Application of stereocontrolled aldol coupling to synthesis of segments of immunosuppressants FK-506 and rapamycin

Article abstract of DOI:10.1016/j.tet.2009.06.030

The sector comprising C24-C34 of FK-506 containing five of the stereogenic centers in this macrolide was synthesized from (-)-quinic acid. Aldol coupling of the C24-C34 unit with a methyl ketone representing C20-C23 of FK-506 proceeded with complete Felkin stereoselectivity to afford the C20-C34 portion of the immunosuppressant. A chelate transition state invoking coordination of a lithium enolate with a trityl ether is proposed to explain this stereoselectivity. The strategy adopted for construction of the C26-C34 moiety of FK-506 was extended to the C34-C42 subunit of rapamycin. A Mukaiyama asymmetric anti-aldol coupling was used to set in place the vicinal diol functionality at C27,28 in the C26-C33 segment of this macrolide.

Full text of DOI:10.1016/j.tet.2009.06.030

Tetrahedron 65 (2009) 6635–6641
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Application of stereocontrolled aldol coupling to synthesis of segments
of immunosuppressants FK-506 and rapamycin
*
James D. White , Jo¨rg Deerberg, Steven G. Toske, Takayuki Yakura
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331-4003, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The sector comprising C24–C34 of FK-506 containing five of the stereogenic centers in this macrolide was
synthesized from (ꢀ)-quinic acid. Aldol coupling of the C24–C34 unit with a methyl ketone representing
C20–C23 of FK-506 proceeded with complete Felkin stereoselectivity to afford the C20–C34 portion of
the immunosuppressant. A chelate transition state invoking coordination of a lithium enolate with
a trityl ether is proposed to explain this stereoselectivity. The strategy adopted for construction of the
C26–C34 moiety of FK-506 was extended to the C34–C42 subunit of rapamycin. A Mukaiyama asym-
metric anti-aldol coupling was used to set in place the vicinal diol functionality at C27,28 in the C26–C33
segment of this macrolide.
Received 19 March 2009
Received in revised form 3 June 2009
Accepted 5 June 2009
Available online 13 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Suppression of the immune response is an important and gen-
erally necessary adjuvant of surgical procedures involving organ or
tissue transplantation.1 The search for immunosuppressive agents
effective in treating host versus graft disease, i.e., tissue rejection,
has centered principally on substances that interfere with the
production of lymphokines by T lymphocytes.2 This technique
suppresses the formation of antibodies against cell surface antigens
of transplanted tissue. The cyclic peptide cyclosporine A (1) has
long been considered the gold standard in clinical medicine for
treatment of host versus graft disease but its prolonged use carries
risks of side effects.3 The nephrotoxicity of cyclosporine A is a par-
ticular concern in this regard.
In 1987, an antibiotic FK-506 (2) was isolated from the soil
fungus Streptomyces tsukubaensis and was found to possess im-
munosuppressive properties similar to cyclosporine A.4 In contrast
to cyclosporine A, FK-506 displays no serious side effects. Discovery
of the immunosuppressive action of FK-506 rekindled interest in
a structurally similar natural product rapamycin (3) that had been
isolated in 1975 from Streptomyces hygroscopicus before cyclo-
sporine A and FK-506 were known.5 Originally investigated for its
antifungal properties, rapamycin was subsequently found to sup-
press the immune response in rats and is now recognized as
a clinically useful immunosuppressive drug.6
* Corresponding author.
E-mail address: james.white@oregonstate.edu (J.D. White).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.030

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J.D. White et al. / Tetrahedron 65 (2009) 6635–6641
The complex architecture of 2 and 3 has inspired a variety of
506. Stereocontrolled aldol coupling of aldehyde 8 with methyl ke-
tone 9 would then afford the complete C20–C34 sector of FK-506
containing all seven of its stereocenters in the correct orientation.
approaches to their synthesis, resulting in five completed syntheses
of rapamycin7 and three of FK-506.8 The presence of structural
motifs common to 2 and 3, particularly a 1,2,4-trisubstituted cyclo-
hexane bearing a polyketide derived side chain,9 led us to propose
a synthetic pathway to this segment which could provide access to
the corresponding subunits of FK-506 and rapamycin. In this report,
we describe a route to the C20–C34 portion of FK-50610 and its ex-
tension to a subunit of rapamycin. A key feature of our synthesis of
the C26–C33 portion of 3 is an asymmetric anti-aldol reaction that
correctly installs vicinal oxygen substituents at C27 and C28.11
Our strategy for constructing the trisubstituted cyclohexane por-
tion of FK-506 and rapamycin envisioned (ꢀ)-quinic acid (4) as the
point of departure (Scheme 1). Although this required stripping away
superfluous hydroxyl groups at C1 and C3 of 4, procedures already
developed in our laboratory12 together with the ready availability of
enantiomerically pure quinic acid made this approach not only eco-
nomically attractive but eminently feasible. The first objective in this
scenariowassynthesis of cyclohexanecarboxaldehyde5 which would
2. Results and discussion
2.1. FK-506 (2): C20–C34 subunit
As previously described, exposure of (ꢀ)-quinic acid (4) to
benzaldehyde in the presence of an acidic catalyst afforded lactone
1014 (Scheme 2) which was oxidized with N-bromosuccinimide and
benzoyl peroxide to bromo benzoate 11.15 The tertiary hydroxyl of
11 was removed by reduction of the derived imidazoyl thioate 1216
with tri-n-butylstannane to give 13. Acidic methanolysis of this
lactone produced hydroxy ester 14 which was reacted with diazo-
methane in the presence of boron trifluoride etherate to yield
methyl ether 15. Basic methanolysis of 15 cleaved the benzoate and
furnished alcohol 16 which was protected as its SEM ether 17. Re-
duction of ester 17 to aldehyde 18 followed by Wittig olefination
with phosphorane 19 furnished (Z) unsaturated ester 20 as a single
be advanced to a,b-unsaturated aldehyde 6. Asymmetric crotylation
of 6 with chiral boronate 713 would set in place syn substituents cor-
responding to the C25 methyl group and C26 oxygen function of FK-
Scheme 1.
Scheme 2.

J.D. White et al. / Tetrahedron 65 (2009) 6635–6641
6637
this result, a different route from alcohol 24 was investigated in
which 24 was converted to its p-methoxybenzyl (PMB) ether 28. This
diene upon Lemieux–Johnson oxidation underwent clean scission of
the vinyl group to afford aldehyde 29 in acceptable yield.
The plan outlined in Scheme 1 for appending a C20–C23 subunit
9 to aldehyde 8 called for aldol coupling of the latter with a pro-
tected (R)-2-allyl-3-oxobutanol. Synthesis of this ketone began
with allylation of the dianion of (S)-ethyl 3-hydroxybutyrate (30) to
give 31,18 reduction of which yielded diol 32 (Scheme 4). The pri-
mary alcohol 32 was protected as its trityl ether 33 and the sec-
ondary alcohol was oxidized to ketone 34.
Aldol coupling of the lithium enolate of 34 with aldehyde 29 at
low temperature produced b-hydroxy ketone 35 as a 4:1 mixture of
C24 epimers (Scheme 5).19 Modification of the reaction conditions
did not appreciably change this ratio. Assignment of configuration at
C24 of 35 was made by converting the mixture to a cyclic p-
methoxyphenyl acetal by treatment with DDQ and using NOE ex-
perimentstoestablishthesyn relationshipofC24 andC26hydrogens.
This analysis proved that the major alcohol from 29 and 34 possessed
(24S) configuration and was therefore the result of Felkin addition.
Scheme 3.
isomer. Subsequent reduction of 20 to alcohol 21 followed by oxi-
dation of the latter with Dess–Martin periodinane gave
a,b-un-
saturated aldehyde 22. This improved ten-step sequence from
(ꢀ)-quinic acid to the C26–C34 portion of 2 proceeds in an overall
15% yield from a readily available, enantiomerically pure starting
material and is easily scalable.
Scheme 5.
Treatment of aldehyde 22 with (Z)-crotylboronate 23, prepared
from the corresponding diethanolamine complex and (R,R)-diiso-
propyl tartrate,13 at low temperature resulted in an excellent yield of
syn homoallylic alcohols 24 and 25 (Scheme 3). Although the ratio of
desired alcohol 24 to its diastereomer 25 was only 2.4:1, 24 was
readilyseparablefromthe mixture. Ithadbeenour initial intentionto
attach the pipecolate residue of FK-506 at C26 of 24 by esterification
with N-Boc pipecolic acid (26)17 and then cleave the terminal alkene
to an aldehyde. However, although esterification of 24 with 26 pro-
ceeded efficiently, oxidative cleavage of 27 produced an intractable
mixture inwhichnoneofthedesiredaldehydewaspresent. Inlightof
Scheme 4.
Scheme 6.

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J.D. White et al. / Tetrahedron 65 (2009) 6635–6641
The mixture of epimers produced in the aldol coupling of 29
22 used in our approach to FK-506 and it was assumed that the
distinguishing feature of 40, its (35R) methyl substituent, could be
installed via directed hydrogenation of (E)-alkene 41. If this hy-
drogenation was to be guided by a suitably positioned allylic al-
cohol at C34, as in Brown’s model which posits anti-selective
delivery of hydrogen in the homogeneous hydrogenation of acyclic
allylic alcohols by a coordinated rhodium species,20 we presumed
that a (34R) hydroxyl substituent was needed for our purpose. The
assumption underlying this plan was that a relatively hindered
trisubstituted alkene would respond selectively to our hydroge-
nation conditions.
with 34 led us to suspect that the p-methoxybenzyl ether of 29 had
played a spoiler role in this reaction through its complexation with
the lithium enolate of 34, thus leading to diminished stereo-
selectivity. In order to test this postulate, alcohol 24 was silylated
and the resulting alkene 36 was cleaved oxidatively to aldehyde 37
(Scheme 6). In this case, coupling of the lithium enolate of 34 with
37 produced a single aldol product 38 with (24S) configuration
corresponding to the major diastereomer of 35 from 29. A proposed
transition state for coupling of 37 with 34 is shown in Figure 1,
where Felkin approach of reactants is reinforced by complexation
of the lithium enolate of 34 with the trityl ether oxygen. It is likely
that this complexation is disrupted by the p-methoxybenzyl ether
of 29 resulting in an ‘intrinsic’ Felkin distribution of ca. 4:1.
Asymmetric aldol coupling of the (ꢀ)-isopinylcampheylboron
enolate of ketone 4421 with aldehyde 22 gave allylic alcohol 45 as
a
single stereoisomer (Scheme 8). However, attempts to
Figure 1. Chelate transition state for coupling of 34 with 37 to yield 38.
The route to the C20–C34 subunit of FK-506 described above com-
pletes a portion of the structure that houses seven of the fourteen ster-
eogenic centers. Further elaboration from 38 requires its connection to
the tricarbonyl segment embedded in the C1–C19 section of the macro-
lide. Efforts along this line will be described in a future publication.
2.2. Rapamycin (3): C34–C42 subunit
Our strategy for assembling the C26–C42 segment of rapamycin
(3) envisioned an aldol connection at C33–C34 between ketone 39
and aldehyde 40 (Scheme 7). The latter is the saturated version of
Scheme 8.
Scheme 7.

J.D. White et al. / Tetrahedron 65 (2009) 6635–6641
6639
hydrogenate alkene 45 in the presence of rhodium catalyst 4622
produced a mixture in which both the ketone and olefin had been
saturated. Therefore, ketone 45 was reduced with tetramethy-
lammonium acetoxyborohydride to anti diol 47,23 which upon de-
hydrogenation with DDQ furnished acetal 48. Unfortunately,
exposure of alkene 48 to hydrogen under pressure in the presence
of 46 failed to give more than a trace of 49.
The disappointing outcome from hydrogenation of 48 and
a subsequent examination of hydrogenation studies carried out by
Kinoshita24 suggested that an exo methylene function would be
a better substrate for alcohol-directed hydrogenation. Imple-
mentation of this plan required a return to aldehyde 18, and ad-
dition of the lithio anion of imine 5025 to 18 followed by acid-
catalyzed Peterson elimination cleanly furnished (E)-enal 51
(Scheme 9). Catalytic hydrogenation of 51 produced saturated al-
dehyde 52 which was subjected to a Mannich reaction with
Eschenmoser’s salt 5326 to give the unstable acrolein derivative 54.
Unfortunately, rapid polymerization of 54 made this substance
unusable as a progenitor of the C34–C42 segment of rapamycin and
it is now clear that an alternative to 22 or 54 will be needed to
install the (35R) methyl substituent of rapamycin.
Scheme 10.
Alkoxythioketene acetals (55) were prepared by silylation at low
temperature of the corresponding -alkoxythioacetate ester (57) in
a
the presence of lithium tetramethylpiperidide and were obtained
predominately as (Z) isomers (Scheme 11). Esters 57 were obtained
from either
a
a
-alkoxyacetyl chlorides 58 or from the corresponding
-alkoxycarboxylic acids 59 (Table 1).27b
Scheme 9.
2.3. Rapamycin (3): C26–C33 segment
Scheme 11.
Ketone 39 envisioned as the aldol partner for 40 in Scheme 7
presents the challenge of establishing an anti diol moiety at C27,28. For
this construction, we planned to draw upon a reaction devised by
Mukaiyama and Kobayashi27 and exemplified in Fukuyama’s synthesis
Table 1
Synthesis of
a
-alkoxythiol esters 57 and
a
-alkoxythioketene acetals 55
of leinomycin28 which employs asymmetric coupling of an
a-alkox-
Entry
Starting
materials
57
55
R
Yield (%)
Yield (%)
Z:E
4:1
12:1
10:1
6:1
ythioketene acetal 55 with an enal 56 (Scheme 10). These components
are derived from thioglycolate 57 and aldehyde 58, respectively.
Uncertainty regarding the feasibility of asymmetric addition of
1
2
3
4
58
58
59
59
Me
Bn
PMB
3,4-DMB
88
88
72
67
36
92
76
58
55 to an
a,b-unsaturated aldehyde such as 56 caused us to first
examine the reaction in the context of the simple enal tiglaldehyde.

6640
J.D. White et al. / Tetrahedron 65 (2009) 6635–6641
Exposure of tiglaldehyde (60) to ketene thioacetals 55, tin(II)
triflate, di-n-butyltin diacetate and (S)-1-methyl-2-[(1-piper-
idyl)methyl]pyrrolidine (61)29 gave anti and syn aldol products 62
and 63, respectively, in good yield for R¼Bn, PMB, and 3,4-DMB and
with good relative and absolute stereoselectivity for anti diol 63
(Table 2). In practical terms, the optimal thioketene acetal for this
asymmetric anti aldol coupling was that prepared from 3,4-dime-
thoxybenzyloxyacetic acid (entry 4).
Table 2
Reaction of a-alkoxythioketene acetals (55) with tiglaldehyde (60)
Entry
Ketene acetal (55) R
Aldol products
Yield (%)
62:63
ee of 62 (%)
1
2
3
4
Me
Bn
PMB
3,4-DMB
32
82
74
80
70:30
85:15
90:10
95:5
87
93
96
92
The projected enol partner for 55 was prepared from alcohol 64
(Scheme 12), the enantiomer of a substance previously obtained by
Baker from methyl (S)-3-hydroxy-2-methylpropionate.30 After
Scheme 13.
protection of 64 as silyl ether 65, the primary alcohol was
unmasked and 66 was oxidized to aldehyde 67 with catalytic per-
ruthenate.31 Condensation of 67 with the lithio anion of imine 68,32
followed by acid-catalyzed Peterson elimination and hydrolysis of
the imine,27 produced a mixture of
a,b-unsaturated aldehydes 69
and 70 in the ratio 2:1, respectively. The (Z)-enal 70 underwent
clean isomerization to (E)-aldehyde 69 in the presence of catalytic
quantities of iodine and tert-butylamine in warm hexane.33
Asymmetric coupling of 69 with alkoxythioketene acetals 55
(R¼Me, PMB, and 3,4-DMB) under conditions used with tiglalde-
hyde (60) afforded anti-aldol product 71 along with syn product 72
in yields and ratios that were dependent on the substituent R
(Scheme 13). As with 60, the optimal reaction favoring anti product
71 was observed with the ketene acetal prepared from ethyl 3,4-
Scheme 14.
Scheme 12.

J.D. White et al. / Tetrahedron 65 (2009) 6635–6641
6641
5. (a) Vezina, D.; Kudelski, A.; Sehgal, S. N. J. Antibiot. 1975, 28, 721; (b) Sehgal, S.
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Hydroxythiol ester 71 obtained above was advanced via silyla-
tion of the free alcohol to its TIPS ether 73; subsequent cleavage of
the p-methoxybenzyl ether then furnished 74 (Scheme 14). This
alcohol was reacted with diazomethane to yield methyl ether 75
representing C26–C33 of rapamycin. This fragment will be linked to
C34–C42 subunit 43 for eventual assembly of the framed segment
of 3 shown in Scheme 7.
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3. Conclusion
Enantiopure quinic acid provides a useful starting material for
acquiring the 1,3,4-trisubstituted cyclohexane unit of FK-506 and
rapamycin. The key C23–C24 connection for FK-506 can be forged
with complete stereospecificity by means of an aldol coupling,
leading to a fragment inwhich all seven of the stereogenic centers as
well as the (E)-trisubstituted alkene in the C20–C42 segment of the
macrolide are installed correctly. Unfortunately, the 35(R) methyl
configuration of rapamycin is not solved by this approach. Never-
theless, an asymmetric aldol protocol does permit access to the anti
diol unit present in the C26–C33 sector of this immunosuppressant.
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Supplementary data
Experimental procedures and characterization data for new
compounds. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.06.030.
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