Synthetic studies toward the bryostatins: A substrate-controlled approach to the A-ring

Article abstract of DOI:10.1021/ol061173h

The synthesis of a C₁-C₁₃ A-ring subunit of bryostatin 1 is detailed. The key features of the approach include the convergent fragment assembly with a highly stereoselective construction of the C₇-C₈ bond indicated above.

Full text of DOI:10.1021/ol061173h

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3667-3670
Synthetic Studies toward the
Bryostatins: A Substrate-Controlled
Approach to the A-Ring
Gary E. Keck,* Dennie S. Welch, and Paige K. Vivian†
Department of Chemistry, UniVersity of Utah, 315 South 1400 East RM 2020,
Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
Received May 12, 2006
ABSTRACT
The synthesis of a C1−C13 A-ring subunit of bryostatin 1 is detailed. The key features of the approach include the convergent fragment
assembly with a highly stereoselective construction of the C7−C8 bond indicated above.
Pettit and co-workers reported in 1982 the isolation and
structural identification of bryostatin 1 (1) from the bryozoan
Bugula neritina.1 Seventeen structurally related congeners
have since been isolated and identified, and the family
remains of significant interest to the biological, medical, and
synthetic communities.2 Bryostatin 1 exhibits an impressive
array of biological properties including anticancer activity,
synergistic anticancer activity with established therapeutic
agents such as vincristine,3 and activity against Alzheimer’s
disease.4 Bryostatin 1 is known to bind to PKCR with
nanomolar affinity, but this elicits different biological
responses than those associated with binding by the tumor-
promoting phorbol esters.5 The reasons for these differences
and the mechanisms by which bryostatin 1 affects the
aforementioned areas of therapeutic interest remain unclear.
In 1990, Masamune and co-workers disclosed the first total
synthesis of bryostatin 7.6 More recently, both the Evans7
and the Yamamura8 groups have reported bryostatin total
syntheses. In addition, the promising biological profile of
bryostatin 1, coupled with its scarcity from natural sources,
has encouraged a number of other synthetic efforts in this
area.9 Wender and co-workers have also reported on the
synthesis and biological studies of several analogues of
bryostatin 1.10
The synthetic strategy chosen for implementation is
detailed in Figure 1. Methodology developed in these
laboratories for the construction of 2,6-disubstituted-4-
methylene tetrahydropyrans9g,h,11 was envisioned to join an
A-ring hydroxy allylsilane 2 and a C-ring enal 3 with
concomitant formation of the B-ring. The A-ring containing
the necessary pendant allylsilane could be derived from
(6) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai,
P.; Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407.
(7) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet,
J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540.
(8) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.;
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290.
(9) For recent synthetic work in this area, see: (a) Voight, E. A.; Seradj,
H.; Roethle, P. A.; Burke, S. D. Org. Lett. 2004, 6, 4045. (b) Voight, E.
A.; Roethle, P. A.; Burke, S. D. Org. Lett. 2004, 6, 4534. (c) Hale, K. J.;
Frigerio, M.; Manaviazar, S.; Hummersome, M. G.; Fillingham, I. J.;
Barsukov, I. G.; Damblon, C. F.; Gerscher, A.; Roberts, G. C. K. Org.
Lett. 2003, 5, 499. (d) Hale, K. J.; Frigerio, M.; Hummersome, M. G.;
Manaviazar, S. Org. Lett. 2003, 5, 503. (e) Ball, M.; Baron, A.; Bradshaw,
B.; Omori, H.; MacCormick, S.; Thomas, E. J. Tetrahedron Lett. 2004, 45,
8747. (f) Keck, G. E.; Yu, T.; McLaws, M. D. J. Org. Chem. 2005, 70,
2543. (g) Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2149. (h) Keck,
G. E.; Truong, A. P. Org. Lett. 2005, 7, 2153. (i) Ball, M.; Bradshaw, B.
J.; Dumeunier, R.; Gregson, T. J.; MacCormick, S.; Omori, H.; Thomas,
E. J. Tetrahedron Lett. 2006, 47, 2223.
† Undergraduate research participant.
(1) Pettit, G. R.; C. L.; Douobek, D. L.; Herald, D. L. J. Am. Chem.
Soc. 1982, 104, 6846.
(2) For reviews, see: (a) Hale, K. J.; Hummersome, M. G.; Manaviazar,
S.; Frigerio, M. Nat. Prod. Rep. 2002, 19, 413. (b) Mutter, R.; Wills, M.
Bioorg. Med. Chem. 2000, 8, 1841.
(3) Al-Katib, A. M.; Smith, M. R.; Kamanda, W. S.; Pettit, G. R.;
Hamdan, M.; Mohamed, A. N.; Chelladurai, B.; Mohammad, R. M. Clin.
Cancer Res. 1998, 4, 1305.
(4) Etcheberrigaray, R.; Tan, M.; Dewachter, I.; Kuiperi, C.; Van der
Auwera, I.; Wera, S.; Qiao, L.; Bank, B.; Nelson, T. J.; Kozikowski, A. P.;
Van Leuven, F.; Alkon, D. L. Proc. Natl. Acad. Sci., U.S.A. 2004, 101,
1141.
(5) Dell’Aquila, M. L.; Herald, C. L.; Kamano, Y.; Pettit, G. R.;
Blumberg, P. M. Cancer Res. 1988, 48, 3702.
10.1021/ol061173h CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/20/2006

Figure 1. Retrosynthetic analysis.
methyl ester 4 through application of the Bunnelle reaction.12
Unraveling 4 to linear synthon 5 reveals the C5 oxygenation
to be 1,3-anti to both of the flanking protected hydroxyl
groups, which suggested that this hydroxyl stereocenter could
be exploited in the installation of both the C3 and C7
stereocenters via 1,3-asymmetric induction. Accordingly, a
PMB ether was deemed to be an appropriate protecting group
for this hydroxyl on the basis of its ability to participate in
chelation-controlled processes13 and its ease of removal under
very specific conditions. This disconnection would, however,
require addition of a nucleophile such as 6 to set the C7
stereocenter and install the gem-dimethyl moiety. Little
precedent exists for such a transformation. In the context of
bryostatin synthesis, with the exception of one report,14 most
A-ring approaches commence with material that already
contains the gem-dimethyl group. Finally, a Mukaiyama aldol
reaction was envisioned for stereoselective introduction of
the C3 stereocenter and the required masked carboxylic acid
functionality at C1.
tioselectivity (Scheme 1). This particular allylation deserves
comment. Complete consumption of the aldehyde was
Scheme 1. Synthesis of Tetrasubstituted Allylstannane 6
observed after just 12 h; typically, the CAA process requires
approximately 72 h to reach completion. The rapidity of this
reaction is likely to be associated with the electron-
withdrawing unsaturated ester moiety; i.e., the substrate is a
vinylogous glyoxalate. This seemingly superfluous unsat-
uration was deemed necessary due to previous observations
made by Brown and co-workers16 in which a boron-mediated
allylation into the saturated aldehyde corresponding to 9 was
accompanied by significant lactonization of the product.
After considerable experimentation, conjugate reduction
of the R,â-unsaturated ester was accomplished efficiently by
application of Semmelhack’s Cu(I)/Red-Al protocol.17 In-
troduction of the gem-dimethyl moiety was accomplished
by condensation of ester 10 with acetone to provide tertiary
alcohol 11. Elimination of the hydroxyl group by treatment
with SOCl2/pyridine yielded the terminal olefin which
The synthesis of allylstannane 6 commenced with a
catalytic asymmetric allylation (CAA)15 reaction on com-
mercially available R,â-unsaturated aldehyde 9 to afford the
desired homoallylic alcohol in exceptional yield and enan-
(10) See, for example: (a) Stone, J. C.; Stang, S. L.; Zheng, Y.; Dower,
N. A.; Brenner, S. E.; Baryza, J. L.; Wender, P. A. J. Med. Chem. 2004,
47, 6638. (b) Wender, P. A.; Baryza, J. L.; Brenner, S. E.; Clarke, M. O.;
Craske, M. L.; Horan, J. C.; Meyer, T. Curr. Drug Discuss. Tech. 2004, 1,
1. (c) Wender, P. A.; Mayweg, A. V. W.; VanDeusen, C. L. Org. Lett.
2003, 5, 277. (d) Wender, P. A.; Baryza, J.; Bennett, C.; Bi, C.; Brenner,
S. E.; Clarke, M.; Horan, J.; Kan, C.; Lacote, E.; Lippa, B.; Nell, P.; Turner,
T. J. Am. Chem. Soc. 2002, 124, 13648.
(11) Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4,
1189.
(12) (a) Bunnelle, W. H.; Narayanan, B. A. Tetrahedron Lett. 1987, 28,
6261. (b) Bunnelle, W. H.; Narayanan, B. A. Org. Synth. 1990, 8, 89.
(13) (a) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986,
51, 5478. (b) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett.
1994, 35, 8537. (c) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462 and
references therein.
(14) Yadav, J. S.; Bandyopadhyay, A.; Kunwar, A. C. Tetrahedron Lett.
2001, 42, 4907.
(15) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467. (b) Keck, G. E.; Krishnamurthy, D. Org. Synth. 1998, 75,
12.
(16) Ramachandran, P.; Krzeminksi, M. P.; Reddy, R. V.; Brown, H. C.
Tetrahedron: Asymmetry 1999, 10, 11.
(17) Semmelhack, M. F.; Stauffer, R. D.; Yamashita, A. J. Org. Chem.
1977, 42, 3180.
3668
Org. Lett., Vol. 8, No. 17, 2006

subsequently underwent base-mediated olefin migration to
afford 12.18 Full reduction of the ester proceeded without
difficulty to afford the corresponding alcohol, setting the
stage for installation of the stannyl group. A one-pot
mesylation/Bu3SnLi displacement19 ensued to provide allyl-
stannane 6. The 37% overall yield for this eight-step
sequence provided expedient access to this stannane.
Our attention was next turned to the synthesis of the C1-
C7 subunit. This first required the generation of Mukaiyama
aldol substrate 16 (Scheme 2). A CAA reaction was relied
aldehyde facial selectivity was observed when the mono-
dentate Lewis acid BF3‚OEt2 was employed (entry 3).
Although it is noteworthy that the aldehyde proved stable
to exposure to TiCl3(OiPr), no enhancement in selectivity
resulted from the use of this Lewis acid (entry 4). A dramatic
improvement in selectivity was realized when TiCl2(OiPr)2
was used in place of TiCl3(OiPr), but the conversion was
modest as 40% of aldehyde 16 was recovered (entry 5).
However, a further increase in aldehyde facial selectivity and
a significant improvement in conversion were observed when
the number of equivalents of the mixed titanium Lewis acid
was increased (entry 6). Optimization of this reaction
revealed that the use of 2.5 equiv of the TiCl2(OiPr)2 afforded
a 95% yield of aldol adduct 17, as a 41:1 mixture of
diastereomers, as ascertained by HPLC analysis (entry 7).20
The suspected relative stereochemical relationship between
the C3 and C5 stereocenters was confirmed by application
of Rychnovsky’s acetonide NMR method.21
Scheme 2. Synthesis of Aldehyde 16
Preliminary coupling studies suggested that the C3 hy-
droxyl protecting group might remotely influence the facial
bias in the stannane addition to the aldehyde. Thus, two
differentially protected aldehydes were synthesized in prepa-
upon once again to provide homoallylic alcohol 14 in 90%
yield and 93% ee. Conversion of the alcohol to PMB ether
15 was accomplished by reaction with p-methoxybenzyl
trichloroacetimidate and catalytic CSA. It is worth noting
that unavoidable silyl migration was observed under the
typical KH/PMBBr conditions. Additionally, the use of CSA
was found to offer results superior to those obtained with
other commonly employed acids such as TfOH, PPTS, and
BF3‚OEt2. Deprotection of the primary TBDPS ether with
TBAF and subsequent Parikh-Doering oxidation gave the
requisite aldehyde 16 in 92% yield over the two reactions.
A variety of Lewis acids and conditions were screened in
the Mukaiyama aldol reaction (Table 1). The use of MgBr2‚
Scheme 3. Synthesis of Two Aldehyde Coupling Partners
ration for the coupling studies (Scheme 3). Secondary alcohol
17 was protected as the TBS ether by treatment with TBSOTf
and lutidine. Ozonolytic cleavage of the terminal olefin
provided aldehyde 18 in an 82% yield over the two steps.
The analogous C3 TBDPS-protected aldehyde was synthe-
sized by silylation with TBDPSCl followed by OsO4/NMO
dihydroxylation and cleavage of the resulting diol by Pb-
(OAc)4.22 Aldehyde 19 was accessed in 91% yield from
alcohol precursor 17.
With both aldehyde and stannane coupling partners in
hand, our attention was directed toward the critical coupling
reaction. Surprisingly, both MgBr2‚OEt2 and TiCl2(OiPr)2
failed to promote this addition. It was reasoned that aldehyde
18 may need increased activation for the addition of the
relatively hindered stannane 6 to occur. Dimethylaluminum
chloride appeared to be a suitable Lewis acid candidate to
explore as it is recognized for its exceptional chelating
ability.23
Table 1. Mukaiyama Aldol Survey
entry
Lewis acid
equiv
temp (°C)
solvent
CH2Cl2
dr
4:1
4.5:1
5:1
1
2
3
4
5
6
7
MgBr2‚OEt2
MgBr2‚OEt2
BF3‚OEt2
2.0
2.0
1.1
1.0
1.0
2.0
2.5
-20
-78 to -20 CH2Cl2
-78
-78
-78
-78
-78
CH2Cl2
PhCH3
PhCH3
PhCH3
TiCl3(OiPr)
TiCl2(OiPr)2
TiCl2(OiPr)2
TiCl2(OiPr)2
5:1
32:1a
37:1b
PhCH3 41:1c
a 40% of 16 recovered. b 10% of 16 recovered. c 95% of 17 isolated.
OEt2 afforded moderate diastereoselectivities for this trans-
formation (entries 1 and 2). A slight improvement in
(18) For a similar synthetic sequence involving introduction of a 1,1-
dimethyl unsaturated olefin, see: Hirai, K.; Ooi, H.; Esumi, T.; Iwabuchi,
Y.; Hatakeyama, S. Org. Lett. 2003, 5, 857.
(20) For a related chelation-controlled Mukaiyama addition involving a
PMB-protected â-hydroxy aldehyde, see ref 7.
(21) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
(19) Weigand, S.; Bru¨ckner, R. Synthesis 1996, 475.
Org. Lett., Vol. 8, No. 17, 2006
3669

In the event, subjection of aldehyde 18 to Me2AlCl (2.5
equiv) in CH2Cl2 gave the desired addition product 20 in
good yield but with modest 3.5:1 diastereoselectivity (Table
2, entry 1).24 An increase in the amount of Lewis acid used
Scheme 4. Completion of the A-Ring Synthesis
Table 2. Optimization of the Coupling Reaction
entry
R
equiva solvent yield (%)b
dr
1
2
3
4
5
TBS
TBS
TBDPS
TBDPS
TBDPS
2.5
5.0
2.5
2.5
5.0
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
PhCH3
83
73
78
79
88
3.5:1
7:1
7:1
single isomerc
single isomerc
minimize the number of chemical operations required to
reach the A-ring target. Unfortunately, no conditions were
found which would effect this transformation. Independent
oxidative operations on the olefins were thus carried out as
follows. Dihydroxylation of the terminal olefin followed by
NaIO4 cleavage of the resulting diol was accomplished in
good yield to provide aldehyde 22. No product resulting from
the dihydroxylation of the C9 olefin was detected, undoubt-
edly as a consequence of the considerable steric demand im-
posed by the proximal gem-dimethyl group. Pinnick oxida-
tion25 of the aldehyde and methylation of the resulting car-
boxylic acid with (trimethylsilyl) diazomethane provided
methyl ester 5 in 91% yield over the two steps. With the
methyl ester in hand, oxidative cleavage of the PMB group
was accomplished in 91% yield by reaction with DDQ.
Finally, ozonolysis of the remaining olefin afforded a mixture
of ketol and open-chain keto-alcohol. This equilibrating mix-
ture underwent conversion to the cyclic methyl ketal with
concomitant deprotection of the TBS ether under acidic
methanolic conditions to give A-ring target 4 in 55% yield
from alkene 5.
In conclusion, A-ring subunit 4 was accessed from alde-
hyde 13 in 17 linear steps in 15% overall yield. This connec-
tive fragment assembly approach provides an efficient means
for introduction of both the gem-dimethyl group and the C7
stereocenter in a highly stereoselective manner. Efforts to
utilize this approach in a total synthesis program are in
progress.
Acknowledgment. Financial support from the National
Institutes of Health (through GM-28961) is gratefully
acknowledged. Dr. Michael R. Wiley of Eli Lilly is acknow-
ledged for helpful discussions regarding the synthesis of
allylstannane 6.
a Refers to Lewis acid. b All reactions were performed with 1.3 equiv
of stannane; yield based on aldehyde. c By H and 13C NMR analysis.
1
to 5.0 equiv improved the level of stereoselectivity observed
(entry 2). Reactions using the TBDPS ether containing
aldehyde 19 confirmed our suspicions that the C3 protecting
group might influence the stereochemical outcome; under
conditions identical to those employed in entry 1, the desired
adduct was obtained in comparable yield but with 7:1
diastereoselectivity (entry 3). A dramatic improvement in
diastereoselectivity was realized by a change of solvent (entry
4). When the same reaction was performed in toluene, a
single addition product was obtained in 79% yield. As entry
5 demonstrates, when the reaction was carried out using 5.0
equiv of Me2AlCl in toluene, an 88% yield of 21 resulted
under these optimized conditions. The expected stereochem-
istry was corroborated via NOE data obtained after closure
of the A-ring (Scheme 4).
The only remaining tasks were formation of the A-ring
and elaboration of the terminal olefin to the methyl ester.
Toward this end, acylation of the newly formed hydroxyl
group was accomplished by exposure to Ac2O and DMAP.
It was anticipated that oxidative cleavage could be carried
out simultaneously on both the C9 and terminal olefins to
(22) This two-step procedure for olefin cleavage was used in lieu of
ozonolysis due to the fact that aldehyde 19, unlike 18, suffered from
deleterious elimination of the PMB group during chromatographic purifica-
tion which proved necessary following reductive workup of the ozonide.
Conversely, subjection of the purified diol to Pb(OAc)4 followed by filtration
and removal of benzene under reduced pressure afforded the aldehyde which
could be carried onto the coupling without the need for further manipulation.
The origin of the difference in stability to chromatography between
aldehydes 18 and 19 is unclear at present.
Supporting Information Available: Full experimental
details as well as spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Evans, D. A.; Allison, B. A.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840.
(24) Because of the disproportionation of Me2AlCl following complex-
ation with an aldehyde, a minimum of 2.5 equiv of Lewis acid is generally
employed in this transformation. It is possible that the reaction proceeds
more efficiently with 5.0 equiv due to the sequestration of Lewis acid by
the thiol ester and/or electron-rich PMB group. Moreover, TBS ethers have
been shown to bind with Me2AlCl (TBDPS ethers do not) and therefore
could be a source of chelate disruption, leading to lower diastereoselectivity
than that observed with the TBDPS-containing aldehydes. See ref 23.
OL061173H
(25) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
3670
Org. Lett., Vol. 8, No. 17, 2006