exoto
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Registered: 16-11-2013
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Need some help on this project and English
Hi guys, I am trying to apply a famous group in synthetic organic chemistry at UIUC. I think it might be a good idea to let the professor to evaluate
me through my project study. So I did one. This plan is not very mature and might have problem with English..(I m ESL).
I hope people here could help me out with English and give some advice on this project.
Also, I have to mention that this is not meant to be real. It is just a material to allow the professor to evaluate me..so I need it to be
professional but not very seriously be real..
Here it is :
A synthetic plan to the synthesis of angular triquinane natural products
Abstract
A synthetic plan is described in this article which aims to achieve the synthesis of Senoxydene, Subergorgic acid, Cantabradienoic acid and
Silphiperfol-t-en-3-ol. The key step involves in a 2-Pi-Methane rearrangement and a following reductive cyclopropane opening.
Figure 1: Some examples of Angular Triquinane and a proposed synthetic plan to the skeleton
Angular Triquinane has a complex cyclic structure, which brings the difficulty on planning a synthesis to the family of these natural products.
However, there have been plenty of successful syntheses of this family, and the majority of total synthesis publications were published during
1980s’ and 1990s’. Some of them are very inspiring to this project for using innovative strategies in solving the problems. For example,
Silphiene, one member of this family, was synthesized by your group in 1997. The key strategy is the silicon-directed Nazarov cyclization developed by
your group (the position of double bond is directed by the silicon functionality + substrate control on multiple chiral centers, nice!). Also,
photochemistry was used in some of these works. In this project, a novel strategy is proposed and an unprecedented four-ring intermediate is generated
during the synthesis. A rough synthetic route is shown in the right side of Figure 1. On the left side of Figure 1, there are some of the featured
natural products in this family, and those that are circled by red squares share the common skeleton of which the proposed synthesis route can be used
to achieve the total synthesis.
i) Retrosynthetic analysis
Deeply inspired by Professor Phil Baran’s total synthesis of Vinigrol, I realize that sometimes an “overbred intermediate” could make the
synthesis much more concise and beautiful. That is to find an intermediate that has slightly higher complexity (contain extra C-C bond(s) that do not
exist in the product) than the product, but such intermediate is possible for some powerful transformations. This is also mentioned by E.J.Corey in
his book “The Logic of Chemical Synthesis”, in which he concludes this idea into “transform-based strategy”.
So I find that a hide pattern that does not exist in the target molecular: the four-ring structure which includes a 2-pi-methane rearrangement retron
(vinylcyclopropane). The precursor 1,4-diene can be easily found by retrosynthetic analysis (FGI), which contains 4,5,6 member rings. Full carbon
four-member ring can be disconnected by a 2+2 cycloaddition. Thus, the double bond on the six-member ring is transformed to ketone through Shapiro
reaction. With carbonyl in hand, the cyclobutene structure can be constructed by a reasonable 2+2 cycloaddition reaction. The initial plan, as shown
in the picture, involves in a photochemical 2+2 cycloaddition between enone and ethyne. TMS protection group is used to lower down the boiling point
of C2H2 so that the liquid form of ethyne is obtained, which makes the reaction more practical for laboratory synthesis.
Most of the stereocenters in the molecular are under substrate control. The first stereocenter, which is generated by conjungative alkylation, is not
under control. However, there are protocols of asymmetric synthesis reported in the literatures. Thus, this synthesis can be easily changed into an
asymmetric synthesis.
Figure2: Optimized structure of the important four-ring intermediate (B3LYP/6-311+G(d,p) level calculation).This compound is about 35kcal/mol higher
in energy than its precursor.
A “solidified” conformer of 1,4 -diene, especially in this case that contains favorable weak interaction for the reaction, might increase the
yield of 2-pi-methane rearrangement. A review by Zimmerman and etc. (Chem. Rev. 1996, 96, 30653112) supports this idea. Thus, I expect a
medium yield from this key step under direct irradiation. And the major byproduct might be the four-member ring opening through a photochemical
electrocyclic mechanism. The photochemical isomerization of double bonds is precluded in this case as a result of ring strain.
e.x., retrosynthetic anaylsis of Senoxydene
Figure 3. Retrosynthetic anaylsis of Senoxydene.The control over several stereocenters in this synthesis plan needs further investigation. A
organmetallic catalytic 2+2 cycloaddition reported by a Japanese group is shown. This might be an option to photochemical 2+2.
ii) A strong evidence from computational chemistry supports
For the three-ring intermediate, I found strong evidence supporting the possible occurrence of this 2-pi-methane rearrangement. I did a structure
optimization on this molecular and surprisingly found that the conformer of the 1,4-diene is somehow close to the diradical intermediate---the 2p
orbital of each Pi bond have already had weak interaction with each other, which is, at the same time, in a sigma-bond style (the heads of two 2p
orbital overlap).
Figure 4: Pi-Pi (HOMO), the node pattern is obvious
Figure 5: spatial distribution of LUMO (Pi(*)+Pi(*)): sigma bond type interaction between 2p AO.
Also, from the calculation result (B3LYP/6-311+(d,p) level calculation), HOMO of the molecular is mainly composed of Pi-Pi, the anti-bond of two Pi
bond orbital. The energy of HOMO is expected to be higher than a normal 1,4-diene which has two Pi orbitals parallel so that such interaction is
precluded (based on perturbation theory). On the other hand, LUMO of the molecular is composed of Pi*+Pi*, thus, LUMO is lower than a normal 1,4-diene
and as a result, the HOMO-LUMO gap is relatively more narrowed. Therefore, a relatively lower power light is expected to initialize this reaction.
This might bring convenience to the laboratory synthesis.
iii) The stereochemistry prediction in the 2-pi-methane rearrangement
Figure 6
Just like most reactions, 2-pi-methane rearrangement is heavily influenced by the reaction condition and the substrate structure. When the substrate
is under direct irradiation, the first singlet excited state, S1 is involved, and the reaction can be formulated as a concerted process. According to
Carey’s Advanced Organic Chemistry, the CI (conical intersection between S1 and S0 potential energy surface) structure, which can also be roughly
understood as the transition state structure on ground state(S0’s potential energy surface), has a Mobius topology orbital array with a phase change
depicted between C1 and C2. Meanwhile, while C3 goes through an inversion, in my case, the same carbon representing C3 cannot go through an inversion
since it will bring an impossibly high strained structure. The only hope is the reaction could occur through other mechanism such as the migration of
the vinyl group or a diradical mechanism as shown in the Figure 1. Fortunately, it is known that 2-pi-methane rearrangement has multiple possible
mechanisms.
iv) Further investigation
1) Photoredox version 2-Pi-methane?
2-Pi-methane rearrangement is a powerful methodology as it can bring a major structure change from the precursor. As a photochemical reaction,
2-Pi-methane rearrangement also makes it possible to generate high-strain polycyclic structures that usually have higher energy than their precursors.
However, this has also made the laboratory synthesis more complex as the reaction normally requires special apparatus. Therefore, I was wondering if I
could find a system where the 2-Pi-methane is thermodynamically feasible so that a photoredox methodology has a chance to be used to achieve the
reaction. The initial attempt was to introduce strain in the starting material and release the strain energy at the end:
Figure 7: A model system:
A double bond is shorter than a single bond, the distance between t-butyl’s quaternary carbon increases in the product, so t-butyl groups’ 1,2
strain is released
However, based on the calculation result on PM6 level theory, the increased ring strain energy is even larger. This plan is a failure. However, there
is still space on exploring other possible systems by this strategy.
The reverse reaction that transform a vinylcyclopropane to 1,4-diene is another plan. However, to find an appropriate system is still very challenging
because, in most cases, vinylecyclopropane analogs go through a 1, 3-migration to form cyclopentene analogs.
2) Application in synthesis of other angular polycyclic molecular?
2-Pi-methane rearrangement is known to be as the key strategy in some classic total synthesis of polycyclic natural products. However, there is still
a lot of space to use this reaction in the synthesis of angular polycyclic natural products.
Figure 8 shows another possible application of this reaction in the synthesis of Cedrene, a sesquiterpene found in the essential oil of cedar, and its
analogs.
Figure 8. A retrosynthetic analysis of the skeleton of Cedrene
All the images are uploaded as attachment.. I don't know how to let them show in the article.. sorry about that.
I am an undergraduate and might make some mistakes on format or knowledge, so if there is something that does not look right, please figure them out!
Thank you guys!
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exoto
Harmless
Posts: 6
Registered: 16-11-2013
Member Is Offline
Mood: No Mood
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oh, I forget to post images!!
here is the link: http://tieba.baidu.com/p/3058677807
thank you guys..
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