epoxides to alkenes: stereochemistry issues

Hi,

I'm trying to design a stereoselective conversion of epoxides to alkenes.  

For cis or trans disubstituted epoxides, the reaction definitions work great.  For example, with the following definition and the substrate C[C@@H]1O[C@H]1C, Reactor properly gives C\C=C/C as the first product set, and gives no second product set.  (I use another definition for the enantiomer and another for the cis epoxide.)

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  <MChemicalStruct>

    <reaction x1="-1.0106250047683716" y1="2.6468749046325684" x2="0.8181250095367432" y2="2.6468749046325684">

      <propertyList>

        <property dictRef="NAME" title="NAME">

          <scalar><![CDATA[trans disubstituted epoxide to alkene]]></scalar>

        </property>

      </propertyList>

      <reactantList>

        <molecule molID="m1">

          <atomArray>

            <atom id="a1" elementType="C" mrvMap="1"

                  x2="-6.212614211852734" y2="2.560591423544322" />

            <atom id="a2" elementType="C" mrvMap="2"

                  x2="-4.672614211852734" y2="2.560591423544322" />

            <atom id="a3" elementType="O"

                  x2="-5.442614211852733" y2="3.8942705453723576" />

            <atom id="a4" elementType="H"

                  x2="-3.1507358751991417" y2="2.29500540217653" />

            <atom id="a5" elementType="C" mrvMap="3"

                  x2="-7.618241804557157" y2="1.9314562467913696" />

            <atom id="a6" elementType="H"

                  x2="-6.792234970338681" y2="1.1338329379090777" />

            <atom id="a7" elementType="C" mrvMap="4"

                  x2="-3.7625885442717433" y2="1.151385208527358" />

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          <bondArray>

            <bond atomRefs2="a1 a6" order="1">

              <bondStereo>W</bondStereo>

            </bond>

            <bond atomRefs2="a1 a5" order="1">

              <bondStereo>H</bondStereo>

            </bond>

            <bond atomRefs2="a1 a3" order="1" />

            <bond atomRefs2="a1 a2" order="1" />

            <bond atomRefs2="a2 a7" order="1">

              <bondStereo>W</bondStereo>

            </bond>

            <bond atomRefs2="a2 a4" order="1">

              <bondStereo>H</bondStereo>

            </bond>

            <bond atomRefs2="a2 a3" order="1" />

          </bondArray>

        </molecule>

      </reactantList>

      <productList>

        <molecule molID="m2">

          <atomArray

              atomID="a1 a2 a3 a4 a5 a6"

              elementType="C C C C H H"

              mrvMap="1 2 4 3 0 0"

              x2="3.8071125223086426 5.347112522308643 6.261586763623176 2.8948472358472266 3.0740560150749765 6.248264524665041"

              y2="2.5652036719766453 2.5652036719766453 3.905792945456781 3.805918001352054 1.2108668759017631 1.2563227975445912"

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          <bondArray>

            <bond atomRefs2="a1 a5" order="1" />

            <bond atomRefs2="a1 a4" order="1" />

            <bond atomRefs2="a1 a2" order="2" />

            <bond atomRefs2="a2 a6" order="1" />

            <bond atomRefs2="a2 a3" order="1" />

          </bondArray>

        </molecule>

      </productList>

    </reaction>

  </MChemicalStruct>

</MDocument>

However, with a similar definition for a trisubstituted epoxide (below) and the substrate CC[C@]1(C)O[C@@H]1C, Reactor gives CC\C(C)=C\C as the first product set and CC\C(C)=C/C as the second product set.  Why?

<?xml version="1.0" ?>

<MDocument>

  <MChemicalStruct>

    <reaction x1="-1.0106250047683716" y1="2.6468749046325684" x2="0.8181250095367432" y2="2.6468749046325684">

      <propertyList>

        <property dictRef="NAME" title="NAME">

          <scalar><![CDATA[trisubstituted epoxide to alkene]]></scalar>

        </property>

      </propertyList>

      <reactantList>

        <molecule molID="m1">

          <atomArray>

            <atom id="a1" elementType="C" mrvMap="1"

                  x2="-6.212614211852734" y2="2.560591423544322" />

            <atom id="a2" elementType="C" mrvMap="2"

                  x2="-4.672614211852734" y2="2.560591423544322" />

            <atom id="a3" elementType="O"

                  x2="-5.442614211852733" y2="3.8942705453723576" />

            <atom id="a4" elementType="H"

                  x2="-3.1507358751991417" y2="2.29500540217653" />

            <atom id="a5" elementType="C" mrvMap="3"

                  x2="-7.618241804557157" y2="1.9314562467913696" />

            <atom id="a6" elementType="C" mrvMap="5"

                  x2="-6.792234970338681" y2="1.1338329379090777" />

            <atom id="a7" elementType="C" mrvMap="4"

                  x2="-3.7625885442717433" y2="1.151385208527358" />

          </atomArray>

          <bondArray>

            <bond atomRefs2="a1 a6" order="1">

              <bondStereo>H</bondStereo>

            </bond>

            <bond atomRefs2="a1 a5" order="1">

              <bondStereo>W</bondStereo>

            </bond>

            <bond atomRefs2="a1 a3" order="1" />

            <bond atomRefs2="a1 a2" order="1" />

            <bond atomRefs2="a2 a7" order="1">

              <bondStereo>H</bondStereo>

            </bond>

            <bond atomRefs2="a2 a4" order="1">

              <bondStereo>W</bondStereo>

            </bond>

            <bond atomRefs2="a2 a3" order="1" />

          </bondArray>

        </molecule>

      </reactantList>

      <productList>

        <molecule molID="m2">

          <atomArray

              atomID="a1 a2 a3 a4 a5 a6"

              elementType="C C C C C H"

              mrvMap="1 2 4 3 5 0"

              x2="3.8071125223086426 5.347112522308643 6.261586763623176 2.8948472358472266 3.0740560150749765 6.248264524665041"

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              />

          <bondArray>

            <bond atomRefs2="a1 a5" order="1" />

            <bond atomRefs2="a1 a4" order="1" />

            <bond atomRefs2="a1 a2" order="2" />

            <bond atomRefs2="a2 a6" order="1" />

            <bond atomRefs2="a2 a3" order="1" />

          </bondArray>

        </molecule>

      </productList>

    </reaction>

  </MChemicalStruct>

</MDocument>

Finally, for the cis epoxide -> trans alkene reaction definition, it works great for monocyclic cis epoxides, but for bicyclic ones like [H][C@@]12CCCC[C@]1([H])O2, it gives the cis cyclic alkene.  It shouldn't; it should give the trans alkene, even though it is geometrically unreasonable.  I should then be able to use a steric energy test on the product to exclude bicyclic epoxides from reacting.  (I can write an awkward reactivity rule to accomplish the same purpose -- !match(ratom(1), "*~1~[#6][C:1]2OC2[#6]~1", 1) && !match(ratom(1), "*~1~*~[#6][C:1]2OC2[#6]~1", 1) && !match(ratom(1), "*~1~*~*~[#6][C:1]2OC2[#6]~1", 1) -- but I'd rather do it the other way because it involves one calculation, not three matches.)

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  <MChemicalStruct>

    <reaction x1="-1.0106250047683716" y1="2.6468749046325684" x2="0.8181250095367432" y2="2.6468749046325684">

      <propertyList>

        <property dictRef="NAME" title="NAME">

          <scalar><![CDATA[cis disubstituted epoxide to alkene]]></scalar>

        </property>

      </propertyList>

      <reactantList>

        <molecule molID="m1">

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            <atom id="a1" elementType="C" mrvMap="1"

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            <atom id="a3" elementType="O"

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            <atom id="a4" elementType="H"

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                  x2="-3.1850884393675685" y2="2.16201009408644" />

          </atomArray>

          <bondArray>

            <bond atomRefs2="a1 a6" order="1">

              <bondStereo>W</bondStereo>

            </bond>

            <bond atomRefs2="a1 a5" order="1">

              <bondStereo>H</bondStereo>

            </bond>

            <bond atomRefs2="a1 a3" order="1" />

            <bond atomRefs2="a1 a2" order="1" />

            <bond atomRefs2="a2 a7" order="1">

              <bondStereo>H</bondStereo>

            </bond>

            <bond atomRefs2="a2 a4" order="1">

              <bondStereo>W</bondStereo>

            </bond>

            <bond atomRefs2="a2 a3" order="1" />

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        <molecule molID="m2">

          <atomArray

              atomID="a1 a2 a3 a4 a5 a6"

              elementType="C C C C H H"

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            <bond atomRefs2="a2 a6" order="1" />

            <bond atomRefs2="a2 a3" order="1" />

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Comments?

-- Bob

bobgr wrote:

However, with a similar definition for a trisubstituted epoxide (below) and the substrate CC[C@]1(C)O[C@@H]1C, Reactor gives CC\C(C)=C\C as the first product set and CC\C(C)=C/C as the second product set.  Why?

This is a bug, only CC\C(C)=C\C should be generated. See also the attached image.

bobgr wrote:

Finally, for the cis epoxide -> trans alkene reaction definition, it works great for monocyclic cis epoxides, but for bicyclic ones like [H][C@@]12CCCC[C@]1([H])O2, it gives the cis cyclic alkene.  It shouldn't; it should give the trans alkene, even though it is geometrically unreasonable.  I should then be able to use a steric energy test on the product to exclude bicyclic epoxides from reacting.  (I can write an awkward reactivity rule to accomplish the same purpose -- !match(ratom(1), "*~1~[#6][C:1]2OC2[#6]~1", 1) && !match(ratom(1), "*~1~*~[#6][C:1]2OC2[#6]~1", 1) && !match(ratom(1), "*~1~*~*~[#6][C:1]2OC2[#6]~1", 1) -- but I'd rather do it the other way because it involves one calculation, not three matches.)

Reactor sets the double bond stereo information to CIS in small rings (ring size < 8). There are not many "automatic corrections" made by reactor, but this was necessary to avoid generating geometrically unreasonable molecules.

Zsolt

Zsolt wrote:

bobgr wrote: However, with a similar definition for a trisubstituted epoxide (below) and the substrate CC[C@]1(C)O[C@@H]1C, Reactor gives CC\C(C)=C\C as the first product set and CC\C(C)=C/C as the second product set.  Why?   This is a bug, only CC\C(C)=C\C should be generated. See also the attached image.

Has the bug already been fixed in a released version -- if so, which one? -- or was the image you generated from a candidate version?

bobgr wrote:

Has the bug already been fixed in a released version -- if so, which one? -- or was the image you generated from a candidate version?

It is not yet fixed, I'm working on it (sorry, for not mentioning this). Presumably it will be fixed in JChem 5.2.2. The version I use also generates two products sets, I attached the image of the second one.

bobgr wrote:

I suggest that you make an option for the user to turn off this automatic correction.  I agree that it should be on by default, but there are some reactions that are so rigidly stereospecific that they would rather generate no product at all than a low-energy diastereomer of a high-energy "expected" product.

Thanks for the suggestion, we will discuss it.

Zsolt

Hi, has this bug been fixed?  What about the option to return no product rather than one with a stereochemical "correction"?

bobgr wrote:

Hi, has this bug been fixed?  What about the option to return no product rather than one with a stereochemical "correction"?

Yes, it has been fixed. 5.3.0.2 version generates only one product:

$ react -r r2.mrv "CC[C@]1(C)O[C@@H]1C"
CC\C(C)=C\C

Optionally turning off any automatic correction is a reasonable thing to do. We will implement also this (presumably in JChem 5.4).

Zsolt