Fluorine-directed diastereoselective iodocyclizations

Article abstract of DOI:10.1002/anie.200703465

(Chemical Equation Presented) An inside job: β-Fluorinated lactones and tetrahydrofurans are synthesized by iodocyclization of various allylic fluorides. The fluorine substituent acts as a highly efficient syn-stereodirecting group for the ring closure. T

Full text of DOI:10.1002/anie.200703465

Angewandte
Chemie
DOI: 10.1002/anie.200703465
Stereoelectronic Effects
Fluorine-Directed Diastereoselective Iodocyclizations**
Matthew Tredwell, Jennifer A. R. Luft, Marie Schuler, Kenny Tenza, Kendall N. Houk, and
VØronique Gouverneur*
In memory of Charles Mioskowski
The imposing number of known fluorinated g-lactones and
tetrahydrofurans, along with their derivatives, clearly reflects
the importance of these molecules, especially in medicinal
chemistry. For example, fluorinated nucleosides are prevalent
among inhibitors of human immunodeficiency viruses.[1] The
electrophile-induced cyclization of fluorinated precursors has
emerged as a suitable route to prepare these heterocycles.
This strategy was applied successfully to homoallylic fluorides
for the preparation of diverse a-fluoro-iodolactones.[2] In
contrast, no iodolactonization and only two examples of
iodoetherification of allylic fluorides have been reported,
despite the undoubted value of the resulting products.[3] The
lack of information in this area is due to the difficulties
associated with the preparation of starting allylic fluorides
featuring the strategically positioned carboxylic acid or
alcohol group. Recently, we developed a robust route to
allylic fluorides from allylsilanes which tolerates a large range
of functional groups.[4] This led us to study the reactivity of
allylic fluorides in iodine-induced cyclizations. Herein, we
document that the iodolactonization and iodoetherification of
allylic fluorides enable the streamlined synthesis of a diverse
collection of b-fluoro-g-lactones and fluorinated tetrahydro-
furans, respectively. The experimental results combined with
theoretical studies provide evidence in support of an “inside
fluoro effect” to account for the sense and high level of
stereocontrol of these reactions.
(Table 1). Compounds 1a–g were prepared by using a cross-
metathesis reaction followed by a fluorodesilylation of the
resulting functionalized allylsilanes by using selectfluor.[4,5]
The synthesis of 1h and 1i was more challenging and relied on
a
multistep ring-closing metathesis and ring-opening
approach to access the allylsilanes required for subsequent
electrophilic fluorinations.[5,6] The synthesis of the allylic
fluorides (Æ )-1g and (Æ )-1h is shown in Scheme 1.
Scheme 1. Synthesis of allylic fluorides (Æ)-1g and (Æ)-1h.
CM=cross-metathesis, DMAP=4-dimethylaminopyridine, RCM=ring-
closing metathesis.
The allylic fluorides 1a–i were prepared to probe the
effect of various substituents on the reaction feasibility and
These compounds were subjected to iodocyclizations
(Table 1). Most reactions were conducted at room temper-
ature in the presence of I2 in CH2Cl2 and aqueous NaHCO3
(conditions A) or in CH3CN in the absence of base (con-
ditions B). N-Iodosuccinimide (NIS) was used in CH3CN
(conditions C) for the ring closure of (Æ )-1e only. The
iodolactonizations of 1a–d led to the b-fluorinated iodolac-
tones 2a–d in high yields, with the exception of 1c, which has
the propensity to decompose (entries 1–4). Conditions A and
B allowed for similar reaction efficiency and a high level of
diastereocontrol, although the use of I2 in CH3CN gave a
cleaner crude mixture for the iodolactonization of 1d
(entry 4). The syn and anti fluorinated acids (+)-1a and
(+)-1b gave the enantiopure b-fluoro-g-lactones (À)-2a and
(À)-2b, respectively, with d.r. > 20:1 (entries 1 and 2). Com-
pounds (Æ )-1c and (Æ )-1d with the fluorinated carbon atom
as the single stereocenter were also converted into the desired
lactones (Æ )-2c and (Æ )-2d, respectively, with excellent
diastereoselectivity (> 20:1; entries 3 and 4). The iodoether-
ifications of the structurally related alcohols (Æ )-1e and (Æ )-
1 f were equally successful in delivering the fluorinated
tetrahydrofurans (Æ )-2e and(Æ)-2 f in high yields. The level
the stereoselectivity of
a number of iodocyclizations
[*] Dr. M. Tredwell, Dr. M. Schuler, Dr. K. Tenza, Dr. V. Gouverneur[+]
Chemistry Research Laboratory
University of Oxford
12 Mansfield Road, Oxford OX1 3TA (UK)
Fax: (+44)1865275644
E-mail: veronique.gouverneur@chem.ox.ac.uk
J. A. R. Luft, Prof. K. N. Houk[+]
Department of Chemistry and Biochemistry
University of California
Los Angeles, California 90095-1569 (USA)
[+] Authors for correspondence: Prof. K. N. Houk for calculations and
Dr. V. Gouverneur for synthesis.
[**] We are grateful to the EPSRC (M.T.), the National Foundation of
South Africa (K.T.), the EU (MEIF CT 2006 03970 (M.S.)), the
National Institute of General Medical Sciences, and the National
Institutes of Health (GM 36700 to K.N.H.)for financial support. We
also thank the NSF-PACI and UCLA-ATS for computing sources.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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357

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Table 1: Iodocyclization of 1a–j and bromocyclization of 1e.
tive yield but with a significant loss
of stereoselectivity (entry 11). The
selectivities summarized in Table 1
are either similar to or an improve-
ment on those reported in the
literature for the iodocyclizations
of allylic alcohols, ethers, or
amines.[7]
The remarkable diastereoselec-
tivity of the iodolactonizations
prompted us to carry out theoretical
studies to determine the origin of
the stereoselectivity in these fluo-
rine-directed cyclizations.[8] The
preferential conformations of start-
ing materials 1a and 1b as well as
the relative energies of the stereo-
isomeric lactones 2a–c and 2j
are given in the Supporting
Entry
1
Substrate
Product[a]
Conditions[b]
Yield [%][c]
d.r.[d]
A
B
86
94
>20:1
>20:1
A
B
95
74
>20:1
>20:1
2
3
A
B
24
25
>20:1[e]
>20:1[e]
A
B
48
72
>20:1
>20:1
4
5
6
A
C
52
81
12:1
5:1
Information.
The
products
A
92
>20:1
observed experimentally are the
most stable, but the relative ener-
gies between stereoisomers are
within 1 kcalmolÀ1 of each other
and do not explain the high diaste-
reoselectivity for the iodolactoniza-
tions. The reactions are likely to be
under kinetic control as the product
ratios do not change over time
under conditions A or B. Optimiza-
tion of the geometry of an unsub-
stituted iodonium ion was carried
out and showed that the iodonium
complex lies between an iodonium
ion and an iodonium–p complex.
The calculated bond lengths (1.44 Š
7
D
A
80
69
88
69
7:1
12:1
9:1
8
9
A
A
10
9:1
A
B
100
100
2:1
2:1
11
À
À
for C C and 2.29 Š for C I) agree
with previous experimental results
and are an improvement on earlier
theoretical studies.[9] Rotamers of
iodonium complexes 3–5 substi-
[a] Major isomer. [b] A: I2, CH2Cl2/aqueous NaHCO3; B: I2, CH3CN; C: N-Iodosuccinimide, CH3CN; D:
N-Bromosuccinimide, CH3CN. [c] Yields of isolated products. [d] Determined by 1H or 19F NMR analysis
of the crude reaction mixture. [e] Determined by 1H or 19F NMR analysis after purification.
of stereocontrol remained excellent for 2 f (d.r. > 20:1) but
was slightly decreased for 2e (d.r. = 12:1; entries 5 and 6).
(Æ )-2e and (Æ )-2k were formed, respectively, in high yields
but with more modest diastereoselectivity by using NIS or N-
bromosuccinimide (NBS), (entries 5 and 7). The method was
extended to the preparation of the fluorinated spiro deriva-
tive (Æ )-2g and of (Æ )-2h and (Æ )-2i, each of which
possesses a methylated quaternary center (conditions A).
The d.r. values were equal or superior to 9:1 (entries 8–10).
The relative stereochemistry was assigned by NOE experi-
ments for 2a–i and by X-ray diffraction analysis for (Æ )-2d.[5]
Both the relative and the absolute configuration of (À)-2b
was confirmed by X-ray crystallography.[5] Compounds 2a–i
all featured a synrelationship between the fluorinated and the
newly formed stereogenic centers. A control experiment
served to support the role of the fluorine substituent, which
appears to be a very effective synstereodirector for these
reactions. Cyclization of (À)-1j afforded (+)-2j in quantita-
tuted with an ethyl, a fluoromethyl, and a fluoroethyl group,
respectively, were considered. For the ethyl-substituted
iodonium 3, rotamers that place the methyl group anti or
outside are equally stable. The rotamer with the methyl group
inside is higher in energy, since this conformer is more
sterically hindered. For the fluoromethyl-substituted iodo-
nium complex 4, the fluorine substituent prefers to reside
inside by 3 kcalmolÀ1 with respect to the outside, and
5 kcalmolÀ1 with respect to the anti arrangements. In the
fluoroethyl iodonium complex 5, the most stable rotamers
5inside, outside and 5inside, anti are equal in energy (Figure 1).
Transition structures necessary for the attack of a
carboxylate or alkoxide on an I2–alkene complex were
À
located. The I2–p complex is loosely associated, with the C
C bond length being the same as an uncoordinated alkene
À
(1.34 Š); the C I bonds are longer (3.14 Š) than those of the
iodonium ion. Attack of a formate ion (HCOOÀ) on an I2–
ethylene complex was examined. Transition state 6 leads to an
358
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Figure 3. Transition state for HCOOÀ attack on an ethyl-substituted
I2–p complex.
Figure 1. Most stable rotamers for substituted iodonium ions, 3–5.
iodide ion complexed with the iodoformate product. The two
iodoformates can interconvert via TS 7 (Figure 2).
Figure 4. Most stable rotamers for TS 8 and 9.
slight preference for anti versus outside. When fluoro and
methyl groups are present, rotamers 9inside, anti and 9inside, outside
are equal in energy because both feature the fluorine
substituent inside, and the methyl group has little conforma-
tional preference for the anti versus outside arrangement.
These isomers are preferred over those with the fluorine
substituent outside by 1 kcalmolÀ1 and over the fluorine
substituent anti by 3 kcalmolÀ1.
Figure 2. Transition state located for HCOOÀ addition to an I2–
ethylene p complex.
Transition structures for intramolecular etherification of
1e were located (Figure 5). Although less symmetric tran-
sition structures were located, these were higher in energy
than 10 and 11. The reaction path is likely to involve a two-
step no-intermediate mechanism as proposed by Singleton
et al. for reactions of singlet oxygen.[12] In transition structures
10 and 11, the fluorine substituent prefers to reside inside by
2.1 kcalmolÀ1.
The preferential conformations of transition states sub-
stituted with ethyl, fluoromethyl, or fluoroethyl groups were
investigated. The attack of one of the formate oxygen atoms
on the more substituted carbon atom occurs with the forming
bond lengths consistently between 2.6 and 2.8 Š. The formate
ion approaches the alkene at an angle of around 1108, thus
indicating attack on the backside of the sCÀI bond.[10] As
*
shown in Figure 3 for the ethyl-substituted I2–p complex, the
second oxygen atom may be either proximal or distal to the
alkene. A proximal orientation provides a stabilizing electro-
static interaction between the negatively charged oxygen
atom and the positively charged carbon atoms of the I2–p
complex. The resulting transition state is at least 4 kcalmolÀ1
more stable than those with the second oxygen atom located
distal.
The transition states for inside, outside, and anti con-
formations of Me and F[11] were considered. The relative
enthalpies are given in the Supporting Information, and the
most stable conformers are shown in Figure 4.
The fluorine substituent in 8 prefers to reside inside rather
than outside by 1 kcalmolÀ1. An allylic methyl group shows a
Figure 5. Intramolecular etherification TS 10 and 11.
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359

Communications
An anti fluorine substituent aligns the electron-withdraw-
accounts for the iodocyclizations of allylic ethers or alco-
hols.[7d]
À
*
ing sCÀF orbital with one of the C I bonds, thereby
destabilizing the I2–p complex. In comparison with the
iodonium ions, preference for the fluorine substituent inside
is lower in the I2–p complex as this complex is neutral
compared to the positively charged iodonium ion. An inside
fluorine substituent minimizes the interaction between the
À
Received: July 31, 2007
Published online: November 16, 2007
Keywords: density functional calculations · fluorine · lactones ·
.
stereoelectronic effect · tetrahydrofurans
*
sCÀF orbital and the C I bond. The positioning of the fluorine
substituent inside also enables its lone pairs of electrons to
stabilize the partial positive charge of the I2–p complex.
Previous studies have shown that the fluorine substituent of
the allylic fluorides prefer to reside inside in polar cyclo-
addition transition states with nitrile oxides and prefer inside
or outside positions in nonpolar cycloaddition transition states
with butadiene.[13] In I2–p complex, an anti fluorine substitu-
ent destabilizes the iodonium ion and is disfavored; an inside
fluorine substituent is stabilizing and preferred.
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iodonium ion. These models clarify how the allylic fluoride
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Scheme 2. Most stable rotamers of 12–13. Bn=benzyl.
In conclusion, b-fluorinated g-lactones and tetrahydrofur-
ans are now accessible by iodocyclization of various allylic
fluorides. The fluorine substituent acts as a highly efficient
syn-stereodirecting group for the ring closure. The “inside
fluoro effect”, which accounts for the observed selectivity,
may prove useful for predicting the stereochemical outcome
of a host of electrophilic reactions with allylic fluorides. The
results are consistent with the “inside alkoxy effect” that
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360
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