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This round of synthesis golf concerns the Corey synthesis of Erythronolide B (J. Am. Chem. Soc. 1978, 100 (14), 4620–4622).

Structure of erythronolide B and fragment

In order to narrow the scope of the challenge, only a small fragment of the natural product will be considered. Fragment 2 was an intermediate on the Corey route, and provided C10-C13 of Erythronolide B.

Crucially, 2 was needed as a single enantiomer and diastereomer. In the original Corey report, 13 steps were needed to accomplish the synthesis of the fragment, a length which prevented significant amounts of material from being made.

The challenge is to propose a synthesis of 2 which sets up the required 1,2-stereochemistry with absolute configuration. You may start from anything commercially available in the Sigma–Aldrich catalogue, including chiral building blocks.

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    $\begingroup$ What is the iodine set up for? Could a triflate suffice here? $\endgroup$ – Beerhunter Jun 12 '17 at 15:38
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    $\begingroup$ I'd like to see future synthesis golf questions where a biosynthetic answer would fit in. There are viable engineered biosynthetic routes to erythronolide B, but since this question is about some random synthetic intermediate that is not biological and is of no use to anyone except synthetic organic chemists, I guess biosynthesis is off-topic for this particular synthesis golf. $\endgroup$ – Curt F. Jun 12 '17 at 16:35
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    $\begingroup$ @CurtF. The intermediate was chosen since some felt that anything larger than a small fragment was too broad (and therefore likely to be flagged/closed). If you'd care to expand, theres a post on meta.chem asking for input! $\endgroup$ – NotEvans. Jun 12 '17 at 17:11
  • $\begingroup$ As an aside, some bio-transformations could still be used to set up the stereochemistry here. There is presumably only one true biosynthesis, which isnt really any individuals work rather than natures. $\endgroup$ – NotEvans. Jun 12 '17 at 17:30
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    $\begingroup$ I think we should switch to another problem. One month period is too long for a such a narrow question. Ten days have passed and there are no new ideas. Either a shortening of the period between two questions or posting questions with a wider scope would in my opinion improve the challenge. $\endgroup$ – EJC Jun 21 '17 at 17:27

I have established the stereochemistry via Evans aldol addition:

Then, after protection of the hydroxyl group, the chiral auxiliary can be transformed to a Weinreb amide which will be attacked by Grignard reagent: enter image description here The methyl ketone is then transformed to an alkyne which is methylated:enter image description here Finally, hydroboration (should be very regioselective) of the alkyne will provide the trans alkenylborane which on treatment with NaOH and iodine will provide target 12: enter image description here

Length (total steps and longest linear sequence): 7 steps

  • 1
    $\begingroup$ Nice! Not free to answer this time round, but I was thinking of something along this line too. $\endgroup$ – orthocresol Jun 12 '17 at 6:43
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    $\begingroup$ @Ben Norris I counted 8 steps. Are one-pot reactions considered one step? $\endgroup$ – EJC Jun 12 '17 at 9:11
  • $\begingroup$ @Marko, for things in the same pot (such as the aldol), its usually written as Bu2BOTf; RCHO, with the semicolon indiciating then. Different numbers do imply (to a bystander at least), different reactions. $\endgroup$ – NotEvans. Jun 12 '17 at 10:35
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    $\begingroup$ @NotEvans Okay, I should have mentioned that I use number designations for different steps in one pot reactions and reactions in different vessels are designated by different arrows. Now I see that hydroboration/iodination is done one pot, too therefore there are 7 steps in total. $\endgroup$ – EJC Jun 12 '17 at 10:52


The key things that need setting up are the 1,2-syn stereochemistry and the vinyl iodide.

  • The 1,2-syn stereochemistry is easiest setup using a syn aldol, via a Z enolate. The Evans' (or variant) is the obvious way to gain control of absolute stereochemistry as well as relative stereochemistry.
  • The vinyl iodide can be made in many ways, but hydrozirconation of a methyl alkyne is a good way of ensuring double bond geometry and regioselectivity for the iodide ending up where it does.

Forward synthesis:

1 → 3: Acylation of the Evans' auxiliary to append the propionyl unit followed by a modified Evans' aldol (Crimmins' type chemistry, avoiding the boron triflate reagents), these conditions give the Evans' syn product.1

3 → 4: TBS protection, fairly hindered alcohol so using TBSOTf along with a lutidine base.

4 → 5: In order to introduce the alkyne, need to first convert the Evans' auxiliary to something functional, an aldehyde would be a good starting point and could be obtained in multiple ways. The two most obvious (both with the same step count) are either direct reduction of the auxiliary to the alcohol followed by oxidation (Parikh Doering often useful in these systems), or formation of the Weinreb amide and DIBAL reduction directly to the aldehyde. In both cases, the aldehyde is chiral at the alpha-position, so must use immediately to avoid possible racemisation of the methyl stereo centre.

5 → 7: An Ohira-Bestmann reaction installs a terminal alkyne. Could also get the same result in a two-step procedure using a Corey-Fuchs (possibly more reliable, but precedence is sound for the Ohira-Bestmann).

7 → 12: Introduction of the methyl group at the end of the alkyne via deprotonation (terminal alkynes have fairly low pKa) alkylation sequence. The alkylated alkyne may then undergo hydrozirconation/trapping to install the vinyl iodide, furnishing 12, as required.

enter image description here


  • 8 steps overall (longest linear and total steps), with all starting materials and reagents being commercially available
  • Control of absolute and relative stereochemistry via the use of an Evans'-type aldol reaction
  • Control of the vinyl iodide geometry using a selective hydrozirconation


1: DOI: 10.1055/s-2004-825626

  • 2
    $\begingroup$ Good call for Ohira-Bestmann reaction. $\endgroup$ – EJC Jun 12 '17 at 10:53

Before my answer, I'd like to inform you that I'm an undergrad student with some knowledge of organic chemistry. If there are any errors in my answers, I'm sure you'll tip me off!

Step 1: (Z)-pent-2-ene reacts with $\ce{HOCl}$ to give the (threo)-2-chloropentan-3-ol. Step 1

Step 2: (Threo)-2-chloropentan-3-ol reacts with 1-propyn-1-yllithium Step 2

Step 3: Reaction with $\ce{TBDMS-Cl}$ Step 3

Step 4: Reaction with $\ce{9-BBN}$ Step 4

Step 5: Reaction with 3 eq. $\ce{NaOH}$ (3M aqueous solution) and 2 eq. $\ce{I2}$ in $\ce{THF}$ at $\ce{23^\circ C}$ for 1 hr. Reference: C. Wang, T. Tobrman, Z. Xu, E.-i. Negishi, Org. Lett., 2009, 11, 4092-4095 Step 5

And finally, for simplicity, enter image description here

I realise that I have represented the incorrect (from the requirement point of view) enantiomer, but seeing that my first step will produce both enantiomers, we should get the required product as 50% of the yield.

Note: I later realized that I have missed a methyl group on the protecting group. Please consider it is there.

  • 1
    $\begingroup$ (1) You did a racemic synthesis, but the stipulation was to set absolute stereochemistry, though. (2) Curious as to how regioselective the first step is? $\endgroup$ – orthocresol Jun 11 '17 at 19:53
  • $\begingroup$ @orthocresol I was thinking the first step would be an electrophilic addition via a chloronium ion intermediate, which gave the anti-diastereoselectivity. $\endgroup$ – Eashaan Godbole Jun 12 '17 at 1:36
  • $\begingroup$ I was also thinking that the first step could be modified to be enantioselective using a bulky chiral catalyst, and using $\ce{TBDMSO-Cl}$, if that works, but I don't think the reagent is available. Further, maybe the substrate is too small (?) for steric interactions to work effectively to prefer one enantiomer over the other. $\endgroup$ – Eashaan Godbole Jun 12 '17 at 1:40
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    $\begingroup$ For someone unversed in organic...with an otherwise fair chemistry (plus physics/coding/math/etc) foundation... this discussion makes my head spin! Usually we phys scientists, in subjects we don't know, can hold our own, or can talk about it at least. I see a benzene in one of the pictures, that's about it for me! If any introductory chem student ever thinks "oh chem must be simple, it's a increasing combinations of these elements, these kinds of bonds", just point them here and watch a head explode? You've won the web's most complex comfortable-sounding comment thread in all history. $\endgroup$ – JeopardyTempest Jun 12 '17 at 14:59
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    $\begingroup$ It's an ethyl vs methyl group - I really don't know how this turns out in the lab, so take what I say with a tablespoon of salt, but on paper it doesn't seem like there is a significant difference in their inductive effects, such that the formation of one regioisomer is strongly favoured. $\endgroup$ – orthocresol Jun 13 '17 at 23:28

A synthesis using Sharpless epoxidation for stereoinduction.

enter image description here

  • $\begingroup$ MeLi will destroy your ester before it opens your epoxide. I’ve seen some chelation-controlled epoxide openings with hydride sources before, but not sure if there’s an analogous one with carbon nucleophiles (surely it exists?). $\endgroup$ – orthocresol May 18 '19 at 11:14
  • $\begingroup$ @orthocresol good point, might have to use something like THP instead, which would still be able to direct the MeLi hopefully. $\endgroup$ – Laksh May 19 '19 at 9:41

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