Ammonium-directed olefinic epoxidation: Kinetic and mechanistic insights

Article

pubs.acs.org/joc

Ammonium-Directed Oleﬁnic Epoxidation: Kinetic and Mechanistic

Insights

Meabh B. Brennan,^†Timothy D. W. Claridge,^†Richard G. Compton,^‡Stephen G. Davies,*^,†

́

Ai M. Fletcher,^†Martin C. Henstridge,^‡David S. Hewings,^†Wataru Kurosawa,^†James A. Lee,^†

Paul M. Roberts,^†Anne K. Schoonen,^†and James E. Thomson^†

^†Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansﬁeld Road, Oxford OX1 3TA, U.K.

^‡Department of Chemistry, Physical & Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1

3QZ, U.K.

S

* Supporting Information

ABSTRACT: The ammonium-directed oleﬁnic epoxidations of a range

of diﬀerentially N-substituted cyclic allylic and homoallylic amines

(derived from cyclopentene, cyclohexene, and cycloheptene) have been

investigated, and the reaction kinetics have been analyzed. The results

of these studies suggest that both the ring size and the identity of the

substituents on nitrogen are important in determining both the overall

rate and the stereochemical outcome of the epoxidation reaction. In

general, secondary amines or tertiary amines with nonsterically

demanding substituents on nitrogen are superior to tertiary amines

with sterically demanding substituents on nitrogen in their ability to

promote the oxidation reaction. Furthermore, in all cases examined, the

ability of the (in situ formed) ammonium substituent to direct the

stereochemical course of the epoxidation reaction is either comparable

or superior to that of the analogous hydroxyl substituent. Much slower rates of ring-opening of the intermediate epoxides are

observed in cyclopentene-derived and cycloheptene-derived allylic amines as compared with their cyclohexene-derived allylic and

homoallylic amine counterparts, allowing for isolation of these intermediates in both of the former cases.

minimized, resulting in formation of epoxide 4. Ring-opening of

4 upon attack of H₂O at the oxirane carbon atom distal to the

ammonium moiety [i.e., at C(5)], followed by lactonization

under the acidic reaction conditions, then leads to 5. A further

four steps realized a concise and highly selective asymmetric

synthesis of methyl N,O-diacetyl-α-^L-acosaminide 6⁶(Scheme

1).

This ammonium-directed oleﬁnic epoxidation has thus been

shown to be synthetically powerful and is general for primary,

secondary, and tertiary amines.^4a,d,eTo obtain further insight

into the origin of selectivity and reactivity in some of the

conformationally constrained (cyclic) allylic and homoallylic

amines studied so far (Figure 1),⁴the eﬀect of variation of the

substituents on nitrogen on the reaction diastereoselectivity,

product distribution, and rate of reaction was explored, and the

results of these investigations are delineated herein.

INTRODUCTION

■

The stereochemical outcome of a reaction is of enormous

importance in organic chemistry, and the ability to predict and

direct stereoselectivity is invaluable in organic synthesis.

Substrates equipped with functionality capable of precoordinat-

ing a reagent may result in subsequent intramolecular delivery

of the reagent and, therefore, oﬀer high levels of diaster-

eoselectivity: such transformations have been termed substrate-

directed reactions by Evans.¹As part of an ongoing research

program employing methods for the chemo- and diastereose-

lective electrophilic functionalization of unsaturated amines at

the oleﬁn,²we have previously developed an ammonium-

directed oleﬁnic epoxidation of allylic and homoallylic amines

to facilitate the diastereoselective synthesis of amino diol

units.^3,4This protocol was utilized in the asymmetric syntheses

of the imino sugars (+)-1-deoxynojirimycin and (+)-1-

deoxyaltronojirimycin,⁵and a derivative of the amino sugar L-

acosamine.⁶In the latter case, the diastereoselective conjugate

addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide

(R)-1⁷to tert-butyl sorbate 2 was followed by treatment of

the resultant β-amino ester 3 with aq HBF₄and then m-CPBA,

which resulted in conversion to lactone 5. This is consistent

with a mechanism involving ammonium-directed epoxidation

of the oleﬁn via a transition state in which 1,3-allylic strain is

RESULTS AND DISCUSSION

■

Oxidation of N-Substituted 3-Aminocyclohex-1-enes.

A range of N-substituted 3-aminocyclohex-1-enes 9−12 were

prepared via Wohl−Ziegler allylic bromination of cyclohexene

Received: May 22, 2012

Published: July 24, 2012

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and 1.6 equiv of m-CPBA⁹gave, on basic aqueous workup using

NaHCO₃, trichloroacetate ester 16 in 95:5 dr and quantitative

yield.¹⁰Transesteriﬁcation of 16 upon treatment with K₂CO₃in

MeOH gave amino diol 20 in 95:5 dr (the minor

diastereoisomer was the corresponding 1,2-anti-2,3-anti-diaster-

eoisomer) and quantitative yield. Application of this protocol to

9−11¹¹gave, in each case, quantitative conversion to the

corresponding trichloroacetate esters 13−15 in ≥95:5 dr.¹⁰

Subsequent transesteriﬁcation using K₂CO₃in MeOH gave

amino diols 17−19 in 67−94% isolated yield, and in ≥95:5 dr

(in each case, the minor diastereoisomer was the corresponding

1,2-anti-2,3-anti-diastereoisomer). The relative conﬁgurations

within 13, 16, 17, and 20 have previously been unambiguously

assigned.^4aThe relative conﬁguration within 14 was established

unambiguously via single-crystal X-ray diﬀraction analysis,¹²

which, therefore, allowed the relative conﬁguration within 18 to

be unambiguously assigned. The relative conﬁgurations within

15 and 19 were determined by chemical correlation: reductive

alkylation of 17 upon treatment with acetone in the presence of

NaB(OAc)₃H gave a sample of 19 in 52% yield, which was

spectroscopically identical to the product obtained from the

ammonium-directed oxidation of 11 (Scheme 3). We have

a

Scheme 1

a

Reagents and conditions: (i) lithium (R)-N-benzyl-N-(α-

Scheme 3

methylbenzyl)amide (R)-1, THF, −78 °C, 2 h; (ii) HBF₄(40%

w/w in H₂O), m-CPBA (4 equiv), CH₂Cl₂, rt, 48 h; (iii) H₂(5 atm),

Pd(OH)₂/C (50% w/w wrt substrate), EtOAc, rt, 48 h; (iv)

DIBAL-H, CH₂Cl₂, −78 °C, 30 min; (v) MeOH, HCl (conc aq), rt,

16 h; (vi) Ac₂O, pyridine, DMAP, rt, 30 min.

a

Reagents and conditions: (i) Cl₃CCO₂H, m-CPBA, CH₂Cl₂, rt, 21 h,

then NaHCO₃(0.1 M aq); (ii) K₂CO₃, MeOH, rt, 16 h; (iii) acetone,

NaB(OAc)₃H, AcOH, rt, 24 h.

Figure 1. Allylic and homoallylic amine substrates (derived from

cyclopentene, cyclohexene, and cycloheptene) for study into

ammonium-directed epoxidation.

previously rationalized the chemoselectivities of the oxidation

reactions of allylic amines 9 and 12 as a result of temporary

protection of the amine functionality from electrophilic reaction

by protonation to give the corresponding ammonium ions. The

diastereoselectivities of these reactions are then due to these

ammonium ions being able to direct the m-CPBA to the syn

face of the oleﬁn by hydrogen-bonding^4a(analogous to the

proposals of Bartlett and Henbest¹³to explain the stereo-

chemical outcome of the oxidation of the corresponding allylic

alcohol).¹⁴Subsequent regioselective and stereospeciﬁc epoxide

ring-opening upon attack of trichloroacetic acid is directed to

the C(1)-oxirane carbon, where the destabilizing electron-

withdrawing inductive eﬀect of the ammonium moiety on the

transition state is less pronounced; also, ring-opening at C(1)

gives a chairlike transition state, resulting in the formation of

the corresponding trichloroacetate esters 13 and 16,

respectively, and transesteriﬁcation gives the corresponding

diols 17 and 20. Both the chemo- and diastereoselectivities of

7 with NBS,⁸followed by displacement of the bromide within 8

by the requisite amine (Scheme 2).

As previously reported,^4asequential treatment of 3-(N,N-

dibenzylamino)cyclohex-1-ene 12 with 5 equiv of Cl₃CCO₂H

a

Scheme 2

a

Reagents and conditions: (i) NBS, (PhCO₂)₂, CCl₄, 90 °C, 1.5 h; (ii)

HNRBn, K₂CO₃, THF, 50 °C, 16 h.

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the dihydroxylations of allylic amines 10 and 11 under these

conditions are also in accordance with this mechanistic

rationale.

oxidations of the corresponding allylic amines 10 and 11

(giving amino diols 18 and 19, respectively, in >99:1 dr)

conﬁrmed the very high diastereoselectivities of these

processes.

To facilitate subsequent analysis during rate studies,

authentic samples of the intermediate epoxides and minor

diastereoisomeric products arising from the oxidations of 10

and 11 were prepared. The use of 3 equiv of TsOH¹¹in place

of 5 equiv of Cl₃CCO₂H¹¹as the Brønsted acid protecting

agent for the oxidations of 10 and 11 (according to our

previously reported procedure)^4agave hydroxy tosylates 21 and

22 (in >99:1 dr in each case) as the major products.

Recrystallization of 21 gave an analytical sample and allowed

its relative conﬁguration to be unambiguously established by

single-crystal X-ray diﬀraction analysis.¹²Meanwhile, treatment

of the crude samples of 21 and 22 with DBU gave syn-epoxides

23 and 24 in 79% and 88% isolated yield, respectively (two

steps), as single diastereoisomers (>99:1 dr) in each case.

Treatment of 23 and 24 with AcOH gave hydroxy acetates 25

and 26 in ≥95:5 dr, which were then isolated in 89% and 88%

yield as single diastereoisomers. The relative conﬁguration

within 25 was unambiguously established by single-crystal X-ray

diﬀraction analysis.¹²Mesylation of the free hydroxyl groups

within acetates 25 and 26 was followed by treatment of the

intermediate mesylates 27 and 28 with K₂CO₃in MeOH,

which resulted in conversion to anti-epoxides 29 and 30 in 67%

and 65% yield, as single diastereoisomers (Scheme 4). Upon

With these authentic samples in hand (from which authentic

samples of the corresponding ammonium species could be

derived simply by addition of Cl₃CCO₂H), the second-order

rate constants for the oleﬁnic oxidation of allylic amines 9−12

in CD₂Cl₂solution were determined.^4a,15In each case, the

1

course of the reaction was monitored by 500 MHz H NMR

spectroscopy, with the concentrations of reactants and products

being determined relative to 1,4-bis(trimethylsilyl)benzene as

an (inert) internal standard, of known (unchanging) concen-

tration: 1,4-bis(trimethylsilyl)benzene gives a characteristic

singlet at δ_H0.31 ppm, remote from any resonances associated

with the various intermediate ammonium species formed

throughout the course of this reaction. This procedure was

ﬁrst applied to N,N-dibenzyl-substituted amine 12. Addition of

Cl₃CCO₂H to a solution of 12 in CD₂Cl₂gave ammonium 33.

Upon subsequent addition of m-CPBA, the consumption of

ammonium 33 was monitored by calculation of the average

integration of the peaks due to C(2)H (δ_H5.86−5.97 ppm)

and C(1)H (δ_H6.31−6.39 ppm), while the consumption of m-

CPBA was monitored by integration of the signals correspond-

ing to two protons at δ_H7.88−7.91 and 7.95−7.97 ppm. The

formation of trichloroacetate ammonium 35 was monitored by

calculation of the average integration of the signals due to

C(3)H (δ_H3.69−3.79 ppm) and C(1)H (δ_H5.15−5.23 ppm).

As previously noted,^4ano signiﬁcant accumulation of the

epoxide ammonium intermediate 34 occurred in this reaction

(Figure 2). A mass discrepancy was noted in the experimental

data (0.32 M initial concentration of 33; 0.31 M ﬁnal

concentration of 35), but is likely associated with the

competing direct formation of diol 20 (as the corresponding

ammonium species) by ring-opening of epoxide ammonium 34

by H₂O (rather than Cl₃CCO₂H to give 35), as well as the

incomplete diastereoselectivity of this reaction (95:5 dr),

resulting in formation of a minor diastereoisomeric epoxide

and associated ring-opened products. Although operation of

neither of these processes was monitored during this

experiment, trace amounts of impurities (∼5%) were evident

at its conclusion. The rates of consumption of both m-CPBA

and ammonium 33 were equal, indicating second-order rather

than ﬁrst-order kinetics.¹⁵Independent analysis of the

concentration proﬁles of both m-CPBA and ammonium 33

using the integrated form of the second-order rate law allowed

determination of the rate constant (at 298 K) as k₁= (7.3

0.5) × 10⁻⁴mol⁻¹dm³s⁻¹. This compares to k₁= 1.9 × 10⁻³

mol⁻¹dm³s⁻¹obtained when this oxidation reaction was

performed by us in CDCl₃.^4aNumerical simulation using the

ﬁnite diﬀerence method was employed to model the behavior

of ammoniums 33, 34, and 35 under these reaction conditions,

allowing estimation of a value for the second-order rate

constant for the epoxide ring-opening reaction as k₂≈ (8

2.0) × 10⁻⁴mol⁻¹dm³s⁻¹.¹⁶

a

Scheme 4

a

Reagents and conditions: (i) TsOH, m-CPBA, CH₂Cl₂, rt, 21 h; (ii)

DBU, CH₂Cl₂, rt, 24 h; (iii) AcOH, 50 °C, 24 h; (iv) MsCl, Et₃N,

CH₂Cl₂, 0 °C, 1 h; (v) K₂CO₃, MeOH, rt, 16 h.

treatment of 29 and 30 with 3 M aq H₂SO₄, the corresponding

amino diols 31 and 32 were formed, and isolated in 62% and

94% yield, and in >99:1 dr in each case (Scheme 5). The

absence of amino diols 31 and 32 in the crude reaction

mixtures produced from the ammonium-directed oleﬁnic

a

Scheme 5

When this procedure was applied to N-benzyl-N-isopropyl-

substituted allylic amine 11, addition of 5 equiv of Cl₃CCO₂H

to 11 to give ammonium 36 rendered the nitrogen atom a

stereogenic center and gave rise to a mixture of two ammonium

diastereoisomers (epimers at the nitrogen atom) in a ratio of

∼1:1. This was particularly evident from the splitting of the

resonances associated with C(1)H, and the diastereotopic

NCH₂Ph and NCHMe₂substituents. Treatment of a sample of

a

Reagents and conditions: (i) H₂SO₄(3 M aq), 1,4-dioxane, 40 °C, 24

h.

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Figure 2. Real-time (¹H NMR data points) and simulated (continuous lines) concentration proﬁles for Cl₃CCO₂H (5 equiv) and m-CPBA (1.6

equiv) promoted oxidation of 12 at 298 K in CD₂Cl₂. [33], blue; [m-CPBA], red; [35], green (for brevity, for ammonium ions 33−35, the

−

Cl₃CCO₂counterions are not shown).

Figure 3. Real-time (¹H NMR data points) and simulated (continuous lines) concentration proﬁles for Cl₃CCO₂H (5 equiv) and m-CPBA (1.6

equiv) promoted oxidation of 11 at 298 K in CD₂Cl₂. [36], blue; [m-CPBA], red; [37], orange; [38], green (for brevity, for ammonium ions 36−38,

−

the Cl₃CCO₂counterions are not shown; 36−38 were observed as mixtures of epimers at nitrogen).

epoxide 24 in CD₂Cl₂(0.4 M) with 5 equiv of Cl₃CCO₂H gave

an authentic sample of epoxide ammonium 37 (an ∼1:1

mixture of epimers at the nitrogen atom), which underwent

ring-opening to give an authentic sample of ammonium 38

(also as a mixture of epimers at the nitrogen atom). These

species were conﬁrmed as being epimeric at the nitrogen atom,

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Figure 4. Real-time (¹H NMR data points) and simulated (continuous lines) concentration proﬁles for Cl₃CCO₂H (5 equiv) and m-CPBA (1.6

equiv) promoted oxidation of 10 at 298 K in CD₂Cl₂. [39], blue; [m-CPBA], red; [40], orange; [41], green (for brevity, for ammonium ions 39−41,

−

the Cl₃CCO₂counterions are not shown; 39−41 were observed as mixtures of epimers at nitrogen).

since treatment of the sample with K₂CO₃in MeOH resulted in

conversion to diol 19 only. To follow the course of the

epoxidation and ring-opening reactions, integration ranges were

carefully chosen so as to include signals arising from both of the

epimers of ammonium species 36, 37, and 38. Hence, the

consumption of ammonium 36 was monitored by calculation of

the average integration of the peaks due to C(2)H (δ_H5.77−

5.84 and 5.89−5.98 ppm) and C(1)H (δ_H6.23−6.34 ppm),

with the consumption of m-CPBA again being monitored by

the disappearance of the signals at δ_H7.88−7.91 and 7.95−7.97

ppm. The formation of ammonium 38 was monitored by

integration of the signal due to C(1)H (δ_H5.15−5.20 and

5.29−5.34 ppm). Unlike during the oleﬁnic oxidation of N,N-

dibenzyl-substituted amine 12, the formation and disappear-

ance of an intermediate species (epoxide ammonium 37) could

be followed by integration of the peaks due to C(1)H rising

and falling (at δ_H3.43−3.47 and 3.50−3.54 ppm). The mass

discrepancy in the experimental data (0.31 M initial

concentration of 36; 0.27 M ﬁnal concentration of 38) in

this case is likely due to the formation of diol 19 (as the

corresponding ammonium species) by ring-opening of epoxide

37 by H₂O (rather than Cl₃CCO₂H), which was evident at the

end of the reaction (∼5−10%). Independent analysis of the

rate of loss of both m-CPBA and ammonium 36 using the

integrated form of the second-order rate law allowed

determination of the rate constant (at 298 K) as k₁= (1.6

0.2) × 10⁻³mol⁻¹dm³s⁻¹. Numerical simulation to model the

behavior of ammoniums 36, 37, and 38 under these reaction

conditions allowed determination of the second-order rate

constant for the epoxide ring-opening reaction as k₂= (6.5

1.0) × 10⁻⁴mol⁻¹dm³s⁻¹; good correlation between the

simulated concentration proﬁles and the experimental data was

noted (Figure 3). The ∼1:1 ratio of ammonium diaster-

eoisomers 36 remained constant throughout the course of this

reaction. As a result, no information regarding the relative rates

of epoxidation of these species can be gleaned from these data,

since this observation is consistent with either very similar rates

of epoxidation of both ammonium diastereoisomers 36 or a

system under Curtin−Hammett control (i.e., rapid equilibra-

tion of both diastereoisomers of 36, but preferential reaction of

only one). Similarly, the ∼1:1 ratio of the two ammonium

diastereoisomers 37 remained constant throughout the

reaction, and so no conclusions as to the relative rate of ring-

opening of these two species can be drawn.

In a similar manner, addition of 5 equiv of Cl₃CCO₂H to 10

gave ammonium 39 as a mixture of two ammonium

diastereoisomers (epimers at the nitrogen atom) in a ratio of

∼1:1. Authentic samples of ammonium species 40 and 41 (also

mixtures of epimers at the nitrogen atom) were prepared upon

addition of 5 equiv of Cl₃CCO₂H to a sample of epoxide 23 in

CD₂Cl₂(0.4 M), and the ring-opening process was monitored

1

by H NMR spectroscopy (over 12 h). Subsequent treatment

with K₂CO₃in MeOH gave diol 18 only. The oxidation of N-

benzyl-N-methyl-substituted allylic amine 10 was then

17

1

monitored by H NMR spectroscopy, and application of

the integrated form of the second-order rate law to the

experimental data so generated gave k₁= (3.7 0.2) × 10⁻³

mol⁻¹dm³s⁻¹at 298 K. The ∼1:1 ratios of ammonium epimers

39 and 40 did not change during the course of these studies. In

this case, numerical simulation using the ﬁnite diﬀerence

method gave k₂= (3.0 1.0) × 10⁻⁴mol⁻¹dm³s⁻¹(Figure 4).

It is, therefore, apparent that the rates of ring-opening of

epoxide ammonium species 34, 37, and 40 are similar.

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An attempt to apply the same procedure for the

determination of the rate constant k₁of the oxidation of N-

benzyl-substituted amine 9 revealed complete consumption of

starting material within 5 min. However, when the reaction was

conducted at higher dilution (0.08 M wrt 9), the rate constant

was determined to be k₁= 3.6 × 10⁻²mol⁻¹dm³s⁻¹. Thus, the

kinetic studies revealed the ammonium-directed epoxidation

reactions of allylic amines 9:10:11:12 to have approximate

relative rates of 49:5:2:1, respectively (Figure 5).

these factors may account for the very much greater rate of

oxidation observed for 9 as compared with 10−12.

To investigate this hypothesis further, secondary and tertiary

3-aminomethylcyclohex-1-enes bearing a range of substituents

on nitrogen were selected for investigation. It was anticipated

that the addition of a methylene group between the carbocyclic

ring and the amino group would confer a greater degree of

conformational ﬂexibility to these substrates, even those

containing a very sterically demanding amino moiety (i.e.,

N,N-dibenzyl- and N-benzyl-N-isopropyl-substituted amino

groups), and so give more insight into their relative

hydrogen-bond-directing ability.

Oxidation of N-Substituted 3-Aminomethylcyclohex-

1-enes. N-Substituted 3-aminomethylcyclohex-1-enes 46−49

were prepared from the common intermediate bromide 45.^4c,18

Substitution using benzylamine and N-benzyl-N-methylamine

gave the corresponding amines 46 and 47 in 61% and 64%

yield, respectively. Attempted substitution of bromide within 45

by N-benzyl-N-isopropylamine gave low levels of conversion to

the desired tertiary amine 48 (<10%), even after extended

reaction times, while displacement with dibenzylamine gave a

sample of 49 that was diﬃcult to purify. The requisite tertiary

amines 48 and 49 were, therefore, prepared through N-

alkylation of secondary amine 46, upon treatment with acetone

in the presence of NaB(OAc)₃H, and BnBr in the presence of

ⁱPr₂NEt, respectively (Scheme 6).

Figure 5. Approximate relative rates of oxidation of allylic amines 9−

12 in CD₂Cl₂.

It has previously been shown by us that the relative rates of

oxidation of 3-(N,N-dibenzylamino)cyclohex-1-ene 12, syn-3-

(N,N-dibenzylamino)-5-tert-butylcyclohex-1-ene 42, and anti-3-

(N,N-dibenzylamino)-5-tert-butylcyclohex-1-ene 43 are approx-

imately 1:1:2^4a(Figure 6). Molecular modeling implied that the

a

Scheme 6

Figure 6. Approximate relative rates of oxidation of allylic amines 12,

42, and 43 in CDCl₃.

ammonium ions derived from protonation of both 12 and syn-

42 adopted essentially identical conformations, as expected,

with the ammonium moiety occupying a pseudoequatorial site

within a half-chair conformation. In the corresponding

ammonium ion derived from anti-43, the minimum energy

conformation was one in which the ammonium moiety lay

midway between a pseudoaxial and pseudoequatorial position

of a half-chair. It was postulated that the latter represented a

better reactive geometry within the hydrogen-bonded transition

state for oleﬁnic oxidation, which, led to an increased rate of

reaction.^4aReduction of the steric bulk of the ammonium

moiety from RNHBn₂(in 33) or RNHⁱPrBn⁺(in 36) to

+

RNHMeBn⁺(in 39) to RNH₂Bn⁺(in the corresponding

ammonium species derived from 9) may allow more facile

distortion of the half-chair ground-state conformation of the

six-membered ring due to the reduced steric interactions that

would be suﬀered by placing the ammonium moiety closer to a

pseudoaxial orientation (i.e., less energy is required to achieve

the optimum reactive conformation). Reaction with the

ammonium moiety in a more favorable reactive geometry

would manifest itself in an increased rate of reaction. The very

large increase in rate on moving from tertiary amines 10−12 to

secondary amine 9 suggests that the secondary amine is better

able to form a hydrogen bond with the peracid: a closer

association between oxidant and substrate is likely to stabilize

the transition state for epoxidation, so increasing the rate of

reaction. The presence of two potential hydrogen-bond donor

sites for the ammonium ion derived from secondary amine 9

may also account for its increased reactivity. A combination of

a

Reagents and conditions: (i) KO^tBu, BuLi, 0 °C to rt, 18 h, then

(CH₂O)_n, 60 °C, 3 h; (ii) NBS, PPh₃, CH₂Cl₂, 0 °C to rt, 17 h; (iii)

BnNH₂, NaI, 50 °C, 20 h; (iv) HNMeBn, K₂CO₃, MeCN, 60 °C, 20 h;

(v) Na(OAc)₃BH, AcOH, acetone, rt, 24 h; (vi) BnBr, Pr₂NEt,

i

CH₂Cl₂, 40 °C, 2 h.

Oxidation of secondary amine 46 and tertiary amines 47−49

upon treatment with 5 equiv of Cl₃CCO₂H and 1.6 equiv of m-

CPBA was followed by transesteriﬁcation with K₂CO₃in

MeOH and gave the corresponding amino diols 50−53 in

≥90:10 dr (in each case, the minor diastereoisomer was the

corresponding 1,2-anti-2,3-anti-diastereoisomer). Chromatog-

raphy allowed isolation of 50−53 in modest to good yield (55−

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a

81%), and in ≥95:5 dr (Scheme 7). It is notable that, in all of

the cases examined here, the directing ability of the (in situ

Scheme 9

a

Scheme 7

a

Reagents and conditions: (i) Cl₃CCO₂H, m-CPBA, CH₂Cl₂, rt, 21 h;

(ii) K₂CO₃, MeOH, rt, 16 h.

formed) ammonium substituent is greater than that oﬀered by

the corresponding hydroxyl substituent: we have previously

reported that, under analogous conditions, dihydroxylation of

cyclohexene-derived homoallylic alcohol 44 gave a 76:24

mixture of the corresponding 1,2-anti-2,3-syn- and 1,2-anti-

2,3-anti-diastereoisomers of 3-hydroxymethylcyclohexane-1,2-

diol.^4c

a

Reagents and conditions: (i) TsOH, m-CPBA, CH₂Cl₂, rt, 21 h; (ii)

DBU, CH₂Cl₂, rt, 24 h; (iii) AcOH, 50 °C, 24 h; (iv) MsCl, Et₃N,

CH₂Cl₂, 0 °C, 1 h; (v) K₂CO₃, MeOH, rt, 16 h.

a

Scheme 10

The relative conﬁgurations within N-benzylamino diol 50

and N,N-dibenzylamino diol 53 have previously been

established unambiguously.^4cThe relative conﬁgurations within

51 and 52 were unambiguously assigned by chemical

correlation, through reductive alkylation of 50 with either

paraformaldehyde or acetone, respectively (Scheme 8).

a

Reagents and conditions: (i) H₂SO₄(3 M aq), 1,4-dioxane, 40 °C, 24

a

h.

Scheme 8

epoxidation of 46:47:48:49 were, therefore, determined to be

approximately 7:2:2:1 (Figure 7).

a

Reagents and conditions: (i) (CH₂O)_n, NaB(OAc)₃H, AcOH,

CH₂Cl₂, rt, 20 h; (ii) acetone, NaB(OAc)₃H, AcOH, rt, 24 h.

Next, authentic samples of the intermediate epoxides and

minor diastereoisomeric products of these oxidation reactions

were prepared. Ammonium-directed oxidation of 47 and 48

employing TsOH, followed by treatment of the crude reaction

mixtures with DBU, gave syn-epoxides 56 (>99:1 dr) and 57

(96:4 dr). A three-step epoxide inversion strategy gave anti-

epoxides 62 and 63 in >99:1 dr in both cases (Scheme 9).¹⁹

Ring-opening of anti-epoxides 62 and 63 upon treatment with

3 M aq H₂SO₄proceeded to give a mixture of diastereoisomers

Figure 7. Approximate relative rates of oxidation of homoallylic

amines 46−49 in CDCl₃.

In comparison to the parent N,N-dibenzyl-substituted allylic

amine 12, the rates of oxidation of all homoallylic amines 46−

49 are faster. This is in accordance with the oleﬁn being more

nucleophilic, as the electron-withdrawing ammonium group is

now located further from it. Furthermore, N-benzyl-N-methyl-

substituted 47, N-benzyl-N-isopropyl-substituted 48, and N,N-

dibenzyl-substituted 49 of the 3-aminomethylcyclohex-1-ene

(homoallylic) series showed similar rates of reaction, which is

consistent with the assertion that the incorporation of a

methylene group between the carbocyclic ring and the amino

group confers greater conformational ﬂexibility to theses

substrates: in each of these cases, the ammonium moiety may

be more able to adopt a favorable geometry to promote

eﬃcient hydrogen-bond-directed oxidation, which is manifest in

similar rates of reaction. It is also noteworthy that oxidation of

N-benzyl-substituted secondary amine 46 is again somewhat

faster than its tertiary amine counterparts 47−49.

20,21

i

(R = Me, 51:64, 31:69 dr; R = Pr, 52:65, 23:77 dr).

The

major diastereoisomers 64 and 65 were isolated in 36% and

48% yield after chromatography, and in >99:1 dr and 95:5 dr,

respectively. The relative conﬁgurations within 64 and 65 were

assigned on the basis of ¹H NMR ³J coupling constant analyses

(Scheme 10).

The oxidation reactions of homoallylic amines 46−49 in

1

CDCl₃solution were next followed by H NMR spectroscopy,

and from the data generated, application of the integrated form

of the second-order rate law gave the second-order rate

constants of k = 9.5 × 10⁻²mol⁻¹dm³s⁻¹(46), k = 2.2 × 10⁻²

mol⁻¹dm³s⁻¹(47), k = 2.1 × 10⁻²mol⁻¹dm³s⁻¹(48), and k

= 1.3 × 10⁻²mol⁻¹dm³s⁻¹(49). The relative rates of

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a

Oxidation of N-Substituted 3-Aminocyclopent-1-

enes. The eﬀect of varying the size of the carbocyclic ring

on this reaction was next explored. N-Substituted 3-amino-

cyclopent-1-enes 68−71 were prepared from 67 by bromide

displacement with the requisite amine (Scheme 11).

Scheme 13

a

Scheme 11

a

i

Reagents and conditions: (i) MeI, Pr₂NEt, CH₂Cl₂, rt, 20 h; (ii)

i

acetone, NaB(OAc)₃H, AcOH, rt, 24 h; (iii) BnBr, Pr₂NEt, CH₂Cl₂,

rt, 20 h.

trichloroacetate esters 76−79 were prepared upon treatment of

syn-epoxides 72−75 with Cl₃CCO₂H (although it was not

possible to isolate pure samples of 76−79 due to the lability of

the trichloroacetate ester moiety), thus unambiguously

conﬁrming that 76−79 arise from in situ ring-opening of

72−75 and, therefore, that the oxidation reaction is completely

diastereoselective in each case. As with the analogous oxidation

of 3-hydroxycyclopentene (which has been reported to proceed

with very high levels of syn diastereoselectivity),^1,24this

stereochemical outcome is consistent with the reaction being

under hydrogen-bond control,²⁵although several examples of

syn-selective osmylation and epoxidation reactions of 3-

substituted cyclopentenes, which proceed in the absence of

any obvious associative interactions (e.g., hydrogen-bonding) in

the transition state, have been reported.²⁶In these cases, it has

been proposed that the diastereoselectivity results from attack

on the syn face being favored in order to minimize torsional

strain in the transition state.²⁷

a

Reagents and conditions: (i) NBS, AIBN, CCl₄, reﬂux, 1 h; (ii)

HNRBn, rt, 1.5 h.

We have previously demonstrated that the epoxidation of

cyclopentene-derived allylic amine 71 using 5 equiv of

Cl₃CCO₂H and 1.05 equiv of m-CPBA is complete within

3.5 h at rt^4cand (unlike its cyclohexene-derived allylic amine

counterpart 12) the corresponding epoxide was isolated rather

than ring-opened product(s). The faster rate of ring-opening of

cyclohexene oxide versus cyclopentene oxide by a range of

nucleophiles²²has previously been associated with the relief of

torsional strain that occurs in the former case.²³On the basis of

these previous observations, it was anticipated that the rate of

oxidation of each member of the cyclopentene-derived series of

allylic amines 68−71 would be greater than that of their

counterpart within the cyclohexene-derived series of allylic

amines 9−12 and would result in formation of the

corresponding syn-epoxide as the major product (rather than

trichloroacetate esters resulting from ring-opening). Indeed,

oxidation of 68−71 with 5 equiv of Cl₃CCO₂H and 1.05 equiv

of m-CPBA gave, in all cases, a mixture comprising only the

corresponding syn-epoxides 72−75 (>99:1 dr) as the major

products (≥88%) and the corresponding trichloroacetate esters

76−79 (>99:1 dr) as the minor products (≤12%). Chromato-

graphic puriﬁcation allowed isolation of syn-epoxides 72−75 in

46−99% yield, and in >99:1 dr in each case (Scheme 12). The

The rates of oxidation of allylic amines 68−71 were next

examined, and the second-order rate constants were

determined as k = 3.7 × 10⁻²mol⁻¹dm³s⁻¹(68), k = 2.6 ×

10⁻²mol⁻¹dm³s⁻¹(69), k = 1.1 × 10⁻²mol⁻¹dm³s⁻¹(70),

and k = 6.1 × 10⁻³mol⁻¹dm³s⁻¹(71). Thus, the relative rates

of oxidation of 68:69:70:71 were determined to be

approximately 6:4:2:1 (Figure 8).

a

Scheme 12

Figure 8. Approximate relative rates of oxidation of allylic amines 68−

71 in CDCl₃.

These data reveal a decrease in epoxidation rate as the series

i

68 (R = H), 69 (R = Me), 70 (R = Pr), and 71 (R = Bn) is

traversed,²⁸so following the same trend as that observed for the

cyclohexene-derived allylic series 9−12 and homoallylic series

46−49. As initially expected, the rates of oxidation of the

cyclopentene-derived tertiary amines 69−71 are greater than

those of their cyclohexene-derived allylic amine counterparts

10−12. This is consistent with the previously reported greater

rate of peracid epoxidation of cyclopentene as compared with

that of cyclohexene,²⁹but may also be indicative that, in the

absence of the exceptional and unique conformational bias

imparted by the six-membered ring in 10−12, distortion of the

ammonium moiety into a more optimal geometry for

epoxidation is possible in all of these cyclopentene-derived

systems, resulting in much similar rates of reaction. In contrast,

however, the rates of oxidation of the cyclopentene-derived

a

Reagents and conditions: (i) Cl₃CCO₂H, m-CPBA, CH₂Cl₂, rt, 3.5 h.

relative syn conﬁgurations within 72−74 were unambiguously

established by chemical correlation to 75, whose relative syn

conﬁguration has previously been established by single-crystal

X-ray diﬀraction analysis.^4cTreatment of 72 with BnBr/ⁱPr₂NEt

gave 75 in 70% yield, while N-alkylation of 72 upon treatment

with MeI/ⁱPr₂NEt or acetone/NaB(OAc)₃H gave 73 and 74,

respectively (Scheme 13). In addition, authentic samples of

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a

tertiary amines 69−71 are of a similar magnitude to those of

their cyclohexene-derived homoallylic amine counterparts 46−

49. In the latter case, the electron-withdrawing ammonium

group is located further from the oleﬁn, which would be

expected to render the oleﬁn more nucleophilic, hence

compensating for the expected inherent decrease in reactivity

of the oleﬁn toward epoxidation in the cyclohexene-derived

homoallylic series compared to the cyclopentene-derived allylic

series.

Scheme 15

Oxidation of N-Substituted 3-Aminocyclohept-1-

enes. Attention next turned to oxidation of the seven-

membered ring system. A range of N-substituted 3-amino-

cyclohept-1-enes 81−84 were prepared upon bromide displace-

ment within 80 by the requisite amines to give 3-amino-

cyclohept-1-enes 81−84 in 64−96% yield after chromato-

graphic puriﬁcation (Scheme 14).

a

Reagents and conditions: (i) Cl₃CCO₂H, m-CPBA (2.5 equiv),

CH₂Cl₂, rt, 20 min; (ii) Cl₃CCO₂H, m-CPBA (1.05 equiv), CH₂Cl₂, rt,

3.5 h; (iii) Cl₃CCO₂H, m-CPBA (1.6 equiv), CH₂Cl₂, rt, 7 h.

a

Scheme 14

a

Scheme 16

a

i

Reagents and conditions: (i) HNRBn, K₂CO₃, THF, 50 °C, 16 h.

Reagents and conditions: (i) MeI, Pr₂NEt, CH₂Cl₂, rt, 20 h; (ii)

i

acetone, NaB(OAc)₃H, AcOH, rt, 24 h; (iii) BnBr, Pr₂NEt, CH₂Cl₂,

rt, 20 h.

Oxidation of N,N-dibenzyl-substituted allylic amine 84 under

our previously reported conditions (treatment with 5 equiv of

Cl₃CCO₂H and 1.05 equiv of m-CPBA for 3.5 h)^4cresulted in

88% conversion to a 94:6 mixture of the known epoxides anti-

88 and syn-92,^4cand under the same conditions, oxidation of

N-benzyl-N-isopropyl-substituted allylic amine 83 gave >95%

conversion to a 93:7 mixture of anti-epoxide 87 and syn-

epoxide 91, respectively. However, the analogous oxidation of

N-benzyl-N-methyl-substituted allylic amine 82 gave only 66%

conversion to a 75:25 mixture of anti-epoxide 86 and syn-

epoxide 90, which suggested, somewhat surprisingly, that the

rate of oxidation of 82 is slower than those of 83 and 84. The

oxidation reaction of 82 could be driven to >95% conversion

within 7 h by increasing the amount of m-CPBA used to 1.6

equiv: a 75:25 mixture of anti-epoxide 86 and syn-epoxide 90

was thus produced, with only a small amount (∼5%) of

products resulting from ring-opening being present. Finally,

oxidation of secondary amine 81 was investigated: using 2.5

equiv of m-CPBA in the presence of 5 equiv of Cl₃CCO₂H

(optimized conditions) aﬀorded a 15:85 mixture of anti-

epoxide 85 and syn-epoxide 89 after 20 min. This result

indicates a hitherto unprecedented reversal in the sense of

epoxidation diastereofacial selectivity between secondary amine

81 and its tertiary amine counterparts 82−84. Chromato-

graphic puriﬁcation gave a 15:85 mixture of 85 and 89 in 83%

combined yield, while exhaustive puriﬁcation allowed isolation

of a diastereoisomerically pure sample of 85 in 51% yield

(Scheme 15).

eoisomeric products resulting from oxidation of the corre-

sponding tertiary allylic amines 82−84. The relative syn

conﬁgurations within epoxides 89−91 could, therefore, be

unambiguously assigned from the known relative syn

conﬁguration within epoxide 92.^4cIn addition, N-benzylation

of the 15:85 mixture of 85:89 upon treatment with BnBr gave a

15:85 mixture of 88:92, thus unambiguously conﬁrming the

relative anti conﬁguration within 88. These analyses also

allowed the relative conﬁgurations within anti-epoxides 86 and

87 to be unambiguously assigned.

Next, the rates of oxidation of allylic amines 81−84 were

examined, and the second-order rate constants were

determined to be k = 1.8 × 10⁻²mol⁻¹dm³s⁻¹(81), k =

7.0 × 10⁻⁴mol⁻¹dm³s⁻¹(82), k = 1.4 × 10⁻³mol⁻¹dm³s⁻¹

(83), and k = 2.2 × 10⁻³mol⁻¹dm³s⁻¹(84). From these data,

the approximate relative rates of oxidation of 81:82:83:84 were

determined to be 26:1:2:3, with the syn:anti reaction

diastereoselectivities being 85:15 (81), 25:75 (82), 7:93 (83),

and 6:96 (84), respectively. Although secondary amine 81

undergoes the most rapid epoxidation in the cycloheptene-

derived series of allylic amines, the observed rate order (and,

indeed, reaction diastereoselectivity) for tertiary amines 82−84

does not follow the pattern that would be expected from the

relative rate order in the cyclohexene-derived allylic amine

series 9−12 and homoallylic amine series 46−49, and

cyclopentene-derived series 68−71 (Figure 9).

The conﬁgurations within syn-epoxides 89−92 were

established by chemical correlation: N-alkylation of syn-epoxide

89 (the major product resulting from the oxidation of N-benzyl-

substituted allylic amine 81) upon treatment with MeI/ⁱPr₂NEt,

acetone/NaB(OAc)₃H, and BnBr/ⁱPr₂NEt gave, in each case, a

sample of the corresponding syn-epoxides 90−92 (Scheme 16),

which were spectroscopically identical to the minor diaster-

We have previously ascribed the high levels of anti

diastereoselectivity in the oxidation of N,N-dibenzyl-substituted

84 to the ability of the amino group to play two distinct roles:

the sterically demanding substituents on nitrogen may enforce a

well-deﬁned chair-type conformation on the otherwise

conformationally labile cycloheptene ring,³⁰such that hydro-

gen-bonding by the in situ formed ammonium moiety results in

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ammonium substituent to direct the stereochemical course of

the epoxidation reaction is either comparable or superior to

that of the analogous hydroxyl substituent. (iii) The relative

rates of epoxidation of the allylic amines are generally all lower

than that for the corresponding homoallylic amine (for

example, 12, 71, and 84 compared to 49). This suggests that

the electron-withdrawing eﬀect of the ammonium moiety is a

key feature here. As previously noted, location of the electron-

withdrawing ammonium moiety further from the oleﬁn (i.e., in

the homoallylic position rather than the allylic position) likely

renders it more nucleophilic (regardless of the size of the ring

system), and as a result, 49 reacts fastest within this series of

cycloalkenyl amines. (iv) The increased rate of reaction for the

cyclopentene-derived allylic amines versus their cyclohexene-

derived allylic amine counterparts parallels that noted for the

parent cycloalkenes (cyclopentene and cyclohexene) in a range

of reactions;³²this observation has often been attributed to

relief of ring strain upon reaction in the former case. (iv) High

levels of syn diastereoselectivity are observed in all cases with

the exception of the cycloheptene-derived allylic amines 81−

84, which give either the corresponding syn- or anti-epoxide as

the major diastereoisomer, depending on the nature of the

amino substituent. (v) Much slower rates of ring-opening of the

intermediate epoxides are observed in cyclopentene-derived

and cycloheptene-derived allylic amines as compared with their

cyclohexene-derived allylic and homoallylic amine counterparts,

allowing for isolation of these intermediates in both of the

former cases. Using the information garnered from these

investigations, further studies of this ammonium-directed

epoxidation reaction to both enhance our mechanistic under-

standing of the process and further exploit its synthetic utility

are underway within our laboratory.

Figure 9. Approximate relative rates of oxidation of allylic amines 81−

84 in CDCl₃, and syn:anti reaction diastereoselectivities.

eﬃcient epoxidation on the (least hindered) anti face.^4cWith a

reduction in steric bulk of the amino group, the cycloheptene

ring presumably becomes less well conformationally deﬁned,

and reaction through multiple conformations can occur

(potentially via both ammonium-directed and nondirected

pathways) to give rise to a mixture of products. The situation

then becomes comparable to the epoxidation of 3-hydrox-

ycycloheptene, which has been reported to proceed with only

low levels of syn diastereoselectivity (∼2:1 dr) upon reaction

with a range of peracids.³¹However, if the hydrogen-bonding

ability of the ammonium species derived from secondary amine

81 is superior to that of the ammonium species derived from its

tertiary amine counterparts 82−84 (as well as that of the

hydroxyl group), then reaction syn to the amino group through

one favorable conformation would result in a highly

diastereoselective reaction.

CONCLUSION

■

The ammonium-directed oleﬁnic epoxidations of a range of

diﬀerentially N-substituted cyclic allylic and homoallylic amines

(derived from cyclopentene, cyclohexene, and cycloheptene)

have been investigated, and the reaction kinetics have been

analyzed. The results of these studies suggest that both the ring

size and the identity of the substituents on nitrogen are

important in determining both the overall rate and the

stereochemical outcome of the epoxidation reaction. Compar-

ison of all of the relative rates (and diastereoselectivities) of the

ammonium-directed epoxidation reactions (Figure 10) allows

the following conclusions to be drawn: (i) Secondary amines or

tertiary amines with nonsterically demanding substituents on

nitrogen are generally superior to tertiary amines with sterically

demanding substituents on nitrogen in their ability to promote

the oxidation reaction. (ii) The ability of the (in situ formed)

EXPERIMENTAL SECTION

■

General Experimental Details. m-CPBA was supplied as a 70−

77% slurry in water and titrated according to the procedure of Swern³³

immediately before use. Water was puriﬁed by an Elix UV-10 system.

Organic solvents were used as supplied (analytical or HPLC grade)

without prior puriﬁcation. Thin-layer chromatography was performed

on aluminum plates coated with 60 F₂₅₄silica. Plates were visualized

using UV light (254 nm), iodine, 1% aqueous KMnO₄, or 10%

ethanolic phosphomolybdic acid. Flash column chromatography was

performed either on Kieselgel 60 silica on a glass column or on an

automated ﬂash column chromatography platform.

Melting points are uncorrected. IR spectra were recorded as either a

thin ﬁlm on NaCl plates (ﬁlm) or a KBr disk (KBr), as stated. Selected

characteristic peaks are reported in cm⁻¹. NMR spectra were recorded

in the deuterated solvent stated. The ﬁeld was locked by external

1

referencing to the relevant deuteron resonance. H−¹H COSY and

¹H−¹³C HMQC analyses were used to establish atom connectivity.

Accurate mass measurements were run on a MicroTOF instrument

internally calibrated with polyalanine.

(RS)-3-Bromocyclohex-1-ene 8. Benzoyl peroxide (70% w/w,

842 mg, 2.43 mmol) and NBS (43.8 g, 246 mmol) were added

sequentially to a stirred solution of 7 (40.0 g, 490 mol) in CCl₄(200

mL). The resultant suspension was heated at 90 °C for 1.5 h, then

allowed to cool to rt before being ﬁltered through Celite (eluent

CH₂Cl₂). The ﬁltrate was washed with 0.1 M aq NaHCO₃(100 mL)

and brine (100 mL), dried (MgSO₄), and concentrated in vacuo.

Puriﬁcation via reduced pressure distillation gave 8 as a yellow oil

(27.6 g, 70%).^4abp 50−52 °C (14 mbar); δ_H(400 MHz, CDCl₃)

1.65−2.28 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 4.83−4.89 (1H, m,

C(3)H), 5.80−5.86 (1H, m, C(1)H), 5.89−5.96 (1H, m, C(2)H).

(RS)-3-(N-Benzylamino)cyclohex-1-ene 9. A stirred mixture of

8 (0.20 mL, 1.62 mmol), benzylamine (0.44 mL, 4.06 mmol), and

K₂CO₃(268 mg, 1.94 mmol) in THF (2 mL) was heated at 50 °C for

Figure 10. Approximate relative rates of epoxidation of allylic and

homoallylic amines (m-CPBA, Cl₃CCO₂H, CH₂Cl₂).

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16 h. The resultant mixture was diluted with H₂O (20 mL) and

CH₂Cl₂(20 mL), and the organic layer was separated and washed with

satd aq NaHCO₃(20 mL) and brine (20 mL), dried (Na₂SO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 30 → 50% Et₂O in 30−40 °C petrol) gave 9 as a

pale yellow oil (240 mg, 79%).^4aδ_H(400 MHz, CDCl₃) 1.35−2.06

(6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 3.21−3.29 (1H, m, C(3)H),

3.79−3.89 (2H, m, NCH₂Ph), 5.61−5.82 (2H, m, C(1)H, C(2)H),

7.21−7.49 (5H, m, Ph).

h, then concentrated in vacuo. H₂O (50 mL) was added, and the

residue was extracted with CH₂Cl₂(4 × 50 mL). The combined

organic layers were washed with brine (100 mL), dried (Na₂SO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

on neutral alumina (gradient elution, 0 → 10% MeOH in CH₂Cl₂)

gave 17 as a white solid (1.11 g, 94%, 95:5 dr).^4amp 150−151 °C; δ_H

(400 MHz, MeOH-d₄) 1.45−1.90 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂),

3.25−3.39 (1H, m, C(3)H), 3.83−4.04 (2H, m, C(1)H, C(2)H),

4.05−4.15 (2H, m, NCH₂Ph), 7.31−7.42 (3H, m, Ph), 7.44−7.51

(2H, m, Ph).

(RS)-3-(N-Benzyl-N-methylamino)cyclohex-1-ene 10. A

stirred mixture of 8 (0.20 mL, 1.62 mmol), N-benzyl-N-methylamine

(0.32 mL, 4.06 mmol), and K₂CO₃(268 mg, 1.94 mmol) in THF (2

mL) was heated at 50 °C for 16 h. The resultant mixture was diluted

with H₂O (20 mL) and CH₂Cl₂(20 mL), and the organic layer was

separated and washed with satd aq NaHCO₃(20 mL) and brine (20

mL), dried (Na₂SO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 2 → 20% Et₂O in 30−40

°C petrol) gave 10 as a pale yellow oil (270 mg, 83%).³⁴δ_H(400

MHz, CDCl₃) 1.48−2.04 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 2.23

(3H, s, NMe), 3.20−3.41 (1H, m, C(3)H), 3.47 (1H, d, J 13.3,

NCH_AH_BPh), 3.67 (1H, d, J 13.3, NCH_AH_BPh), 5.70−5.77 (1H, m,

C(1)H), 5.81−5.88 (1H, m, C(2)H), 7.21−7.37 (5H, m, Ph).

(RS)-3-(N-Benzyl-N-isopropylamino)cyclohex-1-ene 11. A

stirred mixture of 8 (0.20 mL, 1.62 mmol), N-benzyl-N-isopropyl-

amine (0.40 mL, 4.06 mmol), and K₂CO₃(268 mg, 1.94 mmol) in

THF (2 mL) was heated at 50 °C for 16 h. The resultant mixture was

diluted with H₂O (20 mL) and CH₂Cl₂(20 mL), and the organic layer

was separated and washed with satd aq NaHCO₃(20 mL) and brine

(20 mL), dried (Na₂SO₄), and concentrated in vacuo. Puriﬁcation via

ﬂash column chromatography (gradient elution, 2 → 10% Et₂O in 30−

40 °C petrol) gave 11 as a pale yellow oil (243 mg, 65%). ν_max(ﬁlm)

3083, 3061, 2960 (C−H), 1493 (CC); δ_H(400 MHz, CDCl₃) 1.09

(3H, d, J 6.7, NCHMe_A), 1.11 (3H, d, J 6.7, NCHMe_B), 1.53−1.61

(2H, m, C(4)H_A, C(5)H_A), 1.81−1.91 (2H, m, C(4)H_B, C(5)H_B),

1.98−2.02 (2H, m, C(6)H₂), 3.04 (1H, septet, J 6.7, NCHMe₂), 3.49−

3.55 (1H, m, C(3)H), 3.75 (2H, AB system, J 15.7, NCH₂Ph), 5.73−

5.75 (1H, m, C(2)H), 5.80−5.83 (1H, m, C(1)H), 7.22−7.26 (1H, m,

Ph), 7.33 (2H, t, J 7.4, Ph), 7.43 (2H, d, J 7.4, Ph); δ_C(100 MHz,

CDCl₃) 20.6, 21.3 (NCHMe₂), 22.3 (C(5)), 25.2 (C(6)), 28.2 (C(4)),

48.8 (NCHMe₂), 49.9 (NCH₂Ph), 53.8 (C(3)), 126.2 (p-Ph), 127.9,

128.0 (o,m-Ph), 129.4 (C(1)), 132.6 (C(2)), 143.0 (i-Ph); m/z (ESI⁺)

230 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₆H₂₄N⁺([M + H]⁺) requires

230.1903; found 230.1900.

(RS)-3-(N,N-Dibenzylamino)cyclohex-1-ene 12. A stirred mix-

ture of 8 (0.20 mL, 1.62 mmol), dibenzylamine (0.78 mL, 4.06 mmol),

and K₂CO₃(268 mg, 1.94 mmol) in THF (2 mL) was heated at 50 °C

for 16 h. The resultant mixture was diluted with H₂O (20 mL) and

CH₂Cl₂(20 mL), and the organic layer was separated and washed with

satd aq NaHCO₃(20 mL) and brine (20 mL), dried (Na₂SO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 0 → 2% Et₂O in 30−40 °C petrol) gave 12 as a pale

yellow oil (359 mg, 80%).^4aδ_H(400 MHz, CDCl₃) 1.44−1.63 (2H, m,

C(5)H₂), 1.81−2.08 (4H, m, C(4)H₂, C(6)H₂), 3.39 (1H, app br s,

C(3)H), 3.59 (2H, d, J 13.9, N(CH_AH_BPh)₂), 3.79 (2H, d, J 13.9,

N(CH_AH_BPh)₂), ), 5.75−5.88 (2H, m, C(1)H, C(2)H), 7.21−7.49

(10H, m, Ph).

(RS,RS,RS)-3-(N-Benzylamino)cyclohexane-1,2-diol 17. Step

1: Cl₃CCO₂H (4.37 g, 26.7 mmol) was added to a solution of 9

(1.01 g, 5.39 mmol) in CH₂Cl₂(14.8 mL), and the resultant solution

was stirred at rt for 5 min. m-CPBA (77%, 1.96 g, 8.62 mmol) was

added, and the mixture was stirred at rt for 21 h. The mixture was

quenched with satd aq Na₂SO₃until starch-iodide paper indicated that

m-CPBA was not present, and basiﬁed to pH 9 by the addition of 0.1

M aq NaHCO₃. The aqueous layer was extracted with CH₂Cl₂(3 × 30

mL), and the combined organic layers were washed with 0.1 M aq

NaHCO₃(4 × 50 mL) and brine (50 mL), dried (Na₂SO₄), and

concentrated in vacuo to give 13 as a yellow oil that was used without

puriﬁcation.

(RS,RS,RS)-3-(N-Benzyl-N-methylamino)cyclohexane-1,2-diol

18. Step 1: Cl₃CCO₂H (1.62 g, 9.93 mmol) was added to a solution of

10 (400 mg, 1.99 mmol) in CH₂Cl₂(4 mL), and the resultant solution

was stirred at rt for 5 min. m-CPBA (69%, 796 mg, 3.18 mmol) was

added, and the mixture was stirred at rt for 21 h. The mixture was

quenched with satd aq Na₂SO₃until starch-iodide paper indicated that

m-CPBA was not present, and basiﬁed to pH 9 by the addition of 0.1

M aq NaHCO₃. The aqueous layer was extracted with CH₂Cl₂(3 × 50

mL), and the combined organic layers were washed with 0.1 M aq

NaHCO₃(4 × 50 mL) and brine (50 mL), dried (Na₂SO₄), and

concentrated in vacuo to give 14 as a pale yellow solid that was used

without puriﬁcation. Recrystallization of an aliquot from 40−60 °C

petrol/Et₂O (15:1) gave an analytical sample. C₁₆H₂₀Cl₃NO₃requires

C, 50.5; H, 5.3; N, 3.7%; found C, 50.4; H, 5.4; N, 3.6%; mp 92−95

°C; ν_max(KBr) 3395 (O−H), 3086, 3063, 3029, 2946 (C−H), 1764

(CO); δ_H(400 MHz, CDCl₃) 1.51−2.00 (6H, m, C(4)H₂, C(5)H₂,

C(6)H₂), 2.24 (3H, s, NMe), 2.61−2.73 (1H, m, C(3)H), 3.50−3.80

(1H, br s, OH) overlapping 3.62 (1H, d, J 13.4, NCH_AH_BPh) and 3.70

(1H, d, J 13.4, NCH_AH_BPh), 4.11−4.16 (1H, m, C(2)H), 5.31−5.35

(1H, m, C(1)H), 7.24−7.37 (5H, m, Ph); δ_C(100 MHz, CDCl₃) 19.1,

23.7, 23.8 (C(4), C(5), C(6)), 38.5 (NMe), 58.2 (NCH₂Ph), 60.4

(C(3)), 65.4 (C(2)), 77.2 (C(1)), 90.1 (CCl₃), 127.2 (p-Ph), 128.4,

129.0 (o,m-Ph), 138.5 (i-Ph), 160.9 (OCOCCl₃); m/z (ESI⁺) 380 ([M

+

+ H]⁺, 100%); HRMS (ESI⁺) C₁₆H₂₁Cl₃NO₃([M + H]⁺) requires

380.0582; found 380.0571.

Step 2: K₂CO₃(2.75 g, 19.9 mmol) was added to a solution of 14 in

MeOH (7 mL), and the resultant suspension was stirred at rt for 16 h,

then concentrated in vacuo. H₂O (50 mL) was added, and the residue

was extracted with CH₂Cl₂(4 × 50 mL). The combined organic layers

were washed with brine (50 mL), dried (Na₂SO₄), and concentrated in

vacuo. Puriﬁcation via ﬂash column chromatography (gradient elution,

6 → 60% MeOH in EtOAc) gave 18 as a pale yellow oil (316 mg,

67%, >99:1 dr). C₁₄H₂₁NO₂requires C, 71.5; H, 9.0; N, 5.95%; found

C, 71.6; H, 9.0; N, 5.9%; ν_max(ﬁlm) 3394 (O−H), 2938 (C−H); δ_H

(400 MHz, CDCl₃) 1.51−1.92 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂),

2.20 (3H, s, NMe), 2.72 (1H, ddd, J 9.9, 4.7, 3.4, C(3)H), 3.60 (2H,

AB system, J 13.3, NCH₂Ph), 3.95 (1H, app t, J 3.4, C(2)H), 4.12−

4.18 (1H, m, C(1)H), 7.23−7.37 (5H, m, Ph); δ_C(100 MHz, CDCl₃)

19.0, 24.2, 27.5 (C(4), C(5), C(6)), 38.5 (NMe), 58.5 (NCH₂Ph), 60.6

(C(3)), 69.2, 69.4 (C(1), C(2)), 127.1 (p-Ph), 128.4, 128.9 (o,m-Ph),

139.2 (i-Ph); m/z (ESI⁺) 236 ([M + H]⁺, 100%); HRMS (ESI⁺)

+

C₁₄H₂₂NO₂([M + H]⁺) requires 236.1645; found 236.1636.

(RS,RS,RS)-3-(N-Benzyl-N-isopropylamino)cyclohexane-1,2-

diol 19. From 11, Step 1: Cl₃CCO₂H (817 mg, 5.00 mmol) was

added to a solution of 11 (230 mg, 1.00 mmol) in CH₂Cl₂(3.5 mL),

and the resultant solution was stirred at rt for 5 min. m-CPBA (70%,

394 mg, 1.60 mmol) was added, and the mixture was stirred at rt for

21 h. The mixture was quenched with satd aq Na₂SO₃until starch-

iodide paper indicated that m-CPBA was not present, and basiﬁed to

pH 9 by the addition of 0.1 M aq NaHCO₃. The aqueous layer was

extracted with CH₂Cl₂(3 × 50 mL), and the combined organic layers

were washed with 0.1 M aq NaHCO₃(4 × 50 mL) and brine (50 mL),

dried (Na₂SO₄), and concentrated in vacuo to give 15 as a pale yellow

oil that was used without puriﬁcation.

Step 2: K₂CO₃(1.38 g, 10.0 mmol) was added to a solution of 15 in

MeOH (7 mL), and the resultant suspension was stirred at rt for 16 h,

then concentrated in vacuo. H₂O (50 mL) was added, and the residue

was extracted with CH₂Cl₂(4 × 50 mL). The combined organic layers

were washed with brine (50 mL), dried (Na₂SO₄), and concentrated in

vacuo. Puriﬁcation via ﬂash column chromatography (gradient elution,

Step 2: K₂CO₃(7.43 g, 53.9 mmol) was added to a solution of 13 in

MeOH (100 mL), and the resultant suspension was stirred at rt for 16

7251

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Article

50 → 100% EtOAc in 30−40 °C petrol) gave 19 as a pale yellow oil

(185 mg, 70%, >99:1 dr). ν_max(ﬁlm) 3416 (O−H), 3084, 3061, 2962

(C−H); δ_H(400 MHz, CDCl₃) 1.07 (3H, d, J 6.7, NCHMe_A), 1.09

(3H, d, J 6.7, NCHMe_B), 1.45−1.50 (1H, m, C(6)H_A), 1.54−1.70

(4H, m, C(4)H₂, C(5)H₂), 1.65−1.77 (1H, m, C(6)H_B), 3.05−3.10

(1H, m, C(3)H), 3.18 (1H, septet, J 6.7, NCHMe₂), 3.58−3.60 (1H,

m, C(2)H), 3.62 (1H, d, J 15.4, NCH_AH_BPh), 3.86 (1H, d, J 15.4,

NCH_AH_BPh), 3.90−3.99 (1H, m, C(1)H), 7.23−7.33 (5H, m, Ph); δ_C

(100 MHz, CDCl₃) 18.0 (NCHMe₂), 20.0, 25.4, 28.2 (C(4), C(5),

C(6)), 48.7 (NCHMe₂), 50.7 (NCH₂Ph), 57.2 (C(3)), 70.3 (C(1)),

71.5 (C(2)), 126.7 (p-Ph), 127.5, 128.5 (o,m-Ph), 142.4 (i-Ph); m/z

128.8, 129.9 (Ar, o,m-Ph), 133.9, 138.7, 144.8 (Ar, i-Ph); m/z (ESI⁺)

390 ([M + H]⁺, 100%); HRMS (ESI⁺) C₂₁H₂₇NO₄S⁺([M + H]⁺)

requires 390.1734; found 390.1730.

Step 2: DBU (2.67 mL, 17.9 mmol) was added to a stirred solution

of 21 (5.22 g) in CH₂Cl₂(25 mL), and the resultant mixture was

stirred at rt for 24 h. The mixture was diluted with H₂O (100 mL), and

the aqueous layer was extracted with CH₂Cl₂(3 × 175 mL). The

combined organic layers were washed sequentially with H₂O (3 × 200

mL) and brine (200 mL), dried (MgSO₄), and concentrated in vacuo.

Filtration through a pad of silica (eluent EtOAc/40−60 °C petrol, 7:3)

gave 23 as a pale yellow oil (2.56 g, 79%, >99:1 dr). C₁₄H₁₉NO

requires C, 77.4; H, 8.8; N, 6.45%; found C, 77.5; H, 8.8; N, 6.4%; ν_max

(ﬁlm) 3086, 3064, 3026, 2985, 2938, 2861, 2784 (C−H); δ_H(400

MHz, CDCl₃) 1.17−1.32, 1.46−1.92 (6H, m, C(4)H₂, C(5)H₂, C(6)

H₂), 2.36 (3H, s, NMe), 3.00 (1H, ddd, J 10.9, 4.6, 1.3, C(3)H), 3.13

(1H, app t, J 4.3, C(1)H), 3.32 (1H, app d, J 4.6, C(2)H), 3.66 (1H, d,

J 13.4, NCH_AH_BPh), 3.80 (1H, d, J 13.4, NCH_AH_BPh), 7.20−7.40

(5H, m, Ph); δ_C(100 MHz, CDCl₃) 18.9, 21.5, 23.1 (C(4), C(5),

C(6)), 38.9 (NMe), 51.7 (C(1)), 54.6 (C(2)), 58.5 (NCH₂Ph), 60.5

(C(3)), 126.8 (p-Ph), 128.2, 128.8 (o,m-Ph), 140.0 (i-Ph); m/z (ESI⁺)

218 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₄H₂₀NO⁺([M + H]⁺)

requires 218.1539; found 218.1537.

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzyl-N-isopropylamino)-

cyclohexane 24. Step 1: Anhydrous TsOH (675 mg, 3.92 mmol)

was added to a stirred solution of 11 (300 mg, 1.31 mmol) in CH₂Cl₂

(2.6 mL), and the resultant solution was stirred at rt for 5 min. m-

CPBA (77%, 437 mg, 1.96 mmol) was added, and the mixture was

stirred at rt for 21 h. The reaction mixture was quenched with satd aq

Na₂SO₃until starch-iodide paper indicated that m-CPBA was not

present, and then basiﬁed to pH 9 by the addition of 0.1 M aq

NaHCO₃. The resultant mixture was extracted with CH₂Cl₂(3 × 15

mL), and the combined organic extracts were washed sequentially with

0.1 M aq NaHCO₃(3 × 15 mL) and brine (15 mL), dried (MgSO₄),

and concentrated in vacuo to give 22 as a pale yellow oil that was used

without puriﬁcation.

Step 2: DBU (0.24 mL, 1.6 mmol) was added to a stirred solution

of 22 in CH₂Cl₂(2.2 mL), and the resultant mixture was stirred at rt

for 24 h. The mixture was diluted with H₂O (100 mL), and the

aqueous layer was extracted with CH₂Cl₂(3 × 10 mL). The combined

organic layers were washed sequentially with H₂O (3 × 20 mL) and

brine (20 mL), dried (MgSO₄), and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (eluent 30−40 °C

petrol/Et₂O, 15:1) gave 24 as a colorless oil (284 mg, 88%, >99:1 dr).

ν_max(ﬁlm) 2961 (C−H), 1494, 1453 (CC); δ_H(400 MHz, CDCl₃)

1.09 (3H, d, J 6.7, NCHMe_A), 1.10 (3H, d, J 6.7, NCHMe_B), 1.10−

1.84 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 2.98−3.05 (1H, m, C(3)H),

3.09 (1H, app t, J 4.4, C(1)H), 3.18−3.27 (2H, m, C(2)H, NCHMe₂),

3.84 (2H, AB system, J 14.7, NCH₂Ph), 7.18−7.43 (5H, m, Ph); δ_C

(100 MHz, CDCl₃) 20.9 (NCHMe₂), 22.1, 23.0, 23.1 (C(4), C(5),

C(6)), 48.1 (NCHMe₂), 49.8 (NCH₂Ph), 52.2, 55.0, 56.3 (C(1), C(2),

C(3)), 126.3 (p-Ph), 128.0, 128.1 (o,m-Ph), 142.4 (i-Ph); m/z (ESI⁺)

246 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₆H₂₄NO⁺([M + H]⁺)

requires 246.1852; found 246.1850.

(RS,RS,RS)-1-Acetoxy-3-(N-benzyl-N-methylamino)-

cyclohexan-2-ol 25. A stirred solution of 23 (12.2 g, 56.1 mmol) in

AcOH (35 mL) was heated at 50 °C for 24 h. The mixture was

concentrated in vacuo, and the residue was dissolved in CH₂Cl₂(300

mL). The solution was basiﬁed to pH 9 by the addition of 0.1 M aq

NaHCO₃, and the aqueous layer was extracted with CH₂Cl₂(3 × 500

mL). The combined organic extracts were concentrated in vacuo (to a

volume of approximately 400 mL), washed sequentially with 0.1 M aq

NaHCO₃(3 × 400 mL) and brine (400 mL), dried (Na₂SO₄), and

concentrated in vacuo. Puriﬁcation via recrystallization from 40−60 °C

petrol/Et₂O (9:1) gave 25 as a pale yellow solid (13.7 g, 89%, >99:1

dr); C₁₆H₂₃NO₃requires C, 69.3; H, 8.4; N, 5.05%; found C, 69.3; H,

8.3; N, 5.1%; mp 89−91 °C; ν_max(KBr) 3458 (O−H), 3028, 2943,

2867, 2795 (C−H), 1735 (CO); δ_H(400 MHz, CDCl₃) 1.46−1.90

(6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 2.08 (3H, s, COMe), 2.20 (3H, s,

NMe), 2.51−2.64 (1H, m, C(3)H), 3.43 (1H, br s, OH), 3.60 (2H, AB

system, J 13.4, NCH₂Ph), 3.97−4.05 (1H, m, C(2)H), 5.15−5.23 (1H,

+

(ESI⁺) 264 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₆H₂₆NO₂([M +

H]⁺) requires 264.1958; found 264.1950.

From 17: NaB(OAc)₃H (251 mg, 3.95 mmol) was added to a

stirred solution of 17 (207 mg, 0.79 mmol, 95:5 dr) and AcOH (45

μL, 0.79 mmol) in acetone (3 mL) at rt. The resultant mixture was

stirred at rt for 24 h before being concentrated in vacuo. The residue

was dissolved in CH₂Cl₂(50 mL), and the resultant solution was

washed sequentially with satd aq NaHCO₃(3 × 50 mL) and brine (50

mL), dried (MgSO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 40 → 80% EtOAc in 30−

40 °C petrol) gave 19 as a pale yellow oil (112 mg, 52%, 95:5 dr).

(RS,RS,RS)-3-(N,N-Dibenzylamino)cyclohexane-1,2-diol 20.

Step 1: Cl₃CCO₂H (29.5 g, 181 mmol) was added to a solution of

12 (10.0 g, 36.0 mmol) in CH₂Cl₂(120 mL), and the resultant

solution was stirred at rt for 5 min. m-CPBA (77%, 12.9 g, 57.6 mmol)

was added, and the mixture was stirred at rt for 21 h. The mixture was

quenched with satd aq Na₂SO₃until starch-iodide paper indicated that

m-CPBA was not present, and basiﬁed to pH 9 by the addition of 0.1

M aq NaHCO₃. The aqueous layer was extracted with CH₂Cl₂(3 ×

100 mL), and the combined organic layers were washed with 0.1 M aq

NaHCO₃(4 × 200 mL) and brine (200 mL), dried (Na₂SO₄), and

concentrated in vacuo to give 16 as a yellow oil that was used without

puriﬁcation.

Step 2: K₂CO₃(10.0 g, 72.4 mmol) was added to a solution of 16 in

MeOH (500 mL), and the resultant suspension was stirred at rt for 16

h, then concentrated in vacuo. H₂O (100 mL) was added, and the

residue was extracted with CH₂Cl₂(4 × 50 mL). The combined

organic layers were washed with brine (150 mL), dried (Na₂SO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 0 → 100% EtOAc in 30−40 °C petrol) gave 20 as a

pale yellow oil (11.4 g, quant, 95:5 dr).^4aδ_H(400 MHz, CDCl₃) 1.43−

1.89 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 2.14 (1H, br s, OH), 3.10−

3.20 (1H, m, C(3)H), 3.69−3.78 (2H, d, J 14.4, N(CH_AH_BPh)₂),

3.81−3.91 (3H, m, C(2)H, N(CH_AH_BPh)₂), 3.99−4.06 (1H, m, C(1)

H), 7.22−7.38 (10H, m, Ph).

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzyl-N-methylamino)-

cyclohexane 23. Step 1: Anhydrous TsOH (7.69 g, 44.7 mmol) was

added to a stirred solution of 10 (3.00 g, 14.9 mmol) in CH₂Cl₂(30

mL), and the resultant solution was stirred at rt for 5 min. m-CPBA

(69%, 5.60 g, 22.4 mmol) was added, and the mixture was stirred at rt

for 21 h. The reaction mixture was quenched with satd aq Na₂SO₃

until starch-iodide paper indicated that m-CPBA was not present, and

then basiﬁed to pH 9 by the addition of 0.1 M aq NaHCO₃. The

resultant mixture was extracted with CH₂Cl₂(3 × 75 mL), and the

combined organic layers were washed sequentially with 0.1 M aq

NaHCO₃(6 × 100 mL) and brine (125 mL), dried (MgSO₄), and

concentrated in vacuo to give 21 as a green solid (5.22 g) that was

used without puriﬁcation. Recrystallization of an aliquot from 40−60

°C petrol/Et₂O (10:1) gave an analytical sample. C₂₁H₂₇NO₄S

requires C, 64.75; H, 7.0; N, 3.6%; found C, 64.8; H, 7.0; N, 3.7%;

mp 75−83 °C; ν_max(ﬁlm) 3406 (O−H), 3062, 3029, 2947, 2869, 2797

(C−H); δ_H(400 MHz, CDCl₃) 1.37−1.83 (6H, m, C(4)H₂, C(5)H₂,

C(6)H₂), 2.14 (3H, s, NMe), 2.42 (3H, s, ArMe), 2.61 (1H, ddd, J

11.9, 4.3, 2.8, C(3)H), 3.30−3.60 (1H, br s, OH) overlapping 3.48

(1H, d, J 13.4, NCH_AH_BPh), 3.60 (1H, d, J 13.4, NCH_AH_BPh), 3.43−

4.00 (1H, m, C(2)H), 4.76−4.83 (1H, m, C(1)H), 7.17−7.39 (7H, m,

Ar, Ph), 7.79−7.84 (2H, m, Ar); δ_C(100 MHz, CDCl₃) 18.6, 21.6,

23.6, 24.7 (C(4), C(5), C(6), ArMe), 38.2 (NMe), 58.1 (NCH₂Ph),

60.2 (C(3)), 65.8 (C(2)), 79.7 (C(1)), 127.2 (p-Ph), 127.8, 128.4,

7252

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m, C(1)H), 7.20−7.40 (5H, m, Ph); δ_C(100 MHz, CDCl₃) 19.3, 21.3,

23.9, 24.3 (C(4), C(5), C(6), COMe), 38.5 (NMe), 58.2 (NCH₂Ph),

60.8 (C(3)), 66.1 (C(2)), 71.6 (C(1)), 127.0 (p-Ph), 128.3, 128.9

(o,m-Ph), 139.1 (i-Ph), 170.1 (COMe); m/z (ESI⁺) 278 ([M + H]⁺,

(448 mg) that was used without puriﬁcation. δ_H(400 MHz, CDCl₃)

0.99 (3H, d, J 6.7, NCHMe_A), 1.10 (3H, d, J 6.7, NCHMe_B), 1.66−

1.98 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 1.93 (3H, s, COMe), 2.82−

2.90 (1H, m, C(3)H), 2.91 (3H, s, OSO₂Me), 3.00−3.15 (1H, m,

NCHMe₂), 3.80 (2H, AB system, J 13.4, NCH₂Ph), 4.56−4.66 (1H,

m, C(2)H), 5.22−5.28 (1H, m, C(1)H), 7.22−7.38 (5H, m, Ph).

Step 2: K₂CO₃(402 mg, 2.91 mmol) was added to a stirred solution

of 28 (448 mg) in MeOH (8.9 mL). The resultant suspension was

stirred at rt for 16 h, then concentrated in vacuo. H₂O (10 mL) was

added, and the mixture was extracted with CH₂Cl₂(4 × 10 mL). The

combined organic extracts were concentrated in vacuo (to a volume of

approximately 15 mL), washed sequentially with H₂O (2 × 15 mL)

and brine (15 mL), dried (MgSO₄), and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (eluent 30−40 °C

petrol/Et₂O, 9:1) gave 30 as a colorless oil (174 mg, 65%, >99:1 dr).

ν_max(ﬁlm) 2935 (C−H), 1493, 1463 (CC); δ_H(400 MHz, CDCl₃)

1.09 (3H, d, J 6.7, NCHMe_A), 1.11 (3H, d, J 6.7, NCHMe_B), 1.20−

1.48 (4H, m, C(4)H_A, C(5)H₂, C(6)H_A), 1.58−1.75 (2H, m, C(4)H_B,

C(6)H_B), 2.05−2.09 (1H, m, C(3)H), 3.02 (1H, septet, J 6.7,

NCHMe₂), 3.12−3.15 (1H, m C(1)H), 3.18−3.21 (1H, m, C(2)H),

3.83 (2H, AB system, J 15.6, NCH₂Ph), 7.21−7.42 (5H, m, Ph); δ_C

(100 MHz, CDCl₃) 16.5, 20.7, 21.1, 24.9, 26.8 (C(4), C(5), C(6),

NCHMe₂), 49.8 (NCHMe₂), 50.9 (NCH₂Ph), 52.7, 53.4, 56.7 (C(1),

C(2), (C(3)), 126.5 (p-Ph), 127.7, 128.1 (o,m-Ph), 142.1 (i-Ph); m/z

(ESI⁺) 246 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₆H₂₄NO⁺([M +

H]⁺) requires 246.1852; found 246.1845.

+

100%); HRMS (ESI⁺) C₁₆H₂₄NO₃([M + H]⁺) requires 278.1751;

found 278.1757.

(RS,RS,RS)-1-Acetoxy-3-(N-benzyl-N-isopropylamino)-

cyclohexan-2-ol 26. A stirred solution of 24 (326 mg, 1.33 mmol) in

AcOH (0.83 mL) was heated at 50 °C for 24 h. The mixture was

concentrated in vacuo, and the residue was dissolved in CH₂Cl₂(10

mL). The solution was basiﬁed to pH 9 by the addition of 0.1 M aq

NaHCO₃, and the aqueous layer was extracted with CH₂Cl₂(3 × 10

mL). The combined organic extracts were concentrated in vacuo (to a

volume of approximately 10 mL), washed sequentially with 0.1 M aq

NaHCO₃(3 × 10 mL) and brine (10 mL), dried (Na₂SO₄), and

concentrated in vacuo to give 26 as a colorless oil (355 mg, 88%,

>95:5 dr). ν_max(ﬁlm) 3411 (O−H), 2931 (C−H), 1732 (CO); δ_H

(400 MHz, CDCl₃) 1.07 (3H, d, J 6.7, NCHMe_A), 1.10 (3H, d, J 6.7,

NCHMe_B), 1.46−1.70 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 2.06 (3H,

s, COMe), 2.90−2.94 (1H, m, C(3)H), 3.23 (1H, septet, J 6.7,

NCHMe₂), 3.70−3.72 (1H, m, C(2)H), 3.78 (2H, AB system, J 13.4,

NCH₂Ph), 5.00−5.13 (1H, m, C(1)H), 7.14−7.30 (5H, m, Ph); δ_C

(100 MHz, CDCl₃) 18.7, 19.3 (CHMe₂), 20.0, 21.3, 24.6, 24.7 (C(4),

C(5), C(6), COMe), 48.8 (NCHMe₂), 50.1 (NCH₂Ph), 58.2 (C(3)),

68.4 (C(2)), 72.2 (C(1)), 126.5 (p-Ph), 127.3, 128.5 (o,m-Ph), 142.9

(i-Ph), 170.1 (COMe); m/z (ESI⁺) 306 ([M + H]⁺, 100%); HRMS

+

(ESI⁺) C₁₈H₂₈NO₃([M + H]⁺) requires 306.2064; found 306.2064.

(1RS,2RS,3SR)-3-(N-Benzyl-N-methylamino)cyclohexane-1,2-

diol 31. A solution of 29 (1.00 g, 4.60 mmol) in 1,4-dioxane (18 mL)

and 3 M aq H₂SO₄(6 mL) was stirred at 40 °C for 24 h. The mixture

was concentrated in vacuo, and the residue was dissolved in CH₂Cl₂

(100 mL) and washed with satd aq NaHCO₃(180 mL). The aqueous

layer was extracted with CH₂Cl₂(2 × 80 mL), and the combined

organic extracts were washed sequentially with satd aq NaHCO₃(3 ×

250 mL) and brine (250 mL), dried (Na₂SO₄), and concentrated in

vacuo. Puriﬁcation via ﬂash column chromatography (gradient elution,

12 → 100% Et₂O in 40−60 °C petrol) gave 31 as a pale yellow oil

(668 mg, 62%, >99:1 dr). C₁₄H₂₁NO₂requires C, 71.5; H, 9.0; N,

5.95%; found C, 71.5; H, 8.9; N, 5.9%; ν_max(ﬁlm) 3418 (O−H), 2932,

2861, 2799 (C−H); δ_H(400 MHz, CDCl₃) 1.08−1.96 (6H, m, C(4)

H₂, C(5)H₂, C(6)H₂), 2.11 (3H, s, NMe), 2.29−2.45 (1H, m, C(3)H),

3.30 (1H, dd, J 10.1, 8.3, C(2)H), 3.39 (1H, d, J 13.0, NCH_AH_BPh),

3.49 (1H, ddd, J 10.8, 8.3, 4.6, C(1)H), 3.65 (1H, d, J 13.0,

NCH_AH_BPh), 4.00−4.40 (2H, br s, OH), 7.12−7.32 (5H, m, Ph); δ_C

(100 MHz, CDCl₃) 21.1, 21.7, 31.8 (C(4), C(5), C(6)), 36.4 (NMe),

58.2 (NCH₂Ph), 66.1 (C(3)), 74.1 (C(1)), 75.1 (C(2)), 127.1 (p-Ph),

128.4, 128.8 (o,m-Ph), 139.0 (i-Ph); m/z (ESI⁺) 236 ([M + H]⁺,

(1RS,2SR,3RS)-1,2-Epoxy-3-(N-benzyl-N-methylamino)-

cyclohexane 29. Step 1: MsCl (5.70 mL, 73.9 mmol) was added to a

stirred solution of 25 (13.7 g, 49.3 mmol) and Et₃N (23 mL, 165

mmol) in CH₂Cl₂(270 mL) at 0 °C, and the resultant solution was

stirred at 0 °C for 1 h. The reaction mixture was then allowed to warm

to rt and washed with H₂O (350 mL). The aqueous layer was

extracted with CH₂Cl₂(350 mL). The combined organic extracts were

washed sequentially with 10% aq CuSO₄(3 × 500 mL) and brine (500

mL), dried (MgSO₄), and concentrated in vacuo to give 27 as a brown

oil (17.3 g) that was used without puriﬁcation. δ_H(400 MHz, CDCl₃)

1.46−1.84 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 1.93 (3H, s, COMe),

2.36 (3H, s, NMe), 2.82−2.90 (1H, m, C(3)H), 3.13 (3H, s,

OSO₂Me), 3.70 (2H, AB system, J 13.4, NCH₂Ph), 4.81−4.85 (1H, m,

C(2)H), 5.12−5.18 (1H, m, C(1)H), 7.22−7.38 (5H, m, Ph).

Step 2: K₂CO₃(18 g, 130 mmol) was added to a stirred solution of

27 (17.3 g) in MeOH (400 mL). The resultant suspension was stirred

at rt for 16 h, then concentrated in vacuo. H₂O (400 mL) was added,

and the mixture was extracted with CH₂Cl₂(4 × 400 mL). The

combined organic extracts were concentrated in vacuo (to a volume of

approximately 700 mL), washed sequentially with H₂O (2 × 500 mL)

and brine (500 mL), dried (MgSO₄), and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (gradient elution, 0 →

60% EtOAc in 40−60 °C petrol) gave 29 as a pale yellow oil (7.98 g,

67%, >99:1 dr). C₁₄H₁₉NO requires C, 77.4; H, 8.8; N, 6.45%; found

C, 77.4; H, 8.8; N, 6.4%; ν_max(ﬁlm) 3062, 3027, 2978, 2843, 2792

(C−H); δ_H(400 MHz, CDCl₃) 1.18−1.36, 1.43−1.52, 1.61−1.76,

2.06−2.15 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 2.30 (3H, s, NMe),

2.89−2.97 (1H, m, C(3)H), 3.19−3.26 (2H, m, C(1)H, C(2)H), 3.69

(2H, AB system, J 13.3, NCH₂Ph), 7.23−7.39 (5H, m, Ph); δ_C(100

MHz, CDCl₃) 16.1, 22.1, 25.0 (C(4), C(5), C(6)), 38.3 (NMe), 53.2,

55.3 (C(1), C(2)), 58.4 (NCH₂Ph), 58.4 (C(3)), 127.0 (p-Ph), 128.3,

128.7 (o,m-Ph), 139.5 (i-Ph); m/z (ESI⁺) 218 ([M + H]⁺, 100%);

HRMS (ESI⁺) C₁₄H₂₀NO⁺([M + H]⁺) requires 218.1539; found

218.1541.

+

100%); HRMS (ESI⁺) C₁₄H₂₂NO₂([M + H]⁺) requires 236.1645;

found 236.1652.

(1RS,2RS,3SR)-3-(N-Benzyl-N-isopropylamino)cyclohexane-

1,2-diol 32. A solution of 30 (101 mg, 0.41 mmol) in 1,4-dioxane

(1.6 mL) and 3 M aq H₂SO₄(0.54 mL) was stirred at 40 °C for 24 h.

The mixture was concentrated in vacuo, and the residue was dissolved

in CH₂Cl₂(10 mL) and washed with satd aq NaHCO₃(10 mL). The

aqueous layer was extracted with CH₂Cl₂(2 × 10 mL), and the

combined organic extracts were washed sequentially with satd aq

NaHCO₃(3 × 20 mL) and brine (20 mL), dried (Na₂SO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(eluent 30−40 °C petrol/Et₂O, 8:2) gave 32 as a colorless oil (84.1

mg, 94%, >99:1 dr). ν_max(ﬁlm) 3419 (O−H), 2936 (C−H); δ_H(400

MHz, CDCl₃) 1.10 (3H, d, J 6.7, NCHMe_A), 1.11 (3H, d, J 6.7,

NCHMe_B), 1.25−1.96 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 2.41−2.47

(1H, m, C(3)H), 3.07 (1H, septet, J 6.7, NCHMe₂), 3.16 (1H, app t, J

9.7, C(2)H), 3.44−3.49 (1H, m, C(1)H), 3.50 (1H, d, J 13.0,

NCH_AH_BPh), 3.80 (1H, d, J 13.0, NCH_AH_BPh), 7.21−7.38 (5H, m,

Ph); δ_C(100 MHz, CDCl₃) 18.0, 21.9, 22.7, 29.7, 31.5 (C(4), C(5),

C(6), NCHMe₂), 48.1 (NCHMe₂), 49.3 (NCH₂Ph), 59.6 (C(3)),

74.6, 74.8 (C(1), C(2)), 127.1 (p-Ph), 128.4, 128.6 (o,m-Ph), 140.2 (i-

Ph); m/z (ESI⁺) 549 ([2M + Na]⁺, 100%), 264 ([M + H]⁺, 94%);

(1RS,2SR,3RS)-1,2-Epoxy-3-(N-benzyl-N-isopropylamino)-

cyclohexane 30. Step 1: MsCl (0.13 mL, 1.65 mmol) was added to a

stirred solution of 26 (336 mg, 1.10 mmol) and Et₃N (0.51 mL, 3.69

mmol) in CH₂Cl₂(6.0 mL) at 0 °C, and the resultant solution was

stirred at 0 °C for 1 h. The reaction mixture was then allowed to warm

to rt and washed with H₂O (10 mL). The aqueous layer was extracted

with CH₂Cl₂(10 mL). The combined organic extracts were washed

sequentially with 10% aq CuSO₄(3 × 20 mL) and brine (20 mL),

dried (MgSO₄), and concentrated in vacuo to give 28 as a colorless oil

+

HRMS (ESI⁺) C₁₆H₂₆NO₂([M + H]⁺) requires 264.1958; found

264.1958.

7253

dx.doi.org/10.1021/jo3010556 | J. Org. Chem. 2012, 77, 7241−7261

The Journal of Organic Chemistry

Article

(RS)-3-(N,N-Dibenzyl-ammonium)cyclohex-1-ene trichloroa-

cetate 33. Cl₃CCO₂H (196 mg, 1.20 mmol) was added to a solution

of 12 (66 mg, 0.24 mmol) in CDCl₃(0.8 mL); δ_H(400 MHz, CDCl₃)

1.59−2.26 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 4.20 (1H, dd, J 13.4,

6.6, NCH_AH_BPh), 4.25−4.28 (1H, m, C(3)H), 4.32 (1H, dd, J 13.4,

5.6, NCH_AH_BPh), 4.40 (1H, dd, J 13.4, 6.1, NCH_AH_BPh), 4.49 (1H,

dd, J 13.4, 4.3, NCH_AH_BPh), 5.85 (1H, app d, J 10.4, C(1)H), 6.21−

6.33 (1H, m, C(2)H), 7.35−7.43 (10H, m, Ph), 8.45 (1H, br s, NH);

δ_C(100 MHz, CDCl₃) 20.4, 22.6, 22.4 (C(4), C(5), C(6)), 55.0, 55.2

(NCH₂Ph), 60.2 (C(3)), 120.2 (C(1)), 128.6, 128.6 (i-Ph), 128.7,

129.6, 130.3, 130.5, 130.7 (o,m,p-Ph), 137.6 (C(2)).

(RS)-3-(N-Benzyl-N-isopropylammonium)cyclohex-1-ene tri-

chloroacetate 36. Cl₃CCO₂H (196 mg, 1.20 mmol) was added to a

solution of 11 (55 mg, 0.24 mmol) in CDCl₃(0.8 mL). δ_H(400 MHz,

CDCl₃) 1.45−1.52 (6H, m, CHMe₂), 1.62−2.29 (6H, m, C(4)H₂,

C(5)H₂, C(6)H₂), 3.85−3.89 (1H, m, NCHMe₂), 4.23−4.38 (2H, m,

C(3)H, NCH_AH_BPh), 4.41−4.45 (1H, m, NCH_AH_BPh), 5.77 (0.5H,

app d, J 10.4, C(1)H), 5.90 (0.5H, app d, J 10.1, C(1)H), 6.21−6.24

(1H, m, C(2)H), 7.40−7.49 (5H, m, Ph), 7.60 (0.5H, m, NH), 7.68

(0.5H, m, NH); δ_C(100 MHz, CDCl₃) 18.7, 18.8, 18.9 (NCHMe₂),

19.6, 20.5, 23.7, 24.3, 24.4, 25.3 (C(4), C(5), C(6)), 51.2, 52.0

(NCH₂Ph), 56.3, 56.7 (NCHMe₂), 59.7, 60.5 (C(3)), 120.4, 120.7

(C(1)), 129.6, 129.7 (i-Ph), 129.7, 129.8, 130.1, 130.3, 130.4 (o,m,p-

Ph), 136.9, 137.5 (C(2)).

(RS)-3-(N-Benzyl-N-methylammonium)cyclohex-1-ene tri-

chloroacetate 39. Cl₃CCO₂H (196 mg, 1.20 mmol) was added to

a solution of 10 (48 mg, 0.24 mmol) in CDCl₃(0.8 mL). δ_H(400

MHz, CDCl₃) 1.65−2.22 (6H, m, C(4)H₂, C(5)H₂, C(6)H₂), 2.77

(1.5H, d, J 5.1, NMe), 2.80 (1.5H, d, J 5.1, NMe), 4.14 (0.5H, dd, J

12.9, 7.5, NCH_ACH_BPh), 4.21 (1H, dd, J 13.0, 7.2, NCH_ACH_BPh),

4.23−4.30 (1H, m, C(3)H), 4.46 (0.5H, dd, J 13.0, 4.6,

NCH_ACH_BPh), 4.50 (0.5H, dd, J 12.9, 4.1, NCH_ACH_BPh), 5.73

(0.5H, app d, J 10.4, C(1)H), 5.80 (0.5H, app d, J 10.4, C(1)H),

6.21−6.24 (0.5H, m, C(2)H), 6.30−6.33 (0.5H, m, C(2)H), 7.35−

7.46 (5H, m, Ph), 8.68 (0.5H, br s, NH), 8.80 (0.5H, br s, NH); δ_C

(100 MHz, CDCl₃) 20.1, 20.2, 21.1, 23.4, 24.4, 24.5 (C(4), C(5),

C(6)), 35.3, 36.3 (NMe), 57.5, 57.8 (NCH₂Ph), 61.2, 61.4 (C(3)),

118.6, 120.9 (C(1)), 128.4, 128.6 (i-Ph), 129.7, 130.4, 130.5, 130.6

(o,m,p-Ph), 137.0, 138.3 (C(2)).

(RS)-3-(N-Benzylamino)methylcyclohex-1-ene 46. A stirred

mixture of 45 (1.00 g, 5.71 mmol), benzylamine (5 mL, 45.7 mmol),

and NaI (85 mg, 0.57 mmol) was heated at 50 °C for 20 h. The

reaction mixture was cooled to rt and diluted with EtOAc (100 mL).

The mixture was washed with 1 M aq NaOH (100 mL), and the

aqueous layer was extracted with EtOAc (2 × 100 mL). The combined

organic extracts were dried (MgSO₄) and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (eluent 30−40 °C

petrol/Et₂O, 85:15) gave 46 as a yellow oil (700 mg, 61%).³⁵δ_H(400

MHz, CDCl₃) 1.32−1.37 (1H, m, C(6)H_A), 1.52−1.58 (1H, m, C(5)

H_A), 1.71−1.79 (1H, m, C(5)H_B), 1.80−1.86 (1H, m, C(6)H_B), 1.97−

2.03 (2H, m, C(4)H₂), 2.30−2.36 (1H, m, C(3)H), 2.53−2.63 (2H,

m, C(3)CH₂N), 3.79−3.86 (2H, m, NCH₂Ph), 5.60−5.63 (1H, m,

CHCH), 5.72−5.76 (1H, m, CHCH), 7.25−7.35 (5H, m, Ph).

(RS)-3-(N-Benzyl-N-methylamino)methylcyclohex-1-ene 47.

K₂CO₃(943 mg, 6.84 mmol) and N-benzyl-N-methylamine (1.84

mL, 14.3 mmol) were added to a stirred solution of 45 (1.00 g, 5.71

mmol) in MeCN (3 mL) at rt, and the resultant solution was heated at

60 °C for 20 h before being allowed to cool to rt and concentrated in

vacuo. The residue was diluted with H₂O (20 mL) and extracted with

CH₂Cl₂(3 × 30 mL). The combined organic extracts were washed

sequentially with satd aq NaHCO₃(2 × 40 mL) and brine (40 mL),

dried (MgSO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent 30−40 °C petrol/Et₂O, 95:5) gave

47 as a pale yellow oil (768 mg, 64%). ν_max(ﬁlm) 3085, 3062, 2960,

2927 (C−H), 1452 (CC); δ_H(400 MHz, CDCl₃) 1.32−1.36 (1H,

m, C(4)H_A), 1.55−1.65 (1H, m, C(5)H_A), 1.70−1.76 (1H, m, C(5)

H_B), 1.81−1.96 (1H, m, C(4)H_B), 2.02−2.07 (2H, m, C(6)H₂), 2.23

(3H, s, NMe), 2.31−2.40 (2H, m, C(3)CH₂N), 2.39−2.41 (1H, m,

C(3)H), 3.51 (2H, AB system, J 13.4, NCH₂Ph), 5.75−5.80 (2H, m,

C(1)H, C(2)H), 7.26−7.39 (5H, m, Ph); δ_C(100 MHz, CDCl₃) 21.2

(C(5)), 25.6 (C(6)), 27.5 (C(4)), 33.5 (C(3)), 42.6 (NMe), 62.7

(C(3)CH₂N), 63.4 (NCH₂Ph), 126.8 (p-Ph), 127.5, 128.1 (o,m-Ph),

128.9, 130.3 (C(1), C(2)), 139.6 (i-Ph); m/z (ESI⁺) 216 ([M + H]⁺,

100%); HRMS (ESI⁺) C₁₅H₂₂N⁺([M + H]⁺) requires 216.1747;

found 216.1744.

(RS)-3-(N-Benzyl-N-isopropylamino)methylcyclohex-1-ene

48. NaB(OAc)₃H (1.06 g, 5.00 mmol) was added to a stirred solution

of 46 (201 mg, 1.00 mmol) and AcOH (57 μL, 1.00 mmol) in acetone

(5 mL) at rt. The resultant mixture was stirred at rt for 24 h before

being concentrated in vacuo. The residue was dissolved in CH₂Cl₂(50

mL), and the resultant solution was washed sequentially with satd aq

NaHCO₃(3 × 50 mL) and brine (50 mL), dried (MgSO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(eluent 30−40 °C petrol/Et₂O, 98:2) gave 48 as a pale yellow oil (189

mg, 78%). ν_max(ﬁlm) 3084, 3061, 2963, 2926 (C−H), 1493 (CC);

δ_H(400 MHz, CDCl₃) 1.09 (3H, d, J 6.6, NCHMe_A), 1.11 (3H, d, J

6.6, NCHMe_B), 1.25−1.33 (1H, m, C(4)H_A), 1.45−1.60 (1H, m, C(5)

H_A), 1.67−1.70 (1H, m, C(5)H_B), 1.80−1.83 (1H, m, C(4)H_B), 1.98−

2.03 (2H, m, C(6)H₂), 2.22−2.29 (1H, m, C(3)H), 2.29−2.38 (2H,

m, C(3)CH₂N), 2.93 (1H, septet, J 6.6, NCHMe₂), 3.60 (2H, AB

system, J 14.4, NCH₂Ph), 5.73−5.75 (2H, m, C(1)H, C(2)H), 7.23−

7.42 (5H, m, Ph); δ_C(100 MHz, CDCl₃) 17.0, 18.1 (NCHMe₂), 21.2

(C(5)), 25.7 (C(6)), 27.4 (C(4)), 34.0 (C(3)), 49.0 (NCHMe₂), 54.6

(C(3)CH₂N), 54.7 (NCH₂Ph), 126.4 (p-Ph), 127.2, 128.0 (o,m-Ph),

128.4, 130.7 (C(1)), (C(2)), 141.6 (i-Ph); m/z (ESI⁺) 244 ([M + H]⁺,

100%); HRMS (ESI⁺) C₁₇H₂₆N⁺([M + H]⁺) requires 244.2060;

found 244.2055.

(RS)-3-(N,N-Dibenzylamino)methylcyclohex-1-ene 49.

ⁱPr₂NEt (1.1 mL, 6.26 mmol) and BnBr (0.74 mL, 6.26 mmol) were

added sequentially to a stirred solution of 46 (840 mg, 4.17 mmol) in

CH₂Cl₂(10 mL) at rt. The resultant solution was heated to 40 °C for

2 h and allowed to cool to rt. The reaction mixture was diluted with 2

M aq KOH (20 mL) and extracted with Et₂O (2 × 20 mL). The

combined organic extracts were washed with brine (50 mL), dried

(MgSO₄), and concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30−40 °C petrol/Et₂O, 98:2) gave 49 as a

colorless oil (1.05 g, 87%).^4cδ_H(400 MHz, CDCl₃) 1.28−1.35 (1H,

m, C(6)H_A), 1.48−1.61 (2H, m, C(5)H₂), 1.86−1.90 (1H, m, C(6)

H_B), 1.93−1.99 (2H, m, C(4)H₂), 2.32−2.37 (2H, m, C(3)CH₂N),

2.40−2.45 (1H, m, C(3)H), 3.51 (2H, d, J 13.6, N(CH_AH_BPh)₂), 3.68

(2H, d, J 13.6, N(CH_AH_BPh)₂), 5.69−5.74 (2H, m, C(1)H, C(2)H),

7.24−7.43 (10H, m, Ph).

(1RS,2RS,3SR)-3-(N-Benzylamino)methylcyclohexane-1,2-

diol 50. Cl₃CCO₂H (486 mg, 2.98 mmol) was added to a solution of

46 (150 mg, 0.75 mmol) in CH₂Cl₂(2.1 mL), and the resultant

solution was stirred at rt for 5 min. m-CPBA (74%, 486 mg, 2.98

mmol) was added, and the mixture was stirred at rt for 21 h. The

mixture was quenched with satd aq Na₂SO₃until starch-iodide paper

indicated that m-CPBA was not present. MeOH (15 mL) and K₂CO₃

(1.02 g, 7.4 mmol) were then added, and the resultant suspension was

stirred at rt for 16 h before being concentrated in vacuo. H₂O (50 mL)

was then added, and the mixture was extracted with CH₂Cl₂(4 × 100

mL). The combined organic extracts were washed with brine (100

mL), dried (MgSO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 50 → 100% EtOAc in 30−

40 °C petrol) gave 50 as a yellow oil (124 mg, 71%, ∼95% purity, 95:5

dr).^4cδ_H(500 MHz, CDCl₃) 1.22−1.40 (2H, m, C(4)H_A, C(5)H_A),

1.47−1.50 (1H, m, C(6)H_A), 1.55−1.57 (2H, m, C(5)H_B, C(6)H_B),

1.95−1.98 (1H, m, C(4)H_B), 2.23−2.27 (1H, m, C(1)H), 2.75 (1H,

dd, J 14.5, 1.5, C(3)CH_AH_BN), 3.02 (1H, dd, J 14.5, 11.5,

C(3)CH_AH_BN), 3.52 (1H, dd, J 8.2, 4.4, C(2)H), 3.64−3.68 (1H,

m, C(3)H), 3.66 (1H, d, J 13.1, NCH_AH_BPh), 3.81 (1H, d, J 13.1,

NCH_AH_BPh), 7.25−7.35 (5H, m, Ph).

( 1 R S , 2 R S , 3 S R ) - 3 - ( N - B e n z y l - N - m e t h y l a m i n o ) -

methylcyclohexane-1,2-diol 51. From 47: Cl₃CCO₂H (817 mg,

5.00 mmol) was added to a solution of 47 (215 mg, 1.00 mmol) in

CH₂Cl₂(3.5 mL), and the resultant solution was stirred at rt for 5 min.

m-CPBA (70%, 394 mg, 1.60 mmol) was added, and the mixture was

stirred at rt for 21 h. The mixture was quenched with satd aq Na₂SO₃

until starch-iodide paper indicated that m-CPBA was not present.

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MeOH (20 mL) and K₂CO₃(1.38 g, 10.0 mmol) were then added,

and the resultant suspension was stirred at rt for 16 h before being

concentrated in vacuo. H₂O (50 mL) was then added, and the mixture

was extracted with CH₂Cl₂(4 × 100 mL). The combined organic

extracts were washed with brine (100 mL), dried (MgSO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 50 → 100% EtOAc in 30−40 °C petrol) gave 51 as a

pale yellow oil (190 mg, 81%, >99:1 dr). ν_max(ﬁlm) 3405 (O−H),

3061, 2931 (C−H), 1494, 1453 (CC); δ_H(400 MHz, CDCl₃)

1.19−1.27 (2H, m, C(6)H_A, C(5)H_A), 1.27−1.54 (3H, m, C(4)H₂,

C(5)H_B), 1.93−1.98 (1H, m, C(6)H_B), 2.17 (1H, dd, J 12.6, 3.3,

C(3)CH_AH_BN), 2.28 (3H, s, NMe), 2.52−2.58 (1H, m, C(3)H), 3.08

(1H, app t, J 12.6, C(3)CH_AH_BN), 3.30 (1H, d, J 12.9, NCH_AH_BPh),

3.33−3.38 (1H, m, C(1)H), 3.42 (1H, dd, J 9.3, 4.8, C(2)H), 3.72

(1H, d, J 12.9, NCH_AH_BPh), 7.27−7.36 (5H, m, Ph); δ_C(100 MHz,

CDCl₃) 20.0 (C(5)), 28.5 (C(4)), 31.9 (C(6)), 33.8 (C(3)), 42.4

(NMe), 58.9 (C(3)CH₂N), 62.9 (NCH₂Ph), 71.2 (C(1)), 78.9 (C(2)),

127.6, 128.4, 129.4 (o,m,p-Ph), 137.3 (i-Ph); m/z (ESI⁺) 250 ([M +

quenched with satd aq Na₂SO₃until starch-iodide paper indicated that

m-CPBA was not present. MeOH (80 mL) and K₂CO₃(3.55 g, 25.7

mmol) were then added, and the resultant suspension was stirred at rt

for 16 h before being concentrated in vacuo. H₂O (150 mL) was then

added, and the mixture was extracted with CH₂Cl₂(4 × 150 mL). The

combined organic extracts were washed with brine (200 mL), dried

(MgSO₄), and concentrated in vacuo. Puriﬁcation via exhaustive ﬂash

column chromatography (gradient elution, 7 → 60% EtOAc in 30−40

°C petrol) gave 53 as a white solid (916 mg, 55%, >99:1 dr).^4cδ_H(400

MHz, CDCl₃) 1.09−1.14 (2H, m, C(5)H₂), 1.26−1.29 (1H, m, C(6)

H_A), 1.43−1.49 (2H, m, C(4)H₂), 1.71−1.78 (1H, m, C(6)H_B), 2.20−

2.24 (1H, m, C(3)H), 2.55−2.60 (1H, br s, OH), 2.60−2.70 (2H, m,

C(3)CH₂N), 3.07−3.15 (3H, m, C(1)H, N(CH_AH_BPh)₂), 3.36−3.39

(1H, m, C(2)H), 4.05−4.09 (2H, m, N(CH_AH_BPh)₂), 6.78−6.99 (1H,

br s, OH), 7.27−7.42 (10H, m, Ph).

(1RS,2SR,3RS)-1,2-Epoxy-3-(N-benzyl-N-methylamino)-

methylcyclohexane 56. Step 1: Anhydrous TsOH (1.67 g, 9.69

mmol) was added to a stirred solution of 47 (647 mg, 3.23 mmol) in

CH₂Cl₂(6.4 mL), and the resultant solution was stirred at rt for 5 min.

m-CPBA (77%, 1.08 g, 4.85 mmol) was added, and the mixture was

stirred at rt for 21 h. The reaction mixture was quenched with satd aq

Na₂SO₃until starch-iodide paper indicated that m-CPBA was not

present, and then basiﬁed to pH 9 by the addition of 0.1 M aq

NaHCO₃. The resultant mixture was extracted with CH₂Cl₂(3 × 10

mL), and the combined organic layers were washed sequentially with

0.1 M aq NaHCO₃(6 × 30 mL) and brine (30 mL), dried (MgSO₄),

and concentrated in vacuo to give 54 as a yellow oil (1.30 g) that was

used without puriﬁcation.

Step 2: DBU (0.58 mL, 3.89 mmol) was added to a stirred solution

of 54 (1.30 g) in CH₂Cl₂(5.4 mL), and the resultant mixture was

stirred at rt for 24 h. The mixture was diluted with H₂O (10 mL), and

the aqueous layer was extracted with CH₂Cl₂(3 × 10 mL). The

combined organic layers were washed sequentially with H₂O (3 × 30

mL) and brine (30 mL), dried (MgSO₄), and concentrated in vacuo to

give a 90:10 mixture of 56:62. Puriﬁcation via ﬂash column

chromatography (eluent 30−40 °C petrol/Et₂O, 16:1) gave 56 as a

colorless oil (379 mg, 51%, >99:1 dr). ν_max(ﬁlm) 2935 (C−H), 1495,

1453 (CC); δ_H(400 MHz, CDCl₃) 1.12−1.36 (2H, m, C(4)H_A,

C(5)H_A), 1.32−1.45 (1H, m, C(4)H_B), 1.48−1.55 (1H, m, C(5)H_B),

1.72−1.89 (2H, m, C(6)H₂), 2.05−2.09 (1H, m, C(3)H), 2.22 (3H, s,

NMe), 2.36 (1H, dd, J 12.4, 7.0, C(3)H_AH_BN), 2.61 (1H, dd, J 12.4,

7.0, C(3)CH_AH_BN), 3.20 (1H, app t, J 4.0, C(1)H), 3.26−3.28 (1H,

m, C(2)H), 3.54 (2H, app s, NCH₂Ph), 7.20−7.39 (5H, m, Ph); δ_C

(100 MHz, CDCl₃) 19.7, 23.4, 24.0 (C(4), C(5), C(6)), 33.5 (NMe),

43.6 (C(3)), 52.7, 54.8 (C(1), C(2)), 60.8, 62.8 (NCH₂Ph,

C(3)CH₂N), 126.8 (p-Ph), 128.1, 128.8 (o,m-Ph), 139.4 (i-Ph); m/z

(ESI⁺) 232 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₅H₂₂NO⁺([M +

H]⁺) requires 232.1696; found 232.1696.

(1RS,2SR,3RS)-1,2-Epoxy-3-(N-benzyl-N-isopropylamino)-

methylcyclohexane 57. Step 1: Anhydrous TsOH (615 mg, 3.57

mmol) was added to a stirred solution of 48 (290 mg, 0.51 mmol) in

CH₂Cl₂(2.36 mL), and the resultant solution was stirred at rt for 5

min. m-CPBA (77%, 398 mg, 1.79 mmol) was added, and the mixture

was stirred at rt for 21 h. The reaction mixture was quenched with satd

aq Na₂SO₃until starch-iodide paper indicated that m-CPBA was not

present, and then basiﬁed to pH 9 by the addition of 0.1 M aq

NaHCO₃. The resultant mixture was extracted with CH₂Cl₂(3 × 5

mL), and the combined organic layers were washed sequentially with

0.1 M aq NaHCO₃(6 × 15 mL) and brine (15 mL), dried (MgSO₄),

and concentrated in vacuo to give 55 as a yellow oil that was used

without puriﬁcation.

+

H]⁺, 100%); HRMS (ESI⁺) C₁₅H₂₄NO₂([M + H]⁺) requires

250.1802; found 250.1802.

From 50: NaB(OAc)₃H (134 mg, 0.637 mmol), paraformaldehyde

(20 mg, 0.67 mmol), and AcOH (15 μL, 0.212 mmol) were added to a

stirred solution of 50 (50 mg, 0.212 mmol, 95:5 dr) in CH₂Cl₂(1.0

mL) at rt, and the resultant solution was stirred for 20 h at rt before

being concentrated in vacuo. The residue was dissolved in CH₂Cl₂(10

mL), and the resultant solution was washed with satd aq NaHCO₃(3

× 10 mL), dried (MgSO₄), and concentrated in vacuo. Puriﬁcation via

ﬂash column chromatography (eluent EtOAc/30−40 °C petrol, 3:2)

gave 51 as a pale yellow oil (22 mg, 42%, >99:1 dr).

(1RS, 2RS,3SR)-3-(N-Benzyl-N-isopropylamino)-

methylcyclohexane-1,2-diol 52. From 48: Cl₃CCO₂H (187 mg,

1.13 mmol) was added to a solution of 48 (54 mg, 0.225 mmol) in

CH₂Cl₂(0.75 mL), and the resultant solution was stirred at rt for 5

min. m-CPBA (70%, 55 mg, 0.36 mmol) was added, and the mixture

was stirred at rt for 21 h. The mixture was quenched with satd aq

Na₂SO₃until starch-iodide paper indicated that m-CPBA was not

present. MeOH (5 mL) and K₂CO₃(310 mg, 2.25 mmol) were then

added, and the resultant suspension was stirred at rt for 16 h before

being concentrated in vacuo. H₂O (15 mL) was then added, and the

mixture was extracted with CH₂Cl₂(4 × 15 mL). The combined

organic extracts were washed with brine (50 mL), dried (MgSO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 50 → 100% EtOAc in 30−40 °C petrol) gave 52 as a

pale yellow oil (43 mg, 70%, 95:5 dr). ν_max(ﬁlm) 3405 (O−H), 3061,

2931 (C−H), 1494, 1452 (CC); δ_H(400 MHz, CDCl₃) 0.98 (3H,

d, J 6.4, NCHMe_A), 1.14−1.18 (1H, m, C(6)H_A), 1.19 (3H, d, J 6.4,

NCHMe_B), 1.25−1.30 (1H, m, C(5)H_A), 1.44−1.52 (3H, m, C(4)H₂,

C(5)H_B), 1.85−1.90 (1H, m, C(6)H_B), 2.33 (1H, dd, J 13.2, 2.8,

C(3)CH_AH_BN), 2.51−2.54 (1H, m, C(3)H), 2.99−3.14 (4H, m, C(2)

H, C(3)CH_AH_BN, NCHMe₂, NCH_AH_BPh), 3.35−3.39 (1H, m, C(1)

H), 3.92 (1H, d, J 13.2, NCH_AH_BPh), 7.30−7.37 (5H, m, Ph); δ_C(100

MHz, CDCl₃) 12.8, 20.0, 20.9 (C(5), NCHMe₂), 28.6 (C(4)), 31.8

(C(6)), 33.3 (C(3)), 48.4 (NCHMe₂), 50.2 (C(3)CH₂N), 53.7

(NCH₂Ph), 70.9 (C(2)), 78.9 (C(1)), 127.5 (p-Ph), 128.4, 129.0 (o,m-

Ph), 138.3 (i-Ph); m/z (ESI⁺) 278 ([M + H]⁺, 100%); HRMS (ESI⁺)

+

C₁₇H₂₈NO₂([M + H]⁺) requires 278.2115; found 278.2114.

From 50: NaB(OAc)₃H (91 mg, 0.43 mmol) was added to a stirred

solution of 50 (50 mg, 0.215 mmol, 95:5 dr) and AcOH (15 μL, 0.212

mmol) in acetone (2 mL) at rt. The resultant mixture was stirred at rt

for 24 h before being concentrated in vacuo. The residue was dissolved

in CH₂Cl₂(20 mL), and the resultant solution was washed

sequentially with satd aq NaHCO₃(3 × 20 mL) and brine (20

mL), dried (MgSO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 40 → 80% EtOAc in 30−

40 °C petrol) gave 52 as a pale yellow oil (40 mg, 67%, 95:5 dr).

(1RS,2RS,3SR)-3-(N,N-Dibenzylamino)methylcyclohexane-

1,2-diol 53. Cl₃CCO₂H (4.20 g, 25.7 mmol) was added to a solution

of 49 (1.50 g, 5.15 mmol) in CH₂Cl₂(14 mL), and the resultant

solution was stirred at rt for 5 min. m-CPBA (70%, 1.90 g, 7.71 mmol)

was added, and the mixture was stirred at rt for 21 h. The mixture was

Step 2: DBU (0.21 mL, 1.41 mmol) was added to a stirred solution

of 55 in CH₂Cl₂(2.0 mL), and the resultant mixture was stirred at rt

for 24 h. The mixture was diluted with H₂O (5 mL), and the aqueous

layer was extracted with CH₂Cl₂(3 × 5 mL). The combined organic

layers were washed sequentially with H₂O (3 × 15 mL) and brine (15

mL), dried (MgSO₄), and concentrated in vacuo to give an 82:18

mixture of 57:63. Puriﬁcation via ﬂash column chromatography

(eluent 30−40 °C petrol/Et₂O, 32:1) gave 57 as a colorless oil (136

mg, 44%, 96:4 dr). ν_max(ﬁlm) 2964 (C−H), 1494, 1453 (CC); δ_H

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(400 MHz, CDCl₃) 1.00 (3H, d, J 6.7, NCHMe_A), 1.04 (3H, d, J 6.7,

NCHMe_B), 1.08−1.56 (4H, m, C(4)H₂, C(5)H₂), 1.76−1.95 (3H, m,

C(3)H, C(6)H₂), 2.36 (1H, dd, J 13.1, 6.6, C(3)CH_AH_BN), 2.61 (1H,

dd, J 13.1, 8.0, C(3)CH_AH_BN), 2.91 (1H, septet, J 6.7, NCHMe₂),

3.17−3.19 (1H, m, OCH), 3.28−3.30 (1H, m, OCH), 3.64 (2H, AB

system, J 14.6, NCH₂Ph), 7.19−7.42 (5H, m, Ph); δ_C(100 MHz,

CDCl₃) 17.3, 17.8 (NCHMe₂), 19.9, 23.3, 24.1 (C(4), C(5), C(6)),

34.3 (C(3)), 49.8, 52.3, 52.9, 54.9, 55.3 (C(1), C(2), C(3)CH₂N,

NCH₂Ph, NCMe₂), 126.5 (p-Ph), 126.6, 128.1 (o,m-Ph), 141.4 (i-Ph);

m/z (ESI⁺) 260 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₇H₂₆NO⁺([M +

H]⁺) requires 260.2009; found 260.2006.

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzyl-N-methylamino)-

methylcyclohexane 62. Step 1: A stirred solution of 56 (116 mg,

0.72 mmol) in AcOH (0.45 mL) was heated at 50 °C for 24 h. The

mixture was concentrated in vacuo, and the residue was dissolved in

CH₂Cl₂(5 mL). The solution was basiﬁed to pH 9 by the addition of

0.1 M aq NaHCO₃, and the aqueous layer was extracted with CH₂Cl₂

(3 × 10 mL). The combined organic extracts were concentrated in

vacuo (to a volume of approximately 10 mL), washed sequentially with

0.1 M aq NaHCO₃(3 × 10 mL) and brine (10 mL), dried (Na₂SO₄),

and concentrated in vacuo to give 58 as a yellow oil that was used

without puriﬁcation.

Step 3: K₂CO₃(198 mg, 1.43 mmol) was added to a stirred solution

of 61 in MeOH (4.40 mL). The resultant suspension was stirred at rt

for 16 h, then concentrated in vacuo. H₂O (10 mL) was added, and

the mixture was extracted with CH₂Cl₂(4 × 10 mL). The combined

organic extracts were concentrated in vacuo (to a volume of

approximately 10 mL), washed sequentially with H₂O (2 × 10 mL)

and brine (10 mL), dried (MgSO₄), and concentrated in vacuo to give

a 75:25 mixture of 63:57. Puriﬁcation via ﬂash column chromatog-

raphy (eluent 30−40 °C petrol/Et₂O, 9:1) gave 63 as a colorless oil

(86 mg, 61%, >99:1 dr). ν_max(ﬁlm) 2933 (C−H), 1494, 1452 (C

C); δ_H(400 MHz, CDCl₃) 0.75−0.85 (1H, m, C(4)H_A), 0.98 (3H, d,

J 6.7, NCHMe_A), 1.05 (3H, d, J 6.7, NCHMe_B), 1.10−1.38 (2H, m,

C(5)H_A, C(6)H_A), 1.46−1.75 (2H, m, C(4)H_B, C(5)H_B), 1.95−2.09

(2H, m, C(3)H, C(6)H_B), 2.32−2.55 (2H, m, C(3)HCH₂N), 2.95

(1H, septet, J 6.7, NCHMe₂), 3.05−3.08 (2H, m, C(1)H, C(2)H),

3.73 (2H, AB system, J 15.6, NCH₂Ph), 7.11−7.46 (5H, m, Ph); δ_C

(100 MHz, CDCl₃) 16.5, 17.3, 18.5, 25.9, 26.0 (C(4), C(5), C(6),

NCHMe₂), 32.8 (C(3)), 48.9 (NCHMe₂), 52.5 (NCH₂Ph), 52.7, 54.2

(C(1), C(2)), 55.0 (C(3)CH₂N), 126.6 (p-Ph), 128.1, 128.5 (o,m-Ph),

141.1 (i-Ph); m/z (ESI⁺) 260 ([M + H]⁺, 100%); HRMS (ESI⁺)

C₁₇H₂₆NO⁺([M + H]⁺) requires 260.2009; found 260.2004.

(RS,RS,RS)-3-(N-Benzyl-N-methylamino)methylcyclohexane-

1,2-diol 64. A solution of 62 (43 mg, 0.19 mmol) in 1,4-dioxane

(0.72 mL) and 3 M aq H₂SO₄(0.24 mL) was stirred at 40 °C for 24 h.

The mixture was concentrated in vacuo, and the residue was dissolved

in CH₂Cl₂(5 mL) and washed with satd aq NaHCO₃(5 mL). The

aqueous layer was extracted with CH₂Cl₂(2 × 5 mL), and the

combined organic extracts were washed sequentially with satd aq

NaHCO₃(3 × 15 mL) and brine (15 mL), dried (Na₂SO₄), and

concentrated in vacuo to give a 69:31 mixture of 64:51. Puriﬁcation via

ﬂash column chromatography (eluent 100% EtOAc) gave 64 as a

colorless oil (17 mg, 36%, >99:1 dr). ν_max(ﬁlm) 3393 (O−H), 2928,

2802 (C−H); δ_H(500 MHz, CDCl₃) 0.84−0.96 (1H, m, C(4)H_A),

1.25−1.78 (5H, m, C(4)H_B, C(5)H₂, C(6)H_A), 1.92−1.98 (1H, m,

C(6)H_B), 2.24 (3H, s, NMe), 2.38 (1H, dd, J 12.4, 3.0, C(3)-

CH_AH_BN), 2.62 (1H, app t, J 12.4, C(3)CH_AH_BN), 3.21 (1H, app t, J

9.1, C(2)H), 3.37 (1H, d, J 12.9, NCH_AH_BPh), 3.44−3.50 (1H, m,

C(1)H), 3.94 (1H, d, J 12.9, NCH_AH_BPh), 7.16−7.36 (5H, m, Ph); δ_C

(125 MHz, CDCl₃) 23.0 (C(4)), 28.4 (C(5)), 31.1 (C(6)), 37.9

(C(3)), 42.3 (NMe), 63.0 (NCH₂Ph), 64.3 (C(3)CH₂N), 74.9 (C(1)),

82.6 (C(2)), 127.5 (p-Ph), 128.5, 129.1 (o,m-Ph), 137.1 (i-Ph); m/z

Step 2: MsCl (74 μL, 0.94 mmol) was added to a stirred solution of

58 and Et₃N (0.29 mL, 2.10 mmol) in CH₂Cl₂(3.42 mL) at 0 °C, and

the resultant solution was stirred at 0 °C for 1 h. The reaction mixture

was then allowed to warm to rt and washed with H₂O (5 mL). The

aqueous layer was extracted with CH₂Cl₂(3 × 5 mL). The combined

organic extracts were washed sequentially with 10% aq CuSO₄(3 × 15

mL) and brine (15 mL), dried (MgSO₄), and concentrated in vacuo to

give 60 as a yellow oil that was used without puriﬁcation.

Step 3: K₂CO₃(229 mg, 1.66 mmol) was added to a stirred solution

of 60 in MeOH (5.08 mL). The resultant suspension was stirred at rt

for 16 h, then concentrated in vacuo. H₂O (10 mL) was added, and

the mixture was extracted with CH₂Cl₂(4 × 10 mL). The combined

organic extracts were concentrated in vacuo (to a volume of

approximately 10 mL), washed sequentially with H₂O (2 × 10 mL)

and brine (10 mL), dried (MgSO₄), and concentrated in vacuo to give

a 75:25 mixture of 62:56. Puriﬁcation via ﬂash column chromatog-

raphy (eluent 30−40 °C petrol/Et₂O, 4:1) gave 62 as a colorless oil

(84 mg, 58%, >99:1 dr). ν_max(ﬁlm) 2932 (C−H), 1495, 1452 (C

C); δ_H(400 MHz, CDCl₃) 0.75−0.85 (1H, m, C(4)H_A), 1.34−1.40

(2H, m, C(5)H₂), 1.58−1.66 (2H, m, C(4)H_B, C(6)H_A), 2.01−2.20

(2H, m, C(3)H, C(6)H_B), 2.24 (3H, s, NMe), 2.29 (1H, dd, J 11.3,

6.9, C(3)CH_AH_BN), 2.41 (1H, dd, J 11.3, 9.4, C(3)CH_AH_BN), 3.12−

3.14 (2H, m, C(1)H, C(2)H), 3.69 (2H, AB system, J 14.1, NCH₂Ph),

7.24−7.39 (5H, m, Ph); δ_C(100 MHz, CDCl₃) 18.8 (C(5)), 25.0

(C(6)), 26.1 (C(4)), 30.3 (C(3)), 42.6 (NMe), 52.5, 54.8 (C(1),

C(2)), 60.7, 62.7 (C(3)CH₂N, NCH₂Ph), 126.9 (p-Ph), 127.9, 128.6

(o,m-Ph), 139.6 (i-Ph); m/z (ESI⁺) 232 ([M + H]⁺, 100%); HRMS

(ESI⁺) C₁₅H₂₂NO⁺([M + H]⁺) requires 232.1696; found 232.1695.

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzyl-N-isopropylamino)-

methylcyclohexane 63. Step 1: A stirred solution of 57 (147 mg,

0.57 mmol) in AcOH (0.36 mL) was heated at 50 °C for 24 h. The

mixture was concentrated in vacuo, and the residue was dissolved in

CH₂Cl₂(5 mL). The solution was basiﬁed to pH 9 by the addition of

0.1 M aq NaHCO₃, and the aqueous layer was extracted with CH₂Cl₂

(3 × 5 mL). The combined organic extracts were concentrated in

vacuo (to a volume of approximately 10 mL), washed sequentially with

0.1 M aq NaHCO₃(3 × 10 mL) and brine (10 mL), dried (Na₂SO₄),

and concentrated in vacuo to give 59 as a yellow oil that was used

without puriﬁcation.

+

(ESI⁺) 250 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₅H₂₄NO₂([M +

H]⁺) requires 250.1802; found 250.1796.

( R S , R S , R S ) - 3 - ( N - B e n z y l - N - i s o p r o p y l a m i n o ) -

methylcyclohexane-1,2-diol 65. A solution of 63 (56 mg, 0.23

mmol) in 1,4-dioxane (0.87 mL) and 3 M aq H₂SO₄(0.29 mL) was

stirred at 40 °C for 24 h. The mixture was concentrated in vacuo, and

the residue was dissolved in CH₂Cl₂(5 mL) and washed with satd aq

NaHCO₃(5 mL). The aqueous layer was extracted with CH₂Cl₂(2 ×

5 mL), and the combined organic extracts were washed sequentially

with satd aq NaHCO₃(3 × 5 mL) and brine (5 mL), dried (Na₂SO₄),

and concentrated in vacuo to give a 77:23 mixture of 65:52.

Puriﬁcation via ﬂash column chromatography (eluent EtOAc/30−40

°C petrol, 9:1) gave 65 as a colorless oil (29 mg, 48%, 95:5 dr). ν_max

(ﬁlm) 3410 (O−H), 2929, 2856 (C−H); δ_H(500 MHz, CDCl₃)

0.86−1.86 (6H, m, C(4)H₂, C(5)H₂, C(6)H_A, C(3)H) overlapping

0.98 (3H, d, J 6.7, NCHMe_A) and 1.15 (3H, d, J 6.7, NCHMe_B), 1.92−

1.98 (1H, m, C(6)H_B), 2.39−2.42 (1H, m, C(3)CH_AH_BN), 2.45−2.58

(1H, m, C(3)CH_AH_BN), 3.03 (1H, septet, J 6.7, NCHMe₂), 3.11 (1H,

app t, J 9.9, C(2)H), 3.23 (1H, d, J 14.5, NCH_AH_BPh), 3.44−3.49

(1H, m, C(1)H), 3.94 (1H, d, J 14.5, NCH_AH_BPh), 7.18−7.31 (5H, m,

Ph); δ_C(125 MHz, CDCl₃) 11.7, 19.7 (NCHMe₂), 22.1, 27.9, 30.1

(C(4), C(5), C(6)), 36.7 (C(3)), 47.4 (NCHMe₂), 53.4 (C(3)CH₂N),

53.6 (NCH₂Ph), 73.4 (C(1)), 80.2 (C(2)), 126.3 (p-Ph), 127.5, 128.4

(o,m-Ph), 137.4 (i-Ph); m/z (ESI⁺) 278 ([M + H]⁺, 100%); HRMS

Step 2: MsCl (64 μL, 0.81 mmol) was added to a stirred solution of

59 and Et₃N (0.25 mL, 1.81 mmol) in CH₂Cl₂(2.95 mL) at 0 °C, and

the resultant solution was stirred at 0 °C for 1 h. The reaction mixture

was then allowed to warm to rt and washed with H₂O (10 mL). The

aqueous layer was extracted with CH₂Cl₂(3 × 10 mL). The combined

organic extracts were washed sequentially with 10% aq CuSO₄(3 × 10

mL) and brine (10 mL), dried (MgSO₄), and concentrated in vacuo to

give 61 as a yellow oil that was used without puriﬁcation.

+

(ESI⁺) C₁₇H₂₈NO₂([M + H]⁺) requires 278.2115; found 278.2114.

(RS)-3-(N-Benzylamino)cyclopent-1-ene 68. A mixture of 66

(5.00 g, 73.4 mmol), NBS (3.25 g, 18.4 mmol), and AIBN (cat. amt.)

in CCl₄(12.5 mL) was heated at reﬂux for 1 h. The reaction mixture

was cooled to 0 °C, then ﬁltered through a pad of Celite (eluent CCl₄)

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to give a yellow solution of 67. Benzylamine (10.0 mL, 91.7 mmol)

was added to the solution of 67 at 0 °C, and the mixture was then

warmed to rt and stirred for 1.5 h. The mixture was then ﬁltered and

concentrated in vacuo. The residue was dissolved in CH₂Cl₂(150

mL), washed with satd aq NaHCO₃(3 × 100 mL), dried (MgSO₄),

and concentrated in vacuo. Puriﬁcation via ﬂash column chromatog-

raphy (gradient elution, 7 → 60% EtOAc in 30−40 °C petrol) gave 68

as a brown oil (1.63 g, 51%).³⁶δ_H(400 MHz, CDCl₃) 1.44−1.67 (2H,

m), 2.17−2.51 (3H, m), 3.83 (2H, AB system, J 13.0), 3.88−3.94 (1H,

m), 5.82−5.92 (2H, m), 7.22−7.38 (5H, m).

added, and the mixture was stirred at rt for 3.5 h. The mixture was

quenched with satd aq Na₂SO₃until starch-iodide paper indicated that

m-CPBA was not present, and basiﬁed to pH 9 by the addition of 0.1

M aq NaHCO₃. The aqueous layer was extracted with CH₂Cl₂(3 × 30

mL), and the combined organic layers were washed with 0.1 M aq

NaHCO₃(4 × 50 mL) and brine (50 mL), dried (Na₂SO₄), and

concentrated in vacuo to give an 88:12 mixture of 72:76. Puriﬁcation

via ﬂash column chromatography (eluent 5 → 20% EtOAc in 30−40

°C petrol) gave 72 as a pale brown oil (315 mg, 59%, >99:1 dr). ν_max

(ﬁlm) 2027 (C−H), 1453 (CC); δ_H(400 MHz, CDCl₃) 1.15 (1H,

m, C(5)H_A), 1.57−1.68 (1H, m, C(4)H_A), 1.87 (1H, dt, J 13.2, 8.2,

C(5)H_B), 2.08 (1H, dd, J 13.2, 8.2, C(4)H_B), 3.23 (1H, t, J 8.2, C(3)

H), 3.45−3.55 (2H, m, C(1)H, C(2)H), 3.92 (2H, AB system, J 13.1,

NCH₂Ph), 7.23−7.40 (5H, m, Ph); δ_C(100 MHz, CDCl₃) 25.6

(C(4)), 26.3 (C(5)), 52.3 (NCH₂Ph), 56.4, 57.5 (C(1), C(2)), 59.0

(C(3)), 127.0 (p-Ph), 128.2, 128.5 (o,m-Ph), 140.3 (i-Ph); m/z (ESI⁺)

212 ([M + Na]⁺, 30%), 190 ([M + H]⁺, 100%); HRMS (ESI⁺)

C₁₂H₁₆NO⁺([M + H]⁺) requires 190.1226; found 190.1225.

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzyl-N-methylamino)-

cyclopentane 73. From 69: Cl₃CCO₂H (2.19 g, 13.4 mmol) was

added to a solution of 69 (500 mg, 2.67 mmol) in CH₂Cl₂(9.0 mL),

and the resultant solution was stirred at rt for 5 min. m-CPBA (74%,

653 mg, 2.80 mmol) was added, and the mixture was stirred at rt for

3.5 h. The mixture was quenched with satd aq Na₂SO₃until starch-

iodide paper indicated that m-CPBA was not present, and basiﬁed to

pH 9 by the addition of 0.1 M aq NaHCO₃. The aqueous layer was

extracted with CH₂Cl₂(3 × 20 mL), and the combined organic layers

were washed with 0.1 M aq NaHCO₃(4 × 40 mL) and brine (40 mL),

dried (Na₂SO₄), and concentrated in vacuo to give a 92:8 mixture of

73:77. Puriﬁcation via ﬂash column chromatography (eluent 20 →

40% EtOAc in 30−40 °C petrol) gave 73 as a pale yellow oil (256 mg,

46%, >99:1 dr). ν_max(ﬁlm) 3027, 2952 (C−H), 1494, 1453 (CC);

δ_H(400 MHz, CDCl₃) 1.40−1.53 (1H, m, C(4)H_A), 1.53−1.68 (2H,

m, C(5)H_A, C(4)H_B), 2.03−2.14 (1H, m, C(5)H_B), 2.33 (3H, s,

NMe), 3.10 (1H, app dd, J 9.0, 7.5, C(3)H), 3.40 (1H, app d, J 2.5,

C(2)H), 3.49−3.54 (1H, m, C(1)H), 3.64−3.70 (2H, m, NCH₂Ph),

7.22−7.29 (3H, m, Ph), 7.29−7.39 (2H, m, Ph); δ_C(100 MHz,

CDCl₃) 19.1 (C(4)), 26.0 (C(5)), 39.6 (NMe), 54.3 (C(2)), 56.3

(C(1)), 59.9 (NCH₂Ph), 65.3 (C(3)), 126.9 (p-Ph), 128.2, 128.9 (o,m-

Ph), 139.2 (i-Ph); m/z (ESI⁺) 204 ([M + H]⁺, 100%); HRMS (ESI⁺)

C₁₃H₁₈NO⁺([M + H]⁺) requires 204.1383; found 204.1384.

(RS)-3-(N-Benzyl-N-methylamino)cyclopent-1-ene 69. A mix-

ture of 66 (5.00 g, 73.4 mmol), NBS (3.25 g, 18.4 mmol), and AIBN

(cat. amt.) in CCl₄(12.5 mL) was heated at reﬂux for 1 h. The

reaction mixture was cooled to 0 °C, then ﬁltered through a pad of

Celite (eluent CCl₄) to give a yellow solution of 67. N-Benzyl-N-

methylamine (11.8 mL, 91.7 mmol) was added to the solution of 67 at

0 °C, and the mixture was then warmed to rt and stirred for 1.5 h. The

mixture was then ﬁltered and concentrated in vacuo. The residue was

dissolved in CH₂Cl₂(50 mL), washed sequentially with 10% aq citric

acid (3 × 50 mL) and satd aq NaHCO₃(3 × 50 mL), dried (MgSO₄),

and concentrated in vacuo. Puriﬁcation via ﬂash column chromatog-

raphy (gradient elution, 10 → 25% EtOAc in 30−40 °C petrol) gave

69 as a light brown oil (1.21 g, 35%).³⁴δ_H(400 MHz, CDCl₃) 1.78−

2.00 (2H, m), 2.15 (3H, s), 2.24−2.47 (2H, m), 3.49−3.65 (2H, m),

3.93−4.02 (1H, m), 5.77−5.97 (2H, m), 7.21−7.37 (5H, m).

(RS)-3-(N-Benzyl-N-isopropylamino)cyclopent-1-ene 70. A

mixture of 66 (5.00 g, 73.4 mmol), NBS (3.25 g, 18.4 mmol), and

AIBN (cat. amt.) in CCl₄(12.5 mL) was heated at reﬂux for 1 h. The

reaction mixture was cooled to 0 °C, then ﬁltered through a pad of

Celite (eluent CCl₄) to give a yellow solution of 67. N-Benzyl-N-

isopropylamine (15.1 mL, 91.7 mmol) was added to the solution of 67

at 0 °C, and the mixture was then warmed to rt and stirred for 1.5 h.

The mixture was then ﬁltered and concentrated in vacuo. The residue

was dissolved in CH₂Cl₂(50 mL), washed sequentially with 10% aq

citric acid (3 × 50 mL) and satd aq NaHCO₃(3 × 50 mL), dried

(MgSO₄), and concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30−40 °C petrol/EtOAc, 9:1) gave 70 as a

light brown oil (881 mg, 22%). ν_max(ﬁlm) 2962 (C−H), 1493, 1452

(CC); δ_H(400 MHz, CDCl₃) 1.04 (6H, app t, J 6.4, NCHMe₂),

1.66−1.78 (1H, m, C(4)H_A), 1.94−2.07 (1H, m, C(4)H_B), 2.26 (1H,

dd, J 6.5, 2.0, C(5)H_A), 2.31−2.43 (1H, m, C(5)H_B), 2.92 (1H, septet,

J 6.4, NCHMe₂), 3.59 (2H, t, J 16.6, NCH₂Ph), 4.18−4.20 (1H, m,

C(3)H), 5.70−5.76 (1H, m, C(1)H), 5.83−5.85 (1H, m, C(2)H),

7.17−7.24 (1H, m, Ph), 7.30 (2H, t, J 7.5, Ph), 7.33−7.40 (2H, m, Ph);

δ_C(100 MHz, CDCl₃) 20.0, 20.3 (NCHMe₂), 27.5 (C(4)), 31.6

(C(5)), 49.3 (NCHMe₂), 49.5 (NCH₂Ph), 63.6 (C(3)), 126.2 (p-Ph),

127.9, 128.0 (o,m-Ph), 132.2 (C(1)), 134.3 (C(2)), 142.3 (i-Ph); m/z

(ESI⁺) 216 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₅H₂₂N⁺([M + H]⁺)

requires 216.1747; found 216.1746.

From 72: MeI (164 mg, 1.15 mmol) was added to a stirred solution

i

of 72 (218 mg, 1.15 mmol) and Pr₂NEt (0.30 mL, 1.73 mmol) in

CH₂Cl₂(3 mL) at rt. The resultant mixture was stirred for 20 h before

being diluted with CH₂Cl₂(30 mL), washed sequentially with satd aq

Na₂CO₃(3 × 20 mL) and brine (20 mL), dried (MgSO₄), and then

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 20 → 40% EtOAc in 30−40 °C petrol) gave 73 as a

pale yellow oil (105 mg, 45%, >99:1 dr).

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzyl-N-isopropylamino)-

cyclopentane 74. From 70: Cl₃CCO₂H (1.90 g, 11.6 mmol) was

added to a solution of 70 (500 mg, 2.32 mmol) in CH₂Cl₂(7.8 mL),

and the resultant solution was stirred at rt for 5 min. m-CPBA (74%,

567 mg, 2.44 mmol) was added, and the mixture was stirred at rt for

3.5 h. The mixture was quenched with satd aq Na₂SO₃until starch-

iodide paper indicated that m-CPBA was not present, and basiﬁed to

pH 9 by the addition of 0.1 M aq NaHCO₃. The aqueous layer was

extracted with CH₂Cl₂(3 × 20 mL), and the combined organic layers

were washed with 0.1 M aq NaHCO₃(4 × 40 mL) and brine (40 mL),

dried (Na₂SO₄), and concentrated in vacuo to give a 92:8 mixture of

74:78. Puriﬁcation via ﬂash column chromatography (eluent 10 →

20% EtOAc in 30−40 °C petrol) gave 74 as a pale yellow oil (318 mg,

59%, >99:1 dr). ν_max(ﬁlm) 3026, 2964 (C−H); δ_H(400 MHz,

CDCl₃) 1.09 (3H, d, J 6.7, NCHMe_A), 1.11 (3H, d, J 6.7, NCHMe_B),

1.35−1.61 (3H, m, C(4)H₂, C(5)H_A), 2.01 (1H, dd, J 13.1, 7.6, C(5)

H_B), 3.13 (1H, septet, J 6.7, NCHMe₂), 3.26−3.31 (1H, m, C(3)H),

3.31−3.38 (2H, m, C(1)H, C(2)H), 3.78−3.93 (2H, m, NCH₂Ph),

7.19−7.27 (1H, m, Ph), 7.31 (2H, t, J 7.6, Ph), 7.42 (2H, d, J 7.6, Ph);

δ_C(100 MHz, CDCl₃) 19.5, 20.2 (NCHMe₂), 21.8 (C(4)), 25.6

(C(5)), 48.9 (NCHMe₂), 50.3 (NCH₂Ph), 54.1, 57.7 (C(1), C(2)),

(RS)-3-(N,N-Dibenzylamino)cyclopent-1-ene 71. A mixture of

66 (5.00 g, 73.4 mmol), NBS (3.25 g, 18.4 mmol), and AIBN (cat.

amt.) in CCl₄(12.5 mL) was heated at reﬂux for 1 h. The reaction

mixture was cooled to 0 °C, then ﬁltered through a pad of Celite

(eluent CCl₄) to give a yellow solution of 67. Dibenzylamine (17.6

mL, 91.7 mmol) was added to the solution of 67 at 0 °C, and the

mixture was then warmed to rt and stirred for 1.5 h. The mixture was

then ﬁltered and concentrated in vacuo. The residue was dissolved in

CH₂Cl₂(50 mL), washed sequentially with 10% aq citric acid (3 × 50

mL) and satd aq NaHCO₃(3 × 50 mL), dried (MgSO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 1 → 5% Et₂O in 30−40 °C petrol) gave 71 as a pale

yellow oil (1.99 g, 41%).^4cδ_H(400 MHz, CDCl₃) 1.92−2.09 (2H, m,

C(4)H₂), 2.34−2.58 (2H, m, C(5)H₂), 3.59 (2H, d, J 14.0,

N(CH_AH_BPh)₂), 3.81 (2H, d, J 14.0, N(CH_AH_BPh)₂), 4.17−4.25

(1H, m, C(3)H), 5.88−5.95 (1H, m, C(1)H), 5.99−6.05 (1H, m,

C(2)H), 7.32−7.58 (10H, m, Ph).

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzylamino)cyclopentane

72. Cl₃CCO₂H (2.36 g, 14.4 mmol) was added to a solution of 68

(500 mg, 2.89 mmol) in CH₂Cl₂(10 mL), and the resultant solution

was stirred at rt for 5 min. m-CPBA (74%, 720 mg, 3.03 mmol) was

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59.6 (C(3)), 126.3 (p-Ph), 127.9, 128.0 (o,m-Ph), 142.4 (i-Ph); m/z

(ESI⁺) 254 ([M + Na]⁺, 60%), 232 ([M + H]⁺, 100%); HRMS (ESI⁺)

C₁₅H₂₂NO⁺([M + H]⁺) requires 232.1696; found 232.1699.

mL), dried (Na₂SO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 0 → 50% EtOAc in 30−40

°C petrol) gave 83 as a colorless oil (3.70 g, 96%). ν_max(ﬁlm) 2924

(C−H), 1493, 1451 (CC); δ_H(400 MHz, CDCl₃) 1.06 (6H, app t,

J 6.4, NCHMe₂), 1.22−1.35 (1H, m, C(5)H_A), 1.41−1.55 (2H, m,

C(4)H₂), 1.61−1.76 (1H, m, C(6)H_A), 1.94 (2H, m, C(5)H_B, C(7)

H_A), 2.01−2.08 (1H, m, C(6)H_B), 2.12−2.25 (1H, m, C(7)H_B), 3.02

(1H, septet, J 6.4, NCHMe₂), 3.49 (1H, app d, J 7.1, C(3)H), 3.74

(2H, AB system, J 15.4, NCH₂Ph), 5.70−5.79 (1H, m, C(1)H), 5.83−

5.93 (1H, m, C(2)H), 7.18−7.25 (1H, m, Ph), 7.31 (2H, t, J 7.6, Ph),

7.41 (2H, d, J 7.6, Ph); δ_C(100 MHz, CDCl₃) 21.1 (NCHMe₂), 26.8

(C(6)), 28.5, 28.8 (C(4), C(7)), 32.4 (C(5)), 49.1 (NCHMe₂), 50.3

(NCH₂Ph), 58.6 (C(3)), 126.2 (p-Ph), 127.9, 128.0 (o,m-Ph), 129.7

(C(2)), 138.2 (C(1)), 142.8 (i-Ph); m/z (ESI⁺) 244 ([M + H]⁺,

100%); HRMS (ESI⁺) C₁₇H₂₆N⁺([M + H]⁺) requires 244.2060;

found 244.2058.

(RS)-3-(N,N-Dibenzylamino)cyclohept-1-ene 84. A stirred

mixture of 80 (1.00 g, 5.7 mmol), dibenzylamine (2.75 mL, 14.3

mmol), and K₂CO₃(0.95 g, 6.9 mmol) in THF (15 mL) was heated at

50 °C for 16 h. The resultant mixture was diluted with H₂O (20 mL)

and CH₂Cl₂(20 mL), and the organic layer was separated and washed

with satd aq NaHCO₃(20 mL) and brine (20 mL), dried (Na₂SO₄),

and concentrated in vacuo. Puriﬁcation via ﬂash column chromatog-

raphy (gradient elution, 0 → 50% EtOAc in 30−40 °C petrol) gave 84

as a yellow oil (1.43 g, 86%). δ_H(400 MHz, CDCl₃) 1.26−2.23 (8H,

m, C(4)H₂, C(5)H₂, C(6)H₂, C(7)H₂), 3.35 (1H, app d, J 10.4, C(3)

H), 3.59 (2H, d, J 14.2, N(CH_AH_BPh)₂), 3.74 (2H, d, J 14.2,

N(CH_AH_BPh)₂), 5.80−5.89 (1H, m, C(1)H), 5.93−6.00 (1H, m,

C(2)H), 7.20−7.42 (10H, m, Ph).

(1RS,2SR,3RS)-1,2-Epoxy-3-(N-benzyl-N-methylamino)-

cycloheptane 86. Cl₃CCO₂H (3.79 g, 23.2 mmol) was added to a

solution of 82 (1.00 g, 4.64 mmol) in CH₂Cl₂(15.5 mL), and the

resultant solution was stirred at rt for 5 min. m-CPBA (74%, 1.73 g,

7.42 mmol) was added, and the mixture was stirred at rt for 7 h. The

mixture was quenched with satd aq Na₂SO₃until starch-iodide paper

indicated that m-CPBA was not present, and basiﬁed to pH 9 by the

addition of satd aq NaHCO₃. The aqueous layer was extracted with

CH₂Cl₂(3 × 50 mL), and the combined organic layers were washed

with satd aq NaHCO₃(4 × 100 mL) and brine (100 mL), dried

(Na₂SO₄), and concentrated in vacuo to give a 75:25 mixture of 86:90.

Puriﬁcation via ﬂash column chromatography (gradient elution, 0 →

50% EtOAc in 30−40 °C petrol) gave 90 as a yellow oil (46 mg, 4%,

>99:1 dr). R_f0.5 (30−40 °C petrol/EtOAc, 4:1); ν_max(ﬁlm) 2928

(C−H), 1494, 1453 (CC); δ_H(400 MHz, CDCl₃) 0.76 (1H, app q,

J 12.4, C(5)H_A), 1.29−1.61 (3H, m, C(4)H_A, C(6)H₂), 1.68 (1H, m,

C(7)H_A), 1.72−1.86 (2H, m, C(4)H_B, C(5)H_B), 2.26−2.30 (1H, m,

C(7)H_B), 2.32 (3H, s, NMe), 2.93 (1H, dd, J 11.5, 2.2, C(3)H), 3.10

(1H, app t, J 5.2, C(1)H), 3.30 (1H, app d, J 5.2, C(2)H), 3.57 (1H, d,

J 13.4, NCH_AH_BPh), 3.79 (1H, d, J 13.4, NCH_AH_BPh), 7.21−7.40

(5H, m, Ph); δ_C(100 MHz, CDCl₃) 23.2 (C(4)), 24.1 (C(6)), 27.3

(C(5)), 28.1 (C(7)), 38.2 (NMe), 53.2 (C(1)), 58.0 (NCH₂Ph), 60.1

(C(2)), 63.6 (C(3)), 126.8 (p-Ph), 128.2, 128.7 (o,m-Ph), 139.9 (i-

Ph); m/z (ESI⁺) 232 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₅H₂₂NO⁺

([M + H]⁺) requires 232.1696; found 232.1696. Further elution gave

86 as a yellow oil (357 mg, 36%, >99:1 dr). R_f0.2 (30−40 °C petrol/

EtOAc, 4:1); ν_max(ﬁlm) 2927 (C−H), 1494, 1454 (CC); δ_H(400

MHz, CDCl₃) 1.17−1.43 (3H, m, C(5)H_A, C(6)H_A, C(7)H_A), 1.55−

1.67 (1H, m, C(4)H_A), 1.67−1.78 (1H, m, C(6)H_B), 1.88−2.01 (2H,

m, C(4)H_B, C(5)H_B), 2.24−2.34 (1H, m, C(7)H_B), 2.30 (3H, s,

NMe), 2.54 (1H, app dd, J 10.2, 7.5, C(3)H), 3.04 (1H, app dd, J 8.1,

5.4, C(1)H), 3.17 (1H, dd, J 7.5, 5.4, C(2)H), 3.72−3.78 (2H, m,

NCH₂Ph), 7.21−7.40 (5H, m, Ph); δ_C(100 MHz, CDCl₃) 24.1

(C(6)), 28.9 (C(5)), 29.2 (C(7)), 30.8 (C(4)), 38.2 (NMe), 53.2

(C(1)), 55.6 (C(2)), 58.5 (NCH₂Ph), 65.9 (C(3)), 127.0 (p-Ph),

128.2, 129.1 (o,m-Ph), 139.0 (i-Ph); m/z (ESI⁺) 232 ([M + H]⁺,

100%); HRMS (ESI⁺) C₁₅H₂₂NO⁺([M + H]⁺) requires 232.1696;

found 232.1696.

From 72: NaB(OAc)₃H (136 mg, 0.64 mmol) was added to a

stirred solution of 72 (81 mg, 0.43 mmol) and AcOH (25 μL, 0.43

mmol) in acetone (2 mL) at rt. The resultant mixture was stirred at rt

for 24 h before being concentrated in vacuo. The residue was dissolved

in CH₂Cl₂(10 mL), and the resultant solution was washed

sequentially with satd aq NaHCO₃(3 × 10 mL) and brine (10

mL), dried (MgSO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 10 → 30% Et₂O in 30−40

°C petrol) gave 74 as a colorless oil (64 mg, 65%, >99:1 dr).

(1RS,2SR,3SR)-1,2-Epoxy-3-(N,N-dibenzylamino)-

cyclopentane 75. From 71: Cl₃CCO₂H (31.0 g, 190 mmol) was

added to a solution of 71 (10.0 g, 38.0 mmol) in CH₂Cl₂(127 mL),

and the resultant solution was stirred at rt for 5 min. m-CPBA (73%,

9.43 g, 39.9 mmol) was added, and the mixture was stirred at rt for 3.5

h. The mixture was quenched with satd aq Na₂SO₃until starch-iodide

paper indicated that m-CPBA was not present, and basiﬁed to pH 9 by

the addition of 0.1 M aq NaHCO₃. The aqueous layer was extracted

with CH₂Cl₂(3 × 100 mL), and the combined organic layers were

washed with 0.1 M aq NaHCO₃(4 × 200 mL) and brine (200 mL),

dried (Na₂SO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 1 → 8% EtOAc in 40−60

°C petrol) gave 75 as a colorless oil that solidiﬁed on standing to a

white crystalline solid (10.5 g, 99%, >99:1 dr). δ_H(400 MHz, CDCl₃)

1.45−1.59 (3H, m, C(4)H_A, C(5)H₂), 2.00−2.11 (1H, m, C(4)H_B),

3.25−3.31 (1H, m, C(3)H), 3.34 (1H, app d, J 2.7, OCH), 3.47 (1H,

app d, J 2.7, OCH), 3.74 (2H, d, J 14.3, N(CH_AH_BPh)₂), 3.86 (2H, d, J

14.3, N(CH_AH_BPh)₂), 7.22−7.46 (10H, m, Ph).

From 72: BnBr (106 mg, 0.62 mmol) was added to a stirred

i

solution of 72 (78 mg, 0.412 mmol) and Pr₂NEt (0.10 mL, 0.62

mmol) in CH₂Cl₂(1 mL) at rt. The resultant mixture was stirred for

20 h before being diluted with CH₂Cl₂(20 mL), washed sequentially

with water (3 × 10 mL) and brine (10 mL), dried (Na₂SO₄), and then

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 5 → 20% Et₂O in 30−40 °C petrol) gave 75 as a

colorless oil (80 mg, 70%, >99:1 dr).

(RS)-3-(N-Benzylamino)cyclohept-1-ene 81. A stirred mixture

of 80 (1.00 g, 5.7 mmol), benzylamine (1.56 mL, 14.3 mmol), and

K₂CO₃(0.95 g, 6.90 mmol) in THF (15 mL) was heated at 50 °C for

16 h. The resultant mixture was diluted with H₂O (20 mL) and

CH₂Cl₂(20 mL), and the organic layer was separated and washed with

satd aq NaHCO₃(20 mL) and brine (20 mL), dried (Na₂SO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 0 → 50% EtOAc in 30−40 °C petrol) gave 81 as a

yellow oil (731 mg, 64%).³⁷δ_H(400 MHz, CDCl₃) 1.24−1.39 (1H,

m), 1.43−1.72 (3H, m), 1.75−1.83 (1H, m), 1.97 (1H, m), 2.02−2.12

(1H, m), 2.13−2.24 (1H, m), 3.41 (1H, dd, J 1.5, 10.1), 3.81 (2H, dd,

J 13.0, 10.2), 5.71−5.77 (1H, m), 5.80−5.88 (1H, m), 7.22−7.36 (5H,

m).

(RS)-3-(N-Benzyl-N-methylamino)cyclohept-1-ene 82. A

stirred mixture of 80 (1.00 g, 5.7 mmol), N-benzyl-N-methylamine

(1.84 mL, 14.3 mmol), and K₂CO₃(0.95 g, 6.9 mmol) in THF (15

mL) was heated at 50 °C for 16 h. The resultant mixture was diluted

with H₂O (20 mL) and CH₂Cl₂(20 mL), and the organic layer was

separated and washed with satd aq NaHCO₃(20 mL) and brine (20

mL), dried (Na₂SO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 0 → 50% EtOAc in 30−40

°C petrol) gave 82 as a yellow oil (1.14 g, 93%).³⁴δ_H(400 MHz,

CDCl₃) 1.29−1.40 (1H, m), 1.42−1.58 (2H, m), 1.65−1.76 (1H, m),

1.91−2.10 (3H, m), 2.16−2.21 (1H, m), 2.22 (3H, s), 3.37 (1H, d, J

8.9), 3.57 (2H, dd, J 13.0, 23.2), 5.86 (1H, m), 5.88−5.94 (1H, m),

7.22−7.38 (5H, m).

(RS)-3-(N-Benzyl-N-isopropylamino)cyclohept-1-ene 83. A

stirred mixture of 80 (1.35 g, 7.72 mmol), N-benzyl-N-isopropylamine

(3.18 mL, 19.3 mmol), and K₂CO₃(1.28 g, 9.25 mmol) in THF (20

mL) was heated at 50 °C for 16 h. The resultant mixture was diluted

with H₂O (20 mL) and CH₂Cl₂(20 mL), and the organic layer was

separated and washed with satd aq NaHCO₃(20 mL) and brine (20

(1RS,2SR,3RS)-1,2-Epoxy-3-(N-benzyl-N-isopropylamino)-

cycloheptane 87. Cl₃CCO₂H (187 mg, 1.13 mmol) was added to a

solution of 83 (55 mg, 0.23 mmol) in CH₂Cl₂(0.76 mL), and the

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resultant solution was stirred at rt for 5 min. m-CPBA (74%, 57 mg,

0.24 mmol) was added, and the mixture was stirred at rt for 3.5 h. The

mixture was quenched with satd aq Na₂SO₃until starch-iodide paper

indicated that m-CPBA was not present, and basiﬁed to pH 9 by the

addition of satd aq NaHCO₃. The aqueous layer was extracted with

CH₂Cl₂(3 × 10 mL), and the combined organic layers were washed

with satd aq NaHCO₃(4 × 50 mL) and brine (50 mL), dried

(Na₂SO₄), and concentrated in vacuo to give a 93:7 mixture of 87:91.

Puriﬁcation via ﬂash column chromatography (gradient elution, 0 →

50% EtOAc in 30−40 °C petrol) gave 87 as a yellow oil (28 mg, 46%,

>99:1 dr). ν_max(ﬁlm) 2928 (C−H), 1457 (CC); δ_H(400 MHz,

CDCl₃) 1.06 (3H, d, J 6.6, NCHMe_A), 1.10 (3H, d, J 6.6, NCHMe_B),

1.26−1.33 (3H, m, C(4)H_A, C(5)H_A, C(6)H_A), 1.53−1.64 (1H, m,

C(7)H_A), 1.64−1.73 (1H, m, C(5)H_B), 1.80 (1H, d, J 14.7, C(7)H_B),

1.83−1.91 (1H, m, C(6)H_B), 2.22−2.32 (1H, m, C(4)H_B), 2.75 (1H,

app dd, J 10.0, 7.2, C(1)H), 3.00−3.05 (1H, m, C(3)H), 3.05−3.18

(2H, m, C(2)H, NCHMe₂), 3.82 (2H, AB system, J 15.7, NCH₂Ph),

7.18−7.44 (5H, m, Ph); δ_C(100 MHz, CDCl₃) 19.0, 20.4 (NCHMe₂),

24.2 (C(5)), 29.3 (C(6)), 30.0 (C(4)), 32.7 (C(7)), 49.7 (NCHMe₂),

49.8 (NCH₂Ph), 54.6 (C(3)), 58.1 (C(2)), 60.3 (C(1)), 126.4 (p-Ph),

127.7, 128.1 (o,m-Ph), 142.6 (i-Ph); m/z (ESI⁺) 260 ([M + H]⁺,

100%); HRMS (ESI⁺) C₁₇H₂₆NO⁺([M + H]⁺) requires 260.2009;

found 260.2008.

(1RS,2SR,3RS)-1,2-Epoxy-3-(N,N-dibenzylamino)-

cycloheptane 88. Cl₃CCO₂H (5.74 g, 35.2 mmol) was added to a

stirred solution of 84 (2.05 g, 7.03 mmol) in CH₂Cl₂(23 mL), and the

resultant solution was stirred at rt for 5 min. m-CPBA (74%, 1.72 g,

7.38 mmol) was added, and the mixture was stirred at rt for 3.5 h. The

mixture was quenched with satd aq Na₂SO₃until starch-iodide paper

indicated that m-CPBA was not present, and basiﬁed to pH 9 by the

addition of satd aq NaHCO₃. The aqueous layer was extracted with

CH₂Cl₂(3 × 10 mL), and the combined organic layers were washed

with satd aq NaHCO₃(4 × 50 mL) and brine (50 mL), dried

(Na₂SO₄), and concentrated in vacuo to give a 94:6 mixture of 88:92.

Puriﬁcation via ﬂash column chromatography (gradient elution, 2 →

20% Et₂O in 40−60 °C petrol) gave 92 as a colorless oil that solidiﬁed

on standing to a white crystalline solid (94 mg, 4%, ∼95% purity,

>99:1 dr).^4cδ_H(400 MHz, CDCl₃) 0.59−2.31 (8H, m, C(4)H₂, C(5)

H₂, C(6)H₂, C(7)H₂), 2.89 (1H, app dd, J 11.6, 2.8, C(1)H), 3.06

(1H, app t, J 5.3, C(3)H), 3.35 (1H, dd, J 4.8, 1.0, C(2)H), 3.59 (2H,

d, J 13.9, N(CH_AH_BPh)₂), 3.90 (2H, d, J 13.9, N(CH_AH_BPh)₂), 7.21−

7.42 (10H, m, Ph); δ_C(100 MHz, CDCl₃) 23.4, 24.1, 27.1, 28.0 (C(4),

C(5), C(6), C(7)), 53.3 (C(3)), 54.3 (N(CH₂Ph)₂), 58.4 (C(1)), 60.7

(C(2)), 126.7 (p-Ph), 128.1, 128.5 (o, m-Ph), 140.4 (i-Ph). Further

elution gave 88 as a colorless oil that solidiﬁed on standing to a white

crystalline solid (1.49 g, 69%, >99:1 dr).^4cδ_H(400 MHz, CDCl₃)

1.02−2.25 (8H, m, C(4)H₂, C(5)H₂, C(6)H₂, C(7)H₂), 2.66 (1H, app

dd, J 10.4, 7.5, C(3)H), 3.00 (1H, ddd, J 8.0, 6.5, 5.0, C(1)H), 3.24

(1H, dd, J 7.5, 5.0, C(2)H), 3.77 (4H, AB system, J 13.9, N(CH₂Ph)₂),

7.21−7.46 (10H, m, Ph).

(NCH₂Ph), 54.9 (C(1)), 57.6 (C(3)), 60.4 (C(2)), 126.9 (p-Ph),

128.1, 128.4 (o,m-Ph), 140.6 (i-Ph); m/z (ESI⁺) 218 ([M + H]⁺,

100%); HRMS (ESI⁺) C₁₄H₂₀NO⁺([M + H]⁺) requires 218.1539;

found 218.1539.

(1RS,2SR,3SR)-3-(N-Benzyl-N-methylamino)cycloheptane 90.

MeI (28 μL, 0.46 mmol) was added to a stirred solution of 89 (100

i

mg, 0.46 mmol) and Pr₂NEt (0.12 mL, 0.69 mmol) in CH₂Cl₂(0.9

mL) at rt. The resultant mixture was stirred for 20 h before being

diluted with CH₂Cl₂(10 mL), washed sequentially with satd aq

Na₂CO₃(3 × 10 mL) and brine (10 mL), dried (MgSO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, 20 → 40% EtOAc in 30−40 °C petrol) gave 90 as a

pale yellow oil (61 mg, 57%, >99:1 dr).

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzyl-N-isopropylamino)-

cycloheptane 91. NaB(OAc)₃H (64 mg, 0.303 mmol) was added to

a stirred solution of 89 (47 mg, 0.216 mmol) and AcOH (14 μL, 0.216

mmol) in acetone (1.5 mL) at rt. The resultant mixture was stirred at

rt for 24 h before being concentrated in vacuo. The residue was

dissolved in CH₂Cl₂(10 mL), and the resultant solution was washed

sequentially with satd aq NaHCO₃(3 × 10 mL) and brine (10 mL),

dried (MgSO₄), and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, 0 → 20% EtOAc in 30−40

°C petrol) gave 91 as a pale yellow oil (36 mg, 66%, >99:1 dr). ν_max

(ﬁlm) 2927 (C−H), 1452 (CC); δ_H(400 MHz, CDCl₃) 0.60−0.74

(1H, m, C(5)H_A), 1.05 (3H, d, J 6.6, NCHMe_A), 1.08 (3H, d, J 6.6,

NCHMe_B), 1.24−1.38 (1H, m, C(6)H_A), 1.41−1.67 (3H, m, C(4)H_A,

C(6)H_B, C(7)H_A), 1.69−1.82 (2H, m, C(4)H_B, C(5)H_B), 2.21−2.33

(1H, m, C(7)H_B), 2.93 (1H, app dd, J 11.6, 2.4, C(3)H), 3.02 (1H,

app t, J 4.5, C(1)H), 3.22 (1H, app d, J 4.5, C(2)H), 3.27 (1H, septet,

J 6.6, NCHMe₂), 3.81 (2H, AB system, J 14.0, NCH₂Ph), 7.23−7.40

(5H, m, Ph); δ_C(100 MHz, CDCl₃) 20.8, 22.1 (NCHMe₂), 24.1

(C(6)), 27.3 (C(4)), 27.5 (C(5)), 28.2 (C(7)), 48.3 (NCHMe₂), 49.6

(NCH₂Ph), 53.6 (C(1)), 58.6 (C(3)), 61.5 (C(2)), 126.4 (p-Ph),

128.0, 128.1 (o,m-Ph), 142.1 (i-Ph); m/z (ESI⁺) 282 ([M + Na]⁺,

50%) 260 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₇H₂₆NO⁺([M + H]⁺)

requires 260.2009; found 260.2008.

(1RS,2SR,3SR)-1,2-Epoxy-3-(N,N-dibenzylamino)-

cycloheptane 92. BnBr (79 μL, 0.67 mmol) was added to a stirred

i

solution of 89 (100 mg, 0.46 mmol) and Pr₂NEt (0.12 mL, 0.67

mmol) in CH₂Cl₂(0.5 mL) at rt. The resultant mixture was stirred for

20 h before being diluted with CH₂Cl₂(10 mL), washed sequentially

with water (3 × 10 mL) and brine (10 mL), dried (Na₂SO₄), and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatography

(eluent 30−40 °C petrol/EtOAc, 4:1) gave 92 as a colorless oil that

solidiﬁed on standing to a white crystalline solid (65 mg, 47%, ∼95%

purity, >99:1 dr).

ASSOCIATED CONTENT

■

S

* Supporting Information

Copies of ¹H and ¹³C NMR spectra, and crystallographic

information ﬁles (for structures CCDC 839524−839526). This

material is available free of charge via the Internet at http://

pubs.acs.org.

(1RS,2SR,3SR)-1,2-Epoxy-3-(N-benzylamino)cycloheptane

89. Cl₃CCO₂H (4.07 g, 25.0 mmol) was added to a solution of 81

(1.00 g, 5.00 mmol) in CH₂Cl₂(16.7 mL), and the resultant solution

was stirred at rt for 5 min. m-CPBA (70%, 3.08 g, 12.5 mmol) was

added, and the mixture was stirred at rt for 20 min. The mixture was

quenched with satd aq Na₂SO₃until starch-iodide paper indicated that

m-CPBA was not present, and basiﬁed to pH 9 by the addition of satd

aq NaHCO₃. The aqueous layer was extracted with CH₂Cl₂(3 × 50

mL), and the combined organic layers were washed with satd aq

NaHCO₃(4 × 100 mL) and brine (100 mL), dried (Na₂SO₄), and

concentrated in vacuo to give a 15:85 mixture of 85:89. Puriﬁcation via

ﬂash column chromatography (gradient elution, 0 → 50% EtOAc in

30−40 °C petrol) gave 89 as a pale orange solid (550 mg, 51%, >99:1

dr). mp 24−26 °C; ν_max(ﬁlm) 2928 (C−H), 1494, 1453 (CC); δ_H

(400 MHz, CDCl₃) 0.83−0.97 (1H, m, C(5)H_A), 1.24−1.61 (3H, m,

C(4)H_A, C(6)H₂), 1.68−1.84 (3H, m, C(4)H_B, C(5)H_B, C(7)H_A),

2.22−2.35 (1H, m, C(7)H_B), 3.00 (1H, app dd, J 10.9, 2.5, C(3)H),

3.13 (1H, app t, J 5.0, C(1)H), 3.24 (1H, app d, J 5.0, C(2)H), 3.94

(1H, td, J 13.1, 6.1, NCH₂Ph), 7.18−7.48 (5H, m, Ph); δ_C(100 MHz,

CDCl₃) 24.2 (C(6)), 26.7 (C(5)), 28.3 (C(7)), 30.9 (C(4)), 51.1

AUTHOR INFORMATION

Corresponding Author

*E-mail: steve.davies@chem.ox.ac.uk.

■

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The authors would like to thank the National University of

Ireland for a Travelling Studentship; St. Catherine’s College,

Oxford, for a Leathersellers Scholarship and a Light Senior

Scholarship; the University of Oxford for a Prendergast Bequest

(M.B.B.); Ajinomoto Co., Inc. for funding (W.K.); the

European Comission for an Erasmus Scholarship; and the

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The Journal of Organic Chemistry

Article

CPBA and Cl₃CCO₂H does not occur under these conditions and,

therefore, conﬁrms that m-CPBA is the active oxidant in these

reactions.

Department of Organic Chemistry, University of Groningen,

for H. J. Backer-fonds (A.K.S.).

(10) Small amounts (typically <5%) of the corresponding amino diol

17−20 was frequently observed in the crude samples of trichlor-

oacetate esters 13−16, arising from hydrolysis of the labile

trichloroacetate ester functionality.

REFERENCES

■

(1) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,

1307.

(2) For examples of chemo- and diastereoselective cyclopropanations

of allylic amines, see: (a) Davies, S. G.; Ling, K. B.; Roberts, P. M.;

Russell, A. J.; Thomson, J. E. Chem. Commun. 2007, 4029.

(11) Following our previously reported procedure to determine the

number of equivalents of acid required for eﬀective N-protection by

protonation (see ref 4a), the formation of the corresponding

ammonium species from 9−11 in the presence of Cl₃CCO₂H and

́

(b) Csatayova, K.; Davies, S. G.; Lee, J. A.; Ling, K. B.; Roberts, P.

M.; Russell, A. J.; Thomson, J. E. Tetrahedron 2010, 66, 8420. For

examples of chemo- and diastereoselective ring-closing iodoaminations

of unsaturated amines, see: (c) Davies, S. G.; Nicholson, R. L.; Price,

P. D.; Roberts, P. M.; Smith, A. D. Synlett 2004, 901. (d) Davies, S. G.;

Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Savory, E.

D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20,

758. (e) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.;

Thomson, J. E. Org. Lett. 2011, 13, 1594. (f) Davies, S. G.; Lee, J. A.;

Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron Lett. 2011, 52,

6477. (g) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.;

West, C. J. Tetrahedron 2012, 68, 4302. We also developed a protocol

for the diastereoselective oxidation of an allylic tertiary amine N-oxide;

see: (h) Aciro, C.; Davies, S. G.; Kurosawa, W.; Roberts, P. M.;

Russell, A. J.; Thomson, J. E. Org. Lett. 2009, 11, 1333.

1

TsOH was examined by H NMR spectroscopy. The requisite acid

was added in 1 equiv portions to a solution of the requisite amines 9−

11 in CDCl₃, and it was concluded that 5 equiv of Cl₃CCO₂H or 3

equiv of TsOH would be suﬃcient to enable eﬃcient ammonium-

directed oxidation of allylic amines 9−11.

(12) Crystallographic data (excluding structure factors) have been

deposited with the Cambridge Crystallographic Data Centre as

supplementary publication numbers CCDC 839524 (14), CCDC

839525 (21), and CCDC 839526 (25).

(13) (a) Bartlett, P. D. Rec. Chem. Prog. 1950, 11, 47. (b) Henbest, H.

B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958.

(14) For some transition-state modeling studies concerning the

peracid epoxidation of 3-hydroxycyclohex-1-ene and related reactions,

see: (a) Freccero, M.; Gandolfi, R.; Sarzi-Amade,

Org. Chem. 1999, 64, 3853. (b) Freccero, M.; Gandolfi, R.; Sarzi-

Amade, M.; Rastelli, A. J. Org. Chem. 2000, 65, 8948. (c) Freccero, M.;

Gandolfi, R.; Sarzi-Amade, M.; Rastelli, A. J. Org. Chem. 2004, 69,

7479.

̀

M.; Rastelli, A. J.

(3) (a) Emmons, W. D.; Pagano, A. S.; Freeman, J. P. J. Am. Chem.

Soc. 1954, 76, 3472. (b) Quick, J.; Mondello, C.; Humora, M.;

Brennan, T. J. Org. Chem. 1978, 43, 2705. (c) Quick, J.; Khandelwal,

Y.; Meltzer, P. C.; Weinberg, J. S. J. Org. Chem. 1983, 48, 5199.

̀

(d) Asensio, G.; Gonzal

R.; Adam, W. J. Am. Chem. Soc. 1993, 115, 7250. (e) Asensio, G.;

Mello, R.; Boix-Bernardini, C.; Gonzalez-Nunez, M. E.; Castellano, G.

J. Org. Chem. 1995, 60, 3692. (f) Asensio, G.; Boix-Bernardini, C.;

Andreu, C.; Gonzalez-Nunez, M. E.; Mello, R.; Edwards, J. O.;

Castellano, G. J. Org. Chem. 1999, 64, 4705. (g) Gil, L.; Comper

́

ez-Nunez, M. E.; Boix-Bernardini, C.; Mello,

́

̃

(15) (a) Chamberlain, P.; Roberts, M. L.; Whitham, G. H. J. Chem.

Soc. B 1970, 1374. (b) Anslyn, E. V.; Dougherty, D. A. Modern Physical

Organic Chemistry; University Science: Sausalito, CA, 2006.

Attempted fitting of the experimental data to a first-order rate law

yielded a poor fit.

(16) In these calculations, the concentration of Cl₃CCO₂H was

treated as a variable (rather than being held constant), although the

uncertainty in the eﬀective concentration of this species (at any point

in the reaction, 1 equiv is formally present as the trichloroacetate

anion) is the main source of error in the calculation of k₂(manifest in

the much larger error bars associated with the value of k₂as compared

to k₁).

́

̃

́

̃

̀

e, D.;

Guilloteau-Bertin, B.; Chiaroni, A.; Marazano, C. Synthesis 2000, 2117.

(h) Grishina, G. V.; Borisenko, A. A.; Veselov, I. S.; Petrenko, A. M.

Russ. J. Org. Chem. 2005, 41, 272. (i) Aggarwal, V. K.; Fang, G. Y.

Chem. Commun. 2005, 3448. (j) Edwards, A. S.; Wybrow, R. A. J.;

Johnstone, C.; Adams, H.; Harrity, J. P. A. Chem. Commun. 2002,

1542.

(4) (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.;

Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751.

(b) Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.;

Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3762. (c) Bond, C. W.;

Cresswell, A. J.; Davies, S. G.; Kurosawa, W.; Lee, J. A.; Fletcher, A.

M.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org.

Chem. 2009, 74, 6735. (d) Davies, S. G.; Fletcher, A. M.; Kurosawa,

W.; Lee, J. A.; Poce, G.; Roberts, P. M.; Thomson, J. E.; Williamson,

D. M. J. Org. Chem. 2010, 75, 7745. (e) Kurosawa, W.; Roberts, P. M.;

Davies, S. G. Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem., Jpn.)

2010, 68, 1295.

(17) The consumption of ammonium 39 was monitored by

calculation of the average integration of the peaks due to C(2)H

(δ_H5.73−5.90 ppm) and C(1)H (δ_H6.24−6.42 ppm), whereas the

consumption of m-CPBA was monitored by calculation of the

integration of the peak at δ_H7.87−7.93 and 7.95−8.00 ppm. The

formation of ammonium 41 was monitored by integration of the signal

due to NMe (δ_H3.07−3.11 ppm). The intermediate epoxide

1

ammonium 40 was observed in the H NMR spectrum at δ_H3.64−

3.72 ppm; an authentic sample was prepared upon addition of

Cl₃CCO₂H (5 equiv) to a solution of 23 in CD₂Cl₂.

(18) Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1986, 1641.

(19) Ring-opening of syn-epoxides 56 and 57 proceeded to give the

corresponding acetates 58 and 59 as the major products, in addition to

at least three other minor, acetate-containing species (as evidenced by

several signals in the region of δ_H∼ 4.5−5.0 ppm).

(20) For a discussion concerning the regioselectivity of the ring-

opening of the diastereoisomers of 1,2-epoxy-3-hydroxymethylcyclo-

hexane, see ref 4c and references cited therein. Presumably, the

regioselectivity of the ring-opening of syn-epoxides 56 and 57, and

anti-epoxides 62 and 63, is governed by similar factors.

(5) (a) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,

A. J.; Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12, 136. (b) Bagal, S.

K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J.

E. J. Org. Chem. 2010, 75, 8133.

(6) Bagal, S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P.

M.; Scott, P. M.; Thomson, J. E. Tetrahedron Lett. 2011, 52, 2216.

(7) (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,

183. (b) Davies, S. G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.;

Kotchie, L. J.; Price, P. D.; Price Mortimer, A. J.; Russell, A. J.; Smith,

A. D. Tetrahedron: Asymmetry 2006, 17, 1793. (c) Davies, S. G.;

Mulvaney, A. W.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry

2007, 18, 1554. For a review, see: (d) Davies, S. G.; Smith, A. D.;

Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.

(21) The minor diastereoisomers 51 and 52 resulting from these

ring-opening reactions were spectroscopically identical to the major

products arising from the ammonium-directed oxidation of the

corresponding homoallylic amines 47 and 48.

(8) (a) Djerassi, C. Chem. Rev. 1948, 43, 271. (b) Dauben, H. J.;

(22) For example, see: (a) Iranpoor, N.; Shekarriz, M.; Shiriny, F.

Synth. Commun. 1998, 28, 347. (b) Yoo, D.-W.; Yoo, S.-K.; Kim, C.;

Lee, J.-K. J. Chem. Soc., Dalton Trans. 2002, 3931. (c) Iranpoor, N.;

Firouzabadi, H.; Aghapour, G.; Nahid, A. Bull. Chem. Soc. Jpn. 2004,

McCoy, L. L. J. Am. Chem. Soc. 1959, 81, 4863.

(9) A mixture of 5 equiv of Cl₃CCO₂H and 1.6 equiv of m-CPBA in

CDCl₃was monitored by ¹H NMR spectroscopy and showed no

change over 24 h. This indicates that oxygen transfer between m-

7260

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The Journal of Organic Chemistry

Article

77, 1885. (d) Han, J. H.; Hong, S. J.; Lee, E. Y.; Lee, J. H.; Kim, H. J.;

Kwak, H.; Kim, C. Bull. Korean Chem. Soc. 2005, 26, 1434. (e) Singh,

M. C.; Peddinti, R. K. Tetrahedron Lett. 2007, 48, 7354.

(23) Xia, Q.-H.; Chen, X.; Tatsumi, T. J. Mol. Catal. A: Chem. 2001,

176, 179.

(24) (a) Steyn, R.; Sable, H. Z. Tetrahedron 1969, 25, 3579.

̌

́

(b) Kocovsky, P. Tetrahedron Lett. 1988, 29, 2475.

(25) For related examples of syn-selective epoxidations of 3-

substituted cyclopent-1-enes under hydrogen-bonded control, see:

(a) Hasegawa, A.; Sable, H. Z. J. Org. Chem. 1966, 31, 4154. (b) Vince,

R.; Daluge, S. J. Med. Chem. 1974, 17, 578. (c) Baldwin, J. E.;

Adlington, R. M.; Chondrogianni, J.; Edenborough, M. S.; Keeping, J.

W.; Ziegler, C. B. J. Chem. Soc., Chem. Commun. 1985, 816.

(d) O’Brien, P.; Childs, A. C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.;

Dearden, M. J.; Oxenford, S. J.; Rosser, C. M. Org. Lett. 2003, 5, 4955.

(26) (a) Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.;

Winter, J. J. G.; Helliwell, M.; Newcombe, N. J.; Stemp, G. J. Org.

Chem. 2002, 67, 7946. (b) Ward, S. E.; Holmes, A. B.; McCague, R.

Chem. Commun. 1997, 2085. (c) Aggarwal, V. K.; Monteiro, N. J.

Chem. Soc., Perkin Trans. 1 1997, 2531.

(27) (a) Poli, G. Tetrahedron Lett. 1989, 30, 7385. (b) Cheong, P. H.-

Y.; Yun, H.; Danishefsky, S. J.; Houk, K. N. Org. Lett. 2006, 8, 1513.

(28) The oxidation reactions of cyclopentene-derived allylic amines

68−70 (whose epoxidation rates are faster than that of 71), also,

therefore result in the formation of small amounts of ring-opened

trichloroacetate ester products after 3.5 h.

(29) Swern, D. J. Am. Chem. Soc. 1947, 69, 1692.

(30) Leong, M. K.; Mastryukov, V. S.; Boggs, J. E. J. Mol. Struct. 1998,

445, 149.

(31) (a) Itoh, T.; Kaneda, K.; Teranishi, S. Chem. Commun. 1976,

421. (b) Cope, A. C.; Keough, A. H.; Peterson, P. E.; Simmons, H. E.;

Wood, G. W. J. Am. Chem. Soc. 1957, 79, 3900.

(32) For example: Diimide reduction [cyclopentene k_rel= 15.5;

cyclohexene k_rel= 1.0; cycloheptene k_rel= 12.1]; see: (a) Garbish, E.

W., Jr.; Schildcrout, S. M.; Patterson, D. B.; Sprecher, C. M. J. Am.

Chem. Soc. 1965, 87, 2932.

Hydrogenation (P-2 nickel) [cyclo-

pentene k_rel= 100; cyclohexene k_rel= 1; cycloheptene k_rel= 60]; see:

(b) Brown, C. A.; Ahuja, V. J. Org. Chem. 1973, 58, 2226. Ozonolysis

[cyclopentene k_rel= 2.6; cyclohexene k_rel= 1.0; cycloheptene k_rel

=

3.1]; see: (c) Atkinson, R.; Aschmann, S. M.; Carter, W. P. L.; Pitts, J.

N., Jr. Int. J. Chem. Kinet. 1983, 15, 721. Epoxidation by CrO₃/TBHP

[cyclopentene k_rel= 2.4; cyclohexene k_rel= 1.0; cycloheptene k_rel

=

4.0]; see: (d) Agarwal, D. D.; Srivastava, S.; Chadha, P. Polyhedron

1990, 9, 487. Epoxidation by RuCl₃/PhIO [cyclopentene k_rel= 2.2;

cyclohexene k_rel= 1.0; cycloheptene k_rel= 1.8]; see: (e) Agarwal, D.

D.; Jain, R.; Chakravorty, A.; Rastogi, R. Polyhedron 1992, 11, 463.

(33) Swern, D. Org. React. 1953, VII, 392.

(34) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem.

Soc. 2002, 124, 3669.

(35) Sole,

Org. Chem. 1996, 61, 5895.

́ ́

D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A. J.

(36) Fritz, J. A.; Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2006, 8, 2531.

(37) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.;

Gagne, M. R. J. Am. Chem. Soc. 2000, 122, 7905.

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Ammonium-directed olefinic epoxidation: Kinetic and mechanistic insights

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