Stereocontrolled total synthesis of (+)-altohyrtin A/spongistatin 1

Article abstract of DOI:10.1002/1521-3773(20011105)40:21<4055::AID-ANIE4055>3.0.CO;2-H

As an exceptionally potent antimitotic macrolide, altohyrtin A/spongistatin 1 shows great promise in cancer chemotherapy but its extreme scarcity in the natural sponges has halted its further preclinical development. A highly stereocontrolled total synthe

Full text of DOI:10.1002/1521-3773(20011105)40:21<4055::AID-ANIE4055>3.0.CO;2-H

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aldol reaction III
Stereocontrolled Total Synthesis of
(‡)-Altohyrtin A/Spongistatin 1**
15
O
O
16
HO
AcO
OMe
Ian Paterson,* David Y.-K. Chen, Mark J. Coster,
B
A
C
D
Ä
Jose L. Acena, Jordi Bach, Karl R. Gibson,
O
O
O
Linda E. Keown, Renata M. Oballa,
Thomas Trieselmann, Debra J. Wallace,
Andrew P. Hodgson, and Roger D. Norcross
28
29
5
AcO
HO
1
O
O
F
macrolactonization
Wittig
coupling
HO
OH
O
51
E
First reported in 1993 by three groups (Kobayashi and
Kitagawa, Pettit, and Fusetani),[1] the altohyrtins/spongista-
tins/cinachyrolides are a unique family of antimitotic macro-
lides[2±5] which are obtained from marine sponges in trace
amounts by bioassay-guided isolation and display exceptional
potency against a wide variety of human cancer cell lines.
They feature a highly substituted 42-membered macrolide
ring which comprises two spiroacetals (AB and CD rings) and
a bis(tetrahydropyran) unit (E and F rings), including a triene
side chain, along with 24 stereogenic centers (Scheme 1, 1 ± 3).
Initial discrepancies in the configurational assignments were
resolved in 1997 by the first total synthesis of altohyrtin C (3)
by the Evans group,[6] and soon after altohyrtin A (1) by the
Kishi group,[7] which confirmed the full assignment proposed
for the altohyrtins by Kobayashi and Kitagawa,[2d] and that
they were identical to spongistatins 2 and 1, respectively, as
isolated by Pettit et al.[3a,b] More recently, the Smith group has
completed a second total synthesis of 3.[8]
O
H
OH
50
OH
OH
X
1: X = Cl, altohyrtin A = spongistatin 1
2: X = Br, altohyrtin B
3: X = H, altohyrtin C = spongistatin 2
15
H
O
O
16
TESO
AcO
O
OMe
B
A
C
D
O
O
O
28
TBSO
1
OPMB
O
OTCE
4: C1-C15 subunit
5: C16-C28 subunit
29
+
aldol reaction II
PMB
OPMB
F
PPh3I–
O
TBSO
O
51
E
47
O
H
OTBS
Spongistatin 1 (1) constitutes one of the most potent
cytotoxic compounds tested by the US National Cancer
Institute (NCI),[3a,b] having sub-nanomolar growth inhibitory
activity (mean GI50 ˆ 0.03 nm) against highly chemoresistant
tumor types (including lung, colon and brain cancers), while in
vivo human melanoma and ovarian carcinoma xenograft
experiments showed curative responses at extremely low
doses.[3g] It inhibits mitosis by binding to tubulin and blocking
OMe
OPMB
Cl
aldol reaction I
6: C29-C51 subunit
Scheme 1. Representative structures of altohyrtins/spongistatins and key
subunits employed for the synthesis of altohyrtin A/spongistatin 1 (1).
TES ˆ triethylsilyl, TCE ˆ 2,2,2-trichloroethyl, TBS ˆ tert-butyldimethyl-
silyl, PMB ˆ p-methoxybenzyl.
microtubule assembly.[3h] Despite this highly promising pro-
acetal macrolides.[9, 10] Herein, we describe a highly stereo-
controlled total synthesis of the most active congener,
altohyrtin A/spongistatin 1 (1), which produces useful quanti-
ties for further biological evaluation, and enables access to
novel analogues for SAR studies. Throughout our synthesis,
asymmetric boron aldol reactions of ketones are exploited as
a powerful bond-forming and stereodefining process.[11]
As shown in Scheme 1, our proposed synthetic route to 1,
which is based on a threefold disconnection of the 42-
membered macrolide ring, employs macrolactonization as
well as Wittig and aldol couplings. We planned[9] a modular
route based on the late-stage, sequential connection of the
fully functionalized spiroacetal subunits 4 and 5, followed by
the bis(tetrahydropyran) subunit 6. Introduction of the
bridging chain between the AB and CD ring systems in 4
and 5, and the connection of the E to the F ring in 6, were
identified as strategic aldol bond constructions (aldol reac-
tions I and III), along with the installation of the terminal
chlorodiene and isolated C47 stereocenter in 6 (aldol reaction
II).
7
file, the unreliable and extremely meagre supply (3.4 Â 10
%
isolation yield for 1)[3a] has effectively halted further preclin-
ical development in cancer chemotherapy.
The exceptional biological activity, combined with the
supply problem, has provided an impetus to develop a
practical route to these synthetically challenging bis-spiro-
Ä
[*] Prof. Dr. I. Paterson, D. Y.-K. Chen, Dr. M. J. Coster, Dr. J. L. Acena,
Dr. J. Bach, Dr. K. R. Gibson, Dr. L. E. Keown, Dr. R. M. Oballa,
Dr. T. Trieselmann, Dr. D. J. Wallace, Dr. A. P. Hodgson,
Dr. R. D. Norcross
University Chemical Laboratory
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax : (‡44)1223-336-362
E-mail: ip100@cus.cam.ac.uk
[**] Financial support was provided by the EPSRC (GR/L41646), Cam-
bridge Commonwealth Trust (Scholarship to M.J.C.), EC (Marie
Curie Postdoctoral Fellowship to J.L.A.), DFG (Postdoctoral Fellow-
ship to T.T.), NSERC-Canada (Postdoctoral Fellowship to R.M.O.),
Churchill College (Research Fellowship to D.J.W.), Kingꢁs College
and Sims Fund, Cambridge (Scholarship to D.Y.K.C.). We also thank
Merck and AstraZeneca Pharmaceuticals for generous support, and
Dr. Anne Butlin (AZ) and Dr. Nick Bampos (Cambridge) for
valuable assistance.
As outlined in Scheme 2, the synthesis of the F ring subunit
7 began with a boron-mediated anti aldol reaction between
the readily available[12] ketone (R)-8 and acetaldehyde to give
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
[13]
9, followed by reduction with Me4NBH(OAc)3 to the 1,3-
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Introduction of the E ring and chlorodiene side chain were
now required to reach the fully elaborated C29 ± C51 segment
6 of altohyrtin A. The control of the remote (47S)-stereo-
center, as well as that at C35, turned out to be challenging; it
proved best to first protect the C45 ketone then install the E
ring before introducing the delicate side chain (Scheme 3).
Thus, Petasis methylenation[19] of ketone 7 with [Cp2TiMe2]
proceeded cleanly and was followed by TPAP/NMO oxida-
tion[20] to afford the methyl ketone 15 (76% overall). For the
introduction of the E ring, the aldehyde 20 having a chloride
O
O
OH
a)
PMBO 41
PMBO 41
37
(93%)
>97:3 ds
OBn
OBn
9
8
(81%)
80:20 ds
b)
O
O
O
O
O
c), d)
38
43
39
PMBO
MeO
(83%)
OBn
OBn
10
11
(98%)
>97:3 ds
e)
O
O
PMB
O
34
PMBO
33
29
Cl
+
H
O
O
O
O
OH
42S
41R
O
O
7
f)
38
42
38
17
18
41
MeO
MeO
(90%)
a), b) (76%)
PMBO
OPMB
OH
OBn
OH
(98%)
>95:5 ds
d)
O
13
12
PMB
OPMB
F
O
OH
O
g), h) (90%)
PMBO
Cl
PMB
OPMB
O
H
O
O
OPMB
O
PMBO
O
O
19
15
F
i)
39
45
45
43
O
H
(86%)
>95:5 ds
c)
e)–h) (75%)
PMBO
OPMB
OPMB
14
7
PMB
O
OPMB
BcHex2
O
OTES
Scheme 2. Synthesis of the C36 ± C46 subunit 7: a) cHex2BCl, Et3N, Et2O,
788C, 2 h; MeCHO, 78 ! 208C, 16 h; H2O2, MeOH/pH 7 buffer,
0 !208C, 3 h; b) 1. Me4NBH(OAc)3, MeCN/AcOH, 48C, 60 h; 2. PPTS,
Me2C(OMe)2, CH2Cl2, 208C, 16 h; c) 1. DDQ, CH2Cl2/pH 7 buffer, 08C,
90 min; 2. Dess ± Martin periodinane, CH2Cl2, 208C, 3 h; d) (MeO)2-
P(O)CH2CO2Me, LiCl, iPr2NEt, MeCN, 208C, 16 h; e) enriched AD-
mix-b, MeSO2NH2, tBuOH/H2O, 20 8C, 8 h; f) 1. H2, Pd(OH)2/C, NaHCO3,
O
34S
F
H
Cl
33R
45
O
36
H
OPMB
16
20
aldol reaction I
90:10 ds
ˆ
MeOH, 208C, 20 h; 2. PMBO(C NH)CCl3, Ph3CBF4, THF, 08C, 2 h;
PMB
O
OPMB
g) DIBAL-H, CH2Cl2,
788C, 30 min; h) (MeO)2P(O)CH2COMe,
O
OH OTES
F
Ba(OH)2, THF/H2O, 20 8C, 16 h; i) 1. AcOH, THF/H2O, 20 8C, 48 h;
2. KOH, MeOH, 208C, 24 h. Bn ˆ benzyl, PPTS ˆ pyridinium p-toluene-
sulfonate, DDQ ˆ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DIBAL-
H ˆ diisobutylaluminum hydride.
45
35S
O
Cl
H
OPMB
21
i) (85% from 15)
PMB
O
OPMB
F
Cl
anti diol and formation of the acetonide 10. Following
deprotection (and separation of the minor C39 epimer),
Dess ± Martin oxidation and chain extension by Horner±
Wadsworth ± Emmons (HWE) olefination furnished the (E)-
enoate 11. This alkene with a benzyloxy group at C38 proved
to be an excellent substrate for Sharpless dihydroxylation[14]
with enriched AD-mix-b to give solely the (41R,42S)-diol 12
in 98% yield.[15] For the remainder of the synthesis, we now
chose to install PMB protecting groups at the C38, C41, and
C42 hydroxy groups. Hydrogenolysis of 12 (Pd(OH)2, NaH-
CO3), followed by PMB protection with p-(methoxybenzyl)-
trichloroacetimidate under mild catalysis[16] with Ph3CBF4
gave tris-PMB ether 13. Reduction of 13 with DIBAL-H
and HWE chain extension[17] with dimethyl (2-oxopropyl)-
phosphonate and Ba(OH)2 then provided the (E)-enone 14
exclusively (81% from 12). Exposure of 14 to acetic acid in
aqueous THF caused hetero-Michael cyclization by the C39
hydroxy group, to initially produce a mixture (ca. 1:1 at C43)
of tetrahydropyrans. On treatment with KOH in MeOH,
clean equilibration (>95:5) led to the desired F ring ketone 7
(86%), having all the substituents equatorial. This efficient
9-step sequence could be performed on a multigram scale and
proceeded in high overall yield (34%).
O
E
O
H
OH
OMe
OPMB
22
j), k) (85%)
29
Cl
PMB
OPMB
O
O
O
F
E
45
O
OTBS
H
OMe
OPMB
23
Scheme 3. Synthesis of the C29 ± C46 subunit 23: a) [Cp2TiMe2], PhMe,
1208C, 2 h; b) TPAP, NMO, 4 Š-MS, CH2Cl2, 208C, 30 min; c) cHex2BBr,
Et3N, Et2O, 788C, 2.5 h; 20, 78 ! 208C, 16 h; H2O2, MeOH/pH 7
buffer, 0 !208C, 2 h; d) cHex2BCl, Et3N, Et2O,
788C, 60 min; 18,
78 ! 208C, 16 h; H2O2, MeOH/pH 7 buffer, 0 !208C, 2 h; e) TESOTf,
2,6-lutidine, CH2Cl2, 788C, 1 h; f) DDQ, CH2Cl2/pH 7 buffer, 208C, 16 h;
g) LiAlH4, THF, 788C, 30 min; h) Pb(OAc)4, Na2CO3, CH2Cl2, 08C,
40 min; i) PPTS, (MeO)3CH, MeOH, 208C, 1 h; j) TBSCl, Im, Et3N, DMF,
208C, 16 h; k) 1. OsO4, Me3NO, acetone/H2O, 20 8C, 16 h; 2. Pb(OAc)4,
Na2CO3, CH2Cl2, 08C, 40 min. Cp ˆ cyclopentadienyl, TPAP ˆ tetrapro-
pylammonium perruthenate, TESOTf ˆ triethylsilyl trifluoromethanesul-
fonate, Im ˆ imidazole, NMO ˆ N-methylmorpholine N-oxide, MS ˆ mo-
lecular sieves.
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at C29 was selected to enable direct formation of the
phosphonium salt for Wittig coupling. By using our lactate
methodology,[18] a boron-mediated syn aldol reaction between
the PMB-protected ketone 17 and the aldehyde 18 produced
the adduct 19 (98%; >95:5 ds). Following a straightforward
four-step sequence, the (33R,34S)-aldehyde 20 was obtained
cleanly (75%).
The successful boron aldol coupling between ketone 15 and
aldehyde 20 (aldol reaction I) necessitated the use of freshly
prepared cHex2BBr[21] as a more reactive enolizing reagent
than the chloride. Exposure of 15 to cHex2BBr/Et3N at
788C in Et2O, followed by addition of the aldehyde 20, led
to a 90:10 mixture of adducts with (35S)-alcohol 21 as the
major isomer. Subjection to PPTS in MeOH/CH(OMe)3 then
induced TES removal and concomitant formation of the E
ring as the methyl acetal 22.[22] Following TBS protection of
22, oxidative cleavage of the alkene by dihydroxylation and
brief exposure to Pb(OAc)4 regenerated the methyl ketone in
23; this could be prepared on a gram scale in 72% yield over
four steps from 15.
Introduction of the chlorodiene terminus of altohyrtin A,
with control of the isolated C47 stereocenter, was now
required in aldol reaction II (Scheme 4). Ultimately, this
proved remarkably effective using solely substrate control
from the ketone component 23. Here the addition of the
dicyclohexylboron enolate 24 to the chlorodienal 25[10h]
(prepared in three steps from 2-chloroacrolein) proceeded
selectively at 788C. After oxidative workup, the (47S)-
adduct 26 was isolated in 80% yield with 95:5 ds.[23] Notably,
this result is in the 1,5-syn sense, opposite to 1,5-anti stereo-
induction observed for boron aldol reactions of simple b-
alkoxy methyl ketones,[24] indicating the overriding contribu-
tion in this special case from the more remote stereocenters. A
reinforcing effect from the E ring is apparent, as the
analogous reaction with the ketone 29 proceeded with
reduced 80:20 ds in favor of 30. In both these cases, the
corresponding lithium aldol reaction (LiHMDS) gave no
measurable induction. To complete the fully elaborated EF
segment 6, TBS protection gave 27 and methylenation of the
highly functionalized C45 ketone was achieved using a
modified Takai procedure.[25] Overall, this new method for
introducing the altohyrtin/spongistatin side chain proceeds in
high overall yield (60% for 23 !28) and should be applicable
to other congeners, as in altohyrtins B and C (2 and 3), simply
by changing the aldehyde. In preparation for the final Wittig
coupling, direct conversion of 28 into the phosphonium salt 6
was achieved in 91% yield by heating with Ph3P in the
presence of NaI. Thus, the fully functionalized C29 ± C51
subunit 6 was obtained efficiently in high overall yield (54%
from 23).
O
23
H
b)
Cl
a) (76%)
O
PMB
29
OPMB
F
Cl
O
O
cHex2B
O
51
E
47
46
O
H
OTBS
H
OMe
OPMB
Cl
25
24
aldol reaction II
(79%)
29
PMB
OPMB
Cl
O
OR
O
O
51
F
E
47S
O
H
OTBS
OMe
OPMB
Cl
Cl
Cl
1,5-syn
95:5 ds
26: R = H
27: R = TBS
(93%)
c)
d)
(81%)
PMB
O
29
OPMB
Cl
TBSO
O
51
F
E
O
OTBS
H
OMe
OPMB
28
e) (91%)
OPMB
F
+
PPh3I–
PMB
O
29
TBSO
O
51
E
O
H
OTBS
OMe
OPMB
6
PMB
OPMB
F
O
O
OBz
43
O
H
OPMB
29
b)
(71%)
PMB
OPMB
O
O
HO
OBz
51
F
47S
43 O
H
Cl
OPMB
1,5-syn 30
80:20 ds
Scheme 4. Synthesis of the C29 ± C51 phosphonium salt 6: a) 1. (EtO)2-
P(O)CH2CO2Et, NaHMDS, catechol, 78 ! 208C 40 h; 2. DIBAL-H,
CH2Cl2, 788C, 2 h; 3. oxalyl chloride, DMSO, 788C, 1 h; Et3N, 788C,
1 h; b) cHex2BCl, Et3N, Et2O, 78 ! 408C, 90 min; 25, 788C, 16 h;
MeOH/pH 7 buffer then H2O2/pH 7 buffer, 08C, 2.5 h; c) TBSCl, Im, DMF,
208C, 3 h; d) Zn, CH2I2, TiCl4, PbI2, THF/CH2Cl2, 208C, 4 h; e) PPh3, NaI,
iPr2NEt, MeCN/MeOH, D, 20 h. NaHMDS ˆ sodium bis(trimethylsilyl)-
amide, DMSO ˆ dimethylsulfoxide, Bz ˆ benzoyl.
mediated protocols[9f] were explored to produce the required
(15S,16S)-adduct 31, the former (as used independently by
Evans et al.[6c,d]) proved superior on a larger scale. Controlled
(E)-enolization of 5 with cHex2BCl/Et3N in Et2O and addition
of aldehyde 4 led to the formation of 31 (90:10 ds) in 89%
yield,[27] corresponding to preferential Felkin ± Anh attack. A
three-step sequence of acetylation of the C15 hydroxy group,
PMB ether deprotection by DDQ (CH2Cl2, pH7 buffer), and
TPAP oxidation then led to the fully functionalized C1 ± C28
aldehyde 32 (75% overall), without compromising the con-
figurational integrity at C23 in the acid-labile CD spiroacetal.
Scale up of our previously described aldol-based synthe-
ses[9d±f] of the AB and CD spiroacetal units 4 and 5 led to
multi-gram quantities,[26] in readiness for an anti-selective
aldol coupling (aldol reaction III) to produce the ABCD
segment 31 (Scheme 5). Notably, the AB spiroacetal ring is
stabilized by a double anomeric effect, while the CD
spiroacetal subunit benefits from only a single anomeric
effect, and thus epimerizes readily at C23 such that acidic
conditions must be avoided. While both boron[9d] and lithium-
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O
32
+
6
O
18
15
16
O
H
a)
(65%)
TESO
O
OTBS
AcO
O
MeO
+
O
O
O
Cl3C
O
1
TESO
AcO
28
OAc
OMe
C
D
OPMB
5: CD spiroacetal
O
B
A
O
4: AB spiroacetal
O
O
aldol reaction III
28
TBSO
1
a)
R2O
O
OR1
‡
L
+
H
Me
14R
R1O
–
42
O
O
41
B
TBSO
O
E
F
51
15
38
H
H
O
OTBS
L
Me
18
H
OMe
OR1
H
H
Cl
33: R1 = PMB, R2 = TCE
34: R1 = H, R2 = TCE
35: R1 = H, R2 = H
(89%)
(68%) b)
(58%) c)
90:10 ds
(55%) d)
15S
O
16S
TESO
AcO
OR1
OMe
R2
O
C
B
A
O
O
O
TESO
AcO
OAc
OMe
23
O
C
O
D
B
A
O
O
TBSO
O
D
1
TCEO
O
TBSO
31: R1 = H, R2 = CH2OPMB
32: R1 = Ac, R2 = CHO
1
b)–d)
(75%)
O
O
HO
TBSO
O
51
F
E
Scheme 5. Synthesis of C1 ± C28 aldehyde 32: a) cHex2BCl, Et3N, Et2O,
78 !08C, 20 min; 4, 788C, 16 h; SiO2, 208C, 40 min; b) Ac2O, DMAP,
pyr, 208C, 2 h; c) DDQ, CH2Cl2/pH 7 buffer, 08C, 90 min; d) TPAP, NMO,
4 Š-MS, CH2Cl2, 208C, 10 min. DMAP ˆ 4-(dimethylamino)pyridine.
O
OTBS
H
OMe/H
OH
Cl
36
e)
altohyrtin A / spongistatin 1 (1)
Realization of an efficient and reproducible Wittig coupling
of the fully elaborated C1 ± C28 and C29 ± C51 subunits, 32
and 6, was now crucial (Scheme 6).[28] Deprotonation of the
phosphonium salt 6 with LiHMDS in THF/HMPA at 788C
gave an intense orange-colored ylide solution, whereupon the
aldehyde 32 was added, leading on warming to clean Wittig
coupling and isolation of the (Z)-alkene 33 (Z:E >97:3 by
800 MHz 1H NMR) in 65% yield, representing the fully
protected seco-acid of altohyrtin A/spongistatin 1 (1).
Scheme 6. Final steps of the total synthesis of altohyrtin A/spongistatin 1
(1): a) LiHMDS, THF/HMPA, 788C, 10 min; 32, 78 !208C, 40 min;
b) DDQ, CH2Cl2/pH 7 buffer, 08C, 60 min; c) Zn, THF/1m NH4OAc, 208C,
30 min; d) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 208C, 3 h; DMAP,
PhMe, 1008C, 20 h; e) HF, MeCN/H2O, 0 8C, 4 h. LiHMDS ˆ lithium
bis(trimethylsilyl)amide, HMPA ˆ hexamethylphosphoramide. Com-
pounds 34, 35, and 36 were mixtures of the methyl acetal and hemiacetal
in ca. 1.3:1 ratio.
In preparation for macrolactonization, rapid deprotection
of the three PMB ethers was achieved in the presence of the
potentially labile unsaturated side chain,[29] by exposure to
excess DDQ in CH2Cl2/pH7 buffer, to give the triol 34 (68%;
obtained as a ca. 1.3:1 mixture of the E ring methyl acetal and
its hemiacetal hydrolysis product).[30] Subjection of this
mixture to Zn powder in THF/NH4OAc induced deprotec-
tion[31] of the trichloroethyl (TCE) ester to give the seco-acid
35. Regioselective macrolactonization[6c, 7b, 8b, 32] of the triol 35,
which engaged the C41 hydroxy group (in preference to those
at C42 and C38), was performed under modified Yamaguchi
conditions[33] to produce the 42-membered macrolide 36 in
55% yield. Finally, exposure to HF/MeCN led to deprotection
of the four silyl ethers and hydrolysis of the remaining methyl
acetal to provide (‡)-altohyrtin A/spongistatin 1 (1) in 36%
yield.[34] The spectroscopic data [1H NMR (CD3CN and
CD3OD, 500 and 800 MHz), 13C NMR (CD3CN), IR,
HRMS],[35] along with specific rotation [[a]2D0 ˆ ‡21.0 (c ˆ
0.44, MeOH); cf. Kobayashi[2a] [a]D20 ˆ ‡21.7 (c ˆ 1.20,
MeOH) and Pettit[3a] [a]D20 ˆ ‡26.2 (c ˆ 0.32, MeOH)] of the
synthetic material were in excellent agreement with that
reported (and by comparison with the NMR spectra kindly
provided by Professors Pettit and Kishi).[36]
Overall, this highly stereocontrolled total synthesis of
altohyrtin A/spongistatin 1 proceeds in 33 steps and 1.0%
overall yield for the longest linear sequence (based on the AB
subunit). Altogether, this constitutes one of the most testing
applications of boron-mediated aldol methodology for poly-
ketide synthesis, including its use for the side-chain installa-
tion (as in 23 !26) which benefits from a remarkable level of
remote stereoinduction. To date, this synthesis has already
provided useful quantities of altohyrtin A/spongistatin 1 and
thus contributes to replenishing the largely exhausted natural
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material from the initial isolation work[37] and enables more
detailed biological evaluation.
d) G. C. Micalizio, A. N. Pinchuk, W. R. Roush, J. Org. Chem. 2000,
65, 8730; e) J. C. Anderson, B. P. McDermott, E. J. Griffin, Tetrahe-
dron 2000, 56, 8747; f) A. G. M. Barrett, D. C. Braddock, P. D.
de Koning, A. J. P. White, D. J. Williams, J. Org. Chem. 2000, 65,
375; g) H. Kim, H. M. R. Hoffmann, Eur. J. Org. Chem. 2000, 2195;
h) E. Fernandez-Megia, N. Gourlaouen, S. V. Ley, G. J. Rowlands,
Synlett 1998, 991; i) R. Zemribo, K. T. Mead, Tetrahedron Lett. 1998,
39, 3895; j) T. Terauchi, T. Terauchi, I. Sato, T. Tsukada, N. Kanoh, M.
Nakata, Tetrahedron Lett. 2000, 41, 2649; k) P. D. Kary, S. M. Roberts,
Tetrahedron: Asymmetry 1999, 10, 217; l) M. Samadi, C. Munoz-
Letelier, S. Poigny, M. Guyot, Tetrahedron Lett. 2000, 41, 3349; m) S.
Lemaire-Audoire, P. Vogel, J. Org. Chem. 2000, 65, 3346.
Received: August 16, 2001 [Z17739]
[1] The Kobayashi/Kitagawa group[2] obtained the altohyrtins from the
Okinawan sponge Hyrtios altum, while the spongistatins were isolated
from sponges of the genera Spongia and Spirastrella, and reported
concurrently by the Pettit group.[3] Cinachyrolide A, isolated by the
Fusetani group[4] from a sponge of genus Cinachyra is assumed to have
the same structure as 15-desacetylaltohyrtin A and spongi-
statin 4.
[2] a) M. Kobayashi, S. Aoki, H. Sakai, K. Kawazoe, N. Kihara, T. Sasaki,
I. Kitagawa, Tetrahedron Lett. 1993, 34, 2795; b) M. Kobayashi, S.
Aoki, I. Kitagawa, Tetrahedron Lett. 1994, 35, 1243; c) M. Kobayashi,
S. Aoki, H. Sakai, N. Kihara, T. Sasaki, I. Kitagawa, Chem. Pharm.
Bull. 1993, 41, 989; d) M. Kobayashi, S. Aoki, K. Gato, I. Kitagawa,
Chem. Pharm. Bull. 1996, 44, 2142.
[3] 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; b) G. R. Pettit,
Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd, J. Chem. Soc. Chem.
Commun. 1993, 1166; c) 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; d) 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; e) 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; f) R. Bai, Z. A. Cichacz, C. L. Herald,
G. R. Pettit, E. Hamel, Mol. Pharmacol. 1993, 44, 757; g) R. K. Pettit,
S. C. McAllister, G. R. Pettit, C. L. Herald, J. M. Johnson, Z. A.
Cichacz, Int. J. Antimicrob. Agents 1998, 9, 147; h) R. Bai, G. F. Taylor,
Z. A. Cichacz, C. L. Herald, J. A. Kepler, G. R. Pettit, E. Hamel,
Biochemistry 1995, 34, 9714.
[11] For a review of asymmetric aldol reactions using boron enolates, see:
C. J. Cowden, I. Paterson, Org. React. 1997, 51, 1.
[12] Prepared in three steps from methyl (R)-3-hydroxy-2-methylpropio-
nate by the sequence: a) MeONHMe ´ HCl, AlMe3, CH2Cl2, 208C,
ˆ
18 h; b) PMBO(C NH)CCl3, TfOH, Et2O, 0 !208C, 3.5 h;
c) BnOCH2SnBu3, nBuLi, THF, 788C, 20 min. I. Paterson, T.
Nowak, Tetrahedron Lett. 1996, 37, 8243; I. Paterson, R. D. Tillyer, J.
Org. Chem. 1993, 58, 4182.
O
O
a)–d)
PMBO
HO
OMe
(62%)
OBn
8
[13] D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc. 1988,
110, 3560.
[14] a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J.
Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu,
X.-L. Zhang, J. Org. Chem. 1992, 57, 2768; b) H. C. Kolb, M. S. Van
Nieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483.
[15] In contrast, the analogous C38 TBS ether underwent dihydroxylation
with greatly reduced facial selectivity (ca. 67:33 ds).
[16] R. E. Ireland, L. Liu, T. D. Roper, Tetrahedron 1997, 53, 13221.
[17] a) I. Paterson, K.-S. Yeung, J. B. Smaill, Synlett 1993, 774; b) C.
[4] N. Fusetani, K. Shinoda, S. Matsunaga, J. Am. Chem. Soc. 1993, 115,
3977.
[5] For reviews, see: a) J. Pietruszka, Angew. Chem. 1998, 110, 2773;
Angew. Chem. Int. Ed. 1998, 37, 2629; b) R. D. Norcross, I. Paterson,
Chem. Rev. 1995, 95, 2041.
[6] a) D. A. Evans, P. J. Coleman, L. C. Dias, Angew. Chem. 1997, 1090,
2951; Angew. Chem. Int. Ed. Engl. 1997, 36, 2738; b) D. A. Evans,
Â
Â
Ä
Alvarez-Ibarra, S. Arias, G. Banon, M. J. Fernandez, M. Rodríguez, V.
Sinisterra, J. Chem. Soc. Chem. Commun. 1987, 1509.
[18] I. Paterson, D. J. Wallace, S. M. Velazquez, Tetrahedron Lett. 1994, 35,
9083.
[19] a) N. A. Petasis, E. I. Bzowej, J. Am. Chem. Soc. 1990, 112, 6392;
b) N. A. Petasis, S.-P. Lu, Tetrahedron Lett. 1995, 36, 2393.
[20] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994, 639.
[21] H. C. Brown, K. Ganesan, R. K. Dhar, J. Org. Chem. 1993, 58, 147.
[22] The minor C35 epimer could be inverted by oxidation/reduction to
produce more of 22. The stereochemistry in the E ring was assigned by
supportive NOEs and coupling constants.
[23] The desired (47S)-configuration was determined by 1H NMR analysis
of the (R)- and (S)-MTPA esters. I. Ohtani, T. Kusumi, Y. Kashman,
H. Kakisawa, J. Am. Chem. Soc. 1991, 113, 4092.
à Â
B. W. Trotter, B. Cote, P. J. Coleman, Angew. Chem. 1997, 109, 2954;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2741; c) D. A. Evans, B. W.
à Â
Trotter, B. Cote, P. J. Coleman, L. C. Dias, A. N. Tyler, Angew. Chem.
1997, 109, 2957; Angew. Chem. Int. Ed. Engl. 1997, 36, 2744; d) D. A.
à Â
Evans, B. W. Trotter, P. J. Coleman, B. Cote, L. C. Dias, H. A.
Rajapakse, A. N. Tyler, Tetrahedron 1999, 55, 8671.
[7] a) J. Guo, K. J. Duffy, K. L. Stevens, P. I. Dalko, R. M. Roth, M. M.
Hayward, Y. Kishi, Angew. Chem. 1998, 110, 198; Angew. Chem. Int.
Ed. 1998, 37, 187; b) M. M. Hayward, R. M. Roth, K. J. Duffy, P. I.
Dalko, K. L. Stevens, J. Guo, Y. Kishi, Angew. Chem. 1998, 110, 190;
Angew. Chem. Int. Ed. 1998, 37, 192.
[24] a) I. Paterson, K. R. Gibson. R. M. Oballa, Tetrahedron Lett. 1996, 37,
à Â
8585; b) D. A. Evans, P. J. Coleman, B. Cote, J. Org. Chem. 1997, 62,
[8] a) A. B. Smith III, V. A. Doughty, Q. Lin, L. Zhuang, M. D. McBriar,
A. M. Boldi, W. H. Moser, N. Murase, K. Nakayama, M. Sobukawa,
Angew. Chem. 2001, 113, 197; Angew. Chem. Int. Ed. 2001, 40, 191;
b) A. B. Smith III, Q. Lin, V. A. Doughty, L. Zhuang, M. D. McBriar,
J. K. Kerns, C. S. Brook, N. Murase, K. Nakayama, Angew. Chem.
2001, 113, 202; Angew. Chem. Int. Ed. 2001, 40, 196. The Smith route
converged with the Kishi ABCD ring system, which represents a
formal total synthesis of 1.
[9] For our previous work, see: a) I. Paterson, R. M. Oballa, R. D.
Norcross, Tetrahedron Lett. 1996, 37, 8581; b) I. Paterson, K. R.
Gibson, R. M. Oballa, Tetrahedron Lett. 1996, 37, 8585; c) I. Paterson,
L. E. Keown, Tetrahedron Lett. 1997, 38, 5727; d) I. Paterson, R. M.
Oballa, Tetrahedron Lett. 1997, 38, 8241; e) I. Paterson, D. J. Wallace,
K. R. Gibson, Tetrahedron Lett. 1997, 38, 8911; f) I. Paterson, D. J.
Wallace, R. M. Oballa, Tetrahedron Lett. 1998, 39, 8545.
788.
[25] a) K. Takai, Y. Hotta, K. Oshima, H. Nozaki, Tetrahedron Lett. 1978,
19, 2417; b) J. Hibino, T. Okazoe, K. Takai, H. Nozaki, Tetrahedron
Lett. 1985, 26, 5579; c) T. Okazoe, J. Hibino, K. Takai, H. Nozaki,
Tetrahedron Lett. 1985, 26, 5581; d) T. Okazoe, K. Takai, K. Oshima,
K. Utimoto, J. Org. Chem. 1987, 52, 4410; e) K. Takai, T. Kakiuchi, Y.
Kataoka, K. Utimoto, J. Org. Chem. 1994, 59, 2668.
[26] On optimization, some improvements in yields were obtained as
indicated below (TIPS ˆ triisopropylsilyl):
O
24 steps
4
TIPSO
(34.0%)
O
OTBS
16 steps
(16.5%)
5
H
[10] For leading references to synthetic work from other laboratories (see
ref. [8a], footnote 8, for a comprehensive listing): a) M. T. Crimmins,
J. D. Katz, L. C. McAtee, E. A. Tabet, S. J. Kirincich, Org. Lett. 2001,
3, 949; b) G. A. Wallace, R. W. Scott, C. H. Heathcock, J. Org. Chem.
2000, 65, 4145; c) D. Zuev, L. A. Paquette, Org. Lett. 2000, 2, 679;
[27] As with some other sensitive systems, hydrolytic breakdown of the
intermediate boron aldolate by direct exposure to silica gel was
preferred over the usual oxidative workup.[11]
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[28] A range of yields have been reported for this challenging Wittig step
(Evans: 64%; Kishi: 40%; Smith: 34%) under a variety of reaction
conditions.
[29] I. Paterson, C. J. Cowden, V. S. Rahn, M. D. Woodrow, Synlett 1998,
915. In the model tris-PMB ether system A, we encountered compet-
ing oxidation by DDQ of the side chain to the chlorodienone:
However, a similar deprotection of a bis-PMB ether was achieved
without difficulty in the Kishi synthesis.[7b]
hand, 4a-hydroxygermacra-1(10),5-diene (4a-HDG, 2) is a
predominant foliage sesquiterpene in many pine trees (Pinus
radiata).[6] To date, no synthesis for 1 or 2 has yet been
reported.[7] Here we describe the synthesis of cyclodecenones
(Æ)-11 and (Æ)-12, which are direct precursors for (Æ)-2
(Scheme 1), by ring-closing olefin metathesis (RCM). To the
PMB
O
OPMB
F
TBSO
O
51
47
O
H
36
Cl
OPMB
A
[30] A similar result was observed by the Kishi group.[7b]
[31] a) G. Jou, I. Gonzalez, F. Albericio, P. Lloyd-Williams, E. Giralt, J.
Org. Chem. 1997, 62, 354; b) R. B. Woodward, K. Heusler, J. Gosteli, P.
Naegeli, W. Oppolzer, R. Ramage, S. Ranganathan, H. Vorbrüggen, J.
Am. Chem. Soc. 1966, 88, 852.
Scheme 1. Retrosynthesis of 1,6-germacradien-5-ols 1 and 2.
best of our knowledge, this is the first 10-membered carbo-
cycle obtained by using the RCM methodology.[8] Only a few
examples of the formation of ten-membered rings by RCM
have been reported,[9] and all dealt with the synthesis of oxa-
or azacycles.
[32] For a related regioselective macrolactonization employed for swinho-
lide A, see: I. Paterson, K.-S. Yeung, R. A. Ward, J. D. Smith, J. G.
Cumming, S. Lamboley, Tetrahedron 1995, 51, 9467.
[33] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
[34] Purity was determined by reverse-phase HPLC. Prodigy C18 4.6 Â
1
250 mm, 5 mm analytical column; 27.5% H2O/MeOH; 1 mLmin
.
Among the many cyclization reactions, olefin metathesis
[35] See Supporting information for tabulated H and 13C NMR data and
1
ˆ
has emerged as a very powerful tool for the formation of C C
copies of spectra.
bonds.[9, 10] However, as a result of inherent ring strain, the
formation of 8- to 11-membered rings is particularly diffi-
cult,[9] and its success depends on the substitution pattern of
the bis-olefin.[11] The importance of restricted chain mobility is
clearly illustrated by 6a (Scheme 2), in which the conforma-
tional-control element is the aldol moiety. Conversion of this
functional group into an enone completely inhibits the
cyclization, as described hereafter.
[36] We thank Professors Pettit and Kishi for kindly providing comparison
NMR spectra.
[37] Isolation from sponge sources: At present, we have synthesized 4.5 mg
of 1 and 60 mg of its direct precursor 36; optimum conditions for the
final deprotection step are being developed. 13.8 mg from 400 kg of
Spongia sp. by Pettit et al.[3a] ‡ 7.6 mg from 112 kg of Hyrtios altum. by
Kobayashi et al.[2c]
Synthesis of a 10-Membered Carbocycle By
Olefin Metathesis**
Marta Nevalainen and Ari M. P. Koskinen*
Dedicated to Professor Henry Rapoport
The pine sawfly Neodiprion sertifer is a common pest in
pine trees of the northern hemisphere.[1] The population of
larvae can cause extensive defoliation, resulting in serious
economical damage. Therefore, great effort has recently been
directed to monitor and control the population of sawfly
species.[2] It was shown that the resin secreted by pines
interferes with the development of larvae.[3] The main
component of the sesquiterpene fraction of the resin of Pinus
sylvestris is 1,6-germacradien-5-ol (1),[4] first isolated by
Bohlmann et al.[5] from Senecio phonolithicus. On the other
Scheme 2. Synthesis of bis-olefins 6 and 7. a) LDA, THF, 788C (61%);
b) LDA, THF, 788C; then Ac2O (not isolated); c) TBSOTf, 2,6-lutidine,
CH2Cl2, 08C (96%); d) DBU, THF, 08C (56% from 5). DBU ˆ 1,8-
diazabicyclo[5.4.0]undec-7-ene,
LDA ˆ lithium
diisopropylamide,
TBSOTf ˆ tert-butyldimethylsilyl trifluoromethanesulfonate.
Aldehyde 5 was synthesized in 72% overall yield from
isovaleric acid. Condensation of 5 with 5-hexen-1-one deliv-
ered aldol 6a with 3,4-syn/3,4-anti (Felkin) selectivity. In situ
entrapment of 6a with acetic anhydride followed by DBU-
promoted elimination yielded enone 7 (Scheme 2).
The RCM reaction of enone 7 in the presence of the Grubbs
catalyst provided only oligomers, along with unconverted
starting material (Table 1, entry 1). In CH2Cl2 solution, enone
7 adopts a linear conformation in which the olefinic termini
are located at a maximum distance from each other. There-
fore, only acyclic diene metathesis polymerization takes place.
We were thus pleased to observe that the aldol 6a (syn/anti
2/1) underwent the RCM reaction to form 10-membered
[*] Prof. A. M. P. Koskinen, Dr. M. Nevalainen
Laboratory of Organic Chemistry, Department of Chemical Technol-
ogy
Helsinki University of Technology, 02015 HUT, Finland
Fax : (‡358)9-451-2538
E-mail: ari.koskinen@hut.fi
[**] Financial support has been provided by the Academy of Finland and
HUT.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
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