A concise preparation of an appropriately functionalized B-seco taxane derivative

Article abstract of DOI:10.1055/s-1998-1833

A successful route to a B-seco taxoid framework of type 2, which may be further manipulated in the expedient synthesis of taxoid ABC-core using standard synthetic procedures is described.

Full text of DOI:10.1055/s-1998-1833

1010
LETTERS
SYNLETT
A Concise Preparation of an Appropriately Functionalized B-seco Taxane Derivative
Siméon Arseniyadis*, José Ignacio Martín Hernando, José Quílez del Moral, Dmitry V. Yashunsky and Pierre Potier
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Fax: +33 1 69 07 72 47; E-mail:Simeon.Arseniyadis@icsn.cnrs-gif.fr
Received 1 May 1998
Abstract: A successful route to a B-seco taxoid framework of type 2,
which may be further manipulated in the expedient synthesis of taxoid
ABC-core using standard synthetic procedures is described.
Preferential protection of the primary hydroxyl group at C-2 as its tert-
butyldimethylsilyl ether, in the presence of the free secondary alcohol at
C-4 was effected by reaction of 9 with TBDMSCl (1.6 equiv) in the
presence of 4-DMAP (3.2 equiv) in dry CH Cl to give the
corresponding C10-OBz, C2-OTBS-protected alcohol in 98% yield.
Subsequent MOM-protection of the secondary hydroxyl group at C-4,
2
2
In the context of our work on synthetic approaches towards the ABC
1
ring system of taxol, still
a
challenging synthetic target, we
2
concentrated our efforts on a new ring expansion methodology. We
thus investigated the lead tetraacetate mediated oxidative cleavage of
1,2-unsaturated diols derived from the (S)-(+)-Hajos-Parrish ketone
which allowed easy access to conveniently functionalized cyclohexane
derivatives of type 4 (C-10: F= Functional group and C-2/C-4: R=
Protective group). The reaction involves an oxidative cleavage yielding,
as expected, the corresponding dialdehyde, which then undergoes a
series of transformations affording, in one synthetic operation, a ring
enlarged intermediate possessing functionality and absolute
configuration that are suitable for elaboration of the taxoid C-ring
(2.8 equiv of MOMCl, 3.6 equiv of i-Pr NEt in dry CH Cl , rt) gave an
2
2
2
unoptimized 90% yield of 10. Treatment of the latter with excess of
LiAlH in dry THF at 0°C for 30 min yielded quantitatively the desired
4
C-10 free hydroxy compound. Tetrapropylammonium perruthenate
5
(TPAP)-catalyzed oxidation of the C-10 alcohol by treatment with
NMO (1.6 equiv) and catalytic TPAP (0.025 equiv) in dry MeCN (5 mL
per mmol) in the presence of 4Å MS, at room temperature (15 min) led
to the desired aldehyde 11, in high yield (93.5 %). The requisite α-
alkoxyorganostannane 12 was readily prepared from aldehyde 11 by
condensation of lithium tributylstannylate followed by protection of the
resulting alcohol using chloromethyl methyl ether in the presence of
Hunig's base. To this end, 11 (1 equiv) was treated with tri-n-
butylstannyllithium (1 equiv, freshly prepared from equimolar quantities
3
moiety. By appropriate selection of the A-ring counterpart, such as
compound 5 (X=O, 4-oxo-isophorone), various taxoid building blocks
could be synthesized through their top (C10-C11) or bottom (C1-C2)
linking via an A+C connection strategy. So, we envisioned an
expeditious synthesis of the taxoid ABC framework by first effecting the
top linking of a type 4 C-ring component, and type 5 A-ring component,
(six membered ring taxoid subunits used as C-10 nucleophile and C-11
electrophile respectively).
of Bu SnH and LDA) in THF (5 mL per mmol) and protected
3
immediately after with chloromethyl methyl ether (5.5 equiv) in the
presence of iPr NEt (7.2 equiv) at 0°C in dry CH Cl (10 mL per
2
2
2
6
mmol) to afford in a stereorandom manner 12 (ca 75% isolated yield,
nearly 1:1 diastereomeric mixture at C-10 position). SiO flash column
2
chromatography (eluent heptane-ethyl acetate, 92:8) allowed separation
of 12a (faster eluting isomer) and 12b (slower eluting isomer) in their
diastereomerically pure form but with the C-10 configuration undefined.
4-oxo-isophorone 5 (X=O) served as starting material for the required
alkoxy enone 13 which was prepared in its racemic form according to
7
literature. The assembly of C-ring fragment 12 to be used as "C-10 Nu"
for the synthesis of the B-seco taxane derivatives is outlined in Scheme
2.
Having completed construction of left and right-half subunits, 13 and 12
respectively, the synthesis of B-seco taxane framework 14 was
addressed through a C10-C11 coupling. Initial investigations centred on
the addition of an α-alkoxyorganolithium compound derived from
MOM-protected stannyl carbinol 12 to alkoxy enone (±)-13. The α-
alkoxy organolithium reagents prepared by transmetallation of the
chromatographically separated α-alkoxyorganostannanes 12a, and 12b
(faster and slower eluting diastereomers respectively), using Still's
Scheme 1
8
procedure, were individually reacted with the A-ring precursor (±)-13,
to afford the corresponding top linked A-seco taxanes of type 14. Good
yields (ca 75%) of exclusively 1,2-addition products were obtained.
Thus α-alkoxy organostannane 12a (1 equiv) was treated with n-BuLi (1
equiv) in THF (5 mL per mmol) at -70°C for 5 min to give the
corresponding transmetallated intermediate which in turn was reacted
with (±)-13 (2 equiv) for 10 min at -70°C. The crude reaction profile
showed a mixture of two diastereomeric products by TLC and by 400
Following a short functional interconversion, connection of carbons at
C-1 and C-2 of the resulting intermediate, would then provide the
tricyclic taxoid diterpene skeleton. The retrosynthetic analysis involving
disconnection of the strategic bonds indicated by the wavy lines is
presented in Scheme 1. Disassembly of 1 as depicted was expected to
allow for a convergent preparation of B-seco taxane derivative 3. The
latter, assembled in a single operation, would undergo C1-C2 ring
closure in various ways through 2, itself obtained in two linear steps.
1
MHz H-NMR (6:1 ratio), which was purified by column
chromatography (using heptane-ether, 96:4 as eluent) to afford an
9
unseparable mixture of 14aM and 14am in 75% isolated yield together
Key intermediate 7 was readily obtained according to our previous
4
with unreacted organostannane and optically enriched (R)-(+)-13.
Proceeding as for 12a, 12b derived α-alkoxy organolithium reagent led,
upon reaction with (±)-13, to a mixture of diastereomeric B-secotaxanes
14bM and 14bm, in 76% combined yield (in a 5:1 ratio) which were
work, from the (S)-(+)-Hajos-Parrish ketone derived unsaturated diol 6.
Benzoyl protection at C-10 (1.4 equiv of benzoyl chloride, 2.2 equiv of
Et N, in CH Cl , 5 mL per mmol) afforded quantitatively 8. Acetonide
3
2
2
.
cleavage (TosOH H O, EtOH, rt, 30 min) furnished diol 9 in 98% yield.
2

September 1998
SYNLETT
1011
Scheme 2
obtained pure for characterization. This clearly means that a complete
kinetic discrimination is shown in the addition of each epimeric C-10
anion to racemic 13, while diastereoselection in addition to C-11 is high
but not complete. The high levels of selectivity in the C10-C11 coupling
are all the more remarkable. The target intermediate 16, possessing
functionality for the final C1-C2 coupling, was then accessed in two
additional steps, performed separately on diastereomerically pure A-C
linked intermediates 14bM and 14bm and on the unseparable mixture
14aM and 14am as follows. Fluoride deprotection of the TBS-protected
framework, variants of this reaction are under further study and will be
reported in due course.
Acknowledgements We thank Ministerio de Educacion y Cultura
(Spain) for fellowships to Dr José Quílez del Moral and Dr José Ignacio
Martín Hernando.
References and notes
1.
Review articles see: Boa, A. N.; Jenkins, P. R. and Lawrence, N. J.
Contemporary Organic Synthesis 1994, 1, 47-75; Nicolaou, K.C.;
Dai, W.M.; Guy, R.K. Angew. Chem. Int. Ed. Engl. 1994, 33, 15-
44; Total syntheses: Nicolaou, K.C.; Yang, Z.; Liu, J.J.; Ueno, H.;
Nantermet, P.G.; Guy, R.K.; Claiborne, C.F.; Renaud, J.;
Couladouros, E.A.; Paulvannan, K.; Sorensen, E.J. Nature, 1994,
367, 630-634; Holton, R.A.; Somoza, C.; Kim, H.B.; Liang, F.;
Biediger, R.J.; Boatman, P.D.; Shindo, M.; Smith, C.C.; Kim, S.;
Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.;
Murthi, K.K.; Gentile, L.N. and Liu, J.H. J. Am. Chem. Soc. 1994,
116, 1597-1600; Masters, J.J.; Link, J.T.; Snyder, L.B.; Young,
W.B.; Danishefsky, S.J. Angew. Chem. Int. Ed. Engl. 1995, 34,
1723-1726; Wender, P.A.; Badham, N.F.; Conway, S.P.;
Floreansic, P.E.; Glass, T.E.; Houze, J.B.; Krauss, N.E.; Lee, D.;
Marquess, D.J.; McGrane, P.L.; Meng, W.; Natchus, M.G.;
Shuker, A.J.; Sutton, J.C.; Taylor, R.E. J. Am. Chem. Soc. 1997,
119, 2757-2758; Mukaiyama, T.; Shiina, I; Iwadare, H.; Sakoh,
H.; Tani, Y.; Hasegawa, M.; Saitoh, K. Proc. Japan Acad., Ser. B
1997, 73, 95-100.
hydroxyl groups at C-14 and C-2 (n-Bu NF, THF, 50°C, 3 h) furnished
4
cleanly the corresponding diols. Exposure of the diols 15 thus obtained
(each of the diastereomerically pure diols 15bM, 15bm as well as the
mixture 15aM+15am was prepared) to TPAP-NMO oxidation as above,
afforded the desired enone-aldehydes 16 (16bM, 16bm, pure and
16aM+16am as a mixture) with an isolated yield of 89% for the two
steps. This conversion sets the conditions for the following
transformation, the C1-C2 bond formation, but also helps to elucidate
the location of the stereoisomers.
2.
3.
4.
Arseniyadis, S.; Brondi Alves R.; Pereira de Freitas, R.; Muñoz-
Dorado M.; Yashunsky, D.V.; Potier, P.; Toupet, L. Heterocycles
1997, 46, 727-764.
Arseniyadis, S.; Yashunsky, D.V.; Pereira de Freitas, R.; Muñoz-
Dorado M.; Potier, P.; Toupet, L. Tetrahedron 1996, 52, 12443-
12458.
Optical purity was secured via our lipase-catalyzed hydrolysis
rather than using the proline catalyzed asymmetric Robinson
annelation: Arseniyadis, S.; Rodriguez, R.; Muñoz Dorado, M.;
Brondi Alves, R.; Ouazzani, J.; Ourisson, G. Tetrahedron 1994,
50, 8399-8426.
Scheme 3
The three-step sequence illustrated above (Scheme 3), provides an
exceedingly simple route for the preparation of the B-seco taxoid
framework 16, bearing substitution that is required for further
transformation and appears sufficiently promising to warrant
completion. Even though a preliminary aldol type C1-C2 connection
(LDA, THF, -70°C to -40°C, 40 min) was disappointing in that it
furnished unacceptably low yields (ca 5%) of the desired ABC taxoid
5.
6.
Ley, S.V.; Norman, J. ; Griffith, W.P.; Marsden, S.P. Synthesis
1994, 639-666; Griffith, W.P.; Ley, S.V. Aldrichimica Acta 1990,
23, 13.
Still, W.C. J. Am. Chem. Soc. 1978, 100, 1481-1486.

1012
7.
LETTERS
SYNLETT
Tanaka, A.; Yamamoto, H.; Oritani, T. Tetrahedron: Asymmetry
1995, 6, 1273-1278.
reduced pressure to give a crude product which upon silica gel
column chromatography (heptane-ethyl acetate, 1:1 as eluent)
afforded 93% of 15bM (Stereochemistry at C-10, C-11 and C-14
undefined). The same procedure was applied to 14bm as well as to
the diastereomeric mixture 14aM+14am to give 15bm, and
15aM+15am in comparable yields.
8.
Still, W.C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201-
1202. Organometallic carbon nucleophiles generally react with
carbon electrophiles with retention of configuration: Sawyer, J. S.;
Macdonald, T.L.; McGarvey, G.J. J. Am. Chem. Soc. 1984, 106,
3376-3377.
Preparation of enone-aldehydes 16
To a stirred solution of 15bM (212 mg, 0.29 mmol) in dry CH CN
9.
No efforts have been devoted to determine the absolute
configuration at C-10 position of organostannanes 12a and 12b as
this, and the C-11, C-14 centers on the A-C linked intermediates
14, 15 and 16 are programmed to be destroyed in later steps.
However we elected to use stereopure C-ring components (12a
and 12b) in the A+C coupling to facilitate result treatment.
Throughout this letter, we will call 12a and 12b the two
organostannanes (faster and slower eluting isomers respectively)
which are optically pure but the C-10 absolute configuration
undetermined. To help reader's understanding, we give all the
diastereomeric B-seco taxoid intermediates the same number but a
different letter. For example, compounds obtained from the slower
eluting organostannane 12b will carry the letter "b" accompanied
by the letters "M" or "m" (M stands for major, m for minor
isomer).
3
(12 mL) under argon was added 400 mg of powdered 4Å
molecular sieves followed by NMO (1.32 equiv ) and a catalytic
amount of n-Pr NRuO (0.08 equiv) at room temperature. After
4
4
30 min the solvent was removed under reduced pressure and the
reaction mixture was taken up in CH Cl prior to filtration through
2
2
a short silica gel column (eluted with heptane-ethyl acetate, 1:1) to
furnish a 96% isolated yield of the desired enone-aldehyde 16bM.
I.R.(film): 3472, 2975, 1721, 1664, 1627, 1470, 1382, 1187, 1151,
-1
1
1037, 911, 737 cm . H-NMR (200 MHz): 1.05 (3H, s), 1.08 (9H,
s), 1.11 (3H, s), 1.12 (3H, s), 1.48-1.60 (3H, m), 1.82-1.89 (3H,
m), 1.99 (3H, s), 2.20 (1H, d, J=18.0), 2.57 (1H, d, J=18.0), 3.00
(1H, br.d, J=3.4), 3.35 (3H, s), 3.52 (3H, s), 3.87 (1H, dd, J=3.4,
9.5), 4.01 (1H, dd, J=5.3, 10.0), 4.07 (1H, d, J=10.2), 4.54 (1H, s),
4.66 (2H, AB system, J= 7.0), 4.83 (2H, AB system, J= 6.3), 5.94
13
Typical Experimental Procedures
The A+C linking: preparation of 14
(1H, br.s), 9.78 (1H, d, J=2.0). C-NMR (50.3 MHz): 19.0, 21.1,
24.2, 26.8, 27.5, 27.7, 29.0, 38.9, 40.0, 40.8, 50.4, 55.7, 57.2,
58.2, 71.3, 73.6, 74.9, 78.1, 86.0, 95.7, 100.8, 128.3, 163.1, 197.7,
204.4. Proceeding as above, TPAP-NMO oxidation of the minor
To a stirred solution of 12a (752 mg, 1 mmol) in dry THF (5 mL)
at -78°C under argon, was added n-BuLi (0.63mL of a 1.6M
solution in hexane, 1mmol) and the mixture was stirred at this
temperature for 5 min before (±)-13 (538 mg, 2 mmol) was added.
After 15 min at this temperature, the reaction mixture was diluted
diol 15bm afforded enone-aldehyde 16bm in 95% yield: [α] +86
D
(c 0.58). I.R.(film): 3436, 2970, 2948, 1719, 1665, 1628, 1473,
1467, 1460, 1389, 1375, 1369, 1365, 1308, 1213, 1191, 1151,
with ether and quenched with a saturated solution of NH Cl, the
-1 1
4
1087, 1056, 1036, 917, 877, 733 cm . H-NMR (300 MHz): 0.98
layers separated and the aqueous layer extracted with ether. The
combined organic layers were washed with brine, dried over
(3H, s), 1.04 (3H, s), 1.11 (9H, s), 1.16 (3H, s), 1.40-1.68 (2H, m),
1.70-1.90 (2H, m), 1.99 (3H, d, J= 1.2), 2.00-2.22 (2H, m), 2.15
(1H, d, J= 18.0), 2.73 (1H, d, J= 17.8), 2.76 (1H, br.s), 3.32 (3H,
s), 3.54 (3H, s), 3.68 (1H, br.s), 3.73 (1H, d, J= 10.1), 4.09 (1H,
m), 4.57 (2H, AB system, J= 7.0), 4.76 (1H, s), 4.79 (2H, AB
MgSO and concentrated under reduced pressure. SiO column
4
2
chromatography (eluent heptane-ether, 96:4) gave an unseparable
mixture of 14aM and 14am (75% combined isolated yield, 6:1
ratio respectively; stereochemistry at C-10, C-11 and C-14
undefined) along with unreacted 12a, and recovered (+)-13, with
13
system, J= 6.7), 5.98 (1H, s), 9.80 (1H, d, J=1.5). C-NMR (62.5
MHz): 19.8, 20.5, 25.4, 25.9, 26.1, 27.9, 29.1, 37.0, 40.3, 41.8,
50.5, 55.7, 57.4, 58.1, 71.2, 73.4, 73.8, 79.6, 89.2, 95.4, 101.3,
[α] +47°, c 1.0. For optically pure (R)-(+)-13, reference 7 gives
D
[α] +57 (c 0.4). The same procedure was repeated with 12b to
D
+
129.6, 162.3, 198.2, 204.3. CIMS: 499 ([M+H] , 7), 467 (100),
afford
a 76% combined yield of 14bM and 14bm in
375 (38), 319 (18), 301 (8), 239 (95). Analysis: calcd for
approximately 5:1 ratio. These two diastereomeric B-seco taxoid
derivatives were obtained pure after chromatography on silica gel.
Deprotection of the tert-butyldmethylsilyl ethers: Preparation of
15
C
H O +1/2 H O: C 63.88 H 9.33, found: C 63.61 H 9.13.
27 46 8 2
Selected data: 8: [α] +53 (c 1.1); Analysis: calcd for C
H O :
24 36 5
D
C 71.26 H 8.97 O 19.77, found: C 71.19 H 8.85. 9: [α] +30 (c
D
1.2); m.p.: 106-108°C from heptane-ethyl acetate; Analysis: calcd
To a stirred solution of 14bM ( 318 mg, 0.43 mmol) in dry THF
for C
H O : C 69.20 H 8.85 O 21.95, found: C 68.97 H 8.75.
(10 mL) was added a 1 M solution of n-Bu NF in THF (3 mL, 3
21 32 5
4
10: [α] +22 (c 0.8). The first eluted organostannane, (faster
mmol) at room temperature under argon and the mixture was
heated at 50°C. After stirring a further 3-5 h (TLC monitoring) at
this temperature the reaction mixture is diluted with CH Cl , then
D
eluting isomer) 12a: [α] +57 (c 0.8); the second eluted material
D
(slower eluting isomer) 12b: [α] -20 (c 1.0). 14bM [α] +16 (c
D
D
2
2
1.2). 15bM [α] +45 (c 0.9). 15bm [α] +114 (c 0.72). Optical
washed with 1N HCl, water, saturated NaHCO and brine. The
D
D
3
organic layer was dried over MgSO and concentrated under
rotations were measured in chloroform, NMR spectra in CDCl .
3
4