Synthetic studies on norrisolide: Enantioselective synthesis of the norrisane side chain

Article abstract of DOI:10.1021/ol9909785

Norrisolide (1) belongs to a family of marine diterpenes that are characterized by the assembly of a bicyclic core with a unique and highly oxygenated side chain (norrisane side chain). As a prelude to the synthesis of 1, we present herein a short, effici

Full text of DOI:10.1021/ol9909785

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1295-1297
Synthetic Studies on Norrisolide:
Enantioselective Synthesis of the
Norrisane Side Chain
Charles Kim, Richard Hoang, and Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, UniVersity of California,
San Diego, 9500 Gilman DriVe, La Jolla, California 92093-0358
etheodor@ucsd.edu
Received August 23, 1999
ABSTRACT
Norrisolide (1) belongs to a family of marine diterpenes that are characterized by the assembly of a bicyclic core with a unique and highly
oxygenated side chain (norrisane side chain). As a prelude to the synthesis of 1, we present herein a short, efficient, and enantioselective
synthesis of the norrisane side chain 4. The synthetic route toward 4 departs from D-mannose and is short (11 steps), efficient, and
enantioselective.
Norrisolide (1) is a marine natural product, initially isolated
by Faulkner and co-workers from the nudibranch Chromo-
doris norrisi, collected in the Gulf of California.1 The
structure and relative stereochemistry of 1 were established
by extensive spectroscopic and crystallographic studies,
which revealed a unique assembly of a perhydroindane core
to a side chain containing a fused γ-lactone-γ-lactol ring
system. This peculiar side chain was subsequently identified
as a structural motif of other members of the norrisane
family, which currently include macfarlandin C (2) and
dendrillolide A (3) (Figure 1).2
Figure 1. Marine natural products of the norrisane family.
The surprising lack of any synthetic studies toward
norrisolide and related compounds may be attributed to their
initially reported poor antimicrobial activity.2b Recent studies,
however, have indicated that norrisolide (1) interferes with
the structure and promotes the vesiculation of the Golgi
apparatus in vivo.3 Among the few natural products known
to affect the Golgi organization, 1 distinguishes itself as being
the only compound known to induce an irreversible effect.4
The observed inability of the treated cells to recover may
imply that norrisolide forms a covalent interaction with its
biological receptor and points to the side chain of 1 as the
(1) Hochlowski, J.; Faulkner, D. J.; Matsumoto, G.; Clardy, J. J. Org.
Chem. 1983, 48, 1141-1142.
(2) (a) Sullivan, B. J.; Faulkner, D. J. J. Org. Chem. 1984, 49, 3204-
3209. (b) Molinski, T. F.; Faulkner, D. J.; He, C.-h.; Van Duyne, G. D.;
Clardy, J. J. Org. Chem. 1986, 51, 4564-4567. (c) Rudi, A.; Kashman, Y.
Tetrahedron 1990, 46,4019-4022.
(3) Malhotra, V.; Faulkner, D. J. Personal communication, 1999.
(4) (a) Takizawa, P. A.; Yucel, J. K.; Veit, B.; Faulkner, D. J.; Deerinck,
T.; Soto, G.; Ellisman, M.; Malhotra, V. Cell. 1993, 73, 1079-90. (b)
Lippincott-Schwartz, J.; Yuan, L. C.; Bonifacino, J. S.; Klausner, R. D.
Cell. 1989, 56, 801-813.
10.1021/ol9909785 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

potential site where such an interaction can occur. Our
interest in these aspects of this class of compounds led us to
envision a convergent synthesis of norrisolide (1). As a
prelude to this effort, we report herein the construction of
the norrisane side chain 4. Our strategy also represents the
first synthetic entry to this type of fused bicyclic γ-lactone-
γ-lactol ring system.5
to the desired stereochemistry of the acetoxy group of 4
during the Baeyer-Villiger oxidation. Our efforts to bring
this strategy to fruition are shown in Scheme 1.
Scheme 1.a Synthesis of Norrisane Side Chain 4
Respectful of the inherent reactivity of the bicyclic array
of 4 toward nucleophilic attack or acid treatment (oxonium
ion formation), we sought to design its synthesis starting from
the less oxygenated and more stable lactone 5. Installation
of the C16 acetoxy group was then envisioned to occur at
the last step of the synthesis by oxidizing ketone 5 under
Baeyer-Villiger conditions (Figure 2).6 This oxidation was
Figure 2. Retrosynthesis of fragment 4 (norrisane side chain).
advantageous since it proceeds under mild conditions and is
regio- and stereoselective.7 The fused bicyclic system 5 was
expected to be formed from ester 6 via a sequence of
reactions involving cyclopropane opening followed by lac-
tone formation. Further disassembly of the cyclopropyl ester
at the C12 and C15 centers suggested the mannose-derived
glycal 7 as a putative starting material. Taking advantage of
the facial differentiation of 7, a substrate-controlled cyclo-
propanation could introduce the desired chirality at C12
center, ultimately dictating the stereochemical outcome at
the C15 center. Moreover, the chirality inherited from the
structure of D-mannose at the C16 center could be translated
(5) For a catalytic asymmetric Diels-Alder approach to a related tricyclic
γ-lactone-γ-lactol ring system, see: Corey, E. J.; Letavic, M. A. J. Am.
Chem. Soc. 1995, 117, 9616-9617.
(6) For an impressive demonstration of the Baeyer-Villiger reaction in
total synthesis, see: Corey, E. J.; Trybulski, E. J.; Melvin, L. S., Jr.;
Nicolaou, K. C.; Secrist, J. A.; Lett, R.; Sheldrake, P. W.; Falk, J. R.;
Brunelle, D. J.; Haslanger, M. F.; Kim, S.; Yoo, S. J. Am. Chem. Soc. 1978,
100, 4618-4620. Corey, E. J.; Kim, S.; Yoo, S.; Nicolaou, K. C.; Melvin,
L. S., Jr.; Brunelle, D. J.; Falk, J. R.; Trybulski, E. J.; Lett, R.; Sheldrake,
P. W. J. Am. Chem. Soc. 1978, 100, 4620-4622.
(7) (a) Hudlicky, M. Oxidations in Organic Chemistry; American
Chemical Society: Washington, DC, 1990; pp 186-195. (b) Cooper, M.
S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett 1990, 533-535.
(c) Mislow, K.; Brenner, J. J. Am. Chem. Soc. 1953, 75, 2318-2322. For
a discussion on the migratory aptitude involved in Baeyer-Villiger
oxidations, see: (d) Goodman, R. M.; Kishi, Y. J. Am. Chem. Soc. 1998,
120, 9392-9393.
Our synthetic venture departed with transformation of
D-mannose (8) to the known bisacetonide 9 (Scheme 1).8
Superior results were obtained using iodine as a catalyst (as
compared to H2SO4 treatment) and delivered 9 in 85% yield
(8) Kartha, K. P. R. Tetrahedron Lett. 1986, 27, 3415-3416.
Org. Lett., Vol. 1, No. 8, 1999
1296

after a simple filtration and crystallization. Treatment of 9
with p-toluenesulfonyl chloride and triethylamine afforded
the desired glycosyl chloride 10,9 which upon slow addition
to a stirring mixture of sodium naphthalenide in THF gave
rise to glycal 11 in 48% overall yield.10 Compound 11 proved
to be labile upon standing (presumably due to self-oligo-
merization) and was immediately benzylated (BnBr, NaH,
n-Bu4I) to produce vinyl ether 7 in 90% yield. We anticipated
that the bulky acetonide group at C16 in conjuction with
the benzyl ether group at C11 would shield the top face of
vinyl ether 7 and direct the sterically cumbersome rhodium
acetate carbenoid from the â-face of the molecule. Indeed,
this cyclopropanation furnished ester 6 with the desired
configuration at C12 center, albeit in only 45% yield.11,12
To improve upon the yield of this reaction, we altered the
temperature (0 °C to 80 °C in refluxing benzene), rate of
addition, and concentration of reagents. An increase in
temperature had no observable effect in product formation;
however, the reagent concentration appeared to be crucial,
since under dilute conditions an increased amount of byprod-
ucts arising from dimerization of the ethyl diazoacetate was
observed. Best results were obtained upon syringe pump
addition of ethyl diazoacetate (0.1 M in CH2Cl2) into a
concentrated mixture of 7 (2 M in CH2Cl2) and rhodium(II)
acetate at 25 °C. The only diastereomers acquired during
this reaction were produced at the C13 center (4:1 ratio in
favor of the exo adduct) and both were taken forward.
Exposure of 6 to a dilute ethanolic solution of sulfuric
acid induced acetonide deprotection followed by concomitant
opening of the cyclopropane ring afforded compound 12 in
78% overall yield.13,14 After oxidative cleavage of diol 12
(NaIO4), the resulting aldehyde was methylated upon treat-
ment with MeTi(i-OPr)3 (formed in situ by mixing TiCl4,
Ti(iOPr)4, and MeLi)15 to produce 13 in 63% combined yield.
This addition proceeded with excellent chemoselectivity (no
interference with the ester functionality) and diastereoselec-
tivity (about 10:1 mixture of diastereomers at the C17 center,
presumably arising from a chelation-controlled addition).
Oxidation of 13 under Swern conditions gave rise to ketone
14 (79% yield). A series of Bro¨nsted acids or Lewis acids
(TiCl4, BF3‚Et2O, AlCl3, H2SO4, MeSO3H) were evaluated
for the conversion of 14 to 5. Although all these acids
effected the desired transformation in variable yields, best
yields were obtained using methanesulfonic acid, which at
0 °C produced bicycle 5 as a single isomer in 67% yield.16
The stage was now set for the crucial Baeyer-Villiger
oxidation. Several peracids were tested, such as m-CPBA
and H2O2 (30% aqueous), but these proved to be ineffective.
The conversion of 5 to 4 was ultimately achieved using
urea-hydrogen peroxide and trifluoroacetic anhydride and
gave rise to the desired material in 69% yield.17 As predicted,
a single isomer was obtained during this oxidation, the
structure of which was established by COSY and NOE
experiments.18
In conclusion, we have presented herein a concise,
enantioselective approach to the C11-C18 fragment of
norrisolide 1. Our approach departs from commercially
available D-mannose (8) and delivers the fused γ-lactone-
γ-lactol ring system 4 in 11 steps and good overall yield.
The synthetic route takes advantage of the inherent chirality
of D-mannose and is highlighted by a rhodium-catalyzed
substrate-controlled cyclopropanation, followed by an acid-
catalyzed conversion of a cyclopropane ester to a five-
membered lactone and subsequent Baeyer-Villiger oxidation
of a methyl ketone. Extension of the above strategy to the
synthesis of norrisolide (1) and related compounds is
currently underway in our laboratories.
Acknowledgment. Financial support from the Cancer
Research Coordinating Committee, the American Cancer
Society (RPG CDD-9922901), the NSF (Shared Instrumenta-
tion Grant CHE-9709183), and the Hellman Foundation
(Faculty Research Fellowship to E.A.T.) is gratefully ac-
knowledged. We thank J.-M. Senegas for his contributions
to this project. R.H. thanks UCSD for a Chancellor’s
Undergraduate Research Fellowship. We also thank Professor
D. John Faulkner (Scripps Insitute of Oceanography) and
Professor V. Malhotra (UCSD, Department of Biology) for
critical suggestions.
(9) Hwang, C. K.; Li, W. S.; Nicolaou, K. C. Tetrahedron Lett. 1984,
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(10) Eitelman, S. J.; Hall, R. H.; Jordaan, A. J. Chem. Soc., Perkin Trans.
1 1977, 595-600.
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P.; Forbes, D. C. Chem. ReV. 1998, 98, 911-935. (b) Doyle, M. P.;
Protopopova, M. N. Tetrahedron 1998, 54, 7919-7946. (c) Davies, H. M.
L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc.
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A.; Woerpel, K. M.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991,
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M. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 430-432. (d) Lowenthal, R.
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M. L.; Kong, N.; Churchill, M. R. J. Org. Chem. 1998, 63, 6586-6589. (f)
Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J. Tetrahedron Lett. 1996, 37,
4133-4136.
(13) For references on cyclopropyl ring opening, see: (a) Temme, O.;
Taj, S. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 6007-6015. (b) Brown,
S. P.; Bal, B. S.; Pinnick, H. W. Tetrahedron Lett. 1981, 22, 4891-4894.
(c) Wenkert, E.; Alonso, M. E.; Buckwalter, B. L.; Sanchez, E. L. J. Am.
Chem. Soc. 1983, 105, 2021-2029. (d) Beyer, J.; Madsen, R. J. Am. Chem.
Soc. 1998, 120 12137-12138.
(14) For selected examples of related cyclopropane ring openings, see:
(a) Henry, K. J., Jr.; Fraser-Reid, B. Tetrahedron Lett. 1995, 36, 8901-
8904. (b) Alonso, M. E.; Morales, A. J. Org. Chem. 1980, 45, 4530-4532.
(c) Hiyama, T.; Saimoto, H.; Nishio, K.; Shinoda, M.; Yamamoto, H.; Noaki,
H. Tetrahedron Lett. 1979, 2043-2046. (d) Bertinato, P.; Sorensen, E. J.;
Meng, D. F.; Danishefsky, S. J. J. Org. Chem. 1996, 61, 8000-8001.
Supporting Information Available: Experimental pro-
1
cedures and spectral data (including copies of H and 13C
NMR spectra) for compounds 4-7, 9, and 10. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9909785
(15) (a) Weidmann, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1983,
22, 31-45. (b) Reetz, M. Titanium in Organic Synthesis. In Organometallics
in Synthesis: A Manual; Schlosser, M., Ed.; John Wiley & Sons: New
York, 1994; pp 195-282.
(16) For similar transformations using MeSO3H as the reagent of choice,
see: (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Choi, H. S.; Yoon,
W. H.; He, Y.; Fong, K. C. Angew. Chem. Int. Ed. 1999, 38, 1669-1678.
(b) Corey, E. J.; Kamiyama, K. Tetrahedron Lett. 1990, 31, 3995-3998.
(17) Interestingly, no reaction was observed when the above oxidation
was performed under buffered conditions (Na2HPO4) (see ref 7b).
(18) All new compounds exhibited satisfactory spectroscopic and analyti-
cal data (see Supporting Information). Yields refer to spectroscopically and
chromatographically homogeneous materials.
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