Highly regio- and stereoselective iodocyclization of chiral 3- alkoxycarbonyl-4-propenyl-2,2-dimethyl-1,3-oxazolidines: A computational investigation

Article abstract of DOI:10.1016/S0957-4166(99)00084-1

The iodocyclization of allylic carbamates 3a and 3b proceeded with high regio- and stereoselection to give 2-oxobicyclo[4.3.0]nonane 5a as the major product. Both the regio- and diastereoselection of the reaction were investigated with the help of molecular mechanics and quantomechanical calculations. The energetic difference between the competing transition states TS-5a and TS-5b is in good agreement with the experimental results and from the calculated transition structures it appears that steric factors direct the discrimination.

Full text of DOI:10.1016/S0957-4166(99)00084-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1135–1143
Highly regio- and stereoselective iodocyclization of chiral
3-alkoxycarbonyl-4-propenyl-2,2-dimethyl-1,3-oxazolidines: a
computational investigation
Juan Miquel Jordá-Gregori,a M. Eugenia González-Rosende,a José Sepúlveda-Arques,a
Roberta Galeazzi b 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, Ancona, Italy
Received 12 February 1999; accepted 8 March 1999
Abstract
The iodocyclization of allylic carbamates 3a and 3b proceeded with high regio- and stereoselection to give
2-oxobicyclo[4.3.0]nonane 5a as the major product. Both the regio- and diastereoselection of the reaction were
investigated with the help of molecular mechanics and quantomechanical calculations. The energetic difference
between the competing transition states TS-5a and TS-5b is in good agreement with the experimental results and
from the calculated transition structures it appears that steric factors direct the discrimination. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
In recent years, highly regio- and stereoselective iodocyclizations of allylic and homoallylic carba-
mates, have been used to obtain heterocyclic intermediates, suitable for conversion into polyfunctional-
ized structures by cleavage of the heterocyclic ring.1,2
As part of a programme aimed at synthesizing polyfunctionalized acyclic molecules with biological
activity, in the present paper we describe the facile preparation of (4S,5S,6S)-1-aza-5-iodo-4,9,9-
trimethyl-3,8-dioxa-2-oxobicyclo[4.3.0]nonane 5a, which can be a precursor of bioactive products such
as L-2,5-dideoxy-2-aminoarabinose3 1 and β,γ-dihydroxy-α-amino acids4 such as 2 (Scheme 1).
∗
Corresponding author. E-mail: orena@popcsi.unian.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00084-1

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Scheme 1.
2. Results and discussion
Both N-Cbz and N-Boc derivatives 3a5 and 3b6 underwent highly regio- and stereoselective iodo-
cyclization on treatment with iodine or N-iodosuccinimide (NIS) in dichloromethane or chloroform, to
give, in moderate to low yield, the cyclization products 5a (major) and 6a, which were easily isolated by
column chromatography. The possible bicyclic products 5b, 6b, 7a and 7b were never observed in the
reaction mixture (Scheme 2; Table 1).7,8,14
Scheme 2. Reagents and conditions: i. I2 or NIS in CH2Cl2 or CHCl3, 3 days (see Table 1)
These compounds were first assigned as 2-oxobicyclo[4.3.0]nonanes owing to the observed IR absorp-
tion at 1703 cm−1, which is diagnostic for a six-membered ring carbamate.2e The stereochemistry of the
products was subsequently accomplished by 1H NMR spectroscopy supported by molecular mechanics
calculations. Thus, the minimum energy conformations and significant dihedral angles for 5a,b and 6a,b
were calculated by using the AMBER* force field programme9 and are reported in Fig. 1. Compound 5a
0
showed resonances for H5 at δ 3.95 (dd, J5,6 11.3 and J4,5 4.8 Hz), for H4 at δ 4.68 (dq, J4,1 6.6 and J4,5
4.8 Hz) and for H6 at δ 4.09 (ddd, J5,6 11.3, J6,7A 9.5 and J6,7B 5.1). Both the large value of J5,6 (11.3 Hz)
and the small value of J4,5 (4.8 Hz) are typical of a 4,5-cis-, 5,6-trans-relationship and were in agreement
with the calculated dihedral angles H5–C5–C6–H6 and H4–C4–C5–H5, respectively. This assignment was
confirmed by the 13C NMR spectrum, which showed three CH sp3-carbon signals [at δ 18.4 (C5), 56.5
1
(C6) and 76.5 (C4)], and further supported by a two-dimensional H–13C COSY spectrum which shows
a pronounced cross peak between H5 and C5.
On the other hand, the minor product of the reaction could not be assigned as 3b, arising from addition

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1137
Table 1
Product distribution for cyclization of compounds 3a and 3b
Figure 1. Preferred conformations and significant dihedral angle values for compounds 5a, 5b, 6a and 6b
to a Z-double bond, although three CH sp3-carbon signals [at δ 22.7 (C5), 61.5 (C6) and 79.4 (C4)] were
present in its 13C NMR spectrum. In fact, both coupling constants and splitting pattern of H5 (δ 3.55, dd,
J 10.6 and J 10.9) clearly showed a trans,trans-relationship of H5 with both H4 and H6, so that the minor
product was assigned as 6a, arising from iodocyclization of a small amount of both 4a and 4b, which
probably forms under the reaction conditions. These observations allowed us to assign the major product
5a as (4S,5S,6S)-1-aza-5-iodo-4,9,9-trimethyl-3,8-dioxa-2-oxobicyclo[4.3.0]nonane and the minor one
6a as its (4R,5S,6S)-isomer.
The reaction proceeded with total regioselection, since 2-oxobicyclo[4.3.0]nonanes 5a and 6a arising
from a 6-endo mode closure were exclusively isolated from the reaction mixture, whereas products such
as 7a and 7b, which would form through a 5-exo mode cyclization were missing.10 In order to explain
the regioselection of the cyclization, in which electronic effects are not clearly present as in previously
reported examples,2e we first considered the intermediate iodonium ion A derived from 3a (Fig. 2). Thus,
0
we calculated the frontier electron density for nucleophile (fNr ) for both C1 , leading to 5-exo closure, and
0
C2 , leading to 6-endo closure, and the values turned out to be 2.35×10−3 and 0.634, respectively, in
agreement with a 6-endo closure pathway.11
Subsequently, the search for transition states (TSs) leading to bicyclic compounds 5a,b, 6a,b and 7a,b
starting from the corresponding iodonium ions was carried out using the synchronous transit quadratic
method at the AM1 level and the calculated structures are reported in Figs. 3 and 4.12 In addition,
the formation enthalpy values (∆H#) of all the considered transition structures were calculated and

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Figure 2.
are summarized in Table 2. Firstly, it resulted in both TS-7a and TS-7b being largely disfavored with
respect to TS-5a and TS-5b, according to the observed regioselection.13 Moreover, by considering the
transition states TS-5a/TS-5b, leading to 5a and 5b, and TS-6a/TS-6b, leading to 6a and 6b, the observed
diastereoselection could also be explained (Table 2). The energetic difference occurring between TS-5a
and TS-5b (∆∆H#=1.16 kcal/mol) and TS-6a and TS-6b (∆∆H#=1.66 kcal/mol), respectively, is in good
agreement with the related experimental results (only 5a and 6a were observed in the reaction mixture).
The role of the heterocyclic ring on the stereoselection of the reaction can be appreciated by inspection
of the AM1-optimized transition state geometries of both TS-5a and TS-5b, as reported in Fig. 3. As a
matter of fact, it results in the steric factors governing the energy differences between these transition
states. In TS-5b a sterically demanding interaction takes place between the ring and CH3-30, which is
otherwise lacking in TS-5a, the distance between the heterocyclic ring and CH3-30 being 3.33 Å.
Eventually, the molecular mechanics calculations data confirmed that the cyclization reaction proceeds
under kinetic control. In fact, by comparison with 5a, compound 5b was found to be more stable by 1.01
kcal/mol, although only 5a was isolated from the reaction mixture, owing to the irreversible cyclization
proceeding through the lower energy transition state.9,12 The same behavior was also observed for
compound 6a with respect to 6b.
3. Conclusion
The iodocyclization reaction of allylic carbamates 3a and 3b proceeds with high regio- and stereo-
selection leading to 2-oxobicyclo[4.3.0]nonanes 5a and 6a and this behavior has been explained by
molecular mechanics and quantum-mechanical calculations. The major product 5a could be a precursor
of biologically active compounds and work in progress on this subject will be reported in due course.
4. Experimental
4.1. General
All reactions involving air-sensitive reagents were performed under nitrogen using syringe–septum
cap techniques. All glassware was flame-dried prior to use. Flash chromatography was performed using
silica gel (Merck 60, 70–230 mesh). Optical rotations were measured at rt on a Perkin–Elmer 241
polarimeter. 1H and 13C NMR spectra were recorded in CDCl3 at 250 and 69.2 MHz on a Bruker AC-250
spectrometer. Carbon was determined via DEPT and 13C–1H COSY techniques. High-resolution mass
spectra were obtained on a VG Autospec, TRIO 1000 (Fisons) instrument. The ionization modes used in
mass spectrometric analysis were chemical ionization (CI) at 70 eV or fast atom bombardment (FAB).

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1139
Figure 3. Transition states for cyclization of both 3a and 4a in 6-endo mode
4.2. Materials
(S)-N-Benzyloxycarbonyl-4-formyl-2,2-dimethyl-1,3-oxazolidine5 and (Z,R)-3-t-butoxycarbonyl-2,2-
dimethyl-4-(1-propenyl)-1,3-oxazolidine6 3b were prepared following literature methods.

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Figure 4. Transition states for cyclization of 3a in 5-exo mode
Table 2
Formation enthalpies (kcal/mol) of both the theoretical transition state structures (TSs) and the
corresponding iodonium ions
4.3. (Z,R)-3-Benzyloxycarbonyl-2,2-dimethyl-4-(1-propenyl)-1,3-oxazolidine 3a
To a suspension of ethyl triphenylphosphonium halide (17.5 mmol) in dry THF (115 ml) under an
argon atmosphere cooled to −78°C, n-BuLi (2 M solution in hexane; 17.5 mmol; 8.75 ml) was added
dropwise. The mixture was stirred for 15 min, allowing the temperature to reach 0°C, and the resulting
dark red solution was stirred for an additional hour. After cooling to −78°C, (S)-N-benzyloxycarbonyl-
4-formyl-2,2-dimethyl-1,3-oxazolidine5 (10 mmol) dissolved in dry THF (22 ml), was added dropwise
over a 10 min period. The reaction mixture was stirred under argon until the temperature reached 25°C
and then for a further 90 min. The mixture was quenched with saturated aqueous NH4Cl (115 ml) and
extracted with ethyl acetate (3×55 ml). The combined organic phases were washed with water (60 ml)
and brine (60 ml) and dried (MgSO4). After evaporation of the solvent under reduced pressure, the residue
was purified by flash chromatography on silica gel (hexane:ethyl acetate, 80:20) to give 3a in 70% yield
as a colorless oil. Both 1H and 13C NMR spectra showed two sets of signals at room temperature, due to
the presence of a dynamic equilibrium between two conformers (α and β, the α form being predominant).

J. M. Jordá-Gregori et al. / Tetrahedron: Asymmetry 10 (1999) 1135–1143
1141
1H NMR: 1.34–1.64 (m, 9H), 3.53 (dd, 1H, J=8.8, J=2.2), 3.92 (dd, 1H, J=8.8, J=5.9), 4.51–4.62 (m,
1H), 4.96 (s, 2H), 5.30–5.36 (m, 2H), 7.19 (s, 5H); 13C NMR: 12.6 (q, CH3)α+β, 23.7 (q, CH3)α, 25.0
(q, CH3)β, 26.3 (q, CH3)α, 27.2 (q, CH3)β, 53.7 (d, CHN)α, 54.5 (d, CHN)β, 66.5 (t, OCH2C6H5)α+β
,
68.8 (t, CH2O)α+β, 94.0 (s, C2)α+β, 125.8 (d, _CH)α+β, 127.8 (d, 2CHar)α+β, 127.9 (d, CHar)α+β, 128.2
(d, 2CHar)α+β, 129.6 (d, _CH)α+β, 136.4 (s, Car)α+β, 152.2 (s, CON)α+β. [α]D25=85.9 (c 1.23, CHCl3).
Exact mass (CI) calcd for C16H21O3N (M+): 275.1517; found: 275.1521.
4.4. Iodocyclization of carbamates 3a,b
4.4.1. General procedure
Method A. To a solution of alkenyloxazolidine 3a or 3b (10 mmol) in dichloromethane or chloroform
(50 ml), I2 (5.1 g, 20 mmol) was added at room temperature. After 3 days, the reaction was diluted
with dichloromethane or chloroform (50 ml), the organic phase washed with 10% aqueous Na2S2O3 (50
ml), then extracted with dichloromethane (3×50 ml) and 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, 60:40) to give
compounds 5a and 6a as colorless oils. Yields and d.r.s are reported in Table 1.
Method B. To a solution of alkenyloxazolidine 3a or 3b (10 mmol) in dichloromethane (50 ml), NIS
(2.7 g, 12 mmol) was added at room temperature. After stirring for 3 days, the reaction was diluted
with dichloromethane (50 ml), the solution was washed with 10% aqueous Na2S2O3 (50 ml), extracted
with dichloromethane (3×50 ml) and the combined organic layers were washed with 10% HCl (30 ml),
10% aqueous NaHCO3 solution (30 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, 70:30) to
give compounds 5a and 6a as colorless oils. Yields and d.r.s are reported in Table 1.
4.5. (4S,5S,6S)-1-Aza-5-iodo-4,9,9-trimethyl-3,8-dioxa-2-oxobicyclo[4.3.0]nonane 5a
1
IR (CH2Cl2): 1703 cm−1. H NMR: 1.60 (s, 3H), 1.61 (s, 3H), 1.63 (d, 3H, J=6.6), 3.59 (dd, 1H,
H7A, J=8.7, J=9.5), 3.95 (dd, 1H, H5, J=4.8, J=11.3), 4.09 (ddd, 1H, H6, J=5.1 J=9.5, J=11.3), 4.30
(dd, 1H, H7B, J=5.1, J=8.7), 4.68 (dq, 1H, H4, J=6.6, J=4.8). 13C NMR: 17.9 (q, CH3), 18.4 (d, CHI),
23.6 (q, CH3), 26.4 (q, CH3), 56.5 (d, CHN), 70.2 (t, CH2O), 76.5 (d, CHO), 97.3 (s, C), 148.2 (s,
CON). [α]D25=−46.8 (c 1, CHCl3). Exact mass (FAB) calcd for [C9H15O3NI]+ (MH+): 312.0096; found:
312.0098.
4.6. (4R,5S,6S)-1-Aza-5-iodo-4,9,9-trimethyl-3,8-dioxa-2-oxobicyclo[4.3.0]nonane 6a
IR (CH2Cl2): 1705 cm−1. 1H NMR: 1.60 (d, 3H, J=6.2), 1.62 (s, 3H), 1.64 (s, 3H), 3.55 (dd, 1H, H5,
J=10.6, J 10.9), 3.59 (dd, 1H, H7A, J=9.5, J=8.7), 4.04 (ddd, 1H, H6, J=10.6, J=5.8, J=9.5), 4.33 (dd,
1H, H7B, J=5.8, J=8.7), 4.50 (dq, 1H, H4, J=10.9, J=6.2). 13C NMR: 20.4 (q, CH3), 22.7 (d, CHI), 23.8
(q, CH3), 26.2 (q, CH3), 61.5 (d, CHN), 70.1 (t, CH2O), 79.4 (d, CHO), 97.1 (s, C), 148.5 (s, CON).
[α]D25=−85.0 (c 1.02, CHCl3). Exact mass (FAB) calcd for [C9H15O3NI]+ (MH+): 312.0096; found:
312.0097.

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4.7. Computational studies
All simulations were carried out using the BATCHMIN simulation program as implemented in
Macromodel molecular modeling package, version 5.5.9 The AMBER* force field was used, and the
conformational search varied all internal degrees of freedom, by using a Monte Carlo algorithm included
in the package. All conformers with energies within 3.0 kcal/mol were considered. All the calculations
were performed on a Silicon Graphics Indigo2 workstation R10000, 175 MHz.
Transition states (TSs) leading to compounds 5a,b, 6a,b and 7a,b were localized by using the AM1
Hamiltonian combined with the synchronous transit method, included in HyperChem Software Package
5.1.12 In particular, the quadratic synchronous transit method (QST) was employed, which searches for
a maximum along a parabola-connecting reagent and products, and for a minimum in all directions
perpendicular to the parabola. The TS structures found have only one imaginary frequence normal mode
which corresponds to the coordinate of reaction, consisting of a synchronous motion of the two centers
of reaction (O···C).14,15
Acknowledgements
J.S.-A. thanks the Spanish Ministry of Education and Science for his research contract (Project PB95-
1076). M.O. thanks the Italian Ministry of University and Scientific Research (M.U.R.S.T.) for financial
support (Project ‘Chimica dei Composti Organici di Interesse Biologico’).
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J. M. Jordá-Gregori et al. / Tetrahedron: Asymmetry 10 (1999) 1135–1143
1143
J=6.9), 3.40 (dd, 1H, H4B J=7.3, J=8.7), 3.47 (dd, 1H, H4A, J=4.8, J=8.7), 3.78 (m, 1H, H3), 4.18 (dd, 1H, H2 J=4.4,
J=3.5), 4.26 (dq, 1H, J=6.9, J=3.5), 6.40 (br s, 1H, NH). 13C NMR: 21.9 (q, CH3), 27.0 (d, CHI), 27.3 (q, 3CH3), 56.2
25
(d, CHN), 64.2 (t, CH2O), 73.6 (s, C), 81.5 (d, CHO), 158.7 (s, CON). [α]D −53.2 (c 1.00, CHCl3). Exact mass (FAB)
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14. The frequency values are the following: for TS-5a, −59.33 cm−1; for TS-5b, −29.92 cm−1; for TS-6a, −43.18 cm−1; for
TS-6b, −67.12 cm−1; for TS-7a, −276.90 cm−1; for TS-7b, −205.35 cm−1.
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