Diastereoselective synthesis of enantiopure 5-[2-(alkoxyalkyl)-1- (hydroperoxypropyl)]-3-alkoxycarbonyl-2-alkyl furans

Article abstract of DOI:10.1016/S0957-4166(99)00187-1

The diastereoselective approach to enantiomerically pure furyl hydroperoxides of general type 1 has been accomplished starting from (S)-(- )-ethyl lactate. In the first part of the synthesis the alkylating reagents 7a,b were efficiently produced to be use

Full text of DOI:10.1016/S0957-4166(99)00187-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2023–2035
Diastereoselective synthesis of enantiopure
5-[2-(alkoxyalkyl)-1-(hydroperoxypropyl)]-3-alkoxycarbonyl-
2-alkyl furans
Alessandra Lattanzi,∗ Francesco Sagulo and Arrigo Scettri
Dipartimento di Chimica, Università di Salerno, Via S. Allende 1, 84081 Baronissi, Salerno, Italy
Received 5 May 1999; accepted 12 May 1999
Abstract
The diastereoselective approach to enantiomerically pure furyl hydroperoxides of general type 1 has been
accomplished starting from (S)-(−)-ethyl lactate. In the first part of the synthesis the alkylating reagents 7a,b were
efficiently produced to be used in the second part for a 4-step known methodology to obtain furyl hydroperoxides.
The most relevant transformation of the synthesis is the first reported diastereoselective iodoenoletherification of 2-
acetyl-4-heptenoate esters 8a,b possessing a φ-chiral center. Furthermore, the final radical oxidation performed on
(E)-5-alkylidene-4,5-dihydrofurans 11a,b led to formation of hydroperoxides (S,S)-12a,b in a diastereocontrolled
manner due to 1,2-asymmetric induction. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The most relevant employment of alkyl hydroperoxides in organic synthesis is in the Sharpless
asymmetric epoxidation1 of allylic alcohols and its further modification for asymmetric sulfoxidation2 of
prochiral sulfides. Ti(OiPr)4, tert-butylhydroperoxide (TBHP) and L- or D-tartrate esters as chiral ligands
are combined in active complexes that induce high enantioselectivity in the processes. Studies on the
sulfoxidation have shown how different experimental conditions involving ratios of reagents,2 structure
of the hydroperoxides,2d presence of water2b,d and chiral diols3 can provide high asymmetric induction.
We have recently been focusing our attention on the synthesis4 and the reactivity5 of a new class of
oxidants, furyl hydroperoxides, which are a valuable alternative to the commercial TBHP and cumyl
hydroperoxide (CHP) in Sharpless modified oxidations. Furthermore, they have proved, under the same
conditions, to be the most suitable oxidants for the kinetic resolution of racemic methyl aryl sulfoxides6
and β-keto sulfoxides7 (ee values 50–90% of unreacted sulfoxides). The results of this research confirmed
∗
Corresponding author. E-mail: lattanzi@ponza.dia.unisa.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00187-1

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A. Lattanzi et al. / Tetrahedron: Asymmetry 10 (1999) 2023–2035
Figure 1.
and expanded on the previous data reported by Sharpless1 and Kagan2 about the need of the well
established stereoelectronic requirements of hydroperoxides to be used in order to ensure high levels
of enantioselectivity.
Limited investigations have been conducted on asymmetric metal-mediated oxidations carried out with
enantiomerically pure hydroperoxides8 in the absence of chiral ligands. In this case the asymmetric
induction is exclusively promoted by the oxidant. The enantioselectivity of these processes does not
exceed 30% for epoxyalcohols and sulfoxides, however Adam et al. recently reported the best example
of asymmetric sulfoxidation with an enantiomerically pure hydroperoxide9 (ee up to 80%).
No general methodology and only limited examples exist for the synthesis of alkyl hydroperoxides
in optically active form.8a,10 The best results have been achieved by kinetic resolution of the racemic
mixture of hydroperoxides mediated by enzymes such as horseradish peroxidase,11 chloroperoxidase,12
lipase,13 etc. where one enantiomer of the starting oxidants is preferentially obtained at the expense of
the consumption of the other. Herein, we report the diastereoselective synthesis of enantiomerically pure
compounds of general type 1 (Fig. 1).
2. Results and discussion
Our strategy was to proceed from the commercially available and low cost (S)-(−)-ethyl lactate to
introduce a stereodefined moiety next to the carbon bearing the hydroperoxide group. We followed a
suitable modification of a known sequence14 to obtain enantiomerically pure γ-alkoxy-α,β-unsaturated
esters 5 (Scheme 1). After the quantitative protection of (S)-(−)-ethyl lactate 2 as tert-butyldimethylsilyl
ether 3a and as benzyl ether 3b, compounds 3 were selectively reduced with DIBALH to afford
aldehydes 4, which without purification were transformed into α,β-unsaturated esters 5. The Wads-
worth–Horner–Emmons olefination of 4 conducted with triethylphosphonacetate and LiOH·H2O in
THF,15 instead of the reported14 triethylphosphonacetate and NaH in THF, furnished esters 5a,b in good
yield and with higher E/Z ratios. The (E)-esters 5, separated by silica gel chromatography, were reduced
with DIBALH to allylic alcohols 6.
Finally, compounds 6 were treated with tosyl chloride and KOH under phase transfer catalysis16 to
give tosylates 7 quantitatively. This efficient route allowed us to prepare compounds 7a and 7b by simple
transformations with ca. 60% overall yield starting from 2.
In the second part of the synthesis we applied the sequence reported in previous papers4 to obtain furyl
hydroperoxides (Scheme 2).
The alkylation of ethyl acetoacetate with the crude mixture17 of 7 using LiOH·H2O in THF at
50°C18 furnished in good yields the α-mono-alkylated β-ketoesters 8. Compounds 8 were reacted4a
with iodine and Na2CO3 in dry dichloromethane under kinetic control, affording derivatives 9 coming
from the expected stereospecific 5-exo-tet closure.19,4a Moreover, iododihydropyran derivatives coming
from the equally favored19a,b 6-endo-trig closure were not detected. Iodocyclized compounds 9 were
isolated as unseparable mixtures of diastereomers in ratio 86/14 for 9a and 73/27 for 9b as judged by 1H
NMR, whose absolute configurations were impossible to assign. This is the first example of iodine-

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2025
Scheme 1. Reagents and conditions: (a) 3a: TBDMSCl, imidazole, CH2Cl2, 0°C; 3b: NaH, BnBr, CH2Cl2, 0°C. (b) DIBALH,
CH2Cl2, −78°C. (c) LiOH·H2O, THF, 15°C, (EtO)2POCH2CO2Et. (d) DIBALH, CH2Cl2, 0°C. (e) TsCl, (n-Bu)4NHSO4, KOH,
C6H6, rt
Scheme 2. Reagents and conditions: (a) 7, LiOH·H2O, THF, 50°C. (b) 8a: I2, Na2CO3, CH2Cl2, −25°C; 8b −5°C. (c) DBU,
C6H6, 50°C. (d) AIBN, O2, C6H6, 50°C
Figure 2.
induced enoletherification of 2-acetyl-4-heptenoate esters 8a,b possessing a φ-chiral center. Closely
related to this transformation, Chamberlain et al.20 reported the kinetically controlled iodolactonization
of compound 16 but they found nearly equal proportions of the two diastereomers 17 and 18 (Fig. 2).
Interestingly, in our case the stereogenic center with the protected alcoholic function forced the enol of
8 to attack preferentially one of the two diastereoisomeric iodonium intermediates to give high prevalence
for one diastereomer of 9. As a by-product of the iodoenoletherification we isolated compound 10 that
could be derived from an intramolecular SN20 displacement21 of the protected hydroxyl group from the
enol of 8. The nature of the alcoholic protective group greatly affected the iodocyclization and, as a result,
a substantially limited formation of the undesired product 10 occurred, changing from 26% to 4% yield,

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A. Lattanzi et al. / Tetrahedron: Asymmetry 10 (1999) 2023–2035
Figure 3.
Figure 4.
respectively, in going from R=TBDMS to R=Bn. As previously mentioned, the absolute configuration
of the stereogenic centers generated in the iodine-induced enoletherification could not be determined.
However, the stereochemical outcome of the following reaction allowed us to define their configurations
either as 5R,1S or 5S,1R. The elimination of HI conducted on iodoalkyl diastereoisomeric mixtures 9a and
9b with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) took place stereospecifically, leading to satisfactory
1
yields of (E)-5-alkylidene-4,5-dihydrofurans 11a and 11b. In fact, H NMR spectra of 11a and 11b
revealed the presence of the diagnostic olefinic proton of the (E)-isomer only, centered as a double triplet
at 5.3 ppm.4a,22
Finally, the radical oxidation carried out on 11a,b with4b AIBN and bubbling O2 at 50°C furnished
chromatographically separable 12a,b and 13a,b in a diastereoselective manner. The authoritative work
of Giese,23 Curran,24 Porter,25 Guindon,26 Renaud27 and Liotta28 about 1,2-asymmetric induction in
radical reactions allows the establishment of the preferred conformation of the reactive radicals when X
is a substituent planar and in conjugation with the singly occupied orbital,29 on the basis of allylic strain
effects30 (Fig. 3).
Consequently, it is possible to predict with good confidence the direction of 1,2-stereoinduction in
the products of trapped acyclic radicals although the degree of stereoselectivity depends upon the nature
of the radical traps as well as of the substituents on the stereogenic center. In general, the direction
of stereoselectivity for acyclic radicals leads to the prevalent formation of the 20a diastereoisomer.31
Applying these rules to the furyl radical (Fig. 4) involved in the oxidation,4b the absolute configuration
of the major diastereoisomer 12a,b must be S,S and R,S for the minor 13a,b.
Attempts to synthesize the corresponding furyl hydroperoxides 12a,b and 13a,b through the ene
reaction with singlet oxygen32 on 11a,b failed and only complex reaction mixtures were obtained.
Confirmation of the stereochemistry of the newly formed stereogenic carbon as S for the major
diastereoisomers 12a,b and R for the minor 13a,b was accomplished on the corresponding furyl alcohols
of 14a and 15a (Scheme 3) obtained after the reduction of 12a and 13a, respectively, using the Mosher
ester method for the determination of the absolute configuration.33
Furthermore, we confirmed that no racemization of the stereogenic carbon derived from (S)-lactate

A. Lattanzi et al. / Tetrahedron: Asymmetry 10 (1999) 2023–2035
2027
Scheme 3. Reagents and conditions: (a) (i) 12, 13a, (Ph)3P, CH2Cl2, rt, (ii) (R) or (S)-MTPA-Cl, CH2Cl2, Et3N, DMAP, rt
occurred during the synthesis. In fact, no isomer was detected in 1H NMR spectra of (R)- and (S)-Mosher
esters of furyl alcohols 14a and 15a.
3. Conclusion
The general diastereoselective approach to enantiomerically pure furyl hydroperoxides of type 1
has been established representing one of the few reported chemical routes to enantiomerically pure
hydroperoxides. Consequently, furyl hydroperoxide analogues can be synthesized with a similar effort
in a predictable way choosing appropriate starting materials (1,3-dicarbonyl compound and protected
lactate). In addition, this synthetic sequence offers the approach to interesting enantiomerically pure
intermediates such as (E)-5-alkylidene-4,5-dihydrofurans and functionalized furyl 1,2-diols.
4. Experimental
4.1. General
Unless otherwise noted, all reagents were obtained from commercial suppliers and were used without
further purification. All solvents were distilled under nitrogen immediately before use: THF from
sodium/benzophenone, dichloromethane and benzene from calcium hydride. All reactions requiring
anhydrous conditions were conducted under an argon atmosphere in flame dried glassware. Reactions
were monitored by thin layer chromatography (TLC) on Merck silica gel plates and visualized using UV
light followed by charring with 10% sulfuric acid–ethanol spray or 0.5% phosphomolybdic acid in 95%
ethanol. Unless otherwise stated, standard workup refers to the combination of organic extracts, washing
with brine and drying over anhydrous Na2SO4. Flash column chromatography was performed using
1
Kieselgel 60 (Merck, 230–400 mesh). H NMR and 13C NMR spectra were recorded at 400 and 100.6
MHz, respectively, with a Bruker DRX 400 MHz spectrometer. The chemical shifts were measured on
the δ scale relative to the residual signal of CDCl3 (7.26 and 77 ppm) and C6D6 (7.16 and 128.39 ppm).
Optical rotations were measured with a JASCO Dip-1000 digital polarimeter at λ=589 nm. Mass spectra
were determined at an ionizing voltage of 70 eV.
4.2. Synthesis of ethyl (2E,4S)-4-[(tert-butyldimethylsilyl)oxy]-2-pentenoate 5a
To a CH2Cl2 solution (50 mL) of (S)-ethyl lactate (5.7 mL, 50 mmol) at 0°C were added imidazole
(4.1 g, 60 mmol) and TBDMSCl (8.3 g, 55 mmol) and the mixture was stirred for about 5 h at room
temperature. Water (50 mL) was added and the mixture was extracted with CH2Cl2, followed by standard
workup and the solvent was removed in vacuo. The residue was dissolved in dry CH2Cl2 (50 mL) and
a 1 M CH2Cl2 solution of DIBALH (50 mL, 50 mmol) was added dropwise in 45 min at −78°C under

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A. Lattanzi et al. / Tetrahedron: Asymmetry 10 (1999) 2023–2035
an argon atmosphere. The mixture was stirred for 1.5 h and 50 mL of saturated solution of potassium
tartrate was added dropwise at −78°C and stirred overnight till room temperature. The resulting mixture
was extracted with ethyl acetate (2×50 mL), standard workup yielded an oil. The residue was used for
further manipulation without purification. To a solution of triethyl phosphonoacetate (7.9 mL, 40 mmol)
in dry THF (30 mL) were added activated (4 Å) molecular sieves (10 g) and LiOH·H2O (1.68 g, 40
mmol) and they were stirred under an argon atmosphere for 20 min at 40°C. Then the mixture was
cooled at 0°C and the residue containing the aldehyde was added (38 mmol) with 8 mL of THF. The
mixture was stirred for 1 h at 0°C and 10 h at room temperature. The reaction progress was monitored by
TLC. Addition of 100 mL of H2O, extraction with diethyl ether (2×50 mL), standard workup followed by
flash chromatography of ethyl esters (E:Z=95:5) gave 5a (8.7 g, 68% from (S)-ethyl lactate). [α]19=+7.3
D
(c 2.76, CHCl3); 1H NMR (CDCl3) δ 6.94 (dd, J=15.6, 4.3 Hz, 1H), 5.97 (dd, J=15.6, 1.5 Hz, 1H), 4.45
(ddq, J=6.4, 4.3, 1.5 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H), 1.25 (d, J=6.4 Hz, 3H),
0.91 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3) δ 165.2, 151.8, 118.9, 68.4, 60.6, 25.7, 21.2, 18.2, 14.1,
−4.9, −5.3. EIMS m/z (rel. intensity): 258 (M+, 24), 212 (100), 201 (55), 173 (11), 127 (15). Anal. calcd
for C13H26O3Si: C, 60.42; H, 10.14. Found: C, 60.14; H, 10.31.
4.3. Synthesis of ethyl (2E,4S)-4-[(benzyl)oxy]-2-pentenoate 5b
To a suspension of NaH (2.75 g, 55 mmol, 60% in mineral oil) in dry CH2Cl2 (90 mL) at 0°C under
an argon atmosphere was added dropwise a solution of (S)-ethyl lactate (5.7 mL, 50 mmol) in 10 mL of
CH2Cl2; after 10 min benzyl bromide (6.3 mL, 53 mmol) was added. The mixture was stirred for 5 h and
monitored by TLC. Addition of 100 mL of H2O and extraction with CH2Cl2 (3×50 mL) was followed by
standard workup. Then 5b was prepared as described above for 5a. Purification of ethyl esters (E:Z=90:10
flash silica gel) gave 5b (7.1 g, 61% from (S)-ethyl lactate). Colorless oil. [α]22=−46.5 (c 2.48, CHCl3);
D
1H NMR (CDCl3) δ 7.27 (m, 5H), 6.82 (dd, J=15.8, 6.3 Hz, 1H), 5.95 (dd, J=15.8, 1.1 Hz, 1H), 4.49
(AB, J=11.8 Hz, 1H), 4.36 (AB, J=11.8 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 4.04 (ddq, J=6.4, 6.3, 1.1 Hz,
1H), 1.25 (d, J=6.4 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H); 13C NMR (CDCl3) δ 166.2, 149.1, 138.1, 128.5,
127.6, 127.5, 121.2, 73.7, 70.6, 60.3, 20.5, 14.1. EIMS m/z (rel. intensity): 234 (M+, 11), 188 (100), 171
(25), 127 (16), 91 (10). Anal. calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.96; H, 7.50.
4.4. General procedure for the preparation of compounds 6a,b
To a cold solution (0°C) of 5a,b (30 mmol) in dry CH2Cl2 (60 mL) was added dropwise a 1 M CH2Cl2
solution of DIBALH (60 mL, 60 mmol) under an argon atmosphere. The mixture was stirred for 1 h and
60 mL of a saturated solution of potassium tartrate was added dropwise and then stirred for 3 h at room
temperature. The resulting mixture was neutralized and extracted with ethyl acetate (2×60 mL) followed
by standard workup.
4.5. (2E,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-pentenol 6a
After flash chromatography of the residue, alcohol 6a was obtained as a colorless oil (6.3 g, 98%
yield). [α]19=+3.7 (c 2.86, CHCl3); 1H NMR (CDCl3) δ 5.73 (m, 2H), 4.30 (m, 1H), 4.11 (d, J=4.9 Hz,
D
2H), 1.70 (br, 1H), 1.20 (d, J=6.3 Hz, 3H), 0.88 (s, 9H), 0.051 (s, 3H), 0.043 (s, 3H); 13C NMR (CDCl3)
δ 136.2, 127.2, 68.4, 63.0, 25.8, 24.2, 18.2, −4.6, −4.7. EIMS m/z (rel. intensity): 215 (M+−1, 2), 199
(100), 159 (4), 142 (7). Anal. calcd for C11H24O2Si: C, 61.06; H, 11.18. Found: C, 60.75; H, 10.91.

A. Lattanzi et al. / Tetrahedron: Asymmetry 10 (1999) 2023–2035
2029
4.6. (2E,4S)-4-[(Benzyl)oxy]-2-pentenol 6b
After flash chromatography of the residue, alcohol 6b was obtained as a colorless oil (5.4 g, 95%
yield). [α]21=−27.1 (c 2.85, CHCl3); 1H NMR (CDCl3) δ 7.29 (m, 5H), 5.82 (dt J=15.5, 5.3 Hz, 1H),
D
5.68 (ddt, J=15.5, 7.4, 1.2 Hz, 1H), 4.55 (AB, J=11.9 Hz, 1H), 4.42 (AB, J=11.9 Hz, 1H), 4.17 (d, J=4.7
Hz, 2H), 3.97 (quint, J=6.5 Hz, 1H), 1.82 (br, 1H), 1.29 (d, J=6.5 Hz, 3H); 13C NMR (CDCl3) δ 138.7,
133.2, 130.9, 128.3, 127.6, 127.4, 75.1, 70.0, 62.8, 21.3. EIMS m/z (rel. intensity): 193 (M++1, 100), 192
(22), 176 (20), 130 (37), 91 (6), 84 (95). Anal. calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 75.24;
H, 8.60.
4.7. General procedure for the preparation of compounds 7a,b
To a benzene (30 mL) solution of 6a,b (10 mmol), at room temperature, were successively added KOH
solution (30%, 30 mL), (Bu)4NHSO4 (2 mmol) and finally tosyl chloride (12 mmol). The mixture was
vigorously stirred and monitored by TLC. Water was added and extraction with diethyl ether (3×50 mL)
was followed by standard workup. The crude reaction mixture of 7a,b was used for further manipulation
without purification.
4.8. (2E,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-penten-1-yl p-toluensulfonate 7a
1
1
The conversion (98%) was estimated by H NMR. H NMR (CDCl3) δ 7.80 (m, 2H) 7.31 (m, 2H),
5.74 (dd, J=15.6, 4.5 Hz, 1H), 5.60 (dt, J=15.6, 6.4 Hz, 1H), 4.52 (d, J=6.4 Hz, 2H), 4.25 (m, 1H), 2.44
(s, 3H), 1.14 (d, J=6.4 Hz, 3H), 0.86 (s, 9H), 0.01 (s, 3H), −0.002 (s, 3H).
4.9. (2E,4S)-4-[(Benzyl)oxy]-2-penten-1-yl p-toluensulfonate 7b
The conversion (95%) was estimated by 1H NMR. 1H NMR (CDCl3) δ 7.80 (m, 2H), 7.34–7.26 (m,
7H), 5.69 (m, 2H), 4.55 (d, J=5.0 Hz, 2H), 4.47 (AB, J=11.8 Hz, 1H), 4.33 (AB, J=11.8 Hz, 1H), 3.91
(m, 1H), 2.43 (s, 3H), 1.21 (d, J=6.6 Hz, 3H).
4.10. General procedure for the alkylation of ethyl acetoacetate with 7a,b
To a dry THF solution (4 mL) of ethyl acetoacetate (1.27 ml, 10 mmol) under an argon atmosphere,
was added LiOH·H2O (420 mg, 10 mmol) and the mixture was stirred at 50°C for 15 min. Then the
crude mixture of 7a,b (∼10 mmol) dissolved in 2 mL of dry THF was added and stirring was prolonged
for about 24 h. The reaction solution was concentrated in vacuo to give crude 8a,b extracted with diethyl
ether (40 mL) followed by standard workup.
4.11. Ethyl 2-acetyl-(4E,6S)-6-[(tert-butyldimethylsilyl)oxy]-4-heptenoate 8a
After flash chromatography of the residue, 8a was obtained as a colorless oil (2.17 g, 66% yield).
[α]26=−3.9 (c 1.20, CHCl3). Ketone:enol, 10:1. Ketonic form: 1H NMR (CDCl3) δ 5.50 (m, 2H), 4.21
D
(quint, J=6.2 Hz, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.46 (dt, J=6.8, 2.4 Hz, 1H), 2.53 (bt, J=6.8 Hz, 2H),
2.20 (s, 3H), 1.25 (t, J=7.0 Hz, 3H), 1.14 (d, J=6.3 Hz, 3H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13
C
NMR (CDCl3) δ 202.3, 169.2, 137.9, 124.0, 68.8, 61.3, 59.7, 30.6, 29.0, 25.8, 24.4, 18.2, 14.1, −4.6,

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−4.8. EIMS m/z (rel. intensity): 271 (13), 227 (23), 197 (34), 159 (46), 75 (51), 43 (100). Anal. calcd for
C17H32O4Si: C, 62.15; H, 9.82. Found: C, 62.44; H, 10.21.
4.12. Ethyl 2-acetyl-(4E,6S)-6-[(benzyl)oxy]-4-heptenoate 8b
After flash chromatography of the residue, 8b was obtained as a colorless oil (3.14 g, 73% yield).
[α]21=−3.3 (c 3.00, CHCl3). Ketone:enol, 10:1. Ketonic form: 1H NMR (CDCl3) δ 7.31 (m, 5H), 5.54
D
(m, 2H), 4.49 (AB, J=12.0 Hz, 1H), 4.32 (AB, J=12.0 Hz, 1H), 4.18 (q, J=6.3 Hz, 2H), 3.86 (quint,
J=7.0 Hz, 1H), 3.50 (dt, J=7.0, 2.6 Hz, 1H), 2.60 (m, 2H), 2.23 (s, 3H), 1.27 (t, J=7.0 Hz, 3H), 1.24 (d,
J=6.3 Hz, 3H); 13C NMR (CDCl3) δ 202.1, 169.1, 138.7, 135.1, 128.3, 127.9, 127.5, 127.3, 75.2, 69.7,
61.3, 59.5, 30.6, 28.9, 21.5, 14.1. EIMS m/z (rel. intensity): 175 (3), 126 (11), 91 (100), 65 (5), 43 (79).
Anal. calcd for C18H24O4: C, 71.03; H, 7.95. Found: C, 71.29; H, 8.20.
4.13. General procedure of iodoenoletherification of compounds 8a,b
To a dry CH2Cl2 (5 mL) solution of 8a,b (2 mmol), under an argon atmosphere (at −25°C for 8a and
−5°C for 8b), were added anhydrous Na2CO3 (0.42 g, 4 mmol) and dropwise in 45 min a solution of I2
(1.0 g, 4 mmol) dissolved in dry CH2Cl2 (45 mL). The mixture was stirred for 15 h (8a) and 2 days (8b).
Then 0.1N Na2S2O3 solution (10 mL) was added and the resulting mixture was stirred until decoloration
of the organic phase. Then the mixture was diluted with water (30 mL) and extracted with CH2Cl2 (3×40
mL) followed by standard workup.
4.14. 5-[(2S)-2-(tert-Butyldimethylsilyl)oxy-1-iodopropyl]-2-methyl-3-ethoxycarbonyl-4,5-dihydro-
furan (5R,1S,2S/5S,1R,2S) 9a
After flash chromatography of the residue, 9a was obtained as a pale yellow oil of an unseparable
1
mixture of diastereoisomers (dr 86/14), (0.5 g, 55% yield). Major diastereoisomer: H NMR (CDCl3)
δ 4.79 (ddd, J=10.8, 9.6, 8.0 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 4.03 (dd, J=9.6, 2.0 Hz, 1H), 3.46 (dq,
J=6.2, 2.0 Hz, 1H), 3.09 (ddq, J=14.8, 10.8, 1.6 Hz, 1H), 2.79 (ddq, J=14.8, 8.0, 1.6 Hz, 1H), 2.15 (t,
J=1.6 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.18 (d, J=6.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H);
13C NMR (CDCl3) δ 167.0, 165.8, 101.7, 81.9, 65.6, 59.5, 50.2, 37.3, 25.7, 25.0, 22.4, 18.0, 14.4, −4.0,
−5.0. EIMS m/z (rel. intensity): 397 (43), 270 (10), 215 (75), 195 (67), 127 (20), 73 (53), 43 (100). Minor
1
diastereoisomer: H NMR (CDCl3) δ 4.58 (ddd, J=10.8, 8.0, 7.6 Hz, 1H), 4.26 (dd, J=7.6, 5.7 Hz, 1H),
4.15 (q, J=7.1 Hz, 2H), 3.67 (quint, J=5.7 Hz, 1H), 3.02 (ddq, J=14.8, 10.8, 1.6 Hz, 1H), 2.79 (ddq,
overlap), 2.16 (t, J=1.6 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.20 (d, J=6.0 Hz, 3H), 0.89 (s, 3H), 0.07 (s,
3H), 0.06 (s, 3H); 13C NMR (CDCl3) δ 166.9, 165.7, 101.9, 81.6, 68.2, 59.4, 49.0, 36.6, 25.8, 25.0, 22.6,
19.7, 14.1, −4.2, −4.8. EIMS m/z (rel. intensity): 397 (10), 215 (17), 195 (56), 155 (100), 127 (35), 75
(74), 43 (54). Anal. calcd for C17H31O4SiI: C, 44.92; H, 6.88. Found: C, 45.23; H, 7.09.
4.15. 5-[(2S)-2-(Benzyl)oxy-1-iodopropyl]-2-methyl-3-ethoxycarbonyl-4,5-dihydrofuran (5R,1S,2S/5S,
1R,2S) 9b
After flash chromatography of the residue, 9b was obtained as a pale yellow oil of an unseparable
1
mixture of diastereoisomers (dr 73/27), (0.63 g, 74% yield). Major diastereoisomer: H NMR (CDCl3)
δ 4.87 (ddd, J=10.2, 9.1, 7.9 Hz, 1H), 4.69 (AB, J=12.0 Hz, 1H), 4.55 (AB, J=12.0 Hz, 1H), 4.15 (q,
J=7.1 Hz, 2H), 4.12 (dd, J=9.1, 2.4 Hz, 1H), 3.32 (dq, J=6.1, 2.4 Hz, 1H), 3.09 (ddq, J=14.9, 10.2, 1.3

A. Lattanzi et al. / Tetrahedron: Asymmetry 10 (1999) 2023–2035
2031
Hz, 1H), 2.82 (ddq, J=14.9, 7.9, 1.3 Hz, 1H), 2.12 (t, J=1.3 Hz, 3H), 1.29 (d, J=6.1 Hz, 3H), 1.26 (t,
J=7.1 Hz, 3H); 13C NMR (CDCl3) δ 167.0, 165.9, 137.9, 128.3, 127.8, 127.7, 101.9, 81.9, 72.0, 70.7,
59.5, 46.4, 36.6, 20.6, 14.5, 14.1. EIMS m/z (rel. intensity): 385 (4), 197 (41), 167 (18), 149 (20), 107
1
(12), 91 (100), 65 (17), 43 (63). Minor diastereoisomer: H NMR (CDCl3) δ 4.67 (AB, J=12.0 Hz, 1H),
4.65 (ddd, J=10.4, 8.4, 7.4 Hz, 1H), 4.50 (AB, J=12.0 Hz, 1H), 4.44 (dd, J=7.4, 5.8 Hz, 1H), 4.15 (q,
J=7.1 Hz, 2H), 3.40 (quint, J=5.8 Hz, 1H), 3.00 (ddq, J=15.1, 10.4, 1.3 Hz, 1H), 2.77 (ddq, overlap),
2.14 (t, J=1.3 Hz, 3H), 1.35 (d, J=6.1 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) δ 166.9,
165.8, 138.3, 128.4, 127.8, 127.6, 102.0, 81.7, 73.9, 65.3, 59.5, 44.9, 37.3, 18.7, 14.5, 14.0. EIMS m/z
(rel. intensity): 431 (M++1, 2), 197 (28), 167 (21), 149 (39), 107 (11), 91 (100), 77 (13), 43 (66). Anal.
calcd for C18H23O4I: C, 50.25; H, 5.39. Found: C, 50.47; H, 5.61.
4.16. (ꢀ)-2-Methyl-5-(E)-propenyl-3-ethoxycarbonyl-4,5-dihydrofuran 10
After flash chromatography of the residue of iodoenoletherification, (ꢀ)-10 was isolated as a colorless
oil. 1H NMR (CDCl3) δ 5.75 (dq, J=15.6, 6.4 Hz, 1H), 5.56 (ddq, J=15.6, 8.0, 1.3 Hz, 1H), 4.96 (ddd,
J=10.2, 8.5, 8.00 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.00 (ddq, J=14.7, 10.2, 1.4 Hz, 1H), 2.62 (ddq,
J=14.7, 8.5, 1.4 Hz, 1H), 2.16 (t, J=1.4 Hz, 3H), 1.71 (dd, J=6.4, 1.3 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H);
13C NMR (CDCl3) δ 167.4, 166.1, 130.0, 129.5, 101.7, 82.8, 59.3, 35.7, 17.5, 14.4, 14.0. EIMS m/z (rel.
intensity): 197 (M++1, 100), 196 (54), 151 (16), 135 (7), 107 (5). Anal. calcd for C11H16O3: C, 67.31;
H, 8.22. Found: C, 67.59; H, 8.50.
4.17. General procedure for elimination of HI with DBU on 9a,b
To a benzene solution (8 mL) of a diastereoisomeric mixture of 9a,b (1 mmol) was added dropwise
(0.46 mL, 3 mmol) DBU. The reaction was stirred at 60°C for 2 days. The reaction solution was diluted
with diethyl ether (70 mL), water was added then extraction was followed by standard workup.
4.18. 5-[(2S,3E)-2-(tert-Butyldimethylsilyl)oxypropylidene]-2-methyl-3-ethoxycarbonyl-4,5-
dihydrofuran 11a
After flash chromatography of the residue, 11a was obtained as a colorless oil (284 mg, 87% yield).
[α]23=+74.9 (c 0.98, CHCl3); 1H NMR (C6D6) δ 5.30 (dt, J=8.6, 3.1 Hz, 1H), 4.21 (dq, J=8.6, 6.3 Hz,
D
1H), 4.01 (q, J=7.1 Hz, 2H), 3.60 (ABX3, J=20.8, 3.1 Hz, 1H), 3.41 (ABX3, J=20.8, 3.1 Hz, 1H), 2.07
(t, J=1.7 Hz, 3H), 1.18 (d, J=6.3 Hz, 3H), 1.01 (t, J=7.1 Hz, 3H), 0.95 (s, 9H), 0.05 (s, 3H), 0.04 (s,
3H); 13C NMR (C6D6) δ 166.1, 164.5, 153.6, 108.4, 104.4, 66.8, 60.0, 32.5, 26.4, 25.3, 18.6, 14.8, 13.8,
−3.8, −4.2. EIMS m/z (rel. intensity): 283 (100), 220 (65), 191 (61), 159 (10), 105 (10). Anal. calcd for
C17H30O4Si: C, 62.54; H, 9.26. Found: C, 62.21; H, 9.03.
4.19. 5-[(2S,3E)-2-(Benzyl)oxypropylidene]-2-methyl-3-ethoxycarbonyl-4,5-dihydrofuran 11b
After flash chromatography of the residue, 11b was obtained as a colorless oil (212 mg, 70% yield).
[α]19=+83.4 (c 1.06, CHCl3); 1H NMR (C6D6) δ 7.31–7.07 (m, 5H), 5.16 (dt, J=9.4, 2.9 Hz, 1H), 4.49
D
(AB, J=11.9 Hz, 1H), 4.17 (AB, J=11.9 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.77 (dq, J=9.4, 6.2 Hz, 1H),
3.40 (ABX3, J=20.9, 2.8 Hz, 1H), 3.27 (ABX3, J=20.9, 2.8 Hz, 1H), 2.11 (t, J=1.9 Hz, 3H), 1.22 (d,
J=6.2 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H); 13C NMR (C6D6) δ 165.9, 164.4, 156.2, 139.9, 128.8, 128.1,
127.8, 105.1, 104.5, 72.2, 70.1, 60.0, 32.6, 22.2, 14.8, 13.7. EIMS m/z (rel. intensity): 194 (100), 165

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A. Lattanzi et al. / Tetrahedron: Asymmetry 10 (1999) 2023–2035
(50), 123 (18), 108 (19), 91 (77), 79 (34), 57 (32). Anal. calcd for C18H22O4: C, 71.50; H, 7.33. Found:
C, 71.23; H, 7.05.
4.20. General procedure of radical oxidation of 11a,b
To a benzene solution (18 mL) of 11a,b (0.5 mmol) was added AIBN portionwise (16 mg, 0.1 mmol).
The mixture was stirred under O2 bubbling at 50°C for about 36 h for 11b and 2 days for 11a. Then
removal of solvent in vacuo afforded the crude residue.
4.21. 5-[(2S,1S)-2-(tert-Butyldimethylsilyl)oxy-1-hydroperoxypropyl]-2-methyl-3-ethoxycarbonyl furan
12a
After flash chromatography of the residue, 12a was obtained as an amorphous solid (93 mg, 52%
yield). [α]15=−2.8 (c 0.93, CHCl3); 1H NMR (CDCl3) δ 8.30 (br, 1H), 6.68 (s, 1H), 4.69 (d J=5.7 Hz,
D
1H), 4.27 (q J=7.1 Hz, 2H), 4.23 (m, overlap, 1H), 2.56 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.24 (d, J=6.2
Hz, 3H), 0.81 (s, 9H), 0.04 (s, 3H), −0.06 (s, 3H); 13C NMR (CDCl3) δ 163.9, 159.0, 148.8, 114.2, 111.2,
85.1, 67.7, 60.1, 25.5, 20.5, 17.8, 14.2, 13.7, −4.6, −5.2. EIMS m/z (rel. intensity): 341 (18), 325 (100),
282 (70), 166 (32), 106 (43), 77 (47). Anal. calcd for C17H30O6Si: C, 56.95; H, 8.43. Found: C, 57.20;
H, 8.16.
4.22. 5-[(2S,1R)-2-(tert-Butyldimethylsilyl)oxy-1-hydroperoxypropyl]-2-methyl-3-ethoxycarbonyl furan
13a
After flash chromatography of the residue, 13a was obtained as a colorless oil (23 mg, 13% yield).
[α]18=+41.1 (c 0.39, CHCl3); 1H NMR (CDCl3) δ 8.99 (br, 1H), 6.63 (s, 1H), 4.73 (d, J=7.9 Hz, 1H),
D
4.27 (q, J=7.1 Hz, 2H), 4.23 (m, overlap, 1H), 2.56 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.08 (d, J=6.4 Hz,
3H), 0.91 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H); 13C NMR (CDCl3) δ 163.8, 159.4, 148.5, 114.3, 110.7, 85.4,
69.2, 60.2, 25.7, 20.5, 18.0, 14.3, 13.8, −4.7, −5.2. EIMS m/z (rel. intensity): 358 (M+, 65), 364 (28), 204
(100), 95 (44), 80 (21). Anal. calcd for C17H30O6Si: C, 56.95; H, 8.43. Found: C, 57.26; H, 8.18.
4.23. 5-[(2S,1S)-2-(Benzyl)oxy-1-hydroperoxypropyl]-2-methyl-3-ethoxycarbonyl furan 12b
After flash chromatography of the residue, 12b was obtained as a colorless oil (66 mg, 40% yield).
17
1
[α] =−2.5 (c 0.40, CHCl3); H NMR (CDCl3) δ 8.31 (br, 1H), 7.31 (m, 5H), 6.72 (s, 1H), 4.86 (d,
D
J=5.3 Hz, 1H), 4.61 (AB, J=11.9 Hz, 1H), 4.52 (AB, J=11.9 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 4.01
(quint, J=6.1 Hz, 3H), 2.56 (s, 3H), 1.34 (t, J=7.1 Hz, 3H), 1.29 (d, J=6.1 Hz, 3H); 13C NMR (CDCl3)
δ 163.8, 159.2, 148.3, 138.1, 128.4, 128.3, 127.7, 114.4, 111.2, 83.8, 73.8, 71.5, 60.1, 16.5, 14.3, 13.8.
EIMS m/z (rel. intensity): 287 (2), 261 (5), 183 (100), 153 (19), 137 (82), 79 (9), 53 (13). Anal. calcd for
C18H22O6: C, 64.66; H, 6.63. Found: C, 64.30; H, 6.37.
4.24. 5-[(2S,1R)-2-(Benzyl)oxy-1-hydroperoxypropyl]-2-methyl-3-ethoxycarbonyl furan 13b
After flash chromatography of the residue, 13b was obtained as a colorless oil (22 mg, 13% yield).
15
1
[α] =+35.0 (c 0.45, CHCl3); H NMR (CDCl3) δ 9.22 (br, 1H), 7.32 (m, 5H), 6.65 (s, 1H), 4.89 (d,
D
J=8.4 Hz, 1H), 4.71 (AB, J=12.4 Hz, 1H), 4.65 (AB, J=12.4 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.08 (dq,
J=8.4, 6.2 Hz, 1H), 2.56 (s, 3H), 1.34 (t, J=7.1 Hz, 3H), 1.14 (d, J=6.2 Hz, 3H); 13C NMR (CDCl3)

A. Lattanzi et al. / Tetrahedron: Asymmetry 10 (1999) 2023–2035
2033
δ 163.7, 159.5, 148.0, 137.8, 128.5, 127.8, 127.7, 114.4, 111.1, 84.4, 75.7, 72.0, 60.2, 16.8, 14.3, 13.8.
EIMS m/z (rel. intensity): 220 (86), 205 (100), 177 (19), 133 (16), 105 (30), 91 (33), 77 (10), 57 (79).
Anal. calcd for C18H22O6: C, 64.66; H, 6.63. Found: C, 64.39; H, 6.42.
4.25. General procedure of reduction of furyl hydroperoxides
To a CH2Cl2 solution (4 mL) of 12 (13) (20 mg, 0.058 mmol) was added (Ph)3P (15 mg, 0.059 mmol)
at room temperature. At the end of the reaction, monitored by TLC, removal of the solvent in vacuo
afforded the crude residue.
4.26. 5-[(2S,1S)-2-(tert-Butyldimethylsilyl)oxy-1-hydroxypropyl]-2-methyl-3-ethoxycarbonyl furan 14a
After flash chromatography of the residue, 14a was obtained as a colorless oil (17 mg, 89% yield).
18
1
[α] =+6.7 (c 0.57, CHCl3); H NMR (CDCl3) δ 6.53 (s, 1H), 4.49 (t, J=4.5 Hz, 1H), 4.27 (q, J=7.1
D
Hz, 2H), 4.09 (dq, J=6.2, 4.5 Hz, 1H), 2.55 (s, 3H), 1.57 (br, 1H), 1.33 (t, J=7.1 Hz, 3H), 1.12 (d, J=6.2
Hz, 3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3) δ 164.1, 158.4, 151.7, 114.0, 108.1,
72.0, 70.5, 60.0, 25.7, 18.5, 17.9, 14.3, 13.7, −4.5, −5.0. EIMS m/z (rel. intensity): 325 (M+−OH, 51),
297 (19), 165 (68), 103 (67), 73 (100). Anal. calcd for C17H30O5Si: C, 59.62; H, 8.83. Found: C, 59.37;
H, 8.62.
4.27. 5-[(2S,1R)-2-(tert-Butyldimethylsilyl)oxy-1-hydroxypropyl]-2-methyl-3-ethoxycarbonyl furan 15a
After flash chromatography of the residue, 15a was obtained as a colorless oil (16 mg, 79% yield).
[α]16=+38.5 (c 0.42, CHCl3); 1H NMR (CDCl3) δ 6.53 (s, 1H), 4.32 (t, J=5.4 Hz, 1H), 4.27 (q, J=7.1
D
Hz, 2H), 4.07 (quint, J=6.0 Hz, 3H), 2.55 (s, 3H), 1.51 (s, br), 1.33 (t, J=7.1 Hz, 3H), 1.15 (d, J=6.0 Hz,
3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.005 (s, 3H); 13C NMR (CDCl3) δ 164.0, 158.6, 152.1, 114.1, 108.3,
72.2, 70.5, 60.0, 25.7, 20.1, 17.9, 14.3, 13.7, −4.3, −5.0. EIMS m/z (rel. intensity): 325 (M+−OH, 65),
297 (17), 165 (77), 103 (64), 73 (100), 57 (25). Anal. calcd for C17H30O5Si: C, 59.62; H, 8.83. Found:
C, 59.80; H, 8.99.
4.28. General procedure for preparation of MTPA esters
To a dry pyridine solution (35 µL) of 14 and 15a (3.5 mg, 0.01 mmol) was added MTPA-Cl (5.8
µL, 0.03 mmol) and DMAP (2.3 µL, 0.02 mmol). The reaction mixture was stirred for 20 min at room
temperature during which time it was monitored by TLC. The solvent was removed in vacuo and flash
chromatography with benzene as eluent furnished MTPA ester.
4.29. (R)-MTPA ester of 5-[(2S,1S)-2-(tert-butyldimethylsilyl)oxy-1-hydroxypropyl]-2-methyl-3-ethoxy-
carbonyl furan 14a
Colorless oil (4.7 mg, 89% yield); 1H NMR (CDCl3) δ 7.45–7.30 (m, 5H), 6.48 (s, 1H), 5.80 (d, J=5.4
Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.26 (overlap, 1H), 3.56 (s, 3H), 2.49 (s, 3H), 1.34 (t, J=7.1 Hz, 3H),
1.22 (d, J=6.1 Hz, 3H), 0.81 (s, 9H), 0.04 (s, 3H), −0.07 (s, 3H); 13C NMR (CDCl3) δ 165.6, 163.7,
159.0, 147.4, 132.2, 129.5, 128.2, 127.3, 114.1, 110.6, 74.6, 68.3, 60.1, 55.6, 25.5, 19.3, 17.8, 14.3, 13.6,
−4.7, −5.3.

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4.30. (S)-MTPA ester of 5-[(2S,1S)-2-(tert-butyldimethylsilyl)oxy-1-hydroxypropyl]-2-methyl-3-ethoxy-
carbonyl furan 14a
Colorless oil (3.9 mg, 73% yield); 1H NMR (CDCl3) δ 7.46–7.30 (m, 5H), 6.67 (s, 1H), 5.71 (d, J=6.3
Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.19 (quint, J=6.1 Hz, 1H), 3.45 (s, 3H), 2.55 (s, 3H), 1.34 (t, J=7.1
Hz, 3H), 1.08 (d, J=6.1 Hz, 3H), 0.77 (s, 9H), −0.02 (s, 3H), −0.17 (s, 3H); 13C NMR (CDCl3) δ 165.5,
163.7, 159.0, 147.6, 132.2, 129.8, 128.2, 127.3, 114.3, 111.6, 74.3, 68.1, 60.2, 55.4, 25.4, 19.9, 17.7,
14.2, 13.6, −4.7, −5.5.
4.31. (R)-MTPA ester of 5-[(2S,1R)-2-(tert-butyldimethylsilyl)oxy-1-hydroxypropyl]-2-methyl-3-ethoxy-
carbonyl furan 15a
Colorless oil (5.0 mg, 94% yield); 1H NMR (CDCl3) δ 7.50–7.31 (m, 5H), 6.61 (s, 1H), 5.72 (d, J=6.2
Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.22 (quint, J=6.2 Hz, 1H), 3.50 (s, 3H), 2.55 (s, 3H), 1.34 (t, J=7.1 Hz,
2H), 1.04 (d, J=6.2 Hz, 3H), 0.79 (s, 9H), 0.01 (s, 3H), −0.13 (s, 3H); 13C NMR (CDCl3) δ 165.9, 163.7,
159.1, 147.4, 132.1, 129.5, 128.3, 127.3, 114.3, 111.1, 74.9, 67.8, 60.2, 55.4, 25.6, 19.5, 17.8, 14.3, 13.7,
−4.7, −5.1.
4.32. (S)-MTPA ester of 5-[(2S,1R)-2-(tert-butyldimethylsilyl)oxy-1-hydroxypropyl]-2-methyl-3-ethoxy-
carbonyl furan 15a
Colorless oil (3.5 mg, 66% yield); 1H NMR (CDCl3) δ 7.45–7.25 (m, 5H), 6.51 (s, 1H), 5.71 (d, J=6.2
Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.23 (m, overlap), 3.51 (s, 3H), 2.50 (s, 3H), 1.34 (t, J=7.1 Hz, 3H),
1.09 (d, J=6.2 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), −0.01 (s, 3H); 13C NMR (CDCl3) δ 165.9, 163.7,
159.0, 147.4, 131.8, 129.5, 128.2, 127.5, 114.1, 110.7, 75.2, 68.0, 60.1, 55.5, 25.6, 19.8, 17.9, 14.3, 13.6,
−4.6, −4.9.
Acknowledgements
We thank Ministero dell’Università e Ricerca Scientifica e Tecnologica (MURST) and CNR for
financial support.
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