Ring-opening hydrofluorination of 2,3- and 3,4-epoxy amines by HBF 4·OEt2: Application to the asymmetric synthesis of (S, S)-3-deoxy-3-fluorosafingol

Article abstract of DOI:10.1021/jo200517w

Treatment of a range of 2,3- and 3,4-epoxy amines with HBF ₄·OEt₂ at room temperature results in fast and efficient S_N2-type ring-opening hydrofluorination to give stereodefined amino fluorohydrins. Operational simplicity, scalability, and short reaction time at ambient temperature are notable features of this method. The utility of this methodology is exemplified in a concise asymmetric synthesis of (S,S)-3-deoxy-3-fluorosafingol.

Full text of DOI:10.1021/jo200517w

ARTICLE
pubs.acs.org/joc
Ring-Opening Hydrofluorination of 2,3- and 3,4-Epoxy Amines by
HBF4 OEt2: Application to the Asymmetric Synthesis
3
of (S,S)-3-Deoxy-3-fluorosafingol
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
b
ABSTRACT: Treatment of a range of 2,3- and 3,4-epoxy amines with
HBF4 OEt2 at room temperature results in fast and efficient SN2-type ring-
3
opening hydrofluorination to give stereodefined amino fluorohydrins.
Operational simplicity, scalability, and short reaction time at ambient
temperature are notable features of this method. The utility of this
methodology is exemplified in a concise asymmetric synthesis of (S,S)-3-
deoxy-3-fluorosafingol.
Scheme 1
’ INTRODUCTION
Fluorine, perhaps more so than any other element, has generated
huge interest across practically every discipline in organic chemistry.
The dramatic effect that fluorine can impart on the physical,
chemical, and biological properties of molecules is well-
documented,1 and fluoro-organics are now ubiquitous in medicinal
chemistry,2 agrochemistry,3 and materials science.4 Recent estimates
suggest that 20ꢀ25% of drugs (including 5 of the top 10 drugs sold
in 2005) and 30ꢀ40% of agrochemicals contain at least one fluorine
atom.5 In light of this plethora of applications, practical and safe
methods for the regio- and stereocontrolled installation of fluorine
atoms into organic substrates are in high demand: to meet this need,
several fluorination protocols have been developed,6 including
asymmetric procedures.7 However, many of the existing methodol-
ogies for stereoselective fluorination suffer from economical or
practical setbacks, often relating to the fluorinating agents them-
selves. Considering the significant benefits (i.e., low cost, high
fluorine content, and ease of handling in standard glassware), we
Despite the extremely low nucleophilicity of the BF4ꢀ anion,
the nucleophilic trapping of highly reactive cationic intermedi-
ates by fluorine transfer from BF4ꢀ has featured in a number of
fluorination procedures. Aside from C(sp2)ꢀF bond-forming
protocols such as the classic BalzꢀSchiemann synthesis of aryl
fluorides,10 the coꢀnstruction of C(sp3)ꢀF bonds by fluorine
transfer from BF4 to carbocationic intermediates has been
reported in the nitrosative decomposition of aliphatic azides
with NOBF411 and as the termination step in a variety of cation-π
cyclizations.12 SN1-type fluorinations involving the trapping of
oxocarbenium13 and haloꢀcarbenium14 ion intermediates by
fluorine transfer from BF4 to generate glycosyl fluorides and
recently embarked upon investigations into the utility of BF3 OEt2
3
as a nucleophilic fluorine source8 and reported the stereoselective
ring-opening hydrofluorination of substituted aryl epoxides with
BF3 OEt2 under mild conditions for the synthesis of β-
3
fluoroamphetamines.9 For instance, treatment of β-methylstyrene
oxide (R,R)-1 (∼90% ee) with 0.33 equiv of BF3 OEt2 in CH2Cl2
3
at ꢀ20 °C for 5 min gave syn-fluorohydrin 2 as the major product in
81% isolated yield, >99:1 dr, and 92% ee, consistent with a
stereoselective SN1-type process that results in retention of config-
uration. Mesylation of the free hydroxyl group within 2 followed by
displacement with azide gave 3, with Staudinger reduction giving
β-fluoroamphetamine 4 in 68% yield from 2 and with no erosion of
the stereochemical purity of the starting epoxide 1 (Scheme 1).
Received: March 14, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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ARTICLE
gem-difluorides, respectively, have also been described. In terms
of SN2-type processes, Ohmori and co-workers have developed a
variant of the Mitsunobu reaction involving the electrochemical
generation and subsequent thermal decomposition of alkoxy tri-
phenylphosphonium tetrafluoroborate intermediates, allowing for
the direct conversion of alcohols to the corresponding fluorides with
inversion of configuration, although the isolated yields were low in
most cases.15 An attractive strategy in terms of stereoselective
fluorination has been the stereospecific ring opening of iranium
ion intermediates with nucleophilic fluorine sources, and SN2-
type fluorine transfer from BF4ꢀ to chloriranium,16 iodiranium,17
and thiiranium18 ions has previously been observed. As part of
our research program aimed at the development of novel
methods for nucleophilic fluorination,9 we became interested
in the possibility of effecting the ring opening of 2,3-epoxy
amines (previously prepared in our laboratories during investiga-
tions into our ammonium-directed oxidation protocol)19 using
Scheme 2
HBF4 OEt2 as a nucleophilic source of fluorine for the prepara-
3
tion of amino fluorohydrins.20 We describe herein our endeavors
within this area, which culminate in a short asymmetric synthesis of
(S,S)-3-deoxy-3-fluorosafingol.21
Scheme 3
’ RESULTS AND DISCUSSION
The ring-opening hydrofluorination of 2,3-epoxy amine 522 as
a model system was investigated. Treatment of 5 with 2 equiv of
HBF4 OEt2 in CH2Cl2 at rt for 5 min gave amino fluorohydrin 9
3
as a single diastereoisomer (>99:1 dr) in quantitative yield
(Scheme 2). The relative configuration within 9 was unambigu-
ouslyestablishedvia singlecrystal X-raydiffractionanalysis23 and is
consistent with the ring opening proceeding via an SN2-type
ꢀ
mechanism with intermolecular transfer of fluorine from BF4
and inversion of configuration. This is in contrast to our previously
reported ring-opening hydrofluorination of aryl epoxides using
BF3 OEt2, which proceeds via a stereoselective SN1-type process
3
(intramolecular transfer of fluorine from the in situ formed
alkoxyfluoroborate complex and retention of configuration),9
although the speed and mild reaction conditions of both of
these transformations are notable. The importance of the
amino moiety within 5 in promoting this transformation was
underscored by attempted ring-opening hydrofluorination of
cyclohexene oxide and syn-1,2-epoxy-3-benzyloxycyclohexane,
which gave only nonfluorinated polymeric products upon
treatment with HBF4 OEt2.24 The role of the amino group in
3
promoting the transformation of 2,3-epoxy amine 5 to amino
fluorohydrin 9 may therefore lie in its capacity to form an
ammonium moiety in situ, which would discourage ionization
of the oxirane and suppress polymerization or rearrangement
pathways from competing with transfer of fluorine from the
BF4ꢀ ion.25
proceeding via an SN2-type mechanism. The regioselectivities of the
ring-opening processes are consistent with our previous observations
concerning ring opening of a range of 2,3-epoxy amines (including 5
and 7) with a variety of Brønsted acids:19,27 the destabilizing electron-
withdrawing influence of the ammonium moiety on the late transition
state28 is less pronounced if ring opening occurs at the carbon atom
distal to it.
The suitability of the conformationally more labile 2,3- and
3,4-epoxy amines 13ꢀ19 as substrates for this transformation
was also examined.29 Reaction of the diastereoisomeric 2,3-epoxy
amines 13 and 15 gave the diastereoisomeric amino fluorohy-
drins 20 and 22, respectively (Scheme 3). The relative config-
urations within 20 and 22 were unambiguously established by
single crystal X-ray diffraction analyses of the corresponding
p-nitrobenzoate esters 28 and 2930 and are consistent with both
The generality of this process was explored by application to a
range of 2,3-epoxy amines 6ꢀ8.22 In each case, the ring-opening
reaction proceeded via attack of fluorine at the oxirane carbon
atom distal to the ammonium moiety (formed in situ) to give
amino fluorohydrins 10-12 in 71ꢀ89% isolated yield after
chromatography.26 The relative configurations within 11 and
12 were unambiguously established by single crystal X-ray
diffraction analyses.23 On this basis, the relative configuration
3
within 10 could be confidently assigned. NMR J coupling
1
1
19
constant analyses (1Hꢀ H and Hꢀ F) were also supportive
of this assignment. The stereochemical outcomes of these
reactions are therefore consistent, in each case, with the reaction
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ARTICLE
of these ring-opening reactions traversing an SN2-type pathway.
The diastereoisomeric 3,4-epoxy amines 14 and 16 also proved
amenable to this transformation, proceeding to give the corre-
sponding amino fluorohydrins 21 and 23 as the major
products.31 The relative configurations within 21 and 23 were
assigned by analogy to those unambiguously established for 20
and 22 (i.e., on the assumption that both reactions proceed via
SN2-type ring openings). Meanwhile, ring opening of 2,3-epoxy
been investigated for its role in cell regulation, signal transduction,
and protein kinase C inhibition34 (Scheme 4).
Our synthesis of (S,S)-3-deoxy-3-fluorosafingol 43 (Scheme 5)
began with alkylation of O-THP protected propargylic alcohol
32 (commercially available) by treatment with BuLi in the pre-
sence of DMPU and 1-bromopentadecane, which was followed
by O-THP deprotection to give propargylic alcohol 33 in 95%
yield. Reduction of 33 with LiAlH4 gave allylic alcohol (E)-34 in
97% yield and >99:1 dr. Sharpless asymmetric epoxidation35 of
34 gave, after recrystallization, 2,3-epoxy alcohol 35 in 80% isolated
yield and >98% ee.36 Oxidation of the hydroxyl functionality
within 35 with IBX37 followed by reductive amination of the
resultant aldehyde 36 with dibenzylamine and NaB(OAc)3H38
gave 2,3-epoxy amine 37 in 86% yield (2 steps). Ring-opening
amine 17 with HBF4 OEt2 gave amino fluorohydrin 24 (having
3
fluorine at a quaternary center) in 88% yield, and similar treatment
of the diastereoisomerically pure 2,3-epoxy amine 18 gave the
corresponding diastereoisomerically pure amino fluoro-
hydrin 25, which was isolated in quantitative yield. The relative
configuration within 25 was confirmed unambiguously by single
crystal X-ray diffraction analysis.30 Treatment of 2,3-epoxy amine
hydrofluorination of 37 using HBF4 OEt2 gave amino fluorohy-
3
drin 38 in 79% yield and as a single diastereoisomer (>99:1 dr) in
>98% ee.36 The relative configuration within 38 was assigned on
the assumption that the ring opening proceeds via an SN2-type
process, and this assignment was supported by inspection of the
19 with HBF4 OEt2 resulted in formation of an 83:17 mixture of
3
the desired fluorohydrin 26 and ketone 27, presumably a result of a
rearrangement reaction. Chromatographic purification facilitated
isolation of 26 in 62% yield, and ketone 27 in 6%yield (Scheme3).
The utility of this methodology was next demonstrated by
application to an asymmetric synthesis of (S,S)-3-deoxy-3-
fluorosafingol.21 (S,S)-Safingol 30 is an antineoplastic and anti-
psoriatic agent and is a non-naturally occurring diastereoisomer of
the sphingoid base (2R,3S)-sphinganine 31. Given the ubiquity of
sphingoid bases in all eukaryotic cells,32 there is extensive interest
in the synthesis and evaluation of the biological properties of
sphingoidbasesand theiranalogues:33 safingol30, forinstance, has
19
1Hꢀ F 3J coupling constant between C(2)H and C(3)F within
20 (3J = 20.7 Hz), 22 (3J = 11.5 Hz), and 38 (3J = 11.4 Hz).
Chlorination of 38 under Appel conditions39 for 40 min resulted
in complete conversion to an 83:17 mixture of chlorides 40 and
41, presumably via the intermediacy of aziridinium 39. When the
reaction time was extended to 18 h, clean conversion to chloride
41 was observed, consistent with reversible ring opening of
aziridinium 39 resulting initially in primary chloride 40 as the
kinetic product and secondary chloride 41 as the thermodynamic
product.40 Treatment of 41 with KOAc in DMF at 100 °C
followed by transesterification with K2CO3 in MeOH gave 42 as
a single regio- and diastereoisomer (>99:1 dr), which was
isolated in 82% yield and >98% ee36 after chromatographic
purification. Presumably, this reaction also proceeds via the
intermediacy of aziridinium 39, which undergoes irreversible
ring opening by acetate, with attack occurring at the least
substituted carbon atom. Finally, hydrogenolytic removal of the
N-benzyl protecting groups within 42 completed the synthesis of
(S,S)-3-deoxy-3-fluorosafingol 43, which was isolated in 97% yield
(36% overall yield in 11 steps from O-THP protected propargylic
Scheme 4
Scheme 5
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ARTICLE
alcohol 32) as a single diastereoisomer. The relative configuration
within 43 was unambiguously established by single crystal X-ray
diffraction analysis.41 Given the known enantiomeric purities of 35,
38 and 42 (i.e., >98% ee)36 the enantiomeric purities of 36, 37,
39ꢀ41, and 43 can confidently be inferred as >98% ee.
General Procedure 4 for Amination of Mesylates. Dibenzy-
lamine (2.5 equiv) was added to a stirred solution of the requisite
mesylate (1 equiv, 0.4 M in EtOH), and the reaction mixture was heated
at reflux for 48 h. After this time the mixture was allowed to cool to rt and
was concentrated in vacuo. The residue was partitioned between
saturated aqueous NaHCO3 and CH2Cl2. The layers were separated,
and the aqueous layer was extracted twice with CH2Cl2. The combined
organic layers were then dried and concentrated in vacuo.
’ CONCLUSION
In conclusion, treatment of a range of 2,3- and 3,4-epoxy amines
(RS,RS,RS)-2-(N,N-Dibenzylamino)-6-fluorocyclohexan-1-
ol 9. Following General Procedure 1, 5 (108 mg, 0.37 mmol) in CH2Cl2
with HBF4 OEt2 at room temperature results in fast and efficient
3
SN2-type ring-opening hydrofluorination to give stereodefined
amino fluorohydrins. Operational simplicity, scalability, and short
reaction time at ambient temperature are notable features of this
method. The utility of this methodology is exemplified in a concise
asymmetric synthesis of (S,S)-3-deoxy-3-fluorosafingol.
(1.47 mL) was treated with HBF4 OEt2 (100 μL, 0.74 mmol).
3
Purification via flash column chromatography (gradient elution,
5f40% EtOAc in 30ꢀ40 °C petrol) gave 9 as a colorless syrup which
solidified on standing to a white crystalline solid (117 mg, quant,
>99:1 dr); Rf 0.46 (30ꢀ40 °C petrol/EtOAc, 4:1); C20H24FNO
requires C, 76.65; H, 7.7; N, 4.5%; found C, 76.7; H, 7.8; N, 4.4%;
mp 74ꢀ77 °C; νmax (KBr) 3443 (OꢀH), 3085, 3062, 3028, 3004,
2941, 2869, 2805, 2730 (CꢀH), 1494, 1453; δH (400 MHz, CDCl3)
1.43ꢀ1.87 (6H, m, C(3)H2, C(4)H2, C(5)H2), 2.95 (1H, br s, OH),
3.01ꢀ3.09 (1H, m, C(2)H), 3.82 (4H, A2, N(CH2Ph)2), 4.17ꢀ4.24
(1H, app dt, J 6.3, 3.3, C(1)H), 4.84 (1H, app dq, J 45.5, 3.0, C(6)H),
7.22ꢀ7.37 (10H, m, Ph); δC (100 MHz, CDCl3) 19.3 (C(4)), 23.8
(C(3)), 25.6 (d, J 20.8, C(5)), 54.7 (N(CH2Ph)2), 59.3 (C(2)), 67.2 (d,
J 28.8, C(1)), 90.8 (d, J 166, C(6)), 127.0 (p-Ph), 128.4, 128.6 (o,m-
Ph), 139.8 (i-Ph); δF (377 MHz, CDCl3) ꢀ191.8 (app t, J 45.9); m/z
(ESIþ) 649 ([2M þ Na]þ, 100%), 314 ([M þ H]þ, 82%); HRMS
(ESIþ) C20H25FNOþ ([M þ H]þ) requires 314.1915; found
314.1912.
’ 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.42 m-CPBA was supplied
as a 70ꢀ77% slurry in water and titrated according to the procedure of
Swern43 before use. 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 chroma-
tography platform.
(RS,RS,RS)-2-(N-Benzyl-N-methylamino)-6-fluorocyclohe-
xan-1-ol 10. Following General Procedure 1, 6 (217 mg, 1.00 mmol) in
Melting points are uncorrected. Specific rotations are reported in
10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL. IR spectra were
recorded as either a thin film on NaCl plates (film) or a KBr disk (KBr),
as stated. Selected characteristic peaks are reported in cmꢀ1. NMR
spectra were recorded in the deuterated solvent stated. The field was
locked by external referencing to the relevant deuteron resonance.
CH2Cl2 (4.00 mL) was treated with HBF4 OEt2 (272 μL, 2.00 mmol).
3
Purification via flash column chromatography on neutralized silica
gel (gradient elution, 7f60% EtOAc in 30ꢀ40 °C petrol) gave
10 as a yellow oil (211 mg, 89%, >99:1 dr); Rf 0.28 (30ꢀ40 °C
petrol/EtOAc, 7:3); C14H20FNO requires C, 70.9; H, 8.5; N, 5.9%;
found C, 71.0; H, 8.6; N, 5.85%; νmax (film) 3424 (OꢀH), 3086, 3063,
3028, 2943, 2869, 2797 (CꢀH), 1454, 1070, 1002; δH (400 MHz,
CDCl3) 1.44ꢀ1.93 (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), 7.24ꢀ7.38
(5H, m, Ph); δC (100 MHz, CDCl3) 18.7 (C(4)), 23.9 (C(3)), 25.3 (d,
J 20.8, C(5)), 38.3 (NMe), 58.2 (NCH2), 60.8 (C(2)), 65.7 (d, J 30.4,
C(1)), 90.5 (d, J 165, C(6)), 127.2 (p-Ph), 128.4, 128.9 (o,m-Ph), 138.9
(i-Ph); δF (377 MHz, CDCl3) ꢀ193.8 (app td, J 44.7, 9.2); m/z (ESIþ)
507 (100%), 238 ([M þ H]þ, 69%); HRMS (ESIþ) C14H21FNOþ ([M
þ H]þ) requires 238.1602, found 238.1599.
1
1
13
1Hꢀ H COSY and Hꢀ C HMQC analyses were used to establish
atom connectivity.
General Procedure 1 for Ring-Opening Hydrofluorination
of Epoxy Amines with HBF4 OEt2. HBF4 OEt2 (2 equiv) was
3
3
added in one portion to a stirred solution of the requisite epoxy amine
(1 equiv, 0.25 M in CH2Cl2) at rt (unless specified otherwise), and the
reaction mixture was stirred at this temperature for 5 min. Saturated
aqueous NaHCO3 was then added, and the layers were separated. The
organic layer was washed twice with saturated aqueous NaHCO3,
and the combined aqueous layers were extracted twice with CH2Cl2.
The combined organic layers were then dried and concentrated
in vacuo.
(1RS,2SR,6RS)-2-(N,N-Dibenzylamino)-6-fluorocyclohex-
an-1-ol 11. Following General Procedure 1, 7 (402 mg, 1.37 mmol) in
General Procedure 2 for Epoxidation of Alkenyl Alcohols
with m-CPBA. m-CPBA (1.5 equiv) was added to a stirred solution of
the requisite alkenyl alcohol (1 equiv, 0.25 M in CH2Cl2) at 0 °C, and
the reaction mixture was allowed to warm to rt over 24 h. Saturated
aqueous Na2SO3 was then added until starch-iodide paper indicated no
remaining oxidant, and then 5% aqueous NaOH was added and the
layers were separated. The organic layer was washed twice with 5%
aqueous NaOH, and the combined aqueous layers were saturated with
NaCl and extracted twice with CH2Cl2. The combined organic layers
were then dried and concentrated in vacuo.
General Procedure 3 for Mesylation of Alcohols. Et3N
(2 equiv) and MsCl (1.5 equiv) were added sequentially to a stirred
solution of the requisite alcohol (1 equiv, 0.6 M in CH2Cl2) at 0 °C,
and the reaction mixture was allowed to warm to rt over 1 h. Aqueous
HCl (1 M) was then added, and the layers were separated. The
aqueous layer was extracted twice with CH2Cl2, and the combined
organic layers were then dried and concentrated in vacuo.
CH2Cl2 (5.48 mL) was treated with HBF4 OEt2 (373 μL, 2.74 mmol).
3
Purification via flash column chromatography (gradient elution, 5f40%
Et2O in 30ꢀ40 °C petrol) gave 11 as a colorless oil that solidified on
standing to a white crystalline solid (314 mg, 73%, >99:1 dr); Rf 0.26
(30ꢀ40 °C petrol/Et2O, 4:1); C20H24FNO requires C, 76.65; H, 7.7;
N, 4.5%; found C, 76.5; H, 7.6; N, 4.3%; mp 77ꢀ79 °C; νmax (KBr) 3453
(OꢀH), 3085, 3062, 3028, 2941, 2866 (CꢀH), 1454, 1068, 1027, 750,
700; δH (400 MHz, CDCl3) 1.08ꢀ1.22 (1H, m, C(4)HA), 1.29 (1H,
app qd, J 12.6, 3.3, C(3)HA), 1.40ꢀ1.54 (1H, m, C(5)HA), 1.80ꢀ1.90
(1H, m, C(4)HB), 1.90ꢀ1.98 (1H, m, C(3)HB), 2.03ꢀ2.13 (1H, m,
C(5)HB), 2.37ꢀ2.47 (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), 7.24ꢀ7.38 (10H, m, Ph); δC (100 MHz,
CDCl3) 20.7 (d, J 12.8, C(4)), 21.3 (C(3)), 30.2 (d, J 17.6, C(5)), 53.7
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(N(CH2Ph)2), 61.2 (d, J 9.6, C(2)), 72.4 (d, J 17.6, C(1)), 95.1 (d, J 176,
C(6)), 127.4 (p-Ph), 128.6, 129.0 (o,m-Ph), 138.9 (i-Ph); δF (377 MHz,
CDCl3) ꢀ179.0 (app d, J 51.5); m/z (FIþ) 313 ([M]þ, 100%); HRMS
(FIþ) C20H24FNOþ ([M]þ) requires 313.1836, found 313.1843.
(1RS,2SR,6RS)-2-(N-Benzyl-N-methylamino)-6-fluorocy-
clohexan-1-ol 12. Following General Procedure 1, 8 (217 mg, 1.00
(1H, m, C(2)HB), 2.34 (1H, br s, OH), 2.87ꢀ2.94 (1H, m, C(4)H),
3.05ꢀ3.13 (1H, m, C(3)H), 3.75ꢀ3.90 (2H, m, C(1)H2). Following
General Procedure 3, (RS,SR)-3,4-epoxyhexan-1-ol (2.00 g, 17.2 mmol)
in CH2Cl2 (29 mL) was treated with Et3N (4.80 mL, 34.4 mmol) and
MsCl (2.00 mL, 25.8 mmol). Purification via filtration through a pad of
silica gel (eluent CH2Cl2) gave (RS,SR)-3,4-epoxyhexyl methanesulfo-
nate as an orange oil (2.96 g, 89%, >99:1 dr);46 δH (400 MHz, CDCl3)
1.05 (3H, app td, J 7.5, 1.4, C(6)H3), 1.46ꢀ1.63 (2H, m, C(5)H2),
1.79ꢀ1.90 (1H, m, C(2)HA), 2.09 (1H, ddddd, J 14.7, 8.2, 6.3, 4.7, 1.6,
C(2)HB), 2.92ꢀ2.98 (1H, m, C(4)H), 3.04 (3H, s, SO2Me) overlapping
3.03ꢀ3.10 (1H, m, C(3)H), 4.33ꢀ4.46 (2H, m, C(1)H2). Following
General Procedure 4, (RS,SR)-3,4-epoxyhexyl methanesulfonate (500
mg, 2.57 mmol) in EtOH (6.44 mL) was treated with dibenzylamine
(1.24 mL, 6.44 mmol). Purification via flash column chromatography
(gradient elution, 2f20% Et2O in 30ꢀ40 °C petrol) gave 14 as a
colorless oil (558 mg, 74%, >99:1 dr); Rf 0.38 (30ꢀ40 °C petrol/Et2O,
9:1); νmax (film) 3085, 3062, 3027, 2970, 2935, 2876, 2798 (CꢀH),
1494, 1453, 1368, 745, 699; δH (400 MHz, CDCl3) 0.97 (3H, app t,
J 7.5, C(6)H3), 1.34ꢀ1.59 (2H, m, C(5)H2), 1.63ꢀ1.86 (2H, m,
C(2)H2), 2.56ꢀ2.70 (2H, m, C(1)H2), 2.79ꢀ2.87 (1H, m, C(4)H),
2.95ꢀ3.03 (1H, m, C(3)H), 3.62 (4H, AB system, JAB 13.6,
N(CH2Ph)2), 7.19ꢀ7.48 (10H, m, Ph); δC (100 MHz, CDCl3) 10.6
(C(6)), 21.1 (C(5)), 25.7 (C(2)), 50.6 (C(1)), 55.8 (C(3)), 58.2
(C(4)), 58.4 (N(CH2Ph)2), 126.9 (p-Ph), 128.2, 128.8 (o,m-Ph),
139.6 (i-Ph); m/z (ESIþ) 318 ([M þ Na]þ, 61%), 312 (100%), 296
([M þ H]þ, 64%); HRMS (ESIþ) C20H26NOþ ([M þ H]þ) requires
296.2009, found 296.2010.
mmol) in CH2Cl2 (4.00 mL) was treated with HBF4 OEt2 (272 μL,
3
2.00 mmol). Purification via flash column chromatography on neutra-
lized silica gel (gradient elution, 2f20% EtOAc in 30ꢀ40 °C petrol)
gave 12 as a colorless oil which solidified on standing to a white
crystalline solid (169 mg, 71%, >99:1 dr); Rf 0.13 (30ꢀ40 °C petrol/
EtOAc, 9:1); C14H20FNO requires C, 70.9; H, 8.5; N, 5.9%; found C,
71.0; H, 8.35; N, 5.95%; mp 77ꢀ79 °C; νmax (KBr) 3441 (OꢀH), 3086,
3062, 3028, 2943, 2867, 2801 (CꢀH), 1453, 1079, 1010; δH (400 MHz,
CDCl3) 1.15ꢀ1.32 (2H, m, C(3)HA, C(4)HA), 1.40ꢀ1.56 (1H, m,
C(5)HA), 1.76ꢀ1.94 (2H, m, C(3)HB, C(4)HB), 2.07ꢀ2.17 (1H, m,
C(5)HB), 2.22 (3H, s, NMe), 2.35ꢀ2.45 (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), 7.24ꢀ7.37
(5H, m, Ph); δC (100 MHz, CDCl3) 20.6 (d, J 12.0, C(4)), 20.6 (d, J 2.4,
C(3)), 30.3 (d, J 18.4, C(5)), 36.5 (NMe), 58.2 (NCH2), 65.8 (d, J 9.6,
C(2)), 72.6 (d, J 16.0, C(1)), 95.2 (d, J 177, C(6)), 127.3 (p-Ph), 128.5,
128.8 (o,m-Ph), 138.7 (i-Ph); δF (377 MHz, CDCl3) ꢀ178.7 (app d,
J 51.5); m/z (ESIþ) 497 ([2M þ Na]þ, 100%), 238 ([M þ H]þ, 74%);
HRMS (ESIþ) C14H21FNOþ ([M þ H]þ) requires 238.1602, found
238.1599.
(RS,SR)-1-(N,N-Dibenzylamino)-2,3-epoxyhexane 13. Fol-
lowing General Procedure 2, (Z)-hex-2-en-1-ol (5.90 mL, 49.9 mmol) in
CH2Cl2 (200 mL) was treated with m-CPBA (75% w/w in H2O, 17.2 g,
74.9 mmol). Purification via distillation at reduced pressure (1.2 mmHg)
gave (RS,SR)-2,3-epoxyhexan-1-ol as a colorless oil (4.39 g, 76%,
>99:1 dr);44 bp 63ꢀ65 °C (1.2 mmHg); {lit.45 bp 103ꢀ104 °C
(20 mmHg)}; δH (400 MHz, CDCl3) 0.91ꢀ1.03 (3H, m, C(6)H3),
1.39ꢀ1.64 (4H, m, C(4)H2, C(5)H2), 1.92 (1H, br s, OH), 3.01ꢀ3.08
(1H, m, C(3)H), 3.16 (1H, app dt, J 7.1, 4.1, C(2)H), 3.68 (1H, ddd,
J 10.6, 7.2, 3.4, C(1)HA), 3.86 (1H, ddd, J 11.9, 7.2, 4.1, C(1)HB).
Following General Procedure 3, (RS,SR)-2,3-epoxyhexan-1-ol (2.00 g,
17.2 mmol) in CH2Cl2 (29 mL) was treated with Et3N (4.80 mL, 34.4
mmol) and MsCl (2.00 mL, 25.8 mmol). Purification via filtration
through a pad of silica gel (eluent CH2Cl2) gave (RS,SR)-2,3-epoxyhexyl
methanesulfonate as a yellow oil (3.20 g, 96%, >99:1 dr);46 δH (400
MHz, CDCl3) 0.96ꢀ1.02 (3H, m, C(6)H3), 1.41ꢀ1.62 (4H, m,
C(4)H2, C(5)H2), 3.06ꢀ3.12 (1H, m, C(3)H) overlapping 3.11 (3H, s,
SO2Me), 3.28 (1H, app dt, J 7.6, 4.0, C(2)H), 4.24 (1H, dd,
J 11.7, 7.6, C(1)HA), 4.47 (1H, dd, J 11.7, 3.9, C(1)HB). Follow-
ing General Procedure 4, (RS,SR)-2,3-epoxyhexyl methanesulfonate
(500 mg, 2.57 mmol) in EtOH (6.44 mL) was treated with dibenzyl-
amine (1.24 mL, 6.44 mmol). Purification via flash column chromato-
graphy (gradient elution, 2f20% Et2O in 30ꢀ40 °C petrol) gave 13 as a
colorless oil (429 mg, 56%, >99:1 dr);47 Rf 0.33 (30ꢀ40 °C petrol/Et2O,
9:1); δH (400 MHz, CDCl3) 0.96 (3H, app t, J 6.7, C(6)H3), 1.30ꢀ1.60
(4H, m, C(4)H2, C(5)H2), 2.51 (1H, dd, J 13.6, 6.5, C(1)HA), 2.82 (1H,
dd, J 13.6, 3.8, C(1)HB), 2.87ꢀ2.94 (1H, m, C(3)H), 3.17 (1H, app dt,
J 6.5, 4.1, C(2)H), 3.56 (2H, d, J 13.6, N(CHAHBPh)2), 3.87 (2H, d,
J 13.6, N(CHAHBPh)2), 7.27 (2H, app t, J 7.2, Ph), 7.35 (4H, app t, J 7.5,
Ph), 7.43 (4H, app d, J 7.8, Ph).
(RS,RS)-1-(N,N-Dibenzylamino)-2,3-epoxyhexane 15. Fol-
lowing General Procedure 2, (E)-hex-2-en-1-ol (5.89 mL, 49.9 mmol) in
CH2Cl2 (200 mL) was treated with m-CPBA (75% w/w in H2O, 17.2 g,
74.9 mmol). Purification via distillation at reduced pressure (1.2
mmHg) gave (RS,RS)-2,3-epoxyhexan-1-ol as a colorless oil (4.55 g,
78%, >99:1 dr);44 bp 54ꢀ56 °C (1.2 mmHg); {lit.49 bp 57 °C (1.2
mmHg)}; δH (400 MHz, CDCl3) 0.96 (3H, app t, J 7.2, C(6)H3),
1.40ꢀ1.61 (4H, m, C(4)H2, C(5)H2), 1.94 (1H, br s, OH), 2.90ꢀ3.00
(2H, m, C(2)H, C(3)H), 3.58ꢀ3.68 (1H, m, C(1)HA), 3.92 (1H, ddd,
J 12.6, 5.1, 2.4, C(1)HB). Following General Procedure 3, (RS,RS)-2,3-
epoxyhexan-1-ol (2.00 g, 17.2 mmol) in CH2Cl2 (29 mL) was treated
with Et3N (4.80 mL, 34.4 mmol) and MsCl (2.00 mL, 25.8 mmol).
Purification via filtration through a pad of silica gel (eluent CH2Cl2)
gave (RS,RS)-2,3-epoxyhexyl methanesulfonate as a yellow oil (3.20 g,
96%, >99:1 dr);46 δH (400 MHz, CDCl3) 0.97 (3H, app t, J 7.2,
C(6)H3), 1.39ꢀ1.65 (4H, m, C(4)H2, C(5)H2), 2.92 (1H, app td, J
5.5, 2.1, C(3)H), 3.06 (1H, app dt, J 6.5, 2.6, C(2)H), 3.08 (3H, s,
SO2Me), 4.12 (1H, dd, J 12.0, 6.5, C(1)HA), 4.48 (1H, dd, J 12.0, 3.1,
C(1)HB). Following General Procedure 4, (RS,RS)-2,3-epoxyhexyl
methanesulfonate (500 mg, 2.57 mmol) in EtOH (6.44 mL) was treated
with dibenzylamine (1.24 mL, 6.44 mmol). Purification via flash column
chromatography (gradient elution, 2f20% Et2O in 30ꢀ40 °C petrol)
gave 15 as a colorless oil (280 mg, 37%, >99:1 dr);47 Rf 0.35 (30ꢀ40 °C
petrol/Et2O, 9:1); δH (400 MHz, CDCl3) 0.92ꢀ1.01 (3H, m, C(6)H3),
1.38ꢀ1.55 (4H, m, C(4)H2, C(5)H2), 2.53 (1H, dd, J 13.6, 5.8,
C(1)HA), 2.62ꢀ2.69 (1H, br m, C(3)H), 2.73 (1H, dd, J 13.6, 4.0,
C(1)HB), 2.86ꢀ2.92 (1H, br m, C(2)H), 3.60 (2H, d, J 13.8, N-
(CHAHBPh)2), 3.81 (2H, d, J 13.8, N(CHAHBPh)2), 7.18ꢀ7.50 (10H,
m, Ph).
(RS,SR)-1-(N,N-Dibenzylamino)-3,4-epoxyhexane 14. Fol-
lowing General Procedure 2, (Z)-hex-3-en-1-ol (4.54 g, 45.3 mmol) in
CH2Cl2 (181 mL) was treated with m-CPBA (75% w/w in H2O, 15.6 g,
68.0 mmol). Purification via flash column chromatography (gradient elu-
tion, 10f80% EtOAc in 30ꢀ40 °C petrol) gave (RS,SR)-3,4-epoxy-
hexan-1-ol as a colorless oil (4.38 g, 83%, >99:1 dr);48 Rf 0.16 (30ꢀ
40 °C petrol/EtOAc, 3:2); δH (400 MHz, CDCl3) 1.03 (3H, app td,
J 7.5, 1.4, C(6)H3), 1.44ꢀ1.74 (3H, m, C(2)HA, C(5)H2), 1.80ꢀ1.91
(RS,RS)-1-(N,N-Dibenzylamino)-3,4-epoxyhexane 16. Fol-
lowing General Procedure 2, (E)-hex-3-en-1-ol (3.72 g, 37.1 mmol) in
CH2Cl2 (148 mL) was treated with m-CPBA (75% w/w in H2O, 12.8 g,
55.7 mmol). Purification via flash column chromatography (gradient
elution, 10f80% EtOAc in 30ꢀ40 °C petrol) gave (RS,RS)-3,4-
epoxyhexan-1-ol as a colorless oil (3.89 g, 90%, >99:1 dr);44 Rf 0.18
(30ꢀ40 °C petrol/EtOAc, 3:2); δH (400 MHz, CDCl3) 0.98 (3H, app td,
J 7.6, 1.5, C(6)H3), 1.48ꢀ1.73 (3H, m, C(2)HA, C(5)H2), 1.89ꢀ2.00
4621
dx.doi.org/10.1021/jo200517w |J. Org. Chem. 2011, 76, 4617–4627

The Journal of Organic Chemistry
ARTICLE
(1H, m, C(2)HB), 2.39 (1H, br s, OH), 2.73ꢀ2.79 (1H, m, C(4)H), 2.86
(1H, app ddt, J 6.4, 4.3, 2.0, C(3)H), 3.75 (2H, app td, J 6.0, 2.0, C(1)H2).
Following General Procedure 3, (RS,RS)-3,4-epoxyhexan-1-ol (2.00 g, 17.2
mmol) in CH2Cl2 (29 mL) was treated with Et3N (4.80 mL, 34.4 mmol)
and MsCl (2.00 mL, 25.8 mmol). Purification via filtration through a pad
of silica gel (eluent CH2Cl2) gave (RS,RS)-3,4-epoxyhexyl methanesulfo-
nate as an orange oil (2.73 g, 82%, >99:1 dr);50 δH (400 MHz, CDCl3)
1.00 (3H, app t, J 7.5, C(6)H3), 1.54ꢀ1.63 (2H, m, C(5)H2), 1.85 (1H,
app ddt, J 14.7, 6.8, 5.3, C(2)HA), 2.11 (1H, dddd, J 14.7, 7.7, 6.6, 4.4,
C(2)HB), 2.74 (1H, app td, J 5.5, 2.2, C(4)H), 2.83 (1H, ddd, J 6.7, 4.4,
2.2, C(3)H), 3.04 (3H, s, SO2Me), 4.35 (1H, dd, J 5.1, 1.4, C(1)HA), 4.37
(1H, d, J 5.5, C(1)HB). Following General Procedure 4, (RS,RS)-3,4-
epoxyhexyl methanesulfonate (500 mg, 2.57 mmol) in EtOH (6.44 mL)
was treated with dibenzylamine (1.24 mL, 6.44 mmol). Purification via
flash column chromatography (gradient elution, 2f20% Et2O in
30ꢀ40 °C petrol) gave 16 as a colorless oil (500 mg, 66%, >99:1 dr);
Rf 0.41 (30ꢀ40 °C petrol/Et2O, 9:1); νmax (film) 3085, 3062, 3027, 2968,
2934, 2876, 2798 (CꢀH), 1494, 1453, 1367, 745, 699; δH (400 MHz,
CDCl3) 0.96 (3H, app t, J 7.5, C(6)H3), 1.45ꢀ1.74 (3H, m, C(2)HA,
C(5)H2), 1.82 (1H, app dq, J 13.6, 6.8, C(2)HB), 2.57ꢀ2.65 (3H, m,
C(1)H2, C(4)H), 2.72 (1H, app td, J 5.7, 2.0, C(3)H), 3.60 (4H, AB
system, JAB 13.9, N(CH2Ph)2), 7.22ꢀ7.43 (10H, m, Ph); δC (100 MHz,
CDCl3) 9.8 (C(5)Me), 25.0 (C(5)), 30.1 (C(2)), 50.4 (C(1)), 57.2
(C(3)), 58.3 (N(CH2Ph)2), 60.0 (C(4)), 126.9 (p-Ph), 128.2, 128.7 (o,
m-Ph), 139.6 (i-Ph); m/z (ESIþ) 318 ([M þ Na]þ, 48%), 312 (100%),
296 ([M þ H]þ, 98%); HRMS (ESIþ) C20H26NOþ ([M þ H]þ)
requires 296.2009, found 296.2009.
(RS)-1-(N,N-Dibenzylamino)-2,3-epoxy-3-methylbutane 17.
H2O2 (35% in H2O, 1.46 mL, 16.5 mmol) was added dropwise to a stirred
mixture of 3-methylbut-2-enal (1.45 mL, 15.0 mmol) and KHCO3 (1.35 g,
13.5 mmol) in H2O(9.38mL) at0°C, and the resultant mixture was stirred
at this temperature for 2.5 h. Saturated aqueous Na2SO3 was then added
until starch-iodide paper indicated no remaining oxidant. The mixture was
saturated with NaCl and extracted with CH2Cl2 (5 ꢁ 10 mL), and the
combined organic layers were dried and carefully concentrated in vacuo.
The residue was dissolved in 1,2-dichloroethane (50 mL), and dibenzyla-
mine (3.17 mL, 16.5 mmol) and NaB(OAc)3H (4.45 g, 21.0 mmol) were
then sequentially added. The resultant mixture was stirred at rt for 16 h.
Saturated aqueous NaHCO3 (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.
Purification via flash column chromatography (gradient elution, 2f20%
Et2O in 30ꢀ40 °C petrol) gave 17 as a colorless oil (1.66 g, 39%); Rf 0.41
(30ꢀ40 °C petrol/Et2O, 9:1); νmax (film) 3085, 3062, 3028, 2961, 2925,
2884, 2797 (CꢀH), 1494, 1453, 1377, 738, 698; δH (400 MHz, CDCl3)
1.20 (3H, s, C(3)MeA), 1.26 (3H, s, C(3)MeB), 2.58 (1H, dd, J 13.6, 5.8,
C(1)HA), 2.76 (1H, dd, J 13.6, 4.5, C(1)HB), 2.97 (1H, app t, J 5.2,
C(2)H), 3.57 (2H, d, J 13.6, N(CHAHBPh)2), 3.83 (2H, d, J 13.6,
N(CHAHBPh)2), 7.23ꢀ7.49 (10H, m, Ph); δC (100 MHz, CDCl3)
18.9, 24.7 (C(3)Me2), 52.9 (C(1)), 57.5 (C(3)), 58.9 (N(CH2Ph)2),
63.0 (C(2)), 127.0 (p-Ph), 128.3, 128.8 (o,m-Ph), 139.4 (i-Ph); m/z
(ESIþ) 304 ([M þ Na]þ, 86%), 282 ([M þ H]þ, 100%); HRMS
(ESIþ) C19H24NOþ ([M þ H]þ) requires 282.1852, found 282.1851.
(RS,RS)-1-(N,N-Dibenzylamino)-3-fluorohexan-2-ol 20.
Following General Procedure 1, 13 (286 mg, 0.97 mmol) in CH2Cl2
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),
7.22ꢀ7.42 (10H, m, Ph); δC (100 MHz, CDCl3) 13.9 (C(6)), 18.4
(d, J 4.8, C(5)), 32.9 (d, J 22.4, C(4)), 55.4 (d, J 6.4, C(1)), 58.6
(N(CH2Ph)2), 68.7 (d, J 20.8, C(2)), 93.9 (d, J 174, C(3)), 127.4 (p-Ph),
128.5, 129.1 (o,m-Ph), 138.3 (i-Ph); δF (377 MHz, CDCl3) ꢀ196.5
(m); m/z (FIþ) 315 ([M]þ, 100%); HRMS (FIþ) C20H26FNOþ
([M]þ) requires 315.1993, found 315.2006.
(RS,RS)-1-(N,N-Dibenzylamino)-4-fluorohexan-3-ol 21.
Following General Procedure 1, 14 (200 mg, 0.68 mmol) in CH2Cl2
(2.72 mL) was treated with HBF4 OEt2 (184 μL, 1.35 mmol).
3
Purification via flash column chromatography (gradient elution,
5f40% Et2O in 30ꢀ40 °C petrol) gave 21 as a colorless oil (114 mg,
53%, >99:1 dr); Rf 0.23 (30ꢀ40 °C petrol/Et2O, 4:1); νmax (film) 3386
(OꢀH), 3086, 3063, 3029, 2968, 2935, 2880, 2824 (CꢀH), 1495, 1453,
1377, 1137, 1109, 1075, 1028, 953, 749, 733, 699; δH (400 MHz,
CDCl3) 0.98 (3H, app t, J 7.5, C(6)H3), 1.47ꢀ1.78 (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, 4.2, C(1)HA), 2.76ꢀ2.85 (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), 7.25ꢀ7.39 (10H, m, Ph); δC (100 MHz,
CDCl3) 9.7 (d, J 6.4, C(6)), 23.6 (d, J 20.8, C(5)), 27.9 (d, J 4.8, C(2)),
52.2 (C(1)), 58.5 (N(CH2Ph)2), 73.4 (d, J 24.0, C(3)), 97.2 (d, J 173,
C(4)), 127.4 (p-Ph), 128.5, 129.3 (o,m-Ph), 137.9 (i-Ph); δF (377 MHz,
CDCl3) ꢀ195.9 (m); m/z (ESIþ) 653 ([2M þ Na]þ, 100%), 338 ([M
þ Na]þ, 92%), 316 ([M þ H]þ, 68%); HRMS (ESIþ) C20H27FNOþ
([M þ H]þ) requires 316.2071, found 316.2071.
(RS,SR)-1-(N,N-Dibenzylamino)-3-fluorohexan-2-ol 22.
Following General Procedure 1, 15 (156 mg, 0.53 mmol) in CH2Cl2
(2.11 mL) was treated with HBF4 OEt2 (144 μL, 1.06 mmol).
3
Purification via flash column chromatography (gradient elution, 2f
20% Et2O in 30ꢀ40 °C petrol) gave 22 as a colorless oil (129 mg, 77%,
>99:1 dr); Rf 0.28 (30ꢀ40 °C petrol/Et2O, 4:1); C20H26FNO requires
C, 76.2; H, 8.3; N, 4.4%; found C, 76.3; H, 8.45; N, 4.3%; νmax (film)
3444 (OꢀH), 3086, 3063, 3029, 2960, 2935, 2874, 2838, 2807 (CꢀH),
1454, 1076, 1027, 749, 700; δH (400 MHz, CDCl3) 0.93 (3H, app t,
J 7.2, C(6)H3), 1.27ꢀ1.69 (4H, m, C(4)H2, C(5)H2), 2.58ꢀ2.76 (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),
7.23ꢀ7.43 (10H, m, Ph); δC (100 MHz, CDCl3) 13.9 (C(6)), 18.3
(d, J 3.2, C(5)), 33.3 (d, J 20.8, C(4)), 55.3 (d, J 4.8, C(1)), 58.6
(N(CH2Ph)2), 68.3 (d, J 24.0, C(2)), 95.1 (d, J 169, C(3)), 127.4 (p-Ph),
128.5, 129.1 (o,m-Ph), 138.3 (i-Ph); δF (377 MHz, CDCl3) ꢀ194.6
(m); m/z (FIþ) 315 ([M]þ, 100%); HRMS (FIþ) C20H26FNOþ
([M]þ) requires 315.1993, found 315.2003.
(RS,SR)-1-(N,N-Dibenzylamino)-4-fluorohexan-3-ol 23.
Following General Procedure 1, 16 (236 mg, 0.80 mmol) in CH2Cl2
(3.20 mL) was treated with HBF4 OEt2 (218 μL, 1.60 mmol). Purifica-
3
tion via flash column chromatography (gradient elution, 5f40% Et2O
in 30ꢀ40 °C petrol) gave 23 as a colorless oil (179 mg, 71%, >99:1 dr);
Rf 0.33 (30ꢀ40 °C petrol/Et2O, 4:1); νmax (film) 3260 (OꢀH), 3086,
3063, 3029, 3005, 2967, 2935, 2881, 2826 (CꢀH), 1495, 1454, 1375,
1105, 1075, 1028, 952, 749, 733, 699; δH (400 MHz, CDCl3) 0.95 (3H,
app t, J 7.5, C(5)Me), 1.49ꢀ1.87 (4H, m, C(2)H2, C(5)H2), 2.68ꢀ2.81
(2H, m, C(1)H2), 3.46 (2H, d, J 13.1, N(CHAHBPh)2), 3.54ꢀ3.64 (1H,
m, C(3)H), 3.72 (2H, d, J 13.1, N(CHAHBPh)2), 3.84ꢀ4.05 (1H, m,
C(4)H), 6.17 (1H, br s, OH), 7.22ꢀ7.44 (10H, m, Ph); δC (100 MHz,
CDCl3) 9.3(d, J4.8, C(6)), 24.3(d, J20.8, C(5)), 27.0(d, J3.2, C(2)), 51.7
(C(1)), 58.5 (N(CH2Ph)2), 73.8 (d, J 25.6, C(3)), 96.3 (d, J 171, C(4)),
127.5 (p-Ph), 128.5, 129.4 (o,m-Ph), 137.7 (i-Ph); δF (377 MHz, CDCl3)
ꢀ193.6 (m); m/z (ESIþ) 338 ([M þ Na]þ, 93%), 316 ([M þ H]þ,
(3.87 mL) was treated with HBF4 OEt2 (263 μL, 1.94 mmol).
3
Purification via flash column chromatography (gradient elution,
2f20% Et2O in 30ꢀ40 °C petrol) gave 20 as a colorless oil (271 mg,
89%, >99:1 dr); Rf 0.28 (30ꢀ40 °C petrol/Et2O, 4:1); C20H26FNO
requires C, 76.2; H, 8.3; N, 4.4%; found C, 76.3; H, 8.4; N, 4.3%; νmax
(film) 3443 (OꢀH), 3086, 3063, 3028, 2960, 2934, 2873, 2833, 2806
(CꢀH), 1453, 748, 699; δH (400 MHz, CDCl3) 0.93 (3H, app t, J 7.1,
C(6)H3), 1.31ꢀ1.57 (3H, m, C(4)H2, C(5)HA), 1.64ꢀ1.80 (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,
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ARTICLE
100%); HRMS (ESIþ) C20H27FNOþ ([M þ H]þ) requires 316.2071,
found 316.2073.
(RS)-1-(N,N-Dibenzylamino)-3-fluoro-3-methylbutan-2-ol
24. Following General Procedure 1, 17 (200 mg, 0.71 mmol) in CH2Cl2
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), 7.23ꢀ7.36 (10H, m, Ph);
δC (100 MHz, CDCl3) 19.7 (d, J 24.0, C(2)MeA), 20.0 (d, J 4.8,
C(5)MeB), 22.4 (d, J 6.4, C(5)MeA), 26.5 (C(5)), 27.4 (d, J 24.0,
C(2)MeB), 54.3 (N(CH2Ph)2), 61.1 (C(4)), 70.4 (d, J 30.4, C(3)), 96.8
(d, J 168, C(2)), 127.4 (p-Ph), 128.5, 129.4 (o,m-Ph), 138.7 (i-Ph); δF
(377 MHz, CDCl3) ꢀ145.8 (app septet, J 21.8); m/z (FIþ) 343 ([M]þ,
100%); HRMS (FIþ) C22H30FNOþ ([M]þ) requires 343.2306, found
343.2318.
(2.84 mL) was treated with HBF4 OEt2 (193 μL, 1.42 mmol). Purifica-
3
tion via flash column chromatography (gradient elution, 5f40% Et2O
in 30ꢀ40 °C petrol) gave 24 as a colorless oil (189 mg, 88%); Rf 0.36
(30ꢀ40 °C petrol/Et2O, 4:1); νmax (film) 3442 (OꢀH), 3086, 3063,
3029, 2982, 2936, 2889, 2838, 2807 (CꢀH), 1495, 1453, 1372, 1241,
1155, 1096, 1074, 1028, 749, 699; δH (400 MHz, CDCl3) 1.25 (3H, d,
J 22.2, C(3)MeA), 1.29 (3H, d, J 22.0, C(3)MeB), 2.55ꢀ2.68 (2H, m,
C(1)H2), 3.48 (2H, d, J 13.4, N(CHAHBPh)2), 3.61 (1H, br s, OH),
3.65ꢀ3.75 (1H, m, C(2)H), 3.88 (2H, d, J 13.4, N(CHAHBPh)2),
7.25ꢀ7.40 (10H, m, Ph); δC (100 MHz, CDCl3) 22.5 (d, J 24.0,
C(3)MeA), 23.5 (d, J 24.0, C(3)MeB), 53.8 (d, J 4.8, C(1)), 58.3
(N(CH2Ph)2), 71.5 (d, J 25.6, C(2)), 96.1 (d, J 168, C(3)), 127.4
(p-Ph), 128.5, 129.1 (o,m-Ph), 138.2 (i-Ph); δF (377 MHz, CDCl3)
ꢀ149.7 (m); m/z (ESIþ) 324 ([M þ Na]þ, 100%), 302 ([M þ H]þ,
74%); HRMS (ESIþ) C19H25FNOþ ([M þ H]þ) requires 302.1915,
found 302.1916.
(RS,RS)-1-(N,N-Dibenzylamino)-3-fluorohexan-2-yl 40-
nitrobenzoate 28. p-Nitrobenzoyl chloride (263 mg, 1.42 mmol)
was added to a stirred solution of 20 (224 mg, 0.71 mmol) in pyridine
(3.5 mL), and the resultant mixture was stirred at rt for 24 h and then
concentrated in vacuo. The residue was partitioned between saturated
aqueous NaHCO3 (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, 2f20%
Et2O in 30ꢀ40 °C petrol) gave 28 as a pale yellow oil that solidified on
standing to a white crystalline solid (252 mg, 77%, >99:1 dr); Rf 0.36
(30ꢀ40 °C petrol/Et2O, 9:1); mp 105ꢀ107 °C; νmax (KBr) 3111, 3086,
3062, 3029, 2962, 2935, 2875, 2832, 2802 (CꢀH), 1727 (CdO), 1528,
1273; δH (400 MHz, CDCl3) 0.91 (3H, app t, J 7.1, C(6)H3), 1.31ꢀ1.52
(3H, m, C(4)HA, C(5)H2), 1.55ꢀ1.72 (1H, m, C(4)HB), 2.83 (1H, dd,
J 13.6, 5.0, C(1)HA), 2.92 (1H, dd, J 13.6, 7.6, C(1)HB), 3.52 (2H, d,
J 13.4, N(CHAHBPh)2), 3.80 (2H, d, J 13.4, N(CHAHBPh)2), 4.70 (1H,
app ddt, J 47.2, 8.8, 3.3, C(3)H), 5.36 (1H, dddd, J 24.3, 7.6, 5.0, 2.9,
C(2)H), 7.20ꢀ7.33 (10H, m, Ph), 8.19 (2H, d, J 8.8, Ar), 8.31 (2H, d,
J 8.8, Ar); δC (100 MHz, CDCl3) 13.7 (C(6)), 18.3 (d, J 4.8, C(5)), 33.1
(d, J 20.8, C(4)), 53.9 (d, J 4.8, C(1)), 59.1 (N(CH2Ph)2), 73.2 (d,
J 19.2, C(2)), 91.8 (d, J 176, C(3)), 123.5 (C(30), C(50)), 127.1 (p-Ph),
128.3, 128.9 (o,m-Ph), 131.0 (C(20), C(60)), 135.4 (C(10)), 138.8 (i-Ph),
150.7 (C(40)), 164.1 (CdO); δF (377 MHz, CDCl3) ꢀ196.2 (m); m/z
(RS,SR)-1-(N,N-Dibenzylamino)-1-phenyl-3-fluoro-3-met-
hylbutan-2-ol 25. Following General Procedure 1, 18 (143 mg, 0.40
mmol) in CH2Cl2 (1.60 mL) was treated with HBF4 OEt2 (109 μL,
3
0.80 mmol). Purification via flash column chromatography (gradient
elution, 2f20% Et2O in 30ꢀ40 °C petrol) gave 25 as a colorless oil
which solidified on standing to a white crystalline solid (151 mg, quant,
>99:1 dr); Rf 0.23 (30ꢀ40 °C petrol/Et2O, 9:1); C25H28FNOrequires C,
79.5; H, 7.5; N, 3.7%; found C, 79.65; H, 7.3; N, 3.7%; mp 114ꢀ120 °C;
νmax (KBr) 3316 (OꢀH), 3105, 3087, 3063, 3029, 3004, 2980, 2934,
2896, 2847 (CꢀH), 1548, 1495, 1370, 1241, 1151, 1074, 1029, 761, 752,
701; 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), 7.24ꢀ7.50 (15H, m, Ph); δC
(100 MHz, CDCl3) 23.0 (d, J 24.0, C(3)MeA), 24.4 (d, J 25.6, C(3)MeB),
53.6 (N(CH2Ph)2), 62.2 (C(1)), 71.9 (d, J 24.0, C(2)), 96.8 (d, J 171,
C(3)), 127.5, 128.0, 128.3, 128.7, 129.2, 130.2 (p,o,m-Ph), 134.4, 138.2
(i-Ph); δF (377 MHz, CDCl3) ꢀ144.3 (app septet d, J 21.8, 9.2); m/z
(FIþ) 377 ([M]þ, 100%); HRMS (FIþ) C25H28FNOþ ([M]þ) requires
377.2149, found 377.2168.
(ESIþ) 487 ([M þ Na]þ, 100%); HRMS (ESIþ) C27H29FN2NaO4
þ
([M þ Na]þ) requires 487.2004, found 487.1999.
(RS,SR)-1-(N,N-Dibenzylamino)-3-fluorohexan-2-yl 40-
nitrobenzoate 29. p-Nitrobenzoyl chloride (110 mg, 0.59 mmol)
was added to a stirred solution of 22 (93 mg, 0.30 mmol) in pyridine
(1.5 mL), and the resultant mixture was stirred at rt for 24 h then
concentrated in vacuo. The residue was partitioned between saturated
aqueous NaHCO3 (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%
f20% Et2O in 30ꢀ40 °C petrol) gave 29 as a pale yellow oil that
solidified onstanding toa white, crystalline solid (104 mg, 74%, >99:1 dr);
Rf 0.36 (30ꢀ40 °C petrol/Et2O, 9:1); mp 79ꢀ80 °C; νmax (KBr) 3111,
3086, 3062, 3029, 2962, 2935, 2875, 2834, 2802 (CꢀH), 1727 (CdO),
1528, 1273; δH (400 MHz, CDCl3) 0.90 (3H, app t, J 7.3, C(6)H3),
1.18ꢀ1.39 (2H, m, C(4)HA, C(5)HA), 1.43ꢀ1.73 (2H, m, C(4)HB,
C(5)HB), 2.76 (1H, dd, J 13.9, 4.8, C(1)HA), 2.86 (1H, ddd, J 13.9, 7.8,
1.5, C(1)HB), 3.59 (2H, d, J 13.4, N(CHAHBPh)2), 3.70 (2H, d, J 13.4,
N(CHAHBPh)2), 4.67(1H, appddt,J48.0, 9.9, 2.9, C(3)H), 5.47ꢀ5.58 (1H,
m, C(2)H), 7.21ꢀ7.32 (10H, m, Ph), 8.15 (2H, d, J 8.8, Ar), 8.31 (2H, d,
J 8.8, Ar); δC (100 MHz, CDCl3) 13.7 (C(6)), 18.6 (d, J 3.2, C(5)), 32.1 (d,
J20.8, C(4)), 52.6(d, J6.4, C(1)), 59.0(N(CH2Ph)2), 73.9(d, J20.8, C(2)),
93.2 (d, J 174, C(3)), 123.5 (C(30), C(50)), 127.2 (p-Ph), 128.3, 129.0 (o,m-
Ph), 131.0 (C(20), C(60)), 135.5 (C(10)), 138.8 (i-Ph), 150.6 (C(40)), 164.0
(CdO); δF (377 MHz, CDCl3) ꢀ192.9 (m); m/z (ESIþ) 487 ([M þ
Na]þ, 100%); HRMS (ESIþ) C27H29FN2NaO4þ ([M þ Na]þ) requires
487.2004, found 487.2002.
(RS,SR)-2-Fluoro-2,5-dimethyl-4-(N,N-dibenzylamino)he-
xan-3-ol 26. Following General Procedure 1, 19 (241 mg, 0.75 mmol)
in CH2Cl2 (3.00 mL) was treated with HBF4 OEt2 (203 μL, 1.49
3
mmol) to give an 83:17 mixture of 26:27. Purification via flash column
chromatography (gradient elution, 2f20% Et2O in 30ꢀ40 °C petrol)
gave 27 as a colorless oil (15 mg, 6%); Rf 0.24 (30ꢀ40 °C petrol/Et2O,
24:1); νmax (film) 3086, 3063, 3028, 2966, 2932, 2871, 2838, 2807
(CꢀH), 1705 (CdO), 1494, 1465, 1454, 1382, 1366, 1071, 1028, 745,
699; δH (400 MHz, CDCl3) 0.76 (3H, d, J 6.6, C(5)MeA), 0.90 (3H, d,
J 7.1, C(2)MeA), 1.10 (3H, d, J 6.6, C(2)MeB), 1.16 (3H, d, J 6.6,
C(5)MeB), 2.24ꢀ2.38 (1H, m, C(5)H), 2.53 (1H, septet, J 6.9, C(2)H),
3.20 (1H, d, J 10.4, C(4)H), 3.58 (2H, d, J 14.2, N(CHAHBPh)2), 3.96
(2H, d, J 14.2, N(CHAHBPh)2), 7.20ꢀ7.43 (10H, m, Ph); δC (100
MHz, CDCl3) 16.7, 18.1, 20.58, 20.64 (C(2)Me2, C(5)Me2), 27.0
(C(5)), 41.2 (C(2)), 54.6 (N(CH2Ph)2), 68.8 (C(4)), 127.0 (p-Ph),
128.3, 128.8 (o,m-Ph), 139.8 (i-Ph), 214.3 (C(3)); m/z (FIþ) 323
([M]þ, 100%); HRMS (FIþ) C22H29NOþ ([M]þ) requires 323.2244;
found 323.2246. Further elution gave 26 as a colorless oil (159 mg, 62%,
>99:1 dr); Rf 0.12 (30ꢀ40 °C petrol/Et2O, 24:1); C22H30FNO requires
C, 76.9; H, 8.8; N, 4.1%; found C, 77.0; H, 8.85; N, 4.0%; νmax (film)
3241 (OꢀH), 3107, 3087, 3064, 3029, 2980, 2958, 2881, 2842, 2812
(CꢀH), 1455, 1368, 1153, 1062, 750, 700; 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
Octadec-2-yn-1-ol 33. BuLi (2.5 M in hexanes, 14.3 mL, 35.8 mmol)
was added dropwise to a stirred solution of 32 (5.03 mL, 35.8 mmol) in
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ARTICLE
THF (40 mL) at ꢀ78 °C, and the resultant mixture was stirred at this
temperature for 30 min. DMPU (4.72 mL, 39.0 mmol) was then added, and
stirring was continued for a further 10 min. 1-Bromopentadecane (9.33 mL,
32.5 mmol) was then added dropwise, and the resultant mixture was
allowed to warm to rt and then heated at 50 °C for 20 h. The mixture was
allowed to cool to rt, and saturated aqueous NH4Cl (50 mL) was added.
The layers were separated, and the aqueous layer was extracted with Et2O
(2 ꢁ 100 mL). The combined organic layers were then dried and filtered
through a pad of silica gel (eluent Et2O), and the filtrate was concentrated in
vacuo. The residue was dissolved in MeOH (80 mL), and Amberlyst H 15
(1.08 g) was added. The resultant mixture was stirred at 40 °C for 3 h, then
filtered, and concentrated in vacuo. The residue was dissolved in hot
30ꢀ40 °C petrol, and the resultant solution was allowed to cool to rt.
Cooling of the solution to ꢀ78 °C and collection of the resultant precipitate
by filtration (eluent 30ꢀ40 °C petrol) gave 33 as a cream-colored solid
(8.25 g, 95%). Purification of an aliquot via flash column chromatography
(gradient elution, 5f40% Et2O in 30ꢀ40 °C petrol) gave an analytical
sample of 30 as a white solid;51 Rf 0.24 (30ꢀ40 °C petrol/Et2O, 4:1); mp
59ꢀ60 °C; {lit.51 mp 62ꢀ64 °C};δH (400 MHz, CDCl3) 0.89(3H, t, J6.8,
C(18)H3), 1.21ꢀ1.42 (24H, m, C(6)ꢀC(17)H2), 1.47ꢀ1.55 (2H, m,
C(5)H2), 2.21 (2H, tt, J 7.1, 2.1, C(4)H2), 4.26 (1H, br s, C(1)H2).
(E)-Octadec-2-en-1-ol 34. A solution of 33 (8.25 g, 31.0 mmol) in
THF (80 mL) was added dropwise to a stirred solution of LiAlH4 (1.0 M
in THF, 34.1 mL, 34.1 mmol) in THF (25 mL) at 0 °C, and the resultant
mixture was allowed to warm to rt over 20 h. Saturated aqueous
Rochelle’s salt (100 mL) was then added dropwise (cautiously!), and
the resultant mixture was stirred at rt for 18 h. The layers were separated,
and the aqueous layer was extracted with Et2O (2 ꢁ 100 mL). The
combined organic layers were dried and filtered through a pad of silica
gel (eluent Et2O), and the filtrate was concentrated in vacuo to give 34 as
a white solid (8.05 g, 97%, >99:1 dr);52 mp 44ꢀ46 °C; {lit.52 mp
46ꢀ48 °C}; δH (400 MHz, CDCl3) 0.89 (3H, t, J 6.8, C(18)H3),
1.20ꢀ1.43 (26H, m, C(5)ꢀC(17)H2), 2.04 (2H, dt, J 7.5, 6.1, C(4)H2),
4.09 (2H, br m, C(1)H2), 5.59ꢀ5.75 (2H, m, C(2)H, C(3)H).
(2S,3R)-2,3-Epoxyoctadecanal 36. A solution of 35 (6.79 g,
23.9 mmol) in THF (70 mL) was added dropwise to a solution of IBX
(16.7 g, 59.7 mmol) in DMSO (200 mL), and the resultant mixture was
stirred at rt for 3 h. EtOAc (800 mL) and H2O (800 mL) were then
added sequentially, and the resultant mixture was filtered through a pad
of Celite (eluent EtOAc). The layers were separated, the aqueous layer
was extracted with EtOAc (2 ꢁ 350 mL), and the combined organic
layers were washed with H2O (4 ꢁ 500 mL), dried, and concentrated in
vacuo. The residue was dissolved in hot Et2O, filtered through a pad of
Celite (eluent Et2O), and then concentrated in vacuo to give 36 as a
white solid (6.62 g, 98%, >99:1 dr); mp 58ꢀ59 °C; [R]25D ꢀ41.1 (c 1.0
in CHCl3); νmax (KBr) 2953, 2914, 2849 (CꢀH), 1738, 1715, 1470,
854, 719; δH (400 MHz, CDCl3) 0.88 (3H, app t, J 6.8, C(18)H3),
1.21ꢀ1.72 (28H, m, C(4)ꢀC(17)H2), 3.14 (1H, dd, J 6.2, 2.0, C(2)H),
3.24 (1H, ddd, J 5.9, 5.1, 2.0, C(3)H), 9.02 (1H, d, J 6.3, C(1)H); δC
(100 MHz, CDCl3) 14.1 (C(18)), 22.7, 25.8, 29.2, 29.3, 29.4, 29.5,
29.58, 29.64, 29.7, 31.2, 31.9 (C(4)-C(17)), 56.8 (C(3)), 59.1 (C(2)),
þ
198.5 (C(1)); m/z (FIþ) 282 ([M]þ, 100%); HRMS (FIþ) C18H34O2
([M]þ) requires 282.2553, found 282.2558.
(R,R)-1-(N,N-Dibenzylamino)-2,3-epoxyoctadecane 37.
Dibenzylamine (4.51 mL, 23.4 mmol) and NaB(OAc)3H (6.95 g, 32.8
mmol) were sequentially added to a stirred solution of 36 (6.62 g, 23.4
mmol) in 1,2-dichloroethane (160 mL) at 0 °C, and the resultant
mixture was allowed to warm to rt over 3 h. Saturated aqueous NaHCO3
(300 mL) was then added, and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (2 ꢁ 150 mL), and the combined
organic layers were dried and concentrated in vacuo. Purification via flash
column chromatography (gradient elution, 2f20% Et2O in 30ꢀ40 °C
petrol) gave 37 as a colorless oil that solidified on standing to a white
solid (9.60 g, 88%, >99:1 dr); Rf 0.44 (30ꢀ40 °C petrol/Et2O, 9:1);
C32H49NO requires C, 82.9; H, 10.65; N, 3.0%; found C, 82.9; H, 10.6;
N, 3.0%; mp 29ꢀ30 °C; [R]25 þ6.5 (c 1.0 in CHCl3); νmax (KBr)
D
3086, 3063, 3028, 2924, 2853, 2798 (CꢀH), 1495, 1454, 1370, 745, 698;
δH (400 MHz, CDCl3) 0.90 (3H, app t, J 6.8, C(18)H3), 1.21ꢀ1.51
(28H, m, C(4)ꢀC(17)H2), 2.52 (1H, dd, J 13.7, 6.0, C(1)HA), 2.63
(1H, app td, J 5.4, 2.3, C(3)H), 2.70 (1H, dd, J 13.7, 4.0, C(1)HB), 2.87
(1H, ddd, J 6.0, 4.0, 2.3, C(2)H), 3.58 (2H, d, J 13.6, N(CHAHBPh)2),
3.79 (2H, d, J 13.6, N(CHAHBPh)2), 7.21ꢀ7.44 (10H, m, Ph); δC (100
MHz, CDCl3) 14.1 (C(18)), 22.7, 26.0, 29.36, 29.44, 29.5, 29.6, 29.66,
29.70, 31.8, 31.9 (C(4)-C(17)), 55.5 (C(1)), 57.0 (C(2)), 57.3 (C(3)),
58.9 (N(CH2Ph)2), 126.9 (p-Ph), 128.2, 128.8 (o,m-Ph), 139.4 (i-Ph);
m/z (ESIþ) 464 ([M þ H]þ, 100%); HRMS (ESIþ) C32H50NOþ ([M
þ H]þ) requires 464.3887, found 464.3881.
(R,R)-2,3-Epoxyoctadecan-1-ol 35. Ti(OiPr)4 (10.6 mL, 35.7 mmol)
and diethyl D-(ꢀ)-tartrate (8.14 mL, 47.6 mmol) were added sequentially to
CH2Cl2 (330 mL) over powdered 4 Å molecular sieves (21.5 g) at a
temperature between ꢀ20 and ꢀ30 °C (dry ice/acetone bath), and the
resultant mixture was stirred at this temperature for 15 min. A solution of 34
(7.99 g, 29.7 mmol) in CH2Cl2 (60 mL) was added via syringe, and stirring
was continued for a further 10 min. Precooled (ꢀ20 °C) tBuOOH (3.43 M
solution in PhMe,53 26.0 mL, 89.2 mmol) was then added dropwise, and the
resultant mixture was placed in a freezer at ꢀ20 °C for 21 h. The reaction was
then transferred to an ice bath, and a precooled (0 °C) solution of
(2R,3S)-1-(N,N-Dibenzylamino)-3-fluorooctadecan-2-ol 38.
Following General Procedure 1, 37 (9.46 g, 20.4 mmol) in CH2Cl2
FeSO4 7H2O (49.6 g, 178 mmol) and D-(ꢀ)-tartaric acid (13.4 g, 89.2
3
mmol) in H2O (135 mL) was added. The resultant mixture was stirred
vigorously at 0 °C for 10 min and then allowed to warm to rt over 1 h. Celite
was then added until the aqueous slurry became granular, the mixture was
filtered through a pad of Celite (eluent CH2Cl2), and the filtrate was collected.
The filter cake was swirled in hot EtOAc and then filtered through a pad of
Celite (eluent EtOAc), and the filtrate was concentrated in vacuo. The residue
was dissolved in CH2Cl2, and all filtrates were combined then dried and
concentrated in vacuo. The residue was dissolved in Et2O (300 mL) and
treated with a precooled (0 °C) solution of 1 M aqueous NaOH in brine
(300 mL) at0 °C, and theresultant mixture was stirredatthis temperature
for 1 h. The layers were separated, the aqueous layer was extracted with
Et2O (2 ꢁ 200 mL), and then the combined organic layers were dried and
concentratedinvacuo. Purificationvia recrystallization(Et2O) gave35asa
white crystalline solid (6.77 g, 80%, >99:1 dr, >98% ee);52 mp 79ꢀ80 °C;
{lit.52 mp 77ꢀ78 °C}; [R]D25 þ21.4 (c 1.0 in CHCl3); {lit.52 [R]2D3 þ22.5
(c 0.8 in CHCl3)}; δH (400 MHz, CDCl3) 0.89 (3H, app t,
J 6.7, C(18)H3), 1.19ꢀ1.71 (28H, m, C(4)ꢀC(17)H2), 2.91ꢀ2.99
(2H, m, C(2)H, C(3)H), 3.64 (1H, ddd, J 12.4, 7.4, 4.3, C(1)HA), 3.92
(1H, ddd, J 12.4, 5.4, 2.6, C(1)HB).
(82 mL) at 0 °C was treated with HBF4 OEt2 (5.55 mL, 40.8 mmol).
3
Purification via recrystallization from MeCN gave 38 as a white crystalline
solid (6.98 g, 71%, >99:1 dr, >98% ee). The mother liquor was
concentrated in vacuo, and the residue was purified via flash column
chromatography (gradient elution, 2f20% Et2O in 30ꢀ40 °C petrol) to
give additional 38 as a colorless oil that solidified on standing to a white
crystalline solid (825 mg, 8%, >99:1 dr, >98% ee); Rf 0.21 (30ꢀ40 °C
petrol/Et2O, 9:1); mp 42ꢀ43 °C; [R]25D þ35.0 (c 1.0 in CHCl3); νmax
(KBr) 3452 (OꢀH), 3063, 3029, 2924, 2853 (CꢀH), 1454, 748, 699; δH
(400 MHz, CDCl3) 0.90 (3H, app t, J 6.8, C(18)H3), 1.15ꢀ1.68 (28H, m,
C(4)ꢀC(17)H2), 2.63 (1H, dd, J 12.6, 9.6, C(1)HA), 2.70 (1H, ddd,
J 12.6, 3.9, 1.4, C(1)HB), 3.36 (1H, br s, OH), 3.48 (2H, d, J 13.3,
N(CHAHBPh)2), 3.71 (1H, dddd, J 11.4, 9.7, 5.7, 3.9, C(2)H), 3.83 (2H,
d, J 13.3, N(CHAHBPh)2), 4.17ꢀ4.37 (1H, m, C(3)H), 7.26ꢀ7.38 (10H,
m, Ph); δC (100 MHz, CDCl3) 14.1 (C(18)), 22.7, 25.0 (d, J 3.2), 29.36,
29.44, 29.5, 29.57, 29.64, 29.66, 29.70, 31.2(d, J 20.8), 31.9(C(4)-C(17)),
55.3 (d, J 5.6, C(1)), 58.5 (N(CH2Ph)2), 68.2 (d, J 24.0, C(2)), 95.4 (d,
J 169, C(3)), 127.4 (p-Ph), 128.5, 129.1 (o,m-Ph), 138.3 (i-Ph); δF (377
MHz, CDCl3) ꢀ194.3 (m); m/z (ESIþ) 484 ([M þ H]þ, 96%), 464
4624
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The Journal of Organic Chemistry
ARTICLE
([MꢀF]þ, 100%); HRMS (ESIþ) C32H51FNOþ ([M þ H]þ) requires
484.3949, found 484.3946.
(10H, m, Ph); δC (100 MHz, CDCl3) 14.1 (C(18)), 22.7, 24.6 (d, J 4.0),
29.37, 29.44, 29.5, 29.56, 29.64, 29.66, 29.70, 31.9, 32.9 (d, J 20.8)
(C(4)-C(17)), 54.5 (d, J 3.2, N(CH2Ph)2), 57.7 (d, J 10.4, C(1)), 61.0
(d, J 16.8, C(2)), 94.4 (d, J 173, C(3)), 127.3 (p-Ph), 128.5, 129.3 (o,
m-Ph), 139.2 (i-Ph); δF (377 MHz, CDCl3) ꢀ186.9 (m); m/z (ESIþ)
484 ([M þ H]þ, 100%); HRMS (ESIþ) C32H51FNOþ ([M þ H]þ)
requires 484.3949, found 484.3940.
(2R,3S)-1-(N,N-Dibenzylamino)-2-chloro-3-fluorooctade-
cane 41. Method A. CCl4 (289 μL, 3.00 mmol) was added dropwise to a
stirred mixture of 38 (145 mg, 0.30 mmol), PPh3 (197 mg, 0.75 mmol) and
Et3N (418 μL, 3.00 mmol) in MeCN (1.20 mL) at rt, and the resultant
mixture was heated at reflux for 40 min, allowed to cool to rt, and
concentrated in vacuo. Purification via filtration through a pad of silica gel
(eluent CH2Cl2) gave an 83:17 mixture of 40:41 as a yellow oil (153 mg,
quant). Data for 40: δH (500 MHz, CDCl3) [selected peaks] 1.88ꢀ2.01
(1H, m, C(4)HA), 2.80ꢀ2.92 (1H, m, C(2)H), 3.59 (2H, d, J 13.4,
N(CHAHBPh)2), 3.86 (1H, dd, J 10.9, 8.8, C(1)HA), 3.92 (1H, dd,
J 10.9, 4.7, C(1)HB), 4.03 (2H, d, J 13.4, N(CHAHBPh)2), 4.79 (1H, dddd,
J 48.2, 8.0, 4.7, 3.3, C(3)H). A solution of the 83:17 mixture of 40:41 (50.0
mg) in MeCN (0.40 mL) was heated at reflux for 18 h and then concentrated
in vacuo to give 41 as a yellow oil (50.0 mg, quant, >99:1 dr).
(S,S)-2-Amino-3-fluorooctadecan-1-ol [(S,S)-3-deoxy-3-
fluorosafingol] 43. Pd(OH)2/C (100 mg, 50% w/w wrt 42) was
added to a vigorously stirred solution of 42 (200 mg, 0.41 mmol) in
degassed MeOH (2.08 mL), and the resultant suspension was stirred at
rt under H2 (5 atm) for 5.5 h. The reaction mixture was then filtered
through a pad of Celite (eluent hot MeOH) and concentrated in vacuo to
give 43 as a white solid (121 mg, 97%, >99:1 dr); C18H38FNO requires
C, 71.2; H, 12.6; N, 4.6%; found C, 71.3; H, 12.8; N, 4.5%; mp
80ꢀ81 °C; [R]25 ꢀ6.2 (c 1.0 in MeOH); νmax (KBr) 3354, 3270,
D
3196, 3095, 2953, 2918, 2847 (CꢀH), 1626, 1468, 1071, 1052, 938, 907,
872, 722; δH (400 MHz, MeOH-d4) 0.91 (3H, app t, J 6.8, C(18)H3),
1.23ꢀ1.84 (28H, m, C(4)ꢀC(17)H2), 2.76ꢀ2.88 (1H, m, C(2)H),
3.51 (1H, dd, J 10.9, 6.3, C(1)HA), 3.60 (1H, dd, J 10.9, 5.8, C(1)HB),
4.50 (1H, app ddt, J 48.8, 8.8, 4.2, C(3)H); δC (100 MHz, MeOH-d4)
13.5 (C(18)), 22.7, 25.4 (d, J 4.0), 29.5, 29.6, 29.68, 29.71, 29.77, 29.79,
31.7 (d, J 20.8), 32.1 (C(4)-C(17)), 55.8 (d, J 19.2, C(2)), 62.9 (d, J 5.6,
C(1)), 94.0 (d, J 169, C(3)); δF (377 MHz, MeOH-d4) ꢀ198.7 (m);
m/z (ESIþ) 304 ([M þ H]þ, 100%); HRMS (ESIþ) C18H39FNOþ
([M þ H]þ) requires 304.3010, found 304.3006.
Method B. CCl4 (13.6 mL, 141 mmol) was added dropwise to a stirred
mixture of 38 (6.81 g, 14.1 mmol), PPh3 (9.23 g, 35.2 mmol), and Et3N
(19.6 mL, 141 mmol) in MeCN (56 mL) at 0 °C, and the resultant
mixture was allowed to warm to rt and then heated at reflux for 18 h. The
mixture was then allowed to cool to rt and was concentrated in vacuo. The
residue was dissolved inCH2Cl2, filtered through a pad ofsilica gel (eluent
CH2Cl2), and concentrated in vacuo. Purification via flash column
chromatography (gradient elution, 1f8% Et2O in 30ꢀ40 °C petrol)
gave 41 as a yellow oil (6.28 g, 89%, >99:1 dr); Rf 0.53 (30ꢀ40 °C petrol/
Et2O, 24:1); [R]25 ꢀ13.2 (c 1.0 in CHCl3); νmax (film) 3087, 3063,
D
3028, 2924, 2853 (CꢀH), 1454, 747, 698; δH (400 MHz, CDCl3) 0.90
(3H, app t, J 6.8, C(18)H3), 0.99ꢀ1.70 (28H, m, C(4)ꢀC(17)H2), 2.76
(1H, ddd, J 13.9, 6.6, 2.3, C(1)HA), 2.88 (1H, dd, J 13.9, 7.6, C(1)HB), 3.51
(2H, d, J 13.5, N(CHAHBPh)2), 3.75 (2H, d, J 13.5, N(CHAHBPh)2),
4.12ꢀ4.22 (1H, m, C(2)H), 4.67 (1H, dddd, J 47.5, 9.7, 3.9, 2.3, C(3)H),
7.25ꢀ7.39 (10H, m, Ph); δC (100 MHz, CDCl3) 14.1 (C(18)), 22.7, 25.1
(d, J 2.4), 29.4, 29.5, 29.6, 29.65, 29.67, 29.69, 29.71, 29.8, 31.9 (C(4)-
C(17)), 56.6 (d, J 6.4, C(1)), 59.1 (N(CH2Ph)2), 60.9 (d, J 21.6, C(2)),
93.9 (d, J 174, C(3)), 127.3 (p-Ph), 128.3, 129.0 (o,m-Ph), 138.7 (i-Ph); δF
(377 MHz, CDCl3) ꢀ184.8 (m); m/z (ESIþ) 502 ([M(35Cl) þ H]þ,
100%); HRMS (ESIþ) C32H5037ClFNþ ([M(37Cl) þ H]þ) requires
504.3581, found 504.3595; C32H5035ClFNþ ([M(35Cl) þ H]þ) requires
502.3610, found 502.3606.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H, 13C, and 19F
S
b
NMR spectra and files in CIF format for structures CCDC
810176ꢀ810182. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: steve.davies@chem.ox.ac.uk.
(S,S)-2-(N,N-Dibenzylamino)-3-fluorooctadecan-1-ol 42.
KOAc (1.67 g, 17.1 mmol) was added to a stirred solution of 41 (857
mg, 1.71 mmol) in DMF (34 mL), and the resultant suspension was
stirred at 100 °C for 24 h. The mixture was allowed to cool to rt, and
EtOAc (300 mL) and saturated aqueous NaHCO3 (300 mL) were
added sequentially. The layers were separated, and the aqueous layer was
extracted with EtOAc (2 ꢁ 150 mL). The combined organic layers were
washed with H2O (4 ꢁ 200 mL), dried, and concentrated in vacuo.
K2CO3 (236 mg, 1.71 mmol), MeOH (4.27 mL) and THF (4.27 mL)
were added to the residue, and the resultant mixture was stirred at rt for
2.5 h and then concentrated in vacuo. The residue was partitioned
between CH2Cl2 (50 mL) and H2O (50 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.
Purification via flash column chromatography (gradient elution, 2f20%
EtOAc in 30ꢀ40 °C petrol) gave 42 as a yellow oil that solidified on
standing to a cream solid (681 mg, 82%, >99:1 dr, >98% ee); Rf 0.28
(30ꢀ40 °C petrol/EtOAc, 9:1); C32H50FNO requires C, 79.45; H,
10.4; N, 2.9%; found C, 79.5; H, 10.4; N, 2.8%; mp 40ꢀ41 °C; [R]D25
ꢀ50.6 (c 1.0 in CHCl3); νmax (KBr) 3423 (OꢀH), 3086, 3063, 3029,
2924, 2853 (CꢀH), 1455, 750, 699; δH (400 MHz, CDCl3) 0.90 (3H,
app t, J 6.8, C(18)H3), 1.22ꢀ1.68 (28H, m, C(4)ꢀC(17)H2), 3.00 (1H,
app dq, J 12.8, 7.9, C(2)H), 3.13 (1H, br s, OH), 3.42 (2H, app d, J 7.6,
C(1)H2), 3.82 (2H, d, J 12.9, N(CHAHBPh)2), 3.92 (2H, d, J 12.9, N
(CHAHBPh)2), 4.79 (1H, app dtd, J 50.0, 8.5, 2.3, C(3)H), 7.24ꢀ7.38
’ ACKNOWLEDGMENT
The authors would like to thank Syngenta for a CASE
studentship (A.J.C.).
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