Skipped Fluorination Motifs: Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs

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Skipped Fluorination Motifs: Synthesis of Building Blocks and

Comparison of Lipophilicity Trends with Vicinal and Isolated

Fluorination Motifs

Robert I. Troup, Benjamin Je ﬀ ries, Raphael El-Bekri Saudain, Eleni Georgiou, Johanna Fish,

James S. Scott, Elisabetta Chiarparin, Charlene Fallan, and Bruno Linclau *

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ABSTRACT: Given there is an optimal lipophilicity range for

orally bioavailable drugs, structural modiﬁcations applied in the

drug development process are not only focused on optimizing

bioactivity but also on ﬁne-tuning lipophilicity. Fluorine introduc-

tion can be used for both purposes. Insights into how ﬂuorine

introduction aﬀects lipophilicity are thus of importance, and

systematic series of ﬂuorinated compounds with measured

octanol−water partition coeﬃcients are a powerful way to enhance

our qualitative understanding in this regard and are essential as

input for computational log P estimation programs. Here, we report a detailed comparison of all possible vicinal and skipped (1,3-

substituted) ﬂuorination motifs when embedded in structurally equivalent environments (X−CF_nH_2‑n−CF_mH_2−m−X versus X−

CF_nH_2−n−CH₂−CF_mH_2−m−X, with n,m ≠ 0 and X = CH₂OH) to compounds with isolated ﬂuorination (n ≠ 0; m = 0, and

including X−CH₂−CF_nH_2−n−CH₂−X, n = 0−2). It is shown that skipped ﬂuorination is more powerful for log P reduction purposes

compared to single or vicinal ﬂuorination. Eﬃcient stereoselective syntheses of the compounds with skipped ﬂuorination motifs are

reported, which where relevant can be made enantioselective using known chiral building blocks. These compounds, and some

intermediates, will be of interest as advanced ﬂuorinated building blocks.

importance for data input in computational log P calculation

eﬀorts.^14,15While every structural modiﬁcation of a compound

will aﬀect its log P value, ﬂuorine introduction has proven to be

particularly useful in this regard, mainly due to a combination

of its very strong electronegativity and its small size.¹⁶Initiated

INTRODUCTION

■

The realization of the critical importance of simultaneous

optimization of physical properties and of bioactivities in the

drug development process has been a major recent develop-

ment in medicinal chemistry.¹⁻⁸Lipophilicity has been

recognized as a useful proxy for a range of properties related

to absorption, distribution, metabolism, excretion, and toxicity

(ADMET) of orally administered bioactive compounds and is

therefore an often-used parameter in the optimization

process.^3,7,9−11It is deﬁned as the partition coeﬃcient P of a

compound between octanol and water, and expressed as its

logarithm (log P). For ionizable compounds, partitioning is

measured at a particular pH and expressed as the logarithm of

its distribution coeﬃcient (log D_pH). Chromatographic meth-

ods have been developed where retention times are related to

lipophilicities.^12,13These methods have gained in popularity

due to their simplicity and ability to generate a high-

throughput of experimental data, but accuracies are naturally

dependent on the quality of the training set used to establish

the correlation between log P and retention time. The

understanding of how lipophilicity is inﬂuenced by structural

changes is of great importance in drug discovery. Systematic

studies exploring structure−lipophilicity relationships, espe-

cially when using actual octanol−water partition coeﬃcient

values, are thus of great interest. Such studies also have

by the seminal work of Mu

̈

ller and colleagues,¹⁷⁻²²the

inﬂuence of aliphatic chain ﬂuorination on lipophilicities has

been investigated by a number of groups, for example, by

investigating new motifs²³⁻²⁸and introduction of ﬂuorine on

aliphatic systems²⁹⁻³³or in amino acid side chains.³⁴⁻³⁶

A subset of these studies involve vicinal ﬂuorination motifs

(Figure 1). Muller was the ﬁrst to discover the lower

̈

lipophilicity of the vicinal diﬂuoro motif compared to the

geminal analogues¹⁹and that the relative stereochemistry was

not important (compare A2 with A3/A4 and B2-B4 with B5/

B6). He also showed that a further extension to the

triﬂuorinated motif as in B7/B8 only led to a small additional

Received: November 24, 2020

Published: January 5, 2021

https://dx.doi.org/10.1021/acs.joc.0c02810

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Figure 1. Precedent involving aliphatic vicinal and multivicinal ﬂuorine motifs.

log P decrease.¹⁹However, compared to the nonﬂuorinated

“parents” A1/B1, a signiﬁcant decrease in log P was obtained.

In contrast, our group reported that the two vicinal diﬂuoride

compounds C2 and C3 only gave modest lipophilicity

decreases compared to the nonﬂuorinated parent C1, but

conﬁrmed the irrelevance of relative stereochemistry.²⁷Hunter

also recently reported that diastereoisomers of acyclic vicinal

diﬂuorinated compounds gave very similar log P values (not

shown).¹⁴Nevertheless, the lipophilicity-decreasing eﬀect of

the vicinal diﬂuoride motif introduction was convincingly

demonstrated by Gilmour using Gilenya analogues.^37,38The

nonﬂuorinated parent with a pentoxy chain D1 is signiﬁcantly

more lipophilic than D2, while the triﬂuoromethylated D3

only showed a modest decrease. Interestingly, two multivicinal

analogues D4 and D5 were also synthesized,³⁸but showed

similar lipophilicities to the vicinal diﬂuorinated D2, although

the eﬀect of relative stereochemistry is now more pronounced.

Through analysis of all possible ﬂuorination motifs on the

pentan-1-ol 4- and 5-positions, we showed that 4,5-

diﬂuoropentan-1-ol E2 displayed the largest lipophilicity

decrease of all motifs investigated and that its log P value

(+0.11) is even lower than that of propan-1-ol (+0.30, not

shown), which has two fewer carbon atoms.²³It can be seen

that the log P of E2 is much decreased compared to that of the

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Figure 2. Vicinal and skipped ﬂuorination motif matched pairs.

corresponding geminal analogues E3/E4 and that the decrease

is larger compared to that observed in series A and B. We also

showed that the corresponding “motif extension” from a

(geminal) triﬂuoromethyl group (E5) to the vicinal triﬂuori-

nated motifs as in E6/E7 also leads to signiﬁcant log P

decreases. O’Hagan has reported on geminal and vicinal

diﬂuorinated phenyl cyclopropanes,^31,32with the geminal

diﬂuorinated F2 being more lipophilic compared to the vicinal

diﬂuorinated compounds F3 and F4. Perhaps surprisingly,

there was no measurable diﬀerence between the cis and trans-

isomers. The all-cis triﬂuorinated derivative F6 is the most

polar in the series, with its diastereomer F5 having the same

log P as the vicinal diﬂuorinated analogues F3/F4. Finally,

O’Hagan also reported on the signiﬁcant log P decrease when

introducing cis-vicinal diﬂuorination on phenyl cyclohexane

(G1 to G2).

molecules (Scheme 1). Relevant to the motifs reported herein,

the Jacobsen group reported a direct introduction through

Scheme 1. Synthetic Precedence Examples for the Skipped

Diﬂuoro Motif

In contrast to vicinal ﬂuorination motifs, skipped ﬂuorina-

tion motifs are only recently beginning to be investigated for

their eﬀect on lipophilicity. Our group showed that compared

to vicinal ﬂuorination motifs, the corresponding skipped motifs

(Figure 2) had a much lower lipophilicity (compare E8/E9

with E10/E11).²³It is interesting to compare the skipped

ﬂuorination motif with its individual constituent motifs: the

log P decrease caused by the skipped tetraﬂuorination motif in

E10 is in between that of the monoﬂuorinated E12 and the

triﬂuoromethylated E14 (likewise for the other motif). Hence,

the log P decrease caused by a skipped motif is less than the

“sum” of the decrease obtained by introducing its constituents.

O’Hagan has shown that introducing a skipped ﬂuorine in G2,

leading to G3, causes a large log P decrease.³⁹Introducing a

fourth ﬂuorine (G4) did not show much further decrease

however.

oxidative ring-opening of substituted cyclopropanes with HF-

pyridine, illustrated by the conversion of 1 to 2.⁴⁰The Carreira

group reported the synthesis of ﬂuorodanicalipin A 4,⁴¹

a

ﬂuorinated analogue of the chlorosulfolipid danicalipin A, by

the simultaneous stereospeciﬁc nucleophilic deoxyﬂuorination

of the corresponding 1,3-diol groups in 3. The repeating

skipped monoﬂuoro motif has been reported in ﬂuoropol-

ymers, though this chemistry has not been widely explored on

small molecules.⁴²

Synthetically useful examples toward a skipped triﬂuorina-

tion motif within acyclic chains have not been reported,

although the methodology shown in Scheme 2 could, in

principle, be applied. The Studer group reported that

treatment of 5, obtained via 1,2-carboboration of the

Compared to vicinal diﬂuorination patterns, there are a

number of synthetic methodologies reported for the synthesis

of 1,3-skipped ﬂuorination of aliphatic chains in small

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approach, the Chiechi group directly ﬂuorinated β-dithiolane

21, obtained from the corresponding propargylic ketone 20,

using HF-pyridine, to obtain 22. This was subsequently

converted to the skipped 1,3-tetraﬂuoro compound 23 with

Morph-DAST.⁵⁰

Scheme 2. Synthetic Precedence for the Skipped Triﬂuoro

Motif

In this contribution, we report on a systematic investigation

to compare internal vicinal ﬂuorination motifs with their

(internal) skipped counterparts, using the 1,4-butanediol and

1,5-pentanediol scaﬀolds C and H, respectively (Figure 3). For

this investigation, we opted to have a constant structural

feature at the molecule termini, with the structural change

focused on the extension of the two-carbon vicinal motif with

the three-carbon skipped motif without any additional

inﬂuence caused by ﬂuorination motifs being at diﬀerent

distances from a polar functional group or aliphatic chain

terminus.

The syntheses⁵¹and lipophilicities²⁷of C2−C4 have been

reported and are included for discussion purposes, which also

will involve comparison with monoﬂuorinated and geminal

diﬂuorinated analogues C6, C7, and H6−H9, as well as with

the hexaﬂuorinated H10. The synthesis of H2−H5 employs

diﬀerent strategies compared to the literature precedence, and

is, where relevant, fully stereoselective.

corresponding alkene, with SelectFluor and silver nitrate

achieved a radical deboronoﬂuorination to provide the skipped

ﬂuoro species 6 in a moderate yield.⁴³Another interesting

approach was taken by Kitazume and Ishikawa, who

synthesized the motif via alkene reduction of a ﬂuorinated

α,β-unsaturated ester such as 7 with Baker’s yeast, although a

long reaction time (7 days) was required to obtain 8.⁴⁴

Fuchikami and Ojima inadvertently produced the skipped

ﬂuoro pattern while investigating the transition-metal-catalyzed

addition of perﬂuoroalkyl halides to alkenes.⁴⁵The perﬂuor-

ooctylation of vinyl ﬂuoride 10 with 9 aﬀorded a mixture of the

perﬂuoroalkyl iodides 11 and 12, which conveniently

contained the skipped motif alongside a halide handle for

further functionalization at the terminal position.

The skipped tetraﬂuoro motif has perhaps received the most

attention due to its widely reported use in ﬂuorinated polymers

and surfactants (Scheme 3).⁴⁶⁻⁴⁸In a representative example,

the Ameduri group reacted vinylidene ﬂuoride 13 with iodide

14 and obtained telomers of various lengths containing

skipped diﬂuoromethylene groups (15). In their synthesis of

ﬂuorinated palmitic acid derivatives, the O’Hagan group

employed sequential deoxyﬂuorinations in neat diethylamino-

sulfur triﬂuoride (DAST) to obtain the skipped tetraﬂuoro

motif in the center of the long aliphatic chain:⁴⁹following the

ﬁrst deoxoﬂuorination of ketone 16, the pendant alkene in 17

was converted to the epoxide and opened with pentylmagne-

sium bromide. Oxidation of the resultant alcohol to ketone 18

and treatment with DAST then aﬀorded 19. Both ﬂuorinations

required neat DAST at elevated temperatures. In a related

RESULTS AND DISCUSSION

■

Synthesis. Skipped Target Compounds H2−H5Retro-

synthetic Analysis. The approach taken for the synthesis of

these targets is shown in Scheme 4. While for the purposes of

the lipophilicity measurements racemic compounds are

adequate, we sought to develop synthetic routes that allowed

enantioselective synthesis where applicable. For the anti-1,3-

diﬂuorinated H2, the ﬁnal ﬂuorine introduction was envisaged

by deoxyﬂuorination of the ﬂuorohydrin 24, to be accessed by

reductive opening of known lactone 25,⁵²whose synthesis

from lactone 26 has been reported by the Liotta group using a

fully diastereoselective electrophilic ﬂuorination. Lactone 26 is

easily procured from glutamic acid,^53,54conveniently enabling

the synthesis of either enantiomer of H2 depending on the

absolute conﬁguration of the amino acid used. It is worth

mentioning that direct enantioselective monoﬂuorination of

1,5-pentanedialdehyde, for example, using the MacMillan

methodology,⁵⁵which would directly yield H2 (after aldehyde

reduction) was brieﬂy investigated, but no formation of the

desired product was ever observed. The synthesis of the meso-

compound H3 was envisaged from the 2,4-dideoxy-diﬂuori-

nated levoglucosan 28, with the required one-carbon C−C

bond cleavage and alcohol reduction being more than oﬀset by

Scheme 3. Synthetic Precedence for the Skipped Tetraﬂuoro Motif

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Figure 3. Nonﬂuorinated parent substrates with the ﬂuorination motif types studied.

Scheme 4. Retrosynthetic Analysis of the Skipped Fluorinated Pentanediols

Scheme 5. Enantioselective Synthesis of Both Enantiomers of the Skipped Diﬂuorinated H2

the ease of the double ﬂuorine introduction: one-pot bis-

ﬂuorination of the ditosylate 29 has been optimized on large

For the synthesis of H4, an electrophilic α-diﬂuorination/

aldehyde reduction sequence as developed by the Lindsley

group^58,59was envisaged, leading to 30 as a precursor. The

ﬂuorination in 30 was envisaged to be achieved by

56,57

̀

scale by both the Giguere group and us,

making this an

attractive starting point for H3.

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Scheme 6. Synthesis of the syn-1,3-Diﬂuorinated Diol H3

Scheme 7. Synthesis of the Skipped Triﬂuoro Substrate H4

deoxyﬂuorination of known alcohol 31, which can be obtained

from epoxide opening of the commercially available building

block 32. Both enantiomers of 32 are available, so this route

could provide either enantiomer of H4, although only the

racemic synthesis is reported here. To introduce the skipped

tetraﬂuorination to obtain H5, we opted for a diﬀerent strategy

to O’Hagan and Chiechi’s nucleophilic ﬂuorination sequences.

Instead, aldehyde electrophilic ﬂuorination as also proposed

for H4 was envisaged, with aldehyde 33 to be obtained from

known diester 34,⁶⁰which has been obtained by a ﬂuorinated

building block approach involving Michael-type methodology

as originally described by the Kumadaki group.^61,62

nucleophilic deoxyﬂuorination to obtain the anti-1,3-diﬂuoro

compound 40. The use of two equivalents of DAST for 1 h at

0 °C is reported to be compatible with a TBDPS group.^63,64

The purity of the isolated material was low; however,

treatment of the impure mixture with TBAF enabled isolation

of pure 41 in good yields. Finally, treatment with KOH in

methanol provided the diol H2 in a 76−79% yield. The

measured optical activity of the H2 enantiomers conﬁrmed the

stereochemical outcome of the nucleophilic ﬂuorination as

occurring with inversion (as expected) without any trace of

neighboring group participation of the protected alcohol,

which is easily determined since the resulting retention would

give the optically inactive meso-diastereomer H3.

Anti-1,3-diﬂuoro Synthesis (H2). Lactone (S)-26 (Scheme

5) was obtained through a well-documented sequence from ^L-

glutamic acid (S)-37,^53,54involving diazotization and con-

comitant intramolecular stereoretentive cyclization to the

lactone, reduction of the pendant acid to alcohol, and its

protection as a tert-butyl diphenyl silyl ether. The electrophilic

ﬂuorination of (S)-26 with LiHMDS and NFSI gave (2R,4S)-

25 with complete diastereoselectivity, as reported by Liotta et

al.⁵²In our hands, however, the reaction proved capricious,

with a low yield (27%) as our best result, compared to the

reported 50−70%. In a subsequent attempt, the yield of

(2R,4S)-25 was reduced to 10%, but the byproduct 38 was

isolated in a signiﬁcant 15% yield. This suggested that

ammonia, originating from the ammonium chloride reaction

quench, had reacted with the electrophilic lactone ring of

(2R,4S)-25. As a result, the quench was altered to a minimum

quantity of water and the reaction mixture was carefully

concentrated under reduced pressure and telescoped into the

subsequent reduction. Treatment of the crude (2R,4S)-25 with

NaBH₄successfully provided a 50% yield of (2R,4S)-24 across

two steps.

Syn-1,3-Diﬂuoro Synthesis (H3). The diﬂuorinated sugar

derivative 28 (Scheme 6) was obtained from levoglucosan

(42), involving tosylation of the alcohols at positions 2 and 4

to obtain ditosylate 29 (not shown) and their stereoretentive

displacement with ﬂuoride (45% across the two steps).^56,57

Reduction of the 3-OH group was achieved by the tin hydride-

free conditions, as reported by the Roberts group,⁶⁵via the

thiocarbonyl derivative 43.

The 1,6-anhydrobridge was opened using TMSOTf and

acetic anhydride, to provide the acetylated pyranose 27 as an

inseparable mixture of anomers. Simultaneous reduction of the

hemiacetal and both esters gave triol 45 upon which oxidative

cleavage of the vicinal diol was achieved to produce the lactol

46. Finally, reduction of this compound with sodium

borohydride provided an excellent yield of H3.

Skipped Triﬂuoro Synthesis (H4). This synthesis com-

menced with known alcohol 31 (Scheme 7), which is

accessible in one step from commercially available benzyl

glycidol 32.⁶⁶Deoxyﬂuorination using nonaﬂuorobutanesul-

fonyl ﬂuoride (NfF) and triethylamine-HF to give 47 and

oxidative cleavage of the alkene resulted in the required

aldehyde 30 to eﬀect the electrophilic diﬂuorination step. This

was achieved by sequential ﬂuorination of the ^L-proline

enamine intermediate when excess NFSI is present.^58,59The

resulting 2,2-diﬂuorinated aldehyde was reduced without

Repeating this two-step sequence starting from (R)-26 on a

10-fold increase in scale gave a reduced yield of 36%. In both

cases, selective protection of the primary alcohol as a benzoyl

ester aﬀorded 39 in moderate yields. This compound was then

ready for the ﬁnal key step in the synthesis: stereospeciﬁc

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Scheme 8. Synthesis of the Skipped Tetraﬂuoro Diol H5

puriﬁcation to give triﬂuorinated alcohol 48, in an overall 81%

yield from 30. Finally, removal of the benzyl protecting group

using conditions reported by Jung and Lyster⁶⁷aﬀorded the

diol H4.

Scheme 10. Synthesis of the 1,4-Butanediol Targets

For the purposes of log P calculation, the racemic compound

was suﬃcient; however, alcohol 31 is equally accessible in

enantiopure form from commercially available enantiopure

benzyl glycidol.

Skipped Tetraﬂuoro Synthesis (H5). This sequence

commenced with the copper-catalyzed conjugate addition^61,62

of ethyl bromodiﬂuoroacetate 36 to ethyl acrylate 35 (Scheme

8). Acetic acid was added as a protic additive, due to the

resulting improvement in yield reported by the Shin group.⁶⁰

The adduct was directly subjected to NaBH₄treatment, which

led to the selective reduction of the more electrophilic ester

group to give 49. Protection of the obtained alcohol as TBDPS

ether 50 and partial ester reduction yielded aldehyde 33.

Without further puriﬁcation, this aldehyde was subjected to the

same two-step diﬂuorination/reduction sequence as before,

which provided the skipped tetraﬂuoro compound 51. Finally,

alcohol deprotection aﬀorded an excellent yield of the diol H5.

1,5-Pentanediol Targets (H6, H7, H8). Benzoate cleavage

of known 52²³gave target H6 (Scheme 9a). Treatment of

benzyl alcohols aﬀorded the diol C5. Finally, benzoate

methanolysis of known 59 and 60 (Scheme 10b)²³led to

C6 and C7 in modest yield.

Lipophilicity. The lipophilicity data for 1,4-butanediol C1

and its ﬂuorinated derivatives are shown in Figure 4.

Monoﬂuorination (C6) leads to a log P decrease, while

geminal diﬂuorination (C7) leads to an almost equal log P

increase. The contrast with the same types of ﬂuorine

introduction on the monohydroxylated analogue, 1-butanol

I1 (inset, Figure 4), is interesting: monoﬂuorination at its 2- or

3-positions, which have the same relative position of the

ﬂuorination relative to the OH groups in C6, leading to I2 and

I3, leads to a much larger decrease in log P. The same is true

for geminal diﬂuorination at these positions (I4 and I5), albeit

much less pronounced for I4. This is a typical illustration of

the context dependence in log P modulation upon introduction

of a given motif in similar parents having very diﬀerent

lipophilicities: 1,4-butanediol is much more polar than 1-

butanol, hence the ﬂuorine dipole eﬀect will be reduced

relative to hydrophobic eﬀects such as introduction of

hydrophobic surface and alcohol hydrogen-bond basicity and

lone pair polarizability reduction, resulting in a smaller log P

decrease (for monoﬂuorination, C6) or even in a log P increase

(C7).

Scheme 9. Synthesis of Mono- and Geminal Diﬂuorinated

1,5-Pentanediol Targets

commercially available 53 with DAST aﬀorded the ﬂuorinated

compound 54 in excellent yield, and the subsequent reduction

to the diol aﬀorded the diol H7 (Scheme 9b). Finally, benzoate

methanolysis of known 55²³led to H8 (Scheme 9c).

1,4-Butanediol Targets (C5, C6, C7). Alcohol oxidation of

known racemic syn-56⁵¹(Scheme 10a) using Dess−Martin

periodinane gave ketone 57, and subsequent treatment with

excess DAST eﬃciently led to the vicinal triﬂuoro motif in 58.

Simultaneous TMSI-mediated⁶⁷deprotection of the two

While the vicinal diﬂuorinated derivatives C2/C3 are less

lipophilic compared to C1 (see Figure 1/4), the vicinal

triﬂuorinated motif in C5 leads to a higher log P, and there is a

further increase to the vicinal tetraﬂuorinated C4. The

occurrence of antiperiplanar C−F bonds, with their opposing

dipole moments, will be an important reason for this. However,

while the geminal diﬂuorinated C7 is more lipophilic than

parent C1, the corresponding vicinal diﬂuorinated motifs (C2,

C3, same ﬂuorine count) are much more polar, leading to a

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Figure 4. Lipophilicities of ﬂuorinated 1,4-butanediol derivatives, in comparison to relevant ﬂuorinated 1-butanols. Lipophilicity scales for the

compound series are normalized to their nonﬂuorinated parents.

lower log P than C1. This is consistent with Mu

̈

ller’s original

as observed for C1, why geminal diﬂuorination to H8 leads to

a log P increase, while for E1 this leads to a log P decrease.

There is a diﬀerence in trend when comparing mono- and

diﬂuorination between the 2- and 3-positions of H1: the C3-

monoﬂuorinated H7 has a higher log P than the C2-

monoﬂuorinated H6, but the C3-diﬂuorinated H9 has a

lower log P compared to the C2-diﬂuorinated H8. This can be

qualitatively explained, over and above any context depend-

ence issues, by taking into account the relative distance

between the ﬂuorination sites and both OH groups and

comparing these with the 1-pentanol (E1) data (inset, Figure

5): 2,2-diﬂuoropentan-1-ol (E17) is much more lipophilic than

its geminal ﬂuorination regioisomers E5 and E15, resulting in

H8 to have a higher log P than H9. Conversely, 4-

ﬂuoropentan-1-ol E3 is much less lipophilic, which must

dominate the log P of H6, leading to its lower value.

Introduction of the skipped diﬂuorination motif leads to a

strong log P reduction, although the inﬂuence of the relative

stereochemistry is again minimal. Hence, skipped diﬂuorina-

tion is much less lipophilic than geminal diﬂuorination (cf.

H8/H9). Even the skipped triﬂuoro motif in H4 leads to a

log P decrease compared to H1; however, the skipped

tetraﬂuorinated H5 has a higher log P.

observation (see Figure 1).¹⁹

Extending monoﬂuorination at the butanol 3- or 4-position

to 3,4-diﬂuorobutan-1-ol (I2/I3 to I6, Figure 4) has been

shown to lead to a log P decrease.²³In contrast, application of

such a motif extension in the 1,4-butanediol series leads to

lipophilicity increases: introducing a ﬂuorine adjacent to the

existing C−F group in C6 leads to C2/C3, which have slightly

higher lipophilicity. This contrasts with the 0.23 log P decrease

upon monoﬂuorination of C1 to C6. Introducing a ﬂuorine

next to the CF₂group in C7 to give C5 leads to a (larger) log P

increase. Introducing geminal diﬂuorination adjacent to an

existing C−F group leads to a signiﬁcant lipophilicity increase

(C6 to C5), and the same observation is made going from C7

to C4. This contrasts with a modest log P increase upon

geminal diﬂuorination of C1. Hence, for the 1,4-butanediol

parent, vicinal ﬂuorination serves to increase lipophilicities.

For the 1,5-pentanediol derivatives (Figure 5), C2-

monoﬂuorination of H1 to give H6 leads again to a log P

decrease and geminal C2-diﬂuorination (H8) leads to a log P

increase. With 1,5-pentanediol H1 being less polar than 1,4-

butanediol C1, the log P decrease upon monoﬂuorination of

H1 is larger than that of C1 (see Figure S2 for a direct

comparison). The same context dependence-derived eﬀects

apply to the geminal diﬂuorinated derivatives and also explain,

Also, in contrast to the butanediol scenario, introducing a

second ﬂuorine in the skipped position to an existing C−F

(H6 to H2/H3) or to an existing CF₂(H8 to H4) leads to a

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Figure 5. Lipophilicities of ﬂuorinated 1,5-pentanediol derivatives, in comparison to relevant ﬂuorinated 1-pentanols. Lipophilicity scales for the

compound series are normalized to their nonﬂuorinated parents.

lipophilicity decrease. The log P of H4 lies in between that of

the monoﬂuorinated H6 and diﬂuorinated H8. Introducing a

CF₂in the skipped position to an existing C−F (H6 to H4)

and to an existing CF₂group (H8 to H5) leads to a log P

increase, albeit a rather modest one.

H1). The very similar chemical shift values of the CH₂OH

hydrogens in C4 and H10 (4.05 vs 4.10, CDCl₃) suggest that

the tetraﬂuorinated moiety has a similar eﬀect on alcohol

polarizability as the hexaﬂuorinated subunit, indicating that the

larger lipophilicity increase upon inserting a diﬂuoromethylene

group is due to its larger hydrophobicity vs a methylene group.

In comparing hydrocarbon and ﬂuorocarbon containing

amphiphilic compounds, diﬀerences in critical micelle

concentration values led Hatanaka et al. to conclude that the

hydrophobicity of a CF₂group is 1.5 times that of a CH₂

group.⁶⁸However, the context dependence of lipophilicity

values does not allow us to derive similar conclusions from the

observed lipophilicity diﬀerences: with the ﬂuorinated

derivatives being more apolar, the relative inﬂuence of

hydrophobic surface should be reduced, so the log P diﬀerence

could have been expected to be even larger. In addition, there

is a further polarity eﬀect at play: in the tetraﬂuoro motif, all

dipoles potentially compensate each other, while this is not

possible for the hexaﬂuorinated motif. Hence, the latter motif

will be comparatively more polar than the tetraﬂuorinated

motif, indicating that the lipophilicity diﬀerence is even smaller

than would have been the case if just hydrophobic CH₂vs CF₂

surface diﬀerence considerations were made.

A direct comparison of the vicinal and the skipped motifs is

given in Figure 6. It is immediately apparent that for a given

motif comparison, the lipophilicities of the 1,5-pentanediol

compounds are similar to or lower than those of the

corresponding 1,4-butanediol analogues despite the extra

CH₂group. This is in stark contrast to the diﬀerence between

the nonﬂuorinated C1 and H1. So, the 1,ω-diols with the

vicinal and skipped diﬂuoride motifs have similar log P values

(cf C2/C3 with H2/H3), and for the tri- and tetraﬂuorinated

versions, the C5 chain compounds have an even lower log P (cf

C4 with H5 and C5 with H4). This can be easily qualitatively

explained by dipole arguments: in C5 and C4, there will be

abundant conformations with antiperiplanar C−F bonds, while

in the skipped motifs, the C−F bonds will polarize

antiperiplanar C−H bonds (the chemical shift of the central

methylene group in H5 is 2.67 ppm). The large diﬀerence

between the skipped tetraﬂuorinated H5 and the hexaﬂuori-

nated H10 is also worth noting.

The experimental log P values of the 1,4- and 1,5-diol

derivatives were also compared with a set of clog P values (see

the Supporting Information for full details). The correlation

values of most (fragment-based) calculation methods hovered

between 0.8 and 0.9, which is less than that we have typically

observed for the ﬂuorinated alkanol derivatives.^23,25

The data in Figure 6 are also shown on a normalized scale to

the butanediol derivatives (Figure 7), which nicely emphasizes

the relative lipophilicity diﬀerences in light of a one-carbon

chain extension: with mono- or geminal diﬂuorination, there is

a lipophilicity increase; with vicinal diﬂuorination, the log P

remains very similar; and with vicinal tri- and tetraﬂuorination,

a log P reduction is obtained.

The diﬀerence in lipophilicities between 1,4-butanediol C1

and 1,5-pentanediol H1 and that of their stable perﬂuorinated

analogues C4 and H10 (Figure 8) is worth noting.

CONCLUSIONS

■

Lipophilicities of the complete series of vicinal ﬂuorination

motifs within the 1,4-butanediol scaﬀold have been systemati-

cally compared with those of the corresponding skipped

ﬂuorination motifs within the 1,5-pentanediol scaﬀold. For

The increase in lipophilicity is much greater when inserting a

CF₂group (C4 to H10) compared to a CH₂group (C1 to

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Figure 8. Comparing apparent lipophilicity contributions of CH₂vs

CF₂groups. Lipophilicity scales for the compound series are

normalized to the butanediol derivatives.

The C₂-symmetric skipped diﬂuorinated enantiomers were

synthesized from their respective enantiopure glutamic acid

building blocks in nine steps, and the meso-skipped

diﬂuorinated pentanediol was obtained from levoglucosan in

eight steps. In both cases, symmetrization to the diol only

occurred in the ﬁnal steps, with these routes generating

monoprotected building blocks that would allow facile

introduction of these advanced ﬂuorinated substrates in target

compounds. The skipped triﬂuorinated pentanediol was

synthesized starting from protected glycidol in six steps,

while the skipped tetraﬂuorinated target was obtained in seven

steps from ethyl bromodiﬂuoroacetate.

For both the vicinal and skipped ﬂuorination motifs, log P

increased with increasing ﬂuorine number. For the vicinal

ﬂuorination, only the diﬂuorinated analogue had a lower log P

compared to the nonﬂuorinated parent, while for the skipped

ﬂuorination, the triﬂuorinated motif also had a lower log P. In

absolute values, 1,4-butanediol with vicinal diﬂuorination (syn

or anti) has the same log P as 1,5-pentanediol with skipped

diﬂuorination (syn or anti), despite the extra methylene group

in the latter (1,5-pentanediol itself has a higher log P than 1,4-

butanediol). For the corresponding triﬂuorinated and tetra-

ﬂuorinated situations, the pentanediols with the skipped motif

Figure 6. Comparison between vicinal and skipped ﬂuorination

motifs.

each of these series, a comparison with all possible

monoﬂuorinated and geminal diﬂuorinated analogues is

made, and with the perﬂuorinated analogues. This is the ﬁrst

study comparing the lipophilicities of these motifs.

Figure 7. Chain extension with concomitant vicinal to skipped motif reorganization.

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detailed peak assignment was performed through the combined use of

HSQC, HMBC, and COSY NMR experiments as required.

have even lower log P values compared to the equivalent

butanediols.

Determination of Log P. Lipophilicities of the ﬂuorinated

alkanols were determined using a previously published protocol:²⁷

to a 10 mL pear-shaped ﬂask was added the compound (1.0−10 mg)

for log P determination, the reference compound (1.0−10 mg, with

known log P value, e.g., 2,2,2-triﬂuoroethanol, log P: +0.36), water (2

mL), and n-octanol (2 mL). The resulting biphasic mixture was

stirred (at 600 rpm) for 2 h at 25 °C and then left without stirring

for 16 h at 25 °C to allow phase separation. An aliquot of 0.5 mL was

taken from each phase using 1 mL syringes with long needles and

added to two separate NMR tubes. A deuterated NMR solvent (0.1

mL, e.g., acetone-d₆) or a capillary tube containing deuterated NMR

solvent was added to the NMR tubes to enable signal locking. Because

of the volatility of the used compounds, the NMR tubes were sealed

using a blowtorch. For NMR samples with directly added deuterated

solvent, the tubes were inverted 20 times for mixing. For ¹⁹F{¹H}

NMR experiments, NMR parameters were set as follows: D1 30 s for

the octanol sample, D1 60 s for the water sample, and O1P centered

between two diagnostic ﬂuorine peaks. If needed, an increased

number of transients (NS) and/or narrower spectral window (SW)

for a good S/N ratio (typically >300) was applied. After NMR data

processing, integration ratios ρ_octand ρ_aq(ρ_octis deﬁned as the

integration ratio between the compound and the reference compound

in the octanol sample; likewise for ρ_aq) were obtained and used in the

equation log P_X= log P_ref+ log(ρ_oct/ρ_aq) to obtain the log P value of

the compound. The log P measurement of each compound was run in

triplicate. The log P values of nonﬂuorinated compounds were taken

from the literature where available.

Synthesis. Targets C4, H9, and H10 were commercially available.

(2R,4S)-5-((tert-Butyldiphenylsilyl)oxy)-2-ﬂuoropentane-1,4-diol

((2R,4S)-24). Synthesized according to a modiﬁed procedure of Liotta

et al.⁵²To a stirred solution of lactone (S)-26⁵⁴(2.00 g, 5.64 mmol)

and NFSI (1.78 g, 5.64 mmol) in dry tetrahydrofuran (THF, 25 mL)

at −78 °C, LiHMDS (1 M in THF, 6.80 mL, 6.80 mmol) was added

dropwise over 45 min. The solution was stirred at −78 °C for 2 h,

then warmed to room temperature (rt), and stirred for 14 h. The

reaction was quenched by slow addition of water (0.12 mL), stirred

for 30 min, and carefully concentrated in vacuo (bath temperature ≤

30 °C). The residue was redissolved in CH₂Cl₂(50 mL), dried over

MgSO₄, and concentrated in vacuo to aﬀord crude (2R,4S)-25. This

was redissolved in a mixture of dry CH₂Cl₂(3.4 mL) and EtOH (2.3

mL), to which NaBH₄(0.533 g, 14.1 mmol) was added portionwise at

0 °C. The solution was stirred at rt for 16 h, then cooled to 0 °C, and

quenched by cautious addition of sat. aq. NH₄Cl (10 mL). The

mixture was stirred vigorously for 30 min at rt. The phases were

separated, and the aqueous phase was extracted with CH₂Cl₂(3 × 10

mL). The combined organic layers were dried over MgSO₄and

concentrated in vacuo. The crude product was puriﬁed by ﬂash

column chromatography (hexane/EtOAc 40:60) to aﬀord the title

compound (2R,4S)-24 as a colorless crystalline solid (1.06 g, 50%

over two steps). R_f0.24 (hexane/EtOAc 40:60); mp 78−79 °C

(CH₂Cl₂); [α]¹_D⁹−1.3 (c 1.0, CHCl₃); IR 3362 (br w), 3071 (w),

2930 (m), 2858 (m), 1427 (m), 1111 (s) cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 7.69−7.66 (4H, m, H_Ph), 7.49−7.39 (6H, m, H_Ph), 4.77

(1H, dqd, J = 47.9, 5.7, 3.7 Hz, H₂), 4.01−3.95 (1H, m, H₄), 3.85−

3.72 (2H, m, H₁), 3.69 (1H, dd, J = 10.3, 3.6 Hz, H₅), 3.59 (1H, dd, J

= 10.3, 7.2 Hz, H_5′), 2.80 (1H, d, J = 2.5 Hz, OH₄), 2.49 (1H, t, J =

5.1 Hz, OH₁), 1.90−1.80 (2H, m, H₃), 1.10 (9H, s, H_tBu) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 135.5 (C_Ph), 132.9 (C_Ph), 129.9

Starting from both the monoﬂuorinated and geminal

diﬂuorinated 1,4-diols, a small log P increase is observed

when introducing monoﬂuorination at the adjacent carbons,

which is much larger when introducing geminal diﬂuorination

at these carbons. In contrast, starting from both the

monoﬂuorinated and geminal diﬂuorinated 1,5-diols, introduc-

ing monoﬂuorination at the skipped carbon leads to a log P

decrease, which only becomes a small increase when geminal

diﬂuorination is introduced there.

Hence, all of these observations illustrate the greater

lipophilicity-reducing power of the skipped motif and

emphasize the lipophilicity-increasing power of perﬂuoroalky-

lidene moieties.

As an aside, the log P diﬀerence between the nonﬂuorinated

1,4-butanediol and 1,5-pentanediol parents was compared with

the lipophilicity diﬀerence between their stable perﬂuorinated

congeners. This diﬀerence is smaller for the nonﬂuorinated

diols (0.38 vs 0.58 log P units) and shows the larger

hydrophobicity of a CF₂group compared to a CH₂group.

The synthetic work toward the skipped building blocks will

be of general interest for applications in organic and medicinal

chemistry. The insights regarding lipophilicity of the vicinal

and skipped motifs will ﬁnd application in medicinal chemistry,

in particular, in drug development involving compounds with

hydrocarbon/lipid chain appendages (e.g., many steroids,

prostaglandins, etc), as well as taking into account possible

metabolic stability issues.⁶⁹⁻⁷¹Finally, the lipophilicity datasets

will ﬁnd application in the development of computational

approaches toward lipophilicity estimations.

EXPERIMENTAL SECTION

■

General Conditions. All air-/moisture-sensitive reactions were

carried out under an atmosphere of argon in glassware heated under

high vacuum. Where required, reactions were heated using a heating

block (DrySyn). All reagents and solvents were bought from

commercial sources and used as supplied unless otherwise stated.

Flash column chromatography was performed on silica gel (MERCK

Geduran 60 Å; particle size, 40−63 μm) under pressure unless

otherwise stated. All reported solvent mixtures are volume measures.

Reactions were monitored by TLC (MERCK Kieselgel 60 F254,

aluminum sheet), visualized under UV light (254 nm), and/or by

staining with KMnO₄(10% aq.). Fourier transform infrared (IR)

spectra are reported in wavenumbers (cm⁻¹) and were recorded as

neat ﬁlms on a Thermo Scientiﬁc Nicolet iS5 spectrometer using neat

samples (solid or liquid) unless otherwise stated. Electrospray mass

spectra were obtained from a Waters Acquity TQD mass tandem

quadrupole mass spectrometer and recorded in m/z (abundance).

HRMS was obtained from a Bruker Daltonics MaXis time-of-ﬂight

(TOF) mass spectrometer (ESI), a Bruker Daltonics solariX FT-ICR

mass spectrometer equipped with a 4.7T superconducting magnet

(27, 43, 44, 45, 46, H3), a Thermo MAT900 XP double-focusing

sector mass spectrometer (CI), or a LECO Pegasus HRT+ TOF mass

spectrometer (EI). Samples were run in HPLC MeOH or MeCN.

Optical rotations were recorded on an Optical Activity POLAAR

2001 at 589 nm. Melting points were obtained in an open capillary

and are uncorrected.¹H, ¹³C, and ¹⁹F NMR spectra were recorded in

CDCl₃or MeOD using a Bruker Ultrashield 400 or 500 MHz

spectrometer. ¹H and ¹³C chemical shifts (δ) are quoted in ppm

relative to residual solvent peaks as appropriate. ¹⁹F spectra were

externally referenced to CFCl₃. The coupling constants (J) are given

in hertz (Hz). The coupling constants have not been averaged. The

NMR signals were designated as follows: s (singlet), d (doublet), t

(triplet), q (quartet), quin (quintet), sxt (sextet), spt (septet), m

(multiplet), or a combination of the above. For all novel compounds,

(C_Ph), 127.8 (C_Ph), 91.8 (d, J_C‑F= 168.7 Hz, C₂), 68.3 (d, J_C‑F= 5.1

Hz, C₄), 67.5 (C₅), 64.2 (d, J_C‑F= 22.7 Hz, C₁), 34.1 (d, J_C‑F= 20.5

Hz, C₃), 26.8 (C_tBu,Me), 19.2 (C_tBu,quat)ppm; ¹⁹F NMR (376 MHz,

CDCl₃) δ −189.7 (dquin, J = 48.9, 22.5, F₂) ppm; ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ −189.5 (s, F₂) ppm; HRMS (ESI) m/z: [M +

Na]⁺calcd for C₂₁H₂₉FNaO₃Si 399.1762; found 399.1767.

The synthesis was repeated from (R)-26 (25.0 g, 70.5 mmol) to

give (2S,4R)-24 (9.54 g, 36% over two steps). Spectroscopic data

were identical except [α]¹_D⁹+2.1 (c 1.0, CHCl₃).

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1,6-Di-O-acetyl-2,3,4-trideoxy-2,4-ﬂuoro-ß-D-glucopyranose

(27). Synthesized with a procedure of Zottola et al.⁷²To a solution of

44 (431 mg, 2.87 mmol, 1.0) in Ac₂O (70 mL) at 0 °C was added

TMSOTf (0.104 mL, 0.570 mmol) dropwise. The resulting mixture

was stirred at 0 °C for 30 min before being diluted with CH₂Cl₂(20

mL) and quenched with sat. aq. NaHCO₃(15 mL). The aqueous

layer was extracted with CH₂Cl₂(3 × 20 mL), and the combined

organic layers dried over anhydrous MgSO₄and concentrated in

vacuo. The crude product was puriﬁed by ﬂash column chromatog-

raphy (hexane/acetone 90:10 to 80:20) to aﬀord the title compound

27 as a light brown solid (682 mg, 2.70 mmol, 94%). R_f0.23 (hexane/

acetone 80:20); IR 1760 (m), 1739 (s), 1245 (s), 1226 (s), 1124 (m),

1095 (m), 1052 (s), 1000 (s) cm⁻¹; ¹H NMR (500 MHz, CDCl₃, α:β

2.20:1.00) δ 6.27 (1H, t, J = 3.8 Hz, H_1α), 5.74 (1H, dd, J = 7.4, 3.6

Hz, H_1β), 4.66 (1H, ddddd, J = 46.6, 12.0, 5.2, 3.7, 1.5 Hz, H_2α), 4.53

(1H, ddd, J = 48.4, 10.3, 5.1 Hz, H_4β), 4.51 (1H, dddd, J = 48.4, 10.0,

5.2, 1.4 Hz, H_4α), 4.45 (1H, ddddd, J = 48.8, 10.7, 7.3, 5.3, 1.1 Hz,

H_2β), 4.35 (1H, ddd, J = 12.2, 2.9, 1.5 Hz, H_6β), 4.33 (1H, dt, J = 12.0,

2.5 Hz, H_6α), 4.23 (1H, ddd, J = 12.4, 4.9, 1.5 Hz, H_6′α), 4.21 (1H,

ddd, J = 12.3, 5.5, 1.6 Hz, H_6′β), 3.95 (1H, dtt, J = 7.2, 4.6, 2.4 Hz,

H_5α), 3.87 (1H, dddd, J = 8.7, 5.6, 4.5, 3.0 Hz, H_5β), 2.77 (1H, dtt, J =

12.7, 7.8, 5.2 Hz, H_3eqβ), 2.65 (1H, dquin, J = 10.6, 5.2 Hz, H_3eqα),

2.22 (1H, dqd, J = 23.0, 11.4, 9.4 Hz, H_3axα), 2.19 (3H, s, H_Acα), 2.16

(3H, s, H_Acβ), 2.09 (3H, s, H_Acβ), 2.09 (3H, s, H_Acα), 2.06 (1H, dtdd, J

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −188.8 (s, F₄) ppm; HRMS

(EI) m/z: [M^•]⁺calcd for C₁₂H₁₅FO₂210.1051; found 210.1052.

5-((tert-Butyldiphenylsilyl)oxy)-4,4-diﬂuoropentanal (33). To a

solution of ester 50 (4.80 g, 11.4 mmol) in CH₂Cl₂(91 mL) at −78

°C was added DIBAL (1 M in CH₂Cl₂, 13.7 mL, 13.7 mmol) slowly

over 15 min, keeping the internal temperature below −60 °C. The

reaction was stirred for 3 h, then quenched by slow addition of aq.

Rochelle’s salt (90 mL), allowed to warm to rt, and stirred for a

further 1 h. The phases were separated, and the aqueous layer was

extracted with CH₂Cl₂(3 × 100 mL). The combined organic layers

were dried over MgSO₄and concentrated in vacuo to aﬀord the title

compound 33 as a clear colorless oil (4.36 g, quant.). R_f0.50 (hexane/

EtOAc 70:30); IR 2932 (m), 2858 (m), 1726 (m), 1428 (m), 1106

(s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.83 (1H, s, H₁), 7.69−7.65

(4H, m, H_Ph), 7.49−7.39 (6H, m, H_Ph), 3.77 (2H, t, J = 12.0 Hz, H₅),

2.69 (2H, t, J = 7.5 Hz, H₂), 2.35 (2H, tt, J = 17.5, 7.6 Hz, H₃), 1.09

(9H, s, H_tBu) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 200.1 (C₁),

135.6 (C_Ph), 132.4 (C_Ph), 130.0 (C_Ph), 127.8 (C_Ph), 122.6 (t, J_C‑F

=

242.8 Hz, C₄), 65.1 (t, J_C‑F= 34.8 Hz, C₅), 36.3 (t, J_C‑F= 3.7 Hz, C₂),

26.7 (C_tBu,Me), 26.0 (t, J_C‑F= 24.9 Hz, C₃), 19.2 (C_tBu,quat) ppm; ¹⁹F

NMR (376 MHz, CDCl₃) δ −108.0 (tt, J = 17.3, 12.1 Hz, F₄) ppm;

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −108.0 (s, F₄) ppm; HRMS

(ESI) m/z: [M + Na]⁺calcd for C₂₁H₂₆F₂NaO₂Si 399.1562; found

399.1572.

1

= 22.9, 12.4, 10.5, 10.4 Hz, H_3axβ) ppm; H{¹⁹F} NMR (500 MHz,

(2R,4S)-5-((tert-Butyldiphenylsilyl)oxy)-2-ﬂuoro-4-hydroxypen-

tanamide (38). Synthesized according to the procedure of Liotta et

al.⁵²To a stirred solution of lactone (S)-26⁵⁴(200 mg, 0.564 mmol)

and NFSI (178 mg, 0.564 mmol) in THF (2.5 mL) at −78 °C,

LiHMDS (1 M in THF, 0.68 mL, 0.68 mmol) was added dropwise

over 1 h. The solution was stirred at −78 °C for 2 h, then warmed to

rt, and stirred for 1 h. The reaction was quenched by cautious

addition of sat. aq. NH₄Cl (0.1 mL), then diluted with Et₂O (7.5

mL), and washed sequentially with sat. aq. NaHCO₃(2 × 7.5 mL)

and sat. brine (7.5 mL), dried over MgSO₄, and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromatography

(hexane/EtOAc 90:10 to 0:100) to obtain (2R,4S)-25 (22 mg, 10%)

as a white solid and the title compound 38 as a yellow oil (33 mg,

15%). R_f0.24 (hexane/EtOAc 40:60); IR 3323 (br m), 3071 (w),

CDCl₃) δ 6.27 (1H, d, J = 3.6 Hz, H_1α), 5.74 (1H, d, J = 7.4 Hz, H_1β),

4.67 (1H, ddd, J = 12.0, 5.1, 3.7 Hz, H_2α), 4.55−4.49 (2H, m, H_4α+4β),

4.45 (1H, ddd, J = 10.7, 7.3, 5.3 Hz, H_2β), 4.35 (1H, dd, J = 12.2, 2.9

Hz, H_6β), 4.33 (1H, dd, J = 12.0, 2.5 Hz, H_6α), 4.23 (1H, dd, J = 12.3,

4.9 Hz, H_6′α), 4.21 (1H, dd, J = 12.3, 5.5 Hz, H_6′β), 3.95 (1H, ddd, J =

9.7, 4.9, 2.4 Hz, H_5α), 3.87 (1H, ddd, J = 8.7, 5.6, 2.9 Hz, H_5β), 2.77

(1H, dt, J = 12.3, 5.2 Hz, H_3eqβ), 2.64 (1H, dt, J = 11.2, 5.1 Hz,

H_3eqα), 2.24 (1H, q, J = 11.4 Hz, H_3axα), 2.19 (3H, s, H_Acα), 2.16 (3H,

s, H_Acβ), 2.09 (3H, s, H_Acβ), 2.09 (3H, s, H_Acα), 2.05 (1H, ddd, J =

12.3, 10.5, 10.4 Hz, H_3axβ) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃),

δ 170.56 (C_COα), 170.55 (C_COβ), 168.94 (C_COβ), 168.86

(C_COα), 92.7 (dd, J_C‑F= 26.1, 0.8 Hz, C_1β), 87.4 (dd, J_C‑F= 22.9,

1.27 Hz, C_1α), 84.9 (dd, J_C‑F= 185.5, 10.5 Hz, C_2β), 83.6 (dd, J_C‑F

=

1

2930 (m), 2857 (m), 1679 (s), 1427 (m), 1105 (s) cm⁻¹; H NMR

189.5, 12.2 Hz, C_2α), 83.4 (dd, J_C‑F= 182.4, 10.0 Hz, C_4β), 83.3 (dd,

J_C‑F= 182.1, 11.7 Hz, C_4α), 75.3 (dd, J_C‑F= 25.0, 0.9 Hz, C_5β), 69.8

(dd, J_C‑F= 24.4, 0.8 Hz, C_5α), 62.1 (d, J_C‑F= 1.0 Hz, C_6β), 61.9 (C_6α),

33.8 (t, J_C‑F= 20.5 Hz, C_3β), 30.9 (t, J_C‑F= 20.4 Hz, C_3α), 20.9

(400 MHz, CDCl₃) δ 7.68−7.65 (4H, m, H_Ph), 7.47−7.38 (6H, m,

H_Ph), 6.34 (1H, br s, NH₂), 6.09 (1H, br s, NH₂), 5.06 (1H, dt, J =

49.2, 6.2 Hz, H₂), 4.07−4.00 (1H, m, H₄), 3.69 (1H, dd, J = 10.3, 4.0

Hz, H₅), 3.60 (1H, dd, J = 10.3, 7.0 Hz, H₅), 2.82 (1H, d, J = 4.8 Hz,

OH), 2.14 (2H, dt, J = 24.5, 6.2 Hz, H₃), 1.08 (9H, s, H_tBu) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.9 (d, J_C‑F= 20.5 Hz, C₁),

135.5 (C_Ph), 132.94 (C_Ph), 132.91 (C_Ph), 129.9 (C_Ph), 127.8 (C_Ph),

89.2 (d, J_C‑F= 191.5 Hz, C₂), 68.4 (d, J_C‑F= 4.4 Hz, C₄), 67.3 (C₅),

35.5 (d, J_C‑F= 20.5 Hz, C₃), 26.8 (C_tBu,Me), 19.2 (C_tBu,quat) ppm; ¹⁹F

NMR (376 MHz, CDCl₃) δ −186.4 (1F, dtd, J = 49.2, 24.5, 3.5 Hz,

F₂) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −186.3 (1F, s, F₂)

ppm; HRMS (ESI) m/z: [M + Na]⁺calcd for C₂₁H₂₈FNNaO₃Si

412.1715; found 412.1716.

(C_CH3‑Ac;β), 20.8 (C_CH3‑Ac;α), 20.69 (C_CH3‑Ac;β), 20.68 (C_CH3‑Ac;α

)

ppm; ¹⁹F NMR (471 MHz, CDCl₃) δ −188.5 to −188.6 (m, d_obs, J =

48.3 Hz, F_4α), −189.9 to −190.0 (m, d_obs, J = 48.3 Hz, F_4β), −191.0 to

−191.2 (m, d_obs, J = 48.6 Hz, F_2β), −192.4 (ddddd, J = 46.5, 9.3, 4.7,

3.6, 1.4 Hz, F_2α) ppm; ¹⁹F{¹H} NMR (471 MHz, CDCl₃) δ −188.6

(d, J = 3.6 Hz, F_4α), −189.9 (d, J = 5.0 Hz, F_4β), −191.1 (d, J = 5.4

Hz, F_2β), −192.4 (d, J = 3.6 Hz, F_2α) ppm; HRMS (ESI) m/z: [M +

Na]⁺calcd for C₁₀H₁₄F₂NaO₅275.0702; found 275.0702.

5-(Benzyloxy)-4-ﬂuoropentanal (30). To a solution of 47 (538

mg, 2.58 mmol) in a mixture of MeCN (22.1 mL) and water (3.7

mL) at rt was added a solution of RuCl₃in water (2.58 mL, 0.035 M,

0.090 mmol). NaIO₄(1.11 g, 5.17 mmol) was added portionwise over

5 min. The mixture was stirred for 24 h and quenched by slow

addition of sat. aq. Na₂S₂O₃(25 mL). The aqueous phase was

extracted with EtOAc (3 × 50 mL), washed with sat. brine (25 mL),

dried over MgSO₄, and concentrated in vacuo. The crude product was

puriﬁed by ﬂash column chromatography (hexane/EtOAc 70:30) to

aﬀord the title compound 30 as a colorless oil (212 mg, 39%). R_f0.32

(hexane/EtOAc 70:30); IR 3657 (w), 2980 (s), 2889 (m), 1722 (s),

1382 (m), 1092 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 9.81 (1H,

q, J = 1.0 Hz, H₁), 7.39−7.29 (5H, m, H_Ph), 4.79−4.61 (1H, m, H₄),

4.59 (2H, s, H₆), 3.61 (2H, dd, J = 22.7, 4.5 Hz, H₅), 2.72−2.57 (2H,

m, H₂), 2.06−1.94 (2H, m, H₃) ppm; ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 201.1 (C₁), 137.7 (C_Ph), 128.5 (C_Ph), 127.8 (C_Ph), 127.7

(C_Ph), 91.8 (d, J_C‑F= 171.7 Hz, C₄), 73.5 (C_Bn), 71.5 (d, J_C‑F= 22.0

Hz, C₅), 39.2 (d, J_C‑F= 3.7 Hz, C₂), 24.1 (d, J_C‑F= 21.3 Hz, C₃) ppm;

¹⁹F NMR (376 MHz, CDCl₃) δ −188.5 to −188.9 (m, F₄) ppm;

(2R, 4S)-5-((tert-Butyldiphenylsilyl)oxy)-2-ﬂuoro-4-hydroxypen-

tyl Benzoate ((2R,4S)-39). To a solution of (2R,4S)-24 (0.900 g,

2.39 mmol) and Et₃N (0.67 mL, 4.8 mmol) in CH₂Cl₂(12.0 mL) at 0

°C was added benzoyl chloride (0.28 mL, 2.4 mmol) dropwise over 5

min. The mixture was warmed to rt, stirred for 16 h, and then diluted

with CH₂Cl₂(40 mL). The organic layer was washed with water (25

mL), dried over MgSO₄, and concentrated in vacuo. The crude

product was puriﬁed by ﬂash column chromatography (hexane/

EtOAc 90:10 to 70:30) to aﬀord the title compound ((2R,4S)-39) as

a yellow oil (0.768 g, 67%). R_f0.29 (hexane/EtOAc 70:30); [α]_D¹⁹

−11.6 (c 0.5, CHCl₃); IR 3656 (w), 2980 (s), 2889 (m), 1720 (m),

1

1270 (s), 1111 (s) cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.09−8.06

(2H, m, H_Ph), 7.69−7.66 (4H, m, H_Ph), 7.59 (1H, tt, J = 6.9, 1.3 Hz,

H_Ph), 7.48−7.38 (8H, m, H_Ph), 5.10−4.92 (1H, m, d_obs, J = 48.3 Hz,

H₂), 4.58−4.42 (2H, m, H₁), 4.02−3.95 (1H, m, H₄), 3.72 (1H, dd, J

= 10.3, 3.9 Hz, H₅), 3.63 (1H, dd, J = 10.3, 7.1 Hz, H_5′), 2.59 (1H, d,

J = 3.6 Hz, OH), 2.06−1.83 (2H, m, H₃), 1.09 (9H, s, H_tBu) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.2 (C_CO), 135.5 (C_Ph),

1893

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Article

133.2 (C_Ph), 132.91 (C_Ph), 132.89 (C_Ph), 129.9 (C_Ph), 129.72 (C_Ph),

129.69 (C_Ph), 128.4 (C_Ph), 127.8 (C_Ph), 89.3 (d, J_C‑F= 171.7 Hz, C₂),

68.6 (d, J_C‑F= 5.1 Hz, C₄), 67.4 (C₅), 65.9 (d, J_C‑F= 22.0 Hz, C₁),

34.5 (d, J_C‑F= 20.5 Hz, C₃), 26.8 (C_tBu,Me), 19.2 (C_tBu,quat) ppm; ¹⁹F

NMR (376 MHz, CDCl₃) δ −186.6 (dqd, J = 49.0, 24.4, 18.2 Hz, F₂)

ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −186.4 (s, F₂) ppm;

HRMS (ESI) m/z: [M + Na]⁺calcd for C₂₈H₃₃FNaO₄Si 503.2024;

found 503.2029.

66.0 (d, J_C‑F= 22.0 Hz, C₁), 64.7 (d, J_C‑F= 21.3 Hz, C₅), 33.2 (t, J_C‑F

= 20.9 Hz, C₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −189.8 to

−190.2 (m, F₂), −192.7 to −193.1 (m, F₄) ppm; ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −189.9 (s, F₂), −192.8 (s, F₄) ppm; HRMS (ESI)

m/z: [M + Na]⁺calcd for C₁₂H₁₄F₂NaO₃267.0803; found 267.0796.

The synthesis was repeated from (2S,4S)-40 (7.18 g) to give

(2S,4S)-41 (2.71 g, 61% over two steps). Spectroscopic data were

identical except [α]²_D⁰−10.0 (c 1.0, CHCl₃).

The synthesis was repeated from (2S,4R)-24 (9.53 g, 25.3 mmol)

to give (2S,4R)-39 (9.14 g, 75%). Spectroscopic data were identical

except [α]¹_D⁹+10.2 (c 1.0, CHCl₃).

1,6-Anhydro-2,4-dideoxy-2,4-diﬂuoro-3-O-phenylthionoformyl-

β-^D-glucopyranoside (43). To a solution of 28^56,57(1.92 g, 11.6

mmol) in CH₂Cl₂(54 mL) was added pyridine (1.87 mL, 23.1

mmol). The mixture was cooled to 0 °C and O-phenyl

chorothionoformate (1.92 mL, 13.9 mmol) was added dropwise.

The solution was stirred at rt for 24 h. The reaction mixture was

diluted with CH₂Cl₂(50 mL) and quenched with sat. aq. NaHCO₃

(100 mL). The aqueous layer was extracted with CH₂Cl₂(3 × 100

mL), and the combined organic layers were dried over MgSO₄and

concentrated in vacuo. The crude product was puriﬁed by ﬂash

column chromatography (hexane/EtOAc 90:10 to 80:20) to aﬀord

the title compound 43 as an oﬀ-white solid (3.33 g, 95%). R_f0.26

(petroleum ether/EtOAc 90:10); [α]³_D⁰−54.5 (c 1.0, CHCl₃); mp

104−108 °C (not recrystallized); IR 2973 (br w), 2906 (w), 1274 (s),

(2R,4R)-5-((tert-Butyldiphenylsilyl)oxy)-2,4-diﬂuoropentyl Ben-

zoate ((2R,4R)-40). To a stirred solution of (2R,4S)-39 (584 mg,

1.22 mmol) in dry CH₂Cl₂(12.2 mL) at 0 °C was added DAST (0.32

mL, 2.44 mmol) dropwise. The solution was stirred at 0 °C for 1 h

and then quenched by cautious addition of sat. aq. NaHCO₃(36 mL).

The layers were separated, and the aqueous layer was extracted with

EtOAc (3 × 60 mL). The combined organic layers were washed with

sat. brine (36 mL), dried over MgSO₄, and concentrated in vacuo.

The crude product was puriﬁed by ﬂash column chromatography

(hexane/EtOAc 100:0 to 70:30) to aﬀord the title compound

(2R,4R)-40 as a yellow oil (430 mg) containing an unknown

impurity, which was taken forward in the next step. An aliquot was

further puriﬁed by ﬂash column chromatography (Biotage Isolera

One, ZIP KP-SIL 5 g Column, hexane/acetone 100:0 to 70:30) for

analysis. R_f0.49 (hexane/EtOAc 70:30); [α]²_D⁶+9.9 (c 1.2, CHCl₃,

puriﬁed sample); IR 3071 (w), 2932 (w), 2858 (w), 1723 (s), 1269

1

1207 (s), 1057 (s) cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.48−7.43

(2H, m, H_meta), 7.34 (1H, tt, J = 7.5, 1.1 Hz, H_para), 7.15−7.11 (2H,

m, H_ortho), 5.68−5.66 (1H, m, H₁), 5.63 (1H, tquin, J = 16.0, 1.5 Hz,

H₃), 4.87−4.84 (1H, m, H₅), 4.65−4.56 (1H, m, d_obs, J = 43.7 Hz,

H₄), 4.50 (1H, dq, J = 44.3, 1.1 Hz, H₂), 4.01 (1H, dt, J = 8.1, 1.1 Hz,

1

(s), 1111 (s) cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.11−8.08 (2H,

1

H_6endo), 3.89−3.85 (1H, m, H_6exo) ppm; H{¹⁹F} NMR (500 MHz,

m, H_Ph), 7.71−7.67 (4H, m, H_Ph), 7.60 (1H, tt, J = 7.5, 1.3 Hz, H_Ph),

7.49−7.38 (10H, m, H_Ph), 5.11 (1H, dddt, J = 49.3, 9.1, 6.0, 2.9 Hz,

H₂), 4.94−4.77 (1H, m, d_obs, J = 48.7 Hz, H₄), 4.56 (1H, ddd, J =

24.0, 12.0, 2.9 Hz, H₁), 4.47 (1H, ddd, J = 23.7, 12.6, 5.5 Hz, H_1′),

3.88 (1H, ddd, J = 19.7, 11.6, 3.7 Hz, H₅), 3.78 (1H, ddd, J = 25.1,

11.6, 4.3 Hz, H_5′), 2.22−1.96 (2H, m, H₃), 1.08 (9H, s, H_tBu) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 166.1 (C_CO), 135.6 (C_Ph),

135.5 (C_Ph), 133.3 (C_Ph), 133.03 (C_Ph), 132.96 (C_Ph), 129.8 (C_Ph),

CDCl₃) δ 7.48−7.43 (2H, m, H_meta), 7.34 (1H, tt, J = 7.5, 1.1 Hz,

H_para), 7.14−7.11 (2H, m, H_ortho), 5.67 (1H, br t, J = 1.4 Hz, H₁), 5.63

(1H, quin, J = 1.5 Hz, H₃), 4.85 (1H, dq, J = 6.0, 1.7 Hz, H₅), 4.61−

4.61 (1H, m, H₄), 4.51−4.50 (1H, m, H₂), 4.01 (1H, dd, J = 8.1, 1.1

Hz, H_6endo), 3.87 (1H, dd, J = 8.1, 5.9 Hz, H_6exo) ppm; ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 193.1 (C_C=S), 153.3 (C_ipso), 129.8 (C_meta), 127.0

(C_para), 121.6 (C_ortho), 98.4 (d, J_C‑F= 27.9 Hz, C₁), 86.1 (dd, J_C‑F

183.4, 2.9 Hz, C₄), 83.9 (dd, J_C‑F= 185.2, 1.8 Hz, C₂), 76.6 (dd, J_C‑F

=

35.8, 34.1 Hz, C₃), 73.5 (d, J_C‑F= 21.3 Hz, C₅), 63.9 (d, J_C‑F= 8.8 Hz,

C₆) ppm; ¹⁹F NMR (471 MHz, CDCl₃) δ −184.2 (ddddd, J = 44.3,

16.1, 10.4, 5.0, 1.4 Hz, F₄), −189.8 (dddd, J = 44.4, 16.1, 2.1, 1.1 Hz,

F₂) ppm; ¹⁹F{¹H} NMR (471 MHz, CDCl₃) δ −184.2 (s, F₄), −189.8

(s, F₂) ppm; HRMS (ESI) m/z: [M + Na]⁺calcd for C₁₃H₁₂F₂NaO₄S

325.0317; found 325.0316.

129.7 (C_Ph), 129.6 (C_Ph), 128.4 (C_Ph), 127.8 (C_Ph), 89.6 (dd, J_C‑F

173.1, 3.7 Hz, C₄), 87.7 (dd, J_C‑F= 173.1, 3.7 Hz, C₂), 66.1 (d, J_C‑F

=

22.0 Hz, C₁), 65.6 (d, J_C‑F= 23.5 Hz, C₅), 33.7 (t, J_C‑F= 20.9 Hz, C₃),

26.7 (C_tBu,Me), 19.3 (C_tBu,quat) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ

−189.9 to −190.2 (m, F₂), −190.7 to −191.1 (m, F₄) ppm; ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −190.1 (s, F₂), −190.9 (s, F₄) ppm;

HRMS (ESI) m/z: [M + Na]⁺calcd for C₂₈H₃₂F₂NaO₃Si 505.1981;

found 505.1992.

The synthesis was repeated from (2S,4R)-39 (9.13 g, 19.0 mmol)

to give (2S,4S)-40 (7.32 g) containing an unknown impurity, which

was taken forward in the next step. Spectroscopic data were identical

except [α]²_D⁷−10.4 (c 0.5, CHCl₃, puriﬁed sample).

1,6-Anhydro-2,3,4-trideoxy-2,4-diﬂuoro-β-^D-glucopyranose (44).

Synthesized with a procedure of Kirwan et al.⁶⁵To a solution of 43

(3.18 g, 10.5 mmol) in triethylsilane (79.0 mL, 494 mmol) was added

benzoyl peroxide (509 mg, 2.10 mmol). The resulting mixture was

heated to 120 °C for 1 h. The reaction was cooled to rt, a further

aliquot of benzoyl peroxide (509 mg, 2.10 mmol) was added, and the

reaction was reheated to 120 °C for 1 h. This was repeated a further

three times (ﬁve additions in total). The mixture was concentrated in

vacuo and diluted with sat. aq. NaHCO₃(75 mL) and CH₂Cl₂(150

mL). The organic layer was washed with sat. aq. NaHCO₃(3 × 50

mL), dried over MgSO₄, and concentrated in vacuo. The crude

product was puriﬁed by ﬂash column chromatography (hexane/Et₂O

90:10 to 60:40) to aﬀord the title compound 44 as a white powder

with a 5% impurity of benzoic acid by mass (1.32 g, 8.35 mmol, 80%

calculated for the pure compound). An aliquot was dissolved in

CH₂Cl₂, washed three times with sat. NaHCO₃, dried over MgSO₄,

and concentrated in vacuo for analysis. R_f0.55 (Et₂O/hexane 70:30);

[α]²_D⁷−75.6 (c 0.69, CHCl₃); mp 105−109 °C (not recrystallized);

IR 2985 (w), 2910 (w), 2371 (w), 2353 (w), 1145 (m), 1064 (s)

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.56 (1H, br s, H₁), 4.76 (1H,

ddt, J = 7.8, 5.6, 2.7 Hz, H₅), 4.58−4.32 (2H, m, H₂₊₄), 3.85 (1H, dtd,

J = 7.9, 5.3, 2.6 Hz, H_6exo), 3.75 (1H, dt, J = 8.1, 1.2 Hz, H_6endo),

2.34−2.01 (2H, m, H_3eq+3ax) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃)

δ 99.1 (d, J_C‑F= 25.7 Hz, C₁), 84.9 (dd, J_C‑F= 181.9, 1.5 Hz, C₄), 83.3

(dd, J_C‑F= 181.2, 1.5 Hz, C₂), 74.5 (d, J_C‑F= 19.8 Hz, C₅), 64.1 (d,

J_C‑F= 7.3 Hz, C₆), 27.6 (t, J_C‑F= 22.4 Hz, C₃) ppm; ¹⁹F NMR (376

MHz, CDCl₃) δ −180.6 to −181.0 (m, F₄), −186.0 to −186.3 (m, F₂)

ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −180.7 (d, J = 5.2 Hz, F₄),

(2R,4R)-2,4-Diﬂuoro-5-hydroxypentyl Benzoate ((2R,4R)-41). To

a stirred solution of (2R,4R)-40 (500 mg) in dry THF (10 mL) at 0

°C was added TBAF (1 M in THF, 1.25 mL, 1.25 mmol) dropwise.

The mixture was stirred at rt for 2 h before sat. aq. NH₄Cl (10 mL)

was added, and the mixture was stirred vigorously for 30 min. The

layers were separated, and the aqueous layer was extracted with

EtOAc (3 × 10 mL). The combined organic layers were washed with

sat. brine (10 mL), dried over MgSO₄, and concentrated in vacuo.

The crude product was puriﬁed by ﬂash column chromatography

(hexane/EtOAc 90:10 to 60:40) to aﬀord the title compound

(2R,4R)-41 as a yellow solid (195 mg, 56% over two steps). R_f0.14

(hexane/EtOAc 70:30); [α]²_D⁶+11.1 (c 1.0, CHCl₃); mp 51−53 °C

(CH₂Cl₂); IR 3328 (br m), 2971 (m), 1727 (m), 1710 (s), 1284 (s)

1

cm⁻¹cm⁻¹; H NMR (400 MHz, CDCl₃) δ 8.07 (2H, d, J = 7.1 Hz,

H_Ph), 7.59 (1H, t, J = 7.5 Hz, H_Ph), 7.46 (2H, t, J = 8.2 Hz, H_Ph), 5.07

(1H, dddt, J = 48.9, 9.9, 5.6, 2.8 Hz, H₂), 4.87 (1H, dddt, J = 49.3, 9.9,

5.6, 2.9 Hz, H₄), 4.54 (1H, ddd, J = 24.1, 12.8, 2.9 Hz, H₁), 4.44 (1H,

ddd, J = 23.8, 12.6, 5.9 Hz, H_1′), 3.87 (1H, ddd, J = 24.3, 12.5, 2.3 Hz,

H₅), 3.71 (1H, ddd, J = 25.1, 12.1, 5.9 Hz, H_5′), 2.26 (1H, br s, OH),

2.18−1.90 (2H, m, H₃) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

166.2 (C_CO), 133.3 (C_Ph), 129.7 (C_Ph), 129.5 (C_Ph), 128.4 (C_Ph),

90.2 (dd, J_C‑F= 169.8, 2.6 Hz, C₄), 87.6 (dd, J_C‑F= 173.5, 3.3 Hz, C₂),

1894

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J. Org. Chem. 2021, 86, 1882−1900

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Article

−186.0 (d, J = 3.5 Hz, F₂) ppm; HRMS (ESI) m/z: [M + Na]⁺calcd

for C₆H₈F₂NaO₂173.0385; found 173.0390.

mL) was added, and the solution was stirred vigorously for 30 min.

The phases were separated, and the aqueous phase was extracted with

Et₂O (3 × 10 mL). The combined organics were washed with sat.

brine (10 mL), dried over MgSO₄, and concentrated in vacuo. The

crude product was puriﬁed by ﬂash column chromatography (hexane/

EtOAc 100:0 to 90:10) to aﬀord the title compound 47 as a colorless

oil (145 mg, 70%). R_f0.59 (hexane/EtOAc 80:20); IR 3656 (w),

(2R,3S,5R)-3,5-Diﬂuorohexane-1,2,6-triol (45). To a solution of

27 (495 mg, 1.96 mmol) in MeOH (4.0 mL) and water (40 mL) at 0

°C was added NaBH₄(742 mg, 19.6 mmol) portionwise. The

solution was stirred at rt for 3 h before being cooled to 0 °C for

addition of a further portion of NaBH₄(742 mg, 19.6 mmol). The

resulting mixture was stirred at rt for 18 h. The reaction was quenched

with aq. 1 M HCl (40 mL), and the resulting mixture was stirred for 1

h before being concentrated in vacuo. The residue was redissolved in

CH₂Cl₂/acetone, ﬁltered, and concentrated in vacuo. The crude

product was puriﬁed by ﬂash column chromatography (CH₂Cl₂/

MeOH 95:5 to 80:20) to aﬀord the title compound 45 as a yellow oil

(195 mg, 59%). R_f0.40 (CH₂Cl₂/MeOH 90:10); [α]³_D⁰−14.5 (c 0.91,

1

3067 (w), 2980 (s), 1092 (s), 736 (s), 697 (s) cm⁻¹; H NMR (400

MHz, CDCl₃) δ 7.40−7.29 (5H, m, H_Ph), 5.83 (1H, ddt, J = 17.0,

10.3, 6.6 Hz, H₅), 5.07 (1H, dq, J = 17.1, 1.7 Hz, H_6′), 5.02 (1H, dq, J

= 10.2, 1.41 Hz, H_6″), 4.79−4.62 (1H, m, d_obs, J = 49.2 Hz, H₂), 4.61

(2H, s, H_Bn), 3.65−3.63 (1H, m, H₁), 3.59−3.57 (1H, m, H_1′), 2.30−

2.12 (2H, m, H₄), 1.90−1.61 (2H, m, H₃) ppm; ¹³C{¹H} NMR (101

MHz, CDCl₃) 137.9 (C_Ph), 137.4 (C₅), 128.4 (C_Ph), 127.71 (C_Ph),

127.67 (C_Ph), 115.3 (C₆), 92.3 (d, J_C‑F= 170.9 Hz, C₂), 73.4 (C_Bn),

71.8 (d, J_C‑F= 22.0 Hz, C₁), 30.7 (d, J_C‑F= 20.5 Hz, C₃), 29.0 (d, J_C‑F

= 4.4 Hz, C₄) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −187.2 (ddtd, J =

48.0, 31.1, 23.7, 15.6 Hz, F₂) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃)

δ −188.0 (s, F₂) ppm; HRMS (EI) m/z: [M^•]⁺calcd for C₁₃H₁₇FO

208.1258; found 208.1255.

5-(Benzyloxy)-2,2,4-triﬂuoropentan-1-ol (48). To a stirred sol-

ution of 30 (212 mg, 1.00 mmol) in dry THF (5 mL) was added ^L-

proline (46 mg, 0.40 mmol). After 5 min, NFSI (788 mg, 2.50 mmol)

was added portionwise and the mixture was stirred at rt for 23 h. The

reaction mixture was cooled to 0 °C and quenched by slow addition

of dimethyl sulﬁde (0.15 mL, 2.0 mmol). After stirring for 30 min at

rt, the phases were separated and the aqueous phase was extracted

with EtOAc (3 × 5 mL). The combined organic layers were washed

with sat. aq. NaHCO₃(2 × 5 mL), sat. brine (5 mL), dried over

MgSO₄, and concentrated in vacuo. The residue was redissolved in a

mixture of CH₂Cl₂(6 mL) and EtOH (4 mL) and cooled to 0 °C.

NaBH₄(94 mg, 2.5 mmol) was added portionwise, and the mixture

was stirred at rt for 30 min. The reaction was quenched at 0 °C by

cautious addition of sat. aq. NH₄Cl (10 mL) and stirred vigorously for

30 min at rt. The phases were separated, and the aqueous phase

extracted with CH₂Cl₂(3 × 20 mL). The combined organic phases

were dried over MgSO₄and concentrated in vacuo. The crude

product was puriﬁed by ﬂash column chromatography (hexane/

EtOAc 70:30) to aﬀord the title compound 48 as a colorless oil (202

mg, 81%). R_f0.33 (hexane/EtOAc 70:30); IR 3393 (br m), 2980 (m),

1367 (m), 1071 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.40−7.29

(5H, m, H_Ph), 5.07−4.89 (1H, m, d_obs, J = 48.5 Hz, H₄), 4.63 (1H, d, J

= 12.1 Hz, H_Bn), 4.59 (1H, d, J = 12.1 Hz, H_Bn), 3.87−3.78 (2H, m,

H₁), 3.73−3.59 (2H, m, H₅), 2.60−2.18 (2H, m, H₃), 1.92 (1H, t, J =

6.9 Hz, OH) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 137.5 (C_Ph),

128.5 (C_Ph), 127.9 (C_Ph), 127.7 (C_Ph), 121.9 (t, J_C‑F= 242.8 Hz, C₂),

1

MeOH); IR 3340 (br m), 2939 (w), 2359 (w), 1042 (s) cm⁻¹; H

NMR (500 MHz, MeOD) δ 4.78 (1H, dqd, J = 48.8, 6.0, 3.3 Hz, H₅),

4.65 (1H, dddd, J = 48.6, 8.3, 6.0, 3.6 Hz, H₃), 3.76−3.57 (5H, m,

1

H₁₊₂₊₆), 2.21−2.00 (2H, m, H₄) ppm; H{¹⁹F} NMR (500 MHz,

MeOD) δ 4.74 (1H, qd, J = 6.0, 3.3 Hz, H₅), 4.62 (1H, ddd, J = 8.3,

6.0, 3.6 Hz, H₃), 3.74−3.64 (4H, m, H₁₊₂₊₆), 3.59 (1H, dd, J = 11.4,

5.9 Hz, H_1′), 2.16−2.04 (2H, m, H₄) ppm; ¹³C{¹H} NMR (126 MHz,

MeOD), δ 91.7 (dd, J_C‑F= 169.8, 2.7 Hz, C₅), 90.3 (dd, J_C‑F= 170.8,

5.5 Hz, C₃), 72.7 (d, J_C‑F= 23.6 Hz, C₂), 63.3 (d, J_C‑F= 22.7 Hz, C₆),

62.1 (d, J_C‑F= 6.4 Hz, C₁), 32.2 (t, J_C‑F= 20.9 Hz, C₄) ppm; ¹⁹F NMR

(471 MHz, MeOD) δ −189.3 to −189.6 (m, F₅), −191.0 to −191.3

(m, F₃) ppm; ¹⁹F{¹H} NMR (471 MHz, MeOD) δ −189.5 (d, J = 3.2

Hz, F₅), −191.1 (d, J = 2.9 Hz, F₃) ppm; HRMS (ESI) m/z: [M +

Na]⁺, calcd for C₆H₁₂F₂NaO₃193.0647; found 193.0650.

(3S,5R)-3,5-Diﬂuorotetrahydro-2H-pyran-2-ol (46). To a solution

of 45 (218 mg, 1.28 mmol) in water (20 mL) at 0 °C was added

NaIO₄(411 mg, 1.92 mmol). The resulting mixture was warmed to rt

and stirred for 3 h before being diluted with water (20 mL) and

concentrated in vacuo. The residue was redissolved in acetone/

CH₂Cl₂, and the insoluble material was removed by ﬁltration. The

ﬁltrate was concentrated in vacuo. The crude product was puriﬁed by

ﬂash column chromatography (hexane/acetone 80:20) to aﬀord the

title compound 46 as a white crystalline solid (151 mg, 84%). R_f0.32

(hexane/acetone 80:20); [α]³_D⁰+12.9 (c 0.7, CHCl₃); mp 65−68 °C

(hexane/acetone); IR 3394 (br m), 2949 (w), 1098 (s), 1036 (s)

cm⁻¹; ¹H NMR (500 MHz, CDCl₃, α/β 1.00:0.42) δ 5.25 (1H, br d, J

= 7.9 Hz, H_1α), 4.90 (1H, dt, J = 12.2, 2.0 Hz, H_1β), 4.70−4.58 (3H,

m, H_2β+4α+4β), 4.50 (1H, dq, J = 44.9, 3.4 Hz, H_2α), 4.15 (1H, ddd, J =

37.1, 13.4, 1.8 Hz, H_5axα), 4.15−4.09 (1H, m, H_5eqβ), 3.86 (1H, tt, J =

13.5, 2.5 Hz, H_5eqα), 3.74 (1H, dddt, J = 24.5, 12.5, 2.8, 1.1 Hz, H_5axβ),

3.34 (1H, br s, OH_α+β), 2.50 (1H, dttd, J = 14.4, 11.5, 5.9, 2.1 Hz,

H_3eqβ), 2.38−2.10 (4H, m, H_3α+3axβ) ppm; 1H{¹⁹F} NMR (500 MHz,

CDCl₃) δ 5.25 (1H, br d, J = 1.9 Hz, H_1α), 4.89 (1H, d, J = 1.9 Hz,

H_1β), 4.65−4.63 (1H, m, H_4α), 4.62−4.58 (2H, m, H_2β+4β), 4.50 (1H,

q, J = 3.2 Hz, H_2α), 4.15 (1H, dd, J = 13.4, 1.8 Hz, H_5axα), 4.12 (1H,

ddd, J = 12.4, 4.9, 2.0 Hz, H_5eqβ), 3.86 (1H, dt, J = 13.0, 2.5 Hz,

H_5eqα), 3.73 (1H, ddd, J = 12.5, 2.9, 1.0 Hz, H_5axβ), 3.33 (1H, br s,

OH_α+β), 2.49 (1H, dtd, J = 14.4, 5.9, 2.1 Hz, H_3eqβ), 2.33 (1H, dddt, J

= 15.6, 4.7, 3.5, 1.1 Hz, H_3eqα), 2.22 (1H, dt, J = 15.6, 3.5 Hz, H_3axα),

2.19−2.15 (1H, m, H_3axβ) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

91.7 (d, J_C‑F= 19.3 Hz, C_1β), 91.2 (d, J_C‑F= 31.2 Hz, C_1α), 85.6 (dd,

87.8 (ddd, J_C‑F= 171.7, 7.3, 3.7 Hz, C₄), 73.6 (C_Bn), 71.3 (d, J_C‑F

=

23.5 Hz, C₅), 64.2 (ddd, J_C‑F= 33.0, 29.3, 2.9 Hz, C₁), 35.7 (ddd, J_C‑F

= 25.7, 24.2, 22.0 Hz, C₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ

−103.7 to −104.5 (1F, m, d_obs, J = 254.9 Hz, F₂), −108.2 to −109.1

(1F, m, d_obs, J = 254.9 Hz, F_2′), −185.8 to −186.2 (1F, m, F₄) ppm;

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −104.0 (1F, dd, J = 256.6, 5.2

Hz, F₂), −108.5 (1F, dd, J = 254.9, 5.2 Hz, F_2′), −186.0 (1F, t, J = 4.3

Hz, F₄) ppm; HRMS (EI) m/z: [M^•]⁺calcd for C₁₂H₁₅F₃O₂

248.1019; found 248.1019.

J

_C‑F= 182.9, 4.0 Hz, C_2β), 84.6 (d, J_C‑F= 174.3 Hz, C_2α), 83.9 (d, J_C‑F

Ethyl 4,4-Diﬂuoro-5-hydroxypentanoate (49). Synthesized with a

procedure of Kim et al.⁶⁰Cu powder (3.33 g, 52.4 mmol), ethyl

acrylate 35 (2.72 mL, 25.0 mmol), and ethyl bromodiﬂuoroacetate 36

(5.78 mL, 45.1 mmol) were suspended in dry THF (29 mL) and

heated to 50 °C. TMEDA (1.87 mL, 12.5 mmol) and AcOH (1.29

mL, 22.5 mmol) were added sequentially, and the mixture was stirred

for 1 h before being cooled to rt. MTBE (44 mL) and aq. NH₄Cl (10

wt %, 29 mL) were added, and the mixture was stirred for a further 30

min. The organic phase was separated and ﬁltered through a pad of

Celite. The ﬁltrate was washed with aq. NH4Cl 10% (29 mL), dried

over MgSO₄, and concentrated in vacuo to aﬀord a yellow oil. This

was redissolved in a mixture of THF (28 mL) and EtOH (5.6 mL)

and cooled to 0 °C. NaBH₄(950 mg, 25 mmol) was added

portionwise. The mixture was warmed to rt and stirred for 30 min.

The mixture was cooled to 0 °C and quenched by slow addition of

= 177.4 Hz, C_4α), 83.2 (dd, J_C‑F= 178.3, 4.0 Hz, C_4β), 65.0 (d, J_C‑F

=

24.1 Hz, C_5β), 61.5 (d, J_C‑F= 21.9 Hz, C_5α), 31.6 (t, J_C‑F= 20.7 Hz,

C_3β), 28.2 (t, J_C‑F= 20.5 Hz, C_3α) ppm; ¹⁹F NMR (471 MHz, CDCl₃)

δ −183.7 to −184.1 (m, F_4α), −185.6 to −185.9 (m, F_4β), −186.5 to

−186.8 (m, F_2α), −200.7 to −201.0 (m, F_2β) ppm; ¹⁹F{¹H} NMR

(471 MHz, CDCl₃) δ −183.9 (d, J = 14.3 Hz, F_4α), −185.8 (d, J = 9.3

Hz, F_4β), −186.7 (d, J = 14.3 Hz, F_2α), −200.9 (br s, F_2β) ppm;

HRMS (ESI) m/z: [M + Na]⁺calcd for C₅H₈F₂NaO₂161.0385;

found 161.0389.

1-(Benzyloxy)-2-ﬂuorohex-5-ene (47). To a solution of 31⁶⁶(206

mg, 1.0 mmol) in dry THF (4 mL) at rt were added the following in

sequence: Et₃N (0.84 mL, 6.0 mmol), Et₃N·3HF (0.33 mL, 2.0

mmol), and NfF (0.36 mL, 2.0 mmol). After 24 h, the reaction was

quenched by slow addition of sat. aq. NaHCO₃(4 mL). Water (1

1895

https://dx.doi.org/10.1021/acs.joc.0c02810

J. Org. Chem. 2021, 86, 1882−1900

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

sat. aq. NH₄Cl (25 mL). After stirring for a further 30 min, the

mixture was ﬁltered through a pad of Celite to remove the insoluble

solids. The organic solvent was removed in vacuo, and the residue was

subsequently extracted with EtOAc (3 × 100 mL). The combined

organic layers were dried over MgSO₄and concentrated in vacuo. The

crude product was puriﬁed by ﬂash column chromatography (hexane/

acetone 80:20) to aﬀord the title compound 49 as a colorless oil (3.20

g, 70% over two steps). R_f0.10 (hexane/EtOAc 80:20); IR 3449 (br

m), 2985 (w), 1716 (s), 1071 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃)

δ 4.17 (2H, q, J = 7.2 Hz, H_OCH2CH3), 3.73 (2H, t, J = 12.5 Hz, H₅),

2.56 (2H, t, J = 7.5 Hz, H₂), 2.42 (1H, br s, OH), 2.30 (2H, tt, J =

16.8, 7.5 Hz, H₃), 1.28 (3H, t, J = 7.2 Hz, H_OCH2CH3) ppm; ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 172.8 (C₁), 122.5 (t, J_C‑F= 246.5 Hz,

C₄), 63.9 (t, J_C‑F= 32.3 Hz, C₅), 61.0 (C _OCH2CH3), 28.4 (t, J_C‑F= 24.9

Hz, C₃), 26.9 (t, J_C‑F= 5.1 Hz, C₂), 14.1 (C_OCH2CH3) ppm; ¹⁹F NMR

NMR (376 MHz, CDCl₃) δ −104.06 (t, J = 8.7 Hz, F₂), −104.14 (t, J

= 8.7 Hz, F₄) ppm; HRMS (ESI) m/z: [M + Na]⁺calcd for

C₂₁H₂₆F₄NaO₂Si 437.1530; found 437.1535.

Diethyl 3-Fluoropentane-1,5-dioate (54). To a solution of 53 (1.0

g, 4.9 mmol) in dry CH₂Cl₂(49 mL) at 0 °C was added DAST (1.3

mL, 9.8 mmol) dropwise. The solution was stirred at rt for 4 h, then

cooled to 0 °C, and quenched by slow addition of sat. aq. NaHCO₃

(150 mL). After stirring vigorously at rt for 30 min, the phases were

separated and the aqueous phase was extracted with CH₂Cl₂(3 × 100

mL). The combined organics were dried over MgSO₄and

concentrated in vacuo. The crude product was puriﬁed by ﬂash

column chromatography (hexane/acetone 80:20) to aﬀord the title

compound 54 as a yellow oil with a 10% impurity of the elimination

byproduct by mass (973 mg, 87% calculated for the pure compound).

R_f0.39 (hexane/EtOAc 70:30); IR 2984 (m), 1731 (s), 1194 (s),

1

1152 (s), 1024 (s) cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.37 (1H,

(376 MHz, CDCl₃) δ −109.2 (tt, J = 17.3, 12.1 Hz, F₄) ppm; ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −109.2 (s, F₄) ppm; HRMS (EI) m/z:

[M^•]⁺calcd for C₇H₁₂F₂O₃182.0749; found 182.0749.

dtt, J = 46.7, 7.3, 5.1 Hz, H₃), 4.19 (2H, q, J = 7.3 Hz, H_OCH2CH3),

2.84−2.65 (4H, m, H₂₊₄), 1.29 (3H, t, J = 7.2 Hz, H_OCH2CH3) ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.4 (d, J_C‑F= 6.6 Hz, C₁₊₅),

86.5 (d, J_C‑F= 171.7 Hz, C₃), 61.0 (C_OCH2CH3), 39.7 (d, J_C‑F= 23.5

Hz, C₂₊₄), 14.1 (C_OCH2CH3) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ

−179.3 to −179.7 (m, F₃) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ

−184.8 (s, F₃) ppm; HRMS (EI) m/z: [M^•]⁺calcd for C₉H₁₅FO₄

206.0949; found 206.0943.

1,4-Di(benzyloxy)-3-ﬂuorobutan-2-one (57). To a solution of

56⁵¹(2.00 g, 6.57 mmol) in CH₂Cl₂(65 mL) at rt was added Dess−

Martin periodinane (4.18 g, 9.86 mmol) portionwise over 5 min. After

20 h, the mixture was diluted with Et₂O (30 mL), ﬁltered through

Celite (eluting with Et₂O), and concentrated in vacuo. To the residue

was added sat. aq. NaHCO₃(50 mL) and Na₂S₂O₃·5H₂O (3.2 g).

The aqueous phase was extracted with EtOAc (3 × 80 mL), and the

combined organics were washed with sat. brine (50 mL), dried over

MgSO₄, and concentrated in vacuo. The crude mixture was puriﬁed

by ﬂash column chromatography (Biotage Isolera One, SNAP KP-SIL

50 g column, hexane/EtOAc 100:0 to 80:20) to aﬀord the title

compound 57 as a clear colorless oil (1.56 g, 79%). R_f0.45 (hexane/

EtOAc 70:30); IR 3032 (w), 2867 (w), 1742 (m), 1076 (s) cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ 7.38−7.28 (10H, m, H_Ph), 5.06 (1H,

ddd, J = 48.4, 3.7, 2.5 Hz, H₃), 4.65−4.51 (4H, m, H_Bn), 4.48 (2H, m,

H₁), 3.99−3.83 (2H, m, H₄) ppm; ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 204.3 (d, J_C‑F= 24.2 Hz, C₂), 137.1 (C_Ph), 137.0 (C_Ph),

128.48 (C_Ph), 128.45 (C_Ph), 128.02 (C_Ph), 127.98 (C_Ph), 127.9 (C_Ph),

Ethyl 5-((tert-Butyldiphenylsilyl)oxy)-4,4-diﬂuoropentanoate

(50). To a stirred solution of 49 (3.00 g, 16.5 mmol), 1H-imidazole

(1.35 g, 19.8 mmol), and DMAP (100 mg, 0.824 mmol) in dry

CH₂Cl₂(83 mL) at 0 °C was added TBDPSCl (5.43 g, 19.8 mmol)

portionwise. The reaction mixture was allowed to warm to rt and

stirred for 16 h. Water (50 mL) was added, and the aqueous phase

was extracted with CH₂Cl₂(3 × 50 mL). The combined organic

layers were dried over MgSO₄and concentrated in vacuo. The crude

product was puriﬁed by ﬂash column chromatography (hexane/

acetone 90:10) to aﬀord the title compound 50 as a colorless oil (5.94

g, 86%). R_f0.59 (hexane/EtOAc 70:30); IR 3657 (m), 2980 (s), 2889

(s), 1736 (s), 1382 (s), 1088 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃)

δ 7.69−7.66 (4H, m, H_Ph), 7.49−7.40 (6H, m, H_Ph), 4.18 (2H, q, J =

7.1 Hz, H_OCH2CH3), 3.77 (2H, t, J = 12.0 Hz, H₅), 2.57−2.53 (2H, m,

H₂), 2.44−2.31 (2H, m, H₃), 1.29 (3H, t, J = 7.1 Hz, H_OCH2CH3), 1.09

(9H, s, H_tBu) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.4 (C₁),

135.6 (C_Ph), 132.5 (C_Ph), 130.0 (C_Ph), 127.8 (C_Ph), 122.5 (t, J_C‑F

=

242.8 Hz, C₄), 65.1 (t, J_C‑F= 34.1 Hz, C₅), 60.7 (C_OCH2CH3), 28.9 (t,

J_C‑F= 24.2 Hz, C₃), 26.9 (t, J_C‑F= 4.8 Hz, C₂), 26.7 (C_tBu,Me), 19.2

(C_tBu,quat), 14.2 (C_OCH2CH3) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ

−108.5 (tt, J = 17.3, 12.1 Hz, F₄) ppm; ¹⁹F{¹H} NMR (376 MHz,

CDCl₃) δ −108.5 (s, F₄) ppm; HRMS (ESI) m/z: [M + Na]⁺calcd

for C₂₃H₃₀F₂NaO₃Si 443.1824; found 443.1829.

5-((tert-Butyldiphenylsilyl)oxy)-2,2,4,4-tetraﬂuoropentan-1-ol

(51). To a stirred solution of 33 (897 mg, 2.38 mmol) in dry THF (12

mL) was added ^L-proline (109 mg, 0.95 mmol). After 5 min, NFSI

(1.88 g, 5.96 mmol) was added portionwise and the mixture was

stirred at rt for 19 h. The reaction mixture was cooled to 0 °C and

quenched by slow addition of dimethyl sulﬁde (0.35 mL, 4.8 mmol).

After stirring for 30 min at rt, sat. aq. NaHCO₃(25 mL) was added.

The aqueous phase was extracted with EtOAc (3 × 25 mL), and the

combined organic layers washed with sat. brine (25 mL), dried over

MgSO₄, and concentrated in vacuo. The crude oil was redissolved in a

mixture of dry CH₂Cl₂(14.3 mL) and EtOH (9.5 mL) and cooled to

0 °C. NaBH₄(225 mg, 5.96 mmol) was added portionwise, and the

mixture was stirred at rt for 30 min. The reaction was quenched at 0

°C by cautious addition of sat. aq. NH₄Cl (25 mL) and stirred

vigorously for 1 h at rt. The phases were separated, and the aqueous

phase was extracted with CH₂Cl₂(3 × 50 mL). The combined

organic phases were dried over MgSO₄and concentrated in vacuo.

The crude product was puriﬁed by ﬂash column chromatography

(hexane/EtOAc 80:20) to aﬀord the title compound 51 as a colorless

oil (750 mg, 76%). R_f0.25 (hexane/EtOAc 80:20); IR 3656 (w),

3376 (br w), 2980 (s), 2889 (m), 1382 (m), 1113 (s) cm⁻¹; ¹H NMR

(400 MHz, CDCl₃) δ 7.68−7.66 (4H, m, H_Ph), 7.49−7.40 (6H, m,

H_Ph), 3.87 (2H, td, J = 13.0, 7.2 Hz, H₁), 3.82 (2H, t, J = 12.2 Hz,

H₅), 2.80 (2H, quin, J = 15.9 Hz, H₃), 1.93 (1H, t, J = 7.3 Hz, OH),

1.09 (9H, s, H_tBu) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 135.5

(C_Ph), 132.3 (C_Ph), 130.0 (C_Ph), 127.9 (C_Ph), 123.2-118.3 (m, C₂₊₄),

65.3 (t, J_C‑F= 33.4 Hz, C₁), 64.3 (t, J_C‑F= 30.8 Hz, C₅), 36.5 (quin,

J_C‑F= 25.3 Hz, C₃), 26.6 (C_tBu,Me), 19.2 (C_tBu,quat) ppm; ¹⁹F NMR

(376 MHz, CDCl₃) δ −103.9 to −104.3 (m, F₂₊₄) ppm; ¹⁹F{¹H}

127.7 (C_Ph), 94.8 (d, J_C‑F= 187.1 Hz, C₃), 73.7 (C_Bn), 73.43 (d, J_C‑F

=

2.9 Hz, C₁), 73.37 (C_Bn), 69.5 (d, J_C‑F= 19.1 Hz, C₄) ppm; ¹⁹F NMR

(376 MHz, CDCl₃) δ −203.0 to −203.3 (m, F₃) ppm; ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ −203.4 (s, F₃) ppm; HRMS (ESI) m/z: [M +

Na]⁺calcd for C₁₈H₁₉FNaO₃325.1210; found 325.1217.

1,4-Di(benzyloxy)-2,2,3-triﬂuorobutane (58). To a stirred solution

of 57 (1.50 g, 4.96 mmol) in CH₂Cl₂(50 mL) cooled to 0 °C was

added DAST (3.9 mL, 30 mmol) dropwise. The solution was stirred

at rt for 20 h, then cooled to 0 °C, and quenched by slow addition of

sat. aq. NaHCO₃(150 mL). After stirring vigorously at rt for 30 min,

the phases were separated and the aqueous phase was extracted with

CH₂Cl₂(3 × 150 mL). The combined organic layers were dried over

MgSO₄and concentrated in vacuo. The crude mixture was puriﬁed by

ﬂash column chromatography (hexane/EtOAc 100:0 to 80:20) to

aﬀord the title compound 58 as a clear colorless oil (1.33 g, 83%). R_f

0.54 (hexane/EtOAc 80:20); IR 3031 (w), 2980 (w), 2875 (w), 1113

(s), 1085 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.43−7.33 (10H,

m, H_Ph), 5.14−4.95 (1H, m, H₃), 4.68−4.60 (4H, m, H_Bn), 3.99−3.74

(4H, m, H₁₊₄) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 137.4

(C_Ph), 136.9 (C_Ph), 128.50 (C_Ph), 128.45 (C_Ph), 128.0 (C_Ph), 127.9

(C_Ph), 127.7 (C_Ph+ C_Ph), 119.0 (td, J_C‑F= 247.0, 26.0 Hz, C₂), 89.1

(ddd, J_C‑F= 181.9, 33.0, 26.4 Hz, C₃), 74.0 (C_Bn), 73.7 (C_Bn), 67.6

(ddd, J_C‑F= 33.8, 27.1, 1.5 Hz, C₁), 67.0 (ddd, J_C‑F= 21.3, 4.4, 2.9 Hz,

C₄) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −115.5 (1F, dddt, J =

270.8, 19.4, 12.4, 5.6 Hz, F₂), −120.9 (1F, ddq, J = 270.5, 17.8, 9.7

Hz, F_2′), −202.4 to −202.8 (1F, m, F₃) ppm; ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −115.6 (1F, dd, J = 270.5, 5.2 Hz, F₂), −121.0 (1F,

dd, J = 270.5, 12.1 Hz, F_2′), −202.7 (1F, dd, J = 12.1, 5.2 Hz, F₃)

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ppm; HRMS (EI) m/z: [M-CH₂Ph]⁺calcd for C₁₁H₁₂F₃O₂233.0784;

found 233.0785.

aqueous layer was extracted with EtOAc (3 × 10 mL), and the

combined organic layers were dried over MgSO₄and concentrated in

vacuo. The crude product was puriﬁed by ﬂash column chromatog-

raphy (hexane/acetone 60:40) to aﬀord the title compound (2S,4S)-

H2 as a white crystalline solid (91 mg, 79%). R_f0.20 (hexane/EtOAc

40:60); [α]¹_D⁹−31.2 (c 1, MeOH); mp 115−116 °C (MeOH); IR

2,2,3-Triﬂuorobutane-1,4-diol (C5). To a solution of 58 (600 mg,

1.85 mmol) in dry CH₂Cl₂(37 mL) at rt, iodotrimethylsilane (0.68

mL, 4.8 mmol) was added dropwise. After 30 min, MeOH (6 mL)

was added and the mixture was stirred for a further 30 min. EtOAc

(15 mL) and sat. aq. NaHSO₃(5 mL) were added, and the layers

were separated. The aqueous phase was extracted with EtOAc (3 × 15

mL), and the combined organic phases were washed with sat. brine (5

mL), dried over MgSO₄, and concentrated in vacuo. The crude

mixture was puriﬁed by ﬂash column chromatography (hexane/

acetone 100:0 to 60:40) to aﬀord the title compound C5 as a

crystalline solid (216 mg, 81%). R_f0.41 (hexane/EtOAc 40:60); mp

52−54 °C (MeOH); IR 3315 (br m), 3200 (br m), 2980 (m) 1229

(m), 1094 (s), 1055 (s) cm⁻¹; ¹H NMR (400 MHz, MeOD) δ 4.87−

4.68 (1H, m, H₃), 3.95−3.72 (4H, m, H₁₊₄) ppm; ¹³C{¹H} NMR

(101 MHz, MeOD) δ 121.1 (ddd, J_C‑F= 247.2, 245.0, 25.7 Hz, C₂),

179.7 (ddd, J_C‑F= 179.7, 32.3, 27.1 Hz, C₃), 61.6 (ddd, J_C‑F= 31.5,

27.9, 1.5 Hz, C₁), 60.3 (dt, J_C‑F= 21.8, 3.8 Hz, C₄) ppm; ¹⁹F NMR

(376 MHz, MeOD) δ −119.3 (1F, dddt, J = 266.7, 19.2, 13.2, 6.5 Hz,

F₂), −123.5 (1F, ddq, J = 267.0, 13.9, 10.4 Hz, F_2′), −206.8 to −207.1

(1F, m, F₃) ppm; ¹⁹F{¹H} NMR (376 MHz, MeOD) δ −119.3 (1F,

dd, J = 265.3, 5.2 Hz, F₂), −123.5 (1F, dd, J = 265.3, 10.4 Hz, F₂),

−206.9 (1F, dd, J = 12.1, 6.9 Hz, F₃) ppm; HRMS (EI) m/z: [M-

OH₃]⁺calcd for C₄H₄F₃O 125.0214; found 125.0209.

1

3656 (m), 3203 (br m), 2980 (s), 2889 (m), 1382 (m) cm⁻¹; H

NMR (400 MHz, MeOD) δ 4.80−4.62 (2H, m, d_obs, J = 49.6 Hz,

H₂₊₄), 3.76−3.56 (4H, m, H₁₊₅), 1.99−1.79 (2H, m, H₃) ppm;

¹³C{¹H} NMR (101 MHz, MeOD) δ 92.0 (dd, J_C‑F= 170.2, 2.9 Hz,

C

₂₊₄), 65.4 (d, J_C‑F= 22.0 Hz, C₁), 34.4 (t, J_C‑F= 20.9 Hz, C₃) ppm;

¹⁹F NMR (376 MHz, MeOD) δ −191.8 to −192.2 (m, F₂₊₄) ppm;

¹⁹F{¹H} NMR (376 MHz, MeOD) δ −192.1 (s, F₂₊₄) ppm; HRMS

(EI) m/z: [M−CHOH]⁺calcd for C₄H₈F₂O 110.0543; found

110.0537.

The synthesis was repeated from (2R,4R)-41 (32 mg, 0.13 mmol)

to give (2R,4R)-H2 (14 mg, 76%). Spectroscopic data were identical

except [α]²_D⁰+29.0 (c 0.15, MeOH).

2,4-syn-Diﬂuoropentane-1,5-diol (H3). To a solution of 46 (219

mg, 1.59 mmol) in MeOH (20 mL) at 0 °C was added NaBH₄(150

mg, 3.96 mmol) portionwise. The resulting mixture was warmed to rt

and stirred for 3 h. The reaction was quenched with aq. 1 M HCl (5

mL), stirred for 1 h, and concentrated in vacuo. The residue was

redissolved in CH₂Cl₂/acetone, ﬁltered, and concentrated in vacuo.

The crude product was puriﬁed by ﬂash column chromatography

(hexane/acetone 60:40) to aﬀord the title compound H3 as a white

crystalline solid (211 mg, 94%). R_f0.30 (hexane/acetone 60:40); mp

63−66 °C (not recrystallized); IR 3250 (br m), 2940 (m), 1384 (m),

2-Fluorobutane-1,4-diol (C6). To a solution of 59²³(500 mg, 2.36

mmol) in Et₂O (25 mL) at rt, NaOMe (25% w/w in MeOH, 1.07

mL, 4.72 mmol) was added dropwise. After 16 h, the reaction mixture

was neutralized with aq. HCl (2 M), and the aqueous phase was

washed with Et₂O (3 × 20 mL). The combined organic phases were

washed with brine, dried over MgSO₄, and carefully concentrated (30

°C, 750 mbar). The crude mixture was puriﬁed by ﬂash column

chromatography (Et₂O/acetone 95:5) to aﬀord the title compound

C6 as a pale yellow oil (89 mg, 35%). R_f0.12 (hexane/EtOAc 40:60);

IR 3313 (br m), 2954 (m), 2892 (m), 1054 (s) cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 4.87−4.81 (1H, ddddd, J = 48.9, 7.9, 5.5, 4.6, 3.4 Hz,

H₂), 3.94−3.66 (4H, m, H₁₊₄), 2.16−1.77 (2H, m, H₃), ppm;

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 92.2 (d, J_C‑F= 168.0 Hz, C₂),

1

1068 (s), 1044 (s) cm⁻¹; H NMR (400 MHz, MeOD) δ 4.77−4.60

(2H, m, d_obs, J = 48.8 Hz, H₂₊₄), 3.76−3.61 (2H, m, H₁₊₅), 2.18 −

1.88 (2H, m, H₃) ppm; ¹³C{¹H} NMR (101 MHz, MeOD) δ 92.7

(dd, J_C‑F= 169.5, 4.4 Hz, C₂₊₄), 64.9 (d, J_C‑F= 22.7 Hz, C₁₊₅), 33.9 (t,

J

_C‑F= 21.3 Hz, C₃) ppm; ¹⁹F NMR (376 MHz, MeOD) δ −189.2 to

−189.5 (m, F₂₊₄) ppm; ¹⁹F{¹H} NMR (376 MHz, MeOD) δ −189.2

(s, F₂₊₄) ppm; HRMS (ESI) m/z: [M + Na]⁺calcd for C₅H₁₀F₂NaO₂

163.0541; found 163.0544.

2,2,4-Triﬂuoropentane-1,5-diol (H4). To a solution of 48 (180

mg, 0.725 mmol) in dry CH₂Cl₂(1.5 mL) at rt, iodotrimethylsilane

(0.13 mL, 0.94 mmol) was added dropwise. After 30 min, MeOH (2.4

mL) was added. After a further 30 min, sat. aq. sodium bisulﬁte (1

mL) and EtOAc (5 mL) were added and the layers were separated.

The aqueous phase was extracted with EtOAc (3 × 5 mL), and the

combined organic phases were washed with sat. brine (1 mL), dried

over MgSO₄, and concentrated in vacuo. The crude oil was puriﬁed

by ﬂash column chromatography (hexane/acetone 100:0 to 60:40) to

aﬀord the title compound H4 as a beige solid (83 mg, 72%). R_f0.09

(hexane/EtOAc 70:30); mp 60−61 °C (MeOH); IR 3344 (br m),

64.8 (d, J_C‑F= 22.7 Hz, C₁), 58.5 (d, J_C‑F= 5.9 Hz, C₄), 33.9 (d, J_C‑F

=

20.5 Hz, C₃) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −191.5 to −192.0

(m, F₂) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −191.8 (s, F₂)

ppm; HRMS (EI) m/z: [M^•+] calcd for C₄H₉FO₂108.0581; found

108.0580.

2,2-Diﬂuorobutane-1,4-diol (C7). To a solution of 60²³(150 mg,

0.652 mmol) in Et₂O (10 mL) at rt, NaOMe (25% w/w in MeOH,

0.30 mL, 1.30 mmol) was added dropwise. After 16 h, the reaction

mixture was neutralized with aq. HCl (2 M) and the aqueous phase

was washed with CH₂Cl₂(3 × 5 mL). The combined organic phases

were washed with brine, dried over MgSO₄, and carefully

concentrated (30 °C, 750 mbar). The crude mixture was ﬁrst puriﬁed

by column chromatography (acetone/petroleum ether 40−60 °C

50:50) and then by HPLC (Et₂O/pentane 95:5) to aﬀord the title

compound C7 as a colorless crystalline solid (22 mg, 27%). R_f0.16

(hexane/EtOAc 40:60); mp 37−39 °C (MeOH); IR (thin ﬁlm,

CDCl₃) 3352 (br w), 2962 (w), 1374 (w), 1262 (m), 1066 (s), 904

(s) cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 3.90 (2H, t, J = 5.6 Hz, H₄),

3.83 (2H, t, J = 12.6 Hz, H₁), 2.69 (1H, br s, OH₁), 2.25 (2H, tt, J =

1

2955 (w), 1078 (s), 1029 (s) cm⁻¹; H NMR (400 MHz, MeOD) δ

4.90−4.72 (1H, m, d_obs, J = 49.3 Hz, H₄), 3.76−3.58 (4H, m, H₁₊₅),

2.46−2.12 (2H, m, H₃) ppm; ¹³C{¹H} NMR (126 MHz, MeOD) δ

123.7 (td, J_C‑F= 242.1, 1.5 Hz, C₂), 90.4 (ddd, J_C‑F= 107.9, 5.9, 3.7

Hz, C₄), 65.2 (d, J_C‑F= 22.7 Hz, C₅), 64.6 (td, J_C‑F= 30.1, 2.2 Hz,

C₁), 36.3 (td, J_C‑F= 24.2, 22.0 Hz, C₃) ppm; ¹⁹F NMR (471 MHz,

MeOD) δ −105.4 to −106.2 (1F, m, d_obs, J = 251.4 Hz, F₂), −108.4

to −109.2 (1F, m, d_obs, J = 251.4 Hz, F_2′), −188.5 to −188.9 (1F, m,

F₄) ppm; ¹⁹F{¹H} NMR (471 MHz, MeOD) δ −105.8 (1F, dd, J =

251.4, 3.5 Hz, F₂), −108.9 (1F, dd, J = 251.4, 5.2 Hz, F_2′), −188.7

(1F, t, J = 5.2 Hz, F₄) ppm; HRMS (EI) m/z: [M + H]⁺calcd for

C₅H₁₀F₃O₂159.0627; found 159.0628.

2,2,4,4-Tetraﬂuoropentane-1,5-diol (H5). To a stirred solution of

51 (700 mg, 1.69 mmol) in dry THF (17 mL) at 0 °C was added

TBAF (1 M in THF, 2.5 mL, 2.5 mmol) dropwise. The reaction was

stirred at rt for 2 h. The reaction mixture was quenched by slow

addition of sat. aq. NH₄Cl (20 mL). After vigorous stirring for 15 min,

the aqueous phase was extracted with EtOAc (3 × 20 mL) and the

combined organic layers were washed with sat. brine (20 mL), dried

over MgSO₄, and concentrated in vacuo. The crude oil was puriﬁed

by ﬂash column chromatography (hexane/acetone 85:15) to aﬀord

the title compound H5 as a white crystalline solid (286 mg, 96%). R_f

0.55 (hexane/acetone 60:40); mp 87−88 °C (MeOH); IR 3657 (w),

1

15.8, 5.6 Hz, H₃), 2.01 (1H, br s, OH₄) ppm; H{¹⁹F} NMR (500

MHz, CDCl₃) δ 3.90 (2H, t, J = 5.6 Hz, H₄), 3.83 (2H, s, H₁), 2.69

(1H, br s, OH), 2.25 (2H, t, J = 5.6 Hz, H₃), 2.01 (1H, br s, OH)

ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 122.9 (t, J_C‑F= 242.7 Hz,

C₂), 64.4 (t, J_C‑F= 33.1 Hz, C₁), 56.9 (t, J_C‑F= 6.6 Hz, C₄), 36.8 (t,

J

_C‑F= 24.4 Hz, C₃) ppm; ¹⁹F NMR (471 MHz, CDCl₃) δ −105.1 (tt,

J = 15.9, 12.7 Hz, F₂) ppm; ¹⁹F{¹H} NMR (471 MHz, CDCl₃) δ

−105.1 (s, F₂) ppm; HRMS (CI) m/z: [M + H]⁺calcd for C₄H₉F₂O₂

127.0561; found 127.0566.

(2S,4S)-2,4-Diﬂuoropentane-1,5-diol ((2S,4S)-H2). To a stirred

solution of (2S,4S)-41 (200 mg, 0.82 mmol) in MeOH (4 mL) was

added KOH (138 mg, 2.46 mmol) in one portion. The mixture was

stirred at rt for 1 h before addition of sat. aq. NH₄Cl (4 mL). The

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3343 (w), 3248 (w), 2980 (s), 2889 (m), 1387 (m), 1252 (m) cm⁻¹;

¹H NMR (400 MHz, MeOD) δ 3.80−3.63 (4H, m, H₁₊₅), 2.67 (2H,

quin, J = 16.2 Hz, H₃) ppm; ¹³C{¹H} NMR (101 MHz, MeOD) δ

122.5 (tt, J_C‑F= 243.7, 4.2 Hz, C₂₊₄), 65.1−64.4 (m, C₁₊₅), 37.3 (quin,

¹H, ¹³C, and ¹⁹F NMR spectra of all novel compounds;

clog P determination of 1,5-pentanediol; comparison of

the experimental with the clog P values of all ﬂuorinated

diols; and experimental log P determination data (PDF)

J

_C‑F= 25.1 Hz, C₃) ppm; ¹⁹F NMR (376 MHz, MeOD) δ −105.6 to

−105.8 (m, F₂₊₄) ppm; ¹⁹F{1H} NMR (376 MHz, MeOD) δ −105.7

(s, F₂₊₄) ppm; HRMS (EI) m/z: [M + H]⁺calcd for C₅H₉F₄O₂

177.0533; found 177.0530.

AUTHOR INFORMATION

Corresponding Author

■

2-Fluoropentane-1,5-diol (H6). To a stirred solution of 52²³(350

mg, 1.55 mmol) in MeOH (7.7 mL) at rt, KOH (261 mg, 4.65 mmol)

was added portionwise. After 1 h, sat. aq. NH₄Cl (8 mL) was added

and the aqueous layer was extracted with EtOAc (3 × 20 mL). The

combined organic layers were washed with sat. brine (10 mL), dried

over MgSO₄, and concentrated in vacuo. The crude product was

puriﬁed by ﬂash column chromatography (hexane/acetone 60:40) to

aﬀord the title compound H6 as a yellow oil (65 mg, 34%). R_f0.14

(hexane/acetone, 60:40); IR 3338 (br m), 2917 (s), 2849 (s), 1462

(w), 1043 (s) cm⁻¹; ¹H NMR (400 MHz, MeOD) δ 4.60−4.42 (1H,

m, d_obs, J = 49.8 Hz, H₂), 3.70−3.54 (4H, m, H₁₊₅), 1.70−1.58 (4H,

Bruno Linclau − Chemistry, University of Southampton,

Southampton SO17 1BJ, U.K.; orcid.org/0000-0001-

8762-0170; Email: bruno.linclau@soton.ac.uk

Authors

Robert I. Troup − Chemistry, University of Southampton,

Southampton SO17 1BJ, U.K.

Benjamin Jeﬀries − Chemistry, University of Southampton,

Southampton SO17 1BJ, U.K.

Raphael El-Bekri Saudain − Chemistry, University of

Southampton, Southampton SO17 1BJ, U.K.

Eleni Georgiou − Chemistry, University of Southampton,

Southampton SO17 1BJ, U.K.

m, H₃₊₄) ppm; ¹³C{¹H} NMR (101 MHz, MeOD) δ 95.6 (d, J_C‑F

169.5 Hz, C₂), 65.3 (d, J_C‑F= 22.7 Hz, C₁), 62.7 (C₅), 29.3 (d, J_C‑F

=

3.7 Hz, C₄), 28.8 (d, J_C‑F= 21.3 Hz, C₃) ppm; ¹⁹F NMR (376 MHz,

MeOD) δ −189.1 to −189.5 ppm; ¹⁹F{¹H} NMR (376 MHz,

MeOD) δ −189.4 (s, F₂) ppm; HRMS (EI) m/z: [M + H]⁺calcd for

C₅H₁₂FO₂123.0816; found 123.0814.

Johanna Fish − Chemistry, University of Southampton,

Southampton SO17 1BJ, U.K.

James S. Scott − Medicinal Chemistry, Oncology R&D,

AstraZeneca, Cambridge CB4 0WG, U.K.; orcid.org/

0000-0002-2263-7024

Elisabetta Chiarparin − Medicinal Chemistry, Oncology R&D,

AstraZeneca, Cambridge CB4 0WG, U.K.; orcid.org/

0000-0002-2998-1346

3-Fluoropentane-1,5-diol (H7). To a solution of 54 (800 mg, 3.88

mmol) in dry THF (3.9 mL) at 0 °C was added a solution of LiAlH₄

(1 M in THF, 5.0 mL, 5.0 mmol) dropwise. The mixture was stirred

at rt for 1 h, then cooled to 0 °C, and quenched by dropwise addition

of sat. aq. Rochelle’s salt (15 mL). EtOAc (15 mL) was added, and

the mixture stirred for 1 h. The layers were separated, and the

aqueous layer was extracted sequentially with EtOAc (3 × 15 mL)

and a mixture of CHCl₃/i-PrOH (80:20) (3 × 15 mL). The

combined organic layers were washed with sat. brine (15 mL), dried

over MgSO₄, and concentrated in vacuo. The crude product was

puriﬁed by ﬂash column chromatography (hexane/EtOAc 60:40 to

40:60) to aﬀord the title compound H7 as a yellow oil (257 mg,

54%). R_f0.10 (hexane/EtOAc 60:40); IR 3311 (br s), 2955 (m),

1395 (m), 1043 (s) cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.95 (1H,

dtt, J = 49.8, 8.8, 3.4 Hz, H₃), 3.86−3.82 (4H, m, H₁₊₅), 2.03−1.79

(4H, m, H₂₊₄) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 90.6 (d,

Charlene Fallan − Medicinal Chemistry, Oncology R&D,

AstraZeneca, Cambridge CB4 0WG, U.K.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02810

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

J

_C‑F= 165.1 Hz, C₃), 59.2 (d, J_C‑F= 5.1 Hz, C₁₊₅), 37.9 (d, J_C‑F= 19.8

Hz, C₂₊₄) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ −184.6 (dtt, J = 50.3,

33.0, 17.3 Hz, F₃) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −187.4

(s, F₃) ppm; HRMS (EI) m/z: [M + H]⁺calcd for C₅H₁₂FO₂

123.0816; found 123.0821.

The authors are grateful to AstraZeneca for a CASE award and

to the EPSRC for a CASE conversion grant (EP/M508147/1)

and instrument funding (core capability EP/K039466/1).

2,2-Diﬂuoropentane-1,5-diol (H8). To a solution of 55²³(0.20 g,

0.80 mmol) in Et₂O (8 mL) at rt, NaOMe (25% w/w in MeOH, 750

μL, 3.6 mmol) was added dropwise. After 16 h, the reaction mixture

was ﬁltered through a silica plug (eluting with EtOAc) and

concentrated in vacuo. The crude product was puriﬁed by ﬂash

column chromatography (petroleum ether/acetone, 80:22 to 60:40)

to aﬀord the title compound H8 as a colorless oil (31 mg, 27%). R_f

0.32 (hexane/acetone, 60:40); IR 3331 (br m), 2943 (m), 2883 (m),

1179 (m), 1054 (s), 1004 (s) cm⁻¹; ¹H NMR (400 MHz, MeOD) δ

3.65 (2H, t, J = 13.1 Hz, H₁), 3.59 (2H, t, J = 6.5 Hz, H₅), 2.04−1.91

(2H, m, H₃), 1.74−1.67 (2H, m, H₄) ppm; ¹³C{¹H} NMR (101

MHz, MeOD) δ 125.0 (t, J_C‑F= 241.0 Hz, C₂), 64.4 (t, J_C‑F= 32.3 Hz,

C₁), 62.5 (C₅), 31.0 (t, J_C‑F= 24.6 Hz, C₃), 26.2 (t, J_C‑F= 4.4 Hz, C₄)

ppm; ¹⁹F NMR (376 MHz, MeOD) δ −109.1 (tt, J = 17.3, 12.1 Hz,

F₂) ppm; ¹⁹F{¹H} NMR (376 MHz, MeOD) δ −109.1 (s, F₂) ppm;

HRMS (EI) m/z: [M − CHOH]⁺calcd for C₄H₈F₂O 110.0538;

found 110.0537.

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■

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Skipped Fluorination Motifs: Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs

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