Total synthesis of A-315675 based on the cascade Overman rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.12.080

The chiral and stereoselective total synthesis of A-315675 1, an antiinfluenza agent, is described. The vicinal diamino moiety in 1 was stereoselectively constructed by the cascade Overman rearrangement of a vicinal allylic-homoallylic diol derived from d

Full text of DOI:10.1016/j.tetlet.2007.12.080

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1376–1379
Total synthesis of A-315675 based on the cascade
Overman rearrangement
Takayuki Momose, Naoto Hama, Chiharu Higashino, Hideyuki Sato, Noritaka Chida *
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Received 22 November 2007; revised 13 December 2007; accepted 17 December 2007
Available online 23 December 2007
Abstract
The chiral and stereoselective total synthesis of A-315675 1, an antiinfluenza agent, is described. The vicinal diamino moiety in 1 was
stereoselectively constructed by the cascade Overman rearrangement of a vicinal allylic-homoallylic diol derived from D-tartrate.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: A-315675; Antiinfluenza agent; Total synthesis; Cascade Overman rearrangement
A-315675 1 is an antiinfluenza agent developed by the
Abbott scientists and has been reported to show a high
inhibitory activity against neuraminidases.1 The unique
structure of 1, a highly functionalized pyrrolidine core with
a cis-propenyl group as well as four contiguous stereogenic
centers including a vicinal diamino moiety and a tertiary
ether function, is reported to be crucial for its biological
activity, and has offered synthetic challenges. To date, three
chiral syntheses of 1 have appeared. In 2002, the Abbott
group reported the chiral synthesis of 1, in which the
vicinal diamino function was constructed by the stereo-
selective condensation of a chiral imine, derived from
(2E)-2-methylpent-2-en-1-ol by Sharpless asymmetric
epoxidation, with a siloxypyrrole to give the a,b-unsatu-
rated c-lactam possessing the vicinal diamino function.
After introduction of the cis-propenyl group by the conju-
gate addition of cis-1-propenylcuprate, the carboxyl group
at C-2 was created by the reaction of an N-acyliminium
intermediate with TMSCN, followed by hydrolysis.2 The
total synthesis of 1 reported from the Hanessian group in
20023 employed the stereocontrolled addition of a propio-
late ester to a chiral nitrone derived from D-serine for the
construction of the vicinal diamino moiety. After chemo-
and stereoselective reduction of the carbon–carbon triple
bond, the N-hydroxy group was reduced to afford an a,b-
unsaturated c-lactam, which was transformed into 1 by a
method similar to that developed by the Abbott group.
In 2003, the Abbott group reported the improved and prac-
tical synthesis of 1 utilizing the enzymatic resolution of
methyl 2-methoxy-2-methyl-pentanoate.4
In this Letter, we report the chiral and stereoselective
total synthesis of A-315675 1 starting from D-tartrate, in
which the vicinal diamino function was effectively gener-
ated by the cascade Overman rearrangement of a vicinal
allylic-homoallylic diol, and the pyrrolidine ring was
constructed by the lactam formation of a 4,5-diamino-
carboxylic acid derivative.
Our retrosynthetic analysis, taking into account the
successful precedents of the total synthesis, suggested that
c-lactam 2, which had been reported as the synthetic inter-
mediate in the total synthesis of 1 by the Hanessian group3
and the Abbott group,4 would be a suitable target com-
pound (Fig. 1). Lactam 2 was expected to be prepared from
acyclic 4,5-diamino-carboxylic acid derivative 3, whose
acetic acid moiety (–CH2CO2H) was envisioned to be intro-
duced by Claisen rearrangement of allylic alcohol 4 using
triethyl orthoacetate. For the stereoselective construction
of the vicinal diamino structure in 4, the cascade Overman
*
Corresponding author. Tel./fax: +81 45 566 1573.
E-mail address: chida@applc.keio.ac.jp (N. Chida).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.080

T. Momose et al. / Tetrahedron Letters 49 (2008) 1376–1379
1377
Fig. 1. Structure of A-315675 and its retrosynthetic analysis. TBDPS =
–SiPh2(t-Bu), Boc = –C(O)O(t-Bu).
rearrangement of bis-trichloroacetimidate possessing Z-
olefin 5 was planned. It is known that the Overman rear-
rangement is a suprafacial [3,3]-sigmatropic reaction and
the rearrangement of a chiral secondary imidate gives the
corresponding trichloroacetamide with transfer of chirality
via the chair-like transition structure.5 If the cascade Over-
man rearrangement of 5 works as expected, the diamino
function could be constructed in a one-step reaction, and
the two C–O stereochemistries in the starting material 5
would be effectively transferred to the C–N stereogenic
centers in 4 by the sequential chirality transfer. Although
several examples of the stereoselective C–N bond forma-
tion via the chirality transfer utilizing the Overman rear-
rangement and related sigmatropic rearrangements on
secondary allylic alcohols have been reported,5,6 its cascade
versions have received little attention.7 The bis-trichloro-
acetimidate derivative 5, in turn, was envisioned to be
derived from aldehyde 6, which would be readily prepared
from D-tartrate.8
The Z-selective Horner–Wadsworth–Emmons olefin-
ation of the known aldehyde 6,8 prepared from diisopropyl
D-tartrate in four steps with an 83% overall yield, with
Ando-type reagent 79 gave Z-olefin 810 and its E-isomer
in 82% and 12% isolated yields, respectively (Scheme 1).
The treatment of 8 with allylmagnesium chloride afforded
ketone 9 (92%), whose reaction with methylmagnesium
bromide at ꢀ78 °C proceeded with a high stereoselectivity
to provide tertiary alcohol 10 as a single isomer in 98%
yield. The chelation of magnesium between the ketone
carbonyl and the oxygen in the dioxolane ring would be
responsible for the observed high stereoselectivity.11 Ether-
ification of the tertiary alcohol in 10 gave 11 (93% yield),
whose hydrogenation in the presence of Pd on carbon
selectively reduced the sterically unhindered terminal
Scheme 1. P = TBDPS [–Si(t-Bu)Ph2], allyl = CH2@CH–CH2–.
alkene to give 12 in 89% yield. Removal of the acetonide
group in 12 provided the precursor of the cascade Overman
rearrangement, vicinal allylic-homoallylic diol 13, in 83%
yield. The treatment of 13 with trichloroacetonitrile in
the presence of DBU afforded the bis-imidate 5. When
the bis-imidate 5 was heated at 155 °C in o-xylene in the
12
presence of Na2CO3 in a sealed tube, the crucial cascade
Overman rearrangement successfully took place to provide
diamide 14 as a single isomer in 63% yield from 13.
Although the structure of 14 could not be fully determined
by spectroscopic methods at this stage, the successful con-
version of 14 into the Hanessian’s intermediate 2 (vide
infra), whose structure has been unambiguously deter-
mined by an X-ray analysis,3 confirmed the assigned
structure.
In the first Overman rearrangement of 5, there would be
two plausible chair-like transition structures,5 TS-a and
TS-b (Fig. 2). In TS-b which gives rise to an epimeric
rearranged product with a Z-olefin 500, the bulky substitu-
ent (–CH(OCNHCCl3)CH2OTBDPS) is in the disfavored
axial position, and there would be severe non-bonded inter-
actions between the axial substituent and a substituent in
the Z-olefin. Due to these sterically disfavored interactions
in TS-b, the transition structure TS-a would become a
more favored one, thus affording the first rearranged prod-
uct 50 exclusively. Further rearrangement of 50 via a similar
chair-like transition structure to TS-a stereoselectively
afforded doubly rearranged product 14. It is noteworthy

1378
T. Momose et al. / Tetrahedron Letters 49 (2008) 1376–1379
ucts revealed that the major product was the 4,5-cis isomer,
whereas the minor one was the 4,5-trans isomer. Ozonoly-
sis of 16 (1:3 diastereomeric mixture) followed by reductive
workup gave the diastereomeric aldehydes, which was sub-
ject to the base-induced epimerization at C-4 to provide
aldehyde 17 possessing a 4,5-trans stereochemistry as a sin-
gle isomer in 84% yield from 16. Wittig reaction of 17 with
the ylide generated from ethyltriphenylphosphonium bro-
mide with t-BuOK13 at ꢀ20 °C proceeded in a highly Z-
selective manner and afforded 18. The E-isomer of 18 could
1
not be detected in the reaction mixture by the H NMR
analysis.14 The treatment of 18 with Boc2O in the presence
of triethylamine and DMAP gave N-Boc c-lactam 19 in
72% yield from 17. The N-trichloroacetyl group in 19
was deprotected by the action of Cs2CO3 in DMSO,15
and the corresponding amine was acetylated to provide 2,
which is known as the synthetic intermediate of A-
Fig. 2. The plausible transition structures of Overman rearrangement of
5.
that in spite of the considerable steric hindrance in 5 due to
the presence of the Z-olefin as well as the adjacent tertiary
ether, the cascade rearrangement smoothly proceeded in a
concerted manner to generate the 1,2-diamido function in a
one-step reaction with complete chirality transfer. To
introduce the acetate unit to 14, the silyl protecting group
was removed to give 4 (92% yield).
1
315675,3,4 in 71% yield. The H and 13C NMR data of 2
were totally identical to those reported by the Hanessian
group.3
Finally, according to the reported procedure by the
Abbott2,4 and Hanessian3 groups, compound 2 was trans-
formed into A-315675 1 in a four-step reaction sequence
as shown in Scheme 3. Thus, the reduction of the lactam
carbonyl in 2 with DIBAL followed by treatment with
MeOH and p-TsOH gave aminal 20 as an anomeric mix-
ture (ca. 1:1). Introduction of a cyano group into 20 by
the reaction with TMSCN in the presence of CF3SO3H
followed by chromatographic separation afforded 21 as a
single isomer in 70% yield from 2. Acid hydrolysis of 21
followed by purification with the reversed phase (Wakogel
50C18) and ion exchange (Amberlite IR 120B, H+ form)
chromatographies furnished 1 in 57% yield. The spectral
data (1H and 13C NMR) as well as the [a]D value of syn-
The Johnson–Claisen rearrangement of 4 in triethyl
orthoacetate in the presence of a catalytic amount of
pivalic acid as the acid catalyst at 140 °C afforded 15 as a
diastereomeric mixture (1:3) in 82% yield (Scheme 2). The
hydrolysis of the ethyl ester function in 15 with aqueous
NaOH provided the carboxylic acid, which was then trea-
ted with EDCI and HOBt in the presence of DMAP to give
c-lactam 16 as a diastereomeric mixture (1:3) in 68% yield
from 15. The trichloroacetyl group on the nitrogen in the
lactam ring was selectively removed under the stated reac-
tion conditions. At this stage, the diastereoisomers were
1
19
cleanly separated and the H NMR analyses of the prod-
thetic 1 f½aꢁD ꢀ47.7 (c 0.44, H2O)} showed good agreement
with those reported for A-315675 by the Abbott group
{[a]D ꢀ50.2 (c 0.25, H2O)}.2
In summary, a new synthetic route to A-315675 starting
from D-tartrate has been established. This stereoselective
synthesis demonstrated that the cascade Overman rear-
rangement is highly effective for the stereoselective one-step
construction of the vicinal diamino functionality with
chirality transfer. Stereoselective generation of the tertiary
Scheme 2. EDCI = N-(3-dimethylaminopropyl)-N0-ethylcarbodimide hydro-
chloride, HOBt = 1-hydroxybenzotriazole, DMAP = 4-dimethylamino-
pyridine.
Scheme 3. DIBAL = diisobutylaluminum hydride, TMS = –SiMe3.

T. Momose et al. / Tetrahedron Letters 49 (2008) 1376–1379
1379
(a) Savage, I.; Thomas, E. J.; Wilson, P. D. J. Chem. Soc., Perkin
alcohol under chelation control is also noteworthy. Since
vicinal diamino structures are frequently found in biologi-
cally significant natural products as well as chiral ligands
for asymmetric catalysts, the methodology developed in
this study, that is, the cascade Overman rearrangement of
vicinal allylic–homoallylic alcohols, would be applicable
to the preparation of such important compounds. Further
study regarding the synthesis of natural products based on
the methodology employing the cascade sigmatropic rear-
rangement16,17 is now underway.
Trans. 1 1999, 3291–3303; (b) Martin, C.; Prunck, W.; Bortolussi, M.;
¨
Bloch, R. Tetrahedron: Asymmetry 2000, 11, 1585–1592; (c) Roulland,
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E.; Monneret, C.; Florent, J.-C.; Bennejean, C.; Renard, P.; Leonce,
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7. Report of the successful cascade Overman rearrangement on 1,2-
dihydroxy-3-cyclohexene, see: (a) Demay, S.; Kotschy, A.; Knochel,
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Supplementary data
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M.; Lazarides, L.; Aliev, A. E.; Hale, K. J. Org. Lett. 2005, 7, 5369–
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10. All new compounds described in this Letter were characterized by
300 MHz 1H NMR, 75 MHz 13C NMR, IR and mass spectrometric
and/or elemental analyses.
1
The spectrum data and H and 13C NMR spectra of
compounds 9, 10, 12–14, 4, 15, 17, 19, 2, and 1 are avail-
able. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2007.12.080.
References and notes
11. A similar reaction of the E-isomer of 9 with methylmagnesium
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