Syntheses of (-)-Tatarinoid A, (±)-Tatarinoid B, and (-)-Tatarinoid C

Article abstract of DOI:10.1016/j.tetlet.2012.10.104

The syntheses of (-)-Tatarinoid A, (±)-Tatarinoid B, and (-)-Tatarinoid C in one to three steps are described herein. (-)-Tatarinoid A and (-)-Tatarinoid C are both constructed in three steps from 1-bromo-2,4,5-trimethoxybenzene in overall yields of 63% and 74%, respectively. The addition of (1-methoxyethyl)triphenylphosphonium ylide to 2,4,5-trimethoxybenzaldehyde provides (±)-Tatarinoid B in one step in 97% yield.

Full text of DOI:10.1016/j.tetlet.2012.10.104

Tetrahedron Letters 54 (2013) 210–212
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Tetrahedron Letters
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Syntheses of (À)-Tatarinoid A, ( )-Tatarinoid B, and (À)-Tatarinoid C
Yuriy Slutskyy b, William T. Jewell a, Claudia G. Lucero b,
⇑
a University of California, Davis, One Shields Ave., Davis, CA 95616, USA
b Department of Chemistry, California State University, Sacramento, 6000 J Street, Sacramento, CA 95819, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses of (À)-Tatarinoid A, ( )-Tatarinoid B, and (À)-Tatarinoid C in one to three steps are
described herein. (À)-Tatarinoid A and (À)-Tatarinoid C are both constructed in three steps from 1-
bromo-2,4,5-trimethoxybenzene in overall yields of 63% and 74%, respectively. The addition of (1-
methoxyethyl)triphenylphosphonium ylide to 2,4,5-trimethoxybenzaldehyde provides ( )-Tatarinoid B
in one step in 97% yield.
Received 8 October 2012
Revised 22 October 2012
Accepted 24 October 2012
Available online 31 October 2012
Published by Elsevier Ltd.
Keywords:
(À)-Tatarinoid A
( )-Tatarinoid B
(À)-Tatarinoid C
Irregular Wittig reaction
Crossed acyloin condensation
(–)-Tatarinoids A, B, and C are 3 of 19 compounds that have
been isolated from the rhizome of the plant Acorus tatarinowii.1
Used in Chinese medicine, Acorus tatarinowii possesses pharmaco-
logical effects on the central nervous system by regulating cyclic
adenosine monophosphate (cAMP) activity. For example, it is com-
monly prescribed for the improvement of learning and memory.2
The major constituents of Acorus tatarinowii, sesquiterpenoids
and phenylpropanoids, have been found to possess antiepileptic
properties2 as well as anticonvulsive,3 spasmolytic,4 and neuropro-
tective effects.5 Although (À)-Tatarinoids B and C have shown
weak efficacy and (À)-Tatarinoid A has not yet been evaluated
for its activity we continued our efforts toward the syntheses of
these natural products since currently there are no reported syn-
theses of (À)-Tatarinoids A, C, and ( )-Tatarinoid B. Herein we re-
port expeditious routes toward these natural products.
As illustrated in Scheme 1, (À)-Tatarinoid A, and Tatarinoid C
can be accessed from 1-bromo-2,4,5-trimethoxybenzene (2a).
The required organolithium 2b would be accessed through a metal
halogen exchange between the aryl bromide (2a) and n-
butyllithium.
In the case of (À)-Tatarinoid A it would be necessary to convert
the TBS protected methyl (R)-lactate (1a) into the Weinreb amide
(1b) in order to avoid the over addition of the aryllithium (2b) to
the carbonyl and yield only the necessary ketone, a precursor to
the natural product.6
over addition of the aryllithium (2b) and result in the formation
of the tertiary alcohol precursor.
The synthesis of (À)-Tatarinoid A was shown to proceed in
three steps from Weinreb amide 1b8,9 and aryl bromide 2a
(Scheme 2).10 Formation of the aryllithium (2b) proceeded from
the treatment of the aryl bromide (2a) with n-BuLi at À78 °C for
1 h. Initial investigations toward the total synthesis of (À)-Tatari-
noid A included the addition of aryllithium to the TBS protected es-
ter 1a. The mono addition product, ketone 3, was observed as a
minor product. As expected, the over addition of the aryllithium
yielded the tertiary alcohol (4) as the major product; the precursor
to (À)-Tatarinoid C (Scheme 3).
To avoid the formation of the tertiary alcohol, we turned our
attention toward the derivatization of the TBS protected ester 1a
to the Weinreb amide 1b, synthesized from the treatment of ester
1a with N,O-dimethylhydroxylamine hydrochloride salt and
i-PrMgCl in THF. The reaction proceeded smoothly in 99% yield
without purification. As predicted, the mono addition of the arylli-
thium to the amide resulted in the desired ketone, 3, in an 81%
yield, without any of the overaddition product observed. Finally,
removal of the TBS protecting group with TBAF (tetrabutylammo-
nium fluoride)11 in THF, at 0 °C for 2 h, afforded (À)-Tatarinoid A
in 78% yield. Assembly of the natural product was accomplished
in three steps and with an overall yield of 63%.
The synthesis of (À)-Tatarinoid C employed a similar strategy to
that of (À)-Tatarinoid A. In this case, the over addition of the aryl-
lithium (2b) to the TBS protected ester (2a) was crucial to provide
the desired tertiary alcohol 4 (Scheme 3). The reaction was accom-
plished using 3 equiv of both aryl bromide and n-BuLi to yield 4 in
88% yield. Treatment of the tertiary alcohol with BF3ÁOEt2 and
Alternatively, the desired (À)-Tatarinoid C would employ the
TBS protected methyl (R)-lactate (1a),7 in order to allow for the
⇑
Corresponding author. Tel.: +1 916 278 6006; fax: +1 916 278 4986.
E-mail address: cglucero@csus.edu (C.G. Lucero).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.10.104

Y. Slutskyy et al. / Tetrahedron Letters 54 (2013) 210–212
211
OTBS
X
Me
Me
OH
O
OMe
OMe
O
OMe
OMe
OMe
1a, X = OMe
, X = N(OMe)Me
Me
1b
OH
OMe
Br
MeO
MeO
OMe
OMe
(−)-Tatarinoid A
(−)-Tatarinoid C
MeO
OMe
2a, Y = Br
2b
, Y = Li
Scheme 1. Retrosynthesis of (À)-Tatarinoid A and (À)-Tatarinoid C.
C, was completed in three steps from 1-bromo-2,4,5-trimethoxy-
benzene (2a) and methyl (R)-2-(tert-butyldimethylsilyloxy)propio-
nate (1a) with an overall yield of 74%.
A retrosynthetic overview of ( )-Tatarinoid B is illustrated in
Scheme 4. It was expected that the racemic mixture of the natural
product would be accessed in one step from an irregular Wittig
reaction14 using ylide (5a) and 2,4,5-trimethoxybenzaldehyde
(6).15
Indeed, treatment of (1-methoxyethyl)triphenylphosphonium
salt (5b) with n-BuLi, for 20 min, provided the desired Wittig ylide
5a that was then treated with 2,4,5-trimethoxybenzaldehyde (6) at
À78 °C for 30 min to yield the racemic Tatarinoid B in 97% yield
(Scheme 5). No sign of the typical Wittig product was observed.
Currently, we are turning our efforts toward the construction of
(À)-Tatarinoid B in one step from a crossed acyloin condensation16
between 2,4,5-trimethoxybenzaldehyde (6) and acetaldehyde
using a chiral triazolium salt as a catalyst (Scheme 6, 7a–7e).17,18
These catalysts are not commercially available and are themselves
OMe
O
OMe
OMe
Me
Br
1. n-BuLi, -78 °C, 1 h, THF
2.
OTBS
OTBS
OMe
N
MeO
MeO
Me
Me
OMe
2a
3
1b
O
-78 °C to rt, 24 h
81%
OMe
O
Me
TBAF
OH
0 °C, 2 h, THF
78%
MeO
OMe
( )-Tatarinoid A
−
Scheme 2. Synthesis of (À)-Tatarinoid A.
constructed in five to six steps from methyl L-pyroglutamate. Our
continued investigation on the total synthesis of (À)-Tatarinoid
B, high yield and enantioselectivity, will be reported in due course.
In conclusion, we have described the first total syntheses of (À)-
Tatarinoids A and C and racemic Tatarinoid B. The synthesis of (À)-
Tatarinoid A was accomplished in three steps with an overall yield
of 63%. ( )-Tatarinoid B was constructed in one step in 97% yield
NaBH3CN at room temperature for 1 h was expected to only afford
the desired deoxygenated product, which would then be treated
with TBAF for the removal of the protecting group. However, the
reaction afforded (À)-Tatarinoid C in 84% yield, suggesting that
the excess NaBH3CN (3 equiv) permits for the reductive cleavage
of the TBS group.12,13 The resulting natural product, (À)-Tatarinoid
Me
OTBS
OMe
OMe
OMe
Br
OH
1. n-BuLi, -78 °C, THF
2.
OTBS
MeO
OMe
MeO
OMe
OMe
OMe
OMe
4
2a
Me
1a
O
-78 °C to rt, 24 h
88%
Me
OTBS
OMe
Me
OH
OMe
OMe
OMe
OH
BF3·OEt2, rt
NaBH3CN, THF
MeO
OMe
MeO
OMe
84%
OMe
OMe
OMe
(−)-Tatarinoid C
OMe
4
Scheme 3. Synthesis of (À)-Tatarinoid C.

212
Y. Slutskyy et al. / Tetrahedron Letters 54 (2013) 210–212
OMe OH
OMe
OMe
O
Me
PPh3
H
+
O
MeO
MeO
Me
MeO
OMe
5a
6
(+)-Tatarinoid B
Scheme 4. Retrosynthesis of ( )-Tatarinoid B.
OMe OH
BF4
PPh3
Me
Me
1. n-BuLi, -78
2. 6, -78 C, 30 min, THF
97%
°C, 20 min, THF
°
MeO
O
MeO
5b
OMe
(+)-Tatarinoid B
Scheme 5. Synthesis of ( )-Tatarinoid B.
F
F
F
N
N
F
N
OMe
OH
OMe
O
F
BF4
Ph
Ph
OH
Me
H
7a
O
O
6
MeO
MeO
Me
H, Cs2CO3,THF, rt
OMe
(−)-Tatarinoid B
OMe
F
F
F
N
N
N
N
Ph
BF4
F
N
N
Ph
Ph
F
BF4
OTMS
Ph
Ph
OR
7b
7c, R = TMS
7d
7e
, R = TBS
, R = H
Scheme 6. Synthesis of (À)-Tatarinoid B.
2. Liao, W.-E.; Chen, L.; Yi, Y.-H.; Sun, W.-W.; Gao, M.-M.; Su, T.; Yang, S.-Q.
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while (À)-Tatarinoid C was also synthesized in three steps with an
overall yield of 74%.
Acknowledgments
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The authors would like to thank the CSUPERB Presidents’ Com-
mission Scholars Program for funding Yuriy Slutskyy and an NSF-
MRI grant for funding the 500 MHz NMR (CHE MRI-0922676).
Thanks are also due to Erich Bowman, Maddy McCrea-Hendrick,
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.104.
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