Divergent and efficient syntheses of the Lycopodium alkaloids (-)-Lycojaponicumin C, (-)-8-deoxyserratinine, (+)-fawcettimine, and (+)-fawcettidine

Article abstract of DOI:10.1002/anie.201306369

Four from one: The four title alkaloids (structures shown in blue box) have been synthesized by using a common versatile intermediate with a 6/5/5 tricyclic skeleton. This tricyclic intermediate could be easily assembled by using an intramolecular carbene addition/cyclization and a Dieckmann condensation/Tsuji-Trost allylation as key steps. Copyright

Full text of DOI:10.1002/anie.201306369

Angewandte
Chemie
DOI: 10.1002/anie.201306369
Natural Product Synthesis
Divergent and Efficient Syntheses of the Lycopodium Alkaloids
(ꢀ)-Lycojaponicumin C, (ꢀ)-8-Deoxyserratinine, (+)-Fawcettimine,
and (+)-Fawcettidine**
Si-Hua Hou, Yong-Qiang Tu,* Lin Liu, Fu-Min Zhang, Shao-Hua Wang,* and Xiao-
Ming Zhang
The fawcettimine class of Lycopodium alkaloids are a class of
structurally unique natural molecules with more than 80
members,[1] among which lycojaponicumin C (1),[2] 8-deoxy-
serratinine (2),[3] fawcettimine (3),[4] and fawcettidine (4)[5] are
representative ones (Figure 1). In particular, the alkaloid
1 isolated by Yu and co-workers from the traditional Chinese
medicine (L. japonicum THUNB) possesses biological activ-
been accomplished.[6,7] Many of these strategies make use of
the key 6/5/9 tricyclic intermediate 7 (Scheme 1), which is
prepared at least in 10 steps from readily available materi-
al.[6f,i] Using a similar intermediate, we also have finished the
Figure 1. Representative alkaloids of the fawcettimine class.
ity.[2] The structures of the alkaloids of the fawcettimine class
feature the fused tetracyclic ABCD frameworks including
two common AB rings and two differently-sized CD rings
together with highly crowded quaternary stereocenters.
Because of their wide-ranging biological activities and
challenging structures, syntheses of these alkaloids have
attracted great attention, and several total syntheses have
Scheme 1. Retrosynthetic analysis of 1–4. TBS=tert-butyldimethylsilyl.
[*] S.-H. Hou, Prof. Dr. Y.-Q. Tu, L. Liu, Prof. Dr. F.-M. Zhang,
Prof. Dr. S.-H. Wang, Dr. X.-M. Zhang
total synthesis of sieboldine A.[7f] Our next attempt toward
this subject is to explore a more efficient divergent strategy
through designing a versatile common intermediate such as 8,
which contains a 6/5/5 polycyclic system rather than the 6/5/9
system in 7 but contains an azido chain. We expect such an
advanced intermediate allows access not only to the alkaloids
2–4 via subintermediate 6, but also to other important
molecules. Here, we report the first asymmetric total synthesis
of 1 and the improved total syntheses of 2–4 by using this
proposal.
Our retrosynthetic analysis was illustrated in Scheme 1.
Based on the reported biogenetic pathway,[2] the target
molecules 1 and 2–4 could be derived from 5 and 6,
respectively. According to our hypothesis above, both 5 and
6 would be expected to be assembled from the key advanced
State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University
Lanzhou 730000 (P. R. China)
E-mail: tuyq@lzu.edu.cn
Prof. Dr. S.-H. Wang
School of Pharmacy, Lanzhou University
Lanzhou 730000 (P. R. China)
E-mail: wangshh@lzu.edu.cn
[**] This work was supported by the NSFC (21072085, 21102061,
21202073, 21290180, and 21272097), the “973” Program of MOST
(2010CB833203), the “111” Program of MOE, and the Major Project
of MOST (2012ZX 09201101-003). We thank Prof. Shi-Shan Yu of the
Institute of Materia Medica Chinese Academy of Medical Sciences
and Peking Union Medical College for providing a sample of 1.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306369.
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6/5/5 tricyclic intermediate 8 through intramolecular aza-
Wittig reaction and Schmidt N insertion, respectively. Fur-
thermore, 8 would be generated from cis-6/5 bicyclic dione 9
through the sequent Dieckmann condensation/Tsuji–Trost
allylation, then hydroboration and azidation. The dione 9
could be prepared from diazoenolate 10 by using our newly
developed intramolecular carbene addition/cyclization.[8] The
intermediate 10 could be prepared through Mukaiyama–
Michael addition from known enone 11 and vinyl diazoace-
tate 12.
of [Cu(tbs)2] (20 mol%) in PhCl at 1308C was crucial for
forming the intermediate 13,[13] which was directly subjected
to decarboxylation at 1808C without purification to provide 9.
In our later experiment, the dione 9 was prepared in a one-pot
manner and on gram scale directly from 11 and 12 with a total
yield of 51%. Next, treatment of ketone ester 9 with tBuOK
in THF at reflux gave an enolate of tricyclic trione, which was
then quenched with allyl acetate[14] to deliver the olefin 14 in
58% yield. At this stage, we successfully assembled the
tricyclic framework 14 with all carbon atoms of the key
intermediate 8 only by two consecutive one-pot procedures in
30% total yield. Subsequently, we expected direct hydro-
boration and azidation of 14 would lead to the intermediate 8.
However, hydroboration of the olefin 14 did not afford the
desired primary alcohol, which might be attributed to the fact
that the C13 carbonyl group was unprotected. Thus protection
of C13 carbonyl with glycol and then hydroboration of the
double bond under conditions reported by Kabalka and co-
workers[15] furnished the primary alcohol 15 in 65% yield over
two steps. Mitsunobu reaction[16] of the alcohol with diphe-
nylphosphoryl azide (DPPA) produced azidoketone 16, the
structure of which was confirmed by X-ray crystallographic
analysis.[17] Final removal of the glycol afforded the key
intermediate 8 in 53% yield.
Our synthesis commenced initially with the stepwise
preparation of the cis-bicyclic dione 9 from 11[9] and 12[10]
(Scheme 2). Although Doyle and co-workers reported an
efficient Mukaiyama–Michael reaction with zinc triflate as
Having the key advanced intermediate 8 in hand, we then
attempted the regioselective aza-Wittig reaction[18] to con-
struct the last ring D for completing the total synthesis of
alkaloid 1. Initially, the use of unprotected 8 afforded the
compound 5 and other inseparable materials in moderate
yield. Treatment of the protected azidodione 16 with PPh3 in
toluene followed with NaBH3CN in HOAc gave tetracyclic
amine 17 as a single product in excellent yield (Scheme 3).[19]
Removal of the glycol of 17 with 1m HCl aqueous solution
and protection of the secondary amine with CbzCl produced
dione 18 in 83% overall yield from 16. After extensive
Scheme 2. Synthesis of the key intermediate 8. Reagents and condi-
tions: a) 1. Tf2NH, CH2Cl2, ꢀ788C (90%), 2. [Cu(tbs)2], PhCl, 1308C,
then DMSO, NaCl, H2O, 1808C (55%); b) Tf2NH, CH2Cl2, ꢀ788C,
then [Cu(tbs)2], PhCl, 1308C, then DMSO, NaCl, H2O, 1808C (51%,
one pot); c) tBuOK, THF, reflux, then [Pd(PPh3)4], allyl acetate, THF,
08C!608C (58%); d) PTS, glycol, benzene, reflux (76%);
e) BH3·Me2S, cyclohexene, THF, 08C, then NaBO3·4H2O, H2O, RT
(85%); f) DPPA, DIAD, PPh3, THF, 08C! RT (81%); g) PTS, acetone/
H2O (10:1), reflux (53%). Tf2NH=triflimide, [Cu(tbs)2]=bis(N-tert-
butylsalicylaldiminato) copper(II), DMSO=dimethylsulfoxide,
tBuOK=potassium tert-butoxide, [Pd(PPh3)4]=tetrakis(triphenyl-
phosphine) palladium(0), PTS=p-toluenesulfonic acid, Glycol=ethyl-
ene glycol, (Cy)2BH=bis(cyclohexanyl)borane, RT=room temperature,
DPPA=diphenylphosphoryl azide, DIAD=diisopropyl azodicarboxy-
late.
investigations of the olefination conditions,[20,21] bromination
[22]
of 18 with CuBr2
followed by dehydrobromination with
DBU[23] afforded the enone 19 in 58% yield. Finally, the
target alkaloid 1 was obtained by exchanging the Cbz group of
19 with a methyl group. Its structure was identical to the
natural product sample as determined by spectroscopy and
confirmed by X-ray crystallographic analysis.[17] As a result we
successfully completed the first efficient asymmetric total
synthesis of (ꢀ)-lycojaponicumin C (1) in 12 steps and 4.7%
overall yield.
We then turned to investigate the intramolecular regio-
selective Schmidt N insertion to construct the 6/5 rings of the
common intermediate 6 for the total syntheses of alkaloids 2–
4. Although the intramolecular Schmidt reaction has been
proved as an efficient method for constructing the cyclic
lactam and applied in syntheses of many alkaloids,[24] here the
regioselective N insertion of a chained azide to one of the six
possible positions of the trione 8 is challenging. Fortunately,
by careful examination of the reaction conditions using
various Lewis acids (TiCl4, BF3·Et2O, SnCl4), protonic acids
(TFA, TfOH, ClSO3H), and solvents at different temper-
atures, the desired lactam 20 could be obtained in moderate
yield under reaction with an excess of SnCl4 (10 equiv) in
refluxing toluene along with only one minor byproduct 21 (20/
catalyst for the construction of functionalized diazoacetoace-
tates,[11] unfortunately such a condition was not applicable to
our system. Replacement of the catalyst with triflimide could
realize the expected reaction to give the desired product 10 in
90% yield as a single diastereomer. Then we turned our focus
on the designed intramolecular carbene addition/cycliza-
tion[12] for constructing the dione 9. After the screening of
various catalysts, [Cu(tbs)2] gave a satisfying result. Notably
in this experimental process, a slow addition of 10 to a solution
2
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short synthesis of the key and common intermediate 6 was
completed in 9 steps and 2% overall yield.
Finally, the concise total syntheses of the other three
alkaloids 2–4 were also finished according to the literature
procedures.[6f,i] Selective reduction of the carbonyl at C13 of 6
with NaBH4 gave (ꢀ)-8-deoxyserratinine (2) in 89% yield.
ꢀ
Selective cleavage of the C4 N bond of 6 with SmI2 followed
by a in situ aza-ketalization afforded (+)-fawcettimine (3) in
81% yield.[28] Subjecting 6 to harsh reducing conditions (Zn/
HOAc, 1408C) effected the sequent C4–N cleavage, aza-
ketalization, and dehydration to provide (+)-fawcettidine (4)
in 73% yield. The spectroscopic data for synthetic 2–4 were
identical to those reported.[25]
In summary, we have explored a novel and divergent
strategy[29] for syntheses of multiple alkaloids of the fawcetti-
mine class and completed the first efficient asymmetric total
synthesis of (ꢀ)-lycojaponicumin C (1) in 12 steps from the
chiral enone 11 and the more concise improved total
syntheses of the other three members 2–4 in 10 steps. A
major innovation of this strategy involved the design of
a versatile common tricyclic azidotrione intermediate 8,
which can undergo a series of transformations to reach the
synthesis of not only above molecules 1–4 but possibly some
other related members.
Scheme 3. Synthesis of alkaloid 1. Reagents and conditions: a) PPh3,
toluene, reflux, then MeOH, HOAc, NaBH3CN, 08C; b) THF, 1m HCl/
H2O, reflux; c) Na2CO3, CbzCl, THF/H2O (1:1), RT (83%, over 3
steps); d) CuBr2, THF, RT; e) DBU, toluene, RT (58%, over 2 steps);
f) 6m HCl/H2O, reflux; g) HCHO/H2O, NaBH3CN, MeOH, 08C (66%,
over 2 steps). HOAc=acetic acid, CbzCl=benzyl chloroformate,
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
Received: July 22, 2013
Published online: && &&, &&&&
Keywords: alkaloids · aza-Wittig reaction · divergent synthesis ·
.
natural products · Schmidt reaction
21 > 9:1; Scheme 4).[17,25] Subsequent treatment of lactam 20
with Lawessonꢀs reagent in toluene followed by reduction of
the resulting thiolactam[17] using Raney Ni[26] in EtOH gave
the intermediate 6 in 66% yield over two steps. Its spectro-
scopic data were identical to those reported.[6f,i,27] Thus, a very
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LR=Lawesson’s reagent.
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Natural Product Synthesis
S.-H. Hou, Y.-Q. Tu,* L. Liu, F.-M. Zhang,
S.-H. Wang,*
X.-M. Zhang
&&&& — &&&&
Divergent and Efficient Syntheses of the
Lycopodium Alkaloids(ꢀ)-
Lycojaponicumin C, (ꢀ)-8-
Four from one: The four title alkaloids
(structures shown in blue box) have been
synthesized by using a common versatile
intermediate with a 6/5/5 tricyclic skel-
eton. This tricyclic intermediate could be
easily assembled by using an intramo-
Deoxyserratinine, (+)-Fawcettimine, and
(+)-Fawcettidine
lecular carbene addition/cyclization and
a Dieckmann condensation/Tsuji–Trost
allylation as key steps.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!