Metal carbene N-H insertion of chiral α, α′-dialkyl α-diazoketones. A novel and concise method for the stereocontrolled synthesis of fully substituted azetidines

Article abstract of DOI:10.1016/j.tetlet.2004.03.036

The syntheses of all cis substituted azetidines were accomplished in few steps from L-serine in modest to high yields. The key step was based on a rhodium or copper carbenoid N-H insertion of α,α^′- dialkyl-α-diazoketones to furnish cis-2,4-dial

Full text of DOI:10.1016/j.tetlet.2004.03.036

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3355–3358
Metal carbene N–H insertion of chiral a,a0-dialkyl a-diazoketones.
A novel and concise method for the stereocontrolled synthesis
of fully substituted azetidinesq
Antonio Carlos B. Burtoloso and Carlos Roque D. Correia*
ꢀ
~
Instituto de Quımica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, CEP 13083-970, Campinas, Sao Paulo, Brazil
Received 13 November 2003; revised 1 March 2004; accepted 8 March 2004
Abstract—The syntheses of all cis substituted azetidines were accomplished in few steps from L-serine in modest to high yields. The
key step was based on a rhodium or copper carbenoid N–H insertion of a,a0-dialkyl-a-diazoketones to furnish cis-2,4-dialkyl-
azetidin-3-ones as the only observable diastereoisomers.
Ó 2004Elsevier Ltd. All rights reserved.
Azetidine alkaloids are rather rare substances mostly
found in nature as sphingosine-like compounds con-
taining an azetidin-3-ol nucleus.1 Azetidine alkaloids
such as penaresidin A and B and penazetidin A were
isolated from the marine sponges Penares sp.2a and
Penares sollasi,2b respectively, and possess remarkable
pharmacological activities (Fig. 1). Penaresidin A and B
have shown potent actomyosin ATPase-activating
activity,2a whereas penazetidin A displays protein kinase
C inhibitory activity.2b
these azetidine alkaloids and structural analogues (Fig.
2) in the literature.3 With the exception of De Kimpe’s
synthesis,3l;n which involves the alkylation of azetidin-3-
ones4 derivatives, all other syntheses of these azetidine
containing compounds are based on the cyclization of a
suitable 3-amino-1,2-diol intermediate containing all the
stereocenters already fixed.
Herein, we describe our preliminary results toward the
synthesis of azetidine containing compounds in few
steps from 2,4-dialkyl-azetidin-3-ones, prepared from
rhodium or copper carbenoid N–H insertion of a,a0-
dialkyl-a-diazoketones.
In view of their unique structure and pharmacological
properties, there are several reports on the synthesis of
Metal carbene chemistry has been widely used as an
efficient tool in organic chemistry.5 Although there are
many examples in the literature in which rhodium and
copper catalysts are employed in N–H insertion reac-
tions of a-diazoketones, few examples describe an
intramolecular metal N–H cyclization to form a
OH
R2
OH
N
H
HO
R1
Penaresidin A, R1 = Me, R2 = H
Penaresidin B, R1 = H, R2 = Me
OH
N
H
HO
Penazetidin A
Me
OH
Figure 1. Sphingosine type azetidine alkaloids isolated from marine
sponges Penares.
N
H
HO
"mini-Penazetidin"
OH
Keywords: Diazo ketones; Metal carbenes; Azetidines.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.036
N
H
HO
nor-Penazetidin
* Corresponding author. Tel.: +55-19-3788-3114; fax: +55-19-3788-3-
023; e-mail: roque@iqm.unicamp.br
Figure 2. Some synthesized azetidine alkaloids analogues.
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.036

3356
A. C. B. Burtoloso, C. R. D. Correia / Tetrahedron Letters 45 (2004) 3355–3358
O
O
O
O
catalyst
reaction conditions
R
catalyst
catalyst
TBDPSO
R
O
N
P
N
P
TBDPSO
H
NP
N2
PNH
N2
R = alkyl
P = protecting group
3 (P=Boc)
5 (P=Ts)
O
4 (P=Boc)
6 (P=Ts)
O
O
OR
single stereoisomers (0-61%)
H
NP
N2
N
P
OR
Diazoketone Catalyst
conditions
Product
(%)
Rh2(OAc)4
Cu(acac)2
CH2Cl2, 0oC, 1h
CH2Cl2, rt, 12h
Scheme 1. a-Diazoketones employed in the preparation of azetidin-3-
ones via metal carbene N–H insertion.
4 (35)
3
3
complex
mixture
6 (0)
Rh2(OAc)4
Cu(acac)2
CH2Cl2, rt, 1h
CH2Cl2, rt, 2h
5
5
5
5
no reaction
6 (45)
Cu(acac)2 C6H6, 50oC, 5 min
four-membered ring (azetidin-3-ones),6 and to the best
of our knowledge, these are restricted to the preparation
of 2-substituted azetidin-3-ones only (Scheme 1).
Cu(acac)2
C6H6, ∆, 1 min
6 (61)
Scheme 3. The synthesis of the azetidin-3-ones 4 and 6 from a-di-
azoketone 3 and 5 employing different catalysts.
Moreover, in addition to the synthesis of 2,4-disubsti-
tuted azetidin-3-ones, the stereochemical outcome
resulting from the carbenoid insertion arising from a,a0-
dialkyl-a-diazoketones was also a matter of investiga-
tion in our studies.
The cis stereochemistry outcome observed for the
cyclization reaction was strongly suggested by NOE
experiments of the reduced azetidin-3-ones 4 and 6.
Since the hydrogens at C2 and C4of these azetidin-3-
ones have almost identical chemical shifts, NOE experi-
ments could not be carried out directly on 4 and 6. To
circumvent this problem and to provide convincing
evidence of the cis cyclization process described above,
we synthesized the azetidin-3-one 7 (Scheme 4). Aze-
tidinone 7 showed distinguishable chemical shifts for H2
and H4. Irradiation of H2 in azetidinone 7 showed a
NOE with H4of 0.8%, whereas irradiation of the H4,
showed a NOE with H2 of 0.8% (Scheme 4).
We started by preparing the a,a0-dialkyl-a-diazoketone
3 from L-serine as described in Scheme 2. The synthesis
of diazoketone 3 involved the appropriate protection of
N-Boc serine7 and addition of diazobutane to a mixed
anhydride of carboxylic acid 2. The diazoketone 3 was
obtained with an overall yield of 50–55%.
The diazoketone 3, was then submitted to rhodium
carbenoid N–H insertion reaction in the presence of
rhodium acetate Rh2(OAc)4 (1 mol %) in CH2Cl2 at 0 °C
for 1 h to furnish a single diastereomeric azetidin-3-one,
identified as the cis-azetidin-3-one 4, in a somewhat
modest yield of 35%.8 The modest yield obtained in the
cyclization step can be ascribed to the formation of
3-furanones in competition with O–Si and N–H inser-
tion and other side products.
This interesting stereochemical outcome was rational-
ized considering a transition state where both bulk
groups, CH2OTBDPS and MLn (Rh2(OAc)4 or
Cu(acac)2), are positioned trans to each other as illus-
trated in Figure 3. Despite intense investigation on the
mechanism of C–H insertion of rhodium carbenoid,11
the N–H insertion has not been investigated to the same
extent. For C–H insertion, Nakamura12 et al. have
recently reported a complete theoretical study assuming
a concerted but nonsynchronous (three-centered hydride
transfer) transition state. A synchronous three-centered
concerted transition state was proposed by Doyle and
co-workers.11b The N–H insertion is a quite different
case because of the nonbonding electron pair on the N
Aiming at improving the yield for N–H insertion reac-
tion, we then started a study employing different diazo-
ketones and copper-acetylacetonate (Cu(acac)2) as an
alternative catalyst. Best results (45–61% in the cycliza-
tion step) were obtained after the combination of the
copper catalyst (5–10 mol %) and a N-tosyl diazoketone9
(see table in Scheme 3). N-Tosyl diazoketone 5 was
prepared from N-tosyl serine10 in a way similar to that
described in Scheme 2 in comparable yields. In the case
of N-tosyl diazoketone 5 an acyl chloride was used
instead of a mixed anhydride for the reaction with
diazobutane.
O
OCH3
TBDPSO
H
TsN
N2
Cu(acac)2
C6H6, reflux, 1 min
O
0,8%
O
O
O
TBDPSO
TBDPSO
OH
HO
b
OH
a
HNBoc
HNBoc
N2
HNBoc
H2
H4
1
2
3
TBDPSO
OCH3
N
Ts
51%
7
Scheme 2. Preparation of diazoketone 3 from N-Boc serine. a: Imid-
azole, DMF (4M solution), TBDPSCl, rt, 36 h, quantitative; b: (1)
ClCOOEt, Et3N, THF, )20 °C; (2) diazobutane in Et2O, 0 °C to rt, 50–
55%.
Scheme 4. Synthesis and NOE experiments in azetidin-3-one 7.

A. C. B. Burtoloso, C. R. D. Correia / Tetrahedron Letters 45 (2004) 3355–3358
3357
face of the carbonyl in azetidinone 4 was congested by
both C2 and C4groups. Some other results from the
literature6d also demonstrate this trend. Cleavage of the
TBDPS group of 8 with tetrabutylammonium fluoride
(TBAF) followed by treatment of the free diol 9 with
trifluoroacetic acid furnished the azetidine alkaloid
analogue 10 in 71% over two steps (Scheme 5).
O
O
(a)
catalyst
TBDPSO
HNP
N
P
TBDPSO
N2
δ
LnM
TBDPSO
OTBDPS
H
H
P
P
The determination of the cis,cis stereochemistry was
accomplished by NOE experiments of azetidin-3-ols 8
and 9 (Fig. 4). An intense NOE of 6.1% was observed
between H3–H4and H3–H2 when H3 is irradiated,
whereas irradiation of the CH2 at C4, permitted the
observation of a NOE with the secondary hydroxyl of
1.8%.
N
H
δ
δ
δ
N
H
O
O
M
Ln
unfavorable transition state
(highly hindered)
Favorable transition state
O
N
O
For azetidinol 9, it was observed a NOE with H2 (1.5%)
and H4(1.4%) when H3 was irradiated and a NOE with
the secondary hydroxyl group (0.5%) when the CH2 of
the CH2OH group was irradiated.
TBDPSO
cis
N
P
TBDPSO
trans
P
(b)
TBDPSO
To show the applicability of this methodology, we also
have synthesized the azetidine compound 10 from
N-tosylazetidin-3-one 6. It is worth noticing that during
the N–H insertion of diazoketone 5 (Cu(acac)2 as cata-
lyst) to provide 6, we also observed two side products
characterized as the a,b unsaturated ketones 11 and 12
(Scheme 6). Reduction of 6 with NaBH4 at )21 °C in
CH3OH furnished a separable mixture of the cis aze-
tidinol 13a (50%) and trans azetidinol 13b (20%)
(Scheme 6). Cleavage of the tosyl group of 13a with
O
H
P
δ
N
P
TBDPSO
cis
N
O
H
LnM
δ
Figure 3. (a) Three-centered concerted mechanism for the cis and trans
products in the metal carbene N–H insertion of diazoketones 3 and 5.
(b) Ylide mechanism for the cis isomer.
atom. The N–H insertion mechanism is still uncertain,
but a stepwise mechanism involving ylides5 as well as a
concerted three/four-centered transition state13 have
been proposed as possible mechanisms. As depicted in
Figure 3a and b, both the concerted three-centered and
the ylide process can explain the observed stereochemi-
cal results.
6.1%
H
1.8%
O
HO H3
N
H4
H
H2
H
TBDPSO
N
TBDPSO
8
Boc
8
Boc
To construct the fully-substituted azetidine ring, we
continued our synthesis with the azetidin-3-one 4.
Introduction of the alcohol functionality at C3 was
carried out by reducing azetidin-3-one 4 with NaBH4 at
)21 °C in CH3OH (Scheme 5). The only detectable
diastereoisomer, the all cis azetidin-3-ol 8 (Re face
attack of the hydride at C3), was already expected to be
the major or the unique diastereoisomer, since the Si
1.4%
H4
1.5%
H
O
0.5%
H
H
H
HO H3
N
H
H2
N
HO
HO
Boc
9
9
Boc
Figure 4. NOE experiments on azetidin-3-ols 8 and 9.
O
OH
O
a
TBDPSO
N
Boc
N
Boc
TBDPSO
TBDPSO
4
8
H
5
TsN
N2
b
Cu(acac)2
C6H6, reflux, 5min
OH
OH
c
O
O
O
CF3COO
N
HO
N
Boc
HO
9
TBDPSO
+
+
H
H
TBDPSO
H
12
8%
TsN
10
N
Ts
61%
H
11
14%
TsN
TBDPSO
6
Scheme 5. Reduction of azetidin-3-one 4 followed by deprotection. (a)
NaBH4, MeOH, )21 °C, 30 min, 46%; (b) TBAF, THF, 0 °C to rt, 1 h,
71%; (c) TFAA, CH2Cl2, 0 °C, 1 h, quantitative.
Scheme 6. Reaction of diazoketone 5 in the presence of Cu(acac)2.

3358
A. C. B. Burtoloso, C. R. D. Correia / Tetrahedron Letters 45 (2004) 3355–3358
(c) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron:
Asymmetry 1996, 7, 2113; (d) Yashima, A.; Takikawa,
H.; Mori, K. Liebigs Ann. 1996, 7, 1083; (e) Mori, K. J.
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1998, 47, 337; (j) Lin, G. Q.; Liu, D. G. Tetrahedron Lett.
1999, 40, 337; (k) Reference 2j cited in 3l; (l) Salgado, A.;
Boeykens, M.; Gauthier, C.; Declercq, J.; De Kimpe, N.
Tetrahedron 2002, 58, 2763; (m) Yoda, H.; Uemura, T.;
Takabe, K. Tetrahedron Lett. 2003, 44, 977; (n) Salgado,
A.; Boeykens, M.; Gauthier, C.; Dejaegher, Y.; Verniest,
G.; Lopin, C.; Tehrani, K. A.; De Kimpe, N. Tetrahedron
2003, 59, 2231.
O
OH
OH
a
+
N
Ts
N
Ts
N
Ts
TBDPSO
TBDPSO
TBDPSO
6
13a
13b
b
OH
OH
c
N
CF3COO
HO
N
H
TBDPSO
14
H
H
10
Scheme 7. Reduction of azetidinone 6 followed by deprotection. (a)
NaBH4, MeOH, )21 °C, 30 min, 70% (cis + trans); (b) Na/Naphthal-
ene, DME, )78 °C, 1 h; (c) TBAF, THF, rt, 1 h, then ATFA, 50% (two
steps).
4. Dejaegher, Y.; Kuz’nenok, N. M.; Zvonok, A. M.; De
Kimpe, N. Chem. Rev. 2002, 102, 29.
5. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds:
from Cyclopropanes to Ylides; John Wiley and Sons: New
York, 1998.
6. (a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org.
Chem. 1985, 50, 5223; (b) Emmer, G. Tetrahedron 1992,
48, 7165; (c) Hanessian, S.; Fu, J.; Chiara, J. L.; Di Fabio,
R. Tetrahedron Lett. 1993, 34, 4157; (d) Podlech, J.;
Seebach, D. Helv. Chim. Acta 1995, 78, 1238; (e) Sengupta,
S.; Das, D. Synth. Commun. 1998, 28, 403; (f) Desai, P.;
Na/naphthalene in DME followed by treatment of the
crude amine 14 with tetrabutylammonium fluoride
(TBAF), furnished, after acidification with trifluoro-
acetic acid, the azetidine salt 10 in 50% yield14 after the
two steps (Scheme 7).
In summary, we have demonstrated that metal carbe-
noid insertion of a,a0-dialkyl-a-diazoketones can be a
viable and powerful tool for the construction of fully
substituted azetidines in few steps from commercially
available amino acids. The combination of N-tosyl
diazoketones with the cheap Cu(acac)2 catalyst provided
the best results for the N–H insertion reactions. The use
ꢀ
Aube, J. Org. Lett. 2000, 2, 1657; (g) Pusino, A.; Saba, A.;
Desole, G. Gazzeta Chim. Italiana 1985, 115, 33; (h)
Wang, J.; Hou, Y.; Wu, P. J. Chem. Soc., Perkin Trans. 1
1999, 2277.
of amino acids other than
L-serine and other higher
7. Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
8. Yields for 4 were initially higher. However, compound 4
was contaminated with small amounts of an undesirable
side product, which could not be separated by chroma-
tography. Reduction of 4 to azetidinol 8 with NaBH4
permitted the isolation of this side product (inert to
NaBH4 reduction).
diazoalkanes (to prepare different diazoketones) are
under investigation for the construction of other azeti-
dines in our research group.
Supplementary material
9. Typical experimental procedure: 353 mg (0.63 mmol) of
diazoketone 5 was dissolved in 13 mL of dry benzene and
the yellow solution heated under reflux. Next, 16 mg
(10 mol %) of Cu(acac)2 was added to the reaction mixture
turning it brown immediately with liberation of nitrogen.
After 1 min, the reaction mixture was cooled, the solvent
evaporated, and the crude product purified by flash
column chromatography (10% ethyl acetate/hexane) to
1H NMR and 13C NMR spectroscopic data for com-
pounds 2, 3, 4, 5, 6, 7, 8, 9, 15a, and 15b and ESI-MS
and IV for compounds 2, 3, 4, 7, 8, and 9.
Acknowledgements
1
We thank FAPESP (Research Supporting Foundation
~
furnish 205.8 mg (61%) of the azetidin-3-one 6. H NMR
of the State of Sao Paulo) for financial support and
(300 MHz, CDCl3): d 7.28–7.80 (14H, Ar), 4.67 (t,
J ¼ 2:5 Hz, 1H, H2), 4.62 (t, J ¼ 7:3 Hz, 1H, H4), 3.78–
3.90 (2dd, J ¼ 11:7, 2.9 Hz, 2H), 2.44 (s, 3H), 1.92 (q,
J ¼ 7:3 Hz, 2H), 1.51 (m, 2H), 1.04(s, 9H), 0.90 (t,
J ¼ 7:3, 3H). 13C NMR (75 MHz, CDCl3): d 198.4, 144.4,
135.4, 132.4 (2s), 129.6 (2s), 128.1, 127.6, 83.2, 83.6, 61.6,
32.2, 26.6, 21.6, 19.2, 18.4, 13.8.
fellowship, and Professor Spencer Knapp (The State
University of New Jersey) for providing spectral data of
‘mini-penazetidine’.
References and notes
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14. Yield not optimized.
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