Modular asymmetric synthesis of functionalized azaspirocycles based on the sulfoximine auxiliary

Article abstract of DOI:10.1021/ol0706410

A modular asymmetric synthesis of the functionalized azaspirocycles 6 (m = 2, n = 1), 7 (m = 1, n = 2), 8 (m = n = 2), 12, 20, and 24 from the cyclic allylic sulfoximines 1 is described. The synthetic strategy is based on the stereoselective construction

Full text of DOI:10.1021/ol0706410

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2155-2158
Modular Asymmetric Synthesis of
Functionalized Azaspirocycles Based on
the Sulfoximine Auxiliary
Adeline Adrien, Hans-Joachim Gais,* Franz Ko
Gerhard Raabe
1hler, Jan Runsink, and
Institut fu¨r Organische Chemie der Rheinisch-Westfa¨lischen Technischen Hochschule
(RWTH) Aachen, Landoltweg 1, 52074 Aachen, Germany
Gais@RWTH-Aachen.de
Received March 16, 2007
ABSTRACT
A modular asymmetric synthesis of the functionalized azaspirocycles 6 (m
) 2, n ) 1), 7 (m ) 1, n ) 2), 8 (m ) n ) 2), 12, 20, and 24 from
the cyclic allylic sulfoximines 1 is described. The synthetic strategy is based on the stereoselective construction of the carbocycle 4 containing
the amino-substituted tertiary C atom from 1 followed by the generation of the azaspirocycle. Three different routes have been followed for
the synthesis of the heterocyclic ring: N,C-dianion cycloalkylation, ring-closing metathesis, and N-acyl iminium ion formation.
Azaspirocycles of type I (Figure 1) are found as structural
motifs in a number of highly interesting natural products,
particular, the marine alkaloid II containing a 6-azaspiro-
[4.5]decane framework has received much attention in recent
years because of its interesting biological activities and
intricate structure.4 A number of methods have been devel-
oped for the construction of I,5 especially within the context
of total syntheses or synthetic approaches to the aforemen-
tioned and other related target molecules. Although most of
these primarily target-molecule-orientated methods are imagi-
native and high yielding, there is still an interest in the
development of a more general method for the enantiose-
(1) Kotera, M. Bull. Soc. Chim. Fr. 1989, 370-397.
(2) Jilal Miah, M. A.; Hudlicky, T.; Redd, J. W. In The Alkaloids; Cordell,
G. A., Ed.; Academic: San Diego, CA, 1998; Vol. 51, pp 199-269.
(3) Weinreb, S. M. Chem. ReV. 2006, 106, 2531-2549.
(4) Clive, D. L. J.; Yu, M.; Wang, J.; Yeh, V. S. C.; Kang, S. Chem.
ReV. 2005, 105, 4483-4514.
Figure 1. Azaspirocycles I and halichlorine II.
such as histrionicotoxin,1 cephalotaxine,2 cylindricine A,3
lepadiformine,3 halichlorine (II),4 and pinnaic acid.4 In
(5) Dake, G. Tetrahedron 2006, 62, 3467-3492.
10.1021/ol0706410 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/01/2007

lective construction of I. Here, we describe a modular asym-
metric synthesis of functionalized 1-azaspiro[4.5]decanes (I,
m ) 1, n ) 2), 1-azaspiro[5.5]-undecanes (I, m ) 2, n )
2), and 6-azaspiro[4.5]decanes (I, m ) 2, n ) 1) based on
the sulfoximine auxiliary by exploiting its special fea-
tures, including chirality, carbanion stabilization, and nucleo-
fugacity.6
Our synthetic approach to azaspirocycles is based on a
two-step strategy in which the carbocycle with the tertiary
C atom bearing the amino group is constructed followed by
formation of the heterocycle to generate the spiro-ring sys-
tem. The asymmetric synthesis of the amino-substituted car-
bocycle takes advantage of the methods developed in our
laboratories for the synthesis of â-amino acids from sulfox-
imines.7
CO3 in MeOH furnished carbamates 3a and 3b,10 respec-
tively. The crude carbamates 3a and 3b were subjected to a
treatment with 1.3 equiv of n-BuLi, which gave the oxazi-
nones 4a and 4b, respectively, with high diastereoselectivities
in 79 and 77% overall yields, respectively, based on the
starting alcohols 2a and 2b.10 The configuration of oxazinone
4a was determined by X-ray crystal structure analysis.
Having achieved an efficient synthesis of the functional-
ized carbocycles 4a and 4b, which carry three contiguous
stereogenic C atoms, we focused on the construction of the
heterocyclic ring starting from 4a and 4b. Three different
routes were followed, including (1) the cycloalkylation of a
carbamate-sulfoximine dianion, (2) a ring-closing meta-
thesis, and (3) an N-acyl iminium ion formation.
First, the synthesis of the heterocyclic ring through
cycloalkylation of the C,N-dianions of 4a and 4b with
ditosylates was studied.11 Thus, treatment of the five-
membered cyclic sulfoximine 4a with 2.2 equiv of n-BuLi
in THF at low temperatures generated the corresponding
N,C-dianion11 which was stable in solution and gave upon
treatment with the C3-ditosylate 5a tricycle 6 having a
6-azaspiro[4.5]decane skeleton with high diastereoselectivity
in 75% yield (Scheme 2). The configuration of sulfoximine
The starting R-configured cyclic allylic sulfoximines 1a
and 1b (Scheme 1) were prepared as described previously
Scheme 1. Synthesis of Carbocycles Having an
Amino-Substituted Tertiary C Atom
Scheme 2. Synthesis of Azaspirocycles by C,N-Dianion
Cycloalkylation
by the addition-elimination-isomerization route from (R)-
N,S-dimethyl-S-phenylsulfoximine (g98% ee)8 and the cor-
responding cycloalkanones.9 Lithiation of 1a and 1b followed
by the treatment of the lithiated allyl sulfoximines with 2.1
equiv of ClTi(Oi-Pr)3 furnished the corresponding bis(allyl)-
9
titanium complexes admixed with ClTi(Oi-Pr)3 which
reacted with acetaldehyde with high regioselectivities (g95%)
and good diastereoselectivities at the γ-position and afforded
the homoallylic alcohols 2a and 2b, respectively. HPLC and
crystallization of the mixtures of diastereomers gave the
diastereomerically pure alcohols 2a and 2b in 78 and 75%
yield, respectively. Treatment of alcohols 2a and 2b with
trichloroacetyl isocyanate and the subsequent hydrolysis of
the corresponding N-trichloroacetyl carbamates with (NH4)2-
6 was determined by X-ray crystal structure analysis. Double
deprotonation of the six-membered cyclic sulfoximine
5b and treatment of the corresponding N,C-dianion with the
(6) Reggelin, M.; Zur, C. Synthesis 2000, 1, 1-64.
(7) Gais, H.-J.; Loo, R.; Roder, D.; Das, P.; Raabe, G. Eur. J. Org. Chem.
2003, 1500-1526.
(8) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909-912.
(9) Gais, H.-J.; Hainz, R.; Mu¨ller, H.; Bruns, P. R.; Giesen, N.; Raabe,
G.; Runsink, J.; Nienstedt, S.; Decker, J.; Schleusner, M.; Hachtel, J.; Loo,
R.; Woo, C.-W. Eur. J. Org. Chem. 2000, 3973-4009.
(10) Carbamate 3b was obtained as a Z/E mixture (88:12). However,
both isomers afforded oxazinone 4b with high diastereoselectivity.
2156
Org. Lett., Vol. 9, No. 11, 2007

C2-ditosylate 5b afforded tricycle 7 having a 1-azaspiro[4.5]-
decane skeleton with high selectivity in 57% isolated yield
(73% based on conversion). Finally, reaction of the N,C-
dianion derived from the six-membered cyclic sulfoximine
4b with 5a furnished tricycle 8 having a 1-azaspiro[5.5]-
undecane skeleton with high diastereoselectivity in 59%
isolated yield (72% based on conversion). The high diastereo-
selectivities of the cycloalkylation of the N,C-dianions
derived from 4a and 4b are noteworthy. The selective
formation of the S-configured tricycles can be rationalized
by assuming a chelate structure of type 9 for the C,N-
dianions12 and a preferential attack of the ditosylate at the
Si side of the CR atom followed by a cyclization.
ization with formation of the epimeric carbanion epi-10.
The epimer should be thermodynamically preferred over
10 because of the relief of steric interaction between the
sulfoximine group and the carbocycle. Finally, protonation
of 10 preferentially occurs from the direction of pyramidal-
ization and gives epi-7. The selective synthesis of epi-7 from
7 points to the possibility of the realization of highly stereo-
selective reactions of the R-sulfonimidoyl carbanions derived
from the tricyclic sulfoximines 6-8 with electrophiles.
The application of tricycles 6-8 to the synthesis of
azaspirocyclic natural products requires a substitution of the
sulfoximine group. This was accomplished, for example, by
the treatment of sulfoximine 6 with ClCO2CH(Cl)Me, which
gave chloride 12 with high diastereoselectivity in good yield
and sulfinamide 11. The configuration of 12 was determined
by a combination of TOCSY and NOE experiments. Thus,
the substitution of sulfoximine 6 had occurred with retention
of configuration. We had previously shown that sulfinamide
11 is formed in such reactions with complete retention of
configuration at the S atom and can not only be isolated in
high yield but also recycled for the synthesis of 1.13 The
mechanism of the substitution of sulfoximines with chloro-
formates is not known.7,13 Previously, both retention and
inversion of configuration had been observed in the substitu-
tion of secondary sulfoximines. The available evidence
including the formation of 11 suggests an acylation of
sulfoximine 6 at the N atom with formation of the amino-
sulfoxonium salt 13. The formation of chloride 12 from 13
with complete retention of configuration could be the result
of two yet unidentified SN2 reactions or a SN1 reaction with
the intermediate formation of the carbenium ion 14. How-
ever, it is difficult to see why the carbenium ion 14 should
be attacked by the Cl- ion with high selectivity from that
side which seems to be the sterically more hindered one.
The alternative ring-closing metathesis route for the
construction of the heterocyclic ring required the synthesis
of suitable dienes from sulfoximines 4a and 4b via a
substitution of the sulfoximine group by a nucleophilic and
H atom at the N atom by an electrophilic reagent (Scheme
4). Therefore, sulfoximine 4a was treated with a mixture of
ClCO2CH(Cl)Me and NaI, which gave iodide 15 (Scheme
4) in good yield. The reaction of iodide 15 with 1-prope-
nylmagnesium bromide (Z/E mixture) in the presence of CuI
furnished alkene 16 (Z/E ) 2:1) in good yield. Attachment
of an unsaturated substituent at the N atom was accomplished
upon treatment of carbamate 16 with allyl bromide, which
afforded diene 17 (Z/E ) 2:1) in good yield. The treatment
of diene 17 with 5 mol % of catalyst 1814 gave alkene 19
having a 6-azaspiro[4.5]decane skeleton in high yield.
Finally, the hydrolysis of oxazinone 19 with CsOH furnished
the azaspirocycle 20 in good yield. This route could perhaps
also open an access to azaspirocycles having a medium or
large sized heterocyclic ring.
Interestingly, the successive treatment of sulfoximine 7
with n-BuLi and aqueous NH4Cl afforded the epimeric
sulfoximine epi-7 with high diastereoselectivity in good yield
(Scheme 3). Deprotonation of 7 should afford carbanion 10,
Scheme 3. Stereoselective Epimerization and Cl Substitution
of Sulfoximines
which is most likely endowed with a pyramidalized CR atom,
a CR-S conformation as depicted, and a N-Li bond.12
R-Sulfonimidoyl carbanions are configurationally labile,12
and thus, carbanion 10 is expected to undergo an isomer-
(11) For the cycloalkylation of C,N-dianions, see: (a) Costa, A.; Na´jera,
C.; Sansano, J. M. Tetrahedron: Asymmetry 2001, 12, 2205-2211.
(12) Gais, H.-J.; Erdelmeier, I.; Lindner, H. J.; Vollhardt, J. Angew. Chem.
1986, 98, 914-915; Angew. Chem., Int. Ed. Engl. 1986, 25, 938-939. (b)
Gais, H.-J.; Dingerdissen, U.; Kru¨ger, C.; Angermund, K. J. Am. Chem.
Soc. 1987, 109, 3775-3776. (c) Gais, H.-J.; Lenz, D.; Raabe, G.
Tetrahedron Lett. 1995, 36, 7437-7440.
(13) (a) Gais, H.-J.; Babu, G. S.; Gu¨nter, M.; Das, P. Eur. J. Org. Chem.
2004, 1464-1473. (b) Tiwari, S. K.; Gais, H.-J.; Lindenmaier, A.; Babu,
G. S.; Raabe, G.; Reddy, L. R.; Ko¨hler, F.; Gu¨nter, M.; Koep, S.; Iska, V.
B. R. J. Am. Chem. Soc. 2006, 128, 7360-7373. (c) Loo, R. Ph.D. Thesis,
RWTH Aachen, 1999.
(14) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140.
Org. Lett., Vol. 9, No. 11, 2007
2157

Scheme 4. Synthesis of Azaspirocycles by Ring-Closing
Scheme 5. Synthesis of Azaspirocycles by N-Acyl Iminium
Metathesis Reaction
Ion Formation
The stereoselectivity of the formation of acetal 24 is
noteworthy. It is not known at present whether the exclusive
formation of 24 is the result of a thermodynamic or kinetic
control. Acetal 24 should allow a further functionalization
at the R-position to the N atom via the formation of 23.16
In summary, we have developed a modular asymmetric
synthesis of azaspirocycles, the heterocyclic and carbocyclic
rings of which carry different functional groups, from cyclic
allyl sulfoximines. The use of ring-substituted cyclic allylic
sulfoximines17 as starting material should permit an access
to azaspirocycles, the carbocyclic ring of which has two
functional groups.
Having realized syntheses of azaspirocycles with func-
tional groups in the δ-, γ-, and â-position to the N atom of
the heterocyclic ring, it was of interest to see whether an
access to azaspirocycles carrying a functional group at the
R-position could also be opened. Therefore, iodide 15 was
treated with the functionalized cuprate 21,15 which gave
acetal 22 in good yield (Scheme 5). Acetal 22 was submitted
to a treatment with H2SO4 in methanol, which furnished,
perhaps with the intermediate formation of the N-acyl
iminium ion 23, the tricyclic acetal 24 having a 6-azaspiro-
[4.5]decane skeleton with high diastereoselectivity in good
overall yield. The configuration of 24 was determined
through a combination of TOCSY and NOE experiments.
Acknowledgment. Financial support of this work by the
Deutsche Forschungsgemeinschaft (SFB 380 and GK 440)
is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures for 4a, 6, 12, and 24, and copies of the NMR spectra
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0706410
(16) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-
3856.
(17) Rajender, A.; Gais, H.-J. Org. Lett. 2007, 9, 579-582.
(15) Brandaenge, S.; Dahlman, O.; Lindqvist, B.; Maahlen, A.; Moerch,
L. Acta Chem. Scand. B 1984, B38, 837-844.
2158
Org. Lett., Vol. 9, No. 11, 2007