Formal total synthesis of altohyrtin C (spongistatin 2). Part 2: Construction of fully elaborated ABCD and EF fragments

Article abstract of DOI:10.1016/j.tetlet.2003.08.083

Coupling of the C1-C14 (AB) crotylstannane with the C15-C28 (CD) aldehyde followed by stereochemical arrangements gave the C1-C28 (ABCD) fragment of altohyrtin C. The C29-C44 (EF) fragment was also prepared. The syntheses of these two fragments, both of w

Full text of DOI:10.1016/j.tetlet.2003.08.083

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7747–7751
Formal total synthesis of altohyrtin C (spongistatin 2). Part 2:
Construction of fully elaborated ABCD and EF fragments
Takeshi Terauchi, Taisaku Tanaka, Taro Terauchi, Masataka Morita, Kyoko Kimijima, Ippei Sato,
Wataru Shoji, Yasuhiro Nakamura, Tomoharu Tsukada, Takashi Tsunoda, Gouichirou Hayashi,
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 5 August 2003; revised 19 August 2003; accepted 21 August 2003
Abstract—Coupling of the C1ꢀC14 (AB) crotylstannane with the C15ꢀC28 (CD) aldehyde followed by stereochemical arrange-
ments gave the C1ꢀC28 (ABCD) fragment of altohyrtin C. The C29ꢀC44 (EF) fragment was also prepared. The syntheses of these
two fragments, both of which were identical with those prepared by the Smith group, constitute a formal total synthesis of
altohyrtin C.
© 2003 Elsevier Ltd. All rights reserved.
The altohyrtins, spongistatins, and cinachyrolide A (1–
4) were isolated from marine sponges by the Kitagawa,
Pettit, and Fusetani groups, respectively (Fig. 1).1 In
the preceding communication,2 we described an aldol
coupling approach to construct the ABCD (C1ꢀC28)
fragment 53 (Fig. 2). Since it was difficult in our hand
to introduce the C13 exomethylene into 5, we then
pursued a second-generation strategy to combine the
AB (C1ꢀC14) and the CD (C15ꢀC28) fragments.
Among the many possible approaches, we chose a
crotylstannane–aldehyde coupling because (i) it is not
necessary to introduce the C13 exomethylene after the
fragment assembly, and (ii) the stereoselectivity of the
coupling reactions has been well studied4 and it is
known to be controlled by Lewis acids.5 Based on this
analysis, we envisioned that the subtarget 6 or 7 could
be constructed by the coupling between the C1ꢀC14
(AB) crotylstannane 8 and the C15ꢀC28 (CD) aldehyde
9 or 10, respectively.
synthesis needed a total of 32 steps from the starting
3,4,6-tri-O-acetyl-
-glucal.6a Therefore, we developed a
D
more efficient synthesis of 8 as described below (Scheme
2). The synthesis started from the known ketone 137
and aldehyde 14.8 Enantioselective aldol reaction of 13
with 14 by using (−)-diisopinocampheylboron chloride
((−)-Ipc2BCl)9 afforded b-hydroxyketone 15 in moder-
Although crotylstannane 8 could be synthesized in six
steps from aldehyde 11 (through 12, Scheme 1), which
was prepared in the preceding communication,2 the
Keywords: altohyrtins; spongistatins; stereoselective synthesis; crotyl-
stannanes.
* Corresponding author. Tel.: +81-45-566-1577; fax: +81-45-566-1551;
e-mail: msynktxa@applc.keio.ac.jp
† Present address: Antibiotics Laboratory, Discovery Research Insti-
tute, RIKEN (The Institute of Physical and Chemical Research),
2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.083

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T. Terauchi et al. / Tetrahedron Letters 44 (2003) 7747–7751
prepared in five steps from the known alcohol 17.11
That is, o-iodoxybenzoic acid (IBX) oxidation12 fol-
lowed by the Brown’s diastereoselective
isoprenylation13 produced alcohol 18 in high
diastereomeric excess (>98%). Epoxide formation
smoothly proceeded using the usual three-step sequence
to furnish 19 in 35% overall yield from 17. Treatment
of 19 with lithiated 16 produced the coupling product
20 in 84% yield based on the recovered 19 (62%). A
longer reaction time and/or higher temperature caused
the decomposition of 20 in the coupling reaction.
Removal of acetonide and dithioacetal followed by
acid-catalyzed spiroacetallization proceeded in 34%
yield. Sequential protection of the C5 and C9 hydroxy
groups gave the fully protected spiroacetal 21 in 82%
yield.
Finally,
the
palladium(0)-catalyzed
hydrostannation14 of 21 furnished crotylstannane 8 in
58% yield, which was identical with the sample pre-
pared by the method in Scheme 1. The stereochemistry
of the trisubstituted olefin in 8 was determined to be Z
based on the NOE studies. The synthesis of 8 was thus
achieved in 21 total steps. Although there is still room
for improvement of this synthesis, we believe that the
synthetic route described herein is straightforward.
The crucial fragment assembly was achieved via the
crotylstannane–aldehyde coupling of 8 with 92 in the
presence of BF3·OEt2 to furnish bis-spiroacetal 22 in
30% yield as a single adduct (Scheme 3). On the other
hand, the coupling of 8 with 10,6b,15 which has the
a-OMPM group at C17, yielded 23 in 83% yield as a
single adduct. In order to unambiguously confirm the
stereochemistry, we tried to transform the coupling
product 22 into the Smith’s ABCD fragment 25,16 the
intermediate of the total synthesis of altohyrtin C,
through keto-aldehyde 24 in several steps (Scheme 4).
Unfortunately, the obtained product was not identical
Figure 2.
1
with 25 based on the H NMR spectrum. Moreover,
the coupling product 23 led to 24, indicating that 23
also had the undesired configurations. On the basis of
these results and the general rule for crotylstannane–
aldehyde couplings,4,5 the stereochemical consequence
of 22 and 23 was supposed to be C14,15-syn and
5
C15,16-syn. We tried to use Bu2SnCl2 and MgBr2 to
obtain the correct stereochemistry, and found that the
desired coupling reaction did not proceed and only the
protodestannylation of 8 occurred in these cases. There-
fore, it was necessary to isomerize both the C14 and
C15 stereocenters. After Dess–Martin oxidation17 of the
C15 hydroxy group in 23, the resultant ketone 26 was
treated with excess K2CO3 in MeOH–H2O. Fortu-
nately, the desired epimerization at C14 did occur
under these conditions to give a 1:1 inseparable mixture
of C5-de-O-acetyl 2618 and 27. It is noteworthy that no
C16 epimerization18 and olefin isomerizaiton (i.e.
C13ꢀC15 enone formation) were observed. DIBALH
reduction of the mixture proceeded with high stereose-
lectivity and the resultant mixture was subjected to the
four-step sequence (acetylation of the C5 and C15
hydroxy groups, protection of the C9 hydroxy group as
TES ether, oxidative removal of the C1 and C17 MPM
ethers, and Dess–Martin oxidation of the resultant diol)
to afford a 1:1 separable mixture of 2818 and 29. Since
Scheme 1. Synthesis of the AB fragment 8. Reagents and
conditions: (a) vinylmagnesium bromide, ether, −40°C; (b)
Dess–Martin periodinane, pyridine, CH2Cl2, rt (73% for two
steps); (c) Cp2ZrCl2, Zn, CH2I2, THF, rt (75%); (d) PPTS,
CH2Cl2–MeOH, 0°C (70%); (e) Ac2O, Et3N, DMAP, CH2Cl2,
rt (84%); (f) n-Bu3SnH, Pd(PPh3)4, benzene, rt (58%).
ate yield (45%) and moderate enantiomeric excess
(60%). 1,3-syn-Selective reduction of 15 with
DIBALH10 followed by acetonide formation led to
acetonide 16 in 78% yield. The coupling partner 19 was

T. Terauchi et al. / Tetrahedron Letters 44 (2003) 7747–7751
7749
Scheme 2. New synthesis of the AB fragment 8. Reagents and conditions: (a) 13, (−)-Ipc2BCl, Et3N, CH2Cl2, −78°C to rt, then 14
(45%, 60% ee); (b) DIBALH, THF, −78 to −20°C (85%, >96% de); (c) 2,2-dimethoxypropane, PPTS, rt (92%); (d) IBX,
DMSO–THF, rt (82%); (e) isoprene, TMP, n-BuLi, t-BuOK, (−)-Ipc2BOMe, BF3·OEt2, THF, −78°C, then aldehyde, −78 to
−20°C; (f) HCl, MeOH, rt (72% for two steps, >98% de); (g) TsCl, Et3N, CH2Cl2, rt; (h) NaOH, Et2O, rt (60% for two steps);
(i) 16, n-BuLi, HMPA, Et2O, −40°C, then 19, THF, −40°C (84% based on recovered 19 (62%)); (j) 80% aq. AcOH, rt; (k) MeI,
CaCO3, acetone–H2O, 60°C; (l) PPTS, CH2Cl2, rt (34% for three steps); (m) Ac2O, Et3N, DMAP, CH2Cl2, rt (89%); (n) TESOTf,
2,6-lutidine, CH2Cl2, rt (92%); (o) n-Bu3SnH, Pd(PPh3)4, benzene, rt (58%). TMP=2,2,6,6-tetramethylpiperidine, TES=triethylsi-
lyl.
Scheme 3. Coupling of crotylstannane 8 and aldehyde 9 or 10.
the coupling constants (J=10.2, 2.8 Hz) of the
C14ꢀC16 region in the H NMR spectrum of 29 were
prepared allyl alcohol 306c (Scheme 5). Deprotection of
the silyl ether (TBAF) followed by the three-step
sequence (selective protection of the C44 hydroxy
group, removal of trityl group, and protection of the
resultant hydroxy group as TBDPS ether) gave diol 31
in 76% overall yield. Sequential silyl ether formation at
the C35 and C32 hydroxy groups smoothly proceeded.
Oxidative removal of the C30 MPM group followed by
silyl ether formation led to compound 32 in 71% overall
yield. Ozonolysis of the C34 exomethylene was fol-
lowed by the three-step sequence (methylacetal forma-
tion, removal of the benzyl groups using the Iadonisi
conditions,21 and silylation of the C41 and C42 hydroxy
groups) to produce the fully elaborated C29ꢀC44 frag-
ment 33 in 21% overall yield. Compound 33 was identi-
1
close to those of the Smith’s ABCD fragment 25 (J=
9.1, 3.4 Hz), we decided to convert 29 to 25. NaClO2
oxidation of 29 followed by the three-step sequence
(removal of TBDPS ether in the presence of TBS
ether,19 oxidation of the resultant C28 hydroxy group,
and the silyl ester formation) produced 25 in 31%
overall yield. All the spectroscopic data of 25 were
identical with those kindly provided by Professor
Smith.16
We then prepared the C29ꢀC44 (EF) fragment 33, the
intermediate20 that was also employed in the Smith’s
total synthesis of altohyrtin C, from our previously

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T. Terauchi et al. / Tetrahedron Letters 44 (2003) 7747–7751
Scheme 4. Synthesis of the ABCD fragment 25. Reagents and conditions: (a) Dess–Martin periodinane, pyridine, CH2Cl2, rt (88%);
(b) K2CO3, MeOH–H2O, rt; (c) DIBALH, CH2Cl2–hexane, −40°C; (d) Ac2O, Et3N, DMAP, CH2Cl2, rt; (e) TESOTf, 2,6-lutidine,
CH2Cl2, 0°C (83% for four steps); (f) DDQ, CH2Cl2–pH 7 phosphate buffer, rt; (g) Dess–Martin periodinane, pyridine, CH2Cl2,
rt (25% for 28, 25% for 29); (h) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH–H2O, rt; (i) TBAF, AcOH, THF, rt; (j)
Dess–Martin periodinane, pyridine, CH2Cl2, rt; (k) TIPSCl, Et3N, THF, rt (31% for four steps). TIPS=triisopropylsilyl.
Scheme 5. Synthesis of the EF fragment 33. Reagents and conditions: (a) TBAF, THF, 60°C (98%); (b) PivCl, DMAP, CH2Cl2,
0°C (96%); (c) HCO2H–Et2O (3:2), 0°C (81%); (d) TBDPSCl, imidazole, CH2Cl2, rt (100%); (e) TESOTf, 2,6-lutidine, CH2Cl2, −78
to 0°C (72%); (f) TBSOTf, 2,6-lutidine, CH2Cl2, rt (100%); (g) DDQ, CH2Cl2–pH 7 phosphate buffer, rt (98%); (h) TESOTf,
2,6-lutidine, CH2Cl2, rt (100%); (i) O3, CH2Cl2–MeOH, −78°C, then Me2S (95%); (j) PPTS, MeOH–THF, rt (72%); (k) KBrO3,
Na2S2O4, EtOAc–H2O, rt (30%); (l) TESOTf, 2,6-lutidine, CH2Cl2, −78°C (100%). Piv=2,2-dimethylpropionyl.

T. Terauchi et al. / Tetrahedron Letters 44 (2003) 7747–7751
7751
cal in all respects with that prepared by Smith and his
co-workers.20 Thus the syntheses of 25 and 33 consti-
tute a formal total synthesis of altohyrtin C.
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1
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