Macrocyclization by nickel-catalyzed, ester-promoted, epoxide-alkyne reductive coupling: Total synthesis of (-)-gloeosporone

Full text of DOI:10.1002/anie.200902079

Communications
DOI: 10.1002/anie.200902079
Total Synthesis
Macrocyclization by Nickel-Catalyzed, Ester-Promoted, Epoxide–
Alkyne Reductive Coupling: Total Synthesis of (À)-Gloeosporone**
James D. Trenkle and Timothy F. Jamison*
Macrocycles are found in important and diverse molecules
such as naturally occurring peptides (e.g., cyclosporine),
oligosaccharides (cyclodextrins), polyketides (erythromycin),
and synthetic compounds such as crown ethers and polyenes.
The most common strategy to prepare macrocyclic lactones
from these strategies, and, for the first time, uses the C5–C6
bond as the site of macrocyclization, whereby the homoallylic
alcohol product (2) of an epoxide–alkyne reductive coupling
reaction corresponds to the b-hydroxyketone pattern in
gloeosporone. We previously described the use of stereose-
lective, nickel-catalyzed aldehyde–alkyne reductive coupling
reactions to form a 19-membered ring in the total synthesis of
two amphidinolide T natural products.[6] Montgomery and co-
workers have investigated how the size of the formed ring
affects the regioselectivity of alkyne addition in related
reactions.[7] An intermolecular nickel-catalyzed alkyne–epox-
ide reductive coupling, which is a process that we have also
used to construct 5- and 6-membered rings, was also utilized
in our amphidinolide syntheses.[3] Since the successful for-
mation of small rings often does not accurately predict the
outcome of cyclizations to form larger rings, it was not clear
whether these nickel-catalyzed coupling reactions could be
extrapolated to the case of gloeosporone.
Thus, we began our investigation of this question with a
series of esters [3a–g, Eqs. (1) and (2), Table 1], which were
selected to determine not only the suitability of the macro-
cyclization to the synthesis of gloeosporone, but also the
generality of this strategy (Table 1). A preliminary survey of
reaction conditions (data not shown) revealed a critical
interdependence of the concentrations of substrate and
catalyst. In summary, competing intermolecular reductive
coupling processes were minimized under two sets of
conditions: [3a]0 = 0.15m, 20 mol% [Ni(cod)2], and [3a]0 =
0.075m, 100 mol% [Ni(cod)2] (cod = cyclooctadiene). Nota-
bly, the optimum initial substrate concentrations were one to
two orders of magnitude greater than those typically used in
macrocyclization reactions.
À
(macrolides) is by intramolecular C O bond formation to
provide the lactone functional group.[1] Although it is often
successful and high-yielding, this approach is also highly
context-dependent and in some cases provides negligible
amounts of the desired macrocycle.[1] The development of
methods for macrocyclization has thus received much atten-
tion.[2] Herein, we report a new C C bond-forming strategy
À
for macrocyclization, namely nickel-catalyzed epoxide alkyne
reductive coupling,[3] and illustrate its use in the synthesis of
the macrolide natural product (À)-gloeosporone (1).[4]
In the eight reported syntheses of gloeosporone, the 14-
membered ring was constructed by either macrolactonizatio-
n[5a–g] or ring-closing metathesis (Scheme 1).[5h–i] The nickel-
catalyzed approach described herein represents a departure
As shown in Table 1, the number of atoms in the targeted
ring is not as important as two other variables. When the ring
size was kept constant but the number of CH2 groups between
the ester and alkyne was varied, the superiority of three CH2
units (n = 1) versus two or four such units was observed (n = 0
or 2, respectively; Table 1, entries 1–6). With this requirement
satisfied, 12- and 15-membered rings could also be prepared
in this fashion, albeit with reduced efficiency (Table 1,
entries 7–10). The orientation of the ester group relative to
the alkyne group is also significant. When the ester oxygen
atom is situated in the tether (Table 1, entries 11–14), no
product was detected, even in cases with the number of atoms
in the tether backbone (three) was the same as in the cases
that gave the best results (three CH2 groups). These
observations strongly suggest that a temporary interaction
between Ni and the ester[8,9] is necessary for effective
promotion of the macrocyclization, and is in contrast with
reports by Fꢀrstner et al., who observed that certain arrange-
Scheme 1. Retrosynthetic analysis of (À)-gloeosporone (1).
[*] Dr. J. D. Trenkle,[+] Prof. Dr. T. F. Jamison
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-0253
E-mail: tfj@mit.edu
Homepage: http://web.mit.edu/chemistry/jamison
[+] Current address: Gilead Sciences
333 Lakeside Dr., Foster City, CA 94404 (USA)
[**] Support for this work was provided by the National Institute of
General Medical Sciences (GM-72566). We are grateful to Li Li for
obtaining mass spectrometric data for all compounds (MIT
Department of Chemistry Instrumentation Facility, which is sup-
ported in part by the NSF (CHE-9809061 and DBI-9729592) and the
NIH (1S10RR13886-01)).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902079.
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Angew. Chem. Int. Ed. 2009, 48, 5366 –5368

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Chemie
Table 1: Nickel-catalyzed reductive macrocyclization.[a]
Entry Substrate
Reaction
m
n
Product Ring size Yield
[%]
Scheme 2. Preparation of epoxyalcohol 3. a) mCPBA, CH2Cl2; b) (R,R)-
conditions[b]
[Co(salen)(OAc)], H2O, 35% over 2 steps, 99% ee; c) nPr4NRuO4,
NMO, 3 ꢀ M.S., CH2Cl2, 95%; d) 7, (n-C5H11)2Zn, Ti(OiPr)4, À208C,
PhMe, 80%, >95:5 d.r.; e) DCC, DMAP, CH2Cl2, 85%. DCC=1,3-
dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine,
mCPBA=meta-chloroperbenzoic acid, M.S.=molecular sieves,
NMO=N-methylmorpholine N-oxide.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3 f
a
b
a
b
a
b
a
b
a
b
a
b
a
b
3
3
2
2
4
4
4
4
1
1
3
3
2
2
1
1
2
2
0
0
1
1
1
1
1
1
2
2
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2 f
14
14
14
14
14
14
15
15
12
12
14
14
14
14
40
50
5
18
<5
<5
28
53
12
26
<5
<5
<5
<5
3 f
3g
3g
2 f
2g
2g
[a] See the Supporting Information and Equations (1) and (2). [b] Reac-
tion conditions: a) 20 mol% [Ni(cod)2], 40 mol% Bu3P, 1000 mol%
Et3B, THF, initial concentration of starting material=0.15m; b) 100
mol% [Ni(cod)2], 200 mol% Bu3P, 1000 mol% Et3B, THF, initial
concentration of starting material=0.075m.
that at C6. Ozonolytic cleavage of the alkene in 2 and
protection of the secondary alcohol afforded 9 in 94%
yield over the two steps (Scheme 3).[13] When 9 was heated
in tert-butoxy-bis(dimethylamino)methane (Bredereckꢁs
reagent[14]), enamine 10 was generated with excellent regio-
control (> 95:5 site-selectivity[15]), and was immediately
exposed to singlet oxygen.[16] The ensuing [2+2] and retro-
[2+2] cycloaddition reactions afforded the desired 1,2-dike-
tone 11 in 70% overall yield (two steps) by way of a
ments of ester functional groups inhibited macrocyclization
by ring-closing metathesis.[5h,9c–d]
Since the necessary ester–alkyne relationship corre-
sponded to that found in gloeosporone, we hypothesized
that this strategy would be well-suited to the preparation of
the natural product. Epoxy alcohol 4 was prepared in four
steps from 7-octen-1-ol; Jacobsenꢁs hydrolytic kinetic reso-
lution[10] was used to establish the absolute configuration of
the epoxide (Scheme 2). As five methylene groups separate
the epoxide and aldehyde groups, carbonyl addition reactions
of 6 proceeded with no detectable diastereoselection (not
shown). However, a reagent-controlled addition of diamyl-
zinc afforded alcohol 4 in > 95:5 d.r. and 80% yield.[11,12]
Hexynoic acid 8 was prepared from commercially avail-
able 5-hexyn-1-ol in two steps in 80% overall yield. Fragment
coupling by ester formation (DCC/DMAP) provided the
substrate (3) for the catalytic epoxide–alkyne reductive
macrocyclization (Scheme 2). Compound 2 was obtained in
46% yield at 20% Ni loading [Eq. (3)]. Use of stoichiometric
amounts of nickel provided 2 with improved efficiency (67%
yield). When compared to the studies in Table 1 (entries 1 and
2, respectively), these results indicate that the amyl group
plays a small yet beneficial role in the macrocyclization.
With the macrocycle in hand, the major remaining
challenge in the synthesis of (À)-gloeosporone was site-
selective oxidation of the methylene group at C4, rather than
Scheme 3. Completion of the synthesis of (À)-gloeosporone (1). a) O3,
then Ph3P; b) Et3SiOTf, 2,6-lutidine, 94% yield over 2 steps; c) tert-
butoxy-bis(dimethylamino)methane, 608C, >95:5 site selectivity;
d) O2, hn, Rose Bengal, CH2Cl2, 70% yield over 2 steps; e) HF·pyridine,
THF, 90% yield.
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Communications
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Published online: June 17, 2009
À
Keywords: C C coupling · cyclization · nickel ·
reductive coupling · total synthesis
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