Acyclic 1,4-Stereocontrol via the Allylic Diazene Rearrangement: Development, Applications, and the Essential Role of Kinetic e Stereoselectivity in Tosylhydrazone Formation

Article abstract of DOI:10.1021/acs.joc.7b00428

We report full details of a method for 1,3-reductive transposition of α-alkoxy-α,β-unsaturated hydrazones to provide E-alkenes with high 1,4-stereocontrol between the two respective allylic stereocenters. The process couples a chelation-controlled reduction of the hydrazone with an in situ allylic strain controlled retro-ene reaction of an allyl diazene, i.e., an allylic diazene rearrangement. Such stereotriads are frequently observed motifs in natural products. We observed a fortuitous kinetic preference for the E-hydrazone geometry during the hydrazonation reaction, as only the E-isomers could undergo chelation-controlled reduction.

Full text of DOI:10.1021/acs.joc.7b00428

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Article
Acyclic 1,4-Stereocontrol via the Allylic Diazene Rearrangement:
Development, Applications, and the Essential Role of
Kinetic E-Stereoselectivity in Tosylhydrazone Formation
Maha Laxmi Shrestha, Wei Qi, and Matthias C. McIntosh
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Jun 2017
Downloaded from http://pubs.acs.org on June 23, 2017
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Acyclic 1,4-Stereocontrol via the Allylic Diazene Rearrangement: Development, Applications,
and the Essential Role of Kinetic E-Stereoselectivity in Tosylhydrazone Formation
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Maha L. Shrestha, Wei Qi, and Matthias C. McIntosh*
119 Chemistry Bldg, University of Arkansas, Fayetteville, AR 72701
mcintosh@uark.edu
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ABSTRACT
We report full details of a method for 1,3ꢀreductive transposition of αꢀalkoxyꢀα,βꢀ
unsaturated hydrazones to provide Eꢀalkenes with high 1,4ꢀstereocontrol between the two
respective allylic stereocenters. The process couples a chelation controlled reduction of the
hydrazone with an in situ allylic strain controlled retroꢀene reaction of an allyl diazene, i.e. an
allylic diazene rearrangement. Such stereotriads are frequently observed motifs in natural
products. We observed a fortuitous kinetic preference for the Eꢀhydrazone geometry during the
hydrazonation reaction, as only the Eꢀisomers could undergo chelationꢀcontrolled reduction.
INTRODUCTION
Several years ago, we considered undertaking the total synthesis of antascomicin B (1), a
macrolide isolated from a Streptomyces strain that binds with high affinity to FKBP12 (Figure
1).1,2,3 We noted two pairs of stereochemical relationships in the molecule: First, a 1,2ꢀanti
relationship between the C26 alkoxy and C27 methyl stereocenters, and a 1,2ꢀsyn relationship
between the C14 alkoxy and C15 methyl stereocenters; second, a 1,4ꢀanti relationship between
the C14 hydroxy and C11 methyl stereocenters, and a 1,4ꢀsyn relationship between the C26
alkoxy and C23 methyl stereocenters. We recognized immediately that Irelandꢀtype Claisen
rearrangements would be well suited to introduce the 1,2ꢀsyn and 1,2ꢀanti alkoxy and alkyl
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stereocenters at C26ꢀC27 and C14ꢀC15.4 We reasoned that the C14 and C26 alkoxy
stereocenters could potentially be employed as the source of stereocontrol for the remote C11
and C23 stereocenters, respectively, via a stereochemical relay to engender the requisite 1,4ꢀsyn
or 1,4ꢀanti stereocontrol (vide infra).
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In addition to antascomicin B, there are numerous bioactive natural products that possess
2° oxygen and 3° alkyl containing stereocenters in a 1,4ꢀsyn or 1,4ꢀanti relationship.5,6,7,8,9,10,11,12
There are yet additional natural products with 1,4ꢀsyn and 1,4–anti relationships in which the
stereocenters are separated by an intervening Eꢀalkene, such as divergolide B and jerangolid D
(Figure 1).13,14,15,16,17,18,19,20,21,22,23,24,25,26 Since hydrogenation of the intervening alkene could
provide the dihydro adducts needed for natural products such as antascomicin B, a general
method for the preparation of Eꢀ1,4ꢀsyn and Eꢀ1,4ꢀanti stereotriads (inset) had the potential to be
broadly useful in complex molecule synthesis, and hence became our immediate goal.
Figure 1: Representative bioactive natural products containing 1,4ꢀsyn and antiꢀ
stereorelationships.
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In 1976 Kabalka reported a modification27 of an earlier procedure by Hutchins28 of a
reductive transposition of an α,βꢀunsaturated ketone to a 1,2ꢀrearranged propene (Scheme 1).
The twoꢀstep transformation involves an initial conversion of the enone to the corresponding
sulfonyl hydrazone. In the second step, a 1,2ꢀreduction of the hydrazone with catecholborane
(HBCat) is followed by in situ formation of an allylic diazene. The diazene suffers spontaneous
retroꢀene reaction with delivery of the diazene hydrogen to the terminus of the alkene.29 The
retroꢀene reaction is known as the allylic diazene rearrangement (ADR).30
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Scheme 1
We31 and many others32 have employed this protocol in diastereoselective reductive
transpositions of cyclic enones in complex molecule synthesis. However, prior to our work,33
there were no reports of its use in any acyclic systems to generate sp3 stereocenters.34
We reasoned that the sulfonyl hydrazone of an αꢀchiral αꢀalkoxy enone 2 could be
reduced diastereoselectively via either a Cram chelation35,36,37 or a FelkinꢀAnh type pathway38 to
provide intermediate allyl diazene 3 (Scheme 2). Allylic strain directed rearrangement39,40,41
would deliver the diazene hydrogen to the prochiral allylic carbon diastereoselectively.
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Scheme 2
Three issues were of concern at the project’s outset: (i) whether the hydrazones of the
comparatively hindered enones could be readily prepared; (ii) whether the E/Z configuration of
the hydrazone would be relevant, and if so, (iii) whether the E/Z configuration of the hydrazone
could be controlled.
RESULTS AND DISCUSSION
Methodological Studies – Enone Synthesis. We prepared a variety of αꢀchiral αꢀ
alkoxy enones from (S)ꢀ(+)ꢀlactic and either racemic or (S)ꢀ(+)ꢀmandelic acid to test our
hypothesis. Weinreb amide 5a was prepared by methylation of (S)ꢀ(+)ꢀlactic acid with
diazomethane, followed by etherification of the alcohol and ester hydrolysis to provide Oꢀbenzyl
lactic acid in high yield (eq 1, Scheme 3). The amide 5a was prepared via the mixed anhydride.
While 5a was formed without detectable racemization, (S)ꢀ(+)ꢀmandelic acid underwent partial
racemization, likely at the etherification step, to give a ca. 3:1 er of amide 5b.42
Addition of various vinyl Li nucleophiles derived from readily accessible vinyl iodides 6
to the Weinreb amides 5a and 5b provided the requisite Eꢀenones E-7a,b, 8a,b, and 9a,b, and
and Zꢀenones Zꢀ7a,b in good to excellent yields (eq 2, Scheme 3). The siloxymethyl,
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siloxyethyl, and terminal vinyl substituents of the enones were chosen because they are
synthetically flexible groups, and could be elaborated in numerous ways.
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Scheme 3
Hydrazonation Reactions – Kinetic Selectivity for E-Hydrazone. With the requisite
enones in hand, the next step was to form the tosyl hydrazones. Tosyl hydrazones of enones
have been typically prepared by heating an alcoholic solution of the enone with tosyl hydrazide
with or without an acid catalyst. However, we found these and a variety of related conditions to
be unsatisfactory, giving incomplete conversion and/or undesired side products. Treatment of
enone E-7a, for example, with tosyl hydrazide and ethanol gave the desired hydrazone, but also
desilylated and deconjugated43 hydrazones.
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After some experimentation, we discovered that simply mixing the enone with tosyl
hydrazide in neat Ti(OiPr)4 at ambient temperature yielded the hydrazones in generally good
yields (method A, Scheme 4). Under these conditions, the Eꢀhydrazone isomer predominated and
could be isolated in pure form by either crystallization or chromatography. We later found that
hydrazones E-10a and E-10b could be prepared by treatment with TsNHNH2 in CH2Cl2 under
microwave irradiation to yield solely the Eꢀhydrazones in similar yield and shorter reaction time
(method B).
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Scheme 4
The E/Z configuration of the hydrazones was determined by 1H NMR analysis (Figure 2).
Hydrogen bonding of the sulfonamide proton in the Zꢀhydrazone results in a ca. 2 ppm downfield
shift relative to the Eꢀisomer.44
R1
R1
R2
R2
BnO
BnO
R3
Ts
N
R3
N
H
N
N
ca.10 ppm
ca. 8 ppm
H
Ts
E-hydrazone
Z-hydrazone
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Figure 2: Approximate 1HꢀNMR shifts of hydrazone NꢀH protons in Eꢀ and Zꢀhydrazones.
The Eꢀselectivity proved to be fortuitous (vide infra), and we subsequently studied the
issue both experimentally and computationally. We employed Oꢀbenzylbenzoin (13) as a model
system for αꢀalkoxy ketones (Scheme 5). Treatment of 13 with TsNHNH2 in neat Ti(OiPr)4 for
48 h provided a 10.7:1 E:Z mixture of hydrazones 14 in 62% yield. We found that irradiating a
methylene chloride solution of 13 and TsNHNH2 in a microwave for 11 h at 30 °C and 30 watts
gave a quantitative yield of a 7.3:1 E:Z mixture of hydrazones 14. Surprisingly, heating the
reaction mixture in methanol completely reversed the selectivity to provide solely the Zꢀ
hydrazone.
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Ph
O
TsNHNH2
conditions
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+
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O
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N
TsHN
NHTs
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Z-14
E-14
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1
Ti(OiPr)4, rt, 48 h, 62%
7.3
0
1
1
CH2Cl2, ))), 30 W, 30 °C, 11 h, 99%
MeOH, 50 °C, 12 h, 60%
Scheme 5
These results imply that both the thermodynamic and kinetic hydrazone isomers can
selectively be formed by appropriate choice of conditions, but it was not clear which isomer is
the kinetic and which is the thermodynamic. We therefore carried out DFT calculations
(B3LYP/6ꢀ31g*) of simplified E- and Z-hydrazones (Figure 3). We believe that the tolyl group
on the sulfone moiety of hydrazones 14 is remote enough that truncating it to a methyl group for
computational simplicity would have negligible effect on the calculated energy difference
between the E- and Z-isomers.
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The calculations predict a modest preference for the Zꢀhydrazone driven by internal
hydrogen bonding between the ether oxygen and the sulfonamide nitrogen. Hence the Eꢀ
hydrazone would be the kinetic isomer, at least in the case of Oꢀalkyl benzoin sulfonyl
hydrazones, and the Zꢀhydrazone the thermodynamic.
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The Z/E energy difference is significantly larger for the hydrazones derived from
terminally disubstituted enones, with the Eꢀisomer calculated to be 5.3 kcal/mol higher in energy
than the hydrogenꢀbonded Zꢀisomer. There is a loss of conjugation in the Eꢀisomer between the
C=N and C=C double bonds as reflected in the large dihedral angle (64.8°) between them as a
consequence of the steric interaction between the alkene and the sulfonamide moiety. The Zꢀ
isomer lacks this interaction, and has a much smaller dihedral angle (21.6°) and better overlap
across the heterodiene system. This makes the observed Z:E ratio of hydrazones 10ꢀ12 all the
more remarkable (1ꢀ9:1 E/Z in neat Ti(OiPr)4, and >20:1 in CH2Cl2 under microwave
irradiation).
Ph
Me
OMe
N
OMe
2
OMe
N
3
Ph
Ph
4
MeO
H
MeO
H
Me
Ph
Me
N
N
1
N
N
N
HN
NH
NH
SO2Me
SO2Me
SO2Me
SO2Me
SO2Me
E
Z (H-bonded)
0.0
E
Z (H-bonded)
0.0
Z
+1.3
+5.3
1,4-dihedral 64.8°
+7.1
13.3°
21.6°
Figure 3: DFT calculations (B3LYP/6ꢀ31g*) of simplified Eꢀ and Zꢀhydrazones
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These computational results were supported experimentally. Treatment of a CDCl3
solution of Eꢀ14 with a stoichiometric amount of CF3CO2H resulted in ca. 1:1 mixture of Eꢀ and
Zꢀisomers after 4 h at ambient temperature.
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There are a just a handful of reports of the preparation of acyclic αꢀalkoxy
sulfonyl45,46,47,48,49,50 or acyl51,52 hydrazones from ketones, and only a few that report the
hydrazone E/Zꢀconfigurations.53,54,55,56 Alami et al reported a 1.5ꢀ5.7:1 Z:E ratio of hydrazones
15 depending upon the identity of R1 and R2 (Figure 4). The hydrazones were prepared by
stirring the ketones with TsNHNH2 in methanol at ambient temperature. This is consistent with
our observation that the reaction in methanol was selective for the Zꢀhydrazone (cf. Scheme 5).
The authors proposed internal Hꢀbonding to be the driving force for the Zꢀselectivity, which is
also consistent with our computational results.
We speculate that the Eꢀhydrazones were formed by complexation with Ti(OiPr)4 (16,
Figure 4). The reason for the high Eꢀselectivity under microwave conditions in CH2Cl2 is
unclear (cf. Scheme 4, 11). Chlorinated solvents are well known to produce trace amounts of
HCl, so perhaps a chelated proton as in 17, analogous to the model proposed for chelation
control in the reduction step (vide infra, Scheme 7), could favor the Eꢀisomer.
Ts
N
H
N
H
Ti(OiPr)n
N
Ph
O
Ph
O
R2O
OMe
OMe
N
NHTs
Ph
NHTs
Ph
R1
Ph
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Ph
16
OMe
15
Figure 4: Possible complexation modes of EꢀHydrazones bearing αꢀalkoxy substituents.
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We found the Eꢀselectivity carried over to more complex examples as well, although in
these cases exogenous acid was added. Treatment of ketone 18 under the microwave conditions
provided Eꢀhydrazone 19 as a single isomer, albeit in moderate yield (Scheme 6).57 Reaction of
ketone 20 with TsNHNH2 in CH2Cl2 at ambient temperature without microwave irradiation, but
with 0.7 eq of HOAc added, provided Eꢀhydrazone 21 after 2 days in good yield.58
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Scheme 6
Chelation Controlled E-hydrazone Reduction. In our initial planning, we hoped to
identify conditions whereby either the 1,4ꢀsyn or 1,4ꢀanti product could be prepared from the
same hydrazone. A FelkinꢀAnh pathway would give 1,2ꢀsyn selective reduction, which would
provide a net 1,4ꢀanti product after the ADR; a Cram chelation pathway would give 1,2ꢀanti
reduction and a net 1,4ꢀsyn product (Scheme 7). Hence we reasoned that catecholborane, which
cannot chelate, would provide the 1,4ꢀanti product, and Zn(BH4)2 which is known to give
chelation controlled reduction of αꢀalkoxy enones,59,60 should provide the 1,4ꢀsyn product.
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NNHTs
R2
OR1
OR1
OR1
R4
R4
OR1
R3
R2
R2
R4
R2
H
N
CatB
H
N
R3
R3
H
R3
NHTs
N H
OR1
N
R4
R4
Felkin-Anh
1,2-syn
1,4-anti
R2
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R3
Xn
M
NHTs
OR1
OR1
OR1
NHTs
R3
N
R4
R4
R1O
R2
R2
R2
R4
R2
H
N
XnM
H
N
R3
R3
R3
NHTs
N H
R4
Cram chelation
1,2-anti
1,4-syn
Scheme 7
Most literature procedures employing the Kabalka protocol use only a small excess of
catecholborane in the reduction of the tosylhydrazone. However, tosylhydrazone Eꢀ10b reacted
sluggishly with 5 eq of borane at ꢀ42 °C, requiring 22 h to completely reduce. Isomer Zꢀ10b
reacted even more slowly, providing only low yield of product after 2 days at ambient
temperature in the presence of 20 eq of borane.
We fortuitously discovered that addition of silica gel (2 weight eq) to the reaction mixture
greatly accelerated the reduction step, such that it could be performed using 5 eq of
catecholborane at ꢀ42 °C within 1 hour. Treatment of Eꢀ10a under these conditions provided
alkene synꢀ22a in 92% yield with high diastereoselectivity (Scheme 8). The relative
configuration was determined by its conversion to the known61 lactone 24 via cleavage of the
TBS ether to give alcohol 23a, followed by simultaneous hydrogenation of the alkene and
hydrogenolysis of the benzyl group. Jones oxidation of the diol provided cisꢀ2ꢀmethylꢀ5ꢀ
hexanolide (24). This stereochemical outcome was the opposite of what we expected. The syn
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configuration required a 1,2ꢀanti reduction of the hydrazone, which implied a Cram chelation
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pathway.
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1. HBCat
CHCl3
silica gel
-42 °C to rt
1. Pd/C
CH3OH
H2 (70 psi)
O
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OBn
OBn
OBn
nBu4NF
THF
O
OTBS
OH
OTBS
2. Jones
reagent
acetone
0 °C
N
2. NaOAc
reflux
NHTs
E-10a
24 30%
syn-22a 92%, >20:1 dr
23a 86%
Scheme 8
In 1979 Rosini et al had reported the 1,2ꢀanti selective reduction of the tosylhydrazones
of benzoin (R1=H) and some Oꢀprotected derivatives (R1=Me,Et) at pH 3.5 with NaCNBH3
using pTsOH to maintain the low pH (Scheme 9).62 Protonation of the hydrazone imine could
enable chelation via hydrogen bonding. This model has been proposed by Fujita and Hiyama to
rationalize the highly 1,2ꢀanti selective reduction of an αꢀacetoxyꢀOꢀbenzyloxime using
PhMe2SiH in CF3CO2H.63
OR
OR
H
H
NHTs
Ph
pTsOH
THF, rt
NaCNBH3
NHTs
N
Ph
Ph
RO
Ph
N
Ph
RO
Ph
N
N
Ph
NHTs
H
NHTs
Ph
OTs
1,2-anti
Scheme 9
If silica gel was simply a proton source, a soluble, well defined acid would be a more
practical reagent, especially on scale. We indeed found that both acetic and trifluoroacetic acids
were effective substitutes for silica gel, supporting the hydrogen bond chelation model. Use of
acetic acid (6ꢀ10 eq) gave higher yields than the stronger trifluoroacetic acid.
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In optimizing the reduction of Eꢀ10a for catecholborane, we found that 2.2ꢀ2.5 eq gave
the best compromise between reaction time and yield on small scale (entries 1ꢀ6, Table 1), but as
the scale increased, 2.5ꢀ3.0 eq were desirable to drive the reaction to completion (entries 8ꢀ11).
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1. HBCat
HOAc (8 eq)
OBn
OBn
CHCl3
-42 °C to rt
OTBS
OTBS
N
2. NaOAc
reflux
NHTs
E-10a
syn-22a
Table 1. Conversion of Eꢀ10a to synꢀ22a.
HBCat (eq) Time (h) Yield (%) Scale (mg)
1
2
6
4
2
2
97
97
98
96
93
75
52
82
92
92
85
40
“
3
3
4
“
4
2.5
2.2
2
2
“
5
2
“
6
4
“
7
2
22
2
“
8
2.5
2.5
3
100
“
9
4
10
11
4
“
3
4
400
The synthesis of synꢀ22a begins with (S)-lactic acid (cf. eq 1, Scheme 3). From methyl
lactate to hydrazone Eꢀ10a, each intermediate compound was exposed to basic conditions that
potentially could racemize the stereocenter. To test for this possibility, Mosher esters (R)ꢀ and
(S)ꢀ25 of alcohol 23 were prepared and their 1HꢀNMR spectra compared (Figure 5). If any
racemization had occurred, then the products of Mosher esterification would be a mixture of
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diastereomers consistent with the degree of racemization. In fact, each ester showed a unique set
of resonances by 1Hꢀ and 13CꢀNMR analysis.64
7
8
9
OBn
O
OBn
O
H H
H
H
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Ph
Ph
O
O
MeO CF3
F3C OMe
CH3
CH3
(R)-25a
(S)-25a
Figure 5: Mosher esters (R)ꢀ and (S)ꢀ25 of alcohol 23
Unlike (S)ꢀlactic acid, (S)ꢀmandelic acid underwent partial racemization during its
conversion from the acid to its Weinreb amide (Scheme 10). Chiral 1HꢀNMR shift reagent
analysis showed a ca. 2.7:1 (S):(R) enantiomeric ratio of amides. After reductive transposition of
Eꢀ10b, 1HꢀNMR analysis showed 22b as a single syn diastereomer. Mosher ester analysis of the
derived alcohol as above gave a 2.6ꢀ2.9 dr of Mosher esters, indicating that no significant
racemization of the mandelate stereocenter had occurred beyond the stage of amide 5b. The
racemization must have occurred at either the etherification or amidation steps (cf. eq 1, Scheme
3). We are confident that conditions could be found to minimize racemization,65 but it was not a
concern of ours at the time.
Scheme 10
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Using the same protocol, we prepared synꢀ26a,b and synꢀ27a,b (Figure 6). In all cases,
only the syn diastereomer was detectable by 1HꢀNMR analysis.
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Figure 6: Synꢀalkenes prepared from reductive transpositions of hydrazones.
We compared the conditions reported by Rosini et al in the reduction step to our modified
Kabalka conditions (i.e. pTsOH/NaCNBH3/rt vs HBCat/silica gel/ꢀ42 °C) for Eꢀ11b and Eꢀ12b,
and found the two sets of conditions to give equivalent yields of syn-27b from Eꢀ12b, but the
Rosini conditions to give substantially diminished yields of syn-26b from Eꢀ11b. The more
strongly acidic, higher temperature Rosini conditions may not be as compatible with some types
of functionalities.
In order to access the 1,4ꢀanti isomers, we treated the Eꢀhydrazones possessing Zꢀalkenes
Zꢀ10b and Zꢀ11b under the silica gel modification of the Kabalka conditions (Scheme 11). The
desired 1,4ꢀanti products were also obtained a single diastereomers based on 1HꢀNMR analysis.
Scheme 11
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The reductive transposition also performed well in more complex systems (Scheme
12),57,58 although in the most complex hydrazone 30, 3 charges of 6 eq of catecholborane were
needed to drive the reduction to completion. We speculate that this was due to complexation of
the borane by the multiple Lewis basic oxygens. It was necessary to decompose the excess
borane prior to heating the mixture with NaOAc to effect the allylic diazene rearrangement, but
with that intermediate step included, the overall yield was satisfactory.
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Scheme 12
We sought to extend the method further by employing enones with tetrasubstituted
alkenes to provide trisubsubstitued alkenes after rearrangement. To this end, the known Eꢀβꢀ
bromoangelic acid 32,66 prepared in two steps from tiglic acid, was reduced with LiAlH4 and
silylated to provide TBS protected allylic alcohol 33 (Scheme 13). Although there is some
modest precedent for transmetallation of tetrasubstituted vinyl bromides with alkyl lithium
reagents,67 we were unable to effect any transmetallation of vinyl bromide 33 with either nꢀ or tꢀ
butyllithium under a variety of conditions. Using the procedure of Klapars and Buchwald,68 the
bromide was smoothly converted to iodide 34 without alkene isomerization. Transmetallation
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proceeded uneventfully to provide enones 35a and 35b upon reaction with the appropriate
5
6
Weinreb amide.
7
8
9
Unfortunately, despite extensive attempts at hydrazonation of 35a or 35b at varying
temperatures, with various solvents, catalysts, and hydrazide reagents (tosyl hydrazide, tꢀ
butylcarbazate, tꢀbutyl hydrazine), at best equal mixtures of Eꢀ and Zꢀhydrazones were formed
accompanied by inseparable unidentified products. Treatment of the E/Zꢀmixtures of tosyl
hydrazones under our standard reductive transposition conditions yielded no identifiable
compounds. Presumably the steric congestion about the carbonyl carbon was simply too great to
enable efficient hydrazone formation, and we did not pursue the reactions further.
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OBn
OTBS
1. LiAlH4
THF, 68%
CuI, NaI
diamine
OTBS
OTBS
O
t-BuLi, ether
CO2H
35a 58%
Weinreb amide
-78 °C
2. TBSCl
imidazole
DMF, 78%
n-BuOH
120 °C
76%
OBn
Br
Br
I
Ph
OTBS
32
33
34
diamine = NHMeCH2CH2NHMe
O
35b 64%
Scheme 13
As mentioned previously, reduction of Eꢀhydrazones apparently proceeded by chelation
control (cf. Scheme 7). Since Zꢀhydrazones presumably could not effectively chelate, we
explored the possibility of their reduction via a FelkinꢀAhn pathway. Surprisingly, we found that
hydrazone Zꢀ14 (Scheme 14) was impervious to reduction under either the modified Kabalka
conditions (HBCat, HOAc, CHCl3) or the Rosini conditions (NaNCBH3, pTsOH, THF).
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Scheme 14
CONCLUSIONS
We have demonstrated that αꢀalkoxy trisubstituted enones may be converted to Eꢀ1,4ꢀsyn
or Eꢀ1,4ꢀanti stereotriads via a chelation controlled hydrazone reduction, followed by an in situ
allylic diazene rearrangement. The overall 2ꢀstep transformation proceeds in generally good
yield and excellent diastereoselectivity. The protocol proceeds well with simple as well as
complex substrates. The Eꢀhydrazone geometry is essential to the success of the hydrazone
reduction step; fortunately, we have found conditions under which the Eꢀhydrazone can be
prepared selectively.
EXPERIMENTAL SECTION
General Experimental Procedures. Unless otherwise noted, all reactions were carried out
under a positive pressure of nitrogen. Extractive workup is defined as extraction of the reaction
mixture and the indicated aqueous solution three times with ethyl acetate or ether, washing of the
combined organic extracts with saturated NaCl solution, drying of the extracts over anhydrous
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MgSO4, and concentration in vacuo. Flash column chromatography was performed by
employing silica gel (40–63 ꢁm, standard grade, Sorbent Technologies). The same silica gel was
used in the indicated reactions. For purification of acidꢀsensitive Zꢀenones, Florisil (A grade, ꢀ
200 mesh, Sorbent Technologies) was used.
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Materials and Instrumentation. All commercially available compounds were used as received
unless otherwise specified. THF, ether, CH3CN and CH2Cl2 were dried over alumina using the
solvent purification system. Chloroform (99%) was stabilized by amylenes. Elemental analyses
were performed. A chiral capillary column (30m x 0.25mm x 0.12um) was used to analyze
enantiopurity. Microwave reactions were performed by using the Discover model CEM
Microwave Reactor which has external pressure and temperature sensors. The temperature is
sensed by IR whereas the pressure is sensed by the deflection sample lid. A sealed glass reaction
vessel was used.
Weinreb amide 5a.69 Diazomethane in ether was added to a solution of (S)ꢀ(+)ꢀlactic
acid (1 g, 11 mmol) in ether (10 mL) at 0 °C. After disappearance of starting material, the
solution was concentrated in vacuo to give (S)ꢀlactic methyl ester (1.1g, 100%). A mixture of
Ag2O (3.1 g, 13.2 mmol), benzyl bromide (2.3 g, 13.2 mmol) and the ester (1.1 g, 10.6 mmol) in
CH2Cl2 (20 mL) was stirred for 48 h at rt. After filtration, the solution was concentrated to
provide the crude benzyl ether. KOH (0.6 g, 10.6 mmol) in water (10 mL) was added dropwise
to a solution of ester in ethanol (10 mL) at 0 0C, and the reaction mixture stirred for 30 min.
After extraction with ether (10 mL x 2), the aqueous phase was neutralized with 12 N HCl. The
aqueous solution was then extracted with ether (10 mL x 2) and the combined organics dried
over MgSO4 and concentrated in vacuo to give Oꢀbenzylꢀ(S)ꢀlactic acid (1.5 g, 80%).
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Trimethylacetyl chloride (1.1 g, 8.9 mmol) was added to a solution of acid (1.5 g, 8.5
mmol) and NEt3 (0.9 g, 8.9 mmol) at 0 °C. After 30 min, N,Oꢀdimethylꢀhydroxylamine
hydrochloride (0.87 g, 8.9 mmol) was added, followed by NEt3 (1.8 g, 17.8 mmol). The reaction
mixture was then allowed to warm to rt and stirred for 16 h. After extractive workꢀup, the crude
material was purified by flash chromatography over silica gel with 5/95 ethyl acetate/hexane to
give Weinreb amide 5a (1.6 g, 85%) as colorless oil, 1H NMR (300 MHz, CDCl3) δ 1.4 (d, J=6.6
Hz, 3H), 3.2 (s, 3H), 3.57 (s, 3H), 4.39 (m, 1H), 4.41 (d, J=12 Hz, 1H), 4.67 (d, J=12 Hz, 1H),
7.29 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 18.0, 32.4, 61.3, 71.2, 71.4, 127.7, 128.9, 128.4,
137.8, 173.9.
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Weinreb amide 5b. Prepared as above for (S)ꢀ(+)ꢀlactic acid derived Weinreb amide 5a,
(2.05 g, 85%); m.p. 44ꢀ46 0C; 1H NMR (300 MHz, CDCl3) δ 3.18 (s, 3H), 3.35 (s, 3H), 4.63 (s,
2H), 5.31 (s, 1H), 7.39 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 32.4, 60.9, 70.9, 77.3, 127.8,
128.1, 128.4, 128.6, 136.7, 137.6, 172.0.
Determination of enantiomer ratio of (S)ꢀ(+)ꢀWeinreb amide 5b: Europium Dꢀ3ꢀ
trifluoroacetylcamphorate was added in small portions to a sample of Weinreb amide 5b in
chloroformꢀd until baseline separation of the Nꢀmethyl peak was achieved by 1H NMR (see
Supporting Information). Integration of the Nꢀmethyl peaks revealed a 2.7:1 ratio of
enantiomers.
Enone Eꢀ7a. nꢀBuLi (11.5 mL, 2.89 M in hexane, 29.6 mmol) was added to a solution
of the known70 iodide (8.4 g, 26.9 mmol) in ether (30 mL) at ꢀ78 °C. After 30 min, the solution
was added dropwise to Weinreb amide 5a (3.0 g, 13.5 mmol) in ether (15 mL). The solution was
maintained at ꢀ78 0C until starting material disappeared (approximately 30 min). After extractive
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workꢀup, the crude material was purified by flash chromatography over silica gel with 5/95 ethyl
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1
acetate/hexane to give enone Eꢀ7a (4.23 g, 90%) as colorless oil, H NMR (300 MHz, CDCl3) δ
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8
9
0.11 (s, 6H), 0.95 (s, 9H), 1.38 (d, J=6.6 Hz, 3H), 2.11 (s, 3H), 3.98 (q, J=6.9 Hz, 1H), 4.18 (s,
2H), 4.44 (d, J=11.7 Hz, 1H), 4.62 (d, J=11.7 Hz, 1H), 6.84 (s, 1H), 7.28 (m, 5H); 13C NMR (75
MHz, CDCl3) δ ꢀ5.4, 16.3, 18.1, 18.3, 25.8, 67.3, 71.7, 81.3, 115.4, 127.7, 127.8, 128.4, 137.9,
159.3; IR (film) cmꢀ1 3031, 1689, 1627, 1116; calcd for C20H32O3Si, C, 68.92; H, 9.25; found, C,
68.65; H, 9.49.
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Enone Z-7a. Prepared as above for Eꢀ7a using the known Zꢀiodide71 (4.10 g, 74%); 1H
NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.9 (s, 9H), 1.98 (s, 3H), 4.53 (d, J=6.73 Hz, 1H), 4.59
(d, J=6.73Hz, 1H), 4.7 (d, J=17.82 Hz, 1H), 4.83 (d, J=17.82 Hz, 1H), 4.84 (s, 1H), 6.4 (s, 1H),
7.3 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.4, 18.3, 21.9, 25.9, 64.4, 71.2, 86.6, 118.0, 127.2,
127.9, 128.4, 128.5, 128.8, 136.7, 137.6, 165.2, 197.5; IR (film) cmꢀ1 3032, 1694, 1606, 1070.
Enone Eꢀ7b. Prepared as above for Eꢀ7a using the known iodide70 (5.44 g, 95%); 1H
NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.9 (s, 9H), 2.0 (s, 3H), 4.06 (s, 2H), 4.58 (s, 2H), 4.88 (s,
1H), 6.74 (s, 1H), 7.3 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.4, 16.4, 18.3, 26.0, 67.2, 71.1,
87.2, 116.0, 127.3, 127.9, 128.3, 128.5, 128.7, 137.0, 138.0, 159.6, 198.2; IR (film) cmꢀ1 3031,
1690, 1626, 1109.
Enone Z-7b. Prepared as above for Eꢀ7a using the known71 Zꢀiodide (4.70 g, 82%); 1H
NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.88 (s, 9H), 1.96 (s, 3H), 2.82 (t, J=6.3 Hz, 2H), 3.77 (t,
J=6.3 Hz, 2H), 4.56 (d, J=12 Hz, 1H), 4.62 (d, J=12 Hz, 1H), 4.85 (s, 1H), 6.39 (s, 1H), 7.4 (m,
10H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.4, 18.3, 25.9, 27.7, 37.8, 62.4, 71.1, 86.8, 120.0, 127.1,
127.8, 127.9, 128.3, 128.4, 128.7, 136.7, 137.6, 161.2.
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Enone E-8a. Prepared as above for Eꢀ7a using the known iodide70 (4.50 g, 92%); 1H
NMR (300 MHz, CDCl3) δ 0.08 (s, 6H), 0.9 (s, 9H), 1.36 (d, J=6.9 Hz, 3H), 2.24 (s, 3H), 2.41 (t,
J=6.6 Hz, 2H), 3.8 (t, J=6.6 Hz, 2H), 3.94 (q, J=6.9 Hz, 1H), 4.43 (d, J=11.7 Hz, 1H), 4.62 (d,
J=11.7 Hz, 1H), 6.48 (s, 1H), 7.28 (m, 5H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.4, 18.2, 20.1, 25.9,
44.7, 61.2, 71.8, 81.3, 119.7, 127.7, 127.8, 128.4, 137.8, 159.3, 202.5; IR (film) cmꢀ1 1688,
1462; calcd for C21H34O3Si, C, 69.56; H, 9.45; found, C, 69.27; H, 9.78.
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Enone E-8b. Prepared as above for Eꢀ7a using the known iodide71 (4.98 g, 87%); 1H
NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.85 (s, 9H), 2.18 (s, 3H), 2.32 (t, J=6.53 Hz, 2H), 3.71
(t, J=6.53 Hz, 2H), 4.56 (d, J=12 Hz, 1H), 4.59 (d, J=12 Hz, 1H), 4.85 (s, 1H), 6.41 (s, 1H), 7.3
(m, 10H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.2, 18.1, 20.2, 26.0, 44.9, 61.8, 71.3, 86.9, 120.5,
127.2, 127.9, 127.9, 128.3, 128.5, 128.8, 136.8, 137.4, 159.2, 198.1; IR (film) cmꢀ1 1702, 1096;
calcd for C26H36O3Si, C, 73.54; H, 8.54; found, C, 73.52; H, 8.50.
Enone E-9a. Prepared as above for Eꢀ7a using the known iodide70 (2.42 g, 78%); 1H
NMR (300 MHz, CDCl3) δ 1.34 (d, J=6.72 Hz, 3H), 2.3 (s, 3H), 3.93 (q, J=6.72 Hz, 1H), 4.44
(d, J=11.48 Hz, 1H), 4.56 (d, J=11.48 Hz, 1H), 5.48 (d, J=10.5 Hz, 1H), 5.71 (d, J=17.22 Hz,
1H), 6.44 (dd, J=17.20, 10.5 Hz, 1H), 6.50 (s, 1H), 7.3 (m, 5H); 13C NMR (75 MHz, CDCl3) δ
13.8, 18.2, 71.9, 81.6, 121.2, 122.0, 127.9, 128.5, 137.8, 140.9, 153.2, 203.5; IR (film) cmꢀ1
1700, 1619, 1447.
Enone E-9b. Prepared as above for Eꢀ7a using the known iodide70 (2.96 g, 75%); 1H
NMR (300 MHz, CDCl3) δ 2.26 (s, 3H), 4.54 (d, J=11.88 Hz, 1H), 4.6 (d, J=11.88 Hz, 1H), 4.86
(s, 1H), 5.43 (d, J=10.5 Hz, 1H), 5.63 (d, J=17.4 Hz, 1H), 6.35 (dd, J=17.4, 10.5 Hz, 1H), 6.43
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128.4, 128.5, 128.7, 136.6, 137.5, 140.7, 153.4, 199; IR (film) cmꢀ1 1633, 1448, 1066.
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Hydrazone Eꢀ10a. (Method A) A solution of enone Eꢀ7a (2.0 g, 5.7 mmol) and tosyl
hydrazide (1.4 g, 7.5 mmol) in Ti(OiPr)4 (3 mL, 11.5 mmol) was stirred for 16 h at rt. The
reaction mixture was then treated with water (10 mL) and the crude product isolated by
extractive workꢀup. The product was recrystallized from ether to provide hydrazone Eꢀ10a (2.12
g, 72%) as colorless crystals, m.p. 85ꢀ87 °C; 1H NMR (300 MHz, CDCl3) δ 0.1 (s, 6H), 0.92 (s,
9H), 1.22 (d, J=6.6 Hz, 3H), 1.54 (s, 3H), 2.33 (s, 3H), 4.1 (m, 5H), 5.8 (s, 1H), 7.12 (d, J=7.2
Hz, 2H), 7.28 (m, 5H), 7.84 (d, J=7.2 Hz, 2H), 7.85 (s, 1H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.4,
16.3, 18.3, 18.9, 21.5, 25.9, 66.1, 70.3, 78.1, 110.5, 127.5, 127.6, 128.0, 128.3, 129.6, 135.3,
137.9, 144.2, 148.4, 156.9; IR (film) cmꢀ1 3192, 1599, 1451, 1344, 1169; calcd for
C27H40N2O4SSi, C, 62.75; H, 7.80; N, 5.42; found, C, 62.83; H, 7.92; N, 5.33.
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Hydrazone E-10b. Prepared by Method A as above for Eꢀ10a (2.80 g, 85%); 1H NMR
(300 MHz, CDCl3) δ 0.00 (s, 6H), 0.83 (s, 9H), 1.23 (s, 3H), 2.39 (s, 3H), 3.97 (s, 2H), 4.37 (d,
J=16.90 Hz, 1H), 4.40 (d, J=16.90 Hz, 1H), 5.07 (s, 1H), 5.59 (s, 1H), 7.28 (m, 12H), 7.7 (s, 1H),
7.81 (d, J=8.32 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.4, 14.3, 16.2, 18.3, 21.7, 22.8, 25.9,
31.7, 66.1, 70.6, 83.7, 110.5, 126.2, 127.5, 127.6, 128.1, 128.2, 128.4, 129.7, 132.8, 138.0, 138.3,
144.1, 148.6, 156.48; IR (film) cmꢀ1, 3191, 1659, 1598, 1453, 1343, 1169; calcd for
C32H42N2O4SSi, C, 66.40; H, 7.31; N, 4.84; found, C, 66.48; H, 7.44; N, 4.84.
Hydrazone Z-10b. Prepared as above using Method A for Eꢀ10a (2.14 g, 65%); m.p. 97ꢀ
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99 °C ; H NMR (300 MHz, CDCl3) δ 0.0 (s, 6H), 0.88 (s, 9H), 1.82 (s, 3H), 2.47 (s, 3H), 3.49
(d, J=12.3 Hz, 1H), 3.6 (d, J=12.3 Hz, 1H), 4.39 (d, J=11.7 Hz, 1H), 4.45 (d, J=11.7 Hz, 1H),
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5.08 (s, 1H), 5.24 (s, 1H), 7.3 (m, 12H), 7.85 (d, J=8.4 Hz, 2H), 7.93 (s, 1H); 13C NMR (75
MHz, CDCl3) δ ꢀ5.4, 18.3, 20.7, 21.6, 25.9, 63.2, 70.7, 83.6, 112.9, 126.3, 127.6, 127.7, 128.0,
128.1, 128.3, 129.6, 135.7, 137.7, 138.1, 143.9, 148.5, 154.72; IR (film) cmꢀ1, 3203, 3032, 1648,
1453, 1342, 1168; calcd for C32H42N2O4SSi, C, 66.40; H, 7.31; N, 4.84; found, C, 66.13; H,
7.29; N, 5.02.
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Hydrazone E-11a. Prepared as above using Method A for Eꢀ10a (2.14 g, 71%); 1H NMR
(300 MHz, CDCl3) δ 0.1 (s, 6H), 0.88 (s, 9H), 1.23 (d, J=6.3 Hz, 3H), 1.58 (s, 3H), 2.32, (t, J=6
Hz, 2H), 2.35 (s, 3H), 3.77 (t, J=6 Hz, 2H), 4.07 (d, J=11.7 Hz, 1H), 4.09 (q, J=6.6 Hz, 1H),
4.14 (d, J=11.7 Hz, 1H), 5.43 (s, 1H), 7.12 (d, J=7.2 Hz, 2H), 7.28 (m, 5H), 7.8 (s, 1H), 7.84 (d,
J=7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.4, 18.3, 18.8, 19.5, 22.6, 26.0, 42.2, 60.9, 70.4,
78.1, 113.9, 127.6, 128.0, 128.3, 129.5, 135.6, 138.0, 144.0, 147.2, 156.1; IR (film) cmꢀ1 3203,
1598, 1458, 1343, 1167.
Hydrazone E-11b. Prepared as above using Method A for Eꢀ10a (2.12 g, 63%); m.p. 63ꢀ
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65 °C ; H NMR (300 MHz, CDCl3) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H), 1.28 (s, 3H), 2.23
(t, J=6.3 Hz, 2H), 2.39 (s, 3H), 3.65 (t, J=6.3 Hz, 2H), 4.4 (d, J=12 Hz, 1H), 4.46 (d, J=12 Hz,
1H), 5.11 (s, 1H), 5.27 (s, 1H), 7.28 (m, 12H), 7.6 (s, 1H), 7.84 (d, J=8.1 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ ꢀ5.4, 18.3, 19.4, 21.6, 26.0, 42.1, 61.0, 70.6, 83.5, 113.8, 126.3, 127.4, 127.6,
128.0, 128.3, 129.5, 135.6, 137.9, 138.2, 144.0, 147.4, 155.6; IR (film) cmꢀ1 3201, 1649, 1453,
1340, 1168; calcd for C33H44N2O4SSi, C, 66.85; H, 7.48; N, 4.73; found, C, 66.99; H, 7.45; N,
4.90.
Hydrazone Z-11b. Prepared as above using Method A for Eꢀ10a (1.55 g, 46%); m.p.
106ꢀ108 °C; 1H NMR (300 MHz, CDCl3) δ 0.1 (s, 6H), 0.92 (s, 9H), 1.69 (m, 2H), 1.78 (s, 3H),
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2.47 (s, 3H), 3.43 (m, 2H), 4.4 (d, J=8.7 Hz, 1H), 4.49 (d, J=8.7 Hz, 1H), 5.09 (s, 1H), 5.30 (s,
1H), 7.3 (m, 12H), 7.85 (d, J=7.2 Hz, 2H), 8.34 (s, 1H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.4,
18.5, 21.6, 22.6, 26.2, 36.6, 60.3, 70.6, 84.0, 114.9, 126.3, 127.5, 127.6, 128.0, 128.3, 129.5,
135.9, 137.9, 138.4, 143.8, 146.7, 154.5; IR (film) cmꢀ1 3197, 3032, 1650, 1452, 1344, 1168.
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Hydrazone E-12a. Prepared as above using Method A for Eꢀ10a (1.13 g, 50%); m.p. 70ꢀ
72 °C; 1H NMR (300 MHz, CDCl3) δ 1.24 (d, J=6.6 Hz, 3H), 1.76 (s, 3H), 2.38 (s, 3H), 4.1 (d,
J=12 Hz, 1H), 4.17 (d, J=12 Hz, 1H), 5.31 (d, J=10.5 Hz, 1H), 5.44 (d, J=17.1 Hz, 1H), 5.62 (s,
1H), 6.43 (dd, J=17.10, 10.5 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.3 (m, 5H), 7.63 (s, 1H), 7.85 (d,
J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 15.0, 18.9, 21.5, 70.5, 78.1, 117.6, 127.7, 128.0,
128.3, 129.6, 135.3, 137.8, 138.5, 144.2, 144.9, 155.71; IR (film) cmꢀ1, 3201, 1600, 1449, 1342,
1166; calcd for C22H26N2O3S, C, 66.30; H, 6.58; N, 7.03; found, C, 66.05; H, 6.56; N, 7.07.
Hydrazone E-12b. Prepared as above using Method A for Eꢀ10a (1.75 g, 67%); m.p.
115ꢀ117 °C; 1H NMR (300 MHz, CDCl3) δ 1.41 (s, 3H), 2.44 (s, 3H), 4.39 (d, J=11.88 Hz, 1H),
4.45 (d, J=11.88 Hz, 1H), 5.12 (s, 1H), 5.19 (d, J=10.69 Hz, 1H), 5.28 (d, J=17.28 Hz, 1H), 5.43
(s, 1H), 6.28 (dd, J=17.28, 10.69 Hz, 1H), 7.3 (m, 12H), 7.71 (s, 1H), 7.83 (d, J=8.32 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 14.8, 21.7, 70.8, 83.7, 117.4, 117.6, 126.3, 127.6, 127.8, 128.2,
128.2, 128.47, 129.7, 135.5, 137.8, 138.1, 138.6, 144.3, 145.1, 155.4; IR (film) cmꢀ1 3194, 1599,
1341, 1167; calcd for C27H28N2O3S, C, 70.41; H, 6.13; N, 6.08; found, C, 70.56; H, 6.13; N,
6.10.
OꢀBenzylbenzoin (13). To a stirred solution of amide 5b (1.00 g, 3.53 mmol) in ether (9
mL) at ꢀ78 °C, phenyllithium (4.91 mL, 8.83 mmol) was added dropwise. Completion of the
reaction was monitored by TLC. Then the reaction mixture was allowed to warm to room
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temperature and quenched with acetic acid.
Extractive work up followed by flash
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chromatography over silica gel with 5/95 ethyl acetate/hexane provided ketone (0.87 g, 82 %).
1H NMR (400 MHz, CDCl3) δ 4.67 (s, 2H), 5.65 (s, 1H), 7.36 (m, 13 H), 7.98 (d, J=Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 71.0, 83.4, 127.0, 128.0, 130.0, 134.0; IR (film) cmꢀ1 3061, 2360,
1688, 1449, 1100, 695; calcd for C21H18O2 C, 83.42, H, 6.00; found C, 83.22, H, 5.88.
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OꢀBenzylbenzoin hydrazone Eꢀ14. Method A: Tosyl hydrazide (0.605 g, 3.21 mmol) and
titanium(IV) isopropoxide (1.971 g, 2.03 mL, 7.89 mmol) were added to the Oꢀbenzylꢀbenzoin
(0.60 g, 1.98 mmol). The reaction mixture was stirred at room temperature for 48 h. The
reaction mixture was quenched by adding water followed by extractive work up. Eꢀhydrazone
and Zꢀhydrazone were isolated by flash chromatography over silica gel using 6/94 ethyl
acetate/hexane to provide Eꢀ14 (0.93 g, 62%). m.p. 166ꢀ168 °C; 1H NMR (400 MHz, CDCl3) δ
2.49 (s, 3H), 4.51 (s, 2H), 5.36 (s, 1H), 6.74 (d, J= 7.66, 2H), 7.27 (m, 15 H), 7.80 (d, J=8.10,
2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 70.8, 83.6, 126.5, 127.4, 128.1, 128.4, 129.1, 129.6,
130.1, 135.3, 137.6, 144.2, 156.9; IR (film) cmꢀ1 3224, 3060, 2918, 1602, 1357, 1166, 1085;
calcd for C28H26N2O3S C, 71.46, H, 5.57, N, 5.95; found C, 71.27, H, 5.59, N, 6.01.
Method B: A microwave reaction of Oꢀbenzylbenzoin (0.10 g, 0.33 mmol) with
tosylhydrazide (0.074 g, 0.39 mmol) in CH2Cl2 (0.5 mL) for 8 h at 30 watts at 30 °C gave a
mixture of Eꢀhydrazone and Zꢀhydrazone. Flash chromatography over silica gel with 6/94 ethyl
acetate/hexane provided 7.25:1 of Eꢀ14 and Zꢀ14 hydrazones (0.15 g, 99%).
OꢀBenzylbenzoin hydrazone Zꢀ14. Method C: A solution of tosyl hydrazide (0.074 g,
0.39 mmol) and Oꢀbenzylbenzoin (0.108 g, 0.35 mmol) in MeOH was stirred at 50 °C for 12ꢀ28
h. The precipitate was removed by filtration to provide hydrazone Zꢀ14 (0.11 g, 60%) which was
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used without further purification. M.p. 166ꢀ168 °C; H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H),
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4.44 (d, J= 9.24), 4.55 (d, J=9.24), 5.73 (s, 1H), 7.30 (m, 15H), 7.72 (d, J=8.96, 2H), 10.34 (s,
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1H); C NMR (100 MHz, CDCl3) δ 21.6, 28.1, 71.8, 80.4, 126.4, 127.4, 127.8, 128.1, 128.5,
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128.9, 129.6, 135.13, 136.24; IR (film) cmꢀ1 3200, 3027, 1347, 1164; calcd for C28H26N2O3S C,
71.46, H, 5.57, N, 5.95; found C, 71.34, H, 5.63, N, 6.01.
1,4ꢀsynꢀEꢀAlkene 22a. (Method A) Catecholborane (0.22 mL, 2.3 mmol) was added
dropwise to a mixture of hydrazone Eꢀ10a (0.20 g, 0.39 mmol) and silica gel (0.40 g) in CHCl3
(5 mL) at ꢀ42 0C. After 1 h at ꢀ42 0C, NaOAc trihydrate (0.79 g, 5.8 mmol) was added and the
reaction mixture was heated under reflux for 16 h. The reaction mixture was poured into water
and isolated by extractive workꢀup. The crude material was purified by flash chromatography
over silica gel with 5/95 ethyl acetate/hexane to give synꢀ22a (0.12 g, 92%) as colorless oil; 1H
NMR (300 MHz, CDCl3) δ 0.07 (s, 6H), 0.92 (s, 9H), 1.07 (d, J=6.6 Hz, 3H), 1.32 (d, J=6.3 Hz,
3H), 2.39 (m, 1H), 3.51 (qd, J=9.6, 6.6 Hz, 2H), 3.92 (m, 1H), 4.4 (d, J=12 Hz, 1H), 4.59 (d,
J=12 Hz, 1H), 5.45 (dd, J=15.6, 7.5 Hz, 1H), 5.61 (dd, J=15.6, 6.9 Hz, 1H), 7.32 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ ꢀ5.0, 16.6, 18.3, 21.8, 25.9, 39.0, 68.0, 69.6, 75.9, 127.3, 127.7, 128.3,
131.5, 135.7, 139.1; IR (film) cmꢀ1 3032, 1689, 1626, 1453, 1110; calcd for C20H34O2Si, C,
71.80; H, 10.24; found, C, 72.04; H, 10.38.
(Method B) To a mixture of hydrazone Eꢀ10a (0.40 g, 0.78 mmol) and CH3CO2H (0.35
mL, 6.14 mmol) in freshly distilled CHCl3 (9.8 mL), catecholborane (0.25 mL, 2.303 mmol) was
added dropwise at ꢀ42 °C. After 4 h, NaOAC.3H2O (1.566 g, 11.51 mmol) was added and the
reaction mixture was heated to 55 °C for 16 h. After completion of the reaction, the mixture was
poured into water and extracted with ether. The crude material was purified by flash
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chromatography over silica gel with 5/95 ethyl acetate/hexane to obtain pure alkene synꢀ22a as
colorless oil (0.22 g, 85%); 0.04 g scale reaction (0.025 g, 98%); 0.10 g scale reaction (0.06 g,
92%).
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1,4ꢀsynꢀEꢀAlkene 22b. Prepared as above for synꢀ22a, using Method A, (0.07 g, 88%);
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 3H), 0.01(s, 3H), 0.86 (s, 9H), 1.01 (d, J=6.78 Hz, 3H),
2.35 (m, 1H), 3.42 (dd, J=9.68, 6.63 Hz, 1H), 3.48 (dd, J=9.68, 6.43 Hz, 1H), 4.48 (d, J=12.03
Hz, 1H), 4.53 (d, J=12.12 Hz, 1H), 4.79 (d, J=5.85 Hz, 1H), 5.61(dd, J=15.53, 5.95 Hz, 1H), 5.68
(dd, J=15.48, 5.84 Hz, 1H), 7.30 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.3, 16.5, 18.0, 26.0,
39.13, 67.9, 69.9, 81.9, 127.0, 127.5, 127.8, 128.4, 128.4, 128.5, 130.3, 136.3, 138.7, 141.7; IR
(film) cmꢀ1 3100, 1635, 1096; calcd for C25H36O2Si, C, 75.70; H, 9.15; found C, 75.87; H, 9.32.
1,4ꢀantiꢀEꢀAlkene 22b. Prepared as above using Method A for synꢀ22a (0.067 g, 85%).
1H NMR (300 MHz, CDCl3) δ 0.02 (s, 6H), 0.87 (s, 9H), 0.98 (d, J=6.6 Hz, 3H), 2.37 (m, 1H),
3.46 (m, 2H), 4.48 (d, J=12 Hz, 1H), 4.52 (d, J=12 Hz, 1H), 4.79 (d, J=5.54 Hz, 1H), 5.64 (m,
2H), 7.3 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.2, 16.4, 18.4, 26.0, 39.1, 68.0, 69.9, 81.8,
127.0, 127.5, 127.8, 128.4, 128.4, 130.3, 136.4, 138.7, 141.7; calcd for C25H36O2Si, C, 75.70; H,
9.15; found, C, 75.73; H, 9.30.
1,4ꢀsyn-E-Alkene 26a. Prepared as above for synꢀ22a, using Method A (0.06 g, 85%);
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Method B (0.056 g, 80%). H NMR (300 MHz, CDCl3) δ 0.07 (s, 6H), 0.94 (s, 9H), 1.07 (d,
J=6.9 Hz, 3H), 1.31 (d, J=6.3 Hz, 3H), 1.58 (m, 2H), 2.39 (m, 1H), 3.64 (m, 2H), 3.92 (m, 1H),
4.4 (d, J=12 Hz, 1H), 4.59 (d, J=12 Hz, 1H), 5.4 (dd, J=15.6, 7.2 Hz, 1H), 5.53 (dd, J=15.6, 7.5
Hz, 1H), 7.32 (m, 5H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.0, 18.3, 20.8, 21.9, 26.0, 32.9, 39.7,
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61.3, 69.6, 75.8, 127.3, 127.7, 128.3, 130.5, 138.7, 139.0; IR (film) cmꢀ1 3100, 1460, 1098;
calcd for C21H36O2Si, C, 72.35; H, 10.41; found, C, 72.27; H, 10.48.
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1,4ꢀsyn-E-Alkene 26b. Prepared as above using Method A for synꢀ22a, (0.068 g, 83%);
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 3H), 0.01(s, 3H), 0.88 (s, 9H), 1.08 (d, J=6.9 Hz, 3H),
1.54 (m, 2H), 2.35 (m, 1H), 3.57 (m, 2H), 4.52 (d, J=12 Hz, 1H), 4.56 (d, J=12 Hz, 1H), 4.8 (m,
1H), 5.59 (m, 2H), 7.30 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.3, 18.3, 20.5, 25.9, 33.0,
39.6, 61.2, 69.8, 81.7, 126.8, 127.4, 127.7, 128.3, 128.4, 129.3, 138.6, 139.1, 141.8; IR (film)
cmꢀ1 3100, 1636, 1096.
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1,4ꢀantiꢀEꢀAlkene 26b. Prepared as above using Method A for synꢀ22a (0.065 g,
80%); 1H NMR (300 MHz, CDCl3) δ 0.07 (s, 6H), 0.90 (s, 9H), 1.03 (d, J=6.9 Hz, 3H), 1.57 (m,
1H), 2.37 (m, 1H), 3.65 (m, 2H), 4.52 (d, J=12 Hz, 1H), 4.58 (d, J=12 Hz, 1H), 4.82 (m, 1H),
5.62 (m, 2H), 7.3 (m, 10H); 13C NMR (75 MHz, CDCl3) δ ꢀ5.2, 18.3, 20.3, 26.0, 32.9, 39.7,
61.3, 69.9, 81.6, 126.8, 127.4, 127.7, 128.3, 128.4, 129.2, 138.7, 139.1, 141.8; IR (film) cmꢀ1
3100, 1636, 1097; calcd for C26H38O2Si, C, 76.04; H, 9.33; found, C, 76.21; H, 9.57.
1,4ꢀsyn-E-Alkene 27a. Prepared as above using Method A for synꢀ22, (0.035 g, 81%);
1H NMR (300 MHz, CDCl3) δ 1.15 (d, J=6.9 Hz, 3H), 1.30 (d, J=6.3 Hz, 3H), 2.91 (m, 1H), 3.92
(m, 1H), 4.39 (d, J=12 Hz, 1H), 4.57 (d, J=12 Hz, 1H), 5.0 (d, J=10.2 Hz, 1H), 5.04(d, J=17.4
Hz, 1H), 5.4 (dd, J=15.6, 7.8 Hz, 1H), 5.6 (dd, J=15.6, 6.6 Hz, 1H), 5.82 (m, 1H), 7.32 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 19.8, 21.8, 39.9, 69.7, 75.7, 113.1, 127.3, 127.7, 128.3, 130.8,
136.6, 142.5.
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