First total synthesis and structural confirmation of fluvirucinine A 2 via an iterative ring expansion strategy

Article abstract of DOI:10.1021/ol100521v

Figure presented The first asymmetric total synthesis of fluvirucinine A₂ has been accomplished. A key feature of the synthesis is an iterative lactam ring expansion to provide rapid access to the 14-membered lactam skeleton and three stereogenic centers. The excellent remote control of the three stereogenic centers relied on stereoselective amidoalkylation followed by an amide-enolate-induced aza-Claisen rearrangement. In addition, the structure of fluvirucinine A₂ has been completely elucidated by our total synthesis.

Full text of DOI:10.1021/ol100521v

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2040-2043
First Total Synthesis and Structural
Confirmation of Fluvirucinine A2 via an
Iterative Ring Expansion Strategy
Yong-Sil Lee,† Jong-Wha Jung,† Seok-Ho Kim,† Jae-Kyung Jung,‡
Seung-Mann Paek,† Nam-Jung Kim,† Dong-Jo Chang,† Jeeyeon Lee,† and
Young-Ger Suh*,†
College of Pharmacy, Seoul National UniVersity, 599 Gwanakro, Gwanak-gu,
Seoul 151-742, Korea, and College of Pharmacy, Chungbuk National UniVersity,
Cheongju 361-763, Korea
ygsuh@snu.ac.kr
Received March 2, 2010
ABSTRACT
The first asymmetric total synthesis of fluvirucinine A2 has been accomplished. A key feature of the synthesis is an iterative lactam ring
expansion to provide rapid access to the 14-membered lactam skeleton and three stereogenic centers. The excellent remote control of the
three stereogenic centers relied on stereoselective amidoalkylation followed by an amide-enolate-induced aza-Claisen rearrangement. In
addition, the structure of fluvirucinine A2 has been completely elucidated by our total synthesis.
Fluvirucins were isolated from fermentation broths of acti-
nomycete isolates in 1991 by the scientists of Bristol-Myers
Squibb.1 Scientists at Schering-Plough also independently
isolated fluvirucin B1, B2, and B3 from Actinomadura
Vulgaris in 1990.2 The potent activities of fluvirucins against
bacteria, fungi, and especially influenza1a as well as structural
features of this novel class of macrolactams have attracted
interests in the past two decades. In particular, the synthesis
of fluvirucin A1 and A2 has attracted attention due to the
unique structural features of these molecules, which have
promising antiviral activities (ID50s of 4.3 and 4.6 µg/mL,
respectively, against influenza virus) and low toxicity (Figure
1).1a Moreover, the structure of fluvirucinine A2 has not been
† Seoul National University.
‡ Chungbuk National University.
(1) (a) Naruse, N.; Tenmyo, O.; Kawano, K.; Tomita, K.; Ohgusa, N.;
Miyaki, T.; Konishi, M.; Oki, T. J. Antibiot. 1991, 44, 733. (b) Naruse, N.;
Tsuno, T.; Sawada, Y.; Konishi, M.; Oki, T. J. Antibiot. 1991, 44, 741. (c)
Naruse, N.; Konishi, M.; Oki, T.; Inouye, Y.; Kakisawa, H. J. Antibiot.
1991, 44, 756. (d) Tomita, K.; Oda, N.; Hoshino, Y.; Ohkusa, N.;
Chikazawa, H. J. Antibiot. 1991, 44, 940.
Figure 1. Structures of fluvirucins.
fully elucidated. We have been working toward the total
synthesis of fluvirucinine A2 (1), an aglycon of fluvirucin
A2. We report herein the first asymmetric total synthesis of
fluvirucinines A2 and its full structure.
(2) (a) Hegde, V. R.; Patel, M. G.; Gullo, V. P.; Ganguly, A. K.; Sarre,
O.; Puar, M. S.; McPhail, A. T. J. Am. Chem. Soc. 1990, 112, 6403. (b)
Hegde, V. R.; Patel, M.; Horan, A.; Gullo, V.; Marquez, J.; Gunnarsson,
I.; Gentile, F.; Loebenberg, D.; King, A.; Puar, M.; Pramanik, B. J. Antibiot.
1992, 45, 624.
10.1021/ol100521v  2010 American Chemical Society
Published on Web 03/26/2010

Since the Hoveyda group reported the first total synthesis
of fluvirucinine B1,3a inspirations of the synthetic community
due to the unique structures and excellent biological activities
of fluvirucins have led to notable endeavors to facilitate their
total synthesis.3,4a
Scheme 2. Stereoselective Synthesis of (E)-Enol TBS Ether 12
Since we reported the first asymmetric total synthesis of
fluvirucinine A1,4a we have been interested in iterative ring-
expansion strategies (Scheme 1) as one of the most efficient
Scheme 1. Retrosynthesis of Fluvirucinine A2
the first ACR as reported.4a Amide enolate induced aza-
Claisen rearrangement of 5, prepared from lactam 6 via direct
stereoselective vinylation, afforded the ring-expanded lactam
7 as a sole product possessing the second requisite stereo-
genic center corresponding to C6 of fluvirucinine A2. The
10-membered lactam 4 was obtained by olefin hydrogenation
of 7 and subsequent Boc-protection. Taking advantage of
our recent protocol via an N,O-acetal TMS ether,6 we could
further provide the requisite allylazacycle 3, in spite of the
ring-opening propensity of medium or macrolactams. The
Boc-protected lactam 4 was partially reduced with DIBAL-
H, and then the resulting N,O-acetal was trapped with
subsequent addition of Py and TMSOTf to give the N,O-
acetal TMS ether 9. Upon BF3OEt2 treatment of N,O-acetal
TMS ether 9, highly stereoselective amidoalkylation was
achieved at a low temperature, and prolonged stirring at room
temperature allowed subsequent Boc-deprotection to give the
allylazacycle 3, with no detectable stereoisomer in high yield.
Expecting a chairlike transition state during the second ACR,
stereoselective (E)-enol ether formation was required to
facilitate the introduction of newly generated stereochemistry
at C3 as desired. Fortunately, silylation of the aldehyde,
obtained by oxidative cleavage of the corresponding R-al-
lylazacycle 10, under mild conditions (TBSCl, DBU, CH2Cl2,
reflux)7,4c resulted in the highly stereoselective formation of
the desired (E)-enol TMS ether 11 in an excellent yield, along
with a negligible amount of the corresponding (Z)-enol TMS
ether (>10:1).
approaches to the synthesis of macrolactam alkaloids. This
prominent ring-expansion strategy would provide (1) rapid
access to a variety of functionalized macrolactam skeletons
without an extra cyclization step, (2) concomitant stereose-
lective elaborations of the requisite stereogenic centers by a
distal asymmetric induction, and (3) entropic and enthalpic
advantages.5 As shown in Scheme 1, our unique strategy
takes full advantage of the initially introduced C10 chiral
center to control the relative stereochemistries of the remain-
ing remote stereogenic centers (C2, C3, and C6) through a
highly ordered ring expansion via an aza-Claisen rearrange-
ment (ACR). In particular, the second ACR (2 f 1) seems
to offer an attractive alternative to the conventional asym-
metric amide aldol reaction for elaboration of C2 and C3
stereogenic centers.
Shown in Scheme 2, our synthesis commenced with
preparation of the 10-membered lactam 4 from lactam 6 by
(3) (a) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 1995, 117, 2943. (b) Xu, Z.; Johannes, C. W.; Salman, S. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 1996, 118, 10926. (c) Trost, B. M.; Ceschi, M. A.;
Konig, B. Angew. Chem., Int. Ed. 1997, 36, 1486. (d) Martin, M.; Mas, G.;
Upri, F.; Vilarrasa, J. Angew. Chem. 1999, 111, 3274; Angew. Chem., Int.
Ed. 1999, 38, 3086. (e) Liang, B.; Negishi, E. Org. Lett. 2008, 10, 193. (f)
With a reliable protocol established for the synthesis of
functionalized macrolactams, we turned our attention to the
second ACR. A variety of ACR precursors were investigated
Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756
.
(4) (a) Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.;
Koo, B.-A.; Kim, H.-S. Angew. Chem. 1999, 111, 3753; Angew. Chem.,
Int. Ed. 1999, 38, 3545. (b) Suh, Y.-G.; Lee, J.-Y.; Kim, S.-A.; Jung, J.-K.
Synth. Commun. 1996, 26, 1675. (c) Paek, S.-M.; Kim, N.-J.; Shin, D.;
Jung, J.-K.; Jung, J.-W.; Chang, D.-J.; Moon, H.; Suh, Y.-G. Chem.sEur.
J. [Online] http://dx.doi.org/10.1002/chem.200902591 (accessed Mar 18,
(6) (a) Suh, Y.-G.; Kim, S.-H.; Jung, J.-K.; Shin, D.-Y. Tetrahedron
Lett. 2002, 43, 3165. (b) Suh, Y.-G.; Shin, D.-Y.; Jung, J.-K.; Kim, S.-H.
Chem. Commun. 2002, 1064. (c) Shin, D.-Y.; Jung, J.-K.; Seo, S.-Y.; Lee,
Y.-S.; Paek, S.-M.; Chung, Y. K.; Shin, D. M.; Suh, Y.-G. Org. Lett. 2003,
5, 3635. (d) Jung, J.-W.; Shin, D.-Y.; Seo, S.-Y.; Kim, S.-H.; Paek, S.-M.;
Jung, J.-K.; Suh, Y.-G. Tetrahedron Lett. 2005, 46, 573.
2010)
.
(7) Taniguchi, Y.; Inanaga, J.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
30. 1981, 54, 3229.
(5) Martin Castro, A. M. Chem. ReV. 2004, 104, 2939.
Org. Lett., Vol. 12, No. 9, 2010
2041

Scheme 3. Completion of Fluvirucinine A2 Synthesis via Vinylogous Amide Enolate Induced ACR
for production of the 14-membered lactam with the desired
C2-stereochemistry.8 Notably, stereoselectivity for the ACR
of 2 was quite substituent-dependent and the ACR precursor
2b turned out to be best in terms of diastereoselectivity (>10:
1) and yield as shown in Table 1. Both the ethyl substituent
cleavage of 12 followed by stereoselective Grignard addition
to the resulting aldehyde furnished alcohol 14a with the
correct stereochemistry (>20:1) probably by the Felkin-Ahn
rule. Total synthesis of fluvirucinine A2 (1) was finally
completed by TBS deprotection of 14a and hydrogenation
of the remaining olefin. The structure of the synthetic 1 was
confirmed by its conversion into diacetate 15, which exhib-
ited spectral data identical to those of the reported diacetate.1b
Synthesis of epi-fluvirucinine A2 could also be achieved
from 2c. The ꢀ-methyl substituent of the vinylogous amide
enolate of 2c seemed deleterious to stereoselectivity in ACR,
which led to a 1:1 diastereomeric mixture of macrolactam
13. The absence of diastereoselectivity is likely due to
nonselective formation of the (Z)-enolate.9 However, NaBH4
reduction of the methyl ketone prepared by selective oxida-
tive olefin cleavage of the correct diastereomer interestingly
resulted in exclusive formation of the stereoisomer 14b.10 Thus,
we were finally able to synthesize epi-fluvirucinine A2 from
14b by analogy to the synthesis of fluvirucinine A2 (1).11
In conclusion, we have accomplished the first asymmetric
total synthesis of fluvirucinine A2 as well confirmed its
Table 1. Vinylogous Amide Enolate-Induced ACR
substrate
R1
R2
base
LHMDS
yieldb (%) drc (A:B)
2a
2b
2c
H
Me
H
H
H
64
74
78
1.5:1
>10:1
1:1
LHMDS
Me mesitylMgBr4c
a All reactions were conducted in toluene at 130 °C. b Isolated yields.
c Determined by isolation yield of each isomer.
(9) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki,
A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604.
(10) For a mechanism on the 2-alkyl-3-oxo-amide reduction with
borohydride species: (a) Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1985, 26, 4643. (b) Bartoli, G.; Bosco, M.; Marcantoni, E.; Melchiorre,
P.; Rinaldi, S.; Sambri, L. Synlett 2004, 1, 73.
and the (E)-olefin geometry of the acyl side chain seemed
to enhance the stereoselectivity probably by inducing a more
favorable chairlike transition state for the ACR. It is
noteworthy that vinylogous amide enolate-induced ACR has
not been reported to the best of our knowledge. As
anticipated, LHMDS treatment of 2b in toluene effectively
furnished the desired intermediate 12. Selective olefin
(11) To provide solid evidence for the structures of the synthetic
fluvirucinines, an alternate synthesis employing Baeyer-Villiger oxidation
was also undertaken. Spectral data for the synthetic epi-fluvirucinine A2
prepared via vinylogous amide enolate induced ACR (Scheme 3) were
identical to the data for the epi-fluvirucinine A2 synthesized from the 14-
membered macrolactam possessing the (R)-configuration at the stereogenic
center of interest (see the Supporting Information).
(8) Attempted lactam ring expansion of a precursor possessing ꢀ-hy-
droxyl amide in hand under the standard ACR conditions gave the vinyl-
substituted product as a 1.5:1 diastereomeric mixture, possibly via initial
elimination of the labile alkoxy group and subsequent vinylogous amide
enolate induced ACR.
2042
Org. Lett., Vol. 12, No. 9, 2010

structure. In particular, the excellent remote stereocontrol by
our approach attests to the efficiency and synthetic versatility
of our iterative ring-expansion strategy. The first and highly
stereo- and regioselective amide enolate-induced vinylogous
ACR was also reported. Further synthetic applications of our
strategy and detailed investigation into the vinylogous amide
enolate-induced ACR are currently underway.
a grant (2009K001255) from the Brain Research Center of
the 21st Century Frontier Research Program funded by the
Ministry of Education, Science and Technology (MEST), the
Republic of Korea.
Supporting Information Available: Experimental pro-
cedures, characterization data, and stereochemical proofs.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the Center
for Bioactive Molecular Hybrid, Yonsei University, and by
OL100521V
Org. Lett., Vol. 12, No. 9, 2010
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