Utilization of molybdenum- and palladium-catayzed dynamic kinetic asymmetric transformations for the preparation of tertiary and quaternary stereogenic centers: A concise synthesis of Tipranavir

Article abstract of DOI:10.1021/ja028497v

Tipranavir, an important antiviral agent in clinical development for the treatment of HIV, is synthesized in 15 linear steps from readily available starting materials in 25% overall yield by utilizing Pd- and Mo-catalyzed DYKAT reactions to control the qu

Full text of DOI:10.1021/ja028497v

Published on Web 11/06/2002
Utilization of Molybdenum- and Palladium-Catayzed Dynamic Kinetic
Asymmetric Transformations for the Preparation of Tertiary and Quaternary
Stereogenic Centers: A Concise Synthesis of Tipranavir
Barry M. Trost* and Neil G. Andersen
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received September 10, 2002
Scheme 2. Synthesis of the C-6 Key Intermediatea
The development of new therapeutic agents to combat the human
immunodeficiency virus (HIV) continues to be an intense area of
pharmaceutical research. Tipranavir (1),1 a unique, nonpeptidic
protease inhibitor (PI) currently in phase IIb clinical trials, has
demonstrated remarkable pharmacokinetic properties and offers the
significant advantage of oral bioavailability. In addition, HIV-I
clinical isolates exhibiting viral resistance to currently available PI
agents such as ritonavir, saquinavir, indinavir, and nelfinavir, remain
highly sensitive to tipranavir.
Previous syntheses of tipranavir have utilized either chiral
auxiliaries2a or resolutions2b to obtain the two distally related
quaternary C-6 and tertiary C-3R stereogenic centers. In this
communication we describe a short and highly efficient enantiose-
a Conditions: (a) CH2CHMgBr, THF, 0 °C. (b) 1N NaOH, Et2O, 25
°C, 86% (two steps). (c) 1 mol % Pd2(dba)3‚CHCl3, 3 mol % (S,S)-9, 1
lective synthesis of this important antiviral agent based on a double
dynamic kinetic asymmetric transformation (DYKAT) strategy.
mol % Et3B, 1.1 equiv of PMBOH, 69%, 98% ee. (d) PhI, 10 mol %
Employing a late-stage pyrone formation approach, it was envi-
Pd(OAc)2, 40 mol % P(o-Tol)3, toluene, Et3N, reflux, 92%. (e) 5 mol %
sioned that the title compound could be retrosynthesized back to
aldehyde 2, ester 3, and known sulfonyl chloride 42 (Scheme 1). It
was further anticipated that the C-6 key intermediate 2 could be
obtained by Pd-catalyzed asymmetric allylic alkylation (AAA) from
vinyl epoxide 5, while the C3R key intermediate could be prepared
by a Mo-catalyzed AAA reaction from carbonate 6.
Pd/C, H2 (1 atm), MeOH, Pyr, 25 °C, 99%. (f) Dess-Martin periodinane,
CH2Cl2, 25 °C. (g) Ph3PdCH2, THF, reflux, 94% (two steps). (h) Catechol
borane, 1 mol % (Ph3P)3RhCl, THF then 3 N NaOH, 30% H2O2, 25 °C. (i)
Dess-Martin periodinane, CH2Cl2, 25 °C, 88% (two steps).
furnished racemic vinyl epoxide 5 in 86% yield. Subjecting this
material to a palladium- and boron-cocatalyzed DYKAT reaction4
using (S,S)-ligand-9 and p-methoxybenzyl alcohol as the nucleophile
provided allylic ether 10 in a highly regio- and enantioselective
fashion (69% yield, 98% ee). Subsequent Heck arylation (10 mol
% Pd(OAc)2/40 mol % P(o-Tol)3) gave olefin 11 in 92% yield as
a single regioisomer. Attempts to install the required phenyl ring
via reductive Heck procedures or hydroboration/Suzuki cross-
coupling protocols were unsuccessful. Chemoselective hydrogena-
tion of alkene 11 followed by Dess-Martin oxidation and
subsequent Wittig olefination provided compound 12 in 93% yield.
Rh(I)-catalyzed hydroboration of olefin 12 followed by Dess-
Martin oxidation of the resulting alcohol furnished key intermediate
13 in 88% yield (45% yield from ketone 8).
Scheme 1. Retrosynthetic Analysis of Tipranavir
Synthesis of the C-3R key intermediate began by treating known
allylic alcohol 14,5 with Boc2O in CH2Cl2/Et3N and a catalytic amount
of DMAP to provide carbonate 6 in 98% yield (Scheme 3). A key
Scheme 3. Synthesis of the C-3R Key Intermediatea
Synthesis of the C-6 key intermediate started with addition of
vinylmagnesium bromide to 1-chloro-2-pentanone (8)3 (Scheme 2).
Exposure of the resulting chlorohydrin to NaOH in ether smoothly
a Conditions: (a) Boc2O, CH2Cl2, Et3N, DMAP, 25 °C, 98%. (b) 10
mol % Mo(CO)3(C7H8), 15 mol % (R,R)-15, dimethy1 sodiomalonate, THF,
reflux, 94%, 96% ee. (c) 20:1 DMSO/H2O, NaCl, 150 °C, 100%.
* To whom correspondence should be addressed. E-mail: bmtrost@stanford.edu.
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10.1021/ja028497v CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Selected Mo-Catalyzed DYKAT Reactionsa
To complete the synthesis, aldol coupling of aldehyde 13 and
ester 18 was performed (NaHMDS, -78 °C) followed by Dess-
Martin oxidation to give â-ketoester 21 as a 1:1 mixture of C-3
epimers (Scheme 5). After cleavage of the PMB group using
standard conditions, pyrone formation furnished compound 22 in
77% yield (97% brsm (based on recovered starting material)).
Subsequent hydrogenation and treatment of the resulting amine with
5-(trifluoromethyl)-2-pyridinesulfonyl chloride (4)2,10 provided
tipranavir (1) in 92% yield.
c
entry
catalyst
T (°C)
t (h)
% yieldb
%ee
1
2
3
Mo(CO)3(C7H8)/(R,R)-15
Mo(CO)6/(S,S)-15
Mo(CO)6/(S,S)-16
67
24
0.33
0.33
94
92
94
96(R)
94(S)
94(S)
180d
180d
a All reactions were performed in THF (0.2 M in dimethyl sodiomalonate)
using 10 mol % catalyst and 15 mol % ligand. b Isolated yield of the
branched regioisomer. c Determined by chiral HPLC. d Performed under
microwave irradiation.
In conclusion, we have developed a concise, atom-economical9
synthesis (25% overall yield) of tipranavir (1) by employing two
highly regio- and enantioselective DYKAT reactions. The current
strategy is convergent, starts with commercially available materials,
and efficiently addresses the control of two remote stereogenic
centers. Moreover, the synthesis highlights the complementary
nature of Pd- and Mo-catalyzed AAA reactions.
concern in the Mo-catalyzed DYKAT process6 was the impact of
a strongly electron-withdrawing group such as nitro on the
regioselectivity of allylic alkylation. Gratifyingly, subjecting com-
pound 6 to the Mo AAA reaction (10 mol % Mo(CO)3(C7H8), 15
mol % (R,R)-15, 2.0 equiv of dimethyl sodiomalonate) furnished
the desired branched regioisomer 17 in excellent yield (94%) and
enantioselectivity (96% ee) (Table 1, entry 1). Performing the
reaction under microwave irradiation7,8 (180 °C, 20 min) dramati-
cally increased the rate of alkylation with only minimal loss in
stereoselectivity (entry 2). In addition, an enhanced efficacy of Mo-
(CO)6, a more convenient and inexpensive molybdenum source,
was observed under such conditions. Utilization of p-methoxy-
substituted ligand 167 led to a small increase in yield with no effect
on enantioselectivity (entry 3). Interestingly, treatment of sulfona-
mide model system 19 with the standard Mo-catalyzed AAA
conditions smoothly provided product 20 in 95% yield and 94%
ee (Scheme 4). Failure of the 2-pyridyl moiety in substrate 19 to
Acknowledgment. We acknowledge the National Science
Foundation and the National Institute of Health (GM 33049) for
their generous support of our programs. N.G.A. thanks the Alberta
Heritage Foundation for Medical Research and the Natural Sciences
and Engineering Research Council of Canada for postdoctoral
fellowships. Mass spectra were provided by the Mass Spectrometry
Facility, University of San Francisco, supported by the NIH Division
of Research Resources.
Supporting Information Available: Characterization data for
compounds 1, 5, 6, 10-13, 17, 18, and 22 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 4. Mo-DYKAT Investigation of Model System
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Scheme 5. Completion of the Synthesisa
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a Conditions: (a) NaHMDS, THF, -78 °C. (b) Dess-Martin periodinane,
CH2Cl2, 25 °C. (89% two steps). (c) CAN, CH3CN/H2O, 88%. (d) NaOH,
MeOH, 4 °C, 77% (97% brsm). (e) 5 mol % Pd/C, H2 (1 atm), MeOH, 25
°C. (f) 5-(Trifluoromethyl)-2-pyridinesulfonyl chloride (4), CH2Cl2, Pyr,
DMSO, -25 °C, 92%.
JA028497V
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