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The Nature of Persistent Conformational Chirality, Racemization Mechanisms, and Predictions in Diarylether Heptanoid Cyclophane Natural Products
Pattawong, O., Salih, M. Q., Rosson, N. T., Beaudry, C. M., & Cheong, P. H. Y. (2014). The nature of persistent conformational chirality, racemization mechanisms, and predictions in diarylether heptanoid cyclophane natural products. Organic & Biomolecular Chemistry, 12(20), 3303-3309. doi:10.1039/c3ob42550a
10.1039/c3ob42550a
Royal Society of Chemistry
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This journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00 | 1
The Nature of Persistent Conformational Chirality, Racemization Mechanisms, and Predictions in Diarylether Heptanoid Cyclophane Natural Products† Ommidala Pattawong, M. Quamar Salih, Nicholas T. Rosson, Christopher M. Beaudry* and Paul Ha-Yeon Cheong* 5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x
Restricted rotations of chemical bonds can lead to the presence of persistent conformational chirality in molecules lacking stereocenters. We report the development of first-of-10
a-kind predictive rules that enable identification of conformational chirality and prediction of racemization barriers in the diarylether heptanoid (DAEH) natural products that do not possess stereocenters. These empirical rules-of-thumb are based on quantum mechanical 15
computations (SCS-MP2/∞//B3LYP/6-31G*/PCM) of racemization barriers of four representative DAEHs. Specifically, the local symmetry of ring B and the E/Z configuration of the vinylogous acid/ester are critical in determining conformational chirality in the DAEH natural 20
product family.
Molecular chirality is of paramount importance to chemistry, biology, and medicine.1 Small molecules that are chiral by virtue of restricted rotations (atropisomerism), or conformational chirality, are an underdeveloped territory with the potential for 25
new developments of chiral ligands, medicinal compounds, catalysts, and materials. At present, there are no known methods to predict the presence of persistent conformational chirality in these compounds based solely on their molecular architecture without resorting to total synthesis.2,3 Specifically in this report, 30
we have developed predictive rules-of-thumb for the chiral properties of all members in a family of cyclophane natural products called the diarylether heptanoids (DAEHs). Additionally, we elucidate the atomistic and energetic details related to the racemizations. 35
Ket
one/
Este
r Ans
a B
ridge
w
ith U
nsub
stitu
ted
Rin
g B
Viny
logo
us A
cid/
Este
r A
nsa
Brid
ge
O
O
HO
Acerogenin L
OHO
O
Acerogenin C
Ovalifoliolatin B
O
MeO
O
HO
Galeon
O
HO
O
HO
Pterocarine
O
MeO
O
HO
OHMyricatomentogenin
Jugcathanin
O
MeO
O
MeO
OH
O
O
MeO
OMe
O
O
MeO
HO
Garugamblin I
9'-Desmethylgarugamblin I
O
O
O
OMeO
Garugamblin IIO
O
MeO
OMe
MeO
Garuganin I
O
OOMe
MeO
Garuganin IV (reported structure)
O
O
MeO
HOHO
Garuganin VIIO
OMe
MeO
OMeO
Garuganin IIIO
OMe
MeO
O
Garuganin III model
Ket
one
Ans
a B
ridge
w
ith S
ubst
itute
d R
ing
B
A
B
3
4 5
6
2 1
7 8
9 10
11 12
1314
1516
17
18 19
OMeO
O
OHO
Tedarene A
(1,9'-Didesmethylgaruganin III)
Figure 1. All members in the family of diarylether heptanoids (DAEHs). The five representative DAEHs studied are in boxes.
DAEHs are characterized by oxa[1.7]metaparacyclophane molecular architecture (Figure 1).4 We (CMB and MQS) recently prepared the DAEHs that lack stereocenters and showed that 40
some (but not all) are chiral.5 To the best of our knowledge, the
presence of conformational chirality in these natural products cannot be predicted without resorting to total synthesis. In addition, determining the mechanism of racemization proved to be challenging even with the natural compound in hand. We 45
2 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
believed that we could address both challenges through computations of four model DAEHs. The four model DAEHs are expected to be representative of similar members of the family because DAEHs that have similar structure type (e.g. the vinylogous acids) were found experimentally to have nearly 5
identical racemization barriers. We discovered that the complete stereoisomerization of a DAEH requires torsional rotations of all the stereogenic functional groups. The number of possible rotational sequences is equal to the factorial of the number of stereogenic groups in a 10
given DAEH. Therefore, all intermediates and transition structures (TSs) for all possible sequences have been computed for each of the DAEHs discussed at SCS-MP26/def2-∞7 // B3LYP8/6-31G*9 /PCM (dichlorobenzene)10 level of theory.11
Of four representative DAEHs, acerogenin L most closely 15
resembles the parent DAEH structure. There are two substituents: OH at C2 and O at C9. The complete racemization of acerogenin L requires the rotations of 3 stereogenic functional groups: C7–C8, C9O, and C11–C12. There are a total of 3! (6) stereoisomerization pathways for acerogenin L; all were 20
computed (Figure 2, B).
A)
B)
The Minimum Energy Pathway for the Racemization of Acerogenin L
6 Possible Pathways for the Racemization of Acerogenin L
Inta, ∆G = 3.7 Intb, ∆G = 5.6 Intc, ∆G = 2.6
TSc∆G ‡ = 8.8
TSc→
cb
∆G‡ = 6.1
TScb→
cba
∆G‡ =
7.8
TSc→
ca
∆G‡ = 13.8
TSca→
cab
∆G‡ =
7.0
TSb
∆G‡ = 8.0
TSb→
bc
∆G‡ = 12.7TS
b →ba
∆G‡ =
13.
3
TSba→
bac
∆G‡ = 8.8 TS
bc→
bca
∆G‡ =
9.4
TSa
∆G‡ = 12.7
TSa→
ab∆G
‡ = 6
.6
TSa →
ac∆G
‡ = 8
.5
TSab→abc
∆G ‡ = 9.9
TSac→
acb
∆G ‡ = 6.6
O
O
HOAcerogenin L
acerogenin L
∆G (k
cal/m
ol)
2.6
TScRotation
8.8TSc→cb
Rotation6.1
TScb→cbaRotation
7.8
rxn progress
TSc Rotation (RDS)
1.9
ent-acerogenin L
7 89 10
11 12
0.0 0.0
2.52.7 2.3
2.2
a bc
a bc
Acerogenin L∆G = 0.0
ent-Acerogenin L∆G = 0.0
O
O
HO
O
O
HO
7 89 10
11 12
Intab∆G = 2.0
Intac∆G = 2.0
Intba∆G = 2.0
Intbc∆G = 3.7
Intca∆G = 5.6
Intcb∆G = 1.9
Figure 2.12,13 A) The minimum energy path and the RDS for racemization
of acerogenin L. B) Six possible racemization pathways.
The minimum energy pathway for racemization is shown in 25
Figure 2 (A, B in black). Specifically, the sequence of rotation is: i) C11–C12 (∆G‡ = 8.8 kcal/mol); ii) C9O (∆G‡ = 6.1 kcal/mol); iii) C7–C8 (∆G‡ = 7.8 kcal/mol). The rate-determining step (RDS) is the C11–C12 rotation with a half-life (t1/2) of 3.15 x 10-7 s at 25 ºC
(in the box, Figure 2). From these barriers, we predict that 30
acerogenin L is achiral – the enantiomeric conformations racemize rapidly under ambient conditions. The experimental racemization barrier measured at –60 ºC is ≤ 10.5 kcal/mol. Consistent with experiments, the predicted barrier at –60 ºC is 8.6 kcal/mol or t1/2 = 1.03 x 10-4 s.5 35
Galeon differs from acerogenin L by virtue of a C16 methoxy substituent. The chiral properties of galeon are representative of all DAEHs with substituents on ring B. This substitution now renders ring B a stereogenic functional group; therefore, there are a total of 4! (24) stereoisomerization pathways for galeon. All 24 40
racemization pathways for galeon were computed (Figure 3, B). The minimum energy pathway for racemization is shown in Figure 3 (A, B in black). The racemization of galeon begins with the rotation of the facile rotations of the C11–C12, followed by C9O and C7–C8 functional groups (∆G‡ = 8.8, 6.6 and 8.7 45
kcal/mol, respectively), and finally followed by ring B (∆G‡ = 45.2 kcal/mol at 25 ºC, t1/2 = 1.52 x 1020 s, RDS). The high computed barrier of ring B rotation suggests that galeon is conformationally chiral under ambient conditions – in fact, the computed barrier at 201 ºC is an enormous 46.4 kcal/mol (t1/2 = 50
1.71 x 108 s). This value agrees with the experimental data (∆G‡ = 39.6 ± 0.6 kcal/mol).5 The large barrier of ring B rotation in galeon (∆G‡ = 45.2 kcal/mol, Figure 3, A) is due to a gearing mechanism.14 Specifically, the rotation causes trans-annular strain between aryl 55
hydrogens (H18 and H19) and H6 and H11. It is important to note that the ring B rotational barrier for acerogenin L is identical to that of galeon – the trans-annular strain exists in the rotation of ring B in acerogenin L as well. However, ring B in acerogenin L is symmetric, and the racemization does not require its rotation. 60
Only in galeon, where ring B is substituted, does the racemization require ring B rotation. We next turned our attention to DAEHs with unsaturation in the ansa chain. It was apparent after consideration of the NMR spectra of these molecules that they have markedly different 65
racemization rates;5b however, the nature of these differences was not obvious to us. Specifically, DAEHs with E-configured vinylogous esters racemized slowly on the NMR timescale, but DAEHs with vinylogous acids or Z-configured vinylogous ester racemized quickly on the NMR timescale. Interestingly, 9’-70
desmethylgarugamblin I, possessing a vinylogous acid in the ansa chain has different ground state geometric preferences compared to garuganin III, with a vinylogous ester ansa chain. There are a total of five tautomers of 9’-desmethylgarugamblin I (Figure 4): keto, C9-E, C11-E, C9-Z and C11-Z. The designations 75
C9 and C11 describe the position of the carbonyl, and Z/E define the stereochemistry of the vinylogous acid. The Z- are more stable than the E-isomers by ~8–10 kcal/mol, most likely due to the presence of stabilizing H-bonding interaction between the enol and the carbonyl. In fact, our model systems show that 80
almost all the stability differences between the E- and the Z-tautomers arise from the stability of the intramolecular hydrogen bond in the Z (Figure 5). The classical hydrogen bonding interactions present in the Z-isomer, is favored over non-classical hydrogen bonding CH···O interactions present in E-isomers, by 85
8.6 kcal/mol.
This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 3
Me Me
O OH
Z-isomer∆G = 0.0
E-isomer∆G = 8.6
Me
OH
O
Me
Figure 5.13 Magnitude of stabilization from the intramolecular hydrogen bonding in 9’-desmethylgarugamblin I
Galeon∆G = 0.0
Intab, ∆G = 3.4 Intac, ∆G= 4.6 Intad, ∆G= 2.6
Intabc, ∆G=0.7
Intabd, ∆G=2.2
Intacb, ∆G=0.7
Intacd, ∆G=5.8
Intadb, ∆G=3.4
Intadc, ∆G=5.8
TSa→ad
∆G ‡ = 63.4TS
ad→adc
∆G ‡ = 13.9
TSad
c→ad
cb
∆G‡ =
7.6
TSad→
adb
∆G‡ = 6.6
TSad
b→ad
bc∆G
‡ = 1
4.3
TSa→ac
∆G‡ = 12.9
TSac→
acd
∆G‡ = 62.7TS
ac→
acb
∆G‡ =
6.9
TSacb
→acbd
∆G‡ = 45.2 TS
acd →
acdb
∆G‡ =
6.9
TSa→ab
∆G‡ = 6.0
TSab→
abc
∆G‡ =
13.
7TS
ab→
abd
∆G‡ =
50.
9
TSabc→abcd
∆G ‡ = 45.2
TSabd→
abdc
∆G ‡ = 14.3ent-Galeon∆G = 0.0
Inta, ∆G = 2.0
TSa∆G‡ = 7.5
c Rotation First Path d Rotation First Path
a Rotation First Path b Rotation First Path
TScbc→cbad(RDS)
GaleonO
O
HOMeO
7 8
9 10
11 12
B
A
18 19
ent-Galeon
O
O
HO B
A
MeO
A)
B)
2.2
2.12.9
2.82.1
2.62.9
a bc
d
0.0galeon
∆G (k
cal/m
ol)
ent-galeon
2.4 2.6 0.7
TScba→cbadRotation
45.2TSc
Rotation8.8
TSc→cbRotation
6.6
TScb→cbaRotation
8.6
rxn progress0.0
GaleonO
O
HOMeO
7 8
9 10
11 12
B
A
18 19
a bc
d
d R
otat
ion
Firs
t Pat
h
b R
otat
ion
Firs
t Pat
h
c R
otat
ion
Firs
t Pat
h
a R
otat
ion
Firs
t Pat
h
The Minimum Energy Pathway for the Racemization of Galeon
24 Possible Pathways for the Racemization of Galeon
Galeon∆G = 0.0
Intba, ∆G = 2.7 Intbc, ∆G= 2.6 Intbd, ∆G= 3.9
Intbac, ∆G=0.7
Intbad, ∆G=2.2
Intbca, ∆G=0.7
Intbcd, ∆G=2.0
Intbda, ∆G=2.2
Intbdc, ∆G=2.0
TSb→bd
∆G ‡ = 58.5
TSbd→
bdc
∆G ‡ = 17.1
TSbd
c→bd
ca
∆G‡ =
7.5
TSbd→
bda
∆G‡ = 11.5
TSbd
a→bd
ac∆G
‡ = 1
5.3
TSb→bc
∆G‡ = 17.6
TSbc→
bcd
∆G‡ = 52.1TS
bc→
bca
∆G‡ =
8.6
TSbca
→bcad
∆G‡ = 45.3 TS
bcd →
bcda
∆G‡ =
7.5
TSb→ba
∆G‡ = 13.4
TSba→
bac
∆G‡ =
7.2
TSba→
bad
∆G‡ =
50.
9
TSbac→bacd
∆G ‡ = 45.2
TSbad→
badc
∆G ‡ = 15.3
ent-Galeon∆G = 0.0
Intb, ∆G = 5.9
TSb∆G‡ = 7.3
Galeon∆G = 0.0
Intca, ∆G = 4.6 Intcb, ∆G= 2.6 Intcd, ∆G= 3.4
Intcab, ∆G=0.7
Intcad, ∆G=5.8
Intcba, ∆G=0.7
Intcbd, ∆G=2.0
Intcda, ∆G=5.9
Intcdb, ∆G=2.0
TSc→cd
∆G ‡ = 50.6
TScd→
cdb
∆G ‡ = 5.8
TScd
b→cd
ba
∆G‡ =
7.5
TScd→
cda
∆G‡ = 13.9
TScd
a→cd
ab∆G
‡ = 7
.3
TSc→cb
∆G‡ = 6.6
TScb→
cbd
∆G‡ = 52.1TS
cb→
cba
∆G‡ =
8.6
TScba
→cbad
∆G‡ = 45.2 TS
cbd →
cbda
∆G‡ =
7.5
TSc→ca
∆G‡ = 12.4
TSca→
cab
∆G‡ =
6.9
TSca→
cad
∆G‡ =
62.
7
TScab→cabd
∆G ‡ = 45.2
TScad→
cadb
∆G ‡ = 7.6
ent-Galeon∆G = 0.0
Intc, ∆G = 2.4
TSc∆G‡ = 8.8
Galeon∆G = 0.0
Intda, ∆G = 2.6 Intdb, ∆G= 4.6 Intdc, ∆G= 3.4
Intdab, ∆G=2.4
Intdac, ∆G=5.8
Intdba, ∆G=2.4
Intdbc, ∆G=2.0
Intdca, ∆G=5.9
Intdcb, ∆G=2.0
TSd→dc
∆G ‡ = 9.4
TSdc→
dcb
∆G ‡ = 6.0
TSdc
b→cd
ba
∆G‡ =
7.5
TSdc→
dca
∆G‡ = 13.9
TSdc
a→dc
ab∆G
‡ = 7
.3
TSd→db
∆G‡ = 6.9
TSdb→
dbc
∆G‡ = 17.1TS
db→
dba
∆G‡ =
12.
4
TSdba
→dbac
∆G‡ = 14.3 TS
dbc →
dbca
∆G‡ =
7.5
TSd→da
∆G‡ = 12.7
TSda→
dab
∆G‡ =
6.8
TSda→
dac
∆G‡ =
13.
9
TSdab→dabc
∆G ‡ = 14.3
TSdac→
dacb
∆G ‡ = 7.6
ent-Galeon∆G = 0.0
Intd, ∆G = 0.7
TSd∆G‡ = 45.2
Figure 3.12,13 A) The minimum energy path and the RDS for racemization of galeon. B) Twenty four possible racemization pathways. 5
O
O
MeO
O
keto tautomer∆G = 2.6
O
OHO
MeO
H
C9-E tautomer∆G = 8.4
O
HO
MeO
O
H
C11-E tautomer∆G = 10.6
O
O
MeO
OO
O
MeO
O
H H
C11-Z tautomer∆G = 0.8
C9-Z tautomer∆G = 0.0
H H
2.5
2.5
2.7
2.5
2.6
2.5
2.5 2.2
3.2 2.7
2.5
3.7
2.3
3.22.8
3.11.6
3.2 2.8
2.5
3.21.6
2.9
2.5
3.3
Figure 4.13b Five tautomers of 9’-desmethylgarugamblin I.
4 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
O
Me
H
OMeMeO∆Hinteraction = –0.6 ∆Hinteraction = -0.1
Me
O
MeO
∆Hinteraction = –0.7 ∆Hinteraction = 0.6
Me
Me
Models for C9-(E/Z)- 9'-desmethylgarugamblin I
A
B
O
O
MeO
OH
H
A
B O
HO
MeO
O
H
A
B
(E/Z) (E/Z)
HO
Me
H
OMeMeOMe
O
MeO
A
B
H
6
1513
9
11
6
1513
9
11
6
13
156
13
15
MeMe
Models for C11-(E/Z)- 9'-desmethylgarugamblin I
H2C
H H
CH2
Figure 6. Comparison of strengths of CH···O-ketone/enol interactions, and C6H/C15H···O interactions found in tautomers of 9’-desmethylgarugamblin I.
A)
B)
The Minimum Energy Pathways for the Racemization of C9-E-9'-Desmethylgarugamblin I
6 Possible Pathways for the Racemization of C9-E-9'-Desmethylgarugamblin I
Inta, ∆G = 9.6 Intb, ∆G = 15.0
TSb∆G ‡ = 20.8
TSb→bc
∆G‡ = 31.0
TSb→ba
∆G ‡ = 21.2TSa
∆G‡ = 19.3
TS a→ab
∆G‡ =
44.5
TSab→abc
∆G ‡ = ?
TSa→
acb
∆G‡ = 48.6
∆G = 8.4
Intab∆G = 15.0
C9-Z tautomer
8.48.4C9-E tautomer
0.0
∆G (k
cal/m
ol)
24.6
TScRotation
33.2TSc→ca
Rotation26.2
TSca→cabRotation
18.1
rxn progress9.6
TSc Rotation (RDS)
ent-C9-E tautomer
2.5 3.22.2 3.0
3.3146.5ºC9-E 9'-Desmethyl
garugamblin I
O
OHO
MeO
H7 8
9 1011
12
1314
ab
c
C9-E 9'-Desmethyl
garugamblin I
∆G = 8.4
ent-C9-E 9'-Desmethyl
garugamblin I
O
OHO
MeO
H7 8
9 1011
12
1314
O
O
MeOOHH
a b
c
Intc, ∆G = 24.6
TSc
∆G‡ = 33.2
TSc→cb
∆G‡ = 20.8TSc→
ca
∆G‡ =
26.
2
TSca→
cab
∆G ‡ = 18.3
Intca∆G = 9.6
Figure 7.12,13 A) The minimum energy path and RDS for racemization of C9-E-9`-desmethylgarugamblin I. B) Six possible racemization pathways. 5
There is a subtle energetic preference for the C9-regioisomers compared to the C11-regioisomeric vinylogous acid (~1–2 kcal/mol). We originally hypothesized that this is most likely due to the stronger CH···O interactions15,16 between H6 and C9
carbonyl O. Our model system study shows that the ketone 10
oxygen and enol oxygen are similar hydrogen bonding accepters (Figure 6). We thus conclude that the majority of the energetic preference for the C9/C11 arises from subtle conformational and interaction changes from being constrained in a ring.
A)
B)
The Representative Minimum Energy Pathway for the Racemization of C9-Z-9'-Desmethylgarugamblin I
5 Possible Pathways for the Racemization of C9-Z-9'-Desmethylgarugamblin I
Inta, ∆G = 1.9 Intc, ∆G = 4.6
TSc∆G ‡ = 6.0
TSc→
cb
∆G‡ = 9.6
TScb→
cba
∆G‡ =
8.4
TSc→
ca
∆G‡ = 8.4
TSca→
cab
∆G‡ =
9.6
TSbc
∆G‡ = 13.3
TSbc→bca
∆G‡ = 8.4
TSa
∆G‡ = 8.4
TSa→
ab∆G
‡ = 9
.6
TSa →
ac∆G
‡ = 9
.6
TSab→abc
∆G ‡ = 6.0
TSac→
acb
∆G ‡ = 6.0
∆G = 0.0
Intab∆G = 4.6
Intac∆G = 4.6
Intbc∆G = 1.9
Intca∆G = 1.9
Intcb∆G = 1.9
C9-Z 9'-Desmethylgarugamblin I
O
O
MeO
OH
H7 89
1011
12
1314
O
O
MeO
OHH
ent-C9-Z 9'-Desmethylgarugamblin I∆G = 0.0
a b
O
O
MeO
OH
H
C9-Z tautomer
∆G (k
cal/m
ol)
4.6
TScRotation
6.0
TSc→cbRotation
9.6
TScb→cbaRotation
8.4rxn rrogress1.9
ent-C9-Z tautomer
TSc→cb Rotation (RDS)
7 89
1011
12
13
0.0 0.0
6
14
1.6
2.0168.9º
C9-Z 9'-Desmethylgarugamblin I
ca b
c
15
Figure 8.12,13 A) The representative minimum energy path and RDS for racemization of C9-Z-9`-desmethylgarugamblin I. B) Five possible
racemization pathways.
A total of 3! (6) stereoisomerization pathways for the C9-E tautomers of 9’-desmethylgarugamblin I were computed. 20
Surprisingly, only 3 pathways lead to the complete racemization (Figure 7, B). The introduction of an olefin in the ansa chain causes the barrier for functional group rotation to increase dramatically. In particular, TSbèba, TSbèbc and TScècb transition states caused the molecule to revert back (TSbèba) to the ground 25
state or in the latter cases (TSbèbc and TScècb), these led to unproductive isomerization pathways that do not result in racemization due to coupled rotational motions of several functional groups. The minimum energy pathway for racemization is shown in 30
This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 5
Figure 7 (A, B in black). The sequence of rotation is: i) C10-13 (∆G‡ = 33.2 kcal/mol); ii) C7–C8 (∆G‡ = 26.2 kcal/mol); iii) C9O (∆G‡ = 18.3 kcal/mol). The rate-determining step (RDS) is the C10-13 rotation with a half-life (t1/2) of 2.43 x 1011 s at 25 ºC.
A)
B)
The Minimum Energy Pathway for the Racemization of C9-E-Garugamblin I
6 Possible Pathways for the Racemization of C9-E-Garugamblin I
Inta, ∆G = 1.0 Intb, ∆G = 7.7 Intc, ∆G = 15.9
TSc∆G ‡ = 23.8
TSc→
cb
∆G‡ = 17.7
TScb→
cba
∆G‡ =
9.9
TSc→
ca
∆G‡ = 12.3
TSca→
cab
∆G‡ =
9.9
TSb
∆G‡ = 12.9
TSb →
ba∆G
‡ = 1
1.1
TSba→
bac
∆G‡ = 23.8
TSb→
bca
∆G‡ = 23.8
TSa
∆G‡ = 10.7
TSa→
ab∆G
‡ = 1
0.7
TSab→abc
∆G ‡ = 22.4
TSa →
acb
∆G‡
= 18
.1
∆G = 0.0
Intab∆G = 7.7
Intba∆G = 7.2
Intca∆G = 1.0
Intcb∆G = 1.0
∆G = 0.0
C9-E -Garugamblin I
ent-C9-E 9'-Garugamblin I
O
OMeO
MeO
H7 8
9
1011
12
1314
O
O
MeO
OMeH
ab
c
C9-E isomer
∆G (k
cal/m
ol)
1.0
TSa→abc Rotation18.1TSa Rotation
10.7rxn progress0.0
ent-C9-E isomer
TSa→abc Rotation (RDS)
0.0
2.72.2
3.2 3.0169.0º
C9-E -Garugamblin I
O
OMeO
MeO
H7 8
9
1011
12
1314
ab
c
5
Figure 9.12,13 A) The minimum energy path and RDS for racemization of C9-E-garugamblin I. B) Six possible racemization pathways.
The complete racemization processes of the more stable C9-Z tautomers of 9’-desmethylgarugamblin I requires the rotations of 3 stereogenic functional groups: C7–C8, C9-C10, and C12–C13. 10
Theoretically, there should be a total of 3! (6) stereoisomerization pathways for C9-Z tautomers. However, computations showed that the process of C9-C10 first rotation is simultaneous with the rotation of C12-C13. Therefore, there are total of five stereoisomerization pathways for C9-Z-9’-desmethylgarugamblin 15
I (Figure 8, B). Interestingly, there are four equivalent minimum energy pathways found for this process (Figure 8, B in black). The representative minimum energy path is shown in Figure 7, A. The rotation of C12-C13 is found to be a common RDS for all minimum energy pathways with ∆G‡ = 9.6 kcal/mol or t1/2 = 1.22 20
x 10-6 s at 25 ºC. The predicted barrier at -80 ºC is 8.8 kcal/mol, or t1/2 = 1.56 x 10-3 s. This value agrees well with the experimental data (∆G‡ = 9.1 kcal/mol or t1/2 = 3.3 x 10-3 s at -80 ºC). Surprisingly, the racemization barrier of C9-E tautomer of 9’-25
desmethylgarugamblin I is higher than the C9-Z by 23.6 kcal/mol (Figures 7 and 8, respectively). In effect, the C9-E vinylogous acids are locked in one regiomeric and diastereomeric conformation and undergo racemization with a higher barrier than
the vinylogous acids, which can exist in the C9-Z configuration. 30
This larger barrier comes from the geometric distortions sustained by the macrocycle in the E-isomer, as seen by the greater C14 out-of-plane distortion in the RDS (146.5º compared to 168.9º). Since the keto-enol tautomers depicted in Figure 4 are in equilibrium, the molecule will racemize via the reaction 35
coordinate with lowest available transition state. The lowest barrier is the C9-Z tautomer. The calculated barrier corresponds closely with the experimental value. Lastly, we investigated the vinylogous ester DAEHs. Specifically, garugamblin I and its three vinylogous ester isomers 40
were considered.17 Again, the designations C9 and C11 describe the position of the carbonyl, and Z/E define the stereochemistry of the vinylogous ester. Unlike 9’-desmethylgarugamblin I, the Z-stereoisomers of garugamblin I are less stable than the E by ~4–6 kcal/mol due to the inherent steric repulsions in the Z-vinylogous 45
ester. In fact, the Z-conformer is significantly distorted from planarity by ~20º.17 Similar to the 9’-desmethyl analogue, C9-E/Z tautomers are more stable than C11-E/Z tautomers due to stronger CH···O interactions between H6 and C9O.
A)
B)
The Representative Minimum Energy Pathway for the
Racemization of C11-E-Garugamblin I
6 Possible Pathways for the Racemization of C11-E-Garugamblin I
Inta, ∆G = 3.9 Intb, ∆G = 8.6 Intc, ∆G = 1.0
TSc∆G ‡ = 3.5
TSc→
cb
∆G‡ = 15.0
TScb→
cba
∆G‡ =
15.
8
TSc→
ca
∆G‡ = 14.4
TSca→
cab
∆G‡ =
14.
6TSb
∆G‡ = 14.6
TSb→
bc
∆G‡ = 11.2TS
b →ba
∆G‡ =
14.
4
TSba→
bac
∆G‡ = 3.5 TS
bc→
bca
∆G‡ =
15.
8
TSa
∆G‡ = 5.3
TSa →
ac∆G
‡ = 6
.9
TSac→
acb
∆G‡ = 14.6
TSa →
abc
∆G‡
= 14
.6
∆G = 0.0
Intac∆G = 4.8
Intba∆G = 1.0
Intbc∆G = 6.9
Intca∆G = 8.6
Intcb∆G = 6.9
0.0
ent-C11-E isomer
0.0C11-E isomer
∆G (k
cal/m
ol)
TSa Rotation5.3
TSa→abc Rotation14.6
rxn progress3.9
TSa→abc Rotation (RDS)
161.7º
2.72.22.1
C11-E -Garugamblin I
O
MeO
MeO
O
H
7 89 10 11
12
14
ab c
C11-E -Garugamblin I
O
MeO
MeO
O
H
7 89 10 11
12
14
ab c
∆G = 0.0ent-C11-E 9'-Garugamblin I
O
MeO
MeO
O
H
50
Figure 10.12,13 A) The representative minimum energy path and RDS for racemization of C11-E-garugamblin I. B) Six possible racemization
pathways.
All stereoisomerization pathways for the C9-Z and C9-E isomers of garugamblin I were computed. Interestingly, the 55
minimum energy pathway for the racemization of C9-E isomer involves simultaneous rotations of C9O and C10-13 (Figure 9, B in
6 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
black). Consequently, the complete racemization of the C9-E isomer only requires two steps: C7-C8 and C10-13 rotations. The C10–13 rotation is the RDS (∆G‡ = 18.1 kcal/mol, t1/2 = 2.1 s at 25 ºC, Figure 9, A). This value is consistent with the experimental value (∆G‡ = 16.9 kcal/mol, t1/2 = 3.0 x 10-1 s at 25 ºC). For the 5
racemization of C9-Z isomer, the vinylogous ester rotation is the RDS (∆G‡ = 13.8 kcal/mol, t1/2 = 1.46 x 10-3 s at 25 ºC).17 We predict that garugamblin I, isolated as the C9-E isomer, would racemize at room temperature on the time scale of seconds. A total of 3! (6) pathways for complete racemization of C11-E 10
tautomer of garugamblin I were computed (Figure 10, B). Two minimum energy pathways are found for this process. The representative of minimum energy pathways is shown in Figure 10, A. Both asynchronous (TSabèabc) and synchronous (TSaèabc) rotations of the vinylogous ester are the RDS with the barrier of 15
14.6 kcal/mol, or t1/2 = 5.63 x 10-3 s at 25 ºC (at -10 ºC, ∆G‡ = 14.1, or t1/2 = 6.5 x 10-2 s). The experimental values for the C11-E tautomer of garugamblin I are ∆G‡ = 12.7 kcal/mol, t1/2 = 4.4 x 10-3 s at –10 ºC. Molecules with this structure type (such as garuganin III) undergo racemization rapidly at room temperature. 20
O
DAEH Architecture
A
B
3
4 5
6
2 1
7 89 10
1112
1314
151617
18 19
Local Symmetry on Ring B
Yes No
∆G‡ ≈ 45Vinylogous Acid
Yes NoVinylogous Ester
Yes
∆G‡ ≈ 9
Z E Z E
∆G‡ ≈ 10 ∆G‡ ≈ 33 ∆G‡ ≈ 14 C11OC9O
∆G‡ ≈ 18 ∆G‡ ≈ 15 Figure 11.13b Predicted barriers for racemization of conformational
chirality of the four representative diarylether heptanoids used to deduce the data. ∆G‡ are in kcal/mol.
Conclusions 25
In conclusion, quantum mechanical computations predict the barriers of racemization for the four representative DAEHs in good agreement with experiments. These have led to the development of a predictive method that enables the identification of persistent conformational chirality and first order 30
rules-of-thumb prediction of racemization barriers of all DAEHs that do not possess stereocenters (Figure 11). The local symmetry of ring B and the E/Z configuration of the vinylogous acid/ester are critical in determining molecular conformational chirality in the DAEH natural product family. 35
Notes and references Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon, 97331-4003, USA. E-mail: [email protected], [email protected]; Tel: +1 5417376760 40
† Electronic Supplementary Information (ESI) available: Coordinates, energies, additional figures, and full authorship of Gaussian. See DOI: 10.1039/b000000x/
1 E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic Compounds WILEY, 1994.
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3 Previously, molecular mechanics computational study of garuganin I using MMP2 forcefield suggested the molecule existed in single enantiomeric conformation at rt. see: Beyer, A.; Kalchhauser, H.; Wolschann, P. Monatsh. Chem. 1992, 123, 417–423. Experimentally, we found this to be inaccurate, see ref. 5b. Computational data presented in this work using quantum mechanics (SCS-MP2/B3LYP) agrees with experimental findings.
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17 Please see Electronic Supplementary Information (ESI).
