Diastereodivergent hydroxyfluorination of cyclic and acyclic allylic amines: Synthesis of 4-deoxy-4-fluorophytosphingosines

Article abstract of DOI:10.1021/jo301056r

A diastereodivergent hydroxyfluorination protocol enabling the direct conversion of some conformationally biased allylic amines to the corresponding diastereoisomeric amino fluorohydrins has been developed. Sequential treatment of a conformationally biased allylic amine with 2 equiv of HBF ₄·OEt₂ followed by m-CPBA promotes epoxidation of the olefin on the face proximal to the amino group under hydrogen-bonded direction from the in situ formed ammonium ion. Regioselective and stereospecific epoxide ring-opening by transfer of fluoride from a BF ₄^- ion (an S_N2-type process at the carbon atom distal to the ammonium moiety) then occurs in situ to give the corresponding amino fluorohydrin. Alternatively, an analogous reaction using 20 equiv of HBF₄·OEt₂ results in preferential epoxidation of the opposite face of the olefin, which is followed by regioselective and stereospecific epoxide ring-opening by transfer of fluoride from a BF ₄^- ion (an S_N2-type process at the carbon atom distal to the ammonium moiety). The synthetic utility of this methodology is demonstrated via its application to a synthesis of 4-deoxy-4-fluoro-l-xylo- phytosphingosine and 4-deoxy-4-fluoro-l-lyxo-phytosphingosine, each in five steps from Garner's aldehyde.

Full text of DOI:10.1021/jo301056r

Article
pubs.acs.org/joc
Diastereodivergent Hydroxyfluorination of Cyclic and Acyclic Allylic
Amines: Synthesis of 4‑Deoxy-4-fluorophytosphingosines
Alexander J. Cresswell,† Stephen G. Davies,*,† James A. Lee,† Melloney J. Morris,‡ Paul M. Roberts,†
and James E. Thomson†
†Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
‡Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, U.K.
S
* Supporting Information
ABSTRACT: A diastereodivergent hydroxyfluorination protocol
enabling the direct conversion of some conformationally biased
allylic amines to the corresponding diastereoisomeric amino
fluorohydrins has been developed. Sequential treatment of a
conformationally biased allylic amine with 2 equiv of HBF4·OEt2
followed by m-CPBA promotes epoxidation of the olefin on the
face proximal to the amino group under hydrogen-bonded
direction from the in situ formed ammonium ion. Regioselective
and stereospecific epoxide ring-opening by transfer of fluoride from
−
a BF4 ion (an SN2-type process at the carbon atom distal to the
ammonium moiety) then occurs in situ to give the corresponding
amino fluorohydrin. Alternatively, an analogous reaction using 20
equiv of HBF4·OEt2 results in preferential epoxidation of the
opposite face of the olefin, which is followed by regioselective and stereospecific epoxide ring-opening by transfer of fluoride from
a BF4− ion (an SN2-type process at the carbon atom distal to the ammonium moiety). The synthetic utility of this methodology is
demonstrated via its application to a synthesis of 4-deoxy-4-fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-
phytosphingosine, each in five steps from Garner’s aldehyde.
of enantiopure 2,3-epoxy amine 1 with HBF4·OEt2 gave the
corresponding amino fluorohydrin 2 in 79% yield as a single
diastereoisomer. The stereochemical outcome of this process is
consistent with an SN2-type epoxide ring-opening by transfer of
fluoride from a BF4− ion, resulting in inversion of configuration.
A sequence of four further manipulations gave (S,S)-3-deoxy-3-
fluorosafingol 316 (Scheme 1).
We became interested in the possibility of harnessing both
our diastereoselective ammonium-directed olefinic oxidation
reaction17 and regioselective and stereospecific ring-opening
fluorination reaction16 for the development of a one-pot
process for the direct conversion of an allylic amine to the
corresponding amino fluorohydrin. Herein, an efficient,
practical and scalable protocol for the hydroxyfluorination of
an allylic amine upon sequential treatment with HBF4·OEt2
followed by m-CPBA is delineated.18 The diastereofacial
selectivity of the hydroxyfluorination process can be controlled
in certain cases by adjusting the stoicheometry of HBF4·OEt2
employed in the reaction, and the synthetic utility of this
diastereodivergent hydroxyfluorination protocol is exemplified
by application to the synthesis of 4-deoxy-4-fluoro-L-xylo-
phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-phytosphingo-
sine, each in five steps from Garner’s aldehyde.
INTRODUCTION
■
The unique physical, chemical, and biological characteristics of
organofluorine compounds have long fascinated the chemical
community, and the range of beneficial properties that fluorine
can confer on designer molecules1 has led to myriad
applications across medicinal chemistry,2 agrochemistry,3 and
materials science.4 Around 30−40% of agrochemicals and 20%
of pharmaceuticals on the market in 2006 contained at least
one fluorine atom,5 as did 10 of the leading 30 blockbuster
drugs by sale in the USA in 2008.6 Although much attention
has been lavished on the beneficial effects that fluorine can
confer on rationally designed molecules, there has also been
considerable activity in the preparation and biological
evaluation of fluorinated analogues of naturally occurring
amino compounds,7 including α- and β-amino acids,8 amino-
sugars,9 iminosugars,10 amino- and diaminocyclitols,11 and
sphingoid bases and ceramides.12 To meet the ever-increasing
demand for stereodefined, fluorinated organic compounds,5 a
number of nucleophilic and electrophilic fluorination methods
have been developed,13 including asymmetric protocols.14
Unfortunately, many of these approaches suffer from economic
or practical setbacks, which often relate to the fluorinating
agents themselves. In contrast, BF3·OEt2 and HBF4·OEt2 are
inexpensive and easily handled, and we have initiated a research
program to examine the potential of these reagents as
nucleophilic fluorinating agents.15,16 For instance, treatment
Received: May 22, 2012
Published: July 24, 2012
© 2012 American Chemical Society
7262
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
a
Scheme 1
Scheme 3
implying that ring-opening is unlikely to be assisted by another
(N−H) ammonium species acting as a hydrogen-bond donor.
In a separate experiment, however, addition of 1 equiv of
HBF4·OEt2 to the solution of 15 followed by immediate 1H and
19F NMR spectroscopic analyses revealed that complete
consumption of the epoxide had occurred, and fluorohydrin
17 was isolated in quantitative yield and >99:1 dr after aqueous
workup with satd aq NaBF4. An authentic sample of 17 was
prepared upon sequential N-benzylation of amino fluorohydrin
7 and anion exchange of 16 with Ag(MeCN)4BF4 (Scheme 4).
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2, 0 °C, 5
min.
RESULTS AND DISCUSSION
■
Ring-opening fluorination of 2,3-epoxy amine 4 with
HBF4·OEt2 gave amino fluorohydrin 6 as a single diaster-
eoisomer which was isolated in quantitative yield, with the
analogous reaction of 2,3-epoxy amine 5 giving the
corresponding amino fluorohydrin 7 in 89% yield, as previously
reported (Scheme 2).16 A plausible mechanistic rationale for
a
Scheme 4
a
Scheme 2
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2, rt, 5
min.
the stereochemical outcome of this ring-opening fluorination
process involves initial N-protonation of a 2,3-epoxy amine
19
substrate 8 by HBF4 to give ammonium species 9. The
oxirane moiety within 9 may then be activated to nucleophilic
attack through O-protonation to form the dicationic species
a
Reagents and conditions: (i) BnBr, MeCN, reflux, 22 h; (ii)
Ag(MeCN)4BF4, CH2Cl2, rt; (iii) HBF4·OEt2 (1 equiv), rt, then satd
aq NaBF4.
10.20 Transfer of fluoride from a BF4 ion21 to the activated
−
oxirane 10 at the carbon atom distal to the ammonium group
(where its destabilizing inductive electron-withdrawing influ-
ence on the transition state 11 is less pronounced)22 results in
conversion to 12, via an SN2-type pathway. Subsequent basic
aqueous workup gives the amino fluorohydrin 13 (Scheme 3).
In order to verify the requirement for oxirane activation,
tetraalkylammonium tetrafluoroborate salt 15 was synthesized
as a model for the intermediate 2,3-epoxy ammonium species 9.
Thus, 2,3-epoxy amine 5 was treated with BnBr in MeCN to
give tetraalkylammonium bromide salt 14, and subsequent
anion exchange by treatment with Ag(MeCN)4BF4 in
The generality of our ring-opening fluorination reaction with
HBF4·OEt2 was assessed by application to a range of 5-, 6-, and
7-membered carbocyclic 2,3-epoxy amines 18−22,24 which
allowed for evaluation of the effects of both ring size and the
relative stereochemistry between the oxirane and the amino
group on the carbocyclic scaffold on the outcome of the
reaction. The ring-opening fluorination reactions of 18,16 19,16
20, and 22 proceeded to give the corresponding amino
fluorohydrins 23,16 24,16 25, and 27 as single diastereoisomers
(>99:1 dr) in all cases, which were isolated in good yield
(Scheme 5). The relative configurations within amino
fluorohydrins 23−25 and 27 were unambiguously established,
in each case, via single-crystal X-ray diffraction analyses.25 The
stereochemical outcomes of these ring-opening fluorination
reactions are therefore consistent with a reaction pathway
involving an SN2-type epoxide opening by transfer of fluoride
23
CH2Cl2 gave tetraalkylammonium tetrafluoroborate salt 15
in 98% yield and >99:1 dr over two steps. A solution of 15 in
1
CD2Cl2 was allowed to stand at rt and was monitored by H
and 19F NMR spectroscopy. No ring-opening of the epoxide by
the BF4− ion was observed even after several days, suggesting in
this case that oxirane activation is a prerequisite to fluorination.
Addition of 1 equiv of N,N-dibenzyl-N-cyclohexylammonium
tetrafluoroborate to the solution of 15 resulted in no reaction,
−
from a BF4 ion, resulting in inversion of configuration at the
7263
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
a
Scheme 5
Scheme 6
The 2,3-epoxy amine substrates 4, 5, and 18−22 for these
reactions were all prepared from the corresponding cyclic allylic
amines using our protocol for ammonium-directed olefinic
oxidation as the key step,17 which relies upon the in situ
protection of an allylic amine from N-oxidation by conversion
to the corresponding ammonium species on treatment with a
strong Brønsted acid, prior to treatment with m-CPBA.
Therefore, the possibility of employing HBF4·OEt2 as the
acid protecting agent in these reactions was next assessed, in
order to circumvent the need for isolation of the epoxide
intermediate and so develop a direct (“one-pot”) hydroxy-
fluorination protocol. Treatment of allylic amine 29 with either
1 or 1.5 equiv of HBF4·OEt2 followed by m-CPBA (2 equiv)
led to the formation of complex mixtures of products. However,
the use of 2 equiv of HBF4·OEt2 in this reaction gave a
67:12:21 mixture of amino fluorohydrins 6 and 23, and m-CBA
ester 30, respectively. The relative configuration within m-CBA
ester 30 was established unambiguously through treatment of
the 67:12:21 mixture of 6:23:30 with K2CO3 in MeOH, which
resulted in transesterification of 30 to the corresponding known
diol 31,17a while leaving amino fluorohydrins 6 and 23
unchanged. Increasing the amount of HBF4·OEt2 led to
increasing amounts of amino fluorohydrin 23 being produced
in the reaction, until a plateau was reached beyond 30 equiv,
when the ratio of amino fluorohydrins 6:23 was 10:90. A rate
enhancement was also noted at high equivalents of HBF4·OEt2:
when the course of the hydroxyfluorination reactions of allylic
amine 29 were monitored by 1H NMR spectroscopy, complete
consumption of starting material occurred after 2 h when using
20 equiv of HBF4·OEt2, while starting material remained even
after 7 h when using 2 equiv of HBF4·OEt2. The rate
acceleration of epoxidation of isolated alkenes by peracids in
the presence of strong Brønsted acids has been documented
and is postulated to be a result of protonation of the peracid
generating a more electrophilic, and hence more reactive,
oxidizing agent27 (Scheme 7).
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2, rt, 5
min.
Amino fluorohydrin 6 and m-CBA ester 30 presumably arise
from epoxidation of the olefin on the face syn to the ammonium
group (forming epoxide 4 in protonated form), followed by
regioselective and stereospecific ring-opening by either transfer
carbon atom distal to the amino group. For 2,3-epoxy amine
21,24 however, a competitive intramolecular electrophilic
aromatic substitution reaction occurred that resulted in the
formation of bicycle 28 as the major product, thus somewhat
compromising the yield of amino fluorohydrin 26 (Scheme 5).
The relative configuration within amino fluorohydrin 26 was
assigned on the basis of a mechanism of formation involving an
SN2-type epoxide ring-opening, while the relative configuration
within bicycle 28 was unambiguously established via single-
crystal X-ray diffraction analysis.25 Examination of the single-
crystal X-ray diffraction structure of 2,3-epoxy amine 2125
reveals a solid-state conformation in which the bicyclic system
adopts a boatlike conformation26 with a pseudoaxial N,N-
dibenzylamino group. If maintained in solution, this con-
formation would provide ideal positioning of the N,N-
dibenzylamino group for the intramolecular cyclization reaction
leading to bicycle 28 (Scheme 6).
−
of fluoride from a BF4 ion to, or attack of m-CBA at, the
oxirane carbon distal to the ammonium group. Amino
fluorohydrin 23 meanwhile, is consistent with epoxidation on
the face of the olefin anti to the ammonium group (forming
epoxide 18 in protonated form), followed by regioselective and
−
stereospecific ring-opening by transfer of fluoride from a BF4
ion to the oxirane carbon distal to the ammonium group. The
product distributions of these reactions presumably reflect the
relative rate of the former epoxidation process over the latter.
When using 2 equiv of HBF4·OEt2, epoxidation of allylic amine
29 on the face syn to the amino group is favored, presumably as
a result of hydrogen bonding of the peracid to the in situ
formed ammonium ion.28 Increasing the amount of HBF4·OEt2
to 20 equiv promotes protonation of the m-CPBA,27 and this
7264
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
a
of 29 with 20 equiv of HBF4·OEt2 and 2 equiv of m-CPBA
followed by acetylation of the crude product mixture allowed
for the isolation of acetate 33 in 49% yield and >99:1 dr. The
relative configurations within acetates 32 and 33 were
unambiguously established through transesterification (treat-
ment with K2CO3 in MeOH) which gave the corresponding
amino fluorohydrins 6 and 23 in quantitative yield in each case
(Scheme 9).
Scheme 7
a
Scheme 9
a
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2 then m-
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2 then m-
CPBA (2 equiv), rt, 18 h; (ii) K2CO3, MeOH, rt, 1 h. Ar = m-ClC6H4.
CPBA (2 equiv), rt, 18 h; (ii) HBF4·OEt2 (20 equiv), CH2Cl2 then m-
CPBA (2 equiv), rt, 18 h; (iii) Ac2O, pyridine, rt, 20 h; (iv) K2CO3,
MeOH, rt, 3 h.
may serve to decrease the hydrogen-bond acceptor ability of
the peracid, as well as introduce electrostatic repulsive
interactions between the protonated peracid and the
ammonium group. Non-hydrogen-bond-directed epoxidation,
presumably occurring preferentially on the face of the olefin
anti to the ammonium ion due to minimization of unfavorable
steric interactions and/or electronic interactions (minimization
of dipoles),29 may therefore predominate due to activation of
the m-CPBA as a more potent electrophilic oxidant by
protonation,27 thus resulting in a reversal of the sense of
diastereofacial selectivity of epoxidation (Scheme 8).
Unfortunately, attempted separation of the product mixtures
from these hydroxyfluorination reactions proved unsuccessful.
However, treatment of the crude product mixtures with Ac2O
in pyridine facilitated the isolation of diastereoisomerically pure
samples of acetates 32 and 33. Thus, hydroxyfluorination of 29
with 2 equiv of HBF4·OEt2 and 2 equiv of m-CPBA followed by
acetylation of the crude product mixture allowed isolation of
acetate 32 in 45% yield and >99:1 dr, while hydroxyfluorination
The generality of this hydroxyfluorination procedure for
other cyclic allylic amines was next investigated. Hydroxy-
fluorination of tertiary allylic amine 34 using 2 equiv of
HBF4·OEt2 and 2 equiv of m-CPBA gave an 85:3:12 mixture of
amino fluorohydrins 7 and 24 and m-CBA ester 35,
respectively. Treatment of the crude product mixture with
K2CO3 in MeOH to effect transesterification of m-CBA ester
35 to the corresponding known diol 3617i (while leaving
fluorohydrins 7 and 24 unaffected) enabled chromatographic
separation of the mixture and thus allowed isolation of
fluorohydrin 7 in 73% yield as a single diastereoisomer. This
compares to an overall yield of 70% for the two-step conversion
of tertiary allylic amine 34 into fluorohydrin 7 when employing
sequential epoxidation17i and ring-opening fluorination16 steps
(Scheme 10). Under analogous conditions, hydroxyfluorination
of secondary allylic amine 37 gave a 90:10 mixture of amino
fluorohydrin 38 and m-CBA ester 40, respectively. Treatment
Scheme 8
7265
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
a
diastereoselectivity for tertiary amine 34 when using 20 equiv of
HBF4·OEt2 (Scheme 10), although a more subtle effect was
noted for hydroxyfluorination of secondary amine 37, and
amino fluorohydrin 38 remained the major product even when
using 20 equiv of HBF4·OEt2: a second fluorinated species
which appeared in the crude reaction mixture upon increasing
equiv of HBF4 was tentatively assigned as amino fluorohydrin
39 by analogy to the cases of hydroxyfluorination of tertiary
amines 29 and 34, where the configurations within each of the
corresponding fluorohydrin products 6, 7, 23, and 24 were
unambiguously established (Scheme 11). It is noteworthy that
the rates of ammonium-directed olefinic oxidation of allylic
amines 29, 34, and 37 increase in the order 29 < 34 < 37.17i
Presumably, the increased ability of the in situ formed
ammonium ion derived from secondary amine 37 to promote
rapid hydrogen-bond directed epoxidation (leading to amino
fluorohydrin 38) means that, even at high concentrations of
HBF4·OEt2, the rate of the non-hydrogen-bond directed
reaction (leading to amino fluorohydrin 39) is not able to
outpace it.
Scheme 10
Hydroxyfluorination of cyclopentene-derived tertiary allylic
amine 42 (Scheme 12) and cycloheptene-derived tertiary allylic
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv) CH2Cl2 then m-
CPBA (2 equiv), rt, 18 h; (ii) K2CO3, MeOH, rt, 1 h. Ar = m-ClC6H4.
a
Scheme 12
of this mixture with K2CO3 in MeOH to effect trans-
esterification of m-CBA ester 40 to the corresponding known
diol 41,17a followed by chromatography, gave fluorohydrin 38
in 65% yield as a single diastereoisomer (Scheme 11). The
a
Scheme 11
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2 then m-
CPBA (2 equiv), rt, 18 h. Ar = m-ClC6H4.
a
Scheme 13
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2 then m-
a
CPBA (2 equiv), rt, 18 h.
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2 then m-
CPBA (2 equiv), rt, 18 h; (ii) K2CO3, MeOH, rt, 1 h. Ar = m-ClC6H4.
amine 44 (Scheme 13) upon treatment with 2 equiv of
HBF4·OEt2 and 2 equiv of m-CPBA proceeded to give the
corresponding amino fluorohydrins 25 and 27 as the major
products which, after treatment of the crude reaction mixture
with K2CO3 in MeOH,30 were isolated in 46 and 73% yield,
respectively. In comparison, the overall yields for the
corresponding two-step conversions of tertiary allylic amines
42 and 44 into fluorohydrins 25 and 27 (employing sequential
epoxidation17c,i and ring-opening fluorination steps) are 77 and
52%, respectively. The stereochemical outcome of the
hydroxyfluorination reaction of cyclopentene-derived allylic
relative configuration within 38 was unambiguously established
via single-crystal X-ray diffraction analysis.25 The effect of
increasing the number of equivalents of HBF4·OEt2 on the
diastereoselectivities of these hydroxyfluorination reactions was
next studied. For both tertiary amine 34 and secondary amine
37, increasing the amount of HBF4·OEt2 used in the
hydroxyfluorination reaction increased the amount of the
corresponding amino fluorohydrins 24 and 39 arising from
epoxidation on the face of the olefin anti to the in situ formed
ammonium ion. This resulted in a reversal of the reaction
7266
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
a
amine 42 is consistent with initial epoxidation occurring on the
face of the olefin syn to the in situ formed ammonium ion,
followed by regioselective and stereospecific SN2-type epoxide
Scheme 14
−
ring-opening occurring upon transfer of fluoride from a BF4
ion to the oxirane carbon distal to the ammonium group.
Meanwhile, the stereochemical outcome of the hydroxyfluori-
nation reaction of cycloheptene-derived allylic amine 44 is
consistent with initial epoxidation occurring on the face of the
olefin anti to the in situ formed ammonium ion, followed by
regioselective and stereospecific SN2-type epoxide ring-opening
−
occurring upon transfer of fluoride from a BF4 ion to the
oxirane carbon distal to the ammonium group. In both cases,
the diastereoselectivity of the epoxidation reaction and the
regioselectivity of the ring-opening step are entirely consistent
with that previously observed by us during the ammonium-
directed oxidation of these substrates using m-CPBA in the
presence of Cl3CCO2H.17c,i In both cases, we have rationalized
the selectivity of the epoxidation step as being the result of
hydrogen-bonded delivery of the m-CPBA by the in situ formed
ammonium ion, although in the case of cyclopentene-derived
allylic amine 42, attack on the face of the olefin syn to the in situ
formed ammonium moiety may be inherently favored due to
minimization of developing torsional strain in the transition
state.31 When 20 equiv of HBF4·OEt2 in the hydroxyfluorina-
tion of cyclopentene-derived allylic amine 42 was used, a
reduction in the reaction diastereoselectivity was apparent,
although a complete reversal in the sense of facial selectivity
was not observed (Scheme 12). Analogous reaction of
cycloheptene-derived allylic amine 44 resulted in the formation
of a complex mixture of products, of which the major
component was amino fluorohydrin 27. The observations
that the selectivities of the hydroxyfluorinations of 5-membered
ring substrate 42 and 7-membered ring substrate 44 do not
reverse when using 20 equiv of HBF4·OEt2 is consistent with
the much faster rates of ammonium-directed epoxidation of
both cyclopentene-derived 42 and cycloheptene-derived 44
under these conditions, as compared to that of their
cyclohexene-derived counterpart 2917i (i.e., the hydrogen-
bond directed epoxidation would be expected to be the
dominant pathway in both of the former cases). This does not,
however, discount the possibility that epoxidation syn to the
ammonium moiety formed in situ from 42 is inherently
favored.31
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2 then m-
CPBA (2 equiv), rt, 18 h; (ii) HBF4·OEt2 (10 equiv), CH2Cl2 then m-
CPBA (2 equiv), rt, 18 h.
treatment of tertiary alkenyl amines 51−58 with 2 equiv of
HBF4·OEt2 and 2 equiv of m-CPBA gave the corresponding
amino fluorohydrins 60−67 as single diastereoisomers (>99:1
dr), which were isolated after chromatography in modest to
good yield.32 We have previously unambiguously established
the relative configurations within 60, 62, and 67 through single-
crystal X-ray diffraction analyses,25 and therefore, the relative
configurations within the remaining amino fluorohydrin
products of these reactions were assigned on the basis of our
mechanistic proposal for this hydroxyfluorination process.
Under analogous conditions, hydroxyfluorination of allylic
amine 59 gave a mixture of products containing an 88:12
mixture of amino fluorohydrins 68:69, from which the major
product 68 was isolated in 28% yield and >99:1 dr and the
minor product 69 in 7% yield and >99:1 dr. The relative
configuration within 68 was unambiguously established via
single-crystal X-ray diffraction analysis,25 which therefore
allowed the relative configuration within 69 to be assigned
(on the basis of a stereospecific SN2-type epoxide ring-
opening). The expected higher level of 1,3-allylic strain34
associated with allylic amines 57 and 58 as compared to 59 is
thus consistent with the higher reaction diastereoselectivity for
the former two processes over the latter (Scheme 15).
Trisubstitution on the olefin was also tolerated by this
reaction, with the hydroxyfluorination of allylic amine 45 giving
amino fluorohydrin 46 in 95:5 dr, which was isolated in 70%
yield and 95:5 dr after purification. The relative configuration
1
1
within 46 was assigned on the basis of H−1H and H−19F
NMR 3J coupling constant and 1H−19F NMR HOESY analyses
(Scheme 14). Tetrahydropyridine 47 and dihydropyrrole 49
were also investigated as substrates for this reaction. In the
former case, reaction of 47 gave the corresponding 4-
fluoropiperidin-3-ol 48 in 53% yield as a single diaster-
eoisomer.32 In the latter case, 10 equiv of HBF4·OEt2 proved
optimal to ensure complete ring-opening of the epoxide, and
this enabled the isolation of 4-fluoropyrrolidin-3-ol 50 in 58%
yield as a single diastereoisomer.32 The regiochemistry within
The synthetic utility of this methodology was next
demonstrated by application to the synthesis of 4-deoxy-4-
fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-
phytosphingosine; fluorinated analogues of the sphingoid
bases L-xylo-phytosphingosine and L-lyxo-phytosphingosine,
respectively.35 The allylic amine substrate required for these
reactions was prepared from Garner’s aldehyde 70. Wittig
olefination of 70 upon treatment with [C15H31PPh3]+Br− and
NaHMDS gave a mixture of olefin isomers (Z)-71 and (E)-72,
1
although peak overlap in the H NMR spectrum of the crude
1
48 was assigned by H−1H NMR COSY analysis, and the
reaction mixture precluded determination of the (E):(Z) ratio.
Chromatography allowed separation of (Z)-71 and (E)-72,
which were isolated in 77 and 7% yield, respectively. Treatment
of (Z)-71 with HBF4·OEt2 (either 2 equiv or 20 equiv)
followed by m-CPBA (2 equiv) was investigated in the hope of
achieving a one-pot sequential N-deprotection, ammonium-
relative configurations within both 48 and 50 were assigned on
the basis of the reaction proceeding via an SN2-type epoxide
ring-opening step33 (Scheme 14).
The hydroxyfluorination of acyclic allylic and homoallylic
amines was also investigated. Under our optimized conditions,
7267
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
a
achieved using methanolic HCl, and was followed by treatment
with BnBr in the presence of K2CO3 to give 74 in 90% yield
(Scheme 16).
Scheme 15
a
Scheme 16
a
Reagents and conditions: (i) [C15H31PPh3]+Br−, NaHMDS, THF,
hexane, −78 °C to rt, 42 h; (ii) HCl (conc aq), MeOH, reflux, 17 h;
(iii) BnBr, K2CO3, EtOH, reflux, 4 h.
Hydroxyfluorination of 74 upon treatment with HBF4·OEt2
(20 equiv) and m-CPBA (2 equiv) for 18 h gave a 12:88
mixture of amino fluorohydrin 75 and the functionalized
tetrahydrofuran 77. Chromatography allowed isolation of 77 in
73% yield as a single diastereoisomer. The relative config-
uration within 77 was established through hydrogenolysis,
which gave (−)-2-epi-jaspine B [(−)-2-epi-pachasstrissamine]
7836 in 53% yield. Optimization of the reaction conditions
revealed that the use of 4 equiv of m-CPBA and a reaction time
of 30 min resulted in >95% conversion of starting material to
give an 18:66:16 mixture of amino fluorohydrins 75 and 76 and
functionalized tetrahydrofuran 77, respectively. Chromato-
graphic separation gave amino fluorohydrin 76 in 56% isolated
yield and >99:1 dr. Resubjection of the authentic sample of 76
to the reaction conditions resulted in formation of tetrahy-
drofuran 77 as the only product. Thus, the C(2)−C(3) relative
configuration within 76 could be unambiguously assigned, and
is consistent with the epoxidation step proceeding preferentially
via transition-state model 79, in which 1,3-allylic strain is
minimized and the epoxidation proceeds on the face of the
olefin anti to the ammonium group to give epoxide 80 as the
major product. Subsequent in situ regioselective and stereo-
specific SN2-type ring-opening of 80 by transfer of fluoride from
a BF4− ion to the oxirane carbon atom distal to the ammonium
moiety leads to amino fluorohydrin 76, with BF3 assisted37 SN2-
type (5-exo-tet)38 cyclization of 76 under the reaction
conditions leading to tetrahydrofuran 77. In support of this
assertion, treatment of amino fluorohydrin 76 with 2 equiv of
HBF4·OEt2 led only to the return of unreacted starting material
after 18 h, while sequential treatment with 1 equiv of
HBF4·OEt2 followed by 1 equiv of BF3·OEt2 for 18 h gave
complete conversion to tetrahydrofuran 77 (quantitative
isolated yield). From these combined data, it can be deduced
that the intermediate epoxide 80 is formed in 82:18 dr under
these reaction conditions (Scheme 17).
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2 then m-
b
CPBA (2 equiv), rt, 18 h. Reaction was run with 10 equiv of
c
HBF4·OEt2. Yields in parentheses are for the corresponding two-step
(sequential epoxidation17e and ring-opening fluorination16) processes.
d
e
Reaction was run for 30 min. Reaction produced an 88:12
Allylic amine 74 was next treated with 2 equiv of HBF4·OEt2
followed by 2 equiv of m-CPBA and, after a reaction time of 18
h, gave a 67:16:18 mixture of amino fluorohydrins 75 and 76,
and the functionalized tetrahydrofuran 81, respectively. The
observation of amino fluorohydrin 75 as the major product in
this reaction indicates opposite sense of diastereofacial
selectivity as compared to the analogous reaction using 20
equiv of HBF4·OEt2. Purification allowed the isolation of amino
diastereoisomeric mixture of amino fluorohydrins 68:69.
directed epoxidation, and ring-opening fluorination, but
unfortunately, only a complex mixture of products was
furnished in both cases. Therefore, in order to provide an
alternative substrate for evaluation, hydrolysis of the N,O-
acetonide and N-Boc protecting groups within (Z)-71 was
7268
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
a
75. From these combined data it can be deduced that the
intermediate epoxide 84 is formed in 84:16 dr under these
reaction conditions (Scheme 18).
Scheme 17
Hydrogenolytic N-debenzylation of 75 completed the
synthesis of 4-deoxy-4-fluoro-L-xylo-phytosphingosine 85, in
five steps and 33% overall yield from Garner’s aldehyde 70,
while an analogous procedure applied to amino fluorohydrin 76
gave 4-deoxy-4-fluoro-L-lyxo-phytosphingosine 86, in five steps
and 39% overall yield from Garner’s aldehyde 70 (Scheme 19).
a
Scheme 19
a
Reagents and conditions: (i) HBF4·OEt2 (20 equiv), CH2Cl2 then m-
CPBA (2 equiv), rt, 18 h; (ii) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 24
h; (iii) HBF4·OEt2 (20 equiv), CH2Cl2 then m-CPBA (4 equiv), rt, 30
min; (iv) HBF4·OEt2 (1 equiv), BF3·OEt2 (1 equiv), CH2Cl2, rt, 18 h.
Ar = m-ClC6H4.
a
Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 24
h.
fluorohydrin 75 in 47% yield and tetrahydrofuran 81 in 14%
yield. The relative configuration within amino fluorohydrin 75
was assigned on the basis of an ammonium-directed
epoxidation of 74 (via transition state model 83 in which 1,3-
allylic strain is minimized) to give the corresponding
protonated epoxide 84, which undergoes in situ regioselective
CONCLUSION
■
In conclusion, a diastereodivergent hydroxyfluorination proto-
col enabling the direct conversion of conformationally biased
allylic amines to the corresponding diastereoisomeric amino
fluorohydrins has been developed. Sequential treatment of a
conformationally biased allylic amine with 2 equiv of
HBF4·OEt2 followed by m-CPBA promotes epoxidation of
the olefin on the face proximal to the amino group, under
hydrogen-bonded direction from the in situ formed ammonium
ion. Regioselective and stereospecific epoxide ring-opening by
transfer of fluoride from a BF4− ion (an SN2-type process at the
carbon atom distal to the ammonium moiety) then occurs in
situ to give the corresponding amino fluorohydrin. Alter-
natively, an analogous reaction using 20 equiv of HBF4·OEt2
results in preferential epoxidation of the opposite face of the
olefin, which is followed by regioselective and stereospecific
−
SN2-type ring-opening by transfer of fluoride from a BF4 ion
to the oxirane carbon atom distal to the ammonium group. The
relative configuration within tetrahydrofuran 81 was unambig-
uously established through hydrogenolysis, which gave (+)-4-
epi-jaspine B [(+)-4-epi-pachastrissamine] 8239 in 92% yield. A
plausible mechanism for the production of 81 under the
conditions of the hydroxyfluorination reaction would involve
direct cyclization of the terminal hydroxy group onto the
epoxide functionality within 84.40 Furthermore, resubjection of
amino fluorohydrin 75 to the reaction conditions led only to
the recovery of starting material (i.e., 75), indicating that
tetrahydrofuran 81 does not arise from the in situ cyclization of
a
Scheme 18
a
Reagents and conditions: (i) HBF4·OEt2 (2 equiv), CH2Cl2 then m-CPBA (2 equiv), rt, 18 h; (ii) H2 (5 atm), Pd(OH)2/C, EtOAc, rt, 4.5 h. Ar =
m-ClC6H4.
7269
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
−
(0.27 mL, 2.0 mmol). Purification via flash column chromatography on
neutralized silica gel (gradient elution, 7→60% EtOAc in 30−40 °C
petroleum ether) gave 7 as a yellow oil (211 mg, 89%, >99:1 dr):16 Rf
0.28 (30−40 °C petroleum ether/EtOAc, 7:3; neutralized silica gel);
δH (400 MHz, CDCl3) 1.44−1.93 (6H, m, C(3)H2, C(4)H2, C(5)H2),
2.21 (3H, s, NMe), 2.63 (1H, dddd, J 11.6, 4.7, 2.9, 2.6, C(2)H), 3.43
(1H, br s, OH), 3.56 (1H, d, J 13.4, NCHA), 3.74 (1H, d, J 13.4,
NCHB), 4.20 (1H, app dt, J 6.1, 3.1, C(1)H), 4.93 (1H, app dq, J 45.4,
3.1, C(6)H), 7.24−7.38 (5H, m, Ph).
From 34: Following general procedure 2, 34 (161 mg, 0.80 mmol)
in CH2Cl2 (4.6 mL) was treated with HBF4·OEt2 (220 μL, 1.62
mmol) and m-CPBA (0.5 M in CH2Cl2, 3.2 mL, 1.6 mmol) for 18 h to
give an 85:3:12 mixture of 7:24:35. K2CO3 (11.1 mg, 0.08 mmol) and
MeOH (2.0 mL) were then added to the residue, and the resultant
mixture was stirred at rt for 1 h and then concentrated in vacuo. The
residue was partitioned between H2O (10 mL) and CH2Cl2 (10 mL),
and the layers were separated. The aqueous layer was extracted with
CH2Cl2 (2 × 10 mL), and the combined organic layers were dried and
concentrated in vacuo to give an 85:3:12 mixture of 7:24:36.
Purification via flash column chromatography (gradient elution, 7→
60% EtOAc in 30−40 °C petroleum ether) gave 7 as a yellow oil (139
mg, 73%, >99:1 dr).
(1RS,2RS,3SR)-1-(N,N-Dibenzyl-N-methylammonio)-2,3-ep-
oxycyclohexane Tetrafluoroborate (15). Step 1: BnBr (0.36 mL,
3.0 mmol) was added to a stirred solution of 517i (652 mg, 3.00 mmol,
>99:1 dr) in MeCN (15 mL), and the resultant mixture was heated at
reflux for 22 h and then was allowed to cool to rt and concentrated in
vacuo. The residue was triturated with Et2O, and the precipitate was
collected by filtration and washed with Et2O to give 14 as a
hygroscopic pale orange solid (1.14 g, 98%, >99:1 dr): νmax 3004, 2924
(C−H), 1497, 752, 703; δH (400 MHz, CDCl3) 1.27−1.42 (1H, m,
C(5)HA), 1.67−1.91 (3H, m, C(4)H2, C(5)HB), 1.98−2.11 (1H, m,
C(6)HA), 2.18−2.30 (1H, m, C(6)HB), 3.02 (3H, s, NMe), 3.30−3.38
(1H, m, C(3)H), 3.84 (1H, app d, J 4.0, C(2)H), 4.04−4.13 (1H, m,
C(1)H), 4.60 (1H, d, J 13.3, N(CHAHBPh)A), 4.90 (1H, d, J 12.9,
N(CHAHBPh)B), 5.21 (1H, d, J 12.9, N(CHAHBPh)B), 5.40 (1H, d, J
13.3, N(CHAHBPh)A), 7.34−7.73 (10H, m, Ph); δC (100 MHz,
CDCl3) 20.2 (C(5)), 20.9 (C(6)), 21.7 (C(4)), 46.3 (NMe), 49.5
(C(2)), 54.4 (C(3)), 64.1 (N(CH2Ph)A), 64.5 (N(CH2Ph)B), 68.3
(C(1)), 127.3, 129.4, 130.7, 130.8, 133.2, 133.6 (Ph); m/z (ESI+) 308
([M]+, 100); HRMS (ESI+) C21H26NO+ ([M]+) requires 308.2009,
found 308.2001.
Step 2: MeCN (82 μL, 1.6 mmol) and CH2Cl2 (2.5 mL) were
added sequentially to AgBF4 (68.1 mg, 0.35 mmol), and the resultant
solution was added to a stirred solution of 14 (136 mg, 0.35 mmol,
>99:1 dr) in CH2Cl2 (1.0 mL). The resultant mixture was stirred at rt
for 5 min and then filtered and concentrated in vacuo to give 15 as a
hygroscopic white solid (138 mg, quant, >99:1 dr): νmax 3036, 2956
(C−H), 1050, 1030, 754, 727, 703; δH (400 MHz, CDCl3) 1.30−1.44
(1H, m, C(5)HA), 1.71−1.94 (3H, m, C(4)H2, C(5)HB) 1.99−2.19
(2H, m, C(6)H2), 2.93 (3H, s, NMe), 3.34−3.39 (1H, m, C(3)H),
3.65 (1H, app d, J 4.0, C(2)H), 3.81 (1H, app dd, J 9.1, 5.6, C(1)H),
4.36 (1H, d, J 13.4, N(CHAHBPh)A), 4.54 (1H, d, J 12.9,
N(CHAHBPh)B), 4.82−4.93 (2H, m, N(CHAHBPh)A, N-
(CHAHBPh)B), 7.38−7.56 (10H, m, Ph); δC (100 MHz, CDCl3)
19.7 (C(6)), 20.3 (C(5)), 21.6 (C(4)), 46.0 (NMe), 48.9 (C(2)), 54.4
(C(3)), 64.0 (N(CH2Ph)A), 64.5 (N(CH2Ph)B), 68.2 (C(1)), 126.7,
129.5, 130.9, 131.0, 132.9, 133.4 (Ph); δF (377 MHz, CDCl3) −151.2
(s); m/z (ESI+) 308 ([M]+, 100); HRMS (ESI+) C21H26NO+ ([M]+)
requires 308.2009, found 308.2003.
epoxide ring-opening by transfer of fluoride from a BF4 ion
(an SN2-type process at the carbon atom distal to the
ammonium moiety). The synthetic utility of this methodology
is demonstrated via its application to a synthesis of 4-deoxy-4-
fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-
phytosphingosine, each in five steps from Garner’s aldehyde.
EXPERIMENTAL SECTION
■
General Experimental Details. Reactions involving moisture-
sensitive reagents were carried out under a nitrogen atmosphere using
standard vacuum line techniques and glassware that was flame-dried
and cooled under nitrogen before use. Solvents were dried according
to the procedure outlined by Grubbs and co-workers.41 m-CPBA was
supplied as a 70−77% slurry in water and titrated according to the
procedure of Swern42 before use. Dry 0.5 M solutions of m-CPBA
were freshly prepared by treating a solution of titrated m-CPBA (70−
77% with H2O) in CH2Cl2 with MgSO4, followed by filtration of the
supernatant solution through a Pasteur pipet (packed to half depth
with MgSO4) into a volumetric flask, and addition of further CH2Cl2
as necessary. Organic layers were dried over MgSO4. Thin layer
chromatography was performed on aluminum plates coated with 60
F254 silica. 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. Specific rotations are reported in
10−1 deg cm2 g−1 and concentrations in g/100 mL. IR spectra were
recorded using an ATR module. Selected characteristic peaks are
reported in cm−1. NMR spectra were recorded in the deuterated
solvent stated. The field was locked by external referencing to the
relevant deuteron resonance. 1H−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.
General Procedure 1 for Ring-Opening Fluorination of
Epoxy Amines with HBF4·OEt2. HBF4·OEt2 (2 equiv) was added
in one portion to a stirred solution of the requisite epoxy amine (1
equiv, 0.25 M in CH2Cl2) at rt, and the reaction mixture was stirred at
this temperature for 5 min. Satd aq NaHCO3 was then added, and the
layers were separated. The organic layer was washed twice with satd aq
NaHCO3, and the combined aqueous layers were extracted twice with
CH2Cl2. The combined organic layers were then dried and
concentrated in vacuo.
General Procedure 2 for Hydroxyfluorination of Alkenyl
Amines with HBF4·OEt2 and m-CPBA. HBF4·OEt2 was added to a
stirred solution of the requisite alkenyl amine (1 equiv in CH2Cl2)43 at
rt and the resultant mixture was stirred at this temperature for 5 min. A
predried solution of m-CPBA (2 equiv, 0.5 M in CH2Cl2) was added,
and the resultant mixture was stirred at rt for the time stated. Satd aq
Na2SO3 was then added until starch−iodide paper indicated no
remaining oxidant. Satd aq NaHCO3 was added, and the layers were
separated. The organic layer was washed twice with satd aq NaHCO3,
and the combined aqueous layers were extracted twice with CH2Cl2.
The combined organic layers were then dried and concentrated in
vacuo.
(RS,RS,RS)-2-(N,N-Dibenzylamino)-6-fluorocyclohexan-1-ol
(6). Following general procedure 1, 417a (108 mg, 0.37 mmol, >99:1
dr) in CH2Cl2 (1.5 mL) was treated with HBF4·OEt2 (100 μL, 0.74
mmol). Purification via flash column chromatography (gradient
elution, 5→40% EtOAc in 30−40 °C petroleum ether) gave 6 as a
colorless syrup which solidified on standing to a white crystalline solid
(117 mg, quant, >99:1 dr):16 Rf 0.46 (30−40 °C petroleum ether/
EtOAc, 4:1); mp 74−77 °C; δH (400 MHz, CDCl3) 1.43−1.87 (6H,
m, C(3)H2, C(4)H2, C(5)H2), 2.95 (1H, br s, OH), 3.01−3.09 (1H,
m, C(2)H), 3.82 (4H, A2, N(CH2Ph)2), 4.17−4.24 (1H, app dt, J 6.3,
3.3, C(1)H), 4.84 (1H, app dq, J 45.5, 3.0, C(6)H), 7.22−7.37 (10H,
m, Ph).
(RS,RS,RS)-1-(N,N-Dibenzyl-N-methylammonio)-3-fluorocy-
clohexan-2-ol Tetrafluoroborate (17). From 7: Step 1: BnBr (172
μL, 1.45 mmol) was added to a stirred solution of 7 (344 mg, 1.45
mmol, >99:1 dr) in MeCN (7.2 mL), and the resultant mixture was
heated at reflux for 22 h, allowed to cool to rt, and concentrated in
vacuo. The residue was triturated with Et2O, and the precipitate was
collected by filtration and washed with Et2O to give 16 as a
hygroscopic pale brown solid (592 mg, quant, >99:1 dr): δH (400
MHz, CDCl3) 1.50−1.95 (4H, m, C(4)H2, C(5)H2), 2.30−2.55 (2H,
m, C(6)H2), 3.02 (3H, s, NMe), 3.36 (1H, app d, J 12.1, C(1)H), 4.37
(RS,RS,RS)-2-(N-Benzyl-N-methylamino)-6-fluorocyclohexan-
1-ol (7). From 5: Following general procedure 1, 517i (217 mg, 1.00
mmol, >99:1 dr) in CH2Cl2 (4.0 mL) was treated with HBF4·OEt2
7270
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
(1H, d, J 13.1, N(CHAHBPh)A), 4.53 (1H, d, J 13.0, N(CHAHBPh)B),
4.65−4.88 (2H, m, C(2)H, C(3)H), 4.97 (1H, d, J 13.1,
N(CHAHBPh)A), 5.60 (1H, d, J 13.0, N(CHAHBPh)B), 6.08 (1H, d,
J 6.8, OH), 7.27−7.51 (8H, m, Ph), 7.76−7.84 (2H, m, Ph).
N(CH2Ph)2), 4.16 (1H, dd, J 10.2, 4.1, C(1)H), 4.95 (1H, app ddd, J
50.9, 6.5, 1.7, C(5)H), 7.24−7.38 (10H, m, Ph); δC (100 MHz,
CDCl3) 26.9 (C(3)), 29.5 (d, J 22.4, C(4)), 55.7 (N(CH2Ph)2), 65.5
(C(2)), 74.1 (d, J 30.4, C(1)), 97.3 (d, J 174, C(5)), 127.3 (p-Ph),
128.5, 129.0 (o,m-Ph), 138.2 (i-Ph); δF (377 MHz, CDCl3) −176.8
(m); m/z (ESI+) 300 ([M + H]+, 100); HRMS (ESI+) C19H23FNO+
([M + H]+) requires 300.1758, found 300.1756. Anal. Calcd for
C19H22FNO: C, 76.2; H, 7.4; N, 4.7. Found: C, 76.4; H, 7.4; N, 4.6.
From 42: Following general procedure 2, 42 (211 mg, 0.80 mmol)
in CH2Cl2 (4.6 mL) was treated with HBF4·OEt2 (220 μL, 1.62
mmol) and m-CPBA (0.5 M in CH2Cl2, 3.2 mL, 1.6 mmol) for 18 h to
give a 74:26 mixture of 25:43. K2CO3 (11.1 mg, 0.08 mmol) and
MeOH (2.0 mL) were then added to the residue, and the resultant
mixture was stirred at rt for 1 h and then concentrated in vacuo. The
residue was partitioned between H2O (10 mL) and CH2Cl2 (10 mL),
and the layers were separated. The aqueous layer was extracted with
CH2Cl2 (2 × 10 mL), and the combined organic layers were dried and
concentrated in vacuo. Purification via flash column chromatography
(gradient elution, 2→20% EtOAc in 30−40 °C petroleum ether) gave
25 as a white crystalline solid (110 mg, 46%, >99:1 dr).
(1RS,2SR,5RS)-2-(N,N-Dibenzylamino)-5-fluorocyclopentan-
1-ol (26) and (RS,RS,RS)-N(2)-Benzyl-4,5-benzo-2-azabicyclo-
[4.2.1]nonan-9-ol (28). Following general procedure 1, 2117c (140
mg, 0.50 mmol, >99:1 dr) in CH2Cl2 (2.0 mL) was treated with
HBF4·OEt2 (136 μL, 1.00 mmol) to give a 35:65 mixture of 26:28.
Purification via flash column chromatography (gradient elution, 5→
40% EtOAc in 30−40 °C petroleum ether) gave 26 as a white
crystalline solid (52.2 mg, 35%, >99:1 dr): Rf 0.28 (30−40 °C
petroleum ether/EtOAc, 4:1); mp 79−81 °C; νmax 3419 (O−H),
3085, 3062, 3028, 3004, 2962, 2882, 2836, 2805 (C−H), 1494, 1454,
1365, 1075, 1056, 1028; δH (400 MHz, CDCl3) 1.73−2.26 (5H, m,
C(3)H2, C(4)H2, OH), 3.02 (1H, app dd, J 8.9, 8.0, C(2)H), 3.58
(2H, d, J 13.9, N(CHAHBPh)2), 3.82 (2H, d, J 13.9, N(CHAHBPh)2),
4.21 (1H, ddd, J 23.2, 8.0, 3.8, C(1)H), 4.66−4.86 (1H, m, C(5)H),
7.22−7.42 (10H, m, Ph); δC (100 MHz, CDCl3) 20.9 (C(3)), 27.7 (d,
J 22.4, C(4)), 54.9 (N(CH2Ph)2), 65.9 (C(2)), 77.9 (d, J 24.0, C(1)),
98.1 (d, J 179, C(5)), 127.1 (p-Ph), 128.4, 128.6 (o,m-Ph), 139.7 (i-
Ph); δF (377 MHz, CDCl3) −180.5 (m); m/z (ESI+) 621 ([2M +
Na]+, 100), 322 ([M + Na]+, 92), 300 ([M + H]+, 86); HRMS (ESI+)
C19H23FNO+ ([M + H]+) requires 300.1758, found 300.1756. Further
elution gave 28 as a white crystalline solid (77.4 mg, 55%, >99:1 dr):
Rf 0.08 (30−40 °C petroleum ether/EtOAc, 4:1); mp 139−143 °C;
νmax 3385 (O−H), 3062, 3027, 2923 (C−H), 1493, 1452, 1028; δH
(400 MHz, CDCl3) 1.65 (1H, br s, OH), 1.96−2.15 (2H, m, C(7)HA,
C(8)HA), 2.31−2.43 (1H, m, C(7)HB), 2.43−2.55 (1H, m, C(8)HB),
3.24 (1H, app d, J 9.4, C(1)H), 3.35 (1H, d, J 15.9, C(3)HA), 3.54
(1H, app d, J 6.6, C(6)H), 3.62 (1H, d, J 13.4, NCHAHBPh), 3.74 (1H,
d, J 13.4, NCHAHBPh), 4.20 (1H, d, J 15.9, C(3)HB), 4.26 (1H, s,
C(9)H), 6.94 (1H, app d, J 7.3, Ar), 7.06−7.14 (1H, m, Ar), 7.19 (2H,
app d, J 4.0, Ar), 7.24−7.41 (5H, m, Ph); δC (100 MHz, CDCl3) 28.7
(C(7)), 29.5 (C(8)), 51.2 (C(3)), 54.5 (C(1)), 57.2 (NCH2Ph), 71.5
(C(6)), 76.9 (C(9)), 126.0, 127.1, 127.4, 128.4, 129.0, 129.1, 130.8,
138.2, 139.3, 143.2 (Ar, Ph); m/z (ESI+) 280 ([M + H]+, 100); HRMS
(ESI+) C19H22NO+ ([M + H]+) requires 280.1696, found 280.1694.
Anal. Calcd for C19H21NO: C, 81.7; H, 7.6; N, 5.0. Found: C, 81.8; H,
7.4; N, 4.9.
Step 2: MeCN (71 μL, 1.4 mmol) and CH2Cl2 (2.0 mL) were
added sequentially to AgBF4 (58.4 mg, 0.30 mmol), the resultant
solution was added to a stirred solution of 16 (123 mg, 0.30 mmol,
>99:1 dr) in CH2Cl2 (1.0 mL), and the mixture was stirred at rt for 5
min, filtered, and concentrated in vacuo to give 17 as a hygroscopic
white solid (121 mg, 97%, >99:1 dr): νmax 3500 (O−H), 3036, 2953,
2876 (C−H), 1057, 1033, 1009, 750, 726, 703; δH (400 MHz, CDCl3)
1.50−1.95 (4H, m, C(4)H2, C(5)H2), 2.26−2.45 (2H, m, C(6)H2),
2.83 (3H, s, NMe), 3.39 (1H, d, J 11.9, C(1)H), 4.28 (1H, d, J 13.4,
N(CHAHBPh)A), 4.37−4.47 (2H, m, N(CHAHBPh)B, OH), 4.63−4.83
(3H, m, C(2)H, C(3)H, N(CHAHBPh)A), 5.32 (1H, d, J 12.9,
N(CHAHBPh)B), 7.23−7.60 (10H, m, Ph); δC (100 MHz, CDCl3)
19.6 (d, J 32.8, C(4)), 24.1 (d, J 20.0, C(5)), 29.7 (C(6)), 45.4 (NMe),
64.1, 64.7, 64.8, 65.1 (C(2), N(CH2Ph)2), 67.3 (C(1)), 91.3 (d, J 175,
C(3)), 126.6, 127.0, 129.3, 129.5, 130.8, 131.1, 132.6, 133.6 (Ph); δF
−
(377 MHz, CDCl3) −187.2 (m), −150.9 (s, BF4 ); m/z (ESI+) 328
([M]+, 100); HRMS (ESI+) C21H27FNO+ ([M]+) requires 328.2071,
found 328.2069.
From 15: HBF4·OEt2 (8.6 μL, 0.06 mmol) was added to a stirred
solution of 15 (25.0 mg, 0.06 mmol, >99:1 dr) in CD2Cl2 (0.25 mL) at
rt, and the resultant mixture was stirred at rt for 5 min. Satd aq NaBF4
(10 mL) and CH2Cl2 (10 mL) were added, and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (2 × 10 mL),
and the combined organic layers were dried (NaBF4) and
concentrated in vacuo to give 17 as a colorless oil (26.3 mg, quant,
>99:1 dr).
(1RS,2SR,6RS)-2-(N,N-Dibenzylamino)-6-fluorocyclohexan-1-
ol (23). Following general procedure 1, 1817b (402 mg, 1.37 mmol,
>99:1 dr) in CH2Cl2 (5.5 mL) was treated with HBF4·OEt2 (0.37 mL,
2.7 mmol). Purification via flash column chromatography (gradient
elution, 5→40% Et2O in 30−40 °C petroleum ether) gave 23 as a
colorless oil which solidified on standing to a white crystalline solid
(314 mg, 73%, >99:1 dr):16 Rf 0.26 (30−40 °C petroleum ether/Et2O,
4:1); mp 77−79 °C; δH (400 MHz, CDCl3) 1.08−1.22 (1H, m, C(4)
HA), 1.29 (1H, app qd, J 12.6, 3.3, C(3)HA), 1.40−1.54 (1H, m, C(5)
HA), 1.80−1.90 (1H, m, C(4)HB), 1.90−1.98 (1H, m, C(3)HB), 2.03−
2.13 (1H, m, C(5)HB), 2.37−2.47 (1H, app td, J 11.0, 2.8, C(2)H),
3.40 (2H, d, J 13.1, N(CHAHBPh)2), 3.62 (1H, ddd, J 13.0, 10.0, 8.4,
C(1)H), 3.76 (1H, br s, OH), 3.90 (2H, d, J 13.1, N(CHAHBPh)2),
4.23 (1H, dddd, J 51.5, 11.3, 8.4, 5.2, C(6)H), 7.24−7.38 (10H, m,
Ph).
(1RS,2SR,6RS)-2-(N-Benzyl-N-methylamino)-6-fluorocyclo-
hexan-1-ol (24). Following general procedure 1, 1917i (217 mg, 1.00
mmol, >99:1 dr) in CH2Cl2 (4.0 mL) was treated with HBF4·OEt2
(0.27 mL, 2.0 mmol). Purification via flash column chromatography on
neutralized silica gel (gradient elution, 2→20% EtOAc in 30−40 °C
petroleum ether) gave 24 as a colorless oil which solidified on standing
to a white crystalline solid (169 mg, 71%, >99:1 dr):16 Rf 0.13 (30−40
°C petroleum ether/EtOAc, 9:1; neutralized silica gel); mp 77−79 °C;
δH (400 MHz, CDCl3) 1.15−1.32 (2H, m, C(3)HA, C(4)HA), 1.40−
1.56 (1H, m, C(5)HA), 1.76−1.94 (2H, m, C(3)HB, C(4)HB), 2.07−
2.17 (1H, m, C(5)HB), 2.22 (3H, s, NMe), 2.35−2.45 (1H, m, C(2)
H), 3.47 (1H, d, J 13.0, NCHA), 3.55 (1H, ddd, J 12.8, 10.2, 8.3, C(1)
H), 3.74 (1H, d, J 13.0, NCHB), 4.37 (1H, dddd, J 51.5, 11.2, 8.3, 5.2,
C(6)H), 7.24−7.37 (5H, m, Ph).
(RS,RS,RS)-2-(N,N-Dibenzylamino)-5-fluorocyclopentan-1-ol
(25). From 20: Following general procedure 1, 2017c (140 mg, 0.50
mmol, >99:1 dr) in CH2Cl2 (2.0 mL) was treated with HBF4·OEt2
(136 μL, 1.00 mmol). Purification via flash column chromatography
(gradient elution, 2→20% EtOAc in 30−40 °C petroleum ether) gave
25 as a white crystalline solid (118 mg, 78%, >99:1 dr): Rf 0.31 (30−
40 °C petroleum ether/EtOAc, 9:1); mp 68−71 °C; νmax 3457 (O−
H), 3085, 3063, 3029, 2967, 2942, 2919, 2847 (C−H), 1494, 1453,
1046; δH (400 MHz, CDCl3) 1.67−1.91 (2H, m, C(3)HA, C(4)HA),
1.95−2.07 (1H, m, C(4)HB), 2.21−2.41 (1H, m, C(3)HB), 3.27−3.37
(1H, m, C(2)H), 3.50 (1H, br s, OH), 3.74 (4H, A2 system,
(1RS,2SR,7RS)-2-(N,N-Dibenzylamino)-7-fluorocycloheptan-
1-ol (27). From 22: Following general procedure 1, 2217c (307 mg,
1.00 mmol, >99:1 dr) in CH2Cl2 (4.0 mL) was treated with
HBF4·OEt2 (0.27 mL, 2.0 mmol). Purification via flash column
chromatography (gradient elution, 5→40% EtOAc in 30−40 °C
petroleum ether) gave 27 as a colorless oil which solidified on standing
to a white crystalline solid (247 mg, 75%, >99:1 dr): Rf 0.36 (30−40
°C petroleum ether/EtOAc, 9:1); mp 81−82 °C (CHCl3/heptane);
νmax 3375 (O−H), 3105, 3086, 3062, 3028, 3006, 2937, 2863, 2813
(C−H), 1495, 1454; δH (400 MHz, CDCl3) 1.25−1.50 (3H, m, C(3)
HA, C(4)HA, C(5)HA), 1.56−1.93 (4H, m, C(4)HB, C(5)HB, C(6)
H2), 1.99−2.11 (1H, m, C(3)HB), 2.46 (1H, app t, J 10.0, C(2)H),
3.34 (2H, d, J 13.3, N(CHAHBPh)2), 3.73 (1H, ddd, J 19.3, 9.9, 6.1,
C(1)H), 3.86 (2H, d, J 13.3, N(CHAHBPh)2), 4.35 (1H, dddd, J 47.2,
7271
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
8.8, 6.1, 3.4, C(7)H), 4.72 (1H, s, OH), 7.23−7.38 (10H, m, Ph); δC
(100 MHz, CDCl3) 20.0 (d, J 9.6, C(5)), 21.9 (C(3)), 25.4 (C(4)),
29.0 (d, J 21.6, C(6)), 53.1 (N(CH2Ph)2), 58.7 (d, J 10.4, C(2)), 74.5
(d, J 22.4, C(1)), 97.6 (d, J 169, C(7)), 127.5 (p-Ph), 128.6, 129.2
(o,m-Ph), 138.4 (i-Ph); δF (377 MHz, CDCl3) −171.2 (m); m/z
(ESI+) 677 ([2M + Na]+, 100), 328 ([M + H]+, 96); HRMS (ESI+)
C21H27FNO+ ([M + H]+) requires 328.2071, found 328.2067. Anal.
Calcd for C21H26FNO: C, 77.0; H, 8.0; N, 4.3. Found: C, 76.8; H, 7.9;
N, 4.2.
From 44: Following general procedure 2, 44 (175 mg, 0.60 mmol)
in CH2Cl2 (3.4 mL) was treated with HBF4·OEt2 (165 μL, 1.21
mmol) and m-CPBA (0.5 M in CH2Cl2, 2.4 mL, 1.2 mmol) for 18 h.
K2CO3 (8.3 mg, 0.06 mmol) and MeOH (1.5 mL) were then added to
the residue, and the resultant mixture was stirred at rt for 1 h and then
concentrated in vacuo. The residue was partitioned between H2O (10
mL) and CH2Cl2 (10 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL), and the
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 2→
20% EtOAc in 30−40 °C petroleum ether) gave 27 as a white
crystalline solid (144 mg, 73%, >99:1 dr).
(RS)-3-(N,N-Dibenzylamino)cyclohex-1-ene (29). Dibenzyl-
amine (18 mL, 94 mmol) was added to 3-bromocyclohex-1-ene
(6.00 g, 37.3 mmol) at 0 °C, and the resultant mixture was allowed to
warm to rt and then heated at 60 °C for 30 min. The residue was
allowed to cool to rt and was partitioned between CH2Cl2 (400 mL)
and H2O (400 mL). The organic layer was separated and washed
sequentially with 10% aq citric acid (3 × 200 mL) and satd aq
NaHCO3 (3 × 200 mL) and then dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 1→8%
Et2O in 30−40 °C petroleum ether) gave 29 as a colorless syrup which
solidified on standing to a white crystalline solid (7.08 g, 68%):17a,i mp
35−36 °C; δH (400 MHz, CDCl3) 1.78−1.99 (2H, m, C(5)H2), 2.19−
2.49 (4H, m, C(4)H2, C(6)H2), 3.41 (2H, d, J 13.9, N(CHAHBPh)2),
(2H, d, J 13.9, N(CHAHBPh)2), 3.98−4.13 (1H, m, C(3)H), 5.65−
5.85 (2H, m, C(1)H, C(2)H), 7.11−7.49 (10H, m, Ph).
mmol) and m-CPBA (0.5 M in CH2Cl2, 2.4 mL, 1.2 mmol) for 18 h to
give a 16:84 mixture of 6:23. Pyridine (1.0 mL) and Ac2O (0.57 μL,
6.0 mmol) were added to the residue, and the resultant mixture was
stirred at rt for 20 h then concentrated in vacuo. Purification via flash
column chromatography (gradient elution, 5→40% Et2O in 30−40 °C
petroleum ether) gave 33 as a colorless oil which solidified on standing
to a white crystalline solid (105 mg, 49%, >99:1 dr): Rf 0.37 (30−40
°C petroleum ether/Et2O, 4:1); mp 109−111 °C; νmax 3086, 3064,
3030, 2951, 2854, 2810 (C−H), 1733 (CO), 1367, 1234, 1039,
1028, 747, 733, 696; δH (400 MHz, CDCl3) 1.04−1.18 (1H, m, C(4)
HA), 1.40 (1H, app qd, J 12.8, 3.7, C(3)HA), 1.44−1.58 (1H, m, C(5)
HA), 1.77−1.88 (1H, m, C(4)HB), 1.95−2.05 (1H, m, C(5)HB), 2.08−
2.17 (1H, m, C(3)HB), 2.25 (3H, s, COMe), 2.62−2.71 (1H, m, C(2)
H), 3.47 (2H, d, J 13.6, N(CHAHBPh)2), 3.85 (2H, d, J 13.6,
N(CHAHBPh)2), 4.27 (1H, dddd, J 50.6, 11.6, 8.8, 5.2, C(6)H), 5.26
(1H, ddd, J 12.3, 10.7, 8.8, C(1)H), 7.19−7.35 (10H, m, Ph); δC (100
MHz, CDCl3) 20.1 (d, J 12.8, C(4)), 21.4 (COMe), 23.6 (d, J 1.6,
C(3)), 30.6 (d, J 17.6, C(5)), 53.7 (N(CH2Ph)2), 58.8 (d, J 8.0, C(2)),
73.9 (d, J 16.0, C(1)), 93.1 (d, J 181, C(6)), 126.9 (p-Ph), 128.2, 128.7
(o,m-Ph), 139.7 (i-Ph), 170.4 (COMe); δF (377 MHz, CDCl3) −180.5
(app d, J 50.6); m/z (ESI+) 733 ([2M + Na]+, 100), 378 ([M + Na]+,
85), 356 ([M + H]+, 87), 336 ([M − F]+, 71); HRMS (ESI+)
+
C22H27FNO2 ([M + H]+) requires 356.2020, found 356.2013.
K2CO3 (82.9 mg, 0.60 mmol) and MeOH (1.50 mL) were added to
33 (105 mg, 0.30 mmol, >99:1 dr), and the resultant mixture was
stirred at rt for 3 h and then concentrated in vacuo. The residue was
partitioned between H2O (10 mL) and CH2Cl2 (10 mL), and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(2 × 10 mL), and the combined organic layers were dried and
concentrated in vacuo to give 23 as a white, crystalline solid (92.6 mg,
quant, >99:1 dr).
(RS)-3-(N-Benzyl-N-methylamino)cyclohex-1-ene (34). A
stirred mixture of 3-bromocyclohex-1-ene (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 (2.0 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) and then dried and
concentrated in vacuo. Purification via flash column chromatography
(gradient elution, 2→20% Et2O in 30−40 °C petroleum ether) gave
34 as a pale yellow oil (270 mg, 83%):44 δH (400 MHz, CDCl3) 1.48−
1.60, 1.77−1.90, 1.96−2.04 (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,
NCHA), 3.67 (1H, d, J 13.3, NCHB), 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-Benzylamino)cyclohex-1-ene (37). Benzylamine (6.6
mL, 60 mmol) was added to 3-bromocyclohex-1-ene (3.90 g, 24.2
mmol) at 0 °C, and the resultant mixture was allowed to warm to rt
and was then heated at 60 °C for 30 min. The residue was allowed to
cool to rt and was partitioned between CH2Cl2 (100 mL) and satd aq
NaHCO3 (100 mL). The organic layer was separated and washed with
satd aq NaHCO3 (2 × 100 mL), and the combined aqueous layers
were extracted with CH2Cl2 (2 × 100 mL). The combined organic
extracts were then dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30−40 °C petroleum ether/
EtOAc, 4:1; neutralized silica gel) gave 37 as a yellow oil (3.46 g,
76%):17a δH (400 MHz, CDCl3) 1.35−1.61 (2H, m), 1.71−1.81 (1H,
m), 1.85−2.06 (3H, m), 3.21−3.29 (1H, m, C(3)H), 3.79−3.89 (2H,
m, NCH2), 5.61−5.82 (2H, m, C(1)H, C(2)H), 7.21−7.49 (5H, m,
Ph).
(RS,RS,RS)-2-(N-Benzylamino)-6-fluorocyclohexan-1-ol (38).
Following general procedure 2, 37 (150 mg, 0.80 mmol) in CH2Cl2
(4.6 mL) was treated with HBF4·OEt2 (220 μL, 1.62 mmol) and m-
CPBA (0.5 M in CH2Cl2, 3.2 mL, 1.6 mmol) for 18 h to give a 90:10
mixture of 38:40. K2CO3 (11.1 mg, 0.08 mmol) and MeOH (2.0 mL)
were then added to the residue, and the resultant mixture was stirred at
rt for 1 h and then concentrated in vacuo. The residue was partitioned
between H2O (10 mL) and CH2Cl2 (10 mL), and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (2 × 10 mL),
and the combined organic layers were dried and concentrated in vacuo
(RS,RS,RS)-1-Acetoxy-2-(N,N-dibenzylamino)-6-fluorocyclo-
hexane (32). Following general procedure 2, 29 (166 mg, 0.60
mmol) in CH2Cl2 (3.4 mL) was treated with HBF4·OEt2 (165 μL,
1.21 mmol) and m-CPBA (0.5 M in CH2Cl2, 2.4 mL, 1.2 mmol) for 18
h to give a 67:12:21 mixture of 6:23:30. Pyridine (1.0 mL) and Ac2O
(0.57 mL, 6.0 mmol) were added to the residue and the resultant
mixture was stirred at rt for 20 h and then concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 5→
40% Et2O in 30−40 °C petroleum ether) gave 32 as a colorless oil
which solidified on standing to a white crystalline solid (95.2 mg, 45%,
>99:1 dr); Rf 0.42 (30−40 °C petroleum ether/Et2O, 4:1): mp 87−89
°C; νmax 3085, 3063, 3027, 2943, 2871, 2835, 2804 (C−H), 1743
(CO), 1229, 747, 736; δH (400 MHz, CDCl3) 1.49−1.72 (3H, m,
C(4)H2, C(5)HA), 1.75−1.92 (3H, m, C(3)H2, C(5)HB), 2.04 (3H, s,
COMe), 3.04 (1H, app dq, J 12.1, 3.4, C(2)H), 3.75 (4H, A2 system,
N(CH2Ph)2), 4.58−4.75 (1H, m, C(6)H), 5.42−5.47 (1H, m, C(1)
H), 7.19−7.39 (10H, m, Ph); δC (100 MHz, CDCl3) 19.7 (C(4)), 21.3
(COMe), 23.0 (C(3)), 26.1 (d, J 20.8, C(5)), 53.9 (C(2)), 55.1
(N(CH2Ph)2), 71.2 (d, J 29.6, C(1)), 88.1 (d, J 173, C(6)), 126.8 (p-
Ph), 128.2, 128.3 (o,m-Ph), 140.3 (i-Ph), 170.0 (COMe); δF (377
MHz, CDCl3) −188.8 (m); m/z (ESI+) 378 ([M + Na]+, 89), 356
+
([M + H]+, 100); HRMS (ESI+) C22H27FNO2 ([M + H]+) requires
356.2020, found 356.2012.
K2CO3 (82.9 mg, 0.60 mmol) and MeOH (1.5 mL) were added to
32 (95.2 mg, 0.27 mmol, >99:1 dr), and the resultant mixture was
stirred at rt for 3 h and then concentrated in vacuo. The residue was
partitioned between H2O (10 mL) and CH2Cl2 (10 mL), and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(2 × 10 mL), and the combined organic layers were dried and
concentrated in vacuo to give 6 as a white, crystalline solid (83.9 mg,
quant, >99:1 dr).
(1RS,2SR,6RS)-1-Acetoxy-2-(N,N-dibenzylamino)-6-fluorocy-
clohexane (33). Following general procedure 2, 29 (166 mg, 0.60
mmol) in CH2Cl2 (2.0 mL) was treated with HBF4·OEt2 (1.6 mL, 12
7272
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
to give a 90:10 mixture of 38:41. Purification via flash column
chromatography (gradient elution, 7→60% EtOAc in 30−40 °C
petroleum ether) gave 38 as a white crystalline solid (116 mg, 65%,
>99:1 dr): Rf 0.16 (30−40 °C petroleum ether/EtOAc, 7:3); mp 82−
83 °C; νmax 3329 (O−H), 3087, 3063, 3029, 2941, 2867 (C−H), 1455,
1073, 699; δH (400 MHz, CDCl3) 1.39−1.51 (1H, m, C(3)HA), 1.54−
1.77 (4H, m, C(3)HB, C(4)H2, C(5)HA), 1.79−1.98 (1H, m, C(5)
HB), 2.43 (1H, br s, OH), 2.98−3.07 (1H, m, C(2)H), 3.78 (2H, AB
system, NCH2Ph), 3.82−3.88 (1H, m, C(1)H), 4.77 (1H, dtd, J 48.0,
5.7, 3.3, C(6)H), 7.24−7.39 (5H, m, Ph); δC (100 MHz, CDCl3) 18.2
(d, J 4.8, C(4)), 26.4 (C(3)), 27.2 (d, J 19.2, C(5)), 51.1 (NCH2Ph),
55.8 (C(2)), 68.9 (d, J 27.2, C(1)), 91.5 (d, J 168, C(6)), 127.2 (p-Ph),
128.1, 128.6 (o,m-Ph), 140.1 (i-Ph); δF (377 MHz, CDCl3) −191.8
(m); m/z (FI+) 223 ([M]+, 100); HRMS (FI+) C13H18FNO+ ([M]+)
requires 223.1367, found 223.1367. Anal. Calcd for C13H18FNO: C,
69.9; H, 8.1; N, 6.3. Found: C, 70.1; H, 8.1; N, 6.2.
(RS)-3-(N,N-Dibenzylamino)cyclopent-1-ene (42). A mixture
of cyclopentene (119 mL, 1.35 mol), NBS (60.0 g, 337 mmol), and
benzoyl peroxide (70% with H2O, 1.17 g, 3.37 mmol) in CCl4 (216
mL) was heated at reflux for 1 h. The reaction mixture was then cooled
to 0 °C and filtered through a pad of Celite (eluent CCl4) to give a
yellow solution. Dibenzylamine (162 mL, 843 mmol) was immediately
added dropwise at 0 °C, and the resultant mixture was allowed to
warm to rt and was stirred for 30 min. The reaction mixture was then
filtered, heated to 40 °C, and stirred at this temperature for 1 h and
then filtered and stirred at rt for 12 h. The mixture was then filtered
and concentrated in vacuo, and the residue was dissolved in CH2Cl2 (1
L) and washed sequentially with 10% aq citric acid (3 × 500 mL) and
satd aq NaHCO3 (3 × 500 mL) then concentrated in vacuo. The
residue was dissolved in 1 M aq HCl (1 L) and washed with Et2O (3 ×
200 mL). The aqueous layer was then slowly basified by the
portionwise addition of solid NaHCO3 and then extracted with
CH2Cl2 (3 × 300 mL). The combined organic extracts were dried,
filtered, and concentrated in vacuo. Purification via flash column
chromatography (gradient elution, 1%→5% Et2O in 40−60 °C
petroleum ether) gave 42 as a pale yellow oil (36.3 g, 41%):17c,i δH
(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(CHAHBPh)2), 3.81 (2H, d, J 14.0,
N(CHAHBPh)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).
(RS)-3-(N,N-Dibenzylamino)cyclohept-1-ene (44). A mixture
of 3-bromocyclohept-1-ene (16.0 g, 91.4 mmol), dibenzylamine (44
mL, 230 mmol), and K2CO3 (15.2 g, 110 mmol) was stirred at 60 °C
for 35 h. The mixture was then diluted with H2O (1 L) and CH2Cl2 (1
L). The organic layer was separated and washed sequentially with 10%
aq citric acid (3 × 500 mL) and satd aq NaHCO3 (500 mL) and then
dried and concentrated in vacuo. Purification via recrystallization
(iPrOH) gave 44 as a white crystalline solid (21.6 g, 81%):17c,i mp 54−
55 °C; δH (400 MHz, CDCl3) 1.26−2.33 (8H, m, C(4)H2-C(7)H2),
3.35 (1H, app d, J 10.4, C(3)H), 3.59 (2H, d, J 14.2, N(CHAHBPh)2),
3.74 (2H, d, J 14.2, N(CHAHBPh)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).
mL, 45 mmol) in Et2O (50 mL), and the resultant mixture was stirred
at rt for 44 h. Satd aq NH4Cl (10 mL) was then added, and the
resultant mixture was dried, filtered through a pad of silica gel (eluent
Et2O), and concentrated in vacuo. Purification via recrystallization
from 30−40 °C petroleum ether gave (RS)-3-trichloroacetamido-1-
methylcyclohex-1-ene as a white crystalline solid (6.07 g, 53%):45 mp
71−73 °C; δH (400 MHz, CDCl3) 1.55−1.74 (4H, m, C(4)H2, C(5)
H2) overlapping 1.72 (3H, s, Me), 1.84−2.01 (2H, m, C(6)H2), 4.42
(1H, app s, C(3)H), 5.34−5.40 (1H, m, C(2)H), 6.56 (1H, br s, NH).
Step 3: Aqueous NaOH (10 M, 12 mL) was added dropwise to a
stirred solution of (RS)-3-trichloroacetamido-1-methylcyclohex-1-ene
(6.07 g, 23.7 mmol) in EtOH (34 mL) at 0 °C, and the resultant
mixture was allowed to warm to rt over 17 h. The mixture was then
extracted with Et2O/30−40 °C petroleum ether (4:1 v/v, 3 × 50 mL),
and the combined organic layers were washed with H2O (2 × 50 mL),
dried, and concentrated in vacuo. BnBr (1.2 mL, 10.3 mmol), K2CO3
(2.13 g, 15.4 mmol), and MeCN (26 mL) were added to the residue,
and the resultant mixture was heated at reflux for 18 h and then
concentrated in vacuo. The residue was partitioned between EtOAc
(30 mL) and H2O (30 mL), and the layers were separated. The
aqueous layer was extracted with EtOAc (2 × 30 mL), and the
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 1→8%
Et2O in 30−40 °C petroleum ether) gave 45 as a colorless oil (1.13 g,
16%): Rf 0.37 (30−40 °C petroleum ether/Et2O, 19:1); νmax 3104,
3084, 3062, 3026, 3003, 2962, 2928, 2859, 2830, 2799, 2723, 1494,
1453, 743, 697; δH (400 MHz, CDCl3) 1.38−1.53 (2H, m, C(4)HA,
C(5)HA), 1.70 (3H, s, C(1)Me), 1.76−2.05 (4H, m, C(4)HB, C(5)HB,
C(6)H2), 3.34 (1H, br s, C(3)H), 3.55 (2H, d, J 14.1,
N(CHAHBPh)2), 3.77 (2H, d, J 14.1, N(CHAHBPh)2), 5.49 (1H, br
s, C(2)H), 7.19−7.48 (10H, m, Ph); δC (100 MHz, CDCl3) 22.0, 22.8
(C(4), C(5)), 23.8 (C(1)Me), 30.3 (C(6)), 53.8 (N(CH2Ph)2), 54.9
(C(3)), 125.0 (C(2)), 126.5 (p-Ph), 128.1, 128.5 (o,m-Ph), 137.4,
141.1 (i-Ph, C(1)); m/z (ESI+) 292 ([M + H]+, 100); HRMS (ESI+)
C21H26N+ ([M + H]+) requires 292.2060, found 292.2059.
(RS,RS,RS)-2-(N,N-Dibenzylamino)-6-fluoro-6-methylcyclo-
hexan-1-ol (46). Following general procedure 2, 45 (233 mg, 0.80
mmol) in CH2Cl2 (4.6 mL) was treated with HBF4·OEt2 (220 μL,
1.60 mmol) and m-CPBA (0.5 M in CH2Cl2, 3.2 mL, 1.6 mmol) for 18
h. K2CO3 (11.1 mg, 0.08 mmol) and MeOH (2.0 mL) were then
added to the residue, and the resultant mixture was stirred at rt for 1 h
and then concentrated in vacuo. The residue was partitioned between
H2O (10 mL) and CH2Cl2 (10 mL), and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (2 × 10 mL), and the
combined organic layers were dried and concentrated in vacuo to give
46 in 95:5 dr. Purification via flash column chromatography (gradient
elution, 5→40% Et2O in 30−40 °C petroleum ether) gave 46 as a
colorless oil which solidified on standing to a white crystalline solid
(184 mg, 70%, 95:5 dr): Rf 0.32 (30−40 °C petroleum ether/Et2O,
4:1); mp 55−59 °C; νmax 3457, 3085, 3062, 3028, 2937, 2870, 1494,
1453, 1374, 1152, 1072, 1058, 1029, 747, 737, 699; δH (400 MHz,
CDCl3) 1.25−1.39 (1H, m, C(3)HA), 1.45 (3H, d, J 23.0, C(6)Me),
1.50−1.78 (5H, m, C(3)HB, C(4)H2, C(5)H2), 3.12 (1H, ddd, J 12.5,
6.7, 3.2, C(2)H), 3.78 (2H, d, J 14.6, N(CHAHBPh)2), 3.87 (2H, d, J
14.6, N(CHAHBPh)2), 3.89−3.93 (1H, m, C(1)H), 7.21−7.37 (10H,
m, Ph); δC (100 MHz, CDCl3) 19.9 (d, J 1.6, C(4)), 23.5 (C(3)), 25.2
(d, J 22.4, C(6)Me), 31.0 (d, J 21.6, C(5)), 54.5 (N(CH2Ph)2), 60.4
(C(2)), 70.9 (d, J 32.8, C(1)), 95.9 (d, J 165, C(6)), 126.9 (p-Ph),
128.4, 128.5 (o,m-Ph), 140.0 (i-Ph); δF (377 MHz, CDCl3) −156.7
(m); m/z (ESI+) 677 ([2M + Na]+, 100), 350 ([M + Na]+, 59), 328
([M + H]+, 89); HRMS (ESI+) C21H27FNO+ ([M + H]+) requires
328.2071, found 328.2070. Data for minor diastereoisomer: δH (400
MHz, CDCl3) [selected peaks] 1.14 (3H, d, J 23.4, C(6)Me), 2.36−
2.45 (1H, m, C(2)H), 3.38 (2H, d, J 13.3, N(CHAHBPh)2); δF (377
MHz, CDCl3) −133.0 (m).
(RS)-3-(N,N-Dibenzylamino)-1-methylcyclohex-1-ene (45).
Step 1: MeMgCl (3.0 M in THF, 50 mL, 150 mmol) was added
dropwise to a stirred solution of cyclohex-2-enone (9.7 mL, 100
mmol) in THF (350 mL) at 0 °C, and the resultant mixture was
allowed to warm to rt over 18 h. Satd aq NH4Cl (150 mL) was then
added, and the layers were separated. The aqueous layer was extracted
with Et2O (2 × 150 mL), and the combined organic layers were dried
and concentrated in vacuo. Purification via distillation at reduced
pressure (1.2 mmHg) gave (RS)-1-methylcyclohex-2-enol as a
colorless oil (7.54 g, 67%):45 bp 24−26 °C (1.2 mmHg); δH (400
MHz, CDCl3) 1.29 (3H, s, Me), 1.51 (1H, br s, OH), 1.59−1.80 (4H,
m, C(5)H2, C(6)H2), 1.88−2.09 (2H, m, C(4)H2), 5.61−5.67 (1H, m,
C(2)H), 5.76 (1H, app dt, J 9.9, 3.8, C(3)H).
Step 2: A solution of (RS)-1-methylcyclohex-2-enol (5.00 g, 44.6
mmol) in Et2O (25 mL) was added dropwise to a stirred suspension of
KH (268 mg, 6.69 mmol) in Et2O (30 mL) at 0 °C, and the resultant
mixture was stirred at this temperature for 30 min. This mixture was
then added dropwise via cannula to a stirred solution of Cl3CCN (4.5
N(1)-Benzyl-1,2,3,6-tetrahydropyridine (47). MsCl (11 mL,
140 mmol) was added dropwise to a stirred solution of N(1)-benzyl-4-
hydroxypiperidine (24.0 g, 125 mmol) and Et3N (19 mL, 140 mmol)
in PhMe (300 mL) at 0 °C, and the resultant mixture was allowed to
warm to rt over 1.5 h. H2O (75 mL) was then added, and the layers
7273
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
were separated. The organic layer was washed with H2O (75 mL) and
then dried. The resultant solution was diluted with PhMe (150 mL)
and N,N-dimethylacetamide (100 mL), BuOK (18.3 g, 163 mmol)
vacuo. The residue was partitioned between CH2Cl2 (50 mL) and satd
aq NaHCO3 (50 mL), and the layers were separated. The organic layer
was washed with satd aq NaHCO3 (50 mL), and the combined
aqueous layers were extracted with CH2Cl2 (2 × 50 mL). The
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 1→8%
Et2O in 30−40 °C petroleum ether) gave 51 as a colorless oil (2.23 g,
80%, >99:1 dr): Rf 0.33 (30−40 °C petroleum ether/Et2O, 19:1); νmax
3085, 3063, 3026, 2958, 2871, 2822, 2792, 2710, 1494, 1454, 740, 696;
δH (400 MHz, CDCl3) 0.90 (3H, t, J 7.5, C(6)H3), 1.38 (2H, app
sextet, J 7.4, C(5)H2), 1.99 (2H, app q, J 6.8, C(4)H2), 3.09 (2H, d, J
5.1, C(1)H2), 3.60 (4H, s, N(CH2Ph)2), 5.53−5.65 (2H, m, C(2)H,
C(3)H), 7.22−7.44 (10H, m, Ph); δC (100 MHz, CDCl3) 13.8 (C(6)),
22.8 (C(5)), 29.6 (C(4)), 50.1 (C(1)), 58.0 (N(CH2Ph)2), 126.8 (p-
Ph), 127.1 (C(3)), 128.1, 128.8 (o,m-Ph), 132.9 (C(2)), 139.9 (i-Ph);
m/z (ESI+) 280 ([M + H]+, 100); HRMS (ESI+) C20H26N+ ([M +
H]+) requires 280.2060, found 280.2058.
(Z)-1-(N,N-Dibenzylamino)hex-3-ene (52). Et3N (5.6 mL, 40
mmol) and MsCl (2.3 mL, 30 mmol) were added sequentially to a
stirred solution of (Z)-hex-3-en-1-ol (2.4 mL, 20 mmol) in CH2Cl2
(33 mL) at 0 °C, and the resultant mixture was allowed to warm to rt
over 1 h. Aqueous HCl (1 M, 50 mL) was then added, and the layers
were separated. The aqueous layer was extracted with CH2Cl2 (2 × 50
mL), and the combined organic layers were dried and concentrated in
vacuo. The residue was dissolved in EtOH (50 mL), and dibenzyl-
amine (9.6 mL, 50 mmol) was added. The resultant mixture was
stirred and heated at 70 °C for 16 h, allowed to cool to rt, and
concentrated in vacuo. The residue was partitioned between satd aq
NaHCO3 (100 mL) and CH2Cl2 (100 mL), and the layers were
separated. The organic layer was washed sequentially with 10% aq
citric acid (3 × 100 mL) and satd aq NaHCO3 (100 mL), dried, and
concentrated in vacuo. Purification via flash column chromatography
(gradient elution, 1→8% Et2O in 30−40 °C petroleum ether) gave 52
as a colorless oil (3.28 g, 59%, >99:1 dr): Rf 0.38 (30−40 °C
petroleum ether/Et2O, 19:1); νmax 3085, 3063, 3027, 3007, 2962,
2932, 2873, 2795 (C−H), 1494, 1453, 1366, 1126, 1072, 1028, 743,
698; δH (400 MHz, CDCl3) 0.94 (3H, t, J 7.6, C(6)H3), 2.02 (2H, app
quintet, J 7.33 C(5)H2), 2.25−2.33 (2H, app q, J 7.2, C(2)H2), 2.50
(2H, t, J 7.8, C(1)H2), 3.62 (4H, s, N(CH2Ph)2), 5.27−5.36 (1H, m,
C(3)H), 5.37−5.45 (1H, m, C(4)H), 7.22−7.44 (10H, m, Ph); δC
(100 MHz, CDCl3) 14.3 (C(6)), 20.6 (C(5)), 24.9 (C(2)), 53.3
(C(1)), 58.2 (N(CH2Ph)2), 126.75 (p-Ph), 126.81 (C(3)), 128.1,
128.8 (o,m-Ph), 132.5 (C(4)), 139.9 (i-Ph); m/z (ESI+) 280 ([M +
H]+, 100); HRMS (ESI+) C20H26N+ ([M + H]+) requires 280.2060,
found 280.2058.
(E)-1-(N,N-Dibenzylamino)hex-2-ene (53). Step 1: Diethyl
azodicarboxylate (1.4 mL, 8.9 mmol) was added dropwise to a stirred
solution of (E)-hex-2-en-1-ol (888 mg, 8.86 mmol, >99:1 dr), N-
benzyl-2,4-dinitrobenzenesulfonamide (2.30 g, 6.82 mmol), and PPh3
(2.32 g, 8.86 mmol) in THF (8.0 mL) at 0 °C, and the resultant
mixture was allowed to warm to rt over 19 h and was then
concentrated in vacuo. Purification via flash column chromatography
(gradient elution, 5→40% Et2O in 30−40 °C petroleum ether) gave
(E)-N-benzyl-N-(hex-2-enyl)-2′,4′-dinitrobenzenesulfonamide as a
yellow solid (2.86 g, quant, >99:1 dr):47 Rf 0.25 (30−40 °C petroleum
ether/EtOAc, 4:1); mp 68−69 °C; δH (400 MHz, CDCl3) 0.85 (3H, t,
J 7.3, C(6)H3), 1.31 (2H, app sextet, J 7.3, C(5)H2), 1.90−1.98 (2H,
m, C(4)H2), 3.87 (2H, d, J 6.6, C(1)H2), 4.53 (2H, s, NCH2Ph), 5.23
(1H, dtd, J 15.2, 6.6, 1.5, C(2)H), 5.52 (1H, dt, J 15.2, 6.9, C(3)H),
7.21−7.33 (5H, m, Ph), 8.13 (1H, d, J 8.5, Ar), 8.39 (1H, dd, J 8.5, 2.2,
Ar), 8.48 (1H, d, J 2.2, Ar).
Step 2: 2-Mercaptoacetic acid (0.71 mL, 10 mmol) was added to a
stirred solution of (E)-N-benzyl-N-(hex-2-enyl)-2′,4′-dinitrobenzene-
sulfonamide (2.86 g, 6.82 mmol, >99:1 dr) and Et3N (1.9 mL, 14
mmol) in CH2Cl2 (34 mL) and the resultant solution was stirred at rt
for 1 h and then concentrated in vacuo. The residue was dissolved in
EtOAc (40 mL), washed with 5% aq NaOH (3 × 40 mL), dried, and
concentrated in vacuo to give (E)-1-(N-benzylamino)hex-2-ene as an
orange oil (1.17 g, 91%):47 δH (400 MHz, CDCl3) 0.91 (3H, t, J 7.5,
C(6)H3), 1.40 (2H, app sextet, J 7.4, C(5)H2), 1.51 (1H, br s, NH),
t
was added, and the resultant mixture was stirred at rt for 5 days. H2O
(150 mL) was added, and the layers were separated. The organic layer
was washed with H2O (2 × 150 mL), dried, and concentrated in
vacuo. Purification via distillation at reduced pressure (1.1 mmHg)
gave 47 as a colorless oil (17.6 g, 81%):46 bp 75−78 °C (1.1 mmHg);
δH (400 MHz, CDCl3) 2.15−2.22 (2H, m, C(3)H2), 2.58 (2H, t, J 5.6,
C(2)H2), 2.97−3.01 (2H, m, C(6)H2), 3.60 (2H, s, NCH2Ph), 5.65−
5.71 (1H, m, C(4)H), 5.74−5.81 (1H, m, C(5)H), 7.24−7.40 (5H, m,
Ph).
(RS,RS)-N(1)-Benzyl-4-fluoropiperidin-3-ol (48). Following
general procedure 2, 47 (200 mg, 1.15 mmol) in CH2Cl2 (6.6 mL)
was treated with HBF4·OEt2 (0.32 mL, 2.4 mmol) and m-CPBA (0.5
M in CH2Cl2, 4.6 mL, 2.3 mmol) for 18 h. K2CO3 (16.0 mg, 0.12
mmol) and MeOH (2.9 mL) were then added to the residuem and the
resultant mixture was stirred at rt for 1 h and then concentrated in
vacuo. The residue was partitioned between H2O (10 mL) and
CH2Cl2 (10 mL), and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (2 × 10 mL), and the combined organic
layers were dried and concentrated in vacuo. Purification via flash
column chromatography (gradient elution, 12→100% EtOAc in 30−
40 °C petroleum ether) gave 48 as a pale yellow oil (130 mg, 53%,
>99:1 dr): Rf 0.43 (30−40 °C petroleum ether/EtOAc, 1:1); νmax 3385
(O−H), 3087, 3062, 3029, 2951, 2935, 2807 (C−H), 1454, 1060,
1026, 748, 700; δH (400 MHz, CDCl3) 1.77−1.91 (1H, m, C(5)HA),
1.98−2.14 (1H, m, C(5)HB), 2.30−2.46 (2H, m, C(2)HA, C(6)HA),
2.53−2.64 (1H, m, C(6)HB), 2.80 (1H, app dt, J 11.8, 4.3, C(2)HB),
3.02 (1H, br s, OH), 3.54 (2H, app s, NCH2Ph), 3.78−3.86 (1H, m,
C(3)H), 4.38−4.58 (1H, m, C(4)H), 7.24−7.37 (5H, m, Ph); δC (125
MHz, CDCl3) 28.2 (d, J 19.1, C(5)), 49.4 (d, J 5.7, C(6)), 55.8
(C(2)), 62.3 (NCH2Ph), 68.4 (d, J 20.0, C(3)), 91.8 (d, J 177, C(4)),
127.3 (p-Ph), 128.4, 129.1 (o,m-Ph), 137.7 (i-Ph); δF (377 MHz,
CDCl3) −188.1 (m); m/z (FI+) 209 ([M]+, 100); HRMS (FI+)
C12H16FNO+ ([M]+) requires 209.1210, found 209.1213. Anal. Calcd
for C12H16FNO: C, 68.9; H, 7.7; N, 6.7. Found: C, 69.0; H, 7.6; N, 6.6.
(RS,RS)-N(1)-Benzyl-4-fluoropyrrolidin-3-ol (50). Following
general procedure 2, 49 (421 mg, 2.64 mmol) in CH2Cl2 (12 mL)
was treated with HBF4·OEt2 (3.6 mL, 26 mmol) and m-CPBA (0.5 M
in CH2Cl2, 10.6 mL, 5.29 mmol) for 18 h. K2CO3 (36.5 mg, 0.26
mmol) and MeOH (6.6 mL) were then added to the residue, and the
resultant mixture was stirred at rt for 1 h and then concentrated in
vacuo. The residue was partitioned between H2O (10 mL) and
CH2Cl2 (10 mL), and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (2 × 10 mL), and the combined organic
layers were dried and concentrated in vacuo. Purification via flash
column chromatography (gradient elution, 10→80% EtOAc in 30−40
°C petroleum ether) gave 50 as a pale yellow oil (297 mg, 58%, >99:1
dr): Rf 0.26 (30−40 °C petroleum ether/EtOAc, 3:2); νmax 3375 (O−
H), 3088, 3063, 3030, 2961, 2932, 2804 (C−H), 1454, 1096, 1029,
757, 701; δH (400 MHz, CDCl3) 2.56 (1H, dd, J 10.2, 3.2, C(2)HA),
2.69 (1H, dd, J 29.0, 11.6, C(5)HA), 2.92 (1H, dd, J 10.2, 5.3, C(2)
HB), 3.08 (1H, dddd, J 26.8, 11.6, 5.6, 3.2, C(5)HB), 3.68 (2H, AB
system, JAB 12.9, NCH2Ph), 4.31 (1H, app dt, J 18.4, 4.1, C(3)H), 4.90
(1H, app dd, J 52.8, 5.3, C(4)H), 7.25−7.37 (5H, m, Ph); δC (100
MHz, CDCl3) 58.2 (d, J 24.0, C(5)), 59.6 (C(2)), 59.8 (NCH2Ph),
75.7 (d, J 27.2, C(3)), 98.3 (d, J 181, C(4)), 127.3 (p-Ph), 128.4, 128.8
(o,m-Ph), 137.9 (i-Ph); δF (377 MHz, CDCl3) −177.0 (m); m/z (FI+)
195 ([M]+, 100); HRMS (FI+) C11H14FNO+ ([M]+) requires
195.1054, found 195.1056. Anal. Calcd for C11H14FNO: C, 67.7; H,
7.2; N, 7.2. Found C, 67.8; H, 7.3; N, 7.1.
(Z)-1-(N,N-Dibenzylamino)hex-2-ene (51). NBS (1.78 g, 10.0
mmol) was added portionwise to a stirred solution of (Z)-hex-2-en-1-
ol (1.00 g, 10.0 mmol) and PPh3 (2.62 g, 10.0 mmol) in THF (20 mL)
at 0 °C, and the resultant mixture was stirred at this temperature for 1
h. Dibenzylamine (3.9 mL, 20 mmol) was then added, and the
resultant mixture was allowed to warm to rt over 24 h. Et2O (50 mL)
was then added, and the resultant mixture was stirred for 10 min,
filtered through a pad of Celite (eluent Et2O), and concentrated in
7274
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
1.97−2.06 (2H, m, C(4)H2), 3.23 (2H, d, J 5.1, C(1)H2), 3.79 (2H, s,
NCH2Ph), 5.51−5.66 (2H, m, C(2)H, C(3)H), 7.23−7.39 (5H, m,
Ph).
Step 2: DIBAL-H (1.0 M in hexanes, 48 mL, 48 mmol) was added
dropwise to a stirred solution of methyl (E)-4-(N,N-dibenzylamino)-
but-2-enoate (6.35 g, 21.5 mmol) in CH2Cl2 (50 mL) at 0 °C, and the
resultant solution was allowed to warm to rt and was stirred at this
temperature for 18 h. The mixture was then cooled to 0 °C, satd aq
Rochelle’s salt (100 mL) was added dropwise (cautiously!), and the
resultant mixture was stirred vigorously at rt for 23 h. The mixture was
then filtered through a pad of Celite (eluent Et2O) and the layers were
separated. The aqueous phase was extracted with Et2O (3 × 100 mL),
and the combined organic layers were dried and concentrated in
vacuo. Purification via flash column chromatography (gradient elution,
10→80% EtOAc in 30−40 °C petroleum ether) gave 55 as a colorless
oil (5.72 g, 99%, >99:1 dr): Rf 0.13 (30−40 °C petroleum ether/
EtOAc, 4:1); νmax 3328 (O−H), 3085, 3062, 3027, 2921, 2794, 2712
(C−H), 971, 733, 696; δH (400 MHz, CDCl3) 1.64 (1H, br s, OH),
3.11 (2H, d, J 4.3, C(4)H2), 3.62 (4H, s, N(CH2Ph)2), 4.12 (2H, d, J
3.8, C(1)H2), 5.73−5.86 (2H, m, C(2)H, C(3)H), 7.23−7.44 (10H,
m, Ph); δC (100 MHz, CDCl3) 55.2 (C(4)), 58.1 (N(CH2Ph)2), 63.3
(C(1)), 126.9 (p-Ph), 128.2, 128.8 (o,m-Ph), 129.7, 131.9 (C(2),
C(3)), 139.6 (i-Ph); m/z (ESI+) 268 ([M + H]+, 100); HRMS (ESI+)
C18H22NO+ ([M + H]+) requires 268.1696, found 268.1694.
Step 3: BnBr (0.59 mL, 5.0 mmol) was added to a stirred solution
of (E)-1-(N-benzylamino)hex-2-ene (945 mg, 4.99 mmol, >99:1 dr)
and K2CO3 (2.07 g, 15.0 mmol) in MeCN (25 mL) and the resultant
mixture was heated at reflux for 20 h then allowed to cool to rt, filtered
(eluent Et2O) and concentrated in vacuo. Purification via flash column
chromatography (gradient elution, 1→8% Et2O in 30−40 °C
petroleum ether) gave 53 as a colorless oil (1.21 g, 87%, >99:1 dr):
Rf 0.34 (30−40 °C petroleum ether/Et2O, 19:1); νmax 3085, 3062,
3027, 2957, 2926, 2872, 2792, 2711, 1494, 1454, 970, 732, 696; δH
(400 MHz, CDCl3) 0.91 (3H, t, J 7.3, C(6)H3), 1.41 (2H, app sextet, J
7.3, C(5)H2), 2.03 (2H, app q, J 6.7, C(4)H2), 3.03 (2H, d, J 5.8, C(1)
H2), 3.58 (4H, s, N(CH2Ph)2), 5.49−5.65 (2H, m, C(2)H, C(3)H),
7.21−7.43 (10H, m, Ph); δC (100 MHz, CDCl3) 13.7 (C(6)), 22.5
(C(5)), 34.6 (C(4)), 55.5 (C(1)), 57.6 (N(CH2Ph)2), 126.7 (p-Ph),
127.3 (C(3)), 128.1, 128.8 (o,m-Ph), 134.0 (C(2)), 139.9 (i-Ph); m/z
(ESI+) 280 ([M + H]+, 100); HRMS (ESI+) C20H26N+ ([M + H]+)
requires 280.2060, found 280.2055.
(E)-1-(N,N-Dibenzylamino)hex-3-ene( 54). Et3N (5.6 mL, 40.0
mmol) and MsCl (2.3 mL, 30 mmol) were added sequentially to a
stirred solution of (E)-hex-3-en-1-ol (2.3 mL, 20 mmol) in CH2Cl2
(33 mL) at 0 °C, and the resultant mixture was allowed to warm to rt
over 1 h; 1 M aq HCl (50 mL) was then added and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (2 × 50 mL),
and the combined organic layers were dried and concentrated in
vacuo. The residue was dissolved in EtOH (50 mL) and dibenzyl-
amine (9.6 mL, 50 mmol) was added. The resultant mixture was
stirred and heated at 70 °C for 16 h then was allowed to cool to rt and
was concentrated in vacuo. The residue was partitioned between
CH2Cl2 (100 mL) and satd aq NaHCO3 (100 mL) and the layers were
separated. The organic layer was washed sequentially with 10% aq
citric acid (3 × 100 mL) and satd aq NaHCO3 (100 mL) and then
dried and concentrated in vacuo. Purification via flash column
chromatography (gradient elution, 1→8% Et2O in 30−40 °C
petroleum ether) gave 54 as a colorless oil (3.11 g, 56%, >99:1 dr):
Rf 0.38 (30−40 °C petroleum ether/Et2O, 24:1); νmax 3085, 3063,
3027, 2961, 2932, 2873, 2845, 2795 (C−H), 1494, 1453, 1367, 1127,
1073, 1028, 966, 743, 698; δH (400 MHz, CDCl3) 1.00 (3H, t, J 7.5,
C(6)H3), 1.98−2.07 (2H, m, C(5)H2), 2.21−2.30 (2H, app q, J 7.1,
C(2)H2), 2.52 (2H, t, J 7.6, C(1)H), 3.61 (4H, s, N(CH2Ph)2), 5.32−
5.42 (1H, m, C(3)H), 5.45−5.54 (1H, m, C(4)H), 7.22−7.44 (10H,
m, Ph); δC (100 MHz, CDCl3) 13.8 (C(6)), 25.6 (C(5)), 30.4 (C(2)),
53.5 (C(1)), 58.2 (N(CH2Ph)2), 126.7 (p-Ph), 127.2 (C(3)), 128.1,
128.8 (o,m-Ph), 133.0 (C(4)), 140.0 (i-Ph); m/z (ESI+) 280 ([M +
H]+, 100); HRMS (ESI+) C20H26N+ ([M + H]+) requires 280.2060,
found 280.2059.
(E)-1-(N,N-Dibenzylamino)-2-methylbut-2-ene (56). Dibenzyl-
amine (2.9 mL, 15 mmol) and NaBH(OAc)3 (4.45 g, 21.0 mmol)
were added sequentially to a stirred solution of tiglic aldehyde (1.5
mL, 15 mmol) in THF (100 mL) at 0 °C and the resultant mixture
was allowed to warm to rt over 4 h. Satd aq NaHCO3 (200 mL) was
added and the layers were separated. The aqueous layer was extracted
with Et2O (2 × 100 mL), and the combined organic layers were dried
and concentrated in vacuo. Purification via flash column chromatog-
raphy (gradient elution, 1→8% Et2O in 30−40 °C petroleum ether)
gave 56 as a colorless oil (2.14 g, 54%, >99:1 dr): Rf 0.51 (30−40 °C
petroleum ether/Et2O, 19:1); νmax 3085, 3062, 3027, 2977, 2919,
2878, 2792, 2709, 1495, 1453, 744, 697; δH (400 MHz, CDCl3) 1.63−
1.68 (3H, m, C(4)H3), 1.71−1.75 (3H, m, C(2)Me), 2.94 (2H, s, C(1)
H2), 3.54 (4H, s, N(CH2Ph)2), 5.44−5.46 (1H, m, C(3)H), 7.23−7.48
(10H, m, Ph); δC (100 MHz, CDCl3) 13.4, 14.6 (C(2)Me, C(4)), 57.9
(C(1)), 62.8 (N(CH2Ph)2), 121.9 (C(3)), 126.7 (p-Ph), 128.2, 128.8
(o,m-Ph), 134.2 (C(2)), 140.2 (i-Ph); m/z (ESI+) 266 ([M + H]+,
100); HRMS (ESI+) C19H24N+ ([M + H]+) requires 266.1903, found
266.1904.
(RS)-2,5-Dimethyl-4-(N,N-dibenzylamino)hex-3-ene (57). 2-
Methyl-1-propenylmagnesium bromide (0.5 M in THF, 15 mL, 7.5
mmol) was added to a stirred solution of (RS)-1-[α-(N,N-
dibenzylamino)-β-methylpropyl]benzotriazole48 (1.85 g, 5.00 mmol)
in PhMe (25 mL) at rt. The resultant suspension was stirred at 50 °C
for 2 h then was allowed to cool to rt followed by dropwise addition of
satd aq NH4Cl (10 mL). The resultant mixture was diluted with Et2O
(50 mL) and the aqueous layer was extracted with Et2O (3 × 50 mL).
The combined organic layers were washed sequentially with 1 M aq
NaOH (100 mL) and brine (100 mL), dried, and concentrated in
vacuo. Purification via flash column chromatography (eluent 30−40
°C petroleum ether) gave 57 as a white solid (1.35 g, 88%):48 δH (400
MHz, CDCl3) 0.85 (3H, d, J 6.6, C(5)MeA), 1.27 (3H, d, J 6.6, C(5)
MeB), 1.56 (3H, s, C(2)MeA), 1.88−1.93 (1H, m, C(5)H), 1.96 (3H, s,
C(2)MeB), 2.93 (1H, app t, J 10.4, C(4)H), 3.42 (2H, d, J 14.2,
N(CHAHBPh)2), 3.95 (2H, d, J 14.2, N(CHAHBPh)2), 5.29 (1H, d, J
10.6, C(3)H), 7.30−7.33 (2H, m, Ph), 7.41 (4H, app t, J 7.5, Ph), 7.55
(4H, app d, J 7.5, Ph).
(E)-4-(N,N-Dibenzylamino)but-2-en-1-ol (55). Step 1: Diben-
zylamine (6.4 mL, 33 mmol) was added to a stirred solution of methyl
4-bromocrotonate (85%, 4.2 mL, 30 mmol) and K2CO3 (12.4 g, 90.0
mmol) in MeCN (150 mL) and the resultant mixture was heated at
reflux for 21 h and then concentrated in vacuo. The residue was
partitioned between EtOAc (100 mL) and H2O (100 mL) and the
layers were separated. The aqueous layer was extracted with EtOAc (2
× 100 mL) and the combined organic layers were dried and
concentrated in vacuo. Purification via flash column chromatography
(gradient elution, 2→20% Et2O in 30−40 °C petroleum ether) gave
methyl (E)-4-(N,N-dibenzylamino)but-2-enoate as a pale yellow oil
(7.00 g, 79%, >99:1 dr): Rf 0.24 (30−40 °C petroleum ether/Et2O,
9:1); νmax 3085, 3062, 3028, 2949, 2924, 2796, 2713 (C−H), 1721
(CO), 1269, 1169, 737, 697; δH (400 MHz, CDCl3) 3.23 (2H, app
dd, J 5.8, 1.0, C(4)H2), 3.62 (4H, s, N(CH2Ph)2), 3.76 (3H, s, OMe),
6.10 (1H, d, J 15.8, C(2)H), 7.05 (1H, dt, J 15.8, 5.8, C(3)H), 7.23−
7.45 (10H, m, Ph); δC (100 MHz, CDCl3) 51.5 (OMe), 54.1 (C(4)),
61.8 (N(CH2Ph)2), 122.4 (C(2)), 127.1 (p-Ph), 128.3, 128.7 (o,m-Ph),
139.0 (i-Ph), 146.8 (C(3)), 166.8 (C(1)); m/z (ESI+) 296 ([M + H]+,
(RS)-1-(N,N-Dibenzylamino)-1-phenyl-3-methylbut-2-ene
(58). 2-Methyl-1-propenylmagnesium bromide (0.5 M in THF, 15
mL, 7.5 mmol) was added to a stirred solution of (RS)-1-[α-(N,N-
dibenzylamino)benzyl]benzotriazole48 (2.02 g, 5.00 mmol) in PhMe
(25 mL) at rt. The resultant suspension was stirred at 50 °C for 2 h
then was allowed to cool to rt followed by dropwise addition of satd aq
NH4Cl (10 mL). The resultant mixture was diluted with Et2O (50
mL), and the aqueous layer was extracted with Et2O (3 × 50 mL). The
combined organic layers were washed sequentially with 1 M aq NaOH
(100 mL) and brine (100 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30−40 °C
petroleum ether/Et2O, 99:1) gave 58 as a pale yellow oil (1.59 g,
+
100); HRMS (ESI+) C19H22NO2 ([M + H]+) requires 296.1645,
found 296.1642.
7275
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
93%):48 δH (400 MHz, CDCl3) 1.54 (3H, s, C(3)MeA), 1.94 (3H, s,
C(3)MeB), 3.57 (2H, d, J 13.8, N(CHAHBPh)2), 3.77 (2H, d, J 13.8,
N(CHAHBPh)2), 4.58 (1H, d, J 9.8, C(1)H), 5.60 (1H, d, J 9.8, C(2)
H), 7.25−7.28 (3H, m, Ph), 7.34−7.41 (6H, m, Ph), 7.47 (4H, d, J 7.6,
Ph), 7.61 (2H, app d, J 7.3, Ph).
mL) and CH2Cl2 (10 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL), and the
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 5→
40% Et2O in 30−40 °C petroleum ether) gave 62 as a colorless oil
(134 mg, 53%, >99:1 dr):16 Rf 0.28 (30−40 °C petroleum ether/Et2O,
4:1); δH (400 MHz, CDCl3) 0.93 (3H, app t, J 7.2, C(6)H3), 1.27−
1.69 (4H, m, C(4)H2, C(5)H2), 2.58−2.76 (2H, m, C(1)H2), 3.36
(1H, br s, OH), 3.49 (2H, d, J 13.4, N(CHAHBPh)2), 3.72 (1H, dddd,
J 11.5, 9.6, 5.8, 3.8, C(2)H), 3.83 (2H, d, J 13.4, N(CHAHBPh)2), 4.29
(1H, dddd, J 48.5, 8.1, 5.8, 3.6, C(3)H), 7.23−7.43 (10H, m, Ph).
(RS,SR)-1-(N,N-Dibenzylamino)-4-fluorohexan-3-ol (63). Fol-
lowing general procedure 2, 54 (200 mg, 0.72 mmol, >99:1 dr) in
CH2Cl2 (4.1 mL) was treated with HBF4·OEt2 (195 μL, 1.43 mmol)
and m-CPBA (0.5 M in CH2Cl2, 2.9 mL, 1.5 mmol) for 18 h. K2CO3
(9.7 mg, 0.07 mmol) and MeOH (1.8 mL) were then added to the
residue and the resultant mixture was stirred at rt for 1 h and then
concentrated in vacuo. The residue was partitioned between H2O (10
mL) and CH2Cl2 (10 mL) and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (2 × 10 mL) and the combined
organic layers were dried and concentrated in vacuo. Purification via
flash column chromatography (gradient elution, 5→40% Et2O in 30−
40 °C petroleum ether) gave 63 as a colorless oil (109 mg, 48%, >99:1
dr):16 Rf 0.33 (30−40 °C petroleum ether/Et2O, 4:1); δH (400 MHz,
CDCl3) 0.95 (3H, app t, J 7.5, C(6)H3), 1.49−1.87 (4H, m, C(2)H2,
C(5)H2), 2.68−2.81 (2H, m, C(1)H2), 3.46 (2H, d, J 13.1,
N(CHAHBPh)2), 3.54−3.64 (1H, m, C(3)H), 3.72 (2H, d, J 13.1,
N(CHAHBPh)2), 3.84−4.05 (1H, m, C(4)H), 6.17 (1H, br s, OH),
7.22−7.44 (10H, m, Ph).
t
(RS,E)-1-(N,N-Dibenzylamino)-1-phenylbut-2-ene (59). BuLi
(1.7 M in pentane, 8.8 mL, 15 mmol) was added to a stirred solution
of (E)-1-bromoprop-1-ene (0.64 mL, 7.5 mmol) in Et2O (30 mL) at
−78 °C, and the resultant mixture was stirred for 1 h at −78 °C. Solid
MgBr2·OEt2 (1.55 g, 6.00 mmol) was then added, and the reaction
mixture was allowed to warm to 0 °C over 30 min and was then added
to
a solution of (RS)-1-[α-(N,N-dibenzylamino)benzyl]-
benzotriazole48 (2.02 g, 5.0 mmol) in PhMe (30 mL) at 0 °C via
cannula. The resultant mixture was stirred at 0 °C for 2 h then satd aq
NH4Cl (20 mL) was added. The aqueous layer was extracted with
Et2O (3 × 20 mL), and the combined organic layers were washed with
1 M aq NaOH (30 mL) and brine (30 mL), then dried and
concentrated in vacuo. Purification by flash column chromatography
(eluent 30−40 °C petroleum ether/Et2O, 99:1) gave 59 as a white
solid (621 mg, 38%, >99:1 dr):48 δH (400 MHz, CDCl3) 1.97 (3H, d, J
7.1, C(4)H3), 3.65 (2H, d, J 13.7, N(CHAHBPh)2), 3.81 (2H, d, J 13.7,
N(CHAHBPh)2), 4.37 (1H, d, J 8.6, C(1)H), 5.70−5.79 (1H, m, C(3)
H), 5.84−5.90 (1H, m, C(2)H), 7.34 (3H, app q, J 7.0, Ph), 7.42−7.47
(6H, m, Ph), 7.55 (4H, d, J 7.1, Ph), 7.66 (2H, d, J 7.8, Ph).
(RS,RS)-1-(N,N-Dibenzylamino)-3-fluorohexan-2-ol (60). Fol-
lowing general procedure 2, 51 (224 mg, 0.80 mmol) in CH2Cl2 (4.6
mL) was treated with HBF4·OEt2 (220 μL, 1.62 mmol) and m-CPBA
(0.5 M in CH2Cl2, 3.2 mL, 1.6 mmol) for 18 h. K2CO3 (11.1 mg, 0.08
mmol) and MeOH (2.0 mL) were then added to the residue, and the
resultant mixture was stirred at rt for 1 h and then concentrated in
vacuo. The residue was partitioned between H2O (10 mL) and
CH2Cl2 (10 mL), and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (2 × 10 mL), and the combined organic
layers were dried and concentrated in vacuo. Purification via flash
column chromatography (gradient elution, 5→40% Et2O in 30−40 °C
petroleum ether) gave 60 as a pale yellow oil (145 mg, 57%, >99:1 dr):
Rf 0.28 (30−40 °C petroleum ether/Et2O, 4:1); δH (400 MHz,
CDCl3) 0.93 (3H, app t, J 7.1, C(6)H3), 1.31−1.57 (3H, m, C(4)H2,
C(5)HA), 1.64−1.80 (1H, m, C(5)HB), 2.53 (1H, dd, J 12.6, 3.7, C(1)
HA), 2.75 (1H, dd, J 12.6, 9.8, C(1)HB), 3.18 (1H, br s, OH), 3.50
(2H, d, J 13.5, N(CHAHBPh)2), 3.69 (1H, dddd, J 21.5, 9.8, 3.7, 3.5,
C(2)H), 3.84 (2H, d, J 13.5, N(CHAHBPh)2), 4.33 (1H, dddd, J 48.5,
9.0, 3.5, 3.4, C(3)H), 7.22−7.42 (10H, m, Ph).
(RS,SR)-2-Fluoro-4-(N,N-dibenzylamino)butane-1,3-diol (64).
Following general procedure 2, 55 (160 mg, 0.60 mmol, >99:1 dr) in
CH2Cl2 (2.8 mL) was treated with HBF4·OEt2 (0.82 mL, 6.0 mmol)
and m-CPBA (0.5 M in CH2Cl2, 2.4 mL, 1.2 mmol) for 18 h. K2CO3
(8.3 mg, 0.06 mmol) and MeOH (1.5 mL) were then added to the
residue, and the resultant mixture was stirred at rt for 1 h and then
concentrated in vacuo. The residue was partitioned between H2O (10
mL) and CH2Cl2 (10 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and the
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 10→
80% EtOAc in 30−40 °C petroleum ether) gave 64 as a colorless oil
(58.3 mg, 32%, >99:1 dr): Rf 0.23 (30−40 °C petroleum ether/EtOAc,
3:2); νmax 3394 (O−H), 3086, 3062, 3028, 2933, 2837, 2808, 1494,
1452, 1028, 739, 698; δH (400 MHz, CDCl3) 2.64 (1H, dd, J 12.9, 9.6,
C(4)HA), 2.76 (1H, dd, J 12.9, 3.7, C(4)HB), 2.81 (2H, br s, OH),
3.49 (2H, d, J 13.4, N(CHAHBPh)2), 3.71−3.96 (5H, m, C(1)H2, C(3)
H, N(CHAHBPh)2), 4.18−4.36 (1H, m, C(2)H), 7.23−7.43 (10H, m,
Ph); δC (100 MHz, CDCl3) 55.7 (d, J 4.0, C(4)), 58.6 (N(CH2Ph)2),
62.3 (d, J 21.6, C(1)), 66.3 (d, J 25.6, C(3)), 94.5 (d, J 172, C(2)),
127.5 (p-Ph), 128.6, 129.1 (o,m-Ph), 138.1 (i-Ph); δF (377 MHz,
CDCl3) −200.0 (m); m/z (ESI+) 304 ([M + H]+, 100); HRMS (ESI+)
(RS,RS)-1-(N,N-Dibenzylamino)-4-fluorohexan-3-ol (61). Fol-
lowing general procedure 2, 52 (200 mg, 0.72 mmol, >99:1 dr) in
CH2Cl2 (4.1 mL) was treated with HBF4·OEt2 (195 μL, 1.43 mmol)
and m-CPBA (0.5 M in CH2Cl2, 2.9 mL, 1.5 mmol) for 18 h. K2CO3
(9.7 mg, 0.07 mmol) and MeOH (1.8 mL) were then added to the
residue, and the resultant mixture was stirred at rt for 1 h and then
concentrated in vacuo. The residue was partitioned between H2O (10
mL) and CH2Cl2 (10 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL), and the
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 5→
40% Et2O in 30−40 °C petroleum ether) gave 61 as a colorless oil (55
mg, 24%, >99:1 dr): Rf 0.23 (30−40 °C petroleum ether/Et2O, 4:1);
δH (400 MHz, CDCl3) 0.98 (3H, app t, J 7.4, C(6)H3), 1.47−1.78
(3H, m, C(2)HA, C(5)H2), 1.94 (1H, app dtd, J 14.4, 10.5, 3.9, C(2)
HB), 2.62 (1H, app dt, J 12.9, 4.3, C(1)HA), 2.76−2.85 (1H, m, C(1)
HB), 3.29 (2H, d, J 13.1, N(CHAHBPh)2), 3.64 (1H, dddd, J 20.7, 10.0,
3.8, 2.6, C(3)H), 3.89 (2H, d, J 13.1, N(CHAHBPh)2), 4.16 (1H, app
ddt, J 48.1, 8.4, 4.1, C(4)H), 5.59 (1H, br s, OH), 7.25−7.39 (10H, m,
Ph).
+
C18H23FNO2 ([M + H]+) requires 304.1707, found 304.1700.
(RS,SR)-1-(N,N-Dibenzylamino)-2-methyl-3-fluorobutan-2-ol
(65). Following general procedure 2, 56 (212 mg, 0.80 mmol, >99:1
dr) in CH2Cl2 (4.6 mL) was treated with HBF4·OEt2 (220 μL, 1.62
mmol) and m-CPBA (0.5 M in CH2Cl2, 3.2 mL, 1.6 mmol) for 18 h.
K2CO3 (11.1 mg, 0.08 mmol) and MeOH (2.0 mL) were then added
to the residue, and the resultant mixture was stirred at rt for 1 h and
then concentrated in vacuo. The residue was partitioned between H2O
(10 mL) and CH2Cl2 (10 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL), and the
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 2→
20% EtOAc in 30−40 °C petroleum ether) gave 65 as a colorless oil
(135 mg, 56%, >99:1 dr): Rf 0.33 (30−40 °C petroleum ether/EtOAc,
9:1); νmax 3453 (O−H), 3086, 3063, 3028, 2983, 2937, 2804, 1064,
744; δH (400 MHz, CDCl3) 1.05 (3H, d, J 1.5, C(2)Me), 1.26 (3H, dd,
J 24.8, 6.3, C(4)H3), 2.57 (1H, dd, J 14.1, 1.3, C(1)HA), 2.91 (1H, dd,
J 14.1, 1.8, C(1)HB), 2.99 (1H, br s, OH), 3.62 (2H, d, J 13.6,
N(CHAHBPh)2), 3.85 (2H, d, J 13.6, N(CHAHBPh)2), 4.42 (1H, app
(RS,SR)-1-(N,N-Dibenzylamino)-3-fluorohexan-2-ol (62). Fol-
lowing general procedure 2, 53 (224 mg, 0.80 mmol, >99:1 dr) in
CH2Cl2 (4.6 mL) was treated with HBF4·OEt2 (220 μL, 1.62 mmol)
and m-CPBA (0.5 M in CH2Cl2, 3.2 mL, 1.6 mmol) for 18 h. K2CO3
(11.1 mg, 0.08 mmol) and MeOH (2.0 mL) were then added to the
residue, and the resultant mixture was stirred at rt for 1 h and then
concentrated in vacuo. The residue was partitioned between H2O (10
7276
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
dq, J 47.7, 6.3, C(3)H), 7.26−7.40 (10H, m, Ph); δC (100 MHz,
CDCl3) 14.7 (d, J 22.4, C(4)), 20.1 (C(2)Me), 59.5 (d, J 1.6, C(1)),
60.4 (N(CH2Ph)2), 71.8 (d, J 21.6, C(2)), 92.7 (d, J 172.6, C(3)),
127.4 (p-Ph), 128.5, 129.1 (o-, m-Ph), 138.9 (i-Ph); δF (377 MHz,
CDCl3) −180.6 (dq, J 47.7, 24.1); m/z (ESI+) 324 ([M + Na]+, 62),
302 ([M + H]+, 100); HRMS (ESI+) C19H25FNO+ ([M + H]+)
requires 302.1915, found 302.1903.
([M + H]+, 100); HRMS (ESI+) C24H27FNO+ ([M + H]+) requires
364.2071, found 364.2060. Further elution gave 69 as a colorless oil
which solidified on standing to a white crystalline solid (7.8 mg, 7%,
>99:1 dr): Rf 0.23 (30−40 °C petroleum ether/Et2O, 4:1); mp 108−
110 °C; νmax 3458 (O−H), 3086, 3063, 3029, 3004, 2935, 2838 (C−
H), 748, 698; δH (400 MHz, CDCl3) 1.04 (3H, dd, J 25.3, 6.1, C(4)
H3), 1.66 (1H, br s, OH), 3.10 (2H, d, J 13.5, N(CHAHBPh)2), 3.66
(1H, d, J 9.7, C(1)H), 3.88 (2H, d, J 13.5, N(CHAHBPh)2), 4.66 (1H,
ddd, J 14.0, 9.7, 2.9, C(2)H), 5.25 (1H, app dqd, J 46.7, 6.3, 2.9, C(3)
H), 7.24−7.53 (15H, m, Ph); δC (100 MHz, CDCl3) 13.2 (d, J 22.4,
C(4)), 54.6 (N(CH2Ph)2), 64.2 (d, J 8.0, C(1)), 71.7 (d, J 21.6, C(2)),
91.7 (d, J 164, C(3)), 127.3, 128.0, 128.4, 128.5, 129.1, 130.0, 134.2
(Ph); δF (377 MHz, CDCl3) −180.7 (m); m/z (ESI+) 749 ([2M +
Na]+, 99), 386 ([M + Na]+, 95), 364 ([M + H]+, 100), 344 ([M −
F]+, 47); HRMS (ESI+) C24H27FNO+ ([M + H]+) requires 364.2071,
found 364.2058.
tert-Butyl (S,Z)-2,2-Dimethyl-4-(hexadec-1′-en-1′-yl)-
oxazolidine-3-carboxylate (71) and tert-Butyl (S,E)-2,2-Dimeth-
yl-4-(hexadec-1′-en-1′-yl)oxazolidine-3-carboxylate (72).
NaHMDS (1.0 M in THF, 28 mL, 28 mmol) was added dropwise
to a stirred suspension of (n-pentadecyl)triphenylphosphonium
bromide (16.7 g, 30.2 mmol) in THF (300 mL) at 0 °C, and the
resultant mixture was allowed to warm to rt over 30 min. The mixture
was cooled to −78 °C and n-hexane (450 mL) was added, followed by
the dropwise addition of a solution of 70 (3.01 g, 13.1 mmol) in THF
(150 mL). The resultant mixture was then allowed to warm to rt with
stirring over 42 h. The reaction was quenched by addition of satd aq
NH4Cl (20 mL) and concentrated in vacuo. The residue was
partitioned between Et2O (200 mL) and H2O (100 mL) and the layers
were separated. The aqueous layer was extracted with Et2O (2 × 100
mL), and the combined organic layers were dried and concentrated in
vacuo. Purification via flash column chromatography (gradient elution,
2→20% Et2O in 30−40 °C petroleum ether) gave 71 as a colorless oil
(4.26 g, 77%, >99:1 dr):49 Rf 0.38 (30−40 °C petroleum ether/Et2O,
9:1); [α]2D0 −41.9 (c 1.0 in CHCl3); {lit.49a for enantiomer [α]2D6 +53.5
(c 1.0 in CHCl3)}; lit.49b for enantiomer [α]2D1 +50.7 (c 0.9 in
CHCl3)]; δH (400 MHz, CDCl3) 0.88 (3H, app t, J 6.8, C(16′)H3),
1.20−1.64 (24H, m, C(4′)H2-C(15′)H2), 1.93−2.25 (2H, br m, C(3′)
H2), 3.64 (1H, dd, J 8.7, 3.2, C(5)HA), 4.06 (1H, dd, J 8.7, 6.2, C(5)
HB), 4.49−4.78 (1H, br m, C(4)H), 5.33−5.57 (2H, br m, C(1′)H,
C(2′)H). Further elution gave 72 as a white semisolid (378 mg, 7%,
>99:1 dr):49 Rf 0.28 (30−40 °C petroleum ether/Et2O, 9:1); [α]2D0
+3.5 (c 1.0 in CHCl3); {lit.49b for enantiomer [α]2D1 −5.7 (c 1.0 in
CHCl3)}; δH (400 MHz, CDCl3) 0.88 (3H, app t, J 6.8, C(16′)H3),
1.22−1.66 (24H, m, C(4′)H2-C(15′)H2), 1.98−2.06 (2H, m, C(3′)
H2), 3.71 (1H, dd, J 8.7, 2.0, C(5)HA), 4.01 (1H, dd, J 8.7, 6.0, C(5)
HB), 4.14−4.50 (1H, br m, C(4)H), 5.34−5.72 (2H, m, C(1′)H,
C(2′)H).
(RS,SR)-2-Fluoro-2,5-dimethyl-4-(N,N-dibenzylamino)hexan-
3-ol (66). Following general procedure 2, 57 (123 mg, 0.40 mmol) in
CH2Cl2 (2.3 mL) was treated with HBF4·OEt2 (110 μL, 0.81 mmol)
and m-CPBA (0.5 M in CH2Cl2, 1.6 mL, 0.80 mmol) for 30 min.
K2CO3 (5.5 mg, 0.04 mmol) and MeOH (1.0 mL) were then added to
the residue, and the resultant mixture was stirred at rt for 1 h and then
concentrated in vacuo. The residue was partitioned between H2O (10
mL) and CH2Cl2 (10 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL), and the
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 2→
20% Et2O in 30−40 °C petroleum ether) gave 66 as a colorless oil
(112 mg, 82%, >99:1 dr):16 Rf 0.38 (30−40 °C petroleum ether/Et2O,
9:1); δH (400 MHz, CDCl3) 0.79 (3H, d, J 21.5, C(2)MeA), 1.12 (3H,
dd, J 7.3, 0.5, C(5)MeA), 1.17 (3H, dd, J 7.1, 0.8, C(5)MeB), 1.45 (3H,
d, J 23.0, C(2)MeB), 2.34 (1H, app septet d, J 7.3, 2.3, C(5)H), 2.77
(1H, dd, J 8.3, 2.3, C(4)H), 3.54 (2H, d, J 12.9, N(CHAHBPh)2), 3.74
(1H, dd, J 8.3, 3.0, C(3)H), 3.96 (2H, d, J 12.9, N(CHAHBPh)2), 5.40
(1H, br s, OH), 7.23−7.36 (10H, m, Ph).
(RS,SR)-1-(N,N-Dibenzylamino)-1-phenyl-3-fluoro-3-methyl-
butan-2-ol (67). Following general procedure 2, 58 (273 mg, 0.80
mmol) in CH2Cl2 (4.6 mL) was treated with HBF4·OEt2 (220 μL,
1.62 mmol) and m-CPBA (0.5 M in CH2Cl2, 3.2 mL, 1.6 mmol) for 18
h. K2CO3 (11.1 mg, 0.08 mmol) and MeOH (2.0 mL) were then
added to the residue, and the resultant mixture was stirred at rt for 1 h
and then concentrated in vacuo. The residue was partitioned between
H2O (10 mL) and CH2Cl2 (10 mL), and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (2 × 10 mL), and the
combined organic layers were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 2→
20% Et2O in 30−40 °C petroleum ether) gave 67 as a white solid (229
mg, 76%, >99:1 dr):16 Rf 0.23 (30−40 °C petroleum ether/Et2O, 9:1);
mp 114−120 °C; δH (400 MHz, CDCl3) 0.97 (3H, d, J 22.0, C(3)
MeA), 1.11 (3H, d, J 22.2, C(3)MeB), 3.04 (2H, d, J 13.1,
N(CHAHBPh)2), 3.81 (1H, d, J 10.1, C(1)H), 3.96 (2H, d, J 13.1,
N(CHAHBPh)2), 4.27 (1H, app t, J 10.1, C(2)H), 5.41 (1H, br s, OH),
7.24−7.50 (15H, m, Ph).
(1RS,2SR,3RS)-1-(N,N-Dibenzylamino)-1-phenyl-3-fluorobu-
tan-2-ol (68) and (1RS,2RS,3SR)-1-(N,N-Dibenzylamino)-1-phe-
nyl-3-fluorobutan-2-ol (69). Following general procedure 2, 59
(100 mg, 0.31 mmol, >99:1 dr) in CH2Cl2 (1.8 mL) was treated with
HBF4·OEt2 (83 μL, 0.61 mmol) and m-CPBA (0.5 M in CH2Cl2, 1.2
mL, 0.60 mmol) for 18 h. K2CO3 (4.2 mg, 0.03 mmol) and MeOH
(0.8 mL) were then added to the residue, and the resultant mixture
was stirred at rt for 1 h and then concentrated in vacuo. The residue
was partitioned between H2O (10 mL) and CH2Cl2 (10 mL), and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(2 × 10 mL), and the combined organic layers were dried and
concentrated in vacuo to give a mixture of products containing an
88:12 mixture of 68:69. Purification via flash column chromatography
(gradient elution, 5→40% Et2O in 30−40 °C petroleum ether) gave
68 as a colorless oil which solidified on standing to a white crystalline
solid (30.9 mg, 28%, >99:1 dr): Rf 0.38 (30−40 °C petroleum ether/
Et2O, 4:1); mp 111−113 °C; νmax 3496 (O−H), 3086, 3059, 3028,
2984, 2956, 2919, 2848 (C−H), 749, 699; δH (400 MHz, CDCl3) 1.03
(3H, dd, J 24.8, 6.3, C(4)H3), 3.06 (2H, d, J 13.3, N(CHAHBPh)2),
3.54 (1H, dd, J 10.8, 0.5, C(1)H), 3.98 (2H, d, J 13.3, N(CHAHBPh)2),
4.29 (1H, app dqd, J 46.2, 6.3, 2.9, C(3)H), 4.53 (1H, ddd, J 15.4,
10.8, 2.9, C(2)H), 4.58 (1H, s, OH), 7.22−7.50 (15H, m, Ph); δC (100
MHz, CDCl3) 14.2 (d, J 23.2, C(4)), 53.4 (N(CH2Ph)2), 63.4 (d, J 9.6,
C(1)), 69.6 (d, J 20.8, C(2)), 91.4 (d, J 169, C(3)), 127.5, 128.4, 128.6,
128.7, 129.1, 129.8, 133.1, 138.2 (Ph); δF (377 MHz, CDCl3) −178.2
(m); m/z (ESI+) 749 ([2M + Na]+, 30), 386 ([M + Na]+, 80), 364
(S,Z)-2-(N,N-Dibenzylamino)octadec-3-en-1-ol (74). Concen-
trated aq HCl (1.7 mL) was added to a stirred solution of 71 (4.26 g,
10.1 mmol, >99:1 dr) in MeOH (32 mL), and the resultant mixture
was heated at reflux for 17 h and then concentrated in vacuo. The
residue was partitioned between CH2Cl2 (100 mL) and 1 M aq NaOH
(100 mL), and the layers were separated. The organic layer was
washed with 1 M aq NaOH (2 × 50 mL), and the combined aqueous
layers were extracted with CH2Cl2 (2 × 50 mL). The combined
organic layers were then dried and concentrated in vacuo. BnBr (2.6
mL, 22 mmol), K2CO3 (4.17 g, 30.2 mmol), and EtOH (50 mL) were
added to the residue, and the resultant mixture was heated at reflux for
4 h and then concentrated in vacuo. The residue was partitioned
between Et2O (100 mL) and H2O (100 mL) and the layers were
separated. The aqueous layer was extracted with Et2O (2 × 100 mL),
and the combined organic layers were dried and concentrated in
vacuo. Purification via flash column chromatography (gradient elution,
2→20% Et2O in 30−40 °C petroleum ether) gave 74 as a colorless oil
(4.21 g, 90%, >99:1 dr): Rf 0.28 (30−40 °C petroleum ether/Et2O,
9:1); [α]2D0 +7.9 (c 1.0 in CHCl3); νmax 3461 (O−H), 3086, 3063,
3028, 3005, 2922, 2852 (C−H), 1029, 744, 729; δH (400 MHz,
CDCl3) 0.90 (3H, app t, J 6.8, C(18)H3), 1.19−1.45 (24H, m, C(6)
H2-C(17)H2), 1.87−2.04 (2H, m, C(5)H2), 3.33 (1H, dd, J 10.4, 5.2,
7277
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
C(1)HA), 3.36 (2H, d, J 13.5, N(CHAHBPh)2), 3.60 (1H, app t, J 10.4,
C(1)HB), 3.65−3.73 (1H, app td, J 10.1, 5.2, C(2)H), 3.91 (2H, d, J
13.5, N(CHAHBPh)2), 5.38−5.46 (1H, m, C(3)H), 5.80 (1H, app dt, J
11.0, 7.5, C(4)H), 7.23−7.35 (10H, m, Ph); δC (100 MHz, CDCl3)
14.1 (C(18)), 22.7, 28.1, 29.37, 29.39, 29.5, 29.6, 29.66, 29.70, 30.0,
31.9 (C(5)-C(17)), 53.5 (N(CH2Ph)2), 56.8 (C(2)), 61.2 (C(1)),
122.1 (C(4)), 127.2 (p-Ph), 128.5, 128.8 (o,m-Ph), 137.3 (C(3)),
139.3 (i-Ph); m/z (ESI+) 464 ([M + H]+, 100); HRMS (ESI+)
C32H50NO+ ([M + H]+) requires 464.3887, found 464.3871.
CHCl3); νmax 3376 (O−H), 3085, 3029, 2952, 2919, 2850 (C−H),
1113, 1022, 744, 698; δH (400 MHz, CDCl3) 0.90 (3H, app t, J 6.8,
C(18)H3), 1.19−1.78 (26H, m, C(5)H2-C(17)H2), 2.67 (1H, br s,
OH), 2.89 (1H, app q, J 6.2, C(2)H), 3.73 (2H, d, J 13.9,
N(CHAHBPh)2), 3.80−3.91 (4H, m, C(1)HA, C(3)H, N-
(CHAHBPh)2), 3.95 (1H, dd, J 11.4, 6.6, C(1)HB), 4.64 (1H, app
ddt, J 48.3, 8.6, 4.2, C(4)H), 7.22−7.36 (10H, m, Ph); δC (100 MHz,
CDCl3) 14.1 (C(18)), 22.7, 25.1 (d, J 4.8), 29.4, 29.5, 29.6, 29.66,
29.70, 31.2 (d, J 20.8), 31.9 (C(5)-C(17)), 54.6 (N(CH2Ph)2), 59.0
(C(1)), 59.3 (d, J 3.2, C(2)), 71.8 (d, J 19.2, C(3)), 93.9 (d, J 170,
C(4)), 127.2 (p-Ph), 128.4, 128.9 (o,m-Ph), 139.3 (i-Ph); δF (377
MHz, CDCl3) −196.3 (m); m/z (ESI+) 500 ([M + H]+, 100); HRMS
(ESI+) C32H51FNO2+ ([M + H]+) requires 500.3898, found 500.3883.
(2S,3R,4R)-2-Tetradecyl-4-(N,N-dibenzylamino)-
tetrahydrofuran-3-ol (77). Following general procedure 2, 74 (139
mg, 0.30 mmol, >99:1 dr) in CH2Cl2 (1.0 mL) was treated with
HBF4·OEt2 (0.82 mL, 6.0 mmol) and m-CPBA (0.5 M in CH2Cl2, 1.2
mL, 0.6 mmol) for 18 h to give a 12:88 mixture of 75:77. Purification
via flash column chromatography (gradient elution, 2→20% Et2O in
30−40 °C petroleum ether) gave 77 as a colorless oil (105 mg, 73%,
>99:1 dr): Rf 0.17 (30−40 °C petroleum ether/Et2O, 9:1); [α]D20
−19.1 (c 1.0 in CHCl3); νmax 3423 (O−H), 3086, 3063, 3028, 2923,
2853 (C−H), 749, 698; δH (400 MHz, CDCl3) 0.90 (3H, app t, J 6.8,
C(14′)H3), 1.20−1.54 (26H, m, C(1′)H2-C(13′)H2), 3.25−3.33 (1H,
m, C(4)H), 3.64 (2H, d, J 13.9, N(CHAHBPh)2), 3.68−3.74 (1H, m,
C(5)HA), 3.74 (2H, d, J 13.9, N(CHAHBPh)2), 3.82 (1H, dd, J 5.3, 1.8,
C(3)H), 3.90−3.96 (2H, m, C(2)H, C(5)HB), 3.99 (1H, br s, OH),
7.25−7.38 (10H, m, Ph); δC (100 MHz, CDCl3) 14.1 (C(14′)), 22.7,
25.8, 29.4, 29.6, 29.66, 29.69, 31.9, 34.3 (C(1′)-C(13′)), 56.0
(N(CH2Ph)2), 65.4 (C(4)), 68.2 (C(5)), 73.7 (C(3)), 86.6 (C(2)),
127.5 (p-Ph), 128.5, 129.0 (o,m-Ph), 137.6 (i-Ph); m/z (FI+) 479
(2R,3S,4S)-2-(N,N-Dibenzylamino)-4-fluorooctadecane-1,3-
diol (75) and (2S,3S,4R)-2-Tetradecyl-4-(N,N-dibenzylamino)-
tetrahydrofuran-3-ol (81). Following general procedure 2, 74 (2.78
g, 6.00 mmol, >99:1 dr) in CH2Cl2 (34 mL) was treated with
HBF4·OEt2 (1.6 mL, 12 mmol) and m-CPBA (0.5 M in CH2Cl2, 24
mL, 12 mmol) for 18 h. K2CO3 (82.9 mg, 0.60 mmol) and MeOH (15
mL) were then added to the residue, and the resultant mixture was
stirred at rt for 1 h and then concentrated in vacuo. The residue was
partitioned between H2O (100 mL) and CH2Cl2 (100 mL), and the
layers were separated. The aqueous layer was extracted with CH2Cl2
(2 × 50 mL), and the combined organic layers were dried and
concentrated in vacuo to give a 67:16:18 mixture of 75:76:81.
Purification via flash column chromatography (gradient elution, 5→
40% EtOAc in 30−40 °C petroleum ether) gave 81 as a colorless oil
which solidified on standing to a white solid (397 mg, 14%, >99:1 dr):
Rf 0.54 (30−40 °C petroleum ether/EtOAc, 4:1); mp 44−45 °C; [α]D20
+1.9 (c 1.0 in CHCl3); νmax 3455, 3381 (O−H), 3086, 3062, 3028,
2917, 2850 (C−H), 1067, 1028, 747, 732, 697; δH (400 MHz, CDCl3)
0.90 (3H, app t, J 6.7, C(14′)H3), 1.13−1.65 (26H, m, C(1′)H2-
C(13′)H2), 3.37 (1H, app td, J 7.5, 1.6, C(4)H), 3.57−3.67 (3H, m,
C(5)HA, N(CHAHBPh)2), 3.68−3.74 (1H, m, C(2)H), 3.79 (2H, d, J
14.2, N(CHAHBPh)2), 4.07 (1H, app t, J 8.6, C(5)HB), 4.27−4.33
(1H, br m, C(3)H), 7.21−7.39 (10H, m, Ph); δC (100 MHz, CDCl3)
14.1 (C(14′)), 22.7, 26.3, 28.6, 29.4, 29.56, 29.58, 29.7, 29.8, 31.9
(C(1′)-C(13′)), 55.7 (N(CH2Ph)2), 68.4 (C(5)), 71.1 (C(4)), 74.0
(C(3)), 82.9 (C(2)), 127.1 (p-Ph), 128.3, 128.7 (o,m-Ph), 139.2 (i-
+
([M]+, 100); HRMS (FI+) C32H49NO2 ([M]+) requires 479.3758,
found 479.3771.
(2S,3R,4R)-2-Tetradecyl-4-aminotetrahydrofuran-3-ol [(−)-2-
epi-Jaspine B] (78). Pd(OH)2/C (47.3 mg, 50% w/w with respect to
77) was added to a vigorously stirred solution of 77 (94.6 mg, 0.20
mmol, >99:1 dr) in degassed EtOAc (1.0 mL), and the resultant
suspension was stirred at rt under H2 (5 atm) for 4.5 h. The reaction
mixture was then filtered through a pad of Celite (eluent EtOAc) and
concentrated in vacuo to give 78 as a white solid (31.9 mg, 53%, >99:1
dr):36 mp 94−96 °C; {lit.36b mp 106−108 °C}; [α]2D0 −13.3 (c 1.0 in
MeOH); {lit.36b for enantiomer [α]D25 +16.4 (c 0.85 in MeOH)}; δH
(400 MHz, CDCl3) 0.88 (3H, app t, J 6.8, C(14′)H3), 1.18−1.65
(26H, m, C(1′)H2-C(13′)H2), 2.21 (3H, br s, OH, NH2), 3.40 (1H,
dd, J 8.6, 6.8, C(5)HA), 3.43−3.50 (1H, m, C(2)H), 3.58−3.66 (2H,
m, C(3)H, C(4)H), 4.12 (1H, dd, J 8.6, 6.3, C(5)HB).
(2S,3S,4R)-2-Tetradecyl-4-aminotetrahydrofuran-3-ol [(+)-4-
epi-Jaspine B] (82). Pd(OH)2/C (47.3 mg, 50% w/w with respect to
81) was added to a vigorously stirred solution of 81 (94.6 mg, 0.20
mmol, >99:1 dr) in degassed MeOH (1.0 mL) and the resultant
suspension was stirred at rt under H2 (1 atm) for 24 h. The reaction
mixture was then filtered through a pad of Celite (eluent MeOH) and
concentrated in vacuo to give 82 as a white solid (54.3 mg, 92%, >99:1
dr):39 mp 83−85 °C; [α]D20 +1.4 (c 1.0 in MeOH); δH (400 MHz,
CDCl3) 0.88 (3H, app t, J 6.7, C(14′)H3), 1.17−1.70 (26H, m, C(1′)
H2-C(13′)H2), 1.92 (3H, br s, OH, NH2), 3.41 (1H, dd, J 9.2, 3.4,
C(5)HA), 3.45−3.52 (1H, m, C(2)H), 3.80−3.85 (1H, m, C(3)H),
3.87−3.94 (1H, m, C(4)H), 4.22 (1H, dd, J 9.2, 6.0, C(5)HB).
(2R,3S,4S)-2-Amino-4-fluorooctadecane-1,3-diol [4-Deoxy-
4-fluoro-L-xylo-phytosphingosine] (85). Pd(OH)2/C (624 mg,
50% w/w with respect to 75) was added to a vigorously stirred
solution of 75 (1.25 g, 2.50 mmol, >99:1 dr) in degassed MeOH (25
mL), and the resultant suspension was stirred at rt under H2 (1 atm)
for 24 h. The reaction mixture was then filtered through a pad of
Celite (eluent MeOH) and concentrated in vacuo. The residue was
dissolved in CH2Cl2 (50 mL), and the resultant solution was washed
with satd aq NaHCO3 (50 mL), then dried and concentrated in vacuo
to give 85 as a white solid (799 mg, quant, >99:1 dr): mp 97−98 °C;
[α]2D0 −6.7 (c 1.0 in MeOH); νmax 3376, 3324 (O−H, N−H), 2916,
2850 (C−H), 1470, 1115, 1035, 748; δH (400 MHz, MeOH-d4) 0.91
+
Ph); m/z (ESI+) 480 ([M + H]+, 100); HRMS (ESI+) C32H50NO2
([M + H]+) requires 480.3836, found 480.3814. Further elution gave
75 as a colorless oil which solidified on standing to an oily, white solid
(1.42 g, 47%, >99:1 dr): Rf 0.27 (30−40 °C petroleum ether/EtOAc,
4:1); mp 34−36 °C; [α]D20 −17.2 (c 1.0 in CHCl3); νmax 3383 (O−H),
3085, 3062, 3027, 2953, 2916, 2849 (C−H), 746, 723, 697; δH (400
MHz, CDCl3) 0.90 (3H, app t, J 6.8, C(18)H3), 1.19−1.58 (25H, m,
C(5)HA, C(6)H2-C(17)H2), 1.66−1.81 (1H, m, C(5)HB), 1.89 (1H,
br s, OH), 3.05 (1H, app dt, J 9.0, 5.4, C(2)H), 3.65−3.78 (3H, m,
C(3)H, N(CHAHBPh)2), 3.88−3.97 (2H, m, C(1)H2), 4.01 (2H, d, J
13.4, N(CHAHBPh)2), 4.43−4.61 (1H, m, C(4)H), 7.23−7.36 (10H,
m, Ph); δC (100 MHz, CDCl3) 14.1 (C(18)), 22.7, 25.5 (d, J 4.0),
29.35, 29.43, 29.5, 29.6, 29.65, 29.69, 30.8 (d, J 20.8), 31.9 (C(5)-
C(17)), 54.7 (N(CH2Ph)2), 59.1 (C(1)), 59.4 (d, J 4.0, C(2)), 69.8 (d,
J 20.8, C(3)), 93.4 (d, J 173, C(4)), 127.4 (p-Ph), 128.6, 129.1 (o,m-
Ph), 138.9 (i-Ph); δF (377 MHz, CDCl3) −197.9 (m); m/z (ESI+) 500
+
([M + H]+, 100); HRMS (ESI+) C32H51FNO2 ([M + H]+) requires
500.3898, found 500.3892.
(R,R,R)-2-(N,N-Dibenzylamino)-4-fluorooctadecane-1,3-diol
(76). HBF4·OEt2 (2.6 mL, 19 mmol) and m-CPBA (0.5 M in CH2Cl2,
7.7 mL, 3.9 mmol) were sequentially added to 74 (446 mg, 0.96 mmol,
>99:1 dr), and the resultant mixture was stirred at rt for 30 min. The
reaction mixture was then added dropwise to a stirred mixture of satd
aq Na2SO3 (20 mL) and satd aq NaHCO3 (80 mL). EtOAc (100 mL)
was then added, and the resultant mixture was stirred vigorously for 10
min. The layers were separated, the organic layer was washed with satd
aq NaHCO3 (2 × 50 mL), and the combined aqueous layers were
extracted with EtOAc (2 × 50 mL). The combined organic layers were
then dried and concentrated in vacuo to give a 18:66:16 mixture of
75:76:77. Purification via flash column chromatography (gradient
elution, 7→60% EtOAc in 30−40 °C petroleum ether) gave 75 as a
yellow oil (33.1 mg, 7%, >99:1 dr): Rf 0.49 (30−40 °C petroleum
ether/EtOAc, 7:3). Further elution gave 76 as a yellow oil which
solidified on standing to a pale yellow wax (267 mg, 56%, >99:1 dr): Rf
0.26 (30−40 °C petroleum ether/EtOAc, 7:3); [α]2D0 +13.3 (c 1.0 in
7278
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
(3H, app t, J 6.9, C(18)H3), 1.22−1.86 (26H, m, C(5)H2-C(17)H2),
2.90 (1H, app q, J 5.3, C(2)H), 3.46−3.58 (2H, m, C(1)HA, C(3)H),
3.64 (1H, dd, J 10.9, 5.3, C(1)HB), 4.58 (1H, app ddt, J 48.5, 8.8, 3.7,
C(4)H); δC (100 MHz, MeOH-d4) 13.5 (C(18)), 22.7, 25.2 (d, J 4.8),
29.5, 29.68, 29.70, 29.72, 29.72, 29.78, 29.80, 31.4 (d, J 20.8), 32.1
(C(5)-C(17)), 54.4 (d, J 4.0, C(2)), 63.4 (C(1)), 72.3 (d, J 18.4,
C(3)), 94.9 (d, J 171, C(4)); δF (377 MHz, MeOH-d4) −198.5 (m);
m/z (ESI+) 342 ([M + Na]+, 45), 320 ([M + H]+, 100); HRMS
(ESI+) C18H39FNO2+ ([M + H]+) requires 320.2959, found 320.2949.
(R,R,R)-2-Amino-4-fluorooctadecane-1,3-diol [4-Deoxy-4-flu-
oro-L-lyxo-phytosphingosine] (86). Pd(OH)2/C (65.3 mg, 50%
w/w with respect to 76) was added to a vigorously stirred solution of
76 (131 mg, 0.26 mmol, >99:1 dr) in degassed MeOH (2.6 mL), and
the resultant suspension was stirred at rt under H2 (1 atm) for 24 h.
The reaction mixture was then filtered through a pad of Celite (eluent
MeOH) and concentrated in vacuo. The residue was dissolved in
CH2Cl2 (50 mL), and the resultant solution was washed with satd aq
NaHCO3 (50 mL), then dried and concentrated in vacuo to give 86 as
a white solid (83.1 mg, quant, >99:1 dr): mp 96−98 °C; [α]2D0+5.2 (c
1.0 in MeOH); νmax 3353, 3287 (O−H, N−H), 2914, 2848 (C−H),
1469, 1077, 1055, 1042, 880; δH (400 MHz, MeOH-d4) 0.92 (3H, app
t, J 6.9, C(18)H3), 1.13−1.71 (25H, m, C(5)HA, C(6)H2-C(17)H2),
1.78−1.91 (1H, m, C(5)HB), 2.96 (1H, br s, C(2)H), 3.41 (1H, app
dd, J 28.1, 6.3, C(3)H), 3.53−3.61 (1H, m, C(1)HA), 3.81 (1H, app d,
J 8.2, C(1)HB), 4.64−4.80 (1H, m, C(4)H); δC (100 MHz, MeOH-d4)
14.5 (C(18)), 23.8, 26.4 (d, J 4.8), 30.5, 30.68, 30.73, 30.76, 30.81,
30.82, 30.84, 32.3 (d, J 21.0), 33.1 (C(5)-C(17)), 55.0 (C(2)), 64.6
(C(1)), 74.3 (d, J 18.1, C(3)), 94.4 (d, J 172, C(4)); δF (377 MHz,
MeOH-d4) −200.4 (m); m/z (ESI+) 342 ([M + Na]+, 59), 320 ([M +
(7) For a review of the synthesis, biological activity and
pharmaceutical application of β-fluoroalkyl-β′-hydroxy amines, see:
Bravo, P.; Crucianelli, M.; Ono, T.; Zanda, M. J. Fluorine Chem. 1999,
97, 27.
(8) (a) Dave, R.; Badet, B.; Meffre, P. Amino Acids 2003, 24, 245.
(b) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60, 6711.
(c) Qiu, X.-L.; Qing, F.-L. Eur. J. Org. Chem. 2011, 3261.
(9) For the synthesis and applications of fluorinated N-acetylglucos-
amine (GlcNAc), N-acetylgalactosamine (GalNAc), and N-acetylmur-
amic acid (MurNAc), see: (a) Berkin, A.; Szarek, W. A.; Kisilevsky, R.
Carbohydr. Res. 2000, 326, 250. (b) Sackstein, R.; Dimitroff, C. J.;
Bernacki, R. J.; Sharma, M.; Matta, K. L.; Brajeswar, P. US Patent
148997, 2003. (c) Feng, F.; Okuyama, K.; Niikura, K.; Ohta, T.;
Sadamoto, R.; Monde, K.; Noguchi, T.; Nishimura, S.-I. Org. Biomol.
Chem. 2004, 2, 1617. (d) Ueda, T.; Feng, F.; Sadamoto, R.; Niikura,
K.; Monde, K.; Nishimura, S.-I. Org. Lett. 2004, 6, 1753. (e) Markina,
N. A.; Voznyi, Y. V. Russ. J. Bioorg. Chem. 2008, 34, 475. (f) Xue, J.;
Kumar, V.; Khaja, S. D.; Chandrasekaran, E. V.; Locke, R. D.; Matta, K.
L. Tetrahedron 2009, 65, 8325. For the synthesis and applications of
fluorinated sialic acids, see: (g) Burkart, M. D.; Vincent, S. P.; Wong,
C.-H. Chem. Commun. 1999, 1525. (h) Ikeda, K.; Kitani, S.; Sato, K.;
Suzuki, T.; Hosokawa, C.; Suzuki, Y.; Tanaka, K.; Sato, M. Carbohydr.
Res. 2004, 339, 1367. (i) Chokhawala, H. A.; Cao, H.; Yu, H.; Chen, X.
J. Am. Chem. Soc. 2007, 129, 10630. (j) Hartlieb, S.; Gunzel, A.;
̈
Gerardy-Schahn, R.; Munster-Kuhnel, A. K.; Kirschning, A.; Drager, G.
̈
̈
̈
Carbohydr. Res. 2008, 343, 2075.
(10) (a) Reymond, J.-L.; Vogel, V. J. Chem. Soc., Chem. Commun.
1990, 1070. (b) Dax, K.; Graβberger, V.; Stutz, A. E. J. Carbohydr.
̈
Chem. 1990, 9, 903. (c) Kajimoto, T.; Liu, K. K.-C.; Pederson, R. L.;
Zhong, Z.; Ichikawa, J.; Porco, J. A.; Wong, C.-H. J. Am. Chem. Soc.
1991, 113, 6187. (d) Di, J.; Rajanikanth, B.; Szarek, W. J. Chem. Soc.,
Perkin Trans. 1 1992, 2151. (e) Lee, C. K.; Sim, K. Y.; Zhu, J.
Tetrahedron 1992, 48, 8541. (f) Winchester, B.; Al Daher, S.;
Carpenter, N. C.; Cenci di Bello, I.; Choi, S. S.; Fairbanks, A. J.; Fleet,
G. W. J. Biochem. J. 1993, 290, 743. (g) Lee, C. K.; Jiang, H.; Koh, L.
L.; Xu, Y. Carbohydr. Res. 1993, 239, 309. (h) Furneaux, R. H.; Mason,
J. M.; Tyler, P. C. Tetrahedron Lett. 1994, 35, 3143. (i) Lee, C. K.;
Jiang, H. J. Carbohydr. Chem. 1995, 14, 407. (j) Arnone, A.; Bravo, P.;
Donadelli, A.; Resnati, G. Tetrahedron 1996, 52, 131. (k) Andersen, S.
+
H]+, 100); HRMS (ESI+) C18H39FNO2 ([M + H]+) requires
320.2959, found 320.2951.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra and CIFs (for structures CCDC
879943−879947). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
M.; Ebner, M.; Ekhart, C. W.; Gradnig, G.; Legler, G.; Lundt, I.; Stutz,
■
̈
A. E.; Withers, S. G.; Wrodnigg, T. Carbohydr. Res. 1997, 301, 155.
Corresponding Author
*E-mail: steve.davies@chem.ox.ac.uk.
́
(l) Ayad, T.; Genisson, Y.; Broussy, S.; Baltas, M.; Gorrichon, L. Eur. J.
Org. Chem. 2003, 2903. (m) Csuk, R.; Prell, E.; Reiβmann, S.; Korb, C.
Z. Naturforsch. 2010, 65, 445. (n) Qing, F.-L. J. Fluorine Chem. 2011,
132, 838.
Notes
The authors declare no competing financial interest.
(11) (a) Arnone, A.; Cavicchioli, M.; Donadelli, A.; Resnati, G.
Tetrahedron: Asymmetry 1994, 5, 1019. (b) Shitara, T.; Umemura, E.;
Tsuchiya, T.; Matsuno, T. Carbohydr. Res. 1995, 276, 75. (c) Oppong,
K. A.; Hudlicky, T.; Yan, F.; York, C.; Nguyen, B. V. Tetrahedron 1999,
55, 2875.
(12) (a) Kozikowski, A. P.; Wu, J.-P. Tetrahedron Lett. 1990, 31,
4309. (b) De Jonghe, S.; Overmeire, I. V.; Gunst, J.; De Bruyn, A.;
Hendrix, C.; Van Calenburgh, S.; Busson, R.; De Keukeleire, D.;
ACKNOWLEDGMENTS
■
We thank Syngenta for a CASE studentship (A.J.C.).
REFERENCES
■
(1) (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (b) O’Hagan, D.
Chem. Soc. Rev. 2008, 37, 308.
́
Philippe, J.; Herdewijn, P. Biorg. Med. Chem. Lett. 1999, 9, 3159.
(2) (a) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
̈
(c) De Jonghe, S.; Overmeire, I. V.; Poulton, S.; Hendrix, C.; Busson,
R.; Van Calenburgh, S.; De Keukeleire, D.; Spiegel, S.; Herdewijn, P.
Biorg. Med. Chem. Lett. 1999, 9, 3175. (d) Van Overmeire, I.; Boldin, S.
A.; Venkataraman, K.; Zisling, R.; De Jonghe, S.; Van Calenburgh, S.;
De Keukeleire, D.; Futerman, A. H.; Herdewijn, P. J. Med. Chem. 2000,
43, 4189. (e) De Jonghe, S.; Van Overmeire, I.; Van Calenburgh, S.;
Hendrix, C.; Busson, R.; De Keukeleire, D.; Herdewijn, P. Eur. J. Org.
Chem. 2000, 3177. (f) Oldendorf, J.; Haufe, G. Eur. J. Org. Chem.
2006, 4463. (g) Teare, H.; Huguet, F.; Tredwell, M.; Thibaudeau, S.;
Luthra, S.; Gouverneur, V. ARKIVOC 2007, 232. (h) Dubreuil, D.;
Pipelier, M.; Micouin, L.; Lecourt, T.; Lacone, V.; Bonneville, M.;
Lependu, J.; Turcot-Dubois, A.-L. WO Patent 47249, 2008.
(i) Koroniak, K.; Haufe, G. Synthesis 2010, 498.
Muller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637.
̈
(b) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013. (c) Morgenthaler,
M.; Schweizer, E.; Hoffmann-Roder, A.; Benini, F.; Martin, R. E.;
Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.;
Schneider, J.; Diederich, F.; Kansy, M.; Muller, K. ChemMedChem
̈
̈
2007, 2, 1100. (d) Muller, K.; Faeh, C.; Diederich, F. Science 2007,
̈
317, 1881. (e) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(f) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (g) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320.
(3) Jeschke, P. ChemBioChem 2004, 5, 570.
(4) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, 2004.
(5) Thayer, A. M. Chem. Eng. News 2006, 84, 15.
(6) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071.
(13) (a) Gerstenberger, M. R. C.; Haas, A. Angew. Chem., Int. Ed.
1981, 20, 647. (b) Wilkinson, J. A. Chem. Rev. 1992, 92, 505.
7279
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
Wilkinson, J. A. Science of Synthesis; Percy, J., Eds.; Thieme: Stuttgart,
2006; Vol. 34: Fluorine. (c) Furuya, T.; Kuttruff, C. A.; Ritter, T. Curr.
Opin. Drug Discov. Devel. 2008, 11, 803. (d) Mascaretti, O. A.
Aldrichimica Acta 1993, 26, 47.
(14) (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1.
(b) Bobbio, C.; Gouverneur, V. Org. Biomol. Chem. 2006, 4, 2065.
(c) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010,
352, 2708.
(15) Cresswell, A. J.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,
A. J.; Thomson, J. E.; Tyte, M. J. Org. Lett. 2010, 12, 2936.
(16) Cresswell, A. J.; Davies, S. G.; Lee, J. A.; Morris, M. J.; Roberts,
P. M.; Thomson, J. E. J. Org. Chem. 2011, 76, 4617.
(17) (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) 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. (e) 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. (f) Bagal, S. K.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Scott, P. M.; Thomson, J. E. J. Org. Chem. 2010, 75,
8133. (g) Kurosawa, W.; Roberts, P. M.; Davies, S. G. Yuki Gosei
Kagaku Kyokaishi (J. Synth. Org. Chem. Jpn.) 2010, 68, 1295. (h) 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. (i) Brennan, M.
B.; Claridge, T. D. W.; Compton, R. G.; Davies, S. G.; Fletcher, A. M.;
Henstridge, M. C.; Hewings, D. S.; Kurosawa, W.; Lee, J. A.; Roberts,
P. M.; Russell, A. J.; Schoonen, A. K.; Thomson, J. E. J. Org. Chem.
2012, DOI: 10.1021/jo3010556, (previous manuscript).
Ber. 1981, 114, 1858. (g) Griesbaum, K.; Lie, G. O.; Raupp, E. Chem.
Ber. 1981, 114, 3273. (h) Spraul, M.; Griesbaum, K. Chem. Ber. 1983,
116, 2641. (i) Hittich, R.; Mach, H.; Griesbaum, K. Chem. Ber. 1983,
116, 2738. (j) Keul, H.; Pfeffer, B.; Griesbaum, K. Chem. Ber. 1984,
117, 2193. (k) Kunz, H.; Sager, W. Helv. Chim. Acta 1985, 68, 283.
(l) Evans, R. D.; Schauble, J. H. Synthesis 1987, 551. (m) Bloodworth,
A. J.; Bower, K. J.; Mitchell, J. C. Tetrahedron Lett. 1987, 28, 5347.
(n) Barluenga, J.; Gonzalez, J. M.; Campos, P. J.; Asensio, G. Angew.
́
Chem., Int. Ed. 1988, 27, 1546. (o) Faller, J. W.; Linebarrier, D. L.
Organomet. 1990, 9, 3182. (p) Barluenga, J.; Campos, P. J.; Gonzal
́
ez,
J. M.; Suarez, J. L.; Asensio, G. J. Org. Chem. 1991, 56, 2234.
́
(q) Yoshida, J.-I.; Ishichi, Y.; Isoe, S. J. Am. Chem. Soc. 1992, 114,
7594. (r) Blomberg, L.; Norberg, T. J. Carbohydr. Chem. 1992, 11, 751.
(s) Maeda, H.; Koide, T.; Matsumoto, S.; Ohmori, H. Chem. Pharm.
Bull. 1996, 44, 1480. (t) Huang, K.-T.; Winssinger, N. Eur. J. Org.
Chem. 2007, 1887. (u) Olier, C.; Gastaldi, S.; Christie, S. D. R.;
Bertrand, M. P. Synlett 2007, 423. Olier, C.; Gastaldi, S.; Gil, G.;
Bertrand, M. P. Tetrahedron Lett. 2007, 48, 7801. (v) Lop
́
ez, J. C.;
Uriel, C.; Guillamon-Martín, A.; Valverde, S.; Gomez, A. M. Org. Lett.
́
́
2007, 9, 2759. (w) Fujie, S.; Matsumoto, K.; Suga, S.; Yoshida, J.-I.
Chem. Lett. 2009, 38, 1186. (x) Yadav, J. S.; Subba Reddy, B. V.;
́
Ramesh, K.; Narayana Kumar, G. G. K. S.; Gree, R. Tetrahedron Lett.
2010, 51, 1578. (y) Yadav, J. S.; Subba Reddy, B. V.; Anusha, B.; Subba
Reddy, U. V.; Bhadra Reddy, V. V. Tetrahedron Lett. 2010, 51, 2872.
(22) (a) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737.
(b) Addy, J. K.; Parker, R. E. J. Chem. Soc. 1963, 915.
(23) AgBF4 proved to be completely insoluble in CH2Cl2.
(24) 2,3-Epoxy amines 18−22 were prepared following our
previously reported procedures; see refs 17b (18), 17c (20−22),
and 17i (19).
(25) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 733896 (21) (see ref
17c), 810177 (23) (see ref 16), 810178 (24) (see ref 16), 879943
(25·HBF4), 879944 (27), 879945 (28), 879946 (38), 810180 (p-
nitrobenzoate ester derivative of 60) (see ref 16), 810181 (p-
nitrobenzoate ester derivative of 62) (see ref 16), 810179 (67) (see ref
16), and 879947 (68).
(18) The hydroxyfluorination of olefins using electrophilic fluorine
sources such as XeF2 or Selectfluor in the presence of H2O has been
reported; see: (a) Shellhamer, D. F.; Carter, D. L.; Chiaco Chua, M.;
Harris, T. E.; Henderson, R. D.; Low, W. S. C.; Metcalf, B. T.; Willis,
M. C.; Heasley, V. L.; Chapman, R. D. J. Chem. Soc., Perkin Trans.
1991, 2, 401. (b) Xhou, C.; Li, J.; Lu, B.; Fu, C.; Ma, S. Org. Lett. 2008,
̈
10, 581. (c) Wang, W.; Xu, B.; Hammond, G. B. Synthesis 2011, 2383.
An analogous process employing nucleophilic fluorine sources has so
far been limited to the reaction of polyhalogenated olefins with
oxygen-transfer reagents in anhydrous HF; see: (d) German, L. S.;
Knunyantz, I. L. Angew. Chem., Int. Ed. 1969, 8, 349. Berrier and co-
workers have also reported a serendipitous olefinic hydroxyfluorina-
tion of the Aspidosperma alkaloid tabersonine on treatment with H2O2
in HF−SbF5, albeit with poor regio- and stereoselectivity; see:
(e) Berrier, C.; Jacquesy, J. C.; Jouannetaud, M. P.; Vidal, Y.
Tetrahedron 1990, 46, 815.
(26) The preference for cyclopentene oxide to adopt a boat
conformation to minimise torsional strain is well documented; see:
(a) Grostic, M. F.; Duchamp, D. J.; Chidester, C. G. J. Org. Chem.
1971, 36, 2929. (b) Cook, R. L.; Malloy, T. B., Jr. J. Am. Chem. Soc.
1974, 96, 1703. (c) Mastryukov, V. S.; Osina, E. L.; Vilkov, L. V.;
Hilderbrandt, R. L. J. Am. Chem. Soc. 1977, 99, 6855. (d) Kang, P.;
Choo, J.; Jeong, M.; Kwon, Y. J. Mol. Struct. 2000, 519, 75.
(27) (a) Bach, R. D.; Canepa, C.; Winter, J. E.; Blanchette, P. E. J.
Org. Chem. 1997, 62, 5191. (b) Shi, H.; Zhang, Z.; Wang, Y. J. Mol.
Catal. A 2005, 238, 13.
(19) The pKa of HBF4·OEt2 in MeCN has been estimated as 0.1 (on
the basis that the pKa of protonated Et2O in acetonitrile is 0.1); see:
(a) Hu, X.; Brunschwig, B. S.; Peters, J. C. J. Am. Chem. Soc. 2007, 129,
8988. Although there is no consensus on the pKa of aqueous HBF4,
measurements indicate that 72.9% aqueous HBF4 is slightly more
acidic than 100% H2SO4 and is thus classified as a “superacid”; see:
(28) 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, M.; Rastelli, A. J. 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.
̀
̀
̆ ̂
(b) Farcasi̧ u, D.; Hancu, D. J. Chem. Soc., Faraday Trans. 1997, 93,
2161.
(29) Crossley, N. S.; Darby, A. C.; Henbest, H. B.; McCullough, J. J.;
(20) In principle, formation of an intramolecular hydrogen bond
within 9 may also serve to activate the oxirane to subsequent attack,
although this possibility was discounted on the basis of molecular
modeling studies which suggested this to be a geometrically unfeasible
process.
Nicholls, B.; Stewart, M. F. Tetrahedron Lett. 1961, 2, 398.
(30) Transesterification of 43 gave the corresponding known diol,
which therefore allowed unambiguous assignment of the relative
configuration; see ref 17c.
(31) Several instances 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; see: (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. Poli has proposed a model to account for these observations, in
−
(21) For other selected examples of transfer of fluoride from BF4 ,
see: (a) Balz, G.; Schiemann, G. Ber. Deutsch. Chem. Ges. 1927, 60,
1186. (b) Igarashi, K.; Honma, T.; Irisawa, J. Carbohydr. Res. 1970, 13,
49. (c) Koch, V. R.; Miller, L. L.; Clark, D. B.; Fleischmann, M.; Joslin,
T.; Pletcher, D. Electroanal. Chem. Interfac. Electrochem 1973, 43, 318.
(d) Doyle, M. P.; Whitefleet, J. L.; Bosch, R. J. J. Org. Chem. 1979, 44,
2923. (e) Fry, A. J.; Migron, Y. Tetrahedron Lett. 1979, 36, 3357.
(f) Griesbaum, K.; Keul, H.; Kibar, R.; Pfeffer, B.; Spraul, M. Chem.
7280
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281

The Journal of Organic Chemistry
Article
which attack on the syn-face is favored due to minimization of
developing torsional strain in the transition state; see: (d) Poli, G.
Tetrahedron Lett. 1989, 30, 7385. Houk has coined the term “torsional
steering” for this effect; see: (e) Cheong, P. H.-Y.; Yun, H.;
Danishefsky, S. J.; Houk, K. N. Org. Lett. 2006, 8, 1513.
(32) The mass balance comprised a complex mixture of non-
fluorinated, unidentifiable products.
(33) Unfortunately, attempted 1H−1H and 1H−19F NMR 3J coupling
constant, 1H−1H NOE and 1H−19F NMR HOESY analyses of 4-
fluoropiperidin-3-ol 48 and 4-fluoropyrrolidin-3-ol 49 proved
inconclusive in assigning their relative configurations.
(34) Hoffman, R. Chem. Rev. 1989, 89, 1841.
(35) For a review of recent advances in the synthesis of
phytosphingosines, see: (a) Morales-Serna, J. A.; Llaveria, J.; Díaz,
Y.; Matheu, M. I.; Castillon
(36) (a) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez,
́
, S. Curr. Org. Chem. 2010, 14, 2483.
́
́
E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2007, 18,
2510. (b) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.;
Georgiou, M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell,
́ ́
A. J.; Sanchez-Fernandez, E. M.; Scott, P. M.; Smith, A. D.; Thomson,
J. E. Org. Biomol. Chem. 2008, 6, 1665. (c) Abraham, E.; Davies, S. G.;
Roberts, P. M.; Russell, A. J.; Thomson, J. E. Tetrahedron: Asymmetry
2008, 19, 1027.
(37) Hirano, K.; Fujita, K.; Yorimitsu, H.; Shinokubo, H.; Oshima, K.
Tetrahedron Lett. 2004, 45, 2555.
(38) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
̀
(39) (a) Canals, D.; Mormeneo, D.; Fabrias, G.; Llebaria, A.; Casas,
J.; Delgado, A. Bioorg. Med. Chem. 2009, 17, 235. (b) Yoshimitsu, Y.;
Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2010, 75, 3843.
(c) Passiniemi, M.; Koskinen, A. M. P. Org. Biomol. Chem. 2011, 9,
1774.
(40) For other examples of cyclisations of 3,4-epoxy alcohols to
generate tetrahydrofurans, see: Kang, B.; Mowat, J.; Pinter, T.; Britton,
R. Org. Lett. 2009, 11, 1717 and references cited therein.
(41) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(42) Swern, D. Org. React. 1953, VII, 392.
(43) The solvent volume was chosen to ensure a final concentration
of 0.1 M with respect to the alkenylamine, taking into account the
volume of HBF4·OEt2 and m-CPBA solution added.
(44) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2002, 124, 3669.
(45) Aggarwal, V. K.; Fang, G. Y. J. Chem. Commun. 2005, 3448.
(46) (a) Gijsen, H. J. M.; De Cleyn, M. J. A.; Love, C. J.; Surkyn, M.;
Van Brandt, S. F. A.; Verdonck, M. G. C.; Moens, L.; Cuypers, J.;
Bosmans, J.-P. R. M. A. Tetrahedron 2008, 64, 2456. (b) Schramm, H.;
Pavlova, M.; Hoenke, C.; Christoffers, J. Synthesis 2009, 1659.
(47) Blid, J.; Brandt, P.; Somfai, P. J. Org. Chem. 2004, 69, 3043.
́
(48) Csatayova, K.; Davies, S. G.; Lee, J. A.; Ling, K. B.; Roberts, P.
M.; Russell, A. J.; Thomson, J. E. Tetrahedron 2010, 66, 8420.
(49) (a) Imashiro., R.; Sakurai, O.; Yamashita, T.; Horikawa, H.
Tetrahedron 1998, 54, 10657. (b) Shirota, O.; Nakanishi, K.; Berova,
N. Tetrahedron 1999, 55, 13643.
7281
dx.doi.org/10.1021/jo301056r | J. Org. Chem. 2012, 77, 7262−7281