Highly efficient asymmetric synthesis of fluvirucinine A1 via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)-lipase-catalyzed acetylation tandem process

Article abstract of DOI:10.1021/ol702272d

(Chemical Equation Presented) ZACA-lipase-catalyzed acetylation tandem process has been shown to proceed satisfactorily with either TBS-protected 4-penten-1-ol or 3-buten-1-ol to provide the corresponding enantiomerically pure (R)-2-ethyl-1-alkanols. Either (R)-5 or (R)-6 was converted to 3 in seven steps. The other fragment 4 was synthesized in nine steps from (-)-(S)-citronellol. Conversion of 3 and 4 into 99% pure fluvirucinine A ₁ was achieved in four steps via amidation-ring closing metathesis, the overall yield in the longest linear sequence being 34% (13 steps).

Full text of DOI:10.1021/ol702272d

ORGANIC
LETTERS
2008
Vol. 10, No. 2
193-195
Highly Efficient Asymmetric Synthesis
of Fluvirucinine A1 via Zr-Catalyzed
Asymmetric Carboalumination of
Alkenes (ZACA)−Lipase-Catalyzed
Acetylation Tandem Process
Bo Liang and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received October 20, 2007
ABSTRACT
ZACA
1-ol to provide the corresponding enantiomerically pure (R)-2-ethyl-1-alkanols. Either (R)-5 or (R)-6 was converted to 3 in seven steps. The
other fragment 4 was synthesized in nine steps from ( )-(S)-citronellol. Conversion of 3 and 4 into 99% pure fluvirucinine A1 was achieved in
four steps via amidation ring closing metathesis, the overall yield in the longest linear sequence being 34% (13 steps).
−lipase-catalyzed acetylation tandem process has been shown to proceed satisfactorily with either TBS-protected 4-penten-1-ol or 3-buten-
−
−
Fluvirucinine A1 (1a) is an aglycone of fluvirucin A1 (1b),
a member of antibiotics isolated from the fermentation broth
of unidentified actinomycete strains exhibiting considerable
inhibitory activity against influenza A virus.1 It has recently
been synthesized by Suh2 in 22 linear steps in about 3%
overall yield. Our recent development of the ZACA-lipase-
catalyzed acetylation tandem process3 permitting efficient
and selective syntheses of enantiomerically pure 2-methyl-
1-alkanols prompted us to see if this tandem process would
be readily adaptable to the synthesis of 2-alkyl-1-alkanols,
where the 2-alkyl group is ethyl or a higher primary alkyl
group. If so, a convergent and highly efficient synthesis of
1a via 2, which in turn should be obtained from 3 and 4, as
outlined in a retrosynthetic analysis shown in Scheme 1
would be feasible.
The first crucial task of devising efficient and enantiose-
lective routes to 3 was achieved in two similar manners, as
summarized in Scheme 2. In Route I, commercially available
4-penten-1-ol was protected with TBSCl and imidazole in
98% yield and subjected to the ZACA reaction4-6 with Et3-
Al (2 equiv), isobutylaluminoxane (IBAO, 1 equiv) generated
(1) (a) Naruse, N.; Tenmyo, O.; Kawauo, K.; Tomita, K.; Ohgusa, N.;
Miyaki, T.; Konishi, M.; Oki, T. J. Antibiot. 1991, 44, 733-740. (b) Naruse,
N.; Tsuno, T.; Sawada, Y.; Konishi, M.; Oki, T. J. Antibiot. 1991, 44, 741-
755. (c) Naruse, N.; Konishi, M.; Oki, T.; Inouye, Y.; Kakisawa, H. J.
Antibiot. 1991, 44, 756-761. (d) Tomita, K.; Oda, N.; Hoshino, Y.; Ohgusa,
N.; Chikazawa, H. J. Antibiot. 1991, 44, 940-948.
(2) Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.; Koo,
B.-A.; Kim, H.-S. Angew. Chem., Int. Ed. 1999, 38, 3545-3547.
(3) Huang, Z.; Tan, Z.; Novak, T.; Zhu, G.; Negishi, E. AdV. Synth. Catal.
2007, 349, 539-545. ZACA stands for Zr-catalyzed asymmetric carboalu-
mination of alkenes.
(4) (a) Kondakov, D.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771-
10772. (b) Kondakov, D.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577-
1578. (c) Huo, S.; Negishi, E. Org. Lett. 2001, 3, 3253-3256.
(5) (a) For the use of IBAO as a promotor, see: Huo, S.; Shi, J.; Negishi,
E. Angew. Chem., Int. Ed. 2002, 41, 2141-2143. (b) For a seminal
contribution on the use of promotors, such as methylaluminoxane (MAO)
and H2O, see: Wipf, P.; Ribe, S. Org. Lett. 2000, 2, 1713-1716.
10.1021/ol702272d CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/13/2007

Scheme 1
Scheme 2
i
in situ by treating Bu3Al with 1 molar equiv of H2O, and
just 0.1 mol % of (-)-(NMI)2ZrCl2. The crude product
isolated in 82% yield was shown to be 90% ee or 95% R
and purified by selective acetylation with vinyl acetate (5
equiv) and Amano PS lipase (30 mg/mmol) to give enan-
tiomerically pure (g98% ee) (R)-5 in 75% recovery. The
results clearly indicate that the ZACA-lipase-catalyzed
acetylation tandem process promises to provide a very
favorable route to a wide range of (R)-2-ethyl-1-alkanols.
After six additional and conventional steps, including forma-
tion and reduction of an azide, (R)-3 of g98% ee was
obtained in 38% yield over eight steps from 4-penten-1-ol
(Route I in Scheme 2). Similarly, 3-buten-1-ol (Aldrich) was
converted to 4-TBS-protected (R)-2-ethyl-1,4-butanediol (6)
of g98% ee in 67% yield in just two steps and one
purification with vinyl acetate and Amano PS Lipase.
Conversion of 6 into 3 also required six well-known steps,
including cyanation and reduction with LiAlH4 of the nitrile
thus formed. Thus, (R)-3 of g98% ee was produced in 46%
yield over eight steps from 3-buten-1-ol. A somewhat higher
product yield of 46% and the use of less expensive 3-buten-
1-ol make Route II in Scheme 2 somewhat more attractive
than Route I. It should also be noted that both 5 and 6
promise to serve as potentially versatile Et-branched difunc-
tional chiral synthons.
catalyzed oxidative alkene cleavage8 with NaIO4 used twice.
The whole transformation proceeded satisfactorily in 44%
overall yield, as summarized in Scheme 3.
Scheme 3
Preparation of the other key intermediate 4 via ZACA
reaction of TBS-protected 3-buten-1-ol with Me3Al in a
manner similar to that employed in Route II in Scheme 2 is
conceivable and was indeed considered first. In view of the
ready availability of (-)-(S)-â-citronellol, however, its
conversion into 4 (dr g98% by 13C NMR) was performed
in nine steps, including the Brown crotylboration7 and OsO4-
(6) For application of the ZACA reaction to the synthesis of deoxy-
polypropionates, see: (a) Negishi, E.; Tan, Z.; Liang, B.; Novak, T. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5782-5787. (b) Tan, Z.; Negishi, E.
Angew. Chem., Int. Ed. 2004, 43, 2911-2914. (c) Magnin-Lachaux, M.;
Tan, Z.; Liang, B.; Negishi, E. Org. Lett. 2004, 6, 1425-1427. (d) Novak,
T.; Tan, Z.; Liang, B.; Negishi, E. J. Am. Chem. Soc. 2005, 127, 2838-
2839. (e) Liang, B.; Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc.
2006, 128, 2770-2771. (f) Zhu, G.; Negishi, E. Org. Lett. 2007, 9, 2771-
2774.
Conversion of the two key intermediates 3 and 4 into a
14-membered lactam 9 was achieved in two steps in 83%
(7) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-
5923. (b) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988,
110, 1535-1538.
(8) (a) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
Org. Chem. 1956, 21, 478-479. (b) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.;
Jin, Z. Org. Lett. 2004, 6, 3217-3219.
194
Org. Lett., Vol. 10, No. 2, 2008

from (-)-(S)-â-citronellol) (Scheme 4). The 1H and 13C NMR
spectra as well as the specific rotation [R]23 ) +138.6 (c
0.2, CH3OH) are in good agreement with those reported in
the literature.1,2
D
Scheme 4
In summary, the ZACA reaction of TBS-protected 3-buten-
1-ol or 4-penten-1-ol with Et3Al, isobutylaluminoxane (IBAO),
and 0.1 mol % of (-)-(NMI)2ZrCl2 proceeds in about 85%
yield and in 90% ee. Furthermore, the crude product thus
obtained can be readily purified by Amano PS lipase-
catalyzed acetylation with vinyl acetate to give (R)-5 or (R)-
6, respectively, of g98% ee in 75-80% recovery. The ready
access to enantiomerically pure (R)-5 or (R)-6 permits the
preparation of (R)-3 of g98% ee in 46 or 38% yield over
eight steps from 3-buten-1-ol or 4-penten-ol, respectively.
Another satisfactory, albeit conventional, preparation of
isomerically pure 4 from (-)-(S)-â-citronellol in 44% yield
over nine steps followed by a three-step conversion of 3 and
4 into fluvirucinine A1 (1a) in 78% yield over four steps
has provided 1a of g99% isomeric purity in 34% overall
yield in 13 steps from (-)-(S)-â-citronellol.
combined yield. Thus, amidation of 3 with 4 by the use of
N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochlo-
ride (EDCI) and 1-hydroxybenzotriazole (HOBt)9 produced
2 in 90% yield, which was then subjected to the Ru-catalyzed
ring closing metathesis (RCM)10 with 10 mol % of PhCHd
Ru(PCy3)2Cl2 as a catalyst to produce the desired macrolac-
tam 9 in 92% yield. Its hydrogenation over Pd/C (5%)
followed by desilylation with TBAF furnished fluvirucinine
A1 (1a) in 94% yield over two steps (34% over 13 steps
Acknowledgment. We thank the National Institutes of
Health (GM 36792), the National Science Foundation (CHE-
0309613), and Purdue University for support of this research.
We acknowledge related studies by Drs. S. Huo and L.
Anastasia in our laboratories. We also thank Dr. G. Zhu for
his assistance in the manuscript preparation.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra of the reaction
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) Sheehan, J. C.; Preston, J.; Cruickshank, P. A. J. Am. Chem. Soc.
1965, 87, 2492-2493.
(10) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426-
5427. (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446-452.
OL702272D
Org. Lett., Vol. 10, No. 2, 2008
195