Building the Housane: Diastereoselective Synthesis and Characterization of Bicyclo[2.1.0]pentane Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.9b03044

An approach to 1,3-disubstitued bicyclo[2.1.0]pentane (housane) derivatives was developed. The method relied on lithium bis(trimethylsilyl)amide-mediated intramolecular cyclization of trisubstitued cyclopentane carboxylates bearing a leaving group (at the C-4 position) and an additional substituent (at the C-3 atom), in turn synthesized from cyclopent-3-ene carboxylate. The synthetic sequence allowed for the preparation of both cis- and trans-1,3-disubstituted housane-1-carboxylic acids in diastereoselective manner on up to 80 g scale. In particular, bicyclic γ-amino acids - γ-aminobutyric acid analogues - were synthesized. It was shown that the bicyclo[2.1.0]pentane did not significantly affect pK_a of the corresponding derivatives and slightly increased their hydrophilicity (by 0.07-0.25 Log P units) as compared to cyclopentane. X-ray diffraction studies showed that cis- and trans-1,3-disubstituted housanes can be considered as flattened analogues of the corresponding cyclopentane derivatives with fixed envelope conformation of the five-membered ring.

Full text of DOI:10.1021/acs.joc.9b03044

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Article
Building the housane: diastereoselective synthesis and
characterization of bicyclo[2.1.0]pentane carboxylic acids
Volodymyr V. Semeno, Vadym O. Vasylchenko, Bohdan V. Vashchenko, Dmytro O.
Lutsenko, Rustam T. Iminov, Olesia B. Volovenko, and Oleksandr O. Grygorenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03044 • Publication Date (Web): 20 Dec 2019
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The Journal of Organic Chemistry
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Building the housane: diastereoselective synthesis
and characterization of bicyclo[2.1.0]pentane
carboxylic acids
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†
†,‡
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Volodymyr V. Semeno, Vadym O. Vasylchenko, Bohdan V. Vashchenko, Dmytro O. Lutsenko,
†
†
,†,§
Rustam T. Iminov, Olesia B. Volovenko, Dr. Oleksandr O. Grygorenko*
†
Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
‡
National Technical University of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute", Prospect
Peremogy 37, Kyiv 03056, Ukraine
§
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
gregor@univ.kiev.ua
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. An approach to 1,3-disubstitued bicyclo[2.1.0]pentane (housane) derivatives was
developed. The method relied on LiHMDS-mediated intramolecular cyclization of trisubstitued
cyclopentane carboxylates bearing a leaving group (at the C-4 position) and an additional substituent (at
the C-3 atom), in turn synthesized from cyclopent-3-ene carboxylate. The synthetic sequence allowed
for the preparation of both cis- and trans-1,3-disubstituted housane-1-carboxylic acids in
diastereoselective manner on up to 80 g scale. In particular, bicyclic -amino acids – GABA analogues –
were synthesized. It was shown that the bicyclo[2.1.0]pentane did not significantly affect pK of the
a
corresponding derivatives and slightly increased their hydrophilicity (by 0.07–0.25 LogP units) as
compared to cyclopentane. X-Ray diffraction studies showed that cis- and trans-1,3-disubstituted
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housanes can be considered as flattened analogues of the corresponding cyclopentane derivatives with
fixed envelope conformation of the five-membered ring.
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Introduction
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Occurrence of low-molecular-weight alicyclic scaffolds in molecular design has significantly
increased over the last years,1–3 partially due to their high relevance to the «escape from flatland»
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concept favoring compounds with higher sp atom fraction. Thus, cyclopropane derivatives are
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8–12
ubiquitous in natural and synthetic products with a wide range of pharmaceutical applications:
for
example, 6 marketed and 26 investigational drugs contain the cyclopropane carboxylate moiety.
Similarly, cyclobutane fragment is the smallest cyclic moiety which does not significantly alter
chemical properties when incorporated to the target molecules.13–16 In turn, cyclopropane- and
cyclobutane-based conformational restriction is a multipurpose tool in medicinal chemistry providing
enhanced potency, selectivity, and metabolic resistance of drug candidate supplemented with
minimization of entropic penalty within binding to biological targets.17
In this view, bicyclo[2.1.0]pentane (“housane”) derivatives containing both cyclopropane and
cyclobutane rings in their structure are of special interest. The bicyclo[2.1.0]pentane scaffold can be
considered as a constrained surrogate of cyclopentane, which has a proven track of biological relevance
represented by analogues of γ-aminobutyric acid (GABA (1), a chief inhibitory neurotransmitter),18–22
e.g. ACPD (2, mGluR agonist)23–25 or eglumegad (3, LY354740, mGlu orthosteric agonist) used for
2
/3
neuroprotection, treatment of anxiety and drug addiction (Figure 1).26,27
R1
R1
H N
CO H
CO H
2
2
2
H N
2
CO H
2
HO C
2
HO C
H
2
NH2
GABA (1)
R2
R2
cyclopentane
Eglumegad, LY354740 (3)
chief inhibitory
neurotransmitter
(1R,3R)-ACPD (2)
mGluR agonist
housane
mGlu2/3 agonist
Figure 1. Housane – a conformationally constrained analogue of cyclopentane, a scaffold of high
biological relevance
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To date, wide application of bicyclo[2.1.0]pentane derivatives has been hampered by limited synthetic
accessibility of the corresponding building blocks. In particular, the known methods for preparation of
housane carboxylates relied on two-step cyclopropanation of cyclobutene carboxylates with
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diazomethane (Scheme 1). Rhodium-catalysed 1,3-dipolar cycloaddition led to pyrazolines, which
subsequently undergo photochemical denitrogenation providing bicyclo[2.1.0]pentanes (Method A).28–33
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Such transformations are often accompanied with formation of significant amounts of by-products.
Analogous approach relied on the Simmons–Smith reaction (Method B); however, the corresponding
housane was obtained in extremely low yield.34 Another method included intramolecular
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cyclopropanation via the decomposition of δ,ɛ-unsaturated β,β-difluoro-α-diazo esters (Method C). At
the same time, the only example of housane synthesis via intamolecular alkylation was performed with
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-(tosyloxymethyl)cyclobutane carboxylate; however, low yield of the target product was achieved
(
Method D).34 Similar approach was described by Hall and co-workers for the case of 2-
(chloromethyl)cyclobutanecarbonitrile, which was obtained via intramolecular cyclizations of 2-
(chloromethyl)cyclobutanecarbonitrile (14% yield), 3-chlorocyclopentanecarbonitrile (37% yield), or
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methyl 3-chlorocyclopentanecarboxylate (72% yield) (Method E). Several examples of substituted 2-
azabicyclo[2.1.0]pentane-1-carboxylates were also synthesized via intramolecular alkylations.37–39
3
In line with our continuous efforts to synthesize advanced sp -enriched bicyclic building blocks for
drug discovery,40–42 in this work, we have aimed at developing of efficient and scalable
diastereoselective approach to functionalized 1,3-disubstituted housanes. Our approach was similar to
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the method of Hall and co-workers mentioned above and included anionic cyclization of appropriate
trisubstituted cyclopentane derivatives. It was expected that diastereoselectivity of the cyclization of the
corresponding enolate should be defined by relative configuration of the substituent R and the leaving
group in the substrate; on the contrary, configuration at the center adjanced to the ester moiety should be
unimportant due to flattened structure of the corresponding enolate intermediates. In addition to that,
characterization of structural and physico-chemical properties of the aforementioned scaffold as a
promising structural motif for medicinal chemistry was envisaged.
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R2
R2 previous works
R2
Method A:
CH N
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2
h
R
R
N
R
3
293%
5194%
N
CO Me
2
MeO C
CO Me
2
2
1
R = H, Me, cycloalkyl
Method B: R = H; CH I , Zn(Cu), 5%
2
2
2
R = H, CO Me
2
R R2
1
N2
R2
TsO
Method C
Method D
R1
F
NaH
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Rh (OAc)4
CO Et
2
2
F F
CH Cl2
DMF, 11%
CO Bu
2
2
1
2
R and/or R =
reflux
F
CO Et
2
CO Bu
2
H, Me, n-Pr, Ph
5588%
Method E
Cl
Cl
NaH, N-methylpyrroli-
NaNH2, THF
37%
done, 72%
CO Me
CN
2
CO Me
CN
2
O
R
LG
R
R
CO Alk
2
H
LG
CO H
2
CO t-Bu 13 steps CO Alk
2
2
this work
or
or
R
LG
R
H
CO Alk
2
R
LG
CO t-Bu
2
CO H
2
CO Alk
2
LG = Br, I, OSO Ph
2
R = H, Me, Ph, F, Br, OH, OMe, N , NH , NHBoc, NHFmoc
3
2
Scheme 1. Approaches to housane carboxylates (carboxylic acids)
Results and discussion
Synthesis. According to the synthetic plan shown in Scheme 1, it was anicipated that incorporation of
both leaving group necessary for the cyclization step and the target substituents into the cyclopentane
core could be achieved by taking an advantage of cyclopentene carboxylic acid 4. The reaction sequence
commenced with preparation of the corresponding tert-butyl ester 5, which was obtained in 83% yield
on up to 250 g scale (Scheme 2). Epoxydation of 5 under standard conditions (m-CPBA in CH Cl ) gave
2
2
derivative 6 in 88% yield as a diastereomeric mixture (dr = 3:1); this step could be also performed on
large scale (up to 150 g in one run). It should be stressed out that the moderate diastereoselectivity at
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this step was not important since the stereogenic center adjenced to the carboxylate moiety would
undergo epimerization upon further base-promoted cyclization.
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O
1. (COCl) , DMF,
2
CH Cl , 5 °C to rt
2
2
mCPBA
2
. Et N, t-BuOH,
CH Cl2
5 °C to rt
88%
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CO H
CO t-Bu
2
2
CH Cl , 5 °C to rt
2
2
CO t-Bu
2
83%
4
5
6, dr = 3:1
Scheme 2. Synthesis of oxirane 6
Subsequent oxirane ring opening in 6 was perfomed with MeMgCl (–40 °C) or PhMgCl (0 °C) in the
presence of CuI in THF and provided trans alcohols 7a and 7b in 64% and 49% yield, respectively, on
up to 100 g scale (Scheme 3). Sulfonylation of 7a and 7b with PhSO Cl in pyridine gave intermediates
2
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a and 8b in 93% and 78% yield, respectively. It is important to outline that while mesylation of 7a or
b was successful, cyclization of the corresponding mesylates did not proceed in all atempts and
7
resulted in formation of an uninterpreted mixture.
1
. MeMgCl, 40 °C
or PhMgCl, 0 °C
CuI, THF
O
R
OH
R
OSO Ph
2
PhSO Cl
2
2
. aq NH Cl, 20 °C
pyridine
4
5
°C to rt
CO t-Bu
CO t-Bu
CO t-Bu
2
2
2
6
7a, R = Me, 64%
b, R = Ph, 49%
8a, R = Me, 93%
8b, R = Ph, 78%
7
Scheme 3. Synthesis of intermediates 8a and 8b (relative configurations are shown)
Direct introducing of other target substituents and leaving groups in trans relative configuration was
achieved by some common electrophilic addition reactions of alkene 5. In particular, fluorine-contaning
derivative 8c was obtained in 77% yield on up to 150 g scale via fluorobromination using Et N3HF and
3
NBS in CH Cl (Scheme 4). Reaction of 5 with NBS in MeOH resulted in methoxy-substituted bromide
2
2
8
d (85% yield), while treatment of 5 with Br in CHCl gave dibromide 8e in 88% yield. Azide 8f was
2 3
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synthesized from 5 in 75% yield by the reaction with NaN and I in MeOH – H O (3:1, v/v) on up to
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80 g scale. Again, diastereoselectivity of these transformations (dr 2:1 to 1:0) was not critical since the
stereogenic center near the carboxylate moiety would undergo epimerization upon further base-
promoted cyclization.
MeO
Br
Br
Br
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NBS, 5 °C to rt
MeOH
Br , 5 °C to rt
2
CHCl3
85%, dr = 4:1
5
88%, dr = 1
8d
CO t-Bu
8e CO t-Bu
2
2

1. Et N 3HF,
3
NaN I
3, 2
5 °C to rt, THF
F
Br
CO2t-Bu
N3
I
NBS, CH Cl
2
2
5
°C to rt
. aq NaOH
7%, dr = 2:1
MeOH  H2O
2
7
(3:1, v/v)
75%, dr = 2:1
8
c CO t-Bu
8f CO t-Bu
2
2
Scheme 4. Synthesis of intermediates 8c–f (relative configurations are shown)
The cyclization step was optimized for the case of fluorinated derivative 8c, taking an advantage of
1
9
monitoring the reaction progress by F NMR; the corresponding methyl ester or carboxylic acid were
also evaluated. Our preliminary experiments relied on using the methyl ester and 2.4-fold excess of t-
BuOK in THF (Entry 1) or 2-fold excess of t-BuOK in benzene (Entry 2). Unfortunately, only the traces
of cyclization products were detected. Next, the reaction was performed in hexanes at 5 °C to rt, and the
target housane was obtained at these conditions in diastereoselective manner, but only in 29% yield as a
mixture of tert-butyl and methyl esters formed via transesterification reaction (Table 1, Entry 3). Further
increase of the reaction temperature led to formation of the same mixture of esters, but in higher yield
(45%, Entry 4). Thus, it was considered that tert-butyl ester 8c would be more suitable for this
transformation. Its reaction in the aforementioned conditions gave the target housane 9c; unfortunately,
the reaction was accompanied with the bromine elimination, and the corresponding fluorocyclopentene
carboxylate was obtained as a by-product (Entry 5). Attempted cyclizations in the presence of MeONa,
NaH, or DBU were also unsuccessful (Entries 6–8).
Table 1. Synthesis of 3-fluorohousane-1-carboxylic acid or its derivatives
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F
Br
F
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base
conditions
Table 1)
(
CO R
2
CO R
2
Entry
R
Base
Solvent Temperature
THF 5 °C to rt
Time
Yield, %[a]
1
2
3
4
5
6
7
8
9
Me
t-BuOK (2.4 eq)
t-BuOK (2 eq)
t-BuOK (2.2 eq)
t-BuOK (2.2 eq)
t-BuOK (2.2 eq)
MeONa (1.15 eq)
NaH (1.2 eq)
overnight traces[b]
overnight traces[b]
overnight 29[c]
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
Me
benzene 5 °C to rt
hexanes 5 °C to rt
hexanes 68 °C
Me
Me
2 h
2 h
45[c]
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
H
hexanes 68 °C
31[b,d]
MeOH 5 °C to rt
overnight 0
DMF
5 °C to rt
overnight 0
DBU (2.1 eq)
benzene 5 °C to rt
overnight traces[b]
overnight traces[b]
LDA (1.15 eq)
LDA (1.5 eq)
THF
THF
THF
THF
THF
THF
–70 °C to rt
–70 °C to rt
–70 °C to rt
–70 °C to rt
–70 °C to rt
–70 °C to rt
–70 °C to rt
1
1
1
1
1
1
0
1
2
3
4
5
2 h
1 h
1 h
1 h
1 h
1 h
22[b]
0
MeLi (1.05 eq)
LiHMDS (1.1 eq)
LiHMDS (1.5 eq)
LiHMDS (2.5 eq)
0
40
71
0
LiHMDS (2.5 eq)[a]
THF
[a]
Isolated yield. [b] Estimated by H and/or F NMR unless noted otherwise. A mixture of tert-
1
19
[c]
butyl and methyl esters was formed via transesterification. [d] Side bromine elimination occurred, which
gave the corresponding fluorocyclopentene carboxylate as a by-product
In further experiments, a series of lithium-containing bases were tested for the transformation of 8c
into 9c (THF at –70 °C to rt). Thus, using 1.15-fold excess of LDA did not result in formation of target
product (Entry 9), while 1.5-fold excess gave 9c in low yield (22%, Entry 10). Neither 1.05-fold excess
of MeLi (Entry 11) nor 1.1-fold excess of LiHMDS (Entry 12) were sufficient to achieve the required
transformation. Nevertheless, increasing amount of LiHMDS finally resulted in significantly higher
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yields of 9c (Entries 13 and 14). In particular, the best result was obtained by using 2.5-fold excess of
LiHMDS, and the target housane 9c was obtained in 71% yield (Entry 14). It should be noted that
attempted synthesis of 9c starting from the corresponding carboxylic acid instead of ester 8c via the
dianion formation was unsuccessful (Entry 15).
1
2
3
4
5
6
7
8
9
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
The optimized conditions of the cyclization step (2.5-fold excess of LiHMDS, THF, –70 °C to rt, 1 h)
were applied to the series of intermediates 8a–f, and corresponding 1,3-disubstituted housane
carboxylates 9a–f were obtained diastereoselectively in moderate to good yields (47–75% yield, Table
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
). It should be outlined that cyclization of phenyl-substituted derivative 8b into 9b was accompanied
with formation of the corresponding phenylcyclopentene by elimination of bromine atom, presumably
due to energetically favorable formation of the conjugated double bond. For the preparation of
bromohousane derivative 9e, the inversed reagent addition order should be used to prevent
decomposition of the product and tar formation (see the Experimental Part).
Expectedly, cis isomers of the 1,3-disubstituted housanes 9a–f were obtained exclusively, which was
defined by the trans relative configuration of the stereogenic centers at the C-3 and C-4 atoms of
corresponding intermediates 8 (see also below).
Subsequent hydrolysis of tert-butyl esters 9a–f was found to be somewhat challenging. Thus,
common acidic cleavage of tert-butyl group proceeded smoothly only for the case of phenyl (9b) and
bromo (9f) derivatives obtained in 58% yield on 40 g scale (Table 2, Entries 2 and 5). In other cases,
however, this transformation was unruitful due to significant tar formation. Nevertheless, uncommon
alkaline hydrolysis of 9 performed upon reflux in the presence of LiOHH O in MeOH – H O (2:1, v/v)
2
2
gave the target carboxylic acids 10 in 48–79% yield on up to 50 g scale (Entries 1, 3, 4, and 6). The
presence of MeOH as the co-solvent was found to be essential; possibly, in situ base-catalyzed trans-
eseterefication occurred giving the correesponding methyl esters, followed by their alkaline hydrolisis.
In the absence of MeOH, the tert-butyl group cleavage did not occur in all cases.
Table 2. Preparation of 3-substituted bicyclo[2.1.0]pentane-1-carboxylic acids 10
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Method A: LiOH H O
Page 10 of 56

2
1
2
3
4
5
6
7
8
9
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
R
LG
MeOH  H O
1. LiHMDS, THF R
2
R
70 °C to rt
(2:1, v/v), reflux
2
. aq NH Cl,
Method B: TFA,
4

4
20 °C to rt
CO t-Bu CH Cl , 5 °C to rt
2
CO H
2
CO t-Bu
2
2
2
775%
4879%
10af
8af
9af
Entry
R
Leaving
Starting
group (LG) material 8
Ester 9
Carboxylic acid Method
10 (yield, % )
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
[a]
[a]
(yield, % )
9a (65)
9b (50)
9c (71)
1
2
3
4
5
6
Me
Ph
OSO Ph
8a
8b
8c
8d
8e
8f
10a (79)
10b (58)
10c (63)
10d (72)
10e (58)
10f (48)
A
2
OSO Ph
B[b]
A
2
F
Br
Br
Br
I
OMe
Br
9d (75)
9e (47)
A
B
N3
9f (51)
A
[a]
Isolated yield of the products. [b] Side formation of the corresponding cyclopentene occurred
Unfortunately, an attempted preparation of the corresponding γ-hydroxycarboxylate 9g from oxirane
6 via tandem oxirane ring opening - intramolecular cyclization by using LDA or LiHMDS resulted in
significant tar formation. Thus, synthesis of 9g relied on the aforementioned reaction sequence;
however, additional protection – deprotection of the hydroxyl group were requred. Hydroxybromination
of alkene 5 (providing 8g in 76% yield) followed by treatment with TBDMSCl in the presence of
DMAP – imidazole in DMF gave O-protected intermediate 11g in 92% yield (Scheme 5). Subsequent
cyclization of 11g upon common conditions led to bis-protected derivative 12g (79% yield), which was
transformed into the target γ-hydroxyester 9g via Bu NF-mediated silyl protective group cleavage (54%
4
yield). Alkaline hydrolysis of the ester moiety proceeded smoothly by refluxing in MeOH – H O (1.6:1,
2
v/v) in the presence of KOH, and the carboxylic acid 10g was isolated in 73% yield on up to 25 g scale.
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NBS
MeCN  H O
TBDMSCl,
DMAP,
imidazole
1
2
3
4
5
6
7
8
9
HO
Br
TBDMSO
Br
2
(2:1, v/v)
5
°C to rt
76%
DMF, rt
92%
CO t-Bu
2
CO t-Bu
11g CO t-Bu
2
2
5
8g
1
. LiHMDS, THF
70 °C to rt
. aq NH Cl

79%
2
4
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
HO
KOH
MeOH  H O
HO
TBDMSO
Bu NF
2
4
(1.6:1, v/v)
reflux
THF
5 °C to rt
54%
CO H
CO t-Bu
CO t-Bu
2
2
2
10g
73%
9g
12g
Scheme 5. An approach to hydroxycarboxylic acid 10g (relative configurations are shown)
Attempted oxidation of alcohol 9g with the Swern reagent resulted in formation of the corresponding
1
ketone 13g (detected by H NMR), which was transformed exclusively into the corresponding ring-
opened cyclopentenone 14g (72% yield) upon storage at –10 °C overnight (Scheme 6).
HO
O
O
(COCl) , DMSO
10 °C
2
Et N, CH Cl
overnight
72%
3
2
2
CO t-Bu
CO2t-Bu
3g
CO t-Bu
2
2
70 °C
1
9
g
14g
1
detected by H NMR
Scheme 6. Attempted synthesis of ketone 13g (relative configurations are shown)
Next, we have aimed at the preparation of stereoisomeric 1,3-disubstituted housane derivatives with
trans relative configuration of the corresponding substituents. It was envisaged that trans alcohols 7
obtained by ring opening of aforementioned oxirane 6 could be suitable intermediates for synthesis of
the corresponding cis bromides 15 (via the Appel reaction with Br – PPh ) required for transformation
2
3
into the target trans housane carboxylates 16. Indeed, alcohols 7a and 7b bearing methyl and phenyl
substituents, respectively, were prepared according to Scheme 3. Furthermore, reaction of 6 with
Et N3HF in dichloroethane at 80 °C led to fluorinated derivative 7c in 71% yield on up to 80 g scale
3
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(
Scheme 7). Oxirane ring opening with MeONa in MeOH was implemented for the preparation of
1
2
3
4
5
6
7
8
9
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
methoxy-susbtituted derivative; however, this transformation was accompanied with trans-esterification
reaction, which led eclusively to the formation of methyl ester 7d in 57% yield.
F
OH
O
MeO
OH
MeONa,
MeOH, reflux
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

Et N 3HF
3
(CH Cl)2
then HOAc
2
57%
80 °C, 71%
CO t-Bu
CO t-Bu
CO Me
2
2
2
7c
6
7d
Scheme 7. Oxirane ring opening for the preparation of 7c and 7d (relative configurations are shown)
R1
R1
OH
Br
1
5a, 68%
Br , PPh , imidazole
2
3
15b, 73%
1
1
5c, 49%
5d, 45%
CH Cl , 10 °C to rt
(for 7a and 7c)
or benzene, reflux
2
2
2
CO R2
2
CO R
2
1
2
7
a, R = Me, R = t-Bu
(
for 7b and 7d)
1
2
7
b, R = Ph, R = t-Bu
1. LiHMDS, THF
1
2
7c, R = F, R = t-Bu
70 °C to rt
1
2
2
. aq NH Cl,
7
d, R = OMe, R = Me
4
20 °C to rt
R1

LiOH H O, MeOH  H O
2
2
(
2:1, v/v), reflux
R1
16a, 47%
16b, 35%
CO H
2
(for 16a and 16d)
17a, 76%
17b, 46%
16c, 40%
16d, 31% (dr 4:1)
or TFA, CH Cl , 5 °C
2
2
CO R2
(
for 16b)
2
17c, 0%
17d, 52%
Scheme 8. Synthesis of 3-substituted bicyclo[2.1.0]pentane-1-carboxylates 16 and 17 (relative
configurations are shown)
The Appel reaction was applied to trans alcohols 7a–d for the preparation of cis bromides 15a–d in
4
5–73% yield on up to 150 g scale (Scheme 8). Expectedly, cyclization of 15a–c proceeded in
diastereoselective manner and led to housanes 16a–c in moderate yield (35–47% yield), while partial
epimerization occurred in the case of 15d, and housane 16d was obtained in 31% yield (dr 4:1 ratio).
Subsequent tert-butyl group cleavage proceeded smoothly with LiOH in MeOH – H O (for 16a and
2
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1
6d) or with TFA in CH Cl (for 16b) providing the title building blocks 17a, 17b and 17d in 46–76%
2 2
1
2
3
4
5
6
7
8
9
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
yield. Neither of methods was fruitful for hydrolysis of 16c – plausible bicyclo[2.1.0]pentane ring
opening occurred upon both acidic and basic conditions, and no formation of 17c was detected.
It should be outlined that the aforementioned reaction sequence did not work for the preparation of
trans azide 16f (stereisomeric to 9f); preparation of the corresponding intermediate 15f was not fruitful
in that case (the Appel reaction did not proceed due to the side Staudinger reaction). Nevertheless,
preparation of azide 16f could be achieved in 47% yield on up to 110 g scale via the Mitsunobu reaction
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
of alcohol 9g (PPh , DEAD and DPPA in THF) (Scheme 9). The corresponding azido carboxylic acid
3
1
7f was obtained in 41% yield by cleavage of the tert-butyl group with LiOHH O. Unfortunately, the
2
Appel reaction of 9g performed with Br – PPh did not result in the formation of trans γ-bromo
2
3
carboxylate 16e in all attempts (Scheme 9).

LiOH H O
Br
HO
PPh3, DEAD, N3
DPPA, THF
2
N3
Br , PPh
MeOH  H2O
2
3
10 °C to rt
(2:1, v/v)
reflux
imidazole,
CH Cl
CO t-Bu
CO t-Bu
CO t-Bu
CO H
2
17f
2
2
47%
2
2
2
41%
1
6e
9g
16f
Scheme 9. Synthesis of azide 17f (relative configurations are shown)
Next, we anticipated that cis dihydroxylation of alkene 5, followed by monosylilation with
TBDMSCl, sulfonylation and futher transformations similar to those shown in Scheme 5 could be
suitable for the preparation of 17g (a stereoisomer of 9g with trans configuration of the hydroxy group
to the carboxylate moiety). However, sulfonylation of the corresponding monosilyl derivative did not
occur in all attemtps, presumably due to steric hindance from the bulky TBDMS group. In this view, the
Mitsunobu reaction of 9g with 4-nitrobenzoic acid, DEAD and PPh was applied for the configuration
3
inversion, and the product 18g was obtained in 81% yield (Scheme 10). Selective hydrolysis of
ortogonally protected diester 18g with KOH in MeOH gave hydroxyester 16g (62% yield), which was
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Page 14 of 56
trahsformed into the corresponding carboxylic acid 17g in 81% yield on up to 20 g scale with KOH in
1
2
3
4
5
6
7
8
9
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
MeOH – H O (2.25:1, v/v).
2
Further synthetic studies were aimed at the preparation of stereoisomeric housane-derived -amino
acids as promising GABA analogues (Scheme 11). We took an advatage of stereoisomeric azido esters
9
f and 16f, which were successfully reduced to the corresponding cis (19) and trans (20) amino esters
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
with PPh in THF followed by quenching with H O (60% and 63% yield, respectively). The
3
2
corresponding amino acids 21 and 22 were obtained as trifluoroacetates by treatment of 19 and 20 with
TFA in CH Cl in 63% and 78% yields, respectively, on up to 70 g scale.
2
2
NO2
NO2
O
HO
HO C
2
O
DEAD, PPh3
10 °C to rt
1%
CO t-Bu
2
9g
18g CO t-Bu
8
2
KOH, MeOH, rt
62%
HO
KOH, MeOH  H O
HO
2
(2.25:1, v/v)
reflux
81%
CO H
CO t-Bu
2
2
17g
16g
Scheme 10. Synthesis of -hydroxy carboxylic acid 17g (relative configurations are shown)
N3
1. PPh3, THF H N
H N
3
2
10 °C to rt
TFA, 5 °C
2
. H O, rt
CH Cl2
2
2
CO t-Bu
CO t-Bu
CF CO2 CO H
2
2
3
2
.
9
f (cis)
19 (cis), 60%
20 (trans), 63%
21 TFA (cis), 63%
1
6f (trans)
.
22 TFA (trans), 78%
Scheme 11. Synthesis of amino acids 21 and 22 (relative configurations are shown)
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PG = Boc:
1
2
3
4
5
6
7
8
23 (cis), 79%
1
. Na CO , 5 °C
H N
2 3
PGHN
3
24 (trans), 83%
H O  THF (2:1, v/v)
2
2. Boc O or FmocCl,
2
PG = Fmoc:
25
CF CO2 CO H
CO H
2
3
2
THF, 5 °C to rt
(cis), 34%
2
1 (cis) or 22 (trans)
26 (trans), 38%
Scheme 12. Synthesis of N-protected amino acid derivatives 23–26 (relative configurations are shown)
9
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
N-Protected derivatives 23–26 were also obtained using standard procedures, taking into account
possible applications in drug design and peptide synthesis (Scheme 12). Moreover, separation of
enantiomers was performed for both 21 and 22 using chiral stationary phase HPLC (Scheme 13).
Absolute configuration of the products obtained was established by X-Ray diffraction studies (see
below).
H N
3
Cl
H N
3
Cl

CF CO
3
2
CO H
CO H
TMSCl, MeOH
THF, 40 °C
2
2
H N
2
.
.
(1S,2S,4R)-21 HCl
(1R,2R,4S)-21 HCl
chiral
H N
3
Cl
H N
3
Cl
CO H chromatograghy
2
2
2
1.TFA (cis) or
separation
2.TFA (trans)
relative
configuration)
CO H
CO H
2
2
(
.
.
(
1S,2R,4R)-22 HCl
(1R,2S,4S)-22 HCl
Scheme 13. Synthesis of four amino acid hydrochlorides 21 and 22
Finally, the aforementioned strategy was successfully applied to synthesis of the parent housane-1-
carboxylic acid (32). The reaction sequence commenced with transformation of 3-
oxocyclopentanecarboxylic acid (27) into the corresponding tert-butyl ester 28 (79% yield, Scheme 14).
Further steps included reduction of 28 to alcohol 29 with NaBH in MeOH (95% yield, dr = 4:1), and
4
the Appel reaction (Br , PPh , imidazole, CH Cl ), which gave 30 in 68% yield. Intramolecular
2
3
2
2
LiHMDS-mediated cyclization of bromide 30 provided the target tert-butyl bicyclo[2.1.0]pentane-1-
carboxylate 31 in good yield (79%). The protective group cleavage of 31 proceeded smoothly by using
TFA in CH Cl and led to carboxylic acid 32 in 56% yield.
2
2
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1
2
3
4
5
6
7
8
9
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
O
O
OH
t-BuOH
DMAP, DCC
NaBH4
CH Cl
MeOH, 3 °C
2
2
95%
5
°C to rt
9%
CO H
CO t-Bu
CO t-Bu
2
2
2
7
2
7
28
29
PPh , Br , imidazole
3
2
68%
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
CH Cl , 10 °C to rt
2
2
Br
1
. LiHMDS, THF
70 °C to rt
TFA, 5 °C
CH Cl
2
2
CO t-Bu
2. aq NH Cl,
4
CO H
2
2
56%
20 °C to rt
CO t-Bu
2
32
31
79%
30
Scheme 14. Synthesis of housane-1-carboxylic acid (32)
Physico-chemical properties. Dissociation constants (pK ) were measured for the cis and trans
a
housane-derived carboxylic acids, and effect of the housane core on acidity was compared to the
corresponding disubstituted cyclopentanes (Figure 2). It was found that bicyclo[2.1.0]pentane scaffold
bearing hydroxy (10d/17d) or methoxy (10g/17g) group at the γ position to CO H-moiety reduced pK
2
a
by 0.28–0.38 units as compared to that of cyclopentanes 33–35. However, in the case of N-Boc-amino
derivatives, the cis isomer 24 was found to be slightly less acidic (by 0.09 pK units) then cis-
a
disubstituted cyclopentane 36, while acidity of trans housane 25 was comparable to that of 36.
Furthermore, pK value of cis phenyl-substituted housane 10b was close to that of trans cyclopentane
a
3
1
7. Unfortunately, the pK measurement was not successful for the case of trans-disubstituted housane
a
7b, possibly due to the bicyclic ring system opening with alkali. The observed differences in the pKa
values described above are not significant and might be related to some subtle conformational effects.
The obtained results show that the bicyclo[2.1.0]pentane scaffold might be a close mimetic of
cyclopentane in terms of acid-base properties of the corresponding derivatives.
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MeO
33, pK = 4.77
CO H
2
1
2
3
4
5
6
7
8
9
MeO
MeO
a
CO H
CO H
2
2
MeO
CO H
2
1
0d, pK = 4.39
17d, pK = 4.35
a
a
3
4, pK = 4.63
a
HO
HO
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
HO
CO H
2
CO H
CO H
2
2
1
0g, pK = 4.32
17g, pK = 4.29
35, pK = 4.62
a
a
a
BocHN
BocHN
BocHN
CO H
2
CO H
CO H
2
2
2
4, pK = 4.72
25, pK = 4.61
36, pK = 4.63
a
a
a
Figure 2. Measured pK values for the compounds 10, 17, and 33–36
a
In addition to that, LogP were measured for phenyl-substituted housanes 10b and 17b, as well as for
cyclopentane derivative 37 (Figure 3). In the case of trans-3-phenylhousane carboxylic acid 17b,
hydrophililicity increased by 0.25 LogP units as compared to that of 37 (LogP = 2.94). On the other
hand, only a slight decrease of the LogP value (by 0.07 units) was found for the cis counterpart 10b.
Ph
Ph
Ph
CO H
2
CO H
CO H
2
2
1
0b, LogP = 2.87
17b, LogP = 2.69
37, LogP = 2.94
Figure 3. Measured LogP values for the compounds 10b, 17b, and 37
Molecular structures. X-Ray diffraction studies were performed with single crystals of housane
derivatives obtained by slow evaporation of their solutions: cis phenyl-substituted housane carboxylic
acid 10b (in t-BuOMe – hexanes), its trans isomer 17b (in THF), as well as amino acid hydrochlorides
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(
1S,2S,4R)-21HClH O (in МеСN – EtOH), (1R,2R,4S)-21HClH O (in МеСN – EtOH); (1S,2R,4R)-
2
2
1
2
3
4
5
6
7
8
9
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
22HCl (in MeOH), and (1R,2S,4S)-22HCl (in МеСN – EtOH).
The crystals of (1S,2S,4R)-21HClH O, (1R,2R,4S)-21HClH O, (1S,2R,4R)-22HCl, and (1R,2S,4S)-
2
2
2
2HCl contained single type of the conformers in the unit cell; for 10b, two very similar conformers (A
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
and B) were observed for each of the enantiomeric pairs, whereas for 17b, two enantiomers (A and B)
were observed at different positions resulting in crystallographic disorder (Table 3).
Table 3. Molecular geometry of the compounds 10b, 17b, 21HClH O, and 22HCl
2
a
a
||, degb
ORTEP diagramsc
#
1
Compound
r, Å
 , deg  , deg
1
2
10b (A)d
2.188
31.8
48.8
0.4
2
10b (B)d
2.184
33.7
52.8
0.5
3
4
17b (A)e
2.141
2.174
36.2
35.3
46.6
48.4
166.8
160.3
17b (B)e
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The Journal of Organic Chemistry
1
2
3
4
5
5
(1S,2S,4R)-21
2.158
35.3
55.6
3.0
6
7
8
9
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
6
(1R,2R,4S)-21
2.168
31.6
55.9
3.0
7
(1S,2R,4R)-22
2.154
32.9
51.0
176.1
8
(1R,2S,4S)-22
2.161
32.6
47.0
50.5
176.6
9
cis-1,3-C5f
2.425
2.450
56.4
67.2
12.9
–
–
10
trans-1,3-C5f
46.0
150.9
a
b
Defined according to Figure 4. Since the signs of  angle are opposite for different enantiomeric
c
conformations, only absolute values of  are considered. Thermal ellipsoids are shown at 30%
d
d
probability level. Two slightly different conformers in the crystal cell. Two enantiomers in the crystal
f
cell leading to crystallographic disorder. Average values for cis- and trans-1,3-disubstituted
cyclopentane derivatives (from refs. 43 and 44).
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To discuss geometry of the obtained derivatives, an exit vector plot (EVP)-based method was
used,43,44 which had been applied for analysis of various cyclic systems previously.41,45–51 This approach
1
2
3
4
5
6
7
8
9
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
represents the scaffold as a simplified geometrical model with so-called exit vectors n and n starting
1
2
1
3
from the ring atoms C and C decorated with the corresponding substituents (Figure 4). The size of the
1
3
scaffold can be estimated by the distance r between the C and C atoms, while the plane angles φ
1
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
3
3
1
(
between vectors n and C C ), φ (between vectors n and C C ), and the torsion angle θ (defined by
1 2 2
1
3
vectors n , C C , and n ) can be used to describe its three-dimensionality. Exit vector plots (EVP) are
1
2
obtained by depicting values of these parameters in the r – ,  –  / , and/or  / plots.
1
2
1
2
Figure 4. Definition of EVP parameters: (a) exit vectors n and n ; (b) r,  ,  , and .
1
2
1
2
EVP analysis of the compounds 10b, 17b, 21, and 22 showed that cis- and trans-1,3-disubstituted
housane scaffolds are somewhat smaller (r = 2.141–2.188 Å) than the corresponding cyclopentanes
(r ~ 2.4 Å); they are also slightly more flattened ( = 0.4–3.0 and 160.3–176.6 for cis and trans
isomers vs  = 12.9 and 150.9 (on average) for cis- and trans-1,3-disubstituted cyclopentanes,
respectively) (Figure 5). In the  –  plot, the housane derivatives are located closely to the
1
2
corresponding cyclopentane-derived scaffolds, although  / values are somewhat smaller. Therefore,
1
2
cis- and trans-1,3-disubstituted bicyclo[2.1.0]pentane cores can be considered as slightly distorted
analogues of the corresponding cyclopentanes with fixed envelope conformation of the five-membered
ring.
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
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
Figure 5. Geometric parameters of 1,3-disubstituted housanes and cyclopentanes shown in (a) r –  plot
(
polar coordinates); (b)  –  plot. Fused areas and colored data points correspond to all
1
2
experimentally observed and average parameter values for 1,3-disubstituted cyclopentanes,
respectively;43,44 black dots – to the values for 1,3-disubstituted housanes
Conclusions
An efficient approach to 1,3-disubstituted bicyclo[2.1.0]pentane (housane) carboxylic acids was
developed, which was based on intamolecular cyclization of the corresponding trisubstituted
cyclopentanes 7 or 15 bearing a tert-butyl carboxylate function (at the C-1 atom), a leaving group (at C-
4
), and an additional substituent (at C-3). In turn, these intermediates were obtained from cyclopent-3-
ene carboxylic acid (4). Although the aforementioned cyclopentane derivatives were obtained as
mixtures of two diastereomeric pairs, the overall synthetic sequences were highly diastereoselective for
the preparation of either cis- or trans-1,3-disubstituted housane derivatives. The configuration of the
products was defined by relative orientation of the substituents at the C-3 and C-4 atoms in the
corresponding key intermediate. Similar strategy was also applied for the preparation of the parent
bicyclo[2.1.0]pentane-1-carboxylic acid (32) from 3-oxocyclopentanecarboxylic acid (27).
The key step of the approach, i.e. intramolecular cyclization of intermediates 7 or 15, required
thorough optimization; the best results were obtained when 2.5-fold excess of LiHMDS in THF was
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used. The overall reaction sequence was effective for the preparation of cis-1,3-disubstitued housanes
bearing alkyl, aryl, halogene, azide, and alkoxy groups at the C-3 position; for the hydroxy group, the
use of a silyl protection was necessary. For the trans-diastereomers, the method was somewhat less
efficient and worked only for alkyl-, aryl-, fluoro-, and methoxy-substituted derivatives. Other
derivatives were obtained via configuration inversion in cis-3-hydroxyhousane-1-carboxylate 9f.
Synthesis of the target carboxylic acids required removal of the tert-butyl protective group which
appeared to be somewhat challenging in some cases. The standard acidic cleavage was fruitful only for
sterically hindered phenyl and bromo derivatives, whereas for other representatives, less common
alkaline hydrolysis was applied. As a result, 35 housane-derived building blocks were obtained on
multigram scale (up to 80 g). Moreover, -amino acids 21 and 22 – bicyclic GABA analogues – were
obtained.
1
2
3
4
5
6
7
8
9
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
It was also shown that the bicyclo[2.1.0]pentane scaffold does not strongly affect pK values of the
a
corresponding derivatives and decreases their lipophilicity as compared to cyclopentane. X-Ray
diffraction studies demonstrated that cis- and trans-1,3-disubstituted housanes can be considered as
slightly flattened analogues of the corresponding cyclopentanes with fixed envelope conformation of the
five-membered ring. Taking into account the aforementioned properties of the title compounds, as well
their accessibility on a multigram scale, they can be considered as extremely promising building blocks
for organic synthesis and drug discovery, which are now readily available to chemical community.
Further applications of these products might rely on probable susceptibility of the bicyclo[2.1.0]pentane
scaffold towards ring opening, which was observed for some derivatives in this work. This provides
possibilities for design of covalent ligands, which will be discussed in an upcoming study.
Experimental part
5
2
The solvents were purified according to the standard procedures. 4, 27, 33–37 were purchased
from commercial sources. Melting points were measured on an automated melting point system.
Analytical TLC was performed using silica gel plates. Column chromatography was performed using
1
13
19
silica gel (230–400 mesh) as the stationary phase. H, C and F NMR spectra were recorded on a
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NMR spectrometer at 500 MHz for Protons, 126 MHz for Carbon-13, and 470 MHz for Fluorine-19, or
at 400 MHz for Protons, 101 MHz for Carbon-13, and 376 MHz for Fluorine-19. Chemical shifts are
reported in ppm downfield from TMS as an internal standard. Elemental analyses were performed at the
Laboratory of Organic Analysis, Department of Chemistry, National Taras Shevchenko University of
Kyiv. Mass spectra were recorded on an LCMS instrument (chemical ionization (CI)) and GCMS
instrument (electron impact ionization (EI)). High-resolution mass spectra (HRMS) were recorded on an
LC/MSD TOF mass spectrometer by electrospray ionization time of flight reflectron experiments.
Preparative flash chromatography was performed on chromatograph using 40 g columns. CCDC
1961442 (10b), CCDC 1961443 (17b), CCDC 1961444 ((1S,2S,4R)-21), CCDC 1961445 ((1R,2R,4S)-
1
2
3
4
5
6
7
8
9
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
1), CCDC 1961446 ((1S,2R,4R)-22), and CCDC 1961447 ((1R,2S,4S)-22) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
tert-Butyl cyclopent-3-enecarboxylate (5).53,54 Cyclopent-3-enecarboxylic acid 4 (200 g, 1.78 mol)
was dissolved in CH Cl (2000 mL), and DMF (1 mL) was added. The mixture was cooled to 5 °C and
2
2
oxalyl chloride (184 mL, 272 g, 2.14 mol) was added dropwise at 5 °C. The mixture was stirred at rt
overnight, and the solvent was evaporated in vacuo at 45 °C. The residue was dissolved in CH Cl2
2
(
2000 mL), the solution was cooled to 5 °C, and the solution of Et N (495 mL, 359 g, 3.55 mol) and t-
3
BuOH (395 g, 5.33 mol) in CH Cl (500 mL) was added dropwise at 5 °C. The reaction mixture was
2
2
stirred at rt overnight, then washed with 10% aq NaHSO (2500 mL) and brine (500 mL), dried over
4
Na SO , and evaporated in vacuo at 45 °C. The crude compound was purified by distillation in vacuo.
2
4
1
Yield 247 g (83%); yellowish liquid; bp 55–57 °C / 1 mmHg. H NMR (400 MHz, CDCl ) δ 5.62 (s,
3
1
3
1
2H), 3.00 (quint, J = 8.2 Hz, 1H), 2.58 (d, J = 8.2 Hz, 4H), 1.43 (s, 9H). C{ H} NMR (126 MHz,
+
CDCl ) δ 175.5, 129.0, 79.9, 42.5, 36.3, 28.1. HRMS (ESI-TOF) m/z: [M+H] Сalcd. for C H O
3
10 17
2
1
69.1229. Found 169.1231.
tert-Butyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate (6). A solution of alkene 5 (150 g, 0.892 mol) in
CH Cl (3000 mL) was cooled to 5 °C. Then, m-CPBA (231 g, 1.34 mol) was added in portions at 5 °C,
2
2
and the resulting mixture was stirred at rt overnight. The precipitate was filtered off, filtrates were
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washed with 10% aq NaHCO (4500 mL) and brine (500 mL), dried over Na SO , and evaporated in
3
2
4
1
2
3
4
5
6
7
8
9
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
vacuo at 35 °C. The crude product was purified by distillation in vacuo. The compound was obtained as
1
ca. 3:1 mixture of diastereomers. Yield 144 g (88%); colorless liquid; bp 72–74 °C / 1 mmHg. H NMR
(
400 MHz, CDCl ) δ 3.47 (s, 1.5H) and 3.41 (s, 0.5H), 2.63 – 2.48 (m, 1.5H) and 2.27 (dd, J = 14.0, 8.0
3
13
1
Hz, 1.5H) and 1.85 – 1.75 (m, 2H), 1.45 – 1.39 (m, 9H). C{ H} NMR (126 MHz, CDCl ) δ 174.2 and
3
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
73.9, 80.4 and 80.2, 56.3 and 56.1, 38.9 and 38.5, 31.2 and 30.4, 28.0. HRMS (ESI-TOF) m/z: [M+H]+
+
Сalcd. for C H O 185.1178. Found 184.1175. [M+Na] Сalcd. for C H NaO 207.0997. Found
10 17
3
10 16
3
207.0997.
3R*,4R*)-tert-Butyl 3-hydroxy-4-methylcyclopentanecarboxylate (7a). Oxirane 6 (144 g, 0.782
(
mol) was dissolved in THF (2800 mL), and CuI (14.9 g, 78.2 mmol) was added under argon
atmosphere. The mixture was cooled to –40 °C, and 3 M MeMgCl in THF (525 mL, 1.56 mol) was
added dropwise at –40 °C. The reaction mixture was stirred at rt overnight, then cooled to –20 °C and
2
0% aq NH Cl (600 mL) was added in one portion. The resulting mixture was warmed up to rt, EtOAc
4
(
3000 mL) was added, the organic layer was washed with brine (21000 mL), dried over Na SO , and
2
4
evaporated in vacuo at 45 °C. The crude compound was purified by distillation in vacuo. The compound
was obtained as a mixture of ca. 3:2 of diastereomers. Yield 100 g (64%); yellowish liquid; bp 95–97
1
°
C / 1 mmHg. H NMR (400 MHz, CDCl ): major diastereomer δ 4.35 (quint, J = 2.7 Hz, 1H), 2.86 –
3
2
.72 (m, 1H), 2.61 – 2.50 (m, 2H), 2.31 – 1.51 (m, 4H), 1.41 (s, 9H), 1.06 (d, J = 5.9 Hz, 3H); minor
diastereomer δ 4.45 (quint, J = 3.4 Hz, 1H), 3.12 – 3.01 (m, 1H), 2.43 – 2.38 (m, 2H), 2.31 – 1.51 (m,
1
3
1
4H), 1.39 (s, 9H), 1.04 (d, J = 6.4 Hz, 3H). C{ H} NMR (126 MHz, CDCl ) δ 177.0 and 175.7, 80.4
3
and 79.9, 79.7 and 79.2, 42.6 and 42.1, 41.6 and 41.2, 37.3 and 37.2, 35.7 and 35.3, 28.0 and 28.0, 18.0
+
+
and 17.9. GC/MS (EI): m/z = 144 [M–H C=C(CH ) ] , 185 [M–CH ] . Anal. Calcd. for C H O : C,
2
3 2
3
11 20
3
6
5.97; H, 10.07. Found: C, 66.19; H, 10.11.
(3R*,4S*)-tert-Butyl 3-hydroxy-4-phenylcyclopentanecarboxylate (7b). Oxirane 6 (120 g, 0.651
mol) was dissolved in THF (1200 mL), and CuI (13.7 g, 71.7 mmol) was added under argon
atmosphere. The mixture was cooled to 0 °C, and 1 M PhMgCl in THF (717 mL, 0.717 mol) was added
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The Journal of Organic Chemistry
dropwise at 0 °C. The reaction mixture was stirred at rt overnight, then cooled to –20 °C, and 20% aq
1
2
3
4
5
6
7
8
9
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
NH Cl (500 mL) was added in one portion. The resulting mixture was heated to rt, and EtOAc (3000
4
mL) was added. Organic layer was separated, washed with brine (21000 mL), dried over Na SO , and
2
4
evaporated in vacuo at 45 °C. The crude compound was purified by column chromatography on silica
gel using hexanes – EtOAc (3:1) as eluent; R = 0.45. The compound was obtained as ca. 5:2 mixture of
f
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
diastereomers. Yield 83.7 g (49%); yellowish liquid. H NMR (500 MHz, CDCl ): major diastereomer δ
3
7
.43 – 7.24 (m, 5H), 4.23 (q, J = 7.4 Hz, 1H), 3.01 – 2.90 (m, 2H), 2.47 – 2.25 (m, 2H), 2.20 (s, 1H),
2.13 – 1.84 (m, 2H), 1.48 (s, 9H); minor diastereomer δ 7.26 – 7.16 (m, 5H), 4.16 – 4.09 (m, 1H), 3.12
(q, J = 8.2 Hz, 1H), 2.84 – 2.75 (m, 1H), 2.47 – 2.25 (m, 2H), 2.13 – 1.84 (m, 3H), 1.49 (s, 9H).
1
3
1
C{ H} NMR (126 MHz, CDCl ) δ 176.5 and 175.3, 142.4 and 142.0, 128.6 and 128.6, 127.5 and
3
1
27.3, 126.7 and 126.5, 80.8 and 80.3, 79.9 and 78.9, 54.3 and 53.4, 41.4 and 41.4, 37.2, 35.5 and 34.7,
+
28.1 and 28.1. HRMS (ESI-TOF) m/z: [M+Na] Сalcd. for C H NaO 285.1467. Found 285.1463.
1
6
22
3
(3R*,4R*)-tert-Butyl 3-fluoro-4-hydroxycyclopentanecarboxylate (7c). Oxirane 6 (100 g, 0.543
mol) was dissolved in dichloroethane (100 mL), and Et N3HF (131 g, 0.814 mol) was added at rt
3
(NOTE: using less concentrated solutions result in significantly increased reaction time). The mixture
was stirred at 80 °C overnight, then cooled to rt, and CH Cl (1000 mL) was added. The resulting
2
2
mixture was washed with H O (300 ml), 10% aq K CO (600 mL) and brine (300 mL), dried over
2
2
3
Na SO , and evaporated in vacuo at 45 °C. The crude compound was purified by distillation in vacuo.
2
4
1
Yield 78.7 g (71%); colorless liquid; bp 92–95 °C / 1 mmHg. H NMR (400 MHz, CDCl ) δ 4.87 – 4.70
3
(m, 1H), 4.39 – 4.25 (m, 1H), 3.00 – 2.90 (m, 1H), 2.39 – 2.06 (m, 4H), 1.90 – 1.84 (m, 1H), 1.41 (s,
1
3
1
9H). C{ H} NMR (126 MHz, CDCl ) δ 174.7, 98.5 (d, J = 178 Hz), 80.7, 75.8 (d, J = 27.1 Hz), 40.9
3
19
1
(
d, J = 1.5 Hz), 35.0, 33.6 (d, J = 22.0 Hz), 27.9. F{ H} NMR (376 MHz, CDCl ) δ –178.8. HRMS
3
+
(
ESI-TOF) m/z: [M+Na] Сalcd. for C H FNaO 227.1059. Found 227.1057.
1
0
17
3
(3R*,4R*)-Methyl 3-hydroxy-4-methoxycyclopentanecarboxylate (7d). Na (12.8 g, 0.53 mol) was
added to MeOH (2000 mL), and the mixture was refluxed for 2 h. Then, oxirane 6 (196g, 1.06 mol) was
added, and the resulting mixture was refluxed overnight, and cooled to the rt. HOAc (67 g, 1.11 mol)
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was added in one portion, and the resulting mixture was evaporated in vacuo at 45 °C. The residue was
dissolved in t-BuOMe (1000 mL) and washed with brine (2200 mL), dried over Na SO , and
1
2
3
4
5
6
7
8
9
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
2
4
evaporated in vacuo at 45 °C. The crude compound was purified by distillation in vacuo. The compound
was obtained as ca. 3:2 mixture of diastereomers. Yield 106 g (57 %); colorless liquid; bp 60–62 °C / 7
1
mmHg. H NMR (500 MHz, CDCl ): major diastereomer δ 4.19 (dt, J = 6.9, 3.8 Hz, 1H), 3.72 – 3.65
3
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, 3H), 3.61 – 3.56 (m, 1H), 3.34 (s, 3H), 3.00 (quint, J = 8.6 Hz, 1H), 2.44 – 2.09 (m, 3H), 1.89 –
.83 (m, 2H); minor diastereomer δ 4.13 (dt, J = 6.0, 2.9 Hz, 1H), 3.72 – 3.65 (m, 4H), 3.33 (s, 3H),
3.00 (quint, J = 8.6 Hz, 1H), 2.44 – 2.09 (m, 3H), 1.99 (ddd, J = 13.7, 9.3, 2.9 Hz, 1H) , 1.89 – 1.83 (m,
1
13
1
1
4
H). C{ H} NMR (126 MHz, CDCl ) δ 171.2, 82.7 and 82.7, 71.1 and 70.9, 52.2 and 52.1, 47.4 and
3
+
+
7.1, 35.0 and 34.6, 30.9 and 30.5, 28.1 and 27.7. GC/MS (EI): m/z = 141 [M–OCH ] , 174 [M] . Anal.
3
Calcd. for C H O : C, 55.16; H, 8.10. Found: C, 55.51; H, 8.05.
8
14
4
(3S*,4S*)-tert-Butyl 3-methyl-4-((phenylsulfonyl)oxy)cyclopentanecarboxylate (8a). A solution of
alcohol 7a (96.1 g, 0.480 mol) in pyridine (480 mL) was cooled to 5 °C, and PhSO Cl (109 g, 0.620
2
mol) was added dropwise at 5 °C. The mixture was stirred at rt overnight, then evaporated in vacuo at
6
0 °C. The residue was dissolved in CH Cl (1000 mL), the solution was washed with 10% aq NaHSO
2 2 4
(3300 mL) and brine (200 mL), dried over Na SO , and evaporated in vacuo at 45 °C. The crude
2
4
compound was purified by column chromatography on silica gel using hexanes – EtOAc (2:1) as eluent;
R = 0.76. The compound was obtained as ca. 2:1 mixture of diastereomers. Yield 152 g (93%);
f
1
colorless solid. H NMR (400 MHz, CDCl ): major diastereomer δ 7.87 (d, J = 7.6 Hz, 2H), 7.60 (t, J =
3
6.8 Hz, 1H), 7.55 – 7.46 (m, 2H), 4.51 – 4.41 (m, 1H), 2.81 (quint, J = 8.1 Hz, 1H), 2.23 – 2.02 (m, 3H),
2.01 – 1.85 (m, 1H), 1.37 (s, 9H), 1.33 – 1.19 (m, 1H), 0.85 (d, J = 6.1 Hz, 2H) and 0.82 (d, J = 6.7 Hz,
1
H); minor diastereomer δ 7.87 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 6.8 Hz, 1H), 7.55 – 7.46 (m, 2H), 4.34
(q, J = 6.3 Hz, 1H), (quint, J = 7.1 Hz, 1H), 2.23 – 2.02 (m, 3H), 2.01 – 1.85 (m, 1H), 1.37 (s, 9H), 1.33
1
3
1
–
1.19 (m, 1H), 0.85 (d, J = 6.1 Hz, 2H) and 0.82 (d, J = 6.7 Hz, 1H). C{ H} NMR (101 MHz, CDCl )
3
δ 174.3 and 174.1, 137.1 and 137.0, 133.7 and 133.6, 129.2 and 129.1, 127.7, 89.2 and 88.3, 80.5 and
8
0.4, 42.0 and 40.6, 40.4 and 39.2, 35.2 and 34.8, 34.9 and 33.6, 28.0 and 28.0, 17.5 and 16.9. HRMS
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The Journal of Organic Chemistry
+
+
(
ESI-TOF) m/z: [M+NH ] Сalcd. for C H NO S 358.1688. Found 358.1686. [M+Na] Сalcd. for
4 17 28 5
1
2
3
4
5
6
7
8
9
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
C H NaO S 363.1242. Found 363.1242.
1
7
24
5
(3R*,4S*)-tert-Butyl 3-phenyl-4-((phenylsulfonyl)oxy)cyclopentanecarboxylate (8b). A solution
of alcohol 7b (110 g, 0.420 mol) in pyridine (550 mL) was cooled to 5 °C, and PhSO Cl (97.1 g, 0.550
2
mol) was added dropwise at 5 °C. The mixture was stirred at rt overnight, then evaporated in vacuo at
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
6
0 °C. The residue was dissolved in CH Cl (1000 mL), the solution was washed with 10% aq NaHSO
2 2 4
(3300 mL) and brine (200 mL), dried over Na SO , and evaporated in vacuo at 45 °C. The crude
2
4
compound was purified by column chromatography on silica gel using hexanes – EtOAc (2:1) as eluent;
1
R = 0.64. Yield 132 g (78%); colorless solid. H NMR (500 MHz, CDCl ) δ 7.81 – 7.60 (m, 2H), 7.53
f
3
(t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.23 – 7.09 (m, 3H), 7.06 – 6.98 (m, 2H), 4.80 (q, J = 6.7
Hz, 1H), 3.29 – 3.20 (m, 1H), 3.03 (quint, J = 8.7 Hz, 1H), 2.46 – 2.35 (m, 2H), 2.22 – 2.13 (m, 1H),
1
3
1
1.95 – 1.87 (m, 1H), 1.46 (s, 9H). C{ H} NMR (126 MHz, CDCl ) δ 174.0, 140.1, 136.3, 133.4,
3
1
29.0, 128.6, 127.6, 127.2, 126.9, 88.2, 80.8, 51.5, 42.1, 35.7, 34.9, 28.0. HRMS (ESI-TOF) m/z:
+
+
[
M+NH ] Сalcd. for C H NO S 420.1845. Found 420.1841. [M+Na] Сalcd. for C H NaO S
4 22 30 5 22 26 5
4
25.1399. Found 425.1399.
3S*,4S*)-tert-Butyl 3-bromo-4-fluorocyclopentanecarboxylate (8c). Alkene 5 (110 g, 0.654 mol)
was dissolved in CH Cl (1100 mL), and Et N3HF (316 g, 1.96 mol) was added at rt. The mixture was
(
2
2
3
cooled to 5 °C, NBS (140 g, 0.785 mol) was added in one portion, and mixture was stirred at rt
overnight. Then, reaction mixture was washed with H O (300 mL), 10% aq K CO (300 mL) and brine
2
2
3
(200 mL), dried over Na SO , and evaporated in vacuo at 45 °C. The crude compound was purified by
2
4
distillation in vacuo. The compound was obtained as ca. 2:1 mixture of diastereomers. Yield 134 g
1
(77%); colorless liquid; bp 88–90 °C / 1 mmHg. H NMR (500 MHz, CDCl ): major diastereomer: δ
3
5
.22 – 5.08 (m, 1H), 4.40 (dd, J = 12.2, 5.1 Hz, 1H), 3.18 (quint, J = 9.4 Hz, 1H), and 2.73 – 2.47 (m,
H), 2.33 (dd, J = 14.7, 7.9 Hz, 1H), 2.27 – 2.15 (m, 1H), 1.46 (s, 9H); minor diastereomer: δ 5.26 –
2
5.22 (m, 1H), 4.30 – 4.23 (m, 1H), 3.08 – 3.00 (m, 1H), 2.80 – 2.74 (m, 1H), 2.73 – 2.47 (m, 1H), 2.33
1
3
1
(dd, J = 14.7, 7.9 Hz, 1H), 2.27 – 2.15 (m, 1H), 1.46 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ 173.4
3
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and 173.2, 100.0 (d, J = 181 Hz) and 99.0 (d, J = 182 Hz), 80.9 and 80.8, 52.1 (d, J = 27.9 Hz) and 49.8
1
2
3
4
5
6
7
8
9
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
(d, J = 27.0 Hz), 41.8 and 41.6, 37.5 and 37.1, 33.4 (d, J = 22.1 Hz) and 33.2 (d, J = 20.9 Hz), 28.0 and
1
9
1
+
2
8.0. F{ H} NMR (376 MHz, CDCl ) δ –158.4 and –165.7. HRMS (ESI-TOF) m/z: [M+H] Сalcd.
3
+
for C H BrFO 267.0396. Found 267.0379. [M+Na] Сalcd. for C H BrFNaO 289.0215. Found
1
0
17
2
10 16
2
2
89.0216.
3S*,4S*)-tert-Butyl 3-bromo-4-methoxycyclopentanecarboxylate (8d). A solution of alkene 5
77.5 g, 0.461 mol) was dissolved in MeOH (800 mL) was cooled to 5 °C. NBS (86.1 g, 0.484 mol) was
added in portions at 5 °C, resulting mixture was stirred at rt overnight, and evaporated in vacuo at 45
C. The residue was dissolved in CH Cl (700 mL), the solution was washed with brine (2200 mL),
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
2
dried over Na SO , and evaporated in vacuo at 45 °C. The crude compound was purified by distillation
2
4
in vacuo. The compound was obtained as ca. 4:1 mixture of diastereomers. Yield 109 g (85%); colorless
1
liquid; bp 81–83 °C / 1 mmHg. H NMR (400 MHz, CDCl ): major diastereomer δ 4.30 – 4.22 (m, 1H),
3
3
.99 – 3.85 (m, 1H), 3.32 (s, 1H), 3.30 (s, 2H), 3.01 (quint, J = 8.5 Hz, 1H), 2.47 (ddd, J = 14.6, 9.1, 5.9
Hz, 1H), 2.42 – 2.33 (m, 1H), 2.18 (ddd, J = 14.6, 7.9, 2.7 Hz, 1H), 1.92 – 1.82 (m, 1H), 1.39 (s, 9H);
minor diastereomer δ 4.14 – 4.02 (m, 1H), 3.99 – 3.85 (m, 1H), 3.32 (s, 3H), 2.86 (quint, J = 8.6 Hz,
1
H), 2.59 (ddd, J = 14.8, 9.1, 6.6 Hz, 1H), 2.42 – 2.33 (m, 1H), 2.29 – 2.23 (m, 1H),1.92 – 1.82 (m, 1H),
1
3
1
1.40 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ 173.8 and 173.7, 88.8 and 88.7, 80.6 and 80.4, 57.2
3
and 57.1, 52.8 and 50.9, 41.9 and 41.6, 38.0 and 37.6, 33.1 and 32.8, 28.0 and 28.0. HRMS (ESI-TOF)
+
m/z: [M+Na] Сalcd. for C H BrNaO 301.0415/303.0395. Found 301.0414/303.0395.
1
1
19
3
(3S*,4S*)-tert-Butyl 3,4-dibromocyclopentanecarboxylate (8e). A solution of alkene 5 (52.0 g,
0
.309 mol) in CHCl (500 mL) was cooled to 5 °C, and Br (17.5 mL, 54.3 g, 0.34 mol) was added
3
2
dropwise at 5 °C. The reaction mixture was stirred at rt overnight, and washed with 10% aq Na SO
2
3
(
200 mL) and brine (100 mL), dried over Na SO , and evaporated in vacuo at 45 °C. The crude
2 4
compound used in the next step without further purification (decomposed upon distillation in vacuo or
1
chromatographic purification). Yield 89.2 g (88%); colorless liquid. H NMR (400 MHz, CDCl ) δ 4.61
3
– 4.53 (m, 1H), 4.52 – 4.40 (m, 1H), 3.24 – 3.10 (m, 1H), 2.97 – 2.88 (m, 2H), 2.52 – 2.45 (m, 1H), 2.37
1
3
1
(
dd, J = 14.8, 8.7 Hz, 1H), 1.44 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ 173.3, 81.0, 56.6, 54.7,
3
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The Journal of Organic Chemistry
+
4
3
1.9, 37.4, 28.0. HRMS (ESI-TOF) m/z: [M+Na] Сalcd. for C H Br NaO 348.9415. Found
1
0
16
2
2
1
2
3
4
5
6
7
8
9
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
48.9418.
3S*,4S*)-tert-Butyl 3-azido-4-iodocyclopentanecarboxylate (8f). Alkene 5 (186 g, 1.11 mol) was
dissolved in THF (1700 mL), MeOH – H O (800 mL, 3:1, v/v) was added. Then, NaN (252 g, 3.87
(
2
3
mol) was added, and the mixture was cooled to 5 °C. I (701 g, 2.76 mol) was added in portions at 5 °C,
2
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
and the resulting mixture was stirred at rt overnight. Then, 20% aq Na SO (2010 mL, 3.32 mol) was
2
3
added, and the mixture was extracted with t-BuOMe (2100 mL). Combined organic layers were
washed with brine (2300 ml), dried over Na SO , and evaporated in vacuo at 30 °C. The crude was
2
4
used in the next step without further purification. Yield 281 g (75%); brown oil. The compound was
1
obtained as ca. 2:1 mixture of diastereomers. H NMR (500 MHz, CDCl ): major diastereomer δ 4.35 –
3
4.02 (m, 2H), 3.04 (quint, J = 7.1 Hz, 1H), 2.58 – 2.50 (m, 1H), 2.47 – 2.38 (m, 1H), 2.37 – 2.25 (m,
1
H), 1.97 – 1.90 (m, 1H), 1.68 – 1.20 (m, 9H); minor diastereomer δ 4.35 – 4.02 (m, 1H), 4.00 – 3.90
(m, 1H), 2.89 (quint, J = 7.1 Hz, 1H), 2.72 – 2.66 (m, 1H), 2.47 – 2.38 (m, 1H), 2.37 – 2.25 (m, 1H),
1
3
1
1
.90 – 1.84 (m, 1H), 1.68 – 1.20 (m, 9H). C{ H} NMR (101 MHz, CDCl ) δ 173.3 and 173.0, 81.1
3
and 81.0, 70.8 and 70.8, 42.3 and 42.1, 40.1 and 39.6, 33.0 and 32.9, 28.0 and 28.0, 27.0 and 24.7.
+
HRMS (ESI-TOF) m/z: [M+Na] Сalcd. for C H IN NaO 360.0185. Found 360.0182.
1
0
16
3
2
(3S*,4S*)-tert-Butyl 3-bromo-4-hydroxycyclopentanecarboxylate (8g). A solution of alkene 5 (150
g, 0.892 mol) MeCN – H O (2250 mL, 2:1, v/v) was cooled to 5 °C. NBS (168 g, 0.942 mol) was added
2
in portions at 5 °C, the mixture was stirred at rt overnight, then evaporated in vacuo at 45 °C. The
residue was dissolved in CH Cl (1000 mL), the solution was washed with brine (2300 mL), dried over
2
2
Na SO , and evaporated in vacuo at 45 °C. The crude compound was purified by distillation in vacuo.
2
4
The compound was obtained as ca. 3:2 mixture of diastereomers. Yield 180 g (76%); colorless oil; bp
1
1
11–113 °C / 1 mmHg. H NMR (400 MHz, CDCl ): major diastereomer δ 4.56 – 4.23 (m, 1H), 4.24 –
3
4.12 (m, 1H), 3.10 – 3.00 (m, 1H), 2.82 – 2.06 (m, 4H), 1.90 – 1.80 (m, 1H), 1.42 (s, 9H); minor
diastereomer δ 4.56 – 4.23 (m, 1H), 3.95 (q, J = 6.5 Hz, 1H), 3.43 (s, 1H), 2.92 (quint, J = 9.2 Hz, 1H),
13
1
2
.82 – 2.06 (m, 3H), 1.90 – 1.80 (m, 1H), 1.42 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ 176.7 and
3
ACS Paragon Plus Environment
2
9