A stereocontrolled synthesis of (±)-ptilocaulin via a Rh(I)-catalyzed intramolecular [4+2] cycloaddition

Article abstract of DOI:10.1055/s-0029-1218572

A stereospecific Rh(I)-catalyzed intramolecular [4+2] cycloaddition has been used to elaborate the essential carbocyclic core of (±)-ptilocaulin. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218572

LETTER
247
A Stereocontrolled Synthesis of ( )-Ptilocaulin via a Rh(I)-Catalyzed
Intramolecular [4+2] Cycloaddition
Synthesis of
(
)-Pt
a
ilocaulin isheng Shen, Tom Livinghouse*
Department of Chemistry and Biochemistry, 103 CBB, Montana State University, Bozeman, MT 59717, USA
Fax +1(406)9945407; E-mail: livinghouse@chemistry.montana.edu
Received 9 September 2009
accessable from hexahydroindene 5a by sequential hy-
droboration–oxidation. Examination of the relative stereo-
chemical features present in 5a suggested that it would
emanate from enediene 4 by way of a stereocontrolled
Rh(I)-catalyzed cycloaddition, by analogy to an example
previously reported by us (Scheme 1).3e We describe here
the successful implementation of this strategy.
Abstract: A stereospecific Rh(I)-catalyzed intramolecular [4+2]
cycloaddition has been used to elaborate the essential carbocyclic
core of ( )-ptilocaulin.
Key words: cycloaddition reactions, transition-metal catalysts,
rhodium(I)
Transition-metal-catalyzed intramolecular cycloadditions
have become established as versatile vehicles for the ste-
reoselective construction of bicyclic and multiply fused
ring systems.1 Powerful reactions in this category include
stereocontrolled cyclizations catalyzed by complexes of
rhodium,2a,b,g–j ruthenium,2c,f nickel2d and palladium.2e In
contrast to conventional and ‘inverse electron-demand’
Diels–Alder reactions, [4+2] cycloadditions between p-
components that are electronically not well differentiated
typically require excessive temperatures and proceed with
low levels of stereoselectivity. We have previously dem-
onstrated that electron-deficient Rh(I) complexes marked-
ly catalyze formal [4+2] cycloaddition reactions of
nonactivated enedienes and dieneynes.3a,b,e In addition, we
have shown that the enantioselective variation of this re-
action is readily achieved using Rh(I) catalysts modified
by P-chirogenic diphosphines.3b–d In this communication,
we describe an efficient total synthesis of ( )-ptilocaulin
that relies on a diastereospecific [4+2] cycloaddition cat-
alyzed by an achiral Rh(I) complex.
+NH2
H
H
N
N
Me
1
O
O
RO
n-Bu
Me
n-Bu
Me
8
7a (R = TIPS)
7b (R = H)
Me
n-Bu
TIPSO
RO
n-Bu
Me
4
5a
Scheme 1 Retrosynthetic analysis for 1
The structurally intriguing tricyclic guanidine (+)-ptilo-
caulin (1), isolated as the nitrate from the orange Caribbe-
an sponge Ptilocaulis aff. P. spiculifer (Lamarck, 1814),
was described by Rinehart in 1981.4 (+)-Ptilocaulin exhib-
its significant cytotoxicity toward L1210 leukemia cells
and displays a range of antimicrobial activity against both
gram-positive and gram-negative bacteria as well as
yeasts and filamentous fungi.5 In the first reported synthe-
sis of ( )- and (–)-ptilocaulin, Snider reported that enone
8 could be converted directly into 1 by simple exposure to
methanolic guanidine.6a Subsequent to this contribution,
the synthesis of 1 has been reported on six occasions.6b–j
The required starting material, (E)-2-ethylidenehexanal
(2), was readily prepared as an exclusive geometrical iso-
mer on a large (150 mmol) scale by the crossed aldol con-
densation of hexanal with acetaldehyde [Me3BnN+ –OH
(cat.), MeOH, 0 °C] albeit in modest (38%) yield.7 Se-
quential dibromoalkylidenation of 2 (CBr4, Ph3P, CH2Cl2)
followed by stereoselective reduction [n-Bu3SnH, Pd(0)
(cat.)]8 furnished (Z,E)-bromodiene 3 in 73% overall
yield. Lithiation of 3 (t-BuLi, Et2O, –78 °C) followed by
addition of the resultant organolithium to 4-penten-1-al
(THF, –78 °C) gave alcohol 4a, which was directly sily-
lated (TIPOTf, 2,6-lutidine, CH2Cl2) to secure enediene
4b (72% overall from 3). Intramolecular cycloaddition of
4b was achieved stereospecifically3a,e and in 93% yield
(THF, 60 °C) in the presence of a Rh(I) catalyst prepared
in situ from [RhCl(cyclooctene)]2 (2.5 mol%) and P(Oi-
C3HF6)3, (5 mol%) to deliver the hexahydroindene 5a.
This cycloaddition is particularly noteworthy in that it is
only the second example that involves a Z,E-diene con-
The synthetic strategy we envisaged for 8, the penultimate
precursor to ptilocaulin (1), was predicated on its pre-
sumed availability from aldol 7b or silyl ether 7a via b-
elimination. Intermediate 7a, in turn, was expected to be
SYNLETT 2010, No. 2, pp 0247–0249
x
x.
x
x.
2
0
1
0
Advanced online publication: 17.12.2009
DOI: 10.1055/s-0029-1218572; Art ID: S10409ST
© Georg Thieme Verlag Stuttgart · New York

248
K. Shen, T. Livinghouse
LETTER
Me
O
n-Bu
1) t-BuLi, Et2O
RO
Me
1) CBr4, Ph3P
Br
O
2) (n-Bu)3SnH
Pd0 (cat.)
2)
Me
n-Bu
4a (R = H)
2
3 (73%)
TIPOTf
2,6-lutidine
4b (R = TIPS)
(72% overall)
[(i-C3HF6O)3P]2RhCl
THF
60 °C
(5 mol%)
O
O
OH
RO
TIPSO
PCC
RO
n-Bu
n-Bu
Me
n-Bu
n-Bu
TsOH (cat.)
PhH
1a) BMS
–
b) HO2
Me
Me
Me
6
7a (R = TIPS)
5a (R = TIPS)
(93%!)
5b (R = H)
8 (71%)
(95%)
TBAF
TBAF
(80%)
7b (R = H)
guanidine
MeOH
1
Scheme 2
taining substrate,3e and the first in which a stereogenic in 95% isolated yield. Unfortunately, direct heating of ke-
center has been incorporated into the tether. Reliable tones 7a [PTSA (cat.), PhH, reflux] failed to provide
spectroscopic evidence for the relative stereochemistry of enone 8. However, preliminary desilylation (TBAF, THF,
1
5a could not be obtained directly due to overlapping H 23 °C) to furnish alcohols 7b followed by immediate de-
NMR signals. Therefore, 5a was converted into the corre- hydration [PTSA (cat.), PhH, reflux] secured the key pen-
sponding alcohol 5b (TBAF, THF) that was subjected to ultimate intermediates 8 as a mixture of diastereomers in
a series of NOE measurements. Specifically, irradiation of 71% overall yield. Final exposure of 8 to methanolic
H-3ab resulted in a 4.9% enhancement of the H-7ab sig- guanidine according to the procedure of Uyehara et al.6b
nal. In addition, 4.4% and 4.9% enhancements were ob- proceeded without incident in the reported yield, thus
served for H-3b and H-4b, respectively. Conversely, completing the total synthesis of racemic ptilocaulin (1)
irradiation of H-7ab led to a 3.6% intensification of H-3ab (Scheme 2).
but only a 1.7% enhancement of trans-H-1a.
In conclusion, we have shown that the catalytic intramo-
lecular [4+2] cycloaddition of a chiral (6Z)-8-eth-(E)-
ylidene-1,6-dodecadiene templated by an electron-defi-
cient Rh(I) complex proceeds with superb stereocontrol
5.6%
1.7%
H7
H1
HO
H7a
3.6%
and in excellent yield. The utility of the resulting hexahy-
droindene as an intermediate in an efficient synthesis of
( )-ptilocaulin (1) was subsequently demonstrated. The
application of the asymmetric variant of the Rh(I)-cata-
lyzed intramolecular [4+2] cycloaddition for the enantio-
controlled construction of naturally occurring ring
systems will be the topic of future accounts from these
laboratories.
4.9%
Me
H3a
H3
3.0%
H4
4.4%
1.9%
4.9%
Figure 1 NOE enhancements for 5b
Irradiation of the 5b-methyl doublet led to 3.0% and 1.9%
intensifications of the H-4b and H-3ab resonances, re-
spectively (Figure 1). These results are entirely consistent
with the proposed stereostructures for 5b, and therefore
5a.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Sequential hydroboration–oxidation of 5a [1a) BMS (1
equiv), CH2Cl2, b) H2O, c) H2O2, NaOH] proceeded with
a high degree of stereoselectivity to provide alcohol 6 as
the major diastereomer in 80% yield after column chro-
matography. Direct oxidation of this intermediate (PCC,
CH2Cl2) subsequently gave the diastereomeric ketones 7a
Acknowledgment
Generous financial support for this research was provided by the
National Institute of General Medical Science.
Synlett 2010, No. 2, 247–249 © Thieme Stuttgart · New York

LETTER
Synthesis of ( )-Ptilocaulin
249
(4) Harbour, G. C.; Tymiak, A. A.; Reinhart, K. L. Jr.; Shaw,
P. D.; Hughes, R. G. Jr.; Mizsak, S. A.; Coats, J. H.;
Zurenco, G. E.; Li, L. H.; Kuentzel, S. L. J. Am. Chem. Soc.
1981, 103, 5604.
(5) Ruben, R. I.; Snider, B. B.; Hobbs, F. W.; Confalone, P. N.;
Dusak, B. A. Invest. New Drugs 1989, 7, 147.
(6) (a) Snider, B. B.; Faith, W. C. J. Am. Chem. Soc. 1984, 106,
1443. (b) Uyehara, T.; Furuta, T.; Kabawawa, Y.; Yamada,
J.-I.; Kato, T.; Yamamoto, Y. J. Org. Chem. 1988, 53, 3669.
(c) Roush, W. R.; Walts, A. E. J. Am. Chem. Soc. 1984, 106,
721. (d) Hassner, A.; Keshava Murthy, K. S. Tetrahedron
Lett. 1986, 27, 1407. (e) Hassner, A.; Keshava Murthy,
K. S. Isr. J. Chem. 1991, 31, 239. (f) Asaoka, M.; Sakurai,
M.; Takei, H. Tetrahedron Lett. 1990, 31, 4759. (g) Cossy,
J.; BouzBouz, S. Tetrahedron Lett. 1996, 37, 5091.
(h) Schmalz, H.-G.; Schellhaas, K. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2146. (i) Schellhaas, K.; Schmalz, H.-G.;
Bats, J. W. Chem. Eur. J. 1998, 4, 57. (j) For the syntheses
of additional members belonging to this alkaloid family, see:
Min, Y.; Pochapsky, S. S.; Snider, B. B. J. Org. Chem. 2008,
73, 9065.
References and Notes
(1) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
(2) (a) Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Zhang,
L. J. Am. Chem. Soc. 2002, 124, 2876. (b) Wender, P. A.;
Glorius, F.; Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am.
Chem. Soc. 1999, 121, 5348. (c) Trost, B. M.; Toste, F. D.;
Shen, H. J. Am. Chem. Soc. 2000, 122, 2379. (d) Wender,
P. A.; Smith, T. E. Tetrahedron 1998, 54, 1255. (e) Takacs,
J. M.; Zhu, J.; Chandramouli, S. J. Am. Chem. Soc. 1992,
114, 773. (f) Trost, B. M.; Toste, F. D.; Shen, H. J. Am.
Chem. Soc. 2000, 122, 2379. (g) Wender, P. A.;
Deschamps, N. M.; Gamber, G. G. Angew. Chem. Int. Ed.
2003, 42, 1853. (h) Wender, P. A.; Christy, J. P. J. Am.
Chem. Soc. 2006, 128, 5354. (i) Wang, W.; Wang, J.; Su, J.;
Huang, F.; Jiao, L.; Liang, Y.; Yang, D.; Zhang, S.; Wender,
P. A.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 10060.
(j) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782.
(3) (a) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T.
J. Am. Chem. Soc. 1990, 112, 4965. (b) McKinstry, L.;
Livinghouse, T. Tetrahedron 1994, 50, 6145.
(c) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T.
Synlett 1998, 443. (d) Heath, H.; Wolfe, B.; Livinghouse,
T.; Bae, S. K. Synthesis 2001, 2341. (e) O’Mahony, D. J.
R.; Belanger, D. B.; Livinghouse, T. Org. Biomol. Chem.
2003, 1, 2038.
(7) (a) Green, C.; Hickinbottom, W. J. J. Chem. Soc. 1957,
3270. (b) The authors would like to thank Ms. Elisa
Sunsdahl for optimizing the large-scale preparation of 2.
(8) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org.
Chem. 1998, 63, 8965.
Synlett 2010, No. 2, 247–249 © Thieme Stuttgart · New York

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