Stereoselective synthesis of diastereomeric atropisomeric lactam with various ring sizes and their structural characterization

Article abstract of DOI:10.1016/S0040-4039(00)01608-7

Diastereomeric atropisomeric N-ortho-tert-butylphenyl lactams with ring sizes from four to seven were prepared with high diastereoselectivity through an aminocyclization reaction. In the case of four- and five-membered ring formation, thermodynamically stable atropisomeric lactams having a trans-relationship between the ortho-tert-butyl group and the C-4 or C-5 substituent were obtained, while in the six- and seven-membered ring-forming reaction, cis-atropisomeric lactams, kinetic controlled products, were exclusively isolated. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01608-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8539–8544
Stereoselective synthesis of diastereomeric atropisomeric
lactam with various ring sizes and their structural
characterization
Osamu Kitagawa, Masao Fujita, Mitsuteru Kohriyama, Hiroshi Hasegawa and
Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 25 August 2000; accepted 14 September 2000
Abstract
Diastereomeric atropisomeric N-ortho-tert-butylphenyl lactams with ring sizes from four to seven were
prepared with high diastereoselectivity through an aminocyclization reaction. In the case of four- and
five-membered ring formation, thermodynamically stable atropisomeric lactams having a trans-relation-
ship between the ortho-tert-butyl group and the C-4 or C-5 substituent were obtained, while in the six-
and seven-membered ring-forming reaction, cis-atropisomeric lactams, kinetic controlled products, were
exclusively isolated. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: atropisomerism; lactam; isomerization; diastereoselection.
In the course of our work in relation to optically active atropisomeric anilide chemistry,1–3 we
recently reported a diastereoselective reaction using the lithium enolate of optically pure
atropisomeric 5-methoxymethyl-N-ortho-tert-butylphenyl-2-pyrrolidinone trans-2b (Scheme
1).2c,2e,4 In the reactions of the lactam enolate with electrophiles, stereocontrol on the basis of
Scheme 1.
* Corresponding author. Tel and Fax: 81-426-76-3257; e-mail: taguchi@ps.toyaku.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01608-7

8540
CꢀN atropisomerism overcame the usual influence of a chiral carbon (C-5) to preferentially give
3,5-cis-disubstituted-2-pyrrolidinone, which is difficult to obtain through known methodology.5
The optically pure atropisomeric anilide trans-2b having a trans-relationship between the
ortho-tert-butyl group and the C-5 substituent was prepared with a complete stereoselectivity
through an aminocyclization reaction of the mesylate 1b prepared from (S)-5-
(methoxymethyl)butyrolactone and ortho-tert-butylaniline, while the origin of the trans-selectiv-
ity was not clear. In contrast to the complete trans-selectivity in the preparation of the
five-membered lactam, it was found that the six-membered lactam-forming reaction with the
mesylate 1c proceeds with high cis-selectivity (cis/trans=31) (Scheme 2). These contrasting
results prompted us to study the synthesis of diastereomeric atropisomeric lactams with various
ring sizes and their stereochemistries. In this paper, we report a stereoselective synthesis of
diastereomeric atropisomeric N-ortho-tert-butylphenyl lactams with ring sizes from four to
seven and their structural characterization.
Scheme 2.
As mentioned above, the aminocyclization reaction of the mesylate 1c gave cis-6-
methoxymethyl-N-ortho-tert-butylphenyl-2-piperidinone cis-2c with high diastereoselectivity
(cis/trans=31) (Scheme 2).6 The stereochemistry of lactam cis-2c having a cis-relationship
between the ortho-tert-butyl group and the C-6 substituent was determined by X-ray analysis
after conversion to hydroxymethyl derivative cis-3c (Fig. 1). The aminocyclization, which
preferentially formed the cis-2c at rt, should be based on kinetic control, because isomerization
between cis- and trans-2c via the free rotation around the CꢀN bond could hardly be observed
after standing for a week at rt (Scheme 2).
Figure 1. X-ray crystal structure of cis-3c
The isomerization was found to easily occur at 80°C. For example, on heating both
diastereomerically pure cis-2c (30 h) and trans-2c (15 h) at 80°C, each isomer reached the
thermodynamic ratio (cis/trans=1/3.7) (Scheme 2). This result is in contrast to that of a

8541
five-membered lactam which easily and completely isomerizes to trans-2b from cis-2b at rt
(t1/2=ca. 14 h). The higher rotational barrier of 2c (cis-2c: t1/2=602 days at 27°C, rotational
barrier=28.3 kcal/mol)7 than that of 2b could possibly be explained on the basis of the
comparison of the CꢀNꢀC angle obtained by X-ray analysis of trans-2b2c,2e and cis-3c. That is,
the larger C(2)ꢀNꢀC(6) angle (124.1°) of the six-membered lactam cis-3c in comparison with the
C(2)ꢀNꢀC(5) angle (112.7°) of the five-membered lactam trans-2b should result in a higher
barrier of free rotation around the C(Ar)ꢀN bond. It is noteworthy that isomerization to
trans-2c from cis-2c through the formation of a lactam enolate easily occurs even below rt
(Scheme 3).8 Isomerization of the lactam enolate having sp3-nitrogen may occur more easily
than that of lactam cis-2c having sp2-nitrogen, because the tetrahedral structure of nitrogen may
reduce steric repulsion between the tert-butyl group and carbonyl oxygen or the C-6 substituent
during rotation around the CꢀN bond.
Scheme 3.
High cis-selectivity observed in the aminocyclization of 1c may be rationalized on the basis of
the transition-state model shown in Fig. 2. In the six-membered ring chair-type transition-state
model A" and B" having a perpendicular Ar group to the (Z)-potassium iminoalcoholate
plane, a counterclockwise rotation of the iminoalcoholate and Ar moieties may simultaneously
occur with the cyclization. Since the ortho-tert-butyl group is located outside of the six-mem-
bered ring, the counterclockwise rotation should lead to the formation of a lactam having a
b-tert-butyl group and not an a-one. Thus, the reaction through transition-state model A" and
B" gives cis-2c and trans-2c, respectively. From the viewpoint of 1,3-diaxial repulsion, the
reaction via A" having an equatorial methoxymethyl group at the C-6 position should be
preferred more than that via B" having an axial one.
Figure 2. Possible transition state model of aminocyclization of 1c
Although we previously reported that the five-membered lactam-forming reaction (rt, 3 h)
with mesylate 1b exclusively gives trans-2b after extractive work-up and purification by column
chromatography,2c,2e the result of the six-membered lactam-forming reaction prompted us to
1
reinvestigate the reaction of 1b (Scheme 4). When H NMR of the reaction mixture was quickly
measured after aminocyclization of 1b for 30 min at 0°C and subsequent extractive work-up, but
without further purification, cis-2b was found to be formed as a major product (cis-2b/trans-
2b=2.1/1). Under these conditions, starting material 1b was not completely consumed. Further-

8542
more, isomerization of cis-2b to thermodynamically stable trans-2b was observed at rt. This
result indicates that the exclusive formation of trans-2b reported previously should involve the
isomerization of initially formed cis-2b.9 The preferential formation of a trans-five-membered
lactam through isomerization of cis-lactam was also observed in the reaction of mesylate 1e;
that is, a mixture of trans- and cis-2e (trans/cis=1.5), which was obtained by aminocyclization
of 1e for 3 h at rt reached the thermodynamic ratio (trans/cis=20) after standing for several
weeks at rt.10
Scheme 4.
On the basis of these results, it was assumed that aminocyclization leading to the lactam
having a large rotational barrier around the CꢀN bond (large CꢀNꢀC angle) may give a
cis-lactam as a major stereoisomer through kinetic control. On the other hand, for the lactam
having a small rotational barrier (small CꢀNꢀC angle), a trans-lactam may be preferentially
formed through the isomerization of an unstable cis-lactam. To confirm this assumption,
diastereomeric atropisomeric N-ortho-tert-butylphenyl lactams with ring sizes from four to
seven were prepared in accordance with the reaction pathway shown in Scheme 5, and their
stereochemistries were investigated. Four-membered lactam-forming reaction through amino-
cyclization of mesylates 4a and subsequent desilylation gave trans-4-hydroxymethylazetidinone
trans-3a in good yield (71%). Although existence of the cis-isomer could not be detected even
through the enolate formation of 4-methoxymethylazetidinone trans-2a,8 the trans-conformer in
3a could be confirmed by NOE experiment (Scheme 6). In the four-membered lactam, free
rotation around the CꢀN bond may easily occur at rt because of the smaller CꢀNꢀC angle than
that of the five-membered lactam. Contrarily, the seven-membered lactam-forming reaction with
Scheme 5.

8543
mesylate 4d gave cis-lactam cis-3d with complete stereoselectivity at rt, while the chemical yield
is extremely low (Scheme 5). The stereochemistry of lactam cis-3d was determined by X-ray
analysis. Since no isomerization of cis-3d having a large CꢀNꢀC angle (124.2°) similar to that
of six-membered lactam 3c was observed at rt, exclusive formation of cis-3d in aminocyclization
of 4d should be due to kinetic control. Similarly to the preparation of 5- and 6-methoxymethyl
lactams 2b and 2c, five- and six-membered lactam-forming reaction with mesylates 4b and 4c
gave trans-3b and cis-3c with high diastereoselectivity, respectively.
Scheme 6.
In conclusion, we have found that diastereomeric atropisomeric N-ortho-tert-butylphenyll-
actams with various ring sizes can be prepared with high diastereoselectivity. The results
described here should provide useful information on atropisomeric anilide chemistry.
Acknowledgements
We thank the Ministry of Education, Science, Sports and Culture of Japan for financial
support.
References
1. Papers in relation to stereoselective reaction using racemic or achiral atropisomeric anilide: (a) Curran, D. P.; Qi,
H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc. 1994, 116, 3131–3132. (b) Kishikawa, K.; Tsuru, I.;
Kohomoto, S.; Yamamoto, M.; Yamada, K. Chem. Lett. 1994, 1605–1606. (c) Hughes, A. D.; Price, D. A.;
Shishkin, O.; Simpkins, N. S. Tetrahedron Lett. 1996, 37, 7607–7610. (d) Curran, D. P.; Hale, G. R.; Geib, S. J.;
Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron: Asymmetry 1997, 8,
3955–3975. (e) Bach, T.; Schro¨der, J.; Harms, K. Tetrahedron Lett. 1999, 40, 9003–9004.
2. Our papers on optically active atropisomeric anilide chemistry: (a) Kitagawa, O.; Izawa, H.; Taguchi, T.; Shiro,
M. Tetrahedron Lett. 1997, 38, 4447–4450. (b) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.;
Shiro, M. J. Org. Chem. 1998, 63, 2634–2640. (c) Fujita, M.; Kitagawa, O.; Izawa, H.; Dobashi, A.; Fukaya, H.;
Taguchi, T. Tetrahedron Lett. 1999, 40, 1949–1952 (Corrigendum in relation to [h]D of lactam trans-2b: idem.
ibid. 2000, 41, 4997). (d) Kitagawa, O.; Momose, S.; Fushimi, Y.; Taguchi, T. Tetrahedron Lett. 1999, 40,
8827–8831. (e) Fujita, M.; Kitagawa, O.; Yamada, Y.; Izawa, H.; Hasegawa, H.; Taguchi, T. J. Org. Chem. 2000,
65, 1108–1114.
3. Papers on optically active atropisomeric anilide chemistry by other groups: (a) Hughes, A. D.; Simpkins, N. S.
Synlett. 1998, 967–968. (b) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1999,
1295–1304. (c) Kondo, K.; Fujita, H.; Suzuki, T.; Murakami, Y. Tetrahedron Lett. 1999, 40, 5577–5580. (d)
Curran, D. P.; Liu, W.; Chen, C. H. J. Am. Chem. Soc. 1999, 121, 11012–11013. (e) Shimizu, K. D.; Freyer, H.
O.; Adams, R. D. Tetrahedron Lett. 2000, 41, 5431–5434.
4. After publication of our paper (Ref. 2c), Simpkins et al. also reported the asymmetric reaction using optically
active atropisomeric lactam: Godfrey, C. R. A.; Simpkins, N. S.; Walker, M. D. Synlett, 2000, 388–390.

8544
5. For review: Najera, C; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245–2303.
6. The aminocyclization reaction was performed in accordance with our reported procedure (see Refs. 2c and 2e).
1
cis-2c: colorless oil; H NMR (CDCl3) l: 7.53 (1H, dd, J=1.9, 7.9 Hz), 7.24 (2H, m), 7.00 (1H, dd, J=1.9, 7.9
Hz), 3.90 (1H, m), 3.33 (1H, dd, J=8.2, 9.0 Hz), 3.18 (3H, s), 3.16 (1H, dd, J=3.5, 9.0 Hz), 2.39–2.62 (2H, m),
2.20 (1H, m), 2.05 (1H, m), 1.80–1.94 (2H, m), 1.36 (9H, s); 13C NMR (CDCl3) l: 172.7, 147.3, 138.3, 130.1,
1
128.0, 127.3, 127.0, 73.2, 60.8, 58.7, 36.5, 33.6, 32.0, 27.1, 19.6. trans-2c: colorless oil; H NMR (CDCl3) l: 7.54
(1H, dd, J=1.7, 8.0 Hz), 7.24 (2H, m), 6.95 (1H, dd, J=1.6, 8.0 Hz), 3.69 (1H, m), 3.42 (1H, dd, J=6.5, 9.4 Hz),
3.37 (1H, dd, J=3.3, 9.4 Hz), 3.29 (3H, s), 2.59 (1H, m), 2.45 (1H, m), 2.05–2.20 (3H, m), 1.6 (1H, m), 1.36 (9H,
s); 13C NMR (CDCl3) l: 171.7, 146.3, 138.4, 132.6, 129.3, 127.7, 126.2, 72.0, 58.9, 58.6, 35.7, 32.8, 31.7, 25.2,
17.8.
7. Rotational barrier and half-life of cis-2c were calculated from the Eyring equation.
8. The isomerization through the enolate formation has been also observed in five-membered lactam trans-2b (see
Refs. 2c and 2e). Isomerization to thermodynamically unfavorable cis-2b from stable trans-2b partially occurred
through the formation of the lithium enolate and subsequent protonation to give a mixture of cis- and trans-2b
in a ratio of 1: 2.6.
9. Isomerization to a stable diastereomer through the rotation of the atropisomeric axis has also been found in
diastereomeric atropisomeric naphthamide derivative. Clayden, J.; Lai, L. W. Angew. Chem., Int. Ed. 1999, 38,
2556–2558.
10. The decrease in the chemical yield in the reaction of 1e is due to the formation of O-cyclized products as a side
product.
.