Enantioselective formal total synthesis of the antitumor macrolide bryostatin 7

Article abstract of DOI:10.1021/ol061626i

A new enantioselective synthesis of Masamune's AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein-Ponndorf-Verley reduction to set the 0(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)-C(10) bond. Because we have previously published a synthesis of Masamune's C-ring phenyl sulfone 2, our new route to 1 constitutes a formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl₃.

Full text of DOI:10.1021/ol061626i

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4477-4480
Enantioselective Formal Total Synthesis
of the Antitumor Macrolide Bryostatin 7
Soraya Manaviazar,* Mark Frigerio, Gurpreet S. Bhatia, Marc G. Hummersone,
Abil E. Aliev, and Karl J. Hale*
The UCL Center for Chemical Genomics, The Christopher Ingold Laboratories,
The Chemistry Department, UniVersity College London, 20 Gordon Street,
London WC1H 0AJ, U.K.
s.manaViazar@ucl.ac.uk; k.j.hale@ucl.ac.uk
Received July 3, 2006
ABSTRACT
A new enantioselective synthesis of Masamune’s AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein
−
Ponndorf Verley reduction to set the O(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)
−
−
C(10) bond. Because we have previously published a synthesis of Masamune’s C-ring phenyl sulfone 2, our new route to 1 constitutes a
formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl3.
The bryostatins are a structurally novel family of tripyranyl-
ated antitumor macrolides whose prototype, bryostatin 1, was
first reported by Pettit and co-workers more than two decades
ago.1 Ever since that time, biological interest in the bryo-
statins2,3 has risen steadily, mainly because of their powerful
anticancer effects in vivo and their ability to potently activate
and modulate aberrant protein kinase C (PKC) expression
and signaling within human tissues.
Although the extremely low natural abundance of the bryo-
statins did for a long time hamper their human clinical de-
velopment as antitumor drugs, this situation changed quite
dramatically in 2000 when Mendola announced4 that aquac-
ulture could supply bryostatin 1 economically on a large scale
(100-200 g annually). Despite this important advance, clini-
cal interest in bryostatin 1 as a single-agent antitumor drug
has now largely abated, primarily because of its poor clinical
efficacy against solid tumors in man.5 Notwithstanding this
setback, the search for new “bryostatin-like” drug entities
continues, mainly because of their potential for preventing
Alzheimer’s disease onset in animal models.6 As a conse-
quence, new synthetic routes to the bryostatins remain of
interest due to the novel analogues they can potentially
deliver.
To date, three bryostatin total syntheses have been
reported. The first of these was the landmark total synthesis
of bryostatin 7 by Masamune and co-workers in 1990.7 This
was followed eight years later by Evans’ majestic synthetic
route to bryostatin 28 and, not long after this, by Nishiyama
and Yamamura’s excellent enantiospecific total synthesis of
bryostatin 39 which, remarkably, delivered 25 mg of the final
natural product for biological testing.
(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) For reviews on bryostatin chemistry and biology, see: (a) Norcross,
R.; Paterson, I. Chem. ReV. 1995, 95, 2041. (b) Mutter, R.; Wills, M. Bioorg.
Med. Chem. 2000, 8, 1841. (c) Hale, K. J.; Hummersone, M. G.; Manaviazar,
S.; Frigerio, M. Nat. Prod. Rep. 2002, 413.
(4) Mendola, D. In Drugs from the Sea; Fusetani, N., Ed.; Karger: Basel,
2000; p 20.
(5) Some phase II human clinical trials include: (a) Madhusan, S.;
Protheroe, A.; Propper, D.; Han, C.; Corrie, P.; Earl, H.; Hancock, B.; Vasey,
P.; Turner, A.; Balkwill, F.; Hoare, S.; Harris, A. L. Br. J. Cancer 2003,
89, 1418. (b) Brockstein, B.; Samuels, B.; Humerickhouse, R.; Arietta, R.;
Fishkin, P.; Wade, J.; Sosman, J.; Vokes, E. E. InVest. New Drugs 2001,
19, 249. (c) Pagliaro, L.; Daliani, D.; Amato, R.; Tu, S.-M.; Jones, D.;
Smith, T.; Logothetis, C.; Millikan, R. Cancer 2000, 89, 615.
(3) Bryostatin 20: Lopanik, N.; Gustafson, K. R.; Lindquist, N. J. Nat.
Prod. 2004, 67, 1412.
10.1021/ol061626i CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/01/2006

Our own group’s synthetic efforts in the bryostatin area10
have so far culminated in new and fully stereocontrolled
asymmetric routes to Masamune’s bryostatin 7 C-ring phenyl
sulfone 210a-c (Scheme 1) and our own B-ring synthon 1010d
fragment 1 which, given our recent synthesis of 2, constitutes
a new formal enantiospecific total synthesis of bryostatin 7.
We note here that although our new formal total synthesis
of bryostatin 7 does actually proceed in the same overall
number of steps as that of Masamune (64 steps in total) it
does have the added advantage that it much more readily
generates complex BC analogues.11,12 Currently, these are
not readily accessible via the existing Masamune route, which
forges the B-ring domain out of a linear, open-chain, A-ring
precursor. Our new total synthesis of bryostatin 7 thus
augments Masamune’s earlier work on this compound and
offers many exciting new opportunities for probing how the
BC regions11 of the bryostatins interact with different PKCs
to mediate their powerful in vivo biological effects.
Scheme 1. Our Retrosynthetic Strategy for Masamune’s
Bryostatin 7 Advanced AB Intermediate 1
The retrosynthetic strategy that we favored for accessing
1 was based upon the alkylative union9,13 of dithiane 6 with
iodide 5 to forge thioketal 4 (Scheme 1). The latter would
thereafter be converted into the methyl glycoside 3 by
thioketal hydrolysis, O-deacetalation, and Fischer glycosi-
dation. O-Acetylation, O-debenzylation, and C(16) primary
alcohol oxidation would then transform 3 into 1 and allow
intersection with Masamune’s total synthesis.
We envisioned preparing dithiane 6 from the methyl glyco-
side 7 by debenzylative thioketalization and site-selective
protection of the intermediary triol. Compound 7 would itself
be prepared from the pyranone 8 by stereoselective ketone
reduction, O-benzylation (with PMBCl), and one-carbon ho-
mologation at C(4). An attractive progenitor of ketone 8 was
considered to be the known 2-deoxy-3-ketoglycoside 9. The
conversion of 9 into 8 would require a site-selective geminal
dimethylation at C(8) and an excision of the surplus oxygen
functionality at C(6). With this picture of the proposed route
in mind, we will now describe the pathway that was
eventually developed to 1 in more detail in Schemes 2-4.
Our sequence to dithiane 6 (see Schemes 2 and 3) com-
menced with the low-temperature double alkylation of 914
with KH and methyl iodide which, when performed at -20
°C in THF with reasonably pure starting ketone, gave the
desired product 1114 fairly cleanly in 62% yield after SiO2
flash chromatography. Starting with much less pure 9 (see
Supporting Information), ketone 11 was generally obtained
in a lower but, nevertheless, highly reproducible 46% yield
on a 15 g scale. It is presumed that the enolization and double
methylation process occur regioselectively at C(8) (bryostatin
numbering) due to the alternative mode of enolization at C(6)
producing a significantly more strained enolate during both
(Scheme 1). In continuation of this work, we now report on
a stereocontrolled pathway to Masamune’s bryostatin 7 AB
(6) (a) Etcheberrigaray, R.; Tan, M.; Dewachter, I.; Kuiperi, C.; Van
der Auwera, I.; Wera, S.; Qiao, L.; Bank, B.; Nelson, T. J.; Kozikowski,
A. P.; Leuven, F.; Alkon, D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11141.
(b) Sun, M.-K.; Alkon, D. L. Eur. J. Pharmacol. 2005, 512, 43.
(7) (a) Total synthesis of bryostatin 7: 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) Masamune, S. Pure. Appl. Chem. 1988,
60, 1587.
(8) Total synthesis of bryostatin 2: 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.
(9) Total synthesis of bryostatin 3: Ohmori, K.; Ogawa, Y.; Obitsu, T.;
Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Angew. Chem., Int. Ed. 2000,
39, 2290.
(11) For recent work on BC analogue construction, see: (a) Hale, K. J.;
Frigerio, M.; Manaviazar, S.; Hummersone, M. G.; Fillingham, I.; Barsukov,
I.; Damblon, C.; Gescher, A.; Roberts, G. C. K. Org. Lett. 2003, 5, 499.
(b) Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2149.
(12) For some other recent analogue work, see: (a) Wender, P. A.;
Clarke, M. O.; Horan, J. C. Org. Lett. 2005, 7, 1995. (b) Wender, P. A.;
Verma, V. A. Org. Lett. 2006, 8, 1893 and the references therein.
(13) For other dithiane alkylation strategies for constructing the C(9)-
C(10) bond of the bryostatins, see: (a) Vakalopoulos, A.; Lampe, T. F. J.;
Hoffmann, H. M. R. Org. Lett. 2001, 3, 929. (b) Ref 9.
(14) (a) Chapleur, Y. Chem. Commun. 1983, 141. (b) Hong, C. Y.; Kishi,
Y. J. Am. Chem. Soc. 1991, 113, 9693. (c) Generally, we have found it
more convenient and far less sacrificial to conduct this C-methylation with
ketone 9 that has only been recrystallized twice. Generally, two recrystal-
lizations provide material that is approximately 90% pure; the other main
contaminant appears to be 1-phenylpentan-2-ol.
(10) (a) Hale, K. J.; Frigerio, M.; Manaviazar, S. Org. Lett. 2003, 5,
503. (b) Hale, K. J.; Frigerio, M.; Manaviazar, S. Org. Lett. 2001, 3, 3791.
(c) Hale, K. J.; Lennon, J. A.; Manaviazar, S.; Javaid, M. H.; Hobbs, C. J.
Tetrahedron Lett. 1995, 36, 1359. (d) Hale, K. J.; Hummersone, M. G.;
Bhatia, G. S. Org. Lett. 2000, 2, 2189.
4478
Org. Lett., Vol. 8, No. 20, 2006

Scheme 2. Synthesis of Alkene 20
Scheme 3. Conversion of Alkene 20 into Dithiane 6, Union
of 6 with 5, and Elaboration of 4 into Glycoside 3
alkylation steps. With the desired ketone 11 in hand, we set
about excising the C(6)-oxygen atom that lay R to the ketone.
For this, we needed to hydrogenolytically cleave off the
O-benzylidene acetal from 11 using Pearlman’s catalyst in
MeOH, and thereafter, we selectively O-silylated the product
diol 12 with t-BuPh2SiCl. A Barton deoxygenation15 was then
effected on the thiocarbonylimidazolide 14 derived from 13.
The desired C(6)-deoxy ketone 8 was obtained in 67%
overall yield for the four steps.
product alcohol 16 could be reoxidized to 8 with TPAP/
NMO17 and recycled back into the synthesis.
The newly introduced hydroxyl group of 15 was next
protected as a PMB ether with p-methoxybenzyl trichloro-
acetimidate (2 equiv) and PPTS (0.5 equiv) in CH2Cl2 for
48 h; the desired PMB-ether was isolated in 77% yield along
with a 19% yield of recovered starting alcohol 15, which
was recycled. The use of PMBCl/NaH for this alkylation
proved problematic and gave vastly inferior results. Because
the primary TBDPS group had served its purpose, it was
cleaved from the etherified product with n-Bu4NF in THF;
the expected alcohol 17 was isolated in 98% yield.
Several unsuccessful methods were explored for homolo-
gating the C(4) position of 17 by one extra carbon before it
was eventually discovered that this could best be achieved
by sequential TPAP oxidation17 and Kocienski-Julia olefin-
A range of hydride reducing agents were screened for their
ability to stereoselectively reduce the C(7)-ketone to give
the desired equatorial alcohol 15. After much effort, we
eventually discovered that a Meerwein-Ponndorf-Verley
(MPV) reduction with Al(OPr-i)3 in i-PrOH16a gave the best
results with regard to reaction yield and stereoselectivity
(typically 15 was formed with ca. 5.6:1 selectivity). We
attribute this stereochemical outcome to the reversible nature
of the MPV reaction and predominating thermodynamic
control, which clearly would favor formation of the equatorial
alcohol 15 (Scheme 2).16b Significantly, the minor, undesired
(16) (a) Kocienski, P.; Narquizian, R.; Raubo, P.; Smith, C.; Farrugia,
L. J.; Muir, K.; Boyle, F. T. J. Chem. Soc., Perkin Trans. 1 2000, 2357. (b)
Coordination of the Al(OPr-i)3 reagent with the anomeric OMe would also
favor delivery of hydride to the underside of 8 to give 15, but a referee has
argued against this proposal on the basis that, if it did occur, it would most
likely cause loss of the acid-labile C(9)-OMe.
(15) Barton, D. H. R.; Motherwell, W. B.; Stange, A. Synthesis 1981,
743.
(17) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
Org. Lett., Vol. 8, No. 20, 2006
4479

ation18 with 19;19 this combined sequence provided the
desired alkene 20 in 44% overall yield. By way of contrast,
the Wittig reaction of aldehyde 18 with Ph3PdCH2 gave
totally unsatisfactory results, and cyanide displacement of
the iodide derived from 17 was equally problematic.
Of the various hydroboration protocols that were examined
for converting 20 into 7 (see Scheme 3), Evans’ rhodium-
catalyzed procedure with catecholborane20 proved the most
successful, furnishing 7 exclusively in 86% yield after
oxidative workup. By way of contrast, borane-THF was
poorly regioselective in this reaction, leading to a 2:1 mixture
of 1°:2° alcohols enriched in 7. We next converted alcohol
7 into the triol 21 by reacting it with 1,3-propanedithiol and
excess BF3‚Et2O.21 Selective O-silylation of the primary OH
in 21 thereafter provided 22 which was transformed into 6
by O-isopropylidenation.
Scheme 4. Completion of Our Formal Total Synthesis of
Bryostatin 7
To our great delight, the all-important alkylative union9,13
between iodide 5 and dithiane 6 proceeded smoothly when
conducted in THF at -78 °C with HMPA as an additive;10d
the desired coupling product 4 was isolated in 64-76% yield
on a multigram scale (Scheme 3). Iodide 5 was itself prepared
from the previously synthesized alcohol 1010d by displace-
ment of the derived O-tosylate with NaI in butan-2-one at
reflux (Scheme 3). Surprisingly, the Ph3P, I2, imidazole
method failed to give satisfactory results in this system.
Having successfully united the B- and A-ring fragments
5 and 6, we hydrolytically cleaved the dithiane unit from 4
to access ketone 23; Hg(ClO4)2 and CaCO3 in aqueous THF
proved optimal for effecting this conversion10d (Scheme 3).
Ketone 23 was thereafter subjected to a tandem acetal
exchange/Fischer glycosidation reaction with PPTS and
MeOH in the presence of (MeO)3CH9 to obtain the methyl
glycoside 3 (Scheme 3). Surprisingly, the omission of
(MeO)3CH from the reaction mixture led to the hemiketal
being formed rather than the anticipated glycoside 3.
their 1990 JACS paper Supporting Information (see Table 1
in Part 3 of our Supporting Information).
In summary, a new enantiospecific route to Masamune’s
AB fragment22 1 has been completed which, given our
previous synthesis of 2, constitutes a new enantioselective
formal total synthesis of bryostatin 7. The primary advantage
of our new pathway to bryostatin 7 lies in its ability to
generate tailored BC analogues and in its generally high
levels of stereocontrol throughout. Our synthetic work on 1
has also led to the originally published CDCl3 spectral data7a
for the AB fragment 1 being revised. Comprehensive details
1
of the authentic H NMR spectrum for 1 in CDCl3 are
The final stages of our formal total synthesis of bryostatin
7 were O-acetylation of the C(7)-hydroxyl in 3, DDQ-
mediated removal of the C(16)-OPMB group from the
resulting product, and TPAP/NMO17 oxidation of 24 to give
1 (Scheme 4). The latter three steps proceeded in ap-
proximately 43-56% overall yield.
presented in Part 3 of the Supporting Information, which
also describes our unambiguous structure determination of
the UCL version of 1.
Acknowledgment. We thank the EPSRC, the BBSRC,
Novartis Pharma AG (Switzerland), Merck, Sharp & Dohme
(Harlow), Pfizer (Sandwich), Tibotec (Belgium), the Royal
Society, and the University of London Central Research Fund
for their much appreciated financial support of our work on
the bryostatins over many years.
1
Significantly, the 500 MHz H NMR spectrum of our
synthetic 1 in CDCl3 confirmed its proposed structure but
1
did not match up with the 300 MHz H NMR spectral data
that were reported for 1 in CDCl3 by Masamune.7a In Part 3
of our Supporting Information, we will present the new and
completely revised chemical shifts and J values for 1 in
CDCl3. We will show that the originally published7a 1H NMR
data for 1 were not actually gathered in CDCl3, as was
originally stated, but were instead recorded in C6D6. In this
regard, the chemical shifts that we have tabulated for 1 in
C6D6 in the Supporting Information show an excellent
agreement with the chemical shifts that were previously
published for 1 in CDCl3 by Masamune and co-workers in
Supporting Information Available: Full experimental
procedures and detailed spectral data of all key compounds
1
are reported. Copies of 500 MHz H and 125 MHz 13C
spectra are additionally provided, along with HRMS data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL061626I
(22) For other recent approaches to the AB region of the bryostatins,
see: (a) Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D. Org. Lett.
2004, 6, 4045. (b) Ball, M.; Baron, A.; Bradshaw, B.; Omori, H.;
MacCormick, S.; Thomas, E. J. Tetrahedron Lett. 2004, 45, 8737. (c) Keck,
G. E.; Truong, A. P. Org. Lett. 2005, 7, 2153. (d) Ball, M.; Bradshaw, B.
J.; Dumeunier, R.; Gregson, T. J.; MacCormick, S.; Omuri, H.; Thomas,
E. J. Tetrahedron Lett. 2006, 47, 2223. (e) Keck, G. E.; Welch, D. S.; Vivian,
P. K. Org. Lett. 2006, 8, 3667. (f) For earlier work, see: ref 2c. (g) For
some other recent relevant work on the B-ring, see: Trost, B. M.; Yang,
H.; Wuitschik, G. Org. Lett. 2005, 7, 4761.
(18) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
(19) Hale, K. J.; Domostoj, M. M.; Tocher, D. A.; Irving, E.; Scheinmann,
F. Org. Lett. 2003, 5, 2927.
(20) Evans, D. A.; Gage, J. R. J. Org. Chem. 1992, 57, 1958.
(21) Smith, A. B., III; Chen, K.; Robinson, D. J.; Laakso, L. M.; Hale,
K. J. Tetrahedron Lett. 1994, 35, 4271.
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