Total synthesis of fluvirucinine A1

Article abstract of DOI:10.1016/j.tetlet.2011.06.087

An efficient and highly stereocontrolled convergent synthesis of fluvirucinine A₁ is reported herein. In fluvirucinine A₁ both C₅-C₁₃ and C₁-C₄ fragments were accessed from a common intermediate 6 derived from (S)-Roche ester in 15 and 7 steps, respectively. The key steps involve Evans asymmetric alkylation, Sharpless asymmetric epoxidation, amidation and a ring-closing metathesis reaction (RCM) for macrocyclization.

Full text of DOI:10.1016/j.tetlet.2011.06.087

Tetrahedron Letters 52 (2011) 4546–4549
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of fluvirucinine A1
⇑
Palakodety Radha Krishna , Kadimi Anitha
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and highly stereocontrolled convergent synthesis of fluvirucinine A1 is reported herein. In flu-
virucinine A1 both C5–C13 and C1–C4 fragments were accessed from a common intermediate 6 derived
from (S)-Roche ester in 15 and 7 steps, respectively. The key steps involve Evans asymmetric alkylation,
Received 27 April 2011
Revised 20 June 2011
Accepted 22 June 2011
Available online 28 June 2011
Sharpless asymmetric epoxidation, amidation and
macrocyclization.
a
ring-closing metathesis reaction (RCM) for
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Macrolactam antibiotics
Evans asymmetric alkylation
Amidation and a ring-closing metathesis
(RCM)
In 1991, Naruse et al.1–3 reported the isolation and structural
determination of fluvirucins A1, A2, B1–B5 from the fermentation
broth of actinomycete strains. Fluvirucines are a family of macro-
Due to their promising biological activity and interesting struc-
tural features, we designed a flexible synthetic strategy suitable for
accessing both fluvirucinine A1 (1) and A2 (aglycone of II), as they
share close structural similarities. We envisioned that the second
fragment (compound 4), which is the point of structural difference,
could be synthesized by a related strategy. Thus, the present ap-
proach (Scheme 1) involves an independent synthesis of fragments
3 and 4, their connection through amidation and macrocyclization
via ring-closing metathesis6,8 (RCM)/hydrogenation afforded the
important C–C bond, a saturated C4–C5 linked macrocycle.
lactam antibiotics and are potent inhibitors of influenza
A
virus.1–4 Among all aglycones of fluvirucin series, fluvirucinine A1
(1) and A2 (aglycone of II) are particularly important because of
their low toxicity3 and more potent inhibitory activity against
influenza A virus.1–4 Fluvirucinine A1 is aglycone of fluvirucin A1.
To date, three synthesis of fluvirucinine A1 have been reported.5–
Of all, the one reported by Suh et al.5 by an innovative iterative
7
lactam ring-expansion to access the 14-membered lactam skeleton
is note-worthy. Yet another equally significant synthesis by Negi-
shi and co-worker6 employing zirconium catalyzed asymmetric
carboalumination of alkenes-Lipase catalyzed acetylation tandem
process as the key step was recently reported.
Accordingly, the retrosynthetic strategy anticipated for fluviruc-
inine A1 (1) is delineated in Scheme 1. The standard disconnection
of 1 at C4–C5 and C1–N bonds revealed two fragments 3 and 4. We
visualized that 1 could be obtained from fragments 3 and 4 by uti-
lizing amidation and ring-closing metathesis strategy. Both frag-
ments 3 and 4 in turn could be readily accessed from the
commercially available (S)-Roche ester 5, wherein the naturally
endowed methyl stereogenic center could be correlated to C2 and
C6 of the target molecule 1. The stereochemistry at C10 was derived
by invoking the highly diastereoselective Evans asymmetric alkyl-
ation,9 while the hydroxyl functionality at C3 (of fragment 4) was
achieved through Sharpless asymmetric epoxidation.10
OH
NH2
OH
NH2
HO
HO
O
O
O
O
O
O
R1
Thus, the synthesis of 3 commenced with 610 that was easily ac-
cessed in four steps from 5 (Scheme 2). Treatment of 6 with TPP in
presence of iodine and imidazole in THF produced allyl iodide 7 in
76% yield and set the stage for highly diastereoselective Evans
asymmetric alkylation9 to install the C10 ethyl group with the de-
sired stereochemistry. Accordingly, N-butyryl oxazolidinone was
treated with LiHMDS in dry THF at ꢀ78 °C to furnish an enolate
intermediate that was reacted with allylic iodide 7 to afford the
corresponding ethylated product 9 in good yield of 86% and in high
diastereoselectivity. An excess of enolate (1.6) was found necessary
HN
NH
I. Fluvirucin A1 R1 = CH3
III. Fluvirucin B1
II. Fluvirucin A2 R1 = CH(OH)CH3
⇑
Corresponding author. Tel.: +91 40 27193158.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.087

P. Radha Krishna, K. Anitha / Tetrahedron Letters 52 (2011) 4546–4549
4547
6
5
7
O
OPMB
8
9
OPMB
4
3
OH
NH2
+
HO
2
O
O
10
11
3
4
1
NH
NH
12
O
13
2
1
HO
O
(S)-Roche ester
5
Scheme 1. Retrosynthetic analysis.
O
O
Synthesis of C5-C13 fragment 3
N
O
O
a
b,
ref 10
8
Bn
TBSO
OH
I
TBSO
OH
HO
OMe
7
5
6
O
O
O
c
d
TBSO
OMe
TBSO
TBSO
N
O
9
10
11
Bn
O
g
f
e
TBSO
OH
TBSO
OMe
13
12
i
h
TBSO
NHBoc
NHBoc
TBSO
HO
N3
15
14
16
j
NHBoc
17
Scheme 2. Reagents and conditions: (a) TPP, I2, imidazole, THF, 0.5 h, 76%; (b) 8, LiHMDS, ꢀ78 °C, 1 h, 7 after 6 h, ꢀ20 °C, 14 h; (c) NaBH4, MeOH, 0 °C to rt, 1 h, 81%; (d) (i)
IBX, CH2Cl2, DMSO, 0°C to rt, 4 h; (ii) Ph3P CHCOOEt, C6H6, 70°C, 4 h, 85% (over two steps) (e) H2 Pd/C, EtOAc, 4 h, 92%; (f) DIBAL-H, CH2Cl2, ꢀ40 °C, 1 h, 84%; (g) (i) TsCl, Et3N,
CH2Cl2, 0 °C to rt, 3 h; (ii) NaN3, DMF, 80 °C, 4 h, 85% (over two steps); (h) (i) H2, Pd/C, EtoAc, 9 h; (ii) (Boc)2O, Et3N,CH2Cl2, 1 h, 83% (over two steps); (i) TBAF, THF, 3 h, 78%; (j)
+
(i) (COCl)2, DMSO, Et3N, ꢀ78 °C, 1 h (ii) Ph3 PCH3 Iꢀ, tBuOK, THF, ꢀ10 °C to rt, 4 h, 65% (over two steps).
to achieve completion of the reaction. The second diastereoisomer
was not detected either by 1H or 13C NMR of crude reaction mix-
ture, thus suggesting high selectivity and diastereoselectivity and
hence assumed to be >95:5.
into alkene 17 by Swern oxidation and one carbon Wittig olefin-
ation in 65% yield over two steps.
As outlined in Scheme 3, the synthesis of C1–C4 fragment (com-
pound 4) began with 6.10 Sharpless asymmetric epoxidation10 of 6
using (ꢀ)-DIPT afforded epoxy alcohol 18. Compound 18 was trea-
ted with TPP, iodine and imidazole to give the corresponding iodo
derivative, which on treatment with Zn in ethanol11, gave allylic
alcohol 19 (78% yield over two steps). The resulting allylic alcohol
19 was protected (NaH/PMBBr/THF/0 °C to rt/14 h) as its PMB
ether 20 (74%). Later, deprotection (TBAF/THF/0 °C to rt/3 h) of
TBS ether gave alcohol 21 (79%). The oxidation of the resultant pri-
mary alcohol 21 under Swern conditions furnished the aldehyde
which on subsequent oxidation12 (NaClO2/NaH2PO4ꢁ2H2O/2-
methyl 2-butene/12 h) afforded acid 4 (75%).
Compound 17 was treated with TFA in CH2Cl2 to liberate the
free amine 3 which was immediately used for the amidation reac-
tion (Scheme 4). With the requisite fragments 3 and 4 in hand, the
coupling reaction was undertaken. Thus, coupling of 3 and 4 was
achieved by treating the acid 4 with EDCI/HOBT followed by addi-
tion of amine 3 to afford amide 2 (98%). The resulting diene 2 was
Next, reductive cleavage (NaBH4/MeOH/0 °C to rt/1 h) of the
chiral auxiliary gave alcohol 10 (81%). Oxidation of 10 with IBX
provided the corresponding aldehyde, which was subjected to Wit-
tig olefination to afford 11 (85% yield over two steps). Exposure of
11 to hydrogenation in the presence of Pd/C in EtOAc produced the
corresponding saturated ester 12 (92%), which upon treatment
with DIBAL-H in CH2Cl2 gave alcohol 13 (84%). Alcohol 13 was con-
verted to its corresponding tosylate (TsCl/Et3N/CH2Cl2/0 °C to rt/
3 h), which was subsequently transformed into the corresponding
azide 14 (85%, over two steps) under conventional conditions
(NaN3/DMF/80 °C/4 h). The resulting azide 14 was converted to
N-Boc derivative 15 in 83% yield by a two-step process, firstly
reduction of the azide to the amine via hydrogenation (Pd/C–H2/
rt/9 h) followed by the bocylation reaction {(Boc)2O/Et3N/CH2Cl2/
0 °C to rt/1 h}. Later, deprotection (TBAF/THF/0 °C to rt/3 h) of silyl
ether in 15 furnished alcohol 16 (78%). Alcohol 16 was transformed

4548
P. Radha Krishna, K. Anitha / Tetrahedron Letters 52 (2011) 4546–4549
Synthesis of C1-C4 fragment 4
OPMB
OH
O
b
c
a
TBSO
TBSO
TBSO
OH
6
19
20
18
O
OPMB
OPMB
d
e
HO
HO
21
4
Scheme 3. Reagents and conditions: (a) (ꢀ)-DIPT, Ti(OiPr)4, cumene hydroperoxide (CHP), CH2Cl2, ꢀ20 °C, 4–5 h, 86%; (b) (i) TPP, I2, imidazole, THF, 0.5 h; (ii) Zn, EtOH, 80 °C,
3 h, 78% (over two steps); (c) NaH, PMBBr, THF, 0 °C to rt, 14 h, 74%; (d) TBAF, THF, 3 h, 79%; (e) (i) (COCl)2, DMSO, Et3N, ꢀ78 °C, 1 h; (ii) NaClO2 NaH2PO4ꢁ2H2O, 2-Methyl 2-
butene, tBuOH/H2O (3:1), 0 °C to rt, 12 h, 75% (over two steps).
Synthesis of 1
O
OPMB
a
b
+
NH2
17
HO
4
3
OH
OPMB
OPMB
c
d
O
O
O
NH
NH
NH
2
1
22
Scheme 4. Reagents and conditions: (a) TFA, CH2Cl2, 0 °C, 15 min; (b) EDCI, HOBT, CH2Cl2, 98% (over two steps); (c) Grubbs-II, CH2Cl2, 45 °C, 12 h, 79%; (d) H2Pd/C, EtOAc, 3 h,
89%.
6. Liang, B.; Negishi, E. Org. Lett. 2008, 10, 193–195.
7. Fu, G. C.; Son, S. Synfacts 2008, 0907.
8. (a) Radha Krishna, P.; Kadiyala, R. R. Tetrahedron Lett. 2010, 51, 2586–2588; (b)
exposed to the RCM reaction using Grubbs-II catalyst in refluxing
dichloromethane to produce the desired macrolactam 22 (79%)
as an E/Z mixture. Since the isomeric status was irrelevant, no at-
tempts were made to purify compound 22 into separate entities.
Compound 22 was subjected to a hydrogenation reaction (Pd/C–
H2/rt/3 h) wherein both the saturation of the C4–C5 olefinic bond
Radha Krishna, P.; Jagannadgarao, T. Org. Bimol. Chem. 2010, 8, 3130–3132; (c)
Radha Krishna, P.; Ramana, D. V.; Reddy, B. K. Synlett 2009, 2924–2926.
9. (a) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233–4236; (b) John, J.
P.; Jost, J.; Novikov, A. V. J. Org. Chem. 2009, 74, 6083–6091; (c) Crimmins, M. T.;
Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2, 2165–2167; (d) Cribiú, R.; Jäger, C.;
Nevado, C. Angew. Chem., Int. Ed. 2009, 48, 8780–8783; (e) Carter, R. G.; Weldon,
D. J. Org. Lett. 2000, 2, 3913–3916.
10. (a) Fürstner, A.; Bouchez, L. C.; Funel, J. A.; Liepins, V.; Porée, F.-H.; Gilmour, R.;
Beaufis, F.; Laurich, D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265–9270;
(b) Mandlik, M. T.; Cottord, M.; Rein, T.; Helquista, P. Tetrahedron Lett. 1997, 38,
6375–6378.
and C3-OPMB-deprotection occurred in one-pot to furnish
1
(89%).13 The spectroscopic data (1H and 13C NMR) and specific rota-
tion of the synthetic material 1 was in good agreement with the re-
ported data.1–3,13
In summary, we have accomplished a stereoselective synthesis
of 1 from the common intermediate 6,10 using Evans asymmetric
alkylation,9 Sharpless asymmetric epoxidation,10 amidation and
RCM6,8 in an overall yield of 10.5%. Further application of this strat-
egy toward synthesis of fluvirucinine A2 and B1 is under progress
and will be reported elsewhere.
11. Sabita, G.; Reddy, C. N.; Gopal, P.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 5736–
5739.
12. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.
13. Spectral data for selected compounds. Compound 10: Colorless liquid; ½a D25
ꢂ
+1.1 (c 1.04, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.67–5.47 (m, 2H), 3.71–3.50
(m, 4H), 2.47–2.38 (m, 1H), 1.67–1.40 (m, 2H), 1.14–1.08 (m, 9H), 1.05 (s, 9H),
0.19 (s, 6H). 13C NMR (75 MHz, CDCl3): d 134.8, 128.3, 68.3, 65.1, 42.7, 39.6,
34.5, 26.2, 23.3, 18.3, 16.8, 11.5, ꢀ4.9. ESIMS: m/z 309 [M+Na]+, HRMS m/z:
Calcd for
C16H34O2NaSi: 309.2225. Found: 309.2224. Compound 17: Pale
Acknowledgment
yellow liquid; ½a D25
ꢂ
ꢀ7.1 (c 0.57, CHCl3); 1H NMR (500 MHz, CDCl3): d 5.64–
5.47 (m, 1H), 4.90–4.83 (m, 2H), 4.42 (br. s, 1H), 3.04–3.03 (m, 2H), 2.06–2.04
(m, 1H), 1.40 (s, 9H), 1.24–1.20 (m, 13H), 0.94 (d, J = 6.8 Hz, 3H), 0.80 (t,
J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 145.6, 112.9, 78.9, 41.0, 38.7, 37.8,
37.1, 33.2, 30.3, 28.5, 27.4, 25.9, 24.3, 20.6, 10.9. ESIMS: m/z 320 [M+Na]+,
HRMS m/z: Calcd for C18H35NO2Na: 320.2565. found: 320.2559. Compound 4:
One of the authors (K.A.) thanks the CSIR, New Delhi for the
financial support in the form of the fellowship.
Colorless liquid; ½a D25
ꢂ
+50.6 (c 2.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.15 (d,
Supplementary data
J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.84–5.69 (m, 1H), 5.36–5.25 (m, 2H),
4.55 (d, J = 11.5 Hz, 1H), 4.29 (d, J = 11.5 Hz, 1H), 4.02–3.85 (m, 1H), 3.77 (s,
3H), 2.66–2.57 (m, 1H), 1.19 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
179.4, 159.1, 135.5, 129.3, 120.1, 119.2, 113.7, 80.4, 70.1, 55.1, 44.7, 13.3.
ESIMS: m/z 273 [M+Na]+, HRMS m/z: Calcd for C14H18O4Na: 273.1102. found:
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.087.
273.1093. Compound 2: Colorless liquid; ½a D25
ꢂ
+2.5 (c 0.5, CHCl3); 1H NMR
References and notes
(500 MHz, CDCl3): d 7.16 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 6.22 (t,
J = 5.5 Hz, 1H), 5.76–5.57 (m, 2H), 5.29 (d, J = 9.8 Hz, 2H), 4.88 (d, J = 8.3 Hz,
2H), 4.53 (d, J = 11.3 Hz, 1H), 4.25 (d, J = 11.3 Hz, 1H), 3.89–3.83 (m, 1H), 3.79
(s, 3H), 3.25–3.13 (m, 2H), 2.50–2.41 (m, 1H), 2.12–2.03 (m, 1H), 1.47–1.33 (m,
1H), 1.28–1.14 (m, 12H), 1.08 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.0 Hz, 3H), 0.81 (t,
J = 7.5, 3H). 13C NMR (75 MHz, CDCl3): d 173.2, 158.9, 135.2, 129.4, 119.5,
113.9, 112.5, 81.7, 70.7, 55.2, 45.6, 39.7, 38.6, 37.9, 37.2, 33.2, 30.4, 26.9, 25.8,
24.3, 20.3, 12.8, 10.9. ESIMS: m/z 430 [M+H]+, 452 [M+Na]+, HRMS m/z: Calcd
for C27H44NO3: 430.3321. Found: 430.3388. Compound 1: white solid; mp
1. Naruse, N.; Tenmyo, O.; Kawauo, K.; Tomita, K.; Ohgusa, N.; Miyaki, T.; Konishi,
M.; Oki, T. J. Antibiot. 1991, 44, 733–740.
2. Naruse, N.; Tsuno, T.; Sawada, Y.; Konishi, M.; Oki, T. J. Antibiot. 1991, 44, 741–
755.
3. Naruse, N.; Konishi, M.; Oki, T.; Inouye, Y. J. Antibiot. 1991, 44, 756–761.
4. Tomita, K.; Oda, N.; Hoshino, Y.; Ohgusa, N.; Chikazawa, H. J. Antibiot. 1991, 44,
940–948.
5. 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.
229–236 °C.
½ ꢂ
a 2D5 +138.3 (c 0.69, MeOH); 1H NMR (500 MHz, CDCl3:
CD3OD = 1:1): 7.89 (br. s, 1H), 3.61–3.48 (m, 1H), 3.46–3.40 (m, 1H), 2.66–

P. Radha Krishna, K. Anitha / Tetrahedron Letters 52 (2011) 4546–4549
4549
2.56 (m, 1H), 2.28–2.15 (m, 1H), 1.56–1.18 (m, 18H), 1.05 (d, J = 6.9 Hz, 3H),
0.81 (d, J = 6.9 Hz, 3H), 0.77 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz,
CDCl3:CD3OD = 1:1): d 175.7, 72.8, 47.8, 38.3, 36.0, 34.0, 31.8, 31.5, 30.7,
30.0, 27.5, 26.4, 25.2, 20.1, 16.4, 14.0, 10.6. ESIMS: m/z 284 [M+H]+, 306
[M+Na]+, HRMS: m/z [M+Na]+ Calcd for C17H33NO2Na: 306.2408. Found:
306.2405.