Studies towards an enantioselective total synthesis of sarain A: A concise asymmetric construction of the diazatricyclic core

Article abstract of DOI:10.1002/chem.201001582

Figure Presented A powerful chiral building block: A concise enantioselective synthesis of the diazatricyclic core of sarain A has been accomplished. The novel strategy relies upon the versatile chiral building block (R)-1(see scheme), and features a tandem Horner-WadsworthEmmons-aza-Michael reaction, an intramolecular Michael reaction, and the diastereoconvergent formation of the third ring. Diazatricyclic core 2 possesses all of the necessary functionality for further elaboration into sarain A.

Full text of DOI:10.1002/chem.201001582

COMMUNICATION
DOI: 10.1002/chem.201001582
Studies towards an Enantioselective Total Synthesis of Sarain A: A Concise
Asymmetric Construction of the Diazatricyclic Core
Rui-Feng Yang[a] and Pei-Qiang Huang*[a, b]
Sarain A (1) is a structurally
complex alkaloid isolated from
relevant molecules,[8] we have been engaged in attempting
the total synthesis of sarain A.
Our retrosynthetic analysis of the sarain A core is out-
lined in Scheme 1 and comprises compound 2 as the diaza-
tricyclic core and building block 6[9] as the starting material.
the sponge Reniera sarai.[1] This
alkaloid contains seven chiral
centers and a unique diazatricy-
clic core structure connected to
two macrocyclic side rings. The
complex 14-membered macro-
cycle contains a pinacolic sub-
structure bearing vicinal chiral
centers, a triene moiety, and an
unusual polycyclic structure. In
addition to its challenging structural features, sarain A (1)
also exhibits antitumor, antibacterial, and insecticidal activi-
ty,[2] which make it an attractive synthetic target.[3]
The first synthetic study towards the total synthesis of sar-
ain A was reported by Weinreb in 1991.[4] Since then, several
research groups[5,6a] have been working on the construction
of the diazatricyclic core of sarain A. Recently, Porter and
co-workers reported the synthesis of bicyclic aminals and
their evaluation as precursors to the sarain A core.[7] All of
these studies, however, focused on racemic syntheses of the
core of sarain A. Not until 2006 was the first asymmetric
total synthesis of sarain A accomplished by Overmanꢀs
group, which involves a 46-step synthesis.[6] As a continua-
tion of our longstanding interest in the asymmetric synthesis
of bioactive alkaloids and N-containing, pharmaceutically
Scheme 1. Our retrosynthetic analysis of the sarain A core 2. Cbz=ben-
zyloxycarbonyl; Bn=benzyl.
Compound 2 could be constructed from bicyclic intermedi-
ate 3 by deprotection and oxidation. Compound 3 was envi-
sioned to be synthesized from N,O-acetal 5 through a
tandem Horner–Wadsworth–Emmons–aza-Michael reaction
followed by an intramolecular Michael addition reaction.
To assess the feasibility of our synthetic strategy, bicyclic
system 7 was selected as a model system. The synthesis of
model compound 7 started with a regioselective partial re-
duction of the protected (R)-3-hydroxyglutarimide 6.[8g,l]
[a] R.-F. Yang, Prof. Dr. P.-Q. Huang
Department of Chemistry and The Key Laboratory for
Chemical Biology of Fujian Province
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen, Fujian 361005 (P. R. China)
Fax : (+86)592-2186400
Treatment of 3-benzyloxyglutarimide
6
with NaBH4
E-mail: pqhuang@xmu.edu.cn
(6.0 equiv) in a mixture of saturated aqueous NaHCO3 and
THF at À30 to À258C for 1 h produced a regioisomeric mix-
ture of hemiaminals 5 and 8, which were separated by
column chromatography in 82 and 10% yields, respectively
(Scheme 2). Compound 5 contained two diastereomers in a
[b] Prof. Dr. P.-Q. Huang
State Key Laboratory of Bioorganic and Natural Products Chemistry
354 Fenglin Lu, Shanghai 200032 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001582.
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Scheme 2. The tandem Horner–Wadsworth–Emmons–aza-Michael reac-
tion in a model system.
Scheme 3. The intramolecular Michael addition reaction in
system. TMS=trimethylsilyl; TMSOTf=trimethylsilyl triflate; LDA=
lithium diisopropylamide; TFA=trifluoroacetic acid.
a model
ratio of 11:1. The major diastereomer had a larger vicinal
coupling constant between H-5 and H-6 (J5,6 =3.3 Hz) than
that of the minor diastereomer (J5,6 =2.2 Hz). According to
literature precedents,[9a,b] the stereochemistry of the major
diastereomer was, therefore, assigned as cis. We were able
to use the two diastereomers in the subsequent step without
further separation.
To introduce the 2-oxopropyl group at the C-6 position of
intermediate 5, a tandem Horner–Wadsworth–Emmons–aza-
Michael reaction[10] was envisaged. Treatment of the diaste-
reomeric mixture of hemiaminals 5 with the ylide derived
from diethyl 2-oxopropylphosphonate 9, presumably, gave
the intermediate enone 10 and then an intramolecular Mi-
chael addition followed to produce diastereomeric methyl
ketones 11a (trans) and 11b (cis) in a ratio of 77:23 and a
combined yield of 85%. The stereochemistry of the two dia-
stereomers was deduced from their vicinal coupling con-
stants, between H-5 and H-6 (J5,6 =4.7 Hz for the cis-diaste-
reomer and 2.3 Hz for the trans-diastereomer).
In order to obtain the requisite a,b-unsaturated lactam,
the ketone group had to be protected. In the presence of
TMSOTf (0.66 equiv), acetalization of the major diastereo-
mer 11a with 1,2-bis(trimethylsilyloxy)ethane gave the de-
sired lactam–acetal 12 in 92% yield (Scheme 3). Lactam 12
was then converted into a,b-unsaturated lactam 13 by a
known method;[11] namely, treatment of compound 12 with
LDA and PhSeBr, followed by oxidation of the resulting a-
phenylselenide with H2O2, and, finally, in situ elimination of
the selenoxide to give compound 13 in 63% overall yield.
Cleavage of the acetal in 13 was performed with 50% aque-
ous TFA, in acetone at 608C, giving the corresponding
keto–amide 14 in 90% yield.
heated at 708C for 3 h, the desired cyclization product 7 was
obtained in 83% yield.
Having accomplished the synthesis of model compound 7,
we turned our attention to the synthesis of the diazatricyclic
core 2. Treatment of hemiaminals 5 with the ylide generated
from diethyl 2-oxopropylphosphonate 15 and NaH produced
diastereomeric methyl ketones 16a (trans) and 16b (cis) in a
ratio of 3.1:1 and a combined yield of 83% (Scheme 4). The
carbonyl in 16a is more difficult to acetalize than that in
11a, perhaps because of the increased steric hindrance. In
spite of this, in the presence of TMSOTf (1.1 equiv),
lactam–acetal 17 was obtained in 86% yield. Lactam 17 was
then converted into the corresponding a,b-unsaturated
lactam (18) by the same procedure described for lactam 12,
affording 18 in 58% overall yield. Treatment of lactam–
acetal 18 with 50% aqueous TFA, in acetone at 758C, gave
the desired keto–amide 4 in 81% yield.
Next, we investigated the base-promoted intramolecular
Michael addition of compound 4. The challenge in this reac-
tion was caused by b-elimination from the enolate inter-
mediate. To suppress this side reaction, the intramolecular
Michael addition of 4 needed to be run under milder condi-
tions than those used for 14. It was found that treatment of
4 with NaH, in THF, at room temperature, for 15 min pro-
duced cyclization product 3 and its diastereomer 3a smooth-
ly, in a combined yield of 61%. The elimination side prod-
uct 19, produced by a retro-aza-Michael reaction, was isolat-
ed in 23% yield. The two diastereomers 3 and 3a were sepa-
rable by column chromatography and the ratio of 3/3a was
determined to be 1:3. However, if the reaction was carried
out in CH2Cl2, the combined yield of 3 and 3a was signifi-
cantly improved to 84% and that of 19 decreased to 8%; al-
though, the diastereoselectivity was somehow decreased to
1:2.1.
With keto–amide 14 in hand, we then undertook the key
intramolecular Michael addition. Initial attempts involving
the treatment of compound 14 with LDA led to complete
destruction of the starting material. Gratifyingly, if a suspen-
sion of compound 14 and NaH (3.0 equiv) in THF was
To determine the stereochemistry of cyclization products
3 and 3a, 3a was subjected to catalytic hydrogenolysis in the
presence of di-tert-butyl dicarbonate (Boc2O), giving alcohol
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Synthesis of Sarain A
COMMUNICATION
Finally, we investigated the construction of the tricyclic
core from 3. To this end, diastereomer 3 was first subjected
to catalytic hydrogenolysis in the presence of Boc2O, afford-
ing alcohol 22 in 62% yield (Scheme 6). Next, alcohol 22
was subjected to a Swern oxidation and the resulting ketone
was then treated with TFA to cleave the Boc group. After
workup with KOH (2 n), the diazatricyclic core (2) was
formed in 51% yield.
Scheme 6. The diastereoconvergent synthesis of the diazatricyclic core of
sarain A.
As 3a was the predominant diastereomer we synthesized,
the transformation of 3a into core 2 was crucial for the effi-
ciency of our synthetic approach. It was envisaged that the
same procedures developed for the synthesis of 2 from 3
would also be applicable to its diastereomer 3a, because the
final basic workup would allow concomitant epimerization
at C-7, leading to the formation of the thermodynamically
more stable cyclization product 2. Indeed, the Swern oxida-
tion of 20 and treatment of the resulting product with TFA,
followed by a basic workup with KOH (2 n), eventually
gave the diazatricyclic core 2 in 47% yield.
Scheme 4. The construction of the aza-bicyclic core of sarain A.
20 in 89% yield (Scheme 5). Compound 20 was further hy-
drogenolyzed with excess Pd(OH)2/C, to produce debenzy-
1
lated product 21, which gives a well-resolved H NMR spec-
trum. From the observed correlations between H-7 and H-9,
H-7 and H-5, and H-10 and H-3 in the 2D NOESY spec-
trum of 21, we assigned the configuration at C-7 of diaste-
reomer 3a to be R. Thus, the configuration at C-7 of diaste-
reomer 3 was deduced to be S.
Conclusion
Starting from the versatile chiral building block 6, we have
developed a concise asymmetric synthesis of the tricyclic
core (2) of sarain A, the N-propyl group of which could be
cleaved by oxidation[12] to give the corresponding mixed
imide, or by an amide-reduction/N-dealkylation proce-
dure.[13] It is worth mentioning that, although several innova-
tive approaches have been developed for the construction of
the core of sarain A, this is the second enantioselective ap-
proach to the tricyclic core since the first asymmetric total
synthesis by Overman. Work is in progress towards an asym-
metric total synthesis of sarain A.
Scheme 5. The preparation of compound 21 for an indirect establishment
of the stereochemistry of compound 3a by NOESY spectroscopy.
Chem. Eur. J. 2010, 16, 10319 – 10322
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P.-Q. Huang et al.
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Experimental Section
Experimental procedures and characterization for all new compounds
can be found in the Supporting Information.
Acknowledgements
The authors are grateful to the NSF of China (No. 20832005) and the Na-
tional Basic Research Program (973 Program) of China (Grant No.
2010CB833200) for financial support. We think Bo Teng for assistance in
the preparation of some starting materials.
Keywords: alkaloids · asymmetric synthesis · cyclization ·
Michael addition · Sarain A · total synthesis
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Received: June 6, 2010
Published online: July 28, 2010
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