Synthesis of chiral γ-lactams via Rh(II) catalyzed intramolecular C-H insertion: α-substituents and conformational effects

Article abstract of DOI:10.1016/j.tetlet.2004.10.159

Highly functionalized chiral γ-lactams are efficiently synthesized via Rh(II) catalyzed intramolecular C-H insertion from various α-diazoamides. Independent of α-substituents, regio- and stereoselectivities are enhanced through a conformational effect exerted by a bicyclic transition state.

Full text of DOI:10.1016/j.tetlet.2004.10.159

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 143–146
Synthesis of chiral c-lactams via Rh(II) catalyzed intramolecular
C–H insertion: a-substituents and conformational effects
David L. Flanigan, Cheol Hwan Yoon* and Kyung Woon Jung*
Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA
Received 21 September 2004; revised 22 October 2004; accepted 29 October 2004
Available online 21 November 2004
Abstract—Highly functionalized chiral c-lactams are efficiently synthesized via Rh(II) catalyzed intramolecular C–H insertion from
various a-diazoamides. Independent of a-substituents, regio- and stereoselectivities are enhanced through a conformational effect
exerted by a bicyclic transition state.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Rhodium catalyzed intramolecular C–H insertion of
various diazo compounds has been used for the con-
struction of carbocyclic and heterocyclic compounds.1
Usually, the cyclization exhibits a preference for the for-
mation of five-membered rings2 except in the case of cyc-
lization of diazoamides,3 which afford b-, c-lactams, and
stereoisomers depending on the nature of the substrates
examined and rhodium catalyst ligands utilized.4
the efficiency of this methodology in the formation of
c-lactams.
Encouraged by these results we adapted this methodol-
ogy to facilitate the use of a-amino acids.7 Various chi-
ral c-lactams were obtained from a-amino acids derived
a-diazo-a-(phenylsulfonyl)-acetamides via intramolecu-
lar C–H insertion (Scheme 2).8 The cyclizations were
highly regio- and stereoselective affording functionalized
chiral c-lactam motifs in high yields. The gem-dimethyl
moiety forces the diazo-intermediate to adopt an s-cis
conformation, which is the only conformation suitable
for C–H insertion. In the absence of the gem-dimethyl
moiety, the unfavorable s-trans conformer is predomi-
nant and C–H insertion does not occur.9 Based on these
results, conformational factors rather than a-substitu-
ents play a key role in the insertion of the rigid cyclic
system. This prompts our study of a-substituent effects
Recently, we reported rhodium catalyzed intramolecular
C–H insertion of a-diazo-a-(phenylsulfonyl)-acetamides
to afford c-lactams with high regio- and stereoselectiv-
ity.5 The success of this methodology was governed by
the a-phenylsulfonyl moiety, which presumably stabi-
lized the electrophilic carbenoid carbon during the cycli-
zation, resulting in the selective formation of c-lactam
via a relatively late transition state.5a,6 Scheme 1 shows
O
O
R
O
O
t
R
Bu
R
t
t
N
Bu
Bu
R
4
+
+
N
Rh (OAc)
N
N
O
2
N
O
t
2
Bu
NH
N
H
2
PhSO
Rh(II)
2
Ph
O
Ph
PhSO
Ph
N
2
O
CO H
64-97%
2
N
2
R
yield
85%
94%
95%
products
R
R
a
:
:
:
:
:
:
H
32
49
0
51
0
68
0
α-Amino acids
R
b
MeCO
PhSO
100
0
O
R
2
R
O
O
PhSO
2
O
a
b
PhSO
2
N
reference 3(a); reference 3(e)
N
N
O
Rh
H
R
Rh
Rh
O
Scheme 1.
PhSO
H
2
s-trans
chair-like transition state
s-cis
*
Corresponding authors. Tel.: +1 813 974 7306; fax: +1 813 974
0640; e-mail: kjung@shell.cas.usf.edu
Scheme 2.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.159

144
D. L. Flanigan et al. / Tetrahedron Letters 46 (2005) 143–146
on the regio- and stereoselectivities of C–H insertion of
a-diazoamides.
The diazoamides 3–6 used in this study were prepared
from (L)-phenylalanine (1) as shown in Scheme 3. Acyl-
ation of N,O-acetal 2 with bromoacetyl bromide and
TEA in dichloromethane at 0ꢁC, followed by treatment
with sodium benzenesulfinate in DMF at room temper-
ature afforded the a-(phenylsulfonyl)-acetamide. Subse-
quent diazo transfer using p-acetamidobenzenesulfonyl
azide (p-ABSA) and DBU yielded a-diazo-a-(phenyl-
sulfonyl)-acetamide 3. Reaction of 2 with ethyl malonyl
chloride and TEA in dichloromethane gave ethyl malo-
nyl amide, which was subjected to diazo transfer reac-
tion affording a-(carboethoxy)-a-diazoacetamide 4.
Treatment of 2 with diketene in the presence of a cata-
lytic amount of DMAP followed by p-ABSA afforded
a-diazo-a-acetoacetamide 5, which was converted to a-
diazoacetamide 6 via deacetylation under aqueous basic
conditions.
Figure 1. Crystal structure of 10.
O
O
O
R
R
Rh (OAc)
2
4
N
H
N
N
H
+
O
R
O
O
CH Cl
2
2
N
2
reflux
Ph
Ph
reactant
Exposure of diazo-intermediates 3, 4, and 5 to C–H
insertion conditions yielded the corresponding chiral c-
lactams 7,10 8, and 911 with complete regio- and stereose-
lectivities in high yields.12 In the case of 6, however, the
electrophilicity of the carbenoid center is higher than
those of 3, 4, and 5. As a consequence, the preferred reac-
tion pathway is cyclopropanation of the phenyl ring
followed by ring expansion to give the aromatic cycload-
dition product 10 albeit with high yield and excellent
stereoselectivity.3a,d The structure of 10 was con-
firmed by X-ray crystallographic analysis13 as shown in
Figure 1.
yield
product
3 (R = PhSO )
-
-
-
91%
95%
93%
84%
7
2
4 (R = EtO C)
8
9
-
2
5 (R = MeCO)
6 (R = H)
10
Scheme 4.
acid norvaline, which possesses an n-propyl alkyl group.
The synthetic route to the diazo-intermediates of norv-
aline mirrors that of the phenylalanine sequence in
Scheme 3. C–H insertion of the diazo-intermediates
11, 12, and 13 proceeded smoothly furnishing only c-lac-
tams 15, 16, and 17,11 respectively, in high yields
(Scheme 5). Although the potential exists to form b-
and d-lactams, no such products were observed. Reac-
tion of 14 formed a 1:2 mixture of c- and d-lactam,
which can be also explained by the highly reactive carb-
enoid center resulting in decreased selectivity for the
reaction.
In contrast to previous results (Scheme 1), excellent
selectivities were achieved regardless of the a-substitu-
ents used, thus highlighting the conformational effect
that the rigid cyclic system exerts on this transforma-
tion. An increased degree of conformational constraint
is experienced as opposed to the flexible acyclic system
(Scheme 4).
We then focused on studying the regioselectivity of the
methodology on substrates with varied a-substituents
in the presence of multiple C–H activation sites. Our
model substrate was changed to the unnatural a-amino
We also explored an alternate cyclic system to study the
versatility of this methodology. We endeavored to install
an amide function to replace the hydroxyl resulting from
reduction (Scheme 6). The variation was made possible
by substitution of the amino acid methyl ester with
methylamine producing the N-methylaminoamide,
which was then subjected to the acetonide formation
providing the N,N-acetonide 20 almost quantitatively.14
O
NH
2
HN
PhO S
2
a, b
c, d, e
71%
O
N
CO H
O
2
83%
N
2
Ph
Ph
2
1
3
Ph
O
O
O
O
N
O
R
R
Rh (OAc)
2
4
N
H
N
N
H
R
+
O
EtO C
2
R
O
O
CH Cl
N
2
2
N
2
O
f, e
85%
g, e
82%
O
Me
reflux
N
2
N
Et
2
Ph
Ph
4
reactant
yield
product
5 (R = MeCO)
6 (R = H)
h
11 (R = PhSO )
12 (R = MeO C)
-
-
-
91%
90%
93%
84%
15
16
17
18
2
2
Scheme 3. Reagents: (a) LAH, THF; (b) acetone, Na2SO4; (c)
BrCH2COBr, TEA, CH2Cl2; (d) PhSO2Na, DMF; (e) p-ABSA,
DBU, CH3CN; (f) EtO2CCH2COCl, TEA, CH2Cl2; (g) diketene, cat
DMAP, THF; (h) LiOH, aq CH3CN.
13 (R = MeCO)
14 (R = H)
(1:2)
19
Scheme 5.

D. L. Flanigan et al. / Tetrahedron Letters 46 (2005) 143–146
145
O
References and notes
R
NH
2
HN
N
a, b, c
NMe
NMe
1. (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience: New York, 1998; (b)
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003,
103, 861, See also references cited therein.
N
CO H
2
2
O
Ph
Ph
O
Ph
1
20
21 (R = PhSO )
2
22 (R = MeO C)
2
23 (R = MeCO)
2. (a) Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem. Soc.
1986, 108, 7686; (b) Doyle, M. P.; Westrum, L. J.;
Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bageri, V.;
Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958; (c)
Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem.
Soc. 1996, 118, 547; (d) Taber, D. F.; Malcolm, S. C. J.
Org. Chem. 1998, 63, 3717.
Scheme 6. Reagents: (a) SOCl2, MeOH; (b) MeNH2, MeOH; (c)
acetone, DMF.
O
O
R
3. For the synthesis of lactams by intramolecular C–H
insertion, see: (a) Doyle, M. P.; Shanklin, M. S.; Pho, H.
Q. Tetrahedron Lett. 1988, 29, 2639; (b) Doyle, M. P.;
Taunton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397;
(c) Doyle, M. P.; Pieters, R. J.; Taunton, J.; Pho, H. Q. J.
Org. Chem. 1991, 56, 820; (d) Wee, A. G. H.; Liu, B.;
Zhang, L. J. Org. Chem. 1992, 57, 4404; (e) Padwa, A. P.;
Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am.
Chem. Soc. 1993, 115, 8669; (f) Wee, A. G. H.; Slobodian,
J. J. Org. Chem. 1996, 61, 2897; (g) Doyle, M. P.; Kalinin,
A. V. Tetrahedron Lett. 1996, 37, 1371; (h) Hashimoto,
S.-I.; Anada, M. Tetrahedron Lett. 1998, 39, 79; (i) Wee,
A. G. H.; Liu, B.; McLeod, D. D. J. Org. Chem. 1998, 63,
4218; (j) Moody, C. J.; Miah, S.; Slawin, A. M. Z.;
Mansfield, D. J.; Richards, I. C. Tetrahedron 1998, 54,
9689; (k) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org.
Chem. 2003, 3798.
4. (a) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1797; (b) Gois, P. M. P.; Afonso, A. M. Eur. J.
Org. Chem. 2004, 3773.
5. (a) Yoon, C. H.; Zaworotko, M. J.; Moulton, B.; Jung, K.
W. Org. Lett. 2001, 3, 3539; (b) Yoon, C. H.; Nagle, A.;
Chen, C.; Gandhi, D.; Jung, K. W. Org. Lett. 2003, 5,
2259.
6. Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56,
4871.
7. Yoon, C. H.; Flanigan, D. L.; Chong, B.-D.; Jung, K. W.
J. Org. Chem. 2002, 67, 6582.
N
H
Rh (OAc)
2
N
4
NMe
R
NMe
N
2
benzene
reflux
Ph
O
O
Ph
product
24
reactant
21 (R = PhSO )
yield
93%
97%
2
22 (R = MeO C)
25
2
23 (R = MeCO)
99%
26
Scheme 7.
This substrate could then be converted to 21, 22, and 23
by following the same procedures shown in Scheme 3.
To our satisfaction, intramolecular C–H insertion of 21,
22, and 23 occurred readily under refluxing benzene con-
ditions and produced the corresponding c-lactams 24,
25, and 26 with improved yields and excellent stereose-
lectivity (Scheme 7). We attribute this improvement in
yield to the increased rigidity of the N,N-acetonide. In
this case, the diazo-intermediates possess an sp2 center
at the carbonyl as opposed to the sp3 center present in
the N,O-acetonide system. The conformation of the
Rh-carbenoid is likely more restricted resulting in great-
er efficiency of the C–H insertion.
We have described an efficient and versatile method of
synthesizing chiral c-lactams from a-diazoamides con-
taining various a-substituents via a rigid bicyclic transi-
tion state. The Ôconformational lockÕ exerted by the
gem-dimethyl moiety affords the high regio- and stereo-
selectivities. This methodology can be applied to chiral
natural and unnatural a-amino acids with various a-
substituents to yield highly functionalized heterocycles,
which can be tailor made for use in any application.
8. For the C–H insertion of a-diazoamides derived from a-
amino acids, see: (a) Zaragoza, F.; Zahn, G. J. Prakt.
Chem. 1995, 292; (b) Ref. 3g; (c) Anada, M.; Sugimoto, T.;
Watanabe, N.; Nakajima, M.; Hashimoto, S.-I. Hetero-
cycles 1999, 50, 969.
9. (a) For a conformational study of N-acyloxazolidines, see:
Porter, N. A.; Bruhnke, J. D.; Wu, W.-X.; Rosenstein, I.
J.; Beryer, R. A. J. Am. Chem. Soc. 1991, 113, 7788; (b)
Kanemasa, S.; Onimura, K. Tetrahedron 1992, 48, 8631.
10. The structure of 7 was confirmed by X-ray crystallo-
graphic analysis; see Ref. 5a.
11. Hashimoto reported that C–H insertion of a-diazo-a-
acetoacetamide I, the analog of 5 and 13, afforded a trans-
c-lactam II in 84% yield. see Ref. 8c.
Acknowledgements
The authors acknowledge generous financial support
from the National Institutes of Health (RO1 GM
62767). We also thank Dr. M. J. Zaworotko for X-ray
analysis.
O
O
O
O
N
H
Rh (OAc)
2
4
O
N
O
CH Cl
2
2
N
2
84%
I
II
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2004.10.159.
12. General procedure for C–H insertion reactions:
Rh2(OAc)4 (11mg, 2.5mol%) was added to a solution of
an diazoamide compound (1mmol) in dry CH2Cl2 (20mL,

146
D. L. Flanigan et al. / Tetrahedron Letters 46 (2005) 143–146
0.05M). The mixture was refluxed for 12h under N2,
k <= 11, À15 <= l <= 13; Reflections collected: 5844;
Independent reflections: 2161 [R(int) = 0.0283]; Complete-
ness to theta = 24.98ꢁ, 99.8%; Absorption correction:
None; Max. and min. transmission: 1.00 and 0.81;
refinement method: full-matrix least-squares on F2; data/
restraints/parameters: 2161/0/156; Goodness-of-fit on F2:
cooled to room temperature, and concentrated. The
residue was chromatographed to give a lactam compound.
13. Empirical formula: C14H17NO2; formula weight: 231.29;
˚
temperature: 200(2)K; wavelength: 0.71073A; crystal
system: orthorhombic; space group: P2(1)2(1)2(1); unit
˚
cell dimensions: a = 8.3667(19)A, a = 90ꢁ, b = 11.572(3)
1.052; final
wR2 = 0.0778:
R
indices [I > 2sigma(I)]: R1 = 0.0338,
R indices (all data): R1 = 0.0392,
wR2 = 0.0806; largest diff. peak and hole: 0.221 and
3
˚
˚
˚
A, b = 90ꢁ, c = 12.824(3)A, c = 90ꢁ; volume: 1241.6(5)A ;
Z: 4; density (calculated): 1.237Mg/m3; absorption coef-
ficient: 0.083mmÀ1
;
F(000): 496; crystal size:
À0.261eA
.
À3
˚
0.80 · 0.20 · 0.10mm3; theta range for data collection:
2.37ꢁ–24.98ꢁ; index ranges: À9 <= h <= 9, À13 <=
14. Solodin, I.; Goldberg, Y.; Zelcans, G.; Lukevics, E. J.
Chem. Soc., Chem. Commun. 1990, 1321.
ˆ