Total Syntheses of (+)-Grandilodine C

and (+)-Lapidilectine B and

Determination of their Absolute
Stereochemistry
Sharma Group Literature Meeting

Arianne Hunter

13February2016
Natural Products Background
•  Grandilodine C
•  I s o l a t e d from Kopsia
grandifolia.

•  Lapidilectine B
(1 previously known synthesis)
•  Isolated from lapidilecta

•  Both of these plants come from the

Kopsia genus
•  Widely distributed in Southeast
Asia

•  Limited availability from natural

sources
•  No known biological activities

•  Importance: scalable and efficient

preparation of these molecules
could probe their effectiveness as
drug candidates.
Synthetic Targets and Common
Intermediate

•  Common core found in Kopsia

alkaloids: spirodiketone 3

•  Goal: synthesize spirodiketone

efficiently and enantioselectively
•  Prior known synthesis takes
11 steps
Retrosynthetic Analysis
•  Allylacetate and azide functionalities in 5
could be used to construct rings E & F.

•  The lactone in 5 could be synthesized

through the vinyl and hydroxy groups in
6, which could be introduced by the
addition of vinyl and allyl metal reagents
to 8.

•  The initial conjugated vinylation of 8

would proceed from the Re face
(opposite the carbamate) to give 7, and
sequential allylation to the hindered
benzylic carbonyl from the Si face would
give the desired stereochemistry in 6

•  All of this is dependent on the

confirmation of 3b upon enantioselective
deprotonation and success of the
following Saegusa–Ito oxidation
Synthesis of (–)-8
a)  o-iodoaniline (1.0  equiv), TMSCN (1.2  equiv), AcOH,
RT, overnight, 98 %,

b)  K2CO3 (5.0  equiv), ClCO2Me, reflux, 72  h, 100  %

(brsm, 33 % conversion)

c) iPrMgCl (2.3 equiv), THF, 0 °C, 10 min then 1N HCl, 50 

°C, overnight, 89 % (3 steps)

d)  chiral amine 11 (2.5  equiv), nBuLi (2.5  equiv), TMSCl

(5.0 equiv)

e) Pd(OAc)2 (1.5 equiv), MeCN, RT, overnight.

TMS=trimethylsilyl, brsm=based on recovered

starting material, THF=tetrahydrofuran, Tr=trityl.
Synthesis of 18
a)  vinylMgBr (1.5  equiv), CuI (3.0  equiv), THF, −78  °C, 5 
min, 83 %,

b)  (TMSOCH2)2 (1.5  equiv), TMSOTf (0.3  equiv), CH2Cl2,

−78 °C, 3 h, then allylMgBr (2.0 equiv), −78 °C, 10 
min, 96 %,

c)  O 3 , CH 2 Cl 2 , −78  °C, 30  min, then Me 2 S, RT,

overnight,

d)  PDC (1.5  equiv), MS 3A, CH2Cl2, RT, 3  h, e)  NaBH4

(1.0 equiv), EtOH, −20 °C, 40 min, 33 % (3 steps),

f )  P P h 3 ( 1 . 5  e q u i v ) , D P P A ( 1 . 5  e q u i v ) ,
(MeO(CH 2 ) 2 O 2 CN=) 2 (1.5  equiv), THF, RT,
overnight, 73%)

g) PTSA (1.0 equiv), acetone, 40 °C, overnight, quant.

OTf=triflate, PDC=pyridinium dichromate,

DPPA=diphenylphosphoryl azide, PTSA=toluene-p-sulfonic
acid.
Completion of Total Syntheses
a)  vinylMgBr (1.5  equiv), THF, −78  °C, 2  h, 86 
%, d.r.=6:1 (determined by 1H  NMR
analysis)

b) PTSA (0.5 equiv), Ac2O, RT, 40 min, quant

c)  PPh3 (2.0  equiv), H2O/THF, RT, overnight,

quant,

d) Pd(PPh3)4 (30 mol %), NEt3, CH3CN, 65 °C,

3 h, 70 %,

e)  CH2=CHCOCl (10  equiv), iPr2NEt (20 

equiv), CH2Cl2, 0 °C, overnight,

f)  Grubbs  2nd cat. (20  mol  %), CH2Cl2, 50 

°C, overnight, 92 % (2 steps),

g)  Me3O⋅BF4, 2,6-di-tert-Bu Py, MS 4A,

CH2Cl2, RT, 2h, then NaBH4, MeOH, 0°C,
1 h.
Conclusion

¤  Completion of an enantioselective total

synthesis of (+)-Grandilodine C and (+)-
Lapidilectine B
¤  8.4% overall yield, 18 linear steps

¤  Key inter mediate, spirodiketone, was

synthesized in 3 steps
¤  Converted to chiral enone through
enantioselective deprotonation and oxidation
with up to 76% ee (88:12 er)

¤  Key reactions of final phase of synthesis:

palladium catalyzed intramolecular allylic
amination and ring closing metathesis