A stereoconvergent synthesis of the C(19)-C(31) fragment of scytophycin C

Article abstract of DOI:10.1016/S0040-4039(02)01705-7

The C(19)-C(31) fragment of the anti-tumor macrolide, scytophycin C, was realized in a stereoconvergent manner utilizing a desymmetrization approach to create eight contiguous asymmetric centers from a common precursor.

Full text of DOI:10.1016/S0040-4039(02)01705-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7147–7150
A stereoconvergent synthesis of the C(19)ꢀC(31) fragment of
scytophycin C†
J. S. Yadav* and Md. Moinuddin Ahmed
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 April 2002; revised 2 August 2002; accepted 15 August 2002
Abstract—The C(19)ꢀC(31) fragment of the anti-tumor macrolide, scytophycin C, was realized in a stereoconvergent manner
utilizing a desymmetrization approach to create eight contiguous asymmetric centers from a common precursor. © 2002 Elsevier
Science Ltd. All rights reserved.
Moore et al. in 19861 first reported the isolation of a novel
class of polyoxygenated 22-membered macrolides, scyto-
phycins A–E from the cultured terrestrial blue-green alga
Scytonema pseudohofmanni (Fig. 1). Structurally, scyto-
phycins are closely related to swinholides, a group of
44-membered dimeric macrolides from Theonella swin-
hoei.2 They have exhibited potent cytotoxicity against a
variety of human carcinoma cell lines, as well as broad-
spectrum antifungal activity. They act as cytotoxic agents
by microfilament depolymerization3a and have been
shown to circumvent P-glycoprotein medicated multi
drug resistance in tumor cells,3b which gives them thera-
peutic potential for cancer patients.
As a part of our ongoing interest in the synthesis of
biologically active molecules, especially anti-tumor
agents,6 our attention was drawn towards synthetic
studies of this novel class of macrolide (Scheme 1)
The details of our approach towards the synthesis of
scytophycin C are depicted in Scheme 1. A closer survey
reveals two major fragments C(1)–C(18) and C(19)–
C(31). Herein we report a stereoconvergent synthesis of
the C(19)–C(31) fragment. This fragment is further
broken into two smaller fragments, i.e. C(19)–C(25) and
C(26)–C(31). They can be derived from a common
precursor 7 which in turn is easily synthesized.6a,c
The relative stereochemistry at C(2) and C(4) of the
precursor 7 can be correlated to C(22), C(24), C(28)
and C(30) of scytophycin C. The bicyclic compound 7 has
five stereogenic centers and two prostereogenic sp2 sites
To date, an elegant total synthesis of scytophycin C has
been reported by Paterson.4 Other approaches deal with
selective syntheses of important fragments.5
Figure 1.
Keywords: scytophycin C; common precursor; desymmetrization; stereoconvergent.
* Corresponding author. Tel.: +91-040-7193434; fax: +91-040-7160512; e-mail: yadav@iict.ap.nic.in
† IICT Communication No. 020305.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01705-7

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J. S. Yada6, Md. M. Ahmed / Tetrahedron Letters 43 (2002) 7147–7150
basis of our earlier report.6a The physical and spectro-
scopic data were found to be identical in all respects
with those reported for the C(19)–C(27) fragment of
rifamycin-S.6a The resultant triol 9 was converted with
2,2-dimethoxypropane–CSA (cat.) into acetonide 10
(92%) which constituted the main precursor for the
C(19)–C(25) fragment. The alcohol 10 was oxidized to
aldehyde 57 (90%) using IBX in DMSO–THF, see
Scheme 3.
Synthesis of the C(26)–C(31) fragment
Asymmetric hydroboration of olefin 7 using (−)-
diisopinocamphenylborane gave the optically pure alco-
hol 11 (96%). Using the two-step sequence (PCC, B.V.
oxidation), alcohol 11 was converted into the lactone 12
(76%) in high optical purity.
The bicyclic lactone 12 was opened reductively with
LiAlH4 to give the triol 13 (92%), the stereocenters of
the triol 13 were confirmed in the same way as for
fragment 9. Triol 13 was converted into the acetonide
14 (95%). The free hydroxyl moiety of 14 was protected
as its benzyl ether using NaH and BnBr to give the
benzyl ether 15 (98%). The acetonide protection of 15
was cleaved with 2N HCl in THF–H2O to give the diol
16 (95%). The diol 16 was oxidatively cleaved by
RuCl3·3H2O/NaIO4 and the resultant acid was
esterified with diazomethane to yield the ester 17 (60%)
over two steps. The ester 17 was converted into the
phosphonate 68 (70%) by treatment with dimethyl
methane phosphonate and n-BuLi. With this we have
completed the synthesis of the required b-ketophospho-
nate, i.e. the C(26)–C(31) fragment (Scheme 4).
Scheme 1.
which can be used for further functionalization
(Scheme 2).
Synthesis of the C(19)–C(25) fragment
We initiated our synthesis from precursor 7, which we
had developed and utilized for a synthesis of rifamycin-
S6a and (+)-discodermolide6c fragments wherein we had
exploited the desymmetrization approach to create six
stereogenic centers at once. For the synthesis of the
C(19)–C(25) fragment of scytophycin C, we prepared
the triol 9 by an earlier reported method.6a The stereo-
centers of the triol 9 were firmly established on the
Barium hydroxide induced HWE reaction-synthesis of
the C(19)–C(31) fragment
The key factor in realizing the successful synthesis of
the C(19)–C(31) fragment was to achieve an efficient
Horner–Wadsworth–Emmons coupling between the
sterically hindered aldehyde 5 and the b-ketophospho-
nate 6, as reported by Paterson.9 Accordingly b-
ketophosphonate 6 was treated with activated Ba(OH)2
in THF followed by addition of the aldehyde 5 in wet
THF, to realize the desired (E)-enone 4 in a 95%
yield.10 The double bond in (E)-enone 4 was selectively
reduced by LiAlH4/CuI in THF as reported by Ashby11
to furnish the desired C(19) to C(31) fragment 8 (80%)12
(Scheme 5).
In conclusion, this highly stereospecific synthesis of the
C(19)–C(31) fragment illustrates the dynamic utility of
the precursor 7, and the desymmetrization approach to
control the eight required stereocenters to yet another
Scheme 2.
Scheme 3. Reagents and conditions: (a) 2,2-DMP, CSA (cat.), CH2Cl2, 25°C, 1 h; (b) IBX, DMSO–THF, 25°C, 2 h.

J. S. Yada6, Md. M. Ahmed / Tetrahedron Letters 43 (2002) 7147–7150
7149
Scheme 4. Reagents and conditions: (a) (−)-Ipc2BH, −23°C, 24 h, 3N NaOH, 30% H2O2, 25°C, 6 h; (b) PCC, CH2Cl2, 25°C, 3 h;
(c) m-CPBA, NaHCO3, CH2Cl2, 25°C, 10 h; (d) LiAlH4, THF, 0“25°C, 4 h; (e) 2,2-DMP, CSA (cat.), CH2Cl2, 25°C, 1 h; (f)
NaH, BnBr, THF, reflux, 3 h; (g) 2N HCl, THF/H2O, 25°C, 1 h; (h) RuCl3·3H2O, NaIO4, 1:1:3 CH3CN:CCl4:H2O, 25°C, 1 h;
(i) CH2N2 in ether, 0°C, 15 min; (j) (MeO)2 P(O)Me, n-BuLi, THF, −78°C, 1 h.
Scheme 5. Reagents and conditions: (a) Ba(OH)2·8H2O, 40:1 THF/H2O, 25°C, 1 h; (b) LiAlH4/CuI, THF, 0“25°C, 30 min.
important fragment of a biologically active molecule.
Further studies towards the preparation of the C(1)–
C(18) fragment of scytophycin C, leading to its total
synthesis are on-going.
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Acknowledgements
The author M.M.A. thanks CSIR, New Delhi for the
award of fellowship.
References
1. (a) Ishibashi, M.; Moore, R. E.; Patterson, G. M. L.; Xu,
C.; Clardy, J. J. Org. Chem. 1986, 51, 5300; (b) Moore,
R. E.; Patterson, G. M. L.; Mynderse, J. S.; Barchi, J.,
Jr.; Norton, T. R.; Furusawa, E.; Furusawa, S. Pure
Appl. Chem. 1986, 58, 26; (c) Carmeli, S.; Moore, R. E.;
Patterson, G. M. L.; Yoshida, W. Y. Tetrahedron Lett.
1993, 34, 5571.
2. Kitagawa, I.; Kobyashi, M.; Katori, T.; Yamashita, M.;
Tanaka, J.; Doi, M.; Ishida, T. J. Am. Chem. Soc. 1990,
112, 3710.
3. (a) Patterson, G. M. L.; Smith, C. D.; Kimura, L. H.;

7150
J. S. Yada6, Md. M. Ahmed / Tetrahedron Letters 43 (2002) 7147–7150
7. Data for compound 5: 1H NMR (200 MHz, CDCl3) l
128.23, 128.14, 127.74, 127.66, 127.52, 127.45, 127.34,
127.29, 126.98, 126.87, 126.84, 126.78, 97.98, 84.59, 84.43,
83.35, 73.39, 73.23, 73.12, 72.03, 66.23, 39.93, 37.65,
36.89, 36.19, 36.04, 30.18, 19.54, 17.60, 13.95, 12.41,
12.34, 11.42; [h]2D5 −31.34 (c 0.6, CHCl3); IR (liquid film):
1685, 1670, 1630, 1005 cm−1; FABMS m/z 657 (M++H).
Anal. calcd for C42H56O6: calcd: C, 76.79; H, 8.59.
Found: C, 76.75; H, 8.63%.
0.70 (3H, d, J=6.67 Hz), 0.81 (3H, d, J=6.67 Hz), 1.1
(3H, d, J=6.67 Hz), 1.30 (6H, s), 1.79–2.01 (3H, m),
2.62–2.75 (1H, m), 3.40–3.52 (1H, m), 3.62–3.79 (2H, m),
4.59 (2H, ABq), 7.29 (5H, m), 9.79 (1H, s); [h]2D5 +2.89 (c
1.8, CHCl3); IR (liquid film) 2825, 1735 cm−1; FABMS
m/z 335 (M++H). Anal. calcd for C20H30O4: calcd: C,
71.82; H, 9.04. Found: C, 71.93; H, 9.19%.
8. Data for compound 6: 1H NMR (200 MHz, CDCl3) l
1.05 (3H, d, J=6.33 Hz), 1.1 (3H, d, J=6.33 Hz), 1.7
(1H, m), 2.1 (1H, m), 2.9–3.05 (1H, m), 3.15–3.3 (1H, m),
3.4 (1H, m), 3.6 (1H, buried m’s), 3.65 (3H, s), 3.7 (3H,
s), 3.75 (1H, buried m’s), 4.42 (2H, buried ABq), 4.5 (2H,
s), 7.25 (10H, m); [h]2D0 −28.34 (c 0.6, CHCl3); IR (liquid
film): 1720, 1417, 1269, 1035 cm−1; FABMS m/z 471
(M++Na), 341 (M+−107). Anal. calcd for C24H33O6P:
calcd: C, 64.27; H, 7.42. Found: C, 64.35; H, 7.43%.
9. Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
10. Data for compound 4: 1H NMR (200 MHz, CDCl3) l
0.58 (3H, d, J=6.9 Hz), 0.67 (3H, d, J=6.9 Hz), 0.85
(3H, d, J=6.9 Hz), 1.05 (3H, d, J=6.9 Hz), 1.12 (3H, d,
J=6.9 Hz), 1.3 (6H, s), 1.5–1.7 (3H, m), 2.02–2.19 (1H,
m), 2.5–2.7 (1H, m), 3.19–3.33 (1H, m), 3.35–3.5 (3H, m),
3.59–3.79 (2H, m), 3.8–3.9 (1H, m), 4.4–4.62 (6H, m), 6.2
(1H, d, J=15.4 Hz), 7.0 (1H, dd, J=7.69, 15.38 Hz),
7.19–7.39 (15H, m); 13C NMR (75 MHz, CDCl3) l
203.13, 148.69, 139.02, 138.79, 138.73, 130.31, 128.31,
11. Ashby, E. C.; Lin, J. J.; Kovar, R. J. Org. Chem. 1976,
41, 1939.
12. Data for compound 8: 1H NMR (200 MHz, CDCl3) l
0.65 (3H, d, J=6.4 Hz), 0.8 (3H, d, J=6.1 Hz), 0.85 (3H,
d, J=6.1 Hz), 1.05 (3H, d, J=6.4 Hz), 1.22 (3H, d,
J=6.4 Hz), 1.17–1.28 (2H, overlapping m’s), 1.3 (6H, s),
1.8–196 (3H, m), 2.0–2.1 (1H, m), 2.3–2.45 (1H, m),
2.6–2.8 (1H, m), 2.85–2.96 (1H, m), 3.3–3.5 (5H, m),
3.55–3.7 (1H, m), 3.8–3.95 (1H, m), 4.45–4.65 (6H, m),
7.2–7.39 (15H, m); 13C NMR (75 MHz, CDCl3) l 213.14,
139.25, 138.99, 138.87, 128.45, 128.36, 128.24, 127.89,
127.67, 127.63, 127.55, 127.39, 127.21, 126.88, 126.76,
126.71, 126.68, 97.78, 84.51, 84.33, 83.25, 74.39, 73.23,
73.17, 73.09, 70.13, 45.29, 38.33, 37.87, 36.89, 36.29,
36.04, 32.49, 30.27, 19.45, 18.66, 14.37, 13.95, 12.13,
10.95; [h]2D5 −29.31 (c 1.3, CHCl3); IR (liquid film): 1720,
1455, 1096 cm−1; FABMS m/z 659 (M++H). Anal. calcd
for C42H58O6: calcd: C, 76.56; H, 8.87. Found: C, 76.67;
H, 8.69%.