Ene reaction of singlet oxygen, triazolinedione, and nitrosoarene with chiral deuterium-labeled allylic alcohols: The interdependence of diastereoselectivity and regioselectivity discloses mechanistic insights into the hydroxy-group directivity

Article abstract of DOI:10.1021/ja027800p

The ene reaction of singlet oxygen (¹O₂), triazolinedione (TAD), and nitrosoarene, specifically 4-nitronitrosobenzene (ArNO), with the tetrasubstituted 1,3-allylically strained, chiral allylic alcohol 3,4- dimethylpent-3-en-2-ol (2)

Full text of DOI:10.1021/ja027800p

Published on Web 11/12/2002
Ene Reaction of Singlet Oxygen, Triazolinedione, and
Nitrosoarene with Chiral Deuterium-Labeled Allylic Alcohols:
The Interdependence of Diastereoselectivity and
Regioselectivity Discloses Mechanistic Insights into the
Hydroxy-Group Directivity
Waldemar Adam,† Nils Bottke,† Oliver Krebs,*,† Ioannis Lykakis,‡
Michael Orfanopoulos,‡ and Manolis Stratakis‡
Contribution from the Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg,
Am Hubland, D-97074 Wu¨rzburg, Germany, and Department of Chemistry, UniVersity of Crete,
P.O. Box 1470, 71409 Iraklion, Crete, Greece
Received July 22, 2002
Abstract: The ene reaction of singlet oxygen (1O2), triazolinedione (TAD), and nitrosoarene, specifically
4-nitronitrosobenzene (ArNO), with the tetrasubstituted 1,3-allylically strained, chiral allylic alcohol 3,4-
dimethylpent-3-en-2-ol (2) leads to the threo-configured ene products in high diastereoselectivity, a
consequence of the hydroxy-group directivity. Hydrogen bonding favors formation of the threo-configured
encounter complex threo-EC in the early stage of ene reaction. For the analogous twix deuterium-labeled
allylic alcohol Z-2-d3, a hitherto unrecognized dichotomy between 1O2 and the ArNO and TAD enophiles is
disclosed in the regioselectivity of the tetrasubstituted alcohol: Whereas for ArNO and TAD, hydrogen
1
bonding with the allylic hydroxy group dictates the regioselectivity (twix selectivity), for O2, the cis effect
dominates (twin/trix selectivity). From the interdependence between the twix/twin regioselectivity and the
threo/erythro diastereoselectivity, it has been recognized that the enophile also attacks the allylic alcohol
from the erythro π face without assistance by hydrogen bonding with the allylic hydroxy functionality.
Scheme 1. Diastereoselectivities in the Ene Reaction of 1O2,
Introduction
TAD, and ArNO with 1,3-Allylically (1,3A) Strained Chiral Allylic
The ene reaction of singlet oxygen (1O2),1 triazolinedione
(TAD),2 and nitrosoarene, particularly 4-nitronitrosobenzene
(ArNO),1e,3 with 1,3-allylically strained chiral substrates leads
to threo-configured ene products in high diastereoselectivity, a
consequence of the hydroxy-group directivity.4 Because of 1,3-
allylic strain, the hydroxy group is conformationally aligned
toward the threo face of the double bond. Effective hydrogen
bonding with the incoming enophile leads preferably to the
threo-configured ene product (Scheme 1).
Alcohols Controlled by Hydroxy-Group Directivity
* To whom correspondence should be addressed. E-mail: adam@
chemie.uni-wuerzburg.de. Fax: +49-(0)931/888-4756. http://www-organi-
k.chemie.uni-wuerzburg.de/ak_adam/.
† Universita¨t Wu¨rzburg.
‡ University of Crete.
(1) (a) Adam, W.; Nestler, B. J. Am. Chem. Soc. 1993, 115, 5041-5049. (b)
Adam, W.; Bru¨nker, H. G. J. Am. Chem. Soc. 1995, 117, 3976-3982. (c)
Adam, W.; Bru¨nker, H.-G.; Kumar, A. S.; Peters, E.-M.; Peters, K.;
Schneider, U.; von Schnering, H. G. J. Am. Chem. Soc. 1996, 118, 1899-
1905. (d) Linker, T.; Fro¨hlich, L. J. Am. Chem. Soc. 1995, 117, 2694-
2697. (e) Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 12, 1243-
1255. (f) Dussault, P. H.; Schultz, J. A. J. Org. Chem. 1999, 64, 8419-
8422.
The fact should be emphasized that through the control
exercised by the hydroxy-group directivity (the synergetic
interplay of allylic strain and hydrogen bonding), excellent
diastereoselectivities may be achieved for the nitrogen and
oxygen functionalization of chiral allylic alcohols. Such dias-
tereoselective metal-catalyzed and nonmetal-catalyzed, as well
as stoichiometric oxidations, are of current interest in view of
(2) (a) Adam, W.; Nestler, B.; Pastor, A.; Wirth, T. Tetrahedron Lett. 1998,
39, 2625-2629. (b) Stratakis, M.; Vassilikogiannakis, G.; Orfanopoulos,
M. Tetrahedron Lett. 1998, 39, 2393-2396. (c) Gau, A.-H.; Lin, G.-L.;
Uang, B.-J.; Liao, F.-L.; Wang, S.-L. J. Org. Chem. 1999, 64, 2194-2201.
(d) Singleton, D. A.; Hang, C. J. Am. Chem. Soc. 1999, 121, 11885-11893.
(e) Chen, J. S.; Houk, K. N.; Foote, C. S. J. Am. Chem. Soc. 1997, 119,
9852-9855. (f) Vassilikogiannakis, G.; Stratakis, M.; Orfanopoulos, M.
Org. Lett. 2000, 2, 2245-2248.
(3) Adam, W.; Bottke, N. J. Am. Chem. Soc. 2000, 122, 9846-9847.
(4) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710.
9
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J. AM. CHEM. SOC. 2002, 124, 14403-14409
14403

A R T I C L E S
Adam et al.
the synthetic value of selectively nitrogen- and oxygen-
functionalized products of allylic alcohols.4,5
sides of the double bond (twin/trix versus twix/lone) are more
comparable in Z-2-d3, such that steric effects should be more
moderate for the more imposing ArNO enophile; (ii) the allylic
hydrogen atoms of the trix-methyl group provide additional
coordination for the incoming enophile, which is of particular
consequence for the 1O2 enophile in view of the established cis
effect;9 (iii) the trix-methyl group foments 1,2-allylic strain (1,2A)
with the stereogenic lone site, in addition to the already existing
1,3-allylic strain (1,3A) between the twix and lone substituents,
which should affect the conformational alignment of the allylic
hydroxy functionality and in turn the efficiency of hydrogen
bonding with the enophile. Moreover, it should be noted that
the trix substituent generates another regioisomer as the ene
product but no additional diastereomers.
The chiral allylic alcohol in Scheme 1 only provides
stereochemical information through the ratio of threo- and
erythro-diastereomeric ene products. Unless the two geminal
methyl groups at the twin and twix positions are appropriately
differentiated through deuterium labeling, identical ene products
ensue, and regiochemical data are precluded. Hydrogen abstrac-
tion at the chirality center (lone position) takes place to such a
minor extent, that it is of no mechanistic relevance.1-3 This
shortcoming has recently been remedied by examining the
deuterium-labeled chiral allylic alcohol Z-1-d4. Indeed, valuable
Herein we report our unprecedented results on the diastereo-
selectivity and regioselectivity, as well as their interdependence,
for the ene reactions of the deuterium-labeled chiral allylic
1
alcohols Z-1-d4 and Z-2-d3 with the enophiles O2, PTAD (N-
phenyl-1,2,4-triazoline-3,5-dione), and ArNO. Because the
unlabeled tetrasubstituted allylic alcohol 2 has not been studied
for the three enophiles, these ene reactions have also been
conducted to isolate and fully characterize the ene products and
to assess their configuration. The interrelated stereochemical
and regiochemical data provide a detailed mechanistic account
of the enophilic reaction coordinate.
mechanistic insight has been obtained for this allylic substrate
on the diastereoselectivity and regioselectivity in its ene reaction
with 1O2 and TAD (data will be presented and discussed later,
see Figure 1).6 Such selectivity data are not available as yet for
the nitroso enophile, and it was of mechanistic importance to
determine the dependence of the twix/twin regioselectivities on
the threo/erythro diastereoselectivity for 4-nitronitrosobenzene
(ArNO) and compare the results with those of the 1O2 and TAD
enophiles. We have demonstrated previously the value of the
ArNO enophile as a mechanistic probe to map out the preferred
skew trajectory of enophilic attack, a consequence of its greater
Results
The reaction of 3,4-dimethylpent-3-en-2-ol (2) with all three
1
enophiles O2, PTAD, and ArNO proceeded smoothly and in
1
steric demand as compared to O2 and TAD.7 A particular
high yield (Table 1). The product distribution was determined
1
by H NMR spectroscopy directly on the reaction mixture in
incentive of this study was to assess the efficiency of the allylic
hydroxy group to control regioselectivity and diastereoselectivity
(hydroxy-group directivity) of the ArNO ene process.
deuterated solvents. Additionally, preparative runs were con-
ducted, and all ene products were isolated and fully characterized
(see the Supporting Information).
In this context, conspicuous is the fact that for none of the
For 1O2 and PTAD, in addition to the expected gem
regioisomers (abstraction at the twix and twin positions), the
diastereomeric ene products gem-3(threo) and gem-3(erythro),
also hydrogen abstraction at the trix position8 takes place to
afford the trix-3 regioisomer. In contrast, exclusive gem abstrac-
tion is observed for the ArNO enophile. In regard to the threo/
erythro diastereoselectivity, a pronounced solvent effect oper-
ates: In CDCl3 (entries 1, 3, and 5), a high threo selectivity is
observed for the gem regioisomer. This selectivity is signifi-
cantly less in CD3OD (entries 2, 4, and 6); the decrease is most
1
enophiles O2, TAD, and ArNO have the stereochemical and
regiochemical features of their ene reaction with tetrasubstituted
chiral allylic alcohols been scrutinized. For this purpose, we
have chosen the deuterium-labeled allylic alcohol Z-2-d3 to allow
differentiation of the regioisomers. This tetrasubstituted substrate
is structurally closely related to the trisubstituted allylic alcohol
Z-1-d4 and suited for comparison. With the additional methyl
group in the trix position,8 we bargain for a greater degree of
complexity, but the opportunity is offered to gain a more precise
view of the enophilic reaction coordinate.
Comparison of the trisubstituted (Z-1-d4) and tetrasubstituted
(Z-2-d3) allylic substrates discloses the following structural
differences with mechanistic implications on account of the
additional trix substituent: (i) The steric demand of the two
1
pronounced for O2 (entry 2).
The major isomers of the ene products 3a from O2 and 3b
1
from PTAD were separated by silica gel chromatography; for
ArNO, only the threo-configured twix-regioisomer was isolated.
The configuration of the ene products was determined in analogy
to literature.3 For this purpose, the isolated major isomers were
cyclized with 2,2-dimethoxypropane under TsOH catalysis to
the corresponding heterocycles 4a-c (Scheme 2). The relative
configuration of these conformationally rigid derivatives was
assessed by NOE spectroscopy, which clearly displays enhance-
ments for the depicted methyl groups and establishes the threo-
(5) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; VCH: New York, 1993; Chapter 4.1.
(6) (a) Vassilikogiannakis, G.; Stratakis, M.; Orfanopoulos, M.; Foote, C. S.
J. Org. Chem. 1999, 64, 4130-4139. (b) Stratakis, M.; Orfanopoulos, M.;
Foote, C. S. Tetrahedron Lett. 1996, 37, 7159-7162.
(7) (a) Adam, W.; Bottke, N.; Krebs, O. J. Am. Chem. Soc. 2000, 122, 6791-
6792. (b) Adam, W.; Bottke, N.; Krebs, O. Org. Lett. 2000, 2, 3293-
3296. (c) Adam, W.; Bottke, N.; Krebs, O.; Engels, B. J. Am. Chem. Soc.
2001, 123, 5542-5548.
(8) For ease of comparison and convenience of referal in the text, the
regiochemical descriptors of trisubstituted alkenes (twix/twin/lone: see
Scheme 1, ref 7a) have been extended to tetrasubstituted derivatives by
defining the fourth substituent as “trix”; “trix” stands for the contraction
of “trans” and “twix”. It should be noted that if in the deuterium-labeled
tetrasubstituted Z-2-d3 the CD3 group were missing, the trix position would
become twix in the resulting trisubstituted substance, which emphasizes
the regiochemical relationship between the twix and trix descriptors.
(9) (a) Orfanopoulos, M.; Grdina, M. B.; Stephenson, L. M. J. Am. Chem.
Soc. 1979, 101, 275-276. (b) Schulte-Elte, K. H.; Muller, B. L.;
Rautenstrauch, B. HelV. Chim. Acta 1978, 61, 2777-2783. (c) Stephenson,
L. M. Tetrahedron Lett. 1980, 1005-1008. (d) Orfanopoulos, M.; Stratakis,
M. Tetrahedron 2000, 56, 1595-1615. (e) Stratakis, M.; Orfanopoulos,
M.; Foote, C. S. J. Org. Chem. 1998, 63, 1315-1318.
9
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Reaction of 1O , TAD, and ArNO with Allylic Alcohols
A R T I C L E S
2
Table 1. Product Composition in the Ene Reactions of 1O2,
PTAD, and ArNO with the Tetrasubstituted Chiral Allylic Alcohol 2
Scheme 3. Synthesis of Deuterium-Labeled
Z-3,4-Dimethylpent-3-en-2-ol (Z-2-d3)
Table 2. Regioselectivity and Diastereoselectivity in the Ene
Reaction of 1O2, PTAD, and ArNO with the Deuterium-Labeled
Z-3,4-Dimethylpent-3-en-2-ol (Z-2-d3)
selectivitya
c
enophile
X ) Y
mb
convn
[%]a
regio
diastereo
yieldb
[%]
selectivity [%]a,c
d
entry
solvent
[%]a
gem :trixe threo:erythro
enophile
X ) Y
convna,b
[%]
gem(twix)-3
gem(twin)-3
trix-3d
1
2
3
4
5
6
CDCl3
CD3OD
CDCl3
93
84 >95
95 >95
87
64:36
62:38
90:10
75:25
>95:5
>95:5
90:10
63:37
96:4
89:11
>95:5
88:12
66f
73
63
entry
solvent
(threo/erythro)
(threo/erythro)
1O2
3a
3b
3c
1
CDCl3
>95e
>95e
24
(95:5)
22
40
(86:14)
38
36
1O2
PTAD
ArNO
CD3OD >95 >95
2
CD3OD
40
CDCl3
CD3OD
85
90
85
78
(70:30)
(60:40)
3
4
CDCl3
>95e
>95e
60
30
10
29
a Determined by 1H NMR spectroscopy, error ca. 5% of the stated value;
mb stands for material balance. b Isolated material, determined gravimetri-
cally after workup of a preparative run in CH2Cl2. c For the gem regioisomer.
d Sum of twin and twix abstraction. e For descriptor definition, cf. ref 8.
f From the semipreparative run in CDCl3; yield of alcohol obtained by Ph3P
reduction of the hydroperoxide.
PTAD
(98:2)
41
(89:11)
30
CD3OD
(91:9)
(86:14)
5
6
CDCl3
50f
56f
>95
(>95:5)
73
<5
ArNO
CD3OD
27
(90:10)
(86:14)
Scheme 2. Assignment of the threo-Configuration for the Ene
Products gem-3(threo) by Means of NMR Spectroscopy
a Determined by 1H NMR spectroscopy, error ca. 5% of the stated value.
b Based on alkene. c For 1O2 (entries 1 and 2), the ratio of threo (twix +
twin)/erythro (twix + twin)/trix was also determined by GC analysis. d For
the descriptor definition, cf. ref 8. e 1 equiv of olefin. f 1.5 equiv of olefin.
regioisomer were obtained from the areas of the allylic methyl
resonances of the ene products. The areas of the peaks for the
olefinic protons afforded the threo/erythro ratio of the twin
regioisomer, whereas the proton geminal to the hydroxy group
provided the overall threo (twin + twix)/erythro (twin + twix)
ratios. Additionally, the ratios of threo (twin + twix)/erythro
(twin + twix)/trix were determined for 1O2 by GC analysis (see
Table 2, footnote c). The latter ratios are in accord with the
results acquired by 1H NMR spectroscopy, as well as the product
ratio for the unlabeled alcohol 2 (Table 1). In CDCl3, only twix
hydrogen abstraction is observed for ArNO, 60% twix regio-
isomer is formed for PTAD, whereas only 24% twix hydrogen
abstraction takes place for 1O2. A solvent effect on the
regioselectivity is only evident for ArNO and PTAD, but not
for 1O2. The diastereoselectivity for the three enophiles is about
the same (within the experimental error of 5%) for a particular
regioisomer: The threo/erythro ratio is ca. 95:5 for twix
hydrogen abstraction and ca. 85:15 for the twin regioisomer.
For comparison with the already known 1O2 and PTAD
results,6 the selectivities of the ene reaction of ArNO with the
trisubstituted Z-1-d4 substrate were studied (Scheme 4).
The product distribution was determined by 1H NMR
spectroscopy, analogous to Z-2-d3. Only the twix-5 regioisomer
was formed; its threo/erythro ratio was 92:8. The configuration
of the unlabeled nitroso ene product has been assigned previ-
ously.3
configuration. Thus, the gem-3(threo) diastereomer is preferred
in the ene reaction of 1O2, PTAD, and ArNO with the
tetrasubstituted allylic alcohol 2.
The stereochemically deuterium-labeled trisubstituted Z-1-
d4 and the tetrasubstituted Z-2-d3 substrates were prepared to
assess the regioselectivity for twix versus twin hydrogen
abstraction, as well as the diastereoselectivities for both regio-
isomeric ene products.6 For the stereoselective synthesis of the
twix deuterium-labeled Z-3,4-dimethylpent-3-en-2-ol-d3 (Z-2-
d3), the cuprate addition to the phosphonate ester was conducted
in analogy to the preparation of the known twix deuterium-
labeled trisubstituted mesitylol Z-1-d4 substrate (Scheme 3).
The ene reactions of the twix deuterium-labeled Z-3,4-
dimethylpent-3-en-2-ol-d3 (Z-2-d3) with the enophiles 1O2,
PTAD, and ArNO were conducted in CDCl3 and in CD3OD.
The product distribution was determined by means of 1H NMR
spectroscopy (Table 2). The threo/erythro ratios for the twix
This extensive set of regioselectivity and stereoselectivity data
for the ene reactions of 1O2, PTAD, and ArNO with the
9
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A R T I C L E S
Adam et al.
Scheme 4. Regioselectivity and Stereoselectivity in the Ene
Reaction of 4-Nitronitrosobenzene (ArNO) with Z-Mesitylol-d4
(Z-1-d4)
6
deuterium-labeled allylic alcohols Z-1-d4 and Z-2-d3 and the
unlabeled derivatives 11-3 and 2 are in mutual accord in regard
to general trends and shall now be rationalized mechanistically.
Of particular significance and relevance shall be the interde-
pendence between the regiochemical and stereochemical fea-
tures. The present results allow one to recognize the mechanistic
similarities and differences between these three isoelectronic
heteroatom enophiles.
Figure 1. Regioselectivities and diastereoselectivities in the ene reactions
1
of the three heteroatom enophiles O2, PTAD, and ArNO with the chiral
allylic alcohols Z-1-d4 and Z-2-d3; the data for the ene reactions of 1O2 and
PTAD with Z-1-d4 have been taken from ref 6.
Discussion
To facilitate the mechanistic analysis, in Figure 1 are collected
the regioselectivity and the diastereoselectivity data for the ene
1
reactions of the three enophiles O2, PTAD, and ArNO with
the deuterium-labeled allylic alcohols Z-1-d4 and Z-2-d3 in the
form of a comparative overview. For clarification, the relative
values of the twix, twin, and trix regioisomers are placed closest
to the allylic groups, while directly under these are listed in
parentheses the threo:erythro diastereomeric ratios individually
for the twin and twix regioisomers. This matrix-structured
overview allows one to focus on the interdependence between
the threo/erythro and the twix/twin selectivities, an essential
feature for the comparative mechanistic analysis.
As a mechanistic basis, we adopt the established multistep
process in Scheme 1,1-3 with the formation of a three-
membered-ring intermediate (not shown), preceded by a more
loosely aggregated enophile/substrate encounter complex (EC).
The steric interactions and electronic coordination, which control
diastereoselectivity and regioselectivity, manifest themselves
already in the encounter complex, as illustrated for the threo-
EC and the erythro-EC structures derived from the tetrasub-
stituted substrate 2 and the enophile. For the threo-EC case,
Figure 2. Comparative regioselectivities in the ene reaction of 1O2, PTAD,
and ArNO with the olefinic substrates 6 (ref 7a) and 7 (ref 10).
2 (Table 1). Hence, it may be concluded that 1,3-allylic strain
(
1,3A) rather than 1,2-allylic strain (1,2A) dominates also in the
tetrasubstituted substrate, and evidently a relatively large
dihedral angle (R ≈ 130°) operates in the coordination of the
enophile, which is optimal for hydrogen bonding in the less
strained threo-EC structure.4
Clearly, irrespective of trix substitution, all three heteroatom
enophiles obey hydroxy-group directivity, threo control. Thus,
1,3A strain conformationally aligns the chiral allylic alcohol for
the threo attack, which is assisted by hydrogen bonding, as
displayed in the threo-EC encounter complex. The mechanistic
query to be addressed now is to assess how hydrogen bonding
affects the regioselectivity in the ene reaction of the three
enophiles with the two chiral, deuterium-labeled allylic alcohols
Z-1-d4 and Z-2-d3. Also of interest is how the threo/erythro
selectivity differs for the individual twix and twin regioisomers.
Dependence of the Regioselectivity on Hydrogen Bonding.
The pertinent data are displayed in Figure 1; we shall commence
with the more straightforward trisubstituted allylic alcohol Z-1-
d4, because only the twin and twix regioisomers need to be
considered. For all three enophiles, twix hydrogen abstraction
is favored (Figure 1). This becomes apparent on comparison of
the regioselectivity with the unfunctionalized trisubstituted
alkene 6 (Figure 2):7 The three enophiles exhibit a higher twix
selectivity for the corresponding trisubstituted alcohol Z-1-d4,
that is, the ratios of twix regioisomer for the substrates Z-1-d4
versus 6 are 84/40 (1O2), 60/46 (PTAD), and >95/88 (ArNO);
the first value refers to the substrate Z-1-d4, and the second refers
to 6.
1,3-allylic strain (1,3A) is minimized, such that the allylic
hydroxy group points above the substrate plane, to engage in
hydrogen bonding with the enophile attack from the top π face,
which affords preferably the threo-configured ene product. On
the contrary, 1,2-allylic strain (1,2A) is minimized for the erythro-
EC structure, the hydroxy group points below the substrate
plane, and the enophile attacks from the bottom π face to form
the erythro-configured ene product. It should be emphasized
that the allylic alcohols are all racemic and only one enantiomer
is being considered for the EC and TS structures in the
mechanistic analysis.
Such a comparison of the ratios of twix regioisomers for the
tetrasubstituted substrate Z-2-d3 (Figure 1) versus 6 (Figure 2)
discloses a different trend: The twix ratios are 24/40 (1O2), 60/
The experimental facts are that the threo-configuration
prevails for all ene products of the tetrasubstituted allylic alcohol
9
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Reaction of 1O , TAD, and ArNO with Allylic Alcohols
A R T I C L E S
2
Scheme 5. Control of the Diastereoselectivity in the Encounter
Complex threo-EC and Subsequent Control of the Regioselectivity
in the Transition Structures anti-TS and syn-TS for the Ene
Reaction of 1O2 with the Tetrasubstituted Allylic Alcohol Z-2-d3
Scheme 6. Control of the Diastereoselectivity and Regioselectivity
by Hydroxy-Group Directivity in the Encounter Complex threo-EC
and in the Transition Structure syn-TS for the Ene Reaction of
ArNO and PTAD with the Allylic Alcohols Z-1-d4 and Z-2-d3
details in methanol). It should be emphasized that even if the
syn-TS and the anti-TS derive from a common precursor, the
threo diastereoselectivities for the twin and twix regioisomers
are not necessarily the same, because the enophile may also
attack from the erythro face without assistance by hydrogen
bonding (see below!)
46 (PTAD), and >95/88 (ArNO); the first value refers to the
substrate Z-2-d3, and the second refers to 6. Clearly, these twix
ratios are identical for the PTAD and ArNO enophiles with both
the trisubstituted (Z-1-d4) and the tetrasubstituted (Z-2-d3) allylic
A different regioselectivity pattern is exposed by the PTAD
and ArNO enophiles for both the trisubstituted (Z-1-d4) and the
tetrasubstituted (Z-2-d3) allylic alcohols (Figure 1): For PTAD,
twix hydrogen abstraction dominates slightly (twix:twin/trix )
60:40 for both substrates), whereas twix hydrogen abstraction
occurs exclusively with ArNO (twix:twin/trix > 95:5 for both
substrates). That this enhanced twix reactivity derives from
hydrogen bonding is confirmed by comparing the regioselec-
tivities of the allylic alcohols Z-1-d4 and Z-2-d3 (Figure 1) with
related substrates without a hydroxy group, 6 and 7 (Figure 2).
For the trisubstituted pair Z-1-d4 and 6, the corresponding twix:
twin ratios are 60:40 versus 46:54 with PTAD as enophile. The
difference is more pronounced in favor of twix hydrogen
abstraction in the case of the ArNO enophile, for which the
corresponding twix:twin ratios are >95:5 versus 88:12. A similar
trend is displayed by the tetrasubstituted pair Z-2-d3 and 7, but
regioselectivity data are only available for the PTAD enophile.
Furthermore, the sum of regioisomers derived from each side
of the double bond need to be compared: The twix:(twin +
trix) ratio for Z-2-d3 is 60:40 (Figure 1) versus the (twix + lone):
(twin + trix) ratio 47:53 for 7 (Figure 2). For ArNO, the twix
regioisomer is formed exclusively with the Z-2-d3 substrate
(Figure 1). Thus, the allylic hydroxy group promotes ene
reactivity at the twix position through hydrogen bonding with
the PTAD enophile, even more so for ArNO (Scheme 6). This
1
alcohols, but drastically different for O2; that is, the relative
amount of twix regioisomer is 84% for Z-1-d4 but only 24%
for Z-2-d3. Closer inspection of the tetrasubstituted substrate
Z-2-d3 reveals that a total of 76% hydrogen abstraction takes
place by 1O2 at the twin (40%) and the trix (36%) sites (Figure
1), the side of the double bond anti to the allylic hydroxy group.
Thus, mainly the twin and trix regioisomers are generated from
the threo-EC encounter complex through the transition structure
anti-TS, whereas to a minor extent the twix regioisomer results
from syn-TS (Scheme 5). That the threo encounter complex
(threo-EC) serves as main precursor to all regioisomers is
substantiated by the high threo/erythro diastereoselectivities,
which are 86:14 for the twin and 95:5 for the twix regioisomer
(Figure 1). These diastereoselectivities are lower in methanol,
in which intermolecular hydrogen bonding competes with the
hydroxy-directing effect (see the Supporting Information for
details in methanol).
This reveals a novel and mechanistically most significant
feature: Once the 1O2 enophile has selected the favored π face
of the double bond by hydrogen bonding (threo attack condi-
tioned by 1,3A strain), the enophile has still the choice for
hydrogen abstraction between the two sides of the double bond
to afford either the twix regioisomer (syn side) or the twin/trix
regioisomers (anti side). Thus, at first, the 1O2 enophile is weakly
coordinated by hydrogen bonding in the form of the threo-EC
encounter complex before it forms the corresponding transition
structures anti-TS and syn-TS by penetration into the π system
of the double bond to generate a three-membered-ring inter-
1
contrasts the behavior of O2, for which we have seen that the
cis effect9 dominates hydrogen bonding (Scheme 5). Presum-
ably, stabilization of the transition structure syn-TS by hydrogen
bonding becomes more important for ArNO and PTAD than
1
for O2, which is also substantiated by the change of regiose-
1
mediate (perepoxide-like geometry for O2). At this stage, the
lectivity in methanol for ArNO and PTAD, but not for 1O2 (see
the Supporting Information for the details in methanol).
Interdependence of the Regioselectivity on the Diastereo-
selectivity. Examination of the dependence of the twix/twin
regioselectivity on the individual threo and erythro diastereo-
mers and the dependence of the threo/erythro diastereoselectivity
on the individual twix and twin regioisomers illustrates mecha-
nistically important new features on the ene reaction in regard
to hydroxy-group directivity. For convenience, we summarize
the pertinent stereochemical and regiochemical data in Figure
3 for the ene reactions of the trisubstituted (Z-1-d4) and
threo diastereoselectivity is fixed. Nevertheless, in this threo-
1
EC structure, the O2 enophile is still sufficiently mobile to
specify the regioselectivity between the two sides of the double
bond, the twix regioisomer through syn-TS or the twin/trix
regioisomers through anti-TS (Scheme 5). Conspicuous is the
fact that the twin/trix regioisomers are preferred over the twix
one (twin/trix:twix ) 76:24, Figure 1). This indicates that for
the 1O2 enophile, coordination with the allylic hydrogen atoms
(cis effect)9 on the anti side is more effective than hydrogen
bonding with the hydroxy group on the syn side, a hitherto
unrecognized behavior. The fact that the regioselectivity does
not change in the protic methanol solvent supports this
mechanistic interpretation (see the Supporting Information for
1
tetrasubstituted (Z-2-d3) substrates with O2, the enophile that
exhibits the trends more markedly. The bold-faced ratios
represent the overall threo/erythro diastereoselectivities at the
9
J. AM. CHEM. SOC. VOL. 124, NO. 48, 2002 14407

A R T I C L E S
Adam et al.
the erythro-EC2 encounter complex. In this erythro trajectory
without hydrogen bonding, the 1O2 is even more prone to
abstract from the sterically less crowded twin site, as is
experimentally observed (erythro-twin > threo-twin, Figure 3).
These unprecedented results demand that the usually presented
mechanism1-3 in Scheme 1 must be extended to allow enophilic
attack not assisted by hydrogen bonding.
Figure 3. Dependence of the regioselectivities on the diastereoselectivities
1
in the ene reaction of O2 with the allylic alcohols Z-1-d4 and Z-2-d3 (see
1
Briefly, the dependence of the threo/erythro diastereoselec-
tivity on the individual twix and twin regioisomers shall be
the Supporting Information for these O2, PTAD, and ArNO data).
1
considered; these data are shown for all three enophiles O2,
PTAD, and ArNO with both deuterated allylic alcohols Z-1-d4
and Z-2-d3 in Figure 1. All three enophiles display for both
substrates nearly the same diastereoselectivity ratios for a
particular regioisomer; that is, the threo/erythro ratio is from
90:10 to >95:5 for the twix and between 80:20 and 90:10 for
the twin regioisomer (for ArNO, no twin regioisomer is formed).
Proportionally, a higher erythro diastereoselectivity is exhibited
by the twin regioisomer, due to the increased twin regioselec-
tivity from the erythro-EC2 encounter complex, not assisted by
hydrogen bonding (Figure 4).
Diastereoselectivity and Regioselectivity in Methanol. In
the ene reaction with the unlabeled allylic alcohol 2 (Table 1)
and the deuterium-labeled derivative Z-2-d3 (Figure 1), the threo/
erythro diastereoselectivity is lowered in methanol due to
competitive hydrogen bonding with this protic solvent. For 1O2,
the overall threo/erythro diastereoselectivity drops from 90:10
in CDCl3 to 63:37 in D3COD (Table 1), whereas smaller effects
are observed for PTAD (from 96:4 in CDCl3 to 75:25 in D3-
COD) and ArNO (from >95:5 in CDCl3 to 88:12 in D3COD).
We propose that steric effects are responsible for this diaster-
eoselectivity behavior: The allylic hydroxy group is solvated
by the MeOH, and, therefore, its relative size is larger than the
methyl group of the lone substituent. Consequently, the favored
conformation of the substrate changes to a rotamer, in which
the solvated hydroxy group is at the periphery of the alkene, as
shown in the encounter complex EC (MeOH). For this solvated
Figure 4. Structures of the encounter complexes for the enophiles X ) Y
with the allylic alcohols Z-1-d4 (R ) H) and Z-2-d3 (R ) CH3).
geminal position (not differentiated for the twin and twix
regioisomers), that is, threo(gem) and erythro(gem), which are
93:7 for the undeuterated allylic alcohol 1 (Scheme 1) and 90:
10 for the undeuterated substrate 2 (Table 1). As discussed
already, these stereochemical ratios express for both allylic
alcohols the strong preference of the threo attack, conditioned
by minimal 1,3A strain and optimal hydrogen bonding (hydroxy-
group directivity). Below the overall diastereoselectivity ratios
threo(gem):erythro(gem) are given the twin:twix regioselectivity
ratios for each diastereomer, which are labeled threo-twin:threo-
twix for the threo and erythro-twin:erythro-twix for the erythro
diastereomer. For the trisubstituted substrate Z-1-d4, the twin:
twix ratio for the threo diastereomer is 14:86 and for the erythro
diastereomer it is 30:70; thus, substantially more (about twice)
twin abstraction takes place proportionally for the erythro than
for the threo attack. A similar trend is displayed by the
tetrasubstituted substrate Z-2-d3, but is less pronounced; that
is, twin abstraction occurs to the extent of 82% for the erythro
and 60% for the threo attack (Figure 3). This regiochemical
differentiation by 1O2 for the threo and erythro attacks appears
to be general and needs to be rationalized mechanistically. To
account for the distinct twin/twix regioselectivities, we shall see
that different enophilic trajectories are pursued by the 1O2
enophile for the threo and erythro attacks.
In Scheme 1, the threo and erythro trajectories have been
specified in terms of the respective encounter complexes threo-
EC and erythro-EC for the trisubstituted
rotamer, the enophilic attack is still favored from the threo side,
because the erythro attack is sterically hindered by the methyl
group of the lone substituent. Because the steric demand of the
substrate 1. For convenience, these structures are shown for
the ene reactions with both deuterated substrates Z-1-d4 and Z-2-
d3 in Figure 4, in which also the direction of attack has been
specified in terms of the top and bottom faces of the double
1
three enophiles follows the order O2 < PTAD < ArNO, the
diminution of threo selectivity is most pronounced for 1O2, the
smallest enophile.
bond. That the threo attack dominates is a consequence of 1,3
A
strain in this chiral allylic alcohol.
Inspection of the regioselectivities for the ene reactions in
methanol reveals that for O2 no change occurs, as displayed
by the twix:(twin + trix) ratios of 24:76 in CDCl3 versus 22:78
1
Hydrogen bonding between the 1O2 enophile and the hydroxy
functionality of the substrate assists the enophilic attack.
Inspection of the encounter complexes threo-EC and erythro-
EC1 reveals no significant steric interactions that would
differentiate between twin and twix abstraction. Thus, these
structures alone cannot reconcile the observed preference for
twin regioselectivity in the erythro attack. We propose that
in D3COD (Figure 1). As discussed already above, hydrogen
1
bonding has little influence on the regioselectivity for O2. In
contrast, for ArNO and PTAD, the twix regioselectivity de-
creases significantly in methanol versus chloroform. For PTAD,
the twix:twin/trix ratios are 60:40 (CDCl3) versus 41:59 (D3-
COD), a significant drop in the twix regioisomer, and for ArNO,
the values are >95:5 (CDCl3) versus 73:27 (D3COD), with
proportionally still less twix hydrogen abstraction occuring in
1
additionally the O2 attacks the lower-strained substrate con-
former (the one necessary for the threo trajectory, but from
below) without assistance of hydrogen bonding, as shown in
9
14408 J. AM. CHEM. SOC. VOL. 124, NO. 48, 2002

Reaction of 1O , TAD, and ArNO with Allylic Alcohols
A R T I C L E S
2
MeOH. This may again be rationalized in terms of competitive
disturbance of hydrogen bonding with the hydroxy group by
the protic medium, which expectedly depreciates twix reactivity
for PTAD and ArNO. This fact emphasizes the difference in
the regioselective control between 1O2 and the PTAD and ArNO
enophiles: For PTAD and ArNO, regioselectivity is subject to
regioselectivity is subject to hydroxy-group directivity in favor
of twix hydrogen abstraction, whereas O2 prefers hydrogen
1
abstraction at the twin and trix sites, that is, anti to the hydroxy
group. From this finding, we recognize that the regioselectivity
for 1O2 is not controlled by hydrogen bonding, but clearly
dictated by the cis effect.9 Nevertheless, it must be emphasized
that the high threo diastereoselectivity for both the twin and
the twix regioisomers is the consequence of hydrogen bonding
by the allylic hydroxy functionality. Such electronic interaction
steers the attacking enophile to the threo π face of the substrate
(cf. the threo-EC structures in Schemes 5 and 6). Thus, an
important new feature has been recognized on the enophilic
trajectory, that control of diastereoselectivity precedes that of
regioselectivity, because for the latter the enophile must
penetrate deeply into the π system of the double bond to form
the required three-membered-ring structures, the precursors to
the regioisomeric ene products.
1
hydroxy-group directivity but not for O2. Furthermore, the
increase of trix regioselectivity in methanol is observed exclu-
sively for PTAD. This may be rationalized in terms of the
increased steric interactions of the solvated hydroxy group,
which causes mainly hydrogen abstraction at the trix position
of that geminal site (gem effect).11
Conclusion
The trix methyl group in the tetrasubstituted allylic alcohol
2 makes the two sides (twix + lone versus twin + trix) of the
double bond more equal in the steric interactions with the
attacking enophile, as compared to the trisubstituted allylic
alcohol 1; additionally, the regioisomeric trix ene product is
formed in the case of the tetrasubstituted substrate 2. As a
consequence, the latter provides valuable information on the
regioselectivity and the diastereoselectivity of the ene reaction.
Therefrom, a more detailed mechanistic understanding of the
enophilic behavior of 1O2, PTAD, and ArNO has been acquired.
In regard to the diastereoselectivity, the additional 1,2-allylic
strain of trix substitution does not affect the conformational
alignment of the allylic hydroxy functionality; in fact, the
tetrasubstituted allylic alcohol 2 is even more threo-selective
than the trisubstituted derivative 1 with only 1,3-allylic strain.
The regioselectivity for the tetrasubstituted olefin Z-2-d3
The interdependence of the twin/twix regioselectivity and
threo/erythro diastereoselectivity in the deuterium-labeled allylic
1
alcohols Z-1-d4 and Z-2-d3 shows for O2 an increased twin
regioselectivity for the erythro diastereomer. This implies that
for the erythro diastereomer, the enophile attacks also the lower-
strained substrate conformer without assistance by hydrogen
bonding. Remarkable is that the threo/erythro diastereoselec-
tivity for the individual twin/twix regioisomers is the same for
1
all three enophiles O2, PTAD, and ArNO.
Acknowledgment. We thank the Deutsche Akademische
Austauschdienst, the Deutsche Forschungsgemeinschaft, and the
Greek Ministry of Education for generous financial support.
1
revealed an unprecedented dichotomy between the O2 versus
the PTAD and ArNO enophiles: For PTAD and ArNO,
Supporting Information Available: Complete experimental
procedures (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) Clennan, E. L.; Koola, J. J. Tetrahedron 1994, 50, 8569-8578.
(11) (a) Orfanopoulos, M.; Elemes, Y.; Stratakis, M. Tetrahedron Lett. 1990,
31, 5775-5778. (b) Elemes, Y.; Stratakis, M.; Orfanopoulos, M. Tetra-
hedron Lett. 1997, 38, 6437-6440.
JA027800P
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