A Practical and Efficient Synthesis of the C-16-C-28 Spiroketal Fragment (CD) of the Spongistatins

Article abstract of DOI:10.1021/ol035848h

(Equation Presented) A practical and efficient route to the CD spiroketal (C-16-C-28) of the spongistatins is reported. Two stereocenters are introduced from chiral building blocks with the remainder introduced by substrate-controlled transformations. The

Full text of DOI:10.1021/ol035848h

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4815-4818
A Practical and Efficient Synthesis of
the C-16−C-28 Spiroketal Fragment (CD)
of the Spongistatins
Matthew J. Gaunt, David F. Hook, Huw R. Tanner, and Steven V. Ley*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge, CB2 1EW, UK
sVl1000@cam.ac.uk
Received September 24, 2003
ABSTRACT
A practical and efficient route to the CD spiroketal (C-16−C-28) of the spongistatins is reported. Two stereocenters are introduced from chiral
building blocks with the remainder introduced by substrate-controlled transformations. The key â-keto-1,3-dithiane intermediate is generated
by a dithiol conjugate addition to an ynone and the 1,3-dithiane unit in the C-ring plays a key role in the spiroketalization and subsequent
epimerization. The synthesis requires 24 steps, with a longest linear sequence of 19 steps in an overall yield of 14.5% (for the longest linear
sequence).
The spongistatins constitute an important family of archi-
tecturally complex marine macrolides that display exceptional
antitumor activities against a variety of human cancer cell
lines.1 Isolated independently by Pettit,2 Kitagawa,3 and
Fusetani4 in 1993, the spongistatins have attracted significant
interest from the synthetic community, resulting in a number
of total syntheses.5
(5) (a) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Cote, B.; Dias, L.
C.; Rajapaske, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671. Evans. D.
A.; Coleman, P. J.; Dias, L. C. Angew. Chem., Int. Ed. Engl. 1997, 36,
2738. Evans, D. A.; Trotter, B. W.; Cote, B.; Coleman, P. J. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2741. Evans, D. A.; Trotter, B. W.; Cote, B.;
Coleman, P. J.; Dias, L. C.; Tyler, A. N. Angew. Chem., Int. Ed. Engl.
1997, 36, 2744. (b) Guo, J. Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth,
R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 187.
Hayward, M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.; Stevens, K. L.;
Guo, J.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 192. (c) Smith, A. B.,
III; Doughty, V. A.; Lin, Q.; Zhuang, L.; McBriar, M. D.; Boldi, A. M.;
Moser, W. H.; Murase, N.; Nakayama, K.; Sobukawa, M. Angew. Chem.,
Int. Ed. 2001, 40, 191. Smith, A. B., III; Lin, Q.; Doughty, V. A.; Zhuang,
L.; McBriar, M. D.; Kerns, J. K.; Brook, C. S.; Murase, N.; Nakayama, K.;
Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 196. Smith, A. B., III;
Doughty, V. A.; Sfouggatakis, C.; Bennett, C. S.; Koyanagi, J.; Takeuchi,
M. Org. Lett. 2002, 4, 783. (d) Paterson, I.; Chen. D. Y.-K.; Coster, M. J.;
Acena, J. L.; Bach, J.; Gibson, K. R.; Keown, L. E.; Oballa, R. M.;
Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.; Norcross, R. D. Angew.
Chem., Int. Ed. 2001, 40, 4055. (e) Crimmins, M. T.; Katz, J. D.; Washburn,
D. G.; Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661.
(f) Heathcock, C. H.; McLaughlin, M.; Medina, J.; Hubbs, J. L.; Wallace,
G. A.; Scott, R.; Claffey, M. M.; Hayes, C. J.; Ott, G. R. J. Am. Chem.
Soc. 2003, 125, 12844.
(1) Pettit, G. R. J. Nat. Prod. 1996, 59, 812.
(2) Pettit G. R.; Cichacz, Z. A.; Goa, F.; Herald, C. L.; Boyd, M. R.;
Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302. Pettit G.
R.; Cichacz, Z. A.; Goa, F.; Herald, C. L.; Boyd, M. R. J. Chem. Soc.,
Chem. Commun. 1993, 1166. Pettit G. R.; Herald, C. L.; Cichacz, Z. A.;
Goa, F.; Boyd, M. R.; Christie, N. D.; Schmidt, J. M. Nat. Prod. Lett. 1993,
3, 329. Pettit G. R.; Cichacz, Z. A.; Herald, C. L.; Goa, F.; Boyd, M. R.;
Hamel, E.; Bai, R. J. Chem. Soc., Chem. Commun. 1994, 1605. Bai, R.;
Cichacz, Z. A.; Herald, C. L.; Pettit, G. R.; Hamel, E. Mol. Pharmacol.
1993, 44, 757. Pettit, R. K.; McAllister, S. C.; Pettit, G. R. Antimicrob.
Agents 1998, 9, 147. Bai, R.; Taylor, G. F.; Chicacz, Z. A.; Herald, C. L.;
Keplar, J. A.; Pettit, G. R.; Hamel, E. Biochemistry 1995, 34, 9714.
(3) Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.; Kihara, N.; Sasaki,
T.; Kitagawa, I. Tetrahedron Lett. 1993, 34, 2795. Kobayashi, M.; Aoki,
S.; Kitagawa, I. Tetrahedron Lett. 1994, 35, 1243. Kobayashi, M.; Aoki,
S.; Sakai, H.; Kihara, N.; Sasaki, T.; Kitagawa, I. Chem. Pharm. Bull. 1993,
41, 989. Kobayashi, M.; Aoki, S.; Gato, I. K.; Kitagawa, I. Chem. Pharm.
Bull. 1996, 44, 2142.
(4) Fusetani, N.; Shinoda, K.; Matsunaga, S. J. Am. Chem. Soc. 1993,
115, 3977.
10.1021/ol035848h CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/11/2003

We have previously reported studies toward the assembly
of the EF fragment.6 Here, and in the following communica-
tion, we detail our synthesis of the ABCD unit.
from spirocyclization of the â-keto-1,3-dithiane 4. We
recently reported the facile synthesis of â-keto-1,3-dithianes
through a base-mediated conjugate addition of a dithiol to
an ynone,8 and thus, 4 would be readily generated from 5.
Addition of alkyne 6 to aldehyde 7 and subsequent oxidation
would form 5.
A key feature of this approach involved the deployment
of the 1,3-dithiane group on the C ring of the spiroketal. It
was anticipated that this group would aid the spiroketalization
and that the projection of the sulfur atoms may influence
the balance between the fully and partially stabilized
spiroketal structures.
The synthesis began with the addition of triisopropyl-
silylacetylene to (S)-epichlorohydrin 8 through a modified
Hiroa reaction (Scheme 2).9 It was essential to use BF3‚THF
complex, as described by Knight and co-workers, in place
of BF3‚Et2O in order to achieve reproducible results. The
resulting chlorohydrin 9 was then converted cleanly to the
corresponding epoxide 10 in excellent yield using polymer-
supported BEMP as the base. Interestingly, of the wide range
of conditions investigated, the use of the polymer-supported
base was the only method that did not result in partial
â-elimination of the epoxide.10
A unique feature of the spongistatin family of macrolides
is the presence of a partially anomerically stabilized spiro-
ketal (the CD fragment). It is thought that, while lacking
the energetically favorable double-anomeric stabilization, the
CD spiroketal is stabilized by an intramolecular hydrogen
bond between the C25 hydroxyl group and one of the C23
spiroketal oxygen atoms. This postulated interaction has been
the inspiration behind many attempts to synthesize this
moiety with the desired configuration. Smith observed that
Ca2+ ions can control an acid-mediated epimerization of the
fully anomerically stabilized isomer to the desired partially
stabilized CD spiroketal.5c Although other methods have been
utilized to produce the correct C23 configuration under
kinetically controlled conditions, epimerization approaches
have been proved in a variety of systems.7
Scheme 1. Retrosynthesis for the CD Spiroketal Fragment.
Scheme 2. Synthesis of Alkyne 6a
a Conditions: (a) TIPS-CCH, n-BuLi, THF, BF3‚THF, -78 °C
then (S)-epichlorohydrin 8, THF, -78 °C, 4 h; (b) PS-BEMP (2-
tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-
phosphorine), MeCN, rt, 16 h; (c) 2-butenyl bromide, Mg, Et2O
then 1,4-dioxane, then CuI, -40 f 0 °C; (d) TBAF, THF, rt; (e)
TES-Cl, imid, THF, rt.
Epoxide 10 was treated with a 2-butenyl Grignard reagent
in the presence of copper(I) iodide11 and dioxane. The active
species in this process is postulated to be bis(2-butenyl)-
magnesium and not 2-butenylmagnesium bromide.12 When
(6) Fernandez-Megia, E.; Gourlaouen, N.; Ley, S. V.; Rowlands, G. J.
Synlett 1998, 991.
(7) For lead references on other approaches to the CD fragment, see ref
5e. See also: Holson, E. B.; Roush, W. R. Org. Lett. 2002, 4, 3719. Paterson,
I.; Coster, M. J. Tetrahedron Lett. 2002, 43, 3285.
(8) Gaunt, M. J.; Sneddon, H. F.; Orsini, P.; Hewitt, P.; Hook, D. F.;
Ley, S. V. Org. Biolmol. Chem. 2003, 1, 15; Sneddon, H. F.; Gaunt, M. J.;
Ley, S. V. Org. Lett. 2003, 5, 1147.
(9) Evans, A. B.; Knight, D. W. Tetrahedron Lett. 2001, 42, 6947.
(10) All new compounds were characterized by 1H NMR, 13C NMR,
HRMS, IR, and optical rotation. For details, see the Supporting Information.
(11) Lipshultz, B. H. Organocopper Chemistry. In Organometallics in
Synthesis: A Manual; Schlosser, M., Ed.; John Wiley & Sons, Ltd.:
Chichester, 2002; p 740.
Our retrosynthesis, as others, identified ketone 2 as a key
intermediate for the assembly of the ABCD fragment
(Scheme 1). Accordingly, 2 could be generated from 3
through a substrate-controlled reduction at a C21 ketone
(masked as the 1,3-dithiane in 3). In turn, 3 could be realized
4816
Org. Lett., Vol. 5, No. 25, 2003

2-butenylmagnesium bromide was used the main product ob-
served was the bromohydrin observed from bromide opening
of the epoxide. However, treatment of 2-butenylmagnesium
bromide with 1,4-dioxane forms the bis(2-butenyl)magne-
sium species and precipitates a dioxane-magnesium bromide
complex. Addition of catalytic copper(I) iodide followed by
the epoxide 10 to this mixture produces cleanly the desired
homoallylic alcohol 11 in 99% yield with no trace of the
undesired bromohydrin side product. This procedure could
find useful application for epoxide opening reactions where
halide addition is a problematic side reaction. Treatment of
alcohol 11 with TBAF removes the TIPS group, and
protection of the hydroxyl as the TES ether generates 6 in
good yield over two steps. Fragment 6 is assembled in five
steps in 70% overall yield (93% per step) and is readily
adapted to a multigram scale.
in 89% over three steps. Importantly, this three-step sequence
can be performed on a large scale without need for significant
purification until acetonide 16. Removal of the TIPS group
with TBAF liberates the hydroxyl function in 96% yield,
and Swern oxidation16 generates aldehyde 7 in good yield;
however, the aldehyde is not stable and must be used
immediately.
Scheme 4. Synthesis of Spiroketal 18a
The synthesis of aldehyde 7 began with the ethoxide-
mediated double-conjugate addition of 1,3-propanedithiol to
ethyl propiolate 12,8 reduction with LiAlH4, and protection
of the resulting hydroxyl group as a TIPS ether to form
dithiane 13 in 50% yield over three steps (Scheme 3).
Scheme 3. Synthesis of Aldehyde 7a
a Conditions: (a) i-PrMgCl, 6, THF, 2 h, rt, then 7, THF, -20
°C, 1 h; (b) Dess-Martin periodinane, CH2Cl2, rt, 1 h; (c)
HS(CH2)3SH, NaOMe, MeOH-CH2Cl2, -10 °C f rt, 16 h; (d)
10% HClO4 (aq), MeCN-CH2Cl2, rt, 30 min; (e) 3.5% HClO4 (aq),
5 equiv of Ca(ClO4)2‚4H2O, MeCN-CH2Cl2, rt, 18 h.
With the key fragments in hand, union of 6 and 7 was
investigated (Scheme 4). The anion of acetylene 6 was
formed through treatment with i-PrMgCl at room temperature
followed by addition with the freshly prepared aldehyde 7
to form the propargylic alcohol as a 1:1 mixture of diaster-
eomers in 93% yield. Oxidation with Dess-Martin perio-
dinane17 affords cleanly the ynone 5. Dithiol conjugate
addition8 of 1,3-propanedithiol to ynone 5 forms â-keto 1,3-
dithiane 4 in excellent yield and generates the required
functional pattern for the target molecule. Treatment of the
ketone 4 with dilute perchloric acid forms spiroketals 17 and
18 as a 4:1 mixture in favor of the undesired isomer 17.
Facile equilibration using the conditions adapted from
Smith’s procedure5c allowed the clean conversion of 17 to
18 in 84% yield from 4 after three recycles. Interestingly,
the presence of the 1,3-dithiane moiety slows the equilibra-
tion process of 17 to 18 and requires 18 h to reach a 2.2:1
a Conditions: (a) (i) HS(CH2)3SH, NaOEt, EtOH-THF, -10
°C f rt, 16 h, (ii) LiAlH4, THF, 0 °C, 4 h, (iii) TIPSCl, imid,
THF, rt, 12 h; (b) n-BuLi, THF, rt, 10 min then 14, THF, -20 f
0 °C, 2 h; (d) I2, NaHCO3 (aq), MeCN, 0 °C; (e) Et2BOMe, NaBH4,
THF-MeOH, -78 °C, 12 h; (f) Me2C(OMe)2, Me2CO, TsOH‚H2O,
0 °C; 1 h; (g) TBAF, THF, 2 h; (h) (COCl)2, DMSO, CH2Cl2, -78
°C then Et3N, -78 f 0 °C.
Metalation of dithiane 13 with n-BuLi at room temperature13
and interception of the anion with epoxide 14 affords 15 in
98% yield.
Cleavage of the dithiane moiety in 15,14 borane-mediated
syn-reduction15 of the resulting ketone, and protection of the
corresponding diol as the acetonide derivative generates 16
(12) House, H. O.; Repess, W. L.; Whitesides, G. M. J. Org. Chem.
1966, 31, 3128. (b) Schlenk, W.; Schlenk, W. Jnr. Ber. Dtsch. Chem. Ges.
1929, 62, 920. (c) Cope, A. C. J. Am. Chem. Soc. 1935, 57, 2238. (d)
Morrison, J. D.; Atkins, R. L.; Tomaszewski, J. E. Tetrahedron Lett. 1970,
53, 4635.
(15) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
(13) Ide, M.; Nakata, M Bull. Chem. Soc. Jpn. 1999, 72, 2491.
(14) Based on Russell, G. A.; Ochrymowycz, L. A. J. Org. Chem. 1969,
34, 3618.
(16) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(17) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4383.
Org. Lett., Vol. 5, No. 25, 2003
4817

mixture in favor of the desired isomer 18. Significantly, the
two spiroketals are easily separated and the unwanted isomer
can be recycled. This feature aids the purification of the two
spiroketals such that chromatographic separation is trivial,
enabling facile recycling of isomer 17. In contrast to Smith’s
examples our calcium mediated spiroketal epimerization does
not require the presence of a hydroxyl group at the C17 or
C18 position. While in that case5c there is certainly an
additional stabilizing interaction provided by the hydroxyl
group, our system is probably more influenced by the
dithiane moiety at C21 and the hydroxyl at C26 (Figure 1).
Scheme 5. Synthesis of Spiroketal 2d
Figure 1. Epimerization of spiroketal 17.
a Conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C; (b) 2
equiv of PhI(TFA)2, MeOH, 0 °C, 30 min then NaHCO3 (aq);
AcOH-THF-H2O, 30 °C, 5 h; (c) (i) NaBH4, CeCl3‚7H2O, THF,
MeOH, -78 °C, (ii) NaH, MeI, THF, 0 f rt; (d) (cat.) OsO4, NMO,
acetone-H2O then NaIO4, MeOH-H2O (2:1) rt, 2 h.
With the correct CD spiroketal isomer 18 in hand,
protection of the C-25 hydroxyl as the TBS ether formed 3
in excellent yield (Scheme 5). Cleavage of the 1,3-dithiane
unit caused unexpected problems. Initial attempts to remove
the dithiane by a variety of methods led to substantial
decomposition and unacceptable mixtures of products.
Finally, we found that using the Stork-Zhoa procedure in
methanol,18 to form the dimethyl ketal, followed by treatment
with acetic acid in water produced the desired ketone 19 in
82% isolated yield.
the spongipyran natural products. Our synthesis requires the
use of two chiral starting materials and thereafter makes use
of substrate control to introduce the remaining stereocenters.
The synthetic route requires only 24 steps with a longest
linear sequence of 19 steps (overall yield of longest linear
sequence is 14.5%). In the following paper,21 we detail our
synthesis of the AB spiroketal and the formation of the
ABCD fragment.
Reduction of ketone 19 under modified Luche conditions19
generated the desired equatorial C-15 alcohol with 17:1
selectivity. Interestingly, use of L-Selectride, as detailed by
Crimmins and co-workers for a similar ketone reduction,
gave only a 1:1 mixture of isomers.20 The resulting alcohol
was methylated to form 20 in 78% over two steps from
ketone 19. Dihydroxylation of alkene 19 and immediate
periodate cleavage formed the desired ketone 2 in 82% yield
over two steps. The structure of ketone 2 was confirmed by
Acknowledgment. We thank Magdalene College, Cam-
bridge, and The British Ramsay Memorial Trust for a
Fellowship (to M.J.G), the EPSRC for a studentship (to
D.F.H), and Novartis for a studentship (to H.T) and a
Research Fellowship (to S.V.L).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
analysis of the H NOSEY spectrum.
In summary, we have developed a practical and efficient
synthesis of the CD spiroketal required for our synthesis of
OL035848H
(18) Stork, G. Zhoa, K. Tetrahedron Lett. 1989, 30, 287.
(19) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(20) Crimmins, M. T.; Katz, J. D. Org. Lett. 2000, 2, 957.
(21) Gaunt, M. J.; Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook, D.
F.; Ley, S. V. Org. Lett. 2003, 5, 4819.
4818
Org. Lett., Vol. 5, No. 25, 2003