Palladium-catalyzed decarboxylative allylic alkylation of diastereomeric β-ketoesters

Article abstract of DOI:10.1016/j.tet.2014.03.042

The palladium-catalyzed decarboxylative allylic alkylation of diastereomeric β-ketoesters derived from 4-tert-butylcyclohexanone is described. These experiments were performed to elucidate our understanding of stereoablative enantioconvergent catalysis. A

Full text of DOI:10.1016/j.tet.2014.03.042

Tetrahedron 70 (2014) 4208e4212
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed decarboxylative allylic alkylation
of diastereomeric b-ketoesters
*
Sandy Ma, Corey M. Reeves, Robert A. Craig, II, Brian M. Stoltz
Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, CA 91125, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium-catalyzed decarboxylative allylic alkylation of diastereomeric b-ketoesters derived from
Received 21 February 2014
Received in revised form 10 March 2014
Accepted 12 March 2014
4-tert-butylcyclohexanone is described. These experiments were performed to elucidate our un-
derstanding of stereoablative enantioconvergent catalysis. A detailed analysis of the product distribution,
including stereochemical outcome of the products, is included. These studies also reveal an interesting
example of selectivity that is governed by competing modes of substrate and catalyst control.
Ó 2014 Elsevier Ltd. All rights reserved.
Available online 18 March 2014
Dedicated to Professor Sarah Reisman on
receipt of the Tetrahedron Young
Investigator Award
Keywords:
Decarboxylative
Allylic
Alkylation
Ketoesters
Palladium
1. Introduction
The concept of stereoablative enantioconvergent catalysis is il-
lustrated by the use of -quaternary -ketoesters in the palladium-
a
b
catalyzed decarboxylative allylic alkylation and is a subject of in-
terest to our laboratories.1 Typical stereomutative enantio-
convergent processes, such as dynamic kinetic resolution, require
a pre-equilibration epimerization of starting material A followed by
enantioselective conversion to product B (pathway I, Scheme 1).
Quaternary stereocenters are not typically epimerizable and, thus,
in the case of our previous studies1 we believe another pathway is
operative, wherein both enantiomers of the starting material A
convert irreversibly to prochiral intermediate C. This prochiral in-
termediate C can then preferentially form one enantiomer of
product B under the influence of a chiral catalyst (pathway II,
Scheme 1). This alternate pathway has been termed stereoablative
enantioconvergent catalysis. The lability of the stereogenic center is
Scheme 1. Stereomutative versus stereoablative enantioconvergent catalysis.
To provide evidence for stereoablative enantioconvergent ca-
talysis, we envisioned using diastereomeric b-ketoesters 1 and 2 as
substrates for the palladium-catalyzed decarboxylative allylic al-
kylation (Scheme 2). The stereoablative hypothesis is supported if
illustrated with quaternary
b
-ketoesters, where enolate formation
-position.
destroys the stereochemical information at the
a
both
the stereochemistry at
to influence the outcome of the reaction.
b
-ketoesters afford similar diastereomeric product ratios as
a
-position of the -ketoester is not expected
b
* Corresponding author. E-mail address: stoltz@caltech.edu (B.M. Stoltz).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.042

S. Ma et al. / Tetrahedron 70 (2014) 4208e4212
4209
faster than the decarboxylative allylic alkylation of 1, which is
counter-intuitive because stereoelectronic arguments would pre-
dict that 1 should react at a greater rate as orbital overlap between
the carbonyl carbon and the
a-carbon is maximized when the
carboxyl is in the axial position.
To confirm the observed difference in their relative rates of re-
action, 1 and 2 were treated with an achiral catalyst (Scheme 5).
Decarboxylative allylic alkylation of 1 and 2 using PPh3 as ligand
gave the same major and minor products as those observed in the
enantioselective case. Furthermore, the difference in relative rate of
reaction was more dramatic in this case; the decarboxylative allylic
alkylation of 2 was 5.3 times faster than that observed for 1.3,4
Scheme 2. Proposed experiment to test stereoablation hypothesis.
2. Results and discussion
2.1. Experimental results
Diastereomeric
straightforward methods previously employed in our laboratory.2
With -ketoesters 1 and 2 in hand, we treated each -ketoester
b-ketoesters 1 and 2 were prepared by
b
b
with Pd2(dba)3 and (S)-t-Bu-PHOX. We observed similar product
yields, diastereomeric ratios, and enantioselectivities for the
asymmetric decarboxylative allylic alkylation of both 1 and 2
(Scheme 3). Thus, our results support the formation of an enolate
wherein the stereochemistry at the a-position of the b-ketoester
starting material does not influence the outcome of the reaction.
The relative and absolute stereochemistry of the products 3 and 4
were determined by X-ray diffraction of their corresponding crys-
talline semicarbazone derivatives obtained from the asymmetric
variant of the decarboxylative allylic alkylation (Scheme 4).2
Scheme 5. Racemic palladium-catalyzed decarboxylative allylic alkylation of
ketoester.
b-
2.2. Rationalization for lack of stereoelectronic control in
decarboxylation of diastereomeric
b-ketoacids
The surprising observation that
b-ketoester 2, which has the
ester group in an equatorial position, is more reactive for allylic
decarboxylation than -ketoester 1, which has the ester group in an
b
axial position, contradicts stereoelectronic control arguments.
However, this contradiction has also been observed in the de-
carboxylation of diastereomeric
Based on stereoelectronic arguments,
b
-ketoacids.5
b-ketoacid 7 would be
predicted to be more reactive because an axially positioned car-
boxyl group allows for continuous overlap of the incipient p-orbital
with the p-orbital on the carbonyl carbon (Fig. 1). However, Pollack
has reported that
b-ketoacid 8 decarboxylates 3-fold faster than 7
in acidic media.5 Under basic conditions, the relative rate of re-
Scheme 3. Asymmetric palladium-catalyzed decarboxylative allylation of
ketoesters.
b-
actions is more striking: b-ketoacid 8 decarboxylates 15- to 20-fold
faster than 7.
Fig. 1. Kinetic experiments on rate of decarboxylation of b-ketoacids.
Under acidic conditions, Pollack has proposed that the transition
state for decarboxylation is a six-membered intermediate, in which
the OeH bond rests in the same plane as the original C(3)eC(2)]O
bond (Fig. 2).5 The C(1)eC(3) bond that is broken sits perpendicular
to this plane, which allows for the continuous overlap of the in-
Scheme 4. Determination of relative and absolute stereochemistry.
cipient p-orbital with the
p of the carbonyl bond. The proposed
transition states for -ketoacids 7 and 8 are shown in Fig. 2, where
b
However, two other interesting observations were made during
these experiments. Minor product 4 had significantly greater en-
antiomeric excess than that of major product 3 (97% ee vs 39% ee).
Furthermore, decarboxylative allylic alkylation of 2 was two times
the cyclohexene is shown in a half chair conformation with the tert-
butyl group in the equatorial position and the methyl group in the
plane of the carbonecarbon double bond. If the energies of
the transition states are similar, then the relative rate of

4210
S. Ma et al. / Tetrahedron 70 (2014) 4208e4212
a carboxylate intermediate occurs and that unfavorable dipo-
leedipole repulsion, such as those shown in Fig. 4, for the car-
boxylate derived from would make it the more reactive
diastereomer. The formation of palladium carboxylate in-
2
a
termediate in our decarboxylative allylic alkylation has been sup-
ported by subsequent mechanistic studies performed by our
laboratories.7 Furthermore, the possibility that Pd(II) species
formed in situ facilitate decarboxylation via Lewis acid type co-
ordination (in a manner analogous to the Brønsted acid shown in
Fig. 2), can not be precluded.
2.4. Rationale for greater enantioselectivity in minor product
Fig. 2. Proposed transition states under acidic conditions.
The second interesting observation made in our asymmetric
decarboxylative allylation of diastereomeric b-ketoesters is that the
decarboxylation is determined by the relative stabilities of
ketoacids 7 and 8. Based on A values derived from cyclohexanes
-ketoacid 8 is higher in
b-
minor product 4 had much greater enantiomeric excess than major
product 3. We believe that this observation can be attributed to
competing modes of control. To help illustrate our point, we must
consider all four possible products and their relative abundance
(Me¼1.70 kcal/mol, COOH¼1.35 kcal/mol),
b
energy; therefore, it should be more reactive.
Rationalization of the relative rate of decarboxylation of
b-
after the asymmetric decarboxylative allylic alkylation of
b-
ketoacids 7 and 8 under basic conditions is based on a similar ar-
gument. Decarboxylation of the carboxylate anions of -ketoacids
ketoester 1 (Scheme 3). The diastereomers and their enantiomers
are shown in Fig. 5, and the relative percentages of each of the
products are shown in Fig. 6.
b
has not been investigated thoroughly, but studies on the de-
carboxylation of benzoylacetic acids have suggested that the tran-
sition state is late on the reaction coordinate; thus, the transition
state resembles the enolate product (Fig. 3).6 We can apply this
observation to the decarboxylation of carboxylates 7a and 8a. If
steric interactions with the axial hydrogens are ignored in the
transition states shown in Fig. 3, these two transition states should
have similar energies, and the relative rates of reaction reflect the
differences in energy of carboxylates 7a and 8a.
Fig. 5. All possible products from asymmetric decarboxylative allylic alkylation of
ketoester 1.
b-
Fig. 3. Proposed transition states under basic conditions.
To predict the relative energy of 7a and 8a, the dipoleedipole
repulsions between the carboxylate and the carbonyl oxygen
should be considered (Fig. 4). For 8a, the dipoleedipole repulsion is
more significant; hence, 8a is less stable and will decarboxylate
more readily. Evidence that this dipole-dipole interaction is sig-
nificant can be found in the pKa values of 7 and 8. Acid 8 has
a higher pKa than 7 (5.79 vs 5.29 in 70% MeOH in water at 0 ꢀC).6
Fig. 6. Product distribution of asymmetric decarboxylative allylic alkylation of
toester 1.
b-ke-
One type of control believed to be operative is demonstrated in
the non-enantioselective alkylation of 4-tert-butylcyclohexanone
enolates, which are known to have an innate selectivity for one
product (i.e., substrate control, Fig. 7). As shown in Scheme 6, the
electrophile can be attacked by the putative enolate from either its
top face or bottom face. Studies by House and co-workers have
shown that the electrophile and the tert-butyl group have a trans
relationship in the major product.8 Approach from the bottom face
will force the cyclohexane ring into a twist boat conformation and
will install the electrophile on the same face as the tert-butyl group.
On the other hand, approach from the top face will install the
electrophile trans to the tert-butyl group and will lead directly to
the product’s chair conformation. The rationale for the favored
trans relationship between the electrophile and the tert-butyl
group is that the chair-like transition state is lower in energy than
Fig. 4. Dipoleedipole repulsions.
2.3. Rationalization for faster relative rate of reaction for
ketoesters
b-
A possible explanation for the increased reactivity of
2 relative to its diastereomer assumes that the palladium
complex is formed prior to decarboxylation, and that both of these
events occur in a stepwise fashion. It is proposed that formation of
b
-ketoester
p
-allyl

S. Ma et al. / Tetrahedron 70 (2014) 4208e4212
4211
explained by considering the relative amount of each product and
the competing modes of control (Fig. 6). Ketone (2R,4S)-3 com-
prises 52.5% of the product mixture and is the product that is
generated under doubly matched9 (catalyst and substrate) dia-
stereocontrol. Ketone (2S,4R)-3 accounts for 22.5% of the product
mixture and is formed under singly matched (substrate) diaster-
eocontrol. Thus, only ca. 56% of the combined major di-
astereoisomers benefit from catalyst control and, therefore, this
product exhibits depressed ee. Ketone (2R,4R)-4, the major enan-
tiomer of the minor product, is approximately 24% of the product
mixture and is the product of singly matched catalyst control. Ke-
tone (2S,4S)-4 is less than 1% of the product mixture and is the
doubly mismatched product. The minor diastereomer, therefore, is
almost exclusively under catalyst control: this is reflected in the
very high ee observed (96% ee).
From our studies of the asymmetric decarboxylative allylic al-
kylation of
b-ketoesters derived 4-tert-butylcyclohexanone, we
observe a situation in which substrate and catalyst controls match
or mismatch to deliver ketones 3 and 4, with varying degrees of
enantiopurity. This conclusion is supported by the observation that
the relative ratios of the products that are generated under singly
matched diastereocontrol ((2R,4R)-4 and (2S,4R)-3) are similar. The
competition of these two types of control, one dictated by the
catalyst and one dictated by the substrate, impart excellent enan-
tioselectivity to the minor product but only moderate enantiose-
lectivity to the major product (Fig. 7).10
Fig. 7. Distribution of products as governed by two competing modes of control.
3. Conclusion
Our studies on the decarboxylative allylic alkylation of di-
astereomeric b-ketoesters derived from 4-tert-butylcyclohexanone
Scheme 6. Stereoselective alkylation of tert-butylcyclohexanones.
support our hypothesis of a stereoablative enantioconvergent cat-
alytic process. These studies also reveal an interesting example of
selectivity that is governed by competing modes of substrate and
catalyst control and support an interesting model for relative rates
the transition state in a twist boat conformation. Furthermore, al-
though the cis relationship between the electrophile and tert-butyl
group affords a more thermodynamically stable product because
both groups will be in equatorial positions, this reaction is under
kinetic control. Thus, if we apply this model for diastereoselectivity
of decarboxylation for diastereomeric b-keto carboxylates.
4. Selected experimentals
4.1. General
to b-ketoesters 1 and 2, then the preferred products should have
the allyl group trans to the tert-butyl group (Scheme 7), a general
trend that is observed for our decarboxylative allylic alkylation with
PPh3 (Scheme 5).
A representative procedure for the decarboxylative allylic al-
kylation of diastereomeric -ketoesters:
b
Pd2(dba)3 (67 mg, 0.07 mmol) and (S)-t-Bu-PHOX (73.8 mg,
0.19 mmol) were combined in a round bottom flask. The vial was
evacuated for 10 min prior to addition of THF (88 mL). The reaction
mixture was allowed to stir for 30 min prior to addition of
b-
ketoester 2 (739 mg, 2.93 mmol) via syringe and the reaction was
monitored by TLC. Once the reaction was complete, the mixture
was concentrated. Isolation of products was accomplished by col-
umn chromatography (SiO2, 10% ether in pentane).
4.2. Allyl (1R,5S)-5-(tert-butyl)-1-methyl-2-oxocyclohexane-
1-carboxylate (1)
Allyl
carboxylate (1) was prepared according to a known procedure,
see Ref. 1 for details. 1H NMR (300 MHz, CDCl3)
(1R,5S)-5-(tert-butyl)-1-methyl-2-oxocyclohexane-1-
Scheme 7. Predicted products as dictated by mode of control.
d
5.89 (m, J¼10.2 Hz,
16.2 Hz, 1H), 5.32 (m, J¼7.4 Hz, 1.2 Hz, 1H), 5.25 (m, J¼10.2 Hz,
1.5 Hz, 1H), 4.62 (m, 2H), 2.49 (m, 3H), 2.02 (m, 1H), 1.57e1.18
The other source of control arises from the catalyst (i.e., catalyst
control, Fig. 7). In previous experiments, we have found that (S)-t-
Bu-PHOX will generally prefer to incorporate the allyl group from
the Re face;7 the predicted products are shown in Scheme 7. The
high enantioselectivity observed for the minor product can be
(m, 3H), 1.29 (s, 3H), 0.90 (s, 9H). 13C NMR (75 MHz, CDCl3)
d 208.6,
173.2,131.7,119.2, 66.0, 56.5, 44.4, 40.6, 39.9, 32.5, 28.6, 27.7, 21.8; IR
(neat film, NaCl) 2961, 2865, 1717, 1229, 1140 cmꢁ1; HRMS m/z calcd
for C15H24O3 [M]þ: 252.1726, found 252.1714.

4212
S. Ma et al. / Tetrahedron 70 (2014) 4208e4212
4.3. Allyl (1S,5S)-5-(tert-butyl)-1-methyl-2-oxocyclohexane-1-
CDCl3) d 157.3, 156.1, 136.4, 116.6, 48.2, 46.9, 45.1, 42.3, 41.9, 41.3,
carboxylate (2)
39.4, 38.6, 38.0, 35.5, 32.5, 28.2, 27.6, 26.9, 25.6, 23.6, 22.9, 21.0; IR
(neat film, NaCl) 3400, 3194, 2952, 2873, 1672, 1526 cmꢁ1; HRMS
25.1
1H NMR (300 MHz, CDCl3)
d
(dddd, J¼17.4 Hz, 10.5 Hz, 5.7 Hz,
m/z calcd for C25H43N3O [MþH]þ: 402.3484, found 402.3491; [
a]
D
5.7 Hz, 1H), 5.33 (dq, J¼17.4 Hz, 1.2 Hz, 1H), 5.23 (dq, J¼10.5 Hz,
1.2 Hz, 1H), 4.65 (dt, J¼5.7 Hz, 1.2 Hz, 2H), 2.45 (m, 2H), 2.21
(t, J¼12.6, 1H), 2.02 (m, 1H), 1.84 (dt, J¼13.5 Hz, 3.3 Hz, 1H), 1.59
þ29.73ꢀ (c 0.2550, hexane).
Acknowledgements
(m, 2H), 1.46 (s, 3H), 0.93 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 210.5,
173.2, 132.2, 118.3, 66.0, 57.4, 41.9, 38.0, 37.0, 32.6, 27.6, 26.8, 21.0; IR
(neat film, NaCl) 2958, 2876,1740,1712,1459,1367,1249,1227,1165,
1112 cmꢁ1; HRMS m/z calcd for C15H24O3 [M]þ: 252.1726, found
252.1718.
The authors wish to thank NIH-NIGMS (R01GM080269), Abbott
Laboratories (_100001316), Amgen (_100002429),Merck, Bristol-
Myers Squibb (_100002491), Boehringer Ingelheim (_100001003),
the Gordon and Betty Moore Foundation (_100000936) and
Caltech for financial support. C.M.R. gratefully acknowledges the
Rose Hill Foundation for pre-doctoral funding. R.A.C. gratefully ac-
knowledges the support of this work provided by a fellowship from
the National Cancer Institute of the National Institutes of Health
(_100000002) under Award Number F31CA174359. Mr. Lawrence
Henling and Dr. Michael Day are gratefully acknowledged for X-
ray crystallographic structural determination. The Bruker KAPPA
APEXII X-ray diffractometer was purchased via an NSF CRIF:MU
award to the California Institute of Technology, CHE-0639094.
4.4. (trans)-2-Allyl-4-(tert-butyl)-2-methylcyclohexan-1-one
(3)
1H NMR (300 MHz, CDCl3)
2.38e2.23 (m, 4H), 2.03 (m, 1H),1.84 (m,1H),1.70 (m,1H),1.42e1.13
(m, 2H), 1.00 (s, 3H), 0.89 (s, 9H); 13C NMR (75 MHz, CDCl3)
216.0,
d 5.64 (m, 1H), 5.04 (m, 2H),
d
133.0,118.5, 48.2, 42.0, 40.1, 38.5, 32.4, 28.3, 27.7, 22.7; IR (neat film,
NaCl) 2962, 2870, 1709, 1366, 912 cmꢁ1; HRMS m/z calcd for
25.6
C
14H24O [M]þ: 208.1827, found 208.1825; [
a
]
D
ꢁ30.00 (c 1.08,
hexane).
4.5. (cis)-2-Allyl-4-(tert-butyl)-2-methylcyclohexan-1-one (4)
1H NMR (300 MHz, CDCl3)
5.77 (m, 1H), 5.03 (m, 2H), 2.50
Supplementary data
NMR spectra for compounds 1e4, as well as details on the ste-
reochemical assignment of compounds 1 and 2. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2014.03.042.
d
(m, 1H), 2.28 (m, 2H), 2.16 (m, 1H), 2.00 (m, 1H), 1.64 (m, 2H), 1.42
(m, 2H), 1.14 (s, 3H), 0.89 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
216.2,
135.0, 117.9, 47.3, 43.3, 42.3, 38.9, 38.5, 32.5, 27.8, 27.7, 24.2; IR (neat
film, NaCl) 2963, 2870, 1709, 1366, 912 cmꢁ1; HRMS m/z calcd for
25.7
References and notes
C
14H24O [M]þ: 208.1827, found 208.1836; [
a
]
þ77.81ꢀ (c 0.105,
D
hexane).
1. Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed.
2005, 44, 6924e6927.
2. Please see Supplementary data for more information.
3. The relative rate of consumption of starting material was determined by
comparing the negative slopes of Ln[b-ketoester] versus time for b-ketoesters 1
4.6. (E)-2-((2R,4S)-2-Allyl-4-(tert-butyl)-2-methylcyclohexyl-
idene)-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-
yl)hydrazine-1-carboxamide (5)
and 2.
4. Tsuji and co-workers previously reported the allylic alkylation of di-
astereomeric -ketoesters 1 and 2 using PPh3 as ligand. Unfortunately, their
findings as presented are unclear, as the relative stereochemistry between tert-
butyl and -substituents is not explicitly delineated. See, Tsuji, J.; Yamada, T.;
Minami, L.; Yuhara, M.; Nisar, M.; Shimizu, I. J. Org. Chem. 1987, 52, 2988e2995.
5. Kayser, R. H.; Brault, M.; Pollack, R. M.; Bantia, S.; Sadoff, S. F. J. Org. Chem. 1983,
48, 4497e4502.
1H NMR (300 MHz, CDCl3)
d
7.83 (br s, 1H), 6.08 (d, J¼9 Hz, 1H),
b
5.65 (m, 1H), 5.05 (m, 2H), 4.17 (m, 1H), 2.63 (m, 2H), 2.41 (m, 1H),
2.24 (m, 3H), 1.84 (m, 6H), 1.53 (m, 2H), 1.22 (s, 3H), 1.15 (app. dd,
J¼7.2 Hz, 1.0 Hz, 4H), 1.10 (s, 3H), 1.05 (s, 3H), 0.88 (d, 1H, J¼9.9 Hz),
a
0.85 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 156.8, 156.0, 134.1, 117.8,
6. Pollack, R. M. In Transition States of Biochemical Processes; Gandour, R. D.,
Schowen, R. L., Eds.; Plenum: New York, NY, 1978; p 467.
48.3, 48.2, 48.0, 47.1, 42.7, 41.9, 41.8, 39.8, 38.6, 38.1, 35.5, 32.5, 28.2,
7. (a) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.;
Stoltz, B. M. J. Am. Chem. Soc. 2007, 129, 11876e11877; (b) Sherden, N. H.; Be-
henna, D. C.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48,
6840e6843; (c) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.;
27.6, 27.0, 25.0, 23.6, 22.6, 21.0; IR (neat film, NaCl) 3406, 3194,
3075, 2962, 1672, 1526 cmꢁ1; HRMS m/z calcd for C25H43N3O
[MþH]þ: 402.3484, found 402.3487; [
a
]
þ15.31ꢀ (c 0.2250,
25.0
D
ꢀ
Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.; Krout, M. R.; McFadden, R.
CHCl3).
M.; Roizen, J. L.; Enquist, J. A., Jr.; White, D. E.; Levine, S. R.; Petrova, K.; Iwashita,
A.; Virgil, S. C.; Stoltz, B. M. Chem.dEur. J. 2011, 17, 14199e14223; (d) Keith, J. A.;
Behenna, D. C.; Sherden, N. H.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.;
Oxgaard, J.; Stoltz, B. M.; Goddard, W. A., III. J. Am. Chem. Soc. 2012, 134,
19050e19060.
8. House, H. O.; Tefertiller, B. A.; Olmstead, H. D. J. Org. Chem. 1968, 33, 935e942.
9. Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B.; Walker, F. J.
Science 1983, 949e951.
10. It should be noted that the percentages introduced in Fig. 7 are normalized to
100, and that the actual yield of the reaction of 93%. Unreacted starting material
or non-selective protonation products are assumed to account for the re-
maining 4R-t-Bu isomer absent from the allylic alkylation product mixture.
4.7. (E)-2-((2R,4R)-2-Allyl-4-(tert-butyl)-2-methylcyclohexyl-
idene)-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3
yl)hydrazine-1-carboxamide (6)
1H NMR (300 MHz, CDCl3)
d
8.42 (br s, 1H), 6.08 (d, J¼9 Hz, 1H),
5.94 (m, 1H), 5.04 (m, 2H), 4.17 (m, 1H), 2.71 (m, 2H), 2.37 (m, 3H),
1.91 (m, 5H), 1.55 (m, 3H), 1.21 (s, 3H), 1.12 (d, J¼7.5, 3H), 1.10 (s, 3H),
1.04 (s, 3H), 0.87 (d, J¼9.9 Hz, 1H), 0.84 (s, 9H); 13C NMR (75 MHz,