Di- and trisubstituted γ-lactams via Rh(II)-carbenoid reaction of N -Cα-branched, N -Bis(trimethylsilyl)methyl α-diazoamides. Synthesis of (±)-α-allokainic acid

Article abstract of DOI:10.1021/ol1021564

Acyclic N-C_α-branched, N-bis(trimethylsilyl)methyl (N-BTMSM) diazoamides undergo regio-, chemo-, and diastereoselective Rh(II)-carbenoid C-H insertion to give 4,5-disubstituted and 3,4,5-trisubstituted γ-lactams. The conformational influence of

Full text of DOI:10.1021/ol1021564

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5386-5389
Di- and Trisubstituted γ-Lactams via
Rh(II)-carbenoid Reaction of
N-Cr-Branched, N-Bis(trimethylsilyl)methyl
r-Diazoamides. Synthesis of
(()-r-Allokainic Acid
Bao Zhang and Andrew G. H. Wee*
Department of Chemistry and Biochemistry, UniVersity of Regina, Regina,
Saskatchewan, Canada S4S 0A2
andrew.wee@uregina.ca
Received September 9, 2010
ABSTRACT
Acyclic N-Cr-branched, N-bis(trimethylsilyl)methyl (N-BTMSM) diazoamides undergo regio-, chemo-, and diastereoselective Rh(II)-carbenoid
C-H insertion to give 4,5-disubstituted and 3,4,5-trisubstituted γ-lactams. The conformational influence of the N-BTMSM group and the electronic
effect of the O-pivaloyl moiety of the Cr-oxymethylene unit are essential for the observed regioselectivity. The synthesis of r-allokainic acid
demonstrates the utility of the method.
The Rh(II)-carbenoid-mediated intramolecular C-H insertion
of tertiary R-diazoamides is a useful method1 especially for
the preparation of 4-substituted and 3,4-disubstituted γ-lac-
tams. On the other hand, the Rh(II)-catalyzed reaction of
diazoamides 1 (Figure 1), bearing a substituent at the N-CR
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic
Methods for Organic Synthesis With Diazo Compounds; Wiley-Interscience:
New York, 1998. (b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem.
ReV. 2010, 110, 704. (c) Wee, A. G. H. Curr. Org. Synth. 2006, 3, 499. (d)
Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2004, 3773. (e) Davies,
H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (f) Merlic, C. A.;
Zechman, A. L. Synthesis 2003, 1137. (g) He, M.; Bode, J. W. Org. Lett.
2005, 7, 3131. (h) Chen, Z.; Chen, Z.; Jiang, Y.; Hu, W. Synlett 2004,
1763. (i) Yoon, C. H.; Nagle, A.; Chen, C.; Gandhi, D.; Jung, K. W. Org.
Lett. 2003, 5, 2259. (j) Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett.
2000, 41, 9377. (k) Scheidt, K. A.; Roush, W. R.; McKerrow, J. H.; Selzer,
P. M.; Hansell, E.; Rosenthal, P. J. Biorg. Med. Chem. 1998, 6, 2477. (l)
Langlois, N.; Radom, M.-O. Tetrahedron Lett. 1998, 39, 857. (m) Doyle,
M. P.; Shanklin, M. S.; Oon, S. M.; Pho, H. Q.; van der Heide, F. R.; Veal,
W. R. J. Org. Chem. 1988, 53, 3384. (n) Wee, A. G. H.; Liu, B. S.; McLeod,
D. D. J. Org. Chem. 1998, 63, 4218.
Figure 1. Potential C-H insertion sites.
position (here on referred to as N-CR-branched), to form 4,5-
disubstituted and 3,4,5-trisubstituted γ-lactams has not been
10.1021/ol1021564  2010 American Chemical Society
Published on Web 11/10/2010

well explored. The number of potential, competitive metal-
locarbenoid reaction sites (indicated by f) in 1 has increased,
and the control of site- and diastereoselectivity in this system
poses an interesting and challenging question.
The Rh2(OAc)4-catalyzed reaction of the diazoamide4a 9 was
first tested to assess the regioselectivity of the reaction. It is
clear from Table 1 that γ-lactam formation is influenced by
Table 1. Rh2(OAc)4-Catalyzed Reaction of Diazoamide 9
relative yields (%)
entry
diazo
yield (%)a
10
11d
12
13
1
2
3
4
9a
9b
9c
9d
73
82
88
83
89b
34c
80b
78c
0
66
0
11e
0
0
0
20e
8
0
8
6f
a Combined isolated yields. Relative stereochemistry: t ) trans, c )
cis. b 10a, only t,t; 10c, t,t:t,c ) 15:1. c 10b, only t; 10d, t:c ) 20:1. d 11b,
t:c ) 1:1; 11d, only c. e Inseparable t/c diastereomers: 12a, t:c ) 4:1; 12c,
t:c ) 2:1. f Relative stereochemistry was unassigned.
An early study, reported by Zaragoza,2a is the Rh(II)-
catalyzed C-H insertion of R-diazoamide 2 (eq 1), which
occurred with poor regio- and chemoselectivity to give only
a low yield of the desired γ-lactam 3. The products 4 and 5,
which arose from Rh(II)-carbenoid attack at the N-benzhydryl
group, and the imine 6 were also obtained. To circumvent
this difficulty, Hashimoto and co-workers resorted to the use
of the 2,2-dimethyloxazolidine diazoamide (eq 1) 7.2b The
Rh(II)-catalyzed reaction of 7 preferentially led to the desired
γ-lactam 8, and this observation was subsequently further
developed by Jung and co-workers.2c
subtle electronic effects from the R-substituent on the carbenoid
carbon and the O-substituent of the oxymethylene group. With
9a (entry 1), preferential C-H insertion at the butyl group to
give the γ-lactam 10a was observed, and the ꢀ-lactam 12a,
arising from insertion at the N-CR-H unit, was obtained as a
minor product. It is intereting to note that the γ-lactam 10a
was obtained as a single diastereomer having the C3,C4-trans;
C4,C5-trans relative stereochemistry.4b The lactam 11a, which
could be formed via metallocarbenoid attack at the electronically
activated5a ether C-H bond, was not detected. In accord with
our previous results,3 the N-BTMSM group was inert under
the reaction conditions. Unexpectedly, with the unsubstituted
diazoamide 9b (entry 2), insertion at the ether C-H bond is
now favored to afford γ-lactam 11b; the γ-lactam 10b, obtained
only as the trans diastereomer, was the minor product, and the
ꢀ-lactam 12b was not detected.
To dissuade C-H insertion at the N-CR-oxymethylene
moiety, the O-MOM group was replaced with the O-pivaloyl
(Piv) group as in diazoamides 9c,d. It was reasoned that the
electron-withdrawing effect of the O-Piv unit would deac-
tivate the adjacent methylene C-H bonds toward metallo-
carbenoid insertion. Thus, reaction of 9c gave the trans,trans-
10c (major product) and ꢀ-lactam 12c (minor product) as
was observed for the reaction of 9a (entry 1). Interestingly,
We recently reported3 that the N-BTMSM group is a
practical, nonparticipatory N-protecting group which is
effective for controlling site selectivity in Rh(II)-catalyzed
reactions of tertairy R-diazoamides. We noted that the
N-BTMSM unit has a subtle but important influence on the
conformational preferences about the amide N-CR σ bond
in N-CR-branched diazoamides.3c Following this cue, we
initiated studies on the Rh(II)-catalyzed reaction of acyclic
diazoamides of type 1 (R ) BTMSM, Figure 1). We chose
the oxymethylene moiety as one of the CR-substituents as it
provides flexibility for subsequent functional group manipu-
lation in the context of synthetic applications. Herein, we
report the preliminary findings of our studies and demonstrate
the utility of the method in the synthesis of (()-R-allokainic
acid.
(4) (a) The preparation of the diazoamides will be presented elsewhere.
(b) Only the assigned relative stereochemistries of γ-lactams 10, 15, and
20 are provided here. The assignment of the relative stereochemistry of
γ-lactams 10, 15, and 20, the regioisomeric γ-lactams 11, 16, and 21, and
ꢀ-lactams 12 and 28 is based on a combination of the detailed analysis of
1H NMR J values, NOE, and X-ray crystallographic data of key products.
These analyses and results will be detailed elsewhere.
(2) (a) Zaragoza, F. Tetrahedron 1995, 51, 8829. (b) Anada, M.;
Sugimoto, T.; Watanabe, H.; Nakajima, M.; Hashimoto, S.-H. Heterocycles
1999, 50, 969. (c) Jung, Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung,
K. W. J. Org. Chem. 2007, 72, 10114, and references cited therein.
(3) (a) Zhang, B.; Wee, A. G. H. Chem. Commun. 2008, 4837. (b) Wee,
A. G. H.; Duncan, S. C.; Fan, G.-J. Tetrahedron: Asymmetry 2006, 17,
297. (c) Wee, A. G. H.; Duncan, S. C. J. Org. Chem. 2005, 70, 8372.
(5) (a) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116, 3296. (b)
Wang, J.; Chen, B.; Bao, J. J. Org. Chem. 1998, 63, 1853.
Org. Lett., Vol. 12, No. 23, 2010
5387

however, with 9d C-H insertion to the butyl group to give
trans-10d was now more favored over formation of γ-lactam
11d (entries 2 and 4). The formation of 11d and ꢀ-lactam
12d was competitive; unexpectedly, the δ-lactam 13d was
also obtained albeit in low yield.
It is evident that the O-Piv group is especially useful in
suppressing C-H insertion at the N-CR-oxymethylene unit
in R-unsubstituted diazoamides (9b vs 9d). To further assess
the influence of electronic effects on regio- and chemose-
lectivity, the Rh(II)-catalyzed reaction of the R-unsubstituted
diazoamides carrying a N-CR benzyl (14a) and 4-nitrobenzyl
(14b) group was studied.
the presence of the electron-withdrawing nitro group was
expected to suppress the formation of the cycloheptatriene
derivative 18b thereby improving chemoselectivity. Thus, with
Rh2(cap)4 and Rh2(OAc)4 only trans-15b and 16b were formed
(entries 4 and 5), with 15b as the preferred product. For the
Rh2(tfa)4-catalyzed reaction, the formation of 18b is markedly
reduced. Although trans-15b was formed as the major product,
there was a slight increase in the yields of 16b and 17b (entries
3 and 6).
This latter result suggests that the nitro group had not only
deactivated the phenyl ring toward metallocarbenoid attack
but also decreased, somewhat, the reactivity of the benzylic
C-H bonds.5b
Next, the regioselectivity of the Rh(II)-catalyzed reaction of
diazoamides 19 (Table 3) was investigated. In this system,
Table 2. Rh(II)-Catalyzed Reaction of Diaoamide 14a
Table 3. Rh(II)-Catalyzed Reaction of Diazoamide 19f
relative yields (%)
relative yields (%)
entry diazo
catalyst
yields (%)b
20c
21d 22 23e
12
1f
20 10 3g
entry diazo
catalyst
yields (%)b 15c 16d 17 18
1
2
3
4
5
19a Rh2(cap)4
19a Rh2(OAc)4
19a Rh2(tfa)4
19b Rh2(cap)4
19c Rh2(cap)4
87
99
96
95
88
87 (3:1)
67 (5:1)
0
1
2
3
4
5
6
14a
14a
14a
14b
14b
14b
Rh2(cap)4
Rh2(OAc)4
Rh2(tfa)4
Rh2(cap)4
Rh2(OAc)4
Rh2(tfa)4
76
88
90
88
94
90
89
75
44
72
72
77
11
22
7
28
28
9
0
1
9
0
0
0
2
70 (10:1) 10 17 3g
85 (3:1)
82 (3:1)
8
1
0
6f
0
40
0
18
a Relative stereochemistry: t ) trans, c ) cis. b Combined isolated yields.
c Ratio of separable t-20/c-20 in brackets. d Inseparable t-21/c-21. e Relative
stereochemistry was unassigned. f Single diastereomer. g Two inseparable
diastereomers.
0
3
11
a Relative stereochemistry: t ) trans, c ) cis. b Combined isolated yields.
c Only t-diastereomers obtained. d Inseparable mixture of t- and c-16: entry
1, t:c ) 2:1; entry 2, t:c ) 1:6; entry 3, t:c ) 1:2.2; entry 4, t:c ) 2:1;
entry 5, t:c ) 1:5; entry 6, only c-16.
Rh(II)-carbenoid attack at the aryl moiety is not expected on
the basis of our previous studies.3b,c The results show that
metallocarbenoid C-H insertion preferentially occurred at
the phenethyl/arylethyl moiety to give γ-lactams 20 as the
major product. Further, 20 was obtained as a mixture of
readily separable trans- and cis-20, wherein the former
predominated. It is also evident that product distribution was
catalyst dependent. For 19a, Rh2(cap)4 provided the best
regioselectivity favoring formation of γ-lactams 20a and 21a;
ꢀ-lactam 22a was not detected; and δ-lactam 23a was
obtained in very minor amounts (entry 1). In comparison,
Rh2(OAc)4 and Rh2(tfa)4 gave lower regioselectivity as the
ꢀ-lactam 22a was also formed in significant amounts (entries
2 and 3). The Rh2(cap)4-catalyzed reaction of 19b,c revealed
that the electronic effect of a para-substituent5b on the
reactivity of the benzylic C-H bonds was subtle. Thus,
compared to 19a, the electron-donating 4-MeO substituent
in 19b only slightly favored the formation of the δ-lactam
23b, whereas the electron-withdrawing 4-NO2 group in 19c
The results in Table 2 show that Rh(II)-carbenoid C-H
insertion preferentially occurred at the benzylic position to
give γ-lactams 15,4b and the O-Piv group’s effectiveness in
curtailing C-H insertion at the oxymethylene unit was
maintained. With 14a, the Rh2(cap)4-catalyzed reaction gave
only trans-15a and 16a (entry 1), wherein 15a was the major
product. With Rh2(OAc)4 the formation of trans-15a was
still preferred over 16a, but minor amounts of the ꢀ-lactam
17a and the cycloheptatriene 18a were also obtained (entry
2). It should be noted that although Rh2(OAc)4-carbenoid attack
at the phenyl unit was significantly competitive in simpler
N-BTMSM diazoamides3c it was not the case here. In the
Rh2(tfa)4-catalyzed reaction (entry 3) almost equiamounts of
trans-15a and 18a were obtained indicating a significant erosion
of chemoselectivity. However, regioselectivity was still very
good as the γ-lactam 15a was formed along with minor amounts
of 16a and 17a. The reaction of 14b was then explored wherein
5388
Org. Lett., Vol. 12, No. 23, 2010

discouraged metallocarbenoid insertion at the benzylic position
(entries 4 and 5). In this latter case, high regioselectivity, similar
to that observed for 19a, was realized (entries 1 and 5).
The utility of this method is demonstrated by the synthesis
of (()-R-allokainic acid (24),2b,c,6 whose retrosynthesis
(Figure 2) was guided by the above-described combined
oil. Gratifyingly, the ketal diastereomers were amenable to
separation by chromatography, which provided a 21:1 ratio
(based on isolated yields) of 29a:29b. The major diastere-
omer 29a was N-deprotected3b,c to give a 90% yield of
crystalline 30. At this juncture, a single-crystal X-ray analysis
was performed on 30,7b which helped to establish its relative
stereochemistry as C3,C4-trans; C4,C5-trans. For the minor
diastereomer 29b, NOE experiments gave, upon irradiation
of H-5, an 8.7% enhancement of H-4, but none for H-3. This
led us to assign the C3,C4-trans; C4,C5-cis relative stereo-
chemistry to 29b. The combined data also allowed the
assignment of the relative stereochemistry for the major
diastereomers 26a and 29a as C3,C4-trans; C4,C5-trans and
for the minor diastereomers 26b as C3,C4-trans; C4,C5-cis.
Compound 30 was then treated with LiAlH4 in refluxing
THF to reduce the lactam carbonyl unit and effect O-
depivaloylation to obtain the corresponding pyrrolidine
alcohol, which without isolation was converted to N-Boc
carbamate 25 in 63% yield (over two steps). The 4-meth-
oxyphenyl group in 25 was to serve as a carboxylic acid
equivalent. Thus, acid-catalyzed hydrolysis of the ketal unit
followed by RuO4 oxidation8 of the primary alcohol and
4-methoxyphenyl groups provided the crude diacid, which
was immediately methylated (CH2N2) to give 319 in 61%
overall yield (three steps). Subsequent Wittig methylenation
of 31 installed the isopropenyl group, followed by base
hydrolysis and then N-Boc deprotection using TFA to yield
(()-R-allokainic acid (24). Purification (Dowex 50W-H+)
gave (()-24 in 61% yield, which showed melting point and
spectroscopic data in agreement with reported data.2b,6e,f
In summary, intramolecular Rh(II)-carbenoid-mediated
C-H insertion of acyclic N-CR-branched N-BTMSM diaz-
oamides proceeded efficiently with good to excellent regio-,
chemo-, and diastereoselectivity to give highly functionalized
di- and trisubstituted γ-lactams. The high regioselectivity
realized in γ-lactam formation arises from (i) the confor-
mational effect of the N-BTMSM group on the amide
N-C(O) unit and N-CR σ bond and (ii) the electronic effect
of the OPiv unit of the oxymethylene group. The utility of
the method was demonstrated by the total synthesis of (()-
R-allokainic acid (24).
Figure 2. Retrosynthesis of 24.
results. Compound 25 was identified as an intermediate,
which can be prepared from 26a; 26a is to be made from
diazoamide 27.
The synthesis started with the Rh2(OAc)4-catalyzed reac-
tion of 277a (Scheme 1), which efficiently (91%) gave a 3.8:1
Scheme 1. Synthesis of 24
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council, Canada, and the University
of Regina for financial support. We thank Dr. B. Sterenberg
of this department for help with X-ray data.
Supporting Information Available: Spectroscopic data
and copies of spectra of key compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ratio of the readily separable trisubstituted γ-lactam 26 and
the ꢀ-lactam 28; however, each of these lactams was obtained
as an inseparable mixture of two diastereomers. Ketalization
of γ-lactam 26 afforded an 86% yield of the ketal 29 as an
OL1021564
(7) (a) The Rh2(cap)4-catalyzed reaction proceeded only in refluxing
CH2Cl2. The ratio of γ-lactam 26:ꢀ-lactam 28 was 11.5:1, but the
diastereoselectivity realized for 26 was lower; 26a:26b ) 4:1. (b) See
Supporting Information.
(6) (a) Cook, G. R.; Sun, L. Org. Lett. 2004, 6, 2481. (b) Ma, D.; Wu,
W.; Deng, P. Tetrahedron Lett. 2001, 42, 6929. (c) Chevliakov, M. V.;
Montgomery, J. Angew. Chem., Int. Ed. 1998, 37, 3144. (d) Miyata, O.;
Ozawa, Y.; Ninomiya, I.; Aoe, K.; Hiramatsu, H.; Naito, T. Heterocycles
1997, 46, 321. (e) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61,
(8) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
(9) For (2S,3S,4R)-31, see: Baldwin, J. E.; Fryer, A. M.; Pritchard, G. J.
J. Org. Chem. 2001, 66, 2588.
5418. (f) Oppolzer, W.; Andres, H. Tetrahedron Lett. 1978, 3397
.
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