Atom Efficient Synthesis of Selectively Difluorinated Carbocycles through a Gold(I)-Catalyzed Cyclization

Article abstract of DOI:10.1021/acs.joc.8b01121

The intramolecular carbocyclization of difluorinated enol acetals has been achieved for the first time using gold(I) catalysis. Difluorinated enol acetals bearing a pendant alkene group can be cyclized and reduced in one pot to form fluorinated diol motifs. Alternatively, the cyclization of terminal alkynes allows for the synthesis of fluorinated pyran scaffolds. Both cyclization processes can be performed under mild conditions allowing access to complex products rich in functionality. The cyclic systems are synthesized concisely (maximum four steps) from trifluoroethanol, an inexpensive fluorinated feedstock.

Full text of DOI:10.1021/acs.joc.8b01121

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Article
Atom Efficient Synthesis of Selectively Difluorinated
Carbocycles through a Gold(I) Catalyzed Cyclization
Adam W. McCarter, Magdalena Sommer, Jonathan M. Percy,
Craig Jamieson, Alan R. Kennedy, and David Jonathan Hirst
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01121 • Publication Date (Web): 06 Jul 2018
Downloaded from http://pubs.acs.org on July 6, 2018
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Atom Efficient Synthesis of Selectively Difluorinated Carbocycles through a Gold(I)
Catalyzed Cyclization
†
†
†
†
Adam W. McCarter, Magdalena Sommer, Jonathan M. Percy,* Craig Jamieson,* Alan R.
†
‡
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Kennedy, and David J. Hirst
†
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street,
Glasgow G1 1XL, UK.
‡
GlaxoSmithKline R&D Ltd., Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK.
*Email: craig.jamieson@strath.ac.uk; jonathan.m.percy@btinternet.com
Abstract
The intramolecular carbocyclization of difluorinated enol acetals has been achieved for the
first time using gold(I) catalysis. Difluorinated enol acetals bearing a pendant alkene group
can be cyclized and reduced in one pot to form fluorinated diol motifs. Alternatively, the
cyclization of terminal alkynes allows for the synthesis of fluorinated pyran scaffolds. Both
cyclization processes can be performed under mild conditions allowing access to complex
products rich in functionality. The cyclic systems are synthesized concisely (maximum four
steps) from trifluoroethanol, an inexpensive fluorinated feedstock.
Introduction
The design and synthesis of geminal difluoro compounds is an extremely important
objective in medicinal chemistry owing to their unique biological properties, such as enzyme
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inhibition, pKa modulation and improving metabolic stability. However, efficient methods,
starting from sustainable low cost starting materials, for the introduction of the gemꢀ
difluoromethylene group into cyclic molecules are still scarce. One of the most commonly
implemented methods involves fluorination of a cyclic ketone with a nucleophilic
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fluorinating agent such as diethylaminosulfur trifluoride (DAST). An alternative method
recently reported independently by the groups of Amii and Dilman utilizes a
difluorocyclopropanation/ring expansion strategy to effectively introduce the –CF
2
moiety
2,3
(Scheme 1).
Scheme 1. Selection of methods for preparing difluorinated carbocycles.
4
Annulation chemistry based on difluorinated building blocks is much less well established.
In our efforts towards the development of new methods for the synthesis of selectively
difluorinated carbocycles we recently reported the SaegusaꢀIto cyclization as a concise and
efficient protocol for the construction of selectively difluorinated cyclohexenones (Scheme
5
2
).
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Scheme 2. Context of the current study.
Whilst this method represented a novel and exciting synthetic development, it is limited by
poor atom economy arising from the use of two protecting groups, including the very robust
carbamate. A more atom efficient cyclization based on difluorinated enol acetal nucleophiles
would therefore be an attractive approach. While such species have proved effective
substrates in sigmatropic rearrangements, their reactivity as nucleophiles has not been
6
exploited in synthesis. We envisioned that these species could be utilized in a divergent
synthetic strategy to afford either difluorinated diols or pyrans through a gold(I) catalyzed
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cyclization (Scheme 2).
Results and Discussion
Investigation into alkene cyclization. Following protection of trifluoroethanol, the
requisite enol acetal species could be accessed from acetal 1 using our previously established
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oneꢀpot dehydrofluorination/metalation procedure (Scheme 3).
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Scheme 3. Allylic alcohol synthesis
Treatment of 1 with lithium diisopropylamide generates the stabilized organolithium
intermediate 2. Addition of a γ,δꢀunsaturated aldehyde or ketone followed by quenching with
aqueous ammonium chloride delivers the desired allylic alcohols 3. This procedure was
typically performed on a > 10 mmol scale and, where possible, the products were purified by
Kugelrohr distillation. A range of allylic alcohols were synthesized including, heterocyclic,
geminally disubstituted and alicyclic analogues (Table 1).
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Table 1: Difluorinated allylic alcohols 3 prepared from 1.
1
1
1
1
1
1
1
1
1
1
2
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a
b
Electrophile
Product
Yield (%)
dr
c
19:1
trans-3a/cis-3a
69
c, d
32:1
trans-3b
3
2
c
3.5:1
trans-3c/cis-3c
56
c, e
4.9:1
trans-3d/cis-3d
42
MEMO
F
73
-
-
-
-
-
OH
3
e
F
64
f
61
g
31
f
30
3
2:1
c, e
19
trans-3j/cis-3j
a
b
c
e
Isolated yields. All reactions were carried out with 12 mmol of 1 unless otherwise stated.
1
9
Diastereomeric ratio determined by F NMR spectroscopy; for mixtures the major isomer is shown.
d
Isolated as a mixture of cisꢀ and transꢀ diastereoisomers, major isomer shown. At 9.5 mmol scale.
f
g
At 5 mmol scale. At 10 mmol scale. At 8 mmol scale.
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These allylic alcohols were indefinitely stable when stored at 0 °C. With access to the
requisite substrates secured, the allylic alcohol 3a was chosen as a model substrate to
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investigate the proposed novel cyclization. We began our studies using cyclization
0
1
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conditions similar to those reported by Toste for the carbocyclization of silyl enol ethers onto
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gold activated alkynes (Table 2).
Table 2: Optimization of the oneꢀpot cyclization reduction.
Au cat.
(mol%)
AgSbF
(mol%)
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time
(h)
reducing
agent
yield
(%)
Au cat.
a
1
2
3
4
5
6
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
5
5
5
5
5
5
5
22
ꢀ
NaBH
4
42
70
68
51
TBAB
2.5
1
2.5
1
TBAB
TBAB
b
Ph
3
PAuCl
5
5
ꢀ
ꢀ
ꢀ
0
b
IPrAuCl
None
5
ꢀ
ꢀ
0
b
7
ꢀ
5
ꢀ
0
a
Isolated Yield. Product was isolated as a mixture of 1,3ꢀtrans, 1,8aꢀtrans and 1,3ꢀ
b
cis, 1,8aꢀtrans diastereoisomers (2.6:1), Major isomer shown. No cyclized product
could be detected by 19F NMR.
Using silver hexafluoroantimonate(V) as a chloride abstractor (generating the catalytically
active cationic gold species in situ) in conjunction with 5 mol% 1,3ꢀbis(2,6ꢀ
1
0
diisopropylphenylꢀimidazolꢀ2ꢀylidene)gold(I) chloride (IPrAuCl)
ensured a successful
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cyclization and
the difluoroketone intermediate was reduced in situ using
tetrabutylammonium borohydride (TBAB).
The improved solubility of TBAB over sodium borohydride in the reaction media may have
accounted for the higher yield of 4a (Entry 2, 70%, 2.6:1 dr).
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Lower catalyst loadings resulted in diminished yields and more protracted purification
procedures, whilst application of a phosphine based catalyst yielded no cyclized product. The
necessary control reactions in the absence of both silver and gold catalyst were also
performed. In both cases no cyclized product could be detected from the reaction indicating
that both silver and gold components must be present in order for the cyclization to proceed
smoothly. It is possible that the αꢀhydroxy functionality may also provide some stereocontrol
during the reduction process through dihydrogen bonding as no cisꢀdiol was observed in the
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reaction mixture (Scheme 4).
Scheme 4: Selective reduction affording 1,3ꢀtrans, 1,8aꢀtrans 4a (left) and 1,3ꢀcis, 1,8aꢀ
trans 4a (right).
With optimized conditions in hand, we next investigated the scope of the one pot
cyclization/reduction reaction (Table 3).
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Table 3: Scope of oneꢀpot cyclization/reduction method.
0
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b
Allylic Alcohol
Product
Yield(%)
dr
.6:1
2
1
9:1
1
2
70
1, 3ꢀtrans, 1, 8aꢀtrans:
1, 3ꢀcis, 1, 8aꢀtrans
trans-3a/cis-3a
4
.9:1
3
2:1
69
48
1, 3ꢀtrans, 1, 9aꢀtrans:
1, 3ꢀcis, 1, 9aꢀtrans
trans-3b/cis-3b
6
.7:1.4:1
4
a, 5ꢀtrans, 5, 7ꢀtrans:
4a, 5ꢀtrans, 5, 7ꢀcis:
4a, 5ꢀcis, 5, 7ꢀcis
3
.5:1
3
4
trans-3c/cis-3c
3
.4:0.9:1
4
a, 5ꢀtrans, 5, 7ꢀtrans:
4a, 5ꢀtrans, 5, 7ꢀcis:
4.9:1
trans-3d/cis-3d
c
50
4
a, 5ꢀcis, 5, 7ꢀcis
d
>20:1
5
6
3e
3e
25
1
, 2ꢀtrans, 2, 4ꢀtrans
d
>20:1
16
1, 2ꢀtrans, 2, 4ꢀcis
>
20:1
7
8
3f
11
63
1
1
, 2ꢀcis, 2, 4ꢀtrans
>
20:1
, 2ꢀcis, 2, 4ꢀtrans
.3:1:0.1
, 5ꢀtrans, 5, 7ꢀcis:
4, 5ꢀtrans, 5, 7ꢀtrans:
, 5ꢀcis, 5, 7ꢀcis
.8:1
3g
1
4
d
9
3h
3i
29
4
3
1
0
44
6, 7ꢀtrans, 7, 9ꢀtrans:
6, 7ꢀcis, 7, 9ꢀtrans
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.3:1
3, 4aꢀcis:
, 4aꢀtrans
32:1
trans-3j/cis-3j
e
11
29
3
a
b
19
Isolated yield. Diastereomeric ratio determined by F NMR spectroscopy; for mixtures the major
c
d
isomer is shown. 10 days reaction time. Diastereoisomers could be separated by normal phase
e
chromatography. From corresponding alkyne. 15 minutes reaction time and TBAB not added.
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Cyclizations were typically performed on 1 mmol scale. Annelations afforded a range of
fused bicyclic difluorinated diols 4a-4d and the reaction also tolerated the formation of
heterocycles 4cꢀ4d. More challenging annulations could also be performed on both
unsubstituted and substituted cyclization precursors. It was possible to isolate the single
trans, trans diastereoisomers of 4a and 4b by recrystallization of the mixtures by vapor
diffusion using chloroform/pentane. We were able to isolate diastereoisomerically pure trans,
trans 4ea and trans, cis 4eb as well as a mixture of both the cis,cis and trans, trans
diastereoisomers (1.2:1 respectively, 15%) representing an overall yield of 56%. Annulations
generally required a minimum level of substitution on the chain and a lower yield was
obtained for the least substituted system 4f (11 %). Gemꢀdimethyl 4g was isolated in good
yield and diastereoselectivity. In this case the selectivity of the reduction can be rationalized
from consideration of the bulky borohydride reagent preferentially attacking the proꢀ
equatorial face of the ketone, avoiding an unfavorable steric interaction with the axial Cꢀ3
12
methyl substituent of the ring. Consequently, the carbon center which is reduced now bears
an S configuration. Spirocycles 4h and 4i were both isolated as mixtures of diastereoisomers
in moderate yield and for the spiroꢀcyclopropyl analogue, it was also possible to isolate small
quantities of both trans, trans 4h (5%) and trans, cis 4h (6%) as single diastereoisomers
(
representing an overall yield of 40%). The stereochemical outcome of the reduction of spiroꢀ
cyclopentyl 4i is equivalent to gemꢀdimethyl 4g and the two diastereoisomers formed both
have S configuration at the reduced carbon center. Conversely, the three diastereoisomers
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isolated for 4h have the opposite R configuration. This can be rationalized by consideration
of the position of the ‘axial’ methylene group in 4h. The strained cyclopropane ring requires
3
bond angles to be smaller than those of typical sp hybridized carbons; therefore, the
methylene is not adopting a defined axial position, allowing the borohydride reagent to attack
the proꢀaxial face of the ketone. The threeꢀdimensional nature of such spirocyclic derivatives
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are of particular interest in medicinal chemistry and drug discovery. In reactions where
multiple diastereoisomers were formed there structures were elucidated through a
19
1
combination of Xꢀray crystallographic analysis, 2D NMR and Fꢀ H HOESY spectroscopic
14
experiments.
Attempted cyclization of a terminal alkyne substrate did not yield the desired product and
instead afforded nonꢀfluorinated pyran 5. A working hypothesis as to how this product may
be obtained is outlined in Scheme 5. We believe that initial attack of methanol onto the gold
activated alkyne followed by a cyclization/elimination cascade is responsible for the
formation of 5.
Scheme 5. Proposed mechanism for formation of 5.
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Although unexpected this result was encouraging and we hypothesized that we could utilize
the enhanced reactivity of the alkyne functionality to synthesize alternative difluorinated
scaffolds.
Investigation into alkyne cyclization. Pyrans are becoming an increasingly important
1
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heterocyclic scaffold in medicinal chemistry and can be found in a variety of bioactive
1
5
compounds. Only slight modification of the current synthetic route would enable access to
structurally unique difluorinated pyran variants (Scheme 6)
Scheme 6. Retrosynthetic route to difluorinated pyrans.
A small palette of propargyl ethers 6 were synthesized from difluoroallylic alcohols 3 using
(6a)
our published propargylation procedure (Table 4).
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Table 4 – Propargyl ethers 6 synthesized from allylic alcohols 3.
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Allyl Alcohol
Propargyl Ether
Isolated Yield (%)
71
6a
6b
68
88
79
74
6c
6d
6e
6f
88
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Simply treating difluoroallylic alcohols 3 with slight excess of propargyl bromide in a 50%
aqueous solution of sodium hydroxide and a phase transfer catalyst afforded the desired
propargyl ethers in good yield. Alkyne 6a was chosen as a model substrate to investigate the
proposed cyclization. Knowing that the alkyne moiety was susceptible to attack from
methanol, the previously established cyclization conditions were employed in the absence of
this solvent (Table 5).
1
1
1
1
1
1
1
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2
2
2
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4
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Table 5: Optimisation of alkyne cyclization.
Time
a
Au catalyst
Temp (°C)
Solvent
Isolated Yield (%)
(h)
1
2
3
4
5
6
7
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
rt
rt
rt
rt
rt
DCM
Toluene
THF
2ꢀMeTHF
CPME
4
5
3
21
5
21
61
0
65
61
49
b54
b
40
rt
2ꢀMeTHF
2ꢀMeTHF
2
24
Ph
3
PAuCl
a
Yield calculated based on the molecular weight of the hydrate component. Polymerisation
observed.
Using dichloromethane in a single solvent system it was possible to isolate the desired
cyclized product, albeit in low yield. Given that α,αꢀdifluoroketones are known to readily
hydrate the products were often isolated as a mixture of the ketone 7a and corresponding
1
7
hydrate 8a. Upon switching to toluene the reaction was complete after 5 hours, and a
significant increase in yield was observed. Whilst toluene appeared suitable for this particular
substrate we found it to be incompatible with others and instead formed complex mixtures.
As the objective was to identify a generic solvent which was not just substrate specific we
decided to continue with further solvent screening. Polymerization of the reaction mixture
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was observed when tetrahydrofuran was used. Tetrahydrofuran is known to undergo
polymerization in the presence of catalytic quantities of metal halide salts, therefore the
1
7
6
AgSbF used in the reaction is likely to be the trigger for this process. This unwanted
polymerization could be avoided by switching to 2ꢀmethyltetrahydrofuran (2ꢀMeTHF).
Pleasingly, this solvent was not substrate specific and was compatible with other cyclizations.
The ability to conduct the reaction in this inexpensive, sustainable solvent at room
0
1
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0
18
temperature is an attractive feature of the methodology. Using cyclopentyl methyl ether
(CPME) as an alternative ethereal solvent gave similar results to those obtained in toluene
and also proved ineffective with other substrates screened. Following this screen we decided
to use 2ꢀMeTHF as the solvent of choice for moving forward with the investigation.
Increasing the reaction temperature significantly decreased the reaction time; however, this
3
was accompanied by a lower product yield. Ph PAuCl could also be used as a catalyst for the
reaction; however, the best results were achieved by using IPrAuCl.
The reaction tolerated a variety of substituents. Carbocyclic analogue 8b was isolated in
comparable yield to the model substrate and, in this case, the ketone existed as the major
component in the mixture. In contrast heterocycle 8c was isolated exclusively as the hydrate.
This material was recrystallized by vapor diffusion using tetrahydrofuran/pentane and its
structure confirmed by single crystal Xꢀray diffraction. It was also pleasing to note that the
reaction tolerated aromatic substituents. Phenyl analogue 8d and electron withdrawing
(trifluoromethyl) phenyl 8e were isolated in good yield. This result was encouraging as we
had previously been unable to access such cyclic difluorinated systems bearing aromatic
5
substituents. Electron withdrawing aromatic substituents were tolerated; however, we were
unable to isolate electron rich aromatic 8f and the reaction yielded only a complex mixture
(Table 6).
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Table 6 – Scope of Alkyne Cyclization.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
3
4
4
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4
4
4
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4
4
4
5
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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9
0
a
b
Alkyne
Product
Isolated Yield Ketone:Hydrate
c
1
2
3
4
6a
65
1:1
7.3:1
0:1
d
6b
6c
6d
63
62
52
c
c
1:3.8
c
5
6
6e
6f
52
0
1:6.1
ꢀ
a
b
19
Isolated yield. Yield is based upon major component. Ratio determined by F NMR spectroscopy;
c
in each example the hydrate component is shown. Yield calculated based on the molecular weight of
d
the hydrate component. Yield calculated based on the molecular weight of the ketone component.
Conclusion
The methodology described allows for the concise synthesis of either difluorinated diol or
difluorinated pyran scaffolds (3 steps and 4 steps respectively from trifluoroethanol, an
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inexpensive commercial feedstock). Cyclizations are simple to perform and complex diol
fragments can be synthesized via a one pot cyclization/reduction method under mild
conditions in reactions vessels open to air. Alkyne cyclizations can be performed under
similarly mild conditions at room temperature in 2ꢀMethyltetrahydrofuran to afford products
0
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3
rich in functionality and sp character and inaccessible by concise methods.
Experimental Section
General Methods. NMR spectra were recorded on Bruker DPXꢀ400, AVꢀ500 and Avanceꢀ
1
19
13
II+ 600 spectrometers. H, F and C NMR spectra were recorded using the deuterated
solvent as the lock and the residual solvent as the internal reference. The multiplicities of the
spectroscopic data are presented in the following manner: s = singlet, d = doublet, dd =
double doublet, dt = doublet of triplets, dq = doublet of quartets, dquint = doublet of quintets,
ds = doublet of sextets, qd = quartet of doublets, qt = quartet of triplets, ddt = doublet of
double triplets, ddd= doublet of doublet of doublets, dddd = doublet of double doublet of
doublets, dddt = doublet of double doublet of triplets, tdd = triplet of doublet of doublets, td =
triplet of doublets, t = triplet, q = quartet, m = multiplet and br. = broad. Unless stated
3
otherwise, all couplings refer to J homocouplings. IR spectra were recorded on an ATR IR
spectrometer. GC/MS spectra were obtained on an instrument fitted with a DB5ꢀtype column
−1
(
30 m × 0.25 ꢁm) running a 40−320 °C temperature program, ramp rate 20 °C min with
3
−1
helium carrier gas flow at 1 cm min . Chemical ionisation (CI) (methane/ammonia) and
Electron Ionisation (EI) mass spectra were recorded on either an Agilent Technologies 5975C
mass spectrometer or a FINNIGAN MAT 95 high resolution double focussing (BE) mass
spectrometer (EPSRC National Mass Spectrometry Service Centre, Swansea). HRMS
measurements were obtained from a Waters GCT Premier MS (CI), Finnigan Mat 95 XP (EIꢀ
MS and/or APCIꢀMS), Thermo Scientific LTQ Orbitrap XL via Advion TriVersa NanoMate
infusion (ESI) or Waters Xevo G2ꢀS Atmospheric Solids Analysis Probe (APCI, Positive
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mode, Xevo) spectrometers (EPSRC National Mass Spectrometry Service Centre, Swansea).
Thin layer chromatography was performed on preꢀcoated aluminiumꢀbacked silica gel plates
(E. Merck AG, Darmstadt, Germany. Silica gel 60 F254, thickness 0.2 mm). Visualisation
was achieved using potassium permanganate dip or UV detection at 254 nm. Column
chromatography was performed on silica gel (Zeochem, Zeoprep 60 HYD, 40ꢀ63 ꢁm) using a
Büchi Sepacore system. Hexane was distilled before chromatography. [(IPr)AuCl] (IPr =
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
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6
0
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9
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6
1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazoleꢀ2ꢀylidene, 95%) and AgSbF (98%) were purchased
from Strem Chemicals and used as received. THF was dried using a PureSolv system from
Innovative Technology, Inc.. Diisopropylamine was distilled from 4Å molecular sieves (30
°C/140 mbar) and stored under nitrogen over 4Å molecular sieves. All other chemicals were
purchased from Sigma Aldrich, Alfa Aesar, or Fluorochem. All compounds were named
according to the ChemDraw Professional 15.0 package and checked against Scifinder®
chemical database. Singleꢀcrystal data were measured at with Oxford Diffraction CCD
Diffractometers and with sealedꢀtube generated, graphite monochromated radiation. The
exception was 7c for which data was measured by the UK National Crysallography Service
19
using a Rigaku FRE+ rotating anode. The structures were solved by direct methods (SIR92,
2
SHELXS) and refined to convergence on F and against all independent reflections by fullꢀ
20,21
matrix leastꢀsquares using SHELXL programs.
All nonꢀhydrogen atoms were refined
anisotropically and hydrogen atoms were geometrically placed and allowed to ride on their
parent atoms. For compound trans, transꢀ4a, crystals grew as stacked plates. Reprocessing
the raw data for this compound as a twinned sample gave a hklf 5 format reflection file.
Refinement with this gave significantly better R factors and residual electron density features
with BASF = 0.265(23). Table S1 contains selected crystallographic and refinement data.
CCDCꢀ1582563 to CCDCꢀ1582570 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge Crystallographic Data
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6
Centre via www.ccdc.cam.ac.uk/data_request/cif. LDA and nꢀButyllithium (2.5 M solution in
22
hexanes) was titrated according to the method of Duhamel and Plaquevent. The data for
6c,8,23
products 3f, 3g, 3n, and 3p have previously been reported.
General Procedure A: Allylic Alcohol Preparation. Transꢀ2ꢀallylꢀ1ꢀ(2,2ꢀdifluoroꢀ1 ((2ꢀ
methoxyethoxy)methoxy)ethenyl) cyclohexanꢀ1ꢀol (transꢀ3a) and cisꢀ2ꢀallylꢀ1ꢀ(2,2ꢀdifluoroꢀ
1’ ((2ꢀmethoxyethoxy)methoxy)ethenyl) cyclohexanꢀ1ꢀol (cisꢀ3a). Prepared according to the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
method of Percy and coꢀworkers. nꢀButyllithium (12.9 mL of a 1.94 M solution in hexanes,
25 mmol) was added dropwise to a solution of diisopropylamine (3.70 mL, 26 mmol) in THF
(12 mL) at ꢀ78 °C. Following addition the reaction vessel was transferred to an ice bath and
allowed to warm to 0 °C and stirred at this temperature for 45 minutes. The flask was then reꢀ
8
cooled to ꢀ78 °C and acetal 1 (1.90 mL, 12 mmol) was added dropwise over 15 minutes. The
dark orange suspension was stirred at ꢀ78 °C for 30 minutes, then allylcyclohexanone (1.97
mL, 13.2 mmol) was added. The reaction mixture was allowed to warm to rt overnight; the
reaction mixture turned homogeneous and darkened over this time. The mixture was
quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl
4
acetate (4 x 60mL). The combined organic extracts were dried (MgSO ), filtered and
concentrated to afford crude allylic alcohols trans-3a and cis-3a (3.23 g) as a dark brown oil.
The material was taken up in dichloromethane and transferred by pipette to a glass sinter
funnel (diameter 7.5 cm) containing a pad of silica (54 g). The product was then eluted from
the plug with 70% diethyl ether/hexane (600 mL). The solvent was evaporated under reduced
pressure to afford the product as a pale orange oil (2.93 g). The crude allylic alcohol was
purified by Kugelrohr distillation to afford an inseparable mixture of trans-3a and cisꢀ3a as a
f
pale yellow oil (2.53 g, 69 %, 95:5). b.p. = 97 °C / 0.04 mmHg; R = 0.27 (40 % diethyl ether
1
in hexane); H NMR (400 MHz, CDCl
3
): δ = 5.77 (dddd, J = 17.0, 10.1, 8.5, 5.8 Hz, 1H),
5.06ꢀ4.95 (m, 2H), 4.93 (app. s, 2H), 3.94ꢀ3.81 (m, 2H), 3.62ꢀ3.54 (m, 2H), 3.40 (s, 3H), 2.62
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1
3
(br. s, 1H), 2.29ꢀ2.16 (m, 1H), 1.98ꢀ1.88 (m, 1H), 1.86ꢀ1.08 (envelope, 9H) ppm; C NMR
1
2
3
(100 MHz, CDCl ): δ = 154.4 (t, JCꢀF = 287.1 Hz), 137.6, 121.5 (dd, JCꢀF = 33.1, 10.3 Hz),
4
3
4
1
15.8, 98.7 (t, JCꢀF = 4.2 Hz), 73.7 (d, JCꢀF = 5.6 Hz), 71.6, 68.9, 58.9, 41.9 (d, JCꢀF = 4.8
4
Hz), 37.1 (t, J = 2.9 Hz), 35.2, 26.4, 25.3, 21.2 ppm; Major transꢀdiastereoisomer 3a
CꢀF
1
1
1
1
1
1
1
1
1
1
2
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2
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2
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2
2
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3
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6
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1
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4
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7
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9
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9
2
(
assigned on the basis of δ and intensity) F NMR (376 MHz, CDCl ): δ = ꢀ98.8 (d, J = 73.4
3
2
Hz, 1F), ꢀ103.6 (d, J = 73.4 Hz, 1F) ppm;* Minor cisꢀdiastereoisomer 3a (assigned on the
1
9
2
basis of δ and intensity) F NMR (376 MHz, CDCl
3
): δ = ꢀ97.5 (d, J = 68.6 Hz, 1F), 104.4
2
ꢀ1
(d, J = 68.6 Hz, 1F) ppm; νꢀ /(neat) = 3450, 2934, 1738, 1450, 1104, 1059 cm ; HRMS (NSI):
+
calcd for C15
H
28
F
2
O
4
N, 324.1981 [M+NH
4
] , found: 324.1983; MS (CI): m/z (%): 201 (14)
+
+
+
[
MꢀC
4
H
9
O
3
] , 89 (100) [C
4
H
9
O
2
] , 59 (85) [C
3
H
7
O] ; t
R
(GC) = 13.17 minutes**. *this is by
5
comparison with compounds from the SaegusaꢀIto series. ** the cisꢀ and transꢀstereoisomers
appeared as one peak by GC.
transꢀ2ꢀallylꢀ1ꢀ(2,2ꢀdifluoroꢀ1ꢀ((2ꢀmethoxyethoxy)methoxy)vinyl)cycloheptanꢀ1ꢀol
(
transꢀ3b) and cisꢀ2ꢀallylꢀ1ꢀ(2,2ꢀdifluoroꢀ1ꢀ((2ꢀmethoxyethoxy)methoxy)vinyl)cycloheptanꢀ
1
ꢀol (cisꢀ3b). Prepared as for trans-3a and cis-3a from acetal (1.50 mL, 9 mmol), nꢀ
butyllithium (12.8 mL of a 1.48 M solution in hexanes, 19 mmol), diisopropylamine (2.85
5
mL, 20 mmol) and allylcycloheptanone (1.45 g, 9.5 mmol) in THF (12 mL). The crude
allylic alcohol (3.13 g) was purified by Kugelrohr distillation to afford an inseparable mixture
of trans-3b and cis-3b as a pale yellow oil (0.99 g, 32 %, 97:3). b.p. = 93 °C / 0.04 mmHg; R
f
1
=
0.27 (40 % diethyl ether in hexane); H NMR (400 MHz, CDCl
3
): δ = 5.79 (dddd, J = 16.9,
1
2
1
0.2, 8.6, 5.2 Hz, 1H), 5.08ꢀ4.98 (m, 2H), 4.96, 4.92 (ABq, JAB = 6.1 Hz, 2H), 3.94ꢀ3.84 (m,
H), 3.62ꢀ3.52 (m, 2H), 3.40 (s, 3H), 2.79 (br. s, 1H), 2.27ꢀ2.15 (m, 1H), 2.09ꢀ1.99 (m, 1H),
13
.99ꢀ1.89 (m, 1H), 1.87ꢀ1.20 (envelope, 10H) ppm; C NMR (100 MHz, CDCl ): δ = 154.1
3
1
2
4
(t, JCꢀF = 287.5 Hz), 137.6, 121.9 (dd, JCꢀF = 32.2, 10.2 Hz), 115.5, 98.3 (t, JCꢀF = 4.2 Hz),
3
4
76.3 (d, JCꢀF = 6.0 Hz), 71.1, 68.5, 58.5, 45.1 (d, JCꢀF = 5.2 Hz), 39.4, 35.8, 27.7, 26.8, 24.9,
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3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9
20.0 ppm; Major transꢀdiastereoisomer 3b (assigned on the basis of δ and intensity) F NMR
2
2
(376 MHz, CDCl
3
): δ = ꢀ98.6 (d, J = 74.1 Hz, 1F), ꢀ103.9 (d, J = 74.1 Hz, 1F) ppm;* Minor
1
9
cisꢀdiastereoisomer 3b (assigned on the basis of δ and intensity) F NMR (376 MHz,
2
2
CDCl
3
): δ = ꢀ97.7 (d, J = 72.6 Hz, 1F), 103.0 (d, J = 72.6 Hz, 1F) ppm; νꢀ /(neat) = 3464,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ
1
2
921, 1733, 1262, 1050, 952 cm ; HRMS (APCI): calcd for C16
H
30
F
2
O
N
4 1
, 338.2137
+
+
[
M+NH ] , found: 338.2140; MS (CI): m/z (%): 338 (100) [M+NH ] ; t (GC) = 14.17
4
4
R
5
minutes.** *this is by comparison with compounds from the SaegusaꢀIto series. ** the cisꢀ
and transꢀstereoisomers appeared as one peak by GC.
trans-3-allyl-4-(2,2-difluoro-1-((2-methoxyethoxy)methoxy)vinyl)tetrahydro-2H-
pyran-4-ol
(trans-3c)
and
cis-3-allyl-4-(2,2-difluoro-1-((2-
methoxyethoxy)methoxy)vinyl)tetrahydro-2H-pyran-4-ol (cis-3c). Prepared as for trans-3a
and cis-3a from acetal (1.90 mL, 12 mmol), nꢀbutyllithium (12.9 mL of a 1.94 M solution in
5
hexanes, 25 mmol), diisopropylamine (3.70 mL, 26 mmol) and 2ꢀallyltetrahydropyranone
(
1.68 g, 12 mmol) in THF (12 mL). The crude allylic alcohol (3.13 g) was purified by
Kugelrohr distillation to afford an inseparable mixture of trans-3c and cis-3c as a pale yellow
oil (2.06 g, 56 %, 78:22). b.p. = 93 °C / 0.04 mmHg; R
f
= 0.25 (30 % ethyl acetate in hexane);
1
Major transꢀdiastereoisomer 3c (assigned on the basis of δ and intensity) H NMR (400 MHz,
CDCl ): δ = 5.90ꢀ5.65 (m, 1H), 5.21ꢀ4.81 (m, including 4.96 (app. s, 2H) 2H), 4.03ꢀ3.67
3
(envelope, 5H), 3.60 (t, J = 4.7 Hz, 2H), 3.57ꢀ3.49 (m, 1H), 3.41 (s, 3H), 3.16 (br. s, 1H),
1
3
1
2
1
5
.29ꢀ1.39 (envelope, 5H) ppm; C NMR (100 MHz, CDCl
3
): δ = 153.9 (t, JCꢀF = 288.1 Hz),
2
4
3
35.8, 120.5 (dd, JCꢀF = 32.8, 10.4 Hz), 115.9, 98.6 (t, JCꢀF = 4.4 Hz), 71.0, 70.5 (d, JCꢀF
=
4
19
.7 Hz), 68.6, 66.7, 62.9, 58.4, 40.5 (d, JCꢀF = 5.1 Hz), 36.6, 30.4 ppm; F NMR (376 MHz,
2
2
CDCl ): δ = ꢀ98.0 (d, J = 71.8 Hz, 1F), ꢀ103.3 (d, J = 71.8 Hz, 1F) ppm;* Minor cisꢀ
3
1
diastereoisomer 3c (assigned on the basis of δ and intensity) H NMR (400 MHz, CDCl
3
): δ =
1
3
1
3 3
3.41 (s, OCH , 3H) ppm; C NMR (100 MHz, CDCl ): δ = 155.0 (t, JCꢀF = 290.7 Hz), 136.4,
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121.4 (dd, JCꢀF = 31.2, 12.0 Hz), 116.0, 70.9, 68.2, 63.6, 62.5 (d, JCꢀF = 4.8 Hz), 41.7, 40.0,
19
2
2
31.7 ppm; F NMR (376 MHz, CDCl
3
): δ = ꢀ96.7 (d, J = 66.4 Hz, 1F), 104.5 (dt, J = 68.6,
5
ꢀ1
J
FꢀH = 4.9 Hz, 1F) ppm; νꢀ /(neat) = 3443, 2928, 1736, 1100, 1056 cm ; HRMS (APCI):
+
calcd for C14
H
26
F
2
O
5
4
N, 326.1774 [M+NH ] , found: 326.1772; MS (CI): m/z (%): 326 (100)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[
M+NH
4
] ; t
R
(GC) = 13.73 minutes (major transꢀdiastereoisomer), 13.66 minutes (minor cisꢀ
5
diastereoisomer). *this is by comparison with compounds from the SaegusaꢀIto series.
trans-tert-butyl
-3-allyl-4-(2,2-difluoro-1-((2-methoxyethoxy)methoxy)vinyl)-4-
hydroxypiperidine-1-carboxylate (trans-3d) and cis-tert-butyl -3-allyl-4-(2,2-difluoro-1-((2-
methoxyethoxy)methoxy)vinyl)-4-hydroxypiperidine-1-carboxylate (cis-3d). Prepared as for
trans-3a and cis-3a from acetal (0.79 mL, 5mmol), commercial LDA (5.9 mL of a 1.70 M
solution in THF/heptane/ethylbenzene, 24 mmol) and tertꢀbutyl 3ꢀallylꢀ4ꢀoxopiperidineꢀ1ꢀ
5
carboxylate (1.19 g, 5 mmol) in THF (5 mL). The crude allylic alcohol was purified by flash
column chromatography (90 g cartridge, 45% ethyl acetate in hexane) to afford an
f
inseparable mixture of transꢀ3d and cisꢀ3d as a pale orange oil (0.86 g, 42 %, 83:17). R =
1
0
1
3
.59 (50 % ethyl acetate in hexane); H NMR (400 MHz, CDCl
3
): δ = 5.79 (dddd, J = 17.3,
0.1, 8.5, 5.7 Hz, 1H), 5.14ꢀ4.99 (m, 2H), 4.94 (s, 2H), 4.17ꢀ3.71 (m, 4H), 3.70ꢀ3.51 (m, 2H),
.41 (s, 3H), 3.31ꢀ3.04 (m, 2H), 2.87 (br. s, 1H), 2.34ꢀ2.18 (m, 1H), 2.06ꢀ1.73 (m, 4H), 1.47
1
(
s, 9H) ppm (the H NMR gave a clear well resolved spectrum at RT and did not require
13
heating). Major transꢀdiastereoisomer 3d (assigned on the basis of δ and intensity) C NMR
1
2
(
150 MHz, tolueneꢀd
8
, 373 K): δ = 154.7 (t, JCꢀF = 288.1 Hz), 154.2, 137.0, 121.2 (dd, JCꢀF
4
3
=
32.4. 10.7 Hz), 115.5, 98.8 (dd, J = 5.8, 3.4 Hz), 78.4, 72.1 (d, J = 5.2 Hz), 71.5,
CꢀF
CꢀF
4
4
19
6
9.0, 58.0, 44.0, 41.3 (d, JCꢀF = 4.2 Hz), 39.6, 36.5 (t, JCꢀF = 3.2 Hz), 31.9, 28.1 ppm;
F
2
2
(
8
376 MHz, tolueneꢀd , 373 K): δ = ꢀ98.6 (d, J = 74.3 Hz, 1F), ꢀ104.6 (d, J = 74.3 Hz, 1F)
1
3
ppm;* Minor cisꢀdiastereoisomer 3d (assigned on the basis of δ and intensity) C NMR (150
1
MHz, tolueneꢀd
8
, 373 K): δ = 155.7 (t, JCꢀF = 289.3 Hz), 154.6, 136.4, 115.8, 78.3, 72.4 (dd,
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2
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2
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2
2
2
2
3
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3
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3
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5
5
6
3
19
J
CꢀF = 4.6, 2.3 Hz), 71.4, 68.8, 50.1, 42.9, 40.9, 39.7, 32.1, 28.1 ppm; F (376 MHz, tolueneꢀ
2
2
d
2
4
8
, 373 K): δ = ꢀ97.5 (d, J = 69.1 Hz, 1F), ꢀ104.8 (d, J = 69.1 Hz, 1F) ppm; νꢀ /(neat) = 3430,
ꢀ1
32 2 6
926, 1736, 1666, 1426, 1158, 1056, 989 cm ; HRMS (NSIꢀES): calcd for C19H F NO ,
+
+
08.2192 [M+H] , found: 408.2189; MS (CI): m/z (%): 408 (100) [M+H] ; t
R
(GC) = 14.91
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
minutes.** *this is by comparison with compounds from the SaegusaꢀIto series. ** the cisꢀ
and transꢀstereoisomers appeared as one peak by GC.
1,1-difluoro-2-((2-methoxyethoxy)methoxy)-3-methylhepta-1,6-dien-3-ol
(3e).
Prepared as for trans-3a and cis-3a from acetal (1.90 mL, 12 mmol), nꢀbutyllithium (12.9 mL
of a 1.94 M solution in hexanes, 25 mmol), diisopropylamine (3.70 mL, 26 mmol) and 5ꢀ
hexenꢀ2ꢀone (1.39 mL, 12 mmol) in THF (12 mL). The crude product (2.54 g) was purified
by Kugelrohr distillation to afford 3e (2.33 g, 73 %) as a pale yellow oil. b.p. = 78 °C / 0.04
1
mmHg; R
f
= 0.27 (50 % diethyl ether in hexane); H NMR (400 MHz, CDCl
3
): δ = 5.85 (ddt,
4
2
2
J = 16.9, 10.1, 6.5 Hz, 1H), 5.06 (dq, J = 16.9, J = J = 1.9 Hz, 1H), 5.00 (d, J = 6.4 Hz,
4
2
2
1
3
2
H), 4.97 (dq, J = 10.1, J = J = 1.9 Hz, 1H), 4.93 (d, J = 6.4 Hz, 1H), 3.98ꢀ3.81 (m, 2H),
4
.59 (br. t, J = 4.8 Hz, 2H), 3.41 (s, 3H), 3.39 (br. s, 1H), 2.10 (app. qt, J = 7.6, J = 1.9 Hz,
5
13
H), 1.87ꢀ1.68 (m, 2H), 1.42 (d, J = 4.8 Hz, 3H) ppm; C (100 MHz, CDCl ): δ = 154.2
HꢀF
3
1
2
4
(t, JCꢀF = 288.6 Hz), 137.8, 121.0 (dd, JCꢀF = 32.7, 10.5 Hz), 114.0, 98.5 (t, JCꢀF = 4.1 Hz),
3
4
19
7
1.1 (d, JCꢀF = 3.7 Hz), 71.0, 68.5, 58.5, 39.3, 28.1, 24.5 (d, JCꢀF = 7.1 Hz) ppm; F (376
2
2
5
3
MHz, CDCl ): δ = ꢀ98.4 (d, J = 70.9 Hz, 1F), ꢀ103.9 (app. dq, J = 70.9 Hz, JFꢀH = 4.8 Hz,
ꢀ1
1
F) ppm; νꢀ /(neat) = 3447, 2928, 1736, 1102, 1024 cm ; HRMS (NSIꢀES): calcd for
+
C
12 20 2 4
H F O Na, 289.1222 [M+Na] , found: 289.1221; MS (CI): m/z (%): 161 (4) [Mꢀ
+
+
+
C H O ] , 89 (73) [C H O ] , 59 (100) [C H O] ; t (GC) = 11.38 minutes.
4
9
3
4
9
2
3
7
R
1
,1-Difluoro-2-((methoxyethoxy)methoxy)-3-methyl-4-cyclopropyl-hepta-1,6-dien-3-ol
(3h). Prepared as for trans-3a and cis-3a from acetal (1.26 mL, 8 mmol), nꢀbutyllithium (8.3
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mL of a 1.98 M solution in hexanes, 16 mmol), diisopropylamine (2.38 mL, 17 mmol) and 1ꢀ
5
(1ꢀallylcyclopropyl)ethanꢀ1ꢀone (1.00 g, 8 mmol) in THF (8 mL). The crude product (1.41
g) was purified by Kugelrohr distillation to afford 3h (0.730 g, 31 %) as a pale yellow oil.
1
b.p. = 93 °C / 0.06 mmHg; R = 0.54 (40 % ethyl acetate in hexane); H NMR (400 MHz,
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
CDCl ): δ = 5.70 (ddt, J = 17.3, 10.2, 7.3 Hz, 1H), 5.11ꢀ4.96 (m, including 5.05 (d, J = 6.4
3
2
Hz, 1H), 2H), 4.91 (d, J = 6.4 Hz, 1H), 4.00ꢀ3.80 (m, 2H), 3.59 (t, J = 4.8 Hz, 2H), 3.41 (s,
5
3H), 3.12 (br. s, 1H), 2.34ꢀ2.13 (m, 2H), 1.42 (d, JHꢀF = 5.8 Hz, 3H), 0.84ꢀ0.75 (m, 1H), 0.63
2
2
(ddd, J = 9.9, J = 5.8, 4.3 Hz, 1H) 0.45ꢀ0.35 (m, 1H), 0.29 (ddd, J = 9.9, J = 5.5, 4.3 Hz,
1
3
1
2
1
3
2
H) ppm; C (100 MHz, CDCl ): δ = 154.6 (t, J = 288.8 Hz), 135.6, 120.3 (dd, J
=
3
CꢀF
CꢀF
4
3
2.6, 11.5 Hz), 116.0, 98.4 (t, J = 4.2 Hz), 72.1 (d, J = 6.3 Hz), 71.1, 68.6, 58.5, 37.1,
CꢀF
CꢀF
4
19
2
3
5.6, 22.9 (d, JCꢀF = 8.5 Hz), 7.0, 5.1 ppm; F (376 MHz, CDCl ): δ = ꢀ97.7 (d, J = 68.4
2
5
Hz, 1F), ꢀ102.7 (dq, J = 68.4 Hz, JFꢀH = 5.8 Hz, 1F) ppm; νꢀ /(neat) = 3465, 2887, 1736,
ꢀ1
+
1022, 937 cm ; HRMS (ESI): calcd for C14
H
26
F O
2 4
N, 310.1824 [M+NH
4
] , found: 310.1826;
+
+
+
MS (EI): m/z (%): 161 (2) [MꢀC
2.75 minutes.
6
H
9
F
2
O
3
] , 89 (69) [C
4
H
9
O
2
] , 59 (100) [C
3
H
7
O] ; t
R
(GC) =
1
1,1-Difluoro-2-((methoxyethoxy)methoxy)-3-methyl-4-cyclopentyl-hepta-1,6-dien-3-ol
(3i). Prepared as for trans-3a and cis-3a from acetal (1.58 mL, 10 mmol), nꢀbutyllithium (9.8
mL of a 2.04 M solution in hexanes, 20 mmol), diisopropylamine (3.38 mL, 24 mmol) and 1ꢀ
5
(1ꢀallylcyclopentyl)ethanꢀ1ꢀone (1.52 g, 10 mmol) in THF (11 mL). The crude product (2.13
g) was purified by Kugelrohr distillation to afford 3i (0.965 g, 30%) as a pale yellow oil. b.p.
1
=
100 °C / 0.04 mmHg; R
f
= 0.30 (40 % diethyl ether in hexane); H NMR (400 MHz,
2
CDCl
3
): δ = 5.70 (ddt, J = 17.3, 10.1, 7.3 Hz, 1H), 5.11ꢀ4.99 (m, including 5.04 (d, J = 6.3
2
5
Hz, 1H), 2H), 4.88 (dt, J = 6.4, J = 1 Hz, 1H), 3.94ꢀ3.80 (m, 2H), 3.58 (t, J = 4.8 Hz,
HꢀF
2H), 3.40 (s, 3H), 3.12 (br. s, 1H), 2.19 (d, J = 7.3 Hz, 2H), 1.88ꢀ1.74 (m, 2H), 1.68ꢀ1.35 (m,
5
13
1
3
including 1.41 (d, JHꢀF = 5.4 Hz, 3H), 6H) ppm; C (100 MHz, CDCl ): δ = 155.0 (t, JCꢀF =
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288.3 Hz), 136.2, 120.3 (dd, JCꢀF = 32.1, 11.3 Hz), 116.3, 99.0 (t, JCꢀF = 4.7 Hz), 75.9 (d,
3
4
J
CꢀF = 4.8 Hz), 71.1, 68.9, 58.5, 54.1, 41.1, 32.1, 31.6, 25.9, 25.2, 22.3 (d, JCꢀF = 8.6 Hz)
1
9
2
2
5
ppm; F (376 MHz, CDCl
3
): δ = ꢀ97.7 (d, J = 71.0 Hz, 1F), ꢀ101.33 (dq, J = 71.0 Hz, JFꢀH
5
19
=
5.4 Hz, 1F) ppm; the 1.0 Hz J = splitting could not be resolved in the 376 MHz
F
HꢀF
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
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1
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3
4
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6
7
8
9
0
ꢀ1
NMR spectrum; νꢀ /(neat) = 3494, 2944, 1731, 1266, 1065, 909 cm ; HRMS (APCI): calcd for
+
C H F O N, 338.2137 [M+NH ] , found: 338.2143; MS (CI): m/z (%): 338 (100)
16 30
2
4
4
+
[M+NH
4
] ; t
R
(GC) = 13.78 minutes.
Trans-1-(2,2-difluoro-1-((2-methoxyethoxy)methoxy)vinyl)-2-(prop-2-yn-1-yl)cyclohexan-
1
-ol (trans-3j) and cis-1-(2,2-difluoro-1-((2-methoxyethoxy)methoxy)vinyl)-2-(prop-2-yn-1-
yl)cyclohexan-1-ol (cis-3j). Prepared as for trans-3a and cis-3a from acetal (0.79 mL, 5 mmol),
nꢀbutyllithium (5.4 mL of a 1.84 M solution in hexanes, 10 mmol), diisopropylamine (1.69
23
mL, 12 mmol) and 2ꢀ(propꢀ2ꢀynyl)cyclohexanone (0.68 g, 5 mmol) in THF (5 mL). The
crude allylic alcohol was purified by flash column chromatography using a Thompson Single
Step cartridge (90 g cartridge, 20 % ethyl acetate in hexane) to afford an inseparable mixture
of transꢀ3j and cisꢀ3j as a pale orange oil (0.291 g, 19 %, 97:3). R = 0.82 (50 % ethyl acetate
f
1
in hexane); H NMR (400 MHz, CDCl
3
): δ = 4.94 (app. s, 2H), 3.94ꢀ3.81 (m, 2H), 3.59 (app.
2
4
t, J = 4.8 Hz, 2H), 3.41 (s, 3H), 2.93 (s, 1H), 2.34 (dt, J = 16.9, J = J = 2.8 Hz, 1H), 2.20
2
4
4
(
ddd, J = 16.9, J = 8.9, J = 2.8 Hz, 1H), 1.99 (t, J = 2.8 Hz, 1H), 1.94ꢀ1.47 (envelope, 8H),
1
3
1
1
.36ꢀ1.21 (m, 1H) ppm; C NMR (100 MHz, CDCl
3
): δ = 154.0 (t, JCꢀF = 289.2 Hz), 120.8
2
4
3
(dd, J = 32.9. 10.0 Hz), 98.3 (t, J = 4.5 Hz), 83.3, 72.6 (d, J = 5.6 Hz), 71.1, 68.8,
CꢀF
CꢀF
CꢀF
4
4
68.5, 58.5, 41.1 (d, JCꢀF = 4.7 Hz), 36.4 (t, JCꢀF = 3.1 Hz), 26.1, 24.7, 20.6, 19.7 ppm; Major
1
9
transꢀdiastereoisomer 3j (assigned on the basis of δ and intensity) F (376 MHz, CDCl
3
): δ
2
2
=
ꢀ98.0 (d, J = 72.3 Hz, 1F), ꢀ103.1 (d, J = 72.3 Hz, 1F) ppm;* Minor cisꢀdiastereoisomer 3j
1
9
2
(
assigned on the basis of δ and intensity F (376 MHz, CDCl
3
): δ = ꢀ96.7 (d, J = 67.2 Hz,
2
ꢀ1
1
F), ꢀ103.7 (d, J = 67.2 Hz, 1F) ppm; νꢀ /(neat) = 3452, 3302, 2928, 1734, 1216, 1056 cm ;
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+
HRMS (ESI): calcd for C15
H
23
F
2
O
4
, 305.1564 [M+H] , found: 305.1557; MS (CI): m/z (%):
+
+
305 (10) [M+H] , 322 (15) [M+NH
4
] ; t
R
(GC) = 12.90 minutes.** *this is by comparison
5
with compounds from the SaegusaꢀIto series. ** the cisꢀ and transꢀstereoisomers appeared as
one peak by GC.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
4
4
4
4
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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4
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8
9
0
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2
3
4
5
6
7
8
9
0
1
,1-difluoro-2-((2-methoxyethoxy)methoxy)non-1-en-3-ol (3k). Prepared as for trans-
3
a and cis-3a from acetal (1.90 mL, 12 mmol), nꢀbutyllithium (12.9 mL of a 1.94 M solution
in hexanes, 25 mmol), diisopropylamine (3.70 mL, 26 mmol) and heptanal (1.37 g, 12 mmol)
in THF (12 mL). The crude allylic alcohol (2.63 g) was purified by Kugelrohr distillation to
f
afford 3k as a pale yellow oil (2.20 g, 65 %). b.p. = 102 °C / 0.05 mmHg; R = 0.21 (50 %
1
2
diethyl ether in hexane); H NMR (400 MHz, CDCl
3
): δ = 5.00 (d, J = 6.8 Hz, 1H), 4.88 (d,
2
4
2
J = 6.8 Hz, 1H), 4.24 (dtdd, J = 9.3, J = 7.4, JHꢀF = 3.6, 2.0 Hz, 1H), 3.96 (ddd, J = 10.8, J
2
=
6.4, 3.5 Hz, 1H), 3.78 (ddd, J = 10.8, J = 5.0, 3.1 Hz, 1H), 3.66ꢀ3.53 (m, 2H), 3.40 (s,
3H,), 3.20 (d, J = 9.3 Hz, 1H), 1.79ꢀ1.52 (m, 2H), 1.41ꢀ1.20 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H)
1
3
1
2
ppm; C NMR (100 MHz, CDCl ): δ = 154.7 (dd, J = 291.6, 284.7 Hz), 118.2 (dd, J =
CꢀF
3
CꢀF
19
3
6.3. 9.8 Hz), 98.0, 71.4 , 68.4, 67.1, 58.9, 33.9, 31.7, 29.0, 25.4, 22.5, 13.9 ppm; F (376
2
2
19
1
3
MHz, CDCl ): δ = ꢀ100.5 (d, J = 63.7 Hz, 1F), ꢀ110.1 (d, J = 63.7 Hz, 1F) ppm; (the Fꢀ H
1
9
splitting was not resolved in the F NMR spectrum); νꢀ /(neat) = 3421, 2924, 1749, 1232,
ꢀ1
+
1
24 2 4
054, 955 cm ; HRMS (ESI): calcd for C13H F O Na, 305.1535 [M+Na] , found: 305.1532;
+
+
+
+
MS (CI): m/z (%): 283 (1) [M+H] , 265 (2) [MꢀOH] , 89 (78) [C
4
H
9
O
2
] , 59 (100) [C
3
H
7
O] ;
R
t (GC) = 12.41 minutes.
1
,1 Difuoro-2-((2-methoxyethoxy)methoxy) 3-cyclohexyl prop-2-en-3-ol (3l) Prepared
as for trans-3a and cis-3a from acetal (1.90 mL, 12 mmol), nꢀbutyllithium (11.9 mL of a 2.10
M solution in hexanes, 25 mmol), diisopropylamine (3.70 mL, 26 mmol) and
cyclohexanecarboxaldehyde (1.34 g, 12 mmol) in THF (12 mL). The crude allylic alcohol
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2
2
2
2
2
2
3
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3
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4
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4
4
4
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5
5
5
5
5
5
5
6
(3.12 g) was purified by Kugelrohr distillation to afford 3l as a pale yellow oil (2.60 g, 77 %).
1
b.p. = 102 °C / 0.06 mmHg; R
f
= 0.3 (50 % diethyl ether in hexane); H NMR (400 MHz,
2
2
2
CDCl
3
): δ = 5.01 (d, J = 6.8 Hz, 1H), 4.87 (d, J = 6.8 Hz, 1H), 3.96 (ddd, J = 10.8, J = 6.0,
2
3
.1 Hz, 1H), 3.87 (br. d, J = 8.3 Hz, 1H), 3.78 (ddd, J = 10.8, J = 4.8, 3.0 Hz, 1H), 3.65ꢀ3.53
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
(
m, 2H), 3.40 (s, 3H), 3.18 (br. s, 1H), 2.10 (br. d, J = 13.7 Hz, 1H), 1.86ꢀ1.52 (m, 5H),
1
3
1
3
.34ꢀ1.10 (m, 3H), 1.08ꢀ0.94 (m, 1H), 0.94ꢀ0.79 (m, 1H) ppm; C NMR (100 MHz, CDCl ):
1
2
4
δ = 154.6 (dd, JCꢀF = 292.2, 285.2 Hz), 117.0 (dd, JCꢀF = 37.7. 10.0 Hz), 97.5 (t, JCꢀF = 3.6
1
9
Hz), 71.2, 70.9, 68.0, 58.4, 40.2, 29.0, 28.3, 25.9, 25.3, 25.2 ppm; F (376 MHz, CDCl
3
): δ
2
2
=
ꢀ100.6 (d, J = 65.5 Hz, 1F), ꢀ110.6 (d, J = 65.5 Hz, 1F) ppm; νꢀ /(neat) = 3463, 2921, 1749,
ꢀ1
+
1
2
232, 1013, 953 cm ; HRMS (APCI): calcd for C13
H
26
F
2
O
4
N
1
, 298.1824 [M+NH
4
] , found:
+
+
+
98.1819; MS (EI): m/z (%): 204 (2) [MꢀC H F] , 89 (100) [C H O ] , 59 (100) [C H O] ;
4
9
4
9
2
3
7
t
R
(GC) = 12.65 minutes.
1,1-difluoro-2-((2-methoxyethoxy)methoxy)-3-(tetrahydro-2H-pyran-4-yl)prop-2-en-
3-ol (3m). Prepared as for trans-3a and cis-3a from acetal (1.90 mL, 12 mmol), nꢀ
butyllithium (11.9 mL of a 2.10 M solution in hexanes, 25 mmol), diisopropylamine (3.70
mL, 26 mmol) and 4ꢀformyltetrahydropyran (1.37 g, 12 mmol) in THF (12 mL). The crude
allylic alcohol (2.71 g) was purified by flash column chromatography (90 g cartridge, 90 %
f
diethyl ether in hexane) to afford 3m as a pale yellow oil (1.94 g, 57 %). R = 0.30 (90 %
1
diethyl ether in hexane); H NMR (400 MHz, CDCl
3
): δ = 5.00 (d, J = 6.6 Hz, 1H), 4.88 (d,
2
J = 6.6 Hz, 1H), 4.09ꢀ3.84 (m, 4H), 3.77 (ddd, J = 10.8, J = 4.5, 3.1 Hz, 1H), 3.65ꢀ3.52 (m,
2H), 3.45ꢀ3.30 (m, 6H), 2.03ꢀ1.92 (m, 1H), 1.91ꢀ1.75 (m, 1H), 1.52ꢀ1.31 (m, 2H),1.23 (qd, J
13
1
=
11.9, 4.4 Hz, 1H) ppm; C NMR (100 MHz, CDCl
3
): δ = 154.7 (dd, JCꢀF = 292.8, 285.6
2
4
3
Hz), 116.5 (dd, JCꢀF = 37.2, 11.0 Hz), 97.4 (t, JCꢀF = 3.8 Hz), 70.9, 70.8 (t, JCꢀF = 3.0 Hz),
19
2
6
3
8.0, 67.2, 66.9, 58.5, 37.6, 29.3, 28.2 ppm; F NMR (376 MHz, CDCl ): δ = ꢀ99.7 (d, J =
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64.0 Hz, 1F), ꢀ109.9 (d, J = 64.0 Hz, 1F) ppm; νꢀ /(neat) = 3404, 2915, 1749, 1230, 1026, 955
ꢀ1
+
cm ; HRMS (ESI): calcd for C12
H
F
24 2
O
5
N
1
, 300.1617 [M+NH
4
] , found: 300.1620;
+
+
+
MS (EI): m/z (%): 281 (1) [MꢀH] , 89 (92) [C
4
H
9
O
2
] , 59 (100) [C
3
H
7
O] ; t
R
(GC) = 12.88
minutes.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
,1-difluoro-2-((2-methoxyethoxy)methoxy)-3-(4-(trifluoromethyl)phenyl)prop-2-en-
3
-ol (3o). Prepared as for trans-3a and cis-3a from acetal (1.90 mL, 12 mmol), nꢀbutyllithium
(11.9 mL of a 2.10 M solution in hexanes, 25 mmol), diisopropylamine (3.70 mL, 26 mmol)
and pꢀtrifluoromethylbenzaldehyde (2.09 g, 12 mmol) in THF (12 mL). The crude allylic
alcohol (4.99 g) was purified by Kugelrohr distillation followed by flash column
chromatography (90 g cartridge, 60 % diethyl ether in petroleum ether) to afford 3o as a
colourless oil (0.87 g, 21 %). b.p. = 113 °C / 0.05 mmHg; R = 0.62 (5 % acetone in
f
1
dichloromethane); H NMR (400 MHz, CDCl
3
): δ = 7.64 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4
2
2
Hz, 2H), 5.53 (br. d, J = 8.7 Hz, 1H), 4.93 (d, J = 6.7 Hz, 1H), 4.87 (d, J = 6.7 Hz, 1H),
2
2
3.85 (d, J = 8.7 Hz, 1H), 3.76 (ddd, J = 10.8, J = 5.9, 3.8 Hz, 1H), 3.64 (ddd, J = 10.8, J =
13
4
1
3
7
3
.9, 3.1 Hz, 1H), 3.58ꢀ3.48 (m, 2H), 3.39 (s, 3H) ppm; C NMR (100 MHz, CDCl ): δ =
1
2
3
54.5 (dd, J = 293.4, 287.4 Hz), 143.9, 129.3 (q, J = 32.3 Hz), 125.8, 124.7 (q, J =
CꢀF
CꢀF
CꢀF
1
2
4
.5 Hz), 123.6 (q, JCꢀF = 271.8 Hz), 117.3 (dd, JCꢀF = 36.0, 11.3 Hz), 97.3 (t, JCꢀF = 3.9 Hz),
3
19
0.7, 68.0, 67.5 (d, JCꢀF = 3.4 Hz), 58.4 ppm; F NMR (376 MHz, CDCl
3
): δ = ꢀ62.5 (s, 3F),
2
4
2
4
ꢀ
98.5 (dd, J = 60.1, JFꢀH = 2.0 Hz, 1F), ꢀ108.5 (dd, J = 60.1, JFꢀH = 3.2 Hz, 1F) ppm;
ꢀ1
νꢀ /(neat) = 3419, 2930, 1751, 1325, 1112, 1067, 1017 cm ; HRMS (APCI): calcd for
+
+
C
14
H
19
F
5
O
4
N
1
4
, 360.1229 [M+NH ] , found: 360.1231; MS (EI): m/z (%): 323 (1) [MꢀF] , 175
+
+
+
(
9) [C H F O] , 89 (63) [C H O ] , 59 (100) [C H O] ; t (GC) = 12.49 minutes.
8
6
3
4
9
2
3
7
R
General Procedure B: Difluorinated Diol Preparation. (1R*,3R*,4aS*,8aS*)-2,2-
difluoro-3-methyloctahydronaphthalene-1,8a(1H)-diol (1, 3-trans, 1, 8a-trans-4a) and
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2
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2
2
2
2
3
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(1R*,3S*,4aS*,8aS*)-2,2-difluoro-3-methyloctahydronaphthalene-1,8a(1H)-diol (1, 3-cis, 1,
8a-trans-4a).1,3ꢀBis(2,6ꢀdiisopropylphenylꢀimidazolꢀ2ꢀylidene)gold(I) chloride (5 mol %,
0.031 g) was taken up in dichloromethane (1 mL) and added via syringe to dichloromethane
(3.4 mL). The solution was stirred at room temperature then a solution of silver
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
hexafluoroantimonate(V) (5 mol %, 0.017 g) in methanol (0.6 mL) was added as a stream via
syringe. An offꢀwhite precipitate formed after the addition was complete. The flask was fitted
with an air condenser (open to the atmosphere), and the suspension was heated to 40 °C. A
solution of allyl alcohol trans-3a and cis-3a (0.306 g, 1 mmol) in dichloromethane (1 mL)
was added in a stream via syringe. After stirring for 5 hours at 40 °C the reaction was allowed
to cool to room temperature. Solid tetrabutylammonium borohydride (0.258 g, 1 mmol) was
added to the flask in small portions. A slight effervescence was observed as the reducing
agent was added and the reaction mixture darkened from colourless to dark brown. The
reaction mixture was then allowed to stir at room temperature for 18 hours, then was
quenched with hydrogen peroxide (10 mL of a 3wt % aqueous solution), followed by sodium
hydroxide (5 mL of a 10wt% aqueous solution). The mixture was transferred to a separating
funnel and the organic layer was removed. The aqueous layer was extracted with
dichloromethane (4 x 40 mL). The combined organic extracts were then washed with sodium
sulfite (10 mL of a saturated aqueous solution). The organic layer was separated, dried
(
MgSO ) and concentrated under reduced pressure to afford the crude product as aviscous
4
pale yellow oil (0.280 g). The crude material was purified by flash column chromatography
40 g silica, 2 % acetone in dichloromethane) to afford an inseparable mixture of 1, 3-trans,
(
1, 8a-trans-4a and 1, 3-cis, 1, 8a-trans-4a as a colourless solid (0.154 g, 70 %, 2.6:1). R
f
=
0.47 (5 % acetone in dichloromethane); The following signals were attributed to both the
minor 1, 3-cis, 1, 8a-trans-diastereoisomer 4a and major 1, 3-trans, 1, 8a-trans ꢀ
1
diastereoisomer 4a H NMR (400 MHz, CDCl ): δ = 3.60ꢀ3.47 (m, 1H), 2.42ꢀ2.17 (m, 1H),
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1.97ꢀ1.27 (envelope, 17H) ppm; The following signals were attributed to the major 1, 3-trans,
1
1, 8a-transꢀdiastereoisomer 4a (assigned on the basis of δ and intensity); H NMR (400 MHz,
1
3
3
CDCl ): δ = 2.14 (t, J = 2.8 Hz, 1H), 1.06 (d, J = 6.9 Hz, 3H) ppm; C NMR (100 MHz,
1
2
3
CDCl ): δ = 124.0 (t, J = 248.2 Hz), 74.2 (dd, J = 27.7, 21.4 Hz), 72.7 (d, J = 5.2
3
CꢀF
CꢀF
CꢀF
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
Hz), 36.6, 33.7, 32.8 (t, J = 21.4 Hz), 32.6 (d, J = 8.5 Hz), 26.6, 25.1, 19.8, 11.2 (d,
CꢀF
CꢀF
3
19
2
3
4
J
3
CꢀF = 5.6 Hz) ppm; F NMR (376 MHz, CDCl ): δ = ꢀ105.9 (dq, J = 256.5, JFꢀH = JFꢀH =
2
3
3
4
4.8 Hz, 1F), ꢀ116.6 (ddt, J = 256.5, JFꢀH = 30.3, JFꢀH = JFꢀH = 7.6 Hz, 1F) ppm; The
following signals were attributed to the minor 1, 3-cis, 1, 8a-trans-ꢀdiastereoisomer 4a
1
(
assigned on the basis of δ and intensity); H NMR (400 MHz, CDCl ): δ = 2.11 (t, J = 2.7
3
13
1
Hz, 1H) ppm; C NMR (100 MHz, CDCl ): δ = 123.4 (dd, J = 253.8, 242.5 Hz), 75.3
3
CꢀF
2
3
2
(
dd, JCꢀF = 28.9, 21.7 Hz), 72.3 (d, JCꢀF = 5.8 Hz), 35.1 (dd, JCꢀF = 23.4, 21.0 Hz), 31.1,
3
3
19
3
0.8 (d, JCꢀF = 7.3 Hz), 26.8, 25.3, 19.9, 14.2 (dd, JCꢀF = 9.4, 3.7 Hz) ppm; F NMR (376
2
3
3
4
2
3
MHz, CDCl ): δ = ꢀ93.6 (ddt, J = 261.3, JFꢀH = 17.6, JFꢀH = JFꢀH = 8.0 Hz), ꢀ104.5 (d, J =
ꢀ1
261.3 Hz) ppm; νꢀ /(neat) = 3608, 3450, 2919, 1446, 1069, 985 cm ; HRMS (ASAP): calcd
+
+
for C11
H
17
F
2
O
2
, 219.1197 [MꢀH] , found: 219.1194; MS (EI): m/z (%): 220 (3) [M] , 182
+
(
13) [Mꢀ2F] ; t (GC) = 11.27 minutes;* elemental analysis calcd (%) for C H F O : C,
R
11 18
2
2
59.98; H, 8.24; found: C, 59.75; H, 8.17. This analysis was obtained for the amorphous solid
obtained following chromatography so no melting point was recorded.* the individual
diastereoisomers appeared as one peak by GC. Diastereomerically pure 1, 3-trans, 1, 8a-
trans-4a could be obtained by performing three vapour diffusion recrystallizations
(chloroform/pentane) of the mixed solid diol (0.024g, 11%). m.p. = 84ꢀ86 °C (recrystallized
f
from chloroform/pentane vapour diffusion as a colourless plate); R = 0.47 (5 % acetone in
1
dichloromethane); H NMR (400 MHz, CDCl
3
): δ = 3.54 (td, JHꢀF = 6.0, J = 3.2 Hz, 1H),
4
4
2
2
4
.38ꢀ2.16 (m, 1H), 2.14 (td, J = JHꢀF = 3.0, JHꢀF = 1.0 Hz, 1H), 1.85 (tdd, J = J = 13.3, J =
4
13
.9, J = 1.2 Hz, 1H), 1.80ꢀ1.19 (envelope, 11H), 1.08 (d, J = 6.9 Hz, 3H) ppm; C NMR
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