An improved synthesis of the scyphostatin side-chain

Article abstract of DOI:10.1016/j.tetlet.2004.01.156

A formal synthesis of the lipophilic side-chain of scyphostatin has been achieved using a convergent synthesis, in 16% yield over six steps. This synthesis involves enzymatic desymmetrisation of a meso-diol, resolution of 2-methylbutan-1-ol, stereoselective hydrozirconation of a volatile acetylene and a Negishi-style cross coupling.

Full text of DOI:10.1016/j.tetlet.2004.01.156

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2551–2554
An improved synthesis of the scyphostatin side-chain
Graeme D. McAllister and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 22 January 2003; accepted 30 January 2004
Abstract—A formal synthesis of the lipophilic side-chain of scyphostatin has been achieved using a convergent synthesis, in 16%
yield over six steps. This synthesis involves enzymatic desymmetrisation of a meso-diol, resolution of 2-methylbutan-1-ol, stereo-
selective hydrozirconation of a volatile acetylene and a Negishi-style cross coupling.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Scyphostatin 1 was first isolated in 1997 by Ogita et al.
from the mycelial extract of the microorganism
Dasyscyphus mollissimus SANK-13892,1 and its struc-
ture assigned by spectroscopic and derivatisation
methods. Degradation studies by Kogen et al.2 estab-
lished the absolute stereochemistry, and determined the
140R, 100S, 80R configuration of the side-chain. It is one
of a few natural products that selectively inhibit the
enzyme neutral sphingomyelinase (N-SMase).3 This
makes it a lead candidate for the treatment of inflam-
matory and autoimmune disorders where ceramide,
produced in the N-SMase mediated hydrolysis of
sphingomyelin, plays a key role.
Tennakoon reported a stereoselective synthesis of the
side-chain 3,5 the key steps of their synthesis involving
formation of a terminal acetylene 5 from monoacetate 4
and the AlMe3-mediated coupling of 5 with a lactate-
derived triflate (Scheme 1). Oxidation of alcohol 7 fol-
lowed by an immediate Horner–Wadsworth–Emmons
olefination furnished ester 2 in 11 steps and 14% overall
yield.
As part of our synthetic assault on scyphostatin, we
required an efficient route to 3. Our strategy for the
formal synthesis of the side-chain is shown in Scheme 2.
We envisioned alcohol 7 being formed through a Negi-
O
HO
O
O
O
R
HO
N
2
14'
10'
8'
H
OH
O
Scyphostatin 1
CO2Et
3
In recent years, scyphostatin has become a popular
synthetic target,4 with most efforts concentrating on the
highly functionalised cyclohexenone core, although no
total synthesis has yet been reported. Indeed, we recently
reported syntheses of analogues of the core 2 in both
racemic4a and enantiopure forms.4b In 2000, Hoye and
shi-style cross coupling of vinyl iodide 8 with an or-
ganozinc reagent derived from iodide 9. This could be
synthesised from acetate 4 in a manner similar to Hoye,5
whilst vinyl iodide 8 could be formed from acetylene 10
via a stereoselective hydrozirconation/iodination.
Our synthesis (Scheme 3) started with meso-diol 11,
easily available by reduction of dimethylglutaric anhy-
dride.6 Using the procedure developed by Achiwa
et al.,7a treatment of 11 with vinyl acetate in the presence
of porcine pancreatic lipase (PPL)7 gave monoacetate
4 in 47% yield and in >95% ee.8 Silylation with
Keywords: Natural products; Stereoselective synthesis; Enzymes;
Desymmetrisation; Cross-coupling.
* Corresponding author. Tel.: +44-1904-432606; fax: +44-1904-434-
523; e-mail: rjktl@york.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.156

2552
G. D. McAllister, R. J. K. Taylor / Tetrahedron Letters 45 (2004) 2551–2554
(i) Me3Al, Cp2ZrCl2
(ii) MeLi
5 steps
OTBDPS
(iii)
MeO2C
4
5
6
OTBDPS
MeO C
OTf
2
OH
OAc
51%
(i) TPAP, NMO
(ii) LDA,
4 steps
OH
CO2Et
3
7
CO Et
(EtO) P(O)
2
2
81%, 10:1, E,E,E:E,E,Z
Scheme 1. HoyeÕs approach to the scyphostatin side-chain.5
3
OH
I
7
8
9
4
OR
I
OH
OAc
10
Scheme 2. Retrosynthetic strategy.
i
ii,iii
iv
OH
OH
OH
OTBDPS
OTBDPS
OH
OAc
OH
I
11
4
12
13
Br
v
vi,vii
viii
OH
Br
10
(+/-)-14
(+)-14
15
ix
x,xi
I
8
2 steps,
ref. 5
OH
CO2Et
3
7
Scheme 3. Reagents and conditions: (i) PPL, vinyl acetate, THF-H2O, 47%; (ii) TBDPSCl, Et3N, DMAP, CH2Cl2; (iii) K2CO3, MeOH, 89% (two
steps); (iv) I2, PPh3, imidazole, CH2Cl2, 86%; (v) PFL, vinyl acetate, CH2Cl2, 30%; (vi) (COCl)2, DMSO, Et3N, CH2Cl2, )65 ꢂC; (vii) PPh3, CBr4,
CH2Cl2, 72% (two steps); (viii) n-BuLi, THF, )78 ꢂC, then MeI, 84%; (ix) (a) Cp2ZrCl2, Super-Hydride, THF, then 10 (b) I2/CCl4, 73%; (x) ZnCl2,
t-BuLi, THF, 0 ꢂC, then 8, Pd(PPh3)4 (5 mol%), 66%; (xi) TBAF, THF, 68%.
tert-butyldiphenylsilyl chloride followed by acetate
hydrolysis gave alcohol 12 (itself an intermediate in
HoyeÕs side-chain synthesis)5 in 89% yield over two
steps. Finally, iodination with iodine and triphenyl-
phosphine gave iodide 13 in 86% yield.9
that of Effenberger.10 Using this method, we obtained
alcohol (+)-14 in 30% yield and 90% ee.8 Swern oxida-
tion of the enantiomerically enriched alcohol, followed
by Corey–Fuchs olefination11 gave vinyl dibromide 15 in
good overall yield. Treatment of 15 with n-butyllithium
and iodomethane gave the volatile acetylene 10.12 This
acetylene was treated with SchwartzÕs reagent (generated
in situ from zirconocene dichloride and Super-
Hydrideꢁ),13 and the reaction quenched with a saturated
solution of I2 in CCl4 to give vinyl iodide 8 as the sole
For the vinyl iodide coupling partner 8, we required
(+)(R)-2-methylbutan-1-ol 14. This was accessible
through resolution of the racemate with Pseudomonas
fluorescens lipase (PFL), in a procedure adapted from

G. D. McAllister, R. J. K. Taylor / Tetrahedron Letters 45 (2004) 2551–2554
2553
stereo- and regioisomer.14 As mentioned above, we had
planned to join our two coupling partners via a Negishi-
type reaction.15 To this end, we generated the corre-
sponding organozinc reagent from iodide 13 using tert-
butyllithium in the presence of anhydrous zinc chloride.
Addition of vinyl iodide 8 and Pd(PPh3)4 gave a good
yield of coupled product after chromatography,16 with
Marsden, S. P. Tetrahedron Lett. 1994, 35, 2087–2090; (d)
Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001, 493–502.
8. Enantiomeric excesses were determined by comparison of
½aꢀ with literature values: for acetate 4, see Ref. 7d.; for
D
alcohol 14, see: Tachihara, T.; Ishizaki, S.; Kurobayashi,
Y.; Tamura, H.; Ikemoto, Y.; Onuma, A.; Yoshikawa, K.;
Yanai, T.; Kitahara, T. Helv. Chim. Acta 2003, 86, 274–
279.
no traces of homocoupling. Desilylation with TBAF in
9. All new compounds were fully characterised by high field
1H and 13C NMR spectroscopy and HRMS.
10. Barth, S.; Effenberger, F. Tetrahedron: Asymmetry 1993,
4, 823–833.
11. (a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13,
3769–3772; (b) Ramirez, F.; Desai, N. B.; McKelvie, N. J.
Am. Chem. Soc. 1962, 84, 1745–1747.
20
D
THF gave the known alcohol 7 {½aꢀ ꢁ 13:7 (c 0.5,
25
CHCl3), lit.5; ½aꢀ ꢁ 14:4 (c 1.10, CHCl3)}.16 Alcohol 7
D
has previously been converted into ester 3 in two steps
(81%).5
In conclusion, we have completed a formal synthesis of
the scyphostatin side-chain with a longest linear
sequence of six steps, and with an overall yield of 16%
from diol 11. Our convergent approach, combined with
the use of an enzymatic resolution of alcohol 14 makes
the synthesis shorter and more efficient than that pre-
viously reported. Comparison of our observed optical
rotation with the literature data5 confirmed that ste-
reochemical integrity was maintained throughout the
synthesis. Application of this route to the synthesis of
scyphostatin and its analogues is ongoing.
12. Due to the volatility of acetylene 10, it was isolated as a
solution in n-pentane and the yield calculated by integra-
tion of the H NMR spectrum.
13. Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron
Lett. 1990, 31, 7257–7260.
1
14. The stereochemistry of iodide 8 was confirmed by NOE
difference and COSY spectroscopy.
15. (a) Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York,
2002; Vol. I, Part III, pp 215–1119; (b) Benowitz, A. B.;
Fidanze, S.; Small, P. L. C.; Kishi, Y. J. Am. Chem. Soc.
2001, 123, 5128–5129; (c) Smith, A. B., III; Qiu, Y.; Jones,
D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011–
12012.
16. Synthesis of (2R, 4R, 6E, 8R)-tetramethyl-6-decen-1-ol 7:
(a) Alkyl iodide 13 (606 mg, 1.26 mmol) and ZnCl2 (0.5 M
in THF, 2.5 mL, 1.25 mmol) were dissolved in anhydrous
THF (10 mL) and cooled to )78 ꢂC under argon. A
solution of tert-BuLi (1.5 M in hexanes, 2.1 mL,
3.15 mmol) was added dropwise and then the pale yellow
solution stirred at )78 ꢂC for 10 min, then for 20 min at rt.
This solution was transferred by cannula to a stirred
suspension of vinyl iodide 8 (236 mg, 1.06 mmol) and
Pd(PPh3)4 (61 mg, 0.05 mmol, 5 mol%) in THF (6 mL)
under argon and the resulting brown suspension stirred at
rt in the dark overnight. The reaction was quenched with
saturated NaHCO3 (20 mL), then extracted into Et2O
(2 · 50 mL). The combined organic extracts were washed
with saturated brine solution (50 mL), dried (Na2SO4) and
concentrated in vacuo. Chromatography on silica (2%
Acknowledgements
G.D.M. thanks the University of York for postdoctoral
support.
References and notes
1. Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.;
Ogita, T. J. Am. Chem. Soc. 1997, 119, 7871–7872.
2. Saito, S.; Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett.
2000, 2, 505–506.
3. Kolesnick, R.; Golde, D. W. Cell 1994, 77, 325–328; For
recent advances, see: Pitsinos, E. N.; Wascholowski, V.;
Karaliota, S.; Rigou, C.; Couladouros, E. A.; Giannis, A.
Chembiochem 2003, 1223–1225, and references cited
therein.
Et2O in PE) gave the coupled product (312 mg, 0.69 mmol,
20
66%) as a pale yellow oil; ½aꢀ þ 3:0 (c 1.0, CHCl3); found
D
4. (a) Runcie, K. A.; Taylor, R. J. K. Org. Lett. 2001, 3,
3237–3239; (b) Murray, L. M.; OÕBrien, P. A.; Taylor, R.
J. K. Org. Lett. 2003, 5, 1943–1946; (c) Takagi, R.;
Miyanaga, W.; Tamura, Y.; Ohkata, K. Chem. Commun.
2002, 2096–2097; (d) Fujioka, H.; Kotoku, N.; Sawama,
Y.; Nagatomi, Y.; Kita, Y. Tetrahedron Lett. 2002, 43,
4825–4828; (e) Izuhara, T.; Yokota, W.; Inoue, M.;
Katoh, T. Heterocycles 2002, 56, 553–560; (f) Izuhara,
T.; Katoh, T. Org. Lett. 2001, 4, 1653–1656; (g) Gurjar,
M. K.; Hotha, S. Heterocycles 2000, 53, 1885–1889; (h)
Izuhara, T.; Katoh, T. Tetrahedron Lett. 2000, 41, 7651–
7655.
(CI): MHþ, 451.34047. C30H46OSi requires MHþ,
451.33962, 1.9 ppm error; Rf ¼ 0:53 (2% Et2O in
PE);tmax/cmꢁ1 (thin film) 2957, 2929, 2858, 1471, 1428,
1388, 1363, 1158, 1111; dH (400 MHz, CDCl3) 7.70–7.67
(4H, m, Ph–H), 7.44–7.37 (6H, m, Ph–H), 4.85 (1H, d, J
9.4, 7-H), 3.53 (1H, dd, J 5.5, 10.8, 1-HA), 3.43 (1H, dd, J
4.3, 10.8, 1-HB), 2.29–2.20 (1H, m, 8-H), 2.04–1.96 (1H, m,
5-H), 1.82–1.73 (1H, m, 2-H), 1.64–1.60 (2H, m, 4, 5-H),
1.54 (3H, d, J 1.2, 6-CH3), 1.37–1.28 (4H, m, 3-H2, 9-H2),
1.07 (9H, s, t-Bu), 0.96 (3H, d, J 6.4, 8-CH3), 0.92 (3H, d,
J 6.7, 2-CH3), 0.87–0.82 (6H, m, 4-CH3, 10-CH3); dC
(100 MHz, CDCl3) 135.6 (CH), 134.1 (C), 132.9 (CH),
132.4 (C), 129.5 (CH), 127.5 (CH), 68.9 (CH2), 47.9 (CH2),
41.2 (CH2), 34.1 (CH2), 33.2 (CH), 30.5 (CH), 28.2 (CH),
26.9 (CH3), 21.1 (CH3), 19.9 (CH3), 18.1 (C), 17.8 (CH3),
16.1 (CH3), 12.0 (CH3); m=z (CI) 451, 355 (100%), 314,
196; (b) 273 mg (0.61 mmol) of the silyl ether was dissolved
in anhydrous THF (5 mL) under argon. A solution of
TBAF (1 M in THF, 0.73 mL, 0.73 mmol) was added and
the reaction stirred at rt for 6 h. The reaction was
quenched with brine (10 mL) and extracted into Et2O
(2 · 10 mL), the combined organic extracts washed with
5. Hoye, T. R.; Tennakoon, M. A. Org. Lett. 2000, 2, 1481–
1483.
6. Diol 11 was prepared by the LiAlH4 reduction of meso-
3,5-dimethylglutaric anhydride. This was made as de-
scribed by Wiley, P. F.; Gerzon, K.; Flynn, E. H.; Sigal,
M. V.; Weaver, O.; Quarck, U. C.; Chauvette, R. R.;
Monahan, R. J. Am. Chem. Soc. 1957, 79, 6062–6070.
7. (a) Tsuji, K.; Terao, Y.; Achiwa, K. Tetrahedron Lett.
1989, 30, 6189–6192; (b) Lin, G.; Xu, W. Tetrahedron
1996, 52, 5907–5912; (c) Anderson, J. C.; Ley, S. V.;

2554
G. D. McAllister, R. J. K. Taylor / Tetrahedron Letters 45 (2004) 2551–2554
brine (10 mL), dried (Na2SO4) and concentrated in vacuo.
Chromatography on silica (6:1 PE–EtOAc) gave alcohol 7
(87 mg, 0.41 mmol, 68%) as a colourless oil, Rf ¼ 0:24 (6:1,
10.7, 1-HB), 2.27–2.20 (1H, m, 8-H), 2.03–1.98 (1H, m,
5-H), 1.77–1.63 (3H, m, 2, 4, 5-H), 1.56 (3H, d, J 1.6,
6-CH3), 1.36–1.27 (3H, m, OH, 9-H2), 1.26–1.17 (2H, m,
3-H2), 0.94 (3H, d, J 6.7, 8-CH3), 0.91 (3H, d, J 6.4,
2-CH3), 0.84 (3H, t, J 7.3, 10-CH3), 0.82 (3H, d, J 6.1,
4-CH3).
20
1.10, CHCl3); dDH (400 MHz, CDCl3) 4.85 (1H, d, J 9.2,
25
D
PE–EtOAc); ½aꢀ ꢁ13:7 (c 0.5, CHCl3), lit.5 ½aꢀ ꢁ14:4 (c
7-H), 3.53 (1H, dd, J 5.2, 10.7, 1-HA), 3.37 (1H, dd, J 6.7,