Stereoselective gold-catalyzed cycloaddition of functionalized ketoenynes: Synthesis of (+)-orientalol F

Article abstract of DOI:10.1039/b920119j

A stereoselective gold-catalyzed [2 + 2 + 2] cycloaddition of ketoenynes substituted at the propargylic position with OR groups has been applied for the synthesis of (+)-orientalol F and pubinernoid B.

Full text of DOI:10.1039/b920119j

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Stereoselective gold-catalyzed cycloaddition of functionalized ketoenynes:
synthesis of (+)-orientalol Fwz
´
´ ´ ˜
Eloısa Jimenez-Nunez, Kian Molawi and Antonio M. Echavarren*
a
a
ab
Received (in Cambridge, UK) 28th September 2009, Accepted 19th October 2009
First published as an Advance Article on the web 5th November 2009
DOI: 10.1039/b920119j
A stereoselective gold-catalyzed [2 + 2 + 2] cycloaddition of
ketoenynes substituted at the propargylic position with OR
groups has been applied for the synthesis of (+)-orientalol F
and pubinernoid B.
1,6-Enynes with a carbonyl group at the alkenyl side chain
react in the presence of Au(I) catalysts to give oxatricyclic
skeletons by a domino process in which two C–C and one C–O
bonds are assembled by a formal [2 + 2 + 2] alkyne/alkene/
carbonyl cycloaddition.1 The cyclization of ketoenynes 1
functionalized at the propargylic position for the synthesis of
2 would allow a direct entry into natural products such as
orientalol F (3),2 pubinernoid B (4),3 or englerin A (5), a
sesquiterpene that has been shown to selectively inhibit the
growth of renal cancer cell lines at the nanomolar level.4
Although enynes react with gold, platinum, and other
electrophilic metal catalysts to form a diversity of structures,
tolerance to functional groups and stereochemical issues have
not yet been examined in much detail.5 The functionality of 1
posed a challenge since propargylic alcohols are prone to
undergo Meyer–Schuster rearrangement or suffer nucleophilic
attack with gold catalysts6,7 and propargylic carboxylates
readily undergo metal-catalyzed 1,2- or 1,3-acyl migrations.5,8
In addition, we have recently found that propargyl alcohols,
ethers, and silyl ethers 6 react by a new type of gold(I)-
catalyzed intramolecular 1,5-migration of OR groups to give
products 7 (Scheme 1).9
Scheme 1
Therefore, for the desired cyclization of 1 to form 2, the
intramolecular attack of the carbonyl group should be faster
than the migration of the OR group. Furthermore, the
cyclization should proceed stereoselectively through 8a and
9, since the cyclization of the alternative intermediate 8b would
give rise to 10 with the undesired relative configuration
Scheme 2
sesquiterpene. This work also sheds light on the relative rates
of competitive pathways occurring after the initial formation
of the cyclopropylgold carbene1a,10 in enyne cyclizations.
The cyclization proceeded more satisfactorily with TES-
protected substrate 1 (Table 1). Whereas AuCl was inefficient
as the catalyst (Table 1, entry 1), reaction with cationic Au(I)
complexes 12,11 13a, and 13b12 gave oxatricyclic derivative
(ꢀ)-2b as a single stereoisomer, along with rearranged ketone
111,13 (Table 1, entries 2–4). The use of silver-free gold(I)
catalysts was essential to obtain 2 in consistent yields.
Although the reaction was faster with phosphine–gold catalyst
12, the best result was obtained with NHC–gold complex 13b,
which gave (ꢀ)-2 in 65% yield. No reaction was observed with
a complex formed from PtCl2 and P(o-Tol)3 (Table 1, entry 5),
whereas platinacycle 1414 gave rearranged ketone 11 as the
major product (Table 1, entry 6). The cyclization with the free
(Scheme 2).
Here we report that the [2 + 2 + 2] gold-catalyzed
cycloaddition of substrates 1 takes place stereoselectively via
intermediates of type 8a, which allows the first syntheses of
(+)-orientalol
F (3), the structure originally proposed
for pubinernoid B (4), and the corrected structure of this
a Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos
¨
Catalans 16, 43007 Tarragona, Spain. E-mail: aechavarren@iciq.es
b
´
´
´
`
Departament de Quımica Analıtica i Quımica Organica, Universitat
Rovira i Virgili, C/Marcelli Domingo s/n, 43007 Tarragona, Spain
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Synthesis of
starting substrates, characterization and X-ray crystallographic data.
CCDC 747563 and 747564. See DOI: 10.1039/b920119j
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 7327–7329 | 7327

Table 1 Cyclization of enyne 1 with metal catalystsa
Scheme 4
Entry
[M]
t
Products (yield, %)
b
obtained in this work, suggested that this sesquiterpene might
have instead a configuration opposite to that of 4 at the oxa
bridge. Therefore, the synthesis of pubinernoid B required a
substrate 18 with a Z configuration (Scheme 4). In the event,
cyclization of ketoenyne (ꢀ)-18 with catalyst 12 gave (ꢀ)-19 in
modest yield after desilylation of the major cyclization product
in a reaction that presumably proceeds via intermediate 20.
Synthetic (ꢀ)-19 showed NMR data identical to that reported
for pubinernoid B.3
1
2
3
AuCl
12
13a
13b
PtCl2/(Po-Tol3)
14
24 h
20 min
3 h
3 h
24 h
1 h
—
2 (14) + 11 (34)
2 (25) + 11 (12)
2 (65) + 11 (4)
4
b
5c
6
—
2 (28) + 11 (42)
a
Reactions in CH2Cl2 with 3 mol% catalyst and 4 A molecular sieves
b
at 23 1C. Starting material was recovered. Reaction in 1,2-dichloro-
ethane at 70 1C.
c
The synthesis of (+)-orientalol F (3) started from known
(ꢀ)-epoxyfarnesol (21),16 which furnished 22 by Sharpless
epoxidation (99% yield) followed by treatment with CCl4
and PPh3 (93% yield). Reaction of 22 with 5 equiv. of n-BuLi
furnished propargylic alcohol 23 in excellent yield. Regio-
selective reduction of the epoxide of 23 with NaBH3CN and
17
BF3ꢃOEt2 gave the diol (74% yield), which, after oxidation
with DMP (86%) and protection of the hydroxyl group with
TESOTf (96%), provided (S)-1, with 95 : 5 enantiomeric ratio,
which reflects the selectivity of the Sharpless epoxidation.
Gold catalyzed cyclization of enantiomerically enriched (S)-1
using catalyst 13b (3 mol%) gave 2 in 65% yield. After
desilylation of 2 (95% yield), the allylic alcohol 4 was treated
with Collins reagent. Surprisingly, the oxidative allylic
rearrangement led cleanly to syn-epoxy alcohol 24 (78% yield)18
(Scheme 5). When PDC was used as the oxidant, a 74% yield
of a 1 : 1 mixture of 24 and a,b-unsaturated ketone 25, the
product of the expected Dauben oxidation,19 was obtained.
(+)-Orientalol F (3) was obtained by reaction of 24 with WCl6
and n-BuLi20 (73% yield) or by Luche reduction of 25
(quantitative). Orientalol F (3) had NMR data identical to
those reported.2 Chiral-GC analysis showed an enantiomeric
ratio of 94 : 6, that is, within experimental error, the same
value determined for substrate (S)-1, which demonstrates that
no racemization occurs in the gold-catalyzed process via
alcohol (1, R = H) or other protected derivatives gave low
yields of the desired compounds.
Deprotection of (ꢀ)-2 with TBAF gave (ꢀ)-4 (95% yield)
whose 1H NMR (800 MHz) spectrum was clearly distinct from
that reported for pubinernoid B.3 Thus, the olefinic hydrogen
appeared at d 5.72 (d, J = 2.6 Hz), whereas for the natural
product this signal was reported at d 6.07 (br, s). An allylic
rearrangement from (ꢀ)-2 to give (ꢀ)-3 failed using Re2O7.15
Indeed, alcohol (ꢀ)-2 is labile in the presence of acids.
Treatment of (ꢀ)-2 with TFA in CH2Cl2 at ꢂ20 1C gave 15
(80% yield), presumably via allylic carbocation 16 (Scheme 3).
The configuration assigned to (ꢀ)-2 was confirmed by X-ray
diffraction of epoxide (ꢀ)-17.z
1
Analysis of the H NMR data reported for pubinernoid B3
and comparison with those of the synthetic compounds
a
propargyl carbocation. Additionally, the structure of
crystalline (ꢀ)-3 was confirmed by X-ray diffraction.z
The stereochemical control exerted by the tertiary propargyl
stereocenter in the cyclization of substrates 1 is noteworthy.
To clarify the origin of this stereocontrol, we examined the
stereochemical outcome of the cyclization of a substrate such
as 26 bearing a secondary OR at the propargylic position. The
cyclization of 26 in the presence of MeOH and catalyst 12 gave
product 27 exclusively (Scheme 6). The configuration of 27
was determined by NOE experiments and is consistent with a
cyclization proceeding exclusively through intermediate 28 in
which the OR group and the gold carbene are anti oriented,
despite the fact that the bulky OR group is at the most
Scheme 3
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This journal is The Royal Society of Chemistry 2009
7328 | Chem. Commun., 2009, 7327–7329

orientalols and pubinernoid and B. Escudero-Adan and
´
Dr J. Benet-Buchholz (ICIQ) for the X-ray structures of
(ꢀ)-3 and (ꢀ)-17.
Notes and references
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ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 7327–7329 | 7329