New, abridged pathway to Masamune's "southern hemisphere" intermediate for the total synthesis of bryostatin 7.

Article abstract of DOI:10.1021/ol027393m

[reaction: see text] The "Southern Hemisphere" intermediate 2, used by Masamune and co-workers for their asymmetric total synthesis of bryostatin 7 (1), has been synthesized from (E)-1,4-hexadiene (11) by a 24-step pathway that has a longest linear sequen

Full text of DOI:10.1021/ol027393m

ORGANIC
LETTERS
2003
Vol. 5, No. 4
503-505
New, Abridged Pathway to Masamune’s
“Southern Hemisphere” Intermediate for
the Total Synthesis of Bryostatin 7
Karl J. Hale,* Mark Frigerio, and Soraya Manaviazar
The Christopher Ingold Laboratories, The Department of Chemistry,
UniVersity College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
k.j.hale@ucl.ac.uk
Received December 3, 2002
ABSTRACT
The “Southern Hemisphere” intermediate 2, used by Masamune and co-workers for their asymmetric total synthesis of bryostatin 7 (1), has
been synthesized from (E)-1,4-hexadiene (11) by a 24-step pathway that has a longest linear sequence of only 20 steps. This is the shortest
synthesis of 2 so far recorded, and moreover, it is fully stereocontrolled.
Bryostatins1 and their simplified analogues remain at the fore-
front of medical and biological interest due to their powerful
antitumor effects in man and their ability to selectively
modulate protein kinase C (PKC) activity within cells.2
For some time now, we have been involved in the total
synthesis of various bryostatin family members for the
purpose of increasing future clinical supply and for creating
novel analogues that can be used to probe PKC structure
and function by biophysical and biological methods.3
In the accompanying communication,4 we highlighted the
difficulties that we encountered in performing a Julia
olefination with the phenyl sulfone 3 and the aldehyde 4
(Scheme 1). Typically, this merger delivered the desired
Scheme 1. Julia Coupling with Phenyl Sulfone 3
(1) Pettit, G. R.; Gao, F.; Blumberg, P. M.; Herald, C. L.; Coll, J. C.;
Kamano, Y.; Lewin, N. E.; Schmidt, J. M.; Chapuis, J.-C. J. Nat. Prod.
1996, 59, 286.
(2) For reviews on bryostatin chemistry and biology, see: (a) Norcross,
R.; Paterson, I. Chem. ReV. 1995, 95, 2041. (b) Mutter, R.; Wills, M. Biorg.
Med. Chem. 2000, 8, 1841. (c) Hale, K. J.; Hummersone, M. G.; Manaviazar,
S.; Frigerio, M. Nat. Prod. Rep. 2002, 413.
(3) For recent synthetic work from our group, see: (a) Hale, K. J.;
Hummersone, M. G.; Bhatia, G. S. Org. Lett. 2000, 2, 2189. (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, 35, 2041.
alkene 5 in a rather disappointing 8% overall yield for the
two-step sequence. While this union did actually enable us
to complete the synthesis of a novel BC analogue that was
10.1021/ol027393m CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003

needed for NMR binding studies with the CRD2 of human
PKC-R, it did highlight the problems that we would face if
we employed phenyl sulfone 3 for the synthesis of various
bryostatin family members and other analogues.
Our results stood in stark contrast to those reported by
Masamune and co-workers5a for their total synthesis of bryo-
statin 7. They investigated the Julia coupling of phenyl-
sulfone 2 with aldehyde 6 and obtained the desired (E)-alkene
7 in 60% overall yield after desulfonylation (Scheme 2).
of 17 steps,3b we thought it worthwhile to investigate whether
it could be adapted to produce 2 much more expediently.
Herein, we now report success in this undertaking.
The departure point for our synthesis of 2 was the glycal
12 (Scheme 3). It is readily prepared from (E)-1,4-hexadiene
11 by a 13-step protocol3b,c that employs Sharpless AD7 and
Scheme 3. New Pathway to Masamune’s Bryostatin 7
“Southern Hemisphere” (2)a
Scheme 2. Other Julia Couplings in the Bryostatin Area
Likewise, Nishiyama and Yamamura recorded a 52% yield
of alkene 10 when they executed a Julia coupling between
8 and 9 en route to bryostatin 3 (Scheme 2).5b Given the
greatly improved results in bryostatin systems when the Julia
olefinations are performed with O(25)/O(26)-isopropyl-
idenated C-ring phenyl sulfones, we thought it prudent to
pursue future work with the Masamune “Southern Hemi-
sphere” intermediate 2.6 However, the current synthesis of
2 requires 35 synthetic operations to be performed in the
laboratory, notwithstanding its longest linear sequence being
only 21 steps.6 Given that our newly developed pathway to
3 is only 22 steps overall and has a longest linear sequence
a Reagents and conditions: (a) n-Bu4NF (2.8 equiv), THF, rt,
12 h. (b) Me2C(OMe)2 (3 equiv), PPTS (0.25 equiv), Me2CO ([13]
) 0.13 M), 40 °C, 15 min. (c) To 14 and 4 Å MS in MeOH:
Me2C(OMe)2 ([14] ) 0.02 M) at 0 °C was added DMDO (ca. 0.07
M solution in Me2CO) dropwise over 2-3 min. The mixture was
stirred for 12 min, and PPTS (0.01 equiv) was added; the mixture
was warmed to rt and stirred for 10 min. (d) PDC (4 equiv), DMF
([16] ) 0.1 M), rt, 20 h. (e) n-BuLi (2.5 M solution in hex, 2 equiv),
THF, -78 °C, stirring (14 min), addition of 18 (2.5 equiv) in THF
([18] ) 0.15 M), stirring (15 min), warming to 0 °C, stirring (10
min). (f) 19, CeCl3‚7H2O (10 equiv), MeOH ([19] ) 0.07 M), -78
°C, 45 min, addition of NaBH4 in three portions; stirring (20 min),
then warming to rt, 15 min. (g) To 20, CH2Cl2 ([20] ) 0.06 M),
and 2,6-lutidine, 0 °C, was added Et3SiOTf (3 equiv); after 5 min,
the solution was warmed to rt, 1.5 h.
(4) Hale, K. J.; Frigerio, M.; Manaviazar, S.; Hummersone, M. G.;
Roberts, G. C. K.; Fillingham, I.; Gescher, A. Org. Lett. 2002, 4, 499.
(5) (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) Total synthesis of bryostatin 3: Ohmori,
K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.; Yamamura, S.
Angew. Chem., Int. Ed. 2000, 39, 2290. (c) 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. 1998, 37, 2354.
504
Org. Lett., Vol. 5, No. 4, 2003

AE8 reactions as key steps. The actual pathway to 2
commenced with the global O-desilylation of 12 using tetra-
n-butylammonium fluoride in THF; this afforded the diol
13 in 95% yield. Diol 13 was then O-isopropylidenated in
nearly quantitative yield (97%) by treatment with 2,2-
dimethoxypropane in acetone. The epoxidation of glycal 14
was initially attempted under the conditions that we first
developed for the epoxidation of 12;3b that is, with doubly
distilled dimethyldioxirane9 in a mixture of methanol and
acetone at -78 °C. However, when the in situ methanolysis
of 15 was performed according to our original procedure
(by adding 0.2 equiv of PPTS to the crude reaction mixture),
we found that the O-isopropylidene acetal of 16 was also
cleaved and extensive product decomposition quickly ensued.
After considerable effort, we eventually discovered that
the glycal epoxides 15 could be ring-opened cleanly when
the amount of PPTS was cut down to 0.01 equiv and when
the epoxidation/epoxide ring-opening reaction was conducted
in a 1:1 mixture of MeOH and 2,2-dimethoxypropane.
Thereafter, 16 was isolated as a (rather unstable) mixture of
C(20)-alcohol epimers as judged by TLC analysis. Presum-
ably, the axial methyl glycoside emerges from this reaction
for steric reasons, through attack of MeOH on the ring-
opened tertiary oxonium ion. Since the newly introduced
alcohol functionality at C(20) was now destined to be
oxidized, no attempt was made to separate the individual
C(20)-epimers at this stage.
as anticipated, the aldol addition and dehydration sequence
took place in a simple one-pot fashion to provide 19 as a
single geometrical isomer in 75% yield. The Luche reduc-
tion11 of 19 also furnished 20 as essentially one compound
in good yield. The final step in our route to 2 was the
O-triethylsilylation of 20 with TESOTf and 2,6-lutidine,
which was complete within 1.5 h at rt. The latter two steps
proceeded in 82% yield.
In closing, we have devised a new and considerably
abridged asymmetric synthesis of Masamune’s “Southern
Hemisphere” intermediate for bryostatin 7. Significantly, our
new pathway to 2 has a longest linear sequence of only 20
steps, and now requires only 24 synthetic operations to be
performed overall to arrive at the target.12 Further applica-
tions of 2 in the synthesis of a naturally occurring bryostatin,
as well as other PKC-binding analogues, will be reported in
due course.
Acknowledgment. We thank the BBSRC for support
through project grant 31/B09691 and for a studentship to
M.F. We also thank Merck Sharp & Dohme (Harlow) and
Pfizer (Sandwich) for additional financial support and the
London School of Pharmacy for HRMS measurements.
1
Supporting Information Available: 500 MHz H and
125 MHz 13C NMR and mass spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In accordance with our past synthetic findings on 3,3b the
oxidation of 16 proceeded smoothly; ketone 17 was isolated
as a single product in 58% yield for the three steps from 14
(viz. glycal epoxidation, epoxide ring-opening, and oxida-
tion). With ketone 17 in hand, we then addressed the issue
of stereospecific olefination via our previously developed
aldol addition/dehydration tactic involving the Marshall
aldehyde 18.10
OL027393M
(11) Luche, J.-L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc., Chem.
Commun. 1978, 601.
(12) For other bryostatin “Southern Hemisphere” synthetic studies, see:
(a) Roy, R.; Rey, A. W.; Charron, M.; Molino, R. J. Chem. Soc., Chem.
Commun. 1989, 1308. (b) Ohmuri, K.; Suzuki, T.; Miyazawa, K.; Nishi-
yama, S.; Yamamura, S. Tetrahedron Lett. 1993, 34, 4981. (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) Obitsu, T.; Ohmuri, K.; Ogawa, Y.; Hosomi, H.; Ohba, S.;
Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1998, 39, 7349. (f) De
Brabander, J.; Vandewalle, M. Synlett 1994, 231. (g) De Brabander, J.;
Vandewalle, M. Synlett 1994, 231. (h) De Brabander, J.; Vandewalle, M.
Synthesis 1994, 855. (i) 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. (j) Baxter, J.; Mata, E. G.; Thomas, E. J.
Tetrahedron 1998, 54, 14359. (k) Almendros, P.; Rae, A.; Thomas, E. J.
Tetrahedron Lett. 2000, 41, 9565. (l) Lopez-Pelegrin, J. A.; Wentworth,
P., Jr.; Sieber, F.; Metz, W. A.; Janda, K. D. J. Org. Chem. 2000, 65, 8527.
To our great delight, enolization of 17 proceeded readily
when effected with n-butyllithium in THF at -78 °C, and
(6) Masamune, S. Pure Appl. Chem. 1988, 60, 1587.
(7) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992,
114, 7570.
(8) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Org. Chem. 1982, 47, 1378.
(9) (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.
(10) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1996, 61, 8732.
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