Carbanion-accelerated claisen rearrangements: Asymmetric induction with chiral phosphorus-stabilized anions

Article abstract of DOI:10.1021/jo301919e

The carbanion-accelerated Claisen rearrangement has been extended to include phosphorus carbanion-stabilizing groups. The appropriately substituted allyl vinyl ethers are synthesized by the nucleophilic addition of allyl oxides to phosphorus-substituted allenes, which are obtained in one step from simple starting materials. The phosphorus-stabilized, carbanion-accelerated Claisen rearrangements proceed rapidly at room temperature in high yield, and the rearrangements are highly site- and stereoselective. The first examples of asymmetric induction in the Claisen rearrangement with chiral, phosphorus, anion-stabilizing groups are described. The observed asymmetric induction is highly dependent on the structure of the auxiliary and the metal counterion involved. Both internal and relative diastereoselectivity are high. A model for the observed sense of internal diastereoselectivity is proposed that is founded in the current understanding of the structure of phosphorus-stabilized anions.

Full text of DOI:10.1021/jo301919e

Article
pubs.acs.org/joc
Carbanion-Accelerated Claisen Rearrangements: Asymmetric
Induction with Chiral Phosphorus-Stabilized Anions‡
Scott E. Denmark,* John E. Marlin, and G. Rajendra§
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
S
* Supporting Information
ABSTRACT: The carbanion-accelerated Claisen rearrangement
has been extended to include phosphorus carbanion-stabilizing
groups. The appropriately substituted allyl vinyl ethers are
synthesized by the nucleophilic addition of allyl oxides to
phosphorus-substituted allenes, which are obtained in one step
from simple starting materials. The phosphorus-stabilized,
carbanion-accelerated Claisen rearrangements proceed rapidly at room temperature in high yield, and the rearrangements are
highly site- and stereoselective. The first examples of asymmetric induction in the Claisen rearrangement with chiral, phosphorus,
anion-stabilizing groups are described. The observed asymmetric induction is highly dependent on the structure of the auxiliary
and the metal counterion involved. Both internal and relative diastereoselectivity are high. A model for the observed sense of
internal diastereoselectivity is proposed that is founded in the current understanding of the structure of phosphorus-stabilized
anions.
ultimately recoverable unchanged (Scheme 2). A few, but
notable, examples of this concept have been described for
variants of the Claisen rearrangement,3,4 as has the use of
stoichiometric amounts of chiral modifiers.5
INTRODUCTION
■
The aliphatic Claisen rearrangement of allyl vinyl ethers enjoys
recognition as one of the preeminent members of the
important class of [3,3]-sigmatropic rearrangements. The vast
literature on all aspects of the reaction continues to grow
documenting new variations, synthetic applications, and
mechanistic and theoretical details.1 Synthetically, the most
commonly employed variants are the thermally induced
processes illustrated in Scheme 1, which produce a number
of γ,δ-unsaturated carbonyl derivatives with varying degrees of
facility. The highly selective and predictable creation of the new
double bond and stereogenic centers is a hallmark of the
rearrangement. These familiar issues of relative and internal
stereogenesis attend all reactions within or between molecules
containing enantio- or diastereotopic faces.2 A less common
manifestation of relative stereogenesis in the Claisen rearrange-
ment involves the influence of remote stereocenters not
contained within the pericyclic array. This is encountered in
substrates bearing stereogenic carbons attached to positions 1
and 6 (A and B, Scheme 2). An intriguing subset of this
phenomenon is the special case of auxiliary-based, relative
stereocontrol wherein the preexisting stereogenic unit is
Scheme 2
To further extend the synthetic utility and improve
stereoselectivity, catalysis of the Claisen rearrangement
constitutes an important objective.6 Significant rate and
selectivity enhancements are now on record employing catalysis
with Lewis acids (both main group7 and transition metal8),
Brønsted acids,9 antibodies,10 and N-heterocyclic carbenes.11
These advances have significantly improved the rate and
enantioselectivity of the Claisen rearrangement. The continuing
efforts in this area are testimony to the fact that a truly general
solution to asymmetric Claisen rearrangements is still elusive.
In addition, to enable catalysis by Lewis and Brønsted acids,
Lewis basic binding sites (generally a carboalkoxy group at
Scheme 1
Special Issue: Robert Ireland Memorial Issue
Received: September 4, 2012
© XXXX American Chemical Society
A
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Article
C(2)) are required to enable activation and provide rigidity for
stereocontrol. This fact is not so much a criticism as a
statement of opportunity to develop new concepts for
addressing these key issues.
(3) strong diastereofacial bias in the CACR, and (4) facile
cleavage and recovery of the auxiliary unit. In addition to the
stereoselective construction of new carbon−carbon bonds, the
results of this study should provide valuable insights into the
nature of heteroatom-stabilized allyl anions.16
Our study of the Claisen rearrangement stems from a long-
standing interest in the electronic modulation of the rearrange-
ment.12,13 Early reports from our laboratories documented the
accelerating effect of a carbanion (π-donor) at the 2-position of
an allyl vinyl ether, Scheme 3. The arylsulfonyl stabilizing group
(G = ArSO2) has been extensively investigated, and the
resulting carbanion-accelerated Claisen rearrangements
(CACR)14 display the following characteristics: (1) >300-fold
acceleration, (2) exclusive γ-site selectivity, (3) substitution
compatible at all positions, (4) exclusive formation of trans
olefins, and (5) high diastereoselectivity (95:5 dr) for syn or
anti isomers. Although extension of the CACR with other
sulfur-based anion stabilizing groups was unsuccessful, a
number of phosphorus-based groups have shown considerable
potential. As shown in Scheme 3, phosphine oxides,
phosphonates, and phosphonamides are superior to sulfones
in rate and selectivity in the CACR.15
BACKGROUND
■
The application of chiral phosphorus reagents in organic
synthesis is not very common, apart from the ubiquitous use of
chiral phosphines as ligands for transition-metal catalysts.
Chiral organophosphorus reagents have been employed in
asymmetric olefination,17 asymmetric Michael addition,18
asymmetric alkylation and amination,19 and asymmetric
Staudinger reactions.20 A small number of common motifs
have found good use in several of these transformations such as
diazaphospholidines (i), diazaphosphorinanes (ii), oxazaphos-
pholidines (iii, iv), and oxazaphosphorinanes (v, vi) (Chart 1).
Chart 1
Scheme 3
The de novo design of an auxiliary for a phosphorus-
stabilized carbanion was nearly impossible since little was
known at the time about the structure of the anion. Early design
criteria were guided by our own studies in addition to the NMR
and IR spectroscopic studies from Seyden-Penne21 on P-
stabilized carbanions bearing additional stabilizing groups
(−COR, −CO2R, −CN, Ph, etc.). Two limiting structures
were proposed: a parallel, chelated anion vii and an orthogonal,
(C−Li contact) anion viii, Chart 2. It was a priori difficult to
predict which of these two structures the allyl vinyl ether anion
would prefer. Indeed, it embodies features of both being an
unstabilized allyl anion, but also containing a potentially
coordinating β-oxygen. In either case, we reasoned that a key
element in stereocontrol was to desymmetrize the region
around the carbanion by maximally differentiating the groups X
and Y, Chart 2. This condition was satisfied by the N-
substituted 1,3,2-oxazaphosphorinane moiety ix depicted in
Chart 2. The phosphorinane (six-ring) was selected in favor of
the phospholidine (five-ring) for two reasons: (1) to move the
N-ligand closer to the vicinity of the anion and (2) to reduce
reactivity at phosphorus.22
In all of these cases, the anion-stabilizing groups are achiral.
Thus, the two limiting chairlike transition states i and iv are
enantiomeric, giving rise, necessarily, to racemic products ii
(iii) and v (vi), Scheme 4. If, however, G* were chiral, i and iv
would be diastereomeric leading to diastereomers ii and v
which, after removal of G*, constitute enantiomers iii and vi.
Insofar as the anionic charge is responsible for the rate
enhancement, effective desymmetrization of that charge by
chiral groups G* should lead to significant differences in rates of
rearrangement for i and iv. These differences are manifested in
the enantiomeric excess of the products.
The specific objective of the investigation described here is
the development of an auxiliary-based, asymmetric CACR using
chiral, anion-stabilizing groups. The success of this enterprise
rests on the design of the chiral moiety G*, which should satisfy
the following criteria: (1) ready construction from available,
nonracemic materials, (2) effective acceleration of the CACR,
Scheme 4
This structural motif formed the basis for the three types of
substrates examined, Chart 3. Preliminary studies, optimization
and N-group dependence were carried out with model I in
Chart 2
B
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racemic form (derived from an achiral amino alcohol). Models
II (cis) and II (trans) (derived from the same enantiomerically
pure amino alcohol) were used to establish the absolute
stereochemical course of the reaction and to produce
enantiomerically enriched products. The synthesis and
rearrangements of various allyl vinyl ethers in these families
and stereochemical analysis of the keto phosphonamidate
products is described in detail below. Some of these studies
have been described previously in preliminary form.23
1.3. Synthesis of Allyl Vinyl Ethers. Previous studies
demonstrated that very subtle changes in reaction conditions
produce drastic differences in product distribution during allyl
oxide additions to achiral phosphorus-substituted allenes, and
similar behavior with these oxazaphosphorinanes was antici-
pated. Indeed, four products could be isolated following
exposure of potassium or sodium allyloxide to allene 5a
(Table 2): the β,γ- and α,β-unsaturated oxazaphosphorinanes
7aa and 8aa resulting from allyloxide addition and acetylenic
oxazaphosphorinanes 9a and 10a resulting from simple
tautomerization. Formation of the β,γ-unsaturated oxazaphos-
phorinane 7aa required the use of sodium allyl oxide at room
temperature in the presence of tert-butyl alcohol (Table 2, entry
1). tert-Butyl alcohol serves as a proton source to trap the
intermediate allyl anion prior to isomerization. The use of
sodium hydride without tert-butyl alcohol at lower temper-
atures (Table 2, entry 3) afforded a mixture of 7aa and both
acetylenic products. Under no circumstances did the addition
of potassium allyloxide lead to the exclusive formation of 7aa
(Table 2, entries 2, 4−6). However, the α,β-unsaturated
derivative 8aa was cleanly prepared at room temperature in the
absence of tert-butyl alcohol in high yield by the addition of
potassium allyl oxide (Table 2, entry 2).
Chart 3
RESULTS AND DISCUSSION
■
1. Racemic Oxazaphosphorinanes. 1.1. Synthesis of
Amino Alcohol Auxiliaries. The achiral amino alcohols 2a, 2b,
and 2c required for synthesis of model I were prepared by
methylation of the 3-trifluoroacetamidopropanoates (1a−c)
with excess methylmagnesium bromide, Scheme 5. The use of
methyllithium or a simple acetamide protecting group led to
considerably lower yields. Compounds 1a−c were prepared by
simple Michael addition to methyl acrylate followed by
acetylation with trifluoroacetic anhydride.
Table 2. Optimization of Allyloxide Addition to Allene 5a
Scheme 5
t-BuOH
temp
time,
(h)
a
entry MH
(equiv)
(°C)
result
7aa (64%)
1
2
3
4
5
6
NaH
KH
2.4
0
20
20
0.5
0.5
3.5
0.5
0.25
1.0
8aa (71%)
NaH
KH
0
−20
0
7aa:9a:10a (4:3:3)
7aa:9a:10a (1:1:1)
8aa only
2.4
1.8
solvent
1.2. Synthesis of Allenes. The amino alcohols were directly
converted to the required allenes in a one-pot operation via a
facile Horner−Mark [2,3]-rearrangement (4 to 5 or 6, Table
1). Thus, addition of 3-butyn-2-ol (3a) to a cold solution of
PCl3 and 1.0 equiv of N-methylmorpholine (NMM), followed
by sequential addition of an additional 2.0 equiv of NMM and
the amino alcohol 2a, 2b, or 2c produced allenes 5a−c,
respectively. Allene 6 was prepared under identical conditions
by combining 2-methyl-3-butyn-2-ol (3b) with PCl3 and amino
alcohol 2a.
KH
20
KH
20
9a and 10a only
a
All reactions performed with a full equivalent of MH.
The results for all of the optimized allyl and crotyl oxide
additions in this series are collected in Table 3. All additions to
the monomethylated allenes proceed rapidly at room temper-
ature. Crotyl oxide addition to the dimethylated allene 6
proceeded more slowly and was free of contamination from the
corresponding acetylenes or the α,β-unsaturated addition
product. However, a small amount (<5%) of inseparable
thermal Claisen rearrangement product was invariably formed.
1.4. Claisen Rearrangements. All anion-accelerated rear-
rangements in this series were conducted using 2.0−2.5 equiv
of lithium dimsylate generated from either equimolar amounts
of n-BuLi and DMSO in THF or KH in 3:1 DMSO/THF in
the presence of 6 equiv of LiCl. Anion-accelerated rearrange-
ments of all β,γ-unsaturated isomers are complete within 10−
15 min at room temperature, while the corresponding thermal
rearrangements require 2−4 h in refluxing toluene or at 100 °C
in THF (sealed tube). As expected, anion-accelerated
rearrangements of the α,β-unsaturated isomers required
reaction times on the order of 1.5−3 h.
Table 1. Synthesis of Allenes 5 and 6
entry
R1
R2
product
yield (%)
1
2
3
4
t-Bu
1-Ad
Me
H
5a
5b
5c
6
58
70
79
53
H
H
t-Bu
Me
C
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a
Table 3. Allyl and Crotyl Oxide Additions to Allenes 5 and 6
entry
allene
base
t-BuOH (equiv)
time (min)
product
R1
R2
R3
yield (%)
1
2
3
4
5
6
7
5a
5a
5a
5a
5b
5c
6
NaH
KH
2.4
0
20
30
20
20
5
7aa
8aa
7ab
8ab
7ba
7ca
11
t-Bu
t-Bu
t-Bu
t-Bu
1-Ad
Me
H
H
64
71
46
80
34
40
51
H
H
NaH
KH
2.4
0
H
CH3
CH3
H
H
NaH
NaH
KH
2.4
2.4
0
H
2
H
H
180
t-Bu
CH3
CH3
a
All reactions were performed using 1.2 equiv of base and allylic alcohol.
Two types of diastereoselectivity are manifest with chiral
Table 4. Claisen Rearrangement of Oxazaphosphorinanes
7aa
a
phosphorus-stabilized, carbanion-accelerated Claisen rearrange-
ments. The relative asymmetric induction is defined as the
ability of the chiral phosphorus subunit to influence the
creation of the new stereogenic centers in the rearrangement.
The internal asymmetric induction reflects the extent of chair/
boat conformational selectivity. The absolute asymmetric
induction describes the configuration of newly created
stereogenic centers with respect to the configuration of the
existing phosphorus atom. In the racemic series (model I), the
particular substitution pattern of each allyl vinyl ether
determined whether relative asymmetric induction could be
studied separately or coupled with internal asymmetric
induction. Therefore, the rearrangements of each allyl vinyl
ether will be discussed individually. Absolute asymmetric
induction will only be discussed with model II compounds
(vide infra).
time
(h)
yield
(%)
b
c
entry
base
solvent
dr
d
1
none
KDMSO
THF
4.0
90
77
58:42
52:48
2
3
4
DMSO/THF
(3:1)
0.25
e
KDMSO (LiCl) DMSO/THF
0.25
0.25
81
73
91:9
95:5
(3:1)
f
LiDMSO
DMSO/THF
(3:1)
5
6
7
8
LiDMSO
LiDMSO
LiDIPSO
n-BuLi
THF
Et2O
THF
THF
0.50
1.0
64
31
68
51
94:6
90:10
94:6
95:5
Anion-accelerated Claisen rearrangement of allyl vinyl ether
7aa with LiDMSO afforded a mixture of two diastereomers (l-
and u-12aa)24 with as high as 90% diastereoselectivity (Table
4). The diastereomeric ratios were determined by integration of
either the distinct singlets in the proton-decoupled 31P NMR
0.25
1.75
a
b
All anionic rearrangements carried out at room temperature. Usually
c
2.0−2.5 equiv of base used. Diastereoselectivity determined by 31P
d
1
1
NMR or H NMR (500 MHz). Reaction performed at 100 °C in a
e f
spectra or the C(3) methyl doublets in the H NMR spectra.
sealed tube.. 6.0 equiv of LiCl used. Prepared with n-BuLi. The
reagent was insoluble in THF but dissolved upon addition of 7aa.
The thermal rearrangement is nonselective (Table 4, entry 1)
as is the anion-accelerated rearrangement when KDMSO serves
as base (Table 4, entry 2). All rearrangements of anions with
lithium as the counterion gave excellent diastereoselectivities
(Table 4, entries 3−8). The rate of reaction decreased with
decreasing solvent polarity. Interestingly, use of the more bulky
and more strongly basic lithium diisopropyl sulfoxide (Table 4,
entry 7) increased the rate of rearrangement but did not affect
stereoselectivity. Thus, it appears that the reaction rate is
solvent dependent, but stereoselectivity is counterion depend-
ent.
anion-accelerated rearrangements of 7ba (Table 5, entries 2−3)
proceed with the same high stereoselectivity as seen with 7aa.
However, the high degree of stereoselectivity disappears under
anion-forming conditions when the ligand bound to the
oxazaphosphorinane nitrogen is small (R = methyl, Table 5,
entry 5). Thus, a sterically bulky N-substituent is crucial for
proper stereocontrol.
The diastereomeric ratios observed in the rearrangement of
7aa are a direct reflection of the control that the chiral
environment about the phosphorus atom exerts on the
transition state during the rearrangement. Any change in the
chair/boat transition-state selectivity will not affect the
observed product ratio.
The importance of the local environment about the
phosphorus atom was further demonstrated by studying the
rearrangements of the N-adamantyl and N-methyl derivatives
7ba and 7ca (Table 5). Whereas both thermal Claisen
rearrangements are unselective (Table 5, entries 1 and 4),
The α,β-unsaturated oxazaphosphorinane 8aa underwent
Claisen rearrangement under anion-forming conditions to
afford a mixture of (l) and (u) keto oxazaphosphorinanes
12aa (Scheme 6). However, this rearrangement is selective in
the opposite sense when compared to that of compound 7aa.
The origin of the reversal of selectivity may be explained by a
permutation of the allyl anion geometry. Chart 4 shows the
geometries of the favored anions. α-Deprotonation of 7aa gives
E allyl anion 7aa− since the configuration about C(1)−C(2) is
fixed during allyl oxide addition and a high barrier to rotation
relative to rearrangement exists. γ-Deprotonation of 8aa then
D
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a
according to the following arguments. The major product
from the CACR of compound 7ab (δ 31P 15.74 ppm) was
assumed to be a syn-dimethyl diastereomer by analogy to all
other CACRs (i.e., sulfones, phosphonates, etc.) in that
similarly substituted allyl vinyl ethers produce syn-dimethyl
diastereomers.
Table 5. Claisen Rearrangement of 7ba and 7ca
Thermal rearrangements are also syn selective, and thermal
rearrangement of 7ab gave two major diastereomers (δ 31P:
15.74, 16.25 ppm). The anti dimethyl diastereomers were
identified from the anion-accelerated rearrangement of the α,β-
unsaturated oxazaphosphorinane 8ab. These assignments were
also based on analogy to other CACRs of similarly substituted
allyl vinyl ethers which have been shown to be anti selective. To
assign numbers to the internal and relative asymmetric
induction selectivities, we still needed to determine which
transition state was responsible for each product. Making the
reasonable assumption that the major diastereomer in each
rearrangement resulted from a chairlike transition state, all
products can be assigned as having resulted from either a chair-
or boatlike transition state from either face of the allyl anion.
The internal diastereoselectivity is then the sum of the integrals
of the products arising from a chair- versus a boatlike
transitions state. Thus, the internal diastereoselectivities are
98:2 for 7ab and 94:6 for 8ab. The relative diastereoselectivities
are the sum of the integrals of the products arising from
rearrangement on the same face of the allyl anion. Thus, the
relative diastereoselectivities are 92:8 for 7ab and 13:87 for 8ab.
2. Enantiomerically Pure Oxazaphosphorinanes.
Model II. Because CACR products 12xx and 13 are racemic
and noncrystalline, it was not possible to determine the
configuration of the newly formed stereogenic centers by
degradative or X-ray crystallographic methods. Thus, it was
necessary to employ a chiral oxazaphosphorinane which was
generated from enantiomerically pure amino alcohol 15.
2.1. Synthesis of Amino Alcohol 15. Amino alcohol 15 was
chosen for its structural similarity to amino alcohol 2a. Thus,
the oxazaphosphorinane ring, and hence the environment about
the phosphorus atom, would experience minimal perturbation.
The preparation of 15 is shown in Scheme 9. Yeast reduction of
ethyl acetoacetate afforded (S)-ethyl 3-hydroxybutanoate in
55% yield (er 98:2).25 The enantiomeric purity was determined
by optical rotation and GC analysis of the Mosher esters.26 The
observed enantiomeric excess is significantly higher than
previously reported and can only be explained by the brand
of yeast used.27 Amidation without hydroxyl protection by the
method of Weinreb28 gave (S)-N-tert-butyl-3-hydroxybutyr-
amide (14) in 72% yield (er >99:1). This reaction required a
careful quenching protocol followed by acidification to pH ∼6.
At lower pH, β-elimination to the butenamide occurred. The
enantiomeric excess was determined by derivatization to a 3,5-
dinitrophenyl carbamate (14′) and HPLC analysis on a Pirkle
L-naphthylalanine column.29 Diborane reduction then produced
amino alcohol 15 in 67% yield.
time
(h)
yield
(%)
b
c
entry educt
R
base
solvent
dr
d
1
2
3
7ba 1-Ad none
toluene
2.0
93
58
74
60:40
94:6
94:6
7ba 1-Ad LiDMSO THF
0.25
0.25
7ba 1-Ad LiDMSO DMSO/
THF
d
4
5
7ca
7ca
Me
Me
none
toluene
2.5
86
62
53:47
52:48
LiDMSO THF
0.25
a
b
Anionic rearrangements carried out at room temperature. 2.5 equiv
c
of base were used. Diastereoselectivities determined by 1H NMR
d
(500 MHz) Reactions run at 110 °C.
must be selective to form a preponderance of Z allyl anion 8aa−
having the opposite configuration at C(1).
Scheme 6
Chart 4
Rearrangement of the trimethyl-substituted allyl vinyl ether
11 also leads to a mixture of two diastereomeric products (13,
Scheme 7). Although the chair/boat conformational selectivity
does affect the product ratios in this rearrangement, it is not
possible to quantify this internal selectivity. This result implies
that, assuming complete chair selectivity, the minimum relative
asymmetric induction is 92:8. Anything less than complete
chair selectivity would make the relative asymmetric induction
even better.
Scheme 7
2.2. Synthesis and Assignment of Allenes cis- and trans-
16. Allene formation from 15, PCl3, and propargylic alcohol 3a
using standard reaction conditions produced a mixture of four
diastereomers (Scheme 10). From this mixture, diastereomeric
allene pairs cis-16 (54%) and trans-16 (20%) could be easily
separated by chromatography. Assignment of these phosphorus
epimers was tentatively based on the downfield chemical shifts
of phosphorus in the 31P NMR spectrum and the C(6) proton
The rearrangements of allyl vinyl ethers 7ab and 8ab (Table
6) result in the formation of two new stereogenic centers and,
thus, mixtures of four diastereomers. In these cases, it was
possible to quantify the degrees of internal and relative
asymmetric induction. The four diastereomers are distinguish-
able in the 31P NMR spectra (note the 31P chemical shifts in
Scheme 8). Assignment of the diastereomers was made
30
1
in the H NMR spectrum of cis-16. These assignments were
later confirmed by X-ray crystallography (vide infra).
E
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Table 6. Claisen Rearrangement of Oxazaphosphorinanes 7ab and 8ab
b
induction
a
entry
educt
base
solvent
time, h
temp, °C
yield, %
relative
internal
1
2
3
7ab
7ab
8ab
none
THF
4.0
0.25
3.0
100
20
84
80
60
58:42
92:8
77:23
98:2
94:6
c
c
KDMSO/LiCl
DMSO/THF (3:1)
KDMSO/LiCl
DMSO/THF (3:1)
20
13:87
a
b
c
2.0−2.5 equiv of base were used. See text for definition. 6.0 equivalents of LiCl were used.
Scheme 8
Scheme 9
Scheme 11
Scheme 10
The tentative assignments of configuration at the phosphorus
center made earlier on the basis of 1H and 31P NMR
spectroscopic data could be confirmed by single-crystal X-ray
crystallographic determinations of both allyl vinyl ethers cis-17
and trans-17 (Figure 1).31 These structures verified the S-
configuration at phosphorus and a cis relationship between the
C(6) methyl group for cis-17 and the R-configuration at
phosphorus and a trans relationship between the C(6) methyl
group for trans-17. Furthermore, the geometry about the vinyl
ether double bond was also unambiguously established in both
cases. As expected, nucleophilic attack on a monomethylated
2.3. Synthesis and Assignment of Allyl Vinyl Ethers. Allyl
vinyl ethers cis-17 and trans-17 were prepared by sodium allyl
oxide addition to allenes cis- and trans-16, respectively, in the
presence of tert-butyl alcohol (Scheme 11). The formation of
acetylenic tautomers was responsible for the low yield in the
preparation of trans-17.
F
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Figure 1. ORTEP images of cis-17 and trans-17.
a
Table 7. Carbanionic Claisen Rearrangement of cis-17
b
c
d
e
entry
educt
product
base
LiCl, equiv
temp (°C)
yield (%)
relative induction
1
2
3
4
5
6
7
8
cis-17
cis-17
cis-17
cis-17
cis-17
cis-17
cis-17
cis-17
cis-18
cis-18
cis-18
cis-18
cis-18
cis-18
cis-18
cis-18
KDMSO
KDMSO
KDMSO
KDMSO
KDMSO
LiDMSO
none
0
1
20
20
62
77
69
78
65
65
93
90
50:50
65:35
80:20
90:10
89:11
90:10
66:34
64:36
2
20
6
20
12
0
20
f
20
0
100
100
none
6
a
All anionic rearrangements (15 min) were done in 3:1 DMSO/THF except entry 6 which was done in 2:1 THF/DMSO, thermal rearrangements
b
c
d
(240 min) were done in THF. 2−2.5 equiv of freshly prepared base was used. LiCl was added to KDMSO before addition of 17. Yield after
chromatography. See text for explanation. Prepared from n-BuLi.
e
f
allene is governed by steric approach of the allyloxide to the less
hindered face of the allene.
the racemic series, the thermal rearrangement required 4 h at
100 °C and showed poor diastereoselectivity (compare Table 7,
entries 4 and 7). At this point, the effect of added LiCl on the
stereoselectivity of the CACR was studied. In the absence of
LiCl, there is no observed asymmetric induction in the anion-
accelerated rearrangement of cis-17 (Table 7, entry 1). As the
amount of LiCl is increased from 1 to 6 equiv (Table 7, entries
2−4), the diastereomeric ratios improve from ∼2:1 to 9:1. No
further increase in selectivity is observed with additional
equivalents of LiCl (Table 7, entry 5). Note that LiDMSO
prepared from n-BuLi and DMSO in THF also results in high
relative asymmetric induction (Table 4, entry 6). Finally, added
LiCl had no positive effect on the selectivity of the thermal
rearrangement (Table 7, entry 8). The anion-accelerated
rearrangement of trans-17 also proceeded with high selectivity
(Scheme 12).
2.5. Degradation and Assignment. To establish the relative
configuration at the newly created stereogenic centers with that
of the existing phosphorus center, CACR products (S)-(l,l)-18
and (S)-(u,u)-18 were degraded to optically active dimethyl
methylsuccinates as shown in Scheme 13. Treatment of the
keto oxazaphosphorinanes with KHMDS at −78 °C and
trapping with tert-butyldimethylsilyl chloride afforded the silyl
enol ether. Ozonolysis followed by an oxidative workup
Other interesting features of these structures include the
observation that the oxazaphosphorinane ring in cis-17 is nearly
flat with bond angles between the substituents on nitrogen of
approximately 120°. The planarity at nitrogen, in accord with
other reported 1,3,2-oxazaphosphorinanes,32 stems from the
longer P−O and P−N bond lengths that widen the angles
between the atoms in the ring. The wider angles also contribute
to the flattening of the ring. However, the most important
interaction governing the ring conformation is the geminal-
P(1)−N(1) substitution pattern which places the phosphorus
substituent in a pseudoaxial position. Bentrude has shown that
N-unsubstituted 1,3,2-oxazaphosphorinanes exist predomi-
nantly in a chair conformation, whereas N-substituted 1,3,2-
oxazaphosphorinanes exist exclusively in a twist-chair con-
formation.33 Clearly, the geminal P(1)−N(1) interaction in cis-
17 strongly influences 1,3,2-oxazaphosphorinane ring con-
formation. In trans-17, the nitrogen is lightly pyramidalized and
the ring takes up a chairlike conformation wherein the
phosphorus substituent again takes up an axial position.
2.4. Claisen Rearrangements. Under anion-forming con-
ditions, allyl vinyl ether cis-17 (Table 7) rearranged rapidly at
room temperature with high relative diastereoselectivity. As in
G
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display the following characteristics: (1) the anionic carbons are
fully planarized (i.e., sp2 hybridized) and are devoid of contacts
to lithium, (2) the atoms of the anion are all aligned in nearly
eclipsed conformations with respect to the PO moiety such
that the dihedral angle, O(1)−P(1)−C(1)−C(2) spans a mere
10° across all structures, (3) the lithium atoms are coordinated
to the phosphoryl oxygens and to two or more solvent (THF)
molecules, (4) the nitrogen atoms in the 1,3,2-diazaphosphor-
inanes are pyramidalized, and (5) rotational barriers around the
P−C bonds are very low. Although phosphorus-stabilized allyl
anions have been studied only computationally, our exper-
imental observations are consistent with the results of those
studies.
Scheme 12
provided an enantiomerically enriched sample of methylsuc-
cinic acids which were esterified with diazomethane. The
overall yields were 59% from cis-18 and 24% from trans-18.
The currently preferred model proposed to explain relative
diastereoselectivity in the carbanion-accelerated Claisen rear-
rangement incorporates the various steric and electronic
components that have been established in the foregoing
studies. The model, shown in Figure 2, possesses the following
characteristics: (1) a planar carbanion in which the atoms are
aligned parallel to the PO bond, (2) chelation of a lithium
ion between the phosphoryl and vinyl ether oxygens, and (3) a
sterically directed, diastereofacial preference of chair con-
formers such that the allyloxy side chain folds away from the
bulky nitrogen substituent. This model corresponds to the
parallel anion model vii in Chart 2.
Scheme 13
The absolute configuration of the succinate esters could not
be established by optical rotation because the absolute optical
rotation of dimethyl methylsuccinate is quite small.34 With only
limited amounts of material in hand, the use of optical rotation
became inappropriate. The enantiomeric succinates were
instead distinguished by 1H NMR spectroscopy in the presence
of the chiral shift agent (R)-2,2,2-trifluoro-1-(9-anthryl)-
ethanol.35 The methyl ester regions of the spectra clearly
show four singlets. Assignment of the major enantiomers
1
followed from the H NMR spectrum of a mixture of the
racemic succinates enriched with authentic R succinate and the
chiral shift agent. As shown in Scheme 13, cis-18 produced the
(S)-dimethyl methylsuccinate and trans-18 produced the R
enantiomer. These data, coupled with the known configurations
of the vinyl ether double bond (E) and the phosphorus
stereogenic center, allows the unambiguous assignment of the
sense of the chairlike folding in the transition state during the
rearrangement. Thus, the rearrangement of cis-17 proceeds by
bonding to the Re face of the allyl anion at C(1) (cf. Chart 4),
whereas the Si face is preferred for trans-17.
2.6. Proposed Transition States. It is clear that auxiliary
structure, anion structure, counterion effects, and conforma-
tional preferences are crucial to phosphorus-induced diaster-
eoselectivity. Before developing any reasonable model for the
rearrangement, it would be prudent to review the current
understanding of the structure of such phosphorus-stabilized
anions.
Figure 2. CACR transition state models for cis-17 and trans-17.
In this model, the strong preference for the ul transition state
in the anion-accelerated Claisen rearrangements of 1,3,2-
oxazaphosphorinanes is a result of approach of the allyloxy
side chain to the sterically less hindered side, i.e., away from the
large N-tert-butyl group. The effect of the size of this group is
dramatic as selectivity is completely lost in the N-methyl
substrate 7ca but slightly enhanced in the N-adamantyl
substrate 7ba. This model also comports with the high
selectivity observed in the CACR of trans-17, which displayed
an even higher level of diastereoselectivity than cis-17. The high
diastereoselectivity observed with trans-17 is particularly
noteworthy. In a chairlike ring conformation, the allyl vinyl
ether would have an axial orientation (Figure 1). Following the
same logic, the fixed anion conformation and the biased folding
of the allyl ether side chain away from the N-tert-butyl group
leads to the correct prediction for the configuration of the
rearrangement product. However, the higher selectivity for
trans-17 is puzzling and may hint that the ring conformations
are not chairs but rather twist chairs with similar orientations of
The combination of multinuclear, variable-temperature
solution NMR studies, X-ray crystallographic analyses,36 and
computational studies37 provide a very clear picture of the
factors that influence the structure of these species. Anions
derived from 1,3,2-diazaphosphorinanes and 1,3,2-dioxaphos-
phorinanes bearing both P-benzyl and P-isopropyl substituents
H
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adamantyl CH2CH CH2CN), 30.0 (s, adamantyl CH); MS (70 eV)
333 (M+, 0.77), 136 (10), 135 (100), 134 (15). Anal. Calcd for
C16H22F3NO3(333.35): C, 57.65; H, 6.65; N, 4.20; F, 17.10. Found: C,
57.43; H, 6.56; N, 4.25; F, 17.46.
the allyl vinyl ether substituent because of the bulky N-tert-
butyl group.
CONCLUSION
■
Methyl- 3-(N-Methyl-N-trifluoroacetyl)aminopropionate (1c). To
a solution of N-methyl trifluoroacetamide (16.0 g, 123.4 mmol) and
methyl acrylate (28.6 mL, 308.5 mmol) in tert-butyl alcohol (30 mL)
was added potassium tert-butoxide (0.75 g, 6.17 mmol). The resulting
solution was stirred at room temperature for 8.5 h. Acetic acid (0.2
mL) was added and the mixture stirred for an additional 1 h. The
reaction mixture was then quenched with acetic acid (1.0 mL) and
filtered through silica gel (3 in. column), and the column was washed
with Et2O (250 mL). The solvents were removed in vacuo, and the
crude product was purified by vacuum distillation to yield 23.4 g
(89%) of 1c as a clear, colorless oil. Data for 1c: bp 153−154 °C (75
The carbanion-accelerated Claisen rearrangement allyl vinyl
ethers bearing chiral 1,3,2-oxazaphosphorinanes takes place
under extremely mild conditions (room temperature, 15 min)
to afford γ,δ-unsaturated ketones with high levels of internal
and relative diastereoselectivity. The internal diastereoselectiv-
ity followed the well-established paradigm of chairlike transition
structures for these rearrangements. The relative diastereose-
lectivity with respect to the 1,3,2-oxazaphosphorinane ring was
dependent upon the auxiliary structure and the reaction
conditions. Lithium salts were shown to greatly enhance the
diastereoselectivity which was interpreted to arise from
chelation of the phosphoryl oxygen with the allyl vinyl ether
oxygen in the stereodetermining transition structure. The size
of the nitrogen substituent was shown to be critical for high
diastereoselectivity. A model was constructed for the origin of
high selectivity that was grounded in structural studies on
phosphorus-stabilized anions.
1
mmHg); H NMR (500 MHz) major rotamer 3.70−3.67 (m, 2 H),
3.69 (s, 3 H), 3.17 (s, 3 H), 2.65−2.63 (m, 2 H), minor rotamer 3.70−
3.67 (m, 2 H), 3.70 (s, 3 H), 3.02 (s, 3 H), 2.65−2.63 (m, 2 H); 13C
NMR (CDCl3, 125.8 MHz) major rotamer 171.5 (s, C(1)), 156.8 (q, J
= 36.0, CF3CO), 116.2 (q, J = 287.3, CF3), 51.7 (OCH3), 45.7 (C(3)),
35.5 (NCH3), 31.2 (C(2)), minor rotamer 170.6 (C(1)), 156.6 (q, J =
36.1, CF3CO), 116.3 (q, J = 287.4, CF3), 51.8 (s, OCH3), 44.9
(C(3)), 34.3 (NCH3), 32.8 (C(2)); IR (neat) 3378 (w), 2959 (m),
2361 (w), 1738 (s), 1688 (s), 1520 (m), 1497 (w), 1441 (s), 1387
(m), 1319 (s), 1248 (s), 1146 (s), 1096 (s), 1048 (m), 985 (w), 887
(w), 835 (w), 793 (w), 760 (s), 725 (w); MS (70 eV) 213 (M+, 9),
182 (18), 181 (13), 153 (25), 140 (100), 116 (24), 102 (15), 84 (13),
69 (32), 59 (15), 55 (42). Anal. Calcd for C7H10F3NO3(213.15): C,
39.44; H, 4.73; N, 6.57; F, 26.74. Found: C, 39.81; H, 4.95; N, 6.60; F,
27.02.
EXPERIMENTAL SECTION38
■
Racemic 1,3,2-Oxazaphosphorinane 2-Oxides. Methyl 3-(N-
tert-Butyl-N-trifluoroacetyl)aminopropionate (1a). A 15-mL, three-
necked flask equipped with a stirring bar, septum, and N2 inlet was
charged with 5.08 g (25.2 mmol) of methyl 3-tert-butylaminopropi-
onate and 25 mL of CH2Cl2. The mixture was placed in an ice bath,
and 5.35 mL (37.9 mmol) of trifluoroacetic anhydride was added via
syringe over 5 min. The reaction mixture was warmed to room
temperature and stirred for 2 h. The solvent was removed by rotary
evaporation, and the crude product purified by Kugelrohr distillation
to give 5.30 g (84.3%) of amido ester 1a as a colorless oil. Data for 1a:
bp 90 °C (0.3 mmHg); 1H NMR (300 MHz) 3.71 (m, 2 H), 3.66 (s, 3
H), 2.60 (m, 2 H), 1.44 (s, 9 H); 13C NMR (75.5 MHz) 170.5 (C(1)),
157.0 (q, J = 34.3, CF3CO)), 116.4 (q, J = 289.4, CF3), 59.7
((CH3)3C), 51.8 (OCH3), 39.9 (q, J = 3.2, C(3)), 36.0 (C(2)), 27.8
((CH3)3C); IR (neat) 2961 (m), 1742 (s), 1694 (s), 1482 (m), 1439
(s), 1422 (s), 1401 (m), 1383 (s), 1372 (s), 1327 (s), 1294 (m), 1266
(s), 1198 (s), 1123 (s), 1048 (s), 1026 (m), 986 (w), 899 (w), 804
(w); MS (70 eV) 240 (M+ − 15, 38), 208 (38), 199 (38), 168 (30),
167 (1), 166 (20), 139 (11), 57 (100), 56 (15), 55 (42). Anal. Calcd
for C10H16F3NO3 (225.25): C, 47.06; H, 6.32; N, 5.49; F, 22.33.
Found: C, 47.04; H, 6.24; N, 5.56; F, 22.03.
4-(tert-Butylamino)-2-methyl-2-butanol (2a). A 250-mL, three-
necked flask equipped with a mechanical stirrer, addition funnel (with
septum and N2 inlet), and thermometer was charged with 4.00 g (15.7
mmol) of amido ester 1a and 100 mL of Et2O. The mixture was
cooled to 5 °C and the addition funnel charged with 36.2 mL (2.7 M,
99.7 mmol) of methylmagnesium bromide. The Grignard reagent was
added dropwise over 30 min at 0−5 °C. The ice bath was removed,
and the mixture was stirred for 3 h. The mixture was then cooled to 0
°C, and 50 mL of a satd aq K2CO3 solution was added. The mixture
was diluted with 200 mL of a satd aq solution of Rochelle’s salt. The
aqueous layer was extracted with EtOAc (3 × 250 mL), the organic
layers were dried (MgSO4) and filtered, and the solvent was removed
by rotary evaporation. The crude product was purified by Kugelrohr
distillation to yield 1.47 g (58.8%) of 2a as a clear, colorless oil, yield
1
range 59−76%. Data for 2a: bp 80 °C (0.3 mmHg); H NMR (300
MHz) 2.86 (t, 2 H, J = 5.5), 1.57 (t, 2 H, J = 5.5), 1.21 (s, 6 H), 1.10
(s, 9 H); 13C NMR (75.5 MHz) 71.0 (C(2)), 50.4 ((CH3)3C), 40.8
(C(3)), 38.7(C(2)), 29.6 (C(1), CH3C(2)), 28.5 ((CH3)3C); IR
(neat) 3276 (m), 2971 (s), 2932 (s), 2869 (m), 1717 (w), 1653 (w),
1480 (m), 1426 (m), 1391 (m), 1362 (s), 1267 (w), 1233 (m), 1215
(m), 1154 (m), 1086 (w), 1017 (w), 967 (w), 938 (w), 887 (w); MS
(70 eV) 144 (M+ − 15, 100), 126 (90), 88 (14), 86 (30), 81 (11), 70
(75), 58 (43), 57 (11). Anal. Calcd for C9H21NO (159.28): C, 67.87;
H, 13.29; N, 8.79. Found: C, 67.52; H, 13.28; N, 8.84.
Methyl 3-[N-(1-Adamantyl)-N-trifluoroacetyl]aminopropionate
(1b). To a suspension of 1-adamantylamine (12.5 g, 80.2 mmol) in
methanol (50 mL) at 0 °C was added methyl acrylate (8.02 mL, 88.2
mmol) over 20 min. The resulting mixture was stirred for 2.5 days at
room temperature, and then the methanol was removed by rotary
evaporation. The crude product was used without further purification.
The amino ester (19.0 g, 80.2 mmol) was placed in a dry flask,
dichloromethane (100 mL), 4-dimethylaminopyridine (0.49 g, 4.0
mmol), and triethylamine (13.4 mL, 92.2 mmol) were added
sequentially, and the mixture was cooled to 0 °C. A solution of
trifluoroacetic anhydride (13.0 mL, 92.2 mmol) in CH2Cl2 (25 mL)
was added dropwise via addition funnel over 30 min. The solution was
warmed to room temperature and stirred for 2 days. The mixture was
then poured into Et2O (250 mL), washed with satd aq NaHCO3
solution (3 × 50 mL) and brine (50 mL), dried (MgSO4), and filtered,
and the solvents were removed by rotary evaporation. The crude
product was purified by vacuum distillation to give 24.9 g (93% for two
steps) of 1b as a clear, colorless oil. Data for (1b): bp 160 °C (0.6
4-(N-Methylamino)-2-methyl-2-butanol (2c). To a refluxing
ethereal solution of methylmagnesium bromide (3.0 M, 75.1 mL,
225 mmol) under N2 was added dropwise a solution of amido ester 1c
(8.0 g, 37.5 mmol) in Et2O (40 mL) over 30 min. The resulting thick
suspension was refluxed for 1 h and quenched with the dropwise
addition of a satd aq solution of NH4Cl (15 mL). Ether and absolute
ethanol (100 mL each) were added, and the mixture was heated to
reflux for 30 min. The mixture was then cooled and filtered through a
plug of silica gel (5 g). After the silica gel was washed with absolute
ethanol (150 mL), the combined filtrates were evaporated under
reduced pressure. The residue was diluted with methanol, filtered, and
purified by column chromatography (5−15% ammonia-saturated
methanol in Et2O) to give 2.30 g (52.3%) of 2c as a clear, colorless
1
mmHg); H NMR (500 MHz) 3.75−3.72 (m, 2 H), 3.70 (s, 3 H),
2.66−2.63 (m, 2 H), 2.19 (s, 6 H), 2.15 (s, br, 3 H), 1.73−1.66 (m, 6
H); 13C NMR (125.8 MHz) 170.6 (C(1)), 156.8 (q, J = 34.3, CF3C
O), 116.3 (q, J = 289.9, CF3), 61.3 (adamantyl C), 51.8 (OCH3), 39.0
(adamantyl CH2CN), 38.8 (s, C(3)), 36.7 9(s, C(2)), 36.0 (s,
1
oil. Data for 2c: bp 66−68 °C (1.2 mmHg); H NMR (500 MHz)
2.86 (t, 2 H, J = 5.8), 2.40 (s, 3 H), 1.58 (t, 2 H, J = 5.8), 1.22 (s, 6 H);
13C NMR (125.8 MHz) 71.0 (C(2)), 48.4 (C(4)), 39.9 (C((3)), 36.1
I
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(NCH3), 29.7 (C(1) and H3CC(2)); IR (neat) 3293 (s, br, OH, NH),
2967 (s), 2930 (s), 2845 (s), 2799 (m), 1643 (w), 1474 (s), 1377 (s),
1362 (s), 1296 (w), 1266 (m), 1198 (m), 1171 (s), 1142 (m), 1111
(m), 1038 (w), 941 (m), 909 (m), 882 (m), 810 (m), 734 (m); MS
(10 eV) 117 (M+, 12), 102 (10), 84 (13), 59 (20), 58 (10), 44 (100);
high-resolution MS calcd for C6H15NO 117.1157, found 117.1155;
TLC Rf 0.25 (Et2O/MeOH (NH3 satd), 3:1).
Synthesis of 2-Allenyl 1,3,2-Oxazaphosphorinane 2-Oxides.
General Procedure 1. A 250-mL, three-necked, round-bottomed
flask equipped with a stirring bar, septum, thermometer, and N2 inlet
was charged with 100 mL of CH2Cl2 and cooled to 0 °C. Phosphorus
trichloride (13.7 mmol) and N-methylmorpholine (13.7 mmol) were
added sequentially via syringe. After the mixture was stirred for 5 min,
the appropriate propargylic alcohol (13.7 mmol) in 5 mL of CH2Cl2
was added via syringe (0−5 °C). After the mixture was stirred for 20
min, N-methylmorpholine (27.4 mmol) was added. After the mixture
was stirred for 5 min, the appropriate amino alcohol (13.7 mmol) in 5
mL of CH2Cl2 was added. The reaction mixture was warmed to room
temperature and stirred for 16 h. The mixture was diluted with 100 mL
of water and extracted with CH2Cl2 (3 × 100 mL). The organic layers
were washed with water and brine (1 × 50 mL each). The combined
organic layers were dried (MgSO4) and filtered, and the solvent was
removed by rotary evaporation. Purification is given for each individual
compound.
3-tert-Butyl-2-(1′,2′-butadienyl)-6,6-dimethyl-2-oxo-1,3,2-oxaza-
phosphorinane (5a). Following general procedure 1, the crude
product was purified by column chromatography (hexane/acetone;
1:1) to give 2.05 g (58%) of allene 5a. Data for 5a are reported for a
distilled sample: bp 175 °C (0.2 mmHg); 1H NMR (300 MHz) 5.46−
5.42 (m, 1 H), 5.30−5.20 (m, 1 H), 3.26−3.07 (m, 2 H), 1.94−1.80
(m, 2 H), 1.74−1.66 (m, 3 H), 1.44 (d, 3 H, J = 2.5), 1.38 (s, 12 H);
13C NMR (75.5 MHz) 209.6 (C(2′)), 209.2 (C(2′)), 88.7 (d, J = 6.0,
C(3′)), 86.3 (d, J = 6.9, C(3′)), 79.9 (d, J = 6.3, C(6)), 79.8 (d, J =
7.2, C(6)), 54.5 (d, J = 4.2, (CH3)3C), 28.6 ((CH3)3C), 12.2 (d, J =
7.3 C(4′)), 11.7 (d, J = 7.0, C(4′)); the following resonances could not
be unambiguously assigned: 86.4, 86.3, 85.7, 85.5, 38.7, 38.5, 38.4,
38.3, 28.7, 28.5, 28.4; 31P NMR (121.4 MHz) 9.26, 9.24; IR (neat)
2977 (s), 2874 (m), 2357 (w), 1952 (m), 1639 (w), 1466 (m), 1370
(s), 1291 (w), 1254 (s, PO), 1208 (s), 1152 (s), 1102 (m), 1061
(s), 997 (s), 936 (m), 889 (m), 855 (m); MS (70 eV) 257 (M+, 6.9),
243 (13), 242 (100), 204 (11), 201 (47), 186 (94), 174 (40), 148
(91), 146 (59), 145 (58), 84 (16), 70 (61), 69 (48), 58 (37), 57 (78),
56 (13), 55 (19), 53 (28), 43 (15), 42 (20), 41 (82), 39 (13), 31 (19);
high-resolution MS calcd for C13H24NO2P 257.1542, found 257.1577;
TLC Rf 0.40 (hexane/acetone, 1:1).
30 min. The solution was heated reflux for 1.5 h further and then
quenched by the dropwise addition of a satd aq NH4Cl solution (10
mL). Ether and absolute ethanol (150 mL each) were added, and the
mixture was stirred for 1 h and filtered through a pad of Celite. After
the precipitate was washed with absolute ethanol (250 mL), the
combined filtrates were evaporated under reduced pressure. The
residue was diluted with saturated methanolic ammonia in Et2O (1:1,
250 mL), filtered, and twice purified by column chromatography (5−
15% saturated methanolic ammonia in Et2O) to give 6.52 g (65.4%) of
4-[N-(1-adamantyl)amino]-2-methyl-2-butanol (2b).
To a solution of phosphorus trichloride (0.84 mL, 9.69 mmol) in
CH2Cl2 (50 mL) at 0 °C under N2 was added dropwise N-
methylmorpholine (1.12 mL, 10.1 mmol) over 5 min. After the
mixture was stirred for 5 min, ( )-3-butyn-2-ol (0.73 mL, 9.69 mmol)
was added dropwise over a 5 min period. After the mixture was stirred
for an additional 30 min, N-methylmorpholine (2.24 mL, 20.2 mmol)
was added. After an additional 5 min, a solution of 2b (2.0 g, 8.43
mmol) in CH2Cl2 (40 mL) was added by cannula over a 20 min
period. The resulting mixture was stirred for 20 h and poured into
Et2O (400 mL). The mixture was washed with water (30 mL), 1 N
HCl (30 mL), and brine (30 mL). The organic phase was then dried
(MgSO4), filtered, and concentrated in vacuo. The crude product was
purified by column chromatography (EtOAc) to give 2.32 g (70.4%)
of 5b as a clear, colorless oil. Data for 5b: 1H NMR (500 MHz) major
diastereomer 5.50−5.44 (m, 1 H), 5.31−5.24 (m, 1 H), 3.27−3.20 (m,
1 H), 3.143−3.07 (m, 1 H), 2.10 (d, 3 H, J = 10.8), 2.09 (s, 3 H), 1.95
(d, 3 H, J = 10.8), 1.76−1.71 (m, 3 H), 1.63 (s, 6 H), 1.45 (s, 3 H),
1.35 (s, 3 H), minor diastereomer 5.50−5.44 (m, 1 H), 5.31−5.24 (m,
1 H), 3.27−3.20 (m, 1 H), 3.14−3.07 (m, 1 H), 2.10 (d, 3 H, J =
10.8), 2.09 (s, 3 H), 1.95 (d, 3 H, J = 10.8), 1.76−1.71 (m, 3 H), 1.63
(s, 6 H), 1.46 (s, 3 H), 1.36 (s, 3 H); 13C NMR (125.8 MHz) 210.0
(C(2′)), 209.6 (C(2′)), 80.3−80.2 (m, C(6)), 55.92 (adamantyl C),
55.90 (adamantyl C), 41.05 (adamantyl CH2CN), 40.99 (adamantyl
CH2CN), 39.45−39.35 (m, C(5)), 37.1 (C(4)), 36.1 (adamantyl
CH2CH CH2CN), 29.6−29.5 (m, CH3C(6) and adamantyl CH) 28.91
(CHC(6)), 28.87 (CH3C(6)), 12.9 (d, J = 7.0, C(4′)), 12.3 (d, J = 7.0,
C(4′)); the following peaks could not be unambiguously assigned:
88.9, 88.8, 87.4, 86.1, 86.0, 85.7, 85.6; IR (neat) 2977 (s), 2909 (2),
2851 (s), 1952 (m, CCC), 1453 (m), 1370 (s), 1298 (m), 1242
(s, PO), 1204 (s), 1150 (s), 1115 (m), 1094 (s), 995 (s), 930 (m),
891 (m), 808 (s), 776 (m), 752 (m), 706 (m), 669 (m); MS (70 eV)
335 (M+, 7.4), 280 (10), 279 (24), 136 (11), 135 (100), 106 (10), 93
(16), 79 (19), 55 (11), 53 (13); high-resolution MS calcd for
C19H30O2NP 335.2015, found 335.2016; TLC Rf 0.24 (EtOAc).
N-Methyl-2-(1′,2′-butadienyl)-6,6-dimethyl-2-oxo-1,3,2-oxaza-
phosphorinane (5c). From 2c (5.1g, 32.0 mmol) following general
procedure 1, the crude product was purified by column chromatog-
raphy (hexane/acetone, 3/2) to give 6.54 g (79%) of 5c as a clear,
3-tert-Butyl-6,6-dimethyl-2-(3′-methyl-1′,2′-butadienyl)-2-oxo-
1,3,2-oxazaphosphorinane (6). Following general procedure 1, the
crude product was purified by column chromatography (hexane/
acetone, 1:1) to give a 1.36 g (53.1%) of allene 6. Data for 6 are
1
colorless oil. Data for 5c: H NMR (500 MHz) major diastereomer
1
reported for a distilled sample: bp 205 °C (0.15 mmHg); H NMR
5.38−5.35 (m, 1 H), 5.32−5.25 (m, 1 H), 3.21−3.08 (m, 2 H), 2.72
(d, 3 H, J = 9.4), 1.95−1.91 (m, 2 H), 1.76−1.71 (m, 3 H), 1.48 (s, 3
H), 1.41 (s, 3 H), minor diastereomer 5.38−5.35 (m, 1 H), 5.32−5.25
(m, 1 H), 3.21−3.08 (m, 2 H), 2.72 (d, 3 H, J = 9.4), 1.95−1.91 (m, 2
H), 1.76−1.71 (m, 3 H), 1.48 (s, 3 H), 1.40 (s, 3 H); 13C NMR (125.8
MHz) major diastereomer 209.5 (C(2′)), 85.5−84.5 (C(3′)), 82.4 (d,
J = 205.8, C(1′), 81.5 (C(6)), 45.7 (C(4)), 35.8 (C(5)), 34.6 (NCH3),
28.4 (CH3C(6)), 27.5 (CH3C(6)), 12.1 (CH3C(4′)), minor
diastereomer 209.3 (C(2′)), 85.5−84.5 (C(3′)), 82.3 (d, J = 190.2,
C(1′)), 81.5 (C(6)), 45.8 (C(4)), 35.8 (C(5)), 34.6 (NCH3), 28.4
(CH3C(6)), 27.5 (CH3C(6)), 12.3 (CH3C(4′)); 31P NMR (121.5
MHz) 11.9, 11.8; IR (neat) 2977 (m), 2490 (w), 1950 (m, CC
C), 1649 (w), 1470 (m), 1372 (m), 1298 (s), 1248 (s, PO), 1223
(s), 1157 (m), 1227 (s), 1061 (m), 997 (s), 970 (s), 878 (m), 808
(m), 785 (m), 750 (s); MS (70 eV) 215 (M+, 22), 162 (31), 160 (55),
159 (57), 144 (10), 123 (16), 98 (19), 95 (11), 69 (52), 44 (100);
high-resolution MS calcd for C10H18NO2P 215.1071, found 215.1073;
TLC Rf 0.18 (4.5% i-PrOH in CH2Cl2).
(300 MHz) 5.55−5.47 (m, 1 H), 3.20−3.08 (m, 2 H), 2.04−1.94 (m,
2 H), 1.89−1.82 (m, 6 H), 1.57(s, 3 H), 1.48 (s, 12 H); 13C NMR
(75.5 MHz) 207.3 (C(2′)), 95.3 (d, J = 17.2, C(3′)), 86.7 (d, J =
182.9, C(1′)) 80.1 (d, J = 8.6, C(6)), 54.9 (d, J = 5.2, (CH3)3C), 38.9
(d, J = 13.7, C(4)), 38.8 (C(5)), 29.1 (CH3C(6)), 28.9 ((CH3)3C),
28.8 (CH3C(6)), 19.2 (d, J = 6.6, C(4′)), 18.7 (d, J = 7.7, CH3C(3′));
31P NMR (121.4 MHz) 9.6; IR (CCl4) 2980 (s), 2940 (s), 2872 (m),
1964 (m, CCC), 1632 (w), 1559 (w), 1466 (m), 1445 (m), 1395
(m), 1385 (m), 1362 (s), 1291 (s), 1252 (s, PO), 1235 (s), 1204
(s), 1152 (s), 1103 (m), 1061 (m), 999 (s), 932 (m), 889 (m); MS
(70 eV) 271 (M+, 11.5), 257 (1), 256 (76), 215 (73), 201 (11), 200
(94), 198 (15), 188 (28), 160 (56), 159 (75), 148 (99), 132 (15), 126
(12), 84 (24), 70 (73), 69 (50), 67 (29), 58 (49), 57 (80), 56 (11), 55
(19), 43 (38), 42 (20), 41 (100), 39 (19), 31 (27); high-resolution MS
calcd for C14H26NO2P 271.1711, found 271.1706; TLC Rf 0.38
(hexane/acetone, 1:1).
3-Adamantyl-2-(1′,2′-butadienyl)-6,6-dimethyl-2-oxo-1,3,2-ox-
zazphosphorinane (5b). To a refluxing ethereal solution of
methylmagnesium bromide (3.0 M, 84.0 mL, 252 mmol) under N2
was added a solution of 1b (14.0 g, 42.0 mmol) in Et2O (50 mL) over
Synthesis of Allyl Vinyl Ethers. General Procedure 2. A 15-
mL, 3-necked flask equipped with stirring bar, septa, and N2 inlet was
charged with NaH dispersion (50%, 0.48 mmol). The NaH dispersion
J
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was rinsed with hexane (3 × 1 mL/0.1 g NaH) and suspended in 3.0
mL of THF. t-Butyl alcohol (0.96 mmol) and the appropriate allyl
alcohol (0.48 mmol) were added sequentially. After stirring for 10 min,
a solution of the allene (0.40 mmol) in 1.0 mL of THF was added via
syringe, The reaction was monitored by TLC. Upon completion, the
reaction was quenched with 5 mL of water and extracted with Et2O (3
× 15 mL). The organic layers were washed with brine (15 mL), dried
(MgSO4), filtered, and the solvent removed by rotary evaporation.
Purification is given for each individual compound.
(s), 1102 (s), 1065 (m), 997 (s), 926 (m), 901 (m), 847 (m); MS (70
eV) 329 (M+, 10.2), 314 (16), 275 (14), 274 (74), 273 (15), 219 (39),
218 (39), 218 (62), 204 (24), 190 (13), 188 (11), 164 (27), 163 (70),
162 (100), 151 (66), 150 (36), 148 (15), 134 (16), 125 (11), 84 (14),
70 (21), 58 (11); high-resolution MS calcd for C17H32NO3P 329.2120,
found 329.2121; TLC Rf 0.43 (hexane/acetone, 1:1).
(E)-3-tert-Butyl-6,6-dimethyl-2-oxo-[2′-((E)-2-butenyloxy)-1′-bu-
tenyl]-1,3,2-oxaza-phosphorinane (8ab). Following General Proce-
dure 2, the crude product was purified by column chromatography
(hexane/acetone, 1:1) to afford 230 mg (69%) of 8ab. Data for 8ab:
(E)-3-tert-Butyl-6,6-dimethyl-2-oxo-[2′-(2-propenyloxy)-2′-buten-
yl]-1,3,2-oxazaphosphorinane (7aa). Following General Procedure
2, the crude product was purified by radial chromatography (hexane/
1
bp 200 °C (0.5 mmHg); H NMR (300 MHz) 5.83−5.56 (m, 2 H),
4.55 (d, 1 H, J = 7.6), 4.17 (d, 2 H, J = 5.9), 3.27−3.07 (m, 2 H).
2.66−2.47 (m, 2 H). 2.11−2.03 (m, 1 H), 1.88−1.81 (m, 1 H), 1.72
(d, 3 H, J = 5.7), 1.53 (s, 3 H), 1.33 (s, 12 H), 1.10 (t, 3 H, J = 7.5);
13C NMR (75.5 MHz) 171.8 (d, J = 19.5, C(2′)), 130.0 (CH
CHCH3), 125.3 (CHCHCH3), 91.7 (d, J = 195.3, C(1′)), 78.7 (d, J
= 8.6, C(6)), 67.9 (OCH2), 54.6 (d, J = 4.7, (CH3)3C), 40.0 (d, J =
7.5, C(4)), 39.2 (C(5)), 29.8 (CH3C(6)), 29.3 (d, J = 5.6, CH3C(6)),
28.9 ((CH3)3C), 25.5 (C(3′)), 17.6 (CH3CHCH), 11.4 (C(4′));
31P NMR (121.4 MHz) 16.0; IR (neat) 2975 (s), 2876 (m), 2361 (w),
1
acetone, 5:1) to give 155 mg (64%) of 7aa. Data for 7aa: H NMR
(300 MHz) 6.00−5.88 (m, 1 H), 5.29 (dd, 1 H, J = 1.3, 17.4), 5.19
(dd, 1 H, J = 1.1, 10.4, 4.54−4.46 (m, 1 H), 4.20−4.08 (m, 2 H),
3.15−2.93 (m, 3 H)), 2.61−2.50 (m, 1 H), 1.89−1.77 (m, 2 H), 1.62−
1
1.51 (m, 3 H), 1.48 (s, 3 H), 1.37 (s, 9 H), 1.26 (s, 3 H); H NMR
(500 MHz); 13C NMR (75.5 MHz) 149.8 (d, J = 12.2, C(2′)), 133.8
(CHCH2), 116.9 (CHCH2), 93.9 (d, J = 10.2, C(3′)), 79.2 (d, J
= 8.2, C(6)), 67.8 (OCH2), 55.1 ((CH3)3C), 39.4 (C(4)), 39.3
(C(5)), 35.2 (d, J = 134.6, C(1′)), 29.7 (d, J = 8.0, CH3C(6)), 29.1
((CH3)3C), 28.9(CH3C(6)), 12.3 (C(4′)); 31P NMR (121.4 MHz)
20.5; IR (neat) 2980 (s), 2934 (s), 2874 (m), 1665 (s), 1466 (s), 1399
(m), 1387 (m), 1372 (s), 1362 (m), 1348 (m), 1293 (s), 1256 (s),
1231 (s), 1202 (s), 1152 (s), 1102 (s), 1063 (m), 997 (s), 926 (s), 889
(m); MS (70 eV); 315 (M+, 1.42), 300 (13), 274 (22), 242 (15), 218
(25), 186 (15), 174 (18), 162 (100), 150 (33), 148 (36), 146 (12),
126 (15), 84 (16), 80 (14), 70 (73), 69 (29), 58 (36), 57 (46), 56
(10), 55 (16), 53 (11) 42 (14), 41 (73), 39 (14); high-resolution MS
calcd for C16H30NO3P 315.1975, found 315.1969; TLC Rf 0.45
(hexane/acetone, 1:1). Anal. Calcd for C16H30NO3P (315.20): C,
60.93; H, 9.59; N, 4.44; P, 9.82. Found: C, 60.72; H, 9.49; N, 4.53; P,
9.88.
1709 (w), 1613 (s, CC), 1464 (m), 1370 (m), 1347 (m), 1289 (m),
1250 (s. PO), 1223 (s), 1186 (s), 1152 (s), 1094 (s), 1063 (m),
1017 (m), 967 (s), 932 (m), 889 (m); MS (70 eV) 330 (M+ + 1,
11.4), 329 (M+, 30.5), 314 (46), 273 (15), 272 (20), 260 (46), 258
(24), 256 (11), 246 (12), 219 (15), 218 (55), 217 (20), 216 (13), 206
(13), 205 (13), 204 (55), 202 (19), 192 (18), 190 (25), 188 (18), 164
(91), 163 (30), 162 (15), 160 (10), 152 (23), 151 (19), 148 (34), 135
(13), 134 (52), 127 (10), 126 (100), 84 (42), 83 (11), 70 (99), 58
(41), 55 (10); high-resolution MS calcd for C17H32NO3P 329.2120,
found 329.2124; TLC Rf 0.43 (hexane/acetone, 1:1).
(E)-3-Adamantyl-6,6-dimethyl-2-oxo-[2′-(2-propenyloxy)-2′-bu-
tenyl]-1,3,2-oxazaphosphorinane (7ba). From 5b (3.8 g, 11.3 mmol)
following general procedure 2, the crude product was purified by
column chromatography (petroleum/acetone ether, 3:1) to give 1.52 g
(E)-3-tert-Butyl-6,6-dimethyl-2-oxo-[(E)-2′-(2-propenyloxy)-1′-bu-
tenyl]-1,3,2-oxaza-phosphorinane (8aa). Following General Proce-
dure 2, the crude product was purified by column chromatography
(hexane/acetone, 1.5:1) to give 175 mg (71%) of 8aa. Data for 8aa are
1
(34%) of 7ba as a clear, colorless oil. Data for 7ba: H NMR (500
MHz) 6.02−5.94 (m, 1 H), 5.31 (dd, 1 H, J = 17.1, 1.5), 5.20 (d, 1 H,
J = 10.5), 4.53−4.49 (m, 1 H), 4.21−4.11 (m, 2 H), 3.19−3.14 (m, 1
H), 3.03 (dd, 1 H, J = 11.4), 2.07 (s, 3 H), 1.97 (d, 3 H, J = 11.4),
1.86−1.81 (m, 1 H), 1.71 (s, 6 H), 1.66−1.60 (m, 1 H), 1.63 (dd, 3 H,
J = 6.5, 4.4), 1.51 (s, 3 H), 1.27 (s, 3 H); 13C NMR (125.8 MHz)
149.7 (d, J = 12.9, C(2′)), 133.9 (CHCH2), 117.0 (CHCH2),
94.0 (d, J = 10.3, C(3′)), 79.2 (d, J = 9.9, C(6)), 67.8 (OCH2), 56.0
(d, J = 10.3, C(3′)), 41.0 (adamantyl CH2CN), 40.0 (d, J = 6.6, C(5)),
37.3 (d, J = 2.1, C(4)); 36.3 (adamantyl CH2CH CH2CN), 35.5 (d, J =
131.8, C(1′)), 29.7 (s, adamantyl CH), 29.6 (CH3C(6)), 29.5
(CH3C(6)), 12.3 (s, C(4′)); IR (neat) 2977 (m), 2909 (s), 2853
(s), 2681 (w), 2448 (w), 1665 (s), 1456 (m), 1404 (m), 1387 (m),
1362 (m), 1300 (m), 1248 (s, PO), 1200 (s), 1148 (s), 1100 (s),
992 (s), 926 (s), 891 (m), 849 (s), 776 (m); MS (70 eV) 393 (M+,
1.3), 352 (13), 136 (11), 135 (100), 106 (11), 93 (11), 79 (11). Anal.
Calcd for C22H36NO3P (393.50): C, 67.15; H, 9.22; N, 3.56; P, 7.87.
Found: C, 67.41; H, 9.28; N, 3.45; P, 7.82; TLC Rf 0.31 (EtOAc).
(E)-N-Methyl-6,6-dimethyl-2-oxo-[2′-(2-propenyloxy)-2′-buten-
yl]-1,3,2-oxazaphosphorinane (7ca). From 5c (700 mg, 3.25 mmol)
following general procedure 2, the crude product was purified by
column chromatography (CH2Cl2/i-PrOH, 19:1) to give 356 mg
1
reported for a recrystallized sample: mp 60−62 °C; H NMR (300
MHz) 5.99−5.86 (m, 1 H), 5.34−5.20 (m, 2 H), 4.54 (d, 1 H, J = 7.5),
4.23 (d, 2 H, J = 5.1), 3.25−3.05 (m, 2 H), 2.66−2.45 (m, 2 H), 2.09−
2.00 (m, 1 H), 1.86−1.79 (m 1 H), 1.51 (s, 3 H), 1.30 (s, 12 H), 1.09
(t, 3 H, J = 7.5); 13C NMR (75.5 MHz) 171.7 (d, J = 19.7, C(2′)).
132.5 (CHCH2), 117.4 (CHCH2), 92.5 (d, J = 195.4, C(1′)),
78.9 (d, J = 7.5, C(6)), 67.9 (OCH2), 54.7 ((CH3)3C), 40.1 (d, J = 8.1,
C(4)), 39.3 (C(5)), 29.9 (CH3C(6)), 29.4 (d, J = 5.3, CH3C(6)), 29.0
((CH3)3C), 25.5,(C(3′)), 11.4 (C(4′)); 31P NMR (121.4 MHz) 15.8;
IR (CCl4) 2977 (s), 2940 (s), 2874 (m), 1615 (s, CC), 1464 (m),
1394 (m), 1385 (m), 1370 (s), 1362 (m), 1343 (m), 1287 (s), 1248
(s), 1225 (s, PO), 1186 (s), 1150 (s), 1094 (s), 1059 (m), 1015 (s),
968 (s), 926 (s), 887 (s); MS (70 eV) 315 (M+, 19.2), 301 (15), 300
(89), 260 (11), 258 (11), 244 (32), 242 (19), 204 (46), 203 (16), 174
(11), 148 (15), 134 (12), 126 (76), 84 (13), 70 (100), 69 (11), 58
(31); TLC Rf 0.45 (hexane/acetone, 1:1). Anal. Calcd for
C16H30NO3P (315.40): C, 60.93; H, 9.59; N, 4.44; P, 9.82. Found:
C, 60.92; H, 9.65; N, 4.26; P, 9.73.
(E)-3-tert-Butyl-6,6-dimethyl-2-oxo-[2′-((E)-2-butenyloxy)-2′-bu-
tenyl]-1,3,2-oxazaphosphorinane (7ab). Following General Proce-
dure 2, the crude product was purified by column chromatography
(hexane/acetone, 1:1) to give 59.0 mg (46%) of 7ab. Data for 7ab: 1H
NMR (300 MHz) 5.77−5.60 (m, 2 H), 4.52−4.48 (m, 1 H), 4.11−
4.06 (m, 2 H), 3.13−2.94 (m, 3 H), 2.57 (dd, 1 H, J = 18.1, 15.2),
1.87−1.82 (m, 2 H), 1.71 (d, 3 H, J = 5.8) 1.62 (d, 3 H, J = 6.7, 4.5),
1.50 (s), 1.39 (s, 9 H), 1.28 (d, 3 H, J = 1.1); 13C NMR (75.5 MHz)
149.8 (d, J = 15.5, C(2′)), 129.4 (CHCHCH3), 126.7 (CH
CHCH3), 93.7 (d, J = 9.9, C(3′)), 79.2 (d, J = 9.6, C(6)), 67.5
(OCH2), 55.1 ((CH3)3C), 39.3 (d, J = 7.2, C(4)), 35.1 (d, J = 133.5,
C(1′)), 29.7 (CH3C(6)), 29.1 ((CH3)3C), 28.8 (CH3C(6)), 17.7
(CH3CHCH), 12.3 (C(4′)); 31P NMR (121.4 MHz) 19.2; IR
(neat) 2977 (s), 2587 (w), 1719 (w), 1665 (s, CC), 1464 (m), 1397
(m), 1372 (m), 1293 (s), 1256 (s, PO), 1231 (s), 1200 (s), 1152
1
(40%) of 7ca as a clear, colorless oil. Data for 7ca: H NMR (500
MHz) 6.01−5.90 (m, 1 H), 5.32 (dd, 1 H, J = 17.2, 1.4), 5.21 (dd, 1
H, J = 10.5, 1.4), 4.60−4.51 (m, 1 H), 4.20−4.08 (m, 2 H), 3.20−2.90
(m, 2 H), 2.90−2.75 (m, 2 H), 2.72 (d, 3 H, J = 8.8), 1.94−1.66 (m, 2
H), 1.62 (dd, 3 H, J = 6.7, 4.5), 1.50 (s, 3 H), 1.33 (d, 3 H, J = 1.6);
13C NMR (125.8 MHz) 149.1 (d, J = 13.4, C(2′)), 133.4 (CHCH2),
116.7 (CHCH2), 94.1 (d, J = 10.2, C(3′)), 80.9 (d, J = 8.7, C(6)),
67.4 (OCH2), 45.8 (C(4)), 35.9 (C(5)), 34.9 (NCH3), 33.5 (d, J =
46.0, C(1′)), 30.2 (CH3C(6)), 26.0 (CH3C(6)), 11.9 (C(4′)); 31P
NMR (121.5 MHz) 22.2; IR (neat) 2980 (m), 2926 (m), 2442 (w),
2357 (w), 2220 (w), 1968 (w), 1667 (m), 1470 (w), 1387 (m), 1348
(w), 1300 (m), 1252 (s, PO), 1196 (m), 1127 (s), 1100 (m), 1065
(m), 997 (s), 974 (s), 926 (m), 882 (m), 847 (m), 777 (m), 712 (m);
MS (70 eV) 273 (M+, 1.7), 176 (15), 162 (40), 160 (28), 159 (16), 98
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(52), 71 (11), 69 (23), 57 (93), 44 (100), 43 (14); high-resolution MS
calcd for C13H24NO3P 273.1494, found 273.1495; TLC Rf 0.21
(CH2Cl2/i-PrOH 19:1).
2.00−1.95 (m, 1 H), 1.88−1.84 (m, 1 H), 1.51 (s, 3 H), 1.37 (s, 9 H),
1.30 (s, 3 H), 1.06 (d, 3 H, J = 7.0); 13C NMR (125.8 MHz) 206.6 (d,
J = 7.0, C(2′)), 135 (C(5′)), 116.7 (C(6′)), 80.5 (d, J = 7.9, C(6)),
55.2 ((CH3)3C), 46.7 (d, J = 118.3, C(1′)), 45.7 (C(3′)), 40.0(d, J =
7.1, C(4)), 39.3 (C(5)), 36.2 (C(4′)), 29.9 (CH3C(6)), 29.2 (d, J =
7.0, CH3C(6)), 28.8 ((CH3)3C), 16.0 (CH3C(3′)); 31P NMR (121.4
MHz) 47: 15.9, 48: 15.8; IR (neat) 3077 (w), 2975 (s), 2934 (s), 1705
(s, CO), 1642 (w), 1460 (m), 1397 (m), 1291 (s), 1254 (s, PO),
1194 (s), 1102 (m), 1063 (m), 992 (s), 920 (s), 891 (m), 868 (m);
MS (70 eV) 315 (M+, 5.52), 301 (15), 300 (100), 259 (12), 258 (30),
244 (23), 242 (11), 232 (20), 204 (27), 192 (24), 174 (12) 148 (15),
135 (13), 126 (28), 109 (12), 84 (17) 70 (98), 58 (44); TLC Rf 0.39
(benzene/acetone, 2:1). Anal. Calcd for C16H30NO3P (315.40): C,
60.93; H, 9.59; N, 4.44; P, 9.82. Found: C, 60.92; H, 9.34; N, 4.61; P,
10.09.
(E)-3-tert-Butyl-6,6-dimethyl-2-oxo-[2′-((E)-2-butenyloxy)-3′-
methyl-2′-butenyl]-1,3,2-oxazaphosphorinane (11). Following gen-
eral procedure 2, the crude product was purified by column
chromatography (hexane/2-propanol, 10:1) to give 130 mg (51%)
1
of 11. Data for 11: H NMR (300 MHz) 5.72−5.60 (m, 2 H), 4.10−
3.96 (m, 2 H), 3.13−3.04 (m, 2 H), 2.89 (dd, 1 H, J = 18.9, 15.6), 2.62
(dd, 1 H, J = 15.9, 15.5), 1.83 (t, 2 H, J = 6.3), 1.68 (d, 3 H, J = 7.5),
1.67−1.62 (m, 6 H), 1.48 (s, 3 H), 1.37(s, 9 H), 1.25 (s, 3 H); 13C
NMR (75.5 MHz) 142.6 (d, J = 12.5, C(2′)), 127.7 (CHCHCH3),
123.8 (CHCHCH3), 117.5 (d, J = 11.0, C(3′)), 78.8 (d, J = 8.7,
C(6)), 69.2 (OCH2), 54.7 ((CH3)3C), 38.7 (C(4)), 38.6 (C(5)), 32.5
(d, J = 142.7, C(1′)), 29.3 (CH3C(6)), 29.0 ((CH3)3C), 28.9
(CH3C(6)), 19.1 (CHCHCH3), 16.8 (CH3C(3′)), 16.7 (CH3C-
(3′)); 31P NMR (121.4 MHz) 20.5; IR (neat) 2973 (s), 2926 (s),
2732 (m), 1676 (w), 1609 (w), 1464 (m), 1387 (m), 1370 (m), 1293
(s), 1254 (s, PO), 1196 (s), 1152 (s), 1094 (s), 1065 (m), 997 (s),
928 (m), 889 (m); MS (70 eV) 343 (M+, 3.38), 328 (26), 289 (11),
288 (28), 286 (12), 233 (28), 232 (29), 190 (18), 177 (46), 176 (42),
165 (56), 164 (19), 149 (11), 148 (100), 147 (12), 126 (26), 86 (17),
84 (15), 70 (28), 58 (14); high-resolution MS calcd for C18H34NO3P
343.2276, found 343.2278; TLC Rf 0.45 (hexane/acetone, 1:1).
Anion-Accelerated Claisen Rearrangement. A. KH/LiCl/DMSO.
General Procedure 3. A three-necked, 15-mL flask equipped with a
stirring bar, septa, and a vacuum/N2 inlet was charged with 35% KH
dispersion (0.68 mmol). The dispersion was rinsed with hexane (3 ×
0.5 mL/0.1 g of KH), and DMSO (3.0 mL) was added. After stirring
until H2 evolution ceased (∼10 min), LiCl (6 equiv) was added all at
once (if necessary), followed by stirring for an additional 10 min. Then
a solution of allyl vinyl ether (0.30 mmol) in THF (1.0 mL) was added
via syringe. The reaction was monitored by TLC. Upon completion,
the reaction mixture was quenched with water (10 mL) and extracted
with ether (3 × 15 mL). The organic layers were washed with water (3
× 15 mL) and brine (1 × 15 mL). The combined organic layers were
dried over MgSO4 and filtered, and the solvent was removed by rotary
evaporation. Purification is given for each individual compound.
B. n-BuLi/DMSO/THF. A 15-mL, three-necked, round-bottomed
flask equipped with a septum, stirring bar, thermometer, and N2 inlet
was charged with 2.5 mL of THF and 1.5 mL of DMSO. n-BuLi (1.6
M in hexane, 0.46 mmol) was added dropwise via syringe to produce a
clear, colorless solution. After the mixture was stirred for 5 min, a
solution of allyl vinyl ether in 1 mL of THF was added via syringe. The
solution was stirred at room temperature until judged complete by
TLC. The reaction was quenched with water (5 mL) and extracted
with Et2O (3 × 15 mL). The organic layers were washed with water (3
× 5 mL) and brine (1 × 15 mL each). The combined organic layers
were dried over MgSO4 and filtered, and the solvent was removed by
rotary evaporation. Purification is given for each individual compound.
C. LiDMSO/THF. Thermal Claisen Rearrangement. General
Procedure 4. The allyl vinyl ether (0.10 mmol) THF (1.5 mL/
mmol) was placed in a high-pressure sealed vial and heated at 100 °C
until starting material was consumed as judged by TLC. The contents
of the vial were transferred to a pear-shaped flask with ether, and the
solvent was removed in vacuo.
(R,S)-(Pl,3′l)-3-Adamantyl-6,6-dimethyl-2-(3′-methyl-2′-oxo-5′-
hexenyl)-2-oxo-1,3,2-oxazaphosphorinane ((l)-12ba). Anionic Re-
arrangement (n-BuLi). From 7ba (194 mg, 0.490 mmol), the crude
product was purified by column chromatography (acetone/hexane,
2:1) to give 164 mg (74.2%) of 12ba as a clear, colorless oil. Thermal
Rearrangement. From 7ba (270 mg, 0.69 mmol), the crude product
was purified by column chromatography (hexane/acetone, 7/3) to
1
give 251 mg (93.0%) of 12ba. Data for 12ba: H NMR (500 MHz)
major 5.76−5.69 (m, 1 H), 5.04 (d, 1 H, J = 15.9), 5.01 (d, 1 H, J =
10.1), 3.41 (dd, 1 H, J = 13.4, 11.1), 3.26−3.18 (m, 1 H), 3.01−2.87
(m, 3 H), 2.43−2.37 (m, 1 H), 2.12−1.83 (m, 3 H), 2.10 (d, 3 H, J =
11.8), 2.09 (s, 3 H), 1.92 (d, 3 H, J = 11.8), 1.64 (s, 6 H); 1.52 (s),
1.28 (s), 1.09 (d, 3 H, J = 7.1), minor 5.76−5.69 (m, 1 H), 5.05 (d, 1
H, J = 15.9), 5.02 (d, 1 H, J = 10.1), 3.42 (dd, 1 H, J = 13.4, 13.4),
3.26−3.18 (m, 1 H), 3.01−2.87 (m, 3 H), 2.43−2.37 (m, 1 H), 2.12−
1.83 (m, 3 H), 2.10 (d, 3 H, J = 11.8), 2.09 (s, 3 H), 1.92 (d, 3 H, J =
11.8), 1.64 (s, 6 H), 1.52 (s), 1.28 (s), 1.07 (d, 3 H, J = 6.8); 13C NMR
(125.8 MHz) 206.6 (d, J = 6.8, C(2′)), 135.7 (C(5′)), 116.6 (C(6′)),
8.04 (d, J = 8.8, C(6)), 56.1 (d, J = 2.5, adamantyl C), 47.0 (d, J =
117.5, C(1′)), 45.9 (C(3′)), 41.0 (s, adamantyl CH2CN), 40.6 (d, J =
5.3, C(5)), 37.1 (s, C(4)), 36.2 (s, C(4′)), 36.1 (s, adamantyl CH2CH
CH2CN), 30.2 (CH3C(6)), 29.6 (adamantyl CH), 29.2 (d, J = 6.9,
CH3C(3′)); 31P NMR (121.5 MHz) 16.5, 16.4; IR (neat) 2977 (s),
2909 (s), 1707 (s, CO), 1640 (w), 1456 (m), 1387 (m), 1372 (m),
1298 (m), 1244 (s, PO), 1196 (s), 1148 (s), 1115 (m), 1096 (s),
992 (s), 928 (s), 891 (m), 868 (m), 818 (m), 768 (w); MS (70 eV)
343 (M+, 8.9), 258 (22), 136 (11), 135 (100), 106 (37), 93 (21), 79
(17), 69 (13), 67 (10); high-resolution MS calcd for C22H36NO3P
393.2421, found 393.2427; TLC Rf 0.29 (hexane/acetone, 2:1).
(R,S)-(P1,3′1)-N-Methyl-6,6-dimethyl-2-(3′-methyl-2′-oxo-S′-hex-
enyl)-2-oxo-1,3,2-oxazaphosphorinene (12ca). Anionic Rearrange-
ment (Li+DMSO−). From 7ca (125 mg, 0.460 mmol) following
general procedure 4, the crude product was purified by column
chromatography (CH2Cl2/i-PrOH, 19:1) to yield 78 mg (62%) of
12ca as a clear, colorless oil. Thermal rearrangement. From 7ca (88
mg, 0.32 mmol) the crude product was purified by column
chromatography (CH2Cl2/i-PrOH, 19:1) to give 76 mg (86%) of
12ca. Data for 12ca: 1H NMR (500 MHz) major 5.72−5.63 (m, 1 H),
4.99 (d, 1 H, J = 16.0), 4.97 (d, 1 H, J = 9.2), 3.18−2.97 (m, 4 H),
2.84−2.78 (m, 1 H), 2.66 (d, 3 H, J = 9.6), 2.37−2.32 (m, 1 H), 2.08−
2.01 (m, 1 H), 1.90−1.84 (m, 1 H), 1.79−1.74 (m, 1 H), 1.46 (s, 3 H),
1.32 (s, 3 H), 1.05 (d, 3 H, J = 6.4), minor 5.72−5.63 (m, 1 H), 4.99
(d, 1 H, J = 16.0), 4.97 (d, 1 H, J = 9.2), 3.18−2.97 (m, 4 H), 2.84−
2.78 (m, 1 H), 2.662 (d, 3 H, J = 9.7), 2.37−2.32 (m, 1 H), 2.08−2.01
(m, 1 H), 1.90−1.84 (m, 1 H), 1.79−1.74 (m, 1 H), 1.46 (s, 3 H), 1.32
(s, 3 H), 1.03 (d, 3 H, J = 6.6); 13C NMR (125.8 MHz) major 206.6
(d, J = 6.9, C(2′)), 135.3 (C(5′)), 116.9 (C(6′)), 82.12 (d, J = 5.9,
C(6)), 46.4 (C(3′)), 46.0 (C(4)), 43.7 (d, J = 18.3, C(1′)), 36.7
(C(5)), 36.7 (C(4′)), 35.1 (NCH3), 29.9 (CH3C(6)), 26.8 (CH3C-
(6)), 15.5 (CH3C(3′)), minor 206.5 (d, J = 7.2, C(2′)), 135.3 (C(5′)),
116.9 (C(6′)), 82.06 (d, J = 4.5, C(6)), 46.4 (C(3′)), 46.0 (C(4)),
43.7 (d, J = 118.3, C(1′)), 36.7 (C(5)), 36.7 (C(4′)), 36.5 (CH3N),
29.9 (CH3C(6)), 26.8 (CH3C(6)), 15.2 (CH3C(3′)); 31P NMR
(121.5 MHz) 17.05, 16.96; IR (neat) 2979 (s), 2932 (s), 2469 (w),
1705 (s, CO), 1640 (w), 1458 (m), 1389 (m), 1374 (m), 1298 (s),
(R,S)-(Pl,3′l)-3-tert-Butyl-6,6-dimethyl-2-(3′-methyl-2′-oxo-5′-
hexenyl)-2-oxo-1,3,2-oxazaphosphorinane ((l)-12aa). Anionic (gen-
eral procedure 3A): radial chromatography (hexane/acetone, 3:1)
afforded 74.0 mg (81%) of 12aa; thermal: radial chromatography
(hexane/acetone, 3:1) afforded 90.7 mg (90%) of 12aa. Data for (l)-
12aa and (u)-12aa: 1H NMR (500 MHz) major diastereomer (l)-12aa
5.76−5.69 (m, 1 H), 5.07−5.02 (m, 2 H), 3.39 (dd, 1 H, JP−H = 21.5,
JH−H = 13.5), 3.18−3.05 (m, 2 H), 2.93 (dd, 1 H, JP−H = 21.5, JH−H
=
13.5), 2.92−2.87 (m, 1 H), 2.43−2.37 (m, 1 H), 2.09−2.03 (m, 1 H),
2.00−1.95 (m, 1 H), 1.88−1.84 (m, 1 H), 1.51 (s, 3 H), 1.37 (s, 9 H),
1.30 (s, 3 H), 1.09 (d, 3 H, J = 7.2). Minor diastereomer (u)-12aa:
5.76−5.69 (m, 1 H), 5.07−5.02 (m, 2 H), 3.40 (dd, 1 H, JP−H = 21.5,
JH−H = 13.5), 3.18−3.05 (m, 2 H), 2.93 (dd, 1 H, JP−H = 21.5, JH−H
=
13.5), 2.92−2.87 (m, 1 H), 2.43−2.37 (m, 1 H), 2.09−2.03 (m, 1 H),
L
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1252 (s, PO), 1194 (s), 1125 (s), 1063 (s), 1036 (m), 997 (2), 972
(s), 926 (m), 882 (s), 808 (w), 712 (w); MS (70 eV) 273 (M+, 2.4),
174 (11), 162 (63), 160 (34), 159 (32), 98 (40), 69 (50), 44 (100);
high-resolution MS calcd for C13H24NO3P 273.1496, found 273.1495;
TLC Rf 0.18 (CH2Cl2/i-PrOH, 19:1).
1.04 (s, 3 H), 0.89 (d, 3 H, J = 6.8); 13C NMR (75.5 MHz) 208.4 (d, J
= 8.2, C(2′)), 140.6 (C(5′)), 115.6 (C(6′)), 80.3 (d, J = 9.3, C(6)),
55.0 (d, J = 4.8, (CH3)3C), 51.2 (C(3′)), 44.0, (C(4′)), 42.7 (d, J =
127.5, C(1′)), 40.1 (d, J = 7.0, C(4)), 39.1 (C(5)), 30.1 (CH3C(6)),
29.4 (d, J = 7.0, CH3C(6)), 29.0 ((CH3)3C); 21.4 (CH3C(3′)), 20.4
(CH3C(3′)), 14.9 (CH3C(4′)); 31P NMR (121.4 MHz) 16.1; IR
(neat) 2975 (s), 1701 (s, CO), 1636 (w), 1466 (m), 1389 (m),
1372 (m), 1291 (s), 1254 (s, PO), 1233 (s), 1200 (s), 1103 (w),
1065 (m), 997 (s), 920 (s), 891 (m), 853 (w); MS (70 eV) 343 (M+,
7.91), 329 (13), 328 (68), 300 (11), 287 (10), 286 (46), 232 (10), 220
(13), 190 (22), 148 (16), 126 (22), 110 (49), 88 (10), 86 (65), 84
(100), 75 (14), 70 (22), 58 (13); high-resolution MS calcd for
C18H34NO3P 343.2276, found 343.2288; TLC Rf 0.40 (benzene/
acetone, 2:1).
(R,S)-(Pl,3′l,4′u)-3-tert-Butyl-6,6-dimethyl-2-(3′,4′dimethyl-2′-
oxo-5′-hexenyl)-2-oxo-1,3,2-oxazaphosphorinane ((l)-12ab).
Anionic (general procedure 3A): radial chromatography (hexane/
acetone, 1:1) afforded 40.1 mg (80%) of 12ab; thermal: radial
chromatography (hexane/acetone, 1:1) afforded 32.5 mg (84%) of
12ab. Data for 12ab are reported for a distilled sample: bp 150 °C
(0.05 mmHg); 1H NMR (500 MHz) major diastereomer syn-(l)-12ab:
5.81−5.74 (m, 1 H), 5.01−4.96 (m, 2 H), 3.27 (dd, 1 H, JP−H = 17.7,
JH−H = 13.7), 3.16−3.11 (m, 2 H), 2.98 (dd, 1 H, JP−H = 16.9, JH−H
=13.7), 2.81−2.77 (m, 1 H), 2.55−2.51 (m, 1 H), 1.99−1.93 (m, 1 H),
1.88−1.84 (m, 1 H), 1.50 (s, 3 H), 1.36 (s, 9 H), 1.30 (s, 3 H), 1.04
(d, 3 H, J = 7.1), 0.95 (d, 3 H, J = 6.9); minor diastereomer syn-(u)-
12ab: 5.81−5.74 (m, 1 H), 5.01−4.96(m, 2 H), 3.46 (dd, 1 H, J =
18.7, 13.3), 3.16−3.11 (m, 2 H), 2.90 (dd, 1 H, J = 16.9, 13.7), 2.81−
2.77 (m, 1H), 2.55−2.51 (m, 1H), 1.99- 1.93 (m, 1H), 1.88- 1.84 (m,
1 H), 1.50 (s, 3 H), 1.37 (s, 9 H), 1.30 (s, 3 H), 0.99 (d, 3 H, J = 6.9),
0.93 (d, 3 H, J = 6.8); 13C NMR (125.8 MHz) 206.6 (d, J = 4.9,
C(2′)), 142 (C(5′)), 114 (C(6′)), 80.5 (d, J = 66.1, C(6)), 55.3
((CH3)3C), 51.3 (C(3′)), 47.0 (d, J = 120.2 C(1′)), 40.0 (C(4)), 39.3
(C(5)), 38.7 (C(4′)), 30.0 (CH3C(6)), 29.1 ((CH3)3C) 15.3
(CH3C(3′)), 12.3 (CH3C(4′)); 31P NMR (101.3 MHz) 15.2; IR
(neat) 2977 (s), 2878 (m), 1705 (s, CO), 1638 (w), 1456 (m),
1456 (m), 1397 (m), 1372 (s), 1291 (s), 1254 (s, PO), 1196 (s),
1150 (s), 1100 (m), 1063 (m), 995 (s), 918 (m), 891 (m), 868 (m);
MS (70 eV) 329 (M+, 16.5), 315 (26), 314 (100), 273 (25), 272 (43),
258 (20), 256 (10), 246 (16), 218 (18), 206 (27), 205 (10), 190 (16),
189 (13), 188 (11), 148 (12), 126 (33), 124 (12), 109 (10), 86 (22),
84 (21), 70 (65), 58 (25); high-resolution MS calcd for C17H32NO3P
329.2120, found 329.2128; TLC Rf 0.40 (benzene/acetone, 2:1).
(R,S)-(Pl,3′l,4′l)-3-tert-Butyl-6,6-dimethyl-2-(3′,4′dimethyl-2′-oxo-
5′-hexenyl)-2-oxo-1,3,2-oxazaphosphorinane ((u)-12ab). Anionic
(general procedure 3A): radial chromatography (hexane/acetone,
3:1) afforded 48.7 mg (60%) of (u)-12ab. Data for (u)-12ab are given
for a distilled sample: bp 150 °C (0.05 mmHg); 1H NMR (500 MHz)
5.67−5.60 (m, 1 H), 5.02−4.96 (m, 2 H), 3.45 (dd, 1 H, JP−H = 18.1,
Enantiomerically Enriched 1,3,2-Oxazaphosphorinane 2-Oxides.
(S)-3-tert-Butyl-3-hydroxybutyramide ((S)-14). The enantiomeric
composition of ethyl (S)-3-hydroxybutanoate was measured by two
methods. Optical rotation gave an enantiomeric excess of 97%
([α]28 = +42.5 (c 1.4; CHCl3)). Analytical gas chromatographic
589
separation of the Mosher esters26 gave an enantiomeric excess of 96%
(cOV-17, 165 °C, tR = 14.5 (minor diastereomer), tR = 14.9 (major
diastereomer)). A 100-mL, 3-necked, flask equipped with septum,
stirring bar, thermometer, and N2 inlet was charged with 7.95 mL
(75.7 mmol) of tert-butylamine and cooled to 0 °C. Trimethylalumi-
num (2 M in toluene, 37.8 mL, 75.7 mmol) was added slowly via
syringe (0 °C − 10 °C). The mixture was warmed to room
temperature for 30 min. After the mixture was cooled to 0 °C, 5.00 g
(37.8 mmol) of ethyl (S)-3-hydroxybutanoate was added dropwise via
syringe (0 to 10 °C). The mixture was warmed to room temperature
and stirred for 20 h. The mixture was cooled to 0 °C, and water (50
mL) was added dropwise. CAUTION: Upon the initial addition of
water (<1 mL), there is an induction period of several minutes
followed by rapid, exothermic evolution of methane. The mixture was
acidified to pH∼ 6 with 2 N HCl, filtered through a Buchner funnel
and continuously extracted with Et2O for 20 h. The organic layer was
dried (K2CO3) and filtered, and the solvent removed by rotary
evaporation. The crude product was purified by column chromatog-
raphy to afford 4.33 g (71.9%) of (S)-14 as white solid. Data for (S)-
14 are given for a recrystallized sample: mp 89−90 °C; [α]28
=
589
1
+14.2 (c 1.4; CHCl3); H NMR (300 MHz), 5.53−5.37 (m, 1 H),
4.21−4.10 (m, 1 H), 3.92 (d, J = 2.9, 1 H), 2.28−2.14 (m, 2 H), 1.35
(s, 9 H), 1.20 (d, 3 H, J = 6.2); 13C NMR (75.5 MHz) 171.9 ((1)),
64.7 (C(3)), 51.2 ((CH3)3C), 44.4 (C(2)), 28.7 ((CH3)3C), 22.6
(C(4)); IR (CCl4) 3443 (m), 2971 (s), 1744 (w), 1698 (m), 1671 (s,
CO), 1511 (m), 1455 (m), 1420 (m), 1393 (w), 1366 (m), 1250
(w), 1198 (s), 1167 (s), 1142 (s), 928 (w); MS (70 eV) 159 (M+,
11.0), 144 (24), 86 (12), 59 (18), 58 (100), 57 (17). Anal. Calcd for
C8H17NO2 (159.23): C, 60.35; H, 10.76; N, 8.80. Found: C, 60.65; H,
10.99; N, 8.79.
JH−H =13.5), 3.17−3.04 (m, 2 H), 2.87 (dd, 1H, JP−H = 16.7, JH−H
=
13.5), 2.91−2.83 (m, 1 H), 2.52−2.48 (m, 1 H), 2.01−1.95 (m, 1 H),
1.88−1.84 (m, 1 H), 1.52 (s, 3 H), 1.38 (s, 9 H), 1.30 (s, 3 H), 1.04
(d, 3 H, J = 8.6), 1.01 (d, 3 H, J = 8.6); 13C NMR (125.8 MHz) 206.9
(d, J = 7.4, C(2′)), 140.3 (C(5′)), 115.0 (C(6′)), 80.5 (d, J = 7.8,
C(6)), 55.3 ((CH3)3C), 51.3 (C(3′)), 48.5 (d, J = 118.4, C(1′)), 40.1
(C(4′)), 39.4 (C(4)), 39.4 (C(5)), 30.0 (CH3C(6)), 29.2 (CH3C(6)),
29.0 ((CH3)3C), 18.0 (CH3C(3′)), 12.6 (CH3C(4′)); 31P NMR
(121.4 MHz) 16.1; IR (neat) 2975 (s), 2878 (m), 1703 (s, CO),
1639 (m), 1456 (m), 1397 (m), 1372 (s), 1291 (s), 1252 (s, PO),
1190 (s), 1150 (s), 1100 (m), 1063 (s), 995 (s), 918 (s), 891 (s), 868
(m); MS (70 eV) 329 (M+, 16.2), 315 (18), 314 (100), 273 (19), 272
(39), 258 (15), 246 (15), 218 (15), 206 (24.0), 190 (12), 126 (24), 84
(15), 70 (46), 58 (18); high-resolution MS calcd for C17H32NO3P
329.2120, found 329.2122; TLC Rf 0.40 (benzene/acetone, 2:1).
(R,S)-(Pl,4′u)-3-tert-Butyl-6,6-dimethyl-2-(3′,3′,4′trimethyl-2′-
oxo-5′-hexenyl)-2-oxo-1,3,2-oxazaphosphorinane (13). Anionic
(general procedure 3A): radial chromatography (hexane/acetone,
1:1) afforded 89.5 mg (94%) of 13; thermal: radial chromatography
(hexane/acetone, 1:1) afforded 50.0 mg (65.8%) of 13. Data for 13 are
(S)-4-(tert-Butylamino)-4-oxobutan-2-yl 3,5-Dinitrophenyl Car-
bamate ((S)-14′). Compound (S)-14′ was prepared by the method
of Pirkle.29 Data for (S)-14′: H NMR (300 MHz) 9.59−9.54 (m, 1
1
H), 8.84−8.81 (m, 2 H) 8.56−8.52 (m, 1 H) 6.84−6.79 (m, 1 H)
5.36−5.21 (m, 1 H) 2.53 (dd, 1 H, J = 7.2, 19.8), 2.38 (dd, 1 H, J =
7.2, 19.8),1.33 (d, 3 H, J = 7.8 Hz), 1.29 (s, 9 H); HPLC (column B;
hexane/EtOAc, 4:1; 2 mL/min) tR (S)-54, 10.50 min; >99.5%.
Preparation of (S)-4-N-tert-Butylamino-2-butanol ((S)-15). A 500-
mL, three-necked flask equipped with an addition funnel, thermom-
eter, stirring bar, and an N2 inlet was charged with 120 mL (1.0 M, 120
mmol) of BH3·THF and was cooled to 3−5 °C. A solution of the
amide (S)-52 (6.81 g, 42.8 mmol) dissolved in 50 mL of THF was
added dropwise via addition funnel (3−7 °C). The mixture was stirred
at 3−10 °C for 2.5 h and then warmed to room temperature and
stirred for an additional 5 h. The mixture was cooled to 5 °C, and 150
mL of 6 N HCl was cautiously added (N.B.: The first 5 mL was added
3−5 drops at a time maintaining the internal temperature <7 °C. The
remainder was added dropwise (<20 °C) being careful to avoid a
violent exothermic evolution of gas). The mixture was warmed to
room temperature and stirred for 30 min and then cooled to 3−5 °C.
KOH pellets were added cautiously until pH = 11, maintaining a
1
reported for a distilled sample: bp 160 °C (0.05 mmHg); H NMR
(500 MHz) Major diastereomer: 5.68−5.60 (m, 1 H), 5.09−5.00 (m, 2
H), 3.53 (dd, 1 H, JP−H = 17.5, JH−H = 15.7), 3.31−3.26 (m, 1 H),
3.16−3.10 (m, 1 H), 2.80 (dd, 1 H, JP−H = 17.9, JH−H = 15.7), 2.46−
2.43 (m, 1 H), 1.97−1.88 (m, 2 H), 1.51 (s, 3 H), 1.38 (s, 9 H), 1.27
(s, 3 H), 1.11 (s, 3 H), 1.04 (s, 3 H), 0.93 (d, 3 H, J = 6.7). Minor
diastereomer: 5.68−5.60 (m, 1 H), 5.09−5.00 (m, 2 H), 3.54 (dd, 1 H,
JP−H = 17.5, JH−H = 15.7), 3.31−3.26 (m, 1 H), 3.16−3.10 (m, 1 H),
2.79 (dd, 1 H, JP−H = 17.9, JH−H = 15.7), 2.46−2.43 (m, 1 H), 1.97−
1.88 (m, 2 H), 1.51 (s, 3 H), 1.36 (s, 9 H), 1.27 (s, 3 H), 1.11 (s, 3 H),
M
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temperature below 40 °C. The aqueous layer, which contained some
solid KOH, was extracted with 250 mL of Et2O. Water was then added
to dissolve the solid KOH, and the homogeneous aqueous layer was
extracted with Et2O (3 × 250 mL). The combined organic fractions
were dried (K2CO3), filtered, and concentrated by rotary evaporation.
The crude product was purified by Kugelrohr distillation to afford 5.85
g (94.3%) of (S)-53 as a clear, colorless oil. Data for (S)-15: bp 55 °C
(0.15 mmHg); 1H NMR (300 MHz) 3.99−3.92 (m, 1 H), 2.99 (dt, 1
H, J = 11.7, 4.0), 2.67 (td, 1 H, J = 11.4, 2.8), 1.67−1.59 (m, 1 H),
1.44−1.30 (m, 1 H), 1.15 (d, 3 H, J = 7.3), 1.09 (s, 9 H)); 13C NMR
(75.5 MHz) 69.2 (C(2)), 50.1 ((CH3)3C), 41.0 (C(4)), 37.4 (C(3)),
28.4 ((CH3)3C), 23.3 (C(1)); IR (neat) 3278 (s), 2965 (s), 2928 (s),
2867 (s), 1655 (w), 1480 (s), 1443 (s), 1391 (m), 1364 (s), 1335 (m),
1231 (s), 1215 (s), 1138 (s), 1121 (s), 1094 (m), 1030 (m), 976 (m),
911 (m); MS ((70 eV) 145 (M+, 0.69), 130 (100), 112 (22), 72 (17),
70 (17), 58 (16). Anal. Calcd for C8H19NO (145.25): C, 66.15; H,
13.18; N, 9.65. Found: C, 66.12; H, 13.23; N, 9.71.
necked flask equipped with stirring bar, septa, and N2 inlet was
charged with 50% NaH dispersion (221 mg, 4.60 mmol). The NaH
dispersion was rinsed with hexane (3 × 2 mL) and suspended in 40
mL of dry THF. After 5 min, tert-butyl alcohol (930 μL, 9.86 mmol)
and allyl alcohol (307 μL, 4.52 mmol) were added sequentially via
syringe. After 10 min, a solution of cis-16 (1.00 g, 4.11 mmol) in 2 mL
of THF was added via syringe. After an additional 15 min, the reaction
was quenched with 10 mL of water and extracted with EtOAc (50
mL). The water layer was separated and further extracted with CH2Cl2
(3 × 50 mL). The organic layers were washed with brine (1 × 10 mL),
combined, dried (MgSO4), and filtered, and the solvent was removed
by rotary evaporation. The crude product was purified by column
chromatography (hexane/acetone, 2:1) to give 670 mg (54.0%) of cis-
1
17 as a white solid. Data for cis-17: mp 42−44 °C; H NMR (300
MHz) 6.02−5.89 (m, 1 H), 5.30 (dd, 1 H, J = 17.5, 1.2), 5.18 (dd, 1
H, J = 10.4, 1.0); 4.57−4.45 (m, 2 H), 4.21−4.09 (m, 2 H), 3.15−
2.95(m, 3 H), 2.63 (dd, 1 H, J = 17.1, 15.4), 2.01−1.91 (m, 1 H),
1.65−1.51 (m, 4 H), 1.37 (s, 9 H), 1.27 (d, 3 H, J = 6.4); 13C NMR
(75.5 MHz) 149.2 (d, J = 6.4, C(2′)), 133.7 (CHCH2), 116.9
(CHCH2), 94.3 (d, J = 10.6, C(3′)), 70.3 (d, J = 7.9, C(6)), 67.8
(OCH2), 55.1 (d, J = 4.9, (CH3)3C), 40.5 (C(4)), 34.4 (C(5)), 34.1
(d, J = 131.7, C(1′)), 29.4 ((CH3)3C), 22.3 (d, J = 9.0, CH3C(6)),
12.2 (C(4′)); 31P NMR (121.4 MHz) 24.4; IR (CCl4) 2977 (m), 2932
(m), 1667 (m), 1458 (w), 1401 (w), 1364 (w), 1347 (w), 1277 (m),
1258 (s, PO), 1233 (s), 1202 (s), 1146 (m), 1127 (m), 1102 (m),
1044 (m), 1009 (m), 992 (m), 947 (m), 893 (w); MS (70 eV) 301
(M+, 2.9), 286 (14), 260 (52), 204 (100), 162 (36), 110 (24), 70 (11);
high-resolution MS calcd for C15H28NO3P 301.1807, found 301.1799;
TLC Rf 0.35 (hexane/acetone, 1:1).
(S)-(Pl,6l)-3-tert-Butyl-2-(1′,2′-butadienyl)-6-methyl-2-oxo-1,3,2-
oxazaphosphorinane (cis-16) and (R)-(P l,6 u)-3-tert-Butyl-2-(1′,2′-
butadienyl)-6-methyl-2-oxo-1,3,2-oxazaphosphorinane (trans-16).
A 250-mL, three-necked flask equipped with stirring bar N2 inlet,
thermometer, and septum was charged with 100 mL of dry CH2Cl2
and cooled to −5 °C. Phosphorus trichloride (1.20 mL, 13.8 mmol)
and N-methylmorpholine (1.51 mL, 13.8 mmol) were added
sequentially via syringe. After the mixture was stirred for 5 min, a
solution of ( )-3-butyn-2-ol (1.08 mL, 13.8 mmol) in 5 mL of
CH2Cl2 was added via syringe (0−5 °C). After the mixture was stirred
for 20 min, N-methylmorpholine (3.01 mL, 27.6 mmol) was added.
After the mixture was stirred for an additional 5 min, a solution of (S)-
N-tert-butyl-4-amino-2-butanol (1.08 mL, 13.8 mmol) in 5 mL of
CH2Cl2 was added. The reaction mixture was warmed to room
temperature and stirred for 6 h. The mixture was diluted with 100 mL
of water and extracted with CH2Cl2 (3 × 100 mL). The organic layers
were washed with water and brine (1 × 50 mL each). The combined
organic layers were dried (MgSO4) and filtered, and the solvent was
removed by rotary evaporation. The crude product was twice purified
by column chromatography (hexane/acetone, 3:1) to give 650 mg
(19.5%) of trans-16 and 1.82 g (54.3%) of cis-16 as clear colorless oils.
Data for cis-16 are reported for a distilled sample: bp 160 °C (0.03
mmHg); 1H NMR (300 MHz) 5.47−5.39 (m, 1 H), 5.38−5.23 (m, 1
H), 4.62−4.49 (m, 1 H), 3.31−3.03 (m, 2 H), 2.09−1.93 (m, 1 H),
1.76−1.61 (m, 4 H), 1.35 (s, 9 H), 1.32 (d, 3 H, J = 6.3); 13C NMR
(75.5 MHz) 210.6 (C(2′)), 210.3 (C2′)), 54.7((CH3)3C), 40.3
(C(4)), 34.2 (C(5)), 29.1 ((CH3)3C), 29.0 ((CH3)3C), 12.5 (d, J =
6.9, CH3C(6)), 12.1 (d, J = 7.0, CH3C(6)). The following resonances
could not be unambiguously assigned: 87.6, 87.5, 86.3, 86.1, 85.9, 85.7,
85.2, 71.9, 71.8, 71.7, 22.0, 21.9; 31P NMR (121.4 MHz), 13.1, 12.9;
IR (neat) 2975 (s), 1952 (s, CCC), 1653 (w), 1445 (m), 1366
(s), 1279 (s), 1254 (s, PO), 1204 (s), 1129 (s), 1044 (s), 1013 (s),
990 (s), 949 (s), 895 (m), 828 (m), 808 (m); MS (70 eV) 243 (M+,
3.20), 229 (12), 228 (100), 187 (49), 186 (26), 174 (16), 164 (11),
148 (10), 146 (14), 145 (14), 134 (12), 70 (20), 58 (29), 57 (12), 55
(10); high-resolution MS calcd for C12H22NO2P 243.1388, found
243.1385; TLC Rf 0.30 (hexane/acetone, 3:1). Data for trans-16 are
(S)-(Pu,6l)(E)-3-tert-Butyl-6-methyl-2-oxo-[2′-(2-propenyloxy)-2′-
butenyl]-1,3,2-oxazaphosphorinane (trans-17). A 15 mL, three-
necked flask equipped with stirring bar, septa, and N2 inlet was
charged with 50% NaH dispersion (97.1 mg, 2.02 mmol). The NaH
dispersion was rinsed with hexane (3 × 1 mL) and suspended in 16
mL of dry THF. After 5 min, tert-butyl alcohol (380 μL, 4.03 mmol)
and allyl alcohol (137 μL, 2.01 mmol) were added sequentially via
syringe. After an additional 5 min, a solution of allene trans-16 (407
mg, 1.67 mmol) in 1 mL of THF was added via syringe. After being
stirred at room temperature for 15 min, the reaction was quenched
with 10 mL of water and extracted with EtOAc (75 mL). The aqueous
layer was separated and further extracted with CH2Cl2 (3 × 50 mL).
The organic layers were washed with brine (1 × 10 mL), combined,
dried (MgSO4), and filtered, and the solvent was removed by rotary
evaporation. The crude product was purified by column chromatog-
raphy (hexane/acetone, 2:1) to give 220 mg (30.0%) of trans-17 as a
1
white solid. Data for trans-17: mp 72−75 °C; H NMR (500 MHz)
5.99−5.93 (m, 1 H), 5.31 (d, 1 H, J = 17.4), 5.20 (d, 1 H, J = 10.3),
4.58−4.55 (m, 1 H), 4.44−4.40 (m, 1 H), 4.21−4.15 (m, 2 H), 3.28−
3.20 (m, 1 H), 3.05−2.95 (m, 1 H), 2.99 (dd, 1 H, J = 17.9, 15.1), 2.69
(dd, 1 H, J = 16.5, 15.7), 1.80−1.68 (m, 5 H), 1.35 (s, 9 H), 1.31 (d, 3
H, J = 6.2); 13C NMR (125.8 MHz) 163.0 (C(2′)), 133.6 (CH
CH2), 117.2 (CHCH2), 94.6 (d, J = 11.4, C(3′)), 76.0 (d, J = 6.0,
C(6)), 67.9 (OCH2), 55.6 ((CH3)3C), 42.1 (C(4)), 35.1 (C(5)), 32.5
(d, J = 120.5, C(1′)), 29.5 ((CH3)3C), 22.8 (d, J = 7.6, CH3C(6)),
12.2(C(4′); 31P NMR (121.4 MHz) 19.9; IR (CCl4) 2977 (s), 2936
(m), 2870 (m), 1711 (w), 1667 (m), 1553 (m), 1458 (m), 1399 (m),
1385 (m), 1366 (m), 1346 (w), 1281 (s), 1260 (s, PO), 1202 (s),
1102 (s), 1048 (s), 1017 (s), 992 (s), 930 (m), 893 (m); MS (70 eV)
301 (M+, 6.16), 286 (54), 260 (55), 245 (12), 204 (100), 176 (15),
174 (12), 162 (36), 148 (10), 135 (36), 134 (15), 112 (20), 70 (27);
high-resolution MS calcd for C15H28NO3P 301.1807, found 301.1816;
TLC Rf 0.44 (hexane/acetone, 1:1).
1
reported for a distilled sample: bp 160 °C (0.03 mmHg); H NMR
(500 MHz) 5.44−5.39 (m, 1 H), 5.33−5.26 (m, 1 H), 4.35−4.30 (m,
1 H), 3.32−3.23 (m, 1 H), 3.08−3.00 (m, 1 H), 1.80−1.73 (m, 5 H),
1.35 (s, 9 H), 1.34−1.32 (m, 3 H); 13C NMR (125.8 MHz), 210.6
(C(2′)), 210.3 (C(2′)), 55.7 ((CH3)3C), 42.4 (C(4)), 34.9 (C(5)),
29.4 ((CH3)3C). The following resonances could not be unambigu-
ously assigned: 85.9, 85.8, 85.7, 84.7, 84.5, 84.2, 83.1, 82.9, 75.1, 75.0,
74.9, 22.5, 22.4, 13.2, 13.1, 13.0; 31P NMR (121.4 MHz), 9.1, 8.9; IR
(neat) 2975 (s), 2724 (w), 1949 (s, CCC), 1638 (m), 1557 (w),
1474 (w), 1366 (s), 1321 (m), 1281 (s), 1256 (s, PO), 1204 (s),
1152 (s), 1111 (s), 1046 (s), 1016 (s), 989 (s), 893 (s), 853 (s), 810
(s); MS (70 eV) 243 (M+, 4.59), 229 (13), 228 (100), 187 (41), 186
(14), 145 (13), 134 (13); high-resolution calcd for C12H22N2P
243.1388, found 243.1387; TLC Rf 0.39 (hexane/acetone, 3:1).
(S)-(Pl,6l)(E)-3-tert-Butyl-6-methyl-2-oxo[2′-(2-propenyloxy)-2′-
butenyl]-1,3,2-oxazaphosphorinane (cis-17). A 100 mL, three-
(S)-(Pl,6l,3′l)-3-tert-Butyl-6-methyl-2-(3′-methyl-2′-oxo-5′-hexen-
yl)-2-oxo-1,3,2-oxazaphosphorinane (S)-(l,l)-18. Anionic (general
procedure 3A): radial chromatography (hexane/acetone, 1:1) afforded
470 mg (78.3%) of cis-57. Anionic (general procedure 3B): radial
chromatography (hexane/acetone, 1:1) afforded 28.5 mg (65.2%) of
(S)-(l,l)-18. Data for (S)-(l,l)-18 are reported for a distilled sample: bp
160 °C (0.5 mmHg); 1H NMR (300 MHz) major diastereomer:
5.80−5.67 (m, 1 H), 5.09−5.00 (m, 2 H), 4.60−4.54 (m, 1 H), 3.38
N
dx.doi.org/10.1021/jo301919e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(dd, 1 H, J = 17.8, 13.3) 3.21−2.90 (m, 4 H), 2.46−2.35 (m, 1 H),
2.16−2.01 (m, 2 H), 1.70−1.59 (m, 1 H), 1.38 (s, 9 H), 1.30 (d, 3 H, J
= 6.0), 1.10 (d, 3 H, J = 6.8); minor diastereomer: 5.80−5.67 (m, 1
H), 5.09−5.00 (m, 2 H), 4.60−4.54 (m, 1 H), 3.39 (dd, 1 H, J = 17.8,
13.3) 3.21−2.90 (m, 4 H), 2.46−2.35 (m, 1 H), 2.16−2.01 (m, 2 H),
1.70−1.59 (m, 1 H), 1.38 (s, 9 H), 1.30 (d, 3 H, J = 6.0), 1.08 (d, 3 H,
J = 6.6); 13C NMR (75.5 MHz) 206.5 (d, J = 6.8, C(2′)), 135.7
(CHCH2), 116.7 (CHCH2), 70.7 (d, J = 7.1, C(6)), 55.3 (d, J =
3.2, (CH3)3C), 46.3 (C(3′)), 45.5 (d, J = 116.1, C(1′)), 40.1 (C(4′)),
36.4 (C(5)), 34.5 (d, J = 3.5, C(4)), 29.3 ((CH3)3C), 22.2 (d, J = 2.2,
CH3C(6)), 16.0 (CH3C(3′)); 31P NMR (121.4 MHz) 19.2; IR (neat)
2975 (s), 2934 (m), 1707 (s, CO), 1642 (w), 1458 (m), 1399 (m),
1366 (m), 1277 (s), 1254 (s, PO), 1198 (s), 1125 (s), 1044 (s), 990
(s), 947 (m), 893 (m), 870 (m), 810 (m); MS (70 eV) 301 (M+, 5.1),
286 (76), 244 (33), 228 (12), 192 (39), 174 (19),148 (12), 124 (21),
112 (48), 93 (12), 70 (100), 55 (26), 41 (44); high-resolution MS
calcd for C15H28NO3P 301.1807, found 301.1810; TLC Rf 0.28
(benzene/acetone, 2:1).
The dimethyl 2,3-dimethylsuccinates were compared to authentic
meso-and d,1-succinates by capillary GC analysis. The syn diastereomer
was the major diastereomer present. GC (COV-17; 80 °C isothermal)
tR (d,l), 9.95 min; tR (meso), 11.14 min.
(S)[Pl,6l,3′l)-3-tert-Butyl-6-methyl-2-(3′-methyl-2′-(tert-butyldi-
methylsiloxy)-1,5-hexadienyl)-1,3,2-oxazaphosphorinane (cis-19).
1
General Procedure 5. Data for cis-19: H NMR (300 MHz) 5.80−
5.71 (m, 1 H), 5.08−5.01 (m, 2 H), 4.61 (d, 1 H, J = 15.4), 4.15−4.10
(m, 1 H), 3.29−3.20 (m, 1 H), 2.83−2.91 (m, 1 H), 2.42−2.38 (m, 1
H), 2.23−2.18 (m, 1 H), 2.15−2.07 (m, 1 H), 1.34 (s, 9 H) 1.29 (d, 3
H, J = 6.0), 1.08 (d, 3 H, J = 8.1), 0.97 (s, 9 H), 0.30 (s, 3 H), 0.23 (s,
3 H). Ozonolysis/esterification of cis-19 afforded 17.3 mg (59.3%) of
1
dimethyl (S)-(+)-methylsuccinate as assigned above. The H NMR
spectrum was identical to that from an authentic sample of the
racemate.
(R)[Pl,6u,3′l)-3-tert-Butyl-6-methyl-2-(3′-methyl-2′-(tert-butyldi-
methylsiloxy)-1,5-hexadienyl)-1,3,2-oxazaphosphorinane (trans-
1
19). General Procedure 5. Data for trans-19: H NMR (300 MHz)
5.82−5.70 (m, 1 H), 5.10−5.01 (m, 2 H), 4.66 (d, 1 H, J = 15.4),
4.62−4.53 (m, 1 H), 3.19−3.04 (m, 1 H), 2.45−2.35 (m, 1 H), 2.42−
2.38 (m, 1 H), 2.23−2.18 (m, 1 H), 2.15−2.07 (m, 1 H), 1.34 (s, 9 H)
1.33 (d, 3 H, J = 6.1), 1.08 (d, 3 H, J = 6.1), 0.99 (s, 9 H), 0.27 (s, 6
H). Ozonolysis/esterification of trans-19 afforded 3.7 mg (24.1%) of
(S)-(Pu,6l,3′u)-3-tert-Butyl-6-methyl-2-(3′-methyl-2′-oxo-5′-hex-
enyl)-2-oxo-1,3,2-oxaza-phosphorinane (S)-(u,u)-18. Anionic (Gen-
eral Procedure 3.A.): radial chromatography (hexane/acetone, 1:1)
afforded 35.4 mg (70.8%) of (S)-(u,u)-18 as a colorless oil. Data for
(S)-(u,u)-18 are reported for a distilled sample: bp 160 °C (0.5
1
1
dimethyl (R)-(+)-methylsuccinate as assigned above. The H NMR
mmHg); H NMR (500 MHz) major diastereomer: 5.78−5.70 (m, 1
spectrum was identical to that from an authentic sample of the
racemate.
H), 5.07−5.00 (m, 2 H), 4.44−4.37 (m, 1 H), 3.35−3.25 (m, 1 H),
3.30 (dd, 1 H, J = 17.0, 13.0), 3.11−3.00 (m, 3 H), 2.47−2.42 (m, 1
H), 2.13−2.07 (m, 1 H), 1.86−1.73 (m, 2 H), 1.34 (s, 1 H), 1.34−1.31
(m, 3 H), 1.12 (d, 3 H, J = 7.1); minor diastereomer: 5.78−5.70 (m, 1
H), 5.07−5.00 (m, 2 H), 4.44−4.37 (m, 1 H), 3.35−3.25 (m, 1 H),
3.30 (dd, 1 H, J = 17.0, 13.0), 3.11−3.00 (m, 3 H), 2.47−2.42 (m, 1
H), 2.13−2.07 (m, 1 H), 1.86−1.73 (m, 2 H), 1.34 (s, 1 H), 1.34−1.31
(m, 3 H), 1.11 (d, 3 H, J = 7.1); 13C NMR (125.8 MHz) 207.2
(C(2′)), 135.7 (C(5′)), 116.8 (C(6′)), 67.1 (d, J = 9.8, C(6)), 56.0
((CH3)3C), 43.7 (d, J = 105.4, C(1′)), 36.5 (C(4′)), 35.2 (C(5′)),
29.4 ((CH3)3C), 22.6 (d, J = 7.3, CH3C(6)), 16.1(CH3C(3′)); 31P
NMR (121.4 MHz) 14.7; IR (neat) 2977 (s), 1703 (s, CO), 1642
(w), 1458 (w), 1368 (m), 1283 (s), 1256 (s, PO), 1196 (m), 1152
(w), 1109 (m), 1043 (s), 1017 (s), 992 (s), 972 (m), 893 (m), 862
(w); MS (70 eV); 301 (M+, 5.25), 287 (16), 286 (100), 244(17),
192(16), 112 (24), 70 (34); high-resolution MS calcd for
C15H28NO3P 301.1807, found 301.1811; TLC Rf 0.35 (benzene/
acetone, 2:1).
Chiral Shift Agent (CSA) Study of Dimethyl (R)- and (S)-
Methylsuccinates. To a solution of the appropriate dimethyl
methylsuccinate (0.25 M) in CDCl3 was added (R)-2,2,2-trifluoro-1-
(9-anthryl)ethanol in increments of 1.0 equiv until separation was
observed by 1H NMR spectroscopy (500 MHz). The methoxy groups
are diagnostic: for dimethyl (R)-methylsuccinate 3.649 and 3.625 (2
s); for dimethyl (S)-methylsuccinate 3.646 and 3.620 (2 s). These
assignments were verified by spiking with an authentic sample of
dimethyl (R)-methyl succinate.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
General experimental procedures along with copies of H and
13C NMR spectra along with a listing of crystal and positional
parameters, bond lengths, bond angles, and torsional angles for
cis-17 and trans-17. This material is available free of charge via
the Internet at http://pubs.acs.org/.
Degradation and Assignment of Rearrangement Products. Silyl
Enol Ethers. General Procedure 5. A 15-mL, three-necked flask
equipped with septa, stirring bar, and N2 inlet was charged with a
solution of the Claisen rearrangement product (20.2 mg, 0.0613
mmol) in 0.5 mL of THF. The solution was cooled to −78 °C. A
solution of potassium hexamethyldisilazide in THF (0.815 M, 165 μL,
0.134 mmol) was added via syringe. After 2 min, a solution of tert-
butyldimethylsilyl chloride in THF (22.8 mg, 0.151 mmol) was added
via syringe. After being stirred for 30 min at −78 °C, the solution was
warmed to room temperature, transferred to a centrifuge tube, and
centrifuged for 5 min at 5000 rpm. The supernatant was transferred to
a round-bottomed flask and the solvent removed. The resulting silyl
enol ether was carried on without further purification.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sdenmark@illinois.edu.
■
Notes
The authors declare no competing financial interest.
‡Dedicated to the memory of Professor Robert E. Ireland
whose greatest legacy inspired this work.
§Deceased July 13, 1988.
Preparation of Dimethyl Succinates from Degradation. A 15 mL,
three-necked flask equipped with stirring bar, thermometer, and ozone
inlet and outlet tubes (outlet tube connected to a bubbler containing a
0.1 N KI solution) was charged with 3 mL of methyl acetate and
cooled to −10 °C. A solution of the silyl enol ether (0.0613 mmol) in
1 mL of methyl acetate was added via syringe. Ozone was bubbled
through the solution until the blue color persisted. Hydrogen peroxide
(30%, 0.5 mL) and formic acid (88%, 1 mL) were then added
sequentially. The solution was stirred at room temperature for 16 h
and then the solvents were removed in vacuo. The residue was taken
up in 3% NaOH and extracted with Et2O (2 × 15 mL). The water
layer was acidified with 2 N H2SO4 and continuously extracted with
Et2O for 16 h. The Et2O layer was dried (Na2SO4) and filtered, and
the solvents were removed. The resulting 2,3-dimethylsuccinic acids
were esterified by treatment with an ethereal solution of diazomethane.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of Health (R01
GM45521) and the American Chemical Society Petroleum
Research Fund (ACS PRF 18407-AC1-C) for generous
financial support. J.E.M. thanks the U.S. Air Force Institute of
Technology for financial support.
REFERENCES
■
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