Total synthesis of the marine natural product (-)-clavosolide A. A showcase for the Petasis-Ferrier union/rearrangement tactic

Article abstract of DOI:10.1021/ol0611752

The total synthesis of the marine diolide (-)-clavosolide A has been achieved in 17 steps (longest linear sequence) from commercially available crotonaldehyde exploiting the Petasis-Ferrier union/rearrangement tactic to construct the requisite aglycon monomer. A one-pot esterification/ lactonization employing the Yamaguchi protocol, followed by bis-glycosidation, furnished (-)-clavosolide A.

Full text of DOI:10.1021/ol0611752

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3315-3318
Total Synthesis of the Marine Natural
Product ( )-Clavosolide A. A
Showcase for the Petasis Ferrier
−
−
Union/Rearrangement Tactic
Amos B. Smith, III* and Vladimir Simov
Department of Chemistry, Laboratory for Research on the Structure of Matter,
and Monell Chemical Senses Center, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received May 12, 2006
ABSTRACT
The total synthesis of the marine diolide (
crotonaldehyde exploiting the Petasis Ferrier union/rearrangement tactic to construct the requisite aglycon monomer. A one-pot esterification/
lactonization employing the Yamaguchi protocol, followed by bis-glycosidation, furnished ( )-clavosolide A.
−)-clavosolide A has been achieved in 17 steps (longest linear sequence) from commercially available
−
−
In 2002, Faulkner et al.1 disclosed the isolation and structural
elucidation of clavosolides A and B, two novel marine diolide
glycosides, the aglycons of which comprise a C2-symmetric
16-membered macrocycle punctuated with two trans-cyclo-
propylcarbinyl units (Figure 1). Erickson and co-workers2
subsequently reported the structures of clavosolide C and
D, two additional members of this family of marine natural
products.
2005, Willis et al.3 disclosed the first total synthesis of the
reported structure of clavosolide A (Figure 1). A discrepancy,
observed in the 1H NMR spectrum in the cyclopropyl region
1
when compared to the H NMR spectrum of the natural
product, led to a proposed reassignment of the cyclopropyl-
carbinyl stereogenicity. A similar observation was made by
Chakraborty and Reddy4 upon their synthesis of the initially
assigned structure of (-)-clavosolide A. The relative stereo-
chemistry of (+)-clavosolide A (1), and in particular the
cyclopropylcarbinyl moiety, was subsequently secured by
Lee and co-workers in their total synthesis of the natural
product.5 Unfortunately, an error in the sign of the optical
rotation led to an improbable assignment of the absolute
stereochemistry.6
The unique architecture of the clavosolides has attracted
considerable interest within the synthetic community.3-5 In
(1) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 386.
(2) Erickson, K. L.; Gustafson, K. R.; Pannell, L. K.; Beutler, J. A.;
Boyd, M. R. J. Nat. Prod. 2002, 65, 1303.
(3) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.; Harding,
J. R.; Willis, C. L. Chem. Commun. 2005, 40, 5097.
(4) (a) Chakraborty, K. T.; Reddy, R. V. Tetrahedron Lett. 2006, 13,
2099. For an alternate synthesis of the initially assigned aglycon monomer,
see: (b) Yakambram, P.; Puranik, V.; Gurjar, M. Tetrahedron Lett. 2006,
22, 3781.
In this paper, we present a total synthesis of (-)-clavo-
solide A (1) exploiting the Petasis-Ferrier union/rearrange-
(5) Lee, H. D.; Kim, N. Y.; Kim, S. N.; Son, J. B. Org. Lett. 2006, 8,
661.
(6) Addition and Correction: Lee, H. D.; Kim, N. Y.; Kim, S. N.; Son,
J. B. Org. Lett. 2006, 8, 3411.
10.1021/ol0611752 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/28/2006

commercially available crotonaldehyde exploiting a Nagao
acetate aldol,10 followed by application of the Charette
modification11 of the Simmons-Smith cyclopropanation. The
requisite â-hydroxy acid 5 was envisioned to arise via a
Masamune boron-mediated anti-aldol9 involving aldehyde 7.
We began the synthesis with construction of aldehyde 4
employing commercially available crotonaldehyde; seven
steps were required (Scheme 2). A TiCl4-mediated Nagao
Scheme 2
Figure 1. Original and revised structure of clavosolide A.
ment,7a,8 a tactic previously developed and successfully
applied in our laboratory for the construction of a variety
of architectually complex natural products.7b Our focus on
(-)-clavosolide A (1) was to explore the viability of the
Petasis-Ferrier union/rearrangement tactic in a system
possessing a highly acid-labile functionality (i.e., a cyclo-
propylcarbinyl system). Establishment of the absolute
stereochemistry was also a goal.
acetate aldol reaction10 employing thiozilidinone (+)-8 and
crotonaldehyde gave allylic alcohol (+)-9; the yield was 94%
(dr 18:1). Facile conversion to the Weinreb amide,12 followed
by the Charette modification11 of the Simmons-Smith
cyclopropanation, then led to syn-cyclopropylcarbinol
(+)-10 as a single diastereomer (NMR).
From the retrosynthetic perspective (Scheme 1), the
aglycon of (-)-clavosolide A (2) was envisioned to arise
Scheme 1
To correspond with the revised cyclopropylcarbinyl struc-
ture of (-)-clavosolide A (1), inversion of the stereogenicity
at C9 was required.13 To this end, a Mitsunobu reaction14
(7) (a) Petsis, N. A.; Lu, S. P. Tetrahedron Lett. 1996, 37, 141. (b)
(+)-Phorboxazole A: Smith, A. B, III.; Minbiole, K. P.; Verhoest, P. R.;
Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942. Smith, A. B., III; Razler,
M. T.; Ciavarri, P. J.; Hirose, T.; Ishikawa, T. Org. Lett. 2005, 20, 4399.
(+)-Spongistatin 1: Smith, A. B., III; Sfouggatakis, C.; Gotchev, B. D.;
Shirakami, S.; Bauer, D.; Zhu, W.; Doughty, V. A. Org. Lett. 2004, 20,
3637. (+)-Zampanolide and (+)-dactylolide: Smith, A. B., III; Safonov, I.
G.; Corbett, M. R. J. Am. Chem. Soc. 2002, 124, 11102. (-)-Kendomycin:
Smith, A. B., III; Mesaros, E. F.; Meyer, E. A. J. Am. Chem. Soc. 2005,
127, 6948. (+)-Sorangicin A: Smith, A. B., III; Fox, R. J.; Vanecko, J. A.
Org. Lett. 2005, 14, 3099.
(8) Concurrent with our efforts, Willis et al. also achieved the total
synthesis of (-)-clavosolide A; see: Barry, C. S.; Elsworth, J. D.; Sedan,
T. P.; Bushby, N.; Harding, R. J.; Alder, W. R.; Willis, L. C. Org. Lett.
2006, 8, 3319. We thank Professor Willis for helpful discussion during the
course of this synthetic venture.
(9) Abiko, A.; Buske, D. C.; Liu, J.; Inoue, T. J. Org. Chem. 2002, 67,
5250.
(10) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M. J. Org. Chem.
1986, 51, 2391.
(11) Charette, A.; Lebel, H. J. Org. Chem. 1995, 60, 2966.
(12) Rychnovsky, S. D.; Sinz, C. J. Tetrahedron 2002, 58, 6561
(13) Anti-cyclopropanation of the TIPS-protected allylic alcohol led to
a mixture (9:1) favoring the undesired syn-cyclopropylcarbinol (see:
Charette, A. B.; Lacasse, M.-C. Org. Lett. 2002, 20, 3351)
(14) Macor, J. E.; Wehner, J. M. Heterocycles 1993, 35, 349.
via a one-pot dimerization of monomer 3, the product of a
Petasis-Ferrier union/rearrangement, involving aldehyde 4
possesing the acid-labile cyclopropylcarbinyl moiety with
hydroxy acid 5. Aldehyde 4 in turn would derive from
3316
Org. Lett., Vol. 8, No. 15, 2006

with acetic acid furnished an inseparable diastereomeric
mixture favoring the desired acetate (12:1, inversion vs
retention).15 Ester hydrolysis followed by flash chromatog-
raphy furnished the pure anti-cyclopropylcarbinol (-)-11 in
58% yield for the three steps. Access to the first Petasis-
Ferrier union/rearrangement component, aldehyde (-)-4, was
then available via silyl protection of the hydroxyl group
followed by DIBAL reduction.
The requisite â-hydroxy acid (+)-5 was prepared in two
steps. The proposed boron-mediated anti-aldol delivered
alcohol (-)-13 in 96% yield (dr > 20:1). Removal of the
chiral auxiliary furnished hydroxy acid (+)-5 in 86% yield
(Scheme 3).
Lewis acidic conditions. Although the union of the â-hydroxy
acid and aldehyde proceeded smoothly, the Petasis-Ferrier
rearrangement, not surprisingly, was highly dependent on
the temperature, reaction time, and base additives employed.
Best conditions proved to be extremely rapid addition of
Me2AlCl to enol acetal 14 at room temperature; a single
diastereomer (-)-15 resulted in 60% yield. Slower additions
and/or inverse addition in conjunction with lower tempera-
tures or prolonged reaction times resulted either in no reaction
or complete decomposition. Other Lewis acids, as well as
base additives such as Me3Al and 2,6-di-tert-butyl-4-meth-
ylpyridine (DtBMP), were either incompatible or gave no
reaction at room temperature.
With optimized conditions for the union/rearrangement in
hand, we turned our attention to the revised structure of
clavosolide A.3,5 Bis-silylation of â-hydroxy acid (+)-5,
followed by TMSOTf-promoted18 condensation with alde-
hyde (-)-4, furnished dioxanone (-)-16 as an inseparable
mixture (7:1) of diastereomers at C3 in 94% yield. Petasis-
Tebbe methylenation19 followed by immediate rearrangement
of the unstable enol acetal 17, employing the optimal
conditions, led after purification by flash chromatography
to tetrahydropyranone (-)-18 in 65% yield for the two steps
(Scheme 5).
Scheme 3
Scheme 5
Conditions to effect the union/rearrangement via the
Petasis-Ferrier tactic were initially developed and optimized
employing enol acetal 14,17 possessing the earlier assigned
syn relationship in the cyclopropylcarbinyl moeity (Scheme
4). We were well aware of the potential risk of the
Scheme 4
Completion of the aglycon monomer now required four
steps. Sodium borohydride reduction20 of tetrahydropyranone
Me2AlCl-promoted rearrangement due to the lability of the
cyclopropylcarbinyl moiety to facile rearrangement16 under
(16) Poulter, D. C.; Winstein, S. J. Am. Chem. Soc. 1969, 13, 3650.
(17) Enol acetal 14 was prepared in seven steps and 58% overall yield
by a similar sequence as shown in Scheme 5 (excluding the Mitsunobu
inversion).
(15) The order of addition (betaine formation) and temperature (-45
°C in toluene) in the Mitsunobu reaction proved to be critical to achieve
high stereoselectivity.
Org. Lett., Vol. 8, No. 15, 2006
3317

(-)-18 furnished the desired equatorial alcohol (-)-19 in
76% yield (dr > 10:1), which was immediately protected as
the corresponding benzyl ether. Removal of the silyl groups
under acidic conditions then led to diol (+)-20 in 84% yield
for the two steps. Selective oxidation21 of the primary alcohol
employing TEMPO, NaOCl, and tetrabutylammonium chlo-
ride (TBAC) completed construction of monomer (+)-3 in
81% yield.
(+)-21 in 66% yield without noticeable formation of higher
molecular weight congeners. Removal of the benzyl protect-
ing groups by hydrogenolysis furnished aglycon (-)-2 in
64% yield, identical in all respects including chiroptic
properties to those reported by Lee and co-workers.5
Turning to the requisite bis-glycosidation, the challenge
of high diastereoselectivity in the absence of anchimeric
assistance would require an optimal acid (TMSOTf)27 and
solvent (e.g., acetonitrile)25 for the glycosidation protocol.
Unfortunately, such conditions only led to decomposition
of both the aglycon and the glycosyl donor 22,26 presumably
due to the nucleophilic nature of the solvent. Similar
conditions with CH2Cl2 as the solvent did however furnish
(-)-clavosolide A (1) in 12% yield, along with the expected
R,â and R,R anomers in 37% and 20% yield, respectively.
With monomer (+)-3 in hand, we now faced the critical
dimerization (Scheme 6). Several conditions were explored
Scheme 6
1
The H NMR and 13C NMR data of (-)-clavosolide A
(1) proved to be in excellent agreement with the correspond-
ing data for both the natural and synthetic (-)-clavosolide
A, as reported by Faulkner et al.1 and by Lee and co-
workers,5 respectively. However, upon measurement of the
optical rotation, we obtained a value of -42.5 (c 0.10,
CHCl3), in contrast to the value of +52.0 (c 0.165, CHCl3)
reported by Lee and co-workers.5 To resolve this discrepancy,
the relative and absolute stereochemistry of synthetic (-)-1
were confirmed by X-ray crystallography, wherein the
absolute stereochemistry was established based on the
absolute configuration of D-(+)-xylose, employed to con-
struct glycosyl donor 22. We conclude therefore that the
absolute stereochemistry of natural (-)-clavosolide A is as
illustrated in Scheme 6.
In summary, an enantioselective total synthesis of
(-)-clavosolide A has been achieved in 17 steps (longest
linear sequence). Central to this venture was the highly
convergent Petasis-Ferrier union/rearrangement to construct
the cis-tetrahydropyran monomer (+)-3, demonstrating the
viability of this tactic with an acid labile moiety. A one-pot
dimerization then efficiently delivered aglycon (-)-2.
Acknowledgment. Financial support was provided by the
National Institute of Health (National Institute of General
Medical Screening) through Grant No. GM-29028. In ad-
dition, we thank Professor Lee (Sogang University, Korea)
for his helpful resolution of the discrepancy concerning the
sign of the optical rotation of their synthetic clavosolide A.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds, as well as experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0611752
both with the original and revised clavosolide monomers.22
The Corey-Nicolaou “double activation” protocol23 provided
diolide (+)-21 in 30% yield, albeit with low conver-
sion. Pleasingly, the Yamaguchi conditions24 cleanly afforded
(22) Distannoxane catalyst: Panek, J. S.; Porco, J. A., Jr.; Lobkovsky,
E.; Beeler, A. B.; Su, Q. Org. Lett. 2003, 12, 2149. 2-Chloro-1,3-
dimethylimidazolinium chloride: Furstner, A.; Mlynarski, J.; Albert, M. J.
Am. Chem. Soc. 2002, 124, 10274. Phosphoric mixed anhydride: Waka-
matsu, T.; Yamada, S.; Ban, Y. Heterocycles 1986, 24, 309.
(23) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
(24) Yamaguchi, M. A.; Katsuki, T.; Saeki, H.; Hirata, K.; Inanaga, J.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(18) Seebach, D.; Imwinkelried, R.; Stucky, G. HelV. Chim. Acta 1987,
70, 448.
(19) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(20) Wigfield, C. D. Tetrahedron 1979, 35, 449-462.
(21) Davis, N. J.; Flitsch, S. L. Tetrahedron Lett. 1993, 34, 1181.
(25) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694.
(26) See the Supporting Information.
(27) Kong, F.; Yang, G. Carbohydr. Res. 2005, 340, 39.
3318
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