Optically pure 3,6-dioxazocan-2-one derivatives by intramolecular cycloaddition of azidoformates and their opening to substituted α-amino ketones

Article abstract of DOI:10.1002/(sici)1099-0690(199911)1999:11<2709::aid-ejoc2709>3.0.co;2-h

Azidoformates derived from chiral enol ethers, when irradiated, give 3,6-dioxazocan-2-one derivatives 7 by a highly diastereoselective intramolecular cycloaddition. The hydrolysis of 7 gives a single derivative of 2-aminocyclo-hexanone.

Full text of DOI:10.1002/(sici)1099-0690(199911)1999:11<2709::aid-ejoc2709>3.0.co;2-h

SHORT COMMUNICATION
Optically Pure 3,6-Dioxazocan-2-one Derivatives by Intramolecular
Cycloaddition of Azidoformates and their Opening to Substituted
␣-Amino Ketones
Marco de Santis,[a] Stefania Fioravanti,*[a] Lucio Pellacani,*[a] and Paolo A. Tardella*[a]
Keywords: Aminations / Azides / Cyclizations / Nitrogen heterocycles
Azidoformates derived from chiral enol ethers, when
irradiated, give 3,6-dioxazocan-2-one derivatives 7 by a
highly diastereoselective intramolecular cycloaddition. The
hydrolysis of 7 gives a single derivative of 2-aminocyclo-
hexanone.
During our studies on intermolecular amination reac-
tions[1] we have also considered chiral enol ethers and the
early results seem promising.[2] The intramolecular addition
of azidoformates carrying a chiral enol ether function at-
tracted our attention in the hope that we might obtain
asymmetric induction. Examples of the intramolecular
cyclization of azidoformates with generic olefins are very
rare in the literature,[3] while several intramolecular CϪH
insertion reactions, starting from azidoformates are
known.[4]
The desired azides 3 were prepared, in 40Ϫ52% overall
yield, from the ring-opening reaction of spirane ketals 1
with TMSOTf, followed by a desilylation step, to give 2,
which is then reacted sequentially with triphosgene and so-
dium azide to give 3 (Scheme 1).
The azides 3 are stable at room temperature for several
weeks and for a few hours in boiling carbon tetrachloride.
When stored in CH2Cl2 for a longer time the enol ether
function of 3 undergoes complete hydrolysis to give the
hydroxy azides 4, which give 6 by treatment with silica gel.
At higher temperatures (120°C, in a sealed tube for 2 h) the
decomposition of 3 gave 6 directly.
A solution of 3 in dichloromethane was photolyzed for
4Ϫ12 h at room temperature under an argon atmosphere
giving compounds 7 and 4, as shown by NMR spectroscopy
and, after flash-chromatography, compounds 7 (20Ϫ21%)
and 6 (21Ϫ40%) could be isolated (Scheme 2).
The isolation of 7, albeit in moderate yield, is interesting
as the azocan-2-one, and its derivatives, possess important
pharmacological properties.[5] The unusual 3,6-dioxazocan-
2-one skeleton of 7 probably derives from the isomerization
of an unstable tricyclic aziridine, as has previously been
reported.[6] From a stereochemical point of view, the new
CϪN bond is formed with high asymmetric induction Ϫ
only one diastereomer is formed as seen from spectroscopic
and chromatographic evidence.
Scheme 1. Synthesis of azidoformates
The stereochemistry was tentatively assigned assuming le-
ast hindered attack, as observed in the cyclopropanation[7]
and epoxidation[8] of related substrates. The heats of forma-
tion, obtained by semiempirical MO calculations, indicated
that the aziridine 5a, resulting from attack at the si-re face
of the olefin, is more stable than the other aziridine [∆∆H ϭ
Ϫ1.05 kcal/mol (PM3) or ∆∆H ϭ Ϫ1.6 kcal/mol (AM1)].
The enol ether moiety of 7a was finally hydrolyzed with
BF3·Et2O in aqueous methanol to give the N-substituted 2-
aminocyclohexanone 8 in 95% yield as a single stereoisomer
(Scheme 3). Stereochemically pure derivatives of α-amino
ketones are important as they can be employed in a variety
of organic syntheses,[9] and they are also precursors of β-
amino alcohols.[10]
[a]
In conclusion, by using enol ethers tethered with a chiral
chain ending with an azido function it is possible to obtain
optically active derivatives of α-amino ketones through use-
ful medium ring intermediates. Further studies to test the
`
Dipartimento di Chimica dellЈUniversita di Roma “La Sa-
pienza”,
P.le Aldo Moro 2, IϪ00185 Roma, Italy
Fax: (internat.) ϩ 39-06/490631
E-mail: pellacani@uniroma1.it
Eur. J. Org. Chem. 1999, 2709Ϫ2711
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1111Ϫ2709 $ 17.50ϩ.50/0
2709

M. de Santis, S. Fioravanti, L. Pellacani, P. A. Tardella
SHORT COMMUNICATION
(2R,3R)-3-[(Cyclohex-1-enyl)oxy]butan-2-ol (2a): Yield: 79%. Ϫ [α]
RT
ϭ Ϫ 54.6 (c ϭ 1.30, CH2Cl2). Ϫ IR (CCl4): ν˜ ϭ 3592 cmϪ1
,
D
3408, 1666. Ϫ 1H NMR (CDCl3): δ ϭ 1.14 (d, 3 H, CH3), 1.17 (d,
3 H, CH3), 1.50Ϫ1.75 (m, 4 H, CH2), 1.99Ϫ2.10 (m, 4 H, CH2),
2.52 (d, 1 H, OH), 3.59Ϫ3.72 (m, 1 H, CH), 3.75Ϫ3.88 (m, 1 H,
CH), 4.68 (t, 1 H, HCϭC). Ϫ 13C NMR (CDCl3): δ ϭ 15.43, 18.38
(CH3), 22.59, 22.87, 23.49, 27.96 (CH2), 70.92, 76.36 (CH), 96.29
(HCϭC), 152.54 (HCϭC). Ϫ GC-MS; m/z (%): 170 (11) [Mϩ], 127
(22), 98 (100), 97 (51), 83 (64), 81 (27), 79 (22), 70 (87), 55 (58), 43
(29), 41 (31).
(2R,3R)-3-[(Cyclohex-1-enyl)oxy]-1,4-dimethoxybutan-2-ol
(2b):
RT
Yield: 77%. Ϫ [α]D ϭ Ϫ 22.1 (c ϭ 2.44, CH2Cl2). Ϫ IR (CCl4):
1
ν˜ ϭ 3587 cmϪ1, 3466, 1665. Ϫ H NMR (CDCl3): δ ϭ 1.42Ϫ1.70
(m, 4 H, CH2), 1.95Ϫ2.08 (m, 4 H, CH2), 2.68 (d, 1 H, OH), 3.33
(s, 3 H, OCH3), 3.36 (s, 3 H, OCH3), 3.41Ϫ3.65 (m, 4 H, OCH2),
3.91Ϫ4.01 (m, 1 H, CH), 4.10Ϫ4.19 (m, 1 H, CH), 4.77 (t, 1 H,
HCϭC). Ϫ 13C NMR (CDCl3): δ ϭ 22.40, 22.74, 23.36, 27.67
(CH2), 58.99, 59.19 (OCH3), 69.97, 70.71 (OCH2), 73.19, 73.58
(OCH), 96.56 (HCϭC), 153.05 (HCϭC). Ϫ GC-MS; m/z (%): 230
(<1) [Mϩ], 195 (11), 187 (19), 135 (14), 115 (66), 98 (20), 97 (22),
95 (14), 93 (16), 85 (30), 84 (100), 81 (43), 79 (37), 71 (35), 69 (18),
67 (14), 55 (38), 53 (20), 45 (63), 43 (11), 41 (43).
Azides 3: To a stirred solution of 2 (3 mmol) and anhydrous tribu-
tylamine (3 mmol) in 8 mL of anhydrous CH2Cl2 under an atmos-
phere of argon was added dropwise triphosgene (1 mmol) in 0.7 mL
of anhydrous CH2Cl2 at 0°C. After 1 h of stirring, a solution of
NaN3 (6 mmol) in 10 mL of H2O was added and the reaction was
stirred for 1 h. The mixture was then extracted with CH2Cl2 and
the solvent was evaporated. The azides 3 were purified by flash
chromatography on silica gel (hexane/ethyl acetate, 98:2).
Scheme 2. Photolysis of azidoformates
(1R,2R)-2-[(Cyclohex-1-enyl)oxy]-1-methylpropyl Azidoformate
RT
(3a): Yield: 50%. Ϫ [α]D ϭ ϩ20.5 (c ϭ 1.32, CH2Cl2). Ϫ IR
(CCl4): ν˜ ϭ 2188 cmϪ1, 2135, 1729, 1666. Ϫ 1H NMR (CDCl3):
δ ϭ 1.18 (d, 3 H, CH3), 1.27 (d, 3 H, CH3), 1.45Ϫ1.75 (m, 4 H,
CH2), 1.95Ϫ2.10 (m, 4 H, CH2), 4.15 (m, 1 H, CH), 4.70 (t, 1 H,
HCϭC), 4.71 (m, 1 H, CH). Ϫ 13C NMR (CDCl3): δ ϭ 14.79,
14.93 (CH3), 22.57, 22.84, 23.47, 27.82 (CH2), 71.53, 76.51 (OCH),
95.86 (HCϭC), 152.74 (HCϭC) 157.08 (CϭO). Ϫ GC-MS; m/z
(%): 211 (7) [Mϩ Ϫ 28], 140 (40), 128 (11), 127 (100), 98 (21), 56
(16), 55 (38), 43 (12), 41 (16).
Scheme 3. Hydrolysis of 7a
versatility and to optimize the yields of the cyclization reac-
tion are in progress.
Experimental Section
(1R,2R)-2-[(Cyclohex-1-enyl)oxy]-3-methoxy-1-(methoxymethyl)-
propyl Azidoformate (3b): Yield: 70%. Ϫ [α]D ϭ ϩ7.3 (c ϭ 2.62,
RT
General Methods: GC analyses were performed on an HP 5890
Series II gas chromatograph with a capillary column (methyl sili-
cone, 12.5 m ϫ 0.2 mm). GC-MS measurements were carried out
on an HP G1800A GCD System with a capillary column (phenyl
methyl silicone, 30 m ϫ 0.25 mm). The separations by HPLC were
performed with a Varian 9001 instrument equipped with a Varian
RI-4 differential refractometer. Solvents were HPLC-grade. The ke-
tals 1 and the chiral enol ethers were prepared as previously re-
ported.[2] Ϫ Optical rotations: PerkinϪElmer 241 polarimeter
(10 mm, 1 mL) at room temp. Ϫ IR: PerkinϪElmer 1600 Series
FTIR spectrophotometer. Ϫ NMR: Varian XL-300 and Varian
Gemini 200 solvent CDCl3 and CHCl3 as internal standard.
CH2Cl2). Ϫ IR (CCl4) ν˜ ϭ 2189 cmϪ1, 2134, 1732, 1667. Ϫ 1H
NMR (CDCl3): δ ϭ 1.42Ϫ1.67 (m, 4 H, CH2), 1.96Ϫ2.06 (m, 4 H,
CH2), 3.31 (s, 3 H, OCH3), 3.32 (s, 3 H, OCH3), 3.47 (d, 2 H,
OCH2), 3.55 (d, 2 H, OCH2), 4.20Ϫ4.30 (q, 1 H, CH), 4.76 (t, 1
H, HCϭC), 5.16Ϫ5.23 (q, 1 H, CH). Ϫ 13C NMR (CDCl3): δ ϭ
22.33, 22.66, 23.30, 27.53 (CH2), 58.99, 59.20 (OCH3), 70.07, 70.34
(OCH2), 72.47 (OCH), 76.16 (CHOCO), 96.55 (HCϭC), 153.10
(HCϭC), 157.12 (CϭO). Ϫ GC-MS; m/z (%): 271 (<1) [Mϩ Ϫ 28],
201 (10), 200 (77), 188 (11), 187 (100), 115 (59), 85 (17), 55 (18),
45 (25), 41 (12).
Hydrolysis of Azides 3: When stored in dichloromethane for three
months the azides 3 undergo complete hydrolysis to the hydroxy
azides 4.
Alcohols 2: To a stirred solution of the ketal 1 (5 mmol) and N,N-
diisopropylethylamine (6.5 mmol for 1a and 11.0 mmol for 1b) in
10 mL of anhydrous CH2Cl2 under an atmosphere of argon was
(1R,2R)-2-Hydroxy-1-methylpropyl Azidoformate (4a): Yield: 95%.
added TMSOTf (6.5 mmol for 1a and 10.0 mmol for 1b) dropwise Ϫ IR (CCl4): ν˜ ϭ 3479 cmϪ1, 3613, 2188, 2136, 1733. Ϫ H NMR
1
at 0°C. After 4Ϫ22 h at room temperature, Bu4NF (7.5 mL of 1 
solution in THF) was added, the mixture was stirred for 1 h, and
then petroleum ether was added to precipitate the inorganic salts.
After filtration, the product was purified by flash chromatography
on silica gel (hexane/acetone/triethylamine, 85:14:1).
(CDCl3): δ ϭ 1.16 (d, 3 H, CH3), 1.25 (d, 3 H, CH3), 2.95 (br, 1
H, OH), 3.73 (m, 1 H, CH), 4.69 (m, 1 H, CH). Ϫ 13C NMR
(CDCl3): δ ϭ 15.55, 18.32 (CH3), 69.98, 79.48 (CH), 157.06 (Cϭ
O). Ϫ GC-MS, m/z (%): 113 (50) [Mϩ Ϫ 46], 43 (20), 42 (100),
41 (12).
2710
Eur. J. Org. Chem. 1999, 2709Ϫ2711

Optically Pure 3,6-Dioxazocan-2-one Derivatives
SHORT COMMUNICATION
(1R,2R)-2-Hydroxy-3-methoxy-1-(methoxymethyl)propyl
Azido-
2-{[(1R,2R)-2-Hydroxy-1-methyl(propoxycarbonyl)]amino}-
formate (4b): Yield: 95%. Ϫ IR (CCl4): ν˜ ϭ 3588 cmϪ1, 2190, 2135, cyclohexanone (8): To a solution of BF3·OEt2 (1.3 mL, 10 mmol)
1
1728. Ϫ H NMR (CDCl3): δ ϭ 2.64 (br, 1 H, OH), 3.38 (s, 6 H,
and 1 mL of H2O was added 7a (0.5 mmol) in 10 mL of MeOH at
OCH3), 3.46 (d, 2 H, CH2), 3.65 (d, 2 H, CH2), 3.98 (q, 1 H, CH), room temperature. After 2 h at reflux, 50 mL of a saturated NaCl
5.05 (q, 1 H, CH). Ϫ 13C NMR (CDCl3): δ ϭ 59.26, 59.36 (OCH3), solution was added and the mixture was extracted with ethyl ace-
69.56, 71.32 (CH2), 72.93, 77.05 (CH), 157.14 (CϭO).
tate. The recombined organic layers were washed with saturated
NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated.
Compound 8 was obtained as a single product. Yield: 95%. Ϫ IR
(CCl4): ν˜ ϭ 3620 cmϪ1, 3416, 1733, 1715. Ϫ 1H NMR (CDCl3):
δ ϭ 1.20Ϫ1.26 (m, 6 H, CH3), 1.30Ϫ2.60 (m, 8 H, CH2) 3.73 (br,
1 H, OH), 4.29Ϫ4.35 (m, 2 H, CHCH3, CHN), 4.60Ϫ4.64 (m, 1
H, CHCH3), 5.71 (br, 1 H, NH). Ϫ 13C NMR (CDCl3): δ ϭ 14.11,
16.67 (CH3), 24.03, 27.92, 35.72, 41.05 (CH2), 59.42 (CHNH),
70.47, 76.12 (CHCH3), 156.26 (CO2), 207.27 (CO). Ϫ GC-MS; m/z
(%): 239 (9) [Mϩ], 185 (83), 157 (26), 140 (47), 130 (13), 128 (64),
113 (15), 112 (63), 100 (19), 98 (18), 84 (11), 83 (13), 82 (11), 79
(32), 73 (40), 72 (22), 70 (12), 69 (74), 68 (18), 67 (25), 62 (21), 57
(21), 56 (79), 55 (100), 54 (12), 45 (87), 44 (24), 43 (71), 42 (28),
41 (59).
Photolysis of Azides 3: A solution of the azide (1 mmol) in 20 mL
of anhydrous CH2Cl2 was photolyzed in a quartz vessel under an
argon atmosphere at room temperature, using a medium pressure
Hanovia PCR lamp (100 W). When the azide band had disap-
peared from the IR spectrum (4 h for 3a and 12 h for 3b) the sol-
vent was evaporated in vacuo. The products were separated by flash
chromatography on silica gel (hexane/ethyl acetate, 70:30 for 6a and
7a; 45:55 for 6b and 7b).
(4R,5R)-4,5-Dimethyl-1,3-dioxolan-2-one (6a): Yield: 21%. Ϫ [α]
RT
ϭ ϩ5.3 (c ϭ 1.20, CH2Cl2). Ϫ IR (CCl4): ν˜ ϭ 1824 cmϪ1. Ϫ
D
1H NMR (CDCl3): δ ϭ 1.40Ϫ1.45 (m, 6 H, CH3), 4.25Ϫ4.35 (m,
2 H, CH). Ϫ 13C NMR (CDCl3): δ ϭ 18.38 (CH3), 79.85 (CH),
154.45 (CϭO). Ϫ GC-MS; m/z (%): 116 (1) [Mϩ], 45 (24), 44 (27),
43 (100), 41 (10).
(4R,5R)-4,5-Bis(methoxymethyl)-1,3-dioxolan-2-one (6b): Yield:
40%. Ϫ [α]D ϭ ϩ38.9 (c ϭ 3.16, CH2Cl2). Ϫ IR (CCl4): ν˜ ϭ
Acknowledgments
RT
1823 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 3.40 (s, 6 H, CH3),
3.55Ϫ3.61 (m, 4 H, CH2), 4.61Ϫ4.64 (m, 2 H, CH). Ϫ 13C NMR
(CDCl3): δ ϭ 59.56 (OCH3), 71.34 (OCH2), 76.70 (CH), 155.50
(CϭO). Ϫ GC-MS; m/z (%): 176 (<1) [Mϩ], 45 (100).
`
We thank the Italian Ministero dellЈUniversita e della Ricerca
`
Scientifica e Tecnologica (MURST) and the Universita di Roma
“La Sapienza” (National Project “Stereoselezione in Sintesi Or-
ganica. Metodologie ed Applicazioni”) as well as Consiglio Na-
zionale delle Ricerche (CNR) for financial support, and Prof. Paolo
(5R,6R)-5,6-Dimethyl-4,7-dioxa-2-azabicyclo[6.4.0]dodec-8-en-3-
`
Mencarelli (Universita “La Sapienza”) for the MO calculations.
RT
one (7a): Yield: 21%. Ϫ [α]D ϭ ϩ17.2 (c ϭ 2.00, CH2Cl2). Ϫ IR
(CCl4): ν˜ ϭ 3417 cmϪ1, 1738, 1666. Ϫ 1H NMR (CDCl3): δ ϭ 1.19
(d, 3 H, CH3), 1.36 (d, 3 H, CH3), 1.50Ϫ2.30 (m, 6 H, CH2),
3.35Ϫ3.50 (m, 1 H, CH3CHO), 4.20Ϫ4.60 (m, 3 H, CH3CHOCO,
NH, HCϪN), 5.35 (t, 1 H, HCϭC). Ϫ 13C NMR (CDCl3): δ ϭ
17.26, 17.96 (CH3), 21.17, 23.96, 28.82 (CH2), 50.50 (HCϪN),
81.78, 85.61 (OCH), 113.07 (HCϭC), 155.02 (HCϭC), 161.12 (Cϭ
O). Ϫ GC-MS; m/z (%): 211 (18) [Mϩ], 168 (12), 142 (10), 141 (23),
140 (26), 139 (63), 116 (18), 113 (13), 112 (20), 111 (56), 98 (59),
97 (38), 96 (54), 95 (34), 91 (12), 84 (12), 83 (33), 82 (12), 81 (14),
80 (13), 79 (53), 77 (13), 73 (42), 72 (14), 70 (28), 69 (26), 68 (30),
67 (43), 57 (22), 56 (65), 55 (100), 54 (16), 53 (11), 45 (31).
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RT
L. Pellacani, F. Persia, P. A. Tardella, Tetrahedron Lett.
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S. Fioravanti, L. Pellacani, D.
CH2Cl2). Ϫ IR (CCl4): ν˜ ϭ 3418 cmϪ1, 3268, 1736, 1670. Ϫ 1H
NMR (CDCl3): δ ϭ 1.20Ϫ2.20 (m, 6 H, CH2), 3.36 (s, 6 H, OCH3),
3.50Ϫ3.60 (m, 4 H, OCH2), 3.70Ϫ3.75 (m, 1 H, CHN), 4.27 (br,
1 H, NH), 4.53Ϫ4.56 (m, 1 H, CH2CHO), 4.64Ϫ4.67 (m, 1 H,
CH2CHOCO), 5.42 (t, 1 H, HCϭC). Ϫ 13C NMR (CDCl3): δ ϭ
21.06, 23.87, 28.70 (CH2), 50.32 (CHN), 59.46, 59.76 (OCH3),
71.65, 72.48 (OCH2), 80.70, 83.47 (OCH), 113.62 (HCϭC), 154.90
(HCϭC), 160.42 (CϭO). Ϫ GC-MS; m/z (%): 271 (<1) [Mϩ], 139
(24), 133 (10), 115 (100), 111 (18), 101 (17), 96 (12), 95 (14), 87
(31), 85 (30), 83 (12), 79 (13), 75 (10), 71 (16), 69 (11), 68 (15), 67
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Received June 18, 1999
[O99369]
Eur. J. Org. Chem. 1999, 2709Ϫ2711
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