Synthetic studies on altohyrtins (spongistatins): Synthesis of the C15- C28 (CD) spiroacetal portion

Article abstract of DOI:10.1016/S0040-4039(00)00237-9

The C15-C28 portion of altohyrtins (spongistatins) was prepared in a convergent manner from methyl (S)-3-hydroxy-2-methylpropionate, D-arabitol, and diacetone-D-glucose via dithiane couplings with epoxides as the key segment coupling process. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00237-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2649–2653
Synthetic studies on altohyrtins (spongistatins):
synthesis of the C15–C28 (CD) spiroacetal portion
Takeshi Terauchi, Taro Terauchi, Ippei Sato, Tomoharu Tsukada, Naoki Kanoh and
Masaya Nakata ∗
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Received 14 January 2000; revised 31 January 2000; accepted 4 February 2000
Abstract
The C15–C28 portion of altohyrtins (spongistatins) was prepared in a convergent manner from methyl (S)-3-
hydroxy-2-methylpropionate, D-arabitol, and diacetone-D-glucose via dithiane couplings with epoxides as the key
segment coupling process. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: altohyrtins; dithianes; epoxides; spiro compounds.
We have recently reported the synthesis of the C1–C14 (AB) spiroacetal portion 1 of altohyrtins
(spongistatins) from the commercially-available carbohydrate, 3,4,6-tri-O-acetyl-D-glucal, as a chiral
building block (Fig. 1).1 We now report in this letter the synthesis of the C15–C28 (CD) spiroacetal
portion 2. The altohyrtins, spongistatins, and cinachyrolide A have been isolated from marine sponges
by the Kitagawa, Pettit, and Fusetani groups, respectively.2 Their extremely potent antitumor activities
and unique, exciting structures have promoted a number of synthetic studies.3 Recently, the Evans and
Kishi groups have independently succeeded in the total synthesis of altohyrtin C (spongistatin 2) and
altohyrtin A (spongistatin 1), respectively.3
We envisioned that the three consecutive stereocenters of C14, 15, and 16 should be constructed by
an aldol reaction. The C1–C14 ethyl ketone 11 was prepared for a candidate of the ketone segment. We
selected the C15–C28 aldehyde 2 as an aldehyde candidate (Fig. 1). Since stereoselectivity of the aldol
reactions between the structurally complex ethyl ketones and α-methyl-β-alkoxyaldehydes is generally
capricious,4 it is difficult to correctly predict the influence of the C17-configuration in 2 on the selectivity
of our aldol reaction. Therefore, it is essential for future success to obtain both compounds 2a and 2b.
Aldehydes 2a or 2b would be obtained from the acyclic precursors 4a or 4b via spiroacetals 3a or 3b
(Scheme 1). It was expected that 4a or 4b would be obtained from three segments, the C15–C17 dithiane
derivative 5, the C18–C22 diepoxide 6, and the C23–C28 dithiane derivative 7. The dithiane derivative 5
∗
Corresponding author. Tel: +81-45-563-1141; fax: +81-45-563-0446; e-mail: msynktxa@applc.keio.ac.jp (M. Nakata)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00237-9
tetl 16517

2650
Fig. 1.
is known5 and can be prepared from methyl (S)-3-hydroxy-2-methylpropionate (8). Diepoxide 6 is also
known6 but we prepared it from D-arabitol (9) via a new route. The dithiane derivative 7 was prepared
from diacetone-D-glucose (10); the C2- and C4-hydroxy groups of the latter can be used as the C27- and
C25-hydroxy groups of 4a or 4b.
Scheme 1.
To obtain diepoxide 6,6 we first prepared tetraol 11 by Sakai’s procedure7 with modifications (Scheme
2). D-Arabitol (9) was subjected to selective acetonization followed by deoxygenation and deacetoniza-
tion to afford tetraol 11 in 47% yield from 9. Acetyl-bromination8 of 11 followed by alkaline treatment
gave the desired diepoxide 6 in 60% yield.9 The dithiane derivative 7 was prepared from 10 as follows.
Following the literature procedure,10 10 was transformed into the known 12. Bromination of 12 gave
bromide 13,11 which underwent smooth addition by 2-lithio-1,3-dithiane, giving 711 in 93% yield from
12.

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Scheme 2.
The coupling of the anion derived from 55 (1 equiv.) and n-BuLi (1.5 equiv.) with diepoxide 6 (1.8
equiv.) afforded 1411 in 61% yield based on 5 (Scheme 3).12 De-dithioacetalization of 14 with I2 in aq.
acetone13 gave ketone 15 in 85% yield. The stereo- and chemoselective reduction of the carbonyl group
in epoxy-ketone 15 was next investigated. The relevant data are shown in Scheme 3. The C17,19-anti
product 16 was obtained by using Me4NBH(OAc)314 in 91% yield as the only reduction product without
any epoxide opening. In contrast, the C17,19-syn product 17 was obtained as the only reduction product
15
by using Et2BOMe–NaBH4 in 98% yield. The stereochemistries of 16 and 17 were confirmed by 13
C
NMR analysis16 of their acetonides, 1811 and 19.11
Scheme 3.
The second dithiane coupling was conducted by the addition of n-BuLi (1.6 equiv.) to the mixture
of 7 (1.2 equiv.), epoxide 18 (1.0 equiv.), and HMPA (1.0 equiv.) in THF at −20°C, giving the adduct
2011 in 95% yield (Scheme 4). Methylation of 20 (95%) followed by deprotection and reduction gave
21. De-dithioacetalization of 21 with ammonium cerium(IV) nitrate (CAN)17 gave, with concomitant
spiroacetalization, the unnatural spiroacetal 2211 and the desired spiroacetal 2311 in 42 and 14% yields,

2652
1
respectively. The spiroacetal configuration of 22 was verified by H NMR NOE measurements as
shown in Scheme 4. All attempts to effect isomerization of 22 into 23 under protic and Lewis acid
conditions resulted in a ca. 1–3:1 equilibrium mixture of 22 and 23. Moreover, it was found that the
next p-methoxybenzylidenation of the C15- and C17-hydroxy groups in each spiroacetal 22 and 23 was
accompanied by partial isomerization at the spiroacetal center. Therefore, this equilibration was tried at
the next stage. The 3:1 mixture of 22 and 23 was treated with p-methoxybenzaldehyde dimethyl acetal
and ZnCl2 in 10:1 THF–CH2Cl2 at rt for 1 h to afford a separable mixture of 2411 and 2511 in 49 and 24%
yields, respectively. The spiroacetal configuration of 25 was verified by 1H NMR NOE measurements as
shown in Scheme 4. At this stage, the isomerization of 24 into 25 was best achieved by subjecting 24
3n
to the conditions of ZnCl2 (5 equiv.) in CH2Cl2 (rt, 0.5 h), giving a 2:3 mixture of 24 and 25 in 91%
combined yield. The obtained 25 was converted to aldehyde 2a by standard transformations. On the other
hand, the isomer 19 was also converted to 2b by almost the same procedures as described above for the
case of 18.18,19
Scheme 4.
The convergent synthesis described herein makes available the C15–C28 (CD) spiroacetal portion of
the altohyrtins (spongistatins) in significant quantities. The aldol reaction of the ethyl ketone 1 with this
aldehyde 2 and the preparation of the complete C1–C28 portion are now in progress.

2653
Acknowledgements
Financial support by Takeda Science Foundation is gratefully acknowledged.
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