1. Recent Highlights from the
Nicolaou Laboratory
Me H
Me Me
Me
O HN OH H H H O
O Me
OH
O O
H Ph O
Me
O OH
Biyouyanagin A
Truncated Haplophytine Uncialamycin
Christina S. Stauffer
Ch i ti S St ff
February 27, 2008

2. Haplophytine
Me
N
O O
N N
HO
O
MeO N O
H
OMe Me
Haplophytine
p p y
CO2Me
N N
O O
N
9
9' O
15
MeO N O
H
N OMe Me
MeO
OMe CO2Me Aspidophytine
Truncated haplophytine Syntheses: Corey, 1999
Fukuyama, 2003
Padwa, 2006
Marino, 2006
• Potent insecticidal alkaloid
alkaloid.
• Isolated in 1952 by Snyder and co-workers from Mexican plant Haplophyton
cimicidum.
• Consists of a central indole moiety with two tetracyclic heterocycles attached.
attached
• Four reported syntheses of aspidophytine, while only one report of studies towards
the left-hand domain (Corey, 2006).

3. Retrosynthesis of the “Left Domain” of Haplophytin
CO2Me
N
O O
N
9'
15
MeO
M O N
OMe CO2Me
Truncated haplophytine
N
N CO2Me
H HO N
OH CO2Me
CO2Me
Nicolaou, K. C.; Majumder, U.; Roche, S. P.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2007, 46, 4715-4718.

4. Synthesis of indole fragment
NH NCCO2Me, CH2Cl2, 0 °C
N N
H N CO2Me
51% H
CO2Me
CO2Me

5. Synthesis of the indoline fragment
CHO 1. Ac2O, Et3N, cat. DMAP CHO
2. fuming HNO3
HO HO NO2
3. aq. KOH, reflux
OMe OMe
69%
1. K2CO3, BnBr, DMF
2. CH3NO2, NaOH, , NO2 1. Fe, AcOH, tol, 110 °C
MeOH/H2O, 0 °C
2. KHMDS, NCCO2Me,
3. Ac2O, NaOAc, 140 °C BnO NO2 THF, -78 °C
88% OMe 96%
1. Pd/C, H2, MeOH
,
HO N
BnO N 2. BBr3, CH2Cl2,
-78 °C to 0 °C OH CO2Me
OMe CO2Me
86%

6. Coupling of indole and indoline fragments
N CO2Me
PIFA = PhI(CF3CO2)2 OH
O
CH2Cl2, CH3CN, -40 °C
N
N CO2Me HO N O
H 25%
OH CO2Me
N
CO2Me N CO2M
Me
H
CO2Me
N CO2Me N CO2Me
OMe
OM OMe
Cs2CO3, MeI
DMF OMe NaH, THF OMe
60%
N 80% N
N CO2M
Me N CO2Me
O
CO2Me

7. Completion of the construction of the
“left domain” of haplophytin

8. Uncialamycin
Me
O HN OH
O
OH
O OH
Cladonia uncialis
• A recently discovered enediyne antibiotic isolated in 2005 by Anderson from the
surface of the lichen, Cladonia uncialis.
• The scarcity of uncialamycin (300 μg) limited structural elucidation (C26 hydroxyl
group was unassigned).
• Potent biological activity demonstrated against S. aureus, E. coli, and B. cepacia.

9. Nicolaou’s retrosynthesis of uncialamycin
Me
O HN OH
O
OH
O OH
Me
CN N
O
O
OTES H TMS
O
ODMB
Nicolaou, K. C.; Zhang, H.; Chen, J. S.; Crawford, J. J.; Pasunoori, L. Angew. Chem. Int. Ed. 2007, 46, 4704-4707.

10. Synthesis of the substituted quinoline system
O
Me
HN O
CO2H
OMe
O Me
1. 48% aq. HBr, N Me HCO2H, Et3N, N
nBu4NBr, 110 °C O
CH2Cl2, 0 °C
CO2DMB
2. DMBBr, K2CO3, O
nBu4NI, DMF Me Me
ODMB ODMB
55% Ts
Ph N
Ru
N Me
Ph H2 Cl
95%, 98% ee
Me OMe
N
1. DIBAL-H, CH2Cl2 O O
DMB =
2. TESCl, im, DMF OTES Ph OMe
86% OR
ODMB

11. Introduction of the enediyne functionality
TMS
Me Me TMS
1. AcOH, MeCN, Me
N AllocN H2O, 91%
O H TMS O 2. NaBH4, MeOH AllocN OH
O
OTES EtMgBr, AllocCl OTES 3. mCPBA, CH2Cl2
92% 80% (2 steps) OAc
ODMB ODMB 4. AcCl, collidine, 82%
ODMB
TMS
H
Me
1. TESCl, Im, Me
1. Dess-Martin AllocN OH DMF
O AllocN OTES
O
2.
2 NaBH4, MeOH 2.
2 K2CO3, THF
OAc MeOH
90% OH
78%
ODMB
ODMB

12. Intramolecular acetylide addition to form the enediyne ring system
H H
Me 1. Dess-Martin, 87% Me CeCl3, KHMDS
- 78 °C to - 40 °C
AllocN OTES 2. DDQ,
2 DDQ CH2Cl2/H2O AllocN OTES
O O 61%
87%
(30% C17 epimer)
OH O
ODMB OH
Me Me
1. PhI(OAc) MeOH
1 PhI(OA )2, M OH
AllocN OTES 80% N OTES CN
O 17 O
OH OH 1.
2. [Pd(PPh3)2Cl2] O
nBu3SnH, H2O,
CH2Cl2, 74%
O
OH O
LiHMDS, 63%
2. 3HF•Et3N, THF
92%
Me
O HN OH
O
OH
O OH
Uncialamycin

13. Synthesis of Biyouyanagin A
(H. chinense L. var. salicifolium)
• Isolated from the leaves of a Hypericum species in 2005.
• Traditionally used as folk remedy for female disorders.
• Shows significant activity against HIV and lipopolysaccharide-induced cytokine
production.
• Stereochemistry at C24, C17, C18 needs to be elucidated.

14. Structural assignment of biyouyanagin A
H H
Me Me Me Me
Me Me
H H H O H H H O
Me Me
O O O
O
H Ph O H Ph O
Me Me
Originally proposed possible structures
H H
Me Me Me Me
Me
H H H O
Me H
24
H H O
Me Me
17
18 O
O O O
H Ph H Ph O
Me O Me
Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem. Int. Ed. 2007, 46, 4708-4711.

15. Biyouyanagin A retrosynthesis
H H
Me Me Me Me
Me O Me
H H H O Me
H
Me [2 + 2]
O O
O O Ph
H Ph O
Me O Me

16. Synthesis of the terpene-derived diene
Cl
Tf
N N
Tf
Comins reagent

17. Formation of the spirolactone

18. [2+2] Photocycloaddition
H H
Me Me Me Me
O Me Me
H
h , 2'-acetonaphthone H H H O
Me Me
CH2Cl2, rt, 5h
O O O
Ph 46% O
O H Ph O
Me Me
H
Me Me
H
Me
OO
Me
O
O
Me
(exo)