Total Synthesis of (?)-Albocycline

Article abstract of DOI:10.1002/anie.201702530

The macrolactone natural product (?)-albocycline is a promising antibiotic candidate for the treatment of both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant strains. Herein we report a concise total synthesis of (?)-albocycline in 14 steps from commercially available methyl (R)-3-hydroxybutyrate. Novel key steps include the highly regio- and stereoselective reactions of chiral N-sulfinyl metallodienamines (NSMDs) with aldehydes and the Davis oxaziridine, in addition to the Horner–Wadsworth–Emmons olefination of N-sulfinyl imines.

Full text of DOI:10.1002/anie.201702530

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702530
German Edition: DOI: 10.1002/ange.201702530
Natural Product Synthesis
Total Synthesis of (ꢀ)-Albocycline
Vijay K. Chatare and Rodrigo B. Andrade*
Dedicated to Professor Franklin Davis on the occasion of his 78th birthday
Abstract: The macrolactone natural product (ꢀ)-albocycline
is a promising antibiotic candidate for the treatment of both
methicillin resistant Staphylococcus aureus (MRSA) and
vancomycin-resistant strains. Herein we report a concise total
synthesis of (ꢀ)-albocycline in 14 steps from commercially
available methyl (R)-3-hydroxybutyrate. Novel key steps
include the highly regio- and stereoselective reactions of
chiral N-sulfinyl metallodienamines (NSMDs) with aldehydes
and the Davis oxaziridine, in addition to the Horner–Wads-
worth–Emmons olefination of N-sulfinyl imines.
In 1987, Tanner and Somfai reported the first and only total
synthesis of albocycline (i.e., ingramycin) in 40 total steps (21 in
the longest linear sequence).[6] To execute a concise total
synthesis of 1, we required a convergent approach and
asymmetric methodology capable of accessing and coupling
the requisite fragments.[7] In 2013, we reported that chiral, 2,3-
indole fused N-sulfinyl metallodienamines (NSMDs) effi-
ciently engage acrylates to afford cycloadducts that were
elaborated into Aspdiosperma alkaloids.[8] We reasoned that
under the appropriate reaction conditions, acyclic and ambi-
dent NSMDs could both regio- and stereoselectively engage
various electrophiles to expedite the total synthesis of 1.
Retrosynthetically, we envisioned (ꢀ)-albocycline (1)
could be assembled from left-hand C7–C13 fragment 2, N-
(S)-tert-butanesulfinylimine 3, and trimethyl phosphonoace-
tate (4) (Figure 1). Keck macrolactonization of an appropri-
ately protected seco acid, a tactic used by Tanner and Somfai
in their synthesis of 1, would access the 14-membered ring.[6,9]
Ellman elegantly showed that N-sulfinyl metalloena-
mines, derived from the metalation of enolizable N-sulfinyl
imines,[10] efficiently add to electrophilic olefins in a 1,4-
fashion[11] and aldehydes in a 1,2-fashion.[12] Accordingly, we
hypothesized a vinylogous variant (i.e., NSMD derived from
3) could react at its C6 terminus with the C7 aldehyde of 2 in
a regio- and stereoselective manner to convergently prepare
the C7 carbinol in 1. Subsequent metalation and reaction with
the Davis oxaziridine (4)[13] could serve to regio- and
stereoselectively access the tertiary carbinol at C4. Horner–
Wadsworth–Emmons olefination would stereoselectively
deliver the (E)-enoate precursor to the requisite seco acid.
The total synthesis of (ꢀ)-albocycline (1) began with the
preparation of left-hand fragment 2 (Scheme 1). To this end,
commercially available (R)-methyl 3-hydroxybutyrate (6) was
subjected to a stereoselective Frꢀter alkylation (>2 equiv LDA,
MeI in THF/HMPA) to furnish anti-aldol 7 in 82% yield (>95:5
d.r.) and establish C12 and C13 stereocenters.[14] Protection of
the alcohol as its p-methoxybenzyl (PMB) ether using PMB
trichloroacetimidate and catalytic La(OTf)3 proceeded in 80%
yield.[15] Ester reduction with DIBAL-H and tosylation of the
resulting primary alcohol with TsCl and Et3N afforded 8 in
81% yield over two steps. After screening a variety of Cu-
catalyzed cross-coupling reactions of allylmagnesium halides
with tosylate 8, we discovered copper salts were not required
and the use of TMEDA and allylmagnesium bromide in
diethyl ether delivered the desired product in 84% yield.[16]
Cross-metathesis of the intermediary terminal olefin with
methacrolein (5 equiv) and 10 mol% of the Hoveyda–Grubbs
2nd generation catalyst (HG-II) delivered left-hand fragment
2 in a satisfactory 89% yield on multigram scale.[17]
N
atural products, which account for two-thirds of our
antibacterial pharmacopeia, are structurally complex targets
for total synthesis.[1] The threat of bacterial resistance and its
attendant toll on public health have led to a renaissance in
natural product-based antibiotic discovery.[2] In 2013, Tomoda
reported that (ꢀ)-albocycline (1) inhibited methicillin-resist-
ant Staphylococcus aureus (MRSA) as potently as vancomy-
cin, an antibiotic of last resort (Figure 1).[3]
Figure 1. Retrosynthetic analysis of (ꢀ)-albocycline (1).
Albocycline was isolated by the Tanabe Seiyaku Company
in 1967 and Upjohn (as ingramycin) in 1968 from Strepto-
myces strains.[4] The correct structure and absolute stereo-
chemistry of 1 was not established until 1983 by X-ray
crystallography.[5] The potent antibacterial activity and archi-
tectural complexity manifest in albocycline, which includes
a 14-membered macrolactone, four stereogenic centers (two
of which are doubly allylic), and three (E)-alkenes (one of
which is trisubstituted), motivated us to develop a concise
chemical synthesis thereof.
[*] V. K. Chatare, Prof. Dr. R. B. Andrade
Department of Chemistry, Temple University
1901 N. 13thSt., Philadelphia, PA 19122 (USA)
E-mail: randrade@temple.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201702530.
Angew. Chem. Int. Ed. 2017, 56, 1 – 4
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Scheme 1. Total synthesis of (ꢀ)-albocycline (1).
With left-hand fragment 2 in hand, we turned our
attention to accessing the right-hand C1–C6 portion. We
had demonstrated that the reactions of 2,3-indole fused N-
sulfinyl metallodienamines and acrylates afford cycloadducts
that proceed via closed, 6-membered transition states.[8] In
order to effect the regioselective coupling between the N-
sulfinyl metallodienamine derived from 3 (i.e., at C6) and left-
hand fragment 2 (i.e., at aldehydic C7), we required the
reaction proceed via an open transition state to avoid the
undesired cycloaddition (i.e., domino Michael–Mannich)
pathway.[8] Of relevance to this task was the elegant work of
Kobayashi, who showed TiCl4-promoted Mukaiyama aldol
reactions of vinylketene silyl N,O-acetals bearing the Evans
oxazolidinone auxiliary with aldehydes proceed with high
levels of remote 1,7-asymmetric induction.[18] After screening
various Lewis acids [e.g., BF3·OEt2, TiCl4, Ti(OEt)4, La-
(OTf)3], we found that the precomplexation of aldehyde 2
with SnCl4 and subsequent addition of the N-sulfinyl lithio-
dienamine derived from 3 and LiHMDS smoothly furnished
carbinol 10 in 68% yield (d.r. > 95:5). We rationalize the
exquisite remote 1,7-asymmetric induction of this process by
invoking synclinal transition state 9 wherein nonbonded
interactions are minimized (Scheme 1).[18,19] The diastereofa-
cial selectivity of the N-sulfinyl lithiodienamine is presumably
derived from the chelation of the Lewis basic sulfinyl oxygen
with THF-solvated lithium, consistent with stereochemical
models posited by both Davis and Ellman.[20]
with the Davis oxaziridine (4). Thus, we first methylated the
C7 hydroxy using Me3OBF4 and Proton Sponge to furnish 11
in 82% yield. Metalation with LiHMDS gave 12, which was
reacted sequentially with oxaziridine 4 then TMSOTf to
deliver N-sulfinyl imine 13 in 78% yield (d.r. = 4:1) as an
1
inseparable mixture of diastereomers by H NMR. Signifi-
cantly, no elimination of the C7 methoxy group through
a possible E1cb pathway was observed. We rationalize the
stereochemical course of this process by drawing analogy to
the fragment coupling reaction used to access 10. Specifically,
preorganization of the N-sulfinyl lithiodienamine serves to
sterically block the Si-face and favor approach of the Davis
reagent (4) from the Re-face. At this point, we cannot rule out
the participation of lithium in directing 4 through coordina-
tion with either Lewis basic sulfonyl or oxaziridine oxygen.
The highly regioselective nature of this reaction (i.e., a- over
g-attack with 4) parallels that of lithium dienolates.[21] We are
currently in the process of fully investigating the scope and
mechanism of these novel reactions of NSMDs.
Endgame for the synthesis of 1 required 1) two-carbon
homologation; 2) macrocylization; and 3) protecting group
removal. We envisioned the first task could be accomplished
by stepwise hydrolysis of the N-sulfinyl imine in 13 to expose
the aldehyde, followed by a standard olefination protocol.
However, consideration of the electrophilicity of the N-
sulfinyl moiety presented a more efficient and direct alter-
native. Tian had shown that N-sulfonyl imines react with
unstabilized Wittig reagents to afford Z alkenes in analogy
with the classic Wittig reaction of aldehydes.[22] Despite its
diminished reactivity, we reasoned the N-sulfinyl imine in 13
could react with a suitably nucleophilic olefinating reagent. In
Elaboration of the C3–C13 framework of albocycline (1)
required the regio- and stereoselective installation of oxygen
at C4. As previously discussed, we hypothesized this tactic
could be realized by reacting N-sulfinyl metallodienamine 12
2
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 4
These are not the final page numbers!

Angewandte
Communications
Chemie
=
our hands, the stabilized Wittig reagent MeO2C(H)C PPh3
[1] a) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2012, 75, 311–335;
failed to give any product. Alternatively, the more reactive
phosphonate anion derived from 5 and NaH (i.e., the Horner–
Wadsworth–Emmons reaction) proved to be a competent and
stereoselective olefinating agent. In the event, we obtained 14
in 76% yield as a single stereoisomer.
b) D. J. Newman, G. M. Cragg, Future Med. Chem. 2009, 1, 1415–
1427.
[2] a) C. Walsh, Nat. Rev. Microbiol. 2003, 1, 65–70; b) K. Lewis, Nat.
Rev. Drug Discovery 2013, 12, 371–387; c) R. Laxminarayan, A.
Duse, C. Wattal, A. K. M. Zaidi, H. F. L. Wertheim, N. Sumpradit,
E. Vlieghe, G. L. Hara, I. M. Gould, H. Goossens, C. Greko, A. D.
So, M. Bigdeli, G. Tomson, W. Woodhouse, E. Ombaka, A. Q.
Peralta, F. N. Qamar, F. Mir, S. Kariuki, Z. A. Bhutta, A. Coates, R.
Bergstrom, G. D. Wright, E. D. Brown, O. Cars, Lancet Infect. Dis.
2013, 13, 1057–1098; d) K. Bush, P. Courvalin, G. Dantas, J. Davies,
B. Eisenstein, P. Huovinen, G. A. Jacoby, R. Kishony, B. N.
Kreiswirth, E. Kutter, S. A. Lerner, S. Levy, K. Lewis, O.
Lomovskaya, J. H. Miller, S. Mobashery, L. J. V. Piddock, S.
Projan, C. M. Thomas, A. Tomasz, P. M. Tulkens, T. R. Walsh,
J. D. Watson, J. Witkowski, W. Witte, G. Wright, P. Yeh, H. I.
Zgurskaya, Nat. Rev. Microbiol. 2011, 9, 894–896.
[3] N. Koyama, M. Yotsumoto, H. Onaka, H. Tomoda, J. Antibiot.
2013, 66, 303 – 304.
[4] N. Nagahama, M. Suzuki, S. Awataguc, T. Okuda, J. Antibiot.
1967, 20, 261 – 266.
[5] a) A. Furusaki, T. Matsumoto, K. Harada, M. Suzuki, K.
Kinoshita, M. Hayashi, K. Nakatsu, Bull. Chem. Soc. Jpn.
1983, 56, 3042 – 3046; b) R. C. Thomas, C. G. Chidester, J.
Antibiot. 1982, 35, 1658 – 1664.
[6] D. Tanner, P. Somfai, Tetrahedron 1987, 43, 4395 – 4406.
[7] a) N. Z. Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem. Int.
Ed. 2009, 48, 2854 – 2867; Angew. Chem. 2009, 121, 2896 – 2910;
b) P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
Chem. Res. 2008, 41, 40 – 49.
[8] a) S. Zhao, R. B. Andrade, J. Am. Chem. Soc. 2013, 135, 13334 –
13337; b) S. Zhao, R. B. Andrade, J. Org. Chem. 2017, 82, 521–531.
[9] E. P. Boden, G. E. Keck, J. Org. Chem. 1985, 50, 2394 – 2395.
[10] a) M. T. Robak, M. A. Herbage, J. A. Ellman, Chem. Rev. 2010,
110, 3600 – 3740; b) P. Zhou, B. C. Chen, F. A. Davis, Tetrahe-
dron 2004, 60, 8003 – 8030.
[11] H. M. Peltier, J. A. Ellman, J. Org. Chem. 2005, 70, 7342 – 7345.
[12] T. Kochi, T. P. Tang, J. A. Ellman, J. Am. Chem. Soc. 2003, 125,
11276 – 11282.
[13] F. A. Davis, R. T. Reddy, W. Han, R. E. Reddy, Pure Appl.
Chem. 1993, 65, 633 – 640.
[14] G. Frꢀter, U. Muller, W. Gunther, Tetrahedron 1984, 40, 1269–1277.
[15] A. N. Rai, A. Basu, Tetrahedron Lett. 2003, 44, 2267 – 2269.
[16] Z. M. Ruan, D. Dabideen, M. Blumenstein, D. R. Mootoo,
Tetrahedron 2000, 56, 9203 – 9211.
With the full carbon framework of albocycline (1) in hand,
we proceeded to access the 14-membered ring. Preliminary
macrocyclization experiments using Yamaguchi conditions[23]
on seco acid intermediates bearing a free C4-hydroxy resulted
in undesired butenolide formation, presumably arising from
intermediary C2–C3 E!Z olefin isomerization catalyzed by
DMAP.[24] Thus, recourse to protecting the carbinol with
a TMS group was made (i.e., 13). Oxidative removal of the
C13 O-PMB ether in 14 with DDQ furnished 15 in 78% yield.
After surveying a number of conditions for the saponification
of methyl ester 15, we found that TMSOK in THF satisfac-
torily provided seco acid 16 in 82% yield.[25] Keck macro-
cyclization of 16 was realized with DCC, DMAP and
DMAP·HCl as reported by Tanner and Somfai, thus deliver-
ing macrolactone 17.[6] Removal of the C6 O-TMS ether with
TBAF proceeded without incident, furnishing 1 in 80% yield
over two steps. Spectral data (1H and 13C NMR, IR), optical
rotation, and Rf values were in full agreement with those
reported by Tanner and Okuda.[4,6]
In summary, we have completed a concise total synthesis
of (ꢀ)-albocycline (1) in 14 total steps from commercial
methyl (R)-3-hydroxybutyrate, which was previously synthe-
sized in 40 total steps (21 in the longest linear sequence).
Novel chemistry enabling our synthesis includes the highly
regio- and stereoselective reactions of chiral N-sulfinyl
ꢀ
metallodienamines with aldehydes for C C bond formation
and the Davis oxaziridine for a-hydroxylation. In addition,
the first example of the Horner–Wadsworth–Emmons
(HWE) olefination of N-sulfinyl imines is described. We
believe these new methods will find general utility in the
synthesis of complex molecules.
Acknowledgements
[17] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am.
Chem. Soc. 2000, 122, 8168 – 8179.
[18] S. I. Shirokawa, M. Kamiyama, T. Nakamura, M. Okada, A.
Nakazaki, S. Hosokawa, S. Kobayashi, J. Am. Chem. Soc. 2004,
126, 13604 – 13605.
The NSF (CHE-1362461) and Temple University supported
this research. We thank Richard Pederson (Materia) for
catalyst support and Harsh Patel for preparing synthetic
intermediates.
[19] M. Kalesse, M. Cordes, G. Symkenberg, H. H. Lu, Nat. Prod.
Rep. 2014, 31, 563 – 594.
[20] a) F. A. Davis, J. Org. Chem. 2006, 71, 8993 – 9003; b) T. P. Tang,
J. A. Ellman, J. Org. Chem. 1999, 64, 12 – 13.
[21] G. Casiraghi, F. Zanardi, G. Appendino, G. Rassu, Chem. Rev.
2000, 100, 1929 – 1972.
[22] D. J. Dong, H. H. Li, S. K. Tian, J. Am. Chem. Soc. 2010, 132,
5018 – 5020.
[23] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 – 1993.
Conflict of interest
The authors declare no conflict of interest.
Keywords: albocycline · antibiotics ·
N-sulfinyl metallodienamine · total synthesis
[24] T. Takahashi, H. Watanabe, T. Kitahara, Tetrahedron Lett. 2003,
44, 9219 – 9222.
[25] E. D. Laganis, B. L. Chenard, Tetrahedron Lett. 1984, 25, 5831–5834.
Manuscript received: March 9, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 4
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Natural Product Synthesis
An antibiotic candidate: A concise total
synthesis of the macrolactone (ꢀ)-albo-
cycline in 14 steps from methyl (R)-3-
hydroxybutyrate is reported. Key steps are
the highly regio- and stereoselective
reactions of chiral N-sulfinyl metallo-
dienamines with aldehydes and the Davis
oxaziridine, in addition to the Horner–
Wadsworth–Emmons olefination of N-
sulfinyl imines.
V. K. Chatare,
R. B. Andrade*
&&&& — &&&&
Total Synthesis of (ꢀ)-Albocycline
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 4
These are not the final page numbers!