Studies on the total synthesis of sanglifehrin A: Stereoselective synthesis of the C(29)-C(39) fragment

Article abstract of DOI:10.1016/j.tetlet.2006.01.105

A highly stereoselective synthesis of the C(29)-C(39) fragment of the potent immunosuppressant sanglifehrin A has been accomplished by a sequence involving 16 steps (18% overall yield) from N-propionyloxazolidinone 9. Key steps are a diastereoselective hy

Full text of DOI:10.1016/j.tetlet.2006.01.105

Tetrahedron Letters 47 (2006) 2213–2216
Studies on the total synthesis of sanglifehrin A:
stereoselective synthesis of the C(29)–C(39) fragment
Luiz C. Dias* and Airton G. Salles, Jr.
Instituto de Quı´mica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13084-971 Campinas, SP, Brazil
Received 2 January 2006; revised 19 January 2006; accepted 19 January 2006
Available online 7 February 2006
Abstract—A highly stereoselective synthesis of the C(29)–C(39) fragment of the potent immunosuppressant sanglifehrin A has been
accomplished by a sequence involving 16 steps (18% overall yield) from N-propionyloxazolidinone 9. Key steps are a diastereo-
selective hydroboration, and a diastereoselective epoxidation of an allylic alcohol followed by a 1,5-anti boron-mediated aldol reac-
tion of methyl ketone 4 with chiral aldehyde 5.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
contains seven stereogenic centers, six of which are con-
tiguous (C(33)–C(38)). The significant biological proper-
ties of sanglifehrin A have prompted numerous studies
directed toward its synthesis.4 Nicolaou and co-workers
described the first total synthesis of sanglifehrin A,
which was followed by the synthesis of Paquette and
co-workers.4 In addition, many research groups have
reported studies directed toward the synthesis of frag-
ments of sanglifehrin A.5
The potent immunosuppressant sanglifehrin A (SAF)
was isolated from the culture broths of Streptomyces
flaveolus in 1997 by scientists at Novartis (Fig. 1).1 Sang-
lifehrin A (1) shows a remarkably high affinity for
cyclophilin A with an IC50 = 2–4 nM.2,3 SAF has a com-
plex molecular structure, consisting of a 22-membered
macrocyclic lactone, which incorporates piperazic,
aliphatic, and aromatic amino acid fragments. One of
the remarkable features of this molecule is the presence
of a highly substituted spirobicyclic oxaazaspiro[5,5]-
undecanone system (C(33)–N(42)). This spirobicycle
To provide material for further biological studies as well
as access to novel analogues, we initiated a study toward
the synthesis of the spirobicyclic oxaazaspiro[5,5]-
undecanone system of sanglifehrin A. We wish to
describe here our successful efforts toward the prepara-
tion of the C(29)–C(39) fragment, via a diastereoselec-
tive boron-mediated 1,5-anti aldol reaction of methyl
ketone 4 with chiral aldehyde 5 as the key step.
Me
33
Me
Me
26
HO
OH
OH
30
27
37
O
OH
Me
Me
O
Me
HN
O
NH
38
40
41
Me
NH
N
O
O
O
2. Results and discussion
O
Me
O
(1)
Me
NH
Me
Our disconnection strategy summarized in Scheme 1,
involved cleavage of the C(39)–C(40), O–C(37), and N–
C(37) bonds in 2 to give the b-hydroxy ketone 3. Further
synthetic analysis involved the cleavage of the C(31)–
C(32) bond in 3 to give methyl ketone 4 (C(32)–C(39)
fragment) and aldehyde 5 (C(29)–C(31) fragment).
Methyl ketone 4 is viewed as arising from allylic alcohol
6, available from lactone 7. Key steps in this approach
are a diastereoselective hydroboration of aldol adduct
8 to give lactone 7, selective epoxidation of allylic
OH
Figure 1. Sanglifehrin A (1).
Keywords: Immunosuppressant; 1,5-Anti aldol; 1,5-Asymmetric
induction.
*
Corresponding author. Tel.: +55 019 3788 3021; fax: +55 019 3788
3023; e-mail: ldias@iqm.unicamp.br
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.105

2214
L. C. Dias, A. G. Salles, Jr. / Tetrahedron Letters 47 (2006) 2213–2216
TBS
Me
Me
O
O
OH
O
O
TBSCl, imidazol
33
Me2AlCl (3 eq)
MeONHMe.HCl
CH2Cl2, rt, 90%
HO
TBS
TBSO
PMB
O
30
Me
O
O
OH OTBS
DMAP, CH2Cl2
rt, 100%
N
Me
Me
37
O
OH OTBS
Me
Me
34
29
39
7
Me Me OMe
OTBS
NH
38
11
41
2
3
Me Me Me
Me
40
O
TBS
TBS
TBSO
(EtO)2
O
O
TBSO
O
O
DIBAL-H, THF
Me
TBSO
Me
TBS
TBSO
PMB
-78 o
C
H
N
TBS
O
O
O
O
OTBS
O
OH
Me Me OMe
Me Me
+
34
29
39
12
13
Me
H
5
O
P
O
Me Me Me
Me
6
Me Me
4
OEt
TBS
14
TBSO
O
O
NaH (1 eq.), THF
O
TBSO
O
O
O
OEt
E:Z > 95:05
-78 o
C
N
O
Me Me
89% (2 steps)
Me
Me
Me Me
15
Bn
8
7
OTBS
Scheme 3. Lactone opening and HWE reaction.
Scheme 1. Retrosynthetic analysis.
alcohol 6, and a 1,5-anti boron-mediated aldol reaction
between 4 and 5.
leading to Weinreb amide 11 in 90% yield (Scheme 3).8
Protection of the primary OH-function in 11 as its
TBS ether gave Weinreb amide 12, which, after reduc-
tion with DIBAL-H in THF at low temperature pro-
vided aldehyde 13. The unpurified aldehyde was
directly subjected to a Horner–Waddsworth–Emmons
homologation with ketophosphonate 14 to give the
(E)-a,b-unsaturated ester 15 in 89% yield over two steps
(E:Z >95:5 diastereoselectivity).9
Our approach to the C(29)–C(39) fragment of sanglifeh-
rin A began with the asymmetric aldol addition of the
boron enolate derived from N-propionyloxazolidinone
9 with methacrolein to give the corresponding aldol
adduct 10 in 85% yield (ds >95:5) (Scheme 2).6 Silylation
of aldol 10 with TBSOTf and 2,6-lutidine gave 8 in 89%
yield. We were very pleased to find that hydroboration
of aldol 8 with 9-BBN in THF led directly to lactone 7
in 90% isolated yield and >95:05 diastereoselectivity
for the two-step sequence (hydroboration and lactoniza-
tion).7 The corresponding chiral auxiliary was easily
recovered. The relative stereochemistry for lactone 7
Ester 15 was smoothly converted to allylic alcohol 6 on
treatment with excess DIBAL-H (Scheme 4). It is note-
worthy that epoxidation of allylic alcohol 6 with
m-CPBA gave the anti-epoxy alcohol 16 in 90% overall
yield and >95:05 diastereoselectivity.10,11 Treatment of
epoxy alcohol 16 with Me2CuCNLi2 gave diol 17 in
87% yield.12 At this point, the relative stereochemistry
for 1,3-diol 17 was determined after conversion to the
PMP-acetal 18.13 Formation of p-methoxybenzylidene
acetal 18 was accomplished by treatment of the diol 17
with p-methoxybenzaldehyde dimethyl acetal and a cat-
1
was determined by coupling constant analysis in its H
NMR spectra.7 The coupling constants for Ha/Hc
(10.4 Hz), Hc/Hd (3.7 Hz), and Hd/He (3.7 Hz) con-
firmed the stereochemistry of lactone 7. In these stereo-
chemical assignments, both the C(2)-methyl and the
C(3)-OTBS stereocenter configurations served as impor-
tant reference points.
TBS
TBS
The next step involved opening of lactone 7 with N,O-
dimethylhydroxylamine in the presence of Me2AlCl
TBSO
O
OH
TBSO
O
O
DIBAL-H (2 eq.)
OEt
CH2Cl2, -78 o
C
6
15
Me Me
Me Me
O
O
TBSOTf
O
OH
O
n-Bu2BOTf
2,6-lutidine
TBS
Me
TBSO
O
O
OH
m-CPBA, CH2Cl2
Me2CuCNLi2
N
O
N
O
CH2Cl2, rt, 89%
DIPEA, CH2Cl2
methacrolein
-78 oC, 85%
0 oC, 90% (2 steps)
9
Me Me
THF, -78 to -20 o
87%
C
Bn
Bn
10
16
Me Me
ds > 95:05
ds >95:05
PMP
TBS
O
O
O
TBSO
O
TBS
9-BBN, THF
TBSO
O
OH OH
TBSO
O
O
O
N
O
PMB-acetal
EtOH, pH 7.0
Me
7
Me
Me Me
H2O2 30%, 90%
OTBS
PPTS, CH2Cl2
rt, 85%
18
Bn
17
8
ds >95:05
Me
Me Me Me
Me Me Me
Hc
Hd
Hb
Ha, t, J = 10.4 Hz
Hb, dd, JHb-Ha =10.4 Hz and JHb-Hc = 5.0 Hz
Hd, t, J = 3.7 Hz
R
Ha ,dd, J Ha-Hb = 10.7 Hz
Hd, t, J Hb-Hd = 11.0 Hz
Hc, dd, J Hb-Hc = 4.8 Hz
O
Me
Hc
Me
He
O
PMP
O
Hb
He, qd, JHe-Hd = 3.7 Hz
OTBS
Ha
Hd
O
7
H
Ha
Scheme 2. Synthesis of lactone 7.
Scheme 4. Diastereoselective epoxidation.

L. C. Dias, A. G. Salles, Jr. / Tetrahedron Letters 47 (2006) 2213–2216
2215
alytic amount of PPTS (85% yield).13 Coupling con-
stants between Ha–Hb (10.7 Hz), Hb–Hd (11.0 Hz), and
Hb–Hc (4.8 Hz) confirmed the relative stereochemistry
for 18.
PMB
TBS TBS
O
TBS
TBS
OH
PMB
29
Me
OH
O
O
O
OH
O
29
O
O
O
1. HF.pyridine
34
34
39
2. PPTS, MeOH
(68%, 2 steps)
OMe
3
Me Me Me
Me
Me Me Me
21
Hd
Ha
Treatment of PMP-acetal 18 with DIBAL-H in CH2Cl2
at ꢀ78 °C followed by oxidation of the resulting pri-
mary alcohol 19 under standard Swern conditions gave
aldehyde 20 (89%, two steps) (Scheme 5).14 Addition of
MeLi in THF followed by Swern oxidation led to
methyl ketone 4 in 70% for the two-step sequence.14,15
JHa-Hc = 11.0 Hz
JHb-Hc 4.8 Hz
JHc-Hd = 10.4 Hz
JHd-He 4.8 Hz
JHd-Hf = 11.3 Hz
He
O
=
Me
OH
*R
=
Hf
Hb
OMe
Hc
Scheme 6. Determination of the relative stereochemistry for aldol
adduct 3.
At this point, aldehyde 5, corresponding to the C(29)–
C(31) fragment was prepared in three steps and 77%
overall yield from (R)-methyl-3-hydroxy-propanoate
following protection with TBSCl and imidazole, reduc-
tion of the ester to the primary alcohol with excess
DIBAL-H followed by Swern oxidation.16
proved that Ha, Hc, Hd, and Hf are all axial in 21. This
indicates that acetal 21 derives from a 1,5-anti (Felkin)
aldol product.
3. Conclusions
With the requisite C(32)–C(39) and C(29)–C(31) frag-
ments in hand, their coupling was undertaken (Scheme
5).17 This was done by using a 1,5-anti selective boron-
mediated aldol reaction providing b-hydroxyketone 3,
corresponding to the C(29)–C(39) fragment of sanglifeh-
rin A in 81% yield and >95:05 diastereoselectivity.17–20
This approach to the C(29)–C(39) fragment of sanglifeh-
rin A requires 16 steps and produced the desired b-
hydroxy ketone 3 in 18% overall yield. The key step in
this approach involved a 1,5-anti boron-mediated aldol
reaction of methyl ketone 4 with chiral aldehyde 5. As
a result, the route to the C(29)–C(39) fragment of sang-
lifehrin A presented here is, in principle, readily applica-
ble for the preparation of the spirolactam fragment of
sanglifehrin A as well as to additional analogues.22
Extension of this work to the synthesis of the spiro-
lactam fragment of sanglifehrin A and analogues is
underway.
This aldol adduct appeared ideally suited for stereo-
chemical analysis by using the very simple method for
assigning the relative stereochemistry of b-hydroxy
ketones reported in 2002 by Roush and co-workers.20
However, we have reported a refinement of the Roush’s
1
model, in which we show that H HMR ABX pattern
analysis is not applicable to b-hydroxy ketones (e.g.,
aldols) deriving from aldehydes lacking b-branches.21
The relative stereochemistry for aldol adduct 3 was then
determined after conversion to the corresponding acetal
21 (68%, two steps) by treatment of 3 with HFÆpyr fol-
Acknowledgments
We are grateful to FAEP-UNICAMP, FAPESP (Fun-
dac¸ao de Amparo a Pesquisa do Estado de Sao Paulo)
and CNPq (Conselho Nacional de Desenvolvimento
Cientıfico e Tecnologico) for financial support. We also
thank Professor Carol H. Collins for helpful suggestions
about English grammar and style.
lowed by PPTS in MeOH (Scheme 6).20 Analysis of
1
`
˜
˜
the H NMR coupling constants, specifically JH –H
¼
a
c
11:0 Hz, JH –H ¼ 10:4 Hz, and JH –H ¼ 11:3 Hz,
c
d
d
f
´
´
PMP
O
TBS
TBS PMB
(COCl)2, DMSO
OH
Et3N, CH2Cl2
TBSO
TBSO
O
O
TBSO
O
O
DIBAL-H
CH2Cl2
References and notes
-78 oC, 89%
(2 steps)
-78 o
C
Me
Me
Me
18
Me Me Me
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PMB
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O
O
O
O
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O
2)
H
OTBS
29
3
Me Me Me
81% yield
ds > 95:05
Me
-78 oC
5
Me
Scheme 5. Boron-mediated aldol reaction of methyl ketone 4 with
chiral aldehyde 5.

2216
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