1,3-Oxazin-2-ones vs tetrahydrofurans by iodocyclisation of 2-alkoxycarbonylamino-3-alken-1-ols

Article abstract of DOI:10.1016/S0957-4166(00)00323-2

Iodocyclisation of primary homoallylic alcohols 2a-d, containing either a 2-t-butoxy- or a benzyloxycarbonylamino group, was studied, in order to establish the nucleophilic group involved in cyclofunctionalisation. In fact, the N-t-Boc derivative 2a gave the oxazinone 3, exclusively, whereas starting from the N-Cbz derivative 2b a diastereomeric mixture of substituted tetrahydrofurans 4 and 5 resulted in ratios depending upon the reaction conditions. These results were rationalised by means of computational methods. On the contrary, migration of both the t-butyl or benzyl group to the hydroxy group was observed when both 2c and 2d underwent cyclisation to give the corresponding 5-alkoxymethyl oxazolidin-2-ones 7a,b in low yield, but with high regio- and stereocontrol. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00323-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3769–3777
1,3-Oxazin-2-ones vs tetrahydrofurans by iodocyclisation of
2-alkoxycarbonylamino-3-alken-1-ols
Joan Miquel Jorda´-Gregori,a Maria Eugenia Gonza´lez-Rosende,a,*
Patricia Cava-Montesinos,a Jose´ Sepu´lveda-Arques,a Roberta Galeazzib and Mario Orena*b
aDepartment of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Burjassot, Spain
bDipartimento di Scienze dei Materiali e della Terra, University of Ancona, Via Brecce Bianche,
I-60131 Ancona, Italy
Received 31 July 2000; accepted 10 August 2000
Abstract
Iodocyclisation of primary homoallylic alcohols 2a–d, containing either a 2-t-butoxy- or a benzyloxy-
carbonylamino group, was studied, in order to establish the nucleophilic group involved in cyclofunction-
alisation. In fact, the N-t-Boc derivative 2a gave the oxazinone 3, exclusively, whereas starting from the
N-Cbz derivative 2b a diastereomeric mixture of substituted tetrahydrofurans 4 and 5 resulted in ratios
depending upon the reaction conditions. These results were rationalised by means of computational
methods. On the contrary, migration of both the t-butyl or benzyl group to the hydroxy group was
observed when both 2c and 2d underwent cyclisation to give the corresponding 5-alkoxymethyl oxazo-
lidin-2-ones 7a,b in low yield, but with high regio- and stereocontrol. © 2000 Elsevier Science Ltd. All
rights reserved.
1. Introduction
In continuation of our interest in the stereoselective synthesis of polyfunctionalised
molecules,1 we recently reported iodocyclisation of homochiral N-t-Boc and N-Cbz allylic
carbamates to give the bicyclic derivative 1 with high stereoselection (Scheme 1).2
Scheme 1.
* Corresponding authors. E-mail: orena@popcsi.unian.it
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00323-2

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2. Results and discussion
As an extension of our cyclisation strategy towards polyfunctionalised molecules, we report
here on the iodocyclisation of 2-alkoxycarbonylamino-3-alken-1-ols 2a–d,3,4 in which both
hydroxy- and alkoxycarbonyl groups can act as nucleophiles, leading to cyclic carbamates as
well as to cyclic ethers, through competing reaction pathways.
Thus, when the N-t-Boc derivative 2a underwent iodocyclisation, the oxazinone 3 was
exclusively obtained in moderate yield, whose structure was assigned by comparison of its IR
1
and H NMR data with those of related compounds,5 and subsequently confirmed by the 13C
1
NMR and two-dimensional H–13C COSY spectra. Eventually, the configuration of 3 was
determined by the coupling constant values (J4,5=8.0, J5,6=8.5 Hz), which agree with a
trans,trans-relationship. In this case the exclusive 6-endo cyclisation mode seems to be due to
electronic factors, i.e. the phenyl ring stabilisation of the incipient carbocation (Scheme 2).6
Scheme 2. Reagents and conditions: (a) NIS in CH2Cl2, rt, R=t-Bu, 3 (53%), 4 (0%), 5 (0%); R=Bn, 3 (traces), 4
(31%), 5 (9%); (b) I2 in CH2Cl2, rt, R=Bn, 3 (traces), 4 (7%), 5 (13%)
Thus, the energies of both 3 (58.81 kcal/mol) and the corresponding intermediate iodonium
ion A (70.48 kcal/mol) were calculated and then the transition state TS-1, leading to 3, was
localised (DHf=79.99 kcal/mol).7–9 For this transition state, the 3D shapes for HOMO and
LUMO were obtained (EHOMO=−13.677654 eV and ELUMO=−6.337213 eV) with the result that
the HOMO lies mainly on the carbonyl oxygen and nitrogen ( fEr(HOMO) 0.129 and 0.537,
respectively), whereas the LUMO lies mainly at C-4 ( fNr(LUMO), C-4, 0.455, and C-3, 7.38×10−4,
respectively) (Scheme 3).
Scheme 3.

J. M. Jorda´ -Gregori et al. / Tetrahedron: Asymmetry 11 (2000) 3769–3777
3771
Starting from 2a, we considered the formation pathway of oxazinone 6, a diastereomer of 3,
although it was not observed in the reaction mixture, in order to explain the total stereoselection
of the cyclisation process. Therefore, the energies of both iodonium B (80.92 kcal/mol) and 6 (61.59
kcal/mol) were calculated and transition state TS-2, leading to 6, was localised (DHf=83.206
kcal/mol). In addition, the corresponding 3D shapes for both the HOMO and LUMO were
obtained (EHOMO=−13.599336 eV and ELUMO=−6.337 eV) with the result that the HOMO lies
mainly on carbonyl oxygen and nitrogen ( fEr(HOMO) 0.184 and 0.461, respectively), whereas the
LUMO lies mainly at C-4 ( fNr(LUMO), C-4, 0.454, and C-3, 6.77×10−4, respectively). Thus, the overall
process is largely disfavoured, owing to the higher energies involved, although the formation of
6 via a 6-endo mode is allowed (Scheme 4).6
Scheme 4.
On the other hand, when the N-Cbz derivative 2b was treated with NIS in CH2Cl2, besides traces
of the oxazinone 3, a diastereomeric mixture of tetrahydrofurans 4 and 5 was obtained, whose
structures were assigned by inspection of their 1H and 13C NMR spectra supported by molecular
mechanics calculations (Scheme 2).10,11
First, the PhCHO- and -CHI functions in all-trans iodo-tetrahydrofuran 5 were easily identified
by both their coupling pattern (l H-3: 4.27, 1H, dd, J3,2=6.5 and J3,4=6.2 Hz; l H-2: 5.19, 1H,
1
d, J2,3=6.5 Hz) and H–13C correlation spectrum, relying on the upfield shift of the methine
attached to iodine (l 37.3) and the downfield shift of the methine attached to oxygen (l 88.6).
Then, the configuration of 4 and 5 was definitely assigned by comparison of their chemical shifts
and coupling constant values. In fact, the minimum energy conformations have been calculated,
1
in order to explain the corresponding H NMR spectra, and are reported in Fig. 1.
Figure 1. Minimum energy conformations and significant dihedral angles for compounds 4 and 5. (H-2)ꢀ(C-2)ꢀ(C-
3)ꢀ(H-3)=−156.0°, (H-2)ꢀ(C-2)ꢀ(C-3)ꢀ(H-3)=127.9°, (H-3)ꢀ(C-3)ꢀ(C-4)ꢀ(H-4)=43.4°, (H-3)ꢀ(C-3)ꢀ(C-4)ꢀ(H-4)=
−96.8°, (H-4)ꢀ(C-4)ꢀ(C-5)ꢀ(H-5A)=−45°, (H-4)ꢀ(C-4)ꢀ(C-5)ꢀ(H-5A)=−46.2°, (H-4)ꢀ(C-4)ꢀ(C-5)ꢀ(H-5B)=76.8°,
(H-4)ꢀ(C-4)ꢀ(C-5)ꢀ(H-5B)=76.7°

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J. M. Jorda´ -Gregori et al. / Tetrahedron: Asymmetry 11 (2000) 3769–3777
Thus, H-4 in 4 resonates at lower field (l 4.57) than in 5 (l 4.08), owing to the shielding effect
of the C-3 halogen cis to H-4. Moreover, as a result of the phenyl group shielding, in 4, H-3
resonates upfield (l 3.85) with respect to 5 (l 4.27).
A tentative explanation of the reaction outcome can arise from inspection of the minimum
energy conformations of the corresponding iodonium ions C and D, leading to 4 and 5,
respectively.11 In fact, owing to a p-stacking effect12 between the phenyl groups, the carbonyl
group is constrained far from C-4, whereas the distance between the hydroxy group and C-4
,
seems appropriate for the cyclisation (2.64 and 2.68 A, for both C and D, respectively), thus
favouring formation of tetrahydrofurans 4 and 5, vs 1,3-oxazin-2-one 3 (Fig. 2).
Figure 2. Minimum energy conformation for iodonium ions C and D
Furthermore, it is worth mentioning that the d.r. strongly depends upon the cyclisation
conditions. In fact, when NIS in CH2Cl2 was employed, diastereomeric tetrahydrofurans 4 and
5 were obtained in 78:22 d.r., as determined from the 13C NMR spectrum. On the contrary,
cyclisation carried out with iodine in dichloromethane afforded 4 and 5 in low yield and 35:65
d.r. This result could be explained in terms of kinetic vs thermodynamic control of the
cyclisation process.13 In fact, molecular mechanics calculations carried out by using the
AMBER* force field have shown that 5 is 0.9 kcal/mol more stable than 4, owing to a
p-stacking effect12 between the phenyl groups. In agreement with these results, under kinetically
controlled conditions (NIS in CH2Cl2) 4 is the major component of the reaction mixture. On the
contrary, when the reaction was carried out under thermodynamic control (iodine in CH2Cl2),
equilibration takes place to give 5 as the major product.13
Eventually, a rather surprising result was observed when both 2c and 2d underwent cyclisation
with NIS in dichloromethane since oxazolidin-2-ones 7a,b were exclusively obtained in low yield
but with high regio- and stereoselection (Scheme 5).

J. M. Jorda´ -Gregori et al. / Tetrahedron: Asymmetry 11 (2000) 3769–3777
3773
Scheme 5.
The structural assignment of 7a,b was performed on the basis of their spectral data. In fact,
the observed carbonyl absorption of 7a and 7b at 1760 and 1754 cm−1, respectively, was
1
diagnostic for a five-membered ring carbamate.14 In addition, in the H NMR spectrum of 7a,
a peak at 1.17 l suggested that the t-Boc group had been converted to a t-butyl ether.15 On the
other hand, for oxazolidinone 7b the change of the chemical shift of the benzyloxy group from
l 5.06 (in compound 2d) to l 4.48 confirmed the presence of a benzyl ether moiety. Eventually,
the relative stereochemistry of the oxazolidinone ring in both 7a and 7b was assigned as trans,
on the basis of the values of the coupling constants (J4,5=4.0 and 4.5 Hz, respectively).14
3. Conclusion
In summary, we showed that the iodocyclisation of 2-alkoxycarbonylamino-3-alken-1-ols 2a–d
strongly relies on either the substituents of the double bond and the nitrogen protecting group,
which in agreement with computational results direct the process towards formation of
1,3-oxazin-2-one, or tetrahydrofuran derivatives with high stereoselection. Applications of this
process to the synthesis of polyfunctionalised bioactive compounds are currently under study in
our laboratory and will be reported in due course.
4. Experimental
4.1. Materials and methods
Mps were determined with a Kofler hot-stage apparatus and are uncorrected. IR spectra were
1
recorded on a FT-IR spectrometer. H and 13C NMR spectra were recorded at 250 and 69.2
MHz, respectively, on a Bruker AC-250 spectrometer. Chemical shifts are relative to tetra-
methylsilane (TMS) and coupling constants (J) are given in Hz. All assignments were deter-
mined via DEPT and 13C–1H COSY techniques. Optical rotations were measured at rt on a
Perkin–Elmer 241 polarimeter. High-resolution mass spectra were obtained on a VG Autospec,
TRIO 1000 (Fisons) instrument. The ionisation mode used in mass spectra were electron impact
(EI), chemical ionisation (CI) at 70 eV or fast atom bombardment (FAB). Flash chromatogra-
phy was performed using silica gel (Merck 60, 70–230 mesh). Compounds 2a–d were prepared
according to the literature method.3

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4.2. (E,R)-2-t-Butoxycarbonylamino-4-phenyl-3-butenol 2a
1
Yield 66%. White solid. Mp 97–99°C. H NMR: 1.36 (s, 9H), 3.15 (br s, 1H, OH), 3,53 (dd,
1H, J=11.0, J=5.5), 3.64 (dd, 1H, J=11.0, J=4.4), 4.26 (m, 1H, NH), 5.16 (br s, 1H), 6.03 (dd,
1H, J=16.0, J=6.0), 6.46 (d, 1H, J=16.0), 7.19–7.24 (m, 5ArH). 13C NMR: 28.3, 54.4, 65.1,
79.8, 126.4, 126.9, 127.6, 128.4, 131.5, 136.4, 156.0. [h]D −40.1 (c 1.2, CHC13). CI-HRMS
(MH+)=264.1593. Calculated for C15H22NO3 264.1599.
4.3. (E,R)-2-Benzyloxycarbonylamino-4-phenyl-3-butenol 2b
1
Yield 60%. White solid. Mp 110–112°C. H NMR: 2.50 (br s, 1H), 3.64 (dd, 1H, J=11.0,
J=5.5), 3.74 (dd, 1H, J=11.0, J=4.0), 4.37 (m, 1H), 5.03 (s, 2H), 5.31 (d, 1H, J=7.7), 6.04 (dd,
1H, J=15.7, J=5.9), 6.49 (d, 1H, J=15.7), 7.19–7.24 (m, 10ArH). 13C NMR: 54.9, 65.1, 67.0,
126.5, 127.8, 128.2, 128.6, 132.0, 136.2, 156.3. [h]D−34.4 (c 1.05, CHC13). EI-HRMS (M+)=
297.1364. Calculated for C18H19NO3=297.1364.
4.4. (Z,R)-2-t-Butoxycarbonylamino-3-penten-1-ol 2c
1
Yield 78%. White solid. Mp 54–56°C. H NMR 1.45 (s, 9H), 1.73 (dd, 3H, J=6.9, J=1.8),
2.75 (br s, 1H), 3.57–3.62 (m, 2H), 4.48–4.53 (m, 1H), 4.75 (d, 1H, NH, J=6.6), 5.29 (ddq, 1H,
J=10.6, J=8.8, J=1.8), 5.68 (ddq, 1H, J=10.6, J=6.9, J=1.8). 13C NMR 13.5, 28.4, 50.4,
66.4, 79.9, 127.2, 127.7, 156.3. [h]D 39.2 (c 1.0, CHCl3) [lit.3 [h]D 40.7 (c 1.1, MeOH)]. CI-HRMS
(MH+)=202.1434. Calculated for C10H20NO3 202.1443.
4.5. (Z,R)-2-Benzyloxycarbonylamino-3-pentenol 2d
1
Yield 76%. Colourless oil. H NMR: 1.77 (br s, 3H), 3.07 (br s, 1H), 3.52–3.57 (m, 2H), 4.52
(m, 1H), 5.06 (s, 2H), 5.23–5.38 (m, 2H), 5.59–5.66 (m, 1H), 7.30 (m, 5ArH). 13C NMR: 13.3,
50.4, 65.2, 66.8, 127.1, 127.9, 128.0, 128.4, 136.2, 156.5. [h]D 42.1 (c 1.1, CHC13). EI-HRMS
(MH+)=236.1281. Calculated for C13H18NO3 236.1286.
4.6. The iodocyclisation reaction
4.6.1. Method A
To a solution of the appropriate amino alcohol 2 (10 mmol) in dichloromethane (50 ml), NIS
(4.5 g, 20 mmol) was added at room temperature. After stirring for 24 h, the reaction was
diluted with dichloromethane (50 ml), the organic phase washed with 10% aqueous Na2S2O3 (50
ml), and then extracted with dichloromethane (3×50 ml). The combined organic layers were
washed with 10% NaCl (30 ml), 10% aqueous NaHCO3 solution (30 ml) and dried (Na2SO4),
and after removal of the solvent under reduced pressure, the residue was purified by silica gel
flash chromatography using gradient elution (hexane:ethyl acetate, 80:20 to 30:70).
4.6.2. Method B
To a solution of alcohol 2c,d (10 mmol) in dichloromethane (50 ml), I2 (7.65 g, 30 mmol) was
added at room temperature. After 24 h, the reaction was diluted with dichloromethane (50 ml),
the organic phase washed with 10% aqueous Na2S2O3 (50 ml), then extracted with (3×50 ml) and

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3775
the combined organic layers were washed with water (75 ml), brine (75 ml) and dried (Na2SO4).
After removal of the solvent under reduced pressure, the residue was purified by flash
chromatography on silica gel (hexane:ethyl acetate, 80:20).
4.6.3. (4S,5S,6R)-4-Hydroxymethyl-5-iodo-6-phenyl-1,3-oxazin-2-one 3
Starting from 2a, the title compound was obtained in 53% yield following Method A. White
1
solid. Mp 164–165°C. IR (CH2C12): 3321, 1716 cm−1. H NMR: 2.63 (s, 1H, OH), 4.04–4.20 (m,
3H, H-4, H-7a,b), 4.43 (dd, 1H, H-5, J=8.5, J=8.0), 4.93 (d, 1H, H-6, J=8.0), 5.90 (br s, 1H,
NH), 7.32 (m, 5ArH). 13C NMR: 41.7 (d, CHI), 55.6 (d, CHN), 72.4 (t, CH2OH), 79.3 (d,
CHO), 126.7 (d, 2CHAr), 128.9 (d, 2CHAr), 129.1 (d, CAr), 140.9 (s, CAr), 159.1 (s, CON).
[h]D−39.5 (c 1.06, CH3OH). EI-HRMS (MH+): 332.9860. Calculated for C11H12INO3 332.9862.
4.6.4. (2R,3S,4S)-4-(Benzyloxycarbonylamino)-3-iodo-2-phenyltetrahydrofuran 4 and its
(2S,3R,4S)-isomer 5
When iodocyclisation was carried out according to Method A starting from 2b, a diastereo-
meric mixture of 4 and 5 was obtained in 40% overall yield. D.r. 78:22. Compound 4. Yield
1
31%. White solid. Mp 70–73°C. H NMR: 3.85–3.93 (m, 2H, H-5A, H-3), 4.24 (dd, 1H, H-5B,
J=8.7, J=7.3), 4.57 (m, 1H, H-4), 5.10 (m, 3H, H-2+CH2Ph), 5.37 (d, 1H, NH, J=7.3), 7.25
(m, 10ArH). 13C NMR: 31.0 (d, CHI), 62.3 (d, CHN), 67.1 (t, CH2OPh), 71.5 (t, CH2O), 88.9
(d, CHO), 126.1 (d, 2CHAr), 128.1 (d, CHAr), 128.3 (d, CHAr), 128.5 (d, CHAr), 128.6 (d, 2CHAr),
135.9 (s, CAr), 138.1 (s, CAr), 155.6 (s, CON). [h]D 22.1 (c 1.02, CHCl3). CI-HRMS (M+)=
1
424.0425. Calculated for C18H19INO3=424.0410. Compound 5. Yield 9%. Colourless oil. H
NMR: 3.77 (dd, 1H, H-5B J=8.8, J=6.2), 4.08 (m, 1H, H-4), 4.27 (dd, 1H, H-3, J=6.5, J=6.2),
4.34 (dd, 1H, H-5A, J=8.8, J=6.5), 5.07 (m, 3H), 5.19 (d, 1H, H-2, J=6.5), 7.29 (m, 10ArH).
13C NMR: 37.3 (d, CHI), 53.1 (d, CHN), 67.3 (t, OCH2Ph), 71.3 (t, CH2O), 88.6 (d, CHO),
125.8 (d, 2CHAr), 128.2 (d, CHAr), 128.3 (d, CHAr), 128.5 (d, CHAr), 128.6 (d, 2CHAr), 128.7 (d,
2CHAr), 136.0 (s, CAr), 139.2 (s, CAr), 155.5 (s, CON). [h]D 12.9 (c 1.08, CHC13). CI-HRMS
(M+)=424.0418. Calculated for C18H19INO3 424.0410.
4.6.5. (2R,3S,4S)-4-(Benzyloxycarbonylamino)-3-iodo-2-phenyltetrahydrofuran 4 and its
(2S,3R,4S)-isomer 5
When iodocyclisation according to Method B was carried out starting from 2b, besides tars,
a diastereomeric mixture of 4 and 5 was obtained, in 20% overall yield. D.r. 35:65.
4.6.6. (4S,5R,1%S)-4-t-Butoxymethyl-5-(1%-iodoethyl)-1,3-oxazol´ıdin-2-one 7a
When iodocyclisation was carried out according to Method A starting from 2c, tars were
obtained, together with compound 7a which was recovered in 27% yield. White solid. Mp
1
68–70°C. IR (CH2Cl2): 3288, 1760 cm−1. H NMR: 1.17 (s, 9H), 1.90 (d, 3H, J=6.8), 3.40 (dd,
1H, J=7.3, J=8.7), 3.47 (dd, 1H, H, J=4.8, J=8.7), 3.78 (m, 1H, H-4), 4.18 (dd, 1H, H-5,
J=4.2, J=3.6), 4.26 (dq, 1H, J=6.8, J=3.6), 6.43 (br s, 1H, NH). 13C NMR: 21.8 (q, CH3),
27.0 (d, CHI), 27.3 (q, 3CH3), 55.2 (d, CHN), 64.2 (t, CH2O), 73.6 (s, C), 81.5 (d, CHO), 158.7
(s, CON). [h]D−49.6 (c 1.3, CHCl3). FAB-HRMS (MH+) 328.0424. Calculated for C10H19INO3
328.0409.
4.6.7. (4S,5R,1%S)-4-Benzyloxymethyl-5-(1%-iodoethyl)-1,3-oxazolidin-2-one 7b
When iodocyclisation was carried out according to Method A starting from 2d, tars were
obtained, together compound 7b which was recovered in 10% yield. Colourless oil. IR (CH2Cl2):

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1
3284, 1754 cm−1. H NMR: 1.81 (d, 3H, J=7.0), 3.43 (dd, 1H, J=9.5, J=6.2), 3.49 (dd, 1H,
J=9.5, J=4.7), 3.76 (m, 1H, H-4), 4.11 (dd, 1H, H-5, J=4.0, J=3.5), 4.16 (dq, 1H, J=7,0,
J=3.5), 4.48 (s, 2H), 6.13 (br s, 1H), 7.22–7.25 (m, 5ArH). 13C NMR: 21.8 (q, CH3), 26.6 (d,
CHI), 55.7 (d, CHN), 71.9 (t, CH2O), 73.5 (t, CH2O), 81.2 (d, CHO), 127.7 (d, 2CHAr), 128.0
(d, CHAr), 128.6 (d, 2CHAr), 137.2 (s, CAr), 158.5 (s, CON). [h]D−51.1 (c 0.8, CHCl3). EI-HRMS
(MH+)=362.0262. Calculated for C13H17INO3 362.0253.
4.7. Computational methods
Semiempirical calculations were carried out by using the AM1 Hamiltonian as implemented
in HyperChem 5.1 software package. Transition structures were always located by means of the
eigenvector following algorithm and on the optimised structures a complete vibrational analysis
was carried out in order to check the nature of the true transition states. All these TS structures
have only one imaginary normal mode which correspond to the expected c.d.r.
The conformational analysis of the cyclic products was carried out by using the BatchMin
V.5.5 simulation program as implemented in Macromodel molecular modelling package. The
AMBER* force field was used, and the simulation varied all internal degree of freedom
(including the torsional angle of the ring). The conformational search was performed by using
a MonteCarlo algorithm16 included in the package and all the conformers with the energy within
3.0 kcal/mol were considered.
Acknowledgements
We acknowledge both Ministerio de Educacio´n y Ciencia (Spain, Project PB98-1451) and
MURST (Italy, PRIN 2000) for financial support.
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.
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15. For a similar group transfer, see: Farr, R. A.; Holland, A. K.; Huber, E. W.; Pect, N. P.; Weintraub, P. M.
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