J. Org. Chem.

1993,58, 11-13 11

Total Synthesis of the Tetraquinane Diterpenoid (±)-Crinipellin B

Edward Piers* and Johanne Renaud
Department of Chemistry, University of British Columbia, 2036 Main Mall, University Campus, Vancouver,
British Columbia, Canada V6T 1Z1
Received October 14, 1992

Summary: Beginning with 2-methyl-2-cyclopenten-l-one Scheme I1

(5), the total synthesis of the structurally novel tet-
raquinane diterpenoid (±)-crinipellin B (4) has been
accomplished via a 22-step sequence of reactions.
The crinipellane-type diterpenoids are a small family
of structurally unprecedented natural products that share
thel2-isopropyl-4,8,ll-trimethyltetracyclo[6.6.0.01’11.03'7]-
tetradecane skeleton l.1 Three members of this group,
crinipellin A, O-acetylcrinipellin A, and crinipellin B,
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isolated from different strains of the fungus Crinipellis

stipitaria (Agaricales), have been shown to possess the
structures shown in formulas 2-4, respectively.1 Each of
these highly oxygenated substances contains eight ste-
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reogenic centers, three of which consist of contiguous

quaternary chiral carbon atoms (C-l, C-8, C-ll). Com-
pounds 2-4 exhibit interesting biological properties,
including powerful antibiotic activity.1·2

1 2R-H 4
3 R - OAc

A number of reports describing synthetic approaches to

the crinipellins have appeared.3 However, to our knowl-
edge, the total synthesis of one or more of these substances
has not yet been recorded. We describe herein a total (a) -PrMgBr, CuBr-MejS, Me3SiCl, HMPA, THE, -78 °C, 4 h;
Et3N (94%); (b) MeLi, THE, 0 °C; 2-(bromomethyl)-l-butene,
synthesis of (db)-crinipellin B via a route in which two new (PhsP)4Pd, THE, -20 °C, 2 h; 0 eC, 5 h (76%); (c) 03, MeOH-CH2Cl2,
5-membered ring annulation methods play key roles. -78 °C; Me2S, -78 °C to room temperature; concentrate mixture,
Conversion of the enone 5 into the functionalized add 10% HC1-H20 and THE, stir at room temperature for 18 h
(93%); (d) MeONa, MeOH, reflux 15 h (97 %); (e) reagent 19, MesSiBr,
tetraquinane 18 was achieved via the reaction sequence
THE, -78 eC, 8 h; -48 °C, 2 h (83 %); (f) I2, CH2C12, room temperature,
summarized in Scheme I. Copper(I)-catalyzed conjugate 16 h (98%); (g) (PhsPjJ’d (21 mol %), t-BuOK, t-BuOH, THE, room
addition of ¿-PrMgBr to 5 in the presence of MegSiCl and temperature (84%); (h) n-Bu(i-Bu)2Al(H)Li, EtaO, -78 °C, 2 h; 0 °C,
HMP A provided the enol silyl ether 6.4 5As expected (steric 1 h (93%); (i) t-BuMe2Si0S02CF3, Et3N, CH2C12, -78 eC, 75 min;
0 °C, 20 min (98%); (j) Os04, CgHgN, room temperature, 23 h;
approach control), alkylation of the lithium enolate derived
from 6 with 2-(bromomethyl)-l-butene in the presence of NaHS03, H20,1 h; Pb(OAc)4, THE, 0 °C, 30 min; HOCH2CH2OH,
10 min (93%); (k) £-Pr2NLi, THE, -78 eC; (Z)-3-bromo-l-iodopropene,
(PhsP^Pd6 gave, stereoselectively, the monoalkylated room temperature, 7.5 h (76%); (1) n-BuLi (2.5 equiv), THE, -78 eC,
product 7, along with minor amounts of dialkylated 110 min (93%); (m) CsHsN-CrOs-HCl, CH2C12, Celite, room tem-
materials. Base-promoted cyclization of the dione 8, which perature, 3.5 h (51%).
was readily obtained by oxidative cleavage of the alkene laboratory.7 Thus, conjugate addition of the novel cuprate
function in 7,6 produced the bicyclic enone 9 in excellent reagent 19 (see eq 1) to the enone 9 in the presence of
yield.
Transformation of 9 into the triquinane 12 made use of 1) f-BuLi (2 equiv)

a new annulation sequence developed recently in our

MeaGe' X^ I
THF, -98°C
2) CuCN.THF
-7eeCtO-30°C
„
II

Me3Ge^<^Cu(CN)Li
19
'(1)

(1) Anke, T.; Heim, J.; Knock, F.; Mocek, U.; Steffen, B.; Steglich, W.
Angew. Chem., Int. Ed. Engl. 1985, 24, 709. 3 min
(2) Kupka, J.; Anke, T.; Oberwinkler, F.; Schramm, G.; Steglich, W.
J. Antibiot. 1979, 32, 130. MegSiBr, followed by appropriate workup, afforded the
(3) Mehta, G.; Rao, K. S. J. Chem. Soc., Chem. Commun. 1987,1578. keto trimethylgermane 10 (mixture of epimers), which was
Mehta, G.; Rao, K. S.; Reddy, M. S. Tetrahedron Lett. 1988, 29, 5025.
Schwartz, C. E.; Curran, D. P. J. Am. Chem. Soc. 1990,112,9272. Mehta,
G.; Rao, K. S.; Reddy, M. S. J. Chem. Soc., Perkin Trans. 1,1991, 693. (6) The NMR spectrum of the crude product acquired from
(4) All new compounds were spectroscopically characterized and gave subjection of 7 to ozonolyais-MejS (step c, Scheme I) showed MeO signals,
satisfactory elemental analyses and/or high-resolution mass spectrometric indicating the presence of a ketal function. Acid hydrolysis of this material
molecular mass determinations. produced 8 in high yield.
(5) Negishi, E.; John, R. A. J. Org. Chem. 1983, 48, 4098. (7) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454.

0022-3263/93/1958-0011$04.00/0 &copy; 1993 American Chemical Society

12 J. Org. Chem., Vol. 58, No. 1,1993 Communications

converted smoothly into the corresponding keto iodide Scheme II*

11. An efficient Pd(0)-catalyzed cyclization of 11 in the
presence of t-BuOK7 gave 12. The overall conversion of
5 into 12 was highly stereoselective and produced a
functionalized tricycle in which the three contiguous
quaternary stereogenic centers required for the eventual
synthesis of (±)-crinipellin B (4) had been installed cleanly
and efficiently.
A straightforward sequence of reactions served to effect
the efficient conversion of 12 into the keto ether 15 (mp
47-48.5 eC), via the intermediates 13 and 14. Of particular
note was the highly stereoselective reduction of 12 with
the complex metal hydride derived from reaction of i-Bu2-
A1H with n-BuLi.
Construction of the fourth required 5-membered ring
was initially problematic. Although a number of known
cyclopentenone annulation methods8 were attempted,
none were successful. In the present case, the usual
difficulties associated with the conversion of (unsymmet-
rically substituted) cyclopentanones into the correspond-
ing bicyclo[3.3.0]oct-l-en-3-ones are exacerbated by the
hindered nature of the carbonyl function in 15. In view
of these difficulties, a new cyclopentenone annulation
sequence was developed (transformation of 15 into 18, 0
(a) H2O2, NaHCOa, H2O-THF (1:2), room temperature, 55 min
Scheme I).9 (84%); (b) (Me3Si)2NLi, THF, -78 eC; (H2C=NMe2)+I-, -78 °C, 70
min; -70 °C, 18 min; flash chromatography (silica gel) (78%); (c)
Alkylation of 15 with (Z)-3-bromo-l-iodopropene10 was NaBH4, MeOH-THF, -78 °C, 85 min; -63 °C, 15 min (80%); (d)
highly stereoselective and provided the keto iodide 16 t-BuMe2Si0S02CF3, Et3N, CH2C12, -78 °C, 2 h; 0 eC, 70 min (88%);
efficiently. Treatment of 16 with n-BuLi in THF at -78 (e) (Me3Si)2NK, THF, -78 °C; 2-(phenylsulfonyl)-3-phenyloxaziri-
eCu produced, in excellent yield, the allylic alcohol 17 dine, -78 °C, 45 min (68%); (f) n-BiitNF, THF, room temperature,
75 min; (g) Dess-Martin periodinane reagent (ref 18) (4 equiv), CgHeN
(mp 61.5-63 0C). Completion of the necessary annulation (2 equiv), CH2CI2, room temperature; Na2S203, NaHC03, H20 (44%
sequence required oxidative rearrangement of 17 with a from 24); (h) n-Bu(t-Bu)2Al(H)Li (4.6 equiv), EtsO-THF, -78 °C, 30
Cr(VI) reagent. Interestingly, treatment of 17 with excess min (41 %); (i) CsHsN-SOs, Me2SO, Et3N, CH2CI2, room temperature,
PCC in the presence of Celite12 produced, as the major 9.5 h (49%).
product,13 the keto enone 18 (mp 130-131.5 °C). Thus,
in addition to effecting the expected process (cyclopen- complete carbon skeleton of (±)-crinipellin B (4) had been
tenone formation), this reaction also caused oxidative achieved. Intermediate 21 was smoothly transformed, via
conversion of the silyl ether function into the corresponding the alcohol 2216 (mp 146-147.5 °C), into the silyl ether 23
carbonyl group. (mp 187-188.5 °C). The last required oxygen function
was introduced by hydroxylation17 of the potassium enolate
Completion of the synthesis of (±)-4 was carried out as of 23, a process that afforded, stereoselectively, the
summarized in Scheme II. The epoxide 20, readily derived
from 18, was treated sequentially with (MeaSi)2NLi and -hydroxy ketone 2416 (mp 190.5-192 °C). It maybe noted
that 24 possesses the relative configuration at C-10 opposite
dimethyl(methylene)ammonium iodide.14 Flash chroma- to that present in crinipellin A (2).
tography of the resultant amino ketone effected elimi-
nation of ß2 and produced the enone 2115 (mp 157.5- Cleavage of the silyl ether function in 24, followed by
immediate oxidation18 of the resultant product, gave the
158.5 °C). Thus, the stereoselective construction of the
triketone 25 (yellow-orange needles, mp 188-189.5 °C).
Attempts to effect chemoselective reduction of only the
(8) Paquette, L. A. Top. Curr. Chem. 1979, 79, 41; 1984, 119, 1. C-9 carbonyl group in 25 were not successful. However,
Paquette, L. A.; Doherty, A. M. Polyquinane Chemistry (Reactivity and
Structure Concepts in Organic Chemistry)·, Springer-Verlag: Berlin, 1987; low-temperature reduction of this material with n-Bu(t-
Vol. 26. Hudlicky, T.; Price, J. D. Chem. Rev. 1989, 89,1467. Bu)2Al(H)Li provided the keto diol 2619 as the major
(9) The generality of this new, potentially useful method is currently
under investigation. product, along with less polar (TLC) byproducts. Oxi-
(10) This substance was prepared by reduction (i'-Bu2A1H, THF) of dation20 of 26 afforded, in addition to some starting
methyl (Z)-3-iodopropenoate (Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, material (12%) and a minor byproduct, (±)-crinipellin B
57, 709), followed by reaction of the resultant alcohol with Ph3PBr2 in
CH2C12.
(4). This substance (mp 153.5-155 °C) exhibited spectra
(11) Cf. Piers, E.; Marais, P. C. Tetrahedron Lett. 1988, 29, 4053. in full accord with structural formula 4, and its NMR
(12) Paquette, L. A.; Leone-Bay, A. J. Am. Chem. Soc. 1983,105,7352.
(13) Minor products from this oxidation were i and the diketo epoxide
20 (see Scheme II). Interestingly, i did not undergo epoxidation when (15) The structure of 21, and thereby of previous intermediates in the
treated with H202 in the presence of base (Scheme II, step a). synthetic sequence, was confirmed by an X-ray crystallographic study.
We are grateful to Dr. S. J. Rettig for carrying out this structure
H determination. Details will be reported elsewhere.
(16) The relative configuration of the newly introduced stereogenic
.....\ center of this substance was confirmed by NMR spectroscopy. Thus,
in nuclear Overhauser enhancement difference experiments, irradiation
of * ( 4.52 for 22, 4.04 for 24) caused enhancement of the signals due
,
ÓTBDMS to Hb ( 3.52 for 22,1.27-1.37 (m) for 24).
(17) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org.
(14) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem. 1984, 49, 3241.
Chem., Int. Ed. Engl. 1971,10, 330. (18) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
Communications J. Org. Chem., Vol. 58, No. 1,1993 13

spectrum was found to be identical with that of natural Two new cumulation methods developed in our laboratory
(-)-crinipellin B.21 played important roles in the assembly of the required
In summary, a 22-step conversion of 2-methyl-2-cyclo- tetraquinane carbon skeleton (see conversions 9 into 12
and IS into 18).
penten-l-one (5) into (±)-crinipellin B (4) was achieved.
Acknowledgment. We are grateful to NSERC of
Canada for financial support and for a Postgraduate
(19) The overall conversion of 24 into 26 could also be achieved as
follows: (i) oxidation of 24 with tetra-n-propylammonium perruthenate Scholarship (to J.R.). We also thank FCAR, Quebec, and
and IV-methylmorpholine N-oxide in CH2C1s (Griffith, W. P.; Ley, S. V. Bio-Mega Inc., Laval, Quebec, for Scholarships (to J.R.).
Aldrichim. Acta 1990,23,13) (74%); (ii) silyl ether cleavage with ro-Bu*-
NF in THF (68%); (iii) reduction of the C-9 carbonyl group with n-Bu- Supplementary Material Available: Experimental pro-
(i'-Bu)2Al(H)Li in EtpO-THF (53%). Although this sequence was cedures for the preparation and NMR spectra (400 MHz,
somewhat more efficient than that summarized in Scheme II, the CDClg) of compounds 6-18,20-26, and (±)-4, experimental details
intermediates were quite unstable and, therefore, were difficult to purify of the X-ray crystallographic study on intermediate 21, and a
and completely characterize.
stereoview of this substance (40 pages). This material is contained
(20) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89,
5505. in libraries on microfiche, immediately follows this article in the
(21) We are very grateful to Professor W. Steglich for sending us a microfilm version of the journal, and can be ordered from the
copy of the *H NMR spectrum of natural (-)-crinipellin B. ACS; see any current masthead page for ordering information.