Synthetic studies on the bryostatins: Synthetic routes to analogues containing the tricyclic macrolactone core

Article abstract of DOI:10.1021/ol050512o

(Chemical Equation Presented) Synthesis of the first of a projected series of bryostatin analogues has been accomplished in 26 steps and 2.2% overall yield. In this letter, we detail two approaches to the structural core of these tricyclic macrolactone br

Full text of DOI:10.1021/ol050512o

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2153-2156
Synthetic Studies on the Bryostatins:
Synthetic Routes to Analogues
Containing the Tricyclic Macrolactone
Core
Gary E. Keck* and Anh P. Truong
Department of Chemistry, UniVersity of Utah, 315 South 1400 East RM 2020,
Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
Received March 9, 2005
ABSTRACT
Synthesis of the first of a projected series of bryostatin analogues has been accomplished in 26 steps and 2.2% overall yield. In this letter,
we detail two approaches to the structural core of these tricyclic macrolactone bryostatin analogues. The key features of the route include
BITIP-catalyzed asymmetric allylation reactions and Mukaiyama aldol reactions, a chelation-controlled allylation, pyran annulation reactions,
and macrolactonization.
In the previous paper, we described the synthesis of a
potential C9-C27 intermediate for a projected synthesis of
bryostatin 1.1 However, at this point we elected to delay our
efforts on the synthesis of bryostatin 1 itself in favor of
investigations of the synthesis of truncated analogues using
the same basic overall strategies. Biological evaluation of
bryostatin analogues has shown very encouraging results.2
In particular, the efforts of Wender and co-workers in the
bryostatin analogue area have highlighted what can be
achieved in the area of simplified analogue design. Several
interesting facets from Wender’s studies have also shed light
on the structure-activity relationships of these compounds.3
It was our hope that the syntheses of bryostatin analogues
would not only serve as highly advanced “model” studies
for the synthesis of bryostatin 1 itself but also give access
to structurally simplified analogues of the bryostatins that
retained or exceeded the levels of activity exhibited by the
natural materials. Synthetic access to such structures and the
attendant tuning of structure could in turn provide a better
understanding of the mechanism of action of these agents
and better define structure-activity relationships in this area.
In the previous article, we demonstrated that a C-ring enal
could be sucessfully coupled with a simple hydroxy-
allylsilane using the pyran annulation reaction to incorporate
the B-ring carbons in one synthetic step. However, as we
gained more experience with this reaction, it became clear
that it was a particulary robust and high-yielding process
that might be implemented in a more strategic role. In
particular, we were intrigued by the possibility of using this
process to bring together subunits corresponding to rings A
(2) (a) Hale, K. J.; Hummersone, M. G.; Manaviazar, S.; Frigerio, M.
Nat. Prod. Rep. 2002, 19, 413 and references therein. (b) Hale, K. J.;
Frigerio, M.; Hummersone, M. G.; Manaviazar, S. Org. Lett. 2003, 5, 503.
(3) 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.; Nell, P. G.;
Turner, T. M. J. Am. Chem. Soc. 2002, 124, 13648. (b) 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, 120, 4534. (c) Wender,
P. A.; Hinkle, K. W.; Koehler, M. F. T.; Lippa, B. Med. Res. ReV. 1999,
19, 388. (d) Wender, P. A.; Lippa, B. Tetrahedron Lett. 2000, 41, 1007.
(e) Wender, P. A.; Mayweg, A. V. W.; VanDeusen, C. L. Org. Lett. 2003,
5, 277.
(1) Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2149.
10.1021/ol050512o CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/28/2005

and C with concomitant formation of the B-ring, according
to the strategy shown in Scheme 1. As indicated, either the
Scheme 2. Synthesis of the C12-C27 Fragment
Scheme 1. Retrosynthetic Analysis of the Bryostatins
A-ring pyran 8 could itself be accessed by a pyran annulation
between the simple hydroxy allylsilane 9 and aldehyde 10.
We chose to use a thiol ester as the precursor to the
carboxylate at C1 since we anticipated that it could be
selectively hydrolyzed under mild and specific conditions
to liberate the carboxylic acid needed for esterification with
the C26 hydroxyl group of the C-ring fragment. In addition,
using this approach, the catalytic asymmetric Mukaiyama
aldol reaction using BITIP catalysis would provide a very
convenient means to set the C3 stereocenter.5
Scheme 3. Retrosynthesis of the A-Ring Aldehyde
A- or C-ring intermediates could play the role of the hydroxy
allylsilane. In addition, the same approach could be applied
in the service of analogue synthesis, which would serve as
an advanced model study for the synthesis of bryostatin 1
itself. We describe herein the implementation of this strategy
for the synthesis of the tricyclic macrolactone core of the
bryostatins.
The dissection in which ring C played the role of the
hydroxy allylsilane component was examined first. In the
preceding paper, we described the preparation of the C-ring
enal intermediate 5. To obtain the â- hydroxy allylsilane,
our plan was to utilize our catalytic asymmetric allylation
(CAA) reaction with this enal.4 However, the execution of
this simple step was complicated due to the presence of
sensitive functionalities on the C-ring. We were unable to
obtain an acceptable yield using a catalytic amount of the
BITIP catalyst with this enal and the 2-(trimethylsilylmethyl)
allylstannane reagent 6. However, success was obtained using
a large excess of the BITIP reagent. The product 7 was
obtained in modest (67%) yield due to some decomposition
during the reaction.
The synthesis of the aldehyde component, 10, began with
the BITIP-catalyzed Mukaiyama aldol reaction of the PMB-
protected â-hydroxy aldehyde 11 with thiosilyl ketene acetal
12. The resulting alcohol was protected as the TBS ether to
give 13 in 60% overall yield and in 95% ee. The PMB ether
was then removed under standard conditions using DDQ in
a methylene chloride-water mixture. Immediate oxidation
of the crude alcohol so produced with PCC afforded the
desired aldehyde 10 in 76% yield from the PMB ether 11.
Thus, aldehyde 10 was obtained in four simple steps from
readily available starting materials (Scheme 4).
The hydroxy allylsilane 9 was prepared using stannane 6
and (R)-BITIP catalyst to set the stereocenter at C9. This
reaction proceeded in good yield (81%) and excellent
selectivity (95% ee) on a 3-5 g scale.
These two fragments were then coupled via the pyran
annulation reaction to give the desired pyran 14 in excellent
(91% isolated) yield.6 Fortunately, this reaction went smoothly,
despite the possibility of potentially complicating side
reactions such as â-elimination or cleavage of the tert-butyl
thiol ester. Selective deprotection of the BPS group and
The reaction partner needed for this annulative approach
to fragment coupling is an aldehyde incorporating the A-ring
pyran. As indicated in Scheme 3, we envisioned that the
(4) (a) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995,
60, 5998. (b) Keck, G. E.; Krishnamurthy, D. Synth. Commun. 1996, 26,
367. (c) Keck, G. E.; Krishnamurthy, D. Org. Synth. 1998, 75, 12. (d) Keck,
G. E.; Abbott, D. E.; Boden, E. P.; Enholm, E. J. Tetrahedron Lett. 1983,
25, 3927.
(5) Keck. G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363.
(6) Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189.
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Org. Lett., Vol. 7, No. 11, 2005

bryostatin analogues is flexible, we were concerned about
the use of excess chiral promotor in the sequence of reactions
leading to 15. Thus, we decided to investigate an alternative
strategy for the synthesis of the tricycle 15. In this alternative
approach, the tricyclic material was envisioned to arise from
two sequential annulation reactions starting from the enal 5.
The first would use the same hydroxy allylsilane as in our
previous report;1 the second would use a more complex
hydroxy allylsilane component to bring in carbons 1-8 with
the required stereocenters in this fragment already estab-
lished. Thus, we would use the same BC-ring intermediate
prepared earlier1 in a second annulation with the more
complex â-hydroxy allylsilane 19.
Scheme 4. Synthesis of the A-Ring Pyran-aldehyde
The synthesis of the C1-C8 fragment began with readily
available aldehyde 16 (Scheme 6). A catalytic asymmetric
allylation (CAA) reaction using allyltri-n-butylstannane and
our normal CAA conditions afforded the homoallylic alcohol
in excellent yield and with excellent selectivity (90%, 96%
ee). Protection of this alcohol as the PMB ether was best
accomplished using PMBBr and KHMDS to give 17.
Oxidative cleavage of the alkene then gave the desired PMB-
aldehyde 18 in good yield (80% over two steps).
Incorporation of the allylsilane in this instance was
accomplished with the desired stereochemical result at C5
by simply using a chelation-controlled addition with 1,3-
asymmetric induction; asymmetric catalysis was unnecessary.
Thus, as expected,8 reaction of the â-OPMB-aldehyde 18
with silyl stannane 6 using MgBr2‚Et2O at -78 °C proceeded
with complete stereoselectivity at C5, and in quantitative yield
(Scheme 6). With the desired â-hydroxy allylsilane 19 in
hand, the pyran annulation event was found to occur
smoothly. Reaction of this silane with aldehyde 20 and TMS
triflate, in ether at -78 °C, afforded the desired tricyclic
C1-C27 subunit 21 in good yield (80%) and with all requisite
stereocenters now in place (Scheme 6).9
Elaboration of the ABC Tricyclic Core. The C-ring
glycal was elaborated first. Treatment of the ABC tricycle
21 with m-CPBA in MeOH,10 followed by oxidation with
TPAP-NMO, afforded the desired ketone at C20. It is
noteworthy that considerable experimentation was required
to determine a suitable order of functional group manipula-
tions en route to the seco-acid. We first deprotected the PMB
ethers at C3 and C25, followed by the deprotection of the
BPS ether at C1. Many attempts to selectively oxidize the
primary C1 hydroxyl in the presence of the free secondary
hydroxyls at C3 and C25 using PhI(OAc)2 and TEMPO gave
only a trace of the desired product and mainly unidentified
decomposition products. A successful sequence elaborated
C1 to the acid prior to removal of the PMB ethers. Thus, the
BPS ether at C1 was removed first, by reaction with TBAF.
The resulting diol 22 was then oxidized to keto-aldehyde
oxidation of the resulting alcohol then afforded the desired
A-ring aldehyde 8 in good yield. As shown in Scheme 4,
the synthesis of the A-ring aldehyde was completed in seven
steps and in 31% overall yield.
Coupling of the C1-C11 and C12-C27 Fragments Using
the Pyran Annulation Reaction. With the synthesis of the
A-ring aldehyde 8 accomplished, we turned our attention to
the coupling of these fragments by reacting C-ring hydroxy
silane 7 with A-ring aldehyde 8 in the presence of TMS
triflate. We were pleased to find that the annulation reaction
gave us the desired product 15 in good yield (63% isolated
yield) despite the presence of potentially problematic acid-
sensitive functionality such as the enol ether of the C-ring
pyran (Scheme 5).7
Scheme 5. Union of Rings A and C via Pyran Annulation
(8) (a) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986, 5,
5478. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston,
A. B. J. Am. Chem. Soc. 1995, 117, 6619. (c) Evans, D. A.; Dart, M. J.;
Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322.
(9) Aldehyde 20 was prepared from the corresponding BPS ether by
deprotection using TBAF followed by oxidation with TPAP-NMO. For
the synthesis of this BPS ether, see ref 1.
Sequential Annulation Approach to the Bryostatin
Core. Although this synthesis of the tricyclic core of
(7) This synthetic plan is quite flexible since the annulation can be
approached from two different directions to form the B-ring pyran. In fact,
we were able to demonstrate that the pyran annulation reaction worked
equally well with the roles of the annulation partners reversed.
(10) Evans, D. A.; Carter, P. H.; Charette, A. B.; Prunet, J. A.; Lautens,
M. J. Am. Chem. Soc. 1999, 121, 7540.
Org. Lett., Vol. 7, No. 11, 2005
2155

Scheme 6. Completion of the Bryostatin Core Structure
23 using TPAP-NMO. This material was then subjected to
The synthesis of 26 requires 26 steps in total and has a
longest linear sequence of 23 steps, considerably less arduous
than required for the synthesis of a natural bryostatin. Efforts
to elaborate this structure to more closely resemble the
naturally occurring structures, as well as to provide biological
evaluation of these agents, are in progress and will be
reported in due course.
a Pinnick oxidation11 to give the carboxylic acid. Finally,
the PMB ether protecting groups at C3 and C25 were removed
to give the desired dihydroxy acid 24 in good yield (80%).
Having successfully overcome this particular hurdle, we
then faced the critical issue of macrolactonization of the seco-
acid in the presence of the hydroxyls at both C3 and C25 and
also the removal of the Me and BOM ethers at C19 and C26.
Macrolactonization was achieved using a modified Yamagu-
chi mixed anhydride esterification protocol to give the desired
20-membered lactone 25.12 Finally, the BOM group and
methyl ether at C26 and C19 were removed under very mild
and specific conditions (LiBF4, aqueous CH3CN/H2O) to give
the dihydroxy macrolactone 26 in 62% yield.13
Supporting Information Available: Spectral (1H and 13C
NMR) data for materials described herein. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial assistance provided by the
National Institutes of Health (through Grant GM-28961) is
gratefully acknowledged.
OL050512O
(11) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(12) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(13) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003,
125, 7822.
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