Inter-and intramolecular annulation strategies to a cyclopentanone building block containing an all-carbon quaternary stereogenic center

Article abstract of DOI:10.1021/acs.orglett.5b00207

Synthesis of (S)-2-methyl-3-fluorophenyl cyclopentanone methyl ester (1S)-1 has been achieved by both inter-and intramolecular alkylation reactions on multigram scale, using chiral pool reagents. The intramolecular variant is a novel example of a chiral bis-electrophile reacting with a carbon nucleophile to form an enantiomerically pure all-carbon quaternary center.

Full text of DOI:10.1021/acs.orglett.5b00207

Letter
pubs.acs.org/OrgLett
Inter- and Intramolecular Annulation Strategies to a Cyclopentanone
Building Block Containing an All-Carbon Quaternary Stereogenic
Center
Stephen D. Penrose,† Andrew J. Stott,† Perla Breccia,† Alan F. Haughan,† Roland W. Burli,†
̈
Rebecca E. Jarvis,† and Celia Dominguez*,‡
†BioFocus, a Charles River Company, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, United Kingdom
‡CHDI Management/CHDI Foundation Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States
S
* Supporting Information
ABSTRACT: Synthesis of (S)-2-methyl-3-fluorophenyl cyclopentanone
methyl ester (1S)-1 has been achieved by both inter- and intramolecular
alkylation reactions on multigram scale, using chiral pool reagents. The
intramolecular variant is a novel example of a chiral bis-electrophile reacting
with a carbon nucleophile to form an enantiomerically pure all-carbon
quaternary center.
ne-pot, tandem reaction sequences provide an efficient
Ostrategy for the construction of complex natural product
scaffolds as well as novel three-dimensional chemotypes for
drug discovery.1 Such reactions have indisputable benefits in
generating complex molecules in a time- and atom-efficient
manner. Herein, we report complementary tandem approaches
to a synthetically challenging intermediate which incorporates a
chiral quaternary carbon center within a cycloalkane ring.
As part of a recent lead optimization program, we required a
multigram quantity of enantiomerically pure (S)-2-methyl-3-
fluorophenyl cyclopentanone methyl ester (1S)-1. An extensive
search of the literature provided only a limited number of
routes to phenyl substituted cyclopentanone esters, commonly
Figure 1. Synthesis of 3-aryl cyclopentanones.
via hydroboration of the appropriate cyclic alkene followed by
oxidation of the subsequent alcohol (Figure 1).2 To the best of
indicating a modest induction of chirality at the newly formed
quaternary center (Figure 2). Encouraged by this modest
diastereoselectivity in our cyclization, we hoped to use a
protected, enantiomerically pure 1,4-dibromo-2-butanol deriv-
ative to control the stereogenic process and the absolute
configuration of the newly formed quaternary center.
our knowledge, Hoveyda and co-workers have published the
only enantioselective synthesis of a 3-carboxy-3-phenylcyclo-
pentanone ester, utilizing a silver-NHC/diaryl zinc-mediated
conjugate addition reaction.3 This transformation, although
elegant, requires a noncommercial catalyst system and the use
of a glovebox. In addition, the insertion of 2-tolyl zinc reagents
has not been demonstrated previously in such systems (Figure
1).
We envisaged that a tandem alkylation reaction of a
substituted 2-methyl phenylacetic ester enolate with a bis-
electrophile would provide access to 1 (Figure 2). Our initial
synthesis of (rac)-1, by analogy to a described procedure,4 used
TBS-protected, commercially available (rac)-1,4-dibromo-2-
butanol and gave a 3:1 mixture of cyclopentanol diastereomers
Synthesis of 5 was achieved in three steps (Scheme 1).5 In
summary, the commercially available (S)-butane-1,2,4-triol (S)-
2 was selectively mesylated at the primary hydroxy groups using
methanesulfonyl chloride in pyridine. Subsequent silylation of
secondary alcohol 3 with TBDPS chloride incorporated the
sterically demanding protecting group to give dimesylate 4 in
Received: January 21, 2015
Published: February 27, 2015
© 2015 American Chemical Society
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Letter
Our preliminary efforts to couple 5 and 6 using either
potassium tert-butoxide at high temperatures (90 °C, 6 h, entry
1) or lithium hexamethyldisilazide (−78 °C, warming to rt over
6 h, entry 2) gave no conversion to 7. Gratifyingly, the use of
sodium hydride at −20 °C in the presence of potassium iodide
to activate the electrophile furnished the desired cyclopentane 7
in reasonable yield and diastereomeric ratio (entry 3). The
reaction appeared to proceed with increased diastereoselectivity
at higher temperatures (4:1 to 7:1 dr, entries 3−5). Although
this improved selectivity was encouraging, the yields remained
low.
The yield of cyclopentanol 7 was significantly improved by
doubling the quantity of dibromide 5, which gave 7 in 80%
yield (6:1 dr, entry 6). In order to optimize atom efficiency, we
reverted to 1 equiv of 5 and added a catalytic quantity of 18-
crown-6 to activate the enolate, which led to an increased yield
without loss of diastereoselectivity (entry 7). In the literature it
has been observed that adding crown ethers in catalytic
quantities enhances the reactivity of enolates to alkylation by
complexing the sodium ion.7 Optimum conditions were
obtained by portionwise addition of sodium hydride to provide
a low concentration of free base and afforded cyclopentane 7 in
both excellent yield and selectivity (85%, 9:1 dr, entry 8).
The major isomer of the 9:1 mixture of 7 could be isolated in
milligram quantities by careful flash chromatography. However,
on a larger scale this became a protracted process. We
hypothesized that the undesired diastereomer of 7 had an ideal
conformation to undergo intramolecular lactonization, whereas
the desired isomer did not. Indeed, on refluxing a mixture of
cyclopentanols 7 in the presence of DBU, quantitative
conversion of minor isomer (1R,3S)-7 to lactone (1S,4R)-8
was observed whereas the alcohol (1S,3S)-7 remained
unchanged (Scheme 2). The polarity difference between
Figure 2. Proposed route.
Scheme 1. Synthesis of Silyl Protected Dibromide
high yields. Finally, displacement of the mesylate groups with
lithium bromide provided the desired electrophile 5 which was
critical for exploring the intermolecular tandem alkylation.
Based on our previous results, we anticipated that reaction of
5 with the enolate form of 6 would give the silyl-protected
cyclopentanol with modest diastereoselectivity. Conditions for
the tandem alkylation reaction are outlined in Table 1. The
crude cyclization product was treated with TBAF to remove the
silyl group, and the diastereomeric ratio of the crude alcohols 7
was determined by comparison of integrals of the two
diastereomers in the 19F NMR spectrum.6
Scheme 2. Intramolecular Cyclization of 7 to Lactone 8
Table 1. Conditions for Intermolecular Alkylation
a
b
c
entry
base
solvent
temp, °C additive
yield, %
dr
1
2
3
4
5
KOtBu
LHMDS
NaH
toluene
THF
90
−
−
KI
0
N/A
N/A
4:1
(1S,3S)-7 and (1S,4R)-8 greatly simplified purification on a
gram scale. (1S,3S)-7 was treated with Dess-Martin periodinane
to give the desired ketone (1S)-1 in 90% yield and >99% ee.
Encouraged by the facile nature of the intramolecular
lactonization step to generate (1S,4R)-8, we considered
whether the diastereomer of lactone 8 could serve as an
intermediate for an alternative route to our desired ketone
building block. Hence we envisaged that the intramolecular
cyclization of an enantiomerically pure (R)-1,4-dibromo-2-
butanol derivative tethered via an ester linkage to the
phenylacetic acid moiety would lead to the bicyclic lactone
(1R,4S)-8 in a highly stereoselective manner (Scheme 3).
−78
−20
0
0
DMF
DMF
DMF
DMF
DMF
DMF
42
35
18
80
64
85
NaH
KI
5:1
NaH
20
KI
7:1
d
6
NaH
20
KI
6:1
7
NaH
20
18-C-6
7:1
e
8
NaH
20
18-C-6
9:1
a
b
Used 2 equiv of KI or 10 mol % 18-C-6. Isolated yield on 10 mmol
c
scale based on a 1:1 ratio of 5 and 6. Ratio of diastereomers based on
d
e
19F NMR - minor isomer (1R,3S)-7. Used 2 equiv of 5. Portionwise
addition of NaH over 2 h.
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Letter
addition of the second alkyl halide partner to the conforma-
tionally locked cyclic ester enolate.
Scheme 3. Synthesis of (R)-1,4-Dibromobutan-2-ol Ester 11
The O-tethered tandem alkylation protocol was repeated on
a 14 g scale of dibromide 9 to give the lactone (1R,4S)-8 in a
highly efficient manner, as shown in Scheme 4. Ring opening of
Scheme 4. Tethered Synthesis on Multigram Scale
Thus, (R)-1,4-dibromobutan-2-ol (9) was synthesized from
(R)-butane-1,2,4-triol ((R)-2)8 by a modified Appel reaction
(NBS/PPh3/CH2Cl2). Subsequent coupling of 9 to 2-(3-fluoro-
2-methylphenyl) acetic acid (10) using DCC/DMAP gave the
desired (R)-1,4-dibromobutan-2-ol ester 11.
Results for the O-tethered tandem alkylation approach are
summarized in Table 2. Preliminary attempts at lactonization
lactone (1R,4S)-8 with methanol under acidic conditions gave
cyclopentanol (1S,3R)-7 which was converted to 8.7 g of
desired ketone (1S)-1 in 89% yield and 93% ee. Finally,
recrystallization of (1S)-1 from heptane enhanced the
enantiomeric purity to >99% ee.
Table 2. O-Tethered Tandem Alkylation Approach
In summary, a tandem alkylation approach, as well as a novel
O-tethered tandem alkylation protocol, have been developed
using readily available chiral pool intermediates. Both reactions
allow for the multigram synthesis of the key cyclopentanone
intermediate (1S)-1. To the best of our knowledge, the O-
tethered tandem conversion of the dibromide 11 to lactone 8 is
the first example of its type and provides a powerful method of
forming enantiomerically pure cyclopentanes incorporating
quaternary carbon centers.
ab
,
entry
base
NaH
solvent
temp, °C
yield, %
1
2
3
4
DMF
DMF
THF
20
0
LHMDS
LHMDS
0−20
0−20
20
0
c
c
40
73
LHMDS
dioxane
a
b
Isolated yield on 10 mmol scale. Isolated as a single diastereomer.
ASSOCIATED CONTENT
* Supporting Information
■
c
LHMDS (2.2 equiv) added at a rate of 1 mmol/min.
S
Experimental procedures, characterization data, copies of the
1H, 13C, 19F NMR spectra, and chiral SFC data (where
appropriate) for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
using sodium hydride or lithium hexamethyldisilazide in DMF
at 20 °C gave no conversion to (1R,4S)-8 (entries 1, 2).
However, using LHMDS in THF afforded a single diastereomer
of (1R,4S)-8 in modest yield after 2 h (entry 3). Switching
solvent to 1,4-dioxane and using a concentration of 0.1 M 11
with addition of LHMDS (2.2 equiv) in THF at a rate of 1.0
mmol/min resulted in complete consumption of 11 in 2 h and
formation of the product (1R,4S)-8 in an isolated yield of 73%
(entry 4). The reproducibility of this yield was highly
dependent on the rate of addition of LHMDS, and slower
addition rates led to a mixture of products.
To explain the diastereoselective formation of (1R,4S)-8, we
rationalized that the order of formation of either the five- or six-
membered lactone is inconsequential, as both alkylation
pathways would result in the desired product. Similarly, there
was no requirement to control the bond geometry of the initial
ester enolate, as the resulting stereocenter will be eliminated
upon formation of the subsequent enolate. Chirality at the
quaternary center can then be induced by diastereofacial
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: celia.dominguez@chdifoundation.org.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors express their gratitude to Christopher Luckhurst
(BioFocus) for his support, as well as Mark Sandle and
Nicholas Richards (BioFocus analytical team) for SFC analysis.
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