Dinuclear asymmetric Zn aldol additions: Formal asymmetric synthesis of fostriecin

Article abstract of DOI:10.1021/ja042435i

Direct asymmetric aldol reactions constitute a powerful methodology for the efficient synthesis of complex natural products. Herein we report the first application of our recently reported dinuclear Zn-catalyzed direct aldol addition of alkynyl ketones to

Full text of DOI:10.1021/ja042435i

Published on Web 02/23/2005
Dinuclear Asymmetric Zn Aldol Additions: Formal Asymmetric Synthesis of
Fostriecin
Barry M. Trost,* Mathias U. Frederiksen, Julien P. N. Papillon, Paul E. Harrington,
Seunghoon Shin, and Brock T. Shireman
Department of Chemistry, Stanford UniVersity, Stanford, California, 94305-5080
Received December 16, 2004; E-mail: bmtrost@Stanford.edu
Scheme 1. Retrosynthetic Analysis
Direct asymmetric aldol reactions constitute a powerful meth-
odology for the synthesis of biologically active compounds. With
the use of our dinuclear asymmetric zinc complexes we recently
demonstrated the feasibility of using alkynyl methyl ketones as
donors.1 One of the advantages of using terminal benzyldimethyl-
silyl alkynes as donors in this reaction is the potential for employing
the resultant adducts directly in subsequent cross-coupling reac-
tions.2 The strategic potential offered by these reactions led us to
target fostriecin (CI-920, 1), a cytotoxic phosphate ester isolated
from Streptomyces pulVeraceus.3 The natural product displays potent
anticancer activity against leukemia and many other cell lines.4 The
cytotoxic properties of 1 are attributed to its selective inhibition of
protein phosphatase 2A (PP2A).5 The absolute and relative stereo-
chemistry of 1 was established by Boger,6 who also disclosed the
first total synthesis of the natural product7 as well as preliminary
SAR studies of this molecule.8 Several total syntheses have been
published,9 as well as a number of synthetic approaches.10 Herein
we report our efforts in this area, which culminated in a short and
efficient synthesis of dephospho-fostriecin 2.
As shown in Scheme 1, we targeted the tetraol 2, a key
intermediate in Boger’s synthesis.7 We envisioned that 2 could be
disconnected between C13 and C14 to give silane 3 and iodide 4.
In the synthetic direction, an alkenylsilane cross-coupling reaction
would be employed to forge the labile triene unit.2,11 Further
disconnection at the C7-C8 bond gives a vinyl metal species 5
and ketone 6. Finally, ketone 6 would be derived from the aldehyde
7 and ynone 8, utilizing the direct Zn-catalyzed asymmetric aldol
reaction developed in this group.1
Scheme 2. Synthesis of Vinyl Iodide 11a
a Reagents and conditions: (a) NaI, AcOH, 70 °C, (77%); (b) DIBAL-
H, CH2Cl2, -78 °C; (c) BF3‚Et2O, CH2Cl2, (95:5 E:Z); (d) (+)-Ipc2BOMe,
allylmagnesium chloride, Et2O, -90 °C, (49% over 3 steps, 95% ee); (e)
TESCl, imidazole, DMF, (95%).
Scheme 3. Synthesis of Alkynyl Silanea
Our synthesis commenced with the preparation of the metalation
precursor of 5. Thus, ethyl propiolate was converted to the â-E-
iodoacrolein 10 according to literature procedures (Scheme 2).12
The labile aldehyde 10 was allylated according to Brown’s
procedure,13 giving the allylic alcohol in high yield and ee (81%
and 95%, respectively). Finally, silylation under standard conditions
afforded the target vinyl iodide 11.
With an efficient route to 11 in hand, attention shifted to the
preparation of the C8-C13 portion of fostriecin (1) (Scheme 3).
Here we wished to establish the C9 stereochemistry by enantio-
selective direct aldol reaction as reported recently.1 Thus, the
requisite alkynyl ketone 8 was prepared by the addition of ethynyl-
magnesium bromide to benzyldimethylchlorosilane (BDMSCl)
followed by deprotonation and subsequent acylation. Ketone 12
was treated with aldehyde 7 under our standard Zn-catalyzed direct
aldol reaction (3 mol % 13, 6 mol % Et2Zn), affording the aldol
adduct 14 in an excellent ee (99%). It is worth noting that this
reaction could routinely be performed on 50 mmol scale with no
deterioration in yield or ee. Use of 5 mol % catalyst bumped the
yield to 73%. Next, a diasteroselective reduction was envisaged.
Unfortunately, various substrate-controlled methods failed to deliver
the desired anti-diol in useful yield. Reduction under Noyori’s Ru-
a Reagents and conditions: (a) ethynylmagnesium bromide, THF, 0 °C
(99%); (b) nBuLi, MeCON(Me)OMe, THF, -78 to -15 °C (90%); (c) 13
(3 mol %), Et2Zn (6 mol %), 4 Å MS, 7, rt (58-67%, 99% ee); (d) 15 (1
mol %), iPrOH, rt (88%, >10:1 dr); (e) TBSCl, Im, DMF, then CSA,
Me2CO (77% 2 steps); (f) DMBOCH2Cl, TBAI (14 mol %), DIEA, DMF,
40 °C (97%); (g) MgBr2, THF, rt, then 11, iPrMgCl, sBuLi, THF, -78 °C
(75%, >20:1 dr); (h) HF, MeOH, MeCN, rt (91%); (i) acryloyl chloride,
DIEA, CH2Cl2 (99%); (j) TESOTf, DIEA, CH2Cl2 (99%); (k) Grubbs 1
(10 mol %), CH2Cl2, reflux (93%).
catalyzed transfer hydrogenation conditions14 (cf. 15) gave the
desired alcohol 16 in high yield and selectivity. Selective silylation
and hydrolysis of the ketal furnished ketone 17, which was protected
as the DMBO-acetal15 18 in high yield with no detectable
epimerization at the R-stereocenter. Thus, the stage was set for the
introduction of vinyl metal species 5. A chelation-controlled addition
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10.1021/ja042435i CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Completion of the Synthesisa
Acknowledgment. We are grateful to the NIH (GM 33049)
for their continued generous support of our programs. M.U.F thanks
GSK Research and Development Ltd. for partial postdoctoral
support. B.T.S. thanks the NIH for postdoctoral fellowship support.
Supporting Information Available: Experimental details and
characterization for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org
References
(1) Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc. 2004, 126,
2660 and references therein to other direct asymmetric aldol reactions.
(2) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895.
(3) (a) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983, 36,
1595. (b) Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N. E.;
Brankiewicz, A. J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J.
Antibiot. 1983, 36, 1601. (c) Hokanson, G. C.; French, J. C. J. Org. Chem.
1985, 50, 462.
a Reagents and conditions: (a) DDQ, CH2Cl2:H2O (10:1) (94%); (b) 23,
NaHCO3, MeOH, rt (53%, 72% brsm); (c) 4, Pd2(dba)3‚CHCl3 (5 mol %),
TBAF (4 equiv slow addition), THF, 0 °C to room temperature (54%).
(4) Jackson, R. C.; Fry, D. W.; Boritzki, T. J.; Roberts, B. J.; Hook, K. E.;
Leopold, W. R. AdV. Enzyme Reg. 1985, 23, 193.
of the corresponding magnesiate species16 of 11 afforded 19 as a
single diastereomer in very good yield (75%). The unsaturated
lactone moiety was installed by selective removal of the allylic
TES-group, followed by acylation with acrolyl chloride giving 20,
which was subsequently exposed to Grubbs first-generation catalyst,
yielding key intermediate 21 (83% over three steps).
(5) (a) Lewy, D. S.; Gauss, C. M.; Soenen, D. R.; Boger, D. L. Curr. Med.
Chem. 2002, 9, 2005. (b) de Jong, R. S.; Mulder, N. H.; Uges, D. R. A.;
Sleijfer, D. T.; Hoppener, F. J. P.; Groen, H. J. M.; Willemse, P. H. B.;
van der Graaf, W. T. A.; de Vries, E. G. E. Br. J. Cancer 1999, 79, 882.
(6) Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997, 62, 1748.
(7) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001, 123,
4161.
(8) Buck, S. B.; Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C. M.;
Hwang, I.; Swingle, M. R.; Bonness, K. M.; Honkanen, R. E.; Boger, D.
L. J. Am. Chem. Soc. 2003, 125, 15694.
With an ample supply of 21 in hand, the stage was set for
examination of the final steps toward the target, fostriecin precursor,
tetraol 2. Thus, the acetal protecting group was removed by the
addition of DDQ, providing alkyne 22 in 94% yield (Scheme 4).
A cis reduction was required to install the vinyl silane. Attempts
to effect this transformation were hampered by either poor yield
and/or over-reduction. Eventually, using diimide precursor 2317
under mildly basic conditions afforded the cis-vinyl silane 24.
Finally the assembly of the triene unit called upon a Pd-catalyzed
vinyl silane cross-coupling reaction. The susceptibility of the
unsaturated lactone toward base complicated this cross-coupling.
After much experimentation, it was found that the sensitive triene
functionality could be assembled by adding TBAF slowly to a
combination of vinyl silane 24, vinyl iodide 4,18 and catalytic
amounts of Pd2(dba)3‚CHCl3 in THF. As expected, the cross-
coupling also led to concomitant deprotection of the silicon
protecting groups, giving the dephosphofostriecin 2 in good yield.
The conversion of 2 to fostriecin (1) has been demonstrated by
Boger.7
In conclusion, we have completed the synthesis of dephospho-
fostriecin 2, and thereby a formal synthesis of fostriecin 1, in 14
steps for the longest linear sequence and 8.5% overall yield. This
work illustrates for the first time the use of the direct asymmetric
Zn-catalyzed aldol reaction, and the utility of the corresponding
aldol adducts as building blocks for complex molecule synthesis.
It also exemplifies the extraordinary utility of the Pd-catalyzed vinyl
silane cross-coupling as an alternative to more mainstream Pd-
catalyzed cross-coupling reactions, in the synthesis of complex
molecules.
(9) (a) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40, 3667.
(b) Reddy, Y. K.; Falck, J. R. Org. Lett. 2002, 4, 969. (c) Miyashita, K.;
Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T. Chem. Commun.
2002, 742. (d) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.;
Imanishi, T. J. Am. Chem. Soc. 2003, 125, 8238. (e) Wang, Y. G.;
Kobayashi, Y. Org. Lett. 2002, 4, 4615. (f) Esumi, T.; Okamoto, N.;
Hatakeyama, S. Chem. Commun. 2002, 3042. (g) Fujii, K.; Maki, K.;
Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733.
(10) (a) Just, G.; Oconnor, B. Tetrahedron Lett. 1988, 29, 753. (b) Liu, S. Y.;
Huang, D. F.; Huang, H. H.; Huang, L. Chin. Chem. Lett. 2000, 11, 957.
(c) Cossy, J.; Pradaux, F.; BouzBouz, S. Org. Lett. 2001, 3, 2233. (d)
Kiyotsuka, Y.; Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2002, 43,
2725. (e) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197. (f)
Ramachandran, P. V.; Liu, H. P.; Reddy, M. V. R.; Brown, H. C. Org.
Lett. 2003, 5, 3755.
(11) For a review, see: Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002,
35, 835.
(12) Marek, I.; Meyer, C.; Normant, J. F. Org. Synth. 1997, 74, 194.
(13) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(14) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738. (b) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya,
T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285.
(15) Kigoshi, H.; Suenaga, K.; Mutou, T.; Ishigaki, T.; Atsumi, T.; Ishiwata,
H.; Sakakura, A.; Ogawa, T.; Ojika, M.; Yamada, K. J. Org. Chem. 1996,
61, 5326.
(16) (a) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2001, 66, 4333. (b) Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K.
Angew. Chem., Int. Ed. 2000, 39, 2481. (c) Knochel, P.; Dohle, W.;
Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu,
V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.
(17) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetrahedron
1976, 32, 2157.
(18) Vinyl iodide 4 was prepared from ester 9, via DIBAL-H reduction,
Horner-Wadsworth-Emmons reaction and subsequent DIBAL-H reduc-
tion, which afforded 4 in 33% overall yield, see Supporting Information
for more details.
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