Total syntheses of (+)-ricinelaidic acid lactone and of (-)-gloeosporone based on transition-metal-catalyzed C-C bond formations

Article abstract of DOI:10.1021/ja9719945

Total syntheses of the macrolides (R)-(+)-ricinelaidic acid lactone (6) and (-)-gloeosporone (7), a fungal germination self-inhibitor, are presented, which are distinctly shorter and more efficient than any of the previous approaches to these targets repo

Full text of DOI:10.1021/ja9719945

9130
J. Am. Chem. Soc. 1997, 119, 9130-9136
Total Syntheses of (+)-Ricinelaidic Acid Lactone and of
(-)-Gloeosporone Based on Transition-Metal-Catalyzed
C-C Bond Formations
Alois Fu1rstner* and Klaus Langemann
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
D-45470 Mu¨lheim/Ruhr, Germany
ReceiVed June 17, 1997X
Abstract: Total syntheses of the macrolides (R)-(+)-ricinelaidic acid lactone (6) and (-)-gloeosporone (7), a fungal
germination self-inhibitor, are presented, which are distinctly shorter and more efficient than any of the previous
approaches to these targets reported in the literature. Both of them benefit from the remarkable ease of macrocyclization
of 1,ω-dienes by means of ring-closing olefin metathesis (RCM) using the ruthenium carbene 1a as catalyst precursor.
The diene substrates are readily formed via the enantioselective addition of dialkylzinc reagents to aldehydes in the
presence of catalytic amounts of Ti(OiPr)4 and bis-triflamide 18 and/or the stereoselective allylation of aldehydes
developed by Keck et al. using allyltributylstannane in combination with a catalyst formed from Ti(OiPr)4 and (S)-
(-)-1,1′-bi-2-naphthol. Comparative studies show this latter procedure to be more practical than the stoichiometric
allylation reaction employing the allyltitanium-R,R,R′,R′-tetraaryl-1,3-dioxolane-4,5-dimethanol complex 3b. Finally,
a method for the efficient ring closure of 4-pentenoic acid esters by RCM is presented that relies on the joint use of
1a and Ti(OiPr)4 as a binary catalyst system. These results not only expand the scope of RCM to previously unreactive
substrates but also provide additional evidence for the important role of ligation of the evolving ruthenium carbene
center to a polar relay substituent on the substrate which constitutes the necessary internal bias for the RCM-based
macrocyclization process.
Introduction
Scheme 1
Our recent investigations on ring-closing olefin metathesis
(RCM) using either 1a,b or 2 as catalyst precursors have
revealed the remarkable scope of this method for the preparation
of medium-sized and macrocyclic products (Scheme 1).1-4
These reactions are essentially driven by the gain in entropy
upon bisecting the diene substrate.
X Abstract published in AdVance ACS Abstracts, September 15, 1997.
(1) (a) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942. (b)
Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746. (c) Fu¨rstner,
A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005. (d) Fu¨rstner, A.;
Langemann, K. Synthesis 1997, 792. (e) Fu¨rstner, A.; Mu¨ller, T. Synlett
1997, 1010. (f) Fu¨rstner, A.; Koch, D.; Langemann, K.; Leitner, W.; Six,
C. Angew. Chem. In press.
(2) For general reviews on olefin metathesis in organic synthesis, see
the following for leading references: (a) Ivin, K. J.; Mol, J. C. Olefin
Metathesis and Metathesis Polymerization; Academic Press: New York,
1997. (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446. (c) Fu¨rstner, A. Topics in Catalysis In press.
(3) For other examples of macrocyclization reactions via RCM using
various catalysts, see: (a) Borer, B. C.; Deerenberg, S.; Biera¨ugel, H.; Pandit,
U. K. Tetrahedron Lett. 1994, 3191. (b) Miller, S. J.; Grubbs, R. H. J. Am.
Chem. Soc. 1995, 117, 5855. (c) Miller, S. J.; Blackwell, H. E.; Grubbs, R.
H. J. Am. Chem. Soc. 1996, 118, 9606. (d) Clark, T. D.; Ghadiri, M. R. J.
Am. Chem. Soc. 1995, 117, 12364. (e) Ko¨nig, B.; Horn, C. Synlett 1996,
1013. (f) McKervey, M. A.; Pitarch, M. J. Chem. Soc., Chem. Commun.
1996, 1689. (g) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou,
K. C. Angew. Chem. 1997, 109, 170. (h) Nicolaou, K. C.; He, Y.;
Vourloumis, D.; Vallberg, H.; Yang, Z. Angew. Chem. 1996, 108, 2554.
(i) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M. Angew.
Chem. 1997, 109, 543. (j) Bertiano, P.; Sorensen, E. J.; Meng, D.;
Danishefsky, S. J. J. Org. Chem. 1996, 61, 8000. (k) Houri, A. F.; Xu, Z.;
Cogan, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117, 2943. (l)
Martin, S. F.; Liao, Y.; Chen, H.-J.; Pa¨tzel, M.; Ramser, M. N. Tetrahedron
Lett. 1994, 6005. (m) Tsuji, J.; Hashiguchi, S. Tetrahedron Lett. 1980, 2955.
(n) Villemin, D. Tetrahedron Lett. 1980, 1715. (o) Plugge, M. F. C.; Mol,
J. C. Synlett 1991, 507. (p) Descotes, G.; Ramza, J.; Basset, J.-M.; Pagano,
S.; Gentil, E.; Banoub, J. Tetrahedron 1996, 52, 10903.
It was discovered that neither a conformational predisposition
of the starting material toward ring closure nor the ring size
formed are particularly relevant factors,1 although this had been
previously assumed.2b However, the mere presence of a
functional group (ester, ketone, ether, urethane, etc.) in the
starting material was found to be of utmost importance, as well
as the proper distance between this key substituent and the
alkenes to be metathesized.1a,d These results are interpreted in
(4) For the preparation of the ruthenium carbenes 1a,b, see: (a) Nguyen,
S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9858. (b)
Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1992, 114, 3974. (c) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs,
R. H. Angew. Chem. 1995, 107, 2179. (d) For the preparation of 2, see:
Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.;
O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875.
S0002-7863(97)01994-X CCC: $14.00 © 1997 American Chemical Society

Total Syntheses Based on C-C Bond Formations
J. Am. Chem. Soc., Vol. 119, No. 39, 1997 9131
terms of ligation, with the polar group acting as a relay for the
evolving carbene species which assembles the reacting sites
within the coordination sphere of the metal (e.g., complexes of
type A or similar). However, if such an array becomes too
Scheme 2
stable, as might be the case in certain 5- or 6-membered chelate
structures (e.g., B and C), the catalyst can be sequestered in
the form of unproductive complexes and cyclization will not
take place.1 Finally, macrocyclizations by RCM turned out to
be sensitive to steric hindrance near the double bonds. This
finding is deemed to reflect the bulk of the residual ligands L
in chelate complexes such as A, which are formed in situ on
reaction of a diene substrate with one of the standard catalyst
precursors 1a,b or 2.1
The total syntheses of enantiomerically pure (+)-ricinelaidic
acid lactone (6) and (-)-gloeosporone (7) reported below show
that the proper assessment of these key parameters provides a
safe guidance for retrosynthetic planning. Moreover, they
illustrate that RCM in combination with asymmetric catalysis
for the formation of sp3 centers can open up straightforward
avenues to complex target molecules that rival the existing
methodology in all preparative respects. Since the number of
“unproductive” protection/deprotection steps can be reduced to
a minimum, these syntheses are short, flexible, “atom economi-
cal”,5 and remarkably efficient. Finally, we have found a binary
catalyst system that leads to the cyclization of those diene
substrates which are a priori handicapped by an inadequate
distance between the “relay” substituent and the alkene entities.
alcohol 4 was formed in good yield with an enantiomeric excess
(ee) of 91% upon consecutive addition of heptanal and allyl-
tributylstannane to a solution of a catalyst formed in situ from
Ti(OiPr)4 and (S)-(-)-1,1′-bi-2-naphthol ((S)-BINOL) (1:2 ratio)
in the presence of 4 Å molecular sieves (MS). We noticed,
however, that it is essential to use freshly distilled Ti(OiPr)4
for the preparation of the catalytically active species in order
to get a high ee and reproducible results. Esterification of 4
with 9-decenoyl chloride provided compound 5, which was then
subjected to the macrocyclization by RCM. In line with our
previous experiences,1 the reaction of this diene with the
ruthenium carbene 1a (2 mol %) in a dilute, refluxing CH2Cl2
solution led to the very clean formation of the title compound.
Pure (E)-6 was isolated in 72% yield by flash chromatography
of the crude product on silica impregnated with AgNO3.8
In order to evaluate the preparative significance of Keck’s
catalytic allylation reaction in more detail, we have also prepared
alcohol 4 by an independent route. Treatment of heptanal with
1.1 equiv of the allyltitanium complex 3b developed by Duthaler
and Hafner9 afforded the desired product in an excellent ee
(98%). Although this optical purity is slightly higher than that
obtained according to Keck’s method, we nevertheless prefer
the latter procedure since it can be conveniently scaled up, uses
only commercially available reagents, and requires just catalytic
amounts of expensive chiral ligands.
(-)-Gloeosporone. After having established by this route
to 6 that esters of homoallylic alcohols are suitable starting
materials for RCM, we tackled the total synthesis of (-)-
gloeosporone (7), a germination self-inhibitor isolated from
Colletotrichum gloeosporioides.10
Spores of this fungus germinate poorly when crowded due
to a specific response to an endogeneous secondary metabolite
which seems to regulate the dispersion of the species. The
oxocane structure 8 had been assigned to the biologically active
principle isolated from a culture broth;11,12 this original formula,
Results and Discussion
(R)-(+)-Ricinelaidic Acid Lactone. Since ricinelaidic acid
lactone (6) has frequently served as a model to test the efficiency
of macrolactonization reactions,6 we have selected this 13-
membered macrolide as our target in order to probe whether
C-C bond formation can be a competitive strategy for the
formation of large ring compounds. Starting from heptanal, the
synthesis of 6 in enantiomerically pure form has been achieved
in only three steps with an overall yield of ∼45% (Scheme 2).
Specifically, the catalytic asymmetric allylation protocol
developed by Keck et al.7 was employed to install the (R)-
configurated stereogenic center. The desired homoallylic
(5) Trost, B. M. Angew. Chem. 1995, 107, 285.
(6) For previous syntheses, see: (a) Thalmann, A.; Oertle, K.; Gerlach,
H. Org. Synth. 1990, 63, 192. (b) Gerlach, H.; Oertle, K.; Thalmann, A.
HelV. Chim. Acta 1976, 59, 755. (c) Vorbru¨ggen, H.; Krolikiewicz, K.
Angew. Chem., Int. Ed. Engl. 1977, 16, 876. (d) Narasaka, K.; Yamaguchi,
M.; Mukaiyama, T. Chem. Lett. 1977, 959. (e) Inanaga, J.; Hirata, K.; Saeki,
H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. (f)
Venkataraman, K.; Wagle, D. R. Tetrahedron Lett. 1980, 21, 1893. (g)
Kruizinga, W. H.; Kellog, R. M. J. Am. Chem. Soc. 1981, 103, 5183. (h)
Regen, S. L.; Kimura, Y. J. Am. Chem. Soc. 1982, 104, 2064. (i) Steliou,
K.; Poupart, M.-A. J. Am. Chem. Soc. 1983, 105, 7130. (j) Ahmed, A.;
Taniguchi, N.; Fukuda, H.; Kinoshita, H.; Inomata, K.; Kotake, H. Bull.
Chem. Soc. Jpn. 1984, 57, 781. (k) Gais, H. J. Tetrahedron Lett. 1984, 25,
273. (l) Shono, T.; Ishige, O.; Uyama, H.; Kashimura, S. J. Org. Chem.
1986, 51, 546. (m) Otera, J.; Yano, T.; Himeno, Y.; Nozaki, H. Tetrahedron
Lett. 1986, 27, 4501. (n) Matsuyama, H.; Nakamura, T.; Kamigata, N. J.
Org. Chem. 1989, 54, 5218.
(8) Gupta, A. S.; Dev, S. J. Chromatogr. 1963, 12, 189.
(9) (a) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321. (b) For a review,
see: Duthaler, R. O.; Hafner, A. Chem. ReV. 1992, 92, 807.
(10) Lax, A. R.; Templeton, G. E.; Meyer, W. L. Phytopathology 1982,
74, 503.
(7) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467. (b) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827.
(c) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58,
6543.
(11) Meyer, W. L.; Lax, A. R.; Templeton, G. E.; Brannon, M. J.
Tetrahedron Lett. 1983, 24, 5059.

9132 J. Am. Chem. Soc., Vol. 119, No. 39, 1997
Fu¨rstner and Langemann
Scheme 3
however, was found to be wrong. The actual structure of (-)-
gloeosporone (7) was unambiguously established in 1987 with
high-field NMR studies, X-ray crystallography,13 and total
syntheses.14 The latter also proved the absolute configuration
to be 4S,7R,13R. The biological activity of synthetic 7 has been
assayed in some detail, showing that this metabolite exhibits a
high activity against several fungi but does not inhibit the growth
of bacteria.14c,f
Our retrosynthetic analysis of this target is shown in Scheme
3. It is well established in the literature that the 7-hydroxy 4,5-
diketone precursor 9 (R ) H) cyclizes spontaneously to the
correct 4S-configurated hemiketal.14 Since an R-diketone can
be obtained by oxidation of an alkene entity, the obvious site
for ring closure by RCM is the C4-C5 bond. This leads to the
rather simple diene 11 as the starting material, the homoallylic
alcohol part of which can be prepared in optically active form
by one of the allylation protocols for aldehydes outlined above.
However, keeping in mind that a proper distance of the alkene
to be metathesized and the polar “relay” functions is a
fundamental requirement for successful macrocyclizations by
RCM,1 a more detailed evaluation of this concept is appropriate.
If a chelation of the evolving carbene with the ester group plays
a crucial role, the 4-pentenoate substructure in 11 may pose
problems, since it will lead to a 6-membered chelate of the
general type C, which may likely be too stable to be productive
for a RCM event. The model reactions shown in Scheme 4
fully confirm this anticipation: while the 5-hexenoate 12 reacts
without incident to the corresponding macrolide 13,1a,d the
conversion of the 4-pentenoate 14 to the desired 14-membered
ring 15 (which may be considered as a truncated model for
alkene 10 en route to gloeosporone) is poor even after prolonged
reaction time. We therefore faced the problem of finding
appropriate conditions for the cyclization of 4-pentenoates prior
to embarking on the synthesis of (-)-gloeosporone.
Scheme 4
Table 1. Cyclization of the 4-Pentenoate 14 in the Presence of
Additives
entry t (d) T (°C)
additive
14 (%)a 15 (%)a
1
2
3
4
3
3
3
3
25
25
40
25
67
49
7
22
40
55
14
Ti(OiPr)4 (2 equiv)
Ti(OiPr)4 (5 mol %)
LiBr (5 equiv)
79
a Determined by GC.
In order to destabilize a presumably unproductive chelate of
type C, we ran the cyclization of 14 in the presence of Lewis
acids, which may compete with the ruthenium carbene for the
coordination onto the ester group (Table 1). Such an additive
must be compatible with the RCM catalyst, should provoke a
minimum of undesirable acid-induced side reactions, and has
to undergo a kinetically labile coordination with the “relay”
substituent. Strong Lewis acids such as TiCl4 or SnCl4 were
soon ruled out, since they decompose the catalyst, whereas the
addition of LiBr seems to retard rather than promote the
cyclization (entry 4).15 However, Ti(OiPr)4 might meet these
criteria: it is well established that esters do coordinate weakly
trans to alkoxides on a Ti(4+) template and that this lability
secures the catalytic activity of titanium alkoxides in many
cases.16,17 In fact, the yield of the macrolide 15 was almost
doubled when the cyclization reaction of the 4-pentenoate 14
was carried out in the presence of 2 equiv of Ti(OiPr)4 under
otherwise identical conditions (cf. entries 1 and 2). When the
temperature was raised to 40 °C, even catalytic amounts of Ti-
(OiPr)4 were found to be sufficient (entry 3). This binary
(12) For syntheses directed to the proposed oxocane 8 structure, see:
(a) Carling, R. W.; Clark, J. S.; Holmes, A. B.; Sartor, D. J. Chem. Soc.,
Perkin Trans. 1 1992, 95. (b) Carling, R. W.; Holmes, A. B. Tetrahedron
Lett. 1986, 27, 6133. (c) Mortimore, M.; Cockerill, G. S.; Kocienski, P.;
Treadgold, R. Tetrahedron Lett. 1987, 28, 3747.
(13) Meyer, W. L.; Schweizer, W. B.; Beck, A. K.; Scheifele, W.;
Seebach, D.; Schreiber, S. L.; Kelly, S. E. HelV. Chim. Acta 1987, 70, 281.
(14) (a) Adam, G.; Zibuck, R.; Seebach, D. J. Am. Chem. Soc. 1987,
109, 6176. (b) Schreiber, S. L.; Kelly, S. E.; Porco, J. A.; Sammakia, T.;
Suh, E. M. J. Am. Chem. Soc. 1988, 110, 6210. (c) Seebach, D.; Adam, G.;
Zibuck, R.; Simon, W.; Rouilly, M.; Meyer, W. L.; Hinton, J. F.; Privett,
T. A.; Templeton, G. E.; Heiny, D. K.; Gisi, U.; Binder, H. Liebigs Ann.
Chem. 1989, 1233. (d) Curtis, N. R.; Holmes, A. B.; Looney, M. G.; Pearson,
N. D.; Slim, G. C. Tetrahedron Lett. 1991, 32, 537. (e) Takano, S.;
Shimazaki, Y.; Takahashi, M.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1988, 1004. (f) Matsushita, M.; Yoshida, M.; Zhang, Y.;
Miyashita, M.; Irie, H.; Ueno, T.; Tsurushima, T. Chem. Pharm. Bull. 1992,
40, 524.
(15) LiBr may lead to the exchange of the Cl ligands for Br on the catalyst
and thus diminish its activity, cf.: Dias, E. L.; Nguyen, S. T.; Grubbs, R.
H. J. Am. Chem. Soc. 1997, 119, 3887.
(16) For a detailed study on the bonding order of various ligands to
titanium, see inter alia: Gau, H.-M.; Lee, C.-S.; Lin, C.-C.; Jiang, M.-K.;
Ho, Y.-C.; Kuo, C.-N. J. Am. Chem. Soc. 1996, 118, 2936.
(17) For a review on Ti(OiPr)4, see: Banwell, M. G. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York,
1995; p 4932.

Total Syntheses Based on C-C Bond Formations
J. Am. Chem. Soc., Vol. 119, No. 39, 1997 9133
Scheme 5
chloride followed by deprotection of the dimethyl acetal 20
under standard conditions led to the rather labile aldehyde 21.
Reaction of this substrate with allyltributylstannane in the
presence of a catalyst formed in situ from freshly distilled Ti-
(OiPr)4, (S)-BINOL and 4 Å MS furnished the desired product
22 in 77% yield in diastereomerically pure form (diastereomeric
excess (de) > 98%) as evident from careful analysis on chiral
GC columns and the 19F NMR inspection of the corresponding
Mosher ester20 (for details, see the Supporting Information). For
comparative reasons, the allylation of 21 was also carried out
using the Duthaler-Hafner reagent 3b,9 which proved to be
similarly effective for this transformation as far as the conversion
and the optical purity (de > 98%) are concerned. However, in
this case it turned out to be difficult to separate the product 22
from the TADDOL auxiliary ligand by flash chromatography
because of their very similar retention times. Therefore, the
mixture had to be carried through and purification could be
achieved only after the next step.
Alcohol 22 was then converted into the O-benzyl- and O-tBu-
Me2Si-protected compounds 23 and 24, respectively. These
compounds failed to cyclize when treated with the ruthenium
carbene 1a; however, both of them reacted smoothly when
exposed to catalytic amounts of 1a in the presence of catalytic
amounts of Ti(OiPr)4. This example clearly features the
performance of the new binary catalyst system in RCM-based
macrocyclization reactions. Alkenes 25 and 26 were obtained
in excellent yields as a mixture of the E- and Z-isomers, which
were oxidized without separation to the corresponding 1,2-
diketones 27 and 28 when exposed to KMnO4/Ac2O.21 At-
tempted deprotection of the OBn group led to the decomposition
of compound 27. Gratifyingly, however, oxidation and depro-
tection could be conveniently carried out using the O-tBuMe2-
Si-protected cycloalkene 26 as the substrate, with no need to
purify the diketone 28 prior to its desilylation with HF in
aqueous MeCN. The analytical data and in particular the
spectroscopic characteristics of (-)-gloeosporone (7) thus
obtained at 600 MHz perfectly match those reported in the
literature14 (see the Supporting Information).
In summary, we have achieved a total synthesis of the
germination self-inhibiting macrolide (-)-gloeosporone (7) in
enantiomerically pure form in only eight synthetic operations
with an overall yield of 18%. This approach is distinctly shorter
and more efficient than those reported in the literature and seems
to be flexible enough for the synthesis of various analogues of
this macrobicyclic fungizide. Finally, it is worth mentioning
that (i) all C-C bond formations in this sequence are transition-
metal-catalyzed, (ii) the chiral centers are thereby formed in
stereomerically pure form, and (iii) the macrocyclization by
C-C coupling employing the newly developed binary RCM
catalyst system is significantly more productive than the well-
established macrolactonization strategies previously employed.
These aspects highlight the notion that a well-orchestrated
interplay of RCM and other transition-metal-catalyzed reactions
opens up highly flexible, modular and performant avenues to
complex target molecules. Work in our laboratory to further
substantiate these features is in progress.
system, therefore, not only expands the scope of the RCM-based
macrocyclization reaction to those substrates that are handi-
capped by an inappropriate distance between the alkene groups
and the relay substituent but also provides further evidence for
the assumed coordination of the emerging carbene on the polar
functional group of the starting material, which enforces a
proximity of the reacting centers and thereby facilitates the
macrocyclization process.1
This new protocol was then successfully implemented into
our approach to (-)-gloeosporone (7) as depicted in Scheme
5. Ozonolysis of cycloheptene (16) according to Schreiber’s
procedure readily afforded the monoprotected dialdehyde 17.18
The enantioselective addition of dipentylzinc to this substrate
in the presence of Ti(OiPr)4 and catalytic amounts of (S,S)-bis-
trifluoromethanesulfonamide 1819 was highly satisfactory, pro-
viding the corresponding secondary alcohol 19 in 88% chemical
yield with an ee of >98%.
(19) (a) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Koba-
yashi, S. Tetrahedron 1992, 48, 5691. (b) Yoshioka, M.; Kawakita, T.; Ohno,
M. Tetrahedron Lett. 1989, 30, 1657. (c) Takahashi, H.; Kawakita, T.;
Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30, 7095.
For reviews, see: (d) Knochel, P. In ActiVe Metals. Preparation, Charac-
terization, Applications; Fu¨rstner, A., Ed.; VCH: Weinheim, 1996; p 191.
(e) Knochel, P. Synlett 1995, 393. (f) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley: New York, 1994; p 255.
We then again employed Keck’s allylation method7 for
introducing the 7R-configurated homoallylic alcohol part
(gloeosporone numbering): Esterification of 19 with 4-pentenoyl
(20) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
(18) Claus, R. E.; Schreiber, S. L. Org. Synth. 1985, 64, 150.
(21) Jensen, H. P.; Sharpless, K. B. J. Org. Chem. 1974, 39, 2314.

9134 J. Am. Chem. Soc., Vol. 119, No. 39, 1997
Fu¨rstner and Langemann
(R)-(+)-Ricinelaidic Acid Lactone (6). A solution of the ruthenium
carbene 1a (10 mg, 0.012 mmol, 2 mol %) in CH2Cl2 (2mL) was added
to a solution of ester 5 (180 mg, 0.58 mmol) in CH2Cl2 (100 mL) at
reflux temperature. Stirring was continued for 24 h, after which the
solvent was evaporated and the residue was purified by flash chroma-
tography (hexanes/diethyl ether 30:1) using silica gel impregnated with
AgNO3.8 Compound 6 was obtained as a colorless syrup (119 mg,
72%) which is admixed with only e2% of the (Z)-isomer: Rf 0.50
(hexanes/diethyl ether 30:1); [R]rDt ) +46.7° (c ) 0.95, CHCl3) [lit.6d
[R]rDt ) +45.7° (c ) 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ
5.54-5.26 (m, 2H), 4.98-4.92 (m, 1H), 2.38-2.15 (m, 4H), 2.02 (q,
2H, J ) 6.5 Hz), 1.69-1.27 (m, 20H), 0.86 (t, 3H, J ) 8.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 173.8, 134.3, 126.4, 73.1, 37.8, 35.0, 34.1,
32.2, 31.7, 29.2, 27.6, 27.2, 27.0, 25.4, 23.8, 23.1, 22.6, 14.0; IR (neat)
3024, 2929, 2857, 1733, 1460, 1447, 1375, 1337, 1246, 1223, 1179,
1148, 1125, 1077, 1038, 970, 806 cm-1; MS (EI) m/z (rel intensity)
280 ([M+], 31), 166 (14), 137 (12), 124 (13), 109 (17), 98 (100), 81
(31), 67 (35), 55 (41), 41 (42).
Experimental Section
General. All reactions were carried out under Ar using Schlenk
techniques. The Grubbs carbene 1a was purchased from Strem
Chemical Inc.4 Ac2O and Ti(OiPr)4 were distilled under Ar immediately
prior to use. All other commercially available reagents (Aldrich, Fluka)
were used as received. The solvents were dried by distillation over
the following drying agents and were transferred under Ar: Et2O (Na/
K), CH2Cl2 (P4O10), THF (magnesium/anthracene), toluene (Na/K),
DMF (Desmodur, dibutyltin dilaurate). Flash chromatography was on
Merck silica gel 60 (230-400 mesh) using hexanes/ethyl acetate in
various proportions as the eluent. For the instrumentation used, see
the Supporting Information. Elemental analyses were performed by
Dornis & Kolbe, Mu¨lheim.
(R)-Dec-1-en-4-ol (4). Method A. A solution of allylmagnesium
bromide (1 M in Et2O, 702 µL, 0.702 mmol) was added dropwise over
a period of 10 min at 0 °C to the titanium complex 3a (500 mg, 0.82
mmol)9 in Et2O (12 mL). The resulting dark-green mixture was stirred
at that temperature for 1 h. It was then cooled to -78 °C, and heptanal
(72 mg, 0.63 mmol, 88 µL) was added. After an additional 4 h of
stirring at that temperature, aqueous saturated NH4F (8 mL) was added
and the mixture was hydrolyzed for 12 h. A standard extractive work-
up followed by flash chromatography (hexanes/ethyl acetate 12:1)
yielded compound 4 as a colorless syrup (71 mg, 72%): 1H NMR (200
MHz, CDCl3) δ 5.94-5.74 (m, 1H), 5.18-5.09 (m, 2H), 3.70-3.58
(m, 1H), 2.30-2.10 (m, 2H), 1.70 (s, 1H), 1.46-1.29 (m, 10H), 0.92-
0.85 (m, 3H); 13C NMR (50 MHz, CDCl3) δ 135.0, 118.0, 70.7, 42.0,
36.9, 31.8, 29.4, 25.6, 22.6, 14.1; [R]rDt ) -3.2° (c ) 6.4, CH2Cl2),
[lit.23 [R]Drt ) -4.2° (c ) 0.5, CHCl3)]. The enantiomeric excess (ee)
was determined by GC using a chiral column to be 98% (see the
Supporting Information). Method B. A solution of (S)-BINOL (31
mg, 0.11 mmol, 20 mol %) in CH2Cl2 (500 µL) and Ti(OiPr)4 (freshly
distilled, 16 mg, 0.056 mmol, 17 µL, 10 mol %) were added to
powdered molecular sieves (4 Å, 1 g, activated at 160 °C, 10-2 bar for
12 h) in CH2Cl2 (10 mL), and the red suspension was refluxed for 1 h.
The mixture was cooled to room temperature (rt), and a solution of
heptanal (63 mg, 0.55 mmol, 71 µL) in CH2Cl2 (2 mL) was added.
Stirring was continued for 10 min at that temperature prior to the
addition of allyltributylstannane (201 mg, 0.66 mmol) at -78 °C. After
an additional 10 min at that temperature, the flask was sealed and kept
at -18 °C for 15 h. The reaction was quenched with saturated aque-
ous NaHCO3 (10 mL), and the mixture was hydrolyzed for 3 h. A
standard extractive work-up followed by flash chromatography (hex-
anes/ethyl acetate 10:1) afforded alcohol 4 as a colorless syrup (66
(6R)-12,12-Dimethoxydodecan-6-ol (19). The chiral ligand (1S,2S)-
1,2-(N,N′-bis(trifluoromethanesulfonylamino))cyclohexane (18)19 (189
mg, 0.5 mmol, 2 mol %) and Ti(OiPr)4 (8.53 g, 30 mmol, 8.86 mL)
were dissolved in toluene (10 mL), and the mixture was stirred at 40
°C for 30 min. The solution was then cooled to -78 °C, and Zn-
24
(C5H11)2 (6.23 g, 30 mmol) in toluene (2 mL) was added dropwise
followed by a solution of 7,7-dimethoxyheptanal (17)18 (4.35 g, 25
mmol) in toluene (2 mL). Stirring was continued for 30 min at -78
°C, 2 h at -50 °C, and 2 h at -20 °C, after which the reaction was
quenched with aqueous saturated NH4Cl (20 mL). The mixture was
extracted with Et2O (3 × 50 mL), and the combined organic phases
were dried over Na2SO4, filtered, and evaporated to dryness. Flash
chromatography (hexanes/ethyl acetate 10:1 f 8:1) of the residue
afforded 19 as a colorless liquid (5.44 g, 88%): Rf 0.39 (hexanes/ethyl
acetate 2:1); [R]rDt ) -0.34° (c ) 4.7, CH2Cl2); H NMR (200 MHz,
1
CDCl3) δ 4.36 (t, 1H, J ) 5.7 Hz), 3.57 (bs, 1H), 3.11 (s, 6H), 1.61-
1.30 (m, 19H), 0.89 (t, 3H, J ) 6.6 Hz); 13C NMR (50 MHz, CDCl3)
δ 104.5, 71.9, 52.6, 37.5, 37.4, 32.4, 31.9, 29.5, 25.6, 25.3, 24.6, 22.7,
14.0; IR (neat) 3444, 2930, 2858, 2678, 1462, 1384, 1366, 1192, 1126,
1074, 1054, 960, 915, 805, 727 cm-1; MS (EI) m/z (rel intensity) 245
([M+ - 1], 10), 215 (9), 143 (10), 111 (8), 83 (8), 75 (100), 71 (19).
Anal. Calcd for C14H30O3 (246.39): C, 68.25; H, 12.27. Found: C,
68.40; H, 12.27. The ee was determined by inspection of the 19F NMR
spectrum of the corresponding Mosher ester20 to be >98% (see the
Supporting Information).
(6R)-12,12-Dimethoxy-6-dodecyl Pent-4-enoate (20). 4-Pentenoic
acid (1.45 g, 14.5 mmol, 1.48 mL) in CH2Cl2 (5 mL) was added
dropwise at ambient temperature to a solution of N,N-(dimethyl)-1-
amino-1-chloro-2-methyl-1-propene (1.9 g, 14.22 mmol)22 in CH2Cl2
(10 mL). After 1.5 h of stirring at that temperature, the alcohol 19
(3.94 g, 16 mmol), pyridine (5 mL), and 4-(N,N-dimethylamino)pyridine
(DMAP, 20 mg) in CH2Cl2 (10 mL) were added to the flask at 0 °C.
The reaction was complete after 5 h of stirring at ambient temperature
as indicated by TLC. Water (20 mL) was added, and most of the
pyridine was removed by extraction with aqueous saturated NH4Cl (4
× 30 mL). The organic phase was washed with brine and dried over
Na2SO4. Removal of the solvent and flash chromatography (hexanes/
ethyl acetate 12:1) of the residue gave 20 as a colorless oil (4.26 g,
mg, 76%): [R]rt ) -3.1° (c ) 5.9, CH2Cl2). The ee was determined
D
as above to be 91%.
(R)-Dec-1-en-4-yl Dec-9-enoate (5). 9-Decenoic acid (187 mg, 1.1
mmol) in CH2Cl2 (5 mL) was added dropwise at ambient temperature
to a solution of N,N-(dimethyl)-1-amino-1-chloro-2-methyl-1-propene
(146 mg, 1.1 mmol)22 in CH2Cl2 (10 mL). After 1 h of stirring at that
temperature, alcohol 4 (170 mg, 1.09 mmol) and 4-(N,N-dimethylami-
no)pyridine (DMAP, 159 mg, 1.3 mmol) in CH2Cl2 (10 mL) were added
to the flask at 0 °C. The reaction was complete after 4 h of stirring at
ambient temperature as indicated by TLC. The mixture was filtered
through a plug of silica gel, which was washed with CH2Cl2. The
solvent was evaporated, and the residue was purified by flash
chromatography (hexanes/ethyl acetate 20:1) to afford ester 5 as a
colorless syrup (280 mg, 82%): Rf 0.65 (hexanes/ethyl acetate 10:1);
[R]rDt ) +17.3° (c ) 7.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ
5.91-5.65 (m, 2H), 5.11-4.90 (m, 5H), 2.33-2.24 (m, 4H), 2.05-
1.99 (m, 2H), 1.64-1.52 (m, 4H), 1.41-1.27 (m, 16H), 0.88 (t, 3H, J
) 6.8 Hz); 13C NMR (50 MHz, CDCl3) resolved signals δ 173.4, 139.1,
133.9, 117.5, 114.2, 73.0, 38.7, 34.7, 33.8, 33.7, 31.8, 29.1, 29.0, 28.9,
25.3, 25.1, 22.6, 14.1; IR (neat) 3078, 2929, 2857, 1735, 1642, 1465,
1439, 1417, 1378, 1246, 1174, 993, 912, 725 cm-1; MS (EI) m/z (rel
intensity) 308 ([M+], 1), 153 (28), 135 (100), 97 (9), 83 (13), 69 (17),
55 (18), 41 (9). Anal. Calcd for C20H36O2 (308.50): C, 77.87; H,
11.76. Found: C, 77.65; H, 11.66.
91%): Rf 0.55 (hexanes/ethyl acetate 4:1); [R]rt ) +0.12° (c ) 34.8,
D
1
CH2Cl2); H NMR (200 MHz, CDCl3) δ 5.93-5.76 (m, 1H), 5.11-
4.97 (m, 2H), 4.88 (t, 1H, J ) 6.3 Hz), 4.35 (t, 1H, J ) 5.7 Hz), 3.31
(s, 6H), 2.39-2.36 (m, 4H), 1.56-1.44 (m, 6H), 1.35-1.27 (m, 12H),
0.88 (t, 3H, J ) 6.7 Hz); 13C NMR (50 MHz, CDCl3) δ 172.9, 136.8,
115.4, 104.5, 74.3, 52.6, 34.1, 34.1, 33.9, 32.4, 31.7, 29.4, 29.0, 25.3,
25.0, 24.5, 22.6, 14.0; IR (neat) 3080, 2931, 2861, 2830, 1734, 1642,
1463, 1380, 1366, 1290, 1254, 1178, 1128, 1078, 1055, 994, 960, 914,
727 cm-1; MS (EI) m/z (rel intensity) 297 (2), 197 (12), 165 (11), 75
(100), 71 (16), 55 (22). Anal. Calcd for C19H36O4 (328.49): C, 69.47;
H, 11.05. Found: C, 69.36; H, 11.15.
(6R)-12-Oxododec-6-yl Pent-4-enoate (21). Trifluoroacetic acid
(2 mL) and water (2 mL) were added at 0 °C to a solution of the acetal
(22) Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.; Ghosez,
L. Org. Synth. 1979, 59, 26.
(23) Tietze, L. F.; Schiemann, K.; Wegner, C.; Wulff, C. Chem. Eur. J.
1996, 2, 1164.
(24) Nu¨tzel, K. In Houben-Weyl, Methoden der Organischen Chemie;
Mu¨ller, E., Ed.; Thieme: Stuttgart, 1973; Vol. XIII/2a, p 553.

Total Syntheses Based on C-C Bond Formations
J. Am. Chem. Soc., Vol. 119, No. 39, 1997 9135
20 (500 mg, 1.52 mmol) in CH2Cl2 (10 mL), and the resulting mixture
was stirred at that temperature for 6 h. After the solution was
neutralized with aqueous saturated NaHCO3, the product was isolated
by a standard extractive work-up and purified by flash chromatography
(hexanes/ethyl acetate 15:1) to afford 21 as a colorless syrup (387 mg,
90%) (aldehyde 21 should be processed immediately since it was rather
unstable): 1H NMR (300 MHz, CDCl3) δ 9.76 (t, 1H, J ) 1.8 Hz),
5.90-5.75 (m, 1H), 5.09-5.01 (m, 2H), 4.88 (quint., 1H, J ) 6.6 Hz),
2.45-2.36 (m, 6H), 1.65-1.49 (m, 6H), 1.34-1.24 (m, 10H), 0.88 (t,
3H, J ) 7.0 Hz); 13C NMR (75 MHz, CDCl3) resolved signals δ 202.5,
172.8, 136.8, 115.4, 74.1, 43.8, 34.2, 34.0, 33.9, 31.7, 29.0, 25.1, 25.0,
22.6, 22.0, 14.0; IR (neat) 3080, 2932, 2861, 2718, 1731, 1642, 1463,
1416, 1378, 1343, 1291, 1256, 1178, 1111, 997, 915, 729 cm-1; MS
(EI) m/z (rel intensity) 280 (1), 199 (30), 181 (27), 127 (68), 100 (82),
83 (100), 69 (21), 55 (94), 43 (30).
(4R,10R)-4-Hydroxypentadec-1-en-10-yl Pent-4-enoate (22).
Method A. Allylmagnesium bromide (1 M in Et2O, 7.01 mL, 7.01
mmol) was added within 2 min at 0 °C to a solution of titanium complex
3a9 (0.218 M in Et2O, 35.7 mL, 7.79 mmol). After 1 h of stirring, the
mixture was cooled to -78 °C and aldehyde 21 (1.65 g, 5.84 mmol)
in Et2O (10 mL) was slowly added. After 4 h at that temperature,
aqueous saturated NH4F was added and the mixture was stirred at room
temperature for 12 h. A standard extractive work-up and flash
chromatography (hexanes/ethyl acetate 10:1) yielded 3.67 g of a
colorless syrup which consists of a 1:1 mixture of the homoallylic
alcohol 22 and of the ligand (4R,trans)-2,2-dimethyl-R,R,R′,R′-tet-
raphenyl-1,3-dioxolane-3,4-dimethanol which has the same mobility
as 22. This material can be used directly for the synthesis of either
the benzyl ether 23 or the silyl ether 24, since the ligand is unreactive
under the conditions stated.
4.88 (quintet, 1H, J ) 6.8 Hz), 4.57 (d, 1H, J ) 11.8 Hz), 4.41 (d, 1H,
J ) 11.8 Hz), 3.43 (quintet, 1H, J ) 5.5 Hz), 2.42-2.28 (m, 6H),
1.59-1.19 (m, 18H), 0.88 (t, 3H, J ) 6.8 Hz); 13C NMR (50 MHz,
CDCl3) resolved signals δ 172.9, 139.0, 136.9, 135.1, 128.3, 127.8,
127.5, 116.9, 115.4, 78.5, 74.3, 70.9, 38.3, 34.2, 33.9, 33.8, 31.8, 29.6,
29.1, 25.3, 25.3, 25.0, 22.6, 14.0; IR (neat) 3078, 3030, 2931, 2860,
1733, 1641, 1497, 1455, 1378, 1347, 1255, 1176, 1096, 1069, 1028,
993, 914, 734, 697 cm-1; MS (EI) m/z (rel intensity) 414 ([M+], <1),
191 (16), 173 (19), 91 (100), 83 (11), 55 (9). Anal. Calcd for C27H42O3
(414.63): C, 78.21; H, 10.21. Found: C, 78.32; H, 10.16.
(8R,14R)-2-Oxo-8-(benzyloxy)-14-pentyl-1-oxacyclotetradec-5-
ene (25). Compound 24 (200 mg, 0.48 mmol) and Ti(OiPr)4 (41 mg,
0.14 mmol, 43 µL, 0.3 equiv) were dissolved in CH2Cl2 (150 mL),
and the mixture was refluxed for 1 h. A solution of the ruthenium
carbene 1a (8 mg, 0.001 mmol, 2 mol %) in CH2Cl2 (2 mL) was added,
and reflux was continued for 96 h, after which all of the starting material
was consumed as indicated by TLC. The mixture was filtered through
a short pad of silica gel, and the solvent was removed in Vacuo. Flash
chromatography (hexanes/ethyl acetate 15:1) afforded the product 25
as a colorless syrup (147 mg, 79%): Rf 0.38 (hexanes/ethyl acetate
10:1); [R]rt ) +25.0° (c ) 1.6, CH2Cl2); ratio of isomers E:Z ) 3.6:1;
D
1H NMR (400 MHz, CDCl3) δ 7.44-7.16 (m, 5H), 5.55-5.41 (m,
2H), 4.99-4.86 (m, 1H), 4.59 (d, 0.75 H, J ) 11.8 Hz), 4.57 (d, 0.25H,
J ) 11.8 Hz), 4.50 (d, 0.25H, J ) 11.8 Hz), 4.46 (d, 0.75H, J ) 11.8
Hz), 3.45-3.39 (m, 0.25H), 3.37-3.32 (m, 0.75H), 2.47-2.26 (m, 5H),
2.11-2.03 (m, 1H), 1.61-1.15 (m, 18H), 0.89-0.83 (m, 3H); 13C NMR
(100 MHz, CDCl3) (E)-isomer δ 173.0, 139.1, 131.4, 128.3, 127.9,
127.7, 127.4, 77.5, 74.3, 70.6, 36.1, 34.4, 34.3, 33.9, 31.7, 29.8, 27.6,
26.5, 25.3, 22.6, 22.5, 21.9, 14.0; (Z)-isomer (resolved signals) δ 139.0,
130.4, 127.6, 126.7, 78.1, 74.6, 70.4, 35.3, 34.7, 32.7, 31.8, 30.8, 27.5,
25.1, 23.6, 23.4, 23.1; IR (neat) 3064, 3029, 2930, 2859, 1731, 1605,
1586, 1496, 1455, 1439, 1355, 1341, 1248, 1222, 1160, 1095, 1068,
1028, 974, 908, 735, 697 cm-1; MS (EI) m/z (rel intensity) 386 ([M+],
4), 204 (53), 183 (14), 165 (15), 144 (11), 113 (54), 91 (100), 71 (13),
55 (13), 41 (13). Anal. Calcd for C25H38O3 (386.57): C, 77.68; H,
9.91. Found: C, 77.54; H, 9.86.
Method B. Ti(OiPr)4 (16 mg, 0.056 mmol, 17 µL, 10 mol %) was
added to a stirred suspension of (S)-BINOL (31 mg, 0.11 mmol, 20
mol %) and molecular sieves (4 Å, 1.0 g, powdered, activated at 160
°C, 10-2 mbar) in CH2Cl2 (8 mL). The mixture was refluxed for 1 h
and then cooled to ambient temperature. Aldehyde 21 (155 mg, 0.55
mmol) was added to the red suspension, and the solution was stirred
for an additional 10 min. After the flask was cooled to -78 °C,
allyltributylstannane (201 mg, 0.61 mmol, 188 µL) was added dropwise
via canula. After an additional 10 min at that temperature, the flask
was sealed with stoppers and kept at -18 °C for 14 h. The green-
greyish suspension was then treated with aqueous saturated NaHCO3
(20 mL) for 3 h. The layers were separated, and the aqueous phase
was extracted with CH2Cl2 (2 × 20 mL). The combined organic layers
were dried over Na2SO4, filtered, and evaporated. Flash chromato-
graphy (hexanes/ethyl acetate 10:1) afforded product 22 as a colorless
(8R,14R)-2,5,6-trioxo-8-(benzyloxy)-14-pentyl-1-oxacyclotetradec-
ane (27). Finely ground KMnO4 (278 mg, 1.76 mmol, 4 equiv) was
added in portions at 0 °C to a stirred solution of cycloalkene 25 (170
mg, 0.44 mmol) in freshly distilled Ac2O (10 mL). After 4 h of stirring
at that temperature, chilled ethyl acetate was added and the reaction
was quenched with aqueous saturated NaHSO3 (5 mL). The organic
phase was treated for 10 min with aqueous saturated NaHCO3 (50 mL),
washed with brine, dried over Na2SO4, and evaporated. Flash chro-
matography (hexanes/ethyl acetate 20:1 f 15:1) yields the diketone
27 as a bright yellow syrup (81 mg, 44%): Rf 0.58 (hexanes/ethyl
syrup (136 mg, 77%): [R]rDt ) -1.48° (c ) 7.3, CH2Cl2); H NMR
1
acetate 4:1); [R]rDt ) -1.71° (c ) 2.1, CH2Cl2); H NMR (200 MHz,
1
(300 MHz, CDCl3) δ 5.90-5.78 (m, 2H), 5.16-4.98 (m, 4H), 4.91-
4.82 (m, 1H), 3.65 (s, 1H), 2.39-2.22 (m, 5H), 2.20-2.03 (m, 1H),
1.60-1.27 (m, 19H), 0.90-0.86 (m, 3H); 13C NMR (75 MHz, CDCl3)
δ 172.9, 136.8, 134.9, 118.1, 115.4, 74.3, 70.6, 42.0, 36.7, 34.1, 34.1,
33.9, 31.7, 29.5, 29.0, 25.6, 25.3, 25.0, 22.6, 14.0; IR (neat) 3451, 3078,
2932, 2860, 1734, 1641, 1459, 1437, 1418, 1378, 1342, 1258, 1179,
1119, 996, 914, 728, 642 cm-1; MS (EI) m/z (rel intensity) 283 (12),
265 (5), 225 (6), 183 (57), 165 (72), 135 (18), 109 (52), 101 (77), 95
(66), 83 (85), 67 (34), 55 (100), 41 (32). Anal. Calcd for C20H36O3
(324.50): C, 74.03; H, 11.18. Found: C, 74.20; H, 11.13. The
diastereomeric excess (de) was determined by GC analysis with a chiral
column and by inspection of the 19F NMR spectrum of the correspond-
ing Mosher ester20 to be >98% (see the Supporting Information).
(4R,10R)-4-(Benzyloxy)pentadec-1-en-10-yl Pent-4-enoate (23).
The homoallylic alcohol 22 (580 mg, 1.79 mmol) in THF (5 mL) was
added to a suspension of KH (107 mg, 2.69 mmol, 1.5 equiv) in THF
(20 mL) at 0 °C. After the evolution of H2 ceased (ca. 10 min), a
solution of benzyl iodide (586 mg, 2.69 mmol, 1.5 equiv) in THF (5
mL) was added and the mixture was stirred at ambient temperature for
2 h. The reaction was quenched by addition of aqueous saturated NH4-
Cl (30 mL), and the product was extracted into Et2O (3 × 30 mL).
The combined organic phases were dried over Na2SO4, filtered, and
evaporated. Flash chromatography (hexanes/ethyl acetate 15:1) af-
forded 23 as a colorless syrup (264 mg, 87%): Rf 0.31 (hexanes/ethyl
acetate 10:1); [R]rDt ) +14.5° (c ) 2.85, CH2Cl2); 1H NMR (200 MHz,
CDCl3) δ 7.37-7.15 (m, 5H), 5.92-5.75 (m, 2H), 5.13-4.97 (m, 4H),
CDCl3) δ 7.37-7.27 (m, 5H), 4.95-4.83 (m, 1H), 4.61 (d, 1H, J )
11.8 Hz), 4.50 (d, 1H, J ) 11.8 Hz), 3.93-3.81 (m, 1H), 3.32-2.68
(m, 6H), 1.56-1.02 (m, 18H), 0.90-0.84 (m, 3H); 13C NMR (50 MHz,
CDCl3) δ 198.0, 197.4, 171.5, 138.3, 128.4, 127.8, 127.7, 75.0, 74.8,
70.8, 40.3, 33.9, 32.8, 32.1, 32.0, 31.7, 28.7, 26.8, 25.2, 22.5, 22.3,
21.8, 14.0; IR (neat) 2932, 2857, 1727, 1497, 1456, 1399, 1356, 1256,
1190, 1159, 1089, 1068, 1028, 982, 736, 698 cm-1; MS (EI) m/z (rel
intensity) 416 ([M+], <1), 310 (2), 165 (5), 91 (100), 81 (11), 55 (16).
(4R,10R)-4-((tert-Butyldimethylsilyl)oxy)pentadec-1-en-10-yl Pent-
4-enoate (24). Substrate 22 (100 mg, 0.31 mmol) in DMF (10 mL)
was treated with tBuMe2SiCl (60 mg, 0.40 mmol, 1.3 equiv) and
imidazole (27 mg, 0.40 mmol, 1.3 equiv) at ambient temperature for
7.5 h. The mixture was poured into water (30 mL), and the aqueous
layer was extracted with Et2O (3 × 30 mL). The combined organic
phases were dried over Na2SO4, filtered, and evaporated. Flash
chromatography (hexanes/ethyl acetate 30:1) afforded the silyl ether
24 as a colorless syrup (124 mg, 91%): Rf 0.58 (hexanes/ethyl acetate
15:1), 0.40 (hexanes/ethyl acetate 30:1); [R]rDt ) +10.52° (c ) 1.35,
1
CH2Cl2); H NMR (200 MHz, CDCl3) δ 5.90-5.71 (m, 2H), 5.11-
4.98 (m, 4H), 4.88 (quintet, 1H, J ) 6.1 Hz), 3.67 (quintet, 1H, J )
5.5 Hz), 2.43-2.33 (m, 4H), 2.20 (t, 2H, J ) 6.8 Hz), 1.52-1.20 (m,
18H), 0.91-0.85 (m, 12H), 0.04 (s, 3H), 0.04 (s, 3H); 13C NMR (50
MHz, CDCl3) resolved signals δ 172.9, 136.8, 135.5, 116.6, 115.4,
74.4, 72.0, 42.0, 36.7, 34.1, 33.9, 31.7, 29.7, 29.1, 25.9, 25.3, 25.3,
25.0, 22.6, 18.1, 14.0, -4.3, -4.5; IR (neat) 3078, 2932, 2858, 1735,

9136 J. Am. Chem. Soc., Vol. 119, No. 39, 1997
Fu¨rstner and Langemann
1642, 1471, 1463, 1437, 1362, 1255, 1177, 1094, 1065, 1004, 913,
836, 807, 774 cm-1; MS (EI) m/z (rel intensity) 397 (22), 297 (26),
175 (76), 157 (100), 109 (30), 95 (32), 83 (34), 81 (22), 75 (39), 73
(43), 69 (18), 67 (14), 55 (26). Anal. Calcd for C26H50O3Si (438.77):
C, 71.17; H, 11.49; Si, 6.40. Found: C, 71.28; H, 11.36; Si, 6.54.
(8R,14R)-8-((tert-Butyldimethylsilyl)oxy)-2-oxo-14-pentyl-1-oxa-
cyclotetradec-5-ene (26). The silyl ether 24 (200 mg, 0.46 mmol)
and Ti(OiPr)4 (39 mg, 0.14 mmol, 41 µL, 0.3 equiv) were dissolved in
CH2Cl2 (180 mL), and the mixture was refluxed for 1 h. The ruthenium
carbene 1a (8 mg, 0.001 mmol, 2 mol %) in CH2Cl2 (2 mL) was then
added, and reflux was continued for 24 h after which an additional 4
mg (0.0005 mmol, 1 mol %) of 1a in CH2Cl2 (2 mL) was added. After
an additonal 24 h, the mixture was cooled to ambient temperature and
filtered through a short pad of silica gel. The solvent was removed in
Vacuo, and the residue was purified by flash chromatography (hexanes/
ethyl acetate 100:1) to give the macrolide 26 as a colorless syrup (151
and the organic layer was washed with brine, dried over Na2SO4, and
evaporated. The remaining Ac2O was removed under high vacuum.
The resulting bright yellow oil was dissolved in CH3CN (5 mL) and
treated at ambient temperature with 2 mL of a solution of aqueous HF
(40%) in CH3CN (1:10 v/v). After 45 min, the yellow color faded
and the reaction was quenched with aqueous saturated NaHCO3. A
standard extractive work-up followed by flash chromatography (hex-
anes/ethyl acetate 8:1 f 6:1) afforded 7 as a colorless solid (66 mg,
54%): mp 117-118 °C (lit.14b 117-118 °C); Rf 0.19 (hexanes/ethyl
acetate 4:1), 0.44 (hexanes/ethyl acetate 3:1), 0.55 (hexanes/ethyl acetate
2:1); [R]rt ) -63.6° (c ) 1.4, acid free CHCl3) [lit.14b [R]2D7 ) -63.2°
D
1
(c ) 0.34, acid free CHCl3)]; H NMR (600 MHz, CDCl3) δ 5.09-
5.03 (m, 1H), 4.45-4.41 (m, 1H), 3.54 (bs, 1H), 2.74 (dd, 1H, J )
18.7, 6.2 Hz), 2.44 (ddd, 1H, J ) 16.5, 8.5, 3.9 Hz), 2.35 (ddd, 1H, J
) 14.3, 9.0, 3.8 Hz), 2.28 (ddd, 1H, J ) 15.2, 8.9, 3.6 Hz), 2.10 (ddd,
1H, J ) 14.3, 8.3, 3.5 Hz), 2.04 (dd, 1H, J ) 18.8, 8.3 Hz), 1.71-
1.43 (m, 10H), 1.30-1.20 (m, 8H), 0.89-0.86 (m, 3H); 13C NMR (150
MHz, CDCl3) δ 209.0, 174.4, 98.9, 74.4, 73.4, 40.4, 34.6, 32.3, 32.2,
31.7, 30.0, 29.5, 25.9, 25.3, 25.0, 22.5, 21.1, 14.0; IR (KBr) 3337,
2935, 2902, 2870, 2850, 1752, 1715, 1463, 1448, 1422, 1386, 1341,
1238, 1201, 1178, 1150, 1078, 1038, 1002, 967 cm-1; IR (CCl4) 3445,
2956, 2932, 2860, 1772, 1726, 1711, 1277, 1239, 1220, 1144, 1073
cm-1; MS (EI) rel intensity 308 ([M+ - 18], 4), 180 (18), 152 (13),
119 (100), 109 (21), 101 (76), 96 (35), 82 (29), 67 (24), 55 (45), 41
(23).
mg, 80%): Rf 0.26 (hexanes/ethyl acetate 30:1); [R]rt ) +9.9° (c )
D
4.85, CHCl3) [lit.14b [R]D27 ) +13.5° (pure (E)-isomer, c ) 1.2,
CHCl3)]; ratio of isomers E:Z ) 2.7:1; 1H NMR (200 MHz, CDCl3) δ
5.51-5.39 (m, 2H), 4.99-4.88 (m, 1H), 3.96-3.51 (m, 1H), 2.46-
2.02 (m, 6H), 1.63-1.09 (m, 18H), 0.86-0.79 (m, 12H), 0.03 (s, 3H),
0.02 (s, 3H); 13C NMR (50 MHz, CDCl3) (E)-isomer δ 173.1, 131.0,
128.3, 74.2, 71.0, 40.5, 34.4, 34.3, 33.7, 32.5, 31.7, 27.7, 26.5, 25.9,
25.4, 23.3, 22.6, 21.8, 18.1, 14.0, -4.3, -4.7; (Z)-isomer (resolved
signals) δ 129.9, 127.1, 74.6, 71.5, 35.4, 35.0, 34.8, 34.5, 32.8, 31.7,
27.5, 25.1, 23.7, 23.5; IR (neat) 3020, 2956, 2929, 2858, 1735, 1471,
1462, 1376, 1362, 1342, 1254, 1222, 1158, 1091, 1065, 1053, 1007,
974, 940, 836, 774, 665 cm-1; MS (EI) m/z (rel intensity) 353 (65),
335 (58), 297 (31), 261 (28), 243 (33), 219 (12), 171 (100), 165 (38),
109 (49), 95 (51), 75 (75), 73 (96), 67 (23), 55 (20), 41 (13). Anal.
Calcd for C24H46O3Si (410.71): C, 70.19; H, 11.29; Si, 6.84. Found:
C, 70.11; H, 11.21; Si, 6.72.
Acknowledgment. K.L. thanks the Fonds der Chemischen
Industrie, Frankfurt, for a Kekule´ Stipendium.
Supporting Information Available: Compilation of the
instrumentation used and the spectra formats; copies of the 1H
and 13C NMR spectra of new compounds; and details on the
determination of the ee and de, respectively, of compounds 4,
19, and 22 (45 pages). See any current masthead page for
ordering and Internet access instructions.
(-)-Gloeosporone (7). Finely ground KMnO4 (353 mg, 2.24 mmol,
6 equiv) was added in portions to a solution of the cycloalkene 26
(153 mg, 0.37 mmol) in freshly distilled Ac2O (10 mL) at 0 °C. The
mixture was stirred at 0 °C for 2 h and at ambient temperature for 1 h.
Ethyl acetate (10 mL) was then added, and the reaction was quenched
with aqueous saturated NaHSO3 (5 mL). The phases were separated,
JA9719945