Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Philip Garner, H. Umit Kaniskan, Charles M. Keyari, and Laksiri Weerasinghe


Sorry for the long delay but I was a bit busy with my relocation. This piece of work was published a few weeks ago and deals with some interesting chemistry. I am not very familiar with this unusual [3 + 2] or formal [2 + 2 + 1]-cycloaddition reaction.

Let’s take a look at the retro:

Scheme 1


They make use of some old school and some modern chemistry. The bicyclic moiety is accessible by a Strecker reaction. A Pictet-Spengler reaction was used to produce the tetrahydroisoquinoline ring using starting material from a lactamization step. The proline-like motif in turn was formed through this odd cycloaddition step.

 Scheme 2

The aromatic part of Cyanocycline A was synthesized using some well known chemistry. Starting from anisol 1 a Friedel-Crafts acylation and subsequent Baeyer-Villiger oxidation formed 2. Regioselective bromination and saponification yielded phenol 3 which was protected as the benzyl ether 4.

Now to the first cool chemistry used in this paper: a stereoselective Grignard reaction with a D-serine-derived nitrone. The mechanistic rationale is explained at the end of this review. Hydroxylamine reduction was accomplished under Clemmensen conditions followed by Cbz-protection of the free amine to give 6. Acetonide removal and Dess-Martin oxidation then gave aldehyde 7.

Scheme 3


Next the formal [3 + 2]-cycloaddition is used to make three more stereocenters. Condensation of 7 with amine 8 was followed by the addition of silver acetate and methyl acrylate to give 10. Again the mechanism is discussed later on. Removal of both Cbz-groups and benzyl-groups forms the lactam ring and subsequent protection of the pyrrolidinyl nitrogen with Cbz gave 11. Boc-deprotection with TFA and a Pictet-Spengler reaction in acetic acid produced after benzylation of the free alcohol 12.

Scheme 4


Reduction of the Cbz group to a methyl group and cleavage of the chiral auxiliary with LAH in the presence of the amide worked fine. Oxidation of the terminal alcohol of 13 and subsequent Strecker reaction with TMSCN formed 14. Thioamide formation with Lawesson’s reagent and reductive desulfuration then gave imine 15.

 Scheme 5

Heating 15 in MeOH with some equivalents of ethylene oxide in a sealed tube formed 16. Selective debenzylation was accomplished with boron trichloride followed by benzoquinone formation with Mn3+ to give Cyanocycline A.

Scheme 6

And for those who want to know how the key steps might work, here is the mechanistic rationale. First the Grignard reaction:

Scheme 7

The authors explain the outcome of the reaction with an open transition state in which the Grignard reagent attacks the least hindered face of the nitrone. This is probably stabilized by a magnesium ion (when Grignard reagents are used). The reaction proceeds with high diastereoselectivity.

The second key step is somewhat more complicated. First the amide undergoes an imine formation with the aldehyde. Next one of the glycine protons is lost in the presence of silver which forms a tight complex with the imine nitrogen. The result is a positive charge on the nitrogen and a negative charge on one of the two vicinal carbon atoms. Moreover the silver cation forms a second complex with the acrylate which undergoes the cycloaddition and attacks the 1,3-dipole from the least hindered face to give 10.

Scheme 8

Nice chemistry don’t you think? And a really complex target. Comments?

And thx to Bobby for proofreading 😉

2 Responses

  1. Oh my goodness! Amazing article dude! Thank you, However I am experiencing troubles with your RSS.
    I don’t understand the reason why I can’t subscribe to it.
    Is there anybody else getting the same RSS issues? Anyone who knows
    the solution will you kindly respond? Thanks!!

  2. Thx for the kind comment 😉 Usually the subscription should work just by copying the link into your RSS feed reader… Worked for me so far.

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