Control of olefin geometry in the bryostatin B-ring through exploitation of a C2-symmetry breaking tactic and a Smith-Tietze coupling reaction

Article abstract of DOI:10.1021/ol005850y

(equation presented) A completely stereocontrolled asymmetric synthesis of an advanced B-ring synthon for the bryostatin family of antitumor agents is reported. Noteworthy features of our synthesis include the Smith-Tietze bis-alkylation reaction between 12 and 13 en route to C₂-symmetrical ketone 10 and the totally stereoselective conversion of 10 into triol 18 via a Grignard addition tactic. Triol 18 was converted to epoxide 3 in nine steps, and an acid-catalyzed intramolecular Williamson etherification reaction completed the synthesis of 2.

Full text of DOI:10.1021/ol005850y

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2189-2192
Control of Olefin Geometry in the
Bryostatin B-Ring through Exploitation
of a C -Symmetry Breaking Tactic and a
2
Smith−Tietze Coupling Reaction
Karl J. Hale,* Marc G. Hummersone, and Gurpreet S. Bhatia
The Christopher Ingold Laboratories, Department of Chemistry,
UniVersity College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
k.j.hale@ucl.ac.uk
Received March 23, 2000
ABSTRACT
A completely stereocontrolled asymmetric synthesis of an advanced B-ring synthon for the bryostatin family of antitumor agents is reported.
Noteworthy features of our synthesis include the Smith−Tietze bis-alkylation reaction between 12 and 13 en route to C -symmetrical ketone
2
10 and the totally stereoselective conversion of 10 into triol 18 via a Grignard addition tactic. Triol 18 was converted to epoxide 3 in nine
steps, and an acid-catalyzed intramolecular Williamson etherification reaction completed the synthesis of 2.
The bryostatins are an architecturally intriguing family of
antitumor macrolides1 that have shown considerable clinical
promise for the treatment of various human cancers.2
Unfortunately, supply issues continue to overshadow the
development of these agents as antitumor drugs, and this
has led to substantial synthetic interest3,4 in this class, not
only from the perspective of increasing current clinical supply
but also from the standpoint of identifying substantially
simplified analogues with superior anticancer properties.
Some time ago, we reported5 an efficient asymmetric
synthesis of a fully elaborated C-ring intermediate for
bryostatin 1. We now describe our synthetic studies on the
bryostatin B-ring, which have recently culminated in the
development of a fully stereocontrolled asymmetric synthesis
of pyran 2.
(1) Bryostatin 1 isolation and structure determination: Pettit, G. R.;
Herald, C. L.; Clardy, J.; Arnold, E.; Doubek, D. L.; Herald, D. L. J. Am.
Chem. Soc. 1982, 104, 6848.
(2) Philip, P. A.; Rea, D.; Thavasu, P.; Carmichael, J.; Sturat, N. S. A.;
Rockett, H.; Talbot, D. C.; Ganesan, T.; Pettit, G. R.; Balkwill, F.; Harris,
A. L. J. Natl. Cancer Inst. 1993, 85, 1812. Jayson, C. G.; Crowther, D.;
Prendiville, J.; McGown, A. T.; Scheid, C.; Stern, P.; Young, R.; Brenchley,
P.; Owens, S.; Pettit, G. R. Brit. J. Cancer 1995, 72, 461.
(3) (a) For the total synthesis of bryostatin 7, see: Masamune, S. Pure
Appl. Chem. 1988, 60, 1587. Kageyama, M.; Tamura, T.; Nantz, M. H.;
Roberts, J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem.
Soc. 1990, 112, 7407. (b) For the total synthesis of bryostatin 2, see: Evans,
D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens,
M. J. Am. Chem. Soc. 1999, 121, 7540.
Our retrosynthetic thinking for bryostatin 1 (1) (Scheme
1) called for the intermediacy of alcohol 2 as a subtarget
and focused on the possible usage of an intramolecular
Williamson etherification6 strategy to assemble the pyran ring
system. We envisaged creating pyran 2 from the internal
epoxide ring-opening of epoxy-alcohol 3, and further analysis
of 3 duly suggested that it might be obtainable from the R,â-
unsaturated lactone 4 by lactone reduction, selective O-
silylation, O-isopropylidene cleavage, selective O-mesylation,
and base treatment. Compound 4 appeared accessible from
10.1021/ol005850y CCC: $19.00 © 2000 American Chemical Society
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2 with the preparation of ketone 10. This was synthesized
through the aforementioned Smith-Tietze bis-alkylation
reaction9 between homochiral epoxide 1310 and the lithio
anion of 2-TBS-1,3-dithiane (12) (Scheme 2). As found by
Scheme 1. Retrosynthetic Analysis of the Bryostatin 1 B-Ring
Scheme 2. Use of the Smith-Tietze Bisalkylation Reaction
and a C2-Symmetry Breaking Tactic To Prepare Triol 18a
a Reagents and conditions: (a)12, t-BuLi (1 equiv), THF (0.3
M), HMPA (4 equiv), 0.5 h, -78 °C, add 13 (2 equiv), warm to 0
°C, stir 1.5 h, then add TBSCl (1.5 equiv) at -78 °C and warm to
20 °C; (b) Hg(ClO4)2.xH2O (2 equiv), CaCO3 (4 equiv), THF-
H2O (4:1) (0.06 M), 0 °C, 0.3 h; (c) AllMgBr (1 M in THF, 1.2
equiv), THF (0.3 M), 0 °C, 0.3 h; (d) OsO4 (0.04 M in H2O, 0.015
equiv), NaIO4 (6 equiv), THF (0.015 M); (e) (CF3CO)2O (10 equiv),
Et3N (30 equiv), DMAP (0.1 equiv), CH2Cl2 (0.14 M), 45 °C, 16
h; (f) i-Bu2AlH (1.2 equiv), CH2Cl2 (0.3 M), -78 °C, 5 h; (g)
n-Bu4NF (1 M in THF) (2.4 equiv), THF (0.3 M), 20 °C, 8 h.
Smith and Boldi9a in related systems, when HMPA was
present in the reaction mixture, the C-TBS group of the initial
monoalkylation product readily underwent a smooth C- to
O-migration to generate a new 1,3-dithianyl anion. In the
case at hand, this rearrangement led to the remaining
equivalent of 13 being consumed fairly rapidly. After in situ
trapping of the resulting alkoxide with TBSCl, the bis-O-
silylated dithiane 11 was isolated in 87% yield. The keto
group of 10 was liberated by reacting 11 with mercuric
perchlorate10 in THF and water at 0 °C.
enoate 6 by mild acid hydrolysis and chemoselective
protection. Retrosynthetic analysis of 6 suggested that it
might be derived from a Wittig-Horner-Emmons7 or
Peterson8 olefination reaction on ketone 10 with reagents 7,
8, or 9 respectively. The primary dividend that would arise
from following this disconnective pathway would come from
its implementation of the olefination process on a C2-
symmetrical ketone, which would guarantee that only one
possible olefin isomer (6) could emerge. Ketone 10 was
attractive as a synthetic intermediate, for it could potentially
be assembled in two steps via a Smith-Tietze coupling
reaction9 between 12 and 13.
Unfortunately, all our attempts at implementing the
aforementioned Wittig or Peterson olefination chemistry on
(4) Synthetic studies on the bryostatins: (a) Munt, S. P.; Thomas, E. J.
J. Chem. Soc. Chem. Commun. 1989, 480. (b) Roy, R.; Rey, A. W.; Charron,
M.; Molino, R. J. Chem. Soc., Chem. Commun. 1989, 1308. (c) Roy, R.;
Rey, A. W. Synlett 1990, 448. (d) Evans, D. A.; Carreira, E. M. Tetrahedron
Lett. 1990, 31, 4703. (e) Evans, D. A.; Gauchet-Prunet, J. A.; Carreira, E.
M.; Charette, A. B. J. Org. Chem. 1991, 56, 741. (f) De Brabander, J.;
With this in mind, we opened our synthetic campaign on
2190
Org. Lett., Vol. 2, No. 15, 2000

10 were unsuccessful (employing 7, 8, and 9 respectively).
A Reformatsky reaction was therefore investigated between
10 and MeO2CCH2ZnBr in THF, but again this failed. It
had been our intention to dehydrate the aldol addition product
and obtain 6 as a single olefin isomer.11
the allylic hydroxyl was performed with activated manganese
dioxide in chloroform (Scheme 3).12 Initially, this reaction
Scheme 3. Conversion of Triol 18 into Pyran 2a
In light of these difficulties, we modified our strategy to
pyran 2, and now made triol 18 (Scheme 2) our new
subtarget. It was prepared efficiently from ketone 10 in five
steps. Initially 10 was reacted with allylmagnesium bromide
in THF at 0 °C to obtain alcohol 14 in 70-80% yield. The
olefinic bond of 14 was then oxidatively degraded with
osmium tetraoxide and sodium periodate5 to furnish â-hy-
droxy aldehyde 15 in 76% yield. Dehydration was next
effected with trifluoroacetic anhydride and triethylamine, in
the presence of a catalytic quantity of 4-(dimethylamino)-
pyridine; this procedure afforded the pure enal 16 in good
yield (70-80%), along with a trace quantity of an as yet
unidentified product. Reduction of the aldehyde in 16 with
DIBAL next provided the desired allylic alcohol 17, with
excellent efficiency. Finally, the silyl groups were detached
from 17 with TBAF to generate triol 18 as an oil in 81%
yield from 16.
To chemically differentiate the two partially masked
terminal 1,2-diol units in 18, a chemoselective oxidation of
Vanhessche, K.; Vandewalle, M. Tetrahedron Lett. 1991, 32, 2821. (g) De
Brabander, J.; Vandewalle, M. Synlett 1994, 231. (h) De Brabander, J.;
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Garcia-Lopez, R.; Vandewalle, M. Tetrahedron: Asymmetry 1997, 8, 1721.
(j) Ohmuri, K.; Suzuki, T.; Miyazawa, K.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1993, 34, 4981. (k) Ohmuri, K.; Suzuki, T.; Nishiyama,
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(q) Lampe, T. F. J.; Hoffmann, H. M. R. Tetrahedron Lett. 1996, 37, 7695.
(r) Weiss, J. M.; Hoffmann, H. M. R. Tetrahedron: Asymmetry 1997, 8,
3913. (s) Kiyooka, S.; Maeda, H., Tetrahedron: Asymmetry 1997, 8, 3371.
(t) Wender, P. A.; De Brabander, J.; Harran, P. G.; Jimenez, J.-M.; Koehler,
M. F. T.; Lippa, B.; Park, C.-M.; Shiozaki, M. J. Am. Chem. Soc. 1998,
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W.; Lippa, B.; Pettit, G. R. Tetrahedron Lett. 1998, 39, 8625. (v) Obitsu,
T.; Ohmuri, K.; Ogawa, Y.; Hosomi, H.; Ohba, S.; Nishiyama, S.;
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E. J. J. Chem. Soc., Perkin Trans. 1 1998, 2865. (x) Baxter, J.; Mata, E.
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S. P.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1998, 2853. (z) Wender,
P. A.; Lippa, B., Tetrahedron Lett. 2000, 41, 1007.
a Reagents and conditions: (a) MnO2 (30 equiv), CHCl3 (0.15
M), 20 °C, 24 h; (b) CF3CO2H (40 equiv), anisole (30 equiv),
CH2Cl2, -15 °C, 8 h; (c) cyclohexanone (20 equiv), EtOAc (0.3
M), p-TsOH (0.1 equiv), 6 h; (d) p-methoxybenzyl trichloroace-
timidate (2 equiv), PPTS (0.5 equiv), CH2Cl2 (0.26 M), 20 °C, 8
h; (e) NaBH4 (2.4 equiv), CeCl3‚7H2O (2.4 equiv), MeOH (0.4 M),
0 °C, 1.5 h; (f) t-BuPh2SiCl (1 equiv), imidazole (1.5 equiv), DMF
(0.17 M), 0 °C, 1 h; (g) 1,3-propanedithiol (10 equiv), BF3.Et2O
(0.1 equiv), CH2Cl2 (0.16 M), -78 to -10 °C, 1 h; (h) MsCl (1.1
equiv), collidine (10 equiv), CH2Cl2 (0.05 M), 0 °C, 4.5 h; (i) NaH
(2 equiv), imidazole (2 equiv), THF (0.08 M), 0 °C, 0.3 h; (j) CSA
(0.1 equiv), CH2Cl2 (0.06 M), 20 °C, 40 min.
(5) Hale, K. J.; Lennon, J. A.; Manaviazar, S.; Javaid, M. H.; Hobbs, C.
J. Tetrahedron Lett. 1995, 36, 1359.
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B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
afforded the desired enal with complete selectivity. Hemi-
acetal formation then ensued, allowing a second chemo-
selective oxidation to occur to fashion the desired R,â-
unsaturated lactone. The two terminal PMB groups were
detached from this product with TFA/anisole,13 to access triol
19. Regioselective O-isopropylidenation of the 1,2-diol unit
in 19 was next attempted with catalytic iodine in acetone.
The remaining hydroxyl was protected as a PMB ether using
p-methoxybenzyltrichloroacetimidate14 and PPTS; compound
(8) Lansbury, P. T.; Serelis, A. J. Tetrahedron Lett. 1978, 1909.
(9) (a) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc., 1997, 119,
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H.; Trout, R. E. L.; Boldi, A. M. Tetrahedron Lett. 1997, 38, 8671. (c)
Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett 1994, 511. (d)
Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1075. (e)
For the very first report of a C- to O-silyl rearrangement occurring after
epoxide opening with 2-TMS-1,3-dithiane, see: Jones, P. F.; Lappert, M.
F.; Szary, A. C., J. Chem. Soc., Perkin Trans. 1 1973, 2272.
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M. D.; Moser, W. H.; Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin, Q.
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an exocyclic enoate, see: Johnson, W. S.; Christianson, R. G. J. Am. Chem.
Soc. 1951, 73, 5511.
(12) Review on MnO2 oxidation: Evans, R. M. Quart. ReV. Chem.. Soc.
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Org. Lett., Vol. 2, No. 15, 2000
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4 was obtained as an oil. Although the aforementioned
O-isopropylidenation reaction worked reasonably well on
small scale, considerable problems were encountered on
scale-up. We therefore investigated the use of a cyclohex-
ylidene acetal for the protection of this terminal 1,2-diol
grouping in 19. Fortunately, this ketalization process worked
successfully on large scale, and as before, it proved a fairly
simple matter to protect the remaining hydroxyl as a PMB-
ether. Typically, this two-step protocol furnished compound
21 in 79% overall yield.
Our next objective was to selectively reduce the lactone
in 21 to obtain diol 22; this was accomplished with sodium
borohydride and cerium trichloride in methanol.15 The less
sterically hindered allylic hydroxyl in 22 was then selectively
O-silylated with TBDPSCl to gain access to 23, and its
cyclohexylidene group selectively cleaved with 1,3-pro-
panedithiol and catalytic BF3-etherate at low temperature;16
this yielded triol 24. A number of methods were evaluated
for the selective O-sulfonylation of triol 24. The mesyl
chloride-collidine system of Burke and O’Donnell gave the
best results.17 Adherence to their recommended procedure
typically led to the isolation of O-mesylate 25 in 81% yield.
We had hoped to convert compound 25 directly into pyran
2 by treatment with 2 equiv of sodium hydride and imidazole
in THF. However, the only product formed under these
reaction conditions was epoxy alcohol 3, isolated in 80%
yield. To bring about the desired 6-exo-tet ring-closure,6b
epoxide 3 was treated with a catalytic quantity of camphor-
sulfonic acid in dichloromethane6a at room temperature for
40 min. This afforded pyran 2 as the sole reaction product
in 87% yield.
In conclusion, we have developed a conceptually new
synthetic strategy for the control of B-ring olefin geometry
in the bryostatins. We anticipate that similar tactics will prove
useful for the construction of advanced C-ring intermediates
for molecules of the 20-deoxy-bryostatin class (e.g., bry-
ostatin 11).
Acknowledgment. We thank the EPSRC (Project Grants
GR/L18532 and GR/L09899), the BBSRC (Project Grant 31/
B09691), the Royal Society (RSRG 15551), Zeneca, and
Pfizer for generous financial support. The ULIRS Mass
Spectrometry Facility at the London School of Pharmacy is
also thanked for HRMS determinations on all the new
compounds reported in this paper.
1
Supporting Information Available: 500 MHz H and
125 MHz 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Luche, J.-L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc., Chem.
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(16) Smith, A. B., III; Chen, K.; Robinson, D. J.; Laakso, L. M.; Hale,
K. J. Tetrahedron Lett. 1994, 35, 4271.
(17) O’Donnell, C. J.; Burke, S. D. J. Org. Chem. 1998, 63, 8614.
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