Published on Web 06/01/2010

Total Synthesis of (()-Aplykurodinone-1: Traceless Stereochemical Guidance

Yandong Zhang† and Samuel J. Danishefsky*,†,‡
Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway, New York, New York 10027 and
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue,
New York, New York 10065
Received April 26, 2010; E-mail: [email protected]

Scheme 1. Synthetic Strategy toward Aplykurodinone-1 (1)

Abstract: The total synthesis of the highly degraded steroidal
natural product, aplykurodinone-1 (1), has been accomplished.
Key features include a one-flask hydrolysis/retro-aldol/iodolac-
tonization sequence to excise the C8 hydroxymethylene function-
ality with retention of stereochemistry and the stereoselective
installation of the C13 methyl group through hydrogenation with
homogeneous catalyst.

Of all of the classes of natural products, steroids have perhaps

had the most enduring role in prompting new ideas in total
synthesis.1 A not insignificant body of organic chemistry has been
discovered in the context of pursuits directed to the total synthesis contains an array of coordinated functionality, which could well
of steroids. Apparently, this interest continues to the present day.2 enable access to the eventual target system, 1. The plan envisioned
One of the vexing problems in steroid total synthesis is that of halolactonization as the instrumentality for fusing the γ-lactone to
exercising control of the configuration at C20.3 The challenge is the cis-fused hydrindanone, thereby creating a ladder-like topog-
that of correlating the configuration of the presumably “freely raphy. Accordingly, we needed to gain secure control over the
rotating” C20 with the resident stereochemistry of the polycyclic configurational relationship between strategic carbons 3 and 7 in 1
domain. Though ingenious solutions to the “C20 problem” have been (vide infra). It occurred to us that an otherwise unnecessary
advanced, it is still an interesting and thought provoking matter. quaternary function at C8 could orchestrate the required relationship
It was in this setting that we took particular note of the of the angular methyl group at C7 with a soon-to-be-installed acetic
aplykurodines, isolated from marine mollusks of the genus Aplysia.4 acid moiety at C3 (see structures 5 and 6). Iodolactonization leading
This family can well be viewed as a rare class of highly degraded to the γ-lactone could then follow in the wake of excision of the
marine steroids, where C13 in the aplykurodine setting corresponds now traceless C1 fragment.
to C20 in wild-type steroids. Also of note is the cis fusion of the Given the general line of thinking adumbrated above, and a long-
hydrindane sector in contrast to the trans C-D fusion of hydrin- term proclivity for Diels-Alder reactions, we hoped to advance
danes, which is so prevalent in fully mature steroids.5 along such lines. In the event, it was discouraging to find that
We note that various aplykurodines exhibit cytotoxic activity attempted cycloaddition between 29 and 310 failed under various
against a range of human cancer cell lines.4 Notwithstanding the thermal and Lewis acid mediated conditions. However, reaction of
potential elements of chemistry and medicinal chemistry-based 2 with methyllithium generated an operational lithium enolate,11
points of interest, surprisingly little attention at the level of synthesis which did undergo effective cycloaddition with 3, thereby providing
has been directed to the aplykurodines.6 Our laboratory took a 73% yield of 4. It is well recognized that realization of the required
particular note of a recently isolated member of the family, cycloaddition does not, in and of itself, inform as to the limiting,
aplykurodinone-1 (1).7 Following its isolation from the sea hare mechanistic, extremi (two sequential Michael additions or an
Synphonota geographica in 2005, the structure of aplykurodinone-1 anionically mediated Diels-Alder reaction).12
(1) was elucidated through a combination of spectroscopic methods, The enone was regioselectively masked as a thioketal.13 The C9
X-ray crystallography, and chemical correlation. As shown in ketone was then reduced, as shown, and the resultant alcohol was
Scheme 1, 1 was found to possess a cis-fused C-D ring with protected as a MOM ether. Upon reduction of the ester and removal
epimeric C8 (steroidal numbering) and an unsaturated side chain of the dithiane ketal,13a,14 compound 10 was in hand. The primary
(as compared to cholesterol). alcohol was next converted to its diazoacetyl derivative, 11. As
On the basis of considerations advanced above, a total synthesis shown in Scheme 2, intramolecular cyclopropanation onto the
effort directed to this “degraded” steroid was undertaken. Below electron-deficient enone afforded the activated cyclopropane, 5,
is described the inaugural total synthesis of (()-1, resulting from though only in moderate yield (40%).15
this initiative. As will be seen, the program potentially encompassed The next phase entailed the opening of the cyclopropane ring,
several chemistry-level initiatives of broader heuristic value. with concomitant installation of unsaturation at C4-C5. Toward
Using ideas stemming from analysis by pattern recognition,8 we this end, the C5 ketone was converted to an iodide through a two-
envisioned that, in principle, the hypothetical hydrindanone 4 step sequence, commencing with Luche reduction,16 which provided
a 2:1 (:R) epimeric mixture of alcohols.17 These compounds were
†
Columbia University.
readily converted to iodide 12. In the event, upon exposure of 12
‡
Sloan-Kettering Institute for Cancer Research. to SmI2,18 it readily suffered the hoped-for reductive cyclopropane
10.1021/ja1035495  2010 American Chemical Society J. AM. CHEM. SOC. 2010, 132, 9567–9569 9 9567
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Scheme 2. Synthesis of 6 en Route to Aplykurodinone-1 (1) Scheme 4

a
Key: (a) MeLi, DME/THF, -50 °C; TFA, CHCl3, reflux, 73%; (b)
a
Key: (a) 17, t-BuLi, CuCN, BF3 · OEt2, -78 °Cf-98 °C, 73%, 10:1
HSCH2CH2SH, AcOH, p-TSA, 74%; (c) NaBH4, CH2Cl2/MeOH, -78°f dr; (b) Crabtree catalyst, H2, CH2Cl2, 75% conversion, 50% yield (pure);
-40 °C; (d) MOMCl, iPr2NEt, CH2Cl2, 84% over two steps; (e) DIBAL- (c) HF, CH3CN/THF; (d) DMP, CH2Cl2, 87% over two steps; (e) THF,
H, CH2Cl2, -78 °C; (f) Tl(NO3)3, MeOH/THF/H2O, 95% over 2 steps; (g) LiHMDS, -78 °C, 68%.
TsNHN)CHCOCl, PhNMe2, Et3N, CH2Cl2, 0 °C, 88%; (h) bis-(N-tert-
butylsalicylaldiminato) copper(II), PhMe, reflux, 40%; (i) NaBH4, Scheme 5
CeCl3 · 7H2O; (j) I2, PPh3, imidazole, PhMe, reflux, 78% over two steps;
(k) SmI2, THF/MeOH, 85%; (l) HCl, THF/H2O; (m) DMP, CH2Cl2, 80%
over two steps.

Scheme 3

a
Key: (a) 17, t-BuLi, CuCN, Et2O, -78 °C, 51%; (b) Wilkinson catalyst,
H2, benzene, 67%.

a
Key: (a) K2CO3, H2O, 100 °C; (b) NIS, CH2Cl2, 75%; (c) Ra-Ni, accomplished with a high degree of facial selectivity (10:1 dr) to
CH2Cl2/EtOH, 90%; (d) TMSOTf, Et3N, CH2Cl2, 0 °C; Pd(OAc)2, CH3CN, provide intermediate 18. Given the difficulties surrounding the
76% (90% brsm). heterogeneous hydrogenation of the C20-C22 olefin as a means of
installing the C20 stereocenter of trans-fused mature steroids,23 it
opening, to deliver lactone 13 in good yield (85%). The latter was was hoped that homogeneous hydrogenation protocols may be more
converted to 6 in a straightforward fashion, as shown. productive.24 Thus, following exposure to Crabtree catalyst,25 under
The otherwise extraneous C8 oxymethylene functionality had an atmospheric pressure of H2, the trisubstituted olefin was reduced
indeed been exploited as a very useful C3 stereochemical linchpin in a diastereoselective fashion (>5:1) to furnish compound 19, which
(vide supra). Having served its function in mediating the stereo- bears all of the stereocenters of aplykurodinone-1 (1). A single
selective installation of the C3 center, the C1 fragment was cleaved crystal of this advanced intermediate was obtained, and X-ray
via a hydrolysis-retro-aldol sequence following exposure of 6 to crystallographic analysis was found to support the proposed
the action of K2CO3 in water at 100 °C. Subsequent iodolacton- structure. Elaboration of the side chain was accomplished in a
ization19 of the resultant carboxylic acid (14) was accomplished in straightforward fashion, as shown. Thus, cleavage of the TBS
the same flask, to provide 15 in 75% yield from 6. The re-emergence group26 and subsequent oxidation27 delivered aldehyde 20, which
of the cis-junction was confirmed through NOESY analysis of the readily underwent modified Julia olefination28 to furnish the target
methyl ester derivative of 14 and by X-ray diffraction of the compound, aplykurodinone-1 (1). Its spectroscopic properties were
subsequent deiodinated intermediate, 16.20 Finally, Saegusa oxida- the same as those reported for the isolated natural product. In the
tion21 of 16 afforded 7, presenting the tricyclic core of aplykurodi- course of these synthetic studies, we also investigated a different
none-1, in the sense shown (Scheme 3). route for the emplacement of the C11 side chain. The fully elaborated
With compound 7 in hand, the synthesis entered its terminal dienyl fragment could be appended to the core (7) in a single step.
phase, i.e. installation of the C11 side chain. A stepwise strategy It was hoped that the intermediate thus obtained could then be
was set in place. As outlined in Scheme 4, BF3-mediated conjugate converted, in one step, to aplykurodinone-1 (1), through regio- and
addition of the cuprate derived from vinyl bromide 1722 was stereoselective hydrogenation. In the event, the conjugate addition
9568 J. AM. CHEM. SOC. 9 VOL. 132, NO. 28, 2010
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29
of 21 to 7 was accomplished, to provide 22 in moderate yield. (8) For a discussion of the value of pattern analysis as a supplement to strategic
bond disconnection in retrosynthetic analysis, see: Wilson, R. M.; Dan-
Upon exposure to Wilkinson’s catalyst30 under atmospheric H2, ishefsky, S. J. J. Org. Chem. 2007, 72, 4293–4305.
the 13-epi-aplykurodinone-1 isomer (23) was selectively formed (9) Danishefsky, S. J. Acc. Chem. Res. 1981, 14, 400–406.
(10) Hua, D. H.; Venkataraman, S.; King, R. C. Y.; Paukstelis, J. V. J. Am.
(>6:1 dr) (Scheme 5). Perhaps in each of the two hydrogenation Chem. Soc. 1988, 110, 4741–4748.
transition states (18f19; 22f23), the double bond projects from (11) (a) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4464–4465. (b)
the -face of the molecular backbone. The bulky catalyst then Baker, R.; Selwood, D. L.; Swain, C. J.; Webster, N. M. H. J. Chem. Soc.,
Perkin Trans. 1 1988, 471–480.
approaches the olefin from the unhindered portion of the olefin, to (12) (a) Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1010–
provide the observed stereochemical outcome.31 1022. (b) Kanemasa, S.; Kumegawa, M.; Wada, E.; Nomura, M. Bull. Chem.
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In summary, the total synthesis of aplykurodinone-1 (1) has been (13) (a) Bosch, M. P.; Camps, F.; Coll, J.; Guerrero, A.; Tatsuoka, T.; Meinwald,
accomplished. A key feature of the effort involved an anionically J. J. Org. Chem. 1986, 51, 773–784. (b) Golinski, M.; Brock, C. P.; Watt,
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Supporting Information for details.
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