Synthetic studies on altohyrtins (spongistatins): Synthesis of the C29-C44 (EF) portion

Article abstract of DOI:10.1016/S0040-4039(01)01069-3

The C29-C44 portion of altohyrtins (spongistatins) has been prepared from 1,5-pentanediol and D-glucose in a stereoselective manner. The convergent synthesis relied on a coupling reaction of the C29-C37 vinyl bromide and the C38-C44 Weinreb amide, diaster

Full text of DOI:10.1016/S0040-4039(01)01069-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5505–5508
Synthetic studies on altohyrtins (spongistatins):
synthesis of the C29–C44 (EF) portion
Takeshi Terauchi, Masataka Morita, Kyoko Kimijima, Yasuhiro Nakamura, Gouichirou Hayashi,
Taisaku Tanaka, 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 28 May 2001; accepted 11 June 2001
Abstract—The C29–C44 portion of altohyrtins (spongistatins) has been prepared from 1,5-pentanediol and
D-glucose in a
stereoselective manner. The convergent synthesis relied on a coupling reaction of the C29–C37 vinyl bromide and the C38–C44
Weinreb amide, diastereoselective reduction of the C38 ketone, and stereoselective formation of the C33–C37 (E ring) acetal.
© 2001 Elsevier Science Ltd. All rights reserved.
In 1993, the Pettit,1 Kitagawa,2 and Fusetani3 groups
isolated and characterized potent antitumor macrolides,
designated as the spongistatins, altohyrtins, and
cinachyrolides, respectively (Fig. 1). These marine natu-
ral products comprise the most potent anticancer
agents identified.4 Their promising biological activity
and novel architecture have led to wide interest in the
synthetic community. To date, the Evans,5 Kishi,6 and
Smith7 groups have succeeded in the total syntheses of
members of this class. As part of our program directed
toward the total synthesis of altohyrtins,8 we have
developed the stereocontrolled synthesis of the C29–
C44 portion of altohyrtins.
Synthesis of 2 commenced with benzylation of the
known 410c followed by treatment with Ac2O and tri-
fluoroacetic acid to afford an anomeric mixture of diace-
tates 6a13 and 6b13 (Scheme 2). We then installed one
carbon unit corresponding to the C38 position; a mix-
ture of 6a and 6b was treated with trimethylsilyl cya-
nide in the presence of boron trifluoride etherate,14
yielding a mixture of cyanides 7a and 7b. Basic hydroly-
sis of the mixture and methyl ester formation (HCl–
MeOH) gave a separable mixture of the desired methyl
ester (91%) and its C39 epimer (9%). After protection
Me
Me
15
O
O
Our analysis for the synthesis of the C29ꢀC44 portion 1
commenced with disconnection of the C37ꢀC38 (alto-
hyrtins numbering) bond to generate two major sub-
units, i.e. the C38ꢀC44 (F) fragment 2 and the C29ꢀC37
(E) fragment 3 (Scheme 1). The Weinreb coupling9 of 2
and 3 would construct the C37ꢀC38 bond. We envi-
sioned that the C38ꢀC44 fragment 2 could be prepared
from the anhydrosugar derivative 4, which is available
OR2
OMe
HO
Me
C
D
B
A
O
O
O
R1O
HO
29
1
O
O
Me
OH
HO
Me
O
-glucose in eight steps,10,11 and the C29ꢀC37
OH
from
D
F
E
51
37
38
vinyl bromide 3 from 1,5-pentanediol (5) through
O
44
H
OH
OH
Brown crotylboration.12
X
Altohyrtin A (Spongistatin 1): X=Cl, R1=R2=Ac
Altohyrtin B: X=Br, R1=R2=Ac
Altohyrtin C (Spongistatin 2): X=H, R1=R2=Ac
Cinachyrolide A (Spongistatin 4): X=Cl, R1=Ac, R2=H
Keywords: altohyrtins; spongistatins; stereoselective synthesis; Wein-
reb coupling.
* Corresponding author. Tel.: +81-45-566-1577; fax: +81-45-566-1551;
e-mail: msynktxa@applc.keio.ac.jp
†
Present address: Antibiotics Laboratory, RIKEN (The Institute of
Physical and Chemical Research), 2-1 Hirosawa, Wako, Saitama
351-0198, Japan.
Figure 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01069-3

5506
T. Terauchi et al. / Tetrahedron Letters 42 (2001) 5505–5508
the Mandai–Otera protocol.16,17 That is, when alde-
29
OTBDPS
hyde 11 was added to the premixed, sonicated mix-
ture of 2,3-dibromopropene and Sn powder in
THF–EtOH–H2O (8:1:1), the desired alcohol 12 was
obtained as the major product (64%) along with the
undesired diastereomer (13%). The stereochemical
assignment of the newly generated stereocenter in 12
was established by observing NOEs after leading to
its p-methoxybenzylidene acetal derivative 13. Finally,
silylation of 12 provided the C29ꢀC37 vinyl bromide
3.
OBn
F
O
H
Me
BnO
Me
O
E
37
38
OTBS
44
OMe
OTBS
PivO
1
BnO
OTBS
OMPM
BnO
Me
Me
N
29
+
38
37
44
O
OMe Br
OTr
OH
H
O
Me
TBSO
2
3
With both fragments in hand, we next focused on the
coupling of the two fragments and the stereoselective
introduction of the C38 stereocenter (Scheme 4).
Treatment of 3 with t-BuLi in Et2O at −78°C gener-
ated the vinyl lithium reagent which was directly sub-
jected to the coupling with 2, leading to enone 14 in
77% yield. Stereoselective reduction of the C38 ketone
in 14 was accomplished by using the Luche condi-
tions;18,19 reduction of 14 with NaBH4 in the presence
of CeCl3 gave 15 with 18:1 stereoselectivity.20 We also
examined the coupling reaction of 3 with aldehyde
17, which was prepared by DIBALH reduction of 8
in 86% yield, in order to obtain allyl alcohol 15 in
one-step. However, in all cases attempted,21 the
Felkin adduct 16, which has the undesired stereo-
chemistry at the C38 stereocenter was obtained as the
major product.
OH
HO
BnO
Me
5
O
O
4
Scheme 1. Retrosynthetic analysis.
OH
O
OH
O
OBn
O
HO
HO
OH
OH
BnO
ref. 10
Me
BnO
AcO
Me
X
a - c
O
D-glucose
4
6ab, X=OAc
7ab, X=CN
Conversion of 15 into 19 was then achieved in seven
steps through 18. It should be mentioned that the
acid-stable protecting group on the C29 hydroxy
group is critical to the cyclization of the E ring.
When the intermediate having the free C29 hydroxy
group or having trityl group on the C29 hydroxy
group was used for the cyclization, only a small
amount of the desired bis(tetrahydropyran) was
obtained. Temporary protection of the C33 hydroxy
group as its triethylsilyl (TES) ether is also effective
for the cyclization (vide infra).
OBn
BnO
d - g
Me
38
X
44
39
O
8, X=OMe
2, X=N(OMe)Me
TBSO
O
Scheme 2. (a) BnBr, NaH, DMF, rt, 1.5 h (93%); (b) TFA,
Ac2O, 0°C, (a:b=3.5:1); (c) TMSCN, BF3·OEt2,
MeCN, 0°C, 2 h (100% for two steps: a:b=4.5:1); (d) 5 M
aq. NaOH, MeOH, reflux, 2 h; (e) HCl, MeOH, reflux, 5 h
(91% for two steps); (f) TBSCl, imidazole, DMF, rt, 1 h
(97%); (g) MeNH(OMe)·HCl, Me3Al, CH2Cl2, rt, 12 h
(98%).
1
h
Two more steps were needed to complete the synthe-
sis of the fully functionalized C29ꢀC44 fragment 1.
The C37 exo olefin was unmasked at this stage to the
carbonyl group by ozonolysis, producing ketone 20.
This ozonolysis could be carried out without the C33
TES group. But in that case, low yielding was
observed in the E ring cyclization. Finally, treatment
of 20 with PPTS in MeOH–THF afforded bis(tetra-
hydropyran) 1. NOE data shown in Scheme 4 con-
firmed the configuration of the C37 stereocenter and
the conformation of the E ring.
of the primary alcohol as its t-butyldimethylsilyl
(TBS) ether, the resulting
8
was subjected to
transamidation using the Weinreb procedure9 to
provide the C38ꢀC44 fragment 2.
Synthesis of 3 began with monotritylation of 1,5-pen-
tanediol (5) followed by PCC oxidation, yielding alde-
hyde 9 (Scheme 3). The Brown crotylboration12 of 9
afforded alcohol 10 in 90% ee15 and 68% yield from
1,5-pentanediol. Protection of the secondary hydroxy
group in 10 as its p-methoxybenzyl (MPM) ether fol-
lowed by successive oxidations of the terminal olefin
afforded aldehyde 11. Stereoselective introduction of
the 2-bromo-2-propenyl group was achieved by using
In summary, we have accomplished the convergent
synthesis of the C29ꢀC44 portion of altohyrtins. The
Weinreb coupling and the following Luche reduction
were used to set the C38 stereocenter with high
stereoselectivity. Coupling of this fragment with the
C45ꢀC51 side chain and completion of the synthesis
will be reported in due course.

T. Terauchi et al. / Tetrahedron Letters 42 (2001) 5505–5508
5507
O
OH
O
OMPM
a,b
d,e,f
c
HO
OH
H
OTr
OTr
H
OTr
Me
Me
5
9
10
11
MP
Me
O
OR OMPM
Me
O
O
H
29
O
Br
MP
g,h
i
37
12
Br
OTr
OTr
H
Br
H
H
Me
13
12%
9%
12, R=H
3, R=TBS
13%
: NOE
Scheme 3. (a) TrCl, triethylamine, CH2Cl2, 0°C, 1 h (96% from TrCl); (b) PCC, MS4AP, CH2Cl2, rt, 1.5 h; (c) cis-2-butene,
n-BuLi, t-BuOK, (−)-Ipc2BOMe, BF3·OEt2, THF, −78°C, then 9, −78°C (71% for two steps); (d) MPMCl, NaH, DMF, rt, 3 h
(93%); (e) OsO4, N-methylmorpholine N-oxide, acetone–H2O (6:1), rt, 2 days (94%); (f) Pb(OAc)4, benzene, rt, 0.5 h (96%); (g)
2,3-dibromopropene, Sn powder, THF–EtOH–H2O (8:1:1), rt, sonication, 4 h (64% for 12, 13% for its C35 epimer); (h) TBSOTf,
,
2,6-lutidine, CH2Cl2, 0°C, 0.5 h (96%); (i) DDQ, PhH, rt, 45 min (78%). MS4AP=molecular sieves 4 A powder, Ipc=isopinocam-
pheyl, MP=p-methoxyphenyl.
OBn
O
OBn
OTBS
OMPM
Me
BnO
OTBS
OMPM
BnO
XO
Me
a - e
+
29
38
X
Br
OTr
O
H
OTr
Me
TBSO
O
Y
Me
2, X=N(OMe)Me
17, X=H
3
14, X=TBS, Y=O
15, X=TBS, Y=β-OH, α-H
16, X=TBS, Y=α-OH, β-H
18, X=Piv, Y=β-OTBS, α-H
2%
Me
29
O
H
H33
OBn
OTBDPS
OBn
TBSO
O
33
Me
OTBS
OTES
BnO
PivO
Me
BnO
Me
k
f - j
X
O
29
36
37
33
44
OTBS
O
H
OTBDPS
O
H
3
OMe
OTBS
H36
Me
16%
OTBS
Me
PivO
: NOE
1
19, X=CH2
20, X=O
Scheme 4. (a) 3, t-BuLi, Et2O, −78°C, 5 min, then 2, −78°C, 20 min (77%); (b) NaBH4, CeCl3·7H2O, EtOH–THF (4:1), rt, 1 h
(71% for 15, 4% for 16); (c) TBAF, THF, 60°C, 2 h (98%); (d) PivCl, DMAP, CH2Cl2, 0°C, 1 h (96%); (e) TBSOTf, 2,6-lutidine,
CH2Cl2, rt, 0.5 h (99%); (f) HCO2H–Et2O (3:2), 0°C, 10 min (89%); (g) TBDPSCl, imidazole, DMF, rt, 0.5 h (94%); (h) DDQ,
CH2Cl2–pH 7 phosphate buffer (10:1), rt, 0.5 h (94%); (i) TESCl, imidazole, DMF, 60°C, 0.5 h (87%); (j) O3, CH2Cl2–MeOH
(2:1), −78°C, 10 min, then Me2S (91%); (k) PPTS, MeOH–THF (2:1), rt, 1 h (72%). Piv=2,2-dimethylpropionyl, TBDPS=t-
butyldiphenylsilyl.
References
A.; Trotter, B. W.; Coˆte´, B.; Coleman, P. J.; Dias, L. C.;
Tyler, A. N. Angew. Chem., Int. Ed. Engl. 1997, 36,
2744–2747; (d) Evans, D. A.; Trotter, B. W.; Coleman, P.
J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N.
Tetrahedron 1999, 55, 8671–8726.
1. Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.;
Boyd, M. R.; Schmidt, J. M.; Hooper, J. N. A. J. Org.
Chem. 1993, 58, 1302–1304.
2. Kobayashi, M.; Aoki, S.; Sakai, H.; Kawazoe, K.;
Kihara, N.; Sasaki, T.; Kitagawa, I. Tetrahedron Lett.
1993, 34, 2795–2798.
6. (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.
7. (a) Smith, III, A. B.; Zhuang, L.; Brook, C. S.; Boldi, A.
M.; McBriar, M. D.; Moser, W. H.; Murase, N.;
Nakayama, K.; Verhoest, P. R.; Lin, Q. Tetrahedron
Lett. 1997, 38, 8667–8670; (b) Smith, III, A. B.; Zhuang,
L.; Brook, C. S.; Lin, Q.; Moser, W. H.; Trout, R. E. L.;
3. Fusetani, N.; Shinoda, K.; Matsunaga, S. J. Am. Chem.
Soc. 1993, 115, 3977–3981.
4. Pettit, G. R. J. Nat. Prod. 1996, 59, 812–821.
5. (a) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2738–2741; (b) Evans, D.
A.; Trotter, B. W.; Coˆte´, B.; Coleman, P. J. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2741–2744; (c) Evans, D.

5508
T. Terauchi et al. / Tetrahedron Letters 42 (2001) 5505–5508
Boldi, A. M. Tetrahedron Lett. 1997, 38, 8671–8674; (c)
12. (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986,
108, 5919–5923; (b) Brown, H. C.; Bhat, K. S.; Randad,
R. S. J. Org. Chem. 1989, 54, 1570–1576.
13. Satisfactory analytical data (NMR and IR spectra, ele-
mental analyses and/or HRMS, optical rotations) were
obtained for all new compounds.
Smith, III, A. B.; Lin, Q.; Nakayama, K.; Boldi, A. M.;
Brook, C. S.; McBriar, M. D.; Moser, W. H.; Sobukawa,
M.; Zhuang, L. Tetrahedron Lett. 1997, 38, 8675–8678;
(d) Smith, III, A. B.; 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; (e) Smith, III, A. B.;
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.
14. Lo´pez, M.-T. G.; De las Heras, F. G.; Fe´lix, A. S. J.
Carbohydr. Chem. 1987, 6, 273–279.
15. Optical purity and the absolute configuration were deter-
mined by 1H NMR analysis after leading to its MTPA
esters, see: (a) Dale, J. A.; Mosher, H. S. J. Am. Chem.
Soc. 1973, 95, 512–519; (b) Sullivan, G. R.; Dale, J. A.;
Mosher, H. S. J. Org. Chem. 1973, 38, 2143–2147; (c)
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092–4096.
8. (a) Terauchi, T.; Nakata, M. Tetrahedron Lett. 1998, 39,
3795–3798; (b) Terauchi, T.; Terauchi, T.; Sato, I.;
Tsukada, T.; Kanoh, N.; Nakata, M. Tetrahedron Lett.
2000, 41, 2649–2653.
9. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815–3818.
16. Mandai, T.; Nokami, J.; Yano, T.; Yoshinaga, Y.; Otera,
J. J. Org. Chem. 1984, 49, 172–174.
10. (a) David, C.; Gesson, J. P.; Jacquesy, J. C. Tetrahedron
Lett. 1989, 30, 6015–6018; (b) Carlson, L. J. J. Org.
Chem. 1965, 30, 3953–3955; (c) Kochetkov, N. K.; Sviri-
dov, A. F.; Ermolenko, M. S.; Zelinsky, N. D. Tetra-
hedron Lett. 1981, 22, 4315–4318.
11. Sugar-based synthesis of the F ring, see: (a) Fernandez-
Megia, E.; Gourlaouen, N.; Ley, S. V.; Rowlands, G. J.
Synlett 1998, 991–994; (b) Kary, P. D.; Roberts, S. M.;
Watson, D. J. Tetrahedron: Asymmetry 1999, 10, 213–
216; (c) Kary, P. D.; Roberts, S. M. Tetrahedron: Asym-
metry 1999, 10, 217–219.
17. Kishi et al. used a similar reaction in their synthesis of
the C49ꢀC51 side chain of altohyrtin A. See Ref. 6b.
18. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
19. Samadi, M.; Munoz-Letelier, C.; Poigny, S.; Guyot, M.
Tetrahedron Lett. 2000, 41, 3349–3353 and references
cited therein.
20. The C38 stereochemistry was determined using the
modified Mosher’s method. See Ref. 15c.
21. In contrast to our results, Smith et al. and Kishi et al.
obtained the desired anti-Felkin product as the major
products in their C37ꢀC38 coupling. See Refs. 6b and 7a.
.