A short synthetic pathway to a fully-functionalized southern hemisphere of the antitumor macrolide bryostatin 1.

Article abstract of DOI:10.1021/ol016800b

[reaction--see text] An 18-step asymmetric synthesis of the bryostatin 1 "southern hemisphere" fragment (1) has been developed. Key steps include an aldol reaction between 6 and 7 and a dehydration to establish the (E)-exocyclic alkene in 2 and a stereose

Full text of DOI:10.1021/ol016800b

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3791-3794
A Short Synthetic Pathway to a
Fully-Functionalized Southern
Hemisphere of the Antitumor Macrolide
Bryostatin 1
Karl J. Hale,* Mark Frigerio, and Soraya Manaviazar
The Christopher Ingold Laboratories, The Chemistry Department,
UniVersity College London, 20 Gordon Street, London WC1H 0AJ, England
k.j.hale@ucl.ac.uk
Received September 22, 2001
ABSTRACT
An 18-step asymmetric synthesis of the bryostatin 1 “southern hemisphere” fragment (1) has been developed. Key steps include an aldol
reaction between 6 and 7 and a dehydration to establish the (E)-exocyclic alkene in 2 and a stereoselective Luche reduction and protection
with TESOTf to access 1.
The recent cure of a 41-year old woman with advanced non-
Hodgkin’s lymphoma1 has heightened medical and synthetic
interest in bryostatin 12 and has brought to the fore the issue
of scarcity of supply. A large number of synthetic groups
have already attempted to address this problem, with a
number (Masamune,3 Evans,4 and Nishiyama/Yamamura5)
having accomplished impressive total syntheses of various
family members. Wender and associates6 have also recently
reported the first simplified bryostatin analogues with power-
ful antitumor effects and potent PKC-binding activity. Our
own synthetic efforts in this area have resulted in a fully
stereocontrolled asymmetric synthesis of the bryostatin
B-ring (via a novel C2-symmetry-breaking olefination tactic)7
and an advanced C-ring model study.8 In continuation of
these endeavors, we now report a fully stereocontrolled 18-
step asymmetric synthesis of the “Southern Hemisphere”
intermediate 1, which has introduced all the functionality
(1) Varterasian, M. L.; Mohammad, R. M.; Shurafa, M. S.; Hulburd,
K.; Pemberton, P. A.; Rodriguez, D. H.; Spadoni, V.; Eilender, D. S.; Murgo,
A.; Wall, N.; Dan, M.; Al-Katib, A. M. Clin. Cancer Res. 2000, 6, 825.
(2) 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.
(3) For the total synthesis of bryostatin 7, see: (a) Masamune, S. Pure
Appl. Chem. 1988, 60, 1587. (b) Kageyama, M.; Tamura, T.; Nantz, M.
H.; Roberts, J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am.
Chem. Soc. 1990, 112, 7407.
(5) Total synthesis of bryostatin 3, see: (a) Ohmori, K.; Ogawa, Y.;
Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Angew. Chem., Int.
Ed. 2000, 39, 2290. (b) Obitsu, T.; Ohmuri, K.; Ogawa, Y.; Hosomi, H.;
Ohba, S.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1998, 39, 7349.
(c) Ohmuri, K.; Suzuki, T.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1995, 36, 6515. (d) Ohmuri, K.; Nishiyama, S.; Yamamura, S. Tetrahedron
Lett. 1995, 36, 6519. (e) Ohmuri, K.; Suzuki, T.; Miyazawa, K.; Nishiyama,
S.; Yamamura, S. Tetrahedron Lett. 1993, 34, 4981.
(6) Wender, P. A.; Hinkle, K. W.; Koehler, M. F. T.; Lippa, B. Med.
Chem. ReV. 1999, 19, 388.
(7) Hale, K. J.; Hummersone, M. G.; Bhatia, G. S. Org. Lett. 2000, 2,
2189.
(4) For the total synthesis of bryostatin 2, see: Evans, D. A.; Carter, P.
H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem.
Soc. 1999, 121, 7540.
10.1021/ol016800b CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/13/2001

needed for a future convergent total synthesis of bryostatin
1.
Our most recent plan for assembling the bryostatin 1
C-ring called for the intermediacy of phenyl sulfone 1 and
the implementation of a combined aldol/dehydration tactic
on aldehyde 7 and ketone 6 to obtain enone 4 (Scheme 1).
reduction. Given these difficulties and the problems we
encountered in O-silylating alcohol 3, we concluded that the
methyl glyoxalate pathway to 1 was fundamentally flawed.
A successful union between 6 and 7 promised to overcome
these difficulties and enhance the overall convergency of our
final synthesis. With this as background, we now present
details of our pathway to 1.9,10
A central intermediate in the route to ketone 6 was glycal
9; its synthesis is shown in Scheme 2. Our original proposal
for 9 had envisaged constructing its carbon backbone through
a Wadsworth-Horner-Emmons reaction between the â-ke-
tophosphonate 12 and the aldehyde 118 (see Scheme 1). It
Scheme 1
Scheme 2a
The C(20)-alkoxy group was to be introduced by stereocon-
trolled 1,2-ketoreduction and protection. A priori, such a
pathway appeared to offer considerable strategic advantages
over an alternative we had already investigated, in which
methyl glyoxalate 84,6 and 6 were employed for the combined
aldol-dehydration-reduction sequence (Scheme 1). The latter
had afforded an unstable γ-hydroxy-enoate 3 (via enone 5)
that, disappointingly, had shown a distinct preference for
undergoing hydroxyl-directed 1,4-reduction prior to ester
a Reagents and conditions: (a) (PhS)2 (0.55 equiv), Bu3P (0.6
equiv), DMF (0.2 M), 70 °C, 3 h. (b) Oxone (2.8 equiv), THF/
MeOH/H2O rt, 2 h. (c) RuCl3‚xH2O (0.1 equiv), NaIO4 (2.2 equiv),
MeCN/CCl4/H2O (2:2:3) (0.06 M), 0 °C to rt, 2 h. (d) K2CO3 (5
equiv), MeI (10 equiv), DMF (0.4 M), rt, 12 h. (e) (MeO)2P(O)Me
(2.5 equiv), THF (0.3 M), add n-BuLi in hexanes (2.5 equiv) over
40 min, then stir at -78 °C for 1 h 40 min, then add ester 17 over
20 min, then warm to rt for 3-4 h. (f) 11 (1 equiv) and 12 (1.05
equiv), LiCl (2 equiv), i-Pr2NEt (5 equiv), MeCN (0.16 M), rt, 16
h. (g) 20% Pd(OH)2/C (1 g per 5.3 g of 10), H2, EtOAc ([10] )
0.1 M), rt, 12 h. (h) 20% Pd(OH)2/C (0.2 g per 1 g of 10), H2,
MeOH ([10] ) 0.1 M), rt, 2 h. (i) DDQ (1.5 equiv), CH2Cl2/H2O
(18:1) (0.08 M), 0 °C, 0.5 h. (j) CSA (0.05 equiv), C6H6 ([19] )
0.03 M), ∆, 2 h.
(8) (a) Hale, K. J.; Lennon, J. A.; Manaviazar, S.; Javaid, M. H.; Hobbs,
C. J. Tetrahedron Lett. 1995, 95, 2041. (b) Hale, K. J.; Hummersone, M.
G.; Cai, J.; Manaviazar, S.; Bhatia, G. S.; Lennon, J. A.; Frigerio, M.;
Delisser, V. M.; Chumnongsaksarp, A.; Jogiya, N.; Lemaitre, A. Pure. Appl.
Chem. 2000, 72, 1659.
3792
Org. Lett., Vol. 3, No. 23, 2001

transpired that the requisite â-ketophosphonate 12 could be
readily prepared from 13 in five steps as detailed in Scheme
2. 2,2-Dimethylpropane-1,3-diol 13 was selectively thioet-
herified with tri-n-butylphosphine and phenyl disulfide in
DMF11 at 70 °C for 3 h, and the product thioether 14 was
oxidized with oxone in THF/MeOH/H2O11 to access the
phenyl sulfone 15. The primary alcohol group in 15 was then
oxidized with in situ generated ruthenium tetraoxide, and
the acid 16 was esterified with potassium carbonate and
iodomethane in DMF.12 Methyl ester 17 condensed readily
with an excess of the lithio-anion of methyl dimethyl-
phosphonate13,9bb at low temperature to give the desired
â-ketophosphonate 12 in 37% overall yield from 13. Alde-
hyde 11 had previously been prepared in 10 steps from (E)-
1,4-hexadiene during our earlier model work on the C-ring
of bryostatin 1.8 It reacted cleanly with 12 under the Roush-
Masamune coupling conditions14 to produce enone 10 as
essentially a single geometrical isomer in 61-78% yield.
Although compound 10 could be converted directly into
alcohol 19 by catalytic hydrogenation over Pd(OH)2 in
MeOH, higher yields were usually obtained if the alkene in
10 was selectively hydrogenated and the PMB group of 18
was removed with DDQ.15 By following this two-step
protocol, δ-hydroxyketone 19 could typically be isolated in
79% overall yield. The hydrogenolytic route to 19 normally
furnished it in 68% yield. Hydroxy-ketone 19 underwent
rapid ring closure to glycal 9 when heated with camphor-
sulfonic acid in benzene at reflux under Dean-Stark condi-
tions.4 A three-step sequence was needed to arrive at ketone
6, and glycal epoxidation was a key step (Scheme 3). The
Scheme 3a
(9) For other synthetic studies on the bryostatins, see: (a) Munt, S. P.;
Thomas, E. J. J. Chem. Soc., Chem. Commun. 1989, 480. (b) Roy, R.; Rey,
A. W.; Charron, M.; Molino, R. J. Chem. Soc., Chem. Commun. 1989, 1308.
(c) Roy, R.; Rey, A. W. Synlett 1990, 448. (d) Evans, D. A.; Carreira, E.
M. Tetrahedron Lett. 1990, 31, 4703. (e) Evans, D. A.; Gauchet-Prunet, J.
A.; Carreira, E. M.; Charette, A. B. J. Org. Chem. 1991, 56, 741. (f) De
Brabander, J.; Vanhessche, K.; Vandewalle, M. Tetrahedron Lett. 1991,
32, 2821. (g) De Brabander, J.; Vandewalle, M. Synlett 1994, 231. (h) De
Brabander, J.; Vandewalle, M. Synthesis 1994, 855. (i) De Brabander, J.;
Kulkarni, A.; Garcia-Lopez, R.; Vandewalle, M. Tetrahedron: Asymmetry
1997, 8, 1721. (j) Ohmuri, K.; Suzuki, T.; Miyazawa, K.; Nishiyama, S.;
Yamamura, S. Tetrahedron Lett. 1993, 34, 4981. (k) Ohmuri, K.; Suzuki,
T.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1995, 36, 6515. (l)
Ohmuri, K.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1995, 36, 6519.
(m) Hoffmann, R. W.; Stiasny, H. C. Tetrahedron Lett. 1995, 36, 4595. (n)
Kalesse, M.; Eh, M. Tetrahedron Lett. 1996, 37, 1767. (o) Lampe, T. F. J.;
Hoffmann, H. M. R. J. Chem. Soc., Chem. Commun. 1996, 1931. (p) Lampe,
T. F. J.; Hoffmann, H. M. R. J. Chem. Soc., Chem. Commun. 1996, 2637.
(q) Lampe, T. F. J.; Hoffmann, H. M. R. Tetrahedron Lett. 1996, 37, 7695.
(r) Weiss, J. M.; Hoffmann, H. M. R. Tetrahedron: Asymmetry 1997, 8,
3913. (s) Kiyooka, S.; Maeda, H. Tetrahedron: Asymmetry 1997, 8, 3371.
(t) 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. (u) Wender, P. A.; de Brabander, J.; Harran, P. G.; Hinkle, K.
W.; Lippa, B.; Pettit, G. R. Tetrahedron Lett. 1998, 39, 8625. (v) Obitsu,
T.; Ohmuri, K.; Ogawa, Y.; Hosomi, H.; Ohba, S.; Nishiyama, S.;
Yamamura, S. Tetrahedron Lett. 1998, 39, 7349. (w) Gracia, J.; Thomas,
E. J. J. Chem. Soc., Perkin Trans. 1 1998, 2865. (x) Baxter, J.; Mata, E.
G.; Thomas, E. J. Tetrahedron 1998, 54, 14359. (y) Maguire, R. J.; Munt,
S. P.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1998, 2853 (correction,
J. Chem. Soc., Perkin Trans. 1 2001, 1473). (z) Wender, P. A.; Lippa, B.
Tetrahedron Lett. 2000, 41, 1007. (aa) Lopez-Pelegrin, J. A.; Wentworth,
P., Jr.; Sieber, F.; Metz, W. A.; Janda, K. D. J. Org. Chem. 2000, 65, 8527.
(bb) Yadav, J. S.; Bandyopadhyay, A.; Kunwar, A. C. Tetrahedron Lett.
2001, 42, 4907.
a Reagents and conditions: (a) DMDO (0.07 M in Me2CO) (1.4
equiv), MeOH ([9] ) 0.02 M), 4Å MS, 0 °C, 12 min, then add
PPTS (0.2 equiv), warm to rt, stir 10 min. (b) PDC (2 equiv), DMF
(0.1 M), rt, 12 h. (c) n-BuLi in hexanes (2.5 M, 1.5 equiv), THF
([6] ) 0.015 M), -78 °C, 5 min, then add aldehyde 7 (5 equiv) in
THF (0.5 M) in one portion, stir 5 min at -78 °C, then warm to rt
for 20 min. (d) CeCl3‚7H2O (10 equiv), NaBH4 (5 equiv), MeOH
([4] ) 0.05 M), -78 °C for 1 h, then 0 °C for 5 min. (e) Et3SiOTf
(5 equiv), 2,6-lutidine (10 equiv), CH2Cl2 (0.014 M), -78 °C to
rt, then stir for 0.5 h.
(10) For a detailed, up-to-date account of bryostatin chemistry and
biology, see: Hale, K. J.; Hummersone, M. G.; Manaviazar, S.; Frigerio,
M. Nat. Prod. Rep. 2001, in press.
(11) Hale, K. J.; Bhatia, G. S.; Peak, S. A.; Manaviazar, S. Tetrahedron
Lett. 1993, 34, 5343.
(12) Smith, A. B., III; Hale, K. J. Tetrahedron Lett. 1989, 30, 1037.
(13) Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. J.
Am. Chem. Soc. 1988, 110, 4685.
(14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfield, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(15) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
most satisfactory protocol for forming the labile glycal
epoxide 20 reacted 9 with redistilled dimethyldioxirane in
acetone and anhydrous methanol in the presence of 4Å
molecular sieves at 0 °C for 12 min. Under these conditions
a very clean and almost totally stereospecific epoxidation
took place on the R-face of the alkene to provide 20. After
a catalytic quantity of PPTS was added to the reaction
Org. Lett., Vol. 3, No. 23, 2001
3793

mixture, trans-diaxial epoxide ring opening was driven to
completion, and 21 was isolated as essentially a single
product. By way of contrast, when the epoxidation was
conducted with redistilled dimethyldioxirane in acetone and
dry CH2Cl2, a much less satisfactory outcome typically
resulted. The trace amounts of water that were always present
in our redistilled DMDO/acetone solutions invariably caused
a significant amount of epoxide ring opening to give an
unusable hemiketal mixture, even when 4Å sieves were
added. Although ordinarily, this side reaction is not generally
problematic with less-reactive aldose-type glycals, it can be
seriously detrimental when the more reactive ketose-type
glycals are being epoxidized. In our opinion, this new
modification of the Danishefsky-Murray epoxidation method16
offers distinct advantages for the preparation of “simple”
ketose-type glycosides from “reactive” trisubstituted glycals
bearing +I groups.
Continuing with our synthesis of 1, alcohol 21 was
oxidized to ketone 6 in good yield with pyridinium dichro-
mate in DMF. Several sets of conditions were examined for
effecting the key aldol addition/dehydration sequence. The
most effective procedure enolized ketone 6 with n-butyl-
lithium in THF at -78 °C and reacted the resulting enolate
with the known aldehyde 7;17 elimination of the aldol adducts
ensued shortly after the reaction was warmed to room
temperature. The dehydration step delivered 4 as a single
geometric isomer in 73-79% yield. The C(20)-hydroxyl was
introduced stereospecifically via a Luche reduction with
sodium borohydride and cerium trichloride in methanol.18
Unstable 2 was isolated as the sole reaction product in 80%
yield after SiO2 flash chromatography. The final step in the
sequence to 1 was O-triethylsilylation with TES-triflate and
2,6-lutidine. This proceeded rapidly at room temperature to
deliver an inseparable 4.3:1 mixture of 1 and the elimination
product tentatively assigned as 22.
dramatically as a result of the rate of C(18)-C(19) bond
rotation becoming fast on the NMR time scale. Under these
conditions the rotationally averaged spectrum of 1 was
observed. A NOESY experiment in toluene-d8 at 90 °C
revealed cross-peaks between the H(20) singlet at δ 4.38
and the C(18) geminal dimethyl singlets at δ 1.64 and 1.58,
as one would expect. The same NOESY experiment also
revealed an NOE between H(20) and the C(19)-OMe, which
resonated at δ 3.27; this confirmed that both these groups
were cis to one another. H(20) also gave rise to an NOE
cross-peak with the exocyclic olefin multiplet at δ 5.68, while
the exocyclic allylic methylenes of the CH2OTBDPS group
(at ca. δ 4.26 and 4.23) showed NOEs with the equatorial
H(22), which appeared as a multiplet at δ 2.10. These
combined results enabled the alkene and C(20)-alkoxy
stereochemistry of 1 to be assigned with confidence. The
cis relationship between H(23) and the C(19)-OMe was
confirmed by NOE; the H(23) resonance appeared at δ 4.01.
Interestingly, the C(20)-O-acetate derivative 23 obtained from
2 by O-acetylation (with Ac2O/DMAP/pyridine) gave rise
1
to a completely sharp, well-defined, 500 MHz H NMR
spectrum in toluene-d8 (see Supporting Information), which
indicated that the slow room temperature C(18)-C(19) bond
rotation in 1 was a direct consequence of steric hindrance
from the bulky OTES group at C(20).
In conclusion, a fully stereocontrolled 18-step asymmetric
synthesis of the highly functionalized C-ring intermediate 1
has been developed from (E)-1,4-hexadiene. Our route, which
proceeds in 2.57% overall yield, is considerably shorter than
past synthetic pathways to southern hemisphere fragments
with the exocyclic alkene in a form appropriate for further
elaboration.3,5 The great brevity of our route suggests that a
30-step (or less) total synthesis of bryostatin 1 might soon
be possible.
The NMR spectra of 1 were temperature-dependent,
suggesting that the rate of internal rotation for the sterically
congested C(18)-C(19) bond was slow on the NMR time
Acknowledgment. We thank the BBSRC (project grant
31/B09691 and Studentship to M.F.), the Royal Society
(RSRG 15551), Ultrafine, and Pfizer for generous financial
support. The ULIRS MS Facility is also thanked.
1
scale. Thus, in the room temperature 500 MHz H NMR
spectrum of 1 in toluene-d8 there were many broadened
resonances. At 90 °C, however, the spectrum sharpened quite
Supporting Information Available: High-resolution
mass spectra, 500 MHz 1H and 125 MHz 13C NMR spectra
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 6661. (b) Murray, R. W.; Jeyaraman, J. Org. Chem. 1985, 50, 2847.
(17) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1996, 61, 8732.
(18) Luche, J.-L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc., Chem.
Commun. 1978, 601.
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