A New Synthetic Approach to the C Ring of Known as Well as Novel Bryostatin Analogues

Article abstract of DOI:10.1021/ol0355332

(Equation presented) A new approach to the synthesis of the C ring subunit of known and potential bryostatin analogues is described. The convergent approach, Illustrated above, requires fewer steps and offers greater flexibility In rapidly accessing diver

Full text of DOI:10.1021/ol0355332

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4549-4552
A New Synthetic Approach to the
C Ring of Known as Well as Novel
Bryostatin Analogues
Paul A. Wender,* Michael F. T. Koehler,† and Martin Sendzik‡
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
wenderp@stanford.edu
Received August 13, 2003
ABSTRACT
A new approach to the synthesis of the C ring subunit of known and potential bryostatin analogues is described. The convergent approach,
illustrated above, requires fewer steps and offers greater flexibility in rapidly accessing diverse C ring analogues.
The bryostatins are a structurally novel class of macrocyclic
lactones originally isolated from Bugula neritina, a marine
bryozoan, on the basis of their potent antineoplastic activity.1
Their unique mode of action has led to the entry of bryostatin
1 into human clinical trials as a single cancer chemothera-
peutic agent and in combination with other therapies.2
Unfortunately, the low natural abundance of bryostatin has
limited its availability, thereby impeding further clinical trials,
studies on its mode of action, and the identification of
clinically superior analogues. Total synthesis and aquaculture
have been explored to address this supply problem.3,4 Our
own approach to this problem is directed at the design of
clinically superior but structurally simpler analogues that can
be supplied through total synthesis. Two such analogues
(1a,b) have now been reported that meet or exceed the
performance of bryostatin 1 (Ki ) 1.4 nM)5 in binding to
protein kinase C (PKC) and in inhibiting human cancer cell
growth.6 Both are available through synthesis and are
currently in pre-clinical development. Each possesses a
partially modified C ring which we have proposed to play a
critical role in receptor recognition.7 In agreement with this
proposal, this feature is only modestly varied in all natural
and designed compounds possessing activity.8,9 Given the
apparent importance of the C ring, we have explored
alternative strategies that allow for more efficient access to
† Current address: Genentech Inc., 1 DNA Way, South San Francisco,
CA 94080.
‡ Current address: Celera, 180 Kimball Way, South San Francisco, CA
94080.
(4) Mendola, D. In Drugs from the Sea; Fusetani, N., Ed.; Karger: Basel,
2000; pp 120-133.
(5) Pettit, G. R. J. Nat. Prod. 1996, 59, 812-821.
(1) Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold,
E.; Clardy, J. J. Am. Chem. Soc. 1982, 104, 6846-6848.
(2) Mutter, R.; Wills, M. Bioorg. Med. Chem. 2000, 8, 1841-1860.
(3) (a) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai,
P.; Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407-
7408. (b) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette,
A. B.; Lautens, M. Angew. Chem., Int. Ed. Engl. 1998, 37, 2354-2359.
(c) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.;
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290-2294.
(6) (a) Wender, P. A.; DeBrabander, J.; Harran, P. G.; Jimenez, J.-M.;
Koehler, M. F. T.; Lippa, B.; Park, C. M.; Shiozaki, M.; Pettit, G. R. J.
Am. Chem. Soc. 1998, 120, 4534-4535. (b) Wender, P. A.; DeBrabander,
J.; Harran, P. G.; Jimenez, J.-M.; Koehler, M. F. T.; Lippa, B.; Park, C.
M.; Siedenbiedel, C.; Pettit, G. R. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
6624-6629.
(7) Wender, P. A.; Koehler, K. F.; Sharkey, N. A.; Dell’Aquila, M. L.;
Blumberg, P. M. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 4214-4218.
10.1021/ol0355332 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/06/2003

Figure 1. Approaches to the synthesis of the C ring in the preparation of bryostatin analogues 1a and 1b.6a,8b
known analogues and for more flexible access to new C ring
analogues (Figure 1).
The first subgoal of this effort was the preparation of
hydropyranone 12 (Scheme 1). Three separate routes were
examined based on fragments 3, 10, and 11. The preparation
of these fragments started with the alkylation of methyl
isobutyrate with allyl bromide to give ester 15. Free radical
bromination with N-bromosuccinimide provided the allylic
bromide,10 which was treated with p-methoxybenzyl (PMB)
alcohol under basic conditions, to give a mixture of PMB
and methyl esters 16a,b upon quenching with NH4OH.
Weinreb amide 17 is obtained through treatment of this
mixture with the magnesium anion of N,O-dimethylhydroxyl-
amine. Reaction of 17 with MeLi gave methyl ketone 10 in
excellent yield. The formation of acid chloride 3 entailed
hydrolysis of 16a,b to acid 16c and subsequent reaction with
NaH and oxalyl chloride. Diketone 11 was obtained from 3
by reaction of the latter with the enolate of acetone.
The individual conversion of fragments 3, 10, and 11 to
hydropyranone 12 was next examined. Condensation of the
dianion of diketone 11 with aldehyde 4a11 at -78 °C gave
compound 19 with a modest 58% diastereoselectivity (ds)
at C23. Similar selectivity was observed in earlier work using
5, the lower homologue of 11 (Figure 1).6a In an effort to
improve this selectivity, the sequence of bond-forming events
was changed and the enolate of acetone was condensed with
aldehyde 4a to give 18 which was then condensed as its
dianion with acid chloride 3 to give 19 now with an improved
81% ds.12 In a third approach, aldehyde 4a was allylated
following Brown’s protocol13 to give alcohol 20 in 83% ds.
The major isomer was then protected as the TBS ether and
Our previous approaches to bryostatin analogues are based
on the late-stage convergent coupling of the C ring 14 to a
spacer domain 13 through esterification at C25 followed by
a novel macrotransacetalization that establishes a dioxolane
B ring with thermodynamic control of the C15 stereocenter.
The C ring 14 is derived from precursors 6 and 9 through
either C22-C23 or C23-C24 bond formation, allowing for
differences in the timing of introduction of stereochemistry
at C25 and C26. Both approaches require late stage homolo-
gation of C17 to introduce C15 and C16. Initially, this
process required four steps. More recent work involving the
use of an alkoxyvinyl zincate has reduced this homologation
to a single step, although it still requires the use of a densely
and delicately appointed advanced stage intermediate.8b The
strategies reported herein were motivated by the view that
this C15-C17 fragment could be introduced early in the
synthesis thereby avoiding this late stage manipulation. A
further consequence of this approach is increased flexibility
in the C22-C23 bond formation and consequent control of
stereochemistry. Finally, when coupled with our macrotrans-
acetalization strategy, this early introduction of the C15-
C17 fragment allows for the conversion of many interme-
diates along the synthetic path into macrocycles with varied
C rings.
Three strategies are reported herein, each benefiting from
the early introduction of the C15-C17 fragment and differing
by the timing and selectivity of stereogenesis at C23.
(8) (a) Wender, P. A.; Hinkle, K. W. Tetrahedron Lett. 2000, 41, 6725-
6729. (b) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.; Brenner,
S. E.; Clarke, M. O.; Horan, J. C.; Kan, C.; LaCote, E.; Lippa, B. S.; Nell,
P. G.; Turner, T. M. J. Am. Chem. Soc. 2002, 124, 13648-13649.
(9) (a) Hale, K. J.; Frigerio, M.; Manaviazar, S.; Hummersone, M. G.;
Fillingham, I. J.; Barsukov, I. G.; Damblon, C. F.; Gescher, A.; Roberts,
G. C. K. Org. Lett. 2003, 5, 499-502. (b) Hale, K. J.; Frigero, M.;
Manaviazar, S. Org. Lett. 2003, 5, 503-505.
(10) Greenwood, F. L.; Kellert, M. D.; Sedlak, J. In Organic Syntheses;
Rabjohn, N., Ed.; John Wiley & Sons: New York, 1963; Collect. Vol. IV,
pp 108-110.
(11) Prepared in five steps from (R)-(+)-methyl lactate. See ref 6a.
(12) Claffey, M. M.; Heathcock, C. H. J. Org. Chem. 1996, 61, 7646-
7647.
(13) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092-
2093.
4550
Org. Lett., Vol. 5, No. 24, 2003

Scheme 1. Synthesis of the C Ring Precursor 12a
a Reagents and conditions: (a) LDA, THF, allyl Br, -78 °C, 90%; (b) NBS, benzoyl peroxide, CCl4, reflux, 72%; (c) NaH, PMBOH,
THF, 35 °C, NH4OH quench gives 16a,b, 74%; aq quench gives 16c, 74%; (d) NaH, (COCl)2, Et2O; (e) (MeO)NHMe‚HCl, PhMgBr,
-20 °C, then 16a,b, 90%; (f) MeLi, THF, -20 °C, 99%; (g) acetone, LDA (3 equiv), THF, -78 °C, 77%; (h) LDA, THF, -78 °C then
4a, 65%, 58% ds; (i) acetone, LDA (3 equiv), THF, -78 °C, 87%, 81% ds; (j) LDA, THF, -78 °C then 3, 61%; (k) TsOH, 4 Å sieves,
PhCH3, 83%; (l) (-)-MeOB(Ipc)2, allyl MgBr, Et2O, -78 °C, 66%, 83% ds; (m) NaH, TBSCl, DMAP, CH2Cl2, reflux, 86%; (n) OsO4,
NMO, 2:1 THF/H2O; (o) NaIO4, 2:1 THF/H2O, 85% over two steps; (p) 10, LDA, THF, -78 °C, 96%; (q) TPAP, NMO, CH2Cl2, 4 Å
sieves, 55%; (r) HF‚pyridine, pyridine, THF, 70%.
the terminal olefin was cleaved to the aldehyde 21. The latter
was condensed with the enolate of ketone 10 to give 19 after
oxidation of the initially formed alcohols with tetrapropyl-
ammonium perruthenate (TPAP)14 and deprotection with
tetrabutylammonium fluoride (TBAF). Diketone 19 was
readily cyclized to hydropyranone 12, which was spectro-
scopically identical to the major diastereomer produced by
the other two routes.
the E-olefin at C21 in 24. The C20 ketone was then reduced
under Luche conditions and acylated to give 25. Following
Scheme 2. Completion of C Ring Portiona
Scheme 2 depicts the completion of the revised synthesis
of 2, the C ring portion of analogue 1a. This was ac-
complished in a fashion inspired by our first generation
synthesis but now with the C15-C16 fragment in place.
Beginning with the critical hydropyranone intermediate 12,
which provides a point of divergence for accessing a variety
of analogues, Luche reduction gave selectively the equatorial
alcohol15 which in turn directed subsequent epoxidation and
methanolysis to give 22. Treatment of 22 with benzoyl
chloride resulted in selective protection of the equatorial C21
alcohol, allowing oxidation of the C20 alcohol with the
Dess-Martin periodinane.16 Samarium diiodide mediated
elimination of the C21 benzyl ester gave 23. An aldol
reaction with methyl glyoxalate followed by mesylation and
elimination of the resulting â-keto alcohol gave selectively
a Reagents and conditions: (a) NaBH4, CeCl3‚7 H2O, MeOH,
-20 °C; (b) m-CPBA, NaHCO3, MeOH, 0 °C, 71% for two steps;
(c) BzCl, DMAP, CH2Cl2, 0 °C; (d) Dess-Martin periodinane,
CH2Cl2, 89% for two steps; (e) SmI2, -78 °C, THF/MeOH, 87%;
(f) LDA, OHCCO2Me, THF, -78 °C, 88%; (g) ClSO2Me, Et3N,
CH2Cl2, -10 °C, then DBU, THF, 81%; (h) NaBH4, CeCl3‚7H2O,
MeOH, -20 °C; (i) C7H15CO2H, 2,4,6-trichlorobenzoyl chloride,
NEt3, PhCH3, 86% for two steps; (j) DDQ, wet CH2Cl2; (k) MnO2,
CH2Cl2, 42% for two steps.
(14) Lenz, R.; Ley, S. V. J. Chem. Soc., Perkins Trans. 1 1997, 3291-
3292.
(15) Luche, J. L.; Rodriguez-Hahn, L.; Crabbe´, P. J. Chem. Soc., Chem.
Commun. 1978, 601-602.
(16) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
Org. Lett., Vol. 5, No. 24, 2003
4551

deprotection of the C15 and C25 alcohols with DDQ and
selective oxidation to the C15 aldehyde using manganese
dioxide, the completed C ring subunit 2 was obtained.
This new synthetic route to 2 offers a number of
advantages, including a reduction in step count as well as
an increase in selectivity in generating the C23 stereocenter.
The number of steps required has been reduced from 23 steps
in the longest linear sequence to 19. The C23 stereocenter
can now be produced with higher stereoselectivity (81% ds).
In addition to the synthetic improvements this route
provides an important strategic advantage in accessing
diverse analogues since all compounds with a closed C ring
(i.e., from 12 forward and their derivatives) could potentially
be converted into analogues for biological testing by
performing the deprotection (C15, C25) and oxidation (C15)
steps and then coupling the resulting C ring subunit to the
AB ring portion 13 as illustrated for the preparation of 1a,b.
To evaluate this more flexible access to possible analogues,
an early intermediate was taken forward to the macrocycle
analogue stage. Intermediate 22 was selected for this purpose,
as it is produced early in the synthesis, and its vicinal diol
provides a site for end stage diversification.
Toward this end, diol 22 was treated with triphosgene to
give the carbonate 26 in excellent yield (Scheme 3). This
compound was readily deprotected at the C15 and C25
positions through treatment with DDQ and the allylic C15
alcohol was then chemoselectively oxidized with manganese
dioxide to give the corresponding unsaturated aldehyde 27.
Hydrolysis of the C19 mixed ketal, although challenging for
this densely functionalized system and initially problematic,
was finally accomplished through treatment with 48%
aqueous HF in acetonitrile/water at 45 °C, producing the C19
hemiketal. This was then converted to the completed
analogue 30 using our previously introduced macrotrans-
acetalization strategy.6a Thus, the AB ring portion 13 was
joined to the new C ring 28 through esterification at C25
using Yamaguchi’s conditions.17 Treatment with buffered
HF‚pyridine in THF removed the C3 TBS protecting group.
This was followed by acetalization using Amberlyst-15 and
4 Å molecular sieves. Finally, the C26 benzyl protecting
group was removed under standard conditions to give the
completed macrocycle 30.
Scheme 3. Completion of the Macrocyclic Analogue 30a
a Reagents and conditions: (a) triphosgene, pyridine, CH2Cl2,
93%; (b) DDQ, wet CH2Cl2, 66%; (c) MnO2, CH2Cl2, 80%; (d)
48% aq HF, CH3CN/H2O (9:1), 45 °C, 79%; (e) 13, 2,4,6-
trichlorobenzoyl chloride, Et3N, PhCH3, then 28, DMAP, 62%; (f)
HF‚pyridine, pyridine, THF; (g) Amberlyst-15, 4 Å sieves, CH2Cl2,
62% for two steps; (h) H2, Pd(OH)2/C, EtOAc, 88%.
in accessing novel C ring analogues. Synthesis of analogue
30 demonstrates that substantially varied C ring subunits are
now readily incorporated into our macrotransacetalization
strategy, allowing access to new macrocycles. Whereas much
of our earlier work addressed the biological activity resulting
from changes in the spacer domain, this new strategy allows
for a broader exploration of activities associated with changes
in the putative recognition domain encompassing the C ring.
Acknowledgment. Financial support of this work was
provided by a grant from the NIH (CA31845). An Eli Lilly
Graduate Fellowship (M.F.T.K.) and a postdoctoral fellow-
ship from the Deutsche Forschungsgemeinschaft (M.S.) also
supported this work.
This new synthetic approach to the C ring subunit 14 of
the bryostatin analogues provides for greater efficiency and
selectivity and, more significantly, it offers greater flexibility
Supporting Information Available: High-resolution
mass spectra along with FTIR and 1H and 13C NMR spectral
data of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
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