Total synthesis of dipiperamide A and revision of stereochemical assignment

Article abstract of DOI:10.1016/j.tetlet.2004.11.042

The first total synthesis of dipiperamide A has been achieved by employing a solid-state photodimerization of an (E)-cinnamic acid derivative. This critical step results in the cyclobutane ring, which exists in the natural product, with full control of th

Full text of DOI:10.1016/j.tetlet.2004.11.042

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 57–59
Total synthesis of dipiperamide A and revision of
stereochemical assignment
Masaki Takahashi, Masaya Ichikawa, Sakae Aoyagi and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 8 October 2004; revised 25 October 2004; accepted 5 November 2004
Abstract—The first total synthesis of dipiperamide A has been achieved by employing a solid-state photodimerization of an (E)-cin-
namic acid derivative. This critical step results in the cyclobutane ring, which exists in the natural product, with full control of the
regio- and stereochemistry at the four stereogenic centers. Results from these studies indicate that the proposed stereostructure of
natural dipiperamide A should be revised to the structure originally assigned to dipiperamide B.
Ó 2004 Published by Elsevier Ltd.
Dipiperamides A and B,1 isolated from the white pepper
O
O
O
O
O
O
N
N
(Piper nigrum L.), are members of a new class of bisalka-
loids2 consisting of a characteristic cyclobutane ring,
which were assigned structures 1 and 2, respectively,
on the basis of extensive NMR spectroscopic analyses.1
These compounds, recognized as a dimer of piperine (3),
are of interest both because of their unique structures
and the fact that they show potent inhibitory activity
against a drug metabolizing enzyme cytochrome P450
(CYP) 3A4.1 The administration of a potent CYP inhibi-
tor could lead to cost-saving for patients on medication
with expensive drugs, and from the study of CYP inhibi-
tors development of alternative treatment with reduced
drug dosage is expected.2c To our knowledge, no report
of synthesis of this class of alkaloids has appeared in the
literature. Herein, we report the first total synthesis of
dipiperamide A (compound 2), including a stereochemi-
cal revision of the proposed structure 1 of natural di-
piperamide A to structure 2 which had been incorrectly
assigned to dipiperamide B in the original report (Fig.
1).
O
O
O
O
N
N
O
O
1
2
proposed structure
of dipiperamide A
proposed structure
of dipiperamide B
(revised structure of
dipiperamide A)
O
O
O
N
piperine (3)
Figure 1. Proposed structures of dipiperamides A and B.
crystals.3–5 These acids are observed to crystallize in
three polymorphic forms, namely a, b, and c, and, on
photolysis, the well-stacked molecules in the a- and b-
type crystals react to give head-to-tail and head-to-head
dimeric products, a-truxillic and b-truxinic acids
(Ar = Ph for each acid in Fig. 2), respectively, but in
the c-type crystals the molecules do not overlap for
dimerization to occur.6 Based on these topochemical cri-
teria, solid-state photodimerization of the crystalline a-
form of an (E)-cinnamic acid derivative was considered
for the synthesis of compound 2, which is the structure
assigned for dipiperamide B in the original report,1 since
the substitution pattern on the 1,2,3,4-tetrasubstituted
cyclobutane ring and the stereochemistry of 2 corre-
spond to those of the a-truxillic type dimer.
The reaction of (E)-cinnamic acids in the crystalline
state are well-known examples of [2+2] photodimeriza-
tion and the classic studies by Schmidt and co-workers
have demonstrated that such reactions are strictly con-
trolled by the packing arrangement of molecules in the
Keywords: Dipiperamide A; CYP inhibitor; Cyclobutane ring; Solid-
state photodimerization.
*
Corresponding author. Tel.: +81 426 76 3275; fax: +81 426 76
4475; e-mail: kibayasi@ps.toyaku.ac.jp
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.11.042

58
M. Takahashi et al. / Tetrahedron Letters 46 (2005) 57–59
Ar
CO2H
RO
CO2H
Ar
hν
Ar
MeO
TsO
CO2H
hν (solid)
CO2H
anti head-to-tail
MeO
HO2C
HO2C
α-truxillic type
Ar
α-form
OMe
OR
98%
HO2C
6
Ar
CO2H
7 R = Ts
8 R = H
20% KOH, MeOH, rt
80%
CO2H
CO2H
hν
Ar
Ar
syn head-to-head
Ar
CO2H
-form
β
O
1) TsOH, MeOH, refl.
2) AlCl3, Py, CH2Cl2, refl.
-truxinic type
β
CO2Me
3) CH2Br2, CsCO3, DMF, 120 ˚C
O
Figure 2. Topochemical [2+2] photocyclization of (E)-cinnamic acids
in the solid-state.
58%
O
O
MeO2C
9
As described above, the structures of photodimers can
be predicted by the crystalline structures of cinnamic
acids; however, it is difficult to form the desired type
of crystalline structure, for the factors that control crys-
tal packing are not yet well understood. In a series of
3,4-methylenedioxycinnamic acid derivatives, it has
been observed experimentally that the molecules are
arranged in a b-type packing to produce b-truxinic acids,
for example, 3,4-methylenedioxycinnamic acid (4) !
3,3,40,40-bismethylenedioxy-b-truxinic acid (5) (Scheme
1),7 which, however, is not responsible for the structure
of 2. We therefore focused our attention on the prepara-
tion and use of other crystalline derivatives of the 3,4-
dioxygenated cinnamic acid with the a-type structure
for the development of efficient synthesis of the a-truxil-
lic acid. Thus, a number of the O-substituted derivatives
of (E)-ferulic acid (4-hydroxy-3-methoxycinnamic acid)
were synthesized and their crystal chemistry was
explored. When the powdered crystals of these ferulic
acid derivatives were suspended in hexane and subjected
to UV irradiation through Pyrex, the best result, both in
terms of crystalline formation in the head-to-tail a-mod-
ification and the yield of the photodimerization, was
obtained with O-tosylferulic acid (6), leading stereo-
specifically to the a-truxillic acid 7 as a single isomer
in 98% yield (Scheme 2). Confirmation of the a-truxillic
stereochemistry of 7 was provided by a single crystal
X-ray structure of the a-truxillaldehyde 10 derived from
7 (vide infra).
O
O
1) LiAlH4, THF
2) DMSO, Py·SO3, Et3N, CH2Cl2
CHO
77%
O
O
OHC
10
O
CO2Me
Ph3P=CHCO2Me
O
CH2Cl2
MeO2C
55%
O
O
11
Ba(OH)2, H2O
80%
O
O
CO2H
CO2H
O
O
+
O
O
O
HO2C
HO2C
1:1
O
12
13
Scheme 2.
After removal of the tosyl group from 7 followed by
esterification of the resultant bisphenol 8, cleavage of
the methoxy group with AlCl3 and pyridine8 gave the
biscatechol, which was methylenated with CH2Br2 and
CsCO3 to yield the bismethylenedioxy ester 9 (Scheme
2). Reduction of 9 with LiAlH4 and subsequent oxida-
tion (DMSO, sulfur trioxide pyridine complex, Et3N)
of the bisalcohol afforded 3,3,40,40-bismethylenedioxy-
a-truxillaldehyde (10), whose a-truxillic structure was
unambiguously determined by X-ray analysis as
Figure 3. X-ray crystal structure of bisaldehyde 10.
depicted in Figure 3. Wittig olefination of 10 with the
triphenylphosphoranylidenacetate provided the un-
saturated ester 11. Since attempts to convert 11 into
compound
2 by amidation with piperidine were
unsuccessful, in anticipation of the DCC method for
amide formation, ester hydrolysis of 11 was carried
out with Ba(OH)2 in water. However, in this hydrolysis
epimerization was found to occur, resulting in an insep-
arable mixture of biscarboxylic acids 12 and 13 (ca. 1:1).
O
CO2H
CO2H
CO2H
O
O
hν (solid)
O
O
ref 7
Conversion of 10 to compound 2 was successfully
achieved in 94% yield without epimerization via Wittig
olefination using 1-[(triphenylphosphoranylidene)acetyl]-
piperidide (14), prepared9 from chloroacetyl chloride,
4
O
5
Scheme 1.

M. Takahashi et al. / Tetrahedron Letters 46 (2005) 57–59
59
O
O
ural dipiperamide A should be revised to structure 2
originally assigned to dipiperamide B and, thus, the ori-
ginal stereostructure of dipiperamide B will also need to
be revised.
CHO
+
N
O
O
OHC
O
C
H
PPh3
14
10
References and notes
CH2Cl2, refl.
94%
1. Tsukamoto, S.; Cha, B.-C.; Ohta, T. Tetrahedron 2002, 58,
1667–1671.
O
N
2. For isolation and structure determination of the related
bisalkaloids, see: (a) Filho, R. B.; De Souz, M. P.; Mattos,
M. E. O. Phytochemistry 1981, 20, 345–346; (b) Fujiwara,
Y.; Naithou, K.; Miyazaki, T.; Hashimoto, K.; Mori, K.;
Yamamoto, Y. Tetrahedron Lett. 2001, 42, 2497–2499; (c)
Tsukamoto, S.; Tomise, K.; Miyakawa, K.; Cha, B.-C.;
Abe, T.; Hamada, T.; Hirota, H.; Ohta, T. Bioorg. Med.
Chem. 2002, 10, 2981–2985, Also see Ref. 1.
O
O
O
O
N
O
dipiperamide A (2)
3. Cohen, M. D.; Schmidt, G. M. J. J. Chem. Soc. 1964,
1996–2000.
Scheme 3.
4. Cohen, M. D.; Schmidt, G. M. J.; Sonntag, F. I. J. Chem.
Soc. 1964, 2000–2013.
5. Schmidt, G. M. J. J. Chem. Soc. 1964, 2014–2021.
6. For an extensive review of the photochemical reactions of
organic crystals, see: Ramamurthy, V.; Venkatesan, K.
Chem. Rev. 1987, 87, 433–481.
piperidine, and PPh3 (Scheme 3). Our synthetic sample
of 2 showed mp 175–176°C10 and spectral data
(1H and 13C NMR, and IR) that were clearly different
from those reported1 for natural dipiperamide B, but
fully consistent with those reported1 for natural dipiper-
amide A.
7. Desiraju, G. R.; Kamala, R.; Kumari, B. H.; Sarma, J. A.
2 1984, 181–
R. P. J. Chem. Soc., Perkin Trans.
189.
In conclusion, the first total synthesis of dipiperamide A
(2) has been achieved by employing a solid-state photo-
dimerization of the (E)-cinnamic acid derivative 6. This
critical step results in the formation of the cyclobutane
ring with full control of the regio- and stereochemistry
at the four stereogenic centers. Results from these stud-
ies indicate that the stereostructure 1 proposed for nat-
8. Lange, R. G. J. Org. Chem. 1962, 27, 2037–2039.
9. (a) Ishihara, Y.; Kiyota, Y.; Goto, G. Chem. Pharm. Bull.
1990, 38, 3024–3030; (b) Wasserman, H. H.; Ennis, D. S.;
Power, P. L.; Ross, M. J. J. Org. Chem. 1993, 58, 4767–
4785.
10. No description of the melting points of dipiperamides A
and B has been given in Ref. 1.