A novel asymmetric azaspirocyclisation using a Morita-Baylis-Hillman-type reaction

Article abstract of DOI:10.1055/s-0029-1219210

A Morita-Baylis-Hillman-type reaction has been applied to the asymmetric preparation of azaspirocycles in high yield and diastereoselectivity. The optimisation of the reaction is discussed and a model for the origin of diastereoselectivity is proposed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219210

LETTER
579
A Novel Asymmetric Azaspirocyclisation Using a Morita–Baylis–Hillman-
Type Reaction
N
ovel Asy
o
mmetric Az
n
a
tionusinga
t
Morit
h
a–Baylis–Hi
a
n
R
eaction C. Killen,a John Leonard,b Varinder K. Aggarwal*a
a
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Fax +44(0)1179298611; E-mail: v.aggarwal@bristol.ac.uk
b
Process R&D, AstraZeneca plc, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, UK
Received 3 December 2009
This paper is dedicated with deep respect to Gerry Pattenden on the occasion of his 70th birthday
spirocycles by development of methodology previously
published from our group, in which enones 2, activated by
Michael addition of a sulfide (5), were able to react with
in situ generated iminium ions 4 (Scheme 1).4 Morita–
Baylis–Hillman-type (MBH-type) adducts 3 were ob-
tained after elimination of sulfide in a second step.
Abstract: A Morita–Baylis–Hillman-type reaction has been ap-
plied to the asymmetric preparation of azaspirocycles in high yield
and diastereoselectivity. The optimisation of the reaction is dis-
cussed and a model for the origin of diastereoselectivity is pro-
posed.
Key Words: Morita–Baylis–Hillman-type reaction, azaspirocycli-
sation, spiro compounds, asymmetric synthesis, diastereoselectivity
O
O
( )m
( )m
+
OMe
X
X
N
N
The azaspirocyclic motif is found in a large number of
natural products, including the cylindricine1 and
histronicotoxin2 families, halichlorine and the pinnaic
acids (Figure 1).3
PG
( )n
PG
( )n
2
3
1
2. NaHCO3
quench
3. DBU
1. TMSOTf, SMe2,
–78 °C to –20 °C
H
L.A. OMe
( )m
R3
OTMS
O
( )m
O
N
H
HN
R1
X
X
N
R3
N
H
O
PG
( )n
( )n
N
R2
PG
Me2S
Me2S
Me
R1
4
5
6
R2
PG = Ts, Boc or Cbz; m = 1 or 2, n = 0, 1 or 2; X = H, CH2, Me, SEt, OMe.
histrionicotoxins
R1 = OH or H
2 = H, 3-C chain or 5-C chain
3 = H, 2-, 3-, or 4-C chain
Cl
HO
halichlorine
Scheme 1 Morita–Baylis–Hillman-type reaction
R
R
Me
X
An intramolecular version of the reaction employing a
combination of TMSOTf and BF3·OEt2, forming the
Lewis acid BF2OTf in situ,5 was used to prepare the bicy-
clic pyrrolizidine alkaloid (+)-heliotridine.4 The choice of
Lewis acid was critical, since a weaker Lewis acid would
not form a stable sulfide adduct at room temperature6 as
required for ring closure.
O
HN
H
O
X
H
N
HO
X
N
R
O
H
R
Me
cylindricines
R = C6H13 or C4H9
X = Cl, OH, OMe, OAc, SCN or NCS
Cl
HO
pinnaic and tauropinnaic acid
X = OH, NH(CH2)2SO3H
O
H
O
( )m
( )m
Figure 1 Azaspirocycles in natural products
Lewis acid, SR2*
route A
( )n
OMe
H
N
N
( )n
R
R
Ever since their discovery, formation of the asymmetric
spirocentre in these molecules has presented an inspiring
challenge to synthetic chemists. Herein we report a meth-
od for high yielding, highly diastereoselective preparation
of azaspirocycles amenable to a range of further function-
alisation as required. We were able to obtain these aza-
7
8
R = Boc, Cbz, Ts
O
H
O
( )m
( )m
Lewis acid, SR2
route B
( )n
H
O
O
N
O
N
( )n
Ph
Ph
SYNLETT 2010, No. 4, pp 0579–0582
Advanced online publication: 19.01.2010
DOI: 10.1055/s-0029-1219210; Art ID: D35109ST
0
1.
0
3.
2
0
1
0
OH
10
9
Scheme 2 Strategy for asymmetric azaspirocyclisation
© Georg Thieme Verlag Stuttgart · New York

580
J. C. Killen et al.
LETTER
Table 1 Preparation of Azaspirocycle Precursors
The preparation of 9 is shown below (Table 1). The first
two steps are adapted from a known preparation of aminal
13.8 The adaptation (reversing the order of the first two
steps)9 not only made purification of 13 much easier on
the scale required, but also led to a more reproducible and
less capricious process in our hands. Cross metathesis
with acrolein gave the azaspirocycle precursors 9.
O
( )n
THF, –10 °C to r.t., 18 h
MgBr
( )n
HO
O
O
O
O
12
11
( )n
(R)-phenylglycinol
O
N
O
Our investigations of the key azaspirocyclisation step be-
gan by replicating the conditions previously used for in-
tramolecular MBH-type reaction (Table 2, entry 1).4 The
reaction was successful, although low yielding. However,
through variation of the Lewis acid employed we discov-
ered that simply using BF3·OEt2 (entry 3) gave good
yields and good levels of stereocontrol. The reaction
could be extended to the 5,6-spirocycle (entry 4) but not
to the 5,7-spirocycle (entry 5).
PPTS, toluene, Dean–Stark reflux, 18 h
Ph
13
O
( )n
H
Hoveyda–Grubbs II, acrolein
CH2Cl2, reflux, 5 h
O
N
O
Ph
9
n
1
2
3
Yield (%) of 13 (over 2 steps) Yield (%) of 9
It is noteworthy that in all of these cases the sulfide was
eliminated on NaHCO3 workup and separate treatment
with DBU was not required (see Scheme 1).
30
24
27
61
66
56
Variation in the sulfide structure led to further improve-
ments (Table 3). Anisyl methyl sulfide was found to be
optimal (Table 3, entries 5 and 6), providing high levels of
stereocontrol and moderate to good yields. Unfortunately
we were unable to extend this protocol to the 5,7-spirocy-
cles, 6,5- or 6,6-azaspirocycles. In fact the six-membered-
ring cyclic aminals appeared to be very stable to a range
of Lewis acid and nucleophile combinations.10 In all cases
we either recovered starting material or decomposition
occurred.
We have investigated two approaches to asymmetric aza-
spirocycle formation (Scheme 2). Route A employs a ra-
cemic acyclic aminal together with a chiral sulfide. A
chiral sulfide has been used previously in an MBH-type
reaction to generate adducts of the form of 3 (Scheme 1)
with good stereocontrol.4 Unfortunately no methods are
known for preparation of the acyclic aminals required for
our study and our efforts to synthesise them proved unsuc-
cessful.
The two diastereomers could be readily separated by col-
umn chromatography. The stereochemistry of the major
diastereomer was proved by X-ray diffraction analysis
(Figure 2).11 Reduction and deprotection of 10 gave the
enantiopure azaspirocycle 15 (Scheme 3).12
We were successful in preparing the cyclic aminal 9 of
route B. Since the aminal also functions as a chiral auxil-
iary, the need for a chiral sulfide is obviated. Furthermore,
there was precedence for the reaction of related aminals
with nucleophiles showing good levels of stereocontrol.7
Table 2 Lewis Acid and Solvent Optimisation
O
H
O
( )n
H
Lewis acid, SMe2
solvent, temp, 18 h
O
O
N
O
N
( )n
Ph
10
Ph
9
OH
Entry
1
n
1
Lewis acid
Solvent
MeCN
Temperature
–15 °C
Yield (%)
41
dr
TMSOTf + BF3·OEt2
83:17
(3 equiv) each
2
3
4
5
1
1
2
3
TMSOTf
(3 equiv)
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
–15 °C
trace
78
n/a
BF3·OEt2
(3 equiv)
–78 °C to r.t.
–78 °C to r.t.
–78 °C to r.t.
82:18
79:21
n/a
BF3·OEt2
(3 equiv)
81
BF3·OEt2
trace
(3 equiv)
Synlett 2010, No. 4, 579–582 © Thieme Stuttgart · New York

LETTER
Novel Asymmetric Azaspirocyclisation using a Morita–Baylis–Hillman-Type Reaction
581
Table 3 Lewis Acid and Solvent Optimisation
F3B
O
H
Nu:
O
H
SR2
O
H
O
R
O
1. BF3⋅OEt2, (3 equiv),
sulfide (3 equiv)
O
O
BF3
( )n
N
N
H
O
O
O
SN2-type
N
O
N
( )n
N
CH2Cl2, –78 °C to r.t., 18 h
Ph
Ph
O
Ph
10
BF3
Ph
2. DBU (2.5 equiv),
CH2Cl2, r.t., 1 h
OH
10
9
H
9
OH
16
major diastereomer
observed
Entry
n
Sulfide
Step 2
Yield
dr
required? (%)
O
H
1
2
3
4
5
6
7
1
2
1
2
1
2
3
SMe2
no
78
82:18
79:21
93:7
O
N
SMe2
no
81
F3BO
R
:Nu
O
N
PhSMe
no
53
Ph
H
17
Ph
PhSMe
no
35
88:12
89:11
92:8
OH
18
minor
diastereomer
R
MeOC6H4SMe
MeOC6H4SMe
MeOC6H4SMe
yes
yes
yes
73
O
BF3
N
O
SN1-type
63
Ph
O
H
9
trace
n/a
:Nu
electronic
repulsion
O
N
H
R
O
N
F3BO
Ph
19
possible Felkin–Anh
Ph
OH
10
major
conformations of auxiliary
diastereomer
Scheme 4 Model for diastereoselectivity
convex face of the bicyclic aminal. This leads to the major
diastereomer observed.
An alternative SN1 pathway may also be operational. Ap-
plying the Felkin–Anh requirement that the nucleophile
approaches over the smallest substituent (H),13 two con-
formers are possible. Of these, 19 is likely to suffer elec-
tronic repulsion between the carbonyl group and the
trifluoroborate ether as shown.14 Reaction via 17 would
lead to the minor diastereomer.
Figure 2 Single crystal structure of 10
Meyers first proposed this competition between SN1 and
SN2 pathways in nucleophilic addition to bicyclic ami-
nals.7a His findings support the application of the Felkin–
Anh model to explain diastereoselectivity in such sys-
tems. It is reasonable that the SN2 pathway dominates over
the SN1 pathway since the reaction is intramolecular and
would therefore benefit from a degree of bond formation
in the transition state. In addition, the transition state on
the SN2 pathway can be stabilised by the p-stacking of the
boron enolate with the phenyl ring of the auxiliary (16,
Scheme 4).15
O
H
OH
OH
a
b
O
O
O
N
N
N
H
Ph
Ph
15
OH
OH
14
10
Scheme 3 Auxiliary cleavage. Reagents and conditions: (a) NaBH4,
MeOH, –30 °C, 1 h, 56%; (b) Na, NH3(l), THF, –78 °C, 90 s, 61%
In summary, a Morita–Baylis–Hillman-type reaction has
been developed and optimised for the asymmetric prepa-
ration of azaspirocycles. The auxiliary used can be
cleaved using a two-step sequence. The azaspirocycles
formed are potentially highly versatile synthetic interme-
diates with the capacity for a range of further functionali-
sation.
The stereochemical outcome of the reaction can be ratio-
nalised by consideration of the pathways available to the
activated aminal (Scheme 4).
A direct SN2 approach of the trifluoroborate enol ether nu-
cleophile would occur from behind the C–O bond, which
coincidentally is also from the less sterically hindered
Synlett 2010, No. 4, 579–582 © Thieme Stuttgart · New York

582
J. C. Killen et al.
LETTER
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We would like to thank the EPSRC and AstraZeneca for financial
support. We are grateful to Dr Mairi Haddow for X-ray single cry-
stal structure analysis.
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Synlett 2010, No. 4, 579–582 © Thieme Stuttgart · New York