Modular functionalization of allenes to aminated stereotriads

Article abstract of DOI:10.1021/ja304859w

Nitrogen-containing stereotriads, compounds with three adjacent stereodefined carbons, are commonly found in biologically important molecules. However, the preparation of molecules bearing these motifs can be challenging. Herein, we describe a modular oxidation protocol which converts a substituted allene to a triply functionalized amine of the form C-X/C-N/C-Y. The key step employs a Rh-catalyzed intramolecular conversion of the allene to a strained bicyclic methylene aziridine. This reactive intermediate is further elaborated to the target products, often in one reaction vessel and with effective transfer of the axial chirality of the allene to point chirality in the stereotriad.

Full text of DOI:10.1021/ja304859w

Communication
pubs.acs.org/JACS
Modular Functionalization of Allenes to Aminated Stereotriads
Christopher S. Adams, Luke A. Boralsky, Ilia A. Guzei, and Jennifer M. Schomaker*
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
S
* Supporting Information
psymberin, and epi-citreodiol.2c−e Surprisingly, the analogous
ABSTRACT: Nitrogen-containing stereotriads, com-
pounds with three adjacent stereodefined carbons, are
commonly found in biologically important molecules.
However, the preparation of molecules bearing these
motifs can be challenging. Herein, we describe a modular
oxidation protocol which converts a substituted allene to a
triply functionalized amine of the form C−X/C−N/C−Y.
The key step employs a Rh-catalyzed intramolecular
conversion of the allene to a strained bicyclic methylene
aziridine. This reactive intermediate is further elaborated
to the target products, often in one reaction vessel and
with effective transfer of the axial chirality of the allene to
point chirality in the stereotriad.
allene aziridination has received little attention, despite its
synthetic potential for preparing complex amines.3,4
Previous efforts by the Robertson and our group to
transform allenic N-tosyloxycarbamates or carbamates 1 to
bicyclic methylene aziridines 2 gave poor to moderate chemo-
and stereoselectivities (Scheme 1, top).3a−f However, we found
Scheme 1. Allene Oxidation Strategy for the Preparation of
Nitrogen-Containing Stereotriads
ensely functionalized amines bearing stereodefined
D
heteroatom groups located adjacent to the chiral
nitrogen-bearing carbon (X/N/Y stereotriads, where X and Y
represent a halogen, oxygen, nitrogen, or sulfur-containing
group) occur frequently in natural products and biologically
active molecules (Figure 1).1 We were intrigued by the idea of
that switching to an allenic sulfamate 4 gave a highly reactive
methylene aziridine 5 that, in the presence of nucleophiles,
underwent regioselective ring-opening to yield the E-
enesulfamate 6 exclusively. We surmised the cyclic nature of
6 might impart good facial selectivity in its subsequent reaction
with an electrophile, as conformation B minimizes the A1,3
strain present in 6. The favored conformation of the resulting
iminium ion 7 would again minimize A1,3 strain. As the majority
of electrophiles utilized in our work have A values smaller than
that of C5H11, additional shielding of the top face of 7 should
result in stereoselective reduction to yield the 1,2-syn:2,3-syn
product 8 as the major diastereomer.5
Figure 1. X/N/Y stereotriads in bioactive molecules.
developing highly modular and streamlined methods for the
chemo-, regio-, and stereoselective construction of these motifs.
This communication reports the modular preparation of X/N/
Y stereotriads from allenes. These chiral hydrocarbons were
chosen as precursors due to their ease of preparation, potential
for introducing three new heteroatoms in a single reaction
vessel, and the ability to transfer readily available axial chirality
to point chirality in the products.
Allene bis-epoxidation, pioneered by the Crandall and
Williams groups, has been the only major approach thus far
to introduce multiple heteroatoms into these chiral hydro-
carbons.2 The Williams group has further demonstrated the
utility of allene epoxidation in the elegant syntheses of several
natural product targets, including the epoxomicinoids,
Treatment of an allenic sulfamate 9 (Table 1) with PhIO and
catalytic Rh2TPA4 (TPA = triphenylacetate) cleanly yielded the
Received: May 18, 2012
Published: June 18, 2012
© 2012 American Chemical Society
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Communication
Table 1. Tandem Aziridination/Ring-Opening
a
b
entry
Nu-X
equiv
solvent
temp (°C)
time (h)
yield
75%
product
c
1
AcO-H
6
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
5
10
11
12
13
14
15
16
17
2
3
4
5
6
7
8
MeO-H
HO-H
50
rt
1
77%
a
20
rt
0.7
2
74%
PhNH-H
morpholine
piperidine
PhS-H
1.3
1.6
1.3
10
rt
68%
rt
2.5
1
71%
d
rt
75%, 90%
69%
rt
1
a
e
Cl-TMS
1.5
THF
0 °C to rt
8
56% (62%)
a
b
c
d
Solvent exchange. Time for MA ring-opening only. 0.3 mol % catalyst was used. 1H NMR yield based on the use of mesitylene as an internal
e
standard. Based on recovered starting material
desired E bicyclic methylene aziridine 5 (Scheme 1, R = C5H11)
as observed by 1H NMR. A series of weak nucleophiles
promoted ring-opening of this methylene aziridine in situ to
yield the corresponding E enesulfamates. Successful oxygen
nucleophiles included AcOH, methanol, and H2O (entries 1−
3) and gave the products 10−12 in good yields. The unusually
activated nature of the bicyclic methylene aziridine was
demonstrated by its facile reaction with amines that typically
do not open aziridines in the absence of an exogenous Lewis
acid (entries 4−6).6 Finally, PhSH and TMSCl (entries 7, 8)
were also shown to be competent nucleophiles under these
mild conditions.
The enesulfamates proved sufficiently nucleophilic to react
with a range of standard electrophiles. The intermediate
iminium ion 7 (see Scheme 1) was sensitive to hydrolysis, thus,
the dr of the product resulting from the initial nucleophilic
addition step was not determined. Rather, the reductant was
added to the same reaction vessel to supply the final desired
stereotriad and the overall dr of the reaction recorded (Table
2). For example, treatment of 10 with N-bromosuccinimide
(NBS), followed by NaBH3CN (entry 1) gave 18 in 71%
isolated yield and a dr of 12.5:1. The relative stereochemistry of
18 was confirmed as 1,2-syn-2,3-syn by X-ray crystallography
and the minor diastereomer was assigned as 1,2-anti-2,3-syn
1
based on H NMR coupling constants (see the Supporting
Information (SI) for details). The relative stereochemistries of
the remaining products in Table 1 were assigned by analogy to
18.
Modifying the nature of the electrophile allowed us to
control the dr of the stereotriad (Table 2, compare entries 2
and 3). When N-chlorosuccinimide (NCS) was employed, 19
was obtained in 65% NMR yield and a dr of 5:1. However, the
more electrophilic trichloroisocyanuric acid (TCICA, entry 3),
improved both the yield and dr of 19 to 72% and >19:1.
Selectfluor (entry 4) resulted in a 2:1 dr of 20, possibly due
to increased epimerization at C3 caused by the electron-
withdrawing fluorine. The stereochemistry of the major
diastereomer could be assigned by analogy to 18 as 1,2-
syn:2,3-syn; however, the identity of the minor diastereomer
was believed to be 1,2-syn:2,3-anti (see SI for details). Nitrogen
was introduced at C3 using DIAD (entry 5) to provide the
vicinal diaminated stereotriad 21 in 69% yield with a dr of
>19:1.7 PhSCl (entry 6) gave 22 in 80% yield and a dr of 2.9:1,
along with minor amounts of two other stereoisomers.8
Reaction of 10 with DMDO (entry 7) and sodium
triacetoxyborohydride (STABH) as the reductant gave 23 in
lower dr, in this case due to poor facial selectivity in the
addition of the electrophile to the enesulfamate. As in the case
of 20, the major diastereomer was assigned by analogy to 18
Table 2. Stereotriads from Enesulfamates
1
and the minor diastereomer as 1,2-syn:2,3-anti by H NMR
coupling constants. Future improvements in the dr and yield of
this reaction will clarify whether the free oxygen is exerting a
directing effect in the reduction step.
The challenging generation of a complex quaternary amine-
bearing carbon was accomplished by adding carbon nucleo-
philes to the transient iminium ion 7 according to the model
proposed in Scheme 1. For example, employing ethynyl
magnesium bromide (entry 8) in the reaction at low
temperature gave 24 in >19:1 dr, while a Strecker-type reaction
employing TMSCN (entry 9) gave 25 in 73% yield and a dr of
3.3:1.9
a
b
NMR yield using mesitylene as the internal standard. dr of the
c
The allene amination chemistry was quite flexible, as
demonstrated by the conversion of a variety of heteroatom-
substituted enesulfamates to the corresponding X/N/Br
product after purification. 10 mol % Cu(OTf)2 and 11 mol %
Me2N(CH2)2NMe2 were also added to the reaction. Minor amounts
of other diastereomers were formed.
d
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Journal of the American Chemical Society
Communication
stereotriads (Table 3). Ethers, alcohols, amines, mercaptans,
and halogens were all tolerated in the reaction and gave
moderate to good dr of the resulting stereotriads 26−30.
ing allenes, this simplifies the formation of enantioenriched
stereotriads to a diastereoselective process.10a,b As illustrated in
Scheme 2, (R)-9 was smoothly converted into (S,S,R)-29 with
no erosion in the ee.
Table 3. Formation of X/N/Br Stereotriads
Scheme 2. Transfer of Axial to Point Chirality
entry
X
yield
crude dr
isolated dr
19:1
1
2
3
4
5
11
12
15
16
17
OMe
65%
71%
44%
67%
26
27
28
29
30
8:1
a
OH
5.6:1
10:1
>19:1
4:1
Finally, to demonstrate that the X/N/Y stereotriads could be
easily deprotected, the nitrogen of 32 (eq 1) was protected with
a Boc group. Successive treatment of the N-protected 32 with
Bu4NCN and HCl provided 33 in 79% yield over the two
steps.11
piperidine
SPh
19:1
>19:1
b
b
Cl
77%
>19:1
>19:1
a
b
After attempted separation of the two diasteromers. 1H NMR using
mesitylene as the internal standard.
We were pleased to find that the mild reaction conditions,
coupled with the high chemo-, regio-, and diastereoselectivity of
the allene oxidation, allowed for conversion of 9 directly to X/
N/Y stereotriads in a single flask (Table 4). The key to
obtaining high dr hinged on minimizing the time that the
electrophile was allowed to react with the intermediate
enesulfamate (entries 1, 2). The 61% overall yield for the O/
N/Br stereotriad 18 (entry 2) obtained in one pot compared
favorably with the yield that was obtained when the reaction
was performed in two steps (53%, Table 1, entry 1 and Table 2,
entry 1). When MeOH was utilized as the nucleophile (entries
3 and 4), the dr of 26 was lower compared to that obtained by
initiating the stereotriad formation from the isolated
enesulfamate (see Table 3, entry 1), but the one-pot yield of
58% compared favorably with the two-step yield of 50%.
Enantioenriched 9 (entry 5 and Scheme 2) gave 29 in good
yield and excellent dr. The use of DIAD and PhSCl as the
electrophiles with MeOH as the nucleophile (entries 5 and 6)
gave 31 and 32 in 64% and 74% yields, respectively, over the
four consecutive reactions.
In conclusion, a new method for the syntheses of stereotriads
containing three contiguous heteroatom-bearing carbons of the
general pattern X/N/Y has been developed. These trans-
formations utilize easily prepared sulfamoyl allenes and
generally proceed with good chemo-, regio-, and diastereose-
lectivity under mild reaction conditions. The axial chirality of an
enantioenriched allene can be translated into point chirality in
the product with good fidelity. Further studies are underway to
expand the scope of the allene, the nucleophile, and the
electrophile, particularly in the context of generating X/N/C
stereotriads and amines containing two or three contiguous
quaternary carbons. Studies to selectively access all four
possible diastereomers of a given stereotriad are also underway
and will provide a better understanding of the factors
responsible for stereocontrol in our allene amination chemistry.
The ability to transfer the axial chirality of the allene to point
chirality in the stereotriad is an important aspect of this
chemistry.2c−g,10 As many convenient methods are available to
convert enantioenriched propargyl alcohols to the correspond-
Table 4. One-Pot Stereotriad Synthesis
b
entry
NuH
electrophile
rxn time/temp
yield
dr
1
2
3
4
AcOH
AcOH
MeOH
MeOH
PhSH
NBS
NBS
NBS
NBS
NBS
2 h, rt
60%
61%
60%
58%
61%
64%
74%
18
18
26
26
29
31
32
5:1
15 min, 0 °C
45 min, 0 °C
10 min, −10 °C
10 min, 0 °C
2 h, 70 °C
20:1
1.7:1
2.6:1
15:1
4.6:1
2.6:1
c
5
d
6
7
MeOH
MeOH
DIAD
PhSCl
30 min, rt
a
b
Conditions: (1a) 0.5 mol % Rh2TPA4, 1.1 equiv PhIO, CH2Cl2, rt, 1 h, then NuH; (1b) electrophile, NaBH3CN. Time and temperature for the
c
d
addition of the electrophile. See Scheme 2. Celite filtration before addition of the DIAD.
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Communication
(5) Stereochemistry of Organic Compounds; Eliel, E. L., Wilen, S. H.,
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details for the synthesis and characterization of all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
schomakerj@chem.wisc.edu
Notes
Chem. 2006, 78, 197. (d) Krause, N.; Hoffmann-Roder, A. Tetrahedron
̈
The authors declare no competing financial interest.
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.
ACKNOWLEDGMENTS
■
(11) Tanino, T.; Ichikawa, S.; Matsuda, A. Org. Lett. 2011, 13, 4028.
Financial support was provided by the University of Wisconsin,
Madison. The NMR facilities at UW-Madison are funded by
the NSF (CHE-9208463, CHE-9629688) and NIH (RR08389-
01). The authors thank Professors Steven Burke, Sam Gellman,
and Tehshik Yoon, Dr. Dan Wherritt, and Dr. John
Hershberger of the University of Wisconsin-Madison for
helpful discussions. Jahaziel Jahzerah is thanked for assistance
with substrate preparation.
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