Stereocontrolled Syntheses of Seven-Membered Carbocycles by Tandem Allene Aziridination/[4+3] Reaction

Article abstract of DOI:10.1002/anie.201606195

A tandem allene aziridination/[4+3]/reduction sequence converts simple homoallenic sulfamates into densely functionalized aminated cycloheptenes, where the relative stereochemistry at five contiguous asymmetric centers can be controlled through the choice

Full text of DOI:10.1002/anie.201606195

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201606195
German Edition: DOI: 10.1002/ange.201606195
Cycloaddition
Stereocontrolled Syntheses of Seven-Membered Carbocycles by
Tandem Allene Aziridination/[4+3] Reaction
Nels C. Gerstner, Christopher S. Adams, Maik Tretbar, and Jennifer M. Schomaker*
Abstract:
A tandem allene aziridination/[4+3]/reduction
sequence converts simple homoallenic sulfamates into densely
functionalized aminated cycloheptenes, where the relative
stereochemistry at five contiguous asymmetric centers can be
controlled through the choice of the solvent and the reductant.
The products resulting from this chemistry can be readily
transformed into complex molecular scaffolds which contain
up to seven contiguous stereocenters.
D
ensely functionalized seven-membered rings are valuable
synthetic targets occurring in a range of bioactive natural
products and their analogues (Figure 1). Several approaches
Figure 1. Bioactive natural products with seven-membered carbo-
cyclic cores.
to address the challenge of controlling the stereochemical
outcome in the synthesis of seven-membered rings have been
developed, including annulations, ring-closing metatheses,
and an array of cycloaddition reactions.[1] One powerful
strategy involves the [4+3] reaction of a 1,3-diene with
a suitable three-carbon coupling partner, analogous to the
venerable Diels–Alder reaction, with the potential to form
multiple new stereocenters in a highly controlled fashion.[2,3]
Oxyallyl cations are popular coupling partners in [4+3]
cycloadditions. However, use of their nitrogen counterparts is
far less common. Reactive 2-amidoallyl cations for reported
intramolecular [4+3] reactions have been generated from
a-chloroenamines, a-chloroimines, allenes, and methylene
aziridines (Scheme 1a).[3–5] Typically, nitrogen is not retained
in the product and the stereochemical outcome is dictated by
the nature of the substrate. With these limitations in mind, we
wanted to develop an intermolecular, stereodivergent [4+3]
Scheme 1. Stereochemical diversity by allene aziridination.
esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionic acid.
cycloaddition protocol with the ability to rapidly increase
molecular complexity from simple allene precursors.
Our group has reported a suite of highly chemo-, regio-,
and stereoselective oxidative aminations which transform
allenes into a diverse array of amine stereotriads with control
over both the identity and relative stereochemistry of the
three heteroatoms at C1–C3.[6] We envisaged extending this
concept to controlling the relative stereochemistry at each of
the three original allene carbon atoms in the synthesis of
aminated cycloheptenes through a tandem aziridination/
[4+3]/reduction sequence (Scheme 1b). This strategy fea-
tures: 1) a one-pot allene aziridination/ring opening of the
À
C N bond of 2 to yield a 2-amidoallyl cation (3 and 4),
2) intermolecular trapping with inexpensive furan, where the
reaction conditions control the relative stereochemistry at C1
and C3 in 5 and 6, and 3) reagent-controlled reduction of the
imine to yield stereodivergent syntheses of all four stereoiso-
mers of 7 containing functionality for further elaboration into
useful building blocks.[7]
[*] N. C. Gerstner, C. S. Adams, Dr. M. Tretbar, Prof. J. M. Schomaker
Department of Chemistry, University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706 (USA)
E-mail: schomakerj@chem.wisc.edu
Initial efforts to convert 8 into the imines 12 and 13
through the intermediacy of 10 and 11 (Table 1) showed a 1:1
THF/furan mixture successfully transformed 9 into the endo
[4+3] adduct 12 at room temperature (entry 2). The syn C1–
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201606195.
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Table 1: Solvent screen for the formal [4+3] cycloaddition.
Table 2: Scope of the [4+3] reaction in MeNO2 using NaBH3CN as
reductant.
Entry Cosolvent
Yield [%][a,b]
(24 h, RT)
12/13
Yield [%][b]
(24 h, 508C)
12/13
1
2
3
4
5
none
THF
MeCN
MeNO2
CF3CH2OH
0
35
0
0
0
–
–
31
21
31
26
–
>20:1
>10:1
~1:3
<1:10
<1:10
–
–
–
[c]
[a] Reactions at room temperature performed in sealed vials. [b] Yields
and d.r. values determined by 1H NMR spectroscopy with an internal
trimethoxybenzene standard. [c] When run at 658C for 7 h, the yield was
45% with about a 1:6 ratio of 12/13. THF=tetrahydrofuran.
C3 relationship was established by X-ray crystallography (see
the Supporting Information). Reactions in polar aprotic
solvents, such as MeCN and MeNO2 (entries 3 and 4) did
not occur at room temperature, but heating to 508C resulted
in endo cyclization to furnish 13 with a 1,3-anti relationship.
The yield of 13 was increased to 45% over two steps by
heating in MeNO2 at 658C, albeit with a slightly lower
d.r. value.
The differing stereochemical outcomes in 12 and 13
obtained by using THF and MeNO2 were intriguing, and
control experiments showed neither product epimerized
under the reaction conditions. Shimizu[8] noted solvent effects
on the d.r. value of [4+3] cycloadditions of 2-oxyallyl cations.
In contrast to our results, MeNO2 favored 1,3-syn products
with a typical d.r. value of 2:1, while THF/Et2O favored the
1,3-anti products, also with a low d.r. value.[8] We hypothesize
that under our reaction conditions, 12 results from rapid
addition of furan to 11, while THF permits equilibration of
the cation 11 to 10 to relieve the A1,3 strain, thus resulting in
the syn product 12. This strain relief could occur through
rapid reversible addition of the ethereal oxygen atom to the
allyl cation, thus permitting bond rotation and equilibration
to 11 before addition of furan takes place.
The scope of the thermal [4+3] cycloaddition in MeNO2
was explored first (Table 2). The intermediate imines were
reduced using NaBH3CN, thus resulting in attack on the imine
through a pseudo-axial trajectory. The allenes 8 and 14–16,
with monosubstitution at C3 (entries 1–4), delivered 13a–16a
with moderate to good d.r. values. The additional stereocen-
ter a to C3 in 17 (entry 5) exerted an influence on the
d.r. value of 17a, thus resulting in only two major diastereo-
mers in a 4.7:1 ratio.[9,10]
[a] Reaction conditions: a) 1 mol% Rh2(TPA)4, PhIO, 4 ꢀ M.S., CH2Cl2,
RT. b) 1:1 MeNO2/furan, 4 ꢀ M.S., 658C. c) NaBH3CN, AcOH, MeCN,
RT. [b] Treatment with NaBH3CN, AcOH, MeCN, RT, followed by
chromatography and reduction of the remaining imine with 5 equiv
LiBH4, THF, À788C to RT. [c] 500 psi H2 5% Pd/C, EtOAc; then LiBH4,
THF, À788C to RT. [d] Purified by column chromatography at the imine
stage, then reduced with 5 equiv LiBH4, THF, À788C to RT. BPS=tert-
butyldiphenylsilyl, M.S.=molecular sieves, TPA=triphenylacetic acid.
19a. Ultimately, we found olefin hydrogenation (entry 7;
using Pd/C and H2) prior to imine reduction gave reprodu-
cibly high yields of 19a with excellent d.r. values.[10] The
chemistry could even distinguish between a Me and Et group
at C3 of 20 to yield either 20a (entry 8) or 21a (entry 9, Pd/C
and H2 to reduce the alkene) with good d.r. values.[10] Finally,
the trisubstituted allene 22, containing an additional stereo-
center a to C3, gave 22a (entry 12) with a d.r. value com-
parable to that of 17 (entry 5).
Access to the 1,2-syn/2,3-anti diastereomer 13b requires
the hydride to approach the 1,3-anti imine from the same face
as any substituents at C3 of the allene precursor (Table 3).
DIBAL-H and triisobutylaluminum gave 13b as the minor
diastereomer, however, AlH3·Me2NEt furnished the desired
stereochemical outcome. Presumably, AlH3 binds to the
oxygen atom of the [3.2.1] bicyclic ring to direct reduction
to the hindered imine face, although coordination to the
sulfamate O or to the imine is also possible. The challenge of
overriding substrate control is reflected in lower d.r. value
Gratifyingly, 18 (Table 2, entry 6) proved a good substrate
for tandem aziridination/cycloaddition to set the all-carbon
quaternary stereocenter. While NaBH3CN gave low conver-
sion, LiBH4 yielded 18a in 10:1 d.r. When the three-step
transformation was performed in one pot, residual rhodium
catalyzed the reduction of the olefin with LiBH4 to furnish
2
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Table 3: Scope of the [4+3] cycloaddition in MeNO2 with AlH3·Me2NEt
Table 4: Scope of the [4+3] cycloaddition/reduction in THF.
as the reductant.
[a] Reaction conditions: a) 1 mol% Rh2(TPA)4, PhIO, 4 ꢀ M.S., CH2Cl2,
RT. b) 10 mol% AgPF6, 1:1 THF/furan, 4 ꢀ M.S., 458C.
[a] a) 1 mol% Rh2(TPA)4, PhIO, 4 ꢀ M.S., CH2Cl2, RT. b) 1:1 MeNO2/
furan, 4 ꢀ M.S.,658C. c) AlH3·Me2NEt, PhCH3, RT. [b] Yield determined
by 1H NMR spectroscopy.
ability to racemize the axial chirality of the allene during the
cycloaddition process could be used to an advantage to
transfer chirality at the sp3 carbon atom of 17 to the three
carbon atoms of the initial racemic allene to yield 17a
(Scheme 2) in moderate d.r. and excellent ee values.[10,11]
and scope (entries 1–3) compared to the 1,2-anti/2,3-syn
diastereomers. Alane tolerated neither a silicon-protected
oxygen atom in 16 nor branching a to C3 in 17 as 16b and 17b
were observed only in trace amounts (entries 4 and 5). Axial
reduction was noted for trisubstituted allenes (entry 6), and
despite the lower d.r. value, the use of AlH3·Me2NEt gave
more reproducible access to 18a, as compared to the use of
LiBH4 (Table 2, entry 6).
The next goal was to improve access to 1,3-syn imines of
the form 12. Reaction of 8 with a rhodium catalyst, followed
by [4+3] in THF at 508C (Table 1, entry 2) resulted in only
a 31% yield of 12. A variety of Lewis acids (see the
Supporting Information) were tested, with 10 mol% of
AgPF6 providing optimal results. Adoption of these reaction
conditions furnished the 1,3-syn imine 30 (Table 4) in a typical
d.r. of greater than 10:1. To achieve tunable reduction of 30,
we postulated that less bulky hydride sources (NaBH3CN)
should approach from the top face of 30 to favor the 1,2-anti/
2,3-anti diastereomers. In contrast, a bulkier reductant, such
as LiBHEt3, would be expected to favor reduction from the
face opposite the alkene bridge to give the all-syn stereo-
triads. The 1,3-syn imines were much easier to reduce than the
corresponding 1,3-anti imines. For example, NaBH3CN re-
duced syn imines to the anti/anti products 13–16c (entries 1, 3,
5, and 7) with good to excellent d.r. values. Switching the
reductant to LiBHEt3 delivered the syn/syn products 13–16d
(entries 2, 4, 6, and 8), also in good d.r.
Scheme 2. Enantioenriched cycloheptenes by [4+3] reactions.
The cycloheptenes from the tandem allene aziridination/
formal [4+3] are flexible scaffolds for further diversification,
as 12 has four primary reactive functional handles which can
be manipulated (Scheme 3). For example, reduction of 12,
activation of the sulfamate and nucleophilic attack with either
thiophenol or diethyl malonate delivers 23 or 24, respectively,
in good yields.[11,12] Ring contraction to the pyrrolidine 25[5c,6a]
can be achieved or the ether bridge cleaved in an SN2’ fashion
using tBuLi as a nucleophile to give a 1:1 mixture of the
regioisomers 26 and 27.[13] Dihydroxylation of the alkene
yields 28 with high d.r. value, and this sequence sets seven
contiguous stereocenters with high d.r. values over four steps
from a simple allene.[10,14] Carbon nucleophiles also add to 12,
as evidenced by a Strecker reaction to afford 29.
In conclusion, we have described the first examples of
intermolecular [4+3] reactions occurring via 2-amidoallyl
cations arising from direct allene aziridination. The ability to
manipulate the stereochemistry of the intermediate ami-
doallyl cation leads to stereodivergent syntheses of all four
possible diastereomeric cycloheptenes resulting from endo
cyclization. The functional-group diversity of the products
In our previous work, aziridination and subsequent
functionalization of enantioenriched allenes gave excellent
transfer of axial to point chirality.[6a,c] However, the interme-
diacy of an amidoallyl cation in the [4+3] precludes chirality
transfer (see the Supporting Information). Nonetheless, the
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[2] For reviews dedicated to [4+3] cycloadditions, see: a) I. V.
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Ghosh, J. Org. Chem. 2011, 76, 3246.
Scheme 3. Synthetic utility of cycloheptene products. a) NaBH3CN,
AcOH, MeCN; 41%, 16:1 d.r. from 8. b) Boc2O, cat. DMAP, Et3N,
CH2Cl2, RT. c) Thiophenol, K2CO3, CH3CN, RT; 75% from 13. d) Diethyl
malonate, TBAB, Cs2CO3, MeCN, RT; 58% from 13. e) KOtBu, DMAP,
CH2Cl2, 08C; then Ac2O, RT; 96%. f: f) NaI, DMF, 608C; then NaH, 40
to 608C; 83%. g) tBuLi, THF, À408C; 61% of a 1:1 mixture of
regioisomers. h) 10 mol% OsO4, NMO, acetone, H2O, tBuOH, RT;
65%, >20:1 d.r. i) nBu4NCN, MeCN, RT; 80% yield from 12. Boc=
tert-butoxycarbonyl, DMAP=4-(N,N-dimethylamino)pyridine,
DMF=N,N-dimethylformamide, NMO=N-methylmorpholine N-oxide,
TBAB=tetra-n-butylammonium bromide.
enables access to an array of densely functionalized synthetic
building blocks in a few simple steps. While the stereoablative
nature of the chemistry prevents direct transfer of axial-to-
point chirality, the presence of an additional stereocenter can
be employed to yield enantioenriched aminated carbocycles.
Future work is focused on expanding the scope of both allenes
and coupling partners, as well as applying this methodology to
the syntheses of both bioactive natural products and their
aminated analogues.
[8] N. Shimizu, M. Tanaka, Y. Tsuno, J. Am. Chem. Soc. 1982, 104,
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Acknowledgments
J.M.S. thanks the NIH 1R01GM111412-01 and NSF-
CAREER Award 1254397 for funding. The NMR facilities
at UW-Madison are funded by NSF (CHE-9208463, CHE-
9629688) and NIH (RR08389-01). The National Magnetic
Resonance Facility at UW-Madison is supported by NIH
(P41GM103399, S10RR08438, S10RR029220) and NSF
(BIR-0214394). Lu Liu, Josh Taylor, and Nick Dolan of
UW-Madison are thanked for starting materials and assis-
tance with NOE studies. Adrian Amador is acknowledged for
his assistance with SFC analyses.
[10] The relative stereochemistry of product was determined by NOE
studies.
[11] F. Duran, L. Leman, A. Ghini, G. Burton, P. Dauban, R. H.
Dodd, Org. Lett. 2002, 4, 2481.
ˇ
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Keywords: allenes · cycloaddition · heterocycles · rhodium ·
synthetic methods
[14] S. He, R. P. Hsung, W. R. Presser, Z.-X. Ma, B. J. Haugen, Org.
Lett. 2014, 16, 2180.
[1] For selected reviews, see: a) T. V. Nguyen, J. M. Hartmann, D.
Enders, Synthesis 2013, 45, 845; b) M. A. Battiste, P. M. Pel-
phrey, D. L. Wright, Chem. Eur. J. 2006, 12, 3438; c) H. Pellissier,
Adv. Synth. Catal. 2011, 353, 189; d) D. A. Foley, A. R. Maguire,
Tetrahedron 2010, 66, 1131.
Received: June 26, 2016
Published online: && &&, &&&&
4
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Cycloaddition
N. C. Gerstner, C. S. Adams, M. Tretbar,
J. M. Schomaker*
&&&& — &&&&
Stereocontrolled Syntheses of Seven-
Membered Carbocycles by Tandem Allene
Aziridination/[4+3] Reaction
Magic seven: A tandem allene aziridina-
tion/[4+3]/reduction sequence converts
homoallenic sulfamates into aminated
cycloheptanes, where the relative stereo-
chemistry at five contiguous chiral carbon
atoms can be controlled through the
choice of solvent. The resulting products
can be readily transformed into complex
molecular scaffolds that contain up to
seven contiguous stereocenters.
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