A biomimetic route for construction of the [4+2] and [3+2] core skeletons of dimeric pyrrole-imidazole alkaloids and asymmetric synthesis of ageliferins

Article abstract of DOI:10.1021/ja309172t

The pyrrole-imidazole alkaloids have fascinated chemists for decades because of their unique structures. The high nitrogen and halogen contents and the densely functionalized skeletons make their laboratory synthesis challenging. We describe herein an oxidative method for accessing the core skeletons of two classes of pyrrole-imidazole dimers. This synthetic strategy was inspired by the putative biosynthesis pathways and its development was facilitated by computational studies. Using this method, we have successfully prepared ageliferin, bromoageliferin, and dibromoageliferin in their natural enantiomeric form.

Full text of DOI:10.1021/ja309172t

Article
pubs.acs.org/JACS
A Biomimetic Route for Construction of the [4+2] and [3+2] Core
Skeletons of Dimeric Pyrrole−Imidazole Alkaloids and Asymmetric
Synthesis of Ageliferins
Xiao Wang,† Xiaolei Wang, Xianghui Tan,‡ Jianming Lu,§ Kevin W. Cormier, Zhiqiang Ma,
and Chuo Chen*
Division of Chemistry, Department of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines
Boulevard, Dallas, Texas 75390-9038, United States
S
* Supporting Information
ABSTRACT: The pyrrole−imidazole alkaloids have fasci-
nated chemists for decades because of their unique structures.
The high nitrogen and halogen contents and the densely
functionalized skeletons make their laboratory synthesis
challenging. We describe herein an oxidative method for
accessing the core skeletons of two classes of pyrrole−
imidazole dimers. This synthetic strategy was inspired by the
putative biosynthesis pathways and its development was
facilitated by computational studies. Using this method, we
have successfully prepared ageliferin, bromoageliferin, and
dibromoageliferin in their natural enantiomeric form.
INTRODUCTION
■
The pyrrole−imidazole alkaloids, often referred to as the
oroidin family of alkaloids, are a group of structurally diverse
natural products formed through oxidation, cyclization, and
oligomerization of oroidin and its debrominated congeners
(1).1 For example, ageliferins (2),2 massadines (3),3 and
benzosceptrins (4)4 are the [4+2], [3+2], and [2+2]
dimerization products of 1, respectively (Figure 1). While
cycloadditions of 1 are generally believed to be involved in the
biosynthesis of 2−4,5 attempts to dimerize 1 in the test tube
failed to deliver these alkaloids because of the mismatched
electronic properties.6 Recently, Molinski, Romo, and co-
workers used cell-free extracts of the pyrrole−imidazole
alkaloid-producing sponges to induce the dimerization of
oroidin (1c) in vitro giving the [2+2] dimer benzosceptrin C
(4c).7 They further proposed that the dimerization of 1 is
promoted by a single-electron transfer (SET). We have been
interested in studying the biomimetic synthesis of the pyrrole-
imidazole alkaloids and proposed that the dimerization of 1
proceeds through a radical mechanism.8 Agreeing to the
hypothesis put forth by Molinski and Romo, we believed that a
SET oxidation of 1 would give radical cation 1•+ that is highly
active toward cycloadditions. We have further shown that both
the [4+2] and [3+2] dimerization products could be obtained
from an oxidative radical cyclization reaction in model systems.
We describe herein the design of this biomimetic synthetic
strategy and its application to the asymmetric synthesis of
ageliferins (2).
Figure 1. Structures of selected pyrrole−imidazole alkaloids.
The unique structures of the dimeric pyrrole−imidazole
alkaloids have, over several decades, inspired chemists to
Received: September 15, 2012
Published: October 17, 2012
© 2012 American Chemical Society
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develop numerous synthetic strategies and methods. These
include work from the groups of Overman,9 Carreira,10
Romo,11 Lovely,12 Ohta,13 Austin,14 Baran,15 Birman,16
Harran,17 Gin,18 Gleason,19 Namba−Williams−Nishizawa,20
and us.8 Notably, the synthesis of the [2+2] dimer has been
accomplished by Baran and co-workers15a and Birman and co-
workers,16 the [3+2] dimers by Baran and co-workers,15c−h and
the [4+2] dimers by Baran and co-workers15b and us.8c It
should also be noted that Ohta and co-workers have used a
biomimetic Diels−Alder approach to achieve the racemic
synthesis of 12,12′-dimethyl-2a,13 and Romo and co-workers11
and Lovely and co-workers12 have independently developed a
biomimetic skeletal rearrangement approach to synthesize the
core skeleton of 3. Complementary to other reported
approaches, our biomimetic approach comprises a manganese-
(III)-promoted oxidation of a β-ketoester and a radical tandem
cyclization to yield the skeleton of the [4+2] or [3+2] dimer
with control.8a Its development was guided by computational
studies. The realization of this intramolecular radical tandem
cyclization reaction suggests that the SET-mediated oroidin
dimerization is chemically viable.
We thus chose 7 as the model system for 1. We anticipated that
a SET oxidation of 7 would give radical cation 7•+, which
resembles 1•+/1. After losing a proton, radical 7• could undergo
a 5-exo followed by a 6-endo cyclization to afford the ageliferin
core skeleton 8, or a 5-exo followed by another 5-exo
cyclization to afford the massadine core skeleton 9.
Model Studies. We sought to initiate the radical cascade of
7• by oxidizing 7 with a Mn(III) salt.21 The first intramolecular
Mn(III)-promoted radical cyclization of a β-dicarbonyl
compound was reported by Corey and Kang in 1984 as part
of their gingkolide synthesis project.22 Later, Snider and co-
workers achieved asymmetric Mn(III) radical addition reactions
by using chiral auxiliaries,23 and Yang and co-workers found
that chelating lanthanide triflates could enhance both the
diastereoselectivity and the reaction rate.24,25
Our work began with studying the oxidation of 10 (X = H or
Cl). The α-chlorine atom was incorporated to prevent
overoxidation. To our disappointment, treating 10 with various
Mn(III) and Ce(IV) salts led only to complete decomposition
(Scheme 2). We found that the imidazolinone group was
Scheme 2. Realization of the Mn(III)-Promoted Oxidative 5-
Exo/6-Endo Cyclization
RESULTS AND DISCUSSION
■
Research Design. We hypothesized that the biogenic
dimerization of 1 proceeds through a radical mechanism as
shown in Scheme 1. Activation of 1 by a SET oxidation gives
Scheme 1. A Divergent Biomimetic Approach for Synthesis
of the [4+2] and [3+2] Pyrrole−Imidazole Dimers
destroyed but the olefinic group remained intact, indicating that
the oxidation occurred without radical cyclization. We
suspected that radical 10• adopts the anti conformation as
indicated in Scheme 2 to minimize the dipole moment. A 1,5-
hydrogen abstraction of the benzylic proton occurred and
destroyed the imidazolinone group. This anti conformation
could possibly be destabilized by introducing an α-alkyl group
(e.g., 11•). Indeed, we found that oxidation of 11 with
Mn(OAc)3 proceeded cleanly to afford 12 in 63% yield. The
ageliferin skeleton was obtained as the only product.8a
With the working conditions for the biomimetic [4+2]
dimerization reaction in hand, we next studied the asymmetric
synthesis of the ageliferin core skeleton using an allylic
stereocenter as the controlling element (Scheme 3).26 We
found that oxidation of 13 gave 15 and 16 in a 2:1 ratio,
indicating that the two faces of the olefin are slightly
differentiated. We then tested if the C9−C10 relative
stereochemistry could be controlled by the olefin geometry
to afford the nagelamide skeleton.27 Surprisingly, we found that
oxidation of 14 gave the same anti products 15 and 16 in a 2:3
ratio, suggesting that the two cyclizations proceeded stepwisely
and the 6-endo cyclization was slower than the epimerization of
the C10 radical. The relative configurations of 15 and 16 were
determined by 1H NMR experiments. This assignment is
supported by the following experiments. Removal of the TIPS
group of 15 and 16 followed by oxidation of the resulting
radical cation 1•+, which undergoes a [4+2] (path a) or a [3+2]
(path b) cycloaddition with 1 to give 5 or 6. Subsequent SET
and further transformations yield 2 and 3. This cycloaddition
reaction can be either a concerted or a stepwise process.
To test this hypothesis, we designed a model system to study
if the radical cycloaddition of 1 and 1•+ is viable. We envisioned
that the reaction efficiency could be improved significantly by
tethering 1 and 1•+, and replacing the olefin group with an enol.
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The observed regioselectivity for the cyclizations of 11 is
rather unusual. The 5-exo cyclization is normally kinetically
favored over the 6-endo cyclization for alkyl radicals while the
opposite is true for α-acyl radicals. Based on the seminal
computational studies by Houk and co-workers, the planarity of
α-acyl radicals is maintained in the transition states, causing the
reversed regioselectivity.30 We obtained 12 from 11 through a
5-exo cyclization of an α-acyl radical (11• → 19) and a 6-endo
cyclization of an alkyl radical (19 → 21). We are particularly
interested in the mechanism of the second radical cyclization
step because it determines the formation of the [4+2] versus
the [3+2] dimer skeleton. This cyclization could proceed
through a direct 6-endo cyclization (19 → 21), a 5-exo
cyclization followed by a 1,2-shift (19 → 20 → 21), or a
reversible 5-exo cyclization of 19 giving 21 as a thermodynamic
product (20 ⇆ 19 → 21). We therefore analyzed all three
pathways computationally to gain insights into this cyclization
reaction (Figure 2).
Scheme 3. Model Studies of the Mn(III)-Promoted
Oxidative Cyclization Reaction
Curran, Snider, and co-workers previously showed that Mn is
not bound to the substrate during the radical cyclization.31 The
computational studies are therefore less complicated because
the transition metal is not involved. We further simplified the
computational work by replacing the benzyl and phenyl groups
of 19−21 with a methyl group and examined the reactions of
radicals 22−24. Because the stereochemical information of
C11′ in 20 and C15′ in 21 is lost in the product 12, we
calculated the energy levels for both diastereomeric pathways.
We first performed the calculations with Spartan using three
different methods: UHF/6-31G*, UB3LYP/6-31G**//UHF/
6-31G*, and UB3LYP/6-31G**.30c,32 The geometries obtained
from the UB3LYP/6-31G** calculations were further refined
with Gaussian by using the UB3LYP functional and the 6-
311G** basis set. The corresponding energy diagram is shown
in Figure 2. The 6-endo cyclization was found to be both
kinetically and thermodynamically favored by all these
methods; however, the HF/DFT hybrid method significantly
underestimated the activation energies of the 6-endo cyclization
pathway.33 According to the UB3LYP/6-311G** calculations,
the activation barrier for the 6-endo cyclization is 5.7 or 4.1
kcal/mol lower than the 5-exo cyclization for 22, depending on
the configuration of the newly formed stereocenters. The
activation barrier for the 1,2-shift is forbiddingly high (44.7 or
50.8 kcal/mol).
alcohol provided ketones having all identical physical properties
except the direction of optical rotation.8a
We proposed that the stereochemical information of the (Z)-
olefin could be retained by constraining it in a cyclic system.
Pleasingly, we found that oxidation of 17 yielded 18 with the
desired syn C9−C10 configuration corresponding to that of
nagelamides. The diastereoselectivity of the reaction was also
improved as 18 was the only observed product.
The proposed mechanism for the oxidation of 11 is shown in
Scheme 4. It has been reported that the cis-products are
kinetically favored whereas the trans-products are thermo-
dynamically favored in the Mn(III)-promoted oxidative
cyclization of allylic β-ketoesters.28 We therefore believe that
the cis configuration at the 5,6-ring junction in 12 resulted from
trapping of the kinetic cyclization product of 11• (i.e., 19). The
loss of the olefinic stereochemical information in the oxidation
of 14 suggests that epimerization of the radical center of 19 is
faster than the second cyclization. While radical 19 could be
first oxidized to a cation and then cyclized to 12, we consider
the ionic cyclization less likely because of the mismatched
polarization of acylimidazolinone. Also, addition of Cu(OAc)2,
which is known to accelerate the oxidation of secondary radicals
by 350 times,29 had no effect on this reaction.
We note that the 6-endo cyclization product 24 is 16.7 or
11.4 kcal/mol more stable than the 5-exo cyclization product
23. These results agree with the reported ESR studies on the
Scheme 4. Proposed Mechanism of the Mn(III)-Promoted Oxidative 5-Exo/6-Endo Radical Cyclization
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Figure 2. Energy diagram for the 6-endo and 5-exo cyclizations of 22, and the 1,2-shift of 23.
captodative stabilization of radicals,34 which predict 24 to be
16.8 kcal/mol more stable than 23. The synergetic stabilization
of the amino and carbonyl groups results in a 10.8 kcal/mol
captodative effect. We further examined the atomic spin
densities for the transition states that lead to 23 and 24 and
found that the captodative stabilization also greatly contributes
to the kinetic preference for the 6-endo cyclization33 whereas
the steric effects may also play a role.35
On the basis of these results, we predicted that installation of
an electron-withdrawing group to the 15′-position would
introduce captodative stabilization to the 5-exo cyclization
pathway and results in a switch of the pathway selectivity.
Computational studies indicated that the introduction of a
chloro (25) or a cyano group (26) would lower the activation
barrier of the 5-exo cyclization pathway without affecting the 6-
endo cyclization pathway (Figure 3). We subsequently
validated this hypothesis experimentally and identified the
stereochemistry of 20 and 21. We therefore focus herein the
computational results corresponding to the observed stereo-
chemistry. Our calculations suggest that the 6-endo cyclization
pathway is favored for 22 (Oimid) by 4.1 kcal/mol, but the 5-
exo cyclization pathway is favored for 25 (Oimid-Cl) and 26
(Oimid-CN) by 3.7 and 6.2 kcal/mol, respectively. The 6-endo
cyclization product of 25 is also predicted to undergo a
barrierless elimination of the chlorine atom to afford the
imidazolinone directly.
crystal X-ray analysis.8a Replacing the phenyl group of 27 with a
methyl group gave similar results. Oxidation of 30 gave 31 and
32 in a 1:1.4 ratio. We reasoned that trans-29 and trans-32 were
formed because the second cyclization was hindered by the
chlorine atom, rendering the retro-cyclization of the first 5-exo
cyclization competitive. A trans-lactone was thus formed,
further slowing down the second 5-exo cyclization because of
torsional strains.
The computational studies suggested that stronger capto-
dative stabilization could be obtained for the 5-exo cyclization
pathway with a cyano-substituted imidazolinone. Indeed,
oxidation of 33 gave the 5-exo cyclization product 34 as the
only product.35 This reaction delivered the massadine core
skeleton directly through a 5-exo/5-exo radical tandem
cyclization but with an undesired spiro configuration. This
observed stereochemistry supports the proposed conformation
of 11• and 19 shown in Scheme 4.
Because the oxidation of 33 gave the massadine core skeleton
with an undesired spiro configuration, we briefly explored the
potential of constructing the massadine core skeleton through
oxidative ring-contraction of the ageliferin core skeleton, a
method that was also studied by the groups of Romo,11
Lovely,12 and Baran5l (Scheme 6). Unfortunately, the oxidation
of 12 with mCPBA proceeded slowly from the undesired β-
face, giving also 28. The reaction rate was low due to the
presence of a pseudoaxial phenyl group on the β-face while the
concaved α-face of 12 is not accessible.
Synthesis of Ageliferins. We sought to accomplish the
synthesis of ageliferins (2) using the biomimetic radical
cyclization reaction described above.36 We initially planned to
use imidazolinone as the aminoimidazole surrogate. However,
We were pleased to find that the experimental results are
fully in line with the computational predictions (Scheme 5).
Oxidation of the chloro-substituted 27 afforded the 5-exo
cyclization product 28 and the monocyclized product 29 in a
1:1.2 ratio. The structure of 28 has been confirmed by single-
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Figure 3. Energy diagram for the 6-endo versus 5-exo cyclization for 22, 25, and 26.
we were not able to convert imidazolinone to aminoimidazole
at various stages. Activating imidazolinone with thionation,
methylation, sulfonation, or phosphoration followed by
attacking with a nitrogen nucleophile all failed. Model studies
suggested that the activation of imidazolinone occurred
predominantly on the nitrogen instead of the oxygen atom.
We next planned to use thioimidazolinone as the amino-
imidazolinone surrogate but found it too labile to be introduced
early. We therefore decided to explore the feasibility of using
azidoimidazole as a protected aminoimidazole.
We first calculated the activation barrier (UB3LYP/6-
311G**) of the Mn(III)-promoted oxidative cyclization for
imidazole 35 and azidoimidazole 36 to evaluate if the
aromaticity of imidazole would prevent the cyclization to
occur. Encouragingly, the reaction was predicted to proceed as
easily as compared to imidazolinone 22 (Figure 4). Consistent
with the computational predictions, our model studies showed
that oxidative cyclization of imidazole 37 and azidoimidazole 39
gave the ageliferin core skeletons 38 and 40 in 40% and 42%
yield, respectively (Scheme 7). The monocyclized product was
also obtained in ca. 15% yield in both reactions.
We have also tested if the biomimetic oxidative ring-
contraction reaction could be realized with 40. While oxidation
of azidoimidazole 40 occurred without ring-contraction,
reducing the azido group restored the migratory reactivity.
Treating 40 with PPh3 gave a stable phosphine imide that
reacted with mCPBA to give 41 (Scheme 8). Similar to the
oxidation of 12, the oxidant approached from the β-face to
afford the undesired spiro configuration. Removal of the
lactone group and reduction of the azido group by PPh3 gave
42. Subsequent oxidation with mCPBA afforded 43, which also
bears the undesired spiro configuration. The structures of 41,
42, and 43 were confirmed by single-crystal X-ray analyses.37
Returning to the synthesis of ageliferins, we started our work
by coupling azidoimidazole 44 with allylic ester 45 and
prepared 46 (Scheme 9).8b Oxidative cyclization of azidoimid-
azole 46 proceeded uneventfully to give the ageliferin core
skeleton 47. The best results were obtained when the oxidation
was carried out with Mn(OAc)3 in acetic acid at 50−60 °C or
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Scheme 5. Switching the Reaction Pathway through
Controlling the Captodative Stabilization of Radicals
Scheme 8. Biomimetic Oxidative Ring-Contraction
Reactions
The stereochemical outcomes of the oxidation of 46 are in
sharp contrast to those of the oxidation of 13. The existence of
47 as a mixture of C9′ diastereomers suggests that, for 46, the
second, 6-endo radical cyclization was relatively slow and the
first, 5-exo cyclization became reversible. Since the oxidative
cyclization of the azidoimidazole analogue of 13 did not yield a
mixture of C9′ diastereomers,33 we concluded that the slowing
of the 6-endo cyclization is because of the increased steric
effects imposed by the C10 side chain instead of the strong
aromaticity of azidoimidazole.
Scheme 6. Conversion of the Ageliferin Core to the
Massadine Core by an Oxidative Ring-Contraction Reaction
Decarboxylation of the crude mixture of 47 yielded a single
diastereomer. In contrast to 42, the cis product was found to be
thermodynamically more stable. We further found that the cis−
trans ratio is sensitive to the size of the C10 side chain, which
may gear the C9 side chain and increase the equatorial−
equatorial eclipsing of the C9 and C9′ side chains for the trans
isomer.
Converting the revealed hydroxyl group to an amino group
was surprisingly difficult. Eventually we installed this critical
nitrogen atom through activating the hydroxyl group by
mesylation. Converting 48 to an iodide followed by displacing
the iodide by an azide afforded 49 in 11−13% yield over 9
steps. Introducing the azido group by a Mitsunobu reaction or
reacting 48 directly with an azide resulted mainly in
elimination.
With the N7 and N7′ nitrogen functional groups in place, we
next sought to introduce the two pyrrole side chains. A
Staudinger reduction was used to reveal the N7 amine of 49.
We found that only the alkyl triphenylphosphine imide was
hydrolyzed under the neutral conditions. The imidazolyl
phosphine imide was moderately stable even under acidic
conditions, rendering it a suitable protecting group for amino-
imidazole.38 The acetonide and Boc protecting groups could be
selectively hydrolyzed to give 50. The excess triphenylphos-
phine and triphenylphosphine oxide from the Staudinger
reduction were easily removed by washing 50 with diethyl
ether.
Figure 4. Comparing the activation barriers of the radical cyclization
of imidazolinone 22, imidazole 35, and azidoimidazole 36.
Scheme 7. Mn(III)-Promoted Oxidative Cyclization of
Imidazole Substrates
For the synthesis of ageliferin (2a) and dibromoageliferin
(2c), we introduced the pyrrole groups to the less hindered N7
and N7′ amines of 50 selectively. With a careful control of the
reaction time, 51 was obtained as the major products in 66%
yield. The N7′-monoacylated product, obtained as the minor
product in ca. 20% yield, could be recycled to improve the
overall yield of 51. For the synthesis of bromoageliferin (2b),
the dibromopyrrole side chain was first introduced to the N7
amine after the Staudinger reduction of 49. Next, the N7′
with Mn(picolinate)3 in methanol at 90 °C. Purification of 47
was found challenging and reverse-phase silica gel was used to
minimize material loss. While 47 can be obtained as a 2.5−3:1
mixture of the C9′ diastereomers in 18−25% isolated yield, we
found that using crude 47 directly for the following steps gave a
higher overall yield of 49.
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Scheme 9. Synthesis of Ageliferins 2
amine was released and the bromopyrrole group was
introduced to give 51b.
the asymmetric synthesis of ageliferin (2a), bromoageliferin
(2b), and dibromoageliferin (2c). We are currently investigat-
ing the biological functions of these natural products.
To construct the second aminoimidazole group, we first
installed a guanidine group on 51 and oxidized the hydroxyl
group by 2-iodoxybenzoic acid (IBX). The resulting aldehyde
cyclized smoothly with the guanidine to yield 52. When the
reaction was conducted at small scale, this cyclization was slow
but can be facilitated by adding 0.5 equiv of trifluoroacetic acid.
The cyclization product 52 was directly purified by HPLC
without workup to prevent decomposition induced by the IBX
oxidation byproduct.
To complete the synthesis, the C9′ configuration of 52 was
corrected through a slow equilibration under acidic conditions
(60−72 h, d.r. > 10:1). The C10′ carbonyl group was then
removed by sequential reductions to afford 53. The BOM
protecting group was cleaved by treating 53 with boron
trichloride. The resulting chloromethyl group was hydrolyzed
with ammonia in acetonitrile−water. Using the methanolic
ammonia solution for this hydrolysis resulted in the conversion
of the chloromethyl group to a methoxymethyl (MOM) group.
Finally, the triphenylphosphine imide group was hydrolyzed by
hydrochloric acid at 60 °C to afford the ageliferins (2).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and computa-
tional details. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Chuo.Chen@UTSouthwestern.edu
■
Present Addresses
†Department of Chemistry and Biochemistry, The University of
California, San Diego, California
‡ChemPacific Corporation, Baltimore, Maryland
§PerkinElmer, Boston, Massachusetts
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial Support was provided by the NIH (NIGMS R01-
GM079554, R01-GM079554-S1, NCCAM R01-AT006889),
the Welch Foundation (I-1596), and UT Southwestern. C.C. is
a Southwestern Medical Foundation Scholar in Biomedical
Research. We thank Prof. Joseph Ready for the access to the
Gaussian 03 suite of programs. The calculations with Gaussian
09 were supported in part by the National Science Foundation
through TeraGrid resources provided by National Center for
Supercomputing Applications (NCSA) under CHE090129.
The X-ray analysis of 41, 42-TBS, and 43 was performed by Dr.
Muhammed Yousufuddin (University of Texas at Arlington),
SUMMARY
■
Through computational and experimental studies, we demon-
strated that the biogenic dimerization of oroidin (1a) may
proceed through a radical mechanism. Activation of 1 by SET
oxidation is likely used by enzymes to promote the otherwise
difficult cycloaddition reactions. We further designed a
biomimetic synthesis of the [4+2] dimer of 1 using a
manganese(III)-promoted radical tandem cyclization reaction.
Our synthetic strategy allowed for a flexible introduction of the
pyrrole side chains with different bromine patterns, leading to
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Dr. Vincent Lynch (University of Texas at Austin), and Dr.
Joseph Ziller (University of California, Irvine), respectively.
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Journal of the American Chemical Society
Article
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(35) We believe that the steric effects are less important in
determining the 5-exo/6-endo selectivity of the second cyclization.
Replacing the cyano group of 33 with a methyl group did not result in
a switch of the cyclization pathway. Instead, a complex mixture of
reaction products was obtained from the oxidation of 54.
(36) We previously reported the synthesis of ent-2a using ent-45 (ref
8c). The natural enantiomer of 2a is now synthesized for biological
studies.
(37) Based on the crystal structures of 42-TBS, 41, and 43, the
triphenylphosphine imide of aminoimidazole and guanidine exists in
the indicated form with no distortion and no stabilization from the
N14′ nitrogen atom. The typical crystalinic NP, N(sp2)−P, and
N(sp3)−P bond length is 1.597(0.018), 1.651(0.024), and
1.683(0.005) Å, respectively. The NP bond length is 1.587, 1.599,
and 1.596 Å, and the CNP bond angle is 121.6°, 123.1°, and
124.1° in the crystals of 42-TBS, 41, and 43, respectively.
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