Stereoselective preparation of cyclobutanes with four different substituents: Total synthesis and structural revision of pipercyclobutanamide a and piperchabamide G

Article abstract of DOI:10.1002/anie.201203379

Squared away: A general strategy was developed for the diastereo- and enantioselective synthesis of cyclobutanes having four different substituents (see scheme). The strategy involves a Rh^II-catalyzed cyclopropanation, a Ag^I-catalyzed regioselective and stereospecific ring expansion, and a Rh^I-catalyzed addition reaction. The structures of pipercyclobutanamide A and piperchabamide G were synthesized and revised. Copyright

Full text of DOI:10.1002/anie.201203379

Angewandte
Chemie
DOI: 10.1002/anie.201203379
Cyclobutanes
Stereoselective Preparation of Cyclobutanes with Four Different
Substituents: Total Synthesis and Structural Revision of
Pipercyclobutanamide A and Piperchabamide G**
Renhe Liu, Min Zhang, Thomas P. Wyche, Gabrielle N. Winston-McPherson, Tim S. Bugni, and
Weiping Tang*
Four-membered rings are important structural motifs fre-
quently present in bioactive natural products and pharma-
ceutical agents.[1] Pipercyclobutanamides, piperchabamides,
nigramides, and dipiperamides (Figure 1) are tetrasubstituted
cyclobutanes isolated from Piper nigrum and Piper chaba, the
source of white and black pepper and components of tradi-
tional medicines.[2–7] Isolation of various polyene precursors
and stereoisomeric cyclobutanes from these Pipers suggested
that the four-membered rings might be derived from non-
selective photolytic [2+2] cycloaddition of alkenes. Cyclo-
butanes isolated from Piper nigrum and Piper chaba have
broad pharmacological activities.[5–7] For example, pipercy-
clobutanamide A (1) and dipiperamide E (6) are selective
inhibitors for CYP2D6 and CYP3A4, respectively, the two
main P450s responsible for drug metabolism.[4,7] Piperchaba-
mide G, isolated in 2009, inhibits d-GalN/tumor necrosis
factor-a-induced death of hepatocytes and has hepatoprotec-
tive effect.[6]
Among dozens of pipercyclobutanamides, piperchaba-
mides, nigramides, and dipiperamides, only the symmetric
achiral dipiperamide A (5) has been synthesized.[8,9] The
originally proposed structure 4 for dipiperamide A[3] was
revised to 5 after the synthesis reported by Kibayashi and co-
workers.[9] A solid-state [2+2] photolytic homodimerization
was employed by Kibayashi to construct the four-membered
ring with center symmetry. Extensive optimization was
conducted for the crystallization of ferulic acid derivatives
to obtain the a-form crystal,[8] which was required for the
regio- and diastereoselective photolytic homodimerization.
Bergman and Ellman, and Zhang and Jia used the same
Figure 1. Selected four-membered ring natural products.
protocol to prepare the symmetric cyclobutane core of
[*] R. Liu, Dr. M. Zhang, T. P. Wyche, G. N. Winston-McPherson,
Prof. Dr. T. S. Bugni, Prof. Dr. W. Tang
incarvillateine.[10] The [2+2] cycloaddition has been the
main strategy for the synthesis of four-membered ring natural
products[11] with a few exceptions.[12] However, it remains
a demanding synthetic challenge to prepare unsymmetrical
cyclobutanes from heterodimerization of two olefins with
high chemo-, regio-, diastereo-, and enantioselectivity.[13]
The School of Pharmacy, University of Wisconsin
Madison, WI 53705-2222 (USA)
E-mail: wtang@pharmacy.wisc.edu
[**] We thank the NIH (R01GM088285) and the UW-Madison for
funding. W.T. is grateful for a Young Investigator Award from
Amgen. We thank the Analytical Instrumentation Center at the UW-
Madison for the facilities to acquire spectroscopic data. This study
made use of the National Magnetic Resonance Facility at Madison,
which is supported by NIH grants P41RR02301 (BRTP/NCRR) and
P41GM66326 (NIGMS). Additional equipment was purchased with
funds from the UW-Madison, the NIH (RR02781, RR08438), the
NSF (DMB-8415048, OIA-9977486, BIR-9214394), and the USDA.
À
Recently, an elegant sequential cyclobutane C H aryla-
tion strategy was developed by Gutekunst and Baran for the
diastereoselective synthesis of pseudosymmetric cyclobutanes
such as piperarborenine B (7) and the proposed structure of
piperarborenine D (8).[14] The originally proposed structure
8
[3] for piperarborenine D was revised to structure 9 after the
synthesis from Gutekunst and Baran. Herein we report our
strategy for diastereo- and enantioselective introduction of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203379.
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four different substituents onto cyclobutanes in the context of
the total synthesis of the proposed structures of pipercyclo-
butanamide A (1) and piperchabamide G (2). We also
propose revised structures for these two natural products.[15]
We envisioned that both pipercyclobutanamide A (1) and
piperchabamide G (2) could be derived from tetrasubstituted
cyclobutane 10 (Scheme 1). The ester and protected primary
hydroxy group in intermediate 10 would serve as aldehyde
precursors which could be unmasked at different stages for
Scheme 2. Stereoselective synthesis of cyclobutenoate. Reagents and
conditions: a) Bromoacetyl bromide then TsNHNHTs, DBU.
b) 1.0 mol% [Rh2(5S-MEPY)4], CH2Cl2, reflux. c) piperidine, AlMe3,
CH2Cl2, 08C to RT, 20 h. d) DMSO, (COCl)2, Et3N, À788C, 2 h.
e) NaCN, HOAc, MeOH then EtOH/HCl (4m in 1,4-dioxane) (1:1),
08C, 2 days. f) Dess–Martin periodinane, CH2Cl2, RT, 2 h.
g) TsNHNH2, toluene, 808C, then DBU, RT, 12 h. h) 10 mol% AgOTf,
CH2Cl2, RT, 2 h. Bn=benzyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
MEPY=methyl-2-pyrrolidone-5S-carboxylate.
Scheme 1. Proposed strategy for stereoselective synthesis of piper-
cyclobutanamide A and piperchabamide G. PG = protecting group.
olefination. Conjugate addition of an aryl group to the
cyclobutenoate 11 may provide the tetrasubstituted cyclo-
butane 10. The aryl group should approach the four-mem-
bered ring from the a face to avoid steric interactions with the
adjacent amide substituent. The cyclobutenoate 11 could be
prepared from cyclopropane 12 according to a ring expansion
method we recently developed.[16,17] This reaction involved
a cyclopropyl metal carbene intermediate derived from the
transition-metal-catalyzed decomposition of diazo com-
pounds. We have demonstrated that the ring expansion is
stereospecific and regioselective. The regioselectivity is
dependent on the substituents of the cyclopropane ring and
prepared by a rhodium(I)-catalyzed addition of arylboronic
acid to this enoate (Scheme 3).[20] Indeed, the aryl group
approached the cyclobutene ring selectively from the face
away from the amide substituent. The stereoselectivity for the
protonation step, however, was low and a diastereomeric ratio
of 2:1 favoring the isomer 20 was obtained. Simple treatment
of this mixture with NaOEt afforded the thermodynamically
more stable product 20 as a single stereoisomer. Removal of
the benzyl group and subsequent oxidation provided the
aldehyde 22. The stereochemistry of compounds 20 and 22
was confirmed by nOe analysis.[21] For example, a nOe was
observed between Ha/Ha’ and Hb, between Ha/Ha’ and Hd,
between Hb and Hc, and between Hc and Hd of 22.
After successfully preparing the tetrasubstituted cyclo-
butane 22 stereoselectively, we then installed the E olefin in
pipercyclobutanamide A using a Julia–Kocienski olefination
(Scheme 3).[22] Compound 23 was obtained as a single olefin
isomer, but was contaminated with a by-product derived from
reagent A. Both polar solvents DMF and HMPA were
necessary as lower E/Z ratios were observed in either THF
or in DMF without HMPA.[23] Using Andoꢀs reagent B, the
Z olefin of pipercyclobutanamide A (1) was prepared from
the olefination of an aldehyde intermediate, which was
derived from DIBALH reduction (Z/E > 20:1).[24] A Z/E
ratio of 2:1 was obtained when the Still–Gennari olefination
protocol was employed.[25]
À
the choice of catalysts. The cyclopropane C C bond that is
adjacent to the electron-donating group or away from the
electron-withdrawing group could be selectively cleaved
when a silver(I) catalyst was employed.[16a] In the case of
cyclopropane 12, we expected that bond a would be selec-
tively cleaved over bond b. This proposal represents a general
and unique strategy for the diastereo- and enantioselective
synthesis of unsymmetrical cyclobutanes having four different
substituents.
Our synthesis began with the preparation of the diazo
compound 14 from the monoprotected diol 13 (Scheme 2).[18]
The bicyclic lactone 15 was obtained by diastereo- and
enantioselective intramolecular cyclopropanation of a trans-
olefin using the chiral [Rh2(5S-MEPY)4] catalyst.[19] Opening
of the lactone with piperidine and subsequent oxidation
afforded the trisubstituted cyclopropane 16, which was then
converted into the diazo compound 18 through ketoester
intermediate 17 in three steps according to procedures we
have previously established.[16a] Treatment of 18 with a cata-
lytic amount of AgOTf indeed yielded the cyclobutenoate 19
as a single isomer.
With cyclobutenoate 19 in hand, we then turned our
attention to the conjugate addition of an aryl nucleophile to
this enoate. Under various reaction conditions, we were not
able to add an aryl cuprate reagent to 19. We were pleased to
find that the tetrasubstituted cyclobutanes 20 and 21 could be
Our spectra (1H and 13C NMR) for product 1, however,
did not match the data reported in literature for pipercyclo-
butanamide A.[2] We additionally characterized our synthetic
compound 1 by COSY, HMBC, HSQC, ROESY, and HRMS
analyses.[21] All of our spectral data were consistent with the
proposed structure 1.
One of the most significant discrepancies between our
data and that from literature for pipercyclobutanamide A was
the chemical shift of the b-styrene hydrogen H4 (Table 1).[2]
We did not observe any signal between d = 5.0 and 5.5 ppm in
2
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Table 1: Selected 1H and 13C NMR spectral data (dH/dC in ppm) for
compounds 1, 2, 25, and 26.[a]
Position
1 (synthetic)
1 (literature)[2]
25 (literature)[26]
1
4
1’
2’
3’
–/170.2
6.16/128.6
–/165.8
6.03/120.4
5.92/140.5
–/172.2
5.21/128.0
–/171.1
5.75/125.5
5.86/130.3
–/172.2
5.19/128.1
–/171.1
5.73/125.5
5.84/130.3
2 (synthetic)
2 (literature)[6]
26 (literature)[5]
1
–/170.9
–/165.9
5.98/123.1
5.93/142.0
–/173.2
–/170.4
5.84/134.0
5.71/123.2
–/173.2
–/170.4
5.85/134.1
5.71/123.2
1’
2’
3’
[a] See Tables S1–S6 in the Supporting Information for all data.
carbon atoms in natural product pipercyclobutanamide A.[2]
We observed 13C chemical shifts of d = 170.2 and 165.8 ppm
for carbonyl carbon atoms C1 and C1’, respectively, in our
synthetic compound 1. Our observation is consistent with
other closely related natural products.[21] It appeared that the
two carbonyl groups in the natural product pipercyclobuta-
namide A were both nonconjugated. Furthermore, the com-
parison of 13C chemical shifts of the cis-alkene in the natural
product pipercyclobutanamide A, our synthetic compound 1,
and related natural products[21] suggested that the cis alkene
in natural product pipercyclobutanamide A was likely not
conjugated to a carbonyl group. Similar conclusions could
also be made for natural product piperchabamide G.
The ring expansion of vinylcyclobutane 1 through the
cleavage of the C4’–C5’ bond would produce a hypothetical
cyclohexene isomer, which contains a nonconjugated cis
alkene and a nonconjugated carbonyl group. Numerous six-
membered cyclohexenes have been isolated from Piper
nigrum and Piper chaba.[5,26] It was proposed that they were
derived from Diels–Alder cycloaddition of their polyene
precursors.
Based on the above analysis, we turned our attention to
the six-membered ring isomers of structures 1 and 2. After
examining all known six-membered ring natural products
isolated from Piper nigrum and Piper chaba,[5,26] we were
pleased to find that spectral data (1H NMR and 13C NMR) of
natural product chabamide (25) was identical to that of
natural product pipercyclobutanamide A, within experimen-
tal error.[26,27] The unusual d = 5.2 ppm chemical shift of the b-
styrene hydrogen H4 in compound 25 was presumably due to
the shielding effect of the adjacent cis-aryl group. We also
found that spectral data (1H NMR and 13C NMR) of natural
product nigramide F (26) was identical to that of natural
product piperchabamide G, within experimental error.[21]
Scheme 3. Stereoselective synthesis of proposed structures of piper-
cyclobutanamide A and piperchabamide G. Reagents and conditions:
a) 5.0 mol % [{Rh(cod)Cl}2], 1,4-dioxane/H2O (10:1), 3,4-(methylene-
dioxy)phenylboronic acid, RT, 20 h. b) EtONa, EtOH, RT, 10 h. c) Pd/C,
H2, EtOH, RT, 15h. d) Dess–Martin periodinane, CH2Cl2, RT, 2 h.
e) KHMDS, reagent A, DMF/HMPA (3:1), À358C to RT, 6 h.
f) DIBALH, toluene, À788C, 30 min. g) KHMDS, reagent B, THF
À788C to 08C, 2 h. h) Pd/C, H2, MeOH, RT, 15 h. cod=1,5-cyclo-
octadiene, DIBALH=diisobutylaluminum hydride, DMF=N,N’-dime-
thylformamide, HMPA=hexamethylphosphoramide, KHMDS=potas-
sium hexamethyldisilazide.
the 1H NMR spectrum of synthetic compound 1. After
analyzing similar natural products in the literature, we
found that chemical shifts for this type of b-styrene hydrogen
ranged from d = 6.10 to 6.29 ppm.[21] For example, chemical
shifts of the b-styrene hydrogen in nigramide Q (3)[5] and
dipiperamide E (6)[4] are d = 6.14 and 6.29 ppm, respectively.
We then prepared piperchabamide G (2),[6] which did not
have the styrene olefin. Hydrogenation of the intermediate 23
with subsequent DIBALH reduction and olefination with
Andoꢀs reagent B afforded product 2 (Z/E > 20:1) as shown
in Scheme 3. We were surprised that our spectral data (1H and
13C NMR) for product 2, again did not match the data
reported in literature for natural product piperchabamide G
(Table 1).[6] All of our spectral data (COSY, HMBC, HSQC,
ROESY, and HRMS) were consistent with the proposed
structure 2.[21]
After failing to find cyclobutane isomers that could match
the spectral data of natural products pipercyclobutanamide A
and piperchabamide G, we then carefully analyzed all spec-
troscopic differences between our synthetic compounds and
natural products. We found that 13C chemical shifts of d =
172.2 and 171.1 ppm were assigned to the two carbonyl
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In summary, we have developed a new general strategy for
the diastereo- and enantioselective introduction of four
different substituents to a cyclobutane ring. The ring expan-
sion of a cyclopropylsilver(I) carbene derived from the diazo
compound 18 occurred regioselectively and stereospecifically
to afford the cyclobutenoate 19. A rhodium(I)-catalyzed
conjugate addition of aryl boronic acid to this cyclobutenoate
provided the fourth substituent diastereoselectively. Stereo-
selective synthesis of the trans and cis alkenes in the proposed
structure of pipercyclobutanamide A was realized by judi-
cious selection of reaction conditions. After the proposed
structures for pipercyclobutanamide A (1) and piperchaba-
mide G (2) were synthesized, these two natural products were
revised to their six-membered ring isomers chabamide (25)
and nigramide F (26), respectively. These structural revisions
are important for future studies of the biological activities of
the ingredients in white and black peppers, and drug–herb
interactions.
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À
that Baranꢀs group also successfully applied the C H activation
strategy to the synthesis of compound 1: c) W. R. Gutekunst, R.
Gianatassio, P. S. Baran, Angew. Chem. 2012, DOI: 10.1002/
ange.201203897; Angew. Chem. Int. Ed. 2012, DOI: 10.1002/
anie.201203897.
Received: May 2, 2012
Published online: && &&, &&&&
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Keywords: natural products · rhodium · ring expansion ·
.
small ring systems · structure elucidation
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Cyclobutanes
R. Liu, M. Zhang, T. P. Wyche,
G. N. Winston-McPherson, T. S. Bugni,
W. Tang*
&&&& — &&&&
Stereoselective Preparation of
Cyclobutanes with Four Different
Substituents: Total Synthesis and
Structural Revision of
Pipercyclobutanamide A and
Piperchabamide G
Squared away: A general strategy was
developed for the diastereo- and enan-
tioselective synthesis of cyclobutanes
having four different substituents (see
scheme). The strategy involves a RhII-
catalyzed cyclopropanation, a AgI-cata-
lyzed regioselective and stereospecific
ring expansion, and a RhI-catalyzed addi-
tion reaction. The structures of pipercy-
clobutanamide A and piperchabamide G
were synthesized and revised.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!