Concise Synthesis of a New Chiral Cyclopentenone Building Block for Prostaglandins and their Derivatives

Article abstract of DOI:10.1002/ejoc.201900102

(4R,5R)-4,5-O-isopropylidene-2-(dimethoxyphosphoryl)cyclopen-2-enone was obtained in enantiomerically pure form in four steps starting from commercially available 2,3-O-isopropylidene-D-erythronolactone. The key steps involved are diastereoselective lactone ring opening leading in a one-pot procedure to the ε-silyloxy Weinreb-type amide, and the cyclopentenone ring formation by the rhodium catalyzed carbenoid cyclization of the corresponding ε-silyloxy-α-diazo-β-ketophosphonate followed by the elimination of tert-butyldimethylsilanol. During the synthetic study on the construction of the cyclopentanone ring by the intramolecular nucleophilic substitution reaction of an anion generated from ε-bromo-β-ketophosphonate, the formation of cyclopropane derivative was observed. This stereochemical outcome was rationalized using quantum chemical calculations.

Full text of DOI:10.1002/ejoc.201900102

A Journal of
Accepted Article
Title: Concise synthesis of a new chiral cyclopentenone building block
for prostaglandins and their derivatives
Authors: Remigiusz Zurawinski and Beata Lukasik
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10.1002/ejoc.201900102
European Journal of Organic Chemistry
Concise synthesis of a new chiral cyclopentenone building
block for prostaglandins and their derivatives
Remigiusz Żurawiński* and Beata Łukasik
Centre of Molecular and Macromolecular Studies Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź, Poland
*Corresponding author. E-mail address: remzur@cbmm.lodz.pl
Abstract: (4R,5R)-4,5-O-isopropylidene-2-(dimethoxyphosphoryl)cyclopen-2-enone was obtained in enantiomerically pure form
in four steps starting from commercially available 2,3-O-isopropylidene-D-erythronolactone. The key steps involved are
diastereoselective lactone ring opening leading in a one-pot procedure to the -silyloxy Weinreb-type amide, and the
cyclopentenone ring formation by the rhodium catalyzed carbenoid cyclization of the corresponding -silyloxy--diazo--
ketophosphonate followed by the elimination of tert-butyldimethylsilanol. During the synthetic study on the construction of the
cyclopentanone ring by the intramolecular nucleophilic substitution reaction of an anion generated from -bromo--
ketophosphonate, the formation of cyclopropane derivative was observed. This stereochemical outcome was rationalized using
quantum chemical calculations.
Introduction
The cyclopentenone unit is a widespread structural motif present not only in bioactive natural compounds and
pharmaceutical drugs but also in a vast number of chiral intermediates having been used as key synthons for the
synthesis of different types of targets.[1] Popularity of chiral cyclopentenones as powerful building blocks in the total
synthesis is inherently connected with their rich diversity of possible functionalization routes. They can undergo the 1,2-
and 1,4-addition reactions, an addition to a carbon-carbon double bond and functionalization in the allylic and - to
carbonyl group positions. These properties together with the presence of a 5-membered structural core strongly
contribute to a broad application of the cyclopentenone building blocks in the synthesis of prostaglandins (PGs).[2] PGs,
which are hormone-like chemical messengers, constitute a large group of naturally occurring compounds derived from
oxidation of polyunsaturated fatty acids. They regulate a broad range of physiological activities in animals and humans
including cell growth and its differentiation, digestion, reproduction and the contraction and relaxation of smooth muscle
tissue.[3] They are also involved in many pathophysiological processes associated with inflammation[4] and cancer.[5]
Moreover, some PG of A and J series and their derivatives which contain a cross-conjugated ,-unsaturated
functionality show anti-neoplastic,[6] neuroprotective[7] and neuroregenerative activities.[8] The synthesis of PGs and they
derivatives mainly based on 3 types of strategies: (i) sequential installation of - and - chains into the appropriate
functionalized cyclopentane; (ii) cyclization leading to a five-membered cyclic structure encompassing a one chain
followed by introduction of the second chain at the later stage; (iii) a one-pot procedure involving a 1,4-addition of the -
chain to the cyclopentenone building block with the subsequent trapping with the required -chain component as an
electrophile. The third strategy (three-component coupling developed in Noyori’s group[9]) gained a strong interest,
mainly due to its simplicity, efficiency and a general character. It primarily bases on the chiral cyclopentenone building
blocks like protected derivatives of 4-hydroxycyclopent-2-enone 1 and 4,5-dihydroxycyclopent-2-enone 2 (Fig. 1).
Consequently, a considerable number of synthetic methods for their preparation have been developed.[1][10]
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Figure 1. Structures of cyclopentenone building blocks mentioned in the text.
In the frame of our research program aimed at the invention and development of general methods for the
synthesis of bioactive cyclopentenones and cyclopentanones using phosphonate reagents, the diastereoisomeric
camphor protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enones[11] 3 have emerged as particularly
useful starting materials in the synthesis of various chiral cyclopentenone and cyclopentanone derivatives. The utility of
these blocks was demonstrated, among others, via the synthesis of anticancer cyclopentenone PG derivatives
(enantiomers of TEI-9826,[12] NEPP-11 and iso-NEPP-11[13]) and two enantiomerically pure stereoisomers of rosaprostol
– an antiulcer drug.[14]
Herein, we report a simple, four step synthesis of a new chiral cyclopentenone building block 4 which we
consider to be useful in our planned syntheses of cyclopentenone PGs. It will give access to the biologically more stable
PGA series derivatives with the opposite to natural PGs configuration on the isomerase-sensitive carbon atom C(12).[15]
Some preliminary results concerning functionalization of enone 4 via the Michael addition reaction of organometallic
reagents and the Horner olefination reaction are also presented.
Results and discussion
According to our strategy devised for the synthesis of 4 and outlined retrosynthetically in Scheme 1, we envisioned that
the key step in its synthesis involves the cyclopentanone/cyclopentenone ring closure. We assumed that the
cyclopentanone ring formation may be achieved by base-induced intramolecular nucleophilic displacement of a halogen
group in a cis-diol protected -halo--ketophosphonate. The resulted cis-fused bicyclic system containing phosphoryl
and carbonyl functionalities could be easily converted into the target enone 4 in a two-step procedure involving -
selenenylation of the corresponding carbanion followed by the oxidation of the selenide formed. Alternatively,
cyclopentenone skeleton formation could be accomplished via rhodium catalyzed intramolecular carbenoid cyclization[16]
of the corresponding cis-diol protected -silyloxy--diazo--ketophosphonate. Further retrosynthetic analysis of the
reagents for these two alternative approaches to the construction of the cyclopentenone ring revealed that both of them
can be easily accessible from commercially available 2,3-O-isopropylidene-D-erythronolactone (5). We envisioned that
the latter upon treatment with the anion generated from dimethyl methylphosphonate will afford the corresponding -
hydroxy--ketophosphonate which, using simple group transformations, should be converted into the desired -halo- and
-silyloxy--diazo derivatives.
Scheme 1. Retrosynthetic analysis of cyclopentenone 4.
The practical execution of the above synthetic plan based on the intramolecular SN2 reaction is outlined in
Scheme 2. Our synthesis of 4 started with commercially available chiral acetonide 5 (also easy accessible from D-
isoascorbic acid via a known two-step procedure[17]). Reaction of acetonide 5 with the anion generated from dimethyl
methylphosphonate upon treatment with n-BuLi easily afforded addition product 6 in almost quantitative yield. Cis-
configuration of the isopropylidene protected diol group in hemiacetal 6 was confirmed by ROESY analysis. The
absolute configuration of the newly created quaternary stereogenic center was assigned as R based on the generally
accepted mechanism of nucleophilic addition to the carbonyl group, according to which an anion generated from
dimethyl methylphosphonate attacks the carbon atom of the carbonyl group from the less hindered side (opposite to the
cis-diol moiety) to give after protonation hemiacetal 6 with three oxygen atoms adjacent to the cyclopentanone ring in cis
relation. Under basic conditions (KOH/MeOH and MeONa/MeOH) the latter underwent transformation to the
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European Journal of Organic Chemistry
corresponding -hydroxy--ketophosphonate 7. This process proceeded with epimerization at the dioxolane carbon
atom to the carbonyl group, leading to the formation of the thermodynamically more stable trans isomer. -Hydroxy--
ketophosphonate 7 was subsequently treated with tetrabromomethane and triphenylphosphine to give -bromo--
ketophosphonate 8 in 60% yield. We expected, that in the next step, 8 will undergo trans to cis epimerization during
intramolecular SN2 reaction carried out under conditions of thermodynamic control, affording thermodynamically favored
4,5-dihydroxy-2-(dimethoxyphosphoryl)cyclopentanone acetonide with cis-diol configuration. Contrary to our expectation,
heating of 8 with potassium carbonate in the presence of 18-crown-6 in benzene resulted in the formation of
cyclopropane derivative cCy in 78% yield. Under the same reaction conditions mesylate 9 prepared from alcohol 8 and
MsCl in the presence of triethylamine also underwent conversion to cyclopropane derivative cCy. The same
stereochemical outcome was also observed in the reaction of bromide 8 with sodium tert-butoxide in THF.
Scheme 2. Attempt at the synthesis of 4 via intramolecular SN2 reaction.
The formation of the three membered carbon ring instead of the cyclopentanone derivative 2PCP can be
rationalized assuming that enolate C1En generated by deprotonation of 8 with a base under thermodynamic conditions
exists in the equilibrium with enolate C3En (Scheme 3). Moreover, the equilibration of enolates C1En and C3En must be
a fast process (with respect to the rate of products formation) and can occur by a reversible formation of the enols.
Although at the equilibrium the population of C1En can be expected much higher than C3En (enolate C1En is stabilized
by the phosphoryl group), the latter undergoes an irreversible reaction via the lowest energy rate-limiting transition state
affording cyclopropane cCy with cis-configuration of the fused cyclopropane and dioxolane rings. The formation of a
trans-fused system is strongly disfavored due to the high ring strain. Gas-phase quantum chemistry calculations of
model 2,4-dioxabicyclo[3.1.0]hexane carried out applying the CBS-QB3 composite method[18] revealed that the trans-
substituted cyclopropane has an about 74 kcal/mol higher energy than its cis-isomer (see ESI).
Scheme 3. Formation of cCy from 8 under the basic conditions.
To confirm our hypothesis involving formation of cCy and to investigate a possibility of the cyclopentanone ring
formation in the intramolecular SN2 reaction, we performed the DFT calculations taking into account all theoretically
possible reaction routes (Scheme 4). Thus, enolate C1En genetated from 8 by deprotonation at the carbon atom C(1)
can react at the enolate C1En oxygen atom to afford (Z)- or (E)-vinylphosphonates (VP) or at the carbon atom C(1) to
give diastereoisomeric (S)- and (R)-2-(dimethoxyphosphoryl)cyclopentanones (2PCP). On the other hand, enolate C3En
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European Journal of Organic Chemistry
will give dihydrofuran derivative (DHF), as a result of an O-alkylation process, or cis-diol substituted cyclopropane
derivative cCy as a consequence of an intramolecular alkylation at the C(3) position.
Scheme 4. Possible reaction pathways of the anion generated from -bromo--ketophosphonate 8.
All DFT and CBS-QB3 calculations were performed using the ultrafine (“99,590”) Lebedev grid and tight
convergence criteria of the Gaussian 09 program.[19] The preliminary conformational search was carried out using
HyperChem and the MM+ molecular mechanics force field.[20] Transition states were found applying pseudo reaction
coordinate technique connected with conformational search. The obtained structures were fully optimized with the hybrid
GGA B3LYP[21] functional in conjunction with the split-valence double-zeta 6-31+G(d) basis set including polarization
and diffuse functions on heavy atoms. To include solvent effects, calculations were conducted applying the polarizable
continuum model for THF. All stationary points found on the potential energy surface were confirmed to be equilibrium
structures (no imaginary frequencies) or transition states (one imaginary frequency) by calculation of vibrational
frequencies at the level of theory used for the geometry optimization. Due to the known tendency of the B3LYP
functional to underestimate the reaction barrier heights,[22] the optimized structure of enolates, transition states and
products were subsequently subjected to more accurate single-point energy calculations applying the M06-2X[23] hybrid
meta-GGA functional with D3 version of Grimme’s dispersion correction[24] and Dunning’s augmented correlation-
consistent polarized valence aug-cc-pVTZ basis set.[25] To connect the lowest energy TS structures to those of the
products and enolates an Internal Reaction Coordinate (IRC) calculation were conducted at the PCM B3LYP/6-31+G(d)
level. Although in some cases the IRC calculation did not lead to the lowest energy products and enolates we did not
attempt to find pathway connecting this conformers with the corresponding conformers of the lowest energy assuming
that the anion and product obtained from IRC calculation can be easily converted into the corresponding lowest energy
conformers by a simple rotation around single bonds with rotational barrier heights within a range of a few kcal/mol. The
DFT calculations revealed that the formation of 2-(dimethoxyphosphoryl)cyclopentanones 2PCP, dihydrofuran DHF and
cyclopropan cCy derivatives are strongly favorable processes for which the Gibbs free energy of the products is much
lower than the free energy of the starting materials (Grxn<0) (Scheme 5). On the other hand, the processes associated
with the formation of vinylphosphonates VP are less favorable or even unfavorable. In the case of these reactions, Grxn
is -0.3 and +0.2 kcal/mol for (E)- and (Z)-VP, respectively. Although the cyclopentanone derivatives 2PCP constitute the
thermodynamically most stable products, the activation energy for the C(1)-alkylation reactions as well as their TS
energies are the highest among the reactions under discussion. The lowest energy TS was found for the C(3)-alkylation
process. Its energy is lower by 12.8 kcal/mol or 14.7 kcal/mol than the energy of TSs leading to diastereoisomeric
cyclopentanones (S)- and (R)-2PCP, respectively. Moreover, the C(3)-alkylation reaction has also the lowest activation
energy equal to +7.4 kcal/mol. The DFT calculations clearly show that the formation of cyclopropane cCy is a highly
favored process with respect to the other reaction pathways. This observation is in a full agreement with our
experimental results.
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European Journal of Organic Chemistry
Scheme 5. Collective reaction coordinate diagrams for the considered reactions of the anion generated from -bromo--
ketophosphonate 8. The free energies are relative to the lowest energy enolate (Z)-C1EnLo. In parentheses, the free energy of
the most stable enolate/product conformer of the same type as the conformer involved in the reaction is given.
In view of the results obtained from the DFT calculations and experiments directed toward the synthesis of
cyclopentanone 2PCP via the intramolecular nucleophilic substitution reaction, we turned our efforts to an alternative
synthetic strategy based on the rhodium(II) catalyzed intramolecular carbenoid cyclization reaction as a key step in the
synthesis of 4. The practical realization of this strategy is depicted in Scheme 6. Similarly, like in our previous approach,
the synthesis of 4 started from the protected lactone 5 which in a one-pot procedure involving its reaction with N,O-
dimethylhydroxylamine in the presence of trimethylaluminum followed by silylation of the hydroxyamide formed was
transformed into the silyl-protected amide 10. In the next step the amide 10 was subjected to the reaction with an anion
generated from dimethyl methylphosphonate upon treatment with n-BuLi. The resulting -ketophosphonate 11 was
subsequently converted under typical diazo-transfer reaction conditions (TsN3, K2CO3, ACN) into -diazo--
ketophosphonate 12. This intermediate heated in 1,2-dichloroethane at 65 °C in the presence of rhodium(II) acetate
underwent an intramolecular C-H insertion reaction followed by the elimination of tert-butyldimethylsilanol to give the
desired enantiomerically pure 2-(dimethoxyphosphoryl)cyclopent-2-enone 4 in 56% yield.
Scheme 6. Synthesis of 4 via the rhodium(II) catalyzed intramolecular carbenoid cyclization.
Basing on the same methodology, we also made an attempt to obtain cyclopentenone 13 - an analogue of
enone 4 in which cis-diol moiety was protected in the form of open-chain silyl ethers (Scheme 7). For this purpose, D-
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European Journal of Organic Chemistry
erythronolactone was reacted with tert-butyldimethylsilyl chloride in the presence of imidazole to give silyloxy-protected
lactone 14 in nearly quantitative yield. The reaction of 14 with N,O-dimethylhydroxylamine in the presence of
trimethylaluminum afforded -hydroxy Weinreb amide 15. Protection of the hydroxyl group in the form of a silyl ether
followed by the reaction of the amide 16 with lithium salt of methyl dimethoxyphosphonate gave -ketophosphonate 17,
which in turn, upon treatment with p-toluenesulfonyl azide in the presence of potassium carbonate was converted into
the corresponding -diazo--ketophophonate 18. This compound turned out to be much more stable and less reactive
toward the rhodium-mediated intramolecular C-H insertion reaction than its isopropylidene derivative 12. In analogous
reaction conditions it did not undergo the rhodium catalyzed carbenoid cyclization while a prolonged heating at elevated
temperature (above 100 °C) resulted in the formation of a complex mixture of unidentified compounds. The low reactivity
of 18 may be attributed to the lower accessibility of C(5)-H bond for carbenoid insertion due to the steric effect of two
bulky vicinal tert-butyldimethylsilyloxy groups.
Scheme 7. Approach to the synthesis of 13 via the rhodium(II) catalyzed intramolecular carbenoid cyclization.
To illustrate the possible way of functionalization of enone 4 it was subjected to the Michael addition reaction
with organometallic reagents (Scheme 8). It was found that the addition of a mixed organocuprate compound generated
from the Lipshutz reagent[26] and alkyllithium to enone 4 proceeded with complete diastereoselectivity under the
stereocontrol of a chiral diol moiety and afforded enol 19 with an (R)-configuration at the newly formed stereogenic
center C(3). The same stereochemical outcome was observed in the reaction of enone 4 with an organozinc reagent.
Thus, the reaction of diethylzinc with 4 carried out in the presence of p-toluenesulfonamide and copper(I) cyanide gave
adduct 20 in 51% yield. Analysis of the 31P and 13C NMR spectra revealed that adducts 19 and 20 exist in a CDCl3
solution in three tautomeric forms – a major enol form, and two minor keto forms involved with an (R)- or (S)-
configuration at the carbon atom C(2) attached to the phosphoryl group. The purity of 19 and 20 was confirmed by an
elemental analysis. The installation of the alkylidene substituent at the C(2) position was achieved via the Horner
olefination. Thus, the reaction of 20 with gaseous formaldehyde carried out in the presence of t-BuONa afforded
cyclopentanone 21 in 85% yield. The conversion of the isopropylidene protected cis-diol group into a double carbon
bond can be carried out according to the known literature protocol involving reductive deacetalization with aluminum
amalgam followed by the water elimination from the 4-hydroxy derivative formed.[12][27]
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European Journal of Organic Chemistry
Scheme 8. Exemplary functionalization routes of 4.
Conclusions
In
conclusion,
the
short
synthesis
of
enantiomerically
pure
(4R,5R)-4,5-O-isopropylidene-2-
(dimethoxyphosphoryl)cyclopen-2-enone (4) was developed based on commercially available 2,3-O-isopropylidene-D-
erythronolactone (5). Moreover, preliminary investigations concerning possible functionalization routes of enone 4 were
carried out. The installation of an alkyl substituent at the carbon atom C(3) was achieved by the Michael addition
reaction of organocopper and organozinc reagents. On the other hand, the phosphoryl group adjacent to the carbon
atom C(2) was successfully used for functionalization of this position via the Horner olefination reaction. In the course of
our studies toward the synthesis of enone 4 we found that under the basic conditions -bromo--ketophosphonate 8
underwent intramolecular nucleophilic substitution to give cyclopropane cCy. The DFT calculations conducted at the
PCM M06-2x-D3/aug-cc-pVTZ//B3LYP/6-31+G(d) level revealed that the formation of cCy is a highly favored process
with respect to the 2PCP, VP and DHF formation. Its transition state energy is lower by average 13.7 kcal/mol and 9.4
kcal/mol than the energy of TSs leading to diastereoisomeric cyclopentanones 2PCP and vinylphosphonates VP,
respectively. The observed preferences to the C(3)-alkylation process may be attributed to the steric hindrance exerted
by the phosphoryl group in the transition states leading to 2PCP and ring strain of trans-fused 5-membered ring systems
of 2PCP, VP and DHF.
Experimental Section
General remarks: Unless stated otherwise, all air and water sensitive reactions were carried out under an argon
atmosphere using freshly distilled dry solvents. All glassware was dried prior to use by heating under vacuum.
Commercial grade reagents and solvents were used without further purification except as indicated below. THF was
distilled over Na/benzophenone prior to use. Dichloromethane (DCM), 1,2-dichloroethane and triethylamine were dried
under reflux over calcium hydride, distilled and stored over activated 3Å molecular sieves. Benzene and toluene were
dried by refluxing over sodium and distillation. Thin layer chromatography (TLC) was conducted on Silica Gel 60 F254
TLC purchased from Merck. Column chromatography was performed using Merck silica gel (70-230 mesh). NMR
spectra were recorded on Bruker AV 200, Bruker DRX 500 or Bruker Avance III 600 spectrometers. 1H, 13C and 31P
chemical shifts are reported relative to the residual proton resonance in the deuterated solvents or referred to an 85%
aqueous solution of H3PO4, respectively. All chemical shifts () are given in ppm and the coupling constants (J) in Hz.
HRMS measurements were performed on a Finnigan MAT 95 or Waters Synapt HDMS mass spectrometer. Optical
rotations were measured using a Perkin-Elmer MC 241 photopolarimeter. Melting and boiling points are uncorrected.
(2R,3R,4R)-2-hydroxy-2-[(dimethoxyphosphoryl)methyl]-3,4-O-(isopropylidene)tetrahydrofuran (6): To a stirred
solution of dimethyl methylphosphonate (3.98 g, 32.1 mmol) in THF (90 mL), n-BuLi (13.9 mL, 30.7 mmol, 2.2 M in THF)
was added at -78 oC. Stirring was continued for 25 min and a solution of lactone 5 (3.98 g, 14.6 mmol) in THF (15 mL)
was added. After 0.5 h, the cooling bath was removed, and the reaction mixture was allowed to warm to room
temperature. An aqueous saturated solution of NH4Cl was added and the THF was evaporated under reduced pressure.
The residue was extracted with CHCl3 (4 x 30 mL) and the organic layer was dried over anhydrous Na2SO4. The solvent
and the excess of dimethyl phosphonate were removed in vacuo and the crude product was purified by column
chromatography (petroleum ether/acetone 2 : 1) to give 6 (4.10 g, 99%) as a colorless oil. Rf = 0.34 (petroleum ether
20
1
2:1); [α]D -35.7 (c 1.8 in CH2Cl2); 31P NMR (202 MHz, CDCl3) δ 31.64; H NMR (500 MHz, CDCl3) δ 5.00 (br s, 1 H,
OH), 4.82-4.78 (m, 1 H, OCHCH2), 4.37 (d, JHH = 5.8 Hz, 1 H, CHCOH), 4.01 (dd, JHH = 10.3 Hz, JHH = 3.8 Hz, 1 H,
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European Journal of Organic Chemistry
CHAHBO), 3.89 (d, JHH = 10.3 Hz, 1 H, CHAHBO), 3.77 (d, JPH = 11.2 Hz, 3 H, OCH3), 3.69 (d, JPH = 11.1 Hz, 3 H, OCH3),
2.39 (dd, JPH = 17.7 Hz, JHH = 15.4 Hz, 1 H, CHAHBP), 2.20 (dd, JPH = 18.1 Hz, JHH = 15.5 Hz, 1 H, CHAHBP), 1.41 (s, 3
H, CH3C), 1.26 (s, 3 H, CH3C); 13C NMR (126 MHz, CDCl3) δ 112.39(OCO), 103.89 (d, JPC = 7.9 Hz, COH), 85.31 (d, JPC
= 10.8 Hz, CHCOH), 80.44 (CHCH2O), 71.08 (CH2O), 53.29 (d, JPC = 5.9 Hz, OCH3), 51.94 (d, JPC = 6.4 Hz, OCH3),
30.11 (d, JPC = 136.6 Hz, CH2P), 26.11 (CH3), 24.69 (CH3); Anal. calcd for C10H19O7P: C, 42.56; H, 6.79. Found: C,
42.41; H, 6.70; HRMS CI m/z: calcd for C10H20O7P ([M+H]+) 283.0947; found 282.0949.
Dimethyl (3S,4R)-(5-hydroxy-3,4-O-isopropylidene-2-oksopentyl)phosphonate (7): To
a stirred solution of
hemiacetal 6 (1.56 g, 5.53 mmol) in MeOH (13 mL) potassium hydroxide (620 mg, 11.05 mmol) was added and stirring
was continued at room temperature for 24 h. An acetic acid (632 mL) was added, the solvent was evaporated under
reduced pressure and the residue was purified by column chromatography (petroleum ether/acetone 1 : 3) to yield 7
22
(1.34 g, 86%) as a colorless liquid. Rf = 0.18 (petroleum ether/acetone 1:2); [α]D -28.6 (c 2.5 in C6H6); 31P NMR (202
MHz, CDCl3) δ 22.39; 1H NMR (500 MHz, CDCl3) δ 4.40 (d, JHH = 7.6 Hz, 1 H, OCHC(O)), 4.21 (dt, JHH = 7.6 Hz, JHH
=
3.7 Hz, 1 H, OCHCH2), 3.90 (dt, JHH = 12.0 Hz, JHH = 4.2 Hz, 1 H, CHAHXOH), 3.81 (d, JPH = 11.3 Hz, 3 H, OCH3), 3.79
(d, JPH = 11.3 Hz, 3 H, OCH3), 3.74 (ddd, JHH = 12.0 Hz, JHH = 8.2 Hz, JHH =3.8 Hz, 1 H, CHAHXOH), 3.49 (dd, JPH = 22.9
Hz, JHH = 14.1 Hz, 1 H, CHAHXP), 3.31 (dd, JPH = 22.1 Hz, JHH = 14.1 Hz, 1H, CHAHXP), 2.27 (dd, JHH = 8.2, 4.8 Hz, 1 H,
OH), 1.47 (s, 3 H, CH3), 1.42 (s, 3 H, CH3); 13C NMR (126 MHz, CDCl3) δ 202.20 (d, JPC = 6.4 Hz, CO), 110.96 (OCO),
81.32 (CHCO), 77.98 (CHCH2), 62.10 (CH2OH), 53.16 (d, JPC = 6.3 Hz, OCH3), 53.05 (d, JPC = 6.3 Hz, OCH3), 36.72 (d,
J = 131.1 Hz, CH2P), 26.77(CH3), 26.01(CH3); HRMS FAB+ m/z: calcd for C10H20O7P ([M+H]+) 283.0947; found
283.0943.
Dimethyl (3S,4S)-(5-bromo-3,4-O-isopropylidene-2-oxopentyl)phosphonate (8): To a stirred solution of alcohol 7
(118 mg, 0.421 mmol) in dry CH2Cl2 (4 mL), CBr4 (153 mg, 0.463 mmol) and Ph3P (132 mg, 0.505 mmol) were added
o
successively at 0 C. The mixture was stirred for 20 min, and then 24 h at room temperature. Concentration under
reduced pressure followed by flash column chromatography using 2 : 1 petroleum ether/acetone as the eluent yielded 8
(86 mg, 60%) as a colorless liquid. Rf = 0.32 (petroleum ether/acetone 2:1); [α]D25 -42.2 (c 1.6 in CH2Cl2); 31P NMR (202
MHz, C6D6) δ 21.54; 1H NMR (500 MHz, C6D6) δ 4.36 (dt, JHH = 7.0 Hz, JHH = 4.4 Hz, 1 H, CHCH2), 4.28 (d, JHH = 6.9
Hz, 1 H, CHCO), 3.39 (d, JPH = 11.3 Hz, 3 H, OCH3), 3.38 (d, JPH = 11.2 Hz, 3 H, OCH3), 3.32 (dd, JHH = 11.2 Hz, JHH
=
3.8 Hz, 1 H, CHAHBBr), 3.23-3.09 (m, 3 H, CH2P, CHAHBBr), 1.33 (s, 3 H, CH3C), 1.22 (s, 3 H, CH3C); 13C NMR (126
MHz, C6D6) δ 201.56 (d, JPC = 6.6 Hz, CO), 111.45 (OCO), 83.49 (CHCO), 76.62 (CHCH2), 52.56 (d, JPC = 6.2 Hz,
OCH3), 52.51 (d, JPC = 6.2 Hz, OCH3), 37.24 (d, JPC = 128.5 Hz, CH2P), 33.17 (CH2Br), 27.13 (CH3C), 26.39 (CH3C);
Anal. calcd for C10H18BrO6P: C, 34.80; H, 5.26. Found: C, 34.92; H, 5.31; HRMS EI m/z: calcd for C10H18BrO6P:
345.0103; found 345.0101.
Dimethyl (3S,4R)-{3,4-O-isopropylidene-4-[(metanesulfonyl)oksy]-2-oxopentyl}phosphonate (9): To a solution of 7
(51 mg, 0.181 mmol) and Et3N (38mg, 0.38mmol) in dry CH2Cl2 (1 mL) methanesulfonyl chloride (31 mg, 0.271 mmol, 21
o
µL) was added at 0 C under argon atmosphere. Stirring was continued for 0.5 h and saturated aqueous solution of
NaHCO3 was slowly added. The mixture was extracted with CHCl3 (3 x 15 mL), and the combined organic layers were
dried over Na2SO4. After concentration in vacuo, the residue was subjected to flash column chromatography (petroleum
ether/acetone 1 : 1) affording mesylate 9 (56 mg, 86%) as a colorless liquid. Rf = 0.14 (petroleum ether/acetone 2:1);
[α]D22 -26.1 (c 0.6 in C6H6); 31P NMR (202 MHz, C6D6) δ 21.42; 1H NMR (500 MHz, C6D6) δ 4.42-4.35 (m, 1 H, CHCH2)),
4.23 (d, JHH = 7.6 Hz, 1 H, CHCO), 4.20 (dd, JPH = 11.5 Hz, JHH = 2.6 Hz, 1 H, CHAHBOMs), 4.03 (dd, JPH = 11.4 Hz, JHH
= 4.8 Hz, 1 H, CHAHBOMs), 3.38 (d, JPH = 11.2 Hz, 3 H, OCH3), 3.36 (d, JPH = 11.2 Hz, 3 H, OCH3), 3.20-3.07 (m, 2 H,
CH2P), 2.24 (s, 3 H, CH3S), 1.27 (s, 3 H, CH3C), 1.23 (s, 3 H, CH3C); 13C NMR (126 MHz, C6D6) δ 201.28 (d, JPC = 6.8
Hz, CO), 111.65 (OCO), 81.03 (CHCO), 75.70 (CHCH2), 68.42 (CH2OMs), 52.63 (d, JPC = 6.2 Hz, OCH3), 52.53 (d, JPC
=
6.4 Hz, OCH3), 37.27 (d, JPC = 127.9 Hz, CH2P), 36.87 (CH3S), 26.80 (CH3C), 26.21 (CH3C); Anal. calcd for
C11H21O9PS: C, 36.67; H, 5.87. Found: C, 36.78; H, 6.00; HRMS FAB+ m/z: calcd for C11H22O9PS ([M+H]+): 361.0712;
found 361.0707.
Dimethyl (1S,5R)-[2-(3,3-dimethyl-2,4-dioxsabicyclo[3.1.0]heksan-1-yl)-2-oxoethyl]phosphonate (cCy): From
bromide 8 and K2CO3: A mixture of bromide 8 (38 mg, 0.11 mmol), potassium carbonate (20 mg, 0.143 mmol) and 18-
o
crown-6 ether (38 mg, 0.143 mmol) in dry benzene (8 mL) was heated at 70 C for 11 h. The solvent was evaporated
under reduced pressure, water (2 mL) was added and the mixture was extracted with CH2Cl2 (3 x 10 mL). The combine
organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. Flash column chromatography using 2 :
1 petroleum ether/acetone as the eluent yielded cCy (22 mg, 78%) as a colorless liquid. Rf = 0.22 (petroleum
ether/acetone 2 : 1); [α]D20 -128.2 (c 0.4 in C6H6); 31P NMR (202 MHz, CDCl3) δ 22.55; 1H NMR (500 MHz, CDCl3) δ 4.38
(dd, JHH = 5.3 Hz, JHH = 3.4 Hz, 1 H, OCHCH2), 3.81 (d, JPH = 11.2 Hz, 3 H, OCH3), 3.80 (d, JPH = 11.3 Hz, 3 H, OCH3),
3.64 (dd, JPH = 22.3 Hz, JHH = 14.6 Hz, 1 H, CHAHBP), 3.34 (dd, JPH = 21.4 Hz, JHH = 14.6 Hz, 1 H, CHAHBP), 1.96 (dd, J
= 6.0 Hz, J = 5.5 Hz, 1 H, CHAHBCH), 1.58 (dd, JHH = 6.2 Hz, JHH = 3.4 Hz, 1 H, CHAHBCH), 1.47 (s, 3 H, CH3C), 1.46 (s,
3 H, CH3C); 13C NMR (126 MHz, CDCl3) δ 200.66 (d, JPC = 6.9 Hz, CO), 123.51 (OCO), 72.10 (d, JPC = 4.0 Hz, CC(O)),
66.46 (OCHCH2), 53.15 (d, JPC = 6.2 Hz, OCH3), 53.00 (d, JPC = 6.4 Hz, OCH3), 36.97 (d, JPC = 133.8 Hz, CH2P), 35.57
(CHCH2), 26.46 (CH3C), 25.01 (CH3C); Anal. calcd for C10H17O6P: C, 45.46; H, 6.49. Found: C, 45.27; H, 6.56; HRMS EI
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900102
European Journal of Organic Chemistry
m/z: calcd for C10H17O6P 264.0763; found 264.0751. From mesylate 9 and K2CO3: According to the procedure
described above, mesylate 9 was transformed into cyclopropane cCy in 75%. From bromide 8 and tert-BuONa: A
mixture of bromide 8 (36 mg, 0.104 mmol) and tert-BuONa (62 µL, 0.124 mmol, 2 M tert-BuONa in THF) in dry THF (2
mL) was heated under reflux for 12h. The solvent was evaporated under reduced pressure, water (2 mL) was added and
the mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. Flash column chromatography using 2 : 1 petroleum ether/acetone as the eluent yielded
cCy (22 mg, 80 %) as a colorless liquid.
(2R,3R)-4-[(tert-butyldimethylsilyl)oxy]-2,3-O-isopropylidene-N-methoxy-N-methylbutanamide
(10):
To
a
suspension of N,O-dimethylhydroxylamine hydrochloride (0.77 g, 7.89 mmol) in THF (10 mL) was added AlMe3 (4.05
o
mL, 8.1 mmol, 2.0 M in heptane) at 0 C. The reaction mixture was allowed to warm to room temperature over 45 min
and then cooled to -25 oC. A solution of 5 (0.50 g, 3.16 mmol) in THF (5 mL) was added and stirring was continued for
o
o
1.5 h (to disappearance of a white precipitate) at 0 C. The solution was cooled to -25 C and imidazole (1.29 g, 18.9
o
mmol) and TBDMSCl (1.43 g, 9.48 mmol) were added. The reaction mixture was stirred for 1 h at -25 C, and then
overnight at room temperature. The solution was poured into cold aqueous saturated solution of sodium bicarbonate,
and then extracted with CHCl3 (4 x 50 mL). The organic layer was dried over anhydrous Na2SO4. The solvent was
evaporated, and the residue was purified by column chromatography (petroleum ether/acetone 5 : 1) to give 10 (0.50 g,
o
1
57%) as a colorless solid. Mp 53 C; Rf = 0.56 (petroleum ether/acetone 5 : 1); [α]D20 +42.1 (c 1.0 in CH2Cl2); H NMR
(500 MHz, CDCl3) δ 4.98 (d, J = 6.6 Hz, 1 H, CHC(O)), 4.41 (q, J = 6.1 Hz, 1 H, CHCH2), 3.71 (s, 3 H, CH3ON), 3.68 (d,
J = 6.2 Hz, 1 H, CHAHBOSi), 3.58 (dd, J = 10.4 Hz, J = 5.8 Hz, 1 H, CHAHBOSi), 3.16 (s, 3 H, CH3N), 1.57 (s, 3 H,
CH3CO), 1.39 (s, 3 H, CH3CO), 0.87 (s, 9 H, (CH3)3C), 0.04 (s, 3 H, CH3Si), 0.03 (s, 3 H, CH3Si); 13C NMR (126 MHz,
CDCl3) δ 169.30 (CO), 109.89 (OCO), 78.10 (CHCH2), 73.85 (CHC(O)), 62.53 (CH2OSi), 61.30 (CH3ON), 32.43 (CH3N),
27.47 (CH3CO), 25.94 (3 C, (CH3)3C), 25.59 (CH3CO), 18.52 ((CH3)3C), -5.31 (2 C, CH3Si); Anal. calcd for C15H31NO5Si:
C, 54.02; H, 9.37. Found: C, 54.19; H, 9.30; HRMS FAB+ m/z: calcd for C15H32NO5Si ([M+H]+) 334.2049; found
334.2041.
Dimethyl (3R,4R)-{5-[(tert-butyldimethylsilyl)oxy]-3,4-O-isopropylidene-2-oxopentyl}phosphonate (11): To
a
stirred solution of dimethyl methylphosphonate (65 mg, 0.525 mmol) in THF (3.5 mL), n-BuLi (250 µL, 0.483 mmol, 1.93
M in THF) was added at -78 oC. Stirring was continued for 30 min and a solution of 10 (70 mg, 0.210 mmol) in THF (1.5
o
mL) was added. After 2 h an aqueous saturated solution of NH4Cl was added at -78 C and the mixture was extracted
with CHCl3 (3 x 15 mL). The organic layer was dried over anhydrous Na2SO4. The solvent was evaporated, and the
residue was purified by column chromatography (petroleum ether/acetone 3 : 1) to give 11 (77 mg, 93%) as a colorless
oil. Rf = 0.30 (petroleum ether/acetone 3 : 1); [α]D21 +48.2 (c 2.2 in CH2Cl2); 31P NMR (202 MHz, CDCl3) δ 24.96; 1H NMR
(500 MHz, CDCl3) δ 4.62 (d, JHH = 8.0 Hz, 1 H, CHC=O), 4.42-4.37 (m, 1 H, CHCH2), 3.78 (d, JPH = 11.3 Hz, 3 H, OCH3),
3.75 (d, JPH = 11.3 Hz, 3 H, OCH3), 3.71-3.62 (m, 3 H, CHAHBP, CH2OSi), 3.01 (dd, JPH = 22.8, JHH = 14.2 Hz, 1 H,
CHAHBP), 1.54 (s, 3 H, CH3CO), 1.34 (s, 3 H, CH3CO), 0.84 (s, 9 H, (CH3)3C), 0.01 (s, 3 H, CH3Si), 0.01 (s, 3 H, CH3Si);
13C NMR (126 MHz, CDCl3); δ 200.98 (d, JPC = 6.5 Hz, CO), 109.86 (OCO), 80.24 (CHCO), 78.89 (CHCH2), 61.12
(CH2OSi), 53.15 (d, JPC = 5.8 Hz, OCH3), 52.72 (d, JPC = 6.2 Hz, OCH3), 38.28 (d, JPC = 129.8 Hz, CH2P), 26.62
(CH3CO), 25.82 (3 C, (CH3)3C), 24.73 (CH3CO), 18.47 ((CH3)3C), -5.34 (CH3Si), -5.75 (CH3Si); Anal. calcd for
C16H33O7PSi: C, 48.47; H, 8.39. Found: C, 48.42; H, 8.44; HRMS FAB+ m/z: calcd for C16H34O7PSi ([M+H]+) 397.1811;
found 397.1818.
Dimethyl (3R,4R)-{1-diazo-5-[(tert-butyldimethylsilyl)oxy]-3,4-O-isopropylidene-2-oxopentyl}phosphonate (12): A
mixture of 11 (115 mg, 0.290 mmol), tosylazide (69 mg, 0.348 mmol) and anhydrous K2CO3 (44 mg, 0.319 mmol) in
CH3CN (3.4 mL) was vigorously stirred at room temperature for 3 h. The suspension was filtered on a silica gel pad prior
to concentration under reduced pressure. The residue was subjected to column chromatography (petroleum
23
ether/acetone 6 : 1) affording 12 (100 mg, 82%) as a colorless liquid. Rf = 0.31 (petroleum ether/acetone 4 : 1); [α]D
-
20.7 (c 1.6 in CH2Cl2); 31P NMR (202 MHz, CDCl3) δ 14.65; H NMR (500 MHz, CDCl3) δ 4.83 (d, JHH = 6.8 Hz, 1 H,
CHCO), 4.41-4.35 (m, 1 H, CHCH2), 3.80 (d, JPH = 11.9 Hz, 3 H, OCH3), 3.78 (d, JPH = 12.0 Hz, 3 H, OCH3), 3.75 (d, JHH
= 4.3 Hz, 1 H, CHAHBOSi), 3.67 (dd, JHH = 11.2 Hz, JHH = 3.5 Hz, 1 H, CHAHBOSi), 1.50 (s, 3 H, CH3CO), 1.31 (s, 3 H,
CH3CO), 0.84 (s, 9 H, (CH3)3C), 0.03 (s, 3 H, CH3Si), 0.02 (s, 3 H, CH3Si); 13C NMR (126 MHz, CDCl3) δ 188.91 (CO),
110.37 (OCO), 79.86 (CHCO), 78.79 (CHCH2), 62.73 (d, JCP = 218.8 Hz, CN2), 61.52 (CH2OSi), 53.90 (d, JCP = 6.1 Hz,
OCH3), 53.85 (d, JCP = 5.8 Hz, OCH3), 26.00 (CH3CO), 25.88 (3 C, (CH3)3C), 24.60 (CH3CO), 18.56 ((CH3)3C), -5.43
(CH3Si), -5.65 (CH3Si); Anal. calcd for C16H31N2O7PSi: C, 45.49; H, 7.40. Found: C, 45.31; H, 7.47; HRMS FAB+ m/z:
calcd for C16H32N2O7PSi ([M+H]+) 423.1716; found 423.1719.
1
(4R,5R)-4,5-O-isopropylidene-2-(dimethoxyphosphoryl)cyclopent-2-enone (4): A solution of 12 (350 mg, 0.828
mmol) in dry 1,2-dichloroethane (20 mL) with a catalytic amount of rhodium (II) acetate (7 mg, 0.016 mmol) was heated
o
at 80 C for 4 h. After cooling to room temperature a small amount of water was added and the mixture was extracted
with CH2Cl2 (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by flash column chromatography (petroleum ether/acetone 1:1) to
yield enone 4 (121 mg, 56%) as a colorless liquid. Rf = 0.22 (petroleum ether/acetone 1 : 1); [α]D25 -58.6 (c 1.1 in C6H6);
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900102
European Journal of Organic Chemistry
31P NMR (81 MHz, C6D6) δ 10.47; 1H NMR (200 MHz, C6D6) δ 7.71 (dd, JPH = 10.7, JHH = 2.1 Hz, 1 H, CH=C), 4.31 (dd,
JHH = 5.4, JHH = 1.9 Hz, 1 H, CHC(O)), 3.93 (dd, JHH = 5.5, JHH = 1.2 Hz, 1 H, OCHCH=C), 3.49 (d, JPH = 11.3 Hz, 3 H,
OCH3), 3.40 (d, JPH = 11.3 Hz, 3 H, OCH3), 1.19 (s, 3 H, CH3C), 1.10 (s, 3 H, CH3C); 13C NMR (126 MHz, CDCl3) δ
198.51 (d, JPC = 9.4 Hz, (CO), 169.27 (d, JPC = 8.8 Hz), 136.28 (d, JPC = 187.9 Hz), 116.00 (OCO), 77.67 (OCH), 77.55
(d, JPC = 4.7 Hz, OCH), 53.38 (d, JPC = 5.9 Hz, OCH3), 53.23 (d, JPC = 5.9 Hz, OCH3), 27.36 (CH3C), 26.07 (CH3C); Anal.
calcd for C10H15O6P: C, 45.81; H, 5.77. Found: C, 45.93; H, 5.61; HRMS FAB+ m/z: calcd for C10H16O6P ([M+H]+)
263.0684; found 263.0683.
(3R,4R,5R)-4,5-O-izopropylidene-2-dimethoxyphosphoryl-3-[6-(4-methylphenyl)hexyl]cyclopent-1-en-1-ol (19): To
a stirred solution of 1-(6-bromohexyl)-4-methylbenzene (146 mg, 0.572 mmol) in THF (3 mL) t-BuLi (630 μL, 1.144
mmol, 1.7 M in pentane) was added at -78 °C. After 20 min, freshly prepared Lipshuz reagent[26] (1.52 mL, 0.763 mmol,
0.5 M in THF) was added and stirring was continued for 1 h at the same temperature. Then, a solution of enone 4 (0.1 g,
0.381 mmol) in THF (0.5 mL) and BF3·OEt2 (135 mg, 0.953 mmol) were added successively. After 4 h, a mixture of a
saturated aqueous solution of NH4Cl and NH4OH (9 : 1) (3 mL) was added and the reaction mixture was allowed to
warm to room temperature. The mixture was extracted with DCM (4 x 10 mL) and the combined organic layers were
dried over anhydrous Na2SO4. After concentration in vacuo, the residue was subjected to flash chromatography
(petroleum ether/acetone 5 : 1) to afford 19 (91 mg, 54%) as a colorless oil. Rf = 0.24 (petroleum ether/acetone 5 : 1); [α]
23
-12.8 (c 1.7 in CH2Cl2); HRMS ESI (+) m/z: calcd for C23H36O6P ([M+H]+) 439.2250; found 439.2254. Anal. calcd for
D
C23H35O6P: C, 63.00; H, 8.05. Found: C, 63.11; H, 7.99. Enol form: 31P NMR (243 MHz, C6D6) δ 25.74; H NMR (600
1
MHz, C6D6) δ 11.03 (s, 1 H, OH), 7.05 (d, JHH = 8.2 Hz, 2 H, CArH), 7.03 (d, JHH = 8.3 Hz, 2 H, CArH), 4.88 (d, JHH = 5.4
Hz, 1 H, OCHC-OH), 4.16-4.10 (m, 1 H, OCHCH), 3.32 (d, JPH = 11.2 Hz, 3 H, OCH3), 3.30 (d, JPH = 11.0 Hz, 3 H,
OCH3), 2.88 (d, JHH = 8.7 Hz, 1 H, CHCH2), 2.51 (t, JHH = 7.7 Hz, 2 H, CArCH2), 2.16 (s, 3 H, CArCH3), 1.56-1.49 (m, 2 H,
CHCH2), 1.46 (s, 3 H, CH3C), 1.30 (s, 3 H, CH3C), 1.25-1.13 (m, 6 H, CH2), 1.11-0.98 (m, 2 H, CH2); 13C NMR (126 MHz,
C6D6) δ 173.94 (COH), 139.46 (CArCH2), 134.84 (CArCH3), 128.99 (2 C, CArH), 128.34 (2 C, CArH), 111.02 (C(CH3)2),
93.57 (d, JPC = 170.3 Hz, CP), 81.94 (d, JPC = 21.0 Hz, OCH-COH), 81.25 (d, JPC = 14.4 Hz, OCHCH), 51.47 (d, JPC
=
3.2 Hz, OCH3), 51.36 (d, JPC = 3.8 Hz, OCH3), 47.13 (d, JPC = 8.9 Hz, CHCH3), 35.51 (CH2), 32.81 (CH2), 31.56 (CH2),
29.61 (CH2), 29.05 (CH2), 27.61 (CH3C), 26.65 (CH2), 25.80 (CH3C), 20.70 (CArCH3). Major keto tautomer signals: 31
P
NMR (243 MHz, CDCl3) δ 24.03; 1H NMR (600 MHz, C6D6) 3.59 (d, J = 10.9 Hz, 3 H, OCH3), 3.45 (d, J = 11.1 Hz, 3 H,
OCH3); 13C NMR (126 MHz, C6D6) δ 206.60 (CO), 112.31 (OCO), 53.08 (d, JPC = 6.3 Hz, OCH3), 51.84 (d, JPC = 6.5 Hz,
OCH3). Minor keto tautomer signals: 31P NMR (243 MHz, CDCl3) δ 23.43.
(3R,4R,5R)-3-ethyl-4,5-O-isopropylidene-2-(dimethoxyphosphoryl)cyclopent-1-en-1-ol (20): To a cold (0 °C)
solution of CuCN (3 mg, 0.033 mmol) and N-benzyl-4-methylbenzenesulfonamide (12 mg, 0.046 mmol) in toluene (1.5
mL) was added Et2Zn (0.5 mL, 0.5 mmol, 1 M in hexane), and the mixture was stirred for 15 min. Enone 4 (90 mg,
0.343 mmol) in toluene (0.5 mL) was added, and stirring was continued for 3.5 h. The reaction was quenched with a
saturated aqueous solution of NH4Cl. The organic layer was separated, and the aqueous layer was extracted with DCM
(4 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After evaporation
of the solvents the residue was subjected to column chromatography (petroleum ether/acetone 3 : 1) to give 20 (51 mg,
o
22
51%) as a colorless solid. Mp 65-66 C; Rf = 0.21 (petroleum ether/acetone 5 : 1); []D -15.0 (c 0.8 in CH2Cl2); Anal.
calcd for C12H21O6P: C, 49.31; H, 7.24. Found: C, 49.19; H, 7.20. Enol form: 31P NMR (202 MHz, CDCl3) δ 25.27; H
1
NMR (500 MHz, CDCl3) δ 10.06 (s, 1 H, OH), 4.98 (d, JHH = 5.5 Hz, 1 H, OCH-COH), 4.34 (dd, JHH = 5.5, JHH = 3.3 Hz, 1
H, OCHCH), 3.71 (d, JPH = 11.4 Hz, 3 H, OCH3), 3.69 (d, JPH = 11.5 Hz, 3 H, OCH3), 2.72-2.64 (m, 1 H, CHCH2), 1.77-
1.69 (m, 1 H, CHAHB), 1.44 (s, 3 H, CH3C), 1.36 (s, 3 H, CH3C), 1.27-1.17 (m, 1 H, CHAHB), 0.91 (t, JHH = 7.4 Hz, 3 H,
CH3); 13C NMR (126 MHz, CDCl3) δ 172.89 (d, JCP = 10.2 Hz, COH), 111.27 (OCO), 93.39 (d, JCP = 185.2 Hz, CP),
81.66 (d, JCP = 21.0 Hz, OCHC-OH), 80.75 (d, JCP = 14.6 Hz, OCHCH), 52.38 (d, JCP = 4.4 Hz, OCH3), 52.23 (d, JCP
=
5.0 Hz, OCH3), 48.19 (d, JCP = 9.4 Hz, CHCH2), 27.51 (CH3C), 25.56 (CH3C), 25.29 (CH2), 10.80 (CH2CH3); Major keto
1
tautomer signals: 31P NMR (202 MHz, CDCl3) δ 23.95; H NMR (500 MHz, CDCl3) δ 3.82 (d, JPH = 11.0 Hz, 3 H,
OCH3), 3.80 (d, JPH = 11.2 Hz, 3 H, OCH3), 1.46 (s, 3 H, CH3C), 1.35 (s, 3 H, CH3C), 1.04 (t, JHH= 7.3 Hz, 3 H, CH3); 13
NMR (151 MHz, CDCl3) δ 208.02 (d, JCP = 6.1 Hz, CO), 112.58 (s, OCO), 80.21 (d, JCP = 5.6 Hz, OCH), 79.96 (d, JCP
C
=
8.3 Hz, OCH), 53.77 (d, JCP = 6.6 Hz, OCH3), 53.01 (d, JCP = 6.8 Hz, OCH3), 50.27 (d, JCP = 140.2 Hz, HCP), 40.94 (s),
27.66 (d, JCP = 6.8 Hz), 26.51 (s), 25.27 (s), 11.23 (s, CH2CH3); Minor keto tautomer signals: 31P NMR (202 MHz,
CDCl3) δ 23.79; 1H NMR (500 MHz, CDCl3) δ 3.83 (d, JPH = 11.1 Hz, 3 H, OCH3), 3.78 (d, JPH = 11.3 Hz, 3 H, OCH3); 13
C
NMR (126 MHz, CDCl3) δ 112.83 (OCO), 79.59 (d, JCP = 11.9 Hz), 78.44 (d, JCP = 6.8 Hz), 53.24 (d, JCP = 5.6 Hz,
OCH3), 52.56 (d, JCP = 6.9 Hz, OCH3), 48.98 (d, JCP = 147.4 Hz, PCH), 11.82 (CH2CH3).
(3S,4R,5R)-3-ethyl-4,5-O-izopropylideno-2-methylidenecyclopentan-1-one (21): To a stirred solution of enol 20 (40
mg, 0.137 mmol) in THF (3 mL) was added sodium tert-butoxide (80 L, 2 M solution in THF, 0.158 mmol). After 15
min, formaldehyde formed by thermal depolymerization of paraformaldehyde (25 mg, 0.812 mmol) was introduced into
the reaction vessel in a slow current of dry nitrogen (paraformaldehyde was previously dried for two days in a vacuum
desiccator over P2O5). Stirring was continued for 15 min and a saturated water solution of NH4Cl was added. The
reaction mixture was extracted with CHCl3 (4 x 5 mL) and dried over anhydrous Na2SO4. The solvent was evaporated,
and the residue was purified by column chromatography (petroleum ether/acetone 10 : 1) to give 21 (23 mg, 85%) as a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900102
European Journal of Organic Chemistry
colorless oil. Rf = 0.53 (petroleum ether/acetone 5 : 1); []D22 -111.3 (c 0.3 in CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 6.25
(dd, J = 1.2 Hz, J = 0.8 Hz, 1 H, C=CHAHX), 5.49 (d, J = 1.1 Hz, 1 H, C=CHAHX), 4.49 (d, J = 5.2 Hz, 1 H, OCH), 4.43 (d,
J = 5.2 Hz, 1 H, OCH), 2.90 (t, J = 7.4 Hz, 1 H, CHCH2), 1.66-1.58 (m, 1 H, CH3CHAHB), 1.48-1.41 (m, 1 H CH3CHAHB),
1.37 (s, 3 H, CH3C), 1.36 (s, 3 H, CH3C), 1.00 (t, J = 7.4 Hz, 3 H, CH3CH2); 13C NMR (126 MHz, CDCl3): δ 203.73 (CO),
145.29 (C=CH2), 122.80, 111.88 (OCO), 79.61 (OCH), 79.22 (OCH), 45.05 (CHCH2), 27.28 (CH3C), 26.93 (CH3C),
25.41 (CH2), 11.28 (CH3CH2); Anal. calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.25; H, 8.25.
Acknowledgements
The authors gratefully acknowledge financial support from the National Science Foundation (grant NCN
2015/19/N/ST5/02692).
Keywords: chiral pool, total synthesis, prostaglandins, diazo compounds, density functional calculations
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