Total Synthesis of Altohyrtin A (Spongistatin 1): Part 2

Full text of DOI:10.1002/(sici)1521-3773(19980202)37:1/2<190::aid-anie190>3.0.co;2-0

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cyanocuprate[17] derived from 13, to yield the diol. After
cleavage of the silyl protecting groups, 14 was subjected to
NIS-induced dithiane deprotection to form the single spiro-
ketal 15 in good overall yield. Based on literature prece-
dent,[18] we anticipated spiroketal formation to be stereo-
selective in the desired sense; indeed, NOE experiments
(NOE ˆ nuclear Overhauser enhancement) confirmed this
configuration at the spirocenter. By routine synthetic oper-
ations the protecting groups of alcohols in 15 were then
adjusted resulting in tetraol 16. The protecting groups at the
C1 and C17 primary alcohols were differentiated, and the C9
tertiary alcohol was left unprotected. Since the requisite C5
and C15 acetates were compatible with the remaining
synthetic operations, they were installed at this juncture.[19]
The C15 acetyl group was found to migrate readily to the C17
primary alcohol once the TBS protecting group was removed.
Therefore, the C17 alcohol generated from 17 was immedi-
ately subjected without purification to Dess ± Martin oxida-
tion[20] to furnish aldehyde 18.
First, while ring-opening of 20 was accomplished with the
anion of TMS-acetylene allowing earlier incorporation of the
alkyne moiety, clean lithiation of the resultant dithiane
proved difficult. Second, deprotection of the dithiane group
(step f) resulted in a single methyl ketal, whose configuration
was tentatively assigned as indicated but was not established
experimentally. Third, the hydrostannylation of 25, followed
by NIS treatment, yielded mainly the expected product, along
with a small amount of its regio- and stereoisomers. Finally,
the C25 TBDPS protecting group was required for efficient
synthesis of 25 but the final deprotection to form altohyrtin A
(1) necessitated substitution to the more labile TBS protecting
group.
The completion of the synthesis of 32 is illustrated in
Scheme 4. The NiII/CrII-mediated coupling[12] of 26 with 18
proceeded smoothly to yield the two expected allylic alcohols,
which were oxidized to a,b-unsaturated ketone 27. After
hydrolysis to the C23 hemiketal, the crucial intramolecular
Michael cyclization was effected with Triton-B to furnish
spiroketal 28 with concomitant deprotection of the C1
methoxyacetate.[22] Out of four possible products, only one
diastereomer was isolated. ROESY data on the C1 TBS ether
of 28 clearly demonstrated the C19 stereocenter to be desired
but the C23 spirostereocenter to be undesired.[23, 24] In light of
recent work by Heathcock,[7b] the stereochemical outcome at
this spirocenter was not surprising. This stereocenter was
configurationally stable under acidic conditions with a
protected C25 alcohol, but was expected to epimerize readily
if the C25 alcohol was deprotected.[7b] Indeed, deprotection of
28 with HF ´ py in CH3CN provided a separable 1:1 mixture of
desired C23 diastereomer 30 and undesired 29, which could be
recycled efficiently under acidic conditions (HF ´ py/CH3CN
or CSA/CH2Cl2). Reprotection of the C1 and C25 alcohols
with TBSOTf proceeded without compromising the integrity
of C23 spiroketal stereocenter.
Scheme 3 summarizes the synthesis of the trans vinyl iodide
26.[21] The key reactions used in this sequence were funda-
mentally the same as those described for the synthesis of the
C1 ± C17 segment. However, several comments are in order.
O
S
MeO
S
b
a
e
S
S
20
21
O
MeO
OH OR
S
S
HO
OR
18
28
19
24 (R=TBDPS)
O
O
O
O
OR
c
d
I
OR
OR
NMR (NOE) data on the C1 TBS-ether of 31 clearly
demonstrated the desired configurations at C19 and C23.[23,24]
Selective deprotection of the C1 TBS group, followed by
syn/anti >20:1
22 (R=TBDPS)
23 (R=TBDPS)
[26]
TPAP[25] oxidation, NaClO2 oxidation, TBDPSCl protec-
OTBDPS
O
H
O
OMPM
OMe
28
tion,[27] and finally cleavage of the C28 protecting group with
DDQ[28] furnished the desired product. Interestingly, a small
amount of the C23 epimeric spiroketal was isolated during the
DDQ deprotection step. Finally, Dess ± Martin oxidation of
the C28 primary alcohol furnished 32, the ABCD unit of the
target.
H
O
g
f
OMe
24
TBDPSO
TBSO
MeO
MeO
I
18
25
26
Scheme 3. Synthesis of the C18 ± C28 fragment: a) Et3N, TBSCl, DMAP,
CH2Cl2, 90%; 1,3-dithiane, nBuLi, THF, 208C, then DMPU, then
epoxide, THF, 78 ! 208C, 83%; TBAF, THF, quant.; NaH, THF, 08C,
Ts-im, 08C, 79%; b) CuCN, vinyllithium, 788C, then 20, THF, 20 !08C,
85%; NaH, MeI, THF, 08C, 90%; c) Et3N, TBDPSCl, DMAP, CH2Cl2,
90%; CuCN, vinyllithium, 788C, then epoxide, Et2O, 30 !08C, 92%;
nBuLi, Et2O, BOC ON, THF, 78 !208C, 96%; IBr, PhMe, 78 !08C,
78%; d) K2CO3, MeOH, 78%; imidazole, TBDPSCl, CH2Cl2, 91%; e)
tBuONa, nBuLi, pentane, 0 !208C, then 788C, 21, THF, 788C, then 23,
THF, 78 ! 208C, 54% and 44% recovered 23; f) TBAF, THF, 08C,
92%; Et3N, TBDPSCl, DMAP, CH2Cl2, 72%; NIS, CaCO3, MeOH, 08C,
78%; imidazole, TBDPSCl, CH2Cl2, 86%; NMO, OsO4, acetone/H2O;
NaIO4, MeOH/(pH 7 phosphate buffer), 0 !208C; DAMP, tBuOK, THF,
788C, then aldehyde, THF, 788C, 79% over 3 steps; g) nBu3SnH, AIBN,
toluene, 1058C, 67%; CaCO3, NIS, THF, quant.; TBAF, THF, 92%;
iPr2NEt, MPMOCH2Cl,[36] CH2Cl2, 98%; TBAF, THF, quant.; imidazole,
TBSCl, CH2Cl2, 99%.
Using the methods disclosed in the following communica-
tion, we completed the total synthesis of the C23 epimer of
altohyrtin A from intermediate 28 with the hope that the C23
stereocenter might be equilibrated to the natural configura-
tion. Although both altohyrtin A and its C23 epimer were
relatively stable under acidic conditions (HF ´ py/THF, CSA/
CH2Cl2, or HCl/CHCl3), there was no evidence of inversion at
the C23 stereocenter.[29] This experiment demonstrated that
the macrolactone prevents epimerization at the C23 position,
suggesting that the correct C23 configuration must be
installed prior to macrolactonization.
Received: November 17, 1997 [Z11165IE]
German version: Angew. Chem. 1998, 110, 198 ± 202
190
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O
H
O
OMPM
OMe
O
H
O
OMPM
O
H
O
OMPM
28
27
OMe
21
OMe
D
TBSO
H
HO
TBSO
HO
HO
H
MeO
O
O
1
26
18
19
RO
H
H
O
H
O
H
O
O
Me
Me
a
Me
b
c
O
H
O
H
15
O
O
O
A
Me
Me
Me
AcO
AcO
AcO
B
OAc
OAc
OAc
Me
OH
Me
OH
Me
OH
29
27 (R=MeOCH2CO)
28
28CHO
H
O
H
O
OMPM
O
H
O
OMPM
OMe
O
OMe
OMe
21
D
TBSO
HO
TBSO
HO
HO
H
C
1
24
O
O
O
TBDPSO2C
19
H
H
H
H
O
H
O
H
O
O
Me
Me
Me
e
d
O
H
O
H
O
O
O
A
Me
Me
Me
AcO
AcO
AcO
B
OAc
OAc
OAc
Me
OH
Me
OH
Me
OH
30
32
31
Scheme 4. Synthesis of the C1 ± C28 fragment: a) NiCl2/CrCl2, ( )-bispyridinyl ligand,[12c] THF, 86%; Dess ± Martin periodinane, py, CH2Cl2, 83%; b) PPTS,
acetone/H2O; Triton-B, MeOH/ MeOAc, 08C, 50% over 2 steps; c) HF ´ py, CH3CN, 25% (an additional 25% was obtained by equilibration of the C23
epimer 29 with CSA/CH2Cl2); d) 2,6-lutidine, TBSOTf, 788C, 79%; HF ´ py/py/THF, 82%; e) TPAP, NMO, 4 Š molecular sieves, CH2Cl2; NaClO2,
NaH2PO4, tBuOH/2-methyl-2-butene, 83% over 2 steps; Et3N, TBDPSCl, CH2Cl2, 82%; DDQ, CH2Cl2/H2O, 53%; Dess ± Martin periodinane, py, CH2Cl2,
81%.
5727 ± 5730; e) L. Paterson, D. J. Wallace, K. R. Gibson, ibid. 1997, 38,
8911 ± 8914; f) L. A. Paquette, D. Zuev, ibid. 1997, 38, 5115 ± 5118; g)
L. A. Paquette, A. Braun, ibid. 1997, 38, 5119 ± 5122, h) A. B. Smith, Q.
Keywords: altohyrtin ´ antitumor agents ´ natural products
´ spongistatin ´ total synthesis
Lin, K. Nakayama, A. M. Boldi, C. S. Brook, M. D. McBriar, W. H.
Moser, M. Sobukawa, L. Zhuang, ibid. 1997, 38, 8675 ± 8678, and
references therein.
[1] a) G. R. Pettit, Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd, J. M.
Schmidt, J. N. A. Hooper, J. Org. Chem. 1993, 58, 1302 ± 1304; b) G. R.
Pettit, Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd, J. Chem. Soc.
Chem. Commun. 1993, 1166 ± 1168.
[2] a) G. R. Pettit, C. L. Herald, Z. A. Cichacz, F. Gao, J. M. Schmidt,
M. R. Boyd, N. D. Christie, F. E. Boettner, J. Chem. Soc. Chem.
Commun. 1993, 1805 ± 1807; b) G. R. Pettit, C. L. Herald, Z. A.
Cichacz, F. Gao, M. R. Boyd, N. D. Christie, J. M. Schmidt, Nat. Prod.
Lett. 1993, 3, 239 ± 244; c) G. R. Pettit, Z. A. Cichacz, C. L. Herald, F.
Gao, M. R. Boyd, J. M. Schmidt, E. Hamel, R. Bai, J. Chem. Soc.
Chem. Commun. 1994, 1605 ± 1606.
à Â
[8] D. A. Evans, B. W. Trotter, B. Cote, P. J. Coleman, L. C. Dias, A. N.
Tyler, Angew. Chem. 1997, 109, 2957 ± 2961; Angew. Chem. Int. Ed.
Engl. 1997, 36, 2744 ± 2747.
[9] For this reason, we adopted the use of the name altohyrtin A in this
paper. As discussed in the following paper, altohyrtin A is identical to
spongistatin 1.
[10] T. D. Aicher, K. R. Buszek, F. G. Fang, C. J. Forsyth, S. H. Jung, Y.
Kishi, M. C. Matelich, P. M. Scola, D. M. Spero, S. K. Yoon, J. Am.
Chem. Soc. 1992, 114, 3162 ± 3164.
[11] D. P. Negri, Y. Kishi, Tetrahedron Lett. 1987, 28, 1063-1066.
[12] a) H. Jin, J.-i. Uenishi, W. J. Christ, Y. Kishi, J. Am. Chem. Soc. 1986,
108, 5644 ± 5646; b) K. Takai, M. Tagashira, T. Kuroda, K. Oshima, K.
Utimoto, H. Nozaki, ibid. 1986, 108, 6048 ± 6050; c) C. Chen, K.
Tagami, Y. Kishi, J. Org. Chem. 1995, 60, 5386 ± 5387, and references
therein.
[3] N. Fusetani, K. Shinoda, S. Matsunaga, J. Am. Chem. Soc. 1993, 115,
3977 ± 3981.
[4] a) M. Kobayashi, S. Aoki, H. Sakai, K. Kawazoe, N. Kihara, T. Sasaki,
I. Kitagawa, Tetrahedron Lett. 1993, 34, 2795 ± 2798; b) M. Kobayashi,
S. Aoki, H. Sakai, N. Kihara, T. Sasaki, I. Kitagawa, Chem.
Pharm. Bull. 1993, 41, 989 ± 991; c) M. Kobayashi, S. Aoki, I.
Kitagawa, Tetrahedron Lett. 1994, 35, 1243 ± 1246; d) M. Kobayashi,
S. Aoki, K. Gato, I. Kitagawa, Chem. Pharm. Bull. 1996, 44, 2142 ±
2149.
[13] Satisfactory spectroscopic data (1H and 13C NMR, MS, and others)
were obtained for all new compounds.
[14] Abbreviations used: AIBN ˆ 2,2'-azobisisobutyronitrile; BOC-ON ˆ
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile;
CSA ˆ 10-
[5] G. R. Pettit, Pure Appl. Chem. 1994, 66, 2271-2281.
camphorsulfonic acid; DAMP ˆ dimethyl(diazomethyl)phosphonate;
DDQ ˆ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; diketene acetone
adduct ˆ 2,2,6-trimethyl-4H-1,3-dioxan-4-one; DMAP ˆ 4-dimethyl-
aminopyridine; DMDO ˆ dimethyldioxirane; DMPU ˆ 1,3-dimeth-
[6] The spongistatins were shown to exhibit potent antimitotic activity
resulting from strong tubulin binding: R. Bai, G. F. Taylor, Z. A.
Cichacz, C. L. Herald, J. A. Kepler, G. R. Pettit, E. Hamel, Biochem-
istry 1995, 34, 9714 ± 9721.
[7] a) M. M. Claffey, C. H. Heathcock, J. Org. Chem. 1996, 61, 7646 ±
7647; b) C. J. Hayes, C. H. Heathcock, ibid. 1997, 62, 2678 ± 2679;
c) I. Paterson, R. M. Oballa, R. D. Norcross, Tetrahedron Lett.
1996, 37, 8581 ± 8584; d) I. Paterson, L. E. Keown, ibid. 1997, 38,
yl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone;
HMPA ˆ hexamethyl-
phosphoramide; HF ´ py ˆ hydrogen fluoride pyridine complex; B-I-
9-BBN ˆ B-iodo-9-borabicyclo[3.3.1]nonane; LDA ˆ lithium diiso-
propylamide; MPM ˆ para-methoxybenzyl; MsCl ˆ methanesulfonyl
Angew. Chem. Int. Ed. 1998, 37, No. 1/2
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191

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chloride; NCS ˆ N-chlorosuccinimide; NIS ˆ N-iodosuccinimide;
NMO ˆ N-methylmorpholine N-oxide; Piv ˆ pivaloyl; PPTS ˆ pyri-
dinium p-toluenesulphonate; TBAF ˆ tetrabutylammonium fluoride;
TBAI ˆ tetrabutylammonium iodide; TBDPS ˆ tert-butyldiphenyl-
silyl; TBS ˆ tert-butyldimethylsilyl; Tf ˆ triflate; TIPS ˆ triisopropyl-
silyl; TPAP ˆ tetrapropylammonium perruthenate; Ts-im ˆ para-
toluenesulphonyl imidazole; Ts2O ˆ para-toluenesulfonic anhydride.
[15] J. J.-W. Duan, A. B. Smith III, J. Org. Chem. 1993, 58, 3703 ± 3711.
[16] J. B. Nerenberg, D. T. Hung, P. K. Somers, S. L. Schreiber, J. Am.
Chem. Soc. 1993, 115, 12621 ± 12622.
Total Synthesis of Altohyrtin A
(Spongistatin 1): Part 2**
Matthew M. Hayward, Rebecca M. Roth,
Kevin J. Duffy, Peter I. Dalko, Kirk L. Stevens,
Jiasheng Guo, and Yoshito Kishi*
In the preceding communication we reported the synthesis
of the ABCD unit of altohyrtin A.[1] We will now present the
synthesis of the EF unit and the completion of a total synthesis
of altohyrtin A.
[17] B. H. Lipshutz, M. Koerner, D. A. Parker, Tetrahedron Lett. 1987, 28,
945 ± 948.
[18] P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon, Oxford, 1983, Chap. 1.
The first step in the retrosynthetic analysis of EF fragment
B was the C37 ± C38 bond disconnection. In the synthetic
direction, it was expected that this bond formation could be
realized by nucleophilic addition of glycal carbanion F to C38
aldehyde G, followed by acid-catalyzed methanolysis of the
resultant glycal. Fragment G was then disconnected into
carbanion I and glycal epoxide H, which should be available
from the corresponding glycal J.[2] We were particularly
interested in this disconnection strategy because of the
obvious structural similarity between F and J; F and J might
be synthesized with similar chemistry or even via a common
intermediate. These glycals could be prepared from the
corresponding acyclic precursors F' and J', which contain a
typical polypropionate/acetate arrangement of functional
groups. Among the many synthetic methods known for the
preparation of polypropionates/acetates, the chemistry devel-
oped by Roush et al.[3] and by Brown et al.[4] were chosen. The
proposed carbanion I, or its synthetic precursor, contained the
novel chlorodiene functionality which, to the best of our
knowledge, had never been synthesized before. It was
anticipated that the chlorodiene moiety could be incorporated
by the addition of an organometallic species, derived from 2,3-
dichloropropene, to aldehyde L, followed by dehydration.
As illustrated in Scheme 1, the E-ring building block was
synthesized by utilizing sequential crotyl- and allyl-boronate
chemistry.[5, 6] While both the Brown and Roush methods gave
the desired adducts, the Brown methodology was superior in
terms of stereoselectivity. After protection of the C35 alcohol
of 5 and cleavage of the C33 benzyl protecting group, 6 was
transformed into glycal 7 by means of a b-ketoester to
facilitate the thermally induced elimination. Finally, glycal 7
was converted into iodoglycal 8 with the method developed by
Freisen;[7] the TIPS protecting groups at C29 and C35 were
required for clean lithiation of the glycal. Alternatively, 6 was
[19] Careful planning of the protecting group sequence allowed incorpo-
ration of an acetate on both the C5 and C15 alcohols (spongistatin 1)
or only on the C5 alcohol (spongistatin 4). Protection of the C9
tertiary alcohol was also possible with silyl groups.
[20] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 ± 4156.
[21] The cis vinyl iodide corresponding to 26 might be suitable for the
following key Michael cyclization, though this was not tested.
[22] The yields (50% to 80%) for the hydrolysis and subsequent Michael
addition depended on the protecting group arrangement. A substrate
bearing TBS groups on the C5, C9, and C15 alcohols and TBDPS on
the C25 alcohol gave the best result. One of the by-products isolated in
the case of 27 was the a,b-unsaturated ketone resulting from
elimination of the C15 acetate.
[23] These experiments were performed by Dr. Yuan Wang at Eisai
Research Institute, Andover, Massachussetts.
[24] For the C1 TBS ether of 28, distinct NOEs between the C19 and C21
protons and between the C27 and C22(eq) protons were observed. For
the C1 TBS ether of 31, distinct NOEs between the C19 and C21
protons and between the C19 and C24(eq) protons were observed.
[25] a) W. P. Griffith, S. V. Ley, G. P. Whitcombe, A. D. White, J. Chem.
Soc. Chem. Commun. 1987, 1625 ± 1627; b) S. V. Ley, J. Norman, W. P.
Griffith, S. P. Marsden, Synthesis 1994, 639 ± 666.
[26] G. A. Kraus, M. J. Taschner, J. Org. Chem. 1980, 45, 1175 ± 1176.
[27] The Wittig reaction was also studied with the aldehyde bearing the
unprotected carboxylic acid at C1; the olefination did yield the desired
product but in much poorer yield.
[28] K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O. Yonemitsu,
Tetrahedron 1986, 42, 3021 ± 3028.
1
[29] The most diagnostic H NMR signals to distinguish altohyrtin A and
its C23 epimer were the C28 ± C29 olefinic protons; these signals in
altohyrtin A were observed at d ˆ 5.36 and 5.35 ([D6]DMSO), where-
as those in the C23 epimer were at d ˆ 5.80 and 5.37.
[30] a) T. Mukhopadhyay, D. Seebach, Helv. Chim. Acta 1982, 65, 385 ±
391; b) B. H. Lipshutz, H. Kotsuki, W. Lew, Tetrahedron Lett. 1986, 27,
4825 ± 4828.
[31] B. H. Lipshutz, E. Garcia, Tetrahedron Lett. 1990, 31, 7261 ± 7264.
[32] D. R. Hicks, B. Fraser-Reid, Synthesis 1974, 203.
[33] V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976, 23,
1973 ± 1976.
[34] a) D. Seyferth, R. S. Marmor, P. Hilbert, J. Org. Chem. 1971, 36, 1379 ±
1386; b) J. C. Gilbert, V. Weerasooriya, ibid. 1982, 47, 1837 ± 1845; c)
For a more convenient preparation of the DAMP reagent, see: D. G.
Brown, E. J. Velthuisen, J. R. Commerford, R. G. Brisbois, T. R. Hoye,
ibid. 1996, 61, 2540 ± 2541.
[*] Prof. Y. Kishi, Dr. M. M. Hayward, R. M. Roth, Dr. K. J. Duffy,
Dr. P. I. Dalko, Dr. K. L. Stevens, Dr. J. Guo
Department of Chemistry and Chemical Biology
Harvard University
[35] S. Hara, H. Dojo, S. Takinami, A. Suzuki, Tetrahedron Lett. 1983, 24,
731 ± 734.
[36] A. P. Kozikowski, J.-P. Wu, Tetrahedron Lett. 1987, 28, 5125 ± 5128.
Cambridge, MA 02138 (USA)
Fax: Int. code ‡ (1)617495-5150
e-mail: kishi@chemistry.harvard.edu
[**] Financial support from the National Institutes of Health (CA-22215)
and Eisai Pharmaceutical Company is gratefully acknowledged. For
postdoctoral fellowships we thank the NIH (MMH; 5 F32 CA66299),
NATO (PID; 12B93FR) and the American Cancer Society (KLS; PF-
4423). We would like to thank Professor Motomasa Kobayashi for
providing an authentic sample of altohyrtin A. We thank Dr. Yuan
Wang and Dr. Bruce A. Littlefield (Eisai Research Institute, And-
over, MA, USA) for performing NMR experiments and bioassays,
respectively.
192
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Angew. Chem. Int. Ed. 1998, 37, No. 1/2

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OPG
OPG OH
Me
OPG
OHC
E
O
29
OPG
Me
-
OPG
MeO
HO
Me
29
E
H
O
P+Ph3I–
F
F'
38
38
H
H
O
CHO
Me
OPG
H
O
51
H
Me
F
OPG
51
OPG
H
F
Cl
OPG
OPG
Cl
OPG
B
G
OPG
Me
OPG
OPG
Me
OPG
H
O
H
OPG OH
OHC
O
OHC
OPG
L
-
Cl
Cl
OH
OPG
Me
O
Cl
K
I
H
J
J'
Cl
M
Figure. 1. Retrosynthesis of the C29 ± C51 fragment (EF unit). PG ˆ protecting group.
also obtained from intermediate 13, used in the F-ring
synthesis (Scheme 2).
OH
a
b
OHC
OTIPS
OTIPS
The same methods were used to construct the F-ring building
block 14. The TIPS protecting groups for the C38 and C41
alcohol in glycal 14 enhanced the stereoselectivity of epoxida-
tion with DMDO;[2] only epoxide 15 was detected by 1H NMR.
The synthesis of C44 ± C48 segment 18 is also included in
Scheme 2.[8] The C45 ± C46 bond was formed by cuprate
coupling between a-bromoacrolein diethyl ketal 16[9] and (R)-
TBS-glycidol 17 to afford the homoallylic alcohol. Acid
treatment in acetone allowed concomitant deprotection of the
TBS ether, formation of the acetonide, and hydrolysis of the
acetal to form the a,b-unsaturated aldehyde, which was
transformed into the allylstannane 18 in three steps.
Me
2
3
syn/anti %ee
Brown et al. >20:1
Roush et al. 10:1
90
66
OBn
OH OBn
c
OHC
OTIPS
OTIPS
35
33
Me
Me
4
5
syn/anti %ee
Brown et al. 14:1
Roush et al. 2:1
>90
76
d
Simple alkyl cuprate addition to a glycal epoxide was first
reported by this group.[10] The present case required the
addition of a highly functionalized allylic derivative. Although
methallyl cuprates readily added to 15, allyl cuprates bearing
the C47 and C48 functionalities exhibited greatly diminished
reactivity towards epoxide 15. Among a variety of allylstan-
nanes prepared and tested, only acetonide allylstannane 18
gave satisfactory results. While an excess of 18 was required to
drive the reaction to completion, it was readily recovered
from the crude reaction mixture. In this fashion, 19 was
obtained in good yield with high stereoselectivity. As noted
previously,[1] the C41 and C42 alcohols were masked with
identical protecting groups followed by manipulation at C47
and C48 to allow for oxidation to aldehyde 21.
TIPSO
OH
TIPSO
OH
g
OTIPS
OTIPS
Me
Me
6
13
e
OTIPS
Me
OTIPS
Me
f
29
37
O
OTIPS
I
O
OTIPS
H
H
7
8
Scheme 1. Synthesis of the C29 ± C37 fragment: a) ( )-Ipc2-(Z)-crotyl
boronate,[4b] THF, 788C, 65%; b) NaH, BnBr, TBAI, THF, 0 !208C,
97%; NMO, OsO4, THF/H2O; NaIO4, MeOH/H2O, 0 !208C; c) ( )-Ipc2-
Although no methodology existed to install the chloro-
diene, it was known that allylindium species prepared from
allylic halides react with aldehydes under mild conditions.[11]
Coupling of the allylindium reagent derived from 2,3-dichloro-
propene[12] with aldehyde 21 cleanly afforded the two
homoallylic alcohols, which were then dehydrated with
Martinꢁs sulfurane[13] to afford exclusively the trans-chloro-
diene in high overall yield. Cleavage of the C38 TBS
protecting group, followed by Swern oxidation of the primary
alcohol, furnished aldehyde 22.
allyl boronate,[4a] PhMe,
788C, 64% over 3 steps; d) 2,6-lutidine,
TIPSOTf, CH2Cl2, 0 !208C; Li/NH3, THF, 788C, 81% over 2 steps; e)
NMO, OsO4, THF/H2O; NaIO4, MeOH/H2O, 0 !208C; Et3N, diketene
acetone adduct, hexanes, 708C; 1258C, 0.2 Torr, 54% over 4 steps; f) tBuLi,
THF, 78 ! 308C, then Bu3SnCl, 78 !208C; K2CO3, NIS, THF, 08C,
75% over 2 steps; g) Et3N, MsCl, Et2O; HF ´ py/py/THF, 61% over 2 steps
(an additional 15% was obtained by recycling the bis-silylated starting
material once); KOH, MeOH, 92%; sulfone,[30] nBuLi, 78 !208C, 87%;
Li/NH3, THF, 788C, 85%.
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193

COMMUNICATIONS
TIPSO
OH
OH
OBn
OH OBn
a
b
c
d
OTIPS
OHC
OTIPS
OTIPS
OHC
OTIPS
OTIPS
Me
Me
Me
Me
9
10
11
12
13
anti/syn %ee
syn/anti %ee
Brown et al.
Roush et al.
16:1
20:1
87
66
Brown et al.
Roush et al. 5.5:1
5:1
>90
80
e
OTIPS
Me
OTIPS
OTBS
Me
OTIPS
Me
OTIPS
Me
38
H
O
H
O
H
H
O
Me
Me
O
Me
O
Me
i
f
h
O
O
H
H
41
42
O
OMPM
OTIPS
OH
OTIPS
O
OMPM
20
19
15
14
j
Me
SnBu3
Me
O
O
OEt
OEt
g
+
Br
OTBS
Me
38CHO
O
TBSO
38
H
46
H
Me
k
TIPSO
OHC
O
TIPSO
O
18
17
16
H
H
OMPM
OMPM
OMPM
51
Cl
OMPM
21
22
Scheme 2. Synthesis of the C38 ± C51 fragment: a) (S,S)-diisopropyl-(E)-crotyl boronate,[3b] PhMe, 788C, 80%; b) NaH, BnBr, TBAI, THF, 0 !208C,
84%; NMO, OsO4, THF/H2O; NaIO4, MeOH/H2O, 0 !208C; c) (R,R)-diisopropyl-allyl boronate,[3a] PhMe, 788C, 74% over 3 steps; d) 2,6-lutidine,
TIPSOTf, CH2Cl2, 0 !208C; Li/NH3, THF, 788C, 80% over 2 steps; e) NMO, OsO4, THF/H2O; NaIO4, MeOH/H2O, 0 !208C; Et3N, diketene acetone
adduct, hexanes, 708C; 1258C, 0.2 Torr, 61% over 4 steps; f) DMDO,[31] CH2Cl2/acetone, 108C, quant.; g) 16, nBuLi, Et2O, 788C, then CuI, Et2O, 788C,
then 17, 78 !208C, 65%; TsOH ´ H2O, acetone, 64%; CeCl3 ´ H2O, CH2Cl2/MeOH, then 788C, NaBH4, 83%; Ph3P, NCS, CH2Cl2, 08C, 95%; Bu3SnLi,[32]
THF, 788C, 81%; h) Me2Cu(CN)Li2, 18, 08C, then 15, 43 ! 158C, 70%;[33] i) TBAF, THF, quant.; TBSCl, DMAP, CH2Cl2/Et3N, 91%; KH, MPMCl,
DMF/THF, 0 !208C, 81%; j) ZnBr2, H2O, CH2Cl2, 56% and an additonal 5% on resubmission of recovered starting material; PivCl, DMAP, CH2Cl2/py,
80%; 2,6-lutidine, TIPSOTf, CH2Cl2, 91%; LAH, THF, 788C, 61% and an additonal 6% on resubmission of recovered starting material; oxalyl chloride,
DMSO, CH2Cl2, 788C, Et3N, 78 !08C, 95%; k) In, 2,3-dichloropropene, NaI, DMF, then 21; Martinꢁs sulfurane, CH2Cl2, 85% over 2 steps; HF ´ py/py/
THF, 76% and an additonal 10% on resubmission of recovered starting material; oxalyl chloride, DMSO, CH2Cl2, 788C, 10 min, alcohol, Et3N, 78 !08C,
89%.
The crucial coupling of the E- and F-ring building blocks
(Scheme 3) was envisioned to arise from the addition of an E-
ring nucleophile to the highly functionalized aldehyde 22.
Studies on model compounds suggested the importance of a
chelation-controlled addition to obtain the desired config-
uration at C38.[14] Thus, the novel Grignard reagent was
prepared by treatment of 8 with tert-butyllithium, followed by
addition of magnesium dibromide, and was coupled with
aldehyde 22 to furnish the desired alcohol 23 in excellent yield
and with high stereoselectivity.[15] Attempts to form the
methyl ketal directly from glycal 23 by addition of acidic
methanol resulted in undesired Ferrier-type rearrangements.
However, a two step procedure involving iodomethanolysis[16]
and reductive dehalogenation gave a satisfactory result.
Addition of bromobenzene allowed for selective reduction
of the alkyl iodide in the presence of the chlorodiene. The
configuration of the C38 alcohol was established by modified
Mosher ester analysis on the methyl ketal of 23.[17, 18] The TIPS
protecting groups at C29, C35, C47 were switched to the more
labile TBS groups at this stage.[19] After selective cleavage of
the primary C29 TBS group, 24 was converted into phospho-
nium salt 25. The methyl ketal present at C37 was prone to
elimination to form the corresponding glycal under thermal
and acidic conditions. This side reaction was significantly
suppressed by addition of methanol.
tion protocol[20] for Wittig olefination to afford the cis-olefin
26 (JH28,H29 ˆ 10.0 Hz). DDQ cleavage[21] of the C41 and C42
MPM protecting groups occurred with concomitant, but
incomplete, hydrolysis of the methyl ketal. Fluoride induced
removal of the silyl ester and macrolactonization under the
Yamaguchi conditions[22] proceeded smoothly to furnish the
desired macrolactone 27. As anticipated,[1] macrolactonization
occurred selectively at the C41 alcohol.[23] At this stage the
unhydrolyzed C37 methyl ketal could be separated from the
lactol.[24] Finally, cleavage of the three TBS protecting groups
in 27 furnished synthetic altohyrtin A (or spongistatin 1; 1).[25]
The synthetic material was found to be identical (1H NMR in
[D6]DMSO and CD3CN, MS, [a]D, TLC) with the authentic
sample kindly provided by Professor Motomasa Kobayashi at
Osaka University. In addition, the synthetic and natural
materials exhibited the same biological activity.[26,27] It is
exciting and intriguing to note that the C23 epimer of
alothyrtin A[1] also exhibits potent cytotoxicty.[26, 27]
In summary, this synthesis has firmly established the
relative and absolute configuration proposed for altohyrtin A
by the Kitagawa group. To the best of our knowledge, there
has been no direct comparison of altohyrtin A and spongi-
1
statin 1. However, comparison of the H NMR spectra for
both authentic and synthetic altohyrtin A with the spectrum
(CD3CN) of spongistatin 1 deposited in the supplementary
material by Pettit[28] presents a convincing case that they are
indeed the same compound. Thus, this work resolves the
As shown in Scheme 4, 25 and 32 (synthesis described in the
preceding communication) were coupled by utilizing a titra-
194
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COMMUNICATIONS
OTIPS
Me
25
a
OTBS
Me
29
37
32
(previous
I
O
OTIPS
H
MeO
HO
communication)
a
38CHO
8
O
H
H
O
H
H
Me
Me
TBSO
TIPSO
O
O
H
51
H
41
OMe
OMPM
TBSO
OMPM
OMPM
O
1 CO2TBDPS
Cl
Cl
OMPM
22
H
OTIPS
H
O
b
Me
Me
O
H
O
Me
HO
H
AcO
O
OTIPS
38
OAc
H
Me
b
TIPSO
O
Me
OH
H
OMPM
26
Cl
OMPM
OR
Me
23
HO
HO
OTBS
O
30
H
H
H
O
40
Me
Me
RO
O
MeO
HO
H
OMe
50
O
H
Me
OTBS
O
c
RO
H
O
20
Cl
OH
TBSO
O
O
H
H
H
O
O
OMPM
OMPM
Me
H
Cl
O
Me
AcO
24
10
OAc
OTBS
Me
27: R=TBS
1: altohyrtin A (R=H)
Me
OH
c
MeO
HO
29
O
P+Ph3I–
H
H
O
Scheme 4. Synthesis of altohyrtin A (spongistatin 1): a) LDA, THF/
HMPA, 58C, 40%; b) DDQ, CH2Cl2/H2O, 60% as a 3:2 mixture of
hemiketal and methyl ketal; KF, MeOH; Et3N, 2,4,6-trichlorobenzoyl
chloride, PhMe, then DMAP, 50% as a 3:2 mixture of hemiketal and
methyl ketal; c) HF ´ py/py/THF, 20 ± 30%.[25]
Me
TBSO
51
H
OMPM
OMPM
25
Scheme 3. Synthesis of the C29 ± C51 fragment: a) 8, tBuLi, Et2O, 788C,
then MgBr2, 22,
Cl
78 ! 508C, 78%; b) NIS, CaCO3, MeOH/THF/
[3] a) W. R. Roush, A. E. Walts, L. K. Hoong, J. Am. Chem. Soc. 1985,
107, 8186 ± 8190; b) W. R. Roush, K. Ando, D. B. Powers, A. D.
Palkowitz, R. L. Halterman, ibid. 1990, 112, 6339 ± 6348.
[4] a) H. C. Brown, K. S. Bhat, J. Am. Chem. Soc. 1986, 108, 5919 ± 5923;
b) P. K. Jadhav, K. S. Bhat, P. T. Perumal, H. C. Brown, J. Org. Chem.
1986, 51, 432 ± 439.
CH3CN/HC(OMe)3, 0 !208C, 81%; Bu3SnH, AIBN, THF/PhBr, 808C,
54% and an additional 16% on resubmission of recovered starting
material; TBAF, THF, 76%; imidazole, TBSCl, DMF, 75%; c) HF ´ py/
py/THF/MeOH, 78%; Ts2O, DMAP, CH2Cl2/iPr2NEt, 75%; NaI, acetone/
iPr2NEt, 85%; Ph3P, CH3CN/MeOH, 808C, 75% and an additonal 10% on
resubmission of recovered starting material.
[5] Satisfactory spectroscopic data (1H and 13C NMR, MS, and others)
were obtained for all new compounds.
[6] For abbreviations used, see reference 14 in ref. [1] (preceding
communication).
[7] a) R. W. Friesen, C. F. Sturino, A. K. Dalijeet, A. Kolaczewska, J. Org.
Chem. 1991, 56, 1944 ± 1947; b) R. W. Friesen, R. W. Loo, ibid. 1991,
56, 4821 ± 4823.
[8] The allylstannane was also prepared by an alternative synthetic route:
addition of the 1,3-dithiane anion to TBS-glycidol, followed by
cleavage of the TBS protecting group and acetonide formation,
yielded the functionalized 1,3-dithiane, which was further lithiated and
trapped with DMF. Reduction of the resultant aldehyde, followed by
TBS-protection, dithiane deprotection, Wittig-olefination, and TBS-
deprotection, gave an allyl alcohol, which was converted into 18 by
adopting the last two reactions of step g in Scheme 2).
[9] P. A. Grieco, C.-L. J. Wang, G. Majetich, J. Org. Chem. 1976, 41, 726 ±
729.
discrepancies in the configuration between altohyrtin A and
spongistatin 1, and we further speculate that configuration of
all the members in the spongipyran class of natural products is
represented by structure 1.[29]
Received: November 17, 1997 [Z11166IE]
German version: Angew. Chem. 1998, 110, 202 ± 206
Keywords: altohyrtin ´ antitumor agents ´ natural products
´ spongistatin ´ total synthesis
[10] L. L. Klein, W. W. McWhorter, Jr., S. S. Ko, K.-P. Pfaff, Y. Kishi, J.
Am. Chem. Soc. 1982, 104, 7362 ± 7364.
[11] a) S. Araki, H. Ito, Y. Butsugan, J. Org. Chem. 1988, 53, 1831 ± 1833; b)
S. Araki, T. Shimizu, P. S. Johar, S.-J. Jin, Y. Butsugan, ibid. 1991, 56,
2538 ± 2542.
[1] J. Guo, K. J. Duffy, K. L. Stevens, P. I. Dalko, R. M. Roth, M. M.
Hayward, and Y. Kishi, Angew. Chem. 1998, 109, 198 ± 202; Angew.
Chem. Int. Ed. Engl. 1998, 37, 187 ± 192.
[2] R. L. Halcomb, S. J. Danishefsky, J. Am. Chem. Soc. 1989, 111, 6661 ±
6666.
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[12] Example of 2,3-dihalopropenes used in organoindium reactions: X.-
H. Yi, Y. Meng, C.-J. Li, Tetrahedron Lett. 1997, 38, 4731 ± 4734.
[13] R. J. Arhart, J. C. Martin, J. Am. Chem. Soc. 1972, 94, 5003 ± 5010.
[14] Two alternative bond-forming reactions were examined on model
compounds. First, the NiII/CrII-mediated couplings of iodoglucals with
aldehydes proceeded smoothly to yield a diastereomeric mixture of
allylic alcohols; the major product was the undesired stereoisomer.
Second, addition of the 1,3-dithiane anion (THF, HMPA) of an acyclic
E-ring precursor to a model aldehyde gave the undesired dia-
stereomer as the major product.
[15] 1H NMR analysis of the crude product showed the stereoselectivity of
this coupling to be greater than 7:1. The minor undesired C38
diastereomer could be converted stereospecifically into the desired
isomer by oxidation with TPAP/NMO followed by Luche reduction.
[16] R. U. Lemieux, S. Levine, Can. J. Chem. 1964, 42, 1473 ± 1480.
[17] I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc.
1991, 113, 4092 ± 4096.
[18] The chemical shift differences of the (S)- and (R)-Mosher esters at
C38 were positive for the C33 ± C36 region and negative for the C39 ±
C51 region, demonstrating the desired absolute configuration at C38.
[19] Preliminary studies on deprotection of silyl-protected altohyrtin A
demonstrated that removal of the C35 TIPS group required prolonged
and detrimental exposure to HF ´ py (5days).
[20] R. W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka,
W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J.
Martinelli, W. W. McWhorter, Jr., M. Mizuno, M. Nakata, A. E. Stutz,
F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-i. Uenishi, J. B.
White, M. Yonaga, J. Am. Chem. Soc. 1989, 111, 7525 ± 7530.
[21] K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O. Yonemitsu,
Tetrahedron 1986, 42, 3021 ± 3028.
[22] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 ± 1993.
[23] COSY experiments demonstrated exclusive acylation of the C41
alcohol.
[24] While conversion of the C37 methyl ketal in the C37 lactol should be
facile, this has not been tested experimentally.
[25] The deprotection under the specified condition in Scheme 4 was very
clean (TLC analysis), but the yield of the isolated product was only in
the range of 20 ± 30%. It is not yet established whether this low yield is
due to a problem with isolation and/or with unidentified decompo-
sition/side-reactions.
[26] The bioassays were performed by Dr. Bruce Littlefield at Eisai
Research Institute, Andover, Massachussetts.
[27] The cytotoxicity was tested against DLD-1 human colon cancer, U937
human histiocytic lymphoma, and LOX human melanoma cells.
Details of these experiments shall be reported elsewhere.
[28] G. R. Pettit, Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd, J. M.
Schmidt, J. N. A. Hooper, J. Org. Chem. 1993, 58, 1302 ± 1304.
[29] Through the total synthesis of altohyrtin C (spongistatin 2), Evans has
à Â
reached the same conclusion: D. A. Evans, B. W. Trotter, B. Cote, P. J.
Coleman, L. C. Dias, A. N. Tyler, Angew. Chem. 1997, 109, 2957 ± 2961;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2744 ± 2747.
[30] The sulfone was derived from the addition of sodium benzene
sulfinate to the TIPS ether of 3-bromo-1-propanol.
[31] a) R. W. Murray, R. Jeyaraman, J. Org. Chem. 1985, 50, 2847 ± 2853;
b) W. Adam, J. Bialas, L. Hadjiarapoglou, Chem. Ber. 1991, 124,
2377.
[32] W. C. Still, J. Am. Chem. Soc. 1978, 100, 1481 ± 1487.
[33] B. H. Lipshutz, R. Crow, S. H. Dimock, E. L. Ellsworth, R. A. J.
Smith, J. R. Behling, J. Am. Chem. Soc. 1990, 112, 4063 ± 4064.
196
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