In the Classroom
A Simple Algorithm To Convert Complex Organic Molecules into Their Straight-Chain Conformations Dwayne A. Dias Department of Chemistry, University of Western Ontario, London, Ontario, Canada N6A 5B7;
[email protected] The vast majority of organic chemists are concerned with the construction of organic molecules—be it the complex secondary metabolites found in nature, designed molecules for a specific purpose, or simply those that provide the highest level of synthetic challenge (1). Regardless of the target molecule chosen, the overarching strategy toward a suitable synthetic approach comes by way of a thorough retrosynthetic analysis. Quite elegant in its simplicity, the molecule is envisioned as a starting point whereby disconnections are sequentially made until the simplest of chemical precursors become evident. These disconnections are only appropriate if
1. They correspond to known, reliable reactions that are proven in the literature (2) or
2. Suitable synthetic methods do not exist for such a construction, but it is the aim of the investigator to test an envisioned method to perform such a construction.
As powerful as this method may be (no doubt many practitioners have used it over the past 40 years or so since its inception to synthesize some of nature’s most complex molecules; ref 1), there is still one additional step that is usually dismissed as unnecessary, or has fallen by the wayside over time. That last step is to completely deconvolute, or to unravel, a complex molecule decorated with myriad stereochemistry into its simplest form before a systematic retrosynthetic analysis is undertaken. In this article, a general algorithm is described that will enable a molecule (complicated with a lot of stereochemistry or basic with no stereochemistry) to be deconvoluted into its simplest form—that of the straight-chain conformation. Once this skill is attained, a retrosynthetic plan of attack emerges all the more powerful since it becomes even more general and allows the practitioner to envision disconnections that would otherwise be overlooked or not be immediately obvious. A OH Me HO
HO O
H OH
H
H
H
Me
O
O HO
O OH
Cl
O
HO
HO HO
O
OH
OH
What sugar is this?
O H
H O
H
OMe
O
H
O
Me
Me
AcO
OAc Me
OH
spongistatin 1
Figure 1. These compounds must be put into meaningful conformations for further analysis.
194
practical advantage that arises from a mastery of this skill is that students and teachers will be able to systematically interconvert molecules between their Fischer projections, Haworth projections, and straight-chain conformations without having to resort to the use of the Cahn–Ingold–Prelog (CIP) rules (ultimately seen as infallible but highly prone to errors) (3). The need for a method that is able to deconvolute complex molecules into their simpler straight-chain conformations can be appreciated simply by examining the structures in Figure 1. The structure on the left in Figure 1 is a well-known sugar (assuming most synthetic chemists are at least aware of the prominence of the 15 d-aldoses) but because it is in a furanose ring and not the more familiar Fischer projection, revealing its identity becomes cumbersome. Though there are a few publications describing some methods to solve such problems (4), they are far from general and synthetic chemists usually resort to use of the CIP rules in this regard. The natural product shown on the right in Figure 1, spongistatin 1, is a complicated structure consisting of elaborate substructures, a multitude of functionality, and decorated with myriad stereochemistry. Since its discovery, there has been intense activity in the synthetic community evident by the more than 185 publications to date, including those that describe successful routes to its completion (5). However, virtually all retrosynthetic analyses start with the parent molecule as is drawn. This approach is flawed because one is usually forced to make disconnections at the seemingly most obvious points. For example, there are numerous publications describing routes to just the sensitive spiroketal subunits with hopes to build up the rest of the molecule around them. In other words, many chemists perform retrosynthetic disconnections as a result of the way a molecule is presented as opposed to those that would be more reliable, but otherwise hidden in a convoluted structure. If this molecule could be presented in a suitable straight-chain conformation (by treating a ketal like a ketone and two alcohol moieties and other such operations), one could almost be certain that the two retrosynthetic disconnections would be very disparate! In a purely pedagogical format, some fundamentals must be established before the complete method to deconvolute complex structures into their straight-chain conformers is revealed. Consider the structures shown in Figure 2A. Structure 1 in Figure 2A is a penta(deuterio)substituted alkane that consists of ten carbon atoms that all lie in the plane of the paper. There are five deuterium atoms with defined stereochemistry, but it may not be immediately obvious what the relationship (syn or anti) would be between them if the hydrocarbon would be put into its “normal” zig–zag conformation. As a first step to address this issue, we observe that this compound possesses two s-cis configurations, while a “normal” zig–zag conformation would be composed solely of s-trans configurations. It becomes clear that one must rotate around all s-cis single bonds (by 180°) to turn them into s-trans single bonds. Following this paradigm, a rotation about C4–C5 in compound 1 gives us 2. Note that all the
Journal of Chemical Education • Vol. 86 No. 2 February 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Classroom
A
s-cis 2
D
1 5
D 9
s-cis
D
D
D
7
1
D
9
D
7 2
D
5
1
D
5
7
9
D
D
D
2
B
D
s-cis
D 1
D 2
3
s-cis 2
10
OH
1 5
HO
s-cis
HO 2 1
10
4
2
5
OH 5
10
7
5
1
7
7
OH
OH
s-cis
6
Figure 2. Transforming compounds with s-cis single bonds into s-trans single bonds and the effect that it has on the 2D-representation. (A) Two rotations about single bonds must be carried out on a penta(deuterio)substituted alkane with two s-cis single bonds. (B) A practical illustration of the same method on a 1,3-diol.
stereochemical elements to the right of this rotation, throughout the whole molecule, become “inverted” (this makes sense since we rotate by 180° to go from s-cis to s-trans). Those deuterium atoms that were pointing up from C5 and beyond (all of them) now point down into the plane of the paper. A subsequent iteration of this process on the remaining s-cis single bond between C5–C6 in 2 gives us 3. Again, all stereochemical elements to the right of the rotation become “inverted” and we see that those deuterium atoms that were pointing down from C6 and beyond (all of them in 2) now point up. Compound 3 now represents the completely deconvoluted structure consisting of a fully stretched molecule in its “normal” zig–zag pattern composed solely of s-trans single bonds. It now becomes immediately obvious what the relationships among the stereochemical elements are. A more practical example follows upon consideration of the 1,3-diol 4 depicted in Figure 2B. Following the same iterative process, we arrive at a fully deconvoluted structure 6 that reveals an anti-1,3-diol motif. Though one can make use of the CIP rules to arrive at the same conclusion, this can be timeconsuming and extremely prone to errors, especially when much more complicated structures are encountered. As virtually all organic chemists start their training with straight-chain conformations of various molecules, familiarity with these structures coupled with the apparent relationships between stereochemical elements should immediately compel an investigator to deconvolute complex structures into their simplest forms. As well, since a significant amount of purely synthetic methodology publications involve small molecules (and small molecules are mostly in “normal” conformations) that detail stereochemical outcomes of reactions (see for example the venerable boron aldol and Evans aldol reactions; ref 6), it would be easier to take advantage of this wealth of information in the retrosynthetic planning stages from a deconvoluted complex structure. The examples given above represent somewhat simple scenarios—there are molecules that are more complicated than this that exist in nature. For a general deconvolution method to
be practical, it must be applicable to both simple cases and more complicated ones. Consider the molecule given in Figure 3A, RK-397, a 32-membered macrolide that is decorated with many hydroxyl groups along its 32-membered periphery (7). Upon closer inspection of this molecule, a subtle “irregularity” appears in the given structure that would hinder an attempt to put it into its deconvoluted conformation. As seen in structure 7 (Figure 3A), the isopropyl group at C31 is displayed as a substituent on the macrolide and thus, is not in the plane of the paper. To be able to use a general deconvolution algorithm, it is imperative that the appropriate carbon backbone must be (or is seen to be) put into the plane of the paper. Explicitly, the easiest way to do this follows from an examination of structures 8–11 in Figure 3B. These structures show the pertinent region of the molecule—the isopropyl group and the corresponding macrolide region. With the hydrogen drawn explicitly in 9, it should
A O
33
OH
1 13
O 31
Me
OH
21
30
OH OH OH OH OH OH 7
B
31
Me
30
8
O
O
O
33
O
O
H
31
Me
Me 9
O
33
O H
O 31
Me 10
11
Figure 3. (A) A more complex molecule: RK-397. (B) The step-by-step process to put the carbon backbone of the molecule into the plane of the paper.
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In the Classroom
A down
O
33
1
4
6
10
OH
13 15
O 26
30
24
22
O
OH
2
4
8
6
10
12
14
16
18
20
22
24
26
30
28
32 33
12
OH
20
Me
1
OH
17
OH OH OH OH OH OH 7
B down
1
O
33
1
4
6
10
OH
13 15
O 30
26
24
Me
4
22
O
OH 2
20
1
2
4
8
6
OH
12
14
16
18
20
22
24
26
Me
28
OH OH OH OH OH OH OH OH
17
OH OH OH OH OH OH
10
29
33
OH
14
3
13 Figure 4. (A) The first step in the deconvolution algorithm is to put the appropriate carbon backbone into its straight-chain conformation. (B) After denoting the “flips” that need to be performed at all s-cis junctions, the stereochemistry can be filled in with ease in the straight-chain conformation.
now become obvious that if one were to rotate counterclockwise about the C30–C31 bond, the isopropyl group will now lie in the plane of the paper and the hydroxyl group will point down (see structure 11). In practice, such minor operations become trivial mental exercises. Moving on, we now redraw the parent molecule 7 (Figure 4). We scan the molecule, and immediately recognize the “irregularity” in the out-of-plane isopropyl group. We mentally perform the required rotation about the C30–C31 single bond to put the isopropyl group into the plane of the paper and denote that the hydroxy substituent will point down after this rotation. We then label all carbon atoms in the appropriate carbon backbone and draw the corresponding straight-chain conformation 12 (treating the ester as an alcohol and carboxylic acid moiety). We then scan for all s-cis configurations and numerically identify them (Figure 4B). In this macrolide, there are four such s-cis configurations, and therefore, we need to perform four 180° rotations about the appropriate bonds (compound 13). Building upon the discussion earlier (vide infra), all stereochemical configurations “invert” upon rotation about s-cis single bonds. The key part in this algorithm rests upon the simple observation that if an odd number of “flips”, or rotations, are performed before a stereochemical element is encountered, then that stereochemical element becomes “inverted”. Conversely, if an even number of “flips” or rotations, are performed before a stereochemical element is encountered, then that stereochemical element remains as is—it does not “invert”. This makes sense since an even number of 180° rotations is equivalent to a rotation of a multiple of 360°. Thus, filling out the stereochemistry in the straight-chain conformation by using the macrolide structure 13 as a blueprint becomes a trivial task. Progressing down the length of the straight-chain backbone, we fill in the stereochemical elements merely by observation and noting if we are at an even or odd number of “flips” at that stereocenter. Again, that information is used to determine whether the orientation of that stereochemical element stays the same or becomes inverted as compared to the parent structure. Following this protocol, we finally arrive at the completely deconvoluted structure 14. The entire deconvolution method can be summarized in a concise 4-step algorithm: 196
1. Number all carbon atoms in the parent structure and scan for “irregularities”.1
2. Draw the appropriate straight-chain conformer.
3. Perform the “flips” (i.e., the required rotations) about the s-cis single bonds.
4. Fill in the stereochemistry in the corresponding zig–zag carbon backbone.
If one follows these four simple steps, seemingly complex molecules can be delineated into a more familiar form in a matter of a few minutes without the need to resort to the cumbersome CIP rules. Originally, the purpose of this article was to solve the specific problem of going from complex structures to their fully elongated straight-chain conformations. However, as a testament to the flexibility of the method, we now show how the principles described above can be used to interconvert between any structures. Consider the sugar shown in Figure 1. As a simple example, most synthetic chemists would have a hard time elucidating its identity, even when presented with a table of the 15 d-aldoses. This stems from the fact that it is not presented in the more convenient representation that allows for direct comparison—that of a Fischer projection. Thus, a solution to this problem involves conversion of the furanose form of the sugar into its Fischer projection whereupon a comparison to a give table of sugars (usually the d-aldoses) can be made. As a first step, we follow the steps given in the general algorithm to convert this sugar into its straight-chain conformation (Figure 5). The sugar is numbered 15, its appropriate carbon backbone 16 is drawn, and the parent structure is scanned for “irregularities”. We note that the hemiacetal can be seen as a masked form of an aldehyde and an alcohol moiety. Also, to put the carbon backbone into the plane of the paper, we denote that both hydroxyl groups (one is part of the hemiacetal) must point up. There is only one “flip”, or rotation, to be made, and after filling in the stereochemical elements rather easily, we arrive at hexose 17. After a few trivial operations (only one “flip” was needed), we have converted this unknown sugar 15 into a more manage-
Journal of Chemical Education • Vol. 86 No. 2 February 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Classroom
able conformation 17. The next step involves conversion of this all s-trans conformation to an all s-cis conformation. Ostensibly, this seems like a step backward, but the reason for this will become evident momentarily. Thus, as seen in Figure 6, there are three strans configurations and we need to perform three sequential 180° rotations for a conversion to an all s-cis carbon conformation. Drawing the all s-cis carbon backbone, but following the same principles alluded to in the algorithm, we arrive at structure 18.2 The link that enables one to go from a straight-chain representation of a sugar to a Fischer projection is the fact that a straight-chain conformation in an all s-cis configuration gives exactly the same information as that from a Fischer projection. Specifically in this example, the s-cis conformation of the unknown sugar is redrawn in Figure 7. As indicated by the arrows, if one were to look in those directions in succession starting from the aldehyde, the substituents would always point towards us and the carbon chain would always point away. This is exactly the convention adopted in the use of all Fischer projections! Thus, it becomes trivial to go from an s-cis conformation of an unknown sugar to a Fischer projection formula. As illustrated in Figure 7, we have filled out the Fischer projection by noting that those hydroxyl groups that point down in 18 will be on the right-hand side of a Fischer projection and those hydroxyl groups that point up will be on the left-hand side of a Fischer projection. Performing these trivial tasks, we arrive at a Fischer projection 19 of the unknown sugar. Immediately apparent is the fact that it is an l-sugar—and so observing its mirror image 20 tells us that the unknown sugar is l-idose when compared to a given table of the standard d-aldoses. More concisely, a few steps can be omitted in the deconvolution of the unknown sugar in its original representation to that of an all s-cis conformation (we can go directly from a given structure to either an all-trans or an all-cis configuration). As illustrated in Figure 8, the parent sugar 15 must be rotated by 180° around the indicated s-trans single bonds. Drawing the appropriate carbon backbone and filling in the stereochemistry, we immediately arrive at the required all s-cis conformation 18. Putting this into a standard Fischer projection formula confirms (again) that this sugar is l-idose. We are now in a position to give a complete algorithm to interconvert complex structures between any 2D representations:
1. Number all carbon atoms in the parent structure and scan for “irregularities”.1
2. Draw the appropriate straight-chain conformer—the “appropriate” conformation can now consist of any number of s-cis or s-trans configurations.
3. Perform the “flips” (i.e., the required rotations) about the appropriate single bonds.
4. Fill in the stereochemistry in the corresponding carbon backbone.
As a final example to illustrate the power of this straightforward method, we return to spongistatin 1 (see Figure 1). Following the steps outlined in the algorithm, (and decomposing acetals, ketals, and the ester to their component parts), we arrive at a blueprint 21 (Figure 9) needed to unfurl the molecule to its straight-chain conformation.3 After filling in the carbon backbone rather effortlessly, we arrive at the simplest representation for this molecule—compound 22.
up aldehyde
HO
6
H
5
HO
O 3
HO
up
OH
1
4
2
OH
1
15
5
HO
CHO
3
OH
OH
5
3
OH
OH
16
1
CHO OH
17
Figure 5. Putting an unknown sugar into its straight-chain conformation.
OH
OH
2
HO
HO 1
CH2OH
CHO
3
OH
1
HO
1
6
6
OH
HO
17
18
CHO
OH
Figure 6. Converting from an all s-trans conformation to an all s-cis conformation.
1
HO
H
6
CH2OH
HO
1
4
OH
HO
CHO
H
H HO
OH
HO
OH
H 6
18
1
CHO
CHO
HO
H
H
OH
HO
H
H
OH 6
CH2OH 19
CH2OH 20
Figure 7. The relationship between a sugar in its all s-cis conformation with a Fischer projection formula.
up
HO
6
H HO up
1
aldehyde
2
HO O 2
1
HO
OH 15
6
CH2OH
OH
1
CHO
H
HO
CHO 1
HO
OH
HO
H
H
OH
HO
OH 18
H 6
CH2OH 19
Figure 8. Going directly from the unknown sugar to an all s-cis conformation (which gives the same information as a Fischer projection formula).
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In the Classroom
HO
1
O
2
Me Me
4
7
OH OAc O Me OH OH
20
18
13
9
OAc O
28
26
23
OH OMeO
29
OH OH
31
OH
33
22
OH
Me
O
36
ketone 18
OH
HO
17
Me HO
HO
H OH
H
49
38
19
H
O OH
2
AcO
2
1
O 5 3
24
O
H 11
8 4
Me
ketone up 13 6
9
11 21
12
H
OH
OMe
OH 46
Cl
49
10
O
13
H
ketone
O
14
down
O H
OH 40
43
H
26
HO
1
H
down
15
up
O
21
29
Me
O40
43
Cl
16
33
O
cis
Me
38
up 19
Me
9
O
17 8
15 7
Me
OAc
5
OH
Figure 9. Applying the algorithm to spongistatin 1 gives us a blueprint needed for deconvolution, 21. Using the information in the blueprint allows us to draw all the stereochemical elements in the straight-chain representation 22 with relative ease.
As it becomes clearly evident, it is now possible to envision many new ways to approach a retrosynthetic design when presented with a complicated molecule in its simplest representation. At the very least, these new structural representations give chemists new ways of looking at complex molecules—and are sure to inspire new, more powerful approaches to their syntheses. In conclusion, a general algorithm has been unveiled that allows one to interconvert complex molecules between any 2D representations. Extremely useful to students, teachers, and practitioners of organic chemistry, such a method is surely to be embraced owing to its ease of utility and its broad applicability. Notes 1. Other irregularities include unalterable cis double bonds (these cannot be changed), epoxides, and spirocycles. All these elements, however, are compatible with this methodology provided that they are recognized and treated appropriately. 2. Note that this method also provides for interconversions into Haworth projections since 18 can be viewed as such (after a suitable single-bond rotation about C4–C5 followed by ring closure). 3. The spirocycle represents an irregularity, but its treatment is compatible with this methodology (although we will not go into detail here).
Literature Cited 1. (a) Nicolaou, K. C.; Sorenson, E. J. Classics in Total Synthesis; Wiley-VCH: Weinhem, Germany, 1996. (b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-VCH: Weinhem, Germany, 2003. 198
2. Warren, S. Organic Synthesis: The Disconnection Approach; John Wiley and Sons Ltd.: New York, 1982. 3. (a) Ayorinde, F. O. J. Chem. Educ. 1985, 62, 297. (b) Argiles, J. M. J. Chem. Educ. 1986, 63, 927. (c) Signorella, S; Sala, L. F. J. Chem. Educ. 1991, 68, 105. 4. Cahn, R.; Ingold, C. K.; Prelog, V. Angew. Chem., Int. Ed. 1966, 5, 567. 5. (a) Ball, M.; Gaunt, M. J.; Hook, D. F.; Jessiman, A. S.; Kawahara, S.; Orsini, P.; Scolano, A.; Talbot, A. C.; Tanner, H. R.; Yamanoi, S.; Ley, S. V. Angew. Chem., Int. Ed. 2005, 44, 5433. (b) Paterson, I.; Chen, D. Y.-K.; Coster, M. J.; Acena, J. L.; Bach, J.; Gibson, K. R.; Keown, L. E.; Oballa, R. M.; Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.; Norcross, R. D. Angew. Chem., Int. Ed. 2001, 40, 4055. (c) Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang, L.; McBriar, M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama, K.; Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 191. (d) Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 187. 6. (a) Cowden, C. J.; Paterson, I. In Organic Reactions; Paquette, L. A., Ed.; John Wiley and Sons: New York, 1997; Vol. 51, pp 1–200. (b) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stat, T. J. J. Am. Chem. Soc. 1990, 112, 7001. 7. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T. Angew. Chem., Int. Ed. 2007, 46, 1066.
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