A flexible and stereoselective synthesis of azetidin-3-ones through gold-catalyzed intermolecular oxidation of alkynes

Article abstract of DOI:10.1002/anie.201007624

Chiral rings made easy: Chiral azetidin-3-ones have been easily prepared from chiral N-propargylsulfonamides, which in turn are readily accessible through chiral sulfinamide chemistry (see scheme). Using tert-butylsulfonyl as the protecting group avoids unnecessary deprotection and reprotection steps, and allows its removal from the azetidine ring under acidic conditions. Copyright

Full text of DOI:10.1002/anie.201007624

Communications
DOI: 10.1002/anie.201007624
N-Heterocycles
A Flexible and Stereoselective Synthesis of Azetidin-3-ones through
Gold-Catalyzed Intermolecular Oxidation of Alkynes**
Longwu Ye, Weimin He, and Liming Zhang*
À
Azetidine is a strained four-membered nitrogen-containing
heterocycle that can be found in various natural products[1]
and compounds of biological importance. Although b-lactams
(i.e. azetidin-2-ones) are a rich source of antibiotics,[2] their
structural isomer (azetidin-3-ones) with the carbonyl group
one carbon removed from the nitrogen atom, have not been
found in nature but could serve as versatile substrates for the
synthesis of functionalized azetidines.[3]
intramolecular N H insertion by an a-oxo gold carbene using
protected propargylamines as substrates (Scheme 1).
To implement this design, we anticipated that the key was
to find a suitable electron-withdrawing protecting group for
the basic amino group that might deactivate cationic gold
catalysts. While an acyl group is in general not suitable owing
to a competitive carbonyl 5-exo-dig cyclization,[13] the use of a
tosyl group would encounter difficulty in its later removal,
which is typically accomplished under harsh basic/reductive
conditions.[14] We decided to use the tert-butylsulfonyl
(Bus)[15] group as the protecting group for two reasons: 1) it
can be removed under acidic conditions, and 2) it can be
prepared from tert-butylsulfinyl by simple oxidation using m-
CPBA. Importantly, tert-butylsulfinamide derivatives are
easily formed in chiral forms by using Ellmanꢀs chemistry.[16]
As shown in Scheme 2, this protecting-group strategy would
allow us to access various N-tert-butylsulfonylpropargyla-
mines (i.e. 2) with high ee values conveniently from chiral
sulfinamides 1 without additional protection and deprotec-
tion steps, and eventually a range of chiral azetidin-3-ones
could be obtained (Scheme 2).
The synthesis of azetidin-3-ones[3] has been mainly
realized by acid-promoted or metal-catalyzed decomposition
of a-amino-a’-diazo ketones[4] and 4-exo-tet cyclizations of a-
amino ketones. The diazo ketone approach is the most
reliable in terms of substrate scopes, but it often suffers from
competitive reactions and low yields;[4b,5] moreover, diazo
compounds are toxic and potentially explosive.[6] For the
synthesis of chiral azetidin-3-ones,[7] natural amino acids serve
as a convenient and cheap chiral pool, but at the same time
poses limits on substrate scope and configuration. Herein, we
report a straightforward, flexible, and general sequence for
the efficient synthesis of chiral azetidin-3-ones with typically
> 98% ee that bypasses toxic diazo intermediates.
Early in 2010 our research group showed for the first
time[8] that reactive a-oxo gold carbenes[9] could be readily
accessed by simple intermolecular oxidation[10] of terminal
alkynes,[11] therefore allowing substitution of toxic a-diazo
ketones with benign and readily available alkynes
(Scheme 1). This approach was later applied to the prepara-
tion of oxetan-3-ones from easily available propargyl alco-
hols.[12] A further application of this chemistry calls for an
Scheme 2. Design: formation of chiral azetidin-3-ones through tert-
butylsulfinamide derivatives.
We set out to screen different conditions for the key gold-
catalyzed oxidative cyclization of tert-butylsulfonamides.
Using racemic sulfonamide 2a as the substrate, some of the
results are listed in Table 1. As it soon became obvious that
the sulfonamide behaved very differently from its alcohol
counterpart, and azetidin-3-one 3a was formed in only 28%
yield along with a significant amount of mesylate 4a using the
optimized conditions for propargylic alcohol substrates
(Table 1, entry 1).[12] Interestingly, no Wolff rearrangement
product[17] was observed. Varying the N-oxides (Table 1,
entries 2–6), however, revealed that bulky and electron-
deficient 2,6-dibromopyridine N-oxide (5e) was the best
(Table 1, entry 5). Using this optimal oxidant, various gold
catalysts were screened (Table 1, entries 5, 7–11). Those with
2-biphenylphosphine ligands generally performed better
(Table 1, entries 9–11); moreover, a close comparison of the
three 2-biphenylphosphine ligands revealed that the reaction
was slightly more efficient with a bulkier biphenyl group
(compare Table 1, entry 9 and entry 10) but less so if the
Scheme 1. Formation of azetidin-3-ones through alkyne oxidation.
[*] Dr. L. Ye, W. He, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry
University of California
Santa Barbara, CA (USA)
Fax: (+1)805-893-4120
E-mail: zhang@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~zhang/index.html
[**] We thank NIGMS (R01 GM084254) and UCSB for generous
financial support and Dr. Guang Wu for assistance with X-ray
crystallographic analysis. L.Z. is an Alfred P. Sloan fellow.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007624.
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Angew. Chem. Int. Ed. 2011, 50, 3236 –3239

Table 1: Formation of azetidin-3-ones through oxidative cyclization:
functionalized XPhos with MeO groups at the 3- and 6-
positions developed by Buchwald,[18] became an apparent
choice. Complex [BrettPhosAuNTf2] was easily prepared by
following a typical preparative procedure for cationic gold(I)
complexes,[19] and its structure was confirmed by single-crystal
X-ray analysis.[20] To our delight, this new cationic gold(I)
optimization of reaction conditions.[a]
complex offered
a
significant improvement (Table 1,
entry 12). Inspired by our recent work that did not use acid
additives,[11] the reaction was attempted without MsOH.
Pleasingly, azetidin-3-one 2 was formed in an 85% (82%
isolated) yield, and the reaction rate did not decrease to a
significant extent (Table 1, entry 13). Somewhat surprisingly,
dichloro(2-picolinato)gold(III) could also catalyze this reac-
tion with an acceptable efficiency, albeit with the need of
MsOH (Table 1, entry 14). However, PtCl2 did not promote
this reaction (Table 1, entry 15).
Entry Gold catalyst
Oxidant (R) Reaction
conditions
Yield [%][b]
With the optimal reaction conditions secured, the reaction
scope was then studied. Throughout this study, (R)-tert-
butylsulfinamide was used as the chiral auxiliary. As shown in
Table 2, chiral N-propargylsulfinamide derivatives were pre-
pared in excellent diastereoselectivities by following Linꢀs
procedure,[21] and the configuration of the propargyl center
was assigned accordingly. The oxidation of the sulfinamide
using m-CPBA and subsequent gold-catalyzed oxidative
cyclization were performed without column purification of
the sulfonamide intermediate, and the two-step overall yields
are shown. Azetidin-3-one compounds with different sub-
stituents at the 2-position were prepared in mostly good
yields. One exception was a tert-butyl group, where < 35%
yield was observed by 1H NMR analysis, presumably owing to
steric hindrance; in contrast, a cyclohexyl group was readily
3a
28
4a
27
19
–
29
10
15
4
12
10
12
10
4
1
2
3
4
5
6
7
8
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[IPrAuNTf2]
5a (3,5-Cl2) RT, 4 h
5b (4-Ac)
5c (4-Et)
5d (2-Br)
RT, 12 h
RT, 12 h
RT, 4 h
21[c]
<5[d]
30
5e (2,6-Br2) RT, 4 h
RT, 12 h
48
6
22[e]
50
5e (2,6-Br2) RT, 12 h
5e (2,6-Br2) RT, 4 h
[(4-CF3)3PAuNTf2]
[Cy-JohnPhosAuNTf2] 5e (2,6-Br2) RT, 4 h
42
56
58
50
9
10
11
12
13
14
15
[XPhosAuNTf2]
[tBu-XPhosAuNTf2]
[BrettPhosAuNTf2]
[BrettPhosAuNTf2]
AuIII
5e (2,6-Br2) RT, 4 h
5e (2,6-Br2) RT, 4 h
5e (2,6-Br2) RT, 4 h
5e (2,6-Br2) RT, 6 h[f]
5e (2,6-Br2) RT, 30 min
70
85[g]
68
–
<1
–
PtCl2/CO (toluene)
5e (2,6-Br2) 808C, 12 h[f] <5[d]
[a] Reaction conditions: [2a]=0.05m, oxidant (2 equiv). [b] Estimated by
1H NMR analysis using diethyl phthalate as the internal reference.
[c] 20% of 2a remained unreacted. [d] Most 2a remained unreacted.
[e] 10% of 2a remained unreacted. [f] No acid additive, 1.2 equivalents
of 5e. [g] Yield of isolated 3a was 82%. Cy=cyclohexyl, IPr=1,3-bis(2,6-
diisopropylphenyl)imidazolidene, Ms=methanesulfonyl, Tf=trifluoro-
methanesulfonyl.
Table 2: Reaction scope study.[a]
Entry
R
Sulfinamide
Azetidin-4-one
1[b]
Yield d.r.
3
Yield ee
[%][c]
[%][c] [%][d]
1
2
3
4
5
6
7
PhCH2CH2
n-propyl
cyclohexyl
pent-4-en-1-yl
4-bromobutyl
4-azidobutyl
1a
1b
1c
1d
1e
1 f
82
71
78
90
>99:1 3a 82
>99:1 3b 79
>99:1 3c 81
>50:1 3d 80
>99:1 3e 74
>99:1 3 f
>99:1 3g 84
99
99
>99
97
99
98
74
78[e]
76[g]
67[f]
1g
98
8
1h
84
>99:1 3h 78
99
9
10
Ph
2i[h] 71[i]
1j 72
>99:1 3i
>99:1 3j
72[j]
78
98
99
[a] Reaction conditions: [1]=0.05m. [b] Configuration was assignment
based on literature precedents. [c] Yield over two steps. [d] Determined
using HPLC on a chiral stationary phase. [e] Prepared from 1e. [f] The
reaction was run at 408C for 24 h. [g] Prepared from 1 f. [h] The oxidation
with m-CPBA was carried out before desilylation with TBAF. [i] Yield over
three steps. [j] Yield for gold catalysis. Boc=tert-butoxycarbonyl,
cyclohexyl groups were replaced with bigger tert-butyl groups
(compare Table 1, entries 10 and 11). With this trend in mind,
we decided to test dicyclohexylphosphine ligands containing
even bulkier biphenyl moieties. Therefore Brettphos, a
MOM=methoxymethyl,
TBAF=tetra-n-butylammonium
fluoride,
TBDPS=tert-butyldiphenylsilyl, TMS=trimethylsilyl.
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Communications
allowed (Table 2, entry 3). A range of functional groups were
81% ee from the corresponding sulfinamide (d.r. 91:9),[23]
Moreover, the parent N-tert-butylsulfinylazetidin-3-one 3o
was readily prepared using [Et3PAuNTf2] as the catalyst
[Eq. (2)].
À
tolerated, including a remote C C double bond (Table 2,
entry 4), a halogen (Table 2, entry 5), and an azido group
(Table 2, entry 6). In the case of a phenyl group (Table 2,
entry 9), sulfinamide 1i was not stable upon desilylation using
TBAF; instead, m-CPBA oxidation was done before desily-
lation. Pleasingly, the resulting sulfonamide (i.e., 2i) was
stable and underwent the gold-catalyzed oxidative cyclization
easily, and afforded azetidinone 3i in 72% yield (Table 2,
entry 9). Notably, because of the absence of any acid additive,
acid-labile protecting groups such as Boc and MOM were not
affected during the reaction (Table 2, entries 7 and 8). In
addition, a silyl protecting group such as TBDPS was
tolerated (Table 2, entry 10). In all the entries, the azetidin-
4-ones were isolated with excellent ee, which was determined
by HPLC[22] on a chiral stationary phase using racemic
products as references, and essentially no epimerization was
detected. The configuration of the products were assumed
Lately, heterospiro[3.3]heptanes have been proposed as
building blocks in medicinal chemistry.[24] This chemistry, in
combination with our previous oxetan-3-one chemistry,[12]
provided a facile synthesis of oxazaspiro[3.3]heptanone 3p.
The sequence starting from cheap propargyl alcohol is
outlined in Scheme 4, and formation of the azetidine ring
was achieved in a respectable 61% yield. This dual applica-
À
based on the reaction mechanism involving gold carbene N
H insertions.
Interestingly, when furan-containing sulfonamide
2k was subjected to the gold catalysis, the desired
azetidin-3-one was not observed. Instead, conjugated
imine 7 was isolated as a yellow solid in 77% yield, and
its structure was elucidated by single-crystal X-ray
analysis (Scheme 3).[20] This transformation can be
rationalized by invoking a ring opening of the azetidine
intermediate A, facilitated by the electron-rich furan
ring, and subsequent p orbital reorganization.
This chemistry can also be extended to the syn-
thesis of 2,2-disubstituted azetidin-3-ones with service-
able yields [Eq. (1)], and 8-ethylquinoline N-oxide (6)
Scheme 4. Synthesis of oxazaspiro[3.3]heptane 3p. THF=tetrahydrofuran.
was a better oxidant. Notably, 3n was formed with
tion of the a-oxo gold carbene chemistry highlights the
synthetic utility of the gold-catalyzed alkyne oxidation
strategy.
Although linear N-propargylcarboxamides are not suit-
able substrates due to competitive 5-exo-dig cyclization by its
acyl group,[13] lactams such as 1q and 1r with the acyl group
tied back by the ring structure can avoid this issue. Indeed,
these substrates underwent smooth oxidative cyclization, and
led to strained bicyclic lactams 3q and 3r in fairly good yields
and good enantiomeric excesses [Eq. (3)].
Removal of the Bus group was then examined using 3a as
the model substrate (Scheme 5). Direct deprotection under
acidic conditions resulted in a complex mixture, which may be
attributed to the reaction of the carbonyl group with the
newly revealed amine moiety. Consequently, the ketone
Scheme 3. Formation of imine 7.
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[2] C. Hubschwerlen in Comprehensive Medicinal Chemistry II,
Vol. 7, Elsevier, Oxford, 2006, p. 479.
[3] Y. Dejaegher, N. M. Kuz’menok, A. M. Zvonok, N. De Kimpe,
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[5] a) J. Wang, Y. Hou, J. Chem. Soc. Perkin Trans. 1 1998, 1919;
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[6] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclo-
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Scheme 5. Removal of the Bus group.
moiety was reduced with NaBH4. The resulting diastereo-
meric diols were separated, and the trans configuration of the
major isomer (i.e. 8b) was confirmed by single-crystal X-ray
analysis.[20] To our delight, the Bus group in 8b was smoothly
removed under acidic conditions.[15] To facilitate isolation of
the product, the free amine was capped with a Boc group.
In summary, a practical and flexible synthesis of chiral
azetidin-3-ones has been developed. The key reaction is a
gold-catalyzed oxidative cyclization of chiral N-propargylsul-
fonamides. Mechanistically, reactive a-oxo gold carbenes are
generated as intermediates through intermolecular alkyne
À
oxidation and subsequent intramolecular N H insertion. The
use of tert-butylsulfonyl as the protecting group takes
advantage of the chiral tert-butylsulfinimine chemistry and
avoids additional unnecessary deprotection and protection
steps. Moreover, the Bus group can be easily removed from
the azetidine ring under acidic conditions. The extension of
this chemistry using other sulfonyl protecting groups is
currently being examined.
[11] For a study with internal alkynes, see: B. Lu, C. Li, L. Zhang, J.
Am. Chem. Soc. 2010, 132, 14070.
[12] L. Ye, W. He, L. Zhang, J. Am. Chem. Soc. 2010, 132, 8550.
[13] a) A. S. K. Hashmi, P. Weyrauch Jan, W. Frey, W. Bats Jan, Org.
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Organic Synthesis, 4th ed., Wiley-Interscience, Hoboken, NJ,
2007.
[15] P. Sun, S. M. Weinreb, M. Shang, J. Org. Chem. 1997, 62, 8604.
[16] a) M. T. Robak, M. A. Herbage, J. A. Ellman, Chem. Rev. 2010,
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Experimental Section
General procedure for the gold-catalyzed oxidative cyclization: To a
solution of the sulfonamide, generated as a crude residue by m-CPBA
oxidation of sulfinamide 1 in DCE (6 mL), were added N-oxide 5e
(0.36 mmol) and [BrettPhosAuNTf2] (15.3 mg, 0.015 mmol) at RT.
Upon completion of the reaction (as evident by TLC), the reaction
mixture was treated with 1n HCl (15 mL) and extracted with CH2Cl2
(2 ꢁ 30 mL). The combined organic layers were dried with MgSO4,
filtered, and concentrated. The resulting residue was purified by flash
column chromatography on silica gel (eluent: hexanes/ethyl acetate)
to afford the desired azetidin-3-one 3.
[19] N. Mꢅzailles, L. Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133.
[20] CCDC 808743 ([BrettPhosAuNTf2]), 808745 (7), and 808744
(8b) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Received: December 6, 2010
Published online: March 4, 2011
Keywords: azetidines · carbenes · cyclization · gold ·
.
stereoselectivity
[21] B.-L. Chen, B. Wang, G.-Q. Lin, J. Org. Chem. 2010, 75, 941.
[22] Please see the Supporting Information.
[23] A. W. Patterson, J. A. Ellman, J. Org. Chem. 2006, 71, 7110.
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