohydr.
Chem. 2000, 19, 1211–1212; d) G. Banda, I. E. Chakravarthy,
Tetrahedron: Asymmetry 2006, 17, 1684–1687; e) J. S. Yadav, S.
Das, A. K. Mishra, Tetrahedron: Asymmetry 2010, 21, 2443–
2447.
a) B. B. Snider, J. F. Graowski, Tetrahedron 2006, 62, 5171–
5177; b) J. Gierer, O. Lindeberg, Acta Chem. Scand., Ser. B
1980, 34, 161–170; c) J. Gierer, L. Pettersson, Can. J. Chem.
1977, 55, 593–599; d) L. Lonsky, W. Longsky, K. Kratzl, I.
Falkehag, Monatsh. Chem. 1976, 107, 685–695; e) The use of
diacetate 8 instead of diol 9 in the CM failed to give any desired
cross-coupling product (essentially no reaction occurred with
8).
[13]
[14]
[15]
[16]
[25]
[17]
[18]
[19]
J. Rehdorf, A. Lengar, U. T. Bornscheuer, M. D. Mihovilovic,
Bioorg. Med. Chem. Lett. 2009, 19, 3739–3743.
It is interesting to note that in the IR spectra the acetate carb-
onyl stretching band for 14, 14ЈЈ, 19, and so forth appeared at
frequencies higher than normally encountered (1765–1766 cm–1
instead of 1730–1740 cm–1). However, comparable data were
also previously recorded for similar compounds. For details,
see: a) J. E. Baldwin, R. M. Adlington, V. W.-W. Sham, R.
Marquez, P. G. Bulger, Tetrahedron 2005, 61, 2353–2362
(1764 cm–1, for 26 therein); b) C. Changtam, P. Hongmanee,
A. Suksamrarn, Eur. J. Med. Chem. 2010, 45, 4446–4457 (1762
and 1757 cm–1, respectively, for 19 and 20 therein).
[20]
[21]
J. Walker, S. C. Rothman, C. D. Poulter, J. Org. Chem. 2008,
73, 726–729.
[26]
For the preparation as reported for its homologue (with one
more CH2 in the side chain), see: a) G. C. Paddon-Jones,
C. S. P. McErlean, P. Hayes, C. J. Moore, W. A. Konig, W.
Kitching, J. Org. Chem. 2001, 66, 7487–7495; optically active
cis-40 is also known, see: b) J. S. Yadav, V. N. Kumar, R. S.
Rao, P. Srihari, Synthesis 2008, 1938–1942.
D. Menche, F. Arikan, J. Li, S. Rudolph, Org. Lett. 2007, 9,
267–270.
M. Jung, S. Lee, J. Ham, K. Lee, H. Kim, S. K. Kim, J. Med.
Chem. 2003, 46, 987–994 , but without data for 43.
a) B. M. Trost, R. J. Kulawieck, J. Am. Chem. Soc. 1993, 115,
2027–2036; b) A. Bouziane, B. Carboni, C. Bruneau, F. Car-
reaux, J.-L. Renaud, Tetrahedron 2008, 64, 111745–111750; c)
V. Cadierno, P. Crochet, J. Francos, S. E. Garcia-Garrido, J.
Gimeno, N. Nebra, Green Chem. 2009, 11, 1992–2000; d) V.
Cadierno, P. Crochet, J. Gimeno, Synlett 2008, 1105–1124 (a
review).
a) L. Ackermann, D. E. Tom, A. Fürstner, Tetrahedron 2000,
56, 2195–2202; b) M. K. Gurjar, P. Yakambram, Tetrahedron
Lett. 2001, 42, 3633–3636; c) C. D. Edlin, J. Faulkner, D.
Fengas, C. K. Knight, J. Parker, I. Preece, P. Quayle, S. N.
Richards, Synlett 2005, 572–576; to compare another related
case, see: d) D. Finnegan, B. A. Seigal, M. L. Snapper, Org.
Lett. 2006, 8, 2603–2606; for reviews of non-CM reactions cat-
alyzed by Grubbs and related catalysts, see: e) B. Alcaide, P.
Almendros, Chem. Eur. J. 2003, 9, 1258–1262; f) M. Arisawa,
Y. Terada, K. Takahashi, M. Nakagawa, A. Nishida, Chem.
[27]
[28]
[29]
[22]
The ease of the rearrangement of unprotected 5-substituted
pent-1-ene-3,5-diols, which is likely not noticed because it is
never mentioned or discussed in the literature, inevitably re-
duces the yields of the desired CM products and, thus, explains
the lack of reports of CM reactions that involve such diols.
However, comparably protected diols, which are sterically more
hindered and difficult to react than the unprotected diols, were
utilized. See ref.[8f,8g] and ref.[24]
.
2138
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2128–2139

A Chiral Pool and Cross Metathesis Based Synthesis of Gingerdiols
[30] Although the suppression of the isomerization (allylic alcohols
[31]
a) G. S. Forman, A. E. McConnell, R. P. Tooze, W. J.
van Rensburg, W. H. Meyer, M. M. Kirk, C. L. Dwyer, D. W.
Serfontein, Organometallics 2005, 24, 4528–4542; b) G. S.
Forman, R. P. Toose, J. Organomet. Chem. 2005, 690, 5863–
5866.
into ketones) by phenol (at 110 °C) was highlighted in ref.[23]
,
phenol was added as an accelerating agent (cf. the Conclusions
Section therein, earlier reports, and ref.[31a,31b]). However, in
our case, the acceleration by phenol was not apparent because
the time required for completion of the reaction was nearly the
same, perhaps because of the structural differences between the
substrates.
Received: November 17, 2013
Published Online: January 29, 2014
Eur. J. Org. Chem. 2014, 2128–2139
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2139