1,7-asymmetric induction in a nitrogen ring expansion process facilitated by in situ tethering

Article abstract of DOI:10.1021/ol990685b

(formula presented) There are only a few methods for the asymmetric ring expansion of prochiral ketones. Symmetrically substituted cyclohexanones can be converted to the corresponding ring-expanded caprolactam with excellent 1,7-diastereoselectivity (≥93%

Full text of DOI:10.1021/ol990685b

ORGANIC
LETTERS
1999
Vol. 1, No. 3
495-497
1,7-Asymmetric Induction in a Nitrogen
Ring Expansion Process Facilitated by
in Situ Tethering
Kelly Furness and Jeffrey Aube´*
Department of Medicinal Chemistry, UniVersity of Kansas,
Lawrence, Kansas 66045-2506
jaube@ukans.edu
Received May 23, 1999
ABSTRACT
There are only a few methods for the asymmetric ring expansion of prochiral ketones. Symmetrically substituted cyclohexanones can be
converted to the corresponding ring-expanded caprolactam with excellent 1,7-diastereoselectivity (g93% ds) and yields (g86%), using a
chiral hydroxy azide-mediated Schmidt reaction.
Synthetically important ring-expansion reactions include
those that add the elements of carbon, oxygen, or nitrogen
to an existing carbocyclic unit. To date, only a few such
reactions have addressed the issues of asymmetric induction
or remote regiochemical control. Most of this work has
concentrated on biochemically mediated Baeyer-Villiger
reactions,1 although some progress has been recorded on
nonbiological ring expansions leading to lactams,2 lactones,3
and carbocycles.4 Our own interest in nitrogen-insertion
reactions has largely dealt with enabling modes of stereo-
selectivity unavailable to traditional routes such as the
Beckman or Schmidt reactions.5 This work, which resulted
in the first nonresolving method for the group-selective
conversion of ketones to chiral lactams, used a three-pot
protocol that featured the stereoselective photochemical
rearrangement of oxaziridines as first described by Lattes et
al.6 Overall, the selectivities obtained in this scheme topped
out at ca. 7:1 (88% diastereoselectivity (ds)), although
enantiomerically pure lactams could be obtained by separat-
ing the diastereomerically pure N-substituted lactams prior
to removing the chiral group on nitrogen.
(1) (a) Ouazzani-Chadhi, J.; Buisson, D.; Azerad, R. Tetrahedron Lett.
1987, 28, 1109-1112. (b) Taschner, M. J.; Black, D. J. J. Am. Chem. Soc.
1988, 110, 6892-6893. (c) Alphand, V.; Archelas, A.; Furstoss, R.
Tetrahedron Lett. 1989, 30, 3663-3664. (d) Alphand, V.; Archelas, A.;
Furstoss, R. J. Org. Chem. 1990, 55, 437-350. (e) Taschner, M. J.; Chen,
Q.-Z. Bioorg. Med. Chem. Lett. 1991, 1, 535-538. (f) Taschner, M. J.;
Black, D. J.; Chen, Q.-Z. Tetrahedron: Asymmetry 1993, 4, 1387-1390.
(g) Kelly, D. R.; Knowles, C. J.; Mahdi, J.; Taylor, I. N.; Wright, M. A. J.
Chem. Soc., Chem. Commun. 1995, 729-730. (h) Adger, B.; Bes, M. T.;
Grogan, G.; McCague, R.; Pedragosa-Moreau, S.; Roberts, S. M.; Villa,
R.; Wan, P. W. H.; Willetts, A. J. J. Chem. Soc., Chem. Commun. 1995,
1563-1654. (i) Lebreton, J.; Alphand, V.; Furstoss, R. Tetrahedron Lett.
1996, 37, 1011-1014. (j) Lopp, M.; Paju, A.; Kanger, T.; Pehk, T.
Tetrahedron Lett. 1996, 37, 7583-7586. (k) Mazzini, C.; Lebreton, J.;
Alphand, V.; Furtoss, R. Tetrahedron Lett. 1997, 38, 1195-1196. (l) Bolm,
C.; Luong, T. K. K.; Schlingloff, G. Synlett 1997, 1151-1152. (m) Stewart,
J. D.; Reed, K. W.; Zhu, J.; Chen, G.; Kayser, M. M. J. Org. Chem. 1996,
61, 7652-7653. (n) Stewart, J. D.; Reed, K. W.; Martinez, C. A.; Zhu, J.;
Chen, G.; Kayser, M. M. J. Am. Chem. Soc. 1998, 120, 3541-3548. (o)
Kayser, M. M.; Chen, G.; Stewart, J. D. J. Org. Chem. 1998, 63, 7103-
7106.
(3) (a) Bolm, C.; Schlingloff, G.; Weickhardt, K. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1848-1849. (b) Bolm, C.; Luong, T. K. K.; Schlingloff,
G. Synlett 1997, 1151-1152.
(4) (a) Nemoto, H.; Ishibashi, H.; Magamochi, M.; Fukumoto, K. J. Org.
Chem. 1992, 57, 1707-1712. (b) Nemoto, H.; Nagamochi, M.; Ishibashi,
H.; Fukumoto, K. J. Org. Chem. 1994, 59, 74-79. (c) Nemoto, H.; Tanabe,
T.; Fukumoto, K. Tetrahedron Lett. 1994, 35, 6499-6502. (d) Nemoto,
H.; Tanabe, T.; Fukimoto, K. J. Org. Chem. 1995, 60, 6785-6790.
(5) Aube´, J. Chem. Soc. ReV. 1997, 26, 269-277.
(6) (a) Lattes, A.; Oliveros, E.; Rivie`re, M.; Belzecki, C.; Mostowicz,
D.; Abramskj, W.; Piccinni-Leopardi, C.; Germain, G.; Van Meerssche,
M. J. Am. Chem. Soc. 1982, 104, 3929-3934. (b) Aube´, J.; Burgett, P. M.;
Wang, Y. Tetrahedron Lett. 1988, 29, 151-154. (c) Aube´, J.; Wang, Y.;
Hammond, M.; Tanol, M.; Takusagawa, F.; Vander Velde, D. J. Am. Chem.
Soc. 1990, 112, 4879-4891. (d) Aube´, J.; Hammond, M.; Gherardini, E.;
Takusagawa, F. J. Org. Chem. 1991, 56, 499-508; 4086 (correction). (e)
Aube´, J.; Wang, Y.; Ghosh, S.; Langhans, K. L. Synth. Commun. 1991, 21,
693-701.
(2) (a) Lyle, R. E.; Lyle, G. G. J. Org. Chem. 1959, 24, 1679-1684. (b)
Lyle, G. G.; Pelosi, E. T. J. Am. Chem. Soc. 1966, 88, 5276-5279. (c)
Toda, F.; Akai, H. J. Org. Chem. 1990, 55, 4973-4974.
10.1021/ol990685b CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/08/1999

More recently, this laboratory has been exploring the
utilization of 1,2- and 1,3-hydroxy azides as nitrogen ring-
expansion reagents.7 This technique allows for the high-yield
synthesis of N-substituted lactams from ketones in a one-
pot, two-reaction protocol. The key reaction is enabled by
the initial formation of a hemiketal, dehydration to an
oxonium ion, intramolecular attack by the now-attached azido
group, and rearrangement along with the loss of nitrogen
(Scheme 1). Notably, the intermolecular reaction of simple
The use of chiral hydroxy azides would permit the
extension of this chemistry to the synthesis of chiral lactams
in enantiomerically pure form. A few such examples were
noted in the original disclosure; thus, 2-phenyl-2-azidoethanol
combined with 4-tert-butylcyclohexanone to afford lactam
having ds ) ca. 88%.7 Still more promising results (90%
yield, 97.5% ds) were obtained when a single example of a
chiral 1,3-azido alcohol was used with the same substrate,
but the particular reagent used ((2S,4R)-2-azido-4-hydroxy-
pentane) was expensive to prepare. We now wish to present
a 1,3-hydroxy azide that is trivially obtained from a com-
mercially available chiral starting material, gives superior
reactions over the previously published examples (with
respect to rate, yield, and selectivity), and leads to a
remarkable level of 1,7-diastereomeric control in lactam
formation.
Scheme 1
As shown in Scheme 2, (R)-3-chloro-1-phenylpropanol
reacts with sodium azide to provide azide 1 in excellent yield
and g99% ee (HPLC; Chiracel OD-H). BF3‚OEt2 was added
to a mixture of 1 and 4-methylcyclohexanone in CH2Cl2 at
Scheme 2
(non-hydroxy) azides fails under the same conditions.8 A
hydrolytic workup then releases a lactam identical to that
which would have resulted from direct reaction of the azide
portion of the molecule. This procedure is described as “in
situ tethering” because the carbon-oxygen linkage is formed
and released without additional synthetic operations.
(7) (a) Gracias, V.; Milligan, G. L.; Aube´, J. J. Am. Chem. Soc. 1995,
117, 8047-8048. (b) Gracias, V.; Milligan, G. L.; Aube´, J. J. Org. Chem.
1996, 61, 10-11. (c) Gracias, V.; Frank, K. E.; Milligan, G. L.; Aube´, J.
Tetrahedron 1997, 53, 16241-16252. (d) For an application of this
methodology to an attempted alkaloid synthesis, see: Vidari, G.; Tripolini,
M.; Novella, P.; Allegraucci, P.; Garlaschelli, L. Tetrahedron: Asymmetry
1997, 8, 2893-2903.
-82 °C, and the reaction allowed to warm to room
temperature. Hydrolysis of the resulting iminium ether with
KOH afforded a mixture of lactams 3a/4a in 98% yield and
93% ds (HPLC). In contrast, the corresponding reaction of
4-methylcyclohexanone with 2-phenyl-2-azidoethanol in ca.
20:1 cyclohexanone/CH2Cl2 proceeded only in 74% ds (81%
yield) and required temperatures of about -5 °C for
satisfactory conversions (reaction not shown).9 A survey of
reactions of 1 with a variety of substituted ketones shows
that excellent selectivity is preserved for substituted cyclo-
hexanones but that there is room for improvement with four-
(8) Aube´, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem. 1992, 57,
1635-1637.
(9) Representative Procedure. A solution of (R)-3-azido-1-phenylpro-
panol (205 mg, 1.15 mmol) and 4-methylcyclohexanone (188 mg, 1.68
mmol) in 3 mL of CH2Cl2 was cooled to -82 °C (ether/dry ice bath), and
BF3‚OEt2 (0.56 mL, 4.48 mmol) was added dropwise. The reaction was
allowed to come to room temperature over a period of 48 h. The resulting
crude iminium ether was diluted with Et2O (5 mL) and hydrolyzed with
50% KOH (1 mL) added dropwise over 5 min. The solution was stirred for
30 min and partitioned between CH2Cl2 (20 mL) and H2O (10 mL). The
layers were separated, and the water layer was extracted with CH2Cl2 (2 ×
10 mL). The combined organic layers were washed with NH4Cl (5 mL),
dried (MgSO4), filtered, and concentrated. HPLC analysis of the crude
reaction mixture showed a 93:7 ratio of diastereomeric lactams. Flash
chromatography (1:1 f 9:1 EtOAc/MeOH) gave 3a and 4a as transparent
oils in a combined yield of 296 mg (98%). TLC (1:1 hexane/EtOAc): Rf(3a)
) 0.15, Rf(4a) ) 0.20; HPLC tR major (3a) ) 19.9 min, tR minor (4a) )
18.2 min (Chirobotic T; 90% hexane/EtOH; flow rate 1 mL/min; UV 254
nm). Major diastereomer (3a): [R]D ) -4.2 (c 1.02, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 0.99 (d, J ) 6.6, 3H), 1.12-1.31 (m, 3H), 1.62-
1.75 (m, 1H), 1.76-1.98 (m, 4H), 2.42-2.61 (m, 2H), 3.12 (dt, J ) 14.2,
4.4 Hz, 1H), 3.24 (dd, J ) 6.5, 15.2 Hz, 1H), 3.51 (dd, J ) 10.9, 15.2 Hz,
1H), 4.09-4.19 (m, 1H), 4.62 (m, 1H), 7.21-7.28 (m, 1H), 7.31-7.39 (m,
4H); 13C NMR (100.6 MHz, CDCl3) δ 22.6, 31.4, 35.7, 36.1, 37.2, 37.7,
45.7, 49.3, 69.8, 125.5, 127.0, 128.3, 144.1, 177.1; MS (EI) m/e 262 (M+
+ 1), 244(100); HRMS m/e calcd for C16H24NO2 (M+ + 1) 262.1807, found
(M+ + 1) 262.1798. Minor diastereomer (4a): 1H NMR (400 MHz, CDCl3)
δ 0.97 (d, J ) 6.5 Hz, 3H), 1.18-1.30 (m, 2H), 1.65-1.95 (m, 5H), 2.50-
2.56 (m, 2H), 3.01 (m, 1H), 3.32 (dd, J ) 15.1, 5.9 Hz, 1H), 3.47 (J )
15.1, 11.0 Hz, 1H), 4.10-4.25 (m, 1H), 4.53 (br d, J ) 10.4 Hz, 1H),
4.75-4.85 (m, 1H), 7.21-7.29 (m, 1H), 7.29-7.39 (m, 4H); 13C NMR
(100.6 MHz, CDCl3) δ 22.6, 31.3, 35.7, 35.8, 36.3, 37.5, 44.9, 48.4, 69.6,
125.7, 127.0, 128.2, 144.1, 177.2; MS (EI) m/e 262 (M+ + 1), 244; HRMS
m/e calcd for C16H24NO2 (M+ + 1) 262.1807, found (M+ + 1) 262.1797.
496
Org. Lett., Vol. 1, No. 3, 1999

or five-membered rings (Table 1). In most cases, an
enantioselective lactam synthesis is effected by this process.
However, the conversion of (R)-3-methylcyclohexanone to
the corresponding 4-methylcaprolactam (Table, entry 5) is
a relatively rare example of oVerall regiochemical control
as effected by an locally enantioselectiVe process.6,10
Scheme 3
Table 1. Reactions of (R)-3-Azido-1-phenylpropanol (1) with
Ketones
approaches the substituted cyclohexane ring from an equato-
rial direction (presuming that the 4-substituent is also
equatorially aligned). (2) The phenyl group of the hydroxy
azide chain also adopts a pseudoequatorial position. (3) The
reaction proceeds by C f N migration occurring antiperipla-
nar to a pseudoaxial N2+ leaving group to afford the iminium
ether shown. Antiperiplanar migration has long been pre-
sumed to be a feature of such bond migrations12 and has
recently been experimentally supported in the Baeyer-
Villiger reaction as well.13 (4) Hydroxide ion attack at
position a (Scheme 3) leads to the observed product 3c. At
this point, events 2-4 are either on firm theoretical ground
or have been experimentally verified, whereas the equatorial
attack of the azide upon the oxonium ion (event 1 above) is
proposed on the basis of the observed stereochemical course
of the reaction. Further experiments to support this mecha-
nism are currently planned.
There are several noteworthy features of this protocol. The
enhanced selectivity related to previously reported versions
of this reaction are undoubtedly due to the greater reactivity
of this alkyl azide due to a combination of its 1,3-relationship
to the hydroxyl group and the fact that the azido group itself
is primary and not secondary. The overall course of the
reaction allows the control of two stereogenic centers having
a 1,7 relationship to one another; this is made possible by
the intermediacy of the spiro species depicted in Scheme 3.
The structures of the major isomers obtained from the
reactions in entries 1, 3, and 5 were proven by removal of
the nitrogen substituent by PCC oxidation, â-elimination with
NaH (ca. 62% overall yield), and comparison of specific
rotations with known lactams6 (Scheme 3). In addition, the
structure of compound 3c was directly determined by X-ray
crystallographic analysis (see Supporting Information). This
precaution was required to ensure that the hydrolysis of the
iminium ether intermediate did not effect inversion at the
benzylic stereocenter. The other products resulting from
cyclohexanone-derived ketones were assigned by analogy.
From this information, we propose that the observed stereo-
chemistry results from the following sequence of events
(Scheme 3).11 (1) The temporarily tethered alkyl azide group
Acknowledgment. We thank the National Institutes of
Health for support of this work (GM-49093) and Lawrence
Seib for the X-ray crystallographic determination.
(10) Aube´, J.; Hammond, M. Tetrahedron Lett. 1990, 31, 2963-2966.
(11) The transition structure given in ref 7b was incorrectly drawn (the
stereocenters on the side chain were inadvertently inverted relative to the
starting materials and product); it should have also indicated equatorial
attack.
(12) Smith, P. A. S. In Molecular Rearrangements; de Mayo, P., Ed.;
John Wiley & Sons: New York, 1963; Vol. 1, pp 457-591.
(13) (a) Chandreasekhar, S.; Deo Roy, C. Tetrahedron Lett. 1987, 28,
6371-6372. (b) Goodman, R. M.; Kishi, Y. J. Am. Chem. Soc. 1998, 120,
9392-9393.
Supporting Information Available: Details of X-ray
crystallographic determination of 3c. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL990685B
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