A synthesis of petrofuran based on the enantioselective reduction of 1- trimethylsilyl-4-alken-1-yn-3-ones

Article abstract of DOI:10.1055/s-1999-6183

Highly enantioenriched 4-alken-1-yn-3-ol moiety (1), present in many bioactive acetylenic metabolites from sponges, has been efficiently obtained by reduction of the parent 1-trimethylsilyl-4-alken-1-yn-3-one (2) with Alpine-Borane or with BH₃ · SMe₂ in the presence of chiral oxazaborolidines, followed by desilylation of the resulting alcohol. This strategy has been applied to the first stereoselective synthesis of petrofuran 3.

Full text of DOI:10.1055/s-1999-6183

LETTER
429
A Synthesis of Petrofuran Based on the Enantioselective Reduction of 1-
Trimethylsilyl-4-alken-1-yn-3-ones
J. Garcia,* M. López, J. Romeu
Departament de Química Orgànica, Universitat de Barcelona, C/ Martí i Franquès 1-11, 08028-Barcelona, Catalonia, Spain
Fax +34 93 3397878; E-mail: jgg@gsaa1.qo.ub.es
Received 14 December 1998
In the light of our previous work on enantioselective re-
duction of unsaturated ketones,4 we envisaged that the
common 4-alken-1-yn-3-ol (1) moiety could be construct-
ed by reduction of the parent 1-trimethylsilyl-4-alken-1-
Abstract: Highly enantioenriched 4-alken-1-yn-3-ol moiety (1),
present in many bioactive acetylenic metabolites from sponges,
has been efficiently obtained by reduction of the parent 1-trimethyl-
silyl-4-alken-1-yn-3-one (2) with Alpine-Borane or with
BH3∑SMe2 in the presence of chiral oxazaborolidines, followed by yn-3-one (2) (see Scheme 1). We wish to report here our
desilylation of the resulting alcohol. This strategy has been applied
to the first stereoselective synthesis of petrofuran 3.
findings in this connection as well as a synthesis of petro-
furan (3), a metabolite recently isolated from Petrosia
sp.1b and Adocia sp.,5 in which such a reduction is the piv-
Key words: enantioselective reduction, oxazaborolidines, Petrosia
sp., polyacetylenes, sponge metabolites
otal step.
In order to assess the viability of the aforementioned pre-
sumption, we first launched the study of the reduction of
Sponges are probably the most prolific sources of biolog-
a representative, unbranched 1-trimethylsilyl-4-alken-1-
ically active marine natural products. A remarkable class
yn-3-one with a few chiral reducing agents. 1-Trimethyl-
among such sponge metabolites are constituted by the
silyl-4-octen-1-yn-3-one (4), easily obtained as outlined
long-chain acetylenes and polyacetylenes isolated from
in Scheme 2, was chosen as a model. The results are sum-
the genera Siphonocaline, Petrosia, Cribrochalina,
marised in Table 1.
Xestospongia, Pellina, and Haliclona.1 Many of these
compounds show antimicrobial, cytotoxic, immunosup-
pressive, RNA-cleaving, and/or antitumor properties.
Structurally, most of these metabolites possess an un-
Table 1. Enantioselective reduction of ketone 4
OH
O
branched, unsaturated, long-chain backbone in which a
characteristic, terminal 4-alken-1-yn-3-ol (1) moiety is of-
ten present. The strong bioactivity displayed, and the low
natural abundance, which seriously limits the pharmaco-
logical assays in many cases, make these compounds very
attractive as synthetic targets. However, to the best of our
knowledge, only a few stereoselective approaches to this
kind of products are reported in which the stereocenters
arise from the chiral pool2 or derive from an enzymatic
resolution.3
reagent and/or
catalyst
Pr
Pr
0 o
C
TMS
TMS
4
5
Ph
O
Ph
O
Ph
HN
Ph
O
Ph
HN
Ph
Ph
N
B
B
B
Me
(4S,5R)-8
2BCl
Me
Me
(S)-6
(S)-7
B
OH
O
9
10
(–)-Alpine-Borane
(–)-DIP-Chloride
R
R
1
2
TMS
reagent and/or
catalyst
yieldd
eee
entry
t
alcohol
1a
BH3:SMe2 / (S)-6
BH3:SMe2 / (S)-7
BH3:SMe2 / (4S,5R)-8
(–)-9
95%
(S)-5
(S)-5
(S)-5
(R)-5
(R)-5
90%
<15 min
O
2a
3a
4b
5c
<15 min 85% 95%
<15 min 80% 70%
3
3
OH
3
OH
Scheme 1
overnight
93% 92%
overnight
47%
(–)-10
39%
O
O
aReactions were carried out by addition of 4 (1 mmol) to a mixture of
BH3:SMe2 (1.2 mmol) and catalyst (1 mmol) in THF. bReduction was
performed with 2.5 mmol of 4 in neat 9 (10 mmol) according to ref. 10.
i)
Li-C≡C-TMS
Pr
Pr
H
ii) MnO2, hexane
84% overall yield
cReduction was performed with 1.3 mmol of 4 in neat 10 (1.5 mmol) according
to ref. 11. dIsolated yield after chromatography. eDetermined by 19F NMR
analysis of the corresponding Mosher esters.
TMS
4
Scheme 2
Synlett 1999, No. 4, 429–431 ISSN 0936-5214 © Thieme Stuttgart · New York

430
J. Garcia et al.
LETTER
As shown in entries 1 and 2 of Table 1, neat conversions dation of 16 followed by treatment of the resulting alde-
to highly enantioenriched alcohol 5 were accomplished hyde with an excess of Ph3P=CHCO2Me afforded (E)-
when ketone 4 (1 mmol) was added over ~15 min to a so- a,b- unsaturated ester 18.14 Finally, reduction of 18 with
lution of BH3:SMe2 (1.2 mmol) in THF (2 mL) in the pres- DIBAL-H cleanly provided the desired alcohol 14.
ence of oxazaborolidines 6 or 7 (1 mmol);6 these
oxazaborolidines come from phenylglycine4b and pro-
line,7 respectively. However, lower stereoselectivities
were noted with oxazaborolidine 88 (entry 3). The origin
of the enantioselectivity observed9 can be explained, in
agreement with literature precedents,7 through a complex
like 11 in which the ethylenic moiety, acting as a group
“larger” than the acetylenic one, is located far from the B-
Me group.
b
OH
a
OH
C6H13
84%
88%
3
2
15
16
c
d
e
14
CHO
CO2Me
98%
89%
98%
3
3
17
18
(a) i) BuLi, THF, –78 oC; ii) (CH2O)n, –78 oC. (b) H2N(CH2)3NH2, NaH,
55 oC, overnight. (c) Swern oxidn. (d) Ph3P=CHCO2Me, CH2Cl2, rt, 6 h (e)
DIBAL-H, toluene, –78 oC, 1 h.
TMS
Me
Ph
Ph
OH
Scheme 5
H
B
O
Pr
N
Ph
O
H
H
B
Pd-catalysed coupling15 of 14 with 2,5-dibromofuran
proved to be troublesome. Several attempts carried out
with catalytic CuI/Ph3P/ BnPd(Ph3P)2Cl systems in Et3N
led to only poor yields of the desired diol (13) together
with the furan-monosubstituted compound and the diyne
arising from the oxidative dimerization of 14. Fortunately,
we eventually succeeded, by using (PPh3)4Pd as the cata-
lyst (14/ dibromofuran ratio 3:1, 10% mol of (PPh3)4Pd,
refluxing pyrrolidine, 6 h).16 Addition of TMSC≡CLi to
19 provided a mixture of diols 20, which was subjected to
Swern oxidation to yield diketone 12. Reduction of 12
with BH3:SMe2 (3 mmol) in THF in the presence of (S)-6
(2 mmol) afforded (S,S)-2017 (98% e.e.)18 which was des-
ilylated to yield petrofuran (3).19
TMS
Pr
H
(S)-5
H
11
Scheme 3
Alpine-Borane (9) was as efficient as 6 or 7 but longer re-
action times were required to complete the reaction (entry
4). On the other hand, DIP-Chloride (10) led to a mixture
of products from which 5 was isolated in low yield and
with poor e.e. (entry 5).
In the light of the encouraging results obtained in entries
1, 2, and 4, we envisaged that a synthesis of petrofuran (3)
could be feasible via a stereoselective reduction of ketone
12. In our retrosynthetic analysis, 12 could come from 13,
which in turn would arise from a Pd-catalysed, one pot
double coupling of side chains 14 to 2,5-dibromofuran.12
a
b
O
13
96%
91%
Br
Br
O
19
TMS
3
3
TMS
OHC
OHC
O
3
3
12
O
c
d
b
O
12
3
O
85%
TMS
40%
90%
TMS
O
O
3
3
3
3
HO
20
13
OH
OH
3
OH
(a) 14 , (Ph3P)4Pd cat., pyrrolidine, reflux, 6 h . (b) Swern oxidn. (c)
TMSC≡CLi, THF, –78 oC. (d) i) BH3:SMe2, (S)-6, THF, 0 oC; ii) K2CO3,
MeOH–H2O, rt, 45 min.
+
Br
Br
+
3
OH
OH
14
14
Scheme 6
Scheme 4
In summary, we have disclosed an efficient approach to
highly enantioenriched 4-alken-1-yn-3-ol moiety which
seems of general applicability to a number of bioactive
metabolites from sponges. We have applied this strategy
to the first enantioselective synthesis of petrofuran.
Alcohol 14 was synthesised by a standard procedure, as
shown in Scheme 5. Thus, treatment of 1-octyne with
BuLi and (CH2O)n furnished 2-nonyn-1-ol (15) which
was readily transformed into the corresponding terminal
alkyne 16 by NaH in 1,3-propylenediamine.13 Swern oxi-
Synlett 1999, No. 4, 429–431 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Synthesis of Petrofuran Based on Enantioselective Reduction
431
(7) For a review on proline-derived oxazaborolidines, see: Corey,
E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986.
For a review on oxazaborolidine-mediated reductions, see:
Wallbaum, S.; Martens, J. Tetrahedron:Asymmetry 1992, 3,
1475.
(8) Quallich, G. J.; Woodall, T. M. Tetrahedron Lett. 1993, 34,
4145.
(9) Absolute configuration was established by comparison of the
sign of the specific rotation of 5 [[a]D +39.5 (c 2, CHCl3)]
with that given in the literature [ref. 3c: [a]D +38.5 (c 1,
CHCl3) for isomer 3S,4E].
(10) Brown, H. C.; Pai, G. G. J. Org. Chem. 1985, 50, 1384.
The reduction of an exemple of (Z)-5-alken-2-yn-4-one with
Alpine-Borane has been reported: Midland, M. M. Chem. Rev.
1989, 89, 1553.
(11) Brown, H. C.; Chandrasekharan, J. J. Org. Chem. 1986, 51,
3396.
(12) Keegstra, M. A.; Klomp, A. J. A.; Brandsma, L. Synthetic
Commun. 1990, 20, 3371.
(13) Macaulay, S. R. J. Org. Chem. 1980, 45, 734.
14. E isomer was isolated (E/Z ratio >30:1 according to the 1H-
NMR spectrum of the crude product).
Acknowledgement
Financial support from the DGICYT, Ministerio de EducaciÛn y
Cultura (Grant PM95-0061), and from the DirecciÛ General de Re-
cerca, Generalitat de Catalunya (1996SGR 00102), is gratefully
acknowledged. A doctorate studentship from the Universitat de
Barcelona to M.L. is also acknowledged. Thanks are due to Prof. T.
Higa for kindly sending of spectral data for 1 and to Prof. J. Vilar-
rasa for correcting the Ms.
References and Notes
(1) a) Faulkner, D. J. Nat. Prod. Rep. 1997, 14, 259 and references
cited therein. b) Higa, T.; Tanaka, J.; Kitamura, A.; Koyama,
T.; Takahashi, M.; Uchida, T. Pure & Appl. Chem. 1994, 66,
2227.
(2) Lu, W.; Zheng, G.; Cai, J. Synlett 1998, 737. For a related syn-
thesis, see: Iguchi, K.; Kitade, M.; Kashiwagi, T.; Yamada, Y.
J. Org. Chem. 1993, 58, 5690.
(3) a) Ohtani, T.; Kikuchi, K.; Kamezawa, M.; Hamatani, H.; Ta-
chibana, H.; Totani, T.; Naoshima, Y. J. Chem. Soc. Perkin
Trans. 1 1996, 961. b) Sharma, A.; Chattopadhyay J. Org.
Chem. 1998, 63, 6128. c) For a related resolution, see: Allevi,
P.; Ciuffreda, P.; Anastasia, M. Tetrahedron:Asymmetry
1997, 8, 93.
(4) a) Bach, J.; Berenguer, R.; Farràs, J.; Garcia, J.; Meseguer, J.;
Vilarrasa, J. Tetrahedron:Asymmetry 1995, 6, 2683. b) Bach,
J.; Berenguer, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J.
Org. Chem. 1996, 61, 9021. c) Bach, J.; Garcia, J. Tetrahe-
dron Lett. 1998, 39, 6761. d) Bach, J.; Galobardes, M.; Garcia,
J.; Romea, P.; Tey, C.; UrpÌ, F.; Vilarrasa, J. Tetrahedron Lett.
1998, 39, 6765.
(5) Kobayashi, M.; Mahmud, T.; Tajima, H.; Wang, W.; Aoki, S.;
Nakagawa, S.; Mayumi, T.; Kitagawa, I. Chem. Pharm. Bull.
1996, 44, 720. In this paper, isolation of 3 (named adociacety-
lene B by the authors) from an Okinawan marine sponge of
genus Adocia as well as its fully characterization, are de-
scribed.
(6) Slower additions and/or longer reaction times (up to 60 min)
led to poorer chemical yields, probably by concomitant side
reactions (hydroboration). In fact, when a sample of enantio-
enriched 5 was treated with BH3∑SMe2 and 6 under similar
conditions for 1 h, 5 was recovered in only 50% yield, but with
negligible lost of e.e. In this connection, it is worth noting that
when only 0.2 mmols of 6 were used in the reduction step, the
reaction became slower and chemical yield considerably
dropped.
(15) For a review on Pd-catalysed reactions of heterocycles, see:
Kalinin, V. N. Synthesis 1992, 413.
(16) The Pd(0) catalyst had to be washed with EtOH and then with
Et2O before use to obtain good yields.
(17) Compound meso-20 (~17%) was also present in the crude.
Data for (S,S)-20: colourless oil; Rf 0.64 (1:1 hexane/EtOAc);
[a]20D +17.4 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) d
0.19 (s, 18H), 1.32Ð1.87 (m, 16H), 2.06 (m, 4H, CH2-CH=),
2.41 (t, 4H, J = 6.9 Hz, CH2-C≡), 4.82 (br d, 2H, J ~ 6 Hz,
CHOH), 5.58 (tdd, 2H, J = 15.3, 6.3, 1.2 Hz, =CH-CHOH),
5.88 (dtd, 2H, J = 15.3, 6.9, 1.2 Hz, =CH-CH2), 6.34 (s, 2H);
13C NMR (75.4 MHz, CDCl3) d Ð0.2 Me3Si), 19.4 (CH2-C≡),
28.2, 28.6, 28.6, 28.7, 31.8 (CH2-CH=), 63.3 (CHOH), 70.9
(Ar-C≡), 90.5 (TMS-C≡), 95.0 (CH2-C≡), 104.8 (CHOH-
C≡), 114.5 (aromatic CH), 128.8 (CHOH-CH=), 134.0 (CH2-
CH=), 137.2 (aromatic C-C≡); IR (film) 3320, 2940, 2160,
1670. CI-MS (NH3) m/z: 606 (M++18, 10%), 226 (100%).
(18) Stereoisomeric ratios were obtained by HPLC analysis (Sphe-
risorb S3W column, hexane/AcOEt 95:5) of the correspon-
ding Mosher diesters.
(19) Spectral data of 3 fully agree with those reported in ref. 5.
Synlett 1999, No. 4, 429–431 ISSN 0936-5214 © Thieme Stuttgart · New York