Synthesis of the bryostatin 1 northern hemisphere (C1-C16) via desymmetrization by ketalization/ring-closing metathesis

Article abstract of DOI:10.1021/ol0483044

(Chemical Equation Presented) Synthesis of the northern hemisphere (C1-C16) of bryostatin 1, a potent anticancer agent, has been accomplished in 14 steps and 11% overall yield via desymmetrization by ketalization/ring-closing metathesis. A 2,9-dioxabicycl

Full text of DOI:10.1021/ol0483044

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4045-4048
Synthesis of the Bryostatin 1 Northern
Hemisphere (C1 C16) via
−
Desymmetrization by Ketalization/
Ring-Closing Metathesis
Eric A. Voight, Hassan Seradj, Paul A. Roethle, and Steven D. Burke*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
Received August 25, 2004
ABSTRACT
Synthesis of the northern hemisphere (C1
yield via desymmetrization by ketalization/ring-closing metathesis. A 2,9-dioxabicyclo[3.3.1]nonane template facilitated stereoselective A-ring
functionalization, while an efficient hetero-Diels Alder reaction was used to elaborate the B-ring.
−C16) of bryostatin 1, a potent anticancer agent, has been accomplished in 14 steps and 11% overall
−
We recently reported desymmetrization by ketalization/ring-
closing olefin metathesis (K/RCM) as an efficient means to
access the 6,8-dioxabicyclo[3.2.1]octane ring system in the
context of natural product total synthesis1 and spiroketal
construction.2 Each of these endeavors has highlighted the
remarkable selectivity that can be accomplished using a rigid
bicyclic ketal template for functional group introduction. To
expand the utility and generality of our strategy, we sought
to extend the method to 2,9-dioxabicyclo[3.3.1]nonane ring
systems. Toward the goal of developing a practical synthetic
route to the clinically significant bryostatins, we describe
herein a short and efficient synthesis of the bryostatin 1 (1,
Figure 1) northern hemisphere, comprising the C1-C16, AB-
ring subunit, further validating the K/RCM strategy for
rapidly accessing complex synthetic targets.
or in combination with other chemotherapies.3 As one of 18
naturally occurring bryostatins, the anticancer activity and
low toxicity of bryostatin 1 has stimulated considerable
synthetic efforts toward the bryostatins and analogues.4,5 In
particular, total syntheses of bryostatins 7, 2, and 3 by
Masamune,6 Evans,7 and Yamamura,8 respectively, have
provided important precedent for further synthetic efforts.
Despite the variety of bryostatin synthetic studies, an efficient
and general northern hemisphere synthesis remains an
Bryostatin 1 is currently under investigation as a potent
antineoplastic agent in numerous human clinical trials alone
(1) (a) Burke, S. D.; Mu¨ller, N.; Beaudry, C. M. Org. Lett. 1999, 1,
1827. (b) Burke, S. D.; Voight, E. A. Org. Lett. 2001, 3, 237. (c) Voight,
E. A.; Rein, C.; Burke, S. D. Tetrahedron Lett. 2001, 42, 8747. (d) Voight,
E. A.; Rein, C.; Burke, S. D. J. Org. Chem. 2002, 67, 8489.
(2) Keller, V. A.; Martinelli, J. R.; Strieter, E. R.; Burke, S. D. Org.
Lett. 2002, 4, 467.
Figure 1. Bryostatin 1.
10.1021/ol0483044 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/06/2004

Figure 2. Retrosynthetic analysis of bryostatin 1.
important goal, especially one capable of delivering C7 ester
derivatives. Since C7 and C20 are the only primary points
of diversity among the naturally occurring bryostatins, access
to many bryostatins and analogues could be enabled by such
a general route.
% camphorsulfonic acid for 1 h with a Dean-Stark trap,
giving ketal 11 in 87% yield (Scheme 1). Notably, when a
Scheme 1. Synthesis of RCM Product 8
Our retrosynthetic analysis of bryostatin 1 is shown in
Figure 2, beginning with disconnection of the C16-C17
olefin as in previous bryostatin total syntheses.6-8 A C16
aldehyde derived from 2 was seen as a suitable coupling
partner for southern hemisphere phenyl sulfone 3. We
recently reported a formal synthesis of 3 via Hale’s inter-
mediate, glycal 4,9 which was prepared in only six steps from
(R)-2-(benzyloxy)propanal.10 The bryostatin northern hemi-
sphere was seen as coming from A-ring bridged bicycle 5.
The B-ring could be derived from pentylidene-protected
glyceraldehyde11 (6) and siloxydiene 7 via a Lewis-acid-
catalyzed hetero-Diels-Alder reaction. Ring-closing me-
tathesis (RCM) product 8, the precursor to 7, would be
derived from C2-symmetric (R,R)-1,6-heptadiene-3,5-diol 912
and vinylogous carbonate 1013 via desymmetrization by
K/RCM.1,2
â-keto ester was used for this reaction, no ketalization
product was observed, presumably because of the quaternary
center adjacent to the reacting carbon. With triene substrate
11 in hand, ring-closing metathesis proceeded readily using
5 mol % of Grubbs’ first generation catalyst 12 (Scheme
1).14 This reaction was best performed by adding the catalyst
in CH2Cl2 slowly over 4 h to a room-temperature solution
of 11 in CH2Cl2 (0.01 M). After an additional 2 h, bridged
bicyclic ketal 8 was obtained in 93% yield.
With the 2,9-dioxabicyclo[3.3.1]nonane template con-
structed, differentiation of the two olefins in diene 8 was
required (Scheme 2). This was accomplished efficiently by
hydroboration with disiamyl borane (2 equiv, 0 °C, 3 h)
followed by oxidative workup with aqueous sodium perbo-
rate (8 equiv, 1 h). The primary alcohol thus obtained was
protected using tert-butylchlorodiphenylsilane, giving TB-
DPS-protected 13 in 90% yield over two steps. Attempted
To begin the synthesis, diene diol 912 was heated with
vinylogous carbonate 1013 in refluxing benzene with 5 mol
(3) For current information on bryostatin 1 clinical trials, see: http://
www.cancer.gov/search/clinical_trials/.
(4) For reviews, see: (a) Pettit, G. R. The Bryostatins. In Progress in
the Chemistry of Organic Natural Products; Herz, W., Ed.; Springer-
Verlag: New York, 1991; Vol. 57, p 153. (b) Norcross, R. D.; Paterson, I.
Chem. ReV. 1995, 95, 2041. (c) Mutter, R.; Wills, M. Bioorg. Med. Chem.
2000, 8, 1841. (d) Hale, K. J.; Hummersone, M. G.; Manaviazar, S.; Frigerio,
M. Nat. Prod. Rep. 2002, 19, 413.
(5) For analogue studies, see ref 4d and: (a) Wender, P. A.; Baryza, J.
L.; Bennett, C. E.; Bi, C.; Brenner, S. E.; Clarke, M. O.; Horan, J. C.; Kan,
C.; Lacoˆte, E.; Lippa, B.; Nell, P. G.; Turner, T. M. J. Am. Chem. Soc.
2002, 124, 13648. (b) Wender, P. A.; Mayweg, A. V. W.; VanDeusen, C.
L. Org. Lett. 2003, 5, 277. (c) 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.
(12) The enantiomer of 9 has been prepared previously: Hoffmann, R.
W.; Kahrs, B. C.; Schiffer, J.; Fleischhauer, J. J. Chem. Soc., Perkin Trans.
2 1996, 2407. We used D-(-)-diethyltartrate in place of L-(+)-diethyltartrate
in the double Sharpless asymmetric epoxidation step of the published
sequence to obtain the desired enantiomer.
(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) (a) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.;
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290. (b) Ohmori, K. Bull.
Chem. Soc. Jpn. 2004, 77, 875.
(9) Hale, K. J.; Frigerio, M.; Manaviazar, S. Org. Lett. 2003, 5, 503.
(10) Voight, E. A.; Roethle, P. A.; Burke, S. D. J. Org. Chem. 2004,
69, 4534.
(13) Obtained by treatment of ethyl 4,4-dimethyl-3-oxo-5-hexenoate (b)
with (trimethylsilyl)diazomethane (a): (a) Harris, C. R.; Kuduk, S. D.;
Balog, A.; Savin, K.; Glunz, P. W.; Danishefsky, S. J. J. Am. Chem. Soc.
1999, 121, 7050. (b) Aurell, M. J.; Gil, S.; Mestres, R.; Parra, M.; Parra, L.
Tetrahedron 1998, 54, 4357. (c) Shibuya, M.; Kubota, S. Heterocycles 1980,
14, 601. See the Supporting Information for details.
(14) For recent reviews, see: (a) Grubbs, R. H. Tetrahedron 2004, 60,
7117. (b) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199. (c) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012. (d) Schrock, R. R. Tetrahedron
1999, 55, 8141. (e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(f) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(11) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.
4046
Org. Lett., Vol. 6, No. 22, 2004

Scheme 2. Synthesis of Keto Ester 16
Figure 3. Selected NOE data.
for the axial, concave face C7 proton in 17. Furthermore,
significant shielding of Hb was observed in 16, with δ Hb
(16) 3.93 ppm vs δ Hb (17) 4.37 ppm, indicating close
proximity to the ketone carbonyl for Hb (16). These data
also provide support for the chair-chair conformation drawn
for bridged bicyclic compounds up to this point in the
synthesis.21
Continuing with the synthesis, the hindered ketone in 16
proved less reactive toward reducing agents than the ethyl
ester. Therefore, it was possible to selectively reduce ester
16 with diisobutylaluminum hydride (1.2 equiv) in CH2Cl2
(0.1 M) at -90 °C over 30 min. When the anion of diethyl-
2-(oxopropyl)phosphonate in THF (0.2 M) was added to the
reaction mixture, Horner-Wadsworth-Emmons olefination
took place after 10 min at reflux. R,â-Unsaturated ketone
18 could then be isolated in 75% yield. In preparation for
the key hetero-Diels-Alder reaction, siloxydiene 19 was
prepared using diisopropylethylamine (3 equiv) and tert-
butyldimethylsilyl trifluoromethanesulfonate (2 equiv) in
Et2O (0.1 M) for 1 h at 0 °C. When boron trifluoride diethyl
etherate (1.2 equiv) was added to a -78 °C solution of 7
and aldehyde 611 (1.5 equiv) in Et2O (0.1 M), a hetero-Diels-
Alder reaction took place in 91% yield to give an easily
separable 15:4:1 mixture of diastereomers. On the basis of
extensive literature precedence indicating excellent Cram
selectivity in hetero-Diels-Alder reactions with ketal-
protected glyceraldehyde derivatives22 and NMR coupling
constants (vide infra), the major isomer was assigned as
B-ring silyl enol ether 19.
dihydroxylation of the remaining olefin in 13 using catalytic
osmium tetraoxide/N-methylmorpholine N-oxide15 was ex-
tremely sluggish, and catalytic ruthenium(III) chloride/
sodium periodate16 gave low yields. However, when 1.5
equiv of citric acid was added to the OsO4-catalyzed reaction
in 1:1 tert-butyl alcohol/water a dramatic rate enhancement
was observed, and diol 14 was obtained in 97% yield after
8 h at room temperature.17 Notably, no endo-diol was
observed from this reaction, consistent with previous dihy-
droxylation results with 6,8-dioxabicyclo[3.2.1]octane ring
systems.1b,d,2 The equatorial alcohol of diol 14 was oxidized
selectively18 using standard Swern conditions, giving a 6:1
ratio of readily separable regioisomeric keto alcohols in 74%
yield. After one recycle of recovered starting material, the
desired keto alcohol 15 was obtained in 80% yield. Again,
the locked conformation of the bicyclic ketal facilitated this
selectivity. Excision of the undesired hydroxyl in 15 was
accomplished using samarium diiodide (5 equiv) and MeOH
(10 equiv) in THF/HMPA (5:1) at 0 °C for 10 min.19 The
axial orientation of the alcohol in 15 assured optimal orbital
overlap in the reductive elimination step, providing keto ester
16 in 74% yield.
With the B-ring constructed successfully, it remained to
introduce the correct C7 stereocenter, convert the silyl enol
ether to a ketal, effect methanolysis of the bridged bicyclic
ketal, and deprotect and oxidatively cleave the pentylidene-
protected diol. Ketone 19 was reduced with lithium alumi-
num hydride, and acetylation of the resulting secondary
alcohol gave acetate 5 in 87% yield over two steps (Scheme
3). At this stage, the concave face C3 proton was significantly
deshielded (δ 4.96 ppm), more than 1 ppm downfield relative
to its ketone precursors. Only endo-acetate was observed in
To confirm the structure of 16, regioisomeric ketone 17
was prepared20 and NOE studies were carried out (Figure
3). Irradiation of the bridgehead proton of 16 (Ha) showed a
significant enhancement for each R-keto proton, while
irradiation of Ha in 17 showed very little R-keto proton NOE.
The most convincing NOE data were realized when Hb was
irradiated, giving little to no NOE in 16 but a 7.4% NOE
(15) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973.
(16) See: Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353 and
references therein.
(17) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K.
B. AdV. Synth. Catal. 2002, 344, 421. Sharpless has suggested that citric
acid assists osmium-catalyzed dihydroxylations by (1) lowering the pH to
prevent formation of an essentially inert 18-electron diooxoosmate dianion
(which causes the brown color in the original Upjohn process, ref 15) and
(2) by preventing Os(VI) disproportionation through bidentate chelation.
(18) Sasaki, M.; Murae, T.; Takahashi, T. J. Org. Chem. 1990, 55, 528.
(19) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Org. Chem. 1998, 63, 6200.
(20) See the Supporting Information for details.
(21) (a) Lynch, V. M.; Lee, W.-C.; Martin, S. F.; Davis, B. E. Acta
Crystallogr. 1994, C50, 1467. (b) Peters, J. A.; Baas, J. M. A.; Van de
Graaf, B.; Van der Toorn, J. M.; Van Bekkum, H. Tetrahedron 1978, 34,
3313.
(22) (a) Mart´ın, M.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Synlett
2001, 117. (b) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J.
A. J. Org. Chem. 1998, 63, 9728. (c) Cink, R. D.; Forsyth, C. J. J. Org.
Chem. 1997, 62, 5672. (d) Danishefsky, S. J.; Kobayashi, S.; Kerwin, J. F.
J. Org. Chem. 1982, 47, 1981.
Org. Lett., Vol. 6, No. 22, 2004
4047

Scheme 3. Synthesis of AB-Ring Intermediate 5
Scheme 4. Northern Hemisphere Completion
yield) synthesis of the bryostatin 1 northern hemisphere
intermediate 2 has been realized starting from diene diol 9
via desymmetrization by K/RCM. A-Ring functionalization
was facilitated by the steric and conformational constraints
imposed by the rigid 2,9-dioxabicyclo[3.3.1]nonane template.
Protecting group interconversion was avoided due to the
internal keto diol protection inherent in K/RCM sequences.
Furthermore, the C7 acetylation step could be replaced by
an alternative esterification, providing ready access to other
natural and nonnatural bryostatins. Efforts toward completing
the total synthesis of bryostatin 1 continue and will be
reported in due course.
this reaction, again due to the steric requirements of the
bicyclic ketal.
Treatment of 5 with CSA (0.5 equiv) in 1:1 MeOH/CH2-
Cl2 (0.025 M) at room-temperature overnight and 1 h at
reflux, followed by treatment with TBAF to complete
TBDPS cleavage, gave tetraol 20 in 76% yield (Scheme 4).
Five transformations were accomplished in this single
operation, including (1) silyl enol ether methanolysis, (2)
dimethyl ketal formation, (3) A-ring bicyclic ketal opening,
(4) pentylidene ketal methanolysis, and (5) TBDPS cleavage.
The first two steps took place rapidly, followed by A-ring
opening,23 then pentylidene and TBDPS cleavage happened
at similar rates. Importantly, before the fourth axial sub-
stituent was introduced on the A-ring (i.e., 19 f 5), bicyclic
ketal opening was virtually impossible. Treatment of tetraol
20 with sodium periodate (1.5 equiv) in 1:1 MeOH/H2O (0.05
M) for 15 min at 0 °C, followed by addition of sodium
borohydride (20 equiv), gave triol 2 in 83% yield to complete
the bryostatin northern hemisphere (C1-C16) architecture.
Both 20 and 2 were characterized as the corresponding
pentaacetate (21) and tetraacetate (22), respectively, and the
2,6-cis B-ring relative configuration was confirmed by the
large trans-diaxial vicinal coupling constants (J ) 12-12.5
Hz) observed for the C11 and C15 methine protons.
In conclusion, a short (14 step) and efficient (11% overall
Acknowledgment. We thank the NIH [Grant Nos.
GM069352 and CA108488 (S.D.B.) and CBI Training Grant
5 T32 GM08505 (E.A.V.)], the Abbott Laboratories Fel-
lowship in Synthetic Organic Chemistry (E.A.V.), and the
Hilldale Foundation (P.A.R.) for generous support of this
research. The NIH (1 S10 RR0 8389-01) and NSF (CHE-
9208463) are acknowledged for their support of the NMR
facilities at the University of WisconsinsMadison Depart-
ment of Chemistry. We also thank Dr. Charles Fry for
obtaining NOE data for compounds 16 and 17.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 2, 5, 7, 8,
1
10, 11, and 13-22; H and 13C NMR spectra for selected
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) A product with TBDPS and pentylidene ketal still present could be
isolated in 55% yield after 1 h, 45 min under these conditions.
OL0483044
4048
Org. Lett., Vol. 6, No. 22, 2004