Synthesis of 1,3-diaminated stereotriads via rearrangement of 1,4-diazaspiro[2.2]pentanes

Article abstract of DOI:10.1021/ol300269u

The synthesis of 1,3-diaminated stereotriads via the bis-aziridination of allenes is reported. The reactive 1,4-diazaspiro[2.2]pentane intermediates undergo a mild Bronsted acid-promoted rearrangement to yield 1,3-diaminated ketones in good yields with ex

Full text of DOI:10.1021/ol300269u

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1704–1707
Synthesis of 1,3-Diaminated
Stereotriads via Rearrangement
of 1,4-Diazaspiro[2.2]pentanes
Cale D. Weatherly, Jared W. Rigoli, and Jennifer M. Schomaker*
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706,
United States
schomakerj@chem.wisc.edu
Received February 2, 2012
ABSTRACT
The synthesis of 1,3-diaminated stereotriads via the bis-aziridination of allenes is reported. The reactive 1,4-diazaspiro[2.2]pentane intermediates
undergo a mild Brønsted acid-promoted rearrangement to yield 1,3-diaminated ketones in good yields with excellent stereocontrol. Directed
reduction of the ketone can be achieved to yield a CꢀN/CꢀO/CꢀN stereotriad in high dr. The ability to transfer the axial chirality of the substrates
to the products allows for the facile preparation of enantioenriched stereotriads from allenes in two simple steps.
Compounds containing 1,3-diamino-2-ol stereotriads
are prevalent in a number of biologically active natural
products and pharmaceuticals. These include the potent
HIV protease inhibitor palinavir, aminated cyclohexanes
that constitute components of streptomycin and other
antibiotics, the natural product manzacidin B, and key
components of the antibiotic mannopeptimycins known as
the hydroxyenduracididines (Figure 1).1
synthesis of 1,3-diaminated compounds.2ꢀ5 Typical ap-
proaches include the addition of enecarbamates to imines
to yield anti 1,3-diamines,2 the diastereoselective reduction
of ketimines,3 diastereoselective CꢀH amination,4 and the
addition of the R-carbanion of imines to N-protected
imines.5 However, access to complex functionalized
1,3-diaminated compounds of the form CꢀN/CꢀX/CꢀN
using well-established methodology is more limited. We
hypothesized that a highly regio- and stereocontrolled allene
oxidation could provide a new and convenient method to
prepare CꢀN/CꢀO/CꢀN stereotriads in a few simple
synthetic manipulations. Our previous work has already
demonstrated the utility of allene bis-aziridination to
1,4-diazaspiro[2.2]pentanes (DASPs) 2 (Scheme 1) as a
convenient scaffold to access vicinal diaminated synthetic
Due to the privileged nature of these motifs, a number of
methods have been developed for the stereocontrolled
(1) Beaulieu, P.; Lavallee, P.; Abraham, A.; Anderson, P. C.;
Boucher, C.; Bousquet, Y.; Duceppe, J.; Gillard, J.; Gorys, V.; Grand-
Maitre, C.; Grenier, L.; Guindon, Y.; Guse, I.; Plamondon, L.; Soucy,
F.; Valois, S.; Wernic, D.; Yoakim, C. J. Org. Chem. 1997, 62, 3440.
(b) Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.; Ohfune,
Y. Org. Lett. 2010, 12, 2170. (c) Aminoglycoside Antibiotics; Arya, D. P.,
Ed.; John Wiley & Sons: Hoboken, NJ, 2007. (d) He, H.; Williamson, R. T.;
Shen, B.; Graziani, E. I.; Yang, H. Y.; Sakya, S. M.; Petersen, P. J.; Carter,
G. T. J. Am. Chem. Soc. 2002, 124, 9729.
(2) For selected references on the synthesis of 1,3-diamines, see:
(a) Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009,
11, 5546. (b) Vesely, J.; Ibrahem, I.; Rios, R.; Zhao, G.; Xu, Y.; Cordova,
A. Tetrahedron Lett. 2007, 48, 2193. (c) Zhao, C.; Liu, L.; Wang, D.;
Chen, Y. Eur. J. Org. Chem. 2006, 13, 2977. (d) Merla, B.; Risch, N.
Synthesis 2002, 10, 1365. (e) Wu, P.; Lin, D.; Lu, X.; Zhou, L.; Sun, J.
Tetrahedron Lett. 2009, 50, 7249. (f) Matsubara, R.; Kobayashi, S. Acc.
Chem. Res. 2008, 41, 292. (g) Robak, M. T.; Herbage, M. A.; Ellman,
J. A. Chem. Rev. 2010, 110, 3600. (h) Lanter, J. C.; Chen, H.; Zhang, X.;
Sui, Z. Org. Lett. 2005, 7, 5905.
(4) For selected references, see: (a) Espino, C. G.; Wehn, P. M.;
Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935. (b) Kurokawa,
T.; Kim, M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 2777. (c) Liang,
C.; Robert-Peillard, F.; Fruit, C.; Mueller, P.; Dodd, R. H.; Dauban, P.
Angew. Chem., Int. Ed. 2006, 45, 4641.
(5) For selected references, see: (a) Hou, X.; Luo, Y.; Yuan, K.; Dai,
L. J. Chem. Soc., Perkin Trans. 1 2002, 12, 1487. (b) Merla, B.; Risch, N.
Synthesis 2002, 10, 1365. (c) Kiss, L.; Mangelinckx, S.; Sillanpaeae, R.;
Fueloep, F.; De Kimpe, N. J. Org. Chem. 2007, 72, 7199.
(6) (b) Grigg, R. D.; Schomaker, J. M.; Timokhin, V. Tetrahedron
2011, 67, 4318. (c) Boralsky, L. A.; Marston, D.; Grigg, R. D.; Hershberger,
J. C.; Schomaker, J. M. Org. Lett. 2011, 13, 1924. Rigoli, J. W.; Boralsky,
L. A.; Hershberger, J. C.; Meis, A. R.; Marston, D.; Guzei, I. A.;
Schomaker, J. M. J. Org. Chem. 2012, 77, 2446.
(3) Martjuga, M.; Belyakov, S.; Liepinsh, E.; Suna, E. J. Org. Chem.
2011, 76, 2635–2647 and references therein.
r
10.1021/ol300269u
Published on Web 03/20/2012
2012 American Chemical Society

complete conversion of the starting material, with Bi(OTf)3
resulting in a 96% isolated yield of 6.
Table 1. Exploring the Rearrangement of an N,N-Spiroaminal
to a 1,3-Diaminated Ketone
entry
additivesa
conversion entry additivesa conversion
Figure 1. Biologically active 1,3-diamino-2-ols.
1
2
3
4
5
6
CeCl3 7H2O
0%
7
Sc(OTf)3
BF3OEt2
TsOH
100%b
100%
100%
96%c
3
NiCl2 6H2O
0%
8
3
Ti(OiPr)4
ZnCl2
0%
9
motifs.6 In this communication, we report a complementary
reactivity that allows for the conversion of these reactive
intermediates to 3 and stereotriads of the form 4.
0%
10
11
12
Bi(OTf)3
100%b
33%
Bi(OTf)3
Bi(OTf)3
100%
100%
d
Cu(OTf)2
InCl3
e
a 1.0 equiv unless otherwise indicated. b Complete conversion, several
side products observed. c Isolated yield. d 0.2 equiv. e 0.05 equiv.
Scheme 1. Bis-aziridination as a Key Step in the Conversion of
Allenes to 1,3-Diamino-2-ols via DASP Intermediates
Bi(OTf)3 was chosen to further optimize the conversion
of the DASP 7 directly to 6 (Table 2). The addition of
Bi(OTf)3 alone (entry 1) did not promote the desired
rearrangement. Treatment of 7 with AcOH, followed by
addition of 5 mol % of Bi(OTf)3 (entry 2), gave complete
conversion of the DASP to 6; however, the ring opening
with AcOH was slow. Interestingly, the ring opening of 7
with TMSCl, followed by treatment with the Lewis acid
(entry 3), gave only the ring-opened product and none of
the desired rearrangement product. The same result was
observed when thioacetic acid (entry 4) was employed as
the nucleophile to open 7. These results suggested that the
ester was playing an important role in promoting the
rearrangement, and indeed, treatment of 7 with chloroa-
cetic acid and Bi(OTf)3 also initiated the desired rearrange-
ment to 6 (entry 5). We suspected that the role of Bi(OTf)3
might be to simply generate small amounts of TfOH,
and the addition of a catalytic amount of TfOH
(entry 6) to a mixture of 7 and AcOH did promote the
desired rearrangement. Ultimately, in order to decrease the
reaction time, AcOH was added to 7 at 35 °C and the
mixturewas heatedfor 8 h prior toaddition of the Bi(OTf)3
(entry 7) to give 6 in 88% isolated yield over the one-pot,
two-step reaction.
A variety of DASPs were converted to the correspond-
ing 1,3-diaminated ketone products (Table 3) using the
optimized reaction conditions. There was only a slight
difference in yield between the use of the DASP 7 or the
ring-opened DASP 5 (entries 1ꢀ2). DASPs formed from Z
bicyclic methylene aziridines also underwent the desired
rearrangement with high stereoselectivity (entries 3 and 4).
The stereospecific nature of the reaction is illustrated by a
comparison of the 1,3-diaminated ketone 6, obtained in
88% yield from the rearrangement of a DASP 7 derived
from an E methylene aziridine, with the distinct product
A DASP such as 2 can essentially be viewed as a 1,3-
diaminated ketone intramolecularly “protected” as an N,
N-aminal (Scheme 1). We initially envisaged that a simple
hydrolysis would yield the desired 1,3-diaminated ketone 3
directly from 2. However, this transformation was unsuc-
cessful utilizing a variety of Lewis and Brønsted acids,
irrespective of the presence or absence of water. In the case
of mild acids, either no reaction was noted or the DASP
underwent ring opening at C1 of 2.2a The use of stronger
acids generallyresultedin intractablemixturesof products.
We postulated that the recalcitrance of the DASP to
undergo hydrolysis might be due to the fact neither nitro-
gen atom is capable of resonance stabilization of an
intermediate carbocation at C2. The relief of ring strain
might render the heteroatoms better able to stabilize this
carbocation, thus facilitating the desired reaction. In this
vein, the acetate-opened DASP 5 was treated with a series
of Lewis and Brønsted acids (Table 1). Weak Lewis acids,
including CeCl3, Ti(OiPr)4, and ZnCl2 (entries 1ꢀ4), gave
no reaction, and the starting material was recovered un-
changed. InCl3 (entry 6) gave slow conversion to the
desired product, while Cu(OTf)2 and Sc(OTf)3 (entries 5
and 7) yielded an unidentified mixture of products.
BF3OEt2, TsOH, and Bi(OTf)3 (entries 8ꢀ12) all gave
Org. Lett., Vol. 14, No. 7, 2012
1705

stereocenters was high in most cases (>19:1). Not surpris-
ingly, if the product was allowed to remain under the acidic
conditions for extended periods of time, significant isomer-
ization to a mixture of diastereomers did occur.
Table 2. Investigation of the Rearrangement Reaction
One convenient advantage of this methodology arises as
a result of the ability to transfer the axial chirality of an
enantioenriched allene to the 1,3-diaminated products.7
The fidelity of this transfer was verified by subjecting an
enantioenriched DASP 9 to the reaction conditions for the
rearrangement to 10 (eq 1). No degradation of the enan-
tiopurity was indicated by chiral HPLC (see the Support-
ing Information for further details).
entry
conditions
Bi(OTf)3 (1.0 equiv)
conversion to 6
1
2
3
4
5
6
7
0%
AcOH, then Bi(OTf)3 (0.05 equiv)a
TMSCl, then Bi(OTf)3 (0.05 equiv)b
AcSH, then Bi(OTf)3 (0.05 equiv)b
ClCH2CO2H, then Bi(OTf)3 (0.05 equiv)
AcOH, then cat. TfOH
100%
0%
0%
100%
100%
AcOH at 35 °C, then Bi(OTf)3 (0.05 equiv) 100% (88%)c,d
a 40 h reaction time. b The product was the ring-opened DASP. c 12 h
reaction time. d Isolated yield with a dr > 19:1.
The next issue was to determine if stereocontrolled
reduction of the ketone could be achieved. The use of
Na(OAc)3BH (STAB-H) for the reduction of 6 gave the
CꢀN/CꢀO/CꢀN stereotriad 11 in 3:1 dr when THF was
employed as the solvent and in 70% yield with a 9:1 dr
when CH2Cl2 was utilized for the reaction (Scheme 2).8
Treatment of 11 with an excess of p-nitrobenzoyl chloride
gave a crystalline derivative 12 (Scheme 2), containing the
three heteroatoms in a 1,2-syn/2,3-anti relationship. This
indicates that the reduction could be controlled either by
chelation involving the NNPhth group or by FelkinꢀAhn
control via the carbamate. Changing the bulk of the side
chain (Scheme 2, compounds 13ꢀ14) did not affect the dr.
Removing the steric bulk in the carbamate ring, as in 15,
gave decreased stereoselectivity, indicating that Felkinꢀ
Ahn control is likely operative.
We were pleased to find that the conversion of allenic
carbamates 16 and 17 to the resulting 1,3-diaminated
ketones 6 and 8d could be achieved in a single pot
(Scheme 3). Although the yields were only moderate
(approximately 80% per chemical step), the reaction in-
troduces significant complexity into a simple, readily
available substrate. The major loss in yield occurs in the
first allene aziridination, where the formation of the Z
methylene aziridine competes with that of the desired E
methylene aziridine. Our ongoing work in the design of
new catalysts with improved selectivity in the allene azir-
idination should alleviate this issue. Regardless, the Z
methylene aziridine reacts much more slowly in the sub-
sequent reactionsand can be easilyseparated from the final
desired product. The diastereoselectivity of the isolated
products was greater than 19:1, comparable to the dr
observed in the stepwise conversion of the isolated DASPs
to 6 and 8d.
Table 3. Rearrangement of DASPs to 1,3-Diaminated Ketones
entrya
R, R1
R2
E/Zc
n
yield
dr
1b
2
5 C5H11, H
Me
Me
E
E
Z
Z
E
E
E
E
E
E
1
1
1
1
1
1
1
0
1
1
96% 6
>19:1
>19:1
86:12
>19:1
7a C5H11, H
88% 6
3b
4
7b H, CH2CO2Et Me
65% 8b
90% 8c
7c H, C5H11
7d C5H11, H
7d C5H11, H
7e Ph(CH2)2, H
7f C5H11, H
7g iBu, H
Me
H
5b
6
89% 8d >19:1
81% 8d >19:1
H
7
H
60% 8e
78% 8f
57% 8g
>19:1
>19:1
>19:1
8b
9
H
H
10
7h iBu, H
Me
77% 8h >19:1
a The dr of the starting DASPs was >19:1 in all cases. b The starting
material was the acetate-opened DASP with a dr > 19:1. c Stereochem-
istry of the methylene aziridine used to form the DASP.
ketone 8c, obtained in 90% yield from the rearrangement
of a DASP formed from a Z-methylene aziridine (Table 3,
entries 2 and 4, respectively). The rearrangement was not
affected by the absence of alkyl substitution in the tether
(entries 5ꢀ9) or limited to the formation of six-membered
rings, as a five-membered ring product 8f (entry 8) was
obtained in 78% yield. The dr of the two nitrogen-bearing
(7) For selected references on allenes and examples of the transfer of
the axial chirality of an allene to point chirality, see: (a) Ogasawara, M.
Tetrahedron: Asymmetry 2009, 20, 259. (b) Kim, H.; Williams, L. J. Curr.
Opin. Drug Discovery 2008, 11, 870. (c) Ma, S. M. Pure Appl. Chem.
€
2006, 78, 197. (d) Krause, N.; Hoffmann-Roder, A. Tetrahedron 2004,
60, 11671. (e) Modern Allene Chemistry; Krause, N. A., Hashmi, S. K.,
Eds.; Wiley-VHC: Weinheim, 2004. (f) Brawn, R. A.; Panek, J. S. Org. Lett.
2009, 11, 4362. (g) Yue, Z.; Williams, L. J. J. Org. Chem. 2009, 74, 7707
and references therein. (h) Shangguan, N.; Kiren, S.; Williams, L. J. Org.
Lett. 2007, 9, 1093. (i) Lotesta, S. D.; Hou, Y. Q.; Williams, L. J. Org.
Lett. 2007, 9, 869. (j) Joyasawal, S.; Lotesta, S. D.; Akhmedov, N. G.;
Williams, L. J. Org. Lett. 2010, 12, 988.
(8) Huang, Y.; Li, M.; Yu, X.; Yuan, Z. Zhongguo Yiyao Gongye
Zazhi 2008, 39, 695. (b) Abdel-Magid, A. F.; Mehrman, S. J. Org.
Process Res. Dev. 2006, 10, 971. (c) Gribble, G. W.; Abdel-Magid, A. F.
Sodium Triacetoxyborohydride. Encyclopedia of Reagents for Organic
Synthesis; 2001.
1706
Org. Lett., Vol. 14, No. 7, 2012

illustrated in Scheme 4 may be operative. A double dis-
placement at C1 of the DASP via anchimeric assistance
would yield retention of the stereochemistry at this carbon,
while promoting the desired hydrolysis at C2.
Scheme 2. Reduction of Aminoketones and Determination of
the Relative Stereochemistry of the CꢀN/CꢀO/CꢀN Stereo-
triad
Scheme 4. Possible Mechanism for the Rearrangement
In conclusion, allene bis-aziridination to 1,4-diazaspiro-
[2.2]pentanes can serve as a key step in the stereoselective
syntheses of 1,3-diaminated ketones and their correspond-
ing CꢀN/CꢀO/CꢀN stereotriads via stereoselective re-
duction with STAB-H. The factors that control the
stereoselective reductions of these 1,3-diaminated ketones
will be further investigated to provide access to other
CꢀN/CꢀX/CꢀN stereoisomers. Studies to apply allene
oxidation methods to the total synthesis of biologically
active molecules, including manzacidin B and (2R,3S,40S)-
hydroxyenduracididine (Figure 1), are underway and will
be reported in due course.
Scheme 3. One-Pot Conversion of Allenic Carbamates to
1,3-Diaminated Ketones
Acknowledgment. The authors thank Dr. Ilia A. Guzei
of the University of Wisconsin;Madison for assistance
with X-ray crystallography. Funding was provided by
start-up funds from the University of Wisconsin;Madison.
The NMR facilities at UW;Madison are funded by the NSF
(CHE-9208463, CHE-9629688) and NIH (RR08389-01).
Supporting Information Available. Experimental de-
tails and characterization data for all new compounds, as
well as X-ray crystallographic information for 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
We did not carry out detailed mechanistic studies on this
unusual rearrangement. However, the stereoselective nat-
ure of the reaction, the necessity for an ester moiety at C1,
and the relative stereochemistry of the 1,3-diaminated
chiral centers suggests that a mechanism similar to that
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
1707