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

Full text of DOI:10.1002/(sici)1521-3773(19980202)37:1/2<187::aid-anie187>3.0.co;2-d

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eoselective ketene cycloaddition see: A. Kanazawa, P. Delair, M.
Pourashraf, A. E. Greene, J. Chem. Soc. Perkin Trans. 1 1997, 1911.
[9] B. M. Trost, M. Preckel, L. M. Leichter, J. Am. Chem. Soc. 1975, 97, 2224.
[10] Compound 17a (in contrast to the desired 17) undergoes partial
lactonization during workup. This lactone can be converted back to
17a. Epimer 17a can be recycled to the synthetic mainstream by
oxidation, followed by reduction of the common ketone. These
adjustments to the main synthetic stream will be reported in the full
paper.
[11] For a review of the Nozaki ± Kishi reaction see: P. Cintas, Synthesis
1992, 248. See also: M. Eckhardt, R. Brückner, Liebigs Ann. 1996, 473.
[12] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication no.
CCDC-100974. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB21EZ (fax:
int. code ‡(44)1223336-033; e-mail: deposit@ccdc.cam.ac.uk). No
claims, regarding absolute stereochemistry, are based on this data.
[13] Sarcodictyin and eleutherobin were recently synthesized: K. C.
Nicolaou, J.-Y. Xu, S. Kim, T. Ohshima, S. Hosokawa, J. Pfefferkorn,
J. Am. Chem. Soc. 1997, 119, 11353; K. C. Nicolaou, F. van Delft, T.
Ohshima, D. Vourloumis, J. Xu, S. Hosokawa, J. Pfefferkorn, S. Kim,
T. Li, Angew. Chem. 1997, 109, 2630; Angew. Chem. Int. Ed. Engl.
1997, 36, 2520.
protecting group, treatment of 22 with dimethyldioxirane
generates presumably an epoxide of type 9 (X ˆ H, OPiv; see
Scheme 1). Following suitable bond reorganizations, passing
through presumed diketone type 10, the pyranose derivative
23 was in hand. The predicted stereoselective nucleophilic
methylation of the keto function was achieved with methyl-
lithium, giving rise to 24. On treatment of the latter compound
with acetic anhydride, we took advantage of the fact that the
masked secondary alcohol at C8 could be selectively acety-
lated. This paved the way for cyclization of the tertiary alcohol
(corresponding to C7 of the future eleutheside) into the
carbonyl group of the enone of the open form, leading to
formation of compound 25. All structural assignments assert-
ed thus far, were corroborated by an X-ray crystallographic
determination of 25 (Figure 1).[12] Compound 25 has been
[14] Note added in proof: We have recently completed a synthesis of
eleutherobin: X.-T. Chen, B. Zhou, S. K. Bhattacharya, C. E. Gut-
teridge, T. R. R. Pettus, S. J. Danishefsky, Angew. Chem. and Angew.
Chem. Int. Ed., in press.
Total Synthesis of Altohyrtin A
(Spongistatin 1): Part 1**
Figure 1. Crystal structure of 25.
advanced in several directions, including the generation of the
flexible platform compound, ketone 26.
Jiasheng Guo, Kevin J. Duffy, Kirk L. Stevens,
Peter I. Dalko, Rebecca M. Roth,
Matthew M. Hayward, and Yoshito Kishi*
In summary, the novel chemical steps of particular interest
are: 1. the elongation and fragmentation of cyclobutanone 14,
2. the viability of 2-lithio-5-bromofuran as a readily available
and functionally differentiated furano nucleophile 7, 3. the
Nozaki ± Kishi reaction creating a highly strained cyclophane
(19 !20), and 4. the oxidative and ring ± chain tautomerism
manipulations leading to the differentiated eleutheside 25.
Preparations of the natural products and congeners for SAR
purposes are well underway.[13,14]
In 1993 three groups independently reported the isolation
and structural elucidation of a new class of macrolides
(spongipyran) derived from marine sponges of the genus
Spongia[1] and Spirastrella[2] (spongistatins 1 through 9),
Cinachyra[3] (cinachyrolide A), and Hyrtios[4] (altohyrtins
A ± C). These compounds displayed extraordinarily potent
cytotoxicity against a wide variety of cancer cell lines.[5, 6]
Structurally, spongistatin 1 appeared to be identical to alto-
hyrtin A and spongistatin 4 to cinachyrolide A, although no
definitive proof had been previously presented. The Kitagawa
group has proposed the complete structure of altohyrtin A[4c]
to be that shown in structure 1. However, this structure is in
conflict with the relative configuration proposed by the
Pettit[2b] and Fusetani[3] groups. In this and the following
communication, we report the first total synthesis of altohyr-
Received: November 3, 1997 [Z11110IE]
German version: Angew. Chem. 1998, 110, 195 ± 197
Keywords: antitumor agents ´ cyclophanes ´ eleuthesides ´
natural products ´ total synthesis
[1] D. J. Faulkner Nat. Prod. Rep. 1996, 13, 75.
[2] a) W. H. Fenical, P. R. Jensen, T. Lindel (UC), US Patent No. 5473057,
1995 [Chem. Abstr. 1996, 102, 194297z]; b) T. Lindel, W. H. Fenical,
P. R. Jensen, B. H. Long, A. M. Casazza, J. Carboni, C. R. Fairchild, J.
Am. Chem. Soc. 1997, 119, 8744.
[3] a) M. DꢁAmbrosio, A. Guerriero, F. Pietra, Helv. Chim. Acta 1987, 70,
2019; b) ibid. 1988, 71, 964.
[*] Prof. Y. Kishi, Dr. J. Guo, Dr. K. J. Duffy, Dr. K. L. Stevens,
Dr. P. I. Dalko, R. M. Roth, Dr. M. M. Hayward
Department of Chemistry and Chemical Biology,
Harvard University
[4] a) O. Kennard, D. G. Watson, Tetrahedron Lett. 1968, 2879; b) Y. Lin,
C. A. Bowley, D. J. Faulkner, Tetrahedron 1993, 49, 7977.
[5] D. T. Hung, T. F. Jamison, S. L. Schreiber, Chem. Biol. 1996, 3, 623.
[6] (R)-( )-a-Phellandrene 4 is available from Fluka Chemical Corp.
[7] For preparation see: M. A. Keegstra, A. J. A. Klomp, L. Brandsma,
Synth. Commun. 1990, 20, 3371. For use see: U. Wellmar, J. Heterocycl.
Chem. 1995, 32, 1159. For 2-iodo-5-(iodomagnesium) furan see: H.
Gilman, G. F. Wright, J. Am. Chem. Soc. 1933, 55, 3302. For 2-bromo-
5-lithiothiophene see: M.-J. Shiao, L.-H. Shih, W.-L. Chia, T.-Y. Chau,
Heterocycles 1991, 32, 2111.
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, as are
postodctoral fellowships from the American Cancer Society (K.L.S.;
PF-4423), NATO (P.I.D.; 12B93FR), and the NIH (M.M.H.; 5 F32
CA66299). We thank Dr. Yuan Wang (Eisai Research Institute,
Andover, MA, USA) for performing NMR experiments.
[8] For a ketene cycloaddition with a cyclohexadiene see the following: a)
M. L. Greenlee, J. Am. Chem. Soc. 1981, 103, 2425. For a diaster-
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OPG
Me
MeO
HO
29
E
O
P+Ph3I–
H
H
O
Me
40
OPG
51
H
F
OH
Me
OPG
Cl
OPG
HO
HO
29
E
O
28
B
H
H
O
H
40
Me
HO
O
51
H
28
F
OMe
D
CHO
O
H
HO
H
C
O
H
20
1
Cl
OH
O
OMe
O
D
H
O
O
PGO
Me
C
1
O
H
20
PGO2C
O
A
Me
H
O
O
AcO
B
Me
OAc
10
H
O
A
Me
OH
Me
AcO
B
OAc
10
Me
OH
1: altohyrtin A (spongistatin 1)
A
Figure 1. Retrosynthesis of altohyrtin A (spongistatin 1). PG ˆ protecting group.
tin A (spongistatin 1), which firmly establishes the relative
and absolute configuration proposed by Kitagawa.
18
28
I
OPG
All of the members in this class of natural products contain
a 51-carbon chain, 6 pyran rings, and a 42-membered lactone
ring. In addition, the most potent congeners (spongistatins 1,
4, 5, and 9)[5, 6] contain the novel chlorodiene functionality, which
had neither been seen in a natural product nor synthesized
before. We chose altohyrtin A (spongistatin 1) as our syn-
thetic target, due to its historical position in this class of
natural products, the availability of spectroscopic data from
OMe O
OH OH
E'
OPG
H
28
OPG
28
H
O
O
OMe
D
OMe
PGO
OHC
D
PGO
OH
two independent research groups, and finally its position as
the most cytotoxic congener. Several synthetic approaches to
the spongipyran class of natural products have been report-
ed,[7] and most recently a beautiful total synthesis of altohyr-
tin C (spongistatin 2) has been completed by Evans et al.[8]
Upon close examination of the spectroscopic data on
spongipyrans disclosed by the three groups, it became evident
that the correct relative and absolute configuration of
altohyrtin A was most likely that proposed by Kitagawa,[4c]
and thus we chose altohyrtin A (1) as the target for our total
synthesis.[9] In the retrosynthetic analysis, 1 was dissected into
the two segments A and B which could be joined by Wittig
olefination of the C29 phosphonium salt with the C28
aldehyde and subsequent macrolactonization of the C1
carboxylic acid with the C41 alcohol (Figure 1). It might be
expected that, to effect the proposed macrolactonization
selectively, the C41 alcohol must be differentiated from the
remaining alcohols, particularly the C42 alcohol. However, we
recognized the possibility that such macrolactonization might
take place preferentially at the C41 alcohol under controlled
conditions. Therefore, we chose to leave the C41 and C42
alcohols undifferentiated for synthetic simplicity.
A
Me Me
19
18
18
I
E
D
1
PGO2C
AcO
OAc
O
H
O
Me
Me
17
H
O
A
C
CHO
B
OAc
10
Me
OH
Me Me
10
1
17
PGO2C
CHO
Me OH
OH OAc
O
OH
AcO
D'
Figure 2. Retrosynthesis of the C1 ± C28 fragment.
NiII/CrII-mediated coupling[12] between fragments D and E,
followed by oxidation. The two building blocks D and E thus
obtained should be synthetically equivalent to their open
forms D' and E'. Two structural characteristics present in both
D' and E' are noteworthy. A typical polypropionate structure
is apparent in the C14 ± C17 unit, while a 1,3-syn-diol structure
is found repeatedly in the C3 ± C5, C9 ± C11, and C25 ± C27
units. The synthesis of these functionalities has been studied
extensively over the past few decades. We anticipated that,
coupled with a well-precedented regioselective ring-opening
Based on the precedents gained in the halichondrins[10] and
the polyether antibiotic ( )-A23187[11] syntheses, A was
envisioned to arise from the intramolecular Michael addition
of enone C (Figure 2). Enone C could be realized from the
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of terminal epoxides with nucleophiles, the synthesis of D' and
E' could be achieved by a combination of these methods.
Along this line of analysis, the C1 ± C12 segment was
synthesized as summarized in Scheme 1.[13, 14] The two key
reactions in this sequence were 1) regioselective ring-opening
of terminal epoxides with vinyl cuprates and dithiane anions,
and 2) stereoselective iodocarbonylation under the conditions
developed by Smith et al.,[15] followed by base treatment to
furnish the subsequent terminal epoxide.
The C13 ± C17 segment 13 was prepared from the known
alkene 12[16] (Scheme 2). The C12 ± C13 bond formation was
realized by ring opening of 11 with the higher order 2-thienyl
O
HO
TBDPSO
O
RO RO
(R=TBDPS)
S
a
b
c
BnO
BnO
BnO
BnO
S
syn/anti >20:1
2
3
4
5
O
Me OH
O
O
O
OTBS
Me
O
Me
d
e
f
OTBS
OTBS
I
OTBS
OEE
syn/anti >20:1
9
6
7
8
BnO
BnO
5
1
1
OTBDPS
OTBDPS
HO Me
g
h
TBDPSO
OTBS
TBDPSO
O
HO Me
S
S
OEE
12
12
S
S
9
10
11
Scheme 1. Synthesis of the C1 ± C12 fragment: a) CuCN, vinyllithium, 788C, then 2, 30 !08C, 90%; b) nBuLi, Et2O, 788C, BOC ON, THF, 0 !208C,
90%; IBr, PhMe, 78 !08C; K2CO3, MeOH, 73% over 2 steps; imidazole, TBDPSCl, CH2Cl2, 92%; c) 1,3-dithiane, nBuLi, THF, 208C, then 788C,
DMPU, 4, THF, 208C, 97%;[30] imidazole, TBDPSCl, CH2Cl2, 87%; d) 2-bromopropene, tBuLi, Et2O, 788C, then CuI, 6, Et2O, 78 !08C, quant.; e)
nBuLi, Et2O, 788C, BOC ON, THF, 0 !208C, 93%; IBr, PhMe, 78 !08C, 93%; f) HOAc/THF, 81%; ethyl vinyl ether, CH2Cl2, PPTS, 96%; K2CO3,
94%; imidazole, TBSCl, 87%; g) tBuONa, nBuLi, pentane, 0 !208C,[31] then 788C, 5, then 9, 78 ! 208C, 59%; h) PPTS, MeOH, 80%; NaH, THF, 08C,
then Ts-im,[32] 08C, 93%.
1
BnO
Me Me
OH
I
Me Me
b
c
a
HO
OH
O
O
HO Me
O
O
S
17
OR OR
10
S
Me Me
(R=TBS)
13
12
14
BnO
HO
MeOCH2CO2
H
H
Me Me
Me Me
O
O
H
O
H
d
e
O
OH
Scheme 2. Synthesis of the C1 ± C17 fragment: a)
NMO, OsO4,[33] acetone/H2O; Pb(OAc)4, ben-
zene, 81% over 2 steps; DAMP,[34] tBuOK, THF,
788C, then aldehyde, 96%; B-I-9-BBN,[35] pen-
tane, 208C, 88%; HF ´ py, CH3CN, 91%; 1,1-
dimethoxycyclohexane, PPTS, 97%; b) 13, tBuLi,
THF, 788C, then lithium 2-thienylcyanocuprate,
HO
O
O
OH
Me
OH
Me
OH
15
16
1
MeOCH2CO2
f
then 11, THF,
78 !08C, 72%; TBAF, 08C,
MeOCH2CO2
AcO
H
O
H
quant.; c) CaCO3, NIS, CH3CN, 08C, then PPTS,
CH3CN, 68%; d) Li/NH3, THF, 788C, quant.;
methoxyacetyl chloride, CH2Cl2/py, 93%; PPTS,
MeOH, 508C, 87%; e) Et3N, TBSCl, DMAP,
CH2Cl2, 94%; py, Ac2O, DMAP, 96%; f) HF ´ py,
CH3CN, 95%; Dess ± Martin periodinane, CH2Cl2,
91%.
Me Me
OAc
Me Me
OAc
H
O
H
17
O
O
OTBS
CHO
AcO
10
Me
OH
Me
OH
17
18
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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
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