Acyclic Stereoselection in the Ortho Ester Claisen Rearrangement

Article abstract of DOI:10.1021/jo9614250

The ortho ester Claisen rearrangement of trisubstituted allylic alcohols exhibits significant levels of diastereoselection. In E allylic alcohols, a 1,3-diaxial interaction develops in the chairlike transition state leading to the anti isomer, rendering the reaction syn selective by a factor of 3-5 to 1. In Z allylic alcohols, the 1,3-diaxial interaction develops in the transition state leading to the syn isomer, generating an anti:syn selectivity of 6-15 to 1. The relative stereochemistry of the syn isomer was confirmed independently by the synthesis of the mycotoxin botryodiplodin.

Full text of DOI:10.1021/jo9614250

1976
J . Org. Chem. 1997, 62, 1976-1985
Acyclic Ster eoselection in th e Or th o Ester Cla isen Rea r r a n gem en t
G. William Daub,* J ames P. Edwards, Carol R. Okada, J ana Westran Allen,
Claudia Tata Maxey, Matthew S. Wells, Alexandra S. Goldstein, Michael J . Dibley,
Clarence J . Wang, Daniel P. Ostercamp, Steven Chung, Paula Shanklin Cunningham, and
Martin A. Berliner
Department of Chemistry, Harvey Mudd College, Claremont, California 91711
Received J uly 25, 1996X
The ortho ester Claisen rearrangement of trisubstituted allylic alcohols exhibits significant levels
of diastereoselection. In E allylic alcohols, a 1,3-diaxial interaction develops in the chairlike
transition state leading to the anti isomer, rendering the reaction syn selective by a factor of 3-5
to 1. In Z allylic alcohols, the 1,3-diaxial interaction develops in the transition state leading to the
syn isomer, generating an anti:syn selectivity of 6-15 to 1. The relative stereochemistry of the
syn isomer was confirmed independently by the synthesis of the mycotoxin botryodiplodin.
Sch em e 1
Pericyclic processes have proven to be powerful syn-
thetic tools for the preparation of stereochemically com-
plex materials.1 This has been especially true when the
nature of the transition state for a particular process is
well understood and the important nonbonded inter-
actions have been defined. In recent years, work in our
laboratory has centered on determining the nature of the
nonbonded interactions in the ortho ester Claisen re-
arrangement and the effect of the substitution pattern
of the allylic alcohol on the diastereoselectivity of the
reaction.2
Acyclic stereoselection in the Claisen rearrangement
has been thoroughly studied for some of the Claisen
rearrangement variants.1 The first important observa-
tions on this subject are due to Schmid.3 His studies were
modeled on the classic work of Doering and Roth,4 and
they helped to elucidate the preference for the chairlike
transition state in acyclic Claisen processes. There are
three crucial structural elements in determining the
diastereoselectivity of a Claisen rearrangement: (1) the
chair- or boatlike nature of the transition state, (2) the
geometry about the vinylic double bond, and (3) the
geometry about the allylic double bond. A change in any
one of these elements leads to a reversal of any dia-
stereoselectivity if the other two elements remain un-
changed. This fact has made the Claisen rearrangement
very versatile, since a Claisen rearrangement that favors
one relative stereochemistry (e.g. syn)5 will usually favor
the alternative relative stereochemistry (e.g. anti) when
the geometry about one of the olefin bonds is reversed,
as illustrated in Scheme 1.6
selection of a particular vinyl double bond geometry. After
silylation to give an O-silyl ketene acetal, subsequent
rearrangement with high levels of diastereoselectivity can
be realized. Because one can control the geometry of both
double bonds in theory, the Ireland enolate Claisen
provides the most flexible approach to acyclic stereo-
selection using the Claisen rearrangement.
The intermediacy of N,O-ketene acetals also provides
for acyclic stereoselection as illustrated by the work of
Sucrow and Richter7 and Bartlett and Hahne.8 Sucrow
and Richter demonstrated that the amide-acetal Claisen
rearrangement of E allylic alcohols under thermodynamic
control provides for high levels of diastereoselection in
favor of the anti relative stereochemistry, while the syn
relationship predominates when Z alcohols are employed.
Bartlett and Hahne capitalized on the ynamine approach
of Ficini9 and showed that the reverse can be observed
under kinetic conditions; the anti relationship predomi-
nates when a Z alcohol is used, and the syn relative
stereochemistry results from the E allylic alcohol.8
The related ortho ester10 and ketal Claisen rearrange-
ments,11 however, exhibit rather modest levels of acyclic
stereoselection when the allylic double bond is disubsti-
tuted.11,12 By introducing a substituent at the 2-position
By far the most studied and utilized variant of the
Claisen rearrangement is the Ireland enolate Claisen
rearrangement.6 Countless examples can be found where
the proper choice of enolization conditions allows for the
(7) Sucrow, W.; Richter, W. Chem. Ber. 1971, 104, 3679.
(8) Bartlett, P. A.; Hahne, W. F. J . Org. Chem. 1979, 44, 882.
(9) Ficini, J .; Barbara, C. Tetrahedron Lett. 1971, 104, 3679.
(10) J ohnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J .; Li, T.; Faulkner, D. J .; Petersen, M. R. J . Am. Chem. Soc. 1970,
92, 741.
(11) (a) Daub, G. W.; Sanchez, M. G.; Cromer, R. A.; Gibson, L. G.
J . Org. Chem. 1982, 47, 743. (b) Daub, G. W.; McCoy, M. A.; Sanchez,
M. G.; Carter, J . S. J . Org. Chem. 1983, 48, 3876.
(12) (a) Stork, G.; Raucher, S. J . Am. Chem. Soc. 1976, 98, 1583.
(b) Bolton, I. J .; Harrison, R. G.; Lythgoe, B. J . Chem. Soc., C 1971,
2950. (c) Raucher, S.; Hwang, K. J .; McDonald, J . E. Tetrahedron Lett.
1979, 3057. (d) Raucher, S.; McDonald, J . E.; Lawrence, R. F.
Tetrahedron Lett. 1980, 4335. (e) Daub, G. W.; Teramura, D. H.;
Bryant, K. E.; Burch, M. T. J . Org. Chem. 1981, 46, 1485. (f) Daub, G.
W.; Lunt, S. R. Tetrahedron Lett. 1983, 4397.
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) Review articles on the Claisen rearrangement include: (a)
Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (b) Ziegler, F. E. Acc. Chem.
Res. 1977, 10, 227. (c) Bennett, G. B. Synthesis 1977, 589.
(2) For a preliminary report on aspects of this study see: Daub, G.
W.; Shanklin, P. L.; Tata, C. J . Org. Chem. 1986, 51, 3402.
(3) Hansen, H. J .; Schmid, H. Tetrahedron 1974, 30, 1959.
(4) Doering, W. v. E.; Roth, W. R. Tetrahedron 1962, 18, 67.
(5) All structures, while drawn as a single enantiomer, represent
racemates. The syn/ anti stereostructural notation proposed by Masam-
une is used in this paper: Masamune, S.; Ali, S. A.; Snitman, D. L.;
Garvey, D. S. Angew. Chem., Int. Ed. Engl. 1980, 19, 557.
(6) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J . Am. Chem.
Soc. 1976, 98, 2868. (b) Ireland, R. E., Thaisrivongs, S.; Wilcox, C. S.
J . Am. Chem. Soc. 1980, 102, 1155.
S0022-3263(96)01425-9 CCC: $14.00 © 1997 American Chemical Society

Stereoselection in the Ortho Ester Claisen Rearrangement
J . Org. Chem., Vol. 62, No. 7, 1997 1977
Sch em e 2
Sch em e 4
Sch em e 3
Sch em e 5
Acyclic Ster eoselection in Acid -Ca ta lyzed
Cla isen Rea r r a n gem en ts
of the allylic alcohol to generate a trisubstituted double
bond, an additional nonbonded interaction is created in
the transition state that provides for significant levels
of diastereoselection.13-16 Thus, the ortho ester Claisen
rearrangement (Scheme 2) of a trisubstituted allylic
alcohol (1 or 2) and an ortho ester 3 leads to a mixture
of the syn and anti diastereomeric products 4 and 5,
respectively, with significant degrees of diastereoselec-
tivity.2 This paper documents the observations leading
to this conclusion and describes the experimental details
associated with the project.
Prior to the investigations described in this paper,
ortho ester Claisen rearrangements of R-substituted
orthoacetates had exhibited little or no acyclic stereo-
selection.12 A typical example produces syn:anti ratios
of ≈1:1, as shown in Stork’s classic synthesis of PGA2 in
Scheme 4.12a Other examples can be found in the work
of Lythgoe,12b Raucher,12c,d and our own laboratories.12e,f
Similarly, little acyclic stereoselection was observed in
suitable examples of the ketal Claisen rearrangement.11
A potential solution to this problem is suggested in the
work of Faulkner,13 J ohnson,10 and Katzenellenbogen.19
These reports show that the Claisen rearrangements of
secondary allylic alcohols proceed with high E selectivity,
a result that is ascribed to the development of nonbonded
interactions in the transition state leading to the Z
isomer. The chairlike transition state leading to the Z
alkene (Bq) is destablilized relative to the transition state
leading to the E alkene (Aq) by the 1,3 diaxiallike
interaction between R and OEt (Scheme 5). Since
conformational changes like A h B are rapid relative to
the rate of [3,3] rearrangement, the E alkene predomi-
nates by a factor of 9:113 or even higher.10,19
Analogous 1,3-diaxial interactions are present in tran-
sition states Dq and F q (Scheme 6), which suggests that
E trisubstituted allylic alcohols would be expected to
select for the syn relationship and that Z trisubstituted
allylic alcohols would be expected to select for the anti
relationship. To this end, a series of experiments20 were
conducted to determine whether (1) an E trisubstituted
allylic alcohol exhibited more syn diastereoselectivity
than a trans disubstituted allylic alcohol, (2) a Z trisub-
stituted allylic alcohol exhibited more anti diastereo-
selectivity than a cis disubstituted allylic alcohol, and (3)
whether there is any evidence for the rapid interconver-
sion of the E (ground states of Cq or Eq) and Z (ground
states of Dq or F q) ketene acetals relative to the rate of
[3,3] rearrangement.
Syn th esis of E a n d Z Tr isu bstitu ted Allylic
Alcoh ols
A number of di- and trisubstituted allylic alcohols of
known geometry were required for this project. While a
few disubstituted allylic alcohols were available from
commercial sources (E- and Z-8, R2 ) Pr), the trisubsti-
tuted alcohols needed to be prepared (Scheme 3). The E
alcohols could be synthesized by the LiAlH4 reduction of
E trisubstituted acrylic esters. These esters were pre-
pared by two different routes. First, a commerially
available E trisubstituted acrylic acid could be esterified
and reduced (route i), to give alcohol 1a (R2 ) Ph, R3 )
Me). Alternatively, other E trisubstituted alcohols (1b-
e, R3 ) Me, R2 ) Pr, CH2CH2Ph, CH2OBn, pC6H4OCH3)
were synthesized by the Emmons-Wadsworth modifica-
tion of the Wittig reaction and reduction (route ii).17 The
Z allylic alcohols (2a -c, R3 ) Me, R2 ) Ph, Pr, CH2CH2-
Ph) were prepared using Still’s modification of the Wittig
reaction (route iii).18
(13) Faulkner, D. J .; Peterson, M. R. Tetrahedron Lett. 1969, 3243.
(14) The presence of such a 1,3-diaxial interaction in the transition
state does not preclude such a pathway from competing, but it does
demand that other pathways be sterically more demanding. In the
present case, the competing pathway is sterically less demanding and
predominates. See Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T.-F.
J . Am. Chem. Soc. 1985, 107, 2730.
(15) A similar interaction has been described by Parker, K. A.;
Farmar, J . G. Tetrahedron Lett. 1985, 3655.
(16) For examples where selectivity relative to a more distal center
is induced by such an interaction, see: (a) White, J . D.; Amedio, J . C.
J . Org. Chem. 1989, 54, 736. (b) Wovkulich, P. M.; Tang, P. C.; Chadha,
N. K.; Batcho, A. D.; Barrish, J . C.; Uskokovic, M. R. J . Am. Chem.
Soc. 1989, 111, 2596.
(18) Sreekumar, C.; Darst, K. P.; Still, W. C. J . Org. Chem. 1980,
45, 4260.
(19) Katzenellenbogen, J . A.; Christy, K. J . J . Org. Chem. 1974, 39,
3315.
(20) The detection limits for capillary GC analysis were <(1%.
(17) Mori, K; Matsui, M. Tetrahedron 1970, 26, 2801.

1978 J . Org. Chem., Vol. 62, No. 7, 1997
Daub et al.
Ta ble 2. Syn :An ti Selectivity for Keta l Cla isen
Sch em e 6
Rea r r a n gem en t
ratio of
syn:anti
R3
12:13:14a
ratio (12:13)a
% yield
∆[Gq]b
H
Me
53:45:2
79:17:4
54:46
82:18
63
78
0.1
1.2
a
b
Uncertainties are (1%. In kcal/mol, calculated at 398 K:
∆[Gq] ) RT ln (syn/ anti).
Ta ble 1. P r od u cts of Or th o Ester Cla isen
Rea r r a n gem en t a s a F u n ction of Dou ble Bon d Geom etr y
Ta ble 3. Syn :An ti Selectivity for Or th o Ester Cla isen
Rea r r a n gem en t
alkene
geometry
syn:anti
ratioa
% yield
syn:anti
entry
R2
R3
R3
ratio (15:16)a
% yield
∆[Gq]b
a
b
c
d
e
f
trans
E
trans
E
cis
Z
Ph
Ph
Pr
Pr
Pr
Pr
H
Me
H
Me
H
Me
60:40
85:15
62:38
79:21
24:76
9:91
72
65
49
64
41
53
H
Me
60:40
85:15
72
65
0.1
1.2
a
b
Uncertainties are (1%. In kcal/mol, calculated at 398 K:
∆[Gq] ) RT ln (syn/ anti).
a
Uncertainties are (1%.
corresponding ortho ester Claisen rearrangements (Table
3) upon addition of a methyl group at the 2-position of
an E allylic alcohol, very similar increases in selectivity
are exhibited. If one assumes that the Curtin-Hammett
principle is operational in the ortho ester Claisen as it is
in the ketal Claisen variation, one can calculate the
difference in the free energies of the two transition states
(one leading to the syn relationship, the other leading to
the anti) for a given reaction. These are included in
Tables 2 and 3 as ∆Gq and are calculated from the syn:
anti product ratios at 398 K: ∆Gq ) RT ln (syn/ anti). In
both reaction examples, the increase in selectivity results
from the addition of a single methyl group at the
2-position of the allylic alcohol, and the increase corre-
sponds to an additional 1.1 kcal/mol separation between
the relevant transition states. This suggests that, like
the ketal Claisen rearrangement, the ortho ester Claisen
variation operates under Curtin-Hammett control.
A complete accounting of the various ortho ester
Claisen rearrangements of E and Z trisubstituted allylic
Table 1 summarizes the selectivities observed for some
simple di- and trisubstituted allylic alcohols in both the
E and Z series. Clearly, there is a substantial increase
in syn selectivity for the E trisubstituted alcohol relative
to the trans disubstituted alcohol and an enhanced anti
selectivity when a Z trisubstituted alcohol is compared
to a cis disubstituted alcohol. These observations are
consistent with the proposition that the added 1,3-diaxial
interaction in transition states Dq and F q render these
processes slow relative to the reactions proceeding through
transition states Cq and Eq.
It is more difficult to establish whether the E and Z
ketene acetals interconvert rapidly on the time scale of
the [3,3] reaction rate. Until that fact is adequately
demonstrated, it will not be known for certain whether
the selectivity reported in Table 1 represents differences
in the free energies of the transition states (e.g. Cq and
Dq) or differences in the stabilities of the ground state E
and Z ketene acetals. While the evidence below for the
rapid interconversion of the E and Z ketene acetals in
the ortho ester Claisen is only inferential, we have
previously shown that the analogous interconversion of
E and Z vinylic double bonds in the ketal Claisen
rearrangement is more rapid than the rate of [3,3]
rearrangement and that the Curtin-Hammett principle
applies to the ketal Claisen rearrangement.11b
alcohols that were examined is given in Table 4.
A
number of interesting points emerge from these results.
Z Alcoh ols Sh ow Gr ea ter Rela tive Selectivity.
The Z alcohols show better selectivity for the anti product
than the E alcohols show for the syn product. This
generalization means that the difference between the free
energies of the two chairlike transition states (Scheme
7) is greater for Z alcohols (21 and 22) than for E alcohols
(19 and 20). The higher energy transition state is always
the one with the 1,3-diaxial interaction (20 and 22). The
When one compares the increase in syn:anti selectivity
in some ketal Claisen rearrangements (Table 2) and the

Stereoselection in the Ortho Ester Claisen Rearrangement
J . Org. Chem., Vol. 62, No. 7, 1997 1979
Ta ble 4. Su m m a r y of Syn :An ti Selectivity for Or th o
Sch em e 8
Ester Cla isen Rea r r a n gem en t
syn:anti
%
syn:anti
%
entry R1
R2
R
(E isomer)a yield (Z isomer)a yield
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Me Ph
Me
Et
Me
Me
Et
84:16
85:15
83:17
82:18b
79:21
77:23
72:28
76:24
-
80
65
70
60
64
68
67
60
-
-
-
66
74
41
53
68
86
67
58
85
60
67
79
-
Me Ph
Et Ph
Pr Ph
Me Pr
Et Pr
Pr Pr
Me CH2CH2Ph Et
Et CH2CH2Ph Me
Pr CH2CH2Ph Me
14:86
19:81
17:83b
9:91
10:90
9:91
7:93
10:90
8:92
6:94
7:93
8:92
-
Me
Me
demanding sp3 hybrid would narrow the free energy gap
between transition states 23 and 24 and render the
reaction less syn selective, in accord with the observa-
tions.
-
-
Me CH2OBn
Et CH2OBn
Pr CH2OBn
Et
Me
Me
83:17
78:22
73:27
83:17
70
61
74
73c
62d
55
The reverse is observed for Z allylic alcohols. The
R2‚‚‚OEt interaction is present in both transition states
25 and 26. In transition state 25, note that R1 engages
the CH3 group in a 1,3-diaxiallike interaction, making
this transition state higher in energy than transition
state 26. The R1‚‚‚R2 interaction in transition state 26
is expected to be very modest (probably less than a
gauche interaction) due to the rather large dihedral angle
between the C-R2 and C-R1 bonds. As a result, an
increase in steric demand at R2 makes both transitions
states (25 and 26) earlier and slows both reactions.
Evidently the effect is greater on transition state 25,
probably because the R2‚‚‚OEt 1,3-diaxial interaction
magnifies the effect of the original R1‚‚‚CH3 diaxial
interaction and makes carbon-carbon bond formation
very inefficient.
Me p-OMeC6H4 Et
o
Et p-OMeC6H4 Me
81:19
-
-
a
b
Uncertainties are (1%. Syn and anti isomers did not resolve
on GC. Ratio determined by integration of 1H NMR spectrum at
200 MHz. c Acid catalyst was propionic acid. Acid catalyst was
d
mesitoic acid.
Sch em e 7
Va r ia tion in Size of R 1 Ha s Little Effect. An
increase in the bulk of R1 does not increase the syn
selectivity of reactions involving E alcohols, nor does it
increase the anti selectivity for reactions involving Z
alcohols, as one might predict from the analysis given
above. In fact, there is a slight decrease in the syn
selectivity for E alcohols. The increase in the steric bulk
from methyl to ethyl to propyl may not be sufficient to
produce large changes in the R1‚‚‚CH3 interaction (see
23 and 25), or corresponding increases in the nonbonded
interactions between R1 and R2 in the syn transition state
(see R1‚‚‚R2 interaction in transition state 24) may cancel
out any increase in the 1,3-diaxial interaction generated
by changing the size of R1. The decrease in syn selectivity
for E alcohols may be an indication that the R1‚‚‚R2
interaction in transition state 24 is of very real signifi-
cance.
E n oliza t ion P r ocesses Do Not Com p et e w it h
Over a ll Rea ction Ra tes. Enolization of the carbon R
to the ester carbonyl is not rapid under the reaction
conditions, as illustrated by two types of experiments.
First, numerous reactions were monitored for changes
in the syn:anti ratios as a function of reaction time. In
all cases, the syn:anti ratios were invariant (( 1%) during
the course of the reaction. Four additional control
experiments were conducted, in which a single pair of
racemates (Table 4, 17n , 17o, 18n , and 18o) were
resubjected to the original reaction conditions. In all
cases none of the alternative relative stereochemistry
(18n , 18o, 17n , and 17o respectively) could be detected
source of this increased free energy difference is ascribed
to the additional 1,3-diaxial interaction present in the
transition states involving a Z allylic geometry (21 and
22). The second 1,3-diaxial interaction “butresses” the
original interaction in 20, leading to an even less stable
and earlier transition state with less efficient bond
formation. Hence, the free energy gap between transition
states 21 and 22 is larger and the selectivity is greater.
Na tu r e of Hybr id iza tion of Ca r bon Atta ch ed a t
R2. The syn selectivity observed for E allylic alcohols is
greater when the hybridization of the carbon attached
at R2 is sp2. In contrast, the anti selectivity observed for
Z allylic alcohols is greater when the hybridization of the
carbon attached at R2 is sp3. Both of these observations
are consistent with the increased steric demand of an sp3
center over an sp2 center. The chairlike transition state
(Scheme 8) contains two sp2 centers and four centers
intermediate in hybridization between sp2 and sp3, so one
would expect deviations from the classic chair conforma-
tion model of cyclohexane. Perrin and Faulkner’s model
reflects this fact. Models suggest that the newly-forming
carbon-carbon single bond is not staggered in the
classical sense, but, as structures 23-26 suggest, is
approaching a “semieclipsed” conformation. If this is the
case, then one would expect the R1‚‚‚R2 gauche interac-
tion in transition state 23 to be somewhat less than the
R1‚‚‚R2 gauche interaction in transition state 24. Thus,
changing the attachment of R2 to a sterically more

1980 J . Org. Chem., Vol. 62, No. 7, 1997
Ta ble 5. Ch em ica l Sh ift Da ta for Selected Syn a n d An ti Isom er s
Daub et al.
syn isomer:
chemical shift (δ) of
ester group (group)
syn isomer:
chemical shift (δ) of
R alkyl group (group)
anti isomer:
chemical shift of
ester group (group)
anti isomer:
chemical shift (δ) of
R alkyl group (group)
entry
R1
X
R
a
b
Me
Me
H
H
Me
Et
3.69 (CH3)
4.14 (CH2)
1.25 (CH3)
3.69 (CH3)
4.13 (CH2)
1.23 (CH3)
3.67 (CH3)
0.96 (CH3)
0.96 (CH3)
3.41 (CH3)
3.85 (CH2)
0.93 (CH3)
3.39 (CH3)
3.89 (CH2)
0.95 (CH3)
3.39 (CH3)
1.24 (CH3)
1.24 (CH3)
c
d
Et
Me
H
Me
Et
0.79 (CH3)
0.93 (CH3)
0.93 (CH3)
1.22 (CH3)
p-OCH3
e
Et
p-OCH3
Me
0.77 (CH3)
0.89 (CH3)
Ta ble 6. En ola te Cla isen Rea r r a n gem en ts to Con fir m
by capillary GC.20 These observations are in contrast to
some acid-catalyzed ketal Claisen rearrangements re-
ported previously.11,21
Syn :An ti Cor r ela tion s
Th e Na tu r e of th e Ca r boxylic Acid Ca ta lyst Does
Not Affect th e Selectivity. Three different carboxylic
acid catalysts, propionic acid, pivalic acid, and mesitoic
acid, have been employed, and no differences in selectiv-
ity have been observed ((1%). This result is not surpris-
ing, but is worth noting nevertheless.
anti:syn
ratio (31:30)
anti:syn
ratio (33:32)
Deter m in a tion of Rela tive Ster eoch em istr y
ester
% yield
% yield
The accurate determination of the relative stereo-
chemistry of the Claisen products is essential to the
validity of this work. The relative stereochemistry was
established in three independent ways: (1) inference
from 1H NMR spectroscopy, (2) confirmation by inde-
pendent synthesis via enolate Claisen rearrangement,
and (3) by the synthesis of the mycotoxin botryodiplodin,
a known compound whose relative stereochemistry is
firmly established.
29a
29b
29c
3:1
3:1
3:1
23
30
24
3:1
3:1
3:1
42
61
63
Sch em e 9
1
(1) H NMR spectroscopy aided in the assignment of
relative stereochemistry since there were significant
differences in the spectra of syn and anti isomers. One
of the most striking effects was in the series where R2
was an aromatic substituent (entries a, b, c, n, and o in
Table 4). In such cases, the anisotropy introduced by the
aromatic ring led to specific upfield shifts of the R alkyl
group (R1) in the syn isomer 27, and corresponding
upfield shifts in the ester alkoxy group in the anti isomer
28. These spectral correlations are presented in Table
5.
carboxylic acids 31a -c and 30a -c, respectively. The
carboxylic acids 31a -c and 30a -c were then converted
into the corresponding methyl esters (33a -c and 32a -
c) using potassium carbonate and iodomethane in DMSO.
In all three cases, both the syn and anti isomers prepared
in this fashion (32a -c, 33a -c) proved identical to the
compounds assigned as the syn and anti isomers pre-
pared using the ortho ester Claisen by capillary GC and
1
NMR spectroscopy (200 MHz H and 50 MHz 13C).
(2) The enolate Claisen rearrangement variation has
exhibited strong selectivity for either the syn or anti
isomer depending on the enolization conditions as dis-
cussed previously. We used this fact to help confirm the
syn and anti assignments of the products obtained in our
own Claisen studies by preparing mixtures of the same
products according to the work of Ireland.6 We chose to
prepare mixtures under conditions in which the anti
isomer was expected to predominate for stereochemical
correlations as described in Table 6. Enolization of esters
29a -c with lithium diisopropylamide in THF followed
by silylation with tert-butyldimethylsilyl chloride in
HMPA afforded mixtures of the E and Z silyl ketene
acetals in which the E isomer should predominate.6
Sigmatropic rearrangement was conducted at THF re-
flux, and workup provided 3:1 anti:syn mixtures of
(3) In an effort to confirm the assignments of relative
stereochemistry on a chemical basis, we have synthesized
the mycotoxin botryodiplodin (45)22,23 using the ortho
ester Claisen rearrangement (Scheme 9). The results
described in the following section demonstrate the utility
of the diastereoselective ortho ester Claisen rearrange-
ment and clearly establish the syn relationship present
in the major product 35 of the ortho ester Claisen
rearrangement of the E trisubstituted alcohol 34.
(22) (a) Arsenault, G. P.; Althaus, J . R.; Divekar, P. V. J . Chem.
Soc., D 1969, 1414. (b) Moreau, S.; Lablanche-Combier, A.; Biguet, J .;
Foulon, C.; Delfosse, M. J . Org. Chem.1982, 47, 2358.
(23) For other syntheses of botryodiplodin see: (a) McCurry, P. M.,
J r.; Abe, K. J . Am. Chem. Soc. 1973, 95, 5824. (b) McCurry, P. M., J r.;
Abe, K. Tetrahedron Lett. 1973, 4103. (c) Mukaiyama, T.; Wada, M.;
Hanna, J .; Chem. Lett. 1974, 94, 1181. (d) Wilson, S. R.; Myers, R. S.
J . Org. Chem. 1975, 40, 3309. (e) Kurth, M. J .; Yu, C.-M. J . Org.
Chem.1985, 50, 1840. (f) Rehnberg, N.; Frejd, T.; Magnusson, G.
Tetrahedron Lett. 1987, 3589.
(21) Daub, G. W., Griffith, D. A. Tetrahedron Lett. 1986, 6311.

Stereoselection in the Ortho Ester Claisen Rearrangement
J . Org. Chem., Vol. 62, No. 7, 1997 1981
Sch em e 10
Sch em e 11
A Syn th esis of Botr yod ip lod in
Scheme 10 summarizes the synthetic route to the key
intermediate 35. Allylic alcohol 34 was prepared from
the dibenzyl ether of cis 2-buten-1,4-diol (36)24 by ozon-
olysis (76%),25 Emmons-Wadsworth olefination of the
resulting aldehyde with triethyl 2-phosphonopropionate
(to give an 84:16 mixture of E and Z isomers in 72%
yield),17 and LiAlH4 reduction. Allylic alcohol 34 was
obtained in 53% yield after purification by medium
pressure liquid chromatography on silica as a 98:2
mixture of E and Z isomers. Ortho ester Claisen re-
arrangement of alcohol 34 with triethyl orthopropionate
afforded an 84:16 mixture of the desired syn (35) and anti
(37) unsaturated esters in 88% yield after flash chroma-
tography. Independent confirmation of this syn selectiv-
ity would await the sucessful synthesis of botryodiplodin
(45). In all cases, the isomeric ratios were determined
and pyridine (84%). Acetates 47 and 48 each existed as
a pair of R and â anomers consistent with published
observations.29
1
by H NMR and capillary gas chromatography.
The completion of the synthesis is shown in Scheme
11. Saponification of esters 35 and 37 afforded a 76:24
mixture26 of carboxylic acids 38 (syn) and 39 (anti) in 98%
yield. The small change in the ratio of syn and anti
diastereomers is presumably due to enolization under the
basic reaction conditions. Reductive removal of the
benzyl ether moiety in 38/39 was accomplished using 3
equiv of lithium in liquid ammonia.27 Acidification of the
crude reaction mixture afforded an 87% yield of the
γ-lactones (IR: 1772 cm-1) as a 73:27 mixture26 of the
3â,4â (41) and 3R,4â (42) isomers. Lactones 41 and 42
presumably result from lactonization of the carboxylic
acid salts 40 upon acidic workup.
While the individual lactone isomers 41 and 42 could
not be separated in sufficient quantities to be individually
carried on to the final products, there is no doubt in the
stereochemical correlation of the cis isomer 41 with 45
and the trans isomer 42 with 46. Stoichiometry pre-
cludes the possibility that the product obtained is a 30:
70 mixture of 45 and 46. Further, epimerization of lactol
43 to 44 proved to be rapid and complete in the presence
of acid or base, most certainly through the open chain
aldehyde form. This shows that 43 and 44 possess cis
(less stable) and trans (more stable) relationships be-
tween the isopropenyl and methyl groups at positions 4
and 3, respectively. Thus, the major lactol 43 has the
less stable stereochemical relationship and is thus ex-
pected to have a cis relative stereochemistry between the
isopropenyl and methyl groups.
The syntheses of botryodiplodin and epibotryodiplodin
were completed by diisobutylaluminum hydride reduc-
tion28 to the lactol and oxidative cleavage of the terminal
alkene by ozonolysis. Lactols 43 and 44 could be pre-
pared in 75-85% yields as a 71:29 mixture26 of the 3â,4â
(43, mixture of 2R and 2â anomers) and the 3R,4â (44,
mixture of 2R and 2â anomers) isomers. Ozonolysis of
43 and 44 with a reductive workup (Me2S) afforded a 70:
30 mixture of botryodiplodin (45) and epibotryodiplodin
(46) in 55% yield after chromatography.
In this fashion we have prepared the mycotoxin bot-
ryodiplodin (45) and its epimer, epibotryodiplodin (46).
The successful completion of the synthesis confirms that
the relative stereochemistry of the major product 35 of
ortho ester Claisen rearrangement of alcohol 34 with
triethyl orthopropionate is syn.
Compounds 45 and 46 exhibited 1H NMR spectral
features consistent with published data.23 Further char-
acterization was accomplished after conversion of 45/46
to the mixture of acetates 47/48 with acetic anhydride
Con clu sion
The ortho ester Claisen rearrangement of trisubsti-
tuted allylic alcohols exhibits significant levels of dia-
stereoselection, especially when the Z allylic alcohol is
employed. We ascribe the increased selectivity over
(24) Prepared from cis-2-butene-1,4-diol according to Czernecki, S.;
Georgoulis, C.; Proveloenghiou, C. Tetrahedron Lett. 1976, 3535.
(25) The authors would like to thank the Chemistry Departments
of the University of California, Irvine, and Pomona College for the use
of their ozone generators.
(29) Capillary GC analysis of the mixture of acetates indicated the
presence of 4 materials in a 65:3:19:13 ratio. 1H NMR revealed these
to be the R-anomer of botryodiplodin acetate (2R-47), the â-anomer of
botryodiplodin acetate (2â-47), the â-anomer of epibotryodiplodin
acetate (2â-48), and the R-anomer of epibotryodiplodin acetate (2R-
48), respectively.
(26) Isomer ratios were determined using 1H NMR at 200 MHz.
(27) Reist, E. J .; Bartuska, V. J .; Goodman, L.; J ohnson, E. J . Org.
Chem. 1964, 29, 3725.
(28) Corey, E. J .; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J .
Am. Chem. Soc. 1969, 91, 5675.

1982 J . Org. Chem., Vol. 62, No. 7, 1997
Daub et al.
(d, J ) 12.7 Hz), 4.14 (d, 1H, J ) 12.8 Hz), 4.64 (t, 1H, J ) 3.4
Hz), 4.89 (s, 1H), 5.00 (s, 1H). 13C NMR (CDCl3, 50 MHz): δ
19.3, 19.4, 25.4, 30.5, 61.9, 70.6, 97.6, 111.4, 142.1.
disubstituted allylic alcohols to the presence of a 1,3-
diaxiallike interaction that develops in one of the transi-
tion states. In the case of E allylic alcohols, the new
diaxial interaction develops in the transition state leading
to the anti isomer, rendering the reaction syn selective.
In a complementary fashion, Z allylic alcohols exhibit anti
selectivity because the new diaxial interaction develops
in the transition state leading to the syn isomer. We have
taken advantage of this selectivity to synthesize the
mycotoxin botryodiplodin.
Aceton yl Tetr a h yd r op yr a n yl Eth er . Ozone was vigor-
ously bubbled through a 0.15 M solution of 2-methyl-2-propen-
1-yl tetrahydropyranyl ether (5.00 g, 0.032 mol) in 50/50 (v/v)
MeOH/CH2Cl2 (215 mL total) at -78 °C until a blue color
persisted (≈1 h). The ozone flow was stopped, oxygen gas was
bubbled through the reaction mixture for 15 min to remove
any excess ozone, excess Me2S (6 mL, 0.082 mol) was added
to the solution, and the reaction mixture was allowed to warm
to 25 °C over a 2 h period. The reaction mixture was poured
into water and extracted with CH2Cl2. The combined organic
layers were washed with brine and dried over Na2SO4.
Concentration under reduced pressure and vacuum distillation
(68-72 °C, 5.0 mmHg) afforded acetonyl tetrahydropyranyl
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were determined at 200
MHz (FT) and 50 MHz, respectively, in CDCl3. Vapor-phase
chromatograms were obtained on a 30 m DB-1 capillary
column (J and W Scientific). Integrations were not corrected
for varying detector responses. Combustion microanalyses
were performed by Atlantic Microlab, Inc. Flash and MPLC
chromatography were performed on silica gel [0.040-0.063
mm]. Ethylene glycol dimethyl ether (DME), diisopropyl-
amine, and pyridine were distilled from CaH2, tetrahydrofuran
was distilled from sodium/benzophenone ketyl, and hexa-
methylphosphoric triamide (HMPA) was distilled from sodium
under reduced pressure; all other reagents were reagent grade
as supplied by the vendor.
ether (2.94 g, 58%) as a colorless liquid. IR (neat): 1710 cm-1
.
1H NMR (CDCl3, 200 MHz): δ 1.5-2.0 (m, 6H), 2.18 (s, 3H),
3.54 (m, 1H), 3.84 (m, 1H), 4.11 (d, 1H, J ) 17.3 Hz), 4.26 (d,
1H, J ) 17.3 Hz), 4.65 (t, 1H, J ) 3.2 Hz). 13C NMR (CDCl3,
50 MHz): δ 19.1, 25.2, 26.4, 30.2, 62.3, 72.3, 98.7, 206.6.
(Z)-2-Meth yl-3-p h en yl-2-p r op en -1-ol (2a , R2 ) P h ). The
following procedure is a modification of the method of Still.18
Butyllithium (42.0 mmol, 20.0 mL of 2.1 M solution in hexane)
was added via syringe to a mixture of benzyltriphenylphos-
phonium bromide (19.54 g, 45.1 mmol) and THF (130 mL) at
25 °C, and the reaction mixture was allowed to stir for 10 min
and then cooled to -78 °C. Acetonyl tetrahydropyranyl ether
(5.100 g, 32.2 mmol) in THF (20 mL) was added, and the
solution was allowed to warm to 25 °C over a 45 min period.
The reaction was quenched by the addition of hexane (150 mL),
and the resulting slurry was promptly subjected to flash
chromatography on silica gel (3% ethyl acetate/97% hexane).
Fractions were pooled and concentrated under reduced pres-
sure to give a 60:40 mixture (by GC) of (Z)- and (E)-2-methyl-
3-phenyl-2-propen-1-yl tetrahydropyranyl ethers (2.634 g,
35%).
Syn th esis of Allylic Alcoh ols. (E)-Meth yl 2-Meth yl-3-
ph en yl-2-pr open oate. (E)-2-Methyl-3-phenyl-2-propenoic acid
(10.00 g, 61.66 mmol, Aldrich), trimethyl orthoformate (7.20
g, 67.9 mmol), and TsOH‚H2O (0.619 g, 3.25 mmol) were
dissolved in MeOH and heated at reflux for 48 h. The reaction
mixture was concentrated under reduced pressure and dis-
solved in ether. The organic layer was extracted with satu-
rated NaHCO3, and the resulting aqueous layer was back
extracted with additional ether. The combined ether layers
were extracted with water and saturated brine and dried over
MgSO4. Concentration under reduced pressure afforded a low-
melting, colorless liquid (10.45 g, 96%) suitable for subsequent
use. A sample of the ester was purified by recrystallization
from hexane (mp 26-27 °C) to provide a sample suitable for
This mixture of THP ethers was deprotected without further
purification. The mixture of (Z)- and (E)-2-methyl-3-phenyl-
2-propen-1-yl tetrahydropyranyl ethers (2.634 g, 11.4 mmol),
TsOH‚H2O (0.507 g, 2.67 mmol), and MeOH (250 mL) were
allowed to react at 25 °C for 30 min. The reaction mixture
was diluted with ether and washed with saturated NaHCO3,
water, and saturated brine. After drying over MgSO4, the
solution was concentrated under reduced pressure. The crude
product consisted of a 60:40 mixture (1.397 g, 80%) of the Z
and E isomers of 2-methyl-3-phenyl-2-propen-1-ol, respectively.
Medium pressure chromatography on silica gel (1% 2-propanol/
14% ethyl acetate/85% hexane) afforded a pure sample (>99%)
of (Z)-2-methyl-3-phenyl-2-propen-1-ol (0.098 g) plus an ad-
ditional mixture of E and Z alcohols. IR (neat): 3300 (br),
combustion analysis. IR (KBr): 3050, 1711, 1633 cm-1
.
1H
NMR (CDCl3, 200 MHz): δ 2.12 (s, 3H), 3.82 (s, 3H), 7.4 (m,
5H), 7.70 (m, 1H). 13C NMR (CDCl3, 50 MHz): δ 14.0, 52.0,
128.3, 128.4 (2 carbons), 129.6, 136.0, 138.9, 169.1. Anal. Calcd
for C11H12O2: C, 74.98; H, 6.86. Found: C, 75.08; H, 6.81.
(E)-2-Meth yl-3-p h en yl-2-p r op en -1-ol (1a ). A solution of
(E)-methyl 2-methyl-3-phenyl-2-propenoate (8.01 g, 45.2 mmol)
in anhydrous ether (50 mL) was added dropwise over 30 min
to a solution of LiAlH4 (1.806 g, 45.2 mmol) in anhydrous ether
(250 mL) at 0 °C under nitrogen, and the reaction mixture
was allowed to stir at 0 °C for an additional 1 h. The excess
LiAlH4 was destroyed by the addition of saturated Na2SO4.
The aluminum salts were removed by filtration, and the salts
were extracted with hot ether. The combined organic layers
were concentrated, and the resulting liquid was and purified
by bulb-to-bulb distillation (185 °C, 0.8 mm Hg) to afford
colorless product (6.42 g, 95%). IR (neat): 3050, 1711, 1633
1690 cm-1 1H NMR (CDCl3, 200 MHz): Z isomer: δ 1.92 (s,
.
3H), 2.45 (br s, 1H), 4.20 (s, 2H), 6.39 (s, 1H), 7.2-7.3 (m, 5H).
13C NMR (CDCl3, 50 MHz): δ 21.7, 62.2, 126.5, 128.1, 128.3,
128.9, 137.2, 137.5. Anal. Calcd for C10H12O: C, 81.04; H,
8.16. Found: C, 81.17; H, 8.25.
(E)- a n d (Z)-Eth yl 2-Meth yl-5-p h en yl-2-p en ten oa te.
The following procedure is a modification of the method of
Mori.17 A solution of triethyl 2-phosphonopropionate (8.40 g,
35.3 mmol) in DME (30 mL) was added to a slurry of NaH
(1.72 g of 50% oil disp, 35.8 mmol, washed free of oil) and DME
(30 mL). A solution of 3-phenylpropanal (4.77 g, 35.5 mmol)
in DME (30 mL) was then added, and the resulting mixture
was stirred for 3 h at 25 °C and then heated at reflux for 30
min. The reaction mixture was poured into ice-water and
extracted with ether. The combined organic layers were
washed with water and brine and dried over MgSO4. Con-
centration under reduced pressure yielded a 6:1 mixture of
the E and Z isomers of ethyl 2-methyl-5-phenyl-2-pentenoate
(5.96 g, 77%) by capillary GC.
Flash chromatography of a sample of (E)- and (Z)-ethyl
2-methyl-5-phenyl-2-pentenoate (1.5 g) on silica gel (4% ethyl
acetate/96% hexane) provided samples of (E)-ethyl 2-methyl-
5-phenyl-2-pentenoate (0.656 g), Z ethyl 2-methyl-5-phenyl-
2-pentenoate (0.089 g), and a mixture of the two isomers (0.535
g, 85% recovery). IR (neat): 1707, 1644 cm-1. E isomer: 1H
cm-1
.
1H NMR (CDCl3, 200 MHz): δ 1.82 (s, 3H), 3.3 (br s,
1H), 4.10 (s, 2H), 6.48 (s, 1H), 7.2-7.3 (m, 5H). 13C NMR
(CDCl3, 50 MHz): δ 15.2, 68.8, 125.0, 126.3, 128.1, 128.8, and
137.6. Anal. Calcd for C10H12O: C, 81.04; H, 8.16. Found:
C, 81.21; H, 8.21.
2-Meth yl-2-pr open -1-yl Tetr ah ydr opyr an yl Eth er. Over
a period of 15 min, TsOH‚H2O (34.80 g, 0.202 mol) was added
to a solution of 2-methyl-2-propen-1-ol (14.44 g, 0.200 mol) and
3,4-dihydro-2H-pyran (16.83 g, 0.200 mol) in CH2Cl2 (300 mL)
while keeping the reaction temperature at 20 °C. After 3 h,
the reaction mixture was extracted with saturated NaHCO3,
water, and brine and dried over MgSO4. The solvent was
removed under reduced pressure, and the resulting material
was distilled (53 °C, 5 mmHg) to give 2-methyl-2-propen-1-yl
tetrahydropyranyl ether (16.97 g, 54%). IR (neat): 1640 cm-1
.
1H NMR (CDCl3, 200 MHz): δ 1.5-2.0 (m, 9H) including 1.76
(s), 3.53 (m, 1H), 3.8-4.0 (m, 2H) including 3.9 (m) and 3.90

Stereoselection in the Ortho Ester Claisen Rearrangement
J . Org. Chem., Vol. 62, No. 7, 1997 1983
NMR (CDCl3, 200 MHz): δ 1.29 (t, 3H, J ) 7.1 Hz), 1.78 (s,
3H), 2.48 (q, 2H, J ) 8.0 Hz), 2.76 (t, 2H, J ) 8.0 Hz), 4.18 (q,
syn and anti products. Flash chromatography afforded the syn
and anti products in 65% overall yield. IR (neat): 1735, 1644
2H, J ) 7.1 Hz), 6.80 (t, 1H, J ) 8.0 Hz), 7.2-7.3 (m, 5H). 13
C
cm-1
.
1H NMR (CDCl3, 200 MHz): syn isomer: δ 0.96 (d, 3H,
NMR (CDCl3, 50 MHz): δ 12.0, 14.0, 30.3, 34.5, 60.0, 125.8,
128.1, 128.2, 128.3, 140.5, 141.0, 167.7. Z isomer: 1H NMR
(CDCl3, 200 MHz): δ 1.29 (t, 3H, J ) 7.2 Hz), 1.89 (s, 3H),
2.74 (m, 2H), 4.19 (q, 2H, J ) 7.2 Hz), 5.96 (t, 1H, J ) 7.9
Hz), 7.2-7.3 (m, 5H). 13C NMR (CDCl3, 50 MHz): δ 14.3, 20.5,
31.1, 35.5, 60.0, 125.9, 128.0, 128.3, 128.4, 141.3, 141.6, 168.1.
Mixture of E and Z isomers: Mass spectrum: 218 (M+), 91
(100). Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found:
C, 77.25; H, 8.20.
J ) 6.9 Hz), 1.25 (t, 3H, J ) 7.2 Hz), 1.62 (s, 3H), 2.99 (dq,
1H, J d ) 11.8 Hz, J q ) 7.2 Hz), 3.38 (d, 1H, J ) 11.8 Hz), 4.14
(q, 2H, J ) 7.2 Hz), 4.79 (m, 1H), 4.97 (m, 1H), 7.2 (m, 5H);
anti isomer: δ 0.93 (t, 3H, J ) 7.2 Hz), 1.24 (d, 3H, J ) 6.8
Hz), 1.57 (s, 3H), 3.06 (dq, 1H, J d ) 11.5 Hz, J q ) 6.8 Hz),
3.48 (d, 1H, J ) 11.5 Hz), 3.85 (q, 2H, J ) 7.2 Hz), 4.84 (m,
1H), 4.99 (m, 1H), 7.2 (m, 5H). 13C NMR (CDCl3, 50 MHz):
syn isomer: δ 14.2, 16.7, 22.1, 43.2, 56.2, 60.2, 110.1, 126.7,
128.4, 128.5, 140.7, 147.3, 176.1; anti isomer: δ 13.8, 16.7, 19.9,
41.9, 56.9, 60.0, 112.3, 126.5, 128.0, 128.1, 141.5, 145.2, 175.7.
Anal. Calcd for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.46;
H, 8.70.
Cla isen Rea r r a n gem en ts. Gen er a l P r oced u r e for Ke-
ta l Cla isen Rea r r a n gem en t. An allylic alcohol (1 mmol), a
ketal (3 mmol), and a carboxylic acid (0.1 equiv) were combined
in a round-bottom flask equipped with magnetic stirring and
a short-path distillation apparatus, and the mixture was
heated at 125 °C for 20 h.11 The reaction mixture was diluted
with ether and extracted with 10% HCl, saturated NaHCO3,
water, and saturated brine. The resulting organic layer was
dried over MgSO4, filtered, and evaporated under reduced
pressure. Capillary gas chromatography of the crude reaction
mixture revealed the composition of the reaction mixture as a
ratio of the less substituted product, the syn isomer of the more
highly substituted product, and the anti isomer of the more
highly substituted product. Flash chromatography on silica
(5% ethyl acetate/hexane) afforded samples of the three
In a separate experiment, the Z isomer of 2-methyl-3-
phenyl-2-propen-1-ol and triethyl orthopropionate were al-
lowed to react in the presence of pivalic acid to give a 14:86
mixture of syn and anti products in 66% yield after flash
chromatography. The products exhibited identical spectral
characteristics to the corresponding products obtained from
the E alcohol.
E n ola t e Cla isen R ea r r a n gem en t s. (E)-2-Met h yl-3-
p h en yl-2-p r op en yl P r op a n oa te (29a ). Propionic anhydride
(2.60 g, 20.0 mmol) was added via syringe to a solution of
2-methyl-3-phenyl-2-propen-1-ol (1.48 g, 10.0 mmol) in anhy-
drous pyridine (10 mL) at 0 °C, and the resulting solution was
allowed to warm to 25 °C over 2 h and stirred for 24 h at 25
°C. The excess anhydride was quenched by the addition of
water, and the reaction mixture was stirred an additional 30
min. The reaction mixture was poured into saturated NaH-
CO3, and the mixture was extracted with ether. The combined
organic layers were washed with saturated NaHCO3, water,
saturated CuSO4, and brine. The organic layer was dried over
MgSO4, concentrated under reduced pressure, and purified by
bulb-to-bulb distillation (160 °C, 0.15 mmHg) to give the
isomers. These materials were characterized by 1H NMR, 13
NMR, IR, and elemental analysis.
C
Keta l Cla isen Rea r r a n gem en t betw een (E)-2-Meth yl-
3-p h en yl-2-p r op en -1-ol a n d 2,2-Dieth oxybu ta n e. (E)-2-
Methyl-3-phenyl-2-propen-1-ol and 2,2-diethoxybutane were
allowed to react in the presence of propionic acid to give a 4:79:
17 ratio of 6-methyl-5-phenyl-6-hepten-3-one (14, R3 ) CH3):
syn 3,5-dimethyl-4-phenyl-5-hexen-2-one (12, R3 ) CH3):anti
3,5-dimethyl-4-phenyl-5-hexen-2-one (13, R3 ) CH3). Flash
chromatography on silica gel (3% ethyl acetate/hexane) af-
forded the products in 78% combined yield. 6-Methyl-
desired ester (1.850 g, 91%). IR (neat): 1726, 1662 cm-1 1H
.
5-phenyl-6-hepten-3-one: IR (neat): 1711, 1642 cm-1
.
1H
NMR (CDCl3, 200 MHz): δ 1.18 (t, 3H, J ) 7.6 Hz), 1.89 (s,
3H), 2.40 (q, 2H, J ) 7.6 Hz), 4.64 (s, 2H), 6.53 (s, 1H), 7.3 (m,
5H). 13C NMR (CDCl3, 50 MHz): δ 9.1, 15.4, 27.6, 69.9, 126.7,
128.1, 128.9, 132.9, 137.1, 174.1 (one peak is 2 carbons). Anal.
Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.24; H,
7.96.
NMR (CDCl3, 200 MHz): δ 0.97 (t, 3H, J ) 7.3 Hz), 1.62 (s,
3H), 2.3 (m, 2H), 2.79 (dd, 1H, J ) 7.6 Hz, 16.1 Hz), 2.95 (dd,
1H, J ) 7.4 Hz, 16.1 Hz), 3.63 (t, 1H, J ) 7.5 Hz), 4.84 (s,
1H), 4.86 (s, 1H), 7.3 (s, 5H). 13C NMR (CDCl3, 50 MHz): δ
7.6, 21.6, 36.6, 47.0, 47.7, 110.1, 126.5, 127.7, 128.4, 142.6,
147.2, 209.7. Anal. Calcd for C14H18O: C, 83.12; H, 8.97.
Found: C, 82.96; H, 8.78. syn- and anti-3,5-Dimethyl-4-
syn - a n d a n ti-2,4-Dim eth yl-3-p h en yl-4-p en ten oic Acid
(30 a n d 31, R1 ) Me) via En ola te Cla isen . The following
procedure is a modification of the method of Ireland.6 Butyl-
lithium (0.56 mL of 1.95 M solution in hexane, 1.1 mmol) was
added to a solution of diisopropylamine (0.252 g, 1.5 mmol) in
THF (3 mL) at 0 °C under dry nitrogen. The resulting pale
yellow solution was cooled to -78 °C and (E)-2-methyl-3-
phenyl-2-propenyl propanoate (0.204 g, 1.0 mmol) in THF (0.2
mL) was added dropwise over 4 min and stirred an additional
3 min to produce a red solution. A solution of tert-butyldi-
methylsilyl chloride (0.166 g, 1.1 mmol) in HMPA (0.5 mL)
was added, and the now brown reaction mixture was stirred
an additional 2 min at -78 °C, warmed to 25 °C, and heated
at reflux for 1 hr. Aqueous HCl (1 mL of 10% solution) was
added, and the reaction mixture was stirred for 45 min at 25
°C. The resulting mixture was poured into aqueous 5% NaOH
and extracted with ether. Concentrated HCl and ice were
added to the aqueous layer until the solution was cloudy, and
the mixture was extracted with ether. The combined organic
layers were washed with water and brine, dried over MgSO4,
and concentrated under reduced pressure. Removal of vola-
tiles under vacuum (0.3 mmHg) afforded an orange waxy
residue (23%). This solid was shown to be a 3:1 anti:syn
mixture of the desired pentenoic acids by 1H NMR spectros-
phenyl-5-hexen-2-one: IR (neat): 1710, 1644 cm-1 1H NMR
.
(60 MHz): syn isomer: δ 0.86 (d, 3H, J ) 6.9 Hz), 1.62 (s,
3H), 2.20 (s, 3H), 3.15 (dq, 1H, J d ) 11.5 Hz, J q ) 6.9 Hz),
3.39 (d, 1H, J ) 11.5 Hz), 4.82 (s, 1H), 4.90 (s, 1H), 7.3 (s,
5H); anti isomer δ 1.15 (d, 3H, J ) 6.7 Hz), 1.58 (s, 3H), 1.91
(s, 3H), 3.1 (m, 1H), 3.50 (d, 1H, J ) 11.6 Hz), 4.89 (s, 1H),
5.00 (s, 1H), 7.3 (s, 5H); 13C NMR (CDCl3, 50 MHz): syn isomer
δ 16.2, 22.5, 28.2, 50.4, 55.4, 110.1, 126.7, 128.4 (2 carbons),
140.8, 147.6, 211.9; anti isomer δ 16.2, 19.8, 28.9, 48.5, 56.3,
112.4, 126.6, 127.9, 128.4, 141.5, 145.2, 213.7. Mass spec-
trum: 202 (M+), 187, 159, 131 (100), 129, 117, 115, 91. Anal.
Calcd for C14H18O: C, 83.12; H, 8.97. Found: C, 83.24; H, 8.80.
Gen er a l P r oced u r e for Or t h o E st er Cla isen R e-
a r r a n gem en t. An allylic alcohol (1 mmol), an ortho ester (10
mmol), and a carboxylic acid (0.1 equiv) were combined in a
round-bottom flask equipped with magnetic stirring and a
short-path distillation apparatus, and the mixture was heated
at 125 °C for 2 h.2,10 The reaction mixture was diluted with
ether and extracted with 10% HCl, saturated NaHCO3, water,
and saturated brine. The resulting organic layer was dried
over MgSO4, filtered, and evaporated under reduced pressure.
Capillary gas chromatography of the crude reaction mixture
provided syn:anti ratios of the products, and flash chromatog-
raphy on silica (5% ethyl acetate/hexane) afforded samples of
the syn and anti isomers. These materials were characterized
copy. IR (KBr): 3300-2800, 1697 cm-1
.
Anti isomer: 1H
NMR (CDCl3, 200 MHz): δ 1.25 (d, 3H, J ) 6.8 Hz), 1.54 (s,
3H), 2.9-3.1 (m), 3.49 (d, 1H, J ) 11.0 Hz), 4.84 (s, 1H), 4.98
(s, 1H), 7.3 (m, 5H). 13C NMR (CDCl3, 50 MHz): δ 16.8, 19.6,
41.3, 56.2, 112.7, 126.6, 127.8, 128.2, 141.2, 144.9, 181.2. Syn
isomer: 1H NMR (CDCl3, 200 MHz): δ 0.96 (d, 3H, J ) 6.8
Hz), 1.60 (s, 3H), 2.9-3.1 (m), 3.33 (d, 1H, J ) 11.6 Hz), 4.80
1
by H NMR, 13C NMR, IR, and elemental analysis.
syn - an d a n ti-Eth yl 2,4-Dim eth yl-3-ph en yl-4-pen ten oate
(17 a n d 18, R2 ) P h , R1 ) Me). (E)-2-Methyl-3-phenyl-2-
propen-1-ol and triethyl orthopropionate were allowed to react
in the presence of propionic acid to give an 85:15 mixture of

1984 J . Org. Chem., Vol. 62, No. 7, 1997
Daub et al.
(s, 1H), 4.98 (s), 7.3 (m, 5H). 13C NMR (CDCl3, 50 MHz): δ
16.8, 22.2, 43.0, 55.8, 110.2, 126.8, 127.8, 128.9, 140.3, 147.0,
181.2.
indicated the absence of starting material, and the reaction
mixture was cooled and diluted with ether. The ether solution
was extracted with 5% HCl, saturated NaHCO3, and brine and
dried over MgSO4. Concentration under reduced pressure and
flash chromatography on silica with 5% ethyl acetate/hexane
afforded esters 35 and 37 (0.425 g, 88%) as an 84:16 mixture
of syn and anti isomers by capillary GC. IR (neat) 1727, 1643
cm-1. Syn isomer: 1H NMR δ 1.14 (d, 3H, J ) 6.5 Hz), 1.20
(t, 3H, J ) 7.1 Hz), 1.75 (s, 3H), 2.67 (m, 2H), 3.53 (d, 2H, J
) 5.7 Hz), 4.06 (q, 2H, J ) 7.1 Hz), 4.45 (d, 1H, J ) 11.5 Hz),
4.53 (d, 1H, J ) 11.5 Hz), 4.75 (m, 1H), 4.84 (m, 1H), 7.3 (m,
5H). 13C NMR δ 14.1, 14.5, 21.2, 40.6, 49.2, 60.0, 70.1, 73.1,
112.7, 127.5 (2 carbons), 128.3, 138.4, 145.1, 175.6. Anti
isomer: 1H NMR δ 1.07 (d, 3H, J ) 6.8 Hz), 1.19 (t, 3H, J )
7.1 Hz), 1.65 (s, 3H), 2.52 (dq, 1H, J q ) 6.9 Hz, J d ) 10.7 Hz,
6.9 Hz), 2.73 (dt, 1H, J d ) 10.7 Hz, J t ) 8.0 Hz), 4.09 (dd, 1H,
J ) 8.0 Hz, 9.8 Hz), 3.50 (dd, 1H, J ) 8.0 Hz, 9.8 Hz), 4.04 (q,
2H, J ) 7.1 Hz), 4.45 (d, 1H, J ) 11.6 Hz), 4.53 (d, 1H, J )
11.6 Hz), 4.83 (m, 1H), 4.91 (m, 1H), 7.3 (m, 5H). 13C NMR δ
14.1, 15.7, 19.7, 40.1, 50.0, 60.2, 71.5, 72.9, 114.3, 127.4, 127.6,
128.2, 138.5, 143.5, 176.1. Anal. Calcd for C17H24O3: C, 73.88;
H, 8.75. Found: C, 73.88; H, 8.77.
syn - a n d a n ti-Met h yl 2,4-Dim et h yl-3-p h en yl-4-p en -
ten oa te (32 a n d 33, R1 ) Me). A 3:1 mixture of the syn and
anti isomers of 2,4-dimethyl-3-phenyl-4-pentenoic acid (0.090
g, 0.44 mmol), iodomethane (0.160 g, 1.13 mmol), and K2CO3
(0.157 g, 1.14 mmol) were dissolved in DMSO (2 mL) and
allowed to stir at 25 °C for 10 h. The reaction mixture was
diluted with ether and washed with water, 5% HCl, 50%
saturated NaHCO3, water, and brine. The organic layer was
dried over MgSO4 and concentrated under reduced pressure
to give a pale yellow liquid (0.040 g, 42%). The major and
minor isomers (3:1) in this mixture exhibited NMR spectral
data (1H and 13C) identical with those of the minor and major
isomers, respectively, produced in the ortho ester Claisen
rearrangement described previously.
Syn th esis of Botr yod ip lod in . (Ben zyloxy)eth a n a l. A
magnetically stirred solution of cis-1,4-bis(benzyloxy)-2-
butene24 (36, 14.40 g, 53.6 mmol) in 50% (v/v) MeOH-CH2Cl2
(200 mL) was cooled to -78 °C, and ozone was bubbled through
until TLC indicated the complete disappearance of starting
material (2 h). The reaction mixture was purged with oxygen,
and dimethyl sulfide (17.8 g, 285 mmol) was added. After
stirring overnight at 23 °C, the reaction mixture was poured
into water and extracted with CH2Cl2. The combined organic
layers were washed with brine and dried over Na2SO4.
Concentration under reduced pressure and vacuum distillation
(75 °C, 0.25 mm Hg) afforded the desired aldehyde as a
colorless liquid (12.16 g, 76%). 1H NMR δ 4.07 (d, 2H, J ) 0.7
Hz), 4.60 (s, 2H), 7.3 (m, 5H), 9.67 (t, 1H, J ) 0.7 Hz). 13C
NMR δ 73.5, 75.2, 127.9, 128.0, 128.4, 136.8, 200.2.
(E)- a n d (Z)-Eth yl 4-(Ben zyloxy)-2-m eth yl-2-bu ten oa te.
(E)- and (Z)-Ethyl 4-(benzyloxy)-2-methyl-2-butenoate was
prepared according to the method used to make (E)-ethyl
2-methyl-5-phenyl-2-pentenoate. Triethyl 2-phosphonopropi-
onate (30.0 g, 126 mmol), NaH (6.00 g of 50% oil disp, 126
mmol), and (benzyloxy)ethanal (18.96 g, 126 mmol) afforded
a 5.3:1 mixture of (E)- and (Z)-ethyl 4-(benzyloxy)-2-methyl-
2-butenoate as a colorless liquid (21.2 g, 72%). IR (neat) 1709,
1655 cm-1. The E and Z isomers were separated in another
experiment and characterized individually. E isomer: 1H
NMR δ 1.29 (t, 3H, J ) 7.1 Hz), 1.81 (s, 3H), 4.17 (q, 2H, J )
7.1 Hz), 4.17 (d, 2H, J ) 6.0 Hz), 4.51 (s, 2H), 6.87 (t, 1H, J )
6.0 Hz), 7.3 (m, 5H). 13C NMR: δ 12.6, 14.1, 60.5, 66.7, 72.7,
127.6 (2 carbons), 128.3, 129.4, 137.7, 137.8, 167.3. Z isomer:
1H NMR δ 1.27 (t, 3H, J ) 7.1 Hz), 1.91 (s, 3H), 4.17 (q, 2H,
J ) 7.1 Hz), 4.48 (dm, 2H, J d ) 6.0 Hz), 4.51 (s, 2H), 6.14 (t,
1H, J ) 6.0 Hz), 7.3 (m, 5H). 13C NMR: δ 14.1, 19.7, 60.3,
68.7, 72.7, 127.6, 127.7 (2 carbons), 128.3, 138.2, 141.3, 167.2.
Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.68;
H, 7.74.
(E)-4-(Ben zyloxy)-2-m et h yl-2-b u t en -1-ol (34). (E)-4-
(Benzyloxy)-2-methyl-2-butenoate (10.11 g, 43.2 mmol) was
reduced with LiAlH4 according to the procedure used to
prepare (E)-2-methyl-3-phenyl-2-propen-1-ol. Medium pres-
sure chromatography on silica gel (12:1:87 ethyl acetate:
2-propanol:hexane) afforded alcohol (36, 4.54 g, 53%) as a 98:2
E:Z mixture by capillary GC. In a separate experiment,
selected fractions provided small samples of (Z)-4-(benzyloxy)-
2-methyl-2-buten-1-ol for spectral and reaction studies. IR
syn - a n d a n ti-3-[(Ben zyloxy)m eth yl]-2,4-d im eth yl-4-
p en ten oic Acid (38 a n d 39). A sample of 35 and 37 (2.987
g, 10.8 mmol), MeOH (250 mL), and 10% aqueous NaOH (100
mL) were heated at reflux for 90 min at which time TLC
indicated the absence of the ester. The reaction mixture was
cooled and acidified with 5% HCl to pH 1 and extracted with
ether. The combined organic layers were extracted with water
and brine and dried over MgSO4. Concentration under
reduced pressure afforded carboxylic acids 38 and 39 (2.60 g,
98%) as a 76:24 mixture of syn and anti isomers by capillary
GC. The crude products were sufficiently pure to be carried
on to the next step without purification. IR (neat) 3400-2400
(vbr), 1701, 1641 cm-1
.
1H NMR δ 1.06(anti)/1.11(syn) (d/d,
3H, J ) 6.5 Hz), 1.60(anti)/1.71(syn) (s/s, 3H), 2.67 (m, 2H),
3.45(anti)/3.51(syn) (m/d, 2H, J ) 5.7 Hz), 4.45 (m, 2H),
4.71(syn)/4.78(anti) (s/s, 1H), 4.82(syn)/4.87(anti) (s/s, 1H), 7.3
(m, 5H). 13C NMR (syn isomer) δ 14.0, 21.6, 40.5, 48.6, 69.9,
73.0, 112.8, 127.5 (2 carbons), 128.3, 138.3, 144.7, 181.2; (anti
isomer) δ 15.5, 20.0, 39.9, 49.6, 71.4, 72.8, 114.4, 127.5 (2
carbons), 128.3, 138.3, 143.2, 182.0.
cis- a n d tr a n s-2-Meth yl-3-(2-p r op en yl)bu tyr ola cton e
(41 a n d 42). The following procedure is a modification of
Reist.27 Ammonia (100 mL) was distilled from lithium into a
three-necked round-bottom flask equipped with magnetic
stirring, a dry-ice condenser, and a drying tube. The solution
was maintained at -78 °C, and a sample of carboxylic acids
38 and 39 (0.996 g, 4.03 mmol) in anhydrous ether (20 mL)
was added via syringe. Lithium wire was added as small
pieces to the reaction mixture until the characteristic blue color
persisted for 2 min (90 mg, 13 mmol). Solid NH4Cl (≈5 g) was
added to quench the reaction, and the dry-ice bath was
replaced with a water bath. The ammonia was allowed to
evaporate under N2 until a white solid remained. The white
residue was dissolved in water and acidified with HCl to a
pH of 2, and the aqueous solution was extracted with ether.
The combined extracts were dried over MgSO4. The solvent
was removed by distillation at ambient pressure, and the
resulting liquid was purified by bulb-to-bulb distillation (135
°C, 15 mmHg) to afford lactones 41 (cis) and 42 (trans) (0.491
g, 87%) in a 73:27 ratio by VPC. IR (neat) 1772, 1640 cm-1
.
(neat) 3397, 1675 cm-1
.
E isomer: 1H NMR δ 1.65 (s, 3H),
Small amounts of the cis and trans isomers were separated in
another experiment and characterized individually: cis iso-
mer: 1H NMR δ 1.02 (d, 3H, J ) 7.3 Hz), 1.70 (s, 3H), 2.75
(5-plet, 1H), 3.12 (m, 1H), 4.26 (dd, 1H, J ) 4.1, 9.3 Hz), 4.35
(dd, 1H, J ) 6.2, 9.3 Hz), 4.78 (s, 1H), 4.94 (s, 1H); 13C NMR
δ 10.1, 20.9, 37.2, 46.6, 69.8, 114.1, 141.5, 179.3; trans
isomer: 1H NMR δ 1.25 (d, 3H, J ) 7.0 Hz), 1.76 (s, 3H), 2.53
(dq, 1H, J d ) 11.0 Hz, J q ) 6.9 Hz), 2.81 (ddd, 1H, J ) 7.7,
10.6, 11.0 Hz), 3.95 (dd, 1H, J ) 8.9, 10.5 Hz), 4.37 (dd, 1H, J
) 7.8, 8.9 Hz), 4.90 (s, 1H), 4.96 (s, 1H); 13C NMR δ 13.6, 19.6,
38.1, 51.1, 69.4, 113.6, 140.7, 179.1. Anal. Calcd for
C8H12O2: C, 68.55; H, 8.63. Found: C, 68.32; H, 8.66.
cis- a n d tr a n s-2-Hyd r oxy-3-m eth yl-4-(2-p r op en yl)tet-
r a h yd r ofu r a n (43 a n d 44, each as a mixture of R and â
2.2 (br s, 1H), 3.99 (s, 2H), 4.06 (d, 2H, J ) 6.7 Hz), 4.51 (s,
2H), 5.65 (t, 1H, J ) 6.7 Hz), 7.3 (m, 5H). 13C NMR δ 13.7,
66.3, 68.1, 72.4, 121.6, 127.6, 127.8, 128.4, 138.4, 139.2.
Z
isomer: 1H NMR δ 1.80 (s,3H), 2.4 (br s, 1H), 4.03 (d, 2H, J )
6.9 Hz), 4.06 (s, 2H), 4.50 (s, 2H), 5.55 (t, 1H, J ) 6.9 Hz), 7.3
(m, 5H). 13C NMR δ 21.4, 61.8, 65.7, 72.4, 123.6, 127.7, 127.8,
128.4, 138.0, 140.7. Anal. Calcd for C12H16O2: C, 74.97; H,
8.39. Found: C, 74.57; H, 8.11.
syn - a n d a n ti-E t h yl 3-[(Ben zyloxy)m et h yl]-2,4-d i-
m eth yl-4-p en ten oa te (35 a n d 37). A mixture of alcohol 34
(0.330 g, 1.7 mmol), triethyl orthopropionate (6.0 g, 35 mmol),
and propionic acid (0.038 g, 0.5 mmol) were allowed to react
at 110 °C in a round bottom flask equipped with magnetic
stirring and a microdistillation head. After 60 min TLC

Stereoselection in the Ortho Ester Claisen Rearrangement
J . Org. Chem., Vol. 62, No. 7, 1997 1985
anomers). The following procedure is a modification of Corey.28
A 73:27 cis/ trans mixture of lactones 41 and 42 (96 mg, 0.681
mmol) was dissolved in anhydrous toluene under N2 and cooled
to -78 °C. Diisobutylaluminum hydride (0.55 mL of 1.5 M
solution in toluene, 0.817 mmol) was added and the reaction
mixture was allowed to stir for 1.5 h at which time TLC
indicated the absence of starting material. The reaction was
quenched by the addition of sufficient 1 M H2SO4 to redissolve
the precipitated salts. The reaction mixture was allowed to
warm to room temperature and was partitioned between ether
and water. The organic layer was washed with saturated
NaHCO3, water, and brine and dried over Na2SO4. Concen-
tration under reduced pressure and flash chromatography on
silica with 40% ethyl acetate/hexane afforded lactols 43 (cis)
and 44 (trans) (82 mg, 85%) in a 71:29 ratio by VPC. IR (neat)
Botr yod ip lod in Aceta te a n d Ep ibotr yod ip lod in Ace-
ta te (47 a n d 48). A 70:30 mixture of 45 and 46 (39 mg, 0.273
mmol) was dissolved in anhydrous pyridine (2 mL) and treated
with acetic anhydride (0.2 g, 2 mmol) for 20 h at 25 °C. The
mixture was diluted with CH2Cl2, washed with saturated
CuSO4, water, saturated NaHCO3, and brine, and dried over
Na2SO4. Concentration under reduced pressure afforded 47
1
and 48 (43 mg, 84%) as a 68:32 mixture by H NMR. Acetate
47 existed as a 96:4 mixture of R and â anomers while 48 was
1
a 60:40 mixture of â and R anomers. The H NMR spectra of
47 and 48 agreed with published data.29
Ack n ow led gm en t. Acknowledgement is made to
the Donors of the Petroleum Research Fund, adminis-
tered by the American Chemical Society, for the partial
support of this research. Additional support was pro-
vided by the Camille and Henry Dreyfus Foundation
and a Summer Research Fellowship (to C.R.O.) from the
PEW Foundation Science Program in Undergraduate
Education. Funding for the purchase of a capillary GC
(NSF-RUI) and a 200 MHz NMR spectrometer (NSF-
RUI, NSF-CSIP, Research Corporation, Dreyfus Foun-
dation) are also gratefully acknowledged. The authors
thank Professor M. J . Kurth for providing 1H NMR
spectra of botryodiplodin and epibotryodiplodin.
3390, 1642 cm-1
. Small amounts of the cis isomer could be
separated and characterized individually; the trans isomer
could only be characterized as part of a cis-trans mixture: cis
isomer (43, >92% R-anomer): 1H NMR δ 0.81 (d, 3H, J ) 7.2
Hz), 1.76 (s, 3H), 2.31 (5-plet, 1H), 3.10 (br s, 1H), 3.16 (q, 1H,
J ) 8.2 Hz), 3.96 (t, 1H, J ) 8.3 Hz), 4.12 (t, 1H, J ) 8.3 Hz),
4.62 (s, 1H), 4.88 (s, 1H), 5.18 (s, 1H); 13C NMR δ 11.3, 23.2,
42.3, 46.2, 68.9, 104.4, 111.3, 141.9; trans isomer (44, ≈1:1
mixture of R and â anomers): 1H NMR δ distinctive signals
included 1.03/1.09 (d/d, 3H, J ) 6.9 Hz), 1.69/1.74 (s/s, 3H),
5.12/5.37 (t/t, 1H, J ) 4.4 Hz). Anal. Calcd for C8H14O2: C,
67.57; H, 9.92. Found: C, 67.48; H, 8.96.
Botr yod ip lod in a n d Ep ibotr yod ip lod in (45 a n d 46). A
71:29 mixture of lactols 43 and 44 (122 mg, 0.859 mmol) was
dissolved in CH2Cl2 and treated with O3 at -78 °C for 7 min.
The solution was purged with O2 (5 min), (CH3)2S (0.5 mL)
was added, and the reaction mixture was allowed to warm to
25 °C over 30 min. The mixture was poured into water and
extracted with CH2Cl2. The combined organic layers were
washed with brine and dried over Na2SO4. Concentration
under reduced pressure and flash chromatography on silica
with 50% ethyl acetate/hexane afforded 45 and 46 (68 mg,
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
scriptions and spectral and analytical data for other com-
pounds described in this paper (11 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
1
55%) as a 70:30 mixture by VPC. The H NMR spectra of 45
and 46 agreed with published data.
J O9614250