An enantioselective formal total synthesis of (-)-TAN1251A

Article abstract of DOI:10.1055/s-2004-829092

An enantioselective total synthesis of the muscarinic inhibitor (-)-TAN1251A has been achieved. An alkylidene 1,5-CH insertion reaction was used as a key step to produce a [5,5]-spirocyclic intermediate, which was transformed into the [6,5]-spirocyclic co

Full text of DOI:10.1055/s-2004-829092

LETTER
1443
An Enantioselective Formal Total Synthesis of (–)-TAN1251A
F
ormal To
a
tal Synthes
m
is of (-)-T
A
N1251Aes M. A. Auty,a Ian Churcher,b Christopher J. Hayesa
a
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax +44(115)9513564; E-mail: Chris.Hayes@nottingham.ac.uk
b
The Neurosciences Research Centre, Merck Sharp & Dohme, Terlings Park, Harlow, Essex, CM20 2QR, UK
Received 19 April 2004
Dedicated to Professor Clayton H. Heathcock in honour of his many outstanding contributions to organic chemistry
1,5-CH insertion reaction and that these materials could
be transformed into a range of interesting amino acid tar-
get structures. Upon examining the structures of
TAN1251A (1) and B (2) we realised that an alkylidene
Abstract: An enantioselective total synthesis of the muscarinic in-
hibitor (–)-TAN1251A has been achieved. An alkylidene 1,5-CH
insertion reaction was used as a key step to produce a [5,5]-spirocy-
clic intermediate, which was transformed into the [6,5]-spirocyclic
core of the natural product via an oxidative cleavage/aldol conden- carbene insertion reaction could also be used indirectly to
sation sequence. The synthesis of the natural product was then com-
pleted using standard procedures.
access the [6,5]-spirocyclic core of these natural products
and our retrosynthetic analysis is outlined in Scheme 1.
Key words: total synthesis, alkaloid, carbene insertion, asymmetric
synthesis, spiro compounds
Me
O
O
Me
Me
H
N
+
1 (-)-TAN1251A
O
The alkaloids TAN1251A 1 and TAN1251B 2 (Figure 1)
were isolated from a culture of Penicillium thomii RA-89
by researchers at Takeda Chemical Industries Ltd.,1 and
they possess potent cholinergic activity. TAN1251A is a
selective inhibitor of the M1 muscarinic receptor subtype
and the affinity of TAN1251B to a muscarinic acetylcho-
line receptor is stronger than that of atropine.
N
3
O
4
O
Boc
N
Boc
N
OTBS
OMs
Me
O
Me
N
5
6
N
Me
O
H
R
Boc
O
Boc
H
N
N
1 (-)-TAN1251A R=H
OTBS
OTBS
2 (+)-TAN1251B R=OH
MeO2C
Figure 1
8
7
Scheme 1
Since their appearance in the patent literature, 1 and 2
have attracted attention from synthetic organic chemists
and five total syntheses of TAN1251A (1) have been pub-
lished to date.2 TAN1251B (2) has proved to be a more
challenging synthetic target due to the presence of a nitro-
gen-bearing quaternary stereocentre. In fact, only Snider2b
has reported a synthesis of 2 via the a-hydroxylation of
TAN1251A (1), and this transformation could only be ac-
complished in modest yield. Several years ago we initiat-
ed a research programme examining the synthesis of
target structures that contained nitrogen-bearing quaterna-
ry stereocentres as a key structural feature, and we found
that alkylidene carbenes could be used to solve this syn-
thetic problem.3 Our studies had shown that [5,5]-spirocy-
clic structures were especially easy to construct using a
Following the precedent set by Kawahara et al.,2a we first
disconnected (–)-TAN1251A (1) to reveal the aldehyde 3
and the [6,5]-spirocyclic fragment 4 as key late-stage in-
termediates. Further disconnection of 4 via cleavage of
the bridged bicyclic moiety identified the cyclohexenone
6 as an important spirocyclic building block. We envis-
aged that 6 could be accessed from the [5,5]-spirocycle 5
via an oxidative cleavage-aldol condensation sequence.4
The spirocycle 5 would be constructed using an alkyl-
idene carbene 1,5-CH insertion reaction via 7, and the cy-
clisation precursor should be readily available from a
suitably protected trans-hydroxyproline derivative 8.5 We
were particularly attracted to this synthetic route as the cy-
clohexenone 6 should be produced in high enantiomeric
and diastereomeric excess, and will afford us the opportu-
nity to access TAN1251B (2) via conversion of the enone
into an a-hydroxy ketone.6
SYNLETT 2004, No. 8, pp 1443–1445
0
1.
0
7.
2
0
0
4
Advanced online publication: 22.06.2004
DOI: 10.1055/s-2004-829092; Art ID: Y02704ST
© Georg Thieme Verlag Stuttgart · New York

1444
J. M. A. Auty et al.
LETTER
Table 1 The Key 1,5-CH Insertion Reaction
The synthesis of TAN1251A (1) began with the prepara-
tion of 8 from trans-4-hydroxyproline using standard pro-
cedures.5 The ester 8 was then partially reduced with
DIBALH to afford the corresponding aldehyde, which
was then treated with (acetylmethylene)triphenylphos-
phorane to give the resulting a,b-unsaturated ketone in ex-
cellent yield. Catalytic hydrogenation (Pd/C, H2, EtOAc)
of the enone then provided the ketone 9 in quantitative
yield. Having developed an efficient route to 9, we were
able to synthesise the vinylbromide 10 and the vinylchlo-
ride 11 via simple Wittig olefination chemistry. This se-
quence could be performed on large scale and multigram
quantities of the three alkylidene carbene cyclisation pre-
cursors 9, 10 and 11 could be prepared easily (Scheme 2).
Boc
Boc
N
N
conditions
OTBS
OTBS
A or B
X
conditions:
5
X=O 9
X=CHBr 10
X=CHCl 11
A, LiC(TMS)N2, Et2O, -78 °C to r.t.
B, KHMDS, Et2O, r.t.
Cyclisation
precursor
E:Z ratio
Conditions
Isolatedyield
of 5 (%)
9
10
10
10
11
N:A
1:0
A
B
B
B
B
40–86
68
73
66
93
9:1
Boc
Boc
1:2
N
N
i-iii
OTBS
OTBS
2.4:1
MeO2C
8
9
O
were able to cyclise a single 84 g batch of 11 and we ob-
tained a 78% yield of the [5,5]-spirocycle 5. All of these
reactions were performed at between 0 °C and room tem-
perature, and there were no obvious scale-up problems. In
all cases we obtained 5 as a single diastereoisomer, thus
indicating that the CH-insertion process had proceeded
with the expected high level of stereoselectivity.
v
iv
Boc
Boc
N
N
OTBS
OTBS
10
11
Br
Cl
Scheme
2
Reagents: (i) DIBALH, CH2Cl2, –78 °C; (ii)
Having developed an efficient route to the [5,5]-spirocy-
cle 5 we were now ready to explore the remaining steps
needed to complete a synthesis of (–)-TAN1251A (1).
The first task was to perform a ring expansion reaction to
Ph3PCHC(O)CH3, CH2Cl2 (91%, 2 steps); (iii) Pd/C, H2, EtOAc
(100%); (iv) (Ph3PCH2Br)Br, KHMDS, THF (79%), (1.3:1 E:Z); (v)
(Ph3PCH2Cl)I, KHMDS, THF (100%), (2.4:1 E:Z)
We were now in a position to examine the key 1,5-CH in-
sertion reaction and we first chose to examine the cyclisa-
tion of 9. Following the standard procedure as described
by Ohira,7 9 was added to a preformed solution of lithiated
TMS-diazomethane at low temperature (–78 °C) and the
resulting solution was allowed to warm to room tempera-
ture. Nitrogen gas was evolved during the warming pro-
cess, which is indicative of the alkylidene carbene 7 being
formed in solution. Once the reaction was judged com-
plete by TLC analysis, we were pleased to find that the de-
sired [5,5]-spirocyclic product 5 was produced as the
major new product in modest to excellent yield (40–86%).
Boc
N
O
O
OTBS
i
ii, iii
5
6
12
iv-vi
O
OEt
N
Boc
N
N3
vii-ix
NH2
O
O
O
O
13
14
O
Although, we were pleased by this initial success, the
large variation in isolated yield of 5 was not acceptable
and we decided to examine the use of the vinyl halides 10
and 11 as cyclisation precursors. Pleasingly, both 10 and
11 proved to be good substrates for the CH-insertion reac-
tion and treatment of either compound with KHMDS in
Et2O8 afforded the desired spirocycle 5 as the major new
product.9 Separation of the E- and Z-olefin isomers of 10
and 11 proved to be quite difficult on large scale,10 but we
found that the E:Z ratio of the starting vinyl halide made
little or no difference to the isolated yield of the cyclised
products (see Table 1). Our best results were obtained us-
ing the vinylchloride 11 as the CH-insertion precursor and
consistently high yields could be obtained in the cyclisa-
tion reaction. Even on large scale, we were able to obtain
excellent yields for the formation of 5. In one reaction we
x-xii
Me
H
Me
N
xiii, xiv
N
4
Me
O
O
O
xv
15
(-)-TAN1251A 1
Scheme 3 Reagents: (i) K2OsO4·H2O, NMO, acetone–H2O then
NaIO4, THF–H2O (74%, 2 steps); (ii) KOH (5% aq), CH2Cl2, TBAB
(67%) or TBAF (1 M in THF), THF (89%); (iii) MsCl, Et3N, CH2Cl2,
(87%); (iv) H2, Pd/C, EtOAc (98%); (v) NaN3, DMF (87%); (vi)
HOCH2CH2OH, PTSA, PhH (92%); (vii) TFA; (viii) K2CO3,
BrCH2CO2Et, MeCN (64%, 2 steps); (ix) H2, Pd/C, MeOH; (x) LiOH,
H2O; (xi) DPPA, Et3N, DMF (40%, 3 steps); (xii) NaH, MeI, THF
(73%) (xiii) LDA, 2, THF, –78 °C (43%); (xiv) MsCl, Et3N, CH2Cl2
then t-BuOK, THF, 0 °C (92%); (xv) AlH3 (prepared from LiAlH4
and AlCl3), Et2O then HCl (2 N), acetone (10–81%).
Synlett 2004, No. 8, 1443–1445 © Thieme Stuttgart · New York

LETTER
Formal Total Synthesis of (-)-TAN1251A
1445
afford the [6,5]-spirocyclic core of 1 and this was readily enone into an a-hydroxy ketone.6 The results of these
achieved using an oxidative cleavage-aldol condensation studies will be reported in due course.
sequence (Scheme 3). Although ozonolysis worked well
Acknowledgment
on small scale, we found that the two-step dihydroxyl-
ation/periodate cleavage method was most suitable for
large-scale synthesis of the keto-aldehyde 12. A number
of reaction conditions were screened for the key intramo-
lecular aldol condensation reaction and we found that the
use of phase-transfer conditions (tetrabutylammonium
bromide, KOH–CH2Cl2) were particularly effective. Un-
der these conditions we found that the cyclisation pro-
ceeded well to afford the desired cyclohexenone moiety,
but significant amounts of the intermediate aldol product
could also be isolated. In addition to facilitating cyclisa-
tion, the TBS-group was also removed from the protected
secondary hydroxyl group under these conditions. Rather
than being problematic, this deprotection proved to be an
advantage as it eliminated a step later in the synthesis. It
is interesting to note that the TBS-deprotection and aldol–
cyclisation sequence could also be achieved if 12 was
treated with TBAF (1 M in THF). Subsequent treatment of
the mixture of products from the deprotection–aldol con-
densation with mesyl chloride and triethylamine resulted
in the formation of the cyclohexenone 6 as the major new
product (70–80% over 2 steps) and significant quantities
of this material could be brought through this sequence of
reactions.
The Authors thank Merck Sharp & Dohme and the EPSRC for
financial support for this project.
References
(1) Shirafuji, H.; Tubotani, S.; Ishimaru, T.; Harada, S. PCT Int.
Appl., WO9113887, 1991.
(2) (a) Nagumo, S.; Nishida, A.; Yamazaki, C.; Murashige, K.;
Kawahara, N. Tetrahedron Lett. 1998, 39, 4493. (b) Snider,
B. B.; Lin, H. Org. Lett. 2000, 2, 643. (c) Wardrop, D. J.;
Basak, A. Org. Lett. 2001, 3, 1053. (d) Mizutani, H.;
Takayama, J.; Soeda, Y.; Honda, T. Tetrahedron Lett. 2002,
43, 2411. (e) Nagumo, S.; Nishida, A.; Yamazaki, C.;
Matoba, A.; Murashige, K.; Kawahara, N. Tetrahedron
2002, 58, 4917. (f) Nagumo, S.; Matoba, A.; Ishii, Y.;
Yamaguchi, S.; Akutsu, N.; Nishijima, H.; Nishida, A.;
Kawahara, N. Tetrahedron 2002, 58, 9871.
(3) (a) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C.
J. J. Org. Chem. 2002, 67, 7613. (b) Worden, S. M.;
Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 6011.
(c) Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43,
3541. (d) Gabaitsekgosi, R.; Hayes, C. J. Tetrahedron Lett.
1999, 40, 7713.
(4) Taber, D. F.; Christos, T. E. J. Org. Chem. 1996, 61, 2084.
(5) Mori, S.; Ohno, T.; Harada, H.; Aoyama, T.; Shiori, T.
Tetrahedron 1991, 47, 5051.
(6) (a) Magnus, P.; Payne, A. H. US 2002/0120170 A1, 2002.
(b) Inoki, S.; Kato, K.; Isayama, S.; Mukaiyama, T. Chem.
Lett. 1990, 1869.
In order to complete a synthesis of (–)-TAN1251A (1) we
next reduced the cyclohexenone (H2, Pd/C) and displaced
the mesylate with sodium azide. Protection of the ketone
as its ethylene glycol ketal gave the [6,5]-spirocycle 14.
Our next key objective was to synthesise the bridged bicy-
clic intermediate 4, as this would represent a formal syn-
thesis of (–)-TAN1251A (1). The synthesis of 4 from 14
was successfully achieved as follows: Deprotection of 14
with TFA–CH2Cl2, followed by alkylation of the resulting
amine with ethyl bromoacetate and reduction of the azide
(H2, Pd/C, MeOH) afforded the amine 13. As our own
synthesis of 1 was progressing, Kawahara et al. published
their second generation synthesis of 12f and they also pro-
ceeded via the amine 13.11 We were still keen to complete
a synthesis of the bridged bicycle 4, so we used the two-
step route of Kawahara, which involved DPPA-mediated
amide coupling to close the bicyclic ring system and
alkylation of the amide-nitrogen with MeI–NaH. The syn-
thesis of 4 represents a new formal synthesis of (–)-
TAN1251A (1), but for the sake of completeness we
achieved a total synthesis of 1 from 4 via the intermediate
15 following the route described previously in the litera-
ture.2c,e,12
(7) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem.
Commun. 1992, 721.
(8) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143.
(9) Typical CH-Insertion Procedure: KHMDS (0.5 M in
PhMe, 127 mL, 63.4 mmol) was added to a stirring solution
of 11 (12.8 g, 31.7 mmol) in dry Et2O (200 mL) and the
resulting mixture was stirred at r.t. for 1 h. The solvent was
removed in vacuo and the residue was partitioned between
brine (100 mL) and Et2O (100 mL). The separated organic
layer was dried (MgSO4), concentrated in vacuo and purified
by column chromatography [SiO2, petrol (40–60 °C):Et2O
(10:1)] to give 5 as a colourless oil (10.7 g, 93%). [a]D –61.5
(c 1.07, CHCl3). 1H NMR (400 MHz, DMSO-d6, 100 °C): d
= 5.30 (br s, 1 H), 4.30 (app. quin., J = 4.5 Hz, 1 H), 3.55
(ddd, J = 11.2, 5.6, 0.8 Hz, 1 H), 3.20 (ddd, J = 11.2, 4.5, 1.2
Hz, 1 H), 2.40–2.13 (m, 3 H), 2.05 (dd, J = 12.7, 4.5 Hz, 1
H), 1.87–1.79 (m, 2 H), 1.70 (s, 3 H), 1.36 (s, 9 H), 0.90 (s,
9 H), 0.10 (s, 3 H), 0.10 (s, 3 H). HRMS: 368.2638 [MH+]
(C20H38NO3Si requires 368.2621). Anal. Calcd for
C20H37NO3Si: C, 65.4%; H, 10.2%; N, 3.8%. Found: C,
65.1%; H, 9.9%; N, 3.8%.
(10) Flash column chromatography over AgNO3-impregnated
SiO2 allowed small amounts of the (E)-vinylbromide-10 to
be isolated as a single geometric isomer.
(11) Coincidentally, the spirocycle 14 was also a key
intermediate on Kawahara’s second generation route,
although it was synthesised in a different manner. Our 1H
NMR, 13C NMR, HRMS and CHN analysis data were
identical to that reported by Kawahara2f [a]D +9.1 (c 1.03,
CHCl3) (lit2f [a]D +8.9 (c 0.99, CHCl3).
In summary, we have successfully completed a synthesis
of (–)-TAN1251A (1) starting from trans-4-hydroxypro-
line using an alkylidene carbene 1,5-CH insertion reaction
as a key step. We have shown that the key [6,5]-spirocy-
clic amine 14 can be synthesised from the [5,5]-spirocycle
5 via an oxidative cleavage–aldol condensation sequence.
Furthermore, the cyclohexenone 6 will provide the perfect
platform from which we can study the enantioselective
total synthesis of (+)-TAN1251B (2) via conversion of the
(12) We found that the final reduction of 15 was capricious and
that (–)-TAN1251A(1) was quite difficult to isolate in pure
form. These difficulties have not previously been reported
for this compound, but significant losses of material were
incurred upon repeated chromatography.
Synlett 2004, No. 8, 1443–1445 © Thieme Stuttgart · New York