Concise, protecting group free total syntheses of (+)-sattabacin and (+)-4-hydroxysattabacin

Article abstract of DOI:10.1016/j.tetlet.2010.09.147

The first asymmetric total syntheses of the antiviral natural products (+)-sattabacin and (+)-4-hydroxysattabacin are reported. Both total syntheses are remarkably concise and were completed without the use of protecting groups. These syntheses allowed the unambiguous assignment of the absolute configuration of both natural products. The syntheses of these natural products, which exhibit marked antiviral activity, are readily amenable to the preparation of structural analogs and progress in this regard is also reported.

Full text of DOI:10.1016/j.tetlet.2010.09.147

Tetrahedron Letters 51 (2010) 6375–6377
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise, protecting group free total syntheses of (+)-sattabacin
and (+)-4-hydroxysattabacin
⇑
Matthew R. Aronoff, Neil A. Bourjaily, Kenneth A. Miller
Department of Chemistry, Fort Lewis College, 1000 Rim Drive, Durango, CO 81301, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric total syntheses of the antiviral natural products (+)-sattabacin and (+)-4-hydroxy-
sattabacin are reported. Both total syntheses are remarkably concise and were completed without the use
of protecting groups. These syntheses allowed the unambiguous assignment of the absolute configuration
of both natural products. The syntheses of these natural products, which exhibit marked antiviral activity,
are readily amenable to the preparation of structural analogs and progress in this regard is also reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 August 2010
Accepted 27 September 2010
Available online 8 October 2010
The natural products sattabacin (1) and 4-hydroxysattabacin (2)
were isolated from the soil bacteria, Bacillus sp., by Satta and co-
workers (Fig. 1), and these compounds were shown to exhibit anti-
viral activity, most notably against herpes simplex virus type 1
(HSV1) and 2 (HSV2).1 Both natural products are potent antiviral
form was a priority. Also, in order to prepare structural analogs,
we sought a divergent synthesis in which a key intermediate could
be elaborated to a family of structurally different potential antivi-
ral compounds at a late stage. Last, to maximize the greenness and
brevity of each synthesis, protecting groups would be avoided.7
With these goals in mind, we envisioned preparing 1 and 2 from
the addition of an isobutyl organometallic reagent to the appropri-
ate Weinreb amide 3 and 4, respectively. Addition of various other
alkyl and aryl organometallic reagents to these amides would lead
to analogs with varying side chains. The amides 3 and 4 would
arise from the aryl lactic acids 5 and 6, both of which could be ob-
tained in an enantiomerically enriched form.8,9
agents, with ID50 values in the
acin was 3 g/mL against both HSV1 and HSV2, and 4-hydroxysat-
tabacin was an order of magnitude or more potent with ID50 values
of 0.32 and 0.08 g/mL against HSV1 and HSV2, respectively. A
lg-ng/mL range. The ID50 of sattab-
l
l
large majority of the world population is infected with some mem-
ber of the human herpesvirus family,2 and HSV infections can be
life threatening particularly in immunocompromised patients,
pregnant women, and newborns.2 Nucleoside analogs such as acy-
clovir and related compounds remain the standard of care to treat
HSV infections,3 but nucleoside-resistant HSV infections have
become more common especially among immunocompromised
individuals.4 These drawbacks have led to the exploration of new
classes of treatments for HSV infection,5 and these considerations
sparked our interest in studying the sattabacins whose mechanism
of action remains unknown.
To date, no total syntheses of these natural products have been
reported,6 and while specific rotations were originally disclosed,
the isolation chemists did not determine the absolute configura-
tion of either sattabacin or 4-hydroxysattabacin. Due to the inter-
esting biological activity of these natural products, in order to
confirm the absolute configuration of the sattabacins, and to pro-
vide access to the natural products and analogs for further study,
the total syntheses of both sattabacins were undertaken.
The synthesis of sattabacin commenced with L-phenylalanine
(7) (Scheme 2). Diazotization with retention of configuration affor-
ded phenyllactic acid 5,8b which underwent smooth conversion
into the corresponding Weinreb amide 3 in the presence of N,O-
dimethylhydroxylamine, N-methylmorpholine (NMM), and dicy-
clohexylurea (DCC). Initial attempts to form 1 by the addition of
isobutyl magnesium bromide to 3 in either THF or Et2O were low
yielding and purification proved difficult. However, to our delight
treatment of 3 with 2.5 equiv of isobutyl lithium at low tempera-
ture afforded (+)-sattabacin (1) cleanly in excellent yield. The spec-
tral data for synthetic 1 (1H and 13C NMR) were identical with
those previously reported,1 and the optical rotation (½a 2D5
ꢀ
+41 (c
0.1, CH2Cl2)) was comparable to that reported in the literature
O
O
The retrosynthesis of these natural products was guided by a
number of factors (Scheme 1). We sought an asymmetric total syn-
thesis, so access to each natural product in an enantioenriched
OH
OH
HO
1
2
⇑
Corresponding author.
E-mail address: miller_k@fortlewis.edu (K.A. Miller).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.147

6376
M. R. Aronoff et al. / Tetrahedron Letters 51 (2010) 6375–6377
O
O
O
OCH3
N
OH
OH
OH
OH
R
R
R
1: R = H; sattabacin
2: R = OH; 4-hydroxysattabacin
3: R = H
4: R = OH
5: R = H
6: R = OH
Scheme 1.
HNMe(OMe)
NMM
DMAP, DCC
O
Li
O
O
NaNO2
H2SO4/H2O
O
OCH3
(2.5 eq.)
N
OH
OH
OH
THF, -78 C
OH
NH2
81%
CH2Cl2
83%
OH
66%
3
9
7
5
Scheme 4.
O
Li
(2.5 eq.)
O
OCH3
For example, treatment of 3 with n-butyllithium under our previ-
ously optimized conditions gave the n-butyl analog 9 in compara-
ble yield (Scheme 4). Efforts are currently underway to prepare
other side chain analogs and screen these compounds for antiviral
activity.
N
OH
OH
THF, -78 C
80%
1
3
Scheme 2.
In conclusion, the first asymmetric total syntheses of the antivi-
ral natural products (+)-sattabacin and (+)-4-hydroxysattabacin
were each completed in three overall steps from commercially
available starting materials. These syntheses were concise, high
yielding, and protecting group free. The total syntheses of both 1
and 2 allowed for the unequivocal establishment of their absolute
configuration, which was previously unknown. Further, the syn-
thetic strategy employed allows for the simple preparation of side
chain analogs. Preparation of these structural analogs and evalua-
tion of antiviral activity are in progress and will be reported in due
course.
(½a 2D5
ꢀ
+35 (c 0.7, CHCl3)).1 Upon confirming identical optical rota-
tions, both magnitude and sign, we could assign the stereochemis-
try of the hydroxyl group of (+)-sattabacin as (S).
Attempts to prepare 6 by a similar diazotization of L-tyrosine
led to a complicated reaction mixture presumably from oxidation
of the phenol. While one could envision protection of the phenolic
oxygen to avoid these side reactions, we sought a more stream-
lined, protecting group free approach. Thus, asymmetric reduction
of commercially available 4-hydroxyphenylpyruvic acid with (+)-
DIP-Cl gave the alcohol 6 in excellent yield and enantiomeric ex-
cess (Scheme 3).9 Chemoselective coupling of the carboxylic acid
moiety under standard conditions gave the amide 4, and treatment
of this amide with excess iso-butyllithium at low temperature gave
the natural product (+)-4-hydroxysattabacin (2) in modest yield.
Again NMR spectral data were identical to those previously re-
ported and the optical rotation was comparable to that previously
described, both in magnitude and sign. Thus, the absolute configu-
ration of the chiral hydroxyl group in (+)-4-hydroxysattabacin
could also be assigned as (S).
Acknowledgments
The authors would like to thank Timothy Welch for assistance
with optical rotations and Fort Lewis College for financial
support.
Supplementary data
The syntheses of these natural products are readily amenable to
the preparation of various structural analogs. Addition of organo-
metallic reagents to the amide 3 is expected to give several analogs
differing in the nature and substitution of the ketone side chain.
Supplementary data (full characterization of all new com-
pounds (1–4, 9) and copies of NMR spectra) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.09.147.
HNMe(OMe)
NMM
DMAP, DCC
O
O
(+)-DIP-Cl
Et3N
OH
OH
O
THF, -30 C
HO
CH2Cl2
87%
OH
HO
Li
78%, 93% ee
8
6
O
O
OCH3
(5 eq.)
N
OH
OH
THF, -78-rt C
HO
HO
42%
2
4
Scheme 3.

M. R. Aronoff et al. / Tetrahedron Letters 51 (2010) 6375–6377
5. Coen, D. M.; Schaffer, P. A. Nat. Rev. Drug Disc. 2003, 2, 278–288.
6377
References and notes
6. Walsh and co-workers mistakenly reported a racemic synthesis of sattabacin
in 2008, but the structure of the compound they synthesized does not
match that of the natural product. The hydroxyl group and ketone are
transposed. See: Li, H.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130,
3521–3531.
7. Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404–408.
8. (a) Cohen, S. G.; Weinstein, S. Y. J. Am. Chem. Soc. 1964, 86, 5326–5330; (b) Storz,
T.; Dittmar, P.; Fauquex, P. F.; Marschal, P.; Lottenbach, W. U.; Steiner, H. Org.
Process Res. Dev. 2003, 7, 559–570.
1. Lampis, G.; Deidda, D.; Maullu, C.; Madeddu, M. A.; Pompei, R.; Monache, F. D.;
Satta, G. J. Antibiot. 1995, 48, 967–972.
2. Crumpacker, C. S.; Schaffer, P. A. Nat. Med. 2002, 8, 327–328.
3. (a) Schaeffer, H. J.; Beauchamp, L.; De Miranda, P.; Elion, G. B.; Bauer, D. J.;
Collins, P. Nature 1978, 272, 583–585; (b) Perry, C. M.; Faulds, D. Drugs 1996, 52,
754–772; (c) Keating, M. R. Mayo Clin. Proc. 1999, 74, 1266–1283.
4. Kimberlin, D. W.; Crumpacker, C. S.; Straus, S. E.; Biron, K. K.; Drew, W. L.;
Hayden, F. G.; McKinlay, M.; Richman, D. D.; Whitley, R. J. Antiviral Res. 1995, 26,
423–438.
9. Wang, Z.; La, B.; Fortunak, J. M. Tetrahedron Lett. 1998, 39, 5501–5504.