Total synthesis of (-)-pestalotiopsin A

Article abstract of DOI:10.1002/anie.200800253

(Chemical Equation Presented) A big + : The total synthesis of (-)-pestalotiopsin A has been achieved, thereby establishing the absolute stereochemistry of natural (+)-pestalotiopsin A (see scheme). The synthesis features a [2+2] cycloaddition, an aldol reaction, and an intramolecular Nozaki-Hiyama-Kishi reaction to construct the (E)-cyclononene ring.

Full text of DOI:10.1002/anie.200800253

Communications
DOI: 10.1002/anie.200800253
Natural Products
Total Synthesis of (À)-Pestalotiopsin A**
Ken-ichi Takao, Nobuhiko Hayakawa, Reo Yamada, Taro Yamaguchi, Urara Morita,
Soujiro Kawasaki, and Kin-ichi Tadano*
In 1996 two highly oxygenated caryophyllene sesquiterpe-
noids, pestalotiopsins A (1) and B (2) (Scheme 1), were
isolated by Sugawara and co-workers from Pestalotiopsis sp.,
an endophytic fungus associated with the bark and leaves of
Taxus brevifolia (the Pacific yew).[1] Later, several related
fused with both an (E)-cyclononene ring and a g-lactol unit. In
contrast, bicyclic pestalotiopsin B (2) exists as a mixture of
À
two atropisomers at the C4 C5 carbon–carbon double bond.
The synthetically formidable structure of 1 has attracted
considerable attention among chemists concerned with nat-
ural product synthesis. The research groups of Procter,[3]
Paquette,[4] and Markó,[5] in addition to our group,[6] have
reported a number of synthetic studies of 1. Herein, we
describe the first total synthesis of (À)-pestalotiopsin A (1)
and the assignment of its absolute configuration as the
antipode of natural pestalotiopsin A.
Since embarking on this research we have devoted our
efforts to the efficient formation of the strained (E)-cyclo-
nonene moiety in 1. Although early attempts were unsuc-
cessful,[7] we envisioned that a Nozaki–Hiyama–Kishi (NHK)
reaction approach[8] would enable efficient (E)-cyclononene
ring formation. As shown in Scheme 1, we considered 1 could
be synthesized by using the intramolecular NHK reaction of
aldehyde/alkenyl iodide 3 as a key step and subsequent
deoxygenation of the newly formed hydroxy group at C3. The
formation of 3 would, in turn, be achieved by the aldol
reaction of functionalized bicyclic lactone 4 and g-iodo-b,g-
unsaturated aldehyde 5, both in high enantioenriched forms.
We expected that stereogenic centers at C7 and C8 of 3 would
be introduced stereoselectively as desired in the aldol process
by taking advantage of the 2-oxabicyclo[3.2.0]heptan-3-one
structure of 4. This bicyclic g-lactone 4, in turn, would be
prepared from a highly enantioenriched cyclobutane deriva-
tive analogous to that described in our preliminary report.[6]
Earlier we reported[6] the asymmetric synthesis of func-
tionalized cyclobutanes which featured the [2+2] cycloaddi-
tion of the N-propioloyl derivative of Oppolzerꢀs camphor-
sultam (6) (Scheme 2) and ketene bis(trimethylsilyl) acetal.
However, the bis(trimethylsilyl) acetal moiety was not stable
under the conditions used for the removal of the camphor-
sultam, and it gave rise to some additional steps for the
conversion of the cyclobutane derivativeinto the bicyclic
lactone intermediate. To overcome this disadvantage, ketene
dialkyl acetal 7[9] was examined as a partner in the [2+2]
cycloaddition of 6. The reaction of 6 with 7 proceeded under
the ZrCl4-catalyzed conditions to afford a single regioiso-
meric adduct (8). The 1,4-hydride addition to 8 with
l-Selectride and subsequent protonation of the resulting
enolate proceeded with extremely high stereoselectivity to
provide cyclobutane derivative 9 in almost diastereomerically
pure form. Reductive removal of the chiral auxiliary from 9
provided cyclobutanemethanol 10 with excellent enantiose-
lectivity (> 95% ee),[10] and camphorsultam was efficiently
recovered on a multigram scale experiment. Tosylation of the
hydroxy group in 10 and subsequent displacement by a cyano
Scheme 1. Structures of pestalotiopsins A (1) and B (2) and retrosyn-
thetic analysis of 1. P=protecting group.
natural products were found from the species of Pestalotiop-
sis.[2] Among them, pestalotiopsin A showed cytotoxicity and
immunosuppressive activity in the mixed lymphocyte reac-
tion. The structures of the pestalotiopsins were determined by
extensive spectroscopic studies and finally confirmed by
X-ray crystallographic analysis; however, the absolute ste-
reochemistry remained unclear. Pestalotiopsin A (1) consists
of an unprecedented oxatricyclic structure bearing seven
stereogenic centers and it is comprised of a cyclobutane ring
[*] Dr. K. Takao, N. Hayakawa, R. Yamada, T. Yamaguchi, U. Morita,
S. Kawasaki, Prof. Dr. K. Tadano
Department of Applied Chemistry
Keio University
3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
Fax: (+81)45-566-1571
E-mail: tadano@applc.keio.ac.jp
[**] We thank Prof. Fumio Sugawara (Tokyo University of Science) for
providing a sample and the spectral copies of natural pestalotiop-
sin A. This work was supported bya Grant-in-Aid for Young
Scientists (B) from MEXT and the Astellas Pharma Award in
Synthetic Organic Chemistry (Japan).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
reduction strategy. Thus, Dess–Martin oxidation[12] of 15 and
subsequent sodium borohydride reduction of the resulting
ketone provided 14 in a high overall yield of 90%. Protection
of the hydroxy group in 14 with (4-methoxyphenyl)methyl
(MPM) imidate provided 4, the substrate for the planned
aldol reaction.
Chiral aldehyde 5, the coupling partner for the aldol
reaction, was prepared from known compound 16,[13] which
was in turn prepared from d-glyceradehyde acetonide
(Scheme 3). The epoxy chloride 16 was exposed to three
Scheme 3. Synthesis of g-iodo-b,g-unsaturated aldehyde 5: a) nBuLi,
THF, À358C, 1 h, then MeI, HMPA, RT, 1 h; b) TsOH, MeOH, 408C,
62 h, 81% from 16; c) Bu3SnH, Pd(PPh3)2Cl2, THF, RT, 15 min, 61%
for 19, 18% for the regioisomer; d) I2, CH2Cl2, 08C, 15 min, 94%;
e) silica gel supported NaIO4, CH2Cl2, RT, 15 min, 98%. HMPA=hexa-
methylphosphoramide.
Scheme 2. Synthesis of bicyclic lactone 4: a) ZrCl4, CH2Cl2, reflux, 6 d,
85%; b) L-Selectride, toluene, À788C, 30 min, then aq. NH4Cl, warm-
ing from À78 to 08C, 4 h, quant.; c) LiAlH4, THF, RT, 12 h, 94% for
10, 95% for the camphorsultam; d) TsCl, Et3N, DMAP, CH2Cl2, RT,
3 h; e) KCN, DMSO, 808C, 12 h, quant.; f) 1m aq. HCl, silica gel,
equivalents of n-butyllithium[13,14] and trapping the interme-
diary a-alkoxylated acetylenic dianion with iodomethane led
to the C,O-methylated propargyl alcohol 17. The acetonide
group in 17 was hydrolyzed to diol 18, which was then
=
CH2Cl2, 408C, 6 h; g) CH2 CHMgBr, toluene, À788C, 5 min, 45% from
10; h) 5m aq. HCl, THF, 708C, 41 h, 81%; i) AD-mix-a, tBuOH/H2O,
08C, 5 h; j) TBDPSCl, Et3N, DMAP, CH2Cl2, RT, 10 h, 20% for 14, 80%
for 15; k) DMP, CH2Cl2, RT, 3 h; l) NaBH4, MeOH, 08C, 25 min, 90%
for 14, 10% for 15; m) MPMOC(NH)CCl3, TfOH, Et2O, RT, 50 min,
80% for 4, 16% for recovered 14. L-Selectride=lithium tri-s-butylboro-
hydride; Ts=p-toluenesulfonyl; DMAP=4-(dimethylamino)pyridine;
DMSO=dimethyl sulfoxide; TBDPS=tert-butyldiphenylsilyl;
DMP=Dess–Martin periodinane; MPM=(4-methoxyphenyl)methyl;
Tf =trifluoromethanesulfonyl.
subjected to a palladium-catalyzed hydrostannation by using
[15]
Bu3SnH/Pd(PPh3)2Cl2
to provide terminally stannylated
olefin 19 preferentially. Aldehyde 5 was obtained after metal/
halogen exchange of 19 and subsequent oxidative cleavage of
resulting diol 20.
As in our previous experiments performed by using
structurally analogous coupling partners,[6] the aldol reaction
of 4 with 5 proceeded stereoselectively with NaHMDS as the
base (Scheme 4). As expected, this reaction provided anti-
aldol product 21 predominantly, securing the two contiguous
stereogenic centers required for the target molecule.[16] At this
stage, all the skeletal carbons of 1 were introduced. The next
task was to construct the formidable (E)-cyclononene ring,
and this was efficiently accomplished as described. After a
two-step protecting group manipulation of 21 and subsequent
oxidation of resulting 22, substrate 3 was obtained for use in
the intramolecular NHK reaction. We were pleased to find
that the intramolecular NHK reaction of 3 proceeded
smoothly with the use of CrCl2/NiCl2 in DMSO to provide
cyclized product 23 in 92% yield as a single diastereomer and
as a single atropisomer. Considering the highly strained
structure of (E)-cyclononene, the high yield of 23 was
remarkable.[17] The stereochemistry and conformation of 23
were determined by NOE experiments as shown.
group yielded nitrile 11. Acid hydrolysis of the dialkyl acetal
moiety in 11 provided a cyclobutanone, which was subjected
to a Grignard reaction with vinylmagnesium bromide to
furnish adduct 12 as a single diastereomer. The addition of the
Grignard reagent occurred exclusively from the Si face of the
ketone carbonyl group. Acid hydrolysis of the nitrile group
accompanied by g-lactone formation provided bicyclic lac-
tone 13. This new approach enables more convenient access
to key intermediate 13 when compared to the previous
approach. We then examined the Sharpless asymmetric
dihydroxylation[11] of the vinyl group in 13. After selective
O silylation of the primary hydroxy group in the dihydrox-
ylation products obtained by using AD-mix-a or AD-mix-b,
diastereomeric products 14 and 15 were obtained in ratios of
1:4 and 1:2, respectively. Both dihydroxylation conditions
preferentially produced the undesired diol, which was con-
verted into 15. To our delight, we found that the undesired 15
was efficiently converted into the desired 14 by an oxidation/
The final stage of the total synthesis was the removal of
the extra hydroxy group introduced in 23. The Barton radical-
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Communications
Scheme 5. Completion of the total synthesis of (À)-pestalotiopsin A
(1): a) Ms2O, DMAP, pyridine, RT, 4 h, 93%; b) 4m aq. HCl, THF, RT,
3.5 h; c) TESOTf, pyridine, CH2Cl2, 08C, 30 min, 72% from 24;
d) DDQ, CH2Cl2, phosphate buffer, RT, 17 h, 89%; e) Pd2(dba)3, nBu3P,
NaBH4, 1,4-dioxane, RT, 6 h, 87% as a mixture (10:1) of 26 and the
Scheme 4. Construction of the (E)-cyclononene ring: a) NaHMDS,
THF, À788C, 15 min, then to RT, 5 min, 51% for 21, 17% for the
diastereomer, 12% for recovered 4; b) MOMCl, iPr2NEt, CH2Cl2, reflux,
17 h, 96%; c) nBu4NF, AcOH, THF, RT, 19 h, 96%; d) DMP, CH2Cl2,
RT, 3.5 h, 88%; e) CrCl2, NiCl2, DMSO, RT, 19 h, 92%. NaHMDS=
sodium bis(trimethylsilyl)amide, MOM=methoxymethyl.
À
C3 C4 olefin isomer; f) Dibal-H, THF, 08C, 1 h, 78%; g) Ac2O,
pyridine, 408C, 22 h, 82%; h) AcOH/H2O/THF (1:1:1), RT, 3 h, 96%.
Ms=methanesulfonyl; TES=triethylsilyl; DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone; dba=dibenzylideneacetone; Dibal-H=
diisobutylaluminum hydride.
induced deoxygenation strategy[18] proved to be troublesome
because of the geometrical isomerization of the trisubstituted
À
(E)-olefin moiety into the Z form, or C3 C4 olefin migra-
and 3) the intramolecular NHK reaction of 3 for the
construction of the highly strained (E)-cyclononene ring.
The synthetic strategies developed in the total synthesis will
be applicable to the synthesis of related caryophyllenes.[24]
tion.[19] Moreover, the methoxymethyl (MOM) group was
difficult to remove under acidic conditions in the final step.[20]
These issues were solved by using a strategy involving
palladium(0)-catalyzed reductive displacement by hydride
and by switching the MOM group to a triethylsilyl (TES)
group (Scheme 5). Mesylation of 23 and subsequent standard
protecting group manipulations of the resulting allylic mesyl
ester 24 led to TES ether 25 without event. Treatment of 25
Received: January 17, 2008
Published online: March 25, 2008
Keywords: chiral auxiliaries · cyclization · cycloaddition ·
.
[21]
synthesis design
with a combination of Pd2(dba)3/nBu3P and NaBH4 pro-
vided desired deoxygenated product 26 without destruction of
the E configuration.[22] This reaction was accompanied by a
À
small amount (ca. 8%) of the C3 C4 olefin isomer. Dibal-H
reduction of 26 provided g-lactol 27 as the sole a anomer. The
[1] M. Pulici, F. Sugawara, H. Koshino, J. Uzawa, S. Yoshida, E.
Lobkovsky, J. Clardy, J. Org. Chem. 1996, 61, 2122 – 2124.
[2] a) M. Pulici, F. Sugawara, H. Koshino, G. Okada, Y. Esumi, J.
Uzawa, S. Yoshida, Phytochemistry 1997, 46, 313 – 319; b) R. F.
Magnani, E. Rodrigues-Fo, C. Daolio, A. G. Ferreira, A. Q. L.
de Souza, Z. Naturforsch. C 2003, 58, 319 – 324; c) S. T. Deyrup,
D. C. Swenson, J. B. Gloer, D. T. Wicklow, J. Nat. Prod. 2006, 69,
608 – 611.
[3] a) D. Johnston, N. Francon, D. J. Edmonds, D. J. Procter, Org.
Lett. 2001, 3, 2001 – 2004; b) D. Johnston, E. CouchØ, D. J.
Edmonds, K. W. Muir, D. J. Procter, Org. Biomol. Chem. 2003, 1,
328 – 337; c) D. J. Edmonds, K. W. Muir, D. J. Procter, J. Org.
Chem. 2003, 68, 3190 – 3198.
[4] a) L. A. Paquette, N. Cuni›re, Org. Lett. 2002, 4, 1927 – 1929;
b) S. Dong, G. D. Parker, T. Tei, L. A. Paquette, Org. Lett. 2006,
8, 2429 – 2431; c) L. A. Paquette, G. D. Parker, T. Tei, S. Dong, J.
Org. Chem. 2007, 72, 7125 – 7134; d) L. A. Paquette, S. Dong,
G. D. Parker, J. Org. Chem. 2007, 72, 7135 – 7147; e) S. Dong,
L. A. Paquette, Heterocycles 2007, 72, 111 – 114.
[5] N. Maulide, I. E. Markó, Chem. Commun. 2006, 1200 – 1202.
[6] K. Takao, H. Saegusa, T. Tsujita, T. Washizawa, K. Tadano,
Tetrahedron Lett. 2005, 46, 5815 – 5818.
À
C3 C4 olefinic isomer obtained in the former reaction was
removed at this stage. Acetylation of 27 provided diacetate 28
and mild acid hydrolysis uneventfully cleaved the TES group
and the acetyl group in the g-lactol moiety to provide
(À)-pestalotiopsin A (1); the compund was identical in all
respects (mp, TLC, IR, 1H and 13C NMR, and HRMS
methods) to those of natural pestalotiopsin A,[23] except for
the sign of optical rotation [[a]2D1 = À74.7 (c = 0.535, MeOH)
for 1; lit.[1] [a]2D2 = + 76.8 (c = 1, MeOH) for the natural
sample]. This fact verified that synthesized 1 is the antipode
of natural pestalotiopsin A.
In conclusion, we have completed the first total synthesis
of (À)-pestalotiopsin A (1), thereby establishing the absolute
stereochemistry of natural (+)-pestalotiopsin A. The total
synthesis features 1) a [2+2] cycloaddition of N-propioloyl
derivative of Oppolzerꢀs camphorsultam (6) and ketene
dialkyl acetal 7 and subsequent stereoselective 1,4-hydride
addition/protonation to provide a highly enantioenriched
cyclobutane derivative 10, 2) the aldol reaction of bicyclic
lactone 4 with aldehyde 5 to assemble all the skeletal carbons,
[7] We examined the following approaches a)–f) towards
À
À
(E)-cyclononene formation. For C1 C2 or C4 C5 bond forma-
À
tion: a) intramolecular pinacol coupling reactions. For C2 C3
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Angewandte
Chemie
bond formation: b) Dieckmann condensation, c) intramolecular
SmI2-mediated reductive cyclization, d) intramolecular a-sulfo-
nyl anion cyclizations, and e) cyclization by protected cyanohy-
along with 38% yield of an uncyclized disubstituted olefinic
product produced by protonation of the intermediary metallated
olefin.
À
drin and allylic bromide. For C4 C5 double bond formation:
f) ring-closing metathesis.
[18] a) D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans.
1 1975, 1574 – 1585; b) for a review on the radical deoxygenation
of alcohols, see: W. Hartwig, Tetrahedron 1983, 39, 2609 – 2645.
[19] For example, when the methyl xanthate ester of 23 was treated
with tributyltin hydride in refluxing toluene, the desired
deoxygenation proceeded accompanied by isomerization of the
olefin geometry, resulting in the quantitative formation of the
Z isomer.
[20] It was reported that the caryophyllene skeleton is somewhat
sensitive to acids: I. G. Collado, J. R. Hanson, A. J. Macꢁas-
Sꢂnchez, Nat. Prod. Rep. 1998, 15, 187 – 204.
[21] a) R. O. Hutchins, K. Learn, R. P. Fulton, Tetrahedron Lett. 1980,
21, 27 – 30; b) for a review on palladium-catalyzed hydrogenol-
ysis, see: J. Tsuji, T. Mandai, Synthesis 1996, 1 – 24.
[22] Deoxygenation of 24 under the same conditions used for 25
provided a complex mixture. The hydroxy group at C2 in 25
might play an important role in the observed high regioselec-
tivity of the hydride attack. For similar assistance of the
neighboring hydroxy group in the palladium(0)-catalyzed dis-
placement of allylic substrates by hydride, see: a) M. Oshima, H.
Yamazaki, I. Shimizu, M. Nisar, J. Tsuji, J. Am. Chem. Soc. 1989,
111, 6280 – 6287; b) N. Ono, I. Hamamoto, A. Kamimura, A.
Kaji, J. Org. Chem. 1986, 51, 3734 – 3736.
[8] For recent reviews on the synthetic utility of the NHK reaction,
see: a) L. A. Wessjohann, G. Scheid, Synthesis 1999, 1 – 36; b ) A.
Fürstner, Chem. Rev. 1999, 99, 991 – 1045.
[9] Compound 7 was prepared in batches of 25 g from methacrolein
diethylacetal by olefin isomerization with lithium/ethylenedi-
amine in 51% yield.
1
[10] The ee value of 10 was determined by H NMR analysis of the
Mosher esters derived from 10. The absolute stereochemistry of
10 was confirmed after conversion into 12, whose specific
rotation matched well with that of the sample derived by the
previous approach.[6]
[11] For a review on the Sharpless asymmetric dihydroxylation, see:
H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483 – 2547.
[12] a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 – 4156;
b) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277 –
7287; c) R. E. Ireland, L. Liu, J. Org. Chem. 1993, 58, 2899.
[13] S. Takano, K. Samizu, T. Sugihara, K. Ogasawara, J. Chem. Soc.
Chem. Commun. 1989, 1344 – 1345.
[14] J. S. Yadav, P. K. Deshpande, G. V. M. Sharma, Tetrahedron
1990, 46, 7033 – 7046.
[15] a) H. X. Zhang, F. GuibØ, G. Balavoine, J. Org. Chem. 1990, 55,
1857 – 1867; b) for a review on the metal-catalyzed hydrostan-
nation, see: N. D. Smith, J. Mancuso, M. Lautens, Chem. Rev.
2000, 100, 3257 – 3282.
[23] The 1H and 13C NMR spectral copies of natural pestalotiopsin A,
provided by Professor Sugawara, were recorded in a mixed
solution of CDCl3 and CD3OD (10:1).
[24] By using exactly the same reaction sequence, natural
(+)-pestalotiopsin A could be synthesized from (1R)-camphor-
sultam (in place of the 1S isomer used in this communication)
and the a-epoxide isomer (in place of the b-epoxide 16). For the
preparation of the a epoxide, see reference [13].
[16] Stereochemistry of the newly introduced stereogenic centers in
the aldol adduct 21 was confirmed after conversion into 23.
[17] We confirmed that the g-lactol methyl acetal corresponding to 3
also served as a substrate for the intramolecular NHK reaction,
which provided the cyclized product in a lower yield of 52%,
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