An asymmetric synthesis of the pentacyclic core of stemofoline

Article abstract of DOI:10.1016/j.tetlet.2013.01.110

On treatment with acid, an open-chain 5-acylamino-3,8-diketo-ester, methyl (4R,5S,7S)-7-benzyloxy-4-[(S)-1-benzyloxyprop-2-yl]-5-methoxycarbonylamino-3, 8-dioxododecanoate, cyclised via a stereoselective Mannich reaction to give an 8-azabicyclo[3.2.1]octanone. Hydrogenolysis of this with in situ acetal formation, reduction of the ester and a further cyclisation gave a lactam, (4R,5R,8S,9R,10S,12S,13S)-13-butyl-8-methyl-1-aza-6,14-dioxapentacyclo[8.3.0. 0^4,130^5,9.1^5,12]tetradecan-2-one, that corresponds to the pentacyclic core of stemofoline.

Full text of DOI:10.1016/j.tetlet.2013.01.110

Tetrahedron Letters 54 (2013) 2120–2123
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An asymmetric synthesis of the pentacyclic core of stemofoline
⇑
Thomas Burns, Madeleine Helliwell, Eric J. Thomas
School of Chemistry, University of Manchester, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
On treatment with acid, an open-chain 5-acylamino-3,8-diketo-ester, methyl (4R,5S,7S)-7-benzyloxy-4-
[(S)-1-benzyloxyprop-2-yl]-5-methoxycarbonylamino-3,8-dioxododecanoate, cyclised via a stereoselec-
tive Mannich reaction to give an 8-azabicyclo[3.2.1]octanone. Hydrogenolysis of this with in situ acetal
formation, reduction of the ester and a further cyclisation gave a lactam, (4R,5R,8S,9R,10S,12S,13S)-13-
butyl-8-methyl-1-aza-6,14-dioxapentacyclo[8.3.0.04,1305,9.15,12]tetradecan-2-one, that corresponds to
the pentacyclic core of stemofoline.
Received 14 January 2013
Revised 23 January 2013
Accepted 24 January 2013
Available online 1 February 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Mannich reactions
Stereoselectivity
Natural products
Alkaloids
Stemofoline 1 is the parent member of the Stemona alkaloids
that have been isolated from extracts of the roots and leaves of Ste-
monaceae used in traditional medicine in China, Japan and Thai-
land.1 Additional members of this family of interesting natural
products continue to be isolated2 and a biogenetic route has been
proposed.3 Many approaches to the synthesis of these alkaloids
have been described4 and total syntheses of the (E)-isomer of
( )-stemofoline5 and of ( )-asparagamine 2 together with its (E)-
isomer,6 have been reported.
In early work on a synthetic approach to stemofoline, an intra-
molecular Mannich reaction and a regioselective oxidation were
used to prepare the tetracyclic lactam 3 that has the tetracyclic
core structure of stemofoline.7 However, it proved difficult to
incorporate the C(9) side-chain and the remaining five-membered
ring of stemofoline into this synthesis. More recently, 8-azabicy-
clo[3.2.]octanes 4 and 5 were prepared using Mannich chemistry
albeit slightly different conditions led to different configurations
at C(2) in these compounds.8
We now report an asymmetric synthesis of the pentacyclic
core 6 of stemofoline using this chemistry in which the 3,7-bond
(stemofoline numbering) was to be introduced by an intramolecular
⇑
Corresponding author. Tel.: +44 (0)161 275 4613; fax: +44 (0)161 275 4939.
E-mail address: e.j.thomas@manchester.ac.uk (E.J. Thomas).
Figure 1. Outline of the proposed synthesis.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.110

T. Burns et al. / Tetrahedron Letters 54 (2013) 2120–2123
2121
OR
OBn
OBn
O
i, ii
CO2Me
v
iii, iv
CHO
NMeOMe
OBn HN
O
OTBS
OR
11 R = H
10
O
13 R = H
15
vi
12 R = Bn
14 R = TBS
O
S
H
O
S
CO2Me
H
CO2Me
H
tBu
OBn
N
tBu
OBn HN
OBn HN
viii, ix
vii
x
CO2Me
CO2Me
OH
OTBS
OTBS
16
OTES
20
OR
18
19
17
R = H
R =TES
OBn
OBn
OBn
xi
CO 2Me
CO2Me
CO2Me
OBn HN
OBn HN
OH
OBn HN
O
CO2Me
OBn
H
H
H
xiv
CHO
xii, xiii
CO2Me
CO2Me
OTES
21
OP
O
9
24
OBn
22 P = TES
23 P = H
OBn
OBn
Scheme 1. Synthesis of the open-chain ester 9; Reagents and conditions: (i) AD-mix-a
, MeSO2NH2, tBuOH, H2O, 0 °C, 4 d (85%); (ii) CCl3C(NH)OBn, TfOH, DCM, hexane, r.t., 2 h
(81%); (iii) NHMeOMe, MeAlCl2, hexane, DCM, r.t., 2 h; (iv) TBSOTf, 2,6-lutidine, DCM, 0 °C, 1 h (56% from 12); (v) DIBAL-H, DCM, ꢀ78 °C, 2 h (58%); (vi) (S)-tBuS(O)NH2, CuSO4,
DCM, r.t., 18 h (93%); (vii) ester 24, LDA, hexanes, THF, ꢀ78 °C, 3 h, 16, ꢀ60 °C, 60 h (78%); (viii) aq HCl, dioxane, MeOH, r.t., 1 h, then Et3N, MeCOCl, 0 °C to r.t., 1 h (84%); (ix)
TESCl, imid., DCM, 0 °C, 1 h (84%); (x) NaBH4 CaCl2, THF, 0 °C, 30 min, add 19, 0 °C, 3 h (76%); (xi) Dess–Martin periodinane, py.,DCM, 0 °C, 3.5 h; (xii) MeCO2Me, LDA, THF,
hexanes, ꢀ78 °C, 1 h, add 21, ꢀ78 °C, 2 h (74% from 20; a 1:1.8 mixture of epimers); (xiii) TBAF, DCM, 0 °C, 1 h (89%, two epimers); (xiv) PDC, 4 Å sieves, DCM, r.t., 24 h (86%).
Mannich reaction of the acylaminoketone 9. Hydrogenolysis of the
resulting azabicyclo[3.2.1]octanone 8 with cyclisation in situ was
expected to give the tetracyclic acetal 7 and formation of the 5,6-
bond would complete the synthesis, see Figure 1.
moved using acid and the amine protected as its methoxycarbonyl
derivative 18. The tert-butyldimethylsilyl group was lost during
the acidic step and so the alcohol was now resilylated to give the
triethylsilyl ether 19.
A synthesis of the open-chain ester 9 is outlined in Scheme 1.
To avoid competing reduction of the methyl carbamate, the
reduction of the ester 19 was carried out using calcium borohy-
dride12 and oxidation of the resulting alcohol 20 using the Dess–
Martin periodinane gave the aldehyde 21. An aldol condensation
with methyl acetate gave a mixture of the epimeric hydroxyesters
22 that was desilylated to give the dihydroxy-ester 23 still as a
mixture of epimers. Oxidation of this mixture using PDC gave the
diketo-ester 9 ready for the Mannich reaction.
The cyclisation was carried out using trifluoroacetic acid (TFA)
in dichloromethane at ꢀ78 °C. In earlier studies,8 the use of TFA
to effect such a cyclisation, albeit at 0 °C, had given the tropinone
5 in which the methoxycarbonyl group was in the equatorial posi-
tion, although acylation of initially formed 5-membered cyclic imi-
nes had given products with the methoxycarbonyl group axial, for
Sharpless hydroxylation of the known b,
c
-unsaturated ester 109
using AD-mix-
a
10 with cyclisation in situ gave the hydroxylactone
11 that was protected as its benzyl ether 12. Ring-opening using
the Weinreb reagent followed by protection of the 4-hydroxyl
group gave the tert-butyldimethylsilyl ether 14. Reduction then
gave the aldehyde 15 that was condensed with (S)-tert-butyl sul-
finamide to give the sulfinimine 16. The addition of the enolate
of ester 248 mediated by chlorotitanium tris-isopropoxide to this
imine gave predominantly one product (78%) identified as the sul-
foxamine 17 on the basis of precedent.11 The minor products from
this reaction, <10%, were not identified. As the tert-butylsulfinyl
group in earlier work had been found to be unstable under the
conditions to be used in the next stages of the synthesis,8 it was re-
CO2Me
CO2Me
Me
Me
NCO2Me
NCO2Me
ii
i
BnO
9
O
O
H
O
BnO
H
7
8
iii, iv
O
X
Me
Me
N
NCO2Me
v
O
O
O
O
6
25 X = OH
26 X = I
Scheme 2. Synthesis of the pentacyclic core of stemofoline. Reagents and conditions: (i) TFA, DCM, ꢀ78 °C, 12 h (85%); (ii) 10% Pd/C, TFA, EtOAc, rt, 1 h (82%); (iii) DIBAL-H,
DCM, ꢀ78 °C, 1 h (83%); (iv) Ph3P, imid., I2, DCM, 35 °C, 1 h (92%); (v) tBuLi, hexanes, THF, ꢀ78 to 0 °C, 5 min (86%).

2122
T. Burns et al. / Tetrahedron Letters 54 (2013) 2120–2123
H
H
Me
H
H
NCO2Me
Me
NCO2Me
H
BnO
BnO
O
2
OMe
O
O
CO2Me
H
H
BnO
(Z)-enol
BnO
27
CO 2Me
Me
CO2Me
NCO2Me
NCO2Me
Me
BnO
O
BnO
H
HO
H
BnO
H
BnO
8
(E)-enol
Figure 2. Formation of epimers on cyclisation of keto-ester 9.
tert-butyllithium effected halogen-lithium exchange and the
resulting organolithium reacted with the methoxycarbonyl group
of the carbamate with loss of methoxide to give the required pen-
tacyclic lactam 6, see Scheme 2.14
This work constitutes an asymmetric synthesis of the pentacy-
clic core of stemofoline. It remains to reduce the lactam to the cor-
responding amine7 and to attach the tetronic acid fragment to
complete a synthesis of stemofoline itself.
Acknowledgments
We thank the EPSRC for a studentship (to T.B.) and James Rafer-
ty for help with the X-ray crystal data.
References and notes
1. (a) Pilli, R. A.; Rosso, G. B.; Ferreira de Oliveira, M. da C. Nat. Prod. Rep. 2010, 27,
1908; (b) Irie, H.; Masaki, N.; Ohno, K.; Osaki, K.; Taga, T.; Uyeo, S. J. Chem. Soc.,
Chem. Commun. 1970, 1066; (c) Sakata, K.; Aoki, K.; Chang, C.-F.; Sakurai, A.;
Tamura, S.; Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457; (d) Pilli, R. A.; Ferreira
de Oliveira, M. da C. Nat. Prod. Rep. 2000, 17, 117.
2. (a) Sastraruji, T.; Chaiyong, S.; Jatisatienr, A.; Pyne, S. G.; Ung, A. T.; Lie, W. J.
Nat. Prod. 2011, 74, 60; (b) Hitotsuyanagi, Y.; Hikita, M.; Uemura, G.; Fukaya, H.;
Takeya, K. Tetrahedron 2011, 67, 455.
Figure 3. The structure of the acetal 7 as established by X-ray crystallography.
3. Seger, C.; Mereiter, K.; Kaltenegger, E.; Pacher, T.; Greger, H.; Hofer, O. Chem.
Biodivers. 2004, 1, 265.
4. (a) Alibes, R.; Figueredo, M. Eur. J. Org. Chem. 2009, 15, 2421; (b) Shanahan, C. S.;
Fuller, N. O.; Ludolph, B.; Martin, S. F. Tetrahedron Lett. 2011, 52, 4076.
5. Kende, A. S.; Smalley, T. L., Jr.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431.
6. Brüggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.;
Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284.
7. Baylis, A. M.; Davies, M. P. H.; Thomas, E. J. Org. Biomol. Chem. 2007, 5, 3139.
8. Thomas, E. J.; Vickers, C. F. Tetrahedron: Asymmetry 2009, 20, 970.
9. Ragoussis, N. Tetrahedron Lett. 1987, 28, 93.
10. Harcken, C.; Brückner, R. Angew. Chem., Int. Ed. 1997, 36, 2750.
11. (a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819; (b) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984; (c) Morton, D.; Stockman, R. A.
Tetrahedron 2006, 62, 8869.
example, 4.7 In the present case, the product with the methoxycar-
bonyl group axial was the only product obtained, see Scheme 2.
This stereoselectivity is believed to be due to thermodynamic con-
trol. The hydrogen bonded (Z)-enol of the keto-ester would be ex-
pected to give the equatorial product 27. However, this isomer is
destabilised by a syn-gauche interaction with the endo-benzyloxy
group so that if the cyclisation is reversible the more stable axial
epimer 8 can accumulate, see Figure 2.
By analogy with the structure of stemofoline, it was hoped that
the diol formed by hydrogenolysis of the two benzyloxy groups in
the tropinone 8 would readily react with the ketone to generate
the corresponding acetal. In the event, hydrogenolysis in the pres-
ence of trifluoroacetic acid gave the crystalline acetal 7 directly.
The structure of this acetal was confirmed by X-ray crystallography
that established the structure as shown, see Figure 3.13 This X-ray
structure confirmed all of the stereochemical assignments that had
been made earlier in the synthesis, for example, of the sulfinyl-
amine 17.
12. (a) Brown, H. C.; Narasimhan, S.; Choi, Y. M. J. Org. Chem. 1982, 47, 4702; (b)
Brown, H. C.; Choi, Y. M.; Narasimhan, S. Inorg. Chem. 1981, 20, 4454; (c)
Narasimban, S.; Prasad, K. G.; Prasanna, R. Indian J. Chem., Sect. B 1993, 32B, 489.
13. Single crystal X-ray diffraction data were collected on a Bruker AXS SMART
APEX CCD diffractometer at 100 K using graphite monochromated MoK
a
radiation (k = 0.7107 Å). The data were reduced by SAINTPLUS; XPREP was
used to determine the space group. The crystal structure was solved by direct
methods using SHELXS97 and refined by the full-matrix least-squares method
on F2 using SHELXL97. Crystal data: C18H27NO6, M = 353.41, orthorhombic,
P212121, a = 7.0191(12), b = 9.9784(17), c = 25.739(4) Å, V = 1802.7(5) Å3,
Z = 4, 14522 reflections measured, 2163 unique (Rint = 0.0410), 2096
reflections > 2r(I) (R1 = 0.0326 and wR2 = 0.0800), CCDC 916509.
14. (1S,2R,4R,5S,7S)-7-Benzyloxy-4-[(S)-1-benzyloxyprop-2-yl]-1-butyl-2,8-
dimethoxycarbonyl-8-azabicyclo[3.2.1]octan-3-one 8: Trifluoroacetic acid (10
To complete a synthesis of the pentacyclic core of stemofoline,
it was necessary to form the final five-membered ring. This was
carried out by reduction of the ester 7 to give the alcohol 25 that
was converted into the iodide 26. Treatment of this iodide with
lL,
0.13 mol) was added to the diketo-ester 9 (40 mg, 70 lmol) in DCM (3 mL) at
ꢀ78 °C and the solution was stirred for 16 h. Saturated aqueous sodium
hydrogen carbonate (0.3 mL) was added. The aqueous phase was extracted
with DCM (2 ꢁ 1 mL) and the organic extracts were washed with water (1 mL)

T. Burns et al. / Tetrahedron Letters 54 (2013) 2120–2123
2123
and brine (1 mL) then dried (MgSO4). After concentration under reduced
pressure, chromatography of the residue using ether/light petroleum (85:15)
gave the title compound 8 (34 mg, 85%) as an oil, Rf 0.82 (ether) (found: M++Na,
574.2796. C32H41NO7Na requires M, 574.2781); vmax (film) 1730, 1710, 1446,
1368, 1320, 1235, 1198, 1173, 1100, 741 and 697 cmꢀ1; dH (500 MHz, C6D6)
7.23 (10H, m, ArH), 4.54 (1H, dd, J 4, 8, 5-H), 4.32, 4.29 and 4.19 (each 1H, d, J
12, HCHPh), 4.20 (1H, s, 2-H), 3.99 (1H, d, J 12, HCHPh), 3.76 (1H, dd, J 4, 10, 7-
H), 3.63 (1H, dd, J 4, 9, 10-H), 3.52 (1H, dd, J 4, 8.5, 4-H), 3.46 (1H, dd, J 6,9, 10-
H0), 3.40 and 3.22 (each 3H, s, OCH3), 2.36 (2H, m, 20-H and 100-H), 2.06 (1H, td, J
4.5, 12, 100-H0), 1.74 (1H, m, 6-H), 1.36-1.20 (4H, m), 1.18 (1H, m, 6-H0), 0.97
(3H, d, J 7.5, 30-H3) and 0.79 (3H, t, J 7, 400-H3); m/z (ES+) 574 (M++23, 100%).
(1S,3S,4R,5S,8R,10S,11R)-1-Butyl-2,11-dimethoxycarbonyl-5-methyl-7,9-dioxa-2-
azatetracyclo[6.2.1.04,8.13,10]dodecane 7: Palladium (10% on carbon, 2 mg,
(1H, dd, J 3.5, 12, 4-H), 2.30 (1H, m, 5-H), 1.88 (1H, m 10-H), 1.82 (1H, d, J 11.5,
12-H), 1.43-1.36 (4H, m), 1.33 (1H, ddd, J 2, 6, 9, 12-H0), 1.20 (1H, m, 30-H0), 0.97
(3H, t, J 7, 40-H3), 0.89 (3H, d, J 7, 6-CH3); dH (125 MHz, C6D6) 156.13, 130.16,
102.44, 98.75, 78.42, 76.78, 57.69, 51.66, 48.64, 46.59, 43.13, 40.35, 31.81,
27.12, 23.04, 19.63, 14.58 and 11.83; m/z (ES+) 354 (M++1, 100%).
(4R,5R,8S,9R,10S,12S,13S)-13-Butyl-8-methyl-1-aza-6,14-dioxapentacyclo[8.3.0.
04,13.05,9.15,12]tetra-decan-2-one 6: tert-Butyllithium (1.6 M in hexanes, 14
22 mol) was added to the iodide 26 (5 mg, 11 mol) in THF (100
l
L,
l
l
lL) at ꢀ78 °C
and the cooling bath was removed. After stirring for 5 min, saturated aqueous
ammonium chloride (0.5 mL) was added and the organic phase diluted with
ether (1 mL) then washed with water (0.5 mL). The aqueous phase was washed
with ethyl acetate (3 ꢁ 2 mL) and the organic extracts were washed with brine
(0.5 mL) and dried (Na2SO4). After concentration under reduced pressure,
chromatography of the residue using ether/light petroleum gave the title
1.76
lmol) was added to the tropinone 8 (10 mg, 17.6
lmol) in ethyl acetate
(0.5 mL) at room temperature. Trifluoroacetic acid (2
l
L, 26 mol) was added
l
compound 6 (2.5 mg, 9.4 lmol, 86%) as a clear colourless oil, Rf = 0.63 (50:50
and the suspension stirred under an atmosphere of hydrogen at room
temperature for 1 h. The mixture was filtered through silica and the silica
was washed with ethyl acetate (5 mL). The organic extracts were concentrated
under reduced pressure and chromatography of the residue using ether/light
petroleum (50:50) gave the title compound 7 (5 mg, 82%) as a solid that was
ether/light petroleum) (Found: M++H, 278.1744. C16H24NO3 requires M,
278.1751) ½a 2D6
ꢀ17.5 (c 4.2 in CHCl3); vmax 1748, 1734, 1201, 1158, 1091,
ꢂ
1021, 999, 942, 866 and 714 cmꢀ1; dH (500 MHz, C6D6) 4.02 (1H, t, J 8, 7-H),
3.94 (1H, br s, 10-H), 3.81 (1H, br s, 12-H), 3.10 (1H, t, J 8, 7-H0), 2.42 (1H, d J
5.5, 4-H), 2.27 (1H, dd J 5.5, 18.5, 3-H), 2.12 (1H, d, J 18.5, 3-H0), 2.10 (1H, m, 8-
H), 1.72 (1H, dd, J 4, 11, 9-H), 1.58 (1H, d, J 12, 11-H), 1.26–0.70 (7H, m, 11-H0,
10-H2, 20-H2 and 30-H2), 0.66 (3H, t, J 7.5, 40-H3) and 0.38 (3H, d, J 6.5, 8-CH3); dC
(125 MHz, C6D6) 153.46, 73.74, 70.62, 66.53, 50.89, 48.17, 46.98, 31.89, 28.32,
25.06, 18.57, 14.10 and 13.05. m/z (ES+) 278 (M++1, 100).
recrystallised from DCM/hexane, Rf 0.62 (50:50 ether/light petroleum) ½a D26
ꢂ
ꢀ21 (c 3.6, CHCl3); (found: M+ +H, 354.1925. C18H28NO6 requires M, 354.1917);
vmax (film) 1740, 1446, 1378, 1241, 1185, 1163, 1132, 1099, 1080 and
836 cmꢀ1; dH (400 MHz, C6D6) 4.73 (1H, m, 3-H), 4.29 (1H, t, J 8, 6-H), 4.14 (1H,
t, J 3, 10-H), 3.59 (3H, s, OCH3), 3.54 (1H, t, J 8, 6-H0), 3.26 (1H, s, 11-H), 3.20