Enantioselective allylation of tert-butyldimethylsilyl-protected vanillin and synthesis of a lignan derivative isolated from machilus wangchiana

Article abstract of DOI:10.1002/ejoc.201403094

Various enantioselective allylations and crotylations of tert-butyldimethylsilyl-protected vanillin were undertaken to assess the best methodology to provide the corresponding homoallylic alcohols in high yields with high enantiopurity. In general, most of the tested allylations proceeded with high enantioselectivities (>92 % ee) and in the case of crotylation also with excellent diastereoselectivity (96 % ee, >98 % de). The product obtained from the crotylation reaction was used in the enantioselective synthesis of the unnatural diastereoisomer of a recently isolated lignan derivative.

Full text of DOI:10.1002/ejoc.201403094

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403094
Enantioselective Allylation of tert-Butyldimethylsilyl-Protected Vanillin and
Synthesis of a Lignan Derivative Isolated from Machilus wangchiana
Timothée Cadart,[a][‡] Petr Koukal,[a] and Martin Kotora*[a]
Keywords: Synthetic methods / Allylation / Aldehydes / Lewis bases / Lewis acids / Brønsted acids
Various enantioselective allylations and crotylations of tert-
butyldimethylsilyl-protected vanillin were undertaken to as-
sess the best methodology to provide the corresponding
homoallylic alcohols in high yields with high enantiopurity.
In general, most of the tested allylations proceeded with high
enantioselectivities (Ͼ92%ee) and in the case of crotylation
also with excellent diastereoselectivity (96%ee, Ͼ98%de).
The product obtained from the crotylation reaction was used
in the enantioselective synthesis of the unnatural dia-
stereoisomer of a recently isolated lignan derivative.
Second, low yields of aldol reactions have been observed
for electron-rich benzaldehydes[6] and also the retro-aldol
reaction often competes with this reaction.[7,8] On the other
hand, selective crotylation followed by oxidative elaboration
of the double bond (Wacker oxidation) offers an optional
synthetic pathway to access the β-hydroxy ketone (aldol)
moiety. In this regard, vanillin (2) was envisioned as a suit-
able starting material for the preparation of above-men-
tioned lignan derivatives 1a and 1b (Scheme 1).
Introduction
Enantioselective allylation of carbonyl compounds con-
stitutes an important reaction that gives rise to chiral
homoallylic alcohols that can be used as important syn-
thons for syntheses of more complex molecules possessing
various biological activities or those found in nature. In this
respect, numerous methods based on Lewis acid or base
catalysis have been developed.[1] Although various natural
compounds have been synthesized by using enantioselective
allylation, there exists a plethora of other compounds that
could also be prepared on the basis of this methodology.
Recently isolated lignan derivatives 1 from Machilus
wangchiana[2] and Nicotiana tabacum belong to this group
of such substances.[3] Plants containing these compounds
are used in traditional Chinese medicine (Figure 1).[4]
Scheme 1. Retrosynthetic analysis of lignan derivative 1.
Results and Discussion
Allylation and Crotylation Reactions
Figure 1. Lignan derivatives 1a and 1b.
Although several procedures for the enantioselective
allylation of 3,4-dimethoxybenzaldehyde to provide the cor-
responding homoallylic alcohol with enantiopurity in the
range of 10–98%ee have been published,[9] in none of these
cases was an aldehyde used as a starting material for the
synthesis of more complex compounds. As far as tert-butyl-
dimethylsilyl (TBS)-protected vanillin 3 is concerned, only
two reports deal with a racemic simple allylation.[10,11]
Given that there are not many reports on the enantioselec-
tive allylation of electron-rich benzaldehydes bearing two
electron-donating groups (e.g., alkoxy moieties), except
those mentioned above, it was decided to screen several dif-
ferent methods. Lewis acid, Lewis base, and Brønsted acid
catalyzed processes with the use of various allylation and
Although one might argue that these compounds could
be synthesized by stereoselective aldol condensation of the
corresponding aldehyde with 2-butanone, this pathway is,
in general, not easily feasible. First, selective formation of
the thermodynamically more stable enolate from 2-but-
anone is not simple, as there is just a handful of examples.[5]
[a] Department of Organic Chemistry, Faculty of Science, Charles
University in Prague,
Hlavova 8, 128 43 Praha 2, Czech Republic
E-mail: kotora@natur.cuni.cz
https://www.natur.cuni.cz/chemistry/orgchem/kotora?set_langu-
age=en
[‡] Visiting student from Aix-Marseille Université, France.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403094.
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SHORT COMMUNICATION
Scheme 2. Enantioselective allylation of protected vanillin 3.
Table 1. Enantioselective allylation and crotylation of 3 to the corresponding homoallylic alcohols.
Entry
4
XnM
Catalyst (mol-%)
T [°C]
T [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
10
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
BrMg
Cl3Si
Cl3Si
Bu3Sn
(MeO)3Si
(Pin)B
[(+)-Ipc]2B
(Pin)B
(Pin)B
(MeO)3Si
–
0
4
88
65
66
89
14
34
70
70
70
0
–
(R,Rax)-dioxide (2.5)
(R,Sax)-dioxide (2.5)
AgOTf/(S)-BINAP (30:30)
AgOTf/(S)-BINAP/KF/18-crown-6 (2:5:5:5)
(S)-TRIP-PA (5)
–
–
–40
–40
–20
–20
–20
–100
0
18
18
20
18
20
4
4
18
18
93 (S)[c]
95 (R)[d]
92 (R)[d]
92 (R)[d]
89 (R)[d]
94 (S)[c]
–
(S)-TRIP-PA (5)
AgOTf/(S)-BINAP/KF/18-crown-6 (2:5:5:5)
–30
–30
95 (R,S)[c]
–
[a] Yield of isolated product. [b] Determined by Mosher ester method. [c] Assignment of the configuration was based on analysis of the
corresponding Mosher esters. [d] The configuration was assigned by comparison of the signs of the optical rotations of products obtained
from the (R,Rax)-dioxide catalyzed reaction, entry 2.
crotylation agents were chosen as representative procedures 5a in 89% yield with 92%ee (Table 1, entry 4). The latter
(Scheme 2).
[AgOTf (5 mol-%) and (S)-BINAP (2 mol-%)] was executed
At the outset, the reaction of 3, prepared from vanillin under similar reaction conditions [KF and 18-crown-6 were
(2), with allylmagnesium bromide was performed in diethyl used as additives (5 mol-% both)][15] and provided (R)-5a in
ether at 0 °C[10b] to obtain racemic homoallylic alcohol 5a 14% yield with 92%ee (Table 1, entry 5). The obtained re-
as the standard for determination of asymmetric induction sults indicate that the chosen methods were equal with re-
(see below). The reaction with 3 proceeded smoothly and spect to the asymmetric induction. However, a different
homoallylic alcohol 5a was isolated in 88% yield (Table 1, loading of the catalyst could play a significant role. Then,
entry 1).
allylation with allylboronic acid pinacol ester was per-
The first enantioselective allylations of 3 were performed formed in the presence of a chiral phosphoric acid [(S)-
with allyltrichlorosilane under Lewis base catalysis by using TRIP-PA (5 mol-%)].[16] Homoallylic alcohol (R)-5a was
(R,Rax)-dioxide and (R,Sax)-dioxide (2.5 mol-%) (Fig- isolated in a low yield of 34% with a somewhat lower asym-
ure 2).[12] The reactions were performed in THF at –40 °C metric induction of 89%ee (Table 1, entry 6; Pin = pin-
for 18 h, and after workup homoallylic alcohols (S)- and acolyl). It was reported that allylation of benzaldehydes
(R)-5a were isolated in yields of 65 and 66% with enantio- bearing electron-donating or electron-withdrawing groups
meric excesses of 93 and 95%, respectively (Table 1, en- by using the above-mentioned catalytic systems possessing
tries 2 and 3).[13]
the S configuration usually provide products possessing the
S configuration and vice versa. However, we observed that
catalytic systems possessing the S configuration provided
products with the R configuration and vice versa. This is
rather an intriguing aberration that might deserve future
attention. Finally, stoichiometric enantioselective allylation
with (+)-B-allyldiisopinocampheylborane {[(+)-Ipc]2B} in
Et2O at –100 °C[17] was attempted, and this reaction pro-
vided homoallylic alcohol (S)-5a with 94%ee in 70% yield
(Table 1, entry 7). Interestingly, a change in facial selectivity
was observed again.
Figure 2. (R,Rax)- and (R,Sax)-N,NЈ-dioxide catalysts.
AgI-catalyzed reactions in the presence of (S)-2,2Ј-bis(di-
phenylphosphino)-1,1Ј-binaphthyl [(S)-BINAP] were tested
with allyltributylstannane and allyltrimethoxysilane as the
allylation agents. The former [silver trifluoromethanesulfon-
ate (AgOTf, 30 mol-%) and (S)-BINAP (30 mol-%)] was
performed in THF at –20 °C[14] for 20 h and provided (R)-
Then, enantioselective crotylation of 3 (Scheme 1) was
run in an analogical manner. A simple reaction with trans-
crotylboronic acid pinacol ester[16] was performed to obtain
a sample of racemic homoallylic alcohol 5b as the standard
for determination of asymmetric induction.[13] Racemic
homoallylic alcohol 5b was isolated in 70% yield (Table 1,
2
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Enantioselective Allylation and Synthesis of a Lignan Derivative
entry 8). Given that TRIP-PA[16] was shown to be a promis-
To obtain racemic compound 1, deprotection of the TBS
ing catalyst for enantioselective crotylation, the reaction of groups by using classical methods [i.e., tetrabutylammo-
3 with trans-crotylboronic acid pinacol ester was catalyzed nium fluoride (TBAF)] was envisaged. Although deprotec-
by (S)-TRIP-PA (5 mol-%) at –30 °C for 18 h. Desired anti- tion of the TBS groups should not pose any problems,
product (R,S)-5b was isolated in 70% yield with 95%ee attempts to do that proved otherwise. In general, the depro-
(Table 1, entry 9). Notably, in none of the cases was the tection proceeded either at the phenolic hydroxy group to
1
presence of the syn diastereoisomer detected by H NMR give only compound 9 or the product of the retro-aldol re-
spectroscopy, which is indicative of a highly diastereoselec- actionϪvanillin (2)Ϫwas detected (Scheme 4, for details see
tive process (de Ͼ98%). Finally, the reaction was tested Table S2) Thus, deprotection by using TBAF·3H2O in THF
with the catalytic system used in entry 5, but formation of at room temperature[25] resulted in the sole formation of 9
homoallylic alcohol 5b was not detected (Table 1, entry 10). in 84% yield. The same experiment was repeated in the
presence of 4 Å molecular sieves, and it proceeded with the
same result (90% of 9). Under harsher conditions, vanillin
(2) was isolated as the only product in 54% yield. Similar
results were obtained also if trifluoroacetic acid[26] or 4 n
HCl was used:[27] vanillin (2) was isolated in yields of 94
and 50%, respectively. A reasonable explanation for the ob-
served results is that retro-aldolization takes place under
the deprotection conditions, that is, it is induced under both
basic and acid conditions. This is not surprising, because
the retro-aldol reaction of aldols possessing electron-rich
aromatic rings have been previously observed.[7]
Racemic Synthesis of Lignan Derivative
After finding the most suitable catalyst for the enantio-
selective allylation and crotylation of protected vanillin 3,
synthesis of lignan derivative 1a was undertaken. To check
all synthetic steps, the synthesis started from racemic homo-
allylic alcohol anti-5b, which was obtained by crotylation
with trans-crotylboronic acid pinacol ester under previously
described conditions. The next step, conversion of the ter-
minal double bond into corresponding methyl ketone 6,
was envisioned to be performed by Wacker oxidation. Al-
though this method is usually reliable, in this case a number
of obstacles had to be overcome (see Table S1 in the Sup-
porting Information). Initial attempts to convert the double
bond in 5b under the usually applied conditions (see
Table S1 for details)[18–22] directly into methyl ketone were
not met with success. In neither case was desired product 6
detected. The unsuccessful oxidation was ascribed to the
presence of the free benzylic alcohol group. To avoid its
possible oxidation under the reaction conditions, 5b was
treated with tert-butyldimethylsilyl chloride[23] to give bis-
(silylated) compound 7 in 85% yield. The first attempt to
perform oxidation of 7 under the standard conditions by
using a mixture of PdCl2 and CuCl in a mixture of DMF/
H2O[19] under an oxygen atmosphere gave rise to desired
compound 8 in 36% yield. Switching from DMF to dimeth-
ylacetamide (DMA)[24] and the same amount of oxidant
(1.5 equiv. of CuCl) resulted in a considerable improvement:
ketone 8 was isolated in 57% yield and the full conversion
of the starting material was observed (Scheme 3). Further
attempts to improve the yield did not meet with success. If
the oxidation was performed on a larger scale (0.55 mmol
of 7), 8 was isolated in 36% yield.
Scheme 4. Attempts to deprotect 8.
Racemic Synthesis of 1b
With these results in hand, it was decided to switch our
synthetic target from 1a to compound 1b, which is also a
lignin-type natural compound possessing a benzylic meth-
oxy group instead of the hydroxy one.[2] The racemic syn-
thesis of 1b started with O-methylation of benzylic alcohol
5b. The alcohol was treated with NaH in THF at 0 °C,
which was followed by the addition of MeI.[28] Desired
methylated compound 5b was isolated in 44% yield. Then,
the Wacker oxidation was performed by using PdCl2 and
CuCl/O2 in a 4:1 mixture of DMA/H2O,[24] and this yielded
desired ketone 10 in 56% yield. Finally, the deprotection
step of 11 to 1b was performed with TBAF·3H2O in THF
at 20 °C.[25] Although the retro-aldol reaction was not ob-
served, an inseparable mixture of 1b and α,β-unsaturated
ketone 12 was obtained (Scheme 5). A reasonable explana-
tion regarding the formation of 12 during the deprotection
step of 11 is formation of enolate followed by elimination of
the methoxy group. Compound 12 is also a natural lignan
derivative, and its spectral data were in agreement with the
reported data.[29] To avoid its formation, the deprotection
was performed at 0 °C, which gave desired compound 1b in
an almost quantitative yield of 98% with spectral data in
agreement with the published data.[2] In summary, the syn-
thesis of lignan 1b was executed in five steps in an overall
yield of 18% starting from vanillin (Scheme 5).
Scheme 3. Wacker oxidation of 5b and 7.
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SHORT COMMUNICATION
96% yield with Ͼ96%ee (determined by HPLC analysis).
The free benzylic hydroxy group in (R,S)-5b was treated
with MeI in the presence of NaH in THF to give (R,S)-10
in 57% yield. Then, the terminal double bond of (R,S)-10
was submitted to Wacker oxidation by using PdCl2 (25 mol-
%) and CuCl (1.5 equiv.) in a mixture of DMA and H2O
under an oxygen atmosphere to provide ketone (R,S)-11 in
53% yield. Finally, deprotection was performed in THF in
the presence of TBAF·3H2O at 0 °C to provide desired en-
antioenriched lignan (R,S)-1b in 77% yield. Although the
sign of the optical rotation was opposite to that of the com-
pound isolated from natural sources, this synthesis provided
proof of concept regarding the synthetic strategy for this
type of compound. In addition, it validated the initial as-
sumption regarding the absolute configuration determi-
nation deduced from the Mosher ester to be correct. The
structure was unequivocally determined by single-crystal X-
ray analysis, which confirmed the anti arrangement of the
methyl and methoxy groups (Figure 3).
Scheme 5. Racemic synthesis of lignan derivative 1b.
Enantioselective Synthesis of 1b
After finding the best reaction conditions for all steps
starting from racemic homoallylic alcohol 5b, enantioselec-
tive synthesis ensued (Scheme 6). The asymmetric crotyl-
ation reaction of 3 with trans-crotylboronic acid pinacol es-
ter catalyzed by (S)-TRIP-PA (5 mol-%) in toluene at
–30 °C gave rise to chiral homoallylic alcohol (R,S)-5b in
Conclusions
In conclusion, enantioselective allylations and crotyla-
tions of tert-butyldimethylsilyl-protected vanillin as a repre-
sentative electron-rich aldehyde were explored. As far as
allylation is concerned, the highest asymmetric induction
(95%ee) was achieved by using (R,Sax)-dioxide as the cata-
lyst. Also, both Ag-catalyzed procedures provided the cor-
responding product with good enantioselectivity (92%ee)
as did the procedure based on diastereoselective allylation
with (+)-B-allyldiisopinocampheylborane (94%ee). Sur-
prisingly, the (S)-TRIP-PA-catalyzed reaction gave the
product with a somewhat lower enantioselectivity of 89%.
On the other hand, it proved to be a good catalyst for crot-
ylation, as it gave the corresponding homoallylic alcohol
with a high enantioselectivity of 96%. The enantioselective
crotylation was also used as the key step in the enantioselec-
tive synthesis of the unnatural diastereoisomer of recently
Scheme 6. Enantioselective synthesis of unnatural lignan derivative
(R,S)-1b.
Figure 3. PLATON plot of (R,S)-1b showing the atom labeling and displacement ellipsoids at the 30% probability level.
4
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Enantioselective Allylation and Synthesis of a Lignan Derivative
[10]
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five step from vanillin with Ͼ96%ee in 20% overall yield.
Synthesis of 1a was attempted as well; however, removal
of the tert-butyldimethylsilyl group resulted in a retro-aldol
reaction, and this provided the starting vanillin under all
conditions.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, all experimental procedures, and spectral
characterization of the prepared compounds.
[11]
[12]
[13]
The absolute configurations of the obtained products from the
enantioselective allylations were determined by the chemical
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Acknowledgments
This work was supported by grants from the Ministry of Educa-
tion, Youth, and Sports (MSM0021620857) and the Czech Science
Foundation (P207/11/0587). The authors would like to thank to
Dr. Ivana Císarˇová for the X-ray structure elucidation and Dr. Da-
vid Necˇas for kind assistance during GC and HPLC measurements.
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Received: August 18, 2014
Published Online: ᭿
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Job/Unit: O43094
/KAP1
Date: 28-10-14 18:43:25
Pages: 6
T. Cadart, P. Koukal, M. Kotora
SHORT COMMUNICATION
Allylation
T. Cadart, P. Koukal, M. Kotora* ..... 1–6
Enantioselective Allylation of tert-Butyldi-
methylsilyl-Protected Vanillin and Syn-
thesis of a Lignan Derivative Isolated from
Machilus wangchiana
Enantioselective allylation and crotylation
of tert-butyldimethylsilyl (TBS) protected
vanillin proceeds with high asymmetric in-
duction (92–96%ee) by using different
catalytic systems. The product of crotyl-
ation is converted into the unnatural dia-
stereoisomer of a recently isolated lignan
derivative.
Keywords: Synthetic methods / Allylation /
Aldehydes / Lewis bases / Lewis acids /
Brønsted acids
6
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