Total synthesis of altohyrtin A (spongistatin 1): An alternative synthesis of the CD-spiroacetal subunit

Article abstract of DOI:10.1016/S0040-4039(02)00527-0

The CD-spiroacetal containing C₁₆-C₂₈ subunit 2, as used in the total synthesis of the potent cytotoxic macrolide, altohyrtin A (spongistatin 1), was prepared by an alternative route using substrate-based stereocontrol in the two ald

Full text of DOI:10.1016/S0040-4039(02)00527-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3285–3289
Total synthesis of altohyrtin A (spongistatin 1): an alternative
synthesis of the CD-spiroacetal subunit
Ian Paterson* and Mark J. Coster
University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 14 February 2002; accepted 15 March 2002
Abstract—The CD-spiroacetal containing C16–C28 subunit 2, as used in the total synthesis of the potent cytotoxic macrolide,
altohyrtin A (spongistatin 1), was prepared by an alternative route using substrate-based stereocontrol in the two aldol bond
constructions generating the acyclic precursor 4. © 2002 Published by Elsevier Science Ltd.
The altohyrtins/spongistatins comprise an important
family of highly cytotoxic macrolides, isolated from
marine sponges.1,2 They display exceptional growth
inhibitory activity against a wide range of drug-resis-
tant cancer cell lines, functioning by interfering with
tubulin polymerisation. Their complex, highly oxy-
genated structures (e.g. 1, Scheme 1) and potent antim-
itotic action, combined with an extremely meagre
natural supply, have provided a strong impetus for
synthetic efforts. Total syntheses of altohyrtin C
(spongistatin 2) have been achieved by the Evans
group3 and more recently by the Smith group.4 The first
total synthesis of the more active, chlorinated congener,
altohyrtin A/spongistatin 1 (1) by Kishi et al.,5 was
recently followed by our completion of a highly stere-
ocontrolled synthesis, leading to useful quantities for
further preclinical development.6 With a view to further
refining our total synthesis, we now report a new
synthesis of the CD-spiroacetal containing subunit 2
that exploits substrate-based aldol stereocontrol.
The CD-spiroacetal of the altohyrtins/spongistatins
benefits from only a single anomeric effect, necessitat-
ing care in initially establishing the C23 acetal centre
O
15
16
HO
AcO
OMe
O
19
O
16
C
D
B
A
O
O
O
OMe
O
C
D
28
29
AcO
HO
O
O
1
OPMB
O
O
27
TBSO
41
HO
OH
2
51
F
E
O
OH
H
OH
Cl
OH
1: altohyrtin A
(spongistatin 1)
Scheme 1.
Keywords: altohyrtin; spongistatin; boron aldol; cytotoxic; remote stereoinduction.
* Corresponding author. Fax: +44-1223-336362; e-mail: ip100@cus.cam.ac.uk
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00527-0

3286
I. Paterson, M. J. Coster / Tetrahedron Letters 43 (2002) 3285–3289
correctly and subsequently avoiding unwanted epimeri-
sation.7 Accordingly, our revised retrosynthetic analysis
for 2 involved formation of the precursor 3a, incorpo-
rating a C17-methylene, from ketone 4 by removal of
the silyl protecting groups and concomitant spiroacetal
formation (Scheme 2). The aldol coupling of ketone 5
with aldehyde 6 to give the required acyclic precursor 4
would depend on substrate-based stereoinduction in
setting up the C25 stereocentre, as demonstrated in an
analogous system.6c Ketone 5 would arise from 7 by
1,3-anti reduction and various functional group manip-
ulations. The 1,5-anti relationship between the oxygen
functionality in 7 suggested a boron-mediated aldol
reaction8 between the b-alkoxyketone 8 and b,g-unsatu-
rated aldehyde 9, where substrate-based induction
would again be employed productively.
the use of propionaldehyde and catalytic SmI2 proved
efficient, allowing for the production of 11 in good
yield (90%) and with an excellent level of 1,3-stereoin-
duction (>97:3 dr).
Methylation of alcohol 11 required the use of very
mild, near neutral conditions (Scheme 4).17 Subjection
of 11 to MeOTf and 2,6-di-tert-butylpyridine in reflux-
ing CH2Cl2 proved successful, although the yield was
moderate (65%), reaction times were prolonged (16 h)
and unwanted byproducts were apparent. Much more
satisfactory was the use of trimethyloxonium tetra-
fluoroborate and Proton-Sponge® in CH2Cl2, affording
methyl ether 12 rapidly (3 h, 0°C) and in good yield
(90%).
O
The synthesis began with the regioselective enolisation
of methyl ketone 8,9 using (+)-Ipc2BCl and Et3N,10 to
give enol borinate 10 in situ (Scheme 3).11 Reaction of
10 with aldehyde 9,12 followed by oxidative workup,
provided the 1,5-anti aldol adduct 7 as the predominant
diastereomer (91:9 dr), in 51% yield (unoptimised).13
The stereogenicity at C19 and degree of diastereoselec-
H
OH
O
OBn
9
b
+
19
51%
(Ipc)2B
O
OBn
91:9 dr
7
1
tivity were determined by H NMR analysis of the (R)-
90%
c
10
and (S)-MTPA esters,14 and conform to the levels of
1,5-anti selectivity generally observed for aldol reac-
tions of this type.8 Gratifyingly, no isomerisation of
aldehyde 9 to the a,b-unsaturated isomer was observed
under the reaction conditions, illustrating the mild
nature of the boron mediated aldol reaction.15
a
O
O
OH
OBn
O
OBn
17
19
23
The Evans–Tishchenko reduction16 was chosen as the
most appropriate method for conversion of b-hydroxy-
ketone 7 to the mono-protected 1,3-anti diol 11. Pre-
liminary experiments utilising benzaldehyde as the
hydride source were slow and low yielding. However,
>97:3 dr
11
8
Scheme 3. (a) (+)-Ipc2BCl, Et3N, Et2O, −78“0°C, 1 h; (b) 9,
Et2O, −78“−20°C, 90 min; H2O2, MeOH, pH 7 buffer, 20°C,
1 h; (c) SmI2 (cat.), EtCHO, THF, −20°C, 16 h.
Scheme 2. Retrosynthetic analysis.

I. Paterson, M. J. Coster / Tetrahedron Letters 43 (2002) 3285–3289
3287
O
O
O
OH
OBn
O
OMe OBn
a
90%
11
12
b, c
91%
OTBS OMe
5
O
OTBS OMe OBn
d, e
96%
17
23
13
Scheme 4. (a) Me3OBF4, Proton-Sponge®, CH2Cl2, 0°C, 3 h; (b) K2CO3, MeOH, 20°C, 16 h; (c) TBSCl, Im, DMF, 20°C, 16 h;
(d) LiDBB, THF, −78°C, 1 h; (e) Dess–Martin periodinane, pyr., CH2Cl2, 20°C, 40 min.
88% yield). Under anhydrous acid conditions (HCl,
CH2Cl2) the spiroacetals equilibrated to a ca. 1:1 mix-
ture, and were readily separable by flash chromatogra-
phy (43% of the desired isomer 3a and 33% of 3b). The
undesired isomer 3b could then be re-equilibrated to
give more of 3a.
Exchange of the propionate in 12 for a TBS protecting
group proceeded smoothly, providing 13 (91%). Subse-
quent removal of the benzyl ether utilising LiDBB18
and oxidation of the resultant alcohol with Dess–Mar-
tin periodinane19 produced ketone 5 (96%), ready for
aldol coupling.
With CD-spiroacetal 3a in hand, bearing the correct
stereochemistry at the anomeric centre (C23), conver-
sion to the required subunit 2 was straightforward.
Protection of 3a as the corresponding TBS ether was
achieved with TBSOTf and 2,6-lutidine (Scheme 6).
Dihydroxylation with catalytic OsO4 and NMO as co-
oxidant, followed by sodium periodate cleavage of the
resultant diol, provided the desired CD-spiroacetal sub-
unit 2 (63%, three steps), identical in all respects with
material provided by our earlier route.6c
The boron-mediated aldol reaction of aldehyde 6 with
ketone 5 was well precedented from our previously
published route to the CD-spiroacetal subunit 2.6c In
the event, treatment of ketone 5 with (−)-Ipc2BCl and
Et3N led to regioselective enolisation to give enol bori-
nate 14 in situ (Scheme 5). Reaction of this with
aldehyde 6, followed by oxidative workup, gave the
linear C16–C28 fragment 413 (78% yield) as the only
identifiable diastereomer (>97:3 dr). Notably, this
boron-mediated aldol reaction exploits triple asymmet-
ric induction, where the influence of all three chiral
components (aldehyde, ketone and boron reagent) are
matched.
In conclusion, the CD-spiroacetal containing C16–C28
subunit 2 was prepared in this new route in 11.8% yield
over 13 steps from ketone 8. The synthesis presented
here further illustrates the utility of the boron-mediated
aldol reaction for the stereoselective construction of
Treatment of 4 with aqueous HF in acetonitrile led to
the smooth formation of spiroacetals 3a and 3b (1:5,
O
OTES
OPMB
25
27
H
OTBS OMe
O
OH
OTES
b
4
6
OPMB
25
78%
+
B(Ipc)2
>97:3 dr
c
88%
OTBS OMe
O
14
OMe
OMe
a
d
C
O
O
OTBS OMe
5
O
23
1 : 1
O
O
D
OPMB
OPMB
25
25
HO
HO
3a
Desired
3b
Undesired
1 : 5
Scheme 5. (a) (−)-Ipc2BCl, Et3N, Et2O, −78“0°C, 1 h; (b) 6, Et2O, −78“−20°C, 16 h; H2O2, MeOH, pH 7 buffer, 20°C, 1 h; (c)
HF(aq), MeCN, 0°C, 40 min; (d) HCl (cat.), CH2Cl2, 20°C, 30 min.

3288
I. Paterson, M. J. Coster / Tetrahedron Letters 43 (2002) 3285–3289
C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55,
8671–8726.
O
O
16
4. (a) 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, 191–195; (b) Smith, A. B., III;
Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar, M. D.;
Kerns, J. K.; Brook, C. S.; Murase, N.; Nakayama, K.
Angew. Chem., Int. Ed. 2001, 40, 196–199.
OMe
OMe
a - c
63%
C
D
C
D
O
O
O
OPMB
OPMB
HO
TBSO
28
3a
2
5. (a) 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, 187–192; (b) 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, 192–196.
6. (a) Paterson, I.; Chen, D. Y.-K.; Coster, M. J.; Acen˜a, J.
L.; Bach, J.; Gibson, K. R.; Keown, L. E.; Oballa, R. M.;
Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.; Nor-
cross, R. D. Angew. Chem., Int. Ed. 2001, 40, 4055–4060;
(b) Paterson, I.; Wallace, D. J.; Oballa, R. M. Tetra-
hedron Lett. 1998, 39, 8545–8548; (c) Paterson, I.; Wal-
lace, D. J.; Gibson, K. R. Tetrahedron Lett. 1997, 38,
8911–8914; (d) Paterson, I.; Oballa, R. M. Tetrahedron
Lett. 1997, 38, 8241–8244; (e) Paterson, I.; Keown, L. E.
Tetrahedron Lett. 1997, 38, 5727–5730; (f) Paterson, I.;
Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996,
37, 8581–8584.
Scheme 6. (a) TBSOTf, 2,6-lutidine, CH2Cl2, −78°C, 1 h; (b)
OsO4 (cat.), NMO, Me2CO/H2O, 20°C, 6 h; (c) NaIO4,
MeOH/pH 7 buffer, 20°C, 1 h.
polyacetate subunits.20 Combined with the highly
stereoselective and hydroxyl discriminating Evans–
Tishchenko reduction, this provides a powerful tool for
the synthesis of polyketide natural products. Addition-
ally, the use of sensitive b,g-unsaturated aldehydes in
the boron-mediated aldol reaction has been shown to
be effective.
7. Syntheses of the CD-spiroacetal subunit by other groups:
(a) Hayes, C. J.; Heathcock, C. H. J. Org. Chem. 1997,
62, 2678–2679; (b) Paquette, L. A.; Braun, A. Tetra-
hedron Lett. 1997, 38, 5119–5122; (c) Crimmins, M. T.;
Katz, J. D. Org. Lett. 2000, 2, 957–960; (d) Zemribo, R.;
Mead, K. T. Tetrahedron Lett. 1998, 39, 3895–3898; (e)
Terauchi, T.; Terauchi, T.; Sato, I.; Tsukada, T.; Kanoh,
N.; Nakata, M. Tetrahedron Lett. 2000, 41, 2649–2653.
8. (a) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetra-
hedron Lett. 1996, 37, 8585–8588; (b) Evans, D. A.;
Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788–789.
9. Ketone 8 was prepared in enantiomerically pure form in
three steps from methyl (R)-3-hydroxybutyrate (15):
Acknowledgements
We thank the EPSRC (GR/L41646), Cambridge Com-
monwealth Trust and AstraZeneca for support and Dr.
Anne Butlin (AstraZeneca) for helpful discussions.
References
1. For key references on the isolation, structure elucidation
and biological activity of the altohyrtins, spongistatins
and cinachyrolide A, see: (a) Kobayashi, M.; Aoki, S.;
Sakai, K.; Kawazoe, K.; Kihara, N.; Sasaki, T.; Kita-
gawa, I. Tetrahedron Lett. 1993, 34, 2795–2798; (b)
Kobayashi, M.; Aoki, S.; Gato, K.; Kitagawa, I. Chem.
Pharm. Bull. 1996, 44, 2142–2149; (c) Pettit, G. R.;
Chicacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.;
Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58,
1302–1304; (d) Bai, R.; Cichacz, Z. A.; Herald, C. L.;
Pettit, G. R.; Hamel, E. Mol. Pharmacol. 1993, 44, 757–
766; (e) Bai, R.; Taylor, G. F.; Cichacz, Z. A.; Herald, C.
L.; Kepler, J. A.; Pettit, G. R.; Hamel, E. Biochemistry
1995, 34, 9714–9721; (f) Fusetani, N.; Shinoda, K.; Mat-
sunaga, S. J. Am. Chem. Soc. 1993, 115, 3977–3981.
2. For reviews see: (a) Pietruszka, J. Angew. Chem., Int. Ed.
1998, 37, 2629–2636; (b) Norcross, R. D.; Paterson, I.
Chem. Rev. 1995, 95, 2041–2114.
(i) BnTCA, TfOH (cat.)
ii) MeONHMe.HCl, i-PrMgCl
O
OH
O
OBn
21
23
MeO
iii) MeMgBr
15
8
49% (3 steps)
10. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann,
R. C.; McClure, C. K.; Norcross, R. D. Tetrahedron
1990, 46, 4663–4684.
11. For reviews on asymmetric aldol reactions using boron
enolates, see: (a) Cowden, C. J.; Paterson, I. Org. React.
1997, 51, 1–200; (b) Paterson, I.; Cowden C. J.; Wallace,
D. J. In Modern Carbonyl Chemistry; Otera, J., Ed;
Wiley-VCH: Weinheim, 2000; pp. 249–297.
12. Aldehyde 9 was synthesised by Dess–Martin oxidation of
the known alcohol 16: Alexakis, A.; Normant, J.; Vil-
lieras, J. J. Organomet. Chem. 1975, 96, 471–485.
3. (a) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew.
Chem., Int. Ed. 1997, 36, 2738–2741; (b) Evans, D. A.;
Trotter, B. W.; Cote, B.; Coleman, P. J. Angew. Chem.,
Int. Ed. 1997, 36, 2741–2744; (c) Evans, D. A.; Trotter, B.
W.; Cote, B.; Coleman, P. J.; Dias, L. C.; Tyler, A. N.
Angew. Chem., Int. Ed. 1997, 36, 2744–2747; (d) Evans,
D. A.; Trotter, B. W.; Coleman, P. J.; Cote, B.; Dias, L.
O
OH
Dess-Martin
periodinane
H
17
19
9
16

I. Paterson, M. J. Coster / Tetrahedron Letters 43 (2002) 3285–3289
13. All new compounds gave spectroscopic data in agreement
3289
(Ipc)2B
with the assigned structures. 4 had: [h]2D0 −2.5 (c 1.69,
CHCl3); 1H NMR (500 MHz, CDCl3) l 7.24 (2H, d,
J=8.6 Hz), 6.87 (2H, d, J=8.6 Hz), 4.77 (1H, d, J=1.4
Hz), 4.72 (1H, br s), 4.44 (2H, s), 4.23 (1H, m), 4.07 (1H,
m), 3.97 (1H, m), 3.87 (1H, m), 3.80 (3H, s), 3.52 (1H, d,
J=2.2 Hz), 3.41 (1H, dd, J=9.7, 5.1 Hz), 3.37 (1H, dd,
J=9.7, 5.1 Hz), 3.28 (3H, s), 2.72 (1H, dd, J=15.8, 6.5
Hz), 2.60 (1H, dd, J=16.7, 7.9 Hz), 2.53 (1H, dd, J=
16.7, 4.3 Hz), 2.48 (1H, dd, J=15.8, 5.5 Hz), 2.30 (1H,
dd, J=13.6, 4.7 Hz), 2.10 (1H, dd, J=13.6, 4.7 Hz), 1.99
(2H, br q, J=7.3 Hz), 1.61–1.73 (3H, m), 1.34 (1H, ddd,
J=14.2, 8.8, 3.8 Hz), 1.02 (3H, t, J=7.4 Hz), 0.93 (9H, t,
J=8.0 Hz), 0.90 (9H, s), 0.60 (6H, q, J=8.0 Hz), 0.08
(3H, s), 0.07 (3H, s); 13C NMR (100.6 MHz, CDCl3) l
209.1, 159.2, 147.9, 130.1, 129.3, 113.7, 110.8, 74.2, 73.9,
73.0, 70.6, 67.9, 66.0, 56.4, 55.2, 50.8, 48.5, 45.4, 42.0,
41.1, 29.0, 25.9, 18.0, 12.2, 6.8, 4.9, −4.1, −4.6; HRMS
(+ESI) Calcd for C36H66O7Si2Na [M+Na]+: 689.4245,
found: 689.4234.
O
O
OBn
+
H
21
23
(+ 6% trans-crotonaldehyde)
10
87%
OH
O
OBn
OH
O
OBn
17
19
23
18
17
ca. 91 : 9
16. Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990,
112, 6447–6449.
17. Mild conditions for the methylation of alcohols: Evans,
D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. Tetra-
hedron Lett. 1994, 35, 7171–7172.
18. Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988,
110, 854–860.
19. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
14. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092–4096.
15. In a preliminary experiment, reaction of enol borinate 10
with 3-butenal (94:6 mixture with trans-crotonaldehyde)
gave aldol adduct 17 as a mixture (ca. 91:9) with 18
(resulting from reaction with trans-crotonaldehyde):
20. For related work, see: Paterson, I.; Collett, L. A. Tetra-
hedron Lett. 2001, 42, 1187–1191.