Enantioselective total synthesis of reveromycin B

Full text of DOI:10.1021/ja983429n

456
J. Am. Chem. Soc. 1999, 121, 456-457
Enantioselective Total Synthesis of Reveromycin B
Keith E. Drouet and Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry
UniVersity of California, San Diego, 9500 Gilman DriVe
La Jolla, California 92093-0358
ReceiVed September 28, 1998
The reveromycins A (1) and B (2) belong to a new family of
natural products that have been isolated from a soil actinomycete
of the genus Streptomyces.1 Both compounds inhibit eukaryotic
cell growth presumably by interfering with an element associated
with the epidermal growth factor receptor pathway.2,3 The
molecular structures of 1 and 2 are characterized by a [6,6] or
[5,6] spiroketal core respectively, decorated with two highly
unsaturated side-chains ending in carboxylic acid units. The
relative and absolute configuration of 1 was determined by
chemical degradation and spectroscopic analysis, while the
structure of 2 was proposed by analogy to 1.4 Herein, we would
like to disclose a route to the chemical synthesis of 2, which may
also be amenable to the synthesis of other members of this family.5
This reaction sequence constitutes the first total synthesis of a
member of the reveromycin family and unambiguously confirms
the proposed structures for 2 and 1.
Figure 1. Strategic bond disconnections of reveromycin B (2).
Scheme 1. Synthesis of the C8-C20 Fragment 5a
a Reagents and conditions: (a) 1.0 equiv 7, 2.1 equiv t-BuLi, -78
°C, Et2O, 0.5 h, then 1.4 equiv 6, 0.5 h, 84%; (b) 1.2 equiv Dess-Martin
periodinane, CH2Cl2, 25 °C, 1 h, 95%; (c) 1.5 equiv TBAF‚THF, THF,
50 °C, 2 h; (d) 1.5 equiv DDQ, wet CH2Cl2, 15 min, 25 °C, 87% (over
two steps); (e) 0.1 equiv CSA, CH2Cl2/MeOH, 9:1, 25 °C, 3 h, 80%; (f)
3.5 equiv Ac2O, 7.0 equiv Et3N, CH2Cl2, 0 °C, 3 h, 97%; (g) O3, CH2Cl2,
-78 °C, then 5.0 equiv NaBH4, MeOH, 25 °C, 1 h, 97%; (h) 1.5 equiv
Ac2O, 3.0 equiv pyridine, CH2Cl2, 25 °C, 15 min, 97%; (i) O3, CH2Cl2,
-78 °C, then 1.5 equiv Ph3P; (j) 5.0 equiv CBr4, 10 equiv HMPT,
THF, -30 °C, 30 min, 89% (over two steps); (k) 2.1 equiv BuLi, THF,
-78 to -20 °C, 20 min, then 5.0 equiv MeI, THF, -78 to 0 °C, 2 h,
95%.
The strategic bond disconnections of reveromycin B (2) are
outlined in Figure 1. Our plan was based on the use of Negishi6
and Kishi-Nozaki7 coupling reactions for the construction of the
reveromycin framework. The key components of our strategy were
thus defined as vinyl iodide 3, vinyl iodide 4, and alkyne 5.
Compound 5 was further disconnected, revealing aldehyde 6 and
iodide 7 as potential precursors. Application of this plan to the
synthesis of 2 is shown below.8
The synthesis of fragment 5 is illustrated in Scheme 1 and
requires union of aldehyde 69 with iodide 7.9 To this end, lithiation
of 7 (t-BuLi, -78 °C) followed by addition of 6 and subsequent
Dess-Martin periodinane oxidation of the resulting C15 hydroxyl
group afforded ketone 8 (2 steps, 80% overall yield). Sequential
deprotection of C18 and C11 hydroxyl groups (TBAF, DDQ)
furnished spiroketal 9 (2 steps, 87% overall). The structure of 9
was unambiguously confirmed by its conversion to triacetate 10,
which exhibited identical spectroscopic and analytical data with
the known 10, obtained by degradation of the natural reveromycin.5a
Compound 9 was then transformed to the desired alkyne 5 via
ozonolysis of the terminal olefin and treatment of the resulting
aldehyde under the modified Corey-Fuchs conditions (three steps,
85% overall yield).10
(1) Osada, H.; Koshino, H.; Isono, K.; Takahashi, H.; Kawanishi, G. J.
Antibiot. 1991, 44, 259. Koshino, H.; Takahashi, H.; Osada, H.; Isono, K. J.
Antibiotics 1992, 45, 1420. Takahashi, H.; Osada, H.; Koshino, H.; Kudo, T.;
Amano, S.; Shimizu, S.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1409.
(2) Takahashi, H.; Osada, H.; Koshino, H.; Sasaki, M.; Onose, R.;
Nakakoshi, M.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1414.
Takahashi, H.; Yamashita, Y.; Takaoka, H.; Nakamura, J.; Yoshihama, M.;
Osada, H. Oncol. Res. 1997, 9, 7.
(3) For a recent review on the control of cell cycle using natural products
see: Hung, D. T.; Jamison, T. F.; Schreiber S. L. Chem. Biol. 1996, 3, 623.
(4) Ubukata, M.; Koshino, H.; Osada, H.; Isono, K. J. Chem. Soc., Chem.
Commun. 1994, 1877.
(5) For synthetic studies from other laboratories, see: (a) Shimizu, T.;
Kobayashi, R.; Osako, K.; Osada, H.; Nakata, T. Tetrahedron Lett. 1996, 37,
6755. (b) McRae, K. J.; Rizzacasa, M. A. J. Org. Chem. 1997, 62, 1196.
(6) Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B.
I. J. Am. Chem. Soc. 1978, 100, 2254.
(7) Kishi Y. Pure Appl. Chem. 1992, 64, 343. Cintas, P. Synthesis 1992,
248.
The synthesis of the C1-C7 fragment 4 proceeded as depicted
in Scheme 2. Evans’ aldol methodology11 was employed to set
the stereochemistry at the C4 and C5 carbons, and thus, aldehyde
(9) Experimental details for the synthesis of 3, 6, and 7 are included in
Supporting Information.
(8) All new compounds exhibited satisfactory spectral and exact mass data.
Yields refer to spectroscopically and chromatographically homogeneous
materials.
(10) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(11) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
10.1021/ja983429n CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/29/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 2, 1999 457
Scheme 3. Synthesis of Reveromycin B (2)a
Scheme 2. Synthesis of the C1-C7 Fragment 4a
a Reagents and conditions: (a) 1.0 equiv 12, 1.0 equiv Bu2BOTf, 1.2
equiv Et3N, then 1.3 equiv 11, CH2Cl2, -78 to 0 °C, 2 h, 80%; (b) 9.0
equiv AlMe3, 9.0 equiv MeO-NHMe‚HCl, THF, -30 to 0 °C, 2 h; (c)
2.0 equiv TBAF‚SiO2, THF, 25 °C, 3 h; (d) 1.5 equiv TIPSOTf, 3.0 equiv
2,6-lutidine, CH2Cl2, 25 °C, 15 min, 81% (over three steps); (e) 2.5
equiv DIBAL-H, THF -78 °C, 0.5 h; (f) 2.5 equiv Ph3PdCH-CO2SEM,
CH2Cl2, 25 °C, 15 h, 91% (over two steps); (g) 0.02 equiv (Ph3P)2PdCl2,
1.5 equiv Bu3SnH, benzene, 5 °C, 10 min, 91%; (h) I2, CH2Cl2, 0 °C, 5
min, 90%.
11 gave rise to alkyne 14, via amide 13 (6 steps, 59% overall
yield). Hydrostannylation of 14 using catalytic Pd(II) afforded
the vinyl stannane, which upon treatment with iodine generated
the desired vinyl iodide 4 (81% overall).12
a Reagents and conditions: (a) 1.0 equiv 5, 2.0 equiv Cp2ZrHCl, THF,
50 °C, 2 h; (b) 3.0 equiv ZnCl2, THF, 5 min, 25 °C; then 1.1 equiv 4,
0.05 equiv (Ph3P)4Pd, THF, 2 h, 25 °C, 84%; (c) 3.0 equiv PPTS, MeOH,
3 h, 40 °C, 75%; (d) 6.0 equiv NaIO4, THF:H2O (2:1), 2 h, 0 °C, 95%;
(e) 4.0 equiv 3, 24 equiv CrCl2 (with 0.5% NiCl2), DMF, 25 °C, 3 h,
65% (1.2:1 ratio at C19); (f) 10 equiv succinic anhydride, 12 equiv
DMAP, 25 °C, 3 h, 85%; (g) 10 equiv TBAF‚THF, THF, 2 h, 25 °C,
69%.
Having completed the synthesis of the C8-C20 and C1-C7
fragments, our attention was focused on the construction of a
sterically hindered C7-C8 bond. This was successfully achieved
with the utilization of the modified Negishi coupling conditions,
recently reported by Panek and Hu.6,13 Thus, hydrozirconation
of 5, followed by treatment with ZnCl2 and subsequent addition
of vinyl iodide 4 and Pd(PPh3)4, afforded the desired cross-coupled
product 15 in one pot and 84% yield (Scheme 3). It is worthwhile
to comment on the efficiency and superiority of the above
coupling as compared to the Stille-type reaction for the formation
of the C7-C8 bond.14
The final steps of the reveromycin B (2) synthesis are described
in Scheme 3. Acid-catalyzed deprotection of the acetonide
functionality of 15, followed by oxidative cleavage of the resulting
diol, gave rise to aldehyde 16 in 71% overall yield. This set the
stage for the crucial Kishi-Nozaki coupling7 of 16 with 3,9 which
afforded alcohol 17 (1.2:1 ratio at C19, 65% combined yield).
Despite several attempts to increase the yield and d.e. of this
reaction, we observed no significant improvement. Nonetheless,
it is important to recognize the remarkable selectivity of the
organochromium species for a hindered aldehyde in the presence
of other potent electrophilic carbon centers.15
In summary, the first total synthesis of reveromycin B (2) has
been designed and accomplished. Crucial steps of our strategy
included a modified Negishi coupling6,14 and a Kishi-Nozaki
coupling,7 that were applied for the installation of the polyene-
containing side chains of 2. Our synthesis demonstrates the utility
of the above methodologies for the construction of complex,
polysubstituted dienes. The highly convergent route with the
longest sequence of 21 steps could provide access to a variety of
potentially bioactive analogues. Our synthesis also confirms the
proposed stereochemistry of the reveromycins.
Acknowledgment. We gratefully acknowledge the financial support
provided by the Cancer Research Coordinating Committee, the UCSD
Academic Senate, and the Hellman Foundation.
NOE experiments indicated that the minor diastereomer, formed
via the Kishi-Nozaki reaction, had the correct (S) stereochemistry
at the C-19 carbon center. This compound was subsequently
esterified with succinic anhydride to yield the fully protected
reveromycin B (18) (85% yield). Finally, TBAF-induced depro-
tection16 of 18 generated synthetic reveromycin B (2) (69% yield).
Synthetic compound 2 exhibited spectroscopic and analytical
properties identical to those of the natural product.17
Supporting Information Available: Selected experimental proce-
dures and spectral data for compounds 2-18 (PDF). See any current
masthead page for Web access instructions.
JA983429N
(15) For a recent impressive demonstration of the application of the Kishi-
Nozaki coupling to the synthesis of complex spiroketals, see: McCauley, J.
A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.; Semones, M. A.; Kishi, Y.
J. Am. Chem. Soc. 1998, 120, 7647.
(12) Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857.
(13) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912. Panek, J. S.; Hu,
T. J. Org. Chem. 1997, 62, 4914.
(16) Sieber, P. HelV. Chim. Acta 1977, 60, 2711. Lipshutz, B. H.; Miller,
T. A. Tetrahedron Lett. 1989, 30, 7149.
(14) Our earlier attempts to exploit Stille cross-coupling chemistry for this
transformation proved to be either unsuccessful or produced 15 in low yields.
(17) We thank Professor H. Osada (RIKEN Institute, Japan) for providing
us with the NMR data of natural reveromycin B.